WO2002020521A1 - Use of indole derivatives for treating illnesses of the central nervous system - Google Patents

Use of indole derivatives for treating illnesses of the central nervous system Download PDF

Info

Publication number
WO2002020521A1
WO2002020521A1 PCT/EP2001/010443 EP0110443W WO0220521A1 WO 2002020521 A1 WO2002020521 A1 WO 2002020521A1 EP 0110443 W EP0110443 W EP 0110443W WO 0220521 A1 WO0220521 A1 WO 0220521A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinuclidine
indolyl
groups
alkyl
carbamoyl
Prior art date
Application number
PCT/EP2001/010443
Other languages
German (de)
French (fr)
Inventor
Günter Hölzemann
Kai Schiemann
Henning Böttcher
Joachim Leibrock
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
Priority to AU2002212226A priority Critical patent/AU2002212226A1/en
Publication of WO2002020521A1 publication Critical patent/WO2002020521A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to substances which are used for the treatment of diseases in which stimulation of the nicotinic acetylcholine receptors leads to an improvement in the clinical picture.
  • the substances used according to the invention contain an optionally substituted 3-indolyl group which is linked to quinuclidinyl or dehydroquinuclidinyl units.
  • Some members of the well-characterized class of acetylcholine receptors are held responsible for certain clinical pictures of the central nervous system.
  • Known active ingredients that can interact with the class of acetylcholine receptors are, for example, pilocarpine, nicotine, lobeline and epibatidine.
  • the object of the present invention is to provide compounds with which these clinical pictures can be treated. This object is achieved by using substances of the general formula (I)
  • R 1 to R 5 are independently selected from the group consisting of hydrogen, branched and unbranched C 1 -C 4 alkyl groups, branched and unbranched dC alkoxy groups, branched and unbranched C 1 -C 4 alkoxy groups, trifluoromethyl groups, C 6 -C ⁇ o Aryloxy groups, C 7 -Cn aralkyloxy groups, CrC 5 acyloxy groups, C 6 -C 10 aroyloxy groups, CrC 4 alkylsulfonyloxy groups, C 6 -C 10 arylsulfonyloxy groups, linear and branched dC alkoxycarbonyl groups, amino, mono (CrC 5 alkyl) amino and di (C 1 -C 5 alkyl) amino groups, carbamoyl, N-mono (CrC 5 -alkyl) carbamoyl and N- di (CrC 5 -alkyl) carbamoyl group, methylenedioxy
  • R is selected from the group consisting of hydrogen and linear and branched alkyl groups, and (Chin.) Means a 3-quinuclidinyl or a 2,3-dehydro-3-quinuclidinyl group for the manufacture of a medicament for diseases in which an excitation of the nicotinic acetylcholine receptors leads to improvement of the clinical picture.
  • the substances to be used according to the invention are known. They are disclosed in the applicant's EP-B-450345 and are used according to this invention for the treatment of diseases which are characterized by an excess of circulating serotonin or by a serotonergic hyperfunction. These include in particular psychoses, nausea and vomiting (which occur, for example, in the chemo- or radiotherapeutic treatment of cancer), dementia or other cognitive disorders, migraines and addictions. Furthermore, the use as an anxiolytic, antiaggressive, antidepressant and analgesic also belongs to the indications according to this invention.
  • the compounds antagonize the action of serotonin at 5-HT 3 receptors, such as, for example, the von Bezold-Jarisch reflex caused by serotonin (methodology see J.Pharm. Pharmacol. 40 (1988), 301-302 and Nature 316 ( 1985), 126-131).
  • these compounds displace the substance 3 H-GR65630 known as selective 5-HT 3 ligand from homogenized tissue from the endorhinal cortex of the rat (see European J. Pharmacol. 159 (1989), 157-164).
  • the substances of the formula (I) can, in addition to the indication disclosed in EP-B-450 375, also be used specifically for the treatment of diseases in which stimulation of the nicotinic acetylcholine receptors to improve the Disease picture leads.
  • diseases in which stimulation of the nicotinic acetylcholine receptors to improve the Disease picture leads.
  • Examples are known to the person skilled in the art and include schizophrenia, dementia, and in particular Alzheimer's disease, neurodegenerative diseases, Parkinson's disease and Tourette's syndrome.
  • R is preferably hydrogen. It is then preferred if all of the groups R 1 to R 5 in the substances of the formula (I) are hydrogen. In a further embodiment, it is preferred if in the substances of the formula (I) one or two groups R 1 to R 5 have a meaning other than hydrogen, these groups then preferably being in 5, 6 and / or 7-position of the indyl group. In a further embodiment of the invention, preference is also given to substances of the formula (I) in which R is an alkyl group; here too, the radicals R 1 to R 5 preferably have the meaning which was defined above as the preferred embodiment.
  • Preferred radicals R 1 to R 5 are selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, formyloxy, acetyloxy, propanoyloxy, and butanoyloxy, i-butanoyloxy and pivaloyloxy, methanesulfonyloxy, phenoxy, benzyloxy, benzoyloxy, methylenedioxy , Hydroxymethyl, amino and carbamoyl.
  • the compounds of formula (I) is generally carried out according to known methods such as, 3 rd edition in the literature (eg J. March, Advanced Organic Chemistry, John Wiley & Sons, New York or Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions as they are known and suitable for the reactions mentioned. You can also fall back on variants which are known per se and are not mentioned in more detail below.
  • the compounds of the formula (I) which contain a 3-quinuclidinyl radical have at least one asymmetric carbon atom. They can therefore be present in various optically active forms or as a racemate or racemate mixture.
  • a base of the formula (I) can be converted into the associated acid addition salt using an acid.
  • Acids which provide physiologically acceptable salts are preferably suitable for this reaction.
  • inorganic acids can be used, for example sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulphuric acid. famincicre.
  • organic acids for example aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid .
  • Acid addition salts which are not physiologically safe (picrates) can be suitable for the isolation and purification of the bases of the formula (I).
  • a base of the formula (I) can also be liberated from one of its salts with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate.
  • the compounds (I) set out above are used for the production of medicaments which are used for the treatment of diseases which are based on a dysfunction of nicotinic acetylcholine receptors.
  • nicotinic acetylcholine receptors can be divided into two principal classes, depending on the locations where they occur.
  • neuromuscular receptors there are the neuromuscular receptors. These are further divided into ( ⁇ i ⁇ iß ⁇ ) and (o. ⁇ ß ⁇ ) receptors.
  • neuronal nicotinic acetylcholine receptors that are found in the ganglia.
  • ( ⁇ 2- ⁇ ) receptors and the (0: 2 -0: 9) receptors, see also “Basic Neurochemistry”, Ed. Siegel et. Al., Raven Press, New York 1993.
  • the substances of the formula (I) are able to interact with each of these receptors more or less well, for example depending on the structure of the molecule used in each case.
  • Receptor can, for example, be analogous to JM Ward et al., FEBS 1990, 270, 45-48 or DRE Macallan, FEB 1998, 226, 357-363.
  • Diseases that can be treated with the substances according to formula (I) include schizophrenia, dementia, in particular Alzheimer's disease, neurodegenerative diseases, Parkinson's disease, Tourette's syndrome, age-related memory loss, relief of withdrawal symptoms, and also due to the neuroprotective effect Stroke and brain damage from toxic compounds.
  • Another object of the present invention are pharmaceutical preparations containing one or more compounds corresponding to formula (I) and / or their physiologically active salts.
  • these can be brought into a suitable dosage form together with at least one carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • 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. Examples include water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • Tablets, coated tablets, capsules, syrups, juices, drops or suppositories are used in particular for enteral administration, and solutions, preferably for parenteral administration oily or aqueous solutions, also suspensions, emulsions or implants, for topical applications, ointments, creams, plasters or powders.
  • the new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings. If appropriate, they can also contain one or more further active ingredients which do not correspond to the formula (I), for example one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings.
  • they can also contain one or more further active ingredients which do not correspond to the formula (I), for
  • the substances according to the invention are generally administered in analogy to known, commercially available preparations (for example tacrin), preferably in doses between about 5 mg and 100 mg, in particular between 10 and 40 mg per dosage unit.
  • the daily dosage is preferably between about 0.5 and 1 mg / kg body weight.
  • the specific dose for each individual patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and Severity of the respective disease to which the therapy applies.
  • Preferred substances are:
  • Example B coated tablets Analogously to Example A, 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 3- (5-hydroxy-3-indolyl) -quinuclidine hydrochloride in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.
  • Tablets dragees, capsules and ampoules which contain another compound of the formula I and / or one or more physiologically acceptable acid addition salts of a compound of the formula (I) are obtainable analogously.

