NEW THERAPEUTIC COMBINATIONS FOR THE TREATMENT OF
DEPRESSION
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention claims priority to United States provisional patent
application serial number 60/785,454, filed March 24, 2006, the entirety of which is hereby
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to therapeutic combinations of compounds useful for
the treatment or prophylaxis of depression, to pharmaceutical compositions containing such
combinations, and to their use in the treatment or prophylaxis of depression.
BACKGROUND OF THE INVENTION
[0003] Between 5-10% of adults worldwide suffer from depression. Even more
experience depression-related mood disorders such as dysthymia, seasonal affective disorder,
and postpartum depression, bipolar disorder, anxiety disorder, posttraumatic stress disorder,
panic disorder, and obsessive-compulsive disorder.
[0004] The economic costs to society, and person costs to individuals and families,
associated with depression are enormous. Within a 15-month period after having been
diagnosed with depression, sufferers are four times more likely to die as those who do not
have depression. Almost 60% of suicides have their roots in major depression, and 15% of
those admitted to a psychiatric hospital for depression eventually kill themselves. See
Nierenberg, Am J Manag Care 7(11 Suppl): S353-66, 2001. In the U.S. alone, the estimated
economic costs for depression exceeded $44 billion in 1990. The World Health Organization
estimates that major depression is the fourth most important cause worldwide of loss in
disability-adjusted life years, and will be the second most important cause by 2020.
[0005] A variety of pharmacologic agents are available for the treatment of depression.
Significant success has been achieved through the use of seratonin reuptake inhibitors (SRJs),
norepinephrine reuptake inhibitors (NERIs), combined serotonin-norepinephrine reuptake
inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), phosphodiesterase-4 (PDE4)
inhibitors or other compounds. However, even with these options available, many patients
fail to respond, or respond only partially to treatment. Additionally, many of these agents
show delayed onset of activity, so that patients are required to undergo treatment for weeks or

months before receiving benefits. Most currently available antidepressants take 2-3 weeks
or more to elicit a response.
[0006] Traditional therapies can also have significant side effects. For example, more
than third of patients taking SRIs experience sexual dysfunction. Other problematic side
effects include g strointestinal disturb nces, often manifested as nausea and occasional
vomiting, agitation, insomnia, weight gain, onset of diabetes, prolong tion of the heart rate
corrected interval (QTc), agranylocytosis, etc. Depressive patients who also suffer from
psychotic disorders (e.g., schizophreni ) also sometimes suffer extr pyr mid l side effects.
These side effects often discour ge patients from following their recommended ther peutic
regimen.
[0007] There remains a need for the development of improved therapies for the treatment
of depression and/or other mood disorders.
SUMMARY OF THE INVENTION
[0008] The present invention provides new combin tion therapies for the treatment of
depression. In particular, the present invention demonstrates that combinations of 5HT2C
gonist, or partial agonist, with one or more nti-depressive agents for tre ting patients
suffering from or susceptible to depression or rel ted mood disorders. The present invention
therefore provides, mong other things, cert in drug combinations, pharmaceutical
compositions cont ining such combinations, and methods of tre ting patients suffering from
or susceptible to depression or rel ted mood disorders with such combinations or
compositions.
BRIEF DESCRIPTION OF THE DRAWING
[0009] Figure 1 shows the effects of Compound 1, alone or in combin tion with
p roxetine, in the tail suspension test.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0010] The present invention encomp sses the finding that 5-HT2C receptor agonists, or
partial agonists, can be usefully combined with one or more nti-depressive agents in the
treatment or prevention of depression or other mood disorders. In particular, the present
invention provides the surprising finding that combinations of S-HT2C receptor agonists, or
partial agonists, with one or more nti-depressive agents shows incre sed effic cy, without
incre sed side effects such as sexual dysfunction, in the treatment of depression or other

mood disorders. Accordingly, on aspect of the present invention provides a composition
comprising a 5-HT2C receptor agonist, or partial agonist, and one or more anti-depressive
agents.
[0011] In cert in embodiments, the present invention provides combinations of S-HT2C
receptor agonists, or partial agonists, of formul I:

or a pharmaceutically acceptable salt thereof, wherein:
== designates asingle or double bond;
n is 1 or 2;
m is 0 or 1;
R1 and R2 are each independently halogen, -CN, -R, -OR, -C1-6 perfluoroalkyl, or -OC1-6
perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group;
R3 and R4 are taken together, with the carbon atoms to which they are bound, to form a
saturated or unsaturated 4-8 membered ring, wherein said ring is optionally substituted
with 1-3 groups independently selected from halogen, -R, or OR; and
R5 and R6 are each independently -R,
with one or more anti-depressant drugs for the treatment of depression or other mood
disorders.
[0012] In some embodiments, the inventive combinations allow treatment of refractory
depression (i.e., depression that is not responsive to traditional therapies). Alternatively or
ddition lly, the inventive combinations may be employed to treat depression with more rapid
onset of benefit, and/or with fewer side effects. In cert in embodiments, the present
combinations are useful for treating depression with a decre sed level of sexual dysfunction.
In other embodiments, the present combinations are useful for treating depression and
preventing the onset of sexual dysfunction.

1. 5-HT2C Receptor Agonists of Formul I
[0013] The present invention utilizes 5-HT2C receptor agonists, or partial agonists, of
formul I:

or a pharmaceutically acceptable salt thereof, wherein:
== designates asingle or double bond;
n is 1 or 2;
m is O or 1;
R1 and R2 are each independently halogen, -CN, -R, -OR, -C1-6 perfluoroalkyl, or -OC1-6
perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group;
R3 and R4 are taken together, withathe carbon atoms to which they are bound, to form
saturated or unsaturated 4-8 membered ring, wherein said ring is optionally substituted
with 1 -3 groups independently selected from halogen, -R, or OR; and
R5 and R6 are each independently -R,
in combin tion with one or more anti-depressant drugs for the treatment of depression or
other mood disorders.
[0014] As used herein, 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 terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine
or iodine.
[0016] The term "perfluoroalkyl," as used herein refers to an alkyl group, as defined
herein, wherein every hydrogen atom on said alkyl group is repl ced by a fluorine atom. Such
perfluoroalkyl groups include -CF3.
[0017] The terms "effective amount" and "therapeutically effective amount," as used
herein, refer to the amount of a compound or combin tion that, when dministered to an
individual, is effective to treat, prevent, delay, or reduce the severity of a condition from

