MXPA97002092A

MXPA97002092A - Compounds of 1-acil-4-alifatilaminopiperid

Info

Publication number: MXPA97002092A
Application number: MXPA/A/1997/002092A
Authority: MX
Inventors: Ofner Silvio; Jacob Veenstra Siem
Original assignee: Cibageigy Ag; Ofner Silvio; Jacob Veenstra Siem
Priority date: 1994-09-30
Filing date: 1997-03-19
Publication date: 1998-07-03

Abstract

The invention relates to novel 1-acyl-4-aliphatilaminopiperidine compounds of the formula I: wherein R 1 is a benzoyl, naphthoyl, or cycloalkanoyl radical which is unsubstituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl; cycloalkyl or a phenyl or naphthyl radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R4 are together lower alkylene or aza-, oxa-, or thia-lower alkylene; or R3 is lower alkyl, lower alkoxy-lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) nC (= O) -R5 (Ia); and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) nC (= O) -R5 (Ia); R5 is (i) hydrogen, alkyl, or alkyl that is substituted by halogen, lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono - or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, (ii) hydroxyl, cycloalkoxy, lower alkoxy, or lower alkoxy which is substituted by lower alkoxy which is substituted by lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, or (iii) amino, or amino substituted by lower alkyl , cycloalkyl, lower aminoalkyl, mono- or di-lower alkyl, lower alkoxycarbonyl, or lower alkylene, or aza-, -oxa-, or thia-lower alkylene; X1 is methylene, ethylene, a direct bond, a carbonyl group free or ketalized, or a free or etherified hydroxymethylene group, and n is 0, and its salts, to processes for the preparation of the compounds according to the invention, to pharmaceutical compositions containing them, and to their use as pharmaceutical active ingredients.

Description

COMPOUNDS OF l-ACIL-4-ALIFATILAMINOPIPERIDINA The invention relates to novel 1-acyl-4-aliphatilaminopiperidine compounds of the formula I: where: • R! is a benzoyl, naphthoyl, or cycloalkanoyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is cycloalkyl or a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R4 are together lower alkylene or aza-, oxa-, or thia-lower alkylene; or R3 is lower alkyl, lower alkoxy-lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (Ia); and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); R5 is (i) hydrogen, alkyl, or alkyl that is substituted by halogen, lower alkoxy, amino, or substituted amino; by lower alkyl, lower aminoalkyl, mono- or dialkyl inferiotaminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, (ii) hydroxyl, cycloalkoxy, lower alkoxy , or lower alkoxy which is substituted by lower alkoxy, amino, or amino substituted by lower alkyl, lower alkoxy, mono- or di-lower alkyl aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa -, or thia-lower alkylene, or (iii) amino, or amino substituted by lower alkyl, cycloalkyl, lower aminoalkyl, mono- or di-lower alkylaminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza -, oxa-, or thia-lower alkylene; Xj is methylene, ethylene, a direct bond, a free or ketalized carbonyl group, or a free or etherified hydroxymethylene group; and n is 0 or 1, and salts thereof, with the exception of the compound (2R, S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-nitrobenzyl) -piperidin-U-yl] acetamide; to a process for the preparation of the compounds according to the invention, to pharmaceutical preparations containing them, and to their use as pharmaceutical active ingredients. Cycloalkyl and the radicals derived therefrom have, for example, from 3 to 8, in particular from 5 to 7, primary or 6 ring members, and are, for example, cyclopentyl, cyclohexyl or cycloheptyl. Alkyl substituted by halogen, lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa- or lower thia-alkylene, is, for example, haloalkyl, in particular lower haloalkyl, lower alkoxy-alkyl, in particular lower alkoxy-lower alkyl, aminoalkyl, in particular lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, in particular mono- or di-lower alkyl-lower aminoalkyl, lower alkanoyl-aminoalkyl, in particular lower alkanoyl-lower aminoalkyl, lower alkoxycarbonylaminoalkyl, in particular lower alkoxycarbonylamino-lower alkyl, pyrrolidinoalkyl, in particular pyrrolidino-lower alkyl, piperidinoalkyl, in particular lower piperidinoalkyl, free piperazinoalkyl or lower N'-alkylated or N'-lower alkylated, in particular piperazinoa corresponding lower alkyl, morpholinoalkyl, in particular lower morpholinoalkyl, or free or S-oxidized thiomorpholinoalkyl, in particular the corresponding lower thiomorpholinoalkyl. Amino substituted by lower alkyl, cycloalkyl (from 3 to 8 members), lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxy- carbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene is, for example, mono- or di-lower alkyl-amino, cycloalkylamino (from 3 to 8 members), amino-lower alkyl-amino, mono- or di-lower alkyl-amino-lower alkyl-amino, lower-amino alkanoyl, lower alkoxycarbonylamino, pyrrolidine, piperidino, free piperazine or lower N '-alkylated or lower N'-alkylated, morpholino, or free or S-oxidized thiomorpholino. Lower alkoxy which is substituted by lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono-, or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or lower thia-alkylene is, for example, lower alkoxy-lower alkoxy, lower aminoalkoxy, mono-, or di-lower alkyl-lower aminoalkoxy, lower alkanoyl-lower aminoalkoxy, lower alkoxy-lower-alkoxycarbonyl, pyrrolium lower -dinoalkoxy, lower piperidinoalkoxy, free lower piperazinoalkoxy or lower N'-alkylated or N'-lower alkylated, lower morpholinoalkoxy, or free lower or S-oxidized thiomorpholinoalkoxy. Alkyl is, for example, straight or branched chain alkyl of 1 to 14 carbon atoms, in particular alkyl of 1 to 10 carbon atoms, preferably lower alkyl. Free or ketalized carbonyl is, for example, carbonyl or dialkoxy-lower-methylene.

Etherified hydroxymethylene is, for example, lower alkoxymethylene. Lower free piperazinoalkoxy or lower N'-alkylated or N'-lower alkylated is, for example, piperazinoalkoxy lower, N'-lower alkyl-piperazinoalkoxy, or N'-lower alkanoyl-piperazinoalkoxy. Lower free piperazinoalkyl or N 1 -alkylated lower or N'-lower alkylated is, for example, piperazinoalkyl, N'-lower alkyl-piperazinoalkyl, or N'-lower alkanoyl-piperazinoalkyl. The general definitions used above and below, if not defined in a different manner, have the following meanings: The term "lower" means that the corresponding groups or compounds each have up to and including 7, preferably up to and including 4 atoms of carbon. Lower alkyl is, for example, alkyl of 1 to 7 carbon atoms, preferably alkyl of 1 to 4 carbon atoms, such as, in particular, methyl or ethyl secondary, propyl, isopropyl, or butyl, but can also be isobutyl, secondary butyl, tertiary butyl, or an alkyl group of 5 to 7 carbon atoms, such as a pentyl, hexyl, or heptyl group. Lower alkoxy is, for example, alkoxy of 1 to 7 carbon atoms, preferably alkoxy of 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, or butoxy, but also it can be isobutoxy, secondary butoxy, tertiary butoxy, or a pentoxy, hexyloxy, or heptyloxy group. Halogen is, for example, chlorine or iodine, but it can also be fluorine or bromine. Lower alkylene or aza-, oxa-, or thia-lower alkylene is, for example, from 4 to 6 members, and is, for example, alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa- , or 3-thia-alkylene of 4 to 6 carbon atoms. Amino substituted by lower alkylene or aza-, oxa-, or thia-lower alkylene, the group -N (R3) (R4), is preferably pyrrolidino, piperidino, morpholino, or free or S-oxidized thiomorpholino. Lower alkoxy-lower alkyl leads the terminal lower alkoxy group preferably in a position that is not as high as position a, and is, for example, alkoxy of 1 to 7 carbon atoms-alkyl of 2 to 4 carbon atoms, preferably alkoxy from 1 to 4 carbon atoms-alkyl of 2 to 4 carbon atoms, such as 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 4-methoxybutyl, or 4-ethoxybutyl. Lower aminoalkyl is, for example, aminoalkyl of 1 to 7 carbon atoms, preferably aminoalkyl of 1 to 4 carbon atoms, such as aminomethyl, 2-aminoethyl, 3-amino-propyl, or 4-aminobutyl. Mono- or di-lower alkyl-lower aminoalkyl is, for example, mono- or di-alkyl of 1 to 4 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, such as methylamino- or dimethylamino-alkyl of 1 to 4 carbon atoms, ethylamino- or diethylamino-alkyl of 1 to 4 carbon atoms, N-ethyl-N-methylaminoalkyl of 1 to 4 carbon atoms, propylamino- or dipropylamino-alkyl from 1 to 4 carbon atoms, diisopropylaminoalkyl of 1 to 4 carbon atoms, or dibutylaminoalkyl of 1 to 4 carbon atoms, with alkyl of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl or butyl. Lower alkanoyl is, for example, alkanoyl of 1 to 7 carbon atoms, preferably alkanoyl of 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, or butyryl, but can also be valeroyl, pivaloyl, or caproyl. Lower alkoxycarbonyl is, for example, C 1 -C 7 alkoxycarbonyl, preferably C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, or butoxycarbonyl, but also it can be isobutoxycarbonyl, secondary butoxycarbonyl, tertiary butoxycarbonyl, or a pentoxycarbonyl, hexyloxycarbonyl, or heptyloxycarbonyl group. Lower dialkoxymethylene is, for example, dialkoxy of 1 to 4 carbon atoms-methylene, such as dimethoxymethylene, diethoxymethylene, dipropoxymethylene, or dibutoxymethylene. Lower alkoxymethylene is, for example, alkoxy of 1 to 4 carbon atoms-methylene, such as methoxymethylene, ethoxymethylene, propoxymethylene, or butoxymethylene. Lower aminoalkoxy is, for example, aminoalkoxy of 1 to 7 carbon atoms, preferably aminoalkoxy of 2 to 4 carbon atoms, such as 2-aminoethoxy, 3-aminopropoxy, or 4-aminobuto-xi. Lower-amino dialkyl is, for example, dialkyl of 1 to 4 carbon-amino atoms, such as dimethylane, diethylamine, N-ethyl-N-methylamino, dipropylane, diisopropylamino, or dibutylamino. Free or oxidized thiomorfolin is, for example, thio orfo-lino, S-oxythomorpholino or S, S-dioxythiomorpholino. Lower haloalkyl is, for example, halo-, dihalo-, or in particular, trihalo-alkyl of 1 to 4 carbon atoms, such as, in particular, trifluoromethyl, or secondarily trifluoroethyl or trifluoropropyl. Morpholinoalkoxy lower is, for example, morpholinoalkoxy of 1 to 4 carbon atoms, such as morpholino ethoxy or 2-morpholinomethoxy, 3-morpholinopropoxy, or 4-morpholinobutoxy. Morpholino lower alkyl is, for example, morpholinoalkyl of 1 to 4 carbon atoms, such as morpholinomethyl or 2-morpholinoethyl, 3-morpholinopropyl, or 4-morpholinobutyl. N-mono- or N, N-di-lower alkyl-aminoalkoxy is, for example, N-mono- or N, N-di-alkyl of 1 to 4 carbon atoms-aminoalkoxy of 1 to 4 carbon atoms, such as ethylamino- or dimethylamino-alkoxy of 1 to 4 carbon atoms, ethylamino- or diethylamino-alkoxy of 1 to 4 carbon atoms, N-ethyl-N-methylaminoalkaxy of 1 to 4 carbon atoms, propyl- or dipropylamino-alkoxy of 1 to 4 carbon atoms, diisopropylamine-noalkoxy of 4 carbon atoms, or butylaminoalkoxy of 1 to 4 carbon atoms, with alkoxy of 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, or butoxi. N'-lower alkanoyl-piperazinoalkoxy, for example, N '-alkanoyl of 1 to 7 carbon atoms-, such as N'-acetylpiperazino-alkoxy of 1 to 4 carbon atoms, with alkoxy of 1 to 4 carbon atoms , for example, methoxy, ethoxy, propoxy, or butoxy. N '- lower alkyl piperazinoalkoxy is, for example, N' -alkyl of 1 to 7 carbon atoms-, such as N'-methylpiperazino-alkoxy of 1 to 4 carbon atoms, with alkoxy having from 1 to 4 carbon atoms. carbon, for example, methoxy, ethoxy, propoxy, or butoxy. N '-lower-piperazinoalkyl lower alkanoyl is, for example, N' -alkanoyl of 1 to 7 carbon atoms-, such as N '-acetylpiperazino-alkyl of 1 to 4 carbon atoms, with alkyl of 1 to 4 carbon atoms. carbon, for example, methyl, ethyl, propyl or butyl. N "lower alkyl-piperazine-lower alkyl is, for example, N '-alkyl of 1 to 7 carbon atoms- such as N'-methylpiperazino-alkyl of 1 to 4 carbon atoms, with alkyl of 1 to 4 carbon atoms , for example, methyl, ethyl, propyl, or butyl. Lower alkanoyl-aminoalkoxy is, for example, example, alkanoyl of 1 to 7 carbon atoms-aminoalkoxy of 1 to 4 carbon atoms, preferably alkanoyl of 1 to 4 carbon atoms-aminoalkoxy of 2 to 4 carbon atoms, such as formylaminoalkoxy of 2 to 4 atoms carbon, acetylaminoalkoxy of 2 to 4 carbon atoms, propionylaminoalkoxy of 2 to 4 carbon atoms, or butyrylaminoalkoxy of 2 to 4 carbon atoms, with alkoxy of 2 to 4 carbon atoms, for example, ethoxy, propoxy, isopropoxy, or butoxi. Lower alkanoyl-lower aminoalkyl is, for example, alkanoyl of 1 to 7 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, preferably alkanoyl of 1 to 4 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, such as formylaminoalkyl of 1 to 4 carbon atoms, acetylaminoalkyl of 1 to 4 carbon atoms, propionylaminoalkyl of 1 to 4 carbon atoms, or butyrylaminoalkyl of 1 to 4 carbon atoms, with alkyl of 2 to 4 carbon atoms, for example, ethyl, propyl, isopropyl, or butyl. Lower alkoxycarbonylaminoalkoxy is, for example, alkoxy of 1 to 7 carbon atoms-carbonylaminoalkoxy of 2 to 4 carbon atoms, preferably alkoxy of 1 to 4 carbon atoms-carbonylaminoalkoxy of 2 to 4 carbon atoms, such as methoxycarbonylaminoalkoxy of 2 to 4 carbon atoms, ethoxycarbonylaminoalkoxy of 2 to 4 carbon atoms, propoxycarbonylamino-noalkoxy of 2 to 4 carbon atoms, or butoxycarbonylaminoalkoxy of 2 to 4 carbon atoms, with alkoxy having 2 to 4 carbon atoms carbon, for example, ethoxy, propoxy, isopropoxy or butoxy. Lower alkoxycarbonylaminoalkyl is, for example, alkoxy of 1 to 7 carbon atoms-carbonylaminoalkyl of 2 to 4 carbon atoms, preferably alkoxy of 1 to 4 carbon atoms-carbonylaminoalkyl of 2 to 4 carbon atoms, such as methoxycarbonylaminoalkyl of 2 to 4 carbon atoms, ethoxycarbonylaminoalkyl of 2 to 4 carbon atoms, propoxycarbamylaminoalkyl of 2 to 4 carbon atoms, or butoxycarbonylaminoalkyl of 2 to 4 carbon atoms, being alkyl of 2 to 4 carbon atoms , for example, ethyl, propyl, isopropyl, or butyl. Lower alkoxy-lower alkoxy carries the terminal lower alkoxy group preferably in a position higher than position a, and is, for example, alkoxy of 1 to 7 carbon atoms-alkoxy of 2 to 4 carbon atoms, preferably alkoxy from 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms, such as 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 4-methoxybutoxy, or 4-ethoxybutoxy. Lower piperazinoalkoxy is, for example, piperazi- noalkoxy of 1 to 7 carbon atoms, preferably piperazinoalkoxy of 1 to 4 carbon atoms, such as piperazinomethoxy, 2-piperazinoethoxy, 3-piperazinopropoxy, or 4-piperazinobutoxy. Lower piperazinoalkyl is, for example, piperazinealkyl of 1 to 7 carbon atoms, preferably piperazinealkyl of 1 to 4 carbon atoms, such as piperazinomethyl, 2-piperazinoethyl, 3-piperazinopropyl, or 4-piperazinobutyl. Lower piperidinoalkoxy is, for example, piperidi-noalkoxy of 1 to 7 carbon atoms, preferably piperidinoalkoxy of 1 to 4 carbon atoms, such as piperidinomethoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, or 4-piperidinobutoxy. Lower piperidinoalkyl is, for example, piperidinoalkyl of 1 to 7 carbon atoms, preferably piperidinoalkyl of 1 to 4 carbon atoms, such as piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, or 4-piperidinobutyl. Lower pyrrolidinoalkoxy is, for example, pyrrolidi-noalkoxy of 1 to 7 carbon atoms, preferably pyrrolidinoalkoxy of 1 to 4 carbon atoms, such as pyrrolidinomethoxy, 2-pyrrolidinoethoxy, 3-pyrrolidinopropoxy, or 4-pyrrolidinobutoxy. Lower pyrrolidinoalkyl is, for example, pyrrolidinanoalkyl of 1 to 7 carbon atoms, preferably pyrrolidinoalkyl of 1 to 4 carbon atoms, such as pyrrolidinomethyl, 2-pyrrolidinoethyl, 3-pyrrolidinopropyl or 4-pyrrolidinobutyl. Thiomorpholinoalkoxy lower is, for example, thiomorpholinoalkoxy of 1 to 7 carbon atoms, preferably thiomorpholino-noalkoxy of 1 to 4 carbon atoms, such as thiomorpholinomethoxy, 2-thiomorpholinoethoxy, 3-thiomorpholinopropoxy, or 4-thiomorpholino-butoxy. Thiomorpholino-lower alkyl is, for example, thiomorpholinoalkyl of 1 to 7 carbon atoms, preferably thiomorpholinoalkyl of 1 to 4 carbon atoms, such as thiomorpholine- lime, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, or 4-thiomorpholinobutyl. Lower alkylene, or aza-, oxa-, or thia-lower alkylene is, for example, 4- to 6-membered pyrrolidino, piperidino, morpholino, or free or S-oxidized thiomorpholino. Lower-amino alkyl is, for example, alkyl of 1 to 7 carbon atoms-amino, such as methyl-, ethyl-, propyl-, or butyl-amino, but can also be isobutylamino, secondary butylamino, tertiary butylamino, or a alkyl group of 5 to 7 carbon atoms-amino, such as a pentylamino, hexylamino, or heptylamino group. Since the compounds according to the invention have at least two optically active carbon atoms, therefore, mixtures of stereoisomers, and in the form of (essentially) pure diastereomers, may be present in the form of stereoisomers. The corresponding stereoisomers in the same manner are encompassed by the present invention. Preferred compounds of the formula I are those in which the carbon atom to which the group -Xj-R2 is bonded (essentially) has the R configuration and the carbon atoms with which the -N (R3) group is bonded (R4) (essentially) has the S configuration according to Cahn-Ingold-Prelog. The compounds of the formula I have a basic character, or if R3 and / or R4 is carboxyl or is substituted by carboxyl, an amphoteric character, and therefore, can form acid addition salts, and if desired, internal salts. The acid addition salts of the compounds of the formula I are, for example, pharmaceutically acceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example, hydrochlorides, hydrobromides, sulphates, sulfates acids, or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example, methanesulfonates, benzenesulfonates, p-toluenesulfonates, or N-cyclohexyl sulfamates (cyclamates). Pharmaceutically inappropriate salts can also be used for isolation or purification. Only non-toxic pharmaceutically acceptable salts are suitable for therapeutic use, and therefore, are preferred. The compounds prepared according to the invention, including the compound (2R *, 4S *) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-nitrobenzyl) piperidin-4-yl] acetamide, they have pharmacologically useful properties. In particular, they show a pronounced antagonistic action against substance P, and have the typical spectrum of properties for substance P antagonists. The binding of 3H-substance P to the bovine retina in the radio-receptor assay according to H. Bittiger, Ciba Foundation Symposium £ 1, 196-199 (1982) is therefore inhibited in vitro at concentrations of approximately 0.01 micromoles / liter by the compounds of the formula I and their pharmaceutically acceptable salts. Therefore, the following in vitro values were determined, for example, for the objective compounds of Examples 2, 16 (second compound), 28 and 45 (c) and (f): lOmM-llnM-llnM - 7.6nM - 9nM. Substance P is an undecapeptide that naturally occurs in the tachykinin family. It is produced and deposited in the sensory neurons of the spinal cord and the brain of mammals, and acts pharmacologically as a neurotransisor and / or neuromodulator. Substance P antagonists of the formula I prepared according to the invention, and their pharmaceutically acceptable salts, are metabolically stable, and therefore, eminently suitable for the * prophylactic and therapeutic treatment of disorders where substance P has an important part , for example, in attacks of pain, in migraine, in disorders of the central nervous system, such as states of anxiety, schizophrenia, and depression, in certain motor disorders, such as Parson's disease, in inflammatory disorders, such as rheumatoid arthritis and osteoarthritis, in disorders of the respiratory organs, such as asthma, chronic bronchitis, and chronic rhinitis, in disorders of the gastrointestinal system, such as ulcerative colitis and Crohn's disease, in emesis, in particular chemically induced emesis, and in hypertension . In addition, the compounds according to the invention can be used for the inhibition of angiogenesis, and can protect against sunburn. Substance P antagonists of the formula I prepared according to the invention, and their pharmaceutically acceptable salts, including the compound (2R *, 4S *) -N- [1- (3,5-bis-trifluoromethylbenzoyl) -2- (4-nitrobenzyl) piperidin-4-yl] acetamide, according to the foregoing, are entirely suitable for the therapeutic treatment of the aforementioned disorders. The industrial production of active substances is also included in the production of medicines. The invention relates primarily to compounds of the formula I, wherein: Rj is a benzoyl, naphthoyl, or cycloalkanoyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl, R2 is cycloalkyl of 3 to 8 members, or a phenyl or naphthyl radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 is lower alkyl, lower dialkyl-amino, lower alkoxy-lower alkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (la), and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (la), or R3 and R4 are together lower alkylene of 4 to 6 members, or aza-, oxa-, or thia-lower alkylene, R5 is hydrogen, lower alkyl, lower haloalkyl, lower aminoalkyl, N-mopo- or N, N-di-lower alkyl-lower aminoalkyl, lower alkanoyl lower alkylnoal, lower alkoxy-lower carbanylaminoalkyl, lower pyrrolidinoalkyl, lower piperidinoalkyl, pip ' free lower alkyl or lower N'-alkylated or lower N'-alkanoylated, lower morpholinoalkyl, free lower or S-oxidized lower thiomorpholinoalkyl, lower alkanoyl-lower aminoalkyl, lower alkoxy-lower carbonylaminoalkyl, or lower alkylene-amino- or aza-, oxa -, or thia-lower alkylene lower aminoalkyl of 4 to 6 members, lower alkoxy, lower alkoxy-lower alkoxy, lower aminoalkoxy, N-mono- or N, N-di-lower alkyl-aminoalkoxy, lower alkanoyl-lower aminoalkoxy , lower alkoxy-lower carbonylaminoalkoxy, lower pyrrolidinoalkoxy, lower piperidinoalkoxy, free lower piperazinoalkoxy or lower N'-alkylated or lower N'-alkanoylated r, lower morpholinoalkoxy, or free lower or S-oxidized thiomorpholinoalkoxy, Xj is methylene, ethylene, a direct bond, a free or ketalized carbonyl group, or hydroxymethylene, and n is 0 or 1, and salts thereof. The invention relates in particular to compounds of the formula I, wherein: R ^ is a benzoyl, naphthoyl, or cycloalkanoyl radical which is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms carbon, such as methyl, alkoxy of 1 to 4 carbon atoms, such as methoxy, halogen, such as chlorine, and / or trifluoromethyl, R 2 is 3 to 8 membered cycloalkyl, a phenyl or naphthyl radical, which is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, such as methyl, alkoxy of 1 to 4 carbon atoms, such as methoxy, halogen, nitro, cyano, and / or trifluoromethyl, R3 is alkyl of 1 to 7 carbon atoms, such as isopropyl, secondary butyl, isobutyl, or neopentyl, dialkyl of 1 to 4 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, such as dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 3-diethylaminopropyl, or 3- (N-ethyl-N-methylamino) propyl, alkoxy of 1 to 4 carbon atoms-alkyl of 4 carbon atoms, such as 2-methoxyetho-1, 2-ethoxyethyl, or 3-methoxypropyl, or radical of the formula - (CH2) nC (= 0) -R5 (la) and R4 is hydrogen, alkyl of 1 to 4 carbon atoms, such as methyl, or a rad ical of the formula - (CH2) nC (= 0) -R5 (la) or R3 and R4 are together alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, and together with the nitrogen atom linking them, are preferably pyrrolidino, piperidino, morpholino, or free or S-oxidized thiomorpholino, R5 is hydrogen, alkyl of 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, butyl secondary rio, isobutyl, or neopentyl, trihaloalkyl of 1 to 4 carbon atoms, such as trifluoromethyl, trifluoroethyl, or trifluoropropyl, aminoalkyl of 1 to 4 carbon atoms, such as aminomethyl, 2-aminoethyl, 3-aminopropyl or 4- aminobutyl, N-C 1-4 alkyl-aminoalkyl of 1 to 4 carbon atoms, such as methylaminomethyl, 2-methylaminoethyl, ethylaminomethyl, 2-ethylaminoethyl, propylaminomethyl, 2-propylaminoethyl, dibutylaminomethyl, dialkyl of 1 to 4 carbon-aminoalkyl atoms of 1 to 4 carbon atoms, such as dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 3-diethylaminopropyl or 3- (N-ethyl-N-methylamino) propyl, alkanoyl from 1 to 7 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, such as formylaminomethyl, 2-formylaminoethyl, acetylaminomethyl, 2-acetylaminoethyl, propio-nilaminomethyl, 2-propionylaminoethyl or butyrylaminomethyl; C 1-4 alkoxycarbonylaminoalkyl of 1 to 4 carbon atoms, such as methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, isopropoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl, 2-ethoxycarbonylaminoethyl, 2-isopropoxycarbonylamino-noethyl or tertiary butoxycarbonylaminomethyl, - pyrrolidinoalkyl of 1 to 4 carbon atoms, piperidinoalkyl of 1 to 4 carbon atoms, piperazinoalkyl of 1 to 4 free carbon atoms or N'-alkylated with 1 to 4 carbon atoms, such as N'-methylated with 1 to 4 carbon atoms, or N'-alkanoylated with 1 to 4 carbon atoms, such as N'-acetylated with 1 to 4 carbon atoms; morpholinoalkyl of 1 to 4 carbon atoms, thiomorpholinoalkyl of 1 to 4 free carbon atoms or S-oxidized, such as pyrrolidi-nomethyl, piperidinomethyl, piperazinomethyl, morpholinomethyl, or free thiomorpholinomethyl or S-oxidized N '-alkylated with 1 to 4 carbon atoms, such as N '-methylated with 1 to 4 carbon atoms, or N' -alkylated with 1 to 4 carbon atoms, such as N '-acetylated with 1 to 4 carbon atoms; alkanoyl of 1 to 4 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, such as formylaminomethyl, acetylaminomethyl, propionylaminomethyl, or butyrylaminomethyl; C 1 -C 4 -alkoxycarbonylaminoalkyl of 2 to 4 carbon atoms, such as methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl, propoxycarbonylaminoethyl, or butoxycarbonylaminoethyl, C 1 -C 7 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy , or butoxy; 5 to 7 membered cycloalko-xi, such as cyclohexyloxy, alkoxy of 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms, such as 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, -methoxybutoxy, or 4-ethoxybutoxy; aminoalkoxy of 1 to 7 carbon atoms, preferably aminoalkoxy of 2 to 4 carbon atoms, such as 2-aminoethoxy, 3-aminopropoxy or 4-aminobutoxy; N-mono- or N, N-di-alkyl of 1 to 4 carbon atoms-aminoalkoxy of 4 carbon atoms, such as methylamino- or dimethylamino-methoxy, 2-methylamino- or 2-dimethylamino-ethoxy, 3- methylamino- or 3-dimethylami-no-propoxy, ethylamino- or diethylamino-methoxy, 2-ethylamino- or 2-diethylamino-ethoxy, N-ethyl-N-methylaminomethoxy, propylamino methoxy, diisopropylaminomethoxy, or butylamino ethoxy; pyrrolidinoalkoxy of the 4 carbon atoms, such as pyrrolidinomethoxy, piperidinoalkoxy of 1 to 4 carbon atoms, such as piperidinomethoxy, morpholinoalkoxy of 1 to 4 carbon atoms, such as morpholinometoxy, or thiomorpholinoalkoxy of 1 to 4 free carbon atoms or S-oxidized, such as thiomorpholinomethoxy, and Xj is methylene, ethylene, a direct bond, or a free or ketalized carbonyl group, hydroxymethylene, or 4-carbon-methylene alkoxy, such as methoxymethylene, ethoxymethylene, propoxymethylene , or butoxymethylene, and n is 0 or 1, and their salts. The invention relates in particular to compounds of the formula I wherein: Rj is benzoyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl, R 2 is phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl or unsubstituted naphthyl, R 3 is lower alkyl which is unsubstituted or substituted by carboxyl, lower alkoxycarbonyl, lower alkoxy -lower-lower alkoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, carbamoyl, N-mono- or N, N-di-lower alkyl-carbamoyl, or lower-amino-alkyl, lower alkanoyl which is unsubstituted or substituted by halogen, amino, N -mono- or N, N-di-lower alkyl-amino, lower alkanoyl, or morpholino, or lower alkoxycarbonyl, or lower alkyl-lower aminoalkoxycarbonyl, and R 4 is hydrogen or lower alkyl that is unsubstituted or substituted by carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl , 5- to 7-membered cycloalkoxycarbonyl, carbamoyl, N-mono- or N, N-di-lower alkyl-carbamoyl, or lower-amino alkyl; or R3 and R4 together with the nitrogen atom linking them, are pyrrolidino, piperidino, morpholino, or thiomorpholino, and Xj is methylene, and its salts. The invention first relates to all compounds of the formula I wherein: R! is a benzoyl, naphthoyl, or cycloalkanoyl radical that is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, such as methyl, alkoxy of 1 to 4 carbon atoms, such as methoxy, halogen, such as chlorine, and / or trifluoromethyl, R2 is phenyl which is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, such as methyl, alkoxy of 1 to 4 carbon atoms, such as methoxy, or halogen, nitro, cyano, and / or trifluoromethyl, or unsubstituted naphthyl, R3 is alkyl of 3 to 7 carbon atoms, such as isobutyl or neopentyl, alkoxy of 1 to 4 carbon atoms-carbonylalkyl of 1 to 4 carbon atoms, such as methoxycarbo- nylmethyl, isopropoxycarbonylmethyl, or tertiary butoxycarbonylmethyl; C 1-4 alkoxy-C 2 -C 4 -alkoxy-carbonylalkyl of 1 to 4 carbon atoms, such as 2-ethoxyethoxycarbonylmethyl or 2-methoxyethoxycarbonylmethyl; 5 to 7 membered cycloalkoxycarbonylalkyl of the 4 carbon atoms, such as cyclohexyloxycarbonylmethyl, carbamoylalkyl of 1 to 4 carbon atoms, such as carbamoylmethyl, N-alkyl of 1 to 4 carbon atoms-carbamoylalkyl of 1 to 4 carbon atoms carbon, such as isopropylcarbamoylmethyl, N, N-dialkyl of 1 to 4 carbon atoms-carbamoylalkyl of 1 to 4 carbon atoms, such as 2-dimethylaminocarbamoylmethyl; N-alkyl of 1 to 4 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, such as 3-dimethylaminopropyl; alkanoyl of 1 to 7 carbon atoms, such as formyl, acetyl, propionyl, or butyryl; trihaloalkanoyl of 1 to 7 carbon atoms, such as trifluoroacetyl; aminoalka-noyl of 1 to 7 carbon atoms, such as glycinyl; N-alkyl of 1 to 4 carbon atoms-aminoalkanoyl of 1 to 4 carbon atoms, such as tertiary butyl aminoacetyl, N, N-dialkyl of 1 to 4 carbon atoms-aminoalkanoyl of 1 to 4 carbon atoms, as dimethylaminoacetyl, morpholinoalkanoyl of 1 to 7 carbon atoms, such as morpholinoacetyl; alkanoyl of 1 to 7 carbon atoms-aminoalkanoyl of 1 4 carbon atoms, such as acetylaminoacetyl; C 1 -C 4 -alkoxycarbonyl, such as isobutoxycarbonyl; or N, N-dialkyl of 1 to 4 carbon atoms-aminoalkoxy of 2 to 4 carbon atoms-carbonyl- it, such as 2-dimethylaminoethoxycarbonyl; and R 4 is hydrogen or alkoxy of 1 to 4 carbon atoms-carbonylalkyl of 1 to 4 carbon atoms, such as methoxycarbonylmethyl, isopropoxycarbonylmethyl, or tertiary butoxycarbonylmethyl; C 1-4 alkoxy-C 2 -C 4 alkoxy-carbonylalkyl of 1 to 4 carbon atoms, such as 2-ethoxyethoxycarbonylmethyl or 2-ethoxyethoxycarbonylmethyl; 5 to 7 membered cycloalkoxycarbonylalkyl of 1 to 4 carbon atoms, such as cyclohexyloxycarbo-nylmethyl, carbamoylalkyl of 1 to 4 carbon atoms, such as carbamoylmethyl, N-alkyl of 1 to 4 carbon atoms-carbamoylalkyl of 1 to 4 carbon atoms, such as isopropylcarbamoyl-methyl, N, N-dialkyl of 1 to 4 carbon atoms-carbamoylalkyl of 1 to 4 carbon atoms, such as 2-dimethylaminocarbamoylmethyl, N-alkyl of 1 to 4 carbon atoms carbon-aminoalkyl of 1 to 4 carbon atoms, such as 3-dimethylaminopropyl, or R3 and R4, together with the nitrogen atom linking them, are morpholino, and Xj is methylene, and salts thereof. The invention relates primarily to a compound of the formula I wherein: Rj is a benzoyl, naphthoyl, or cycloalkane noyl radical of 3 to 8 members that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is 3 to 8 membered cycloalkyl, or a phenyl or naphthyl radical that is unsubstituted or substituted by alkyl lower, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R are together lower alkylene or aza-, oxa-, or thia-lower alkylene; or R3 is lower alkyl, lower alkoxy-lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); R5 is (i) hydrogen, alkyl of 1 to 14 carbon atoms, or alkyl of 1 to 14 carbon atoms which is substituted by halogen, lower alkoxy, amino, or amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, (ii) hydroxyl, 3 to 8 membered cycloalkyl, lower alkoxy, or lower alkoxy which is substituted by lower alkoxy, amino, or by amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxy -carbonyl, or lower alkylene, or 3-aza-, 3-oxa-, or 3-thia-alc [uylene of 4 to 6 carbon atoms, or (iii) amino, or amino which is substituted by lower alkyl, cycloalkyl from 3 to 8 members, lower aminoalkyl, mono-, or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxy r -carbonyl, or lower alkylene, or 3-aza-, 3-oxa-, or 3- thia-alkylene of 4 to 6 carbon atoms, -Xi is methylene, ethylene, a direct bond, a carbonyl group, dialkoxy lower methylene, hydroxymethylene, or lower alkoxymethylene; and n is 0 or 1; or a salt of it. The invention relates primarily to a compound of the formula I wherein: R j is benzoyl or naphthoyl radical, which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is 5- to 7-membered cycloalkyl, or a phenyl or naphthyl radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R4 are together alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3-oxa- or 3-thia-pentylene, or R3 is lower alkyl, lower alkoxy-lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (la); and R 4 is hydrogen, lower alkyl, or a radical of the formula - (CH 2) n C (= 0) -R 5 (la), - R 5 is (i) hydrogen, alkyl of 1 to 14 carbon atoms, or alkyl of 1 to 14 carbon atoms that is replaced by halogen, lower alkoxy, amino, or amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3-oxa-, or 3-thia-pentylene, (ii) hydroxyl, cycloalkoxy from 3 to 8 members, lower alkoxy, or lower alkoxy which is substituted by lower alkoxy, amino, or amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl , or alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3-oxa-, or 3 -thia-pentylene, or (iii) amino, or amino which is substituted by lower alkyl, cycloalkyl of 5 to 7 carbon atoms, lower aminoalkyl, mono- or dialkyl lower-aminoalkyl, alkane the lower, lower alkoxycarbonyl, or alkylene of 4 to 6 carbon atoms, or 3-aza-, 3 -oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3-oxa-, or 3-thia-pentylene; Xj is methylene, ethylene, a direct bond, a carbonyl group, dialkoxy lower methylene, hydroxymethylene, or lower alkoxymethylene; and n is 0 or 1; or a salt thereof; The invention relates primarily to a compound of the formula I wherein: R is benzoyl, or benzoyl which is substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is phenyl, phenyl which is substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl, or naphthyl. R3 and R4 are together alkylene of 4 to 6 carbon atoms, or R3 is lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); R5 is (i) hydrogen, lower alkyl, or lower haloalkyl; (ii) hydroxy, cycloalkoxy of 4 to 6 carbon atoms, lower alkoxy, lower alkoxy-lower alkoxy, or lower dialkylamino-lower alkoxy, - or (iii) amino, lower alkyl-amino, lower-dialkylamino, cycloalkyl of to 7 carbon-amino atoms, or lower dialkyl-amino-lower alkyl-amino. Xj is methylene; and n is 0 or 1; or a salt of it. The invention relates first of all to a compound of the formula I wherein: R is benzoyl, or benzoyl which is substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is phenyl, phenyl which is substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl, or naphthyl; R3 and R4 are together alkylene of 4 to 6 carbon atoms, -or R3 is lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (the); and R4 is hydrogen; R5 is (i) hydrogen, lower alkyl, or lower haloalkyl, - (ii) hydroxyl, cycloalkoxy of 4 to 6 carbon atoms, lower alkoxy, lower alkoxy-lower alkoxy, or lower dialkyl-aminoalkoxy lower, or (iii) amino , lower-amino alkyl, lower-amino dialkyl, cycloalkyl of 5 to 7 carbon-amino atoms, or lower dialkyl-amino-lower alkyl-amino, -Xj is methylene; and n is 0 or 1; or a salt of it. The invention relates first of all to a compound of the formula I wherein: Rt is benzoyl which is disubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, and / or trifluoromethyl, in particular in positions 3 and 5; R 2 is phenyl, phenyl which is substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, nitro, cyano, and / or trifluoromethyl, in particular in the 4-position, or naphthyl; (i) R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la), - R4 is hydrogen; n is 0 and R 5 is alkyl of 1 to 7 carbon atoms, cycloalkyl of 5 to 7 carbon atoms-amino, or dialkyl of 1 to 4 carbon atoms-aminoalkoxy of 2 to 4 carbon atoms; or (ii) R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la), - R is hydrogen; n is 1; and R5 is amino, - and Xt is methylene; or a salt of it. The invention relates firstly to a compound of the formula I in which: Ri is benzoyl which is disubstituted by trifluoromethyl, in particular in the 3 and 5 positions; R 2 is phenyl, or phenyl which is monosubstituted by halogen, such as chlorine, in particular in the 4-position; R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la); R4 is hydrogen; R5 is alkyl of 1 to 7 carbon atoms, such as ethyl or propyl, cycloalkyl of 5 to 7 carbon atoms-amino, such as cyclohexylamino, or dialkyl of 1 to 4 carbon atoms- aminoalkoxy of 2 to 4 carbon atoms, such as 3-dimethylamino-propoxy; n is 0; and Xj is methylene; or a salt thereof, The invention relates first of all to a compound of the formula I wherein: R j is 3,5-bistrifluoromethylbenzoyl, - R 2 is phenyl, or phenyl which is monosubstituted by halogen, such as chlorine, in particular in position 4; R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la); R4 is hydrogen; n is 0; R5 is alkyl of 1 to 4 carbon atoms, such as ethyl or propyl, or cycloalkyl of 5 to 7 carbon atoms-amino, such as cyclohexylamino, - and X is methylene; or a salt of it. The invention relates especially to the compounds of the formula I mentioned in the examples, and to their salts, in particular their pharmaceutically acceptable salts. The invention also relates to a process for the preparation of the compounds according to the invention, based on methods known per se. This is characterized because: a) the radical R ^ is introduced into a compound of the formula II wherein R2, R3, R ^, and Xj are as defined, or b) compounds of formula III: and Y2-R3 IV) "wherein Yj is a group of the formula -N (/ j) -H and Yg is hydroxyl, reactive esterified hydroxyl, or, if R is a radical of the formula (the); and n is 0, is etherified hydroxyl, or Y < is free esterified or reactive hydroxyl, and Y2 is a group of the formula -N (Rj) -H, where R R2 »R- ^, R« and X «as defined, or their salts condense with each other , or c) for the preparation of compounds of the formula I, wherein R 4 is hydrogen, the group Y 3 is removed from a compound of the formula V: wherein Y3 is an amino protecting group, and R1 # R2, R3, and Xj are as defined, or a salt thereof, or d) for the preparation of compounds of formula I, wherein R3 is lower alkyl, lower dialkyl-lower aminoalkyl, or lower alkoxy lower alkyl, and R 4 is hydrogen or lower alkyl, a compound of formula VI: where Rj, R2, R4 and X { they are as defined, or a salt thereof, is reacted under reducing conditions with an appropriate aldehyde of the formula 0 = CH-R (VII) or e) for the preparation of compounds of the formula I, wherein R3 and R4 are together lower alkylene, or aza-, oxa-, or thia-lower alkylene, a compound of the formula VIII: wherein R1 (R2, and Xj are as defined, or a salt thereof, is condensed with a reactive diester of a lower alkanediol or an appropriate aza-, oxa-, or thia-alkanediol, of) for the preparation of compounds of the formula I, wherein Xj is a carbonyl or hydroxymethylene group, the compounds of the formula IX: and Y5-R2 (X), wherein one of the radicals Y4 and Y5 is formyl or a carboxyl group that is free, converted to an anhydride, or esterified, and the other is a metal radical, and R2, R3, and R they are as defined, they are condensed with each other, and if desired, a compound which is obtained is converted into another compound of the formula I, an isomeric mixture is separated which is can be obtained according to the process in the components, and in each case the preferred isomer is separated, and / or a free compound that can be obtained according to the process is converted into a salt, or a salt obtainable from According to the process, it becomes the corresponding free compound. The reactions according to the process, and the preparation of novel starting materials or intermediates, are carried out in analogy to the manner of reaction and formation of known starting materials or intermediates. Even when not mentioned explicitly hereinafter, the auxiliaries customary in each case are used, such as catalysts, condensation and solvolysis agents, and / or solvents or diluents, and the reaction conditions, such as temperature conditions and pressure, and also, if desired, protective gases. The salts of the starting materials having at least one basic center, for example of the formulas II or VI, are corresponding acid addition salts, while the salts of the starting substances having an acid group are present as salts with bases, in each case as mentioned above in relation to the corresponding salts of the formula I. The reactions described hereinafter and subsequently herein in the variants, are carried out in the manner known per se, for example, in absence, or by custom in the presence of a suitable solvent or diluent, or of a mixture thereof, the reaction being carried out, if required, with cooling, at room temperature, or with heating, for example, on a temperature scale from about 80 ° C to the boiling point of the reaction medium, preferably from about -10 ° C to about + 200 ° C, and if necessary, in a closed vessel, under pressure, in an inert gas atmosphere, and / or under anhydrous conditions. The introduction of the radical Rj by reaction with an agent which introduces the radical R ^ according to the process variant a) is carried out in a customary manner, for example, by reaction with an N-acylating agent of the formula (HA), wherein R has one of the definitions given at the beginning, and Yg is free or etherified hydroxyl, such as hydroxyl, lower alkoxy, or unsubstituted or substituted phenoxy, or reactive esterified hydroxyl, such as halogen, in particular chlorine, or a radical of the formula -0-Rj. If necessary, the reaction is carried out with thermal decomposition of the intermediately formed ammonium salts, or in the presence of a condensing agent, such as a dehydration agent, or basic condensation agents, and in the presence of a solvent or diluent. The customary condensation agents are, for example, carbodiimides, such as diethyl-, dipropyl-, N-ethyl-N '- (3-dimethylaminopropyl) -carbodi-imi- or, in particular, dicyclohexylcarbodiimide, and also suitable carbonyl compounds, for example, carbonyldiimidazole, 1,2-oxazolium compounds, for example, 3'-sulfonate, 2-ethyl-5-phenyl-1, 2-oxazolium and 2-butyl tertiary-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, and also activated phosphoric acid derivatives, by example, difluorphosphoryl azide, diethylphosphoryl cyanide, phenyl N-phenylphosphoram-docloridate, bis (2-oxo-3-oxazolidinyl) phosphoryl chloride, or l-benzotriazolyloxytris (dimethylamino-phosphonium) hexafluorophosphate. In this way, the reaction is carried out using acids (IIA1, Y = C00H) preferably in the presence of a dehydrating agent, such as N, N-dicyclohexylcarbodiimide, or with thermal decomposition of the primary ammonium salt, while the reaction with acid anhydrides (IIA1; Y = halogen or preferably it is carried out in the presence of a basic condensation agent, such as of an alkali metal hydroxide or carbonate, for example, potassium carbonate, or of a sterically hindered tertiary or secondary organic amine, such as of a lower trialkyl amine, for example, of triethyl amine or di-isopropyl amine, or of an aromatic nitrogen base, for example, of pyridine. The starting substances of the formula II can be prepared in a customary manner, preferably by introducing the radical Rj, and if desired, Rj, into a 2- (R2-X?) - aminopiperidine intermediately protected in the 1-position by an amino-protecting group, for example, by tertiary-carbonyl butoxy, and the amino-protecting group is removed in the customary manner, for example, by its treatment with trifluoroacetic acid. If R 4 is hydrogen, in this case the corresponding starting compound of the formula II protected by trifluoroacetyl is obtained on the exocyclic nitrogen atom. The introduction of the radical R3 and, if desired, R4, in this case, is preferably carried out as described hereinafter under the variant of process b). The starting substances of the formula II wherein R3 is a group of the formula - (CH2) nC (= 0) -R5 (la), wherein n is 0 and R5 is unsubstituted lower alkyl, or lower alkyl which is substituted by halogen, lower eylkoxy, or unsubstituted amino or amino which is substituted by lower alkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, and R 4 is hydrogen or lower alkyl , preferably they can be prepared by treating a lower alkyl N- [1- (Xj-R2) but-3-enyl] carbamate with sodium hydride, for example in boiling tetrahydrofuran, and then reacting with a lower chloromethylalkyl ether, the N- [1- (X 1 -R 2) but-3-enyl] carbamate of N-lower alkoxymethyl obtained is reacted with a corresponding nitrile of the formula R 5-CN and chlorosulfonic acid with cooling to, and the esterified 1-carboxylic acid group is removed from the ester of 2- (X 1 -R 2) - - (Rc 0) -piperidine-l-carboxylic acid obtained, for example, by its treatment with hydrogen bromide in acid acetic. In the starting substances of the formula III or IV according to the process variant b). reactive esterified hydroxyl is, for example, a halogen atom, such as chlorine, bromine, or iodine, or if Rj has a saturated carbon atom in the position or, for example, if n is a sulfonyloxy group, for example. , methanesulfonyloxy or p-toluenesulfonyloxy, or if it retains a carbonyl group in the position or, for example, n is 1, a group of the formula -0- (C = 0) -Rg. Etherified hydroxyl is, for example, lower alkoxy, such as methoxy or ethoxy, or substituted or unsubstituted phenoxy. The compounds of the formulas III and IV are reacted in a customary manner, for example, with thermal decomposition of the intermediately formed ammonium salts, or in the presence of a condensing agent, such as a dehydrating agent, for example , of N, N-dicyclohexylcarbodi-i ida, or of bis (2-oxo-3-oxazolidinyl) phosphinoyl chloride, or of a basic condensation agent, preferably of pyridine, or of a lower trialkyl amine, by example, of triethyl amine, or of an alkali metal carbonate or acid carbonate, if necessary in the presence of a solvent or diluent. Accordingly, the reaction is performed using acids of the formula IV (Y2 = 0H), preferably in the presence of bis (2-oxo-3-oxazolidinyl) phosphinoyl chloride, and of a lower trialkyl amine, for example in a halohydrocarbon, such as dichloromethane, or a cyclic aliphatic ether, such as tetrahydrofuran or dioxane. The reaction with reactive esters of formula IV or III (Y2 or Yj = esterified reactive hydroxy), or with acid anhydrides of formula IV (Y2 = hydroxyl which is converted to an anhydride) is carried out, in particular, in the presence of a basic condensation agent, such as a heterocyclic base, for example, pyridine, 4-dimethylaminopyridine, or preferably N-methyl morpholine, or a lower trialkylene amine, for example, of triethyl amine or diisopropyl amine, for example, in a halohydrocarbon, such as dichloromethane, or a cyclic aliphatic ether, such as tetrahydrofuran or dioxane, or an aliphatic nitrile, for example in acetonitrile. If a primary amine of the formula III (Yj = NH 2) is reacted with a lower alkyl halide jS-branched of the formula IV (Y 2 = halogen; R 3 = lower alkyl) in the presence of a carbonate or carbonate acid metal alkaline, the incorporation of carbon dioxide may occur. In addition to, or instead of, the objective compound of the formula I, wherein R3 is lower alkyl, then the corresponding compound of the formula I which is N-substituted by the group - (C = 0) -0 is obtained -R3 The starting substances of the formula III in which Yj is primary amino are obtained, for example, by the treatment of an appropriate 4-amino-2- (Xr-R2) -piperidine or its trifluoroacetate with trifluoroacetic anhydride, the condensation of the N- [2- (X1-R2) piperidin-4-yl] trifluoroacetamide resulting with an N-acylating agent of the formula RfYa (HA), wherein R has one of the definitions given at the beginning, and Y_ is free hydroxyl, etherified, or reactive esterified, for example, as indicated under the process variant a), and the treatment of the resulting N- [l-R1 ~ 2- (X1-R2 ^ piperidin-4-yl] trifluoroacetamide with a solution of strong sodium hydroxide, for example, about 5-normal.

