WO1996022280A1 - 1-acylaminoalkylpiperidines n-substituees pour le traitement de troubles cerebraux et de depressions - Google Patents

1-acylaminoalkylpiperidines n-substituees pour le traitement de troubles cerebraux et de depressions Download PDF

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Publication number
WO1996022280A1
WO1996022280A1 PCT/EP1996/000020 EP9600020W WO9622280A1 WO 1996022280 A1 WO1996022280 A1 WO 1996022280A1 EP 9600020 W EP9600020 W EP 9600020W WO 9622280 A1 WO9622280 A1 WO 9622280A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
chain
straight
substituted
fluorine
Prior art date
Application number
PCT/EP1996/000020
Other languages
German (de)
English (en)
Inventor
Bernd-Wieland Krüger
Stephan Lensky
Reiner Fischer
Klaus Tietjen
Christoph Methfessel
Albrecht Marhold
Hermann Hagemann
Alfred Maelicke
Bernard Schmidt
Franz-Josef Van Der Staay
Original Assignee
Bayer Aktiengesellschaft
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
Priority claimed from DE1995101365 external-priority patent/DE19501365A1/de
Priority claimed from DE1995101366 external-priority patent/DE19501366A1/de
Priority claimed from DE1995101367 external-priority patent/DE19501367A1/de
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU44838/96A priority Critical patent/AU4483896A/en
Publication of WO1996022280A1 publication Critical patent/WO1996022280A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to substituted pipendins, ner processes for their preparation and their use in medicaments, in particular for the treatment of
  • the present invention relates to piperidines of the general formula I.
  • R 1 represents straight-chain or branched haloalkyl with up to 6 carbon atoms and up to 4 fluorine or chlorine atoms or stands for straight-chain or branched alkenyl or alkynyl with up to 10 carbon atoms and up to 3 multiple bonds, which may be replaced by one or several halogen atoms or straight-chain or branched alkoxy with up to 8 carbon atoms can be substituted or represents a group ZD,
  • Z represents an alkylene chain with up to 6 carbon atoms
  • D represents a pyridyl radical which is carried out one or more times
  • R 2 and R 3 are identical or different and for hydrogen, cycloalkyl having up to 8 carbon atoms or for straight-chain or branched alkyl having up to 8
  • the number means zero, 1 or 2 and
  • R denotes straight-chain or branched alkyl, alkoxy or alkylthio with up to 8 carbon atoms or straight-chain or branched haloalkyl or haloalkoxy having up to 6 carbon atoms and up to 6 fluorine and / or chlorine atoms or means halogen,
  • R has the meaning of R or means hydrogen
  • R 7 and R 9 are hydrogen or halogen
  • R 8 and R 10 are halogen
  • R 11 and R 12 are halogen
  • n stands for a number 1, 2 or 3
  • R 1 , R 2 , R 3 and m have the meaning given below [A], and
  • R 4 for a group of the formula stands in what
  • p represents a number 1, 2 or 3,
  • R 1 represents hydrogen, or represents straight-chain or branched alkyl having up to 10 carbon atoms, or represents benzyl or benzoyl, the phenyl radical of these two
  • Alkyl, alkoxy or alkylthio having up to 8 carbon atoms can be substituted by trifluoromethyl, trifluoromethoxy or trifluoromethylthio, or
  • the compounds of formula (I) are suitable for the treatment and prevention of cognitive and affective diseases, in particular for the treatment of senile and presenile dementia, dementia of the Alzheimer type, AIDS-related dementia, cognitive deficits in Parkinson's or Huntington's, or brain disorders as a result of infarction and for the treatment of depression.
  • the substituted piperidines according to the invention can also be present in the form of their salts.
  • salts with organic or inorganic acids may be mentioned here.
  • physiologically acceptable salts are preferred.
  • Physiologically acceptable salts of the substituted piperidines according to the invention can be salts with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
  • Toluenesulfonic acid benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • the Neritatien invention can in stereoisomeric forms, which are either like image and mirror image (enantiomers) or which are not like image and
  • the invention relates to both the enantiomers and diastereomers and their respective mixtures.
  • the ⁇ -substituted piperidines according to the invention have a considerably better activity than the piperidines known from the prior art.
  • R 1 represents straight-chain or branched haloalkyl having up to 6 carbon atoms and up to 4 fluorine or chlorine atoms, or straight-chain or branched alkenyl or alkynyl having up to
