Note: Descriptions are shown in the official language in which they were submitted.
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PIPERIDIN-4-YL-AZETIDINE DIAMIDES AS MONOACYLGLYCEROL
LIPASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT
The research and development of the invention described below was not
federally sponsored.
BACKGROUND OF THE INVENTION
Cannabis sativa has been used for the treatment of pain for many years. 49-
tetrahydrocannabinol is a major active ingredient from Cannabis sativa and an
agonist
of cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two
cannabinoid G protein-coupled receptors have been cloned, cannabinoid receptor
type 1
(CBI Matsuda et al., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2
(CB2
Munro et al., Nature, 1993, 365, 61-5). CBI is expressed centrally in brain
areas, such
as the hypothalamus and nucleus accumbens as well as peripherally in the
liver,
gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di
Marzo et al.,
Curr Opin Lipidol, 2007, 18, 129-140). CB2 is predominantly expressed in
immune
cells, such as monocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-
H1134), and
under certain conditions, also in the brain (Benito et al., Brit J Pharmacol,
2008, 153,
277-285) and in skeletal (Cavuoto et al., Biochem Biophys Res Commun, 2007,
364,
105-110) and cardiac (Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-
252)
muscle. An abundance of pharmacological, anatomical and electrophysiological
data,
using synthetic agonists, indicate that increased cannabinoid signaling
through
Ca1/CB2 promotes analgesia in tests of acute nociception and suppresses
hyperalgesia
in models of chronic neuropathic and inflammatory pain (Cravatt et al., J
Neurobiol,
2004, 61, 149-60; Guindon et al., Brit J Pharmacol, 2008, 153, 319-334).
Efficacy of synthetic cannabinoid receptor agonists is well documented.
Moreover, studies using cannabinoid receptor antagonists and knockout mice
have also
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implicated the endocannabinoid system as an important modulator of
nociception.
Anandamide (AEA) (Devane et al., Science, 1992, 258, 1946-9) and 2-
arachidinoylglycerol (2-AG) (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-
90;
Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97) are two major
endocannabinoids. AEA is hydrolyzed by fatty acid amide hydrolase (FAAH) and 2-
AG is hydrolyzed by monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci,
2003, 4, 873-884). Genetic ablation of FAAH elevates endogenous AEA and
results in
a CBi-dependent analgesia in models of acute and inflammatory pain (Lichtman
et al.,
Pain, 2004, 109, 319-27), suggesting that the endocannabinoid system functions
naturally to inhibit pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60).
Unlike the
constitutive increase in endocannabinoid levels using FAAH knockout mice, use
of
specific FAAH inhibitors transiently elevates AEA levels and results in
antinociception
in vivo (Kathuria et al., Nat Med, 2003, 9, 76-81). Further evidence for an
endocannabinoid-mediated antinociceptive tone is demonstrated by the formation
of
AEA in the periaqueductal grey following noxious stimulation in the periphery
(Walker
et al., Proc Nall Acad Sci USA, 1999, 96, 12198-203) and, conversely, by the
induction
of hyperalgesia following antisense RNA-mediated inhibition of CBI in the
spinal cord
(Dogrul et al., Pain, 2002, 100, 203-9).
With respect to 2-AG, intravenous delivery of 2-AG produces analgesia in the
tail flick (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90) and hot
plate
(Lichtman et al., J Pharmacol Exp Ther, 2002, 302, 73-9) assays. In contrast,
it was
demonstrated that 2-AG given alone is not analgesic in the hot plate assay,
but when
combined with other 2-monoacylglycerols (i.e., 2-linoleoyl glycerol and 2-
palmitoyl
glycerol), significant analgesia is attained, a phenomenon termed the
"entourage effect"
(Ben-Shabat et al., Eur J Pharmacol, 1998, 353, 23-31). These "entourage" 2-
monoacylglycerols are endogenous lipids that are co-released with 2-AG and
potentiate
endocannabinoid signaling, in part, by inhibiting 2-AG breakdown, most likely
by
competition for the active site on MGL. This suggests that synthetic MGL
inhibitors
will have a similar effect. Indeed, URB602, a relatively weak synthetic MGL
inhibitor,
showed an antinociceptive effect in a murine model of acute inflammation
(Comelli et
al., Brit J Pharmacol, 2007, 152, 787-794)..
Although the use of synthetic cannabinoid agonists has conclusively
demonstrated that increased cannabinoid signaling produces analgesic and anti-
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inflammatory effects, it has been difficult to separate these beneficial
effects from the
unwanted side effects of these compounds. An alternative approach is to
enhance the
signaling of the endocannabinoid system by elevating the level of 2-AG, the
endocannabinoid of highest abundance in the central nervous system (CNS) and
gastrointestinal tract, which may be achieved by inhibition of MGL. Therefore,
MGL
inhibitors are potentially useful for the treatment of pain, inflammation, and
CNS
disorders (Di Marzo et al., Curr Pharm Des, 2000, 6, 1361-80; Shaveri et al.,
Brit J
Pharmacol, 2007, 152, 624-632; McCarberg Bill et al., Amer J Ther, 2007, 14,
475-
83), as well as glaucoma and disease states arising from elevated intraocular
pressure
(Njie, Ya Fatou; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp. Eye Res.,
2008,
87(2):106-14).
SUMMARY OF THE INVENTION
The present invention is directed to a compound of Formula (I)
0 \ R 0
y ___________________________________________ CN-1(
Y
Formula (I)
wherein
Y and Z are independently selected from Group a) or Group b) such that
one of Y and Z is Group a) and the other is Group b);
Group a) is
i) C6_10 aryl is unsubstituted or substituted with a substituent selected
from
the group consisting of fluoro, chloro, Ci_4allcyl, Ci_4alkoxy, cyano, and
trifluoromethyl; or
ii) an unsubstituted heteroaryl selected from the group consisting of
thiazolyl, isothiazolyl, and 1H-pyrroly1;
Group b) is
i) C6-10 aryl;
ii) a heteroaryl selected from the group consisting of
benzoxazolyl,
benzothiazolyl, benzimidazolyl, benzothienyl, indazolyl, and indolyl;
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iii) phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is
unsubstituted or substituted with trifluoromethyl or fluoro; or
iv) 1,3-dihydro-3H-benzimidazol-2-on-y1;
wherein Group b) other than phenylmethyl-phenyl is unsubstituted or
substituted with one or two substitutents each of which is independently
selected from the group consisting of bromo, chloro, fluoro, iodo, Ci_4alkyl,
C1_
4alkoxy, and Rb; provided that no more than one substituent is Rb; and
Rb is selected from the group consisting of trifluoromethyl, 2,2,2-
trifluoroethyl, 3,3,3-trifluoropropyl, 4,4-difluorocyclohexyl, thienyl,
pyridinyl,
and phenyl; wherein said thienyl, pyridinyl, and phenyl of Rb are
unsubstituted
or substituted with one or two substitutents each of which is independently
selected from the group consisting of trifluoromethyl, methyl, chloro, cyano,
and fluoro;
R is hydrogen or hydroxy;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts
thereof
The present invention also provides, inter alia, a pharmaceutical composition
comprising, consisting of and/or consisting essentially of a pharmaceutically
acceptable
carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically
acceptable
diluent, and a compound of Formula (I) or a pharmaceutically acceptable salt
form
thereof
Also provided are processes for making a pharmaceutical composition
comprising, consisting of, and/or consisting essentially of admixing a
compound of
Formula (I) or a pharmaceutically acceptable salt form thereof, and a
pharmaceutically
acceptable carrier, a pharmaceutically acceptable excipient, and/or a
pharmaceutically
acceptable diluent.
The present invention further provides, inter alia, methods for treating or
ameliorating a MGL-modulated disorder in a subject, including a human or other
mammal in which the disease, syndrome, or condition is affected by the
modulation of
the MGL enzyme, such as pain and the diseases that lead to such pain,
inflammation
and CNS disorders, using a compound of Formula (I) or a pharmaceutically
acceptable
salt form thereof
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The present invention also provides, inter alia, methods for producing the
instant compounds and pharmaceutical compositions and medicaments thereof
DETAILED DESCRIPTION OF THE INVENTION
With reference to substituents, the term "independently" refers to the
situation
where when more than one substituent is possible, the substituents may be the
same or
different from each other.
The term "alkyl" whether used alone or as part of a substituent group, refers
to
straight and branched carbon chains having 1 to 8 carbon atoms. Therefore,
designated
numbers of carbon atoms (e.g., C1_8) refer independently to the number of
carbon atoms
in an alkyl moiety or to the alkyl portion of a larger alkyl-containing
substituent. In
substituent groups with multiple alkyl groups such as, (Ci_6alky1)2amino-, the
Ci_6alkyl
groups of the dialkylamino may be the same or different.
The term "alkoxy" refers to an -0-alkyl group, wherein the term "alkyl" is as
defined above.
The terms "alkenyl" and "alkynyl" refer to straight and branched carbon chains
having 2 to 8 carbon atoms, wherein an alkenyl chain contains at least one
double bond
and an alkynyl chain contains at least one triple bond.
The term "cycloalkyl" refers to saturated or partially saturated, monocyclic
or
polycyclic hydrocarbon rings of 3 to 14 carbon atoms. Examples of such rings
include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
The term "benzo-fused cycloalkyl" refers to a 5- to 8- membered monocyclic
cycloalkyl ring fused to a benzene ring. The carbon atom ring members that
form the
cycloalkyl ring may be fully saturated or partially saturated.
The term "heterocycly1" refers to a nonaromatic monocyclic or bicyclic ring
system having 3 to 10 ring members that include at least 1 carbon atom and
from 1 to 4
heteroatoms independently selected from N, 0, and S. Included within the term
heterocyclyl is a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2
members
are N, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1 or 2
members are N
and up to 2 members are 0 or S and at least one member must be either N, 0, or
S;
wherein, optionally, the ring contains 0 to 1 unsaturated bonds, and,
optionally, when
the ring is of 6 or 7 members, it contains up to 2 unsaturated bonds. The
carbon atom
ring members that form a heterocycle ring may be fully saturated or partially
saturated.
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The term "heterocycly1" also includes two 5 membered monocyclic
heterocycloalkyl
groups bridged to form a bicyclic ring. Such groups are not considered to be
fully
aromatic and are not referred to as heteroaryl groups. When a heterocycle is
bicyclic,
both rings of the heterocycle are non-aromatic and at least one of the rings
contains a
heteroatom ring member. Examples of heterocycle groups include, and are not
limited
to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),
pyrrolidinyl,
imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,
morpholinyl,
thiomorpholinyl, and piperazinyl. Unless otherwise noted, the heterocycle is
attached
to its pendant group at any heteroatom or carbon atom that results in a stable
structure.
The term "benzo-fused heterocycly1" refers to a 5 to 7 membered monocyclic
heterocycle ring fused to a benzene ring. The heterocycle ring contains carbon
atoms
and from 1 to 4 heteroatoms independently selected from N, 0, and S. The
carbon
atom ring members that form the heterocycle ring may be fully saturated or
partially
saturated. Unless otherwise noted, benzo-fused heterocycle ring is attached to
its
pendant group at a carbon atom of the benzene ring.
The term "aryl" refers to an unsaturated, aromatic monocyclic or bicyclic ring
of 6 to 10 carbon members. Examples of aryl rings include phenyl and
naphthalenyl.
The term "heteroaryl" refers to an aromatic monocyclic or bicyclic aromatic
ring system having 5 to 10 ring members and which contains carbon atoms and
from 1
to 4 heteroatoms independently selected from the group consisting of N, 0, and
S.
Included within the term heteroaryl are aromatic rings of 5 or 6 members
wherein the
ring consists of carbon atoms and has at least one heteroatom member. Suitable
heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5 membered
rings, the
heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur
and, in
addition, up to 3 additional nitrogens. In the case of 6 membered rings, the
heteroaryl
ring preferably contains from 1 to 3 nitrogen atoms. For the case wherein the
6
membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. Examples
of
heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,
pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl,
benzothienyl,
indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl,
benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl.
Unless
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otherwise noted, the heteroaryl is attached to its pendant group at any
heteroatom or
carbon atom that results in a stable structure.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine
atoms.
The term "formyl" refers to the group ¨C(=0)H.
The term "oxo" refers to the group (=0).
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in
a
name of a substituent (e.g., arylalkyl, alkylamino) the name is to be
interpreted as
including those limitations given above for "alkyl" and "aryl." Designated
numbers of
carbon atoms (e.g., C1-C6) refer independently to the number of carbon atoms
in an
alkyl moiety, an aryl moiety, or in the alkyl portion of a larger substituent
in which
alkyl appears as its prefix root. For alkyl and alkoxy substituents, the
designated
number of carbon atoms includes all of the independent members included within
a
given range specified. For example Ci_6 alkyl would include methyl, ethyl,
propyl,
butyl, pentyl and hexyl individually as well as sub-combinations thereof
(e.g., C1_2, Cl
-
3, C1-4, C1-5, C2-6, C3-6, C4-6, C5_6, C2_5, etc.).
In general, under standard nomenclature rules used throughout this disclosure,
the terminal portion of the designated side chain is described first followed
by the
adjacent functionality toward the point of attachment. Thus, for example, a
"Ci-C6
alkylcarbonyl" substituent refers to a group of the formula:
0
4_11
_Cl-C6 alkyl
The term "R" at a stereocenter designates that the stereocenter is purely of
the
R-configuration as defined in the art; likewise, the term "S" means that the
stereocenter
is purely of the S-configuration. As used herein, the terms "*R" or "*S" at a
stereocenter are used to designate that the stereocenter is of pure but
unknown
configuration. As used herein, the term "RS" refers to a stereocenter that
exists as a
mixture of the R- and S-configurations. Similarly, the terms "*RS" or "*SR"
refer to a
stereocenter that exists as a mixture of the R- and S-configurations and is of
unknown
configuration relative to another stereocenter within the molecule.
Compounds containing one stereocenter drawn without a stereo bond
designation are a mixture of 2 enantiomers. Compounds containing 2
stereocenters
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both drawn without stereo bond designations are a mixture of 4 diastereomers.
Compounds with 2 stereocenters both labeled "RS" and drawn with stereo bond
designations are a 2-component mixture with relative stereochemistry as drawn.
Compounds with 2 stereocenters both labeled "*RS" and drawn with stereo bond
designations are a 2-component mixture with relative stereochemistry unknown.
Unlabeled stereocenters drawn without stereo bond designations are a mixture
of the R-
and S-configurations. For unlabeled stereocenters drawn with stereo bond
designations,
the absolute stereochemistry is as depicted.
Unless otherwise noted, it is intended that the definition of any substituent
or
variable at a particular location in a molecule be independent of its
definitions
elsewhere in that molecule. It is understood that substituents and
substitution patterns
on the compounds of Formula (I) can be selected by one of ordinary skill in
the art to
provide compounds that are chemically stable and that can be readily
synthesized by
techniques known in the art as well as those methods set forth herein.
The term "subject" refers to an animal, preferably a mammal, most preferably a
human, who has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" refers to an amount of an active
compound or pharmaceutical agent, including a compound of the present
invention,
which elicits the biological or medicinal response in a tissue system, animal
or human
that is being sought by a researcher, veterinarian, medical doctor or other
clinician,
which includes alleviation or partial alleviation of the symptoms of the
disease,
syndrome, condition, or disorder being treated.
The term "composition" refers to a product that includes the specified
ingredients in therapeutically effective amounts, as well as any product that
results,
directly, or indirectly, from combinations of the specified ingredients in the
specified
amounts.
The term " MGL inhibitor" is intended to encompass a compound that
interacts with MGL to substantially reduce or eliminate its catalytic
activity, thereby
increasing the concentrations of its substrate(s). The term "MGL-modulated" is
used
to refer to the condition of being affected by the modulation of the MGL
enzyme
including the condition of being affected by the inhibition of the MGL enzyme
such as
pain, and the diseases that lead to such pain, inflammation and CNS disorders.
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As used herein, unless otherwise noted, the term "affect" or "affected" (when
referring to a disease, syndrome, condition or disorder that is affected by
inhibition of
MGL) includes a reduction in the frequency and / or severity of one or more
symptoms
or manifestations of said disease, syndrome, condition or disorder; and / or
include the
prevention of the development of one or more symptoms or manifestations of
said
disease, syndrome, condition or disorder or the development of the disease,
condition,
syndrome or disorder.
The compounds of Formula (I) are useful in methods for treating, ameliorating
and / or preventing a disease, a syndrome, a condition or a disorder that is
affected by
the inhibition of MGL. Such methods comprise, consist of and/or consist
essentially of
administering to a subject, including an animal, a mammal, and a human in need
of
such treatment, amelioration and / or prevention, a therapeutically effective
amount of a
compound of Formula (I), or an enantiomer, diastereomer, solvate or
pharmaceutically
acceptable salt thereof In particular, the compounds of Formula (I), or an
enantiomer,
diastereomer, solvate or pharmaceutically acceptable salt thereof are useful
for treating,
ameliorating and / or preventing pain; diseases, syndromes, conditions, or
disorders
causing such pain; inflammation and / or CNS disorders. More particularly, the
compounds of Formula (I), or an enantiomer, diastereomer, solvate or
pharmaceutically
acceptable salt thereof are useful for treating, ameliorating and / or
preventing
inflammatory pain, inflammatory hypersensitivity conditions and / or
neuropathic pain,
comprising administering to a subject in need thereof a therapeutically
effective amount
of a compound of Formula (I), or an enantiomer, diastereomer, solvate or
pharmaceutically acceptable salt thereof as herein defined.
Examples of inflammatory pain include pain due to a disease, condition,
syndrome, disorder, or a pain state including inflammatory bowel disease,
visceral pain,
migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back
pain, lower back
pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases,
skin
diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite,
spider
bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract
infection, rhinitis,
contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,
enteritis,
irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain
syndrome,
menstrual pain, endometriosis, pain due to physical trauma, headache, sinus
headache,
tension headache, or arachnoiditis.
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One type of inflammatory pain is inflammatory hyperalgesia /
hypersensitivity. Examples of inflammatory hyperalgesia include a disease,
syndrome, condition, disorder, or pain state including inflammation,
osteoarthritis,
rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal
diseases,
skin diseases, post operative pain, headaches, toothache, burn, sunburn,
insect sting,
neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract
infection,
cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact
dermatitis/hypersensitivity and/or dermal allergy, itch, eczema, pharyngitis,
enteritis,
irritable bowel syndrome, inflammatory bowel diseases including Crohn's
Disease,
ulcerative colitis, benign prostatic hypertrophy, and nasal hypersensitivity.
