HK1098694A

HK1098694A - The combination of a serotonin reuptake inhibitor and a glycine transporter type 1 inhibitor for the treatment of depression

Info

Publication number: HK1098694A
Application number: HK07105188.4A
Authority: HK
Inventors: Michael Didriksen; Sandra Hogg Willigers; Jørn ARNT
Original assignee: H. Lundbeck A/S
Priority date: 2003-08-21
Filing date: 2004-08-18
Publication date: 2007-07-27

Description

Combination of a 5-hydroxytryptamine reuptake inhibitor and a type 1 glycine transporter inhibitor for the treatment of depression

no marking

The present invention relates to combinations of 5-hydroxytryptamine reuptake inhibitors (SRI) and glycine transporter type 1 (GlyT-1) inhibitors. Accordingly, the present invention relates to the use of certain compounds, and compositions of compounds having 5-hydroxytryptamine reuptake inhibitor activity and GlyT-1 inhibitor activity, for the treatment of depression and other affective disorders.

Background

Selective 5-hydroxytryptamine reuptake inhibitors (hereinafter SSRIs) have become the first choice therapy for the treatment of depression, certain types of anxiety and social phobia because of their efficacy, good tolerability and good safety profile compared to classical tricyclic antidepressants.

However, clinical studies on depression and anxiety disorders have shown that SSRIs are not effective to a considerable extent, up to 30%. In addition, a factor that is often overlooked in antidepressant therapy is compliance, which has a rather profound effect on the patient's motivation to continue medication.

First, there is a delay in the efficacy of SSRIs. Sometimes symptoms even worsen during the first week of treatment. Second, sexual dysfunction is a side effect common to all SSRIs. Without addressing these problems, there is no real advance in pharmacotherapy for depression and anxiety.

To address the inefficiency, psychiatrists sometimes employ augmentation strategies. Enhancement of antidepressant therapy can be achieved by co-administration of mood stabilizers such as lithium carbonate or triiodothyronine or by the use of electric shocks.

In 1993, Artigas et al described an enhancement strategy using pindolol (trends Pharmacol. Sci.1993, 14, p 262-. The Artigas approach is based on intracerebral microdialysis experiments in animals. Indeed, subsequent neurochemical studies by Blier and his colleagues based on the desensitization hypothesis showed that the delay in efficacy of antidepressants was associated with progressive desensitization of the 5-hydroxytryptamine autoreceptors (Blier et al j. clin. psycipcharacol.1987, 7suppl.6, 24S-35S). The key point in their hypothesis is that the SSRI is on a controlled release somatic tree autoreceptor (5-HT)_1A) The effect of (a) limits the release of 5-hydroxytryptamine in the distal regions and thus has an inhibitory effect on the uptake of 5-hydroxytryptamine in these regions. This hypothesis was supported by rat microdialysis experiments showing that an increase in extracellular 5-HT induced by a single dose of SSRI is co-administered with 5-HT_1AAutoreceptor antagonist potentiation (Invernizzi et al brain Res, 1992, 584, p 322-324 and Hjorth, S., J. neurochem, 1993, 60, p 776-779).

The combined administration of a compound that inhibits 5-hydroxytryptamine reuptake and 5-HT has been evaluated in several studies_1AEffect of receptor antagonists (Innis, R.B.et al. Eur.J.Pharmacol.1987, 143, p.1095-204and Gartside, S.E., Br.J.Pharmacol, 1995, 115, p1064-1070, Blier, P.et al. trends inPharmacol, science 1994, 15, 220). These studies found that 5-HT_1AReceptor antagonists abrogate the 5-hydroxytryptamine neurotransmission initiation brake caused by 5-hydroxytryptamine reuptake inhibitors, thus allowing immediate enhancement of 5-hydroxytryptamine transmission and rapid onset of therapeutic action.

Several patent applications have been filed, including 5-HT_1AUse of a combination of an antagonist and a 5-hydroxytryptamine reuptake inhibitor for the treatment of depression (see, e.g., EP-A2-687472 and EP-A2-714663).

Another method of increasing peripheral 5-HT is by blocking 5-HT_1BAn autoreceptor. The microdialysis experiments in rats did show an experimental 5-HT_1BThe receptor antagonist GMC2-29 potentiates the effect of citalopram on increasing hippocampal 5-HT.

Several patent applications have also been filed, including SSRI and 5-HT_1BCombinations of antagonists or partial agonists (WO 97/28141, WO 96/03400, EP-A-701819 and WO 99/13877).

Glutamate is the most important excitatory neurotransmitter in the brain, and its effects are mediated through ionotropic and metabotropic receptors. Ionic NMDA receptors are involved in glutamatergic excitation of GABAergic, 5-hydroxytryptotaminergic, dopaminergic and adrenergic neurons.

NMDA receptors are positively regulated by glycine. The functional NMDA receptor complex is formed by binding of the NR1 and NR2 subunits, which contain glycine and glutamate recognition sites, respectively (Danysz W & Parsons C.G., Pharmacological reviews, vol 50: pp597-664 (1998)).

GlyT-1 transporters located in adjacent glial cells modulate endogenous glycine levels surrounding the NMDA receptor complex. Thus, inhibition of the GlyT-1 transporter results in increased glycine levels and NMDA receptor activation (Danysz W & Parsons C.G., pharmaceutical reviews, vol 50: pp597-664 (1998)).

Preclinical models of depression (chronic severe stress and chronic mild stress) have been shown to involve the NMDA receptor complex (Novak g.et al, Polish Journal of Pharmacology, vol 58: pp365-369 (1998)). Furthermore, partial agonists of the glycine site in the chronic mild stress model showed antidepressant-like effects (Papp M. & Moryl E., European journal of Pharmacology, vol 316: pp145-151 (1996)).

