WO2006034788A1

WO2006034788A1 - Combinations of n-(indolecarbonyl-)piperazine derivatives and serotonin reuptake inhibitors

Info

Publication number: WO2006034788A1
Application number: PCT/EP2005/010024
Authority: WO
Inventors: Gerd Bartoszyk
Original assignee: Merck Patent Gmbh
Priority date: 2004-09-28
Filing date: 2005-09-16
Publication date: 2006-04-06
Also published as: TW200626129A; PE20060463A1; AR052770A1

Abstract

The invention relates to combinations of N-(Indolecarbonyl-)piperazine derivatives and Serotonin Reuptake Inhibitors and their use for the preparation of a medicament for the treatment of depression.

Description

Combinations of N-(lndolecarbonyl-)piperazine derivatives and Serotonin Reuptake Inhibitors

The invention relates to combinations of N-(lndolecarbonyl-)piperazine derivatives and Serotonin Reuptake Inhibitors and their use for the preparation of a medicament for the treatment of depression.

Background of the invention

Novel N-(indolecarbonyl)piperazine derivatives and processes for their preparation are disclosed in EP 1 198 453 B1. While being well tolerated, the substances exhibit, inter alia, effects on the central nervous system and have valuable pharmacological properties. They have strong affinity to 5-HT_2A receptors and have 5-HT2A receptor-antagonistic properties. A number of medical uses of these derivatives, e.g. sleep disorders and schizophrenia, are disclosed in EP 1 198 453 B1. Further medical uses are described in WO 03/45392 and WO 04/32932.

The present invention had the object of finding further valuable pharma¬ ceutical uses for the above-mentioned N-(indolecarbonyl)piperazine deri¬ vatives.

It is widely accepted that serotonin neurotransmission plays a pivotal role in pathogenesis of depression and the mechanism of action of antidepressant drugs (ADs). Serotonin reuptake inhibitors (SRIs) are one of the classes of ADs which antidepressant activity is believed to exert by an elevation of extracellular concentrations of 5-HT in limbic regions of the brain that can act on various postsynaptic receptors (1 ). Up to now, at least 14 different subtypes of 5-HT receptors have been identified (2) but the clarification of their physiological role has been hampered by multiplicity of their subtypes and the complexity of their pharmacology. It is still unclear which of them are relevant to the mechanism of antidepressant action but clinical and animal studies have implicated 5-HT_1A, 5-HTIB and 5-HΪ2 receptors as playing an essential role in the antidepressant response (3, 4, 5, 6). The precise mechanism of this activity is not yet established, this fact has been attributable, in part, to the unavailability of selective ligands.

It is well known, however, that all currently used ADs show therapeutic efficacy in a maximum 60-70% of depressive patients. Therefore, the need 10 exists to identify new ADs or new combinations of ADs with the aim to provide a therapy for a larger number of depressive patients.

Numerous SRIs are known in the art, such as citalopram, fluvoxamin, _j 5 paroxetine, venlafaxine, nefazodone, duloxetine or mirtazapine (7, 8). However, the most widely used SRI is fluoxetine. The preparation of fluoxetine hydrochloride (hereinafter referred to as FLU) is described, e.g., in DE-OS 25 00 110 or US 4,314,081.

20

When tested for an antidepressant activity in the "forced swimming test"

(Porsolt test) carried out with mice, the N-(lndolecarbonyl-)piperazine derivatives according to the present invention (like other previously studied 5-HT_2A antagonists, e.g. ketanserin, 9, 10) are devoid of any effect a the 25 tested doses. Fluoxetine at the tested doses shows only a moderate effect.

Surprisingly, it has now been found by the inventors of the present patent application that the co-administration of SRI and N-(lndolecarbonyl- 2_Q )piperazine derivatives induce marked antidepressant effects. Obviously, these two classes of substances interact in a synergistic way.

