TITLE: NOVEL CENTRAL-NERVOUS SYSTEM ACTING COMPOUNDS AND METHODS FOR THE TREATMENT OF CNS DISORDERS FIELD OF THE INVENTION The present invention relates to a new class of central nervous system-acting butylamine derivatives. The compounds are useful for treating diseases or conditions for which inhibition of both serotonin and dopamine reuptake is beneficial, for example, depression. The compounds, at higher doses, are also useful in blocking dopamine D2 receptors and alleviating psychosis and related mental disorders, while having low or no risk of eliciting extrapyramidal side effects, hyperprolactinemia or tardive dyskinesia. The present invention further relates to new methods for the effective treatment of CNS disorders, such as depression. BACKGROUND OF THE INVENTION Depression and antidepressants Clinical depression is common, occuring in about one in five people during their lifetime, and among the top four most common illnesses internationally as listed by the World Health Organization. The syndrome of depression may include persistent sadness, loss of self-esteem, difficulty concentrating, guilt, hopelessness, avoiding other people, loss of appetite, lack of enjoyment, and suicidal thoughts. 1. Types of antidepressants and their mechanisms of action

There are many types of antidepressants used in clinical practice. The various types of antidepressant drugs can be grouped according to nine basic mechanisms of action. The following antidepressant groups of drugs are recognized: 1.1 Antidepressants which mainly inhibit the uptake of norepinephrine (noradrenaline) and to a lesser extent inhibit the uptake of dopamine and serotonin:

This group includes imipramine (Tofranil®), desipramine (Pertofrane®), trimipramine (Surmontil®), amitriptyline (Elavil®), nortriptyline (Aventil®), protriptyiline (Vivactil®), doxepine (Sinaequan®), and maprotiline (Ludiomil®). These drugs primarily, but not selectively, inhibit the re-uptake of norepinephrine normally released from the terminals of norepinephrine-containing nerve cells. By blocking the transport of norepinephrine by the norepinephrine transporter protein, the concentration of norepinephrine increases in the synaptic space outside the nerve

terminal. This increase in norepinephrine over a matter of 1 to 2 weeks causes fewer norepinephrine receptors to be needed on the post-synaptic nerve cell. Thus, the postsynaptic nerve cell synthesizes fewer adrenoceptors (i.e., fewer beta-1 adrenoceptors) and the density of beta-1 adrenoceptors in the cerebral cortex of rats generally falls by approximately 20% during the first week or two.

It is this consistent fall in the density of cortical beta- 1 adrenoceptors which is associated with the clinical alleviation of depression. In fact, a fall in beta-1 density is also seen in the cerebral cortex of animals subjected to a wide variety of antidepressant therapies, including electroshock treatment, light therapy, and maintained wakefulness.

These tricyclic antidepressants are currently used as often as the serotonin- selective uptake inhibitors (Pincus et al, JAMA 279: 526-531, 1998). Although these drugs are commonly used in the dose range of 100-200 mg per day, a meta-analysis reveals equally effective antidepressant action, with significantly fewer side-effects, when using doses less than 100 mg per day (Furukawa et al., Brit. Med. J. 325: 1-9, 2002).

1.2. Antidepressants which selectively inhibit the uptake of serotonin (5-hydroxy- tryptophan):

This group includes paroxetine (Paxil®), citalopram (Celexa®) or its S- enantiomer, S-citalopram (Lexapro®), fluoxetine (Prozac®), fluvoxamine (Luvox®), or sertraline (Zoloft®). These drugs are relatively selective in their ability to inhibit the re-uptake of serotonin normally released from the terminals of serotonin- containing nerve cells. By blocking the transport of serotonin by the serotonin transporter protein, the concentration of serotonin increases in the synaptic space outside the nerve terminal. This increase in serotonin over a matter of 1 to 2 weeks is associated with the alleviation of depression. Although the increase in extracellular serotonin would be expected to cause a fall in the density of serotonin receptors, this has not been found. Moreover, using this class of antidepressants, there is no change in the density of beta- 1 adrenoceptors in the cerebral cortex, as occurs with those antidepressants which generally block the uptake of norepinephrine (A. Frazer & S. Benmansour, MoI. Psychiat. 7: S23-S28, 2002).

Although all of the five major serotonin-selective uptake inhibitors are associated with weight gain, about one in four patients on paroxetine gain significant weight (>7%) over six months (M. Fava. J. Clin. Psychiat. 61 Suppl. 11 : 37-41, 2000). 1.3. Antidepressants which inhibit the uptake of dopamine:

This group includes bupropion (Wellbutrin®), methylphenidate (Ritalin®), nomifensine (discontinued), and amineptine (Survector®; not in the U.S.A.). These drugs relatively selectively inhibit the re-uptake of dopamine normally released from the terminals of dopamine-containing nerve cells. By blocking the transport of dopamine by the dopamine transporter protein, the concentration of dopamine increases in the synaptic space outside the nerve terminal. This increase in extracellular dopamine in a matter of hours or a few days activates or stimulates dopamine receptors (of which there are five types in the nervous system) situated on a variety of nerve cells, resulting in increased locomotion and elevated mood. The release and build-up of endogenous dopamine in the synaptic space is generally associated with euphoria. For this reason, therefore, such drugs may lead the individual to become addicted to them. Moreover, excessive release of endogenous dopamine can cause confusion, dizziness and even hallucinations by stimulating the high-affinity state of the dopamine type-2 receptor. Because the dopamine and norepinephrine neurotransmission systems interact with one another, drugs which inhibit the uptake of dopamine also indirectly affect the norepinephrine system. Thus, antidepressant drugs which inhibit the uptake of dopamine also cause the density of beta- 1 adrenoceptors to decrease in the cerebral cortex. 1.4. Antidepressants which inhibit the uptake of both norepinephrine and serotonin:

This group of drugs includes clomipramine (Anafranil®) and venlafaxine (Effexor®). These compounds simultaneously inhibit the uptake of norepinephrine and serotonin, thus providing a wider range of action, as well as a wider range of side- effects, compared to the more selective drugs above.

7.5. Antidepressants which inhibit the serotonin type 2 receptor:

These compounds include nefazodone (Serzone-5HT2®) and mirtazapine

(Remeron®). The block of serotonin type 2 receptors by these drugs appears to conflict with the principle of providing more synaptic serotonin to alleviate depression. Nevertheless, nefazodone has a clinical antidepressant time-course of action similar to that of imipramine.

1.6. Antidepressants which inhibit monoamine oxidase:

Although less commonly used currently, this group of compounds includes isocarboxazid (Marplan®), phenelzine (Nardil®), tranylcypramine (Parnate®) and moclobemide (Manerix®). By inhibiting the metabolism of epinephrine and dopamine, these monoamine oxidase inhibitors make more catecholamine available to elevate mood.

/.7 Antidepressants which stimulate adrenoceptors or dopamine receptors directly: Although reboxetine (Edronax®) is effective in stimulating adrenoceptors and has unique clinical antidepressant action, this compound has considerable side-effects and has been declined for use in the U.S.A.

Low doses of drugs which directly stimulate the dopamine D2 receptor, such as bromocriptine or roxindole, are just as effective as the standard tricyclic antidepressants (C. Theohar et al., Curr. Ther. Res. 30: 830-841, 1981; J. Waehrens &

J. Gerlach, J. Affective Disord. 3: 193-202, 1981 ; P. Willner, Int. Clin.

Psychopharmacol. 12: S7-S14, 1997).

1.8 Mood stabilizers/preventives:

Although lamotrigine (Lamictal®) and topiramate, both anticonvulsants, and lithium are not effective in treating acute depression, they do reduce or prevent relapse into depression. Lamotrigine enhances neurotransmission in the gamma- amino-butyric acid neurotransmitter system. Lithium salts have many sites of action when replacing about 1% of the sodium ions in the body, but lithium's major mode of action may be in modifying the intracellular events immediately after various receptors are stimulated or inhibited.

1.9 Antipsychotics which act as antidepressants:

Although the use of antipsychotics for depression has been controversial (M. Robertson and M.R. Trimble, J. Affective Disorders 4: 173-193, 1982), amoxapine (Asendin®) and trazodone (Desyrel®) are effective for both types of illnesses, depression and psychosis (R. Apiquian et al., Schizophr. Res. 59: 35-39, 2003). Robertson and Trimble summarized many studies showing that thioridazine, chlorpromazine, perphenazine, fluphenazine, thiothixene, flupenthixol, and chlorprothixene are as effective as imipramine, amitriptyline, or doxepin in treating depression. However, the doses of these antipsychotics are generally lower in treating depression, and it is possible that the antipsychotics are actually only removing the element of anxiety within the clinical depression (M.M. Katz et al., Depression & Anxiety 4: 257-267, 1996-97).

More recently, reviews have summarized that low doses of the antipsychotic amisulpride (50-100 mg/day) or levo-sulpiride (50-150 mg/day) are effective in depression, while higher doses (100-400 mg/day) are effective against psychosis (L. Pani & G.L. Gessa, MoI. Psychiat. 7: 247-253, 2002; A. Mucci et al. Pharmacolog. Res. 31 : 95-101, 1995). The antipsychotic doses of these two compounds are related to their dissociation constants at the dopamine D2 receptor, with that for S- amisulpride being 1.8 nM and that for S-sulpiride being 9.9 nM (P. Seeman. Canad. J. Psychiat. 47: 27-38, 2002).

While the antipsychotic actions of the benzamides are consistent with their affinities at the dopamine D2 receptor, the basis for their antidepressant action is speculative. 2. Animal models of depression The animal models of depression are limited (S. Kapur & JJ. Mann, Biol.

Psychiat. 32: 1-17, 1992). There are four types of such models.

1. The "learned helplessness" model, where animals are exposed to inescapable stressors such as to decrease spontaneous activity and decrease the effort to escape, effects which are reversed by imipramine, desipramine, amitryptiline, doxepin, iprindole, mianserin, iproniazid and pargyline or by electroshock (A. D. Sherman et al., Pharmacol. Biochem. Behav. 16: 449-454, 1982).

2. The "forced swim test" or "behavioural despair" is where rats are forced to swim in a limited space. After some hopeless attempts at escape, the rats become immobile, an effect which some antidepressants may reverse.

The relevance of these animal "frustration" models to clinical depression have been questioned (P. Willner, Psychopharmacology 83: 1-16, 1984).

3. There are many types of rat behaviour tests for motivation and reward. Although dopamine is central to these behaviours, and although antidepressants may have effects on such tests, the clinical relevance of such tests to human depression has been questioned (Refs. In S. Kapur & J.J. Mann, Biol. Psychiat. 32: 1-17, 1992). 4. Although not a behavioural test, a consistent and reliable index of antidepressant action is the reduction in the density of beta-adrenoceptors in the rat cortex after 10 days or two weeks of antidepressant treatment, with the single exception of serotonin-selective uptake inhibitors. This effect holds not only for the various classes of antidepressants listed above, but also for other types of antidepressant treatment, such as nitric oxide synthase inhibitors (B. Karolewicz et al., Eur. J. Pharmacol. 215-220, 1999),

PCT patent application publication number WO2001/062713 describes certain phenyl-substituted butylamine compounds as inhibitors of nitric oxide synthase for the treatment or prophylaxis of inflammatory disease and pain. There is a continuing need for new classes of central nervous system acting drugs for the treatment of, for example, psychoses and/or depression SUMMARY OF THE INVENTION

Compounds disclosed herein are examples of novel chemical entities in a new category of therapeutic agents having the surprising and desirable feature of balanced serotonin/dopamine transporter blockade. The compounds disclosed herein, in their balanced inhibition of dopamine and/or serotonin reuptake, are also expected to affect the norepinephrine system by inhibiting the uptake of norepinephrine, thus acting as triple uptake inhibitors with the novel feature of balanced serotonin/dopamine reuptake inhibition. Finally, the compounds disclosed herein, in their balanced inhibition of dopamine and/or serotonin reuptake are further expected to induce a state of dopamine supersensitivity, which will enhance their therapeutic effects, in particular as antidepressants.

In addition, the compounds of the invention are new chemical entities in a new category of antipsychotic compounds having the unexpected feature of D2 receptor blockade with low affinity for the dopamine D2 receptor.

This present invention therefore relates to a new class of substituted butylamine compounds. The present invention therefore includes a compound of Formula I:

wherein R ¹ and R ² are independently selected from the group consisting of H, halo, Cι _-6 alkyl, and OH; and

R ³ is Ci _-6 alkyl, and pharmaceutically acceptable salts, solvates and prodrugs thereof. The present invention further includes all enantiomers and diasteromers of the compounds of Formula I and mixtures thereof.

The present invention further includes a pharmaceutical composition comprising a compound of Formula I, an enantiomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise, in addition to a pharmaceutically acceptable carrier, two or more compounds selected from compounds of Formula I, enantiomers thereof and pharmaceutically acceptable salts, solvates and prodrugs thereof.

The class of compounds to which the compounds of the present invention belong do not exhibit deleterious side effects when used in medications, for example, antidepressant medications. Accordingly, the present invention relates to a method of treating a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial comprising administering to a subject in need thereof an effective amount of one or more compounds selected from a compound of Formula

I, enantiomers thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further relates to a use of one or more compounds selected from a compound of Formula I, enantiomers thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, for the treatment of a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial and a use of one or more compounds selected from a compound of Formula I, enantiomers thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, to prepare a medicament for the treatment of a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial. The present invention also includes the use of one or more compounds selected from a compound of Formula I, enantiomers thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, as a medicament.

The present invention further includes a method of treating a condition or disease comprising administering, to a subject in need thereof, an effective amount of a balanced serotonin and dopamine reuptake inhibitor, wherein said condition or disease is responsive to selective serotonin reuptake inhibitors and benefits from an increase in concentration of dopamine in the synapse. In an embodiment, the balanced serotonin and dopamine reuptake inhibitor further inhibits the reuptake of norepinephrine and/or induces dopamine supersensitivity. In a further embodiment, the balanced serotonin and dopamine reuptake inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof. In an embodiment, the condition or disease is depression.

The compounds of Formula I can also exert antipsychotic action at higher doses than that used for their antidepressant effects, by virtue of their D2-blocking action. Accordingly, the present invention also includes a method of treating psychoses comprising administering to a subject in need thereof an effective amount of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further relates to a use of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, for the treatment of psychoses and a use of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and

pharmaceutically acceptable salts, hydrates and solvates thereof, to prepare a medicament for the treatment of psychoses.

The compounds of Formula I represent a new class of therapeutic compounds by virtue of their novel mechanism of balanced inhibition of serotonin and dopamine reuptake. Accordingly, the present invention further includes a method of identifying an agent that treats a disease for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial comprising contacting cloned serotonin and dopamine receptors with one or more test agents in competition with a radioligand and determining the relative potency, at those receptors, of the one or more test agents and selecting those agents that exhibit balanced inhibition of both serotonin and dopamine reuptake. In a further embodiment, the method further includes identifying agents that, in addition to balanced inhibition of both serotonin and dopamine reuptake, also inhibit the reuptake of norepinephine and/or that induce dopamine supersensitivity. Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

It is here hypothesized that the antidepressant action of low doses of antipsychotics is based on their ability to inhibit presynaptic dopamine D2 receptors. When dopamine is released from nerve terminals, it acts on two general groups of dopamine D2 receptors, situated either pre-synaptically on nerve terminals or post- synaptically on neuron cell bodies. The pre-synaptic dopamine receptors on dopamine nerve terminals are also termed autoreceptors.

Dopamine acts on the pre-synaptic dopamine D2 receptors by inhibiting the release of dopamine from the nerve terminals. Low doses or low concentrations of antipsychotic drugs which block dopamine D2 receptors generally block pre-synaptic dopamine D2 receptors more readily than post-synaptic receptors. The basis for this is thought to be that pre-synaptic D2 receptors are more readily exposed along the

nerve terminals, while the post-synaptic D2 receptors are less readily accessible within the synaptic space. Although it is known that the D2 receptor can exist in three molecular forms, D2short, D2Long and D2Longer, antipsychotic drugs have almost identical affinities for the three forms. Therefore, although D2short is mostly on the pre-synaptic terminals, while D2Long is mostly on the post-synaptic side (A. Usiello et al., Nature 408:199-203, 2000), these different localizations do not explain why low concentrations of antipsychotics act on pre-synaptic D2 receptors, because the drugs have similar affinities for the three forms of D2.

Since low doses or low concentrations of antipsychotics act preferentially on pre-synaptic D2 receptors, these low doses inhibit the inhibiting action of dopamine on dopamine release. Thus, low concentrations of antipsychotics enhance the impulse-associated release of dopamine, activating motion and mood. The activating effect has been found for low doses of haloperidol in rats. High doses in the antipsychotic range, however, will inhibit the action of dopamine on post-synaptic dopamine D2 receptors, thus depressing motion and mood.

It is known that individuals with clinical depression release abnormally low amounts of norepinephrine and dopamine (G. Lambert et al., Arch. Gen. Psychiat. 57: 787-793, 2000). Although high doses of antipsychotic drugs readily increase the release of dopamine in various regions of the brain in animals and humans, this increased release is not effective in alleviating depression because the high doses block most of the dopamine D2 receptors (T. Zetterstrom et al., Eur. J. Pharmacol. 106: 27-37, 1984; B.H.C. Westerink et al., Eur. J. Pharmacol. 361 : 27-33, 1998; R. Davila et al., Arch. Gen. Psychiat. 45: 564-567, 1988; I. Elman et al., Neuropsychopharmacology 27: 293-300, 2002). As noted above, the dopamine and norepinephrine neurotransmission systems interact with one another, accordingly drugs which inhibit the uptake of dopamine also indirectly affect the norepinephrine system. Further, it has been shown the treatment with antidepressant drugs produces a sensitization of behavioural responses to agonists acting at dopamine D2/D3 receptors (so-called dopamine supersensitivity, Willner, P. International Clin. Psychopharm. 12 (Supplement 3):S7-S14, 1997; Healy, E. et al. J. Psychopharm. 14:152-156m 2000).

The Applicant's work presented herein describes a new class of balanced serotonin/dopamine transporter inhibitor therapeutics.

The present invention therefore includes a compound of Formula I:

wherein R and R are independently selected from the group consisting of H, halo, C]-6alkyl, and OH; and R ³ is C _)-6 alkyl, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

As stated above, the compounds of Formula I include those in which R ¹ and R ² are independently selected from the group consisting of H, halo, Ci _-6 alkyl, Q- ₆ alkoxy, halo-substituted Ci _-6 alkyl, halo-substituted and OH. In certain embodiments, R ¹ and R ² are independently selected from the group consisting of H, halo, Ci _-4 alkyl, Ci _-4 alkoxy, halo-substituted d. ₄ alkyl, halo-substituted d^alkoxy and OH. In other embodiments, R ¹ and R ² are independently selected from the group consisting of H, F, Cl, CH ₃ , OCH ₃ , CF ₂ H, CF ₃ , OCF ₃ and OH. In other embodiments, R ² is H and R ¹ is selected from the group consisting of H, F, Cl, CH ₃ , OCH ₃ , CF ₂ H, CF ₃ , OCF ₃ and OH. In other embodiments, R ² is H and R ¹ is CF ₃ . In other embodiments, R ² is Cl and R ¹ is selected from the group consisting of H, F, Cl, CH ₃ , OCH ₃ , CF ₂ H, CF ₃ , OCF ₃ and OH. In other embodiments, R ² is H and R ¹ is CF ₃ . In other embodiments, R ¹ is CF ₃ and R ² is selected from the group consisting of H, F, Cl, CH ₃ , OCH ₃ , CF ₂ H, CF ₃ , OCF ₃ and OH. The groups R ¹ and R ² may be attached at any position of the phenyl ring. In other embodiments, R ¹ and R ² are attached at the 4-position of the phenyl rings.

The compounds of Formula I also include those in which R ³ is Ci _-6 alkyl. In other embodiments. R ³ is C _1-4 alkyl. In other embodiments, R ³ is selected from the

group consisting of CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ and CH(CH ₃ ) ₂ . In another embodiment, R ³ isCH ₃ .

In specific embodiments, the compound of Formula I is selected from N-methyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane- 1 -amine; N-ethyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane- 1 -amine;

N-methyl-4-(4-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy ]butane-l -amine; N-ethyl-4-(4-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]but ane-l -amine; N-methyl-4-(3-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]bu tane- 1 -amine; and N-ethyl-4-(3-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]but ane-l -amine; and pharmaceutically acceptable salts, solvates, prodrugs and enantiomers thereof.

In particular the compound of Formula I is selected from N-methyl-4-phenyl- 4-[4-(trifluorornethyl)phenoxy]butane- 1 -amine; (¥i?, ⁾ -N-methyl-4-phenyl-4-[4-

(trifluoromethyl)phenoxy]butane-l -amine; (¥S)-N-methyl-4-phenyl-4-[4-

(trifluorornethyl)phenoxy]butane-l -amine, mixtures thereof and pharmaceutically acceptable salts, solvates and prodrugs thereof.

All of the compounds of the invention have at least one asymmetric centre at carbon 4 of the butane chain. Where the compounds according to the invention possess more than one asymmetric centre, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. It is to be understood that while the stereochemistry of the compounds of the invention may be as provided for in any given compound listed herein, such compounds of the invention may also contain certain amounts (e.g. less than 20%, preferably less than 10%, more preferably less than 5%) of compounds of the invention having alternate stereochemistry.

The term "Ci _-6 alkyl" as used herein means straight and/or branched chain alkyl groups containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl, pentyl, hexyl and the like.

The term "Ci- ₆ alkoxy" as used herein means straight and/or branched chain alkoxy groups containing from one to six carbon atoms and includes methoxy, ethoxy, propyoxyl, isopropyloxy, t-butoxy, hexyloxy and the like.

The term "Ci _-4 alkyl" as used herein means straight and/or branched chain alkyl groups containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.

The term "Ci _-4 alkoxy" as used herein means straight and/or branched chain alkoxy groups containing from one to four carbon atoms and includes methoxy, ethoxy, propyoxyl, isopropyloxy, t-butoxy and the like.

The term "halo-substituted as used herein means straight and/or branched chain alkyl groups containing from one to six carbon atoms in which one or more, including all, of the hydrogen atoms are replaced with a halogen atom, in particular a fluorine atom, and includes difluoromethyl, trifluoromethyl, pentafluoroethyl heptafluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and the like.

The term "halo-substituted Ci _-6 alkoxy" as used herein means straight and/or branched chain alkoxy groups containing from one to six carbon atoms in which one or more, including all, of the hydrogen atoms are replaced with a halogen atom, in particular a fluorine atom, and includes difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, heptafluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentoxy and the like.

The term "halo-substituted Ci. ₄ alkyl" as used herein means straight and/or branched chain alkyl groups containing from one to four carbon atoms in which one or more, including all, of the hydrogen atoms are replaced with a halogen atom, in particular a fluorine atom, and includes difluoromethyl, trifluoromethyl, pentafluoroethyl and the like.

The term "halo-subsituted Q ^alkoxy" as used herein means straight and/or branched chain alkoxy groups containing from one to four carbon atoms in which one or more, including all, of the hydrogen atoms are replaced with a halogen atom, in particular a fluorine atom, and includes difluoromethoxy, trifluoromethoxy, pentafluoroethoxy and the like.

The term "halo" as used herein means halogen and includes chloro, flouro, bromo and iodo.

The term "compound(s) of the invention" as used herein means compound(s) of Formula I, enantiomers thereof and/or pharmaceutically acceptable salts, solvates and/or prodrugs thereof.

It is to be clear that the present invention also includes mixtures comprising two or more of the compounds of Formula I, enantiomers of the compounds of

Formula I, pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable solvates of compounds of the invention and prodrugs of compounds of the invention.

The term "pharmaceutically acceptable" means compatible with the treatment of animals, in particular, humans.

The term "pharmaceutically acceptable salt" means an acid addition salt which is suitable for or compatible with the treatment of patients.

The term "pharmaceutically acceptable acid addition salt" as used herein means any non-toxic organic or inorganic salt of any base compound of the invention, or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of the compounds of the invention are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g. oxalates, may be used, for example, in the isolation of the compounds of the invention, for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. In an embodiment of the invention, salts of the compounds of Formula I are HCl salts.

The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method. The term "solvate" as used herein means a compound of the invention, or a pharmaceutically acceptable salt of a compound of the invention, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate". The formation of solvates of the compounds of the invention will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The present invention includes within its scope, prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into the compound from which it is notionally derived. Prodrugs of the compounds of the invention may be conventional esters formed with available hydroxy, or amino group. For example, an available OH or NH group in a compound of the invention may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C ₈ -C ₂₄ ) esters, acyloxymethyl esters, carbamates and amino acid esters. In further embodiments, the prodrugs of the compounds of the invention are those in which one or more of the hydroxy groups in the compounds is masked as groups which can be converted to hydroxy groups in vivo. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985.

The present invention includes radiolabeled forms of compounds of the invention, for example, compounds of the invention labeled by incorporation within the structure ³ H or ¹⁴ C or a radioactive halogen such as ¹²⁵ I. A radiolabeled compound of the invention may be prepared using standard methods known in the art.

For example, tritium may be incorporated into a compound of the invention using standard techniques, for example by hydrogenation of a suitable precursor to a compound of the invention using tritium gas and a catalyst. Alternatively, a compound of the invention containing radioactive iodo may be prepared from the corresponding trialkyltin (suitably trimethyltin) derivative using standard iodination conditions, such as [ ¹²⁵ I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide. The trialkyltin compound may be prepared from the corresponding non-radioactive halo, suitably iodo, compound using standard palladium-catalyzed stannylation conditions, for example hexamethylditin in the presence of tetrakis(triphenylphosphine) palladium (0) in an inert solvent, such as dioxane, and at elevated temperatures, suitably 50-100 ⁰ C.

The compounds of the invention can be prepared from known starting materials using procedures known in the art. For Example, the compounds of the invention may be prepared using the general procedures shown in Schemes 1-3. Accordingly, a compound of Formula I may be prepared by reacting a compound of Formula II, wherein R ¹ is as defined in Formula I and LG is a suitable leaving group, such as halo, in particular Cl, with a compound of Formula III, wherein R ² and R ³ are as defined in Formula I, which had been pretreated with a strong base, such as sodium hydride, in an inert solvent at elevated temperatures, suitably at about 50-100 ⁰ C, more suitably at about 60-80 ⁰ C.

Scheme 1

III

Compounds of Formula III are readily available from the corresponding ketone, for example a compound of Formula IV, wherein R ² is as defined in Formula I and PG is a suitable protecting group, such as benzyl, using standard reduction conditions, for example using hydride reducing agents such as sodium borohydride, followed by removal of the protecting group (if present).

Scheme 2

IV III

Compounds of Formula IV may be prepared, for example, by reacting a compound of Formula V, wherein R ² is as defined in Formula I and LG is a suitable leaving group such as halo, for example Cl or I, with a compound of Formula VI, wherein R ³ is as defined in Formula I and PG is any suitable protecting group, such as benzyl, in the presence of a base under standard substitution reaction conditions.

Scheme 3

IV

Compounds of Formula II and VI are either commercially available or may be prepared using methods available in the art.

An enantiomer of a compound of Formula I may be prepared by starting with enantionmerically pure or enantiomerically enriched starting materials, for example, the R or S enantiomer of a compound of Formula III. Compounds of Formula III may be prepared in enantiomerically pure form using chiral reducing agents that are available in the art. Alternatively, the compounds of Formula I, or compounds of

Formula III may be resolved into their separate enantiomers by reaction with chiral salts or other chiral auxilaries to produce diastereomers that can be separated using chromatography. Once the diastereomers are separated, the chiral auxiliary may be removed using standard chemistries to provide the enantiomers of a compound of

Formula I or III.

In some cases the chemistries outlined above may have to be modified, for instance by use of protective groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents. This may be achieved by means of conventional protecting groups, for example as described in "Protective Groups in

Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T. W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons,

1991.

The compounds of the invention, and intermediates in the preparation of the compounds of the invention, may be isolated from their reaction mixtures and purified

(if necessary) using conventional techniques, including, for example, extraction, chromatography, distillation and recrystallization.

Many of the unwanted clinical side-effects of the selective serotonin reuptake inhibitor (SSRI) antidepressants are related to the fact that the compounds are

extremely selective in blocking the serotonin transporter. For example, citalopram is 28,000 times more potent in inhibiting the uptake of serotonin than it is at inhibiting the uptake of dopamine (see Table 1). A principle within the present invention is that the inhibitory potency of the SSRI 's is the basis for sexual difficulties and side-effects about which patients complain. Such complaints include the whole gamut of the sexual experience, ranging from lack of desire in both men and women, erection difficulties in men, related difficulties in women, and lack of orgasm by both sexes. Other difficulties relate to weight gain, drowsiness and sedation.

The compounds of Formula I balance the serotonin selectivity by also blocking the transport of dopamine into the nerve terminals. This results in an increase in the concentration of dopamine in the synapse and thereby an increase in dopamine neurotransmission. Such increased neurotransmission elevates feelings of reward and pleasure known to be associated with increased dopamine transmission. The increased release of dopamine causes the individual to have less drowsiness, less sedation and less weight gain.

Hence, by inhibiting both the serotonin and dopamine transporters, the compounds of Formula I minimize the clinical side-effects caused by the serotonin uptake blockade. The results shown in Table 1 indicate that the serotonin selectivities are very high for the SSRI types of molecules. The compounds of Formula I are more balanced in their potency for blocking serotonin uptake and dopamine uptake. This balance minimizes clinical side-effects in accordance with a balanced increase in both dopamine and serotonin neurotransmission.

Accordingly, the present invention also relates to a method of treating a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial comprising administering to a subject in need thereof an effective amount of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further relates to a use of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, for the treatment of a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial and a use of one or more compounds selected from a compound of Formula

I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, to prepare a medicament for the treatment of a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial.

In an embodiment of the invention, the disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial is any disease or condition that is responsive to selective serotonin reuptake inhibitors (SSRJ) and that would benefit from the increase in the concentration of dopamine in the synapse and thereby an increase in dopamine neurotransmission. Examples of such SSRI responsive disorders include, for example, depression, dysthymia, premenstrual dysphoric disorder, panic disorder, obsessive compulsive disorder, social phobia, post-traumatic stress disorder, generalised anxiety disorder, obesity, bulimia nervosa, alcoholism, trichotillomania, paraphilia and related disorders, borderline personality disorder, smoking cessation and drug abuse. In an embodiment of the invention, the disease or condition for which a balanced or equal inhibition of both serotonin and dopamine reuptake is beneficial is depression. By "depression" it is meant "clinical depression" or "major depressive disorder".

The "balanced inhibition of both serotonin and dopamine reuptake" by a compound referred to herein means a compound that balances an effective amount of serotonin reuptake inhibition with an effective amount of dopamine reuptake inhibition. In an embodiment, a compound having "balanced inhibition of both serotonin and dopamine reuptake" will have a selectivity ratio between the serotonin- transporter-inhibition potency and the dopamine-transporter-inhibition potency (serotonin-transporter-inhibition potency /dopamine-transporter-inhibition potency) ranging from 0.05 to 20, suitably 0.1 to 10, and a dopamine-transporter-inhibition potency of ranging from 1 nM to 200 nM, suitably 10 nM to 150 nM, more suitably 50 nM to 10O nM.

In an embodiment of the invention, the compound of Formula I also inhibits the reuptake of norepinephrine and/or induces dopamine supersensitivity. Alternatively, the methods and uses described above include the contemporaneous administration of an effective amount of one or more compounds known to treat the disease or condition for which a balanced or equal inhibition of both serotonin and dopamine reuptake is beneficial. In an embodiment, the methods and uses described

above include the contemporaneous administration of an effective amount of known antidepressant compounds, for example, norepinephrine reuptake inhibitors and/or compounds that induce dopamine supersensitivity.

Norepinephrine reuptake inhibitors are known in the art and this term is meant to include those known compounds that are selective norepinephrine reuptake inhibitors and those that are non-selective norepinephrine reuptake inhibitors.

Examples of such compounds include bupropion (Wellbutrin) and nomifensine

(Merital).

Compounds that induce dopamine supersensitivity are also known in the art and include, for example, most SSRTs. To "induce dopamine supersensitivity" refers to compounds that can produce an increased number or elevated density of D2 ^Hlgh receptors in a subject's brain. Methods of determining if a subject is in a state of dopamine supersensitivity are described, for example, in Applicant's co-pending PCT patent application publication number WO 2006/047861. The present invention further includes a method of treating a condition or disease comprising administering, to a subject in need thereof, an effective amount of a balanced serotonin and dopamine reuptake inhibitor, wherein said condition or disease is responsive to selective serotonin reuptake inhibitors (SSRIs) and benefits from an increase in concentration of dopamine in the synapse. In an embodiment, the balanced serotonin and dopamine reuptake inhibitor further inhibits the reuptake of norepinephrine and/or induces dopamine supersensitivity. In a further embodiment, the balanced serotonin and dopamine reuptake inhibitor is a compound of Formula I, an enantiomer thereof, or a pharmaceutically acceptable salt, hydrate or prodrug thereof. Examples of such SSRI responsive disorders include, for example, depression, dysthymia, premenstrual dysphoric disorder, panic disorder, obsessive compulsive disorder, social phobia, post-traumatic stress disorder, generalised anxiety disorder, obesity, bulimia nervosa, alcoholism, trichotillomania, paraphilia and related disorders, borderline personality disorder, smoking cessation and drug abuse. In an embodiment of the invention, the disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial is depression. By "depression" it is meant "clinical depression" or "major depressive disorder".

In addition to antidepressant action, the compounds of Formula I can exert antipsychotic action at higher doses than that used for their antidepressant effects, by virtue of their D2-blocking action. Accordingly, the present invention also includes a method of treating psychoses comprising administering to a subject in need thereof an effective amount of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof. The invention further relates to a use of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, for the treatment of psychoses and a use of one or more compounds selected from a compound of Formula I, an enantiomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, to prepare a medicament for the treatment of psychoses.

The term "higher doses" as used herein refers to doses of the compound that are approximately 3 times to 15 times, suitably 5 times to 10 times, higher than the doses expected to provide an antidepressant action.

As used herein, "administered contemporaneously" means that two substances are administered to a subject such that they are both biologically active in the subject at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens are routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e. within minutes of each other, or in a single composition that comprises both substances. The term a "therapeutically effective amount", "effective amount" or a

"sufficient amount " of a compound of the present invention is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount" or synonym thereto depends upon the context in which it is being applied. For example, in the context of inhibiting dopamine and/or serotonin reuptake it is an amount of the compound sufficient to achieve such an inhibition in dopamine and/or serotonin reuptake as compared to the response obtained without administration of the

compound. In the context of disease, therapeutically effective amounts of the compounds of the present invention are used to treat, modulate, attenuate, reverse, or effect a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial, for example, depression and/or psychoses, in a subject. An "effective amount" is intended to mean that amount of a compound that is sufficient to treat, prevent or inhibit a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial, for example, depression and/or psychoses. The amount of a given compound of the present invention that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. Also, as used herein, a "therapeutically effective amount" of a compound of the present invention is an amount which prevents, inhibits, suppresses or reduces a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial, for example, depression and/or psychoses (e.g., as determined by clinical symptoms), in a subject as compared to a control. As defined herein, a therapeutically effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art.

As used herein, and as well understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission

(whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

"Palliating" a disease or disorder means that the extent and/or undesirable clinical manifestations of a disorder or a disease state are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

The term "prevention" or "prophylaxis", or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial, for example, depression and/or psychoses, or manifesting a symptom associated said disease or condition.

To "inhibit" or "suppress" or "reduce" a function or activity, such as neurotransmitter (e.g. dopamine, serotonin or epinephrine) reuptake, is to reduce the function or activity when compared to otherwise same conditions except for a condition or parameter of interest, or alternatively, as compared to another conditions. The term "subject" or "patient" or synonym thereto, as used herein includes all members of the animal kingdom, especially mammals, including human. The subject or patient is suitably a human.

The present invention also includes the use of one or more compounds selected from a compound of Formula I, enantiomers thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, as a medicament.

All compounds described herein, including the compounds of the invention, are suitably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Therefore the present invention further includes a pharmaceutical composition comprising a compound of Formula I, an enantiomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise, in addition to a pharmaceutically acceptable carrier, two or more compounds selected from compounds of Formula I, enantiomers thereof, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

Also included herein is a composition for the treatment of a disease or condition for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial comprising an effective amount of balanced serotonin and dopamine reuptake inhibitor and a pharmaceutically acceptable carrier. In an embodiment, the effective amount of balanced serotonin and dopamine reuptake inhibitor in an composition for oral delivery is 0.1 mg to 100 mg, suitably 1 mg to 75 mg, more suitably, 5 mg to 50 mg. In an embodiment, the composition is in the form of a

controlled release system, for example, for oral delivery. In a further embodiment the compositions for the treatment of depression and comprises an anti-depressant- effective amount of the balanced serotonin and dopamine reuptake inhibitor.

The compositions described herein can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle. Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985). On this basis, the compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.

The compounds of the invention may be used in the form of the free base, in the form of salts and/or solvates. All forms are within the scope of the invention.

In accordance with the methods of the invention, the described compounds, salts or solvates thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compositions of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

Compounds described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or may be enclosed in hard or soft shell gelatin capsules, or may be compressed into tablets, or may be incorporated directly with the food of the diet. For oral therapeutic administration, the compounds may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Compounds described herein may also be administered parenterally. Solutions can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (1990 - 18th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersion and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. Ampoules are convenient unit dosages.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.

Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal

administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions for topical administration may include, for example, propylene glycol, isopropyl alcohol, mineral oil and glycerin. Preparations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in- water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops; or solid controlled release forms such as transdermal patches. In addition to the aforementioned ingredients, the topical preparations may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

Sustained or direct release compositions can be formulated, e.g. liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the compounds of the invention and use the lypolizates obtained, for example, for the preparation of products for injection.

The compounds of the invention may be administered to a subject alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.

The dosage of the compounds and/or compositions described herein can vary depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. Oral preparations may be formulated, preferably as tablets, capsules, or drops, containing from 0.1-100 milligrams, suitably 1-75 millgrams, more suitably 5-50 milligrams of a compound described herein, per dosage unit. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.

In addition to the above-mentioned therapeutic uses, the compounds of the invention are also useful in diagnostic assays, screening assays and as research tools.

The compounds of Formula I represent a new class of therapeutic compounds by virtue of their novel mechanism of balanced inhibition of serotonin and dopamine reuptake. Accordingly, the present invention further includes a method of identifying an agent that treats a disease for which a balanced inhibition of both serotonin and dopamine reuptake is beneficial comprising contacting cloned serotonin and dopamine receptors with one or more test agents in competition with a radioligand and determining the relative potency, at those receptors, of the one or more test agents and selecting those agents that exhibit balanced inhibition of both serotonin and dopamine reuptake. In a further embodiment, the method further includes identifying agents that, in addition to balanced inhibition of both serotonin and dopamine reuptake, also inhibit the reuptake of norepinephine and/or that induce dopamine supersensitivity. In an embodiment the agents that are selected are those with a selectivity ratio between the serotonin-transporter-inhibition potency and the dopamine-transporter- inhibition potency ranging from 0.05 to 20, suitably 0.1 to 10, and a dopamine- transporter-inhibition potency ranging from 1 nM to 200 nM, suitably 20 nM to 150 nM, more suitably from 50 nM to 100 nM. The one or more test agents may be any substance which one wishes to test including, but not limited to, proteins (including antibodies), peptides, nucleic acids (including RNA, DNA, antisense oligonucleotide, peptide nucleic acids, RNA or DNA aptamers, ribozymes or deoxyribozymes), fragments of proteins, peptides, and nucleic acids, carbohydrates, organic compounds, inorganic compounds, natural products, library extracts and bodily fluids. The one or more test agents may be in liquid or gaseous form. Typically a solution of known concentration of the one or more test agents is employed.

It is an embodiment herein that the contacting of the cloned serotonin and dopamine receptors in the present invention is performed using standard radiolabeled competition experiments (for example as described hereinbelow in the Examples) in cells expressing the desired receptor.

The present invention further includes an agent identified using the assay described above, as well as a pharmaceutical compositions comprising an agent identified using the assay described above and a pharmaceutically acceptable carrier. The following non-limiting examples are illustrative of the present invention: EXAMPLES

All reactions were monitored by thin-layer chromatography and structures of the products were confirmed by H-NMR (300 MHz) and mass spectrometry. Example I (a): Synthesis of 4-(N-benzyl-N-methylamino)- 1 -phenylbutan- 1 -one (Precursor 1): A solution of 4-chloro-l -phenylbutan- 1 -one (10.0 g, 0.05 mole) in 75 ml of acetone that had been saturated with sodium iodide (NaI) was refluxed overnight. The acetone was removed at reduced pressure. Water (20 ml) was added, and the crude product was obtained by extracting with ether (2 x 20 ml). The combined ether layer was washed with fresh water and brine and dried over magnesium sulfate (MgSO ₄ ). After removing the ether on a rotary evaporator, a reddish oily crude product was obtained and used as such for the next step. The crude product obtained in the previous step was dissolved in 50 ml acetone, and 2.42 g (0.05 mole) of N- benzyl methylamine and 6.91 g (0.05 mole) of potassium carbonate (K ₂ CO ₃ ) was then added. The reaction mixture was refluxed overnight. After removing acetone at reduced pressure, water was added and the product was isolated in dichloromethane from the aqueous solution. The organic layer was washed with fresh water and brine, and dried over magnesium sulfate. The product (9.52 g, 80%) was obtained as reddish oil after removing dichloromethane on a rotary evaporator. In a like manner, the following additional compounds may also be prepared: (b) 4-(N-benzyl-N-ethylamino)-l -phenylbutan- 1 -one, from 4-chloro-l -phenylbutan- 1-one and benzyl ethylamine;

(c) 4-(N-benzyl-N-methylamino)-l-(4-chlorophenyl)butan-l-one, from 4-chloro-l -(4- chlorophenyl)butan-l-one and benzyl methylamine;

(d) 4-(N-benzyl-N-ethylamino)-l-(4-chlorophenyl)butan-l-one, from 4-chloro-l -(4- chlorophenyl)butan-l-one and benzyl ethylamine;

(e) 4-(N-benzyl-N-methylamino)-l-(3-chlorophenyl)butan-l-one, from 4-chloro-l -(3- chlorophenyl)butan-l-one and benzyl methylamine; and

(f) 4-(N-benzyl-N-ethylamino)-l-(3-chlorophenyl)butan-l-one, from 4-chloro-l-(3- chlorophenyl)butan-l-one and benzyl ethylamine.

Example 2(a): 4-(N-benzyl-N-methylamino)-l-phenylbutan-l-ol (Precursor 2):

9.52 g (0.036 mole) of 4-(N-benzyl-N-methylamino)-l-phenylbutan-l-one (Example l(a))was dissolved in 25 ml methanol (CH ₃ OH). 2.27 g (0.06 mole) of

NaBH ₄ was added slowly while stirring the reaction mixture at low temperature (5-10 "C). After stirring the reaction mixture at room temperature for two hours, methanol was removed on a rotary evaporator. Water was added and the product was isolated in dichloromethane (2 x 20 ml). The combined organic layers were washed with fresh water brine and dried over magnesium sulfate. The product (7.53 g, 77.7%) was isolated as a reddish oil. In a like manner, the following additional compounds may also be prepared:

(b) 4-(N-benzyl-N-ethylamino)-l-phenylbutan-l-ol, from Example l(b);

(c) 4-(N-benzyl-N-methylamino)-l-(4-chlorophenyl)butan-l-ol, from from Example l(c);

(d) 4-(N-benzyl-N-ethylamino)-l-(4-chlorophenyl)butan-l-ol, from Example l(d);

(e) 4-(N-benzyl-N-methylamino)-l-(3-chlorophenyl)butan-l-ol, from Example l(e); and

(f) 4-(N-benzyl-N-ethylamino)-l-(3-chlorophenyl)butan-l-ol, from Example l(f). Example 3(a): 4-(methylamino)-l-phenylbutan-l-ol (Precursor 3):

7.53 g (0.028 mole) of 4-(N-benzyl-N-methylamino)-l-phenylbutan-l-ol (Example 2(a)) was dissolved in 40 ml ethanol in a pressure vessel. 0.5 g of Pd/C was added to the vessel as catalyst, after purging with argon for considerable time. The reaction vessel was fixed in a Parr shaker-type hydrogenator. After removing air from the vessel under vacuum, the reaction mixture was agitated under 40 psi pressure overnight. The reaction mixture was filtered over Celite, and the product (4.13 g, 82.1%) was obtained as oily material after removing the ethanol under reduced pressure. In a like manner, the following additional compounds may also be prepared: (b) 4-(ethylamino)-l-phenylbutan-l-ol, from Example 2(b);

(c) 4-(methylamino)-l-(4-chlorophenyl)butan-l-ol, from from Example 2(c);

(d) 4-(ethylamino)-l-(4-chlorophenyl)butan-l-ol, from Example 2(d);

(e) 4-(niethylamino)-l-(3-chlorophenyl)butan-l-ol, from Example 2(e); and

(f) 4-(ethylamino)-l-(3-chlorophenyl)butan-l-ol, from Example 2(f). Example 4 (a) : N-methyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane- 1 -amine (Compound Ia): A solution of 4-(methylamino)-l-phenylbutan-l-ol (Example 3(a), 4.13 g,

0.023 mole) was dissolved in 50 ml N,N-dimethylacetamide in a round-bottom flask. 1.10 g (0.046 mole) of sodium hydride (NaH) was carefully added to this flask, and the reaction mixture heated to 70 °C with continuous stirring. After two hours, the reaction was cooled to room temperature, and 4.15 g (0.023 mole) of 4- chlorobenzotrifluoride was added with continuous stirring. The temperature was raised to around 90 ⁰ C and the mixture stirred for three hours, and then cooled down to room temperature. Water was added and the crude product was isolated in dichloromethane (2 x 100 ml) from the aqueous solution. The combined organic layers were washed with brine and fresh water and dried over magnesium sulfate (MgSO ₄ ). The product (5.86 g, 78.3%), purified on silica gel with n- hexane/ethylacetate/methanol, was obtained as a thick reddish oil. NMR (300 MHz, CDCl ₃ ) — 1.40 (IH, broad s, NH), 1.54-1.66 (IH, mult), 1.68-1.80 (IH, mult), 1.86- 1.98 (IH, mult), 2.04-2.16 (IH, mult), 2.48 (3H, s), 2.68 (2H, t), 5.19 (IH, dd), 6.92 (2H, d), 7.22-7.34 (5H, mult), 7.46 (2H, d). Mass spectrum (electron impact) m/e 323 (M ⁺ , 13%), 178 (M ⁺ - C ₆ H ₄ CF ₃ , 14%), 162 (M+ - OC ₆ H ₄ CF ₃ , 100%), 131 (100%). In a like manner, the following additional compounds may be prepared:

(b) N-ethyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane-l -amine, from Example 3(b);

(c) N-methyl-4-(4-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]bu tane- 1 -amine, from Example 3(c);

(d) N-ethyl-4-(4-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]but ane- 1 -amine, from Example 3(d);

(e) N-methyl-4-(3-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]bu tane-l -amine, from Example 3(e); and (f) N-ethyl-4-(3-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]but ane-l -amine, from Example 3(f).

Example 5: HCl salt ofN-methyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane-l- amine (Compound IaHCl)

N-Methyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane- 1 -amine was dissolved in a minimum amount of dry ether. An equivalent amount of HCl (1.0 molar in ether) was slowly added dropwise to the solution. The solution was kept overnight at room temperature. White crystals of the HCl salt of N-methyl-4-phenyl- 4-[4-(trifluoromethyl)phenoxy]butane-l -amine came out of solution. These crystals were filtered and dried (M.P. 105-107 ⁰ C). NMR (300 MHz, CDCl ₃ ) — 1.95-2.20 (4H, mult), 2.60 (3H, broad s), 3.0 (2H, mult), 5.21 (IH, dd), 6.92 (2H, d), 7.26-7.40 (5H, mult), 7.48 (2H, d), 9.6 (2H, broad s, NH2). Mass spectrum (electrospray), m/e 324 (MH+).

In a like manner, the following additional compounds may be prepared: (b) N-ethyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane-l -amine HCl, from Example 4(b); (c) N-methyl-4-(4-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]bu tane-l-amine HCl, from Example 4(c);

(d) N-ethyl-4-(4-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy] butane- 1 -amine HCl, from Example 4(d);

(e) N-methyl-4-(3-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]bu tane-l -amine HCl, from Example 4(e); and

(f) N-ethyl-4-(3-chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]but ane- 1 -amine HCl, from Example 4(f).

Example 6: In vitro tests (a) Tissues Rat brains were purchased from Pel-Freez (Rogers, AR) and stored at -70 "C.

Before each experiment, the striata or the frontal cerebral cortex (free of myelin) was dissected from the partly thawed rat brain on a glass plate on a bed of dry ice. The dissected tissue was suspended in buffer (50 mM Tris-HCl, pH 7.4 at 20 ^° C, 1 mM EDTA, 5 mM KCl, 120 mM NaCl, 1.5 mM CaC12, 4 mM MgCl ₂ ) at 4 mg original wet weight per ml suspension. The suspension was homogenized for 5 s with a Polytron (PT-10 probe, Brinkmann Instruments, Inc, Westbury, NY; setting 5) without any subsequent washing, centrifugation or preincubation, procedures known

to result in a loss of 23-37% of receptors (J. Neurochem. 43: 221-235, 1984). (b) Cloned receptors in tissue culture cells

Human dopamine Dl receptors (in Sf9 cells or COS cells), human dopamine D2Long receptors (in Sf9 cells or CHO cells), rat dopamine D3 receptors, human serotonin- IA receptors, and human muscarinic Ml receptors, all expressed in Sf9 cells, were purchased from Research Biochemicals International (Natick, MA). The frozen membranes containing the receptors were directly suspended at approximately 100 μg protein/ml and the cell suspension was homogenized for 5 s (Polytron, setting 5) without any further washing. (c) fHJLigands

[N-methyl- ¹ H]SCH23390 (for labelling dopamine Dl receptors; 70-87 Ci/mmol), [ ¹ H]raclopride (for D2 receptors; 70-80 Ci/mmol), [ ¹ H]QNB or L-[N- methyl--H]quinuclidinyl benzilate methyl chloride (for muscarinic receptors; 84 Ci/mmol), [ ¹ H]S-OH-DPAT or ^HJ-δ-hydroxy-dipropylaminotetralin (for serotonin- 1 receptors; 163 Ci/mmol), [^prazosin (for alpha- 1 -adrenoceptors; 80 Ci/mmol), ^HJyohimbine (for alpha-2-adrenoceptors; 71 Ci/mmol), [ ¹ HJdUIy droalprenolol (for beta-adrenoceptors; 106 Ci/mmol), [ethylene-^ηJketanserin (for serotonin-2 receptors; 60-90 Ci/mmol), and ^HJpyrilamine (20 Ci/mmol, for labelling histamine H-I receptors), were purchased from New England Nuclear Life Science Products (through Mandel, Guelph, Ontario, Canada); ^HJcitalopram (70 - 87 Ci/mmol, for labeling serotonin transporters), and [ ¹ H]WIN 35,428 (60 - 87 Ci/mmol, for labeling dopamine transporters), were purchased from PerkinElmer Life and Analytical Sciences (Woodbridge, Ontario, Canada). (d) Competitive Binding Assays The competition between a compound and a [ ³ H]ligand for binding at the various receptors was done as follows. Each incubation tube (12 x 75 mm glass) received, in the following order, 0.5 ml buffer (50 mM Tris-HCl, pH 7.4 at 20 °C, 1 mM EDTA, 5 mM KCl, 120 mM NaCl, 1.5 mM CaCl ₂ , 4 mM MgCl ₂ , with or without an excess of another drug to define nonspecific binding, as noted later), 0.25 ml [ ³ H]ligand, and 0.25 ml of tissue suspension. The tubes, containing a total volume of 1 ml, were incubated for 2 h at room temperature (20 "C), after which the incubates were filtered, using a 12-well cell harvester (Titertek, Skatron, Lier, Norway) and

buffer-presoaked glass fiber filter mats (No. 1 1734, Skatron, Sterling, VA). After filtering the incubate, the filter mat was rinsed with buffer for 15 s (7.5 ml buffer). The filters were pushed out and placed in scintillation minivials (Packard Instruments, Chicago, IL). The minivials received 4 ml each of scintillant (CytoScint, ICN, CA), and were monitored 6 h later for tritium in a Beckman Coulter LS5000TA scintillation spectrometer at 55% efficiency.

The competitive potencies of the compounds at the cloned dopamine Dl receptors were measured using a final concentration of 1.25 nM [ ³ H]SCH23390 (Kd was 0.5 nM) and using 1 μM (+)-butaclamol to define nonspecific binding. Drug competition at the cloned dopamine D2 receptors (either D2short or D21ong) were measured using 2 nM [ ³ H]raclopride (Kd was 1.9 nM) and using 10 μM S-sulpiride to define nonspecific binding. Competition at the cloned dopamine D3 receptors was done using 2 nM [ ³ H]raclopride (Kd was 1.6 nM) and using 10 μM S-sulpiride to define nonspecific binding. Competition at the muscarinic receptors was done using either the cloned Ml receptors or the rat frontal cortex, 0.6 nM [ ³ H]QNB, and using 200 nM atropine to define nonspecific binding. Competition at the cloned serotonin- IA receptors was done with 1.4 nM [ ³ H]8-OH-DPAT (Kd was 1.5 nM) and using 100 μM serotonin to define nonspecific binding. Competition at the serotonin-2A receptors was done using either rat frontal cerebral cortex tissue or cloned serotonin- 2A receptors, 1 nM [ ³ H]ketanserin and using 10 μM serotonin to define nonspecific binding; the cortex and the cloned receptors gave very similar results. Competition at alpha- 1 -adrenoceptors was done using rat cerebral cortex tissue, 1.5 nM [ ³ H]prazosin and using 10 μM adrenaline to define nonspecific binding. Competition at alpha-2A- adrenoceptors was done using human cloned rat receptors (in Sf9 cells), 2.InM [ ³ H]yohimbine and using 100 μM adrenaline to define nonspecific binding. Competition at beta-adrenoceptors was done using rat cerebral cortex tissue, 0.5 nM [ ³ H]dihydroalprenolol and using 200 nM propranolol to define nonspecific binding. Competition at the serotonin transporter was done using rat striatal tissue, 0.9 nM [ ³ H]citalopram and using 100 μM serotonin to define non-specific binding. Competition at the dopamine transporter was done using rat striatal tissue, 24.6 nM [ ³ H] WIN 35,428 and using 100 μM dopamine to define non-specific binding. The compound dissociation constant, K, was calculated as usual as C50%/[l+C*/Kd],

where C50% was the drug concentration which inhibited ligand binding by 50%, where C* was the ligand concentration, and where Kd was the dissociation constant of the ligand, as obtained from a separate experiment using a range of ligand concentrations. (e) Test results

The test results for Compound Ia are given in Table 1. (f) Analysis of Test Results

The test results summarized above indicate that the butylamine compound of the invention exhibited a number of features not found in prior art compounds. As shown in Table 1, the current antidepressants are highly selective in blocking the serotonin transporter, and have low affinity for the dopamine transporter. Surprisingly, the invention compound, N-Methyl-4-phenyl-4-[4- (trifluoromethyl)phenoxy]butane-l -amine (Compound Ia), although related to fluoxetine, has a much higher affinity for the dopamine transporter, yielding an optimal serotonin/dopamine transporter selectivity of 6.5-fold, compared to fluoxetine's selectivity of 1, 200-fold. Moreover, the receptor profile in Table 1 indicates low affinity of compound I(a) for Ml muscarinic receptors, serotonin-2 receptors, alpha- 1 -adrenoceptors, HERG channels, and histamine Hl receptors. These low affinities would be associated with a surprisingly low prevalence of side-effects ordinarily occurring with antidepressants, including the anti-cholinergic side-effects of dry mouth, constipation, blurred vision, and changes in heart rate. Moreover, no cardiovascular disturbances would be expected with the invention compound, because its affinities for the HERG channel and the adrenoceptors are very low, with dissociation constants of 6,700 nM at the HERG channel, 4,200 nM at the alpha- 1- adrenoceptor, and 11,000 nM at the beta-2-adrenoceptor.

N-Methyl-4-phenyl-4-[4-(trifluoromethyl)phenoxy]butane- 1 -amine. HCl (Compound Ia.HCl) bound to the serotonin uptake site at 12 nM, while more weakly binding to the dopamine uptake site at 78 nM. Therefore, because the invention compound has a double action on binding to the re-uptake sites for both serotonin and dopamine, it was important to determine whether prolonged treatment with the invention compound would lower the density of rat cortex beta-adrenoceptors, as found with all antidepressants except those of the SSRI type (serotonin selective re-

uptake inhibitors). This was done by administering Compound Ia (15 mg/day intraperitoneal^) into rats for 10 days. A control group of rats was injected with 0.9% NaCl in buffer (pH 7.4), and a comparison group was injected with 15 mg/day desipramine. After 10 days of injections, the animals were killed on day eleven, the brains removed, and the frontal cerebral cortices were dissected. The tissues were homogenized and used at a final concentration of 1 mg original tissue per ml of incubate. The density of beta-adrenoceptors was measured by means of a saturation experiment, using 0.1 to 5 nM [ ³ H]dihydroalprenolol (final concentrations). Although it was found that the density of [ ³ H]dihydroalprenolol sites in the rat cerebral cortex was reduced by 20% in the desipramine-treated rats, the density of beta-adrenoceptors in the cerebral cortex of rats treated for 9 days with 15 mg/kg of Compound Ia.HCl revealed a normal density of beta-adrenoceptors, in keeping with the literature which reports no change in beta-adrenoceptors after long-term SSRI treatment, and suggesting that the serotonin-reuptake inhibiting action dominates over the dopamine reuptake inhibiting action in vivo. This dominant, but not selective or exclusive action on serotonin reuptake, is consistent with a predicted clinical antidepressant action, yet providing sufficient inhibiting potency on dopamine re-uptake to prevent side-effects of excessive blockade of serotonin reuptake.

While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

TABLE 1: IN VITRO PROPERTIES OF METHYL- [4-PHENYL-4- (TRIFLUOROMETHYL-PHENOXY)-BUTYL]-AMINE (COMPOUND IA):

^♦ Cleralnc

**Tatsumietal,Eur J Pharmacol (1997)