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EP1633742A1 - Indole derivative in the form of serotonin reabsorbing inhibitors - Google Patents

Indole derivative in the form of serotonin reabsorbing inhibitors

Info

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
Authority
EP
European Patent Office
Prior art keywords
disorders
derivatives
formula
solvates
mixtures
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Withdrawn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
EP04734520A
Other languages
German (de)
French (fr)
Inventor
Timo Heinrich
Henning Böttcher
Kai Schiemann
Günter Hölzemann
Christoph Van Amsterdam
Gerd Bartoszyk
Joachim Leibrock
Christoph Seyfried
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1633742A1 publication Critical patent/EP1633742A1/en
Withdrawn legal-status Critical Current

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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/12Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10Drugs for genital or sexual disorders; Contraceptives for impotence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/02Drugs for disorders of the nervous system for peripheral neuropathies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/22Anxiolytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • AHUMAN NECESSITIES
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    • A61P27/00Drugs for disorders of the senses
    • AHUMAN NECESSITIES
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P27/02Ophthalmic agents
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    • A61P27/16Otologicals
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    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
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    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/06Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/14Heterocyclic 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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Abstract

The invention relates to compounds of formula (I) used for producing drugs for treating diseases related to a serotonin receptor and/or a serotonin reabsorption, in particular for producing drugs like anxiolitic, antidepressive, neuroleptic and/or antihypertensive drugs and/or for positively influencing obsessional compulsive troubles, sleep disorders, tardive dyskinesia, learning troubles, gerontal memory loss, eating disorders such as bulimia and/or irritable bowel syndrome and/or sexual function troubles. Said compounds are associated with to a 5-HT1A receptor.

Description

INDOL-DERIVATE ALS SEROTONIN-WIEDERAUFNAHME-INHIBITOREN INDOL DERIVATIVES AS SEROTONIN REINVENTION INHIBITORS
Die vorliegende Erfindung betrifft neue Indol-Derivate, Verfahren zu deren Herstellung und Verwendung der Verbindungen zur Herstellung von Medikamenten zur Behandlung und Prophylaxe von Krankheiten, die mit der Serotonin-Wiederaufnahme und/oder Serotonin-Rezeptoren zusammenhängen (Serotonin, 5-Hydroxytryptamin, 5-HT).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).
Vom 5-HT-Rezeptor sind z.B. folgende Typen bekannt: 5-HTIA, 5-HT-IB, 5- HTID, 5-HT2Al 5-HT2B, 5-HT2C, 5-HT3, 5-HT4( 5-HT6, 5-HT7. Weiterhin findet man Subtypen wie beispielsweise 5-HT-iDα und 5-HT-iDß, die sich in Gewebespezifität, Wirkungsweise und weiteren Eigenschaften unterscheiden.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. There are also subtypes such as 5-HT-iDα and 5-HT-iDß which differ in tissue specificity, mode of action and other properties.
Aus der WO9951575 sind Indolderivate bekannt, die 5-HT1A-From WO9951575 indole derivatives are known which 5-HT 1A -
Autorezeptoren und 5-HT-Transporter beeinflussen und zur Behandlung von Depressionen eingesetzt werden können.Can influence autoreceptors and 5-HT transporters and can be used to treat depression.
Die DE19514567 beschreibt Piperazinylbenzofurane mit Wirkungen auf das Zentralnervensystem, die EP0655442 beschreibt Piperazinderivate mit Tachykinin-antagonistischer Wirkung.DE19514567 describes piperazinylbenzofurans with effects on the central nervous system, EP0655442 describes piperazine derivatives with a tachykinin-antagonistic effect.
Indolpiperazinderivate sind aus der EP0648767, US5532241 , EP0407844, EP0376607, BE771285, GB1075156, GB118064, FR1551082 und aus der EP 0 736 525 bekannt. Diese Verbindungen stellen wirksame Serotonin- Wiederaufnahmehemmer und 5-HTιA-Rezeptoragonisten dar.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.
Aus der WO9616056, WO9617842, WO9718202, WO9718203, WO9745432 und WO9719943 sind Indolpiperidin- und Indolpiperazinderivate bekannt, die wirksame 5-HT1Dα-Rezeptoragonisten darstellen. Die darin offenbarten Verbindungen werden aufgrund ihrer vasokonstriktorischen Wirkung zur Behandlung von Krankheiten in Zusammenhang mit Migräne verwendet.From WO9616056, WO9617842, WO9718202, WO9718203, WO9745432 and WO9719943, indole piperidine and indole piperazine derivatives are known which are effective 5-HT 1Dα receptor agonists . The connections disclosed therein are based on their vasoconstrictive effect used to treat diseases related to migraines.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen aufzufinden, die zur Herstellung von Medikamenten verwendet werden können.The invention was based on the task of finding new compounds which can be used for the production of medicaments.
Es wurde gefunden, dass die erfindungsgemäßen Verbindungen der Formel I und ihre physiologisch unbedenklichen Säureadditionssalze bei guter Verträglichkeit wertvolle pharmakologische Eigenschaften aufweisen. Überraschend wurde gefunden, dass die erfindungsgemäßenIt has been found that the compounds of the formula I according to the invention and their physiologically acceptable acid addition salts have valuable pharmacological properties with good tolerability. It has surprisingly been found that the inventive
Verbindungen der Formel 1 Wirkungen auf das Zentralnervensystem aufweisen. Sie wirken als selektive Serotonin-Wiederaufnahmehemmer, zeigen serotonin-agonistische und -antagonistische Eigenschaften und beeinflussen so die serotoninerge Transmission. Insbesondere zeigen sie 5-HT-iA-agonistische Wirkungen und eine Affinität zum Serotoin Rezeptor Subtyp 5-HT4.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.
Gegenstand der Erfindung sind deshalb Verbindungen der Formel IThe invention therefore relates to compounds of the formula I.
X = N oder CH,X = N or CH,
R1, R3 = unabhängig voneinander H, OH, OA, CN, Hai, COR4 oder CH2R4, R2 = H, ein gegebenenfalls durch Hai ein oder mehrfach substituiertes, lineares oder verzweigtes Alkyl mit 1-6 C-Atomen, Alkaryl, Alkheteroaryl, oder Heteroaryl, R4 = OH, OA, NH2, NHB oder NB2, A, B = unabhängig voneinander Alkyl mit 1-6 C-Atomen, m = 2, 3, 4, 5 oder 6 und n = 0, 1 , 2, 3 oder 4 ist, sowie deren physiologisch unbedenklichen Salze, Derivate, Solvate undR 1 , R 3 = independently of one another H, OH, OA, CN, shark, COR 4 or CH 2 R 4 , R 2 = H, a linear or branched alkyl which is unsubstituted or substituted by shark, with 1-6 C- Atoms, alkaryl, alkheteroaryl, or heteroaryl, R 4 = OH, OA, NH 2 , NHB or NB 2 , A, B = independently of one another alkyl with 1-6 C atoms, m = 2, 3, 4, 5 or 6 and n = 0, 1, 2, 3 or 4, and their physiologically acceptable salts, derivatives, solvates and
Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Stereoisomers, including their mixtures in all proportions.
Hai bedeutet vorzugsweise F, Cl oder Br, aber auch I.Shark preferably means F, Cl or Br, but also I.
A und B sind unabhängig voneinander vorzugsweise unverzweigt und haben 1, 2, 3, 4, 5, oder 6 C-Atome.A and B are preferably unbranched independently of one another and have 1, 2, 3, 4, 5 or 6 carbon atoms.
Alkyl mit 1-6 C-Atomen bedeutet vorzugsweise Methyl, Ethyl, n-Propyl, weiterhin bevorzugt Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.-Butyl, aber auch n-Pentyl, neo-Pentyl, Isopentyl oder n-Hexyl.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 bedeutet Alkyl mit 1-6 C-Atomen verbunden mit einem aromatischen Ringsystem aus 6 oder 10 Zentren wie z. B. Benzyl oder Phenethyl.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 bedeutet Alkyl mit 1-6 C-Atomen verbunden mit einem aromatischen Heterocyclus aus 5, 6 oder 10 Zentren wie z. B. Pyridin-2- ylmethyl.Alkheteroaryl means alkyl with 1-6 C atoms combined with an aromatic heterocycle from 5, 6 or 10 centers such as. B. pyridin-2-ylmethyl.