35 - A -

Figures

Fig. 1 : The effect of EMD 281014 (0.003, 0.03, 0.3 and 3 mg/kg) on the immobility time of mice in the forced swimming test after its acute (single) administration (A), 7-day treatment (B) or 14-day treatment (C). All treatments were by p.o. route. Duration of immobility was recorded during the last 4-min of a 6-min test. Values are expressed as mean ±SEM (n=10) (Dunnett's test).

Fig. 2: The effect of EMD 281014 (0.003 and 0.3 mg/kg) given in combination with fluoxetine (FLU, 5, 10 and 20 mg/kg) on the immobility time of mice in the forced swimming test after its acute (single) administration (A), 7-day treatment (B) or 14-day treatment (C). All treatments were by p.o. route. Duration of immobility was recorded during the last 4-min of a 6-min test. Values are expressed as mean ±SEM (n=10) (Dunnett's test).

Detailed description of the invention

As to the N-(lndolecarbonyl-)piperazine derivatives, use is preferably made here of the following compounds, most of which are characterised in greater detail in WO 01/07435 - where appropriate in the form of one of their salts:

(1H-lndol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, Hydrochlorid;

(3-Cyan-1H-indol-7-yl)-[4-(2,4-difluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

(3-Cyan-1H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid; (3-Cyan-1 H-indol-7-yl)-[4-(2-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochloric!;

(3-Aminocarbonyl-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]- methanon, Hydrochlorid;

4-Fluoro-7-(1-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanoyl)-1 H- indole-3-carboxylic acid amide;

1-{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-1-(1 H-indol-4-yl)-methanone;

(3-Cyan-1H-indol-4-yl)-[4-(2-fluorphenethyl)-piperazin-1-yl]-methanon, 10 Hydrochlorid;

(3-Cyan-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Methansulfonat;

(3-Cyan-1 H-indol-7-yl)-(4-phenethyl-piperazin-1 -yl)-methanon, _j r Hydrochlorid;

1 -[7-(1 -{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanoyl)-1 H-indol-3- yl]-ethanone;

4-Fluoro-7-(1-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanoyl)-1 H- indole-3-carbonitrile; 0

(2,3-Dimethyl-1 H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon;

(3-Cyan-1 H-indol-5-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

(1 H-lndol-5-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon; 5 1-{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-1-(1 H-indol-7-yl)-methanone;

(1 H-lndol-4-yl)-(4-phenethyl-piperazin-1-yl)-methanon, Hydrochlorid;

(1 H-lndol-7-yl)-(4-phenethyl-piperazin-1 -yl)-methanon, Hydrochlorid;

(1 H-lndol-4-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon, 2_Q Hydrochlorid;

(3-Formyl-1H-indol-7-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

(3-Formyl-1 H-indol-5-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

35

(3-Cyan-1H-lndol-7-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]- methanon, Hydrochlorid; 7-(1-{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanoyl)-1 H-indole-3- carbonitrile;

(1 H-lndol-7-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]-methanon,

Hydrochloric!;

(3-Cyan-1 H-indol-4-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

(1 H-lndol-6-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid; (3-Formyl-1 H-indol-6-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

(1 H-lndol-4-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]-methanon,

Hydrochlorid; 7-(1 -{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1 -yl}-methanoyl)-1 H-indole-3- carboxylic acid methylamide;

5-Fluoro-7-(1-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanoyl)-1 H- indole-3-carbonitrile;

1-{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-1-(1H-indol-6-yl)-methanone;

(3-Cyan-1 H-indol-6-yl)-[4-(4-fluorphenethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

2,2,2-Trifluoro-1-[7-(1-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}- methanoyl)-1 H-indol-3-yl]-ethanone; 1-(1 H-lndol-4-yl)-1-[4-(1-methyl-2-phenyl-ethyl)-piperazin-1-yl]-methanone;

7-[1 -(4-Phenethyl-piperazin-1 -yl)-methanoyl]-1 H-indole-3-carboxylic acid methylamide;

