CS234048B2 - Process for preparing piperidine derivatives - Google Patents

Abstract

Process for the preparation of piperidine derivatives of the general formula I R3 | (I), Ar-Y-C11R9-(CHR2) n -N -------φφ1CXN-ZR where the general symbols have the meaning given in the main point of the subject of the invention. The compounds prepared by the process according to the invention are characterized by psychotropic activity and can be used as antidepressants. They are specific inhibitors of 5-hydroxytryptamine uptake and may therefore be suitable for therapeutic use where such pharmacological specificity is desired.

Description

The invention relates to a process for the preparation of novel piperidine derivatives, in particular piperidinoureas, thioureas and guanidines, which are characterized by pharmaceutical activity, in particular psychotropic activity in standard pharmacological tests and can be used prospectively as antidepressants. In general, these compounds are specific inhibitors of 5-hydroxytryptamine reuptake in vitro and in vivo and may therefore also be suitable for any other therapeutic uses where such pharmacological specificity may be desirable.

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

R ³

Ar-Y-CHR ⁹ -(CHR ² ) _r -N - NR ¹ CXN-ZR where

Ar represents a cyclic radical of the general formula Ia (I), (Ia), where

8 represents oxygen, sulfur_or a -CR -CR o4 group

R ⁷ and R ⁸ , £

X

Y

Z or -N=CR or -N=N-, and each of the symbols R**, R ⁹ and R ⁸ , but also R ⁷ and R ⁸ , if present, means hydrogen, halogen or an alkyl group with 1 to 6, preferably 1 to 4 carbon atoms, an alkenyl group with 2 to 6, preferably 2 to 4 carbon atoms, an alkoxy group with 1 to 6, preferably 1 to 4 carbon atoms, a haloalkyl group with 1 to 6, preferably 1 to 4 carbon atoms, a nitro group, an amino group optionally substituted by one or two alkyl groups each with 1 to 6, preferably 1 to 4 carbon atoms, an aoyl group with 2 to 7 carbon atoms or a gulfonyl group, furthermore an alkoxycarbonyl group with 1 to 6, preferably 1 to 4 carbon atoms in the alkoxyl part, a cyano group or a hydroxyl group, and optionally the symbols R ⁴ and R , if they are bonded to adjacent carbon atoms, or the symbols R and R ⁸ , if they are bonded to adjacent carbon atoms, together with the carbon atoms to which they are bonded, also mean a fused five- or six-membered carbocyclic or heterocyclic ring containing oxygen, nitrogen or sulfur as a heteroatom, and optionally substituted by one or more of the above-mentioned substituents, means an aryl or heteroaryl or cycloalkyl radical with 5 to 7 carbon atoms optionally substituted by the above-mentioned substituents, wherein the heteroaryl radical contains oxygen, nitrogen or sulfur as a heteroatom, each of the symbols r', R ² , R ³ and R ⁹ means hydrogen or an alkyl group and 1 to 6, preferably 1 to 4 carbon atoms, means 0 or 1, means oxygen = 0, sulfur = S or an imino group = NH, and represents oxygen -O- or a direct bond and represents a group -CO- or -CH-, wherein when Ar represents an unsubstituted phenyl radical and ^R9 represents hydrogen, then Y represents oxygen -O-, and when Z represents a methylene group _-CH2- and Ar represents an optionally substituted phenyl or optionally substituted pyridyl radical, then R9 represents hydrogen.

we know3

Examples of substituted amino groups include groups such as an alkyl or dialkylamino group having 1 to 6 carbon atoms in each of the alkyl moieties, an acylamino group, i.e. an alkylcarbonylamino group having 1 to 6 carbon atoms in the alkyl moiety, or a sulfonylamino group, for example an alkylsulfonamido group having 1 to 6 carbon atoms or a dialkylsulfonylamino group having 1 to 6 carbon atoms in each of the alkyl moieties.

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

Examples of alkyl amino groups and dialkylamino groups 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 trifluoroethyl.

Examples of alkoxycarbonyl groups are methoxycarbonyl and ethoxycarbonyl.

Preferred halogen substituents are chlorine and bromine.

