EP1633742A1 - Indole derivative in the form of serotonin reabsorbing inhibitors - Google Patents
Indole derivative in the form of serotonin reabsorbing inhibitorsInfo
- Publication number
- EP1633742A1 EP1633742A1 EP04734520A EP04734520A EP1633742A1 EP 1633742 A1 EP1633742 A1 EP 1633742A1 EP 04734520 A EP04734520 A EP 04734520A EP 04734520 A EP04734520 A EP 04734520A EP 1633742 A1 EP1633742 A1 EP 1633742A1
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- Prior art keywords
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- 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
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- 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
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-HTIA, 5-HT-IB, 5-HTID, 5-HT 2Al 5-HT 2B , 5-HT 2C , 5-HT 3 , 5-HT 4 ( 5-HT 6 , 5-HT 7.
- 5-HT-iD ⁇ and 5-HT-iDß 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 1D ⁇ 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-i A agonistic effects and an affinity for the serotoin receptor subtype 5-HT4.
- the invention therefore relates to compounds of the formula I.
- a and B are preferably unbranched independently of one another and have 1, 2, 3, 4, 5 or 6 carbon atoms.
- Alkyl with 1-6 C atoms preferably means methyl, ethyl, n-propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n- hexyl.
- Alkaryl means alkyl with 1-6 C atoms connected with an aromatic ring system of 6 or 10 centers such as e.g. B. benzyl or phenethyl.
- Alkheteroaryl means alkyl with 1-6 C atoms combined with an aromatic heterocycle from 5, 6 or 10 centers such as.
- Heteroaryl means a monovalent monocyclic or bicyclic heterocycle with 5-12 ring atoms, which has at least one aromatic ring, 1, 2 or 3 ring atoms being selected from N, O or S. Heteroaryl is optionally independently substituted with 1-4 substituents, for example selected from alkyl, cycloalkyl.cycloalkylalkyl, shark, NO, CN, alkoxy, NH 2 , acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy or heteroalkyl.
- heteroaryls are pyridyl, furanyl, thienyl, Thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, Pyrazoiyl, pyrazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, benzoimidazolyl, benzisoxazolyl or benzothienyl and derivatives from that.
- R 4 OH, NH 2 , NHB or NB 2 ,
- 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
- 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
- the invention also relates to mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers e.g. in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. Mixtures of two stereoisomeric compounds are particularly preferred.
- the invention also relates to a process for the preparation of the compounds of the formula I, characterized in that
- R 2 has the meanings given above and Z represents a leaving group known to the person skilled in the art, such as, for example, p-tosyl, trifluoromethanesulfonyl,
- 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 (preferred for the substitution on
- 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 dimethylformamide (DMF); Nitriles such as acetonitrile; Esters like
- Ethyl acetate carboxylic acids or acid anhydrides, such as. B. such as acetic acid or acetic anhydride, nitro compounds such as nitromethane or nitrobenzene, optionally also mixtures of the solvents mentioned with one another or mixtures with water.
- the reaction can also be carried out in a heterogeneous phase, an aqueous phase and a benzene or toluene phase being preferably used.
- a phase transfer catalyst such as tetrabutylammonium iodide and optionally an acylation catalyst such as dimethylaminopyridine are used.
- 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 organic base such as, for example, triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.
- Suitable reaction temperatures are from 10 to 180 ° C., preferably from 20 to 150 ° C. and very particularly preferably from 40 to 100 ° C.
- Is preferably carried out at a pressure of 1 to 200 bar and at temperatures between -80 ° and + 150 ° C, particularly preferably at room temperature and normal pressure. Preferably at 1.5 to 120 bar and in particular at 2 to 100 bar.
- a pH of 6 to 10 is preferred.
- 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. When using a microwave, the response time can be reduced to 1 to 60 minutes.
- An acid of the formula I can be converted with a base into the associated addition salt, for example by reacting equivalent amounts of the acid and the 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 (e.g. 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 that provide physiologically acceptable salts such as e.g. Ethanolamine.
- 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, ferric organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or polybasic carbon, sulfonic or Sulfuric acids, e.g.
