CS234043B2 - Process for producing piperidine derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of novel piperidine derivatives, in particular piperidinoureas, thioureas and guanidines, which exhibit pharmaceutical activity, in particular psychotropic activity in standard pharmacological tests and may be prospectively useful as antidepressants. In general, these compounds are specific inhibitors of the reuptake of 5-hydroxytryptamine in vitro and in vivo and may therefore also be suitable for any other therapeutic use 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 according to the invention, which compounds can be described by the general formula I

Description

The invention relates to a process for the preparation of novel piperidine derivatives, in particular piperidinoureas, thioureas and guanidines, which exhibit pharmaceutical activity, in particular psychotropic activity in standard pharmacological tests and may be prospectively useful 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 use 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 compounds can be described by the general formula I

Ar-Y-CHR ⁹ -(CHR ² )n·

-ONR ¹ CXN - ZR (I), where the dashed line indicates a possible bond,

234043 2

Ar represents a ring radical of the general formula Ia

where

Q represents oxygen, sulfur, the group -CR^=CR ⁸ - or -N=CR ⁸ - or -N=N-, and each of the symbols R^, R ³ , R ⁸ , as well as R? and R ⁸ , means hydrogen, halogen, 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 nitro group, a haloalkyl group with 1 to b, preferably 1 to 4 carbon atoms, an amino group, optionally substituted by one or two alkyl groups each with 1 to 6 carbon atoms, an acyl group with 2 to 7 carbon atoms or a sulfonyl group, furthermore an alkoxycarbonyl group with 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy part, a cyano group or a hydroxy group, and optionally the symbols R ⁴ and R ³ , if they are bonded to adjacent carbon atoms, or the symbols R ⁸ and R ⁸ , when bonded to adjacent carbon atoms, together with the carbon atoms to which they are bonded, also mean an unfused five- or six-membered carbocyclic or heterocyclic ring containing oxygen, nitrogen or sulfur as a heteroatom, optionally substituted by one or more of the above-mentioned substituents,

R represents an aryl or heteroaryl radical or a cycloalkyl radical with 5 to 7 carbon atoms optionally substituted by the above-mentioned substituents, the heteroaryl radical containing oxygen, nitrogen or sulfur as a heteroatom,

3 9 each of the symbols R , R , R ^J and R represents hydrogen or an alkyl group with 1 to 6, preferably 1 to 4 carbon atoms, n represents 0 or 1,

X represents oxygen =O, sulfur =S, or the imino group -NH,

Y represents oxygen -0- or a direct bond and

Z represents a carbonyl group -CO- or a methylene group -CH-, wherein when Ar represents an unsubstituted phenyl radical and R- represents hydrogen, then Y represents oxygen -O-, or when Z represents a methyl group -CH- and Ar represents an optionally substituted phenyl or pyridyl radical, then R represents hydrogen.

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

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 alkylamino and dialkylamino are methylamino, ethylamino, diethylamino, 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 the group Ar where Q represents oxygen or sulfur are the residues of the formulas

especially furan-2-yl, thiophen-2-yl, benzo[b]furan-3-yl, benzo[b]thiophen-3-yl. Examples of Ar where Q represents a group -C1J=GR- are

Examples of Ar where Q represents the group -N = CR ⁸ - are n®

R·

.8

R®

FI

Examples of Ar when the symbol Q represents the group -N=N- are

,R

.6

If the symbol Ar represents a monosubstituted phenyl or pyridyl radical, 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 radical, a 3,4,5-trimethylphenyl radical, a 3,4,5-trimethoxyphenyl radical, a 3,4-dichloro-2-methylphenyl radical, a 2,3-diethylphenyl radical, a 3-methyl-4-vinylphenyl radical, a 2,4-dichloropyrid-6-yl radical or a 2,4-dimethylpyrid-6-yl radical.

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

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

Examples of groups in the meaning of the symbol R are aryl residues, such as a phenyl residue, which may be optionally substituted, for example, with substituents indicated in the meaning of the symbol Η ¹ *, _{such as} , for example, a methyl group (e.g., 4-methyl, ethyl, propyl, nitro (e.g., 3- or 4-nitro), hydroxy (e.g., 4-hydroxy), methoxy, ethoxy, fluorine, bromine or chlorine (e.g., 3,4-dichloro-). Heteroaryl residues in the meaning of the symbol R include thienyl (e.g., thien-2-yl), furyl (e.g., fur-2-yl) and pyridyl (e.g., pyrid-2-yl), which residues are optionally substituted as described above for the phenyl residue in the meaning of the symbol Ar.

Preferred meanings of the symbol Ar are a phenyl radical substituted by at least one alkyl group or alkoxy group with 2 to 6 carbon atoms, e.g. 4-ethylphenyl,

3,4-dimethylphenyl or 3,4-dimethoxyphenyl residue; furthermore, a phenyl residue with an unfused five- or six-membered carbocyclic ring, for example, naphth-1-yl and naphth-2-yl residue, which residues 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 (for example, a methylamino group), a dialkylamino group (for example, a dimethylamino group) with 1 to 6, preferably 1 to 4 carbon atoms in each of the alkyl parts or a cyano group.

from

Preferably, n is O, R is hydrogen or methyl, and R ¹ is hydrogen. X is preferably oxygen.