Examples of groups in the meaning of the symbol Ar when Q represents oxygen or sulfur are groups of the formula

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

δ

Examples of groups in the meaning of the symbol Ar, where Q means the group -CR =CR are groups of the formula

R ⁶

R® (i.e.

the symbols n and fc mean a group

Examples of groups in the meaning of the symbol Ar, where Q represents the group -N=CR ⁸ -, are groups of the formulae

Examples of groups in the meaning of the symbol Ar, when Q represents the group -N=N-, are groups of the formulae

If the symbol Ar represents a monosubstituted phenyl or monosubstituted pyridyl radical, then it may be, for example, a 4-tert-butylphenyl, 4-cumenyl, 4-n-butoxyphenyl, 4-nitrophenyl, 4-dimethylaminophenyl, 3-vinylphenyl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 4-methylpyrid-3-yl, 4-chloropyrid-2-yl, 2-methylpyrid-4-yl or 2-bromopyrid-4-yl radical.

If the symbol Ar represents a polysubstituted phenyl or pyridyl radical, then it can be, for example, a 3,4-dichlorophenyl, 3,4,5-trimethylphenyl, 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 radical.

Examples of the symbol Ar, when it represents a phenyl radical with a fused five- or six-membered carbocyclic or heterocyclic ring, are naphth-1-yl, naphth-2-yl, benzo[1,4]dioxan-6-yl, 3,4-methylenedioxyphenyl, 1,2,3,4-tetrahydro-naphth-6-yl, 1,4-dihydro-naphth-6-yl, benzo[b]thiophen-6-yl, indol-6-yl, benzo[b]furan-6-yl, quinol-6-yl or quinol-5-yl.

Examples of the meaning of the symbol Ar when it represents a pyridyl radical with a fused five- or six-membered carbocyclic or heterocyclic ring are quinol-4-yl, quinol-2-yl, 5,6,7,8-tetrahydro-quinol-4-yl or 5,6,7,8-tetrahydro-quinol-2-yl. Examples of such groups when substituted on the unfused ring are 6-methoxynaphth-2-yl, 7-methoxynaphth-2-yl and 4-methylnaphth-2-yl. Preferred heterocyclic groups in the meaning of the symbol Ar with fused heterocyclic rings contain oxygen, nitrogen or sulfur as the heteroatom.

An example of an aryl radical in the meaning of the symbol R is a phenyl radical, which may be optionally substituted, for example, by substituents given in the meaning of the symbol R^, such as, for example, a methyl group (for example, a 4-methyl group), an ethyl group, a propyl group, a nitro group (such as a 3- or 4-nitro group), a hydroxy group (for example, a 4-hydroxy group), a methoxy group, an ethoxy group, a fluoro-, bromo-, chloro-, (for example, 3,4-dichloro-).

Heteroaryl radicals in the meaning of the symbol φ include a thienyl radical (for example, a thien-2-yl radical), a furyl radical (for example, a fur-2-yl radical) and a pyridyl radical (for example, a pyrid-2-yl radical), these radicals being optionally substituted as described above for a phenyl radical in the meaning of the symbol Ar.

Preferred meanings of the symbol Ar are a phenyl radical substituted by one or more alkyl groups or alkoxy groups with 2 to 6 carbon atoms, for example 4-ethylphenyl, 3,4-dimethylphenyl or 3,4-dimethoxyphenyl, furthermore a phenyl radical with an unfused five- or six-membered carbocyclic ring, such as naphth-1-yl and naphth-2-yl, which radicals are optionally substituted by at least one alkyl group with 1 to 6, preferably 1 to 4 carbon atoms, an alkoxy group with 1 to 6, preferably 1 to 4 carbon atoms, a halogen, a nitro group, a trifluoromethyl group, an amino group, an alkylamino group with 1 to 6, preferably 1 to 4 carbon atoms (for example methylamino), a dialkylamino group with 1 to 6, preferably 1 to 4 carbon atoms in each of the alkyl parts (for example dimethylamino group) or cyano group.

q

Preferably, n is zero, R is hydrogen or methyl, and R ¹ is hydrogen.

The preferred meaning of the symbol X is oxygen.

Preferably, the symbol Z represents a group -CO- and R represents a phenyl group, optionally substituted in position 4 by an alkoxy group having 1 to 6, preferably 1 to 4, carbon atoms, for example by a methoxy group.

The symbol Y preferably represents a direct bond.

If the symbol 3 represents a methylene group -CH 2 , ^{R 8} is preferably a phenyl radical.

Preferred compounds prepared by the process of the 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-benzoyl-3-1-(5,6,7,8-tetrabydronaphth-2-ylmethyl)piperid-4-yl urea,

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

1-benzoyl-3-1-(indan-5-ylmethyl)piperid-4-yl urea,

1-benzoyl-3-1-(.1-/naphth-2-yl/ethyl)piperid-4-yl urea and

1-Benzoyl-3-1-(4-ethylbenzyl)piperid-4-yl urea.

