WO1995025721A1 - New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor - Google Patents

New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor Download PDF

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Publication number
WO1995025721A1
WO1995025721A1 PCT/DE1995/000442 DE9500442W WO9525721A1 WO 1995025721 A1 WO1995025721 A1 WO 1995025721A1 DE 9500442 W DE9500442 W DE 9500442W WO 9525721 A1 WO9525721 A1 WO 9525721A1
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Prior art keywords
piperidyl
ketone
naphthyloxy
propyl
unsubstituted
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PCT/DE1995/000442
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German (de)
French (fr)
Inventor
Dieter Seidelmann
Andreas Huth
Martin Krüger
Eckhard Ottow
Graham Jones Jones
Roland Neuhaus
Lechoslaw Turski
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Schering Aktiengesellschaft
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Priority to SK1201-96A priority Critical patent/SK120196A3/en
Priority to JP7524306A priority patent/JPH09510460A/en
Priority to PL95316382A priority patent/PL316382A1/en
Priority to EP95915116A priority patent/EP0751936A1/en
Priority to KR1019960705269A priority patent/KR970701695A/en
Priority to AU22125/95A priority patent/AU2212595A/en
Publication of WO1995025721A1 publication Critical patent/WO1995025721A1/en
Priority to MXPA/A/1996/004201A priority patent/MXPA96004201A/en
Priority to FI963786A priority patent/FI963786A/en
Priority to NO963984A priority patent/NO963984D0/en

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    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D211/20—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 singly bound oxygen or sulphur atoms
    • C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen 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
    • C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

  • the invention relates to new piperidine derivatives, processes for their preparation and medicaments containing these compounds.
  • Piperidine derivatives are known to have pharmacological effects and are suitable, for example, for the treatment of psychotropic and cerebral vascular disorders. Surprisingly, it has now been found that the piperidine derivatives according to the invention functionally influence the glutamate receptor or the glutamate receptor-dependent ion channel.
  • the invention relates to the compounds of the formula I.
  • R.1 substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted or substituted or unsubstituted tetra-benzofuran, substituted or unsubstituted benzofuran unsubstituted tetrahydroisoquinoline, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphtalin, substituted or unsubstituted indane, substituted or unsubstituted indanone, substituted or unsubstituted tetralone, substituted or unsubstituted chromene-2-one, substituted
  • R2 and R 3 are the same or different and are hydrogen, hydroxy, C ⁇ - alkyl, C ⁇ _4-alkoxy or C- _6-alkanoyloxy,
  • R 4 straight-chain or branched, C j .g-alkyl, - CO - ⁇ - ⁇ or a phenyl-, benzyl- optionally substituted with C ⁇ _4-alkyl, C ⁇ - alkoxy, halogen, hydroxy, - CF3 or - O - CF3 , Benzoyl, ⁇ -hydroxy-benzyl, pyridinyl or naphthoyl radical means, where the substituent can be identical or different from one to three times and
  • Y is oxygen, sulfur or - NH -
  • the substituent R 1 can be substituted one to three times by the same or different means
  • R5 and R ⁇ are the same or different and are hydrogen, C ⁇ alkyl, phenyl, C ⁇ .g- alkanoyl or together with the nitrogen atom represent a 5- or 6-membered saturated or unsaturated heterocycle which is repeated one or more times with C ⁇ _4- Alkyl or phenyl may be substituted and may contain a further O, N or S atom.
  • Examples include piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 2,6-dimethylmorpholine, phenylpiperazine as saturated heterocycles and imidazole, pyrazole, pyrrole or triazole as unsaturated heterocycles.
  • Halogen is to be understood as fluorine, chlorine, bromine or iodine.
  • Alkyl means in each case a straight-chain or branched alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl, hexyl.
  • the C 1-6 alkanoyl radical is derived in each case from straight-chain or branched aliphatic carboxylic acids, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethyl acetic acid or caproic acid. If Rl is substituted, the substituent can be in any position.
  • radicals Rl are: pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1-naphthyl, 2-naphthyl, isoquinolin-5-yl, isoquinolyl-4-yl, isoquinolin-6-yl , Quinolin-4-yl, Quinolin-5-yl, Quinolin-6-yl, 1, 2, 3, 4-tetrahydro-5-naphthyl, l, 2,3,4-tetrayhydro-6-naphthyl, 7.8 - Dihydro-2-naphthyl, 7,8-dihydro-l-naphthyl, chromen-2-one-7-yl, chromen-2-one-4-yl, 1-oxo-l, 2,3,4-tetrahydro -5-naphthyl, l-oxo-l, 2,3,4-tetrahydro-6-naphthyl
  • Oxygen is to be regarded as the preferred meaning of Z and C 4 alkylene, which can be straight-chain or branched and can be substituted at any position, is to be mentioned as the preferred meaning of X. Combinations with hydrogenated or non-hydrogenated naphthyl derivatives are particularly preferred.
  • the physiologically compatible salts are derived from inorganic and organic acids.
  • Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic acids such as aliphatic or aromatic mono- or dicarboxylic acids such as formic acid, acetic acid are suitable; Maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example C 4 alkanesulfonic acids such as methanesulfonic acid or optionally substituted by halogen or C 4 alkyl benzenesulfonic acids such as p-toluenesulfonic acid.
  • the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as the readily soluble alkali and alkaline earth metal salts and N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexadiamine, Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, sovak base, l-amino-2,3,4-butanetriol.
  • the compounds of formula I include all possible optical isomers and their mixtures.
  • X and B have the meaning given above, reacted according to Mitsunobu with a compound of the formula R ⁇ -OH and then, if desired, reducing a carbonyl group or esterifying or etherifying a hydroxyl group or forming the physiologically tolerable salts or separating the isomers.
  • the nucleophilic substitution of the leaving group A according to process variants a) and b) is carried out according to the usual methods in an organic solvent which is inert under the reaction conditions under basic conditions.
  • Suitable escape groups A are, for example, halogens such as chlorine, bromine or iodine or organic sulfonic acid residues such as the rest of an alkanesulfonic acid, for example mesylate, triflate or the rest of an aromatic sulfonic acid, for example toluenesulfonic acid or bromobenzenesulfonic acid.
  • Suitable inert organic solvents are polar solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or alcohols such as ethanol, methanol or cyclic ethers such as dioxane, tetrahydrofuran, halogenated hydrocarbons, aromatic hydrocarbons or mixtures of the solvents mentioned.
  • Inorganic and organic bases are suitable as bases.
  • organic bases are alkali or alkaline earth metal hydroxide, carbonates, bicarbonates or alcoholates.
  • Examples of organic bases are tertiary organic amines such as tripropylamine, triethylamine, N-alkylmorpholine, N-alkylpiperidine, Hunig base, 1,4-diazabycyclo (2,2,2) octane, 1,5-diazabycyclo (5,4,0 ) undec-5-en.
  • the reaction temperature can be between room temperature and the boiling point of the solvent.
  • procedure c) generally takes place. in protic solvents such as alcohols at elevated temperatures up to the boiling point.
  • the Mitsunobi reaction (process d) is carried out in the presence of triphenylphosphine and azodicarboxylic acid ethyl ester in inert solvents at elevated temperature or in the presence of an organic acid at room temperature (Synthesis, 1981, 1).
  • the reduction of the carbonyl group can be carried out with conventional reducing agents, such as, for example, with sodium borohydride to give the corresponding hydroxy compound or with triethylsilane and trifluoroacetic acid at room temperature to give the methylene compound. If esterification is desired, this is done in a manner known per se by reaction with an activated acid derivative such as, for example, acid anhydride, acid halide or acid imidazolide.
  • conventional reducing agents such as, for example, with sodium borohydride to give the corresponding hydroxy compound or with triethylsilane and trifluoroacetic acid at room temperature to give the methylene compound.
  • esterification is desired, this is done in a manner known per se by reaction with an activated acid derivative such as, for example, acid anhydride, acid halide or acid imidazolide.
  • the optional etherification of the hydroxyl group is carried out by the customary methods in the presence of bases, for example by reaction with methyl iodide in ethylene glycol dimethyl ether in the presence of sodium hydride.
  • the compounds of the formula I can be isolated from the reaction mixture and purified in a manner known per se.
  • Acid addition salts can be converted into the free bases in a conventional manner and, if desired, these can be converted into physiologically compatible acid addition salts in a known manner, for example by adding a concentrated solution of the desired acid to the solution.
  • the optically active compounds can be obtained from the racemates starting from optically active starting compounds or in a manner known per se.
  • the enantiomer separation can be carried out, for example, by chromatography over optically active carrier materials, by reaction with optically active acids and subsequent fractional crystallization.
  • the compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their functional action on the glutamate receptor or the ion channel dependent on the glutamate receptor.
  • mice Male NMRI mice weighing 18-22 g with were kept under controlled conditions (6 -18 00 0 ° clock light / dark cycle, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5 - 16 animals. The animals were observed between 8 a.m. and 1 p.m.
  • AMPA was injected into the left ventricle by freely moving mice.
  • the applicator consisted of a cannula with a stainless steel device that limits the depth of the injection to 3.2 mm.
  • the applicator was on an injection pump connected.
  • the injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow.
  • the animals were observed for up to 180 seconds until clonic or tonic cramps occurred.
  • the clonic movements that lasted longer than 5 seconds were counted as convulsions.
  • the beginning of the clonic convulsions was used as the end point for the determination of the convulsive threshold.
  • the dose required to increase or decrease the seizure threshold by 50% (THRD50) was determined in 4-5 experiments.
  • the THRD50 and confidence limits were determined in a regression analysis.
  • Treatment with the compounds according to the invention prevents or delays the cell damage and functional disorders which occur as a result of the disease and reduces the symptoms which arise as a result.
  • Diseases that can be triggered by the dysfunction of excitatory amino acids or altered glutamate neurotransmission include, for example, neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, multi-infarct dementia, AIDS dementia, AIDS encephalopathy, amyotrophs Lateral sclerosis, olivoponto cerebellar degeneration, epilepsy; Cell damage due to hypoglycemia, hypoxia, ischemia and disorders of the energy metabolism; neuronal damage caused by brain damage such as stroke, brain trauma and asphyxia as well as psychoses, schizophrenia, anxiety, pain, migraines and vomiting.
  • neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, multi-infarct dementia, AIDS dementia, AIDS encephalopathy, amyotrophs Lateral sclerosis, olivoponto cerebellar degeneration, epilepsy
  • Functional disorders such as memory disorders (amnesia), disorders of the learning process, vigilance symptoms and withdrawal symptoms after chronic use of addictive substances such as sedative drugs, hallucinogens, alcohol, cocaine and opiates are based on the dysfunction of glutamaterergic neurotransmission.
