WO2004020437A1

WO2004020437A1 - S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole and acid addition salts thereof

Info

Publication number: WO2004020437A1
Application number: PCT/DK2003/000564
Authority: WO
Inventors: Benny Bang-Andersen; Klaus Peter Hertel; Pernille Gundorf Drewes
Original assignee: H Lundbeck AS
Current assignee: H Lundbeck AS
Priority date: 2002-08-29
Filing date: 2003-08-27
Publication date: 2004-03-11
Anticipated expiration: 2005-02-28
Also published as: AU2003257407A1

Abstract

The present invention relates to the compound S-(+)-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro-1H-indole or a pharmaceutically acceptable salt thereof and the use thereof for the preparation of a pharmaceutical composition for the treatment diseases and disorders responsive to 5-HT reuptake inhibition and/or diseases and disorders responsive to dopamine D4 receptor antagonism.

Description

S-(+)-3-{l-[2-(2,3-Dihydro-lH-indol-3-yl)ethyl]-3,6-dihydro-2fl-pyridin-4-yl}-6- chloro-LH-indole and acid addition salts thereof

The present invention relates to S-(+)-3-[l-[2-(2,3-dihydro-lH-indol-3-yl)ethyl]-3,6- dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole and pharmaceutically acceptable salts thereof and the use thereof for the treatment of diseases or disorders responsive to 5-ΗT reuptake inhibition and/or diseases responsive to dopamine D₄ receptor antagonism.

Background of the Invention

The present invention relates to a compound which has antagonistic effect at dopamine D₄ receptors and 5-HT reuptake inhibiting effect.

There are mounting evidences showing that blockade of 5-HT reuptake has antidepressant effects in patients (Montgomery Psychopharmacology: The fourth generation of progress, ed: Meltzer HY, Raven Press, New York, 1995, pp 1043-1051) and today, treatment with 5-HT reuptake inhibitors is the standard first-line treatment for major depression (Berman et al. Neurobiology of mental illness, eds: Charney DS, Nestler EJ, Bunney BS, Oxford University Press, Oxford, 1999, 31, 419-432). Furthermore, it is well recognised that 5-HT reuptake inhibitors are effective in the treatment of dysthymic disorder (Thase et al. Arch Gen Psychiatry, 1996, 53, 777-784).

5-HT reuptake inhibitors may also be useful in the treatment of anxiety disorders. Clinical studies have shown that 5-HT reuptake inhibitors have beneficial effects in generalized anxiety disorder (see e.g. Rocca et al. Ada Psychiatr Scand, 1997, 95, 444- 450). It is also well accepted that 5-HT reuptake inhibitors are effective against panic anxiety/panic disorder (see e.g. Sheehan and Harnett-Sheehan J Clin Psychiatry, 1996, 10, 51-58). Clear efficacy of 5-HT uptake inhibitors has also been demonstrated in obsessive compulsive disorder (McDougle Neurobiology of mental illness, eds: Charney DS, Nestler EJ, Bunney BS, Oxford University Press, Oxford, 1999, 37, 518-533). There is accumulating data implicating the central 5-HT system in the pathogenesis of post traumatic stress disorder (Charney et al. Arch Gen Psychiatry, 1993, 50, 295-305). In line with this, 5-HT reuptake inhibitors have been shown efficacious in post traumatic stress disorder and these type of agents are generally the first line of treatment of this disorder (Rothbaum et al. J Trauma Stress, 1996, 9, 865-871; Goddard et al. Neurobiology of mental illness, eds: Charney DS, Nestler EJ, Bunney BS, Oxford University Press, Oxford, 1999, 39, 548-563). Furthermore, clinical data indicate that blockade of the 5-HT reuptake has beneficial effects in the treatment of acute stress disorder (Robert et al. J Burn Care Rehabil, 1999, 20, 250-258.) 5-HT reuptake inhibitors are also useful in the treatment of phobia, particularly social phobia/anxiety disorder. Thus, clinical studies have indicated a role of the central 5-HT system in the patophysiology of phobias (Potts et al. Int Clin Psychopharmacol, 1996, 11, Suppl 3, 43-48) and it is well accepted that 5-HT reuptake inhibitors are effective in treating social phobia/anxiety disorder (see e.g. van den Linden et al. Int Clin Psychopharmacol, 2000, 15, Suppl 2, 15-23).