Heteroaryl bedeutet ein monovalenter monocyclischer oder bicyclischer Heterocyclus mit 5-12 Ringatomen, der wenigestens einen aromatischen Ring aufweist, wobei 1 , 2 oder 3 Ringatome ausgewählt sind unter N, O oder S. Heteroaryl ist gegebenenfalls unabhängig voneinander mit 1-4 Substituenten substituiert, beispielsweise ausgewählt unter Alkyl, Cycloalkyl.Cycloalkylalkyl, Hai, NO, CN, Alkoxy, NH2, Acylamino, Monoalkylamino, Dialkylamino, Halogenalkyl, Halogenalkoxy oder Heteroalkyl. Beispiele für Heteroaryle sind Pyridyl, Furanyl, Thienyl, Thiazolyl, Isothiazolyl, Triazolyl, Imidazolyl, Isoxazolyl, Pyrrolyl, Pyrazoiyl, Pyrazinyl, Pyrimidinyl, Benzofuranyl, Tetrahydrobenzofuranyl, Isobenzofuranyl, Benzothiazolyl, Benzoisothiazolyl, Benzotriazolyl, Indolyl, Isoindolyl, Benzoxazolyl, Chinolyl, Tetrahydrochinolyl, Isochinolyl, Benzoimidazolyl, Benzisoxazolyl, oder Benzothienyl oder Derivate davon.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. Examples of 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.
Bervorzugt sind die Verbindungen der Formel I, worinPreference is given to the compounds of the formula I in which
X = N,X = N,
R1, R3 = unabhängig voneinander CN, COR4 oder CH2R4, R2 = ein lineares oder verzweigtes Alkyl mit 1-6 C-Atomen, Alkaryl,R 1 , R 3 = independently of one another CN, COR 4 or CH 2 R 4 , R 2 = a linear or branched alkyl having 1-6 C atoms, alkaryl,
Alkheteroaryl, oder Heteroaryl,Alkheteroaryl, or heteroaryl,
R4 = OH, NH2, NHB oder NB2,R 4 = OH, NH 2 , NHB or NB 2 ,
A, B = unabhängig voneinander Alkyl mit 1-6 C-Atomen, m = 4 und n = 0 ist, sowie deren physiologisch unbedenklichen Salze, Derivate, Solvate undA, B = independently of one another alkyl with 1-6 C atoms, m = 4 and n = 0, and their physiologically acceptable salts, derivatives, solvates and
Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Stereoisomers, including their mixtures in all proportions.
Besonders bevorzugt sind die Verbindungen a) 5-{4-[4-(5-Cyano-1 -ethyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid b) 5-{4-[4-(5-Cyano-1 -isopropyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- . benzofuran-2-carbonsäureamid c) 5-{4-[4-(1 -Benzyl-5-cyano-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid d) 5-{4-[4-(5-Cyano-1 -propyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid e) 5-{4-[4-(5-Cyano-1 -pyridin-2-ylmethyl-1 H-indol-3-yl)-butyl]-piperazin- 1 -yl}-benzofuran-2-carbonsäureamid und f) 5-{4-[4-(5-Cyano-1-phenethyl-1 H-indol-3-yl)-butyl]-piperazin-1-yl}- benzofuran-2-carbonsäureamid und insbesondere die Verbindung 5-{4-[4-(5-Cyano-1-methyi-1H-indol-3-yl)- butyl]-piperazin-1-yl}-benzofuran-2-carbonsäureamid.The compounds a) 5- {4- [4- (5-cyano-1-ethyl-1H-indol-3-yl) -butyl] -piperazin-1 -yl} - benzofuran-2-carboxamide b are particularly preferred ) 5- {4- [4- (5-Cyano-1-isopropyl-1H-indol-3-yl) butyl] piperazin-1-yl} -. benzofuran-2-carboxamide c) 5- {4- [4- (1-benzyl-5-cyano-1 H -indol-3-yl) butyl] -piperazin-1-yl} - benzofuran-2-carboxamide d ) 5- {4- [4- (5-Cyano-1-propyl-1H-indol-3-yl) -butyl] -piperazin-1 -yl} - benzofuran-2-carboxamide e) 5- {4- [4- (5-cyano-1-pyridin-2-ylmethyl-1 H -indol-3-yl) butyl] piperazin-1-yl-benzofuran-2-carboxamide and f) 5- {4- [ 4- (5-Cyano-1-phenethyl-1H-indol-3-yl) butyl] piperazin-1-yl} - benzofuran-2-carboxamide and especially the compound 5- {4- [4- (5-cyano-1-methyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide.
Erfindungsgemäß sind auch alle physiologisch unbedenklichen Salze,According to the invention, all physiologically acceptable salts,
Derivate, Solvate und Stereoisomere dieser Verbindungen, einschließlich deren Mischungen in allen Verhältnissen.Derivatives, solvates and stereoisomers of these compounds, including their mixtures in all proportions.
Gegenstand der Erfindung sind auch die optisch aktiven Formen (Stereoisomeren), die Enantiomeren, die Racemate, die Diastereomeren sowie Hydrate und Solvate dieser Verbindungen.The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.
Unter pharmazeutisch oder physiologisch unbedenklichen Derivaten versteht man z.B. Salze der erfindungsgemäßen Verbindungen, als auch sogenannte Prodrug-Verbindungen. Unter Prodrug-Verbindungen versteht man mit z.B. Alkyl- oder Acylgruppen, Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßen Verbindungen gespalten oder freigesetzt werden. Hierzu gehören auch bioabbaubare Polymerderivate der erfindungsgemäßen Verbindungen, wie dies z.B. in Int. J. Pharm. 115 (1995), 61-67 beschrieben ist.Pharmaceutically or physiologically acceptable derivatives 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.
Als Säureadditionssalze kommen anorganische oder organische Salze aller physiologisch oder pharmakologisch unbedenklichen Säuren in Frage, beispielsweise Halogenide, insbesondere Hydrochloride oderSuitable acid addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or
Hydrpbromide, Lactate, Sulfate, Citrate, Tartrate, Maleate, Fumarate, Oxalate, Acetate, Phosphate, Methylsulfonate oder p-Toluolsulfonate. Unter Solvaten der Verbindungen der Formel I werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen der Formel I verstanden, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind beispielsweise Hydrate, wie Monohydrate oderHydrp bromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methyl sulfonates 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
Dihydrate oder Alkoholate, d.h. Additionsverbindungen mit Alkoholen wie beispielsweise mit Methanol oder Ethanol.Dihydrates or alcoholates, i.e. Addition compounds with alcohols such as methanol or ethanol.
Gegenstand der Erfindung sind auch Mischungen der erfindungsgemäßen Verbindungen der Formel I, z.B. Gemische zweier Diastereomere z.B. im Verhältnis 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 oder 1 :1000. Besonders bevorzugt handelt es sich um Mischungen zweier stereoisomerer Verbindungen.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.
Gegenstand der Erfindung ist außerdem ein Verfahren zur Herstellung der Verbindungen der Formel I, gekennzeichnet dadurch,The invention also relates to a process for the preparation of the compounds of the formula I, characterized in that
a) dass man eine Verbindung der Formel II, worin R1 und m die oben angegebenen Bedeutungen haben und Y ein Halogen, insbesondere Chlor, ist oder ein mit einer dem Fachmann bekannten Schutzgruppe versehener Alkohol ist,a) a compound of the formula II in which R 1 and m have the meanings given above and Y is a halogen, in particular chlorine, or is an alcohol provided with a protective group known to the person skilled in the art,
mit einer Verbindung III umsetzt, worin R2 die oben angegebenen Bedeutungen hat und Z eine dem Fachmann bekannte Abgangsgruppe darstellt, wie beispielsweise p-Tosyl, Trifluormethansulfonyl,reacted with a compound III, in which 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,
Methansulfonyl, Benzolsulfonyl, Br, Cl oder I R2— ZMethanesulfonyl, benzenesulfonyl, Br, Cl or I. R 2 - Z
undand
b) dass man die nach a) erhaltene Verbindung der Formel IVb) that the compound of formula IV obtained according to a)
mit einer Verbindung der Formel V oder einem Salz davon, worin R3, X und n die oben angegebenen Bedeutungen habenwith a compound of formula V or a salt thereof, wherein R 3 , X and n have the meanings given above
in einem Lösungsmittel gegebenenfalls unter Basenzusatz bei derin a solvent, optionally with the addition of base at
Siedetemperatur des Lösungsmittels umsetzt, oderReacting boiling point of the solvent, or
c) dass man die Base einer Verbindung der Formel I durch Behandlung mit einer Säure in eines ihrer Salze überführt.c) converting the base of a compound of formula I into one of its salts by treatment with an acid.
