The present invention relates to compounds comprising a substructure of formula 1 , especially for the treatment of CNS disorders, and to pharmaceutical compositions and methods of treatment including these compounds.

Background of invention

Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including CNS disorders, psychiatric disorders, motor activity, feeding behaviour, sexual activity, and neuroendocrine regulation among others.

Serotonergic neurotransmission is modulated by clearance of serotonin (5- hydroxytryptamine or 5-HT). The clearance of 5-HT from the synaptic cleft is maintained by the serotonin transporter (SERT). The transporter therefore affects the magnitude and duration of the signalling, and thus plays a key role in the spatio temporal fine tuning of serotonergic neurotransmission SERT is a well-established molecular target of drugs of abuse (cocaine and

amphetamines), as well as a number of high-affinity antidepressants. Multiple classes of antidepressants including tricyclic antidepressants, 5-HT selective reuptake inhibitors and antidepressants with dual or triple actions are directed towards SERT. They enhance serotonergic neurotransmission by inhibiting 5-HT reuptake in a competitive manner with inhibitory constants in the low nanomolar range (Barker and Blakely, 1995;Owens et al., 1997;Tatsumi et al., 1997).

The serotonin transporter (SERT), which belongs to a family of sodium/chloride- dependent transporters, is the major pharmacological target in the treatment of several clinical disorders, including depression and anxiety.

Depression is a common, life-disrupting, potentially lethal illness that can affect both sexes and all ages. Untreated major depression remains a serious public health problem and its incidences are staggering. Its peak onset is in the early adult years. Suicide occurs in as many as 15% of patients with depression, especially those with recurrent episodes and hospitalizations. Therefore it becomes evident that treatment of depression is a matter of prime importance. Depression has no single cause; often, it results from a combination of factors. Whatever its cause, depression is not just a state of mind; it is related to physical changes in the brain, and connected to an imbalance of neurotransmitters. Among the most important neurotransmitters related with depression are serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Serotonin plays a very important role in the mood disorders, especially in anxiety and depression, aggression and impulsivity. Regulation of the mood disorders is possible either by agonistic or antagonistic action on a certain type of the serotonin receptors.

Serotonin-selective reuptake inhibitors (SSRIs) are primarily used for the treatment of depression, but are also used in the treatment of diseases like panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain.

Accordingly, the serotonin transporter (SERT) is an important player in the treatment of depression. By inhibiting this transporter, the serotonin concentration in the synaptic cleft will increase, and the signal will not be terminated as quickly. There are three main types of SERT inhibitors. These are tricyclic antidepressants, which also inhibit NET, selective serotonin reuptake inhibitors (SSRIs), which mainly inhibit SERT, and serotonin norepinephrine reuptake inhibitors (SNRIs), which inhibit both SERT and NET. There are adverse effects associated with all three types of antidepressants. These adverse effects are mainly caused by inhibition of receptors such as histamine- 1 , musacarinic and adrenergic receptors (Charney 1999). The tricyclic antidepressants are associated with more severe adverse effects than the SSRIs, but not all types of depression can be effectively treated with SSRIs (Charney 1999). The TCA's have been shown to be more efficacious than the SSRI's for treatment of severely depressed patients (Anderson, J Affect Disord. 2000 Apr;58(1): 19-36). Imipramine is an example of a tricyclic antidepressant, Citalopram is an example of a SSRI, and duloxetine is an example of a SNRI. Any of the known antidepressants escitalopram, imipramine, clomipramine and cianopramine have a dimethylated amine (-NH(CH ₃ ) ₂ ) amine on an aliphatic tail. Apart from the adverse effects, there is also the problem that some patients experience a latency period of several weeks before they experience the clinical effect (Rodrigo Machado-Vieira and M.A. 2008). This is seen even though the serotonin level in the synaptic cleft is increased within a few hours after administration.

There is thus a need for new and better antidepressants. Summary of invention

The objective of the present invention is to provide compounds that are useful in treatment of CNS disorders.

In its most broadest aspect, the present invention relates to a compound, which is a SERT inhibitor, said compound comprising a substructure of below formula 1 : X - CH - CH - Y ⁺ - C Formula 1 wherein the substituents are as defined herein, or a salt or prodrug thereof, in particular a pharmaceutically acceptable salt. Another aspect of the present invention relates to a compound which is a SERT inhibitor, such as for example a serotonin reuptake inhibitor (SSRI), said compound comprising a substructure of below formula 3:

Formula 3

wherein the substituents are as defined herein, or a salt or prodrug thereof, in particular a pharmaceutically acceptable salt.

The compounds of the present invention are SERT inhibitor and may also be subdivided as serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tetracyclic antidepressants, norepinephrine-dopamine reuptake inhibitors (NDRIs) and/or serotonin-norepinephrine- dopamine reuptake inhibitors (SDNRIs). Moreover the invention provides a pharmaceutical composition comprising a compound or salt or prodrug as defined herein, such as a pharmaceutical composition comprising a compound or salt or prodrug as defined herein for treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain.

The invention also provides the use of a compound or salt or prodrug as defined herein for the preparation of a medicament for the treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain.

Further, the invention also provides a method for the treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain.

The invention furthermore relates to a compound or salt or prodrug as defined herein for treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain.

The invention furthermore relates to a compound or salt or prodrug as defined herein for use as a medicament, preferably for treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain. The invention furthermore relates to the use of a compound or salt or prodrug as defined herein in a combination treatment with one or more further active substances, preferably one or more psychiatric medications, such as e.g. an antidepressant. Figure legends

Figure 1 A and 1 B: Comparison of the sulphur and selenium containing imipramine analogues with imipramine and the nitrogen containing imipramine analogues. The affinity improves when the nitrogen in imipramine is exchanged by either sulphur or selenium. Both the sulphur- and the selenium- containing analogues follow the same affinity pattern as the nitrogen containing analogues when a methyl group is removed or a chloride is added to the 3-position. This indicates that the binding orientation of these analogues is the same as for imipramine. P-values from unpaired t-tests are shown.

Figure 2: Comparison of sulphur and selenium containing citalopram analogues with S-citalopram and S-demethylcitalopram. Both Mj1-54 and Mj1-55 have higher affinities than S-citalopram. Just as S-citalopram, both analogues lose affinity upon

demethylation. P-values from unpaired t-tests are shown.

Figure 3: The results from Tables 8 and 9 are depicted as line diagrams in Figure 3. The effect of Clomipramine (0, 1 , 2.5, 10 and 40 mg/kg) and MJ-53 (0, 0.01 , 0.25, 1 , 4 and 16 mg/kg) on the time of immobility during the last 5 min of the 7-min testing period in the mouse forced swim test. Results are expressed as mean ± S.E.M. The drugs were administered i.p. 30 min prior to testing.

Detailed description of the invention

Compounds of the invention and salts and prodrugs thereof

The present invention relates to compounds or salts or prodrugs comprising a substructure of formula 1 , and in particular compounds or salts or prodrugs comprising a substructure of formula 3, for the treatment of CNS disorders. The inventors have surprisingly found that compounds and salts and prodrugs of the invention can be used in the treatment of CNS disorders. Accordingly, it is an object of the present invention to provide compounds that can be used for the treatment of CNS disorders. The compounds and salts and prodrugs of the invention have been found to have an improved activity profile as compared to imipramine, 3-cyanoimipramine, cianopramine, clomipramine, S-citalopram and R/S-citalopram.

Furthermore, the inventors of the present invention have surprisingly found that compounds and salts of the invention are highly selective towards the serotonin transporter (SERT), such as the human serotonin transporter (hSERT). Accordingly, the inventors furthermore, surprisingly, found that compounds and salts of the invention are highly selective for SERT over the dopamine transporter such as the human dopamine transporter (hDAT). Moreover, the inventors of the present invention have surprisingly found that compounds and salts of the invention are highly selective for SERT over the norepinephrine transporter such as the human norepinephrine transporter (hNET). Furthermore, it has surprisingly been found that the compounds and salts of the invention are highly selective for SERT over the dopamine transporter such as the human dopamine transporter (hDAT). Moreover, it has surprisingly been found that the compounds and salts of the invention are highly selective for the norepinephrine transporter over the dopamine transporter such as the human dopamine transporter (hDAT). As with other antidepressants, the affinity for DAT of the compounds and salts of the invention is poor and therefore the SERT vs DAT selectivity is higher than the SERT vs NET selectivity.

Accordingly, it is an object of the present invention to provide compounds that increases the efficacy in treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive- compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain.

A first aspect of the present invention relates to a compound comprising a substructure having the backbone given in below formula 1 : X - CH - CH - Y ⁺ - C Formula 1 or a salt or prodrug thereof, such as a pharmaceutically acceptable salt;

wherein:

- X is an atom selected from the group consisting of O, N and C which may be further substituted and which is attached to the remainder of the compound; and - Y is an atom or chemical group capable of possessing a positive charge, such as but not limited to an atom or chemical group selected from the group consisting of O, S, Se and N-CH ₃ .

A second aspect of the present invention relates to a compound comprising a substructure of below formula 3:

Formula 3

or a salt or prodrug thereof, such as a pharmaceutically acceptable salt;

wherein:

Z is selected from the group consisting of N and C; and

- Y is an atom or chemical group capable of possessing a positive charge, such as but not limited to an atom or chemical group selected from the group consisting of O, S, -NC or Se.

A third aspect of the present invention relates to a compound or salt or prodrug thereof as defined herein for use as a medicament.

A forth aspect of the present invention relates to a compound or salt or prodrug thereof for use as a SERT inhibitor. In particular, the compounds of the present invention may be used as serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tetracyclic antidepressants, norepinephrine-dopamine reuptake inhibitors (NDRIs) and/or serotonin-norepinephrine- dopamine reuptake inhibitors (SDNRIs).

A fifth aspect of the present invention relates to a compound or salt or prodrug as defined herein for treatment of a CNS disorder, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain.

A sixth aspect of the present invention relates to use of a compound or salt or prodrug as defined herein for the manufacture of a medicament for the treatment of a CNS disorder, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, posttraumatic stress disorder (PTSD), and neuropathic pain.

A seventh aspect of the present invention relates to a compound or salt or prodrug as defined herein for treatment of a CNS disorder, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain, wherein a compound or salt of the invention is administered in combination with one or more further active substance, such as e.g. one or more further psychiatric

medications. In an embodiment of the compound or salt or prodrug of the invention, said compound or salt or pro mula 4:

ormula 4

wherein the phenyl group may be isolated or fused to one or more carbocyclic or heterocyclic rings.

In further embodiments, the invention relates to a compound of the invention which is of below formula 5:

Formula 5 or a salt or prodrug thereof, such as a pharmaceutically acceptable salt;

wherein:

- Y is selected from the group consisting of O, S, -NR6 and Se;

Z is selected from the group consisting of N and CR3;

- R1 is selected from the group consisting of Ci. ₆ -alk(en/yn)yl, C ₃ . ₈ -cycloalk(en)yl and halo-C ₁ -6-alk(en/yn)yl;

R2 is selected from the group consisting of Ci. ₆ -alk(en/yn)yl, C ₃ . ₈ -cycloalk(en)yl and halo-Ci-6-alk(en/yn)yl;

R3 is selected from the group consisting of hydrogen, Ci. ₆ -alk(en/yn)yl, C ₃ . ₈ - cycloalk(en)yl, halogen, cyano, halo-Ci. ₆ -alk(en/yn)yl, halo-C ₃ . ₈ -cycloalk(en)yl and aryl; wherein aryl may be substituted or un-substituted;

R4 is selected from the group consisting of hydrogen, Ci. ₆ -alk(en/yn)yl, cyano, halogen, halo-Ci. ₆ -alk(en/yn)yl and hydroxy-Ci. ₆ -alk(en/yn)yl;

R5 is selected from the group consisting of hydrogen, Ci. ₆ -alk(en/yn)yl, cyano, halogen, halo-Ci. ₆ -alk(en/yn)yl and hydroxy-Ci. ₆ -alk(en/yn)yl;

R6 is selected from the group consisting of Ci. ₆ -alk(en/yn)yl, C ₃ . ₈ -cycloalk(en)yl and halo-Ci-6-alk(en/yn)yl; and

together with Z and the phenyl group to which it is attached, A cyclic structureforms a fused ring system comprising 2, 3 or 4 carbocyclic or heterocyclic rings wherein each ring atom is selected from the group consisting of C, N, O and S

with the proviso that R5 may be present or it may be absent.

In further embodiments, the invention relates to a compound of formula 5, wherein the fused ring system formed by A, Z and the phenyl group as disclosed is of formula 6:

Formula 6

or a salt or prodrug thereof, such as a pharmaceutically acceptable salt;

wherein

- V is selected from the group consisting of S, O, C, CH and CH ₂ ; and - W is selected from the group consisting of C, CH, CH ₂ , C-C, CH-C, CH ₂ -C, CH- CH, CH-CH ₂ , CH2-CH2-, C-C, C-CH, C-CH ₂ , C-C-C, C-CH-C, C-CH ₂ -C, C-CH-CH, C-CH-CH ₂ and C-CH2-CH2-, CH-C-C, CH-CH-C, CH-CH ₂ -C, CH-CH-CH, CH-CH- CH ₂ and CH-CH ₂ -CH ₂ -, CH ₂ -C-C, CH ₂ -CH-CH ₂ and CH ₂ -CH ₂ -CH ₂ -; and

- any two adjacent carbon atoms selected from C and C and comprised in V or W may form part of an aryl.

In further embodiments, the invention relates to a compound of formula 5, wherein R4 i rmulae 9 or 10:

Formula 10

In further embodiments, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising the

substructure of formula 6, wherein R4 is attached as indicated in formula 9.

In further embodiments, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising the

substructure of formula 6, wherein R4 is attached as indicated in formula 10.

In further embodiments, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; wherein the phenyl group, Z and A together form a fused ring system comprising 2 or 3 independently selected carbocyclic or heterocyclic rings wherein each ring atom is selected from the group consisting of C, N, O and S. In an embodiment, the phenyl group, Z and A together form a ring comprising 2 independently selected carbocyclic- or heterocyclic rings. In another embodiment, the phenyl group, Z and A together form a fused ring system comprising 3 rings each of which is independently selected from the group of carbocyclic and heterocyclic rings. In an embodiment, the phenyl group, Z and A together form a ring system comprising at least 2 heterocyclic rings, such as 2 heterocyclic ring. In an embodiment, the phenyl group, Z and A together form a ring system comprising at least 1 carbocyclic ring, such as 1 carbocyclic ring. In an embodiment, the phenyl group, Z and A together form a ring system comprising 1 carbocyclic ring and 1 heterocyclic ring. In an embodiment, the phenyl group, Z and A together form a ring system comprising 2 carbocyclic rings and 1 heterocyclic ring. In an embodiment, each ring comprised in the fused ring system formed by the phenyl group, Z and A consists of 4-8 ring atoms, such as 5, 6 or 7 ring atoms. In an embodiment, said fused ring system comprises at least one ring consisting of 5 ring atoms, such as exactly one ring consisting of 5 ring atoms. In an embodiment, said fused ring system comprises at least one ring consisting of 6 ring atoms, such as exactly one ring consisting of 6 ring atoms. In an embodiment, said fused ring system comprises at least one ring consisting of 7 ring atoms, such as exactly one ring consisting of 7 ring atoms. In an embodiment, said fused ring system comprises one ring consisting of 7 ring atoms and 2 rings each consisting of 6 ring atoms. In an embodiment, said fused ring system comprises one ring consisting of 5 ring atoms and 1 ring consisting of 6 ring atoms.

In further embodiments, the invention relates to a compound of formula 5, such as a compound comprising a substructures of any one of formulae 4, 6, 9, 10, 1 1 or 12 or salts or prodrugs thereof, such as pharmaceutically acceptable salts; wherein Z is N. In another embodiment, Z is CR3.

In further embodiments, the invention relates to a compound of formula 5, such as a compound comprising a substructures of any one of formulae 3, 4, 6, 9 or 10, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising a substructure of below formula 8:

Formula 8

In further embodiments, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising the substructure of any one of formulae 6, 8, 9 or 10, wherein V is O or C. In a particular embodiment, V is an oxygen atom. In another embodiment, V is a carbon atom.

In further embodiments, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising a substructure of any one of formulae 6, 8, 9 or 10, wherein W is selected from the group consisting of C, CH, CH ₂ , C-C-C, C-CH-C, C-CH ₂ -C, C-CH-CH, C-CH-CH ₂ , C-CH ₂ -CH ₂ -, CH-C-C, CH-CH-C, CH-CH ₂ -C, CH-CH-CH, CH-CH-CH ₂ , CH-CH ₂ -CH ₂ -, CH ₂ -C-C, CH ₂ -CH- CH ₂ and CH ₂ -CH ₂ -CH ₂ -.

In another embodiment, W is selected from the group consisting of C, CH and CH ₂ . In yet another embodiment, W is selected from the group consisting of C-C-C, C-CH- C, C-CH ₂ -C, C-CH-CH, C-CH-CH ₂ , C-CH ₂ -CH ₂ -, CH-C-C, CH-CH-C, CH-CH ₂ -C, CH- CH-CH, CH-CH-CH ₂ , CH-CH ₂ -CH ₂ -, CH ₂ -C-C, CH ₂ -CH-CH ₂ and CH ₂ -CH ₂ -CH ₂ .

In yet another embodiment, W is selected from the group consisting of C-C-C, C-CH- C, C-CH ₂ -C, C-CH-CH, C-CH-CH ₂ , C-CH ₂ -CH ₂ -, CH-C-C, CH-CH-C, CH-CH ₂ -C and CH ₂ -C-C. In a further embodiment thereof, W is selected from the group consisting of CH ₂ and C-CH ₂ -CH ₂ -.

In a preferred embodiment, W is CH ₂ .

I another preferred embodiment, W is C-CH ₂ -CH ₂ -. In a preferred embodiment, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising the substructure of any one of formulae 6, 8, 9 or 10, wherein any two adjacent carbon atoms selected from C and CH and comprised in V or W form part of an aryl. In another preferred embodiment, any two adjacent carbon atoms selected from C and C and comprised in V or W do not form part of an aryl.

In specific embodiments, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising the

substructure of any one of formula 6, 8, 9 or 10, wherein V is selected from the group consisting of O and C and W is selected from the group consisting of CH ₂ and CH ₂ - CH ₂ -C; wherein any two adjacent C and C may form part of an aryl, such as a phenyl group.

In further embodiments, the invention relates to a compound of formula 5, such as a compound comprising the substructure of any one of formulae 6, 8, 9 or 10, or salts or prodrugs thereof; said compound comprising the substructure of formula 11 which is formed by A, a 5:

rmula 1 1

In further embodiments, the invention relates to a compound of formula 5, such as a compound comprising the substructure of any one of formulae 6, 8, 9 or 10, or salts or prodrugs thereof; said compound comprising the substructure of formula 7 which is

5:

Formula 7

In further embodiments, the invention relates to a compound of formula 5, such as a compound comprising the substructure of any one of formulae 6, 8, 9 or 10, or salts or prodrugs thereof; said compound comprising the substructure of formula 12 which is formed by A, Z and the phenyl group of formula 5:

Formula 12

In further embodiments, the invention relates to a compound of formula 5, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; comprising the

substructure of formula 7, wherein R5 is attached in position 7. In a particular embodiment, R4 is attached in position 3 as is also indicated in formula 10 and R5 is attached in position 7.

In further embodiments, the invention relates to a compound of formula 5 or a compound comprising a substructure of any of formulae 3 or 4, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; such as a compound comprising the substructure of formula 8, wherein Y is selected from the group consisting of S, - NC, e.g. -NCR6, and Se. In a preferred embodiment, Y is S. In another preferred embodiment, Y is Se. In yet another preferred embodiment Y is -NC. In yet another preferred embodiment Y is -NR6.

In an embodiment, R1 is selected from the group consisting of Ci_ ₆ -alk (en/yn)yl and C ₃ . ₈ -cycloalk(en)yl. In an embodiment, R1 is C ₃ . ₈ -cycloalk(en)yl, such as cyclopropyl. In an embodiment R1 is Ci. ₆ -alk(en/yn)yl, such as Ci _-6 -alkyl, e.g. selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl. In a particular embodiment, R1 is selected from the group consisting of methyl and ethyl. In an embodiment, R1 is ethyl. Preferably, R1 is methyl.

In an embodiment, R2 is selected from the group consisting of Ci_ ₆ -alk (en/yn)yl and C ₃ . ₈ -cycloalk(en)yl. In an embodiment, R2 is C ₃ . ₈ -cycloalk(en)yl, such as cyclopropyl. In an embodiment thereof R2 is Ci. ₆ -alk(en/yn)yl, such as Ci _-6 -alkyl, e.g. selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl. In a particular embodiment, R2 is selected from the group consisting of methyl and ethyl. In an embodiment, R2 is ethyl. Preferably, R2 is methyl.

In further embodiments, the invention relates to a compound of formula 4, or salts or prodrugs thereof, such as pharmaceutically acceptable salts; such as compounds comprising the substructure of formula 6, 8, 9, 10, 11 or 12, wherein Z is CR3 and R3 is selected from the group consisting of C ₃ . ₈ -cycloalk(en)yl, halo-C ₃ . ₈ -cycloalk(en)yl and aryl; wherein aryl may be substituted or un-substituted. In a further embodiment, R3 is aryl. In a further embodiment, R3 is aryl which is un-substituted. In a further embodiment, R3 is aryl which is substituted, such as aryl which is substituted with 1 , 2 or 3 substituents. In an embodiment, R3 is aryl which is substituted, such as which 1 or 2 substituents, e.g. with 1 substituent.

When R3 is aryl which is substituted, then the one or more substituents are

independently selected from the group consisting of Ci. ₆ -alk(en/yn)yl, c ₃ . ₈ - cycloalk(en)yl, halogen, cyano, halo-Ci. ₆ -alk(en/yn)yl and halo-C ₃ . ₈ -cycloalk(en)yl. In an embodiment, said one or more substituents are independently selected from the group consisting of Ci. ₆ -alk(en/yn)yl, cyano, halo-Ci. ₆ -alk(en/yn)yl and halogen. In an embodiment, R3 is substituted aryl, wherein each substituent is independently selected from the group consisting of Ci. ₆ -alk(en/yn)yl, cyano and halogen, such as aryl which is substituted with exactly one fluoro atom.

