MXPA01002661A - Treatment of depression - Google Patents

Abstract

The compound 1'-[4-[1-(4-fluorophenyl)-1H- indole-3-yl]-1-butyl]- spiro[isobenzo-furan-1(3H, 4'-piperidine]is active in models predictive of antidepressant effects and is useful for the preparation of a medicament for the treatment of depression or diseases associated with depressive symptoms.

Description

DEPRESSION TREATMENT DESCRIPTIVE MEMORY Field of the invention The present invention relates to the use of the compound 1'- [4- [1- (4-fluorophenyl)] -lH-indol-3-yl] -1-butyl] spiro [isobenzofuran-1 (3H), 4'-piperidine] or a pharmaceutically acceptable salt thereof, for the preparation of medicaments for the treatment of depression.

BACKGROUND OF THE INVENTION International Patent Publication No. WO 92/22554 describes a series of ligands of sigma receptors considered useful for the treatment of a range of psychic and neurological disorders. The structure-activity relationship of these compounds has been investigated subsequently by Perregaard, J. and collaborators, J. Med. Chem., 1995, 38, 11, p.1998-2008. Among numerous other compounds, said patent publication describes the compound 1 '- [4- [1- (4-fluorophenyl) -1H-indol-3-yl] -1-butyl] -spiro [iso-benzofuran-1 (3H ), 4 'piperidine], which is the subject of the present invention. This compound was disclosed in Perregaard, J. et al., J. Med. Chem., 1995, 38, 11, p.1998-2008, as a potent and selective sigma ligand, in particular a sigma2 ligand. In addition, the anxiolytic potential of the compound was determined in the black / white screening test in rats, which is an animal predictive model for the effect in the treatment of generalized anxiety disorder. It was found to be active over a wide range of dosages. The results of other trials in generalized anxiety disorder models are reported in J. Pharmacol. Exp. Ther., 1997, 283, No. 2. The co-pending Danish patent applications numbers 1267/97, 0071/98 and 0501/98 refer to the compound's hydrochloride, the effect of the compound in the treatment of drug addiction. and other substances of abuse, and the use of the compound in the treatment of panic attacks, respectively. Evidence has been presented, from studies of the biology and function of sigma receptors, that ligands of sigma receptors may be useful in the treatment of a range of psychic and neurological disorders, including psychoses and movement disorders, such as dystonia and dyskinesia, and motor alterations associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, JM et al., Pharmacological Reviews, 1990, 42, 355). The known sigma receptor ligand rimcazole shows clinical effects in the treatment of psychosis (Snyder, SH, Largent, BL, J. Neuropsychiatry, 1989, 1, 7), and a group of ligands of sigma receptors have been described that present antialucinogenic activity in animal models (International Patent Publication No. WO 9103243). It has also been reported that ligands of sigma receptors are involved in the modulation of NMDA receptor-mediated events in the brain, and that they act as anti-squamic agents in in vivo tests (Rao, TS et al., Molecular Pharmacology, 1990, 37 , 978). In addition to ischemia, ligands of sigma receptors may also be useful in the treatment of other such NMDA receptor-mediated events, for example epilepsy and seizure. It has also been found that some ligands of sigma receptors have anti-amnestic effects in an animal model (Early et al., Brain Research, 1991, 546, 281-286). It has been shown that sigma binders influence central acetylcholine levels in animal models (Matsuno et al., Brain Research, 1992, 575, 315-1319); Junien et al., Eur. J. Pharm. , 1991, 200, 343-345) and, therefore, may have potential in the treatment of senile dementia of the Alzheimer's type. Finally, it has been disclosed that some guanidine derivatives having sigma receptor activity are useful as anxiolytics (International Patent Publication No. WO 9014067), and some ligands of sigma receptors have been found to bind to the cocaine binding site. in the dopamine transporter, and it has been found that others inhibit dopamine uptake (Izen asser, S. et al., Eur. J. Pharmacol., 243, 201-205, and Woodward, JJ and Harms, J., Eur. J. Pharmacol. , 210, 265-270). Depression is now well recognized as an extremely damaging and disabling disorder and has a widespread frequency. It is often associated with suicidal behavior and the people who suffer from it have a very low quality of life. Selective serotonin reuptake inhibitors are now first-line treatments for depression disorders. However, they are only effective after 3-4 weeks of treatment and are not effective in all patients. Accordingly, there is a need for alternative therapies useful in the treatment of disorders associated with depression.