Detailed Description

It has now surprisingly been found that GlyT-1 inhibitors enhance the effect of SRI, in particular the effect of SSRIs on extracellular 5-HT levels.

It is therefore suggested that the combination of an SSRI and a GlyT-1 inhibitor provides both 5-HT reuptake inhibition properties and GlyT-1 inhibitor properties, with better therapeutic efficacy and faster onset than SSRI alone.

The present invention therefore provides:

use of a GlyT-1 inhibitor for the preparation of a pharmaceutical composition for use in combination with a 5-hydroxytryptamine reuptake inhibitor (SRI).

The present invention relates to the use of a compound which is an inhibitor of 5-hydroxytryptamine reuptake and another compound which is an inhibitor of GlyT-1 for the preparation of a pharmaceutical composition for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disease responsive to an inhibitor of 5-hydroxytryptamine reuptake.

The invention also relates to the use of a GlyT-1 inhibitor for the preparation of a pharmaceutical composition for enhancing and accelerating the efficacy of a 5-hydroxytryptamine reuptake inhibitor. Furthermore, the present invention relates to the use of a GlyT-1 inhibitor for the preparation of a pharmaceutical composition for enhancing or accelerating the efficacy of a 5-hydroxytryptamine reuptake inhibitor.

Furthermore, the present invention relates to the use of a combination of a compound which is a 5-hydroxytryptamine reuptake inhibitor and a compound which is a GlyT-1 inhibitor for the preparation of a pharmaceutical composition or kit of parts for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disease responsive to a 5-hydroxytryptamine reuptake inhibitor.

Furthermore, the present invention relates to the use of compounds which are inhibitors of 5-hydroxytryptamine reuptake and compounds which are inhibitors of GlyT-1 for the preparation of a kit for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disease responsive to inhibitors of 5-hydroxytryptamine reuptake.

In another aspect the invention relates to a pharmaceutical composition comprising a combination of a compound that is a 5-hydroxytryptamine reuptake inhibitor and another compound that is a GlyT-1 inhibitor, and optionally a pharmaceutically acceptable carrier or diluent.

In another aspect the invention relates to a kit comprising a combination of a compound that is a 5-hydroxytryptamine reuptake inhibitor and another compound that is a GlyT-1 inhibitor, and optionally a pharmaceutically acceptable carrier or diluent.

In yet another aspect the present invention relates to a method of treating depression, anxiety and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disease responsive to an inhibitor of 5-hydroxytryptamine reuptake, which method comprises administering to a patient in need thereof a therapeutically effective amount of a combination of a compound which is an inhibitor of 5-hydroxytryptamine reuptake and a compound which is an inhibitor of GlyT-1.

In another aspect, the invention relates to a method of treating depression, anxiety and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disorder responsive to an inhibitor of 5-hydroxytryptamine reuptake, which method comprises administering to a subject in need thereof a compound which is a GlyT-1 inhibitor and a compound which is an inhibitor of 5-hydroxytryptamine reuptake, or a compound which causes an increase in extracellular 5-hydroxytryptamine levels.

In another aspect, the invention relates to a method of enhancing and/or accelerating the efficacy of a priming 5-hydroxytryptamine reuptake inhibitor or other compound that causes an increase in extracellular 5-hydroxytryptamine levels, the method comprising administering a GlyT-1 inhibitor to an individual that is about to be, or is being, treated with a 5-hydroxytryptamine reuptake inhibitor or other compound that causes an increase in extracellular 5-hydroxytryptamine levels. Such an individual is preferably a human, such as a male or female, child, adult or elderly person.

Various medical indications: depression, anxiety disorders and other affective disorders such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disorder responsive to SRI are all intended to be independent embodiments. Accordingly, each of the indications described above may be claimed independently whenever mentioned in the specification.

Whenever reference is made to the indications depression, anxiety and other affective disorders involving the use of GlyT-1 inhibitors and SRIs, such as general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disease responsive to SRIs, pharmaceutical compositions, kits, methods of treatment and methods of identifying compounds for use in the treatment of each indication are intended to be separate embodiments. Accordingly, each of the indications set forth above may be claimed separately along with the use of GlyT-1 inhibitors with SRIs, pharmaceutical compositions, kits, methods of treatment, and methods of identifying compounds for treating each indication.

In a particular embodiment, the SRI is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI).

In another embodiment, a GlyT-1 inhibitor selective for a type 1 glycine transporter is used in accordance with the present invention.

The pharmaceutical composition or kit of the invention may be administered by simultaneous administration. The term "concurrently administered" as used herein means that the GlyT-1 inhibitor and SRI are administered no more than 15 minutes apart, such as up to 10 minutes, such as up to 5 minutes or such as up to 2 minutes apart. The GlyT-1 inhibitor and the SRI may be contained in the "same unit dosage form" or in "separate dosage forms". The term "same unit dosage form" as used herein refers to a dosage form that contains both an SRI and a GlyT-1 inhibitor. The term "isolated dosage form" as used herein means that the GlyT-1 inhibitor is contained in one dosage form and the SRI is contained in another dosage form.

Simultaneous administration of the GlyT-1 inhibitor and the SRI may optionally be combined with administration of supplemental doses of the GlyT-1 inhibitor. For example, a supplemental dose of the GlyT-1 inhibitor may be administered 1, 2, 3, or 4 times a day, while the "co-administered" SRI and GlyT-1 inhibitor may be administered 1 or more times a day, e.g., 1 time per day or e.g., 2 times per day. Correspondingly:

a) the GlyT-1 inhibitor and the SRI may be administered 1 time per day by simultaneous administration, while a supplemental dose of the GlyT-1 inhibitor may be administered 1, 2, 3 or 4 times per day, e.g., 1, 2 or 3 times per day, e.g., 1 or 2 times per day, e.g., 2 times per day or e.g., 1 time per day, or

b) The GlyT-1 inhibitor and the SRI may be administered by simultaneous administration 2 times per day, while a supplemental dose of the GlyT-1 inhibitor may be administered 1, 2, 3 or 4 times per day, e.g., 1, 2 or 3 times per day, e.g., 1 or 2 times per day, e.g., 2 times per day or e.g., 1 time per day.