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. methanesulfonate and p-toluenesulfonate), acetate, maleate, citrate, fumarate, tartrate, malonate and formate.

The compounds of general formula I, prepared by the process according to the invention, were subjected to tests for psychotropic activity, which was evaluated by their ability to inhibit p-chloroamphetamine-induced hyperactivity and/or by their ability to inhibit 5-hydroxytryptamine uptake in thin brain preparations.

The procedure described below was used to determine the ability of these compounds to inhibit hyperactivity induced by p-chloroamphetamine.

Three groups of 4 female mice (weighing 20 to 24 g) are orally administered the test compounds (50 mg/kg) and the fourth group receives the appropriate amount of vehicle. Thirty minutes after the administration, 20 mg/kg of p-chloramphetamine is administered intraperitoneally to all experimental animals. The groups of mice are then immediately placed in rectangular plastic cages equipped with a locomotor activity monitor. The locomotor activity of the animals is recorded for 10 to 30 minutes after the administration of p-chloramphetamine. This procedure is repeated three more times, so that four groups of mice are used for each test compound and each of the activity monitors is used alternately in all experiments. The inhibition of hyperactivity induced by p-chloramphetamine is calculated according to the relationship.

C - T _ x 100%,

C where

C represents the average activity of the control groups in the interval 10 to 30 minutes after administration of p-chloramphetamine, and

T represents the average activity of the treated groups in the interval 10 to 30 minutes after administration of p-chloramphetamine.

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

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

Compound Inhibition of hyperactivity induced by p-chloroamphetamine no (%) 1-benzoy 1-3-01-(naphth-2-ylmethyl)piperid-4-yl urea 67.5 1-Benzoyl 1-3-01-(naphtho-,-ylmethyl)piperid-4-yl urea 56.4 1-benzoyl-3-0-(4-isopropylbenzyl)piperid-4-yl]urea· 49 1-benzoyl-3-0-(5,6,7,8-tetrahydronaphth-2-ylmethyl)piperid-4-yl]- urea 69.4 73.5 1-Benzoyl-3-O1-(3,4-dimethylbenzyl)piperid-4-yl]urea 68.9 1-benzoyl-3-O1-(incan-4-ylmethyl)piperid-4-yl]urea 59.3 1-benzoyl-3-O1-(1-naphth-2-yl ethyl)piperid-4-yl]urea 71.7 1-Benzoyl 1-3-O1-(4-ethylbenzyl)piperid-4-yl]urea 72.9

The ability of the compounds of general formula I prepared by the process according to the invention to inhibit the uptake of 5-hydroxytryptamine by a brain tissue preparation was tested by the following method:

The effect of the test compound on the neuronal uptake of 5-hydroxytryptamine by a preparation of cerebral cortex prepared from rat brain is determined by the method described by Synder, Green and Hendley in the article Kinetics of accumulation of H^-norepinephrine in preparations of cerebral tissue from various parts of the rat brain (J.Pharm.Exp.Therap. 164. pp. 90 to 102 (1968)). This method produces curves showing the dependence of the effect of the test compound and the standard (imipramine) on concentration. The efficacy of the test compound is expressed in relation to the efficacy of imipramine. Thus, the efficacy of the test compound is given by the relationship between the molar concentration of imipramine, which provides 50% inhibition of 5-hydroxytryptamine uptake and the molar concentration of the test compound, which provides 50% inhibition of 5-hydroxytryptamine uptake.

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

In this test, 1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea was found to be particularly effective, having an 8.8-fold greater potency than imipramine (potency of imipramine = 1.0).

In vivo, the inhibition of 5-hydroxytryptamine uptake by the compounds prepared according to the invention was determined by a procedure involving the 5-hydroxy-L-tryptophan-induced withdrawal syndrome in experimental animals. Mice administered a large dose of 5-hydroxy-1-tryptophan exhibit a behavioral syndrome consisting of tremor, hindpaw abduction, lateral head tilting, and forepaw stamping. In addition to these symptoms, rats also exhibit head jerking and head circling. In the experiments described below, the presence of this syndrome is presumed if at least three of these symptoms occur in mice and at least four in rats. If the experimental animals receive a small dose of 5-hydroxy-L-tryptophan, which alone is not sufficient to induce the syndrome, it can be induced by prior administration of 5-hydroxytryptamine uptake inhibitors. This test can therefore be used as an indication of inhibition of 5-hydroxytryptamine uptake in vivo.

a) Dose-response test in mice

Groups of 12 (two subgroups of 6) female mice (weighing between 18 and 22 g) were used for each dose, each group being housed separately in a separate pen for the duration of the experiment. The mice were orally dosed with either the test compound or vehicle (0.5% HPMC) and then, 30 minutes later, with a threshold dose (60 mg/kg) of 5-hydroxy-L-tryptophan intraperitoneally, and were then placed in 30 cm diameter Perspex cylindrical containers. After a further 20 minutes, the mice were observed for 5 minutes to determine whether the described syndrome was present or not.

The dose which will produce the syndrome in 50% of the mice is calculated by the method of Litehfield and Wilcoxon, J.Pharm.Exp.Ther., 95, pp. 95-113 (1949).

b) Rat dose-response test

Groups of 6 male rats (weighing 150 g) were administered 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 recorded between 20 and 30 minutes after 5-hydroxy-L-tryptophan administration was recorded. A linear regression analysis of the results was performed and the ΕΏ^θ value was calculated from it.

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

Compound Values for potentiation of 5-hydroxy-L-tryptophan-induced syndrome in mouse (mg/kg p. o.) rat (mg/kg i. p, 1-benzoyl-3-O1-(naphth-2-ylmethyl)piperi d-4-yl]urea 7.2 5.3 clomipramine 18 39.2

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

Ar-Y-CHR ⁹ - (CHR ² ) _n -N , I

NR CXN-ZR (VII)

Ar-Y-CHR ⁹ -(CHR ² ) _η ·ΛΓ^>~ UR ¹ CXií-ZR (VIII), where

2 3 9 Θ n, Ar, X, Y, Z, R, R , R , R and R have the above-mentioned characteristics, and B represents an anion, is reduced and optionally the alkoxyl group bound to the compound of general formula I is dealkylated to form a hydroxyl group or the nitro group bound to the compound of general formula I is reduced to form an amino group or the amino group bound to the compound of general formula I is acylated to form an acylamino group, and optionally the obtained base of general formula I is converted into an acid addition salt or into a quaternary ammonium salt, or the acid addition salt of the compound of general formula I is converted into a free base.

The piperidine compounds of formula I are obtained according to the invention by reduction of compounds of formula VII or VIII, for example by catalytic hydrogenation when X is oxygen, for example in the presence of Raney nickel or platinum as a catalyst. The reduction can also be carried out by the process described and protected by British Patent δ. 1542137. In such reduction processes, an alkali metal borohydride is used in a secondary alkanol of 3 to 5 carbon atoms, for example in isopropanol.

When a compound of the general formula I is obtained which has a reactive group as a substituent, this compound can be converted into another compound of the general formula I by a known process. For example, when the symbol Ar represents a group which has an alkoxy group or an arylalkoxy group with 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy part as a substituent on the aromatic nucleus, the corresponding compound of the general formula I can be prepared by dealkylation, where a hydroxyl group is bonded to the group represented by the symbol Ar. In the case where the symbol Ar represents a radical with a nitro group on the aromatic nucleus, then this nitro group can be converted into an amino group by reduction (for example catalytic hydrogenation). Such amino groups can be anoylated.

The above processes may also involve the conversion of the acid addition salt to the free base and vice versa. Quaternization of the tertiary nitrogen of the piperidine ring may constitute an optional further step, for example using alkyl halides having 1 to 6, preferably 1 to 4 carbon atoms in the alkyl moiety, such as methyl iodide or benzyl chloride.

Compounds of general formula VIII can be prepared by reacting a compound of general formula III

Ar-Y-CHR ⁹ - (CHR ³ ) -W where

W represents halogen, especially bromine, and 3 9

Ar, and ^R have the above meaning, is reacted with a compound of general formula XIV

CXNZR (III), (XIV)f where

X, Z, R, r' and R ³ have the meanings given above.

The invention also describes pharmaceutical compositions containing as active ingredient compounds of general formula I as described above. The active compound may optionally be finely divided. In addition to the active ingredient, these compositions also contain a pharmaceutically acceptable carrier.

Any suitable known carrier may be used to prepare pharmaceutical compositions.

In these compositions, the carrier may be a solid, a liquid or a mixture of a solid and a liquid. Compositions in solid form include powders, tablets and capsules. The solid carrier may consist of one or more substances which may also function as, for example, a sweetener, lubricant, solubilizer, suspending agent, binder or tablet disintegrating agent; the carrier 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 a suitable proportion with a carrier which has the necessary binding properties and the resulting mixture is compressed into a tablet of the desired shape. The powders and tablets preferably contain 5 to 99%, especially 10 to 50%, of the active ingredient.

Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax and cocoa butter. The term composition herein also includes the formulation of the active ingredient with an encapsulating material as a carrier, thereby obtaining a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier which is thus associated with it. Similarly, the use of wafers.

Sterile liquid compositions include sterile solutions, suspensions, emulsions, elixirs and syrups. 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 of these. A liquid carrier which is 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 sparingly soluble for this purpose, it may often be dissolved in a suitable organic solvent, for example, an aqueous solution of propylene glycol or polyethylene glycol. Generally, an aqueous solution of propylene glycol containing the glycol in a concentration by weight of from 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, arachis oil. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be administered by intramuscular, intraperitoneal, or subcutaneous injection. In many cases, the active compound is active when administered orally and can be administered in the form of a liquid or solid composition.

Preferably, the pharmaceutical composition is in unit dosage form. In such form, the composition may be further subdivided into smaller unit dosages containing suitable quantities of the active ingredients; the unit dosage may take the form of a sachet containing a specific quantity of the composition, such as sachets of powder or vials or ampoules. The unit dosage may be in a capsule, cachet or tablet, or a suitable number of any of these packaged forms. The amount of active ingredient in a unit dosage form of the composition may vary or be selected from 5 mg or less to 500 mg or more according to the need and potency of the active ingredient. Pharmaceutical compositions also include compounds prepared by the method of the invention alone without a carrier, where such compounds are in unit dosage form.

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

The invention is further illustrated by the following examples.

Example

1-benzoyl-2-[j-(naphth-2-ylmethyl)piperid-4-yl]urea

2-Bromomethylnaphthalene is heated with 4-benzoylureidopyridine in acetonitrile solvent to give 1-benzoyl-3-[j-(naphth-2-ylmethyl)-4-pyridinium]urea bromide with a melting point in the range of 247-248 °C. The resulting compound is reduced with sodium borohydride in an isopropyl alcohol solvent by heating under reflux to give the title compound with a hemihydrate melting point in the range of 232-234 °C.

Example 1 and 2

1-benzoyl-3-[1-(naphth-2-ylmethyl)-3,4-dehydro-piperid-4-yl]urea

a) 1-Benzoyl-3-[[(naphth-2-ylmethyl)-4-pyridinium]urea bromide is reduced with sodium borohydride in methanol solvent to give the title compound with a quaternary hydrate melting point in the range of 191-193 °C.

b) The compound obtained by the procedure in paragraph a) can then be reduced with sodium borohydride in isopropyl alcohol solvent by heating under reflux to give 1-benzoyl·

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

Examples 3 to 42

The following compounds of general formula I are prepared by the procedure described in Example 41 by reacting the corresponding compound of general formula III, where W is chlorine or bromine, with 4-benzoylureidopyridine and subsequently reducing the resulting product:

Example no.

Compound

1

1-benzoyl-3-0-(2-[naphth-,-yloxy]ethyl) piperid-4-yl] urea (melting point of the hydrochloride tetrahydrate in the range of 226 to 229 °C) 1-benzoyl-3-0-(3, 4-dichlorobenzyl)piperid-4-ylI urea (melting point of the hydrochloride hemihydrate in the range of 244 to 245 °C) ,-benzoyl-3-0-(4-tert.butylbenzyl)piperid-4-yl| urea Λ4 (melting point of the hydrochloride quaternary hydrate in the range of 202 to 204 °C) 1-benzoyl-3-0-(4-n-butoxybenzyl)piperid-4-yl] urea (melting point of the hydrochloride hemihydrate in the range of 214 to 217 °C)

1-benzoyl-3-O-(3-nitrobenzyl)piperid-4-yl]urea (melting point of the hydrochloride quaternary hydrate between 255 and 257 °C)

1-benzoyl-3-O-(5,6,7,8-tetrahydronaphth-2-ylmethyl) piperid-4-yl] urea (with a melting point of the hydrochloride between 233 and 335 °C) 1-benzoyl-3—£ 1 — (4-ethylbenzyl) piperid-4-yl] urea (with a melting point of the hydrochloride between 234 and 236 °C) ,-benzoyl-3-O-(3,4-dibromobenzyl) piperid-4-yl] urea (with a melting point of the hydrochloride between 228 and 230 °C) 1-benzoyl-3-O-(2,5-dimethylbenzyl) piperid-4-yl] urea (with a melting point of the hydrochloride between 231 and 232 °C)

1-benzoyl-3-O-(4-n-propoxybenzyl)piperid-4-yl] urea (melting point of the hydrochloride between 232 and 234 °C)

1-Benzyl-3-O-(2-(naphth-2-oxy)ethyl)piperid-4-yl]urea (with a melting point of the hydrochloride between 215 and 2.8 °C)

1-benzoyl-3-O-(indan-5-ylmethyl)piperid-4-yl] urea (with a melting point of the hydrochloride between 253 and 256 °C) ,-benzoyl-3-O-(,-/naphth-2-yl/ethyl)piperid-4-yl] urea (with a melting point of the hydrochloride between ,72 and ,74 °C)

- benzoyl-3-0-(4-methyl-3-nitrobenzyl)piperid-4-yl]urea (with a melting point of the hydrochloride between 232 and 234 °C)

1-benzoyl-3-O-(3-bromo-4-methylbenzyl)piperid-4-yl] urea 1-benzoyl-3-O-(echinol-4-ylmethyl)piperid-4-yl] urea (with a melting point of the sesquihydrochloride between 211 and 213 °C) 1-benzoyl-3-O-(quinol-2-ylmethyl)piperid-4-yl] urea (with a melting point of the dihydrochloride between 213 and 215 °C) 1-benzoyl-3-O-(3,5-dimethylbenzyl)piperid-4-yl]urea p.

(melting point of the hydrochloride quaternary hydrate between 248 and 252 °C) ,-benzoyl-3-O-(2,4-dimethylbenzyl) piperid-4-yl] urea (melting point of the hydrochloride quaternary hydrate between 230 and 232 °C)

1-benzoyl-3-O-(3-bromobenzyl)piperid-4-yl]urea (melting point of the hydrochloride quaternary hydrate between 222 and 224 °C)

1-benzoyl-3-O-(3-iodobenzyl)piperid-4-yl] urea (with a melting point of the hydrochloride between 217 and 2.9 °C) ,-benzoyl-3-O-(pyrid-4-ylmethyl)piperid-4-yl] urea (with a melting point of the dihydrochloride between 236 and 238 °C)

1-benzoyl-3-O-(3-trifluoromethylbenzyl) piperid-4-yl] urea (with a melting point of the hydrochloride between 241 and 243 °C) ,-benzoyl-3-O-(4-methoxycarbonylbenzyl) piperid-4-yl] urea (with a melting point of the hydrochloride between 247 and 249 °C)

Example no.

Compound

1-benzoyl-3-[]1-(6-methylnaphth-2-ylmethyl)piperid-4-yl] urea (with a melting point of the hydrochloride hemihydrate between 250 and 253 °C) 1-benzoyl-3-|]1-( 1-/benzofuran-2-yl/ethyl)piperid-4-yl] urea (with a melting point of the hydrochloride between 148 and 149 °C)

1-[1-(5-acetamido-2-hydroxybenzyl)piperid-4-yl]-3-benzoylurea (melting point of 3/4 hydrate of hydrochloride between 230 and 232 °C) 1-benzoyl-3-[1-(2-/naphth-2-yl/ethyl)piperid-4-yl]urea (melting point of hydrochloride between 230 and 232 °C)

1-benzoyl-3-[]l-(6-cyanonaphth-2-ylmethyl)piperid-4-yl]urea (with a melting point of the hydrochloride polyhydrate in the range of 242 to 246 °C) 1-benzoyl-3-[]l-(6-fluoronaphth-2-ylmethyl)piperid-4-yl]]urea 1-benzoyl-3-[]l-(6-bromonaphth-2-ylmethyl)piperid-4-yl] 1-benzoyl-3-[j-(1-(naphth-2-yl/propyl)piperid-4-yl]urea 1-benzoyl-3-[/-(equinoxalin-6-yl-methyl)piperid-4-yl]urea 1-benzoyl-3-[j-(cinnolin-3-ylmethyl)piperid-4-yl]urea 1-benzoyl-3- [ 1 - (i so quinolin-6-ylmethyl) piperid- 4-yl] urea 1-benzoyl-3-El-(naphth-1-ylmethyl)piperid-4-yl] urea (melting point of the hydrochloride hemihydrate between 185 and 186 °C) 1-benzoyl-3- Π1—(4-isopropylbenzyl)piperid-4-yl] urea (melting point of the hydrochloride hemihydrate between 240 and 242 °C) 1-benzoyl-3-O-(6-methoxynaphth-2-ylmethyl)piperid-4-yl] urea (melting point of the hydrochloride hemihydrate between 243 and 244 °C)

3-benzoyl-1-[Ί-( 1,4-benzodioxan-6-ylmethyl)piperid-4-yl] urea (melting point of the hydrochloride quaternary hydrate between 231 and 235 °C) 1-benzoyl-3-[j-(3,4-dimethylbenzyl)piperid-4-yl] urea (melting point of the hydrochloride quaternary hydrate between 239 and 240 °C)

Examples 43 to 47

Using a procedure similar to that described in Example 1, 2-bromo-oethylnaphthalene is reacted with each of the following ureas:

4-Q3,4-diethylbenzoylureido]pyridine,

4- [3-trifluoromethylbenzoylureido] pyridine,

4-f 4-nitrobenzoylureido] pyridine,

4-[(pyrid-4-oyl)ureido]pyridine a

4-[p-fluorobenzoylureido] pyridine, and the resulting product is reduced to give the following compounds:

Example No. Compound 43 1-(3,4-dimethylbenzoyl)-3-[j-(naphth-2-ylmethyl)piperid-4-yl]urea- wine (0 melting point of the hydrochloride quaternary hydrate between 223 and 226 °C) i* 44 1-[j-(naphth-2-ylmethyl)piperid-4-yl]-3-(3- trifluoromethyl benzoyl) » urea (melting point between 251 and 253 °C) 45 1-[1-(naphth-2-ylmethyl)piperid-4-yl]-3-(4-nitrobenzoyl)urea (melting point of hydrochloride between 264 and 265 ^° C) 46 1-(pyrid-4-oyl)-3-C'-(naphth-2-ylmethyl)piperid-4-yl] urea (melting point between 254 and 255 ^° C)

Example No. Compound

1-(p-fluorobenzoyl)-3-[](naphth-2-ylmethyl)piperid-4-yl] urea (melting point of the hydrochloride quaternary hydrate between 242 and 245 °C (aa decomposition))

Claims (12)