  • Z represents an alkylene chain with up to 6 carbon atoms
  • D represents a pyridyl radical which is substituted one or more times by halogen, straight-chain or branched alkyl, alkoxy or Alkylthio with up to 8 carbon atoms or substituted by trifluoromethyl, cyano or nitro or optionally by one or more halogen, straight-chain or branched alkyl, alkoxy or alkylthio with up to 8 carbon atoms, trifluoromethyl, cyano or nitro substituted furyl, thienyl, pyryl , Oxazolyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, isoxazolyl, benzofuryl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, benzisoxazolyl, quinolyl, isoquinolyl, quinazolinyl, acridyrinylid
  • R 2 and R 3 are the same or different and stand for hydrogen, or stand for straight-chain or branched alkyl with up to 6 carbon atoms,
  • R> 4 represents a group of the formula in which
  • R 7 and R 9 are hydrogen, fluorine, chlorine or bromine, and
  • R 8 and R 10 are fluorine, chlorine or bromine
  • R 11 and R 12 are chlorine, fluorine or bromine and
  • n a number 1 or 2
  • R 1 represents straight-chain or branched haloalkyl having up to 4 carbon atoms and up to 4 fluorine and / or chlorine atoms or straight-chain or branched alkenyl or alkynyl having up to
  • Z represents an alkylene chain with up to 4 carbon atoms
  • R 2 , R 3 and m have the meaning given above under [A],
  • p represents a number 1 or 2, or in which
  • R 1 represents hydrogen, or represents straight-chain or branched alkyl having up to 8 carbon atoms, or stands for benzyl or benzoyl, the phenyl ring in these groups being substituted one or more times by fluorine, chlorine or bromine, straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms or can be substituted by trifluoromethyl or trifluoromethoxy, or represents hydroxymethyl, or represents pyridyl or pyridylmethyl, and R 2 , R 3 , R 4 and m have the meaning given above under [A],
  • Z represents an alkylene chain with up to 6 carbon atoms
  • D represents a pyridyl radical which is substituted one or more times by halogen, straight-chain or branched alkyl, alkoxy or alkylthio having up to 8 carbon atoms or by trifluoromethyl, cyano or nitro or, if appropriate, by one or more halogen, straight-chain or branched alkyl, Alkoxy or alkylthio with up to 8 carbon atoms, trifluoromethyl, cyano or nitro substituted furyl, thienyl, pyryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, isoxazolyl,
  • R 2 and R 3 are the same or different and stand for hydrogen, or stand for straight-chain or branched alkyl having up to 4 carbon atoms,
  • R> 4 represents a group of the formula in which
  • R 'de notes straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms or trifluoromethyl, trifluoromethoxy, trifluoromethylthio, fluorochloromethyl or fluorine or chlorine, or
  • R has the meaning of R or means hydrogen
  • R 7 and R 9 represent hydrogen or fluorine
  • R 8 and R 10 represent fluorine
  • R 11 and R 12 represent fluorine
  • R 1 represents trifluoromethyl or straight-chain or branched aikenyl with up to 6
  • Z represents a methylene group
  • D is pyridyl substituted by fluorine, chlorine, straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms or trifluoromethyl, or furyl substituted by fluorine, chlorine, straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms or trifluoromethyl, Thienyl, thiazolyl,
  • X is SO 2 or in which
  • R 1 represents hydrogen, or represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents benzyl or benzoyl, the phenyl ring being in each case by fluorine, chlorine or bromine, straight-chain or branched alkyl or alkoxy with bis may be substituted to 4 carbon atoms or by trifluoromethyl, or is hydroxymethyl, or is pyridyl or pyridylmethyl, and
  • T represents a typical leaving group, preferably halogen
  • the ner driving according to the invention can be exemplified by the following scheme:
  • organic solvents which do not change under the reaction conditions are suitable as solvents for the production process.
  • solvents preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether; Hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions; Halogenated hydrocarbons such as dichloromethane, trichloroethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene; Alcohols such as methanol, ethanol, propanol or isopropanol or solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, ⁇ -methylpyrrolidone, acetone or ⁇ itromethane. It is also possible to use mixtures of the solvents mentioned and mixtures of the solvents mentioned with water.
