SEROTONERGIC AGENTS FOR TREATING SEXUAL DYSFUNCTION
This patent application is a continuation-in-part of co-pending application
Serial No. 11/330907, filed on January, 11,2006; which is a continuation of
application serial no. 10/441,536, filed May, 20,2003; which is a continuation of
application serial no. 10/218,251, filed on August 14,2002; which is a continuation of
application Serial No. 10/010,575, filed November 13,2001; which claims the benefit
of provisional application Serial No. 60/253,301, filed November 28,2000 and
provisional application Serial No. 60/297,814, filed June 13, 2001, each of which is
hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
The invention relates to the use of novel piperazine derivatives, their use for
treating, e.g., sexual dysfunction, and to pharmaceutical compositions containing the
compounds. The novel compounds are useful as 5-HT1A binding agents,
particularly as 5-HT1A receptor antagonists.
BACKGROUND
Sexual dysfunction is associated with various drug treatments including
treatments using antidepressant drugs, antipsychotic drugs, and anticonvulsant
drugs. This manifestation of drug treatment is a significant cause of patient non-
compliance with drug treatments. Accordingly, there is a need to identify
compounds that are effective for ameliorating or preventing sexual dysfunction
associated with drug treatment.
U.S. Patent No. 6,127,357 discloses compounds of the general formula (I):
(I)
and pharmaceutically acceptable acid addition salts thereof wherein:
A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more
lower alkyl groups,

Z is oxygen or sulfur,
R is H or lower alkyl,
R1 is a mono or bicyclic aryl or heteroaryl radical,
R2 is a mono or bicyclic heteroaryl radical, and
R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl,
aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR4R5
[where R4 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R5 is hydrogen, lower
alkyl, -CO(lower)alkyl, aryl, -Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-
(lower)alkyl or R4 and R5 together with the nitrogen atom to which they are both
attached represent a saturated hytrocyclic ring which may contain a further
heteroatom], or a group of formula OR6 [where R6 is lower alkyl, cycloalkyl,
cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].
WO 97/03982 discloses compounds of the general formula (II):

including enantiomers and the pharmaceutically acceptable acid addition salts
thereof.
The compounds of formula (II) fall within the disclosure of U.S. Patent
No. 6,127,357 but are not specifically disclosed therein. Compounds of Formula II
were taught to have potent 5-HT1A antagonist activity in vivo when administered by
the oral route.

SUMMARY
It has been found that compounds that are 5-HT1A receptor antagonists are
useful for treating sexual dysfunction, e.g., sexual dysfunction associated with drug
treatment such as drug treatment with an antidepressant, an antipsychotic, or an
anticonvulsant. Accordingly, the invention relates to a method for treating sexual
dysfunction associated with drug treatment in a patient in need thereof. The method
includes administering to the patient an effective amount of a compound that is a 5-
HT1A antagonist. In some embodiments, the drug treatment is antidepressant drug
treatment, antipsychotic drug treatment, or anticonvulsant drug treatment. The
compound can be a compound of formula (I),

or a pharmaceutically acceptable acid addition salt thereof such that
A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more
lower alkyl groups,
Z is oxygen or sulfur,
R is H or lower alkyl,
R1 is a mono or bicyclic aryl or heteroaryl radical,
R2 is a mono or bicyclic heteroaryl radical, and
R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl,
aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR4R5
[where R4 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R5 is hydrogen, lower
alkyl, -CO(lower)alkyl, aryl, -Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-
(lower)alkyl or R4 and R5 together with the nitrogen atom to which they are both
attached represent a saturated hytrocyclic ring which may contain a further
heteroatom], or a group of formula OR6 [where R6 is lower alkyl, cycloalkyl,
cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].

In other embodiments, the compound is a compound of formula (III), as
described herein or a pharmaceutically acceptable salt thereof. In yet other
embodiments, the compound is a compound of formula (IV) as described herein.
The compound can be (R)-4-cyano-N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-
yl)-piperazin-1-yl]propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable
acid addition salt thereof (Example compound 1), N-[2-[4-(2-methoxyphenyl)-1-
piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (Example compound 2) or
a pharmaceutically acceptable acid addition salt thereof, or (R)-N-(2-methyl-(4-
indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide (Example
compound 3) or a pharmaceutically acceptable acid addition salt thereof.
In certain embodiments of the invention the drug associated with sexual
dysfunction is a selective serotonin reuptake inhibitor (SSRI) (for example,
fluoxetine, citolopram, escitalopram oxalate, fluvoxamine maleate, paroxetine, or
sertraline), a tricyclic antidepressant (for example, desipramine, amitriptiyline,
amoxipine, clomipramine, doxepin, imipramine, nortriptyline, protriptyline, or
trimipramine, an aminoketone class compound (for example, bupropion). In some
embodiments, the drug is a monoamine oxidase inhibitor (MAOI) (for example,
phenelzine), a serotonin and norepinepherine reuptake inhibitor (SNRI) (for
example, venlafaxine, nefazodone, milnacipran, duloxetine), a norepinephrine
reuptake inhibitor (NRI) (for example, reboxetine), a partial 5-HT2A agonist (for
example, buspirone), a 5-HT2A receptor antagonist (for example, nefazodone), a
typical antipsychotic drug, or an atypical antipsychotic drug. Examples of such
antipsychotic drugs include aliphatic phethiazine, a piperazine phenothiazine, a
butyrophenone, a substituted benzamide, and a thioxanthine. Additional examples
of such drugs include haloperidol, olanzapine, clozapine, risperidone, pimozide,
aripiprazol, and ziprasidone. In some cases, the drug is an anticonvulsant, e.g.,
phenobarbital, phenytoin, primidone, or carbamazepine. In some cases, the patient
in need of treatment for sexual dysfunction is being treated with at least two drugs
that are antidepressant drugs, antipsychotic drugs, anticonvulsant drugs, or a
combination thereof.

