WO 2006/116165 PCT/US2006/015208
CHROMANE AND CHROMENE DERIVATIVES AND USES THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to United States Provisional Patent Application
serial number 60/673,820, 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 or partial 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 receptor agonists or partial agonists and
uses thereof. In one aspect, the invention relates to chromane and chromene derivatives that
act as agonists or partial agonists of the 5-HT2C receptor. The compounds can be used, for
example, to treat schizophrenia and the concomitant mood disorders and cognitive
impairments of schizophrenia and depression. 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 can also be used for the
treatment of obesity and its comorbidities. Compounds of the present invention are also
useful for treating a variety of psythotic, depression and related disorders, and cognitive
disorders as described in detail herein.
[0007] In certain embodiments, the invention provides a compound of formula I:


WO 2006/116165 PCT/US2006/015208
or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2;
n is 0 or 1;
= designates a single or double bond;
Ax is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more
Rx groups;
each Rx is independently -Ph, halogen, -CN, -R or -OR;
each R is independently hydrogen, C1-6 aliphatic or halo-substituted C1-6 aliphatic;
y is 0-3;
each R1 is independently -R, -CN, halogen or -OR;
R2 is hydrogen, C1-3 alkyl, or -O(C1-3 alkyl); and
each of R3 and R4 is independently hydrogen, C1-6 aliphatic or fluoro-substituted C1-6
aliphatic;
[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, or other conditions or
disorders as described herein, 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 compounds of the present invention are agonists or partial agonists of the 2C
subtype of brain serotonin receptors.
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[0011] In certain embodiments, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2;
n is 0 or 1;
== designates a single or double bond;
Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more
Rx groups;
each Rx is independently -Ph, halogen, -CN, -R or -OR;
each R is independently hydrogen, C1-6 aliphatic or halo-substituted C1-6 aliphatic;
y is 0-3;
each R1 is independently -R, -CN, halogen or -OR;
R2 is hydrogen, C1-3 alkyl, or -O(C1-3 alkyl); and
each of R3 and R4 is independently hydrogen, C1-6 aliphatic or fluoro-substituted C1-6
aliphatic;
provided that:
when == designates a single bond and n is 0, then R1 is not -OH in the 6-position; and
when == designates a single bond and n is 0, then Rl is not -OR in the 7-position.
[0012] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain
(i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is
completely saturated or that contains one or more units of unsaturation, or a monocyclic
hydrocarbon that is completely saturated or that contains one or more units of unsaturation,
but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or
"cycloalkyl"), that has a single point of attachment to the rest of the molecule. In certain
embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms, and in yet other
embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments,
"cycloaliphatic" (or "carbocycle") refers to a monocyclic C3-C6 hydrocarbon that is
completely saturated or that contains one or more units of unsaturation, but which is not
aromatic, that has a single point of attachment to the rest of the molecule. Such
cycloalrphatic groups include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Suitable
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aliphatic groups include, but are not limited to, linear or branched, substituted or
unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0013] The term "unsaturated," as used herein, means that a moiety has one or more units
of unsaturation.
[0014] 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.
[0015] The term "alkoxy," as used herein, refers to the group -OR*, wherein R* is a lower
alkyl group.
[0016] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine
or iodine.
[0017] The term "halo-substituted," as used herein, or as part of a moiety such as
"haloalkoxy" refers to an aliphatic group, as defined herein, that has one or more halogen
substiruents. In certain embodiment, every hydrogen atom on said alkyl group is replaced by
a halogen atom. Such halo-substituted aliphatic groups include -CF3. Such haloalkoxy
groups include -OCF3.
[0018] The term "fluoro-substituted aliphatic, "as used herein, an aliphatic group, as
defined herein, that has one or more fluorine substiruents. In certain embodiment, a fluoro-
substituted aliphatic group is a fluoroalkyl group.
[0019] The term "fluoroalkyl," as used herein, or as part of a moiety such as
"fluoroalkoxy" refers to an alkyl group, as defined herein, that has one or more fluorine
substituents. In certain embodiment, every hydrogen atom on said alkyl group is replaced by
a fluorine atom.
[0020] The term "Ph," as used herein, refers to a phenyl group.
[0021] The term "alkenyl," as used herein refers to an aliphatic straight or branched
hydrocarbon chain having 2 to 8 carbon atoms that may contain 1 to 3 double bonds.
Examples of alkenyl groups include vinyl, prop-1-enyl, allyl, methallyl, but-1-enyl, but-2-
enyl, but-3-enyl, or 3,3-dimethylbut-l-enyl. In some embodiments, the alkenyl is preferably
a branched alkenyl of 3 to 8 carbon atoms. The term "lower alkenyl" refers to an alkenyl
group having 1 to 3 carbon atoms.
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[0022] 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. 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, epilepsy,
pain, or any other disorder as described herein.
[0023] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable
salt" includes acid addition salts, that is 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. Where a compound
of formula I contains a substituent with acidic properties, for instance, phenolic hydroxyl as
R1 or Rx , the term also includes salts derived from bases, for example, sodium salts. In
certain embodiments, the present invention provides the hydrochloride salt of a compound of
formula I.
[0024] The term "patient," as used herein, refers to a mammal. In certain embodiments,
the term "patient", as used herein, refers to a human.
[0025] 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.
[0026] The terms "treat" or "treating," as used herein, refers to partially or completely
alleviating, inhibiting, preventing, ameliorating and/or relieving the condition.
[0027] 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.
2. Description of Exemplary Compounds:
[0028] In certain embodiments, the invention relates to a compound of formula I:
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or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2;
nis Oor 1;
=■=■= designates a single or double bond;
Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more
R* groups;
each Rx is independently -Ph, halogen, -CN, -R or -OR;
each R is independently hydrogen, C1-6 aliphatic or halo-substituted C1-6 aliphatic;
y is 0-3;
each R1 is independently -R, -CN, halogen or -OR;
R2 is hydrogen, C1-3 alkyl, or -O(C1-3 alkyl); and
each of R3 and R4 is independently hydrogen, C1-6 aliphatic or fluoro-substituted C1-6
aliphatic.
[0029] As defined generally above, the n group of formula I is 0 or 1. In certain
embodiments, n is 0 thus forming a compound of formula la:

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Ar, y, and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0030] According to another embodiment, the n group of formula I is 1, thus forming a
compound of formula Ib:

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or a pharmaceutically acceptable salt thereof, wherein R1,R2,R3,R4, Ar, y, and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0031] As defined generally above, y is 0-3 and each R1 group of formula I is
independently -R, -CN, halogen or -OR. In certain embodiments, each R1 group of formula I
is independently hydrogen, C1-3 aliphatic, halogen, -OMe or -CF3. In still other
embodiments, y is 1, and R is halogen.
[0032] According to one embodiment, y is 1, n is 1, and R1 is at the 7-position of the
bicyclic ring of formula I, thus forming a compound of formula IIa or IIb:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R4, Ar, and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0033] According to another embodiment, y is 1, n is 0, and R1 is at the 6- or 7-position
of the bicyclic ring of formula I, thus forming a compound of formula IIc, IId, IIe or IIf:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R4, Ar, and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0034] As defined generally above, each of the R3 and R4 groups of formula I is
independently hydrogen, C1-6 aliphatic or fluoro-substituted C1-6 aliphatic. In certain
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embodiments, each of the R3 and R4 groups of formula I is independently hydrogen, methyl,
ethyl, 2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl. In other embodiments, one of the R3
and R4 groups of formula I is hydrogen and the other R3 or R4 is hydrogen, methyl, ethyl, 2-
fluoroethyl, 2,2-difluoroethyl or cyclopropyl. In other embodiments, neither of the R3 and R4
groups of formula I is hydrogen. In still other embodiments, both of the R3 and R groups of
formula I are hydrogen.
[0035] As defined generally above, each R1 group of formula I is independently -R, -CN,
halogen or -OR. In certain embodiments, each R1 group of formula I is hydrogen. In other
embodiments, at least one each R1 group of formula I is halogen. According to another
aspect of the present invention, one R1 group of formula I is hydrogen and the other R1
groups of formula I are independently halogen, -OH, lower alkyl, lower alkoxy,
trifluoromethyl, trifluoromethoxy, or -CN. Yet another aspect of the present invention
provides a compound of formula I wherein y is 1 and R1 is halogen. In certain embodiments,
y is 1 and R1 is fluoro or chloro.
[0036] As defined generally above, the Ar group of formula I is thienyl, furyl, pyridyl, or
phenyl, wherein said phenyl is optionally substituted with one or more Rx subsituents
independently selected from -Ph, -R, -CN, halogen or -OR. 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 Rx substituent in the ortho position. In other embodiments, the Ar
group of formula I is phenyl with at least one Rx substituent in the ortho position selected
from -Ph, 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. In certain
embodidments, Ar is phenyl subsituted at both ortho-positions with independently selected
halogen or methyl. Exemplary substituents on the phenyl moiety of the Ar group of formula
I include -OMe, fluoro, chloro, methyl, and trifluoromethyl.
[0037] According to one embodiment, Ar is phenyl substituted with Rx in the ortho-
position thus forming a compound of formula IIIa or IIIb:
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or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R4, Rx, y and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0038] According to another embodiment, the present invention provides a compound of
formula IIIc or Hid:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R4, Rx, y and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0039] In certain embodiments, the Ar group of formula I is selected from the following:

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[0040] According to another embodiment, the Ar group of formula I is pyridyl.
[0041] As defined generally above, the R2 of formula I is hydrogen, C1-3 alkyl, or -O(C1-3
alkyl). In certain embodiments, the R2 of formula I is hydrogen, methyl, or methoxy. In
other embodiments, the R2 of formula I is hydrogen or methyl. In still other embodiments,
the R2 of formula I is hydrogen.
[0042] Compounds of the present invention contain asymmetric carbon atoms and thus
give rise to stereoisomers, including enantiomers and diastereomers. Accordingly, it is
contemplated that the present invention relates to all of these stereoisomers, as well as to
mixtures of the stereoisomers. Throughout this application, the name of the product of this
invention, where the absolute configuration of an asymmetric center is not indicated, is
intended to embrace the individual stereoisomers as well as mixtures of stereoisomers. In
certain embodiments of the invention, compounds having an absolute (R) configuration are
preferred.
[0043] la certain embodiments, the present invention provides a compound of formula
IVa,IVb,IVc,orIVd:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R4, Ar, y and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
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[0044] According to another embodiment, the present invention provides a compound of
any of formula Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, R4, Rx, y and m are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0045] Where an enantiomer is preferred, it may, in some embodiments be provided
substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of
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the corresponding enantiomer refers to a compound which is isolated or separated via
separation techniques or prepared free of the corresponding enantiomer. "Substantially free,"
as used herein, means that the compound is made up of a significantly greater proportion of
one enantiomer. In certain embodiments the compound is made up of at least about 90% by
weight of a preferred enantiomer. In other embodiments of the invention, the compound is
made up of at least about 99% by weight of a preferred enantiomer. Preferred enantiomers
may be isolated from racemic mixtures by any method known to those skilled in the art,
including chiral high pressure liquid chromatography (HPLC) and the formation and
crystallization of chiral salts or prepared by methods described herein. See, for example,
Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,
1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon
Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical
Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972)..
[0046] It is further 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.
[0047] Exemplary compounds of formula I are set forth in Table 1, below.
Table 1: Exemplary Compounds of Formula I:

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[0048] It will be appreciated that for each racemic compound disclosed in Table 1, above,
both enantiomers are separately contemplated and included herein. For example, for
compound 1-1 depicted above as a racemate, each of its enantiomers of structures I-1a and I-
lb:
are contemplated and included herein.
[0049] It will be appreciated that for each enantiomer disclosed in Table 1, above, the
opposite enantiomer is contemplated and included herein. For example, for compounds 1-36
and 1-57 depicted above as a single enantiomer, their opposite enantiomers of structures I-
36a and I-57a:
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are also contemplated and included herein.
[0050] In addition, for each enantiomer disclosed in Table 1, above, the racemate of that
compound is also contemplated and included herein. For example, for compounds 1-36 and
1-57 depicted above as a single enantiomer, their racemates of structures I-36b and I-57b:

are also contemplated and included herein.
3. General Methods of Providing the Present Compounds:
[0051] Compounds of the present invention may be prepared by methods known to one
of ordinary skill in the art, for instance, by
(i) alkylation of a compound HNR3R4 with, as alkylating agent, a compound of the formula X

where Y is a leaving group, e.g. -OTs :
(ii) reduction of a compound Xa

(iii) subiecting a compound having the formula Xb
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where Ra is selected from R3 and a removeable monovalent protecting group whilst Rb is a
removeable monovalent protecting group or Ra and Rb together represent a divalent
protecting group (e.g. -NR3R being phthalimido) to treatment to remove the protecting
group(s); and, if desired a resultant compound having formula I is converted into a
pharmaceutically acceptable salt thereof.. In particular the compounds may be prepared by
methods illustrated in Scheme 1-17, below. Unless otherwise noted, all variables are as
defined above and in classes and subclasses described above and herein.
[0052] The chroman and 2H-chromene derivatives of formula Ia of the present invention
are prepared as illustrated in Scheme 1, below. Unless otherwise noted the variables are as
defined above. Specifically, Suzuki coupling of the appropriately substituted bromide or
triflate (1) with a suitable coupling partner, such as arylboronic acids, using a palladium
catalyst under basic conditions affords the biaryl derivative (2). The source of palladium is
normally tetrakis(triphenylphosphine) palladium (0) or another suitable source such as trans-
dichlorobis(tri-o-tolylphosphine)palladium (II). The normal choices for the reaction base are
sodium or potassium carbonate, cesium or potassium fluoride or potassium phosphate, and
the solvent choices include tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, water
and toluene. Displacement of the tosylate leaving group in (2) with a monoalkylamine or
dialkylamine affords a compound of formula la. The reaction can be executed in a suitable
aprotic solvent including but not limited to tetrahydrofuran or dimethyl sulfoxide at
temperatures ranging from room temperature to 100 °C.
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[0053] Alternatively, the tosylate (2) can be converted to the azide (3), on treatment with
sodium azide, and the azide reduced to amine with a suitable reducing agent such as
triphenylphosphine in tetrahydrofuran and water to afford compounds of formula la, wherein
R3 and R4 are hydrogen, Scheme 2.