5-HT reuptake inhibitors appear also effective in the treatment of impulse control disorders (Durst et al. CNS Drugs, 2001, 15, 185-195; Hollander et al. Psychiatr Clin North Am, 2000, 23, 629-642; Christenson and Crow J Clin Psychiatry, 1996, Suppl 8, 42-47). In particular, 5-HT reuptake inhibition may reduce aggression, probably due to positive effects on the serotonergic dysfunction that is implicated in aggressive behaviour directed towards oneself or others (for review see Walsh & Dinan Acta Psychiatr Scand, 2001, 104, 84-91).

Both clinical and preclinical studies indicate that the central 5-HT system is involved in cognitive functions. For example, drug-induced destruction of 5-HT terminals, as evident by a reduction in 5-HT reuptake sites, is associated with impaired memory in both animals and humans (Morgan Psychopharmacology, 1999, 141, 30-36). It has also been shown that blockade of the 5-HT reuptake improves cognitive function in elderly depressed patients (Meltzer et al. Neuropsychopharmacology, 1998, 18, 407-430). Finally, treatment with agents that increase serotonergic neurotransmission has been reported to ameliorate cognitive deficits in schizophrenic patients (Sumiyoshi et al. Am J Psychiatry, 2001, 158, 1722-1725). These findings collectively suggest that 5-HT reuptake inhibitors may be effective in the treatment of cognitive disorders.

It has previously been described that 5-HT reuptake inhibitors are effective in the treatment of premenstrual syndrom (see e.g. Eriksson et al. Neuropsychopharmacology, 1995, 12, 167-176). Several findings support that serotonergic mechanisms are involved in the discriminative, reinforcing and subjective effects of drugs of abuse (see e.g. Walsh and Cunningham Psychopharmacology, 1997, 130,41-58). Thus, studies in humans have shown that blockade of the 5-HT reuptake attenuates the subjective effects of psychomotor stimulants such as cocaine (Walsh et al. J Clin Psychopharmacology, 1994, 14, 396-407). 5-HT reuptake inhibitors may also be useful in treatment of alcohol abuse (see Sellers et al. J Clin Psychiatiy, 1991, 52, 49-54). Therefore, 5-HT reuptake inhibitors may be beneficial in the treatment of drug abuse.

5-HT reuptake inhibitors have been demonstrated to be effective in the treatment of both bulimia nervosa as well as in anorexia nervosa (see Kaye et al. Biol Psychiatry, 1998, 44, 825-838). Clinical studies have indicated that treatment with 5-HT reuptake inhibitors show superiority over placebo in reducing the frequency of binge eating episodes (Goldstein et al. Br J Psychiatiy, 1995, 166, 660-666). Moreover, published data suggest that 5-HT reuptake inhibitors improves outcome and prevents relapse in people with anorexia nervosa (Kaye et al. Biol Psychiatry, 1998, 44, 825-838). Thus, it seems clear that 5-HT reuptake inhibitors are useful in the pharmacotherapy of eating disorders including bulimia and anorexia.

Finally, clinical studies have indicated a beneficial role of 5-HT reuptake inhibitors in pharmacological intervention of obesity. Thus, treatment with 5-HT reuptake inhibitors has been reported to be effective in inducing significant weight loss in both obese males and females (Ricca et al. J Endocrinol Invest, 1996, 19, 727-733; Lawton et al. Obes Res, 1995, 3, 345-356).

Compounds with combined effects at the 5-HT transporter and the dopamine D₄ receptor have the further benefit of improved effect on depressive and negative symptoms in schizophrenic patients.

WO 98/28293 describes a series of substituted indane or dihydroindole compounds having effect at dopamine D₄ receptors. The compounds described are considered useful for the treatment of a range of psychiatric and neurological disorders, including the positive and negative symptoms of schizophrenia and other psychoses. This application contains a disclosure of the racemate of 3-[l-[2-(2,3-dihydro-lH-indol-3- yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole as the oxalate salt and the (+) and (-) form of a closely related compound having an acetyl group instead of hydrogen in position 1 of the 2,3 -dihydro-indole.

It has now been found that S-(+)-3-[l-[2-(2,3-dihydro-lH-indol-3-yl)ethyl]-3,6- dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole having the formula

and pharmaceutically acceptable salts thereof have potent 5-ΗT reuptake inhibiting effect in addition to effect at the dopamine D₄ receptor.