Alternatively, the pharmaceutical compositions or kits of the invention are administered by sequential administration. The term "sequential administration" as used herein refers to administration of 1 or more doses per day of the GlyT-1 inhibitor and 1 or more doses per day of the SRI with a time interval between administrations of greater than 15 minutes but less than 4 hours, such as greater than 2 hours but less than 4 hours, such as greater than 15 minutes but less than 2 hours, such as greater than 1 hour but less than 2 hours, such as greater than 30 minutes but less than 1 hour, such as greater than 15 minutes but less than 30 minutes. The SRI or GlyT-1 inhibitor may be administered first. The GlyT-1 inhibitor and the SRI are contained in separate dosage forms, optionally in the same container or package. Typically, the GlyT-1 inhibitor may be administered at 1, 2, 3, 4, or 5 doses per day and the SRI at 1 or 2 doses per day. Correspondingly:

a) the GlyT-1 inhibitor and the SRI may be administered 1 time per day, and the GlyT-1 inhibitor may be administered 1, 2, 3, 4 or 5 times per day, e.g., 1, 2, 3 or 4 times per day, e.g., 1, 2 or 3 times per day, e.g., 1 or 2 times per day, e.g., 2 times per day or e.g., 1 time per day, or

b) The GlyT-1 inhibitor and the SRI may be administered 2 times per day, and the GlyT-1 inhibitor may be administered 1, 2, 3, 4 or 5 times per day, e.g., 1, 2, 3 or 4 times per day, e.g., 1, 2 or 3 times per day, e.g., 1 or 2 times per day, e.g., 2 times per day or 1 time per day.

Accordingly, the pharmaceutical compositions or kits of the invention may be adapted for simultaneous administration of the active ingredients or for sequential administration of the active ingredients. When the pharmaceutical compositions or kits are for simultaneous administration, the active ingredients may be contained in the same unit dosage form. When the pharmaceutical composition or kit is for sequential administration, the active ingredients are contained in separate dosage forms, optionally in the same container or package. As used herein, "active ingredient" refers to an SRI or GlyT-1 inhibitor.

A kit comprises an article of manufacture in a first unit dosage form of a GlyT-1 inhibitor and a second unit dosage form of SRI, the container being referred to as containing the first and second dosage forms described above.

In another embodiment, the GlyT-1 inhibitor is selected from any of the compounds disclosed in WO0208216, such as any of the following compounds:

1) ethyl N- {3- [ 5-cyano-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } glycine,

2) n- {3- [ 5-cyano-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine ethyl ester,

3) n- {3- [ 5-cyano-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } glycine,

4) n- {3- [ 5-cyano-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

5) n- {3- [1- (3-chlorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

6) n- {3- [1- (3-trifluoromethylphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

7) n- {3- [1- (3-trifluoromethylphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methyl (1-ethyl) glycine,

8) n- {3- [1- (4-methylphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl) -N-methylglycine,

9) n- {3- [1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

10) n- {3- [1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylalanine,

11) n- {3- [1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methyl (1-ethyl) glycine,

12) n- {3- [ 4-chloro-1- (3-methyl-4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

13) n- {3- [ 4-chloro-1- (4-chlorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

14) n- {3- [ 5-chloro-1- (4-chlorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylalanine,

15) n- {3- [ 6-chloro-1- (3-methyl-4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

16) n- {3- [ 6-chloro-1- (4-chlorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

17) n- {3- [ 6-chloro-1- (4-methylphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

18) n- {3- [ 6-chloro-1- (4-methoxyphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

19) n- {3- [ 5-fluoro-1- (4-chlorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

20) n- {3- [ 5-fluoro-1- (4-methoxyphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

21) n- {3- [ 5-trifluoromethyl-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

22) n- {3- [ 5-trifluoromethyl-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylalanine,

23) n- {3- [ 5-cyano-1- (3-methyl-4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

24) n- {3- [ 5-cyano-1- (4-cyanophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylalanine,

25) n- {3- [ 5-cyano-1- (4-methoxyphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

26) n- {3- [ 5-cyano-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

27) n- {2- [ 5-cyano-1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] ethyl } -N-methylglycine,

28) n- {3- [ 5-chloro-1- (4-chloro-phenyl) -indan-1-yl ] -propyl } -N-methylglycine,

29) n- {3- [ 5-chloro-1- (4-chloro-phenyl) -indan-1-yl ] -propyl } -N-methylalanine,

30) n- {3- [ 3-Ring-1- (4-methylphenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

31) n- [3- (3, 3-dimethyl-1-phenyl-1, 3-dihydro-benzo [ c ] thiophen-1-yl) -propyl ] -N-methylglycine,

32) n- [3- (3, 3-dimethyl-1-phenyl-1, 3-dihydro-benzo [ c ] thiophen-1-yl) -propyl ] -N-methylalanine,

33) n- {3- [1- (4-fluoro-phenyl) -3, 3-dimethyl-1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methylglycine,

34) n- {3- [ 5-bromo-1- (4-chlorophenyl) -1, 3-dihydroisobenzofuran-1-yl ] -1-propyl } -N-methylglycine,

35) n- {2- [1- (4-chloro-phenyl) -3, 3-dimethyl-1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methylglycine,