Es ist auch möglich die Reaktion jeweils stufenweise durchzuführen.It is also possible to carry out the reaction in stages.
Die Ausgangsverbindungen der Formel II, III, VI und V sind in der Regel bekannt. Sind sie neu, so können sie nach an sich bekannten Methoden hergestellt werden. Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so dass man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt.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.
Die Ausgangsstoffe können in Abwesenheit eines Lösungsmittels in einem verschlossenen Reaktionsgefäß oder einem Autoklav zusammengeführt (verschmolzen) werden. Es ist jedoch auch möglich, die Ausgangsstoffe in Anwesenheit eines inerten Lösungsmittels reagieren zu lassen.In the absence of a solvent, 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.
Als inerte Lösungsmittel eignen sich z.B. Heptan, Hexan, Petrolether, Benzol, Toluol, Xylol, Trichlorethylen-, 1 ,2- Dichlorethantetra- chlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether (bevorzugt für die Substitution amSuitable 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
Indolstickstoff), Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmonomethyl- oder monoethylether (Methylglykol oder Ethylglykol), Ethylenglykoldimethy-Iether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid, N-Methylpyrrolidon (NMP) oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Ester wieIndole nitrogen), 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 dimethylformamide (DMF); Nitriles such as acetonitrile; Esters like
Ethylacetat, Carbonsäuren oder Säureanhydride, wie z. B. wie Essigsäure oder Acetanhydrid, Nitroverbindungen wie Nitromethan oder Nitrobenzol, gegebenenfalls auch Gemische der genannten Lösungsmittel untereinander oder Gemische mit Wasser.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.
Die Reaktion kann auch in heterogener Phase ausgeführt werden, wobei vorzugsweise eine wässrige Phase und eine Benzol- oder Toluol-Phase verwendet werden. Hier kommt ein Phasentransfer-Katalysator zum Einsatz, wie beispielsweise Tetrabutylammoniumiodid und gegebenenfalls ein Acylierungskatalysator, wie beispielsweise Dimethylaminopyridin. Die Menge des Lösungsmittels ist nicht kritisch, vorzugsweise können 10 g bis 500 g Lösungsmittel je g der umzusetzenden Verbindung der Formel l zugesetzt werden.The reaction can also be carried out in a heterogeneous phase, an aqueous phase and a benzene or toluene phase being preferably used. Here 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.
Vorteilhaft kann die Zugabe eines säurebindenden Mittels sein, z.B. einThe addition of an acid-binding agent, e.g. on
Alkalimetall oder Erdalkalimetallhydroxid, -carbonat oder -bicarbonat oder andere Alkalimetall- oder Erdalkalimetallsalze schwacher Säuren, vorzugsweise ein Kalium-, Natrium- oder Calciumsalz, oder die Zugabe einer organischen Base, wie beispielsweise an Triethylamin, Dimethylamin, Pyridin oder Chinolin, oder ein Überschuss der Aminkomponente.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 of an organic base such as, for example, triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.
Geeignete Reaktionstemperaturen liegen bei Temperaturen von 10 bis 180°C, vorzugsweise bei 20 bis 150°C und ganz besonders bevorzugt bei 40 bis 100°C.Suitable reaction temperatures are from 10 to 180 ° C., preferably from 20 to 150 ° C. and very particularly preferably from 40 to 100 ° C.
Bevorzugt wird bei einem Druck von 1 bis 200 bar und bei Temperaturen zwischen -80° und +150°C gearbeitet, besonders bevorzugt bei Raumtemperatur und Normaldruck. Vorzugsweise bei 1 ,5 bis 120 bar und insbesondere bei 2 bis 100 bar.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.
Bevorzugt wird bei einem pH-Wert von 6 bis 10 gearbeitet.A pH of 6 to 10 is preferred.
Die Dauer der Umsetzung hängt von den gewählten Reaktionsbedingungen ab. In der Regel beträgt die Reaktionsdauer 0.5 Stunden bis 10 Tage, vorzugsweise 1 bis 24 Stunden. Bei Verwendung einer Mikrowelle kann die Reaktionszeit aufwerte von 1 bis 60 Minuten reduziert werden.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.
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach bekannten Methoden hergestellt, wie sie in der Literatur beschrieben sind (z. B: in Standardwerken wie Houben- Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) so z.B. unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher beschriebenen Varianten Gebrauch machen.The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by known methods as described in the literature (for example: in standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart), for example under reaction conditions, for the reactions mentioned are known and suitable. It is also possible to use variants which are known per se and are not described in more detail here.
Durch übliche Aufarbeitungsschritte wie z. B. Wasserzugabe zum Reaktionsgemisch und Extraktion können die Verbindungen der Formel II nach Entfernung des Lösungsmittels erhalten werden. Es kann vorteilhaft sein, zur weiteren Reinigung des Produktes eine Destillation oder Kristallisation anzuschließen.Through usual work-up steps such. B. Water addition to the reaction mixture and extraction, 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.
Eine Säure der Formel I kann mit einer Base in das dazugehörige Additionssalz überführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Säure und der Base in einem inerten Lösungsmittel wie Ethanol und einschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Basen in Frage, die physiologisch unbedenkliche Salze liefern. So kann die Säure der Formel I mit einer Base (z.B. Natrium- oder Kaliumhydroxid oder -carbonat) in das entsprechende Metall-, insbesondere Alkali- oder Erdalkalimetall- oder in das entsprechende Ammoniumsalz umgewandelt werden. Für diese Umsetzung kommen auch organische Basen in Frage, die physiologisch unbedenkliche Salze liefern, wie z.B. Ethanolamin.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. Thus 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.
Andererseits kann eine Base der Formel I mit einer Säure in das zugehörige Säureadditionssalz überführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wir Orthophosphorsäure, Sulfaminsäure, ferrier organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische, ein- oder mehrbaslge Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfonsäure, Ethandisulfonsäure, 2-On the other hand, 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. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, 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. formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethane
Hydroxysulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Naphthalin- mom- und disulfonsäuren oder Laurylschwefelsäure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und/oder Aufreinigung der Verbindungen der Formel I verwendet werden.Hydroxysulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mom and disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
Es wurde gefunden, dass die Verbindungen der Formel I und ihre physiologisch unbedenklichen Säureadditionssalze gut verträglich sind und wertvolle pharmakologische Eigenschaften besitzen, da sie besondere Wirkungen auf das Zentralnervensystem zeigen. Insbesondere hemmen sie die 5-HT-Wiederaufnahme. Die Verbindungen weisen außerdem eine hohe Affinität zu dem 5-HTx-Rezeptoren auf (bei 5-HTx bedeutet X: 1A oder 4) und zeigen serotonin-agonistische und -antagonistische Eigenschaften. Durch eine 5-HT-agonistische Wirkung und eine 5-HT- Wiederaufnahmehemmung verbleibt Serotonin länger im synaptischen Spalt und die Serotonin-Wirkung wird verstärkt. Wirkstoffe mit derartigen Eigeschaften eignen sich deshalb insbesondere als Antidepressiva und Anxiolytika. Die Verbindungen der Formel I hemmen die Bindung von tritiierten Serotoninliganden an hippocampale Rezeptoren (Cossery et al., European J. Pharmacol. 140 (1987), 143-155) und die synaptosomaleIt 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 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
Serotoninwiederaufnahme (Sherman et al., Life Sei. 23 (1978), 1863-1870).Serotonin reuptake (Sherman et al., Life Sci. 23 (1978), 1863-1870).