It has also been found that this compound has more optimal properties for use as a pharmaceutical than the S-enantiomer of the corresponding compound having an acetyl group in position 1 of the 2,3-dihydro-indole (i.e the above mentioned (+)-enantiomer). For example, the half-life for the compound in humans appears to be longer and the volume of distribution in humans appears to be smaller than the half life and volume of distribution of the corresponding S-enantiomer having an acetyl group in position 1 of the 2,3-dihydro-indole. These findings indicate a better stability of the compound of the present invention in the human body. Further, the compound of the invention is a metabolite of the corresponding S-enantiomer having an acetyl group in position 1 of the 2,3-dihydro-indole in humans and it may thus be more convenient to use the compound of the invention as a pharmaceutical.

In vitro studies show that the compound of the invention is more potent than the corresponding racemate and the corresponding S-enantiomer having an acetyl group in position 1 of the 2,3-dihydro-indole, at the dopamine D₄ receptor and the 5-HT transporter. Furthermore, preliminary studies indicate that the compound is a safe drug with few side effects.

Summary of the Invention

Accordingly, the present invention relates to the compound S-(+)-3-[l-[2-(2,3-dihydro- lH-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole having the formula

or a pharmaceutically acceptable salt thereof and the use of this compound for the treatment diseases and disorders responsive to 5-ΗT reuptake inhibition.

The compound may also be used for the treatment of diseases or disorders responsive to dopamine D₄ receptor antagonism.

Diseases and disorders responsive to inhibition of 5-HT reuptake are depression, anxiety disorders and other affective disorders, including generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder or social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders including aggression and drug abuse.

Diseases or disorders responsive to dopamine D₄ receptor antagonists are psychoses, positive and negative symptoms of schizophrenia, cognitive disorders, ADHD and dyskinesia resulting from treatment of Parkinson's disease with L-Dopa. In particular, the compound of the invention is considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects and in the treatment of depression.

Detailed Description of the Invention

The racemate of the compound S-(+)-3-[l-[2-(2,3-dihydro-lH-indol-3-yl)ethyl]-3,6- dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole was first disclosed in WO 98/28293, an application covering compounds having affinity for the dopamine D receptor. Although it is indicated that some of the compounds disclosed in WO 98/28293 have effect at 5-ΗT_1A and 5-HT₂ receptors and/or have 5-HT reuptake inhibiting effect, the application is silent as regards the effect of 3-[l-[2-(2,3-dihydro-lH-indol-3-yl)ethyl]- 3,6-dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole and its enantiomers at these receptors and the 5-ΗT transporter.

It has now surprisingly been found that the compound S-(+)-3-[l-[2-(2,3-dihydro-lH- indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole is a very potent 5- ΗT reuptake inhibitor. Thus, the present invention covers the use of this compound for the treatment of diseases or disorders responsive to 5-ΗT reuptake inhibition.

An additional advantage of the compound of the invention is that the free base exists in a crystalline form, which have some advantages with regard to formulation of a pharmaceutical composition containing the compound. For example, a crystalline base may be formulated both as an oral solid unit dosage form, e.g. a tablet and in a capsule containing the base in an organic or oily phase.

The compound of formula (I) may be prepared by reduction of the acid group of (+)-(l- tert-butoxycarbonyl-2,3-dihydro-lH-indol-3-yl)acetic acid and conversion of the hydroxy group of the resulting alcohol to a halogen group and thereafter reaction with 6-chloro-3-(3,6-dihydro-2H-pyridin-4-yl)-lH-indole to give the boc-protected analogue of the compound of formula (I). The compound of formula (I) may be obtained by deprotection of the Boc-analogue by the use of trifluoro acetic acid. The compounds (+)-(l-tert-butoxycarbonyl-2,3-dihydro-lH-indol-3-yl)acetic acid and 6-chloro-3-(3,6- dihydro-2H-pyridin-4-yl)-lH-indole may be prepared as described in WO 98/28293.

Suitable salts of the compound of the invention may suitable be prepared by reacting the compound with either the calculated amount of an organic or inorganic acid in a water miscible solvent, with subsequent isolation of the salt by concentration and cooling, or with an excess of an organic or inorganic acid in a water immiscible solvent, with the salt separating spontaneously.

