U.S. patent application number 17/239726 was filed with the patent office on 2021-11-04 for n-[2-(1 -benzylpiperidin-4-yl)ethyl]-4-(pyrazin-2-yl)-piperazine-1 -carboxamide derivatives and related compounds as muscarinic receptor 4 (m4) antagonists for treating neurological diseases.
The applicant listed for this patent is Neurocrine Biosciences, Inc.. Invention is credited to Nicole Harriott, Nicholas Pagano.
Application Number | 20210338653 17/239726 |
Document ID | / |
Family ID | 1000005712661 |
Filed Date | 2021-11-04 |
United States Patent
Application |
20210338653 |
Kind Code |
A1 |
Harriott; Nicole ; et
al. |
November 4, 2021 |
N-[2-(1 -BENZYLPIPERIDIN-4-YL)ETHYL]-4-(PYRAZIN-2-YL)-PIPERAZINE-1
-CARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS MUSCARINIC
RECEPTOR 4 (M4) ANTAGONISTS FOR TREATING NEUROLOGICAL DISEASES
Abstract
Provided herein are small molecule compounds of the following
formula (I): or a stereoisomer, tautomer, solvate, ester or
pharmaceutically acceptable salt thereof, wherein A, B, C, L.sub.i,
L.sub.2, R.sub.i, R.sub.2, R.sub.3, R.sub.4, R.sub.5, w, x, y and z
are as defined herein. Methods for treating diseases/disorders by
antagonizing muscarinic receptors, including specifically
antagonizing muscarinic receptor 4 (M4), are also disclosed. Such
diseases/disorders are e.g. neurological diseases/disorders such as
e.g. Alzheimer's Disease, Lewy Body Dementia and the cognitive
deficits associated with schizophrenia, Parkinson's Disease, drug
induced Parkinsonism, dyskinesias, dystonia, chorea, levodopa
induced dyskinesia, cerebral palsy, progressive supranuclear palsy,
and Huntington's disease. Preferred compounds are e.g.
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(pyrazin-2-yl)-piperazine-1-carboxa-
mide derivatives and related compounds wherein the pyrazine has
been replaced by e.g. pyridazine, pyrimidine, pyridine or phenyl.
##STR00001##
Inventors: |
Harriott; Nicole; (San
Diego, CA) ; Pagano; Nicholas; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Neurocrine Biosciences, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000005712661 |
Appl. No.: |
17/239726 |
Filed: |
April 26, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15773915 |
May 4, 2018 |
11033539 |
|
|
PCT/US2016/060659 |
Nov 4, 2016 |
|
|
|
17239726 |
|
|
|
|
62275708 |
Jan 6, 2016 |
|
|
|
62252179 |
Nov 6, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/496 20130101;
A61P 25/16 20180101; A61P 25/18 20180101; A61K 31/444 20130101;
C07D 211/26 20130101; C07D 401/12 20130101; A61P 25/28 20180101;
A61K 31/506 20130101; A61K 31/4545 20130101; A61K 31/519 20130101;
C07D 211/40 20130101 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; C07D 401/12 20060101 C07D401/12; C07D 211/40 20060101
C07D211/40; C07D 211/26 20060101 C07D211/26; A61P 25/28 20060101
A61P025/28; A61P 25/18 20060101 A61P025/18; A61P 25/16 20060101
A61P025/16; A61K 31/444 20060101 A61K031/444; A61K 31/496 20060101
A61K031/496; A61K 31/506 20060101 A61K031/506; A61K 31/519 20060101
A61K031/519 |
Claims
1-61. (canceled)
62. A pharmaceutical composition comprising a compound selected
from:
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoro-
methyl)pyrimidin-2-yl]piperazine-1-carboxamide;
(2S,6R)--N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,-
6-dimethylpiperazine-1-carboxamide;
(2R,6R)--N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,-
6-dimethylpiperazine-1-carboxamide;
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5-(trifluoromethyl)-
pyrimidin-2-yl]piperazine-1-carboxamide;
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoro-
methyl)pyrazin-2-yl]piperazine-1-carboxamide; and
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5-fluorophenyl)-2-me-
thylpiperazine-1-carboxamide; or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable
excipient.
63. A method for treating a neurological disease or disorder in a
subject in need thereof, comprising administering to the subject a
therapeutically effective amount of a compound selected from:
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoro-
methyl)pyrimidin-2-yl]piperazine-1-carboxamide;
(2S,6R)--N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,-
6-dimethylpiperazine-1-carboxamide;
(2R,6R)--N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,-
6-dimethylpiperazine-1-carboxamide;
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5-(trifluoromethyl)-
pyrimidin-2-yl]piperazine-1-carboxamide;
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoro-
methyl)pyrazin-2-yl]piperazine-1-carboxamide; and
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5-fluorophenyl)-2-me-
thylpiperazine-1-carboxamide; or a pharmaceutically acceptable salt
thereof, wherein the neurological disease or disorder is selected
from the group consisting of Alzheimer's Disease, Lewy body
dementia, a cognitive deficit associated with schizophrenia,
Parkinson's disease, drug induced Parkinsonism, dyskinesia,
dystonia, chorea, cerebral palsy, progressive supranuclear palsy,
and Huntington's disease.
Description
BACKGROUND
Technical Field
[0001] Compounds are provided herein that selectively antagonize
muscarinic receptors, in particular muscarinic receptor 4 (M4), as
well as methods for treating diseases and/or disorders that would
benefit from the same.
Description of the Related Art
[0002] Muscarinic acetylcholine receptors are autonomic receptors
that form G protein-receptor complexes in the cell membranes of
certain neurons and other cell types (e.g., endothelial cells of
blood vessels). Muscarinic receptors are located postsynaptically
at the parasympathetic neuroeffector junction, from where the
receptors function to increase or decrease the activity of the
effector cells. Extrapyramidal symptoms are observed in patients
treated with antipsychotic therapeutics and in patients who have
neuroleptic malignant syndrome, brain damage (e.g., athetotic
cerebral palsy), encephalitis, and meningitis. Drugs other than
antipsychotics also cause extrapyramidal symptoms, for example
antidopaminergic drugs (e.g., the antiemetic metoclopramide and the
antidepressant amoxapine) and selective serotonin reuptake
inhibitors (SSR*), which indirectly decrease dopamine. Conditions
associated with extrapyramidal symptoms include acute dystonic
reactions, akathisia, pseudoparkinsonism, and tardive dyskinesia.
Extrapyramidal symptoms caused by antipsychotic therapeutics are
being treated with anticholinergic drugs that lack selectivity for
any of the five muscarinic receptor subtypes (see, e.g.,
Erosa-Rivero et al., Neuropharmacology 81:176-87 (2014)). Because
anticholinergic drugs that effect multiple muscarinic receptors may
cause distinct and in certain instances opposing effects,
therapeutics that exhibit selectivity for particular receptors are
desired.
BRIEF SUMMARY
[0003] Provided herein are compounds that antagonize muscarinic
receptors. In particular embodiments, compounds are provided that
selectively antagonize muscarinic receptor 4 (M4). Such compounds
are useful in the treatment of a number of diseases and/or
disorders, particularly neurological conditions, diseases, and
disorders including cognitive disorders such as Alzheimer's
Disease, Lewy Body Dementia and the cognitive deficits associated
with schizophrenia. In other embodiments, methods are provided for
treating or preventing movement disorders which may include
Parkinson's Disease, drug induced Parkinsonism, dyskinesias,
dystonia, chorea, levodopa induced dyskinesia, cerebral palsy and
progressive supranuclear palsy, and Huntington's disease,
particularly chorea associate with Huntington's disease.
[0004] In one embodiment, compounds are provided having the
structure of formula (I):
##STR00002##
or a stereoisomer, tautomer, solvate, ester, prodrug, or
pharmaceutically acceptable salt thereof, wherein A, B, C, L.sub.1,
L.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, w, x, y and z
are as defined below. More specific embodiments are also described
within Tables 1-14, as well as the more specific formulas noted
herein below.
[0005] In another embodiment, pharmaceutical compositions are
provided comprising a compound of formula (I), including one or
more of the specific compounds described herein, and at least one
pharmaceutically acceptable excipient. The compounds, as well as
the pharmaceutical compositions comprising the compounds, may be
used for antagonizing a muscarinic receptor, such as muscarinic
receptor 4 (M4). In certain embodiments, the compound is a
selective M4 antagonist.
[0006] These and other embodiments will be apparent upon reference
to the following detailed description. To this end, various
references are set forth herein that describe in more detail
certain background information, procedures, compounds and
compositions, and are each hereby incorporated by reference in
their entirety.
DETAILED DESCRIPTION
[0007] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments. However, one skilled in the art will understand that
the invention may be practiced without these details. In other
instances, well-known structures have not been shown or described
in detail to avoid unnecessarily obscuring descriptions of the
embodiments. Unless the context requires otherwise, throughout the
specification and claims which follow, the word "comprise" and
variations thereof, such as, "comprises" and "comprising," are to
be construed in an open, inclusive sense, that is, as "including,
but not limited to." In addition, the term "comprising" (and
related terms such as "comprise" or "comprises" or "having" or
"including") is not intended to exclude that in other certain
embodiments, for example, an embodiment of any composition of
matter, composition, method, or process, or the like, described
herein, may "consist of" or "consist essentially of" the described
features. Headings provided herein are for convenience only and do
not interpret the scope or meaning of the claimed embodiments.
[0008] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment. Thus, the appearances of the
phrases "in one embodiment" or "in an embodiment" in various places
throughout this specification are not necessarily all referring to
the same embodiment. Furthermore, the particular features,
structures, or characteristics may be combined in any suitable
manner in one or more embodiments.
[0009] Also, as used in this specification and the appended claims,
the singular forms "a," "an," and "the" include plural referents
unless the content clearly dictates otherwise. Thus, for example,
reference to "a non-human animal" may refer to one or more
non-human animals, or a plurality of such animals, and reference to
"a cell" or "the cell" includes reference to one or more cells and
equivalents thereof (e.g., plurality of cells) known to those
skilled in the art, and so forth. When steps of a method are
described or claimed, and the steps are described as occurring in a
particular order, the description of a first step occurring (or
being performed) "prior to" (i.e., before) a second step has the
same meaning if rewritten to state that the second step occurs (or
is performed) "subsequent" to the first step. The term "about" when
referring to a number or a numerical range means that the number or
numerical range referred to is an approximation within experimental
variability (or within statistical experimental error), and thus
the number or numerical range may vary between 1% and 15% of the
stated number or numerical range. It should also be noted that the
term "or" is generally employed in its sense including "and/or"
unless the content clearly dictates otherwise. The term, "at least
one," for example, when referring to at least one compound or to at
least one composition, has the same meaning and understanding as
the term, "one or more."
[0010] Provided herein are compounds useful for treating diseases
and/or disorders treatable by antagonizing one or more muscarinic
receptors. In particular embodiments, compounds are provided that
are selective for muscarinic receptor 4 (M4) (also referred herein
as the M4 receptor).
[0011] Provided herein are compounds having a structure of the
following formula (I):
##STR00003##
or a stereoisomer, tautomer, solvate, ester, prodrug, or
pharmaceutically acceptable salt thereof, wherein:
[0012] A, B and C are each independently a carbocycle or
heterocycle;
[0013] R.sub.1 is, at each occurrence, H, C.sub.1-4alkyl,
C(.dbd.O)OC.sub.1-4alkyl or aryl;
[0014] R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently
--OH, --NH.sub.2, --NH(C.sub.1-4alkyl), --N(C.sub.1-4alkyl).sub.2,
--C.dbd.N, --C(.dbd.O)NH.sub.2, halo, C.sub.1-4alkyl,
C.sub.1-4alkylOH, C.sub.1-4haloalkyl, C.sub.1-4alkoxy or
C.sub.1-4haloalkoxy;
[0015] w, x, y and z are each independently 0, 1, 2 or 3;
[0016] L.sub.1 is a heteroalkylene linker having at least one N, O
or S heteroatom, and wherein the heteroalkylene may be a straight
chain or cyclized and optionally substituted with oxo, --OH,
C.sub.1-4alkyl or C.sub.1-4alkoxy; and
[0017] L.sub.2 is an optional linker that is not present or, when
present, is --O(CH.sub.2).sub.m-- where m is 0 or 1.
[0018] In one embodiment of formula (I), R.sub.1 is H at both
occurrences.
[0019] In one embodiment of formula (I), one R.sub.1 is H and the
other R.sub.1 is methyl.
[0020] In one embodiment of formula (I), R.sub.1 is methyl at both
occurrences.
[0021] In one embodiment of formula (I), A is a non-aromatic
carbocyle, and more specifically cyclohexyl.
[0022] In one embodiment of formula (I), A is an aromatic
carbocyle, and more specifically aryl.
[0023] In one embodiment of formula (I), A is phenyl or
naphthyl.
[0024] In one embodiment of formula (I), A is phenyl.
[0025] In one embodiment of formula (I), A is an aromatic
heterocycle, and more specifically one of the following:
##STR00004##
[0026] In one embodiment of formula (I), w is 0 and R.sub.2 is not
present.
[0027] In one embodiment of formula (I), w is 1, 2 or 3, and
R.sub.2 is at each occurrence --OH, --CN, halo, or
C.sub.1-4alkyl.
[0028] In one embodiment, compounds are provided of formula (I)
wherein -A(R.sub.2).sub.w is:
##STR00005##
[0029] In one embodiment of formula (I), x is 0 and R.sub.3 is not
present.
[0030] In one embodiment of formula (I), x is 1 or 2 and R.sub.3 is
at each occurrence --OH or C.sub.1-4alkyl-OH.
[0031] In one embodiment of formula (I), L.sub.1 is a a
heteroalkylene linker having at least one N or O heteroatom, and
wherein the heteroalkylene may be a straight chain or cyclized and
optionally substituted with oxo, --OH, C.sub.1-4alkyl or
C.sub.1-4alkoxy, and more specifically one of the following:
##STR00006## ##STR00007##
[0032] In one embodiment of formula (I), B is a non-aromatic
carbocyle, and more specifically cyclohexyl.
[0033] In one embodiment of formula (I), B is an aromatic
carbocyle, and more specifically aryl.
[0034] In one embodiment of formula (I), B is phenyl or
naphthyl.
[0035] In one embodiment of formula (I), B is phenyl.
[0036] In one embodiment of formula (I), B is a non-aromatic
heterocycle.
[0037] In one embodiment of formula (I), B is piperazinyl,
piperadinyl or pyrrolidinyl, and more specifically one of the
following:
##STR00008##
[0038] In one embodiment of formula (T), B an aromatic heterocycle,
and more specifically
##STR00009##
[0039] In one embodiment of formula (I), y is 0 and R.sub.4 is not
present.
[0040] In one embodiment of formula (I), y is 1 and R.sub.4 is
methyl.
[0041] In one embodiment of formula (I), B is piperazinyl, y is 1
and R.sub.4 is methyl and, in a more specific embodiment, such
moiety has the following structure:
##STR00010##
[0042] In one embodiment of formula (I), y is 2 and R.sub.4 at both
occurrences is methyl.
[0043] In one embodiment of formula (I), B is piperazinyl, y is 2
and R.sub.4 at both occurrences is methyl and, in a more specific
embodiment, such moiety has one of the following structures:
##STR00011##
[0044] In one embodiment of formula (I), L.sub.2 is not
present.
[0045] In one embodiment of formula (I), L.sub.2 is --O--
[0046] In one embodiment of formula (I), L.sub.2 is
--OCH.sub.2--.
[0047] In one embodiment of formula (I), C is an aromatic 5-12
membered carbocycle or heterocycle.
[0048] In one embodiment of formula (I), C is an aromatic
carbocyle, and more specifically aryl.
[0049] In one embodiment of formula (I), C is phenyl.
[0050] In one embodiment of formula (I), C is an aromatic
heterocycle, and more specifically one of the following:
##STR00012##
[0051] In one embodiment of formula (I), z is 0 and R.sub.5 is not
present.
[0052] In one embodiment of formula (I), z is 1, 2 or 3, and each
occurrence of R.sub.5 is independently-OH, --NH.sub.2,
--NH(C.sub.1-4alkyl), --N(C.sub.1-4alkyl).sub.2, --CN, halo,
C.sub.1-4alkyl, C.sub.1-4alkyl-OH, C.sub.1-4haloalkyl,
C.sub.1-4alkoxy or C.sub.1-4haloalkoxy.
[0053] In one embodiment of formula (I), compounds are provided
having a structure of the following formula (TI) or (ITT):
##STR00013##
[0054] In one embodiment of formula (I), compounds are provided
having a structure of the following formula (IV) or (V):
##STR00014##
[0055] In one embodiment of formula (I), compounds are provided
having a structure of the following formula (VI):
##STR00015##
[0056] In one embodiment of formula (I), compounds are provided
having a structure of the following formula (VII), (VIII) or
(IX):
##STR00016##
[0057] In one embodiment of formula (I), compounds are provided
having a structure of the following formula (X) or (XI):
##STR00017##
[0058] In one embodiment of formula (I), compounds are provided
having a structure of the following formula (XII), (XIII) or
(XIV):
##STR00018##
[0059] In one embodiment of formula (I), compounds are provided
having a structure of the following formula (XV), (XVI) or
(XVII):
##STR00019##
[0060] In one embodiment, compounds are provided of formula (XV),
(XVI) or (XVII) wherein y is 0.
[0061] In one embodiment, compounds are provided of formula (XV),
(XVI) or (XVII) wherein y is 1 or 2, and R.sub.4 is at each
occurrence C.sub.1-4alkyl.
[0062] In one embodiment, compounds are provided of formula (XV),
(XVI) or (XVII) wherein y is 1 or 2, and R.sub.4 is at each
occurrence methyl.
[0063] In one embodiment, compounds are provided of formula (XV),
(XVI) or (XVII) wherein --C(R.sub.5).sub.z is one of the
following:
##STR00020##
[0064] In one embodiment of the --C(R.sub.5).sub.z groups noted
immediately above, z is 0 and R.sub.5 is not present.
[0065] In one embodiment of the --C(R.sub.5).sub.L groups noted
immediately above, z is 1, 2 or 3, and each occurrence of R.sub.5
is independently-OH, --NH.sub.2, --NH(C.sub.1-4alkyl),
--N(C.sub.1-4alkyl).sub.2, --C.dbd.N, halo, C.sub.1-4alkyl,
C.sub.1-4alkyl-OH, C.sub.1-4haloalkyl, C.sub.1-4alkoxy or
C.sub.1-4haloalkoxy.
[0066] In one embodiment, a compound of formula (I) is one or more
of the following compounds (with cal. ion m/z listed in
parentheses): [0067]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrazin-2-yl)-2,6--
dimethylpiperazine-1-carboxamide (462.3); [0068]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-cyanopyridazin-3-yl)-2,-
6-dimethylpiperazine-1-carboxamide (462.3); [0069]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-cyanopyrimidin-5-yl)-2,-
6-dimethylpiperazine-1-carboxamide (462.3); [0070]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyanophenyl)-2,6-dimeth-
ylpiperazine-1-carboxamide (460.3); [0071]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyridin-2-yl)-2,6--
dimethylpiperazine-1-carboxamide (461.3); [0072]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyano-4-methoxypyrimidi-
n-2-yl)-2,6-dimethylpiperazine-1-carboxamide (492.3); [0073]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-chloropyrimidin-2-yl)-2-
,6-dimethylpiperazine-1-carboxamide (471.3); [0074]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-chloropyrazin-2-yl)-2,6-
-dimethylpiperazine-1-carboxamide (471.3); [0075]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-chloropyridazin-3-yl)-2-
,6-dimethylpiperazine-1-carboxamide (471.3); [0076]
(2R,6R)-4-(4-amino-5-chloropyrimidin-2-yl)-N-[2-(1-benzylpiperidin-4-yl)e-
thyl]-2,6-dimethylpiperazine-1-carboxamide (486.3); [0077]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-chloropyridin-3-yl)-2,6-
-dimethylpiperazine-1-carboxamide (470.3); [0078]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[6-(trifluoro-
methyl)pyridazin-3-yl]piperazine-1-carboxamide 505.3 [0079]
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-methoxypyrimidin-2-yl)-2-m-
ethylpiperazine-1-carboxamide (453.3); [0080]
(2R,6S)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-methoxypyrimidin-2-yl)--
2,6-dimethylpiperazine-1-carboxamide (467.3); [0081]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-methoxypyrimidin-2-yl)--
2,6-dimethylpiperazine-1-carboxamide (467.3); [0082]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-methoxypyrazin-2-yl)-2,-
6-dimethylpiperazine-1-carboxamide (467.3); [0083]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-methoxypyridazin-3-yl)--
2,6-dimethylpiperazine-1-carboxamide (467.3); [0084]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-methoxypyrimidin-5-yl)--
2,6-dimethylpiperazine-1-carboxamide (467.3); [0085]
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-(difluoromethoxy)pyrimidin-
-2-yl]-2-methylpiperazine-1-carboxamide (489.3); [0086]
(2R,6S)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-(difluoromethoxy)pyrimi-
din-2-yl]-2,6-dimethylpiperazine-1-carboxamide (503.3); [0087]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-(difluoromethoxy)pyrimi-
din-2-yl]-2,6-dimethylpiperazine-1-carboxamide (503.3); [0088]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-(difluoromethoxy)pyrazi-
n-2-yl]-2,6-dimethylpiperazine-1-carboxamide (503.3); [0089]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[6-(difluoromethoxy)pyrida-
zin-3-yl]-2,6-dimethylpiperazine-1-carboxamide (503.3); [0090]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[2-(difluoromethoxy)pyrimi-
din-5-yl]-2,6-dimethylpiperazine-1-carboxamide (503.3); [0091]
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5-(trifluoromethoxy-
)pyrimidin-2-yl]piperazine-1-carboxamide (507.3); [0092]
(2R,6S)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoro-
methoxy)pyrimidin-2-yl]piperazine-1-carboxamide (521.3); [0093]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoro-
methoxy)pyrimidin-2-yl]piperazine-1-carboxamide (521.3); [0094]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoro-
methoxy)pyrazin-2-yl]piperazine-1-carboxamide (521.3); [0095]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[6-(trifluoro-
methoxy)pyridazin-3-yl]piperazine-1-carboxamide (521.3); [0096]
(2R,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[2-(trifluoro-
methoxy)pyrimidin-5-yl]piperazine-1-carboxamide (521.3); [0097]
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-methoxypyrimidin-2-yl)piperazine-
-1-carboxamide (439.3); [0098]
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-(difluoromethoxy)pyrimidin-2-yl]-
piperazine-1-carboxamide (475.3); and [0099]
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-(trifluoromethoxy)pyrimidin-2-yl-
]piperazine-1-carboxamide (492.2).
[0100] In even more specific embodiments, specific compounds of
formula I are as listed in Tables 1-19 herein.
[0101] In other embodiments, pharmaceutical compositions are
provided that comprise a compound of Formula I, including one or
more of the specific compounds described herein (see, e.g., Tables
1-19), and at least one pharmaceutically acceptable excipient.
[0102] In another embodiment, a method is provided for antagonizing
a muscarinic receptor in a cell comprising contacting the cell and
a compound of Formula I, including specific compounds described
herein, for a time sufficient and under appropriate conditions to
permit interaction between the cell and the compound. In certain
embodiments, the cell is in a subject who is in need of treatment
with a compound disclosed herein. For example, the subject may have
or be at risk for developing a neurological disease, condition, or
disorder including cognitive and movement neurological diseases,
conditions, and disorders. In certain embodiments, methods are
provided for preventing (i.e., reducing the likelihood of
occurrence of) or treating Alzheimer's Disease, Lewy Body Dementia
and the cognitive deficits associated with schizophrenia;
Parkinson's Disease, drug induced Parkinsonism, dyskinesias,
dystonia, chorea, levodopa induced dyskinesia, cerebral palsy and
progressive supranuclear palsy, and Huntington's disease, including
chorea associate with Huntington's disease. A person skilled in the
medical or neurological art will readily appreciate that many of
the aforementioned neurological diseases have both cognitive
deficits and movement deficiencies or difficulties associated with
them.
[0103] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated.
[0104] Certain chemical groups named herein are preceded by a
shorthand notation indicating the total number of carbon atoms that
are to be found in the indicated chemical group. For example;
C.sub.1-C.sub.4alkyl describes an alkyl group, as defined below,
having a total of 1 to 4 carbon atoms, and
C.sub.4-C.sub.12cycloalkylalkyl describes a cycloalkylalkyl group,
as defined below, having a total of 4 to 12 carbon atoms. The total
number of carbons in the shorthand notation does not include
carbons that may exist in substituents of the group described. For
example, the following terms have the meaning indicated.
[0105] "C.sub.1-C.sub.6alkyl" refers to an alkyl radical as defined
below containing one to six carbon atoms. The C.sub.1-C.sub.6alkyl
radical may be optionally substituted as defined below for an alkyl
group. "C.sub.1-C.sub.4alkyl" refers to an alkyl radical as defined
below containing one to four carbon atoms. The C.sub.1-C.sub.4alkyl
radical may be optionally substituted as defined below for an alkyl
group.
[0106] "C.sub.2-C.sub.4alkenyl" refers to an alkenyl radical as
defined below containing two to six carbon atoms. The
C.sub.2-C.sub.12alkenyl radical may be optionally substituted as
defined below for an alkenyl group.
[0107] "C.sub.2-C.sub.6alkynyl" refers to an alknyl radical as
defined below containing two to six carbon atoms. The
C.sub.2-C.sub.12alknyl radical may be optionally substituted as
defined below for an alkenyl group.
[0108] "C.sub.1-C.sub.4alkoxy" refers to an alkoxy radical as
defined below containing one to twelve carbon atoms. The alkyl part
of the C.sub.1-C.sub.4alkoxy radical may be optionally substituted
as defined below for an alkyl group.
