WO 2006/116151 PCT/US2006/015193
BENZOFURANYL ALKANAMINE DERIVATIVES AND USES THEREOF AS 5-HT2C AGONISTS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to United States Provisional Patent Application
serial number 60/674,129, filed April 22, 2005, the entirety of which is hereby incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to 5-HT2C receptor agonists, processes for their
preparation, and uses thereof.
BACKGROUND OF THE INVENTION
[0003] Schizophrenia affects approximately 5 million people. The most prevalent
treatments for schizophrenia are currently the 'atypical' antipsychotics, which combine
dopamine (D2) and serotonin (5-HT2A) receptor antagonism. Despite the reported
improvements in efficacy and side-effect liability of atypical antipsychotics relative to typical
antipsychotics, these compounds do not appear to adequately treat all the symptoms of
schizophrenia and are accompanied by problematic side effects, such as weight gain (Allison,
D. B., et. al., Am. J. Psychiatry, 156: 1686-1696, 1999; Masand, P. S., Exp. Opin.
Pharmacother. I: 377-389, 2000; Whitaker, R., Spectrum Life Sciences. Decision Resources.
2:1-9,2000).
[0004] Atypical antipsychotics also bind with high affinity to 5-HT2C receptors and
function as 5-HT2C receptor antagonists or inverse agonists. Weight gain is a problematic side
effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has
been suggested that 5-HT2C antagonism is responsible for the increased weight gain.
Conversely, stimulation of the 5-HT2C receptor is known to result in decreased food intake
and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P. J., et. al.,
Human Psychopharmacology 10: 385-391, 1995; Rosenzweig-Lipson, S., et. al., ASPET
abstract, 2000).
[0005] Several lines of evidence support a role for 5-HT2C receptor agonism or partial
agonism as a treatment for schizophrenia. Studies suggest that 5-HT2C antagonists increase
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synaptic levels of dopamine and may be effective in animal models of Parkinson's disease
(Di Matteo, V., et. al., Neuropharmacology 37: 265-272, 1998; Fox, S. H., et. al.,
Experimental Neurology 151: 35-49, 1998). Since the positive symptoms of schizophrenia
are associated with increased levels of dopamine, compounds with actions opposite to those
of 5-HT2c antagonists, such as 5-HT2C agonists and partial agonists, should reduce levels of
synaptic dopamine. Recent studies have demonstrated that 5-HT2C agonists decrease levels
of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al.,
Neuropharmacology 37: 953-955,1998; Di Matteo, V., et. al., Neuropharmacology 38: 1195-
1205, 1999; Di Giovanni, G., et. al., Synapse 35: 53-61, 2000), brain regions that are thought
to mediate critical antipsychotic effects of drugs like clozapine. However, 5-HT2C agonists
do not decrease dopamine levels in the striatum, the brain region most closely associated with
extrapyramidal side effects. In addition, a recent study demonstrates that 5-HT2C agonists
decrease firing in the ventral tegmental area (VTA), but not in the substantia nigra. The
differential effects of 5-HT2C agonists in the mesolimbic pathway relative to the nigrostriatal
pathway suggest that 5-HT2C agonists have limbic selectivity, and will be less likely to
produce extrapyramidal side effects associated with typical antipsychotics.
SUMMARY OF THE INVENTION
[0006] The present invention relates to 5-HT2C agonists and uses thereof. In one aspect,
the invention relates to novel 7-aryl-(1-benzofuran-2-yl)alkanamine derivatives that act as
agonists or partial agonists of the 5-HT2C receptor. The compounds are useful, for example,
to treat schizophrenia and the concomitant mood disorders and cognitive impairments of
schizophrenia. In certain embodiments, compounds of the present invention are less likely to
produce the body weight increases associated with current atypical antipsychotics. The
compounds of the present invention are also useful for the treatment of obesity and its
comorbidities.
[0007] In certain embodiments, the present invention provides a compound of formula I:

or pharmaceutically acceptable salts thereof, wherein:
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each of R1 and R1 is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl
or cyclopropyl;
each of R2, R3 and R4 is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy,
trifluoromethyl, trifluoromethoxy, or CN;
Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more
Rx groups;
each Rx is independently halogen, -OH,-CN, lower alkyl, lower alkoxy, -CF3, or -OCF3; and
n is one or two.
[0008] In certain other embodiments, the invention relates to methods for treating a
patient suffering from schizophrenia, schizophreniform disorder, schizoaffective disorder,
delusional disorder, substance-induced psychotic disorder, L-DOPA-induced psychosis,
psychosis associated with Alzheimer's dementia, psychosis associated with Parkinson's
disease, psychosis associated with Lewy body disease, dementia, memory deficit, intellectual
deficit associated with Alzheimer's disease, bipolar disorders, depressive disorders, mood
episodes, anxiety disorders, adjustment disorders, eating disorders, epilepsy, sleep disorders,
migraines, sexual dysfunction, substance abuse, addiction to alcohol and various other drugs,
including cocaine and nicotine, gastrointestinal disorders, obesity, or a central nervous system
deficiency associated with trauma, stroke, or spinal cord injury that includes administering to
the patient a therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0009] In still other embodiments, the invention relates to compositions comprising a
compound of formula I or a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable carriers, excipients, or diluents.
DETAILED DESCRIPTION OF THE INVENTION
1. Compounds and Definitions:
[0010] The present invention relates to novel 7-[aryl]-(1-benzofuran-2-yl)alkanamine
derivatives that are agonists or partial agonists of the 2C subtype of brain serotonin receptors.
[0011] The term "lower alkyl," as used herein, refers to a hydrocarbon chain having up to
4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms.
The term "alkyl" includes, but is not limited to, straight and branched chains such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.
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[0012] The term "alkoxy," as used herein, refers to the group -OR*, wherein R* is a lower
alkyl group.
[0013] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine
or iodine.
[0014] The terms "effective amount" and "therapeutically effective amount," as used
herein, refer to the amount of a compound of formula I that, when administered to a patient,
is effective to at least partially treat a condition from which the patient is suffering from.
Such conditions include, but are not limited to, schizophrenia, schizoaffective disorder,
schizophreniform disorder, L-DOPA-induced psychosis, bipolar disorder, obesity, obsessive
compulsive disorder, depression, panic disorder, sleep disorders, eating disorders, and
epilepsy.
[0015] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable
salt" includes acid addition salts, namely salts derived from treating a compound of formula I
with an organic or inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric,
succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic,
toluenesulfonic, salicylic, benzoic, or similarly known acceptable acids. In certain
embodiments, the present invention provides the hydrochloride salt of a compound of
formula I. Where the compound having formula I has an acidic function, for instance, where
R2, R3 or R4 is phenolic hydroxyl, the term "pharmaceutically acceptable salts" or
"pharmaceutically acceptable salt" includes salts derived from bases, for instance sodium
salts.
[0016] The term "patient," as used herein, refers to a mammal. In certain embodiments,
the term "patient", as used herein, refers to a human.
[0017] The terms "administer," "administering," or "administration," as used herein, refer
to either directly administering a compound or composition to a patient, or administering a
prodrug derivative or analog of the compound to the patient, which will form an equivalent
amount of the active compound or substance within the patient's body.
[0018] The terms "treat" or "treating," as used herein, refers to partially or completely
alleviating, inhibiting, preventing, ameliorating and/or relieving the condition.
[0019] The terms "suffer" or "suffering" as used herein refers to one or more conditions
that a patient has been diagnosed with, or is suspected to have.
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2. Description of Exemplary Compounds:
[0020] In certain embodiments, the invention relates to a compound of formula I:

or pharmaceutically acceptable salts thereof, wherein:
each of R1 and R1 is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl
or cyclopropyl;
each of R2, R3 and R4 is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy,
trifluoromethyl, trifluoromethoxy, or CN;
Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more
Rx groups;
each Rx is independently halogen, -OH, -CN, lower alkyl, lower alkoxy, -CF3, or -OCF3; and
n is one or two.
[0021] In certain embodiments, the n group of formula I is 1.
[0022] In other embodiments, the n group of formula I is 2.
[0023] As defined generally above, each of the R1 and R1 groups of formula I is
independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl. In
certain embodiments, one of the R1 and R1 groups of formula I is hydrogen and the other of
R1 and R1 groups of formula I is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or
cyclopropyl. In other embodiments, neither of the R1 and R1 groups of formula I is
hydrogen. In still other embodiments, both of the R1 and R1 groups of formula I are
hydrogen.
[0024] As defined generally above, each of the R2, R3 and R4 groups of formula I is
independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl,
trifluoromethoxy, or CN. In certain embodiments, the R2, R3 and R4 groups of formula I are
all hydrogen. In other embodiments, at least one of the R2, R3 and R4 groups of formula I is
halogen. According to another aspect of the present invention, the R2 group of formula I is
hydrogen and the R3 and R4 groups of formula I are independently halogen, OH, lower alkyl,
lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN. Yet another aspect of the present
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invention provides a compound of formula I wherein R2 and R4 are both hydrogen and R3 is
lower alkyl or lower alkoxy. Yet another aspect of the present invention provides a
compound of formula I wherein R2 and R4 are both hydrogen and R3 is halogen. In certain
embodiments, the R2 and R4 groups of formula I are both hydrogen and R3 is fluoro or
chloro. In other embodiments, the R2 and R3 groups of formula I are both hydrogen and R4 is
fluoro or chloro.
[0025] As defined generally above, the Ar group of formula I is thienyl, furyl, pyridyl, or
phenyl, wherein Ar is optionally substituted with one or more Rx subsituents, wherein each
Rx is independently selected from halogen, -OH, -CN, lower alkyl, lower alkoxy, -CF3, or -
OCF3. In certain embodiments, the Ar group of formula I is unsubstituted phenyl. In other
embodiments, the Ar group of formula I is phenyl with at least one substituent in the ortho
position. In other embodiments, the Ar group of formula I is phenyl with at least one
substituent in the ortho position selected from halogen, lower alkyl, lower alkoxy, or
trifluoromethyl. According to one aspect the present invention provides a compound of
formula I wherein Ar is phenyl di-substituted in the ortho and meta positions with halogen,
lower alkyl, or lower alkoxy. Yet another aspect of the present invention provides a
compound of formula I wherein Ar is phenyl di-subsituted in the ortho and para positions
with halogen, lower alkyl, or lower alkoxy. Yet another aspect of the present invention
provides a compound of formula I wherein Ar is phenyl di-subsituted in both ortho positions
with halogen, lower alkyl, or lower alkoxy. Exemplary substituents on the phenyl moiety of
the Ar group of formula I include OMe, fluoro, chloro, methyl, and trifluoromethyl.
[0026] In certain embodiments, the Ar group of formula I is selected from the following:

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[0027] According to another embodiment, the present invention provides a compound of
formula II:

or pharmaceutically acceptable salts thereof, wherein each Rx is independently halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN, and each of R1, R1, R2,
R3 and R4 are as defined generally above and in classes and subclasses described above and
herein.
[0028] According to yet another embodiment, the present invention provides a compound
of formula III:

or pharmaceutically acceptable salts thereof, wherein each Rx is independently halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN, and each of R1, R1, R2,
R3 and R4 are as defined generally above and in classes and subclasses described above and
herein.
[0029] According to yet another embodiment, the present invention provides a compound
of formula IV:
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or pharmaceutically acceptable salts thereof, wherein each Rx is independently halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN, and each of R1, R1, R2,
R3 and R4 are as defined generally above and in classes and subclasses described above and
herein.
[0030] According to yet another embodiment, the present invention provides a compound
of formula V:

or pharmaceutically acceptable salts thereof, wherein each Rx is independently halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN, and each of R1, R1, R6,
R3 and R4 are as defined generally above and in classes and subclasses described above and
herein.
[0031] According to yet another embodiment, the present invention provides a compound
of formula VI:
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or pharmaceutically acceptable salts thereof, wherein each Rx is independently halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN, and each of R1, R1, R2,
R3 and R4 are as defined generally above and in classes and subclasses described above and
herein.
[0032] According to yet another embodiment, the present invention provides a compound
of formula VII:
or pharmaceutically acceptable salts thereof, wherein each Rx is independently halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN, and each of R1, Rl, R ,
R3 and R4 are as defined generally above and in classes and subclasses described above and
herein.
[0033] It is recognized that atropisomers of the present compounds may exit. The present
invention thus encompasses atropisomeric forms of compounds of formula I as defined
above, and in classes and sublcasses described above and herein.
[0034] Exemplary compounds of formula I are set forth in Table 1, below.
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Table 1: Exemplary Compounds of Formula I:

3. General Methods of Providing the Present Compounds:
[0035] The 7-[biaryl]-1-benzofuran-2-yl}methyl)amines of formula I may be prepared as
illustrated by the following schemes. An appropriately substituted 2-bromo-6-
hydroxybenzaldelvyde or bromosalicylaldehyde (2) is reacted with diethyl bromomalonate in
the presence of a suitable base such as potassium tert-butoxide in a solvent such
tetrahydrofuran and ethanol (Scheme 1) to provide 2-carboalkoxybenzofuran (3).
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Additionally, the 2-carboalkoxybenzofuran (3) may be prepared via cyclization of the
appropriately substituted bromosalicylaldehyde with ethyl bromacetate in the presence of a
base such as potassium carbonate in a solvent such as N,N-dimethylformamide. The 2-
bromo-6-hydroxybenzaldehydes appropriate for the synthesis of compounds of formula I are
either known compounds or can be readily prepared by one skilled in the art. The resulting 2-
carboalkoxybenzofuran (3) is then hydrolyzed with aqueous sodium hydroxide or other
suitable alkoxide to provide a carboxylic acid that can then be reduced to the alcohol (4) by
treatment with an appropriate reducing agent such as borane in tetrahydrofuran in a solvent
such as tetrahydrofuran. Treatment of the alcohol (4) with phthalimide under standard
Mitsunobu conditions, such as triphenylphoshine and diisopropylazodicarboxylate in a
solvent such as toluene, provides the phthalimide (5). Introduction of the biaryl functionality
is achieved by a palladium-catalyzed cross-coupling reaction (i.e. Suzuki reaction) with the
desired boronic acid. Treatment of (5) with a catalyst such as dichlorobis(tri-o-
tolylphosphine)-palladium(II) in the presence of a suitable base such as potassium carbonate
in a solvent such as dioxane provides the biaryl product (5a). Subsequent removal of the
phthalimide system by treatment of (5a) with methylamine in a solvent such as ethanol
provides the compounds of formula I. Treatment of the phthalimide derivative 5a with
methylamine in ethanol allows the mild deprotection of the terminal amino group to give the
primary amine, namely a compound having formula I where each of R1 and R1 is hydrogen.
The primary amine may be converted into a secondary or tertiary amine conforming with
formula I in known manner, for instance, by alkylation or reductive alkylation.
Scheme 1

[0036] Alternatively, the biaryl system may be introduced directly onto the 2-
carboalkoxybenzofuran (3) via a palladium-catalyzed cross-coupling reaction (i.e. Suzuki
reaction). Treatment of the 2-carboalkoxy-7-methoxybenzofuran (3a) with boron tribromide
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(Scheme la) in a solvent such as dichloromethane provides the phenol (3b). Reaction of the
phenol (3b) with trifluoromethanesulfonic anhydride in the presence of a base such as
triethylamine in a solvent such as dichloromethane provides the triflate (3c). Introduction of
the biaryl functionality is achieved by a palladium-catalyzed cross-coupling reaction (i.e.
Suzuki reaction) with the desired boronic acid. Therefore, treatment of either (3) or (3a) with
a catalyst such as dichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of a suitable
base such as potassium carbonate in a solvent such as dioxane provides the biaryl product
(3d). The carboalkoxy functionality present in (3d) can be reduced with a suitable reducing
agent such as lithium borohydride in a solvent such as tetrahydrofuran to provide the alcohol
(4a) directly. Reaction of the alcohol (4a) with phthalimide under standard Mitsunobu
conditions, such as triphenylphoshine and diisopropylazodicarboxylate in a solvent such as
toluene, provides the phthalimide (5a).

[0037] For certain compounds of formula I, it is useful to introduce the biaryl system at
the beginning of the synthesis via a palladium-cataiyzed cross-coupling reaction (i.e. Suzuki
reaction) of an appropriately substituted 2-methoxybromobenzene (6) with the desired
boronic acid (Scheme 2). Treatment of (6) with a catalyst such as
tetrakis(triphenylphosphine)palladium(0) in the presence of a suitable base such as potassium
carbonate in a solvent such as ethylene glycol dimethyl ether provides the biaryl
methoxybenzene (6a). Removal of the methoxy group in (6a) is accomplished with hydrogen
bromide (30 wt % in acetic acid ) to provide phenol (6b). The phenol (6b) is alkylated with an
appropriately substituted allyl bromide or alcohol in the presence of a suitable base such as
potassium carbonate in a solvent such as N,N-dimethylformamide to afford the allyl ether (7).
The resulting allyl ether (7) is treated in refluxing mesitylene or other suitable high boiling
solvent to afford the desired Claisen rearrangement product (8). The double bond present in
(8) is isomerized by refluxing with bis(acetonitrile)dichloropalladium(II) in a solvent such as
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dichloromethane to provide the 2-propenyl phenol (9). Oxidation of the double bond present
in (9) by treatment with osmium tetroxide and sodium periodate in a solvent system such as
tetrahydrofuran and water provides the 2-hydroxybenzaldehyde (2c).

[0038] Alternatively, treatment of the methoxybenzene (6a) with bromine in acetic acid
in the presence of iron(0) provides the 2-bromomethoxybenzene (6c). Reaction of (6c) with
isopropylmagnesium chloride and 1-formylpiperidine in a solvent such as tetrahydrofuran
affords the 2-methoxybenzaldehyde (2d). Removal of the methyl group is accomplished by
reaction of the 2-methoxybenzaldehyde (2d) with boron tribromide in a solvent such as
dichloromethane to give the 2-hydroxybenzaldehyde (2c).

[0039] Alternatively, treatment of the biaryl phenol (6b) with 1,1 -dichlorodimethyl ether
in the presence of titanium tetrachloride in a solvent such as dichloromethane provides the 2-
hydroxybenzaldehyde (2c) directly.

[0040] Although certain exemplary embodiments are depicted and described above and
herein, it will be appreciated that compounds of the invention can be prepared according to
the methods described generally above using appropriate starting materials by methods
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generally available to one of ordinary skill in the art. Additional embodiments are
exemplified in more detail herein.
4. Uses, Formulation and Administration
[0041] Compounds of the present invention have affinity for and agonist or partial
agonist activity at the 2C subtype of brain serotonin receptors and are thus of interest for the
treatment of a variety of disorders and/or the alleviation of one or more associated symptoms.
Such disorders associated with modulations of the 2C subtype of brain serotonin receptors are
described in detail below. The present invention contemplates that compounds of the present
invention are associated with a rapid onset of action. In addition, compounds of the present
invention lack the side-effect of sexual dysfunction.
[0042] Compounds of the present invention are useful for treating one or more psychotic
disorders, as described herein, without causing diabetogenesis. Diabetogenesis is a side-
effect associated with atypical antipsychotic agents. Without wishing to be bound by any
particular theory, it is believed that the diabetogenesis associated with atypical antipsychotic
agents results from the fact that those agents are 5-HT2C antagonists. As described herein, the
present compounds are 5-HT2C agonists, or partial agonists, and therefore are not associated
with diabetogenesis.
[0043] Compounds of the present invention are useful for treating one or more psychotic
disorders such as schizophrenia including paranoid type, disorganized type, catatonic type,
and undifferentiated type, schizophreniform disorder, schizoaffective disorder, delusional
disorder, substance-induced psychotic disorder, and psychotic disorder not otherwise
specified; L-DOPA-induced psychosis; psychosis associated with Alzheimer's dementia;
psychosis associated with Parkinson's disease; and psychosis associated with Lewy body
disease.
[0044] Compounds of the present invention are also useful for treating symptoms related
to psychotic disorders of the schizophrenic types, including the so called "positive" and
"negative" symptoms of schizophrenia. These symptoms include for example
hallucinations, delusions, paranoia, anxiety, agitation, excessive aggression, tension, thought
disorder, blunted affect, and social or emotional withdrawal in psychotic patients. Other
symptoms often associated with psychotic disorders include cognition disorders or deficits
such as poor attention and impaired function, depression, suicide, metabolic syndrome, and
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substance abuse. Thus, another embodiment of the present invention provides a method for
treating one or more symptoms associated with a psychotic disorder.
[0045] In other embodiments, the present compounds are useful for treating anxiety
disorders such as panic attack, agoraphobia, panic disorder, specific phobia, social phobia,
social anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, acute
stress disorder, generalized anxiety disorder, separation anxiety disorder, substance-induced
anxiety disorder, and anxiety disorder not otherwise specified.
[0046] According to another embodiment, the present compounds are useful for treating
bipolar disorders. Such bipolar disorders include bipolar I disorder, bipolar II disorder, and
cyclothymic disorder; bipolar mania, dementia, and depression with psychotic features. The
present compounds are also useful for treating (including the preventing) of cycling that may
occur between bipolar depression and bipolar mania.
[0047] A more complete description of the aforementioned mental disorders can be found
in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Washington, DC,
American Psychiatric Association (1994), incorporated herein by reference in its entirety.
[0048] In certain embodiments, compounds of the present invention are administered in
combination with one or more anti-psychotic agents. Such anti-psychotic agents are well
known in the art and include clozapine (e.g., Clozaril®), risperidone (e.g., Risperidal®),
olanzapine (e.g., Zyprexa®), quetiapine (e.g., Seroquel®), ziprasidone (e.g., Geodon®),
aripiprazole, amisulpiride, chlorpromazine, fluphenazine, haloperidol (e.g., Haldol®),
loxapine, mesoridazine, molindone, perphenazine, pimozide, seroquel, sulpiride, thioridazine,
thiothixene, trifluoperazine, and bifeprunox to name a few.
[0049] The combination of a compound of the present invention with one or more anti-
psychotic agents is useful for treating schizophrenia including paranoid type, disorganized
type, catatonic type, and undifferentiated type, schizophreniform disorder, schizoaffective
disorder, delusional disorder, substance-induced psychotic disorder, and psychotic disorder
not otherwise specified; L-DOPA-induced psychosis; psychosis associated with Alzheimer's
dementia; psychosis associated with Parkinson's disease; psychosis associated with Lewy
body disease; bipolar disorders such as bipolar I disorder, bipolar II disorder, and
cyclothymic disorder; bipolar mania, dementia, and depression with psychotic features. In
some embodiments, these combinations are useful in the treatment of bipolar disorder,
including for example treating the cycling between bipolar depression and bipolar mania.
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[0050] In other embodiments, administration of a compound of the present invention with
an anti-psychotic agent provide anti-psychotic benefits while eliminating or minimizing
certain side affects (e.g., akathisia, dystonia, Parkinsonism dyskinesia and late dyskinesia and
the like) typically observed when the anti-psychotic agent(s) is/are taken alone.
[0051] In other embodiments, compounds of the present invention are useful for treating
one or more depressive disorders such as major depressive disorder, seasonal affective
disorder, dysthymic disorder, substance-induced mood disorder, depressive disorder not
otherwise specified, and treatment resistant depression.
[0052] Another aspect of the present invention provides a method for treating one or
more mood episodes such as major depressive episode, manic episode, mixed episode, and
hypomanic episode; and adjustment disorders such as adjustment disorders with anxiety
and/or depressed mood.
[0053] Compounds of the present invention are also useful for treating symptoms related
to depressive disorders including somatic symptoms such as neuropathic pain and sexual
dysfunction. Other somatic symptoms include hopelessness, helplessness, anxiety and
worries, memory complaints with or without objective signs of cognitive impairment, loss of
feeling of pleasure (anhedonia), slowed movement, irritability, and lack of interest in
personal care, such as poor adherence to medical or dietary regimens.
[0054] In certain embodiments, the present invention provides a method of treating
sexual dysfunction related to depression. In other embodiments, the present invention
provides a method of treating sexual dysfunction associated with administering a serotonin
reuptake inhibitor (SRI) for treating a depressive or other disorder, Such methods of treating
sexual dysfunction are described in detail below.
[0055] In certain embodiments, compounds of the present invention are administered in
combination with one or more antidepressive agents. Suitable antidepressant agents include,
for example, serotonin reuptake inhibitors (SRIs), norepinephrine reuptake inhibitors (NRIs),
combined serotonin- norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase
inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs),
phosphodiesterase-4 (PDE4) inhibitors, corticotropin releasing factor (CRF) antagonists,
alpha.-adrenoreceptor antagonists or other compounds including atypical antidepressants.
Additional antidepressants for administering in combination with compounds of the present
invention include triple uptake inhibitors such as DOV 216303 and DOV 21947...; melatonin
agonists such as agomelotine, super neurotransmitter uptake blockers (SNUBs; e.g., NS-2389
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from GlaxoSmithKline and Neurosearch; (R)-DDMA from Sepracor), and/or substance
P/neurokinin receptor antagonists (e.g., aprepitant/MK-869 from Merck; NKP-608 from
Novartis; CPI-122721 from Pfizer; R673 from Roche; TAK637 from Takeda; and GW-97599
from GlaxoSmithKline).
[0056] Another class of antidepressant agents for administering in combination with
compounds of the present invention are noradrenergic and specific serotonergic
antidepressants (NaSSAs). A suitable example of a NaSSA is mirtazepine.
[0057] Suitable NRIs for administering in combination with compounds of the present
invention include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples
of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine (See
United States Patent 2,554,736, incorporated herein by reference in its entirety) and
trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary
amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and
protriptyline, and pharmaceutically acceptable salts thereof.
[0058] Another NRI for administering in combination with compounds of the present
invention is reboxetine (Edronax™; 2-[.alpha.-(2-ethoxy)phenoxy-benzyl]morpholine,
usually administered as the racemate; See United States Patent. 4,229,449, incorporated
herein by reference in its entirety).
[0059] Suitable SSRIs for administering in combination with compounds of the present
invention include: citalopram (1-[3-(dimethylamino)propyl]-(4-fluorophenyl)-1,3-dihydr-o-5-
isobenzofurancarbonitrile; See United States Patent 4,136,193; Christensen et al., Eur. J.
Pharmacol. 41:153, 1977; Dufour et al., Int. Clin. Psychopharmacol. 2:225; 1987:
Timmerman et al., ibid., 239, each of which is incorporated herein by reference in its
entirety); fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine
marketed in the hydrochloride salt form and as the racemic mixture of its two isoforms; see,
for example, United States Patent 4,314,081; Robertson et al., J. Med. Chem. 31:1412, 1988,
each of which is incorporated herein by reference); fluoxetine/olanzapine in combination;;
fluvoxamine (5-methoxy-l-[4-(trifluoromethyl)phenyl]-l-pentanone O-(2-aminoethyl)oxime;
See United States Patent 4,085,225; Claassen et al., Brit. J. Pharmacol. 60:505, 1977; De
Wilde et al., J. Affective Disord. 4:249, 1982; Benfield et al., Drugs 32:313, 1986, each of
which is incorporated herein by reference in its entirety); paroxetine (trans-(-)-3-[(1,3-
benzodioxol-5-yloxy)methyl]-4-(4-fluo- rophenyl)piperidine; See United States Patent
3,912,743; United States Patent 4,007,196; Lassen, Eur. J. Pharmacol. 47:351, 1978; Hassan
17