7-(1 -{4-[2-(4-Cyano-phenyl)-ethyl]-piperazin-1 -yl}-methanoyl)-1 H-indole-3- carbonitrile;

(6,7,8,9-Tetrahydro-5H-carbazol-3-yl)-(4-phenethyl-piperazin-1-yl)- methanon, Hydrochlorid;

(1 H-lndol-4-yl)-[4-(2,5-dichlor-thiophen-3-ylethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

7-(1 -{4-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1 -yl}-methanoyl)-1 H-indole-3- carbonitrile; (1H-lndol-6-yl)-[4-(5-chlor-thiophen-2-ylethyl)-piperazin-1-yl]-nnethanon,

Hydrochloric!;

7-{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-carbonyl}-1 H-indole-2,3-dion;

(3-Cyan-1 H-indol-7-yl)-[4-(naphth-2-ylethyl)-piperazin-1-yl]-methanon,

Hydrochlorid;

(1 H-lndol-6-yl)-[4-(thiophen-3-ylethyl)-piperazin-1-yl]-methanon;

(1H-lndol-6-yl)-[4-(2,5-dichlor-thiophen-3-ylethyl)-piperazin-1-yl]-methanon,

Hydrochlorid; 1-(1H-lndol-4-yl)-1-{4-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}- methanone;

2-Chloro-7-(1-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-methanoyl)-1 H- indole-3-carbonitrile; 7-(1 -{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1 -yl}-methanoyl)-1 H-indole-3- carboxylic acid amide.

For the purposes of the invention, particular preference is given to the use of (3-cyano-1 H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1 -yljmethanone and (3-aminocarbonyl-1 H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1 -ylj¬ methanone.

Very particular preference is given to (3-cyano-1 H-indol-7-yl)-[4-(4-fluoro- phenethyl)piperazin-1-yl]methanone, hereinafter referred to as EMD 281014. Its preparation is described in EP 1 198 453 B1 and EP 1 353 906 B1.

A preferred SRI is fluoxetine (FLU). The preparation of FLU hydrochloride is described, e.g., in DE-OS 25 00 110 or US 4,314,081. The forced swimming test according to Porsolt is carried out in the following manner:

Animals

The experiments are carried out on mice (male Albino-Swiss, 27-30 g), housed in groups (6 or 10 per cage, respectively) in a controlled environment at a temperature of 22±2 ⁰C under a 12- hour light/dark cycle (the light on at 7 a.m.). The animals have free access to food (standard laboratory pellets, LSM, Bacutil) and tap water. The studies are conducted between 8 a.m. and 3 p.m. Each group consists of 10 animals.

Substances EMD 281014 and fluoxetine hydrochloride (FLU) are suspended in a 1% water solution of Tween 80 and administered perorally (p.o.) with a stomach tube, in a volume of 10 ml/kg in mice.

Procedure

EMD 281014 (0.003, 0.03, 0.3 and 3 mg/kg), FLU (5, 10 and 20 mg/kg) and a combination of EMD 281014 (0.003 and 0.3 mg/kg) and FLU (5, 10 and 20 mg/kg) is administered to mice as single peroral injections, 2 h (FLU) and 1 h (EMD 281014) before the test, according to the following three experimental schedules: 1/ acute treatment;

2/ subchronic treatment - once daily for 7 days; 3/ subchronic treatment - once daily for 14 days.

Forced swimming (Porsolt's) test

The mice are dropped into glass beakers (2 I), filled with water (21-23 ⁰C) up to a height of 6 cm, 1 h after a single dose or the last injection

(subchronic repeated treatment) of the compound studied. The immobility time is assessed during the last 4 min of a 6-min test (11 ). Water in the beakers is changed for each mouse.

Statistical analysis

The results are expressed as the mean ± SEM (standard error of the mean) of 10 animals. The data are analysed by an ANOVA (analysis of variance) which - when significant - is followed by the Dunnett test for post- hoc comparisons.

