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EP1076658A1 - Agents serotoninergiques - Google Patents

Agents serotoninergiques

Info

Publication number
EP1076658A1
EP1076658A1 EP99920078A EP99920078A EP1076658A1 EP 1076658 A1 EP1076658 A1 EP 1076658A1 EP 99920078 A EP99920078 A EP 99920078A EP 99920078 A EP99920078 A EP 99920078A EP 1076658 A1 EP1076658 A1 EP 1076658A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
compound
acceptable salt
alkyl
indol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99920078A
Other languages
German (de)
English (en)
Inventor
Michael Gerard Kelly
Young Hee Kang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
American Home Products Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of EP1076658A1 publication Critical patent/EP1076658A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • This invention relates to novel indolyl derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy.
  • the novel compounds are useful for the treatment of central nervous system disorders, particularly depression, by virtue of their ability to inhibit the uptake of serotonin.
  • Depression is a psychiatric condition thought to be associated with decreased serotonin release. Most antidepressant agents potentiate the effects of serotonin by blocking the termination of its activity through re-uptake into nerve terminals.
  • X is O, NH, or S
  • A, B, D, E and F are C, N, O or S.
  • U.S. Pat. No. 5,639,772 discloses 3-amino-5-aryl- and 5- heteroarylchromans which are useful in the treatment of 5-hydroxytryptamine-mediated disorders of the central nervous system.
  • R is selected from H, -OH, -OR 3 , F, CI, Br, or I;
  • R 3 and R 4 are independently selected from H, C, to C 6 alkyl or (CH 2 )nAr, the alkyl and Ar groups being optionally substituted by from 1 to 3 groups selected from NO 2 , F, CI, Br, I, -OH, -OR 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -CF 3 , -CN, -S-C,-C 6 alkyl, or -NH 2 ; n is an integer selected from 0, 1 or 2;
  • X is CH or CH 2 ;
  • Ar is monocyclic or bicyclic aryl or heteroaryl moieties, each optionally substituted by from one to three groups selected from -NO 2 , F, CI, Br, I, -OH, -OR 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -CF 3 , -CN, -S-C,-C 6 alkyl, or -NH 2 ; or a pharmaceutically acceptable salt thereof.
  • the preferred aryl and heteroaryl groups referred to herein as Ar include phenyl, benzyl, pyridinyl, pyrimindinyl, pyrazinyl, furyl, thienyl, pyrrolyl, indolyl, napthyl, benzodioxanyl, or quinolyl.
  • Ar groups are phenyl, pyridinyl, furyl and napthyl moieties, optionally substituted.
  • the pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable inorganic acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, furmaric, acetic, lactic or methanesulfonic acid. - 4
  • Compounds of the present invention may be prepared using conventional methods.
  • the appropriately substituted indole (A) can be coupled with a chloromethylamide (B) using a base such as diisopropylethylamine.
  • the amide so produced can be used to form a pharmaceutically acceptable salt, or optionally may be reduced to the a ine using a hydride reducing agent such as lithium aluminium hydride.
  • Compounds of the present invention inhibit with very high affinity the binding of paroxetine to the serotonin transporter and, consequently, they are useful as antidepressant and anxiolytic agents and cognition enhancement agents for the treatment of central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, and related problems, as well as in being useful in cognition enhancement or in inhibition of depletion thereof.
  • compounds of the present invention may be used in conjunction with an agonist or antagonist of the serotonin- 1 receptor (5-HT1) to aid or enhance the compounds biological properties.
  • Such compositions are useful for the above mentioned 5-HT1- related disorders in addition to the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, obesity and migraine.
  • the present invention includes methods for treating each of these maladies, the methods comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more compounds herein, or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. Variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient.
  • the novel method of the invention for treating conditions related to or are affected by the reuptake of serotonin comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of this invention or a non- toxic, pharmaceutically acceptable addition salt thereof.
  • the compounds may be administered orally, rectally, parenterally, or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method of treatment and condition treated.
  • An effective dose of 0.01 - lOOOmg/Kg may be used for oral application, preferably 0.5 - 500 mg/Kg, and an effective amount of 0.1 - 100 mg/Kg may be used for parenteral application, preferably 0.5 - 50 mg/Kg.
  • the present invention also includes pharmaceutical compositions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • Applicable solid carriers or excipients can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or 7 -
  • liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the affinity of drugs for the serotonin transporter was determined by assessing the ability of agents to displace specifically bound 3H-paroxetine binding from rat cortical membranes. This procedure is a modification of that used by Cheetham et al., 1993 (Neuropharmacol. 32:737-743, 1993). Nonspecific binding was determined using fluoxetine. Using this assay, the following Ki's were determined for a series of standard serotonin uptake inhibitors. 3 H-Paroxetine Binding to Assess Affinity of Drugs for the Serotonin Transporter:
  • Pulverized potassium carbonate was added to a mixture of 4-(5-fluoro-lH- indol-3-ylmethyl)piperidine (0.58 g, 2.5 mmole) and 2-(2-chloroacetamido)pyridine (0.43 g, 2.5 mmole) in 50 ml of DMF.
  • the resulting solution was heated at 80 °C for 15 hours and the cooled mixture was partitioned between methylene chloride and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue was chromatographed over silica gel using ethyl acetate as eluant.
  • Lithium aluminum hydride (0.21 g, 5.5 mmole) in dry THF (50 ml) was placed in a three- necked flask under a nitrogen atmosphere.
  • 2-[4-(5-Fluoro-lH-indol-3- ylmethyl)-piperidin-l-yl]-N-pyridin-2-yl-acetamide ( 0.4 g, 1.1 mmole) was dissolved in 25 ml of dry THF, and the resulting solution was slowly introduced dropwise to the above stirred suspension at 0 °C. The mixture was then heated to a gentle reflux and stirred for 15 hours.
  • the title compound is produced by adding pulverized potassium carbonate to a mixture of 4-(5-fluoro-lH-indol-3-ylmethyl)piperidine (0.58 g, 2.5 mmole) and N- chloroacetyl-2,6-dimethylanaline (0.49 g, 2.5 mmole) in 50 ml of DMF. The resulting solution is then heated at 75 °C for 15 hours and the cooled mixture was partitioned between methylene chloride and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue is chromatographed over silica gel using ethyl acetate as eluant.
  • the title compound is produced by adding pulverized potassium carbonate to a mixture of 4-(2-methyl-5-fluoro-lH-indol-3-ylmethyl)piperidine (0.59 g, 2.5 mmole) and ⁇ -chloro-2-nitroacetanilide (0.54 g, 2.5 mmole) in 50 ml of DMF.
  • Lithium aluminum hydride (0.21 g, 5.5 mmole) in dry THF (50 ml) is placed in a three- necked flask under a nitrogen atmosphere.
  • 2-[4-(5-Methoxy-lH-indol-3- ylmethyl)-piperidin-l-yl]-N-(4-fluorophenyl)-acetamide ( 0.5 g, 1.2 mmole) is dissolved in 25 ml of dry THF, and the resulting solution is slowly introduced dropwise to the above stirred suspension at 0 °C. The mixture is then heated to a gentle reflux and stirred for 15 hours.
  • reaction mixture is cooled to room temperature and the excess hydride is destroyed with the addition of 5 ml of 1:1 mixture of THF and water at 0 °C. Stirring is continued as 15 ml of 2.5 N NaOH solution is added to coagulate the precipitate of aluminum hydroxide.
  • the mixture is filtered, washed with 25 % isopropanolic methylene chloride solution, and the solution dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • the crude product is chromatographed on silica gel using ethyl acetate and 5 % methanolic ethyl acetate as eluents to give 0.33 g (68 %, 0.86 mmole) of the expected product as an oily liquid.
  • the free base is dissolved in 10 ml of ethanol, treated with 1.4 ml of 1 M ethereal HC1 (1.7 mmol) to give a white solid, which is recrystallized further from ethanol to afford the title compound. 13 -
  • the title compound is produced by adding pulverized potassium carbonate to a mixture of 4-(l-methyl-5-methoxyindol-3-ylmethyl)piperidine (0.61 g, 2.5 mmole) and 2-chloro-N-(2,6-dichlorophenyl)acetamide (0.59 g, 2.5 mmole) in 50 ml of DMF.
  • the resulting solution is heated at 75 °C for 14 hours and the cooled mixture is partitioned between methylene chloride and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • the oily residue is chromatographed over silica gel using ethyl acetate as eluant.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des composés représentés par la formule générale (1) dans laquelle R1 est sélectionné parmi H, OH, OR¿3?, F, Cl, Br ou I. R2 dans chaque cas représente H ou les deux ensemble sont =O. R3 et R4 sont indépendamment sélectionnés parmi H, alkyle C1 à C6 ou (CH2)nAr, les groupes alkyle et Ar étant éventuellement substitués par 1 à 3 groupes sélectionnés parmi NO2, F, Cl, Br, I, -OH, -OR3, alkyle C1-C6, alcoxy C1-C6, -CF3, -CN, alkyle -S-C1-C6 ou -NH2; n est sélectionné parmi 0, 1 ou 2; X représente CH ou CH2; R2 représente H ou pris ensemble sont = O; Ar représente aryle ou hétéroaryle, les deux étant éventuellement substitués. L'invention concerne également un sel pharmaceutiquement acceptable de ces derniers, ainsi que des procédés et des compositions pharmaceutiques utilisant ces composés pour l'inhibition de la capture de la sérotonine et le traitement des troubles du système nerveux central, y compris la dépression.
EP99920078A 1998-04-29 1999-04-28 Agents serotoninergiques Withdrawn EP1076658A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US6904198A 1998-04-29 1998-04-29
US69041 1998-04-29
PCT/US1999/009128 WO1999055697A1 (fr) 1998-04-29 1999-04-28 Agents serotoninergiques

