EP0898569A1 - Piperidines and pyrrolidines - Google Patents

Piperidines and pyrrolidines

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Publication number
EP0898569A1
EP0898569A1 EP97920673A EP97920673A EP0898569A1 EP 0898569 A1 EP0898569 A1 EP 0898569A1 EP 97920673 A EP97920673 A EP 97920673A EP 97920673 A EP97920673 A EP 97920673A EP 0898569 A1 EP0898569 A1 EP 0898569A1
Authority
EP
European Patent Office
Prior art keywords
formula
ethyl
pyridyl
pyrrolidin
piperidin
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Withdrawn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
EP97920673A
Other languages
German (de)
English (en)
French (fr)
Inventor
Joachim März
Henning Böttcher
Ralf Devant
Hartmut Greiner
Gerd Bartoszyk
Jürgen Harting
Christoph Seyfried
Ronny Andersson Bengt
Lars Olov Hansson
Clas Ake Sonesson
Nils Peter STJERNLÖF
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP0898569A1 publication Critical patent/EP0898569A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to compounds of the formula I
  • R 1 is phenyl which is unsubstituted or mono-, di- or trisubstituted by A, A-O- , OH, Hal, CN, N0 2 ,
  • R 2 is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-O, OH, Hal and/or CN
  • R 3 is H, A, A-O-, Ph, NHR 4 or NR 5 R 6
  • R 4 is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-O- , OH, Hal and/or CN or cycloalkyl having 3 to 10 C atoms
  • R and R 6 together are an alkylene chain having 4 , 5 or
  • A is straight-chain or branched alkyl having
  • R can be a mono-, bicyclic or heterocyclic radical
  • A can be a branched or unbranched alkylene chain and the heterocyclic ring can have a double bond.
  • R is a thiophene, 1,4-benzodioxane, 4-indolyl or methoxyphenyl ring.
  • Corresponding compounds exhibit 5-HT 1A receptor binding.
  • Piperazine derivatives having 5-HT 1A -antago- nistic action are described, for example, in WO 95/33743.
  • the invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have particularly useful pharmacological properties combined with good tolerability, as, in particular, they have actions on the central nervous system, especially 5-HT 1A - antagonistic and in particular 5-HT-reuptake-inhibiting actions.
  • Compounds of the formula I and their physiologi ⁇ cally acceptable acid addition salts have particularly useful pharmacological properties combined with good tolerability, as, in particular, they have actions on the central nervous system, especially 5-HT ⁇ - antagonistic and 5-HT-reuptake-inhibiting actions. They inhibit the binding of tritiated serotonin receptor ligands to hippocampal receptors (Cossery et al. , European J. Pharmacol. 140 (1987) , 143-155) and inhibit synaptosomal serotonin reuptake (Sherman et al. , Life
  • the 5-HT 1A -antagonistic action is demonstrated in vitro, for example, by inhibition of the abolition of the electrically induced contraction of the guinea-pig ileum caused by 8-OH-DPAT (Fozard and Kilbinger, Br. J. Pharmacol. 86 (1985) 601P) .
  • the inhibition of the 5-HT accumulation decreased by 8-OH-DPAT (Seyfried et al . , European J. Pharmacol. 16Q (1989), 31-41) and the antagonization of the effects induced by 8-OH-DPAT in the ultrasound vocalization test (DeVry, Psychopharmacol. 121 (1995), 1-26) are used to demon ⁇ strate the 5-HT 1A -antagonistic action.
  • Synaptosomal uptake inhibition Wang et al. , Neuropsychopharmacol .
  • the compounds of the formula I are therefore suitable both in veterinary and in human medicine for the treatment of functional dis ⁇ orders of the central nervous system and of inflammations. They can be used for the prophylaxis and for the control of sequelae of cerebral infarcts (apoplexia cerebri) such as stroke and cerebral ischaemias, and also for the treatment of extrapyramidal motor side effects of neuroleptics and also of Parkinson's disease.
  • apoplexia cerebri apoplexia cerebri
  • Parkinson's disease extrapyramidal motor side effects of neuroleptics and also of Parkinson's disease.