Zum in-vitro Nachweis der 5-HT-Wiederaufnahmehemmung wird die synaptosomale Wiederaufnahmehemmung (Wong et al., Neuropsycho- pharmacology 8 (1993), 22-33) und der p-Chloramphetaminantagonismus (Füller et al. J. Pharmacol. Exp. Ther. 212 (1980), 115-119) gemessen. Die Serotonin-Wiederaufnahmehemmung kann darüber hinaus auch mithilfe der Waldmeier-Methode ex-vivo im Hirngewebe der Maus untersucht werden (European J. Pharmacol. 1977, 46, 387-92), sowie durch die von DiChiara beschriebene Mikrodialyse (Trends in Pharmacol. Sei., ü (1990), 116-121). Dazu wird eine physiologische Lösung durch einen in ein Rattenhirn implantierten Mikrodialyse-Behälter perfundiert. Die Lösung nimmt dabei die im Gehirn freigesetzten Neurotransmitter auf und wird nachfolgend analysiert. So ist der 5-HT-Gehalt in der Lösung nach Perfusion zur im Gehirn freigesetzten Menge proportional und er steigt beispielsweise nach Gabe eines 5-HT-Wiederaufnahmehemmers an (Gardier et al., Fundam. Clin. Pharmacol., 10 (1996), 16-27).For in-vitro detection of 5-HT reuptake inhibition, synaptosomal reuptake inhibition (Wong et al., Neuropsychopharmacology 8 (1993), 22-33) and p-chloroamphetamine antagonism (Füller et al. J. Pharmacol. Exp. Ther 212: 115-119 (1980). 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). For this purpose, 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).
Die 5-HTiA-agonistische Wirkung kann man in-vitro beispielsweise mithilfe des (Serotonin-) Bindungstests messen, wie von Matzen et al. (J. Med. Chem., 43 (2000), 1149-57) beschrieben, insbesondere auf Seite 1156 mit Verweis auf Eur. J. Pharmacol., 140 (1987), 143-155. Darüber hinaus kann die 5-HT-iA-agonistische Wirkung mithilfe des von Newman-Tancredi et al. (Eur. J. Pharmacol. 307 (1996), 107-11) beschriebenen GTPgammaS- Tests gemessen werden.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. In addition, 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.
Weiterhin können nach Gabe der Verbindungen der Formel IAfter administration of the compounds of the formula I
Veränderungen der DOPA-Akkumulation im Striatum und der 5-HT- Akkumulation im N. raphe auftreten (Seyfried et al., Europ. J. Pharmacol. 160 (1989), 31-41). Außerdem können analgetische und blutdrucksenkende Wirkungen auftreten. So wird bei kathedertragenden wachen, spontan hypertonen Ratten (Methode vergl. Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960), 646-648) der direkt gemessene Blutdruck nach peroraler Gabe der Verbindungen gesenkt. Verbindungen der Formel I eignen sich deshalb auch zur Prophylaxe und Behandlung der Folgen cerebraler Infarktgeschehen (Apoplexia cerebri) wie Schlaganfall und cerebraler Ischämien. Gegenstand der Erfindung ist insbesondere die Verwendung der Verbindungen der Formel I sowie ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen als Serotonin-Rezeptor-Liganden und/oder zur Serotonin-Wiederaufnahmehemmung. Erfindungsgemäß ist insbesondere die Verwendung der Verbindungen der Formel l als 5-HT1A- Agonisten und als Inhibitoren der 5-HT-Wiederaufnahme.Changes in the DOPA accumulation in the striatum and the 5-HT accumulation in the N. raphe occur (Seyfried et al., Europ. J. Pharmacol. 160 (1989), 31-41). In addition, analgesic and hypotensive effects can occur. For example, in catheter-bearing awake, spontaneously hypertensive rats (method see Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960), 646-648), the directly measured blood pressure is reduced after oral administration of the compounds. Compounds of the formula I are therefore also suitable for the prophylaxis and treatment of the consequences of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia. 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. In particular, 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.
Gegenstand der Erfindung ist somit insbesondere auch die Verwendung von Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zur Herstellung eines Medikaments zur Behandlung von Krankheiten, insbesondere von Krankheiten, die mit dem Serotonin-Rezeptor und/oder der Serotonin- Wiederaufnahme in Zusammenhang stehen.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.
Erfindungsgemäße Verbindungen der Formel I können aufgrund ihrer Molekülstruktur chiral sein und können dementsprechend in verschiedenen enantiomeren Formen auftreten. Sie können daher in racemischer oder in optisch aktiver Form vorliegen. Da sich die pharmazeutische Wirksamkeit der Racemate bzw. der Stereoisomere der erfindungsgemäßen Verbindungen unterscheiden kann, kann es wünschenswert sein, die Enantiomere zu verwenden. In diesem Fällen kann das Endprodukt oder aber bereits die Zwischenprodukte in enantiomere Verbindungen, durch dem Fachmann bekannte chemische oder physikalische Maßnahmen, aufgetrennt oder bereits als solche bei der Synthese eingesetzt werden.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.
Da Verbindungen der Formel I die Serotonin-Wiederaufnahme hemmen und gleichzeitig 5-HTiA-agonstische Eigenschaften aufweisen, eignen sie sich insbesondere als Antidepressiva und Anxiolytika. Gegenstand der Erfindung ist deshalb auch die Verwendung von Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate, und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zur Herstellung eines Medikaments als Anxiolytikum, Antidepressivum, Neuroleptikum und/oder Antihypertonikum und/oder zur positiven Beeinflussung von Zwangsverhalten (OCD), Schlafstörungen, tardiver Dyskinesien, Lernstörungen, altersabhängiger Erinnerungsstörungen, Eßsstörungen wie Bulimie oder IBS und/oder Sexualfunktionsstörungen. Besonders bevorzugt ist die Verwendung zur Herstellung eines Medikaments als Antidepressivum. Verbindungen derSince 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. The use for the production of a medicament as an antidepressant is particularly preferred. Connections of the
Formel I können weiterhin und auch als Zwischenprodukte zur Herstellung anderer Arzneimittelwirkstoffe verwendet werden.Formula I can also be used as intermediates for the preparation of other active pharmaceutical ingredients.
Die Verbindungen der Formel I eignen sich sowohl in der Veterinär- als auch in der Humanmedizin zur Behandlung von Funktionsstörungen des Zentralnervensystems sowie von Entzündungen.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.
