U.S. patent application number 12/466415 was filed with the patent office on 2009-09-03 for compounds, compositions containing them, preparation thereof and uses thereof i.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Ziping Liu, Daniel Page, Maxime Tremblay, Christopher Walpole, Hua Yang.
Application Number | 20090221657 12/466415 |
Document ID | / |
Family ID | 37492537 |
Filed Date | 2009-09-03 |
United States Patent
Application |
20090221657 |
Kind Code |
A1 |
Page; Daniel ; et
al. |
September 3, 2009 |
Compounds, Compositions Containing Them, Preparation Thereof and
Uses Thereof I
Abstract
Compounds of Formula I, or pharmaceutically acceptable salts
thereof: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, and G are as defined in the specification as well as salts
and pharmaceutical compositions including the compounds are
prepared. They are useful in therapy, in particular in the
management of pain.
Inventors: |
Page; Daniel; (Quebec,
CA) ; Liu; Ziping; (Quebec, CA) ; Tremblay;
Maxime; (Quebec, CA) ; Walpole; Christopher;
(Quebec, CA) ; Yang; Hua; (Quebec, CA) |
Correspondence
Address: |
ASTRA ZENECA PHARMACEUTICALS LP;GLOBAL INTELLECTUAL PROPERTY
1800 CONCORD PIKE
WILMINGTON
DE
19850-5437
US
|
Assignee: |
ASTRAZENECA AB
Sodertalje
SE
|
Family ID: |
37492537 |
Appl. No.: |
12/466415 |
Filed: |
May 15, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11419603 |
May 22, 2006 |
7550495 |
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12466415 |
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PCT/SE2005/001403 |
Sep 22, 2005 |
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11419603 |
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60640306 |
Dec 30, 2004 |
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Current U.S.
Class: |
514/394 |
Current CPC
Class: |
C07D 405/06 20130101;
A61P 25/28 20180101; A61P 25/16 20180101; A61P 25/22 20180101; A61P
29/02 20180101; A61P 9/00 20180101; A61P 35/00 20180101; C07D
235/10 20130101; A61P 25/00 20180101; A61P 1/00 20180101; C07D
235/08 20130101 |
Class at
Publication: |
514/394 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; A61P 35/00 20060101 A61P035/00; A61P 25/00 20060101
A61P025/00; A61P 9/00 20060101 A61P009/00; A61P 1/00 20060101
A61P001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 24, 2004 |
GB |
PCT/GB2004/004124 |
Claims
1-10. (canceled)
11. A method for the treatment of anxiety disorders comprising the
step of administering to said animal in need of such therapy a
therapeutically effective amount of a compound of formula I, a
pharmaceutically acceptable salt thereof, diastereomers,
enantiomers, or mixtures thereof: ##STR00091## wherein G is
selected from --O-- and --CF.sub.2--; R.sup.1 is selected from
C.sub.1-6alkyl and C.sub.3-6cycloalkyl; R.sup.2 is selected from
--H and methyl; and R.sup.3, R.sup.4 and R.sup.5 are independently
selected from fluoro and methyl.
12. A method for the treatment of cancer, multiple sclerosis,
Parkinson's disease, Huntington's chorea, Alzheimer's disease,
gastrointestinal disorders and cardiovascular disorders comprising
the step of administering to said animal in need of such therapy a
therapeutically effective amount of a compound of formula I, a
pharmaceutically acceptable salt thereof, diastereomers,
enantiomers, or mixtures thereof: ##STR00092## wherein G is
selected from --O-- and --CF.sub.2 R.sup.1 is selected from
C.sub.1-6alkyl and C.sub.3-6cycloalkyl; R.sup.2 is selected from
--H and methyl; and R.sup.3, R.sup.4 and R.sup.5 are independently
selected from fluoro and methyl.
13. (canceled)
14. A method for the therapy of pain in a warm-blooded animal,
comprising the step of administering to said animal in need of such
therapy a therapeutically effective amount of a compound of formula
I, a pharmaceutically acceptable salt thereof, diastereomers,
enantiomers, or mixtures thereof: ##STR00093## wherein G is
selected from --O-- and --CF.sub.2--; R.sup.1 is selected from
C.sub.1-6alkyl and C.sub.3cycloalkyl; R.sup.2 is selected from --H
and methyl; and R.sup.3, R.sup.4 and R.sup.5 are independently
selected from fluoro and methyl.
15. (canceled)
16. The method as claimed in claim 14, wherein R.sup.1 is selected
from C.sub.1-4alkyl and C.sub.3-4cycloalkyl.
17. The method as claimed in claim 14, wherein G is --O--; R.sup.1
is selected from ethyl, propyl and cyclopropyl; and R.sup.3,
R.sup.4 and R.sup.5 are independently selected from fluoro and
methyl with R.sup.3, R.sup.4 and R.sup.5 being the same.
18. The method as claimed in claim 14, wherein G is --CF.sub.2--;
R.sup.1 is selected from ethyl, propyl and cyclopropyl; and
R.sup.3, R.sup.4 and R.sup.5 are independently selected from fluoro
and methyl with R.sup.3, R.sup.4 and R.sup.5 being the same.
19. The method as claim 14, wherein the compound is selected from
##STR00094## ##STR00095##
20. The method as claimed in claim 14, wherein G is selected from
--O--, --CHF-- and --CF.sub.2--; R.sup.1 is selected from
C.sub.1-6alkyl and C.sub.3-6cycloalkyl; R.sup.2 is selected from
--H and methyl; and R.sup.3, R.sup.4 and R.sup.5 are independently
selected from fluoro and methyl.
21. The method as claimed in claim 20, wherein G is selected from
--CHF-- and --CF.sub.2--.
22. The method as claimed in claim 20, wherein R.sup.1 is selected
from ethyl, propyl, t-butyl and cyclopropyl.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention is related to therapeutic compounds,
pharmaceutical compositions containing these compounds,
manufacturing processes thereof and uses thereof. Particularly, the
present invention is related to compounds that may be effective in
treating pain, cancer, multiple sclerosis, Parkinson's disease,
Huntington's chorea, Alzheimer's disease, anxiety disorders,
gastrointestinal disorders and/or cardiovascular disorders.
[0003] 2. Discussion of Relevant Technology
[0004] Pain management has been studied for many years. It is known
that cannabinoid receptor (e.g., CB.sub.1 receptor, CB.sub.2
receptor) ligands including agonists, antagonists and inverse
agonists produce relief of pain in a variety of animal models by
interacting with CB.sub.1 and/or CB.sub.2 receptors. Generally,
CB.sub.1 receptors are located predominately in the central nervous
system, whereas CB.sub.2 receptors are located primarily in the
periphery and are primarily restricted to the cells and tissues
derived from the immune system.
[0005] While CB.sub.1 receptor agonists, such as
.DELTA..sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC) and
anadamide, are useful in anti-nociception models in animals, they
tend to exert undesired CNS side-effects, e.g., psychoactive side
effects, the abuse potential, drug dependence and tolerance, etc.
These undesired side effects are known to be mediated by the
CB.sub.1 receptors located in CNS. There are lines of evidence,
however, suggesting that CB.sub.1 agonists acting at peripheral
sites or with limited CNS exposure can manage pain in humans or
animals with much improved overall in vivo profile.
[0006] Therefore, there is a need for new CB.sub.1 receptor ligands
such as agonists that may be useful in managing pain or treating
other related symptoms or diseases with reduced or minimal
undesirable CNS side-effects.
DESCRIPTION OF THE EMBODIMENTS
[0007] The present invention provides CB.sub.1 receptor ligands
which may be useful in treating pain and/or other related symptoms
or diseases.
[0008] The term "C.sub.m-n" or "C.sub.m-n group" used alone or as a
prefix, refers to any group having m to n carbon atoms.
[0009] The term "alkyl" used alone or as a suffix or prefix, refers
to a saturated monovalent straight or branched chain hydrocarbon
radical comprising 1 to about 12 carbon atoms. Illustrative
examples of alkyls include, but are not limited to, C.sub.1-4alkyl
groups, such as methyl, ethyl, propyl, isopropyl,
2-methyl-1-propyl, 2-methyl-2-propyl, butyl, isobutyl, t-butyl.
[0010] The term "cycloalkyl," used alone or as suffix or prefix,
refers to a saturated monovalent ring-containing hydrocarbon
radical comprising at least 3 up to about 12 carbon atoms. Examples
of cycloalkyls include, but are not limited to, C.sub.3-7cycloalkyl
groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cycloheptyl, and saturated cyclic and bicyclic terpenes. A
cycloalkyl can be unsubstituted or substituted by one or two
suitable substituents. Preferably, the cycloalkyl is a monocyclic
ring or bicyclic ring.
[0011] The term "alkoxy" used alone or as a suffix or prefix,
refers to radicals of the general formula --O--R, wherein R is an
alkyl. Exemplary alkoxy includes methoxy, ethoxy, propoxy,
isopropoxy, butoxy, t-butoxy, and isobutoxy.
[0012] Halogen includes fluorine, chlorine, bromine and iodine.
[0013] "RT" or "rt" means room temperature.
[0014] In one aspect, an embodiment of the invention provides a
compound of Formula I, a pharmaceutically acceptable salt thereof,
diastereomers, enantiomers, or mixtures thereof:
##STR00002##
wherein
[0015] G is selected from --O--, --CHF-- and --CF.sub.2--;
[0016] R.sup.1 is selected from C.sub.1-6alkyl and
C.sub.3-6cycloalkyl;
[0017] R.sup.2 is selected from --H and methyl; and
[0018] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
fluoro and methyl.
[0019] In another embodiment, the compounds may be those of formula
I, wherein
[0020] G is selected from --O-- and --CF.sub.2--;
[0021] R.sup.1 is selected from C.sub.1-6alkyl and
C.sub.3-6cycloalkyl;
[0022] R.sup.2 is selected from --H and methyl; and
[0023] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
fluoro and methyl.
[0024] Another embodiment of the invention provides a compound of
formula I,
wherein
[0025] G is selected from --O-- and --CF.sub.2--;
[0026] R.sup.1 is selected from C.sub.1-4alkyl and
C.sub.3-4cycloalkyl;
[0027] R.sup.2 selected from --H and methyl; and
[0028] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
fluoro and methyl.
[0029] A further embodiment of the invention provides a compound of
formula I, wherein
[0030] G is --O--;
[0031] R.sup.1 is selected from ethyl, propyl and cyclopropyl;
[0032] R.sup.2 selected from --H and methyl; and
[0033] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
fluoro and methyl with R.sup.3, R.sup.4 and R.sup.5 being the
same.
[0034] An even further embodiment of the invention provides a
compound of formula I,
wherein
[0035] G is --CF.sub.2--;
[0036] R.sup.1 is selected from ethyl, propyl and cyclopropyl;
[0037] R.sup.2 selected from --H and methyl; and
[0038] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
fluoro and methyl with R.sup.3, R.sup.4 and R.sup.5 being the
same.
[0039] An even further embodiment of the invention provides a
compound of formula I,
wherein
[0040] G is --CHF--;
[0041] R.sup.1 is selected from ethyl, propyl, t-butyl and
cyclopropyl;
[0042] R.sup.2 selected from --H and methyl; and
[0043] R.sup.3, R.sup.4 and R.sup.5 are independently selected from
fluoro and methyl with R.sup.3, R.sup.4 and R.sup.5 being the
same.
[0044] In another embodiment, R.sup.1 of formula I is selected from
ethyl, propyl, t-butyl and cyclopropyl.
[0045] In another embodiment, G of formula I is --CHF-- or
--CF.sub.2--.
[0046] In another embodiment, R.sup.3, R.sup.4 and R.sup.5 of
formula I are selected from fluoro and methyl with R.sup.3, and
R.sup.5 being the same.
[0047] In another embodiment, the compound of the invention may be
selected from
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]--
N-methylcyclopropanesulfonamide; [0048]
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]--
N-methylpropane-1-sulfonamide; [0049]
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]--
N-methylbutane-1-sulfonamide; [0050]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}--
N-methylbutane-1-sulfonamide; [0051]
N-methyl-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-ben-
zimidazol-5-yl]propane-1-sulfonamide; [0052]
N-methyl-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-ben-
zimidazol-5-yl]cyclopropanesulfonamide; [0053]
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]--
N-methylpentane-1-sulfonamide; [0054]
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]--
N-methylethanesulfonamide; [0055]
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]--
N,2-dimethylpropane-2-sulfonamide; [0056]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}--
N-methylpropane-1-sulfonamide; [0057]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}--
N-methylethanesulfonamide; [0058]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}p-
ropane-1-sulfonamide; [0059]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}m-
ethanesulfonamide; [0060]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}e-
thanesulfonamide; [0061]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}c-
yclopropanesulfonamide; [0062]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}--
N-methylcyclopropanesulfonamide; [0063]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}--
2-methylpropane-2-sulfonamide; [0064]
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benzimidaz-
ol-5-yl]cyclopropanesulfonamide; [0065]
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benzimidaz-
ol-5-yl]ethanesulfonamide; [0066]
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benzimidaz-
ol-5-yl]-2-methylpropane-2-sulfonamide; [0067]
N-[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidaz-
ol-5-yl]-N-methylethanesulfonamide; [0068]
N-[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidaz-
ol-5-yl]-N-methylpropane-1-sulfonamide; [0069]
N-[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidaz-
ol-5-yl]-N-methylcyclopropanesulfonamide; [0070]
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}ethan-
esulfonamide; [0071]
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}cyclo-
propanesulfonamide; [0072]
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-2-me-
thylpropane-2-sulfonamide; and pharmaceutically acceptable salts
thereof.
[0073] A further embodiment of the invention provides a compound
selected from
##STR00003## ##STR00004##
[0074] It will be understood that when compounds of the present
invention contain one or more chiral centers, the compounds of the
invention may exist in, and be isolated as, enantiomeric or
diastereomeric forms, or as a racemic mixture. The present
invention includes any possible enantiomers, diastereomers,
racemates or mixtures thereof, of a compound of Formula I. The
optically active forms of the compound of the invention may be
prepared, for example, by chiral chromatographic separation of a
racemate, by synthesis from optically active starting materials or
by asymmetric synthesis based on the procedures described
thereafter.
[0075] It will also be appreciated that certain compounds of the
present invention may exist as geometrical isomers, for example E
and Z isomers of alkenes. The present invention includes any
geometrical isomer of a compound of Formula I. It will further be
understood that the present invention encompasses tautomers of the
compounds of the Formula I.
[0076] It will also be understood that certain compounds of the
present invention may exist in solvated, for example hydrated, as
well as unsolvated forms. It will further be understood that the
present invention encompasses all such solvated forms of the
compounds of the Formula I.
[0077] Within the scope of the invention are also salts of the
compounds of the Formula I. Generally, pharmaceutically acceptable
salts of compounds of the present invention may be obtained using
standard procedures well known in the art, for example by reacting
a sufficiently basic compound, for example an alkyl amine with a
suitable acid, for example, HCl or acetic acid, to afford a
physiologically acceptable anion. It may also be possible to make a
corresponding alkali metal (such as sodium, potassium, or lithium)
or an alkaline earth metal (such as a calcium) salt by treating a
compound of the present invention having a suitably acidic proton,
such as a carboxylic acid or a phenol with one equivalent of an
alkali metal or alkaline earth metal hydroxide or alkoxide (such as
the ethoxide or methoxide), or a suitably basic organic amine (such
as choline or meglumine) in an aqueous medium, followed by
conventional purification techniques.
[0078] In one embodiment, the compound of Formula I above may be
converted to a pharmaceutically acceptable salt or solvate thereof,
particularly, an acid addition salt such as a hydrochloride,
hydrobromide, phosphate, acetate, fumarate, maleate, tartrate,
citrate, methanesulphonate orp-toluenesulphonate.
[0079] We have now found that the compounds of the invention have
activity as pharmaceuticals, in particular as modulators or ligands
such as agonists, partial agonists, inverse agonist or antagonists
of CB.sub.1 receptors. More particularly, the compounds of the
invention exhibit selective activity as agonist of the CB.sub.1
receptors and are useful in therapy, especially for relief of
various pain conditions such as chronic pain, neuropathic pain,
acute pain, cancer pain, pain caused by rheumatoid arthritis,
migraine, visceral pain etc. This list should however not be
interpreted as exhaustive. Additionally, compounds of the present
invention are useful in other disease states in which dysfunction
of CB.sub.1 receptors is present or implicated. Furthermore, the
compounds of the invention may be used to treat cancer, multiple
sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's
disease, anxiety disorders, gastrointestinal disorders and
cardiovascular disorders.
[0080] Compounds of the invention are useful as immunomodulators,
especially for autoimmune diseases, such as arthritis, for skin
grafts, organ transplants and similar surgical needs, for collagen
diseases, various allergies, for use as anti-tumour agents and anti
viral agents.
[0081] Compounds of the invention are useful in disease states
where degeneration or dysfunction of cannabinoid receptors is
present or implicated in that paradigm. This may involve the use of
isotopically labelled versions of the compounds of the invention in
diagnostic techniques and imaging applications such as positron
emission tomography (PET).
[0082] Compounds of the invention are useful for the treatment of
diarrhea, depression, anxiety and stress-related disorders such as
post-traumatic stress disorders, panic disorder, generalized
anxiety disorder, social phobia, and obsessive compulsive disorder,
urinary incontinence, premature ejaculation, various mental
illnesses, cough, lung oedema, various gastro-intestinal disorders,
e.g. constipation, functional gastrointestinal disorders such as
Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's
disease and other motor disorders, traumatic brain injury, stroke,
cardioprotection following myocardial infarction, spinal injury and
drug addiction, including the treatment of alcohol, nicotine,
opioid and other drug abuse and for disorders of the sympathetic
nervous system for example hypertension.
[0083] Compounds of the invention are useful as an analgesic agent
for use during general anaesthesia and monitored anaesthesia care.
Combinations of agents with different properties are often used to
achieve a balance of effects needed to maintain the anaesthetic
state (e.g. amnesia, analgesia, muscle relaxation and sedation).
Included in this combination are inhaled anesthetics, hypnotics,
anxiolytics, neuromuscular blockers and opioids.
[0084] Also within the scope of the invention is the use of any of
the compounds according to the Formula I above, for the manufacture
of a medicament for the treatment of any of the conditions
discussed above.
[0085] A further aspect of the invention is a method for the
treatment of a subject suffering from any of the conditions
discussed above, whereby an effective amount of a compound
according to the Formula I above, is administered to a patient in
need of such treatment.
[0086] Thus, the invention provides a compound of Formula I or
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined for use in therapy.
[0087] In a further aspect, the present invention provides the use
of a compound of Formula I or a pharmaceutically acceptable salt or
solvate thereof, as hereinbefore defined in the manufacture of a
medicament for use in therapy.
[0088] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The term "therapeutic" and
"therapeutically" should be construed accordingly. The term
"therapy" within the context of the present invention further
encompasses to administer an effective amount of a compound of the
present invention, to mitigate either a pre-existing disease state,
acute or chronic, or a recurring condition. This definition also
encompasses prophylactic therapies for prevention of recurring
conditions and continued therapy for chronic disorders.
[0089] The compounds of the present invention are useful in
therapy, especially for the therapy of various pain conditions
including, but not limited to: acute pain, chronic pain,
neuropathic pain, back pain, cancer pain, and visceral pain.
[0090] In use for therapy in a warm-blooded animal such as a human,
the compound of the invention may be administered in the form of a
conventional pharmaceutical composition by any route including
orally, intramuscularly, subcutaneously, topically, intranasally,
intraperitoneally, intrathoracially, intravenously, epidurally,
intrathecally, transdermally, intracerebroventricularly and by
injection into the joints.
[0091] In one embodiment of the invention, the route of
administration may be oral, intravenous or intramuscular.
[0092] The dosage will depend on the route of administration, the
severity of the disease, age and weight of the patient and other
factors normally considered by the attending physician, when
determining the individual regimen and dosage level at the most
appropriate for a particular patient.
[0093] For preparing pharmaceutical compositions from the compounds
of this invention, inert, pharmaceutically acceptable carriers can
be either solid and liquid. Solid form preparations include
powders, tablets, dispersible granules, capsules, cachets, and
suppositories.
[0094] A solid carrier can be one or more substances, which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or table disintegrating agents; it can
also be an encapsulating material.
[0095] In powders, the carrier is a finely divided solid, which is
in a mixture with the finely divided compound of the invention, or
the active component. In tablets, the active component is mixed
with the carrier having the necessary binding properties in
suitable proportions and compacted in the shape and size
desired.
[0096] For preparing suppository compositions, a low-melting wax
such as a mixture of fatty acid glycerides and cocoa butter is
first melted and the active ingredient is dispersed therein by, for
example, stirring. The molten homogeneous mixture in then poured
into convenient sized moulds and allowed to cool and solidify.
[0097] Suitable carriers are magnesium carbonate, magnesium
stearate, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
[0098] The term composition is also intended to include the
formulation of the active component with encapsulating material as
a carrier providing a capsule in which the active component (with
or without other carriers) is surrounded by a carrier which is thus
in association with it. Similarly, cachets are included.
[0099] Tablets, powders, cachets, and capsules can be used as solid
dosage forms suitable for oral administration.
[0100] Liquid form compositions include solutions, suspensions, and
emulsions. For example, sterile water or water propylene glycol
solutions of the active compounds may be liquid preparations
suitable for parenteral administration. Liquid compositions can
also be formulated in solution in aqueous polyethylene glycol
solution.
[0101] Aqueous solutions for oral administration can be prepared by
dissolving the active component in water and adding suitable
colorants, flavoring agents, stabilizers, and thickening agents as
desired. Aqueous suspensions for oral use can be made by dispersing
the finely divided active component in water together with a
viscous material such as natural synthetic gums, resins, methyl
cellulose, sodium carboxymethyl cellulose, and other suspending
agents known to the pharmaceutical formulation art.
[0102] Depending on the mode of administration, the pharmaceutical
composition will preferably include from 0.05% to 99% w (percent by
weight), more preferably from 0.10 to 50% w, of the compound of the
invention, all percentages by weight being based on total
composition.
[0103] A therapeutically effective amount for the practice of the
present invention may be determined, by the use of known criteria
including the age, weight and response of the individual patient,
and interpreted within the context of the disease which is being
treated or which is being prevented, by one of ordinary skills in
the art.
[0104] Within the scope of the invention is the use of any compound
of Formula I as defined above for the manufacture of a
medicament.
[0105] Also within the scope of the invention is the use of any
compound of Formula I for the manufacture of a medicament for the
therapy of pain.
[0106] Additionally provided is the use of any compound according
to Formula I for the manufacture of a medicament for the therapy of
various pain conditions including, but not limited to: acute pain,
chronic pain, neuropathic pain, back pain, cancer pain, and
visceral pain.
[0107] A further aspect of the invention is a method for therapy of
a subject suffering from any of the conditions discussed above,
whereby an effective amount of a compound according to the Formula
I above, is administered to a patient in need of such therapy.
[0108] Additionally, there is provided a pharmaceutical composition
comprising a compound of Formula I or a pharmaceutically acceptable
salt thereof, in association with a pharmaceutically acceptable
carrier.
[0109] Particularly, there is provided a pharmaceutical composition
comprising a compound of Formula I or a pharmaceutically acceptable
salt thereof, in association with a pharmaceutically acceptable
carrier for therapy, more particularly for therapy of pain.
[0110] Further, there is provided a pharmaceutical composition
comprising a compound of Formula I or a pharmaceutically acceptable
salt thereof, in association with a pharmaceutically acceptable
carrier use in any of the conditions discussed above.
[0111] In a further aspect, the present invention provides a method
of preparing the compounds of the present invention.
[0112] In one embodiment, the invention provides a process for
preparing a compound of Formula I, comprising:
##STR00005##
reacting a compound of Formula II with a compound of formula
III,
##STR00006##
[0113] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and G
are as defined above.
[0114] Compounds of the present invention may also be prepared
according to the synthetic routes as depicted in Schemes 1, 2 and
3.
##STR00007##
##STR00008##
##STR00009##
Biological Evaluation
[0115] hCB.sub.1 and hCB.sub.2 receptor binding
[0116] Human CB.sub.1 receptor from Receptor Biology (hCB.sub.1) or
human CB.sub.2 receptor from BioSignal (hCB.sub.2) membranes are
thawed at 37.degree. C., passed 3 times through a 25-gauge
blunt-end needle, diluted in the cannabinoid binding buffer (50 mM
Tris, 2.5 mM EDTA, 5 mM MgCl.sub.2, and 0.5 mg/mL BSA fatty acid
free, pH 7.4) and aliquots containing the appropriate amount of
protein are distributed in 96-well plates. The IC.sub.50 of the
compounds of the invention at hCB.sub.1 and hCB.sub.2 are evaluated
from 10-point dose-response curves done with .sup.3H--CP55,940 at
20000 to 25000 dpm per well (0.17-0.21 nM) in a final volume of 300
.mu.l. The total and non-specific binding are determined in the
absence and presence of 0.2 .mu.M of HU210 respectively. The plates
are vortexed and incubated for 60 minutes at room temperature,
filtered through Unifilters GF/B (presoaked in 0.1%
polyethyleneimine) with the Tomtec or Packard harvester using 3 mL
of wash buffer (50 mM Tris, 5 mM MgCl.sub.2, 0.5 mg BSA pH 7.0).
The filters are dried for 1 hour at 55.degree. C. The radioactivity
(cpm) is counted in a TopCount (Packard) after adding 65 .mu.l/well
of MS-20 scintillation liquid.
hCB_and hCB.sub.2 GTP.gamma.S Binding
[0117] Human CB.sub.1 receptor from Receptor Biology (hCB.sub.1) or
human CB.sub.2 receptor membranes (BioSignal) are thawed at
37.degree. C., passed 3 times through a 25-gauge blunt-end needle
and diluted in the GTP.gamma.S binding buffer (50 mM Hepes, 20 mM
NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl.sub.2, pH 7.4, 0.1% BSA).
The EC.sub.50 and E.sub.max of the compounds of the invention are
evaluated from 10-point dose-response curves done in 300 .mu.l with
the appropriate amount of membrane protein and 100000-130000 dpm of
GTPg.sup.35S per well (0.11-10.14 nM). The basal and maximal
stimulated binding is determined in absence and presence of 1 .mu.M
(hCB.sub.2) or 10 .mu.M (hCB.sub.1) Win 55, 212-2 respectively. The
membranes are pre-incubated for 5 minutes with 56.25 .mu.M (hCB2)
or 112.5 .mu.M (hCB.sub.1) GDP prior to distribution in plates (15
.mu.M (hCB.sub.2) or 30 .mu.M (hCB.sub.1) GDP final). The plates
are vortexed and incubated for 60 minutes at room temperature,
filtered on Unifilters GF/B (presoaked in water) with the Tomtec or
Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM
MgCl.sub.2, 50 mM NaCl, pH 7.0). The filters are dried for 1 hour
at 55.degree. C. The radioactivity (cpm) is counted in a TopCount
(Packard) after adding 65 .mu.l/well of MS-20 scintillation liquid.
Antagonist reversal studies are done in the same way except that
(a) an agonist dose-response curve is done in the presence of a
constant concentration of antagonist, or (b) an antagonist
dose-response curve is done in the presence of a constant
concentration of agonist.
[0118] Based on the above assays, the dissociation constant (Ki)
for a particular compound of the invention towards a particular
receptor is determined using the following equation:
K.sub.i=IC.sub.50/(1+[rad]/Kd),
[0119] Wherein IC.sub.50 is the concentration of the compound of
the invention at which 50% displacement has been observed;
[0120] [rad] is a standard or reference radioactive ligand
concentration at that moment; and
[0121] Kd is the dissociation constant of the radioactive ligand
towards the particular receptor.
[0122] Using the above-mentioned assays, the Ki towards human
CB.sub.1 receptors for certain compounds of the invention are in
the range of between 3 nM and 195 nM. EC.sub.50 for these compounds
are in the range of between 2.3 nM and 300 nM. Emax for these
compounds are in the range of between 109% and 144%.
Assay Condition for Measuring Solubility
[0123] A 30 mM DMSO stock is prepared of the sample and then a 25
.mu.L aliquot is added to a 96-well plate and genevac at 40.degree.
C. for 4 hours. To the genevac compound add 250 .mu.L of sodium
phosphate buffer (pH 7.4) and then mix at 1200 rpm for 24 h using
an Eppendorf Thermomixer at 25.degree. C. After mixing solution is
transferred to a 96-well Whatman GF/B filter plate and then
filtered under vacuum. The supernatant is then injected onto the
LC/MS for analysis and quantitation is performed using a 1-point
calibration for the compound of interest.
Metabolic Stability Assays in Rat and Human Liver Microsomes
[0124] A solution of 500 .mu.l of 100 .mu.M compound in DMSO is
incubated with human or rat liver microsomes (843 .mu.l of
microsomes of 0.5618 mg/mL in 30 ml 0.1 M KH.sub.2PO.sub.4 buffer
pH7.4) at 37.degree. C. for 10 min in a 96-deep well plate. NADPH
(46 .mu.L) at a concentration of 8.33 mg/ml in 100 mM
KH.sub.2PO.sub.4 buffer pH 7.4 is added to start the reaction. The
reaction mixtures are transferred to a 384-well plate containing
acetonitrile to quench the reaction at time 0, 10, 20, 30 minutes.
The 384 well plate is centrifuged for 30 min at 9000 g, at
4.degree. C., from which samples are analyzed by LC/MS (model: XDB
Eclipse C18). Three references are analyzed by LC/MS as a positive
control. Data are processed following a standard procedure. The
metabolic stability of assayed compounds is expressed as
.mu.L/min/mg
[0125] In addition, metabolic stabilities (hClint and rClint) and
soluabilities (aqueous) of selected compounds of the invention are
determined using one or more assays described above. It is found
that the selected compounds have improved metabolic stabilities
and/or soluabilities in water. The metabolic stabilities and
soluabilities for these selected compounds are illustrated in Table
1 below.
TABLE-US-00001 TABLE 1 Metabolic stabilities (hClint and rClint)
and soluabilities: Solubility (M) hCLint (ul/min/mg) rCLint
(ul/min/mg) ##STR00010## 3.78945E-06 10.69 8.04 ##STR00011##
7.35806E-06 5.76 11.74 ##STR00012## 4.3035E-06 7.41 23.38
##STR00013## 0.00000593 7.77 10.24 ##STR00014## 0.000051855 5.27
<4.0 ##STR00015## 0.000353337 5.72 62.60 ##STR00016## 0.00000061
8.03 15.36 ##STR00017## 0.00000051 <4.000 6.87 ##STR00018##
0.00023307 <4.00 N/A ##STR00019## 0.00015418 11.51 N/A
EXAMPLES
[0126] The invention will further be described in more detail by
the following Examples which describe methods whereby compounds of
the present invention may be prepared, purified, analyzed and
biologically tested, and which are not to be construed as limiting
the invention.
Example 1
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-
-methylcyclopropanesulfonamide
##STR00020##
[0127] Step A:
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]--
N-methylcyclopropanesulfonamide
##STR00021##
[0129]
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimi-
dazol-5-amine (for preparation, see following steps B to F) (50 mg,
0.166 mmol) and a catalytic amount of DMAP were dissolved in 5 mL
of DCM. Cyclopropanesulfonyl chloride (30 mg, 0.216 mmol) was added
dropwise and the solution was stirred at rt overnight. The solution
was washed with saturated aqueous NaHCO.sub.3 solution, brine and
dried over anhydrous MgSO.sub.4. The product was purified by
reversed-phase HPLC using 10-70% CH.sub.3CN/H.sub.2O and
lyophilized affording the title compound as the corresponding TFA
salt. Yield: 56 mg (65%). .sup.1H NMR (400 MHz, METHANOL-D.sub.4)
.delta. 0.90-0.94 (m, 2H), 0.97-1.02 (m, 2H), 1.53-1.59 (m, 2H),
1.59-1.65 (m, 2H), 1.69 (s, 9H), 2.36-2.42 (m, 1H), 2.60-2.65 (m,
1H), 3.36 (m, 2H), 3.43 (s, 3H), 3.94 (d, J=3.58 Hz, 1H), 3.96 (d,
J=3.07 Hz, 1H), 4.55 (d, J=7.68 Hz, 2H), 7.74 (dd, J=8.96, 2.05 Hz,
1H), 7.81 (d, J=1.54 Hz, 1H), 7.98 (d, J=8.96 Hz, 1H); MS (ESI)
(M+H).sup.+ 406.0.
Step B: Methyl (4-fluoro-3-nitrophenyl)carbamate
##STR00022##
[0131] Methyl chloroformate (13.2 mL, 170.2 mmol) was added
dropwise to a cold (0.degree. C.) dichloromethane (200 mL) solution
of 4-fluoro-3-nitro aniline (24.15 g, 154.7 mmol) and DIPEA (35 mL,
201 mmol). The reaction mixture was stirred at rt overnight. The
solution was then diluted with 200 mL of dichloromethane and washed
with 2M HCl, brine and dried over anhydrous MgSO.sub.4. The solvent
was concentrated and the product was directly used for the next
step without further purification. Yield: 35.5 g (99%). .sup.1H NMR
(400 MHz, CHLOROFORM-D) .delta. 3.81 (s, 3H), 7.02 (s, 1H), 7.23
(m, 1H), 7.72 (d, J=8.59 Hz, 1H), 8.17 (dd, J=6.35, 2.64 Hz,
1H).
Step C: Methyl
{3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate
##STR00023##
[0133] Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol)
and 4-aminomethyl tetrahydropyran (1.28 g, 11.2 mmol) were stirred
in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75.degree.
C. for 48 h. The solvent was evaporated. The residue was dissolved
in EtOAc and washed with aqueous 5% KHSO.sub.4, saturated aqueous
NaHCO.sub.3 solution, brine and dried over anhydrous MgSO.sub.4.
The crude product was purified by silica gel flash chromatography
using 1:1/hexanes:EtOAc as eluent. Yield: 2.53 g (88%). .sup.1H NMR
(400 MHz, CHLOROFORM-D) .delta. 1.42 (m, 2H), 1.73 (d, J=1.76 Hz,
1H), 1.76 (d, J=1.95 Hz, 1H), 1.88-2.01 (m, 1H), 3.22 (dd, J=6.74,
5.57 Hz, 2H), 3.42 (m, 2H), 3.78 (s, 3H), 4.01 (d, J=4.30 Hz, 1H),
4.04 (d, J=3.51 Hz, 1H), 6.48 (br.s, 1H), 6.85 (d, J=9.37 Hz, 1H),
7.65 (br.s, 1H), 8.03-8.09 (m, 2H).
Step D: Methyl
{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate
##STR00024##
[0135] Methyl
{3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate
(2.53 g, 8.18 mmol) was dissolved in 50 mL of EtOAc containing a
catalytic amount of 10% Pd/C. The solution was shaken under H.sub.2
atmosphere (40 psi) using a Parr hydrogenation apparatus overnight
at rt. The solution was filtered through Celite and the solvent was
evaporated. Yield: 2.29 g (99%). .sup.1H NMR (400 MHz,
CHLOROFORM-D) .delta. 1.40 (m, 2H), 1.70-1.74 (m, 1H), 1.74-1.77
(m, 1H), 1.81-1.92 (m, 1H), 2.99 (d, J=6.64 Hz, 2H), 3.34 (br.s,
2H), 3.41 (m, 2H), 3.74 (s, 3H), 3.99 (d, J=3.51 Hz, 1H), 4.02 (d,
J=3.51 Hz, 1H), 6.38 (br.s, 1H), 6.55-6.60 (m, 1H), 6.62-6.68 (m,
1H), 6.95 (br.s, 1H).
Step E: Methyl
[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]car-
bamate
##STR00025##
[0137] Methyl
{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate
(2.29 g, 8.20 mmol) and DMAP (0.20 g, 1.64 mmol) were dissolved in
75 mL of DCM. Trimethylacetyl chloride (1.10 mL, 9.02 mmol) was
added dropwise and the solution was stirred at rt for 2 h. The
solution was washed with aqueous NaHCO.sub.3 solution, brine and
dried over anhydrous MgSO.sub.4. The residue was dissolved in 25 mL
of AcOH and was heated at 125.degree. C. for 1 h using a Personal
Chemistry microwave apparatus. The solvent was evaporated. The
residue was dissolved in EtOAc and washed with aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The crude
product was purified by silica gel flash chromatography using
4:3/hexanes:acetone as eluent. Yield: 1.81 g (64%). .sup.1H NMR
(400 MHz, CHLOROFORM-D) .delta. 1.48-1.54 (m, 4H), 1.56 (s, 9H),
2.23-2.35 (m, 1H), 3.27-3.35 (m, 2H), 3.78 (s, 3H), 3.96 (t, J=2.93
Hz, 1H), 3.99 (t, J=3.03 Hz, 1H), 4.18 (d, J=7.42 Hz, 2H), 6.63
(br.s, 1H), 7.24-7.28 (m, 1H), 7.41 (br.s, 1H), 7.61 (d, J=1.95 Hz,
1H).
Step F:
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzim-
idazol-5-amine
##STR00026##
[0139] Methyl
[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]car-
bamate (1.80 g, 5.21 mmol) was dissolved in 75 mL of THF at
0.degree. C. 1M HCl/ether (7.3 mL, 7.29 mmol) was added dropwise
and the solution was stirred at 0.degree. C. for 15 min.
LiAlH.sub.4 (988 mg, 26.1 mmol) was added slowly and the solution
was stirred at rt overnight. The reaction was quenched at 0.degree.
C. by the addition of MeOH (5 mL) followed by water (10 mL) and the
solution was left to stir at rt for 30 min. Anhydrous
Na.sub.2SO.sub.4 (10 g) was added and the solution was stirred at
rt for another 30 min. The solution was filtered and the solvent
was evaporated. The residue was dissolved in EtOAc and washed with
aqueous NaHCO.sub.3 solution, brine and dried over anhydrous
MgSO.sub.4. The solvent was evaporated. Yield: 1.54 g (98%).
.sup.1H NMR (400 MHz, CHLOROFORM-D) .delta. 1.49-1.53 (m, 4H),
1.53-1.57 (m, 9H), 2.22-2.32 (m, 1H), 2.87 (s, 3H), 3.26-3.35 (m,
2H), 3.95 (t, J=3.03 Hz, 1H), 3.97-4.00 (m, 1H), 4.13 (d, J=7.42
Hz, 2H), 6.61 (dd, J=8.59, 2.15 Hz, 1H), 6.99 (d, J=1.95 Hz, 1H),
7.11 (d, J=8.59 Hz, 1H).
Example 2
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-
-methylpropane-1-sulfonamide
##STR00027##
[0141]
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimi-
dazol-5-amine (for preparation, see Steps B to F of Example 1) (50
mg, 0.166 mmol) and a catalytic amount of DMAP were dissolved in 5
mL of DCM. 1-Propanesulfonyl chloride (0.024 mL, 0.216 mmol) was
added dropwise and the solution was stirred at rt for 3 h. The
solution was washed with saturated aqueous NaHCO.sub.3 solution,
brine and dried over anhydrous MgSO.sub.4. The product was purified
by reversed-phase HPLC using 10-70% CH.sub.3CN/H.sub.2O and
lyophilized affording the title compound as the corresponding TFA
salt. Yield: 60 mg (69%); .sup.1H NMR (400 MHz, METHANOL-D.sub.4)
.delta. 1.02 (t, J=7.42 Hz, 3H), 1.54-1.59 (m, 2H), 1.60-1.66 (m,
2H), 1.69 (s, 9H), 1.76-1.83 (m, 2H), 2.36-2.42 (m, 1H), 3.09-3.13
(m, 2H), 3.36 (m, 2H), 3.40 (s, 3H), 3.94 (d, J=3.58 Hz, 1H), 3.95
(d, J=3.58 Hz, 1H), 4.55 (d, J=7.68 Hz, 2H), 7.70 (dd, J=8.96, 2.05
Hz, 1H), 7.81 (d, J=1.79 Hz, 1H), 7.98 (d, J=8.96 Hz, 1H); MS (ESI)
(M+H).sup.+ 408.0.
Example 3
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-
-methylbutane-1-sulfonamide
##STR00028##
[0143]
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimi-
dazol-5-amine
[0144] (for preparation see Steps B, C, D, E and F of Example 1)
(38 mg, 0.126 mmol) and 1-butanesulfonyl chloride (0.025 mL, 0.189
mmol) were stirred in 3 mL of DCM containing a catalytic amount of
DMAP at rt overnight. The solvent was evaporated and the product
was purified by reversed-phase HPLC using 10-60%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 39 mg (58%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4): .delta. 0.88-0.94 (m, 3H), 1.43 (m, 2H),
1.53-1.59 (m, 2H) 1.59-1.66 (m, 2H), 1.69 (s, 9H), 1.71-1.77 (m,
2H), 2.35-2.42 (m, 1H), 3.10-3.16 (m, 2H), 3.35 (m, 2H), 3.40 (s,
3H), 3.93 (d, J=3.12 Hz, 1H), 3.96 (d, J=3.71 Hz, 1H), 4.54 (d,
J=7.42 Hz, 2H), 7.69 (dd, J=8.98, 2.15 Hz, 1H), 7.81 (d, J=1.56 Hz,
1H), 7.97 (d, J=8.98 Hz, 1H); MS (ESI) (M+H).sup.+ 422.2; Anal.
Calcd for C.sub.22H.sub.35N.sub.3O.sub.3S+1.3 TFA+1.2H.sub.2O: C,
49.96; H, 6.60; N, 7.10.
[0145] Found: C, 49.98; H, 6.67; N, 6.83.
Example 4
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-
-methylbutane-1-sulfonamide
##STR00029##
[0146] Step A:
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}--
N-methylbutane-1-sulfonamide
##STR00030##
[0148]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-N-methyl-1H-benzimi-
dazol-5-amine (for preparation see following Steps B, C, D, E, F
and G) (46 mg, 0.137 mmol) and 1-butanesulfonyl chloride (0.063 mL,
0.411 mmol) were stirred in 3 mL of DCM containing a catalytic
amount of DMAP at rt for 6 h. The solvent was evaporated and the
product was purified by reversed-phase HPLC using 10-75%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 48 mg (62%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4): .delta. 0.92 (t, J=7.32 Hz, 3H), 1.43 (m,
2H), 1.52-1.63 (m, 2H), 1.69 (s, 9H), 1.70-1.76 (m, 4H), 1.76-1.84
(m, 2H), 2.02-2.12 (m, 2H), 2.22-2.31 (m, 1H), 3.10-3.17 (m, 2H),
3.41 (s, 3H), 4.56 (d, J=7.62 Hz, 2H), 7.69 (dd, J=8.98, 2.15 Hz,
1H), 7.82 (d, J=1.76 Hz, 1H), 7.96 (d, J=9.18 Hz, 1H); MS (ESI)
(M+H).sup.+ 456.
Step B: tert-Butyl [(4,4-difluorocyclohexyl)methyl]carbamate
##STR00031##
[0150] 4-N-Boc-aminomethyl cyclohexanone (1.00 g, 4.4 mmol) was
dissolved in 30 mL of DCM at 0.degree. C. DAST (1.45 mL, 11.0 mmol)
was added dropwise and the solution was stirred at rt overnight.
The solution was washed with aqueous 5% KHSO.sub.4 solution,
saturated aqueous NaHCO.sub.3 solution, brine and dried over
anhydrous MgSO.sub.4. The crude product was purified by silica gel
flash chromatography using 3:1/hexanes EtOAc as eluent. Yield: 508
mg (46%). .sup.1H NMR (400 MHz, CHLOROFORM-D): .delta. 1.19-1.36
(m, 2H), 1.44 (s, 9H), 1.51-1.56 (m, 1H), 1.59-1.75 (m, 2H),
1.75-1.84 (m, 2H), 2.01-2.16 (m, 2H), 3.03 (t, J=6.54 Hz, 2H), 4.62
(br.s, 1H).
Step C: [(4,4-Difluorocyclohexyl)methyl]amine hydrochloride
##STR00032##
[0151] tert-Butyl [(4,4-difluorocyclohexyl)methyl]carbamate (505
mg, 2.03 mmol) was stirred in 5 mL of 1M HCl/AcOH at rt for 2 h.
The solvent was evaporated. The residue was washed with ether,
filtered and dried. Yield: 330 mg (88%). .sup.1H NMR (400 MHz,
METHANOL-D.sub.4): .delta. 1.28-1.40 (m, 2H), 1.71-1.82 (m, 2H),
1.84 (d, J=3.12 Hz, 2H), 1.86-1.89 (m, 1H), 2.03-2.15 (m, 2H), 2.85
(d, J=7.03 Hz, 2H).
Step D: Methyl
(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)carbamate
##STR00033##
[0153] Following the same procedure as in Step C of Example 1 using
[(4,4-difluorocyclohexyl)methyl]amine hydrochloride (210 mg, 1.12
mmol), methyl (4-fluoro-3-nitrophenyl)carbamate (200 mg, 0.934
mmol) and TEA (0.390 mL, 2.80 mmol) in 10 mL of EtOH. The crude
product was purified by silica gel flash chromatography using 5%
ether/DCM as eluent. Yield: 200 mg (62%). .sup.1H NMR (400 MHz,
CHLOROFORM-D): .delta. 1.34-1.47 (m, 2H), 1.65-1.75 (m, 2H),
1.78-1.85 (m, 1H), 1.90-1.93 (m, 1H), 1.94-1.97 (m, 1H), 2.10-2.21
(m, 2H), 3.23 (dd, J=6.64, 5.66 Hz, 2H), 3.78 (s, 3H), 6.48 (br.s,
1H), 6.83 (d, J=9.18 Hz, 1H), 7.66 (br.s, 1H), 8.05 (br.s, 1H),
8.07 (d, J=2.54 Hz, 1H).
Step E: Methyl
(3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)carbamate
##STR00034##
[0155] Following the same procedure as in Step D of Example 1 using
methyl
(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)carbamate
(200 mg, 0.583 mmol) and a catalytic amount of 10% Pd/C in 20 mL of
EtOAc. Yield: 185 mg (99%). MS (ESI)(M+H).sup.+ 314.29.
Step F: Methyl
{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}car-
bamate
##STR00035##
[0157] Methyl
(3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)carbamate
(185 mg, 0.590 mmol) and DMAP (15 mg, 0.118 mmol) were dissolved in
10 mL of DCM. Trimethylacetyl chloride (0.080 mL, 0.649 mmol) was
added dropwise and the solution was stirred at rt for 2 h. The
solution was washed with aqueous NaHCO.sub.3 solution, brine and
dried over anhydrous MgSO.sub.4. The solvent was concentrated. The
residue was dissolved in 4 mL of DCE and P.sub.2O.sub.5 (catalytic)
was added and the solution was heated at 125.degree. C. for 1 h
using a Personal Chemistry microwave apparatus.
[0158] The solution was washed with aqueous NaHCO.sub.3 solution,
brine and dried over anhydrous MgSO.sub.4. The crude product was
purified by silica gel flash chromatography using 50 to 75%
EtOAc/hexanes. Yield: 122 mg (54%); .sup.1H NMR (400 MHz,
CHLOROFORM-D): .delta. 1.43-1.52 (m, 2H), 1.55 (s, 9H), 1.57-1.66
(m, 2H), 1.67-1.74 (m, 2H), 2.08-2.18 (m, 3H), 3.79 (s, 3H), 4.19
(d, J=7.42 Hz, 2H), 6.63 (br.s, 1H), 7.23 (d, J=8.79 Hz, 1H),
7.37-7.46 (m, 1H), 7.62 (d, J=1.76 Hz, 1H).
Step G:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-N-methyl-1H-benzim-
idazol-5-amine
##STR00036##
[0160] Methyl
{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}car-
bamate (115 mg, 0.303 mmol) was dissolved in 10 mL of THF at
0.degree. C. 1M HCl/ether (0.425 mL, 0.424 mmol) was added and the
solution was stirred at 0.degree. C. for 15 min. LiAlH.sub.4 (57
mg, 1.52 mmol) was added slowly and the solution was stirred at rt
overnight. The reaction was quenched at 0.degree. C. by the
addition of MeOH (1 mL) and water (2 mL). Anhydrous
Na.sub.2SO.sub.4 (5.0 g) was added and the solution was stirred at
rt for 30 min. The solution was filtered and the solvent was
evaporated. The residue was dissolved in EtOAc and washed with
saturated aqueous NaHCO.sub.3 solution, brine and dried over
anhydrous MgSO.sub.4. Yield: 95 mg (93%). .sup.1H NMR (400 MHz,
CHLOROFORM-D): .delta. 1.41-1.51 (m, 2H), 1.54 (s, 9H), 1.57-1.67
(m, 2H), 1.68-1.76 (m, 3H), 2.07-2.17 (m, 3H), 2.87 (s, 3H), 4.15
(d, J=7.42 Hz, 2H), 6.61 (dd, J=8.59, 2.34 Hz, 1H), 7.01 (d, J=1.95
Hz, 1H), 7.09 (d, J=8.59 Hz, 1H).
Example 5
N-Methyl-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benz-
imidazol-5-yl]propane-1-sulfonamide
##STR00037##
[0161] Step A:
N-Methyl-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-ben-
zimidazol-5-yl]propane-1-sulfonamide
##STR00038##
[0163] Propane-1-sulfonyl chloride (27 uL, 34 mg, 0.24 mmol) was
added to a solution of
N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzim-
idazol-5-amine (63 mg, 0.20 mmol) (see following steps B, C, D, E,
F and G for preparation), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP
(5 mg, 0.04 mmol) in DCM (6 mL) at 0.degree. C. The reaction
mixture was stirred overnight at room temperature, diluted with DCM
(50 mL), washed with saturated NaHCO.sub.3 (2.times.10 mL) and
dried over Na.sub.2SO.sub.4. The crude product was purified by MPLC
using Hex/EtOAc (1:1) on silica gel to give 40 mg (47%) of a white
solid as the title compound. .sup.1HNMR (400 MHz,
METHANOL-D.sub.4): .delta. 1.00 (t, J=7.42 Hz, 3H), 1.38-1.53 (m,
4H), 1.70-1.88 (m, 2H), 2.15-2.30 (m, 1H), 3.01-3.11 (m, 2H),
3.28-3.33 (m, 2H), 3.35 (s, 3H), 3.88-3.91 (m, 2H), 4.30 (d, J=7.62
Hz, 2H), 7.55 (dd, J=8.79, 1.76 Hz, 1H), 7.75 (d, J=8.98 Hz, 1H),
7.82 (d, J=1.56 Hz, 1H). MS (ESI) (M+H).sup.+=420.0. Anal. Calcd
for C.sub.18H.sub.24F.sub.3N.sub.3O.sub.3S+0.20H.sub.2O+0.30
CH.sub.3OH(432.68): C, 50.80; H, 5.96; N, 9.71; Found: C, 50.79; H,
5.91; N, 9.69.
Step B. N-(4-fluoro-3-nitrophenyl)acetamide
##STR00039##
[0165] 4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in
portions to acetic anhydride (150 mL) at room temperature. The
reaction mixture was stirred at room temperature for 2 h. The white
solid was collected and dried in vacuo to give the title compound
(42.0 g, 70%). .sup.1H NMR (400 MHz, CHLOROFORM-D): .delta. 2.23
(s, 3H), 7.26 (m, 1H), 7.50 (s broad, 1H), 7.87 (m, 1H), 8.23 (dd,
J=6.44, 2.73 Hz, 1H).
Step C: N-(4-fluoro-3-nitrophenyl)-N-methylacetamide
##STR00040##
[0167] Sodium hydride (4.22 g, 60%, 106 mmol) was added portionwise
to a solution of N-(4-fluoro-3-nitrophenyl)acetamide (13.9 g, 70
mmol) in THF (200 mL) at 0.degree. C. Stirring for 20 min,
iodomethane (18.5 g, 130 mmol) was added. The reaction mixture was
stirred at room temperature for 2 h, quenched with saturated
NaHCO.sub.3 (30 mL) and extracted with EtOAc (3.times.100 mL). The
combined organic phases were washed with saturated NaCl (2.times.50
mL). After filtration and concentration, 13.1 g (88%) of the title
compound was obtained as a yellow solid. .sup.1H NMR (400 MHz,
CHLOROFORM-D): .delta. 1.92 (s, 3H), 3.30 (s, 3H), 7.38 (s, 1H),
7.52 (s, 1H), 7.95 (s, 1H).
Step D.
N-methyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}acetamide
##STR00041##
[0169] 4-Aminomethyltetrahydropyran (10.0 g, 86.5 mmol) was added
to a mixture of N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (15.6
g, 73.3 mmol) and TEA (15.3 mL, 11.1 g, 110 mmol) in EtOH (300 mL)
at room temperature. The reaction mixture was heated for 6 h at
reflux. Upon evaporation of ethanol, the residue was dissolved in
EtOAc (400 mL), washed with H.sub.2O (3.times.50 mL), saturated
NaCl (3.times.50 mL), and dried over Na.sub.2SO.sub.4. After
filtration and concentration, 21.7 g (96%) of the title compound
was obtained as an orange-red solid. .sup.1H NMR (400 MHz,
CHLOROFORM-D): .delta. 1.38-1.52 (m, 2H), 1.72-1.81 (m, 2H), 1.90
(s, 3H), 1.93-2.02 (m, 1H), 3.23 (s, 3H), 3.23-3.27 (m, 2H),
3.36-3.49 (m, 2H), 4.01-4.07 (m, 2H), 6.91 (d, J=9.18 Hz, 1H), 7.29
(dd, J=9.08, 2.64 Hz, 1H), 8.05 (d, J=2.34 Hz, 1H), 8.22 (t, J=5.37
Hz, 1H). MS (ESI) (M+H).sup.+=309.12.
Step E.
N-{3-Amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-meth-
ylacetamide
##STR00042##
[0171]
N-Methyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}acetamide (21.7 g, 70.5 mmol) was hydrogenated in ethyl acetate
(500 mL) catalyzed by 10% Pd/C (1.0 g) at 30-40 psi H.sub.2 in Parr
shaker for 18 h at room temperature. After filtration through
celite and concentration, 19.6 g (100%) of a purple solid was
obtained. .sup.1H NMR (400 MHz, CHLOROFORM-D): .delta. 1.35-1.50
(m, 2H), 1.67 (s, 1H), 1.73-1.81 (m, 2H), 1.88 (s, 3H), 1.88-1.99
(m, 1H), 3.04 (d, J=6.64 Hz, 2H), 3.20 (s, 3H), 3.33-3.48 (m, 4H),
3.97-4.08 (m, 2H), 6.54 (d, J=1.76 Hz, 1H), 6.60-6.63 (m, 2H); MS
(ESI) (M+H).sup.+: 278.7
Step F.
N-Methyl-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-
-1H-benzimidazol-5-yl]acetamide
##STR00043##
[0173] A solution of
N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylaceta-
mide hydrochloride (2.77 g, 10 mmol) in trifluoroacetic acid (60
mL) was heated to reflux for 18 h. After evaporation of the
solvent, the residue was dissolved in EtOAc (200 mL), washed with
2N NaOH (2.times.10 mL) and dried over Na.sub.2SO.sub.4. The crude
product was purified by MPLC using EtOAc on silica gel to give 3.18
g (90%) of a white solid as the title compound. MS (ESI)
(M+H).sup.+=356.02.
