EP1633741A1 - Derives d'indole en tant qu'inhibiteurs de la recapture de la serotonine - Google Patents

Derives d'indole en tant qu'inhibiteurs de la recapture de la serotonine

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Publication number
EP1633741A1
EP1633741A1 EP04734515A EP04734515A EP1633741A1 EP 1633741 A1 EP1633741 A1 EP 1633741A1 EP 04734515 A EP04734515 A EP 04734515A EP 04734515 A EP04734515 A EP 04734515A EP 1633741 A1 EP1633741 A1 EP 1633741A1
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EP
European Patent Office
Prior art keywords
disorders
derivatives
solvates
stereoisomers
physiologically acceptable
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.)
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Application number
EP04734515A
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German (de)
English (en)
Inventor
Timo Heinrich
Henning Böttcher
Kai Schiemann
Günter Hölzemann
Christoph Van Amsterdam
Gerd Bartoszyk
Joachim Leibrock
Christoph Seyfried
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Merck Patent GmbH
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Merck Patent GmbH
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Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1633741A1 publication Critical patent/EP1633741A1/fr
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
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    • 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
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A—HUMAN NECESSITIES
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    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to new indole derivatives, processes for their preparation and use of the compounds for the manufacture of medicaments for the treatment and prophylaxis of diseases which are related to serotonin reuptake and / or serotonin receptors (serotonin, 5-hydroxytryptamine, 5- HT).
  • 5-HT receptor The following types of 5-HT receptor are known, for example: 5-HT 1A , 5-HT 1B , 5-HTID, 5-HT 2A , 5-HT 2 B, 5-HT 2C , 5-HT 3 , 5-HT 4 , 5-HT 6 , 5-HT 7 .
  • subtypes such as 5-HT ⁇ D ⁇ and 5-HT ⁇ D ß, which differ in tissue specificity, mode of action and other properties.
  • EP0655442 describes piperazine derivatives with a tachykinin-antagonistic effect.
  • Indole piperazine derivatives are known from EP0648767, US5532241, EP0407844, EP0376607, BE771285, GB1075156, GB118064, FR1551082 and from EP 0 736 525. These compounds are effective serotonin reuptake inhibitors and 5-HT- A receptor agonists.
  • indole piperidine and indole piperazine derivatives are known, which are effective 5-HT-t D ⁇ receptor agonists .
  • the connections disclosed therein are based on their vasoconstrictive effect used to treat diseases related to migraines.
  • the invention was based on the task of finding new compounds which can be used for the production of medicaments.
  • Compounds of formula 1 have effects on the central nervous system. They act as selective serotonin reuptake inhibitors, show serotonin agonistic and antagonistic properties and thus influence serotoninergic transmission. In particular, they show 5-HT- A agonistic effects.
  • the invention therefore relates to compounds of the formula I.
  • R 1 , R 2 , R 3 independently of one another OH, OA, CN, shark, COR 4 or CH 2 R 4 ,
  • R 4 OH, OA, NH 2 , NHB or NB 2 ,
  • a and B independently of one another are alkyl, are preferably unbranched and have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl is particularly preferred.
  • Alkenyl preferably stands for allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, further preferred is 4-pentenyl, isopentyl or 5-hexenyl.
  • Alkoxy means -O (CH 2 ) m CH 3 , where m means 1, 2, 3, 4, 5, 6, 7, 8 or 9, but in particular 2.
  • Alkoxyalkyl means - (CH 2 ) nO (CH 2 ) mCH 3 , for example methoxymethylene or propoxypropylene, where m or n can independently be 1, 2, 3, 4, 5 or 6.
  • the compounds of the formula I according to the invention comprise the compounds of the formulas Ia and Ib, in which X, R 1 , R 2 , R 3 , Q, m and n have the meanings given above
  • Preferred compounds of the formula I are those in which
  • R 1 , R 2 , R 3 independently of one another CN, OH, COR 4 or CH 2 R 4 ,
  • R 4 OH, NH 2 , NHB or NHB 2 ,
  • the invention are also all physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, including their mixtures in all proportions.
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.
  • compositions are understood to mean e.g. Salts of the compounds according to the invention, as well as so-called prodrug compounds.
  • Prodrug connections mean e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly split or released in the organism to the active compounds of the invention.
  • This also includes biodegradable polymer derivatives of the compounds according to the invention, such as e.g. in Int. J. Pharm. 115 (1995), 61-67.