In certain embodiments, the invention includes oral delivery of the compound
for treating sexual dysfunction. The compound can be, in some cases, delivered as
a sustained release compound sustained release compound. In other embodiments
of the invention, the sexual dysfunction comprises a deficiency in penile erection.
The invention also relates to a method of improving sexual function in a
patient in need thereof. The method includes administering to the patient a
pharmaceutically effective amount of a compound that is a 5-HT1A antagonist. In
some embodiments, the compound is a compound of formula (I)

or a pharmaceutically acceptable acid addition salt thereof, wherein
A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more
lower alkyl groups,
Z is oxygen or sulfur,
R is H or lower alkyl,
R1 is a mono or bicyclic aryl or heteroaryl radical,
R2 is a mono or bicyclic heteroaryl radical, and
R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl,
aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR4R5
[where R4 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R5 is hydrogen, lower
alkyl, -CO(lower)alkyl, aryl, -Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-
(lower)alkyl or R4 and R5 together with the nitrogen atom to which they are both
attached represent a saturated hytrocyclic ring which may contain a further
heteroatom], or a group of formula OR6 [where R6 is lower alkyl, cycloalkyl,
cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl]; or
formula (III)


such that R1 is cyano, nitro, trifluoromethyl or halogen, or a pharmaceutically
acceptable acid addition salt thereof; or formula (IV)

such that, Ra and Rb are each hydrogen or methyl and Rc is hydrogen, halo or C 1 -
4 alkyl; or a pharmaceutically acceptable acid addition salt thereof. In some
embodiments, of the method, the compound is Example compound 1, Example
compound 2, or Example compound 3.
In another aspect, the invention relates to a pharmaceutical composition for
treating sexual dysfunction associated with drug treatment, the composition
including a compound of formula (I), formula (III), or formula (IV). In some
embodiments, the drug is an antidepressant, an antipsychotic, or an anticonvulsant.

In other embodiments, the compound is effective for ameliorating sexual dysfunction
in an animal model of sexual dysfunction associated with drug treatment, for
example, in an animal model of sexual dysfunction that is an antidepressant drug-
induced model of sexual dysfunction.
Yet another aspect of the invention relates to a package comprising a 5-
HT1A antagonist and instructions, such that the instructions comprise instructions
for treating sexual dysfunction, e.g., the instructions are for treating sexual
dysfunction associated with drug treatment.
In another aspect, the invention relates to a method for treating memory
deficits or cognitive disorders; treating alcohol, nicotine, or drug withdrawal; treating
Parkinson's disease or motor disorders; treating migraine; treating eating disorders;
treating sexual dysfunction; treating urinary incontinence, treating stroke; treating
endocrine disorders; treating sleep disorders; treating attention deficit disorders;
treating Tourette's syndrome, autism, social phobias, hyperactivity disorders or
thermoregulatory disorders in a patient in need thereof, comprising providing to the
patient a therapeutically effective amount of a compound of formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
Unless otherwise defined, all technical and scientific terms used herein have
the same meaning as commonly understood by one of ordinary skill in the art to
which this invention belongs. Although methods and materials similar or equivalent
to those described herein can be used in the practice or testing of the present

invention, suitable methods and materials are described below. Ail publications,
patent applications, patents, and other references mentioned herein are
incorporated by reference in their entirety. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the
detailed description, drawings, and from the claims.
DESCRIPTION OF THE DRAWINGS
Fig. 1 is a bar graph depicting the results of experiments assaying the
number of non-contact penile erections in a 30 minute test period in sexually
experienced rats that were treated with intraperitoneally (i.p.) with vehicle alone
(0.9% saline), bupropion (20 mg/kg), desipramine (10 mg/kg), or fluoxetine (10
mg/kg)for 14 days.
Fig. 2 is a bar graph depicting the results of experiments assaying the
number of non-contact penile erections in a 30 minute test period in sexually
experienced rats that were administered vehicle for 6 days and administered
fluoxetine on day 7, administered fluoxetine for 7 days (subchronic); or administered
fluoxetine for 14 days (chronic). Animals were tested immediately following the final
administration of vehicle or drug in vehicle.
Fig. 3 is a bar graph depicting the results of experiments assaying the
number of non-contact penile erections in a 30 minute test period in sexually
experienced rats that were treated with vehicle (0.9% saline) only, N-[2-[4-(2-
methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexanecarboxamide)
(Example compound 2), (acutely or subchronically), fluoxetine, or Example
compound 2 and fluoxetine. The treatment groups were as follows (from left to right
in the Fig.): Group 1 = vehicle on days 1-6, a single dose of Example compound 2
on day 7; Group 2 = Example compound 2 on days 1-7; Group 3 = vehicle only on
days 1-7; Group 4 = fluoxetine on days 1-7; Group 5 =fluoxetine on days 1-6 and
Example compound 2 + fluoxetine on day 7; Group 6 = Example compound 2 +
fluoxetine on days 1-7. Animals were tested immediately after the final treatment.
Drugs and compounds were delivered in vehicle.

Fig. 4 is a bar graph depicting the results of experiments assaying the
number of non-contact penile erections in a 30 minute test period in sexually
experienced rats that were treated with the following: (from left to right in the Fig.)
Group 1 = vehicle only on days 1-13 + a single administration of 0.1 mg/kg (R)-N-(2-
methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
(Example compound 3) on day 14; Group 2 = vehicle only on days 1-13 + a single
acute administration of 1.0 mg/kg Example compound 3 on day 14; Group 3 =
vehicle only on days 1-14; Group 4 = fluoxetine on days 1-14; Group 5 = fluoxetine
only on days 1-13 + single administration of 0.1 mg/kg Example compound 3 +
fluoxetine on day 14; Group 6 = fluoxetine days 1-13 + single administration of 1.0
mg/kg Example compound 3 + fluoxetine on day 14. Animals were tested
immediately after the final treatment on day 14. Drugs and compounds were
delivered in vehicle.
Fig. 5 is a bar graph depicting the results of experiments assaying the
number of non-contact penile erections in a 30 minute test period in sexually
experienced rats that were treated with the following: (from left to right in the graph):
Group 1 = Example compound 2 for 14 days; Group 2 = Example compound 3 for
14 days; Group 3 = vehicle alone for 14 days; Group 4 = fluoxetine for 14 days;
Group 5 = Example compound 2 + fluoxetine for 14 days; Group 6 = Example
compound 3 + fluoxetine for 14 days. Animals were tested immediately after
administration of the final treatment. Drugs and compounds were delivered in
vehicle.
Fig. 6 is a drawing representing the chemical structures of Example
compound 1, Example compound 2, and Example compound 3.

DETAILED DESCRIPTION OF THE INVENTION
Novel compounds of the invention have the structural formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
Halogen, as used herein, refers to chlorine, fluorine, bromine and iodine.
The compounds of Formula III contain an asymmetric carbon atom.
Accordingly, they may exist in different stereoisomeric forms. In some
embodiments, the (R) stereoisomer having the formula (IlIa) is used.

In accordance with some embodiments of the invention, the (R) stereoisomer
is substantially free of the (S) stereoisomer. Substantially free, as used herein,
means that the compound is made up of a significantly greater proportion of its (R)
stereoisomer than the (S) stereoisomer. In certain embodiments, the compound is
made up of at least about 90% by weight of its (R) stereoisomer and about 10% by
weight or less of its (S) stereoisomer. In other embodiments of the invention, the
compound is made up of at least about 99% by weight of its (S) stereoisomer and
about 1% by weight or less of the (R) stereoisomer. In some cases, stereoisomers

may be isolated from racemic mixtures by any method known to those skilled in the
art, including high performance liquid chromatography (HPLC) and the formation
and crystallization of chiral salts. 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).
Examples of compounds useful for treating sexual dysfunction such as
sexual dysfunction associated with the use of a drug such as an antidepressant
drug, antipsychotic drug, or anticonvulsant drug include, compounds disclosed in
U.S. Patent No. 6,127,357 (compounds of formula (I); compounds disclosed in
WO 95/33725; compounds disclosed in WO 95/33743 such as compounds of
formula (IV),

wherein, Ra and Rb are each hydrogen or methyl and Rc is hydrogen, halo or C 1 -4
alkyl; or a pharmaceutically acceptable acid addition salt thereof; and compounds
disclosed herein.
Useful compounds are those that exhibit activity as 5-HT1A antagonists and
can inhibit or prevent sexual dysfunction (e.g., as shown using an animal model of

sexual dysfunction due to administration of a drug). Non-limiting examples of
compounds useful in the invention are (R)-4-cyano-N-{2-[4-(2,3-dihydro-
benzo[1,4]dioxin-5-yl)-piperazin-1-yl]propyl}-N-pyridin-2-yl-benzamide and
pharmaceutically acceptable acid addition salts thereof (Example compound 1), N-
[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide
(Example compound 2) and pharmaceutically acceptable acid addition salts thereof,
and(R)-N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)
cyclohexanecarboxamide (Example compound 3) and pharmaceutically acceptable
acid addition salts thereof (Fig. 6).
The pharmaceutically acceptable salts are generally the acid addition salts
which can be formed from a compound of a general formula described herein and a
pharmaceutically acceptable acid such as, for example, benzoic, phosphoric,
sulfuric, hydrochloric, hydrobromic, citric, maleic, malic, mandelic, mucic, nitric,
fumaric, succinic, tartaric, acetic, lactic, pamoic, pantothenic, benzenesulfonic, or
methanesulfonic acid. In some embodiments of the invention the acid addition salt
is hydrochloric acid. Other pharmaceutically acceptable salts known to those in the
art can be used.
The compounds of the present invention can be prepared by known methods
from known starting materials that are available by conventional methods. For
example the compounds may be prepared by the general methods disclosed in EP-
A-0512755 and WO 97/03982.
Such disclosed methods include acylating an amine of formula (IV) with a
known benzoyl chloride (V) or an alternative acylating derivative thereof. Examples
of acylating derivatives include the acid anhydride, imidazolides (e.g., obtained form
carbonyldiimidazole), or activated esters.


(IV) (V)
wherein R1 is cyano, halogen, trifluoromethyl or nitro.
Novel compounds of the present invention are potent 5-HT1A binding agents
that selectively bind to the 5-HT1A receptor. Furthermore, the novel compounds of
the invention are 5-HT1A receptor antagonists when tested by standard
pharmacological procedures.
In addition, the novel compounds of formula (III) are unique from previously
disclosed 5-HT1A receptor antagonists in that they possess a superior duration of
action as a 5-HT1A receptor antagonist when administered in vivo.
EXAMPLES
The present invention is illustrated by reference to the following examples
and additional information. The examples of experiments are provided for illustrative
purposes only. They are not to be construed as limiting the scope or content of the
invention in any way. Those skilled in the art of organic synthesis may be aware of
still other synthetic routes to the invention compound. The reagents and
intermediates used herein are either commercially available or prepared according to
standard literature procedures.
Methods of testing the effect of an invention compound on sexual dysfunction
are described infra. Such methods are useful for identifying 5-HT1A antagonists
(i.e., 5-HT1A receptor antagonists) that are effective for treating sexual dysfunction.
Other methods of testing the effect of a compound on sexual dysfunction are known
in the art and include, e.g., paired mating observations (for example, of mounting,
mount attempts, intromission, mount frequency, ejaculation, mount with intromission,
ejaculation latency, intromission frequency, copulation efficiency, anogenital sniffing,
or post-ejaculatory interval), or assay of penile erections {e.g., determining
intracavemosal blood pressure or observation of non-contact penile erections in
sexually naive male rats).

EXAMPLE 1
(R)-4-Cyano-N-{2-[4-(2,3-Dihydro-Benzo[1,4]dioxin-5-yl)-Piperazin-1-yl]-
Propy[}-N-Pyridin-2-yl-Benzamide (Example compound 1)
A solution of {(R)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yI]propyl}-
pyridin-2-ylamine (0.846 g, 2.38 mmo!) in dichloromethane (20 mL) was treated at
0°C with the dropwise addition of a dichloromethane solution of 4-cyanobenzoyl
chloride (1.1 equivalents, 2.63 mmol in 5 mL). After stirring for 16 hours the mixture
was poured onto hexane (100 mL) to precipitate the titled compound as its mono-
hydrochloride salt (white solid, 1.2 g, 97% yield), which was recrystallized from
dichloromethane/hexane.
MS (+) 484 (M + H)+.
m.p. 239-240°C
[a] 25/D = + 56 (c = 0.6, MeOH)
Elemental Analysis for: C28H29N5O3 • 1.0 HCI
Calculated: C, 64.67; H, 5.81; N, 13.47:
Found: C, 64.69; H, 5.93; N, 13.52:
In order to demonstrate the superior duration of action of the compounds of
formula (III), Example 1 was compared to representative compounds of U.S. Patent
No. 6,127,357 and WO 97/03892.
Representative compounds of U.S. Patent No. 6,127,357 possess a
cyclohexylamide moiety and a 2-methoxyphenylpiperazine grouping. The most
potent example of this general structure (and the most potent compound taught in
U.S. Patent No. 6,127,357) is compound A, described as "Example 3" in U.S. Patent
No. 6,127,357. The only other class of compounds in U.S. 6,127,357 for which data
are given is that which possess a cyclohexylamide moiety and a
benzodioxinylpiperazine grouping ("Example 17" in U.S. Patent No. 6,127,357). A
small subset of this class of compounds is specifically claimed in WO97/03892, with
the preferred compound being compound B ("Example A1" in WO97/03892).
Therefore, these two preferred examples from EP-A-0512755 and WO 97/03892
have been chosen as representatives for comparison to the compounds of formula
(III).


EXAMPLE 2
BINDING PROFILE
Compounds were tested for binding to cloned human 5-HT1A receptors
stably transfected into CHO cells using [3H]8-OH-DPAT as the 5-HT1A radioligand
(according to general procedure described in J. Dunlop et a!., J. Pharmacol. Tox.
Methods. 40,47-55 (1998)). As shown in Table 1, compounds of the present
invention display high affinity for the 5-HT1A receptor.
EXAMPLE 3
IN VITRO FUNCTIONAL ACTIVITY
A clonal cell line stably transfected with the human 5-HT1A receptor was
utilized to determine the intrinsic activity of compounds (according to the general
procedure described in J. Dunlop et al.. J. Pharmacol. Tox. Methods. 40, 47-55
(1998)). Data are provided in Table 1. As shown in Table 1, compounds of the
present invention antagonized the ability of 10 nM 8-OH-DPAT to inhibit forskolin-
stimulated cAMP production in a concentration-related fashion.



EXAMPLE 4
IN VIVO FUNCTIONAL ACTIVITY
The ability of the compounds to function in vivo as 5-HT1A antagonists was
assessed in rats using a Fixed Responding Model (D. Blackman, in "Operant
Conditioning: An Experimental Analysis of Behavior", J. Butcher, ed., Methuen and
Co., Ltd., London). In this model rats are trained to respond (lever pressing) under a
fixed-ratio 30 schedule of food presentation in order to receive a food pellet
reinforcer. Administration of the 5-HT1A agonist 8-OH-DPAT reduces the control
response rate (assessed by administration of vehicle placebo). The 5-HT1A
antagonist activity of a test compound is determined by measuring its ability to
antagonize this agonist-induced decrease in response rate. A full antagonist effect
is considered one in which the test compound completely reverses the agonist-
induced response rate, returning it to control levels. The data given in Table 2
demonstrate that a 1 mg/kg dose of the compound of Example 1 completely
reverses the decrease in response rate induced by administration of a 0.3 mg/kg
dose of 8-OH-DPAT. Thus, compounds of the present invention function as 5-HT1A
antagonists in vivo.

EXAMPLE 5
DURATION OF ACTION IN VIVO

The duration of action in the Fixed Responding Model was assessed by pre-
treating animals with test compound and then challenging with a 0.3 mg/kg dose of
the 5-HT1A agonist 8-OH-DPAT at various time intervals after the administration of
test compound. All drug and vehicle administrations were made by the
subcutaneous route. Doses of the test compounds selected for comparison were
those that caused a ten-fold shift in the 8-OH-DPAT dose-response curve when
administered 30 minutes prior to agonist. The doses selected for the duration of
action comparison are listed in Table 3.

Data are presented for pre-treatment of the animals with test compound at
0.5 hours, 2 hours, and 4 hours prior to administration of a 0.3 mg/kg dose of 8-OH-
DPAT. Results are normalized to control values, with 100% being the control
response rate observed when vehicle is administered rather than the agonist 8-OH-
DPAT.



As can be seen from Table 4, all three test compounds (Compound A, B, and
Example compound 1) completely antagonize the agonist-induced decrease in
responding 30 minutes after their administration, returning the response rate to
control levels. However, when agonist is given 2 hours following test drug
administration (Column 3), the 5-HT1A antagonist effects of compounds A and B no
longer return the response rate to control levels while Example compound 1 still
displays complete 5-HT1A antagonist effects. By four hours post-administration
(Column 4), the 5-HT1A antagonist effects of Compounds A and B are completely
lost, while Example compound 1 continues to provide complete antagonism of the
agonist-induced decrease in response rate. Thus, the duration of action of Example
compound 1 is longer than 4 hours, while those of Compounds A and B are
somewhere between 30 minutes and 2 hours.
The increased duration of action of the novel compounds of the present
invention, compared to that of the classes of compounds disclosed in U.S. Patent
No. 6,127,357 and WO 97/03892 is particularly advantageous in that a smaller
number of doses of the compound can be administered to produce a similar
therapeutic effect.
Compounds of the present invention may be used to treat a subject suffering
from CNS disorders such as schizophrenia, (and other psychotic disorders such as
paranoia and mano-depressive illness), Parkinson's disease and other motor
disorders, anxiety (e.g., generalized anxiety disorders, panic attacks, and obsessive
compulsive disorders), depression (such as by the potentiation of serotonin reuptake
inhibitors and serotonin norepinephrine reuptake inhibitors), Tourette's syndrome,
migraine, autism, attention deficit disorders and hyperactivity disorders. Compounds
of the present invention may also be useful for the treatment of sleep disorders,
social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary
incontinence, vasospasm, stroke, eating disorders such as for example obesity,
anorexia and bulimia, sexual dysfunction, and the treatment of alcohol, drug and
nicotine withdrawal.

Compounds of the present invention including those disclosed herein and
those disclosed in U.S. Patent No. 6,127,357 and WO 95/33743 are useful for
treating sexual dysfunction, e.g., sexual dysfunction associated with a drug
treatment. Sexual dysfunction can be in a male or female subject. The condition
can include erectile dysfunction as well as disorders of arousal, motivation, desire,
decreased libido, anorgasmia, delayed ejaculation, premature ejaculation, and
sexual anxiety disorders, sexual pain disorders, sexual aversion disorders. The
cause can be undefined or can be due to a known cause, e.g., substance-related
sexual dysfunction.
Drugs associated with sexual dysfunction that can be treated as described
herein include antidepressant drugs (antidepressants). Such antidepressant drugs
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 (e.g., compounds described in International Patent Specification
Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO
94/13677), alpha.-adrenoreceptor antagonists, atypical antidepressants (e.g.,
buproprion, lithium, nefazodone, trazodone, viloxazine, and pharmaceutically
acceptable salts thereof, and sibutramine). Additional examples of such
antidepressants include triple uptake inhibitors such as DOV 216303 and DOV 2194;
melatonin agonists such as agomelotine, super neurotransmitter uptake blockers
(SNUBs; e.g., NS-2389 from GlaxoSmithKIine and Neurosearch; (R)-DDMA from
Sepracor), and 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 GlaxoSmithKIine).
Another class of antidepressant agents that may be associated with sexual
dysfunction that can be treated as described herein is noradrenergic and specific
serotonergic antidepressants (NaSSAs).

Examples of NRIs include tertiary amine tricyclics and secondary amine
tricyclics. Specific examples of tertiary amine tricyclics include, without limitation,
amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and
pharmaceutically acceptable salts thereof. Suitable examples of secondary amine
tricyclics include, without limitation, amoxapine, desipramine, maprotiline,
nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Another NRI that may be associated with sexual dysfunction is reboxetine (2-
[.alpha.-(2-ethoxy)phenoxy-benzyl]morpholine), usually administered as the
racemate.
SSRIs that may be associated with sexual dysfunction that can be treated
using compounds and methods described herein include, without limitation,
citalopram (1 -[3-(dimethylamino)propyl]-(4-fluorophenyl)-1,3-dihydr-o-5-
isobenzofurancarbonitrile; fluoxetine(N-methyl-3-(p-trifluoromethylphenoxy)-3-
phenylpropylamine, marketed in the hydrochloride salt form and as the racemic
mixture of its two isoforms; fluoxetine/olanzapine in combination; fluvoxamine (5-
methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone O-(2-aminoethyl)oxime;
paroxetine (trans-(-)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-
f luorophenyl)piperidine); sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-N-methyl-1-naphthylamine hydrochloride; escitalopram; new 5HT1A
agonists variza, alnespirone, gepirone, sunepitron, MKC242, vilazodone, eptapirone,
and ORG12962 from Organon; and pharmaceutically acceptable salts thereof.
MAOIs that may be associated with sexual dysfunction that can be treated
using the methods and compounds disclosed herein include, without limitation,
isocarboxazid, phenelzine, selegiline and tranylcypromine, and pharmaceutically
acceptable salts thereof. Reversible MAOIs that may be associated with sexual
dysfunction include, without limitation, moclobemide (4-chloro-N-[2-(4-morpholinyl)-
ethyljbenzamide; selegiline, and pharmaceutically acceptable salts thereof.
SNRIs that can be associated with sexual dysfunction that can be treated as
described herein include, without limitation, venlafaxine and pharmaceutically
acceptable salts and analogs, including the O-desmethylvenlafaxine succinate salt;

milnacipran(N,N-diethyI-2-aminomethyl-1-phenylcycIopropanecarboxamide;
mirtazapine; nefazodone; duloxetine; and pharmaceutically acceptable salts thereof.
Examples of specific antidepressants that can be associated with sexual
dysfunction suitable for treatment using a compounds and methods described herein
include, without limitation, adinazolam, alaproclate, alnespirone, amineptine,
amitriptyline, amitriptyline/chlordiazepoxide combination, amoxapine, aprepitant,
atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline,
bipenamol, brofaromine, buproprion, caroxazone, cericlamine, cianopramine,
dmoxatone, 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.
In some cases, anti-anxiety agents are associated with sexual dysfunction,
which can be treated using compounds and methods described herein. Such anti-
anxiety agents may include, without limitation, neurokinin receptor (NK) antagonists
(e.g., saredutant and osanetant) and corticotropin releasing factor (CRF)
antagonists.
Antipsychotic drugs are also associated with sexual dysfunction that can be
treated using a 5-HT1A antagonist as described herein. Such drugs include, without

limitation, a typical or atypical antipsychotic drug, for example, an aliphatic
phethiazine, a piperazine phenothiazine, a butyrophenone, a substituted benzamide,
or a thioxanthine. Additional examples of such drugs include amisulpiride,
aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, Ioxapine,
mesoridazine, molindone, olanzapine, perphenazine, pimozide, quetiapine,
risperidone, seroquel, supiride, thioridazine, thiothixene, trifluoperazine, ziprasidone,
and(S)-2-(benzylamino-methyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indo!-8-one,
a D2 partial agonist, that is disclosed in U.S. Patent No. 5,756,532; or
pharmaceutically acceptable salts thereof.
5-HT1A receptor antagonists are also useful for treating sexual dysfunction in
patients being treated with a combination of drugs, e.g., a combination of one or
more antidepressant and antipsychotic compounds. Anticonvulsant treatment is
also associated with sexual dysfunction that can be treated with compounds
disclosed herein. Examples of anticonvulsants associated with sexual dysfunction
include phenobarbital, phenytoin, primidone, and carbamazepine.
Compounds of the present invention are also useful for the treatment of
cognitive dysfunction. Thus, compounds of the present invention may be useful for
the treatment of cognitive dysfunction associated with mild cognitive impairment
(MCI) Alzheimer's disease and other dementias including Lewy Body, vascular, and
post stroke dementias. Cognitive dysfunction associated with surgical procedures,
traumatic brain injury or stroke may also be treated in accordance with the present
invention. Further, compounds of the present invention may be useful for the
treatment of diseases in which cognitive dysfunction is a co-morbidity such as, for
example, Parkinson's disease, autism and attention deficit disorders.
"Provided", as used herein with respect to providing a compound or substance
covered by this invention, means either directly administering such a compound or
substance, or administering a prodrug, derivative, or analog which will form an
equivalent amount of the compound or substance within the body. Prodrugs can be
prepared such as described in Design of Prodrugs. Bundgaard, H. ed., (Elsevier,
New York 1985); Prodruqs as Novel Drug Delivery Systems. Higuchi, T and Stella, V.
eds, (American Chemical Society, Washington, D.C. 1975); Design of

Biopharmaceutical Properties through Prodrugs and Analogs. Roche, E. ed.,
(American Pharmaceutical Association Academy of Pharmaceutical Sciences,
Washington, D.C., 1977); and Metabolic Considerations in Prodrug Design, Balant,
L.P. and Doelker, E. in Burger's Medicinal Chemistry amd Drug Discovery. Fifth
Edition, Wolff, M., ed, Volume 1, pages 949-982, (John Wiley & Sons, Inc. 1995).
Compounds as described herein are useful for the preparation of a
medicament for use in treating a sexual disorder, e.g., a sexual disorder associated
with use of a drug such as an antidepressant drug, an antipsychotic drug, an
anticonvulsant drug, or a combination of one or more of such drugs.
The compounds of the present invention may be administered orally or
parentally, neat or in combination with conventional pharmaceutical carriers.
Applicable solid carriers can include one or more substances which may also act as
flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders, tablet-disintegrating agents or encapsulating materials.
In powders, the carrier is a finely divided solid that is in admixture with the finely
divided active ingredient. In tablets, the active ingredient is mixed with a carrier
having the necessary compression properties in suitable proportions and compacted
in the shape and size desired. The powders and tablets may contain up to 99% of
the active ingredient. Suitable solid carriers include, for example and without
limitation, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin,
starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may
be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The
active ingredient of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an organic solvent, a
mixture of both, or pharmaceutically acceptable oils or fat. The liquid carrier can
contain other suitable pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening
agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable
examples of liquid carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g., cellulose derivatives, preferably
sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols

and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g.,
fractionated coconut oil and arachis oil). For parenteral administration the carrier
can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid
carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions that are sterile solutions or suspensions can be
utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.
Sterile solutions can also be administered intravenously. Oral administration may be
either in liquid or solid composition form. Preferably, the pharmaceutical
compositions containing the present compounds are in unit dosage form, e.g., as
tablets or capsules. In such form, the composition is sub-divided in unit dosages
containing appropriate quantities of the active ingredients. The unit dosage forms
can be packaged compositions, for example, packaged powders, vials, ampoules,
prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form
can be, for example, a capsule or tablet itself, or it can be the appropriate number of
any such compositions in package form. The therapeutically effective dosage to be
used may be varied or adjusted by the physician and generally ranges from 0.5 mg
to 750 mg, according to the specific condition(s) being treated and the size, age and
response pattern of the patient. A packaged composition can also include
instructions for use, e.g., to treat a pre-existing condition of sexual dysfunction or to
prevent or ameliorate an anticipated condition of sexual dysfunction such as sexual
dysfunction associated with a drug treatment (e.g., treatment with an antidepressant
such as an SSRI, an antipsychotic drug, or an anticonvulsant drug).
Example 6
Treatment of Sexual Dysfunction
An animal model was used to demonstrate the utility of treating or preventing
sexual dysfunction, e.g., sexual dysfunction associated with SSRI treatment, with a
compound that can act as a 5-HT1A antagonist. The animal model is based on the
finding that sexually experienced rats that are administered an SSRI, a drug used to
treat certain conditions such as depression, display a reduction in the number of
non-contact penile erections. SSRI treatment is associated with sexual dysfunction
in human subjects. In general, the animal model exposes sexually experienced
male rats (Sprague-Dawley rats) to female rats in estrous in a novel testing arena
that is not the regular housing environment. The number of non-contact penile

erections is assayed over a specified test period, e.g., 30 minutes (Sukoff Rizzo et
at., 2006, Society for Neuroscience Abst. #559.4; U.S. Provisional Application Serial
No. 60/682,3379, filed May 19,2005). In the experiments described herein, animals
were generally treated either with 0.9% saline (vehicle) or a drug in the vehicle.
The ability of various drugs associated with sexual dysfunction in humans to
cause sexual dysfunction in the animal model was tested using three different drugs,
bupropion (20 mg/kg), desipramine (10 mg/kg), and fluoxetine (10 mg/kg), or vehicle
alone (0.9% saline), each administered intraperitoneally (i.p.), once per day for
14 days. After the treatment period, animals were tested for the frequency of non-
contact penile erections over a 30 minute trial period.
All three compounds produced a decrease in sexual function under the
experimental conditions compared to treatment with vehicle alone (Fig. 1). These
data demonstrate that sexual dysfunction is induced in the animal model using drugs
that are associated with sexual dysfunction in humans, thereby providing support for
the validity of using the animal model.
To examine the time course of the effects of a drug that causes sexual
dysfunction, rats that were handled and tested as described above were treated
acutely: rats were treated with vehicle for 6 days, and on the test day (day 7) instead
of vehicle, the animals received a single dose of fluoxetine in vehicle (i.p.). For a
subchronic (7 day) study, fluoxetine was administered each day for 7 days and the
animals were evaluated on test day 7. For the chronic 14 day study, fluoxetine was
administered each day for 14 days and the animals were tested on day 14. Each
fluoxetine dose was 10 mg/kg in vehicle and was delivered i.p. on each of the test
days as described above. The testing session for each section of the study was
begun immediately following compound administration and the behavior observed
for 30 minutes immediately following the drug administration.
It was found that both sub-chronic and chronic administration of fluoxetine
were associated with a significant increase in sexual dysfunction (Fig. 2), further
demonstrating the utility of the animal model for sexual dysfunction testing.

To test the ability of a 5-HT1A antagonist to ameliorate the effects of sexual
dysfunction, sexually experienced rats were administered an SSRI using an acute or
subchronic (7 day) schedule and then tested for sexual function as described above.
A single acute dose of a compound (Example compound 2) ameliorated
sexual dysfunction when the compound was administered after a period of time in
which some level of drug-induced sexual dysfunction had occurred. Thus, acute
treatment of sexual dysfunction can result in an increased (e.g., normal) level of
sexual functioning. This is supported by the data of those treatment groups in Fig.
3, Fig. 4, and Fig. 5, in which Example compound 2 or Example compound 3 were
administered acutely after 7 or 14 days of fluoxetine treatment, and produced a
complete and significant reversal of fluoxetine-induced sexual dysfunction. These
data indicate that acute administration of a 5-HT1A antagonist with a drug that
induces sexual dysfunction is useful for ameliorating the effects of the drug
associated with sexual dysfunction. These data also indicate that acute treatment
with a 5-HT1A antagonist alone improves sexual function (Fig. 3).
In an additional test of the ability of a 5-HT1A antagonist to ameliorate sexual
dysfunction, Example compound 3 was administered to sexually experienced male
rats using an acute schedule. In these experiments, rats were treated with vehicle
only on days 1-13 then administered a single acute dose of 0.1 mg/kg of the
compound (group 1), vehicle only for days 1-13 and a single dose of 1.0 mg/kg
compound in vehicle on day 14 (group 2), only vehicle on days 1-14 (group 3),
fluoxetine on days 1-14 (group 4), fluoxetine on days 1-13 and a single
administration of 0.1 mg/kg of the compound and fluoxetine on day 14 (group 5);
and fiuoxetine on days 1-13 and a single dose of 1.0 mg/kg compound with
fluoxetine on day 14 (group 6). For each group, behavior testing was performed for
30 minutes immediately following drug administration on day 14 only. In these
experiments, two different doses of the compound were administered, 0.1 mg/kg or
1.0 mg/kg, and either dosage resulted in a full reversal of the deficits in the number
of non-contact penile erections, produced by chronic (14 day) treatment with an
SSRI, fluoxetine (10 mg/kg/day, i.p.). These data further indicate the efficacy of

using a compound of the invention to treat sexual dysfunction, and also provide
examples of effective dosages and an example of a dosage range (Fig 4, Fig 5).
Experiments were conducted to assess the ability of a 5-HT1A antagonist to
prevent the effects of SSRI treatment. Rats, as described supra, were co-
administered a 5-HT1A antagonist and an SSRI. The 5-HT1A antagonist was either
Example compound 3 (1 mg/kg) or Example compound 2 (0.3 mg/kg). The
administered SSRI was fluoxetine (10 mg/kg). The 5-HT1A antagonist and SSRI
were co-administered for 7 or 14 days with the SSRI. Under these conditions, 5-
5-HT1A antagonist prevented the deficit in non-contact penile erections produced by
chronic fluoxetine treatment alone. These data demonstrate that chronic treatment
with a 5-HT1A antagonist, when co-administered with an SSRI, can prevent or
ameliorate sexual dysfunction associated with SSRI treatment (Fig. 5, Fig. 6)
Taken together these data demonstrate the efficacy of a 5-HT1A antagonist
for treating sexual dysfunction, e.g., that is associated with antidepressant
treatment, whether treatment with the 5-HT1A antagonist is initiated at the same
time as antidepressant treatment (e.g., SSRI treatment) or when treatment with the
5-HT1A is provided after initiation of treatment with the antidepressant.
The effects of 14 day chronic treatment of the animal model is tested in an
animal provided with a 5-HT1A antagonist that is administered orally (p.o.) or i.p., or
fluoxetine (i.p.). The effect of the two treatments on penile erections in sexually
experienced male rats is tested. The ability of the compounds to affect the number
of non-contact penile erections relative to vehicle treated animals is determined and
the results between the two treatment regimes are compared. It is expected that a
compound useful for treating SSRI-related sexual dysfunction is will exhibit minimal
or no effects on sexual function as determined by the assay relative to SSRl-treated
animals.
The Examples provided supra illustrate methods that can be used to test
compounds described herein for their ability to ameliorate sexual dysfunction

associated with drug treatment. Other models known in the art for testing sexual
dysfunction associated with antidepressant, antipsychotic, or anticonvulsant
treatment can be used.
OTHER EMBODIMENTS
The present invention may be embodied in other specific forms without
departing from the spirit and essential attributes thereof and, accordingly, reference
should be made to the appended claims, rather than to the foregoing specification,
as indicating the scope of the invention.

CLAIMS
WHAT IS CLAIMED IS:
1. A method for treating sexual dysfunction associated with drug treatment in a
patient in need thereof, the method comprising administering to the patient an
effective amount of a compound that is a 5-HT1A antagonist.
2. The method of claim 1, wherein the drug treatment is antidepressant drug
treatment, antipsychotic drug treatment, or anticonvulsant drug treatment.
3. The method of claim 1, wherein the compound is a compound of formula (I)

or a pharmaceutically acceptable acid addition salt thereof wherein:
A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more
lower alkyl groups,
Z is oxygen or sulfur,
R is H or lower alkyl,
R1 is a mono or bicyclic aryl or heteroaryl radical,
R2 is a mono or bicyclic heteroaryl radical, and
R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl,
aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR4R5
[where R4 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R5 is hydrogen, lower
alkyl, -CO(lower)alkyl, aryl, -Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-
(lower)alkyl or R4 and R5 together with the nitrogen atom to which they are both
attached represent a saturated hytrocyclic ring which may contain a further
heteroatom], or a group of formula OR6 [where R6 is lower alkyl, cycloalkyl,
cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].

4. The method of claim 3, wherein the compound is a compound of formula (III) or a
pharmaceutically acceptable salt thereof.
5. The method of claim 1, wherein the compound is (R)-4-cyano-N-{2-[4-(2,3-
dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]propyl}-N-pyridin-2-yl-benzamide or a
pharmaceutically acceptable acid addition salt thereof (Example compound 1), N-[2-
[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cycIohexanecarboxamide
(Example compound 2) or a pharmaceutically acceptable acid addition salt thereof,
or (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)
cyclohexanecarboxamide (Example compound 3) or a pharmaceutically acceptable
acid addition salt thereof.
6. The method of claim 1, wherein the drug is a selective serotonin reuptake
inhibitor (SSRI).
7. The method of claim 6, wherein the SSRI is fluoxetine, citolopram, escitalopram
oxalate, fluvoxamine maleate, paroxetine, or sertraline.
8. The method of claim 1, wherein the drug is a tricyclic antidepressant.
9. The method of claim 8, wherein the tricyclic antidepressant is desipramine,
amitriptiyline, amoxipine, clomipramine, doxepin, imipramine, nortriptyline,
protriptyline, or trimipramine.
10. The method of claim 1, wherein the drug is an aminoketone class compound.
11. The method of claim 10, wherein the aminoketone class compound is bupropion.
12. The method of claim 1, wherein the drug is a monoamine oxidase inhibitor
(MAOI).
13. The method of claim 12, wherein the monoamine oxidase inhibitor is phenelzine.

14. The method of claim 1, wherein the drug is a serotonin and norepinepherine
reuptake inhibitor (SNRI).
15. The method of claim 14, wherein the SNRI is venlafaxine, nefazodone,
rnilnacipran, or duloxetine.
16. The method of claim 1, wherein the drug is a norepinephrine reuptake inhibitor
(NRI).
17. The method of claim 16, wherein the drug is reboxetine.
18. The method of claim 1, wherein the drug is a partial 5-HT1A agonist.
19. The method of claim 18, wherein the drug is buspirone.
20. The method of claim 1, wherein the drug is a 5-HT2A receptor antagonist.
21. The method of claim 20, wherein the drug is nefazodone.
22. The method of claim 1, wherein the drug is a typical antipsychotic drug.
23. The method of claim 1, wherein the drug is an atypical antipsychotic drug.

24. The method of claim 1, wherein the drug is an aliphatic phethiazine, a piperazine
phenothiazine, a butyrophenone, a substituted benzamide, or a thioxanthine.
Additional examples of such drugs include haloperidol, olanzapine, clozapine,
risperidone, pimozide, aripiprazol, and ziprasidone.
25. The method of claim 1, wherein the drug is phenobarbital, phenytoin, primidone,
or carbamazepine.

26. The method of claim 2, wherein the patient is being treated with at least two
drugs that are antidepressant drugs, antipsychotic drugs, anticonvulsant drugs, or a
combination thereof.
27. The method of claim 1, wherein the method comprises oral delivery of the
compound.
28. The method of claim 1, wherein the method comprises delivery of a sustained
release compound.
29. The method of claim 1, wherein the sexual dysfunction comprises a deficiency
in penile erection.
30. A method of improving sexual function in a patient in need thereof, the method
comprising administering to the patient a pharmaceutically effective amount of a
compound that is a 5-HT1A antagonist.
31. The method of claim 30, wherein the compound is a compound of formula (I)

or a pharmaceutically acceptable acid addition salt thereof, wherein
A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more
lower alkyl groups,
Z is oxygen or sulfur,
R is H or lower alkyl,
R1 is a mono or bicyclic aryl or heteroaryl radical,
R2 is a mono or bicyclic heteroaryl radical, and
R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl.
ary|(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR4R5
[where R4 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R5 is hydrogen, lower

alkyl, -CO(lower)alkyl, aryl, -Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-
(lower)alkyl or R4 and R5 together with the nitrogen atom to which they are both
attached represent a saturated hytrocyclic ring which may contain a further
heteroatom], or a group of formula OR6 [where R6 is lower alkyl, cycloalkyl,
cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl]; a
compound of formula (III)

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof, or formula (IV)

wherein, Ra and Rb are each hydrogen or methyl and Rc is hydrogen, halo or C 1 -
4 alkyl; or a pharmaceutically acceptable acid addition salt thereof.
32. The method of claim 30, wherein the compound is Example compound 1,
Example compound 2, or Example compound 3.

33. A pharmaceutical composition for treating sexual dysfunction associated with
drug treatment, the composition comprising a compound of formula (I), formula (III),
or formula (IV).
34. The pharmaceutical composition of claim 33, wherein the drug is an
antidepressant, an antipsychotic, or an anticonvulsant.
35. The pharmaceutical composition of claim 33, wherein the compound is effective
for ameliorating sexual dysfunction in an animal model of sexual dysfunction
associated with drug treatment.
36. The pharmaceutical composition of claim 35, wherein the animal model of
sexual dysfunction is an antidepressant drug-induced model of sexual dysfunction.
37. A package comprising a 5-HT1A antagonist and instructions, wherein the
instructions comprise instructions for treating sexual dysfunction.
38. The package of claim 37, wherein the instructions are for treating sexual
dysfunction associated with drug treatment.
39. A method for treating memory deficits or cognitive disorders in a patient in need
thereof, comprising providing to the patient a therapeutically effective amount of a
compound of formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.

40. A method for treating alcohol, nicotine and drug withdrawal in a patient in
need thereof, comprising providing to the patient a therapeutically effective amount
of the compound of formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
41. A method for treating Parkinson's disease and motor disorders in a patient in .
need thereof, comprising administering to the patient an effective amount of a
compound of Formula III:

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
42. A method for treating migraine in a patient in need thereof, comprising
administering to the patient an effective amount of a compound of formula (III):


wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
43. A method for treating eating disorders in a patient in need thereof,
comprising administering to the patient an effective amount of a compound of
formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
44. A method for treating sexual dysfunction in a patient in need thereof,
comprising administering to the patient an effective amount of a compound of
formula (III):

(Ill)
wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
45. A method for treating urinary incontinence in a patient in need thereof,
comprising administering to the patient an effective amount of a compound of
formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
46. A method for treating stroke in a patient in need thereof, comprising
administering to the patient an effective amount of a compound of formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.

47. A method for treating endocrine disorders in a patient in need thereof,
comprising administering to the patient an effective amount of a compound of
formula (III):
wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
48. A method for treating sleep disorders in a patient in need thereof, comprising
administering to the patient an effective amount of a compound of formula (III):

wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
49. A method for treating attention deficit disorders in a patient in need thereof,
comprising administering to the patient an effective amount of a compound of
formula (III):


wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.
50. A method for treating Tourette's syndrome, autism, social phobias,
hyperactivity disorders or thermoregulatory disorders in a patient in need thereof,
comprising administering to the patient an effective amount of a compound of
formula (III):
wherein R1 is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable
acid addition salts thereof.

Methods and compositions are provided for treating sexual dysfunction, e.g., sexual dysfunction associated with
drug treatment, using 5-HT1A receptor antagonists.