CS234048B2 - Method of piperidine derivatives making - Google Patents

Abstract

Process for preparing piperidine derivatives of formula (I) R3 | (AND), Ar-Y-C 1 R 9 - (CHR 2) n -N ------- f 1 CXN-ZR where the general symbols have the meanings given in the main point of the invention. Compounds produced by the process of the invention of the invention are characterized by psychotropic efficacy and can be used as antidepressants. They are specific inhibitors of 5-hydro-intake xytryptamine and may therefore be suitable for therapeutic use where such pharmacologic specificity is desirable.

Description

The present invention relates to a process for the production of novel piperidine derivatives, in particular piperidinureas, thioureas and guanidines, which are characterized by pharmaceutical activity, in particular psychotropic activity in standard pharmacological tests and which can be used as antidepressants in the future. In general, these compounds are specific inhibitors of 5-hydroxytryptamine re-uptake 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 can be represented by the general formula I

R ³

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

Ar is a ring radical of formula (Ia) (Ia), wherein

8 is oxygen, sulfur, or -CR -CR 14

R ⁷ and R ⁸ , £

X

Y

Z or -N = CR or -N = N-, and each of R **, R ⁹ and R ⁸ , but also R ⁷ and R ⁸ , if present, represents hydrogen, halogen or an alkyl group having from 1 to 2 carbon atoms; 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 C 4 -C 4 nitro, amino optionally substituted by one or two C 1 -C 6 alkyl groups, preferably C 1 -C 4 alkyl groups, C 2 -C 7 aoyl or gulfonyl groups, furthermore C 1 -C 6 alkoxycarbonyl, preferably 1-4 carbon atoms in the alkoxy moiety, a cyano group or a hydroxyl group, and optionally either R ⁴ and R 8 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, also a condensate a 3- or 6-membered carbocyclic or heterocyclic ring containing as heteroatom an oxygen, nitrogen or sulfur and optionally substituted by one or more of the above-mentioned substituents means optionally substituted by an aryl or heteroaryl or cycloalkyl of 5 to 7 carbon atoms, the heteroaryl radical contains, as heteroatom, oxygen, nitrogen or sulfur, each of r 1, R ² , R ³ and R ⁹ is hydrogen or an alkyl group and 1 to 6, preferably 1 to 4 carbon atoms, is 0 or 1, is oxygen = 0 , sulfur = S or imino = NH, and is oxygen -O- or a direct bond and is -CO- or -CHg-, wherein when Ar is unsubstituted phenyl and R ⁹ is hydrogen, then Y is -O-, and when Z represents a methylene group -CH ₂ - and Ar represents optionally substituted phenyl or optionally-substituted pyridyl radical, then R n hydrogen.

known3

Examples of the substituted amino group include groups such as an alkyl or dialkylamino group of 1 to 6 carbon atoms in each alkyl moiety, an acylamino group, i.e., an alkylcarbonylamino group having 1 to 6 carbon atoms in the alkyl moiety or a sulfonylamino group, e.g. 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 groups. Examples of alkoxy are methoxy, ethoxy, isopropoxy, butoxy, and hexoxy. Examples of cycloalkyl groups are cyclohexyl and cyclopentyl.

Examples of alkyl amino 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 groups.

Examples of alkoxycarbonyl groups are methoxycarbonyl and ethoxycarbonyl.

Preferred halogen substituents are chlorine and bromine.

Examples of Ar groups when Q is oxygen or sulfur are those of the formula

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

δ

Examples of groups in the meaning of the symbol Ar, where Q represents a group -CR = CR are groups of formulas

R ⁶

R® (i.e.

n and fc denote a group

Examples of groups represented by Ar, wherein Q is -N = ^CR8 -, are groups of the formulas

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

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-dimethylaminophenyl, 3-vinylphenyl, 3-methylpyridine. 2-yl, 4-methylpyrid-2-yl, 4-methylpyrid-3-yl, 4-chloropyrid-2-yl, 2-methylpyrid-4-yl or 2-bromopyrid-4-yl.