It has now been discovered, surprisingly, that the compound of the invention has a beneficial effect in the treatment of depression.

Description of the invention According to the present invention, a novel use of 1 '- [4- [1- (4-fluorophenyl) -lH-indol-3-yl] -1-butyl] -spiro [isobenzofuran- 1 (3H), 4'-piperidine], for the preparation of a medicament useful in the treatment of depression. The term "depression" covers all diseases and conditions that are associated with depression, including those classified in the IDC-10 and DSM-IV rating scales. These diseases or disorders comprise major depression, dysthymic disorder, depressive episodes of bipolar disorders and depressive episodes associated with other mood disorders, including seasonal mood disorders and mood disorders due to a general medical condition and mood disorders induced by substances. The term "depression treatment" encompasses the relief of symptoms, and the cure or prevention of the disease or condition.

According to the invention, the compound./ l '- [4- [l- (-fluorophenyl) -lH-indol-3-yl] -1-butyl] -spiro [iso-bensofuran-1] (3H), 4'-piperidine] can be used as the base of the compound or as a pharmaceutically acceptable acid addition salt thereof, or as an anhydrate or hydrate of said salt. The salts of the compound used in the invention are salts formed with non-toxic organic or inorganic acids. Examples of the organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic acids. , citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulphonic and theophylline acetic, and also the 8-haloteofilines, for example 8-bromo-theophylline. Examples of inorganic salts are those with hydrochloric, brohydric, sulfuric, sulfamic, phosphoric and nitric acids. Preferably, the compound is used as the base, the hydrochloride or the fumarate. It has been found that chronic administration of the compounds used in the method of the invention causes a reversal of induced anhedonia for mild chronic stress in rats in the mild chronic stress (CMS) model. The CMS model is a well-recognized model of depression (Willner, Paul, Psychopharmacology, 1997, 134, 319-329).

According to the invention, the compound l '- [4- [l- (4-fluorophenyl) -lH-indol-3-yl] -1-butyl] -spiro [isobenzofuran-1] (3H), 4'-piperidine], or a pharmaceutically acceptable salt thereof, can be administered in any suitable manner, such as orally or parenterally, and can be presented in any suitable form for such administration, for example in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. Preferably, and in accordance with the purpose of the present invention, the compound of the invention is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule, or in the form of a suspension, solution or dispersion for injection. Methods for the manufacture of solid pharmaceutical preparations are well known in the art. Thus, tablets can be prepared by mixing the active ingredients with common adjuvants and / or diluents, and subsequently compressing the mixture in a convenient tabletting machine. Examples of adjuvants or diluents comprise: corn starch, lactose, talc, magnesium stearate, gelatin, gums and the like. Other adjuvants or additives, such as colorants, flavors, preservatives, etc., may also be used, so long as they are compatible with the active ingredients. The compound of the invention is more conveniently administered in oral form in unit dosage forms, such as tablets or capsules containing the active ingredient in an amount of from about 10 μg / kg to 10 mg / kg of body weight, preferably from 25 μg / day / kg to 2.0 mg / day / kg, more preferably from 0.1 mg / day / kg to 1.0 mg / day / kg of body weight. The fumarate of 1 '- [4- [1- (4-fluorophenyl) -lH-indol-3-yl] -1-butyl] -spiro [isotenzofuran-1 (3H), 4'-piperidine] can be prepared as described in Perregaard, J. et al., J. Med. Chem., 1995, 38, 11, p. 1998-2008 (compound 14f), and the base and other pharmaceutically acceptable salts can be obtained from the same pair standard procedures. Thus, the acid addition salts according to the invention can be obtained by treatment of l '- [4- [l- (4-fluorophenyl) -lH-indol-3-yl] -1-butyl] -spiro [isobenzofuran] (3H), 4'-piperidine] with the acid in an inert solvent, followed by precipitation, isolation and optionally recrystallization by known methods and, if desired, micronization of the crystalline product by wet or dry milling or other convenient process, or preparation of particles from an emulsification process in solvent. The precipitation of the salt is preferably carried out in an inert solvent, for example a polar inert solvent such as an alcohol (for example ethanol, 2-propanol and n-propanol).