In further embodiments, said one or more substituents are independently selected from the group consisting of halogen, cyano and halo-Ci. ₆ -alk(en/yn)yl. In yet another embodiment, said one or more substituents are independently selected from the group consisting of Ci. ₆ -alk(en/yn)yl and halogen, such as the group consisting of CI, Br, F, I, methyl, ethyl, propyl or cyano. In another embodiment, said one or more substituents are independently selected from the group consisting of chloro, fluoro, bromo, iodo, cyano, methyl, ethyl, n-propyl and isopropyl. In yet another embodiment, said one or more substituents are independently selected from the group consisting of one or more independently selected halogen atoms, such as one or more atoms independently selected from F, CI, Br and I. In yet another embodiment, said one or more substituents are fluoro (F) atoms, such as 1 , 2 or 3 fluoro atoms. In a preferred embodiment, R3 is aryl which is substituted with exactly one fluoro atom. In particular embodiments, R3 is phenyl or naphthalenyl, such as phenyl which is substituted or un-substituted, such as phenyl which is substituted with 1 , 2 or 3 substituents wherein said substituents may e.g. be independently selected from the group consisting of Ci. ₆ -alk(en/yn)yl, C ₃ . ₈ -cycloalk(en)yl, halogen, cyano, halo-Ci_ ₆ - alk(en/yn)yl and halo-C ₃ . ₈ -cycloalk(en)y. In a specific embodiment wherein R3 is phenyl which is substituted with exactly one substituent, the substituent is selected from the group consisting of halogen, cyano and halo-Ci. ₆ -alk(en/yn)yl, such as wherein the substituents are selected from the group consisting of Ci. ₆ -alk(en/yn)yl and halogen atoms. In a particular embodiment, said substituent is selected from the group consisting of CI, Br, F, I, methyl, ethyl, propyl or cyano. In another embodiment, said substituent is selected from the group consisting of chloro, fluoro, bromo, iodo, cyano, methyl, ethyl, n-propyl and isopropyl. In a preferred embodiment, R3 is a phenyl group which is substituted with a fluoro atom, which is preferably attached in the para position.

In yet further embodiments wherein R3 is a phenyl group which is substituted, at least one substituent which is attached in the para position of said phenyl group. In another embodiment, said phenyl is substituted at least in the meta position. In yet another embodiment, said phenyl is substituted at least in the ortho position. In yet another embodiment, said phenyl is substituted with exactly one substituent which is attached in the para position.

In further embodiments, R4 is selected from the group consisting of hydrogen, Ci_ ₆ - alk(en/yn)yl, cyano, halogen, halo-Ci. ₆ -alk(en/yn)yl and hydroxy-Ci. ₆ -alk(en/yn)yl. In another embodiment, R4 is selected from the group consisting of hydrogen, cyano and halogen, such as hydrogen, chloro and cyano. In a particular embodiment, R4 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, cyano, methyl, ethyl, n-propyl and isopropyl. R4 is selected from the group consisting of chloro, fluoro, bromo, iodo, cyano, methyl, ethyl, n-propyl and isopropyl. In a particular embodiment, R4 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, methyl, hydroxyl-methyl, cyano and CF ₃ . In a particular embodiment, R4 is hydrogen. In another particular embodiment, R4 is cyano. In yet another particular embodiment, R4 is halogen such as a fluoro atom or a chloro atom. In a specific embodiment, R4 is a chloro atom. In another specific embodiment, R4 is a fluoro atom. In further embodiments, R5 is selected from the group consisting of hydrogen, Ci_ ₆ - alk(en/yn)yl, cyano, halogen, halo-Ci. ₆ -alk(en/yn)yl and hydroxy-Ci. ₆ -alk(en/yn)yl. in another embodiment, R5 is selected from the group consisting of hydrogen, cyano and halogen, such as hydrogen, chloro and cyano. In a particular embodiment, R5 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, methyl, hydroxyl- methyl, cyano and CF ₃ . In a particular embodiment, R5 is hydrogen. In another particular embodiment, R5 is cyano. In yet another particular embodiment, R5 is halogen such as a fluoro atom or a chloro atom. In a specific embodiment, R5 is a chloro atom. In another specific embodiment, R5 is a fluoro atom. In one embodiment, R5 is present. In another embodiment, R5 is absent.

R6 is selected from the group consisting of Ci. ₆ -alk(en/yn)yl, C ₃ . ₈ -cycloalk(en)yl and halo-Ci-6-alk(en/yn)yl. In an embodiment, R6 is selected from the group consisting of Ci-6-alk (en/yn)yl and C ₃ . ₈ -cycloalk(en)yl. In an embodiment, R6 is C ₃ . ₈ -cycloalk(en)yl, such as cyclopropyl. In an embodiment thereof R6 is Ci. ₆ -alk(en/yn)yl, such as Ci_ ₆ - alkyl, e.g. selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl. In a particular embodiment, R6 is selected from the group consisting of methyl and ethyl. In an embodiment, R6 is ethyl. Preferably, R6 is methyl. In a specific embodiment of the salt or compound of the invention:

R4 is attached as indicated in formula 10;

Z, A and the phenyl group together form a ring system comprising 2 carbocyclic rings and 1 heterocyclic ring;

- Z is N;

- V is a carbon atom;

the two carbon atoms comprised in V and W are adjacent and together form part of an aryl such as a phenyl group;

- Y is selected from the group consisting of S and Se;

- R1 is methyl;

- R2 is methyl;

R4 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, cyano, methyl, ethyl, n-propyl and isopropyl; and

R5 is hydrogen. In a preferred embodiment of the salt or compound of the invention:

R4 is attached as indicated in formula 10;

Z, A and the phenyl group together form a ring system comprising 2 carbocyclic rings and 1 heterocyclic ring;

- Z is N;

- V is a carbon atom;

The two carbon atoms comprised in V and W are adjacent and together form part of an aryl, such as a phenyl group;

- Y is selected from the group consisting of S and Se;

R1 is methyl;

- R2 is methyl;

R4 is selected from the group consisting of hydrogen, chloro and cyano; and R5 is hydrogen.

In a specific embodiment of the salt or compound of the invention:

R4 is attached as indicated in formula 9,

Z, A and the phenyl group together form a ring system comprising 1 carbocyclic rings and 1 heterocyclic ring;

- Z is CR3;

- V is an oxygen atom;

- W is CH ₂ ;

- Y is selected from the group consisting of S and Se;

R1 is methyl;

- R2 is methyl;

R3 is a phenyl group which is substituted such as with exactly one substituent which is selected from the group consisting of chloro, fluoro, bromo, iodo, cyano, methyl, ethyl, n-propyl and isopropyl and which is attached in the para position; R4 is selected from the group consisting of chloro, fluoro, bromo, iodo, cyano, methyl, ethyl, n-propyl and isopropyl;

R5 is hydrogen.

In a preferred embodiment of the salt or compound of the invention:

R4 is attached as indicated in formula 9, Z, A and the phenyl group together form a ring system comprising 1 carbocyclic rings and 1 heterocyclic ring;

- Z is CR3;

- V is an oxygen atom;

- W is CH ₂ ;

- Y is selected from the group consisting of S and Se;

R1 is methyl;

- R2 is methyl;

R3 is a phenyl group which is substituted such as with exactly one substituent which is a fluoro atom which is attached in the para position;

R4 is a cyano group;

R5 is hydrogen.

A specific embodiment of the invention relates to compounds selected from the group consisting of:

3-(10,1 1-dihydro-5/-/-dibenzo[ 5J]azepin-5-yl)propyl)dimethylsulfonium;

3-(3-chloro-10, 1 1-dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylsulfonium;

(3-(10,1 1-dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylselenonium

(3-(3-chloro-10, 11-dihydro-5/-/-dibenzo[ 5J]azepin-5-yl)propyl)dimethylselenonium; (3-(3-cyano-10, 11-dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylsulfonium;

(3-(3-cyano-10, 11-dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylselenonium;

(S)-(3-(5-cyano-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-1-yl) - propyl)dimethylsulfonium;

(S)-(3-(5-cyano-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-1-yl) propyl) dimethyl- selenonium;

(R/S) 3-(5-cyano-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-1-yl)-/V, N, N- trimethylpropan-1-ammonium; and

3-(10,1 1-dihydro-5/-/-debenzo[ 5JJazepin-5-yl)-/\/,A/,A/-trimethylpropan-1 -ammonium; as the free base or a salt or a prodrug thereof. Any of the specific compounds of the invention as the free base or a salt or a prodrug thereof is an independent embodiment and may be claimed individually in a separate claim.

Another embodiment relates to an intermediate for the preparation of a compound of the invention, said intermediate being selected from the group consisting of:

5-allyl-10, 1 1-dihydro-5/-/-dibenzo[ 5JJazepine; 3-(10,1 1-dihydro-5/-/-dibenzo[ 5J]azepine-5-yl)propan1-ol;

3-(10,1 1-dihydro-5/-/-dibenzo[ 5J]azepine-5-yl)propyl methanesulfonate;

3-(10,1 1-dihydro-5/-/-dibenzo[ 5J]azepine-5-yl)propyl ethanethioate;

5-(3-(methylthio)propyl)-10, 11-dihydro-5/-/-dibenzo[ 5J]azepine;

5-allyl-3-chloro-10, 11-dihydro-5/-/-dibenzo[ 5JJazepine;

3-(3-chloro-10, 1 1 -dihydro-5/-/-dibenzo[ 5JJazepine-5-yl)propan 1 -ol;

3-(3-chloro-10, 1 1-dihydro-5/-/-dibenzo[ 5JJazepine-5-yl)propyl methanesulfonate;

3-(3-chloro-10, 1 1-dihydro-5/-/-dibenzo[ 5JJazepine-5-yl)propyl ethanethioate;

3-chloro-5-(3-(methylthio)propyl)-10, 11-dihydro-5/-/-dibenzo[ 5J]azepine;

5-(3-(methylselanyl)propyl)-10, 11-dihydro-5/-/-dibenzo[ 5J]azepine;

3-chloro-5-(3-(methylselanyl)propyl)-10, 1 1-dihydro-5/-/-dibenzo[ 5,/]azepine;

3-cyano-iminodibenzyl;

5-allyl-10, 1 1-dihydro-5/-/-dibenzo[ 5JJazepine-3-carbonitrile;

5-(3-hydroxypropyl)-10, 11-dihydro-5/-/-dibenzo[ 5JJazepine-3-carbonitrile;

3-(3-cyano-10, 11-dihydro-5/-/-dibenzo[ 5JJazepine-5-yl)propyl methanesulfonate;

5-(3-(methylthio)propyl)-10, 11-dihydro-5/-/-dibenzo[ 5J]azepine-3-carbonitrle;

5-(3-(methylselanyl)propyl)-10, 11-dihydro-5/-/-dibenzo[ 5J]azepine-3-carbonitrile;

(S)-1-(3-chloropropyl)-1 (4-fluorophenyl)-1 ,3-dihydroisobenzofuran-5-carbonitrile;

(S)-1 (4-fluorophenyl)-1-(3-(methylthio)propyl)-1 ,3-dihydroisobenzofuran-5-carbonitrile; and

(S)-1 (4-fluorophenyl)-1-(3-(methylselanyl)propyl)-1 ,3-dihydroisobenzofuran 5- carbonitrile;

as the free base or a salt or a prodrug thereof. Any of the intermediates as the free base or a salt or a prodrug thereof is an independent embodiment and may be claimed individually in a separate claim.

In yet another embodiment of the present invention the compound or salt or prodrug thereof comprises a substructure of below formula 2: X - (CR7R8) - (CR9R10) - (Y ⁺ R1 1 R12) Formula 2 wherein:

- X is a carbon atom, which forms part of a -CH ₂ -group, which CH ₂ may optionally be substituted; or X is a carbon ring atom, which forms part of phenyl or naphthalenyl, which phenyl or naphthalenyl may optionally be substituted with one or more substituents selected from the group consisting of -OH, -0-CH ₃ and -CI;

- Y is an atom or chemical group capable of possessing a positive charge, such as but not limited to an atom or chemical group selected from the group consisting of O, S, Se and N-CH ₃ ;

R7 and R8 are independently selected from the group consisting of H, C ₃ . ₈ - cycloalk(en)yl such as such as C ₃ . ₆ -cycloalkyl optionally substituted with hydroxy such as cyclohexyl optionally substituted with hydroxy, and Ci. ₆ -alk(en/yn)yl such as Ci-4-alkyl such as methyl; or

R7 and R8 together form an oxo-group; or

C, R7 and R8 together form a cyclobutyl-group;

R9 and R10 are independently selected from the group consisting of H and Ci_ ₆ - alk(en/yn)yl, such as Ci _-4 -alkyl such as e.g. methyl or isobutyl; and

R1 1 and R12 are independently selected from the group consisting of hydrogen and Ci_6-alk(en/yn)yl, such as Ci _-4 -alkyl such as e.g. methyl or tert-butyl;

with the proviso that when Y is N-CH ₃ then neither R1 1 nor R12 is hydrogen; or

- Y ⁺ , R11 and R12 togeth group represented by the formula: which group may optionally be substituted; or - X, CR7CR8, CR9CR10, Y ⁺ and R1 1 may together form a group represented by the formula: wherein M is selected from the group consisting of N, and C;

which group may be fused or isolated and which group may optionally be substituted; or

CR7CR8, CR9CR10 a together form a group represented by the formula: which group may be fused or isolated and which may optionally be substituted; when fused a bicydic ring-system is formed wherein R7, R8, R9 and/or R10 may be present or absent; or

CR7CR8, CR9CR10, Y ⁺ and R1 1 may together form a group represented by the formula:

which group may be isolated or fused and which group may optionally be substituted; or

CR7CR8, CR9CR10, Y ⁺ and R1 1 may together form a group represented by the formula: which group may optionally be substituted; or

R8 is absent a and X together form a group represented by the formula: which group may optionally be substituted. In some embodiments relating to compounds of formula 2, X represents a carbon atom, which forms part of a -CH ₂ -group, whereas in other embodiments X represents a carbon ring atom, which forms part of phenyl or naphthalenyl. When X represents a carbon atom, which forms part of a -CH ₂ -group, said CH ₂ may optionally be substituted with one or more substituents selected from the group consisting of phenyl, -O- methylphenyl, -O-trifluoromethylphenyl, -O-naphthalenyl, thiophenyl, 5-cyano-1 (4- fluorophenyl)-1 ,3-dihydroisobenzofuranyl, 5-methoxy-2-oxo-3,4-dihydroquinolinyl, 5h- dibenzo[a,d][7]annulenyl, 10, 11-dihydro-5h-dibenzo[a,d][7]annulenyl, 10, 11-dihydro-5h- dibenzo[b,f]azepinyl optionally substituted with chloro or cyano, 6, 11-dihydro- dibenzo[b,e]oxepinyl, 6, 11-dihydro-dibenzo[b,e]thiepinyl and 9, 10-dihydro-9,10- ethanoanthracenyl. In some embodiments the CH ₂ -group and the substituent is bonded together by a single bond, whereas in other embodiments the CH ₂ -group and the substituent is bonded together by a double bond. In other embodiments, when X represents a carbon ring atom, which forms part of phenyl or naphthalenyl, said phenyl or naphthalenyl may optionally be substituted with one or more substituents selected from the group consisting of -OH, -0-CH ₃ and -CI.

In further embodiments relating to compounds of formula 2, Y is an atom or chemical group capable of possessing a positive charge, such as an atom or chemical group selected from the group consisting of O, S, Se and N-CH ₃ , preferably selected from the group consisting of S, Se and N-CH ₃ .

In further embodiments relating to compounds of formula 2, the Y atom is bonded to the carbon atom in the (CR9R10) group and to R1 1 and R12. In embodiments, where

Y represents O, S and Se, R 11 and R12 may independently of each other represent hydrogen or Ci_ ₄ -alkyl, preferably methyl and/or tert-butyl. In other embodiments, when

Y represents N-CH ₃ , R 1 1 and R12 may independently of each other represent Ci_ ₄ - alkyl. In embodiments where Y represents N-CH ₃ , then neither R11 nor R12 may represent hydrogen. Hence, in such cases a quaternary ammonium group has been formed, in which the N atom is bonded to the carbon atom in the (CR9R10) group and to three Ci_ ₄ -alkyl groups. The three Ci_ ₄ -alkyl groups may be selected independently of each other, but preferably, the three Ci_ ₄ -alkyl groups are three methyl groups. In further embodiments relating to compounds of formula 2, R9 and R10 may be selected from the group consisting of H and Ci_ ₄ -alkyl. Preferably R9 and R10 represent hydrogen and/or methyl and/or isobutyl.

In further embodiments relating to compounds of formula 2, R7 and R8 are

independently selected from the group consisting of H, C ₃ . ₆ -cycloalkyl and Ci_ ₄ -alkyl. In some embodiments the C ₃ . ₆ -cycloalkyl may be substituted with hydroxy. In preferred embodiments R7 and R8 are independently selected from the group consisting of H, hydroxy-cyclohexyl, and methyl. In other embodiments R7 and R8 together form an oxo-group, and in yet other embodiments C, R7 and R8 together form a cyclobutyl group.

In further embodiments relating to compounds of formula 2, Y ⁺ , R11 and R12 together form a group represented ula:

This group may optionally be substituted chloroph

In further embodiments relating to compounds of formula 2, X, CR7CR8, CR9CR10, Y ⁺ and R1 1 may together form a group represented by the formula:

This group may be fused or isolated, this group M may represent a C atom or M may represent a N atom. In some embodiments where M represents a C atom the group is preferably isolated and the group may further be substituted with one or more substituents selected from the group consisting of fluorophenyl, -O-benzo-dioxolyl, - phenyl-S-methylphenyl and phenyl-S-dimethylphenyl. In other embodiments, where M represents an N atom the group is isolated and optionally be substituted with dibenzooxazepinyl. In other embodiments, where M represents an N atom the group is fused so as to form a pyridobenzapine group In further embodiments relating to compounds of formula 2, CR7CR8, CR9CR10 and X may together form a group ted by the formula:

This group is preferably fused so as to form tetrahydronaphthalenyl group optionally substituted with dichlorophenyl.

In further embodiments relating to compounds of formula 2, CR7CR8, CR9CR10, Y ⁺ and R1 1 may together form a group represented by the formula:

This group is preferably fused so as to form thiabicyclo[1.3.0]hexanyl or

selenabicyclo[1.3.0]hexanyl, which groups may optionally be substituted with dichlorophenyl.

In further embodiments relating to compounds of formula 2, CR7CR8, CR9CR10, Y ⁺ and R1 1 may together for represented by the formula:

and X is a carbon atom, which forms part of a -CH ₂ -group, which CH ₂ may optionally be substituted with phenyl and/or -O-ethoxyphenyl.