[0054] The intermediate tosylates (1), wherein X is OTf, can be prepared as illustrated in
Scheme 3. Wittig reaction of an appropriately substituted 2-hydroxy-3-
methoxybenzaldehyde (4) with a phosphorus ylid gives an alkene (5). Mitsunobu
etherification of (5) on treatment with a substituted allylic alcohol (6), diethyl
azodicarboxylate and triphenylphosphine affords diene (7). The diene (7) is then subjected to
a ring closing metathesis reaction on treatment with bis(tricyclohexylphosphine)benzylidine
ruthenium (TV) dichloride (Schwab, P. et al. Journal of the American Chemical Society 1996,
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118, 100) to give 2H-chromene derivative (8). Hydrogenation of the double bond of the 2H-
chromene derivative (8) in the presence of a metal catalyst gives the chroman derivative (9).
Suitable metal catalysts include palladium on activated carbon, platinum (IV) oxide or
sulfided platinum on carbon and the choice of catalyst is dependent on the substituents on the
aromatic ring. The methyl ether present on (9) is cleaved on treatment with
iodotrimethylsilane in a halogenated solvent such as 1,2-dichloroethane to give phenol (10).
The phenol (10) is reacted with trifluoromethanesulfonic anhydride in the presence of a base
such as pyridine or N, N-diisopropylethylamine to give the triflate (1), wherein R is
hydrogen, X is OTf and == represents a single bond.

[0055] Alternatively, the intermediate tosylate (1), wherein X is bromide, can be prepared
as illustrated in Scheme 4 and Scheme 5.
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[0056] The substituted 2-bromophenol (11) is alkylated with allyl bromide in the
presence of a suitable base such as sodium hydride or potassium carbonate to give (12).
Claisen rearrangement of (12) in a re fluxing high-boiling point solvent such as 1-methyl-2-
pyrrolidinone or ethylene glycol gives phenol derivative (13). The double bond in (13) is
isomerized to give (14), in which the double bond is in conjugation with the aromatic ring, on
treatment with a suitable palladium catalyst such as bis(acetonitrile) palladium (II) dichloride.
Mitsunobu etherification of (14) on treatment with a substituted allylic alcohol (6), diethyl
azodicarboxylate and triphenylphosphine affords diene (15), wherein R2 is hydrogen.
Alternatively, treatment of phenol (14) with a substituted vinyloxirane (16) in the presence of
a suitable palladium catalyst, such as tetrakis(triphenylphosphine) palladium (0), will give the
diene (17) (Goujon, J-Y. et al. Journal of the Chemical Society Perkin Trans 1 2002, 496).
Treatment of the alcohol (17) with p-toluenesulfonyl chloride in the presence of a suitable
base such as pyridine or N, Af-diisopropylethylamine gives the tosylate (15), wherein R2 is d.
3 alkyl and m is 1.
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[0057] As illustrated in Scheme 5, subjecting diene (15) to a ring closing metathesis
reaction on treatment with bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride
gives 2H-chromene derivative (18). Hydrogenation of the double bond of the 2H-chromene
derivative (18) without reduction of the aryl bromide can be achieved using a suitable catalyst
such as platinum (IV) oxide or sulfided platinum to give a chroman derivative of formula 1,
wherein == represents a single bond and X is bromide.

[0058] Alternatively, the intermediate 8-arylchroman or 8-aryl-2H-chromene
intermediates (2) can be prepared as illustrated in Scheme 6.

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[0059] Diene (19) is subjected to a ring closing metathesis reaction on treatment with
bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride to give 2H-chromene
derivative (20). Hydrogenation of the double bond of the 2H-chromene derivative (20) can
be achieved using a suitable catalyst such as platinum (IV) oxide or sulfided platinum to give
the chroman derivative (2), wherein == represents a single bond, Scheme 6.
[0060] Synthesis of an intermediate diene of formula 19 is illustrated in Scheme 7.

[0061] Suzuki coupling of 2-methoxyphenylboronic acids (21) with different aryl halides
using a palladium catalyst under basic conditions affords anisole derivatives (22). The source
of palladium is normally tetrakis(triphenylphosphine) palladium (0) or another suitable
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source such as trans-dichlorobis(tri-o-tolylphosphine)palladium (II). Typically, the reaction
base is sodium or potassium carbonate, cesium or potassium fluoride or potassium phosphate,
and the solvent includes tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, water,
toluene and mixtures thereof. Cleavage of the methyl ether in (22) with boron tribromide
gives phenol (23) that can be alkylated with allyl bromide in the presence of a suitable base to
give allyl ether derivatives (24). Claisen rearrangement of (24) in a refluxing high-boiling
point solvent such as 1-methyl-2-pyrrolidinone or ethylene glycol gives phenol derivative
(25). The double bond in (25) is isomerized to give (26), in which the double bond is in
conjugation with the aromatic ring, on treatment with bis(acetonitrile) palladium (II)
dichloride in refluxing dichloromethane. Mitsunobu etherification of (26) on treatment with
a substituted allylic alcohol (6), diethyl azodicarboxylate and triphenylphosphine affords
diene (19), wherein R2 is hydrogen. Alternatively, treatment of phenol (26) with a substituted
vinyloxirane (16) in the presence of a suitable palladium catalyst, such as
tetrakis(triphenylphosphine) palladium (0), will give the diene (27) (Goujon, J-Y. et al.
Journal of the Chemical Society Perkin Trans 1 2002, 496). Treatment of the alcohol (27)
with p-toluenesulfonyl chloride in the presence of a suitable base such as pyridine or N, N-
diisopropylethylamine gives the tosylate (19), wherein R2 = C1-3 alkyl and m is 1, Scheme 7.
[0062] An alternative synthesis of compounds of formula (la) is illustrated in Scheme 8
and Scheme 9.

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[0063] Diene (27) is subjected to a ring closing metathesis reaction on treatment with
bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride to give 2H-chromene
derivative (28). Hydrogenation of the double bond of the 2H-chromene derivative (28) can
be achieved using a suitable catalyst such as platinum (IV) oxide or sulfided platinum to give
the chroman derivative (29), Scheme 8.

[0064] Mitsunobu homologation of the chroman or 2H-chromene alcohol (30) with
acetone cyanohydrin in the presence of N,N,N',N'-tetramethylazodicarboxamide and
tributylphosphine (Tsunoda, T. et al. Tetrahedron Letters 1999, 40, 7355) gives nitrile (31).
The nitrile (31) may be reduced to give the corresponding aldehyde (32) on treatment with a
suitable metal hydride reducing agent, such as diisobutylaluminium hydride. Reductive
animation then gives the compounds of formula la, wherein m is 2.
[0065] The 2,3,4,5-tetrahydro-benzo[b]oxepine derivatives (Ib) of the present invention
are prepared as illustrated in Scheme 10.

[0066] Displacement of the tosylate leaving group in (33) with a monoalkylamine or
dialkylamine affords a compound of formula Ib. The reaction can be executed in a suitable
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aprotic solvent including but not limited to tetrahydrofuran or dimethyl sulfoxide at
temperatures ranging from room temperature to 100 °C.

[0067] Alternatively, a tosylate (33) can be converted to azide (34), on treatment with
sodium azide, and the azide reduced to amine with a suitable reducing agent such as
triphenylphosphine in tetrahydrofuran and water to give the compounds of formula Ib,
wherein R3 and R4 are hydrogen, Scheme 11.
[0068] Synthesis of the intermediate tosylate (33) is illustrated in Scheme 12.

[0069] Diene (35) is subjected to a ring closing metathesis reaction on treatment with
bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride to give 2H-chromene
derivative (36). Hvdroeenation of the double bond of the 2H-chromene derivative (36) can
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be achieved using a suitable catalyst such as platinum (IV) oxide or sulfided platinum to give
the chroman derivative (33), wherein = represents a single bond, Scheme 12. Isomerization
of the double bond can be achieved by treatment of 36 with
dichlorobis(acetonitrile)palladium (II) in refluxing methylene chloride to give the chroman
derivative (33), wherein == represents a double bond, Scheme 12.
[0070] Synthesis of the diene (35) is illustrated in Scheme 13.

[0071] Mitsunobu etherification of (25) on treatment with a substituted allylic alcohol (6),
diethyl azodicarboxylate and triphenylphosphine affords diene (35), wherein R2 is hydrogen.
Alternatively, treatment of phenol (25) with a substituted vinyloxirane (16) in the presence of
a suitable palladium catalyst, such as tetrakis(triphenylphosphine) palladium (0), will give the
diene (37) (Goujon, J-Y. et al. Journal of the Chemical Society Perkin Trans 1 2002, 496).
Treatment of the alcohol (37) with p-toluenesulfonyl chloride in the presence of a suitable
base such aspyridine or N, iV-diisopropylethylamine gives the tosylate (35), wherein R2 = C1.
3 alkyl and in is 1, Scheme 13.
[0072] Scheme 14, below, depicts an alternative method for preparing compounds of the
present invention.
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[0073] In step S-1 a compound of formula H is allowed to react via conjugate addition
with a compound of formula J, following which the Ra groups are removed to afford the
product of formula G, as depicted in Scheme 15, below. One of ordinary skill in the art will
appreciate that a wide variety of reaction conditions may be employed to promote this
transformation, therefore a wide variety of reaction conditions are envisioned; see generally,
March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith
and J. March, 5th Edition, John Wiley & Sons, 2001 and Comprehensive Organic
Transformaions, R. C. Larock, 2nd Edition, John Wiley & Sons, 1999. For example, the
conjugate addition step may be run in the presence or absence of a base, and with or without
heating. In certain embodiments, the conjugate addition is run in the presence of potassium
carbonate, potassium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide,
benzyltrimethylammonium hydroxide, triethylbenzylammonium hydroxide, 1,1,3,3-
tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine,
diisopropylethylamine, tetramethylethylenediamine, pyridine, or triethylamine. In certain
embodiments, the reaction is carried out in a suitable medium. A suitable medium is a
solvent or a solvent mixture that, in combination with the combined reacting partners and
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reagents, facilitates the progress of the reaction therebetween. The suitable solvent may
solubilize one or more of the reaction components, or, alternatively, the suitable solvent may
facilitate the suspension of one or more of the reaction components; see, generally, March
(2001). In certain embodiments the present transformation is run in excess of the phenol
reagent (corresponding to formula H), diphenyl ether, dioxane, anisole, acetone,
tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethylformamide, ethylene glycol,
toluene, water, diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine,
acetonitrile, N-methylpyrrolidine, or mixtures thereof. In other embodiments the reaction is
conducted at temperatures between around 25 °C and about 110 °C. In yet other
embodiments, the reaction is conducted at around 25 °C. hi other embodiments, the
conjugate addition is carried out according to the procedures outlined in Ruhemann, S. J.
Chem. Soc. 1900, 77,1121, Gudi, M. N. et al. Indian J. Chem. 1969, 7, 971, Cairns, H. et al.
J. Med Chem. 1972, 75, 583, Stoermer, M. J. and Fairlie, D. P. Aust. J. Chem. 1995, 48, 677,
and Fitzmaurice, C. et al. British Patent No. 1262078, (filed 24 May, 1968).