36) n- [3- (3-methyl-1-phenyl-1H-inden-1-yl) -propyl ] -N-methylglycine,

37) n- [3- (5-chloro-1-thiophen-2-yl-1, 3-dihydro-isobenzofuran-1-yl) -propyl ] -N-methylglycine,

38) n- [3- (5-chloro-1-thiophen-2-yl-1, 3-dihydro-isobenzofuran-1-yl) -propyl ] -N-methyl (1-ethyl) -glycine,

39) n- [3- (3-methyl-1-phenyl-1, 3-dihydro-isobenzofuran-1-yl) -propyl ] -N-methylalanine,

40) n- [3- (3-methyl-1-phenyl-1, 3-dihydro-isobenzofuran-1-yl) -propyl ] -N-methyl (1-ethyl) -glycine,

41) n- [3- (3, 3-dimethyl-1-phenyl-1, 3-dihydro-isobenzofuran-1-yl) -ethyl ] -N-methylalanine,

42) n- [3- (3, 3-dimethyl-1- (4-fluoro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl) -ethyl ] -N-methylalanine,

43) n- [3- (3, 3-dimethyl-1-phenyl-1, 3-dihydro-isobenzofuran-1-yl) -ethyl ] -N-methyl- (1-ethyl) glycine,

44) n- [3- (3, 3-dimethyl-1- (4-fluoro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl) -ethyl ] -N-methyl- (1-ethyl) glycine,

45) n- [3- (3, 3-diethyl-1-phenyl-1, 3-dihydro-isobenzofuran-1-yl) -propyl ] -N-methylalanine,

46) n- [3- (3, 3-diethyl-1- (4-chloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl) -propyl ] -N-methylalanine,

47) n- [3- (3, 3-diethyl-1- (4-chloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl) -propyl ] -N-methylglycine,

48) n- [3- (1-phenyl-1, 3-dihydro-benzo [ c ] thiophen-1-yl) -propyl ] -N-methylalanine,

49) n- {3- [1- (4-chloro-phenyl) -3, 3-dimethyl-indan-1-yl ] -propyl } -N-methylglycine,

50) n- {3- [1- (4-chloro-phenyl) -3, 3-diethyl-1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-alanine,

51) n- [2- (3-methyl-1-phenyl-indan-1-yl) -ethyl ] -amino } -N-methylalanine,

52) n- [3- (1-phenyl- (1H) -inden-1-yl) -propyl ] -N-methyl-alanine,

53) n- {3- [1- (4-fluoro-phenyl) -5- (4-trifluoromethyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

54) n- {3- [ 5-chloro-1- (4-chloro-phenyl) -indan-1-yl ] -propyl } -N-methyl-glycine,

55) n- {3- [ 5-chloro-1- (4-chloro-phenyl) -indan-1-yl ] -propyl } -N-methyl-alanine,

56) n- {3- [1- (4-chloro-phenyl) -5- (4-trifluoromethyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

57) n- {3- [1- (4-chloro-phenyl) -5- (4-methyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

58) n- {3- [1- (4-chloro-phenyl) -5- (4-methoxy-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

59) n- {3- [1- (4-chloro-phenyl) -5- (2-thienyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

60) n- {3- [1- (4-chloro-phenyl) -5- (4-methyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

61) n- {3- [1- (4-chloro-phenyl) -5- (4-methoxy-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

62) n- {3- [1- (4-chloro-phenyl) -5- (4-trifluoromethyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

63) n- {3- [1- (4-chloro-phenyl) -5- (4-chloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

64) n- {2- [1- (4-chloro-phenyl) -5- (5-chloro-thiophen-2-yl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

65) n- {3- [1- (4-chloro-phenyl) -5- (3-methyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

66) n- {3- [1- (4-chloro-phenyl) -5- (2-methyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

67) n- {3- [1- (4-chloro-phenyl) -5- (2, 5-dichloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

68) n- {3- [1- (4-chloro-phenyl) -5- (3-trifluoromethyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl } -N-methyl-glycine,

69) n- {3- [1- (4-chloro-phenyl) -5- (3-trifluoromethyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

70) n- {3- [1- (4-chloro-phenyl) -5- (3, 4-dichloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -ethyl ] -N-methyl-glycine,

71) n- {3- [1- (4-chloro-phenyl) -5- (4-chloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

72) n- {3- [1- (4-chloro-phenyl) -5- (3-methyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

73) n- {3- [1- (4-chloro-phenyl) -5- (2-methyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

74) n- {3- [1- (4-chloro-phenyl) -5- (2, 5-dichloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

75) n- {3- [1- (4-chloro-phenyl) -5- (3, 4-dichloro-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

76) n- {3- [1- (4-chloro-phenyl) -5- (2-trifluoromethyl-phenyl) -1, 3-dihydro-isobenzofuran-1-yl ] -propyl } -N-methyl-glycine,

or a pharmaceutically acceptable addition salt thereof.

In another embodiment, the GlyT-1 inhibitor is selected from any one of the compounds disclosed in WO03/053942, such as any one of the following compounds:

1) (+/-) - {4- [2- (4-methoxy-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

2) (+/-) - {4- [2- (4-chloro-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

3) (+/-) - {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

4) (+/-) - {4- [2- (4-fluoro-phenylsulfanyl) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

5) (+/-) - {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

6) (+/-) - {4- [2- (4-isopropyl-phenylthio) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

7) (+/-) -2- {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -trans-2, 5-dimethylpiperazin-1-yl } -propionic acid,

8) {4- [ 5-chloro-2- (4-methoxy-phenylthio) -phenyl ] -2(R) -methyl-piperazin-1-yl } -acetic acid,

9) {4- [2- (4-methoxy-phenylthio) -phenyl ] -2(R), 5(S) -dimethyl-piperazin-1-yl } -acetic acid,