Abstract

The invention relates to the use of compounds of general formula (I) wherein R1 to R5 are independently selected from the group consisting of hydrogen, branched and unbranched C¿1-?C4--alkyl groups, branched and unbranched C1-C4--alkoxy groups, branched and unbranched C1-C4--alkythio groups, trifluoromethyl groups, C6-C10--aryloxy groups, C7-C11--aralkyloxy groups, C1-C5--acyloxy groups, C6-C10--aroyloxy groups, C1-C4--alkylsulfonyloxy groups, C6-C10--arylsulfonyloxy groups, linear and branched C1-C4--alkoxycarbonyl groups, amino, mono(C1-C5-Alkyl)amino and di(C1-C5--alkyl)amino groups, carbamoyl, N-mono(C1-C5--alkyl)carbamoyl and N-bi(C1-C5--alkyl)carbamoyl groups, methylene dioxy groups, hydroxy groups, hydroxymethyl groups, and fluorine and chlorine; R is selected from the group consisting of hydrogen and linear and branched alkyl groups; and (chin.) represents a 3-quinuclidinyl or a 2,3-dehydro-3-quinuclidinyl group, or the physiologically tolerable salts of said compounds, for producing a medicament against illnesses whereby stimulating the nicotinic acetylcholine receptors leads to an improvement in the clinical picture.