- 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 compounds also have a high affinity for the 5-HT x receptor (for 5-HT x means X: 1A or 4) and show serotonin agonistic and antagonistic properties. Through a 5-HT agonistic effect and a 5-HT reuptake inhibition, 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 inhibition can also help the Waldmeier method can be examined ex vivo in the brain tissue of the mouse (European J. Pharmacol. 1977, 46, 387-92), and by the microdialysis described by DiChiara (Trends in Pharmacol. Sei., ü (1990), 116- 121).
- a physiological solution is perfused through a microdialysis container implanted in a rat brain.
- 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-HTi 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-HT-i A agonistic effect can be achieved using the method described by Newman-Tancredi et al. (Eur. J. Pharmacol. 307 (1996), 107-11) described GTPgammaS tests.
- 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 proportions, for the manufacture of a medicament for the treatment of diseases, in particular diseases associated with the Serotonin receptor and / or serotonin reuptake related.
- Compounds of formula I according to the invention can be chiral due to their molecular structure and can accordingly occur in various enantiomeric forms. They can therefore be in racemic or optically active form. Since the pharmaceutical activity of the racemates or the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In this case, 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-HTi A agonistic properties, they are particularly suitable as antidepressants and anxiolytics.
- the invention therefore also relates to the use of compounds of the formula I and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament as an anxiolytic, antidepressant, neuroleptic and / or antihypertensive and / or to positively influence compulsive behavior (OCD), sleep disorders, tardive dyskinesias, learning disorders, age-related memory disorders, eating disorders such as bulimia or IBS and / or sexual dysfunction.
- OCD compulsive behavior
- sleep disorders tardive dyskinesias
- learning disorders learning disorders
- age-related memory disorders eating disorders such as bulimia or IBS and / or sexual dysfunction.
- eating disorders such as bulimia or IBS and / or sexual dysfunction.
- Formula I can also be used as intermediates for the preparation of other active pharmaceutical ingredients.
- the compounds of the formula I are suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and of inflammation.
- the invention thus relates to the use of compounds of the formula I and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment of psychoses, schizophrenia, schizoaffective psychosis, cyclothymia, epilepsy, Convulsions, depression (subtypes of severe depression and cyclothymic depression), pathological anxiety (subtypes of panic attacks with or without agoraphobia), overexcitation, hyperactivity, stress disorders, post-traumatic stress disorders, sleep disorders, narcolepsy, cyclical manic depressive disorders, attention disorders in children and adolescents, profound developmental disorders and disorders of social behavior with mental retardation, obsessive-compulsive illnesses (OCD) and wider senses (OCSD), addictions, disorders in food intake or eating disorders, for example Bulimi e, obesity or anorexia nervosa, especially irritable bowl syndrome (IBS), fibromyalgia, as well as
- Parkinson's disease Alzheimer's disease, Huntington's disease, lathyrism, amyotrophic lateral sclerosis, Lewy body dementia, Tourette syndrome, sexual dysfunction, premenstrual syndrome, acromegaly, hypogonadism, secondary amenorrhea, unwanted puerperal lactation, extrapyramidal
- Movement disorders for the treatment of side effects that occur in the treatment of extrapyramidal movement disorders with conventional anti-Parkinson medication and of extrapyramidal symptoms (EPS), states of tension, side effects of hypertension treatment that are induced by neuroleptics (e.g. with ⁇ -methyldopa) or for Prophylaxis, treatment and control of cerebral infarction (apoplexia cerebri), such as stroke and cerebral ischemia or for the treatment of pain, in particular chronic pain, migraine, CNS trauma, hypoglycemia, asthma, glaucoma, cytomegaly and for the treatment of other degenerative retinal diseases, incontinence , Tinnitus, or to treat hearing loss induced by aminoglycoside antibiotics.
- neuroleptics e.g. with ⁇ -methyldopa
- Prophylaxis e.g. with Prophylaxis
- apoplexia cerebri e.g. with ⁇ -methyldopa
- apoplexia cerebri e
- 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 (for example 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.