In further embodiments relating to compounds of formula 2, R8 is absent and CR7 and X together form a group represented by the formula: This group may optionally be substituted with -S-phenyl, which phenyl may optionally be substituted with one or more substituents selected from the group consisting of fluoro, chloro, iodo, methyl, fluoromethyl, NH ₂ and hydroxymethyl. A specific embodiment of the invention relates to compounds selected from the group consisting of:

3-(10,1 1-dihydro-5/-/-dibenzo[ 5J]azepin-5-yl)propyl)dimethylsulfonium;

3-(3-chloro-10, 1 1-dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylsulfonium;

(3-(10, 1 1 -dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylselenonium

(3-(3-chloro-10, 11-dihydro-5/-/-dibenzo[ 5J]azepin-5-yl)propyl)dimethylselenonium;

(3-(3-cyano-10, 11-dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylsulfonium;

(3-(3-cyano-10, 11-dihydro-5/-/-dibenzo[ 5JJazepin-5-yl)propyl)dimethylselenonium;

(S)-(3-(5-cyano-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-1-yl) - propyl)dimethylsulfonium;

(S)-(3-(5-cyano-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-1-yl) propyl) dimethyl- selenonium;

(R/S) 3-(5-cyano-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-1-yl)-/V, N, N- trimethylpropan-1 -ammonium;

3-(10,1 1-dihydro-5/-/-debenzo[ 5JJazepin-5-yl)-/\/,A/,A/-trimethylpropan-1 -ammonium; (S)-dimethyl(3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propyl) selenonium;

(S)-dimethyl(3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propyl) sulfonium;

(2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)ethyl)dimethylse lenonium;

(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)dimethylsu lfonium;

(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)dimethylse lenonium;

2-methyl-1 ,2,3,4, 10, 14b-hexahydrobenzo[c]pyrido[3,2-f][1 ,4]selenazino[4,3-a]azepin-2- ium;

2-methyl-1 ,2,3,4, 10, 14b-hexahydrobenzo[c]pyrido[3,2-f][1 ,4]thiazino[4,3-a]azepin-2- ium;

(3R,4R)-3-((benzo[d][1 ,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1-methyl- hexahydroselenopyrylium;

(3R,4R)-3-((benzo[d][1 ,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1-methyl- hexahydrothiopyrylium;

((1S,4S)-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydronaphthalen-1-yl)dimethylselenonium; ((1S,4S)-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydronaphthalen-1-yl)dimethylsulfonium; dimethyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)selen onium; dimethyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)sulfo nium;

tert-butyl(1-(3-chlorophenyl)-1-oxopropan-2-yl)(methyl)se lenonium; tert-butyl(1-(3-chlorophenyl)-1-oxopropan-2-yl)(methyl)sulfo nium;

(2-(7-methoxynaphthalen-1-yl)ethyl)dimethylselenonium;

(2-(7-methoxynaphthalen-1-yl)ethyl)dimethylsulfonium;

1-(3,4-dichlorophenyl)-3-methyl-3-selenabicyclo[3.1.0]hexan- 3-ium; 1-(3,4-dichlorophenyl)-3-methyl-3-thiabicyclo[3.1.0]hexan-3- ium;

(R)-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutyl)dimet hylselenonium; (R)-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutyl)dimethyl sulfonium; (1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutyl)dimethylsele nonium; (1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutyl)dimethylsulf onium; 4-(3-chlorophenyl)-1-(3-(5-methoxy-2-oxo-3,4-dihydroquinolin -1 (2H)- yl)propyl)thiomorpholin-1-ium;

4-(3-chlorophenyl)-1-(3-(5-methoxy-2-oxo-3,4-dihydroquinolin -1 (2H)- yl)propyl)thiomorpholin-1-ium;

1-methyl-4-(2-(p-tolylthio)phenyl)hexahydroselenopyrylium;

1-methyl-4-(2-(p-tolylthio)phenyl)hexahydrothiopyrylium;

4-(2-((2,4-dimethylphenyl)thio)phenyl)-1-methylselenomorphol in-1-ium;

4-(2-((2,4-dimethylphenyl)thio)phenyl)-1-methylthiomorpho lin-1-ium; (2-((4-chloro-2-(hydroxymethyl)phenyl)thio)benzyl)dimethylse lenonium;

(2-((4-chloro-2-(hydroxymethyl)phenyl)thio)benzyl)dimethy lsulfonium;

(2-((2-(hydroxymethyl)-4-iodophenyl)thio)benzyl)dimethyls elenonium;

(2-((2-(hydroxymethyl)-4-iodophenyl)thio)benzyl)dimethyls ulfonium;

(2-((2-amino-4-iodophenyl)thio)benzyl)dimethylselenonium;

(2-((2-amino-4-iodophenyl)thio)benzyl)dimethylsulfonium;

(2-((2-amino-4-cyanophenyl)thio)benzyl)dimethylselenonium;

(2-((2-amino-4-cyanophenyl)thio)benzyl)dimethylsulfonium;

(2-((2-amino-4-(fluoromethyl)phenyl)thio)benzyl)dimethylsele nonium;

(2-((2-amino-4-(fluoromethyl)phenyl)thio)benzyl)dimethyls ulfonium; ((2-((2-amino-4-bromophenyl)thio)benzyl)dimethylselenonium;

(2-((2-amino-4-bromophenyl)thio)benzyl)dimethylsulfonium;

(2-((2-amino-4-methylphenyl)thio)benzyl)dimethylselenonium;

(2-((2-amino-4-methylphenyl)thio)benzyl)dimethylsulfonium;

(2-((2-amino-4-fluorophenyl)thio)benzyl)dimethylselenonium;

(2-((2-amino-4-fluorophenyl)thio)benzyl)dimethylsulfonium ; (3-(10,1 1-dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)propyl)dimethy lselenonium; (3-(10,1 1-dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)propyl)dimethy lsulfonium; (3-(5H-dibenzo[a,d][7]annulen-5-yl)propyl)dimethylselenonium ;

(3-(5H-dibenzo[a,d][7]annulen-5-yl)propyl)dimethylsulfoni um;

(3-(10,1 1-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methylpropyl)dimethy lselenonium; (3-(10,1 1-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methylpropyl)dimethy lsulfonium;

(E/Z)-(3-(dibenzo[b,e]thiepin-1 1 (6H)-ylidene)propyl)dimethylselenonium;

(E/Z)-(3-(dibenzo[b,e]thiepin-1 1 (6H)-ylidene)propyl)dimethylsulfonium;

(+/-)-(3-(10,1 1-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2-methylpropyl)- dimethylselenonium;

(+/-)-(3-(10,1 1-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2-methylpropyl)- dimethylsulfonium;

(E/Z)- (3-(dibenzo[b,e]oxepin-1 1 (6H)-ylidene)propyl)dimethylselenonium;

(E/Z)- (3-(dibenzo[b,e]oxepin-1 1 (6H)-ylidene)propyl)dimethylsulfonium;

(3-(9, 10-dihydro-9, 10-ethanoanthracen-9-yl)propyl)dimethylselenonium;

(3-(9, 10-dihydro-9, 10-ethanoanthracen-9-yl)propyl)dimethylsulfonium;

4-(dibenzo[b,f][1 ,4]oxazepin-1 1-yl)-1-methylselenomorpholin-1-ium;

4-(dibenzo[b,f][1 ,4]oxazepin-1 1-yl)-1-methylthiomorpholin-1-ium;

(R/S)- 2-((2-ethoxyphenoxy)methyl)-4-methyl-1 ,4-oxaselenan-4-ium;

(R/S)- 2-((2-ethoxyphenoxy)methyl)-4-methyl-1 ,4-oxathian-4-ium;

(R)-dimethyl(3-phenyl-3-(o-tolyloxy)propyl)selenonium;

(R)-dimethyl(3-phenyl-3-(o-tolyloxy)propyl)sulfonium;

(R*,R*)-2-((2-ethoxyphenoxy)(phenyl)methyl)-4-methyl-1 ,4-oxaselenan-4-ium; and (R*,R*)-2-((2-ethoxyphenoxy)(phenyl)methyl)-4-methyl-1 ,4-oxathian-4-ium

as the free base or a salt or a prodrug thereof. Any of the specific compounds of the invention as the free base or a salt or a prodrug thereof is an independent embodiment and may be claimed individually in a separate claim.

The compounds of the present invention are SERT inhibitors. SERT inhibitors may be divided into serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tetracyclic antidepressants, norepinephrine-dopamine reuptake inhibitors (NDRIs) serotonin-norepinephrine- dopamine reuptake inhibitors (SDNRIs) and/or norepinephrine reuptake inhibitors (NRIs). Examples of SSRIs include, but are not limited to, (S)-(3-(5-cyano-1-(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran-1-yl)propyl)dimethylselenonium, (S)-(3-(5-cyano-1-(4- fluorophenyl)-1 ,3-dihydroisobenzofuran-1-yl)propyl)dimethylsulfonium, (3R,4R)-3- ((benzo[d][1 ,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1-methylhexahyd ro- selenopyrylium, (3R,4R)-3-((benzo[d][1 ,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1- methylhexahydrothiopyrylium, ((1 S,4S)-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro- naphthalen-1-yl)dimethylselenonium, ((1 S,4S)-4-(3,4-dichlorophenyl)-1 , 2,3,4- tetrahydronaphthalen-1-yl)dimethylsulfonium, dimethyl(3-phenyl-3-(4-(trifluoro- methyl)phenoxy)propyl)selenonium, dimethyl(3-phenyl-3-(4-(trifluoromethyl)- phenoxy)propyl)sulfonium, 4-(2-((2,4-dimethylphenyl)thio)phenyl)-1-methyl- selenomorpholin-1-ium and 4-(2-((2,4-dimethylphenyl)thio)phenyl)-1-methylthio- morpholin-1-ium.

Examples of TCAs include, but are not limited to, (3-(10,1 1-dihydro-5H-dibenzo[b,f] azepin-5-yl)propyl)dimethylselenonium, (3-(10, 11-dihydro-5H-dibenzo[b,f]azepin-5- yl)propyl)dimethylsulfonium, (3-(3-chloro-10, 11-dihydro-5H-dibenzo[b,f]azepin-5- yl)propyl)dimethylselenonium, (3-(3-chloro-10, 1 1-dihydro-5H-dibenzo[b,f]azepin-5- yl)propyl)dimethylsulfonium, (3-(10,1 1-dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene) propyl)dimethylselenonium, (3-(10, 11-dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene) propyl)dimethylsulfonium, (3-(5H-dibenzo[a,d][7]annulen-5-yl)propyl)dimethyl- selenonium, (3-(5H-dibenzo[a,d][7]annulen-5-yl)propyl)dimethylsulfonium, (3-(10,1 1- dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methylpropyl)dimethyls elenonium, (3-(10, 11- dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-methylpropyl)dimethyls ulfonium, (E/Z)-(3- (dibenzo[b,e]thiepin-1 1 (6H)-ylidene)propyl)dimethylselenonium, (E/Z)-(3-(dibenzo[b,e] thiepin-1 1 (6H)-ylidene)propyl)dimethylsulfonium, (+/-)-(3-(10,1 1-dihydro-5H- dibenzo[a,d][7]annulen-5-yl)-2-methylpropyl)dimethylselenoni um, (+/-)-(3-(10,1 1- dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2-methylpropyl)dimet hylsulfonium, (E/Z)- (3- (dibenzo[b,e]oxepin-1 1 (6H)-ylidene)propyl)dimethylselenonium and (E/Z)- (3- (dibenzo[b,e]oxepin-1 1 (6H)-ylidene)propyl)dimethylsulfonium.

Examples of SNRIs include, but are not limited to, (S)-dimethyl(3-(naphthalen-1-yloxy)- 3-(thiophen-2-yl)propyl)selenonium, (S)-dimethyl(3-(naphthalen-1-yloxy)-3-(thiophen-2- yl)propyl)sulfonium, (2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)ethyl)dimethyl- selenonium, (2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)ethyl)dimethylsu lfonium, (2- (1 -hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)dimethylselenon ium and (2-(1 - hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)dimethylsulfoniu m.

Examples of tetracyclic antidepressants include, but are not limited to, 2-methyl- 1 ,2,3,4, 10, 14b-hexahydrobenzo[c]pyrido[3,2-f][1 ,4]selenazino[4,3-a]azepin-2-ium, 2- methyl-1 ,2,3,4, 10, 14b-hexahydrobenzo[c]pyrido[3,2-f][1 ,4]thiazino[4,3-a]azepin-2-ium, (3-(9, 10-dihydro-9, 10-ethanoanthracen-9-yl)propyl)dimethylselenonium, (3-(9, 10- dihydro-9,10-ethanoanthracen-9-yl)propyl)dimethylsulfonium, 4-(dibenzo[b,f][1 ,4] oxazepin-1 1-yl)-1-methylselenomorpholin-1-ium and 4-(dibenzo[b,f][1 ,4]oxazepin-11- yl)-1-methylthiomorpholin-1-ium.

Examples of NDRIs include, but are not limited to tert-butyl(1-(3-chlorophenyl)-1- oxopropan-2-yl)(methyl)selenonium and tert-butyl(1-(3-chlorophenyl)-1-oxopropan-2- yl)(methyl)sulfonium.

Examples of SDNRIs include, but are not limited to 1-(3,4-dichlorophenyl)-3-methyl-3- selenabicyclo[3.1.0]hexan-3-ium, 1-(3,4-dichlorophenyl)-3-methyl-3-thiabicyclo[3.1.0] hexan-3-ium, ((R)-(1-(1-(4-chlorophenyl)cyclobutyl)-3-methylbutyl)dimethy lselenonium, (R)-(1 -(1 -(4-chlorophenyl)cyclobutyl)-3-methylbutyl)dimethylsulfonium , (1 -(1 -(4- chlorophenyl)cyclobutyl)-3-methylbutyl)dimethylselenonium, (1-(1-(4-chlorophenyl) cyclobutyl)-3-methylbutyl)dimethylsulfonium, 1-methyl-4-(2-(p-tolylthio)phenyl) hexahydroselenopyrylium and 1-methyl-4-(2-(p-tolylthio)phenyl)hexahydrothiopyrylium.

Examples of NRIs include, but are not limited to (R/S)- 2-((2-ethoxyphenoxy)methyl)-4- methyl-1 ,4-oxaselenan-4-ium, (R/S)- 2-((2-ethoxyphenoxy)methyl)-4-methyl-1 ,4- oxathian-4-ium, (R)-dimethyl(3-phenyl-3-(o-tolyloxy)propyl)selenonium, (R)-dimethyl(3- phenyl-3-(o-tolyloxy)propyl)sulfonium, (R*,R*)-2-((2-ethoxyphenoxy)(phenyl)methyl)-4- methyl-1 ,4-oxaselenan-4-ium and (R*,R*)-2-((2-ethoxyphenoxy)(phenyl)methyl)-4- methyl-1 ,4-oxathian-4-ium.

Salts of the invention

The salts of the present invention, such as pharmaceutically acceptable salts, e.g. pharmaceutically acceptable acid addition salts, refers to the relatively non-toxic, inorganic and organic addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free acid or base form with a suitable organic or inorganic compound and isolating the salt thus formed. The compounds of the present invention are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be

pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the base compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert to the free base compound by treatment with an alkaline reagent and thereafter convert the free base to a pharmaceutically acceptable acid addition salt.

The pharmaceutically acceptable acid addition salts of the compounds of the present invention are prepared by contacting the compounds with a sufficient amount of the desired acid to produce the salt in the conventional manner. The compounds as such may be regenerated by contacting the salt form with a base and isolating it in a conventional manner. The compounds as such differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective compounds for purposes of the present invention. Salts may e.g. be prepared from inorganic acids comprising sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,

dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, tnfluoromethanesulfonate, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts may also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, tnfluoromethanesulfonate and the like. (See, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci.,

1977;66: 1-19 which is incorporated herein by reference.)

Particularly preferred are the iodide and the trifluoromethanesulfonate salts of the compounds of the present invention. In a preferred embodiment of the invention, the salts are trifluoromethanesulfonate salts. In another preferred embodiment of the invention, the salts are iodides.

Also intended as pharmaceutical acceptable acid addition salts are the hydrates which the compounds of the present invention are able to form.

The compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be

encompassed within the scope of the present invention.

Prodrugs of the invention

The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.

Examples of prodrugs include pharmaceutically acceptable, non-toxic esters of the compounds of the present invention, including C C ₆ alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C ₅ -C ₇ cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C C ₄ alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods "March's Advanced Organic Chemistry, 5 ^th Edition". M. B. Smith & J. March, John Wiley & Sons, 2001.

Stereochemistry of the compounds of the invention

Compounds or salts or prodrugs of the present invention may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and all stereoisomers of the compounds or salts of the present invention, both as racemic mixtures and as individual enantiomers and diastereoismers ((+)- and (-)-optically active forms), and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined herein that contain or employ them, respectively. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.

Labelled compounds or salts of the present invention

The present invention also includes isotopically-labelled compounds or salts or prodrugs of the present invention wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphor, fluorine, iodine, and chlorine, such as ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ¹²³ l and ¹²⁵ l.

Compounds and salts of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹ C and ¹⁸ F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵ l isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds or salts of the present invention can generally be prepared by carrying out the procedures disclosed in the synthesis Schemes and/or in the

Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

Definitions

The expression 'Ci. ₆ -alk (en/yn)yl' means a Ci _-6 -alkyl, a C ₂ -6-alkenyl or a C ₂ -6-alkynyl group; wherein: - 'Ci-e-alkyr refers to a branched or unbranched alkyl group having from one to six carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl; 'Ci _-4 -alkyr refers to a branched or unbranched group having from one to four carbon atoms, which may in particular include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl; and

- 'C ₂ - ₆ -alkenyr refers to a straight or branched hydrocarbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes. Examples of preferred alkenyl groups of the invention include ethenyl; 1- or 2-propenyl; 1-, 2- or 3-butenyl, or 1 ,3- butenyl; 1-, 2-, 3- or 4-pentenyl, or 1 ,3-pentenyl or 1 ,4- pentenyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1 ,3-hexenyl, or 1 ,3,5-hexenyl; and 'C ₂ - ₆ -alkynyr refers to a straight or branched hydrocarbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes. Examples of preferred alkynyl groups of the invention include ethynyl; 1- or 2-propynyl; 1-, 2- or 3-butynyl, or 1 ,3-butynyl; 1-, 2-, 3- or 4- pentynyl, or 1 ,3-pentynyl, or 1 ,4- pentynyl.

The expression 'C ₃ . ₈ -cycloalk(en)yr means a C ₃ . ₈ -cycloalkyl or a C ₃ . ₈ -cycloalkenyl group; wherein:

- 'C ₃ - ₈ -cycloalkyr refers to a cyclic alkyl group containing from three to eight

carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. 'C ₃ . ₆ -cycloalkyr refers to a cyclic alkyl group containing from three to six carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

- 'C ₃ - ₈ -cycloalkenyr refers to a cyclic alkyl group containing one or more double bonds. Examples of preferred C ₃ . ₈ -cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.

The terms 'halogen' and 'halo' means fluoro, chloro, bromo or iodo.

The term 'hydroxy' and means a OH-group.

The term 'methoxy' and 'ethoxy' refers to -0-CH ₃ and 0-CH ₂ -CH ₃ , respectively.

The term 'cyano' means a CN-group. In the expression 'halo-Ci. ₆ -alk(en/yn)yr, 'halo-C ₃ . ₈ -cycloalk(en)yr and 'hydroxy-Ci. ₆ - alk(en/yn)yl', the terms 'Ci. ₆ -alk(en/yn)yr, 'C ₃ . ₈ -cycloalk(en)yr, 'hydroxy' and 'halo' are as defined above.

The term 'aryl' refers to a carbocyclic aromatic group, such as phenyl or naphthalenyl, in particular phenyl and includes both substituted and unsubstituted carbocyclic aromatic groups. Thus, the aryl is optionally substituted with one or more substituents selected from the substituent list as defined herein. Accordingly, the term aryl as used herein means an optionally substituted carbocyclic aromatic group, e. g. phenyl or naphthalenyl, such that said aromatic group is substituted with one or more substituents selected from the substituent list defined below, e. g., Ci. ₆ -alk(en/yn)yl or halogen. The aryl is preferably mono-or bicyclic. The term 'carbocyclic ring' refers to an aliphatic or aromatic ring structure wherein all ring atoms are carbon atoms. Such carbocyclic rings may be isolated or it may be fused to one or more carbocyclic or heterocyclic rings. Both substituted and unsubstituted carbocyclic rings are included. Thus the carbocyclic ring is optionally substituted with one or more substituents selected from the substituent list as defined below. Accordingly, the term carbocyclic ring as used herein means an optionally substituted aliphatic or aromatic ring wherein all ring atoms are carbon atoms; such as but not limited to rings consisting of 4-8 ring atoms, such as 5, 6 or 7 ring atoms. Particularly preferred are carbocyclic rings consisting of 6 ring atoms, e.g. phenyl, which may be substituted or not and which may be isolated or fused to one or more carbocyclic or heterocyclic rings.

The term 'heterocyclic ring' refers to an aliphatic or heteroaromatic ring structure wherein each ring atom is selected from the group consisting of C, N, O and S. Such heterocyclic ring may be isolated or it may be fused to one or more carbocyclic or heterocyclic rings. Both substituted and un-substituted heterocyclic rings are included. Thus the heterocyclic ring is optionally substituted with one or more substituents selected from the substituent list as defined below. Accordingly, the term heterocyclic ring as used herein means an optionally substituted aliphatic or heteroaromatic ring wherein each ring atom is selected from the group consisting of C, N, O and S.

Preferably, the heterocyclic ring has 1 or 2 ring atoms which are selected from the group consisting of N, O and S such as 1 nitrogen atom or 1 sulphur atom; while the remainder of the ring atoms are carbon atoms. Such heterocyclic rings preferably consist of 4-8 ring atoms, such as 5, 6 or 7 ring atoms. Particularly preferred are heterocyclic rings consisting of 5 or 7 ring atoms, e.g. furane, thiophene and azepine, which may be substituted or not and which may be isolated or fused to one or more carbocyclic or heterocyclic rings.

The term 'substituent list' as used herein means substituents selected from the group consisting of Ci. ₆ -alk(en/yn)yl (e.g. Ci _-6 -alkyl such as methyl), C ₃ . ₈ -cycloalk(en)yl, halogen, cyano, halo-Ci. ₆ -alk(en/yn)yl and halo-C ₃ . ₈ -cycloalk(en)yl.

The terms 'treating' and 'treatment', as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

The term 'psychiatric medication', as used herein, refers to active substances having an effect on CNS disorders, including but not limited to, known and future licensed psychoactive drugs. The term 'pharmaceutical acceptable salt' as used herein refers to those acid additions salts of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

Activity profile

The inventors have surprisingly found that compounds and salts of the present invention have an improved activity profile compared to previously reported

compounds.

The compounds, salts and prodrugs of the invention thus have an increased affinity for SERT as compared to compounds known from literature. Accordingly, replacement of a nitrogen atom in the tail with a sulphur or selenium atom reduces the K, for SERT with at least a factor 1 ,5, such as with at least a factor 2, e.g. at least a factor 3. In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a chloride is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom reduces the K, for SERT with at least a factor 2, such as at least a factor 3.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a hydrogen is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom reduces the K, for SERT with at least a factor 3, such as at least a factor 5.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a cyano is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom reduces the K, for SERT with at least a factor 1 ,5; such as at least a factor 2.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 8 wherein V is oxygen, replacement of a nitrogen atom in the tail with a sulphur or selenium atom reduces the K, for SERT with at least a factor 3, such as at least a factor 12.

Furthermore, the compounds, salts and prodrugs of the invention have an increased specificity for SERT as compared to compounds known from literature. Accordingly, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio DAT / SERT with at least a factor 2, such as with at least a factor 3.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a chloride is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the Kj ratio DAT / SERT.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a hydrogen is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio DAT / SERT with at least a factor 2, such as with at least a factor 4.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a cyano is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio DAT / SERT with at least a factor 2, such as with at least a factor 5. In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 8 wherein V is oxygen, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio DAT / SERT with at least a factor 3, such as at least a factor 12. Furthermore, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio NET / SERT with at least a factor 1 ,5, such as at least a factor 2, e.g. at least a factor 3.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a hydrogen is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio NET / SERT with at least a factor 2, such as with at least about factor 3. In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 7 wherein a cyano is present in the 3-position and Z is N, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio NET / SERT with at least a factor 1 ,5 such as with at least a factor 17.

In specific embodiments wherein the compound, salt or prodrug of the invention comprises the substructure of formula 8 wherein V is oxygen, replacement of a nitrogen atom in the tail with a sulphur or selenium atom increases the K, ratio NET / SERT with at least a factor 3, such as with at least a factor 12. In even more specific embodiments, the compounds, salts and prodrugs of the invention show poor affinity for DAT, such as a Ki for DAT of at least 14000 nM, e.g. at least 75000 nM, such as at least 121000 nM. Moreover, the compounds, salts and prodrugs of the invention are positively charged at the tail which provides an at least 9 fold increase in affinity for SERT as compared to compounds known from literature which are not positively charged. In a specific embodiment thereof, Z is a nitrogen atom such as a nitrogen atom which is methylated with 3 methyl groups.

The compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N show poor affinity for DAT, and are very specific for SERT over DAT. Trimethyl imipramine is more specific than clomipramine which is more specific for SERT over DAT than imipramine, which is again more specific than desipramine.

Compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N, selenium on the tail and a chloride on the 3-position, has a higher affinity for SERT than clomipramine.

Compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N, chloride on the 3-postion and sulphur on the tail has a higher affinity for SERT than clomipramine. Compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N and, a cyano group on the 3-position and S or Se in the tail are more specific for SERT than 3-cyanoimipramine. They are very specific for SERT over DAT. Thus the cyano group on the 3-position is preferred for both the affinity for SERT and the specificity for SERT over DAT. No significant change in binding affinities towards SERT is seen when exchanging the chloride with a cyano group. However, binding affinity toward DAT is significantly lowered when the chloride is exchanged with a cyano group. This shows that it is the cyano group on the 3-position, in combination with selenium or sulphur on the tail, which gives the high specificity for SERT over DAT. Compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N are less specific for SERT over NET than for SERT over DAT. Some compounds of the invention even have a higher affinity for NET than for SERT. Unlike for the specificity for SERT over DAT, the specificity of trimethylimipramine for SERT over NET is higher than for imipramine.

Compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N and having a sulphur in the tail generally have a better specificity for SERT over NET, than those compounds having nitrogen or selenium in the tail.

However only as long as there is hydrogen or cyano in the 3-position.

For those compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N and having sulphur or selenium in the tail, the specificity for SERT over NET increases going from -H to -CI to -C≡N on the 3-position. For the analogues with a nitrogen in the tail, the specificity decreases going from a chloride to a cyano group on the 3-position.

Those compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N, sulphur or selenium on the tail and a cyano group on the three-position have a significantly lower binding affinity for hNET, than corresponding compounds with a chloride on the 3-position. It has thus been shown that the combination of both a cyano group on the 3-position and either sulphur or selenium on the tail leads to a high specificity for SERT over NET.

For those compounds, salts and prodrugs of the invention comprising the substructure of formula 7 wherein Z is N, the cyano group on the 3-position has been shown to be important for both the SERT over DAT specificity and the hSERT over hNET specificity. In both cases, the highest specificity was observed when the cyano group on the 3- position was combined with a sulphur in the tail.

CNS disorders

The present invention relates to compounds, salts or prodrugs of the present invention, for use as a medicament, and especially for treating CNS disorders, such as e.g.

depression. The present invention further relates to use of compounds of a compound or salt of the present invention for the preparation of a medicament for the treatment of CNS disorders.

In one embodiment of the invention the CNS disorders to be treated by compounds of the present invention is selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain. In a preferred embodiment of the invention the CNS disorder is selected from the group consisting of depression, panic disorder, anxiety, and obsessive-compulsive disorder. In a more preferred embodiment of the invention the CNS disorder is selected from the group consisting of depression and anxiety. In an even more preferred embodiment of the invention the CNS disorder is depression.

Pharmaceutical compositions

One aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention or a salt or prodrug thereof. A compound or salt of the present invention or a salt or prodrug thereof may be administered alone or in combination with pharmaceutically acceptable carriers, diluents, or excipients in either single or multiple doses. Suitable pharmaceutical acceptable carriers, diluents and excipients include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining a compound or salt of the present invention with pharmaceutical acceptable carriers, diluents or excipients can be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, suppositories, injectable solutions and the like. In powders, the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium

carboxymethylcellulose, a low melting wax, cocoa butter, and the like. A preferred form for oral use are capsules, which include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient size molds, allowed to cool, and thereby to solidify.

For parenteral administration, solutions containing a compound of this invention or a pharmaceutically acceptable salt, solvate or prodrug thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

It is preferred to use parenteral administration for compounds of the invention, wherein the active part of the molecule contains acid labile groups, such as e.g. ester groups. By using parenteral administration the acidic environment of the stomach is avoided together with the first-pass metabolism. When compounds of the invention is formulated as a prodrug, which relies on the first-pass metabolism for releasing the active part of the molecule, oral administration is preferred instead (or another appropriate administration form which result in a first-pass metabolism).

A compound or salt of the present invention may be administered orally, transdermal^ (e.g., through the use of a patch), parenterally (e.g. intravenously), rectally, or topically. In general, the daily dosage for treating a CNS disorder will generally range from about 0.0001 to about 50.0 mg/kg body weight of the patient to be treated, preferably from about 0.0001 to about 40 mg/kg body weight of the patient to be treated, such as e.g., from about 0.0002 to about 30 mg/kg, from about 0.001 to about 20 mg/kg, from about 0.0015 to about 15 mg/kg, from about 0.01 to about 10 mg/kg, from about 0.1 to about 10 mg/kg, from about 0.5 to about 20 mg/kg, and from about 0.5 to about 20 mg/kg. As an example, a compound or salt of the present invention may be administered for treatment of a CNS disorder to an adult human of average weight (about 70kg) in a dose ranging from about 0.01 mg up to about 2000 mg per day, preferably from about 0.1 to about 1000 mg per day, such as e.g., from about 0.1 to about 500 mg per day, and from about 0.1 to about 100 mg per day, or such as e.g., from about 1 to about 1000 mg per day, from about 10 to about 1000 mg per day, from about 100 to about 1000 mg per day, from about 200 to about 1000 mg per day, and from about 500 to about 1000 mg per day, in single or divided (i.e., multiple) portions.

In general, the therapeutically-effective compounds or salts of the present invention are present in pharmaceutical compositions at concentration levels ranging from 5% to 95 % by weight, preferably from 10% to 95% by weight, such as e.g., from 20% to 95% by weight, from 30% to 95% by weight, from 40% to 95% by weight, more preferably from 50% to 95% by weight, such as e.g., from 60% to 95% by weight, and from 70% to 95% by weight.

Variations based on the aforementioned dosage ranges may be made by a physician of ordinary skill taking into account known considerations such as the weight, age, and condition of the person being treated, the severity of the affliction, and the particular route of administration chosen. The pharmaceutical preparations of the invention are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The compounds of the invention may also be formulated in a pharmaceutical composition comprising one or more further active substances alone, or in combination with pharmaceutically acceptable carriers, diluents, or excipients in either single or multiple doses. The suitable pharmaceutical acceptable carriers, diluents and excipients are as described herein above, and the one or more further active substances may be any active substances, or preferably an active substance as described in the section "combination treatment" herein below.

Combination treatment

The present invention furthermore relates to a combination treatment of a CNS disorder, wherein a compound of the present invention is administered in combination with one or more further active substance, preferably a psychiatric medication, such as e.g., antidepressants, stimulants, antipsychotics, mood stabilizers, anxiolytics, or depressants, more preferably one or more anti-depressants. The psychiatric medication may preferably be selected from the group consisting of Selective serotonin reuptake inhibitors (SSRIs), Tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), Noradrenergic and specific serotonergic antidepressants (NASSAs), Norepinephrine reuptake inhibitors (NRIs), Dopamine Reuptake Inhibitors (DARIs), Norepinephrine-dopamine reuptake inhibitors (NDRIs), and Serotonin- norepinephrine-dopamine-reuptake-inhibitors (SNDRIs); even more preferably one or more psychiatric medications may be selected from the group consisting of SSRIs, TCAs, SNRIs, NRIs and SNDRIs; yet even more preferably SSRIs.

In one embodiment of the present invention the compounds or salt of the present invention is administered in combination with one or more further active substances for the treatment of a CNS disorder, also denoted psychiatric medication. In a preferred embodiment of the invention the one or more further active substances is one or more antidepressants.

Examples of anti-depressants that can be combined with one or more compounds or salts of the present invention in a combination treatment according to the present invention, include, but are not limited to, SSRI, TCA, SNRI, NDRI and SNDRI. In a preferred embodiment of the invention the antidepressant is selected from the group consisting of SSRIs, TCAs, SNDRIs and SNRIs. Examples of SSRIs that can be combined with one or more compounds or salts of the present invention in a method for treatment, a combination treatment or a

pharmaceutical composition include, but are not limited to, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, fluvoxamine, venlafaxine, duloxetine, zimelidine, and dapoxetine. In a preferred embodiment of the present invention the SSRIs are selected from the group consisting of citalopram, escitalopram, fluoxetine, paroxetine, sertraline, fluvoxamine, venlafaxine, and duloxetine. Other SSRIs may be combined or administered in combination with a compound or salt of the present invention.

Examples of TCAs that can be combined with one or more compounds or salts of the present invention, include, but are not limited to, imipramine, amitrypline, butriptyline, amoxapine, clomipramine, desipramine, dosulepin, doxepin, iprindole, lofepramine, nortriptyline, opipramol, protriptyline, and trimipramine.

Examples of SNRIs that can be combined with one or more compounds or salts of the present invention include, but are not limited to, venlafaxine and duloxetine. An example of a NASSA that can be combined with one or more compounds of formula 1 , or their pharmaceutically acceptable salts, solvates or prodrugs, includes, but is not limited to, mirtazapine. Examples of NRIs that can be combined with one or more compounds or salts of the present invention include, but are not limited to,

Atomoxetine, Reboxetine, Viloxazine, Maprotiline, Nortriptyline, Bupropion and

Radafaxine.

Examples of NDRIs that can be combined with one or more compounds or salts of the present invention, include, but are not limited to, Bupropion and Nomifensine. Serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs) are also termed Triple reuptake inhibitors, or TRIs, as these compounds block the uptake of serotonin, norepinephrine and dopamine. Examples of SNDRIs that can be combined with one or more compounds or salts of the present invention, include, but are not limited to, tesofensine, brasofensine, diclofensine, and NS2359.

The compounds or salts of the present invention and the one or more further active substance, such as e.g., a SSRI, can be administered to the mammal at the same time and/or at different times. Moreover, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The therapeutically effective amount of a further active substance can generally be determined by a person skilled in the art. A proposed effective daily dosage range for a further active substance, such as preferably a SSRI, in combination with a compounds or salts of the present invention is from about 0.01 to about 500 mg/kg body weight.

The effective daily amount of the compounds or salts of the present invention generally will be between about 0.0001 to about 10 mg/kg body weight. In some embodiments of the invention, the amount of the further active substance, such as preferably a SSRI, and/or the amount of compounds or salts of the present invention, in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating depression or anxiety, due to the observed synergistic effect of combining compounds or salts of the present invention with e.g. a SSRI.

Use of a compound or salt or prodrug of the present invention

In a further aspect the present invention relates to a method of treating diseases in a subject, said method comprises administering to said subject a therapeutically effective amount of a compound comprising the substructure of formula 1 or salt or prodrug as defined herein to a subject in need of such treatment. The disease may be any disease or disorder as mentioned herein, such as for example mentioned in the section 'CNS disorders', and the compound may be administered alone or in a pharmaceutical composition, such as for example mentioned in the section 'Pharmaceutical compositions'.

In a preferred embodiment of this aspect of the invention the method is a method of treating a CNS disorder in a subject, said method comprises administering to said subject a therapeutically effective amount of a compound comprising a fragment of formula 1 or a salt or prodrug as defined herein to a subject in need of such treatment. The CNS disorder may be any CNS disorder as described herein above. Accordingly, the invention provides a method for the treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain. Preferably the CNS disorder is depression. In one embodiment of the method according to the invention, the compound comprising the substructure of formula 1 or salt or prodrug as defined herein is administered in combination with one or more further active substances. The active substances may be any active substances, and preferably an active substance as described herein above in the section 'combination treatment'. More preferably the one or more additional active substances are selected from the group consisting of SSRI, TCA, SNDRI or SNRI. Even more preferably the one or more further active substances are SSRIs.

Moreover the invention provides a pharmaceutical composition comprising a compound or salt or prodrug as defined herein, such as a pharmaceutical composition comprising a compound or salt or prodrug as defined herein for treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain. Preferably the CNS disorder is depression.

The invention also provides the use of a compound or salt or prodrug as defined herein for the preparation of a medicament for the treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain. Preferably the CNS disorder is depression.

The invention furthermore relates to a compound or salt or prodrug as defined herein for treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain. Preferably the CNS disorder is depression.

The invention furthermore relates to a compound or salt or prodrug as defined herein for use as a medicament, preferably for treatment of CNS disorders, such as e.g. a CNS disorder selected from the group consisting of depression, panic disorder, anxiety, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social phobia, bulimia nervosa, anorexia nervosa, post-traumatic stress disorder (PTSD), and neuropathic pain. Preferably the CNS disorder is depression.

All patent and non-patent references cited in the application, or in the present application, are also hereby incorporated by reference in their entirety.

Synthesis

The following Examples illustrate the present invention. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following Examples. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples.

General description of preparation of compounds possessing a positive charge

Formation of sulfonium and selenonium salts can be obtained by two different routes of synthesis.

In one route of synthesis the bioactive sulfonium and/or selenonium salts are formed from neutral drug analogues possessing sulfides and/or selenides, respectively, by alkylation using e.g. Meerwein's salts, alkyl triflate, alkyl tosylate, alkyl iodide, alkyl bromide or equivalent alkylating reagents. This route of synthesis is illustrated below.

Θ

Alk-X X

R R R In an alternative route of synthesis, sulfur or selenium can be introduced as a sulfonium or selenonium salts by treatment a drug analogue containing e.g. an iodide, bromide, triflate, tosylate or other nucleopfuge by reaction with dialkyl sulfide or dialkyl selenide, respectively. This alternative route of synthesis is illustrated below.

Examples

Synthesis of intermediates and compounds of the invention

Synthesis overview: In the examples below commercial available starting materials and reagents were used without further purification. Solvents were dried according to standard procedures. Columns for flash chromatography were packed with silica gel (60 A). TLC plates (Kieselgel 60 F254) were visualized by UV-light or the use of a "Ce- Mol" solution (Ce(IV)sulfate (10 g) and ammonium molybdate (15 g) dissolved in 10% H2SO4 (1 L)) and heated until colored spots appeared. ¹ H and ¹³ C NMR experiments were recorded on a Varian Mercury 400 NMR instrument. Mass spectral analyses were carried out as electrospray experiments on a Micromass LC-TOF instrument.

Synthesis overview

37 38 39

Preparation of intermediates

Example 1 : Compound Mj1-02

5-allyl-10,11 -dihydro-5H-dibenzo[b, ]azep

NaH 60 % (2.462 g., 61.5 mmol) was placed in a sealed flask under N ₂ atm., and added a solution of iminodibenzyl 1 (1.998 g., 10.2 mmol) in dry DMF (15 ml_). The reaction mixture was stirred for 20 min at room temperature, followed by slow addition of allyl bromide (3.4 ml_, 40.19 mmol), and was then stirred for 1 hour at room temperature. The reaction mixture was transferred to a separation funnel with EtOAc and ice-water, and the organic phase was washed four times with H ₂ 0 and sat. NaCI ₍ aq ₎ . The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 :9) to afford 2.206 g. of 2 as clear oil (9.37 mmol, 92%). R _f : 0.54 (CH ₂ CI ₂ /pentane 1 :9) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.16 (m, 6H), 7.00 (m, 2H), 5.85 (m, 1 H), 5.31 (ddd, 1 H, J 1.6 Hz, J 17.2 Hz), 5.15 (ddd, 1 H, J 1.6 Hz, J 10.4 Hz), 4.46 (dt, 2H, J 1.6 Hz, J 6.0 Hz), 3.23 (s, 4H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.2, 135.7, 134.2, 129.8, 126.3, 122.5, 120.5, 1 17.2, 54.4, 32.6. GC-MS (El):

Calculated for Ci ₇ H ₁₇ N m/z 235.1361. Found m/z 235.

Example 2: Compound Mj 1 - 10

3-(10,11 -dihydro-5H-dibenzo[b, ]azepine-5-yl)propan1 -ol, 3.

A 0.5 M solution of 9-BBN in THF (40 mL, 20 mmol) was added to 2 (1.499 g., 6.37 mmol) under N ₂ atm., and was then stirred for 24 hours at room temperature. The reaction mixture was cooled to 0°C and added dropwise 6 N NaOH (6.4 mL, 38.4 mmol) followed by 35% H ₂ 0 ₂ (4.5 mL, 50.9 mmol). The reaction mixture was then stirred overnight at room temperature followed by 2 hours at 50°C. The mixture was cooled to room temperature and added H ₂ 0 (30 mL) and extracted three times with

Et ₂ 0. The organic phase was washed with sat. NaCI _(aq) , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/pentane 1 :4) to afford 1.431 g. of 3 as clear oil (5.65 mmol, 89%).

R _f : 0.27 (EtOAc/pentane 1 :3) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.23 (m, 6H), 7.04 (m, 2H), 3.91 (t, 2H, J 6.4 Hz), 3.67 (t, 2H, J 6.4 Hz), 3.27 (s, 4H), 2.34 (bs, 1 H), 1.87 (quintet, 2H, J 6.4 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.4, 134.3, 129.9, 126.5, 122.7, 120.0, 60.9, 47.2, 32.3, 30.9. HR-MS (ES): Calculated for d ₇ H ₁₉ NONa m/z 276.1364. Found m/z 276.1366. Spectral data were in accordance with previously published (Andersen, K. E.;

Sorensen, J. L; Lau, J. ; Lundt, B. F. ; Petersen, H. ; Huusfeldt, P. O. ; Suzdak, P. D. ; Swedberg, M . D. B. J. Med. Chem. 2001 , 44, 2152-2163). Example 3

3-(10,1 1 -dihydro-5H-dibenzo b, ]azepine-5-yl)propyl methanesulfonate, 4.

A solution of 3 (1 .431 g. , 5.65 mmol) in dry Et ₂ 0 (20 mL) at 0°C was added distilled Et ₃ N (1 .6 mL, 1 1 .5 mmol) followed by MsCI (0.7 mL, 9.03 mmol), and the reaction mixture was stirred for 1 hour at 0°C. The reaction mixture was dissolved in CH ₂ CI ₂ and washed with mildly acidic H ₂ 0, H ₂ 0 and last with sat. NaHC0 ₃₍ aq ₎ The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 1 .639 g. of 4 as a thick yellow oil. The crude product was pure enough for the next reaction.

R _f : 0.41 (EtOAc/pentane 1 :3) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.13 (m, 6H), 6.96 (m, 2H), 4.28 (t, 2H, J 6.4 Hz), 3.90 (t, 2H, J 6.4 Hz), 3.19 (s, 4H), 2.87 (s, 3H), 2.04 (quintet, 2H, J 6.4 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 147.8, 134.4, 130.1 , 126.6, 123.0, 1 19.8, 67.9, 46.4, 37.2, 32.2, 27.6. HR-MS (ES): Calculated for Ci ₈ H ₂₁ N0 ₃ SNa m/z 354.1 140. Found m/z 354.1 138.

Example 4

3-(10,1 1 -dihydro-5H-dibenzo[b, ]azepine-5-yl)propyl ethanethioate, 5.

To a solution of 4 (0.807 g., 2.43 mmol) in dry DMF (5 mL) was added a solution of potassium thioacetate (0.564 g. 4.94 mmol) in dry DMF (10 mL), and then stirred at room temperature for 16 hours. The reaction mixture was added EtOAc (20 mL) and washed with four times with H ₂ 0 and sat. NaCI _(aq) . The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 702 mg. of 5 as yellow oil. The crude product was pure enough for the next reaction.

R _f : 0.13 (CH ₂ CI ₂ /pentane 1 :9) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.16 (m, 6H), 6.95 (m, 2H), 3.82 (t, 2H, J 6.8 Hz), 3.18 (s, 4H), 2.91 (t, 2H, J 6.8 Hz), 2.30 (s, 3H), 1.88 (quintet, 2H, J 6.8 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 195.8, 148.2, 134.4, 130.0, 126.5, 122.7, 1 19.9, 49.4, 32.3, 30.7, 27.8, 27.0. LR-MS (ES): Calculated for C19H21 NOSNa m/z 31 1.1344. Found m/z 31 1.1

Example 5: Compound S-desipramine

5-(3-(methylthio)propyl)-10,11 -dihydro-5H-dibenzo[/3, ]azep

To a solution of 5 (702 mg, 2.25 mmol) in degassed and dry MeOH (15 mL) was added Na(s) (210 mg, 9.13 mmol). The reaction mixture was stirred for 45 min. at room temperature before Mel (1.1 mL, 17.5 mmol) was added dropwise. The mixture was stirred for 20 min. at room temperature before sat. NaHC0 _3(aq) (10 mL) was added and the mixture concentrated under reduced pressure. The aqueous residue was extracted three times with CH ₂ CI ₂ , and the combined organic phases were dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 : 19) to afford 281 mg. of 6 as clear oil (0.99 mmol, 44% over three steps).

R _f : 0.13 (CH ₂ CI ₂ /pentane 1 :9) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.14 (m, 6H), 6.95 (m, 2H), 3.87 (t, 2H, J 7.2 Hz), 3.19 (s, 4H), 2.54 (t, 2H, J 7.2 Hz), 2.03 (s, 3H), 1.89 (quintet, 2H, J 7.2 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.3, 134.3, 129.9, 126.5, 122.6, 120.0, 49.5, 32.3, 32.0, 27.4, 15.6. HR-MS (ES): Calculated for Ci ₈ H ₂ i NSNa m/z 284.1473. Found m/z 284.1475

Example 6: Compound Mj1-1 1

5-allyl-3-chloro-10,11 -dihydro-5H-dibenzo[/3, lazepine, 9.

NaH 60% (2.855 g., 71.4 mmol) was placed in a sealed flask under N ₂ atm., and added a solution of 3-chloro-iminodibenzyl 8 (4.099 g., 17.8 mmol) in dry DMF (25 ml_). The reaction mixture was stirred for 20 min. at room temperature, followed by slow addition of allyl bromide (4.5 ml_, 53.2 mmol). The mixture was then stirred for 1 hour at room temperature before transferred to a separation funnel with EtOAc and ice-water, and the organic phase washed four times with H ₂ 0 and sat. NaCI _(aq) . The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /heptane 1 : 19) to afford 4.669 g. of 9 as clear oil (17.3 mmol, 97 %).