which the patient is suffering. In particular, a therapeutically effective amount in accordance
with the present invention is an amount sufficient to treat, prevent, delay onset of, or
otherwise meliorate at least one symptom of a depressive.
[0018] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable
salt" refers to salts derived from treating a compound of formula I with an organic or
inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric,
maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric,
nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,
benzoic, or similarly known acceptable acids. In certain embodiments, the present invention
provides the hydrochloride salt of a compound of formula I.
[0019] The term "patient," as used herein, refers to a mammal. In certain embodiments,
the term "patient" refers to a human.
[0020] The terms " dminister," " dministering," or " dministr tion," as used herein, refer
to either directly dministering a compound or composition to a patient, or dministering
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.
[0021] The compounds of formula I, as defined bove or in classes and subclasses as
described herein, have affinity for and agonist or partial agonist activity at the 2C subtype of
brain serotonin receptors.
2. Description of Exemplary Compounds:
[0022] In certain embodiments, == designates asingle bond. In other embodiments,
== designates a double bond.
[0023] In certain embodiments, the R1 group of formula I is R, OR, halogen, cyano, or -
C1-3 perfluoroalkyl. In other embodiments, the R1 group of formula I is hydrogen, halogen,
cyano, -OR wherein R is C1-3 alkyl, or trifluoromethyl. According to another embodiment,
the R1 group of formula I is hydrogen.
[0024] In certain embodiments, the R2 group of formula I is R, OR, halogen, cyano, or -
C1-3 perfluoroalkyl. In other embodiments, the R2 group of formula I is hydrogen, halogen,
cyano, -OR wherein R is hydrogen, C1-3 alkyl, or trifluoromethyl. According to another
embodiment, the R2 group of formula I is hydrogen.
[0025] According to one aspect of the present invention, at least one of R1 and R2 groups
of formula I is -OH. According to another aspect of the present invention, both of the R"halod
R2 groups of formula I are -OH.

[0026] According to another embodiment, each of the R1 and R2 groups of formula I is
hydrogen. According to yet another embodiment, each of the R5 and R6 groups of formula I
is hydrogen.
[0027] As defined generally above, the R3 and R4 groups of formula I are taken together
to form asaturated or unsaturated 4-8 membered ring, wherein said ring is optionally
substituted with 1-3 groups independently selected from halogen, -R, or OR. According to
one embodiment, the R3 and R4 groups of formula I are taken together to form asaturated or
unsaturated 5-8 membered ring, wherein said ring is optionally substituted with 1-3 groups
independently selected from halogen, -R, or OR. In certain embodiments, the R3 and R4
groups of formula I are taken together to form asaturated or unsaturated 5-6 membered ring,
wherein said ring is optionally substituted with 1-3 groups independently selected from
halogen, -R, or OR. The 4-8 membered (preferably 5-8 membered, more preferably 5-6
membered) ring is preferably a c rbocyclic ring. The 4-8 membered (preferably 5-8
membered, more preferably 5-6 membered) ring is preferably saturated. However if the 4-8
membered (preferably 5-8 membered, more preferably 5-6 membered) ring is unsaturated, the
uns turation may be olefinic or aromatic.
[0028] As defined generally above, n is 1 or 2. Accordingly, the present invention
provides a compound of formulae I- and I-b:

or a pharmaceutically acceptable salt thereof, wherein each of m, R1, R2, R3, R4, R5, and R6 is
as defined above for compounds of formula I and described in classes and subclasses above and herein.
[0029] As defined generally above, m is 0 or 1. Accordingly, the present invention
provides a compound of formulae I-c and I-d:

or a pharmaceutically acceptable salt thereof, wherein each of n, R1, R2, R3, R4, R3, and R6 is
as defined above for compounds of formula I and described in classes and subclasses above
and herein.
[0030] In other embodiments, n is 1, m is 1, and the R3 and R4 groups of formula I are
taken together to form asaturated 5-membered ring and said compound is of formula II:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, and R6 is as defined
above for compounds of formula I and described in classes and subclasses above and herein.
[0031] According to another aspect of the present invention, a compound is provided,
wherein n is 1, m is 0, and the R3 and R4 groups of formula I are taken together to form a
saturated 5-membered ring and said compound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5,
and R6 is as defined above for compounds of formula I and described in classes and subclasses above and herein.

[0032] Compounds of the present invention contain asymmetric carbon atoms and thus
give rise to stereoisomers, including enantiomers and diastercomers. Accordingly, it is
contemplated that the present invention relates to all of these stereoisomers, as well as to
mixtures of the stereoisomers. Throughout this pplic tion, the n me of the product of this
invention, where the bsolute configur tion of an asymmetric center is not indicated, is
intended to embrace the individual stereoisomers as well as mixtures of stereoisomers.
[0033] According to another aspect, the present invention provides a compound of either
of formulae I-e or I-f:

or a pharmaceutically acceptable salt thereof, wherein each of n, m, R1, R2, R3, R4, R5, and R6
is as defined above for compounds of formula I and described in classes and subclasses above
and herein.
[0034] In certain embodiments, the present invention provides a compound of either of
formulae IV or V:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R5, and R6 are as defined
above for compounds of formula I and in classes and subclasses as described above and
herein.
[0035] Where an enantiomer is preferred, it may, in some embodiments be provided
substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of
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 m de up of a significantly greater proportion of
one enantiomer. In certain embodiments the compound is m de up of at aleast about 90% by
weight of a preferred enantiomer. In other embodiments of the invention, the compound is
m de up of at aleast 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 form tion and
crystallization of chiral salts or prepared by methods described herein. See, for example,
Jacques, et al., En ntiomers, Racemates and Resolutions (Wiley Interscience, New York,
1981); Wilen, S.H., et al., Tetr hedron 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 (EX. Eliel, Ed., Univ. of Notre D me Press, Notre D me, IN 1972).
[0036] Exemplary compounds useful for the methods of the present invention are set
forth in Table 1, below.
Table 1. Exemplary Compounds of Formula I
2-bromo-4,5,6,7,9,9, 10,11,12,12 -decahydrocyclopent [e][1,4]diazepino [6,7,1 -ij]quinoline;
2-bromo-4,5,6,7,9,9 , 10,11,12,13,14,14 -dodecahydrocyclohepta[c] [1,4 ]diazepino[6,7,1-
ij]quinoline;
2-chloro-4,5,6,7,9,9, 10,11,12,1 2 -decahydrocyclopent [c][ 1,4]diazepino [6,7,1-ij]quinoline;
2-chloro-4,5,6,7,9,9 , 10,11,12,13,14,14 -dodecahydrocyclohepta[c] [1,4] diazepino[6,7,1-
ij]quinoline;
2-phenyl-4,5,6,7,9,9,10,11,12,12 -decahydrocyclopent [c][1,4]diazepino [6,7,1-ij]quinoline;
2-methoxy-4,5,6,7,9,9,10,11,12,12 -decahydrocyclopent [c][1,4]diazepino [6,7,1-
ij]quinoline;
1-fluoro-4,5,6,7,9,9, 10,11,12,12-decahydrocyclopent [c][ 1,4]diazepino [6,7,1-ij]quinoline;
1-fluoro-4,5,6,7,9,9, 10,11,12,13,14,14 -dodecahydrocyclohepta[c][1,4]diazepino[6,7,1 -
ij]quinoline;
1-(trifluoromethyl)-4,5,6,7,9,9,10,11,12,12 -decahydrocyclopent [c][1,4] diazepino[6,7,1 -
ij]quinoline;
1 -fluoro-2-methoxy-4,5,6,7,9,9 ,10,11,12,12 -decahydrocyclopent [c] [1,4] diazepino[6,7,1 -
ij]quinoline;
1-fluoro-2-methoxy-4,5,6,7,9,9 ,10,11,12,13,14,14 -dodecahydrocyclo-
hepta[c][1,4]diazepino[6,7,1-ij]quinoline;
4,5,6,7,9,9a,10,11,12,12 -decahydrocyclopent [c][1,4]diazepino[6,7,1 -ij] quinoline;

