WO2004020437A1 - S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole et sels d'addition d'acide de ce dernier - Google Patents

S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole et sels d'addition d'acide de ce dernier Download PDF

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Publication number
WO2004020437A1
WO2004020437A1 PCT/DK2003/000564 DK0300564W WO2004020437A1 WO 2004020437 A1 WO2004020437 A1 WO 2004020437A1 DK 0300564 W DK0300564 W DK 0300564W WO 2004020437 A1 WO2004020437 A1 WO 2004020437A1
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WO
WIPO (PCT)
Prior art keywords
disorders
dihydro
diseases
compound
disorder
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PCT/DK2003/000564
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English (en)
Inventor
Benny Bang-Andersen
Klaus Peter Hertel
Pernille Gundorf Drewes
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H. Lundbeck A/S
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Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to AU2003257407A priority Critical patent/AU2003257407A1/en
Publication of WO2004020437A1 publication Critical patent/WO2004020437A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • 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- ⁇ T reuptake inhibition and/or diseases responsive to dopamine D 4 receptor antagonism.
  • the present invention relates to a compound which has antagonistic effect at dopamine D 4 receptors and 5-HT reuptake inhibiting effect.
  • 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).
  • 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).
  • 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).
  • 5-HT reuptake inhibitors are effective in the treatment of premenstrual syndrom (see e.g. Eriksson et al. Neuropsychopharmacology, 1995, 12, 167-176).
  • 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.
  • WO 98/28293 describes a series of substituted indane or dihydroindole compounds having effect at dopamine D 4 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.
  • 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).
  • 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.
  • 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.
  • 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
  • the compound may also be used for the treatment of diseases or disorders responsive to dopamine D 4 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 D 4 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.
  • 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.
  • 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- ⁇ T reuptake inhibitor.
  • the present invention covers the use of this compound for the treatment of diseases or disorders responsive to 5- ⁇ T reuptake inhibition.
  • 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.
  • 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.
  • a D 4 . 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 MgCl 2 , 5 mM EDTA, 5 mM KCl, 1.5 mM CaCl 2 , pH 7.4. Clozapine (10 ⁇ M) was used as non-specific displacer. The homogenate was incubated with test compound and 0.06 nM [ 3 H]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.
  • 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.
  • 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 D 4 receptors.
  • 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 pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
  • 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.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le composé S-(+)-3-[1-[2-(2,3-dihydro-1H-indol-3-yl)éthyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro-1H-indole de formule (I) ou un sel de celui-ci, acceptable au plan pharmaceutique, et son utilisation pour la préparation d'une composition pharmaceutique pour le traitement de maladies et de troubles sensibles à l'inhibition de la réabsorption de 5-HT et/ou de maladies ou de troubles sensibles à l'antagonisme du récepteur D4 de la dopamine.
PCT/DK2003/000564 2002-08-29 2003-08-27 S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole et sels d'addition d'acide de ce dernier WO2004020437A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003257407A AU2003257407A1 (en) 2002-08-29 2003-08-27 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

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US40753602P 2002-08-29 2002-08-29
US60/407,536 2002-08-29
DKPA200201272 2002-08-29
DKPA200201272 2002-08-29

Publications (1)

Publication Number Publication Date
WO2004020437A1 true WO2004020437A1 (fr) 2004-03-11

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PCT/DK2003/000564 WO2004020437A1 (fr) 2002-08-29 2003-08-27 S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole et sels d'addition d'acide de ce dernier

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AU (1) AU2003257407A1 (fr)
WO (1) WO2004020437A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005108388A1 (fr) * 2004-05-11 2005-11-17 Egis Gyógyszergyár Nyrt. Derives pyridine d'alkyl oxindoles utiles en tant qu'agents actifs se liant au recepteur 5-ht7
WO2006061373A2 (fr) * 2004-12-07 2006-06-15 Solvay Pharmaceuticals B.V. Indoles de tetrahydropyridine-4-yle comportant une combinaison de sites a affinite avec des recepteurs de dopamine d2 et inhibant la reabsorption de la serotonine
US7371769B2 (en) 2004-12-07 2008-05-13 Solvay Pharmaceuticals B.V. Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites
US8101619B2 (en) 2004-12-08 2012-01-24 Solvay Pharmaceuticals B.V. Phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028293A1 (fr) * 1996-12-20 1998-07-02 H.Lundbeck A/S Derives d'indane ou de dihydroindole
WO1999067237A1 (fr) * 1998-06-19 1999-12-29 H. Lundbeck A/S Derives de 4, 5, 6, et 7-indole ou d'indoline, leur preparation, et leur utilisation
WO2001096328A1 (fr) * 2000-06-14 2001-12-20 H. Lundbeck A/S Derives indoliques utilises dans le traitement de troubles du systeme nerveux central (snc)
WO2002000645A1 (fr) * 2000-06-29 2002-01-03 H. Lundbeck A/S Derives indoliques utiles pour le traitement des troubles du systeme nerveux central

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028293A1 (fr) * 1996-12-20 1998-07-02 H.Lundbeck A/S Derives d'indane ou de dihydroindole
WO1999067237A1 (fr) * 1998-06-19 1999-12-29 H. Lundbeck A/S Derives de 4, 5, 6, et 7-indole ou d'indoline, leur preparation, et leur utilisation
WO2001096328A1 (fr) * 2000-06-14 2001-12-20 H. Lundbeck A/S Derives indoliques utilises dans le traitement de troubles du systeme nerveux central (snc)
WO2002000645A1 (fr) * 2000-06-29 2002-01-03 H. Lundbeck A/S Derives indoliques utiles pour le traitement des troubles du systeme nerveux central

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005108388A1 (fr) * 2004-05-11 2005-11-17 Egis Gyógyszergyár Nyrt. Derives pyridine d'alkyl oxindoles utiles en tant qu'agents actifs se liant au recepteur 5-ht7
JP2007537225A (ja) * 2004-05-11 2007-12-20 エギシュ ヂョヂセルヂャール エンニュ・エル・テー ５−ｈｔ７活性剤としてのアルキルオキシインドールのピリジン誘導体
EA010154B1 (ru) * 2004-05-11 2008-06-30 Эгиш Дьёдьсердьяр Нирт. Пиридиновые производные алкилоксиндолов в качестве агентов, активных в отношении рецептора 5-нт7
WO2006061373A2 (fr) * 2004-12-07 2006-06-15 Solvay Pharmaceuticals B.V. Indoles de tetrahydropyridine-4-yle comportant une combinaison de sites a affinite avec des recepteurs de dopamine d2 et inhibant la reabsorption de la serotonine
WO2006061373A3 (fr) * 2004-12-07 2006-09-21 Solvay Pharm Bv Indoles de tetrahydropyridine-4-yle comportant une combinaison de sites a affinite avec des recepteurs de dopamine d2 et inhibant la reabsorption de la serotonine
US7371769B2 (en) 2004-12-07 2008-05-13 Solvay Pharmaceuticals B.V. Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites
US8101619B2 (en) 2004-12-08 2012-01-24 Solvay Pharmaceuticals B.V. Phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof

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