SUBJECT OF THE INVENTION A process for the preparation of piperidine derivatives of the general formula I R ³ Ar-Y-CHE ⁹ - (CHR ² ) _n - n \ - NE ¹ CXN-ZR (I) where Ar is a ring moiety of formula (Ia) wherein Q is oxygen, sulfur, the group -CR 1 = CR ⁸ -, -N = CR ⁸ - or -N = N -, and each of R ⁶ , R ⁹ , R 7, and R 7, but IR and B, are- if present, it is hydrogen, halogen, 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 atoms C 1 -C 6 -haloalkyl, preferably C 1 -C 4 -haloalkyl, nitro, amino optionally substituted by one or two C 1 -C 6 -alkyl, preferably C 1 -C 4 -alkyl, or C 2 -C 7 -acyl groups; or sulfonyl group, as an alkoxycarbonyl group having 1-6, preferably 1-4 carbon atoms in the alkoxy, cyano or hydroxyl, and optionally bu5 R and R ^9, when attached to adjacent carbon atoms, or R ⁸ and R ⁸ , when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached are bound, also non-fused five- or six-membered carbocyclic or heterocyclic books containing, as heteroatom, oxygen, nitrogen or atrium and optionally substituted with one or more of the above-mentioned substituents, R is optionally substituted aryl or heteroaryl or cycloalkyl of 5 to 7 carbon atoms by the above substituents, wherein the heteroaryl radical contains 12 o as heteroatom oxygen, nitrogen or sulfur, each of R, R, R and R being hydrogen or an alkyl group having 1 to 6, preferably 1 to 4, carbon atoms, and is 0 or 1, X is -O-, sulfur -S-, or an imino group > NH, Y is -O- or a direct bond and Z is -CO- or -CH? -, wherein when Ar is an unsubstituted phenyl radical and R is hydrogen, then Y is oxygen -0-, and when Z represents a methylene group -CH, -, and Ar is optionally substituted ^and Nu i a phenyl or optionally substituted pyridyl radical, then R is hydrogen, as well as their acid addition salts and their quaternary ammonium salts, characterized in that the compound of formula (VII) or (VI) Ar-Y-CHR ⁹ - (CHR ² ) -NR ¹ CXN-ZR (VII), Ar-Y-CHR ⁹ - (CHR ² ) _n 14 R ¹ CXN-ZR (VIII), where 12 3 9 © Ar, X, Y, Z, R, R, R, R- ¹ , R and a are as defined above and B is an anion, reduced and optionally the alkoxy group bound to the compound of formula I is dealkylated to form a hydroxy group, or nitro bonded to a compound of formula I is reduced to form an amino group or the amino group bound to a compound of formula I is acylated to form an acylamino group as defined above, and optionally the base of formula I obtained is converted to an acid or quaternary ammonium salt or an addition salt of the compound of formula (I) with an acid converts into the free base. 2. The process of claim 1, wherein the compound of the formula is reduced VII or VIII, where η, X, Y, Z, R, R ¹ , R ² , R ³ , R ⁹ and optionally have the meaning given in point 1 and Ar represents a phenyl group substituted with at least one radical comprising an alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, a halogen, an alkoxy group having 1 to 6, preferably 1 to 4 carbon atoms, or a naphthyl, benzofuranyl benzothiophenyl, tetrahydronaphthyl, indanyl, benzodioxanyl, quinolinyl, isoquinolinyl, cinnolyl, 4-, 5-, 6- or 7-indolyl groups, each of which is optionally substituted with at least one of halogen including an alkyl group of 1 to 1; 6, preferably 1 to 4 carbon atoms, alkoxy of 1 to 6, preferably 1 to 4 carbon atoms, and cyano. 3. Method according to claim 1 or 2, characterized by reducing a compound of »VIX or Formula VIII wherein Ar, X, Y, Z, R, R ^1, R ^2, R ³ and R ⁹ are as defined in and Y is a direct bond and n is zero, to form a compound of formula 1 wherein - the dashed line is absent. - ♦ 4. Process according to claims 1-3, characterized by reducing a compound of formula VII or VIII, wherein A, Ar, X, Y, Z, Br, R ^2, R ^ and R ^ are as defined in point 1 and R is a phenyl group optionally substituted by at least one of halogen, C1-6 alkyl, preferably 1-4 carbon atoms, C1-6 alkoxy, hydroxy and nitro; , or a thienyl group or a pyridyl group. 5. The process of item 1 for the preparation of 1-benzoyl-3-Q- (naphth-2-ylmethyl) piperid-4-yl] urea, characterized in that 1-benzoyl-3- [j- (naphthyl) bromide is reduced. -2-ylmethyl) -4-pyridinium] urea. 6. The process of item 1 for the preparation of 1-benzoyl-3- [j- (naphth-1-ylmethyl) piperid-4-yl] urea, characterized in that 1-benzoyl-3- [j- ( naphth-1-ylmethyl) -4-pyridinyl] urea. 7. A process according to claim 1 for the production of 1-benzoyl-3- [1- (4-isopropylbenzyl) piperid-4-yl] urea, which comprises reducing 1-benzoyl-3-Q1- (4-isopropylbenzyl) chloride. -4-pyridinium, urea. 8. The method of claim 1 to produce 1-benzoyl-3- | j ^_ (5,6,7,8-tetrahydroneft-2-ylmethyl) piporid-4-yl] urea, characterized in that reducing the chloride of 1- benzoyl-3-O- (5,6,7,8-tetrahydronaphth-2-ylmethyl) -4-pyridinium] urea. 9. The process of item 1 for the preparation of 1-benzoyl-3- [N - (3,4-dimethylbenzyl) piperid-4-yl] urea, characterized in that 1-benzoyl-3- [i- (3,4-diethylbenzyl) -4-pyridinium] urea. 10. The process of item 1 for the preparation of 1-benzoyl-3- [j- (indan-5-ylmethyl) piperid-4-yl] urea, characterized in that 1-benzoyl-3- [j- ( indan-5-ylmethyl) -4-pyridinyl] urea. 11. The process of item 1 for the preparation of 1-benzoyl-3-Q1- (1- (naphth-2-yl) ethyl) piperid-4-yl urea, characterized in that 1-benzoyl-3- chloride is reduced. [1- (1- (Naphth-2-yl) ethyl) -4-pyridinium] urea. 12. The method of item 1 for the preparation of 1-benzoyl-3-O, 4-ethylbenzyl) piperid-4-yl] urea, characterized in that the chloride, -benzoyl-3- [1- (4-ethylbenzyl)] is reduced. -4-pyridinium] urea.