Pharmacological tests The model of anhedonia induced by chronic stress in mild rats. The effect of the compound of the invention in the treatment of depression was analyzed in the model of anhedonia induced by mild chronic stress in rats. This model is based on the observation that mild chronic stress causes a gradual decrease in sensitivity to rewards, for example sucrose consumption, and that this decrease is reversed in a dose-dependent manner by chronic treatment with antidepressants. The method has been described above, and more information regarding the test is found in Willner, Paul, Psychopharmacology, 1997, 134, 319-329.

Experimental procedure Wistar male rats were trained to consume a 1% sucrose solution through nine 1-hour baseline tests, in which sucrose was presented in the home cage after 14 hours of water and feed deprivation. A group of animals underwent a mild chronic stress procedure for a period of 9 consecutive weeks. Each week of the stress regime consisted of two periods of deprivation of water and food, two periods of inclination of the cage in 45 large, two periods of intermittent lighting (light on and off every 2 hours), two periods of dirty cage (bed of sawdust with 250 ml of water), two periods of paired accommodation, two periods of low strobe lighting (150 flashes / min) and two periods without stress. All periods of stress were 12-14 5 hours long and continued continuously, day and night. The control animals were housed in separate rooms with freely available food and water, except for a period of 14 hours before each sucrose test, and had no contact with the stressed animals. 10 The stressed animals and also the control animals were divided into equal subgroups, and during the subsequent five weeks they received daily intraperitoneal injections (1 ml / kg of body weight) of vehicle (minimum amount of propylene glycol and methane acid).

Sulphonic (1: 1) diluted with water) or test compound. The sucrose tests were carried out 24 hours after the last drug treatment.

Results 20 In the final baseline test, all animals consumed about 16 g of sucrose solution. After three weeks, the intake remained at 14 g in the control group, while it fell to around 9.5 g in the stressed animals. These levels persisted for the rest of the 9-week period, resulting in a significant group effect. The compound of the invention did not significantly affect the consumption of sucrose in the control animals. The compound of the invention was able to reverse the deficit of sucrose intake induced by mild chronic stress, at a dose of 1.0 mg / kg. In stressed animals treated with 1.0 mg / kg, the intake increased significantly from the initial scores after three, four and five weeks, and at the end of the treatment period, the intake of sucrose did not differ significantly from that of the controls treated with vehicle (p = 0.130), and was significantly higher than that of stressed animals treated with vehicle (p = 0.003). Citalopram, a well-known serotonin reuptake inhibitor, was included in the tests for comparison purposes. Citalopram (10 mg / kg) did not affect sucrose consumption in the control animals, however it was able to reverse the sucrose deficit induced by mild chronic stress. Intake in stressed animals increased significantly from the initial scores after two weeks, and remained thereafter. At the end of the treatment period, the intake of sucrose did not differ significantly from that of the controls treated with vehicle ^^ - ^^ ¿&^ ^ ^^ - -? IHfa, ^ L (p = 0.177), and was significantly higher than that of stressed animals treated with vehicle (p = 0.001).

Claims (6)

1. Use of l '- [4- [l- (4-fluorophenyl) -lH-indol-3-yl] -1-butyl] -spiro [isobenzofuran-1 (3H), 4'-piperidine] or a pharmaceutically acceptable salt of the same, characterized in that it serves for the preparation of a medicament for the treatment of depression.

2. The use according to claim 1, characterized in that the compound is used in the form of the base, the fumarate or the hydrochloride.

3. The use according to claim 1 or 2, characterized in that the medicament serves for administration as a unit dose.

4. The use according to claim 3, characterized in that the unit dose contains the active ingredient in an amount of about 10 mg / kg to 10 mg / kg of body weight, preferably 25 mg / day / kg to 2. , 0 mg / day / kg, more preferably 0.1 mg / day / kg to 1.0 mg / day / kg body weight.

5. The use according to claim 4, characterized in that the unit dose contains the active ingredient in an amount of 0.1 mg / day / kg to 2.0 mg / day / kg of body weight.

6. Use according to any of claims 1 to 5, characterized in that the medicament serves for the treatment of major depression, dysthymic disorder, depressive episodes of bipolar disorders or depressive episodes associated with other mood disorders. REJJMEN Compound 1 '- [4- [1- (4-fluorophenyl) -lH-indol-3-yl] -1-butyl] -spiro [isobenzofuran-1 (3H), 4'-piperidine] is active in predictive models of antidepressant effects, and is useful for the preparation of a medication for the treatment of depression or diseases associated with depressive symptoms.