CS234046B2 - Method of piperidine derivatives making - Google Patents

Description

The invention also encompasses the preparation of acid addition salts and quaternary ammonium salts of the compounds prepared by the process of the invention, which may be represented by the general formula I

R ³

Ar-Y-CHR ⁹ - (CHR ') _n -O- -nr'cxn-zr (I), wherein

A.r represents a ring radical of formula (Ia)

where

Y S Q

Q is oxygen, sulfur, or a group -CR -CR- or -N = CH- or -N = N-, and 45-6-78 each of R, R and R, as well as R and R, is hydrogen, halogen or an alkyl group of 1 to 6, preferably 1 to 4 carbon atoms, an alkenyl group of 2 to 6, preferably 2 to 6 carbon atoms;

234046 2 carbon atoms having an alkoxy group having 1 to 6, preferably 1 to 4 carbon atoms, a haloalkyl group having 1 to 6, preferably 1 to 4 carbon atoms, a nitro group, an amino group optionally substituted by one or two alkyl groups having 1 to 6 each, preferably 1 to 4 carbon atoms, an acyl group having 2 to 7 carbon atoms or a sulfonyl group, furthermore an alkoxycarbonyl group having 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy moiety, a cyano group or a hydroxyl group, and optionally R ⁴ and R ^, when attached to adjacent carbon atoms, or R ^ and R®, when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached also represent an unfused five- or six-membered carbocyclic or heterocyclic ring containing oxygen, nitrogen or sulfur heteroatom optionally substituted by one or more of the above-mentioned substituents,

R is as defined above an optionally substituted C 5 -C 7 aryl or heteroaryl or cycloalkyl radical, wherein the heteroaryl radical contains oxygen, nitrogen or sulfur as the heteroatom,

Each of R, R, R and R is hydrogen or alkyl of 1 to 6, preferably 1 to 4 carbon atoms, β is 0 or 1,

X.j represents oxygen = O, sulfur = S or imino = NH,

Y is -O- or a direct bond, and

Z is a carbonyl group -CO- or a methylene group -CH _O -, *

wherein when Ar is unsubstituted phenyl and R is hydrogen, Y is -O-, or when Z is methylene -CH, and Ar is optionally substituted phenyl or optionally substituted pyridyl, R is hydrogen.

Examples of substituted amino include groups such as alkyl or dialkylamino of 1 to 6 carbon atoms in each of the alkyl moieties, ecylamino such as alkylcarbonylamino of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms in the alkyl moiety, ureidoamino or sulfonylamino, for example, alkylsulfonamido having 1 to 6, preferably 1 to 4 carbon atoms, or dialkylsulfonylamino having 1 to 6, preferably 1 to 4 carbon atoms in each of the alkyl moieties.

Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert. butyl, neopentyl and n-hexyl groups. Examples of alkoxy are methoxy, ethoxy, isopropoxy, butoxy, and hexoxy. Examples of cycloalkyl groups are cyclohexyl and cyclopentyl.

Examples of alkylamino and dialkylamino are methylamino, ethylamino, dimethylamino, isopropylamino and butylamino.

Examples of alkenyl groups are vinyl, propenyl, but-1-enyl and but-2-enyl.

Examples of haloalkyl groups are chloroethyl and trifluoromethyl.

Examples of alkoxycarbonyl groups are methoxycarbonyl and ethoxycarbonyl.

Preferred halogen substituents are chlorine and bromine

Examples of Ar groups wherein Q is oxygen or sulfur are groups of formulas

R ⁶

especially fursn-2-yl, thiophen-2-yl, benzo [b] furan-3-yl and benzo [b] thiophen-3-yl.

/ Groups in the meaning of the symbol Ar, wherein Q is -CR-CR of formulas R ⁵ R ⁶ R R ⁶ t ·· R ⁷ O ^ 7 _b, ⁷ R (i.e., R ^ and R ^ means Γ ')

are groups

Examples of Ar groups when Q is -N = CR- are groups of formulas

^R · I ^and -TL

-N ^ _R8

Examples of Ar groups when Q is -N = N- are groups of formulas

R® A ⁶ '42r

R

Her, 6

When Ar is a mono-substituted phenyl or monosubstituted pyridyl radical, it may be, for example, 4-tert-butylphenyl, 4-cumenyl, 4-n-butoxyphenyl, 4-nitrophenyl, 4-diinethylaminophenyl, 3-vinylphenyl, 3-vinylphenyl, 3-vinylphenyl, -methylpyrid-2-yl, 4-methylpyrid-2-yl, 4-methylpyrid-3-yl, 4-chloro-pyrid-2-yl, 2-methylpyrid-4-yl or 2-bromo-pyrid-4-yl residue.