WO 2006/116151 PCT/US2006/015193
et al, Brit. J. Clin. Pharmacol. 19:705, 1985; Laursen et al., Acta Psychiat. Scand. 71:249,
1985; Battegay et al., Neuropsychobiology 13:31, 1985, each of which is incorporated herein
by reference in its entirety); sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-
methyl-1-naphthylamine hydrochloride; See United States Patent 4,536,518, incorporated
herein by reference in its entirety); escitalopram (see United States Patent RE34,712); and
pharmaceutically acceptable salts thereof.
[0060] Suitable MAOIs for administering in combination with compounds of the present
invention include: isocarboxazid, phenelzine, selegiline and tranylcypromine, and
pharmaceutically acceptable salts thereof.
[0061] Suitable reversible MAOIs for administering in combination with compounds of
the present invention include: moclobemide (4-chloro-N-[2-(4-morpholinyl)-
ethyl]benzamide; See United States Patent 4,210,754, incorporated herein by reference in its
entirety), selegiline, and pharmaceutically acceptable salts thereof.
[0062] Suitable SNRIs for administering in combination with compounds of the present
invention include venlafaxine (see United States Patent 4,535,186, incorporated herein by
reference in its entirety; see also United States Patents 5,916,923, 6,274,171, 6,403,120,
6,419,958, 6,444,708, each of which is incorporated herein by reference in its entirety), and
pharmaceutically acceptable salts and analogs, including the O-desmethylvenlafaxine
succinate salt; milnacipran (N,N-diethyl-2-aminomethyl-l-phenylcyclopropanecarboxamide;
see United States Patent 4,478,836; Moret et al., Neuropharmacology 24:1211-19, 1985, each
of which is incorporated herein by reference in its entirety); nefazodone (available from
Bristol Myers Squibb and Dr, Reddy Labs Inc.); duloxetine; and pharmaceutically acceptable
salts thereof.
[0063] Suitable CRF antagonists for administering in combination with compounds of the
present invention include those compounds described in International Patent Specification
Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
[0064] Suitable atypical antidepressants for administering in combination with
compounds of the present invention include: bupropion (Wellbutrin™; (.+-.)-1-(3-
chlorophenyl)-2-[(1,1-dim- ethylethyl)amino]-1-propanone), lithium, nefazodone, trazodone
and viloxazine, and pharmaceutically acceptable salts thereof. Another suitable atypical
antidepressant is sibutramine.
[0065] Particular antidepressants for administering in combination with compounds of
the present invention include, but are not limited to, adinazolam, alaproclate, alnespirone,
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WO 2006/116151 PCT/US2006/015193
amineptine, amitriptyline, amitriptyline/chlordiazepoxide combination, amoxapine,
aprepitant, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline,
bipenamol, brofaromine, buproprion, caroxazone, cericlamine, cianopramine, cimoxatone,
citalopram, clemeprol, clomipramine, clovoxamine, dazepinil, deanol, demexiptiline,
desipramine, O-desmethylvenlafaxine, dibenzepin, dothiepin, doxepin, droxidopa,
duloxetine, elzasonan, enefexine, eptapirone, escitalopram, estazolam, etoperidone,
femoxetine, fengabine, fezolamine, fluotracen, fluoxetine, fluvoxamine, gepirone, idazoxan,
imipraraine, indalpine, indeloxazine, iprindole, isocarboxazid, levoprotiline, litoxetine,
lofepramine, maprotiline, medifoxamine, metapramine, metralindole, mianserin, milnacipran,
minaprine, mirtazapine, moclobemide, montirelin, nebracetam, nefopam, nefozodine,
nemititide, nialamide, nomifensine, norfluoxetine, nortriptyline, orotirelin, oxaflozane,
paroxetine, pheneizine, pinazepam, pirlindone, pizotyline, protryptiline, reboxetine,
ritanserin, robalzotan, rolipram, selegiline, sercloremine, sertraline, setiptiline, sibutramine,
sulbutiamine, sulpiride, sunepitron, teniloxazine, thozalinone, thymoliberin, tianeptine,
tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, tranylcypromine, trazodone,
trimiprimine, venlafaxine, veralipride, vilazodone, viloxazine, viqualine, zimelidine and
zometrapine, and pharmaceutically acceptable salts thereof, and St. John's wort herb, or
Hypencuin perforatum, or extracts thereof.
[0066] Suitable classes of anti-anxiety agents for administering in combination with
compounds of the present invention include 5-HTIA agonists or antagonists, especially 5-
HTIA partial agonists, neurokinin recepter (NK) antagonists (e.g., saredutant and osanetant)
and corticotropin releasing factor (CRF) antagonists. Suitable 5-HTIA receptor agonists or
antagonists that may be used in the present invention include, in particular, the 5-HTIA
receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and
pharmaceutically acceptable salts thereof. An example of a compound with 5-HTIA receptor
antagonist/partial agonist activity is pindolol. new 5HTIA agonists variza, alnespirone,
gepirone, sunepitron, MKC242, vilazodone, eptapirone, and ORG12962 from Organon; new
5HTIA antagonists such as robalzotan; new 5-HTIB agonists such as elzasonan; new 5HT2
antagonists such as YM-992 (from Yamanouchi Pharmaceuticals) and nemifitide.
[0067] According to the present invention, the inventive combinations may be
administered in conjunction with one or more other agents that is useful in treating depression
or other mood disorders. Alternatively or additionally, inventive combinations may be
administered with one or more other pharmaceutical agents active in treating any other
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WO 2006/116151 PCT/US2006/015193
symptom or medical condition present in the mammal that is related or unrelated to the
depression or mood disorder being experienced by the mammal. Examples of such
pharmaceutical agents include, for example, anti-angiogenic agents, anti-neoplastic agents,
anti-diabetic agents, anti-infective agents, pain-relieving agents, anti-psychotic agents,
gastrointestinal agents, etc., or combinations thereof. Other pharmaceutical agents useful in
the practice of the present invention include, for example, adjunctive therapies typically used
to enhance the effects of an antidepressant. Such adjunctive agents may include, for instance,
mood stabilizers (e.g., lithium, valproic acid, carbamazepine, etc.); pindolol, stimulants (e.g.,
methylphenidate, dextroamphetamine, etc.); or thyroid augmenting agents (e.g., T3); anti-
psychotics, anti-anxiety agents (e.g., benzodiazepines), and/or agents that relieve sexual
dysfunction (e.g., buspirone, which also has anti-anxiety effects; dopaminergic agents such as
amantadine, pramipexole, bupropion, etc.).
[0068] As 5-HT2C modulators, compounds of the present invention are useful for treating
a variety of disorders. Such disorders include premenstrual syndrome (PMS), premenstrual
dysphoric disorder (PMDD), motion or motor disorders such as Parkinson's disease; chronic
fatigue syndrome, anorexia nervosa, disorders of sleep (e.g., sleep apnea), and mutism.
[0069] Premenstrual dysphoric disorder, or PMDD, is a severe form of PMS. Like PMS,
PMDD typically occurs the week before the onset of menstruation and disappears a few days
after. PMDD is characterized by severe monthly mood swings and physical symptoms that
interfere with everyday life, especially a woman's relationships with her family and friends.
PMDD symptoms go far beyond what are considered manageable or normal premenstrual
symptoms.
[0070] PMDD is a combination of symptoms that may include irritability, depressed
mood, anxiety, sleep disturbance, difficulty concentrating, angry outbursts, breast tenderness
and bloating. The diagnostic criteria emphasize symptoms of depressed mood, anxiety, mood
swings or irritability. The condition affects up to one in 20 American women who have
regular menstrual periods. According to another embodiment, the present invention provides
a method for treating one or more symptoms associated with PMDD.
[0071] Selective serotonin reuptake inhibitors (SSRIs) are the current preferred method
for treating symptoms associated with PMDD. According to another aspect, the present
invention provides a method for treating PMDD, or one or more symptoms associated with
PMDD, by administering a compound of formula I in combination with an SSRI. In certain
embodiments, the SSRI is fluoxetine, venlafaxine, paroxetine, duloxetine, or sertraline.
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[0072] According to another embodiment, compounds of the present invention are useful
for treating a variety of eating disorders. In certain embodiments, the eating disorder is
hyperphagia, bulimia or anorexia nervosa. In certain embodiments, compounds of the
present invention are useful for treating gastrointestinal disorders, such as malfunction of
gastrointestinal motility or intestinal propulsion. Compounds of the present invention are
also useful in connection with weight loss or control (e.g., reduction in calorie or food
intake, and/or appetite suppression). Such methods are particularly useful for treating
obesity with its consequent comorbidities including diabetes insipidus, Type II diabetes,
cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall
bladder disease, gout, some cancers, some infertility, and early mortality.
[0073] In certain embodiments, compounds of the present invention are administered in
combination with one or more anti-obesity agents. Such anti-obesity agents are known in the
art and include apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-
B/MTP) inhibitors, 11β -hydroxy steroid dehydrogenase-1 (11β-HSD type 1) inhibitors,
PYY3.36 and analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists,
monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, R3
adrenergic receptor agonists, dopamine agonists (such as bromocriptine), melanocyte-
stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists (e.g., rimonabant),
melanin concentrating hormone antagonists, leptins (the OB protein), leptin analogs, leptin
receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e.
orlistat), anorectic agents (such as a bombesin agonist), Neuropeptide-Y receptor antagonists,
thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid receptor
agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists,
glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (such as AxokineTA ),
human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor
antagonists or inverse agonists, and neuromedin U receptor agonists.
[0074] In other embodiments, a compound of the present invention is administered in
combination with an anti-obesity agent selected from orlistat, sibutramine, bromocriptine,
ephedrine, leptin, rimonabant, pseudoephedrine, PYY3.36 or an analog thereof, and 2-oxo-
N-(5-phenyipyrazinyl)spiro-[isobenzofuran-1(3H),4 -piperidine]-1-carboxamide. According
to another aspect of the invention, a compound of the present invention is administered in
combination with an anti-obesity agent in conjunction with typical treatments for obesity
such as exercise and a sensible diet.
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[0075] According to another embodiment, a compound of the present invention is
administered in combination with one or more agents for treating diabetes and associated
conditions. In certain embodiments, a compound of the present invention is administered in
combination with one or more such agents including insulin and insulin analogs (e.g., LysPro
Insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH2; sulfonylureas and analogs
thereof: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide,
Glypizide®, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin,
buformin; "2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan,
efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166; glitazones:
ciglitazone, Actos® (pioglitazone), englitazone, troglitazone, darglitazone, Avandia
(BRL49653); fatty acid oxidation inhibitors: clomoxir, etomoxir; glucosidase inhibitors:
acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; 13-
agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243; or
phosphodiesterase inhibitors: L-386,398.
[0076] In other embodiments, a compound of the present invention is administered in
combination with one or more lipid-lowering agents: benfluorex: vanadate and vanadium
complexes (e.g., Nagiivan®) and peroxovanadium complexes; amylin antagonists; glucagon
antagonists; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents: nicotinic
acid, acipimox, WAG 994, pramlintide (Symlin" ), AC 2993, nateglinide, aldose reductase
inhibitors (e.g., zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenase
inhibitors, sodium-hydrogen exchanger type 1 (NNE-1) inhibitors and/or cholesterol
biosynthesis inhibitors or cholesterol absorption inhibitors, especially a HMG-CoA reductase
inhibitor, or a HMG-CoA synthase inhibitor, or a HMG-CoA reductase or synthase gene
expression inhibitor, a CETP inhibitor, a bile acid sequesterant, a fibrate, an ACAT inhibitor,
a squalene synthetase inhibitor, or an anti-oxidant. In other embodiments, a compound of the
present invention is administered in combination with one or more naturally occurring
compounds that acts to lower plasma cholesterol levels. Such naturally occurring compounds
are commonly referred to as nutraceuticals and include, for example, garlic extract, Hoodia
plant extracts, and niacin.
[0077] In certain embodiments, compounds of the present invention are useful for
inducing, assisting or maintaining desirable bladder control in a mammal. The methods are
particularly useful for treating a mammal that is experiencing or susceptible to bladder
instability or urinary incontinence. Inventive methods include prevention, treatment or
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WO 2006/116151 PCT/US2006/015193
inhibition of bladder-related urinary conditions and bladder instability, including idiopathic
bladder instability, nocturnal enuresis, nocturia, voiding dysfunction and urinary incontinence
(including, for example, stress incontinence, urge incontinence, and/or mixed incontinence).
Also treatable or preventable by administration of a compound of this invention is bladder
instability secondary to prostate hypertrophy, as is a method for enhancing urethral tone and
reducing undesirable urine leakage even in an otherwise healthy person. For example, the
inventive methods are applicable to alleviating urine leakage often occurring in women
during the first year after childbirth.
[0078] In other embodiments, the present compounds are useful for treating urine
retention or detrusor sphinctor dyssynergia. Patients suffering from urine retention include
those suffering from spinal cord injuries or male patients with benign prostatic hyperplasia.
[0079] According to the present invention, a compounds of the present invention is also
useful in promoting the temporary delay of urination whenever desirable. Such compounds
may be utilized in accordance with the present invention to stabilize the bladder in any
applicable context. Inventive methods therefore may be utilized to allow a recipient to
control the urgency and frequency of urination.
[0080] In some embodiments of the invention, compounds of the present invention are
administered to a mammal in need thereof for the treatment, prevention, inhibition and/or
amelioration of urge urinary incontinence (also known as bladder instability, neurogenic
bladder, voiding dysfunction, hyperactive bladder, detrusor overactivity, detrusor hyper-
reflexia or uninhibited bladder) or mixed urinary incontinence. Inventive uses include, but
are not limited to, those for bladder activities and instabilities in which the urinary urgency is
associated with prostatitis, prostatic hypertrophy, interstitial cystitis, urinary tract infections
or vaginitis. The methods of this invention may also be used to assist in inhibition or
correction of the conditions of Frequency-Urgency Syndrome, and lazy bladder, also known
as infrequent voiding syndrome.
[0081] Compounds of the present invention may also be used to treat, prevent, inhibit, or
limit the urinary incontinence, urinary instability or urinary urgency associated with or
resulting from administrations of other medications, including diuretics, vasopressin
antagonists, anticholinergic agents, sedatives or hypnotic agents, narcotics, alpha-adrenergic
agonists, alpha-adrenergic antagonists, or calcium channel blockers.
[0082] Compounds of the present invention are useful for inducing or assisting in urinary
bladder control or preventing or treating the maladies described herein in humans in need of
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such relief, including adult and pediatric uses. They may also be utilized for veterinary
applications, particularly including canine and feline bladder control methods. If desired, the
methods herein may also be used with farm animals, such as ovine, bovine, porcine and
equine breeds.
[0083] According to the present invention, compounds of the present invention may be
administered alone to modulate bladder activity, or alternatively may be administered in
combination with (whether simultaneously or sequentially) one or more other pharmaceutical
agents useful in the modulation of bladder activity. Alternatively or additionally, the
compounds of the present invention may be administered in combination with one or more
other pharmaceutical agents useful in the treatment or prevention of one or more other
symptoms, disorders, or diseases suffered by the individual in need of bladder activity
modulation.
[0084] Other pharmaceutical agents useful in the modulation of bladder activity, and
particularly for treatment, prevention, inhibition, and/or amelioration of urinary incontinence,
include, for example, desmopressin acetate (available as DDAVP® Nasal Spray and
DDAVP® tablets from Aventis Pharmaceuticals), as well as a desmopressin acetate rhinal
tube (available from Ferring Pharmaceuticals Inc.). Other products include, for example,
tolterodine tartrate (available as Detroltm tablets from Pharmacia & Upjohn), oxybutinin
chloride (available in the form of Ditropan® tablets and syrup and Ditropan XL® extended
release tablets from ALZA Pharmaceuticals), propanthaline bromide (available in tablet form
from Roxane Laboratories, Inc.), hyoscyamine and hyoscyamine sulfate (available,
respectively, as Cystopaz® tablets and Cystopaz-M® timed release capsules from
PolyMedica Pharmaceuticals (U.S.A.), Inc.), hyoscyamine hydrobromide, flavoxate HCl
(available in Urispas® 100 mg tablets from ALZA Pharmaceuticals), imipramine HCl
(available in 10 mg, 25 mg and 50 mg tablets from Geneva Pharmaceuticals, Inc.),
phenylpropanolamine, midodrine HCl (available in 2.5 mg and 5 mg Proamatine® tablets
from Shire US Inc.), phenoxybenzamine HCl (available as Dibenzyline® capsules from
WellSpring Pharmaceuticals Corporation), and prazosin HCl (available in Minipress®
capsules from Pfizer Inc.). Each of these medicaments may be administered in the
pharmaceutically effective amounts and regimens known in the art, including those listed in
the Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics
Company, Inc. at Monvale, NJ 07645-1742, the relevant portions of which are incorporated
herein by reference.
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[0085] Yet other pharmaceutical agents that can act to modulate bladder activity include,
for example, other regulators of the 5HT2C receptor. For example, United States Patent
Application 2004/0235856 (previously incorporated herein by reference in its entirety)
describes a variety of 5HT2C receptor modulators that are useful in accordance with the
practice of the present invention. Additional 5HT2C agonists are exemplified in Bishop et al,
Expert Opin. Ther. Patent 13:1691-1705, 2003, the entire contents of which are incorporated
herein by reference.
[0086] Still other pharmaceutical agents that can act to modulate bladder activity include,
for example, modulators of one or more KCNQ potassium channels. In some embodiments
of the present invention, compounds of the present invention are administered in conjunction
with one or more agonists of KCNQ 2/3 or KCNQ3/5. Such KCNQ modulators include, for
example, compounds described in United States Patent Number 5,384,330 and those
described in United States Patent Number 5,565,483, as well as those described in United
States Patent Application Number 2002/0183395; and United States Patent Application
Number 2004/0029949. The entire contents of each of these patents and patent applications
is incorporated herein by reference. In some embodiments of the present invention,
compounds of the present invention are administered with retigabine.
[0087] In some embodiments of the present invention, compounds of the present
invention are administered in conjunction with one or more compounds which act as
vasopressin agonists including, but not limited to those described in U.S. Patent No.
6,194,407 (Failli et al.), U.S. Patent No. 6,090,803 (Failli et al.), U.S. Patent No. 6,096,736
(Ogawa et al.), and U.S. Patent No. 6,096,735 (Ogawa et al.).
[0088] In general, it will often be desirable in accordance with the present invention to
administer one or more compounds of the present invention in conjunction with one or more
alpha-adrenergic receptor agonists and/or one or more other sympathomimetic drugs.
[0089] According to the present invention, compounds of formula I may be used to treat,
prevent, or alleviate dependence, withdrawal, or symptoms thereof for any of a variety of
substances including, for example, recreational substances (e.g., alcohol, tobacco [for
example, nicotine]), pharmacologic agents (e.g., pain relievers [for example, Vicodin®,
Lortab®, Lorcet®, Percocet®, Percodan®, Tylox®, Hydrocodone, OxyContin®, methadone,
Tramadol, etc], tranquilizers, stimulants, or sedatives), and illicit drugs (e.g., marijuana,
heroine, cocaine, ecstasy, LSD, PCP, methamphetamine, etc.).
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[0090] The term "substance abuse", as used herein, may be defined with reference to
criteria set form in the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (1994)
("DSM-IV"), which was prepared by the Task Force on Nomenclature and Statistics of the
American Psychiatric Association. A feature of substance abuse is a maladaptive pattern of
substance use manifested by recurrent and significant adverse consequences related to the
repeated use of substances. As recited in the DSM-IV, substance abuse is defined as
maladaptive pattern of substance abuse leading to clinicalyl significant impairment or
distress, as manifested by one(or more) of the following, occurring within a 12-month period:
(1) recurrent substance use resulting in a failure to fulfill major role obligations at work,
school, or home; (2) recurrent substance use in situations in which it is physically hazardous;
(3) recurrent substance-related legal problems; and (4) continued substance use despite
having persistent or recurrent social or interpersonal problems cause or exacerbated by the
effects of the substance. In addition, the DMS-IV requires that the symptoms of substance
abuse do not meet the criteria for substance dependence.
[0091] The term "substance dependence", as used herein, may be defined with reference
to criteria set form in the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed.
(1994) ("DSM-IV"), which was prepared by the Task Force on Nomenclature and Statistics
of the American Psychiatric Association. The criteria for substance dependence set forth in
DSM-IV is a pattern of substance use, leading to clinically significant impairment or distress
as manifested by at least three selected from the following group, occurring at any time
within the same twelve month period: (1) tolerance as defined by either (a) a need for
substantially increased amounts of the substance to achieve the desired effect; or (b)
substantially diminished effect with continued use of the same amount of the substance; (2)
withdrawal, as demonstrated by either (a) the characteristic withdrawal syndrome for the
specific substance; or (b) the same, or a closely related substance is taken to relieve or avoid
withdrawal symptoms; (3) the substance is often taken in larger amounts or over a longer
period then was intended; (4) there is a persistent desire or unsuccessful efforts to cut down
or control substance use; (5) a great deal of time is spent in activities to obtain the substance,
use the substance, or recover from its effects; (6) important social, occupational or
recreational activities are given up or reduced because of substance use; and (7) the substance
use is continued despite knowledge of having a persistent or recurrent physical or
psychological problem that is likely to have been caused or exacerbated by the substance.
Substance dependence can be with physiological dependence; that is evidence of tolerance or
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withdrawal is present, or without physiological dependence, where no evidence of tolerance
or withdrawal is present. Four of the conditions set forth in DSM-IV include remission.
These types of remission are based on the interval of time that has elapsed since the cessation
of dependencies and whether there is continued presence of one or more of the symptoms