In an embodiment, the present invention is directed to a method for treating,
ameliorating and / or preventing inflammatory visceral hyperalgesia in which a
enhanced visceral irritability exists, comprising, consisting of, and/or
consisting
essentially of the step of administering to a subject in need of such
treatment a
therapeutically effective amount of a compound, salt or solvate of Formula
(I). In a
further embodiment, the present invention is directed to a method for treating
inflammatory somatic hyperalgesia in which a hypersensitivity to thermal,
mechanical
and/or chemical stimuli exists, comprising administering to a mammal in need
of such
treatment a therapeutically effective amount of a compound of Formula (I) or
an
enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof
A further embodiment of the present invention is directed to a method for
treating, ameliorating and / or preventing neuropathic pain. Examples of a
neuropathic pain include pain due to a disease, syndrome, condition, disorder,
or pain
state including cancer, neurological disorders, spine and peripheral nerve
surgery, brain
tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain
syndrome,
fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral
neuropathy,
bilateral peripheral neuropathy, diabetic neuropathy, central pain,
neuropathies
associated with spinal cord injury, stroke, amyotrophic lateral sclerosis
(ALS),
Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint
neuralgia,
peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony
fractures, oral
neuropathic pain, Charcot's pain, complex regional pain syndrome I and II
(CRPS I/II),
radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth
syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental
neuritis,
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Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,
geniculate
neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic
neuralgia,
intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary
neuralgia,
occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia,
Sluder's neuralgia,
splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia,
vulvodynia, or
vidian neuralgia.
One type of neuropathic pain is neuropathic cold allodynia, which can be
characterized by the presence of a neuropathy-associated allodynic state in
which a
hypersensitivity to cooling stimuli exists. Examples of neuropathic cold
allodynia
include allodynia due to a disease, condition, syndrome, disorder or pain
state including
neuropathic pain (neuralgia), pain arising from spine and peripheral nerve
surgery or
trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic
neuralgia,
causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke,
peripheral
neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II)
and
radiculopathy.
In a further embodiment, the present invention is directed to a method for
treating, ameliorating and / or preventing neuropathic cold allodynia in which
a
hypersensitivity to a cooling stimuli exists, comprising, consisting of,
and/or consisting
essentially of the step of administering to a subject in need of such
treatment a
therapeutically effective amount of a compound of Formula (I) or an
enantiomer,
diastereomer, solvate or pharmaceutically acceptable salt thereof
In a further embodiment, the present invention is directed to a method for
treating, ameliorating and / or preventing CNS disorders. Examples of CNS
disorders
include anxieties such as, social anxiety, post-traumatic stress disorder,
phobias, social
phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute
stress
disorder, separation anxiety disorder, and generalized anxiety disorder, as
well as
depression such as, major depression, bipolar disorder, seasonal affective
disorder, post
natal depression, manic depression, and bipolar depression.
Embodiments of the present invention include a compound of Formula (I)
0, __________________________________
N1 )1IR 0
Y \ Z
Formula (I)
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wherein
Y and Z are independently selected from Group a) or Group b) such that
one of Y and Z is Group a) and the other is Group b); and
a) Group a) is unsubstituted phenyl or an unsubstituted heteroaryl selected
from
the group consisting of thiazolyl, isothiazolyl, and 1H-pyrroly1;
b) Group a) is unsubstituted phenyl or an unsubstituted heteroaryl selected
from
the group consisting of thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,
isothiazolyl, 1H-
pyrrol-2-yl, and 1H-pyrrol-3-y1;
c) Group b) is
i) phenyl;
ii) a heteroaryl selected from the group consisting of benzoxazolyl,
benzimidazolyl, benzothienyl, and indolyl;
iii) phenylmethyl-phenyl wherein the phenyl group of phenylmethyl
isunsubstituted or substituted with with trifluoromethyl or fluoro; or
iv) 1,3-dihydro-3H-benzimidazol-2-on-y1;
wherein Group b) other than phenylmethyl-phenyl is unsubstituted or
substituted with one or two substitutents each of which is independently
selected from the group consisting of chloro, fluoro, methyl, and Rb; provided
that no more than one substituent is Rb; and
Rb is selected from the group consisting of trifluoromethyl, 2,2,2-
trifluoroethyl, 3,3,3-trifluoropropyl, 4,4-difluorocyclohexyl, thienyl,
pyridinyl,
and phenyl; wherein said thienyl, pyridinyl, and phenyl of Rb are
unsubstituted
or substituted with one or two substituents each of which is independently
selected from the group consisting of trifluoromethyl, methyl, chloro, and
fluoro;
d) Group b) is
i) phenyl;
ii) a heteroaryl selected from the group consisting of benzoxazolyl,
benzimidazolyl, benzothienyl, and indolyl;
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iii) phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is
unsubstituted or substituted with trifluoromethyl; or
iv) 1,3-dihydro-3H-benzimidazol-2-on-y1;
wherein Group b) other than phenylmethyl-phenyl is unsubstituted or
substituted with one or two substitutents independently selected from the
group
consisting of chloro, fluoro, methyl, and Rb; provided that no more than one
substituent is Rb; and
Rb is selected from the group consisting of trifluoromethyl, thienyl,
PYridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of Rb are
optionally independently substituted with one to two trifluoromethyl, methyl,
chloro, or fluoro substituents;
e) R is hydrogen;
and any combination of embodiments a) through e) above, provided that it is
understood that combinations in which different embodiments of the same
substituent
would be combined are excluded;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts
thereof
An embodiment of the present invention includes a compound of Formula (I)
0 \ R 0
y ___________________________________________ CN-1(
Y
Formula (I)
wherein
Y and Z are independently selected from Group a) or Group b) such that one of
Y and Z is Group a) and the other is Group b);
Group a) is an unsubstituted phenyl or an unsubstituted heteroaryl selected
from
the group consisting of thiazolyl, isothiazolyl, and 1H-pyrroly1;
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Group b) is
i) phenyl;
ii) a heteroaryl selected from the group consisting of benzoxazolyl,
benzimidazolyl, benzothienyl, and indolyl;
iii) phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is
unsubstituted or substituted with trifluoromethyl or fluoro; or
iv) 1,3-dihydro-3H-benzimidazol-2-on-y1;
wherein Group b) other than phenylmethyl-phenyl is unsubstituted or
substituted with one or two substitutents independently selected from the
group
consisting of chloro, fluoro, methyl, and Rb; provided that no more than one
substituent is Rb; and
Rb is selected from the group consisting of trifluoromethyl, 2,2,2-
trifluoroethyl, 3,3,3-trifluoropropyl, 4,4-difluorocyclohexyl, thienyl,
pyridinyl,
and phenyl; wherein said thienyl, pyridinyl, and phenyl of Rb are
unsubstituted
or substituted with one or two substituents independently selected from the
group consisting of trifluoromethyl, methyl, chloro, and fluoro;
R is hydrogen;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts
thereof
An embodiment of the present invention includes a compound of Formula (I)
0 \ R 0
y ___________________________________________ CN-1(
Y
Formula (I)
wherein
Y and Z are independently selected from Group a) or Group b) such that one of
Y and Z is Group a) and the other is Group b);
Group a) is an unsubstituted phenyl or an unsubstituted heteroaryl selected
from
the group consisting of thiazolyl, isothiazolyl, and 1H-pyrroly1;
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Group b) is
i) phenyl;
ii) a heteroaryl selected from the group consisting of benzoxazolyl,
benzimidazolyl, benzothienyl, and indolyl;
iii) phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is
unsubstituted or substituted with trifluoromethyl; or
iv) 1,3-dihydro-3H-benzimidazol-2-on-y1;
wherein Group b) other than phenylmethyl-phenyl is unsubstituted or
substituted with one or two substitutents independently selected from the
group
consisting of chloro, fluoro, methyl, and Rb; provided that no more than one
substituent is Rb; and
Rb is selected from the group consisting of trifluoromethyl, thienyl,
PYridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of Rb are
unsubstituted or substituted with one or two substitutents independently
selected
from the group consisting of trifluoromethyl, methyl, chloro, and fluoro;
R is hydrogen or hydroxy;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts
thereof
An embodiment of the present invention includes a compound of Formula (I)
0 \ R 0
y ___________________________________________ CN-1(
Y
Formula (I)
wherein
Y and Z are independently selected from Group a) or Group b) such that one of
Y and Z is Group a) and the other is Group b);
Group a) is unsubstituted phenyl or an unsubstituted heteroaryl selected from
the group consisting of thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,
isothiazolyl, 1H-pyrrol-
2-yl, and 1H-pyrrol-3-y1;
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Group b) is
i) phenyl;
ii) a heteroaryl selected from the group consisting of benzoxazolyl,
benzimidazolyl, benzothienyl, and indolyl;
iii) phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is
unsubstituted or substituted with trifluoromethyl; or
iv) 1,3-dihydro-3H-benzimidazol-2-on-y1;
wherein Group b) other than phenylmethyl-phenyl is unsubstituted or
substituted with one or two substitutents independently selected from the
group
consisting of chloro, fluoro, methyl, and Rb; provided that no more than one
substituent is Rb; and
Rb is selected from the group consisting of trifluoromethyl, thienyl,
PYridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of Rb are
unsubstituted or substituted with one or two substituents independently
selected
from the group consisting of trifluoromethyl, methyl, chloro, and fluoro;
R is hydrogen or hydroxy;
and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts
thereof
An embodiment of the present invention includes a compound of Formula (I)
0 \ R 0
y ___________________________________________ CN-1(
Formula (I)
selected from the group consisting of
the compound wherein Y is thiazol-4-yl, Z is biphenyl-4-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is biphenyl-4-yl, and R is H;
the compound wherein Y is isothiazol-5-yl, Z is biphenyl-4-yl, and R is H;
the compound wherein Y is 1H-pyrrol-3-yl, Z is biphenyl-4-yl, and R is H;
the compound wherein Y is thiazol-5-yl, Z is biphenyl-4-yl, and R is H;
the compound wherein Y is phenyl, Z is 5-trifluoromethyl-benzothien-2-yl, and
R is
OH;
the compound wherein Y is thiazol-4-yl, Z is 3-chloro-6-fluoro-benzothien-2-
yl, and R
is H;
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the compound wherein Y is thiazol-2-yl, Z is 3-chloro-6-fluoro-benzothien-2-
yl, and R
is H;
the compound wherein Y is thiazol-4-yl, Z is 2-fluoro-4-phenyl-phenyl, and R
is H;
the compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylpheny1)-
phenyl, and
R is H;
the compound wherein Y is thiazol-4-yl, Z is 3-(3-fluoropheny1)-phenyl, and R
is H;
the compound wherein Y is thiazol-4-yl, Z is 4-(5-trifluoromethylthien-2-ye-
phenyl,
and R is H;
the compound wherein Y is thiazol-4-yl, Z is 4-(3-trifluoromethylphenylmethyl)-
phenyl, and R is H;
the compound wherein Y is thiazol-4-yl, Z is 3-methy1-6-trifluoromethyl-
benzothien-2-
yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 2-fluoro-4-phenyl-phenyl, and R
is H;
the compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylpheny1)-
phenyl, and
R is H;
the compound wherein Y is thiazol-2-yl, Z is 3-(3-fluoropheny1)-phenyl, and R
is H;
the compound wherein Y is thiazol-2-yl, Z is 4-(5-trifluoromethylthien-2-ye-
phenyl,
and R is H;
the compound wherein Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenylmethyl)-
phenyl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 3-methy1-6-trifluoromethyl-
benzothien-2-
yl, and R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 2-fluoro-4-phenyl-phenyl, and R
is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 4-(3-trifluoromethylphenye-
phenyl,
and R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 3-(3-fluoropheny1)-phenyl, and
R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 4-(5-trifluoromethylthien-2-ye-
phenyl,
and R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 4-(3-
trifluoromethylphenylmethyl)-
phenyl, and R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 3-methy1-6-trifluoromethyl-
benzothien-2-yl, and R is H;
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the compound wherein Y is thiazol-2-yl, Z is 4-(4-trifluoromethylphenylmethyl)-
phenyl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 2-phenyl-benzoxazol-6-yl, and R
is H;
the compound wherein Y is thiazol-2-yl, Z is 3-chloro-6-trifluoromethyl-
benzothien-2-
yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoropheny1)-1H-indo1-5-yl,
and R
is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-trifluoromethylpheny1)-1H-
indo1-5-
yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(3,4-difluoropheny1)-1H-indo1-5-
yl, and
R is H;
the compound wherein Y is thiazol-4-yl, Z is 4-(4-trifluoromethylphenylmethyl)-
phenyl, and R is H;
the compound wherein Y is thiazol-4-yl, Z is 2-phenyl-benzoxazol-6- yl, and R
is H;
the compound wherein Y is thiazol-4-yl, Z is 3-chloro-6-trifluoromethyl-
benzothien-2-
yl, and R is H;
the compound wherein Y is thiazol-4-yl, Z is 1-(4-fluoropheny1)-1H-indo1-5-yl,
and R
is H;
the compound wherein Y is thiazol-4-yl, Z is 1-(4-trifluoromethylpheny1)-1H-
indo1-5-
yl, and R is H;
the compound wherein Y is thiazol-4-yl, Z is 1-(3,4-difluoropheny1)-1H-indo1-5-
yl, and
R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 4-(4-
trifluoromethylphenylmethyp-
phenyl, and R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 2-phenyl-benzoxazol-6- yl, and
R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 3-chloro-6-trifluoromethyl-
benzothien-2-yl, and R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 1-(4-fluoropheny1)-1H-indo1-5-
yl, and
R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 1-(4-trifluoromethylpheny1)-1H-
indo1-
5-yl, and R is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 1-(3,4-difluoropheny1)-1H-indo1-
5-yl,
and R is H;
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the compound wherein Y is 2-fluoro-4-phenyl-phenyl, Z is thiazol-2-yl, and R
is H;
the compound wherein Y is 2-fluoro-4-phenyl-phenyl, Z is thiazol-4-yl, and R
is H;
the compound wherein Y is 1H-pyrrol-2-yl, Z is 2-fluoro-4-phenyl-phenyl, and R
is H;
the compound wherein Y is 4-(3-trifluoromethylphenye-phenyl, Z is thiazol-2-
yl, and
R is H;
the compound wherein Y is 4-(3-trifluoromethylphenye-phenyl, Z is thiazol-4-
yl, and
R is H;
the compound wherein Y is 4-(3-trifluoromethylphenye-phenyl, Z is 1H-pyrrol-2-
yl,
and R is H;
the compound wherein Y is 3-(3-fluoropheny1)-phenyl, Z is thiazol-2-yl, and R
is H;
the compound wherein Y is 3-(3-fluoropheny1)-phenyl, Z is thiazol-4-yl, and R
is H;
the compound wherein Y is 3-(3-fluoropheny1)-phenyl, Z is 1H-pyrrol-2-yl, and
R is H;
the compound wherein Y is 4-(5-trifluoromethyl-thien-2-ye-phenyl, Z is thiazol-
2-yl,
and R is H;
the compound wherein Y is 4-(5-trifluoromethyl-thien-2-y1)-phenyl, Z is
thiazol-4-yl,
and R is H;
the compound wherein Y is 4-(5-trifluoromethyl-thien-2-y1)-phenyl, Z is 1H-
pyrrol-2-
yl, and R is H;
the compound wherein Y is 4-(3-trifluoromethylphenylmethyl)-phenyl, Z is
thiazol-2-
yl, and R is H;
the compound wherein Y is 4-(3-trifluoromethylphenylmethyl)-phenyl, Z is
thiazol-4-
yl, and R is H;
the compound wherein Y is 4-(3-trifluoromethylphenylmethyl)-phenyl, Z is 1H-
pyrrol-
2-yl, and R is H;
the compound wherein Y is 3-methyl-6-trifluoromethyl-benzothien-2-yl, Z is
thiazol-2-
yl, and R is H;
the compound wherein Y is 3-methy1-6-trifluoromethyl-benzothien-2-yl, Z is
thiazol-4-
yl, and R is H;
the compound wherein Y is 3-methyl-6-trifluoromethyl-benzothien-2-yl, Z is 1H-
pyrrol-2-yl, and R is H;
the compound wherein Y is 4-(4-trifluoromethylphenylmethyl)-phenyl, Z is
thiazol-2-
yl, and R is H;
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the compound wherein Y is 4-(4-trifluoromethylphenylmethyl)-phenyl, Z is
thiazol-4-
yl, and R is H;
the compound wherein Y is 4-(4-trifluoromethylphenylmethyl)-phenyl, Z is 1H-
pyrrol-
2-yl, and R is H;
the compound wherein Y is 2-phenyl-benzoxazol-6-yl, Z is thiazol-2-yl, and R
is H;
the compound wherein Y is 2-phenyl-benzoxazol-6-yl, Z is thiazol-4-yl, and R
is H;
the compound wherein Y is 2-phenyl-benzoxazol-6-yl, Z is 1H-pyrrol-2-yl, and R
is H;
the compound wherein Y is 3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is
thiazol-2-
yl, and R is H;
the compound wherein Y is 3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is
thiazol-4-
yl, and R is H;
the compound wherein Y is 3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is 1H-
pyrrol-2-yl, and R is H;
the compound wherein Y is 1-(4-fluoropheny1)-1H-indo1-5-yl, Z is thiazol-2-yl,
and R
is H;
the compound wherein Y is 1-(4-fluoropheny1)-1H-indo1-5-yl, Z is thiazol-4-yl,
and R
is H;
the compound wherein Y is 1-(4-fluoropheny1)-1H-indo1-5-yl, Z is 1H-pyrrol-2-
yl, and
R is H;
the compound wherein Y is 1-(4-trifluoromethylpheny1)-1H-indo1-5-yl, Z is
thiazol-2-
yl, and R is H;
the compound wherein Y is 1-(4-trifluoromethylpheny1)-1H-indo1-5-yl, Z is
thiazol-4-
yl, and R is H;
the compound wherein Y is 1-(4-trifluoromethylpheny1)-1H-indo1-5-yl, Z is 1H-
pyrrol-
2-yl, and R is H;
the compound wherein Y is 1-(3,4-difluoropheny1)-1H-indo1-5-yl, Z is thiazol-2-
yl, and
R is H;
the compound wherein Y is 1-(3,4-difluoropheny1)-1H-indo1-5-yl, Z is thiazol-4-
yl, and
R is H;
the compound wherein Y is 1-(3,4-difluoropheny1)-1H-indo1-5-yl, Z is 1H-pyrrol-
2-yl,
and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoropheny1)-1H-
benzimidazol-5-yl,
and R is H;
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the compound wherein Y is thiazol-2-yl, Z is 1-(3,4-difluoropheny1)-1H-
benzimidazol-
5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-trifluoromethylpheny1)-1H-
benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(2,2,2-trifluoroethyl)-1H-
benzimidazol-
5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(3,3,3-trifluoropropy1)-1H-
benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-phenyl-2-methyl-1H-benzimidazol-
5-yl,
and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoropheny1)-2-methy1-1H-
benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(3,4-difluoropheny1)-2-methy1-
1H-
benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-trifluoromethylpheny1)-2-
methy1-
1H-benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(2,2,2-trifluoroethyl)-2-methy1-
1H-
benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(3,3,3-trifluoropropy1)-2-
methy1-1H-
benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4,4-difluorocyclohexyl)-2-
methy1-1H-
benzimidazol-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(5-chloropyridin-2-y1)-1H-indo1-
5-yl,
and R is H;
the compound wherein Y is thiazol-2-yl, Z is 6-trifluoromethyl-benzothien-2-
yl, and R
is OH;
the compound wherein Y is thiazol-2-yl, Z is 1-(2-methylpyridin-4-y1)-1H-indo1-
5-yl,
and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-pheny1-1,3-dihydro-3H-
benzimidazol-
2-on-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-fluoropheny1)-1,3-dihydro-3H-
benzimidazol-2-on-5-yl, and R is H;
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the compound wherein Y is thiazol-2-yl, Z is 1-(3,4-difluoropheny1)-1,3-
dihydro-3H-
benzimidazol-2-on-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4-trifluoromethylpheny1)-1,3-
dihydro-
3H-benzimidazol-2-on-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(3,3,3-trifluoropropy1)-1,3-
dihydro-3H-
benzimidazol-2-on-5-yl, and R is H;
the compound wherein Y is thiazol-2-yl, Z is 1-(4,4-difluorocyclohexyl)-1,3-
dihydro-
3H-benzimidazol-2-on-5-yl, and R is H;
and pharmaceutically acceptable salt forms thereof
For use in medicine, salts of compounds of Formula (I) refer to non-toxic
"pharmaceutically acceptable salts." Other salts may, however, be useful in
the
preparation of compounds of Formula (I) or of their pharmaceutically
acceptable salt
forms thereof Suitable pharmaceutically acceptable salts of compounds of
Formula (I)
include acid addition salts that can, for example, be formed by mixing a
solution of the
compound with a solution of a pharmaceutically acceptable acid such as,
hydrochloric
acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid,
benzoic acid,
citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore,
where the
compounds of Formula (I) carry an acidic moiety, suitable pharmaceutically
acceptable
salts thereof may include alkali metal salts such as, sodium or potassium
salts; alkaline
earth metal salts such as, calcium or magnesium salts; and salts formed with
suitable
organic ligands such as, quaternary ammonium salts. Thus, representative
pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate,
bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate,
camsylate,
carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,
edisylate, estolate,
esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate,
methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-
methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,
pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,
subacetate,
succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.