Gegenstand der Erfindung ist somit die Verwendung von Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zur Herstellung eines Medikaments zur Behandlung von Psychosen, Schizophrenie, schizoaffektiver Psychose, Cyclothymie, Epilepsien, Krämpfen, Depression (Subtypen schwerer Depression und cyclothymische Depression), krankhaften Angstzuständen (Subtypen von Panikattacken mit oder ohne Agoraphobie), Übererregung, Hyperaktivität, Stresserkrankungen, posttraumatischen Stressstörungen, Schlafstörungen, Narkolepsie, zyklische manisch depressive Erkrankung, Aufmerksamkeitsstörungen bei Kindern und Jugendlichen, tiefgreifenden Entwicklungsstörungen und Störungen des Sozialverhaltens mit geistiger Retardierung, Zwangserkrankungen im ehgeren (OCD) und weiteren Sinne (OCSD), Suchterkrankungen, Störungen in der Nahrungsaufnahme oder Eßstörungen, beispielsweise Bulimie, Übergewicht oder Anorexia nervosa, insbesondere Irritible Bowl Syndrom (IBS), Fibromyalgie, sowie psychiatrischen Symptomen im Rahmen der Altersdemenz und der Demenz vom Alzheimer-Typ, kognitiven Leistungsstörungen (Lern- und Erinnerungsstörungen), insbesondere altersabhängiger Erinnerungsstörungen, Demenz, tardiven Dyskinesien, neurodegenerativenThe 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 psychiatric symptoms in the context of age dementia and dementia of the Alzheimer type, cognitive performance disorders (learning and memory disorders), especially age-related memory disorders, dementia, tardive dyskinesias, neurodegenerative
Erkrankungen, wie Parkinsonsche Krankheit, Morbus Alzheimer, Huntington-Krankheit, Lathyrismus, amyotropher Lateralsklerose, Lewy Körperchen Demenz, Tourette Syndrom, sexuellen Funktionsstörungen, prämenstruellem Syndrom, Akromegalie, Hypogonadismus, sekundärer Amenorrhoe, unerwünschter puerperaler Laktation, extrapyramidalerDiseases such 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
Bewegungserkrankungen, zur Behandlung von Nebenwirkungen, die bei der Behandlung von extrapyramidalen Bewegungserkrankungen mit konventionellen Anti-Parkinson-Medikamenten auftreten und von extrapyramidalen Symptomen (EPS), Spannungszuständen, Nebenwirkungen der Hypertoniebehandlung, die durch Neuroleptika (z.B. mit α-Methyldopa) induziert werden oder zur Prophylaxe, Behandlung und Kontrolle von cerebralen Infarktgeschehen (Apoplexia cerebri), wie Schlaganfall und cerebraler Ischämien oder zur Behandlung von Schmerz, insbesondere chronischer Schmerz, Migräne, ZNS-Trauma, Hypoglykämie, Asthma, Glaukom, Zytomegalie und zur Behandlung von anderen degenerativen Retinaerkrankungen, Inkontinenz, Tinnitus, oder zur Behandlung von durch Aminoglycosid-Antibiotika induziertem Verlust des Gehörs.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 α-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.
Insbesondere sind sie jedoch geeignet als Arzneimittelwirkstoffe fürIn particular, however, they are suitable as active pharmaceutical ingredients for
Anxiolxytika, Antidepresiva, Antipsychotika, Neuroleptika, Antihypertonika und/oder zur positiven Beeinflussung von Zwangsverhalten (OCD), Schlafstörungen, tardiver Dyskinesien, Lernstörungen, altersabhängiger Erinnerungsstörungen, Eßstörungen wie Bulimie oder IBS und/oder Sexualfunktionsstörungen. Die Verbindungen der Formel I können zur Herstellung pharmazeutischer Zubereitungen verwendet werden, insbesondere auf nicht-chemischem Wege. Hierbei werden sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoff(en) in eine geeignete Dosierungsform gebracht.Anxiolxytics, antidepressants, antipsychotics, neuroleptics, antihypertensives 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. 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).
Ein weiterer Gegenstand der Erfindung sind deshalb pharmazeutische Zubereitungen, enthaltend wenigstens eine Verbindung der Formel I und/oder ihre physiologisch unbedenklichen Salze, Derivate, Solvate, und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen. Gegenstand der Erfindung sind insbesondere auch solche pharmazeutische Zubereitungen, die weitere Träger- und/oder Hilfsstoffe enthalten, sowie auch solche pharmazeutische Zubereitungen, die wenigstens einen weiteren Arzneimittelwirkstoff enthalten.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.
Gegenstand der Erfindung ist insbesondere auch ein Verfahren zur Herstellung einer pharmazeutischen Zubereitung, dadurch gekennzeichnet, dass man eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze, Derivate, Solvate, und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zusammen mit einem festen, flüssigen oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls mit einem weiteren Arzneimittelwirkstoff in eine geeignete Dosierungsform bringt.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.
Die erfindungsgemäßen pharmazeutischen Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden.The pharmaceutical preparations according to the invention can be used as medicaments in human or veterinary medicine.
Als Trägersubstanzen kommen organische oder anorganische Stoffe in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle (wie Sonnenblumenöl oder Lebertran), Benzylalkohole, Polyethylenglykole, Gelatine, Kohlehydrate wie Laktose oder Stärke, Magnesiumstearat, Talk, Lanolin oder Vaseline. Welche Hilfsstoffe für die gewünschte Arzneimittelformulierung geeignet sind, ist dem Fachmann auf Grund seines Fachwissens geläufig. Neben Lösungsmitteln z.B. Wasser, physiologische Kochsalzlösung oder Alkohole wie z.B. Ethanol, Propanol oder Glycerin, Zuckerlösungen wie Glucose oder Mannitlösungen oder eine Mischung der genannten Lösungsmittel, Gelbildnern, Tablettenhilfsstoffen und anderen Wirkstoffträgern können beispielsweise Gleitmittel, Stabilisatoren und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Antioxidantien,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. The person skilled in the art is familiar on the basis of his specialist knowledge with the auxiliaries which are suitable for the desired pharmaceutical formulation. In addition to 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,
Dispergiermittel, Entschäumer, Puffersubstanzen, Geschmacks- und/oder Aromastoffe bzw. Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler oder Farbstoffe verwendet werden. Falls erwünscht, können erfindungsgemäße Zubereitungen oder Medikamente einen oder mehrere weitere Wirkstoffe enthalten, beispielsweise ein oder mehrere Vitamine.Dispersants, defoamers, buffer substances, flavoring and / or aroma substances or flavoring agents, preservatives, solubilizers or colorants are used. If desired, preparations or medicaments according to the invention can contain one or more further active ingredients, for example one or more vitamins.
Gegenstand der Erfindung ist auch ein Set (Kit) bestehend aus getrennten Packungen von a) einer wirksamen Menge einer Verbindung der Formel I und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen und b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.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.
Das Set enthält geeignete Behälter, wie Schachteln oder Kartons, individuelle Flaschen, Beutel oder Ampullen. Das Set kann z.B. separate Ampullen enthalten, in denen jeweils eine wirksame Menge einer Verbindung der Formel I und/oder ihrer pharmazeutische unbedenklichen Derivate, Solvate, Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und eine wirksame Menge eines weiteren Arzneimittelwirkstoffs gelöst oder in lyophilisierter Form vorliegt. Zur enteralen Applikation (oral oder rektal) dienen insbesondere Tabletten, Dragees, Kapseln, Sirupe, Säfte, Tropfen oder Suppositorien, zur parenteralen Applikation (subkutan oder intravenös) Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen,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),
Emulsionen oder Implantate, für die topische Anwendung Salben, Creme, Pasten, Lotionen, Gele, Sprays, Schäume, Aerosole, Lösungen (z.B. Lösungen in Alkoholen wie Ethanol oder Isopropanol, Acetonitril, DMF, Dimethylacetamid, 1 ,2-Propandiol oder deren Gemischen untereinander und/oder mit Wasser) oder Puder. Insbesondere für topische Anwendungen kommen auch liposomale Zubereitungen in Betracht. Die Verbindungen und/oder deren physiologisch unbedenklichen Salze und Solvate können auch lyophilisiert und die erhaltenden Lyophilisate beispielsweise zur Herstellung von Injektionspräparaten verwendet werden. Sie können ferner als Nasensprays verabreicht werden.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. 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.
Die erfindungsgemäßen Verbindungen können an Menschen oder Tiere, insbesondere Säugetiere, wie Affen, Hunde, Katzen, Ratten oder Mäuse verabreicht werden und bei der therapeutischen Behandlung des menschlichen oder des tierischen Körpers sowie bei der Bekämpfung der oben aufgeführten Krankheiten verwendet werden. Sie können weiterhin als Diagnostika oder als Reagenzien Verwendung finden.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.
Bei Verwendung von erfindungsgemäßen Zubereitungen oder Medikamenten werden die erfindungsgemäßen Verbindungen und/oder dessen physiologisch unbedenklichen Salze und Solvate in der Regel analog zu bekannten, käuflich erhältlichen Zubereitungen oder Präparaten verwendet, vorzugsweise in Dosierungen zwischen 0,1 und 500 mg, insbesondere 5 und 300 mg pro Anwendungseinheit. Die tägliche Dosierung liegt vorzugsweise zwischen 0,001 und 250 mg/kg, insbesondere 0,01 und 100 mg/kg Köpergewicht. Die Zubereitung kann ein- oder mehrmals pro Tag verabreicht werden, z.B. zwei-, drei- oder viermal am Tag. Jedoch hängt die individuelle Dosierung für einen Patienten von einer großen Zahl individueller Faktoren ab, wie beispielsweise von der Wirksamkeit der jeweils verwendeten Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, Ernährung, vom Verabreichungszeitpunkt und -weg, von der Ausscheidungsrate, von der Kombination mit anderen Arzneimitteln und von der Schwere und Dauer der jeweiligen Erkrankung. Die orale Applikation ist bevorzugt.When preparations or medicaments according to the invention are used, 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. However, 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.