Preferably, the symbol Z represents the group -CO- and the symbol R represents a phenyl radical, 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.

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

Preferred compounds prepared by the process of the invention are:

1-benzoyl-3-[1-naphth-2-yl-methyl]piperid-4-yl]urea,

-benzoyl-3-p-(naphth-1-ylmethyl)piperid-4-yl3-urea,

-benzoyl-3-[j-(4-isopropylbenzyl)piperid-4-yl]urea,

-benzoyl-3-p-(5,6,7,8-tetrahydronaphth-2-yl-methyl)piperid-4-yl]urea,

-benzoyl-3-p-(3,4-dimethylbenzyl)piperid-4-yl]urea,

-benzoyl-3-[j-indan-5-yl-methyl)piperid-4-yl]urea,

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

-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 such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, sulfonate (e.g. methanesulfonate and p-toluenesulfonate), acetate, maleate, citrate, fumarate, tartrate, malonate and formate).

The compounds of formula I were tested for psychotropic activity, which was assessed by their ability to inhibit hyperactivity induced by p-chloroamphetamine and/or by their ability to inhibit 5-hydroxytryptamine uptake in thin brain preparations.

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

Three groups of four 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. After 30 minutes, 20 mg/kg of p-chloramphetamine is administered intraperitoneally to all experimental animals. The mice are then immediately transferred, in groups, to rectangular plastic cages equipped with a device for monitoring locomotor activity: The locomotor activity of the animals is recorded for a period of 10 to 30 minutes after the administration of p-chloramphetamine. This procedure is then repeated three more times, so that four groups of mice are used in one experiment and each activity monitoring device is used alternately in all experiments. The inhibition of hyperactivity induced by p-chloramphetamine is calculated according to the relationship:

where

C represents the average activity of the control groups in the interval 10 to 30 minutes after administration of parachloramphetamine and

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

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

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

Compound

Inhibition of hyperactivity induced by p-chloramphetamine (%)

1-benzoyl-3-[j-(naphth-2-yl-methyl)piperid-4-yl]urea 67.5% i-benzoyl-3-[j-(naphth-1-yl-methyl)piperid-4-yl]urea 56.4% ,8-tetrahydro-naphth-2-yl-methyl)pipei'id-4-yl]urea 69.4% 73.5%

1-benzoyl-3-['-(3,4-dimethylbenzyl)piperid-4-ylurea 68.9%

1-benzoyl-3-[i-(indan-5-yl-methyl)piperid-4-yl-3-urea 59.3%

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

1-benzoy 1-3-[i-(4-ethylbenzyl)piperid-4-yl]urea 72.9%

The ability of the compound of general formula I to inhibit the uptake of 5-hydroxytryptamine by brain tissue preparations was tested using the following procedure:

The effect of the test compound on the neuronal uptake of 5-hydroxytryptamine in cerebral cortex preparations prepared from rat brain is determined by the method described by Snyder, Green and Hendley, Kinetics of H^-norep-inephrine accumulation in cerebral tissue preparations 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. The efficacy of the test compound is therefore given by the relationship:

molar concentration of imipramine providing 50% inhibition of 5-hydroxytryptamine uptake molar concentration of the test compound providing 50% inhibition of o-hydroxytryptamine uptake

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

In such a test, 1-benzoyl-3-[1-(nisulf-2-yl-methyl)piperid-4-yl]urea was found to be particularly effective, having an 8.8-fold potency compared to imipramine (potency = 1.0).

In vivo, the inhibition of 5-hydroxytryptamine uptake by the compounds of the invention was determined by a procedure involving the 5-hydroxy-L-tryptophan-induced behavioral syndrome in experimental animals. Mice given a high dose of 5-hydroxy-L-tryptophan exhibited a behavioral syndrome consisting of tremors, hindpaw abduction, lateral head tilting, and forepaw stamping. In addition to these symptoms, rats also exhibited head jerking and head circling.

In the experiments described below, the syndrome was assumed to be present if at least 3 of these signs were present in mice and at least 4 in rats. If the experimental animals receive a small dose of 5-hydroxy-L-tryptophan, which does not itself 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 5-hydroxytryptamine uptake inhibition in vivo.

a) Dose-dependence test in mice

Groups of 12 (2 subgroups of 6) female mice (weighing between 18 and 22 g) are used for each dose, with each group housed separately in a separate cage for the duration of the experiment. Mice receive orally either the test compound or vehicle (0.5%

HPMC), and after 30 minutes, the mice receive an intraperitoneal threshold dose (80 mg/kg) of 5-hydroxy-L-tryptophan and are placed in perspex cylindrical containers with a diameter of 30 cm.

After another 20 minutes, the mice are observed for 5 minutes to see whether the syndrome is present or not.