Pharmacological Testing

The compound S-(+)-3-[l-[2-(2,3-dihydro-lH-indol-3-yl)ethyl]-3,6-dihydro-2H- pyridin-4-yl]-6-chloro-lH-indole has been tested in a well-recognised and reliable test for measuring 5-ΗT reuptake inhibition and dopamine D receptor affinity.

Inhibition of [³H]YM-09151-2 binding to D₄ receptor

A D₄. expressing CHO cell line was generated in house using standard stable transfection techniques. Cells were harvested, homogenised and tested in 50 mM Tris containing 5 mM MgCl₂, 5 mM EDTA, 5 mM KCl, 1.5 mM CaCl₂, pH 7.4. Clozapine (10 μM) was used as non-specific displacer. The homogenate was incubated with test compound and 0.06 nM [³H]YM-09151-2 for 60 minutes at 25 °C. The assay was terminated by vacuum filtation on GF/B filters and counted in a scintillation counter (Wallac Trilux). The compound of the invention has a KI value of 1.3 nM in this test, whereas the corresponding racemate have a KI value of 4.5 nM and the corresponding S-(+)~enantiomer of a compound having an acetyl group in position 1 of the 2,3- dihydroindole has a KI value of 4.4 in this test.

Measurement of [³H]5-HT uptake into rat whole brain synaptosomes

Using this method, the ability of the drugs to inhibit the accumulation of [ H]-5-HT into whole rat brain synaptosomes is determined in vitro. The assay was performed as described by Hyttel, J. Psychopharmacology 1978, 60, 13. S-(+)-3-[l-[2-(2,3-dihydro-lH-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro- lH-indole have an IC₅₀ value of 5.3 nM in this test and the S-(+)-enantiomer having an acetyl group in position 1 of the 2,3-dihydroindole has a IC₅₀ value of 8.7 in this test.

Functional Dopamine D assay

The compound of the invention has also been tested in a functional assay described by Gazi et al. in Br. J. Pharmacol. 1999, 128, 613-629. In this test, the compound of the invention, the racemate and the S-(+)-enantiomer having an acetyl group in position 1 of the 2,3-dihydroindole were shown to be an antagonists at dopamine D₄ receptors.

Example

S-(+)-3-{l-[2φ2,3-Dihydro-lH-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6- chloro-lH-indole

S-(+)-(l-tert-Butoxycarbonyl-2,3-dihydro-lH-indol-3-yl)acetic acid (compound 33a, WO 98/28293) (7.4 g) was dissolved in tetrahydrofuran (100 mL) and subsequently added to a suspension of LiAlΗ₄ (3.0 g) in tetrahydrofuran (250 mL) at 5 °C. The reaction was quenched by sequential addition of water (6 mL), 15% NaOH (3 mL) and water (15 mL), and then added MgSO₄. The mixture was stirred at room temperature for 30 min, filtered and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 1:1) to give a colorless oil (5.4 g). A mixture of the crude oil (5.4 g), triethylamine (3.4 mL) and tetrahydrofuran (100 mL) was cooled (5 °C) and subsequently added a solution of methanesulfonyl chloride (1.7 mL) in tetrahydrofuran (50 mL) at 5-10 °C. The resulting mixture was stirred at room temperature for 30 min, filtered and concentrated in vacuo. The residue was dissolved in acetone (100 mL), added LiBr (8.9 g) and boiled under reflux for 2 h. The mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography (heptane/ethyl acetate 4:1) to give a colorless oil (5.9 g). The crude oil (4.0 g) was then dissolved in butanone (100 mL) and subsequently added drop wise to a mixture of 6- chloro-3-(3,6-dihydro-2H-pyridin-4-yl)-lH-indole (3.4 g) and TEA (8.6 mL) in butanone (300 mL). The resulting mixture was boiled under reflux for 12 h, concentrated in vacuo and purified by flash chromatography (ethyl acetate/ethanol/triethylamine 20:2:1) to give a crude amorphous product (3.9 g). The crude product was dissolved in a mixture of dichloromethane (40 mL) / tetrahydrofuran (25 mL) and cooled (5 °C) and subsequently added trifluoro acetic acid (30 mL). The mixture was stirred at room temperature for 16 h and then poured onto an ice/water mixture. The aqueous phase was made alkaline with aqueous ammonia and extracted with ethyl acetate. The combined organic phase was washed with brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/ethanol/triethylamine 100:4:4) to give crude target product that was crystallized from ethyl acetate and subsequent ethanol to give pure target product (0.5 g). Analysis: enantiomeric excess > 98.0 %; [α]_D = +58.1 ° (c = 0.21, methanol); mp 166-169 °C; 1H NMR (DMSO- 6) δ 1.60-1.70 (m, 1H); 1.90-2.05 (m, 1H); 2.40-2.55 (m, 4 H); 2.60- 2.70 (m, 2H); 3.05-3.15 (m, 3H); 3.15-3.25 (m, 1H); 3.55 (t, 1H); 5.40 (s, 1H); 6.10 (s, 1H); 6.50 (d, 1H); 6.55 (t, 1H); 6.90 (t, 1H); 7.00-7.05 (m, 2H); 7.40-7.45 (m, 2H); 7.80 (d, 1H); 11.25 (s, lH).