Ein Maß für die Aufnahme eines Arzneimittelwirkstoffs in einen Organismus ist seine Bioverfügbarkeit. Wird der Arzneimitelwirkstoff in Form einer Injektionslösung dem Organismus intravennös zugeführt, so liegt seine absolute Bioverfügbarkeit, d.h. der Anteil des Pharmakons, der unverändert im systemischen Blut, d.h. in den großen Kreislauf gelangt, bei 100%. Bei oraler Gabe eines therapeutischen Wirkstoffs liegt der Wirkstoff in der Regel als Feststoff in der Formulierung vor und muss sich daher zuerst auflösen, damit er die Eintrittsbarrieren, beispielsweise den Gastrointestinaltrakt, die Mundschleimhaut, nasale Membranen oder die Haut, insbesondere das Stratum corneum, überwinden kann bzw. vom Körper resorbiert werden kann. Daten zur Pharmakokinetik, d.h. zur Bioverfügbarkeit können analog zu der Methode von J. Shaffer et al., J. Pharm. Sciences, 88 (1999), 313-318 erhalten werden.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%. When a therapeutic active ingredient is administered orally, 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.
Auch ohne weitere Ausführungsformen wird davon ausgegangen, dass ein Fachmann die obige Beschreibung im weitesten Umfang nutzen kann. Die bevorzugten Ausführungsformen sind deshalb lediglich als beschreibende, keineswegs aber als in irgendeiner Weise limitierende Offenbarung aufzufassen.Even without further embodiments, it is assumed that a person skilled in the art can use the above description in the broadest scope. The preferred embodiments are therefore only to be understood as a descriptive disclosure, but in no way as a limitation in any way.
Die folgenden Beispiele sollen somit die Erfindung erläutern, ohne sie zu begrenzen. Sofern nichts anderes angegeben ist, bedeuten Prozentangaben Gewichtsprozent. Alle Temperaturen sind in Grad Celsius angegeben. "Übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH- Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oderThe following examples are thus intended to illustrate the invention without limiting it. Unless otherwise stated, percentages mean percentages by weight. All temperatures are given in degrees Celsius. "Normal work-up": if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to Values between 2 and 10, extracted with ethyl acetate or
Dichlormethan, trennt ab, trocknet die organische Phase überDichloromethane, separates, the organic phase dries over
Natriumsulfat, filtriert, dampft ein und reinigt durch Chromatographie anSodium sulfate, filtered, evaporated and purified by chromatography
Kieselgel und /oder durch Kristallisation.Silica gel and / or by crystallization.
Rf-Werte an Kieselgel;Rf values on silica gel;
Massenspektrometrie: El (Elektronenstoßionisation): M+ Mass spectrometry: El (electron impact ionization): M +
FAB (Fast Atom Bombardment): (M+H)+ THF (Tetrahydrofuran), NMP (N-Methlpyrrolidon), DMSO (Dimethlysulfoxid), EE (Ethylacetat), MeOH (Methanol), DC (Dünnschichtchromatographie)FAB (Fast Atom Bombardment): (M + H) + THF (tetrahydrofuran), NMP (N-methyl pyrrolidone), DMSO (dimethyl sulfoxide), EE (ethyl acetate), MeOH (methanol), DC (thin layer chromatography)
Die folgenden Substanzen wurden synthetisiert und charakterisiert. Die Herstellung und Charakterisierung der Substanzen ist jedoch auch auf anderen Wegen für den Fachmann durchführbar.The following substances were synthesized and characterized. However, the manufacture and characterization of the substances can also be carried out in other ways for the person skilled in the art.
Beispiel 1:Example 1:
Synthese von 5-{4-[4-(5-Cyano-1-methyl-1 H-indol-3-yl)-butyl]-piperazin-1- yl}-benzofuran-2-carbonsäureamidSynthesis of 5- {4- [4- (5-cyano-1-methyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran-2-carboxamide
a.: Es werden 0,8 g (20 mmol) NaH in 20 ml THF suspendiert und bei Raumtemperatur eine Lösung von 4,6 g (20 mmol) 3-(4-Chloro-butyl)-1 H- indol-5-carbonitril in 50 ml THF zugetropft. Die gelbe Lösung wird 30 Minuten nachgerührt und dann eine Lösung von 1 ,2 ml (20 mmol) lodmethan in 30 ml THF zugetropft. Die gelbe Lösung wird 1 h bei Raumtemperatur gerührt. Anschließend wird die Reaktionslösung eingeengt und der Rückstand mit Ethylacetat und Wasser ausgeschüttelt. Die organische Phase wird mit Wasser gewaschen, mit Natriumsulfat getrocknet und eingeengt. Man erhält 5,4 g öligen Rückstand, welcher mit 15 ml. Diethylether und 5 ml Petrolether kristallisiert, abgesaugt und mit wenig Diethylether gewaschen wird. Nach dem Trocknen an Luft erhält man 3,2 g grobe hellgelbe Kristalle [M+H+] ESI-MS 457.a .: 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. 5.4 g of an oily residue are obtained, which crystallize with 15 ml of diethyl ether and 5 ml of petroleum ether, filtered off with suction and washed with a little diethyl ether. After drying in air, 3.2 g of coarse light yellow crystals [M + H + ] ESI-MS 457 are obtained.
b.: 540 mg (2,2 mmol) des nach a. erhaltenen Indols werden zusammen mit 490 mg (2 mmol) 5-Piperazin-1-yl-benzofuran-2-carbonsäureamid und 0,9 ml Triethylamin in 5 ml NMP suspendiert und erhitzt. Die entstandene Lösung wird zweimal 4 Stunden bei 120°C Badtemperatur gerührt und über 10 Stunden auf Raumtemperatur abgekühlt.b .: 540 mg (2.2 mmol) of the after a. Indoles obtained are suspended together with 490 mg (2 mmol) of 5-piperazin-1-yl-benzofuran-2-carboxamide and 0.9 ml of triethylamine in 5 ml of NMP and heated. The resulting solution is stirred twice for 4 hours at a bath temperature of 120 ° C. and cooled to room temperature over 10 hours.
Das Reaktionsgemisch wird in 100 ml Wasser eingerührt. Dabei fallen feine Kristalle aus. Diese werden abgesaugt, mit Wasser gewaschen und über Nacht an der Luft getrocknet. Die resultierenden 0,9 g hellbraune Kristalle werden schließlich chromatographisch zu 0,8 g heller Kristalle aufgereinigt. Diese werden in Aceton heiß gelöst und mit einem Milliliter ethanolischer HCI versetzt. Es fallen sofort weiße Kristalle aus. Diese werden nochmals heiß verrührt, abgesaugt und mit Aceton gewaschen.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.
Berechnet C=61 ,4 H=5,9 N=13,2 Cl=13,4 Gefunden C=60,7 H=6,0 N=13,1 Cl=12,7 Berechnet auf DihydrochloridCalculated C = 61.4 H = 5.9 N = 13.2 Cl = 13.4 Found C = 60.7 H = 6.0 N = 13.1 Cl = 12.7 Calculated on dihydrochloride
Beispiel 2:Example 2:
Analog Beispiel 1 werden u.a. folgenden Produkte hergestellt:Analogously to example 1, manufactured the following products:
Beispiel 3: Ergebnisse der RezeptorbindungstestsExample 3: Results of Receptor Binding Tests
Eine Vielzahl der synthetisierten Verbindungen besitzt nanomolare Affinität zu den 5-HTιA-Rezeptoren, sowie eine nanomolare Wiederaufnahmehemmung von Serotonin.A large number of the synthesized compounds have nanomolar affinity for the 5-HTι A receptors, as well as a nanomolar inhibition of serotonin reuptake.