R _f : 0.27 (pentane). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.17-6.95 (m, 6H), 6.8 (dd, 1 H, J 2 Hz, J 8 Hz), 5.77 (m, 1 H), 5.28 (ddd, 1 H, J 1.6 Hz, J 17.2 Hz), 5.14 (ddd, 1 H, J 1.6 Hz, J 10.4 Hz), 4.38 (dt, 2H, J 1.6 Hz, J 5.6 Hz), 3.15 (m, 4H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5c 148.7, 147.8, 135.0, 131.5, 131.2, 129.4, 126.5, 123.3, 122.0, 121.0, 120.3, 117.8, 54.4, 32.5, 31.8. GC-MS (El): Calculated for d ₇ H ₁₆ ³⁵ CIN m/z 269.0971. Found m/z 269.

Example 7: Compound Mj 1 - 12

3-(3-chloro-10,11 -dihydro-5H-dibenzo[b, ]azepine-5-yl)propan1 -ol, 10.

A 0.5 M solution of 9-BBN in THF (37 mL, 18.5 mmol) was added to 9 (1.679 g., 6.22 mmol) under N ₂ atm., and was then stirred for 24 hours at room temperature. The reaction mixture was cooled to 0°C before 6 N NaOH (6.3 mL, 37.8 mmol) and then 35% aq. H ₂ 0 ₂ (4.4 mL, 49.8 mmol) were added in a dropwise fashion. The reaction mixture was then stirred overnight at room temperature followed by 2 hours at 50°C. The mixture was cooled to room temperature and added H ₂ 0 (30 mL) and extracted three times with Et ₂ 0. The organic phase was washed with sat. NaCI _(aq) , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/pentane 1 :9) to afford 1.245 g. of 10 as yellow solid (4.33 mmol, 69%).

R _f : 0.33 (EtOAc/pentane 1 :4) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.18-7.07 (m, 4H), 6.98 (m, 2H), 6.87 (dd, 1 H, J 2 Hz, J 8 Hz), 3.83 (t, 2H, J 6.4 Hz), 3.68 (t, 2H, J 6.4 Hz), 3.13 (m, 4H), 1.83 (quintet, 2H, J 6.4 Hz), 1.45 (bs, 1 H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 149.1 , 147.9, 135.2, 131.7, 131.7, 131.4, 129.7, 126.7, 123.5, 122.3, 120.5, 119.9, 60.8, 47.4, 32.2, 31.6, 30.8. HR-MS (ES): Calculated for Ci ₇ H ₁₈ ³⁵ CINONa m/z

310.0975 . Found m/z 310.0974

Example 8

3-(3-chloro-10,11 -dihydro-5H-dibenzo[/3, ]azepine-5-yl)propyl methanesulfonate, 11.

A solution of 10 (1.245 g., 4.33 mmol) in dry Et ₂ 0 (20 mL) at 0°C was added distilled Et ₃ N (1.2 mL, 8.66 mmol) followed by MsCI (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 hour at 0°C. The reaction mixture was dissolved in CH ₂ CI ₂ and washed with mildly acidic H ₂ 0, H ₂ 0 and last with sat. NaHC0 _3(a q _). The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 1.546 g. of 11 as yellow oil. The crude product was pure enough for the next reaction. R _f : 0.33 (EtOAc/pentane 1 :4) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.16 (m, 2H), (7.09-6.97 (m, 4H), 6.90 (dd, 1 H, J 2 Hz, J 8 Hz), 4.26 (t, 2H, J 6.4 Hz), 3.85 (t, 2H, J 6.4 Hz), 3.14 (m, 4H), 2.90 (s, 3H), 2.02 (quintet, 2H, J 6.4 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C

148.7, 147.4, 135.2, 131.8, 131.7, 131.5, 129.8, 126.8, 123.8, 122.6, 120.4, 119.7, 67.6, 46.5, 37.4, 32.1 , 31.5, 27.5. HR-MS (ES): Calculated for Ci ₈ H ₂ o ³⁵ CIN0 ₃ SNa m/z 388.0750. Found m/z 388.0746.

Example 9: Compound Mj1-22

-(3-chloro-10,11 -dihydro-5H-dibenzo[/3, ]azepine-5-yl)propyl ethanethioate, 12.

To a solution of 11 (0.803 g., 2.19 mmol) in dry DMF (5 ml_) was added a solution of KSAc (0.505 g. 4.42 mmol) in dry DMF (10 ml_), and then stirred at room temperature for 17 hours. The reaction mixture was added EtOAc (20 ml_) and washed with four times with H ₂ 0 and sat. NaCI _(aq) . The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 676 mg. of 12 as orange oil. The crude product was pure enough for the next reaction.

¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.14 (m, 2H), 7.07-6.96 (m, 4H), 6.88 (dd, 1 H, J 2 Hz, J 8 Hz), 3.77 (t, 2H, J 6.8 Hz), 3.13 (m, 4H), 2.89 (t, 2H, J 6.8 Hz), 2.30 (s, 3H), 1.85 (quintet, 2H, J 6.8 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 195.7, 148.9, 147.7, 135.2,

131.8, 131.6, 131.4, 129.7, 126.7, 123.6, 122.4, 120.5, 1 19.9, 49.4, 32.2, 31.6, 30.7, 27.6, 26.9. HR-MS (ES): Calculated for Ci ₉ H ₂₀ ³⁵ CINOSNa m/z 368.0852. Found m/z 38.0847.

Example 10: Compound M j 1 - 18

3-chloro-5-(3-(methylthio)propyl)-10,11 -dihydro-5H-dibenzo[/3, ]azep

(The thioacetate procedure) To a solution of 12 (664 mg, 1 .92 mmol) in degassed and dry MeOH (15 mL) was added Na(s) (177 mg, 7.7 mmol). The reaction mixture was stirred for 30 min. at room temperature before Mel (0.9 mL, 14.3 mmol) was added in a dropwise fashion. The mixture was stirred for 30 min. at room temperature and then added sat. NaHC0 ₃₍ aq ₎ (10 mL) and concentrated under reduced pressure. The aqueous layer was extracted three times with CH ₂ CI ₂ , and the combined organic phases were dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 : 19) to afford 347 mg. of 13 as clear oil (1 .09 mmol, 57% over three steps).

(Alternative reductive addition procedure) Dimethyl disulfide (0.35 mL, 3.88 mmol) and then 99.9% EtOH (10 mL) were added to a suspension of NaBH ₄ (428 mg, 1 1 .3 mmol) in dry THF (10 mL) under N ₂ atmosphere in a dropwise fashion. The reaction mixture was stirred at room temperature for 30 min., before a solution of 11 (1 .379 g., 3.77 mmol) in dry THF (7 mL) was added in dropwise. The reaction mixture was stirred for additional 20 hours at room temperature before diluted with CH ₂ CI ₂ and sat.

NaCI ₍ aq ₎ . The layers were separated, and the aqueous phase was extracted three times with CH ₂ CI ₂ . The combined organic phases were dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (gradient eluent system CH ₂ CI ₂ /pentane 1 : 19 to1 :9) to afford 586 mg. of 13 as clear oil (1.85 mmol, 49% over two steps; recovered yield 66%).

R _f : 0.37 (CH ₂ CI ₂ /pentane 1 :4) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.16 (m, 4H), 7.01 (bt, 2H, J 8.0 Hz), 6.91 (dd, 1 H, J 2.0 Hz, J 8.0 Hz), 3.83 (t, 2H, J 7.0 Hz), 3.16 (m, 4H), 2.54 (t, 2H, J 7.0 Hz), 2.04 (s, 3H), 1.89 (quintet, 2H, J 7.0 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.9, 147.7, 135.1 , 131 .6, 131.3, 129.5, 126.6, 123.4, 122.2, 120.5, 1 19.8, 49.4, 32.2, 31.8, 31.6, 27.1 , 15.5. HR-MS (ES): Calculated for Ci ₈ H ₂₀ ³⁵ CINSK m/z 356.0642. Found m/z 356.0842.

Example 1 1 : Compound Mj1 -20

5-(3-(methylselanyl)propyl)-10,1 1 -dihydro-5H-dibenzo[b, ]azep

Dimethyl diselenide (0.2 mL, 2.1 1 mmol) and then 99.9% EtOH (2 mL) were added in a dropwise fashion to a suspension of NaBH ₄ (451 mg, 1 1 .9 mmol) in dry THF (6 mL) under N ₂ atmosphere. The resulting solution was stirred at room temperature for 10 min. , before a solution of 4 (658 mg, 1 .99 mmol) in dry THF (4 mL) was added. The reaction mixture was stirred for 40 min. at room temperature before diluted with CH ₂ CI ₂ and sat. NaCI _(aq) . The layers were separated, and the aqueous phase was extracted three times with CH ₂ CI ₂ . The combined organic phases were dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 615 mg of 21 as yellow oil. The product was obtained without further purification (1.86 mmol, 94%).

R _f : 0.39 (CH ₂ CI ₂ /pentane 1 :3) ¹ H-NMR (400 M Hz, CDCI ₃ ) δ _Η 7.15 (m, 6H), 6.95 (m, 2H), 3.87 (t, 2H, J 6.8 Hz), 3.20 (s, 4H), 2.58 (t, 2H, J 7.2 Hz), 1.96 (quintet, 2H, J 6.8 Hz, J 7.2 Hz), 1 .91 (s, 3H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.2, 134.3, 129.9, 126.5, 122.6, 120.0, 50.3, 32.3, 28.3, 22.9, 4.2. HR-MS (ES): Calculated for Ci ₈ H ₂₁ NSeNa m/z 354.0732. Found m/z 354.0732.

Example 12: Compound Mj1 -21

3-chloro-5-(3-(methylselanyl)propyl)-10,1 1 -dihydro-5H-dibenzo[/3, ]azepine, 23.

Dimethyl diselenide (0.15 mL, 1.58 mmol) and then 99.9% EtOH (1 .5 mL) were added in a dropwise fashion to a suspension of NaBH ₄ (171 mg, 4.52 mmol) in dry TH F (4 mL) under N ₂ -atmosphere. The resulting solution was stirred at room temperature for 10 min. , before a solution of 11 (548 mg, 1.50 mmol) in dry THF (4 mL) was added. The reaction mixture was stirred for 40 min. at room temperature before diluted with CH ₂ CI ₂ and sat. NaCI _(aq) . The layers were separated, and the aqueous phase was extracted three times with CH ₂ CI ₂ . The combined organic phases was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (15% CH ₂ CI ₂ in pentane) to afford 447 mg. of 23 as clear oil (1 .23 mmol, 82%). R _f : 0.45 (CH ₂ CI ₂ /pentane 1 :4) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.1 1 (m, 4H), 6.98 (m, 2H), 6.87 (dd, 1 H, J 2.0 Hz, J 8.0 Hz), 3.81 (t, 2H, J 6.8 Hz), 3.12 (m, 4H), 2.54 (t, 2H, J 7.2 Hz), 1.92 (quintet, 2H, J 6.8 Hz, J 7.2 Hz), 1.89 (s, 3H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5c 149.0, 147.9, 135.2, 131.7, 131.4, 129.7, 126.7, 123.5, 122.3, 120.7, 119.9, 50.4, 32.3, 31.7, 28.1 , 22.9, 4.2.

Example 13

3-cyano-iminodibenzyl, 15.

To a solution of 3-chloro-iminodibenzyl 8 (1.090 g, 4.35 mmol) in NMP (15 mL) was added NaCN (426 mg. 8.70 mmol) and NiBr ₂ 3H ₂ 0 (1.833 g. 4.35 mmol). The reaction was conducted under microwave irradiation at 200°C for 30 min. The mixture was cooled to room temperature and diluted with EtOAc (30 mL) and washed five times with sat. NaCI ₍ aq ₎ (30 mL). The organic phase was dried over MgS0 ₄ , filtered and

concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/pentane 9:1) to afford 315 mg. of 15 as white solid

(1.43 mmol, 33 %).

¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 143.4, 141.6, 133.7, 131.9, 130.8, 129.1 , 127.4, 122.6, 121.1 , 120.8, 119.3, 118.6, 1 10.7, 35.6, 34.5. LR-MS (ES): Calculated for Ci ₅ H ₁₃ N ₂ m/z 220.1000. Found m/z 221.1.

Example 14:

5-allyl-10,11 -dihydro-5H-dibenzo /3, lazepine-3-carbonitrile, 16.

NaH 60% (649 mg. 16.2 mmol) was placed in a sealed flask under N ₂ atm., and added a solution of 3-cyano-iminodibenzyl 15 (893 mg. 4.06 mmol) in dry DMF (15 mL). The reaction mixture was stirred for 20 min at room temperature, followed by slow addition of allyl bromide (1.05 mL, 12.2 mmol). The reaction mixture was stirred for 1 hour at room temperature before transferred to a separation funnel with EtOAc and ice-water. The layers were separated and the organic phase was washed four times with H ₂ 0 and sat. NaCI ₍ aq ₎ . The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 1.00 g of 16 (3.84 mmol, 95%). The crude product was pure enough for the next reaction.

LR-MS (ES): Calculated for Ci ₈ H ₁₆ N ₂ Na m/z 283.121 1. Found m/z 283.2. Example 15

5-(3-hydroxypropyl)-10,11 -di /3, ]azepine-3-carbonitrile, 17.

A 0.5 M solution of 9-BBN in THF (37 mL, 18.5 mmol) was added to 16 (1.00 g., 3.84 mmol) under N ₂ atm., and was then stirred for 24 hours at room temperature. The reaction mixture was cooled to 0°C before6 N NaOH (3.85 mL, 23.0 mmol) and then aq. 35% H ₂ 0 ₂ (2.71 mL, 30.7 mmol) were added in a dropwise fashion. The reaction mixture was then stirred overnight at room temperature followed by 2 hours at 50°C. The mixture was cooled to room temperature and added H ₂ 0 (15 mL) before extracted three times with Et ₂ 0. The organic phase was washed with sat. NaCI _(aq) , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/pentane 1 :4) to afford 953 mg. of 17 as yellow oil (3.42 mmol, 89%).

LR-MS (ES): Calculated for Ci ₈ H ₁₈ N ₂ NaO m/z 301.1317. Found m/z 301.2. Example 16

3-(3-cyano-10,11 -dihydro-5H-dibenzo[/3, ]azepine-5-yl)propyl methanesulfonate, 18.

Distilled Et ₃ N (1.0 mL, 7.17 mmol) followed by MsCI (0.4 mL, 5.17 mmol) were added to a solution of 17 (953 mg. 3.42 mmol) in dry Et ₂ 0 (20 mL) at 0°C.The reaction mixture was stirred for 1 hour at 0°C before diluted with CH ₂ CI ₂ and washed with mildly acidic H ₂ 0, H ₂ 0 and last with sat. NaHC0 ₃₍ aq ₎ . The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 1.17 g. (3.28 mmol) of 18 as yellow oil. The crude product was pure enough for the next reaction.

HR-MS (ES): Calculated for Ci ₉ H ₂ oN ₂ Na0 ₃ S m/z 379.1092. Found m/z 379.1086.

Example 17: Compound ALN2-058

5-(3-(methylthio)propyl)-10,11 -dihydro-5H-dibenzo[/3, ]azepine-3-carbonitrle, 19.

Dimethyl disulfide (0.10 mL, 1.12 mmol) and then 99.9% EtOH (3 mL) were added to a suspension of NaBH ₄ (1 15 mg, 3.05 mmol) in dry THF (4 mL) in a dropwise fashion. The resulting solution was stirred at room temperature for 10 min., followed by addition of a solution of 18 (362 mg, 1.02 mmol) in dry THF (4 mL). The reaction mixture was stirred for 1 hour at room temperature before diluted with CH ₂ CI ₂ and sat. NaCI _(aq) . The layers were separated, and the aqueous phase was extracted three times with CH ₂ CI ₂ . The combined organic phases were dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography

(CH ₂ CI ₂ /pentane 1 : 1) to afford 218 mg. of 19 (0.71 mmol, 69%) ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 147.6, 138.8, 135.6, 131.6, 129.6, 127.1 , 125.5, 125.5, 124.2, 123.2, 121.1 , 1 19.4, 110.3, 49.7, 33.5, 31.9, 31.2, 27.1 , 15.7. HR-MS (ES): Calculated for C ₁₉ H ₂ oN ₂ NaS m/z 331.1245. Found m/z 331.1251. Example 18: Compound ALN2-057

5-(3-(methylselanyl)propyl)-10,11 -dihydro-5H-dibenzo[/3, ]azepine-3-carbonitrile, 25.

Dimethyl diselenide (0.17 mL, 1.80 mmol) and then 99.9% EtOH (1.6 mL) were added to a suspension of NaBH ₄ (187 mg, 4.92 mmol) in dry THF (4 mL) under N ₂ - atmosphere in as dropwise fashion. The resulting solution was stirred at room temperature for 10 min., followed by addition of a solution of 18 (585 mg, 1.64 mmol) in dry THF (4 mL). The reaction mixture was stirred for 1 hour, at room temperature before diluted with CH ₂ CI ₂ and sat. NaCI _(aq) . The layers were separated, and the aqueous phase extracted three times with CH ₂ CI ₂ . The combined organic phases were dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 : 1) to afford 407 mg. of 25 as clear oil (1.14 mmol, 70%). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.7, 147.6, 138.7, 135.5, 131.6, 129.6, 127.1 , 125.5, 124.1 , 123.2, 121.1 , 119.4, 110.3, 50.6, 33.5, 31.2, 28.1 , 22.8, 4.4. HR-MS (ES): Calculated for C ₁₉ H ₂₀ N ₂ NaSe m/z 379.0689. Found m/z 379.0694.

Example 19

(S)-1 -(3-chloropropyl)-1 (4-fluorophenyl)-1 ,3-dihydroisobenzof uran-5-carbonitrile, 31.

Escitalopram 27 (1.568 g, 4.83 mmol) was dissolved in 1-chloroethyl chloroformate (9 mL). The reaction mixture was stirred at reflux for 5 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL) and stirred overnight at reflux before the mixture was cooled to room temperature and concentrated under reduced pressure. The crude mixture was dissolved in THF (6 mL) and added 1 N NaOH (6 mL). After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc (20 mL), and washed with 1 N NaOH (20 mL) and three times with mildly acidic H ₂ 0 (15 mL). The organic phase was dried over

Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to afford 0.987 g. of crude 31 as thick yellow oil. The acidic aqueous phase was alkalised with cone. NaOH, and extracted three times with CH ₂ CI ₂ (15 mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to afford 0.738 g. of /V-desmethyl- escitalopram 29 as clear oil (2.38 mmol, 49%). The crude 31 was purified on column chromatography (pentane/ CH ₂ CI ₂ 1 :2) to afford 211 mg. of 31 as clear oil (0.67 mmol, 14%).

A mixture of crude /V-desmethylescitalopram 29 (0.738 g., 2.38 mmol), ethyl bromoacetate (0.32 mL, 2.85 mmol) and K ₂ C0 ₃ (0.657 g., 4.76 mmol) was stirred at reflux for 2 hours in dry THF (15 mL). After cooling to room temperature the mixture was filtered and the residue concentrated under reduced pressure. The remaining residue was dissolved in CH ₂ CI ₂ and washed three times with sat. NaCI _(aq). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure yielding 1.064 g. of crude 30 as yellow oil. The residue was dissolved in dry toluene (15 mL) and ethyl chloroformate (0.3 mL, 3.22 mmol) was added. The reaction mixture was stirred at reflux for 4 hours, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography

(pentane/ CH ₂ CI ₂ 1 :2) to afford 407 mg. of 31 as clear oil (1.29 mmol, 54%). The overall combined yield of 31 over four steps was 618 mg. (1.96 mmol, 41 %).

R _f : 0.30 (pentane/CH ₂ CI ₂ 1 :2) ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.60 (d, 1 H, J 7.2), 7.51 (s, 1 H), 7.42 (m, 3H), 7.02 (t, 2H, J 8.4 Hz), 5.19 (d, 1 H, J 13.0 Hz), 5.14 (d, 1 H, J 13.0 Hz), 3.52 (m, 2H), 2.22-2.38 (m, 2H), 1.74-1.84 (m, 1 H), 1.61-1.71 (m, 1 H). ¹³ C-NMR (100 MHz, CDCIs) 5c 162.2 (d, J244.8 Hz), 149.1 , 140.3, 139.2 (d, J3.1 Hz, 132.0, 126.8 (d, J 8.1 Hz), 125.4, 122.8, 1 18.6, 1 15.5 (d, J 21.2 Hz), 11 1.9, 90.8, 71.3, 45.1 , 38.5, 27.4. ¹⁹ F-NMR (376 MHz, CDCI ₃ ) 5 _F -1 15.46. [a] _D ²² + 8.5 (c 1 , MeOH).

Spectral data were in accordance with previously published (Jin, C. Y.; Boldt, K. G.; Rehder, K. S.; Brine, G. A. Synth. Commun. 2007, 37, 901-908; Madsen, J.; Elfving, B.; Andersen, K.; Martiny, L; Knudsen, G. M. J. Labelled Compd. Radiopharm. 2004, 47, 335-348).

Example 20: Compound Mj1-49

(S)-1 (4-fluorophenyl)-1 -(3-(methylthio)propyl)-1 ,3-dihydroisobenzofuran-5- carbonitrile, 32.