Representative acids and bases that may be used in the preparation of
pharmaceutically acceptable salts include acids including acetic acid, 2,2-
dichloroacetic
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acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-
aspartic acid,
benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric
acid,
camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic
acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric
acid, ethane-
1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid,
formic acid,
fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-
glucoronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric
acid,
hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, ( )-DL-lactic acid,
lactobionic
acid, maleic acid, (-)-L-malic acid, malonic acid, ( )-DL-mandelic acid,
methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic
acid, 1-
hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic
acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic
acid, 4-
amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid,
tannic acid,
(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic
acid; and
bases including ammonia, L-arginine, benethamine, benzathine, calcium
hydroxide,
choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol,
ethanolamine,
ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,
magnesium hydroxide, 4-(2-hydroxyethyl)-morpholin, piperazine, potassium
hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine,
tromethamine, and zinc hydroxide.
Embodiments of the present invention include prodrugs of compounds of
Formula (I). In general, such prodrugs will be functional derivatives of the
compounds
that are readily convertible in vivo into the required compound. Thus, in the
methods
of treating or preventing embodiments of the present invention, the term
"administering" encompasses the treatment or prevention of the various
diseases,
conditions, syndromes and disorders described with the compound specifically
disclosed or with a compound that may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to a patient.
Conventional procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard,
Elsevier, 1985.
Where the compounds according to embodiments of this invention have at least
one chiral center, they may accordingly exist as enantiomers. Where the
compounds
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possess two or more chiral centers, they may additionally exist as
diastereomers. It is
to be understood that all such isomers and mixtures thereof are encompassed
within the
scope of the present invention. Furthermore, some of the crystalline forms for
the
compounds may exist as polymorphs and as such are intended to be included in
the
present invention. In addition, some of the compounds may form solvates with
water
(i.e., hydrates) or common organic solvents, and such solvates are also
intended to be
encompassed within the scope of this invention. The skilled artisan will
understand
that the term compound as used herein, is meant to include solvated compounds
of
Formula (I).
Where the processes for the preparation of the compounds according to certain
embodiments of the invention give rise to mixture of stereoisomers, these
isomers may
be separated by conventional techniques such as, preparative chromatography.
The
compounds may be prepared in racemic form, or individual enantiomers may be
prepared either by enantiospecific synthesis or by resolution. The compounds
may, for
example, be resolved into their component enantiomers by standard techniques
such as,
the formation of diastereomeric pairs by salt formation with an optically
active acid
such as, (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoy1-1-tartaric
acid followed
by fractional crystallization and regeneration of the free base. The compounds
may
also be resolved by formation of diastereomeric esters or amides, followed by
chromatographic separation and removal of the chiral auxiliary. Alternatively,
the
compounds may be resolved using a chiral HPLC column.
One embodiment of the present invention is directed to a composition,
including
a pharmaceutical composition, comprising, consisting of, and/or consisting
essentially
of the (+)-enantiomer of a compound of Formula (I) wherein said composition is
substantially free from the (-)-isomer of said compound. In the present
context,
substantially free means less than about 25 %, preferably less than about 10
%, more
preferably less than about 5 %, even more preferably less than about 2 % and
even
more preferably less than about 1 % of the (-)-isomer calculated as
(mass (+)-enantiomer)
%(+) - enantiomer ¨ ____________________________________ x 100
(mass (+)- enantiomer) + (mass(¨)- enantiomer)
Another embodiment of the present invention is a composition, including a
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pharmaceutical composition, comprising, consisting of, and consisting
essentially of
the (-)-enantiomer of a compound of Formula (I) wherein said composition is
substantially free from the (+)-isomer of said compound. In the present
context,
substantially free from means less than about 25 %, preferably less than about
10 %,
more preferably less than about 5 %, even more preferably less than about 2 %
and
even more preferably less than about 1 % of the (+)-isomer calculated as
(mass (¨) - enantiomer)
%(¨) - enantiomer =x 100
(mass (+) - enantiomer) + (mass(¨)- enantiomer)
During any of the processes for preparation of the compounds of the various
embodiments of the present invention, it may be necessary and/or desirable to
protect
sensitive or reactive groups on any of the molecules concerned. This may be
achieved
by means of conventional protecting groups such as those described in
Protective
Groups in Organic Chemistry, Second Edition, J.F.W. McOmie, Plenum Press,
1973;
T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley
&
Sons, 1991; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic
Synthesis,
Third Edition, John Wiley & Sons, 1999. The protecting groups may be removed
at a
convenient subsequent stage using methods known from the art.
Even though the compounds of embodiments of the present invention (including
their pharmaceutically acceptable salts and pharmaceutically acceptable
solvates) can
be administered alone, they will generally be administered in admixture with a
pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient
and/or a
pharmaceutically acceptable diluent selected with regard to the intended route
of
administration and standard pharmaceutical or veterinary practice. Thus,
particular
embodiments of the present invention are directed to pharmaceutical and
veterinary
compositions comprising compounds of Formula (I) and at least one
pharmaceutically
acceptable carrier, pharmaceutically acceptable excipient, and/or
pharmaceutically
acceptable diluent.
By way of example, in the pharmaceutical compositions of embodiments of the
present invention, the compounds of Formula (I) may be admixed with any
suitable
binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing
agent(s), and
combinations thereof
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Solid oral dosage forms such as, tablets or capsules, containing the compounds
of the present invention may be administered in at least one dosage form at a
time, as
appropriate. It is also possible to administer the compounds in sustained
release
formulations.
Additional oral forms in which the present inventive compounds may be
administered include elixirs, solutions, syrups, and suspensions; each
optionally
containing flavoring agents and coloring agents.
Alternatively, compounds of Formula (I) can be administered by inhalation
(intratracheal or intranasal) or in the form of a suppository or pessary, or
they may be
applied topically in the form of a lotion, solution, cream, ointment or
dusting powder.
For example, they can be incorporated into a cream comprising, consisting of,
and/or
consisting essentially of an aqueous emulsion of polyethylene glycols or
liquid paraffin.
They can also be incorporated, at a concentration of between about 1 % and
about 10 %
by weight of the cream, into an ointment comprising, consisting of, and/or
consisting
essentially of a wax or soft paraffin base together with any stabilizers and
preservatives
as may be required. An alternative means of administration includes
transdermal
administration by using a skin or transdermal patch.
The pharmaceutical compositions of the present invention (as well as the
compounds of the present invention alone) can also be injected parenterally,
for
example, intracavernosally, intravenously, intramuscularly, subcutaneously,
intradermally, or intrathecally. In this case, the compositions will also
include at least
one of a suitable carrier, a suitable excipient, and a suitable diluent.
For parenteral administration, the pharmaceutical compositions of the present
invention are best used in the form of a sterile aqueous solution that may
contain other
substances, for example, enough salts and monosaccharides to make the solution
isotonic with blood.
For buccal or sublingual administration, the pharmaceutical compositions of
the
present invention may be administered in the form of tablets or lozenges,
which can be
formulated in a conventional manner.
By way of further example, pharmaceutical compositions containing at least one
of the compounds of Formula (I) as the active ingredient can be prepared by
mixing the
compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically
acceptable
diluent, and/or a pharmaceutically acceptable excipient according to
conventional
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pharmaceutical compounding techniques. The carrier, excipient, and diluent may
take
a wide variety of forms depending upon the desired route of administration
(e.g., oral,
parenteral, etc.). Thus, for liquid oral preparations such as, suspensions,
syrups, elixirs
and solutions, suitable carriers, excipients and diluents include water,
glycols, oils,
alcohols, flavoring agents, preservatives, stabilizers, coloring agents and
the like; for
solid oral preparations such as, powders, capsules, and tablets, suitable
carriers,
excipients and diluents include starches, sugars, diluents, granulating
agents, lubricants,
binders, disintegrating agents and the like. Solid oral preparations also may
be
optionally coated with substances such as, sugars, or be enterically coated so
as to
modulate the major site of absorption and disintegration. For parenteral
administration,
the carrier, excipient and diluent will usually include sterile water, and
other ingredients
may be added to increase solubility and preservation of the composition.
Injectable
suspensions or solutions may also be prepared utilizing aqueous carriers along
with
appropriate additives such as, solubilizers and preservatives.
A therapeutically effective amount of a compound of Formula (I) or a
pharmaceutical composition thereof includes a dose range from about 0.1 mg to
about
3000 mg, or any particular amount or range therein, in particular from about 1
mg to
about 1000 mg, or any particular amount or range therein, or, more
particularly, from
about 10 mg to about 500 mg, or any particular amount or range therein, of
active
ingredient in a regimen of about 1 to about 4 times per day for an average (70
kg)
human; although, it is apparent to one skilled in the art that the
therapeutically effective
amount for a compound of Formula (I) will vary as will the diseases,
syndromes,
conditions, and disorders being treated.
For oral administration, a pharmaceutical composition is preferably provided
in
the form of tablets containing about 1.0, about 10, about 50, about 100, about
150,
about 200, about 250, and about 500 milligrams of a compound of Formula (I).
Advantageously, a compound of Formula (I) may be administered in a single
daily dose, or the total daily dosage may be administered in divided doses of
two, three
and four times daily.
Optimal dosages of a compound of Formula (I) to be administered may be
readily determined and will vary with the particular compound used, the mode
of
administration, the strength of the preparation and the advancement of the
disease,
syndrome, condition or disorder. In addition, factors associated with the
particular
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subject being treated, including subject gender, age, weight, diet and time of
administration, will result in the need to adjust the dose to achieve an
appropriate
therapeutic level and desired therapeutic effect. The above dosages are thus
exemplary
of the average case. There can be, of course, individual instances wherein
higher or
lower dosage ranges are merited, and such are within the scope of this
invention.
Compounds of Formula (I) may be administered in any of the foregoing
compositions and dosage regimens or by means of those compositions and dosage
regimens established in the art whenever use of a compound of Formula (I) is
required
for a subject in need thereof
As MGL Inhibitors, the compounds of Formula (I) are useful in methods for
treating and preventing a disease, a syndrome, a condition or a disorder in a
subject,
including an animal, a mammal and a human in which the disease, the syndrome,
the
condition or the disorder is affected by the modulation, including inhibition,
of the
MGL enzyme. Such methods comprise, consist of and/or consist essentially of
administering to a subject, including an animal, a mammal, and a human in need
of
such treatment or prevention a therapeutically effective amount of a compound,
salt or
solvate of Formula (I).
GENERAL SYNTHETIC METHODS
Representative compounds of the present invention can be synthesized in
accordance with the general synthetic methods described below and illustrated
in the
schemes and examples that follow. Since the schemes are an illustration, the
invention
should not be construed as being limited by the chemical reactions and
conditions
described in the schemes. The various starting materials used in the schemes
and
examples are commercially available or may be prepared by methods well within
the
skill of persons versed in the art. The variables are as defined herein.
Abbreviations used in the instant specification, particularly the schemes and
examples, are as follows:
AcC1 acetyl chloride
AcOH glacial acetic acid
aq. aqueous
Bn or Bzl benzyl
Boc tert-butyloxycarbonyl
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conc. concentrated
DBE 1,2-dibromoethane
DCC NN'-dicyclohexyl-carbodiimi de
DCE 1,2-dichloroethane
DCM dichloromethane
DIPEA diisopropylethylamine
DMAP 4-(NN-dimethylamino)pyridine
DMA N,N-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DPPA diphenylphosphoryl azide
EDC N-(3-dimethylaminopropy1)-N'-ethylcarbodiimide
hydrochloride
ESI electrospray ionization
Et0Ac ethyl acetate
Et0H ethanol
hour(s)
HATU 0-(1H-7-azabenzotriazol-1-y1)-1,1,3,3-
tetramethyluronium hexafluorophosphate
HBTU 0-(1H-benzotriazol-1-y1)-1,1,3,3-
tetramethyluronium hexafluorophosphate
HEK human embryonic kidney
HEPES (4-(2-hydroxyethyl)-1-piperazineethane
sulfonic acid
HMPA hexamethylphosphoramide
HPLC high performance liquid chromatography
mCPBA meta-chloroperoxybenzoic acid
MeCN acetonitrile
Me0H methanol
Me0Tf methyl triflate
MHz megahertz
min minutes
MS mass spectrometry
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NMR nuclear magnetic resonance
PIPES piperazine-N,N'-bis(2-ethanesulfonic acid)
PyBrOP bromo-tris-pyrrolidinophosphonium
hexafluorophosphate
RP reverse-phase
Rt retention time
TEA or Et3N triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS tetramethylsilane
Scheme A illustrates a route for the synthesis of intermediates that are
useful
for the preparation of compounds of Formula (I) wherein R is hydrogen.
Scheme A
1) Zn/TMS-Cl/DBE
DMA, 65 C, 1 h /_ BnBr
I¨CN¨P ________________ 3.- \ _____________ MeCN CN¨P ___________ i
Bn¨Ni+¨) CN¨P
i
/¨
Al 2) N /¨I A3
¨1 A3 A4
______________________ A2
Pd- Cross-Coupling
NaBH4, Et0H i Pd(OH)2, H2 (50 psi)
/ __________________________________________________ )
______________ Bn¨N CN¨P ______________ - HN
________________________________________________________ N¨P
Et0H
A5 A6
A compound of formula Al (wherein P is a conventional amino protecting group)
is
either commercially available or may be prepared by known methods described in
the
scientific literature. A compound of formula Al may be treated with zinc metal
in the
presence of TMS-C1, in an aprotic solvent, followed by addition of a compound
of
formula A2, in the presence of palladium catalyst to afford a compound of
formula A3.
Treatment with benzyl bromide affords the pyridinium bromide of formula A4. A
compound of formula A4 may be reduced to a compound of formula A5 in the
presence
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of a hydride source such as, sodium borohydride, in an organic alcoholic
solvent such
as, ethanol. Removal of the benzyl group and reduction of the double bond may
be
achieved by palladium catalyzed hydrogenation to afford the desired
intermediate of
formula A6.
Scheme B illustrates a route for the preparation of compounds of Formula (I)-B
wherein Y and Z are as defined herein and R of Formula (I) is hydrogen.
Scheme B
0
,P Z-C(0)-Q, B2 JJ
C-1N
r.11\1H amide coupling rf.11\1 Z
Amino
or
( I
acid chloride acylation I
N Deprotection N __________________ 2.- N
A3 B1 B3
Y-C(0)-Q, B5 0
0 amide coupling A
Reductionor
NAZ acid chloride acylation r.C. iN Z
_... _______________________________ .
Y).r N
HN
B4 0 Formula (I)-B
The amino protecting group (P) of a compound of formula A3 may be removed by
conventional synthetic methods to afford a secondary amine of formula Bl. The
amino
group may be coupled with a carboxylic acid of formula B2 (wherein Q is
hydroxy) in
the presence of an appropriate coupling agent such as HATU, DCC, EDC, HBTU,
PyBrOP, and the like, optionally in the presence of a base such as DIPEA, to
afford an
amide of formula B3. Similarly, an acid chloride of formula B2 (wherein Q is
chloro)
may be used to effect the acylation of a compound of formula Bl. In such case
a non-
nucleophilic base such as pyridine may be added to afford an amide of formula
B3.
Reduction of the pyridine ring of a compound of formula B3 may be achieved by
palladium catalyzed hydrogenation to afford a compound of formula B4. A second
acylation with an appropriately Y-substituted carboxylic acid or acid chloride
of
formula B5 affords a compound of Formula (I)-B wherein R of Formula (I) is
hydrogen.
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Scheme C illustrates an alternate route for the preparation of compounds of
Formula (I)-B wherein Y and Z are as defined herein and R of Formula (I) is
hydrogen.
Scheme C
P
r.C.IN" r.C.INH
amide coupling Amino
______________________________ ..
HN Y. N
or Deprotection YYN
A6 Cl C2
acid chloride acylation 0 0
0
r.C.INAZ
Z-C(0)-Q, B2
amide coupling
_________________________ ' Y).r N
or
acid chloride acylation 0 Formula (I)-B
The compound of formula A6 may be acylated according to the synthetic methods
described under Scheme B to afford the acylated compound of formula Cl.
Conventional amino deprotection affords the amine of formula C2, which may
undergo
a second acylation as previously described to afford a compound of Formula (I)-
B.
Scheme D illustrates a route for the preparation of compounds of Formula (I)-D
wherein Y and Z are as defined herein and R of Formula (I) is hydroxy.
Scheme D
o o
Ph 0 SmI2, .1\1).LY NAY
PhNI -1\1)(\( HMPA, THE Amino
\..
PhõNO1-1
I 0 Deprotection
HN OH
Dl 02 T
Ph 03 D4
0
NAY
Z-C(0)-Q, B2
amide coupling
_________________________ Z NiD1*-1
Or v. y
acid chloride acylation 0 Formula (I)-D
Compounds of formulae D1 and D2 are either commercially available or may be
prepared by known methods described in the scientific literature. A compound
of
formula D1 may be treated with samarium iodide in the presence of HMPA, in an
aprotic solvent, followed by the addition of a ketone of formula D2 to afford
the
condensed product of formula D3. Removal of the benzhydryl group may be
effected
by palladium catalyzed hydrogenation to afford the free amine of formula D4.
The
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amine of formula D4 may be acylated with a Z ¨substituted compound of formula
B2
by the methods previously described herein to afford a compound of Formula (I)-
D.
Scheme E illustrates an alternate route for the preparation of compounds of
Formula (I)-D wherein Y and Z are as defined herein and R of Formula (I) is
hydroxy.