5-{4-[4-(5-Cyano-1 -methyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}-benzofuran-5- {4- [4- (5-Cyano-1-methyl-1H-indol-3-yl) butyl] piperazin-1-yl} benzofuran
2-carbonsäureamid (siehe Beispiel 1)2-carboxamide (see example 1)
SSRI 2.6 nmol/l (IC50) SSRI 2.6 nmol / l (IC50)
5HT4 21 nmol/l (IC50)5HT 4 21 nmol / l (IC50)
Beispiel 4: InjektionsgläserExample 4: Injection glasses
Eine Lösung von 100 g einer Verbindung der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg einer Verbindung der Formel I. Beispiel 5: SuppositorienA 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
Man schmilzt ein Gemisch von 20 g einer Verbindung der Formel I mit 100 g Sojälecithin und 1400 g Kakaobutter, gießt in Formen und lässt erkalten. Jedes Suppositorium enthält 20 mg einer Verbindung der Formel I.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.
Beispiel 6: LösungExample 6: Solution
Man bereitet eine Lösung aus 1 g einer Verbindung der Formel I, 9,38 gA solution is prepared from 1 g of a compound of formula I, 9.38 g
NaH2PO4 2 H2O, 28,48 g Na2HPO4- 12 H2O und 0,1 gNaH 2 PO 4 2 H 2 O, 28.48 g Na 2 HPO 4 - 12 H 2 O and 0.1 g
Benzalkoniumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.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.
Beispiel 7: SalbeExample 7: Ointment
Man mischt 500 mg einer Verbindung der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of a compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel 8: TablettenExample 8: tablets
Ein Gemisch von 1 kg einer Verbindung der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpresst, derart, dass jede Tablette 10 mg einer Verbindung der Formel I enthält.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.
Beispiel 9: Dragees Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.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.
Beispiel 10: KapselnExample 10: Capsules
2 kg einer Verbindung der Formel I werden in üblicherweise in Hartgelatinekapseln gefüllt, so dass jede Kapsel 20 mg einer Verbindung der Formel I enthält.2 kg of a compound of the formula I are usually filled into hard gelatin capsules, so that each capsule contains 20 mg of a compound of the formula I.
Beispiel 11: AmpullenExample 11: Ampoules
Eine Lösung von 1 kg einer Verbindung der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg einer Verbindung der Formel I. 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.

Claims

Ansprüche Expectations
1. Verbindungen der Formel1. Compounds of the formula
X = N oder CH,X = N or CH,
R1, R3 = unabhängig voneinander H, OH, OA, CN, Hai, COR4 oderR 1 , R 3 = independently of one another H, OH, OA, CN, Hai, COR 4 or
CH2R4,CH 2 R 4 ,
R2 = H, ein gegebenenfalls durch Hai ein oder mehrfach substituiertes, lineares oder verzweigtes Alkyl mit 1-6 C-Atomen, Alkaryl,R 2 = H, a linear or branched alkyl with 1-6 C atoms which is optionally substituted one or more times by shark, alkaryl,
Alkheteroaryl, oder Heteroaryl,Alkheteroaryl, or heteroaryl,
R4 = OH, OA, NH2, NHB oder NB2,R 4 = OH, OA, NH 2 , NHB or NB 2 ,
A, B = unabhängig voneinander Alkyl mit 1-6 C-Atomen, m = 2, 3, 4, 5 oder 6 und n = 0, 1 , A, B = independently of one another alkyl with 1-6 C atoms, m = 2, 3, 4, 5 or 6 and n = 0, 1,
2, 3 oder 4 ist, sowie deren physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen2, 3 or 4, and their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all
Verhältnissen.Conditions.
Verbindungen nach Anspruch 1 , worinCompounds according to claim 1, wherein
X = N,X = N,
R1, R3 = unabhängig voneinander CN, COR4 oder CH2R4,R 1 , R 3 = independently of one another CN, COR 4 or CH 2 R 4 ,
R2 = ein lineares oder verzweigtes Alkyl mit 1-6 C-Atomen, Alkaryl,R 2 = a linear or branched alkyl having 1-6 C atoms, alkaryl,
Alkheteroaryl, oder Heteroaryl,Alkheteroaryl, or heteroaryl,
R4 = OH, NH2, NHB oder NB2, A, B = unabhängig voneinander Alkyl mit 1-6 C-Atomen, m = 4 und n = 0 ist, sowie deren physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allenR 4 = OH, NH 2 , NHB or NB 2 , A, B = independently of one another is alkyl having 1-6 C atoms, m = 4 and n = 0, and their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all
Verhältnissen.Conditions.
3. Verbindungen nach Anspruch 1 oder 2 a) 5-{4-[4-(5-Cyano-1 -methyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid b) 5-{4-[4-(5-Cyano-1 -ethyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid c) 5-{4-[4-(5-Cyano-1 -isopropyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid d) 5-{4-[4-(1 -Benzyl-5-cyano-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid e) 5-{4-[4-(5-Cyano-1 -propyl-1 H-indol-3-yl)-butyl]-piperazin-1 -yl}- benzofuran-2-carbonsäureamid f) 5-{4-[4-(5-Cyano-1 -pyridin-2-ylmethyI-1 H-indol-3-yl)-butyl]- piperazin-1 -yl}-benzof uran-2-carbonsäureamid g) 5-{4-[4-(5-Cyano-1-phenethyl-1 H-indol-3-yl)-butyl]-piperazin-1-yl}- benzofuran-2-carbonsäureamid3. Compounds according to claim 1 or 2 a) 5- {4- [4- (5-cyano-1-methyl-1 H -indol-3-yl) butyl] piperazin-1-yl} - benzofuran-2 -carboxamide b) 5- {4- [4- (5-cyano-1-ethyl-1H-indol-3-yl) -butyl] -piperazin-1 -yl} - benzofuran-2-carboxamide c) 5- {4- [4- (5-Cyano-1-isopropyl-1 H -indol-3-yl) butyl] piperazin-1-yl} - benzofuran-2-carboxamide d) 5- {4- [4- (1-Benzyl-5-cyano-1 H -indol-3-yl) -butyl] -piperazin-1 -yl} - benzofuran-2-carboxamide e) 5- {4- [4- (5-Cyano-1 -propyl-1 H -indol-3-yl) -butyl] -piperazin-1 -yl} - benzofuran-2-carboxamide f) 5- {4- [4- (5-cyano-1-pyridin-2-ylmethyI -1 H-indol-3-yl) -butyl] -piperazin-1 -yl} -benzof uran-2-carboxamide g) 5- {4- [4- (5-cyano-1-phenethyl-1 H-indole -3-yl) -butyl] -piperazin-1-yl} - benzofuran-2-carboxamide
4. Verfahren zur Herstellung der Verbindungen der Formel I, gekennzeichnet dadurch, dass man4. A process for the preparation of the compounds of formula I, characterized in that
a) eine Verbindung der Formel II, worin R1 und m die in Anspruch 1 angegebenen Bedeutungen haben und Y ein Halogen ist oder ein mit einer dem Fachmann bekannten Schutzgruppe versehener Alkohol ist, a) a compound of the formula II, in which R 1 and m have the meanings given in claim 1 and Y is a halogen or an alcohol provided with a protective group known to the person skilled in the art,
mit einer Verbindung der Formel III umsetzt, worin R die in Anspruch 1 angegebenen Bedeutungen hat und Z eine dem Fachmann bekannte Abgangsgruppe darstellt, wie beispielsweise p-Tosyl, Trifluormethansulfonyl, Methansulfonyl, Benzolsulfonyl, Br, Cl oder Iwith a compound of formula III, wherein R has the meanings given in claim 1 and Z represents a leaving group known to the person skilled in the art, such as, for example, p-tosyl, trifluoromethanesulfonyl, methanesulfonyl, benzenesulfonyl, Br, Cl or I.
