WO1995011895A1 - N-benzoyl-4-oxy/thio-piperidines a substitution en position utilisees comme antagonistes du recepteur de la substance p - Google Patents

N-benzoyl-4-oxy/thio-piperidines a substitution en position utilisees comme antagonistes du recepteur de la substance p Download PDF

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Publication number
WO1995011895A1
WO1995011895A1 PCT/EP1994/003394 EP9403394W WO9511895A1 WO 1995011895 A1 WO1995011895 A1 WO 1995011895A1 EP 9403394 W EP9403394 W EP 9403394W WO 9511895 A1 WO9511895 A1 WO 9511895A1
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Prior art keywords
unsubstituted
substituted
piperidine
bistrifluoromethylbenzoyl
radical
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PCT/EP1994/003394
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English (en)
Inventor
Silvio Ofner
Silvio Roggo
Walter Schilling
Siem J. Veenstra
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Ciba-Geigy Ag
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Priority to AU78561/94A priority Critical patent/AU7856194A/en
Publication of WO1995011895A1 publication Critical patent/WO1995011895A1/fr

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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
    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms

Definitions

  • the invention relates to novel 1,2,4-trisubstituted piperidine compounds of formula I
  • Ri is an unsubstituted or substituted aralkyl, aryloxyal yl, heteroaralkyl, aroyl, hetero ⁇ aroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or aryl ⁇ carbamoyl radical, or is the acyl radical of an ⁇ -amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,
  • R 2 is cycloalkyl or an unsubstituted or substituted aryl or heteroaryl radical
  • R 3 is an unsubstituted or substituted, optionally hydrogenated aryl or heteroaryl radical or, when n is 1, X 2 is imino that is unsubstituted or substituted by lower alkyl or by cycloalkyl and X 3 is lower alkylene, R 3 is lower alkyl or free or esterified or amidated carboxy,
  • R 4 is hydrogen, alkyl or aryl
  • X is oxy or thio
  • Xi is methylene, ethylene, a direct bond, a free or ketalised carbonyl group or a free or etherified hydroxymethylene group,
  • X 2 is lower alkylene, imino that is unsubstituted or substituted by lower alkyl or by cycloalkyl, or a direct bond,
  • X 3 is lower alkylene or a direct bond
  • X 4 is oxo or thioxo and n is 1 or, when X 2 is lower alkylene and X 3 is a direct bond, n is 0, and to the salts thereof, to processes for the preparation of the compounds according to the invention, to pharmaceutical compositions comprising those compounds and to the use thereof as active ingredients of medicaments.
  • Aryl, cycloalkyl and heteroaryl radicals also as constituents of aralkyl, aryloxyalkyl, aroyl, aralkanoyl, aralkoxycarbonyl, arylcarbamoyl, cycloalkylcarbonyl, heteroaralkyl, heteroaroyl and heteroarylalkanoyl radicals, optionally partially hydrogenated heteroaryl radicals, heteroaroyl radicals and the like, may be unsubstituted or substituted, such as mono-, di- or tri-substituted, especially mono- or di-substituted, for example by aromatic- ally bonded lower alkyl, lower alkoxy, phenoxy, halogen, free or esterified or amidated carboxy, cyano, nitro and/or by trifluoromethyl.
  • Aryl, aralkyl, aryloxyalkyl, cycloalkyl ⁇ carbonyl and aroyl radicals are preferably mono- or di-substituted, such as 3- or 4-mono- or 3,5-di-substituted, as indicated.
  • Aryl radicals R 2 are, for example, phenyl radicals that are unsubstituted or mono- or di- substituted by lower alkyl, lower alkoxy, halogen, free or esterified or amidated carboxy, cyano, nitro and/or by trifluoromethyl, such as phenyl, 4-lower alkoxy-, such as 4-methoxy-phenyl, 4-nitrophenyl, free or amidated 4-carboxyphenyl, such as 4-carboxy- or 4-carbamoyl-phenyl, 3-trifluoromethylphenyl, 2,4-di-lower alkoxy-, such as 2,4-di- methoxy-phenyl, 2,4-dihalo-, such as 2,4-dichloro-phenyl, or 3,4-dihalo-, such as 3,4-di- chlorophenyl.
  • aryl radicals R 3 are, for example, phenyl, cyclohexyl, naphthyl or tetrahydronaphthyl radicals that are unsubstituted or mono- or di-substituted by lower alkyl, lower alkoxy, phenoxy, halogen, free or esterified or amidated carboxy, cyano and/- or by trifluoromethyl, such as phenyl, cyclohexyl, naphthyl, 3-lower alkoxy-, such as 3-methoxy- or 3-isopropyloxy-phenyl, 4-phenoxyphenyl, 4-lower alkoxy-, such as 4-methoxy- or 4-isopropyloxy-phenyl, 3- or 4-halo-, such as 3- or 4-chloro-phenyl, free or esterified 4-carboxyphenyl, such as 4-carboxy- or 4-lower alkoxycarbonyl-phenyl, 4-cyanophen
  • Aralkyl radicals are, for example, phenyl- or diphenyl-lower alkyl or naphthyl-lower alkyl that is unsubstituted or substituted in the phenyl or naphthyl moiety.
  • Aryloxyalkyl radicals are, for example, aryloxy-lower alkyl radicals, such as phenoxy- lower alkyl radicals that are unsubstituted or substituted in the phenyl moiety.
  • Heteroaralkyl radicals are, for example, heteroaryl-lower alkyl radicals containing as heteroaryl radical 6-membered monocyclic azaheteroaryl or bicyclic azaheteroaryl consisting of a 6-membered ring and a 5- or 6-membered ring.
  • Aroyl radicals are, for example, unsubstituted or substituted benzoyl radicals, such as benzoyl, 3-lower alkyl-, 3-lower alkoxy-, 3-halo-, 3-dimethylamino-, 3,5-di-lower alkyl-, 3,5-di-lower alkoxy-, 3,5-dihalo- or 3,5-ditrifluoromethyl-benzoyl, or, less preferably, unsubstituted or substituted naphthoyl radicals, such as 1- or 2-naphthoyl.
  • Heteroaroyl radicals are, for example, 6-membered monocyclic azaheteroaroyl radicals or bicyclic azaheteroaroyl radicals consisting of a 6-membered and a 5- or 6-membered ring, such as pyridylcarbonyl or quinolinylcarbonyl.
  • Cycloalkylcarbonyl radicals are, for example, unsubstituted or substituted 3- to 8-membered, especially 5- to 7-membered, cycloalkylcarbonyl radicals, such as cyclohexylcarbonyl, 3-lower alkyl-, 3-lower alkoxy-, 3-halo-, 3-dimethylamino-, 3,5-di-lower alkyl-, 3,5-di-lower alkoxy-, 3,5-dihalo- or 3,5-ditrifluoromethyl-cyclohexyl- carbonyl.
  • Aralkanoyl radicals are, for example, phenyl- or diphenyl-lower alkanoyl radicals that are unsubstituted or substituted in the phenyl moiety.
  • Heteroarylalkanoyl radicals are, for example, heteroaryl-lower alkanoyl radicals contain ⁇ ing as heteroaryl radical 6-membered monocyclic azaheteroaryl or bicyclic azaheteroaryl consisting of a 6-membered and a 5- or 6-membered ring.
  • Aralkoxycarbonyl radicals are, for example, phenoxycarbonyl radicals that are unsubstituted or substituted in the phenyl moiety.
  • Arylcarbamoyl radicals are, for example, N-phenylcarbamoyl radicals that are unsubstituted, or unsubstituted or substituted in the phenyl moiety.
  • Acyl radicals of ⁇ -amino acids that are unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl are derived especially from ⁇ -amino acids that occur naturally as peptide building blocks and that are optionally lower alkanoylated, for example N-C 2 -C 7 alkanoylated, such as ⁇ -amino acids substituted by acetyl, propionyl, butyryl or pivaloyl.
  • Such acyl radicals are, for example, groups of formula — C-CH- NH- Re (Ia),
  • R 5 is hydrogen, or a lower alkyl radical, such as a C ⁇ -C a3 yl radical, that is unsubstituted or substituted by hydroxy, amino, mercapto, unsubstituted or hydroxy- substituted phenyl, carboxy, carbamoyl or by ureido, for example methyl, isopropyl, isobutyl, secondary butyl, hydroxymethyl, mercaptomethyl, 2-methylmercaptoethyl, 3-ureidopropyl, 4-aminobutyl, carboxymethyl, carbamoylmethyl, 2-carboxyethyl, 2-carbamoylethyl, benzyl or 4-hydroxybenzyl, and
  • R 6 is lower alkanoyl, for example C 2 -C 7 alkanoyl, such as acetyl, propionyl, butyryl or pivaloyl.
  • Such an acyl radical may also, however, be the acyl group of a heterocyclic ⁇ -amino acid that occurs naturally as a peptide building block, such as prolyl, tryptophanyl or histidinyl.
  • Cycloalkyl radicals are, for example, 5- to 7-membered cycloalkyl radicals, such as especially cyclohexyl or, less preferably, cyclopentyl or cycloheptyl.
  • Heteroaryl radicals are, for example, 5-membered monocyclic oxa- or thia-aryl radicals, such as furyl or thienyl, 6-membered monocyclic aza- or diaza-aryl radicals, such as pyridyl or pyrimidinyl, or heteroaryl radicals consisting of a 5- or 6-membered mono- or diaza- or oxa-heteroaryl radical and a 6-membered aryl radical, such as benzofuranyl, for example benzofuran-2-yl or -3-yl, indolyl, for example indol-2-yl or -3-yl, or 1 -lower alkyl-, such as l-methyl-indol-2-yl, benzimidazolyl, for example benzimidazol-2-yl, or quinolyl, for example quinolin-4-yl.
  • Hydrogenated heteroaryl radicals are especially partially hydrogenated heteroaryl radicals, for example partially hydrogenated heteroaryl radicals consisting of a partially hydrogen ⁇ ated 5- or 6-membered mono- or diaza- or oxa-heteroaryl radical and a 6-membered aryl radical, such as 2,3-dihydroindolyl, for example 2,3-dihydroindol-2-yl or -3-yl, or 1,2,3,4- tetrahydroquinolinyl radicals, for example l,2,3,4-tetrahydroquinolinyl-4-yl.
  • partially hydrogenated heteroaryl radicals consisting of a partially hydrogen ⁇ ated 5- or 6-membered mono- or diaza- or oxa-heteroaryl radical and a 6-membered aryl radical, such as 2,3-dihydroindolyl, for example 2,3-dihydroindol-2-yl or -3-yl, or
  • Ketalised carbonyl groups are ketalised, for example, by an aliphatic alcohol or dialcohol, such as a lower alkanol or a lower alkanediol and are, for example, di-lower alkoxy- methylene or lower alkylenedioxymethylene.
  • Etherified hydroxymethylene groups are etherified, for example, especially by an aliphatic alcohol, such as a lower alkanol, and are, for example, lower alkoxymethylene.
  • Unsubstituted or lower alkyl- or cycloalkyl-substituted imino is, for example, imino, N-lower alkylimino or N-cycloalkylimino.
  • lower radicals and compounds are to be understood, for example, as being lower radicals and compounds having up to and including 7, preferably up to and including 4, carbon atoms (C atoms).
  • Lower alkyl is, for example, C r C 7 alkyl, preferably C 1 -C 4 alkyl, such as especially methyl or, less preferably, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, secondary butyl, tertiary butyl or a Cs-C ⁇ alkyl group, such as a pentyl, hexyl or heptyl group.
  • Lower alkylene is, for example, C 1 -C 7 alkylene, preferably -Qalkylene, such as methyl ⁇ ene, ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene.
  • Lower alkoxy is, for example, C C 7 alkoxy, preferably - alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, secondary butyloxy, tertiary butyloxy or a pentyloxy, hexyloxy or heptyloxy group.
  • Halogen is, for example, halogen having an atomic number of up to and including 35, such as chlorine or fluorine, also bromine.
  • Phenyl-lower alkyl that is unsubstituted or substituted in the phenyl moiety is, for example, corresponding phenyl-C 1 -C 4 alkyl, such as benzyl, 2,4-dichlorobenzyl, 3,5-ditri- fluoromethylbenzyl or 2-phenylethyl.
  • Diphenyl-lower alkyl that is unsubstituted or substituted in the phenyl moieties is, for example, corresponding diphenyl-Ci- alkyl, such as 2,2-diphenylmethyl.
  • Naphthyl-lower alkyl that is unsubstituted or substituted in the naphthyl moiety is, for example, corresponding naphthyl-C 1 -C 4 alkyl, such as 1- or 2-naphthylmethyl.
  • Phenoxy-lower alkyl that is unsubstituted or substituted in the phenyl is, for example, phenoxy-C r C 4 alkyl substituted by halogen and/or by triazolyl, such as 2-[2-(lH-l,2,4-tri- azol- 1 -yl)-4-chloro-phenoxy] ethyl.
  • Heteroaryl-lower alkyl containing as heteroaryl radical 6-membered monocyclic aza ⁇ heteroaryl or bicyclic azaheteroaryl consisting of a 6-membered and a 5- or 6-membered ring is, for example, pyridyl-C r C 4 alkyl, such as pyridyhnethyl, or quinolinyl-C r C 4 alkyl, such as 4-quinolinylmethyl.
  • Phenyl-lower alkanoyl that is unsubstituted or substituted in the phenyl moiety is, for example, phenyl-C r C 4 alkanoyl, such as phenylacetyl, 2,4-dichlorophenylacetyl, 3,5-ditri- fluoromethylphenylacetyl or 2-phenylpropionyl.
  • Diphenyl-lower alkanoyl that is unsubstituted or substituted in the phenyl moiety is, for example, diphenyl-C r C alkanoyl, such as diphenylacetyl.
  • Heteroaryl-lower alkanoyl containing as heteroaryl radical 6-membered monocyclic aza ⁇ heteroaryl or bicyclic azaheteroaryl consisting of a 6-membered and a 5- or 6-membered ring is, for example, pyridyl-C 1 -C 4 alkanoyl, such as pyridylacetyl, or quinolinyl- C 1 -C alkanoyl, such as 4-quinolinylacetyl.
  • Di-lower alkoxymethylene is, for example, di-C 1 -C alkoxymethylene, such as dimethoxy- methylene, diethoxymethylene, dipropyloxymethylene or dibutyloxymethylene.
  • Lower alkylenedioxymethylene is, for example, 5- to 8-membered, especially 5- or 6-membered, l,3-dioxacycloalk-2-yl, such as l,3-dioxacyclobut-2-yl, 1,3-dioxacyclopent- 2-yl (l,3-dioxolan-2-yl), l,3-dioxacyclohex-2-yl (l,3-dioxan-2-yl) or 1,3-dioxacyclohept- 2-yl.
  • l,3-dioxacycloalk-2-yl such as l,3-dioxacyclobut-2-yl, 1,3-dioxacyclopent- 2-yl (l,3-dioxolan-2-yl), l,3-dioxacyclohex-2-yl (l,3-dioxan-2-yl
  • Lower alkoxymethylene is, for example, C 1 -C 4 alkoxymethylene, such as methoxymethyl- ene, ethoxymethylene, propyloxymethylene or butyloxymethylene.
  • N-Lower alkylimino is, for example, N-Cj- alkylimino, such as methylimino, ethyl- imino, propylimino, isopropylimino or butylimino, but may also be isobutylcarbamoyl.
  • N-Cycloalkylimino is, for example, 3- to 8-membered, especially 5- to 7-membered, N-cycloalkylimino, such as cyclohexylimino.
  • the compounds of formula I are of basic character and are accordingly capable of forming acid addition salts.
  • Acid addition salts of compounds of formula I are, for example, the pharmaceutically acceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates).
  • suitable mineral acids such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates,
  • the compounds provided according to the invention have valuable pharmacological properties. In particular, they exhibit a pronounced antagonistic action towards compound P and have the spectrum of properties typical of compound-P-antagonists.
  • the compounds of formula I and the pharmaceutically acceptable salts thereof inhibit in vitro the binding of 3 H-compound-P to bovine retina in the radio receptor assay according to H. Bittiger, Ciba Foundation Symposium 91., 196-199 (1982) in concentra ⁇ tions of approximately 0.01 ⁇ mol/litre and above.
  • an IC 50 value of 0.011 ⁇ mol/litre is found.
  • the antagonistic action at the human compound-P receptor can be determined in accordance with CM. Lee et al., J. Neurochem. 59, 406-411 (1992), from the inhibition of the compound-P-induced increase in the inositol monophos- phate content in human astrocytoma cells (U-373 MG) in concentrations of approximately 0.01 ⁇ mol/litre and above.
  • Compound P is a naturally occurring undecapeptide of the tachykinin family. It is produced and deposited in sensory neurones of the spinal bone marrow and of the brain in mammals and acts pharmacologically as a neurotransmitter and/or neuromodulator.
  • the compound-P-antagonists of formula I provided according to the invention and the pharma ⁇ ceutically acceptable salts thereof are metabolically stable and are accordingly outstand ⁇ ingly suitable for the prophylactic and therapeutic treatment of diseases in which compound P plays an essential role, for example in the case of painful conditions, in migraines, in disorders of the central nervous system, such as anxiety states, schizophrenia and depression, in certain motor disorders, such as Parkinson's disease, in inflammatory diseases, such as rheumatoid arthritis and osteoarthritis, in diseases of the respiratory organs, such as asthma, chronic bronchitis and chronic rhinitis, in diseases of the gastro ⁇ intestinal system, such as ulcerative colitis and Crohn's disease, in vomiting, especially chemically induced vomiting, and in hypertension.
  • diseases in which compound P plays an essential role for example in the case of painful conditions, in migraines, in disorders of the central nervous system, such as anxiety states, schizophrenia and depression, in certain motor disorders, such as Parkinson's disease, in inflammatory diseases, such as rheuma
  • the invention relates especially to compounds of formula I wherein
  • R is a phenyl-, diphenyl-, naphthyl- or fluorenyl-lower alkyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; a phenoxy-lower alkyl radical that is unsubstituted or substituted in the phenyl moiety by halogen and/or by triazolyl; a heteroaryl-lower alkyl radical containing as heteroaryl radical 6-membered monocyclic azaheteroaryl or bicyclic azaheteroaryl consisting of a 6-membered and a 5- or 6-membered ring; a benzoyl, naphthoyl, fluorenoyl or 3- to 8-membered cycloalkylcarbonyl radical that is unsubstituted or substituted by lower alkyl, lower al
  • R 2 is 5- to 7-membered cycloalkyl or a phenyl, naphthyl or 6-membered monocyclic aza ⁇ heteroaryl radical that is unsubstituted or substituted by aromatically bonded lower alkyl, lower alkoxy, halogen, cyano, nitro, carboxy, carbamoyl and/or by trifluoro ⁇ methyl,
  • R 3 is an unsubstituted or lower alkyl-, lower alkoxy-, phenoxy-, halogen-, carboxy-, lower alkoxycarbonyl-, carbamoyl-, cyano- and/or trifluoromethyl-substituted phenyl, cyclohexyl, naphthyl, tetrahydronaphthyl, 5-membered monocyclic oxa- or thia-aryl, 6-membered monocyclic aza- or diaza-aryl or optionally partially hydrogenated heteroaryl radical consisting of a 5- or 6-membered mono- or diaza- or oxa-heteroaryl radical and a 6-membered aryl radical, or when n is 1, X 2 is unsubstituted or lower alkyl- or cycloalkyl-substituted imino and X 3 is lower alkylene, R 3 is lower alkyl, carboxy, lower alkoxycarbon
  • R 4 is hydrogen, lower alkyl or phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, phenoxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, nitro and/or by trifluoromethyl,
  • X is oxy or thio
  • Xj is methylene, ethylene, a carbonyl group that is free or ketalised by a lower alkanol or by a lower alkanediol, a hydroxymethylene group that is free or etherified by a lower alkanol, or is a direct bond;
  • X 2 is a lower alkylene radical, an imino group that is unsubstituted or substituted by lower alkyl or by 5- to 7-membered cycloalkyl, or is a direct bond;
  • X 3 is lower alkylene or a direct bond
  • X 4 is oxo or thioxo, and n is 1 or, when X 2 is lower alkylene and X 3 is a direct bond, n is 0, and to the salts thereof.
  • the invention relates more especially, for example, to compounds of formula I wherein R ! is a phenyl-, diphenyl-, naphthyl- or fluorenyl-lower alkyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; a phenoxy-lower alkyl radical that is unsubstituted or substituted in the phenyl moiety by halogen and/or by triazolyl; a heteroaryl-lower alkyl radical containing as heteroaryl radical 6-membered monocyclic azaheteroaryl or bicyclic azaheteroaryl consisting of a 6-membered and a 5- or 6-membered ring; a benzoyl, naphthoyl, fluorenoyl or 3- to 8-membered cycloalkylcarbonyl radical
  • R 5 is hydrogen, or C r C 4 alkyl that is unsubstituted or substituted by hydroxy, mercapto, amino, unsubstituted or hydroxy-substituted phenyl, carboxy, carbamoyl or by ureido, and
  • R 6 is C 2 -C 7 alkanoyl
  • R is 5- to 7-membered cycloalkyl, or a phenyl, naphthyl or 6-membered monocyclic azaheteroaryl radical that is unsubstituted or substituted by aromatically bonded lower alkyl, lower alkoxy, halogen, cyano, nitro and/or by trifluoromethyl,
  • R 3 is a phenyl, naphthyl or pyridyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl, or a heteroaryl radical, consisting of an optionally partially hydrogenated 5- or 6-membered mono- or diaza- or oxa-heteroaryl radical and a 6-membered aryl radical, that is unsubstituted or C-substituted by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl and, as the case may be, N-substituted by lower alkanoyl,
  • R 4 is hydrogen or lower alkyl
  • X is oxy or thio
  • X I is methylene, ethylene, a carbonyl group that is free or ketalised by a lower alkanol or by a lower alkanediol, a hydroxymethylene group that is free or etherified by a lower alkanol, or is a direct bond,
  • X is a lower alkylene radical, an imino group that is unsubstituted or substituted by lower alkyl or by 5- to 7-membered cycloalkyl, or is a direct bond
  • X 3 is a direct bond
  • X 4 is oxo
  • n is 1 or, when X 2 is a lower alkylene radical, n is 0, and to the salts thereof.
  • the invention relates especially to compounds of formula I wherein
  • Ri is benzoyl that is unsubstituted or substituted by C r C 4 alkyl, C r C 4 alkoxy, di-
  • C j - alkylamino, halogen and/or by trifluoromethyl such as benzoyl, 3-C r C 4 alkyl-, 3-C 1 -C 4 alkoxy-, 3-halo-, 3-dimethylamino-, 3,5-di-C r C 4 alkyl-, 3,5-di-C r C 4 alkoxy-, 3,5-dihalo- or 3,5-ditrifluoromethyl-benzoyl, or is unsubstituted naphthoyl,
  • R 2 is phenyl that is unsubstituted or substituted by C 1 -C 4 alkyl, Cj- alkoxy, halogen, cyano, nitro, carboxy, carbamoyl and or by trifluoromethyl,
  • R 3 is phenyl or naphthyl that is unsubstituted or substituted by -Qalkyl, Cx- alkoxy, phenoxy, halogen, carboxy, C 1 -C 4 alkoxycarbonyl, carbamoyl, cyano and/or by tri ⁇ fluoromethyl, or is unsubstituted pyridyl, benzofuranyl, unsubstituted or Cj-Qalkyl- N-substituted indolyl or 2,3-dihydroindolyl, benzimidazolyl, quinolyl or 1,2,3,4-tetra- hydroquinolinyl, or, when n is 1, X 2 is imino that is unsubstituted or substituted by C r C 4 alkyl and X 3 is C r C alkylene, R 3 is C ⁇ C ⁇ alkyl, carboxy, C 1 -C 4 alkoxycarbonyl or carbamoyl,
  • R 4 is hydrogen or Ci- alkyl
  • X is oxy or thio
  • Xi is methylene
  • X 2 is C 1 -C 4 alkylene, imino, C 1 -C alkylimino or a direct bond,
  • X 3 is C 1 -C 4 alkylene or a direct bond
  • X 4 is oxo or thioxo, and n is 1 or, when X 2 is C 1 -C 4 alkylene and X 3 is a direct bond, n is 0, and to the salts thereof.
  • the invention relates very especially to compounds of formula I wherein
  • Ri is benzoyl that is unsubstituted or substituted by C 1 -C alkyl, Cj-Qalkoxy, di-
  • R 2 is phenyl that is unsubstituted or substituted by C 1 -C 4 alkyl, such as methyl,
  • C r C 4 alkoxy such as methoxy, halogen, such as chlorine, cyano, nitro, carboxy, carbamoyl and/or by trifluoromethyl
  • R 3 is indolyl that is unsubstituted or N-substituted by C 1 -C alkyl, such as methyl, or is unsubstituted quinolyl or 1,2,3,4-tetrahydroquinolinyl
  • R 4 is hydrogen
  • X is oxy
  • X I is methylene
  • X 2 is C 1 -C 4 alkylene, such as methylene, imino or a direct bond,
  • X 3 is methylene or a direct bond
  • X 4 is oxo or thioxo, and n is 1 or, when X 2 is C r C 4 alkylene and X 3 is a direct bond, n is 0, and to the salts thereof.
  • R j is benzoyl that is unsubstituted or substituted by C 1 -C 4 alkyl, C r C 4 alkoxy, di-
  • C 1 -C 4 alkylamino, halogen and/or by trifluoromethyl such as benzoyl, 3- - alkyl-, 3-C r C 4 alkoxy-, 3-halo-, 3-dimethylamino-, 3,5-di-Ci-Qalkyl-, 3,5-di-C r C 4 alkoxy-, 3,5-dihalo- or 3,5-ditrifluoromethyl-benzoyl,
  • R 2 is phenyl that is unsubstituted or substituted by C 1 -C 4 alkyl, such as methyl,
  • C 1 -C 4 alkoxy such as methoxy, halogen, such as chlorine, cyano, nitro and or by tri ⁇ fluoromethyl,
  • R 3 is unsubstituted quinolyl or 1,2,3,4-tetrahydroquinolinyl
  • R 4 is hydrogen
  • X is oxy or thio
  • X x is methylene
  • X 2 is C ⁇ Qalkylene, such as methylene, imino or a direct bond,
  • X 3 is a direct bond
  • X is oxo, and n is 1 or, when X 2 is C 1 -C alkylene, n is 0, and to the salts thereof.
  • the invention relates specifically to the compounds of formula I mentioned in the Examples and to the salts thereof.
  • the invention relates further to a process, based on methods known per se, for the prepara ⁇ tion of the compounds of the invention. That process comprises
  • Rj, R 2 , R 3 , R 4 , X lf X 2 , X 3 , X 4 and n are as defined and one of the radicals Yj and Y 2 is hydroxy or mercapto, optionally in the form of a salt, and the other is hydroxy or reactive esterified hydroxy or, when n is 1, etherified hydroxy, or wherein
  • R j , R 2 , R 3 , R 4 , X lf X 2 , X 3 and X 4 are as defined, Yj is hydroxy esterified by a carboxylic acid, Y 2 is hydroxy that is free or etherified or in the form of a salt, and n is 1, or
  • R 2 , R 3 , R 4 , X, X lf X 2 , X 3 and n are as defined, and if desired, converting a resulting compound into a different compound of formula I, separating a mixture of isomers obtainable in accordance with the process into its components and isolating the preferred isomer, and/or converting a free compound obtain ⁇ able in accordance with the process into a salt or converting a salt obtainable in accord ⁇ ance with the process into the corresponding free compound.
  • hydroxy Yi esterified by a carboxylic acid for example, hydroxy or mercapto esterified by an aliphatic carboxylic acid, such as a lower alkanoic acid, for example formic or acetic acid, an aromatic carboxylic acid, for example an unsubstituted or nitro-substituted benzoic acid, or a semiester of carbonic acid, for example an alkyl-, benzyl- or phenyl-monocarbonic acid ester.
  • a carboxylic acid for example, hydroxy or mercapto esterified by an aliphatic carboxylic acid, such as a lower alkanoic acid, for example formic or acetic acid, an aromatic carboxylic acid, for example an unsubstituted or nitro-substituted benzoic acid, or a semiester of carbonic acid, for example an alkyl-, benzyl- or phenyl-monocarbonic acid ester.
  • Etherified hydroxy groups are, for example, lower alkoxy, such as methoxy or ethoxy, or unsubstituted or substituted phenyloxy groups.
  • reaction of compounds of formulae II and UI is carried out in customary manner, for example in the presence of a condensation agent, such as a water-binding agent, or a basic condensation agent, or, starting from compounds of formulae ⁇ and Ifl wherein Yj is hydroxy, n is 1 and Y 2 is etherified hydroxy, with removal of the liberated water, for example by azeotropic distillation, and in both cases advantageously in the presence of a solvent or diluent.
  • a condensation agent such as a water-binding agent, or a basic condensation agent
  • Starting materials of formula H wherein Y, is hydroxy can be prepared, for example, by reacting a compound of formula ⁇ a wherein R is a group R j or a customary amino-protecting group, such as carbobenzoxy, in customary manner, for example in the presence of benzyltributylammonium chloride in dichloromethane/sodium hydroxide solution, with a halomethyl alkyl ether, treating the resulting compound of formula Hb
  • a compound of formula ⁇ wherein Yj is reactive esterified hydroxy can be prepared by reaction with an agent that introduces a reactive esterified hydroxy group, such as a sulfonic acid halide, for example methanesulfonic acid chloride, or a halogenating agent, such as thionyl chloride, preferably in the presence of pyridine;
  • an agent that introduces a reactive esterified hydroxy group such as a sulfonic acid halide, for example methanesulfonic acid chloride, or a halogenating agent, such as thionyl chloride, preferably in the presence of pyridine;
  • the introduction of the radical R ! in accordance with Process variant b) is carried out in customary manner, for example by reaction with an agent that introduces the radical R lt such as a compound of the formula R 1 - 3 (VI), wherein R x has one of the meanings given above and Y 3 is reactive esterified hydroxy, or under reducing conditions with a compound of the formula R' ⁇ O (VII), wherein R is an unsubstituted or substituted aralkylidene, aryloxyalkylidene or heteroaralkylidene radical.
  • an agent that introduces the radical R lt such as a compound of the formula R 1 - 3 (VI), wherein R x has one of the meanings given above and Y 3 is reactive esterified hydroxy, or under reducing conditions with a compound of the formula R' ⁇ O (VII), wherein R is an unsubstituted or substituted aralkylidene, aryloxyalkylidene or heteroaralkylid
  • Compounds of formula (VI) are, for example, N-acylating agents wherein in formula VI R j is an unsubstituted or substituted aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl or aryl ⁇ carbamoyl radical or the acyl radical of an optionally N-alkanoylated ⁇ -amino acid and Y 3 is free or etherified hydroxy, such as hydroxy, lower alkoxy or unsubstituted or substituted phenoxy, or reactive esterified hydroxy, such as halogen, especially chlorine, or a radical of the formula -O-R lt or aralkylating, aryloxyalkylating or heteroarylalkylating agents of formula VI wherein R x is an unsubstituted or substituted aralkyl, aryloxyalkyl or hetero ⁇ aralkyl radical and Y 3 is reactive esterified
  • reaction is carried out if necessary with the thermal decomposition of ammonium salts formed as intermediates or in the presence of a condensation agent, such as a water- binding agent, or a basic condensation agent, and in the presence of a solvent or diluent
  • a condensation agent such as a water- binding agent, or a basic condensation agent
  • aralkylating, aryloxy- alkylating or heteroarylalkylating agents of formula VI is carried out preferably in the presence of a basic condensation agent, such as an alkali metal hydroxide or carbonate, or of a teriary or sterically hindered secondary organic amine, such as a tri-lower alkylamine, for example triethylamine or d ⁇ sopropylamine, or of an aromatic nitrogen base, for example pyridine.
  • a basic condensation agent such as an alkali metal hydroxide or carbonate
  • a teriary or sterically hindered secondary organic amine such as a tri-lower alkylamine, for example triethylamine or d ⁇ sopropylamine, or of an aromatic nitrogen base, for example pyridine.
  • the reaction with compounds of formula VH is carried out, for example, in the presence of hydrogen and a hydrogenation catalyst, such as a platinum or palladium catalyst, or Raney nickel, or in the presence of a di-light metal hydride, such as sodium borohydride or sodium cyanoborohydride, preferably in a solvent that is inert under the reaction conditions, such as a lower alkanol, such as methanol or ethanol, or a di-lower alkyl ether or lower alkylene ether, such as diethyl ether, dioxane or tetrahydrofuran.
  • a hydrogenation catalyst such as a platinum or palladium catalyst, or Raney nickel
  • a di-light metal hydride such as sodium borohydride or sodium cyanoborohydride
  • solvent that is inert under the reaction conditions such as a lower alkanol, such as methanol or ethanol, or a di-lower alkyl ether or lower alkylene ether, such as
  • the starting materials of formula IV can be prepared in customary manner, for example by reacting with one another compounds of formulae
  • R is an amino-protecting group, such as carbobenzoxy, for example as described above under Process variant a), and removing the amino-protecting group in customary manner.
  • compounds of formula I wherein X x is carbonyl can be reduced in customary manner to the corresponding compounds of formula I wherein X 1 is hydroxymethylene, for example as described under Process variant b) or for the preparation of intermediates of formulae H and IH.
  • X ! is hydroxymethylene and/or n is 1 to the correspond ⁇ ing compounds of formula I wherein X ! and or n is 0, and X 2 is methylene or an alkylene radical lengthened by one methylene group.
  • the carbonyl group can be freed in customary manner, for example by treatment with an acid.
  • carbonyl X x can be ketalised by reaction with a corresponding alcohol, such as a lower alkanol or a lower alkanediol.
  • a radical other than hydrogen can be introduced, for example by customary alkylation or cycloalkylation.
  • the alkyl group can be removed by treatment with a haloformic acid ester, such as formic acid methyl ester.
  • Resulting salts can be converted into the free compounds in a manner known er se, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or another salt-forming base mentioned at the beginning, or with an acid, such as a mineral acid, for example with hydrogen chloride, or another salt-forming acid mentioned at the beginning.
  • a base such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia
  • an acid such as a mineral acid, for example with hydrogen chloride, or another salt-forming acid mentioned at the beginning.
  • Resulting salts can be converted into different salts in a manner known per se, for example by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a differ ⁇ ent acid in a suitable solvent in which an inorganic salt that forms is insoluble and is thus excluded from the reaction equilibrium, and base salts by freeing the free acid and converting it into a salt again.
  • a suitable metal salt such as a sodium, barium or silver salt
  • the compounds of formula I may also be obtained in the form of hydrates or may include the solvent used for crystallisation.
  • Resulting mixtures of diastereoisomers and mixtures of racemates can be separated in known manner into the pure diastereoisomers or racemates on the basis of the physico- , chemical differences between the constituents, for example by chromatography and/or fractional crystallisation.
  • Resulting racemates can also be separated into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, with the aid of micro ⁇ organisms or by reaction of the resulting diastereoisomeric mixture or racemate with an optically active auxiliary compound, for example according to the acidic, basic or functionally modifiable groups present in compounds of formula I with an optically active acid, base or an optically active alcohol, into mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from which the desired enantiomer can be freed in customary manner.
  • an optically active auxiliary compound for example according to the acidic, basic or functionally modifiable groups present in compounds of formula I with an optically active acid, base or an optically active alcohol, into mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from which the desired enantiomer can be free
  • Suitable bases, acids and alcohols are optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylan ⁇ ine, 3-pipecoline, ephedrine, amphet ⁇ amine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluoyltartaric acid, D- or L-malic acid, D- or L-mandelic acid or r> or L-camphorsulfonic acid, or optically active alcohols, such as borneol or D- or L-(l-phenyl)ethanol.
  • optically active alkaloid bases such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylan ⁇ ine, 3-pipecoline, ephedrine, amphet ⁇
  • the invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or in which a starting material is used in the form of a salt or, especially, is formed under the reaction conditions.
  • the invention relates also to the novel starting materials developed specifically for the preparation of the compounds of the invention, especially to those starting materials resulting in the compounds of formula I described at the beginning as being preferred, to processes for the preparation thereof and to their use as intermediates.
  • R 5 is hydrogen, formyl or carbamoyl
  • R j , R , R 4 , X and X t are each as defined at the beginning for compounds of formula I.
  • Compounds of formula V wherein R 5 is hydrogen likewise have compound-P-antagonistic properties and can accordingly also be used as active ingredients of medicaments in pharmaceutical compositions for the treatment of the diseases mentioned at the beginning.
  • Compounds of formula V wherein R 5 is formyl or carbamoyl are used preferably as inter ⁇ mediates in the preparation of active ingredients of medicaments, for example of formula I.
  • R j is an unsubstituted or substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, hetero ⁇ aroyl, cycloalkylcarbonyl, aralkanoyl, heteroaiylalkanoyl, aralkoxycarbonyl or aryl ⁇ carbamoyl radical, or the acyl radical of an ⁇ -amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,
  • R 2 is cycloalkyl or an unsubstituted or substituted aryl or heteroaryl radical
  • R 4 is hydrogen or alkyl
  • R 5 is hydrogen, formyl or carbamoyl
  • X is oxy or thio
  • X ! is methylene, ethylene, a direct bond, a free or ketalised carbonyl group or a free or etherified hydroxymethylene group, and to the salts thereof and to processes for the preparation thereof.
  • the invention relates preferably to those compounds of formula V wherein
  • R 5 is hydrogen or formyl
  • Rj, R 2 , R 4 , X and Xx are each as defined for the compounds of formula I described at the beginning as being preferred.
  • R and R' are each a group R l t and R 2 , R and Xi are as defined for formula I, and to corresponding 4-carbamoyloxypiperidine compounds.
  • X is oxy
  • X 2 and X 3 are each a direct bond
  • R 4 is hydrogen
  • X is oxy or thio
  • X 2 and X 3 are each a direct bond
  • X and R 4 are as defined for formula I.
  • the invention relates further to a process, based on methods known per se, for the prepara ⁇ tion of compounds of formula V wherein X is oxy. That process comprises subjecting a compound of formula lib
  • alkyl is alkyl, especially lower alkyl
  • R is a group R lt and Rj, R 2 , R 4 and X 1 are each as defined for compounds of formula I, to intramolecular condensation, for example under acidic conditions, such as treatment with an excess of formic acid, and subjecting the resulting compound of formula V wherein R 5 is formyl to acid hydrolysis, for example in the presence of concentrated hydrochloric acid, to form the corresponding compound of formula V wherein R 5 is hydrogen.
  • Starting compounds of formula lib can be obtained in the manner described under Process variant a) from corresponding compounds of formula Ha.
  • the novel compounds of formula I can be used, for example, in the form of pharmaceut ⁇ ical compositions that comprise a therapeutically effective amount of the active ingred ⁇ ient optionally together with inorganic or organic, solid or liquid pharmaceutically accept ⁇ able carriers that are suitable for enteral, for example oral, or parenteral administration.
  • tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • diluents for example lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Tablets can also comprise binders, for example magnesium aluminium silicate, starches, such as corn, wheat rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, colouring agents, flavourings and sweeteners.
  • binders for example magnesium aluminium silicate, starches, such as corn, wheat rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone
  • disintegrators for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, colouring agents, flavourings and sweeteners.
  • the novel compounds of formula I
  • Such solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilised compositions that comprise the active ingredient on its own or together with a carrier, for example mannitol, can be prepared before use.
  • the pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • compositions in question which, if desired, may comprise further pharma ⁇ cologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and comprise approximately from 0.1 % to 100 %, especially from approx ⁇ imately 1 % to approximately 50 %, in the case of lyophilisates up to approximately 100 %, active ingredient
  • the present invention relates also to pharmaceutical compositions and medicaments comprising one of the compounds of formula I according to the invention or a pharma ⁇ ceutically acceptable salt thereof.
  • the pharmaceutical compositions according to the invention are especially pharmaceutical compositions intended for local administration, and especially for administration by inhalation, for example in the form of an aerosol, micronised powders or a finely sprayed solution, to mammals, especially humans, that comprise the active ingredient alone or together with a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions for topical and local use are, for example for the treatment of the skin, lotions and creams which comprise a liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (which preferably comprise a preservative).
  • Suitable for the treatment of the eyes are eye drops which comprise the active ingredient in aqueous or oily solution, and eye ointments which are preferably manufactured in sterile form.
  • Suitable for the treatment of the nose are aerosols and sprays (similar to those described below for the treatment of the respiratory tract), coarse powders which are administered by rapid inhalation through the nostrils, and especially nose drops which comprise the active ingredient in aqueous or oily solution;
  • suitable for local treatment of the buccal cavity are lozenges which comprise the active ingredient in a mass generally formed of sugar and gum arabic or tragacanth, to which flavourings may be added, and pastilles which comprise the active ingredient in an inert mass, for example of gelatin and glycerol or sugar and gum arabic.
  • compositions suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compound of formula I according to the invention with a suitable pharmaceutically acceptable solvent such as, especially, ethanol and water, or a mixture of such solvents.
  • a suitable pharmaceutically acceptable solvent such as, especially, ethanol and water, or a mixture of such solvents.
  • ком ⁇ онентs such as non-ionic or anionic surface-active agents, emulsifiers and stabilisers, and also active ingredients of other kinds, and especially advantageously they can be mixed with a propellant gas, such as an inert gas under elevated pressure or especially with a readily volatile liquid, preferably a liquid that boils under normal atmospheric pressure below customary room temperature (for example from approximately -30 to +10°C), such as an at least partially fluorinated polyhalogen- ated lower alkane, or a mixture of such liquids.
  • a propellant gas such as an inert gas under elevated pressure or especially with a readily volatile liquid, preferably a liquid that boils under normal atmospheric pressure below customary room temperature (for example from approximately -30 to +10°C), such as an at least partially fluorinated polyhalogen- ated lower alkane, or a mixture of such liquids.
  • Such pharmaceutical compositions which are used predominantly as intermediates or stock mixtures for the preparation of the corresponding medicaments in finished form, comprise the active ingredient customarily in a concentration of from approximately 0.1 to approximately 10 % by weight, especially from approximately 0.3 to approximately 3 % by weight
  • suitable containers such as flacons and pressurised bottles, which are provided with a spray device or valve suitable for such purposes.
  • the valve is preferably constructed in the form of a metering valve which when operated releases a predetermined amount of liquid, corres ⁇ ponding to a predetermined dose of the active ingredient
  • appropriate amounts of the pharmaceutical composition present in stock solution form and of the propellant to be introduced separately into the containers and to be mixed with one another only at that stage.
  • the dose of the compound of formula I to be administered and the frequency of administration depend upon the effectiveness and the duration of efficacy of each individual compound, upon the severity of the disease to be treated and its symptoms, and upon the sex, age, weight and individual responsiveness of the mammal to be treated.
  • the recommended daily dose of a compound of formula I according to the invention for a mammal (especially a human) weighing 75 kg might be in the range of from approximate ⁇ ly 10 to approximately 500, preferably from approximately 25 to approximately 250 mg, which can advantageously be administered in several doses per day, as necessary.
  • the invention relates also to the use of the compounds of formula I according to the invention in the alleviation or relief of pathological conditions and/or symptoms of the body of a mammal, especially of a human, that are attributable to the action of leuco- trienes and that occur especially in the case of asthma.
  • That use, and the corresponding method of treatment comprises treating the affected body or body part with an antiallerg- ically active amount of a compound of formula I on its own or in the form of a medica ⁇ ment, especially a pharmaceutical composition intended for inhalation.
  • antiallergically effective amount is to be understood as denoting an amount of active ingredient that is sufficient to ensure significant inhibition of the constriction caused by leucotrienes.
  • the invention relates further to the use of the compounds of formula I, preferably in the form of pharmaceutical compositions.
  • the dose can depend upon various factors, such as the mode of administration, the species, age and or individual condition.
  • the daily doses to be administered are, in the case of oral administration, from approximately 0.25 to approximately 10 mg kg, and, in the case of warm-blooded animals having a body weight of approximately 70 kg, they are preferably from approximately 20 mg to approximately 500 mg.
  • Example 1 (2R*.4S*)-2-benzyl- l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolyl- methoxy)-piperidine
  • the starting compound therefor is prepared as follows:
  • the reaction mixture is then stirred for a further 1 hour, the temperature rising to 16°.
  • the phases are separated and the organic phase is washed once with IN hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation using a rotary evaporator. 8.8 g (96 %) of a slightly coloured oil that solidifies when left to stand for a few days are obtained.
  • the product is used further in the crude state, but can be purified by crystallisation from toluene/hexane.
  • the mixture is washed once with water and once with saturated sodium chloride solution, and the organic phases are dried over sodium sulfate and concentrated by evaporation using a rotary evaporator.
  • the crude product is chromato ⁇ graphed on silica gel (toluene/ethyl acetate 95:5) and the title compound is obtained in the form of an oil.
  • reaction solution is taken up in ethyl acetate and extracted once with 0.1N hydrochloric acid solution and once with water, and then washed twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation using a rotary evaporator.
  • the crude product is chromato ⁇ graphed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of crystals. M.p.: 174-177°.
  • reaction solution is taken up in ethyl acetate and extracted once with 0.1N hydrochloric acid solution and once with water, and then washed twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation using a rotary evaporator.
  • the crude product is chromato ⁇ graphed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of crystals. M.p.: 212-215°.
  • N-[l-(4-Chloro-benzyl)-but-3-enyl]-N-ethoxyethyl-3 ⁇ -dimethyl-benzamide (680 mg, 1.76 mmol) is stirred for 90 minutes at 0-5° in 10 ml of formic acid. The mixture is concentrated by evaporation under reduced pressure, and the residue is then taken up in dichloromethane and saturated NaHCO3 solution. The organic phase is separated off, then washed with saturated sodium chloride solution, dried over Na 2 SO and concentrated by evaporation under reduced pressure.
  • the starting materials can be prepared as follows:
  • reaction mixture is then stirred for 1 hour at room temperature, and then concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (10:1) as eluant.
  • the starting material can be prepared, for example, as follows: a) 2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-hvdroxy-piperidine
  • Example 23 In a manner analogous to that described in Examples 1 to 22 it is also possible to prepare:
  • Example 23 Tablets, each comprising 50 mg of (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoro- methylbenzoyl)-4-(3-quinolylmethoxy)-piperidine or a salt, for example the hydro ⁇ chloride, thereof, can be prepared as follows:
  • composition (10000 tablets)
  • the active ingredient is mixed with the lactose and 292 g of potato starch and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silicon dioxide are added and the mixture is compressed to form tablets, each weighing 145.0 mg and containing 50.0 mg of active ingredient which can, if desired, be provided with breaking notches for finer adaptation of the dose.
  • Example 24 Film-coated tablets, each comprising 100 mg of (2R*,4S*)-2-benzyl- l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolylmethoxy)-piperidine or a salt, for example the hydrochloride, thereof, can be prepared as follows:
  • composition for 1000 film-coated tablets
  • the active ingredient, the lactose and 40 g of the maize starch are mixed and moistened with a paste prepared from 15 g of maize starch and water (with heating) and granulated.
  • the granules are dried and the remainder of the maize starch, the talc and the calcium stearate are added and mixed with the granules.
  • the mixture is compressed to form tablets (weight: 280 mg) which are then coated with a solution of the hydroxypropyl methyl ⁇ cellulose and the shellac in methylene chloride; final weight of each film-coated tablet: 283 mg.
  • Example 25 Dry-filled gelatin capsules, each containing 100 mg of active ingredient for example (2R*,4S*)-2-benzyl-l-(3,5-bistrifiuoromethylbenzoyl)-4-(3-quinolylmethoxy)- piperidine or a salt, for example the hydrochloride, thereof, can be prepared, for example, as follows:
  • Composition for 1000 capsules
  • active ingredient 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 g magnesium stearate 8.0 g
  • the sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve of 0.2 mm mesh size.
  • the two components are intimately mixed. First the lactose is added through a sieve of 0.6 mm mesh size and then the microcrystalline cellulose is added through a sieve of 0.9 mm mesh size. Then the mixture is intimately mixed again for 10 minutes. Finally the magnesium stearate is added through a sieve of 0.8 mm mesh size. After a further 3 minutes' mixing, the resulting formulation is introduced into size 0 dry- filled gelatin capsules in portions of 390 mg each.
  • 500 mg of finely ground powder ( ⁇ 5.0 ⁇ m) of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient is suspended in a mixture of 3.5 ml of Myglyol® 812 and 0.08 g of benzyl alcohol.
  • the suspension is introduced into a container having a metering valve.
  • 5.0 g of Freon® 12 are introduced under pressure into the container through the valve.
  • the Freon® is dissolved in the Myglyol®/benzyl alcohol mixture by shaking.
  • the spray container contains approximately 100 single doses which can be administered individually.
  • Example 27 In a manner analogous to that described in Examples 23 to 26 above, it is also possible to prepare pharmaceutical compositions comprising a different compound of formula I in accordance with one of the above Preparation Examples.

Abstract

Composés de piperidines trisubstituée en position 1, 2 et 4, répondant à la formule (I), dans laquelle R1 représente un radical aralkyle, aryloxyalkyle, hétéroaralkyle, aroyle, hétéroaroyle, cycloalkylcarbonyle, aralcanoyle, hétéroarylalcanoyle, aralcoxycarbonyle ou arylcarbamyle substitué ou non substitué, ou représente le radical acyle d'un α-aminoacide non substitué ou N-substitué par alcanoyle inférieur ou par carbamyle-alcanoyle inférieur; R2 représente cycloalkyle ou un radical aryle ou hétéroaryle substitué ou non substitué; R3 représente un radical aryle ou hétéroaryle non substitué ou substitué, éventuellement hydrogéné, ou, lorsque n vaut 1, X2 représente imino non substitué ou substitué par alkyle inférieur ou par cycloalkyle, et X3 représente alkylène inférieur, R3 représente alkyle inférieur ou carboxy libre ou estérifié ou amidé; R4 représente hydrogène ou alkyle, X1 représente méthylène, éthylène, une liaison directe, un groupe carbonyle libre ou cétalisé ou un groupe hydroxyméthylène libre ou éthérifié; X2 représente alkylène inférieur, imino non substitué ou substitué par alkyle inférieur ou par cycloalkyle, ou une liaison directe; X3 représente alkylène inférieur ou une liaison directe; X4 représente oxo ou thioxo, et n vaut 1, ou, lorsque X2 représente alkylène inférieur et X3 une liaison directe, n vaut 0. Ces composés, ainsi que leurs sels, présentent des caractéristiques antagonistes par rapport au composé P, et peuvent être utilisés comme principes actifs dans des médicaments.
PCT/EP1994/003394 1993-10-26 1994-10-14 N-benzoyl-4-oxy/thio-piperidines a substitution en position utilisees comme antagonistes du recepteur de la substance p WO1995011895A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010562A1 (fr) * 1994-09-30 1996-04-11 Novartis Ag Composes 1-acyl-4-aliphatylaminopiperidine
US5604247A (en) * 1995-04-24 1997-02-18 Ciba-Geigy Corporation Chromone Derivatives
WO1997016440A1 (fr) * 1995-10-30 1997-05-09 Janssen Pharmaceutica N.V. Derives de piperazine a substitution en positions 1-(diperidinyle a disubstitution en positions 1,2)-4
US7186730B2 (en) 2001-05-25 2007-03-06 Smithkline Beecham P.L.C. Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials
WO2010000073A1 (fr) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines et composés apparentés ayant une activité d'inhibition de nos
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330461A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de pipéridine
EP0528495A1 (fr) * 1991-08-20 1993-02-24 Merck Sharp & Dohme Ltd. Composés azacycliques, leur préparation et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330461A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de pipéridine
EP0528495A1 (fr) * 1991-08-20 1993-02-24 Merck Sharp & Dohme Ltd. Composés azacycliques, leur préparation et compositions pharmaceutiques les contenant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY., vol. 35, no. 3, 1992, WASHINGTON US, pages 490 - 501 *
TETRAHEDRON LETTERS., vol. 33, no. 22, 1992, OXFORD GB, pages 3133 - 3136 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010562A1 (fr) * 1994-09-30 1996-04-11 Novartis Ag Composes 1-acyl-4-aliphatylaminopiperidine
US5935951A (en) * 1994-09-30 1999-08-10 Novartis Finance Corporation 1-acyl-4-aliphatylaminopiperidine compounds
US5604247A (en) * 1995-04-24 1997-02-18 Ciba-Geigy Corporation Chromone Derivatives
WO1997016440A1 (fr) * 1995-10-30 1997-05-09 Janssen Pharmaceutica N.V. Derives de piperazine a substitution en positions 1-(diperidinyle a disubstitution en positions 1,2)-4
US6197772B1 (en) 1995-10-30 2001-03-06 Janssen Pharmaceutica N.V. 1- (1,2-disubstituted piperidinyl) -4-substituted piperazine derivatives
USRE37886E1 (en) * 1995-10-30 2002-10-15 Janssen Pharmaceuticals, N.V. 1-(1,2-Disubstituted piperidinyl)-4-substituted piperazine derivatives
US6521621B1 (en) 1995-10-30 2003-02-18 Janssen Pharmaceutica N.V. 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives
CN1117744C (zh) * 1995-10-30 2003-08-13 詹森药业有限公司 1－(1,2－双取代哌啶基)－4－取代哌嗪衍生物
CN100415716C (zh) * 1995-10-30 2008-09-03 詹森药业有限公司 1－(1，2－双取代哌啶基)－4－取代哌嗪衍生物
US7186730B2 (en) 2001-05-25 2007-03-06 Smithkline Beecham P.L.C. Bicyclic nitrogen-containing heterocyclic derivatives for use as antibacterials
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
WO2010000073A1 (fr) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines et composés apparentés ayant une activité d'inhibition de nos

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