Scheme E
Ph N-P NH
SmI2,
+ Th\i HMPA, THF
Ph)1\1\.. ____________________ a
,N11--) Amino
F1 _________________________________________________ a
Ph ,NI-J-)(:)F1
I (:) Ph ) Deprotection
T
DI El I E2 (P) E3
Ph Ph
0
Y-C(0)-Q, B5 A
N Y 0
amide coupling
_______________ a
Ph NIDII*F1 Benzhydryl A
N Y
or Removal
acid chloride acylation __ 1 a
E4E5
Ph HNIf.)0F1
0
Z-C(0)-Q, B2 N1).LY
amide coupling
_______________ a
or ZõNrO
.)-1
acid chloride acylation bi Formula (I)-D
A compound of formula D1 may be condensed with a compound of formula El in the
presence of samarium iodide and HMPA to afford a compound of formula E2.
Removal of the amino protecting group (P) using conventional synthetic methods
affords a compound of formula E3. Acylation with a compound of formula B5
affords
a compound of formula E4, which, upon benzhydryl removal, affords a free amine
of
formula E5. A second acylation with an appropriately substituted Z-
substituted
carboxylic acid or acid chloride of formula B2 affords a compound of Formula
(I)-D.
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Example 1
1) Zn/TMS-C1/DBE BnBr
DMA, 65 C, 1 h 1d
/¨ /-
1¨CN¨Boc ______________ ii- \ ) __ CN¨Boc __ MeCN . Bn¨N\+\ )
CN¨Boc
/¨ Br-
la 2) \ 1 1c 80 C, 1 h (100%) le
1b
Pd(dppf)C12 / Cul, DMA,
80 C, 2 h (89%)
NaBH4, Et0H i Pd(OH)2, H2 (50 psi)
____________________ Bn¨N ) _____________ CN-Boc __ ''' HN/ ) CN¨Boc
20 C, 1 h (91%)
\ Et0H, 20 C, 96 h \
If (100%) 1g
S 0
0
N OH
1h TFA, CH2Cl2
o / o /
____________ 2 \ CN¨Boc ¨11" CNH
_?¨N\ )
HATU, Et3N, S--\\¨N ) S
CH2C12
N 1i L,N 1j
CI
HO0
S CF3 r.c.IN ---
1k
HATU, Et3N, S
CF3
CH2Cl2 o Cpd 29
A. tert-Butyl 3-(pyridin-4-yl)azetidine-1-carboxylate, lc. A 1-liter 3-neck
round bottom flask equipped with a thermocouple, magnetic stirrer, condenser,
heating
mantle, and N2 inlet adapter was charged with anhydrous dimethylacetamide
(DMA,
100 mL) and zinc (42.94 g, 650.2 mmol). The mixture was stirred at 20 C while
a
mixture of 1,2-dibromoethane (DBE, 5.38 mL, 62.34 mmol) and trimethylsilyl
chloride
(TMS-C1, 7.54 mL, 59.28 mmol) was added at a rate to maintain the temperature
below
65 C over 30 min. The resulting slurry was aged for 15 min. A solution of
tert-butyl
3-iodoazetidine-1-carboxylate la (122.78 g, 420.69 mmol) in DMA (201 mL) was
added dropwise over 1 h at a rate to maintain the temperature below 65 C and
the
milky suspension was stirred for 30 min while slowly cooling to 20 C.
Another 3-liter 4-neck round bottom flask equipped a thermocouple, mechanical
stirrer, condenser, heating mantle, and N2 inlet adapter was charged with
[1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex
(4.73 g, 5.74 mmol), cuprous iodide (2.19 g, 11.47 mmol), and 4-iodopyridine
lb (80.0
g, 382.44 mmol) in DMA (255 mL) under N2. The resulting mixture was degassed
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with alternate vacuum/N2 purges. The above prepared zinc iodide reagent of
compound la in DMA was added as a suspension. The mixture was degassed with
vacuum/N2 twice and then heated to 80 C. (Note: The reaction was exothermic.)
The
progress of the reaction was monitored by HPLC and LC-MS and was complete
after 2
h. The reaction mixture was cooled to 40 C; Et0Ac (1.6 L) was added and the
mixture was stirred for 10 min. The insoluble material (excess Zn and Cu
complexes/salts) was removed by passing through a diatomaceous earth pad,
which was
washed with Et0Ac (200 mL x 2). The combined filtrate was stirred with 1 N
aqueous
NH4C1 (0.8 L) at 20 C for 30 min and the aqueous layer (pH = 5-6) was
adjusted to pH
= 9-10 using 3 N aqueous NaOH solution (-480 mL) while a significant amount of
brown precipitate was formed. The precipitate was removed by paper filtration
and
was washed with deionized water (100 mL). The separated aqueous phase was
extracted with Et0Ac (1 L), and the combined organic phases were treated with
saturated aqueous NH4C1 (0.8 L x 2) and stirred for 15 min (repeated again),
washed
with 5% aqueous NaHS03 (500 mL) and brine (1 L), and dried over MgSO4. The
organic solvent was concentrated at 66 C under house vacuum (-120 mmHg) and
then
high-vacuum (12 mmHg) to afford 80.1 g (89% isolated yield) of crude compound
lc
as an oil (88% purity at 254 nm and 86% purity at 230 nm; HPLC area%.
Retention
time = 2.39 min), which was used in the next step without further
purification.
B. 1-Benzy1-4-(1-(tert-butoxycarbonyl)azetidin-3-yppyridin-1-ium
bromide, le. A 2-liter 4-neck round bottom flask equipped a thermocouple,
mechanical stirrer, condenser, and N2 inlet adapter was charged with crude
compound
lc (78.22 g, 290.5 mmol) and acetonitrile (503 mL). The mixture was stirred at
20 C
and benzyl bromide id (36.41 mL, 299.2 mmol) was added. The mixture was warmed
to 80 C and stirred for 1 h. The reaction was cooled to 20 C and the solvent
was
concentrated at 60 C under house-/ high-vacuum. The resulting material was
chased
with Me0H (100 mL) once to afford 128.9 g (109% isolated yield; 80-84% purity;
HPLC area%. HPLC retention time = 3.61 min) of crude le as a syrup, which was
used
in next step without further purification.
C. tert-Butyl 3-(1-benzy1-1,2,3,6-tetrahydropyridin-4-ypazetidine-1-
carboxylate, if. A 3-liter 4-neck round bottom flask equipped a thermocouple,
mechanical stirrer, condenser, and N2 inlet adapter was charged with crude
compound
le (117.73 g, 232.4 mmol) and Et0H (1.04 L). The solution was cooled to 0 C
with
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stirring; sodium tetrahydroborate (17.8 g, 464.7 mmol) was added and the
mixture was
stirred at 0 C for 10 min, then gradually warmed to 20 C and stirred for 1
h. The
mixture was cooled to 0 C and quenched with half-saturated NaHCO3 (100 mL,
prepared by adding 50 mL of deionized water to 50 mL of saturated NaHCO3). The
organic solvent was concentrated at 60 C under house vacuum to a wet solid,
which
was dissolved in Et0Ac (1.5 L) and stirred for 10 min with half saturated
NaHCO3
(14 After phase separation, the milky aqueous layer (pH = 6-7) was adjusted to
pH =
10-11 using 3 N aqueous NaOH solution and extracted with Et0Ac (500 mL). The
combined organic phases were washed with brine (500 mL) and then concentrated
at
60 C under house-/high-vacuum to afford 98.7 g of crude if as a syrup, which
was
purified using flash column chromatography (silica gel, Et0Ac/heptane/Me0H
20/80/0
¨ 50/50/3) to afford 67.11 g (91% isolated yield, 95% purity at 210 nm; HPLC
area%)
of compound if as a yellow syrup.
D. tert-Butyl 3-(piperidin-4-yl)azetidine-l-carboxylate, lg. A 500-mL Parr
pressure bottle was charged with compound if (18.4 g, 54.3 mmol), Et0H (152
mL),
and Pd(OH)2 (1.91 g). The mixture was purged twice with N2 and then shaken
under a
50 psi H2 atmosphere at 20 C. After 40 h, the H2 was removed and additional
Pd(OH)2 (1.9 g) was added to the mixture of if, dihydro-if, and lg, which was
purged
twice with N2 and shaken under a 50 psi H2 atmosphere at 20 C for an
additional 56 h.
The catalyst was removed by filtration though a diatomaceous earth pad, which
was
washed with Me0H (50 mL x 3). Concentration of the filtrate at 50 C under
high-
vacuum (-10 mmHg) afforded 13.4 g (103% isolated yield, 97% pure at 210 nm,
HPLC area%) of pure compound lg as a slight yellowish, thick oil, which
contained a
trace amount of Et0H residue by 1H-NMR analysis.
E. tert-Butyl 3-(1-(thiazole-2-carbonyl)piperidin-4-yl)azetidine-l-
carboxylate, li. To a stirring solution of compound lg (14.3 mmol, 3.44 g) and
thiazole-2-carboxylic acid lh (15.7 mmol, 2.03 g) in 50 mL of CH2C12 was added
Et3N
(42.9 mmol, 5.98 mL). After 20 min at 20 C, HATU (17.2 mmol, 6.53 g) was
added
and the mixture was stirred at 20 C for 5 h. Water was added to the mixture
and the
organic layer was separated, dried over MgSO4, and concentrated. The residue
was
purified using flash column chromatography (silica gel, 30-70% Et0Ac/heptane)
to
give 3.8 g (75% yield) of compound li. MS m/z 374.2 (M+Na+), 296.1 (M+H-C4H8),
252.1 (M+H-05H802).
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F. (4-(Azetidin-3-yl)piperidin-1-y1)(thiazol-2-yOmethanone, 1j. A portion of
TFA (20 mL) was added to a solution of compound li (10.8 mmol, 3.8 g) in 100
mL of
CH2C12. The solution was stirred at 20 C for 5 h. The solvent was removed
under
vacuum and the residue was partitioned between CH2C12 and 1N aqueous NaOH. The
organic layer was dried over MgSO4 and concentrated to give 2.6 g (85% yield)
of
compound 1j, which was used in the next reaction without purification. MS m/z
252.1
(M+H+).
G. 4-(1-{13-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyllazetidin-3-y1)-1-(1,3-thiazol-2-ylcarbonyDpiperidine, Cpd 29. To a
stirring solution of compound lj (1.59 mmol, 0.40 g) and 3-chloro-6-
(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 1k (1.75 mmol, 0.49 g) in
10 mL
of CH2C12 was added Et3N (6.37 mmol, 0.89 mL). After 20 min at 20 C, HATU
(1.91
mmol, 0.73 g) was added and the mixture was stirred at 20 C for 20 h. The
solvent
was removed and the crude residue was purified by preparative reverse-phase
chromatography to give 210 mg (26% yield) of Cpd 29. 1H NMR (CD30D, 400
MHz): 6 = 8.40 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.93 (br. s., 1H), 7.75-7.85
(m, 2H),
5.31 (t, J=10.8 Hz, 1H), 4.63 (t, J=11.0 Hz, 1H), 4.37 (t, J=8.2 Hz, 1H), 4.28
(t, J=9.3
Hz, 1H), 4.10 (br. s., 1H), 4.00 (br. s., 1H), 3.15-3.29 (m, 1H), 2.82-3.00
(m, 1H), 2.47-
2.63 (m, 1H), 1.67-2.02 (m, 3H), 1.05-1.34 (m, 2H). MS m/z 514.0 (M+H+).
Following the procedure described above for Example 1 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
Cpd Name and data
4-(1- l[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyll azetidin-3-y1)-1-(1,3-thiazol-4-ylcarbonyl)piperidine.
1H NMR (CD30D, 400 MHz): 6 = 9.04 (br. s., 1H), 8.39 (s, 1H),
35 8.08 (d, J=8.6 Hz, 1H), 8.01 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 4.56-
4.73 (m, 1H), 3.87-4.44 (m, 5H), 3.05-3.24 (m, 1H), 2.76-2.97 (m,
1H), 2.47-2.64 (m, 1H), 1.57-1.94 (m, 3H), 1.06-1.30 (m, 2H).
MS m/z 514.0 (M+H+).
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Cpd Name and data
4-(1- [3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyll azetidin-3-y1)-1-(1H-pyrrol-2-ylcarbonyl)piperidine.
1H NMR (CD30D, 400 MHz): 6 = 8.41 (s, 1H), 8.10 (d, J = 8.6
Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 6.90 (dd, J = 2.4, 1.2 Hz, 1H),
41 6.54 (dd, J = 3.7, 1.2 Hz, 1H), 6.13 - 6.21 (m, 1H), 4.57 (t, J =
13.2
Hz, 2H), 4.33 - 4.42 (m, 1H), 4.29 (t, J = 9.4 Hz, 1H), 4.10 (dd, J =
9.4, 6.2 Hz, 1H), 3.94 - 4.04 (m, 1H), 3.05 (br. s., 2H), 2.49 - 2.63
(m, 1H), 1.70- 1.98 (m, 3H), 1.06- 1.25 (m, 2H). MS m/z 496.2
(M+H+).
1- { [3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyll -
69 4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperidine. MS m/z
514.0 (M+H+).
1- { [3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyll -
70 4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperidine. MS m/z
514.0 (M+H+).
1- { [3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyll -
71 441-(1H-pyrrol-2-ylcarbonyl)azetidin-3-yl]piperidine. MS m/z
496.0 (M+H+).
Example 2
0 CI
0
SOCl2, CI S fI aCIN
HO pyridine 0 / S
F CI r 3 , 2 2 S r Et 3N, CH CI
2a 2b 0 Cpd 8
A. 3-Chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride, 2b. Thionyl
chloride (73.7 mmol, 5.36 mL) was added to a mixture of 4-fluorocinnamic acid
2a
(21.1 mmol, 3.5 g) and pyridine (2.53 mmol, 0.2 mL). The mixture was heated at
135
C for 30 min and then cooled to room temperature. The crude mixture was
triturated
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with hot hexanes to remove the solid pyridinium hydrochloride by-product.
Compound
2b was isolated from the combined hexanes solutions.
B. 4-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyljazetidin-3-y1}-
1-(1,3-thiazol-2-ylcarbonyl)piperidine, Cpd 8). A solution of compound 2b
(0.45
mmol, 112 mg) in 4 mL of CH2C12 was added to a solution of compound lj mono-
TFA
salt (0.41 mmol, 150 mg) in Et3N (2.46 mmol, 0.34 mL) at 0 C. The reaction
mixture
was stirred at 0 C for 3 h. The crude product was purified by preparative
reverse-
phase chromatography to afford 18 mg (9% yield) of Cpd 8. 1H NMR (CD30D, 400
MHz): 6 = 7.88-7.97 (m, 2H), 7.81 (d, J=2.9 Hz, 1H), 7.76 (dd, J=8.8, 2.2 Hz,
1H), 7.36
(td, J=9.0, 2.3 Hz, 1H), 5.22-5.37 (m, 1H), 4.55-4.70 (m, 1H), 4.32-4.44 (m,
1H), 4.23-
4.32 (m, 1H), 4.11 (br. s., 1H), 3.91-4.05 (m, 1H), 3.15-3.28 (m, 1H), 2.84-
3.00 (m,
1H), 2.48-2.62 (m, 1H), 1.70-2.02 (m, 3H), 1.10-1.29 (m, 2H). MS m/z 464.1
(M+H+).
Following the procedure described above for Example 2 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compound of the present invention was prepared:
Cpd Name and data
4- {1-[(3 -Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-
7 3-y11 -1-(1,3-thiazol-4-ylcarbonyl)piperidine. MS m/z
464.1
(M+H+).
Example 3
NH
ON-
0 0
0 /¨0O2Me Ho
S/N j
F 400 HS 3b
NaH, THE, S 40, ___________
S
HATU, Et3N,
3a CF3 DMSO
3c
CH2Cl2
CF3
CF3 0 Cpd 20
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A. 3-Methyl-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 3c.
Methyl thioglycolate 3b (30.3 mmol, 2.76 mL) was added dropwise to a
suspension of
NaH (60% oil dispersion, 75.8 mmol, 3.03 g) in 10 mL of THF and 50 mL of DMSO
at
20 C. The mixture was stirred for 15 min and a solution of 1-(2-fluoro-4-
(trifluoromethyl)phenyl)ethanone 3a (24.3 mmol, 5.0 g) in 10 mL of DMSO was
added. The reaction mixture was stirred at 20 C for 4 h and water was added.
The
mixture was extracted with Et0Ac. The organic layer was dried over MgSO4 and
concentrated to give compound 3c as a white solid.
B. 4-(1-{13-Methy1-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyllazetidin-3-y1)-1-(1,3-thiazol-2-ylcarbonyl)piperidine, Cpd 20. To
a
stirring solution of compound lj mono-TFA salt (0.27 mmol, 100 mg) and
compound
3c (0.30 mmol, 78 mg) in 4 mL of CH2C12 was added Et3N (1.09 mmol, 0.15 mL).
After 20 min at 20 C, HATU (0.33 mmol, 125 mg) was added and the mixture was
stirred at 20 C for 20h. The solvent was removed and the crude residue was
purified
by preparative reverse-phase chromatography to give 34 mg (25% yield) of Cpd
20.
1H NMR (CD30D, 400 MHz): 6 = 8.29 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.93 (br.
s.,
1H), 7.81 (d, J=3.2 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 5.31 (br. s., 1H),
4.564.69 (m, 1H),
4.324.42 (m, 1H), 4.26 (t, J=9.2 Hz, 1H), 4.09 (br. s., 1H), 3.98 (br. s.,
1H), 3.23 (br. s.,
1H), 2.92 (br. s., 1H), 2.61 (s, 3H), 2.472.59 (m, 1H), 1.702.00 (m, 3H),
1.031.35 (m,
J=9.3 Hz, 2H). MS m/z 494.1 (M+H+).
Following the procedure described above for Example 3, and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
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WO 2012/054716 PCT/US2011/057085
Cpd Name and data
4-(1- [3-Methy1-6-(trifluoromethyl)-1-benzothiophen-2-
14 yl]carbonyll azetidin-3-y1)-1-(1,3-thiazol-4-
ylcarbonyl)piperidine.
MS m/z 494.1 (M+H+).
4-(1- [3-Methy1-6-(trifluoromethyl)-1-benzothiophen-2-
26 yl]carbonyll azetidin-3-y1)-1-(1H-pyrrol-2-
ylcarbonyl)piperidine.
MS m/z 476.2 (M+H+).
1- [3-Methy1-6-(trifluoromethyl)-1-benzothiophen-2-
60 yl]carbonyll -441-(1,3-thiazol-2-ylcarbonyl)azetidin-3-
yl]piperidine. MS m/z 494.1 (M+H+).
1- [3-Methy1-6-(trifluoromethyl)-1-benzothiophen-2-
61 yl]carbonyll -441-(1,3-thiazol-4-ylcarbonyl)azetidin-3-
yl]piperidine. MS m/z 494.1 (M+H+).
1- [3-Methy1-6-(trifluoromethyl)-1-benzothiophen-2-
62 yl]carbonyll -441-(1H-pyrrol-2-ylcarbonyl)azetidin-3-
yl]piperidine. MS m/z 476.2 (M+H+).