Description

Verwendung von Indolderivaten zur Behandlung von Erkrankungen des zentralen Nervensystems Use of indole derivatives for the treatment of diseases of the central nervous system
Die vorliegende Erfindung betrifft Substanzen, die zur Behandlung von Krankheiten eingesetzt werden, bei denen eine Anregung der nikotinischen Acetylcholinrezeptoren zur Verbesserung des Krankheitsbildes führt. Die erfindungsgemäß verwendeten Substanzen enthalten eine gegebenenfalls substituierte 3-lndolylgruppe, die mit Chinuclidinyl- oder De- hydrochinuclidinyleinheiten verbunden ist.The present invention relates to substances which are used for the treatment of diseases in which stimulation of the nicotinic acetylcholine receptors leads to an improvement in the clinical picture. The substances used according to the invention contain an optionally substituted 3-indolyl group which is linked to quinuclidinyl or dehydroquinuclidinyl units.
Von der gut charakterisierten Klasse der Acetylcholinrezepetoren werden einige Mitglieder für bestimmte Krankheitsbilder des zentralen Nervensystems verantwortlich gemacht. Bekannte Wirkstoffe, die mit der Klasse der Acetylcholinrezeptoren wechselwirken können, sind beispielsweise Pilo- carpin, Nicotin, Lobelin und Epibatidin.Some members of the well-characterized class of acetylcholine receptors are held responsible for certain clinical pictures of the central nervous system. Known active ingredients that can interact with the class of acetylcholine receptors are, for example, pilocarpine, nicotine, lobeline and epibatidine.
Es besteht jedoch weiterhin ein Bedarf an Verbindungen, die zur Behandlung von Krankheitsbildern eingesetzt werden können, die durch eine Dysfunktion nikotinischer Acetylcholinrezeptoren hervorgerufen werden.However, there is still a need for compounds which can be used to treat clinical pictures which are caused by a dysfunction of nicotinic acetylcholine receptors.
Die Aufgabe der vorliegenden Erfindung ist es, Verbindungen zur Verfügung zu stellen, mit denen diese Krankheitsbilder behandelt werden können. Diese Aufgabe wird gelöst durch die Verwendung von Substanzen der allgemeinen Formel (I)The object of the present invention is to provide compounds with which these clinical pictures can be treated. This object is achieved by using substances of the general formula (I)
Figure imgf000003_0001
Figure imgf000003_0001
in der R1 bis R5 unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Wasserstoff, verzweigten und unverzweigten C1-C4- Alkylgruppen, verzweigten und unverzweigten d-C -Alkoxygruppen, verzweigten und unverzweigten Cι-C -Alkythiogruppen,Trifluormethylgruppen, C6-Cιo-Aryloxygruppen, C7-Cn-Aralkyloxygruppen, CrC5-Acyloxy-gruppen, C6-C10-Aroyloxygruppen, CrC4-Alkylsulfonyloxygruppen, C6-C10- Arylsulfonyloxygruppen, linearen und verzweigten d-C - Alkoxycarbonylgruppen, Amino-, Mono(CrC5-Alkyl)amino- und Di(Cι-C5- Alkyl)aminogruppen, Carbamoyl-, N-Mono(CrC5-Alkyl)carbamoyl- und N- Di(CrC5-Alkyl)carbamoylgruppe, Methylendioxygruppen, Hydroxygruppen,in which R 1 to R 5 are independently selected from the group consisting of hydrogen, branched and unbranched C 1 -C 4 alkyl groups, branched and unbranched dC alkoxy groups, branched and unbranched C 1 -C 4 alkoxy groups, trifluoromethyl groups, C 6 -Cιo Aryloxy groups, C 7 -Cn aralkyloxy groups, CrC 5 acyloxy groups, C 6 -C 10 aroyloxy groups, CrC 4 alkylsulfonyloxy groups, C 6 -C 10 arylsulfonyloxy groups, linear and branched dC alkoxycarbonyl groups, amino, mono (CrC 5 alkyl) amino and di (C 1 -C 5 alkyl) amino groups, carbamoyl, N-mono (CrC 5 -alkyl) carbamoyl and N- di (CrC 5 -alkyl) carbamoyl group, methylenedioxy groups, hydroxyl groups,
Hydroxymethylgruppen, Fluor und Chlor,Hydroxymethyl groups, fluorine and chlorine,
R ausgewählt ist aus der Gruppe bestehend aus Wasserstoff und linearen und verzweigten Alkylgruppen, und (Chin.) eine 3-Chinuclidinyl- oder eine 2,3-Dehydro-3-chinuclidinylgruppe bedeutet, zur Herstellung eines Medikaments gegen Krankheiten, bei denen eine Anregung der nikotinischen Acetylcholinrezeptoren zur Verbesserung des Krankheitsbildes führt.R is selected from the group consisting of hydrogen and linear and branched alkyl groups, and (Chin.) Means a 3-quinuclidinyl or a 2,3-dehydro-3-quinuclidinyl group for the manufacture of a medicament for diseases in which an excitation of the nicotinic acetylcholine receptors leads to improvement of the clinical picture.
Die erfindungsgemäß einzusetzenden Substanzen sind bekannt. Sie sind offenbart in der EP-B- 450345 der Anmelderin und werden gemäß dieser Erfindung eingesetzt zur Behandlung von Erkrankungen, die durch einen Überschuß an zirkulierendem Serotonin oder durch eine serotonerge Ü- berfunktion charakterisiert sind. Dazu gehören insbesondere Psychosen, Nausea und Erbrechen (die beispielsweise bei der chemo- oder radiotherapeutischen Behandlung von Krebserkrankungen auftreten), Dementia o- der andere kognitive Erkrankungen, Migräne und Suchterkrankungen. Weiterhin zählen auch die Anwendung als Anxiolytikum, Antiaggressivum, Antidepressivum und Analgetikum zu den Indikationen gemäß dieser Er- findung. Dabei antagonisieren die Verbindungen die Wirkung von Serotonin an 5-HT3-Rezeptoren, wie z.B. den durch Serotonin hervorgerufenen von-Bezold-Jarisch-Reflex (Methodik siehe J.Pharm.Pharmacol. 40 (1988), 301-302 und Nature 316 (1985), 126-131). Außerdem verdrängen diese Verbindungen die als selektiver 5-HT3-Ligand bekannte Substanz 3H- GR65630 von homogenisiertem Gewebe aus dem endorhinalen Cortex der Ratte (siehe Europ.J.Pharmacol. 159 (1989), 157-164).The substances to be used according to the invention are known. They are disclosed in the applicant's EP-B-450345 and are used according to this invention for the treatment of diseases which are characterized by an excess of circulating serotonin or by a serotonergic hyperfunction. These include in particular psychoses, nausea and vomiting (which occur, for example, in the chemo- or radiotherapeutic treatment of cancer), dementia or other cognitive disorders, migraines and addictions. Furthermore, the use as an anxiolytic, antiaggressive, antidepressant and analgesic also belongs to the indications according to this invention. The compounds antagonize the action of serotonin at 5-HT 3 receptors, such as, for example, the von Bezold-Jarisch reflex caused by serotonin (methodology see J.Pharm. Pharmacol. 40 (1988), 301-302 and Nature 316 ( 1985), 126-131). In addition, these compounds displace the substance 3 H-GR65630 known as selective 5-HT 3 ligand from homogenized tissue from the endorhinal cortex of the rat (see European J. Pharmacol. 159 (1989), 157-164).
Es wurde nun überraschend gefunden, daß die Substanzen der Formel (I) neben den in der EP-B- 450 375 offenbarten Indikation auch spezifisch zur Behandlung von Krankheiten eingesetzt werden können, bei denen eine Anregung der nikotinischen Acetylcholinrezeptoren zur Verbesserung des Krankheitsbildes führt. Beispiele sind dem Fachmann bekannt und umfassen Schizophrenie, Demenz, dabei auch insbesondere Morbus Alzheimer, neurodegenerative Erkrankungen, Parkinson'sche Krankheit und Touret- te's Syndrom.It has now surprisingly been found that the substances of the formula (I) can, in addition to the indication disclosed in EP-B-450 375, also be used specifically for the treatment of diseases in which stimulation of the nicotinic acetylcholine receptors to improve the Disease picture leads. Examples are known to the person skilled in the art and include schizophrenia, dementia, and in particular Alzheimer's disease, neurodegenerative diseases, Parkinson's disease and Tourette's syndrome.
Vorzugsweise ist in den Molekülen der Formel (I) R Wasserstoff. Dabei ist es dann bevorzugt, wenn in den Substanzen der Formel (I) sämtliche Gruppen R1 bis R5 Wasserstoff sind. In einer weiteren Ausführungsform ist es bevorzugt, wenn in den Substanzen der Formel (I) ein oder zwei Grup- pen R1 bis R5eine andere Bedeutung als Wasserstoff haben, wobei diese Gruppen sich dann vorzugsweise in 5-, 6- und/oder 7-Position der Indo- lylgruppe befinden. Bevorzugt sind auch in einer weiteren Ausführungsform der Erfindung Substanzen der Formel (I), in denen R eine Alkylgrup- pe ist; dabei besitzen auch hier die Reste R1 bis R5 vorzugsweise die Be- deutung, die vorstehend als bevorzugte Ausführungsform definiert wurde.In the molecules of formula (I), R is preferably hydrogen. It is then preferred if all of the groups R 1 to R 5 in the substances of the formula (I) are hydrogen. In a further embodiment, it is preferred if in the substances of the formula (I) one or two groups R 1 to R 5 have a meaning other than hydrogen, these groups then preferably being in 5, 6 and / or 7-position of the indyl group. In a further embodiment of the invention, preference is also given to substances of the formula (I) in which R is an alkyl group; here too, the radicals R 1 to R 5 preferably have the meaning which was defined above as the preferred embodiment.
Bevorzugte Reste R1 bis R5sind ausgewählt aus der Gruppe bestehend aus Wasserstoff, Methyl, Hydroxy, Methoxy, Formyloxy, Acetyloxy, Propa- noyloxy, und Butanoyloxy, i-Butanoyloxy und Pivaloyloxy, Methansulfony- loxy, Phenoxy, Benzyloxy, Benzoyloxy, Methylendioxy, Hydroxymethyl, A- mino und Carbamoyl.Preferred radicals R 1 to R 5 are selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, formyloxy, acetyloxy, propanoyloxy, and butanoyloxy, i-butanoyloxy and pivaloyloxy, methanesulfonyloxy, phenoxy, benzyloxy, benzoyloxy, methylenedioxy , Hydroxymethyl, amino and carbamoyl.