10) {4- [ 5-chloro-2- (4-methoxy-phenylthio) -phenyl ] -2, 2-dimethyl-piperazin-1-yl } -acetic acid,

11) (+/-) - {4- [ 5-chloro-2- (4-trifluoromethyl-phenylthio) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

12) {4- [ 5-chloro-2- (3-methoxy-phenylthio) -phenyl ] -2(R) -methyl-piperazin-1-yl } -acetic acid,

13) (+/-) - {4- [2- (4-phenyl-phenoxy) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

14) (+/-) - {4- [2- (4-methyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

15) (+/-) -4- [2- (4-isopropyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

16) (+/-) - {4- [2- (2, 4-dimethyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

17) (+/-) -2- {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -3-methylpiperazin-1-yl } -propionic acid,

18) {4- [2- (4-isopropyl-phenylthio) -phenyl ] -piperazin-1-yl } -acetic acid,

19) (+/-) -2- {4- [2- (4-methoxy-phenylthio) -phenyl ] -3-methyl-piperazin-1-yl } -propionic acid, or a pharmaceutically acceptable acid addition salt thereof.

The term "2" described herein³H]Glycine uptake "typical GlyT-1 inhibitors show IC lower than 20000nM₅₀。

The present invention also includes GlyT-1 inhibitors identified by this method, without limitation to these assays.

In accordance with the present invention, it has been found that co-administration of a GlyT-1 inhibitor and a 5-hydroxytryptamine reuptake inhibitor causes a significant increase in 5-hydroxytryptamine levels in the peripheral region as compared to the administration of the 5-hydroxytryptamine reuptake inhibitor alone, as determined by microdialysis experiments.

According to the present invention, animal experiments show that the GlyT-1 inhibitor can rapidly start the therapeutic effect of the 5-hydroxytryptamine reuptake inhibitor and enhance the anxiolytic ability of the 5-hydroxytryptamine reuptake inhibitor.

The use of a combination of a GlyT-1 inhibitor and a 5-hydroxytryptamine reuptake inhibitor can greatly reduce the dosage of the 5-hydroxytryptamine reuptake inhibitor necessary for the treatment of depression and other affective disorders, and thus reduce the side effects caused by the 5-hydroxytryptamine reuptake inhibitor. In particular, a combination of a lower dose of SRI and a GlyT-1 inhibitor may reduce the risk of SSRI-induced sexual dysfunction and sleep disorders.

The co-administration of a GlyT-1 inhibitor and a 5-hydroxytryptamine reuptake inhibitor may also be used to treat treatment-resistant depression, such as depression not amenable to treatment by the administration of a 5-hydroxytryptamine reuptake inhibitor alone. Typically, GlyT-1 inhibitors are useful as an adjunct therapy to enhance SRI responsiveness in patients in which at least 40-60% of the symptoms are not reduced within the first six weeks of treatment with SRI.

Various antidepressants having 5-hydroxytryptamine reuptake inhibition have been described in the literature. Any pharmacologically active compound that exerts a therapeutic effect, in whole or in part, by inhibiting 5-hydroxytryptamine reuptake in the central nervous system, may benefit from the potentiating effects of GlyT-1 inhibitors.

The following list contains a variety of 5-hydroxytryptamine reuptake inhibitors, all of which can benefit from the potentiating effect of GlyT-1 inhibitors: citalopram, escitalopram, fluoxetine, R-fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, desmethylvenlafaxine, duloxetine, dapoxetine, vilazodone, nefazodone, imipramine N-oxide, desipramine, pyrantene, azelner, nefopam, phenfuralaline, fezolamide, femoxetine, clomipramine, cyanamide (cianimipramine), ritoxetine, cyclam, celecoxib, WY27587, WY 27866, imeldine, efoxetine, indlazine, tiflorbine, vequine, milnacipran, piperazinopram, YM 922, S33005, F98-TA, FI 4503, a 80426, EMD 86006, paseze, S2389, S33005, cypress 14523, cyazopropyl, cyoxazamine, OPC, meglumine, quindoxine, N5607, mex 5726, mex, VN 2222, L792339, rochelle, YM 35992, OI 77, Org 6582, Org6997, Org6906, amitriptyline N-oxide, nortriptyline, CL 255.663, pirlindole, indatrilin, LY 280253, LY 285974, LY 113.821, LY 214.281, CGP 6085A, RU25.591, nepanidazole, diclofenac, trazodone, BMY 42.569, NS 2389, sercloremine, Nitroquipamine, ademetionine, sibutramine, desmethylsuramin, didesmethylsuramin, and clevoxamine. The above-mentioned compounds may be used in the form of a base or a pharmaceutically acceptable acid addition salt thereof. Each of the 5-hydroxytryptamine reuptake inhibitors described above is intended to be a separate embodiment. Accordingly, each of them and the respective use may be claimed individually.

Preferred compounds are for example citalopram, escitalopram, fluoxetine, R-fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, desmethylvenlafaxine, duloxetine, dapoxetine, vilazodone, nefazodone, imipramine, N-oxipramine, desipramine, piradamine, azepinil, nefopam, benzfluraline, fezolamide, femoxetine, clomipramine, cyanamide, rituximab, celecoxib, imeldine, ifoxetine, indolozine, teflucabene, vequinazine, milnacipran, piperazinone, alapropyl, cyclanodothiepine, trimipramine, quinupramine, duloxetine, amoxapine, nitroxapine, rocyline, zemipramine, octriptyline, nortriptyline, ritriptyline, rituximab, and mefenazaline, Nitroquipamine, ademetionine, sibutramine, desmethylsurtramine, didesmethylsurtramine, desmervultramine, [ trans-6- (2-chlorophenyl) -1, 2, 3, 5, 6, 10 b-hexahydropyrrole- (2, 1-a) isoquinoline ] (McN 5707), (d 1-4-exo-amino-8-chloro-benzo- (b) -bicyclo [3.3.1] non-2-6 α (10 α) -diene) (Org6997), hydrochloric acid (d1) - (5 α, 8 α, 9 α) -5, 8, 9, 10-tetrahydro-5, 9-methanobenzocycloocten-8-amine (Org6906), - [2- [4- (6-fluoro-1H-indol-3-yl) -3, 6-dihydro-1 (2H) -pyridinyl ] ethyl ] -3-isopropyl-6- (methylsulfonyl) -3, 4-dihydro-1H-2, 1, 3-benzothiadiazine-2, 2-dioxide (LY393558), [4- (5, 6-dimethyl-2-benzofuranyl) -piperidine ] (CGP 6085), dimethyl- [5- (4-nitro-phenoxy) -6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-7-yl ] -amine (RU25.591),