  • the indications can be shown by conventional pharmacological tests.
  • the invention also encompasses pharmaceutical compositions which contain the compounds mentioned, their preparation and the use of the compounds according to the invention for the production of medicaments which are used for the treatment and prophylaxis of the abovementioned diseases.
  • the medicaments are produced by methods known per se by bringing the active ingredient into the form of a pharmaceutical preparation with suitable carriers, auxiliaries and / or additives which is suitable for enteral or parenteral administration.
  • the application can take place orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs or emulsions or rectally in the form of suppositories or in the form of injection solutions which may also be used subcutaneously.
  • auxiliaries for the desired pharmaceutical formulation are the inert organic and inorganic carrier materials known to the person skilled in the art, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Serving, stabilizing, wetting agents, emulsifiers or salts to change the osmotic pressure or buffer may be included.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions.
  • Auxiliary materials such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. They can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • the dosage of the active ingredients can vary depending on the type of application, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the compounds are administered in a dose unit of 0.05 to 100 mg of active substance in a physiologically acceptable Carrier introduced. In general, a dose of 0.1 to 500 mg day, preferably 0.1 to 50 mg / day, is used.
  • the (4-fluorophenyl) -l- [l- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone is obtained by methods known from the literature by alkylation of 4- (4-fluorobenzoyl) piperidine with 3-bromopropanol-1 and Potassium carbonate in dimethylformamide and subsequent reaction with methanesulfonic acid and triethylamine in methylene chloride.
  • the (4-chlorobutyl) - (3-dimethylaminophenyl) ether required as starting material is obtained by etherification of 3-dimethylaminophenol with l-bromo-4-chlorobutane and potassium carbonate in dimethylformamide.
  • the (3-dimethylaminophenyl) - (2,3-epoxypropyl) ether required as starting material is obtained by reacting 3-dimethylaminophenol with epichlorohydrin and sodium hydride in dimethylformamide.
  • 700 mg of (4-fluorophenyl) -1- [1- (3-hydroxypropyl) -4-piperidyl] ketone, 700 mg of triphenylphosphine and 0.45 ml of diethyl azodicarboxylate are added and the mixture is heated to a bath temperature of 80 ° C. for 20 minutes.
  • the reaction solution is mixed with 50 ml of water and then extracted with ethyl acetate.
  • the (4-fluorophenyl) -1- [1- (3-hydroxypropyl) -4-piperidyl] ketone is obtained by methods known from the literature by alkylation of 4- (4-fluorobenzoyl) piperidine with 3-bromopropanol. 1 and potassium carbonate in dimethylformamide.

Abstract

Compounds having the formula (I) are disclosed, as well as their preparation and use in medicaments.

Description

Neue 1 ,4-Di substitui erte Pi peri di n-Deri vate al s auf den Gl utamat-Rezeptor wi rkende ArzneimittelNew 1,4-di-substituted pi peri di n-derivatives as drugs that act on the glutamate receptor
Die Erfindung betrifft neue Piperidin-Derivate, Verfahren zu deren Herstellung und Arzneimittel enthaltend diese Verbindungen.The invention relates to new piperidine derivatives, processes for their preparation and medicaments containing these compounds.
Von Piperidin-Derivaten ist bekannt, daß sie pharmakologische Wirkungen besitzen und beispielsweise zur Behandlung psychotroper und cerebral vaskulärer Störungen geeignet sind. Überraschenderweise wurde nun gefunden, daß die erfindungsgemäßen Piperidin- Derivate funktionell den Glutamatrezeptor oder den Glutamatrezeptor abhängigen Ionenkanal beeinflussen.Piperidine derivatives are known to have pharmacological effects and are suitable, for example, for the treatment of psychotropic and cerebral vascular disorders. Surprisingly, it has now been found that the piperidine derivatives according to the invention functionally influence the glutamate receptor or the glutamate receptor-dependent ion channel.
Gegenstand der Erfindung sind die Verbindungen der Formel IThe invention relates to the compounds of the formula I.
R1— Z— X— N B (I),R 1 - Z— X— NB (I),
worinwherein
R.1 substituiertes oder unsubstituiertes Phenyl, substituiertes oder unsubstituiertes Pyridin, substituiertes oder unsubstituiertes Naphthalin, substituiertes oder unsubstituiertes Quinolin, substituiertes oder unsubstituiertes Isoquinolin, substituiertes oder unsubstituiertes Indol, substituiertes oder unsubstituiertes Benzothiophen, substituiertes oder unsubstituiertes Benzofuran, substituiertes oder unsubstituiertes Tetrahydrochinolin, substituiertes oder unsubstituiertes Tetrahydroisochinolin, substituiertes oder unsubstituiertes Tetralin, substituiertes oder unsubstituiertes Dihydronaphtalin, substituiertes oder unsubstituiertes Indan, substituiertes oder unsubstituiertes Indanon, substituiertes oder unsubstituiertes Tetralon, substituiertes oder unsubstituiertes Chromen-2-on, substituiertes oder unsubstituiertes Naphthochinon,R.1 substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted or substituted or unsubstituted tetra-benzofuran, substituted or unsubstituted benzofuran unsubstituted tetrahydroisoquinoline, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphtalin, substituted or unsubstituted indane, substituted or unsubstituted indanone, substituted or unsubstituted tetralone, substituted or unsubstituted chromene-2-one, substituted or unsubstituted or unsubstituted
Z Sauerstoff, Schwefel, SO oder SO2,Z oxygen, sulfur, SO or SO 2 ,
X — (CH2)m— CR2R3— (CH2)p oderX - (CH 2 ) m - CR2R3— (CH 2 ) p or
Figure imgf000003_0001
Figure imgf000003_0001
B XCH— R4 und m, p, g jeweils 0, 1, 2 oder 3,B X CH— R 4 and m, p, g each 0, 1, 2 or 3,
R2 und R3 gleich oder verschieden sind und Wasserstoff, Hydroxy, C^^-Alkyl, Cι_4-Alkoxy oder C- _6-Alkanoyloxy bedeuten,R2 and R 3 are the same or different and are hydrogen, hydroxy, C ^^ - alkyl, Cι_4-alkoxy or C- _6-alkanoyloxy,
R4 geradkettiges oder verzweigtes, Cj.g-Alkyl, — CO — {- Ϋ oder einen gegebenenfalls mit Cι_4-Alkyl, C^^-Alkoxy, Halogen, Hydroxy, — CF3 oder — O — CF3 substituierten Phenyl-, Benzyl-, Benzoyl-, α-Hydroxy-Benzyl-, Pyridinyl- oder Naphthoyl-Rest bedeutet, wobei der Substituent gleich oder verschieden ein- bis dreifach stehen kann undR 4 straight-chain or branched, C j .g-alkyl, - CO - {- Ϋ or a phenyl-, benzyl- optionally substituted with Cι_4-alkyl, C ^^ - alkoxy, halogen, hydroxy, - CF3 or - O - CF3 , Benzoyl, α-hydroxy-benzyl, pyridinyl or naphthoyl radical means, where the substituent can be identical or different from one to three times and
Y Sauerstoff, Schwefel oder — NH — bedeuten,Y is oxygen, sulfur or - NH -,
sowie deren physiologisch verträgliche Salze und Isomeren.and their physiologically tolerable salts and isomers.
Der Substituent Rl kann ein- bis dreifach gleich oder verschieden substituiert sein mitThe substituent R 1 can be substituted one to three times by the same or different means
C*j__4-Alkyl, Cχ_4-Alkoxy, Halogen, N02, CF3, — OCF3, Hydroxy, Carboxyl, C1.4-C * j__4-alkyl, Cχ_4-alkoxy, halogen, N0 2 , CF3, - OCF3, hydroxy, carboxyl, C1.4-
Alkoxycarbonyl, Foπnyl, Cι_4-Alkylcarbonyl, Phenyl, Phenoxy, Benzyl, R5 R5 Alkoxycarbonyl, Foπnyl, Cι_4-alkylcarbonyl, phenyl, phenoxy, benzyl, R 5 R 5
— N oder— -S02— N , wobei- N or - -S0 2 - N, where
\ Rö \ *6\ Rö \ * 6
R5 und RÖ gleich oder verschieden sind und Wasserstoff, C^-Alkyl, Phenyl, C^.g- Alkanoyl oder gemeinsam mit dem Stickstoffatom einen 5- oder 6-gliedrigen gesättigten oder ungesättigten Heterocyclus bedeuten, der ein- oder mehrfach mit Cι_4-Alkyl oder Phenyl substituiert sein kann und ein weiteres O-, N- oder S-Atom enthalten kann. Beispielsweise seien genannt Piperidin, Pyrrolidin, Morpholin, Thiomorpholin, Piperazin, N-Methylpiperazin, 2,6-Dimethyl-morpholin, Phenylpiperazin als gesättigte Heterocyclen und Imidazol, Pyrazol, Pyrrol oder Triazol als ungesättigte Heterocyclen.R5 and R Ö are the same or different and are hydrogen, C ^ alkyl, phenyl, C ^ .g- alkanoyl or together with the nitrogen atom represent a 5- or 6-membered saturated or unsaturated heterocycle which is repeated one or more times with Cι_4- Alkyl or phenyl may be substituted and may contain a further O, N or S atom. Examples include piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 2,6-dimethylmorpholine, phenylpiperazine as saturated heterocycles and imidazole, pyrazole, pyrrole or triazole as unsaturated heterocycles.
Unter Halogen ist Fluor, Chlor, Brom oder Jod zu verstehen.Halogen is to be understood as fluorine, chlorine, bromine or iodine.
Alkyl bedeutet jeweils einen geradkettigen oder verzweigten Alkylrest wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek. Butyl, Pentyl, Isopentyl, Hexyl.Alkyl means in each case a straight-chain or branched alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl, hexyl.
Der C^.g-Alkanoylrest leitet sich jeweils von geradkettigen oder verzweigten aliphatischen Carbonsäuren ab wie beispielsweise Ameisensäure, Essigsäure, Propionsäure, Buttersäure, Trimethylessigsäure oder Capronsäure. Liegt Rl substituiert vor, so kann der Substitent an beliebiger Position stehen. Als Reste Rl seien beispielsmäßig genannt: Pyridin-2-yl, Pyridin-3-yl, Pyridin-4-yl, 1-Naphthyl, 2- Napthyl, Isochinolin-5-yl, Isochinolyl-4-yl, Isochinolin-6-yl, Quinolin-4-yl, Quinolin-5-yl, Quinolin-6-yl, 1, 2, 3, 4-Tetrahydro-5-napthyl, l,2,3,4-Tetrayhydro-6-naphthyl, 7,8- Dihydro-2-naphthyl, 7,8-Dihydro-l-naphthyl, Chromen-2-on-7-yl, Chromen-2-on-4-yl, 1- Oxo-l,2,3,4-tetrahydro-5-naphthyl, l-Oxo-l,2,3,4-tetrahydro-6-naphthyl, 2-Oxo-l,2,3,4- tetrahydro-5-napthyl, 2-Oxo-l,2,3,4-tetrayhydro-6-napthyl, Indan-4-yl, Indan-5-yl, Indan- l-on-4-yl, Naphthochinon.The C 1-6 alkanoyl radical is derived in each case from straight-chain or branched aliphatic carboxylic acids, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethyl acetic acid or caproic acid. If Rl is substituted, the substituent can be in any position. Examples of radicals Rl are: pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1-naphthyl, 2-naphthyl, isoquinolin-5-yl, isoquinolyl-4-yl, isoquinolin-6-yl , Quinolin-4-yl, Quinolin-5-yl, Quinolin-6-yl, 1, 2, 3, 4-tetrahydro-5-naphthyl, l, 2,3,4-tetrayhydro-6-naphthyl, 7.8 - Dihydro-2-naphthyl, 7,8-dihydro-l-naphthyl, chromen-2-one-7-yl, chromen-2-one-4-yl, 1-oxo-l, 2,3,4-tetrahydro -5-naphthyl, l-oxo-l, 2,3,4-tetrahydro-6-naphthyl, 2-oxo-l, 2,3,4-tetrahydro-5-napthyl, 2-oxo-l, 2,3 , 4-tetrayhydro-6-naphthyl, indan-4-yl, indan-5-yl, indan-on-4-yl, naphthoquinone.
Als bevorzugte Bedeutung von Z ist Sauerstoff zu betrachten und als bevorzugte Bedeutung von X ist Cι_4-Alkylen, das geradkettig oder verzweigt sein kann und an beliebiger Position substituiert sein kann, zu nennen. Besonders bevorzugt sind Kombinationen mit hydrierten oder nicht hydrierten Naphthylderivaten.Oxygen is to be regarded as the preferred meaning of Z and C 4 alkylene, which can be straight-chain or branched and can be substituted at any position, is to be mentioned as the preferred meaning of X. Combinations with hydrogenated or non-hydrogenated naphthyl derivatives are particularly preferred.
Die physiologisch verträglichen Salze leiten sich von anorganischen und organischen Säuren ab. Geeignet sind anorganische Säuren wie beispielsweise Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure oder organische Säuren wie beispielsweise aliphatische oder aromatische Mono- oder Dicarbonsäuren wie Ameisensäure, Essigsäure; Maleinsäure, Fumarsäure, Succinsäure, Milchsäure, Weinsäure, Zitronensäure, Oxalsäure, Glyoxylsäure oder Sulfonsäuren, beispielsweise Cι_4- Alkansulfonsäuren wie Methansulf onsäure oder gegebenenfalls durch Halogen oder Cι_4- Alkyl substituierte Benzolsulfonsäuren wie p-Toluolsulfonsäure.The physiologically compatible salts are derived from inorganic and organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic acids such as aliphatic or aromatic mono- or dicarboxylic acids such as formic acid, acetic acid are suitable; Maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example C 4 alkanesulfonic acids such as methanesulfonic acid or optionally substituted by halogen or C 4 alkyl benzenesulfonic acids such as p-toluenesulfonic acid.
Ist eine saure Funktion enthalten, sind als Salze die physiologisch verträglichen Salze organischer und anorganischer Basen geeignet wie beispielsweise die gut löslichen Alkali- und Erdalkalisalze sowie N-Methyl-glukamin, Dimethyl-glukamin, Ethyl-glukamin, Lysin, 1,6-Hexadiamin, Ethanolamin, Glukosamin, Sarkosin, Serinol, Tris -hydroxy -methyl- amino-methan, Aminopropandiol, Sovak-Base, l-Amino-2,3,4-butantriol.If an acidic function is present, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as the readily soluble alkali and alkaline earth metal salts and N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexadiamine, Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, sovak base, l-amino-2,3,4-butanetriol.
Die Verbindungen der Formel I umfassen alle möglichen optischen Isomeren und deren Gemische.The compounds of formula I include all possible optical isomers and their mixtures.
Die Herstellung der Verbindungen der Formel I und deren physiologisch verträglichen Salze erfolgt in an sich bekannter Weise, indem manThe compounds of the formula I and their physiologically tolerable salts are prepared in a manner known per se by:
a) eine Verbindung der Formel π R1— Z— H (II).a) a compound of the formula π R 1 - Z - H (II).
worin R und Z die obige Bedeutung haben, mit einer Verbindung der Formel IIIwherein R and Z have the above meaning, with a compound of formula III
A— X— N B (DT),A - X - N B (DT),
worin X und B die obige Bedeutung haben und A eine Fluchtgruppe darstellt, umsetzt oderwherein X and B have the above meaning and A represents a refugee group, implement or
b) eine Verbindung der Formel IVb) a compound of formula IV
A— X— Z— R1 (IV),A— X— Z— R 1 (IV),
worin X, Z und R die obige Bedeutung haben und A eine Fluchtgruppe darstellt mit einem Amin der Formel Vwherein X, Z and R have the meaning given above and A represents a leaving group with an amine of the formula V.
H— N B (V),H— N B (V),
worin B die obige Bedeutung hat, umsetzt oderwhere B has the above meaning, implements or
c) eine Epoxid der Formel VIc) an epoxy of the formula VI
Rl— Z— (CH2)m— CH— CH2 (VI),Rl— Z— (CH 2 ) m - CH— CH 2 (VI),
worin Rl, Z und m die obige Bedeutung haben mit einem Amin der Formel Vwherein Rl, Z and m have the above meaning with an amine of formula V
H— N B (V) umsetzt oderH— N B (V) or
d) eine Verbindung der Formel VLId) a compound of the formula VLI
HO— X— N B (VΗ)HO— X— N B (VΗ)
worin X und B die obige Bedeutung haben, nach Mitsunobu mit einer Verbindung der Formel R^-OH umsetzt und anschließend gewünschtenfalls eine Carbonylgruppe reduziert oder eine Hydroxygruppe verestert oder verethert oder die physiologisch verträglichen Salze bildet oder die Isomeren trennt. Die nucleophile Substitution der Fluchtgruppe A nach den Verfahrensvarianten a) und b) wird nach den üblichen Methoden in einem unter den Reaktionsbedingungen inerten organischen Lösungsmittel unter basischen Bedingungen vorgenommen.where X and B have the meaning given above, reacted according to Mitsunobu with a compound of the formula R ^ -OH and then, if desired, reducing a carbonyl group or esterifying or etherifying a hydroxyl group or forming the physiologically tolerable salts or separating the isomers. The nucleophilic substitution of the leaving group A according to process variants a) and b) is carried out according to the usual methods in an organic solvent which is inert under the reaction conditions under basic conditions.
Als Fluchtgruppen A eignen sich beispielsweise Halogene wie Chlor, Brom oder Jod oder organische Sulfonsäurereste wie der Rest einer Alkansulf onsäure beispielsweise Mesylat, Triflat oder der Rest einer aromatischen Sulfonsäure beispielsweise der Toluolsulfonsäure oder Brombenzolsulfonsäure.Suitable escape groups A are, for example, halogens such as chlorine, bromine or iodine or organic sulfonic acid residues such as the rest of an alkanesulfonic acid, for example mesylate, triflate or the rest of an aromatic sulfonic acid, for example toluenesulfonic acid or bromobenzenesulfonic acid.
Als inerte organische Lösungsmittel eignen sich polare Lösungsmittel wie Dimethylform- amid, Dimethylacetamid, Dimethylsulfoxid oder Alkohole wie Ethanol, Methanol oder cyclische Ether wie Dioxan, Tetrahydrofuran, halogenierte Kohlenwasserstoffe, aromatische Kohlenwasserstoffe oder Gemische aus den genannten Lösungsmitteln.Suitable inert organic solvents are polar solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or alcohols such as ethanol, methanol or cyclic ethers such as dioxane, tetrahydrofuran, halogenated hydrocarbons, aromatic hydrocarbons or mixtures of the solvents mentioned.
Als Basen sind anorganische und organische Basen geeignet. Beispiele organischer Basen sind Alkali- oder Erdalkali-hydroxid, -carbonate, -hydrogencarbonate oder -alkoholate. Beispiele organischer Basen sind tertiäre organische Amine wie Tripropylamin, Triethyl- amin, N-Alkylmorpholin, N-Alkylpiperidin, Hünig Base, l,4-Diazabycyclo(2,2,2)octan, l,5-Diazabycyclo(5,4,0)undec-5-en.Inorganic and organic bases are suitable as bases. Examples of organic bases are alkali or alkaline earth metal hydroxide, carbonates, bicarbonates or alcoholates. Examples of organic bases are tertiary organic amines such as tripropylamine, triethylamine, N-alkylmorpholine, N-alkylpiperidine, Hunig base, 1,4-diazabycyclo (2,2,2) octane, 1,5-diazabycyclo (5,4,0 ) undec-5-en.
Die Reaktionstemperatur kann zwischen Raumtemperatur und Siedetemperatur des Lösungsmittels liegen.The reaction temperature can be between room temperature and the boiling point of the solvent.
Die Umsetzung nach Verfahren c) erfolgt i.a. in protischen Lösungsmitteln wie Alkoholen bei erhöhter Temperatur bis zur Siedetemperatur.The implementation according to procedure c) generally takes place. in protic solvents such as alcohols at elevated temperatures up to the boiling point.
Die Umsetzung nach Mitsunobi (Verfahren d) erfolgt in Gegenwart von Triphenylphosphin und Azodicarbonsäureethylester in inerten Lösungsmitteins bei erhöhter Temperatur oder auch in Gegenwart einer organischen Säure bei Raumtemperatur (Synthesis, 1981, 1).The Mitsunobi reaction (process d) is carried out in the presence of triphenylphosphine and azodicarboxylic acid ethyl ester in inert solvents at elevated temperature or in the presence of an organic acid at room temperature (Synthesis, 1981, 1).
Die Reduktion der Carbonylgruppe kann mit üblichen Reduktionsmitteln vorgenommen werden, wie beispielsweise mit Natriumborhydrid zur entsprechenden Hydroxy- Verbindung oder mit Triethylsilan und Trifluoressigsäure bei Raumtemperatur zur Methylen-Verbindung. Wird eine Veresterung gewünscht, so geschieht das in an sich bekannter Weise durch Umsetzung mit einem aktivierten Säurederivat wie beispielsweise Säureanhydrid, Säurehalogenid oder Säureimidazolid.The reduction of the carbonyl group can be carried out with conventional reducing agents, such as, for example, with sodium borohydride to give the corresponding hydroxy compound or with triethylsilane and trifluoroacetic acid at room temperature to give the methylene compound. If esterification is desired, this is done in a manner known per se by reaction with an activated acid derivative such as, for example, acid anhydride, acid halide or acid imidazolide.
Die fakultative Veretherung der Hydroxygruppe erfolgt nach den üblichen Methoden in Gegenwart von Basen, beispielsweise durch Umsetzung mit Methyljodid in Ethylenglykol- dimethylether in Gegenwart von Natriumhydrid.The optional etherification of the hydroxyl group is carried out by the customary methods in the presence of bases, for example by reaction with methyl iodide in ethylene glycol dimethyl ether in the presence of sodium hydride.
Die Verbindungen der Formel I können auf an sich bekannte Weise aus dem Reaktionsge¬ misch isoliert und gereinigt werden. Säureadditionssalze können in üblicher Weise in die freien Basen überführt werden und diese gewünschtenfalls in bekannter Weise in physiologisch verträgliche Säureadditionssalze, beispielsweise indem man die Lösung mit einer konzentrierten Lösung der gewünschten Säure versetzt.The compounds of the formula I can be isolated from the reaction mixture and purified in a manner known per se. Acid addition salts can be converted into the free bases in a conventional manner and, if desired, these can be converted into physiologically compatible acid addition salts in a known manner, for example by adding a concentrated solution of the desired acid to the solution.
Falls die Verbindungen der Formel I ein oder mehrere chirale Atome besitzen , können die optisch aktiven Verbindungen ausgehend von optisch aktiven Ausgangsverbindungen oder in an sich bekannter Weise aus den Racematen erhalten werden. Die Enantiomeren- trennung kann beispielsweise durch Chromatographie über optisch aktive Träger¬ materialien, durch Umsetzung mit optisch aktiven Säuren und anschließende fraktionierte Kristallisation erfolgen.If the compounds of the formula I have one or more chiral atoms, the optically active compounds can be obtained from the racemates starting from optically active starting compounds or in a manner known per se. The enantiomer separation can be carried out, for example, by chromatography over optically active carrier materials, by reaction with optically active acids and subsequent fractional crystallization.
Die Verbindungen der Formel I sowie deren physiologisch verträgliche Salze sind auf Grund ihrer funktionellen Einwirkung auf den Glutamatrezeptor oder den Glutamatrezeptor abhängigen Ionenkanal als Arzneimittel verwendbar.The compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their functional action on the glutamate receptor or the ion channel dependent on the glutamate receptor.
Die pharmakologische Wirksamkeit der Verbindungen der Formel I wurde mittels der nachfolgend beschriebenen Teste bestimmt:The pharmacological activity of the compounds of the formula I was determined using the tests described below:
Männliche NMRI Mäuse mit einem Gewicht von 18-22 g wurden unter kontrollierten Verhältnissen (600-180° Uhr Hell/Dunkelrythmus, bei freiem Zugang zu Futter und Wasser) gehalten und ihre Zuordnung zu Gruppen wurde randomisiert. Die Gruppen bestanden aus 5 - 16 Tieren. Die Beobachtung der Tiere wurde zwischen 8°° und 13°° Uhr vorgenommen.Male NMRI mice weighing 18-22 g with were kept under controlled conditions (6 -18 00 0 ° clock light / dark cycle, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5 - 16 animals. The animals were observed between 8 a.m. and 1 p.m.
AMPA wurde in den linken Ventrikel von frei beweglichen Mäusen gespritzt. Der Applikator bestand aus einer Kanüle mit einer Vorrichtung aus rostfreiem Stahl, die die Tiefe der Injektion auf 3,2 mm begrenzt. Der Applikator war an eine Injektionspumpe angeschlossen. Die Injektionsnadel wurde perpendicular zu der Oberfläche des Schädels nach den Koordinaten von Montemurro und Dukelow eingeführt. Die Tiere wurden bis zum Auftreten von clonischen bzw. tonischen Krämpfen bis zu 180 sec. beobachtet. Die clonischen Bewegungen, die länger als 5 sec. andauern, wurden als Krämpfe gezählt. Der Anfang der clonischen Krämpfe wurde als Endpunkt für die Bestimmung der Krampf¬ schwelle verwendet. Die Dosis, die notwendig war, um die Krampfschwelle um 50% herauf- bzw. herabzusetzen (THRD50) wurde in 4-5 Experimenten bestimmt. Die THRD50- und die Vertrauensgrenze wurde in einer Regressionsanalyse bestimmt.AMPA was injected into the left ventricle by freely moving mice. The applicator consisted of a cannula with a stainless steel device that limits the depth of the injection to 3.2 mm. The applicator was on an injection pump connected. The injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow. The animals were observed for up to 180 seconds until clonic or tonic cramps occurred. The clonic movements that lasted longer than 5 seconds were counted as convulsions. The beginning of the clonic convulsions was used as the end point for the determination of the convulsive threshold. The dose required to increase or decrease the seizure threshold by 50% (THRD50) was determined in 4-5 experiments. The THRD50 and confidence limits were determined in a regression analysis.
Die Ergebnisse dieser Versuche zeigen, daß die Verbindung der Formel I und deren Säureadditionssalze funktioneile Störungen des AMPA-Rezeptors beeinflussen. Sie eignen sich daher zu Herstellung von Arzneimitteln zur symptomatischen und präventiven Behandlung von Erkrankungen, die durch Veränderung der Funktion des AMPA- Rezeptor-Komplexes ausgelöst werden.The results of these experiments show that the compound of the formula I and its acid addition salts influence functional disorders of the AMPA receptor. They are therefore suitable for the manufacture of medicinal products for the symptomatic and preventive treatment of diseases which are triggered by changes in the function of the AMPA-receptor complex.
Die Behandlung mit den erfindungsgemäßen Verbindungen verhindert bzw. verzögert die infolge der Erkrankung auftretenden Zellschädigungen und funktionellen Störungen und vermindert die dadurch entstehenden Symptome.Treatment with the compounds according to the invention prevents or delays the cell damage and functional disorders which occur as a result of the disease and reduces the symptoms which arise as a result.
Zu den Krankheiten, die von der Dysfunktion excitatorischer Aminosäuren bzw. veränder¬ ter glutamaterger Neurotransmission ausgelöst werden können, gehören beispielsweise neurodegenerative Störungen wie Morbus Parkinson, Morbus Huntington, Morbus Alz¬ heimer, Senile Demenz, Multiinfarkt Demenz, Aids Demenz, Aids Encephalopathie, Amyotrophe Lateralsklerose, olivopontozerebellare Degeneration, Epilepsie; Zellschäden durch Hypoglykämie, Hypoxie, Ischämie und Störungen des Energiestoff- wechseis; neuronale Schäden, die durch Schädigung des Gehirns ausgelöst werden wie Schlaganfall, Gehirntrauma und Asphyxie sowie Psychosen, Schizophrenie, Angstzustände, Schmerzzustände, Migräne und Emesis. Auch funktionelle Störungen wie Gedächtnisstörungen (Amnesie), Störungen des Lernprozesses, Vigilanzerscheinungen und Entzugserscheinungen nach chronischer Einnahme von Suchtmitteln wie sedative Arzneimittel, Halluzinogenen, Alkohol, Kokain und Opiaten basieren auf der Dysfunktion glutamaterger Neurotransmission.Diseases that can be triggered by the dysfunction of excitatory amino acids or altered glutamate neurotransmission include, for example, neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, multi-infarct dementia, AIDS dementia, AIDS encephalopathy, amyotrophs Lateral sclerosis, olivoponto cerebellar degeneration, epilepsy; Cell damage due to hypoglycemia, hypoxia, ischemia and disorders of the energy metabolism; neuronal damage caused by brain damage such as stroke, brain trauma and asphyxia as well as psychoses, schizophrenia, anxiety, pain, migraines and vomiting. Functional disorders such as memory disorders (amnesia), disorders of the learning process, vigilance symptoms and withdrawal symptoms after chronic use of addictive substances such as sedative drugs, hallucinogens, alcohol, cocaine and opiates are based on the dysfunction of glutamaterergic neurotransmission.
Durch übliche pharmakologische Teste können die Indikationen gezeigt werden.The indications can be shown by conventional pharmacological tests.
Die Erfindung umfaßt auch pharmazeutische Mittel, die die genannten Verbindungen enthalten, deren Herstellung sowie die Verwendung der erfindungsgemäßen Verbindungen zur Herstellung von Arzneimitteln, die zur Behandlung und Prophylaxe der vorstehend genannten Krankheiten eingesetzt werden. Die Arzneimittel werden nach an sich bekann¬ ten Verfahren hergestellt, indem man den Wirkstoff mit geeigneten Träger-, Hilfs- und/ oder Zusatzstoffen in die Form eines pharmazeutischen Präparates bringt, das für die en- terale oder parenterale Applikation geeignet ist. Die Applikation kann oral oder sublingual als Feststoff in Form von Kapseln oder Tabletten oder als Flüssigkeit in Form von Lösun¬ gen, Suspensionen, Elixieren oder Emulsionen oder rektal in Form von Suppositorien oder in Form von gegebenenfalls auch subcutan anwendbaren Injektionslösungen erfolgen. Als Hilfsstoffe für die gewünschte Arzneimittelformulierung sind die dem Fachmann bekann¬ ten inerten organischen und anorganischen Trägermaterialien geeignet wie zum Beispiel Wasser, Gelantine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole usw.. Gegebenenfalls können darüber hinaus Kon- servierungs-, Stabilisierungs-, Netzmittel, Emulgatoren oder Salze zur Veränderung des osmotischen Druckes oder Puffer enthalten sein.The invention also encompasses pharmaceutical compositions which contain the compounds mentioned, their preparation and the use of the compounds according to the invention for the production of medicaments which are used for the treatment and prophylaxis of the abovementioned diseases. The medicaments are produced by methods known per se by bringing the active ingredient into the form of a pharmaceutical preparation with suitable carriers, auxiliaries and / or additives which is suitable for enteral or parenteral administration. The application can take place orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs or emulsions or rectally in the form of suppositories or in the form of injection solutions which may also be used subcutaneously. Suitable auxiliaries for the desired pharmaceutical formulation are the inert organic and inorganic carrier materials known to the person skilled in the art, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Serving, stabilizing, wetting agents, emulsifiers or salts to change the osmotic pressure or buffer may be included.
Die pharmazeutischen Präparate können in fester Form zum Beispiel als Tabletten, Dragees, Suppositoren, Kapseln oder in flüssiger Form zum Beispiel als Lösungen, Suspensionen oder Emulsionen vorliegen.The pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions.
Als Trägersysteme können auch grenzflächennahe Hilfsstoffe wie Salze der Gallensäuren oder tierische oder pflanzliche Phospholipide, aber auch Mischungen davon sowie Liposome oder deren Bestandteile verwendet werden.Auxiliary materials such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
Für die orale Anwendung sind insbesondere Tabletten, Dragees oder Kapseln mit Talkum und/oder Kohlenwasserstoffträger oder -binder, wie zum Beispiel Lactose, Mais- oder Kartoffelstärke, geeignet. Die Anwendung kann auch in flüssiger Form erfolgen, wie zum Beispiel als Saft, dem gegebenenfalls ein Süßstoff beigefügt wird.Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. They can also be used in liquid form, for example as juice, to which a sweetener may be added.
Für die parenterale Anwendung sind insbesondere Injektionslösungen oder Suspensionen, insbesondere wäßrige Lösungen der aktiven Verbindungen in polyhydroxyethoxyliertem Rizinusöl, geeignet.Injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
Die Dosierung der Wirkstoffe kann je nach Art der Anwendung, Alter und Gewicht des Patienten, Art und Schwere der zu behandelnden Erkrankung und ähnlichen Faktoren variieren. Die tägliche Dosis kann als einmal zu verabreichende Einzeldosis oder unterteilt in 2 oder mehrere Tagesdosen gegeben werden. Die Verbindungen werden in einer Dosiseinheit von 0,05 bis 100 mg aktiver Substanz in einem physiologisch verträglichen Träger eingebracht. Im allgemeinen wird eine Dosis von 0,1 bis 500 mg Tag, vorzugsweise 0,1 bis 50 mg/Tag, angewendet.The dosage of the active ingredients can vary depending on the type of application, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose can be given as a single dose to be administered once or divided into 2 or more daily doses. The compounds are administered in a dose unit of 0.05 to 100 mg of active substance in a physiologically acceptable Carrier introduced. In general, a dose of 0.1 to 500 mg day, preferably 0.1 to 50 mg / day, is used.
Soweit die Herstellung der Ausgangsverbindungen nicht beschrieben wird, sind diese bekannt oder analog zu bekannten Verbindungen oder hier beschriebenen Verfahren herstellbar.If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds or processes described here.
Die nachfolgenden Beispiele sollen die Herstellung der Verbindungen der Formel I erläutern: The following examples are intended to illustrate the preparation of the compounds of the formula I:
Beispiel 1example 1
{l-[3- 3-Dimethylaminophenoxy)-propyl]-4-piperidyl}- 4-fluorphenyπ-keton{l- [3- 3-Dimethylaminophenoxy) propyl] -4-piperidyl} - 4-fluorophenyπ-ketone
265 mg 3-Dimethylaminophenyl werden in 20 ml Aceton vorgelegt, mit 265 mg Kaliumcarbonat und 824 mg (4-Fluorphenyl)-[l-(3-methylsulfonyloxypropyl)-4- piperidyl]-keton versetzt und 3 Stunden unter Argon am Rückfluß erhitzt. Nach dem Einengen der organischen Phase wird über Kieselgel mit Methylenchlorid und Aceton = 1 + 1 chromatographiert. Man erhält 375 mg {l-[3-(-Dimethylaminophenoxy)-propyl]-4- piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 48 - 50 °C.265 mg of 3-dimethylaminophenyl are placed in 20 ml of acetone, mixed with 265 mg of potassium carbonate and 824 mg of (4-fluorophenyl) - [l- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone and heated under reflux for 3 hours under argon. After concentrating the organic phase, the mixture is chromatographed on silica gel with methylene chloride and acetone = 1 + 1. 375 mg of {l- [3 - (- dimethylaminophenoxy) propyl] -4- piperidyl} - (4-fluorophenyl) ketone, melting point 48-50 ° C., are obtained.
Das (4-Fluorphenyl)-l-[l-(3-methylsulfonyloxy-propyl)-4-piperidyl]-keton erhält man nach literaturbekannten Methoden durch Alkylierung von 4-(4-Fluorbenzoyl)-piperidin mit 3-Brompropanol-l und Kaliumcarbonat in Dimethylformamid und anschließender Umsetzung mit Methansulfonsäure und Triethylamin in Methylenchlorid.The (4-fluorophenyl) -l- [l- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone is obtained by methods known from the literature by alkylation of 4- (4-fluorobenzoyl) piperidine with 3-bromopropanol-1 and Potassium carbonate in dimethylformamide and subsequent reaction with methanesulfonic acid and triethylamine in methylene chloride.
In analoger Weise werden hergestellt:The following are produced in an analogous manner:
{l-[3-(2-Dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (2-Dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(4-Dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (4-Dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(3-Morpholinophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 110 - 111 °C{l- [3- (3-Morpholinophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 110-111 ° C
{l-[3-(l-Naphtyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 61 - 64 °C{l- [3- (l-Naphtyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 61-64 ° C
{l-[3-(2-Naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 114 - 115 °C{l- [3- (2-Naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 114-115 ° C
{l-[3-(3-Dibutylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (3-Dibutylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(2-Nitro-l-naphtyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (2-Nitro-l-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(l-Nitro-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 137 - 138 °C {l-[3-(2,4-Dinitro-l-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (l-Nitro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 137-138 ° C {l- [3- (2,4-Dinitro-l-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(3-Anilinophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 75 - 78 °C{l- [3- (3-anilinophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 75-78 ° C
{l-[3-(l-Brom-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 97 - 100 °C{l- [3- (l-Bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 97-100 ° C
{l-[3-(4-Chlor-l-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (4-Chloro-l-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(3-Acetylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 108 - 111 °C{l- [3- (3-Acetylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 108-111 ° C
(4-Fluorphenyl)-{l-[3-(5-isochinolyloxy)-propyl]-4-piperidyl}-keton, Schmelzpunkt 31 - 33 °C(4-fluorophenyl) - {l- [3- (5-isoquinolyloxy) propyl] -4-piperidyl} ketone, melting point 31-33 ° C
(4-Fluorphenyl)-{l-[3-(3-pyridyloxy)-propyl]-4-piperidyl}-keton, Schmelzpunkt 52 - 55 °C(4-fluorophenyl) - {l- [3- (3-pyridyloxy) propyl] -4-piperidyl} ketone, melting point 52-55 ° C
(4-Fluorphenyl)-{l-[3-(3-(N-methylanilino)-phenoxy)-propyl]-4-piperidyl}-keton, Schmelzpunkt 75 - 77 °C(4-fluorophenyl) - {l- [3- (3- (N-methylanilino) phenoxy) propyl] -4-piperidyl} ketone, melting point 75-77 ° C
4-{3-[4-(4-Fluorbenzoyl)-l-piperidyl]-propoxy}-indan-l-on, Schmelzpunkt 126 - 127 °C4- {3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy} -indan-l-one, melting point 126-127 ° C
5-{3-[4-(-Fl :)rbenzoyl)-l-piperidyl]-propoxy}-3,4-dihydronaphthalin-l(2H)-on (Öl)5- {3- [4 - (- Fl:) rbenzoyl) -l-piperidyl] -propoxy} -3,4-dihydronaphthalene-l (2H) -one (oil)
{l-[3-(7,8-Dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 72 - 74°C{l- [3- (7,8-Dihydro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 72-74 ° C
{l-[3-(7,8-Dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3,4-difluorphenyl)-keton{l- [3- (7,8-Dihydro-2-naphthyloxy) propyl] -4-piperidyl} - (3,4-difluorophenyl) ketone
{l-[3-(7,8-Dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-keton{l- [3- (7,8-Dihydro-2-naphthyloxy) propyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone
(4-Fluorphenyl)-{l-[3-(2-(lH-imidazol-l-yl)-phenoxy)-propyl]-4-piperidyl}-keton (Öl) (4-Fluorphenyl)-{l-[3-(4-hydroxy-3,5-di-tert.-butyl-phenoxy)-propyl]-4-piperidyl}-keton(4-fluorophenyl) - {l- [3- (2- (lH-imidazol-l-yl) phenoxy) propyl] -4-piperidyl} ketone (oil) (4-fluorophenyl) - {l- [3- (4-hydroxy-3,5-di-tert-butylphenoxy) propyl] -4-piperidyl} ketone
7-{3-[4-(4-Fluorbenzoyl)-l-piperidyl]-propoxy}-2H-chromen-2-on, Schmelzpunkt 128 - 129 °C7- {3- [4- (4-Fluorobenzoyl) -l-piperidyl] propoxy} -2H-chromen-2-one, melting point 128-129 ° C
7-{3-[4-(4-Fluorbenzoyl)-l-piperidyl]-propoxy}-4-methyl-2H-chromen-2-on, Schmelzpunkt 139 - 140 °C7- {3- [4- (4-Fluorobenzoyl) -l-piperidyl] propoxy} -4-methyl-2H-chromen-2-one, melting point 139-140 ° C
4-{3-[4-(4-Fluorbenzoyl)-l-piperidyl]-propoxy}-2H-chromen-2-on, Schmelzpunkt 132 - 133 °C4- {3- [4- (4-fluorobenzoyl) -l-piperidyl] propoxy} -2H-chromen-2-one, melting point 132-133 ° C
{l-[3-(6-Brom-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 126 - 127 °C{l- [3- (6-Bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 126-127 ° C
{l[3-(2-Naphtyloxy)-propyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-keton, Schmelzpunkt 107 - 108 °C{l [3- (2-Naphtyloxy) propyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone, melting point 107-108 ° C
Beispiel 2Example 2
l-{l-[3- 3-DimethylaminophenoxyVpropyl]-4-piperidyl}-l-(4-fluorphenylVmethanoll- {l- [3- 3-DimethylaminophenoxyVpropyl] -4-piperidyl} -l- (4-fluorophenylVmethanol
384 mg {l-[3-(3-Dimethylaminophenoxy)-propyl]-4-piperidyl}(4-fluorphenyl)-keton werden portionsweise bei Raumtemperatur zu einer Lösung von 15 ml Ethanol und 80 mg Natriumborhydrid gegeben. Nach 4 Stunden Rühren wird die Reaktionslösung neutralisiert, mit Wasser versetzt und anschließend mit Essigester extrahiert. Nach dem Trocknen der organischen Phase wird eingeengt und der Rückstand über Kieselgel mit Aceton + Methylenchlorid = 1 + 1 chromatographiert. Man erhält 154 mg l-{l-[3-(3- Dimethylaminophenoxy)-propyl]-4-piperidyl}-l-(4-fluorphenyl)-methanol, Schmelzpunkt 63 - 64 °C.384 mg {l- [3- (3-Dimethylaminophenoxy) propyl] -4-piperidyl} (4-fluorophenyl) ketone are added in portions at room temperature to a solution of 15 ml ethanol and 80 mg sodium borohydride. After 4 hours of stirring, the reaction solution is neutralized, water is added and then extracted with ethyl acetate. After the organic phase has dried, the mixture is concentrated and the residue is chromatographed on silica gel using acetone + methylene chloride = 1 + 1. 154 mg of l- {l- [3- (3-dimethylaminophenoxy) propyl] -4-piperidyl} -l- (4-fluorophenyl) -methanol are obtained, melting point 63-64 ° C.
In analoger Weise werden hergestellt:The following are produced in an analogous manner:
l-{l.-[3-(l-Naphthyloxy)-propyl]-4-piperidyl}-l-(4-fluorphenyl)-methanoll- {l .- [3- (l-naphthyloxy) propyl] -4-piperidyl} -l- (4-fluorophenyl) methanol
l-{ 1 -[3-(2-Naphthyloxy)-propyl]-4-piperidyl}-l -(4-fluorphenyl)-methanol Schmelzpunkt 136 - 137 °C Beispiel 3l- {1 - [3- (2-Naphthyloxy) propyl] -4-piperidyl} -l - (4-fluorophenyl) methanol melting point 136-137 ° C Example 3
-DimethylaminophenylV{3[4 4-fluorbenzylVl-piperidyl]-propyl}-ether-DimethylaminophenylV {3 [4 4-fluorobenzylVl-piperidyl] propyl} ether
2 g Triethylsilan werden tropfenweise zu einer Lösung von 384 mg {l-[3-(3- Dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton in 25 ml Trifluoressigesäure gegeben. Das Reaktionsgemisch wird 3 Tage nachgerührt. Danach wird zur Trockene eingeengt und der Rückstand in Ether aufgenommen und dreimal mit In HCL ausgeschüttelt. Die vereinigten Extrakte werden basisch gestellt, mit Ether extrahiert, getrocknet und eingeengt. Man erhält 197 mg (3-Dimethylaminophenyl)-{3- [4(4-fluorbenzyl)- 1 -piperidy 1] -propy 1} -ether (Öl).2 g of triethylsilane are added dropwise to a solution of 384 mg of {l- [3- (3-dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone in 25 ml of trifluoroacetic acid. The reaction mixture is stirred for 3 days. The mixture is then evaporated to dryness and the residue is taken up in ether and extracted three times with In HCL. The combined extracts are made basic, extracted with ether, dried and concentrated. 197 mg of (3-dimethylaminophenyl) - {3- [4 (4-fluorobenzyl) - 1 -piperidy 1] -propy 1} ether (oil) are obtained.
In analoger Weise werden hergestellt:The following are produced in an analogous manner:
1 -Naphthy l-{3 -[4-(4-fluorbenzyl)- 1-piperidyl] -propy 1} -ether1 -Naphthy l- {3 - [4- (4-fluorobenzyl) -1-piperidyl] propy 1} ether
2-Naphthy l-{3 -[4-(4-fluorbenzyl)-l -piperidy 1] -propyl} -ether, Schmelzpunkt 79 - 80 °C 2-Naphthy l- {3 - [4- (4-fluorobenzyl) -l -piperidy 1] -propyl} ether, melting point 79-80 ° C
Beispiel 4Example 4
{l-[l-(3-Dimethylaminophenyloxy)-butyl}-4-piperidyl}-(4-fluorphenyl)-keton{l- [l- (3-Dimethylaminophenyloxy) butyl} -4-piperidyl} - (4-fluorophenyl) ketone
630 mg (4-Chlorbutyl)-(3-Dimethylaminophenyl)-ether werden in 25 ml Dimethylformamid mit 950 mg 4-(4-Fluorbenzoyl)-piρeridin und 0,5 ml Triethylamin bei 100 °C Badtemperatur 8 Stunden unter Argon gerührt. Nach dem Abdestillieren des Lösungsmittels wird in Methylenchlorid aufgenommen und je einmal mit Wasser und ges. Kochsalzlösung gewaschen. Die organische Phase wird getrocknet, filtriert und eingeengt. Der Rückstand wird über Kieselgel mit Aceton + Methylenchlorid = 1 + 1 chromatographiert. Man erhält 420 mg {l-[l-(3-Dimethylaminophenoxy)-butyl]-4- piperidyl}-(4-fluorphenyl)-keton.630 mg (4-chlorobutyl) - (3-dimethylaminophenyl) ether are stirred in 25 ml dimethylformamide with 950 mg 4- (4-fluorobenzoyl) -piperidine and 0.5 ml triethylamine at 100 ° C bath temperature for 8 hours under argon. After the solvent has been distilled off, it is taken up in methylene chloride and washed once with water and sat. Washed saline. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel with acetone + methylene chloride = 1 + 1. 420 mg of {l- [l- (3-dimethylaminophenoxy) butyl] -4-piperidyl} - (4-fluorophenyl) ketone are obtained.
Den als Ausgangsmaterial benötigten (4-Chlorbutyl)-(3-dimethylaminophenyl)-ether erhält man durch Veretherung von 3-Dimethylaminophenol mit l-Brom-4-Chlorbutan und Kaliumcarbonat in Dimethylformamid.The (4-chlorobutyl) - (3-dimethylaminophenyl) ether required as starting material is obtained by etherification of 3-dimethylaminophenol with l-bromo-4-chlorobutane and potassium carbonate in dimethylformamide.
Beispiel 5Example 5
{l-[l- 3-DimethylaminophenyloxyVethyl]-4-piperidyl}-(4-fluorphenyI)-keton{l- [l-3-DimethylaminophenyloxyVethyl] -4-piperidyl} - (4-fluorophenyl) ketone
Aus 590 mg (2-Chlorethyl)-(3-Dimethylaminophenyl)-ether und 950 mg 4-From 590 mg (2-chloroethyl) - (3-dimethylaminophenyl) ether and 950 mg 4-
(Fluorbenzoyl)-piperidin erhält man analog dem Verfahren gemäß Beispiel 4(Fluorobenzoyl) piperidine is obtained analogously to the process according to Example 4
590 mg {l-[l-(3-Dimethylaminophenoxy)-ethyl]-4-piperidyl}-(4-fluorphenyl)-keton (Öl).590 mg {l- [l- (3-Dimethylaminophenoxy) ethyl] -4-piperidyl} - (4-fluorophenyl) ketone (oil).
Beispiel 6Example 6
{ 1 - [3 -[3-Dimethy laminophenoxy V2-hydroxypropy 1] -4-piperidy 1 } -( 4-fluorpheny IVketon{1 - [3 - [3-Dimethy laminophenoxy V2-hydroxypropy 1] -4-piperidy 1} - (4-fluoropheny IVketone
380 mg (3-Dimethylaminophenyl)-(2,3-epoxypropyl)-ether werden in 50 ml Methanol gelöst und mit 430 mg 4-(4-Fluorbenzoyl)-piperidin versetz. Nach dreistündigem Erhitzen wird das Lösungsmittel abdestilliert, der Rückstand in 50 ml IN Salzsäure aufgenommen und mehrfach mit 1 Chloroform extrahiert. Die wäßrige Phase wird mit 2 N Natronlauge alkalisch gestellt und anschließend mit Essigester extrahiert. Die vereinigten Essigesterphasen werden gewaschen, getrocknet, filtriert und eingeengt. Der Rückstand wird über Kieselgel mit Aceton + Methylenchlorid = 1 + 1 chromatographiert. Man erhält 446 mg {l-[3-(3-Dimethylaminophenoxy)-2-hydroxypropyl]-4-piperidyl}-(4- fluorρhenyl)-keton, Schmelzpunkt 117 - 119 °C.380 mg (3-dimethylaminophenyl) - (2,3-epoxypropyl) ether are dissolved in 50 ml of methanol and 430 mg of 4- (4-fluorobenzoyl) piperidine are added. After heating for three hours, the solvent is distilled off, the residue is taken up in 50 ml of 1N hydrochloric acid and extracted several times with 1 chloroform. The aqueous phase is made alkaline with 2 N sodium hydroxide solution and then extracted with ethyl acetate. The combined ethyl acetate phases are washed, dried, filtered and concentrated. The residue is chromatographed on silica gel with acetone + methylene chloride = 1 + 1. You get 446 mg {l- [3- (3-Dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 117-119 ° C.
Den als Ausgangsmaterial benötigten (3-Dimethylaminophenyl)-(2,3-epoxypropyl)-ether erhält man durch Umsetzen von 3-Dimethylaminophenol mit Epichlorhydrin und Natriumhydrid in Dimethylformamid.The (3-dimethylaminophenyl) - (2,3-epoxypropyl) ether required as starting material is obtained by reacting 3-dimethylaminophenol with epichlorohydrin and sodium hydride in dimethylformamide.
In analoger Weise werden hergestellt:The following are produced in an analogous manner:
3-[4-(4-Fluorbenzyl)-piperidino)-2-hydroxypropoxy]-dimethylaminoanilin, Schmelzpunkt 85 - 87 °C3- [4- (4-fluorobenzyl) piperidino) -2-hydroxypropoxy] dimethylaminoaniline, melting point 85-87 ° C
{l-[3-(3-Morpholinophenoxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (3-Morpholinophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone
2-[4-(4-Fluorbenzyl)-piperidino)-2-hydroxypropoxy]-naphthalin, Schmelzpunkt 89 - 90 °C2- [4- (4-fluorobenzyl) piperidino) -2-hydroxypropoxy] naphthalene, melting point 89-90 ° C
l-[4-(4-Fluorbenzyl)-piperidino)-2-hydroxypropoxy]-naphthalin, Schmelzpunkt 104 - 105 °C1- [4- (4-fluorobenzyl) piperidino) -2-hydroxypropoxy] naphthalene, melting point 104-105 ° C
{l-(3-(l-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-4-fluorphenyl)-keton{l- (3- (l-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} -4-fluorophenyl) ketone
{l-[3-(2-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 136 - 137 °C{l- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 136-137 ° C
(4-Fluorphenyl)-{l-[3-(l-oxo-l,2,3,4-tetrahydro-5-naphthyloxy)-2hydroxypropyl]-4- piperidyl}-keton, Schmelzpunkt 128 - 131 °C(4-fluorophenyl) - {l- [3- (l-oxo-l, 2,3,4-tetrahydro-5-naphthyloxy) -2hydroxypropyl] -4-piperidyl} ketone, melting point 128-131 ° C
{l-[3-(l-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-keton{l- [3- (l-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone
{ 1 -[3 -(1 -Naphthy loxy)-2-hydroxypropy l]-4-piperidy 1} -(3,4-fluorphenyl)-keton{1 - [3 - (1-Naphthyloxy) -2-hydroxypropyl] -4-piperidy 1} - (3,4-fluorophenyl) ketone
{l-[3-(2-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-fluorphenyl)-keton{l- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-fluorophenyl) ketone
Beispiel 7Example 7
{ l-[3- 3 -Dimethylaminophenoxy V2-acetoxypropyl]-4-piperidyl } -f4-fluorpheny IVketon 250 mg {l-[3-(3-Dimethylaminophenoxy)-2-hydroxypropyl]-4-piperidyl}-(4- fluorpheny.)-keton werden in 10 ml trockenem Pyridin gelöst. Nach Zugabe von 0,15 ml Acetanhydrid erhitzt man 3 Stunden unter Rückfluß. Nach dem Abkühlen wird das Reaktionsgemisch im Vakuum eingeengt. Der Rückstand wird über Kieselgel mit Methylenchlorid + Ethanol =1800 +75 chromatogaphiert. Man erhält 125 mg {l-[3-(3- Dimethylaminophenoxy)-2-acetoxy-propyl]-4-piperidyl}-(4-fluorphenyl)-keton (Öl).{l- [3- 3 -Dimethylaminophenoxy V2-acetoxypropyl] -4-piperidyl} -f4-fluoropheny IVketone 250 mg {l- [3- (3-Dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluoropheny.) - ketone are dissolved in 10 ml dry pyridine. After adding 0.15 ml of acetic anhydride, the mixture is heated under reflux for 3 hours. After cooling, the reaction mixture is concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride + ethanol = 1800 +75. 125 mg of {l- [3- (3-dimethylaminophenoxy) -2-acetoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone (oil) are obtained.
In analoger Weise werden hergestellt:The following are produced in an analogous manner:
2-[4-(4-Fluorbenzyl)-piperidino)-2-acetoxypropoxy]-naphthalin2- [4- (4-fluorobenzyl) piperidino) -2-acetoxypropoxy] naphthalene
{ 1 -[3 -(1 -Naphthy loxy)-2-acetoxypropyl]-4-piperidyl} -(4-fluorphenyl)-keton{1 - [3 - (1-Naphylyoxy) -2-acetoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(2-Naphthyloxy)-2-acetoxypropyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (2-Naphthyloxy) -2-acetoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(l-Naphthyloxy)-2-acetoxypropyl]-4-piperidyl}-(3,4-difluorphenyl)-keton{l- [3- (l-Naphthyloxy) -2-acetoxypropyl] -4-piperidyl} - (3,4-difluorophenyl) ketone
Beispiel 8Example 8
{l-[3- 3-Dimethylaminophenoxy)-2-methoxypropyl]-4-piperidyl}- 4-fluorphenyl)-keton{l- [3- 3-Dimethylaminophenoxy) -2-methoxypropyl] -4-piperidyl} - 4-fluorophenyl) ketone
250 mg { l-[3-(3-Dimethylaminophenoxy)-2-hydroxypropyl]-4-piperidyl}-(4- fluorphenyl)-keton werden in 10 ml Ethylenglykoldimethylether gelöst, mit 20 mg Natriumhydrid (90%ig) versetzt und im Eisbad gekühlt. Nach Zugabe von 106 mg Methyljodid wird das Reaktionsgemisch 4 Stunden in der Kälte und 1 Stunde bei RT gerührt. Nach dem Einengen der organischen Phase wird über Kieselgel mit Methylenchlorid + Ethanol =1800 +75 chromatogaphiert. Man erhält 150 mg {l-[3-(3- Dimethylaminophenoxy)-2-methoxypropyl]-4-piperidyI}-(4-fluorphenyl)-keton (Öl).250 mg {l- [3- (3-dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone are dissolved in 10 ml ethylene glycol dimethyl ether, mixed with 20 mg sodium hydride (90%) and in Chilled ice bath. After adding 106 mg of methyl iodide, the reaction mixture is stirred for 4 hours in the cold and for 1 hour at RT. After concentrating the organic phase, the mixture is chromatographed on silica gel with methylene chloride + ethanol = 1800 +75. 150 mg of {l- [3- (3-dimethylaminophenoxy) -2-methoxypropyl] -4-piperidyI} - (4-fluorophenyl) ketone (oil) are obtained.
In analoger Weise werden hergestellt:The following are produced in an analogous manner:
2-[4-(4-Fluorbenzyl)-piperidino)-2-methoxypropoxy]-naphthalin,2- [4- (4-fluorobenzyl) piperidino) -2-methoxypropoxy] naphthalene,
{l-[3-(l-Naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(4-fluoφhenyl)-keton,{l- [3- (l-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluoφhenyl) ketone,
{l-[3-(2-Naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(4-fluoφhenyl)-keton,{l- [3- (2-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluoφhenyl) ketone,
{l-[3-(l-Naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-keton Beispiel 9{l- [3- (l-Naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone Example 9
f4-FluorphenylV{l-[3-(1.2.3.4-tetrahvdro-5-naphthyloxyVpropyl]-4-piperidyl}-ketonf4-fluorophenylV {l- [3- (1.2.3.4-tetrahvdro-5-naphthyloxyVpropyl] -4-piperidyl} ketone
Eine Lösung aus 200 mg l,2,3,4-Tetrahydro-5-naphthol in 25 ml Tetrahydrofuran p.A. wird mit 700 mg (4-Fluorphenyl)-l-[l-(3-hydroxypropyl)-4-piperidyl]-keton, 700 mg Triphenylphosphin und 0,45 ml Azodicarbonsäurediethylester versetzt und 20 Minuten unter Rühren auf 80 °C Badtemperatur erhitzt. Die Reaktionslösung wird mit 50 ml Wasser versetzt und anschließend mit Essigester extrahiert. Nach dem Trocknen der organischen Phase wird eingeengt und der Rückstand über Kieselgel mit Methylenchlorid + Ethanol = 9 + 1 chromatographiert. Man erhält 264 mg (4-Fluorphenyl)-{l-[3-(l,2,3,4- tetrahydro-5-naphthyloxy)-propyl]-4-piperidyl}-keton.A solution of 200 mg l, 2,3,4-tetrahydro-5-naphthol in 25 ml tetrahydrofuran p.A. 700 mg of (4-fluorophenyl) -1- [1- (3-hydroxypropyl) -4-piperidyl] ketone, 700 mg of triphenylphosphine and 0.45 ml of diethyl azodicarboxylate are added and the mixture is heated to a bath temperature of 80 ° C. for 20 minutes. The reaction solution is mixed with 50 ml of water and then extracted with ethyl acetate. After the organic phase has dried, the mixture is concentrated and the residue is chromatographed on silica gel using methylene chloride + ethanol = 9 + 1. 264 mg (4-fluorophenyl) - {l- [3- (l, 2,3,4-tetrahydro-5-naphthyloxy) propyl] -4-piperidyl} ketone are obtained.
Das (4-Fluorphenyl)-l-[l-(3-hydroxypropyl)-4-piperidyl]-keton erhält man nach literatur¬ bekannten Methoden durch Alkylierung von 4-(4-Fluorbenzoyl)-piperidin mit 3-Brom- propanol-1 und Kaliumcarbonat in Dimethylformamid.The (4-fluorophenyl) -1- [1- (3-hydroxypropyl) -4-piperidyl] ketone is obtained by methods known from the literature by alkylation of 4- (4-fluorobenzoyl) piperidine with 3-bromopropanol. 1 and potassium carbonate in dimethylformamide.
In analoger Weise werden hergestellt:The following are produced in an analogous manner:
(4-Fluorphenyl)-{l-[3-(indan-4-yloxy)-propyl]-4-piperidyl}-keton, Schmelzpunkt 70 - 72 °C(4-fluorophenyl) - {l- [3- (indan-4-yloxy) propyl] -4-piperidyl} ketone, melting point 70-72 ° C
(4-Fluorphenyl)-{l-[3-(indan-5-yloxy)-propyl]-4-piperidyl}-keton, Schmelzpunkt 49 - 52 °C(4-fluorophenyl) - {l- [3- (indan-5-yloxy) propyl] -4-piperidyl} ketone, melting point 49-52 ° C
(3,4-Difluorphenyl)-{l-[3-(indan-4-yloxy)-propyl]-4-piperidyl}-keton(3,4-difluorophenyl) - {l- [3- (indan-4-yloxy) propyl] -4-piperidyl} ketone
{l-[3-(4-Benzylphenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton, Schmelzpunkt 105 - 107 °C{l- [3- (4-Benzylphenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, melting point 105-107 ° C
(4-Fluorphenyl)-{l-[3-(l,2,3,4-tetrahydro-6-naphthyloxy)-propyl]-4-piperidyl}-keton (4-fluorophenyl) - {l- [3- (l, 2,3,4-tetrahydro-6-naphthyloxy) propyl] -4-piperidyl} ketone

Claims

Patentansprüche claims
1.) Verbindungen der Formel I1.) Compounds of formula I.
R1— Z— X— N B (I),R 1 - Z— X— NB (I),
worinwherein
Rl substituiertes oder unsubstituiertes Phenyl, substituiertes oder unsubstituiertes Pyridin, substituiertes oder unsubstituiertes Naphthalin, substituiertes oder unsubstituiertes Quinolin, substituiertes oder unsubstituiertes Isoquinolin, substituiertes oder unsubstituiertes Indol, substituiertes oder unsubstituiertes Benzothiophen, substituiertes oder unsubstituiertes Benzofuran, substituiertes oder unsubstituiertes Tetrahydrochinolin, substituiertes oder unsubstituiertes Tetrahydroisochinolin, substituiertes oder unsubstituiertes Tetralin, substituiertes oder unsubstituiertes Dihydronaphtalin, substituiertes oder unsubstituiertes Indan, substituiertes oder unsubstituiertes Indanon, substituiertes oder unsubstituiertes Tetralon, substituiertes oder unsubstituiertes Chromen-2-on, substituiertes oder unsubstituiertes Naphthochinon,Rl substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted or unsubstituted tetra-unsubstituted unsubstituted benzofuran, unsubstituted or substituted benzofuran , substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphthalene, substituted or unsubstituted indane, substituted or unsubstituted indanone, substituted or unsubstituted tetralone, substituted or unsubstituted chromen-2-one, substituted or unsubstituted naphthoquinone,
Z Sauerstoff, Schwefel, SO oder S02,Z oxygen, sulfur, SO or S0 2 ,
X — (CH2)m— CR2R3— (CH2)p oderX - (CH 2 ) m - CR2R3— (CH 2 ) p or
— (CH2)m— CHR2— (CH2)g— CHR3— (CH2)p— ,- (CH 2 ) m - CHR2— (CH 2 ) g - CHR3— (CH 2 ) p -,
B _^CB.— R4 undB _ ^ CB.— R 4 and
m, p, g jeweils 0, 1, 2 oder 3,m, p, g each 0, 1, 2 or 3,
R*-* und R3 gleich oder verschieden sind und Wasserstoff, Hydroxy, Cι_4-Alkyl, Cι_4-Alkoxy oder Ci.g-Alkanoyloxy bedeuten,R * - * and R 3 are the same or different and are hydrogen, hydroxy, Cι_4-alkyl, Cι_4-alkoxy or Ci.g-alkanoyloxy,
R4 geradkettiges oder verzweigtes, C^.ö-Alkyl, — CO- - Y oder einen gegebenenfalls mit C]__4-Alkyl, C^_4-Alkoxy, Halogen, Hydroxy, — CF3 oder — O — CF3 substituierten Phenyl-, Benzyl-, Benzoyl-, -Hydroxy-Benzyl-, Pyridinyl- oder Naphthoyl-Rest bedeutet, wobei der Substituent gleich oder verschieden ein- bis dreifach stehen kann undR 4 straight-chain or branched, C ^ .ö-alkyl, - CO- - Y or a phenyl-, benzyl optionally substituted with C ] __4-alkyl, C ^ _4-alkoxy, halogen, hydroxy, - CF3 or - O - CF3 -, Benzoyl-, -Hydroxy-Benzyl-, Pyridinyl- or Naphthoyl radical means, where the substituent can be identical or different one to three times and
Y Sauerstoff, Schwefel oder — NH — bedeuten,Y is oxygen, sulfur or - NH -,
sowie deren physiologisch verträgliche Salze und Isomeren.and their physiologically tolerable salts and isomers.
2.) {l-[3-(l-Naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton2.) {l- [3- (l-Naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(2-Naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (2-Naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(2-Nitro-l-napththyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (2-Nitro-l-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(l-Nitro-2-napththyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (l-Nitro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(2,4-Dinitro-l-napththyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (2,4-Dinitro-l-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
(4-Fluorphenyl)-{l-[3-(5-isochinolyloxy)-propyl]-4-piperidyl}-keton(4-fluorophenyl) - {l- [3- (5-isoquinolyloxy) propyl] -4-piperidyl} ketone
{l-[3-(l-Brom-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{l- [3- (l-bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{l-[3-(4-Chlor-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluoφhenyl)-keton{l- [3- (4-Chloro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophene) ketone
{l-(3-(l-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-4-fluoφhenyl)-keton{l- (3- (l-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} -4-fluorophene) ketone
{l-[3-(2-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluoφhenyl)-keton{l- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophene) ketone
l-{l-[3-(l-Naphthyloxy)-propyl]-4-piperidyl}-l-(4-fluoφhenyl)-methanoll- {l- [3- (l-Naphthyloxy) propyl] -4-piperidyl} -l- (4-fluoro-phenyl) methanol
l-{l-[3-(2-Naphthyloxy)-propyl]-4-piperidyl}-l-(4-fluoφhenyl)-methanoll- {l- [3- (2-Naphthyloxy) propyl] -4-piperidyl} -l- (4-fluoro-phenyl) methanol
l-Naphthyl-{3-[4-(4-fluorbenzyl)-l-piperidyl]-propyl}-etherl-Naphthyl {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether
2-Napthyl-{3-[4-(4-fluorbenzyl)-l-piperidyl]-propyl}-ether2-Napthyl {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether
{l-[3-(l-Brom-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton {l-[3-(4-Chlor-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluoφhenyl)-keton{l- [3- (l-bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone {l- [3- (4-Chloro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophene) ketone
4-{3-[4-(4-Fluorbenzoyl)-l-piperidyl]-propoxy}-indan-l-on4- {3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy} -indan-l-one
5-{3-[4-(-Fluorbenzoyl)-l-piperidyl]-propoxy}-3,4-dihydronaphthalin-l(2H)-on5- {3- [4 - (- Fluorobenzoyl) -l-piperidyl] propoxy} -3,4-dihydronaphthalene-l (2H) -one
{l-[3-(7,8-Dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluoφhenyl)-keton{l- [3- (7,8-Dihydro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophene) ketone
{l-[3-(7,8-Dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3,4-difluθφhenyl)-keton{l- [3- (7,8-Dihydro-2-naphthyloxy) propyl] -4-piperidyl} - (3,4-difluθφhenyl) ketone
{l-[3-(7,8-Dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-keton{l- [3- (7,8-Dihydro-2-naphthyloxy) propyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone
7-{3-[4-(4-Fluorbenzoyl)-l-piperidyl]-propoxy}-2H-chromen-2-on7- {3- [4- (4-Fluorobenzoyl) -1-piperidyl] propoxy} -2H-chromen-2-one
7-{3 - [4-(4-Fluorbenzoy 1)- 1 -piperidyl] -propoxy } -4-methy 1 -2H-chromen-2-on7- {3 - [4- (4-Fluorobenzoy 1) -1 -piperidyl] propoxy} -4-methyl 1 -2H-chromen-2-one
4-{3-[4-(4-Fluorbenzoyl)-l-piperidyl]-propoxy}-2H-chromen-2-on4- {3- [4- (4-Fluorobenzoyl) -1-piperidyl] propoxy} -2H-chromen-2-one
{l-[3-(6-Brom-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluoφhenyl)-keton{l- [3- (6-Bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluoro-phenyl) ketone
{l-[3-(2-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluoφhenyl)-keton{l- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophene) ketone
(4-Fluoφhenyl)-{l-[3-(l-oxo-l,2,3,4-tetrahydro-5-naphthyloxy)-2hydroxypropyl]-4- piperidyl}-keton(4-Fluoφhenyl) - {l- [3- (l-oxo-l, 2,3,4-tetrahydro-5-naphthyloxy) -2hydroxypropyl] -4-piperidyl} ketone
{l-[3-(l-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-keton{l- [3- (l-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone
{l-[3-(l-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-fluoφhenyl)-keton{l- [3- (l-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-fluorophene) ketone
{l-[3-(2-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-fluoφhenyl)-keton{l- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-fluorophene) ketone
2-[4-(4-Fluorbenzyl)-piperidino)-2-methoxypropoxy]-naphthalin2- [4- (4-fluorobenzyl) piperidino) -2-methoxypropoxy] naphthalene
{ 1 -[3 -(1 -Naphthyloxy)-2-methoxypropyl] -4-piperidyl}-(4-fluoφhenyl)-keton{1 - [3 - (1-Naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophene) ketone
{l-[3-(2-Naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(4-fluoφhenyl)-keton {l-[3-(l-Naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-keton{l- [3- (2-Naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluoφhenyl) ketone {l- [3- (l-Naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone
(4-Fluoφhenyl)-{l-[3-(l,2,3,4-tetrahydro-5-naphthyloxy)-propyl]-4-piperidyl}-keton(4-Fluoφhenyl) - {l- [3- (l, 2,3,4-tetrahydro-5-naphthyloxy) propyl] -4-piperidyl} ketone
(4-Fluoφhenyl)-{l-[3-(indan-4-yloxy)-propyl]-4-piperidyl}-keton(4-Fluoφhenyl) - {l- [3- (indan-4-yloxy) propyl] -4-piperidyl} ketone
(4-Fluoφhenyl)-{l-[3-(indan-5-yloxy)-propyl]-4-piperidyl}-keton(4-Fluoφhenyl) - {l- [3- (indan-5-yloxy) propyl] -4-piperidyl} ketone
(3,4-Difluorphenyl)-{l-[3-(indan-4-yloxy)-propyl]-4-piperidyl}-keton(3,4-difluorophenyl) - {l- [3- (indan-4-yloxy) propyl] -4-piperidyl} ketone
(4-Fluoφhenyl)-{l-[3-(l,2,3,4-tetrahydro-6-naphthyloxy)-propyl]-4-piperidyl}-keton nach Anspruch 1.(4-Fluoφhenyl) - {l- [3- (l, 2,3,4-tetrahydro-6-naphthyloxy) propyl] -4-piperidyl} ketone according to claim 1.
3.) Arzneimittel auf Basis der Verbindungen nach Anspruch 1 und 2.3.) Medicaments based on the compounds according to claim 1 and 2.
4.) Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man4.) Process for the preparation of the compounds according to claim 1, characterized in that
a) eine Verbindung der Formel IIa) a compound of formula II
R1— Z— H (U),R 1 - Z— H (U),
worin Rl und Z die obige Bedeutung haben, mit einer Verbindung der Formel mwherein Rl and Z have the above meaning, with a compound of formula m
A— x— N B an),A— x— N B an),
worin X und B die obige Bedeutung haben und A eine Fluchtgruppe darstellt, umsetzt oderwherein X and B have the above meaning and A represents a refugee group, implement or
b) eine Verbindung der Formel IVb) a compound of formula IV
A— X— Z— R1 (IV),A— X— Z— R 1 (IV),
worin X, Z und R die obige Bedeutung haben und A eine Fluchtgruppe darstellt mit einem Amin der Formel Vwherein X, Z and R have the meaning given above and A represents a leaving group with an amine of the formula V.
H— N B (V),H— N B (V),
worin B die obige Bedeutung hat, umsetzt oder c) eine Epoxid der Formel VIwhere B has the above meaning, implements or c) an epoxy of the formula VI
Rl— Z— (CH2)m— CH— CH2 (VI),Rl— Z— (CH 2 ) m - CH— CH 2 (VI),
worin R , Z und m die obige Bedeutung haben mit einem Amin der Formel Vwherein R, Z and m have the above meaning with an amine of formula V
H— N BH - N B
umsetzt oderimplements or
d) eine Verbindung der Formel VTId) a compound of the formula VTI
HO— X— N B (VTI)HO— X— N B (VTI)
worin X und B die obige Bedeutung haben, nach Mitsunobu mit einer Verbindung der Formel Rl-OH umsetzt und anschließend gewünschtenfalls eine Carbonylgruppe reduziert oder eine Hydroxygruppe verestert oder verethert oder die physiologisch verträglichen Salze bildet oder die Isomeren trennt. wherein X and B have the meaning given above, after Mitsunobu, reacting with a compound of the formula R1-OH and then, if desired, reducing a carbonyl group or esterifying or etherifying a hydroxyl group or forming the physiologically tolerable salts or separating the isomers.
PCT/DE1995/000442 1994-03-23 1995-03-23 New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor WO1995025721A1 (en)

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JP7524306A JPH09510460A (en) 1994-03-24 1995-03-23 Novel piperidine derivative
PL95316382A PL316382A1 (en) 1994-03-24 1995-03-23 Novel derivatives of piperidine
EP95915116A EP0751936A1 (en) 1994-03-23 1995-03-23 New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor
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MXPA/A/1996/004201A MXPA96004201A (en) 1994-03-24 1996-09-20 New piperid derivatives
FI963786A FI963786A (en) 1994-03-24 1996-09-23 New 1,4-disubstituted piperidine derivatives useful as drugs acting on the glutamate receptor
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