Formulation

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.

Thus, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or fillers and diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants, diluents or fillers comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Alternatively, capsules containing the compound of the invention in an organic and/or oily phase may be used.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

The daily dose of the compound of the invention may depend on the disease or disorder to be treated. A suitable daily dose is 0.1-500 mg, more suitable 1-150 mg and more suitable 5-100 mg, even more suitable 10-50 mg, an still more suitable 20-30 mg, depending on the condition to be treated.

Claims

Patent Claims

1. The compound S-(+)-3-[l-[2-(2,3-dihydro-lH-indol-3-yl)ethyl]-3,6-dihydro-2H- pyridin-4-yl]-6-chloro-lH-indole having the formula

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein the compound is S-(+)-3-[l-[2-(2,3- dihydro-lH-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro-lH-indole in the form of the crystalline free base.

3. A pharmaceutical composition comprising a compound according to any of claims 1-2 together with pharmaceutically acceptable carriers, fillers or diluents.

4. The use of the compound of any of claims 1-2 for the preparation of a pharmaceutical composition for the treatment diseases and disorders responsive dopamine D₄ receptor antagonism.

5. The use of the compound of any of claims 1-2 for the preparation of a pharmaceutical composition for the treatment diseases and disorders responsive to 5-ΗT reuptake inhibition.

6. The use according to claim 4 wherein diseases or disorders responsive to dopamine D₄ antagonism is psychoses, positive and negative symptoms of schizophrenia, cognitive disorders, ADHD and dyskinesia resulting from treatment of Parkinson's disease with L-Dopa.

7. The use according to claim 6 wherein the disease or disorder responsive to dopamine D₄ antagonism is psychosis and the positive and negative symptoms of schizophrenia.

8. The use according to claim 5 wherein the diseases or disorders responsive to 5-

HT reuptake inhibition is selected from depression, anxiety disorders and other affective disorders, including generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder or social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders including aggression and drug abuse.

9. The use according to claim 8 wherein the diseases or disorders responsive to 5-HT reuptake inliibition is depression.

10. A method for the treatment of diseases or disorders responsive to dopamine D₄ antagonism comprising administering a compound according to claim 1 or a pharmaceutically acceptable salts thereof to an individual in need thereof.

11. A method for the treatment of diseases or disorders responsive to 5-HT reuptake inhibition comprising administering a compound according to claim 1 or a pharmaceutically acceptable salts thereof to an individual in need thereof.

12. The method according to claim 10 wherein the diseases or disorders responsive to dopamine D₄ ligands are psychoses, positive and negative symptoms of schizophrema, cognitive disorders, ADHD and dyskinesia resulting from treatment of Parkinson's disease with L-Dopa.

13. The method according to claim 12 wherein the diseases or disorders responsive to dopamine D₄ ligands are psychoses and positive and negative symptoms of schizophrenia.

14. The method according to claim 11 wherein the diseases or disorders responsive to 5-HT reuptake inhibition is selected from depression, anxiety disorders and other affective disorders, including generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder or social anxiety disorder, eating disorders such as bulimia, anorexia and obesity, phobias, dysthymia, premenstrual syndrome, cognitive disorders, impulse control disorders including aggression and drug abuse.

15. The method according to claim 14 wherein the disease or disorder responsive to 5- HT reuptake inhibition is depression.