the above-mentioned compounds may be used in the form of a base or a pharmaceutically acceptable acid addition salt thereof. Each of the 5-hydroxytryptamine reuptake inhibitors described above is intended to be a separate embodiment. Accordingly, each of them and the respective use may be claimed individually.

In another embodiment, the SRI is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, vilazodone, duloxetine, nefazodone, imipramin, femoxetine and clomipramine, preferably citalopram or escitalopram.

The term "inhibit" as described herein³H]In experiments in which uptake of 5-hydroxytryptamine into intact rat brain synaptosomes "was observed, a typical 5-hydroxytryptamine reuptake inhibitor showed less than 10000nM (IC)₅₀) 5-hydroxytryptamine reuptake inhibition.

Other therapeutic compounds that may benefit from the potentiating effect of GlyT-1 inhibitors include compounds that, while not 5-hydroxytryptamine reuptake inhibitors, cause an increase in extracellular 5-HT levels in the synaptic cleft. One such compound is tianeptine.

Accordingly, compounds that cause an increase in extracellular 5-hydroxytryptamine levels in addition to SRI may be used in place of SRI in various aspects of the invention described herein.

The above list of 5-hydroxytryptamine reuptake inhibitors and other compounds that cause an increase in extracellular 5-hydroxytryptamine levels is not to be construed as limiting.

The term selective 5-hydroxytryptamine reuptake inhibitor (SSRI) refers to an inhibitor of the monoamine transporter which inhibits the 5-hydroxytryptamine transporter more strongly than the dopamine transporter and norepinephrine transporter. Particularly preferred SSRIs according to the present invention are citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, duloxetine, vilazodone and paroxetine.

Pharmaceutical composition

The various active ingredients of the present invention may be administered alone, together, in single or multiple doses, or in combination with a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions of the present invention may be formulated with a pharmaceutically acceptable carrier or diluent and any other known adjuvants and excipients in accordance with conventional techniques, for example as described in Remington: the formulation is prepared by the technique disclosed in the science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be formulated in a specific dosage form for administration by any suitable route, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, preferably oral routes. It will be appreciated that the preferred route will depend upon the general condition and age of the patient to be treated, the nature of the disease to be treated and the particular active ingredient or ingredients selected.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they may be coated, e.g., enterically coated, or otherwise formulated so as to provide controlled (e.g., sustained or extended) release of the active ingredient(s) according to methods known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also included within the scope of the invention.

Other suitable dosage forms for administration include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like.

The pharmaceutical composition of the invention or produced according to the invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups or the like, or parenterally in the form of solutions. To prepare such compositions, methods known in the art may be employed, and any pharmaceutically acceptable carrier, diluent, excipient, or other additive commonly used in the art may be employed.

Typical oral dosages for each active ingredient range from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50mg/kg body weight per day, more preferably from about 0.05 to about 10mg/kg body weight per day, given in 1 or more, e.g., 1-3 doses. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject to be treated, the nature and severity of the condition to be treated and any complications to be treated, as well as other factors apparent to those skilled in the art.

For parenteral routes of administration, such as intravenous, intrathecal, intramuscular and similar modes of administration, a typical dose is about half that used for oral administration.

The compounds of the invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. One example is the use of base addition salts of the compounds with the free acid. When the active ingredient contains a free acid, such salts are prepared in conventional manner by treating a free acid solution or suspension of the active ingredient with a chemical equivalent of a pharmaceutically acceptable base.

For parenteral administration, sterile aqueous solutions, aqueous propylene glycol solutions, aqueous vitamin E solutions or solutions of sesame or peanut oil of one or more of the active ingredients may be employed. If necessary, such aqueous solutions should be suitably buffered and the liquid diluent first rendered isotonic with sufficient salt or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed is readily prepared by standard techniques known to those skilled in the art.

Injectable solutions may be prepared by dissolving one or more active ingredients and possible additives in a portion of the injectable solvent (preferably sterile water), adjusting the solution to the desired volume, sterilizing the solution and filling it in suitable ampoules or vials. Any appropriate additive commonly used in the art may be added, such as tonicity agents, preservatives, antioxidants, and the like.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like.

Any other adjuvants or additives conventionally used for coloring, flavoring, preserving, etc. may be used, provided that they are compatible with the active ingredient or ingredients already used.

Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may comprise any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Pharmaceutical compositions formed by admixing one or more of the active ingredients of the present invention with a pharmaceutically acceptable carrier may then be conveniently administered in a variety of dosage forms suitable for the disclosed route of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

The active ingredients of the present invention may be formulated as similar or dissimilar pharmaceutical compositions and unit dosage forms thereof.

If solid carriers are employed for oral administration, the formulations may be in the form of tablets, powders or pellets placed in hard gelatin capsules, or may be in the form of lozenges or pastilles.

The amount of solid carrier varies greatly, but is generally from about 25mg to about 1 g.