- vegetable oils such as sunflower oil or Cod liver oil
- benzyl alcohols polyethylene glycols
- gelatin carbohydrates such as lactose or starch
- magnesium stearate magnesium stearate
- talc lanolin or petroleum jelly
- solvents such as water, physiological saline or alcohols such as ethanol, propanol or glycerin, sugar solutions such as glucose or mannitol solutions or a mixture of the solvents mentioned, gel formers, tablet excipients and other excipients, for example lubricants, stabilizers and / or wetting agents, emulsifiers, salts for influencing osmotic pressure, antioxidants,
- Dispersants 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 contain, for example, separate ampoules, each containing 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, dissolved or in lyophilized form is present.
- Tablets, dragees, capsules, syrups, juices, drops or suppositories are used in particular for enteral administration (orally or rectally), solutions, preferably oily or aqueous solutions, furthermore suspensions, for parenteral administration (subcutaneously or intravenously),
- Emulsions or implants for topical use ointments, creams, 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.
- 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
- 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 lyophilizates obtained can be used, for example, for the production of injectables. They can also be administered as nasal sprays.
- 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, for example two, three or four times during the 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, i.e. the proportion of the drug that remains unchanged in the systemic blood, i.e. enters the large cycle at 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 can be absorbed by the body.
- 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)
- 0.8 g (20 mmol) NaH is suspended in 20 ml THF and a solution of 4.6 g (20 mmol) 3- (4-chlorobutyl) -1 H-indole-5- at room temperature carbonitrile added dropwise in 50 ml of THF.
- the yellow solution is stirred for 30 minutes and then a solution of 1.2 ml (20 mmol) iodomethane in 30 ml THF is added dropwise.
- the yellow solution becomes 1 h at Room temperature stirred.
- the reaction solution is then concentrated and the residue is shaken out with ethyl acetate and water.
- the organic phase is washed with water, dried with sodium sulfate and concentrated.
- the reaction mixture is stirred into 100 ml of water. Fine crystals precipitate out. These are suctioned off, washed with water and air-dried overnight. The resulting 0.9 g of light brown crystals are finally purified by chromatography to 0.8 g of light crystals. These are dissolved in hot acetone and mixed with one milliliter of ethanolic HCI. White crystals immediately fall out. These are stirred again while hot, suction filtered and washed with acetone.
- 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 5 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 formula I, 9.38 g
- Benzalkonium chloride in 940 ml of double distilled 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.
- a mixture of 1 kg of a compound of formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of a compound of Formula I contains.
- Example 9 Dragees Analogously to 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Ophthalmology & Optometry (AREA)
- Psychology (AREA)
- Reproductive Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Anesthesiology (AREA)
- Addiction (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Hematology (AREA)
- Gynecology & Obstetrics (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10326940A DE10326940A1 (en) | 2003-06-16 | 2003-06-16 | Indole derivatives |
PCT/EP2004/005546 WO2004113325A1 (en) | 2003-06-16 | 2004-05-24 | Indole derivative in the form of serotonin reabsorbing inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1633742A1 true EP1633742A1 (en) | 2006-03-15 |
Family
ID=33495050
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04734520A Withdrawn EP1633742A1 (en) | 2003-06-16 | 2004-05-24 | Indole derivative in the form of serotonin reabsorbing inhibitors |
Country Status (12)
Country | Link |