Dimethyl disulfide (0.25 mL, 2.58 mmol) and then 99.9% EtOH (4 mL) was added to a suspension of NaBH ₄ (146 mg, 3.87 mmol) in under N ₂ -atmosphere in a dropwise fashion. This was followed by addition of a solution of 31 (401 mg, 1.29 mmol) in dry THF (4 mL). The reaction mixture was stirred overnight at reflux before added an additional portion of NaBH ₄ (150 mg, 3.97 mmol) and stirred at reflux for another 3 hours. The reaction mixture was cooled to room temperature and diluted with CH ₂ CI ₂ and sat. NaCI _(aq) . The layers were separated, and the aqueous phase extracted three times with CH ₂ CI ₂ . The combined organic phases were dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (pentane/ CH ₂ CI ₂ 4:6) to afford 255 mg. of 32 as clear oil (0.78 mmol, 60%). R _f : 0.44 (CH ₂ CI ₂ ). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.58 (d, 1 H, J 8.0), 7.49 (s, 1 H), 7.41 (m, 3H), 7.00 (t, 2H, J 8.6 Hz), 5.18 (d, 1 H, J 12.8 Hz,), 5.13 (d, 1 H, J 12.8 Hz), 2.46 (t, 2H, J 7.0 Hz), 2.17-2.33 (m, 2H), 1.98 (s, 3H), 1.54-1.65 (m, 1 H), 1.39-1.51 (m, 1 H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 162.0 (d, J 244.6 Hz), 149.3, 140.3, 139.5 (d, J3.1 Hz), 131.9, 126.8 (d, J 8.0 Hz), 125.3, 122.8, 118.6, 115.4 (d, J 21.2 Hz), 11 1.8, 91.0, 71.3, 40.0, 34.2, 23.3, 15.3. ¹⁹ F-NMR (376 MHz, CDCI ₃ ) 5 _F -1 15.6. [a] _D ²² + 14.9 (c 1 , MeOH).

Example 21 : Compound Mj1-48

(S)-1 (4-fluorophenyl)-1 -(3-(methylselanyl)propyl)-1 ,3-dihydroisobenzofuran 5- carbonitrile, 34.

Dimethyl diselenide (0.05 mL, 0.53 mmol) and then 99.9% EtOH (1 mL) were added to a suspension of NaBH ₄ (51 mg, 1.34 mmol) in dry THF (1 mL) under N ₂ -atmosphere in a dropwise fashion. The solution was stirred at room temperature for 10 min., followed by addition of a solution of 31 (211 mg, 0.67 mmol) in dry THF (4 mL). The reaction mixture was stirred for 2 hours at room temperature before diluted with CH ₂ CI ₂ and sat. NaCI ₍ aq ₎ . The layers were separated, and the aqueous phase was extracted three times with CH ₂ CI ₂ . The combined organic phases were dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to afford 155 mg. of 34 as clear oil. The product was obtained without further purification (0.41 mmol, 62%).

R _f : 0.26 (pentane/CH ₂ CI ₂ 1 :2,). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.59 (d, 1 H, J 7.2), 7.49 (s, 1 H), 7.41 (m, 3H), 7.00 (t, 2H, J 8.6 Hz), 5.19 (d, 1 H, J 13.2 Hz), 5.13 (d, 1 H, J 13.2 Hz), 2.50 (t, 2H, J 7.0 Hz), 2.17-2.34 (m, 2H), 1.88 (s, 3H), 1.60-1.71 (m, 1 H), 1.45- 1.56 (m, 1 H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 162.0 (d, J 244.6 Hz, 149.3, 140.3, 139.4 (d, J3.1 Hz), 131.9, 126.7 (d, J 7.9 Hz), 125.3, 122.7, 118.6, 1 15.4 (d, J 21.2 Hz), 1 11.8, 90.9, 71.3, 41.1 , 25.4, 24.3, 3.9. ¹⁹ F-NMR (376 MHz, CDCI ₃ ) 5 _F -1 15.6. [a] _D ²² + 12.5 (c 1 , MeOH).

Example 22:

3-chloro-1 -(thiophen-2-yl)propan-1 -one (38).

AICI ₃ (12.081 g, 96.00 mmol) was added in portions to a solution of thiophene (36, 7.357 g, 87.44 mmol) and 3-chloropropionyl chloride (37, 9.20 ml_, 96.0 mmol) in dry CH ₂ CI ₂ (90 ml_) at 0°C. After stirring at room temperature for 18 hours the reaction mixture was carefully quenched with ice water (40 ml_) and 1 M HCI (6 ml_). The precipitate was filtered off and washed with CH ₂ CI ₂ , while the filtrate was transferred to a separation funnel. The phases were separated, and the aqueous phase was extracted three times with CH ₂ CI ₂ . The combined organic phases were washed twice with sat. NaCI _(aq) , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Et ₂ 0/pentane 1 :9 to 1 :4) to afford 10.694 g of 38 as pale yellow oil (61.2 mmol, 70%).

R _f : 0.37 (Et ₂ 0/pentane 1 :4). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.75 (dd, 1 H, J 3.8 Hz, J 1.1 Hz), 7.68 (dd, 1 H, J 4.9 Hz, J 1.1 Hz), 7.15 (dd, 1 H, J 4.9 Hz, J 3.8 Hz), 3.90 (t, 2H, J 6.8 Hz), 3.39 (t, 2H, J6.8 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 189.6, 143.8, 134.5, 132.5, 128.4, 41.9, 38.7. HR-MS (ES): Calculated for C ₇ H ₇ ³⁵ CIOSNa m/z 196.9804. Found m/z 196.9798. Spectral data for 38 were in accordance with previously published (Liu, H; Hoff, H. B.; Anthonsen, T. Chirality, 2000, 12, 26-29).

Example 23:

(S)-3-chloro-1 -(thiophen-2-yl)propan-1 -ol (39).

Using a syringe pump, ketone 38 (9.152 g, 52.4 mmol) in dry toluene (40 ml_) was added to a stirring solution of 10 M Me ₂ SBH ₃ (9.34 ml_, 94.3 mmol) and (ft)-CBS (1.151 g, 4.153 mmol) in dry toluene (20 ml_) at 0°C over 6 hours. After additional 6½ hours of stirring at 0°C the reaction mixture was slowly quenched by MeOH (20 ml_) followed by 1 M HCI (20 ml_). The aqueous phase was extracted three times with CH ₂ CI _2, and the combined organic phases were washed with sat. NaCI _(aq) , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (Et ₂ 0/pentane 1 :4) to afford 8.751 g of 39 as clear oil (49.5 mmol, 95%). R _f : 0.41 (Et ₂ 0/pentane 1 :4). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.27 (dd, 1 H, J 4.9 Hz, J 1.2 Hz), 6.99 (m, 2H), 5.18 (m, 1 H), 3.73 (m, 1 H), 3.57 (m, 1 H), 2.50 (bs, 1 H), 2.30 (m, 1 H), 2.19 (m, 1 H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 147.4, 126.8, 124.9, 124.1 , 67.2, 41.5, 41.4. HR-MS (ES): Calculated for C ₇ H ₉ ³⁵ CIOSNa m/z 198.9960. Found m/z

198.9955. The ee was determined by GC using a chiral Chrompack CP Chirasil-Dex Οβ column; Temperature ramp: 70-200°C (10°C/min); T _ma j ₀ r = 15.28min, T _mi nor = 15.23 min (94% ee). [a] _D ²² -4.9 (c 1 , MeOH).

Spectral data for 39 were in accordance with previously published (Liu, H; Hoff, H. B.; Anthonsen, T. Chirality, 2000, 12, 26-29).

Example 24:

(S)-3-(methylselanyl)-1 - thiophen-2-yl)propan-1 -ol (40)

Dimethyl diselenide (2.14 mL, 22.6 mmol) and then 99.9% EtOH (20 mL) was added to a suspension of NaBH ₄ (3.416 g, 90.3 mmol) in dry THF (20 mL) at 0°C in a dropwise fashion. The solution was stirred at room temperature for 10 min., before a solution of

39 (7.977 g, 45.2 mmol) in dry THF (20 mL) was added. The reaction mixture was stirred for 16 hours at room temperature before diluted with CH ₂ CI ₂ and sat. NaCI _(aq) .

The layers were separated and the aqueous phase extracted three times with CH ₂ CI ₂ .

The combined organic phases were dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography

(Et ₂ 0/pentane 1 :9) to afford 8.505 g of selenide 40 as clear oil (36.16 mmol, 80%).

R _f : 0.32 (Et ₂ 0/pentane 1 :4). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.17 (m, 1 H), 6.91 (m, 2H), 4.99 (m, 1 H), 2.55 (m, 2H), 2.35 (bs, 1 H), 2.10 (m, 2H), 1.94 (s, 3H). ¹³ C-NMR (100 MHz, CDCIs) 5c 148.1 , 126.8, 124.8, 123.9, 69.9, 39.2, 21.3, 4.2. HR-MS (ES):

Calculated for C ₈ H ₁₂ OSSeNa m/z 258.9672. Found m/z 158.9667. The ee was determined by UltraPerformance Convergence Chromatography (UPCC) (Chiralpak IC column, 10% MeOH in supercritical C0 ₂ , 3 mL/min, 120 bar, 40°C) x _maj0 r = 1 -82 min, T _min or = 2.00 min (94% ee). [a] _D ²² -12.2 (c 1 , MeOH).

Compound 40 (8.475 g, 36.0 mmol) was dissolved in dry DMSO (60 mL) and cooled to 0°C before NaH 60% (2.162 g, 54.05 mmol) was carefully added. The mixture was stirred at room temperature for 30 min. before addition of 1-fluoronaphthalene (6.05 mL, 46.9 mmol). The temperature was then raised to 50°C and after stirring for 5½ hours, the reaction mixture was cooled to room temperature and transferred to a separation funnel with ice water and EtOAc. The phases were separated and the organic layer was washed four times with H ₂ 0 and sat. NaCI _(aq) , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 :9) to afford 6.003 g of 41 as a clear oil (16.6 mmol, 46%; recovered yield 64%). R _f : 0.32 (CH ₂ CI ₂ /pentane 1 :4). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 8.36 (m, 1 H), 7.79 (m,

1 H), 7.50 (m, 2H), 7.42 (m, 1 H), 7.28 (m, 1 H), 7.23 (m, 1 H), 7.09 (m, 1 H), 6.95 (m, 1 H), 6.89 (m, 1 H), 5.83 (m, 1 H), 2.77 (m, 2H), 2.65 (m, 1 H), 2.39 (m, 1 H), 2.01 (s, 3H). ¹³ C- NMR (100 MHz, CDCI ₃ ) 5 _C 153.4, 144.7, 134.7, 127.6, 126.7, 126.5, 126.2, 125.8, 125.4, 125.0, 124.9, 122.2, 120.8, 107.1 , 75.8, 39.2, 21.2, 4.4 HR-MS (ES): Calculated for Ci ₈ H ₁₈ OSSeNa m/z 385.0141. Found m/z 385.0138. The ee was determined by UltraPerformance Convergence Chromatography (UPCC) (Chiralpak IB column, 10% MeOH in supercritical C0 ₂ , 3 mL/min, 120 bar, 40°C) T _ma j ₀ r = 2-74 min, T _mi nor = 3.42 min (90% ee). [a] _D ²² +64.7 (c 1 , CHCI ₃ ). Example 26:

ferf-Butyl 2-bromophenylcarbamate (44). Boc ₂ 0 (6.960 g, 31.9 mmol) was added to 2-bromoanailine (43) (3.659 g, 21.3 mmol) in dry THF (40 mL) and the reaction mixture was stirred at reflux for 3 days. The reaction mixture was then cooled to room temperature and subsequently concentrated under reduced pressure. The crude product was purified by column chromatography

(CH ₂ CI ₂ /pentane 1 :4) to afford 4.419 g of 44 as clear oil (16.2 mmol, 76%).

R _f : 0.36 (CH ₂ CI ₂ /pentane 1 :4). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 8.15 (m, 1 H), 7.49 (m, 1 H), 7.28 (m, 1 H), 7.01 (bs, 1 H), 6.89 (m, 1 H), 1.53 (s, 9H). ¹³ C-NMR (100 MHz, CDCIs) 5c 152.5, 136.4, 132.3, 128.4, 123.9, 120.2, 1 12.5, 81.2, 28.4. HR-MS (ES): Calculated for Cn H ₁₄ ⁷⁹ BrN0 ₂ Na m/z 294.0106. Found m/z 294.0121.

Spectral data for 44 were in accordance with previously published (Bellezza, F;

Cipiciani, A.; Ruzziconi, R.; Spizzichino, S.; Journal of Fluorine Chemistry, 2008,

129, 97-107). Example 27:

ferf-Butyl 2-(2,4-dimethylphenylthio)phenylcarbamate 45.

Bromide 44 (1.126 g, 4.14 mmol), Pd ₂ dba ₃ (95 mg, 0.10 mmol), DPEPhos (223 mg, 0.41 mmol) and fBuOK (510 mg, 4.55 mmol) were suspended in dry toluene (18 mL) in a microwave vial and lastly added 2,4-dimethylbenzenethiol (0.67 mL, 4.96 mmol). The reaction mixture was stirred at 100°C for 21 hours before cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 :4 to 1 :2) to afford 1.399 g of 45 as clear oil. The product was pure enough for further reaction.

R _f : 0.25 (CH ₂ CI ₂ /pentane 1 :3). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 8.17 (m, 1 H), 7.46 (bs, 1 H), 7.36 (m, 2H), 7.02 (m, 1 H), 6.99 (m, 1 H), 6.86 (m, 1 H), 6.74 (m, 1 H), 2.40 (s, 3H), 2.27 (s, 3H), 1.48 (s, 9H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 152.8, 140.2, 136.9, 136.5, 135.5, 134.1 , 131.5, 130.1 , 128.6, 127.7, 123.4, 120.6, 1 19.4, 80.8, 28.4, 20.9, 20.4. HR-MS (ES): Calculated for Ci ₉ H ₂₃ N0 ₂ SNa m/z 352.1347. Found m/z 352.1345. Example 28: 2-(2,4-dimethylphenylthio)aniline (46).

Boc-protected aniline 45 (1.399 g) was dissolved in dry CH ₂ CI ₂ (10 ml_) and TFA (10 ml_) and stirred at room temperature for 90 mins. The mixture was diluted with CH ₂ CI ₂ and alkalised with 1 M aq. NaOH, and the aqueous phase extracted twice with CH ₂ CI ₂ before dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford 0.905 mg of 46 as clear oil (3.95 mmol, 95 % over 2 steps). The crude product was pure enough for further reaction.

R _f : 0.37 (CH ₂ CI ₂ /pentane 1 :2). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.39 (m, 1 H), 7.24 (m, 1 H), 7.04 (s, 1 H), 6.89 (d, 1 H, J 8.0 Hz), 6.79 (m, 2H), 6.75 (d, 1 H, J 8.0 Hz), 4.24 (bs, 2H), 2.43 (s, 3H), 2.30 (s, 3H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.5, 136.7, 135.9, 135.4, 131.8, 131.3, 130.6, 127.4, 126.7, 1 18.9, 1 15.4, 115.2, 20.9, 20.1. HR-MS (ES) Calculated for C ₁₄ H ₁₆ NS m/z 230.1003. Found m/z 230.0994.

Example 29:

4-(2-(2,4-dimethylphenylthio)phenyl)thiomorpholine-3,5-dione (47).

DMAP (192 mg, 1.57 mmol) and 1 ,4-oxathiane-2,6-dione (see, Cathala et al.

Tetrahedron, 1996, 52, 9793-9804) (1.245 g, 9.42 mmol) were placed in a microwave vial and evacuated and filled with N ₂ (g). Aniline 46 (720 mg, 3.14 mmol) in dry CH ₂ CI ₂ (10 ml_) and then Et ₃ N (3.48 ml_, 25.13 mmol) were added in a dropwise fashion. The mixture was heated under microwave irradiation conditions for 35 min. at 80°C. The reaction mixture was concentrated under reduced pressure and flushed with N ₂ (g). The resulting crude intermediate was then dissolved in dry CH ₂ CI ₂ (10 ml_) before DMAP (192 mg, 1.57 mmol), Oxymapure (669 mg, 4.71 mmol) and lastly EDC (901 mg, 4.71 mmol) were added. After stirring at room temperature for 18 hours the reaction mixture was diluted with CH ₂ CI ₂ and washed with 1 M aq. HCI, sat. NaHC0 ₃₍ aq ₎ , and three times with sat. NaCI ₍ aq ₎ , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 : 1 to 2: 1 ) to afford 617 mg of 47 as white solid (1 .79 mmol, 57%).

R _f : 0.54 (CH ₂ CI ₂ ). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.31 (m, 1 H), 7.24 (m, 2H), 7.12 (m, 1 H), 7.00 (m, 1 H), 6.93 (m, 1 H), 3.74 (d, 2H, J 16.5 Hz), 3.65 (d, 2H, J 16.5 Hz), 2.34 (s, 3H), 2.30 (s, 3H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 168.1 , 141 .4, 139.1 , 136.8, 135.3, 133.5, 131 .7, 129.6, 129.2, 129.2, 127.8, 127.4, 126.6, 32.6, 21 .2, 20.6. HR-MS (ES): Calculated for C ₁₈ H ₁₇ N0 ₂ S ₂ Na m/z 366.0598. Found 366.0593.

Example 30:

4-(2-(2,4-dimethylphenylthio)phenyl)thiomorpholine (48).

Imide 47 (584 mg, 1.70 mmol) dissolved in dry THF (7 ml_) under N ₂ -atmosphere before Me ₂ SBH ₃ (0.65 ml_, 6.80 mmol) was added in a dropwise fashion. The reaction mixture was stirred at reflux for 90 mins. cooled to room temperature and quenched by addition of MeOH (2 ml_) and 1 M aq. HCI (3 ml_). The mixture was left stirring for 10 min and then extracted three times with CH ₂ CI ₂ . The combined organic phases were washed with sat. NaCI _(aq) , dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (CH ₂ CI ₂ /pentane 1 :4) to afford 412 mg of 48 as clear oil (1 .31 mmol, 77%).

R _f : 0.35 (CH ₂ CI ₂ /pentane 1 :4). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.39 (m, 1 H), 7.16 (s, 1 H'), 7.07 (m, 3H), 6.88 (m, 1 H), 6.54 (m, 1 H), 3.30 (m, 4H), 2.86 (dd, 4H, J 10.8 Hz, J 6.0 Hz), 2.40 (s, 3H), 2.34 (s, 3H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 150.2, 142.4, 139.3, 136.2, 135.2, 131 .8, 128.0, 127.9, 126.2, 125.5, 124.7, 120.7, 54.4, 28.6, 21.3, 20.7. HR-MS (ES): Calculated for Ci ₈ H ₂₁ NS ₂ Na m/z 338.1013. Found m/z 338.1003. Example 31 :

3-Chloro-1 -phenylpropane-1 -one (50).

3-Chloropropionyl chloride (0.151 g; 1.19 mmol) followed by anhydrous benzene (0.084 g; 1.08 mmol) were added in a dropwise fashion to a solution of aluminum trichloride

(0.173 g; 1.30 mmol) dissolved in anhydrous CH ₂ CI ₂ (1 ml_), under N ₂ atmosphere at 0

°C. The reaction mixture was allowed to warm to room temperature and left overnight.

The reaction mixture was then cooled to 0°C and quenched by lumps of ice. The aqueous phase was extracted with CH ₂ CI ₂ and the combined organic phases were dried over MgS0 ₄ , filtered and concentrated. The product was purified by column chromatography (pentane) and isolated as yellow crystals in quantitative yield (0.200 g;

1.19 mmol).

R _f (pentane) 0.31. Mp (uncorr.): 45.9-48.7°C. ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 8.00-7.93 (m, 2H), 7.64-7.55 (m, 1 H), 7.53-7.44 (m, 2H), 3.93 (t, 2H, J 6.8 Hz), 3.46 (t, 2H, J 6.8 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 196.8, 136.5, 133.7, 128.9, 128.2, 41.4, 38.8. The NMR data are in accordance with those previously reported (Moriyama, K.;

Takemura, M.; Togo, H. Org. Lett. 2012, 14, 2414-2417). Example 32:

3-(methylthio)-1 -phenylpropane-1 -ol (51 ).

Ketone 50 was added to a solution of NaBH ₄ (0.755 g; 20.0 mmol; 10 eq.) in anhydrous THF (12 ml_) and 99.9% ethanol (3 ml_) under a N ₂ atmosphere. The mixture was stirred for 15 min. before dimethyl disulfide (0.376 g; 3.99 mmol) was added, and the reaction was left overnight. When the reaction had run to completion it was quenched by H ₂ 0, and the aqueous phase extracted with CH ₂ CI ₂ . The combined organic phases were dried over MgS0 ₄ , filtered and concentrated. The product was purified by column chromatography (pentane/EtOAc 10:1) and isolated as colourless oil in 69% yield (0.252 g; 1.38 mmol). R _f (pentane/EtOAc 6: 1) 0.50. ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.35 (d, 4H, J 4.4 Hz),

7.28 (ddd, 1 H. J 1 1.4 Hz, 4.3 Hz, 3.3 Hz), 4.87-4.79 (m, 1 H), 2.58 (dd, 2H, J 10.7 Hz, 3.2 Hz), 2.35 (bs, 1 H), 2.12-1.92 (m, 3H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 144.3, 128.6, 127.8, 125.9, 73.5, 38.0, 30.7, 15.5. Example 33:

Methyl(3-phenyl-3-(4-(trifluorometh l)phenoxy)propyl)sulfane (52).

NaH 60% (0.017 g; 0.43 mmol) was added to a solution of alcohol 51 (0.053 g; 0.29 mmol) dissolved in anhydrous DMSO (0.8 ml_) under a N ₂ -atmosphere. The mixture was heated to 55°C for 45 min before 1-chloro-4-(trifluoromethyl)benzene (0.068 g;

0.38 mmol) was added and the reaction mixture was further heated to 95 °C for 1 hour. When the reaction had run to completion it was cooled to room temperature and diluted by cold H ₂ 0. The aqueous phase was extracted with Et ₂ 0 and the combined organic phases were dried over MgS0 ₄ , filtered and concentrated. The product was purified by column chromatography (pentane) and isolated as a brown oil in 87% yield (0.082 g; 0.25 mmol).

R _f (pentane/EtOAc 10: 1) 0.38. ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.44 (d, 2H, J 8.5 Hz), 7.35 (d, 4H, J 4.4 Hz), 7.31-7.25 (m, 1 H), 6.91 (d, 2H J 8.6 Hz), 5.35 (dd, 1 H, J 8.3 Hz, 4.6 Hz), 2.72-2.60 (m, 2H), 2.38-2.25 (m, 1 H), 2.15-2.04 (m, 4H). ¹⁹ F-NMR (377 MHz, CDCIs) δρ -61.6. ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 160.6, 140.7, 129.0, 128.1 , 126.9 (q, J 3.8 Hz), 126.0, 123.1 (q, J 32.5 Hz), 1 15.9, 78.7, 38.1 , 30.4, 15.7. The signal from CF ₃ was not detected.