Step G.
N-Methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-
-benzimidazol-5-amine
##STR00044##
[0175]
N-Methyl-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)--
1H-benzimidazol-5-yl]acetamide (3.18 g, 8.95 mmol) was dissolved in
hydrochloric acid
[0176] (37%, 60 mL) and then heated overnight at 95.degree. C.
After concentration, the residue was treated with 20 mL of 2N NaOH,
extracted with EtOAc (4.times.50 mL). The combined organic phases
were washed with brine (20 mL) and dried over Na.sub.2SO.sub.4.
After evaporation, 2.80 g (100%) of a purple white solid was
obtained as the title product, which was used directly for Step H.
MS (ESI) (M+H).sup.+=314.20.
Example 6
N-Methyl-N-[1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benz-
imidazol-5-yl]cyclopropanesulfonamide
##STR00045##
[0178] Following the procedure in Example 5, using
cyclopropanesulfonyl chloride (34 mg, 0.24 mmol),
N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzim-
idazol-5-amine (63 mg, 0.20 mmol) (for preparation, see the step G
in example 1), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04
mmol) in DCM (6 mL) at 0.degree. C. The crude product was purified
by MPLC using Hex/EtOAc (1:1) on silica gel to give 81 mg (97%) of
a white solid as the title compound. .sup.1HNMR (400 MHz,
METHANOL-D.sub.4): .delta. 0.85-0.92 (m, 2H), 0.93-1.01 (m, 2H),
1.37-1.52 (m, 4H), 2.18-2.31 (m, 1H), 2.55-2.65 (m, 1H), 3.30-3.36
(m, 2H), 3.38 (s, 3H), 3.86-3.95 (m, 2H), 4.32 (d, J=7.62 Hz, 2H),
7.58 (dd, J=8.89, 2.05 Hz, 1H), 7.76 (d, J=8.79 Hz, 1H) 7.86 (d,
J=1.95 Hz, 1H). MS (ESI) (M+H).sup.+=418.0. Anal. Calcd for
C.sub.18H.sub.22F.sub.3N.sub.3O.sub.3S+0.10H.sub.2O+0.20 CH.sub.3OH
(425.66): C, 51.36; H, 5.45; N, 9.87; Found: C, 51.39; H, 5.49; N,
9.92.
Example 7
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-
-methylpentane-1-sulfonamide
##STR00046##
[0180]
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimi-
dazol-5-amine (65 mg, 0.216 mmol) and a catalytic amount of DMAP
were dissolved in 3 mL of DCE. n-Pentylsulfonyl chloride (44 mg,
0.259 mmol) was added and the solution was stirred at rt for 4 h.
The solution was washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The solvent
was evaporated and the product was purified by reversed-phase HPLC
using 10-70% CH.sub.3CN/H.sub.2O and lyophilized affording the
title compound as the corresponding TFA salt. Yield: 89 mg (75%).
.sup.1H NMR (400 MHz, METHANOL-D.sub.4) .delta. 0.89 (t, J=7.13 Hz,
3H), 1.26-1.34 (m, 2H), 1.34-1.43 (m, 2H), 1.52-1.58 (m, 2H),
1.58-1.66 (m, 2H), 1.69 (s, 9H), 1.71-1.80 (m, 2H), 2.34-2.43 (m,
1H), 3.09-3.16 (m, 2H), 3.36 (td, J=11.47, 2.64 Hz, 2H), 3.40 (s,
3H) 3.93 (d, J=3.12 Hz, 1H), 3.95-3.97 (m, 1H), 4.55 (d, J=7.62 Hz,
2H), 7.69 (dd, J=9.08, 2.05 Hz, 1H), 7.81 (d, J=1.56 Hz, 1H), 7.97
(d, J=8.59 Hz, 1H); MS (ESI) (M+H).sup.+ 436.0; Anal. Calcd(%) for
C.sub.23H.sub.37N.sub.3O.sub.3S+1.1 TFA+0.9H.sub.2O; C, 52.43; H,
6.97; N, 7.28. Found: C, 52.39; H, 6.96; N, 7.43.
Example 8
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-
-methylethanesulfonamide
##STR00047##
[0182]
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimi-
dazol-5-amine (50 mg, 0.166 mmol) and a catalytic amount of DMAP
were dissolved in 3 mL of DCE. Ethanesulfonyl chloride (0.020 mL,
0.215 mmol) was added and the solution was stirred at rt for 12 h.
The solution was washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The solvent
was evaporated and the product was purified by reversed-phase HPLC
using 10-70% CH.sub.3CN/H.sub.2O and lyophilized affording the
title compound as the corresponding TFA salt. Yield: 70 mg (83%).
.sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 1.31 (t, J=7.30 Hz, 3H),
1.53-1.58 (m, 2H), 1.58-1.65 (m, 2H), 1.69 (s, 9H), 2.35-2.42 (m,
1H), 3.16 (m, 2H), 3.35 (m, 2H), 3.41 (s, 3H), 3.94 (d, J=3.84 Hz,
1H), 3.95 (d, J=3.84 Hz, 1H), 4.54 (d, J=7.68 Hz, 2H), 7.69 (dd,
J=9.09, 1.92 Hz, 1H), 7.81 (d, J=1.79 Hz, 1H), 7.97 (d, J=8.96 Hz,
1H); MS (ESI) (M+H).sup.+ 394.0; Anal. Calcd(%) for
C.sub.20H.sub.31N.sub.3O.sub.3S+1.4 TFA: C, 49.50; H, 5.90; N,
7.60. Found: C, 49.51; H, 6.00; N, 7.24.
Example 9
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N-
,2-dimethylpropane-2-sulfonamide
##STR00048##
[0184]
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimi-
dazol-5-amine (50 mg, 0.166 mmol) and DMAP (20 mg, 0.166 mmol) were
dissolved in 3 mL of DCM. t-Butylsulfinyl chloride (0.027 mL, 0.215
mmol) was added and the solution was stirred at rt for 2 h. The
solution was washed with saturated aqueous NaHCO.sub.3 solution,
brine and dried over anhydrous MgSO.sub.4. 3-Chloroperoxybenzoic
acid (37 mg, 0.166 mmol) was added and the solution was stirred at
rt for 1 h. The solution washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The product
was purified by reversed-phase HPLC using 10-70%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 34 mg (38%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4) .delta. 1.37 (s, 9H), 1.52-1.58 (m, 2H),
1.59-1.66 (m, 2H), 1.69 (s, 9H), 2.34-2.44 (m, 1H), 3.36 (m, 2H),
3.48 (s, 3H), 3.93 (d, J=3.32 Hz, 1H), 3.95-3.97 (m, 1H), 4.54 (d,
J=7.62 Hz, 2H), 7.78 (dd, J=9.08, 2.05 Hz, 1H), 7.92 (d, J=2.15 Hz,
1H), 7.96 (d, J=9.18 Hz, 1H); MS (ESI) (M+H).sup.+ 422.0.
Example 10
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-
-methylpropane-1-sulfonamide
##STR00049##
[0186]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-N-methyl-1H-benzimi-
dazol-5-amine (45 mg, 0.134 mmol) and a catalytic amount of DMAP
were dissolved in 3 mL of DCE. Propanesulfonyl chloride (0.020 mL,
0.174 mmol) was added and the solution was stirred at rt for 4 h.
The solution was washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The solvent
was evaporated and the product was purified by reversed-phase HPLC
using 10-70% CH.sub.3CN/H.sub.2O and lyophilized affording the
title compound as the corresponding TFA salt. Yield: 55 mg (74%).
.sup.1H NMR (400 MHz, METHANOL-D.sub.4) .delta. 1.00 (t, J=7.42 Hz,
3H), 1.51-1.60 (m, 2H), 1.66 (s, 9H), 1.68-1.73 (m, 2H), 1.73-1.81
(m, 4H), 2.00-2.11 (m, 2H), 2.18-2.29 (m, 1H) 3.06-3.12 (m, 2H),
3.38 (s, 3H), 4.54 (d, J=7.62 Hz, 2H), 7.67 (dd, J=9.08, 2.05 Hz,
1H), 7.79 (d, J=1.56 Hz, 1H), 7.94 (d, J=8.98 Hz, 1H); MS (ESI)
(M+H).sup.+ 442.0; Anal. Calcd(%) for
C.sub.22H.sub.33N.sub.3O.sub.2SF.sub.2+1.0 TFA+1.6H.sub.2O: C,
49.32; H, 6.42; N, 7.10. Found: C, 49.39; H, 6.66; N, 6.71.
Example 11
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-
-methylethanesulfonamide
##STR00050##
[0188]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-N-methyl-1H-benzimi-
dazol-5-amine (49 mg, 0.146 mmol) and a catalytic amount of DMAP
were dissolved in 3 mL of DCM. Ethanesulfonyl chloride (0.018 mL,
0.190 mmol) was added and the solution was stirred at rt for 12 h.
The solution was washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The solvent
was evaporated and the product was purified by reversed-phase HPLC
using 10-70% CH.sub.3CN/H.sub.2O and lyophilized affording the
title compound as the corresponding TFA salt. Yield: 58 mg (73%).
.sup.1H NMR (600 MHz, MeOD) .delta. 1.31 (t, J=7.42 Hz, 3H),
1.34-1.41 (m, 2H), 1.54-1.62 (m, 2H), 1.69 (s, 9H), 1.72-1.80 (m,
2H), 2.03-2.11 (m, 2H), 2.23-2.30 (m, 1H), 3.17 (q, J=7.25 Hz, 2H),
3.41 (s, 3H), 4.56 (d, J=7.68 Hz, 2H), 7.70 (dd, J=8.96, 2.05 Hz,
1H), 7.82 (d, J=2.05 Hz, 1H), 7.96 (d, J=8.96 Hz, 1H); MS (ESI)
(M+H).sup.+ 428.0.
Example 12
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}pr-
opane-1-sulfonamide
##STR00051##
[0189] Step A:
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}p-
ropane-1-sulfonamide
##STR00052##
[0191]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-a-
mine (for preparation, see the following steps B to E) (45 mg,
0.140 mmol) and a catalytic amount of DMAP were dissolved in 3 mL
of DCM. Propanesulfonyl chloride (0.020 mL, 0.182 mmol) was added
and the solution was stirred at rt for 4 h. The solution was washed
with saturated aqueous NaHCO.sub.3 solution, brine and dried over
anhydrous MgSO.sub.4. The solvent was evaporated and the product
was purified by reversed-phase HPLC using 10-70%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 39 mg (51%). .sup.1H NMR (600
MHz, CD.sub.3OD) .delta. 1.00 (t, J=7.55 Hz, 3H), 1.53-1.61 (m,
2H), 1.67 (s, 9H), 1.70-1.77 (m, 3H), 1.77-1.85 (m, 3H), 2.02-2.11
(m, 2H), 2.22-2.29 (m, 1H), 3.08-3.13 (m, 2H), 4.53 (d, J=7.42 Hz,
2H), 7.41 (dd, J=9.09, 1.92 Hz, 1H), 7.75 (d, J=1.79 Hz, 1H), 7.89
(d, J=9.22 Hz, 1H); MS (ESI) (M+H).sup.+ 428.0.
Step B:
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)acetami-
de
##STR00053##
[0193] N-(4-Fluoro-3-nitrophenyl)acetamide (1.15 g, 5.84 mmol) and
[(4,4-difluorocyclohexyl)methyl]amine hydrochloride (1.30 g, 7.59
mmol) were stirred in 30 mL of EtOH containing TEA (2.40 mL, 17.5
mmol) at 80.degree. C. for 48 h. The solvent was evaporated. The
residue was dissolved in EtOAc and washed with aqueous 5%
KHSO.sub.4 solution, saturated aqueous NaHCO.sub.3 solution,
saturated aqueous NaCl solution and dried over anhydrous
Na.sub.2SO.sub.4. The product was crystallized from EtOAc. The left
over mother liquor was purified by silica gel flash chromatography
using 2:1/hexanes:acetone as eluent. Yield: 1.50 g (78%). .sup.1H
NMR (400 MHz, CHLOROFORM-D) .delta. 1.33-1.47 (m, 2H), 1.66-1.77
(m, 2H), 1.77-1.86 (m, 1H), 1.89-1.93 (m, 1H), 1.93-1.97 (m, 1H),
2.10-2.17 (m, 2H), 2.18 (s, 3H), 3.23 (dd, J=6.74, 5.76 Hz, 2H),
6.83 (d, J=9.37 Hz, 1H), 7.15 (s, 1H), 7.80 (dd, J=9.18, 2.54 Hz,
1H), 8.09 (d, J=2.54 Hz, 2H).
Step C:
N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetami-
de
##STR00054##
[0195]
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)acetamid-
e (1.48 g, 4.52 mmol) was dissolved in 50 mL of EtOAc containing a
catalytic amount of 10% Pd/C. The solution was shaken in a Parr
hydrogenation apparatus under H.sub.2 atmosphere (45 psi) at rt for
24 h. The solution was filtered through Celite and the solvent was
evaporated. Yield: 1.32 g (98%). .sup.1H NMR (400 MHz,
CHLOROFORM-D) .delta. 1.31-1.43 (m, 2H), 1.64-1.73 (m, 2H),
1.74-1.82 (m, 1H), 1.89-1.93 (m, 1H), 1.93-1.96 (m, 1H), 2.08-2.17
(m, 5H), 3.00 (d, J=6.64 Hz, 2H), 3.27-3.46 (m, 2H), 6.55 (d,
J=8.40 Hz, 1H), 6.70 (dd, J=8.40, 2.34 Hz, 1H), 7.01 (s, 1H), 7.13
(d, J=2.34 Hz, 1H).