[0109] "C.sub.2-C.sub.6alkoxyalkyl" refers to an alkoxyalkyl
radical as defined below containing two to six carbon atoms. Each
alkyl part of the C.sub.2-C.sub.6alkoxyalkyl radical may be
optionally substituted as defined below for an alkyl group.
[0110] "C.sub.7-C.sub.12aralkyl" refers to an aralkyl group as
defined below containing seven to twelve carbon atoms. The aryl
part of the C.sub.7-C.sub.12aralkyl radical may be optionally
substituted as described below for an awl group. The alkyl part of
the C.sub.7-C.sub.12aralkyl radical may be optionally substituted
as defined below for an alkyl group.
[0111] "C.sub.7-C.sub.12aralkenyl" refers to an aralkenyl group as
defined below containing seven to twelve carbon atoms. The aryl
part of the C.sub.7-C.sub.12aralkenyl radical may be optionally
substituted as described below for an aryl group. The alkenyl part
of the C.sub.7-C.sub.12aralkenyl radical may be optionally
substituted as defined below for an alkenyl group.
[0112] "C.sub.3-C.sub.12cycloalkyl" refers to a cycloalkyl radical
as defined below having three to twelve carbon atoms. The
C.sub.3-C.sub.12cycloalkyl radical may be optionally substituted as
defined below for a cycloalkyl group.
[0113] "C.sub.4-C.sub.12cycloalkylalkyl" refers to a
cycloalkylalkyl radical as defined below having four to twelve
carbon atoms. The C.sub.4-C.sub.12cycloalkylalkyl radical may be
optionally substituted as defined below for a cycloalkylalkyl
group.
[0114] In addition to the foregoing, as used in the specification
and appended claims, unless specified to the contrary, the
following terms have the meaning indicated:
[0115] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to twelve carbon atoms, one to
eight carbon atoms, or one to six carbon atoms, or one to four
carbon atoms, and which is attached to the rest of the molecule by
a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl
(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),
3-methylhexyl, 2-methylhexyl, and the like.
[0116] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one double bond, having from two to twelve
carbon atoms, preferably two to eight carbon atoms and which is
attached to the rest of the molecule by a single bond, e.g.,
ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl,
and the like.
[0117] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing no unsaturation and having from one to twelve
carbon atoms or from one to four carbon atoms, e.g., methylene,
ethylene, propylene, n-butylene, and the like. The alkylene chain
is attached to the rest of the molecule through a single bond and
to the radical group through a single bond. The points of
attachment of the alkylene chain to the rest of the molecule and to
the radical group can be through one carbon or any two carbons
within the chain.
[0118] "Alkenylene" or "alkenylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one double bond and having from two
to twelve carbon atoms, e.g., ethenylene, propenylene,
n-butenylene, and the like. The alkenylene chain is attached to the
rest of the molecule through a single bond and to the radical group
through a double bond or a single bond. The points of attachment of
the alkenylene chain to the rest of the molecule and to the radical
group can be through one carbon or any two carbons within the
chain.
[0119] "Carbocyclyl" refers to a stable 3- to 18-membered aromatic
or non-aromatic ring radical which consists of 3 to 18 carbon
atoms. Unless stated otherwise specifically in the specification,
the carbocyclyl radical may be a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems, and may be partially or fully saturated. Non-aromatic
carbocyclyl radicals include cycloalkyl, while aromatice
carbocyclyl redicals include aryl.
[0120] "Cycloalkyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which may include fused or bridged ring systems,
having from three to fifteen carbon atoms, preferably having from
three to ten carbon atoms, and which is saturated or unsaturated
and attached to the rest of the molecule by a single bond.
Monocyclic radicals include, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptly, and cyclooctyl. Polycyclic
radicals include, for example, adamantyl, norbornyl, decalinyl,
7,7-dimethyl-bicyclo-[2.2.1]heptanyl, and the like.
[0121] "Aryl" refers to a hydrocarbon ring system radical
comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic
ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems. Aryl radicals include, but are not limited to, aryl
radicals derived from aceanthrylene, acenaphthylene,
acephenanthrylene, anthracene, azulene, benzene, chrysene,
fluoranthene, fluorene, as-indacene, s-indacene, indane, indene,
naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and
triphenylene. In one embodiment, aryl is phenyl or naphthyl, and in
another embodiment is phenyl.
[0122] "Heterocyclyl" refers to a stable 3- to 18-membered aromatic
or non-aromatic ring radical which consists of two to twelve carbon
atoms and from one to six heteroatoms selected from the group
consisting of nitrogen, oxygen and sulfur. Unless stated otherwise
specifically in the specification, the heterocyclyl radical may be
a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which
may include fused or bridged ring systems; and the nitrogen, carbon
or sulfur atoms in the heterocyclyl radical may be optionally
oxidized; the nitrogen atom may be optionally quaternized; and the
heterocyclyl radical may be partially or fully saturated. Examples
or aromatic hetercyclyl radicals are listed below in the definition
of heteroaryls (i.e., heteroaryl being a subset of heterocyclyl).
Examples of non-aromatic heterocyclyl radicals include, but are not
limited to, dioxolanyl, thienyl[1,3]dithianyl,
decahydroisoquinolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, pyrazolopyrimidinyl,
quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trioxanyl,
trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl,
thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl.
[0123] "Heteroaryl" refers to a 5- to 14-membered ring system
radical comprising hydrogen atoms, one to thirteen carbon atoms,
one to six heteroatoms selected from the group consisting of
nitrogen, oxygen and sulfur, and at least one aromatic ring. For
purposes of this invention, the heteroaryl radical may be a
monocyclic, bicyclic, tricyclic or tetracyclic ring system, which
may include fused or bridged ring systems; and the nitrogen, carbon
or sulfur atoms in the heteroaryl radical may be optionally
oxidized; the nitrogen atom may be optionally quaternized. Examples
include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl,
benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,
benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,
benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,
benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
(benzothiophenyl), benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl,
benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl,
dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl,
indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,
isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl,
2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,
1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl,
pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl,
pryrimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl,
quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl,
quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl,
thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl,
thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl,
and thiophenyl (i.e. thienyl).
[0124] Unless stated otherwise specifically in the specification,
each of alkyl, alkenyl, alkylene, alkenylene, carbocyclyl,
cycloalkyl, aryl, heterocyclyl and heteroaryl as defined above may
be optionally substituted by one or more substituents selected from
the group consisting of alkyl, alkenyl, halo, haloalkyl,
haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
heteroarylalkyl, --R.sup.41--OR.sup.40,
--R.sup.41--OC(O)--R.sup.40, --R.sup.41--N(R.sup.40).sub.2,
--R.sup.41--C(O)R.sup.40, --R.sup.41--C(O)OR.sup.40,
--R.sup.41--C(O)N(R.sup.40).sub.2,
--R.sup.41--N(R.sup.40)C(O)OR.sup.42,
--R.sub.41--N(R.sub.40)C(O)R.sub.42,
--R.sub.41--N(R.sub.40)S(O).sub.tR.sup.42 (where t is 1 to 2),
--R.sup.41--N.dbd.C(OR.sup.40)R.sup.40,
--R.sup.41--S(O).sub.tOR.sup.42 (where t is 1 to 2),
--R.sup.41--S(O).sub.pR.sup.42 (where p is 0 to 2), and
--R.sup.41--S(O).sub.tN(R.sup.40).sub.2 (where t is 1 to 2) where
each R.sup.40 is independently hydrogen, alkyl, alkenyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R.sup.41 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain; and each R.sup.42 is alkyl, alkenyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0125] "Amino" refers to the --NH.sub.2 radical.
[0126] "Cyano" refers to the --CN radical.
[0127] "Hydroxy" refers to the --OH radical.
[0128] "Nitro" refers to the --NO.sub.2 radical.
[0129] "Oxo" refers to the .dbd.O substituent.
[0130] "Thioxo" refers to the .dbd.S substituent.
[0131] "Trifluoromethyl" refers to the --CF.sub.3 radical.
[0132] "Trifluoromethoxy" refers to the --OCF.sub.3 radical.
[0133] "Acyl" refers to a radical --C(O)R, wherein R is alkyl,
aralkyl, carbocyclyl, aryl, heteroaryl, or heterocyclyl, as defined
herein. When R is methyl, the acyl group is also referred to as
acetyl.
[0134] "Heteroalkylene" or "heteroalkylene chain" refers to a
straight or branched divalent hydrocarbon chain linking the rest of
the molecule to a radical group, consisting of carbon and hydrogen
and at least one heteroatom selected from N, O, and S.
[0135] "Alkoxy" refers to a radical of the formula --OR.sub.a where
R.sub.a is an alkyl, or haloalkyl radical as defined above
containing one to six carbon atoms. Representative alkoxy groups
include methoxy and ethoxy. Unless stated otherwise specifically in
the specification, an alkoxy group may be optionally substituted.
An alkoxy that is substituted with halo may be called herein a
haloalkoxy, which includes for example trifluoromethoxy,
trichloromethoxy and the like.
[0136] "Heteroalkenylene" or "heteroalkenylene chain" refers to a
straight or branched divalent hydrocarbon chain linking the rest of
the molecule to a radical group, consisting of carbon and hydrogen
and at least one heteroatom selected from N, O, and S.
[0137] "Aralkyl" refers to a radical of the formula
--R.sub.b--R.sub.e where R.sub.b is an alkylene chain as defined
above and R, is one or more aryl radicals as defined above, for
example, benzyl, diphenylmethyl and the like. The alkylene chain
part of the aralkyl radical may be optionally substituted as
described above for an alkylene chain. The aryl part of the aralkyl
radical may be optionally substituted as described above for an
aryl group.
[0138] "Cycloalkylalkyl" refers to a radical of the formula
--R.sub.bR.sub.g where R.sub.b is an alkylene chain as defined
above and R.sub.g is a cycloalkyl radical as defined above. The
alkylene chain and the cycloalkyl radical may be optionally
substituted as defined above.
[0139] "Fused" refers to any ring system described herein which is
fused to an existing ring structure in the compounds of the
invention. When the fused ring system is a heterocyclyl or a
heteroaryl, any carbon in the existing ring structure which becomes
part of the fused ring system may be replaced with a nitrogen.
[0140] "Halo" refers to bromo, chloro, fluoro or iodo.
[0141] "Haloalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
e.g., trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
The alkyl part of the haloalkyl radical may be optionally
substituted as defined above for an alkyl group.
[0142] "Haloalkenyl" refers to an alkenyl radical, as defined
above, that is substituted by one or more halo radicals, as defined
above. The alkenyl part of the haloalkyl radical may be optionally
substituted as defined above for an alkenyl group.
[0143] "Haloalkoxy" refers to an alkoxy radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy,
2,2,2-trifluoroethoxy, 3-bromo-2-fluoropropyloxy, and the like. The
alkoxy part of the haloalkoxy radical may be optionally substituted
as defined above for an alkoxy group.
[0144] "N-heterocyclyl" refers to a heterocyclyl radical as defined
above containing at least one nitrogen. An N-heterocyclyl radical
may be optionally substituted as described above for heterocyclyl
radicals.
[0145] "Heterocyclylalkyl" refers to a radical of the formula
--R.sub.bR.sub.h where R.sub.b is an alkylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
if the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkyl radical at the nitrogen
atom. The alkylene chain of the heterocyclylalkyl radical may be
optionally substituted as defined above for an alkyene chain. The
heterocyclyl part of the heterocyclylalkyl radical may be
optionally substituted as defined above for a heterocyclyl
group.
[0146] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl
radical may be optionally substituted as described above for
heteroaryl radicals.
[0147] "Heteroarylalkyl" refers to a radical of the formula
--R.sub.bR.sub.i where R.sub.b is an alkylene chain as defined
above and R.sub.t is a heteroaryl radical as defined above. The
heteroaryl part of the heteroarylalkyl radical may be optionally
substituted as defined above for a heteroaryl group. The alkylene
chain part of the heteroarylalkyl radical may be optionally
substituted as defined above for an alkylene chain.
[0148] "Hydroxyalkyl" refers to a radical of the formula
--R.sub.bOH where R.sub.b is an alkylene chain as defined above.
The --OH group can be attached to any carbon in the alkylene chain.
The alkylene chain part of the heteroarylalkyl radical may
additionally be optionally substituted as defined above for an
alkylene chain.
[0149] The compounds described herein may generally be used as the
free acid or free base. Alternatively, the compounds may be used in
the form of acid or base addition salts. Acid addition salts of the
free amino compounds may be prepared by methods well known in the
art, and may be formed from organic and inorganic acids. Suitable
organic acids include maleic, fumaric, benzoic, ascorbic, succinic,
methanesulfonic, acetic, trifluoroacetic, oxalic, propionic,
tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic,
aspartic, stearic, palmitic, glycolic, glutamic, and
benzenesulfonic acids. Suitable inorganic acids include
hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
Base addition salts included those salts that form with the
carboxylate anion and include salts formed with organic and
inorganic cations such as those chosen from the alkali and alkaline
earth metals (for example, lithium, sodium, potassium, magnesium,
barium and calcium), as well as the ammonium ion and substituted
derivatives thereof (for example, dibenzylammonium, benzylammonium,
2-hydroxyethylammonium, and the like). Thus, the term
"pharmaceutically acceptable salt" of the compounds described
herein is intended to encompass any and all acceptable salt
forms.
[0150] Compounds described herein may sometimes be depicted as an
anionic species. One of ordinary skill in the art will recognize
that the compounds exist with an equimolar ratio of cation. For
instance, the compounds can exist in the fully protonated form, or
in the form of a salt such as sodium, potassium, ammonium or in
combination with any inorganic base as described above. When more
than one anionic species is depicted, each anionic species may
independently exist as either the protonated species or as the salt
species.
[0151] With regard to stereoisomers, the compounds described herein
may have one or more chiral (or asymmetric) centers and may thus
give rise to enantiomers, diastereomers, and other stereoisomeric
forms that may be defined, in terms of absolute stereochemistry, as
(R)- or (S)-. When the compounds described herein contain olefinic
double bonds or other centers of geometric asymmetry, and unless
specified otherwise, it is intended that the compounds include both
E and Z geometric isomers (e.g., cis or trans). Likewise, unless
otherwise indicated, all possible isomers, as well as their racemic
and optically pure forms, and all tautomeric forms are also
intended to be included. It is therefore contemplated that various
stereoisomers and mixtures thereof include "enantiomers," which
refers to two stereoisomers whose molecules are nonsuperimposeable
mirror images of one another. Thus, the compounds may occur in any
isomeric form, including racemates, racemic mixtures, and as
individual enantiomers or diastereomers.
[0152] Furthermore, some of the crystalline forms of the compounds
may exist as polymorphs, which are contemplated herein. In
addition, some of the compounds may also form solvates with water
or other organic solvents. Such solvates are similarly included
within the scope of the compounds described herein.
[0153] As one of skill in the art would appreciate, any of the
aforementioned compounds may incorporate radioactive isotopes.
Accordingly, also contemplated is use of isotopically-labeled
compounds identical to those described herein, wherein one or more
atoms are replaced by an atom having an atomic mass or mass number
different from the atomic mass or mass number usually found in
nature. Examples of isotopes that can be incorporated into these
compounds include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine and chlorine, such as, but not limited to,
.sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl respectively.
Certain isotopically-labeled compounds, for example those into
which radioactive isotopes such as .sup.3H and 14C are
incorporated, are also useful in drug or substrate tissue
distribution assays. Tritiated hydrogen (.sup.3H) and carbon-14
(.sup.14C) isotopes are particularly preferred for their ease of
preparation and detectability. Substitution with heavier isotopes
such as deuterium (.sup.2H) can provide certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dose requirements and,
therefore, may be preferred in some circumstances. To this end,
reference to an element, such as hydrogen (H) or carbon (C), is
intended to encompass all isotopes of the same. Thus, reference to
H encompasses .sup.1H (protium), .sup.2H (deuterium) and .sup.3H
(tritium), and reference to C encompasses .sup.12C, .sup.13C and
.sup.14C. For example, compounds of formula (I) wherein both
R.sub.1 groups are .sup.2H (deuterium) are encompassed within the
scope of this invention by reference to R.sub.1 being, in one
embodiment, hydrogen (H). Isotopically-labeled compounds can
generally be prepared by performing procedures routinely practiced
in the art.
[0154] "Prodrug" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound described herein. Thus, the term
"prodrug" refers to a metabolic precursor of a compound described
herein that is pharmaceutically acceptable. A prodrug may be
inactive when administered to a subject in need thereof, but is
converted in vivo to an active compound as described herein.
Prodrugs are typically rapidly transformed in vivo to yield the
parent compound described herein, for example, by hydrolysis in
blood. The prodrug compound often offers advantages of solubility,
tissue compatibility or delayed release in a mammalian organism
(see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24
(Elsevier, Amsterdam). A discussion of prodrugs is provided in
Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S.
Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug
Design, ed. Edward B. Roche, American Pharmaceutical Association
and Pergamon Press, 1987, both of which are incorporated in full by
reference herein.
[0155] The term "prodrug" is also meant to include any covalently
bonded carriers which release the active compound as described
herein in vivo when such prodrug is administered to a mammalian
subject. Prodrugs of a compound described herein may be prepared by
modifying functional groups present in the compound described
herein in such a way that the modifications are cleaved, either in
routine manipulation or in vivo, to the parent compound described
herein. Prodrugs include compounds described herein wherein a
hydroxy, amino or mercapto group is bonded to any group that, when
the prodrug of the compound is administered to a mammalian subject,
cleaves to form a free hydroxy, free amino or free mercapto group,
respectively. Examples of prodrugs include, but are not limited to,
ester and amide derivatives of hydroxy, carboxy, mercapto or amino
functional groups in the compounds described herein and the
like.
[0156] In general, the compounds used in the reactions described
herein may be made according to organic synthesis techniques known
to those skilled in this art, starting from commercially available
chemicals and/or from compounds described in the chemical
literature. "Commercially available chemicals" may be obtained from
standard commercial sources including Acros Organics (Pittsburgh
Pa.), Aldrich Chemical (Milwaukee Wis., including Sigma Chemical
and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research
(Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall,
U.K.), Chemservice Inc. (West Chester Pa.), Crescent Chemical Co.
(Hauppauge N.Y.), Eastman Organic Chemicals, Eastman Kodak Company
(Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), Fisons
Chemicals (Leicestershire UK), Frontier Scientific (Logan Utah),
ICN Biomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall
U.K.), Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co.
Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz &
Bauer, Inc. (Waterbury Conn.), Polyorganix (Houston Tex.), Pierce
Chemical Co. (Rockford Ill.), Riedel de Haen AG (Hanover, Germany),
Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America
(Portland Oreg.), Trans World Chemicals, Inc. (Rockville Md.), and
Wako Chemicals USA, Inc. (Richmond Va.).
[0157] Methods known to one of ordinary skill in the art may be
identified through various reference books and databases. Suitable
reference books and treatise that detail the synthesis of reactants
useful in the preparation of compounds of the present disclosure,
or provide references to articles that describe the preparation,
include for example, "Synthetic Organic Chemistry," John Wiley
& Sons, Inc., New York; S. R. Sandler et al., "Organic
Functional Group Preparations," 2nd Ed., Academic Press, New York,
1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A.
Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,
"Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York,
1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms
and Structure," 4th Ed., Wiley-Interscience, New York, 1992.
Additional suitable reference books and treatise that detail the
synthesis of reactants useful in the preparation of compounds of
the present disclosure, or provide references to articles that
describe the preparation, include for example, Fuhrhop, J. and
Penzlin G. "Organic Synthesis: Concepts, Methods, Starting
Materials", Second, Revised and Enlarged Edition (1994) John Wiley
& Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry,
An Intermediate Text" (1996) Oxford University Press, ISBN
0-19-509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd
Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th
Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,
J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:
3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Quin,
L. D. et al. "A Guide to Organophosphorus Chemistry" (2000)
Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T. W. G.
"Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN:
0-471-19095-0; Stowell, J. C., "Intermediate Organic Chemistry" 2nd
Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial
Organic Chemicals: Starting Materials and Intermediates: An
Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN:
3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John
Wiley & Sons, in over 55 volumes; and "Chemistry of Functional
Groups" John Wiley & Sons, in 73 volumes.
[0158] Specific and analogous reactants may also be identified
through the indices of known chemicals prepared by the Chemical
Abstract Service of the American Chemical Society, which are
available in most public and university libraries, as well as
through on-line databases (the American Chemical Society,
Washington, D.C., may be contacted for more details). Chemicals
that are known but not commercially available in catalogs may be
prepared by custom chemical synthesis houses, where many of the
standard chemical supply houses (e.g., those listed above) provide
custom synthesis services. A reference for the preparation and
selection of pharmaceutical salts of the present disclosure is P.
H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts,"
Verlag Helvetica Chimica Acta, Zurich, 2002.
Compound Synthesis
[0159] Detailed compound synthesis methods are described herein in
the Examples. A person having ordinary skill in the chemical art
would be able to make a compound of Formula I, including specific
compounds described herein, by these methods or similar methods or
other methods practiced by a person skilled in the art. In general,
starting components may be obtained from commercial sources.
Methods of Treatment
[0160] Methods are provided herein for treating or preventing
(i.e., reducing the likelihood of occurrence of neurological
condition, disease or disorder including but not limited to
Alzheimer's Disease, Lewy Body Dementia and the cognitive deficits
associated with schizophrenia; Parkinson's Disease, drug induced
Parkinsonism, dyskinesias, dystonia, chorea, levodopa induced
dyskinesia, cerebral palsy and progressive supranuclear palsy, and
Huntington's disease, including chorea associate with Huntington's
disease. While some of these diseases are considered cognitive
disorders (e.g., Alzheimer's disease), and other diseases are
considered neurological movement diseases/disorders, several have
both cognitive and movement deficiencies or conditions associated
with them (e.g., Parkinson's disease, Huntington's disease).
[0161] The effectiveness of a muscarinic receptor antagonist, such
as a selective M4 antagonist, with respect to treating a
neurological condition, disease or disorder described herein can
readily be determined by a person skilled in the medical and
clinical arts. One or any combination of diagnostic methods
appropriate for the particular disease or disorder, which methods
are well known to a person skilled in the art, including physical
examination, patient self-assessment, assessment and monitoring of
clinical symptoms, performance of analytical tests and methods,
including clinical laboratory tests, physical tests, and
exploratory surgery, for example, may be used for monitoring the
health status of the subject and the effectiveness of the
inhibitor. The effects of the methods of treatment described herein
can be analyzed using techniques known in the art, such as
comparing symptoms of patients suffering from or at risk of a
particular disease or disorder that have received the
pharmaceutical composition comprising an antagonist with those of
patients who were not treated with the inhibitor or who received a
placebo treatment.
[0162] As understood by a person skilled in the medical art, the
terms, "treat" and "treatment," refer to medical management of a
disease, disorder, or condition of a subject (i.e., patient) (see,
e.g., Stedman's Medical Dictionary). In general, an appropriate
dose and treatment regimen provide the M4 antagonist in an amount
sufficient to provide therapeutic and/or prophylactic benefit.
Therapeutic benefit for subjects to whom the M4 antagonist
compound(s) described herein are administered, includes, for
example, an improved clinical outcome, wherein the object is to
prevent or slow or retard (lessen) an undesired physiological
change associated with the disease, or to prevent or slow or retard
(lessen) the expansion or severity of such disease. As discussed
herein, effectiveness of the one or more M4 antagonists may include
beneficial or desired clinical results that comprise, but are not
limited to, abatement, lessening, or alleviation of symptoms that
result from or are associated with the disease to be treated;
decreased occurrence of symptoms; improved quality of life; longer
disease-free status (i.e., decreasing the likelihood or the
propensity that a subject will present symptoms on the basis of
which a diagnosis of a disease is made); diminishment of extent of
disease; stabilized (i.e., not worsening) state of disease; delay
or slowing of disease progression; amelioration or palliation of
the disease state; and remission (whether partial or total),
whether detectable or undetectable; and/or overall survival.
[0163] "Treatment" can also mean prolonging survival when compared
to expected survival if a subject were not receiving treatment.
Subjects in need of treatment include those who already have the
disease or disorder as well as subjects prone to have or at risk of
developing the disease or disorder, and those in which the disease,
condition, or disorder is to be prevented (i.e., decreasing the
likelihood of occurrence or recurrence of the disease or
disorder).
[0164] A subject (i.e., patient, individual) in need of treatment
with an M4 antagonist as described herein may be a human or may be
a non-human primate or other animal (i.e., veterinary use) who has
developed symptoms of a hyperkinetic disease or disorder or who is
at risk for developing a hyperkinetic disease or disorder.
Non-human animals that may be treated include mammals, for example,
non-human primates (e.g., monkey, chimpanzee, gorilla, and the
like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets,
rabbits), lagomorphs, swine (e.g., pig, miniature pig), equine,
canine, feline, bovine, elephants, bears and other domestic, farm,
and zoo animals.
Pharmaceutical Compositions
[0165] The present disclosure further provides for pharmaceutical
compositions comprising any one of the M4 antagonist compounds
described herein (a compound of Formula I, including specific
compounds described herein) and a pharmaceutically acceptable
excipient for use in the methods for treating hyperkinetic
disorders. A pharmaceutically acceptable excipient is a
physiologically and pharmaceutically suitable non-toxic and
inactive material or ingredient that does not interfere with the
activity of the active ingredient; an excipient also may be called
a carrier. The formulation methods and excipients described herein
are exemplary and are in no way limiting. Pharmaceutically
acceptable excipients are well known in the pharmaceutical art and
described, for example, in Rowe et al., Handbook of Pharmaceutical
Excipients: A Comprehensive Guide to Uses, Properties, and Safety,
5.sup.th Ed., 2006, and in Remington: The Science and Practice of
Pharmacy (Gennaro, 21.sup.st Ed. Mack Pub. Co., Easton, Pa.
(2005)). Exemplary pharmaceutically acceptable excipients include
sterile saline and phosphate buffered saline at physiological pH.