4,5,6,7,9,9 , 10,11,12,13,14,14 -dodecahydrocyclohepta[c] [ 1,4]diazepino [6,7,1 -ij]quinoline;
(-)-4,5,6,7,9,9 10,11,12,12 -decahydrocyclopent [c][1,4]diazepino[6,7,1 -ij] quinoline;
(9 R, 14 S)-4,5,6,7,9,9 , 10,11,12,13,14,14 -dodecahydrocyclohepta[c][ 1,4] diazepino[6,7,1 -
ij]quinoline;
(9S,14 R)-4,5,6,7,9,9 ,10,11,12,13,14,14 -dodecahydrocyclohepta[c][1,4]diazepino[6,7,1-
ij]quinoline;
4,5,6,7,9,10,11,12,13,13 -decahydro-9H-[1,4]diazepino[6,7,1-de]phen nthridine;
1,2,3,4,8,9,10,10 -hexahydro-8H-cyclopent [b][1,4]diazepino[6,7,-hi]indole;
1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent[b][1,4]diazepino[6,7,1 -hi]indole;
(7bS, 10aS)-1,2,3,4,8,9,10,10-octahydro-7bH-cyclopent [b][ 1,4]diazepino[6,7,1 -hi]indole;
(7bR, 10aR)-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent -[b] 11,4]diazepino[6,7,1 - hi]indole;
(7bR, 10aR) 1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent -[b][ 1,4]diazepino[6, 7,1 -hi]indole;
6-methyl-1,2,3,4,9,10-hexahydro-8H-cyclopent [b][1,4]diazepino[6,7,1-hi]indole;
2S)-(rel-7bR, 10aR)-2-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b]
[1,4]diazepino[6,7,1-hi]indole;
(2S)-(rel-7bR, 10aR)-2-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b]
[1,4]diazepino[6,7,1 -hi]indole;
(2S)-(rel-7bS,10aS)-2-methy]-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b]
[1,4]diazepinol6,7,1-hi]indole;
(2R)-(rel-7bR, 10aR)-2-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b]
[1,4]diazepino[6,7,1 -hi]indole;
(2R)(rel-7bR,10aR)-2-methyl-l,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b
][1,4]diazepino [6,7,1-hi]indole;
(2R)-(rel-7bS, 10aS)-2-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b]
[1,4]diazepino[6,7,1 -hi]indole;
rel-(4S,7bS,10aS)-4-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-
cyclopent [b][1,4]diazepino[6,7,1-hi]indole
rel-(4S,7bS,10aS)-4-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b]-
[ 1,4]diazepino[6,7,1 -hi] indole;
rel-(4R,7bS, 10aS)-4-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-
cyclopent [b] [1,4]diazepino[6,7,1 -hi] indole;
9-methyl-l,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b][1,4]diazepino[6,7,1-hi]indole;
(7bR,9R, 10aR)-9-methyl-1,2,3,4,8,9,10,10 -octahydro-7bH-cyclopent [b][1,4]d
iazepino[6,7,1 -hi]indole;

9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [1,4]diazepino[6,7,1-hi]indole;
(7bR.10aR)-9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent[b][1,4]
diazepino(6,7,l-hi]indole; and
(7bS,10aS)-9,9-dimethyl-l,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b] [1,4]
diazepino[6,7,1 -hi]indole;
or a pharmaceutically acceptable salt thereof. Another aspect of the present invention
provides the hydrochloride salt of each of the above compounds.
[0037] Also, it will be appreciated by those of ordinary skill in the art that reference to a
compound herein is intended to include reference to any and all related forms such as
polymorphs, hydrates, etc. Also, compounds may be provided as pro-drugs or other forms
converted into the active agent during manufacture, processing, formulation, delivery, or in
the body.
[0038] It will additionally be appreciated that the principles of the present invention apply
all radiolabeled forms of the compounds recited herein, including, for example, those where
the radiolabels are selected from as 3H, 11C, 14C, 18F, 123I and 125I. Such radiolabeled
compounds are useful as research and diagnostic tools in metabolism pharmacokinetics
studies and in binding assays in both animals and humans.
[0039] Compounds of formula I for use in accordance with the present invention may be
obtained or produced according to any available means including methods described in detail
in US patent No. 7,129,237 (United States patent application serial number 10/422,524, filed
April 24, 2003), and in WO2006/052768 (claiming priority to United States provisional
patent application serial number 60/625,300, filed November 5, 2004), the entirety of each of
which is hereby incorporated herein by reference.
2. Aantidepressant Agents
[0040] In certain embodiments, compounds of the present invention are administered in
combination with one or more andtidepressive agents. Suitable antidepressant agents include,
for example, serotonin reuptake inhibitors (SRIs), norepinephrine reuptake inhibitors (NRIs),
combined serotonin- norepinephrine reuptake inhibitors (SNRIs), mono mine oxidase
inhibitors (MAOIs), reversible inhibitors of mono mine oxidase (RIMAs),
phosphodiesterase-4 (PDE4) inhibitors, corticotropin rele sing factor (CRF) antagonists,
alpha.-adrenoreceptor antagonists or other compounds including atypical antidepressants.
Additional antidepressants for dministering in combination with compounds of the present
invention include triple uptake inhibitors such as DOV 216303 and DOV 21947; melatonin

agonists such as agomelotinc, 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).
[0041] Another class of antidepressant agents for dministering in combination with
compounds of the present invention are noradrenergic and specific serotonergic
antidepressants (NaSSAs). A suitable example of a NaSSA is mirtazepine.
[0042] Suitable NRIs that may be used in the present invention include tertiary mine
tricyclics and secondary mine tricyclics. Suitable examples of tertiary mine tricyclics
include: mitriptyline, 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 mine tricyclics
include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and
pharmaceutically acceptable salts thereof.
[0043] Another NRI that may be used in 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);.
[0044] Suitable SSRIs for dministering in combination with compounds of the present
invention include: cit lopr m (1-[3-(dimethyl mino)propyl]-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofur ncarbonitrile; See United States Patent 4,136,193; Christensen et al., Eur. J.
Pharm col. 41:153, 1977; Dufour et al., Int. Clin. Psychopharm col. 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-phenylpropyl mine, 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;
fluvox mine (5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentaxione O-(2-aminoethyl)oxime;
See United States Patent 4,085,225; Claassen et al., Brit. J. Pharm col. 60:505, 1977; De
Wilde et al., J. Affective Disord. 4.249, 1982; Benfield et al., Drugs 32:313, 1986, each of
which is incorporated herein by reference in its entirety); paroxetine (trans-(-)-3-[(1,3-
benzodioxol-5-yloxy)methyl]-4-(4-fluo- rophenyl)piperidine; See United States Patent
3,912,743; United States Patent 4,007,196; L ssen, Eur. J. Pharm col. 47:351, 1978; Hassan
et al., Brit. J. Clin. Pharm col. 19:705, 1985; Laursen et al., Act Psychiat. Scand. 71:249,