  • Suitable acid addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.
  • halides in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.
  • Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction.
  • Solvates are, for example, hydrates such as monohydrates or dihydrates or alcoholates, i.e. Addition compounds with alcohols such as methanol or ethanol.
  • the invention also relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000th Especially it is preferably mixtures of two stereoisomeric compounds.
  • the invention also relates to a process for the preparation of the compounds of the formula I, characterized in that
  • the starting compounds of the formula II, III, VI and V are generally known. If they are new, they can be manufactured according to methods known per se. If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.
  • the starting materials can be combined (fused) in a sealed reaction vessel or in an autoclave. However, it is also possible to react the starting materials in the presence of an inert solvent.
  • Suitable inert solvents are e.g. Heptane, hexane, petroleum ether, benzene, toluene, xylene, trichlorethylene, 1,2-dichloroethane tetrachloromethane, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylform
  • the amount of solvent is not critical, preferably 10 g to 500 g of solvent can be added per g of the compound of formula I to be reacted.
  • an acid-binding agent for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other alkali metal or alkaline earth metal salts of weak acids, preferably a potassium, sodium or calcium salt, or the addition an organic base, such as triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.
  • an acid-binding agent for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other alkali metal or alkaline earth metal salts of weak acids, preferably a potassium, sodium or calcium salt
  • organic base such as triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.
  • Suitable reaction temperatures are at temperatures of 10 to 180 ° C, preferably 20 to 150 ° C and very particularly preferably
  • Is preferably carried out at a pressure of 1 to 200 bar and at temperatures between -80 ° and + 150 ° C, particularly preferably at 40 to 100 ° C and normal pressure. Preferably at 1.5 to 120 bar and in particular at 2 to 100 bar.
  • the duration of the reaction depends on the reaction conditions chosen. As a rule, the reaction time is 0.5 hours to 10 days, preferably 1 to 24 hours.
  • the compounds of formula II can be obtained after removal of the solvent. It may be advantageous to connect a distillation or crystallization to further purify the product.
  • An acid of the formula I can be converted into the associated addition salt with a base, for example by reaction equivalent amounts of the acid and base in an inert solvent such as ethanol and including evaporation.
  • Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
  • the acid of formula I can be converted with a base (eg sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali or alkaline earth metal or into the corresponding ammonium salt.
  • Organic bases which provide physiologically acceptable salts, such as ethanolamine, are also suitable for this reaction.
  • a base of formula I can be converted into the associated acid addition salt with an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and then evaporating them.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or polybasic carboxylic, sulfonic or sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, Pimeiinklare, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic , p-toluene
  • Salts with physiologically unacceptable acids for example picrates, can be used for the isolation and / or purification of the compounds of the formula I. It has been found that the compounds of the formula I and their physiologically acceptable acid addition salts are well tolerated and have valuable pharmacological properties because they have particular effects on the central nervous system. In particular, they inhibit 5-HT reuptake. The connections also have a high
  • serotonin remains longer in the synaptic cleft and the serotonin effect is enhanced.
  • Active ingredients with such properties are therefore particularly suitable as antidepressants and anxiolytics.
  • the compounds of formula I inhibit the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol. 140 (1987), 143-155) and the synaptosomal serotonin reuptake (Sherman et al., Life Sei. 23 (1978 ), 1863-1870).
  • Rat brain implanted microdialysis container perfused.
  • the solution picks up the neurotransmitters released in the brain and is subsequently analyzed.
  • the 5-HT content in the solution after perfusion is proportional to the amount released in the brain and it increases, for example, after administration of a 5-HT reuptake inhibitor (Gardier et al., Fundam. Clin. Pharmacol., 10 (1996), 16-27).