Step D:
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-
-5-yl}acetamide
##STR00055##
[0197]
N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetamid-
e (1.32 g 4.44 mmol) was dissolved in 100 mL of DCM containing DMAP
(108 mg, 0.89 mmol). Trimethylacetyl chloride (0.60 mL, 4.88 mmol)
was added dropwise and the solution was stirred at rt for 2 h. The
solution was washed with saturated aqueous NaHCO.sub.3 solution,
saturated aqueous NaCl solution and dried over anhydrous
Na.sub.2SO.sub.4. Part of the product precipitated during the
washings and was filtered. The organic phase was evaporated and
combined with the precipitate. The product was dissolved in 30 mL
of AcOH and placed in 6 sealed tubes (5 mL/tube). Each tube was
heated at 150.degree. C. in a Personal Chemistry microwaves
instrument for 2.5 h. The fractions were pooled and the solvent was
evaporated. The product was dissolved in EtOAc and washed with
aqueous NaHCO.sub.3 solution, saturated aqueous NaCl solution and
dried over anhydrous Na.sub.2SO.sub.4. The product was purified by
silica gel flash chromatography using 2:1/acetone:hexanes as
eluent. Yield: 1.11 g (68%). .sup.1H NMR (400 MHz,
METHANOL-D.sub.4) .delta. 1.40-1.49 (m, 2H), 1.52 (s, 9H),
1.60-1.65 (m, 2H), 1.67-1.77 (m, 1H), 1.96-2.06 (m, 3H), 2.11 (s,
3H), 2.15-2.23 (m, 1H), 4.28 (d, J=7.62 Hz, 2H), 7.35-7.39 (m, 1H),
7.40-7.44 (m, 1H), 7.85 (d, J=1.76 Hz, 1H).
Step E:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5--
amine
##STR00056##
[0199]
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol--
5-yl}acetamide (500 mg, 1.37 mmol) was dissolved in 10 mL of
1:1/EtOH:2M HCl. The solution was divided into two sealed tubes (5
mL/tube). Each tube was heated at 120.degree. C. in a Personal
Chemistry microwaves instrument for 1 h. The fractions were pooled
and the solvent was evaporated. The residue was diluted with 2M
NaOH and extracted (3.times.) with EtOAc. The organic phase was
washed with saturated aqueous NaCl solution and dried over
anhydrous Na.sub.2SO.sub.4. The solvent was evaporated. Yield: 440
mg (99%). .sup.1H NMR (400 MHz, CHLOROFORM-D) .delta. 1.40-1.52 (m,
2H), 1.52-1.54 (m, 9H), 1.56-1.66 (m, 4H), 1.68-1.75 (m, 2H),
2.07-2.17 (m, 3H), 4.14 (d, J=7.62 Hz, 2H), 6.65 (dd, J=8.50, 2.25
Hz, 1H), 7.04-7.09 (m, 2H).
Example 13
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}me-
thanesulfonamide
##STR00057##
[0201]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-a-
mine (40 mg, 0.124 mmol) and a catalytic amount of DMAP were
dissolved in 3 mL of DCM. Methanesulfonyl chloride (0.012 mL, 0.149
mmol) was added and the solution was stirred at rt for 2 h. The
solution was washed with saturated aqueous NaHCO.sub.3 solution,
brine and dried over anhydrous MgSO.sub.4. The solvent was
evaporated and the product was purified by reversed-phase HPLC
using 10-70% CH.sub.3CN/H.sub.2O and lyophilized affording the
title compound as the corresponding TFA salt. Yield: 50 mg (79%).
.sup.1H NMR (600 MHz, MeOD) .delta. 1.53-1.61 (m, 2H), 1.67 (s,
9H), 1.71-1.76 (m, 3H), 1.76-1.82 (m, 1H), 2.04-2.11 (m, 2H),
2.23-2.29 (m, 1H), 3.01 (s, 3H), 4.54 (d, J=7.68 Hz, 2H), 7.42 (dd,
J=9.22, 2.05 Hz, 1H), 7.75 (d, J=1.79 Hz, 1H), 7.91 (d, J=8.96 Hz,
1H); MS (ESI) (M+H).sup.+ 400.0; Anal. Calcd(%) for
C.sub.19H.sub.27N.sub.3O.sub.2SF.sub.2+1.9 TFA+0.1H.sub.2O: C,
44.32; H, 4.75; N, 6.80. Found: C, 44.34; H, 4.78; N, 6.55.
Example 14
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}et-
hanesulfonamide
##STR00058##
[0203]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-a-
mine (440 mg, 1.37 mmol) and DMAP (165 mg, 1.37 mmol) were
dissolved in 50 mL of DCM. Ethanesulfonyl chloride (0.170 mL, 1.78
mmol) was added dropwise and the solution was stirred at rt for 2.5
h. The solution was washed with saturated aqueous NaHCO.sub.3
solution, saturated aqueous NaCl solution and dried over anhydrous
Na.sub.2SO.sub.4. The product was purified by silica gel flash
chromatography using EtOAc as eluent. The fractions were
concentrated and the residue was dissolved in 25 mL of MeOH. TFA
(0.155 mL, 2.06 mmol) was added dropwise and the solution was
stirred at rt for 30 min. The solvent was evaporated and the
product was precipitated in ether affording the title compound as
its corresponding TFA salt. Yield: 565 mg (78%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4) .delta. 1.29 (t, J=7.42 Hz, 3H), 1.48-1.60
(m, 2H), 1.64 (s, 9H), 1.66-1.72 (m, 2H), 1.73-1.82 (m, 2H),
1.99-2.09 (m, 2H), 2.18-2.28 (m, 1H), 3.11 (m, 2H), 4.50 (d, J=7.62
Hz, 2H), 7.38 (dd, J=9.08, 2.05 Hz, 1H), 7.72 (d, J=2.15 Hz, 1H),
7.85 (d, J=8.98 Hz, 1H); MS (ESI) (M+H).sup.+ 414.0.
Example 15
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}cy-
clopropanesulfonamide
##STR00059##
[0205]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-a-
mine (300 mg, 0.934 mmol) and DMAP (115 mg, 0.934 mmol) were
dissolved in 10 mL of DCM. Cyclopropanesulfonyl chloride (170 mg,
1.21 mmol) was added and the solution was stirred at rt for 2 h.
The solution was washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The product
was purified by silica gel flash chromatography using EtOAc as
eluent. The fractions were concentrated and the residue was
dissolved in 25 mL of MeOH. TFA (0.143 mL, 1.86 mmol) was added
dropwise and the solution was stirred at rt for 30 min. The solvent
was evaporated and the product was precipitated in ether affording
the title compound as its corresponding TFA salt. Yield: 390 mg
(77%). .sup.1H NMR (400 MHz, METHANOL-D.sub.4) .delta. 0.91-0.97
(m, 2H), 1.02-1.08 (m, 2H), 1.48-1.60 (m, 2H), 1.65 (s, 9H),
1.67-1.75 (m, 3H), 1.75-1.82 (m, 1H), 2.00-2.10 (m, 2H), 2.18-2.28
(m, 1H), 2.53-2.61 (m, 1H), 4.50 (d, J=7.42 Hz, 2H), 7.42 (dd,
J=8.98, 2.15 Hz, 1H), 7.74 (d, J=1.56 Hz, 1H), 7.85 (d, J=8.79 Hz,
1H); MS (ESI) (M+H).sup.+ 426.0; Anal. Calcd(%) for
C.sub.21H.sub.29N.sub.3O.sub.2SF.sub.2+1.0 TFA; C, 51.20; H, 5.60;
N, 7.79. Found: C, 51.38; H, 5.66; N, 7.56.
Example 16
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N-
-methylcyclopropanesulfonamide
##STR00060##
[0207]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-a-
mine (65 mg, 0.202 mmol) and a catalytic amount of DMAP were
dissolved in 5 mL of DCM. Cyclopropanesulfonyl chloride (34 mg,
0.242 mmol) was added and the solution was stirred at rt for 6 h.
The solution was washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The solvent
was evaporated. The residue was dissolved in 5 mL of DMF at
0.degree. C. and NaH (12 mg, 0.303 mmol) was added. The solution
was stirred at 0.degree. C. for 15 min. Methyl iodide (0.025 mL,
0.404 mmol) was added and the solution was stirred at rt for 2 h.
The reaction was quenched with saturated aqueous NaHCO.sub.3
solution and the solvent was evaporated. The product was dissolved
in EtOAc and washed with aqueous NaHCO.sub.3 solution, saturated
aqueous NaCl solution and dried over anhydrous Na.sub.2SO.sub.4.
The solvent was evaporated and the product was purified by
reversed-phase HPLC using 10-70% CH.sub.3CN/H.sub.2O and
lyophilized affording the title compound as the corresponding TFA
salt. Yield: 60 mg (54%). .sup.1H NMR (600 MHz, CD.sub.3OD) .delta.
0.90-0.94 (m, 2H), 0.97-1.01 (m, 2H), 1.54-1.62 (m, 2H), 1.68 (s,
9H), 1.73-1.81 (m, 4H), 2.03-2.11 (m, 2H), 2.23-2.30 (m, 1H),
2.59-2.65 (m, 1H), 3.43 (s, 3H), 4.56 (d, J=7.68 Hz, 2H), 7.72 (d,
J=9.47 Hz, 1H), 7.81 (s, 1H), 7.95 (d, J=8.96 Hz, 1H); MS (ESI)
(M+H).sup.+ 440.0.
Example 17
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-2-
-methylpropane-2-sulfonamide
##STR00061##
[0209]
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-a-
mine (66 mg, 0.205 mmol) and DMAP (25 mg, 0.205 mmol) were
dissolved in 5 mL of DCM. t-Butylsulfinyl chloride (0.031 mL, 0.246
mmol) was added and the solution was stirred at rt for 2 h. The
solution was washed with saturated aqueous NaHCO.sub.3 solution,
brine and dried over anhydrous MgSO.sub.4. 3-Chloroperoxybenzoic
acid (90 mg, 0.410 mmol) was added and the solution was stirred at
rt for 12 h. The solution washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The product
was purified by reversed-phase HPLC using 10-70%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 55 mg (48%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4) .delta. 1.35 (s, 9H), 1.49-1.60 (m, 2H),
1.64 (s, 9H), 1.68-1.75 (m, 3H), 1.76-1.82 (m, 1H), 2.00-2.09 (m,
2H), 2.19-2.28 (m, 1H), 4.50 (d, J=7.42 Hz, 2H), 7.42 (dd, J=9.08,
2.05 Hz, 1H), 7.81-7.86 (m, 2H); MS (ESI) (M+H).sup.+ 442.0; Anal.
Calcd(%) for C.sub.22H.sub.33N.sub.3O.sub.2SF.sub.2+1.2
TFA+0.2H.sub.2O; C, 50.35; H, 5.99; N, 7.22. Found: C, 50.36; H,
5.73; N, 7.08.
Example 18
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benzimidazo-
l-5-yl]cyclopropanesulfonamide
##STR00062##
[0210] Step A:
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benzimidaz-
ol-5-yl]cyclopropanesulfonamide
##STR00063##
[0212]
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benz-
imidazol-5-yl]acetamide (for preparation see the following step B)
(95 mg, 0.256 mmol) was heated in 5 mL of 1:1/2M HCl:EtOH at
120.degree. C. for 1 h using a Personal Chemistry microwaves
instrument. The solvent was evaporated. The residue was basified
with 2M NaOH and extracted (3.times.) with EtOAc. The organic phase
was washed with saturated aqueous NaCl solution and dried over
anhydrous Na.sub.2SO.sub.4. The solvent was evaporated. The product
was dissolved in 5 mL of DCM containing DMAP (31 mg, 0.256 mmol)
and cyclopropanesulfonyl chloride (53 mg, 0.384 mmol) was added.
The solution was stirred at rt for 3 h. The solution was washed
with saturated aqueous NaHCO.sub.3 solution, brine and dried over
anhydrous MgSO.sub.4. The solvent was evaporated and the product
was purified by reversed-phase HPLC using 10-70%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 35 mg (25%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4) .delta. 0.88-0.95 (m, 2H), 0.98-1.03 (m,
2H), 1.39-1.51 (m, 2H), 1.61-1.68 (m, 3H), 1.70-1.79 (m, 1H), 2.03
(s, 2H), 2.15 (s, 1H), 2.23 (m, 3H), 2.47-2.55 (m, 1H), 4.35 (d,
J=7.62 Hz, 2H), 7.39 (dd, J=8.79, 1.95 Hz, 1H), 7.65 (d, J=8.79 Hz,
1H), 7.67 (d, J=2.15 Hz, 1H); MS (ESI) (M+H).sup.+ 434.0; Anal.
Calcd(%) for C.sub.19H.sub.23N.sub.3O.sub.2SF.sub.4+0.7 TFA; C,
47.74; H, 4.65; N, 8.19. Found: C, 47.88; H, 4.68; N, 8.19.
Step B:
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-ben-
zimidazol-5-yl]acetamide
##STR00064##
[0214]
N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetamid-
e (99 mg, 0.333 mmol), DIPEA (0.087 mL, 0.500 mmol), HATU (140 mg,
0.366 mmol) and 2,2-difluoropropionic acid (40 mg, 0.366 mmol) were
stirred in 5 mL of DMF at rt for 1 h. The solvent was evaporated.
The residue was dissolved in 3 mL of glacial AcOH and heated at
80.degree. C. for 2 h. The solvent was evaporated. The product was
dissolved in EtOAc and washed with aqueous NaHCO.sub.3 solution,
saturated aqueous NaCl solution and dried over anhydrous
Na.sub.2SO.sub.4. The product was purified by silica gel flash
chromatography using EtOAc as eluent. Yield: 100 mg (81%). .sup.1H
NMR (400 MHz, CHLOROFORM-D) .delta. 1.39-1.52 (m, 2H), 1.57-1.63
(m, 1H), 1.64-1.71 (m, 3H), 2.06-2.16 (m, 3H), 2.22 (s, 3H), 2.29
(m, 3H), 4.25 (d, J=7.42 Hz, 2H), 7.31 (s, 1H), 7.35 (d, J=8.79 Hz,
1H), 7.60 (dd, J=8.89, 1.86 Hz, 1H), 7.86 (d, J=1.76 Hz, 1H).
Example 19
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benzimidazo-
l-5-yl]ethanesulfonamide
##STR00065##
[0216]
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benz-
imidazol-5-yl]acetamide (80 mg, 0.215 mmol) was heated in 5 mL of
1:1/2M HCl:EtOH at 120.degree. C. for 1 h using a Personal
Chemistry microwaves instrument. The solvent was evaporated. The
residue was basified with 2M NaOH and extracted (3.times.) with
EtOAc. The organic phase was washed with saturated aqueous NaCl
solution and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
evaporated. The product was dissolved in 5 mL of DCM containing
DMAP (31 mg, 0.256 mmol) and ethanesulfonyl chloride (0.026 mL,
0.280 mmol) was added. The solution was stirred at rt for 2 h. The
solution was washed with saturated aqueous NaHCO.sub.3 solution,
brine and dried over anhydrous MgSO.sub.4. The solvent was
evaporated and the product purified by reversed-phase HPLC using
10-70% CH.sub.3CN/H.sub.2O and lyophilized affording the title
compound as the corresponding TFA salt. Yield: 22 mg (19%). .sup.1H
NMR (400 MHz, METHANOL-D.sub.4) .delta. 1.29 (t, J=7.42 Hz, 3H),
1.36-1.49 (m, 2H), 1.58-1.66 (m, 3H), 1.67-1.78 (m, 1H), 1.96-2.06
(m, 2H), 2.11-2.15 (m, 1H), 2.21 (m, 3H), 3.04 (m, 2H), 4.33 (d,
J=7.62 Hz, 2H), 7.34 (dd, J=8.98, 1.95 Hz, 1H), 7.64 (dd, J=5.47,
3.32 Hz, 2H); MS (ESI) (M+H).sup.+ 421.9; Anal. Calcd(%) for
C.sub.18H.sub.23N.sub.3O.sub.2SF.sub.4+0.8 TFA+0.1H.sub.2O: C,
45.76; H, 4.70; N, 8.17. Found: C, 45.73; H, 4.52; N, 7.80.
Example 20
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benzimidazo-
l-5-yl]-2-methylpropane-2-sulfonamide
##STR00066##
[0218]
N-[1-[(4,4-Difluorocyclohexyl)methyl]-2-(1,1-difluoroethyl)-1H-benz-
imidazol-5-yl]acetamide (185 mg, 0.498 mmol) was heated in 5 mL of
1:1/2M HCl:EtOH at 120.degree. C. for 1 h using a Personal
Chemistry microwaves instrument. The solvent was evaporated. The
residue was basified with 2M NaOH and extracted (3.times.) with
EtOAc. The organic phase was washed with saturated aqueous NaCl
solution and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
evaporated. The residue was dissolved in 5 mL of DCM and
t-butylsulfinyl chloride (0.075 mL, 0.598 mmol) and DMAP (25 mg,
0.498 mmol) were added. The solution was stirred at rt for 1 h. The
solution was washed with saturated aqueous NaHCO.sub.3 solution,
brine and dried over anhydrous MgSO.sub.4. 3-Chloroperoxybenzoic
acid (225 mg, 0.996 mmol) was added and the solution was stirred at
rt for 4 h. The solution washed with saturated aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The product
was purified by reversed-phase HPLC using 10-70%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 70 mg (25%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4) .delta. 1.33 (s, 9H), 1.37-1.49 (m, 2H),
1.60-1.65 (m, 3H), 1.68-1.78 (m, 1H), 1.97-2.06 (m, 2H), 2.11-2.14
(m, 1H), 2.21 (m, 3H), 4.32 (d, J=7.62 Hz, 2H), 7.40 (dd, J=8.89,
2.05 Hz, 1H), 7.59 (d, J=8.79 Hz, 1H), 7.70 (d, J=1.95 Hz, 1H); MS
(ESI) (M+H).sup.+ 449.8.
Example 21
N-[2-(1,1-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazo-
l-5-yl]-N-methylethanesulfonamide
##STR00067##
[0219] Step A.
N-[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidaz-
ol-5-yl]-N-methylethanesulfonamide
##STR00068##
[0221] Ethanesulfonyl chloride (55 .mu.L, 0.58 mmol) was added to a
solution of
2-(1,1-difluoroethyl)-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benz-
imidazol-5-amine (150 mg, 0.48 mmol) and DMAP (71 mg, 0.58 mmol) in
DCM (15 mL) at ambient temperature. The reaction mixture was
stirred overnight and the solvent was concentrated. The product was
purified by reverse-phase preparative HPLC using MeCN 10 to 90%
gradient in water to provide the TFA salt of the title compound as
white solid. Yield: 70 mg (28%); .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 1.24-1.37 (m, 3H), 1.36-1.53 (m, 4H), 2.12-2.32 (m, 3H),
3.05-3.17 (m, 2H), 3.25-3.31 (m, 2H), 3.33 (d, J=3.71 Hz, 1H), 3.36
(s, 2H), 3.89 (m, 2H), 4.33 (d, J=7.42 Hz, 2H), 7.49 (dd, J=8.79,
1.95 Hz, 1H), 7.69 (d, J=8.98 Hz, 1H), 7.77 (d, J=1.76 Hz, 1H); MS
(ESI) (M+H).sup.+ 402.0;
Step B.
N-{5-[Acetyl(methyl)amino]-2-[(tetrahydro-2H-pyran-4-ylmethyl)amin-
o]phenyl}-2,2-difluoropropanamide
##STR00069##
[0223] HATU (1.44 g, 3.78 mmol) and
N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylaceta-
mide (1.00 g, 3.60 mmol) (for preparation, see Example 1, steps B
to E) were added to a solution of 2,2-difluoropropanoic acid (0.40
g, 3.60 mmol) and DIPEA (0.75 mL, 4.32 mmol) in DMF (100 mL) at
room temperature. The reaction mixture was stirred overnight. The
solvent was concentrated and the crude product was recovered in
EtOAc. The organic was washed with water, saturated NaHCO.sub.3
solution and brine. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and filtered. The solvent was concentrated giving
the title compound that was used for the next step without further
purification. Yield: 1.00 g (75%); MS (ESI) (M+H).sup.+: 370.2.
Step C.
N-[2-(1,1-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-ben-
zimidazol-5-yl]-N-methylacetamide
##STR00070##
[0225]
N-{5-[Acetyl(methyl)amino]-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}-2,2-difluoropropanamide (1.00 g, 2.70 mmol) was heated to
90.degree. C. overnight in acetic acid (20 mL). The solvent was
concentrated. The crude product was purified by flash
chromatography on silica gel, using MeOH 3.5% and acetone 8% in DCM
as eluent, giving the title compound. Yield: 0.48 g (50%); MS (ESI)
(M+H).sup.+: 352.0.
Step D.
2-(1,1-difluoroethyl)-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)--
1H-benzimidazol-5-amine
##STR00071##
[0227]
N-[2-(1,1-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benz-
imidazol-5-yl]-N-methylacetamide (0.48 g, 1.37 mmol) was heated to
80.degree. C. overnight in concentrated HCl (80 mL). The reaction
mixture was cool to 0.degree. C. and brought to slightly basic pH
using NaOH solution. The compound was extracted with EtOAc
(3.times.) and the combined organic layers were washed with brine,
dried over anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was
concentrated giving the title compound that was used for the next
step without further purification. Yield: 0.42 g (98%); MS (ESI)
(M+H).sup.+: 310.2.
Example 22
N-[2-(1,1-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazo-
l-5-yl]-N-methylpropane-1-sulfonamide
##STR00072##
[0229] Following the procedure of step A in example 21 and using
propanesulfonyl chloride (65 .mu.L, 0.58 mmol) provided the TFA
salt of the title compound as a white solid. Yield: 68 mg (26%);
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.02 (t, J=7.42 Hz, 3H),
1.40-1.54 (m, 4H), 1.74-1.87 (m, 1H), 2.17-2.34 (m, 3H), 3.05-3.15
(m, 2H), 3.32-3.37 (m, 2H), 3.37 (s, 3H), 3.85-3.97 (m, 2H), 4.35
(d, J=7.62 Hz, 2H), 7.50 (dd, J=8.89, 2.05 Hz, 1H), 7.71 (d, J=8.79
Hz, 1H), 7.78 (d, J=1.95 Hz, 1H); MS (ESI) (M+H).sup.+ 416.0; Anal.
Calcd for C.sub.19H.sub.27F.sub.2N.sub.3O.sub.3S+0.1 MeCN: C,
54.96; H, 6.56; N, 10.35. Found: C, 55.02; H, 6.40; N, 10.24.
Example 23
N-[2-(1,1-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazo-
l-5-yl]-N-methylcyclopropanesulfonamide
##STR00073##
[0231] Following the procedure of step A in example 21 using
cyclopropanesulfonyl chloride (81 .mu.L, 0.58 mmol) and heating to
60.degree. C. overnight, provided the TFA salt of the title
compound as a white solid. Yield: 135 mg (52%); .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 0.85-0.93 (m, 2H), 0.93-1.03 (m, 2H),
1.39-1.55 (m, 4H), 2.24 (m, 3H), 2.55-2.66 (m, 1H), 3.31-3.38 (m,
3H), 3.39 (s, 3H), 3.86-3.97 (m, 2H), 4.36 (d, J=7.42 Hz, 2H), 7.52
(dd, J=8.79, 2.15 Hz, 1H), 7.70 (d, J=8.79 Hz, 1H), 7.81 (d, J=2.15
Hz, 1H); MS (ESI) (M+H).sup.+ 414.0; Anal. Calcd for
C.sub.19H.sub.25F.sub.2N.sub.3O.sub.3S+0.1H.sub.2O: C, 54.95; H,
6.12; N, 10.12. Found: C, 54.91; H, 6.09; N, 9.68.
Example 24
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}ethane-
sulfonamide
##STR00074##
[0232] Step A:
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}ethan-
esulfonamide
##STR00075##
[0234]
2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-amine
(for preparation see following steps B to F) (60 mg, 0.198 mmol)
and DMAP (24 mg, 0.198 mmol) were dissolved in 5 mL of DCM.
Ethanesulfonyl chloride (0.025 mL, 0.257 mmol) was added and the
solution was stirred at rt for 2 h. The solution was washed with
saturated aqueous NaHCO.sub.3 solution, brine and dried over
anhydrous MgSO.sub.4. The solvent was evaporated and the product
was purified by reversed-phase HPLC using 10-70%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 50 mg (50%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4) .delta. 1.29 (t, J=7.42 Hz, 3H), 1.34-1.41
(m, 2H), 1.43-1.51 (m, 1H), 1.53-1.62 (m, 1H), 1.63-1.66 (m, 9H),
1.69-1.75 (m, 2H), 1.96-2.04 (m, 1H), 2.06-2.12 (m, 2H), 3.12 (q,
J=7.42 Hz, 2H), 4.44-4.49 (m, 2H), 7.39 (dd, J=9.08, 2.05 Hz, 1H),
7.73 (d, J=2.15 Hz, 1H), 7.85 (d, J=9.18 Hz, 0.7H), 7.85-7.88 (d,
J=9.18 Hz, 0.3H); MS (ESI) (M+H).sup.+ 396.0; Anal. Calcd(%) for
C.sub.20H.sub.30N.sub.3O.sub.2SF+1.3 TFA+0.5H.sub.2O: C, 49.11; H,
5.89; N, 7.60. Found: C, 49.10; H, 5.84; N, 7.52.
Step B: tert-Butyl
[(4-fluorocyclohex-3-en-1-yl)methyl]carbamate
##STR00076##
[0236] 4-N-Boc-aminomethyl cyclohexanone (4.95 g, 21.8 mmol) was
dissolved in 80 mL of THF. DAST (4.3 mL, 32.7 mmol) was added
dropwise and the solution was stirred at 50.degree. C. for 5 h. The
solvent was concentrated and the product purified by silica gel
flash chromatography using 3:1/hexanes:EtOAc as eluent. Yield: 1.62
g (30%). .sup.1H NMR (400 MHz, CHLOROFORM-D) .delta. 1.36-1.42 (m,
1H), 1.44 (s, 9H), 1.70-1.80 (m, 2H), 1.82-1.90 (m, 1H), 2.09-2.17
(m, 1H), 2.17-2.29 (m, 2H), 3.04-3.11 (m, 2H), 4.61 (s, 1H),
5.11-5.15 (m, 0.5H), 5.16-5.19 (m, 0.5H).
Step C: [(4-Fluorocyclohex-3-en-1-yl)methyl]amine hydrochloride
##STR00077##
[0238] tert-Butyl [(4-fluorocyclohex-3-en-1-yl)methyl]carbamate
(1.62 g, 7.06 mmol) was stirred in 25 mL of 1M HCl/AcOH at rt for 2
h. The solvent was evaporated and the product was precipitated in
ether, filtered and dried under vacuum. Yield: 1.13 g (97%).
.sup.1H NMR (400 MHz, METHANOL-D.sub.4) .delta. 1.44-1.53 (m, 1H),
1.80-1.89 (m, 2H), 1.90-1.98 (m, 1H), 2.16-2.23 (m, 2H), 2.26-2.34
(m, 1H), 2.88 (d, J=6.25 Hz, 2H), 5.12-5.19 (m, 1H).
Step C:
N-(4-{[(4-Fluorocyclohex-3-en-1-yl)methyl]amino}-3-nitrophenyl)ace-
tamide
##STR00078##
[0240] N-(4-Fluoro-3-nitrophenyl)acetamide (460 mg, 2.32 mmol) and
[(4-fluorocyclohex-3-en-1-yl)methyl]amine hydrochloride (350 mg,
2.11 mmol) were stirred in 20 mL of EtOH containing TEA (0.735 mL,
5.28 mmol) at 75.degree. C. for 48 h. The solvent was concentrated.
The residue was dissolved in EtOAc and washed with aqueous 5%
KHSO.sub.4, saturated aqueous NaHCO.sub.3 solution, brine and dried
over anhydrous MgSO.sub.4. The crude product was purified by silica
gel flash chromatography using 2:1/hexanes:acetone as eluent.