If a liquid carrier is employed, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

If desired, the pharmaceutical compositions of the present invention may contain one or more active ingredients and other pharmacologically active substances, such as the aforementioned substances.

Materials and methods

[³H]Glycine uptake

In a well-established and reliable assay for glycine uptake, GlyT-1 inhibitors used in combination with SRIs, such as SSRIs, were tested:

cells transfected with human GlyT-1b were seeded onto 96-well plates. HBS (10mM Hepes-tris (pH7.4), 2.5mM KCl, 1mM CaCl) before the experiment₂，2.5mM MgSO₄) The cells are washed twice and preincubated for 6 minutes with the test compound. Then, 10nM of the sample was added³H-Glycine was added to each well and incubation was continued for 15 minutes. Cells were washed twice in HBS. Adding scintillation liquid, and performing scintillation reaction on a Trilux (Wallac) scintillation counterPlates were counted.

Based on this experiment, compounds that are GlyT-1 inhibitors show IC in the above assay₅₀An inhibitory effect of less than 20000nM, preferably less than 10000 nM.

Para 2³H]Inhibition of uptake of 5-hydroxytryptamine into rat brain synaptosomes

In a well-established and reliable assay for 5-hydroxytryptamine uptake, the inhibitory effect of SRI on 5-hydroxytryptamine uptake was examined:

inhibition by the compound in vitro³H]5-hydroxytryptamine reuptake inhibition was examined for their ability to take up 5-hydroxytryptamine into the brain synaptosomes of intact rats. The assay was performed as described in Hyttel Psychopharmacology 1978, 60, 13.

Based on this experiment, compounds that are SRI show less than 10000nM (IC) in the above assay₅₀) 5-hydroxytryptamine inhibition.

Animal(s) production

Male Wistar-derived germlock (285- & 320 g; Harlan, Zeist, The Netherlands) were used in this experiment. Before surgery, rats were housed individually in plastic cages (35X 40cm) with free access to food and water. Animals were maintained on a 12 hour light schedule (lights on 7 am). The experiment followed the declaration of helsinki and was allowed by the institute for animal protection of the mathematical and natural sciences department of the university of groingen.

Medicine

The following drugs were used: citalopram hydrobromide and NFPS having the structure:

(LU 2736N) (Lundbeck A/S, Copenhagen, Denmark). The drug was dissolved in saline and administered by subcutaneous injection.

Surgery

Microdialysis is carried out on the 5-hydroxytryptamine level of the brain by adopting AN I-type probe which is made of polyacrylonitrile/sodium methanesulfonate copolymer dialysis fiber (i.d.220 mu m, o.d.0.31 mu m, AN 69, Hospal, Italy). Preoperative isoflurane (O)₂/N₂O; 300/300ml/min) were anesthetized. Lidocaine hydrochloride at 10% (m/v) was used for local anesthesia. Rats were placed on a stereotaxic apparatus (Kopf, USA) and the probe was inserted into the ventral hippocampus (V.Hippo, L +4.8mm, IA: +3.7mm, V: -8.0mm) (Paxinos and Watson, 1982). After insertion, the probe was fixed with dental cement.

Microdialysis experiments

Rats recovered at least 24 hours after surgery. Will contain 147mM NaCl, 3.0mM KCl, 1.2mM CaCl₂And 1.2mM MgCl₂The artificial cerebrospinal fluid of (3) was perfused into the probe at a flow rate of 1.5. mu.l/min (Harvard appaatus, SouthNatick, Ma., USA). A15 minute microdialysis sample was collected into an HPLC vial containing 7.5. mu.l 0.02M acetic acid and analyzed for 5-hydroxytryptamine.

5-Hydroxytryptamine analysis:

mu.l of the microdialysis sample was injected by means of an autosampler (CMA/200 recovered microsampler, CMA, Sweden) into a 100X 2.0mm C18 Hypersil 3. mu.m column (Bester, Amstelven, the Netherlands) and separated with a mobile phase pH 4.65 containing 5g/L diammonium sulfate, 500mg/L EDTA, 50mg/L heptanesulfonic acid, 4% methanol (v/v) and 30. mu.l/L triethylamine at a flow rate of 0.4ml/min (Shimadzu LC-10 AD). Ampere detection of 5-hydroxytryptamine was performed with 500mV glassy carbon electrode against Ag/AgCl (Antec Leyden, Leiden, the Netherlands). The detection limit was 0.5fmol 5-hydroxytryptamine per 20. mu.l sample (signal to noise ratio of 3).

Expression and statistical analysis of data

Four consecutive microdialysis samples with a variance of less than 20% were used as controls and set to 100%. Data are expressed as a percentage of the time relative to the control level (mean ± s.e.m.). Statistical analysis was performed using Sigmastat for Windows (SPSS, Jandel Corporation). Comparison of treatment groups to control groups was performed using a bilateral analysis of variance (ANOVA) with repeated measures. Followed by Student Newman Keuls test. Single-sided anova graded assessment of drug efficacy replicate measurements. The level of significant difference was set at P < 0.05.

Results

Effect of citalopram and NFPS Co-administration on 5-hydroxytryptamine levels in the ventral hippocampus

The glycine transporter inhibitor NFPS (LU 2736N) was administered by subcutaneous injection at a dose of 10. mu. mol/kg without any significant effect on 5-hydroxytryptamine levels in the ventral hippocampus of rats (X)² ₁₀5.45P 0.857). The effect of citalopram on hippocampal 5-hydroxytryptamine levels was significantly enhanced by the co-administration of citalopram (10 μmol/kg s.c.) and the glycine transporter inhibitor NFPS (10 μmol/kg s.c.) (treatment group F (1, 9) ═ 5.35, P ═ 0.044, treatment group vs. time F (1,104) ═ 2.12, P ═ 0.033).