---|---|
US (1) | US20060160824A1 (en) |
EP (1) | EP1633742A1 (en) |
JP (1) | JP2006527706A (en) |
KR (1) | KR20060021896A (en) |
CN (1) | CN1805954A (en) |
AR (1) | AR044713A1 (en) |
AU (1) | AU2004249371A1 (en) |
BR (1) | BRPI0411456A (en) |
CA (1) | CA2529298A1 (en) |
DE (1) | DE10326940A1 (en) |
MX (1) | MXPA05013537A (en) |
WO (1) | WO2004113325A1 (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
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DE10326939A1 (en) * | 2003-06-16 | 2005-01-05 | Merck Patent Gmbh | Indole derivatives |
US7994331B2 (en) * | 2005-07-13 | 2011-08-09 | Msd K.K. | Heterocycle-substituted benzimidazole derivative |
EP2110374A1 (en) * | 2008-04-18 | 2009-10-21 | Merck Sante | Benzofurane, benzothiophene, benzothiazol derivatives as FXR modulators |
US8367676B2 (en) * | 2009-06-30 | 2013-02-05 | Astrazeneca Ab | 2-carboxamide-7-piperazinyl-benzofuran derivatives 774 |
AU2011345381A1 (en) * | 2010-12-20 | 2013-06-13 | Astrazeneca Ab | 2-carboxamide-4-piperazinyl-benzofuran derivative |
CN102993186B (en) * | 2012-12-20 | 2015-11-18 | 北京海步国际医药科技发展有限公司 | A kind of novel bridged piperazine derivatives |
CN104337812B (en) | 2013-07-29 | 2018-09-14 | 广东东阳光药业有限公司 | Substituted heteroaryl compound and its application method and purposes |
CN106243088B (en) | 2015-06-03 | 2019-01-04 | 广东东阳光药业有限公司 | Substituted diethylenediamine compound and its application method and purposes |
CA3077383A1 (en) | 2017-09-29 | 2019-04-04 | Sunshine Lake Pharma Co., Ltd. | Substituted pyrimidine piperazine compound and use thereof |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8830312D0 (en) * | 1988-12-28 | 1989-02-22 | Lundbeck & Co As H | Heterocyclic compounds |
DE4333254A1 (en) * | 1993-09-30 | 1995-04-06 | Merck Patent Gmbh | Piperidines and piperazines |
AU736596B2 (en) * | 1997-07-25 | 2001-08-02 | H. Lundbeck A/S | Indole and 2,3-dihydroindole derivatives, their preparation and use |
DE10112151A1 (en) * | 2001-03-14 | 2002-09-19 | Merck Patent Gmbh | New 5-(4-(indolyl-alkyl)-piperazino)-benzofuran-2-carboxamides useful e.g. for treating depression, anxiety, psychiatric or cerebral disorders or pain, are 5-HT-1A receptor agonists and 5-HT reuptake inhibitors |
EP1395257A1 (en) * | 2001-06-12 | 2004-03-10 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
UA76758C2 (en) * | 2001-06-19 | 2006-09-15 | Мерк Патент Гмбх | Polymorph forms of hydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine |
DE10259244A1 (en) * | 2002-12-17 | 2004-07-01 | Merck Patent Gmbh | N- (Indolethyl-) cyclo amine compounds |
DE10326939A1 (en) * | 2003-06-16 | 2005-01-05 | Merck Patent Gmbh | Indole derivatives |
-
2003
- 2003-06-16 DE DE10326940A patent/DE10326940A1/en not_active Withdrawn
-
2004
- 2004-05-24 CA CA002529298A patent/CA2529298A1/en not_active Abandoned
- 2004-05-24 CN CNA2004800167485A patent/CN1805954A/en active Pending
- 2004-05-24 MX MXPA05013537A patent/MXPA05013537A/en unknown
- 2004-05-24 EP EP04734520A patent/EP1633742A1/en not_active Withdrawn
- 2004-05-24 JP JP2006515786A patent/JP2006527706A/en active Pending
- 2004-05-24 KR KR1020057024100A patent/KR20060021896A/en not_active Application Discontinuation
- 2004-05-24 US US10/560,737 patent/US20060160824A1/en not_active Abandoned
- 2004-05-24 AU AU2004249371A patent/AU2004249371A1/en not_active Abandoned
- 2004-05-24 BR BRPI0411456-6A patent/BRPI0411456A/en not_active Application Discontinuation
- 2004-05-24 WO PCT/EP2004/005546 patent/WO2004113325A1/en not_active Application Discontinuation
- 2004-06-16 AR ARP040102079A patent/AR044713A1/en unknown
Non-Patent Citations (1)
Title |
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See references of WO2004113325A1 * |
Also Published As
Publication number | Publication date |
---|---|
CN1805954A (en) | 2006-07-19 |
AR044713A1 (en) | 2005-09-21 |
CA2529298A1 (en) | 2004-12-29 |
KR20060021896A (en) | 2006-03-08 |
WO2004113325A1 (en) | 2004-12-29 |
MXPA05013537A (en) | 2006-03-09 |
AU2004249371A1 (en) | 2004-12-29 |
JP2006527706A (en) | 2006-12-07 |
DE10326940A1 (en) | 2005-01-05 |
US20060160824A1 (en) | 2006-07-20 |
BRPI0411456A (en) | 2006-07-18 |
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