  • the 5-HT-i A agonistic effect can be measured in vitro, for example using the (serotonin) binding test, as described by Matzen et al. (J. Med. Chem., 43 (2000), 1149-57), in particular on page 1156 with reference to Eur. J. Pharmacol., 140 (1987), 143-155.
  • the 5-HTi A agonistic effect can be achieved using the method described by Newman-Tancredi et al.
  • the invention relates in particular to the use of the compounds of the formula I and their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios as serotonin receptor ligands and / or for serotonin reuptake inhibition.
  • the use of the compounds of the formula I as 5-HT 1A agonists and as inhibitors of 5-HT reuptake is according to the invention.
  • the invention thus relates in particular to the use of compounds of the formula I and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios for the preparation of a Medicament for the treatment of diseases, in particular diseases related to the serotonin receptor and / or serotonin reuptake.
  • the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art, or can already be used as such in the synthesis.
  • compounds of the formula I inhibit serotonin reuptake and at the same time have 5-HT 1A agonistic properties, they are particularly suitable as antidepressants and anxiolytics.
  • the invention therefore also relates to the use of
  • the invention thus relates to the use of compounds of
  • CNS trauma hypoglycemia, asthma, glaucoma, cytomegaly and for the treatment of other degenerative retinal diseases, incontinence, tinnitus, or for the treatment of hearing loss induced by aminoglycoside antibiotics.
  • anxiolxytics are suitable as active pharmaceutical ingredients for anxiolxytics, antidepressants, antipsychotics, neuroleptics, antihypertensives and / or for positively influencing obsessive-compulsive behavior (OCD), sleep disorders, tardive dyskinesias, learning disorders, age-related memory disorders, eating disorders such as bulimia and / or sexual dysfunction.
  • OCD obsessive-compulsive behavior
  • the compounds of the formula I can be used for the production of pharmaceutical preparations, in particular by a non-chemical route. Here, they are brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredient (s).
  • the invention therefore furthermore relates to pharmaceutical preparations containing at least one compound of the formula I and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios.
  • the invention also relates in particular to those pharmaceutical preparations which contain further carriers and / or auxiliaries, and also to those pharmaceutical preparations which contain at least one further active pharmaceutical ingredient.
  • the invention in particular also relates to a process for the preparation of a pharmaceutical preparation, characterized in that a compound of the formula I and / or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions together with a solid , liquid or semi-liquid carrier or auxiliary and optionally with a further active pharmaceutical ingredient in a suitable dosage form.
  • the pharmaceutical preparations according to the invention can be used as medicaments in human or veterinary medicine.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils (such as sunflower oil or cod liver oil), benzyl alcohols, polyethylene glycols, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin or petroleum jelly.
  • enteral e.g. oral
  • parenteral or topical application do not react with the new compounds
  • benzyl alcohols e.g., benzyl alcohols, polyethylene glycols, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin or petroleum jelly.
  • auxiliaries which are suitable for the desired pharmaceutical formulation.
  • preparations or medicaments according to the invention can contain one or contain several other active ingredients, for example one or more vitamins.
  • the invention also relates to a set consisting of separate packs of a) an effective amount of a compound of the formula I and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios and b) an effective one Amount of another drug ingredient.
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • the set can e.g. contain separate ampoules, in each of which an effective amount of a compound of the formula I and / or its pharmaceutically acceptable derivatives, solvates, stereoisomers, including their mixtures in all ratios, and an effective amount of a further active pharmaceutical ingredient are dissolved or in lyophilized form.
  • tablets, dragees, capsules, syrups, juices, drops or suppositories are used, for parenteral application (subcutaneously or intravenously) solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use
  • parenteral application subcutaneously or intravenously solutions
  • solutions preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants
  • Topical use Application ointments, cream, pastes, lotions, gels, sprays, foams, aerosols, solutions (e.g. solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1, 2-propanediol or their mixtures with one another and / or with water) or Powder.
  • Liposomal preparations are also particularly suitable for topical applications.
  • the compounds and / or their physiologically acceptable salts and solvates can also be lyophilized and the ly
  • the compounds according to the invention can be administered to humans or animals, in particular mammals, such as monkeys, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in combating the diseases listed above. They can continue to be used as diagnostics or as reagents.
  • the compounds according to the invention and / or their physiologically acceptable salts and solvates are generally used analogously to known, commercially available preparations or preparations, preferably in doses between 0.1 and 500 mg, in particular 5 and 300 mg per application unit.
  • the daily dosage is preferably between 0.001 and 250 mg / kg, in particular 0.01 and 100 mg / kg body weight.
  • the preparation can be administered one or more times a day, e.g. two, three or four times a day.
  • the individual dosage for a patient depends on a large number of individual factors, such as, for example, the effectiveness of the compound used, the age, body weight, general health, gender, diet, the time and route of administration, the rate of excretion, the Combination with other drugs and the severity and duration of the disease. Oral application is preferred.
  • a measure of the absorption of an active pharmaceutical ingredient into an organism is its bioavailability. If the active pharmaceutical ingredient is administered intravenously to the organism in the form of a solution for injection, its absolute bioavailability, ie the proportion of the drug that remains unchanged in the systemic blood, ie in the large circulation, is 100%.
  • the active ingredient is usually present in the formulation as a solid and must therefore first dissolve so that it can overcome the entry barriers, for example the gastrointestinal tract, the oral mucosa, nasal membranes or the skin, in particular the stratum corneum or from
  • Body can be absorbed.
  • Pharmacokinetic data i.e. Bioavailability can be obtained analogously to the method of J. Shaffer et al., J. Pharm. Sciences, 88 (1999), 313-318.
  • FAB Fluorescence Bombardment: (M + H) + THF (tetrahydrofuran), NMP (N-methyl pyrrolidone), DMSO (dimethyl sulfoxide), EE (ethyl acetate), MeOH (methanol), DC (thin layer chromatography)
  • THF tetrahydrofuran
  • NMP N-methyl pyrrolidone
  • DMSO dimethyl sulfoxide
  • EE ethyl acetate
  • MeOH methanol
  • DC thin layer chromatography
  • a large number of the synthesized compounds have nanomolar affinity for the 5-HT ⁇ A receptors, as well as a nanomolar inhibition of serotonin reuptake.
  • a solution of 100 g of a compound of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of a compound of formula I.
  • Example 7 Suppositories
  • a mixture of 20 g of a compound of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool.
  • Each suppository contains 20 mg of a compound of formula I.
  • a solution is prepared from 1 g of a compound of the formula I, 9.38 g of NaH 2 PO 4 2 H 2 O, 28.48 g of Na 2 HPO 4 - 12 H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distillation Water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
  • 500 mg of a compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • a solution of 1 kg of a compound of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of a compound of formula I.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Psychology (AREA)
  • Reproductive Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Anesthesiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I), leur utilisation pour produire un médicament servant à traiter des maladies en rapport avec le récepteur de la sérotonine et/ou la recapture de la sérotonine, notamment pour produire un médicament servant d'anxiolytique, d'antidépresseur, de neuroleptique et/ou d'anti-hypertonique, et/ou servant à influencer positivement des troubles obsessionnels compulsifs, des troubles du sommeil, des dyskinésies tardives, des troubles d'apprentissage, des troubles de la mémoire liés à l'âge, des troubles de l'alimentation comme la boulimie et/ou des troubles de la fonction sexuelle. Les composés (I) se lient au récepteur 5-HT1A.
EP04734515A 2003-06-16 2004-05-24 Derives d'indole en tant qu'inhibiteurs de la recapture de la serotonine Withdrawn EP1633741A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10326939A DE10326939A1 (de) 2003-06-16 2003-06-16 Indol-Derivate
PCT/EP2004/005547 WO2004113326A1 (fr) 2003-06-16 2004-05-24 Derives d'indole en tant qu'inhibiteurs de la recapture de la serotonine

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EP1633741A1 true EP1633741A1 (fr) 2006-03-15

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EP04734515A Withdrawn EP1633741A1 (fr) 2003-06-16 2004-05-24 Derives d'indole en tant qu'inhibiteurs de la recapture de la serotonine

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US (1) US7829565B2 (fr)
EP (1) EP1633741A1 (fr)
JP (1) JP2006527707A (fr)
KR (1) KR20060010839A (fr)
CN (1) CN1805953A (fr)
AR (1) AR044712A1 (fr)
AU (1) AU2004249372B2 (fr)
BR (1) BRPI0411533A (fr)
CA (1) CA2529299C (fr)
DE (1) DE10326939A1 (fr)
MX (1) MXPA05013538A (fr)
WO (1) WO2004113326A1 (fr)

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US8163892B2 (en) * 2002-07-08 2012-04-24 Oncolys Biopharma, Inc. Oncolytic virus replicating selectively in tumor cells
DE10326940A1 (de) * 2003-06-16 2005-01-05 Merck Patent Gmbh Indol-Derivate
US7994331B2 (en) 2005-07-13 2011-08-09 Msd K.K. Heterocycle-substituted benzimidazole derivative
EP2110374A1 (fr) * 2008-04-18 2009-10-21 Merck Sante Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs FXR
UA107657C2 (uk) * 2009-03-10 2015-02-10 Такеда Фармасьютікал Компані Лімітед Похідні бензофурану
US8367676B2 (en) * 2009-06-30 2013-02-05 Astrazeneca Ab 2-carboxamide-7-piperazinyl-benzofuran derivatives 774
KR20130132932A (ko) * 2010-12-20 2013-12-05 아스트라제네카 아베 2-카르복스아미드-4-피페라지닐-벤조푸란 유도체
CN102617558A (zh) * 2012-03-26 2012-08-01 上海泛凯生物医药科技有限公司 一种维拉佐酮的制备方法
US9382233B2 (en) 2012-06-13 2016-07-05 Apotex Inc. Forms of vilazodone and processes for the preparation thereof
CN104337812B (zh) 2013-07-29 2018-09-14 广东东阳光药业有限公司 取代的杂芳基化合物及其使用方法和用途
CN106243088B (zh) 2015-06-03 2019-01-04 广东东阳光药业有限公司 取代的哌嗪化合物及其使用方法和用途
WO2019062662A1 (fr) 2017-09-29 2019-04-04 Sunshine Lake Pharma Co., Ltd. Composé de pyrimidine pipérazine substitué et son utilisation

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DE69819173T2 (de) * 1997-07-25 2004-04-15 H. Lundbeck A/S Indole und 2,3-dihydroindolderivate, ihre herstellung und verwendung
UA76130C2 (en) * 2000-11-20 2006-07-17 Merck Patent Gmbh Use of compounds combining properties of selective inhibitors of serotonin re-uptake and agonists of 5-ht1a receptor for treatment of irritable bowel syndrome
DE10112151A1 (de) * 2001-03-14 2002-09-19 Merck Patent Gmbh Substituierte Benzofuran-2-carbonsäureamide
UA76758C2 (uk) * 2001-06-19 2006-09-15 Мерк Патент Гмбх Поліморфні форми гідрохлориду 1-'4-(5-ціаноіндол-3-іл)бутил-4-(2-карбамоїлбензофуран-5-іл)піперазину
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Also Published As

Publication number Publication date
AR044712A1 (es) 2005-09-21
AU2004249372B2 (en) 2010-04-29
US20070099933A1 (en) 2007-05-03
KR20060010839A (ko) 2006-02-02
DE10326939A1 (de) 2005-01-05
CA2529299A1 (fr) 2004-12-29
AU2004249372A1 (en) 2004-12-29
CN1805953A (zh) 2006-07-19
US7829565B2 (en) 2010-11-09
JP2006527707A (ja) 2006-12-07
BRPI0411533A (pt) 2006-08-01
WO2004113326A1 (fr) 2004-12-29
MXPA05013538A (es) 2006-03-09
CA2529299C (fr) 2012-07-03

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