Preservatives, stabilizers, dyes, buffers, and the like may be
provided in the pharmaceutical composition. In addition,
antioxidants and suspending agents may also be used.
[0166] For compositions formulated as liquid solutions, acceptable
carriers and/or diluents include saline and sterile water, and may
optionally include antioxidants, buffers, bacteriostats and other
common additives. The compositions can also be formulated as pills,
capsules, granules, or tablets which contain, in addition to an M4
antagonist, diluents, dispersing and surface active agents,
binders, and lubricants. One skilled in this art may further
formulate the M4 antagonist in an appropriate manner, and in
accordance with accepted practices, such as those disclosed in
Remington, supra.
[0167] Methods of administration include systemic administration of
an M4 antagonist described herein, preferably in the form of a
pharmaceutical composition as discussed above. As used herein,
systemic administration includes oral and parenteral methods of
administration. For oral administration, suitable pharmaceutical
compositions include powders, granules, pills, tablets, and
capsules as well as liquids, syrups, suspensions, and emulsions.
These compositions may also include flavorants, preservatives,
suspending, thickening and emulsifying agents, and other
pharmaceutically acceptable additives. For parental administration,
the compounds of the present invention can be prepared in aqueous
injection solutions which may contain, in addition to the M4
antagonist, buffers, antioxidants, bacteriostats, and other
additives commonly employed in such solutions.
[0168] As described herein optimal doses are generally determined
using experimental models and/or clinical trials. The optimal dose
of the M4 antagonist may depend upon the body mass, weight, blood
volume, or other individual characteristics of the subject. For
example, a person skilled in the medical art can consider the
subject's condition, that is, stage of the disease, severity of
symptoms caused by the disease, general health status, as well as
age, gender, and weight, and other factors apparent to a person
skilled in the medical art. In general, the amount of a compound
described herein, that is present in a dose ranges from about 0.1
mg to about 2 mg per kg weight of the subject. In certain
embodiments, a daily dose is about 10-150 mg. The use of the
minimum dose that is sufficient to provide effective therapy is
usually preferred. Subjects may generally be monitored for
therapeutic effectiveness by clinical evaluation and using assays
suitable for the condition being treated or prevented, which
methods will be familiar to those having ordinary skill in the art
and are described herein. The level of a compound that is
administered to a subject may be monitored by determining the level
of the compound in a biological fluid, for example, in the blood,
blood fraction (e.g., plasma, serum), and/or in the urine, and/or
other biological sample from the subject. Any method practiced in
the art to detect the compound may be used to measure the level of
compound during the course of a therapeutic regimen.
[0169] Pharmaceutical composition comprising an M4 antagonist may
formulated for timed release (also called extended release,
sustained release, controlled release, or slow release). Such
compositions may generally be prepared using well known technology
and administered by, for example, oral, rectal or subcutaneous
implantation, or by implantation at the desired target site.
Sustained-release formulations may contain the compound dispersed
in a carrier matrix and/or contained within a reservoir surrounded
by a rate controlling membrane. Excipients for use within such
formulations are biocompatible, and may also be biodegradable;
preferably the formulation provides a relatively constant level of
active component release. The amount of active compound contained
within a sustained release formulation depends upon the site of
implantation, the rate and expected duration of release, and the
nature of the condition to be treated or prevented.
[0170] The pharmaceutical compositions described herein that
comprise at least one of the M4 antagonist compounds described
herein may be administered to a subject in need by any one of
several routes that effectively deliver an effective amount of the
compound. Such administrative routes include, for example, oral,
parenteral (e.g., subcutaneous, intravenous, intramuscular,
intrasternal, intracavernous), enteral, rectal, intranasal, buccal,
sublingual, intramuscular, and transdermal.
[0171] Kits with unit doses of one or more of the compounds
described herein, usually in oral or injectable doses, are
provided. Such kits may include a container containing the unit
dose, an informational package insert describing the use and
attendant benefits of the drugs in treating pathological condition
of interest, and optionally an appliance or device for delivery of
the composition.
EXAMPLES
Example 1
##STR00021##
[0172] Step 1A:
5-[(3R)-3-methylpiperazin-1-yl]-2-(trifluoromethoxy)benzonitrile
[0173] To a solution of tert-butyl
(2R)-2-methylpiperazine-1-carboxylate (5.0 g, 25 mmol, 1.0 eq) and
5-bromo-2-(trifluoromethoxy)benzonitrile (3.8 mL, 25 mmol, 1 eq) in
toluene (100 mL) was added sodium tert-butoxide (7.2 g, 75 mmol,
3.0 eq), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.6
g, 2.5 mmol, 0.10 eq), and lastly
tris(dibenzylideneacetone)dipalladium(0) (2.3 g, 2.5 mmol, 0.10
eq), and the reaction mixture heated to 100.degree. C. overnight.
The resulting dark reaction mixture was cooled, passed thru a pad
of celite, and concentrated in vacuo. Silica gel column (80 g) was
dry loaded and run using an increasing gradient of EtOAc (0-50%) in
hexanes over 25 min. The chromatographed material was dissolved in
dioxane (40 mL) and treated with a solution of 4M HCl in dioxane
(10 mL). The resulting thick suspension was concentrated, dissolved
in MeOH, and made basic with the addition of MP-carbonate.
Following removal of the resin and concentration of the filtrate,
the free base of
5-[(3R)-3-methylpiperazin-1-yl]-2-(trifluoromethoxy)benzonitrile 1a
(5.2 g, 18 mmol, 72% over two steps) was isolated as an orange
oil.
[0174] In general, this reaction is completed with stirring
overnight, however if necessary, additional acid equivalents and/or
gentle heat (50.degree. C.) can be used to push the reaction.
[0175] Other compounds made using the above synthetic scheme
include: [0176] 1-(3,4-difluorophenyl)piperazine 1b; [0177]
3-(piperazin-1-yl)benzonitrile 1c; [0178]
2-fluoro-5-(piperazin-1-yl)benzonitrile 1d; [0179]
3-fluoro-5-(piperazin-1-yl)benzonitrile 1e; [0180]
1-[4-(trifluoromethoxy)phenyl]piperazine 1f; [0181]
1-[3-(trifluoromethoxy)phenyl]piperazine 1g; [0182]
1-(3,4,5-trifluorophenyl)piperazine 1h; [0183]
(3R)-3-methyl-1-[4-(trifluoromethyl)phenyl]piperazine 1i; [0184]
2-fluoro-5-[(3R)-3-methylpiperazin-1-yl]benzonitrile 1j; [0185]
3-fluoro-5-[(3R)-3-methylpiperazin-1-yl]benzonitrile 1k; [0186]
(3R)-3-methyl-1-(3,4,5-trifluorophenyl)piperazine 1l; [0187]
(3R)-3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]piperazine 1m;
[0188]
(3R)-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-3-methylpiperazine
1n; [0189]
(3R)-3-methyl-1-[5-(trifluoromethoxy)pyridin-2-yl]piperazine 1o;
and [0190]
(3R)-3-methyl-1-[6-(trifluoromethoxy)pyridin-3-yl]piperazine
1p.
Example 2
##STR00022##
[0191] Step 2A:
2-[(3R)-3-methylpiperazin-1-yl]-5-(trifluoromethyl)pyrimidine
[0192] To a solution of tert-butyl
(2R)-2-methylpiperazine-1-carboxylate (2.2 g, 11.0 mmol, 1.0 eq)
and 2-chloro-5-(trifluoromethyl)pyrimidine (2.0 g, 11.0 mmol, 1.0
eq) in 1-methyl-2-pyrrolidone (NMP, 10 mL) was added
N,N-diisopropylethylamine (5.7 mL, 44.0 mmol, 4.0 eq) and the
reaction mixture heated to 100.degree. C. for 1 hr. The reaction
mixture was cooled, diluted heavily with EtOAc, and washed
repeatedly with brine (5.times.). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. Silica gel column (80 g) was
loaded using methylene chloride and run using an increasing
gradient of EtOAc (5-90%) in hexanes over 20 min. The
chromatographed material was dissolved in dioxane (25 mL) and
treated with a solution of 4M HCl in dioxane (6 mL). The resulting
thick white suspension was concentrated, dissolved in MeOH, and
made basic with the addition of MP-carbonate. Following removal of
the resin and concentration of the filtrate, the free base of
2-[(3R)-3-methylpiperazin-1-yl]-5-(trifluoromethyl)pyrimidine 2a
(1.9 g, 7.6 mmol, 69% over two steps) was isolated as a white
solid.
[0193] In general, this reaction is completed with stirring
overnight, however if necessary, additional acid equivalents and/or
gentle heat (50.degree. C.) can be used to push the reaction.
[0194] Other compounds made using the above synthetic scheme
include: [0195]
4-(dimethylamino)-2-[(3R)-3-methylpiperazin-1-yl]pyrimidine-5-carb-
onitrile 2b; [0196]
2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidine-5-carbonitrile
2c; [0197]
2-[(3R)-3-methylpiperazin-1-yl]-5-(trifluoromethyl)pyrimidin-4-amine
2d; [0198] 2-[(3R)-3-methylpiperazin-1-yl]pyrimidine-5-carbonitrile
2e; [0199]
2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidine-5-carbonitrile 2f;
[0200]
2-{2,5-diazabicyclo[2.2.2]octan-2-yl}pyrimidine-5-carbonitrile 2g;
[0201] 2-{2,6-diazaspiro[3.3]heptan-2-yl}pyrimidine-5-carbonitrile
2h; [0202]
2-{3,6-diazabicyclo[3.1.1]heptan-3-yl}pyrimidine-5-carbonitrile 2i;
[0203]
2-{3,8-diazabicyclo[3.2.1]octan-3-yl}pyrimidine-5-carbonitrile 2j;
[0204] 5-chloro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidine 2k;
[0205] 5-chloro-2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidine
2l; [0206] 6-[(3R,5
S)-3,5-dimethylpiperazin-1-yl]-5-fluoropyridine-3-carbonitrile 2m;
and [0207]
6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridine-3-carbonitrile
2n.
Example 3
##STR00023##
[0208] Step 3A:
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-cyano-4-(trifluoromethoxy)-
phenyl]-2-methylpiperazine-1-carboxamide
[0209] Triphosgene (2.1 g, 7.2 mmol, 0.40 eq) was dissolved in
methylene chloride (50 mL) and a solution of
5-[(3R)-3-methylpiperazin-1-yl]-2-(trifluoromethoxy)benzonitrile 1a
(5.2 g, 18 mmol, 1.0 eq) and N,N-diisopropylethylamine (6.0 mL, 36
mmol, 2.0 eq) in methylene chloride (50 mL) was added dropwise at
room temperature. Once the addition was complete, the reaction
mixture was stirred for 10 min before a solution of
2-(1-benzylpiperidin-4-yl)ethan-1-amine (4.8 g, 22 mmol, 1.2 eq)
and N,N-diisopropylethylamine (6.0 mL, 36 mmol, 2.0 eq) in
methylene chloride (50 mL) was added and stirred at room
temperature for an additional 1 hr. Then, the reaction was diluted
further with methylene chloride and washed with sat. NH.sub.4Cl
followed by sat. NaHCO.sub.3. The combined organic layers were
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Silica gel
column (80 g) was loaded using methylene chloride and run with an
increasing gradient of MeOH (0-20%) in methylene chloride over 20
min to provide
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-cyano-4-(trifluoromethoxy)-
phenyl]-2-methylpiperazine-1-carboxamide 3-1 (5.2 g, 9.8 mmol, 54%)
as an orange oil. The table below provides the observed (Obs) ion
m/z ratio for 3-1 (first compound listed in Table 1) and other
compounds that were made according to the procedure as described in
this example.
TABLE-US-00001 TABLE 1 Cpd. No. Compound Name Obs Ion (m/z) 3-1
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-cyano-4- 530.2
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 3-2
(1S)-1-(1-benzylpiperidin-4-yl)-2-{[(2R)-4-(3-cyano-4- 522.25
fluorophenyl)-2-methylpiperazine-1-carbonyl]amino}ethyl acetate 3-3
(2R)-N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-4-(3- 494.2
cyano-4-fluorophenyl)-N,2-dimethylpiperazine-1-carboxamide 3-4
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4- 478.2
fluorophenyl)-N,2-dimethylpiperazine-1-carboxamide 3-5
(2R)-N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-4-[3-cyano-
546.2 4-(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide
3-6 (2R)-N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-methoxyethyl]-4-(3-
494.2 cyano-4-fluorophenyl)-2-methylpiperazine-1-carboxamide 3-7
(2R)-4-[3-cyano-4-(trifluoromethoxy)phenyl]-N-(2-{1-[(4- 656.1
iodophenyl)methyl]piperidin-4-yl}ethyl)-2-methylpiperazine-1-
carboxamide 3-8
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[6- 506.2
(trifluoromethoxy)pyridin-3-yl]piperazine-1-carboxamide 3-9
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5- 491.2
(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide 3-10
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-fluoro-5- 508.2
(trifluoromethyl)pyridin-2-yl]-2-methylpiperazine-1- carboxamide
3-11 (2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5- 464.2
fluorophenyl)-2-methylpiperazine-1-carboxamide 3-12
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(3,4,5- 475.2
trifluorophenyl)piperazine-1-carboxamide 3-13
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5- 506.2
(trifluoromethoxy)pyridin-2-yl]piperazine-1-carboxamide 3-14
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5- 490.2
(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide 3-15
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyanopyrimidin- 448.2
2-yl)-2-methylpiperazine-1-carboxamide 3-16
(2R)-N-[(2R)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-2- 491.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 3-17
(2R)-N-{2-[1-benzyl-3-(hydroxymethyl)piperidin-4-yl]ethyl}-2- 505.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 3-18
(2R)-N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-4-(3- 480.2
cyano-4-fluorophenyl)-2-methylpiperazine-1-carboxamide 3-19
N-{2-[1-benzyl-3-(hydroxymethyl)piperidin-4-yl]ethyl}-4- 491.2
(3,4,5-trifluorophenyl)piperazine-1-carboxamide 3-20
(2R)-N-{2-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]ethyl}-2- 505.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 3-21
(2R)-N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-4-[3- 546.2
cyano-4-(trifluoromethoxy)phenyl]-2-methylpiperazine-1- carboxamide
3-22 (2R)-N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-2-
491.2 methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 3-23
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyridin-
461.1 2-yl)-2,6-dimethylpiperazine-1-carboxamide
##STR00024##
Step 4A:
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methylpiperazine-1-c-
arboxamide
[0210] Triphosgene (1.2 g, 4.0 mmol, 0.40 eq) was dissolved in
methylene chloride (20 mL) and a solution of tert-butyl
(3R)-3-methylpiperazine-1-carboxylate (2.0 g, 10 mmol, 1.0 eq) and
N,N-diisopropylethylamine (1.6 mL, 10 mmol, 1.0 eq) in methylene
chloride (30 mL) was added dropwise at room temperature. Once
complete, the reaction mixture was stirred for 10 min before a
solution of 2-(1-benzylpiperidin-4-yl)ethan-1-amine (2.6 g, 12
mmol, 1.2 eq) and N,N-diisopropylethylamine (1.6 mL, 10 mmol, 1.0
eq) in methylene chloride (30 mL) was added. Stirring at room
temperature, the reaction was complete within 1 hr. The reaction
mixture was diluted further with methylene chloride and washed with
sat. NH.sub.4Cl followed by sat. NaHCO.sub.3. The combined organic
layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
Silica gel column (40 g) was loaded using methylene chloride and
run with an increasing gradient of MeOH (0-25%) in methylene
chloride over 20 min. The chromatographed material was dissolved in
dioxane (40 mL) and treated with a solution of 4M HCl in dioxane (5
mL). In general, this reaction is completed with stirring
overnight, however if necessary, additional acid equivalents and/or
gentle heat (50.degree. C.) can be used to push the reaction. The
resulting light yellow suspension was concentrated, dissolved in
MeOH, and made basic with the addition of MP-carbonate.
[0211] Following removal of the resin and concentration of the
filtrate, the free base of
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methylpiperazine-1-carboxamid-
e 4a (2.0 g, 5.8 mmol, 58% over two steps) was isolated as a yellow
oil.
(2S,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-car-
boxamide 4b was made according to the same procedure, but with
appropriately modified starting materials.
Step 4B:
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4-fluorophen-
yl)-2-methylpiperazine-1-carboxamide
[0212] To a solution of
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methylpiperazine-1-carboxamid-
e 4a (20 mg, 0.06 mmol, 1.0 eq) and 5-bromo-2-fluoro-benzonitrile
(12 mg, 0.06 mmol, 1.0 eq) in 1:1 dioxane:toluene (1 mL) was added
sodium tert-butoxide (17 mg, 0.18 mmol, 3.0 eq), racemic
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (3.7 mg, 0.006 mmol,
0.10 eq), and lastly tris(dibenzylideneacetone)-dipalladium(0) (5.5
mg, 0.006 mmol, 0.10 eq), and the reaction mixture stirred
vigorously at 100.degree. C. overnight. The resulting dark
suspension was cooled, passed through an HPLC filter and
concentrated in vacuo. The crude material was treated with 1.5 mL
of MeOH, passed through an additional HPLC filter (leaving any
precipitate behind), and submitted for directly for preparative
chromatography yielding
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4-fluorophenyl)-2-me-
thylpiperazine-1-carboxamide 4-1. The table below provides the
observed (Obs) ion m/z ratio for 4-1 (first compound listed in
Table 2) and other compounds that were made according to the
procedure as described in this example.
TABLE-US-00002 TABLE 2 Cpd. No. Compound Name Obs Ion (m/z) 4-1
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4- 464.2
fluorophenyl)-2-methylpiperazine-1-carboxamide 4-2
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-methoxypyrimidin-2-
453.3 yl)-2-methylpiperazine-1-carboxamide 4-4
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-3- 460.3
methylphenyl)-2-methylpiperazine-1-carboxamide 4-5
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[4- 489.2
(trifluoromethyl)phenyl]piperazine-1-carboxamide 4-6
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2,2-difluoro-2H-1,3-
501.2 benzodioxol-5-yl)-2-methylpiperazine-1-carboxamide 4-8
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-methoxypyridin-2-
452.3 yl)-2-methylpiperazine-1-carboxamide 4-9
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(6- 436.3
methylpyridin-3-yl)piperazine-1-carboxamide 4-10
(2S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[4- 505.2
(trifluoromethoxy)phenyl]piperazine-1-carboxamide 4-11
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chloro-6- 496.2
cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide 4-12
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[4- 490.2
(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide 4-13
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-fluoro-4- 453.3
methylphenyl)-2-methylpiperazine-1-carboxamide 4-14
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyanopyrimidin-
462.2 2-yl)-2,6-dimethylpiperazine-1-carboxamide 4-15
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3,4-difluorophenyl)-2-
457.2 methylpiperazine-1-carboxamide 4-16
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[3- 505.2
(trifluoromethoxy)phenyl]piperazine-1-carboxamide 4-17
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-4-(3,4,5- 475.2
trifluorophenyl)piperazine-1-carboxamide 4-18
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-4-[4- 505.2
(trifluoromethoxy)phenyl]piperazine-1-carboxamide 4-19
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-fluoro-6- 454.2
methylpyridin-2-yl)-2-methylpiperazine-1-carboxamide 4-20
(2S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4- 464.2
fluorophenyl)-2-methylpiperazine-1-carboxamide 4-21
(2S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-cyano-4- 530.2
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 4-22
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-fluoro-4- 523.2
(trifluoromethoxy)phenyl]-3-methylpiperazine-1-carboxamide 4-23
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyridin-3-yl)-
447.2 2-methylpiperazine-1-carboxamide 4-24
(2S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(3,4,5- 475.2
trifluorophenyl)piperazine-1-carboxamide 4-25
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyanophenyl)-2- 446.2
methylpiperazine-1-carboxamide 4-26
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyano-4- 478.2
methoxypyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 4-27
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-fluoro-4- 471.2
methoxypyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 4-28
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-cyano-4- 491.4
(dimethylamino)pyrimidin-2-yl]-2-methylpiperazine-1-carboxamide
4-28 (2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4- 476.3
methoxyphenyl)-2-methylpiperazine-1-carboxamide 4-30
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-fluorophenyl)-2-
439.2 methylpiperazine-1-carboxamide 4-31
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyridin-2-yl)-
447.2 2-methylpiperazine-1-carboxamide 4-33
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2,4-difluorophenyl)-2-
457.2 methylpiperazine-1-carboxamide 4-34
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[6- 490.3
(tnfluoromethyl)pyridin-3-yl]piperazine-1-carboxamide 4-35
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-fluoropyridin-3-yl)-
440.2 2-methylpiperazine-1-carboxamide 4-36
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(2,4,5- 475.2
trifluorophenyl)piperazine-1-carboxamide 4-37
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2,3-difluorophenyl)-2-
457.2 methylpiperazine-1-carboxamide 4-38
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4,6-dicyanopyrimidin-
473.2 2-yl)-2-methylpiperazine-1-carboxamide 4-39
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5- 476.3
methoxyphenyl)-2-methylpiperazine-1-carboxamide 4-40
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(quinolin-3-
472.3 yl)piperazine-1-carboxamide 4-41
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-fluoropyrimidin-2-
441.3 yl)-2-methylpiperazine-1-carboxamide 4-43
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-2- 464.3
fluorophenyl)-2-methylpiperazine-1-carboxamide 4-44
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanothiophen-2-yl)-
452.2 2-methylpiperazine-1-carboxamide 4-45
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2,5-difluorophenyl)-2-
457.2 methylpiperazine-1-carboxamide 4-46
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-fluoropyridin-2-yl)-
440.2 2-methylpiperazine-1-carboxamide 4-47
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4- 421.3
phenylpiperazine-1-carboxamide 4-48
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3,5-difluoropyridin-2-
458.2 yl)-2-methylpiperazine-1-carboxamide 4-49
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-fluorophenyl)-2-
439.2 methylpiperazine-1-carboxamide 4-50
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 522.2
methylpiperazin-1-yl]-6-methyl-N-(propan-2-yl)pyrimidine-4-
carboxamide 4-51
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-methoxypyridin-2-
452.3 yl)-2-methylpiperazine-1-carboxamide 4-52
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-chloro-4,5- 491.2
difluorophenyl)-2-methylpiperazine-1-carboxamide 4-53
(2S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-fluoro-4- 523.2
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 4-54
(2S,6R)-4-(4-amino-5-cyanopyrimidin-2-yl)-N-[2-(1- 477.3
benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-carboxamide
4-55 (2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-5- 466.2
fluoropyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 4-56
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-methoxyphenyl)-3- 451.3
methylpiperazine-1-carboxamide 4-60
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3,5-difluoro-4- 541.2
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 4-61
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-fluoropyridin-3-yl)-
440.2 2-methylpiperazine-1-carboxamide 4-62
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(pyridin-2-
422.2 yl)piperazine-1-carboxamide 4-63
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(5- 436.3
methylpyridin-3-yl)piperazine-1-carboxamide 4-64
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-(pyrimidin-2-
423.2 yl)piperazine-1-carboxamide 4-68
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyanophenyl)-2- 446.2
methylpiperazine-1-carboxamide 4-69
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyano-4- 492.2
methoxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide 4-70
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-fluoro-4- 469.3
methoxyphenyl)-2-methylpiperazine-1-carboxamide 4-71
(3S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-4-(3,4,5- 475.2
trifluorophenyl)piperazine-1-carboxamide 4-72
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3,5-difluorophenyl)-2-
457.25 methylpiperazine-1-carboxamide 4-73
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[2-fluoro-4- 507.2
(trifluoromethyl)phenyl]-2-methylpiperazine-1-carboxamide 4-74
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3,4,5- 461.3
trifluorophenyl)piperazine-1-carboxamide 4-75
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4,6-dicyanopyrimidin-
473.2 2-yl)-2-methylpiperazine-1-carboxamide 4-76
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4- 475.2
(trifluoromethyl)phenyl]piperazine-1-carboxamide 4-77
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-(trifluoromethyl)pyridin-
476.1 2-yl]piperazine-1-carboxamide 4-78
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyano-3- 479.2
fluoropyridin-2-yl)-2,6-dimethylpiperazine-1-carboxamide 4-79
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[2- 491.17
(trifluoromethyl)pyrimidin-5-yl]piperazine-1-carboxamide 4-80
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-cyanopyrimidin-5-
448.15 yl)-2-methylpiperazine-1-carboxamide
Example 5
##STR00025##
[0213] Step 5A:
(2R)-4-(4-amino-5-cyanopyrimidin-2-yl)-N-[2-(1-benzylpiperidin-4-yl)ethyl-
]-2-methylpiperazine-1-carboxamide
[0214] To a solution of
(2R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methylpiperazine-1-carboxamid-
e 4a (0.20 g, 0.58 mmol, 1.0 eq) and
4-amino-2-chloropyrimidine-5-carbonitrile (0.90 g, 0.58 mmol, 1.0
eq) in NMP (2 mL) was added N,N-diisopropylethylamine (0.38 mL, 2.3
mmol, 4.0 eq) and the reaction mixture heated to 100.degree. C. for
1 hr. In some cases, lower temperatures or longer reaction times
were used. The reaction mixture was cooled, diluted heavily with
EtOAc, and washed repeatedly with brine (3.times.). The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated. Silica gel
column (24 g) was loaded using methylene chloride and run using an
increasing gradient of MeOH (0-20%) in methylene chloride over 20
min to provide
(2R)-4-(4-amino-5-cyanopyrimidin-2-yl)-N-[2-(1-benzylpiperidin-4-yl)ethyl-
]-2-methylpiperazine-1-carboxamide 5-1 (0.14 g, 0.31 mmol, 53%) as
an off-white foam. The table below provides the observed (Obs) ion
m/z ratio for 5-1 (first compound listed in Table 3) and other
compounds that were made according to the procedure as described in
this example.
TABLE-US-00003 TABLE 3 Cpd. Obs Ion No. Compound Name (m/z) 5-1
(2R)-4-(4-amino-5-cyanopyrimidin-2-yl)-N-[2-(1-benzylpiperidin-
463.2 4-yl)ethyl]-2-methylpiperazine-1-carboxamide 5-2
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 467.2
methylpiperazin-1-yl]pyrimidine-5-carboxylic acid 5-3
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4,5- 491.1
dichloropyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 5-4
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-{5-cyano-4-[(2,2,2-
559.2
trifluoroethyl)amino]pyrimidin-2-yl}-2,6-dimethylpiperazine-1-
carboxamide 5-5
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chloro-6- 482.2
cyanopyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 5-6
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4- 477.2
(trifluoropyrimidin-2-yl)piperazine-1-carboxamide 5-7
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-{5-cyano-4-[(2,2,2-
545.2 trifluoroethyl)amino]pyrimidin-2-yl}-2-methylpiperazine-1-
carboxamide 5-8
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[4- 491.2
(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide 5-9
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chloro-5- 475.2
fluoropyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 5-10
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-bromo-4- 537.1
chloropyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 5-11 methyl
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 515.1
methylpiperazin-1-yl]-6-chloropyrimidine-4-carboxylate 5-12 methyl
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 495.2
methylpiperazin-1-yl]-6-methylpyrimidine-4-carboxylate 5-13
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrimidin-2-
448.3 yl)-2-methylpiperazine-1-carboxamide 5-14
(2S,6R)-4-(4-amino-5-cyanopyrimidin-2-yl)-N-[2-(1- 477.3
benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-carboxamide
5-15 (2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-cyano-4- 491.4
(dimethylamino)pyrimidin-2-yl]-2-methylpiperazine-1- carboxamide
5-16 (2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyano-4- 478.2
methoxypyrimidin-2-yl)-2-methylpiperazine-1-carboxamide 5-17
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyano-4- 492.2
methoxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide 5-18
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-chloropyrimidin-
471.2 2-yl)-2,6-dimethylpiperazine-1-carboxamide 5-19
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-fluoropyrimidin-
455.25 2-yl)-2,6-dimethylpiperazine-1-carboxamide 5-20
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrimidin-
462.3 2-yl)-2,6-dimethylpiperazine-1-carboxamide 5-21
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-cyano-4- 491.3
(methylamino)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxamide
5-22
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-chloropyrimidin-2-
457.2 yl)-2-methylpiperazine-1-carboxamide 5-23
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5-cyano-4- 477.2
(methylamino)pyrimidin-2-yl]-2-methylpiperazine-1-carboxamide 5-24
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5- 477.15
(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide 5-25
(3S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrimidin-2-
464.2 yl)-3-(hydroxymethyl)piperazine-1-carboxamide 5-26
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrimidin-2-
464.2 yl)-2-(hydroxymethyl)piperazine-1-carboxamide 5-27
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-
505.1 (trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide 5-28
(2R,6S)-4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-N-[2-(1-
520.1
benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-carboxamide
5-29 (2R)-4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-N-[2-(1-
506.1 benzylpiperidin-4-yl)ethyl]-2-methylpiperazine-1-carboxamide
5-30 4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-N-[2-(1- 492.1
benzylpiperidin-4-yl)ethyl]piperazine-1-carboxamide 5-31
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-bromopyrimidin-2-
501.2 yl)-2-methylpiperazine-1-carboxamide 5-32
(2R)-4-(4-amino-5-chloropyrimidin-2-yl)-N-[2-(1- 472.0
benzylpiperidin-4-yl)ethyl]-2-methylpiperazine-1-carboxamide 5-33
4-(4-amino-5-chloropyrimidin-2-yl)-N-[2-(1-benzylpiperidin-4- 458.0
yl)ethyl]piperazine-1-carboxamide 5-34
4-(4-amino-5-fluoropyrimidin-2-yl)-N-[2-(1-benzylpiperidin-4- 442.0
yl)ethyl]piperazine-1-carboxamide
##STR00026##
Example 6
Step 6A:
(2R)-2-methyl-N-[2-(piperidin-4-yl)ethyl]-4-(3,4,5-trifluoropheny-
l)piperazine-1-carboxamide
[0215] Triphosgene (1.3 g, 4.4 mmol, 0.40 eq) was dissolved in
methylene chloride (30 mL) and a solution of
(3R)-3-methyl-1-(3,4,5-trifluorophenyl)piperazine 1l (2.5 g, 11
mmol, 1.0 eq) and N,N-diisopropylethylamine (3.6 mL, 22 mmol, 2.0
eq) in methylene chloride (30 mL) was added dropwise at room
temperature. Once the addition was complete, the reaction mixture
was stirred for 10 min before a solution of tert-butyl
4-(2-aminoethyl)piperidine-1-carboxylate (2.9 g, 13 mmol, 1.2 eq)
and N,N-diisopropylethylamine (3.6 mL, 22 mmol, 2.0 eq) in
methylene chloride (30 mL) was added. Stirring at room temperature,
the reaction was complete within 1 hr. The reaction mixture was
diluted further with methylene chloride and washed with sat.
NH.sub.4Cl followed by sat. NaHCO.sub.3. The combined organic
layers were dried over Na.sub.2SO.sub.4, concentrated in vacuo, and
loaded onto a silica gel column (40 g). Elution with an increasing
gradient of EtOAc (0-100%) in hexanes over 25 min yielded
tert-butyl
4-(2-{[(2R)-2-methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carbonyl]amino-
}ethyl)piperidine-1-carboxylate 6a. This chromatographed material
was dissolved in dioxane (60 mL) and treated with a solution of 4M
HCl in dioxane (10 mL). After stirring overnight, the resulting
light yellow suspension was concentrated, dissolved in MeOH, and
made basic with the addition of MP-carbonate.
[0216] Following removal of the resin and concentration of the
filtrate, the free base of
(2R)-2-methyl-N-[2-(piperidin-4-yl)ethyl]-4-(3,4,5-trifluorophenyl)pipera-
zine-1-carboxamide 6b (2.2 g, 5.8 mmol, 53% over two steps) was
isolated as a brown foam.
(2S,6R)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-[2-(piperidin-4-yl)ethyl-
]piperazine-1-carboxamide 6c was made according to the same
procedure, but with appropriately modified starting materials.
Step 6B:
(2R)--N-{2-[1-(1H-indol-5-ylmethyl)piperidin-4-yl]ethyl}-2-methyl-
-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide
[0217] To NMP solutions of
(2R)-2-methyl-N-[2-(piperidin-4-yl)ethyl]-4-(3,4,5-trifluorophenyl)pipera-
zine-1-carboxamide 6b (0.05 mL, 0.50 M, 1 eq) and
1H-indole-5-carbaldehyde (0.05 mL, 0.50 M, 1 eq) was added an
ethanolic solution of borane-pyridine complex (0.10 mL, 0.50 M, 2
eq) followed by acetic acid (5 .mu.L) and the mixture stirred at RT
overnight. The reaction mixture was diluted to a total volume of 1
mL using MeOH and submitted directly for preparative chromatography
yielding
(2R)--N-{2-[1-(1H-indol-5-ylmethyl)piperidin-4-yl]ethyl}-2-methyl-4-(3,4,-
5-trifluorophenyl)piperazine-1-carboxamide 6-1. The table below
provides the observed (Obs) ion m/z ratio for 6-1 (first compound
listed in Table 4) and other compounds that were made according to
the procedure as described in this example.
TABLE-US-00004 TABLE 4 Cpd. Obs Ion No. Compound Name (m/z) 6-1
(2R)-N-{2-[1-(1H-indol-5-ylmethyl)piperidin-4-yl]ethyl}-2- 514.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-2
(2R)-N-(2-{1-[(4-cyanophenyl)methyl]piperidin-4-yl}ethyl)-2- 500.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-3
(2R)-N-{2-[1-(2,3-dihydro-1-benzofuran-7-ylmethyl)piperidin-4-
517.2 yl]ethyl}-2-methyl-4-(3,4,5-trifluorophenyl)piperazine-1-
carboxamide 6-4
(2R)-N-(2-{1-[(4-fluorophenyl)methyl]piperidin-4-yl}ethyl)-2- 493.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-5
(2R)-N-(2-{1-[(2-fluorophenyl)methyl]piperidin-4-yl}ethyl)-2- 493.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-6
(2R)-N-{2-[1-(cyclohexylmethyl)piperidin-4-yl]ethyl}-2-methyl-
481.3 4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-7
(2R)-2-methyl-N-{2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]ethyl}-
476.2 4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-8
(2R)-2-methyl-N-{2-[1-(1,2,3-thiadiazol-4-ylmethyl)piperidin-4-
483.2 yl]ethyl}-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide
6-9 (2R)-N-{2-[1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-
533.2 4-yl]ethyl}-2-methyl-4-(3,4,5-trifluorophenyl)piperazine-1-
carboxamide 6-10
(2R)-N-(2-{1-[(3-fluorophenyl)methyl]piperidin-4-yl}ethyl)-2- 493.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-11
1-(5-cyanopyridin-2-yl)-N-{2-[1-(1H-indol-5-ylmethyl)piperidin-
471.3 4-yl]ethyl}piperidine-4-carboxamide 6-12
(2R)-2-methyl-N-(2-{1-[(2-methyl-1,3-thiazol-4- 496.2
yl)methyl]piperidin-4-yl}ethyl)-4-(3,4,5-
trifluorophenyl)piperazine-1-carboxamide 6-13
(2R)-N-[2-(1-{[2-(difluoromethoxy)phenyl]methyl}piperidin-4- 541.2
yl)ethyl]-2-methyl-4-(3,4,5-trifluorophenyl)piperazine-1-
carboxamide 6-14
(2R)-2-methyl-N-{2-[1-(1-phenylethyl)piperidin-4-yl]ethyl}-4- 489.2
(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-15
4-(benzyloxy)-N-(2-{1-[(4-fluorophenyl)methyl]piperidin-4- 447.6
yl}ethyl)benzamide 6-16
(2R)-N-(2-{1-[(4-carbamoylphenyl)methyl]piperidin-4-yl}ethyl)-
518.17 2-methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide
6-17
(2R)-N-(2-{1-[(2,3-difluorophenyl)methyl]piperidin-4-yl}ethyl)-2-
511.2 methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-18
(2R)-N-(2-{1-[(3-cyanophenyl)methyl]piperidin-4-yl}ethyl)-2- 500.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-19
(2R)-2-methyl-N-(2-{1-[(5-methyl-1,3,4-oxadiazol-2- 557.2
yl)(phenyl)methyl]piperidin-4-yl}ethyl)-4-(3,4,5-
trifluorophenyl)piperazine-1-carboxamide 6-20
(2R)-2-methyl-N-[2-(1-{[3- 559.2
(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)ethyl]-4-(3,4,5-
trifluorophenyl)piperazine-1-carboxamide 6-21
(2R)-2-methyl-N-[2-(1-{[2- 559.2
(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)ethyl]-4-(3,4,5-
trifluorophenyl)piperazine-1-carboxamide 6-22
(2R)-2-methyl-4-(3,4,5-trifluorophenyl)-N-(2-{1-[(2,3,4- 529.1
trifluorophenyl)methyl]piperidin-4-yl}ethyl)piperazine-1-
carboxamide 6-23
(2R)-N-(2-{1-[(3,5-difluorophenyl)methyl]piperidin-4-yl}ethyl)-2-
511.2 methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-24
(2R)-2-methyl-N-[2-(1-{[4- 559.2
(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)ethyl]-4-(3,4,5-
trifluorophenyl)piperazine-1-carboxamide 6-25
(2R)-N-(2-{1-[(2,5-difluorophenyl)methyl]piperidin-4-yl}ethyl)-2-
511.2 methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-26
(2R)-2-methyl-N-{2-[1-(thiophen-2-ylmethyl)piperidin-4- 481.2
yl]ethyl}-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-27
(2R)-N-(2-{1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-2-
491.2 methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-28
(2R)-N-(2-{1-[(2,6-difluorophenyl)methyl]piperidin-4-yl}ethyl)-2-
511.2 methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-29
(2R)-N-(2-{1-[(2-cyanophenyl)methyl]piperidin-4-yl}ethyl)-2- 500.2
methyl-4-(3,4,5-trifluorophenyl)piperazine-1-carboxamide 6-30
(2R)-N-(2-{1-[(4-cyano-2-fluorophenyl)methyl]piperidin-4- 518.1
yl}ethyl)-2-methyl-4-(3,4,5-trifluorophenyl)piperazine-1-
carboxamide 6-31
(2R)-2-methyl-N-{2-[1-(pyridin-4-ylmethyl)piperidin-4-yl]ethyl}-
492.2 4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide
6-32
(2R)-2-methyl-N-{2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]ethyl}-
492.2 4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide
6-33
(2R)-2-methyl-N-{2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]ethyl}-
492.2 4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide
6-34 (2R)-N-(2-{1-[(2-cyanophenyl)methyl]piperidin-4-yl}ethyl)-2-
516.1 methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-35
(2R)-2-methyl-N-(2-{1-[(2-methylphenyl)methyl]piperidin-4- 505.2
yl}ethyl)-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-36
(2R)-N-(2-{1-[(3-fluorophenyl)methyl]piperidin-4-yl}ethyl)-2- 509.1
methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-37
(2R)-N-(2-{1-[(4-fluorophenyl)methyl]piperidin-4-yl}ethyl)-2- 509.1
methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-38
(2R)-N-(2-{1-[(2-fluorophenyl)methyl]piperidin-4-yl}ethyl)-2- 509.2
methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-39
(2R)-2-methyl-N-{2-[1-(pyrimidin-5-ylmethyl)piperidin-4- 492.3
yl]ethyl}-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-40
(2R)-N-(2-{1-[(3-cyanophenyl)methyl]piperidin-4-yl}ethyl)-2- 516.1
methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-41
(2R)-N-(2-{1-[(4-cyanophenyl)methyl]piperidin-4-yl}ethyl)-2- 516.1
methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-
carboxamide 6-42
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(4-hydroxyphenyl)- 478.1
methyl]piperidin-4-yl}ethyl)-2,6-dimethylpiperazine-1- carboxamide
6-43 (2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-[2-(1-{[4-(dimethylamino)-
505.1 phenyl]methyl}piperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-
carboxamide 6-44
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1-(2- 476.0
phenylethyl)piperidin-4-yl]ethyl}piperazine-1-carboxamide 6-45
(2R,6S)-N-(2-{1-[(4-cyanophenyl)methyl]piperidin-4-yl}ethyl)-4-
487.0 (5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide
6-46 (2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(3-fluorophenyl)-
480.1 methyl]piperidin-4-yl}ethyl)-2,6-dimethylpiperazine-1-
carboxamide 6-47
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-{2-[1-(1H-indol-5- 501.0
ylmethyl)-piperidin-4-yl]ethyl}-2,6-dimethylpiperazine-1-
carboxamide 6-48 (2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(4-
480.0 fluorophenyl)methyl]-piperidin-4-yl}ethyl)-2,6-
dimethylpiperazine-1-carboxamide 6-49
(2R,6S)-N-(2-{1-[(4-hydroxy-3-methylphenyl)methyl]piperidin-4-
535.1 yl}ethyl)-2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-
yl]piperazine-1-carboxamide 6-50
(2R,6S)-N-{2-[1-(1H-indol-5-ylmethyl)piperidin-4-yl]ethyl}-2,6-
544.1 dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]piperazine-1-
carboxamide 6-51
(2R,6S)-N-(2-{1-[(3-fluorophenyl)methyl]piperidin-4-yl}ethyl)-
523.1
2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]piperazine-1-
carboxamide 6-52
(2R,6S)-N-(2-{1-[(2-fluorophenyl)methyl]piperidin-4-yl}ethyl)-
523.0
2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]piperazine-1-
carboxamide 6-53
(2R,6S)-N-[2-(1-{[4-(dimethylamino)phenyl]methyl}piperidin-4- 548.1
yl)ethyl]-2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-
yl]piperazine-1-carboxamide 6-54
(2R,6S)-N-(2-{1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-
521.1
2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]piperazine-1-
carboxamide 6-55
(2R,6S)-N-(2-{1-[(4-fluorophenyl)methyl]piperidin-4-yl}ethyl)-
523.1
2,6-dimethyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]piperazine-1-
carboxamide 6-56
(2R,6S)-2,6-dimethyl-N-{2-[1-(2-phenylethyl)piperidin-4- 519.1
yl]ethyl}-4-[2-(trifluoromethyl)pyrimidin-5-yl]piperazine-1-
carboxamide 6-57
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(4-hydroxy-3- 492.0
methylphenyl)methyl]piperidin-4-yl}ethyl)-2,6-
dimethylpiperazine-1-carboxamide 6-58
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1- 464.1
(pyrimidin-2-ylmethyl)piperidin-4-yl]ethyl}piperazine-1-
carboxamide 6-59
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(3-methoxyphenyl)- 492.1
methyl]piperidin-4-yl}ethyl)-2,6-dimethylpiperazine-1- carboxamide
6-60
(2R,6S)-N-{2-[1-(1-benzofuran-5-ylmethyl)piperidin-4-yl]ethyl}-
502.0
4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide 6-61
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1- 463.1
(pyridin-3-ylmethyl)piperidin-4-yl]ethyl}piperazine-1- carboxamide
6-62 (2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1- 463.1
(pyridin-4-ylmethyl)piperidin-4-yl]ethyl}piperazine-1- carboxamide
6-63 (4-{[4-(2-{[(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-
506.1 piperazine-1-carbonyl]amino}ethyl)piperidin-1-
yl]methyl}phenyl)boronic acid 6-64
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(2-fluoropyridin-3-
481.1 yl)methyl]piperidin-4-yl}ethyl)-2,6-dimethylpiperazine-1-
carboxamide 6-65
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(4-methoxyphenyl)- 492.1
methyl]piperidin-4-yl}ethyl)-2,6-dimethylpiperazine-1- carboxamide
6-66 (2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-(2-{1-[(1-
517.0 methyl-1H-1,2,3-benzotriazol-5-yl)methyl]piperidin-4-
yl}ethyl)piperazine-1-carboxamide 6-67
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(2-methoxyphenyl)- 492.0
methyl]piperidin-4-yl}ethyl)-2,6-dimethylpiperazine-1-
carboxamide
Example 7
##STR00027##
[0218] Step 7A:
(2R)--N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-2-methyl-4-(3,4,5-tri-
fluorophenyl)piperazine-1-carboxamide
[0219] A solution of
(3R)-3-methyl-1-(3,4,5-trifluorophenyl)piperazine 1l (0.30 g, 1.3
mmol, 1.0 eq) and triethylamine (0.34 mL, 2.6 mmol, 2.0 eq) in
methylene chloride (20 mL) was prepared and cooled to 0.degree. C.
Then, 4-nitrophenyl chloroformate (0.29 g, 1.4 mmol, 1.1 eq) was
added dropwise and the mixture stirred for 10 min at 0.degree. C.
before removing the ice bath and stirring for an additional 15 min.
The reaction mixture was diluted with methylene chloride, washed
with sat. NH.sub.4Cl, dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. Purification on a silica gel column (12 g) using an
increasing gradient of MeOH (0-10%) in methylene chloride provided
(2R)--N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-2-methyl-4-(3,4,5-tri-
fluorophenyl)piperazine-1-carboxamide 7a (0.40 g, 1.0 mmol, 78%) as
a yellow oil.
Step 7B: (3R)-3-methyl-1-(3,4,5-trifluorophenyl)piperazine
4-(2-aminoethyl)-1-benzylpiperidin-4-ol
[0220] To NMP solutions of
(2R)--N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-2-methyl-4-(3,4,5-tri-
fluorophenyl)piperazine-1-carboxamide 7a (0.05 mL, 0.50 M, 1.0 eq)
and 4-(2-aminoethyl)-1-benzylpiperidin-4-ol 14b (0.05 mL, 0.50 M,
1.0 eq) was added a NMP solution of triethylamine (0.05 mL, 2.0 M,
4.0 eq) and the mixture stirred at RT overnight. The reaction was
diluted to a total volume of 1 mL using MeOH and submitted directly
for preparative chromatography yielding
(3R)-3-methyl-1-(3,4,5-trifluorophenyl)piperazine
4-(2-aminoethyl)-1-benzylpiperidin-4-ol 7-1. The table below
provides the observed (Obs) ion m/z ratio for 7-1 (first compound
listed in Table 5) and other compounds that were made according to
the procedure as described in this example.
TABLE-US-00005 TABLE 5 Cpd. Obs Ion No. Compound Name (m/z) 7-1
(2R)-N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-2-methyl-4-
491.2 (3,4,5-trifluorophenyl)piperazine-1-carboxamide 7-2
(2R)-N-{2-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]ethyl}-4- 494.2
(3-cyano-4-fluorophenyl)-2-methylpiperazine-1-carboxamide 7-3
(2R)-N-[2-(4-benzylpiperazin-1-yl)ethyl]-4-[3-cyano-4- 531.2
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 7-4
(2R)-N-[(2R)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-4-(3- 480.3
cyano-5-fluorophenyl)-2-methylpiperazine-1-carboxamide 7-5
(2R)-N-{2-[(3S)-1-benzylpyrrolidin-3-yl]ethyl}-2-methyl-4- 461.2
(3,4,5-trifluorophenyl)piperazine-1-carboxamide 7-6
(2R)-N-[2-(4-benzylpiperazin-1-yl)ethyl]-2-methyl-4-(3,4,5- 476.2
trifluorophenyl)piperazine-1-carboxamide 7-7
(2R)-N-[2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl]-2-methyl-4-
491.2 (3,4,5-trifluorophenyl)piperazine-1-carboxamide 7-8
(2R)-N-{2-[(3S)-1-benzylpyrrolidin-3-yl]ethyl}-4-(3-cyano-5- 450.2
fluorophenyl)-2-methylpiperazine-1-carboxamide 7-9
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-(difluoromethyl)-
489.2 4-fluorophenyl]-2-methylpiperazine-1-carboxamide 7-10
(2R)-N-[(2R)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-4-[3- 546.2
cyano-4-(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide
7-11 (2R)-N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-4-(3-cyano-
480.2 4-fluorophenyl)-2-methylpiperazine-1-carboxamide 7-12
(2R)-N-[(2R)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-4-(3- 480.2
cyano-4-fluorophenyl)-2-methylpiperazine-1-carboxamide 7-13
(2R)-N-(2-{[(3R,5R)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3- 520.2
yl](methyl)amino}ethyl)-2-methyl-4-(3,4,5-
trifluorophenyl)piperazine-1-carboxamide
Example 8
##STR00028##
[0221] Step 8A: 4-Nitrophenyl
N-[2-(1-benzylpiperidin-4-yl)ethyl]carbamate
[0222] A solution of 2-(1-benzylpiperidin-4-yl)ethan-1-amine (0.50
g, 2.3 mmol, 1.0 eq) in methylene chloride (10 mL) was prepared and
added dropwise to a cooled methylene chloride solution (10 mL,
0.degree. C.) of 4-nitrophenyl chloroformate (0.51 g, 2.5 mmol, 1.1
eq) and triethylamine (0.64 mL, 4.6 mmol, 2.0 eq). The reaction
mixture was diluted further with methylene chloride, washed with
sat. NH.sub.4Cl, dried over MgSO.sub.4 and concentrated in vacuo.
Silica gel column was loaded using methylene chloride and run with
an increasing gradient of MeOH (0-10%) in methylene chloride to
provide 4-nitrophenyl N-[2-(1-benzylpiperidin-4-yl)ethyl]carbamate
8a (0.51 g, 1.0 mmol, 57%) as a yellow oil. Phenyl
N-[2-(1-benzylpiperidin-4-yl)ethyl]carbamate 8b was made according
to the same procedure, but with appropriately modified starting
materials.
Step 8B:
N-[2-(1-Benzylpiperidin-4-yl)ethyl]-4-[4-(trifluoromethyl)phenyl]-
piperidine-1-carboxamide
[0223] To a NMP solution of 4-nitrophenyl
N-[2-(1-benzylpiperidin-4-yl)ethyl]carbamate 8a (0.05 mL, 0.50 M, 1
eq) and 4-(4-trifluoromethylphenyl)piperidine (0.05 mL, 0.50 M, 1
eq) was added a NMP solution of triethylamine (0.05 mL, 2.0 M, 4
eq) and the mixture stirred at RT overnight. The reaction was
diluted to a total volume of 1 mL using MeOH and submitted directly
for preparative chromatography which yielded
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4-(trifluoromethyl)phenyl]piperidi-
ne-1-carboxamide 8-1. The table below provides the observed (Obs)
ion m/z ratio for 8-1 (first compound listed in Table 6) and other
compounds that were made according to the procedure as described in
this example.
TABLE-US-00006 TABLE 6 Cpd. Obs Ion No. Compound Name (m/z) 8-1
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4- 474.3
(trifluoromethyl)phenyl]piperidine-1-carboxamide 8-2
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3- 491.3
(trifluoromethoxy)phenyl]piperazine-1-carboxamide 8-3
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3- 474.3
(trifluoromethyl)phenyl]piperidine-1-carboxamide 8-4
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4- 440.3
chlorophenyl)piperidine-1-carboxamide 8-5
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3- 436.1
methoxyphenyl)piperidine-1-carboxamide 8-6
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2- 436.1
methoxyphenyl)piperidine-1-carboxamide 8-7
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chloro-2- 466.2
cyanophenyl)piperazine-1-carboxamide 8-8
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4- 491.3
(trifluoromethoxy)phenyl]piperazine-1-carboxamide 8-9
1-[2-(1-benzylpiperidin-4-yl)ethyl]-3-[1-(5-bromopyridin-2- 500.2
yl)pyrrolidin-3-yl]-3-methylurea 8-10
4-(1-benzothiophen-3-yl)-N-[2-(1-benzylpiperidin-4- 462.4
yl)ethyl]piperidine-1-carboxamide 8-11
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3- 441.4
chlorophenyl)piperazine-1-carboxamide 8-12
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[2-cyano-4- 500.2
(trifluoromethyl)phenyl]piperazine-1-carboxamide 8-13
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4- 441.3
chlorophenyl)piperazine-1-carboxamide 8-14
4-(1,3-benzothiazol-2-yl)-N-[2-(1-benzylpiperidin-4- 463.4
yl)ethyl]piperidine-1-carboxamide 8-15
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-chloro-5- 510.1
(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide 8-16
1-[2-(1-benzylpiperidin-4-yl)ethyl]-3-{1-[3-chloro-5- 524.2
(trifluoromethyl)pyridin-2-yl]pyrrolidin-3-yl}-3-methylurea 8-17
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3- 475.3
(trifluoromethyl)phenyl]piperazine-1-carboxamide 8-18
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5- 450.23
fluorophenyl)piperazine-1-carboxamide 8-19
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-hydroxy-4-[3- 490.4
(trifluoromethyl)phenyl]piperidine-1-carboxamide 8-20
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-fluorophenyl)piperidine-
424.2 1-carboxamide 8-21
1-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-3-{1-[4- 489.3
(trifluoromethyl)phenyl]pyrrolidin-3-yl}urea 8-22
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4- 450.3
fluorophenyl)piperazine-1-carboxamide 8-23
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chlorophenyl)-4- 456.2
hydroxypiperidine-1-carboxamide 8-24
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4- 436.1
methoxyphenyl)piperidine-1-carboxamide 8-25
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyanophenyl)piperazine-
432.3 1-carboxamide 8-26
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-fluorophenyl)piperidine-
424.1 1-carboxamide 8-27
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyanophenyl)piperazine-
432.7 1-carboxamide 8-28 N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-
423.4 hydroxyphenyl)piperazine-1-carboxamide 8-29
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(pyrimidin-2-yl)piperazine-
409.3 1-carboxamide 8-30
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(1H-indol-3-yl)piperidine-
445.1 1-carboxamide 8-31
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[3-(propan-2-yl)-1,2,4- 440.2
oxadiazol-5-yl]piperidine-1-carboxamide 8-32
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-fluorophenyl)piperidine-
424.1 1-carboxamide 8-33
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-cyano-4-phenylpiperidine-
431.1 1-carboxamide 8-34 N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-
425.3 fluorophenyl)piperazine-1-carboxamide 8-35
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4- 425.45
fluorophenyl)piperazine-1-carboxamide 8-36
4-(4-acetylphenyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]piperazine-
449.2 1-carboxamide 8-37
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-ethylpiperazin-1- 442.4
yl)piperidine-1-carboxamide 8-38
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-phenylpiperidine-1- 406.3
carboxamide 8-39 1-[2-(1-benzylpiperidin-4-yl)ethyl]-3-[1-(4- 439.4
fluorophenyl)piperidin-4-yl]urea 8-40
3-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[1-(3- 446.3
cyanophenyl)piperidin-4-yl]urea 8-41
3-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4-phenoxyphenyl)urea 430.2
8-42 N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-hydroxy-4-(2- 452.2
methoxyphenyl)piperidine-1-carboxamide 8-43
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[2-(hydroxymethyl)-4- 451.2
methylphenyl]piperazine-1-carboxamide 8-44
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-oxo-1,2,3,4- 476.2
tetrahydroquinazolin-3-yl)piperidine-1-carboxamide 8-45
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyridin-2- 433.5
yl)piperazine-1-carboxamide 8-46
4-(1H-1,2,3-benzotriazol-1-yl)-N-[2-(1-benzylpiperidin-4- 447.2
yl)ethyl]piperidine-1-carboxamide 8-47
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-chloropyridin-2- 442.3
yl)piperazine-1-carboxamide 8-48
N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-(5-cyanopyrimidin-2-yl)-
460.0 3,8-diazabicyclo[3.2.1]octane-8-carboxamide
Example 9
##STR00029##
[0224] Step 9A:
1-[4-(Trifluoromethoxy)phenyl]piperidine-4-carboxylic acid
[0225] To a solution of tert-butyl piperidine-4-carboxylate (1.6 g,
8.7 mmol, 1.0 eq) and 1-iodo-4-(trifluoromethoxy)benzene (2.5 g,
8.7 mmol, 1.0 eq) in toluene (100 mL) was added sodium
tert-butoxide (2.5 g, 25 mmol, 3.0 eq), racemic
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.54 g, 0.87 mmol,
0.10 eq), and lastly tris(dibenzylideneacetone)-dipalladium(0)
(0.80 g, 0.87 mmol, 0.10 eq), and the reaction mixture heated to
100.degree. C. overnight. The resulting dark reaction mixture was
cooled, passed thru a pad of celite, and concentrated in vacuo.
Silica gel column (40 g) was dry loaded and run using an increasing
gradient of EtOAc (0-50%) in hexanes over 25 min yielding
tert-butyl 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylate
9a. The chromatographed material 9a was dissolved in 20% TFA in
methylene chloride (50 mL) and heated to 60.degree. C. overnight.
Following concentration, solid material was obtained by
precipitation from hexanes and ether. The resulting white solid was
collected by vacuum filtration to provide
1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid 9b (1.5
g, 5.2 mmol, 60% over two steps).
Step 9B:
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4-(trifluoromethoxy)phenyl-
]piperidine-4-carboxamide
[0226] To a solution of acid 9b (0.30 g, 1.0 mmol, 1.0 eq) and
2-(1-benzylpiperidin-4-yl)ethan-1-amine (0.26 g, 1.2 mmol, 1.2 eq)
in methylene chloride (5 mL) was added triethylamine (0.41 mL, 3.0
mmol, 3.0 eq) followed by HATU (0.46 g, 1.2 mmol, 1.2 eq) and the
mixture was stirred at room temperature overnight. The reaction
mixture was diluted with sat. NH.sub.4Cl and extracted with
methylene chloride. The combined organic layers were dried over
MgSO.sub.4 and concentrated. A silica gel column was loaded using
methylene chloride and run using an increasing gradient of MeOH
(0-20%) in methylene chloride over 20 min to provide
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4-(trifluoromethoxy)phenyl]piperid-
ine-4-carboxamide 9-1 (0.39 g, 0.80 mmol, 80%). The table below
provides the observed (Obs) ion m/z ratio for 9-1 (first compound
listed in Table 7) and other compounds that were made according to
the procedure as described in this example.
TABLE-US-00007 TABLE 7 Cpd. Obs Ion No. Compound Name (m/z) 9-1
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4- 490.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-2
N-(1-benzylpiperidin-4-yl)-N-cyclopropyl-4-phenylbenzamide 411.3
9-3 N-[2-(1-benzylpiperidin-4-yl)ethyl]-N-(2-hydroxyethyl)-1-[4-
534.3 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-4
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(4-chlorophenyl)-4- 454.1
methyl-1,3-thiazole-5-carboxamide 9-5
(2R)-N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-4-(3- 480.2
cyano-5-fluorophenyl)-2-methylpiperazine-1-carboxamide 9-6
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-fluoro-4-[4- 501.2
(trifluoromethoxy)phenyl]benzamide 9-7
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4- 483.15
(trifluoromethoxy)phenyl]benzamide 9-8
N-[2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-1-[4- 506.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-9
N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-1-[3-fluoro-4- 524.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-10
(2R)-N-{2-[(3S)-1-benzylpyrrolidin-3-yl]ethyl}-4-[3-cyano-4- 516.2
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 9-11
N-{2-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]ethyl}-1-[3- 520.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-12
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chlorophenyl)-2- 451.2
fluorobenzamide 9-13
N-{2-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]ethyl}-1-[4- 520.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-14 methyl
4-(4-{[2-(1-benzylpiperidin-4- 457.25
yl)ethyl]carbamoyl}phenyl)benzoate 9-15
N-[(2R)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-1-(3-cyano-
465.2 4-fluorophenyl)piperidine-4-carboxamide 9-16
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4- 467.3
(trifluoromethyl)phenyl]benzamide 9-17
N-(2-{[(3S)-1-benzylpyrrolidin-3-yl](methyl)amino}ethyl)-1-[4-
505.3 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-18
4-chloro-3-(3-cyanoquinolin-2-yl)-N-[(3R)-1- 473.2
cyclohexylpyrrolidin-3-yl]-N-methylbenzamide 9-19
N-[2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl]-2-[4- 539.2
(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridine-7-carboxamide 9-20
N-{2-[(3R)-1-benzylpyrrolidin-3-yl]ethyl}-4-chloro-3-(4-chloro-
468.1 6-methylpyridin-3-yl)benzamide 9-21
1-(1-benzylpiperidin-4-yl)-4-{1-[3-chloro-5- 550.2
(trifluoromethyl)pyridin-2-yl]piperidine-4-carbonyl}piperazine 9-22
N-(2-{[(3R)-1-benzylpyrrolidin-3-yl](methyl)amino}ethyl)-1-[3-
505.3 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-23
N-[1-(1-benzylpiperidin-4-yl)pyrrolidin-3-yl]-N-methyl-1-[4- 545.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-24
N-{2-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]ethyl}-1-(3- 479.2
cyano-4-fluorophenyl)piperidine-4-carboxamide 9-25
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-[4- 523.2
(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridine-7-carboxamide 9-26
N-(2-{[(3R)-1-benzylpyrrolidin-3-yl](methyl)amino}ethyl)-1-[4-
505.3 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-27
N-[2-(1-benzyl-3-hydroxypiperidin-4-yl)ethyl]-1-[4- 506.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-28
N-(2-{[(3R)-1-benzylpyrrolidin-3-yl]amino}ethyl)-1-[3-fluoro-4-
509.2 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-29
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4- 431.5
cyanophenyl)piperidine-4-carboxamide 9-30
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4- 424.3
cyanophenyl)benzamide 9-31
N-(2-{[(3S)-1-benzylpyrrolidin-3-yl](methyl)amino}ethyl)-1-[3-
505.3 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-32
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methyl-2-[4- 488.2
(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxamide 9-33
N-[(3R)-1-benzylpyrrolidin-3-yl]-N-methyl-1-{1-[4- 545.3
(trifluoromethoxy)phenyl]piperidine-4-carbonyl}piperidin-4- amine
9-34 N-[2-(1-benzylpiperidin-4-yl)ethyl]-N-methyl-1-[4- 504.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-35
N-(2-{[1-benzyl-4-(hydroxymethyl)pyrrolidin-3- 553.3
yl](methyl)amino}ethyl)-1-[3-fluoro-4-
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-36
3-(1-benzylpiperidin-4-yl)-N-{1-[4- 490.2
(trifluoromethoxy)phenyl]piperidin-4-yl}propanamide 9-37
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-bromopyrimidin-2- 488.1
yl)piperidine-4-carboxamide 9-38
N-(2-{[(3R)-1-benzylpyrrolidin-3-yl](methyl)amino}ethyl)-4- 414.2
phenylbenzamide 9-39
N-(2-{[(3R)-1-benzylpyrrolidin-3-yl](methyl)amino}ethyl)-4-[4-
498.3 (trifluoromethoxy)phenyl]benzamide 9-40
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-fluoro-4-(4- 431.25
methylphenyl)benzamide 9-41
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4- 417.3
fluorophenyl)benzamide 9-42
1-benzyl-1-methyl-4-[2-(N-methyl-1-{1-[4- 518.3
(trifluoromethoxy)phenyl]piperidin-4-
yl}formamido)ethyl]piperidin-1-ium 9-43
2-[4-(benzyloxy)phenyl]-N-[2-(1-benzylpiperidin-4- 443.3
yl)ethyl]acetamide 9-44
N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-1-(3-cyano-4- 465.2
fluorophenyl)piperidine-4-carboxamide 9-45
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2,6-dioxo-1,3-dipropyl-
557.3 2,3,6,9-tetrahydro-1H-purin-8-yl)benzamide 9-46
N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-1-[3- 506.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-47
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyridin-2- 432.3
yl)piperidine-4-carboxamide 9-48
N-(1-benzylpiperidin-4-yl)-N-cyclopropyl-2-[4- 535.2
(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridine-7-carboxamide 9-49
N-{2-[(3S)-1-benzylpyrrolidin-3-yl]ethyl}-1-[4- 476.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-50
3-(1-benzylpiperidin-4-yl)-N-{1-[3- 490.2
(trifluoromethoxy)phenyl]piperidin-4-yl}propanamide 9-51
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(4-methoxyphenyl)-7- 484.25
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 9-52
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4-methylpyridin-2- 421.3
yl)piperidine-4-carboxamide 9-53
N-(1-benzylpiperidin-4-yl)-N-cyclopropyl-4-(thiophen-2- 417.2
yl)benzamide 9-54
N-(2-{[(3R)-1-benzylpyrrolidin-3-yl]amino}ethyl)-1-[3- 491.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-55
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(thiophen-2-yl)benzamide
405.2 9-56 N-[2-(1-benzylpiperidin-4-yl)ethyl]-4- 423.1
[(trifluoromethyl)sulfanyl]benzamide 9-57
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(6-fluoropyridin-3-yl)-4-
438.1 methyl-1,3-thiazole-5-carboxamide 9-58
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-chloro-5 549.2
(trifluoromethyl)pyridin-2-yl]-N-cyclopropylpiperidine-4-
carboxamide 9-59
N-[2-(1-benzylpiperidin-4-yl)ethyl]-5-(4-methoxyphenyl)-7- 538.2
(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide 9-60
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-chloro-3-(3- 509.2
cyanoquinolin-2-yl)benzamide 9-61
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2,4-dichlorophenyl)-5- 471
methyl-1H-imidazole-4-carboxamide 9-62
N-{2-[1-benzyl-3-(hydroxymethyl)piperidin-4-yl]ethyl}-1-[4- 520.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-63
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-chloro-5 509.2
(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide 9-64
N-{2-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]ethyl}-1-[3- 538.2
fluoro-4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-65
N-[(1-benzylpiperidin-4-yl)methyl]-1-[3-chloro-5- 495.1
(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide 9-66
N-{2-[(3R)-1-benzylpyrrolidin-3-yl]ethyl}-1-[4- 476.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-67
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-chloro-3-(4-chloro-6- 482.2
methylpyridin-3-yl)benzamide 9-68
N-[2-(4-benzylpiperidin-1-yl)ethyl]-2-[4- 523.1
(trifluoromethoxy)phenyl]imidazo[1,2-a]pyridine-7-carboxamide 9-69
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4- 415.05
hydroxyphenyl)benzamide 9-70
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4- 483.15
(trifluoromethoxy)phenyl]benzamide 9-71
N-[2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-1-[4- 506.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-72
N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-1-[3-fluoro-4- 524.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 9-73
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3-cyano-4- 449.3
fluorophenyl)piperidine-4-carboxamide 9-74
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyridin-2-yl)-2-
429.1 methyl-1H-imidazole-4-carboxamide 9-75
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyridin-2-yl)-1H-
415.1 imidazole-4-carboxamide
Example 10
##STR00030##
[0227] Step 10A:
N-[2-(1-benzylpiperidin-4-yl)ethyl]piperidine-4-carboxamide
[0228] To a solution of
1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (2.0 g, 8.7
mmol, 1.0 eq) and 2-(1-benzylpiperidin-4-yl)ethan-1-amine (2.2 g,
9.6 mmol, 1.1 eq) in methylene chloride (20 mL) was added
triethylamine (4.3 mL, 26.1 mmol, 3.0 eq) followed by HATU (4.0 g,
10.4 mmol, 1.2 eq) and the reaction stirred at room temperature
overnight. The reaction mixture was diluted with saturated
NH.sub.4Cl and extracted with methylene chloride. The combined
organic layers were dried over MgSO.sub.4 and concentrated. A
silica gel column was loaded using methylene chloride and run using
an increasing gradient of MeOH (0-10%) in methylene chloride over
20 min yielding tert-butyl
4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}piperidine-1-carboxylate
10a. A portion of the chromatographed 10a (1.0 g, 2.3 mmol) was
dissolved in 20% TFA in methylene chloride (5 mL) and heated to
50.degree. C. overnight. The reaction mixture was concentrated,
dissolved in MeOH, and made basic with the addition of
MP-carbonate. Following removal of the resin and concentration of
the filtrate, the free base of
N-[2-(1-benzylpiperidin-4-yl)ethyl]piperidine-4-carboxamide 10b
(0.62 g, 1.9 mmol, 83%) was isolated as a yellow oil.
[0229]
(3R,4R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methylpiperidine-4-c-
arboxamide 10c was synthesized following the same overall
procedure.
Step 10B:
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[5-(trifluoromethoxy)pyrid-
in-2-yl]piperidine-4-carboxamide
[0230] To a solution of 10b (20 mg, 0.06 mmol, 1.0 eq) and
2-bromo-5-(trifluoromethoxy)pyridine (14 mg, 0.06 mmol, 1.0 eq) in
toluene (1 mL) was added sodium tert-butoxide (17 mg, 0.18 mmol,
3.0 eq), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (3.7
mg, 0.006 mmol, 0.10 eq), and lastly
tris(dibenzylideneacetone)-dipalladium(0) (5.5 mg, 0.006 mmol, 0.10
eq), and the reaction mixture stirred vigorously at 100.degree. C.
overnight. The resulting dark suspension was cooled, passed through
an HPLC filter and concentrated. Then, the crude material was
treated with 1.5 mL of MeOH, passed through an additional HPLC
filter (leaving any precipitate behind), and submitted for directly
for preparative chromatography yielding
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[5-(trifluoromethoxy)pyridin-2-yl]p-
iperidine-4-carboxamide 10-1. The table below provides the observed
(Obs) ion m/z ratio for 10-1 (first compound listed in Table 8) and
other compounds that were made according to the procedure as
described in this example.
TABLE-US-00008 TABLE 8 Cpd. Obs Ion No. Compound Name (m/z) 10-1
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[5 491.2
(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxamide 10-2
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3-cyano-4- 461.3
methoxyphenyl)piperidine-4-carboxamide 10-3
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-phenylpiperidine-4- 406.3
carboxamide 10-4 N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methyl-1-[2-
504.2 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-5
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(2,2-difluoro-2H-1,3- 486.3
benzodioxol-5-yl)piperidine-4-carboxamide 10-6
N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-1-[4- 504.25
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-7
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3,4,5- 460.3
trifluorophenyl)piperidine-4-carboxamide 10-8
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-fluoro-4- 508.5
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-9
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4- 474.3
(trifluoromethyl)phenyl]piperidine-4-carboxamide 10-10
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-methoxy-4- 520.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-11
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4-fluoro-3- 508.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-12
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[2-fluoro-4- 523.2
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 10-13
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4-cyano-3- 515.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-14
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3-cyano-5- 449.3
fluorophenyl)piperidine-4-carboxamide 10-15
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyridin-3- 432.3
yl)piperidine-4-carboxamide 10-16
N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-1-[2- 504.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-17
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-fluoro-1-[2- 508.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-18
N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-1-[3- 504.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-19
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3- 490.4
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-20
N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-1-[3-cyano-4- 531.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-21
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3,4- 442.2
difluorophenyl)piperidine-4-carboxamide 10-22
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3,5- 442.3
difluorophenyl)piperidine-4-carboxamide 10-23
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-cyano-5- 515.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-24
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[5-(trifluoromethyl)pyridin-
475.3 2-yl]piperidine-4-carboxamide 10-25
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methyl-1-[3- 504.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-26
2-(1-benzylpiperidin-4-yl)-N-({1-[3- 490.2
(trifluoromethoxy)phenyl]piperidin-4-yl}methyl)acetamide 10-27
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(6-chloropyridin-3- 441.2
yl)piperidine-4-carboxamide 10-28
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-methoxypyridin-2- 437.2
yl)piperidine-4-carboxamide 10-29
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-methoxy-5- 520.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-30
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4- 476.3
(trifluoromethyl)pyrimidin-2-yl]piperidine-4-carboxamide 10-31
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methyl-1-[4- 504.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-32
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4-(trifluoromethyl)pyridin-
475.2 2-yl]piperidine-4-carboxamide 10-33
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4-methoxy-3- 520.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-34
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[6- 491.2
(trifluoromethoxy)pyridin-3-yl]piperidine-4-carboxamide 10-35
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4-fluorophenyl)piperidine-
424.3 4-carboxamide 10-36
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-cyano-4- 531.2
(trifluoromethoxy)phenyl]-4-hydroxypiperidine-4-carboxamide 10-37
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[2-fluoro-4- 508.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-38
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methoxy-1-[4- 520.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-39
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3-fluoro-4- 454.4
methoxyphenyl)piperidine-4-carboxamide 10-40
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-hydroxy-1-(3,4,5- 476.3
trifluorophenyl)piperidine-4-carboxamide 10-41
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-fluoro-4- 524.2
(trifluoromethoxy)phenyl]-4-hydroxypiperidine-4-carboxamide 10-42
N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-1-[4- 504.25
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-43
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3,4,5- 460.3
trifluorophenyl)piperidine-4-carboxamide 10-44
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-fluoro-4- 508.5
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-45
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(2,2-difluoro-2H-1,3- 486.3
benzodioxol-4-yl)piperidine-4-carboxamide 10-46
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-cyano-5- 531.2
(trifluoromethoxy)phenyl]-4-hydroxypiperidine-4-carboxamide 10-47
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methoxy-1-[4- 505.2
(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide 10-48
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methoxy-1-[5- 505.2
(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide 10-49
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3- 476.15
(trifluoromethoxy)phenyl]pyrrolidine-3-carboxamide 10-50
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4-cyano-2- 449.3
fluorophenyl)piperidine-4-carboxamide 10-51
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3-cyano-4-fluorophenyl)-4-
465.25 hydroxypiperidine-4-carboxamide 10-52
(3S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3- 476.2
(trifluoromethoxy)phenyl]pyrrolidine-3-carboxamide 10-53
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3- 436.3
methoxyphenyl)piperidine-4-carboxamide 10-54
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3-cyano-5- 461.6
methoxyphenyl)piperidine-4-carboxamide 10-55
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-fluoro-1-[4- 508.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-56
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-methyl-4- 504.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-57
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-cyano-4- 515.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-58
N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-1-(3-cyano-4-
465.2 fluorophenyl)piperidine-4-carboxamide 10-59
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(2-fluorophenyl)piperidine-
424.3 4-carboxamide 10-60 N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4-
436.35 methoxyphenyl)piperidine-4-carboxamide 10-61
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-hydroxy-1-[5- 507.2
(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxamide 10-62
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-hydroxy-1-[3- 506.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-63
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methoxy-1-[5- 521.2
(trifluoromethoxy)pyridin-2-yl]piperidine-4-carboxamide 10-64
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(2,5-difluorophenyl)-4- 458.2
hydroxypiperidine-4-carboxamide 10-65
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3- 484.3
methanesulfonylphenyl)piperidine-4-carboxamide 10-66
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4-cyanopyridin-2- 432.3
yl)piperidine-4-carboxamide 10-67
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(2-cyanophenyl)piperidine-
431.25 4-carboxamide 10-68
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[6-(trifluoromethyl)pyridin-
475.3 3-yl]piperidine-4-carboxamide 10-69
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(2-cyano-4- 449.4
fluorophenyl)piperidine-4-carboxamide 10-70
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[2- 490.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-71
(3S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4- 476.2
(trifluoromethoxy)phenyl]pyrrolidine-3-carboxamide 10-72
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4- 476.25
(trifluoromethoxy)phenyl]pyrrolidine-3-carboxamide 10-73
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-fluoropyridin-2- 425.3
yl)piperidine-4-carboxamide 10-74
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4,6-dimethylpyrimidin-2-
436.4 yl)piperidine-4-carboxamide 10-75
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-methoxy-1-[2- 520.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 10-76
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[4- 472.3
(difluoromethoxy)phenyl]piperidine-4-carboxamide 10-77
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(3-cyanophenyl)piperidine-
431.3 4-carboxamide 10-78
N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(4-cyano-3- 449.4
fluorophenyl)piperidine-4-carboxamide 10-79
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyridin-2-yl)-
446.2 3-methylpiperidine-4-carboxamide 10-80
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-1-[5- 489.2
(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxamide 10-81
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-[3-fluoro-5- 507.15
(trifluoromethyl)pyridin-2-yl]-3-methylpiperidine-4-carboxamide
Example 11
##STR00031##
[0231] Step 11A:
N-[2-(piperidin-4-yl)ethyl]-1-[4-(trifluoromethoxy)phenyl]piperidine-4-ca-
rboxamide
[0232] To a solution of
1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxylic acid 9b (0.30
g, 1.0 mmol, 1.0 eq) and tert-butyl
4-(2-aminoethyl)piperidine-1-carboxylate (0.27 g, 1.2 mmol, 1.2 eq)
in methylene chloride (5 mL) was added triethylamine (0.41 mL, 3.0
mmol, 3.0 eq) followed by HATU (0.46 g, 1.2 mmol, 1.2 eq) and the
reaction was stirred at room temperature overnight. The reaction
mixture was diluted with sat. NH.sub.4Cl and extracted with
methylene chloride. The combined organic layers were dried over
MgSO.sub.4 and concentrated. A silica gel column was loaded using
methylene chloride and run using an increasing gradient of MeOH
(0-5%) in methylene chloride over 20 min yielding tert-butyl
4-[2-({1-[4-(trifluoromethoxy)phenyl]piperidin-4-yl}formamido)ethyl]-pipe-
ridine-1-carboxylate 11a. The chromatographed 11a was dissolved in
20% TFA in methylene chloride (5 mL) and heated to 50.degree. C.
overnight. The reaction mixture was concentrated, dissolved in
MeOH, and made basic with the addition of MP-carbonate. Following
removal of the resin and concentration of the filtrate, the free
base of
N-[2-(piperidin-4-yl)ethyl]-1-[4-(trifluoromethoxy)phenyl]piperidine-4-ca-
rboxamide 11b was isolated as a foam.
Step 11B:
N-(2-{1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-1-[4-(tri-
fluoromethoxy)phenyl]piperidine-4-carboxamide
[0233] To NMP solutions of 11b (0.05 mL, 0.50 M, 1 eq) and
4-hydroxybenzaldehyde (0.05 mL, 0.50 M, 1 eq) was added an
ethanolic solution of borane-pyridine complex (0.10 mL, 0.50 M, 2
eq) followed by acetic acid (5 .mu.L) and the mixture stirred at RT
overnight. The reaction was diluted to a total volume of 1 mL using
MeOH and submitted directly for preparative chromatography yielding
N-(2-{1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-1-[4-(trifluoromet-
hoxy)phenyl]piperidine-4-carboxamide 11-1. The table below provides
the observed (Obs) ion m/z ratio for 11-1 (first compound listed in
Table 9) and other compounds that were made according to the
procedure as described in this example.
TABLE-US-00009 TABLE 9 Obs Ion Cpd. No. Compound Name (m/z) 11-1
N-(2-{1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-1-[4- 506.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-2
N-(2-{1-[(2-fluoropyridin-3-yl)methyl]piperidin-4-yl}ethyl)-4-
434.3 phenoxybenzamide 11-3
4-(benzyloxy)-N-(2-{1-[(2-hydroxyphenyl)methyl]piperidin-4- 445.2
yl}ethyl)benzamide 11-4
N-(2-{1-[(2-methyl-1,3-thiazol-4-yl)methyl]piperidin-4-yl}ethyl)-
511.2 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-5
N-(2-{1-[(2-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-4- 431.2
phenoxybenzamide 11-6 methyl 2-phenyl-2-{4-[2-({l-[4- 548.2
(trifluoromethoxy)phenyl]piperidin-4-
yl}formamido)ethyl]piperidin-1-yl}acetate 11-7
4-(benzyloxy)-N-{2-[1-(2,3-dihydro-1,4-benzodioxin-5- 487.2
ylmethyl)piperidin-4-yl]ethyl}benzamide 11-8
1-(5-cyanopyridin-2-yl)-N-{2-[1-(cyclohexylmethyl)piperidin-4-
438.2 yl]ethyl}piperidine-4-carboxamide 11-9
4-(benzyloxy)-N-(2-{1-[(2-hydroxy-3- 475.2
methoxyphenyl)methyl]piperidin-4-yl}ethyl)benzamide 11-10
N-(2-{1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-4- 498.2
phenoxybenzamide 11-11
N-{2-[1-(1,2,3-thiadiazol-4-ylmethyl)piperidin-4-yl]ethyl}-1-[4-
520.3 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-12
N-{2-[1-(2-hydroxy-1-phenylethyl)piperidin-4-yl]ethyl}-1-[4- 448.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-13
N-(2-{1-[(3-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-4- 431
phenoxybenzamide 11-14
4-(benzyloxy)-N-{2-[1-(1-phenylethyl)piperidin-4- 443.3
yl]ethyl}benzamide 11-15
N-(2-{1-[(1-methyl-1H-pyrrol-2-yl)methyl]piperidin-4-yl}ethyl)-
493.3 1-[4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-16
1-(5-cyanopyridin-2-yl)-N-{2-[1-(2,3-dihydro-1,4-benzodioxin-5-
490.2 ylmethyl)piperidin-4-yl]ethyl}piperidine-4-carboxamide 11-17
1-(5-cyanopyridin-2-yl)-N-(2-{1-[(4- 448.3
hydroxyphenyl)methyl]piperidin-4-yl}ethyl)piperidine-4- carboxamide
11-18 N-{2-[1-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)piperidin-4-
473.3 yl]ethyl}-4-phenoxybenzamide 11-19
N-{2-[1-(3-methylbutyl)piperidin-4-yl]ethyl}-1-[4- 430.1
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-20
4-(benzyloxy)-N-{2-[1-(pyridin-3-ylmethyl)piperidin-4- 433.4
yl]ethyl}benzamide 11-21
N-{2-[1-(cyclohexylmethyl)piperidin-4-yl]ethyl}-1-[4- 496.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-22
N-{2-[1-(1H-indol-5-ylmethyl)piperidin-4-yl]ethyl}-1-[4- 529.2
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-23
N-{2-[1-(cyclohexylmethyl)piperidin-4-yl]-2-hydroxyethyl}-1-[4-
512.3 (trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-24
4-(benzyloxy)-N-(2-{1-[(3-fluorophenyl)methyl]piperidin-4- 446.9
yl}ethyl)benzamide 11-25 1-(5-cyanopyridin-2-yl)-N-(2-{1-[(2- 448.3
hydroxyphenyl)methyl]piperidin-4-yl}ethyl)piperidine-4- carboxamide
11-26 1-(5-cyanopyridin-2-yl)-N-(2-{1-[(2- 447.5
hydroxyphenyl)methyl]piperidin-4-yl}ethyl)piperidine-4- carboxamide
11-27 N-{2-[1-(2,2-dimethylpropyl)piperidin-4-yl]ethyl}-1-[4- 435.3
(trifluoromethoxy)phenyl]piperidine-4-carboxamide 11-28
4-phenoxy-N-{2-[1-(3-phenylpropyl)piperidin-4- 431.2
yl]ethyl}benzamide 11-29
N-{2-[1-(2,3-dihydro-1-benzofuran-7-ylmethyl)piperidin-4- 532.2
yl]ethyl}-1-[4-(trifluoromethoxy)phenyl]piperidine-4- carboxamide
11-30
N-(2-{l-[(6-methoxypyridin-2-yl)methyl]piperidin-4-yl}ethyl)-1-
521.1 [4-(trifluoromethoxy)phenyl]piperidine-4-carboxamide
Example 12
##STR00032##
[0234] Step 12A: 2-(1-Benzylpiperidin-4-yl)ethyl chloroformate
[0235] A solution of 2-(1-benzylpiperidin-4-yl)ethan-1-ol (0.50 g,
2.3 mmol, 1.0 eq) and triphosgene (0.81 g, 2.7 mmol, 1.2 eq) in
anhydrous THE (7 mL) was prepared and cooled to 0.degree. C. Then,
pyridine (0.27 g, 3.4 mmol, 1.5 eq) was added dropwise upon which a
precipitate formed. After stirring for 20 min, the resulting
suspension was filtered and concentrated to provide
2-(1-benzylpiperidin-4-yl)ethyl chloroformate 12a (0.40 g, 1.4
mmol, 62%) as an oil.
Step 12B: 2-(1-benzylpiperidin-4-yl)ethyl
4-[4-(trifluoromethoxy)phenyl]piperazine-1-carboxylate
[0236] To a solution of 1-[4-(trifluoromethoxy)phenyl]piperazine if
(0.10 g, 0.41 mmol, 1.0 eq) and 12a (0.13 g, 0.45 mmol, 1.1 eq) in
methylene chloride (3 mL) was added triethylamine (0.17 mL, 1.2
mmol, 3.0 eq) and the reaction mixture stirred at RT. After 10 min,
the reaction mixture was diluted with methylene chloride, washed
with sat. NH.sub.4Cl, dried over MgSO.sub.4 and concentrated. A
silica gel column was loaded using methylene chloride and run using
an increasing gradient of MeOH (0-15%) in methylene chloride over
20 min to provide 2-(1-benzylpiperidin-4-yl)ethyl
4-[4-(trifluoromethoxy)phenyl]piperazine-1-carboxylate 12-1 (0.15
g, 0.31 mmol, 75%) as a foam. The table below provides the observed
(Obs) ion m/z ratio for 12-1 (first compound listed in Table 10)
and other compounds that were made according to the procedure as
described in this example.
TABLE-US-00010 TABLE 10 Obs Ion Cpd. No. Compound Name (m/z) 12-1
2-(1-benzylpiperidin-4-yl)ethyl 4-[4- 492.2
(trifluoromethoxy)phenyl]piperazine-1-carboxylate 12-2
2-(1-benzylpiperidin-4-yl)ethyl 4-(3-cyanophenyl)piperazine-1-
433.25 carboxylate 12-3 2-(1-benzylpiperidin-4-yl)ethyl
4-(4-fluorophenyl)piperazine-1- 426.3 carboxylate 12-4
2-(1-benzylpiperidin-4-yl)ethyl 4-[3- 492.7
(trifluoromethoxy)phenyl]piperazine-1-carboxylate 12-5
2-(1-benzylpiperidin-4-yl)ethyl N-[1-(3-cyanophenyl)piperidin-
447.3 4-yl]carbamate 12-6 2-(1-benzylpiperidin-4-yl)ethyl
N-[1-(4-fluorophenyl)piperidin- 440.3 4-yl]carbamate 12-7
2-(1-benzylpiperidin-4-yl)ethyl 4-hydroxy-4-phenylpiperidine-1-
423.1 carboxylate 12-8 2-(1-benzylpiperidin-4-yl)ethyl
4-phenylpiperidine-1-carboxylate 407.2 12-9
2-(1-benzylpiperidin-4-yl)ethyl 4-(3-cyano-5- 451.2
fluorophenyl)piperazine-1-carboxylate 12-10
2-(1-benzylpiperidin-4-yl)ethyl 4-(3-cyano-4- 451.3
fluorophenyl)piperazine-1-carboxylate 12-11
2-(1-benzylpiperidin-4-yl)ethyl N-{1-[4- 506.2
(trifluoromethoxy)phenyl]piperidin-4-yl}carbamate 12-12
2-(1-benzylpiperidin-4-yl)ethyl 4-(3,4,5- 462.2
trifluorophenyl)piperazine-1-carboxylate
Example 13
##STR00033##
[0237] Step 13A: Ethyl
(4E)-1-benzyl-4-(cyanomethylidene)piperidine-3-carboxylate
[0238] To a solution of diethyl cyanomethylphosphonate (0.5 g, 2.8
mmol, 1.2 eq) in anhydrous THF (5 mL) was added K.sub.2CO.sub.3
(0.4 g, 2.8 mmol, 1.2 eq) and the mixture was stirred at room temp
for 15 min, then heated to reflux for 20 min. The mixture was
cooled and ethyl 1-benzyl-4-oxopiperidine-3-carboxylate (0.6 g, 2.3
mmol, 1.0 eq) was added and refluxed for 12 hours. The mixture was
cooled, diluted with EtOAc (10 mL) and washed with sat.
NaHCO.sub.3. The organic layer was dried over MgSO.sub.4, filtered
and concentrated. The crude product was purified by via ISCO
chromatography with an increasing gradient from 0% to 60% EtOAc in
hexanes. Two peaks were combined as they will merge on reduction to
a racemic mixture to give ethyl
(4E)-1-benzyl-4-(cyanomethylidene)piperidine-3-carboxylate 13a (0.4
g, 1.4 mmol, 50% yield).
Step 13B: [4-(2-aminoethyl)-1-benzylpiperidin-3-yl]methanol
[0239] (4E)-1-benzyl-4-(cyanomethylidene)piperidine-3-carboxylate
(0.4 g, 1.4 mmol, 1.0 eq) was dissolved in anhydrous THF (10 mL)
and LAH (0.14 g, 4.23 mmol, 3.0 eq) was added and the mixture
stirred for one hour. The reaction was quenched with H.sub.2O (0.5
mL) and diluted with EtOAc and filtered. The organic layer was
concentrated to give
[4-(2-aminoethyl)-1-benzylpiperidin-3-yl]methanol 13b (0.35 g, 1.4
mmol, 100% yield).
Example 14
##STR00034##
[0240] Step 14A:
2-(1-benzyl-4-hydroxypiperidin-4-yl)acetonitrile
[0241] n-BuLi (2 M in pentane, 7.3 mL, 1.1 eq) was added dropwise
to solution of MeCN (0.76 mL) in THF (6 mL) at -78.degree. C. and
stirred 20 minutes. Next, a solution of 1-benzylpiperidine-4-one
(2.5 g, 13.2 mmol, 1.0 eq) in 4 mL THF was added dropwise at
-78.degree. C. The reaction mixture was warmed to room temperature
slowly overnight. The mixture was diluted with EtOAc and extracted
from water. The crude product was purified via ISCO silica
chromatography eluting with a gradient of 0% to 50% (80-18-2
CHCl.sub.3/MeOH/NH.sub.3) in DCM to give
2-(1-benzyl-4-hydroxypiperidin-4-yl)acetonitrile 14a (2.6 g, 11.4
mmol) in a 86% yield.
Step 14B: 4-(2-aminoethyl)-1-benzylpiperidin-4-ol
[0242] 2-(1-Benzyl-4-hydroxypiperidin-4-yl)acetonitrile 14a (2.6 g,
11.4 mmol, 1.0 eq) was dissolved in anhydrous THF (30 mL) and LAH
(1.1 g, 28 mmol, 2.5 eq) was added. The reaction mixture was
stirred at room temp for 30 min then slowly quenched with water and
excess EtOAc. The reaction was filtered through celite and
concentrated to give 4-(2-aminoethyl)-1-benzylpiperidin-4-ol 14b
(1.9 g, 7.9 mmol) in a 72% yield.
Example 15
##STR00035##
[0243] Step 15A: Ethyl
1-benzyl-4-(cyanomethyl)piperidine-4-carboxylate
[0244] Ethyl 1-benzylpiperidine-4-carboxylate (2.0 g, 8.1 mmol, 1.0
eq) was dissolved in anhydrous THF (20 mL) and cooled to
-78.degree. C. Next, LDA (2.0M in THF, 8.1 mL, 2.0 eq) was added
dropwise and stirred for one hour at -78.degree. C. A solution of
bromoacetonitrile (1.9 g, 16.2 mmol, 2.0 eq) in THF (10 mL) was
added dropwise at 78.degree. C. and stirred at this temperature for
3 hours then warmed to room temperature. The reaction mixture was
diluted with EtOAc and washed with sat. NH.sub.4Cl and brine. The
organic layer was dried over MgSO.sub.4, filtered and concentrated.
The crude product was purified via ISCO silica chromatography
eluting with an increasing gradient of EtOAc (0% to 100%) in
hexanes to give ethyl
1-benzyl-4-(cyanomethyl)piperidine-4-carboxylate 15a (1.3 g, 4.5
mmol) in a 56% yield.
Step 15B: [4-(2-Aminoethyl)-1-benzylpiperidin-4-yl]methanol
[0245] Ethyl 1-benzyl-4-(cyanomethyl)piperidine-4-carboxylate 15a
(0.9 g, 3.1 mmol, 1.0 eq) was dissolved in anhydrous THF (10 mL)
and LAH (0.21 g, 6.3 mmol, 2.0 eq) was added. The mixture was
stirred at room temp for 30 min then slowly quenched with water and
excess EtOAc. The reaction was filtered through celite and
concentrated to give
[4-(2-aminoethyl)-1-benzylpiperidin-4-yl]methanol 15b (0.77 g, 3.1
mmol) in a quantitative yield.
Example 16
##STR00036##
[0246] Step 16A: Benzyl 4-(oxiran-2-yl)piperidine-1-carboxylate
[0247] Trimethylsulfoxonium iodide (13.5 g, 60.7 mmol, 1.5 eq) was
added in two portions to a solution of NaH (1.5 g, 60.7 mmol, 1.5
eq) in anhydrous DMSO (15 mL). This mixture was stirred for one
hour at room temp. Then a solution of benzyl
4-formylpiperidine-1-carboxylate (10.0 g, 40.4 mmol, 1.0 eq) in
anhydrous DMSO (20 mL) was added and the mixture stirred two hours.
The reaction was poured into water and extracted twice with
Et.sub.2O. The organic layer was dried over MgSO.sub.4, filtered,
and concentrated. The crude product was purified on ISCO with 0% to
70% EtOAC in hexanes to give benzyl
4-(oxiran-2-yl)piperidine-1-carboxylate 16a as a clear oil (6.8 g,
26.1 mmol) in a 65% yield.
Step 16B: Benzyl 4-[(2S)-oxiran-2-yl]piperidine-1-carboxylate
[0248]
(S,S)-(+)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanedi-
aminocobalt(II) [88264-84-8] (0.40 g, 0.65 mmol, 0.02 eq) was
dissolved in toluene (10 mL) and acetic acid (0.07 mL, 1.3 mmol,
0.04 eq) was added and the mixture stirred for one hour. The
mixture was then concentrated and dried on a high vacuum to give a
solid. Benzyl 4-(oxiran-2-yl)piperidine-1-carboxylate 16a (6.8 g,
26.1 mmol, 1.0 eq) was dissolved in anhydrous THF (15 mL) and the
catalyst dissolved in minimal anhydrous THF was added and cooled to
0.degree. C. and water (0.26 mL, 14.6 mmol, 0.6 eq) was added
dropwise. The reaction slowly warmed to room temperature and
stirred overnight. LCMS showed slow reaction so additional water
(0.05 mL, 2.8 mmol, 0.1 eq) was added and the reaction was stirred
overnight. The reaction mixture was concentrated and purified by
ISCO column chromatography eluting with a gradient of 0% to 70%
EtOAc in hexanes. Benzyl
4-[(2S)-oxiran-2-yl]piperidine-1-carboxylate 16b (3.4 g, 12.9 mmol)
was determined to be 99% ee by chiral chromatography compared to
the racemic mixture.
Step 16C: Benzyl
4-[(1S)-2-azido-1-hydroxyethyl]piperidine-1-carboxylate
[0249] Benzyl 4-[(2S)-oxiran-2-yl]piperidine-1-carboxylate 16b (3.4
g, 12.9 mmol, 1.0 eq) was dissolved in EtOH (9 mL) and water (1 mL)
and sodium azide (1.7 g, 25.8 mmol, 2.0 eq) and ammonium chloride
(1.4 g, 25.8 mmol, 2.0 eq) were added. The reaction mixture was
heated to 55.degree. C. and stirred overnight. EtOH was removed in
vacuo and the reaction mixture was diluted with DCM and extracted
from sat. NaHCO.sub.3. The organic layer was dried over MgSO.sub.4,
filtered and concentrated to give benzyl
4-[(1S)-2-azido-1-hydroxyethyl]piperidine-1-carboxylate 16c (3.9 g,
12.7 mmol) in 98% yield.
Step 16D: Benzyl
4-[(1S)-2-{[(tert-butoxy)carbonyl]amino}-1-hydroxyethyl]-piperidine-1-car-
boxylate
[0250] Benzyl
4-[(1S)-2-azido-1-hydroxyethyl]piperidine-1-carboxylate 16c (3.9 g,
12.7 mmol, 1.0 eq) was dissolved in anhydrous MeOH (100 mL) then
dichloronickel hexahydrate (3.0 g, 12.7 mmol, 1.0 eq) and
NaBH.sub.4 (0.96 g, 25.4 mmol, 2.0 eq) were added and the mixture
stirred for one hour. MeOH was removed in vacuo and the product was
redissolved in DCM, filtered through celite and concentrated. The
crude product was then redissolved in DCM (100 mL) and
triethylamine (5.3 mL, 38.1 mmol, 3.0 eq) and di-tert-butyl
dicarbonate (5.5 g, 25.4 mmol, 3.0 eq) were added and the reaction
was stirred overnight. An additional 0.2 equiv of TEA and
di-tert-butyl dicarbonate were added along with MeOH (10 mL) for
solubility and reaction stirred for one hour. Solvent was removed
in vacuo and crude product redissolved in DCM and washed with sat.
NH.sub.4Cl. The organic layer was dried over MgSO.sub.4, filtered
and concentrated. The crude product was purified by ISCO column
chromatography elution with a 0% to 100% of EtOAc in hexanes to
afford benzyl
4-[(1S)-2-{[(tert-butoxy)carbonyl]amino}-1-hydroxyethyl]piperidine-
-1-carboxylate 16d (3.98 g, 10.5 mmol) in a 83% yield.
Step 16E: (1S)-2-amino-1-(1-benzylpiperidin-4-yl)ethan-1-ol
[0251] Benzyl
4-[(1S)-2-{[(tert-butoxy)carbonyl]amino}-1-hydroxyethyl]piperidine-1-carb-
oxylate 16d (3.98 g, 10.5 mmol, 1.1 eq) was dissolved in MeOH and
10% Pd/C was added. The sealed vessel was purged with H.sub.2 and
the reaction was stirred one hour. The reaction was filtered
through celite and concentrated to afford the crude amine which was
used without further purification. The crude amine (2.4 g, 9.8
mmol, 1.0 eq) was dissolved in EtOH (75 mL) and acetic acid (0.55
mL, 10.5 mmol, 1.1 eq) and benzaldehyde (1.6 mL, 15.8 mmol, 1.6 eq)
were added followed by sodium cyanoborohydride (1.0 g, 15.8 mmol,
1.6 eq) and the reaction was stirred for 2 hours Additional
benzaldehyde (1.0 mL, 8.0 mmol) was added and reaction complete
after one hour of stirring. The reaction mixture was quenched with
water and MeOH was removed in vacuo. The reaction mixture was
redissolved in DCM and extracted with sat. NaHCO.sub.3 (2.times.).
The organic layer was dried over MgSO.sub.4 and filtered and
concentrated. The crude product was purified by ISCO column
chromatography eluting with a gradient of MeOH from 0% to 30% in
DCM to yield the benzyl protected amine (3.1 g, 9.3 mmol) in a 95%
yield. Next, the benzylamine (3.1 g, 9.3 mmol, 1.0 eq) was
dissolved in DCM (50 mL) and TFA (10 mL) was added and the reaction
mixture was stirred for one hour. The reaction mixture was
concentrated and redissolved in MeOH and MP-carbonate resin was
added until the solution was basic. The reaction was filtered and
concentrated to afford
(1S)-2-amino-1-(1-benzylpiperidin-4-yl)ethan-1-ol 16e (2.1 g, 9.0
mmol) in a 97% yield.
[0252] (1R)-2-Amino-1-(1-benzylpiperidin-4-yl)ethan-1-ol 16f was
synthesized following the same overall procedure but using
(R,R)-(.+-.)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediami-
nocobalt(II) in Step 16B.
Example 17
##STR00037##
[0253] Step 17A: Ethyl
2-bromo-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate
[0254] A solution of 3-bromo-1H-pyrazol-5-amine (4.2 g, 26 mmol,
1.0 eq) and ethyl
(3Z)-3-[(dimethylamino)methylidene]-4-oxopentanoate (4.9 g, 26
mmol, 1.0 eq) in ethanol (300 mL) was prepared and heated to reflux
for 2 hrs. The reaction mixture was concentrated. Silica gel column
was loaded using methylene chloride and run using an increasing
gradient of MeOH (0-5%) in methylene chloride over 20 min to
provide ethyl
2-bromo-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate 17a (6.0 g,
21 mmol, 81%) as a white solid.
Step 17B:
7-methyl-2-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine--
6-carboxylic acid
[0255] To a solution of ethyl
2-bromo-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate 17a (2.0 g,
7.0 mmol, 1.0 eq) in anhydrous dioxane (45 mL) was added
[3-(trifluoromethyl)phenyl]boronic acid (2.0 g, 10 mmol, 1.5 eq)
followed by aq. K.sub.2CO.sub.3 (7 mL, 22.5 mmol, 3.2 eq) and the
resulting solution purged with nitrogen for 10 min. Then,
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.52
g, 0.70 mmol, 0.1 eq) was added and the reaction heated to
90.degree. C. overnight. The resulting dark reaction mixture was
cooled, diluted heavily with EtOAc, and washed with brine. The
organic layer was washed again with brine, dried over
Na.sub.2SO.sub.4, and concentrated. Silica gel column (80 g) was
loaded using methylene chloride and run using an increasing
gradient of EtOAc (5-95%) in hexanes over 20 min. The
chromatographed material was then suspended in MeOH (50 mL) and
treated with an aq. solution of 1 M LiOH (5 mL). After stirring at
RT overnight, the dark orange suspension was concentrated and the
resulting solid re-dissolved in water. Then, the suspension was
made acidic with careful addition of 6 M HCl. The precipitate was
collected and dried to provide
7-methyl-2-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxy-
lic acid 17b (1.6 g, 4.9 mmol, 70% over two steps) as a tan
solid.
Step 17C:
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-[3-(trifluorometh-
yl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide
[0256] To a solution of
7-methyl-2-[3-(trifluoromethyl)phenyl]pyrazolo-[1,5-a]pyrimidine-6-carbox-
ylic acid 17b (1.6 g, 4.9 mmol, 1.0 eq) and
2-(1-benzylpiperidin-4-yl)ethan-1-amine (1.1 g, 4.9 mmol, 1.0 eq)
in NMP (20 mL) was added triethylamine (2.7 mL, 20 mmol, 4.0 eq)
followed by HATU (1.9 g, 4.9 mmol, 1.0 eq) and the reaction stirred
at room temperature overnight. The resulting dark reaction mixture
was diluted heavily with EtOAc and washed repeatedly with brine.
During the course of the extraction, a large amount of orange
precipitate formed; thus after evaporating all organic solvent, the
aqueous layers were left to sit overnight. Then, all precipitate
was collected by vacuum filtration and washed with water. Silica
gel column (120 g) was dry loaded and run using MeOH (0-20%) in DCM
over 25 min to provide
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-[3-(trifluoromethyl)phenyl-
]pyrazolo[1,5-a]pyrimidine-6-carboxamide 17-1 (1.5 g, 2.9 mmol,
59%) as an off-white solid. The table below provides the observed
(Obs) ion m/z ratio for 17-1 (first compound listed in Table 11)
and other compounds that were made according to the procedure as
described in this example.