  • Bases are generally organic or inorganic bases. This includes preferably alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, alkali metal or alkaline earth metal hydrogen carbonates such as sodium or potassium hydrogen carbonate or alkali metal or alkaline earth metal alcoholates such as sodium or
  • Potassium methylate, sodium or potassium ethylate or potassium tert-butoxide or organic amines such as triethylamine, cyclohexylamine, diisopropylamine, diisopropylethylamine, pyridine, diaminopyridine, methylpiperidine, morpholine, methylmorpholine or DBU.
  • reaction temperatures can be varied over a wide range. In general, a range from -20 ° C. to + 130 ° C., preferably from 0 ° C. to 100 ° C., particularly preferably from 25 ° C. to 80 ° C.
  • the reaction can be carried out under normal but also under increased or reduced pressure.
  • Compounds are generally used in 1 mol of the piperidine of the formula (II) up to 2 mol of the compound of the formula (III), preferably 1.2 to 1.5 mol of compound (III).
  • the reaction mixture is generally stirred at room temperature or with heating. After cooling, there are several ways of working up:
  • the product can generally be precipitated from a concentrated solution in an organic solvent with ether or with hydrocarbons which are liquid at room temperature.
  • the compounds of the general formulas (II) and (III) are known or can be prepared by known methods.
  • the effectiveness of the substances according to the invention in the treatment and prevention of cognitive disorders is demonstrated with the aid of an animal model which is based on spatial memory.
  • rats In this test, originally described by Morris (RGM Morris, J. Neurosci. Methods 11: 47-60, 1984), rats have to learn to locate an invisible platform as the only way out of a water pool.
  • the animals old, male rats, approx. 20 months old
  • the latency for finding the platform and the distance covered is measured. As the training progresses, both the latency and the swim distance are shortened by appropriating one
  • Test substances are applied once a day (60 minutes before the first training run). Control animals receive an appropriate amount of the vehicle.
  • the platform is removed from the water and a further swimming test is carried out to determine whether the test animals are looking for the platform in a defined, narrow radius of the training position (retention test).
  • the test results show that the compounds described have a positive effect on the learning behavior of the animals and also on the retention of what has been learned.
  • the described compounds according to the invention can therefore be used both for the therapeutic and for the preventive treatment of cognitive disorders in general, in particular of dementias of the Alzheimer's type.
  • the compounds according to the invention shorten the duration of immobility and lead to an activation of behavior.
  • the compounds described are also suitable for the treatment of affective disorders, in particular depression.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions or lysols, using inert non-toxic pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as a diluent, organic if necessary
  • Solvents can be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally or parenterally, in particular parlingually or intravenously.
  • the application can also be transdermal e.g. done by plaster.
  • Example II analogously to Example III: bp: 133-4 ° C./18 mbar.
  • the compound is obtained analogously to Example V from IV. Sp: 128-30 ° C / 18 mbar.
  • Example 3 is an oil. It was characterized by mass spectrometry. MS (70 eV) m / z (%): 610 (1; C 30 H 32 7 C1F 3 N 2 O 4 S), 608 (3; M + ), 517 (15; M + -C 6 H 5 CH 2 ), 231
  • Example 9 is an oil. It was characterized by mass spectrometry: MS (70 eV) m / z (%): 416 (8, M + ), 415 (9, M + -H), 325 (100, fC ⁇ CH ⁇ .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Selon l'invention, on produit des pipéridines substituées en réalisant, selon des procédés classiques, une substitution au niveau de l'azote de la pipéridine. Les pipéridines N-substituées peuvent être utilisées comme principes actifs dans des médicaments, en particulier dans des médicaments utilisés pour traiter les troubles cérébraux et les dépressions.
PCT/EP1996/000020 1995-01-18 1996-01-04 1-acylaminoalkylpiperidines n-substituees pour le traitement de troubles cerebraux et de depressions WO1996022280A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44838/96A AU4483896A (en) 1995-01-18 1996-01-04 N-substituted 1-acylaminoalkyl piperidines for treatment of cerebral disorders and depressions