included in the criteria for dependencies.
[0092] In certain embodiments, compounds of the present invention are useful for
treating alcoholism (e.g., alcohol abuse, addiction and/or dependence including treatment for
abstinence, craving reduction and relapse prevention of alcohol intake) and/or tobacco abuse
(e.g., smoking addiction, cessation and/or dependence including treatment for craving
reduction and relapse prevention of tobacco smoking).
[0093] In evaluating substance abuse in accordance with the present invention, reference
may be made, for example, to the National Survey on Drug Use and Health (NSDUH), which
obtains information on nine different categories of illicit drug use: marijuana, cocaine, heroin,
hallucinogens, inhalants, and nonmedical use of prescription-type pain relievers,
tranquilizers, stimulants, and sedatives. In these categories, hashish is included with
marijuana, and crack is considered a form of cocaine. Several drugs are grouped under the
hallucinogens category, including LSD, PCP, peyote, mescaline, mushrooms, and "Ecstasy"
(MDMA). Inhalants include a variety of substances, such as amyl nitrite, cleaning fluids,
gasoline, paint, and glue. The four categories of prescription-type drugs (pain relievers,
tranquilizers, stimulants, and sedatives) cover numerous drugs available through prescriptions
and sometimes illegally "on the street." Methamphetamine is considered a type of stimulant.
Respondents are asked to report only uses of drugs that were not prescribed for them or drugs
they took only for the experience or feeling they caused. Over-the-counter drugs and
legitimate uses of prescription drugs are not included. NSDUH reports combine the four
prescription-type drug groups into a category referred to as "any psychotherapeutics."
[0094] The NSDUH categorizes alcohol abuse through use of questions about the
frequency of the consumption of alcoholic beverages, such as beer, wine, whiskey, brandy,
and mixed drinks. An extensive list of examples of the kinds of beverages covered is given to
respondents prior to the question administration. A "drink" is defined as a can or bottle of
beer, a glass of wine or a wine cooler, a shot of liquor, or a mixed drink with liquor in it.
Times when the respondent only had a sip or two from a drink are not considered as
consumption. For this report, estimates for the prevalence of alcohol use are reported
primarily at three levels defined for both males and females and for all ages as follows:
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Current use - At least one drink in the past 30 days (includes binge and heavy use).
Binge use - Five or more drinks on the same occasion at least once in the past 30 days
(includes heavy use).
Heavy use - Five or more drinks on the same occasion on at least 5 different days in the past
30 days
[0095] The NSDUH also characterizes the use of tobacco products, including cigarettes,
chewing tobacco, snuff, cigars, and pipe tobacco. For analytic purposes, data for chewing
tobacco and snuff are combined as "smokeless tobacco." Cigarette use is defined as smoking
"part or all of a cigarette." Questions to determine nicotine dependence among current
cigarette smokers also are included in NSDUH. Nicotine dependence is based on criteria
from the Nicotine Dependence Syndrome Scale (NDSS) or the Fagerstrom Test of Nicotine
Dependence (FTND).
[0096] In other embodiments, compounds of the present invention are useful for treating
withdrawal from drug addiction including addiction to nicotine, alcohol, and other substances
of abuse. Individuals often suffer the symptoms of nicotine withdrawal as a consequence of
the discontinued use of tobacco in any form, including, but not limited to smoking of
cigarette, cigar, or pipe tobacco, or the oral or intranasal ingestion of tobacco or chewing
tobacco. Such oral or intranasal tobacco includes, but is not limited to snuff and chewing
tobacco. The cessation of nicotine use or reduction in the amount of nicotine use, is often
followed within 24 hours by symptoms including dysphoric, depressed mood; light-
headedness; insomnia; irritability, frustration or anger; anxiety; nervous tremor; difficulty
concentrating; restlessness; decreased heart rate; increased appetite or weight gain; and the
craving for tobacco or nicotine. These symptoms often cause clinically significant distress or
impairment in social, occupational, or other important areas of functioning.
[0097] The discontinued or reduction in administration of an opioid, typically self-
administration, through injection or orally, through smoking or intranasal ingestion, often
results in the presence of a characteristic opioid withdrawal condition. This withdrawal
condition can also be precipitated by administration of an opioid antagonist such as naloxone
or naltrexone after opioid use. Opioid withdrawal is characterized by symptoms that are
generally opposite to the opioid agonist effects. These withdrawal symptoms may include
anxiety; restlessness; muscle aches, often in the back and legs; craving for opioids; irritability
and increased sensitivity to pain; dysphoric mood; nausea or vomiting; lacrimation;
rhinorrhoea; papillary dilation; piloerection; sweating; diarrhea; yawning; fever; and
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insomnia. When dependence is on short-acting opioids, such as heroin, withdrawal symptoms
usually occur within 6-24 hours after the last dose, while with longer-acting opioids, such as
methadone, symptoms may take 2-4 days to emerge. These symptoms often cause clinically
significant distress or impairment in social, occupational or other important areas of
functioning. The present invention is most preferably used to alleviate one or more symptoms
attributed to opioid withdrawal when such symptoms are not due to a general medical
condition and are not better accounted for by another medical disorder.
[0098] The discontinued or reduction in use of ethanol (ethanol containing beverages)
results in the onset of ethanol withdrawal conditions. Ethanol withdrawal conditions are
characterized by symptoms that begin when blood concentrations of ethanol decline sharply,
within 4 to 12 hours after ethanol use has been stopped or reduced. These ethanol withdrawal
symptoms include craving for ethanol; autonomic hyperactivity (such as sweating or pulse
rate greater than 100); hand tremor; insomnia; nausea; vomiting; transient visual, tactile, or
auditory hallucinations or illusions; psychomotor agitation; anxiety; and grand mal seizures.
These symptoms often cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning. The present invention is most
preferably used to alleviate one or more symptoms attributed to ethanol withdrawal when
such symptoms are not due to a general medical condition and are not better accounted for by
another medical disorder.
[0099] According to another embodiment, a compound of the present invention is
administered in combination with one or more agents useful for treating substance abuse. In
certain embodiments, a compound of the present invention is administered in combination
with one or more agents to treat tobacco abuse. Such agents include nicotine receptor partial
agonists bupropion hypochloride (Zyban™) and nicotine replacement therapies.
[00100] According to yet another embodiment, a compound of the present invention is
administered in combination with one or more agents to treat alcoholism, such as opioid
antagonists (e.g., naltrexone, ReVia™), nalmefene, disulfiram (Antabuse™), and
acamprosate (Campral M).
[00101] In certain embodiments, a compound is administered in combination with one or
more agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-
blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin™). In other
embodiments of the invention, therapy utilizing compounds of the present invention is
administered concomitantly with, in connection with, and/or subsequent to an educational
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and/or behavioral modification program to enhance continued abstinence from substance
dependence or abuse. The method of the present invention may be particularly useful in
treating symptoms of withdrawal often observed in rehabilitation or other treatment
programs. Therefore, the programs can be more effective by focusing on educational and
behavioral modification goals, further reducing the incidence of program non-completion.
[00102] In certain embodiments, compounds of the present invention are useful for
treating one or more intellectual deficit disorders comprising administering a compound of
the present invention. In other embodiments, such intellectual deficit disorders include
dementia, such as dementia of aging, vascular dementia, mild cognitive impairment, age-
related cognitive decline, and mild neurocognitive disorder; Alzheimer's disease, and
memory deficit, attention deficit disorders (ADD, also known as Attention Deficit
Hyperactivity Disorder or ADHD) in both children and adults. In certain embodiments, the
present invention provides a method of treating ADD and/or ADHD in a pediatric patient
comprising administering to said patient a compound of formula I or pharmaceutical
composition thereof.
[00103] In other embodiments, the present invention provides a method of treating one or
more cognition disorders. According to another aspect, the cognition disorder is a learning
disorder. Such learning disorders are known in the art and include autism, dyslexia,
Asperger's syndrome, a neurobiological disorder similar to autism and characterized by
serious deficits in social and communication skills; specific learning disability, a disorder in
one or more of the basic psychological processes involved in understanding or in using
spoken or written language, which may manifest itself in an imperfect ability to listen, think,
speak, read, write, spell or to do mathematical calculations; dysgraphia, a disorder that causes
difficulty with forming letters or writing within a defined space; dyscalculia, a disorder that
causes people to have problems doing arithmetic and grasping mathematical concepts;
dyspraxia, a problem with the body's system of motion that interferes with a person's ability
to make a controlled or coordinated physical response in a given situation; visual perceptual
deficit, difficulty receiving and/or processing accurate information from the sense of sight,
although there is nothing wrong with vision; and auditory perceptual deficit, difficulty
receiving accurate information through auditory means, even though there is no problem with
hearing.
[00104] In certain embodiments, the present invention provides a method for treating one
or more impulsivity disorders (e.g. borderline personality disorder), disruptive behavior
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disorders, or impulse control disorders. In certain embodiments, the present invention
provides a method for treating Tourette's syndrome (TS), an inherited, neurological disorder
characterized by repeated and involuntary body movements (tics) and/or uncontrollable vocal
sounds.
[00105] According to another aspect, the present invention provides a method for treating
one or more behavioral addictions and addictive disorders. Behavioral addictions and
addictive disorders result from the intoxication one senses from the release of brain
chemicals (e.g., serotonin, adrenaline, epinepherine, etc.) during certain activities. Such
disorders are known in the art and include gambling, sex addiction, eating disorders,
spending addiction, rage/anger, workaholism, exercise addiction, risk taking addictions, and
perfectionism to name a few.
[00106] In certain embodiments, a compound of the present invention is administered in
combination with one or more cognitive improvement agents. Such agents are well known in
the art and include donepezil hydrochloride (Aircept™) and other acetylcholinesterase
inhibitors; galantamine, neuroprotective agents (e.g., memantine); ADD/ADHD agents (e.g.,
methylphenidate (RitalinTn""), atomoxetine (Strattera™), methylphenidate, sustained release
(Concerta™) and amphetamine/dextroamphetamine (Adderall™).
[00107] According to another aspect, the present invention provides a method for treating
sexual dysfunction comprising administering a compound of the present invention. In certain
embodiments, the sexual dysfunction is associated with a depressive disorder. In other
embodiments, the sexual dysfunction is associated with treatment of a disorder by
administration of a serotonin reuptake inhibitor. Compounds of the present invention are
useful for treating sexual dysfunction in the male and in the female. Such disorders include
male erectile dysfunction (MED) and female sexual dysfunction (FSD), e.g. female sexual
arousal disorder (FSAD).
[00108] In other embodiments, the present invention provides a method for treating one or
more disorders associated with sexual dysfunction including: HSDD, characterized by a
deficiency, or absence of, sexual fantasies and desire for sexual activity; FSAD, characterized
by a persistent or recurrent inability to attain, or to maintain until completion of the sexual
activity, an adequate lubrication-swelling response of sexual excitement; FOD characterized
by persistent or recurrent delay in, or absence of, orgasm following a normal sexual
excitement phase; Sexual Pain Disorders such as dyspareunia and vaginismus; and/or
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HSDD characterized by a woman who has no or little desire to be sexual, and has no or few
sexual thoughts or fantasies.
[00109] According to another embodiment, a compound of the present invention is
administered in combination with one or more agents for treating male sexual dysfunction
(e.g., male erectile dysfunction). Such agents are known in the art and include a
dopaminergic agent (e.g. D2, D3 or D4 agonists and apomorphine); an NPY (neuropeptide
Y) (preferably an NPY-1 and/or NPY-5 inhibitor); a melanocortin receptor agonist or
modulator or melanocortin enhancer; an NEP inhibitor; a PDE inhibitor (preferably, a
cGMP PDE-5 inhibitor); a bombesin receptor antagonist or modulator, and a soluble secreted
endopeptidase inhibitor (SEPi).. In certain embodiments, a compound of the present
invention is administered in combination with one or more agents for treating male sexual
dysfunction such as alprostadil or sildenafil.
[00110] According to yet another embodiment, a compound of the present invention is
administered in combination with one or more agents for treating female sexual dysfunction.
Such agents are known in the art and include estrogen receptor modulators (e.g., estrogen
agonists and/or estrogen antagonists); testosterone replacement agents, testostemone
(Tostrelle), dihydrotestosterone, dehydroepiandrosterone (DHEA), a testosterone implant;
eg dehydroandrostendione, estrogen, estrogen, medroxyprogesterone, medroxyprogesterone
acetate (MPA), a combination of estrogen and a methyl testosterone hormone replacement
therapy agent; Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo,
Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro, Prempak,
Premique, Estratest, Estratest HS, Tibolone, a dopaminergic agent; eg apomorphine or a
selective D2, D3 or D2/D3agonist such as, pramipexole and ropirinol, a NPY (neuropeptide
Y) inhibito; eg a NPY (neuropeptide Y) inhibitor such as a NPY1 or NPY5 inhibitor,
preferably NPY1 inhibitor, a melanocortin receptor modulator or a melanocortin enhancer;
eg melanotan II, PT-14, PT-141, a NEP (neutral endopeptidase) inhibitor; a PDE
(phosphodiesterase) inhibitor; eg sildenafil, and/or a bombesin receptor modulator.
[00111] According to the present invention, compounds of the present invention are useful
for treating any of a variety of different types of pain experienced by mammals, such as
humans. For example, the compounds of the present invention may be used to treat treating
acute pain (short duration) or chronic pain (regularly reoccurring or persistent), whether
centralized or peripheral.
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[00112] Examples of pain that can be acute or chronic and that can be treated in
accordance with the methods of the present invention include inflammatory pain,
musculoskeletal pain, bony pain, lumbosacral pain, neck or upper back pain, visceral pain,
somatic pain, neuropathic pain, cancer pain, pain caused by injury or surgery such as burn
pain, or headaches such as migraines or tension headaches, or combinations of these pains.
One skilled in the art will recognize that these pains may overlap one another. For example,
a pain caused by inflammation may also be visceral or musculoskeletal in nature.
[00113] In one embodiment of the present invention, one or more compounds of the
present invention is/are administered in mammals to treat chronic pain such as neuropathic
pain associated for example with damage to or pathological changes in the peripheral or
central nervous systems; cancer pain; visceral pain associated with for example the
abdominal, pelvic, and/or perineal regions or pancreatitis; musculoskeletal pain associated
with for example the lower or upper back, spine, fibromylagia, temporomandibular joint, or
myofascial pain syndrome; bony pain associated with for example bone or joint degenerating
disorders such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headaches such
migraine or tension headaches; or pain associated with infections such as HIV, sickle cell
anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoarthritis or
rheumatoid arthritis.
[00114] In some embodiments, the compounds of the present invention are used to treat
chronic pain that is neuropathic pain, visceral pain, musculoskeletal pain, bony pain,
headache, cancer pain or inflammatory pain or combinations thereof, in accordance with the
methods described herein. Inflammatory pain can be associated with a variety of medical
conditions such as osteoarthritis, rheumatoid arthritis, surgery, or injury. Neuropathic pain
may be associated with for example diabetic neuropathy, peripheral neuropathy, post-herpetic
neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia,
glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome,
nerve root avulsion, or nerve damage cause by injury resulting in peripheral and/or central
sensitization such as phantom limb pain, reflex sympathetic dystrophy or postthoracotomy
pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral or bacterial infections
such as shingles or HIV, or combinations thereof. Inventive treatment methods further
include treatments in which the neuropathic pain is a condition secondary to metastatic
infiltration, adiposis dolorosa, burns or central pain conditions related to thalamic conditions.
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[00115] Neuropathic pains described above may also be, in some circumstances, classified
as "painful small fiber neuropathies" such as idiopathic small-fiber painful sensory
neuropathy, or "painful large fiber neuropathies" such as demylinating neuropathy or axonal
neuropathy, or combinations thereof. Such neuropathies are described in more detail, for
example, in the J. Mendell et al., N. Engl. J, Med. 2003, 348:1243-1255, which is hereby
incorporated by reference in its entirety.
[00116] In another embodiment, the compounds useful in the present invention may be
administered to totally or partially inhibit a neuropathic pain condition from developing. For
example, compounds of the present invention may be administered to a mammal who is at
risk for developing a neuropathic pain condition such as a mammal who has contracted
shingles or a mammal who is being treated for cancer.
[00117] In one embodiment, the compounds useful in the present invention may be
administered prior to or during a surgical procedure to partially or totally inhibit development
of pain associated with the surgical procedure.
[00118] As mentioned previously, the methods of the present invention may be used to
treat pain that is somatic and/or visceral in nature. For example, somatic pain that can be
treated in accordance with the methods of the present invention includes pain associated with
structural or soft tissue injury experienced during surgery, dental procedures, burns, or
traumatic body injuries. Examples of visceral pain that can be treated in accordance with the
methods of the present invention include those types of pain associated with or resulting from
maladies of the internal organs such as ulcerative colitis, irritable bowel syndrome, irritable
bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis,
infections of the organs, or biliary tract disorders, or combinations thereof. One skilled in the
art will also recognize that the pain treated according to the methods of the present invention
may also be related to conditions of hyperalgesia, allodynia, or both. Additionally, chronic
pain to be treated in accordance with the present invention may be with or without peripheral
or central sensitization.
[00119] The present invention also provides use of the compounds of the present invention
to treat acute and/or chronic pains associated with female conditions, which may also be
referred to as female-specific pain. Such types of pain include those that are encountered
solely or predominately by females, including pain associated with menstruation, ovulation,
pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a
follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis,
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WO 2006/116151 PCT/US2006/015193
endometriosis, infection and inflammation, pelvic organ ischemia, obstruction, intra-
abdominal adhesions, anatomic distortion of the pelvic viscera, ovarian abscess, loss of pelvic
support, tumors, pelvic congestion or referred pain from non-gynecological causes.
[00120] In certain embodiments, a compound of the present invention is administered in
combination with a pain relieving agent. Examples of pain relieving agents that may be
administered with compounds of the present invention include, but are not limited to,
analgesics such as non-narcotic analgesics or narcotic analgesics; anti-inflammatory agents
such as non-steroidal anti-inflammatory agents (NSAIDs), steroids or anti-rheumatic agents;
migraine preparations such as beta adrenergic blocking agents, ergot derivatives, or
isometheptene; tricyclic antidepressants such as amitryptyline, desipramine, or imipramine;
anti-epileptics such as gabapentin, carbamazepine, topiramate, sodium valproate or
phenytoin; α2 agonists; or selective serotonin reuptake inhibitors/selective norepinepherine
uptake inhibitors, or combinations thereof.
[00121] One skilled in the art will recognize that some agents described herein act to
relieve multiple conditions such as pain and inflammation, while other agents may just
relieve one symptom such as pain. A specific example of an agent having multiple properties
is aspirin, where aspirin is anti-inflammatory when given in high doses, but at lower doses is
just an analgesic. The pain relieving agent may include any combination of the
aforementioned agents, for example, the pain relieving agent may be a non-narcotic analgesic
in combination with a narcotic analgesic.
[00122] Non-narcotic analgesics useful in the practice of the present invention include, for
example, salicyiates such as aspirin, ibuprofen (Motrin®, Advil®), ketoprofen (Orudis®),
naproxen (Naprosyn®), acetaminophen, indomethacin or combinations thereof. Examples of
narcotic analgesic agents that may be used in combination with compounds of the present
invention include opioid analgesics such as fentenyl, sufentanil, morphine, hydromorphone,
codeine, oxycodone, buprenorphine or pharmaceutically acceptable salts thereof or
combinations thereof. Examples of anti-inflammatory agents that may be used in
combination with compounds of the present invention include but are not limited to aspirin;
ibuprofen; ketoprofen; naproxen; etodolac (Lodine®); COX-2 inhibitors such as celecoxib
(Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®\ parecoxib, etoricoxib (MK663),
deracoxib, 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[l,5-b] pyridazine, 4-
(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, darbufelone, flosulide, 4-(4-
cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide), meloxicam, nimesulide, 1-
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Methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene, 4-(1,5-
Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-c)pyrazol-1-
yl)benzenesulfonamide, 4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclo- butenone,
4-Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzene sulfonamide, l-(7-tert-
butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropyl butan-1-one, or their
physiologically acceptable salts, esters or solvates; sulindac (Clinoril®); diclofenac
(Voltaren®); piroxicam (Feldene®); diflunisal (Dolobid®), nabumetone (Relefen®), oxaprozin
(Daypro®), indomethacin (Indocin®); or steroids such as Pediaped® prednisolone sodium
phosphate oral solution, Solu-Medrol® methylprednisolone sodium succinate for injection,
Prelone® brand prednisolone syrup.
[00123] Further examples of anti-inflammatory agents that may be used for treating pain,