The starting substances of the formula III, wherein Y "is hydroxyl, are obtained, for example, by the reaction of an appropriate l- (R2-Xj) -l- (R? -amino) but-3-ene with a lower halomethylalkyl ether in the presence of benzyltrimethyl ammonium bromide, the treatment of lower-methylamino) but-3-ene resulting with an excess of formic acid, and the hydrolyzation of the l-R1-2- formate (Xl-R2pi eri-din-4-yl resulting with strong hydrochloric acid, to give the - Rí-2- (Xj-R2) piperidin-4-ol corresponding to formula III (Yi = hydroxyl) Compounds of formula III wherein Y. is reactive esterified hydroxyl, can be prepared from these, by the reaction with an agent that introduces a group reactive esterified hydroxyl, such as a sulfonyl halide, for example, with methanesulfonyl chloride, or a halogenating agent, such as thionyl chloride, preferably in the presence of pyridine. The amino protecting group Y3 according to the process variant c) is, for example, a free lower alkanoyl or halogenide group, such as trifluoroacetyl, or an acyl group derived from a carbonic acid half ester, such as a group lower alkoxycarbonyl or lower phenylalkoxycarbonyl, for example, tertiary butoxycarbonyl or benzyloxycarbonyl, or a silyl group, such as trialkyl lower-silyl, for example, tri-ethylsilyl. The amino protecting group is removed in a customary manner, for example, by treatment with acid, or starting from the compounds V, wherein Y3 is halogenated lower alkyl, such as trifluoroacetyl, by reductive elimination, for example by treatment with a light metal dihydride, such as sodium borohydride, preferably in a lower alkanol, such as methanol. The starting substances of the formula V can be prepared, for example, in analogy to the process variant a), starting from N-Y3-N- [2-. { Xj-R2) piperidin-4-yl] amines appropriate. The reaction of the compounds of the formula VI with the aldehydes of the formula VII according to the variant of the process d) is carried out, for example, in the presence of water and a hydrogenation catalyst, such as a platinum or palladium catalyst, or a Raney nickel, or in the presence of a light metal dihydride, such as sodium borohydride or sodium cyanoborohydride, preferably in a solvent which is inert under the conditions of the reaction, such as of a lower alkanol, such as methanol or ethanol, or of a lower dialkyl ether or lower alkylene, such as ether diethyl, dioxane, or tetrahydrofuran. In a reactive diester of a lower alkane-diol or aza-, oxa-, or thia-lower alkane-diol according to the process variant e). the esterified reactive hydroxyl is, for example, a halogen atom, such as chlorine, bromine, or iodine, or a sulfonyloxy group, for example methanesulfonyloxy or p-toluenesul-foniloxy. The condensation is preferably carried out in the presence of a basic condensation agent, such as a metal base, for example, of an alkali metal carbonate, if necessary with heating, for example, on the temperature scale from about 60 ° C to approximately 140 ° C, if desired, at elevated pressure. In the starting substances of formulas IX and X according to the variant of process f). the carboxyl Y4 or Y5 which is free, converted into an anhydride, or esterified, is, for example, halocarbonyl, or in the case of Y5, a group of the formula R2-C (= 0) -0-, and a radical metallic Y4 or Y5 is, for example aalkali metal atom or a group of the formula -M I! / 2 or MII -hal, wherein M II is a metal atom of group IIb of the Periodic Table of the Elements, such as Mg or Zn. The condensation of the compounds of the formulas IX and X is carried out in a customary manner, for example, in an ether solvent, such as an aliphatic or cycloaliphatic ether, for example, in diethyl ether, methoxybutane, dibutyl ether, tetrahydrofuran, or dioxane. . The starting substances of the formula IX in which Y4 is formyl or carboxyl which is free, converted into an anhydride, or esterified, are prepared, for example, in an analogous manner, as described under the variants of process a) and b ), starting from appropriate starting substances having a radical Y4 instead of the group -Xj-R2. The compounds that can be obtained according to the process can be converted into other compounds of the formula I in a customary manner. The carboxyl group, therefore, can be esterified in a customary manner, in compounds of the formula I wherein the radical R3 contains carboxyl. The free or esterified carboxyl group can also be amidated in compounds of the formula I wherein R3 contains carboxyl pound or esterified. Conversely, the esterified or amidated carboxyl group can be hydrolyzed in carboxyl, in the compounds of the formula I in where Rj contains carboxyl esterified or amidated. The compounds of the formula I wherein Xj is carbonyl, can also be reduced in a customary manner in the corresponding compounds of the formula I wherein X. is hydroxymethylene, for example, as described under the process variant f). In an analogous manner, the resulting compounds of the formula I wherein X * is hydroxymethylene can also be reduced in the corresponding compounds of the formula I wherein Xj is methylene. In the resulting compounds of the formula I wherein X ^ is ketalized carbonyl, the carbonyl group can be released in a customary manner, for example by treatment with acid. In contrast, the carbonyl X, can be ketalized by its reaction with an appropriate alcohol, such as a lower alkanol or a lower alkane-diol. In the resulting compounds of the formula I wherein R ^ is hydrogen, it is also possible to introduce a radical R ^ which is different from hydrogen, lower alkyl, for example, by customary alkylation, and if desired as indicated, substituted alkanoyl by acylation customary. In contrast, in the resulting compounds of formula I where Rj is lower alkyl, in particular methyl, the lower alkyl group can be removed by treatment with an ester of haloformic acid, such as methyl haloformate.

In the same way, in the resulting compounds of the formula I wherein R 4 is trifluoroacetyl, the trifluoroacetyl group can be removed in a customary manner, in particular by its treatment with a light metal dihydride, for example, with sodium borohydride in a lower alkanol, such as methanol. The resulting salts can be converted to the free compounds in a manner known per se, for example, by treatment with a base, such as an alkali metal hydroxide, an acid carbonate or metal carbonate, or other salt forming base. mentioned at the beginning, or with an acid, such as a mineral acid, for example, with hydrochloric acid, or another salt-forming acid mentioned at the beginning. The resulting salts can be converted into other salts in a manner known per se, the acid addition salts, for example, by treatment with a suitable metal salt, such as a sodium, barium, or silver salt, of another acid in a suitable solvent where a formed inorganic salt is insoluble, and thus, is precipitated from the equilibrium of the reaction, and salts of bases by liberation of the free acid and formation of fresh salt. The compounds of formula I, including their salts, may also be obtained in the form of hydrates, or may include the solvent used for crystallization.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinafter and subsequently herein, the free compounds and their salts are understood in an analogous and convenient manner to mean also , where appropriate, the corresponding free salts or compounds. The mixtures of diastereomers and mixtures of resulting racemates can be separated into the pure diastereomers or racemates in a known manner, based on the physico-chemical differences of the constituents, for example, by chromatography and / or fractional crystallization. The resulting racemates can also be redissolved in the optical antipodes by known methods, for example, by recrystallization from an optically active solvent, with the aid of micro-organisms, or by reaction of the resulting diastereomer mixture or the racemate with an optically active auxiliary compound, for example, corresponding to acidic, basic, or functionally modifiable groups contained in the compounds of the formula I with an optically active acid, a base, or an optically active alcohol, in mixtures of diastereomeric salts or functional derivatives, such as esters, and their separation into diastereomers, from which the desired enantiomers can be liberated in each case in the customary manner in each case. The bases, acids, and alcohols suitable for this purpose are, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L- (1-phenyl) ethyl amine, 3-pipecoline, ephedrine, amphetamine, and similar synthetically accessible bases, carboxylic or sulfonic acids optically active ingredients, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid, or D- or L- acid camphorsulfonic, or optically active alcohols, such as borneol or D- or L- (1-phenyl) ethanol. The invention also relates to the process modes according to which a compound that can be obtained from any stage of the process as an intermediate is used as a starting compound, and the missing steps are performed, A substantial starting material is used in the form of a salt, or in particular, it is formed under the conditions of the reaction. The novel starting substances, which were developed especially for the preparation of the compounds according to the invention, in particular the choice of the starting substance which leads to the compounds of the formula 1 characterized as preferred at the beginning, the processes for their preparation and their use as intermediaries, also form an object of the invention. In the same way, the invention relates to pharmaceutical preparations containing compounds according to the invention, or pharmaceutically acceptable salts [including those of the compound (2R * 4S *) -N- [1- (3,5-bistrifluoromethylbenzoyl) lo) -2- (4-nitrobenzyl) piperidin-4-yl] acetamidase thereof as active ingredients, and to processes for their preparation. The novel compounds of the formula I can be used, for example, in the form of pharmaceutical preparations containing a therapeutically effective amount of the active substance, if appropriate together with pharmaceutically acceptable inorganic or organic, solid or liquid excipients, which are suitable for enteral, for example, oral or parenteral administration. Accordingly, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lubricants, for example, siliceous earth, talc, stearic acid. , or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. In the same way, the tablets may contain binders, for example, magnesium aluminum silicate, starches, such as corn starch, wheat, rice, or carob bean, gelatin, tragacanth, methyl cellulose, carboxymethyl sodium and / or polyvinyl cellulose, and if desired, disintegrants, eg, starches, agar, alginic acid, or a salt thereof, for example, sodium alginate, and / or effervescent mixtures, or absorbents, colorants, flavors, and sweeteners. The novel compounds of the formula I can also be used in the form of parenterally adisistrable preparations, or of solutions for infusion. These solutions are preferably solutions or aqueous isotonic suspensions, it being possible to prepare these before use, for example, in the case of freeze-dried preparations containing the active substance by themselves, or together with a vehicle, for example, mannitol. The pharmaceutical preparations can be sterilized and / or contain excipients, for example, preservatives, stabilizers, wetting agents, and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure, and / or pH regulators. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically active substances, are prepared in a manner known per se, for example, by means of conventional mixing, granulating, sugar coating, dissolving, or lyophilizing processes, and contain from about 0.1 percent to 100 percent, in particular from about 1 percent to about 50 percent, of lyophilizates, and up to about 100 percent, of the active substance. In the same way, the invention relates to the use of the compounds of the formula I, including the compound (2R *, 4S *) - N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-nitrobenzyl) piperidin-4-yl] acetamide, preferably in the form of pharmaceutical preparations. The dose may depend on different factors, such as the manner of administration, the species, the age, and / or the condition of the individual. In the case of oral administration, the doses to be administered daily are between approximate 1 and about 50 milligrams / kilogram, and for warm-blooded animals having a body weight of about 70 kilograms, preferably between about 80 milligrams and about 250 milligrams.

The following examples serve to illustrate the invention; temperatures are indicated in degrees Celsius, and pressures in bar.

Example 1: (2R.4S) -2-12-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl-amino-1-acetate-methyl (2R.4S) -2-f T2-benzyl-1- ( 3,5-bistrifluorornethylbenzoyl) piperidin-4-yl-1-ethoxycarbonylmethylaminolacetate Add 800 milligrams (5.23 millimoles) of methyl 2-bro or acetate at room temperature to a solution of 1.5 grams (3.49 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3, 5-bistrifluoromethylbenzoyl) piperidine in 4 milliliters of tetrahydrofuran. After 105 minutes, 353 are added milligrams (3.49 mmol) of triethyl amine to the yellowish solution, and the suspension is stirred at room temperature for another 16 hours. The reaction mixture is evaporated on a rotary evaporator, the residue is taken up in methylene chloride, and the solution is washed with an aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is passed through chromatography on silica gel, using ethyl acetate / hexane (1: 3). The title compounds are each obtained as colorless oils. Thin Layer Chromatography (TLC): methylene chloride / methanol / concentrated ammonia (95: 4.5: 0.5) Rf = 0.55 and Rf = 0.90. FD-MS: M + = 353 and 574.

Example 2; (2R.4S) -2- .2-benzyl-l- (3,5-bistri-fluoroethylbenzoyl) piperidin-4-ylamino] -acetamide hydrochloride Ammonia gas is passed into a solution of 350 milligrams (0.696 millimoles) of (2R, 4S) -2- [2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] -acetic acid methyl ester in 5 milliliters of methanol at 0 ° C for 10 minutes, and the reaction mixture is allowed to stand at room temperature for 60 hours. The reaction mixture is evaporated on a rotary evaporator, and the residue is chromatographed on silica gel using methylene chloride / methanol / concentrated ammonia (92: 7.2: 0.8). The title compound is crystallized as the hydrochloride from toluene / ether. P.f. 130-133 ° C; TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) R, = 0.36, FD-MS: M + = 487.

E-iemolo 3; (2R.4S) -2-. { [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] -carbamoylmethylamino} * < ,, «» «» ™ -i » In a manner analogous to Example-2, 350 milligrams (0.61 millimoles) of (2R, 4S) -2-. { [2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] methoxycarbonylmethylamino} methyl acetate in 5 milliliters of methanol, treated with ammonia gas. The crude product is passed through chromatography on silica gel, using methylene chloride / methane / concentrated ammonia (90: 9: 1) The title compound is obtained as white crystals. P.f. 96-98 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) R, = 0.21, FD-MS: M + = 544; [] D = 8.7 degrees (c = 1, methylene chloride).

Example 4: Acid (2R, 4S) -2- [2-benzyl-l- (3, 5-bistrifluorome-tylbenzoiDpiperidin-4-ylamino] acetic acid A solution of 350 milligrams (0.70 millimoles) of (2R, 4S) -2- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] methyl acetate in 5 milliliters of tetrahydrofuran is stirred vigorously at room temperature with 5 milliliters of a 1 N aqueous solution of sodium hydroxide for 2 hours. The tetrahydrofuran is evaporated on a rotary evaporator, and the reaction mixture is adjusted to a pH of 7.4 using hydrochloric acid, and extracted with methylene chloride and ethyl acetate. The title compound is crystallized from ethyl acetate / hexane. P.f. 199-201 ° C. TLC: methylene chloride / meta-nol / acetic acid (80: 18: 2) Rf = 0.19. FD-MS: M + = 488.

And 5; (2R.4S) -2- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) piperidin-4-ylamino-1 - N- (S-dimethylaminoetiDace * - * "'? ^? 147 milligrams (0.58 millimoles) of bis (2-oxo-3-oxazolidinyl) phosphinoyl chloride are added to a solution of 256 milligrams (0.52 millimoles) of (2R, 4S) -2- [2-benzyl-1- ( 3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] acetic acid and 51 milligrams (0.58 millimoles) of 2-dimethylaminoethyl amine in 23 milliliters of methylene chloride, and the reaction mixture is stirred at room temperature for 18 hours. It is then diluted with methylene chloride, and the organic phase is extracted with a 1 N aqueous solution of potassium carbonate, dried over sodium sulfate, and evaporated to dryness. The crude product is chromatographed on silica gel using methylene / methanol / concentrated ammonia chloride (90: 9: 1). The title compound is obtained as a yellow oil. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) 0. 23, FD-MS: M + = 558.

Element 6: (2R.4S) -N-ir2-benzyl-1- (3,5-bistrifluoroethylbenzoyl) piperidin-4-yl-carbamoyl-1-methyl} tertiary butyl carbamate In a manner analogous to Example 5, 400 milligrams (0.93 millimoles) of (2R.4S) -4-amino-2-benzyl-1- (3,5-bistrifluoro- methylbenzoyl) piperidine in 10 milliliters of methylene chloride, are reacted with 285 milligrams (1.1 millimoles) of bis (2-oxo-3-oxazalidinyl) phosphinoyl chloride, 206 milligrams (2.04 millimoles) of triethyl amine, and 179 milligrams ( 1.02 millimoles) of glycerin N-butoxi tertiary-carbopilica. The title compound is obtained as a yellow oil. TLC: methylene / methanol / concentrated ammonia chloride (90: 9: 1) R.p 0.57, FD-MS: M + = 587.

Example 7: (2R.4S) -2-amino-N-r2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-in-acetamide hydrochloride 325 milligrams (0.533 millimoles) of (2R, 4S) -N-. { [2-benz i1-1- (3,5-bistrifluciro etilbenzoi 1) piperidin-4-ilearba-moil] methyl} Tertiary butyl carbamate in 5 milliliters of trifluoroacetic acid is stirred for 30 minutes. The trifluoroacetic acid is evaporated on a rotary evaporator, the reaction mixture is taken up in methylene chloride, and the solution is extracted with an aqueous 2N potassium carbonate solution, dried over magnesium sulfate, and evaporated to dryness. The residue is dissolved in ethyl acetate, and treated with a solution of hydrogen chloride in ether. The title compound crystallizes on white needles. P.f. 137-140 ° C; TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rt = 0.35, FAB-MS: M + = 487.

Example 8; (2R, 4S) -2- [2-benzyl-l- (3, 5-bistrieuromethylbenzoyl) piperidin-4-ylamino] tertiary butyl hydrochloride, and (2R.4S) -2- hydrochloride. { [2-Benzyl-1 - (3, 5-bistrifluoromethyl-benzoyl) piperidin-4-yl] -butoxy-tertiary-carbonyl <-> - iiatnino} tertiary butyl a-cetate In a manner analogous to Example 1, 400 milligrams (0.929 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine are reacted with 290 milligrams (1.49 millimoles) ) of tertiary butyl 2-bromoacetate and 94 milligrams (0.929 millimoles) of triethyl amine in 4 milliliters of tetrahydrofuran. The hydrochlorides of the title compounds are each obtained as white crystals. P.f .: 175-177 ° C and 85-87 ° C; TLC: hexane / ethyl acetate (1: 1) Rr = 0.44 and Rf = 0.87. FD-MS: M + = 544 and 658.

Example 9; (2R.4S) -2-f2-Benzyl-l- (3, 5-biatrifluoromethylbenzoyl) piperidin-4-ylamido-1-isopropyl acetate hydrochloride, and (2R, 4S) -2 - ([2 -benzyl] hydrochloride -l- (3.5-bistrlf luor orne t liben-zoil) piperidin-4-yl] isopropoxycarboni • »« «» < * <1 to the "PÍno> isopropyl acetate" In a manner analogous to Example 1, 402 milligrams (0.934 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine are reacted with 270 milligrams (1.49 millimoles) ) of isopropyl 2-bromoacetate and 95 milligrams (0.934 millimoles) of triethyl amine in 4 milliliters of tetrahydrofuran. The hydrochlorides of the title compounds are each obtained as white crystals. P.f. 179-181 ° C and 90-92 ° C; TLC: hexane / ethyl acetate (1: 1) Rf = 0.41 and Rf = 0.79. FD-MS: M * = 530 and 630. Example 10; (2R.4S) -2- .2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) plperidin-4-ylamino] cetamide N-isopropyl. v (2R, 4S) -2- rf2-benzyl-1- (3, 5-bistrifluoromethylbenzoyl) piperldin-4-yl1 - (N- In a manner analogous to Example 1, 391 milligrams (0.908 mmol) of (2R, 4S) -4-amino-2-benzyl-1- (3, 5-bistri-fluoromethylbenzoyl) piperidine, are reacted with 245 milligrams (1.36 millimoles) of acetamide 2-bromo-N- isopropyl and 114 milligrams (1.36 millimoles) of sodium hydrogen carbonate in 4 milliliters of acetonitrile. The title compounds are each obtained as white crystals. P.f. : 115-116 ° C and 156-158 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.44 and Rf = 0.51. FD-MS: M + = 529 and 628.

Example 11: (2R.4S) -2- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] 2-ethoxyethyl acetate and (2R.4S) -N- [[2 -benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] - (N- (2-ethoxyethoxycarbonylmethyl)) mino] 2-ethoxyethyl acetate In a manner analogous to Example 1, 427 milligrams (0.993 mmol) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine are reacted with 265 milligrams (1.59 millimoles) of 2-ethoxyethyl 2-chloroacetate , Y 686 milligrams (4.97 millimoles) of potassium carbonate in 5 milliliters of dioxane. The title compounds are each obtained as yellow oils. TLC: methylene chloride / acetone (100: 5) R, = 0.09 and R, = 0.43. FD-MS: M + = 560 and 690.

Example 12: (2R.4S) -N- [2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] -2-dime * - • »" '"" "" oacetamide In a manner analogous to Example 5, 168 milligrams (0.391 mmol) of (2R, 4S) -4-amino-2-benzyl-1- (3, 5-bistri-fluoromethylbenzoyl) iperidine, in 5 milliliters of methylene chloride, are reacted with 109 milligrams (0.43 millimoles) of bis (2-oxo-3-oxazolidinyl) phosphinoyl chloride, 119 milligrams (1.18 millimoles) of triethyl amine, and 44 milligrams (0.43 millimoles) of N, N-dimethyl glycine. The hydrochloride of the title compound is obtained as white crystals. P.f. 233-238 ° C; TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.61, FD-MS: M + = 515.

Example 13: (2R.4S) -2- .2-Benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidin-4-ylamino] -N, N-dimethylacetamide hydrochloride. v (2R.4S) -2-. { .2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) pÍperidin-4- il] dime ilcarbamoylmethylamino} -N, N-dimethylacetamide In a manner analogous to Example 1, 434 milligrams (1.01 mmol) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) iperidine are reacted with 195 milligrams (1.61 mmol). millimoles) of acetamide 2-chloro-N, N-dimethyl and 1.11 grams (8.05 millimoles) of potassium carbonate in 5 milliliters of dioxane. The title compounds are obtained as white crystals or as a white foam. P.f .: 127-130 ° C; TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.49 and Rf = 0.56. FD-MS: M + = 515 and 600.

Example 14: (2R, 4S) -N- [2-benzyl-1- (3,5-bistrifluorome ilben-zpiljpjperidin-4-ill -2- (morpholin-4-yl) acetamide In a manner analogous to Example 5, 215 milligrams (0.50 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine in 2 milliliters of dioxane are reacted with 178 milligrams (0.70 millimoles) of bis- (2-oxo-3-oxazolidyl) phosphinoyl chloride, 400 milligrams (4 millimoles) of triethyl amine, and 109 milligrams (0.75 millimoles) of morpholin-4-ylacetic acid, prepared from 69.7 milligrams (0.8 millimoles) of morpholine and 104 milligrams (0.75 millimoles) of bromoacetic acid. The title compound is crystallized from hexane / ether on white needles. P.f. 116-120 ° C; TLC: methylene chloride / methanol / concentrated ammonia (95: 4.5: 0.5) Rf = 0.39, FD-MS: M + = 557.

Example 15: (2R.4S) -2- [2-benzyl-l- (3,5-bistri-fluoromethylbenzoiDpiperidin - * - '? »Tn-inn] -" cyclohexyl oetate, and (2R, 4S) hydrochloride ) -2- { [2-benzyl-l- (3, 5-bistrifluoromethyl-benzoyl) piperidin-4-yl] -N- (cyclo-exoxycarbonylmethyl) »™ -" - -> -. of cyclohexyl In a manner analogous to Example 1, 427 milligrams (0.993 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3, 5-bistri-fluoromethylbenzoyl) iperidine are reacted with 298 milligrams (1.69 millimoles) ) of cyclohexyl 2-chloroacetate and 700 milligrams (5.07 millimoles) of potassium carbonate in 5 milliliters of dioxane. The hydrochlorides of the title compounds are each obtained as white crystals. P.f .: 172-174 ° C and 185-190 ° C; TLC: methylene chloride / acetone (10: 1) Rf = 0.08 and Rf = 0.43. FD-MS M + = 570 and 710.

Example 16: (2R.4S) -4-amino-2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) -N- (3-dimethylaminopropyl) piperidine dihydrochloride and (2R.4S) -N- [2-benzyl- 1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] carb »™» < - ^ 3-dimethylaminopropyl In a manner analogous to Example 1, 432 milligrams (1.00 mmol) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine are reacted with 286 milligrams (1.81 mmol) of l-chloro-3 hydrochloride -dimetila- minopropane and 793 milligrams (5.74 millimoles) of potassium carbonate in 5 milliliters of acetonitrile. The title compounds are obtained as white crystals, m.p. 198-202 ° C or as a white foam; TLC: methylene chloride / methanol / concentrated ammonia (85: Í3.5: 1.5) Rf = 0.18 and Rf = 0.39. FD-MS: M + = 515 and 559.

Example 17: (2R.4S) -2-benzyl-1- (3,5-bistrifluoromethylbenzoiD- -morpholin-4-ylpjperidine 342 milligrams (2.39 millimoles) of 2,2 * -dichloro-diethyl ether and 750 milligrams (5.43 millimoles) of potassium carbonate are added to a solution of 234 milligrams (0.544 millimoles) of (2R, S) -4-amino -2-benzyl-1- (3, 5-bistrifluoromethyl-benzoyl) piperidine in 30 milliliters of dioxane, and the mixture is stirred at 120 ° C in a pressure tube for 14 days. The solid is then filtered, the filtrate is diluted with methylene chloride, and the organic phase is extracted with an aqueous solution of 1 N potassium carbonate, dried over sodium sulfate, and evaporated to dryness. The crude product is passed through chromatography on silica gel using ethyl acetate / acetone (95: 5). He compound of the title is obtained as a white foam. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) R, = 0.53, FD-MS: M + = 500.

Example 18: (2R.4S) -4-amino-2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) -N-isobutyl-4-piperidine hydrochloride. v (2R.4S) -N- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) piperidin-4-yl] isobutyl carbamate In a manner analogous to Example 1, 404 milligrams (0.939 mmol) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine are reacted with 220 milligrams (1.60 millimoles) of isobutyl bromide and 1.2 grams (8.5 millimoles) of potassium carbonate in 5 milliliters of dioxane. The title compounds are obtained as clear chestnut foams: TLC: ether / hexane (3: 1) Rf = 0.14 and Rf = 0.48. FD-MS: M + = 486 and 530. rcit »1? 19; (2R, 4S) -4-amino-2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) -N- (2,2-dimethylpropyl) piperidine hydrochloride 111 milligrams (1.3 millimoles) of pivalic aldehyde and 500 milligrams of magnesium sulfate are added to a solution of 429 milligrams (0.997 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3, 5- bistrifluoromethylbenzoyl) piperidine in 1 milliliter of methylene chloride, and the mixture is stirred at room temperature for 18 hours. Then it is filtered, the filtrate is concentrated on a rotary evaporator and the residue is dissolved in methanol. 50 miLigrams (1.3 mmol) of sodium borohydride are added at 0 ° C, and the mixture is stirred for 1 hour. It is then treated with acetone, subsequently stirred for 1 hour, and evaporated to dryness on a rotary evaporator. The crude product is chromatographed on silica gel using ether / hexane (3: 1). After treatment with an ethereal solution of hydrogen chloride, the title compound is obtained as a light brown foam. TLC: ether / hexane (3: 1) Rf = 0.37, FD-MS: M + = 500.

Example 20: (2R, 4S) -2- .2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4 • »T»? or] 2-methoxyethyl acetate and (2R, 4S) - [[2-benzyl-1- (3,5-bistrifluoromethyl-benzoiDpiperidin-4-yl] -N- (2- methoxyethoxycarbonylmethyl) aminol 2-methoxyethyl acetate In a manner analogous to Example 1, 442 milligrams (0.993 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine are reacted with 282 milligrams (1.85 milligrams). millimoles) of 2-methoxyethyl chloroacetate and 700 milligrams (5.07 millimoles) of potassium carbonate in 5 milliliters of dioxane. The title compounds are each obtained as brown oils. TLC: methylene chloride / acetone (3: 1) Rf = 0.33 and Rf = 0.83. FD-MS: M = 546 and 662.

Example 21: (2R.4S) -N- [2-benzyl- (3, 5-bistrifluoromethylbenzoyl) piperidin-4-yl] carbamate 2-dime * "i t? ™,» noethyl In a manner analogous to Example 17, 403 milligrams (0.936 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistri-fluoromethylbenzoyl) piperidine are reacted with 230 milligrams (1.50 millimoles) of l-chloro-2-dimethylaminoethane hydrochloride and 647 milligrams (4.68 millimoles) of potassium carbonate in 5 milliliters of diaxane in a pressure tube. The title compound is obtained as a beige foam. TLC: metilepo / methanol / concentrated onylamide chloride (90: 9: 1) R- = 0.49. FD-MS: M + = 545.

Example 22: (2R.4S) -N-r2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl acetate 95 milligrams (0.934 millimoles) of acetic anhydride are added to a solution of 200 milligrams (0.467 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidine and 95 milligrams ( 0.934 millimoles) of triethyl amine in 2 milliliters of methylene chloride, and the reaction mixture is stirred at room temperature for 2.5 hours. It is then diluted with methylene chloride, and the organic phase is extracted once with an aqueous solution of 1N sodium hydroxide and once with 1N aqueous hydrochloric acid, dried over sodium sulfate, and evaporated to dryness. The crude product is passed through chromatography on silica gel, using methyl ether tertiary butyl / methanol / concentrated cimoniac (95: 4.5: 0.5). The title compound is obtained as a yellow oil. TLC: methyl tertiary butyl ether / methane / concentrated ammonia (95: 4.5: 0.5) R, = 036, FD-MS: M + = 472.

Example 23: (2R, 4S) -N- [2-benzyl-l- (3,5-dimethylbenzoyl) pjperi-din-4-illbutyramide In a manner analogous to Example 22, 200 milligrams (0.62 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-dimethylbenzoyl) piperidine (European Patent Number EP 532456 A) is they react with 73 milligrams (0.682 millimoles) of butyryl chloride and 72 milligrams (0.713 millimoles) of triethyl amine in 2 milliliters of tetrahydrofuran. The title compound is obtained as white crystals. P.f: 151-154 ° C; hexane / ethyl acetate (1: 5) Rf = 0.28. FD-MS: M + = 392. g-jam io 34 • (2R, 4S) -N- [2-benzyl-l- (3,5-dichlorobenzoyl) piperi-din-4-yl] butyramide In a manner analogous to Example 22, 200 milligrams (0.62 millimoles) of (2R, 4S) -4-amino-2-benzyl-1- (3,5-dichlorobenzoyl) piperidine (European Patent Number EP 532456 A) is they react with 70 milligrams (0.661 millimoles) of butyryl chloride and 111 milligrams (1.1 millimeters) of triethyl amine in 2 milliliters of methylene chloride. The title compound is obtained as white crystals. P.f. 122 ° C; TLC: hexane / ethyl acetate (1: 2) Rf = 0.24. FD-Ms: M + = 432.

Example 25: (2R.4S) -N- ri- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-ip formamide A solution of 200 milligrams (0.43 mmol) of amine (2R, 4S) -1- (3,5-bistrifluoramethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl in 5 milliliters of butyl formate was heat at reflux for 90 minutes. After cooling, the reaction mixture is evaporated under reduced pressure. The residue is crystallized from ethyl acetate / hexane. The title compound is obtained with white crystals. P.f .: 196-198 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.55, FD-MS: M + = 492; [o] D = -13.1 degrees (c = l, EtOH).

The starting compound can be prepared, for example, as follows: a) Methyl (1-4-chlorobenzyl) but-3-enyl ethoxymethylcarbamate A suspension of 10.0 grams of sodium hydride (80 percent in mineral oil, 333 mmol) in dry THF (tetrahydrofuran), is heated under reflux under argon . A solution of 60.5 grams (238 millimoles) of methyl [l- (4-chlorobenzyl) but-3-enyl] carbamate in 50 milliliters of dry tetrahydrofuran is added dropwise over the course of 1 hour. The mixture is then refluxed for an additional 2 hours until gas evolution ceases. The mixture is cooled to 0 ° C, and chloromethyl ethyl ether is added dropwise, so that the temperature of the reaction does not rise above 5 ° C. After this, the mixture is heated slowly to 25 ° C, and stirred for 12 hours. The excess of sodium hydride is destroyed with caution with one milliliter of water before adding more water. The phases are separated, and the aqueous phase is extracted again with methyl tertiary butyl ether. The combined organic phases are washed with brine, dried over sodium sulfate, and evaporated. The crude product is distilled at 0.1 mbar, and has a boiling scale of 120-125 ° C. TLC: ethyl acetate / hexane (1: 6) Rf = 0.34, FD-MS: M + = 311 (313). b) (2R * .4S *) -4-acetylamino-2- (4-chlorobenzyl) piperidin-1-methyl carboxylate Initially 20.6 milliliters (308 millimoles) of chlorosulfonic acid are introduced into 500 milliliters of acetonitrile at -40 ° C . A solution of 48.0 grams (154 millimoles) of methyl [1- (4-chlorobenzyl) but-3-enyl] ethoxymethylcarbamate in 50 milliliters of acetonitrile is added dropwise, so that the reaction temperature does not rise further. beyond -10 ° C. The mixture is then stirred at -15 ° C for a further 20 minutes, before the reaction is treated with 370 milliliters of a 2N sodium hydroxide solution and 100 milliliters of an aqueous solution of sodium hydrogen carbonate at a concentration of 10%. percent. The phases are separated and the aqueous phase is extracted twice more with toluene. The combined organic phases are dried over sodium sulfate. The crude product is crystallized from toluene, and gives the title compound as white crystals. P.f .: 169-170 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.42, FD-MS M + = 325. c_L (2R * .4S *) -N- \ 2 - (4-chlorobenzyl) piperidin-4-ill acetamide It is treated (2R *, 4S *) -4-acetylamino-2- (4-chlorobenzDpipe-ridin-l- Methyl carboxylate (30.0 grams, 92.3 millimoles) with 51.8 milliliters of hydrogen bromide at a concentration of 33 percent in acetic acid After 16 hours, the mixture is treated with 200 milliliters of water, and washed twice with toluene The aqueous phase is made basic and extracted twice with ethyl acetate. The organic phases are dried over potassium carbonate and evaporated on a rotary evaporator. The title compound is crystallized from EtOH / ethyl acetate as the hydrochloride. P.f. 288-289 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.17, FD-MS: (M + l) + = 267. d) Acetate of (2 'S, 2R.4S) -2- [4-acetylamino-2- (4-chlorobenzylo) piperidin-1-ill-2-oxo-1-phenylethyl Initially N-hydrochloride is introduced [2- (4-Chlorobenzyl) piperidin-4-yl] acetamide racemic (20.5 grams, 67.6 mmol) in 34 milliliters of a 2N sodium hydroxide solution, 150 milliliters of an aqueous solution of sodium hydrogen carbonate at a concentration of 10 percent, and 50 milliliters of methylene chloride, with vigorous stirring at 0 ° C. S (+) - O-acetylmandeloyl chloride [2] (14.9 grams, 70 mmol) is added dropwise to this mixture over the course of 1 hour. The mixture is subsequently stirred at + 4 ° C for 1 hour. The phases are separated, and the organic phase is dried over sodium sulphate and evaporated on a rotary evaporator. The title compound is isolated as a pure diastereomer after being crystallized twice from methylene chloride / tertiary butyl methyl ether. P.f .: 209-211 ° C. TLC: methylene chloride / isopropanol (9: 1) Rf = 0.65, FD-MS: M + = 443. [c.] D = +77.5 degrees (c = 1, methylene chloride). The mother liquors mainly contain the non-crystalline diastereomer (2'S, 2S, 4R) -N- | 2- (4-chlorobenzyl) -l- (aceto-xyphenylacetyl) piperidin-4-yl] acetamide. TLC: methylene chloride / isopropanol (9: 1) Rf = 0.70. (2R.4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine. (2'S, 2R, 4S) -2- [4-acetylamino-2- (4-acetate) is boiled. -chlorobenzyl) piperidin-1-yl] -2-oxo-1-phenylethyl (37.4 grams, 84.5 mmol) under reflux for 2 days in 370 milliliters of 6N hydrochloric acid. After cooling, the mixture is made basic with sodium hydroxide, and extracted with methylene chloride. The combined organic phases are dried over potassium carbonate, and evaporated on a rotary evaporator. The residue, consisting of (2R, 4S) -4-amino-2- (4-chlorobenzyl) piperidine almost pure (19.0 grams, 84.5 millimoles, 100 percent), is treated with 8.5 milliliters (84.5 millimoles) of benzene aldehyde , and the mixture is concentrated twice on a rotary evaporator using 150 milliliters of toluene. The oily residue is recovered in 180 milliliters of methylene chloride and 15.3 milliliters (110 millimoles) of triethyl amine, and the solution is cooled to 10 ° C. Bistrifluoromethylbenzoyl chloride (25.7 grams, 92.9 millimoles) is added dropwise during the course 15 minutes, and the mixture is then stirred at 25 ° C for 1 hour. The mixture of The reaction is treated with 250 milliliters of 1 N HCl, and the methylene chloride is removed under reduced pressure on a rotary evaporator. Hexane and ethanol are added until two homogeneous phases result. After separating the organic phase, the aqueous phase is further washed with hexane, until all the benzene aldehyde has been removed. The mixture is made basic with solid sodium hydroxide, and extracted repeatedly with methylene chloride. The organic phases are dried over sodium sulfonate and concentrated on a rotary evaporator. Crystallization from tertiary butyl methyl ether / hexane gives the title compound as white crystals. P.f .: 79-81 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1), Rf = 0.21, FD-MS: (M + l) + = 465. [a] D = -12.7 degrees (c = 1, chloride methylene).

Example 26: (2R.4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -acetamide (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine (232 milligrams, 0.5 mmol) is treated with 102 milligrams (1 millimole) of acetic anhydride in 0.5 milliliters of pyridine. After 1 hour, 0.5 milliliters of a 1N sodium hydroxide solution are added, and they are stirred for 2 hours. The mixture is taken up in ethyl acetate, washed with HCl, 1N, brine, and a 10 percent aqueous sodium carbonate solution, dried over sodium sulfate, and evaporated on a rotary evaporator. The crude product is crystallized from diethyl ether, and gives the title compound as white crystals. P.f .: 120-123 ° C. TLC: methylene chloride / methanol (19: 1) Rf = 0.60, FD-MS: M + = 506 (508). [a] D = -5.0 degrees (c = 1, EtOH).

R-jynpln 27- (2R.4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chloroben-yl) piperidin-4-yl] -propione ida In a manner analogous to Example 26, 232 milligrams (0.5 millimoles) of (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine are reacted with 130 milligrams ( 1 millimole) of propionic anhydride in 0.5 milliliters of pyridine. The title compound is obtained as white crystals, mp .: 106-110 ° C. TLC: methylene chloride / methanol (19: 1) Rf = 0.50, FD-MS: M + = 520 (522) [? F] D * -11.3 degrees (C = 1, EtOH).

Example 28: (2R.4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-ill-butyramide In a manner analogous to Example 26, 232 milligrams (0.5 millimoles) of (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine are reacted with milligrams (1 millimole) of butyric anhydride in 0.5 milliliters of pyridine. The title compound is obtained as white crystals, M.p .: 143-145 ° C. TLC: methylene chloride / methanol (19: 1) Rf = 0.53, FD-MS: M + = 534 (536) [? F] D = -13.7 degrees (c = 1, EtOH).

B-j «am io 2; N-.2-benzyl-1- (3,5-dimethylbenzoyl) pjperidin-4-yl] 2,2,2-trifluoroacetamide The (2R, 4S) -4-amino-2-benzyl-1- (3,5-dimethylbenzoyl) piperidine (European Patent Number EP 532456 A) (200 milligrams, 0.62 millimole), is reacted with 104 milligrams (0.682 millimeter) - 3) of trifluoroacetic anhydride in 3 milliliters of methylene chloride. After 2 hours, the mixture is diluted with ethyl acetate, and washed with an aqueous solution of sodium carbonate in a concentration of 10 percent. The organic phase is dried over sodium sulfate, and evaporated. The crude product is passed through chromatography on silica gel, using ethyl acetate / hexane (1: 2). The title compound is obtained as a yellow foam. TLC: hexane / ethyl acetate (1: 1) Rf = 0.37. FAB-MS: (M + H) + = 419.

Example 30: (2R.4S) -2-Acetylamino-N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] - * n * ft-fmi? M (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine (195 milligrams, 0.42 millimole) is treated with 49 milligrams (0.42 millimoles) of N-acetylic glycine , 101 milligrams of triethyl amine (1 millimole), and 117 milligrams (0.46 millimoles) of bis (2-oxo-3-oxazolidinyl) phosphinoyl chloride in 3 milliliters of methylene chloride. After 48 hours, the mixture is diluted with ethyl acetate, and washed with an aqueous solution of sodium carbonate in a concentration of 10%. percent, 1N hydrochloric acid, and brine. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is passed through chromatography on silica gel, using methylene chloride / methanol (95: 5). The title compound is obtained as a white lyophilizate. TLC: methylene chloride / methanol (95: 5). Rf = 0.38, FD-MS: M + = 563 (565); [a] D = -6.4 degrees (c = 1, EtOH).

Example 31: (2R.4S) -N-. 1 - (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -H -> isobutyl In a manner analogous to Example 1, 250 milligrams (0.87 millimoles) of (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine, are reacted with 220 milligrams (1.60 millimoles) of isobutyl bromide and 1.2 grams (8.5 millimoles) of potassium carbonate in 5 milliliters of dioxane. The title compound is obtained as white crystals. P.f .: 128-130 ° C. TLC: ethyl acetate / hexane (1: 1) Rf = 0.78, FAB-MS: (M + H) + = 565; [a] D = -12.8 degrees (c = l, EtOH), Example 32: (2R, 4S) -2- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-ylamino] acetamide Ammonia gas is passed into a solution of 130 milligrams (0.24 millimoles) of (2R, 4S) -2- [1- (3, 5-bistri-fluorome-ilbenzoyl) -2- (4-chlorobenzyl) piperidin-4 -amino] methyl acetate, in 5 milliliters of methanol at 0 ° C for 10 minutes, and the reaction mixture is allowed to stand at room temperature for 60 hours. Evaporation of the reaction mixture affords the title compound as a colorless oil. TLC: methylene chloride / methanol (95: 5) Rf = 0.10, FD-MS: M + = 521; [a] D = -13.1 degrees (c = 1, EtOH).

The starting compound can be prepared, for example, as follows: (2R.4S) -2- TI- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-ylaminol methyl acetate, v (2R.4S) -2-y- (3.5-bistri -fluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl-1-N-methoxycarbonylmethylamino} methyl acetate In a manner analogous to Example 1, the title compounds are each obtained from 400 milligrams (0.86 millimoles) of (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4 -chlorobenzyl) piperidine and 156 milligrams (1.03 millimoles) of methyl bromoacetate as colorless oils. TLC: methylene chloride / methanol (95: 5) Rf = 0.75 and Rf = 0.48. Compound with Rf = 0. 75 (methylene chloride / methanol (95: 5)): ^ -RMN (200 MHz, CDC13): d (mixture of rotamers) 7.90--7.80 (m, 1H), 7.52 (s, 1H), 7.34-7.17 (m, 4H), 6.85-6.78 (m, 1H), 5.31-5.17 (m, 0.5H), 4.80-4.67 (m, 0.5H), 3.93-3.80 (m, 0.5H), 3.70 (s, 6H) , OMe), 3.64-3.54 (m, 4H, CH2C00Me), 3.5-2.9 (m, 3.5H), 2.69-2.57 (m, 0.5H), 2.17-1.83 (m, 2H), 1.56-1.23 (m, 2H). Compound with Rf = 0.48 (methylene chloride / methanol (95: 5)):? -NRM (CDC13): d (mixture of rotamers) 7.90-7.80 (m, 1H), 7.55 (s, 1H), 7.37-7.13 * (m, 4H), 6.88-6.80 (m, 1H), 5.34-5.18 (m, 0.5H), 4.80-4.68 (m, 0.5H), 3.92-3.77 (m, 0.5H), 3.78 (s, 3H), 3.50-3.43 (m, 2H), 3.5-2.9 (m, 3.5H), 2.68-2.55 (m, 0.5H), 2.2-1.2 (m, 4H).

Example 33: (2R.4S) -2-. { [1- (3,5-blstrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl) -N-carbamoylmethylamino} acetamide In a manner analogous to Example 32, 140 milligrams (0.22 millimoles) of (2R, 4S) -2-. { [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -N-methoxycarbonylmethylamino} methyl acetate in 5 milliliters of methanol, treated with ammonia gas. The crude product is crystallized from diethyl ether / hexane. The title compound is obtained as white crystals. P.f. 168-170 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.19, FD-MS: M * = 578; [? f] D * -6.4 degrees (c = 1, EtOH).

Example 34: (2R * .4S *) -N- [1- (3,5-dimethylbenzoyl) -2- (4-nitrobenzyl) piperidin-4-ill actamide 188 milligrams (1.11 millimoles) of 3,5-dimethylbenzoyl chloride are added to a stirred suspension of 370 milligrams (1.11 millimoles) of (2R *, 4S *) -N- [2- (4-nitrobenzyl) piperidin-4- il] acetamide in 5 milliliters of methylene chloride and 5 milliliters of an aqueous solution of sodium hydrogencarbonate in a concentration of 10 percent at 0-5 ° C within 1 hour. The mixture is subsequently stirred at 25 ° C for an additional 1 hour. The organic phase is dried over sodium sulphate and evaporated. The crude product is crystallized from ethyl acetate / ether, and gives the title compound as white crystals. P.f .: 198-200 ° C. TLC: methylene chloride / methanol (9: 1) Rf = 0.40. FD-MS: M + = 409.

The starting compound can be prepared, for example, as follows: a) Benzyl 2- (4-nitrobenzyl) but-3-enyl carbamate 2- (4-nitrobenzyl) pent-4-enoic acid (9.3 grams, 40.0 mmol) is treated in toluene with 11.55 grams (42.0 mmol) of diphenylphosphoryl azide at 50 ° C in the presence of triethyl amine (5.6 milliliters, 40.0 mmol) and benzyl alcohol (5.18 grams, 48.0 mmol). After 20 minutes, the temperature increases slowly, and then the mixture is boiled under reflux for another 3 hours. After cooling, the reaction mixture is washed twice with a solution of 1N sodium hydroxide, twice with 1N hydrochloric acid, and twice with brine, dried over sodium sulfate, and evaporated on a rotary evaporator. The title compound is obtained as white crystals after crystallization of the crude product from toluene / hexane. P.f .: 94-95 ° C. TLC: ethyl acetate / hexane (1: 3) Rf 0.22. b) benzyl n- (4-nitrobenzyl) but-3-enyl-1-ethoxymethylcarbamate A mixture of 10 milliliters of an aqueous solution of sodium hydroxide in a concentration of 50 percent, 25 milliliters of methylene chloride, and 130 milligrams (0.4 millimoles) of benzyltributyl ammonium chloride, vigorously stirred at 5-10 ° C. Benzyl [1- (4-nitrobenzyl) but-3-enyl] carbamic acid (6.8 grams, 20.0 mmol) is added in one portion, followed by 2.64 grams (28 mmol) of chloromethyl ethyl ether over a period of 2 hours. The mixture is then stirred at room temperature for 1 hour, diluted with ice and water, and extracted with methylene chloride. The organic phase is dried over sodium sulphate, evaporated and chromatographed on silica gel (hexane / ethyl acetate (10: 1)). The title compound is obtained as a colorless oil. TLC: ethyl acetate / hexane (1: 3) Rf = 0.41. FD-MS: M +: 398. b) (2R. **. 4.S- * ') -. Benzyl-4-acetylamino-2- (4-nitrobenzyl) piperidine-1-carboxylate In a manner analogous to Example 25b, 5.0 grams (12.6 millimoles) of benzyl [1- (4-nitrobenzyl) but-3-enyl] -ethoxymethylcarbamate are reacted with 1.77 grams (25.2 millimoles) of chlorosulfonic acid in acetonitrile. Chromatography on silica gel (methylene chloride / methanol 95: 5) gives the title compound as a colorless resin. TLC: methylene chloride / methanol (9: 1) Rf = 0.40; FD-MS: (M + H) +: 412. ci (2R * .4S *) -N- \ 2- (4-nitrobenzyl) piperidin-4-yl-1-acetamide The (2R *, 4S *) -4-acetylamino-2- (4-nitrobenzyl) piperidin-1- Benzyl carboxylate (2.65 grams, 6.45 mmol) is treated with concentrated hydrochloric acid, and heated at 55 ° C for 2 hours, with gas evolution occurring. The reaction mixture is washed twice with hexane, and evaporated under reduced pressure on a rotary evaporator. The hydrochloride of the title compound is obtained as white crystals containing 3 molecules of water of crystallization. P.f. > 250 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.29. ? -NRM (200 MHz, D20): d 8.26 (d, 2H), 7.59 (d, 2H), 4.26-4.17 (m, 1H), 3.90-3.72 (m, 1H), 3.40-3.02 (m, 4H ), 1.99 (s, 3H), 2.06-1.75 (m, 4H).

Example 35: (2R, 4S) -N- [1- (3, 5-dimethylbenzoyl) -2- (4-cyanoben-cyl) piperidin-4-yl] -acetamide In a manner analogous to Example 34, the title compound is obtained as white crystals. P.f. 154-157 ° C; FD-MS: M +: 389.

Example 36: (2R *, 4S *) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-cyanobenzyl) piperidin-4-yl] -acetamide In a manner analogous to Example 34, the title compound is obtained as a white foam. TLC: chloride methylene / methanol / concentrated ammonia (90: 9: 1) Rf = 0.50, FD-MS: M + = 497.

Example 37: (2R *, 4S *) -N- [1- (3,5-dichlorobenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -acetamide In a manner analogous to Example 34, the title compound is obtained as white crystals. P.f. 176-179 ° C. TLC: methylene chloride / methanol (19: 1) Rf = 0.37, FAB-MS: (M + H) + = 439.

Example 38: (2R *. 4S *) -N- [1- (3,5-dimethylbenzoyl) -2- (4-methoxybenzyl) piperidin-4-yl] -acetamide In a manner analogous to Example 34, the title compound is obtained as white crystals. P.f. 175-176 ° C. TLC: methylene chloride / methanol (9: 1) Rf = 0.54, FD-MS: M + = 394 Example 39: (2R, 4S) -N- Cl- (3,5-bistrif luoromethylbenzoyl) -2- (3-methoxybenzyl) piperidin-4-ill -acetamide In a manner analogous to Example 34, the title compound is obtained as a lightly colored resin. TLC: methylene chloride / methanol (9: 1) Rf = 0.49, FD-MS: M + = 502.

Example 40: (2R *, 4S *) -N- ti- (3, 5-dimethylbenzoyl) -2- (4-trifluoro-methylbenzyl) piperidin-4-ill -acetamide In a manner analogous to Example 34, the title compound is obtained as white crystals. P.f. 210-212 ° C. TLC: methylene chloride / methanol (9: 1) Rf = 0.46, FD-MS: M + «432.

Example 41: (2R, 4S) -N- [1 - (3,5-dimethyl-l-benzoyl-1) -2- (2,4-dichlorobenzyl) -piperidin-4-yl] -acetamide In a manner analogous to Example 34, the title compound is obtained as white crystals. P.f. 214-219 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.65; FD-MS: M + = 432.

Example 42: (2R * .4S *) -N- [1- (3, 5-dimethylbenzoyl) -2- (2-naphthyl) pi-peridin-4-yl] -a ^ t * "" "1 * In a manner analogous to Example 34, the title compound is obtained as white crystals. P.f. 190-192 ° C. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0. 57; FAB-MS (M + H) = 415.

Example 43: (2R, 4S) -N- [1- (3, 5-dimethylbenzoyl) -2- (4-vodobenzyl) piperidin-4-yl] -acetamide In a manner analogous to Example 34, the title compound is obtained as a colorless resin. TLC: methylene chloride / methanol / concentrated ammonia (90: 9: 1) Rf = 0.50, FD-MS: (M + H) + = 491. rcirr1"4A? (2R.4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] - en * -ftn ^ n-iH" To a solution of 15.0 grams (32.3 mmol) of (2R, 4S) -4-amino-1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidine (see Example 25e) in 40 milliliters of chloride of methylene and 20 milliliters of 2N NaOH, is cooled to 0 ° C with vigorous stirring using an ice / salt bath. A solution of 3.97 grams (32.94 millimoles) of valeryl chloride in 3 milliliters of methylene chloride is added rapidly, so that the temperature of the reaction does not exceed 5 ° C. Subsequently the mixture is stirred for an additional 1 hour. The mixture is diluted with methylene chloride, and the aqueous phase is separated. The organic phase is washed with 1 N NaOH, and dried over Na 2 SO 4. After concentrating on a rotary evaporator, the title compound is crystallized as colorless needles from ethyl acetate / hexane. P.f. 163-165 ° C. TLC: ethyl acetate, Rf = 0.67, FAB-MS: (M + H) + = 549, (M-H) '= 549. [alpha] D = -13.6 degrees (c = 1, EtOH).

Example 45: (2R, 4S) -1- (1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-tertiary butyl-urea 1.18 grams (11.9 millimoles) of tertiary butyl isocyanate are added dropwise at 0 ° C to a solution of 5.0 grams (10.8 millimoles) of (2R, 4S) -4-amino-1- (3, 5-bistrifluorome- tylbenzoyl) -2- (4-chlorobenzyl) piperidine and 0.26 grams (2.2 mmol) of 4-dimethyl aminopyridine in 50 milliliters of methyl tertiary butyl ether over the course of 1 minute. Then the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with tertiary butyl methyl ether, and washed with 1N hydrochloric acid and with brine, dried over magnesium sulfate, and evaporated on a rotary evaporator. The title compound is crystallized from methyl tertiary butyl ether / hexane as white crystals. P.f .: 117 ° C; FD-MS: M + = 563 and 565; [alpha] D = -3.0 degrees (c = 1, C flr). The following can be prepared, for example, in an analogous manner: (b) (2R, 4S) -1- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) pi? Eridin-4-yl ] -3-isopropylurea; (c) (2R, 4S) -1- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-ethylurea; (d) (2R, 4S) -1- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-cyclohexylurea; (e) (2R, 4S) -1- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) iperidin-4-yl] -3-propylurea; (f) (2R, 4S) -l- [2-benzyl-1- (3,5-bistrifluoromethylben- zoil) piperidin-4-yl] -3-cyclohexylurea; (g) (2R, 4S) -l- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] -3-tertiary butyl-urea; and (h) (2R, 4S) -l- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] -3-isopropylurea.

Example 46: The following can be prepared in an analogous manner, for example, as described in one of Example 1 a 44 previous. (2R, 4S) -2- [2-benzyl-1- (3, 5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] octyl acetate, and (2R, 4S) -2-. { [2-benzyl-1- (3, 5-b istrif luoromet i1 ben-zoyl) piperidin-4-yl] -methoxycarbonylmethylamino} normal octyl acetate; (2R, 4S) -2- [2-benzyl-1- (3, 5-bistrifluoromethylbenzoyl) pi-peridin-4-ylamino] decyl acetate, normal; and (2R, 4S) -2-. { [2-benzyl 1-1- (3, 5-bistrif luoromet ilben-zoyl) piperidin-4-yl] -methoxycarbonylmethylamino} decile acetate normal. (2R, 4S) -2- [2-benzyl-1- (3, 5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] dodecyl acetate, and (2R, 4S) -2-. { [2-benzyl-1- (3, 5-b is trifluoromet i l ben-zoi l) piperidin-4-yl] -methoxycarbonylmethyllamino} normal dodecyl acetate. g1? mp'lf * 7; You can prepare tablets that contain, for example 50 milligrams each, for example, of (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] butyramide or a salt, for example , the hydrochloride, as follows: Composition (10,000 tablets) Active ingredient 500.0 grams Lactose 500.0 grams Potato starch 352.0 grams Gelatine 8.0 grams Talcum 60.0 grams Magnesium stearate 10.0 grams Silica (highly dispersed) 20.0 grams Ethanol q.s.

The active ingredient is mixed with lactose and 292 grams of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin, and granulated through sieve. After drying, the rest of the potato starch, magnesium stearate, talc, and silica are mixed and the mixture is compressed into tablets weighing 145.0 milligrams each and containing 50.0 milligrams of active ingredient. which, if desired, can be provided with notches for cut, for a finer adjustment of the dose.

Example 48: Film-coated tablets containing, for example, 100 milligrams each can be prepared, for example, from (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl ) piperidin-4-yl] butyramide, or a salt, for example, the hydrochloride thereof, as follows: Composition (for 1,000 film coated tablets) Active ingredient 100.0 grams Lactose 100.0 grams Corn starch 70.0 grams Talc 8.5 grams Calcium stearate 1.5 grams Hydroxypropylmethyl cellulose 2.36 grams "Shellac" 0.64 grams Water is, methylene chloride c.s, The active ingredient, lactose, and 40 grams of corn starch, are mixed and moistened with a paste prepared from 15 grams of corn starch and water (with heating), and granulated. The granules are dried, and the rest of the corn starch, talc, and calcium stearate are added, and they mix with the granules. The mixture is compressed to give tablets (weight: 280 milligrams) and these are coated with a solution of the hydroxypropylmethyl cellulose and the "Shellac" in methylene chloride; final weight of the film-coated tablet: 283 milligrams.

Example 49: Hard gelatin capsules containing 100 milligrams of active ingredient can be prepared, for example, (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin -4-yl] butyramide, or a salt, for example, the hydrochloride thereof, for example, as follows: Composition (for 1,000 capsules) Active ingredient 100.0 grams Lactose 250.0 grams Microcrystalline cellulose 30.0 grams Sodium lauryl sulfate 2.0 grams Magnesium stearate 8.0 grams Sodium lauryl sulfate is sieved into the lyophilized active ingredient through a sieve having a mesh width of 0.2 millimeters. Both components are intimately mixed. The lactose is then sieved first through a sieve having a mesh width of 0.6 millimeters and then sieves the microcrystalline cellulose through a sieve that has a mesh width of 0.9 millimeters. After this, the constituents are again mixed intimately for 10 minutes. Finally, the magnesium stearate is sieved through a sieve having a mesh width of 0.8 millimeters. After mixing for another 3 minutes, 390 milligrams of the formulation obtained is filled into each of size 0 hard gelatin capsules.

Example 50: In an analogous manner, for example, as described in Examples 47 to 49 above, pharmaceutical compositions containing another compound of formula I, or a salt thereof, can also be prepared according to one of the examples of previous preparation.

Claims

1. An l-acyl-4-aliphatilaminopiperidine compound of the formula I: wherein: Rj is a benzoyl, naphthoyl, or cycloalkanoyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is cycloalkyl or a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R ^ are together lower alkylene or aza-, oxa-, or thia-lower alkylene; or R3 is lower alkyl, lower alkoxy-lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CHC (= 0) -R (la); and R ^ is hydrogen, lower alkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (Ia); R5 is (i) hydrogen, alkyl, or alkyl that is substituted by halogen, lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono- or lower dialkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or alkylene lower, or aza-, oxa-, or thia-lower alkylene, (ii) hydroxyl, cycloalkoxy, lower alkoxy, or lower alkoxy which is substituted by lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, or (iii) amino, or amino substituted by lower alkyl, cycloalkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, - Xj is methylene, ethylene, a direct bond, a free carbonyl group or ketalized, or a hydroxymethylene group free or etherified; and n is 0 or 1, or a salt thereof.

2. A compound according to claim 1, with the exception of the compound (2R *, 4S *) -N- [l- (3,5-bistrifluoromethylbenzoyl) -2- (4-nitrobenzyl) -piperidin-4-yl ] acetamide.

3. A compound according to claim 1 or 2, of the formula I, wherein: Rt is a benzoyl, naphthoyl, or cycloalkanoyl radical of 3 to 8 members that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is 3 to 8 membered cycloalkyl, or a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R4 are together lower alkylene or aza-, oxa-, or thia-lower alkylene, - or R3 is lower alkyl, lower alkoxy-lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (la); and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); R5 is (i) hydrogen, alkyl of 1 to 14 carbon atoms, or alkyl of 1 to 14 carbon atoms which is substituted by halogen, lower alkoxy, amino, or amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, (ii) hydroxyl, 3 to 8 membered cycloalkyl, lower alkoxy, or lower alkoxy which is substituted by lower alkoxy, amino, or by amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, alkanoyl lower, lower alkoxycarbonyl, or lower alkylene, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, or (iii) amino, or amino that is substituted by lower alkyl , 3- to 8-membered cycloalkyl, lower aminoalkyl, mono-, or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or 3-aza-, 3-oxa-, or 3-thiazole alkylene of 4 to 6 carbon atoms, - Xj is methylene, ethylene, a direct bond, a carbonyl, dialkoxy lower-methylene, hydroxymethylene, or lower alkoxy-methylene group; and n is 0 or 1; or a salt of it.

4. A compound according to claim 1 or 2, of formula I, wherein: Ri is benzoyl or naphthoyl radical, which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is 5- to 7-membered cycloalkyl, or a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R4 are together alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3-oxa- , or 3-thia-pentylene, or R3 is lower alkyl, lower alkoxy-alkyl lower, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); and R 4 is hydrogen, lower alkyl, or a radical of the formula - (CH 2) n C (= 0) -R 5 (la), - R 5 is (i) hydrogen, alkyl of 1 to 14 carbon atoms, or alkyl of 1 to 14 carbon atoms which is substituted by halogen, lower alkoxy, amino, or amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3-oxa-, or 3-thia-pentylene, (ii) hydroxyl, 3- to 8-membered cycloalkoxy, lower alkoxy, or lower alkoxy which is substituted by lower alkoxy, amino, or amino which is substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, alkanoyl lower, lower alkoxycarbonyl, or alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3-oxa-, or 3-thia-pentylene, or (iii) amino, or amino which is substituted by lower alkyl, cycloalkyl of 5 to 7 carbon atoms, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, alkanoyl lower, lower alkoxycarbonyl, or alkylene of 4 to 6 carbon atoms, or 3-aza-, 3-oxa-, or 3-thia-alkylene of 4 to 6 carbon atoms, in particular 3-aza-, 3 -oxa-, or 3-thia-pentylene, - X! it's methylene, ethylene, a direct link, a group carbonyl, lower dialkoxymethylene, hydroxymethylene, or lower alkoxymethylene; and n is 0 or 1; or a salt thereof, -

5. A compound according to claim 1 or 2, of the formula I, wherein: Rt is benzoyl, or benzoyl which is substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl; R 2 is phenyl, phenyl which is substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl, or naphthyl. R3 and R4 are together alkylene of 4 to 6 carbon atoms, or R3 is lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (la), - and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (la), - R5 is (i) hydrogen, lower alkyl, or lower haloalkyl; (ii) hydroxy, cycloalkoxy of 4 to 6 carbon atoms, lower alkoxy, lower alkoxy-lower alkoxy, or lower dialkylamino-lower alkoxy, - or (iii) amino, lower alkyl-amino, lower-dialkylamino, cycloalkyl of to 7 carbon-amino atoms, or lower dialkyl-amino-lower alkyl-amino. Xt is methylene; Y n is 0 or 1, - or a salt thereof.

6. A compound of formula I, wherein: Rj is a benzoyl, naphthoyl, or cycloalkanoyl radical that is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, and or trifluoromethyl, R2 is phenyl which is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, nitro, cyano, and / or trifluoromethyl, or unsubstituted naphthyl, R3 is alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 4 carbon atoms-carbonylalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms-alkoxy of 2 to 4 carbon atoms-carbonylalkyl of 1 to 4 carbon atoms carbon, cycloalkoxy of 5 to 7 members-carbonylalkyl of 1 to 4 carbon atoms, carbamoylalkyl of 1 to 4 carbon atoms, N-alkyl of 1 to 4 carbon atoms-carbamoylalkyl of 1 to 4 carbon atoms, N, N -dialkyl of 1 to 4 carbon atoms-carbamoylalkyl of 1 to 4 carbon atoms, N-alkyl of 1 to 4 carbon-aminoalkyl atoms of 1 to 4 carbon atoms, alkanoyl of 1 to 7 carbon atoms, trihaloalkanoyl of 1 to 7 carbon atoms, aminoalkanoyl of 1 to 7 carbon atoms, N-alkyl of 1 to 4 carbon atoms -aminoalkanoyl of 1 to 4 carbon atoms, N, N-dialkyl of 1 to 4 carbon atoms-aminoalkanoyl of 1 to 4 carbon atoms, morpholinoalkanoyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms-aminoalkanoyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms-carbonyl, or N, N-dialkyl of 1 to 4 carbon atoms-aminoalkoxy of 2 to 4 carbon atoms-carbonyl, and R 4 is hydrogen or alkoxy of 1 to 4 carbon atoms-carbonylalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms-alkoxy from 2 to 4 carbon atoms-carbonylalkyl of 1 to 4 carbon atoms, cycloalkoxy of 5 to 7 members-carbonylalkyl of 1 to 4 carbon atoms, carbamoylalkyl of 1 to 4 carbon atoms, N-alkyl of 1 to 4 atoms carbon-carbamoylalkyl of 1 to 4 carbon atoms, N, N-dialkyl of 1 to 4 carbon atoms-carbamoylalkyl of 1 to 4 carbon atoms, N-alkyl of 1 to 4 carbon atoms-aminoalkyl of 1 to 4 carbon atoms, or R3 and R4, together with the nitrogen atom that binds them, are morpholino, and Xj is methylene, or a salt thereof.