Example 34: 3-(Methylselanyl)-1 -phenylpropane-1 -ol (54)

3-Chloro-1-phenylpropane-1-one (50) (0.214 g; 1.27 mmol) was added to a solution of NaBH ₄ (0.485 g; 12.82 mmol) dissolved in anhydrous THF (7.5 ml_) and 99.9% EtOH (2 ml_) under a N ₂ -atmosphere. The mixture was stirred for 15 min. before dimethyl diselenide (0.487 g; 2.54 mmol; 2 eq.) was added, and the reaction was left overnight. When the reaction had run to completion it was quenched with H ₂ 0, and the aqueous phase extracted with CH ₂ CI ₂ . The combined organic phases were dried over MgS0 ₄ , filtered and concentrated. The product was purified by column chromatography (pentane/EtOAc 10: 1) and isolated as colourless oil in 90% yield (0.262 g; 1.14 mmol). R _f (pentane/EtOAc 6: 1) 0.54. ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.39-7.33 (m, 4H), 7.29 (ddd, 1 H, J 7.7 Hz, 6.7 Hz, 2.2 Hz), 4.83 (ddd, 1 H, J 8.1 Hz, 4.9 Hz, 3.4 Hz), 2.62 (t, 2H, J 7.4 Hz), 2.24-1.95 (m, 5H), 1.58 (bd, 1 H, J 2.7 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5c 144.3, 128.7, 128.5, 127.8, 126.1 , 126.0, 74.2, 39.1 , 21.5, 4.2.

Example 35:

Methyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)selane (55).

NaH 60% (0.053 g; 0.75 mmol) was added to a solution of alcohol 54 (0.1 14 g; 0.50 mmol) dissolved in anhydrous DMSO (1.5 ml_) under a N ₂ -atmosphere. The mixture was heated to 55°C for 45 min before 1-chloro-4-(trifluoromethyl)benzene (0.117 g;

0.65 mmol) was added and the reaction mixture was further heated to 95°C for 1 hour. When the reaction had run to completion it was cooled to room temperature and diluted with cold H ₂ 0. The aqueous phase was extracted with Et ₂ 0 and the combined organic phases were dried over MgS0 ₄ , filtered and concentrated. The product was purified by column chromatography (pentane) and isolated as an orange oil in 96% yield (0.179 g; 0.48 mmol).

R _f (pentane/EtOAc 10: 1) 0.52. ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.44 (d, 2H, J 9.0 Hz), 7.35 (d, 4H, J 4.5 Hz), 7.31-7.26 (m, 1 H), 6.91 (d, 2H, J 8.5 Hz), 5.33 (dd, 1 H, J 8.2 Hz, 4.6 Hz), 2.68 (t, 2H, J 7.6 Hz), 2.38 (dt, 1 H, J 14.9 Hz, 6.8 Hz), 2.19-2.10 (m, 1 H), 1.99 (s, 3H, J 5.1 Hz). ¹⁹ F-NMR (377 MHz, CDCI ₃ ) 5 _F -61.6. ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 160.6, 140.7, 129.0, 128.1 , 126.9 (q, J 3.7 Hz), 126.0, 123.0 (q, J 32.7 Hz), 115.8, 79.5, 39.0, 21.3, 4.3. The signal from CF ₃ was not detected

Preparation of the specific compounds of the invention

Example 36: Compound Mj1-50

3-(10,11 -dihydro-5H-dibenzo[/3, ]azepin-5-yl)propyl)climethylsulfon

MeOTf (0.3 ml_, 2.35 mmol was added to a solution of 6 (224 mg. 0.79 mmol) in dry CH ₂ CI ₂ (8 ml_).The reaction mixture was stirred overnight at room temperature before toluene was added and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (Gradient eluent system

MeOH/CH ₂ CI ₂ , 1 : 19 to 1 :9) to afford 336 mg. of 7 as clear thick oil (0.75 mmol, 95%).

¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.16-7.02 (m, 6H), 6.94 (m, 2H), 3.86 (t, 2H, J 6.4 Hz), 3.29 (t, 2H, J 7.8 Hz) 3.14 (s, 4H), 2.74 (s, 6H), 2.02 (m, 2H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5c 147.3, 134.3, 130.4, 126.9, 123.6, 119.8, 48.1 , 41.1 , 32.2, 24.9, 22.2. ¹⁹ F- NMR (376 MHz, CDCI ₃ ) 5 _F -78.86. HR-MS (ES): Calculated for Ci ₉ H ₂₄ NS m/z

298.1624. Found m/z 298.1627.

Example 37: Compound Mj1-51 3-(3-chloro-10,1 1 -dihydro-5H-dibenzo[/3,^azepin-5-yl)propyl)dimethylsulfonium , 14.

MeOTf (0.3 mL, 2.65 mmol) was added to a solution of 13 (249 mg. , 0.79 mmol) in dry CH ₂ CI ₂ .The reaction mixture was stirred overnight at room temperature before toluene (5 mL) was added and the mixture concentrated under reduced pressure. The crude product was purified by column chromatography (gradient eluent system MeOH/CH ₂ CI ₂ 1 : 19 to 1 :9) to afford 367 mg. of 14 as clear thick oil (0.76 mmol, 97%). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.13 (m, 2H), 7.00 (m, 4H), 6.88 (dd, 1 H, J 2.0 Hz, J 8.0 Hz), 3.81 (t, 2H, J 6.4 Hz), 3.28 (t, 2H, J 7.8 Hz), 3.09 (m, 4H), 2.76 (s, 6H), 1 .99 (m, 2H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.5, 146.7, 135.3, 131 .8, 131.8, 130.1 , 127.1 , 124.3, 123.1 , 120.3, 1 19.6, 48.2, 40.9, 32.0, 31 .4, 24.9, 22.2. ¹⁹ F-NMR (376 MHz, CDCIs) δρ -78.8. HR-MS (ES): Calculated for Ci ₉ H ₂₃ ³⁵ CINS m/z 332.1234. Found m/z 332.1305.

Example 38: Compound Mj1 -52

(3-(10,1 1 -dihydro-5H-dibenzo[/3, ]azepin-5-yl)propyl)dimethylselenonium, 22.

MeOTf (0.65 mL, 5.66 mmol) was added to a solution of 21 (598 mg. , 1 .81 mmol) in dry CH ₂ CI ₂ (15 mL). The reaction mixture was stirred at room temperature for 4 hours before toluene (10 mL) was added and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (gradient eluent system MeOH/CH ₂ CI ₂ 1 : 19 to1 :9) to afford 684 mg. of 22 as thick yellow oil (1.38 mmol, 76%). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.02-7.16 (m, 6H), 6.94 (t, 2H, J 7.4 Hz), 3.84 (t, 2H, J 6.2 Hz), 3.21 (t, 2H, J 8.0 Hz) 3.15 (s, 4H) 2.50 (s, 6H) 2.02 (m, 2H). ¹³ C-NMR (100 MHz, CDCIs) 5c 147.4, 134.3, 130.3, 126.9, 123.4, 1 19.8, 48.9, 38.1 , 32.2, 22.9, 20.3 ¹⁹ F-NMR (376 MHz, CDCI ₃ ) 5 _F -78.76 . HR-MS (ES): Calculated for Ci ₉ H ₂₄ NSe m/z 346.1048. Found m/z 346.1068.

Example 39: Compound Mj1-53

(3-(3-chloro-10,11 -dihydro-5H-dibenzo[/3, ]azepin-5-yl)propyl)climethyl

selenonium, 24.

MeOTf (0.32 mL, 2.85 mmol) was added to a solution of 23 (347 mg. 0.95 mmol) in dry CH ₂ CI ₂ (8 mL). The reaction mixture was stirred at room temperature for 4 hours before toluene (6 mL) was added and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH/CH ₂ CI ₂ , 1 :19) to afford 397 mg. of 24 as pale yellow foam (0.75 mmol, 79%).

R _f : 0.48 (MeOH, CH ₂ CI ₂ 1 :9). ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.14 (m, 2H), 6.99 (m, 4H), 6.87 (dd, 1 H, J 2.0 Hz, J 8.0 Hz), 3.78 (t, 2H, J 6.4 Hz), 3.21 (t, 2H, J 7.8 Hz), 3.09 (m, 4H), 2.54 (s, 6H), 1.98 (m, 2H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.5, 146.6, 135.2, 131.7, 131.7, 129.9, 126.9, 124.1 , 122.8, 120.3, 1 19.5, 48.9, 37.8, 31.9, 31.3, 22.8, 20.2. ¹⁹ F-NMR (376 MHz, CDCI ₃ ) 5 _F -78.8. HR-MS (ES): Calculated for Ci ₉ H ₂₃ ³⁵ CINSe m/z 380.0679. Found m/z 380.0693.

Example 40: Compound ALN2-060

(3-(3-cyano-10,11 -dihydro-5H-dibenzo[/3, ]azepin-5-yl)propyl)dimethylsulfonium,

20.

MeOTf (0.19 mL, 1.71 mmol) was added to a solution of 19 (176 mg. 0.57 mmol) in dry CH ₂ CI ₂ (5 mL). The reaction mixture was stirred overnight at room temperature before toluene (6 mL) was added and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH/CH ₂ CI ₂ , 1 : 19) to afford 138 mg. of 20 (0.29 mmol, 51 %).

¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.4, 146.4, 138.9, 135.8, 131.9, 129.9, 127.4, 126.2, 124.9, 122.8, 120.8, 119.2, 1 10.3, 48.6, 41.1 , 33.3, 30.9, 25.1 , 22.5. HR-MS (ES): Calculated for C2 ₀ H2 ₃ N2S m/z 323.1576. Found m/z 323.1576.

Example 41 : Compound ALN2-059

(3-(3-cyano-10,11 -dihydro-5H-dibenzo[/3,^azepin-5-yl)propyl)dimethylselenoniu m, 26.

MeOTf (0.35 mL, 3.19 mmol) was added to a solution of 25 (378 mg. 1.06 mmol) in CH ₂ CI ₂ (8 mL). The reaction mixture was stirred for four hours at room temperature before toluene (6 mL) was added and the mixture was concentrated under reduced pressure to afford 391 mg of 26 as white solid (1.05 mmol, 99%).

¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 148.1 , 146.1 , 139.0, 135.7, 132.0, 130.1 , 129.3, , 127.4, 126.5, 125.1 , 123.7 (q), 123.1 , 122.2, 121.0, 119.2, 119.1 , 1 10.2, 49.8, 37.8, 33.2, 30.9, 23.1 , 20.5. HR-MS (ES): Calculated for C ₂ oH23N ₂ Se m/z 371.1021. Found m/z 371.1021.

Example 42: Compound Mj1-54

(S)-(3-(5-cyano-1 -(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-1 -yl) - propyl)dimethylsulfonium trifluoromethanesulfonate 33.

MeOTf (0.25 mL, 2.21 mmol) was added to a solution of 32 (223 mg, 0.68 mmol) in dry CH ₂ CI ₂ (10 mL), and the reaction mixture was stirred for 23 hours at room temperature before toluene (6 mL) was added and the mixture concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH/CH ₂ CI ₂ 1 :9) to afford 98 mg. of 33 as clear oil (0.20 mmol, 29%).

¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.61 (d, 1 H, J 8.0 Hz), 7.45 (s, 4H), 7.03 (t, 2H, J 8.4 Hz), 5.22 (d, 1 H, J 13.2 Hz), 5.14 (d, 1 H, J 13.2 Hz), 3.32 (m, 2H), 2.69 (s, 3H), 2.67 (s, 3H), 2.38 (m, 1 H), 2.36 (m, 1 H), 1.78-1.68 (m, 2H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 162.3 (d, J 245.1 Hz), 148.6, 140.0, 138.6, 132.4, 126.8 (d, J 8.1 Hz), 125.5, 123.0, 1 18.7, 1 15.8 (d, J 21.3 Hz), 112.2), 90.7, 71.5, 41.2, 39.8, 20.5, 20.5, 20.3. ¹⁹ F-NMR (376 MHz, CDCI ₃ ) δρ -78.8, -1 14.9. [a] _D ²² +13.2 (c 1 , MeOH).

Example 43: Compound Mj1-55

(S)-(3-(5-cyano-1 -(4-fluorophenyl)-1 ,3-dihydroisobenzof uran-1 -yl) propyl) dimethyl-selenonium trifluoromethanesulfonate, 35.

MeOTf (0.25 mL, 2.21 mmol) was added to a solution of 34 (138 mg, 0.37 mmol) in dry CH ₂ CI ₂ (10 mL) and the reaction mixture stirred for 23 hours at room temperature before toluene (6 mL) was added and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH/CH ₂ CI ₂ 1 :19) to afford 316 mg of product contaminated with silica. The mixture was dissolved in CHCI ₃ and drops of MeOH and the silica was filtered off (was done 3 times) to afford 278 mg of 35 as pale yellow foam with silica impurity. An ¹ H-NMR experiment in CD ₃ OD with a known amount of 1,4-dioxane determined the amount of 35 in the sample to be 47%, which corresponds to an overall yield of 131 mg (0.243 mmol, 66%).

¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.60 (d, 1 H, J 8.4 Hz), 7.46 (m, 4H), 7.03 (t, 2H, J 8.8 Hz), 5.22 (d, 1H, J 13.0 Hz), 5.14 (d, 1H, J 13.0 Hz), 3.46-3.33 (m, 2H), 2.88 (s, 3H), 2.86 (s, 3H), 2.44-2.37 (m, 1H), 2.31-2.24 (m, 1H), 1.77-1.66 (m, 2H). ¹³ C-NMR(100 MHz, CDCI ₃ ) 5c 162.4 (d, J 246.3 Hz), 148.5, 140.0, 138.4, 132.4, 126.8 (d, J 8.1 Hz), 125.5, 123.0, 118.7, 115.8 (d, J21.2 Hz), 112.2, 90.7, 71.5, 43.5, 38.8, 24.9, 24.9, 19.5. ¹⁹ F-NMR(376 MHz, CDCI ₃ ) 5 _F -78.8, -114.9. [a] _D ²² + 0.3 (c1, MeOH).

Example 44: Compound Mj1-38

(R/S) 3-(5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl) -/V, N, N- trimethylpropan-1 -ammonium iodide, 57.

Mel (0.87 mL, 13.79 mmol) was added to a solution of citalopram (639 mg, 1.97 mmol) in dry Et ₂ 0 (10 mL). The reaction mixture was stirred at room temperature for 2 hours and white precipitates appeared. The precipitates were filtered off and washed with dry Et ₂ 0 to afford 827 mg of 57 as white solids (1.77 mmol, 90%).

¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.61 (m, 2H), 751 , (s, 1 H), 7.47 (m, 2H), 7.04 (t, 2H, J 8.8 Hz), 5.28 (d, 1H, J 13.2 Hz), 5.14 (d, 1H, J 12.8 Hz), 3.85 (m, 1H) 3.72 (m, 1H) 3.31 (s, 9H), 2.67 (s, 3H), 2.37 (m, 1H), 2.26 (m, 1H), 1.79-1.66 (m, 2H). HR-MS (ES): Calculated for C ₂ i H ₂₄ FN ₂ 0 m/z 339.1873. Found m/z 339.1575.

Example 45: Compound trimethylimipramine

3-(10,11 -dihydro-5H-debenzo[/3, ]azepin-5-yl)-V,V,V-trimethylpropan-1 - ammonium iodide, 58.

Mel (0.35 mL, 5.57 mmol) was added to a solution of imipramine (251 mg, 0.79 mmol) in dry Et ₂ 0 (15 mL). The reaction mixture was stirred for 20 hours at room temperature during which time a white precipitates appeared. The precipitates were filtered off and washed with dry Et ₂ 0 to afford 329 mg of 58 as white solids (779 mmol, 98%).

¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.12 (m, 6H), 6.97 (m, 2H), 3.88 (t, 2H, J 6.2 Hz), 3.63 (t, 2H, J 6.4 Hz), 3.22 (s, 9H), 3.16 (s, 4H), 2.07 (m, 2H).

Example 46: (Mj3-1 19)

(S)-dimethyl(3-(naphthalene-1 -yloxy)-3-(thiophen-2-yl)propyl)selenon

tetrafluoroborate (42).

MeCN (20 mL) from an MBraun solvent purification system was further dried by stirring with freshly activated molecular sieves (3 A) and bubbling with N ₂ for 30 min. The same was done with predried acetone (20 mL). A fresh batch of trimethyloxonium

tetrafluoroborate was added to the dried MeCN and the solution cooled to 0°C before selenide 41 in dry acetone (15 mL of above mentioned dried acetone) was added. The mixture was stirred for 90 mins. at 0°C and then at room temperature for 20 hours and lastly 2 hours at 45°C. The molecular sieves was removed by filtration and washed with dry MeOH and the residue was concentrated under reduced pressure. The crude product was purified by column chromatography (first CH ₂ CI ₂ and then MeN0 ₂ /CH ₂ CI ₂ , 1 :2) to afford 817 mg of 42 as pale yellow sticky foam (1.76 mmol, 33%; recovered yield 58%). R _f : 0.26 (MeN0 ₂ /CH ₂ CI ₂ 1:1). ¹ H-NMR(400 MHz, CDOD ₃ ) δ _Η 8.20 (m, 1H), 7.67 (m, 1H), 7.39 (m, 2H), 7.32 (m, 1H), 7.19 (m, 2H), 7.09 (m, 1H), 6.92 (m, 1H), 6.81 (m, 1H), 5.93 (m, 1H), 3.47 (m, 1H), 3.33 (m, 1H), 2.64 (m, 1H), 2.62 (s, 3H), 2.51 (m, 4H). ¹³ C- NMR(100MHz, CD ₃ OD) 5 _C 153.3, 144.1, 136.1, 128.67, 127.9, 127.5, 127.4, 127.3, 126.7, 126.7, 126.6, 122.8, 122.5, 109.1, 76.3, 38.8, 34.9, 21.3, 20.9. F-NMR(376 MHz, CDODs) 5 _F -153.0. HR-MS (ES): Calculated for Ci ₉ H ₂₁ OSSe m/z 377.0473. Found m/z 377.0480 [a] _D ²² +42.0 (c 1, MeOH).

Example 47 (ΜΪ3-123)

4-(2-(2,4-dimethylphenylthio)phenyl)-1-methylthiomorpholin-1

tetrafluoroborate (49).

Trimethyloxonium tetrafluoroborate (49 mg, 0.33 mmol) was added to a solution of 48 (70 mg, 0.22 mmol) in dry CH ₂ CI ₂ (2 ml_). The reaction mixture was stirred at room temperature for 4 hours before diluted with toluene (0.5 ml_) and concentrated under reduced pressure. The crude product was purified by column chromatography (first CH ₂ CI ₂ then CH ₂ CI ₂ /MeN0 ₂ 1:2) to afford 70 mg of 49 as clear sticky oil (0.17 mmol, 76%).

R _f : 0.46 (CH ₂ CI ₂ /MeN0 ₂ 1:2). ¹ H-NMR(400 MHz, CDCI ₃ ) δ _Η 7.31 (m, 1H), 7.21 (m, 2H) 7.12 (m, 1H), 7.05 (m, 1H), 6.92 (m, 1H), 6.50 (m, 1H), 3.73 (m, 2H), 3.62 (m, 2H), 3.40 (m, 4H), 3.04 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 149.4, 143.3, 141.0, 137.0, 135.9, 132.8, 129.0, 128.5, 127.4, 127.1, 126.9, 122.3, 47.5, 37.7, 21.8, 20.7. HR-MS (ES): Calculated forCi ₉ H ₂₄ NS ₂ m/z 330.1345. Found m/z 330.1353.

Example 48: (Ab3-152)

Dimethyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)sulfonium tetrafluoroborate (53).

Trimethyloxonium tetrafluoroborate (0.047 g; 0.32 mmol) was added to a solution of sulfide 52 (0.094 g; 0.29 mmol; 1 eq.) dissolved in anhydrous CH ₂ CI ₂ (2.5 ml_) under a N ₂ -atmosphere. The reaction mixture was stirred overnight at room temperature. When the reaction had run to completion it was diluted with H ₂ 0 and the aqueous phase was extracted with CH ₂ CI ₂ . The combined organic phases were dried over MgS0 ₄ , filtered and concentrated. The product was purified by column chromatography (first CH ₂ CI ₂ then CH ₂ CI ₂ /MeOH 20: 1) and isolated as a yellow oil in 18% yield (0.023 g; 0.05 mmol).

R _f (CH ₂ CI ₂ /MeOH 10: 1) 0.23. ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.41-7.23 (m, 7H), 6.90 (d, 2H, J 8.6 Hz), 5.44 (t, 1 H, J 6.8 Hz), 3.55 (dt, 1 H, J 15.3 Hz, 7.7 Hz), 3.41 (dt, 1 H, J 13.2 Hz, 6.6 Hz), 2.85 (s, 3H), 2.79 (s, 3H), 2.32 (q, 2H, J 7.3 Hz). ¹⁹ F-NMR (377 MHz, CDCIs) 5 _F -61.5, -148.3 (d, J 18.9 Hz). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5 _C 159.3, 138.8, 129.3, 128.8, 127.1 (q, J 3.8 Hz), 125.8, 123.6 (q, J 32.5 Hz), 116.1 , 78.3, 40.8, 33.0, 25.2, 24.5. The signal from CF ₃ was not detected.

HRMS (ES+): m/z calc for Ci ₈ H ₂ oF ₃ OS: 341.1187, found m/z 341.1 186.

Example 49: (AB3-151)

Dimethyl(3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyle)s elenonium

tetrafluoroborate (56).