for example associated with rheumatoid arthritis, in accordance with the present invention
include naproxen, which is commercially available in the form of EC-Naprosyn® delayed
release tablets, Naprosyn®, Anaprox® and Anaprox® DS tablets and Naprosyn® suspension
from Roche Labs, Celebrex® brand of celecoxib tablets, Vioxx® brand of rofecoxib,
Celestone® brand of betamethasone, Cupramine® brand penicillamine capsules, Depen®
brand titratable penicillamine tablets, Depo-Medrol® brand of methylprednisolone acetate
injectable suspension, Arava™ leflunomide tablets, Azulfidine EN-tabs® brand of
sulfasalazine delayed release tablets, Feldene® brand piroxicam capsules, Cataflam®
diclofenac potassium tablets, Voltaren® diclofenac sodium delayed release tablets, Voltaren®-
XR diclofenac sodium extended release tablets, or Enbrel® etanerecept products.
[00124] Examples of yet other agents used to treat inflammations, especially rheumatoid
arthritis, include immunosuppressants such as Gengraf™ brand cyclosporine capsules,
Neoral® brand cyclosporine capsules or oral solution, or Imuran® brand azathioprine tablets
or IV injection; Indocin® brand indomethacin capsules, oral suspension or suppositories;
Plaquenil® brand hydroxychloroquine sulfate; or Remicade® infliximab recombinant for IV
injection; or gold compounds such as auranofin or Myochrisyine® gold sodium thiomalate
injection.
[00125] As 5-HT2C modulators, compounds of the present invention are useful for treating
a variety of disorders. Such disorders include premenstrual syndrome, motion or motor
disorders such as Parkinson's disease and epilepsy; migraines, chronic fatigue syndrome,
anorexia nervosa, disorders of sleep (e.g., sleep apnea), and mutism.
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WO 2006/116151 PCT/US2006/015193
[00126] In other embodiments, compounds of the present invention are useful for treating
one or more central nervous system deficiencies associated, for example, with trauma, stroke,
and spinal cord injuries, neurodegenerative diseases or toxic or infective CNS diseases (e.g.,
encephalitis or meningitis), or Parkinson's disease. The compounds of the present invention
can therefore be used to improve or inhibit further degradation of central nervous system
activity during or following the malady or trauma in question. Included in these
improvements are maintenance or improvement in motor and motility skills, control,
coordination and strength.
5. Pharmaceutically acceptable compositions
[00127] In other embodiments, the invention relates to compositions comprising at least
one compound of formula I or VII, or a pharmaceutically acceptable salt thereof, and one or
more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions
include pharmaceutical compositions for treating or controlling disease states or conditions of
the central nervous system. In certain embodiments, the compositions comprise mixtures of
one or more compounds of formula I or VII.
[00128] In certain embodiments, the invention relates to compositions comprising at least
one compound of formula I or VII, or a pharmaceutically acceptable salt thereof, and one or
more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions are
prepared in accordance with acceptable pharmaceutical procedures, such as, for example,
those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R.
Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by
reference in its entirety. Pharmaceutically acceptable carriers are those carriers that are
compatible with the other ingredients in the formulation and are biologically acceptable.
[00129] The compounds of formula I or VII can be administered orally or parenterally,
neat, or in combination with conventional pharmaceutical carriers. Applicable solid carriers
can include one or more substances that can also act as flavoring agents, lubricants,
solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-
disintegrating agents, or encapsulating materials. In powders, the carrier is a finely divided
solid that is in admixture with the finely divided active ingredient. In tablets, the active
ingredient is mixed with a carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The powders and tablets preferably
contain up to 99% of the active ingredient. Suitable solid carriers include, for example,
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WO 2006/116151 PCT/US2006/015193
calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,
cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low
melting waxes and ion exchange resins.
[00130] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups
and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically
acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a
pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers,
preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors,
viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for
oral and parenteral administration include water (particularly containing additives as above,
e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols
(including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives,
and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the
carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid
carriers are used in sterile liquid form compositions for parenteral administration. The liquid
carrier for pressurized compositions can be halogenated hydrocarbon or other
pharmaceutically acceptable propellant.
[00131] Liquid pharmaceutical compositions that are sterile solutions or suspensions can
be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection.
Sterile solutions can also be administered intravenously. Compositions for oral
administration can be in either liquid or soiid form.
[00132] The compounds of formula I or VII can be administered rectally or vaginally in
the form of a conventional suppository. For administration by intranasal or intrabronchial
inhalation or insufflation, the compounds of formula I or VII can be formulated into an
aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
The compounds of formula I can also be administered transdermally through the use of a
transdermal patch containing the active compound and a carrier that is inert to the active
compound, is non-toxic to the skin, and allows delivery of the agent for systemic absoiption
into the blood stream via the skin. The carrier can take any number of forms such as creams
and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous
liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised
of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active
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WO 2006/116151 PCT/US2006/015193
ingredient can also be suitable, A variety of occlusive devices can be used to release the
active ingredient into the blood stream such as a semipermeable membrane covering a
reservoir containing the active ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the literature.
[00133] Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets,
capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such
form, the composition is sub-divided in unit dose containing appropriate quantities of the
active ingredient; the unit dosage forms can be packaged compositions, for example,
packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit
dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate
number of any such compositions in package form.
[00134] The amount of compound of formula I or VII provided to a patient will vary
depending upon what is being administered, the purpose of the administration, such as
prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In
therapeutic applications, compounds of formula I are provided to a patient suffering from a
condition in an amount sufficient to treat or at least partially treat the symptoms of the
condition and its complications. An amount adequate to accomplish this is a "therapeutically
effective amount" as described previously herein. The dosage to be used in the treatment of a
specific case must be subjectively determined by the attending physician. The variables
involved include the specific condition and the size, age, and response pattern of the patient.
The treatment of substance abuse follows the same method of subjective drug administration
under the guidance of the attending physician. Generally, a starting dose is about 5 mg per
day with gradual increase in the daily dose to about 150 mg per day, to provide the desired
dosage level in the patient.
[00135] In certain embodiments, the present invention is directed to prodrugs of
compounds of formula I. The term "prodrug," as used herein, means a compound that is
convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula I,
Various forms of prodrugs are known in the art such as those discussed in, for example,
Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in
Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and
Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191
(1991), Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38(1992), Bundgaard, J. of
Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as
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WO 2006/116151 PCT/US2006/015193
Novel Drug Delivery Systems, American Chemical Society (1975), each of which is hereby
incorporated by reference in its entirety.
EXAMPLES
[00136] As depicted in the Examples below, in certain exemplary embodiments,
compounds are prepared according to the following general procedures. It will be
appreciated that although the general methods depict the synthesis of certain compounds of
the present invention, the following general methods, in addition to the Schemes set forth
above and other methods known to one of ordinary skill in the art, can be applied to all
compounds and subclasses and species of each of these compounds, as described herein.
Intermediate 1
(7-bromo-5-chloro-l-benzofuran-2-yl)methanol: To a solution of 3-bromo-5-chloro-2-
hydroxybenzaldehyde (47.09 g, 0.20 mol) in (1:1) tetrahydrofuran:ethanol (1000 mL) was added
diethyl bromomalonate (57.38 g, 0.24 mol) and potassium tert-butoxide (26.93 g, 0.24 mol) and the
reaction mixture was heated at 70 °C for 12 h. The reaction mixture was allowed to cool to room
temperature and the solvent was removed in vacuo to provide a crude solid. The solid was dissolved
in tetrahydrofuran (1000 mL) and aqueous sodium hydroxide (1.0 M, 250 mL) was added and the
reaction mixture was allowed to stir at room temperature for 4 h. The reaction mixture was acidified
(pH 1-2) with concentrated aqueous hydrogen chloride and the aqueous layer was extracted with
ethyl acetate (3 x 250 mL), the combined organic layers washed with water (2 x 250 mL), saturated
aqueous sodium chloride (250 mL), dried (magnesium sulfate), and the solvent removed in vacuo to
provide the carboxylic acid as a crude solid. To a solution of the carboxylic acid (2.75 g, 0.01 mol)
in tetrahydrofuran (100 mL) cooled to 0 °C was added borane-tetrahydrofuran complex (1.0 M, 30
mL) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction
mixture was quenched by the slow addition of methanol. The solvent was removed in vacuo and the
residue was purified by flash column chromatography (silica, ethyl acetate:hexanes 3:7) to provide
(7-bromo-5-chloro-l-benzofuran-2-yl)methanol 1.59 g (61%) as a white solid, mp 123-126 °C;
Anal, calcd for C9H9BrCl02: C, 41.34; H, 2.31. Found: C, 41.68; H, 2.04.
Intermediate 2
2-[(7-bromo-5-chloro-1-benzofuran-2-yI)methyl]-lH-isoindole-1,3(2H)-dione:
To a solution of triphenylphoshine (1.44 g, 5.48 mmol) in toluene (50 mL) cooled to 0
°C was added the diisopropylazadicarboxylate (1.11 g, 5.48 mmol) followed by the
phthalimide (0.81 g, 5.48 mmol) and the reaction mixture allowed to stir for 10 min.
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The (7-bromo-5-chloro-l-benzofuran-2-:yl)methanol (1.37 g, 5.22 mmol) was then
added and the reaction was allowed to stir at 0 °C an additional 1 h. The reaction
mixture was then quenched with water (1mL) and the solvent was removed in
vacuo to provide a crude solid. The solid was suspended in water (100 mL) and the
aqueous layer was extracted with ethyl acetate (3 x 100 mL), the combined organic
extracts were washed with saturated aqueous sodium chloride (50 mL), dried
(magnesium sulfate), and the solvent removed in vacuo to provide a crude residue.
Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:5)
provided 1.73 g (85%) of 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-
isoindole-1,3(2H)-dione as a white solid, mp 194-198 °C; HRMS-ESI (m/z): [M + H]+
caled for C17H9BrClNO3, 388.94545; found, 389.9553.
Intermediate 3
2-[(5-chloro-7-phenyl-l-benzofuran-2-yI)methyl]-1H-isoindoIe-1,3(2H)-dione:
To a suspension of the 2-[(7-bromo-5-chloro-l-benzofuran-2-yl)methyl]-1H-
isoindole-1,3(2H)-dione (0.500g, 1.28 mmol), dichlorobis(tro-o-
tolylphosphine)palladium(II) (0.101 g, 0.128 mmol), and potassium carbonate
(0.531 g, 3.84 mmol) in dioxane (20 mL) and water (1 mL) heated to 90 °C was
added phenylboronic acid (0.390 g, 3.20 mmol) and the reaction allowed to stir for
1 h. The reaction was cooled to room temperature, filtered (celite), and the solvent
removed in vacuo to provide a crude residue. Purification by flash column
chromatography (silica, ethyl acetate:hexanes 1:4) gave 0.422 g (85%) of 2-[(5-
chloro-7-phenyl-l-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white
solid, mp 163-166 °C.
[00137] The following compounds were prepared generally according to the procedure
described for Intermediate 3:
Intermediate 4
2-{[5-chIoro-7-(2-fluorophenyl)-l-benzofuran-2-yl] methyl}-1H-isoindole-1,3(2H)-dione:
From 2-[(7-bromo-5-chloro-l-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2}l)-dione and 2-
fluorophenylboronic acid gave 2-{[5-chloro-7-(2-fluorophenyl)-l-benzofuran-2-yl]methyl}-1H-
isoindole-1,3(2H)-dione (63%) as a white solid, mp 138-143 °C.
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Intermediate 5
2- { [5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione:
From 2 [(7-bromo-5-ch]oro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione and 2-
chlorophenylboronic acid gave 2-{[5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl]methyl}-
1H-isoindole-1,3(2H)-dione(69%)as.awhite solid, mp 153-158 °C.
Intermediate 6
2-{[5-chloro-7-(2-methylphenyl)-1-benzofuran-2-yl] methyl)-1H-isoindole-1,3(2H)-dione:
From 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione and 2-
methylphenylboronic acid gave 2-{[5-chloro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}-
lH-isoindole-1,3(2H)- dione (62%) as awhite solid, mp 163-167 °C.
Intermediate 7
2- {[5-chIoro-7-(2-methoxyphenyl)-1-benzofuran-2-yl] methyl}-1H-isoindole-1,3(2H)-dione:
From 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione and 2-
methoxyphenylboronic acid gave 2-{(5-chloro-7-(2-methoxyphenyl)-1-benzofuran-2-
yl]methyl)-1H-isoindole-1,3(2H)- dione (63%) as a white solid, mp 149-153 °C.
Intermediate 8
2-((5-chloro-7-[2-(trifluoromethyl) phenyl] -1-benzofuran-2-yl}methyl)-1H- isoindole-
1,3(2H)-dione: From 2- [(7-bromo-5-chloro- 1 -benzo furan-2- yl)methyl]- 1H- isoindole- 1, 3
(2H)-dione and 2-(trifluoromethyi)phenylboronic acid gave 2-((5-chloro-7-[2-
(trifluoromethyl)phenyl]-1-benzoruran-2-yl}methyl)-1H- isoindole-1,3(2H)-dione (60%) as a
Avhite solid, mp 160-163 °C.
Example 1
[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]amine: To a suspension of 2-[(7-phenyl-5-
chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.382 g, 0.985 minol) in
ethanol (10 mL) was added the methylamine (33% in ethanol, 20 mL) and the reaction mixture
was heated to 70 °C and allowed to stir for 1 h. The reaction mixture was allowed to cool to
room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl
acetate (50 mL) and washed with water (2 x 20 mL), saturated aqueous sodium bicarbonate
(20 mL), saturated aqueoussodium chloride (20 mL), dried (magnesium sulfate), and the
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WO 2006/116151 PCT/US2006/015193
solvent removed in vacuo. Purification by flash column chromatography (silica, 10%
ammonium hydroxide in methanol:ethyl acetate 1:9) provided a colorless oil that was
dissolved in isopropanol (2 mL) and hydrogen chloride (1.0 N in diethyl ether, 5 mL) was
added. The resulting precipitate was filtered, washed (diethylether), and dried to afford
0.165 g (57%) of [(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]amine as a white solid, mp
>225 °C.
[00138] The following compounds were prepared generally according to the
procedure described for Example 1:
Example 2
{[5-chloro-7-(2-fluorophenyl)-1-benzofuran-2-yl] methyl}amine: From 2-{ [5-chloro-7-(2-
fluorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione gave {[5-chloro-7-(2-
fluorophenyl)-1-benzofuran-2-yl]methyl}amine (25%) as a white solid, mp 218-223 °C
(dec).
Example 3
{[5-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl] methyl} amine: From 2-{[5-chloro-7-
(2-chlorophenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dione gave {[5-chloro-7-
(2-chlorophenyl)-1-benzofuran-2-yl]methyl}amine (32%) as a white solid, mp 247-250 °C
(dec).
Example 4
{[5-chloro-7-(2-methyIphenyl)-1-benzofuran-2-yl] methyl} amine: From 2-{[5-chloro-7-
(2-methylphenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)- dione gave { [5-chloro-
7-(2-methylphenyl)-1-benzo fur an-2-yl]methyl} amine (33%) as a white solid, mp 219-222
°C (dec).
Example 5
{[5-chIoro-7-(2-methoxyphenyl)-1-benzofuran-2-yl] methyl}amine: From 2-{[5-chloro-7-
(2-methoxyphenyl)-1-benzofuran-2-yl]methyl}-1H-isoindole-1,3(2H)-dionegave.{[5-
chloro-7-(2-methoxyphenyl)-1-benzofuran-2-yl]methyl}amine (36%) as a white solid, mp
228-231 °C (dec).
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Example 6
({5-chloro-7-[2-(trifluoro methyl) phenyl]-1-benzofuran-2-yl}methyl)amine: From 2-({5-
chloro-7-[2-(tnfluoromethyl)phenyl]-1-benzofuran-2-yl}methyl)-1H-isoindole-1,3(2H)-dione
gave ({5-chloro-7-[2-(trifluoromethyl)phenyl]-1-benzofuran-2-yl}methyl)amine (20%) as a
white solid, mp 215-218 °C (dec)
Example 7
{[7-(2, 6-dichloropb.enyl)-5-fIuoro-1-benzofuran-2-yl] methyl) amine: From 2-[7-(2,6-
dichloro-phenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dione gave {[7-(2,6-
dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methyl} amine as a white solid, mp 213-215 °C.
Example 8
{ [5-fluoro-7-(2-methylphenyl)-1-benzofuran-2-yl]methyl}amine: From 2-(5-fluoro-7-(2-
methylphenyl)-benzofuran-2-ylmethyl)-isoindole-1,3-dione gave {[5-fluoro-7-(2-
methylphenyl)-1-benzofuran-2-yl]methyl}amine as a white solid, mp 193-194 °C.
Example 9
{[7-(2,4-dichlorophenyl)-5-fluor o-1-benzofuran-2-yl] methyl}amine; From 2-17-(2,4-
dichlorophenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-l,3-dione gave {[7-(2,4-
dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methyl}amine as a white solid, mp 190 °C (dec).
Example 10
l-[5-fluoro-7-(2-methoxyphenyl)-1-benzofuran-2-yl] methanamine: From 2-[5-fluoro-7-
(2-methoxyphenyl)-benzoruran-2-ylmethyl]-isoindole-1,3-dione gave l-[5-fluoro-7-(2-
methoxyphenyl)-1-benzofuran-2-yl]methanamine as a white solid, mp 128-130°C.
Example 11
l-[7-(2,5-dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methanamine: From 2-[7-(2,5-
dichlorophenyl)-5-fluoro-benzoruran-2-ylmethyl]-isoindole-l,3-dione gave l-[7-(2,5-
dichlorophenyl)-5-fluoro-1-benzofuran-2-yl]methanamine as a white solid, mp 245-247 °C.
Example 12
l-[7-(2-methylphenyl)-1-benzofuran~2-yl] methanamine: From 2-(7-(2-methylphenyl)-1-
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WO 2006/116151 PCT/US2006/015193
benzofuran-2-ylmethyl)-isoindole-l ,3-dione gave 1-[7-(2-methylphenyl)-1-benzofuran-2-
yl]methanamine as a white solid, mp 222-224 °C.
Example 13
l-[7-(4-chloro-2-methylphenyl)-5-fluoro-1-benzofuran-2-yl] methanamine: From 2-[7-(4-
chloro-2-methylphenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dione gave 1-[7-(4-
chloro-2-methylphenyl)-5-fluoro-1-benzofuran-2-yllmethanamine as a white solid, mp 172-
174 °C.
Example 14.
l-[7-(5-chloro-2-methylphenyl)-5-fluoro-1-benzofuran-2-yl] methanamine: From 2-[7-(5-
chloro-2-methylphenyl)-5-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dione gave 1-[7-(5-
chloro-2-methylphenyl)-5-fluoro-1-benzoturan-2-yl]methanamine as a white solid, mp 208-
210 °C.
Example 15
l-[7-(2,6-dichlorophenyl)-1-benzofuran-2-yll methanamine: From 2-[7-(2,6-
dichlorophenyl)-benzofuran-2-ylmethyl]-isoindole-1,3-dione gave1-[7-(2,6-dichlorophenyl)-
l-benzofuran-2-yl]methanamine as a white solid, mp 260-262 °C.
Example 16
l-[6-chloro-7-(2-chlorophenyl)-1-benzofuran-2-yl] methanamine: From 2-[6-chloro-7-(2-
chlorophenyl)-benzofuran-2-ylmethyl]-isoindole-1,3-dione gave [6-chloro-7-(2-
chlorophenyl)-1-benzofuran-2-yl]methanamine as a white solid, mp 208-210 °C.
Example 17
l-[7-(2-chlorophenyl)-6-fluoro-1-benzofuran-2-yl] methanamine: From 2-[7-(2-
chlorophenyl)-6-fluoro-benzofuran-2-ylmethyl]-isoindole-1,3-dione gave l-[7-(2-
chlorophenyl)-6-fluoro-1-benzofuran-2-yl]methanamine as a white solid, mp >250 °C.
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WO 2006/116151 PCT/US2006/015193
Biological Assays
[00139] The ability of the compounds of this invention to act as 5-HT2C agonists and
partial agonists was established using several standard pharmacological test procedures; the
procedures used and results obtained are provided below. In the test procedures, 5-HT stands
for 5-hydroxytryptamine, mCPP stands for meta-chlorophenylpiperazine, and DOI stands for
l-(2,5-dimethoxy-4-iodophenyl)isopropylamine.
[00140] To evaluate the affinity of various compounds of formula I for activity at the 5-
HT2C receptor, a CHO (Chinese Hamster Ovary) cell line transfected with the cDNA
expressing the human 5-hydroxytryptamine-2C (h5-HT2c) receptor was maintained in
DMEM (Dulbecco's Modified Eagle Media) supplied with fetal calf serum, glutamine, and
the markers: guaninephosphoribosyl transferase (GTP) and hypoxanthinethymidine (HT).
The cells were allowed to grow to confluence in large culture dishes with intermediate
changes of media and splitting. Upon reaching confluence, the cells were harvested by
scraping. The harvested cells were suspended in half volume of fresh physiological phosphate
buffered saline (PBS) solution and centrifuged at low speed (900 x g). This operation was
repeated once. The collected cells were then homogenized with a polytron at setting #7 for 15
sec in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA. The homogenate was
centrifuged at 900 x g for 15 min to remove nuclear particles and other cell debris. The pellet
was discarded and the supernatant fluid recentrifuged at 40,000 x g for 30 min. The resulting
pellet was resuspended in a small volume of Tris.HCl buffer and the tissue protein content
was determined in aliquots of 10-25 μL volumes. Bovine Serum Albumin (BSA) was used as
the standard in the protein determination by the method of Lowry et al., (J. Biol. Chern.,
193:265 (1951). The volume of the suspended cell membranes was adjusted with 50 mM
Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mM pargyline and 4 mM CaCb to give a
tissue protein concentration of 1-2 mg per ml of suspension. The preparation membrane
suspension (many times concentrated) was aliquoted in 1 ml volumes and stored at -70 C
until used in subsequent binding experiments.
[00141] Binding measurements were performed in a 96 well microtiter plate format, in a
total volume of 200 μL. To each well was added: 60 μL of incubation buffer made in 50 mM
Tris.HCl buffer, pH 7.4 and containing 4 mM CaCl2; 20 μL of [125I] DOI (S.A., 2200
Ci/mmol, NEN Life Science).
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WO 2006/116151 PCT/US2006/015193
[00142] The dissociation constant, KD of [125I] DOI at the human serotonin 5-HT2C
receptor was 0.4 nM by saturation binding with increasing concentrations of [12SI] DOI. The
reaction was initiated by the final addition of 100 μL of tissue suspension containing 50 μg of
receptor protein. Nonspecific binding is measured in the presence of 1 μM unlabeled DOI
added in 20.0 μL volume. Test compounds were added in 20.0 uL. The mixture was
incubated at room temperature for 60 min. The incubation was stopped by rapid filtration.
The bound ligand-receptor complex was filtered off on a 96 well unifilter with a Packard
®Filtermate 196 Harvester. The bound complex caught on the filter disk was dried in a
vacuum oven heated to 60° C and the radioactivity measured by liquid scintillation with 40
μL Microscint-20 scintillant in a Packard TopCount® equipped with six (6) photomultiplier
detectors.
[00143] Specific binding is defined as the total radioactivity bound less the amount bound
in the presence of 1 μM unlabeled DOI. Binding in the presence of varylng concentrations of
test drugs is expressed as percent of specific binding in the absence of drug. These results are
then plotted as log% bound vs log concentration of test drug. Non linear regression analysis
of data points ylelds both the IC50 and the Ki values of test compounds with 95% confidence
limits. Alternatively, a iinear regression line of decline of data points is plotted, from which
the IC50 value can be read off the curve and the Ki value determined by solving the following
equation:

where L is the concentration of the radioactive ligand used and the KD is the dissociation
constant of the ligand for the receptor, both expressed in nM.
[00144] The following K;'s (95% confidence interval) are provided for various reference
compounds in Table 2, below:
Table 2: K, Data for Reference Compounds

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WO 2006/116151 PCT/US2006/015193
Methiothepin 4.6 (4.0 - 6.0) nM
Methysergide 6.3 (4.6 - 8.6) nM
Loxapine 33.0 (24.0 - 47.0) nM
mCPP 6.5 (4.8 - 9.0) nM
DOI 6.2 (4.9 - 8.0) nM
[00145] The ability of the compounds of formula I to produce an agonist response at brain
5-HT2C was assessed by determining their effect on calcium mobilization using the following
procedure: CHO cells stably expressing the human 5-HT2C receptor were cultured in
Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum
and non-essential amino acids. Cells were plated at a density of 40K cells/well in 96-well
clear-bottom black-wall plates 24 hours prior to the evaluation of 5-HT2C receptor-stimulated
calcium mobilization. For calcium studies, cells were loaded with the calcium indicator dye
Fluo-3-AM in Hank's buffered saline (HBS) for 60 minutes at 37 °C. Cells were washed with
HBS at room temperature and transferred to the fluorometric imaging plate reader (FLIPR,
Molecular Devices, Sunnyvale, CA) for acquisition of calcium images, Excitation at 488 nm
was achieved with an Argon ion laser and a 510-560 nm emission filter was used.
Fluorescence images and relative intensities were captured at 1 second intervals and cells
were stimulated by addition of agonist after 10 baseline measurements using the internal
fluidics module of the FLIPR. An increase in fluorescence counts corresponds to an increase
in intracellular calcium.
[00146] For the evaluation of agonist pharmacology the calcium changes in response to
different concentrations of agonist were determined using a maximum minus minimum
calculation of the raw fluorescence count data. Calcium changes were then expressed as a
percentage of the response observed with a maximally effective concentration of 5-HT. EC50
values were estimated by non-linear regression analysis of the log-concentration% maximum
5-HT response curves using the 4-parameter logistic function. In certain embodiments,
compounds of the present invention provide an EC50 of ≤ about 1000 nM. In other
embodiments, compounds of the present invention provide an EC50 of ≤ about 100 nM, in yet
other embodiments < about 20 nM, in still other embodiments ≤ about 5 nM, and certain
embodiments ≤ about 2 nM.
[00147] The following EC50's are provided for various reference compounds in Table 3,
below
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WO 2006/116151 PCT/US2006/015193
Table 3: EC50 Data for Reference Compounds:

[00148] Table 4 below shows the results of the activity of selected compounds of this
invention in the assays described above. The compound numbers correspond to the
compound numbers in Table 1, supra. Compounds having an activity designated as "A"
provided a Kj value between 0.01 to 1 nM; compounds having an activity designated as "B"
provided a Kj value between 1 nM and 10 nM; and compounds having an activity designated
as "C" provided a Ki value between 10 nM and 100 nM. Compounds having an activity
designated as "D" provided an EC50 value of less than 10 nM; compounds having an activity
designated as "E" provided a an EC50 value between 10 nM and 200 nM; and compounds
having an activity designated as "F" provided a an EC50 value between 200 nM and 2000 nM.
Table 4. 5-HT?c Activity of Selected Compounds

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WO 2006/116151 PCT/US2006/015193
[00149] The compounds of this invention thus have affinity for and agonist or partial
agonist activity at brain serotonin 5-HT2C receptors. They are therefore of interest for the
treatment of the central nervous system conditions described previously herein.
[00150] The entire disclosure of each patent, patent application, and publication cited or
described in this document is hereby incorporated by reference.
[00151] While we have presented a number of embodiments of this invention, it is
apparent that our basic construction can be altered to provide other embodiments which
utilize the compounds and methods of this invention. Therefore, it will be appreciated that
the scope of this invention is to be defined by the appended claims rather than by the specific
embodiments which have been represented by way of example.
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WO 2006/116151 PCT/US2006/015193
CLAIMS
We claim:
1. A compound of formula I:

or pharmaceutically acceptable salts thereof, wherein:
each of R1 and R1 is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difiuoroethyl
or cyclopropyl;
each of R2, R3 and R4 is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy,
trifluoromethyl, trifluoromethoxy, or CN;
Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more
Rx groups;
each Rx is independently halogen, -OH, -CN, lower alkyl, lower alkoxy, -CF3, or -OCF3; and
n is one or two.
2. The compound according to claim 1, wherein one of R1 and R1' is hydrogen
and the other of R1 and R1 groups of formula I is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-
difluoroethyl or cyclopropyl.
3. The compound according to claim 2, wherein both of R1 and R1 is hydrogen.
4. The compound according to claim 1, wherein neither R1 nor R1 is hydrogen.
5. The compound according to claim 1, wherein R2, R3 and R4 are all hydrogen.
6. The compound according to claim 1, wherein at least one of R2, R3 and R4 is
independently halogen.
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WO 2006/116151 PCT/US2006/015193
7. The compound according to claim 1, wherein R2 is hydrogen and R3 and R4
are independently halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy,
or CN.
8. The compound according to claim 7, wherein R2 and R4 are both hydrogen and
R3 is halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy.
9. The compound according to claim 7, wherein R2 and R3 are both hydrogen and
R4 is halogen, OH, lower alkyl, lower alkoxy, trifluoromethyl, or trifluoromethoxy.
10. The compound according to claim 1, wherein Ar is unsubstituted phenyl.
11. The compound according to claim 1, wherein Ar is phenyl with at least one
substituent in the ortho position.
12. The compound according to claim 11, wherein Ar is phenyl with at least one
substituent in the ortho position selected from halogen, lower alkyl, lower alkoxy, or
trifluoromethyl.
13. The compound according to claim 1, wherein Ar is selected from:

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WO 2006/116151 PCT/US2006/015193
14. The compound according to claim 1, wherein said compound is of formula II,
III, IV, V, VI, or VII:

or a pharmaceutically acceptable salt thereof, wherein each Rx is independently halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or CN.
15. The compound according to claim 1, wherein said compound is selected from:

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WO 2006/116151 PCT/US2006/015193

16. A pharmaceutical composition comprising a compound according to claim 1,
and one or more pharmaceutically acceptable carriers.
17. The composition of claim 16, further comprising an additional pharmaceutical
agent selected from an anti-psychotic agent, an antidepressive agent, an anti-obesity agent, an
agent useful in the modulation of bladder activity, an opioid antagonist, an agent for treating
ADD or ADHD, a cognitive improvement agent, an agent for treating sexual dysfunction, or
a pain relieving agent.
18. A method for treating a condition selected from at least one of psychotic
disorder, an anxiety disorder, a bipolar disorder, a depressive disorder, premenstrual
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WO 2006/116151 PCT/US2006/015193
syndrome (PMS), premenstrual dysphoric disorder (PMDD), an eating disorder, a bladder
control disorder, substance abuse or substance dependence, a cognition disorder, ADD or
ADHD, an impulsivity disorder, an addictive disorder, male or female sexual dysfunction,
pain, a motion or motor disorder, Parkinson's disease epilepsy, migraine, chronic fatigue
syndrome, anorexia nervosa, a sleep disorder, mutism, or one or more central nervous
system deficiencies in a patient, comprising administering to the patient a therapeutically
effective amount of a compound according to claim 1 or a composition comprising a
compound according to claim 1.
19. The method of claim 18 wherein the psychotic disorder is schizophrenia,
paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia,
undifferentiated type schizophrenia, a schizophreniform disorder, a schizoaffective disorder,
a delusional disorder, substance-induced psychotic disorder, a psychotic disorder not
otherwise specified; L-DOPA-induced psychosis; psychosis associated with Alzheimer's
dementia; psychosis associated with Parkinson's disease; or psychosis associated with Lewy
body disease
20. The method of claim 18, wherein the condition is bipolar disorder and is
selected from bipolar I disorder, bipolar II disorder, cyclothymic disorder; bipolar mania,
dementia, depression with psychotic features, or cycling between bipolar depression and
bipolar mania.
21. The method of claim 18, wherein the depressive disorder is major depressive
disorder, seasonal affective disorder, dysthymic disorder, substance-induced mood disorder,
depressive disorder not otherwise specified, treatment resistant depression, major depressive
episode.
22. The method of claim 21, further comprising administering to the patient an
antidepressive agent selected from serotonin reuptake inhibitors (SRIs), norepinephrine
reuptake inhibitors (NRIs), combined serotonin- norepinephrine reuptake inhibitors (SNRIs),
monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase
(RIMAs), phosphodiesterase-4 (PDE4) inhibitors, corticotropin releasing factor (CRF)
antagonists, alpha.-adrenoreceptor antagonists, triple uptake inhibitors, melatonin agonists,
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super neurotransmitter uptake blockers (SNUBs), noradrenergic and specific serotonergic
antidepressants (NaSSAs), or substance P/neurokinin receptor antagonists.
23. The method of claim 18, wherein the cognitive disorder is a learning disorder.
24. The method of claim 18, wherein the patient is treated for obesity.
25. The method of claim 18, wherein the patient is treated for ADD or ADHD.
26. The method of claim 18, wherein the substance abuse substance dependence is
of a recreational substance, a pharmacologic agent, a tranquilizer, a stimulant, sedative, or
illicit drug.
27. The method of claim 18, further comprising administering to the patient an
additional pharmaceutical agent selected from an anti-psychotic agent, an antidepressive
agent, an anti-obesity agent, an agent useful in the modulation of bladder activity, an opioid
antagonist, an agent for treating ADD or ADHD, a cognitive improvement agent, an agent for
treating sexual dysfunction, or a pain relieving agent.
28. A method for treating schizophrenia in a patient, comprising administering to
the patient a therapeutically effective amount of a composition according to claim 16.
29. A method for treating bipolar disorder in a patient, comprising administering
to the patient a therapeutically effective amount of a composition according to claim 16.
30. A method for treating depression in a patient, comprising administering to the
patient a therapeutically effective amount of a composition according to claim 16.
31. Use of a compound as claimed in any one of claims 1 to 15 to prepare a
medicament for treating a condition selected from at least one of psychotic disorder, an
anxiety disorder, a bipolar disorder, a depressive disorder, premenstrual syndrome (PMS),
premenstrual dysphoric disorder (PMDD), an eating disorder, a bladder control disorder,
substance abuse or substance dependence, a cognition disorder, ADD or ADHD, an
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impulsivity disorder, an addictive disorder, male or female sexual dysfunction, pain, a
motion or motor disorder, Parkinson's disease epilepsy, migraine, chronic fatigue syndrome,
anorexia nervosa, a sleep disorder, mutism, or one or more central nervous system
deficiencies.
57

Compounds of formula I pr pharmaceutically acceptable salts thereof are provided: wherein each of R1, R1', R2, R3, R4, n, and Ar are as defined in the description which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.