Schließlich sind Verbindungen der Formel (I) bevorzugt, die einen 3- Chinuclidinylrest enthalten.Finally, compounds of the formula (I) are preferred which contain a 3-quinuclidinyl radical.
Mögliche Herstellungsverfahren sind beispielsweise: Umsetzen einer Verbindung der Formel (II):Possible production processes are, for example: reacting a compound of the formula (II):
Figure imgf000005_0001
Figure imgf000005_0001
in der R1 bis R5 die oben angegebene Bedeutung haben, mit 3- Chinuclidinon oder einem seiner Salze zur 2,3-Dehydro-3- chinuclidinylverbindung entsprechend (I) mit (Chin) = 2,3-Dehydro-3- chinuclidinyl und, soweit gewünscht, Reduktion zur 3- Chinuclidinylverbindung, entsprechend (I) mit (Chin) = 3-Chinuclidinyl; Überführen einer Verbindung, die sonst der Formel (I) entspricht, aber an Stelle eines oder mehrerer H-Atome eine abspaltbare Schutzgruppe enthält, durch Abspaltung dieser Schutzgruppe in eine Verbindung der Formel (I); Umwandeln in einer Verbindung der Formel (I) des Indolylrests in einen anderen Indolylrest; Umwandeln einer Base der Formel (I) durch Behandeln mit einer Säure in eines ihrer Salze; Freisetzen einer Substanz der Formel (I) aus einem Salz dieser Substanz mittels einer starken Base.in which R 1 to R 5 have the meaning given above, with 3-quinuclidinone or one of its salts to give 2,3-dehydro-3- quinuclidinyl compound corresponding to (I) with (quin) = 2,3-dehydro-3-quinuclidinyl and, if desired, reduction to the 3-quinuclidinyl compound, corresponding to (I) with (quin) = 3-quinuclidinyl; Converting a compound which otherwise corresponds to the formula (I) but contains a removable protective group instead of one or more H atoms, by removing this protective group into a compound of the formula (I); Converting the indolyl group in another compound of formula (I) to another indolyl group; Converting a base of formula (I) into one of its salts by treatment with an acid; Release of a substance of formula (I) from a salt of this substance using a strong base.
Die Herstellung der Verbindungen der Formel (I) erfolgt generell nach an sich bekannten Methoden, wie sie in der Literatur (z.B. J. March, Advances Organic Chemistry, 3rd edition, John Wiley & Sons, New York oder Hou- ben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, wie sie für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch auf an sich bekannte, nachfolgend nicht näher erwähnte Varianten zurückgreifen.The compounds of formula (I) is generally carried out according to known methods such as, 3 rd edition in the literature (eg J. March, Advanced Organic Chemistry, John Wiley & Sons, New York or Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions as they are known and suitable for the reactions mentioned. You can also fall back on variants which are known per se and are not mentioned in more detail below.
Die vorstehend dargelegten Herstellungsverfahren von Verbindungen der Formel (I) sind in der EP-B- 450 345 der Anmelderin näher erläutert. Diese dort aufgeführten Herstellungsverfahren sind durch Referenz in die vorliegende Anmeldung eingeschlossen.The preparation processes of compounds of the formula (I) set out above are explained in more detail in EP-B-450 345 by the applicant. These manufacturing processes listed there are included in the present application by reference.
Die Verbindungen der Formel (I), die einen 3-Chinuclidinylrest enthalten, weisen zumindest ein asymmetrisches Kohlenstoffatom auf. Sie können daher in verschiedenen optisch aktiven Formen oder auch als Racemate bzw. Racematgemisch vorliegen.The compounds of the formula (I) which contain a 3-quinuclidinyl radical have at least one asymmetric carbon atom. They can therefore be present in various optically active forms or as a racemate or racemate mixture.
Eine Base der Formel (I) kann mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden. Für diese Umsetzung eignen sich bevorzugt Säuren, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, beispielsweise Schwefelsäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Salpetersäure, Sul- faminsäure. Ebenfalls eignen sich organische Säuren, beispielsweise a- liphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, wie Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure,A base of the formula (I) can be converted into the associated acid addition salt using an acid. Acids which provide physiologically acceptable salts are preferably suitable for this reaction. Thus, inorganic acids can be used, for example sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulphuric acid. faminsäure. Also suitable are organic acids, for example aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid .
Milchsäure, Weinsäure, Äpfelsäure, Benzoesäure, Salicylsäure, 2- Phenylpropionsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotin- säure, Isonicotinsäure, Methan- und Ethansulfonsaure, Benzolsulfonsaure, p-Toluolsulfonsäure, Napthalin-mono- und -disulfonsäuren, Laurylschwe- feisäure. Säureadditionssalze, die nicht physiologisch unbedenklich sind (Pikrate), können sich zur Isolierung und Aufreinigung der Basen der Formel (I) eignen.Lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane and ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acid, lauryl. Acid addition salts which are not physiologically safe (picrates) can be suitable for the isolation and purification of the bases of the formula (I).
Eine Base der Formel (I) kann ebenfalls aus einem ihrer Salze mit starken Basen wie Natrium- oder Kaliumhydroxid, Natrium- oder Kaliumcarbonat in Freiheit gesetzt werden.A base of the formula (I) can also be liberated from one of its salts with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate.
Die oben dargelegten Verbindungen (I) werden zur Herstellung von Arzneimitteln verwendet, die zur Behandlung von Krankheiten eingesetzt wer- den, die auf einer Dysfunktion nikotinischer Acetylcholinrezeptoren beruhen.The compounds (I) set out above are used for the production of medicaments which are used for the treatment of diseases which are based on a dysfunction of nicotinic acetylcholine receptors.
Diese nikotinischen Acetylcholinrezeptoren lassen sich in zwei prinzipielle Hauptklassen unterteilen, in Abhängigkeit von den Orten, an denen sie vorkommen.These nicotinic acetylcholine receptors can be divided into two principal classes, depending on the locations where they occur.
Zum einen sind dies die neuromuskulären Rezeptoren. Diese werden weiter unterteilt in (αiαißεδ) - und (o.ιαιßγδ) - Rezeptoren. Zum anderen existieren die neuronalen nikotinischen Acetylcholinrezeptoren, die in den Ganglien gefunden werden. Bei diesen unterscheidet man zwischen den (ß2-ßδ) - Rezeptoren und den (0:2-0:9) - Rezeptoren, siehe hierzu auch „Basic Neurochemistry", Ed. Siegel et. al., Raven Press, New York 1993.First, there are the neuromuscular receptors. These are further divided into (αiαißεδ) and (o.ιαιßγδ) receptors. On the other hand, there are the neuronal nicotinic acetylcholine receptors that are found in the ganglia. In these, a distinction is made between the (β2-βδ) receptors and the (0: 2 -0: 9) receptors, see also “Basic Neurochemistry”, Ed. Siegel et. Al., Raven Press, New York 1993.
Die Substanzen der Formel (I) sind in der Lage, mehr oder weniger gut, etwa in Abhängigkeit von der Struktur des jeweils eingesetzten Moleküls, mit jedem dieser Rezeptoren eine Wechselwirkung einzugehen. Beson- ders gut wechselwirken die Substanzen der Formel (I), dabei insbesondere die nachstehend als bevorzugt beschriebenen, mit dem nikotinischen α - Rezeptor.The substances of the formula (I) are able to interact with each of these receptors more or less well, for example depending on the structure of the molecule used in each case. special the substances of the formula (I), in particular those described below as preferred, interact well with the nicotinic α-receptor.
Ein in-vitro Nachweis der Wechselwirkungen mit dem nikotinischen α7-An in vitro detection of the interactions with the nicotinic α 7 -
Rezeptor kann beispielsweise analog zu J.M. Ward et al., FEBS 1990, 270, 45-48 oder D.R.E. Macallan, FEB 1998, 226, 357-363, erfolgen. Weitere in-vitro Tests für nikotinische Rezeptoren sind in F.E. D'Amour et al., Manual for Laboratory Work in Mammalian Physiology, 3rd Ed., The U- niversity of Chicago Press (1965), W. Sihver et al., Neuroscience 1998,Receptor can, for example, be analogous to JM Ward et al., FEBS 1990, 270, 45-48 or DRE Macallan, FEB 1998, 226, 357-363. Other in vitro tests for nicotinic receptors in FE D'Amour et al., Manual for Laboratory Work in Mammalian Physiology, 3rd Ed., The U niversity of Chicago Press (1965), W. Sihver et al., Neuroscience 1998
85, 1121 -1133 oder B. Latli et al., J.Med. Chem. 1999, 42, 2227-2234, beschrieben.85, 1121-1133 or B. Latli et al., J.Med. Chem. 1999, 42, 2227-2234.
Krankheiten, die mit den Substanzen gemäß Formel (I) behandelt werden können, umfassen Schizophrenie, Demenz, dabei insbesondere Morbus Alzheimer, neurodegenerative Erkrankungen, Parkinson'sche Krankheit, Tourette's Syndrom, altersbedingte Gedächtnisschwäche, Linderung von Entzugserscheinungen, außerdem durch die neuroprotektive Wirkung Anwendung bei Schlaganfall und Schädigung des Gehirns durch toxische Verbindungen.Diseases that can be treated with the substances according to formula (I) include schizophrenia, dementia, in particular Alzheimer's disease, neurodegenerative diseases, Parkinson's disease, Tourette's syndrome, age-related memory loss, relief of withdrawal symptoms, and also due to the neuroprotective effect Stroke and brain damage from toxic compounds.