7. A compound according to claim 1 or 2, of the formula I, wherein: Ri is benzoyl, or benzoyl which is substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl, - R2 is phenyl, phenyl which is substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl, or naphthyl; R3 and R4 are together alkylene of 4 to 6 carbon atoms; or R3 is lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) n-C (= 0) -R5 (la); and R4 is hydrogen; R5 is (i) hydrogen, lower alkyl, or lower haloalkyl; (ii) hydroxyl, cycloalkoxy of 4 to 6 carbon atoms, lower alkoxy, lower alkoxy-lower alkoxy, or lower dialkyl-aminoalkoxy lower, or (iii) amino, lower alkyl-amino, lower dialkyl-amino, cycloalkyl of 5 to 7 carbon-amino atoms, or lower dialkyl-amino-lower alkyl amino; X1 is methylene; and n is 0 or 1; or a salt of it.

8. A compound according to claim 1 or 2, of the formula I, wherein: R x is benzoyl which is disubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, and / or trifluoromethyl; R 2 is phenyl, phenyl which is substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, nitro, cyano, and / or trifluoromethyl or naphthyl; (i) R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la), - R is hydrogen; n is 0 and R 5 is alkyl of 1 to 7 carbon atoms, cycloalkyl of 5 to 7 carbon atoms-amino, or dialkyl of 1 to 4 carbon atoms-aminoalkoxy of 2 to 4 carbon atoms; or (ii) R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la), - R4 is hydrogen; n is 1; and R5 is amino; and Xj is methylene; or a salt of it.

9. A compound according to claim 1 or 2, of formula I, wherein: Rj is benzoyl which is disubstituted by trifluoromethyl; R2 is phenyl, or phenyl which is substituted by halogen, - R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la); R4 is hydrogen; R5 is alkyl of 1 to 7 carbon atoms, cycloalkyl of 5 to 7 carbon atoms-amino, or dialkyl of 1 to 4 carbon atoms-aminoalkoxy of 2 to 4 carbon atoms, - n is 0; and Xj is methylene; or a salt of it.

10. A compound according to claim 1 or 2, of the formula I, wherein: Rt is 3,5-bistrifluoromethylbenzoyl, - R 2 is phenyl or phenyl which is substituted by halogen; R3 is a radical of the formula - (CH2) n-C (= 0) -R5 (la); R4 is hydrogen; n is 0; R5 is alkyl of 1 to 4 carbon atoms, or cycloalkyl of 5 to 7 carbon atoms-amino, - and Xj is methylene; or a salt of it.

11. A compound according to one of the claims 1 to 9, of the formula I, wherein the carbon atom to which the group -X2-R2 is bonded (essentially) has the R configuration, and the carbon atom with which the group -N (R3) (R4) is linked (essentially) has the S configuration according to Cahn-Ingold-Prelog.

12. A compound according to claim 1 or 2, selected from the group consisting of: (2R, 4S) -2- [2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] acetamide; (2R, 4S) -2- [2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] methyl acetate, - (2R, 4S) -2-. { [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] methoxycarbonylmethylamino} methyl acetate; (2R, 4S) -2- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamino} acetamide, - (2R, 4S) -2-. { [2-benzyl-l- (3, 5-bistrif luoromet-ilben-zoyl) piperidin-4-yl] carbamoylmethylamino} acetamide; Acid (2R, 4S) -2- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamine] acetic, - (2R, 4S) -2- [2-benzyl-1- (3 , 5-bistrif luoromethylbenzoyl) pi-peridin-4-ylamino] -N- (2-dimethylaminoethyl) acetamide (2R, 4S) -2-. { [2-benzyl-l- (3, 5-bistrif luoromet-ilben-zoiDpiperidin-lylcarbamoyl] methyl} tertiary butyl carbamate (2R, 4S) -2-amino-N- [2-benzyl-1- ( 3, 5-bistrif luoromet il-benzoyl) piperidin-4-yl] acetamide; (2R, 4S) -2- [2-benzyl-l- (3, 5-bistrif luoromet ilbenzoiDpi-peridin-4-ylamino] acetate from tertiary butyl, - (2R, 4S) -2- { [2-benzyl-l- (3,5-bistrifluoromet-ilben-zoyl) -piperidin-4-yl] -butoxy-tertiary-carbonylmethylamino} tertiary butyl acetate; (2R, 4S) -2- [2-benzyl-1- (3, 5-bistrifluoromethyl-4-benzoiDpi -peridin-4-ylamino] -isopropyl acetate; (2R, 4S) -2- { [2-benzyl -l- (3, 5-bistrif luoromet ilben-zoyl) piperidin-4-yl] -isopropoxycarbonylmethylamino} isopropyl acetate; (2R, 4S) -2- [2-benzyl-1- (3, 5-bistrip luoromet ilbenzoiDpi -peridin-4-ylamino] -N- isopropylacetamide, - (2R, 4S) -2- [[2-benzyl-l- (3,5-bistrif luoromet-ilben-zoyl) piperidin-4-yl] - ( N-isopropylcarbamoylmethyl) amino] -N-isopro-pilacet amide, - (2R, 4S) -2- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoiDpi-peridin-4-ylamino] ethoxyethyl acetate; (2R, 4S) -N- [[2-benzyl-1- (3 , 5-bistrifluoromethylbenzoyl) piperidin-4-yl] - (N- (2-ethoxyethoxycarbonylmethyl)) amino] 2-ethoxyethyl acetate; (2R, 4S) -N- [2-benzyl-1- (3, 5 BistrifluoromethylbenzoiDpi-peridin-4-yl] -2- (dimethylamino) -acetamide; (2R, 4S) -2- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] -N , N-dimethylacetamide; (2R, 4S) -2- { [2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] dimethylcarbamoylmethylamino] -N, N-dimethylacetamide , - (2R, 4S) -N- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) pi-peridin-4-yl] -2- (morpholin-4-yl) -acetamide; (2R, 4S) -2- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) piperidin-4-ylamino] cyclohexyl acetate, - (2R, 4S) -2- { [2-benzyl-1- (3 , 5-bistrifluoromethylbenzoyl) piperidin-4-yl] -N- (cyclohexyloxycarbonylmethyl) aminohectate cyclohexyl, - (2R, 4S) -4-amino-2-benzyl-1-dihydrochloride (3, 5-b) istrifluoromethylbenzoyl) -N- (3-dimethylaminopropyl) -piperidine. (2R, 4S) -N- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoiDpi-peridin-4-yl] -carbamic acid 3-dimethylaminopropyl ester; (2R, 4S) -2-benzyl-1- (3, 5-bistrifluoromethylbenzoyl) -4-morpholin-4-yl-piperidine, - (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) -N-isobutylpiperidine, - (2R, 4S) -N- [2-benzyl-1- (3, 5-bistrifluoromethylbenzoyl) ) -piperidin-4-yl] isobutyl carbamate; (2R, 4S) -4-amino-2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) -N- (2,2-dimethylpropyl) piperidine; (2R, 4S) -2- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) -pyridin-4-ylamino] 2-methoxyethyl acetate; (2R, 4S) - 2-methoxyethyl, - (2R, 4S) - [[2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) -pyridin-4-yl] -N- (2-methoxyethoxycarbonylmethyl) amino] acetate] - (2R, 4S) -N- [2-benzyl-l- (3, 5-bistrifluoromethylbenzoyl) pi-ridin-4-yl] -carbamic acid 2-dimethylaminoethyl ester; (2R, 4S) -N- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) pi-ridin-4-yl] acetamide, - (2R, 4S) -N- [2-benzyl-1- (3 , 5-dimethylbenzoyl) iridin-4-yl] butyramide; (2R, 4S) -N- [2-benzyl-1- (3,5-dichlorobenzoyl) pyridin-4-yl] butyramide, - (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) - 2- (4-chlorobenzyl) piperidin-4-yl] formamide; (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] acetamide; (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] propionamide; (2R, 4S) -N- [1- (3,5-bis trifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] but-iramide, -N- [2-benzyl-1- (3, 5-dimethyl-ilbenzoyl) piperidin-4-yl] -2,2, 2-trifluoroacetamide, - (2R, 4S) -2-acetylamino-N- [1- (3, 5-bistrif luoromethylbenzoyl) -2- (4- chlorobenzyl) piperidin-4-yl] -acetamide; (2R, 4S) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -isobutylcarbamate; (2R, 4S) -2- [1- (3, 5-bistrif luoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-ylamino] -acetamide; (2R, 4S) -2-. { [1- (3, 5-bis trifluoromet-ilbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl 3-N-carbamoylmethylamino} acetamide, - (2R *, 4S *) -N- [1- (3, 5 -dimet-ilbenzoyl) -2- (4-nitrobenzyl) piperidin-4-yl] acetamide; (2R *, 4S *) -N- [1- (3, 5 -dimet-il-benzoyl) -2- (4-cyanobenzyl) -piperidin-4-yl] -acetamide; (2R *, 4S *) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-cyanobenzyl) piperidin-4-yl] acetamide "• (2R *, 4S *) -N- [l- (3,5-dichlorobenzoyl) -2- (4-chlorobenzyl) pi-peridin-4-yl] acetamide; (2R *, 4S *) -N- [1- (3,5-dimethyl-l-benzoyl) -2- (4-methoxybenzyl) piperidin-4-yl] acetamide; (2R *, 4S *) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (3-methoxybenzyl) piperidin-4-yl] acetamide, - (2R *, 4S *) - N- [1- (3, 5-dimethylbenzoyl) -2- (4-trifluoromethyl-benzyl) piperidin-4-yl] acetamide, - (2R *, 4S *) -N- [ 1- (3,5-dimethylbenzoyl) -2- (2,4-dichlorobenzyl) piperidin-4-yl] acetamide; (2R *, 4S *) -N- [1- (3,5-dimethylbenzoyl) -2- (2-naphthyl) pi-peridin-4-yl] acetamide; and (2R *, 4S *) -N- [1- (3,5-dimethylbenzoyl) -2- (4-iodobenzyl) piperidin-4-yl] acetamide; or in each case, a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 or 2, selected from the group consisting of: (2R, 4S) -N- ti- (3, 5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4 -yl] -pentanamide; (2R, 4S) -1- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-tertiary butyl-urea, - (2R, 4S) -l- [ l- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-isopropylurea, - (2R, 4S) -l- [1- (3, 5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-ethylurea; (2R, 4S) -l- [l- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-cyclohexylurea; (2R, 4S) -l- [l- (3,5-bistrifluoromethylbenzoyl) -2- (4-chlorobenzyl) piperidin-4-yl] -3-propylurea, - (2R, 4S) -1- [2-benzyl] -l- (3,5-bistrifluoromethylbenzoyl) pi- peridin-4-yl] -3-cyclohexylurea, - (2R, 4S) -1- [2-benzyl-1- (3,5-bistrifluoromet-ilbenzoyl) -piperidin-4-yl] -3-tertiary butyl- urea, - (2R, 4S) -1- [2-benzyl-1- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] -3-isopropylurea. (2R, 4S) -2- [2-benzyl-l- (3, 5-bistrif luoromethylbenzoiDpi-peridin-4-ylamino] octyl acetate, normal, and (2R, 4S) -2- { [2-benzyl -l- (3, 5-bistrif luoromet-ilbenzoyl) piperidin-4-yl] -methoxycarbonylmethylamino} - octyl acetate, normal (2R, 4S) -2- [2-benzyl-1- (3, 5-bistrip) luoromethylbenzoyl) pi -peridin-4-ylamino] normal decyl acetate; and (2R, 4S) -2- { [2-benzyl-l- (3,5-bistrif luoromet-ilbenzoyl) piperidin-4-yl ] methoxycarbonylmethylamino.] normal decyl acetate (2R, 4S) -2- [2-benzyl-1- (3, 5-bistrif luoromet-ylbenzoyl) pi-peridin-4-ylamino] -dodecyl acetate, and (2R) , 4S) -2- { [2-benzyl-l- (3,5-bistrifluoromethylbenzoyl) piperidin-4-yl] -methoxycarbonylmethylamino} - acetatededodecyl or, in each case, a pharmaceutically acceptable salt thereof.

14. A compound according to any of claims 13, including the compound (2R *, 4S *) -N- [1- (3,5-bistrif luoromethylbenzoyl) -2- (4-nitrobenzyl) piperid in- 4- il] acetamide, for the treatment of the human animal body.

15. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any of claims 1 to 14, including the compound (2R *, 4S *) -N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-nitrobenzyl) piperidin-4-yl] acetamide, or a pharmaceutically acceptable salt thereof, in addition to customary excipients and pharmaceutical vehicles.

16. The use of a compound according to any of claims 14, including the compound (2R *, 4S *) - N- [1- (3,5-bistrifluoromethylbenzoyl) -2- (4-nitrobenzyl) piperidin- 4-yl] acetamide, for the preparation of a pharmaceutical composition for the treatment of disorders that are induced by substance P.

17. A process for the preparation of a compound of the formula I according to any of claims 1 to 13 , wherein: a) the radical R] is introduced into a compound of formula II: where Rg, R3, ^, and Xj are as defined, or b) compounds of formula III: e V2 ~ R3 (I), where Yj is a group of the formula -N (R¿p-H and Yg is hydroxyl, reactive esterified hydroxyl, or, if R3 is a radical of the formula (the); and n is 0, is etherified hydroxyl, or Yj is free or reactive esterified hydroxyl, and Yg is a group of the formula -N (R¿pH, where Rj, R ^ R3, Rjj and Xj as defined, or their salts are condensed with each other, or c) for the preparation of compounds of the formula I, wherein R ^ is hydrogen, the group Y- * is removed from a compound of the formula v: where Y is an amino protecting group, and Rj, g » and X [are as defined, or of a salt thereof, or d) for the preparation of compounds of the formula I, wherein R3 is lower alkyl, lower dialkyl-lower aminoalkyl, or lower alkoxy-lower alkyl, and R4 is hydrogen or lower alkyl, a compound of formula VI: wherein R ,, R2, R4 and Xj are as defined, or a salt thereof, is reacted under reducing conditions with an appropriate aldehyde of the formula 0 = CH-R (VII) or e) for the preparation of compounds of the formula I, wherein R3 and R4 are together lower alkylene, or aza-, oxa-, or thia-lower alkylene, a compound of the formula VIII: where R { , R2, and X, are as defined, or a salt thereof, it is condensed with a reactive diester of a lower alkanediol or an appropriate aza-, oxa-, or thia-alkanediol, of) for the preparation of compounds of the formula I, wherein Xj is a carbonyl or hydroxymethylene group, the compounds of formulas IX: and Y5-R9 (X) «where one of the radicals Y¿, and Y? is formyl or a carboxyl group that is free, converted into an anhydride, or esterified, and the other is a metal radical, and R ^ Rj, and j are as defined, condense with one another, and if desired , a compound that is obtained is converted into another compound of the formula I, an isomeric mixture is separated that can be obtained rding to the process in the components, and in each case the preferred isomer is separated, and / or a free compound that can be obtained rding to the process becomes a salt, or a salt that can be obtained rding to the process becomes the corresponding free compound. SUMMARY The invention relates to novel l-acyl-4-aliphatilaminopiperidine compounds of the formula I: wherein: R t is a benzoyl, naphthoyl, or cycloalkanoyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, and / or trifluoromethyl, - R 2 is cycloalkyl or a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, nitro, cyano, and / or trifluoromethyl; R3 and R4 are together lower alkylene or aza-, oxa-, or thia-lower alkylene; or R3 is lower alkyl, lower alkoxy-lower alkyl, lower dialkyl-lower aminoalkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (Ia), - and R4 is hydrogen, lower alkyl, or a radical of the formula - (CH2) nC (= 0) -R5 (Ia), - R5 is (i) hydrogen, alkyl, or alkyl that is substituted by halogen, lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono- or lower dialkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or alkylene lower, or aza-, oxa-, or thia-lower alkylene, (ii) hydroxyl, cycloalkoxy, lower alkoxy, or lower alkoxy which is substituted by lower alkoxy, amino, or amino substituted by lower alkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, or (iii) amino, or amino substituted by lower alkyl, cycloalkyl, lower aminoalkyl, mono- or di-lower alkyl-aminoalkyl, lower alkanoyl, lower alkoxycarbonyl, or lower alkylene, or aza-, oxa-, or thia-lower alkylene, - Xj is methylene, ethylene, a direct bond, a free carbonyl group or ketalized, or a hydroxymethylene group free or etherified; and n is 0 or 1, and its salts, to processes for the preparation of the compounds rding to the invention, to pharmaceutical compositions containing them, and to their use as pharmaceutical active ingredients. * *