Trimethyloxonium tetrafluoroborate (0.038 g; 0.25 mmol; 1.1 eq.) was added to a solution of selenide 55 (0.086 g; 0.23 mmol; 1 eq.) dissolved in anhydrous CH ₂ CI ₂ (2.0 ml_) under a N ₂ -atmosphere. The reaction mixture was stirred overnight at room temperature. When the reaction had run to completion it was diluted with H ₂ 0 and the aqueous phase extracted with CH ₂ CI ₂ . The combined organic phases were dried over MgS04, filtered and concentrated. The product was purified by column

chromatography (first CH ₂ CI ₂ then CH ₂ CI ₂ /MeOH 20: 1) and isolated as a yellow oil in 34% yield (0.037 g; 0.08 mmol).

R _f (CH ₂ CI ₂ /MeOH 10: 1) 0.25. ¹ H-NMR (400 MHz, CDCI ₃ ) δ _Η 7.40 (d, 2H, J 8.7 Hz), 7.36-7.24 (m, 5H), 6.91 (d, 2H, J 8.7 Hz), 5.47 (t, 1 H, J 6.0 Hz), 3.59 (dt, 1 H, J 12.1 Hz, 7.8 Hz), 3.34 (dt, 1 H, J 12.0 Hz, 5.8 Hz), 2.76-2.67 (s, 3H), 2.66-2.57 (s, 3H), 2.44-2.32 (m, 2H). ¹⁹ F-NMR (377 MHz, CDCI ₃ ) 5 _F -61.6, -148.5 (m). ¹³ C-NMR (100 MHz, CDCI ₃ ) 5c 158.9, 138.7, 129.3, 128.8, 127.1 (q, J 3.6 Hz), 125.8, 124.0, 123.6 (q, J 32.5 Hz), 1 16.2, 79.1 , 38.2, 33.8, 20.9, 20.1. The signal from CF ₃ was not detected. HRMS

(ES+): m/z calc for C ₁₈ H ₂ oF ₃ OSe: 389.0631 , found m/z 389.0629.

Transporter affinity and selectivity

Materials and Methods

Midi Prep

50-100ml bacterial culture was grown over night. Cells were isolated by centrifugation, resuspended and lysed under alkaline conditions. Plasmid DNA was purified using the Pure Yield midiprep kit (Promega). The concentration of the purified DNA was determined with a spectrophotometer.

Cell culture

The cell line used for all uptake assays was the Human Embryonic Kidney cell line HEK-293-MSR (invitrogen). The growth medium used was Dulbeccos Modified Eagles Medium (DM EM) supplemented with 10% foetal bovine serum, 0.6 mg/ml geneticin, 100 units/ml penicillin, 0.1 mg/ml streptomycin, and non-essential amino acids. The cell culture was kept at 37°C with a C0 ₂ concentration of 5% and a humidity of 95%. The cells were regularly split to keep them mono-layered. This was done by first washing the cells with phosphate buffered saline (PBS: 0.137M NaCI, 2.7 mM KCI, 10 mM Na ₂ HP0 ₄ *12 H ₂ 0, 1.4 mM KH ₂ P0 ₄ ), and then with Versene (1 ml/100 cm ² cells). Finally Trypsin-EDTA solution (1 ml/100 cm ² cells) was used to detach the cells and the desired amount of cells were removed. Transfection for uptake assay

DMEM was mixed with lipofectamine, and was left to incubate for five minutes before plasmid DNA was added. This mixture incubated for 20 minutes before adding the HEK cells. The HEK cells were detached and removed from the cell culture flask as described above. 100 μΙ cell solution with DNA-transfection-reagent complex, was added to each well in white 96 well plates. The plates were stored for incubation for two days at 37°C, 95% humidity and a C0 ₂ concentration of 5%.

IC ₅₀ Uptake assay

After two days of incubation, the transfected cells were used for uptake assays. Prior to the assay, a dilution series of 12 concentrations and a four-fold dilution with PBSCM (PBS supplemented with 1.0 mM MgCI and 0.1 mM CaCI ₂ ) for each step, had been made for each of the ligands to be tested. First the plates with transfected cells were washed and preincubated for approximately 25 minutes with 40 μΙ of the dilution series. After preincubation, the cells were incubated for 10 minutes with 40 μΙ dilution series now added a radioactive substrate (5HT 5-[1 ,2- ³ H[N]] in a final concentration of 70 nM when the serotonin transporter was tested, or dopamine 3,4-,[ring-2,5,6- ³ H] in a final concentration of 20 nM when hDAT and hNET was tested). The assay was stopped by washing with PBS. To lyse the cells and facilitate quantification of the accumulated radioactive ligand, 50 μΙ of MicroScint- 20 was added. The quantification was done in a Packard TopCounter NXT microplate scintillation counter. Data

The data from the IC ₅₀ uptake assay was fit to a sigmoidal dose-response curve using the program GraphPad Prism. It has been shown that imipramine and citalopram are competitive inhibitors of SERT (Apparsundaram, Stockdale et al. 2008), and it is therefore assumed that the analogues tested also show competitive inhibition. Provided competitive inhibition and a constant substrate concentration during the assay, the IC ₅₀ values obtained can be converted to the inhibition constants (K,) using the Cheng Prusoff equation (Cheng and Prusoff 1973). Where [S] is the substrate concentration and K _m is the michaelis constant.

The K _m values used for the conversion to K, are from previous studies in our group and are listed in table 2. The K _m values for hSERT are for serotonin, whereas the K _m values listed for hDAT and hNET are for dopamine. hSERT hDAT hNET

K _m (μΜ) 1.34 6.8* 0.165*

Table 1 : The K _m values for hSERT, hDAT, hNET and three different mutants of hSERT. *For hDAT and hNET the K _m values for dopamine instead of serotonin are listed.

T-tests are also made using the program Graph Pad Prism.

Results

The affinity towards the human dopamine and human norepinephrine transporters (hDAT and hNET respectively) have been tested. Comparisons of the inhibitory potency towards the different transporters are shown in tables 2 and 3.

Ki(nM) K, ratios

Name hSERT hDAT hNET hDAT/ hNET/ hSERT hSERT

Imipramine -(CH ₂ )3-N-(CH ₃ )2 -H 59 146000 360 2500 6.1

Clomipramine -(CH ₂ )3-N-(CH ₃ )2 -CI 1 1 .5 49000 1210 4300 105

Desipramine -(CH ₂ )3-N-CH ₃ 910 71000 18.3 78 0.020

Trimethyl- -(CH ₂ )3-N-(CH ₃ )3 -H 10.1 174000 330 17200 32 imipramine Mj1 -03 -(CH ₂ ) ₃ -N ⁺ -(0-) 260 >1000000 1 150 >3800 (CH ₃ ) ₂

Mj1 -50 -(CH ₂ )3-S ⁺ -(CH ₃ )2 17 210000 310 12400

Mj1 -51 -(CH ₂ )3-S ⁺ -(CH ₃ )2 3.6 17000 560 4700

S- -(CH ₂ ) ₃ -S-CH ₃ >95000 >1000000 >920000

Desipramine

Mj1 -18 -(CH ₂ ) ₃ -S-CH ₃ -CI >95000 >1000000 >920000

Mj1 -52 -(CH ₂ ) ₃ -Se ⁺ -(CH ₃ ) ₂ -H 1 1 .1 75000 155 6800

Mj1 -53 -(CH ₂ ) ₃ -Se ⁺ -(CH ₃ ) ₂ -CI 14000 400 2800.00

Mj1 -20 -(CH ₂ ) ₃ -Se-CH ₃ -H >95000 >1000000 >920000 Mj1 -21 -(CH ₂ ) ₃ -Se-CH ₃ -CI >95000 >1000000 >920000 Mj1 -22 -(CH ₂ ) ₃ -S(=0)(CH ₃ ) -CI 2400 1 16000 56000 48

Mj1 -23 -(CH ₂ ) ₃ -S(=0) ₂ (CH ₃ ) 20000 >1000000 >920000 >50 Mj1 -24 -(CH ₂ ) ₃ -S(=0) ₂ (CH ₃ ) >95000 >1000000 240000

Mj1 -10 -(CH ₂ ) ₃ -OH >95000 570000 44000 <6.0

Mj1 -12 -(CH ₂ ) ₃ -OH -CI >95000 >1000000 95000 Mj1 -02 -CH ₂ CHCH ₂ >95000 >1000000 >920000 Mj1 -1 1 -CH ₂ CHCH ₂ -CI 7100 >1000000 >920000 >141

Mj1 -56 -(CH ₂ ) ₂ CH ₃ -CI >95000 >1000000 >920000

3-Cyano- -(CH ₂ ) ₃ -N-(CH ₃ ) ₂ -C≡N 6.8 1 14000 154 16800 imipramine

ALN2-060 -(CH ₂ ) ₃ -S ⁺ -(CH ₃ ) ₂ -C≡N 4.1 340000 1660 83000

ALN2-058 -(CH ₂ ) ₃ -S-CH ₃ -C≡N 1400 >1000000 >920000 >710

ALN2-059 -(CH ₂ ) ₃ -Se ⁺ -(CH ₃ ) ₂ -C≡N 3.4 121000 870 36000

ALN2-057 -(CH ₂ ) ₃ -Se-CH ₃ -C≡N 2400 >1000000 >920000 >420 Table 2: The specificity of the imipramine analogues. The K, values in nM for hSERT, hDAT and hNET are listed. The ratios between the K, values, hDAT/hSERT and hNET/hSERT, are shown in the two right columns.

Kj (nM) K, ratios

Name Enantiome hSERT hDAT hNET hDAT/ hNET/ r hSERT hSERT

S-citalopram -N(CH ₃ )2 17 100000 85000 >5900 >5000.0

0

R/S-citalopram -N(CH ₃ ) ₂ R/S 22 100000 85000 >4500 >3900

Mj1-38 -N ⁺ (CH ₃ ) ₃ R/S 220 100000 85000 >450 >390

Mj1-08 -N ⁺ (0-)(CH ₃ ) ₂ 95000 100000 85000

Mj1-54 -S ⁺ (CH ₃ ) ₂ 5.9 100000 85000 >16900 >14400

Mj1-49 -S-CH ₃ 95000 100000 85000

Mj1-55 -Se ⁺ (CH ₃ ) ₂ S 1 .8 100000 85000 >56000 >47000

Mj1-48 -Se-CH ₃ 95000 100000 85000

Table 3: The specificity of the citalopram analogues. The K, values in nM for hSERT, hDAT and hNET are listed. The ratios between the K, values, hDAT/hSERT and hNET/hSERT, are shown in the two right columns.

Affinity for hSERT and specificity for hSERT over hDAT

All of the tested compounds of table 2 show poor affinity for hDAT, and are thus very specific for hSERT over hDAT. It is seen that clomipramine is more specific for hSERT over hDAT than imipramine, which is again more specific than desipramine. Trimethyl imipramine is even more specific than clomipramine. This indicates that there is not enough room for the extra methyl group in the hDAT binding site. Mj1-53, which has selenium on the tail and a chloride on the 3-position, has a higher affinity for hSERT than clomipramine. It is however not as specific for hSERT over hDAT as clomipramine is, but has a specificity comparable to imipramine.

Mj1-51 , which has a chloride on the 3-postion and sulphur on the tail, also has a higher affinity for hSERT than clomipramine. It has a selectivity for hSERT over hDAT comparable to clomipramine.

ALN2-059 and ALN2-060, which have a cyano group on the 3-position are more specific for hSERT than 3-cyanoimipramine. They are very specific for hSERT over hDAT. In fact, they are even much more specific than clomipramine. ALN2-057 and

ALN2-058, which are the demethylated forms of ALN2-059 and ALN2-060 respectively, have a low affinity for hSERT but are not as specific for hSERT over hDAT as clomipramine. They are however still much more specific than desipramine. The cyano group on the 3-position has thus been shown to be important for both the affinity for hSERT and the specificity for hSERT over hDAT.

As mentioned, the comparison of K _r values of Mj1-53 with ALN2-059 and Mj1-51 with ALN2-060 showed that there were no significant changes in binding affinities towards hSERT when exchanging the chloride with a cyano group.

Making the same comparison of K _r values of Mj1-53 with ALN2-059 and Mj1-51 with ALN2-060 toward hDAT shows that the exchange of the chloride with a cyano group significantly lowers the binding affinity (p=0.0218 comparing Mj1-53 with ALN2-059; p=0.0181 comparing Mj1-51 with ALN2-060 using unpaired t-test).

One exception being the comparison of 3-cyanoimipramine with clomipramine

(p=0.0898), but here it should be noted that the confidence interval for 3- cyanoimipramine is very broad. This shows that it is the cyano group on the 3-position, in combination with selenium or sulphur on the tail, which gives the high specificity for hSERT over hDAT. This is considered to be due to stearic hindrance of the cyano group in the binding site of hDAT.

All of the compounds listed in table 3 are very specific for hSERT over hDAT.

Furthermore, Mj1-54 and Mj1-55 having S or Se in the tail have a high affinity for hSERT, Specificity for hSERT over hNET

Any compound listed in table 2 is less specific for hSERT over hNET than it is for hSERT over hDAT. Desipramine and Mj1-10, even have a higher affinity for hNET than for hSERT. Again, the specificity is greater for clomipramine than for imipramine. Unlike for the specificity for hSERT over hDAT, the specificity of trimethylimipramine for hSERT over hNET is less than for clomipramine, but it is still higher than for imipramine.

K \ G -(CH ₂ ) ₃ -N-(CH ₃ )2 -(CH ₂ ) ₃ -S ⁺ -(CH ₃ )2 -(CH ₂ ) ₃ -Se ⁺ -(CH ₃ ) ₂

-H 6.1 (Imipramine) 18.2 (Mj 1-50) 14.0 (Mj 1-52)

-CI 105 (Clomipramine) 156 (Mj1-51) 80(Mj1-53)

-C≡N 23 (3-cyanoimipramine) 400 (ALN2-60) 260 (ALN2-059)

Table 4: The K, ratios (hNET/hSERT) for selected imipramine analogues with different R ¹ and R ² groups. The name of the compound is shown in parentheses.

It is seen from table 4 that compounds having a sulphur in the R ¹ group generally have a better specificity for hSERT over hNET, than the analogues with nitrogen or selenium in the R ¹ group. One exception is when R ² is a chloride. In this case the specificity is in the same range as for clomipramine. It is also seen from table 4 that for compounds having a sulphur or selenium in the tail, the specificity increases going from -H to -CI to -C≡N on the 3-position. For the analogues with a nitrogen in the R ¹ group, the specificity decreases going from a chloride to a cyano group on the 3-position.

Comparison of the binding affinities for hNET for Mj1 -53 with ALN2-059 (p=0.0160, unpaired t-test) and Mj1 -51 with ALN2-060 (p=0.0017, unpaired t-test), , shows that ALN2-059 and ALN2-060 with a cyano group on the three-position have a significantly lower binding affinity for hNET, than their corresponding analogues with a chloride on the 3-position. It has thus been shown that the combination of both a cyano group on the 3-position and either a sulphur or selenium on the tail is required to get a high specificity for hSERT over hN ET.

All of the compounds listed in table 4 are very specific for hSERT over hN ET.

General considerations of specificity

The cyano group on the 3-position of imipramine has been shown to be important for both the hSERT over hDAT specificity and the hSERT over hNET specificity. In both cases, the highest specificity was observed when the cyano group on the 3-position was combined with a sulphur in the R ¹ group.

Duloxetine analogues

The affinity towards the human dopamine and human norepinephrine transporters (hDAT and hNET respectively) were also tested for Duloxetine and some of its analogues. Comparisons of the inhibitory potency towards the different transporters are shown in table 5.

Table 5: The specificity of Duloxetine analogues. The K, values in nM for hSERT, hDAT and hNET are listed. Compared to duloxetine the dimethylated seleno-analogues had 3-4-fold reduced hSERT inhibitory potency. This decrease is due to the additional methyl group or the seleno-atom as MJ3-107 and MJ3-1 19 are equipotent to J3-42. There was no gain in affinity from the pure enantiomer of the seleno-analogue relative to the racemic mixture and the pure enantiomer exhibited lower hSERT selectivity due to surprisingly little inhibitory potency against hDAT and hNET for the racemate. All compounds are very specific for hSERT over hNET.

Fluoxetine analogues

The affinity towards the human dopamine and human norepinephrine transporters (hDAT and hNET respectively) were also tested for Fluoxetine and some of its analogues. Comparisons of the inhibitory potency towards the different transporters are shown in table 6. T and hNET are listed.

Dimethylation of fluoxetine had a negative effect on hSERT inhibitory potency as seen from the 7-fold loss of potency of AB3-161 compared to fluoxetine. The seleno- analogue (AB3-151) showed no gain of hSERT potency and showed modestly decreased hSERT selectivity. The sulfur-analogue of AB3-161 has increased potency for SERT potency. All compounds are very specific for hSERT over hNET.

LuAA21004 analogues

The affinity towards the human dopamine and human norepinephrine transporters (hDAT and hNET respectively) were also tested for LuAA21004 and some of its analogues. Comparisons of the inhibitory potency towards the different transporters are shown in table 7.

hDAT and hNET are listed.

Methylation of LuAA2104 as in JCH5-61 has in itself negative effects, whereas the permanent positive charge by substitution of the nitrogen with a sulphur atom increases potency 3.5-fold. All compounds are very specific for hSERT over hNET.

Forced Swim Test

A widely used method to test the effect of antidepressants, the forced swim test (FST), have been used to assess the antidepressant activity of the novel compound Mj1 -53 and compare its potential antidepressant effect with the conventional antidepressant clomipramine. The major parameter measured during the forced swim sessions is time spent by the animal being immobile (without any active movements, just floting keeping head over the water surface). The effect of antidepressant activity is evaluated in dose- response studies in mice (Porsolt et al. , 1978). Materials and Methods

The FST protocol is based on the method established by Porsolt et al, 1978 and further described by Dulawa et al, Neuropsychopharmacology (2004) and Holick et al, Neuropsychopharmacolog (2008). Briefly, during the test animals are placed in the water filled cylinder (subjected to the short-term, inescapable stress) and perform swimming behavior interrupted by periods of immobility. The result of the test is expressed as the total duration of immobility within the last 5 minutes in 7-min test session. NMRI male 12-18 weeks old mice were used in the experiment. Mice were housed six per cage in a colony room under the standard conditions (12 h light/dark cycle started at 6:00; 21°C RT and 50% humidity). Food and water were available ad libitum. FSTs were performed during the light phase of the day cycle between 10:00 and 16:00. Mj1- 53 was dissolved in 10% beta-hydroxy-cyclodextrin and incubated overnight at 4°C on a tilting table. Clomipramine solution was prepared using sterile saline.

Clomipramine and Mj1-53 were injected intraperitoneally 30 min prior the test in doses shown in tables 8 and 9. Vehicle treated animals received the equivalent volume of the solvent. A transparent plexiglass cylinder (20 cm in diameter) was filled with 26°C tap water and each FST session lasted for 7 min. Swimming sessions were video recorded and recordings were analyzed either manually by a scorer blind to the drug treatment or using the analyzing software (Ethovision XT, Noldus, Netherlands). After the session mice were wiped with a towel, placed under a heating lamp for 15 min, and returned to their home cages.

Statistical analysis was performed using Microsoft Excel and GraphPad Prism platform. Results were analyzed by ANOVA following Dunnett's multiple comparison test evaluating the effect of different drug doses according to the effect of vehicle with the established level of significance lower than 5%.

Results

Clomipramine (mg/kg)

Dose Vehicle 40 10 2.5 1

Number

of

animals 33 13 32 39 7 Immobility

time (sec) 240.9 ± 9.0 191 .3 ± 20.1 187.2 ± 1 1 .1 191 ± 9.7 236 ± 1 1 .7 ± SEM

ANOVA,

Dunnett's ns

Table 8. Effect of Clomipramine on the duration of immobility time in FST in mice *-p<0.05 by Dunnett's post ANOVA test, ns - non-significant

Table 8 shows the effect of clomipramine on the duration of immobility in the forced swim test. Clomipramine was tested at the doses: 0, 40, 10 and 2.5 mg/kg. The corresponding mean immobility time (sec) ± standard error of mean (S.E.M) are also shown.

Clomipramine has a significant (F _(4, p<0.0001) effect on mice immobility ^' FST in dose dependent manner ( Table 8).

Table 9. Effect of Mj1-53 on the duration of immobility time in FST in mice

*-p<0.05 by Dunnett's post ANOVA test, ns - non-significant

Table 9 shows the effect of MJ-53 on the duration of immobility in the FST.

Mj1-53 applied in doses of 1 mg/kg, 0.25 mg/kg, and 0.01 mg/kg significantly reduced immobility time. The overall effect of Mj1-53 was also significant p<0.05), but Mj1-53 in doses of 16 mg/kg and 4 mg/kg was inefficient (Table 9). Important to notice that Mj1-53 is efficient in doses 250 times lower compared with doses applied using the conventional antidepressant clomipramine. References

Apparsundaram, S., D. J. Stockdale, et al. (2008). "Antidepressants targeting the serotonin reuptake transporter act via a competitive mechanism."

J. Pharmacol. Exp.Ther. 327(3): 982-990.

Barker EL, Blakely RD. 1995. Norepinephrine and serotonin transporters. Molecular targets of antidepressant drugs. In: Bloom FE, Kupfer DF, editors.

Psychopharmacology: the fourth generation of progress. Vol. 28. New York: Raven Press.

Charney, D. S. N., Eric J and Bunney, Benjamin S, Ed. (1999). Neurobiology of mental illness. New York Oxford, Oxford University Press Cheng, Y. C. and W. H. Prusoff (1973). "Relationship between the inhibition constant (k1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction." Biochem. Pharmacol 22 3099-3108.

Dulawa SC, Holick KA, Gundersen B, Hen R. 2004. Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology. 29(7): 1321 -30.

Owens MJ, Morgan WN, Plott SJ, and Nemeroff CB. 1997. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283: 1305-1322.

Rodrigo Machado-Vieira, M. D., Ph.D., Giacomo Salvadore, M.D., David A.

Luckenbaugh, and H. K. M. M.A., M.D., F.R.C.P.C., and Carlos A. Zarate Jr., M.D. (2008). "Rapid Onset of Antidepressant Action: A New Paradigm in the Research and Treatment of Major Depression." J Clin Psychiatry 69(6): 946-958.