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE19501367.0 1995-01-18
DE1995101365 DE19501365A1 (de) 1995-01-18 1995-01-18 Substituierte Piperidine
DE1995101366 DE19501366A1 (de) 1995-01-18 1995-01-18 N-substituierte Piperidine
DE19501365.4 1995-01-18
DE19501366.2 1995-01-18
DE1995101367 DE19501367A1 (de) 1995-01-18 1995-01-18 Benzamidoalkyl-substituierte Piperidine

Publications (1)

Publication Number Publication Date
WO1996022280A1 true WO1996022280A1 (fr) 1996-07-25

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Country Status (2)

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AU (1) AU4483896A (fr)
WO (1) WO1996022280A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1194505A (en) * 1968-05-21 1970-06-10 Science Union & Cie Piperidinol Derivatives and Process for Preparing Them
EP0229391A1 (fr) * 1985-12-27 1987-07-22 Eisai Co., Ltd. Dérivé de la pipéridine, son application et composition pharmaceutique le contenant
EP0296560A2 (fr) * 1987-06-22 1988-12-28 Eisai Co., Ltd. Pipéridines 1,4-substituées comme inhibiteurs de l'acétylcholinestérase et leur utilisation dans le traitement de la maladie d'Alzheimer
WO1993005038A1 (fr) * 1991-09-12 1993-03-18 Smithkline Beecham Plc Antagonistes de recepteurs 5-hydroxytriptamine 4
JPH05201971A (ja) * 1992-01-28 1993-08-10 Hokuriku Seiyaku Co Ltd 環状アミン含有ベンゼンスルホンアミド誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1194505A (en) * 1968-05-21 1970-06-10 Science Union & Cie Piperidinol Derivatives and Process for Preparing Them
EP0229391A1 (fr) * 1985-12-27 1987-07-22 Eisai Co., Ltd. Dérivé de la pipéridine, son application et composition pharmaceutique le contenant
EP0296560A2 (fr) * 1987-06-22 1988-12-28 Eisai Co., Ltd. Pipéridines 1,4-substituées comme inhibiteurs de l'acétylcholinestérase et leur utilisation dans le traitement de la maladie d'Alzheimer
WO1993005038A1 (fr) * 1991-09-12 1993-03-18 Smithkline Beecham Plc Antagonistes de recepteurs 5-hydroxytriptamine 4
JPH05201971A (ja) * 1992-01-28 1993-08-10 Hokuriku Seiyaku Co Ltd 環状アミン含有ベンゼンスルホンアミド誘導体

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
EFANGE, S. M. N. ET AL: "Synthesis and biological evaluation of radioiodinated N-2-(4-piperidyl)ethylbenzamides", NUCL. MED. BIOL. (1993), 20(4), 527-38 CODEN: NMBIEO;ISSN: 0883-2897 *
PATENT ABSTRACTS OF JAPAN vol. 17, no. 644 (C - 1134)<6273> 30 November 1993 (1993-11-30) *
SARGES, REINHARD ET AL: "Sulfamylurea hypoglycemic agents. 6. High-potency derivatives", J. MED. CHEM. (1976), 19(5), 695-709 CODEN: JMCMAR *
SUGIMOTO, HACHIRO ET AL: "Novel piperidine derivatives. Synthesis and anti- acetylcholinesterase activity of 1-benzyl-4-[2-(N- benzoylamino)ethyl]piperidine derivatives", J. MED. CHEM. (1990), 33(7), 1880-7 CODEN: JMCMAR;ISSN: 0022-2623 *

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