Ein weiterer Gegenstand der vorliegenden Erfindung sind pharmazeutische Zubereitungen enthaltend eine oder mehrere Verbindungen entsprechend der Formel (I) und/oder deren physiologisch wirksame Salze. Dazu können diese zusammen mit mindestens einem Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Darreichungsform gebracht werden. Diese Zubereitungen können als Arzneimittel in der Human- und Veterinärmedizin eingesetzt werden. Als Trägersubstanzen kommen organische oder anor- ganische Stoffe in Frage, die sich für die enterale (beispielsweise orale), parenterale oder topische Applikation eignen und mit den neuen Verbindungen nicht reagieren. Beispiele umfassen Wasser, pflanzliche Öle, Ben- zylalkohole, Polyethylenglykole, Gelatine, Kohlenhydrate wie Lactose oder Stärke, Magnesiumstearat, Talk und Vaseline. Zur enteralen Applikation dienen insbesondere Tabletten, Dragees, Kapseln, Sirupe, Säfte, Tropfen oder Suppositorien, zur parenteralen Applikation Lösungen, vorzugsweise ölige oder wäßrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendungen, Salben, Cremes, Pflaster oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyophilisate beispielsweise zur Herstellung von Injektionspräparaten verwendet werden.Another object of the present invention are pharmaceutical preparations containing one or more compounds corresponding to formula (I) and / or their physiologically active salts. For this purpose, these can be brought into a suitable dosage form together with at least one carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients. These preparations can be used as medicinal products in human and 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. Examples include water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, coated tablets, capsules, syrups, juices, drops or suppositories are used in particular for enteral administration, and solutions, preferably for parenteral administration oily or aqueous solutions, also suspensions, emulsions or implants, for topical applications, ointments, creams, plasters or powders. The new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injectables.
Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, E- mulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffer- Substanzen, Färb-, Geschmacks- und/oder Aromastoffe enthalten. Sie können gegebenenfalls auch einen oder mehrere weitere Wirkstoffe enthalten, die nicht der Formel (I) entsprechen, beispielsweise ein oder mehrere Vitamine.The specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings. If appropriate, they can also contain one or more further active ingredients which do not correspond to the formula (I), for example one or more vitamins.
Dabei werden die erfindungsgemäßen Substanzen in der Regel in Analogie zu bekannten, im Handel befindlichen Präparaten (beispielsweise Tac- rin) verabreicht, vorzugsweise in Dosierungen zwischen etwa 5 mg und 100 mg, insbesondere zwischen 10 und 40 mg pro Dosierungseinheit. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,5 und 1 mg/kg Körpergewicht.The substances according to the invention are generally administered in analogy to known, commercially available preparations (for example tacrin), preferably in doses between about 5 mg and 100 mg, in particular between 10 and 40 mg per dosage unit. The daily dosage is preferably between about 0.5 and 1 mg / kg body weight.
Die spezielle Dosis für jeden einzelnen Patienten hängt von verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinem Ge- sundheitszustand, Geschlecht, von der Kost, vom Verabfolgungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt.The specific dose for each individual patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and Severity of the respective disease to which the therapy applies.
Die orale Anwendung ist bevorzugt.Oral use is preferred.
Beispiele für die erfindungsgemäße Substanzen der Formel (I) sind nachfolgend aufgeführt.Examples of the substances of the formula (I) according to the invention are listed below.
3-(3-lndolyl)-2,3-dehydrochinuclidin 3-(4-Methoxy-3-indolyl)-2,3-dehydro-chinuclidin 3-(5-Methoxy-3-indolyl)-2,3-dehydro-chinuclidin -(5-Ethoxy-3-indolyl)-2,3-dehydro-chinuclidin -(5-Propoxy-3-indolyl)-2,3-dehydro-chinuclidin -(6-Methoxy-3-indoloyl)-2,3-dehydro-chinuclidin -(5,6-Dimethoxy-3-indolyl)-2,3-dehydro-chinuclidin -(5,6-Methylendioxy-3-indolyl)-2,3-dehydro-chinuclidin -(4,5,6-Trimethoxy-3-indolyl)-2,3-dehydro-chinuclidin -(5-Methylthio-3-indolyl)-2,3-dehydro-chinuclidin -(5-Fluor-3-indolyl)-2,3-dehydro-chinuclidin -(5-Chlor-3-indölyl)-2,3-dehydro-chinuclidin -(5-Trifluormethyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Chlor-5-methoxy-3-indolyl)-2,3-dehydro-chinuclidin -(6-Methyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Methoxy-1-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Ethoxy-1-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Propoxy-1-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Methoxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(2-Methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Ethoxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Propoxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Methoxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5,6-Dimethoxy-2-methyl-3-indoloyl)-2,3-dehydro-chinuclidin -(5,6-Methylendioxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(4,5,6-Trimethoxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Methylthio-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Fluor-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Chlor-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Trifluormethyl-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Chlor-5-methoxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(2,6-Dimethyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Methoxy-1,2-dimethyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Ethoxy-1 ,2-dimethyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Propoxy-1 ,2-dimethyl-3-indolyl)-2,3-dehydro-chinuclidin -(3-lndolyl)-chinuclidin -(4-Methoxy-3-indolyl)-chinuclidin -(5-Methoxy-3-indolyl)-chinuclidin -(5-Ethoxy-3-indolyl)-chinuclidin -(5-Propoxy-3-indolyl)-chinuclidin -(6-Methoxy-3-indolyl)-chinuclidin -(5,6-Dimethoxy-3-indoloyl)-chinuclidin -(5,6-Methylendioxy-3-indolyl)-chinuclidin -(4,5,6-Trimethoxy-3-indolyl)-chinuclidin -(5-Methylthio-3-indolyl)-chinuclidin -(5-Fluor-3-indolyl)-chinuclidin -(5-Chlor-3-indolyl)-chinuclidin -(5-Trifluormethyl-3-indolyl)-chinuclidin -(6-Chlor-5-methoxy-3-indolyl)-chinuclidin -(6-Methyl-3-indolyl)-chinuclidin -(6-Methoxy-1-methyl-3-indolyl)-chinuclidin -(6-Ethoxy-1-methyl-3-indolyl)-chinuclidin -(6-Propoxy-1-methyl-3-indolyl)-chinuclidin -(2-Methyl-3-indolyl)-chinuclidin -(5-Methoxy-2-methyl-3-indolyl)-chinuclidin -(5-Ethoxy-2-methyl-3-indoloyl)-chinuclidin -(5-Propoxy-2-methyl-3-indolyl)-chinuclidin -(6-Methoxy-2-methyl-3-indolyl)-chinuclidin -(5,6-Dimethoxy-2-methyl-3-indolyl)-chinuclidin -(5,6-Methylendioxy-2-methyl-3-indolyl)-chinuclidin -(4,5,6-Trimethoxy-2-methyl-3-indolyl)-chinuclidin -(5-Methylthio-2-methyl-3-indolyl)-chinuclidin -(5-Fluor-2-methyl-3-indolyl)-chinuclidin -(5-Chlor-2-methyl-3-indolyl)-chinuclidin -(5-Trifluormethyl-2-methyl-3-indolyl)-chinuclidin -(6-Chlor-5-methoxy-2-methyl-3-indolyl)-chinuclidin -(2,6-Dimethyl-3-indolyl)-chinuclidin -(5-Methoxy-1 ,2-dimethyl-3-indolyl)-chinuclidin -(6-Ethoxy-1 ,2-dimethyl-3-indolyl)-chinuclidin -(6-Propoxy-1 ,2-dimethyl-3-indolyl)-chinuclidin -(5-Benzyloxy-3-indolyl)-2,3-dehydro-chinuclidin -(6-Benzyloxy-3-indolyl)-2,3-dehydro-chinuclidin -(6-Benzyloxy-1-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Benzyloxy-3-indolyl)-2,3-dehydro-chinuclidin -(5-Benzyloxy-1-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Benzyloxy-2~methyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Benzyloxy-2-methyl-3-indolyl)-2,3-dehydro-chinuclidin -(6-Benzyloxy-1 ,2-dimethyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Benzyloxy-1 ,2-dimethyl-3-indolyl)-2,3-dehydro-chinuclidin -(5-Hydroxy-3-indolyl)-2,3-dehydro-chinuclidin -(6-Hydroxy-3-indolyl)-chinuclidin -(6-Hydroxy-1-methyl-3-indolyl)-chinuclidin -(5-Hydroxy-3-indolyl)-chinuclidin -(5-Hydroxy-1-methyl-3-indolyl)-chinuclidin -(6-Hydroxy-2-methyl-3-indolyl)-chinuclidin -(5-Hydroxy-2-methyl-3-indolyl)-chinuclidin -(6-Hydroxy-1 ,2-dimethyl-3-indolyl)-chinuclidin -(5-Hydroxy-1 ,2-dimethyl-3-indolyl)-chinuclidin -(5-Acetoxy-3-indolyl)-chinuclidin -(5-Pivaloyloxy-3-indoloyl)-chinuclidin -(5-Propanoyloxy-3-indolyl)-chinuclidin -(5-Butanoyloxy-3-indolyl)-chinuclidin -(5-Methansulfonyloxy-3-indolyl)-chinuclidin -(6-Acetoxy-3-indolyl)-chinuclidin -(6-Pivaloyloxy-3-indoloyl)-chinuclidin -(6-Propanoyloxy-indolyl)-chinuclidin -(6-Butanoyloxy-3-indolyl)-chinuclidin -(6-Methansulfonyloxy-3-indolyl)-chinuclidin -(5-Acetoxy-2-methyl-3-indolyl)-chinuclidin -(5-Pivaloyloxy-2-methyl-3-indolyl)-chinuclidin -(5-Propanoyloxy-2-methyl-3-indolyl)-chinuclidin -(5-Butanoyloxy-2-methyl-3-indolyl)-chinuclidin -(5-Methansulfonyloxy-2-methyl-3-indolyl)-chinuclidin -(6-Acetoxy-2-methyl-3-indolyl)-chinuclidin -(6-Pivaloyloxy-2-methyl-3-indoloyl)-chinuclidin -(6-Propanoyloxy-2-methyl-3-indolyl)-chinuclidin -(6-Butanoyloxy-2-methyl-3-indolyl)-chinuclidin -(6-Methansulfonyloxy-2-methyl-3-indolyl)-chinuclidin -(5-Methoxy-2-methyl-3-indolyl)-chinuclidin -(5-Methoxy-3-indolyl)-chinuclidin -(6-Hydroxymethyl-3-indolyl)-2,3-dehydro-chinuclidin 3-(4-Hydroxymethyl-3-indolyl)-2,3-dehydrochinuclidin3- (3-indolyl) -2,3-dehydroquinuclidine 3- (4-methoxy-3-indolyl) -2,3-dehydro-quinuclidine 3- (5-methoxy-3-indolyl) -2,3-dehydro- quinuclidine - (5-Ethoxy-3-indolyl) -2,3-dehydro-quinuclidine - (5-propoxy-3-indolyl) -2,3-dehydro-quinuclidine - (6-methoxy-3-indoloyl) -2,3 -dehydro-quinuclidine - (5,6-dimethoxy-3-indolyl) -2,3-dehydro-quinuclidine - (5,6-methylenedioxy-3-indolyl) -2,3-dehydro-quinuclidine - (4,5, 6-trimethoxy-3-indolyl) -2,3-dehydro-quinuclidine - (5-methylthio-3-indolyl) -2,3-dehydro-quinuclidine - (5-fluoro-3-indolyl) -2,3-dehydro -quinuclidine - (5-chloro-3-indolyl) -2,3-dehydro-quinuclidine - (5-trifluoromethyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-chloro-5-methoxy-3- indolyl) -2,3-dehydro-quinuclidine - (6-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-methoxy-1-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-Ethoxy-1-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-propoxy-1-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-methoxy- 2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-ethoxy-2-methyl-3-indolyl) -2 , 3-dehydro-quinuclidine - (5-propoxy-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-methoxy-2-methyl-3- indolyl) -2,3-dehydro-quinuclidine - (5,6-dimethoxy-2-methyl-3-indoloyl) -2,3-dehydro-quinuclidine - (5,6-methylenedioxy-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (4,5,6-trimethoxy-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-methylthio-2-methyl-3-indolyl) -2 , 3-dehydro-quinuclidine - (5-fluoro-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-chloro-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-Trifluoromethyl-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-chloro-5-methoxy-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - ( 2,6-dimethyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-methoxy-1,2-dimethyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-ethoxy-1, 2-dimethyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-propoxy-1,2-dimethyl-3-indolyl) -2,3-dehydro-quinuclidine - (3-indolyl) -quinuclidine - ( 4-methoxy-3-indolyl) -quinuclidine - (5-methoxy-3-indolyl) -quinuclidine - (5-ethoxy-3-indolyl) -quinuclidine - (5-propoxy-3-indolyl) -quinuclidine - (6-methoxy-3-indolyl) -quinuclidine - (5,6-dimethoxy-3-indoloyl) -quinuclidine - (5,6-methylenedioxy-3-indolyl) -quinuclidine - (4,5,6-trimethoxy-3-indolyl) -quinuclidine - (5-methylthio-3-indolyl) -quinuclidine - (5-fluoro-3-indolyl) -quinuclidine - (5-chloro-3- indolyl) -quinuclidine - (5-trifluoromethyl-3-indolyl) -quinuclidine - (6-chloro-5-methoxy-3-indolyl) -quinuclidine - (6-methyl-3-indolyl) -quinuclidine - (6-methoxy- 1-methyl-3-indolyl) -quinuclidine - (6-ethoxy-1-methyl-3-indolyl) -quinuclidine - (6-propoxy-1-methyl-3-indolyl) -quinuclidine - (2-methyl-3- indolyl) -quinuclidine - (5-methoxy-2-methyl-3-indolyl) -quinuclidine - (5-ethoxy-2-methyl-3-indoloyl) -quinuclidine - (5-propoxy-2-methyl-3-indolyl) -quinuclidine - (6-methoxy-2-methyl-3-indolyl) -quinuclidine - (5,6-dimethoxy-2-methyl-3-indolyl) -quinuclidine - (5,6-methylenedioxy-2-methyl-3- indolyl) -quinuclidine - (4,5,6-trimethoxy-2-methyl-3-indolyl) -quinuclidine - (5-methylthio-2-methyl-3-indolyl) -quinuclidine - (5-fluoro-2-methyl- 3-indolyl) -quinuclidine - (5-Chloro-2-methyl-3-indolyl) quinuclidine - (5-trifluoromethyl-2-methyl-3-indolyl) quinuclidine - (6-chloro-5-methoxy-2-methyl-3-indolyl) - quinuclidine - (2,6-dimethyl-3-indolyl) -quinuclidine - (5-methoxy-1, 2-dimethyl-3-indolyl) -quinuclidine - (6-ethoxy-1, 2-dimethyl-3-indolyl) - quinuclidine - (6-propoxy-1,2-dimethyl-3-indolyl) -quinuclidine - (5-benzyloxy-3-indolyl) -2,3-dehydro-quinuclidine - (6-benzyloxy-3-indolyl) -2, 3-dehydro-quinuclidine - (6-benzyloxy-1-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-benzyloxy-3-indolyl) -2,3-dehydro-quinuclidine - (5-benzyloxy -1-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-Benzyloxy-2 ~ methyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-benzyloxy-2-methyl-3-indolyl) -2,3-dehydro-quinuclidine - (6-benzyloxy- 1,2-dimethyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-benzyloxy-1,2-dimethyl-3-indolyl) -2,3-dehydro-quinuclidine - (5-hydroxy-3- indolyl) -2,3-dehydro-quinuclidine - (6-hydroxy-3-indolyl) -quinuclidine - (6-hydroxy-1-methyl-3-indolyl) -quinuclidine - (5-hydroxy-3-indolyl) -quinuclidine - (5-Hydroxy-1-methyl-3-indolyl) -quinuclidine - (6-hydroxy-2-methyl-3-indolyl) -quinuclidine - (5-hydroxy-2-methyl-3-indolyl) -quinuclidine - ( 6-hydroxy-1,2-dimethyl-3-indolyl) -quinuclidine - (5-hydroxy-1,2-dimethyl-3-indolyl) -quinuclidine - (5-acetoxy-3-indolyl) -quinuclidine - (5- Pivaloyloxy-3-indoloyl) -quinuclidine - (5-propanoyloxy-3-indolyl) -quinuclidine - (5-butanoyloxy-3-indolyl) -quinuclidine - (5-methanesulfonyloxy-3-indolyl) -quinuclidine - (6-acetoxy- 3-indolyl) -quinuclidine - (6-pivaloyloxy-3-indoloyl) -quinuclidine - (6-propanoyloxy-indolyl) -quinuclidine - (6-butanoyloxy-3-indolyl) -quinuclidine - (6-methanesulfone yloxy-3-indolyl) -quinuclidine - (5-acetoxy-2-methyl-3-indolyl) -quinuclidine - (5-pivaloyloxy-2-methyl-3-indolyl) -quinuclidine - (5-propanoyloxy-2-methyl- 3-indolyl) -quinuclidine - (5-butanoyloxy-2-methyl-3-indolyl) -quinuclidine - (5-methanesulfonyloxy-2-methyl-3-indolyl) -quinuclidine - (6-acetoxy-2-methyl-3- indolyl) -quinuclidine - (6-pivaloyloxy-2-methyl-3-indoloyl) -quinuclidine - (6-propanoyloxy-2-methyl-3-indolyl) -quinuclidine - (6-butanoyloxy-2-methyl-3-indolyl) -quinuclidine - (6-methanesulfonyloxy-2-methyl-3-indolyl) -quinuclidine - (5-methoxy-2-methyl-3-indolyl) -quinuclidine - (5-methoxy-3-indolyl) -quinuclidine - (6- hydroxymethyl-3-indolyl) -2,3-dehydro-quinuclidine 3- (4-hydroxymethyl-3-indolyl) -2,3-dehydroquinuclidine
3-(5-Hydroxymethyl-3-indolyl)-2,3-dehydrochinuclidin3- (5-hydroxymethyl-3-indolyl) -2,3-dehydroquinuclidine
3-(4-Hydroxymethyl-3-indolyl)-chinuclidin3- (4-hydroxymethyl-3-indolyl) quinuclidine
3-(5-Hydroxymethyl-3-indolyl)-chinuclidin3- (5-hydroxymethyl-3-indolyl) quinuclidine
3-(6-Hydroxymethyl-3-indolyl)-chinuclidin3- (6-hydroxymethyl-3-indolyl) quinuclidine
Bevorzugte Substanzen sind:Preferred substances are:
3-(5-Hydroxymethyl-3-indolyl)-chinuclidin3- (5-hydroxymethyl-3-indolyl) quinuclidine
3-(5-Fluor-3-indolyl)-chinuclidin3- (5-fluoro-3-indolyl) quinuclidine
3-(5-Hydroxy-3-indolyl)-chinuclidin3- (5-hydroxy-3-indolyl) quinuclidine
3-(5-Amino-3-indolyl)-chinuclidin3- (5-amino-3-indolyl) quinuclidine
3-(7-Hydroxy-3-indolyl)-chinuclidin3- (7-hydroxy-3-indolyl) quinuclidine
3-(3-lndolyl)-chinuclidin3- (3-indolyl) quinuclidine
3-(5-Methoxy-3-indolyl)-chinuclidin3- (5-methoxy-3-indolyl) quinuclidine
3-(6-Hydroxymethyl-3-indolyl)-chinuclidin3- (6-hydroxymethyl-3-indolyl) quinuclidine
3-(5,6-Methylendioxy-3-indolyl)-chinuclidin3- (5,6-methylenedioxy-3-indolyl) quinuclidine
3-(5,6-Dimethoxy-3-indolyl)-chinuclidin3- (5,6-dimethoxy-3-indolyl) quinuclidine
3-(5-Methoxy-6-Chlor-indolyl)-chinuclidin3- (5-methoxy-6-chloro-indolyl) quinuclidine
3-(5-Carbamoyl-3-indolyl)-chinuclidin3- (5-carbamoyl-3-indolyl) quinuclidine
Die nachstehenden Beispiele betreffen pharmazeutische Zubereitungen, die Substanzen der Formel I oder eines ihrer Säureadditionssalze enthalten:The following examples relate to pharmaceutical preparations which contain substances of the formula I or one of their acid addition salts:
Beispiel A: TablettenExample A: tablets
Das Gemisch von 1 kg 3-(5-Hydroxy-3-indolyl)-chinuclidinhydrochlorid, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstea- rat wird in üblicher Weise zu Tabletten verpreßt, so daß jede Tablette 10 mg Wirkstoff enthält.The mixture of 1 kg of 3- (5-hydroxy-3-indolyl) -quinuclidine hydrochloride, 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, so that each tablet contains 10 mg of active ingredient.
Beispiel B: Dragees Analog Beispiel A werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Example B: coated tablets Analogously to Example A, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel C: KapselnExample C: capsules
2 kg 3-(5-Hydroxy-3-indolyl)-chinuclidin-hydrochlorid werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg Wirkstoff enthält.2 kg of 3- (5-hydroxy-3-indolyl) -quinuclidine hydrochloride are filled into hard gelatin capsules in the usual way, so that each capsule contains 20 mg of active ingredient.
Beispiel D: AmpullenExample D: ampoules
Eine Lösung von 1 kg 3-(5-Hydroxy-3-indolyl)-chinuclidinhydrochlorid in 60I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, un- ter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff.A solution of 1 kg of 3- (5-hydroxy-3-indolyl) -quinuclidine hydrochloride in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.
Analog sind Tabletten Dragees, Kapseln und Ampullen erhältlich, die eine andere Verbindung der Formel I und/oder ein oder mehrere physiologisch unbedenkliche Säureadditionssalze einer Verbindung der Formel (I) enthalten. Tablets dragees, capsules and ampoules which contain another compound of the formula I and / or one or more physiologically acceptable acid addition salts of a compound of the formula (I) are obtainable analogously.