Example 4
NH
(Ho)2B
HO
0 0
HO SN lj
Nj
F3C 4, \_=/
____________________________________________ r-N (Ci a
= HATU, Et3N,
Pd(dppf)C12
Br CH2012
0s2003
4a 4c F30 0 Cpd 16
clioxane-Et0H CF3
A. 3'-(Trifluoromethyl)-11,1'-biphenyl]-4-carboxylic acid, 4c. A portion of
Pd(dppf)C12 (1.49 mmol, 1.09 g) was added to a suspension of 4-bromobenzoic
acid 4a
(14.9 mmol, 3.0 g), 3-trifluoromethylboronic acid 4b (17.9 mmol, 3.4 g), and
Cs2CO3
(37.3 mmol, 12.2 g) in 30 mL of dioxane and 7.5 mL of Et0H. The mixture was
stirred
at 80 C for 2 h. After cooling, the solid was collected by filtration and
washed with
Me0H. The filtrate was concentrated and partitioned between Et0Ac and 1N
aqueous
HC1. The organic layer was washed with brine, dried over Mg504, and
concentrated.
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CH2C12 was added to the residue and the resulting solid was collected by
filtration,
washed with CH2C12, and dried to give 3.58 g (86% yield) of compound 4c, which
was
used in the next step without further purification.
B. 1-(1,3-Thiazol-2-ylcarbony1)-4-(1-{13'-(trifluoromethyl)biphenyl-4-
yl]carbonyl}azetidin-3-yl)piperidine, Cpd 16. To a stirring solution of
compound lj
mono-TFA salt (0.27 mmol, 100 mg) and compound 4c (0.30 mmol, 80 mg) in 4 mL
of
CH2C12 was added Et3N (1.09 mmol, 0.15 mL). After 20 min at 20 C, HATU (0.33
mmol, 125 mg) was added and the mixture was stirred at 20 C for 20 h. The
solvent
was removed and the crude residue was purified by preparative reverse-phase
chromatography to give 57 mg (42% yield) of Cpd 16. 1H NMR (CD30D, 400 MHz):
6 = 7.93 (br. s., 3H), 7.73-7.83 (m, 5H), 7.63-7.73 (m, 2H), 5.24-5.38 (m,
1H), 4.64 (t,
J=10.8 Hz, 1H), 4.46 (t, J=8.2 Hz, 1H), 4.13-4.31 (m, 2H), 3.90-4.01 (m, 1H),
3.15-
3.29 (m, 1H), 2.84-2.99 (m, 1H), 2.44-2.60 (m, 1H), 1.73-2.00 (m, 3H), 1.08-
1.32 (m,
2H). MS m/z 500.3 (M+H+).
Following the procedure described above for Example 4 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following intermediate compounds were prepared:
F3C
F
0 s-,
el
SiF 0 0
0 OH 0 OH 0 OH
4-11 4-12 4-13
S. IS so F30 40 0
Si 0 Me0 0
CI lei 0 Si
0 OH 0 OH 0 OH 0 OH 0 OH 0 OH
4-14 4-15 4-16 4-17 4-18 4-19
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SI 40 40 F 0 OMe op
0
'F F' I. 0 S40
F F CI
0 OH 0 OH 0 OH 0 OH 0 OH 0 OH
4-110 4-111 4-112 4-113 4-114 4-115
F
0. OMe 0.
40 w wi F
CI
0 OH 0 OH 0 OH wi0 OH 0 OH
4-116 4-117 4-118 4-119 4-120
F
WI i 40 0 Me0 0 0 40F3c 0
F w 0 c3 ,
c3 ir 0 F3c
0 OH 0 OH 0 OH 0 OH 0 OH 0 OH
4-121 4-122 4-123 4-124 4-125 4-126
5 Following the procedure described above for Example 4, and
substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
Cpd Name and data
4- {1-[(3-Fluorobipheny1-4-yl)carbonyl]azetidin-3-yll -1-(1,3-
9
thiazol-4-ylcarbonyl)piperidine. MS m/z 450.1 (M+H+).
1-(1,3-Thiazol-4-ylcarbony1)-4-(1- { [3'-
10 (trifluoromethyl)bipheny1-4-yl]carbonyll azetidin-3-
yl)piperidine. MS m/z 500.3 (M+H+).
4- {1- [(3'-Fluorobipheny1-3-yl)carbonyl]azetidin-3-yll -1-
11
(1,3-thiazol-4-ylcarbonyl)piperidine. MS m/z 450.2 (M+H+).
1-(1,3-Thiazol-4-ylcarbony1)-441-( {445-
12 (trifluoromethyl)thiophen-2-yl]phenyllcarbonyl)azetidin-3-
yl]piperidine. MS m/z 506.1 (M+H+).
4- {1- [(3-Fluorobipheny1-4-yl)carbonyl]azetidin-3-yll -1-(1,3-
thiazol-2-ylcarbonyl)piperidine. MS m/z 450.1 (M+H+).
17
4- {1- [(3'-Fluorobipheny1-3-yl)carbonyl]azetidin-3-yll -1-
(1,3-thiazol-2-ylcarbonyl)piperidine. MS m/z 450.1 (M+H+).
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Cpd Name and data
1-(1,3-Thiazol-2-ylcarbony1)-441-( {445-
18 (trifluoromethyl)thiophen-2-yl]phenyllcarbonyl)azetidin-3-
yl]piperidine. MS m/z 506.1 (M+H+).
21
4- {1-[(3 -Fluorobipheny1-4-yl)carbonyl] azetidin-3 -y11-1-(1H-
pyrrol-2-ylcarbonyl)piperidine. MS m/z 432.1 (M+H+).
1-(1H-Pyrrol-2-ylcarbony1)-4-(1- { [3'-
22 (trifluoromethyl)bipheny1-4-yl]carbonyll azetidin-3-
yl)piperidine. MS m/z 482.2 (M+H+).
23
4- {1-[(3'-Fluorobipheny1-3-yl)carbonyl]azetidin-3-yll -1-
(1H-pyrrol-2-ylcarbonyl)piperidine. MS m/z 432.1 (M+H+).
1-(1H-Pyrrol-2-ylcarbony1)-441-({445-
24 (trifluoromethyl)thiophen-2-yl]phenyllcarbonyl)azetidin-3-
yl]piperidine. MS m/z 488.3 (M+H+).
45143-Fluorobipheny1-4-yl)carbonyl]-441-(1,3-thiazol-2-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 450.1 (M+H+).
46
143-Fluorobipheny1-4-yl)carbonyl]-441-(1,3-thiazol-4-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 450.1 (M+H+).
1-[(3-Fluorobipheny1-4-yl)carbonyl]-4-[1-(1H-pyrrol-2-
47
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 432.1 (M+H+).
4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-y1]-1- { [3'-
48 (trifluoromethyl)bipheny1-4-yl]carbonyllpiperidine.
MS m/z 500.3 (M+H+).
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-y1]-1- { [3'-
49 (trifluoromethyl)bipheny1-4-yl]carbonyllpiperidine.
MS m/z 500.1 (M+H+).
4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-y1]-1- { [3'-
50 (trifluoromethyl)bipheny1-4-yl]carbonyllpiperidine.
MS m/z 482.2 (M+H+).
1-[(3'-Fluorobipheny1-3-yl)carbonyl]-441-(1,3-thiazol-2-
51 ylcarbonyl)azetidin-3-yl]piperidine.
MS m/z 450.1 (M+H+).
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Cpd Name and data
1-[(3'-Fluorobipheny1-3-yl)carbonyl]-441-(1,3-thiazol-4-
52 ylcarbonyl)azetidin-3-yl]piperidine.
MS m/z 450.1 (M+H+).
1-[(3'-Fluorobipheny1-3-yl)carbonyl]-441-(1H-pyrrol-2-
53 ylcarbonyl)azetidin-3-yl]piperidine.
MS m/z 432.1 (M+H+).
4- [1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3 -y1]-1-( {4- [5-
54 (trifluoromethyl)thiophen-2-yl]phenylIcarbonyl)piperidine.
MS m/z 506.1 (M+H+).
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-y1]-1-({445-
55 (trifluoromethyl)thiophen-2-yl]phenylIcarbonyl)piperidine.
MS m/z 506.1 (M+H+).
4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-y1]-1-( {445 -
56 (trifluoromethyl)thiophen-2-yl]phenylIcarbonyl)piperidine.
MS m/z 488.3 (M+H+).
Example 5
(1-10)251_ 0 0
Me0 HO
Me0 1N aq NaOH,
F3C gu A, Et0H
WI _________________________________________________ 3
Pd(dppf)Cl2
11
Na2CO3 5b 5c
5a Br dioxane-H20
CF3 CF3
r.C./NH
0
S/N lj
rCir\I = I.
CF3
HATU, Et3N,
CH2Cl2
0 Cpd 19
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A. Methyl 4-(3-(trifluoromethyl)benzyl)benzoate, 5b. A portion of
Pd(dppf)C12 (0.87 mmol, 0.64 g) was added to a suspension of methyl 4-
(bromomethyl)benzoate 5a (8.73 mmol, 2.0 g), 3-trifluoromethylboronic acid 4b
(10.5
mmol, 1.99 g), and Na2CO3 (17.5 mmol, 1.85 g) in 20 mL of dioxane and 5 mL of
water. The mixture was stirred at 80 C for 3 h. After cooling, the solid was
collected
by filtration and washed with Et0Ac. The filtrate was washed with 1N aqueous
HC1
and brine, dried over MgSO4, and concentrated. The crude product was purified
by
flash column chromatography (silica gel, 0-10% Et0Ac:heptane) to give 2.2 g
(85%
yield) of compound 5b. MS m/z 295.2 (M+H+).
B. 4-(3-(Trifluoromethyl)benzyl)benzoic acid, 5c. 1N aqueous NaOH (12.9
mmol, 12.9 mL) was added to a suspension of compound 5b (6.46 mmol, 1.9 g) in
75
mL of Et0H. The mixture was stirred at 20 C for 20 h. The reaction mixture
was
concentrated and the residue was acidified with 1N aqueous HC1. The resulting
solid
was collected by filtration and dried to afford 1.6 g (87%) of compound 5c,
which was
used in the next reaction without further purification. MS m/z 281.1 (M+H+).
C. 1-(1,3-Thiazol-2-ylcarbony1)-441-({4-13-
(trifluoromethyl)benzyflphenyl}carbonyl)azetidin-3-yflpiperidine, Cpd 19. To a
stirring solution of compound lj mono-TFA salt (0.27 mmol, 100 mg) and
compound
5c (0.30 mmol, 84 mg) in 4 mL of CH2C12 was added Et3N (1.09 mmol, 0.15 mL).
After 20 min at 20 C, HATU (0.33 mmol, 125 mg) was added and the mixture was
stirred at 20 C for 20 h. The solvent was removed and the crude residue was
purified
by preparative reverse-phase chromatography to give 46 mg (33% yield) of Cpd
19.
1H NMR (CD30D, 400 MHz): 6 = 7.92 (br. s., 1H), 7.79 (d, J=3.2 Hz, 1H), 7.57-
7.64
(m, J=8.1 Hz, 2H), 7.43-7.53 (m, 4H), 7.28-7.36 (m, J=8.1 Hz, 2H), 5.29 (t,
J=10.0 Hz,
1H), 4.61 (t, J=10.9 Hz, 1H), 4.38 (t, J=8.6 Hz, 1H), 4.20 (t, J=9.3 Hz, 1H),
4.10 (s,
2H), 4.07-4.15 (m, 1H), 3.85-3.96 (m, 1H), 3.10-3.27 (m, 1H), 2.78-2.96 (m,
1H), 2.36-
2.53 (m, 1H), 1.66-1.93 (m, 3H), 1.03-1.29 (m, 2H). MS m/z 514.2 (M+H+).
Following the procedure described above for Example 5 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following intermediate compound was prepared:
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0
is
HO 0 CF3
5-11
Following the procedure described above for Example 5, and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
Cpd Name and data
1-(1,3-Thiazol-4-ylcarbony1)-441-(1443-
13 (trifluoromethyl)benzyl]phenyll c arbonyl)azetidin-3 -
yl]piperidine.
MS m/z 514.2 (M+H+).
1-(1H-Pyrrol-2-ylcarbony1)-441-(1443-
25 (trifluoromethyl)benzyl]phenyll c arbonyl)azetidin-3 -
yl]piperidine
MS m/z 497.2 (M+H+).
1-(1,3-Thiazol-2-ylcarbony1)-441-(1444-
27 (trifluoromethyl)benzyl]phenyll c arbonyl)azetidin-3 -
yl]piperidine
MS m/z 514.2 (M+H+).
1-(1,3-Thiazol-4-ylcarbony1)-441-(1444-
(trifluoromethyl)benzyl]phenyll c arbonyl)azetidin-3 -
33
yl]piperidine
MS m/z 514.2 (M+H+).
1-(1H-Pyrrol-2-ylcarbony1)-441-(1444-
(trifluoromethyl)benzyl]phenyll c arbonyl)azetidin-3 -
39
yl]piperidine
MS m/z 496.2 (M+H+).
4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-y1]-1-(1443-
57 (trifluoromethyl)benzyl]pheny11 carbonyl)piperidine
MS m/z 514.2 (M+H+).
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Cpd Name and data
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-y1]-1-({4-[3-
58 (trifluoromethyl)benzyl]pheny11 carbonyl)piperidine
MS m/z 514.2 (M+H+).
4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-y1]-1-({443-
59 (trifluoromethyl)benzyl]pheny11 carbonyl)piperidine
MS m/z 496.2 (M+H+).
4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-y1]-1-({444-
63 (trifluoromethyl)benzyl]pheny11 carbonyl)piperidine
MS m/z 514.2 (M+H+).
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-y1]-1-({444-
64 (trifluoromethyl)benzyl]pheny11 carbonyl)piperidine
MS m/z 514.2 (M+H+).
4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-y1]-1-({444-
65 (trifluoromethyl)benzyl]pheny11 carbonyl)piperidine
MS m/z 496.2 (M+H+).
Example 6
r.../N1H
e
OHC OH 0,,N
OM b 0 0 SZN lj
6b
rf../N 40
0 6 ____________________
0 rN N
HATU, Et3N,
6a 6c IP /
NH2 1) Pb(0Ac)4, Me0H 0 1
OH then CH3CN CH2Cl2 S
2) 3N aq NaOH 0 Cpd 28
41
A. 2-Phenylbenzo[d]oxazole-6-carboxylic acid, 6c. A solution of methyl 4-
amino-3-hydroxybenzoate 6a (29.9 mmol, 5.0 g) and benzaldehyde 6b (29.9 mmol,
3.02 mL) in 150 mL of Me0H was stirred at 20 C for 3 h. The solvent was
removed
under vacuum and the residue was mixed with 150 mL of acetonitrile. Lead (IV)
acetate (29.9 mmol, 13.3 g) was added in one portion and the mixture was
refluxed for
min. After cooling, the precipitate was removed by filtration and washed with
acetonitrile. The filtrate and wash solutions were stirred with 3N aqueous
NaOH (120
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mmol, 40 mL) at 50 C for 20 h. After cooling, the reaction mixture was
acidified and
filtered to give 6.0 g (79%) of compound 6c. MS m/z 240.0 (M+H+).
B. 2-Pheny1-6-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yljazetidin-1-
yl}carbony1)-1,3-benzoxazole, Cpd 28. To a stirring solution of compound lj
(0.40
mmol, 100 mg) and compound 6c (0.44 mmol, 100 mg) in 4 mL of CH2C12 was added
Et3N (1.59 mmol, 0.22 mL). After 20 min at 20 C, HATU (0.48 mmol, 180 mg) was
added and the mixture was stirred at 20 C for 20 h. The solvent was removed
and the
crude residue was purified by preparative reverse-phase chromatography to give
75 mg
(39% yield) of Cpd 28. 1H NMR (CD30D, 400 MHz): 6 = 8.23-8.32 (m, 2H), 8.01
(s,
1H), 7.89-7.97 (m, 1H), 7.77-7.85 (m, 2H), 7.73 (dd, J=8.3, 1.2 Hz, 1H),
7.54-7.68 (m,
3H), 5.30 (t, J=11.0 Hz, 1H), 4.64 (t, J=12.0 Hz, 1H), 4.43-4.54 (m, 1H), 4.18-
4.34 (m,
2H), 3.92-4.05 (m, 1H), 3.16-3.29 (m, 1H), 2.84-2.99 (m, 1H), 2.47-2.60 (m,
1H), 1.72-
2.02 (m, 3H), 1.10-1.34 (m, 2H). MS m/z 473.1 (M+H+).
Following the procedure described above for Example 6, and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
Cpd Name and data
2-Phenyl-6-( {3 - [1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-
34 yl]azetidin-l-ylIcarbonyl)-1,3-benzoxazole. MS m/z 473.1
(M+H+).
2-Phenyl-6-( {3 -[1-(1H-pyrrol-2-ylcarbonyl)piperidin-4-
40 yl]azetidin-l-ylIcarbonyl)-1,3-benzoxazole. MS m/z 455.3
(M+H+).
2-Phenyl-6-( {4- [1-(1,3-thiazol-2-ylcarbonyl)azetidin-3 -
66 yl]piperidin-1-yllcarbony1)-1,3-benzoxazole. MS m/z 473.1
(M+H+).
2-Phenyl-6-( {4- [1-(1,3-thiazol-4-ylcarbonyl)azetidin-3 -
67 yl]piperidin-1-yllcarbony1)-1,3-benzoxazole. MS m/z 473.1
(M+H+).
2-Phenyl-6-( {441-(1H-pyrrol-2-ylcarbonyl)azetidin-3 -
68 yl]piperidin-1-yllcarbony1)-1,3-benzoxazole. MS m/z 455.3
(M+H+).
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Example 7
Br 0 0
Me0 0 Me0 HO
7b
LION
K2 CO3, Cul
HN
220 C 41110
H20, THF
7a 7c 7d
0
SVN 1 j
r.CJNI r\,
N
HATU, Et3N,
CH2Cl2
0 Cpd 30 =
A. Methyl 1-(4-fluoropheny1)-indole-5-carboxylate, 7c. A mixture of methyl
indole-5-carboxylate 7a (0.5 g, 2.85 mmol), 1-bromo-4-fluoro-benzene 7b (2 mL,
18.21 mmol), CuI (0.544 g, 2.85 mmol), and K2CO3 (0.591 g, 4.28 mmol) was
heated
in a microwave reactor at 220 C for 2.5 h. The reaction mixture was diluted
with
CH2C12 and filtered. The solution was concentrated and the residue was
purified by
flash column chromatography (silica gel, 15% Et0Ac/heptane) to give 0.58 g of
compound 7c. MS m/z 270.1 (M+H+).
B. 1-(4-Fluoropheny1)-indole-5-carboxylic acid, 7d. A mixture of methyl 1-
(4-fluoropheny1)-indole-5-carboxylate 7c (0.58 g, 2.15 mmol) and LiOH H20
(0.36 g,
8.6 mmol) in THF (15 mL) and H20 (10 mL) was stirred at room temperature for 5
days. Aqueous 10% HC1 solution was added to the reaction mixture to adjust pH
= 3
4. The resulting mixture was extracted with Et0Ac (2x). The organic solution
was
washed with aq. NaC1, dried over Na2504 and concentrated to give 0.5 g of
compound
7d. MS m/z 256.2 (M+H+).
C. 1-(4-Fluoropheny1)-5-({341-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yljazetidin-1-yl}carbony1)-1H-indole, Cpd 30. To a stirring solution of
compound lj
(0.40 mmol, 100 mg) and compound 7d (0.44 mmol, 110 mg) in 4 mL of CH2C12 was
added Et3N (1.59 mmol, 0.22 mL). After 20 min at 20 C, HATU (0.48 mmol, 180
mg)
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was added and the mixture was stirred at 20 C for 20 h. The solvent was
removed and
the crude residue was purified by preparative reverse-phase chromatography to
give
165 mg (85% yield) of Cpd 30. 1H NMR (CD30D, 400 MHz): 6 = 7.99 (s, 1H), 7.92
(br. s., 1H), 7.79 (d, J=3.2 Hz, 1H), 7.44-7.58 (m, 5H), 7.30 (t, J=8.7 Hz,
2H), 6.77 (d,
J=3.4 Hz, 1H), 5.28 (br. s., 1H), 4.53-4.69 (m, 1H), 4.39-4.51 (m, 1H), 4.10-
4.29 (m,
2H), 3.95 (br. s., 1H), 3.10-3.27 (m, 1H), 2.89 (t, J=10.5 Hz, 1H), 2.33-2.56
(m, 1H),
1.65-1.98 (m, J=10.8 Hz, 3H), 1.19 (br. s., 2H). MS m/z 489.1 (M+H+).
Following the procedure described above for Example 7, and substituting the
appropriate reagents, starting materials, and purification methods known to
those
skilled in the art, the following intermediate compounds were prepared:
0 0
HO 101 \ HO 0 \
N N
7-11 411 7-12 01
CF3 CI
0 0 0 0
HO 101 \ HO 101 \ HO 40 N ,3 , H O so "N
,
N
CF3 N
F N
7-13 di CF3 7-14 40 7-15 it 7-16 *
F
0 0
HO 0\ HO 0 \
N N
7-17 --""1\1 7-18 -----N
N\R N)F
Following the procedure described above for Example 7, and substituting the
appropriate reagents, starting materials, and purification methods known to
those
skilled in the art, the following compounds of the invention were prepared:
Cpd Name and data
5-( {341-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl] azetidin-1-
31 ylIcarbony1)-144-(trifluoromethyl)phenyl]-1H-indole. MS m/z
539.1 (M+H+).
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Cpd Name and data
36
1-(4-Fluoropheny1)-5-( {3 - [1 -(1,3 -thiazol-4-ylc arb onyl)pip eridin-4-
yl]azetidin-1-ylIcarbonyl)-1H-indole. MS m/z 489.1 (M+H+).
5-( {34141,3 -Thiazol-4-ylcarbonyl)piperidin-4-yl] azetidin-1-
37 ylIcarbony1)-144-(trifluoromethyl)phenyl]-1H-indole. MS m/z
539.2 (M+H+).
42
1-(4-Fluoropheny1)-5-( {3 - [1-(1H-pyn-o1-2-ylcarbonyl)pip eridin-4-
yl]azetidin-l-ylIcarbonyl)-1H-indole. MS m/z 472.2 (M+H+).
5-( {341-(1H-Pyrrol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
43 ylIcarbony1)-144-(trifluoromethyl)phenyl]-1H-indole. MS m/z
521.3 (M+H+).
72 1-(4-Fluoropheny1)-5-( {4- [1 -(1,3 -thiazol-2 -ylc arbonyl)azetidin-3 -
yl]piperidin-l-y1 1 carbonyl)-1H-indole. MS m/z 489.1 (M+H+).
1-(4-Fluoropheny1)-5-( {4- [1 -(1,3 -thiazol-4-ylc arbonyl)azetidin-3 -
73
yl]piperidin-l-ylIcarbonyl)-1H-indole. MS m/z 489.1 (M+H+).
1-(4-Fluoropheny1)-5-( {4- [1-(1H-pyrrol-2-ylc arb onyl)azetidin-3 -
74
yl]piperidin-l-y1 1 c arb ony1)-1H-indo le. MS m/z 471.3 (M+H+).
5-( {44141,3 -Thiazol-2-ylcarbonyl)azetidin-3 -yl]piperidin-1-
75 ylIcarbony1)-144-(trifluoromethyl)phenyl]-1H-indole. MS m/z
539.2 (M+H+).
5-( {44141,3 -Thiazol-4-ylcarbonyl)azetidin-3 -yl]piperidin-1-
76 ylIcarbony1)-144-(trifluoromethyl)phenyl]-1H-indole. MS m/z
539.2 (M+H+).
5-( {441-(1H-Pyrrol-2-ylcarbonyl)azetidin-3 -yl]piperidin-1-
77 ylIcarbony1)-144-(trifluoromethyl)phenyl]-1H-indole. MS m/z
521.3 (M+H+).
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Cpd Name and data
1-(5-Chloropyridin-2-y1)-5-( {3 -[1-(1,3 -thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-l-yll carbonyl)-1H-indole. 1H
NMR (CDC13) 6 = 8.51 (d, J=2.5 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H),
7.95 (d, J=1.4 Hz, 1H), 7.87 (br. s., 1H), 7.81 (dd, J=8.7, 2.6 Hz,
1H), 7.70 (d, J=3.5 Hz, 1H), 7.59 (dd, J=8.7, 1.5 Hz, 1H), 7.53 (d,
93
J=3.2 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 6.77 (dd, J=2.9, 0.6 Hz, 1H),
5.40-5.54 (m, 1H), 4.73 (t, J=9.8 Hz, 1H), 4.37-4.49 (m, 1H), 4.21-
4.32 (m, 1H), 4.03-4.12 (m, 1H), 3.93-4.03 (m, 1H), 3.57-3.72 (m,
1H), 3.06-3.22 (m, 1H), 2.36-2.51 (m, 1H), 1.67-1.94 (m, 3H),
1.10-1.32 (m, 2H). MS m/z 506 (M+H+).
Example 8
1 \
¨NH NH 0 0
Me0 0 = F Me0 HO
1.1 8a F
N ___________________________________________________ 3. 41 1
N
LION
/ K3PO4, Cul, toluene
HN * H20, THF
110 O
7a 8b * 8c
F F
F F
rC../NH
(),N
0
SN lj
_________________ r-N rir\I 101 \
N
HATU, Et3N7
CH2Cl2 =-,
0 Cpd 32 * F
F
A. Methyl 1-(3,4-difluoropheny1)-indole-5-carboxylate, 8b. A mixture of
methyl indole-5-carboxylate 7a (2 g, 11.4 mmol), 1-iodo-3,4-difluoro-benzene
8a (1.5
mL, 12.5 mmol), CuI (0.22 g, 1.14 mmol), trans-N, N'-dimethylcyclohexane-1,2-
diamine (0.54 mL, 3.43 mmol), and K3PO4 (6.06 g, 28.5 mmol) in toluene (12 mL)
was
heated at 110 C for 7 h. The reaction mixture was diluted with CH2C12 and
filtered.
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The solution was concentrated and the residue was purified by flash column
chromatography (silica gel, 20% Et0Ac/heptane) to give 3.0 g of compound 8b.
MS
m/z 288.1 (M+H+).
B. 1-(3,4-Difluoropheny1)-indole-5-carboxylic acid, 8c. A mixture of methyl
1-(3,4-difluoropheny1)-indole-5-carboxylate 8b (3.0 g, 10.4 mmol) and LiOH
(1.0 g,
41.8 mmol) in THF (120 mL) and H20 (60 mL) was stirred at room temperature for
5
days. Aqueous 10% HC1 solution was added to the reaction mixture to adjust pH
= 3 ¨
4. The resulting mixture was extracted with Et0Ac (2x). The organic solution
was
washed with brine, dried over Na2504 and concentrated to give 2.85 g of
compound 8c.
MS m/z 274.2 (M+H+).
C. 1-(3,4-Difluoropheny1)-5-({3-14-(1,3-thiazol-2-ylcarbonyl)piperazin-1-
yljazetidin-1-yl}carbony1)-1H-indole, Cpd 32. To a stirring solution of
compound lj
(0.40 mmol, 100 mg) and compound 8c (0.44 mmol, 120 mg) in 4 mL of CH2C12 was
added Et3N (1.59 mmol, 0.22 mL). After 20 min at 20 C, HATU (0.48 mmol, 180
mg)
was added and the mixture was stirred at 20 C for 20 h. The solvent was
removed and
the crude residue was purified by preparative reverse-phase chromatography to
give
118 mg (58% yield) of Cpd 32. 1H NMR (CD30D, 400 MHz): 6 = 8.00 (s, 1H), 7.93
(br. s., 1H), 7.81 (d, J=2.9 Hz, 1H), 7.51-7.60 (m, 4H), 7.44-7.52 (m, 1H),
7.33-7.42
(m, 1H), 6.79 (d, J=3.2 Hz, 1H), 5.22-5.38 (m, 1H), 4.55-4.71 (m, 1H), 4.48
(t, J=8.8
Hz, 1H), 4.14-4.33 (m, 2H), 3.89-4.04 (m, 1H), 3.14-3.28 (m, 1H), 2.83-2.99
(m, 1H),
2.43-2.58 (m, 1H), 1.70-2.00 (m, 3H), 1.09-1.32 (m, 2H). MS m/z 507.1 (M+H+).
Following the procedure described above for Example 8, and substituting the
appropriate reagents, starting materials, and purification methods known to
those
skilled in the art, the following intermediate compounds were prepared:
0
HO 101 \
N
8-11
---)........_
-N
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O 0 0 0 0
HO 0 \ HO =\ HO 10 \ HO 0 \ HO 0 \
N N N F N N
. F . F
0 0 0
8-12 F F 8-13 F 8-14 F 8-15 OCF3 F3C0 8-
16
O 0 H 0 H 0 0
C..3 C. .3 CH3 CH3
HO 0 \ HO IS \ HO 0 \ HO 0 \ HO 10 \
N N N N N
8-17 * F 8-18 0 8-19 0 8-110 lp F 8-111 0
F
CI F F
0 0 0 0
HO 0"N HO 0 "N HO 0 \ N HO 0 \ N
NI 1\1 NI NI
8-112 0 8-113 0 8-114 0 8-115 0
F F F F C F3
O 0 0 0 0
HO 0 \ HO 0 \ HO 0 \ HO 0 \ HO 0 \
N N N N N
-
b ON
N
o
8-116 OMe 8-117 --___ N 8-118 --___ N 8-119 8-120 --..
-N
OMe
0 0 0 0 0
HO 0 \ HO 0 \ HO 0 \ HO 0 \ HO =\
N N N N N
/ N
8-1248-121 \
8-122 / N\j bl
----.. ------S\
N,....../N
8-123
8-125 -- N
F CF3 CF3
O 0 0 0
HO 0 \ HO 0 \ HO =\ HO 0 \
N N N N
----N
0 ti).L .....
8-126 -.._ 8-127 \ 8-128 \ 8-129
-N
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0
HO HO 40
as a 2:1 ¨
mixture
CF 3 F3C
8-130a 8-130b
HO 0 HO HO
0 0
101 \ N\
1101 N 101 N\
4114
8-131 4111 8-132 OH 8-133 8-134 F
0
0 0
1\1
HO HO ."====
n =
8-135 * 8-136 * 0
8-137
Following the procedure described above for Example 8, and substituting the
appropriate reagents, starting materials, and purification methods known to
those
skilled in the art, the following compounds of the present invention were
prepared:
Cpd Name and data
1-(3,4-Difluoropheny1)-5-({3-[1-(1,3-thiazol-4-
38 ylcarbonyl)piperidin-4-yl]azetidin-l-yll carbony1)-1H-
indole). MS m/z 507.1 (M+H+).
1-(3,4-Difluoropheny1)-5-( {3 41-(1H-pyrrol-2-
44 ylcarbonyl)piperidin-4-yl]azetidin-l-yll carbony1)-1H-
indole). MS m/z 489.3 (M+H+).
1-(3,4-Difluoropheny1)-5-({441-(1,3-thiazol-2-
78 ylcarbonyl)azetidin-3-yl]piperidin- 1 -yll carbonyl)-1H-indole.
MS m/z 507.1 (M+H+).
1-(3,4-Difluoropheny1)-5-({441-(1,3-thiazol-4-
79 ylcarbonyl)azetidin-3-yl]piperidin- 1 -yll carbonyl)-1H-indole.
MS m/z 507.1 (M+H+).
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Cpd Name and data
1-(3,4-Difluoropheny1)-5-( {4-[1-(1H-pyrrol-2-
80 ylcarbonyl)azetidin-3-yl]piperidin- 1 -yll carbonyl)-1H-indole.
MS m/z 489.2 (M+H+).
1-(2-Methylpyridin-4-y1)-5-( {3- [1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl] azetidin-l-ylIcarbonyl)-1H-indole.
1H NMR (CDC13) 6 = 8.63 (d, J=5.4 Hz, 1H), 8.00 (s, 1H),
7.87 (br. s., 1H), 7.70 (d, J=8.7 Hz, 1H), 7.61 (dd, J=8.7, 1.4
Hz, 1H), 7.53 (d, J=3.1 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H),
7.24-7.36 (m, 2H), 6.79 (d, J=3.3 Hz, 1H), 5.50 (d, J=12.5
Hz, 1H), 4.64-4.84 (m, 1H), 4.37-4.53 (m, 1H), 4.21-4.37
(m, 1H), 3.91-4.14 (m, 2H), 3.06-3.25 (m, 1H), 2.73-2.89
(m, 1H), 2.67 (s, 3H), 2.46 (d, J=8.1 Hz, 1H), 1.65-1.94 (m,
3H), 1.09-1.35 (m, 2H).
Example 9
NH2 0 0
0
NO2 F 9b me0 NO2 SnCl2 2H20 Me0 NH2
Me0 = F DIPEA/ DMF NH Et0H NH
9a 9c 01 9d
0 F 0
Me0 N
1N NaOH HO
DMF 9e * Et0H 9f *
_____________ CNH 0
N
1j N N,
HATU, Et3N, CH2Cl2 S
0 Cpd 81
5
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A. Methyl 4-((4-fluorophenyl)amino)-3-nitrobenzoate, 9c. A mixture of
methyl 4-fluoro-3-nitrobenzoate 9a (1 g, 5.02 mmol), 4-fluoroaniline 9b (4.34
mL, 5.02
mmol), and DIPEA (1.04 mL, 6.03 mmol) in DMF (10 mL) was stirred at room
temperature for 2 h. Water was added to the mixture, the resulting solid was
collected
by filtration, washed with water, and dried. The crude compound 9c was used in
the
next reaction without further purification.
B. Methyl 3-amino-4-((4-fluorophenyl)amino)benzoate, 9d. A mixture of
compound 9c (1.4 g, 4.8 mmol) and SnC12.2H20 (4.9 g, 21.7 mmol) in Et0H (50
mL)
was stirred at 80 C. After 4 h, the mixture was cooled to room temperature and
was
slowly added to saturated aqueous NaHCO3. The solid was collected by
filtration and
washed with H20. The solid was triturated with Et0Ac and the filtrate was
concentrated. The crude compound 9d was used in the next reaction without
further
purification. MS m/z 261.1 (M+H+).
C. Methyl 1-(4-fluoropheny1)-1H-benzo[d]imidazole-5-carboxylate, 9e. A
mixture of compound 9d (0.18 g, 0.693 mmol) and trimethyl orthoformate (0.7
mL,
6.39 mmol) in DMF (2 mL) was refluxed for 5 h and then cooled to room
temperature.
Water was added to the mixture. The resulting solid was collected by
filtration, washed
with water, and dried. The crude compound 9e was used in the next reaction
without
further purification. MS m/z 271.1 (M+H+).
D. 1-(4-Fluoropheny1)-1H-benzo[d]imidazole-5-carboxylic acid, 9f. To a
solution of compound 9e (0.18 g, 0.666 mmol) in Et0H (10mL) was added 1N
aqueous
NaOH (2.5 mL, 2.5 mmol). The mixture was stirred at room temperature for 4 d.
The
solvent was evaporated and 1N aqueous HC1 was added, followed by extraction
with
Et0Ac. The organic layer was dried over Mg504 and concentrated. The crude
compound 9f was purified by preparative reverse phase chromatography. MS m/z
257.1 (M+H+).
E. 1-(4-Fluoropheny1)-5-({341-(1,3-thiazol-2-ylcarbonyflpiperidin-4-
yljazetidin-1-ylIcarbony1)-1H-benzimidazole, Cpd 81. To a solution of compound
lj (0.058 g, 0.178 mmol) and HATU (0.081 g, 0.214 mmol) in 3 mL of CH2C12 was
added Et3N (0.099 mL, 0.713 mmol). The mixture was stirred at 20 C for 30
min, and
then compound 9f (0.050g, 0.196 mmol) was added. The reaction mixture was
stirred
at 20 C for 20 h. Water (6 mL) was added and the mixture was extracted with
Et0Ac.
The organic layer was dried over Mg504 and concentrated. The crude product was
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purified by preparative reverse phase chromatography to give 46 mg (47% yield)
of
Cpd 81. 1H NMR (CD30D) 6 = 8.14 (s, 1H), 7.93 (br. s., 1H), 7.78-7.84 (m, 2H),
7.67-7.78 (m, 3H), 7.45 (t, J=8.7 Hz, 2H), 5.23-5.38 (m, 1H), 4.57-4.71 (m,
1H), 4.44-
4.54 (m, 1H), 4.29 (t, J=9.7 Hz, 1H), 4.22 (br. s., 1H), 4.00 (br. s., 1H),
3.17-3.27 (m,
1H), 2.85-2.99 (m, 1H), 2.48-2.61 (m, 1H), 1.70-2.02 (m, 3H), 1.09-1.34 (m,
2H) MS
m/z 490.2 (M+H+).
Following the procedure described above for Example 9 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following intermediate compounds were prepared.
HO HO HO HO HO
0 0 0 0 0
N N N
L.N LiõN N L.N
F3C
) 9-11 9-12 09-13 Am 9-14 411, 9-15
F
CF3
C F3
HO
0
N
N
- 9-16
Following the procedure described above for Example 9 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
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Cpd Name and data
1-(3,4-Difluoropheny1)-5-( {341-(1,3 -thiazol-2-
82 ylcarbonyl)piperidin-4-yl]azetidin-l-ylIcarbonyl)-1H-
benzimidazole. MS m/z 508.2 (M+H+).
54 {341-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl] azetidin-1-
83 yll carbonyl)- 1 - [4-(trifluoromethyl)pheny1]-1H-
benzimidazo le.
MS m/z 540.2 (M+H+).
-( {341-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl] azetidin-1-
84 ylIcarbony1)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole. MS
m/z
478.2 (M+H+).
5 -( {341-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl] azetidin-1-
85 yll carbonyl)-1-(3,3,3-trifluoropropy1)-1H-benzimidazole.
MS m/z
492.1 (M+H+).
Example 10
0 o o
NH 2 Ox0
Me0 0 1N NaOH Me0 0 I\1_ HO 0 N,
0, N
N _D.
9d 0 DMF
10a 4 Et0H 10b 411
F F F
¨N/ \ ) _______ CNN 0
N ij
HATU, Et3N, CH2Cl2 S N
0 Cpd 87 it
F
5
A. Methyl 2-methy1-1-(4-fluoropheny1)-1H-benzo[d]imidazole-5-
carboxylate, 10a. The title compound 10a was prepared using the method
described in
Example 9, substituting trimethyl orthoacetate for trimethyl orthoformate in
Step C.
The crude compound 10a was used in the next reaction without further
purification.
MS m/z 285.1 (M+H+).
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B. 2-Methyl-1-(4-fluoropheny1)-1H-benzo[d]imidazole-5-carboxylate, 10b.
The title compound 10b was prepared using the method described in Example 9,
substituting compound 10a for compound 9e in Step D. The crude product 10b was
used in the next reaction without further purification. MS m/z 271.2 (M+H+).
C. 1-(4-Fluoropheny1)-2-methy1-5-({341-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yljazetidin-1-ylIcarbony1)-1H-benzimidazole, Cpd 87.
The
title compound Cpd 87 was prepared using the method described in Example 9,
substituting compound 10b for compound 9f in Step E. The crude product was
purified
by preparative reverse phase chromatography to give 23 mg (50% yield) of Cpd
87. 1H
NMR (CD30D) 6 = 8.08 (s, 1H), 7.93 (br. s., 1H), 7.76-7.84 (m, 2H), 7.68 (dd,
J=8.7,
4.5 Hz, 2H), 7.50 (t, J=8.6 Hz, 2H), 7.43 (d, J=8.8 Hz, 1H), 5.31 (br. s.,
1H), 4.64 (t,
J=13.0 Hz, 1H), 4.45 (t, J=8.4 Hz, 1H), 4.29 (t, J=9.7 Hz, 1H), 4.15-4.24 (m,
1H), 4.00
(br. s., 1H), 3.17-3.27 (m, 1H), 2.83-2.99 (m, 1H), 2.71 (s, 3H), 2.55 (q,
J=7.7 Hz, 1H),
1.74-2.00 (m, 3H), 1.15-1.31 (m, 2H). MS m/z 504.0 (M+H+).
Following the procedure described above for Example 10 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following intermediate compounds were prepared:
HO HO HO HO HO HO
0 0 0 0 0 0
N* N* N* N* N* N*
L
*
F3C)
CF3 F
F CF3 F
10-11 10-12 1 0-13 10-14 10-15 10-16
Following the procedure described above for Example 10 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
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Cpd Name and data
2-Methyl-l-pheny1-5-( {3- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
86 yl]azetidin-1-yllcarbony1)-1H-benzimidazole. MS m/z 486.1
(M+H+).
1-(3,4-Difluoropheny1)-2-methy1-5-( {3- [1-(1,3 -thiazol-2-
88
ylcarbonyl)piperidin-4-yl]azetidin-1-yllcarbony1)-1H-
benzimidazole.
MS m/z 522.0 (M+H+).
2-Methyl-5-( {3- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
89
yl]azetidin-l-yll carbony1)-1- [4-(trifluoromethyl)pheny1]-1H-
benzimidazole.
MS m/z 554.1 (M+H+).
2-Methyl-5-( {3- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yll c arb ony1)-1-(2,2,2-trifluoro ethyl)-1H-
benzimidazole.
MS m/z 492.1 (M+H+).
2-Methyl-5-( {3- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
91
yl]azetidin-l-yll c arb ony1)-1-(3,3,3 -trifluoropropy1)-1H-
benzimidazole.
MS m/z 506.2 (M+H+).
1-(4,4-Difluorocyclohexyl)-2-methy1-5-( {3- [1-(1,3-thiazol-2-
92
ylcarbonyl)piperidin-4-yl]azetidin-1-yllcarbony1)-1H-
benzimidazole.
MS m/z 528.3 (M+H+).
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Example 11
/---z---N
0 o.....-N\ 0 0
H
401 NH2 r-N\
Me0
N.../ Me0 0
CD
µ HO el Ns
0
1N NaOH N
9d 0 DMF
11a Ale Et0H
11b .
F F F
0 /
H
S N
N 1j
N (Cir \I 001 NO
,, .
HATU, Et3N, CH2Cl2 s "
'y
0 Cpd 97 IIIP
F
A. Methy11-(4-fluoropheny1)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-
carboxylate, ha. A mixture of compound 9d (0.20 g, 0.826 mmol) and 1,1'-
carbonyldiimidazole (0.535 g, 3.3 mmol) in DMF (8 mL) was heated at 90 C for 2
h.
The solvent was removed and the residue was triturated with water (15 mL). The
resulting precipitate was collected by filtration and washed several times
with water.
The crude product ha was used in the next reaction without further
purification. MS
m/z 287.1 (M+H+).
B. 1-(4-Fluoropheny1)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-
carboxylate, 11b. The title compound llb was prepared using the method
described
in Example 9, substituting compound ha for compound 9e in Step D. The crude
product lib was used in the next reaction without further purification. MS m/z
273.1
(M+H+).
C. 1-(4-Fluoropheny1)-5-({3-11-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yljazetidin-1-ylIcarbony1)-1,3-dihydro-2H-benzimidazol-2-one, Cpd 97. The
title
compound Cpd 97 was prepared using the method described in Example 9,
substituting compound llb for compound 9f in Step E. The crude product was
purified by preparative reverse phase chromatography to give 51 mg (32% yield)
of
Cpd 97. 1FINMR (CD30D) 6 = 7.93 (br. s., 1H), 7.81 (d, J=3.2 Hz, 1H), 7.51-
7.59
(m, 2H), 7.45 (s, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 1H), 7.33 (t, J=8.7 Hz, 2H),
7.04 (d,
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J=8.1 Hz, 1H), 5.30 (br. s., 1H), 4.56-4.69 (m, 1H), 4.40-4.51 (m, 1H), 4.21-
4.29 (m,
1H), 4.18 (br. s., 1H), 3.95 (br. s., 1H), 3.15-3.27 (m, 1H), 2.83-2.99 (m,
1H), 2.43-
2.58 (m, 1H), 1.71-2.00 (m, 3H), 1.22 (br. s., 2H). MS m/z 506.1 (M+H+).
Following the procedure described above for Example 11 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following intermediate compounds were prepared.
HO HO HO HO HO
0 0 0 0 0
N = N = N N = N =
OtNO 0-1\1
lat F
C F3
CF3
11-11 11-12 11-13 11-14 11-15
HO
0
N
0 \
/
F3L.,
11-16
Following the procedure described above for Example 11 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared.
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Cpd Name and data
1-Pheny1-5-( {3- [1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
96 yl]azetidin-l-yll carbonyl)-1,3-dihydro-2H-benzimidazol-2-
one.
MS m/z 488.1 (M+H+).
1-(3,4-Difluoropheny1)-5-( {3- [141,3 -thiazol-2-
98
ylcarbonyl)piperidin-4-yl]azetidin-l-yll carbony1)-1,3-dihydro-2H-
benzimidazol-2-one.
MS m/z 524.1 (M+H+).
54 {341-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yllcarbony1)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-
benzimidazol-2-one.
1H NMR (CD30D) 6 = 7.84-7.97 (m, 3H), 7.74-7.83 (m, 3H),
99
7.38-7.48 (m, 2H), 7.19 (d, J=8.3 Hz, 1H), 5.22-5.36 (m, 1H),
4.56-4.69 (m, 1H), 4.39-4.53 (m, 1H), 4.11-4.30 (m, 2H), 3.90-
4.01 (m, 1H), 2.83-3.00 (m, 1H), 2.43-2.59 (m, 1H), 1.68-2.01 (m,
3H), 1.13-1.29 (m, 2H).
-( {341-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl] azetidin-1-
100
yll carbony1)-1-(3,3,3-trifluoropropy1)-1,3-dihydro-2H-
benzimidazol-2-one.
MS m/z 508.2 (M+H+).
1-(4,4-Difluorocyclohexyl)-5-({3-[1-(1,3-thiazol-2-
101
ylcarbonyl)piperidin-4-yl]azetidin-l-yll carbony1)-1,3-dihydro-2H-
benzimidazol-2-one.
MS m/z 530.2 (M+H+).
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Example 12
HO Oi
N,Boc 0
3N aq HCI 12b
(C/
THE 1.1
HBTU, DIEA, DMF I
lc 12a r\J 12c
0 0 0
H2, 10% Pd-C H0)-(3
1N aq HCI, 111 \
=
Et0H r N
HN
HBTU, DIEA, DMF
12d Cpd 2
A. 3-(Pyridin-4-yl)azetidine, 12a. Compound lc was dissolved in a mixture
5 of 3N aqueous HC1 and THF and stirred until compound lc was completely
consumed.
The mixture was concentrated under reduced pressure and the aqueous residue
was
lyophilized to give compound 12a as the di-hydrochloride salt, which was used
in the
next step without further purification.
B. [1,1'-Bipheny1]-4-y1-(3-(pyridin-4-yl)azetidin-1-y1)methanone, 12c.
10 Compound 12a (4.5 mmol, 928 mg), [1,1'-biphenyl]-4-carboxylic acid 12b
(4.95 mmol,
980 mg), HBTU (6.43 mmol, 2.44 g), and DIEA (20.2 mmol, 3.49 mL) were combined
in DMF and stirred at 20 C for 20 h. The crude reaction mixture was purified
by
preparative reverse-phase HPLC to give compound 12c. 1H NMR (CD30D, 400 MHz):
6 = 8.68 (d, J=6.6 Hz, 2H), 7.92 (d, J=6.8 Hz, 2H), 7.68-7.77 (m, 2H), 7.60-
7.68 (m,
15 2H), 7.57 (dd, J=8.3, 1.2 Hz, 2H), 7.38 (t, J=7.5 Hz, 2H), 7.23-7.34 (m,
1H), 4.56-4.68
(m, 1H), 4.43-4.56 (m, 1H), 4.12-4.34 (m, 2H).
C. [1,1'-Bipheny1]-4-y1-(3-(piperidin-4-yl)azetidin-1-y1)methanone, 12d.
Compound 12c and 10% palladium on carbon were combined in a 1:5 mixture of 1N
aqueous HC1 and ethanol in a Parr pressure bottle. The mixture was purged with
N2
20 and then shaken under a 55 psi H2 atmosphere at 20 C. When the reaction
was
complete, the catalyst was removed by filtration through a diatomaceous earth
pad.
The filtrate was concentrated and lyophilized to provide compound 12d in
quantitative
yield as the hydrochloride salt.
D. 4-[1-(Bipheny1-4-ylcarbonyl)azetidin-3-y1]-1-(1,3-thiazol-2-
25 ylcarbonyl)piperidine, Cpd 2. A solution of compound 12d HC1 salt (0.28
mmol, 98
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mg), thiazole-2-carboxylic acid lh (0.33 mmol, 43 mg), and HBTU (0.33 mmol,
126
mg) in 2.5 mL of DMF was stirred for 10 min. DIEA (1.1 mmol, 0.2 mL) was added
and the mixture was stirred at 20 C for 20 h. The crude reaction mixture was
purified
by preparative reverse-phase HPLC to give Cpd 2. 1H NMR (CD30D, 400 MHz): 6 =
7.84 (br. s., 1H), 7.69-7.75 (m, 1H), 7.60-7.69 (m, 4H), 7.53-7.60 (m, 2H),
7.37 (t,
J=7.5 Hz, 2H), 7.24-7.33 (m, 1H), 5.13-5.29 (m, 1H), 4.54 (t, J=11.6 Hz, 1H),
4.38 (t,
J=8.7 Hz, 1H), 4.04-4.22 (m, 2H), 3.80-3.94 (m, 1H), 3.07-3.18 (m, 1H), 2.73-
2.91 (m,
1H), 2.35-2.50 (m, 1H), 1.63-1.91 (m, 3H), 0.99-1.25 (m, 2H). MS m/z 432.0
(M+H+).
Following the procedure described above for Example 12 and substituting the
appropriate reagents, starting materials and purification methods known to
those skilled
in the art, the following compounds of the present invention were prepared:
Cpd Name and data
1
4-[1-(Bipheny1-4-ylcarbonyl)azetidin-3-y1]-1-(1,3-thiazol-4-
ylcarbonyl)piperidine. MS m/z 432.0 (M+H+).
4-[1-(Bipheny1-4-ylcarbonyl)azetidin-3-y1]-1-(isothiazol-5-
3
ylcarbonyl)piperidine. MS m/z 432.0 (M+H+).
4-[1-(Bipheny1-4-ylcarbonyl)azetidin-3-y1]-1-(1H-pyrrol-3-
4
ylcarbonyl)piperidine. MS m/z 414 (M+H+).
5 4-[1-(Bipheny1-4-ylcarbonyl)azetidin-3-y1]-1-(1,3-thiazol-
5-
ylcarbonyl)piperidine. MS m/z 432.0 (M+H+).
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Example 13
Ph
SmI2
r"--,N)Ph SI i\L ,
HMP NI Ph
A, THF 0 OH
1.------1 N.
0
13a 13b 0 13c
0
HO
s__ 0
ofikl ---
of.INIH 13e 0
CF , 0
H2 (50 psi) 0 OH _________________________ OH S AO, CF3
__________ - N N
10% Pd-C, HBTU, DIEA, DMF
Et0H 0 13d 0 Cpd 6
A. (4-(1-Benzhydrylazetidin-3-y1)-4-hydroxypiperidin-1-
yl)(phenyl)methanone, 13c. A solution of 1-benzhydry1-3-iodoazetidine 13a (1.4
mmol, 490 mg) in 5 mL of THF was added to a stirring mixture of SmI2 (0.1 M
THF
solution, 3 mmol, 30 mL) and 1.7 mL of HMPA. After 5 min, a solution of 1-
benzoylpiperidin-4-one 13b (3.1 mmol, 626 mg) in 5 mL of THF was added. The
reaction mixture was stirred for 2 h. Saturated aqueous NH4C1 solution (20 mL)
was
added and the suspension was filtered through a diatomaceous earth pad. The
solids
were washed with chloroform and the combined organic layers were washed with
brine, dried, and concentrated. The crude residue was purified by preparative
reverse-
phase chromatography to give 400 mg (55% yield) of compound 13c (mono-TFA
salt)
as a yellow oil. MS m/z 401.2 (M+H+).
B. (4-(Azetidin-3-y1)-4-hydroxypiperidin-1-y1)(phenyl)methanone, 13d.
Compound 13c mono-TFA salt (0.34 mmol, 180 mg) and 10% palladium on carbon (40
mg) were combined in a 30 mL of ethanol in a Parr pressure bottle. The mixture
was
purged with N2 and then shaken under a 50 psi H2 atmosphere at 20 C for 20 h.
The
catalyst was removed by filtration through a diatomaceous earth pad and the
filtrate
was concentrated. Water, CH2C12, and aqueous HC1 were added and the mixture
was
frozen and lyophilized to give 82 mg (81% yield) of compound 13d (mono-HC1
salt).
MS m/z 261.1 (M+H+).
C. 1-(Phenylcarbony1)-4-(1-{15-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}azetidin-3-yl)piperidin-4-ol, Cpd 6. A solution of 5-
(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 13e (0.30 mmol, 75 mg),
DIEA
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(0.83 mmol, 0.15 mL), and HBTU (0.33 mmol, 126 mg) in 2 mL of DMF was stirred
for 10 min. The HC1 salt of compound 13d (0.28 mmol, 82 mg) was added and the
mixture was stirred at 20 C for 20 h. The reaction mixture was filtered
through 3 g of
silica gel carbonate and 3 g of aminopropyl silica gel using CH3CN as eluant.
The
CH3CN was removed under reduced pressure and the residue was purified by
preparative reverse-phase HPLC to give 45 mg (33% yield) of Cpd 6. 1H NMR
(CD30D, 400 MHz): 6 = 8.13-8.24 (m, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.82-7.90 (m,
1H),
7.60 (d, J=8.6 Hz, 1H), 7.27-7.42 (m, 5H), 4.44-4.59 (m, 2H), 4.25-4.39 (m,
J=15.0, 2.8
Hz, 1H), 3.98-4.19 (m, 2H), 3.42-3.54 (m, 1H), 3.32-3.42 (m, 1H), 2.79 (quin,
J=7.4
Hz, 1H), 1.57-1.69 (m, 1H), 1.31-1.56 (m, 3H). MS m/z 489.1 (M+H+).
Example 14
Ph Ph
Ph
r0
SmI2 CJNILPh
L Ph
Ph N,
Boc' HMPA THF Boc'Na TEA, CH2Cl2 OH r
IN
HN
13a 14a 14b 14c
0 Ph
HOJc_...s
Aµ .õC.INJ)Ph CI 0
NH
1 N (-31r r OH 0 OEt /1- r -<011
\ N
HBTU, DIEA, DMF S CH2Cl2, N--
0 14d then Me0H 0 14e
0
HO
S 0
14f CF3 S
OH
SN
HBTU, DIEA, DMF CF3
0 Cpd 94
A. (tert-Butyl 4-(1-benzhydrylazetidin-3-y1)-4-hydroxypiperidine-1-
carboxylate, 14b. A solution of 1-benzhydry1-3-iodoazetidine 13a (4.75 mmol,
1.66 g)
in 10 mL of THF was added to a stirring mixture of 5mI2 (0.1 M THF solution,
9.98
mmol, 99.8 mL) and 5.6 mL of HMPA. After 15 min, a solution of tert-butyl 4-
oxopiperidine-l-carboxylate 14a (4.75 mmol, 0.95 g) in 15 mL of THF was added.
The reaction mixture was stirred for 18 h. Saturated aqueous NH4C1 solution
(40 mL)
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was added and the suspension was filtered through a diatomaceous earth pad.
The
solids were washed with chloroform and the combined organic layers were washed
with brine, dried, and concentrated. The crude residue was purified by
preparative
reverse-phase chromatography to give 1.0 g (45% yield) of 90% pure compound
14b as
a clear oil. MS m/z 423.3 (M+H+).
B. 4-(1-Benzhydrylazetidin-3-yl)piperidin-4-ol, 14c. Compound 14c was
prepared according to the procedure described in Example 1, Step F,
substituting
compound 14b for compound li.
C. (4-(1-Benzhydrylazetidin-3-y1)-4-hydroxypiperidin-1-y1)(thiazol-2-
yl)methanone, 14d. A solution of thiazole-2-carboxylic acid lh (1.79 mmol, 232
mg),
DIEA (6.53 mmol, 1.12 mL), and HBTU (1.96 mmol, 742 mg) in 11 mL of DMF was
stirred for 10 min. Compound 14c (1.63 mmol, 526 mg) was added and the mixture
was stirred at 20 C for 20 h. The reaction mixture was purified by
preparative reverse-
phase HPLC to give 298 mg (33% yield) of compound 14d as a buff powder. MS m/z
434.2 (M+H+).
D. 4 (4-(Azetidin-3-y1)-4-hydroxypiperidin-1-y1)(thiazol-2-yl)methanone,
14e. 1-Chloroethyl chloroformate (7.06 mmol, 0.76 mL) was added dropwise to a
solution of compound 14d in 20 mL of CH2C12 in an ice-water bath. After 30
min, the
cooling bath was removed and the reaction mixture was stirred for 2 h at 20
C. The
CH2C12 was evaporated, 20 mL of Me0H was added, and the resulting solution was
refluxed for 2 h. The solvent was evaporated and the residue was partitioned
between
CH2C12 and 0.2 N aqueous HC1. The aqueous layer was lyophilized to give
compound
14e, which was carried on to the next step without purification. MS m/z 267.7
(M+H+).