1985; Battegay et at., Neuropsychobiology 13:31, 198S, each of which is incorporated herein
by reference in its entirety); sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-
methyl-1-naphthylamine hydrochloride; See United States Patent 4,536,518, incorporated
herein by reference in its entirety); escitalopram (see United States Patent RE34,712); and
pharmaceutically acceptable salts thereof.
[0045] Suitable MAOIs that may be used in the present invention include: isocarboxazid,
phenelzine, selegiline and tranylcypromine, and pharmaceutically acceptable salts thereof.
[0046] Suitable reversible MAOIs that may be used in 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.
[0047] Suitable SNRIs that may be used in 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-1-phenylcyclopropanecarboxamide; see United States Patent 4,478,836; Moret
et al., Neuropharm cology 24:1211-19, 1985, each of which is incorporated herein by
reference in its entirety); mirtazapine (see, for example, United States Patent 5,178,878, the
entire contents of which are incorporated herein by reference); nefazodone (available from
Bristol Myers Squibb and Dr. Reddy Labs Inc.); duloxetine; and pharmaceutically acceptable
salts thereof.
[0048] Suitable CRF antagonists that may be used in 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.
[0049] Suitable atypical antidepressants for administering in combination with
compounds of the present invention include: bupropion (Wellbutrin™; (.+-.)-1-(3-
chlorophenyl)-2-[(1,1-dim- ethylethyl) mino]-1-prop none), lithium, nefazodone, trazodone
and vilox zine, and pharmaceutically acceptable salts thereof. Another suitable atypical
antidepressant is sibutramine.
[0050] Particular antidepressants that may be used in 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, droxidop , duloxetine, elzasonan,
enefexine, eptapirone, escitalopram, estazolam, etoperidone, fermoxetine, 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, nefozodtne, nemititide, nialamide,
nomifensine, norfluoxetine, nortriptyline, orotirelin, oxaflozane, paroxetine, phenelzine,
pinazepam, pirlindone, pizotyline, protryptiline, reboxetine, ritanserin, robalzotan, rolipram,
selegiline, sercloremine, sertraline, setiptiline, sibutrarnine, sulbutiamine, sulpiride,
sunepitron, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin,
tofisopam, toloxatone, tomoxetine, tranylcypromine, trazodone, trimiprimine, venlafaxine,
veralipride, vilazodone, viloxazine, viqualine, zimelidine and zometr pine, and
pharmaceutically acceptable salts thereof, and St. John's wort herb, or Hypencuin perforatum,
or extracts thereof.
[0051] 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-HT1A
receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically
acceptable salts thereof. An example of a compound with 5-HT1A receptor ant gonist/partial
agonist activity is pindolol, new 5HT1A agonists variza, alnespirone, gepirone, sunepitron,
MKC242, vilazodone, eptapirone, and ORG12962 from Organon; new 5HTlA antagonists
such as robalzotan; new 5-HT1B agonists such as elzasonan; new 5HT2 antagonists such as
YM-992 (from Yamanouchi Pharmaceuticals) and nemifitide.
[0052] Aantidepressant agents for use in accordance with the present invention may be
obtained or produced according to any available means.
3. Other Agents
[0053] Inventive combinations may further include one or more additional
pharmaceutically active agents. For example, 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 enh nce 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., benzodi zepines),and/or agents
that relieve sexual dysfunction (e.g., buspirone, which also has anti-anxiety effects;
dop minergic agents such as amantadine, pramipexole, bupropion, etc.).
[0054] A more complete list of pharmaceutically active agents, can be found in the
Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics Co., Inc.,
Montvale, NJ. E ch of these agents may be administered in conjunction with one or more
compounds of formula I according to the present invention. For most or all of these agents,
recommended effective dosages and regimes are known in the art; many can be found in the
above-referenced Physicians' Desk Reference, 55 Edition, 2001, published by Medical
Economics Co., Inc., Montvale, NJ.
[0055] Particular pharmaceutical agents useful in conjunction with the inventive
combinations are those discussed, for example, in United States Patent Application
2003/0092770, United States Patent Application 2004/0029972, United States Patent
Application 2004/00220274, United States Patent Application 2005/0054676, or United
States Patent Application 2005/0069936, each of which is incorporated herein by reference in
its entirety.
4. Pharmaceutical Compositions
[0056] While it is possible for the active ingredients of the inventive combination to be
administered as raw chemicals, it is often desir ble to present them in the context of one or
more pharmaceutical formulations. Pharmaceutical formulations according to the present
invention comprise a combination according to the invention togetherawith one or more
pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.

[0057] The present invention thus provides a pharmaceutical composition comprising one
or more 5-HT2C receptor agonists, or partial agonists, of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
== designates asingle or double bond;
n is 1 or 2;
m is 0 or 1;
R1 and R2 are each independently halogen, -CN, -R, -OR, -C1-6 perfluoroalkyl, or -OC1-6
perfluoro lky];
each R is independently hydrogen or a C1-6 alkyl group;
R3 and R4 are taken together, with the carbon atoms to which they are bound, to form a
saturated or unsaturated 4-8 membered ring, wherein said ring is optionally substituted
with 1-3 groups independently selected from halogen, -R, or OR; and
R5 and R6 are each independently -R;
and one or more antidepressant agents as a combined preparation for simult neous, separate
or sequential administration to treat a patient suffering from or susceptible to depression or
other mood disorder.
[0058] Agents used in inventive combinations or compositions may be administered
simult neously, in the some or different pharmaceutical formulation, or sequentially. The
timing of the sequential administration may desirably be selected to preserve the
advantageous effects of the combination and said timing can be determined by a skilled
practitioner.
[0059] A therapeutically effective amount of the combination will be understood to be an
amount which treats, inhibits, prevents or meliorates one or more symptoms of the
depression or mood disorder in question. In certain embodiments of the invention, the
combination will show improved efficacy as compared with that chieved by administration
of the some amount of either the compound of formula I or the antidepressant agent alone.
Furthermore, in certain embodiments, the effective amount of the combination produces

fewer side effects than are observed when the antidepressant agent is administered alone at
dose that chieves substantially similar therapeutic efficacy.
[0060] The dosages of each of the drugs in the inventive combination may be determined
by a physician and will often depend upon the specific circumstances of the depression or
mood disorder, as well as the size, age and response pattern of the patient. Dosage guidelines
are provided here. For the combination, the dosage guideline for each of the drugs of the
combination would be considered.
[0061] In general, suitable doses of compound of formula I from about 0.5 mg per day to
about 500 mg per day; in some embodiments from about 1 to about 500 mg per day.
[0062] A suitable dose of antidepressant agent may be in the range recommended by the
manufacturer or reported in the liter ture. In some embodiments of the invention, the
antidepressant agent is used at the low end of the range recommended by the manufacturer, or
even below the range, in light of synergistic benefits that can be chieved according to the
present invention. The following guidelines are provided for certain antidepressants useful in
the practice of the present invention:
Amitryptiline: typically about 100-300 mg/day maintenance dose;
Buproprion: from about 100 to about 300 mg/day;
Citalopram: from about 5 to about 50 mg once/day; preferred, from about 10 to
about 30 mg once/day;
Clomipramine: typically about 100-250 mg/day maintenance dose;
Duloxetine: from about 1 to about 30 mg once/day; preferred, from about 5 to
about 20 mg once/day;
Fluoxetine: from about 1 to about 80 mg, once/day; preferred, from about 10 to
about 40 mg once/day;
Fluvoxamine: from about 20 to about 500 mg once/day; preferred, from about 50
to about 300 mg once/day;
Tmipr mine: typically about 100-300 mg/day maintenance dose;
Isocarboxazid: typically about 10-20 mg/day maintenance dose;
Maprotiline: typically about 100-200 mg/day maintenance dose;
Mi nserin: typically about 30-90 mg/day maintenance dose;
Milnacipran: from about 10 to about 100 mg once-twice/day; preferred, from
about 25 to about 50 mg twice/day;
Mirtazapine: typically about 14-45 mg/day maintenance dose;
Moclobemide: typically about 300-600 mg/day maintenance dose;

Nefazodone: typically about 150-300 mg/day maintenance dose;
Nortriptyline: typically about 50-200 mg/day maintenance dose;
Paroxetine: from about 20 to about 50 mg once/day; preferred, from about 20 to
about 30 mg once/day;
Phenelzine: typically about 15-60 mg/day maintenance dose;
Reboxetine: from about 1 to about 30 mg, once to four times/day; preferred, from
about 5 to about 30 mg once/day;
Sertraline: from about 20 to about 500 mg once/day; preferred, from about 50 to
about 200 mg once/day;
Tranylcypromine: typically about 30-60 mg/day maintenance dose;
Trazodone: typically about 75-300 mg/day maintenance dose;
Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred, from
about 25 to about 125 mg thrice/day or about 30 to about 200 mg once a day, for example
37.5 mg, 75 mg, or 150 mg once a day;
[0063] Useful carriers for use in inventive pharmaceutical formulations are compatible
with the other ingredients in the composition. According to the present invention,
compounds of formula I may be administered with antidepressant agents in asingle
pharmaceutical formulation, or in multiple formulations. Where multiple formulations are
employed, each may include bothathe compound of formul 1 and the antidepressant agent, or
alternatively, each may include only one.
[0064] An inventive combination of one or more compounds of formula I and one or
more antidepressant agents may conveniently be presented as a pharmaceutical formulation in
a unitary dosage form. A convenient unitary dosage formulation contains the active
ingredients in amounts from 0.1 mg to 1 g each, for example 1 mg to 500 mg. Typic l unit
doses may, for example, contain about 0.5 to about 500 mg, or about 1 mg to about 500 mg,
of a compound of formula I.
[0065] According to the present invention, pharmaceutical formulations may be prepared
as "patient packs" containing the whole course of treatment in asingle package, for example a
blister pack. Patient packs have an advantage over traditional prescriptions, where a
pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the
patient always has access to the package insert contained in the patient pack, normally
missing in traditional prescriptions. The inclusion of a package insert has been shown to
improve patient compliance with the physician's instructions.

[0066] It will be understood that the administration of the inventive combination by
means of asingle patient pack, or patient packs of each formulation, with a package insert
directing the patient to the correct use of the invention is a desirable additional feature of this
invention.
[0067] According to a further aspect of the invention, there is provided a patient pack
comprising at aleast one active ingredient of the combination of the invention and an
information insert containing directions on the use of the combination of the invention.
[0068] According to the present invention, combinations of one or more compounds of
formula I and one or more antidepressant agents may be formulated for any mode of delivery
including, for example, oral, rectal, nasal, topical (including transdermal, buccal and
sublingual), vaginal or parenter l (including subcutaneous, intramuscular, intravenous and
intradermal) administration. The formulations may be prepared by any methods well known
in the art of pharmacy, for example, using methods such as those described in Gennaro et al.,
Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see
especially Part 8: Pharmaceutical Preparations and their Manufacture). Such methods
typically include a step of bringing into association the active ingredient(s) with the carrier
which constitutes one or more accessory ingredients. Such accessory ingredients include, for
example, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents and
wetting agents.
[0069] Formul tions suitable for oral administration may be presented, for example, as
discrete units such as pills, tablets or capsules each containing a predetermined amount of
active ingredient; as a powder or granules; as asolution or suspension. The active
ingredient(s) may also be present as a bolus or paste, or may be contained within liposomes.
[0070] For oral administration, tablets containing various excipients such as
microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and
glycine may be employed along with various disintegrants such as starch (and preferably corn,
potato or tapioca starch), alginic acid and certain complex silicates, together with granulation
binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents
such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting
purposes. Solid compositions of a similar type may also be employed as fillers in gelatin
capsules; preferred materials in this connection also include lactose or milk sugar as well as
high molecul raweight polyethylene glycols.
[0071] Formul tions suitable for oral administration may alternatively be presented, for
example, as liquids. When aqueous suspensionsand/or elixirs are desired for oral

administration, the active ingredient(s) may be combined with various sweetening or
flavoring agents, coloring matter or dyes,"halod, if so desired, emulsifyingand/or suspending
agents as well, together a with a such diluents as water, ethanol, propylene glycol, glycerin and
various like combinations thereof. Liquid formulations may be particularly useful for
administration to children. In general, when preparing liquid formulations for administration
to children, it is desirable to void or minimize use of alcohol in the formulation.
[0072] Formulations for rectal administration may be presented, for example, as a
suppository or enema.
[0073] For parenter l administration, solutions ofatherapeutic agent(s) in either sesame or
peanut oil or in aqueous propylene glycol may be employed. Aqueous solutions may be
suitably buffered if necessary, and the liquid diluent may be rendered isotonic. Aqueous
solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intrarticular,
intramuscular and subcutaneous injection purposes. The preparation of all these
solutions under sterile conditions is readily accomplished by standard pharmaceutical
techniques well known to those skilled in the art. Parenter l formulations may be presented
in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be
stored in a freeze dried (lyophilized) condition requiring only the addition ofathe sterile liquid
carrier, for example, water prior to use.
[0074] Preferred compositions for administration of inventive combinations by injection
include those comprising the therapeutic agent(s) in association with a surface-active agent
(or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water
emulsion). Suitable surface-active agents include, in particular, non-ionic agents, such as
polyoxyethylenesorbitans (e.g., Tween.TM. 20, 40, 60, 80 or 85) and other sorbitans (e.g.,
Span.TM. 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently
comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It
will be appreciated that other ingredients may be added, for example mannitol or other
pharmaceutically acceptable vehicles, if necessary.
[0075] Suitable emulsions may be prepared using commercially available fat emulsions,
such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The
therapeutic agent(s) may be either dissolved in a pre-mixed emulsion composition or
alternatively may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil,
sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid
(e.g., eggs phospholipids, soybean phospholipids or soybean lecithin) and water. It will be
appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the

tonicity ofathe emulsion. Suitable emulsions will typically contain up to 20% oil, for example,
between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and
1.0 .mu.m, particularly 0.1 and 0.5 .mu.m, and have a pH in the range of 5.5 to 8.0.
[0076] Compositions for inhalation or insufflation include solutions and suspensions in
pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof, and powders.
The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients
as set out above. Preferably the compositions are administered by the oral or nasal respiratory
route foralocal or systemic effect. Compositions in preferably sterile pharmaceutically
acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be
breathed directly from the nebulising device or the nebulising devise may be attached to a
face mask, tent or intermittent positive pressure breathing machine. Solution, suspension, or
powder compositions may be administered, preferably orally or nasally, from devices which
deliver the formulation in an appropriate manner.
[0077] Compositions ofathe present invention may also be presented for administration in
the form of transdermal patches using conventional technology. The compositions may also
be administered via the buccal cavity using, for example, absorption wafers.
5. Uses
[0078] Administr tion ofathe inventive combinations is useful to treat, prevent, delay, or
reduce the severity of depression or another mood disorder from which the individual suffers
or to which the individual is susceptible, or from one or more symptoms of depression or
other mood disorder. For example, according to the present invention, combinations of one
or more compounds of formula I and one or more antidepressive are useful in the treatment of
disorders, for example, single episodic or recurrent major depressive disorders, dysthymic
disorders, depressive neurosis, and neurotic depression; melancholic depression including
anorexia, weight loss, insomni and early morning waking, and psychomotor retardation;
atypical depression (or reactive depression) including increased appetite, hypersomnia,
psychomotor agitation or irritability, anxiety and phobias, seasonal affective disorder, or
bipolar disorders or manic depression, for example, bipolar 1 disorder, bipolar II disorder and
cyclothymic disorder. In some embodiments, inventive combinations are used to treat
depression. In some embodiments, inventive combinations are used to treat bipolar disorder.
[0079] In other embodiments, compounds of the present invention are useful for treating
one or more depressive disorders such as major depressive disorder, seasonal affective

disorder, dysthymic disorder, substance-induced mood disorder, depressive disorder not
otherwise specified, and treatment resistant depression.
[0080] 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.
[0081] Combinations 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 person l
care, such as poor adherence to medical or dietary regimens.
[0082] 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.
[0083] Combinations of the present invention are useful for treating sexual dysfunction in
the male (e.g. male erectile dysfunction - MED) and in the female - female sexual dysfunction
(FSD), e.g. female sexual arousal disorder (FSAD).
[0084] In other embodiments, the present invention provides a method for treating one or
more disorders associated with sexual dysfunction including: HSDD, characterized by a
deficiency, or absence of, sexual fantasies and desire for sexual activity; FSAD, characterized
by a persistent or recurrent inability to attain, or to maintain until completion of the sexual
activity, an adequate lubrication-swelling response of sexual excitement; FOD characterized
by persistent or recurrent delay in, or absence of, orgasm following a normal sexual
excitement phase; Sexu l 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 fewasexual
thoughts or fantasies.
[0085] It was surprisingly found that compounds of the present invention provide a rapid
onset of action as compared with other therapeutic agents typically used for treating
depression and depressive disorders.
[0086] Alternatively or additionally, inventive combinations may be useful in the
treatment of other mood disorders such as dysthymic disorder with early or late onset and
with or without atypical features; dementia of the Alzheimer's type, with early oralate onset,

with depressed mood; vascular dementi with depressed mood, disorders induced by alcohol,
amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives,
hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type;
and adjustment disorder with depressed mood.
[0087] The term "treatment," as used herein, refers to reversing, alleviating, delaying the
onset of, inhibiting the progress of, or preventing depression or another mood disorder, or one
or more symptoms thereof, as described herein. In some embodiments, treatment may be
applied after one or more symptoms have developed. In other embodiments, treatment may
be administered in the absence of symptoms. For example, treatment may be administered
prior to symptoms (e.g., in light of a history of symptoms and/or one or more other
susceptibility factors), or after symptoms have resolved, for example to prevent or delay their
reoccurrence.
[0088] Individuals to be treated in accordance with the present invention include those
suffering from depression or a mood disorder, and those susceptible to depression or a mood
disorder. In general, a patient is considered to be suffering from depression or a mood
disorder if that patient shows an appropriate collection of accepted symptoms. A patient is
considered to be susceptible to depression or a mood disorder if, for example, that patient has
a familial history of depression or of the mood disorder, or carries a known genetic
susceptibility trait. A patient may also be considered to be susceptible if the patient has
shown one or more symptoms of depression, or of the mood disorder, or has experienced an
episode of depression or of the mood disorder, in the past.
[0089] In some embodiments the inventive combinations are useful for treatment-
resistant depression. In other embodiments, the inventive combinations, when administered
to treat depression or other mood disorders, show fewer undesirable side effects than are
observed upon administration of the antidepressant alone in an amount that achieves
comparabale relief of depression. Alternatively or additionally, the inventive combinations
show more rapid onset of activity than do the antidepressants alone.
[0090] Those of ordinary skill in the art will also appreciate that, particularly given the
high comorbidity of depression and psychotic disorders, inventive combinations may also be
used to treat one or more psychotic disorders, or symptoms thereof. For example, in some
embodiments, inventive combinations may be used in the treatment of psychotic disorders or
episodes. For example, according to the present invention, combinations of one or more
compounds of formula I and one or more anti-psychotic agents may be used in the treatment
of schizophreni including paranoid type, disorganized type, catatonic type, and

undifferenti ted type, schizophreniform disorder, schizo affective disorder, delusional
disorder, substance-induced psychotic disorder, and psychotic disorder not otherwise
specified; L-DOPA-induced psychosis; psychosis associated with Alzheimer's dementia;
psychosis associated with Parkinson's disease; psychosis associated with Lewy body disease;
bipolar disorders such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder;
dementia, and depression with psychotic features. In some embodiments, inventive
combinations are useful in the treatment of bipolar disorder. A more complete description of
the aforementioned mental disorders can be found in the Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, W shington, DC, American Psychiatric Association (1994),
incorporated herein by reference in its entirety. In some embodiments, the inventive
combinations are used to treat schizophrenia. In some embodiments, the inventive
combinations are used to treat bipolar disorder.

[0091] Compound 1, H was used to exemplify the effectiveness of
compounds of the present invention in the tail suspension test. While not a direct model of
depression, the tail suspension test is an assay that can evaluate antidepressant-like effects of
drugs. Clinically effective drugs such as Prozac (fluoxetine) are effective in this assay.
Specifically, they decrease the amount of time the mice spend immobile after being hung
upside down by their tails during the test. It is impossible to determine if a mouse is indeed
depressed. However, the fact that clinically effective antidepressants reduce immobility lends
predictive validity to the model.
Animals
[0092] Male Swiss Webster mice (Charles River) weighing 25-35 g were used throughout
this study. They were housed in groups of five per cage in an AALAC-accredited facility that
was maintained on a 12-h light dark cycle (lights on at 0600 h) and had free access to food
and water. Experimental groups consisted of 12 mice, randomly assigned to treatment
groups. All experiments were performed between 9:00 AM and noon in accordance to the

Guide for the Care and Use of Laboratory Animals as dopted and promulgated by the
National Institutes of Health (Pub. 85-23, 1985).
Drugs and reagents
[0093] Solutions of Compound 1 and paroxetine were freshly prepared; each adissolved in
distilled water. All drugs were injected i.p. at a volume of 10 ml/kg body weight.
Combination treatments were cotreated, 30 minutes prior to the test.
[0094] The procedure followed in this study was a variant of the one originally described
by Steru et al. (1985). 30 minutes following treatment, the mice were suspended upside down
by the tail using dhesive laboratory tape (VWR International), to a flat metal bar connected
to a strain gauge within a tail suspension chamber (Med Associates). The time spent
immobile during a 6-minute test session was automatically recorded. 8 mice were
simult neously tested within separate chambers. Data collected were expressed as a mean of
immobility time and statistical analysis was performed using a one-way ANOVA with least
significant difference (LSD) post-hoc test.
Results
[0095] Neither dose of Compound 1 (1 or 3 mg/kg) produced an antidepressant-like effect
alone. 30 mg/kg of paroxetine produced an 18% decrease in immobility (ns) alone. The
combination of 30 mg/kg of paroxetine with 1 and 3 mg/kg of Compound 1 produced
decreases in immobility time of 24% and 35% respectively, indicating an enhancement of the
antidepressant-like effects of paroxetine. See Figure 1.
[0096] The entire disclosure of each patent, patent application, and publication cited or
described in this document is hereby incorporated by reference.
[0097] While we have presented a number of embodiments of this invention, it is
apparent that our basic construction can be altered to provide other embodiments which
utilize the compounds and methods of this invention. Therefore, it will be appreciated that
the scope of this invention is to be defined by the appended claims rather than by the specific
embodiments which have been represented by way of example.