Claims

Patentansprüche claims
1. Verwendung von Verbindungen der allgemeinen Formel (I)1. Use of compounds of the general formula (I)
Figure imgf000015_0001
Figure imgf000015_0001
in der R1 bis R5 unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Wasserstoff, verzweigten und unverzweigten C C4- Alkylgruppen, verzweigten und unverzweigten CrC4-Alkoxygruppen, verzweigten und unverzweigten C1-C4- Alkythiogruppen, Trifluor- methylgruppen, C6-Cι0-Aryloxygruppen, C7-Cι Aralkyloxygruppen, C C5-Acyloxygruppen, C6-Cιo-Aroyloxygruppen, C1-C4- Alkylsulfonyloxygruppen, Cβ-Cio-Arylsulfonyloxygruppen, linearen und verzweigten Cι-C4-Alkoxycarbonylgruppen, Amino-, Mono(C|-C5- Alkyl)amino- und Di(CrC5-Alkyl)aminogruppen, Carbamoyl-, N-in which R 1 to R 5 are independently selected from the group consisting of hydrogen, branched and unbranched CC 4 alkyl groups, branched and unbranched CrC 4 alkoxy groups, branched and unbranched C 1 -C 4 alkythio groups, trifluoromethyl groups, C 6 -Cι 0 aryloxy, C 7 -C ι aralkyloxy, CC 5 acyloxy groups, C 6 -Cιo-aroyloxy, C 1 -C 4 - alkylsulfonyloxy, Cβ-Cio-arylsulfonyloxy groups, linear and branched Cι-C 4 -alkoxycarbonyl, Amino, mono (C | -C 5 alkyl) amino and di (CrC 5 alkyl) amino groups, carbamoyl, N-
Mono(Cι-C5-Alkyl)carbamoyl- und N-Di(CrC5-Alkyl)carbamoylgruppen, Methylendioxygruppen, Hydroxygruppen, Hydroxymethylgruppen, Fluor und Chlor, R ausgewählt ist aus der Gruppe bestehend aus Wasserstoff und linea- ren und verzweigten Alkylgruppen, undMono (-C 5 -alkyl) carbamoyl and N-di (CrC 5 -alkyl) carbamoyl groups, methylenedioxy groups, hydroxyl groups, hydroxymethyl groups, fluorine and chlorine, R is selected from the group consisting of hydrogen and linear and branched alkyl groups, and
(Chin.) eine 3-Chinuclidinyl- oder eine 2,3-Dehydro-3- chinuclidinylgruppe bedeutet, oder deren physiologisch verträglichen(Chin.) Is a 3-quinuclidinyl or a 2,3-dehydro-3-quinuclidinyl group, or their physiologically acceptable
Salzen, zur Herstellung eines Medikaments gegen Krankheiten, bei denen eine Anregung der nikotinischen Acetylcholinrezeptoren zu einer Verbesserung des Krankheitsbildes führt.Salts, for the manufacture of a medicament for diseases in which stimulation of the nicotinic acetylcholine receptors leads to an improvement in the clinical picture.
2. Verwendung nach Anspruch 1 , dadurch gekennzeichnet,daß die Krankheiten ausgewählt sind aus der Gruppe bestehend aus Schizophrenie, Demenz, insbesondere Morbus Alzheimer, neurodegenerativen Erkrankungen, Parkinson'sche Krankheit, Tourette's Syndrom, altersbedingte Gedächtnisschwäche, Linderung von Entzugserscheinungen, Anwendung bei Schlaganfall und Schädigung des Gehirns durch toxische Verbindungen.2. Use according to claim 1, characterized in that the diseases are selected from the group consisting of schizophrenia, dementia, in particular Alzheimer's disease, neurodegenerative diseases, Parkinson's disease, Tourette's syndrome, age-related Weak memory, relief of withdrawal symptoms, use in stroke and damage to the brain due to toxic compounds.
3. Verwendung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die3. Use according to claim 1 or 2, characterized in that the
Verbindung der Formel (I) ausgewählt ist aus der Gruppe bestehend ausCompound of formula (I) is selected from the group consisting of
3-(5-Hydroxymethyl-3-indolyl)-chinuclidin3- (5-hydroxymethyl-3-indolyl) quinuclidine
3-(5-Fluor-3-indolyl)-chinuclidin 3-(5-Hydroxy-3-indolyl)-chinuclidin3- (5-fluoro-3-indolyl) quinuclidine 3- (5-hydroxy-3-indolyl) quinuclidine
3-(5-Amino-3-indolyl)-chinuclidin3- (5-amino-3-indolyl) quinuclidine
3-(7-Hydroxy-3-indolyl)-chinuclidin3- (7-hydroxy-3-indolyl) quinuclidine
3-(3-lndolyl)-chinuclidin3- (3-indolyl) quinuclidine
3-(5-Methoxy-3-indolyl)-chinuclidin 3-(6-Hydroxymethyl-3-indolyl)-chinuclidin3- (5-methoxy-3-indolyl) quinuclidine 3- (6-hydroxymethyl-3-indolyl) quinuclidine
3-(5,6-Methylendioxy-3-indolyl)-chinuclidin3- (5,6-methylenedioxy-3-indolyl) quinuclidine
3-(5,6-Dimethoxy-3-indolyl)-chinuclidin3- (5,6-dimethoxy-3-indolyl) quinuclidine
3-(5-Methoxy-6-Chlor-indolyl)-chinuclidin3- (5-methoxy-6-chloro-indolyl) quinuclidine
3-(5-Carbamoyl-3-indolyl)-chinuclidin3- (5-carbamoyl-3-indolyl) quinuclidine
4. Substanz der Formel4. Substance of the formula
Figure imgf000016_0001
in der R1 bis R5 unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Amino-, Mono (Cι-C5-Alkyl) amino- und Di(CrC5- Alkyl)aminogruppen, Carbamoyl-, N-Mono(Cι-C5-Alkyl)carbamoyl- und
Figure imgf000016_0001
in which R 1 to R 5 are independently selected from the group consisting of amino, mono (C 5 -C 5 alkyl) amino and di (CrC 5 - alkyl) amino groups, carbamoyl, N-mono (C 1 -C 5 alkyl) carbamoyl and
N-Di(CrC5-Alkyl)carbamoylgruppen,N-di (CrC 5 alkyl) carbamoyl groups,
R ausgewählt ist aus der Gruppe bestehend aus Wasserstoff und linearen und verzweigten Alkylgruppen, und (Chin.) eine 3-Chinuclidinyl- oder eine 2,3-Dehydro-3- chinuclidinylgruppe bedeutet. R is selected from the group consisting of hydrogen and linear and branched alkyl groups, and (Chin.) Is a 3-quinuclidinyl or a 2,3-dehydro-3-quinuclidinyl group.
5. 3-(5-Amino-3-indolyl)chinuclidin 3-(5-Carbamoyl-3-indolyl)chinuclidin 5. 3- (5-Amino-3-indolyl) quinuclidine 3- (5-carbamoyl-3-indolyl) quinuclidine
PCT/EP2001/010443 2000-09-11 2001-09-10 Use of indole derivatives for treating illnesses of the central nervous system WO2002020521A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002212226A AU2002212226A1 (en) 2000-09-11 2001-09-10 Use of indole derivatives for treating illnesses of the central nervous system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10045112.8 2000-09-11
DE10045112A DE10045112A1 (en) 2000-09-11 2000-09-11 Use of indole derivatives for the treatment of diseases of the central nervous system

Publications (1)

Publication Number Publication Date
WO2002020521A1 true WO2002020521A1 (en) 2002-03-14

Family

ID=7655956

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/010443 WO2002020521A1 (en) 2000-09-11 2001-09-10 Use of indole derivatives for treating illnesses of the central nervous system

Country Status (3)

Country Link
AU (1) AU2002212226A1 (en)
DE (1) DE10045112A1 (en)
WO (1) WO2002020521A1 (en)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101987A1 (en) * 2002-05-30 2003-12-11 Neurosearch A/S 3-substituted quinuclidines and their use
WO2005100351A1 (en) * 2004-04-14 2005-10-27 Astrazeneca Ab NOVEL 2-(1-AZA-BICYCLO[2.2.2]OCT-3-yl)-2,3-DIHYDROISOINDOL-l-ONE/5,6-DIHYDRO-FURO[2,3-c]PYRROL-4ONE DERIVATIVES LIGANDS FOR ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR
US7001914B2 (en) 2000-02-18 2006-02-21 Astrazeneca Ab Compounds
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
WO2012131539A1 (en) 2011-03-31 2012-10-04 Pfizer Inc. Novel bicyclic pyridinones
WO2012172449A1 (en) 2011-06-13 2012-12-20 Pfizer Inc. Lactams as beta secretase inhibitors
WO2013030713A1 (en) 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano [3,4-d][1,3] thiazin-2-amine compounds
WO2014045156A1 (en) 2012-09-21 2014-03-27 Pfizer Inc. Novel bicyclic pyridinones
US8697722B2 (en) 2007-11-02 2014-04-15 Sri International Nicotinic acetylcholine receptor modulators
WO2014128585A1 (en) 2013-02-19 2014-08-28 Pfizer Inc. Azabenzimidazole compounds as inhibitors of pde4 isozymes for the treatment of cns and other disorders
US8822456B2 (en) 2012-12-11 2014-09-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8865706B2 (en) 2013-02-13 2014-10-21 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8962616B2 (en) 2012-05-04 2015-02-24 Pfizer Inc. Heterocyclic substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2015049616A1 (en) 2013-10-04 2015-04-09 Pfizer Inc. Novel bicyclic pyridinones as gamma-secretase modulators
US9062042B2 (en) 2010-01-11 2015-06-23 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
WO2015150957A1 (en) 2014-04-01 2015-10-08 Pfizer Inc. Chromene and 1,1 a,2,7b-tetrahydrocyclopropa[c]chromene pyridopyrazinediones as gamma-secretase modulators
US9233981B1 (en) 2013-02-15 2016-01-12 Pfizer Inc. Substituted phenyl hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2016012896A1 (en) 2014-07-24 2016-01-28 Pfizer Inc. Pyrazolopyrimidine compounds
WO2016020786A1 (en) 2014-08-06 2016-02-11 Pfizer Inc. Imidazopyridazine compounds
US9260455B2 (en) 2012-09-20 2016-02-16 Pfizer Inc. Alkyl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9315520B2 (en) 2014-04-10 2016-04-19 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9403846B2 (en) 2012-12-19 2016-08-02 Pfizer Inc. Carbocyclic- and heterocyclic-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2016125048A1 (en) 2015-02-03 2016-08-11 Pfizer Inc. Novel cyclopropabenzofuranyl pyridopyrazinediones
WO2016203347A1 (en) 2015-06-17 2016-12-22 Pfizer Inc. Tricyclic compounds and their use as phosphodiesterase inhibitors
US9611264B1 (en) 2015-09-24 2017-04-04 Pfizer Inc. N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides
WO2017145013A1 (en) 2016-02-23 2017-08-31 Pfizer Inc. 6,7-dihydro-5h-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide compounds
US9751895B2 (en) 2015-09-24 2017-09-05 Pfizer Inc. N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)-1,3-thiazol-4-yl]amides
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
WO2018002760A1 (en) 2016-07-01 2018-01-04 Pfizer Inc. 5,7-dihydro-pyrrolo-pyridine derivatives for treating neurological and neurodegenerative diseases
WO2018234953A1 (en) 2017-06-22 2018-12-27 Pfizer Inc. Dihydro-pyrrolo-pyridine derivatives
WO2019183636A1 (en) 2018-03-23 2019-09-26 Pfizer Inc. Piperazine azaspiro derivaves

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10121217A1 (en) 2001-04-30 2002-10-31 Merck Patent Gmbh 6H-Oxazolo [4,5-e] indole derivatives as nicotinic acetylcholine receptor ligands and / or serotonergic ligands

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0450345A1 (en) * 1990-03-24 1991-10-09 MERCK PATENT GmbH Indole derivatives
EP0512350A2 (en) * 1991-05-10 1992-11-11 MERCK PATENT GmbH Indole derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0450345A1 (en) * 1990-03-24 1991-10-09 MERCK PATENT GmbH Indole derivatives
EP0512350A2 (en) * 1991-05-10 1992-11-11 MERCK PATENT GmbH Indole derivatives