When Ar is a multiply substituted phenyl or pyridyl radical, it may be, for example, 3,4-dichlorophenyl, 3,4,5-triraethylphenyl, 3,4,5-trimethoxyphenyl,

3,4-dichloro-2-methylphenyl, 2,3-diethylphenyl, 3-methyl-4-vinylphenyl, 2,4-dichloropyrid-6-yl or 2,4-dimethylpyrid-6-yl.

Examples of Ar when phenyl is fused with a fused 5- or 6-membered carbocyclic or heterocyclic ring are naphth-1-yl, naphth-2-yl, benzo [1,4] dioxan-6-yl, 3,4-meth. 1,4-dihydronaphth-6-yl, 1,4-dihydronaphth-6-yl, benzo [b] thiophen-6-yl, indol-6-yl, benzo [b] furan-6- an aryl, quino 1-6-, yl or ehinol-5-yl residue.

Examples of Ar when the pyridyl radical is an unfused five- or six-membered carbocyclic or heterocyclic ring are quinol-4-yl, quinol-2-yl, 5,6,7,8-tetrahydroquinol-4-yl or 5,6,7,7-tetrahydroquinol-4-yl. , 8-tetrahydroquinol-2-yl. Examples of such groups, when substituted on an unfused ring, are the 6-methoxynsft-2-yl, 7-methoxynaphth-2-yl and 4-methylnaphth-2-yl radicals. Preferred Ar heterocyclic groups with fused heterocyclic rings contain oxygen, nitrogen or sulfur as heteroatom.

An example of an aryl radical R is a phenyl radical which may be optionally substituted, for example, by a substituent r 'such as methyl (e.g. 4-methyl), ethyl, propyl, nitro-like 3 or 4-nitro, hydroxy, for example 4-hydroxy, methoxy, ethoxy, fluoro, bromo, or chloro, for example 3,4-dichloro. Heteroaryl radicals R denote a thienyl (for example, thien-2-yl) radical, a furyl (for example fur-2-yl) radical and a pyridyl (for example pyrid-2-yl) radical, which radicals are optionally substituted as described above for a phenyl radical Ar.

Preferred meanings of Ar are a phenyl radical substituted with at least one C 2 -C 6 alkyl or alkoxy group, for example a 4-ethylphenyl, 3,4-dimethylphenyl or 3,4-dimethoxyphenyl radical; further a phenyl radical having a fused five- or six-membered carbscyclic ring, for example a naphth-1-yl and a naphth-2-yl radical, the radicals of which are optionally substituted by at least one alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, 1 to 6, preferably 1 to 4, carbon atoms, halogen, nitro, trifluoromethyl, amino, alkylamino (e.g. methylamino), dialkylamino (e.g. dimethylamino) of 1 to 6, preferably 1 to 4, carbon atoms in each alkyl or cyano.

Preferably, the symbol n represents O, R denotes hydrogen or methyl and R @ ¹ is hydrogen. The preferred meaning of X is oxygen.

Preferably Z is -CO- and R is phenyl optionally substituted in the 4-position by alkoxy having 1 to 6, preferably up to 4, carbon atoms, for example methoxy.

Preferably, Y is a direct bond.

When Z represents a methylene group -CH ₂ -, R is preferably a phenyl radical.

Preferred compounds of the present invention are 1-benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea.

1-Benzoyl-3- [1- (naphth-1-ylmethyl) piperid-4-yl] urea

1-Benzoyl-3- [1- (4-isopropylbenzyl) piperid-4-yl] urea,

1- (5,6,7,8-tetrahydro-2-ylmethyl) -piperidin-4-yl] -urea, 1- _(3> 4-dimethylbenzyl) piperidin-4-yl] mo thiourea, 1- (indan- 5-ylmethyl) piperid-4-yl] urea,

1- (1-Naphth-2-ylethyl) piperid-4-yl] urea and 1- (4-ethylbenzyl) piperid-4-yl urea.

1-Benzoyl-31-benzoyl-31-benzoyl-31-benzoyl-31-benzoyl-3 Examples of acid addition salts are those compounds which are prepared using inorganic and organic acids, especially pharmaceutically acceptable acids; examples of salts are hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, sulfonate (e.g., methanesulfate and p-toluenesulfonate), acetate, maleate, citrate, fumarate, tartrate, malonate and formate.

The compounds of formula (I) produced by the process of the invention have been tested for psychotropic activity, which has been evaluated for their ability to inhibit p-chloramphetamine-induced hyperactivity and / or their ability to inhibit 5-hydroxytryptamine uptake in thin brain preparations.

The assay described below was used to determine the ability of these compounds to inhibit p-chloramphetamine-induced hyperactivity.

Three groups of four female mice (20-24 g) were dosed orally (50 mg / kg) and the fourth group received the appropriate amount of carrier. After 30 minutes, all animals were injected intraperitoneally with 20 mg / kg p-chloramphetamine. The animals are then transferred in groups into rectangular cages of plastic material, equipped with a device for monitoring physical activity, in groups. Movement activity of the animals is recorded for 10 to 30 minutes after p-chloramphetamine administration. This procedure is then repeated three more times, so that four groups of mice are used in one experiment and each activity monitor is used alternately in all experiments. The inhibition of p-chloramphetamine-induced hyperactivity is calculated according to the relationship

C-I _. 100%

C where

C represents the mean activity of the control groups at 10 to 30 minutes after p-chloramphetamine administration, and

T represents the mean activity of the treated groups at 10 to 30 minutes after p-chloramphetamine administration.

This assay is used as an in vivo screening assay to detect 5-hydroxytryptamine uptake inhibitors.

Compounds having inhibition greater than 50% are considered to be particularly significant. The following compounds have been found to be particularly effective in this test:

p-chloramphetamine-induced hypersctivity inhibition compound (%)

1-Benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea 67.5

1-Benzoyl-3- [1- (naphth-1-ylmethyl) -1H-mercapto-2-ol piperid-4-yl] urea 56.4

1-Benzoyl-3- [1- (4-isopropylbenzyl) piperidin-4-yl] urea. 49

1-Benzoyl-3- [1- (5,6,7,8-tetrahydronaphth-2-ylmethyl) piperid-4-yl] urea 69.4 73.5

-benzoyl-3- [1- (3,4-dimethylbenzyl) piperid-4-yl] urea 68.9

-benzoyl-3- [Ί - (indan-5-ylmethyl) piperid-4-yl] urea 59.3

1-Benzoyl-3- [1- (1-naphth-2-yl-ethyl) piperid-4-yl] urea 71.7

1-Benzoyl-3- [1- (4-ethylbenzyl) piperid-4-yl] Urea · 72.9

The ability of the compounds of formula (X) produced by the method of the invention to inhibit the uptake of 5-hydroxytraptamine by brain tissue preparations was tested as follows:

The effect of the test compound on the neuronal uptake of 5-hydroxytryptamine by cortex preparations prepared from rat brain is determined by the method described by Snydor, (Ireen and Hendley in Kinetics of Accumulation of H 2 -reprepephrine), brain tissue preparations from various parts of rat brain. Pharm.Exp.Therap, 1664 pp. 90-102, 1,968). This method yields curves showing the concentration-dependency of the effect of the test compound and the standard (imipramine). The potency of the test compound is expressed relative to the potency of imipramine. Thus, the potency of the test compound is given by the molar concentration of imipramine giving 50% inhibition of 5-hydroxytryptamine uptake by the molar concentration of the test compound giving 50% inhibition of 5-hydroxytryptamine uptake

Compounds which do not achieve 50% inhibition are considered ineffective.

In such a test, 1-benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] -urea was found to be particularly effective and had 8.8-fold greater potency compared to imipramine (potency = 1, 0).

In vivo, the inhibition of 5-hydroxytryptamine uptake induced by the compounds produced by the method of the invention was determined by a method including 5-hydroxy-L-tryptophan-induced behavioral syndrome in experimental animals. In mice receiving the high dose administered 5-hydroxy-L-tryptofsnu ₇ 234045 manifests behavioral syndrome consisting of tremor, abduction rear paws, in the lateral tilting of the head and forepaws in trampling. In addition to these symptoms, rats also exhibit head twitching and circular head movements. In the experiments described below, this syndrome is believed to be present if at least three of these symptoms occur in mice and at least four of these symptoms in rats. If the test animals receive a small dose of 5-hydroxy-L-tryptophan that does not induce the syndrome itself. it can be induced by prior administration of 5-hydroxytryptamine uptake inhibitors. Thus, this assay can be used as an indication of inhibiting 5-hydroxytropyptamine uptake in vivo.

a) Dose-dependency test in mice

Groups of 12 (two subgroups of 5) female mice (weighing between 18 and 22 g) were used at each dose, each group being kept separately in a separate pen for the duration of the experiment. Mice are dosed orally with either test compound or vehicle (0.5% HPMC) and then, after 30 minutes, intraperitoneally a threshold dose (80 mg / kg) of 5-hydroxy-L-tryptophan and placed in 30 cm diameter perspex cylindrical containers. After an additional 20 minutes, the mice are monitored for 5 minutes whether or not the described syndrome is present.

Following the procedure of Litchfield and Wilcoxon, J. Pharm. Exp. Ther., 96, pp. 99-113 (1949), calculate the dose that induces the syndrome in 50% of the mice.

(b) Dose-dependency test in rats

Groups of 6 male rats (150 g) are treated with the test compound suspended in HPMC. After 30 minutes, 5-hydroxy-L-tryptophan (70 mg / kg) was administered intraperitoneally and the number of symptoms per rat was measured between 20 and 35 minutes after 5-hydroxy-L-tryptophan was applied. A linear regression analysis of the results is performed and the value ΕΒ ^ θ is calculated.

The results obtained for 1-benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea and for the antidepressant clomipramine are as follows:

compound of ΕΒ ^ θ value for the potential of 5-hydroxy-Ltryptophanem-induced syndrome in mice (mg / kg p.o.) of rats (mg / kg i.p.)

1-Benzoyl-3-fl- (naphth-2-ylmethylpiperid-4-yl) urea

7.2

5.3 clomipramine

39.2

The process according to the invention for the preparation of compounds of the formula I or their acid addition salts or their quaternary ammonium salts is characterized in that the compound of the formula IV

Ar - Ϊ -. CHR ⁹ - (CHR ² ) »-O

NHR ¹ (IV) wherein

9

Ar, ^Y > R, ^R , as defined above, are reacted with a compound of formula Va

R-Z-M (Va), where

R and Z are as defined above with s

M represents a group -NCO, -NOS, -NR 6 -CXNH 8 or -NR 6 -CN, wherein a) when M represents -NCO or -NCS, in the resulting compound of the formula IR is hydrogen and X is oxygen or sulfur , and b) when M is -NR 1 -CN, then in the resulting compound of formula XX is -NH, ε optionally the alkoxy group is not bonded. the compound of formula (I) is dealkylated to form a hydroxyl group, or the nitro group bound to the compound of formula (1) is reduced to form an amino group, or the amino group bound to the compound of formula (I) is acylated to form an aeylamino group; with an acid or a quaternary ammonium salt, or the acid addition salt of a compound of formula I is converted into the free base.

When the process according to the invention for the preparation of the compounds of the formula I consists in reacting the compound of the formula IV with a compound of the formula

R-Z-M where

R, Z are as defined above and M is -NCO or -NCS to give a compound of formula I wherein X is oxygen or sulfur and R is hydrogen, then the reaction can be carried out at room temperature. The starting compound of formula IV, wherein r 'is hydrogen, can be prepared according to the procedures described in British Patent Specification δ. The starting compound of formula IV, wherein r 'is C 1 -C 6 -alkyl, may be prepared by alkylation of the corresponding compound of formula IV, wherein R is hydrogen, or by procedures similar to those described in the aforementioned British Patent Specification δ. 1,345,872.

When the process for preparing compounds of formula I comprises reacting a compound of formula IV with a compound of formula RZM, wherein M is -NR -CX-NHg, the reaction may be carried out without solvent, but is usually carried out by heating the reactants in the presence of a suitable an inert organic solvent such as toluene, pyridine, xylene, chlorobenzene, dimethylformemide or dioxane. The preferred solvent is pyridine. It is often preferred to heat the reactants in a solvent under reflux until the reaction is complete. High yields can be achieved, for example in the range of 80 to 90%. Preferably, the solvent has a boiling point above 100 ° C.

It is preferred to use equimolar amounts of reactants.

When the process for the preparation of the compounds of formula I wherein X is NH, the compound of formula XV

R - Z - NCN (XV) where

R, ^RJ and Z are as defined above, reacted with a compound of formula IV as described above, and can be carried out in an inert solvent such as toluene with heating.

Once formed, a compound of formula (I) having a reactive group as a substituent may be converted into another compound of formula (I) by known methods. For example, when Ar represents a radical having from 1 to 6 alkoxy as a substituent, preferably 1-4 carbon atoms, the corresponding compound of formula (I) wherein the hydroxyl group is bonded to the Ar group may be desalkylated.

When Ar is a nitro radical on the aromatic ring, the nitro radical can be converted by reduction (e.g., catalytic hydrogenation) to an amino group. Such amino groups may optionally be acylated.

The above processes may also include converting the acid addition salt into the free base or vice versa. The quaternization of the tertiary nitrogen of the piperidine ring may be included as a further optional step, for example using alkyl halides or aryl-alkyl halides of 1 to 6, preferably 1 to 4 carbon atoms in the alkyl moiety, such as methyl iodide or benzyl chloride.

If necessary, in any of the reactions described above, the reactive groups contained as substituents may be blocked and later released again. For example, the amino group may be protected by a benzyloxycarbonyl group which may then be removed after the reaction is completed using hydrogen and a palladium catalyst. The dehydropiperidine compounds of formula I which contain a single double bond are also useful as intermediates for the preparation of piperidines of formula I in which they are converted by reduction. The acylurea compounds of formula I are also useful as intermediates in the preparation of other acylurea compounds of formula I by hydrolysis to give ureas of formula VIa.

Ar - Y - CHH ⁹ - (CHK ²

Which are then acylated again.

The invention also provides pharmaceutical compositions comprising as active ingredient a compound of formula I as described above. The active ingredient may optionally be finely powdered. In addition to the active ingredient, these compositions also comprise a pharmaceutically acceptable carrier. Any suitable carrier known in the art may be used to prepare such pharmaceutical compositions. In such compositions, the carrier can be a solid, a liquid, or a mixture of a solid and a liquid. Solid forms of pharmaceutical compositions include powders, tablets, and capsules. The solid carrier may consist of one or more substances which may also act as, for example, a sweetener, a lubricant, a solubilizer, a suspending agent, a binder or a tablet disintegrating agent, and may also be an encapsulating material. In powders, the carrier is a finely powdered solid which is mixed with the finely powdered active ingredient. In tablets, the active ingredient is mixed in appropriate proportions with a carrier having the necessary binding properties, and the resulting mixture is compressed into a tablet of the desired shape and size. The powders and tablets preferably contain 5 to 99%, in particular 10 to 80%, of the active ingredient.

Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low wax and cocoa butter. The term composition herein also includes the formulation of the active ingredient with the encapsulating material as the carrier, so that the composition is in the form of a capsule in which the active ingredient (with or without another carrier) is surrounded by the carrier associated therewith. The same is true when using wafers.

Sterile liquid compositions include sterile solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier such as sterile water, a sterile organic solvent, or a mixture thereof. A liquid carrier suitable for parenteral injection is preferred. If the active ingredient is sufficiently soluble, it may be dissolved in normal saline as the carrier; if it is too poorly soluble for this purpose, it can often be dissolved in a suitable organic solvent, for example an aqueous solution of propylene glycol or polyethylene glycol. In general, an aqueous solution of propylene glycol containing glycol in a concentration by weight of 10 to 75% is suitable. In other cases, the composition may be prepared by dispersing the finely powdered active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose, optionally in a suitable oil, for example a peanut oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be administered by intremuscular, intraperitoneal or subcutaneous injection. In many cases, the active compound is active when administered orally and can therefore be administered in the form of a liquid or solid composition.

The pharmaceutical composition is preferably in the form of a dosage unit. In such form, the composition may be subdivided into smaller dosage units containing appropriate amounts of the active ingredients; the dosage unit may be in the form of a sachet containing a certain amount of composition, for example, sachet. powders or vials or ampoules. The unit dose may be formulated in a capsule, cachet, or tablet, or it may be the appropriate number of any of these packaged forms. The amount of active ingredient per unit dose of the composition may vary or be adjusted in the range of 5 mg or less to 500 mg or more depending on the need and efficacy of the active ingredient. they are in unit dosage form.

The amount of compound used will depend on the compound administered, the intensity and nature of the depression, and the animal being treated. In large animals (about 70 kg body weight), the oral dose is preferably in the range of about 5 to 75 mg, especially in the range of 10 to 25 mg every four hours, or as needed. For parenteral administration, the dose is preferably in the range of 2 to 35 mg as needed. Ideally, treatment should be initiated at lower doses, followed by dose escalation until the desired antidepressant effect is achieved.

The invention is illustrated by the following examples.

Example 1

1-Benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea

1.0 g of 4-amino-1- (naphth-2-ylmethyl) piperidine (0.0042 mol) and 0.69 g of benzoyl isothiocyanate (0.0042 mol) in 120 ml of toluene were stirred at room temperature for 6 hours. The solvent was evaporated and the resulting gum was dissolved in isopropanol to give a solution which was acidified with ethanolic hydrogen chloride solution. The solvent was evaporated and the residue was dissolved in ethyl acetate. The title compound crystallizes from the solution, which is filtered off and dried. It is obtained in the form of the monohydrochloride quarter hydrate, m.p. 212-214 ° C.

Example 2

- [1- (Naphth-2-ylmethyl) piperid-4-yl] -3- (then-2-oyl) urea

1.0 g of 4-amino-1- (naphth-2-ylmethyl) piperidine (0.0047 mol) and 0.65 g of 1- (then-2-oyl) urea (0.0042 mol) in 5 ml of pyridine was heated at reflux for 9.5 hours. The solvent was evaporated, water was added and the precipitated title compound was filtered off and washed thoroughly with water. Recrystallization from ethanol is converted to the hydrochloride by treatment with an ethanolic hydrogen chloride solution, and recrystallization from ethanol yields 0.5 g of hydrochloride having a melting point of 217-219 ° C.

Example 3

1-Benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] guanidine

1.0 g of 4-amino-1- (naphth-2-ylmethyl) piperidine (0.0042 mol) and 0.67 g of benzoyl cyanomide (0.0042 mol) in 100 ml of toluene were refluxed for 15 hours. . Then the solvent was evaporated and the residue was recrystallized from as little isopropyl alcohol as possible and twice more from ethanol to give 0.65 g of the title compound as dihydrochloride quarter hydrate, mp 260-262 ° C.

Examples 4 to 7

Following a procedure similar to that described in Example 2, 4-amino-1- (naphth-2-ylmethyl) piperidine was reacted with the following urea derivatives:

3,4-dimethylbenzolurea

3- (Trifluoromethyl) benzoylurea

4-nitrobenzoylurea and 1- (pyrid-4-oyl) urea to give the following compounds:

Example No. Compound

1- (3,4-Dimethylbenzoyl) -3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea, m.p. hydrochloride (quarter hydrate), 223-226 ° C

1- [1- (Naphth-2-ylmethyl) piperid-4-yl] -3- (3-trifluoromethylbenzoyl) urea, m.p. 251-253 ° C

1- [1- (N-t-2-yl-meth, 1) piperid-4-yl] -3- (4-nitrobenzoyl) Urea m.p. 264-265 ° C

1- (pyrid-4-oyl) -3- [1- (n-naphth-2-ylmethyl) -piperid-4-yl] urea, m.p. 254-255 ° C

Examples 8 to 34

Following the procedure described in Example 1, the following compounds of formula I are prepared by reacting the corresponding compound of formula IV with benzoyl isocyanate:

Example No. 1-benzoyl-3- [1- (2- (naphth-1-yloxy) ethyl) piperid-4-yl] urea m.p. 226-229 ° C.

1-Benzoyl-3- (1- (3,4-dichlorobenzyl) piperid-4-yl) urea, m.p. hydrochloride wire, 244-245 ° C

1-Benzoyl-3- [1- (4-tert-butylbenzyl) oioerid-4-yl] -urea compound, m.p. 202-204 ° C.

1-Benzoyl-3- [1- (4-n-butoxybenzyl) piperid-4-yl] -urea, m.p. hydrochloride wire, 214-217 ° C

1-Benzoyl-3- [1- (3-nitrobenzyl) piperid-4-yl] -urea, m.p. 255-257 ° C.

1-Benzoyl-3- [1- (5,6,7,8-tetrahydro-naphth-2-ylmethyl) -piperidin-4-yl] -urea m.p. 233-235 ° C

-benzoyl-3- [1- (4-ethylbenzyl) piperid-4-yl] urea, m.p. 234-236 ° C

1-Benzoyl-3- [1- (3,4-dibromobenzyl) piperid-4-yl] urea, m.p.

1-Benzoyl-3- [1- (2,5-dimethylbenzyl) piperid-4-yl] urea, m.p. 231-232 ° C

1-Benzoyl-3- [1- (4-n-propoxybenzyl) piperid-4-yl] -urea m.p. 232-234 ° C

1-Benioyl- [1- (2- (naphth-2-oxy) ethyl) pioerid-4-yl] -urea, m.p. hydrochloride, 215-218 ° C

1-Benzoyl-3-ij- (indan-5-ylmethyl) -piperid-4-yl] -urea, m.p. hydrochloride, 253-256 ° C

1-Beazoyl-3-O- (1- (naphth-2-yl) ethyl) piperid-4-yl] urea, m.p. 172-174 ° C

1-Benzoyl-3- 1- (4-methyl-3-nitrobenzyl) piperid-4-yl urea m.p. 232 DEG-234 DEG C. 1-Benzoyl-3- 1- (3-bromo-4-methylbenzyl) (piperidin-4-yl) urea

-benzoyl-3 - ['- (quinol-4-ylmethyl) piperid-4-yl] -urea, m.p.

-benzoyl-3- [1- (quinol-2-ylmethyl) piperid-4-yl] -urea with a melting point of dihydrochloride of 213-215 ° C

1-Benzoyl-3- [1- (3,5-dimethylbenzyl) piperid-4-yl] -urea, m.p. 248-252 ° C.

1-Benzoyl-3- [1- (2,4-dimethylbenzyl) piperid-4-yl] -urea, m.p. 230-232 ° C.

Example No Compound

3,3'-Benzoyl-3- [1- (3-bromobenzyl) pioerid-4-yl] -urea, m.p. hydrochloride quarter hydrate in the range 22 to 224 ° C

1-Benzoyl-3- [1- (3-iodobenzyl) piperid-4-yl] -urea, m.p. 217-2.9 ° C

O o

1-Benzoyl-3 - [- (pyrid-4-ylmethyl) piperid-4-yl] -urea, m.p. dihydrochloride, 236-238 ° C

1-Benzoyl-3- [1- (3-trifluoromethylbenzyl) -piperid-4-yl] urea, m.p.

benzoyl-3- [1 - (4-methoxycarbonylbenzyl) -piperidin-4-yl] urea hydrochloride, mp range 247 SZ 249 ^for G

1-Benzoyl-3- [1- (6-methyl-naphth-2-ylmethyl) -oiperid-4-yl] urea, m.p. hydrochloride wire, 250-253 ° C

1-Benzoyl-3- [1- (1H-benzofuran-2-yl) ethyl] pioerid-4-yl] urea, m.p. hydrochloride, 148-149 ° C

- [I - (5-acetamido-2-hydroxybenzyl) pioerid-4-yl -3-bensaylmo- qo thiourea m.p. hydrochloride 3/4 hydrate in the range of 230 to 232 ^c C

1-Benzoyl-3- (1-naphth-1-ylmethyl) piperid-4-yl] -urea having a melting point of hydrochloride wire of 185-186 ° C

1-Benzoyl-3- [1- (4-isopropylbenzyl) piperid-4-yl] -urea, m.p. hydrochloride wire, 240-242 ° C

1-Benzoyl-3-L- (6-methoxynaphth-2-ylmethyl) -piperid-4-yl] urea, m.p. hydrochloride wire, 243-244 ° C

3-Benzoyl-1- [1- (1,4-benzodioxan-6-ylmethyl) -piperid-4-yl] -urea, m.p.

235 ° C _o % o - o

-benzoyl-3- (1- (3,4-dimethylbenzyl) piperid-4-yl) urea, m.p. 239-240 ° C;

1-Benzoyl-1-methyl-3- [1- (n-Bt-2-ylmethyl) -piperid-4-yl] -urea m.p.

234046 Example δ compound

4,

1-Benzoyl-3- [1- (2- (naphth-2-yl) ethyl] piperidin-4-yl) -urea, m.p. hydrochloride, 230-232 ° C

1-Benzoyl-3- [1- ( ^6- cyano-naphth-2-ylmethyl) -piperid-4-yl] -urea m.p. -ylmethyl) -piperid-4-yl] -urea

1-Benzoyl-3- [1- (6-bromo-naphth-2-ylmethyl) -piperid-4-yl] -urea

-benzoyl-3- [1- (1- (naphth-2-yl) propyl) piperidin-4-yl] urea

1-Benzoyl-3- [1- (quinoxalin-6-ylmethyl) -piperid-4-yl] -urea

-benzoyl-3- [1- (cinnolin-3-ylmethyl-piperidin-4-yl) -urea

1-Benzoyl-3- [1- (isoquinolin-6-ylmethyl) -piperid-4-yl] -urea

1-Benzoyl-1-methyl-3- [1- (naphth-2-ylmethyl) -piperid-4-yl] urea, m.p. hydrochloride wire, 164-166 ° C

1-Benzoyl-3-methyl-3- [1- (naphth-2-ylmethyl) -piperid-4-yl] -urea m.p.

Claims (12)