TABLE-US-00011 TABLE 11 Obs Ion Cpd. No. Compound Name (m/z) 17-1
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-[3- 522.2
(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide
17-2 N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2- 454.2
phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide 17-3
N-[2-(1-benzyl-4-hydroxypiperidin-4-yl)ethyl]-7-methyl-2-[3- 538.14
(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide
17-4 N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(4-chlorophenyl)-7-
488.2 methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 17-5
N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-7-methyl-2-
538.1 [3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-
carboxamide 17-6
N-[(2R)-2-(1-benzylpiperidin-4-yl)-2-hydroxyethyl]-7-methyl-2-
538.1 [3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-
carboxamide 17-7
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-(thiophen-2- 460.3
yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 17-8
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-[4- 522.2
(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide
Example 18
##STR00038##
[0257] Step 18A:
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-bromo-7-methylpyrazolo[1,5-a]pyrimi-
dine-6-carboxamide
[0258] To a solution of ethyl
2-bromo-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate 17a (1.0 g,
3.6 mmol, 1.0 eq) in THE/water (4:1) was added solid NaOH (0.21 g,
5.3 mmol, 1.5 eq). After stirring at RT overnight, the organic
solvent was concentrated and the remaining aqueous phase made
acidic with careful addition of 6 M HCl. The resulting precipitate
was collected and dried to provide
2-bromo-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid 18a. A
portion of this material (0.70 g, 2.7 mmol, 1.0 eq) together with
2-(1-benzylpiperidin-4-yl)ethan-1-amine (0.90 g, 4.1 mmol, 1.5 eq)
in methylene chloride/DMF 2:1 (15 mL) was treated with
triethylamine (1.5 mL, 11 mmol, 4.0 eq) and HATU (1.4 g, 3.6 mmol,
1.0 eq) and stirred at RT overnight. The reaction mixture was
diluted with methylene chloride, washed with sat. NH.sub.4Cl, dried
over MgSO.sub.4 and concentrated. Silica gel column was loaded
using methylene chloride and run using an increasing gradient of
MeOH (0-20%) in methylene chloride over 20 min to provide
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-bromo-7-methylpyrazolo[1,5--
a]pyrimidine-6-carboxamide 18b (1.1 g, 2.6 mmol, 94%).
Step 18B:
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2,4-difluorophenyl)-7-met-
hyl-pyrazolo[1,5-a]pyrimidine-6-carboxamide
[0259] To an NMP solution of
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-bromo-7-methylpyrazolo[1,5-a]pyrimi-
dine-6-carboxamide 18b (0.20 mL, 0.13 M, 1.0 eq) was added a
spatula tip of (2,4-difluorophenyl)boronic acid followed by aq.
K.sub.3PO.sub.4 (0.05 mL, 1.5 M, 2.9 eq). Then, a generous spatula
tip of PS--Pd(PPh.sub.3) was added and the reaction mixture heated
to 90.degree. C. In general, this reaction and others of its kind
are complete within 2 hrs, however additional PS--Pd(PPh.sub.3)
and/or longer reaction times can be used to push the coupling. The
resulting dark suspension was cooled, passed through an HPLC
filter, diluted to 1 mL using MeOH, and submitted for directly for
preparative chromatography to yield
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2,4-difluorophenyl)-7-methyl-pyraz-
olo[1,5-a]pyrimidine-6-carboxamide 18-1. The table below provides
the observed (Obs) ion m/z ratio for 18-1 (first compound listed in
Table 12) and other compounds that were made according to the
procedure as described in this example.
TABLE-US-00012 TABLE 12 Obs Ion Cpd. No. Compound Name (m/z) 18-1
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2,4-difluorophenyl)-7-
490.15 methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-2
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-(pyridin-2- 456.0
yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 18-3
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(4-cyanophenyl)-7- 479.2
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-4
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(4-fluorophenyl)-7- 472.2
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-5
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(3,5-difluorophenyl)-7- 490.2
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-6
N-[2-(1-benzylpiperidin-4-yl)ethyl]2-(3-fluorophenyl)-7- 472.2
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-7
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2,3-difluorophenyl)-7- 490.2
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-8
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(3-cyanophenyl)-7- 479.1
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-9
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2-methoxyphenyl)-7- 484.2
methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-10
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2,5-difluorophenyl)-7-
490.15 methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-11
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-[2- 522.1
(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6- carboxamide
18-12
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(4-cyano-3-fluorophenyl)-
497.2 7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-13
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-[4- 538.2
(trifluoromethoxy)phenyl]pyrazolo[1,5-a]pyrimidine-6- carboxamide
18-14
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2-methoxypyridin-3-yl)-7-
485.3 methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-15
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(6-fluoropyridin-3-yl)-7-
473.1 methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-16
N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-[3- 538.1
(trifluoromethoxy)phenyl]pyrazolo[1,5-a]pyrimidine-6- carboxamide
18-17 N-[2-(1-benzylpiperidin-4-yl)ethyl]-7-methyl-2-(3,4,5- 508.1
trifluorophenyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide 18-18
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2-fluoropyridin-3-yl)-7-
473.2 methylpyrazolo[1,5-a]pyrimidine-6-carboxamide 18-19
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(6-methoxy-4- 499.2
methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-
carboxamide 18-20
N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-(2-fluoropyridin-4-yl)-7-
473.2 methylpyrazolo[1,5-a]pyrimidine-6-carboxamide
Example 19
##STR00039##
[0260] Step 19A:
7-methyl-N-[2-(piperidin-4-yl)ethyl]-2-[3-(trifluoromethyl)phenyl]pyrazol-
o[1,5-a]pyrimidine-6-carboxamide
[0261] To a solution of
7-methyl-2-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxy-
lic acid 17b (0.09 g, 0.27 mmol, 1.0 eq) and tert-butyl
4-(2-aminoethyl)piperidine-1-carboxylate (0.07 g, 0.32 mmol, 1.2
eq) in methylene chloride was added triethylamine (0.11 mL, 0.81
mmol, 3.0 eq) followed by HATU (0.12 g, 0.32 mmol, 1.2 eq) and the
reaction stirred at room temperature overnight. The reaction
mixture diluted with sat. NH.sub.4Cl and extracted with methylene
chloride. The combined organic layers were dried over MgSO.sub.4
and concentrated. Silica gel column was loaded using methylene
chloride and run using an increasing gradient of MeOH (0-10%) in
methylene chloride yielding tert-butyl
4-[2-({7-methyl-2-[3-(trifluoromethyl)phenyl]-pyrazolo[1,5-a]pyrimidin-6--
yl}formamido)ethyl]piperidine-1-carboxylate 19a. The
chromatographed 19a was dissolved in 20% TFA in methylene chloride
and stirred at RT overnight. The reaction mixture was concentrated,
dissolved in MeOH, and made basic with the addition of
MP-carbonate. Following removal of the resin and concentration of
the filtrate, the free base of
7-methyl-N-[2-(piperidin-4-yl)ethyl]-2-[3-(trifluoromethyl)phenyl]pyrazol-
o[1,5-a]pyrimidine-6-carboxamide 19b (0.08 g, 0.19 mmol, 70% over
two steps) was isolated as an oil.
Step 19B:
7-methyl-N-{2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]ethyl}-2-[3--
(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide
[0262] To NMP solutions of
7-methyl-N-[2-(piperidin-4-yl)ethyl]-2-[3-(trifluoromethyl)phenyl]pyrazol-
o[1,5-a]pyrimidine-6-carboxamide 19b (0.05 mL, 0.50 M, 1 eq) and
pyridine-3-carbaldehyde (0.05 mL, 0.50 M, 1 eq) was added an
ethanolic solution of borane-pyridine complex (0.10 mL, 0.50 M, 2
eq) followed by acetic acid (5 .mu.L) and the mixture stirred at RT
overnight. The reaction was diluted to a total volume of 1 mL using
MeOH and submitted directly for preparative chromatography yielding
7-methyl-N-{2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]ethyl}-2-[3-(trifluor-
omethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-carboxamide 19-1. The
table below provides the observed (Obs) ion m/z ratio for 19-1
(first compound listed in Table 13) and other compounds that were
made according to the procedure as described in this example.
TABLE-US-00013 TABLE 13 Obs Ion Cpd. No. Compound Name (m/z) 19-1
7-methyl-N-{2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]ethyl}-2- 523.1
[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6- carboxamide
19-2 N-{2-[1-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)piperidin-4-
512.2 yl]ethyl}-7-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-
carboxamide 19-3
N-{2-[1-(cyclohexylmethyl)piperidin-4-yl]ethyl}-7-methyl-2- 528.2
[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6- carboxamide
19-4 N-(2-{1-[(2-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-7-
470.1 methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide 19-5
7-methyl-N-{2-[1-(pyridin-4-ylmethyl)piperidin-4-yl]ethyl}-2- 523.2
[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6- carboxamide
19-6 7-methyl-N-{2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]ethyl}-2-
523.2 [3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-6-
carboxamide 19-7
N-(2-{1-[(3-methoxyphenyl)methyl]piperidin-4-yl}ethyl)-7- 484.3
methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide 19-8
N-(2-{1-[(4-hydroxyphenyl)methyl]piperidin-4-yl}ethyl)-7- 470.2
methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide
Example 20
##STR00040##
[0263] Step 20A:
(3R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyrimidin-2-yl)-3-met-
hylpiperidine-4-carboxamide
[0264] To NMP solutions of
(3R,4R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methylpiperidine-4-carboxa-
mide 10c (0.05 mL, 0.50 M, 1 eq) and 2-chloro-5-cyanopyrimidine
(0.025 mmol, 1 eq) was added a NMP solution of trimethylamine
(0.100 mL, 1.0 M, 4 eq) and the mixture stirred at 100.degree. C.
overnight. The reaction was diluted to a total volume of 1 mL using
MeOH and submitted directly for preparative chromatography yielding
(3R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyrimidin-2-yl)-3-met-
hylpiperidine-4-carboxamide 20-1. The table below provides the
observed (Obs) ion m/z ratio for 20-1 (first compound listed in
Table 13) and other compounds that were made according to the
procedure as described in this example.
TABLE-US-00014 TABLE 14 Obs Ion Cpd. No. Compound Name (m/z) 20-1
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-cyanopyrimidin-2-
447.2 yl)-3-methylpiperidine-4-carboxamide 20-2
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-3-methyl-1-[5- 490.14
(trifluoromethyl)pyrimidin-2-yl]piperidine-4-carboxamide 20-3
(3R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-1-(5-chloropyrimidin-2-
456.1 yl)-3-methylpiperidine-4-carboxamide
Example 21
##STR00041##
[0265] Step 21A:
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-{2-[1-(cyclohexylmethyl)piperidin-4-y-
l]ethyl}-2,6-dimethylpiperazine-1-carboxamide
[0266] To NMP solutions of
(2S,6R)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-[2-(piperidin-4-yl)ethyl-
]piperazine-1-carboxamide 6c (0.20 mL, 0.12 M, 1.0 eq) and
N,N-diisopropylethylamine (0.05 mL, 0.5 M, 4.0 eq) was added
(bromomethyl)cyclohexane (4.4 mg, 0.025 mmol, 1.0 eq) and the
reaction mixture heated at 50.degree. C. overnight. The reaction
mixture was diluted to a total volume of 1 mL using MeOH and
submitted directly for preparative chromatography yielding
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-{2-[1-(cyclohexylmethyl)piperidin-4-y-
l]ethyl}-2,6-dimethylpiperazine-1-carboxamide 21-1. The table below
provides the observed (Obs) ion m/z ratio for 21-1 (first compound
listed in Table 15) and other compounds that were made according to
the procedure as described in this example.
TABLE-US-00015 TABLE 15 Obs Ion Cpd. No. Compound Name (m/z) 21-1
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-{2-[1- 468.1
(cyclohexylmethyl)piperidin-4-yl]ethyl}-2,6-
dimethylpiperazine-1-carboxamide 21-2
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-(2-{1-[.alpha.,.alph-
a.- 469.1
.sup.2H-benzyl]piperidin-4-yl}ethyl)piperazine-1-carboxamide 21-3
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1- 463.1
(pyridin-2-ylmethyl)piperidin-4-yl]ethyl}piperazine-1- carboxamide
21-4 (2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-{2-[l-(2,3-dihydro-1H-
488.1 inden-2-yl)piperidin-4-yl]ethyl}-2,6-dimethylpiperazine-1-
carboxamide 21-5 (2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-{2-[1- 440.4
(cyclobutylmethyl)piperidin-4-yl]ethyl}-2,6-dimethylpiperazine-
1-carboxamide 21-6
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1-(2- 428.1
methylpropyl)piperidin-4-yl]ethyl}piperazine-1-carboxamide 21-7
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-(2-{1-[2- 472.1
(trimethylsilyl)ethyl]piperidin-4-yl}ethyl)piperazine-1-
carboxamide 21-8
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1-(3- 442.1
methylbutyl)piperidin-4-yl]ethyl}piperazine-1-carboxamide 21-9
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-{2-[1-(oxan- 470.1
2-ylmethyl)piperidin-4-yl]ethyl}piperazine-1-carboxamide 21-10
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-(2-{1-[(3- 456.1
methyloxetan-3-yl)methyl]piperidin-4-yl}ethyl)piperazine-1-
carboxamide 21-11
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-N-(2-{1-[(1,1-dioxo-1-thian-
518.1 3-yl)methyl]piperidin-4-yl}ethyl)-2,6-dimethylpiperazine-1-
carboxamide 21-12
(2R,6S)-N-[2-(1-{bicyclo[1.1.1]pentan-1-ylmethyl}piperidin-4- 452.1
yl)ethyl]-4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-
carboxamide 21-13
(2R,6S)-N-{2-[1-(cuban-1-ylmethyl)piperidin-4-yl]ethyl}-4-(5- 488.1
cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide 21-14
(2R)-2-methyl-N-(2-{1-[.alpha.,.alpha.-.sup.2H-benzyl]piperidin-4-yl-
}ethyl)-4- 493.1
[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide 21-15
(2R,6S)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethyl-N-(2-{1-[.alpha.,.alp-
ha.- 464.2
.sup.2H-benzyl]piperidin-4-yl}ethyl)piperazine-1-carboxamide 21-16
(2R)-4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]- 507.3
2-methyl-N-(2-{1-[.alpha.,.alpha.-
.sup.2H-benzyl]piperidin-4-yl}ethyl)piperazine-1-carboxamide 21-17
(2R)-4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-2-methyl-N-
512.3
(2-{1-[.alpha.,.alpha.-.sup.2H-benzyl]piperidin-4-yl}ethyl)piperazine-1-
carboxamide
Example 22
##STR00042##
[0267] Step 22A:
(2R,6S)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[2-(trifluoro-
methyl)pyrimidin-5-yl]piperazine-1-carboxamide
[0268] To a solid mixture of
(2S,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-car-
boxamide 4b (15 mg, 0.04 mmol, 1.0 eq),
5-bromo-2-(trifluoromethyl)pyrimidine (9.4 mg, 0.04 mmol, 1.0 eq),
sodium tert-butoxide (11 mg, 0.12 mmol, 3.0 eq), and lastly
bis(tri-tert-butylphosphine)palladium(0) (3.1 mg, 0.006 mmol, 0.15
eq) was added dioxane (1 mL) and reaction mixture stirred
vigorously at 50.degree. C. overnight. The resulting dark
suspension was cooled, passed through an HPLC filter and
concentrated in vacuo. The crude material was treated with 1.5 mL
of MeOH, passed through an additional HPLC filter (leaving any
precipitate behind), and purified by preparative chromatography
yielding
(2R,6S)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[2-(trifluoro-
methyl)pyrimidin-5-yl]piperazine-1-carboxamide 22-1. The table
below provides the observed (Obs) ion m/z ratio for 22-1 (first
compound listed in Table 16) and other compounds that were made
according to the procedure as described in this example. For some
less reactive halides,
methanesulfanato(2-di-t-butylphosphino-2',4',6'-tri-1-propyl-1,1'-bipheny-
l)(2' amino-1,1'-biphenyl-2-yl) palladium (II) was used in place of
bis(tri-tert-butylphosphine)palladium(0). These reactions were
carried out at 100.degree. C. for 1-2 hrs.
TABLE-US-00016 TABLE 16 Obs Ion Cpd. No. Compound Name (m/z) 22-1
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[2-
505.1 (trifluoromethyl)pyrimidin-5-yl]piperazine-1-carboxamide 22-2
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyanophenyl)-
460.1 2,6-dimethylpiperazine-1-carboxamide 22-3
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-2- 478.1
fluorophenyl)-2,6-dimethylpiperazine-1-carboxamide 22-4
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-3- 478.1
fluorophenyl)-2,6-dimethylpiperazine-1-carboxamide 22-5
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3,5- 472.1
difluoropyridin-2-y1)-2,6-dimethylpiperazine-1-carboxamide 22-6
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4- 489.2
(2,4,5-trifluorophenyl)piperazine-1-carboxamide 22-7
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-chloro-4,5- 505.1
difluorophenyl)-2,6-dimethylpiperazine-1-carboxamide 22-8
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-chloro-5- 488.0
fluoropyridin-3-yl)-2,6-dimethylpiperazine-1-carboxamide 22-9
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-3,5- 496.1
difluorophenyl)-2,6-dimethylpiperazine-1-carboxamide 22-10
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-2,5- 482.1
difluorophenyl)-2-methylpiperazine-1-carboxamide 22-11
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-chloropyridin-3-
456.1 yl)-2-methylpiperazine-1-carboxamide 22-12
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-3,5- 482.1
difluorophenyl)-2-methylpiperazine-1-carboxamide 22-13
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chloro-3,5- 491.1
difluorophenyl)-2-methylpiperazine-1-carboxamide 22-14
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-chloro-3- 473.1
fluorophenyl)-2-methylpiperazine-1-carboxamide 22-15
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-3- 464.1
fluorophenyl)-2-methylpiperazine-1-carboxamide 22-16
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-methoxypyridin- 452.1
4-yl)-2-methylpiperazine-1-carboxamide 22-17
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4-cyano-3- 530.1
(trifluoromethoxy)phenyl]-2-methylpiperazine-1-carboxamide 22-18
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-fluoropyridin-4-
440.1 yl)-2-methylpiperazine-1-carboxamide 22-19
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4- 423.1
(pyrimidin-5-yl)piperazine-1-carboxamide 22-20
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2- 453.0
methoxypyrimidin-5-yl)-2-methylpiperazine-1-carboxamide 22-21
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[2- 466.3
(dimethylamino)pyrimidin-5-yl]-2-methylpiperazine-1- carboxamide
22-22 (2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5- 491.1
(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxamide 22-23
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-
505.1 (trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxamide 22-24
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-4- 490.1
methoxyphenyl)-2,6-dimethylpiperazine-1-carboxamide 22-25
N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[5- 476.9
(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxamide 22-26
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4-cyano-3- 489.1
(dimethylamino)phenyl]-2-methylpiperazine-1-carboxamide 22-27
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrazin-2- 448.1
yl)-2-methylpiperazine-1-carboxamide 22-28
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-3- 476.0
methoxyphenyl)-2-methylpiperazine-1-carboxamide 22-29
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[2- 490.0
(trifluoromethyl)pyridin-4-yl]piperazine-1-carboxamide 22-30
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2,6-difluoropyridin-
458.1 4-yl)-2-methylpiperazine-1-carboxamide 22-31
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-[4-cyano-3- 514.1
(trifluoromethyl)phenyl]-2-methylpiperazine-1-carboxamide 22-32
(2R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(4-cyano-3-fluoro-5-
494.1 methoxyphenyl)-2-methylpiperazine-1-carboxamide
Example 23
##STR00043##
[0269] Step 23A:
(2S,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-cyanopyrimidin-5-yl)-2,-
6-dimethylpiperazine-1-carboxamide
[0270] To a solid mixture of
(2S,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-car-
boxamide 4b (30 mg, 0.08 mmol, 1.0 eq),
5-bromopyrimidine-2-carbonitrile (22 mg, 0.12 mmol, 1.5 eq) and
cesium carbonate (39 mg, 0.12 mmol, 1.5 eq) was added NMP (1 mL)
and reaction mixture stirred at 45.degree. C. over the weekend. The
resulting suspension was cooled, passed through an HPLC filter
diluting to 1 mL with MeOH and submitted for directly for
preparative chromatography yielding
(2S,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-cyanopyrimidin-5-yl)-2,-
6-dimethylpiperazine-1-carboxamide 23-1. The table below provides
the observed (Obs) ion m/z ratio for 23-1 (first compound listed in
Table 17) and other compounds that were made according to the
procedure as described in this example.
TABLE-US-00017 TABLE 17 Obs Ion Cpd. No. Compound Name (m/z) 23-1
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-cyanopyrimidin-
462.2 5-yl)-2,6-dimethylpiperazine-1-carboxamide 23-2
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrazin-2-
462.1 yl)-2,6-dimethylpiperazine-1-carboxamide 23-3
(2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(6-cyanopyridazin-
462.1 3-yl)-2,6-dimethylpiperazine-1-carboxamide
Example 24
##STR00044##
[0271] Step 24A:
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]pyrimidine-5-carbonitrile
[0272] To a suspension of (2R,6R)-2,6-dimethylpiperazine
dihydrochloride (0.250 g, 1.34 mmol, 1.0 eq) and
2-chloropyrimidine-5-carbonitrile (0.187 g, 1.34 mmol, 1.0 eq) in
acetonitrile (5 mL) was added triethylamine (0.93 mL, 6.7 mmol, 5.0
eq) and reaction mixture stirred at room temperature overnight. The
resulting suspension was filtered to remove triethylamine
hydrochloride and concentrated to yield
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]pyrimidine-5-carbonitrile 24a
as an orange solid. The crude material was carried to Example 26
without further purification.
[0273] Other compounds made using the above synthetic scheme
include: [0274]
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-(trifuoromethyl)pyrimidin-
-4-amine 24b; [0275]
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)pyrimidine
24c; and
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)pyrimidine
[0276]
2-[(3S,5S)-3,5-dimethylpiperazin-1-yl]pyrimidine-5-carbonitrile
24d.
Example 25
##STR00045##
[0277] Step 25A:
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)pyrazine
[0278] To a solid mixture of (2R,6R)-2,6-dimethylpiperazine
dihydrochloride (0.08 g, 0.44 mmol, 1.0 eq), sodium tert-butoxide
(0.21 g, 2.2 mmol, 5.0 eq) and
bis(tri-tert-butylphosphine)palladium(0) (34 mg, 0.07 mmol, 0.15
eq) was added dioxane (4 mL) followed by
2-bromo-5-(trifluoromethyl)pyrazine (0.10 g, 0.44 mmol, 1.0 eq) and
the reaction mixture stirred at 50.degree. C. overnight. The
resulting suspension was filtered thru a pad of celite using EtOAc
and concentrated. Silica gel column (24 g) was loaded using
methylene chloride and run using an increasing gradient of MeOH
(0-20%) in methylene chloride over 25 min. Following concentration
of the product eluents,
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)pyrazi-
ne 25a (0.09 g, 0.33 mmol, 75%) was isolated as a yellow oil. The
purified material was carried to Example 26.
[0279]
5-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-2-(trifluoromethyl)pyrimidin-
e 25b was made in a similar fashion.
Example 26
##STR00046##
[0280] Step 26A:
(2R,6R)-4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-N-[2-(1-benzylpiper-
idin-4-yl)ethyl]-2,6-dimethylpiperazine-1-carboxamide
[0281] To a solution of phenyl
N-[2-(1-benzylpiperidin-4-yl)ethyl]carbamate 8b (15 mg, 0.04 mmol,
1.0 eq) and crude
2-[(3R,5R)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)pyrimidin-4-ami-
ne 24b (22 mg, 0.08 mmol, 2.0 eq) in NMP (0.50 mL) was added
triethylamine (0.02 mL, 0.16 mmol, 4.0 eq) and reaction mixture
stirred at 100.degree. C. overnight. The reaction mixture was
filtered and diluted to a total volume of 1 mL using MeOH and
submitted directly for preparative chromatography yielding
[0282]
(2R,6R)-4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-N-[2-(1-benzy-
lpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-carboxamide 26-1.
The table below provides the observed (Obs) ion m/z ratio for 26-1
(first compound listed in Table 18) and other compounds that were
made according to the procedure as described in this example.
TABLE-US-00018 TABLE 18 Obs Ion Cpd. No. Compound Name (m/z) 26-1
(2R,6R)-4-[4-amino-5-(trifluoromethyl)pyrimidin-2-yl]-N-[2-(1-
520.1
benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-carboxamide
26-2
(2R,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrimidin-
462.1 2-yl)-2,6-dimethylpiperazine-1-carboxamide 26-3
(2S,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(5-cyanopyrimidin-
462.1 2-yl)-2,6-dimethylpiperazine-1-carboxamide 26-4
(2R,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-
505.1 (trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxamide 26-5
(2R,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-
505.0 (trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide 26-6
(2R,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[2-
505.05 (trifluoromethyl)pyrimidin-5-yl]piperazine-1-carboxamide
Example 27
##STR00047##
[0283] Step 27A:
2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-dimethylpip-
erazin-1-yl]-N-cyclopropylpyrimidine-5-carboxamide
[0284] To a 0.5 M NMP solution of
(2S,6R)--N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-car-
boxamide 4b (1.0 mL, 0.50 mmol, 1.0 eq) and triethylamine (0.28 mL,
2.0 mmol, 4 eq) was added 2-chloropyrimidine-5-carboxylic acid (79
mg, 0.50 mmol, 1.0 eq) and the reaction mixture stirred at
50.degree. C. overnight. Then, a 75 .mu.L aliquot was treated with
NMP solutions of cyclopropylamine (0.10 mL, 0.5 M, 1.3 eq),
triethylamine (0.10 mL, 2.0 M, 5.2 eq) and HATU (0.10 mL, 0.5 M,
1.3 eq) and again stirred at 50.degree. C. overnight. The reaction
mixture was passed through an HPLC filter diluting to 1 mL with
MeOH and purified by preparative chromatography yielding 2-[(3R,5
S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-dimethylpiperazin-1-
-yl]-N-cyclopropylpyrimidine-5-carboxamide 27-1. The table below
provides the observed (Obs) ion m/z ratio for 27-1 (first compound
listed in Table 19) and other compounds that were made according to
the procedure as described in this example.
