WO1995011895A1

WO1995011895A1 - N-benzoyl-4-oxy/thio-2-substituted piperidines as substance-p receptor antagonists

Info

Publication number: WO1995011895A1
Application number: PCT/EP1994/003394
Authority: WO
Inventors: Silvio Ofner; Silvio Roggo; Walter Schilling; Siem J. Veenstra
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1993-10-26
Filing date: 1994-10-14
Publication date: 1995-05-04
Anticipated expiration: 1996-04-26
Also published as: AU7856194A

Abstract

1,2,4-Trisubstituted piperidine compounds of fomula (I), wherein R1 is an unsubstituted or substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl radical, or is the acyl radical of an α-amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl; R2 is cycloalkyl or an unsubstituted or substituted aryl or heteroaryl radical; R3 is an unsubstituted or substituted, optionally hydrogenated aryl or heteroaryl radical or, when n is 1, X2 is imino that is unsubstituted or substituted by lower alkyl or by cycloalkyl and X3 is lower alkylene, R3 is lower alkyl or free or esterified or amidated carboxy, R4 is hydrogen or alkyl; X1 is methylene, ethylene, a direct bond, a free or ketalised carbonyl group or a free or etherified hydroxymethylene group; X2 is lower alkylene, imino that is unsubstituted or substituted by lower alkyl or by cycloalkyl, or a direct bond; X3 is lower alkylene or a direct bond; X4 is oxo or thioxo; and n is 1 or, when X2 is lower alkylene and X3 is a direct bond, n is 0; and the salts thereof, have compound-P-antagonistic properties and can be used as active ingredients of medicaments.

Description

N-BENZ0YL-4-0XY/THI0-2-SUBSTITUTED PIPERIDINES AS SUBSTANCE-P RECEPTOR ANTAGONISTS

The invention relates to novel 1,2,4-trisubstituted piperidine compounds of formula I

wherein

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 α-amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₂ is cycloalkyl or an unsubstituted or substituted aryl or heteroaryl radical,

R₃ is an unsubstituted or substituted, optionally hydrogenated aryl or heteroaryl radical or, when n is 1, X₂ is imino that is unsubstituted or substituted by lower alkyl or by cycloalkyl and X₃ is lower alkylene, R₃ is lower alkyl or free or esterified or amidated carboxy,

R₄ 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,

X₂ is lower alkylene, imino that is unsubstituted or substituted by lower alkyl or by cycloalkyl, or a direct bond,

X₃ is lower alkylene or a direct bond,

X₄ is oxo or thioxo and n is 1 or, when X₂ is lower alkylene and X₃ 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 R₂ 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.

Optionally hydrogenated aryl radicals R₃ 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-cyanophenyl, 3-trifluoromethylphenyl, 3,5-dihalo-, such as 3,5-difluoro-phenyl, or 3,4-dihalo-, such as 3,4-dichloro-phenyl.

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 (cycloalkanoyl 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 α-amino acids that are unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl are derived especially from α-amino acids that occur naturally as peptide building blocks and that are optionally lower alkanoylated, for example N-C₂-C₇alkanoylated, such as α-amino acids substituted by acetyl, propionyl, butyryl or pivaloyl. Such acyl radicals are, for example, groups of formula — C-CH- NH- Re (Ia),

O wherein

R₅ is hydrogen, or a lower alkyl radical, such as a Cι-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

R₆ is lower alkanoyl, for example C₂-C₇alkanoyl, such as acetyl, propionyl, butyryl or pivaloyl.

Such an acyl radical may also, however, be the acyl group of a heterocyclic α-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.

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.

Hereinbefore and hereinafter, 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_rC₇alkyl, preferably C₁-C₄alkyl, such as especially methyl or, less preferably, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, secondary butyl, tertiary butyl or a Cs-Cγalkyl group, such as a pentyl, hexyl or heptyl group.

Lower alkylene is, for example, C₁-C₇alkylene, preferably -Qalkylene, such as methyl¬ ene, ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene.

Lower alkoxy is, for example, C C₇alkoxy, 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-C₁-C₄alkyl, 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-C₁-C₄alkyl, such as 1- or 2-naphthylmethyl.

Phenoxy-lower alkyl that is unsubstituted or substituted in the phenyl is, for example, phenoxy-C_rC₄alkyl 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_rC₄alkyl, such as pyridyhnethyl, or quinolinyl-C_rC₄alkyl, such as 4-quinolinylmethyl.

Phenyl-lower alkanoyl that is unsubstituted or substituted in the phenyl moiety is, for example, phenyl-C_rC₄alkanoyl, 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_rC 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-C₁-C₄alkanoyl, such as pyridylacetyl, or quinolinyl- C₁-C alkanoyl, such as 4-quinolinylacetyl.

Di-lower alkoxymethylene is, for example, di-C₁-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.

Lower alkoxymethylene is, for example, C₁-C₄alkoxymethylene, 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).

For isolation or purification purposes, it is also possible to use pharmaceutically unaccept¬ able salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically and those salts are therefore preferred.

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. For example, the compounds of formula I and the pharmaceutically acceptable salts thereof inhibit in vitro the binding of ³H-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 μmol/litre and above. For example, in the case of (2R*,4S*)- 2-benzyl- l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolylmethoxy)-piperidine, an IC₅₀ value of 0.011 μmol/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 μmol/litre and above. For example, in the case of (2R*,4S*)-2-benzyl-l-(3,5-bistri- fluoromethylbenzoyl)-4-(3-quinolylmethoxy)-piperidine, an IC₅₀ value of 0.00076 μmol/litre is found.

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.

The compound-P-antagonists of formula I provided in accordance with the invention and the pharmaceutically acceptable salts thereof are therefore outstandingly suitable for the therapeutic treatment of the mentioned diseases.

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 alkoxy, hydroxy, di-lower alkyl¬ amino, halogen, cyano and/or by trifluoromethyl; a phenyl- or diphenyl-lower alkanoyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; a hetero¬ aryl-lower alkanoyl radical containing as heteroaryl radical 6-membered monocyclic azaheteroaryl or bi- or tri-cyclic azaheteroaryl consisting of a 6-membered and one or two 5- or 6-membered ring(s); a phenyl-lower alkoxycarbonyl or N-phenylcarbamoyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; or the acyl radical of an α-amino acid that occurs naturally as a peptide building block and that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₂ 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,

R₃ 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, X₂ is unsubstituted or lower alkyl- or cycloalkyl-substituted imino and X₃ is lower alkylene, R₃ is lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl,

R₄ 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;

X₂ 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;

X₃ is lower alkylene or a direct bond;

X₄ is oxo or thioxo, and n is 1 or, when X₂ is lower alkylene and X₃ 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 that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, di-lower alkyl¬ amino, halogen, cyano and/or by trifluoromethyl; a phenyl- or diphenyl-lower alkanoyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; a hetero¬ aryl-lower alkanoyl radical containing as heteroaryl radical 6-membered monocyclic azaheteroaryl or bi- or tri-cyclic azaheteroaryl consisting of a 6-membered and one or two 5- or 6-membered ring(s); a phenyl-lower alkoxycarbonyl or N-phenylcarbamoyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; or a group of formula Ia

— C-CH-NH- F (Ia) o wherein

R₅ is hydrogen, or C_rC₄alkyl that is unsubstituted or substituted by hydroxy, mercapto, amino, unsubstituted or hydroxy-substituted phenyl, carboxy, carbamoyl or by ureido, and

R₆ is C₂-C₇alkanoyl,

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,

R₃ 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,

R₄ 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, X₃ is a direct bond, X₄ is oxo, and n is 1 or, when X₂ 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_rC₄alkyl, C_rC₄alkoxy, di-

C_j- alkylamino, halogen and/or by trifluoromethyl, such as benzoyl, 3-C_rC₄alkyl-, 3-C₁-C₄alkoxy-, 3-halo-, 3-dimethylamino-, 3,5-di-C_rC₄alkyl-, 3,5-di-C_rC₄alkoxy-, 3,5-dihalo- or 3,5-ditrifluoromethyl-benzoyl, or is unsubstituted naphthoyl,

R₂ is phenyl that is unsubstituted or substituted by C₁-C₄alkyl, Cj- alkoxy, halogen, cyano, nitro, carboxy, carbamoyl and or by trifluoromethyl,

R₃ is phenyl or naphthyl that is unsubstituted or substituted by -Qalkyl, Cx- alkoxy, phenoxy, halogen, carboxy, C₁-C₄alkoxycarbonyl, 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, X₂ is imino that is unsubstituted or substituted by C_rC₄alkyl and X₃ is C_rC alkylene, R₃ is C^C^alkyl, carboxy, C₁-C₄alkoxycarbonyl or carbamoyl,

R₄ is hydrogen or Ci- alkyl,

X is oxy or thio,

Xi is methylene,

X₂ is C₁-C₄alkylene, imino, C₁-C alkylimino or a direct bond,

X₃ is C₁-C₄alkylene or a direct bond,

X₄ is oxo or thioxo, and n is 1 or, when X₂ is C₁-C₄alkylene and X₃ 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 C₁-C alkyl, Cj-Qalkoxy, di-

C alkylamino, halogen and or by trifluoromethyl, such as benzoyl, 3-C₁-C₄alkyl-,

3-C_rC₄alkoxy-, 3-halo-, 3-dimethylamino-, 3,5-di-C₁-C₄alkyl-, 3,5-di-C₁-C₄alkoxy-,

3,5-dihalo- or 3,5-ditrifluoromethyl-benzoyl, R₂ is phenyl that is unsubstituted or substituted by C₁-C₄alkyl, such as methyl,

C_rC₄alkoxy, such as methoxy, halogen, such as chlorine, cyano, nitro, carboxy, carbamoyl and/or by trifluoromethyl, R₃ is indolyl that is unsubstituted or N-substituted by C₁-C alkyl, such as methyl, or is unsubstituted quinolyl or 1,2,3,4-tetrahydroquinolinyl, R₄ is hydrogen,

X is oxy,

X_I is methylene,

X₂ is C₁-C₄alkylene, such as methylene, imino or a direct bond,

X₃ is methylene or a direct bond,

X₄ is oxo or thioxo, and n is 1 or, when X₂ is C_rC₄alkylene and X₃ is a direct bond, n is 0, and to the salts thereof.

The invention relates above all, for example, to compounds of formula I wherein

R_j is benzoyl that is unsubstituted or substituted by C₁-C₄alkyl, C_rC₄alkoxy, di-

C₁-C₄alkylamino, halogen and/or by trifluoromethyl, such as benzoyl, 3- - alkyl-, 3-C_rC₄alkoxy-, 3-halo-, 3-dimethylamino-, 3,5-di-Ci-Qalkyl-, 3,5-di-C_rC₄alkoxy-, 3,5-dihalo- or 3,5-ditrifluoromethyl-benzoyl,

R₂ is phenyl that is unsubstituted or substituted by C₁-C₄alkyl, such as methyl,

C₁-C₄alkoxy, such as methoxy, halogen, such as chlorine, cyano, nitro and or by tri¬ fluoromethyl,

R₃ is unsubstituted quinolyl or 1,2,3,4-tetrahydroquinolinyl,

R₄ is hydrogen,

X is oxy or thio,

X_x is methylene,

X₂ is C^Qalkylene, such as methylene, imino or a direct bond,

X₃ is a direct bond,

X is oxo, and n is 1 or, when X₂ is C₁-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

a) condensing with one another compounds of formulae π and in

X₂- X₃- R₃ (HI),

wherein

Rj, R₂, R₃, R₄, X_lf X₂, X₃, X₄ and n are as defined and one of the radicals Yj and Y₂ 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, R₂, R₃, R₄, X_lf X₂, X₃ and X₄ are as defined, Yj is hydroxy esterified by a carboxylic acid, Y₂ is hydroxy that is free or etherified or in the form of a salt, and n is 1, or

b) introducing the radical Rx into a compound of formula IV

wherein

R₂, R₃, R₄, X, X_lf X₂, X₃ 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.

The reactions of the process and the preparation of novel starting materials and intermed¬ iates are carried out by analogy with the mode of reaction and formation of known starting materials and intermediates. In those reactions, even when not expressly mentioned below, the customary auxiliaries, such as catalysts, condensation and solvolysis agents and solvents and/or diluents, and the customary reaction conditions, such as temperature and pressure conditions, and, where appropriate, protective gases, are used.

In starting materials of formula π or El according to Process variant a), reactive esterified hydroxy is, for example, a halogen atom, such as a chlorine, bromine or iodine atom, or a sulfonyloxy group, for example methanesulfonyloxy or p-toluenesulfonyloxy, and, in the case of Y₂, if n is 1, a group of the formula -O-C(=X )-X₂-X₃-R₃.

There come into consideration as 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.

Etherified hydroxy groups are, for example, lower alkoxy, such as methoxy or ethoxy, or unsubstituted or substituted phenyloxy groups.

The 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 π and Ifl wherein Yj is hydroxy, n is 1 and Y₂ 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.

For example, the reaction of alcohols or mercaptans of formula π (Y₁ = hydroxy or mercapto) with acids or thioxo acids of formula Dl (Y₂ = hydroxy; n = 1) is carried out preferably in the presence of an acidic agent, such as a mineral acid, for example sulfuric acid, or in the presence of a water-binding agent, such as N,N-dicyclohexylcarbodiimide, while the reaction of alcohols and mercaptans of formula π 0^= hydroxy or mercapto) with reactive esters of formula HI (Y₂= reactive esterified hydroxy; n = 0) or with acid halides and acid anhydrides of formula in (Y₂ = halogen or anhydridised hydroxy of the formula -O-C(=X₄)-X₂-X₃-R₃; n = 1) is carried out preferably in the presence of a basic condensation agent, such as an alkali metal hydroxide or carbonate, or a tertiary or sterically hindered secondary organic amine, such as a tri-lower alkylamine, for example triethylamine or diisopropylamine, or of an aromatic nitrogen base, for example pyridine.

The reaction of alcohols and mercaptans of formula π (Yi = hydroxy or mercapto) with carboxylic acid esters of formula in (Y₂= etherified hydroxy or mercapto; n= 1) and the reaction of compounds of formula π (Yι= hydroxy esterified by a carboxylic acid) with acids or esters of formula in (Y₂= free or etherified hydroxy or mercapto; n= 1) is carried out under customary transesterification conditions, for example in the presence of an acidic agent or of a basic condensation agent, such as one of those mentioned.

Starting materials of formula H wherein Y, is hydroxy, can be prepared, for example, by reacting a compound of formula πa

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

with an excess of formic acid, and hydrolysing the resulting compound of formula He

under acidic conditions, for example in the presence of concentrated hydrochloric acid, and condensing the resulting compound of formula Hd

wherein R' is a group Ri or hydrogen, in customary manner, if necessary in a mixture of dichloromethane and aqueous sodium hydrogen carbonate solution, with a compound of the formula R₁-Y₃ (VI, Y₃= reactive esterified hydroxy) to form the corresponding compound of formula H (Yι= hydroxy).

Further starting materials of formula π can be prepared from those starting materials as follows 1) a compound of formula π 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;

2) compounds of formula π wherein Yi is hydroxy esterified by a carboxylic acid can be prepared by customary reaction with a reactive carboxylic acid derivative, such as a lower alkanoic acid halide or lower alkanoic acid anhydride.

Starting materials of formula El are known or can be prepared analogously to the formation of known starting materials of formula HI.

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 R₁- ₃ (VI), wherein R_x has one of the meanings given above and Y₃ 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. 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 α-amino acid and Y₃ 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 Y₃ is reactive esterified hydroxy, such as halogen, for example chlorine, bromine or iodine, or a sulfonyloxy group, such as an alkanesulfonyloxy group or an unsubstituted or substituted benzenesulfonyloxy group, for example methane-, ethane-, benzene-, p-toluene- or p-bromobenzene-sulfonyloxy.

The 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 For example, the reaction with acids of formula VI (Y₃= hydroxy) is carried out preferably in the presence of a water-binding agent, such as N,N-dicyclohexylcarbodiimide, or with thermal decomposition of the ammonium salt formed initially, while the reaction with acid anhydrides of formula VI (Y₃= halogen or -O-(C=O)-R_!) and with 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 dϋsopropylamine, 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.

The starting materials of formula IV can be prepared in customary manner, for example by reacting with one another compounds of formulae

wherein 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 obtainable according to the process can be converted in customary manner into different compounds of formula I.

For example, compounds of formula I wherein X_x is carbonyl can be reduced in customary manner to the corresponding compounds of formula I wherein X₁ is hydroxymethylene, for example as described under Process variant b) or for the preparation of intermediates of formulae H and IH. In an analogous manner it is also possible to reduce resulting compounds of formula I wherein X_! is hydroxymethylene and/or n is 1 to the correspond¬ ing compounds of formula I wherein X_! and or n is 0, and X₂ is methylene or an alkylene radical lengthened by one methylene group. In resulting compounds of formula I wherein Xj is ketalised carbonyl, the carbonyl group can be freed in customary manner, for example by treatment with an acid. Conversely, carbonyl X_x can be ketalised by reaction with a corresponding alcohol, such as a lower alkanol or a lower alkanediol.

Furthermore, in resulting compounds of formula I wherein X₂ is unsubstituted imino, a radical other than hydrogen can be introduced, for example by customary alkylation or cycloalkylation. Conversely, in resulting compounds of formula I wherein X₂ is imino substituted by alkyl, especially methyl, 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.

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.

The compounds of formula I, including their salts, may also be obtained in the form of hydrates or may include the solvent used for crystallisation.

In view of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as including the corresponding salts or free compounds, respectively, as appropriate and expedient

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. Examples of suitable bases, acids and alcohols are optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylanιine, 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.

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.

The above applies preferably to compounds of formula V

wherein

R₅ is hydrogen, formyl or carbamoyl, and

R_j, R , R₄, X and X_t are each as defined at the beginning for compounds of formula I. Compounds of formula V wherein R₅ 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 R₅ is formyl or carbamoyl are used preferably as inter¬ mediates in the preparation of active ingredients of medicaments, for example of formula I.

The invention accordingly relates also to compounds of formula V wherein

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 α-amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₄ is hydrogen or alkyl, and

R₅ is hydrogen, formyl or carbamoyl,

X is oxy or thio, and

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

R₅ is hydrogen or formyl, and

Rj, R₂, R₄, X and Xx are each as defined for the compounds of formula I described at the beginning as being preferred.

Compounds of formula V to which the invention relates include especially compounds of formulae lie and nd

(πc) and ai ),

wherein

R and R' are each a group R_{l t} and R₂, R and Xi are as defined for formula I, and to corresponding 4-carbamoyloxypiperidine compounds.

Those compounds can also be represented by formula I shown at the beginning, wherein n is 1,

X is oxy,

X₂ and X₃ are each a direct bond, and

R₄ is hydrogen.

X is oxy or thio,

X₂ and X₃ are each a direct bond, and

X and R₄ 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

wherein alkyl is alkyl, especially lower alkyl, and R is a group R_lt and Rj, R₂, R₄ and X₁ 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 R₅ is formyl to acid hydrolysis, for example in the presence of concentrated hydrochloric acid, to form the corresponding compound of formula V wherein R₅ 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. There are used, for example, 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. 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. The novel compounds of formula I can also be used in the form of parenterally administrable compositions or in the form of infusion solutions. 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. The pharmaceutical 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.

Pharmaceutical 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. They may, as necessary, comprise other pharmaceutical excipients, 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. 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 For the preparation of medica¬ ments in finished form, such a pharmaceutical composition is introduced into 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 In the preparation of the finished medicament form, it is also possible for 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. On average, 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. The expression "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.

The following Examples illustrate the invention; temperatures are given in degrees Celsius and pressures in mbar. Example 1 : (2R*.4S*)-2-benzyl- l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolyl- methoxy)-piperidine

26 mg (1.08 mmol) of sodium hydride washed with hexane are added at room temperature to a solution of 117 mg (0.27 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(trifluoromethyl)- benzoyl)-4-hydroxy-piperidine in 1 ml of N,N-dimethylformamide. After 15 minutes, 99 mg (0.327 mmol) of 4-bromomethylquinoline are added to the clear solution and the mixture is heated to 80°. After 2 hours, water is added and extraction is carried out with methylene chloride. The organic phases are dried over sodium sulfate and concentrated using a rotary evaporator. The title compound crystallises from diethyl ether. M.p.: 108-110°. TLC: methylene chloride/methanol/conc. ammonia (95:4.5:0.5) R_f= 0.48, FD-MS: M⁺= 572.

The starting compound therefor is prepared as follows:

a) N-(l-benzyl-but-3-en-l-yl)-carbamic acid benzyl ester

5.3 g (31 mmol) of chloroformic acid benzyl ester are added dropwise in the course of 1 hour to a vigorously stirred and ice-cooled suspension of 5.0 g (31 mmol) of 1-benzyl- but-3-en-l-ylamine (McCarty, F.J.; Rosenstock, P.D.; Paolini, J.D.; Micucci, D.D.; Ashton, L.; Bennetts, W.W.; Palopoli, F.P., J. Med. Chem. 11, 534(1968)) in 20 ml of methylene chloride and 20 ml of 10 % aqueous sodium hydrogen carbonate solution in such a manner that the temperature does not rise above 8°. 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.

M.p.: 47-48°. TLC: hexane/ethyl acetate (3:1) R_f= 0.60.

b) N-(l-benzyl-but-3-en-l-yl)-N-ethoxymethyl-carbamic acid benzyl ester

3.515 g (37.2 mmol) of chloromethyl ethyl ether are added in small portions in the course of 2 hours to a vigorously stirred suspension, cooled to 5°, of 8.8 g (30 mmol) of N-(l-benzyl-but-3-en-l-yl)-carbamic acid benzyl ester and 0.193 g (0.62 mmol) of benzyl- tributylammonium chloride in 5 ml of methylene chloride and 20 ml of 50 % aqueous sodium hydroxide solution. The mixture is then stirred vigorously for 6 hours at from 5° to 10° to complete the reaction, and then diluted with water and methylene chloride. The phases are separated and the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated using a rotary evaporator. 11 g of a liquid oil are obtained which are chromatographed on silica gel with ethyl acetate/hexane 1:10. 8.4 g (80 %) of the title compound are obtained. TLC: hexane/ethyl acetate (6:1) R_f=0.36.

^XH-NMR (200 MHz, chloroform): rotamer mixture, 7.45-7.02 (m, 10H), 5.87-5.60 (m, IH), 5.25-4.92 (m, 4H), 4.88-4.37 (m, 2H), 4.17-3.95 (m, IH), 3.55-2.85 (m, 4H), 2.85-2.25 (m, 2H), 1.20-1.00 (m, 3H).

c) (2R*,4S*)-2-benzyl-l-benzyloxycarbonyl-4-formyloxy-piperidine

8.4 g (23.7 mmol) of N-(l-benzyl-but-3-en-l-yl)-N-ethoxymethyl-carbamic acid benzyl ester are added dropwise in the course of 1 hour, at 5°, to 150 ml of 100 % formic acid. The reaction mixture is then stirred for 2 hours at 25° to complete the reaction. The reaction mixture is concentrated by evaporation using a rotary evaporator, and the residue is taken up in ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated by evaporation using a rotary evaporator. The product is chromatographed with ethyl acetate/hexane (1:3). The title compound (5.4 g, 64 %) is obtained in the form of a colourless oil. TLC: ethyl acetate hexane (1:3) R_f= 0.30, FD-MS: M⁺= 353.

d) (2R*,4S*)-2-benzyl-4-hvdroxy-piperidine

A suspension of 5.4 g (15.3 mmol) of (2R*,4S*)-2-benzyl-l-benzyloxycarbonyl-4-formyl- oxy-piperidine in 15 ml of 37 % hydrochloric acid is heated for 2 hours at 60°. The slightly yellow reaction mixture is cooled and then rendered basic with 5N sodium hydroxide solution, saturated with sodium chloride and extracted twice with methylene chloride. The combined organic phases are dried over potassium carbonate and concentra¬ ted using a rotary evaporator. The title compound crystallises from ethyl acetate methyl- ene chloride (2.0 g, 68 %) in the form of white crystals. M.p.: 124-126°. TLC: methylene chloride/methanol/conc. ammonia (180:19:1) R_f= 0.33, FD-MS: M⁺=191.

e) (2R*.4S*)-2-benzyl-l-(3.5-bis(trifluoromethyl)benzoyl)-4-hvdroxy-piperidine

2.16 g (7.8 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride are added dropwise in the course of 30 minutes to a vigorously stirred suspension, cooled to 5°, of 1.66 g (8.67 mmol) of (2R*,4S*)-2-benzyl-4-hydroxy-piperidine in 5 ml of methylene chloride and 10 ml of 10 % aqueous sodium hydrogen carbonate solution. The reaction is completed by stirring for 16 hours at room temperature. The phases are separated and the aqueous phase is extracted again with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concen¬ trated using a rotary evaporator. The residue crystallises from ethyl acetate/hexane to yield the title compound (2.92 g, 78 %) in the form of white crystals. M.ρ.: 93-96°, TLC: ethyl acetate/hexane (1:1) R_f= 0.3.

Example 2: (2R*,4S*)-quinoline-3-carboxylic acid ^r2-benzyl-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-vn ester

At 0°, 100 mg (0.44 mmol) of quinoline-3-carboxylic acid chloride-hydrochloride are added to a solution of 147 mg (0.34 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(trifluoro- methyl)benzoyl)-4-hydroxy-piperidine, 103 mg (1.02 mmol) of triethylamine and 9 mg (0.07 mmol) of N,N-dimethylaminopyridine in 2 ml of methylene chloride. After 5 minutes the ice bath is removed and the reaction mixture is stirred for 2 hours at room temperature. The mixture is washed once with 10 % citric acid and once with saturated sodium chloride solution and the organic phases are dried over sodium sulfate and concen¬ trated by evaporation using a rotary evaporator. The title compound crystallises from methylene chloride/diethyl ether in the form of white crystals. M.p.: 184°. TLC: methyl¬ ene chloride/ethyl acetate (1:1) R_f= 0.64, FD-MS: M⁺= 586.

Example 3: (2R*.4S*)-2-benzyl- l-(3.5-bistrifluoromethylbenzoyl)-4-(3-Quinolyl- methoxy)-piperidine

Analogously to Example 1, 117 mg (0.27 mmol) of (2R*,4S*)- 2-benzyl-l-(3,5-bis(tri- fluoromethyl)benzoyl)-4-hydroxy-piperidine in 1 ml of N,N-dimethylformamide are reacted with 26 mg (1.08 mmol) of sodium hydride and 99 mg (0.327 mmol) of 3-bromo- methylquinoline. The title compound crystallises from diethyl ether. M.p.: 157°. TLC: methylene chloride/methanol/conc. ammonia (190:9:1) R_f= 0.77, FD-MS: M⁺= 572.

Example 4: (2R*.4S*)-quinoline-4-carboxylic acid r2-benzyl-l-(3.5-bis(trifluoromethyl)- benzoyl)-piperidin-4-yll ester

Analogously to Example 2, 123 mg (0.28 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(tri- fluoromethyl)benzoyl)-4-hydroxy-piperidine, 86 mg (0.85 mmol) of triethylamine and 7 mg (0.06 mmol) of N,N-dimethylaminopyridine in 2 ml of methylene chloride are reacted with 84 mg (0.37 mmol) of quinoline-4-carboxylic acid chloride-hydrochloride. The crude product is chromatographed on silica gel with methylene chloride/ethyl acetate (4:1). The title compound is obtained in the form of a colourless foam. TLC: methylene chloride/ethyl acetate (4:1) R_f= 0.56, FD-MS: M⁺= 586. C31H24F6N2O3, calculated: C 63.48 %, H 4.12 %, N 4.78 %; found: C 63.32 , H 4.23 %, N 4.67 %.

Example 5: (2R S*)-3.5-dimethoχyphenylacetic acid r2-benzyl-l-(3.5-bis(trifluoro- methyl)benzoyl)-piperidin-4-vIl ester

CH₃O

Analogously to Example 2, 147 mg (0.34 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(tri- fluoromethyl)benzoyl)-4-hydroxy-piperidine, 103 mg (1.02 mmol) of triethylamine and 9 mg (0.07 mmol) of NJM-dimethylaminopyridine in 2 ml of methylene chloride are reacted with 94 mg (0.44 mmol) of 3,5-dimethoxyphenylacetic acid chloride. The title compound is obtained in the form of an oil. TLC: methylene chloride/ethyl acetate (10:1) R_f= 0.63, DCI-MS: M⁺= 609.

Example 6: (2R*.4S*)-2-benzyl- l-(3.5-bistrifluoromethylbenzoyl)-4-(N-phenylcarbam- oyloxy)-piperidine

149 mg (1.2 mmol) of phenyl isocyanate and 30 mg (0.25 mmol) of 4-dimethylamino- pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis- (trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 4 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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.

Exam^ple 7: (2R*.4S*)-2-benzyl-l-(3.5-bistrifluoromethylbenzoyl)-4-rN-(l-naphthyl)carb- amoyloxyl-piperidine

200 mg (1.2 mmol) of 1 -naphthyl isocyanate and 30 mg (0.23 mmol) of 4-dimethyl- amino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)-2-benzyl- l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 4 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. The mixture is washed once with water and three times 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 chromatographed on silica gel (hexane/ethyl acetate 7:3). The title compound is obtained in the form of crystals. M.p.: 90-100°.

Example 8: (2R*.4S*)-2-benzyl-l-(3.5-bis fluoromethylbenzoyl)-4-rN-(3-trifluoro- methylphenvDcarbamoyloxyl-piperidine

220 mg (1.2 mmol) of 3-trifluoromethylphenyl isocyanate and 30 mg (0.23 mmol) of 4-dimethylamino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)- 2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 4.5 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. The mixture is washed once with water and once with sodium chloride solution, and the organic phases are dried over sodium sulfate and concentrated by evaporation using a rotary evaporator. The crude product is chromatographed on silica gel (hexane/ethyl acetate 7:3). The title compound is obtained in the form of crystals. M.p.: 80-90°. Example 9: (2R*.4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-rN-(2.4-difluoro- difluorophenvDcarbamoyloxyl-piperidine

290 mg (1.2 mmol) of 2,4-difluorophenyl isocyanate and 30 mg (0.23 mmol) of 4-dimethylamino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)- 2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 4 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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 chromatographed on silica gel (hexane/ethyl acetate 9:1). The title compound is obtained in the form of crystals. M.p.: 80-90°.

Example 10: (2R*.4S*)-2-benzyl- l-(3.5-bistrifluoromethylbenzoyl)-4-(N-cvclohexylcarb- amoyloxy)-piperidine

150 mg (1.2 mmol) of cyclohexyl isocyanate and 90 mg (0.69 mmol) of 4-dimethyl- amino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)-2-benzyl- l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 26 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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 chromatographed on silica gel (hexane/ethyl acetate 7:3). The title compound is obtained in the form of crystals. M.p.: 65-68°.

Example 11: (2R*.4S*)-2-benzyl-l-(3.5-bistrifluoromethylbenzoyl)-4-rN-(3-methoxy)- phenyDcarbamoyloxyl-piperidine

90 mg (0.6 mmol) of 3-methoxyphenyl isocyanate and 15 mg (0.12 mmol) of 4-dimethyl- amino-pyridine are added to a solution of 250 mg (0.6 mmol) of (2R*,4S*)-2-benzyl- l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 10 ml of toluene and the reaction mixture is stirred for 5 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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 chromatographed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of crystals. M.p.: 140-142°. Example 12: (2S*.4R*.rR)-2-benzyl-l-(3.5-bistrifluoromethylbenzoyl)-4-(N-r2-(l- naphthyDethvncarbamoyloxy ) -piperidine

230 mg (1.2 mmol) of (R)-l-naphthyl-ethyl isocyanate and 30 mg (0.23 mmol) of 4-dimethylamino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)- 2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 24 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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 chromatographed on silica gel (toluene/ethyl acetate 98:2). The title compound is obtained in the form of crystals. M.p.: 85-90°.

Example 13: (2R*,4S*.l^,R)-2-benzyl-l-(3.5-bistrifluoromethylbenzoyl)-4-(N-r2-(l- naphthvDethvHcarbamoyloxy } -piperidine

Example 14: (2R*.4S*)-2-benzyl-l-(3.5-bistrifluoromethylbenzoyl)-4-rN-(4-phenoxy)- phenvDcarbamoyloxyl-piperidine

250 mg (1.2 mmol) of 4-phenoxyphenyl is Iocyanate and 30 mg (0.23 mmol) of 4-dimethyl- amino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)-2-benzyl- l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 4 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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 chromatographed on silica gel (hexane/ethyl acetate 7:3) and the title compound is obtained in the form of a foam. Example 15: (2R*.4S*)-2-benzyl- l-(3.5-bistrifluoromethylbenzoyl)-4-rN-(4-isopropyl- oxy)phenyl)carbamoyloxyl-piperidine

500 mg (2.8 mmol) of 4-isopropoxyphenyl isocyanate and 30 mg (1.2 mmol) of 4-di- methylamino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)- 2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 20 ml toluene and the reaction mixture is stirred for 4 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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 chromatographed on silica gel (hexane/ethyl acetate 9:1). The title compound is obtained in the form of crystals. M.p.: 80-87°.

Example 16: (2R*,4S *)-2-benzyl- l-(3.5-bistrifluoromethylbenzoyl)-4-rN-(3-isopropyl- oxy-phenyl)carbamoyloxy1-piperidine

500 mg (2.8 mmol) of 3-isopropoxyphenyl isocyanate and 30 mg (1.2 mmol) of 4-di- methylamino-pyridine are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)- 2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)-4-hydroxy-piperidine in 15 ml of toluene and the reaction mixture is stirred for 4 hours at 80°. The resulting solution is cooled to room temperature and taken up in ethyl acetate. 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 chromatographed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of crystals. M.p.: 137-140°.

Example 17: (2R*.4S*)-2-benzyl-l-(3.5-bistrifluoromethvIbenzoyl)-4-rN-(l-naphthyl)- thiocarbamoyloxyl-piperidine

Under argon, 135 mg (1.2 mmol) of potassium tert-butanolate are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)- 4-hydroxy-piperidine in 10 ml of toluene. The resulting yellowish solution is stirred for 30 minutes at room temperature and then 220 mg (1.2 mmol) of 1 -naphthyl isothiocyanate are added thereto. After 2 hours, 10 ml of water are added dropwise to the reaction solution which is then rendered acidic with 2 ml of IN hydrochloric acid solution. Ethyl acetate is added and the organic phase is then washed once with water and twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evapor¬ ation using a rotary evaporator. The crude product is chromatographed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of crystals. M.p.: 164-167°. Examρle l8: (2R*.4S*)-2-benzyl-l-(3.5-bistrifluoromethylbenzoyl)-4-rN-(4-ρhenoxy- phenvDthiocarbamoyloxyl-piperidine

Under argon, 140 mg (1.2 mmol) of potassium tert-butanolate are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)- 4-hydroxy-piperidine in 10 ml of toluene. The resulting yellowish solution is stirred for 30 minutes at room temperature and then 270 mg (1.2 mmol) of 4-phenoxy-phenyl isothio¬ cyanate are added thereto. After 3 hours, the 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°.

Example 19: (2R S*)-2-benzyl- l-(3,5-bistrifluoromemylbenzoylV4-PN-(4-ethoxy- carbonylphenyDthiocarbamoyloxyl-piperidine

Under argon, 135 mg (1.2 mmol) of potassium tert-butanolate are added to a solution of 500 mg (1.2 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)- 4-hydroxy-piperidine in 10 ml of toluene. The resulting yellowish solution is stirred for 30 minutes at room temperature and then 250 mg (1.2 mmol) of 4-ethoxycarbonyl-phenyl isothiocyanate are added thereto. After 3 hours, the 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°.

Example 20: (2R*,4S*)-phenylacetic acid r2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)- piperidin-4-yll ester

Analogously to Example 2, 149 mg (0.34 mmol) of (2R*,4S*)-2-benzyl-l-(3,5-bis(tri- fluoromethyl)benzoyl)-4-hydroxy-piperidine, 105 mg (1.04 mmol) of triethylamine and 9 mg (0.07 mmol) of N,N-dimethylaminopyridine in 2 ml of methylene chloride are reacted with 64 mg (0.42 mmol) of phenylacetic acid chloride. The title compound is obtained in the form of an oil. TLC: toluene/ethyl acetate (10:1) R = 0.2, FD-MS: M⁺= 549. Example 21: (2R*.4S*)-2-(4-chlorobenzyl)-l-(3.5-dimethylbenzoyl)-4-formyloxy-piperid- ine

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 Na₂SO and concentrated by evaporation under reduced pressure. Chromatography on silica gel with ethyl acetate/- hexane (1:4) as eluant yields 160 mg (23 %) of the title compound in the form of a colour¬ less oil; TLC (ethyl acetate/hexane: 1:3): R_f = 0.30; MS: 385 (M⁺).

The starting materials can be prepared as follows:

a) N-[ l-(4-chlorobenzyl)-but-3-envn-3.5-dimethyl-benzamide

In the course of 2 hours, 4.3 g (25.6 mmol) of 3,5-dimethylbenzoyl chloride are added to a solution, stirred at 0°, of 5.0 g (25.6 mmol) of l-(4-chloro)phenyl-pent-4-en-2-ylamine and 5.33 ml (38.4 mmol) of triethylamine in 100 ml βf dichloromethane. The reaction mixture is then stirred for a further 1 hour, IN hydrochloric acid is added thereto and extraction is carried out with dichloromethane. The organic phase is washed neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evapor¬ ation under reduced pressure. The crude product is crystallised from ethyl acetate/hexane and yields 7.36 g (88 %) of white crystals; m.p.: 116-118°; TLC (hexane/ethyl acetate; 3:1): R_f = 0.37

b) N-ri-(4-chlorobenzyl)-but-3-enyll-N-ethoxyethyl-3,5-dimethyl-benzamide

In the course of 2 hours, at 0-5°, 2.36 ml (25.2 mmol) of chloromethyl ethyl ether are added in small portions to a vigorously stirred solution of 5.5 g (16.8 mmol) of N-[l-(4-chlorobenzyl)-but-3-enyl]-3,5-dimethyl-benzamide and 100 mg of benzyltributyl- ammonium chloride in 15 ml of 50 % aqueous sodium hydroxide solution and 15 ml of dichloromethane. The organic phase is taken up in dichloromethane and water, and the organic phase is separated off, dried over sodium sulfate and concentrated to dryness by evaporation under reduced pressure. The oily residue is purified by chromatography on silica gel with ethyl acetate hexane (1:4) as eluant and yields 2.42 g (37 %) of the title compound in the form of a colourless oil; TLC (ethyl acetate/hexane; 1:3): R = 0.41; tø-NMR (300 MHz, chloroform): mixture of rotamers, d = 7.31-7.18 (m, 4H), 7.04-6.85 (m, 2.6H), 6.42 (br, s, 0.4H), 5.92-5.60 (m, IH), 5.20-5.02 (m, 2H), 4.54-4.24 (m, 2H), 3.96-3.67 (m, IH), 3.25-2.40 (m, 6H), 2.28 (s, approx. 5H), 2.24 (s, approx. IH), 1.34-1.21 (m, approx. 0.5H), 1.08 (t J = 7, approx. 2.5H).

Example 22: (2R S*)-r2-benzyl-l-(3.5-bistrifluoromemylbenzoyl)-piperidin-4-yl1 thio- ether

85 mg (1.96 mmol) of a 55 % suspension of sodium hydride in mineral oil are added to a solution of 607 mg (4.89 mmol) of benzylmercaptan in 5 ml of dimethyl sulfoxide. The reaction mixture is allowed to react for 15 minutes at room temperature and then, in the course of 2 hours, with stirring, a solution of 498 mg of 2-benzyl-l-(3,5-bistrifluoro- methylbenzoyl)-4-sulfonyloxy-piperidine in 2 ml of dimethyl sulfoxide is added dropwise thereto. The 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 title compound is obtained in the form of an oil; TLC (hexane/ethyl acetate, 5:1) R_f = 0.23; FD-MS: M⁺ = 517.

The starting material can be prepared, for example, as follows: a) 2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-hvdroxy-piperidine

Analogously to Example le), 280 mg (1.46 mmol) of 2-benzyl-piperidin-4-ol in 2 ml of methylene chloride and 4 ml of 10 % aqueous sodium hydrogen carbonate solution are reacted with 366 mg (1.33 mmol) of 3,5-bistrifluoromethylbenzoyl chloride. The title compound is obtained in the form of an oil.

b) 2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-sulfonyloxy-piperidine

While cooling with ice, 0.20 ml (2.6 mmol) of methanesulfonic acid chloride is added dropwise to a solution of 560 mg (1.30 mmol) of 2-benzyl-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-ol in 3 ml of pyridine. The reaction mixture is then stirred for 30 minutes at 0° and for 2 hours at room temperature, concentrated using a rotary evapor¬ ator and taken up in ethyl acetate. The title compound is obtained after washing with water and saturated sodium chloride solution, drying over magnesium sulfate and further concentration by evaporation using a rotary evaporator.

Example 23: In a manner analogous to that described in Examples 1 to 22 it is also possible to prepare:

(2R*,4S*)-2-(4-nitrobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(2,4-dichlorobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(3,4-dichlorobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-methoxybenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(2,4-dimethoxybenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-carboxybenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-nitrobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperidine; (2R*,4S*)-2-(2,4-dichlorobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperid- ine;

(2R*,4S*)-2-(3,4-dichlorobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperid- ine;

(2R*,4S*)-2-(4-methoxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperid- ine;

(2R*,4S*)-2-(2,4-dimethoxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy- piperidine;

(2R*,4S*)-2-(4-carboxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperid- ine;

(2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy- piperidine;

(2R*,4S*)-2-(4-nitrobenzyl)-l-(3,5-bistrifluoromemylr>enzoyl)-4-(4-quinolinylmethoxy)- piperidine;

(2R*,4S*)-2-(2,4-dicMorobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(3,4-dicMorobenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(4^uinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-memoxybenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(2,4-dimethoxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-carboxybenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine; (2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-nifrobenzyl)-l-(3,5-bistrifluorome ylbenzoyl)-4-(3-qumolinylmethoxy)- piperidine;

(2R*,4S*)-2-(2,4-dicMororjenzyl)-l-(3,5-bistrmuoromemylbenzoyl)-4-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(3,4-dicWorobenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-memoxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(2,4-dimethoxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-3-(3-quinolinyl- methoxy)-ρiperidine;

(2R*,4S*)-2-(4-carboxyber yl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(3-qumolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(3-qumo--inyl- methoxy)-piperidine;

(2R*,4S*)-quinoline-3-carboxyUc acid [2-(4-nitrobenzyl)-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(2,4-dichlorobenzyl)- l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(3,4-dichlorobenzyl)- l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(4-methoxybenzyl)-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester; (2R*,4S*)-quinoline-3-carboxylic acid [2-(2,4-dimethoxybenzyl)- l-(3,5-bistrifluoro- methylbenzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(4-carboxybenzyl)- l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(4-carboxamidobenzyl)- l-(3,5-bistrifluoro- methylbenzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(4-nitrobenzyl)- l-(3,5-bistrifluoromethyl)- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(2,4-dichlorobenzyl)- l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester,

(2R*,4S*)-quinoline-4-carboxylic acid [2-(3,4-dichlorobenzyl)- l-(3,5-bist-rifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-qu--noline-4-carboxyUc acid [2-(4-methoxybenzyl)-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(2,4-dimethoxybenzyl)- l-(3,5-bistrifluoro- methylbenzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(4-carboxybenzyl)- l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(4-carboxamidobenzyl)- l-(3,5-bistrifluoro- methylbenzoyl)-piperidin-4-yl] ester;

(2R*,4S*)- l-methyl-2-indolecarboxylic acid [2-benzyl-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-3,5-dimethoxyphenylacetic acid [2-benzyl- l-(3,5-dimethylbenzoyl)-piperidin- 4-yl] ester; (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(N-benzylcarbamoyloxy)-piper- idine;

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(3-cyanophenyl)carbamoyl- oxy]-piperidine;

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(N-heptyl)carbamoyloxy)-piper- idine;

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(N-diisopropylcarbamoyloxy)- piperidine;

(2R*,4S*)-[2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-piperidin-4-yloxycarbonyl- amino]-acetic acid ethyl ester,

(2R*,4S*)-[2-ben-^l-l-(3,5-bistrifluoromemylbenzoyl 4-[N-ethoxycarbonylcarbamoyl- oxy] -piperidine;

(2R*,4S*)-[2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-ethoxycarbonylthio- carbamoyloxy] -piperidine;

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluorome ylbenzoyl)-4-(4-quinolylmethylthio)-piperid- ine and

(2R*,4S*)-2-benzyl-l-(3,5-b-«trifluoromethylbenzoyl)-4-(3-quinolylmethylthio)-piperid- ine.

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)

active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silicon dioxide (highly dispersed) 20.0 g ethanol q.s.

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)

active ingredient 100.0 g lactose 100.0 g maize starch 70.0 g talc 8.5 g calcium stearate 1.5 g hydroxypropyl methylcellulose 2.36 g shellac 0.64 g water q.s. methylene chloride q.s.

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.

Example 26: Nasal spray:

500 mg of finely ground powder (<5.0 μm) 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.

Claims

What is claimed is:

1. A novel 1,2,4-trisubstituted piperidine compound of formula I

wherein

Ri is an unsubstituted or substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, hetero¬ aroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or aryl¬ carbamoyl radical, or is the acyl radical of an α-amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₄ is hydrogen, alkyl or aryl,

X is oxy or thio,

X_I is methylene, ethylene, a direct bond, a free or ketalised carbonyl group or a free or etherified hydroxymethylene group,

X₂ is lower alkylene, imino that is unsubstituted or substituted by lower alkyl or by cycloalkyl, or a direct bond, X₃ is lower alkylene or a direct bond, X₄ is oxo or thioxo and n is 1 or, when X₂ is lower alkylene and X₃ is a direct bond, n is 0, or a salt thereof.

2. A compound according to claim 1 of formula I wherein

R_x 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 alkoxy, hydroxy, di-lower alkyl¬ amino, halogen, cyano and/or by trifluoromethyl; a phenyl- or diphenyl-lower alkan¬ oyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; a heteroaryl- lower alkanoyl radical containing as heteroaryl radical 6-membered monocyclic aza¬ heteroaryl or bi- or tri-cyclic azaheteroaryl consisting of a 6-membered and one or two 5- or 6-membered ring(s); a phenyl-lower alkoxycarbonyl or N-phenylcarbamoyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; or the acyl radical of an α-amino acid that occurs naturally as a peptide building block and that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₃ 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, X₂ is unsubstituted or lower alkyl- or cycloalkyl-substituted imino and X₃ is lower alkylene, R₃ is lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl,

R 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,

Xi 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;

X₃ is lower alkylene or a direct bond;

X₄ is oxo or thioxo, and n is 1 or, when X₂ is lower alkylene and X₃ is a direct bond, n is 0, or a salt thereof.

3. A compound according to claim 1 of formula I wherein

R_j 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 alkoxy, hydroxy, di-lower alkyl¬ amino, halogen, cyano and/or by trifluoromethyl; a phenyl- or diphenyl-lower alkan¬ oyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; a heteroaryl- lower alkanoyl radical containing as heteroaryl radical 6-membered monocyclic aza¬ heteroaryl or bi- or tri-cyclic azaheteroaryl consisting of a 6-membered and one or two 5- or 6-membered ring(s); a phenyl-lower alkoxycarbonyl or N-phenylcarbamoyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; or a group of formula Ia

— C -CH- NH- Re (la)

O wherein

R₅ is hydrogen, or C₁-C₄alkyl that is unsubstituted or substituted by hydroxy, mercapto, amino, unsubstituted or hydroxy-substituted phenyl, carboxy, carbamoyl or by ureido, and

R₆ is C₂-C₇alkanoyl,

R₂ 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,

R₃ 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 unsubstituted or N-substituted by lower alkanol, X is oxy or thio, X_j 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, X₂ 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, X₃ is a direct bond, X₄ is oxo, and n is 1 or, when X₂ is a lower alkylene radical, n is 0, or a salt thereof.

4. A compound according to claim 1 of formula I wherein

Ri is benzoyl that is unsubstituted or substituted by C₁-C₄alkyl, - alkoxy, di- C_rC₄alkylamino, halogen and/or by trifluoromethyl, or is unsubstituted naphthoyl,

R₂ is phenyl that is unsubstituted or substituted by C₁-C₄alkyl, C₁-C₄alkoxy, halogen, cyano, nitro, carboxy, carbamoyl and/or by trifluoromethyl,

R₃ is phenyl or naphthyl that is unsubstituted or substituted by C alkyl, C_rC₄alkoxy, phenoxy, halogen, carboxy, C₁-C₄alkoxycarbonyl, carbamoyl, cyano and/or by tri¬ fluoromethyl, or is unsubstituted pyridyl, benzofuranyl, unsubstituted or C_j-Qalkyl- N-substituted indolyl or 2,3-dihydroindolyl, benzimidazolyl, quinolyl or 1,2,3,4-tetra- hydroquinolinyl, or, when n is 1, X₂ is imino that is unsubstituted or substituted by C_rC₄alkyl and X₃ is C C₄alkylene, R₃ is C_rC₇alkyl, carboxy, C_rC₄alkoxycarbonyl or carbamoyl,

R₄ is hydrogen or Cj- alkyl,

X is oxy or thio,

X_I is methylene,

X₂ is C₁-C₄alkylene, imino, C₁-C₄alkylimino or a direct bond,

X₃ is Cj-Qalkylene or a direct bond,

X₄ is oxo or thioxo, and n is 1 or, when X₂ is C_rC₄alkylene and X₃ is a direct bond, n is 0, or a salt thereof.

5. A compound according to claim 1 of formula I wherein

Rj is benzoyl that is unsubstituted or substituted by C_rC₄alkyl, C_rC₄alkoxy, di- C₁-C alkylamino, halogen and/or by trifluoromethyl, R₂ is phenyl that is unsubstituted or substituted by C C alkyl, C C₄alkoxy, halogen, cyano, nitro, carboxy, carbamoyl and/or by trifluoromethyl, R₃ is indolyl that is unsubstituted or N-substituted by C_rC₄alkyl, or is unsubstituted quinolyl or 1,2,3,4-tetrahydroquinolinyl, R is hydrogen,

X is oxy,

X_I is methylene,

X₂ is C₁-C₄alkylene, imino or a direct bond,

X₃ is methylene or a direct bond,

X₄ is oxo or thioxo, and n is 1 or, when X₂ is C₁-C₄alkylene and X₃ is a direct bond, n is 0, or a salt thereof.

6. A compound according to claim 3 of formula I wherein

R_x is benzoyl that is unsubstituted or substituted by C₁-C₄alkyl, C₁-C₄alkoxy, di-

C₁-C alkylamino, halogen and/or by trifluoromethyl, R₂ is phenyl that is unsubstituted or substituted by C₁-C₄alkyl, C₁-C₄alkoxy, halogen, cyano, nitro and/or by trifluoromethyl, R₃ is unsubstituted quinolyl or 1,2,3,4-tetrahydroquinolinyl, R₄ is hydrogen,

X is oxy or thio,

X_I is methylene,

X₂ is C_rC₄alkylene, imino or a direct bond,

X₃ is a direct bond,

X₄ is oxo, and n is 1 or, when X₂ is C_rC₄alkylene, n is 0, or a salt thereof.

7. (2R*,4S*)-2-benzyl-l-(3,5-bist-rffluoromemylbenzoyl)-4-(4-quinolylmethoxy)-piperid- ine or a salt thereof.

8. (2R*,4S*)-quinoline-3-carboxylic acid [2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)- piperidin-4-yl] ester or a salt thereof.

9. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolylmethoxy)-piperid- ine or a salt thereof.

10. (2R*,4S*)-quinoline-4-carboxylic acid [2-benzyl-l-(3,5-bis(trifluoromethyl)benzoyl)- piperidin-4-yl] ester or a salt thereof.

11. (2R*,4S*)-3,5-dimethoxyphenylacetic acid [2-benzyl-l-(3,5-bis(trifluoromethyl)- benzoyl)-piperidin-4-yl] ester or a salt thereof.

12. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(N-phenylcarbamoyloxy)- piperidine or a salt thereof.

13. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(l-naphthyl)carbamoyl- oxy] -piperidine or a salt thereof.

14. (2R*,4S*)-2-benzyl-l-(3,5-bistr uoromethylbenzoyl)-4-[N-(3-trifluoromethyl- phenyl)carbamoyloxy] -piperidine or a salt thereof.

15. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(2,4-difluoroρhenyl)- carbamoyloxy] -piperidine or a salt thereof.

16. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(N-cyclohexylcarbamoyl- oxy)-piperidine or a salt thereof.

17. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(3-methoxy)-phenyl)- carbamoyloxy]-piperidine or a salt thereof.

18. (2S*,4R*,l'R)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-{N-[2-(l-naphthyl)- ethyl]carbamoyloxy} -piperidine or a salt thereof.

19. (2R*,4S*,l'R)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-{N-[2-(l-naphthyl)- ethyl]carbamoyloxy } -piperidine or a salt thereof.

20. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(4-phenoxy)phenyl)- carbamoyloxy] -piperidine or a salt thereof.

21. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(4-isopropyloxy)phenyl)- carbamoyloxyl-piperidine or a salt thereof.

22. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(3-isopropyloxy-phenyl)- carbamoyloxy]-piperidine or a salt thereof.

23. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(l-naphthyl)thiocarbam- oyloxy]-piperidine or a salt thereof.

24. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(4-phenoxyphenyl)thio- carbamoyloxy]-piperidine or a salt thereof.

25. (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-(4-ethoxycarbonyl- phenyl)thiocarbamoyloxy]-piperidine or a salt thereof.

26. (2R*,4S*)-phenylacetic acid [2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-piperidin-4- yl] ester or a salt thereof.

27. (2R*,4S*)-[2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-piperidin-4-yl]-thioether or a salt thereof.

28. (2R*,4S*)-2-(4-nitrobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(2,4-dicMorobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(3,4-dicMorobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-methoxybenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-carboxybenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-carboxyben-^l)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperid- ine;

(2R*,4S*)-2-(4-nitrobenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(4-quinolinylmethoxy)- piperidine;

(2R*,4S*)-2-(2,4-dicMororen-^l)-l-(3,5-bistrifluorome ylbenzoyl)-4-(4^uinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(3,4-dicMorobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-memoxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-carboxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine; (2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(4-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-nifrobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolinylmethoxy)- piperidine;

(2R*,4S*)-2-(2,4-dicWorobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(3,4-dichlorobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-memoxybenzyl)-l-(3,5-bi-5trifluoromemylbenzoyl)-4-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(2,4-dimemoxybenzyl)-l-(3,5-bistrmuoromemylbenzoyl)-3-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-carboxybenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolinyl- methoxy)-piperidine;

(2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-bistrifluoromemylbenzoyl)-4-(3-qumolinyl- methoxy)-piperidine;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(4-nitrobenzyl)-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(3,4-dichlorobenzyl)-l-(3 ,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-3-carboxylic acid [2-(4-methoxybenzyl)-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester; (2R*,4S*)-quinoline-3-carboxylic acid [2-(2,4-dimethoxybenzyl)-l-(3,5-bistrifluoro- methylbenzoyl)-piperidin-4-yl]-ester,

(2R*,4S*)-quinoline-3-carboxylic acid [2-(4-carboxamidobenzyl)-l-( 3,5-bistrifluoro- methylbenzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinol--ne-4-carboxyUc acid [2-(2,4-dichlorobenzyl)-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(3,4-dichlorobenzyl)- l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(4-methoxybenzyl)-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-quinoline-4-carboxylic acid [2-(2,4-dimethoxybenzyl)-l-( 3,5-bistrifluoro- methylbenzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-l-methyl-2-indolecarboxylic acid [2-benzyl-l-(3,5-bistrifluoromethyl- benzoyl)-piperidin-4-yl] ester;

(2R*,4S*)-3,5-dimethoxyphenylacetic acid [2-benzyl-l-(3,5-dimethylbenzoyl)-piperidin- 4-yl] ester; (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(N-benzylcarbamoyloxy)-piper- idine;

(2R*,4S*)-[2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-piperidin-4-yloxycarbonyl- amino] -acetic acid ethyl ester;

(2R*,4S*)-[2-benzyl-l-(3,5-bi-strifluoromemylbenzoyl)-4-|N-ethoxycarbonylcarbamoyl- oxy]-piperidine;

(2R*,4S*)-[2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-[N-ethoxycarbonylthiocarbam- oyloxy]-piperidine;

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromemylbenzoyl)-4-(4-quinolylmethylthio)-piperid- ine

or

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolylmethylthio)-piperid- ine

or a salt thereof in each case.

29. A compound according to any one of claims 1 to 28 for use in a method for the thera¬ peutic treatment of the human or animal body.

30. A pharmaceutical composition comprising as pharmaceutical active ingredient, in addition to customary pharmaceutical excipients, a compound according to any one of claims 1 to 29 in free form or in the form of a pharmaceutically acceptable salt

31. A pharmaceutical composition comprising as pharmaceutical active ingredient, in addition to customary pharmaceutical excipients, a compound according to any one of claims 3 and 6 to 11 in free form or in the form of a pharmaceutically acceptable salt

32. A process for the preparation of a novel 1,2,4-trisubstituted piperidine compound of formula I

wherein

Ri is an unsubstituted or substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, hetero¬ aroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycaitonyl or aryl¬ carbamoyl radical, or is the acyl radical of an α-amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₄ is hydrogen or alkyl,

X is oxy or thio,

X₃ is lower alkylene or a direct bond,

X₄ is oxo or thioxo and n is 1 or, when X₂ is lower alkylene and X₃ is a direct bond, n is 0, or a salt thereof, which process comprises

a) condensing with one another compounds of formulae π and IH X₂- X₃- R₃ (m),

wherein

R_lf R₂, R₃, R₄, X_j, X₂, X₃, X₄ and n are as defined and one of the radicals Y_j and Y₂ 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

Rj, R₂, R₃, R₄, X_lt X₂, X₃ and X₄ are as defined,

Y_l is hydroxy esterified by a carboxylic acid,

Y₂ is hydroxy that is free or etherified or in the form of a salt, and n is 1, or

b) introducing the radical Rj into a compound of formula IV

wherein

R₂, R₃, R₄, X, X_j, X₂, X₃ 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.

33. A method for the prophylactic and therapeutic treatment of diseases in which compound P plays an essential role, which method comprises administering to a warm¬ blooded animal requiring treatment a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to either claim 29 or claim 30.

34. A method of treatment according to claim 33 for the treatment of painful conditions, migraines, disorders of the central nervous system, certain motor disorders, inflammatory diseases, diseases of the respiratory organs, diseases of the gastrointestinal system, vomiting and/or hypertension, which method comprises administering to a warm-blooded animal requiring treatment a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to either claim 29 or claim 30.

35. The use of a compound according to any one of claims 1 to 28 in a method for the treatment of diseases in which compound P plays an essential role, or in the manufacture of a medicament intended therefor.

36. A compound of formula V

wherein

R₄ is hydrogen or alkyl,

R₅ is hydrogen, formyl or carbamoyl,

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, or a salt thereof.

37. A compound according to claim 36 of formula V 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 alkoxy, hydroxy, di-lower alkyl¬ amino, halogen, cyano and/or by trifluoromethyl; a phenyl- or diphenyl-lower alkan¬ oyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; a heteroaryl- lower alkanoyl radical containing as heteroaryl radical 6-membered monocyclic aza¬ heteroaryl or bi- or tri-cyclic azaheteroaryl consisting of a 6-membered and one or two 5- or 6-membered ring(s); a phenyl-lower alkoxycarbonyl or N-phenylcarbamoyl radical that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, di-lower alkylamino, halogen and/or by trifluoromethyl; or the acyl radical of an α-amino acid that occurs naturally as a peptide building block and that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₄ is hydrogen or alkyl,

R₅ is hydrogen or formyl,

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 a direct bond, or a salt thereof.

38. A compound according to claim 36 of formulae He and Hd

wherein

R_j is benzoyl that is unsubstituted or substituted by C C₄alkyl, Cj-C₄alkoxy, di- Cj- alkylamino, halogen and/or by trifluoromethyl, or is unsubstituted naphthoyl, R₂ is phenyl that is unsubstituted or substituted by C_rC₄alkyl, C_rC₄alkoxy, halogen, cyano, nitro, carboxy, carbamoyl and/or by trifluoromethyl, R₄ is hydrogen or alkyl, R₅ is hydrogen or formyl, and Xj is methylene, or a salt thereof.

39. A compound according to claim 36 of formulae D-b and He wherein

R is benzoyl that is unsubstituted or substituted by C_rC₄alkyl, C₁-C₄alkoxy, di-

C_rC₄alkylamino, halogen and/or by trifluoromethyl, R₂ is phenyl that is unsubstituted or substituted by C₁-C₄alkyl, Cx-Qalkoxy, halogen, cyano, nitro, carboxy, carbamoyl and/or by trifluoromethyl, R₄ is hydrogen, R₅ is hydrogen or formyl, and X_x is methylene, or a salt thereof.

40. (2R*,4S*)-2-(4-chlorobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine or a salt thereof.

41. (2R*,4S*)-2-benzyl-l-(3^-bistrifluoromethylbenzoyl)-4-hydroxy-piperidine or a salt thereof.

42. (2R*,4S*)-2-(4-nitrobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-methoxybenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-carboxybenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-dimethylbenzoyl)-4-formyloxy-piperidine; (2R*,4S*)-2-(4-nitrobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperidine;

(2R*,4S*)-2-(2,4-dichlorobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy-piperid- ine;

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(l-heptyl)-4-carbamoyloxy- piperidine;

(2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbeήzoyl)-4-(l-heptyl)-carbamoyloxy-piper- idine or

(2R*,4S*)-2-(4-carboxamidobenzyl)-l-(3,5-bistrifluoromethylbenzoyl)-4-formyloxy- piperidine

or a salt thereof in each case.

43. A process for the preparation of a compound of formula V

wherein R_x is an unsubstituted or substituted aralkyl, aryloxyalkyl, heteroaralkyl, aroyl, hetero¬ aroyl, cycloalkylcarbonyl, aralkanoyl, heteroaiylalkanoyl, aralkoxycarbonyl or aryl¬ carbamoyl radical, or is the acyl radical of an α-amino acid that is unsubstituted or N-substituted by lower alkanoyl or by carbamoyl-lower alkanoyl,

R₄ is hydrogen or alkyl, and

R₅ is hydrogen, formyl or carbamoyl,

X is oxy, and

Xj is methylene, ethylene, a direct bond, a free or ketalised carbonyl group or a free or etherified hydroxymethylene group, or a salt thereof, which process comprises subjecting a compound of formula lib

wherein alkyl is alkyl, especially lower alkyl, and

R is a group R_lr and

R_x, R₂, R₄ and X_! are each as defined for compounds of formula I, to intramolecular condensation and subjecting the resulting compound of formula V wherein R₅ is formyl to acid hydrolysis to form the corresponding compound of formula V wherein R₅ is hydrogen.

44. The use of a compound according to any one of claims 36 to 40 as an intermediate in the preparation of compounds of formula I according to any one of claims 1 to 29.