E. 1-(1,3-Thiazol-2-ylcarbony1)-4-(1-{16-(trifluoromethyl)-1-
benzothiophen-2-yl]carbonyl}azetidin-3-yl)piperidin-4-ol, Cpd 94. A solution
of 6-
(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 14f (0.30 mmol, 75 mg),
DIEA
(0.98 mmol, 0.17 mL), and HBTU (0.30 mmol, 112 mg) in 2 mL of DMF was stirred
for 10 min. Compound 14e (0.25 mmol, 66 mg) was added and the mixture was
stirred
at 20 C for 20 h. The reaction mixture was purified by preparative reverse-
phase
HPLC to give 77 mg (62% yield) of Cpd 94 as a white powder. 1H NMR (DMSO-d6):
6 = 8.39 (s, 1H), 8.29 (d, J=8.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.00 (s, 2H),
7.76 (dd,
J=8.6, 1.5 Hz, 1H), 4.99 (d, J=12.7 Hz, 1H), 4.46-4.56 (m, 2H), 4.25 (d,
J=12.2 Hz,
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1H), 4.06-4.15 (m, 1H), 3.97-4.06 (m, 1H), 3.17-3.27 (m, 2H), 2.74-2.86 (m,
J=14.8,
7.3, 7.3 Hz, 1H), 1.36-1.66 (m, 4H). MS m/z 496.1 (M+H+).
Biological Examples
In Vitro Methods
Example 1
MGL Enzyme Activity Assay
All rate-based assays were performed in black 384-well polypropylene PCR
microplates (Abgene) in a total volume of 30 pt. Substrate 4-
methylumbelliferyl
butyrate (4MU-B; Sigma) and either purified mutant MGL (mut-MGLL 11-313 L1795
L1865) or purified wild type MGL (wt-MGLL 6H-11-313) were diluted separately
into
mM PIPES buffer (pH = 7.0), containing 150 mM NaC1 and 0.001% Tween 20.
Compounds of Formula (I) were pre-dispensed (50 nL) into the assay plate using
a
15 Cartesian Hummingbird prior to adding 4MU-B (25 pi of 1.2X solution to a
final
concentration of 10 pM) followed by enzyme (5 pi of a 6X solution to a final
concentration of 5 nM) to initiate the reaction. Final compound concentrations
ranged
from 17 to 0.0003 M. The fluorescence change due to 4MU-B cleavage was
monitored with excitation and emission wavelengths of 335 and 440 nm,
respectively,
20 and a bandwidth of 10 nm (Safire2, Tecan) at 37 C for 5 min.
The IC50 values for compounds of Formula (I) were determined using Excel
from a fit of the equation to the concentration-response plot of the
fractional activity as
a function of inhibitor concentration.
Biological Data Table 1
Cpd MGL mutant MGL wild type
inh IC50 (pM ) inh IC50 (IM)
1 0.079 0.258
2 <0.005 <0.005
3 0.0339
4 0.154
5 0.0876
6 0.918
7 0.0565
8 0.007
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Cpd MGL mutant MGL wild type
inh 1050 (iLtM ) inh IC50 (PM)
9 0.114
0.0155
11 0.498
12 0.01
13 <0.005
14 0.005
0.007
16 0.007
17 0.0173
18 0.0125
19 <0.005
<0.005
21 0.0124
22 0.008
23 0.368
24 0.0379
0.0120
26 <0.005
27 0.00900
28 0.0164
29 0.00600
<0.005
31 <0.005
32 <0.005
33 <0.005
34 0.0544
<0.005
36 <0.005
37 <0.005
38 0.005
39 <0.005
0.00900
41 <0.005
42 <0.005
43 <0.005
44 <0.005
<0.005
46 0.111
47 0.0379
48 <0.005
49 0.00600
<0.005
51 <0.005
52 0.0715
53 0.0466
54 <0.005
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Cpd MGL mutant MGL wild type
inh 1050 (iLiM ) inh ICso (PM)
55 0.0130
56 <0.005
57 0.0170
58 <0.005
59 0.011
60 0.01
61 0.211
62 <0.005
63 <0.005
64 <0.005
65 <0.005
66 0.0192
67 0.0665
68 0.0621
69 <0.005
70 0.008
71 0.0120
72 0.0170
73 0.0120
74 0.0138
75 <0.005
76 0.0114
77 <0.005
78 <0.005
79 0.00900
80 <0.005
81 0.0232
82 0.0355
83 0.00916
84 0.175
85 0.280
86 0.0187
87 0.0316
88 0.00949
89 0.0341
90 0.173
91 0.237
92 0.163
93 <0.005
94 0.01
95 0.0140
96 0.0781
97 0.0340
98 0.0166
99 0.0173
100 0.101
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Cpd MGL mutant MGL wild type
inh IC50 (iiiM ) inh IC50 (PM)
101 0.104
Example 2
2-AG Accumulation assay
To measure the accumulation of 2-AG due to inhibition of MGL, one g rat
brain
was homogenized using a Polytron homogenizer (Brinkmann, PT300) in 10 mL of 20
mM HEPES buffer (pH = 7.4), containing 125 mM NaC1, 1 mM EDTA, 5 mM KC1
and 20 mM glucose. Compounds of Formula (I) (10 laM) were pre-incubated with
rat
brain homogenate (50 mg). After a 15-min incubation time at 37 C, CaC12 (final
concentration = 10 mM) was added and then incubated for 15 min at 37 C in a
total
volume of 5 mL. The reactions were stopped with 6 mL organic solvent
extraction
solution of 2:1 chloroform/methanol. Accumulated 2-AG in the organic phase was
measured by a HPLC/MS method, according to the following equation:
percent vehicle = (2-AG accumulation in the presence of compound/2-AG
accumulation in vehicle) x 100.
Biological Data Table 2
Rat Brain 2AG %VehCntrl
Cpd (%) gl litM
1 109
2 329
3 135
7 185
8 523
10 194
12 134
13 335
14 231
15 281
16 493
17 184
18 457
19 559
728
21 287
22 470
24 298
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Rat Brain 2AG %VehCntrl
Cpd (%) gl litM
25 540
26 303
27 634
28 777
29 800
30 443
31 779
32 1026
33 696
34 517
35 724
36 507
37 163
38 425
39 371
40 361
41 272
42 498
43 611
44 107
45 385
47 153
48 1022
49 908
50 561
51 266
52 193
53 225
54 736
55 733
56 285
57 869
58 370
59 346
60 508
62 422
63 435
64 383
65 241
66 889
67 590
68 453
69 539
70 561
71 552
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Rat Brain 2AG %VehCntrl
Cpd (%) glIJM
73 875
74 788
75 1135
76 731
77 714
78 1046
79 946
80 860
Example 3
MGL ThermoFluor Assay - mutant
The ThermoFluor (TF) assay is a 384-well plate-based binding assay that
measures thermal stability of proteins1'2. The experiments were carried out
using
instruments available from Johnson & Johnson Pharmaceutical Research &
Development, LLC. TF dye used in all experiments was 1,8-ANS (Invitrogen: A-
47).
Final TF assay conditions used for MGL studies were 0.07 mg/ml of mutant MGL,
100
pM ANS, 200 mM NaC1, 0.001% Tween-20 in 50 mM PIPES (pH = 7.0).
Screening compound plates contained 100% DMSO compound solutions at a
single concentration. For follow-up concentration-response studies, compounds
were
arranged in a pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds
were
serially diluted in 100% DMSO across 11 columns within a series. Columns 12
and 24
were used as DMSO reference and contained no compound. For both single and
multiple compound concentration-repsonse experiments, the compound aliquots
(46
nL) were robotically predispensed directly into 384-well black assay plates
(Abgene:
TF-0384/k) using the Hummingbird liquid handler. Following compound
dispension,
protein and dye solutions were added to achieve the final assay volume of 3
L. The
assay solutions were overlayed with 1 pt of silicone oil (Fluka, type DC 200:
85411)
to prevent evaporation.
Bar-coded assay plates were robotically loaded onto a thermostatically
controlled PCR-type thermal block and then heated from 40 to 90 C degrees at
a ramp-
rate of 1 C/min for all experiments. Fluorescence was measured by continuous
illumination with UV light (Hamamatsu LC6), supplied via fiber optics and
filtered
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through a band-pass filter (380-400 nm; > 6 OD cutoff). Fluorescence emission
of the
entire 384-well plate was detected by measuring light intensity using a CCD
camera
(Sensys, Roper Scientific) filtered to detect 500 25 nm, resulting in
simultaneous and
independent readings of all 384 wells. A single image with 20-sec exposure
time was
collected at each temperature, and the sum of the pixel intensity in a given
area of the
assay plate was recorded vs temperature and fit to standard equations to yield
the Tnil.
1. Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V. S.,
Myslik, J.,
Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R.
(2001) J Biomol Screen 6,429-40.
2. Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005)
Biochemistry
44, 5258-66.
The Kd values for compounds of Formula (I) were determined from a fit of the
equation to the concentration-response plot of the fractional activity as a
function of Tni.
For some experiments, quantitative NMR spectroscopy (qNMR) was used to measure
concentration of the initial 100% DMSO compound solutions and, using the same
fitting method, qKd values were determined.
Biological DataTable 3
Cpd MGL mutant MGL mutant
ThermoFluor Kd (p.M ) ThermoFluor qKd
(p.M) (using qNMR
conc.)
1 0.100
2 0.0089
3 0.0557
4 0.162
5 0.0641
6 0.258
7 0.0250
8 0.0040
9 0.100
10 0.0110
11 0.732
12 0.0220
13 0.0280
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Cpd MGL mutant MGL mutant
ThermoFluor Kd (p.M ) ThermoFluor qKd
(p.M) (using qNMR
conc.)
14 0.0050
15 0.0090
16 0.0020
17 0.0990
18 0.0030
19 0.0090
20 0.0010 0.0013
21 0.0286
22 0.0066
23 0.500
24 0.0199
25 0.0275
26 0.0036
27 0.0133
28 0.0111
29 0.0003 0.0012
30 0.0025
31 0.0026
32 0.0006
33 0.0626
34 0.198
35 0.0025 0.0057
36 0.0225
37 0.0160
38 0.0155
39 0.0489
40 0.0946
41 0.0041 0.0031
42 0.0245
43 0.0264
44 0.0213
45 0.0122
46 0.0200
47 0.0767 0.0333
48 0.0010
49 0.0010
50 0.0010
51 0.0180
52 0.0304 0.0322
53 0.0333
54 0.0018
55 0.0020
56 0.0055 0.0033
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Cpd MGL mutant MGL mutant
ThermoFluor Kd (p.M ) ThermoFluor qKd
(p.M) (using qNMR
conc.)
57 0.0059
58 0.0069
59 0.0202 0.0094
60 0.0008 0.0005
61 0.0006 0.0005
62 0.0013 0.0006
63 0.0174
64 0.0189
65 0.0404
66 0.0067
67 0.0066
68 0.0145
69 0.0012
70 0.0006
71 0.0012
72 0.0027
73 0.0048
74 0.0080
75 0.0039
76 0.0083
77 0.0050
78 0.0023
79 0.0033
80 0.0049
81 0.0148
82 0.0228
83 0.0136
84 0.0663
85 0.0645
86 0.0106
87 0.0075
88 0.0133
89 0.0077
90 0.0237
91 0.0325
92 0.0034
93 0.0055
94 0.0249
95 0.0386
96 0.0247
97 0.0221
98 0.0436
99 0.0167
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Cpd MGL mutant MGL mutant
ThermoFluor Kd (iLtM ) ThermoFluor qKd
(ILEM) (using qNMR
conc.)
100 0.0888
101 0.0039
In Vivo Methods
Example 4
CFA-Induced Paw Radiant Heat Hypersensitivity
Each rat was placed in a test chamber on a warm glass surface and allowed to
acclimate for approximately 10 min. A radiant thermal stimulus (beam of light)
was
focused through the glass onto the plantar surface of each hind paw in turn.
The
thermal stimulus was automatically shut off by a photoelectric relay when the
paw was
moved or when the cut-off time was reached (20 sec for radiant heat at ¨5
amps). An
initial (baseline) response latency to the thermal stimulus was recorded for
each animal
prior to the injection of complete Freund's adjuvant (CFA). Twenty-four hours
following intraplantar CFA injection, the response latency of the animal to
the thermal
stimulus was re-evaluated and compared to the animal's baseline response time.
Only
rats that exhibited at least a 25% reduction in response latency (i.e., are
hyperalgesic)
were included in further analysis. Immediately following the post-CFA latency
assessment, the indicated test compound or vehicle was administered orally.
Post-
compound treatment withdrawal latency was assessed at fixed time intervals,
typically
30, 60, 120, 180, and 300 min.
The percent reversal (%R) of hypersensitivity was calculated in one of two
different ways: 1) using group mean values or 2) using individual animal
values. More
specifically:
Method 1. For all compounds, the %R of hypersensitivity was calculated using
the mean value for groups of animals at each time point according to the
following
formula:
% reversal = [(group treatment response ¨ group CFA response)/(group
baseline response ¨ group CFA response)] x 100
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Results are given for the maximum % reversal observed for each compound at any
time
point tested.
Method 2. For some compounds, the %R of hypersensitivity was calculated
separately for each animal according to the following formula:
% reversal = [(individual treatment response ¨ individual CFA
response)/(individual baseline response ¨ individual CFA response)] x 100.
Results are given as a mean of the maximum % reversal values calculated for
each
individual animal.
Biological DataTable 4
last time
Method 1: Method 2:
Cpd dose no. of point peak %
peak %
No. (mg/kg, p.o.) vehicle animals (min) reversal
reversal
30 20% HP13CD 8 300 -6.7 Not
calculated
29 30
10% NMP / 8 300 179 Not
.
20% solutol calculated
Example 5
15 CFA-Induced Paw Pressure Hypersensitivity
Prior to testing, rats may be acclimated to the handling procedure twice a day
for a period of two days . The test consists of placing the left hindpaw on a
polytetrafluoroethylene platform and applying a linearly increasing mechanical
force
20 (constant rate of 12.5 mmHg/s) in between the third and fourth
metatarsal of the
dorsum of the rat's hindpaw, with a dome-tipped plinth (0.7 mm in radius),
using an
analgesy-meter (Stoelting, Chicago, IL), also known as a Randall-Selitto
apparatus.
The endpoint may be automatically reached upon hindpaw withdrawal, and the
terminal
force may be noted (in grams). An initial (baseline) response threshold to the
mechanical stimulus may be recorded for each animal prior to the injection of
complete
Freund's adjuvant (CFA). Forty hours following intraplantar CFA injection, the
response threshold of the animal to the mechanical stimulus may be re-
evaluated and
compared to the animal's baseline response threshold. A response may be
defined as a
withdrawal of the hindpaw, a struggling to remove the hindpaw, or
vocalization. Only
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rats that exhibit at least a 25% reduction in response threshold (i.e.,
hyperalgesia) may
be included in further analysis. Immediately following the post-CFA threshold
assessment, rats may be administered the indicated test compound or vehicle.
Post-
treatment withdrawal thresholds may be assessed at 1 h. Paw withdrawal
thresholds
may be converted to percent reversal of hypersensitivity according to the
following
formula:
% reversal = [(post treatment response-predose response)/(baseline response-
predose response)] x 100.
Example 6
Chronic constriction injury (CCI)-induced model of neuropathic pain ¨ cold
acetone-hypersensitivity test
Male Sprague-Dawley rats (225-450 g) may be used to evaluate the ability of
selected compounds to reverse CCI-induced cold hypersensitivity. Four loose
ligatures
of 4-0 chromic gut may be surgically placed around the left sciatic nerve
under
inhalation anesthesia as described by Bennett et al. (Bennett GJ, Xie YK. Pain
1988,
33(1): 87-107). Fourteen to 35 days following CCI surgery, subjects may be
placed in
elevated observation chambers containing wire mesh floors, and five
applications of
acetone (0.05 mL/application separated by approximately 5 minutes) may be
spritzed
onto the plantar surface of the paw using a multidose syringe. An abrupt
withdrawal or
lifting of the paw may be considered a positive response. The number of
positive
responses may be recorded for each rat over the five trials. Following
baseline
withdrawal determinations, compounds may be administered in the indicated
vehicle,
by the indicated route (see Table 6). The number of withdrawals may be re-
determined
1 to 4 hr after compound administration. Results may be presented as a percent
inhibition of shakes, which may be calculated for each subject as [1-(test
compound
withdrawals / pre-test withdrawals)] x 100 and then averaged by treatment.
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Example 7
Spinal nerve ligation (SNL) model of neuropathic pain ¨ tactile allodynia test
For lumbar 5 (L5) spinal nerve ligation (SNL) studies, anesthesia may be
induced and maintained on isoflurane inhalation. Fur may be clipped over the
dorsal
pelvic area, and a 2-cm skin incision may be made just left of midline over
the dorsal
aspect of the L4¨S2 spinal segments, followed by separation of the paraspinal
muscles
from spinous processes. The transverse process of L6 may be carefully removed,
and
the L5 spinal nerve may be identified. The left L5 spinal nerve may be ligated
tightly
with 6-0 silk thread, the muscle may be sutured with 4-0 vicryl, and the skin
may be
closed with wound clips. Following surgery, s.c. saline (5 mL) may be
administered.
Behavioral testing may be performed four weeks post-ligation. Following
baseline von Frey determinations to verify the presence of mechanical
allodynia, L5
SNL rats may be orally administered the indicated vehicle or drug. Tactile
allodynia
may be quantified at 30, 60, 100, 180, and 300 min post-dosing by recording
the force
at which the paw ipsilateral to the nerve ligation is withdrawn from the
application of a
series of calibrated von Frey filaments (0.4, 0.6, 1.0, 2.0, 4, 6, 8 and 15 g;
Stoelting;
Wood Dale, IL). Beginning at an intermediate stiffness (2.0 g), filaments may
be
applied to the mid-plantar hind paw for approximately 5 seconds to determine
the
response threshold, a brisk paw withdrawal leads to the presentation of the
next lighter
stimulus, whereas a lack of a withdrawal response leads to the presentation of
the next
stronger stimulus. A total of four responses after the first threshold
detection may be
collected. The 50% withdrawal thresholds may be interpolated by the method of
Dixon
as modified by Chaplan et.al., and when response thresholds fall above or
below the
range of detection, respective values of 15.0 or 0.25 g may be assigned.
Threshold data
from von Frey filament testing may be reported as withdrawal threshold in
grams. Data
may be normalized and results may be presented as % MPE (maximum possible
effect)
of the drug calculated according to the following formula:
% MPE = x g/force ¨ baseline g/force X 100
15 g/force ¨ baseline g/force
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While the foregoing specification teaches the principles of the present
invention,
with examples provided for the purpose of illustration, it will be understood
that the
practice of the invention encompasses all of the usual variations, adaptations
and/or
modifications as come within the scope of the following claims and their
equivalents.
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