Claims

1. Use of a compound which is an inhibitor of 5-hydroxytryptamine reuptake and a compound which is an inhibitor of GlyT-1 for the preparation of a pharmaceutical composition for the treatment of depression, anxiety disorders and other affective disorders, such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disease responsive to an inhibitor of 5-hydroxytryptamine reuptake.

Use of a GlyT-1 inhibitor for the preparation of a pharmaceutical composition for use in combination with a 5-hydroxytryptamine reuptake inhibitor.

Use of a GlyT-1 inhibitor for the preparation of a pharmaceutical composition for enhancing and/or accelerating the efficacy of a start-up 5-hydroxytryptamine reuptake inhibitor.

4. Use according to any one of claims 2 to 3, wherein the 5-hydroxytryptamine reuptake inhibitor is used for the treatment of depression, anxiety disorders and other affective disorders, including generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse or any other disease responsive to SRI.

5. Use according to any one of claims 1 to 4, wherein the SRI is selected from an SSRI.

6. The use of any one of claims 1 to 5, wherein the SRI is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine.

7. The use of any one of claims 1-6, wherein the GlyT-1 inhibitor is selected from the group consisting of:

36) n- [3- (3-methyl-1-phenyl-1H-inden-1-yl) -propyl ] -N-methylglycine,

51) n- [2- (3-methyl-1-phenyl-indan-1-yl) -ethyl ] -amino } -N-methylalanine,

52) n- [3- (1-phenyl- (1H) -inden-1-yl) -propyl ] -N-methyl-alanine,

77) (+/-) - {4- [2- (4-methoxy-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

78) (+/-) - {4- [2- (4-chloro-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

79) (+/-) - {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

80) (+/-) - {4- [2- (4-fluoro-phenylsulfanyl) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

81) (+/-) - {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

82) (+/-) - {4- [2- (4-isopropyl-phenylthio) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

83) (+/-) -2- {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -trans-2, 5-dimethylpiperazin-1-yl } -propionic acid,

84) {4- [ 5-chloro-2- (4-methoxy-phenylthio) -phenyl ] -2(R) -methyl-piperazin-1-yl } -acetic acid,

85) {4- [2- (4-methoxy-phenylthio) -phenyl ] -2(R), 5(S) -dimethyl-piperazin-1-yl } -acetic acid,

86) {4- [ 5-chloro-2- (4-methoxy-phenylthio) -phenyl ] -2, 2-dimethyl-piperazin-1-yl } -acetic acid,

87) (+/-) - {4- [ 5-chloro-2- (4-trifluoromethyl-phenylthio) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

88) {4- [ 5-chloro-2- (3-methoxy-phenylthio) -phenyl ] -2(R) -methyl-piperazin-1-yl } -acetic acid,

89) (+/-) - {4- [2- (4-phenyl-phenoxy) -phenyl ] -2-methyl-piperazin-1-yl } -acetic acid,

90) (+/-) - {4- [2- (4-methyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

91) (+/-) -4- [2- (4-isopropyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

92) (+/-) - {4- [2- (2, 4-dimethyl-phenylthio) -phenyl ] -trans-2, 5-dimethyl-piperazin-1-yl } -acetic acid,

93) (+/-) -2- {4- [2- (4-tert-butyl-phenylthio) -phenyl ] -3-methylpiperazin-1-yl } -propionic acid,

94) {4- [2- (4-isopropyl-phenylthio) -phenyl ] -piperazin-1-yl } -acetic acid,

95) (+/-) -2- {4- [2- (4-methoxy-phenylthio) -phenyl ] -3-methyl-piperazin-1-yl } -propionic acid, or a pharmaceutically acceptable acid addition salt thereof.

8. A pharmaceutical composition comprising a compound that is a 5-hydroxytryptamine reuptake inhibitor and a compound that is a GlyT-1 inhibitor, and optionally a pharmaceutically acceptable carrier or diluent.

9. The pharmaceutical composition of claim 8, wherein the SRI is selected from SSRIs.

10. The pharmaceutical composition of claim 8 or 9, wherein the GlyT-1 inhibitor is "[ solution ], [ solution ] described herein³H]Glycine uptake experiments show IC₅₀An inhibitory effect of less than 20000nM, e.g.less than 10000 nM.

11. The pharmaceutical composition of any one of claims 8-10, wherein the GlyT-1 inhibitor is selected from any one of the inhibitors of claim 7.

12. Pharmaceutical composition according to any one of claims 8 to 11, characterized in that the 5-hydroxytryptamine uptake inhibitor is selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, dapoxetine, duloxetine, vilazodone, nefazodone, imipramine, femoxetine and clomipramine.

13. A pharmaceutical composition according to any one of claims 8 to 12, which is adapted for simultaneous administration of the active ingredients.

14. The pharmaceutical composition of claim 13, wherein the active ingredients are contained in the same unit dosage form.

15. A pharmaceutical composition according to any one of claims 8 to 12, which is suitable for sequential administration of the active ingredients.

16. The pharmaceutical composition of any one of claims 13 and 15, wherein the active ingredients are contained in separate dosage forms.

17. A kit comprising a compound that is a 5-hydroxytryptamine reuptake inhibitor and a compound that is a GlyT-1 inhibitor, and optionally a pharmaceutically acceptable carrier or diluent.

18. A method of treating depression, anxiety and other affective disorders such as generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder and social anxiety disorder, eating disorders such as binge eating disorder, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder, drug abuse, or any other disease responsive to inhibitors of 5-hydroxytryptamine reuptake, which comprises administering to a human in need thereof a therapeutically effective amount of a compound which is an inhibitor of 5-hydroxytryptamine reuptake and a compound which is an inhibitor of GlyT-1.