Results

7-day treatment with EMD 281014, 0.003 mg/kg, slightly (by ca. 9%), but negligibly, decreases the immobility time of the mice (Figure 1B). EMD 281014 in other doses and experimental schedules is inactive (Figure 1A-

C).

It is generally accepted that statistically significant difference by about 20 % at least may be considered as functionally important, i.e. meaningful effect in Porsolt's test. From this point of view, the slight changes induced by

EMD 281014 after a 7-day treatment at 0.003 mg/kg (Figure 1B) can be recognized as negligible. Thus, EMD 281014 is devoid of any antidepressant activity in Porsolt's test.

FLU shows a moderate anti-immobility effect at the dose of 10 mg/kg after 7 days of treatment (by ca. 15%) (Figure 2B) and at the dose of 20 mg/kg after 14 days of treatment (by ca. 14%) (Figure 2C); in other experimental schedules FLU is inactive (Figure 2A-C).

Acute treatment with EMD 281014, 0.3 mg/kg and FLU, 10 mg/kg, induces a significant anti-immobility effect (by ca. 22%) (Figure 2A). EMD 281014 at doses of 0.003 and 0.3 mg/kg, co-administered with FLU, 10 mg/kg, for 7 days induces the decrease of immobility time, both by ca. 25% (the effect is not dose-dependent) (Figure 2B). A similar but weaker effect (by ca. 16%) is observed after joint treatment with FLU, 20 mg/kg, and EMD 281014, 0.003 mg/kg (Figure 2B), and after 14-day treatment with FLU, 10 mg/kg, and EMD 281014, 0.3 mg/kg (by ca. 20,8%) (Figure 2C).

It is evident that the N-(lndolecarbonyl-)piperazine derivatives according to the invention, as exemplified by EMD 281014, significantly enhance the antidepressant effects of SRIs, exemplified by FLU.

As another promising aspect of the present invention, the combination of SRIs with N-(lndolecarbonyl-)piperazine derivatives offers the possibility to reduce the daily dosing of SRIs, without affecting the overall therapeutic antidepressant effect. Thereby, common side effects of SRIs (e.g. 12, 13, 14), often requiring additional other medications, amongst them erectile dysfunction (e.g. 15, 16), weight loss or weight gain (e.g. 17, 18), serotonin syndrome consisting of disorientation, confusion, agitation, restlessness, and autonomic nervous system dysfunction (fever, shivering, diaphoresis, diarrhea) (19, 20), dermatological reactions (21, 22) including rush (23), or discontinuation syndrome (24, 25), can be diminished or avoided.

Therefore, the present invention relates to a mixture of compounds, comprising at least one N-(lndolecarbonyl-)piperazine derivative selected from a group consisting of

(a) (3-aminocarbonyl-1 H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1 - yl]methanone,

(b) (3-cyano-1 H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1 -yl]methanone, and at least one SRl, and stereoisomers, physiologically acceptable salts and solvates of each such compound.

Preferably, the N-(lndolecarbonyl-)piperazine derivative is (3-cyano-1 H- indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone and the SRI is citalopram, fluvoxamin, paroxetine, venlafaxine, nefazodone, duloxetine or mirtazapine, fluoxetine or mixtures thereof. An especially preferred SRI is fluoxetine. Moreover, the present invention relates to the use of the said compound mixture for the preparation of a medicament for the treatment of depression.

Thirdly, the invention relates to a pharmaceutical preparation comprising the said compound mixture according to the invention and optionally excipients and/or adjuvants and, optionally, further active ingredients.

The medicaments here can be converted into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or adju¬ vant and optionally in combination with one or more further active ingredi- ent(s).

In the depression therapy according to the invention, the compound mixture is generally administered analogously to known preparations, preferably in doses of between about 0.1 μg and 100 mg per compound, in particular between 1 μg and 10 mg, per compound and dosage unit. The daily dose per compound is preferably between about 1 μg and 100 mg/kg, in particular between 3 μg and 50 mg/kg, of body weight. However, the specific dose for each particular patient depends on a very wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, medicament combination and severity of the particular disease to which the therapy applies. Oral administration is preferred.

The compound mixture may also be employed together with other active ingredients, in particular other antidepressant drugs, in the treatment of depression. The pharmaceutical preparations according to the invention can be employed as medicaments in human and veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or Vaseline. Suitable for enteral adminis¬ tration are, in particular, tablets, coated tablets, capsules, syrups, juices, drops or suppositories, suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emul¬ sions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.

The preparations indicated may be sterilised and/or comprise adjuvants, such as lubricants, preservatives, stabilisers and/or wetting agents, emul- sifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or aroma substances. They can, if desired, also comprise one or more further active ingredients, for example one or more vitamins.

The examples below relate to pharmaceutical preparations:

Example A1 : Injection vials

A solution of 100 g of a mixture of active ingredients according to the invention and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredients. Example A2: Suppositories

20 g of a mixture of active ingredients according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredients.

Example A3: Solution

A solution is prepared from 1 g of a mixture of active ingredients according to the invention, 9.38 g of NaH₂PO₄ x 2 H₂O, 28.48 g of NaH₂PO₄ x 12 H₂O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradia¬ tion. This solution can be used in the form of eye drops.

Example A4: Ointment

500 mg of a mixture of active ingredients according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.

Example A5: Tablets

A mixture of 1 kg of a mixture of active ingredients according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredients.

Example A6: Coated tablets

Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, traga- canth and dye.

Example A7: Capsules

2 kg of a mixture of active ingredients according to the invention are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredients. Example A8: Ampoules

A solution of 1 kg of a mixture of active ingredients according to the invention in 60 I of bidistilled water is transferred into ampoules, lyophilised under aseptic conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredients.

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10. Yamada J, Sugimoto Y. Effects of 5-HT2 receptor antagonists on the anti-immobility effects of imipramine in the forced swimming test with mice. Eur J Pharmacol 2001 ; 427; 221-225.

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13. Spigset O. Adverse reactions of selective serotonin reuptake inhibitors: reports from a spontaneous reporting system. Drug Saf 1999; 20: 277-287. 14. Dording CM, Mischoulon D, Petersen TJ, Kornbluh R, Gordon J₁ Nierenberg AA, Rosenbaum JE, Fava M. The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists.

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Claims

Patent Claims

5 1. Compound mixture, comprising at least one N-(lndolecarbonyl-

)piperazine derivative selected from a group consisting of

(a) (3-aminocarbonyl-1 H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1 ■ yl]methanone,

(b) (3-cyano-1 H-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1 -yl]- methanone, and at least one compound selected from the SRI group of compounds, and/or stereoisomers, physiologically acceptable salts and solvates ¹⁵ of each such compound.

2. Compound mixture according to Claim 1 , wherein the N-

(lndolecarbonyl-)piperazine derivative is (3-cyano-1 H-indol-7-yl)-[4- 20 (4-fluorophenethyl)piperazin-1 -yl]methanone.

3. Compound mixture according to Claim 1 or 2, wherein the SRI is citalopram, fluvoxamin, paroxetine, venlafaxine, nefazodone, duloxetine or mirtazapine or fluoxetine.

25

4. Compound mixture according to Claim 3, wherein the SRI is fluoxetine.

i n

5. Use of a compound mixture according to Claim 1 , 2, 3 or 4, and stereoisomers, physiologically acceptable salts and solvates of each such compound for the preparation of a medicament for the treatment of depression.

35

6. Pharmaceutical preparation, comprising the compound mixture according to Claim 1 , 2, 3 or 4 and optionally excipients and/or adju¬ vants and, optionally, further active ingredients.