CLAIMS
Wh t is claimed is:
1. A composition comprising:
(a ) one or more antidepressants;
(b) pharmaceutically acceptable carrier, adjuvant, or vehicle; and
(c) compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
== designates asingle or double bond;
n is 1 or 2;
m is O or 1;
R1 and R2 are each independently halogen, -CN, -R, -OR, -C1-6 perfluoroalkyl, or -OC1-6
perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group;
R1 and R4 are taken together, with the carbon atoms to which they are bound, to form a
saturated or unsaturated 4-8 membered ring, wherein said ring is optionally substituted
with 1-3 groups independently selected from halogen, -R, or OR; and
R5 and R6 are each independently -R.
2. The composition according to claim 1, wherein == designates asingle bond.
3. The composition according to claim 1 or claim 2, wherein:
R1 is R, OR, halogen, cyano, or -C1-3 perfluoroalkyl; and
R2 is R, OR, halogen, cyano, or -C1-3 perfluoroalkyl.

4. The composition according to claim 3, wherein at aleast one of R1 and R2 is -
OH.
5. The composition according to any one of claims 1 to 4, wherein R3 and R4 are
taken together, with the carbon atoms to which they are bound, to form asaturated or
unsaturated 5-8 membered ring, wherein said ring is optionally substituted with 1-3 groups
independently selected from halogen, -R, or OR.
6. The composition according to any one of claims 1 to S, wherein said
compound is of formula I- or I-b:

or a pharmaceutically acceptable salt thereof.
7. The composition according to any one of claims 1 to 5, wherein said
compound is of formula I-c or I-d:

or a pharmaceutically acceptable salt thereof.
8. The composition according to claim 7, wherein said compound is of formula
II or III:


or a pharmaceutically acceptable salt thereof.
9. The composition according to any one of claims 1 to 5, wherein said
compound is of formula I-e or I-f:

or a pharmaceutically acceptable salt thereof.
10. The composition according to claim 9, wherein said compound is of formula
IV or V:
or a pharmaceutically acceptable salt thereof.
11. The composition according to claim 1, wherein said compound of formula I is
selected from:
2-bromo-4,5,6,7,9,9 , 10,11,12,12a-decahydrocyclopent [c] [1,4]diazepino [6,7,1 -ij]quinoline;

2-bromo-4,5,6,7,9,9 , 10,11,12,13,14,14 -dodecahydrocyclohepta[c][1,4 ]diazepino[6,7,1-
ij]quinoline;
2-chloro-4,5,6,7,9,9 ,10,11, 12,12a-decahydrocyclopent [c][1,4]diazepino [6,7,1 -ij]quinoline;
2-chloro-4,5,6,7,9,9 , 10,11,12,13,14,14a-dodecahydrocyclohepta[c] [ 1,4] diazepino[6,7,1 -
ij]quinoline;
2-phenyl-4,5,6,7,9,9 , 10,11,12,12a-decahydrocyclopent [c][ 1,4]diazepino [6,7,1 -ij]quinoline;
2-methoxy-4,5,6,7,9,9 , 10,11,12,12 -decahydrocyclopent [c][ 1,4]diazepino [6,7,1 -
ij]quinoline;
1 -fluoro-4,5,6,7,9,9 , 10,11,12,12a-decahydrocyclopent [cl[ 1,4]diazepino [6,7,1 -ij]quinoline;
1-fluoro-4,5,6,7,9,9 ,10,l 1,12,13,14,14a-dodecahydrocyclohepta[c][1,4] diazepino[6,7,1-
ij]quinoline;
1-(trifluoromethyl)-4,5,6,7,9,9,10,11,12,12a-decahydrocyclopent [c] [1,4] diazepino[6,7,1 -
ij]quinoline;
1 -fluoro-2-methoxy-4,5,6,7,9,9 , 10,11,12,12 -decahydrocyclopent [c] [1,4] diazepino[6,7,1 -
ij]quinoline;
1-fluoro-2-methoxy-4,5,6,7,9,9 , 10,11,12,13,14,14 -dodecahydrocyclo-
hepta[c] [1,4]diazepino [6,7,1 - ij]quinoline;
4,5,6,7,9,9 10,11,12,12 -decahydrocyclopent [c][1,4]di zepirio[6,7,1 -if] quinoline;
4,5,6,7,9,9 ,10,11,12,13,14,14 -dodecahydrocyclohepta[c][1,4]diazepino[6,7,l-ij]quinoline;
(-)-4,5,6,7,9,9 10,11,12,12 -decahydrocyclopent [c][ 1,4]diazepino[6,7,1 -ij] quinoline;
(9 R, 14 S)-4,5,6,7,9,9 , 10,11,12,13,14,14 -diodecahydrocyclohepta[c] [ 1,4] diazepino[6,7,1 -
ij]quinoline;
(9 S, 14 R)-4,5,6,7,9,9 , 10,11,12,13,14,14 -dodecahydrocyclohepta[c][ 1,4] diazepino[6,7,1 -
ij]quinoline;
4,5,6,7,9 , 10,11,12,13,13 -decahydro-9H-[ 1,4]diazepino[6,7,1 -de]phenanthridine;
1,2,3,4,9,10-hexahydro-8H-cyclopent [b] [1,4]diazepino[6,7,-hi] indole;
1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent -[b][1,4]diazepino[6,7,1 - hi]indole;
(7bS.10aS)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent -[b][1,4]diazepino[6,7,1 - hi]indole;
(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent -[b][1,4]diazepino[6,7,1- hi]indole;
(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent -[b][1,4]diazepino[6, 7,1 -hi]indole;
6-methyl-1,2,3,4,9,10-hcx hydro-8H-cyclopent [b] [ 1,4]diazepino{6,7,1 -hi] indole;
2S0-(rel-7bR, 10aR)-2-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b]
[ 1,4]diazepino[6,7,1 -hi]indole;