  • the compounds of the formula I and their physio ⁇ logically acceptable acid addition salts can therefore be used as pharmaceutical active compounds for anxio- lytics, antidepressants, antipsychotics, neuroleptics and/or antihypertensives, and for positively affecting obsessive-compulsive behaviour, eating disorders such as bulimia, tardive dyskinesias, learning disorders and age-dependent memory disorders.
  • the invention thus relates to the compounds of the formula I and their physiologically acceptable acid addition salts.
  • the invention relates in particular to compounds of the formula I selected from the group consisting of
  • the compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine. They can further be employed as intermediates for the preparation of further pharmaceutical active compounds.
  • the invention accordingly relates to the compounds of the formula I and to a process for the preparation of compounds of the formula I according to Claim 1, characterized in that
  • R , n and m have the meanings given in Claim 1 and Q is Cl, Br, I or a free or reactive functionally modified OH group,
  • the radicals R 1 , R 2 , R 3 , L, Q, k, 1, m and n have the meanings indicated in the formulae I, II, III, IV, V, VI, VII, VIII, IX, X and XI, if not expressly stated otherwise.
  • the invention likewise relates to medicaments of the formula I and their physiologically acceptable salts having 5-HT 1A -antagonistic and 5-HT-reuptake- inhibiting action.
  • the invention relates to the compounds of the formula I according to Claim 1, and to their enantiomers and diastereomers and to their salts.
  • Alkyl has 1 to 10, preferably 1, 2, 3, 4, 5 or 6 C atoms.
  • Alkyl is therefore in particular, for example, methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3 , 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-l- methylpropyl, l-ethyl-2-methylpropyl , 1,1,2- or 1, 2, 2-trimethylpropyl, further also fluoromethyl, difluoromethyl, trifluoromethyl, 1, 1, 1-trichloroethyl or pen
  • A-O- is in particular, for example, methoxy, ethoxy, propoxy or butyloxy.
  • Cycloalkyl is in particular, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-adamantyl.
  • Ph is phenyl .
  • R 1 is phenyl which is unsubstituted, mono-, di- or trisubstituted, but in particular mono- or disubstituted, by A, A-O- , OH, Hal, CN, N0 2 , NH 2 , Ph, - 0-S0 2 A or -0-S0 2 -CF 3 ; 1- or 2-naphthyl or 2- or 3- indolyl, which can likewise be unsubstituted, mono-, di- or trisubstituted, in particular mono- or disubstituted, by A, A-O- , OH, Hal or CN, and further is also 1,4-benzodioxan-5- or -6-yl.
  • R 1 is therefore preferably, for example, 1- or 2-naphthyl, 2- or 3-indolyl, 5- or 6-methylindol-2-yl, 5- or 6-methylindol-3-yl, 5- or 6-methoxyindol-2-yl, 5- or 6-methoxyindol-3-yl, 5- or 6-hydroxyindol-2-yl, 5- or 6-hydroxyindol-3-yl, 5- or 6-f luoroindol-2-yl, 5- or 6-fluoroindol-3-yl, 5- or 6-cyanoindol-2-yl , 5- or 6-cyanoindol-3-yl, phenyl, o-, m- or p-tolyl, o- , m- or p-trif luoromethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p- hydroxyphenyl,
  • R 2 is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-0-, OH, Hal or CN and is preferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-trif luoromethylphenyl , o-, m- or p-methoxyphenyl, o-, m- or p- hydroxyphenyl , o-, m- or p- fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl, o-, m- or p-ethylphenyl, 2-, 3- or 4-pyridyl, 3-, 4-, 5- or 6-fluoropyridin-2-yl, 2- or 3-fluoropyridin-4-yl, 3-, 4-,
  • R 3 is preferably, for example, H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert- butyl, methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, further also pentyl, hexyl, trifluoromethyl, pentaf luoroethyl , cyclopentyl, cyclo ⁇ hexyl, 1-adamantyl, anilino, o-, m- or p-tolylamino, o- , m- or p-trif luoromethylanilino, o- , m- or p-methoxyanilino, o-, m- or p-hydroxyanilino, o-, m- or p-fluoroanilino, o-, m- or p-ch
  • R 3 is furthermore preferably pyrrolidin-1-yl, 1-piperidinyl or 1-azepanyl.
  • R 4 is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-0-, OH, Hal or CN, and also cycloalkyl having 3-10 C atoms and is pre ⁇ ferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl, o-, m- or p-ethylphenyl, 2-
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following subformulae Ia to lh, which correspond to the formula I and in which the radicals not described in greater detail have the meaning indicated in the formula I, but in which
  • Ia k 0, 1 is 1, m is 2 and n is 1 or 2;
  • Ic R H, k is 0 , 1 is 0 and m is 2 ;
  • R 3 is cycloalkyl having 3-10 C atoms
  • A is straight-chain or branched alkyl having 1-6 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms, k is 0,
  • A is straight-chain or branched alkyl having 1-6 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms, k is 0, 1 is 1, m is 2 and n is 1 or 2;
  • R 3 is NHR 4 or NR 5 R 6 .
  • A is straight-chain or branched alkyl having 1-6 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms;
  • R 1 is phenyl, which is mono- or disubstitued by methoxy, F, Cl, Br, OH, CN, Ph, -0-S0 2 CH 3 or -0-S0 2 CF 3 , or 2- or 3-indolyl which is monosubstituted by F and/or CN, 1, 4-benzodioxan-5- or -6-yl or 1- or 2-naphthyl,
  • R 2 is phenyl or 2-pyridyl, which is mono- substituted by F
  • R 3 is cycloalkyl having 5 or 6 C atoms, A-O- , NHR 4 or NR 5 R ⁇
  • R 4 is phenyl or pyridyl, which is monosubstituted by A, A-0-, Hal or CN or cycloalkyl having 5 or 6 C atoms, k is 0, 1 is 1, m is 2 and n is 1 or 2;
  • R x is phenyl which is mono- or disubstituted by methoxy, F, Cl, Br, OH, CN, Ph, -0-S0 2 CH 3 or
  • R 2 is phenyl which is monosubstituted by F or A
  • R 3 is cycloalkyl having 5 or 6 C atoms, A-O-,
  • R 4 is phenyl or pyridyl, which is mono- substituted by A, A-0-, Hal or CN or cycloalkyl having 5 or 6 C atoms, R 5 and R together are an alkylene chain having
  • these are compounds selected from the group consisting of: 2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] -N- (2-pyridyl) - acetamide
  • the compounds are also suitable for use as intermediates for the preparation of the compounds of formula I according to the invention.
  • the compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry] , Georg-Thieme-Verlag, Stuttgart) , namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail .
  • L in the compounds of the formula III, V and VIII or Q in the compounds of the formula IX is Cl, Br, I or a free or reactive esterified OH group.
  • L or Q is a reactive esterified OH group
  • this is preferably trichloromethoxy, alkoxy, such as, for example, methoxy, ethoxy, propoxy or butoxy, and further phenoxy, alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolyl- sulfonyloxy, and further also 2-naphthalene- sulfonyloxy) .
  • the starting substances can also be formed in situ such that they are not isolated from — — the reaction mixture, but immediately reacted further to give the compounds of the formula I .
  • the compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the starting substances of the formulae II and III are known in some cases. If they are not known, they can be prepared by methods known per se.
  • N-acylation of suitable derivatives of the compounds of the formula III are acid halides, preferably chlorides, azides, anhydrides, imidazolides (which can be obtained, for example, from carbodiimidazoles) , activated esters or O-acylureas, which are obtained from suitable carboximides, such as dialkylcarbodiimides, in particular cyclohexyl- carbodiimide. It may be necessary before carrying out this reaction to exclude further amino groups contained in the compound of the formula II from the acylation reaction by introduction of suitable protective groups.
  • acid halides preferably chlorides, azides, anhydrides, imidazolides (which can be obtained, for example, from carbodiimidazoles) , activated esters or O-acylureas, which are obtained from suitable carboximides, such as dialkylcarbodiimides, in particular cyclohexyl- carbodiimide. It may be necessary before carrying out this reaction to exclude further amino groups contained in the compound
  • the reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent, preferably of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or of an excess of the amide component of the formula II or of the alkylating derivative of the formula III may also be favourable.
  • the reaction time depending on the conditions used, is between a few minutes and 14 days, and the reaction temperature is between approximately 0° and 150°, normally between 20° and 130°.
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetra- chloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol) , ethylene glycol dimethyl ether (diglyme) ; ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide
  • DMF dimethyl sulfoxide
  • nitriles such as acetonitrile
  • sulfoxides such as dimethyl sulfoxide (DMSO)
  • carbon disulfide carboxylic acids such as formic acid or acetic acid nitro compounds such as nitromethane or nitrobenzene esters such as ethyl acetate or mixtures of the solvents mentioned.
  • amino protective group is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at another position in the molecule.
  • groups are, in particular, unsubstituted or substituted acyl, aryl (e.g. dinitrophenyl (DNP) , aralkoxymethyl (e.g. benzoxymethyl (BOM)) or aralkyl groups (e.g. benzyl, 4-nitrobenzyl, triphenylmethyl) .
  • acyl group in this connection is to be interpreted in the widest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups .
  • acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenacetyl; aroyl such as benzoyl or tolyl; aryloxyalkanoyl such as phenoxy- acetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl, iso- propoxycarbonyl, tert-butoxycarbonyl (BOC) , 2-iodo- ethoxycarbonyl; aralkyloxycarbonyl such as benzyloxy- carbonyl (CBZ) , 4-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (FMOC) .
  • alkanoyl such as acetyl, propionyl, butyryl
  • aralkanoyl such as phenacety
  • Preferred amino protective groups are BOC, DNP and BOM, and further CBZ, benzyl and acetyl.
  • a crucial factor in the choice of the protective group employed is the possibility of being able to remove this selectively again after the actual reaction.
  • Amines of the formula II can be prepared by methods known per se, such as described, for example, in EP 512755 A2, by reductive alkylation of compounds of the formula IV.
  • the starting substances of the formulae IV and V are known in some cases. If they are not known, they can be prepared by methods known per se. The reaction is carried out in solvents and at temperatures as described above.
  • the starting substances of the formula IV and VI are known in some cases. If they are not known, they can be prepared by methods known per se.
  • the reducing amination can be carried out in the presence of reducing agents such as, for example, NaBH 3 CN and NaBH(0Ac) 3 .
  • reducing agents such as, for example, NaBH 3 CN and NaBH(0Ac) 3 .
  • an amino protective group preferably by a tert-butoxycarbonyl group
  • the protective group can be removed again in a simple manner known to the person skilled in the art after reductive amination has taken place. If, for example, this protective group is a tert-butoxycarbonyl group, it can be removed by treatment with tri ⁇ fluoroacetic acid or in dilute hydrochloric acid.
  • Compounds of the formula I can futhermore preferably be obtained by reaction of compounds of the formula VII with compounds of the formula VIII.
  • VIII are known in some cases. If they are not known, they can be prepared by methods known per se. The reaction is carried out in solvents and at temperatures as described above.
  • the starting substances of the formulae VII and IX are known in some cases. If they are not known, they can be prepared by methods known per se . The reaction is carried out in solvents and at temperatures as described above.
  • a further method of preparing the compounds according to the invention consists in reacting a compound of the formula X in which R 1 , R 3 , m and n have the given meanings, with a suitable phenyl or pyridyl derivative.
  • phenyl or pyridyl derivative e.g., phenyl or pyridyl derivatives.
  • Those suitable are, for example, appro ⁇ priate fluoro-substituted compounds which can be employed for the reaction in the presence of a strong, non-nucleophilic base, such as, for example, Li diiso- propylamide.