[0074] At step S-2, a compound of formula G is cyclized to afford a compound of
formula F. One of ordinary skill in the art will recognize that there are a wide variety of
reaction conditions that can. be employed to cyclize compounds of formula G, therefore, a
wide variety of conditions are envisioned; see generally, March, (2001) and Larock (1999).
In certain embodiments, the cyclization is promoted by treating a compound of fomula G
with a suitable Bransted acid. Exemplary acids include hydrochloric, sulfuric, phosphoric,
polyphosphoric, methanesulfonic, Eaton's reagent (P2O5/MeSO3H), chlorosulfonic,
camphorsulfonic, and p-toluenesulfonic. In other embodiments, additional reagents are
employed, including, for example, phosphorus pentoxide, phosphorus trichloride, phosphorus
pentachloride, acetyl chloride, or acetic anhydride. One of ordinary skill in the art will
recognize that some of the conditions described will promote formation of an intermediate
acylchloride prior to undergoing cyclization. In yet another embodiment, the reaction is
conducted with acetyl chloride or water as solvent. In still other embodiments, the
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cyclization is conducted as described in Ruhemann (1900), Gudi (1969), Cairns (1972),
Stoermer (1995), or Fitzmaurice, C. et al British Patent No. 1262078, (filed 24 May, 1968).
[0075] In step S-3, a compound of formula F is reduced to afford a compound of formula
E. One of ordinary skill in the art will recognize that compounds of formulae E, D, C, A, II,
and II'HX contain a stereogenic carbon. Accordingly, this invention encompasses each
individual enantiomer of compounds of formulae E, D, C, A, II, and II'HX as well as
mixtures thereof. While a single stereochemical isomer is depicted for formulae E, D, C, A,
II, and II»HX in Scheme 14, it will be appreciated that mixtures of enantiomers of these
formulae are accessible enriched in either enantiomer via the present invention. As used
herein, the terms "enantiomerically enriched" and "enantioenriched" denote that one
enantiomer makes up at least 75% of the preparation. In certain embodiments, the terms
denote that one enantiomer makes up at least 80% of the preparation. In other embodiments,
the terms denote that at least 90% of the preparation is one of the enantiomers. In other
embodiments, the terms denote that at least 95% of the preparation is one of the enantiomers.
In still other embodiments, the terms denote that at least 97.5% of the preparation is one of
the enantiomers. In yet another embodiment, the terms denote that the preparation consists of
a single enantiomer to the limits of detection (also referred to as "enantiopure"). As used
herein, when "enantioenriched" or "enantiomerically enriched" are used to describe a
singular noun (e.g., "an enantioenriched compound of formula II" or "an enantioenriched
chiral amine"), it should be understood that the "compound" or "acid" may be enantiopure, or
may in fact be an enantioenriched mixture of enantiomers. Similarly, when "racemic" is used
to describe a singular noun (e.g., "a racemic compound of formula E"), it should be
understood that the term is in fact describing a 1:1 mixture of enantiomers.
[0076] In one aspect of the present invention, step S-3 is carried out by (a) first subjecting
the compound of formula F to hydrogenation conditions, (b) forming diastereomeric salts by
combining the racemic mixture of the hydrogenation product with an enantioenriched chiral
amine, (c) selectively crystallizing one of the diastereomeric salts to afford a
diastereomerically enriched mixture of salts, and (d) recovering the acid in enantioenriched
form from the diastereomerically enriched salt, as depicted in Scheme 16, below. In certain
embodiments, the hydrogenation in (a) is conducted in the presence of a palladium catalyst.
In other embodiments, the palladium catalyst is palladium on carbon. In still other
embodiments, the hydrogenation is run in methanol, ethanol, or acetic acid. According to one
aspect of the present invention, the hydrogenation is run in methanol. In yet other
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embodiments, the hydrogenation is conducted in the presence of sulfuric acid, acetic acid, or
both. In some embodiments, the hydrogenation is conducted in the presence of sulfuric acid.
In still other embodiments, the hydrogenation is conducted as described in Witiak, D. T. et al.
J. Med. Chem. 1975,18, 934. In another aspect of the present invention, the enantioenriched
chiral amine is (R)-l-phenyI-propylamine. In certain embodiments, the crystallization in step
(c) is conducted in acetonitrile, methanol, ethanol, isopropanol, ethyl acetate, isopropyl
acetate, diethyl ether, tert-butyl methyl ether, benzene, toluene, dichloromethane or the like.
In certain embodiments, the free acid is liberated in step (d) by treating the salt with
hydrochloric acid or sulfuric acid. In other embodiments, step (d) is conducted in toluene,
water, or mixtures thereof. In other embodiments, the resolution step is conducted as
described in Wigerinck, P. T. B. P. et al, International patent application number WO
9929687 Al (1999); Van Lommen, G. R. E. et al, European patent application publication
number EP 145067 A2 (1985); or Schaff, T. K. et al J. Med. Chem. 1983,26, 328.

[0077] In another aspect of the present invention, step S-3 is carried out by (a) first
subjecting the compound of formula F to hydrogenation conditions, (b) resolving the racemic
reduced product by enzymatic means. In certain embodiments, the enzymatic resolution is
carried out according to Schutt, H., German patent application publication number DE
4430089 Al (1996); Urban, F. J., European patent application publication number EP
0448254 A2 (1991); and Rossi, R. F., Jr., international patent application publication number
WO 9640975 Al (1996).
[0078] In yet another aspect of the present invention, step S-3 is carried out by (a)
hydrogenating a compound of formula F in an asymmetric fashion to afford an intermediate
ketone-containing compound in enantiomerically enriched form, and (b) hydrogenating said
intermediate to reduce the keto moiety and afford a compound of formula E in
enantiomerically enriched form, as shown in Scheme 17, below. In certain embodiments, the
asymmetric hydrogenation in step (a) is catalyzed by a suitable chiral catalyst. In certain
embodiments, the chiral catalyst is a complex comprising a transition metal species and a
suitable chiral ligand. In certain embodiments, the transition metal species is a late transition
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metal species (e.g., a Ru, Rh, Pd, Ir, or Pt species). In other embodiments the transition metal
species is a rhodium or ruthenium species. In certain embodiments, the chiral ligand contains
a phosphorus moiety that is capable of binding a transition metal species (e.g., a phosphine or
phosphite moiety). In other embodiments the chiral ligand contains an olefinic moiety that is
capable of binding a transition metal species. In yet other embodiments, the chiral ligand
contains a carbene moiety that is capable of binding to a transition metal species. Suitable
chiral ligands for asymmetric hydrogenation are well known in the art; see, e.g.,
Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Silen, 1994, John Wiley and
Sons; Asymmetric Catalysis in Organic Synthesis, R. Noyori, 1994, John Wiley and Sons; X.
Cui and K. Burgess, Chem. Rev. 2005, 105, 3272; and W. Tang and X. Zhang, Chem. Rev.
2003, 103, 3029. Additional exemplary chiral ligands include, but are not limited to,
JosiPhos-type, MandyPhos™-type, WalPhos-type, TaniaPhos™-type, RoPhos-type,
DIPAMP-type, Butiphane-type, BPE-type, QUINAP-type, BINAP-type, NorPhos-type,
MonoPhos™-type, TunePhos-type, MalPhos-type, DuPhos-type, PHOX-type, KetalPhos-
type, f-KetalPhos-type, TangPhos-type, BIPHEP-type, ferrotane-type, Binaphane-type, f-
Binaphane-type, Binapine-type, FAP-type, MOP-type, DIOP-type, ChiraPhos-type, BPPM-
type, and BICP-type. The term "asymmetric hydrogenation," as used herein refers to the
hydrogenation of an achiral or chiral substrate which results in an enantiomerically enriched
chiral product. In certain embodiments the asymmetric hydrogenation is catalyzed by a chiral
transition metal-containing species. In certain embodiments, the hydrogenation in step (b) is
is conducted in the presence of a palladium catalyst. In other embodiments, the palladium
catalyst is palladium on carbon. In still other embodiments, the hydrogenation is run in
methanol. In yet other embodiments, the hydrogenation is conducted in the presence of
sulfuric acid and acetic acid.

[0079] In step S-4, a compound of formula E is amidated to afford a compound of
formula D. One of ordinary skill in the art will recognize that there are a wide variety of
reaction conditions that can be employed to amidate compounds of formula G, therefore, a
wide variety of conditions are envisioned; see generally, March (2001); Larock (1999); Benz,
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G. "Synthesis of Amides and Related Compounds." in Comprehensive Organic Synthesis,
Trost, B. M., Editor, Pergamon Press: New York, NY, Vol. 6; and Bailey, P. D. et al.
"Amides" in Comprehensive Organic Functional Group Transformation, Katritzky, et. al.
Editors, Pergamon: New York, NY, Vol. 5. In certain embodiments, the amidation is
conducted by first activating the carboxylic acid to facilitate acylation (e.g., by reaction with
SOCl2 or similar reagents), and subsequently treating the activated species with a source of
ammonia [e.g., ammonia gas or solution in tetrahydrofuran toluene, heptane, tert-butyl
methyl ether, diethyl ether, ethyl acetate, isopropyl acetate, dichloromethane, chloroform,
dichloroethan, or water (e.g., NH4OH)]. In other embodiments, this reaction is conducted by
first activating the carboxylic acid to facilitate acylation by reaction with SOCl2 and
subsequently treating the activated species with NH4OH. In still other embodiments, the
reaction is run in toluene, benzene, ethyl acetate, dichloromethane, chloroform,
dichloroethane, combinations thereof. In some embodiments, the cyclization is run in the
absence of solvent. In other embodiments, the reaction is run at a temperature between about
25 °C and 150 °C. In still other embodiments, the reaction is run at a temperature between
about 50 °C and about 100 °C. In yet other embodiments, the reaction is conducted according
to Zhang, M. et al. Tetrahedron Lett. 2004, 45, 5229 or Devant, R. International patent
application publication number WO05037817 (2005).
[0080] In step S-5, the amide moiety in compounds of formula D is reduced to an amine,
and the resulting amine is protected to afford compounds of formula C. In compounds of
formulae C and A, PG1 and PG2 are amino protecting groups. Protected amines are well
known in the art and include those described in detail in Greene (1999). Suitable mono-
protected amines further include, but are not limited to, aralkylamines, carbamates, allyl
amines, amides, and the like. Examples of suitable mono-protected amino moieties include t-
butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino,
trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc),
benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn),
fluorenylmethylcarbonyl (-NHFmoc), formamido, acetamido, chloroacetamido,
dichloroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido, t-
butyldiphenylsilyl, and the like. Suitable di-protected amines include amines that are
substituted with two substituents independently selected from those described above as
mono-protected amines, and further include cyclic imides, such as phthalimide, maleimide,
succinimide, and the like. Suitable di-protected amines also include pyrroles and the like,
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and 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine and the like. Notwithstanding the definition
above, one of either PG1 or PG2 in compounds of formulae Cand A may be hydrogen.
According to one aspect of the invention, the -N(PG')(PG2) moiety of formulae C and A, is t-
butyloxycarbonylamino (-NHBOC).
[0081] One of ordinary skill in the art will recognize that there are a wide variety of
reaction conditions that can be employed to reduce an amide, therefore, a wide variety of
conditions are envisioned; see generally, March, (2001) and Larock (1999). In certain
embodiments, the reduction step is performed by treating a compound of formula D with
Red-Al [sodium bis(2-methoxyethoxy)aluminumhydride] or lithium aluminum hydride. In
other embodiments, the reduction step is run in toluene, benzene, tetrahydrofuran, diethyl
ether, to"/-butyl methyl ether, or a mixture thereof. In certain embodiments, the reduction
step is run at a temperature between about -40 °C and about 100 °C. In other embodiments,
the reduction step is run at a temperature between about 0 °C and 40 °C. In still other
embodiments the reduction is conducted as described in Gross, J. L. Tetrahetron Lett. 2003,
44, 8563; Mayweg, A. et al, U.S. patent application publication number US 05250769
(2005); Devant, R. et al, International patent application publication number WO 05037817
(2005); Mitsuda, M. et al, International patent application publication number WO 03040382
(2003); Bokel, H. et al, International patent application publication number WO 02020507
(2002); or Bokel, H. et al.,, German patent application publication number DE 10120619
(2002).
[0082] Similarly, one of ordinary skill in the art will recognize that there are a wide
variety of methods that can be employed to protect an amine, therefore, a wide variety of
conditions are contemplated; see generally, Green (1999).
[0083] In step S-6, a CG1 group is introduced at the open ortho position relative to the
sp2-hybridized carbon bearing the chromane oxygen in formula C. The CG1 group of
formula A is a coupling group that facilitates transition metal-mediated Csp2-Csp2 coupling
between the attached Csp2 carbon and the Csp2 carbon bearing a CG2 coupling group in
compounds of formula B, as shown in step S-7. Suitable coupling reactions are well known
to one of ordinary skill in the art and typically involve one of the coupling groups being an
electron-withdrawing group (e.g., Cl, Br, I, OTf, etc.), such that the resulting polar carbon-
CG bond is susceptible to oxidative addition by an electron-rich metal (e.g., a low-valent
palladium or nickel species), and the complementary coupling group being an electropositive
group (e.g., boronic acids, boronic esters, boranes, stannanes, silyl species, zinc species,
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aluminum species, magnesium species, zirconium species, etc.), such that the carbon which
bears the electropositive coupling group is susceptible to transfer to other electropositive
species (e.g., a PdII-IV species or a NiII-IV species). Exemplary reactions and coupling groups
include those described in Metal-Catalyzed Cross-Coupling Reactions, A. de Meijere and F.
Diederich, Eds., 2nd Edition, John Wiley & Sons, 2004; and Handbook of Organopalladium
Chemistry for Organic Synthesis, Negishi, E., de Meijere, A. Editors, Wiley: New York, NY,
2002. In certain embodiments, CG1 in compounds of formula A is a boronic acid, a boronic
ester, or a borane. In other embodiments, CG1 in compounds of formula A is a boronic ester.
According to one aspect of the present invention, CG1 in compounds of formula A is a
boronic acid.
[0084] Reactions and reaction sequences that are used to promote the transformation
depicted in step S-6 include initial directed orthometallation followed by treatment with
suitable reagent to afford a compound of formula A. In certain embodiments, directed
orthometallation is succeeded with treatment with a borate ester, which is optionally
subsequently hydrolyzed to afford a boronic acid; see, e.g., Snieckus, V. Chem. Rev. 1990,
90, 879 and Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376. Another exemplary
sequence involves halogenation followed by a metallation/transmetallation sequence to afford
a compound of formula A. In certain embodiments, halogenation and transmetallation is
succeeded with treatment with a borate ester, which is optionally subsequently hydrolyzed to
afford a boronic acid; see, generally, de Meijere (2004) and Snieckus (1990). According to
one aspect of the present invention, a compound of formula C is first subjected to
orthometallation to afford an intermediate arylmetal compound that is allowed to react with a
borate ester to afford, following aqueous workup, a compound of formula A. In certain
embodiments, the orthometallation is accomplished by treating a compound of formula C
with an alkyl lithium reagent. In other embodiments the alkyllithium reagent employed is
selected from tert-butyllithium, n-butyllithium, s-butyllithium, hexyllithium, and the like. In
other embodiments the alkyllithium reagent employed is fert-butyllithium. In yet other
embodiments, the reaction is run in tetrahydrofuran, diethyl ether, dimethoxyethane, tert-
butyl methyl ether, or combinations thereof. In other embodiments, the lithiation reaction is
run in tetrahydrofuran. In still other embodiments the reaction is run at a temperature
between about 0 °C and about -90 °C. In still other embodiments the reaction is run at a
temperature between about -30 °C and about -50 °C. In cetain embodiments, the lithiation is
run in the presence of one or more of N,N,N',N'-tetramethylethylenediamine, or
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hexamethylphosphoric triamide. In other embodiments, the borate ester is triisopropylborate
[B(OiPr)3]. According to another aspect of the present invention, a compound of formula C
is first brominated, then is subjected to halogen-metal exchange to afford an intermediate
arylmetal compound that is allowed to react with a borate ester to afford, optionally following
hydrolysis (by, e.g., treatment with aqueous hydrochloric acid, aqueous sulfuric acid, or the
like) to the boronic acid, a compound of formula A.
[0085] In step S-7, a compound of formula A is coupled to a compound of formula B, via
a Csp2-Csp2 coupling reaction between the carbon centers bearing complementary coupling
groups CG1 and CG2 to provide a compound of formula II. Suitable coupling reactions and
suitable coupling groups are as described above (see the description of embodiments for CG1,
above). In certain embodiments, CG2 in compounds of formula B is Br, I, or OTf.
According to one aspect of the present invention, CG2 in compounds of formula B is Br. In
certain embodiments, the transformation is catalyzed by a palladium species. According to
one aspect of the invention, the transformation is catalyzed by palladium tetrakis
triphenylphosphine. In certain embodiments, the coupling reaction is run with
dimethylacetamide, tetrahydrofuran, dimethoxyethane, toluene, dimethylformamide, N-
methylpyrrolidine, or mixtures thereof, as solvent. In certain embodiements the coupling
reaction is run with dimethylacetamide as solvent. According to another aspect of the present
invention, the reaction is run in the presence of potassium phosphate or potassium carbonate.
In other embodiments, the reaction is heated. According to one aspect of the invention, the
reaction is heated to a temperature of about 100 °C.
[0086] One of ordinary skill in the art will appreciate that a compound of formula II, as
prepared by the methods of the present invention, may be treated with a suitable Bronsted
acid, HX, as depicted in step S-8, to form a salt thereof (represented by formula II-HX).
Exemplary acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and
phosphoric acid. According to one aspect of the present invention, a compound of formula II
is treated with HC1 to form a compound of formula II-HX wherein X is Cl. In certain
embodiments, where the acid is HC1, it is introduced into the medium containing the
compound of formula II in gaseous form. In other embodiments, the acid is introduced into
the medium containing the compound of formula II as a solution in methanol, ethanol,
isopropanol, or water. In yet other embodiments, the acid is introduced into the medium
containing the compound of formula II as a solution in isopropanol. In certain embodiments,
the medium containing the compound of formula II is isopropanol. According to one aspect
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of the present invention, the deprotection step of step S-7 and the salt formation of step S-8
are conducted in a single step by employing the acid HX in the deprotection step.
[0087] 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
generally available to one of ordinary skill in the art. Additional embodiments are
exemplified in more detail herein.
4. Uses, Formulation and Administration
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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
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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
substance abuse. Thus, another embodiment of the present invention provides a method for
treating one or more symptoms associated with a psychotic disorder.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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, sulphide, thioridazine,
thiothixene, trifluoperazine, and bifeprunox to name a few.
[0096] 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
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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.
[0097] 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.
[0098] la 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.
[0099] 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.
[00100] 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.
[00101] 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.
[00102] 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.
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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
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).
[00103] 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.
[00104] 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.
[00105] 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).
[00106] Suitable SSRIs for administering in combination with compounds of the present
invention include: citalopram (l-[3-(dimethylamino)propyl]-(4-fluorophenyl)-l,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
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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
et al., Brit, J. Clin. Pharmacol. 19:705, 1985; Laursen et al, Ada Psychiat. Scand. 71:249,
1985; Battegay et al., Neuropsychobiology 13:31, 1985, each of which is incorporated herein
by reference in its entirety); sertraline, (lS-cis)-4-(3,4-dichlorophenyl)-la2,3,4-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.
[00107] Suitable MAOIs for administering in combination with compounds of the present
invention include: isocarboxazid, phenelzine, selegiline and tranylcypromine, and
pharmaceutically acceptable salts thereof.
[00108] 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.
[00109] 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.
[00110] 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.
[00111] 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]-l-propanone), lithium, nefazodone, trazodone
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and viloxazine, and pharmaceutically acceptable salts thereof. Another suitable atypical
antidepressant is sibutramine.
[00112] Particular antidepressants for administering in combination with compounds of
the present invention include, but are not limited to, adinazolam, alaproclate, alnespirone,
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,
imipramine, 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.
[00113] 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-HT1A 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.
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[00114] 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
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.).
[00115] 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.
[00116] 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.
[00117] 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.
[00118] Selective serotonin reuptake inhibitors (SSRIs) are the current preferred method
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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.
[00119] 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.
[00120] 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, 11 -hydroxy steroid dehydrogenase-1 (11(-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.
[00121] 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-
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N-(5-phenyipyrazinyl)spiro-[isobenzofuran-l(3H),4 -piperidine]-l -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.
[00122] 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, glibencl amide, 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.
[00123] 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.
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[00124] 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
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.
[00125] 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.
[00126] 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.
[00127] 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.
[00128] 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
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antagonists, anticholinergic agents, sedatives or hypnotic agents, narcotics, alpha-adrenergic
agonists, alpha-adrenergic antagonists, or calcium channel blockers.
[00129] 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
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.
[00130] 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.
[00131] 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 HC1
(available in Urispas® 100 mg tablets from ALZA Pharmaceuticals), imipramine HC1
(available in 10 mg, 25 mg and 50 mg tablets from Geneva Pharmaceuticals, Inc.),
phenylpropanolamine, midodrine HC1 (available in 2.5 mg and 5 mg Proamatine® tablets
from Shire US Inc.), phenoxybenzamine HC1 (available as Dibenzyline® capsules from
WellSpring Pharmaceuticals Corporation), and prazosin HC1 (available in Minipress®
capsules from Pfizer Inc.). Each of these medicaments may be administered in the
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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.
[00132] 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.
[00133] 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.
[00134] 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.).
[00135] 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.
[00136] 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®,
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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.).
[00137] 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-TV, 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-FV requires that the symptoms of substance
abuse do not meet the criteria for substance dependence.
[00138] 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
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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
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.
[00139] 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).
[00140] 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."
[00141] 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.
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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:
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
[00142] 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).
[00143] 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.
[00144] 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
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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
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.
[00145] 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.
[00146] 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.
[00147] 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™).
[00148] In certain embodiments, a compound is administered in combination with one or
more agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-
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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
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.
[00149] 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.
[00150] 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
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receiving accurate information through auditory means, even though there is no problem with
hearing.
[00151] In certain embodiments, the present invention provides a method for treating one
or more impulsivity disorders (e.g. borderline personality disorder), disruptive behavior
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.
[00152] 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.
' [00153] 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 (RitalinTM), atomoxetine (Strattera™), methylphenidate, sustained release
(Concerta™) and amphetamine/dextroamphetamine (Adderall™).
[00154] 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).
[00155] 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
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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
HSDD characterized by a woman who has no or little desire to be sexual, and has no or few
sexual thoughts or fantasies.
[00156] 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.
[00157] 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, testosternone
(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.
[00158] 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
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acute pain (short duration) or chronic pain (regularly reoccurring or persistent), whether
centralized or peripheral.
[00159) 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.
[00160] 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.
[00161] 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
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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.
[00162] 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.
[00163] 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.
[00164] 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.
[00165] 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 seusitization.
[00166] 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,
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pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of a
follicular or corpus luteum cyst, irritation of the pelvic viscera, uterine fibroids, adenomyosis,
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.
[00167] 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; 2 agonists; or selective serotonin reuptake inhibitors/selective norepinepherine
uptake inhibitors, or combinations thereof.
[00168] 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.
[00169] Non-narcotic analgesics useful in the practice of the present invention include, for
example, salicylates 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-
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(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, darbufelone, flosulide, 4-(4-
cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide), meloxicam, nimesulide, 1-
Methylsulfonyl-4-(l, 1 -dimethyl-4-(4-fiuorophenyl)cyclopenta~2,4-dien-3-yl)benzene, 4-(l ,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, 1 -(7-tert-
butyl-2,3-dihydro-3,3-dimethyl-5-berizo-furanyl)4-cyclopropyl. butan-1-one, or their
physiologically acceptable salts, esters or solvates; sulindac (Clinoril®); diclofenac
(Voltarerr); 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.

WO 2006/116165 PCT/US2006/015208
CLAIMS
We claim:
1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2;
n is 0 or 1;
== designates a single or double bond;
Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more
Rx groups;
each Rx is independently halogen, -Ph, -CN, -R or -OR;
each R is independently hydrogen, C1-6 aliphatic or halo-substituted C1-6 aliphatic;
y is 0-3;
each R1 is independently -R, -CN, halogen or -OR;
R2 is hydrogen, C1-3 alkyl, or -O(C1-3 alkyl); and
each of R3 and R4 is independently hydrogen, C1-6 aliphatic or fluoro-substituted C1-6
aliphatic.
2. The compound according to claim 1, wherein said compound is of formula la:

or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein each R1 is independently -R, -
CN, halogen or -OR.
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4. The compound according to claim 3, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4, wherein Ar is thienyl, furyl, or pyridyl.
6. The compound according to claim 4, wherein Ar is unsubstituted phenyl.
7. The compound according to claim 4, wherein said compound is of formula
Illborllld:

or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 7, wherein each Rx is independently
selected from -R, -CN, halogen or -OR.
9. The compound according to claim 2, wherein:
each R1 is independently -R, -CN, halogen or -OR;
R2 is hydrogen, methyl, or methoxy;
Ar is pyridyl, pyrimidinyl, thienyl, furanyl, or phenyl optionally substituted with one or more
Rx groups;
each Rx is independently selected from -R, -CN, halogen or -OR; and
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each of R3 and R4 is independently hydrogen, methyl, ethyl, cyclopropyl, 2-fluoroethyl, or
2,2-difluoroethyl.
10. The compound according to claim 1, wherein said compound is of formula Ib:

or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 10, wherein each R1 is independently -R, -
CN, halogen or -OR.
12. The compound according to claim 11, wherein said compound is of formula
Ha or lib:

or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 12, wherein Ar is thienyl, furyl, or pyridyl.
14. The compound according to claim 13, wherein Ar is unsubstituted phenyl.
15. The compound according to claim 13, wherein said compound is of formula
IlIa or IIIc:
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or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 15, wherein each Rx is independently
selected from R, CN, halogen or OR.
17. The compound according to claim 10, wherein:
each R1 is independently -R, -CN, halogen or -OR;
R2 is hydrogen, methyl, or methoxy;
Ar is pyridyl, pyrimidinyl, thienyl, furanyl, or phenyl optionally substituted with one or more
Rx groups;
each Rx is independently selected from -R, -CN, halogen or -OR; and
each of R3 and R4 is independently hydrogen, methyl, ethyl, cyclopropyl, 2-fluoroethyl, or
2,2-diiluoroethyl.
18. The compound according to claim 1, wherein Ar is selected from:

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20. A composition comprising a compound according to any one of claims 1 to
19, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
21. The composition of claim 20, 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.
22. A method 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 impulsivity disorder, an addictive disorder, male or female sexual dysfunction,
pain, late luteal phase syndrome, 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 any one of claims 1 to 19 or a
composition comprising a compound according to any one of claims 1 to 19.
23. The method of claim 22 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
24. The method of claim 22, 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.
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25. The method of claim 22, 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.
26. The method of claim 25, 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,
super neurotransmitter uptake blockers (SNUBs), noradrenergic and specific serotonergic
antidepressants (NaSSAs), or substance P/neurokinin receptor antagonists.
27. The method of claim 22, wherein the cognitive disorder is a learning disorder.
28. The method of claim 22, wherein the patient is treated for obesity.
29. The method of claim 22, wherein the patient is treated for ADD or ADHD.
30. The method of claim 22, wherein the substance abuse substance dependence is
of a recreational substance, a pharmacologic agent, a tranquilizer, a stimulant, sedative, or
illicit drug.
31. The method of claim 22, 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.
32. A method for treating schizophrenia in a patient, comprising administering to
the patient a therapeutically effective amount of a composition according to claim 20.
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33. A method for treating obesity in a patient, comprising administering to the
patient a therapeutically effective amount of a composition according to claim 20.
34. A method for treating bipolar disorder in a patient, comprising administering
to the patient a therapeutically effective amount of a composition according to claim 20.
35. A method for treating depression in a patient, comprising administering to the
patient a therapeutically effective amount of a composition according to claim 20.
36. Use of a compound according to any one of claims 1 to 19 for preparing a
medicament fortreating 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
impulsivity disorder, an addictive disorder, male or female sexual dysfunction, pain, late
luteal phase syndrome, 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.
37. A process for the manufacture of a compound having the formula I:

or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2;
n is 0 or 1;
== designates a single or double bond;
Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more
Rx groups;
each Rx is independently halogen, -Ph, -CN, -R or -OR;
each R is independently hydrogen, C1-6 aliphatic or halo-substituted C1-6 aliphatic;
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y is 0-3;
each R1 is independently -R, -CN, halogen or -OR;
R2 is hydrogen, C1-3 alkyl, or -O(C1-3 alkyl); and
each of R3 and R4 is independently hydrogen, C1-6 aliphatic or fluoro-substituted C1-6
aliphatic; which comprises
(i) alkylation of a compound HNR3R4 with, as alkylating agent, a compound of the formula X

where Y is a leaving group and the other symbols are as defined above:
(ii) reduction of a compound Xa

where the symbols are as defined above; or
(iii) subjecting a compound having the formula Xb

Xb
where Ra is selected from R3 and a removeable monovalent protecting group whilst Rb
is a removeable monovalent protecting group or Ra and Rb together represent a divalent
protecting group and the other symbols are as defined aboveto treatment to remove the
protecting group(s); and, if desired a resultant compound having formula I is converted into a
pharmaceutically acceptable salt thereof.
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Compounds of formula I or pharmaceutically acceptable salts thereof are provided: wherein each of R1, R2, R3, R4, y, m, n, and Ar are as defined, and described in classes and subclasses herein, 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.