When Ar is a multiply substituted phenyl or pyridyl radical, it may be, for example, 3,4-dichlorophenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, 3,4-dichloro-2-methylphenyl, 2-methylphenyl or 2-methylphenyl. 3-diethylphenyl, 3T-ethyl-4-vinylphenyl, 2,4-dichloropyrid-6-yl or 2,4-dimethyl-pyrid-6-yl.

Examples of Ar when a phenyl moiety having 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- A 6-yl, quinol-6-yl or quinol-5-yl residue.

Examples of the meaning of Ar when a pyridyl radical having a fused 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 , 7,8-tetrahydroquinol-2-yl. Examples of such groups when substituted on an unfused ring are a 6-methoxynaphth-2-yl, 7-methoxy-naphth-2-yl and 4-methyl-naphth-2-yl radical. 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 @ 1, such as a methyl group (e.g. 4-methyl), ethyl, propyl, nitro (such as 3). or 4-nitro), hydroxy (e.g. 4-hydroxy), methoxy, ethoxy, fluoro, bromo, chloro (e.g. 3,4-dichloro).

Heteroaryl radicals phi include thienyl radicals (e.g. thien-2-yl radicals), furyl radicals (e.g. fur-2-yl radicals) and pyridyl radicals (e.g. pyrid-2-yl radicals), these radicals being are optionally substituted as described above for the phenyl radical Ar.

Preferred meanings of Ar are a phenyl radical substituted by one or more C 2 -C 6 alkyl or alkoxy groups, for example a 4-ethylphenyl, 3,4-dimethylphenyl or 3,4-dimethoxyphenyl radical, a phenyl radical with a non-fused five- or six-membered carbocyclic a ring such as 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, an alkoxy group having 1 to 6 preferably 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, amino, alkylamino of 1 to 6, preferably 1-4 carbon atoms (e.g. methylamino), dialkylamino of 1 to 6, preferably 1-4 carbon atoms in each alkyl moiety (e.g. dimethylamino) or cyano.

q

Preferably, the symbol n denotes zero, 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 b, preferably 1 to 4, carbon atoms, for example methoxy.

Preferably, Y is a direct bond.

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

Preferred compounds produced 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 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, low salt and formate.

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

The following procedure was used to determine the ability of these compounds to inhibit p-chloramphetamine-induced hyperactivity.

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

C - T x 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 average activity of the treated groups at 10-30 minutes after p-chloramphetamine administration.

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

Compounds giving an inhibition greater than 50% are considered to be particularly significant. The following compounds have been found to be particularly useful in the test:

Compound Inhibition of hyperactivity induced by β-chloramphetas nem (%) 1-Benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea 67.5 1-Benzoyl-3- [1- (naphth-1-ylmethyl) piperid-4-yl] urea 56.4 1-Benzoyl-3-O- (4-isopropylbenzyl) piperid-4-yl] urea · 49 1-Benzoyl-3-0- (5,6,7,8-tetrahydro-dronaph-2-ylmethyl) piperidin-4-yl] - urea 69.4 73.5 1-benzoyl-3- [1- (3,4-dimethylbenzyl) piperid-4-yl] urea 68.9 1-Benzoyl-3- [1- (in-4-ylmethyl) piperid-4-yl] urea 59.3 1-Benzoyl-3-01- (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 I produced by the method of the invention to inhibit the uptake of 5-hydroxytryptamine by brain tissue preparation was tested by the following method:

The effect of the test compound on the neuronal uptake of 5-hydroxytryptamine by the cortex preparation prepared from rat brain is determined by the method described by Synder, Green and Hendley in the article. Therap., 164: 90-102 (1968)). 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 this test, 1-benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea was found to be particularly effective, with 8.8-fold greater potency than imipramine (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 withdrawal syndrome in experimental animals. Mice treated with a large dose of 5-hydroxy-1-tryptophan exhibit a behavioral syndrome consisting of tremor, hind paw abduction, lateral tilt of the head, and tramping of the front paws. In addition to these symptoms, rats also exhibit head twitching and circular head movements. 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 of these symptoms in rats. If the test animals receive a small dose of 5-hydroxy-L-tryptophan, which alone is not enough to induce the syndrome, it can be induced by prior administration of 5-hydroxytryptamine uptake inhibitors. Thus, this assay can be used as an indication of inhibiting 5-hydroxytryptamine uptake in vivo.

a) Mouse test to determine dose-response

Groups of 12 (two subgroups of 6) 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 the test compound or vehicle (0.5% HPMC) and then, after 30 minutes, an intraperitoneal threshold dose (60 mg / kg) of 5-hydroxy-L-tryptophan, then placed in perspex cylindrical vessels of 30 cm. After an additional 20 minutes, the mice are monitored for 5 minutes whether or not the described syndrome is present.