(2S)-(rel-7bR, 10aR)2-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b]
[1,4]diazepino[6,7,1-hi]indole;
(2S)-(rel-7bS,10aS)-2-methyl-l,2,3,4,8,9>10,10a-octahydro-7bH-cyclopent [b]
[ 1,4]diazepino[6,7,1 -hi] indole;
(2R)-(rel-7bR,10aR)-2-methy1-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b]
[1,4]diazepino[6,7,1 -hi]indole;
(2R)-(rel-7bR, 10aR)-2-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b
] [ 1,4]diazepino[6,7,1-hi]indole;
(2R)-(rel-7bS,10aS)-2-methyl-l,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b]
[1,4]diazepino[6,7,1 -hi]indole;
rel-(4S,7bS,10aS)-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-
cyclopent [b] [1,4]diazepino[6,7,1 -hi]indole
rel-(4S,7bS, 10aS)-4-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b]-
[1,4]diazepino[6,7,1 -hi]indole;
rel-(4R,7bS,10aS)-4-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-
cyclopent [b][1,4]diazepino[6,7,1 -hi]indole;
9-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent[b][1,4]diazepino[6,7,1 -hi]indole;
(7bR,9R, 10aR)-9-methyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b][1,4]d
iazepino[6,7,1-hi]indole;
9,9-dimethyl-l,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [1,4]diazepino[6,7,1-hi]indole;
(7bR, 10aR)-9,9-dimethyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b] [1,4]
diazepino[6,7,1-hi]indole; and
(7bS, 10aS)-9,9-dimethyl-l,2,3,4,8,9,10,10a-octahydro-7bH-cyclopent [b][ 1,4]
diazepino[6,7,l-hi]indole;
or a pharmaceutically acceptable salt thereof.
12. The composition of any one of claims 1 to 11, wherein said compound is the
hydrochloride salt.
13. A product comprising (a) one or more antidepressants; (b) a pharmaceutically
acceptable carrier, adjuvant, or vehicle; and (c) a compound of formula I as defined in any
one of claims 1 to 12 as a combined preparation for sequential, simultaneous or separate
administration for the treatment or prevention of depression or other mood disorders.

14. The composition or product according to any one of claims 1 to 13 wherein the
antidepressant is selected from the group consisting of serotonin reuptake inhibitors (SRIs),
norepinephrine reuptake inhibitors (NERIs), combined serotonin-norepinephrine reuptake
inhibitors (SNRIs), mono mine oxidase inhibitors (MAOIs), reversible inhibitors of
mono mine oxidase (RIMAs), phosphodiesterase-4 (PDE4) inhibitors, corticotropin releasing
factor (CRF) antagonists, alph .-adrenoreceptor antagonists, and combinations therof.
15. The composition or product according to claim 14, wherein the antidepressant
is selected from the group consisting of adinazolam, alaproclate, mineptine, mitriptyline, mitriptyline/chlordiazepoxide combination, amoxapine, 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, droxidop , duloxetine, enefexine, escitalopiam, estazolam,
etoperidone, femoxetine, fengabine, fezolamine, fluotracen, fluoxetine, fluvoxarnine,
idazoxan, imipramine, indalpine, indeloxazine, iprindole, isocarboxazid, levoprotiline,
lithium, litoxetine, lofepramine, maprotiline, medifox minc, mctapramine, metralindole,
mianserin, milnacipran, minaprine, mirtazapine, moclobemide, montirelin, nebracetam,
nefazodone, nefopam, netazodane, nialamide, nomifensine, norfluoxetine, nortriptyline,
orotirelin, oxaflozane, paroxetine, phenelzine, pinazepam, pirlindone, pizotyline,
protriptyline, reboxetine, ritanserin, rolipram, selegiline, sercloremine, sertraline, setiptiline,
sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine,
tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, tranylcypromine, trazodone,
trimipramine, venlafaxine, veralipride, viloxazine, viqualine, zimelidine, zometr pine,
pharmaceutically acceptable salts thereof, and combinations thereof.
16. A method ofatreating a patient suffering from a depression or a mood disorder
comprising administering to said patient a composition according to any one of claims 1 to
12.
17. A method ofatreating a patient suffering from anxiety comprising administering to said patent an anxiety-reducing amount of or composition according to any
one of claims 1 to 12.

18. A method ofatreating a patient suffering from a psychotic disorder comprising administering to said patient a composition according to any one of claims 1 to 12.
19. The method of claim 18 wherein the patient is suffering from schizophreni .
20 The method of claim 18 wherein the patient is suffering from bipolar disorder.
21. The method according to claim 16, wherein the antidepressant is selected from
the group consisting of ser tonin reuptake inhibitors (SRIs), norepinephrine reuptake
inhibitors (NERIs), combined serotonin-norepinephrine reuptake inhibitors (SNRIs),
mono mine oxidase inhibitors (MAOIs), reversible inhibitors of mono mine oxidase
(RIMAs), phosphodiesterase^ (PDE4) inhibitors, corticotropin releasing factor (CRF) antagonists, alph .-adrenoreceptor antagonists, and combinations therof.
22. The method according to claim 16, wherein the antidepressant is selected
from . the group consisting of adinazolam, alaproclate, mineptine, mitriptyline, mitriptyline/chlordiazepoxide combination, amoxapine, atipamezole, azamianserin,
bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, buproprion,
caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clomipramine,
clovoxamine, dazepinil, deanol, demexiptiline, desipramine, O-dcsmethylvenlafaxine,
dibenzepin, dothiepin, doxepin, droxidop , duloxetine, enefexine, escit lopi m, estazolam,
etoperidone, femoxetine, fengabine, fezolamine, fluotracen, fluoxetine, fluvoxamine,
idazoxan, imipramine, indalpine, indeloxazine, iprindole, isocarboxazid, levoprotiline,
lithium, litoxetine, lofepramine, maprotiline, medifoxamine, metapramine, metralindole,
mianserin, milnacipran, minaprine, mirtazapine, moclobemide, montirelin, nebracetam,
nefazodone, nefopam, netazodane, nialamide, nomifensine, norfluoxetine, nortriptyline,
orotirelin, oxaflozane, paroxetine, phenelzine, pinazepam, pirlindone, pizotyline,
protriptyline, reboxetine, ritanserin, rolipram, selegiline, sercloremine, sertraline, setiptiline,
sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine,
tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, tranylcypromine, trazodone,
trimipramine, venlafaxine, veralipride, viloxazine, viqualine, zimelidine, zometrapine,
pharmaceutically acceptable salts thereof, and combinations thereof.

23. The method according to claim 16, wherein administration of the composition
is oral.
24. The method according to claim 16, wherein the patient is suffering from
depression.
25. The method according to claim 16, wherein the patient is suffering from anxiety.
26. The method according to claim 16, wherein the patient is further suffering
from a psychotic disorder.
27. The method according to claim 26, wherein the patient is suffering from
schizophreni .
28. The method of claim 26 wherein the patient is suffering from bipolar disorder.
29. The method according to claim 16, wherein the patient is suffering from a
mood disorder selected from the group consisting of dysthymic disorderawith early or late
onset and with or without atypical features; dementia of the Alzheimer's type, with early or
late onset, withadepressed mood; vascular dementia withadepressed mood, disorders induced
by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine,
sedatives, hypnotics, anxiolytics; schizoaffective disorder of the depressed type; adjustment
disorder with depressed mood; and combinations thereof.

Therapeutic combinations useful in the treatment or prevention of depression or other mood disorders, comprising a compound of Formula (1), or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, n, and m are as defined and described herein and one or more antidepressants.