  • a compound of the formula X is preferably reacted with 2-fluoropyridine N-oxide and then reduced to the desired 2-pyridyl com ⁇ pound of the formula I in the presence of a suitable reducing agent, such as, for example, phosphorus trichloride.
  • a further method of preparing compounds of the formula I in which R 3 is NHR 4 consists in the reaction of compounds of the formula II with compounds of the formula XI.
  • the starting substances of the formula XI are known in some cases. If they are not known, they can be prepared by methods known per se.
  • a radical R 1 , R 2 and/or R 4 in a compound of the formula I into another radical R , R and/or R , e.g. by reducing nitro groups (for example by hydrogenation on Raney Nickel or Pd/carbon in an inert solvent such as methanol or ethanol) to amino groups, hydrolysing cyano groups to COOH groups or cleaving an ether by, for example, converting an aromatic methoxy group into the corresponding hydroxyl derivative.
  • reducing nitro groups for example by hydrogenation on Raney Nickel or Pd/carbon in an inert solvent such as methanol or ethanol
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation.
  • possible acids are in particular those which yield physiologically acceptable salts.
  • inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, further organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • Salts with physiologically unacceptable acids can be used for the isolation and/or purification of the compounds of the formula I .
  • compounds of the formula I can be converted using bases (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts.
  • bases e.g. sodium or potassium hydroxide or carbonate
  • Compounds of the formula I according to the invention can be chiral on account of their molecular structure and can accordingly occur in two enantiomeric or two or more diastereomeric forms. On account of one or more chiral centres, they can therefore be present in racemic or in optically active form.
  • the pharmaceutical activity of the racemates or of the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the diastereomers or enantiomers.
  • the final product or else even the intermediates can be resolved into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed in the synthesis as such.
  • diastereomers are formed from the mixture by reaction with an optically active resolving agent.
  • Suitable resolving agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl- tartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonyl- proline) or the various optically active camphor- sulfonic acids.
  • N-protected amino acids e.g. N-benzoylproline or N-benzenesulfonyl- proline
  • camphor- sulfonic acids are also advantageous.
  • a chromatograpic resolution of enantiomers with the aid of an optically active resolving agent e.g.
  • eluents for this purpose are aqueous or alcoholic solvent mixtures such as, for example, hexane/isopropanol/acetonitrile, e.g. in the ratio 82:15:3.
  • optically active bases such as, for example, the R and S form of
  • 1-phenylethylamine, 1-naphthylethylamine, dihydro- abietylamine, cinchonine or cinchonidine can analogously be used.
  • the enantiomeric or diastereomeric acids can be decarboxylated to give the corresponding enantiomeric intermediates (e.g. the corresponding pyrrolidones) .
  • Suitable enzymes for the ester cleavage are lipases (such as, for example, lipase of Pseudomonas cepacia) and esterases.
  • lipases such as, for example, lipase of Pseudomonas cepacia
  • esterases e.g., a particularly favourable case is if the chiral centre is in the ⁇ -position to the escer group.
  • the undesired enantiomer can be racemized via enolization and thus subjected to a fresh racemate resolution. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
  • test results of the 5-HT 1A receptor binding and the 5-HT reuptake-inhibiting actions of some representative compounds of the formula I are compiled in Table I which follows.
  • the inhibition constants IC 50 are indicated (concentrations in nmol/litre) for the inhibition of the binding of tritiated ligands to hippocampal serotonin-IA receptors (method analogous to Cossery et al. ) , and for the inhibition of synaptosomal serotonin reuptake (method analogous to Sherman et al.) .
  • the invention further relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular in a non-chemical way.
  • they can be brought into a suitable dose form together with at least one solid, liquid and/or semiliquid excipient or auxiliary and if appropriate in combination with one or more of the further active compounds.
  • the invention further relates to pharmaceutical preparations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
  • preparations can be used as medicaments in human or veterinary medicine.
  • Possible excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petro ⁇ leum jelly.
  • Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used in particular for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used for parentaral admini ⁇ stration, and ointments, creams or powders are used for topical application.
  • the novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.
  • the preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.
  • the compounds of formula I according to the invention are generally administered in analogy to other known commercially available preparations for the indications claimed (e.g. imipramine, fluoxetin, clomi- pramine) , preferably in doses of between 0.1 mg and 500 mg, in particular between 5 and 300 mg per dose unit.
  • the daily dose is preferably between approxi- mately 0.01 and 250 mg/kg, in particular between 0.02 and 100 mg/kg of body weight.
  • the substances according to the invention are generally preferably administered in doses of between approximately 1 and 500 mg, in par- ticular between 5 and 100 mg per dose unit.
  • the daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight.
  • the specific dose for each patient depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceu ⁇ tical combination and severity of the particular dis ⁇ order to which the therapy relates. Oral administration is preferred.
  • Example 3 1.02 g of ⁇ 2- [4- (6-f luoroindol- 3-yl) piperidin- l-yl] ethylamino ⁇ -2-pyridine and 0.44 g of 3- fluorophenyl isocyanate are stirred at room temperature for 2 hours in 20 ml of THF. The solvent is removed and the residue thus obtained is purified by chromatography on a silica gel column (eluent: ethyl acetate/CH 3 OH 9:1) .
  • the reduction of the nitro group is carried out by reaction with ammonium formate and Pd/C in ethanol. After separating off the catalyst and customary working up, a mixture of 4- (2-methoxy-3-aminophenyl) - 1- (trifluoroacetyl)piperidine, formate and 4- (2-methoxy- 5-aminophenyl) -1- (trifluoro- cetyl)piperidine, formate is obtained.
  • substitution of the amino group by fluorine is carried out by reaction with NaN0 2 in aqueous hydrochloric acid and addition of 65% hexafluoro-phosphoric acid (HPFJ at temperatures between 0 and -10°. After customary workup, the solid is heated, stirred for one hour, methanolic potassium hydroxide solution is added, the mixture is stirred for a further hour and worked up in the customary manner and 4- (3- fluoro-2-methoxyphenyl) piperidine and 4- (3-fluoro-6- methoxyphenyl)piperidine is obtained.
  • (2-pyridyl)pyrrolidine-1-carboxamide El 394 with 2- (2- [4- (2-methoxyphenyl)piperidin-l-yl] ethylamino ⁇ - pyridine N- ⁇ 2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl ⁇ -N- (2- pyridyl)pyrrolidine-1-carboxamide, R f 0.55 (methanol) .
  • Amount of substance per loading 55 mg
  • Amount separated 55 mg
  • Yield in each case 20 mg per enantiomer
  • Amount of substance per loading 300 mg
  • Amount of substance per loading 200 mg
  • the ethyl acetate phase separated off is washed twice more with hydrochloric acid.
  • the aqueous phase is adjusted to an alkaline pH using 32% NaOH.
  • the aqueous phase is then extracted several times with dichloromethane.
  • the organic phase is dried over MgS0 4 , filtered and concentrated to give a residue.
  • Residue A 1.2 g (dark brown, viscous mass) .
  • the aqueous, alkaline phase is extracted once with n-butanol .
  • the butanol phase is likewise concentrated to give a residue.
  • Residue B 2.6 g (processed further without working up) .
  • the cleavage of the acetal is carried out using 10% aqueous oxalic acid and 15% sulfuric acid. After customary working up, N- (2-oxoethyl) -N-phenylcyclohexane-carboxamide is obtained.
  • a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 1 of double-distilled water using 2 N hydrochloric acid, sterile-filtered, filled into injection vials and lyophilized under sterile conditions, and the vials are aseptically sealed. Each injection vial contains 5 mg of active compound.
  • a mixture of 20 g of an active compound of the formula I is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.
  • a solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH 2 P0 4 .2H 2 0, 28.48 g of Na 2 HP0 4 .12H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The pH is adjusted to 6.8, and the solution is made up to
  • 500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example E Tablets A mixture of 1 kg of active compound of the formula I,
  • Example E Analogously to Example E, tablets are pressed which are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colourant.
  • Example G Capsules
  • a solution of 1 kg of active compound of the formula I in 60 1 of double-distilled water is sterile- filtered, filled into ampoules and lyophilized under sterile conditions, and the ampoules are aseptically sealed. Each ampoule contains 10 mg of active compound.

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  • General Health & Medical Sciences (AREA)
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  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
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  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
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EP97920673A 1996-04-18 1997-04-14 Piperidines and pyrrolidines Withdrawn EP0898569A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19615232 1996-04-18
DE19615232A DE19615232A1 (de) 1996-04-18 1996-04-18 Neue Carbamoylderivate und deren Verwendung als 5-HT ¶1¶¶A¶-Antagonisten
PCT/EP1997/001853 WO1997040038A1 (en) 1996-04-18 1997-04-14 Piperidines and pyrrolidines

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ATE227718T1 (de) * 1998-04-08 2002-11-15 Wyeth Corp N-aryloxyethyl-indolyl-alkylamine zur behandlung von depressionen
US6150533A (en) * 1998-04-08 2000-11-21 American Home Products Corp. N-aryloxyethyl-indoly-alkylamines for the treatment of depression
CN1307576A (zh) * 1998-04-29 2001-08-08 美国家用产品公司 5－羟色胺能药物
WO1999065887A1 (en) * 1998-06-15 1999-12-23 American Home Products Corporation Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents
US6376494B1 (en) 1998-06-15 2002-04-23 American Home Products Corporation Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents
US6239126B1 (en) 1998-12-17 2001-05-29 American Home Products Corporation Arylpiperidine and aryl-1,2,5,6-tetra-hydropyridine urea derivatives
DE69925160T2 (de) * 1998-12-17 2006-02-16 Wyeth Arylpiperidin- und aryl-1,2,5,6-tetrahydropyridinamid-derivate mit 5ht1a rezeptor aktivität
US6326381B1 (en) 1998-12-17 2001-12-04 American Home Products Corporation Arylpiperidine and aryl-1,2,5,6-tetrahydropyidine amide derivates
EP1140831A1 (en) * 1998-12-17 2001-10-10 American Home Products Corporation Arylpiperidine and aryl-1,2,5,6-tetrahydropyridine urea derivatives having 5ht1a receptor activity
CA2360683A1 (en) * 1999-01-28 2000-08-03 Joseph P. Yevich Antidepressant heterocyclic compounds
CN100557016C (zh) * 2000-12-27 2009-11-04 爱克西欧詹妮西斯公开股份有限公司 用于细胞特异和发育特异性选择分化的胚干细胞、成人干细胞和胚种系细胞的系统
KR100459917B1 (ko) * 2001-12-14 2004-12-03 (주)바이오뉴트리젠 페놀릭산 유도체 및 이를 포함하는 혈중 지질 농도 관련질환의 예방 및 치료용 조성물
DE10337184A1 (de) * 2003-08-13 2005-03-10 Gruenenthal Gmbh Substituierte 3-Pyrrolidin-Indol-Derivate
UY36390A (es) * 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen
BR112017008809A2 (pt) 2014-11-05 2017-12-19 Flexus Biosciences Inc agentes imunorreguladores
US20240286998A1 (en) * 2021-06-02 2024-08-29 Saint Joseph's University Fluorinated tryptamine compounds, analogues thereof, and methods using same
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WO1997040038A1 (en) 1997-10-30
PL329351A1 (en) 1999-03-29
NO984861L (no) 1998-10-16
NO984861D0 (no) 1998-10-16
JP2000508670A (ja) 2000-07-11
CZ330598A3 (cs) 1999-01-13
ZA973301B (en) 1997-10-24
AR006690A1 (es) 1999-09-08
HUP9901389A3 (en) 2000-09-28
HUP9901389A2 (hu) 1999-08-30
SK141998A3 (en) 1999-03-12
CA2252385A1 (en) 1997-10-30
AU2696797A (en) 1997-11-12
KR20000005505A (ko) 2000-01-25
BR9708677A (pt) 1999-08-03

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