By the method of Litehfield and Wilcoxon, J.Pharm.Exp.Ther., 9S. p. 9S to 113 (1949), the dose that produces the syndrome in 50% of the dishwasher is calculated.

(b) Rat test to determine dose-response

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 recorded between 20 and 30 minutes after 5-hydroxy-L-tryptophan was observed. A linear regression analysis of the results is performed and the value ΕΏ ^ 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 Values for potencializaoi 5-hydroxy-L-tryptophan-induced syndrome u mice (mg / kg p.o.) rats (mg / kg i.p. 1-Benzoyl-3- [1- (naphth-2-ylmethyl) piperidin-4-yl] urea 7.2 5.3 clomipramine 18 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 VII or VIII

Ar-Y-CHR ⁹ - (CHR ² ) _n -N, I

NR CXN-ZR

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

Ar, X, Y, Z, R, R, R, R, and R are as previously defined, and B is an anion, reduced, and optionally the alkoxy group attached 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 the amino group bound to the compound of formula I is acylated to form an acylamino group, and optionally the base of the formula I obtained is converted into an acid addition salt or quaternary ammonium salt or the acid salt of the compound of formula (I) is converted into the free base.

The piperidine compounds of formula (I) according to the invention are obtained 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 according to the procedure described and protected by the British patent δ. In such reduction processes, alkali metal borohydride is used in a C 3 -C 5 secondary alkanol, for example isopropanol.

When a compound of formula I having a reactive group as a substituent is obtained, it can be converted into another compound of formula I by known methods. For example, when Ar is a group having an alkoxy or arylalkoxy group having 1 to 6 substituents on the aromatic ring. and preferably 1 to 4 carbon atoms in the alkoxy moiety, the corresponding compound of formula I may be prepared by desalkylation, wherein a hydroxyl group is attached to the Ar group. When Ar is a nitro moiety in the aromatic ring, the nitro moiety can be converted to an amino moiety by reduction (e.g., catalytic hydrogenation). These amino groups may be aoylated.

The above processes may also include converting the acid addition salt into the free base and vice versa. The tertiary nitrogen quaternization of the piperidine ring may form an optional additional 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 formula (VIII) may be prepared by reacting a compound of formula (III)

Ar-Y-CHR ⁹ - (CHR ³ ) -W where

W is halogen, especially bromine, and 39

Ar 1 and ^{R 2} are as defined above, reacted with a compound of formula XIV

CXNZR (III), (XIV) f where

X, Z, R, r 'and R ³ are as defined above.

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

Any suitable known carrier may be used in the preparation of the pharmaceutical compositions.

In such compositions, the carrier may be a solid, a liquid, or a mixture of a solid and a liquid. Formulations in solid form include powders, tablets and capsules. The solid carrier may consist of one or more substances which may also function, for example, as a sweetener, lubricant, solubilizer, suspending agent, tablet or disintegrant; 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 ratio with a carrier having 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%, in particular 10 to 50% of the active ingredient.

Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, natriuracarboxymethylcellulose, low melting wax, and cocoa butter. The term composition also encompasses the formulation of the active ingredient with the encapsulating material as the carrier, thereby obtaining a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier so associated therewith. The same is true when using 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 thereof. A liquid carrier suitable for parenteral injection is preferred. If the active ingredient is sufficiently soluble, it can be dissolved in normal saline as a carrier; if it is too low 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. Generally, an aqueous propylene glycol solution containing 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 may 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 subdivided into smaller unit doses containing appropriate quantities of the active ingredients; the unit dose may take the form of a sachet containing a certain amount of composition, such as, for example, sachet powders or vials or ampoules. The unit dose may be 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 selected in the range of 5 mg or less to 500 mg or more depending on the need and efficacy of the active ingredient. The pharmaceutical compositions also include the compounds produced by the process of the invention alone without a carrier, wherein the compounds are in unit dosage form.

The amount of compound used will depend on the kind of 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 and preferably is in the range of about 5 to 75 mg, especially in the range of about 10 to about 25 mg, every four hours or as needed. For parenteral administration, the dosage is preferably in the range of about 2 to 35 mg as needed. Ideally, treatment should be initiated with lower doses, then the doses should be increased until the desired antidepressant effect is achieved.

The invention is illustrated by the following examples.

He did

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

2-Bromomethylnaphthalene is heated with 4-benzoylureidopyridine in acetinitrile solvent to give 1-benzoyl-3- [1- (naphth-2-ylmethyl) -4-pyridinium] urea bromide, m.p. 247-248 ° C. The resulting compound is reduced to sodium borohydride in an isopropyl alcohol solvent by heating under reflux to give the title compound, m.p. 232-234 ° C.

Example 1 a d 2

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

a) 1-Benzoyl-3- [1- (naphth-2-ylmethyl) -4-pyridinium urea bromide was reduced with sodium borohydride in methanol solvent to give the title compound, m.p. 191-203 ° C.

b) The compound obtained in 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

Following the procedure described in Example 41, the following compounds of formula (I) are prepared by reacting the corresponding compound of formula (III) wherein W is chlorine or bromine with 4-benzoylureidopyridine and subsequent reduction of the product formed:

Example #

Compound

1

1-Benzoyl-3-O- (2- (naphth-, -yloxy) ethyl) piperid-4-yl] urea (m.p. hydrochloride quarter hydrate in the range 226-229 ° C) 1-Benzoyl-3-O- (3,4-Dichloro-benzyl) -piperid-4-yl-urea (m.p. hydrochloride wire of 244-245 ° C), -benzoyl-3-O- (4-tert-butyl-benzyl) -piperid-4-yl | urea Λ4 (m.p. 202-204 ° C) 1-benzoyl-3-O- (4-n-butoxybenzyl) piperid-4-yl] urea (mp 214-217 °) C)

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

1-Benzoyl-3-O- (5,6,7,8-tetrahydronaphth-2-ylmethyl) piperid-4-yl] urea (m.p. 233 DEG-335 DEG C.) 1- (4-ethylbenzyl) piperid-4-yl] urea (m.p. 234-236 ° C), -benzoyl-3-O- (3,4-dibromobenzyl) piperid-4-yl] urea ( having a melting point of hydrochloride of 228 to 230 ° C) 1-benzoyl-3-O- (2,5-dimethylbenzyl) piperid-4-yl] urea (melting point of hydrochloride of 231 to 232 ° C)

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

1-Benzyol-3-O- (2- (naphth-2-oxy / ethyl) piperid-4-yl) urea (m.p. hydrochloride, 215-2.8 ° C)

1-Benzoyl-3-O- (indan-5-ylmethyl) piperid-4-yl] wine (m.p. hydrochloride, 253-256 ° C), -benzoyl-3-O- (, - / naphtha) t-2-yl / ethyl) piperid-4-yl] urea (m.p. hydrochloride, 72-74 ° C)

- benzoyl-3- 0- (4-methyl-3-nitrobenzyl) piperidin-4-yl] monohydrate and (m.p. hydrochloride in the range 232 to 234 ° C)

1-Benzoyl-3-O- (3-bromo-4-methylbenzyl) piperid-4-yl] urea 1-Benzyl-3- O- (ehinol-4-ylmethyl) piperid-4-yl] urea (m.p. sesquihydrochloride ranging from 211 to 213 ° C) 1-benzoyl-3-O- (quinol-2-ylmethyl) piperid-4-yl] urea (m.p. dihydrochloride ranging from 213 to 215 ° C) 1-benzoyl-3- O- (3,5-dimethylbenzyl) piperid-4-yl] uridine.

(m.p. 248-252 ° C), -benzoyl-3-O- (2,4-dimethylbenzyl) piperid-4-yl] urea (mp 230-232 ° C)

1-Benzoyl-3-O- (3-bromobenzyl) piperid-4-yl] urea (m.p. 222-224 ° C)

1-Benzoyl-3-O- (3-iodobenzyl) piperid-4-yl] urea (m.p. 217-2.9 ° C), -benzoyl-3-O- (pyrid-4-ylmethyl) piperid-4-yl] urea (m.p. dihydrochloride, 236-238 ° C)

1-Benzoyl-3-O- (3-trifluoromethylbenzyl) piperid-4-yl] urea (m.p. 241-243 ° C), -benzoyl-3-O- (4-methoxycarbonylbenzyl) piperidine-4- yl] urea (m.p. 247-249 ° C)

Example #

Compound

1-Benzoyl-3 - [] 1- (6-methylnaphth-2-ylmethyl) piperid-4-yl] urea (m.p. hydrochloride wire 250-253 ° C) 1-benzoyl-3- | (1- (benzofuran-2-yl) ethyl) piperid-4-yl] urea (m.p. 148-149 ° C)

1-Q1- (5-acetamido-2-hydroxybenzyl) piperid-4-yl] -3-benzoylurea (m.p. 3/4 hydrochloride hydrate, 230-232 ° C) 1-benzoyl-3- [1- ( 2- (Naphth-2-yl) ethyl) piperid-4-yl] urea (m.p. hydrochloride 230-232 ° C)

1-Benzoyl-3 - [] 1- (6-cyanonephth-2-ylmethyl) piperid-4-yl] urea (m.p. hydrochloride salt of 242-246 ° C) 1-benzoyl-3 - [] 1 - (6-Fluoro-naphth-2-ylmethyl) -piperid-4-yl] -urea 1-Benzoyl-3 - [] 1- (6-bromo-naphth-2-ylmethyl) -piperid-4-yl] -urea 1-Benzoyl-3- [ 1- (1- (Naphth-2-yl) propyl) piperid-4-yl] urea 1-benzoyl-3 - [[(quinoxalin-6-ylmethyl) piperid-4-yl] urea 1-benzoyl- 3- [1- (quinolin-3-ylmethyl) piperidin-4-yl] urea 1-benzoyl-3- [1- (isoquinolin-6-ylmethyl) piperid-4-yl] urea 1- benzoyl-3-N - (naphth-1-ylmethyl) piperid-4-yl] urea (m.p. hydrochloride wire of 185-186 ° C) 1-benzoyl-3- (1- (4-isopropylbenzyl) piperid-4) 1-benzoyl-3-O- (6-methoxynaphth-2-ylmethyl) piperid-4-yl] urea (melting point of the hydrochloride wire in the range of 243 to 242 ° C) up to 244 ° C)

3-Benzoyl-1- [(- (1,4-benzodioxan-6-ylmethyl) piperid-4-yl] urea (m.p. 231-235 ° C) 1-benzoyl-3- [i- (3,4-dimethylbenzyl) piperid-4-yl] urea (m.p. 239-240 ° C)

Examples 43 to 47

Following a procedure similar to that described in Example 1, 2-bromoethyl ethylnaphthalene is reacted with each of the following ureas:

4-Q3,4-diaethylbenzoylureido] pyridine,

4- [3-Trifluoromethylbenzoylureido] pyridine

4- (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 # Compound 43 1- (3,4-Dimethylbenzoyl) -3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea wine (0 melting point hydrochloride quartrate hydrate in the range 223 to 226 ° C) and* 44 1- [1- (Naphth-2-ylmethyl) piperidin-4-yl] -3- (3-trifluoromethyl benzoyl) » Urea (0 Melting point: 251-253 ° C) 45 1- [1- (Naphth-2-ylmethyl) piperid-4-yl] -3- (4-nitrobenzoyl) urea (melting point hydrochloride, 264-265 ^e C) 46 1- (pyrid-4-oyl) -3-C'- (naphth-2-ylmethyl) piperidin-4-yl] urea (0, melting point 254-255 C. ^e)

Example No. Compound

1- (p-fluorobenzoyl) -3 - [] (naphth-2-ylmethyl) piperid-4-yl] urea (m.p. 242-245 ° 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.