Publications (1)

Publication Number Publication Date
EP1076658A1 true EP1076658A1 (fr) 2001-02-21

Family

ID=22086346

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99920078A Withdrawn EP1076658A1 (fr) 1998-04-29 1999-04-28 Agents serotoninergiques

Country Status (7)

Country Link
EP (1) EP1076658A1 (fr)
JP (1) JP2002513018A (fr)
CN (1) CN1307576A (fr)
AR (1) AR015035A1 (fr)
AU (1) AU3765899A (fr)
CA (1) CA2330577A1 (fr)
WO (1) WO1999055697A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002243394A1 (en) 2000-11-16 2002-06-24 Wyeth Aryloxy piperidinyl derivatives for the treatment of depression
HUP0400682A2 (hu) 2000-12-22 2004-06-28 Wyeth 5-Hidroxitriptamin-6-ligandumként használható heterociklilalkilindol- és -azaindol-származékok, eljárás az előállításukra és ezeket tartalmazó gyógyszerkészítmények
AR072297A1 (es) 2008-06-27 2010-08-18 Novartis Ag Derivados de indol-2-il-piridin-3-ilo, composicion farmaceutica que los comprende y su uso en medicamentos para el tratamiento de enfermedades mediadas por la sintasa aldosterona.
WO2016073738A2 (fr) 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Agents immunorégulateurs
UY36390A (es) 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1271352B (it) * 1993-04-08 1997-05-27 Boehringer Ingelheim Italia Derivati dell'indolo utili nel trattamento dei disturbi del sistema nervoso centrale
DE19615232A1 (de) * 1996-04-18 1997-10-23 Merck Patent Gmbh Neue Carbamoylderivate und deren Verwendung als 5-HT ¶1¶¶A¶-Antagonisten
US5846982A (en) * 1996-06-14 1998-12-08 Eli Lilly And Company Inhibition of serotonin reuptake

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9955697A1 *

Also Published As

Publication number Publication date
JP2002513018A (ja) 2002-05-08
AU3765899A (en) 1999-11-16
CA2330577A1 (fr) 1999-11-04
CN1307576A (zh) 2001-08-08
AR015035A1 (es) 2001-04-11
WO1999055697A1 (fr) 1999-11-04

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