TABLE-US-00019 TABLE 19 Obs Ion Cpd. No. Compound Name (m/z) 27-1
2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-
520.1 dimethylpiperazin-1-yl]-N-cyclopropylpyrimidine-5-carboxamide
27-2 (2R,6S)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-
534.1
(pyrrolidine-1-carbonyl)pyrimidin-2-yl]piperazine-1-carboxamide
27-3 2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-
536.2 dimethylpiperazin-1-yl]-N-methyl-N-(propan-2-yl)pyrimidine-5-
carboxamide 27-4
2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-
520.2 dimethylpiperazin-1-yl]-N-(prop-2-en-1-yl)pyrimidine-5-
carboxamide 27-5
2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-
534.2 dimethylpiperazin-1-yl]-N-(cyclopropylmethyl)pyrimidine-5-
carboxamide 27-6
2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-
534.1 dimethylpiperazin-1-yl]-N-cyclobutylpyrimidine-5-carboxamide
27-7 2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-
526.1 dimethylpiperazin-1-yl]-N-(2-fluoroethyl)pyrimidine-5-
carboxamide 27-8
2-[(3R,5S)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3,5-
536.2
dimethylpiperazin-1-yl]-N-(butan-2-yl)pyrimidine-5-carboxamide 27-9
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 508.3
methylpiperazin-1-yl]-N-ethyl-N-methylpyrimidine-5-carboxamide
27-10 2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3-
480.3 methylpiperazin-1-yl]-N-methylpyrimidine-5-carboxamide 27-11
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 536.3
methylpiperazin-1-yl]-6-methyl-N-(2-methylpropyl)pyrimidine-4-
carboxamide 27-12
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 522.3
methylpiperazin-1-yl]-N-(2-methylpropyl)pyrimidine-5- carboxamide
27-13 2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3-
522.2 methylpiperazin-1-yl]-6-methyl-N-(propan-2-yl)pyrimidine-4-
carboxamide 27-14
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 520.3
methylpiperazin-1-yl]-N-cyclopropyl-6-methylpyrimidine-4-
carboxamide 27-15
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 508.3
methylpiperazin-1-yl]-N-(propan-2-yl)pyrimidine-5-carboxamide 27-16
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 494.2
methylpiperazin-1-yl]-N-ethylpyrimidine-5-carboxamide 27-17
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 494.2
methylpiperazin-1-yl]-N,N-dimethylpyrimidine-5-carboxamide 27-18
2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3- 522.3
methylpiperazin-1-yl]-N-ethyl-N,6-dimethylpyrimidine-4- carboxamide
27-19 2-[(3R)-4-{[2-(1-benzylpiperidin-4-yl)ethyl]carbamoyl}-3-
508.3
methylpiperazin-1-yl]-N-ethyl-6-methylpyrimidine-4-carboxamide
Biology Examples
Binding Assay
[0285] Binding affinity (Ki) of compounds was measured by
inhibition of radioligand binding to membranes from CHO cells
expressing human M1, M2, M3, M4 and M5 receptors. Membranes were
prepared by nitrogen cavitation and differential centrifugation as
previously described (Hoare et al., Mol. Pharmacol. 2003 March;
63(3): 751-65). The radioligand employed was tritiated
N-methylscopolamine, used at a concentration of 1.5 nM. A
dose-response of twelve concentrations of compound was used,
ranging from 10 .mu.M to 32 pM. The assay buffer was 50 mM HEPES,
100 mM NaCl, 5 mM MgCl.sub.2, 1 mM ethylenediaminetetraacetic acid,
pH-adjusted to pH 7.4. Membranes, radioligand and compound were
incubated together for 90 minutes at 37.degree. C., in a total
volume of 150 .mu.l in a 96-well plate. Receptor-bound radioligand
was then collected by harvesting the assay over glass fiber filters
pretreated with polyethylenimine to trap the cell membranes, using
rapid vacuum filtration. Harvesting and radioactivity counting was
conducted as previously described (see, e.g., Hoare et al., Mot.
Pharmacol. 2003 63(3):751-65); Erratum at Mol. Pharmacol. 2005
July; 68(1): 260).
[0286] Binding affinities of all the exemplified compounds, which
are described in the examples and listed in the tables above, are
less than 1 .mu.M against the M4 receptor. More specifically,
specificity for the M4 receptor for each of the compounds listed in
Table 20 is as follows: (1) "+" means the compound had a Ki against
the M4 receptor of less than 1 .mu.M (1,000 nM) but greater or
equal to 100 nM; (2) "++" means the compound had a Ki against the
M4 receptor of less than 100 nM but greater or equal to 10 nM; and
(3) "+++" means that the compound had a Ki against the M4 receptor
of less than 10 nM.
TABLE-US-00020 TABLE 20 Cpd. No. Ki 3-1 +++ 3-2 ++ 3-3 + 3-4 + 3-5
+++ 3-6 ++ 3-7 ++ 3-8 +++ 3-9 +++ 3-10 +++ 3-11 +++ 3-12 +++ 3-13
+++ 3-14 +++ 3-15 ++ 3-16 +++ 3-17 +++ 3-18 +++ 3-19 +++ 3-20 ++
3-21 +++ 3-22 +++ 3-23 +++ 4-1 +++ 4-2 + 4-4 + 4-5 +++ 4-6 +++ 4-8
+ 4-9 + 4-10 +++ 4-11 +++ 4-12 +++ 4-13 +++ 4-14 +++ 4-15 +++ 4-16
+++ 4-17 +++ 4-18 +++ 4-19 +++ 4-20 +++ 4-21 +++ 4-22 +++ 4-23 +
4-24 ++ 4-25 ++ 4-26 ++ 4-27 ++ 4-28 ++ 4-28 ++ 4-30 ++ 4-31 ++
4-33 ++ 4-34 ++ 4-35 ++ 4-36 ++ 4-37 ++ 4-38 ++ 4-39 ++ 4-40 ++
4-41 ++ 4-43 ++ 4-44 ++ 4-45 ++ 4-46 ++ 4-47 ++ 4-48 ++ 4-49 + 4-51
+ 4-52 +++ 4-53 +++ 4-54 +++ 4-55 + 4-56 + 4-60 +++ 4-61 + 4-62 +
4-63 + 4-64 + 4-68 +++ 4-69 ++ 4-70 ++ 4-71 +++ 4-72 +++ 4-73 +++
4-74 ++ 4-75 ++ 4-76 +++ 4-77 +++ 4-78 ++ 4-79 +++ 4-80 +++ 5-1 +++
5-2 + 5-3 + 5-4 ++ 5-5 +++ 5-6 ++ 5-7 ++ 5-8 +++ 5-9 + 5-10 + 5-11
+ 5-12 + 5-13 ++ 5-14 +++ 5-15 ++ 5-16 ++ 5-17 +++ 5-18 +++ 5-19 ++
5-20 +++ 5-21 + 5-22 +++ 5-23 +++ 5-24 +++ 5-25 + 5-26 + 5-27 +++
5-28 +++ 5-29 +++ 5-30 +++ 5-31 +++ 5-32 +++ 5-33 ++ 5-34 + 6-1 +++
6-2 + 6-3 +++ 6-4 +++ 6-5 ++ 6-6 ++ 6-7 ++ 6-8 ++ 6-9 ++ 6-10 ++
6-11 ++ 6-12 ++ 6-13 ++ 6-14 ++ 6-15 ++ 6-16 ++ 6-17 ++ 6-18 ++
6-19 + 6-20 + 6-21 + 6-22 + 6-23 + 6-24 + 6-25 + 6-26 +++ 6-27 +++
6-28 + 6-29 + 6-30 + 6-31 + 6-32 ++ 6-33 + 6-34 + 6-35 +++ 6-36 +++
6-37 +++ 6-38 ++ 6-39 + 6-40 +++ 6-41 ++ 6-42 +++ 6-43 ++ 6-44 +
6-45 + 6-46 +++ 6-47 +++ 6-48 +++ 6-49 + 6-50 +++ 6-51 ++ 6-52 ++
6-53 ++ 6-54 ++ 6-55 ++ 6-56 ++ 6-57 ++ 6-58 + 6-59 ++ 6-60 ++ 6-61
+ 6-62 + 6-63 + 6-64 + 6-65 ++ 6-66 + 6-67 ++ 7-1 +++ 7-2 ++ 7-3 ++
7-4 ++ 7-5 + 7-6 + 7-7 + 7-8 + 7-9 +++ 7-10 +++ 7-11 +++ 7-12 +++
7-13 + 8-1 +++ 8-2 ++ 8-3 ++ 8-4 ++ 8-5 + 8-6 + 8-7 + 8-8 ++ 8-9 ++
8-10 ++ 8-11 ++ 8-12 ++ 8-13 ++ 8-14 ++ 8-15 ++ 8-16 ++ 8-17 ++
8-18 ++ 8-19 ++ 8-20 + 8-21 + 8-22 + 8-23 + 8-24 + 8-25 + 8-26 +
8-27 + 8-28 + 8-29 + 8-30 + 8-31 + 8-32 + 8-33 + 8-34 + 8-35 + 8-36
+ 8-37 + 8-38 + 8-39 + 8-40 +
8-41 + 8-42 + 8-43 + 8-44 + 8-45 + 8-46 + 8-47 + 8-48 +++ 9-1 +++
9-2 + 9-3 + 9-4 + 9-5 +++ 9-6 +++ 9-7 +++ 9-8 +++ 9-9 +++ 9-10 +++
9-11 ++ 9-12 ++ 9-13 ++ 9-14 ++ 9-15 ++ 9-16 ++ 9-17 ++ 9-18 + 9-19
+ 9-20 + 9-21 ++ 9-22 ++ 9-23 ++ 9-24 ++ 9-25 ++ 9-26 ++ 9-27 ++
9-28 ++ 9-29 ++ 9-30 ++ 9-31 ++ 9-32 ++ 9-33 ++ 9-34 + 9-35 + 9-36
+ 9-37 + 9-38 + 9-39 ++ 9-40 ++ 9-41 ++ 9-42 + 9-43 + 9-44 ++ 9-45
++ 9-46 ++ 9-47 + 9-48 + 9-49 + 9-50 + 9-51 + 9-52 + 9-53 + 9-54 +
9-55 + 9-56 + 9-57 + 9-58 + 9-59 + 9-60 + 9-61 + 9-62 +++ 9-63 +++
9-64 +++ 9-65 + 9-66 + 9-67 + 9-68 + 9-69 + 9-70 +++ 9-71 +++ 9-72
+++ 9-73 +++ 9-74 + 9-75 + 10-1 ++ 10-2 + 10-3 + 10-4 + 10-5 +++
10-6 +++ 10-7 +++ 10-8 +++ 10-9 +++ 10-10 +++ 10-11 +++ 10-12 +++
10-13 +++ 10-14 +++ 10-15 + 10-16 + 10-17 + 10-18 +++ 10-19 +++
10-20 +++ 10-21 +++ 10-22 +++ 10-23 +++ 10-24 ++ 10-25 ++ 10-26 +
10-27 + 10-28 + 10-29 ++ 10-30 ++ 10-31 ++ 10-32 ++ 10-33 ++ 10-34
++ 10-35 ++ 10-36 ++ 10-37 ++ 10-38 ++ 10-39 ++ 10-40 ++ 10-41 ++
10-42 +++ 10-43 +++ 10-44 +++ 10-45 ++ 10-46 ++ 10-47 ++ 10-48 +
10-49 + 10-50 + 10-51 + 10-52 + 10-53 + 10-54 +++ 10-55 ++ 10-56
+++ 10-57 +++ 10-58 +++ 10-59 + 10-60 + 10-61 + 10-62 + 10-63 +
10-64 + 10-65 + 10-66 + 10-67 + 10-68 + 10-69 + 10-70 + 10-71 +
10-72 + 10-73 + 10-74 + 10-75 + 10-76 ++ 10-77 ++ 10-78 ++ 10-79
+++ 10-80 +++ 10-81 +++ 11-1 ++ 11-2 ++ 11-3 ++ 11-4 + 11-5 + 11-6
++ 11-7 ++ 11-8 + 11-9 + 11-10 + 11-11 + 11-12 + 11-13 + 11-14 +
11-15 + 11-16 + 11-17 + 11-18 + 11-19 + 11-20 + 11-21 + 11-22 +
11-23 + 11-24 + 11-25 + 11-26 + 11-27 + 11-28 + 11-29 + 11-30 +
12-1 ++ 12-2 + 12-3 + 12-4 ++ 12-5 + 12-6 + 12-7 + 12-8 + 12-9 +
12-10 + 12-11 ++ 12-12 ++ 17-1 +++ 17-2 + 17-3 +++ 17-4 ++ 17-5 +++
17-6 +++ 17-7 + 17-8 ++ 18-1 +++ 18-2 + 18-3 + 18-4 +++ 18-5 +++
18-6 ++ 18-7 ++ 18-8 ++ 18-9 ++ 18-10 ++ 18-11 ++ 18-12 ++ 18-13 ++
18-14 ++ 18-15 + 18-16 +++ 18-17 +++ 18-18 + 18-19 + 18-20 ++ 19-1
+ 19-2 ++ 19-3 + 19-4 + 19-5 + 19-6 + 19-7 + 19-8 + 20-1 ++ 20-2
+++ 20-3 +++ 21-1 ++ 21-2 +++ 21-3 + 21-4 ++ 21-5 + 21-6 +
21-7 +++ 21-8 + 21-9 + 21-10 + 21-11 + 21-12 + 21-13 ++ 21-14 +++
21-15 +++ 21-16 +++ 21-17 +++ 22-1 ++ 22-2 +++ 22-3 +++ 22-4 +++
22-5 +++ 22-6 ++ 22-7 +++ 22-8 +++ 22-9 +++ 22-10 +++ 22-11 ++
22-12 +++ 22-13 +++ 22-14 +++ 22-15 +++ 22-16 ++ 22-17 +++ 22-18 ++
22-19 ++ 22-20 NT 22-21 NT 22-22 +++ 22-23 +++ 22-24 +++ 22-25 +++
22-26 ++ 22-27 ++ 22-28 ++ 22-29 ++ 22-30 +++ 22-31 +++ 22-32 +++
23-1 + 23-2 ++ 23-3 ++ 26-1 +++ 26-2 +++ 26-3 + 26-4 +++ 26-5 +++
26-6 +++ 27-1 ++ 27-2 + 27-3 + 27-4 + 27-5 + 27-6 + 27-7 + 27-8 +
27-9 + 27-10 + 27-11 ++ 27-12 ++ 27-13 + 27-14 + 27-15 + 27-16 +
27-17 + 27-18 + 27-19 +
[0287] For the compounds of Table 20 above with Ki values against
the M4 receptor of less than 10 nM (i.e., the "+++" compounds),
their selectivity over the M1, M2, M3 and M5 receptors are set
forth in Table 21 below. In Table 21, activity is expressed as
follows: (1) "+++" means the compound had a Ki against the noted
receptor of less than 10 nM; (2) "++" means the compound had a Ki
against the noted receptor of less than 100 nM but greater than or
equal to 10 nM; (3) "+" means the compound had a Ki against the
noted receptor of less than 1 .mu.M (1,000 nM) but greater or equal
to 100 nM; and (4) "-" means the compound had a Ki against the
noted receptor of 1 .mu.M (1,000 nM) or greater or that activity
was not detected against the noted receptor. ("NT" in Table 21
means that the compound was not tested against the muscarinic
receptor noted.)
TABLE-US-00021 TABLE 21 Cpd No M1 M2 M3 M5 3-1 + ++ - - 3-5 - + - -
3-8 + ++ + - 3-9 + ++ + - 3-10 + ++ + - 3-11 - + - - 3-12 + ++ - -
3-13 + + - - 3-14 + ++ - - 3-16 - - - - 3-17 - + - - 3-18 - - - -
3-19 - + - - 3-21 - + - - 3-22 - + - - 3-23 - + - - 4-1 + + - - 4-5
+ ++ - - 4-6 + ++ NT - 4-10 + ++ + + 4-11 + ++ - - 4-12 + ++ + -
4-13 - + - - 4-14 - + NT - 4-15 + + - - 4-16 + + NT - 4-17 - + - -
4-18 - + - - 4-19 + + - - 4-20 + ++ - - 4-21 + ++ + - 4-22 - + - +
4-52 + ++ + - 4-53 + ++ + + 4-54 + + - - 4-60 + ++ + + 4-68 + + - -
4-71 + + - - 4-72 + + NT - 4-73 + ++ + - 4-76 - + - - 4-77 + ++ - -
4-79 + ++ - - 4-80 + + - - 5-1 - + - - 5-5 + + - - 5-8 - ++ + -
5-14 + + - - 5-17 + + + - 5-18 - ++ - - 5-20 - + - - 5-22 + ++ - -
5-23 + ++ - - 5-24 + ++ - - 5-27 + + - - 5-28 + + - - 5-29 - + - -
5-30 - + - - 5-31 ++ +++ ++ + 5-32 - ++ - - 6-1 + +++ + + 6-3 + ++
+ - 6-4 + + - - 6-26 + ++ - - 6-27 + ++ + - 6-35 + ++ + - 6-36 + +
- - 6-37 + ++ - - 6-40 + ++ + - 6-42 - ++ + - 6-46 - +++ - - 6-47 +
+++ + + 6-48 - ++ - - 6-50 + ++ + - 7-1 - - - - 7-9 + + - - 7-10 -
+ - - 7-11 - - - - 7-12 - - - - 8-1 + + + + 8-48 ++ +++ + + 9-1 - +
- - 9-5 - - - - 9-6 + ++ + + 9-7 + + - - 9-8 - + - - 9-9 + + - -
9-10 + + + - 9-62 + + - - 9-63 ++ +++ ++ + 9-64 + + - - 9-70 + + -
- 9-71 - + - - 9-72 + + - - 9-73 - + - - 10-5 + ++ - - 10-6 + + - -
10-7 - + - - 10-8 - + - - 10-9 - + - - 10-10 + + - - 10-11 + + - -
10-12 + ++ + + 10-13 + + - - 10-14 - + - - 10-18 - + - - 10-19 + +
- - 10-20 - + - - 10-21 - + - - 10-22 - + - - 10-23 + ++ - - 10-42
+ + - - 10-43 - + - - 10-44 - + - - 10-54 + ++ - - 10-56 + ++ + -
10-57 + ++ - - 10-58 - - - - 10-79 + ++ - + 10-80 ++ ++ + + 10-81
++ ++ ++ + 17-1 - + - - 17-3 + + - - 17-5 + ++ - - 17-6 - + - -
18-1 - ++ - - 18-4 + + - - 18-5 - + - - 18-16 - + - - 18-17 - + - -
20-2 ++ ++ ++ + 20-3 + + + - 21-2 - + - - 21-7 ++ +++ ++ + 21-14 +
++ + - 21-15 - + - - 21-16 ++ +++ ++ + 21-17 ++ +++ ++ + 22-2 - + -
- 22-3 - + - - 22-4 - ++ - - 22-5 + ++ - + 22-7 + ++ + + 22-8 + ++
- - 22-9 + ++ - - 22-10 - + - - 22-12 - ++ - + 22-13 + ++ + + 22-14
+ ++ + + 22-15 + ++ - + 22-17 + ++ - + 22-22 + ++ - - 22-23 + +++ +
+ 22-24 + ++ - - 22-25 - ++ - - 22-30 + ++ - - 22-31 ++ ++ - +
22-32 + + - + 26-1 + ++ - - 26-2 - + - - 26-4 - + - - 26-6 ++ ++ +
+
Functional Assay
[0288] Functional antagonism of acetylcholine responses were
evaluated using a .sup.35S-GTP.gamma.S binding assay. Acetylcholine
binding to the muscarinic receptors activates G-proteins.
Activation of G-proteins can be determined by their binding of the
radiolabeled GTP analogue .sup.35S-GTP.gamma.S. In the assay,
acetylcholine stimulates the binding of .sup.35S-GTP.gamma.S to
G-proteins associated with cell membranes, and the incorporated
.sup.35S-GTP.gamma.S can be collected by harvesting the membranes.
Antagonist activity of the compounds was determined as the IC50 for
inhibition of the acetylcholine response. The assay buffer used was
50 mM HEPES, 100 mM NaCl, 5 mM MgCl.sub.2, 1 mM
ethylenediaminetetraacetic acid, pH-adjusted to pH 7.4.
Acetylcholine, compound (a dose-response of twelve concentrations
ranging from 10 .mu.M to 32 pM) and membranes from CHO cells
expressing M4 or M2 receptors were incubated together in 150 .mu.l
buffer for 30 minutes at 30.degree. C. in a 96-well plate.
.sup.35S-GTP.gamma.S was then added, to a final concentration of
0.2 nM and a final volume of 175 .mu.l. Twenty minutes later,
membranes were harvested by rapid vacuum filtration onto
non-treated glass fiber filters, as previously described (see,
e.g., Hoare et al., Mol. Pharmacol. 2003 63(3):751-65); Erratum at
Mol. Pharmacol. 2005 July; 68(1): 260). The concentration of
acetylcholine used was that which stimulated 80% of the maximal
response (3 .mu.M for the M4 receptor, 1 .mu.M for M2). Many of the
compounds described above have been evaluated in the functional
assay.
Electrophysiology Assay
[0289] Adult (>8 weeks) female Lister hooded rats (Harlan, UK)
were killed by decapitation and the brain was removed and placed
into ice-cold oxygenated sucrose Krebs' medium containing (mM):
sucrose 202, KCl 2, KH.sub.2PO.sub.4 1.25, MgSO.sub.4 10,
CaCl.sub.2 0.5, NaHCO.sub.3 26, glucose 10. The brain was
hemisected along the midline and 300 .mu.M parasagittal slices were
prepared with an oscillating microtome (Integraslice; Campden
Instruments Ltd., Loughborough, UK). Slices were then transferred
to a recovery chamber at room temperature containing oxygenated
Krebs' solution (mM): NaCl 124, KCl 2, KH.sub.2PO.sub.4 1.25,
MgSO.sub.4 1, CaCl.sub.2 2, NaHCO.sub.3 26, glucose 10. Following
at least 1 hour of recovery, individual slices were transferred to
an interface recording chamber where they were perfused with Krebs'
solution (33.degree. C.). Extracellular field potential recordings
were made with an Axoprobe 1A amplifier (Axon Instruments Ltd.,
USA) via a Krebs'-filled glass micropipette (resistance 2-5 M12)
positioned in the stratum radiatum of the CAI, digitized (10 kHz)
via a CED1401 interface and stored on a computer with Spike2
software (Cambridge Electronic Design Ltd., Cambridge, UK). Field
excitatory postsynaptic potential (fEPSP) responses were evoked
(pair of 0.02 ms pulses, separated by 40 ms; applied every 10 s;
adjusted to approximately 60% of the maximal spike-free response)
by a bipolar stimulating electrode positioned in the stratum
radiatum near the CA3-CA1 border.
[0290] The cholinergic agonist carbachol (aza-acetylcholine,
resistant to degradation by acetylcholinesterase) was used to
stimulate muscarinic receptors. The M1 muscarinic receptor was
blocked using 5 .mu.M VU0255035, a selective M1 antagonist. The
resulting inhibitory signal was primarily M4-mediated, based on its
sensitivity to the M4 activator VU010010. The effect of M4
antagonists on this M4-mediated inhibition of fEPSPs was measured
by adding M4 compound 20 minutes prior to application of
carbachol.
6-OHDA Surgical Lesion and Behavioral Testing Procedures
[0291] 6-OHDA Lesion protocol: Male Sprague-Dawley rats were
anesthetized with isoflurane and placed into the stereotaxic frame.
Thirty minutes prior the injection of 6-OHDA, rats received
desipramine (15 mg/kg, i.p.) to prevent the entry of the toxin into
the noradrenergic cells. A unilateral lesion was induced by
injections of 6-OHDA (8 .mu.g/4 .mu.l/site/rat; flow rate 1
.mu.l/min; dissolved in 0.9% NaCl with 0.02% ascorbic acid) or
vehicle into the left and right medial forebrain bundle at the
following coordinates: AP -4.4. mm; L .+-.1.2 mm; V -7.8 mm
relative to Bregma (Paxinos and Watson, 2007). The rats were
allowed to recover for 14 days and were then tested for locomotor
activity induced by novelty (placing the rat in a new cage, 30 min)
and for contraversive (contralateral) rotational behavior induced
by apomorphine (0.2 mg/kg, s.c.).
[0292] Experimental animal selection criteria: Only the rats with
activity higher than 5 turns/min following apomorphine treatment
were enrolled in the study; rats not fulfilling the criteria were
excluded from the study (typically 20%). Turning activity was then
recorded for each group once per week for four consecutive
weeks.
Locomotor Activity
[0293] Young adult male, Sprague-Dawley rats (240-250 g) were
purchased from Charles River Laboratories and assessed in the Open
Field (Kinder Scientific, CA) task during the light hours of a
12:12 L:D cycle and were tested under bright light conditions.
Animals were allowed to acclimate to the facility for at least one
week prior to use. On the day of testing, animals were acclimated
to the test room for at least 1 hour and were then treated orally
with the Neurocrine compound and placed into the test chamber 30
minutes later. Animals were allowed to freely ambulate for 60
minutes. Measurements taken included, but were not limited to,
total horizontal and vertical beam breaks.
[0294] The various embodiments described above can be combined to
provide further embodiments. All U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications, and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet are incorporated herein by reference in their entirety.
Aspects of the embodiments can be modified, if necessary to employ
concepts of the various patents, applications and publications to
provide yet further embodiments.
[0295] The disclosures of U.S. provisional patent application Ser.
No. 62/252,179, filed Nov. 6, 2015, and U.S. provisional patent
application Ser. No. 62/275,708, filed Jun. 1, 2016, are
incorporated herein by reference in their entirety.
[0296] These and other changes can be made to the embodiments in
light of the above-detailed description. In general, in the
following claims, the terms used should not be construed to limit
the claims to the specific embodiments disclosed in the
specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents
to which such claims are entitled. Accordingly, the claims are not
limited by the disclosure.
* * * * *