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7001914B2 (en) 2000-02-18 2006-02-21 Astrazeneca Ab Compounds
US7214688B2 (en) 2000-02-18 2007-05-08 Astrazeneca Ab Compounds
US7491734B2 (en) 2000-02-18 2009-02-17 Astrazeneca Ab 2-(pyridine-4-yl)-N-(quinuclidin-2-yl)thiazole-4-carboxide nicotinic acetylcholine receptor ligands
WO2003101987A1 (en) * 2002-05-30 2003-12-11 Neurosearch A/S 3-substituted quinuclidines and their use
US7332507B2 (en) 2002-05-30 2008-02-19 Neurosearch A/S 3-substituted quinuclidines and their use
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
US7566727B2 (en) 2004-04-14 2009-07-28 Astrazeneca Ab 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydro-isoindole-1-one/5,6-dihydro-furo[2,3-c] pyrrol-4-one derivative ligands for alpha 7 nicotinic acetylcholine receptor
WO2005100351A1 (en) * 2004-04-14 2005-10-27 Astrazeneca Ab NOVEL 2-(1-AZA-BICYCLO[2.2.2]OCT-3-yl)-2,3-DIHYDROISOINDOL-l-ONE/5,6-DIHYDRO-FURO[2,3-c]PYRROL-4ONE DERIVATIVES LIGANDS FOR ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR
US8697722B2 (en) 2007-11-02 2014-04-15 Sri International Nicotinic acetylcholine receptor modulators
US9670198B2 (en) 2010-01-11 2017-06-06 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
US9062042B2 (en) 2010-01-11 2015-06-23 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
WO2012131539A1 (en) 2011-03-31 2012-10-04 Pfizer Inc. Novel bicyclic pyridinones
WO2012172449A1 (en) 2011-06-13 2012-12-20 Pfizer Inc. Lactams as beta secretase inhibitors
WO2013030713A1 (en) 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano [3,4-d][1,3] thiazin-2-amine compounds
US9550795B2 (en) 2011-08-31 2017-01-24 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8933221B2 (en) 2011-08-31 2015-01-13 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8962616B2 (en) 2012-05-04 2015-02-24 Pfizer Inc. Heterocyclic substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9260455B2 (en) 2012-09-20 2016-02-16 Pfizer Inc. Alkyl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2014045156A1 (en) 2012-09-21 2014-03-27 Pfizer Inc. Novel bicyclic pyridinones
US8822456B2 (en) 2012-12-11 2014-09-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9045498B2 (en) 2012-12-11 2015-06-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9198917B2 (en) 2012-12-11 2015-12-01 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9403846B2 (en) 2012-12-19 2016-08-02 Pfizer Inc. Carbocyclic- and heterocyclic-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9192612B2 (en) 2013-02-13 2015-11-24 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8865706B2 (en) 2013-02-13 2014-10-21 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9045499B2 (en) 2013-02-13 2015-06-02 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9233981B1 (en) 2013-02-15 2016-01-12 Pfizer Inc. Substituted phenyl hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2014128585A1 (en) 2013-02-19 2014-08-28 Pfizer Inc. Azabenzimidazole compounds as inhibitors of pde4 isozymes for the treatment of cns and other disorders
WO2015049616A1 (en) 2013-10-04 2015-04-09 Pfizer Inc. Novel bicyclic pyridinones as gamma-secretase modulators
WO2015150957A1 (en) 2014-04-01 2015-10-08 Pfizer Inc. Chromene and 1,1 a,2,7b-tetrahydrocyclopropa[c]chromene pyridopyrazinediones as gamma-secretase modulators
US9315520B2 (en) 2014-04-10 2016-04-19 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9428523B2 (en) 2014-04-10 2016-08-30 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9605007B2 (en) 2014-04-10 2017-03-28 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US10028962B2 (en) 2014-04-10 2018-07-24 Pfizer Inc. 2-amino-6-methy1-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9744173B2 (en) 2014-04-10 2017-08-29 Pfizer Inc. 2-amino 6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
WO2016012896A1 (en) 2014-07-24 2016-01-28 Pfizer Inc. Pyrazolopyrimidine compounds
WO2016020786A1 (en) 2014-08-06 2016-02-11 Pfizer Inc. Imidazopyridazine compounds
WO2016125048A1 (en) 2015-02-03 2016-08-11 Pfizer Inc. Novel cyclopropabenzofuranyl pyridopyrazinediones
WO2016203347A1 (en) 2015-06-17 2016-12-22 Pfizer Inc. Tricyclic compounds and their use as phosphodiesterase inhibitors
EP3766885A1 (en) 2015-06-17 2021-01-20 Pfizer Inc Tricyclic compounds and their use as phosphodiesterase inhibitors
US9611264B1 (en) 2015-09-24 2017-04-04 Pfizer Inc. N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
US9751895B2 (en) 2015-09-24 2017-09-05 Pfizer Inc. N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)-1,3-thiazol-4-yl]amides
US10112958B2 (en) 2015-09-24 2018-10-30 Pfizer Inc. N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-YL)-1,3-thiazol-4-YL] amides
WO2017145013A1 (en) 2016-02-23 2017-08-31 Pfizer Inc. 6,7-dihydro-5h-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide compounds
WO2018002760A1 (en) 2016-07-01 2018-01-04 Pfizer Inc. 5,7-dihydro-pyrrolo-pyridine derivatives for treating neurological and neurodegenerative diseases
EP3872078A1 (en) 2016-07-01 2021-09-01 Pfizer Inc. 5,7-dihydro-pyrrolo-pyridine derivatives for use in the treament of depression, anxiety or panic disorders
WO2018234953A1 (en) 2017-06-22 2018-12-27 Pfizer Inc. Dihydro-pyrrolo-pyridine derivatives
WO2019183636A1 (en) 2018-03-23 2019-09-26 Pfizer Inc. Piperazine azaspiro derivaves
EP4219464A1 (en) 2018-03-23 2023-08-02 Pfizer Inc. Piperazine azaspiro derivaves

Also Published As

Publication number Publication date
DE10045112A1 (en) 2002-03-21
AU2002212226A1 (en) 2002-03-22

Similar Documents

Publication Publication Date Title
WO2002020521A1 (en) Use of indole derivatives for treating illnesses of the central nervous system
DE19542281C2 (en) Use of Epinastin for the treatment of migraines
DE60212148T2 (en) COMPOSITIONS FOR TREATING PARKINSON'S DISEASE CONTAINING ANTAGONISTS OF THE CB1 RECEPTORS AND ACTIVATING SUBSTANCES OF THE DOPAMINE NEUROTRANSMISSION IN THE BRAIN
DE60019473T2 (en) (S, S) reboxetine for the treatment of peripheral neuropathies
DE69815090T2 (en) USE OF CHOLINESTERASE INHIBITORS FOR TREATING CONCENTRATIONAL DISORDER
DE69231395T3 (en) New medical indication for tachykinin antagonists
DE69924375T2 (en) USE OF OPTICALLY PURE (+) - NORCISAPRIDE FOR THE TREATMENT OF REIZDARY SYNDROME
DE69725345T2 (en) USE OF 5-HT4 ANTAGONISTS TO OVERCOME THE GASTROINTESTINAL DAMAGE CAUSED BY SEROTONIN REINVISION INHIBITORS
EP0752246A2 (en) Kappa opiate agonists for inflammatory gut diseases
DE69914935T2 (en) 8-AZABICYCLO [3.2.1] OCT-2-EN- AND -OKTANDERIVATE
DE60225943T2 (en) Topoisomerase GIFT FUNDS
EP0871437B1 (en) Use of boswellic acid for treating brain tumours
DE60028538T2 (en) CONDENSED HETEROCYCLIC COMPOUNDS AND THEIR USE FOR THE TREATMENT OF NEURODEEGENERATIVE DISEASES
WO2006086978A2 (en) Use of deuterated n-[2-(5-methoxy-1h-indol-3-yl)-ethyl]acetamides and the pharmaceutically acceptable salts thereof, and medicaments containing said compounds
EP1485057B9 (en) Derivatives of azaspiro compounds for the treatment of pain
DE69924488T2 (en) USE OF OPTICALLY PURE (-) NORCISAPRIDE IN THE TREATMENT OF REIZDARY SYNDROME
EP1317430B1 (en) (2-azabicyclo [2.2.1]hept-7-yl)methanol derivatives as nicotinic acetylcholine receptor agonists
EP0471388B1 (en) Medicament for the treatment of cardiac insufficiency
DE2113866A1 (en) New indole derivatives, processes for their preparation and a therapeutic composition containing these compounds
DE60203106T2 (en) AZOLYLCARBYNOL DERIVATIVES OF ARYL (OR HETEROARYL) FOR THE TREATMENT OF RESPIRATORY DISEASES
EP0369286A2 (en) Dibenzozepine derivatives for treating acute and chronic obstructive diseases of the respiratory tract
EP0417637A2 (en) Use of dopamine autoreceptor agonists in the treatment of drug dependency
DE10163421A1 (en) Use of (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol as an anti-emetic
EP0192098B1 (en) Use of 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin for the preparation of a medicament for the treatment of Parkinson's disease, or of parkinsonism
DE2749075C2 (en)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP