DE4410822A1 - New piperidine derivatives - Google Patents

New piperidine derivatives

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Publication number
DE4410822A1
DE4410822A1 DE4410822A DE4410822A DE4410822A1 DE 4410822 A1 DE4410822 A1 DE 4410822A1 DE 4410822 A DE4410822 A DE 4410822A DE 4410822 A DE4410822 A DE 4410822A DE 4410822 A1 DE4410822 A1 DE 4410822A1
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Germany
Prior art keywords
piperidyl
fluorophenyl
propyl
ketone
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE4410822A
Other languages
German (de)
Inventor
Dieter Dr Seidelmann
Andreas Dr Huth
Martin Dr Krueger
Eckhard Dr Ottow
Graham Hugh Dr Jones
Roland Dr Neuhaus
Lechoslaw Dr Turski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to DE4410822A priority Critical patent/DE4410822A1/en
Priority to EP95915116A priority patent/EP0751936A1/en
Priority to PCT/DE1995/000442 priority patent/WO1995025721A1/en
Priority to JP7524306A priority patent/JPH09510460A/en
Priority to CA002186010A priority patent/CA2186010A1/en
Priority to SK1201-96A priority patent/SK120196A3/en
Priority to HU9602607A priority patent/HUT75653A/en
Priority to CZ962770A priority patent/CZ277096A3/en
Priority to CN95192230A priority patent/CN1145618A/en
Priority to KR1019960705269A priority patent/KR970701695A/en
Priority to IL11310395A priority patent/IL113103A0/en
Priority to AU22125/95A priority patent/AU2212595A/en
Priority to PL95316382A priority patent/PL316382A1/en
Priority to ZA952431A priority patent/ZA952431B/en
Publication of DE4410822A1 publication Critical patent/DE4410822A1/en
Priority to MXPA/A/1996/004201A priority patent/MXPA96004201A/en
Priority to FI963786A priority patent/FI963786A/en
Priority to NO963984A priority patent/NO963984L/en
Withdrawn legal-status Critical Current

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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

Abstract

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

Description

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.

Gegenstand der Erfindung sind die Verbindungen der Formel IThe invention relates to the compounds of the formula I.

worin
R¹ 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,
Z Sauerstoff, Schwefel, SO oder SO₂,
X -(CH2)m-CR²R³-(CH₂)p,
-(CH₂)m-CHR²-(CH₂)g-CHR³-(CH₂)p-,wherein
R¹ 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-benzo-unsubstituted unsubstituted or unsubstituted tetra-benzo-substituted ,
Z oxygen, sulfur, SO or SO₂,
X - (CH2) m -CR²R³- (CH₂) p ,
- (CH₂) m -CHR²- (CH₂) g -CHR³- (CH₂) p -,

m, p, g jeweils 0, 1, 2 oder 3,
R² und R³ gleich oder verschieden sind und Wasserstoff, Hydroxy, C1-4-Alkyl oder C1-4-Alkoxy bedeuten,
R⁴ Wasserstoff, C1-6-Alkyl geradkettig oder verzweigt,m, p, g each 0, 1, 2 or 3,
R² and R³ are the same or different and are hydrogen, hydroxy, C 1-4 -alkyl or C 1-4 -alkoxy,
R⁴ hydrogen, C 1-6 alkyl straight-chain or branched,

oder einen gegebenenfalls mit C1-4-Alkyl, C1-4-Alkoxy, Halogen, Hydroxy, -CF₃ oder -O- CF₃ substituierten Phenyl-, Benzyl-, Benzoyl-, α-Hydroxy-Benzyl- oder Pyridin-Rest und
Y Sauerstoff, Schwefel oder -NH- bedeuten,
sowie deren physiologisch verträgliche Salze und Isomeren.or an optionally substituted with C 1-4 alkyl, C 1-4 alkoxy, halogen, hydroxy, -CF₃ or -O- CF₃, phenyl, benzyl, benzoyl, α-hydroxy-benzyl or pyridine radical and
Y is oxygen, sulfur or -NH-,
and their physiologically tolerable salts and isomers.

Der Substituent R¹ kann ein- bis dreifach gleich oder verschieden substituiert sein mit C1-4-Alkyl, C1-4-Alkoxy, Halogen, NO₂, CF₃, -OCF₃, Hydroxy, Carboxyl, C1-4- Alkoxycarbonyl, Formyl, C1-4-Alkylcarbonyl, Phenyl, Phenoxy,The substituent R¹ can be monosubstituted or trisubstituted by identical or different substituents with C 1-4 alkyl, C 1-4 alkoxy, halogen, NO₂, CF₃, -OCF₃, hydroxy, carboxyl, C 1-4 alkoxycarbonyl, formyl, C 1-4 alkylcarbonyl, phenyl, phenoxy,

wobei
R⁵ und R⁶ gleich oder verschieden sind und Wasserstoff, C1-4-Alkyl, Phenyl, C1-6- Alkanoyl oder gemeinsam mit dem Stickstoffatom einen 5- oder 6-gliedrigen gesättigten Heterocyclus bedeuten, der ein- oder mehrfach mit C1-4-Alkyl 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.in which
R⁵ and R⁶ are the same or different and are hydrogen, C 1-4 -alkyl, phenyl, C 1-6 -alkanoyl or together with the nitrogen atom represent a 5- or 6-membered saturated heterocycle which is repeated one or more times with C 1- 4 -Alkyl can be substituted and can contain a further O, N or S atom. Examples include piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 2,6-dimethyl morpholine.

Unter Halogen ist Fluor, Chlor, Brom oder Jod zu verstehen, insbesondere Fluor.Halogen is to be understood as fluorine, chlorine, bromine or iodine, in particular fluorine.

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, for example Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, pentyl, isopentyl, hexyl.

Der C1-6-Alkanoylrest leitet sich von geradkettigen oder verzweigten aliphatischen Carbonsäuren ab wie beispielsweise Ameisensäure, Essigsäure, Propionsäure, Buttersäure, Trimethylessigsäure oder Capronsäure.The C 1-6 alkanoyl radical is derived 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.

Als bevorzugt sind Verbindungen zu betrachten, worin R¹ substituiertes oder unsubstituiertes Naphthyl bedeutet und Z Sauerstoff ist.Compounds in which R 1 is substituted or are to be regarded as preferred means unsubstituted naphthyl and Z is oxygen.

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 C1-4- Alkansulfonsäuren wie Methansulfonsäure oder gegebenenfalls durch Halogen oder C1-4- 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 1-4 alkanesulfonic acids such as methanesulfonic acid or optionally substituted by halogen or C 1-4 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, 1-Amino-2,3,4-butantriol.If an acidic function is included, the salts are the physiologically acceptable salts Suitable organic and inorganic bases such as the readily soluble alkali and Alkaline earth metal salts as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glukamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl amino methane, aminopropanediol, Sovak base, 1-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 sieh bekannter Weise, indem manThe preparation of the compounds of formula I and their physiologically tolerable Salts are carried out in a known manner by:

  • a) eine Verbindung der Formel II R¹-Z-H (II),worin R¹ und Z die obige Bedeutung haben, mit einer Verbindung der Formel IIIA-X-N B III),worin X und B die obige Bedeutung haben und A eine Fluchtgruppe darstellt, umsetzt odera) a compound of formula II R¹-Z-H (II), in which R¹ and Z have the above meaning, with a compound of the formula IIIA-X-N B III), in which X and B have the above meaning and A represents a leaving group, or
  • b) eine Verbindung der Formel IV A-X-Z-R¹ (IV),worin X, Z und R¹ die obige Bedeutung haben und A eine Fluchtgruppe darstellt mit einem Amin der Formel VH-N B (V),worin B die obige Bedeutung hat, umsetzt oderb) a compound of formula IV A-X-Z-R¹ (IV), wherein X, Z and R¹ have the above meaning and A represents a leaving group with an amine of the formula VH-N B (V), in which B has the above meaning, or
  • c) eine Epoxid der Formel VI worin R¹, Z und m die obige Bedeutung haben mit einem Amin der Formel V umsetzt und anschließend gewünschtenfalls eine Carbonylgruppe reduziert oder die physiologisch verträglichen Salze bildet oder die Isomeren trennt.c) an epoxy of the formula VI wherein R¹, Z and m have the above meaning with an amine of formula V. implemented and then, if desired, reduced a carbonyl group or forms the physiologically tolerable salts or separates the isomers.

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.The nucleophilic substitution of leaving group A according to process variants a) and b) is inert according to the usual methods under the reaction conditions organic solvents under basic conditions.

Als Fluchtgruppen A eignen sich Halogene wie Chlor, Brom oder Jod oder organische Sulfonsäurereste wie der Rest einer Alkansulfonsäure beispielsweise Mesylat, Triflat oder der Rest einer aromatischen Sulfonsäure beispielsweise der Toluolsulfonsäure oder Brombenzolsulfonsäure.Halogens such as chlorine, bromine or iodine or organic are suitable as escape groups A. 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.Polar solvents such as dimethyl form are suitable as inert organic solvents amide, 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, 1,4-Diazabycyclo(2,2,2)octan, 1,5-Diazabycyclo(5,4,0)undec-5-en.Inorganic and organic bases are suitable as bases. Examples of organic bases are alkali or alkaline earth hydroxide, carbonates, bicarbonates or alcoholates. Examples of organic bases are tertiary organic amines such as tripropylamine, triethyl amine, N-alkylmorpholine, N-alkylpiperidine, Hünig base, 1,4-diazabycyclo (2,2,2) octane, 1,5-diazabycyclo (5,4,0) undec-5-ene.

Die Reaktionstemperatur kann zwischen Raumtemperatur und Siedetemperatur des Lösungsmittels liegen.The reaction temperature can be between room temperature and the boiling point of Solvent.

Die Umsetzung nach Verfahren e) erfolgt i.a. in protischen Lösungsmitteln wie Alkoholen bei erhöhter Temperatur bis zur Siedetemperatur.The implementation according to procedure e) generally takes place. in protic solvents such as alcohols at elevated temperatures up to the boiling temperature.

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.The carbonyl group can be reduced using conventional reducing agents be, such as with sodium borohydride to the corresponding hydroxy  Compound or with triethylsilane and trifluoroacetic acid at room temperature Methylene compound.

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 prepared in a manner known per se from the reaction gene mixed isolated and cleaned. Acid addition salts can be added in the usual way free bases are converted and if desired in a known manner physiologically acceptable acid addition salts, for example by using the solution a concentrated solution of the desired acid.

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 formula I have one or more chiral atoms, the optically active connections based on optically active starting compounds or can be obtained from the racemates in a manner known per se. The enantiomers separation can be done, for example, by chromatography over optically active supports materials, by reaction with optically active acids and subsequent fractionated Crystallization take place.

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 formula I and their physiologically tolerable salts are on Because of their functional impact on the glutamate receptor or Glutamate receptor dependent ion channel can be used as a drug.

Die pharmakologische Wirksamkeit der Verbindungen der Formel I wurde mittels der nachfolgend beschriebenen Teste bestimmt:
Männliche NMRI Mäuse mit einem Gewicht von 18-22 g wurden unter kontrollierten Verhältnissen (6.00-18.00 Uhr Hell/Dunkelrhythmus, 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 8.00 und 13.00 Uhr vorgenommen.The pharmacological activity of the compounds of the formula I was determined using the tests described below:
Male NMRI mice weighing 18-22 g were kept under controlled conditions (6 a.m. to 6 p.m. light / dark rhythm, 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 TRRD₅₀- und die Vertrauensgrenze wurde in einer Regressionsanalyse bestimmt.AMPA was injected into the left ventricle by freely moving mice. Of the Applicator consisted of a cannula with a stainless steel device that the Injection depth limited to 3.2 mm. The applicator was on an injection pump connected. The injection needle became perpendicular to the surface of the skull introduced according to the coordinates of Montemurro and Dukelow. The animals were up observed for the occurrence of clonic or tonic cramps up to 180 sec. The clonic movements lasting longer than 5 seconds were counted as convulsions. Of the The beginning of the clonic convulsions was used as the end point for the determination of the convulsions  threshold used. The dose that was necessary to reduce the seizure threshold by 50% up or down (THRD₅₀) was determined in 4-5 experiments. The TRRD₅₀ and the confidence limit was determined in a regression analysis.

Die Ergebnisse dieser Versuche zeigen, daß die Verbindung der Formel I und deren Säureadditionssalze funktionelle Störungen des AMPA-Rezeptors beeinflussen. Sie eignen sieh 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 formula I and their Acid addition salts affect functional disorders of the AMPA receptor. You are suitable therefore see the manufacture of medicines for symptomatic and preventive Treatment of diseases caused by changes in the function of the AMPA Receptor complex are triggered.

Zu den Krankheiten, die von der Dysfunktion exeitatorischer 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, Amyotrophe Lateralsklerose, Epilepsie; Zellschäden durch Hypoglykämie, Hypoxie, Ischämie und Störungen des Energiestoff­ wechsels; neuronale Schäden, die durch Schädigung des Gehirns ausgelöst werden wie Schlaganfall, Gehirntrauma und Asphyxie sowie Psychosen, Schizophrenie, Angstzu­ stände, Sehmerzzustände, 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.Among the diseases that change from the dysfunction of exeitatory amino acids or The glutamatergic neurotransmission can be triggered, for example neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alz's disease heimer, senile dementia, multi-infarct dementia, amyotrophic lateral sclerosis, epilepsy; Cell damage from hypoglycemia, hypoxia, ischemia and disorders of the energy substance alternating; neuronal damage caused by brain damage such as Stroke, brain trauma and asphyxia as well as psychoses, schizophrenia, anxiety levels, sensory ore states, migraines and vomiting. Also functional disorders like Memory disorders (amnesia), disorders of the learning process, vigilance symptoms and Withdrawal symptoms after chronic use of addictive substances such as sedative Medicines, hallucinogens, alcohol, cocaine and opiates are based on the dysfunction 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 containing the compounds mentioned contain, their preparation and the use of the compounds according to the invention for the manufacture of medicaments for the treatment and prophylaxis of the above diseases mentioned are used. The drugs are known per se ten processes prepared by the active ingredient with suitable carriers, auxiliaries and / or additives in the form of a pharmaceutical preparation that for the teral or parenteral application is suitable. The application can be oral or sublingual as a solid in the form of capsules or tablets or as a liquid in the form of a solution genes, suspensions, elixirs or emulsions or rectally in the form of suppositories or in the form of injection solutions which may also be used subcutaneously. When Auxiliaries for the desired pharmaceutical formulation are known to the person skilled in the art inert organic and inorganic carrier materials such as, for example  Water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. If necessary, con 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, Coated tablets, suppositories, capsules or in liquid form, for example as solutions, Suspensions or emulsions are present.

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 can also be used as carrier systems or animal or vegetable phospholipids, but also mixtures thereof as well Liposomes or their components can be used.

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 are particularly suitable for oral use and / or hydrocarbon carriers or binders, such as lactose, maize or Potato starch, suitable. The application can also be in liquid form, such as 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.For parenteral use, especially injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated Castor oil, suitable.

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 Patients, type and severity of the disease to be treated and similar factors vary. The daily dose can be divided into single doses or divided once given in 2 or more daily doses. The connections are in one Dose unit from 0.05 to 100 mg of active substance in a physiologically acceptable Carrier introduced. Generally, a dose of 0.1 to 500 mg / day, preferably 0.1 to 50 mg / day.

Soweit die Herstellung der Ausgangsverbindungen nicht beschriebe wird, sind diese bekannt oder analog zu bekannten Verbindungen oder hier beschriebenen Verfahren herstellbar.As far as the production of the starting compounds is not described, these are known or analogous to known compounds or processes described here producible.

Die nachfolgenden Beispiele sollen die Herstellung der Verbindungen der Formel I erläutern: The following examples are intended to prepare the compounds of formula I. explain:  

Beispiel 1example 1 {1-[3-(3-Dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton{1- [3- (3-Dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone

265 mg 3-Dimethylaminophenyl werden in 20 ml Aceton vorgelegt, mit 265 mg Kaliumcarbonat und 824 mg (4-Fluorphenyl)-[1-(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 {1-[3-(-Dimethylaminophenoxy)-propyl]-4- piperidyl}-(4-fluorphenyl)-keton.265 mg of 3-dimethylaminophenyl are placed in 20 ml of acetone, with 265 mg Potassium carbonate and 824 mg (4-fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4- piperidyl] ketone was added and the mixture was heated under reflux for 3 hours under argon. After this Concentrate the organic phase over silica gel with methylene chloride and acetone 1 + 1 chromatographed. 375 mg of {1- [3 - (- dimethylaminophenoxy) propyl] -4- are obtained. piperidyl} - (4-fluorophenyl) ketone.

Das (4-Fluorphenyl)-1-[1-(3-methylsulfonyloxy-propyl)-4-piperidyl]-keton- erhält man nach literaturbekannten Methoden durch Alkylierung von 4-(4-Fluorbenzoyl)-piperidin mit 3-Brompropanol-1 und Kaliumcarbonat in Dimethylformamid und anschließender Umsetzung mit Methansulfonsäure und Triethylamin in Methylenchlorid.The (4-fluorophenyl) -1- [1- (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:
{1-[3-(2-Dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(4-Dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(3-Morpholinophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-ket on
{1-[3-(1-Naphtyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(2-Naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(3-Dibutylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(2-Nitro-1-naph tyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(1-Nitro-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(2,4-Dinitro-1-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(3-Anilinophenoxy)-pro pyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(1-Brom-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(4-Chlor-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(3-Acetylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
(4-Fluorphen yl)-{1-[3-(5-isochinolyloxy)-propyl]-4-piperidyl}-keton
(4-Fluorphenyl)-{1-[3-(3-pyridyloxy)-propyl]-4-piperidyl}-keton
{1-[3-(3-Dimethylaminophenoxy)-propyl]-4-piperazinyl}-(4-fluorphenyl)-keton
(4-Fluorphenyl)-{1-[3-(3-(N-met hylanilino)-phenoxy)-propyl]-4-piperidyl}-ketonThe following are produced in an analogous manner:
{1- [3- (2-Dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (4-Dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (3-Morpholinophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (1-Naphtyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (2-Naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (3-Dibutylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (2-Nitro-1-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (1-Nitro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (2,4-Dinitro-1-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (3-anilinophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (1-Bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (4-Chloro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (3-Acetylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
(4-fluorophen yl) - {1- [3- (5-isoquinolyloxy) propyl] -4-piperidyl} ketone
(4-fluorophenyl) - {1- [3- (3-pyridyloxy) propyl] -4-piperidyl} ketone
{1- [3- (3-Dimethylaminophenoxy) propyl] -4-piperazinyl} - (4-fluorophenyl) ketone
(4-fluorophenyl) - {1- [3- (3- (N-metylanilino) phenoxy) propyl] -4-piperidyl} ketone

Beispiel 2Example 2 1-{-1-[3-(3-Dimethylaminophenoxy)-propyl]-4-piperidyl}-1-(4-fluorphenyl-methanol1 - {- 1- [3- (3-Dimethylaminophenoxy) propyl] -4-piperidyl} -1- (4-fluorophenyl-methanol

384 mg {1-[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.384 mg {1- [3- (3-Dimethylaminophenoxy) propyl] -4-piperidyl} (4-fluorophenyl) ketone are added in portions at room temperature to a solution of 15 ml of ethanol and 80 mg Given sodium borohydride. After 4 hours of stirring, the reaction solution neutralized, mixed with water and then extracted with ethyl acetate. After this Drying of the organic phase is concentrated and the residue is added to silica gel Acetone + methylene chloride = 1 + 1 chromatographed.

In analoger Weise werden hergestellt:
1-{1-[3-(1-Naphthyloxy)-propyl]-4-piperidyl}-1-(4-fluorphenyl)-methanol
1-{1-[3-(2-Naphthyloxy)-propyl]-4-pipendyl}-1-(4-fluorphenyl)-methanolThe following are produced in an analogous manner:
1- {1- [3- (1-Naphthyloxy) propyl] -4-piperidyl} -1- (4-fluorophenyl) methanol
1- {1- [3- (2-Naphthyloxy) propyl] -4-pipendyl} -1- (4-fluorophenyl) methanol

Beispiel 3Example 3 (3-Dimethylaminophenyl)-{3[4(4-fluorbenzyl)-1-piperidyl]-propyl}-ether(3-Dimethylaminophenyl) - {3 [4 (4-fluorobenzyl) -1-piperidyl] propyl} ether

2 g Triethylsilan werden tropfenweise zu einer Lösung von 384 mg {1-[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 1n 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-piperidyl]-propyl}-ether.2 g of triethylsilane are added dropwise to a solution of 384 mg {1- [3- (3- Dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone in 25 ml Trifluoroacetic acid given. The reaction mixture is stirred for 3 days. After that is evaporated to dryness and the residue taken up in ether and three times with 1n HCL shaken out. The combined extracts are made basic with ether extracted, dried and concentrated. 197 mg (3-dimethylaminophenyl) - {3- [4 (4-fluorobenzyl) -1-piperidyl] propyl} ether.

In analoger Weise werden hergestellt:
1-Naphthyl-{3-[4-(4-fluorbenzyl)-1-piperidyl]-propyl}-ether
2-Naphthyl-{3-[4-(4-fluorbenzyl)-1-piperidyl]-propyl}-ether The following are produced in an analogous manner:
1-Naphthyl {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether
2-Naphthyl {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether

Beispiel 4Example 4 {1-[1-(3-Dimethylaminophenyloxy)-butyl}-4-piperidyl}-(4-fluorphenyl)-keton{1- [1- (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)-piperidin 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 {1-[1-(3-Dimethylaminophenoxy)-butyl]-4- piperidyl}-(4-fluorphenyl)-keton.630 mg (4-chlorobutyl) - (3-dimethylaminophenyl) ether are dissolved in 25 ml Dimethylformamide with 950 mg of 4- (4-fluorobenzoyl) piperidine and 0.5 ml of triethylamine 100 ° C bath temperature stirred under argon for 8 hours. After distilling off the Solvent is taken up in methylene chloride and once each with water and sat. Washed saline. The organic phase is dried, filtered and concentrated. The residue is over silica gel with acetone + methylene chloride = 1 + 1 chromatographed. 420 mg of {1- [1- (3-dimethylaminophenoxy) butyl] -4- are obtained. piperidyl} - (4-fluorophenyl) ketone.

Den als Ausgangsmaterial benötigten (4-Chlorbutyl)-(3-dimethylaminophenyl)-ether erhält man durch Veretherung von 3-Dimethylaminophenol mit 1-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 1-bromo-4-chlorobutane and Potassium carbonate in dimethylformamide.

Beispiel 5Example 5 {1-[1-(3-Dimethylaminophenyloxy)-ethyl]-4-piperidyl}-(4-fluorphenyl-keton{1- [1- (3-Dimethylaminophenyloxy) ethyl] -4-piperidyl} - (4-fluorophenyl ketone

Aus 590 mg (2-Chlorethyl)-(3-Dimethylaminophenyl)-ether und 950 mg 4- (Fluorbenzoyl)-piperidin erhält man analog dem Verfahren gemäß Beispiel 4 590 mg {1-[1-(3-Dimethylaminophenoxy)-ethyl]-4-piperidyl}-(4-fluorphenyl)-keton.From 590 mg (2-chloroethyl) - (3-dimethylaminophenyl) ether and 950 mg 4- (Fluorobenzoyl) piperidine is obtained analogously to the process according to Example 4 590 mg {1- [1- (3-Dimethylaminophenoxy) ethyl] -4-piperidyl} - (4-fluorophenyl) ketone.

Beispiel 6Example 6 {1-[3-[3-Dimethylaminophenoxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluorphenyl)-keton{1- [3- [3-Dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone

380 mg (3-Dimethylaminophenyl)-(2,3-epoxypropyl)-ether werden in 50 ml Methanol gelöst und mit 430 mg 4-(4-Fluorbenzoyl)-piperidin versetzt. Nach dreistündigem Erhitzen wird das Lösungsmittel abdestilliert, der Rückstand in 50 ml 1N 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 {1-[3-(3-Dimethylaminophenoxy)-2-hydroxypropyl]-4-piperidyl}-(4- fluorphenyl)-keton.380 mg (3-dimethylaminophenyl) - (2,3-epoxypropyl) ether are dissolved in 50 ml of methanol dissolved and mixed with 430 mg of 4- (4-fluorobenzoyl) piperidine. 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 with 2 N sodium hydroxide solution made alkaline and then extracted with ethyl acetate. The United Ethyl ester phases are washed, dried, filtered and concentrated. The residue is chromatographed on silica gel with acetone + methylene chloride = 1 + 1. You get  446 mg {1- [3- (3-Dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4- fluorophenyl) ketone.

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:
3-[4-(4-Fluorbenzyl)-piperidino)-2-hydroxypropoxy]-dimethylaminoanil-in
{1-[3-(3-Morpholinophenoxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluorphenyl)-keton
2-[4-(4-Fluorbenzyl)-piperidino)-2-hydroxypropoxy]-naphthalin
1-[4-(4-Fl uorbenzyl)-piperidino)-2-hydroxypropoxy]-naphthalin
{1-(3-(1-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-4-fluorphenyl)-keton
{1-[3-(2-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluorphenyl)-keton.The following are produced in an analogous manner:
3- [4- (4-fluorobenzyl) piperidino) -2-hydroxypropoxy] dimethylaminoaniline
{1- [3- (3-Morpholinophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone
2- [4- (4-fluorobenzyl) piperidino) -2-hydroxypropoxy] naphthalene
1- [4- (4-Fluorbenzyl) piperidino) -2-hydroxypropoxy] naphthalene
{1- (3- (1-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} -4-fluorophenyl) ketone
{1- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone.

Claims (4)

1. Verbindungen der Formel I worin
R¹ 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,
Z Sauerstoff, Schwefel, SO oder SO₂,
X -(CH₂)m-CR²R³-(CH₂)p,
-(CH₂)m-CHR²-(CH₂)g-CHR³-(CH₂)p-, m, p, g jeweils 0, 1, 2 oder 3,
R² und R³ gleich oder verschieden sind und Wasserstoff, Hydroxy, C1-4-Alkyl oder C1-4-Alkoxy bedeuten,
R⁴ Wasserstoff, C1-6-Alkyl, geradkettig oder verzweigt, oder einen gegebenenfalls mit C1-4-Alkyl C1-4-Alkoxy, Halogen, Hydroxy, -CF₃ oder -O- CF₃ substituierten Phenyl-, Benzyl-, Benzoyl-, α-Hydroxy-Benzyl- oder Pyridin-Rest und
Y Sauerstoff, Schwefel oder -NH- bedeuten,
sowie deren physiologisch verträgliche Salze und Isomeren. 1. Compounds of formula I. wherein
R¹ 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-benzo-unsubstituted unsubstituted or unsubstituted tetra-benzo-substituted ,
Z oxygen, sulfur, SO or SO₂,
X - (CH₂) m -CR²R³- (CH₂) p ,
- (CH₂) m -CHR²- (CH₂) g -CHR³- (CH₂) p -, m, p, g each 0, 1, 2 or 3,
R² and R³ are the same or different and are hydrogen, hydroxy, C 1-4 -alkyl or C 1-4 -alkoxy,
R⁴ is hydrogen, C 1-6 alkyl, straight-chain or branched, or an optionally substituted with C 1-4 alkyl C 1-4 alkoxy, halogen, hydroxy, -CF₃ or -O- CF₃ phenyl, benzyl, benzoyl, α-hydroxy-benzyl or pyridine radical and
Y is oxygen, sulfur or -NH-,
and their physiologically tolerable salts and isomers. 2. {1-[3-(1-Naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(2-Naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(2-Nitro-1-napththyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(1-Nitro-2-naptht hyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(2,4-Dinitro-1-napththyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
(4-Fluorphenyl)-{1-[3-(5-isochinolyloxy)-propyl]-4-piperidyl}-keton
{1-[3-(1-Brom-2-naphthyloxy)-pro pyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-[3-(4-Chlor-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorphenyl)-keton
{1-(3-(1-Naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-4-fluorphenyl)-keton
{1-[3-(2-Naphthyloxy)-2-hydroxypropyl]-4-pi peridyl}-(4-fluorphenyl)-keton
1-{1-[3-(1-Naphthyloxy)-propyl]-4-piperidyl}-1-(4-fluorphenyl)-methanol
1-{1-[3-(2-Naphthyloxy)-propyl]-4-piperidyl}-1-(4-fluorphenyl)-methanol
1-Naphthyl-{3-[4-(4-fluorbenzyl)-1-piperidyl]-propyl} -ether
2-Napthyl-{3-[4-(4-fluorbenzyl)-1-piperidyl]-propyl}-ether.2. {1- [3- (1-Naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (2-Naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (2-Nitro-1-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (1-Nitro-2-naphthylyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (2,4-Dinitro-1-napththyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
(4-fluorophenyl) - {1- [3- (5-isoquinolyloxy) propyl] -4-piperidyl} ketone
{1- [3- (1-Bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- [3- (4-Chloro-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone
{1- (3- (1-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} -4-fluorophenyl) ketone
{1- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone
1- {1- [3- (1-Naphthyloxy) propyl] -4-piperidyl} -1- (4-fluorophenyl) methanol
1- {1- [3- (2-Naphthyloxy) propyl] -4-piperidyl} -1- (4-fluorophenyl) methanol
1-Naphthyl {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether
2-Napthyl {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether. 3. Arzneimittel auf Basis der Verbindungen nach Anspruch 1 und 2.3. Medicament based on the compounds according to claim 1 and 2. 4. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man
  • a) eine Verbindung der Formel II R¹-Z-H (II),worin R¹ und Z die obige Bedeutung haben, mit einer Verbindung der Formel III worin X und B die obige Bedeutung haben und A eine Fluchtgruppe darstellt, umsetzt oder
  • b) eine Verbindung der Formel IV A-X-Z-R¹ (IV),worin X, Z und R¹ die obige Bedeutung haben und A eine Fluchtgruppe darstellt mit einem Amin der Formel V worin B die obige Bedeutung hat, umsetzt oder
  • c) eine Epoxid der Formel VI worin R¹, Z und m die obige Bedeutung haben mit einem Amin der Formel V umsetzt und anschließend gewünschtenfalls eine Carbonylgruppe reduziert oder die physiologisch verträglichen Salze bildet oder die Isomeren trennt.
4. A process for the preparation of the compounds according to claim 1, characterized in that
  • a) a compound of formula II R¹-ZH (II), wherein R¹ and Z are as defined above, with a compound of formula III wherein X and B have the above meaning and A represents a refugee group, implement or
  • b) a compound of the formula IV AXZ-R¹ (IV), in which X, Z and R¹ have the above meaning and A represents a leaving group with an amine of the formula V. where B has the above meaning, implements or
  • c) an epoxy of the formula VI wherein R¹, Z and m have the above meaning with an amine of formula V. implemented and then, if desired, reduced a carbonyl group or forms the physiologically tolerable salts or separates the isomers.
DE4410822A 1994-03-23 1994-03-24 New piperidine derivatives Withdrawn DE4410822A1 (en)