SUBJECT OF THE INVENTION A process for the preparation of piperidine derivatives of the general formula I Ar-Y-CHR ⁹ - (CHR ² '-O Nr’cXN - ZR (Ii) where Ar is a ring radical of formula (Ia) (Ia) wherein Q is oxygen, sulfur, the group -CR 1 = CR ® -, -N-CR ® - or -Ν = Ν-, and each of the symbols II 'R'. and ,, R ^ as well as R? and R6 is hydrogen, halogen or alkyl of 1 to 6, preferably 1 to 4 carbon atoms, alkenyl of 2 to 6, preferably 2 to 4 carbon atoms, alkoxy of 1 to 6, preferably 1 to 4 carbon atoms, haloalkyl of 1 to 6, preferably 1 to 4 carbon atoms, nitro, amino optionally substituted by one or two alkyl groups of 1 to 6, preferably 1 to 4 carbon atoms, acyl of 2 to 7 carbon atoms or a sulfonyl group, furthermore an alkoxycarbonyl group having 1 to 6, preferably 1 to 4, carbon atoms in the alkoxy moiety, a cyano group or a hydroxyl group, optionally with R @ 1 and R @ 2 when attached to adjacent carbon atoms or R symboly and R ³ , when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, also represent a fused five- or six-membered carbocyclic or heterocyclic ring containing both o an oxygen, sulfur or nitrogen heteroatom optionally substituted by one or more of the above substituents, R is optionally substituted aryl or heteroaryl or cycloalkyl of 5 to 7 carbon atoms as defined above, wherein the heteroaryl residue contains oxygen, nitrogen or sulfur as heteroatom, Each of R, R, R and R is hydrogen or alkyl of 1 to 6, preferably 1 to 4 carbon atoms, n is 0 or 1, X is oxygen = O, sulfur = S, or imino = NH, Y is -O- or a direct bond; e Z is carbonyl -CO- or methylene -CH, - wherein when Ar is unsubstituted phenyl and R is hydrogen, Y is -O-, or when Z is methylene -CHg- and Ar is optionally substituted phenyl or an optionally substituted pyridyl radical, then R is hydrogen, as well as their acid addition salts or their quaternary ammonium salts, characterized in that the compound of formula IV Ar-Y-CHR ⁹ - (CHR ² ; _n -1 / -NHR ¹ (IV), wherein 1 2 9 Ar, Y, R, R, R, and, more generally, react with a compound of formula Va R - Z - M (Va) where R and Z are as defined above and M is the group -NCO, -NCS, -NR ^J -CXNH -Iffi ^ _O, or -CN, wherein when M is the group -NCO or -NCS, then in the resulting compound of formula IR ^ is hydrogen and X is oxygen or sulfur; optionally when M is -NR 4 -CN, then in the resulting compound of formula (IX) is -NH, and optionally the alkoxy group bound to the compound of formula I is dealkylated to form a hydroxyl group, or the nitro group bound to the compound of formula I is reduced to form an amino group, or an amino group bound to a compound of formula I is acylated to form the above acylamino group, and optionally the base of formula I obtained is converted into an acid addition salt or a quaternary ammonium salt, or with acid transforms into the free base. 2. A process according to claim 1, wherein - reacting a compound of formula IV wherein Y, n, R, R and R are as defined in point 1 and Ar is a phenyl group substituted with one or more residues of C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, halogen or C 1 -C 6, preferably C 1 -C 4, alkoxy or naphthyl, benzofuranyl, benzothiophenyl, tetrahydronaphthyl, indanyl, benzodioxanyl, quinolinyl, isoquinolinyl , a cinnolyl, or 4-, 5-, 6- or 7-indolyl group, each of which is optionally substituted with at least one of a radical comprising a halogen, an alkyl group of 1 to 6, preferably 1 to 6, C 4 -C 6 alkoxy, C 1 -C 6 alkoxy, preferably C 1 -C 4, and cyano, with a compound of formula Va, wherein R, Z and M are as defined above. 3. A process according to claim 1 or 2, wherein the compound is of the formula 12 9 IV, wherein Ar, R, R and R are as defined in 1, Y is a direct bond and n is zero, is reacted with a compound of formula Va wherein R, Z and M are as defined above. in point 1. 4. A process according to any one of claims 1 to 3, wherein the compound of formula (IV): Wherein Ar, Y, j, R, R and R are as defined in 1, react with a compound of formula Va wherein Z and M are as defined in 1 and R is phenyl optionally substituted with at least one of halogen, alkyl of 1 to 6, preferably 1 to 4 carbon atoms, alkoxy of 1 to 6, preferably 1 to 4 carbon atoms, hydroxy or nitro; R is thienyl or pyridyl. 5. The process of claim 1, wherein 4-emino-1- (naphth-2-ylmethyl) piperidine is reacted with a benzoyl isocyanate to form r-bezoyl-3- [1- (naphth-2-ylmethyl) piperide. -4-yl] urea. 6. The process of claim 1, wherein 4-amino-1, (naphth-1-ylmethyl) piperidine is reacted with benzoyl isocyanate to form 1-benzoyl-3- [i- (naphth-1-ylmethyl) benzoyl isocyanate. , yl) piperid-4-yl] urea. 7. The method of claim 1, wherein 4-amino-1- (4-isopropylbenzyl) piperidine is reacted with benzoyl isocyanate to give 1-benzoyl-3- [1- (4-isopropylbenzyl) piperid-4-yl]. ureas. 8. The process of claim 1, wherein 4-amino-1- (5,6,7,8-tetrahydronaphth-2-ylmethyl) piperidine is reacted with benzoyl isocyanate to give 1-benzoyl-3- [1- (5 _t 6 _{(7,8-tetrahydro-naphth-2-ylmethyl5} piperidin-4-yl] urea. 9. The process of claim 1, wherein 4-amino-1- (3,4-dimethylbenzyl) piperidine is reacted with benzoyl isocyanate to give 1-benzoyl-3- [1- (3,4-dimethylbenzyl) - piperid-4-yl] urea. 10. The process of claim 1, wherein 4-amino-1- (inden-5-ylmethyl) piperidine is reacted with benzoyl isocyanate to form 1-benzoyl-3- [1- (indan-5-ylmethyl) piperidine. -4-yl] urea. 11. The process of claim 1, wherein 4-amino-1- (naphth-2-ylethyl) piperidine is reacted with benzoyl isocyanate to form 1-benzoyl-3- [1- (1- / naphth-2-). yl / ethyl) piperid-4-yl] urea. 12. The process of claim 1, wherein 4-amino-1- (4-ethylbenzyl) piperidine chloride is re-treated with benzoyl isocyanate to give 1-benzoyl-3- {T- (4-ethylbenzyl) piperid-4-yl. ureas.