The dose that will produce the syndrome in 50% of the mice is calculated by the method of Litchfield and Wileoxon, J. Pharm. Exp. Ther. 96, pp. 99-113 (1949).

b) Dose-dependence test in rats

Groups of 6 male rats (weighing 150 g) were given the test compound suspended in HPMC. After 30 minutes, 5-hydroxy-L-tryptophan (70 mg/kg) was administered intraperitoneally and the number of symptoms in 1 rat was recorded between 20 and 35 minutes after 5-hydroxy-L-tryptophan administration. A linear regression analysis of the results was performed and the ED^q value was calculated.

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

Compound Εβ^θ values for potentiation of 5-hydroxy-L-tryptamine-induced syndrome in mouse (mg/kg p. o.) rat (mg/kg i. p.) 1-Benzoyl 1-3-[j-(naphth-2-yl-methyl)piperid-4-yl-urea 7.2 5.3 clomipramine 18 39.2

compound

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 general formula II

(II), where the dashed line R, r’, R^, X and Z have the meaning given under general formula I, is reacted with a compound of general formula III

Ar - Y - CHR ⁹ - (CHR ² ) - W n where |

9

Ar, Y, H, R and n have the meanings given under general formula I, and

W represents a leaving group or a hydroxyl group, and the reaction is carried out in the presence of a nickel catalyst in the case where W represents a hydroxyl group, in other cases in the presence of a base or by heating in an inert solvent, and optionally the alkoxy 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 base of general formula I obtained 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 leaving group in the meaning of the symbol V1 may be, for example, chlorine, bromine or iodine, an organic sulfonyloxy group, for example tosyloxy, mesyloxy, or a residue of the general formula -OSOgOR, where R represents a group of the formula Ar - Y - CHic - (CHR ) _n ~, i.e. sulfate.

When the symbol V1 represents a leaving group, the reaction of the compound of general formula II with the compounds of general formula III is preferably carried out in the presence of a base, for example potassium carbonate or triethylamine, or the reaction is carried out under heating in the presence of an inert solvent, for example toluene.

A process according to the invention for the preparation of compounds of general formula I, which comprises reacting a compound of general formula IX

Ar - Y - CHR ⁹ - (CHR ² ) _n - OH (IX), where

9 ,

Ar, Y, K, Ran have the above-mentioned properties, is reacted with a compound of general formula II, where X represents oxygen* is carried out in the presence of a catalyst, for example in the presence of a nickel catalyst such as Haney nickel.

Once a compound of formula I having a reactive group as a substituent is obtained, this compound can be converted into other compounds of formula I by known methods. For example, in the case where Ar represents a group having an alkoxy group or an arylalkoxy group with 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy moiety as a substituent on the aromatic nucleus, the corresponding compound of formula I can be prepared by dealkylation, where a hydroxyl group is bonded to the group represented by Ar. In the case where Ar represents a residue 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 acylated.

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

The starting compounds used in the above processes are known compounds or can be prepared by analogous processes. For example, a compound of general formula II, where X is oxygen, can be prepared by reducing the corresponding compound of general formula XIV

V- RN ¹ CXNHZR (XIV), for example by catalytic hydrogenation. Compounds of the general formula XIV, where H is hydrogen and X is oxygen or sulfur, can be prepared by reacting 4-aminopyridine with a compound of the general formula RZNCX. Compounds of the general formula I or XIV, where Z is -CO and R ³ is an alkyl group with 1 to 6, preferably with 4 carbon atoms, can be prepared by alkylation of the corresponding compound of the general formula I or XIV, where R ³ is hydrogen (for example by using an alkali metal hydride and alkyl halides).

Two general reactions for the preparation of starting compounds of general formula II are illustrated by the reaction scheme below:

To ³

R ³

oxygen

NR ¹ CXNHZS rzn-cxnh ₂

Δ ^{; c} 6 ^H 5 ^CH 2 ^N >

NR ¹ CXNZR catalytic hydrogenation c ₆ h ₅ ch ₂ n.

NR* CXNZR

HN

nr'cxnhzr (II) (II) (where X is oxygen or sulfur)

If necessary, in any of the above-described reactions, reactive groups contained as substituents can be blocked and then released again later. For example, the amino group can be protected with a benzyloxycarbonyl group, which can then be removed after the reaction is complete. The dehydropiperidine compounds of formula I (which contain the optional bond mentioned) 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 for the preparation of other acylurea compounds of formula I by hydrolysis, thereby obtaining ureas of formula VI, which are then acylated again.

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

Any suitable known carrier may be used in the preparation of pharmaceutical compositions. In such compositions, the carrier may be a solid, a liquid or a mixture of a solid and a liquid. Solid forms of compositions include powders, tablets and capsules. The solid carrier may consist of one or more substances which may also be sweeteners, lubricants, solubilizers, suspending agents, binders or disintegrants; it 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 having the necessary binding properties and the resulting mixture is compressed into a tablet of the desired shape and size. Powders and tablets preferably contain from y to 99%, especially from 10 to 50%, of the active ingredient.

Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax and cocoa butter. The term composition. here also includes a formulation of the active ingredient with an encapsulating material as a carrier, so that the composition is in the form of a capsule in which the active ingredient (with or without a carrier) is surrounded by the carrier, which is thus associated with it. Similarly, 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 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 insoluble 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 10 to 75% by weight of glycol 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 carboxymethyl cellulose, or 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 therefore be administered in the form of a liquid or solid composition.

The pharmaceutical composition is preferably in unit dosage form. In such form, the composition may be subdivided into smaller dosage units containing suitable quantities of the active ingredients; a unit dosage may take the form of a packet containing a specific quantity of the composition, for example, packeted powders or vials or ampoules. The unit dosage may be presented 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 adjusted from 5 mg or less to 500 mg or more according to the particular need and potency of the active ingredient. Pharmaceutical compositions also include the compounds alone without a carrier, where the compounds are in unit dosage form.

1

The amount of compound used will depend on the compound administered, the severity and nature of the depression, and the animal being treated. For large animals (body weight of about 70 kg), the oral dose is preferably in the range of about 5 to 73 mg, especially 10 to 23 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, after which the doses should be increased until the desired antidepressant effect is achieved.

The invention is further illustrated by the following examples.

Example 1

1-benzoyl-3- N -(naphth-2-yl-methyl)piperid-yl]urea

1.28 g (0.005 mol) of 4-benzoylureidopiperidine, 1.1 g (0.005 mol) of 2-(bromomethyl)naphthalene with 0.6 g (0.006 mol) of triethylamine are stirred in 25 ml of dimethylformamide for 23 hours at room temperature. Water is then added, the solid precipitate that forms is filtered off and washed thoroughly with water. The solid obtained is suspended in ethanol under heat, acidified with ethanolic hydrogen chloride solution and then heated until all the solid has dissolved. The title compound crystallizes from the solution and is isolated in the form of the hydrochloride hemihydrate, with a melting point in the range of 232-234 °C. The yield is 1.6 g.

Analysis for ^{C24H25N302'HG1} * ^{1/<2H20 calculated} : ^66.58 % C, 6.29% H, 9.70% N ^;

found: 66.57% C, 6.43% H, 9.45% N.

Example 2

1-Benzoyl-3-[1-(naphth-1-yl-methyl)-piperidin-4-yl]urea

0.88 g (0.005 mol) of 1-chloromethylnaphthalene, 1.28 g (0.005 mol) of 4-benzoylureidopiperidine and 0.6 g of triethylamine are stirred in 25 ml of dimethylformamide for 24 hours at room temperature.

Water is then added and the precipitate formed is filtered off. The solid obtained is suspended in isopropyl alcohol and the suspension is acidified with ethanolic hydrogen chloride solution. The title compound is filtered off and dried; it is obtained in the form of the hydrochloride hemihydrate with a melting point in the range of 185-186 °C. The yield is 1.2 g.

Analysis for ^C24H25N3 °2 ^* ^2θ calculated: 66.58% C, 6.29% H, 9.70% N ^;

found: 66.19% C, 6.52% H, 9.72% N.

Example 3

-benzoyl-3-[j-(4-isopropylbenzyl)piperid-4-yl]urea

0.84 g (0.005 mol) of 4-isopropylbenzyl chloride, 1.28 g (0.005 mol) of 4-benzoylureidopiperidine and 0.6 g of triethylamine are stirred in 25 ml of dimethylformamide for 24 hours at room temperature. Water is then added and the precipitate formed is filtered off. The solid obtained is suspended in isopropyl alcohol and the suspension is acidified with ethanolic hydrogen chloride solution. The title compound is separated, filtered off and dried. It is obtained in the form of the hydrochloride hemihydrate with a melting point in the range of 240-242 °C. The yield is 1.2 g.

Analysis for ^C 23 ^H 29 ^N 3°2 ' ^HC1 * ¹ ^ ^{2 H} 2° calculated: 65.01% C, 7.35% H, 9.89% Nj found: 65.24% C, 7.66% H, 9.67% N.

Example 4

1-Benzoyl-3-[j-(6-methoxynaphth-2-yl-methyl)piperid-4-yl-3-urea

0.94 g (0.005 mol) of 6-methoxynaphth-2-yl-methanol is heated in 10 ml of anhydrous benzene under reflux for 3 hours with 3 ml of thionyl chloride. The solvent is then evaporated and the residue is treated three times with benzene and then evaporated. 1.28 g (0.005 mol) of 4-benzoylureidopiperidine, 1.5 g (0.015 mol) of triethylamine and 25 ml of dimethylformamide are added to the residue and the resulting reaction mixture is stirred at 50°C for 2 hours. The solution is then filtered and diluted with water. The solid precipitate that forms is washed with water, dissolved in chloroform and the chloroform extract is washed with water and then dried over magnesium sulphate. Evaporation gives a solid which is suspended in ethanol, the resulting suspension is acidified with ethanolic hydrogen chloride solution and heated until all the solid is dissolved. Cooling crystallizes the title compound, which is filtered off and dried. It is obtained in the form of a hemihydrate of hydrochlorides with a melting point in the range of 243-244 °C. The yield is 1.3 g.