R2— ZR2- Z
undand
dass man die nach a) erhaltene Verbindung der Formel IVthat the compound of formula IV obtained according to a)
mit einer Verbindung der Formel V oder einem Salz davon, worin R3, X und n die in Anspruch 1 angegebenen Bedeutungen habenwith a compound of formula V or a salt thereof, wherein R 3 , X and n have the meanings given in Claim 1
in einem Lösungsmittel gegebenenfalls unter Basenzusatz bei der in a solvent, optionally with the addition of base at
Siedetemperatur des Lösungsmittels umsetzt, oderReacting boiling point of the solvent, or
c) dass man die Base einer Verbindung der Formel I durchc) that the base of a compound of formula I by
Behandlung mit einer Säure in eines ihrer Salze überführt.Treatment with an acid converted to one of its salts.
5. Verbindungen nach einem der Ansprüche 1 bis 3 sowie ihre physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen als Serotonin-Rezeptor-Liganden und/oder zur Serotonin- Wiederaufnahmehemmung.5. Compounds according to any one of claims 1 to 3 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.
6. Pharmazeutische Zubereitung, enthaltend wenigstens eine Verbindung nach einem der Ansprüche 1 bis 3 und/oder ihre physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.6. Pharmaceutical preparation containing at least one compound according to one of claims 1 to 3 and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios.
7. Pharmazeutische Zubereitung, nach Anspruch 6 enthaltend weitere Träger- und/oder Hilfsstoffe.7. Pharmaceutical preparation according to claim 6 containing further carriers and / or auxiliaries.
8. Pharmazeutische Zubereitung, enthaltend wenigstens eine Verbindung nach einem der Ansprüche 1 bis 3 und/oder ihre physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen sowie wenigstens einen weiteren Arzneimittelwirkstoff.8. Pharmaceutical preparation containing at least one compound according to one of claims 1 to 3 and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions and at least one further active pharmaceutical ingredient.
9. Verfahren zur Herstellung einer pharmazeutischen Zubereitung, dadurch gekennzeichnet, dass man eine Verbindung nach einem der Ansprüche 1 bis 3 und/oder eines ihrer physiologisch unbedenklichen9. A method for producing a pharmaceutical preparation, characterized in that a compound according to one of claims 1 to 3 and / or one of its physiologically acceptable
Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zusammen mit einem festen, flüssigen oder halbfiüssigen Träger- oder Hilfsstoff in eine geeignete Dosierungsform bringt.Salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions together with a solid, brings liquid or semi-liquid carrier or auxiliary into a suitable dosage form.
10. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 3 und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zur Herstellung eines Medikaments zur Behandlung von Krankheiten.10. Use of compounds according to any one of claims 1 to 3 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.
11. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 3 und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zur Herstellung eines Medikaments zur Behandlung von Krankheiten, die mit dem Seroton in-Rezeptor und/oder der Serotonin- Wiederaufnahme in Zusammenhang stehen.11. Use of compounds according to any one of claims 1 to 3 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 associated with the serotonin in receptor and / or related to serotonin reuptake.
12. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 3 und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zur Herstellung eines Medikaments als Anxiolytikum,12. Use of compounds according to one of claims 1 to 3 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,
Antidepressivum, Neuroleptikum und/oder Antihypertonikum und/oder zur positiven Beeinflussung von Zwangsverhalten (OCD), Schlafstörungen, tardiver Dyskinesien, Lemstörungen, altersabhängiger Erinnerungsstörungen, Eßstörungen wie Bulimie oder IBS und/oder Sexualfunktionsstörungen.Antidepressant, neuroleptic and / or antihypertensive and / or to positively influence compulsive behavior (OCD), sleep disorders, tardive dyskinesia, lem disorders, age-related memory disorders, eating disorders such as bulimia or IBS and / or sexual dysfunction.
13. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 3 und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen zur Herstellung eines Medikaments zur Behandlung von13. Use of compounds according to one of claims 1 to 3 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
Psychosen, Schizophrenie, schizoaffektiver Psychose, Cyclothymie, Epilepsien, Krämpfen, Depression (Subtypen schwerer Depression und cyclothymische Depression), krankhaften Angstzuständen (Subtypen von Panikattacken mit oder ohne Agoraphobie), Übererregung, Hyperaktivität, Stresserkrankungen, posttraumatischen Stressstörungen, Schlafstörungen, Narkolepsie, zyklische manisch depressive Erkrankung, Aufmerksamkeitsstörungen bei Kindern undPsychoses, 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, cyclic manic depressive disorders, attention disorders in children and
Jugendlichen, tiefgreifenden Entwicklungsstörungen und Störungen des Sozialverhaltens mit geistiger Retardierung, Zwangserkrankungen im engeren (OCD) und weiteren Sinne (OCSD), Suchterkrankungen, Störungen in der Nahrungsaufnahme oder Eßstörungen, beispielsweise Bulimie, Übergewicht oder Anorexia nervosa, insbesondere IrritibleAdolescents, profound developmental disorders and disorders of social behavior with mental retardation, obsessive-compulsive illnesses in the narrower (OCD) and wider sense (OCSD), addictive illnesses, disorders in the intake of food or eating disorders, e.g. bulimia, overweight or anorexia nervosa, especially irritable
Bowl Syndrom (IBS), Fibromyalgie, sowie psychiatrischen Symptomen im Rahmen der Altersdemenz und der Demenz vom Alzheimer-Typ, kognitiven Leistungsstörungen (Lern- und Erinnerungsstörungen), insbesondere altersabhängiger Erinnerungsstörungen, Demenz, tardiven Dyskinesien, neurodegenerativen Erkrankungen, wieBowl syndrome (IBS), fibromyalgia, as well as psychiatric symptoms in the context of age dementia and dementia of the Alzheimer type, cognitive impairment (learning and memory disorders), in particular age-related memory disorders, dementia, tardive dyskinesias, neurodegenerative diseases, such as
Parkinsonsche Krankheit, Morbus Alzheimer, Huntington-Krankheit, Lathyrismus, amyotropher Lateralsklerose, Lewy Körperchen Demenz, Tourette Syndrom, sexuellen Funktionsstörungen, prämenstruellem Syndrom, Akromegalie, Hypogonadismus, sekundärer Amenorrhoe, unerwünschter puerperaler Laktation, extrapyramidalerParkinson'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
Bewegungserkrankungen, zur Behandlung von Nebenwirkungen, die bei der Behandlung von extrapyramidalen Bewegungserkrankungen mit konventionellen Anti-Parkinson-Medikamenten auftreten und von extrapyramidalen Symptomen (EPS), Spannungszuständen, Nebenwirkungen der Hypertoniebehandlung, die durch NeuroleptikaMovement 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), tension states, side effects of hypertension treatment caused by neuroleptics
(z.B. mit α-Methyldopa) induziert werden oder zur Prophylaxe, Behandlung und Kontrolle von cerebralen Infarktgeschehen (Apoplexia cerebri), wie Schlaganfall und cerebraler Ischämien oder zur Behandlung von Schmerz, insbesondere chronischer Schmerz, Migräne, ZNS-Trauma, Hypoglykämie', Asthma, Glaukom, Zytomegalie und zur Behandlung von anderen degenerativen Retinaerkrankungen, Inkontinenz, Tinnitus, oder zur Behandlung von durch Aminoglycosid- Antibiotika induziertem Verlust des Gehörs.(e.g. with α-methyldopa) or for the prophylaxis, treatment and control of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia or for the treatment of pain, especially chronic pain, migraine, CNS trauma, hypoglycemia ' , asthma, Glaucoma, cytomegaly and to treat other degenerative retinal diseases, Incontinence, tinnitus, or to treat hearing loss induced by aminoglycoside antibiotics.
14. Set (Kit) bestehend aus getrennten Packungen von a) einer wirksamen Menge einer Verbindung nach einem der Ansprüche 1 bis 3 und/oder ihrer physiologisch unbedenklichen Salze, Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen und b) einer wirksamen Menge eines weiteren Arzneimitteiwirkstoffs. 14. Set (kit) consisting of separate packs of a) an effective amount of a compound according to any one of claims 1 to 3 and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios and b) an effective Amount of another drug ingredient.
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