Yield: 553 mg (85%). .sup.1H NMR (400 MHz, CHLOROFORM-D) .delta.
1.51-1.61 (m, 1H), 1.84-1.93 (m, 1H), 1.96-2.03 (m, 2H), 2.16-2.18
(m, 3H), 2.22-2.32 (m, 3H), 3.26 (m, 2H), 5.19 (m, 1H), 6.84 (d,
J=9.37 Hz, 1H), 7.21 (s, 1H), 7.79 (dd, J=9.18, 2.54 Hz, 1H), 8.09
(d, J=2.54 Hz, 2H).
Step D:
N-(3-Amino-4-{[(4-fluorocyclohexyl)methyl]amino}phenyl)acetamide
##STR00079##
[0242]
N-(4-{[(4-Fluorocyclohex-3-en-1-yl)methyl]amino}-3-nitrophenyl)acet-
amide (340 mg, 1.11 mmol) was dissolved in 25 mL of EtOAc
containing a catalytic amount of 10% Pd/C. The solution was shaken
under H.sub.2 atmosphere (40 psi) using a Parr hydrogenation
apparatus at rt for 48 h. The solution was filtered through celite
and the solvent was evaporated. Yield: 308 mg (99%). MS (ESI)
(M+H).sup.+ 279.95.
Step E:
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-y-
l}acetamide
##STR00080##
[0244]
N-(3-Amino-4-{[(4-fluorocyclohexyl)methyl]amino}phenyl)acetamide
(300 mg, 1.07 mmol) and DMAP (25 mg, 0.214 mmol) were dissolved in
10 mL of DCM. Trimethylacetyl chloride (0.145 mL, 1.18 mmol) was
added dropwise and the solution was stirred at rt for 1 h. The
solution was washed with aqueous NaHCO.sub.3 solution, brine and
dried over anhydrous MgSO.sub.4. The residue was dissolved in 5 mL
of AcOH and was heated at 150.degree. C. for 2.5 h using a Personal
Chemistry microwave apparatus. The solvent was evaporated. The
residue was dissolved in EtOAc and washed with aqueous NaHCO.sub.3
solution, brine and dried over anhydrous MgSO.sub.4. The crude
product was purified by silica gel flash chromatography using
2:1/acetone:hexanes as eluent. Yield: 196 mg (53%). .sup.1HNMR (400
MHz, CHLOROFORM-D) .delta. 1.14-1.25 (m, 2H), 1.37-1.45 (m, 1H),
1.43-1.51 (m, 1H), 1.54-1.57 (m, 9H), 1.70-1.78 (m, 2H), 1.70-1.77
(m, 1H), 2.02-2.08 (m, 1H), 2.10-2.17 (m, 1H), 2.19-2.21 (m, 3H),
4.12-4.19 (m, 2H), 4.53 (m, 0.3H), 4.73 (m, 0.3H), 4.78 (m, 0.2H),
4.90 (m, 0.2H), 7.21-7.29 (m, 1H), 7.30 (s, 1H), 7.50-7.57 (m, 1H),
7.64-7.67 (m, 1H).
Step F:
2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-amin-
e
##STR00081##
[0246]
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl-
}acetamide (190 mg, 0.550 mmol) was heated in 5 mL of 1:1/2M
HCl:EtOH at 120.degree. C. for 1 h using a Personal Chemistry
microwaves apparatus. The solvent was evaporated. The residue was
basified with 2M NaOH and extracted (3.times.) with EtOAc. The
organic phase was washed with saturated aqueous NaCl solution and
dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated.
Yield: 154 mg (92%). .sup.1H NMR (400 MHz, METHANOL-D.sub.4)
.delta. 1.28-1.39 (m, 2H), 1.41-1.50 (m, 1H), 1.53-1.59 (m, 1H),
1.61-1.64 (m, 9H), 1.69 (d, J=7.81 Hz, 2H), 1.95-2.03 (m, 0.7H),
2.05-2.11 (m, 2H), 2.13-2.22 (m, 0.3H), 4.37-4.44 (m, 2.7H),
4.47-4.56 (m, 0.3H), 7.11 (t, J=2.05 Hz, 0.5H) 7.13 (t, J=2.05 Hz,
0.5H), 7.15-7.18 (m, 1H), 7.67-7.73 (m, 1H).
Example 25
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}cyclop-
ropanesulfonamide
##STR00082##
[0248]
2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-amine
(56 mg, 0.199 mmol) and DMAP (25 mg, 0.199 mmol) were dissolved in
5 mL of DCM. Cyclopropanesulfonyl chloride (42 mg, 0.298 mmol) was
added and the solution was stirred at rt for 3 h. The solution was
washed with saturated aqueous NaHCO.sub.3 solution, brine and dried
over anhydrous MgSO.sub.4. The solvent was evaporated and the
product was purified by reversed-phase HPLC using 10-70%
CH.sub.3CN/H.sub.2O and lyophilized affording the title compound as
the corresponding TFA salt. Yield: 58 mg (56%). .sup.1H NMR (400
MHz, METHANOL-D.sub.4) .delta. 0.91-0.98 (m, 2H), 1.03-1.09 (m,
2H), 1.32-1.43 (m, 2H), 1.45-1.52 (m, 1H), 1.54-1.62 (m, 1H),
1.64-1.67 (m, 9H), 1.68-1.76 (m, 1H), 1.97-2.05 (m, 1H), 2.06-2.13
(m, 2H), 2.54-2.62 (m, 1H), 4.44-4.50 (m, 2H), 4.53 (m, 0.5H), 4.73
(m, 0.5H), 7.43 (dd, J=9.08, 2.05 Hz, 1H), 7.75 (d, J=1.95 Hz, 1H),
7.83-7.89 (m, 1H); MS (ESI) (M+H).sup.+ 408.0.
Example 26
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-2-met-
hylpropane-2-sulfonamide
##STR00083##
[0250]
2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-amine
(53 mg, 0.175 mmol) and DMAP (21 mg, 0.175 mmol) were dissolved in
5 mL of DCM. t-Butylsulfinyl chloride (0.026 mL, 0.210 mmol) was
added and the solution was stirred at rt for 1 h. The solution was
washed with saturated aqueous NaHCO.sub.3 solution, brine and dried
over anhydrous MgSO.sub.4. 3-Chloroperoxybenzoic acid (78 mg, 0.350
mmol) was added and the solution was stirred at rt for 2 h. The
solution washed with saturated aqueous NaHCO.sub.3 solution, brine
and dried over anhydrous MgSO.sub.4. The product was purified by
reversed-phase HPLC using 10-70% CH.sub.3CN/H.sub.2O and
lyophilized affording the title compound as the corresponding TFA
salt. Yield: 47 mg (50%). .sup.1H NMR (400 MHz, METHANOL-D.sub.4)
.delta. 1.36 (s, 9H), 1.38-1.44 (m, 2H), 1.44-1.51 (m, 1H),
1.54-1.60 (m, 1H), 1.63-1.66 (m, 9H), 1.69-1.75 (m, 2H), 1.96-2.04
(m, 1H), 2.06-2.14 (m, 2H), 4.42-4.48 (m, 2H), 4.53 (m, 0.5H), 4.72
(m, 0.5H), 7.42 (dd, J=8.98, 2.15 Hz, 1H), 7.79-7.86 (m, 2H); MS
(ESI) (M+H).sup.+ 424.0.
Example 27
N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}et-
hanesulfonamide
##STR00084##
[0251] Step A.
N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}e-
thanesulfonamide
##STR00085##
[0253]
N-{2-{[(4,4-difluorocyclohexyl)methyl]amino}-5-[(ethylsulfonyl)amin-
o]phenyl}-2,2-dimethylpropanamide (22.3 g, 0.051 mol) (for
preparation, see the following steps B to E), PTSA*H.sub.2O (10.8
g, 0.057 mol) and DMSO (100 mL) were mixed together and heated to
120.degree. C. overnight. The room temperature cooled down reaction
mixture was poured in cold water (600 mL). The product was
extracted with DCM (5.times.200 mL).
[0254] The combined organic phases were washed with NaHCO.sub.3
saturated solution (4.times.200 mL), brine and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was removed and the crude product was
purified on silica gel (EtOAc:hexane 1:1) by flash chromatography
(and treated with activated charcoal) to provide
N-{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}e-
thanesulfonamide (18.4 g) as white solid.
Step B. N-(4-Fluoro-3-nitrophenyl)ethanesulfonamide
##STR00086##
[0256] EtSO.sub.2Cl (21.5 mL, 0.22 mol) was added drop wise to a
mixture of 4-fluoro-3-nitroaniline (29.6 g, 0.19 mol) and pyridine
(100 mL) at 0.degree. C. The reaction mixture was allowed to warm
to room temperature and stirred overnight. The reaction mixture was
diluted with EtOAc (1 L). The resulting solution was washed with
HCl 2N (4.times.200 mL), NaHCO.sub.3 saturated solution
(4.times.200 mL) and water (4.times.200 mL). The organic phase was
dried over anhydrous Na.sub.2SO.sub.4 and the solvent was removed
to provide the title product as beige solid (46.3 g)
Step C.
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)ethanes-
ulfonamide
##STR00087##
[0258] N-(4-Fluoro-3-nitrophenyl)ethanesulfonamide (26 g, 0.107
mol), [(4,4-difluorocyclohexyl)methyl]amine (approx. 15 g), DIPEA
(20 mL) and DMSO (100 mL) were mixed together and heated to
65.degree. C. overnight. Ethanolamine (5 g) was added and the
reaction mixture was stirred until complete disappearance of
N-(4-fluoro-3-nitrophenyl)ethanesulfonamide (approx. 4-5 hrs.). The
room temperature cooled down reaction mixture was poured in cold
water (900 mL). The product was extracted with DCM (5.times.200
mL). The combined organic phases were washed with HCl 2N
(3.times.200 mL) and dried over anhydrous Na.sub.2SO.sub.4. The
solvent was removed and the crude product was purified on silica
gel by flash chromatography (this material can be re-crystallized
using a mixture of EtOAc and hexane) to provide the title product
(24.2 g) as orange solid.
Step D.
N-(3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)ethanes-
ulfonamide
##STR00088##
[0260]
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)ethanesu-
lfonamide (23.4 g) and Pd/C 10% in EtOAc (800 mL) were shaken
together overnight under H.sub.2 atmosphere (50 PSI) in a Parr
hydrogenation apparatus. The reaction mixture was diluted with MeOH
(400 mL) and filtered over celite bed. The solvent was removed to
provide the desired title product (22.2 g) as beige solid.
Step E.
N-{2-{[(4,4-difluorocyclohexyl)methyl]amino}-5-[(ethylsulfonyl)ami-
no]phenyl}-2,2-dimethylpropanamide
##STR00089##
[0262] A solution of t-BuCOCl (7.6 g, 0.063 mol) in DCM (150 mL)
was slowly added to a solution of
N-(3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)ethanesulfonam-
ide (22 g, 0.063 mol) and Et.sub.3N (9.7 mL, 0.069 mol) in DCM (500
mL) at 0.degree. C. The reaction mixture was stirred for 3 hrs. at
0.degree. C. DCM (300 mL) and water (200 mL) were added. The
organic layer was separated and washed with water (3.times.200 mL),
brine and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
removed and the crude product was purified on silica gel by flash
chromatography (EtOAc:hexane 1:1) to provide the title product
(23.3 g) as beige solid.
Example 28
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}ethane-
sulfonamide (isomers)
##STR00090##
[0264]
N-{2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl-
}ethanesulfonamide (60 mg, TFA salt, 0.117 mmol) was separated on a
chiral AD column using 10% EtOH/hexanes (0.1% diethylamine) giving
respectively Isomer A (16 mg) and Isomer B (31 mg).
[0265] Isomer A: .sup.1H NMR (400 MHz, METHANOL-D4) .delta. 1.30
(t, J=7.42 Hz, 3H), 1.41-1.52 (m, 3H), 1.54-1.63 (m, 3H), 1.65 (s,
9H), 1.97-2.05 (m, 2H), 2.15-2.24 (m, 1H), 3.13 (q, J=7.29 Hz, 2H),
4.47 (d, J=7.62 Hz, 2H), 4.72 (s, 0.5H), 4.85 (s, 0.5H), 7.38 (dd,
J=8.98, 2.15 Hz, 1H), 7.73 (d, J=1.95 Hz, 1H), 7.85 (d, J=8.98 Hz,
1H); MS (ESI) (M+H).sup.+ 395.8; Chiral AD 15% EtOH/hexanes (0.1%
DEA) k'=2.97.
[0266] Isomer B: .sup.1H NMR (400 MHz, METHANOL-D4) .delta. 1.30
(t, J=7.32 Hz, 3H), 1.34-1.39 (m, 2H), 1.39-1.45 (m, 2H), 1.65 (s,
9H), 1.70-1.75 (m, 2H), 2.06-2.13 (m, 3H), 3.13 (q, J=7.42 Hz, 2H),
4.37-4.43 (m, 0.5H), 4.45 (d, J=7.62 Hz, 2H), 4.49-4.56 (m, 0.5H),
7.39 (dd, J=9.08, 2.05 Hz, 1H), 7.73 (d, J=2.15 Hz, 1H), 7.84 (d,
J=9.18 Hz, 1H); MS (ESI) (M+H).sup.+ 395.8; Anal. Calcd for
C.sub.20H.sub.30N.sub.3O.sub.2SF+1.2 TFA+0.2H.sub.2O: C, 50.20; H,
5.94; N, 7.84. Found: C, 50.13; H, 5.81; N, 7.74; Chiral AD 15%
EtOH/hexanes (0.1% DEA) k'=3.81.
TABLE-US-00002 Sol. pH hClint Ki hCB1 EC50 hCB1 Emax hCB1 7.4
(.mu.L/min/ Isomer (nM) (nM) (%) (.mu.M) mg) A 148 -- -- 64 -- B
14.8 4.9 103 381 7.7
* * * * *