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DE4410822A DE4410822A1 (en) 1994-03-24 1994-03-24 New piperidine derivatives
KR1019960705269A KR970701695A (en) 1994-03-24 1995-03-23 New 1.4-Disubstituted Piperidine Derivatives Useful as Medicaments Acting on The Glutamate Receptor
IL11310395A IL113103A0 (en) 1994-03-24 1995-03-23 Piperidine derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same
JP7524306A JPH09510460A (en) 1994-03-24 1995-03-23 Novel piperidine derivative
CA002186010A CA2186010A1 (en) 1994-03-24 1995-03-23 New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor
SK1201-96A SK120196A3 (en) 1994-03-24 1995-03-23 1,4-disubstituted piperidine derivatives, process for producing them and medicaments containing these substances
HU9602607A HUT75653A (en) 1994-03-24 1995-03-23 1,4-disubstituted piperidine derivatives acting on the glutamate receptor process for producing them and pharmaceutical compositions containing the said compounds
CZ962770A CZ277096A3 (en) 1994-03-24 1995-03-23 1,4-disubstituted derivatives of piperidine, process of their preparation and medicaments in which such derivatives are comprised
CN95192230A CN1145618A (en) 1994-03-24 1995-03-23 New piperidine derivatives
EP95915116A EP0751936A1 (en) 1994-03-23 1995-03-23 New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor
PCT/DE1995/000442 WO1995025721A1 (en) 1994-03-24 1995-03-23 New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor
AU22125/95A AU2212595A (en) 1994-03-24 1995-03-23 New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor
PL95316382A PL316382A1 (en) 1994-03-24 1995-03-23 Novel derivatives of piperidine
ZA952431A ZA952431B (en) 1994-03-24 1995-03-25 New piperidine derivatives
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
NO963984A NO963984L (en) 1994-03-24 1996-09-23 New, 1,4-disubstituted piperidine derivatives useful as drugs acting on glutamate receptors

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US5824662A (en) 1996-09-27 1998-10-20 Guilford Pharmaceuticals Inc. Treatment of global and focal ischemia using naaladase inhibitors
US6017903A (en) 1996-09-27 2000-01-25 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors
US6124317A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
WO2000075109A1 (en) * 1999-06-08 2000-12-14 F. Hoffmann-La Roche Ag Ethanesulfonyl-piperidine derivatives
US6413948B1 (en) 1996-09-27 2002-07-02 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of effecting a neuronal activity in an animal using naaladase inhibitors
US6448270B1 (en) 1995-12-22 2002-09-10 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6534522B2 (en) 1995-12-22 2003-03-18 Warner-Lambert Company Subtype-selective NMDA receptor ligands and the use thereof
US7615550B2 (en) 2002-10-16 2009-11-10 Glaxo Group Limited Substituted piperazines,(1,4) diazepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine H1 and/or H3 antagonists or histamine H3 reverse antagonists

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US6407235B1 (en) 2000-08-21 2002-06-18 Hoffmann-La Roche Inc. Prodrug acid esters of [2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethansulfonyl]phenol
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JP2020527133A (en) 2017-06-20 2020-09-03 インブリア ファーマシューティカルズ， インコーポレイテッド Compositions and Methods for Increasing the Efficiency of Cardiac Metabolism
CN110437136A (en) * 2019-07-30 2019-11-12 东南大学 1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its preparation method and application
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US11530184B2 (en) 2020-06-30 2022-12-20 Imbria Pharmaceuticals, Inc. Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
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US6124317A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US6534522B2 (en) 1995-12-22 2003-03-18 Warner-Lambert Company Subtype-selective NMDA receptor ligands and the use thereof
EP0869792A4 (en) * 1995-12-22 1999-09-22 Warner Lambert Co 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
EP0869792A2 (en) * 1995-12-22 1998-10-14 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
US6534525B1 (en) 1995-12-22 2003-03-18 Warner-Lambert & Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US6448270B1 (en) 1995-12-22 2002-09-10 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6124323A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US5985855A (en) 1996-09-27 1999-11-16 Guilford Pharmaceuticals Inc. Treatment of global and focal ischemia using NAALADase inhibitors
US6413948B1 (en) 1996-09-27 2002-07-02 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of effecting a neuronal activity in an animal using naaladase inhibitors
US6017903A (en) 1996-09-27 2000-01-25 Guilford Pharmaceuticals Inc. Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors
US6004946A (en) 1996-09-27 1999-12-21 Guilford Pharmaceuticals Inc. Treatment of global and focal ischemia using naaladase inhibitors
US5824662A (en) 1996-09-27 1998-10-20 Guilford Pharmaceuticals Inc. Treatment of global and focal ischemia using naaladase inhibitors
WO2000075109A1 (en) * 1999-06-08 2000-12-14 F. Hoffmann-La Roche Ag Ethanesulfonyl-piperidine derivatives
US7615550B2 (en) 2002-10-16 2009-11-10 Glaxo Group Limited Substituted piperazines,(1,4) diazepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine H1 and/or H3 antagonists or histamine H3 reverse antagonists

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FI963786A (en) 1996-09-23

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