Analysis ^{for C25H27N303'HCl'1 ^ 2H20} calculated ^: 64.85% C, 6.31% H, 9.07% N ^;

found: 64.59% C, 6.40% H, 8.90% N.

Example 5

3-Benzoyl-1-[i-(1,4-benzodioxan-pha-yl-methyl)piperid-4-yl-3-urea

1.55 g (9.34 mmol) of 1,4-benzodioxan-6-yl-methanol and 1.7 g (14.29 mmol) of thionyl chloride are heated in 30 ml of sodium-dried diethyl ether for 3 hours, after which the solvent and excess thionyl chloride are evaporated. The residue is dissolved in 20 ml of toluene, 1.7 g (14.29 mmol) of thionyl chloride are added and the solution is heated and stirred for 3 hours at 80 °C. Evaporation of the solvent gives a residue, to which 2.0 g (8.1 mmol) of 4-benzoylureidopiperidine and 1.09 g (10 mmol) of triethylamine are added, and the resulting mixture is heated in isopropyl alcohol overnight under reflux. The isopropyl alcohol is then evaporated and the residue is triturated with water.

The water was decanted and the residue was crystallized from isopropyl alcohol (yield 1.64 g).

The resulting base is suspended in isopropyl alcohol, ethanolic hydrogen chloride solution is added and the mixture is filtered. The filtrate is cooled overnight to 5°C, whereby the title compound is precipitated, which is isolated and dried. The hydrochloride quaternary hydrate of the title compound is obtained, melting at 23°-235°C. The yield is 1.46 g.

Analysis for C ₂ 2 ^H 25 ^N 3°4 * ^HC1 ' ^{1/4 H} 2° calculated: 60.55% C, 6.12 56 H, 9.63 56 Nj found: 60.74% C, 6.27% H, 9.38 56 N.

Example 6

-benzoyl-3-E ¹ -(3,4-dimethylbenzyl)piperid-4-yl3-urea

To 0.68 g (0.005 mol) of 3,4-dimethylbenzyl alcohol in 10 ml of anhydrous benzene was added 3 ml of thionyl chloride and the mixture was heated under reflux for 3 hours. The solvent was then evaporated and the residue was treated with benzene three times and evaporated. To the residue after evaporation were added 1.28 g (0.05 mol) of 4-benzoylureidopiperidine, 1.5 g (0.015 mol) of triethylamine and 25 ml of dimethylformamide and the resulting reaction mixture was stirred for 2 hours at 50°C. The solution was then filtered and the filtrate was diluted with water. The solid precipitate that separated was filtered off, dissolved in chloroform and the solution was washed thoroughly with water, dried over magnesium sulphate and evaporated to give a solid. This solid is suspended in ethanol and the resulting suspension is acidified with ethanolic hydrogen chloride solution to give the title compound, which is isolated after recrystallization from ethanol as the hydrochloride quaternary hydrate with a melting point in the range of 239-240 °C.

Analysis for: ^22 ^H 27 ^N 3°2 ' ^H 2° calculated: 65.01% G, 7.07% H, 10.34% N;

found: 64.62% C, 7.05% H, 10.15% N.

Example 7

-benzoyl-3-[[(3-aminobenzyl)piperid-4-yl]-urea

4.47 g of 1-benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea from Example 13 were hydrogenated at atmospheric pressure at room temperature using 0.5 g of a catalyst consisting of activated carbon containing 5% palladium until hydrogen was absorbed. The catalyst was then filtered off and the filtrate was evaporated. The residue was dissolved in water and the resulting solution was made alkaline with ammonia solution of specific gravity 0.880. The solid that separated was filtered off, washed thoroughly with water, dried, treated with activated carbon and evaporated to give 1.9 g of the title compound. After recrystallization from ethanolic hydrogen chloride solution, it was obtained in the form of the dihydrochloride monohydrate with a melting point in the range of 194-195 °C.

Example 8

1-Benzoyl-3-[j-(3-dimethansulfonylaminobenzyl)piperid-4-yl]urea

With stirring at room temperature, 0.55 g of methanesulfonyl chloride is added to a solution of 1.69 g of the product from Example 7 and 0.5 g of triethylamine in 10 ml of chloroform. After the addition is complete, the solution is stirred for 3 hours, then washed with water, dried and evaporated. The residue is purified by trituration with ethanol at the boiling point of the solvent. The product is suspended in ethanol, the suspension is acidified with ethanolic hydrogen chloride solution, heated for 5 minutes, then cooled and the hydrochloride formed in the header of the said compound is filtered off.

The yield is 0.5 g, the melting point is in the range of 189 to 191 °C.

Analysis for ^22^28^4^6^2 ’ · 1/2 HgO calculated: 47.69% C, 5.46% H, 10.11% K;

found: 47.56% G, 5.23% H, 9.74% K.

Examples 9 to 35

According to the procedure described in Example 1, the following compounds of general formula I are prepared by reacting the appropriate compound of general formula III, where ff represents chlorine or bromine, with 4-benzoylureidopiperidine:

Example no.

Compound

1-benzoyl-3-O-(2-O-laphth-1-yl-oxy-ethyl)-piperid-4-yl urea (hydrochloride quaternary hydrate with a melting point between 226 and 229 °C),

0 1-benzoyl-3-0-(3,4-dichlorobenzyl)piperid-4-yl]urea (hydrochloride hemihydrate with a melting point between 244 and 245 °C),

1 1-benzoyl-3-O-(4-tert-butylbenzyl)piperid-4-yl3 urea (hydrochloride quaternary hydrate with a melting point between 202 and 204 °C),

2 1-benzoyl-3-[i-(4-n-butoxybenzyl)piperid-4-yl]urea (hydrochloride hemihydrate with a melting point between 214 and 217 °C),

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

4 1 -benzoyl-3-0 -(5,6,7,8-tetrahydronaphth-2-yl-methyl)piperid-4-yl] urea (hydrochloride with a melting point between 233 and 235 °C),

5 1-benzoyl-3-O-(4-ethylbenzyl)piperid-4-yl]-urea (hydrochloride with a melting point between 234 and 236 °C),

1-benzoyl-3-O-(3,4-dibromobenzyl)piperid-4-yl] thiocyanate (melting point of hydrochloride between 228 and 230 °C),

1-benzoyl-3-O-(2,5-dimethylbenzyl)piperid-4-yl] urea (hydrochloride with a melting point between 23° and 232°C),

1-benzoyl-3-[1-(4-n-propoxybenzyl)piperid-4-yl] urea (hydrochloride with a melting point between 232 and 234 °C),

1-benzoyl-3-O-[2-(n-2-oxy)ethyl]piperid-4-yl urea (hydrochloride with a melting point between 215 and 218 °C),

1-benzoyl-3-[(indan-5-ylmethyl)piperid-4-yl] urea (hydrochloride with a melting point between 253 and 256 °C),

1-benzoyl-3-O-(1-(naphth-2-yl)ethyl)piperid-4-yl]urea (hydrochloride, melting point 172-174 °C),

1-benzoyl-3-O-(4-methyl-3-nitrobenzyl)piperid-4-yl]urea (hydrochloride with a melting point between 232 and 234 °C), '-benzoyl-3-O-(3-bromo-4-methylbenzyl)piperid-4-yl]urea,

1-benzoyl-3-O-(quinol-4-ylmethyl)piperid-4-yl]urea (sesquihydrochloride with a melting point between 211 and 213 °C),

1-benzoyl-3-O-(quinol-2-yl-methyl)-piperidin-4-yl urea (dihydrochloride with a melting point between 213 and 215 °C),

1-benzoyl-3-O-(3,5-dimethylbenzyl)piperid-4-yl] urea (hydrochloride quaternary hydrate with a melting point between 248 and 252 °C),

1-benzoyl-3-O-(2,4-dimethylbenzyl)piperid-4-yl urea (hydrochloride quaternary hydrate with a melting point between 230 and 232 °C),

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

Example No. Compound 29 1-benzoyl-3-[j-(3-iodobenzyl)piperid-4-yl]-urea (hydrochloride, melting point 217-219 °C), 30 1 -benzoyl-3-O -(pyrid-4-yl-methyl)piperid-4-yl] urea (dihydrochloride with a melting point between 236 and 238 °C), 3’ 1 1 -benzoyl-3-O-(3-trifluoromethylbenzyl)piperid-4-yl] urea (hydrochloride, melting point 241-243 °C), 32 1 -benzoyl-3~[1-(4-methoxycarbonylbenzyl)piperid-4-yl]urea (hydro- ³³ chloride with a melting point between 247 and 249 °C), 1-benzoyl-3-O-(6-methylnaphth-2-yl-methyl)piperid-4-yl] urea (hydrochloride hemihydrate with a melting point between 250 and 253 °C), 34 1 -benzoyl 1-3-0 -(1-[benzofuran-2-yl] ethyl)piperid-4-yl| urea (hydrochloride with a melting point between 148 and 149 °C), 35 1-O-(5-acetamido-2-hydroxybenzyl)piperid-4-yl]-3-benzoylurea (3/4 hydrochloride hydrate, melting point 230-232 °C).

Examples 36 to 39. Using a procedure similar to that described in Example 1, 2-bromomethylnaphthalene is reacted with the compounds listed below:

4-(3,4-dimethylbenzoyl)ureidopiperidine,

4-(3-trifluoromethylbenzoyl)ureidopiperidine,

4-(4-nitrobenzoyl)ureidopiperidine and

with 4-(pyrid-4-oyl)ureidopiperidine to give the following compounds:

Example No. Compound 36 1-(3,4-dimethylbenzoyl)-3-O-(naphth-2-ylmethyl)piperid-4-yl] urea with a melting point of the hydrochloride quaternary hydrate between 223 and 226 °C, 37 1-O-(naphth-2-ylmethyl) ^piperidine -4-yl-3-(3-trifluoromethylbenzoyl)urea with a melting point between 251 and 253 °C, 38 1-O-(naphth-2-ylmethyl)piperid-4-yl]-3-(4-nitrobenzoyl)urea (hydrochloride, melting point 264-265 °C), 39 1 - (pyrid-4-yl)-3-0 -(naphth-2-ylmethyl)piperid-4-yl]urea with a melting point between 2 54 and 2 55 'O

Examples 40 to 4'

Using a procedure analogous to that described in Example 1, 2-bromomethylnaphthalene is reacted with the compounds of general formula II listed below:

4-benzylureidopiperidine,

4-(p-fluorobenzoyl)ureidopiperidine, thereby obtaining the following compounds of general formula I:

Example no.

Compound

1-Benzyl-3-O-(naphth-2-yl-methyl)-piperid-4-yl[urea (hydrochloride quaternary hydrate, melting point 243-247 °C (decomposition)),

1-(p-fluorobenzoyl)-3-[j-(naphth-2-yl-methyl)piperid-4-yl]urea (hydrochloride quaternary hydrate with a melting point in the range of 242 to 245 °C (with decomposition/).

Examples 42 to 50

Using a procedure analogous to that described in Example 1, 4-benzoyl-ureidopiperidine is reacted with the compounds listed below:

2-(naphth-2-yl)ethyl tosylate,

6-cyanonaphth-2-ylmethyl bromide,

6-fluoronaphth-2-ylmethyl bromide,

6-bromonaphth-2-yl methyl bromide, 1-(naphth-2-yl propyl chloride, di-(naphth-2-ylmethyl)sulfate,

6-chloromethylquinoxaline,

3-chloromethylcinnoline,

6-chloromethylisoquinoline, thereby obtaining the following compounds:

Example No. Compound

1-benzoyl-3-O-(2-[trifluoromethyl]ethyl)piperidin-4-yl]urea (hydrochloride with a melting point between 230 and 232 °C),

1-benzoyl-3-O-(6-cyanonaphth-2-yl-methyl)-piperid-4-yl] urea (hydrochloride hemihydrate with a melting point between 264 and 266 °C),

1-benzoyl-3-0-(6-fluoronaphth-2-yl-1-methyl)piperid-4-yl]urea,

1 -benzoyl- ^3-0- (6-bromo-naphth-2-yl-methyl)piperid-4-yl]urea,

1-benzoyl-3-[j-(naphth-2-yl)propyl]piperid-4-yl]urea,

1-benzoyl-3-O-(naphth-2-yl-methyl)piperid-4-yl]urea (hydrochloride hemihydrate with a melting point between 232 and 234 °C),

1-benzoyl-3-0-(quinoxalin-6-yl-1-methyl)piperid-4-yl]urea,

Example δ. Compound '-benzoyl-3-jj -(cinnolin-3-yl-methyl)-piperid-4-yl-2urea,

1-Benzoyl-3-[j-(isoquinolin-6-yl-methyl)-piperid-4-yl] urea.

Examples 51 to 56

Using a procedure similar to that of Example 1, 2-bromomethylnaphthalene is reacted with the following compounds:

4-benzoylthioureidopiperidine,

4-(thien-2-yl)ureidopiperidine,

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

1-Benzcyl-3-methyl-3-(piperid-4-yl)urea,

1-benzoyl-3-(piperid-4-yl)guanidine, and 1-benzoyl-3-(3,4-dehydropiperid-4-yl)urea, to give:

Example No.

Compound

1-benzoyl-3-[j-(naphth-2-ylmethyl)piperid-4-yl]thiourea (melting point of the hydrochloride quaternary hydrate between 212 and 214 °C)

1-[1-(naphth-2-ylmethyl)piperid-4-yl]-3-(then-2-oyl)urea (hydrochloride, melting point 217-219 °C)

1-benzoyl-1-methyl-3-0-(naphth-2-ylmethyl)-piperid-4-yl|urea (melting point of the hydrochloride wire position in the range of 164 to 166 °C),

1-benzoyl-3-methyl 1-3-[2'-(naphth-2-yl-methyl)-piperid-4-yl]urea (melting point of the hydrochloride polyhydrate in the range of 207 to 209 °C),

1-benzoyl-3-E'-(naphth-2-yl-methyl)-piperid-4-yl]guanidine (melting point of the dihydrochloride quaternary hydrate between 260 and 262 °C)

1 -benzoyl-3-0-( ^naph '' ^t ~ ² -y ¹ - ^|net y ¹ )3,4-dehydropiperid-4-yl] urea (melting point of the quaternary hydrate in the range of 191 to 193 °C)

Claims (12)

Process for the preparation of piperidine derivatives of the general formula I Ar - Y - GB & (CHH ² ) CXN - WS U), where the dashed line represents an optional bond, Ar is a ring radical of formula (Ia) (Ia) wherein 7 8 8 Q represents an alkyl, sulfur, -CR-C8- or -N-CR- or -N = N- group, and AC £ * 7 ft each of the symbols R *, R ^? and R as well as R 'and R' are hydrogen, 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, nitro, a haloalkyl group having 1 to 6, preferably 1 to 4 carbon atoms, an amino group (optionally substituted with one or two alkyl groups in each case having 1 to 6 carbon atoms, an acyl group having 2 to 7 carbon atoms, or sulfohylovou group, hereinafter eíkoxykarboriylovou group having 1-6, preferably 1-4 carbon atoms in the alkoxy part, kyahoškupinu or hydroxy, and optionally BU3 R ^a and R, when attached to adjacent carbon atoms, or R ^ and R @ 2, when attached to adjacent carbon atoms, together with the carbon atoms to which they are bonded, means an unfused five- or six-membered carbocyclic or heterocyclic ring containing as the heteroatom oxygen, nitrogen or the sulfur optionally substituted by one or more of the abovementioned substitiienty, R represents the above substituents, an optionally substituted aryl or heteroaryl radical or a C 5 -C 7 cycloalkyl radical, wherein the heteroaryl radical contains as heteroatom oxygen, nitrogen or sulfur, each of Η, H, and E represents hydrogen or an alkyl group of 1 from 1 to 4, preferably from 1 to 4, carbon atoms,? represents 0 or 1, X is oxygen = O, sulfur = S, or imino = NH, Y represents oxygen -O- or a direct bond and Z is carbonyl -CO- or methylene -CHg-, wherein when Ar is a non-unsubstituted phenyl moiety and R 8 is hydrogen, then Y is oxygen-O-, or when Z is methylene -CHg- and Ar is optionally substituted phenyl or a pyridyl radical, then R ¹ represents hydrogen, as well as their acid addition salts and quaternary amohium salts, (II), characterized in that the compound of formula (II): The dotted line, R, R, R, X and Z are as defined in formula I, reacted with a compound of formula III Ar - Y - CHR ⁹ - (CHR ² ) _n - W (III), where 2 9 Ar, Y, R, R ⁷ and n are as defined under formula I and W is a leaving group or a hydroxyl group, and the reaction is carried out in the presence of a nickel catalyst when W is a hydroxyl group, in other cases the reaction is carried out in the presence of or without a base in an inert solvent; 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 the amino group bound to the compound of formula I is acylated to form the above acylemino group and optionally obtained base of formula I is converted into an addition salt 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. 2. A process according to claim 1, wherein the Ar is a phenyl radical substituted by at least one group selected from the group consisting of alkyl having 1 to 6, preferably 1 to 4 carbon atoms, halogen or alkoxy having 1 to 6, preferably 1 to 4 carbon atoms, naphthyl, benzofuranyl, benzothiophenyl, tetrahydronaphthyl, indanyl, benzodioxanyl, quinolinyl, isoquinolinyl, cinnolyl or 4-, 5-, 6- or A 7-indolyl radical, each of which is optionally substituted by at least one group selected from the group consisting of halogen, an alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, an alkoxy group having 1 to 6, preferably 1 to 4 atoms carbon, cyano and other substituents are as defined above. 3. The process of claim 1, wherein Y is a direct bond, n is 0 and the dotted line is absent and the other substituents are as defined above. 4. A process according to any one of claims 1 to 3, wherein the starting compounds are those in which R is a phenyl radical optionally substituted by at least one group selected from the group consisting of halogen, an alkyl group having 1 to 6, preferably 1 to 4, or R is a thienyl or pyridyl radical and the other substituents are as defined above. 5. The process of item 1 to obtain 1-benzoyl-3- (naphth-2-ylmethyl) piperid-4-yl] urea, wherein 2-bromomethylnaphthalene is reacted with 4-benzoylureidopiperidine. 6. The method of item 1 to obtain 1-benzoyl-3 - [[- (1'-1-ylmethyl) piperid-4-yl] urea, characterized in that 1-bromomethylnaphthalene is reacted with 4-benzoylureidopiperidine . 7. The method of item 1 to obtain 1-benzoyl-3- [1- (4-isopropylbenzyl) piperid-4-ylurea, wherein 4-isopropylbenzyl chloride is reacted with 4-benzoylureidopiperidine. 8. The process of item 1 for obtaining i-benzoyl-3- [1- (5,6,7,8-tetrahydronaphth-2-ylmethyl) piperid-4-yl] urea, characterized in that 2-bromomethyl- 3, 6, 7,8-tetrahydro-naphthalene is reacted with 4-banzoylureidopiperidine. 9. The process of item 1 to obtain 1-benzoyl-3- [1- (3,4-dimethylbenzyl) piperid-4-yl] urea, characterized in that 3,4-dimethylbenzyl chloride is reacted with 4-benzoyluredopiperidine. 10. The process of item 1 to obtain 1-benzoyl-3- [1- (indan-5-ylmethyl) piperid-4-yl] urea, wherein 5-bromomethylindane is reacted with 4-benzoylureidopiperidine. 11. The process of item 1 for obtaining 1-benzoyl-3- [1- [1- (naphth-2-yl) ethyl) piperid-4-yl] urea, characterized in that 2- (2-bromoethyl) is reacted. Naphthalene is reacted with 4-benzoylureidopiperodine. 12. The method of item 1 for obtaining 1-benzoyl-3- [1- (4-ethylbenzyl) piperid-4-yl] urea, which comprises reacting 4-ethylbenzyl chloride with 4-benzoylureidopiperidine.