CS234047B2 - Method of piperidine derivatives making - Google Patents

Abstract

Process for preparing piperidine derivatives of formula (I) Ar-X-CHR 9 - (CHR 2) n- Nr'cXN-COR (I), where the general symbols may have the meaning given in point 1 of the invention. Compounds produced by the process of the invention of the invention are characterized by paychotropic activity and can be used as antidepressants. Are Specific Inhibitors of 5- hydroxytryptamine and may therefore be suitable for therapeutic use where such pharmacological specificity is desirable.

Description

The invention relates to a process for the preparation of novel piperidine derivatives, in particular piperidineureas, thioureas and guanidines, which are characterized by pharmaceutical activity, in particular psyohotropic activity in standard pharmacological tests and can be used as antidepressants in the future. 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 encompasses the preparation of acid addition salts and quaternary ammonium salts of the compounds prepared by the process of the invention, which may be represented by the general formula 1:

Ar-Y-CHH ⁹ - (CHR ² ) _n -N

R ³

NR ¹ CXN-COR (I), wherein

Ar is a ring moiety of formula Ia, ^R5 ~ O ^(Ia)>

where

Q is oxygen, sulfur, the group -CR 1 = CR ⁸ -, -N = CR ⁸ - or -N = N-, and each of R 1, R 2 and R 6, as well as R 6, R 6 and R 6; and R ^8, if present, represents hydrogen, halogen or alkyl having from 1 to 6, preferably 1 to 4 carbon atoms, alkenyl having from 2 to 6, preferably 2 to 4 carbon atoms, alkoxy of 1 to 6 preferably 1 to 4 carbon atoms, haloalkyl of 1 to 6, preferably 1 to 4 carbon atoms, nitro, amino optionally substituted by one or two alkyl groups of 1 to 6, preferably 1 to 4 carbon atoms, acyl having 2 to 7 carbon atoms, i.e. an alkylcarbonyl group having 1 to 6, preferably 1 to 4, carbon atoms in the alkyl moiety or a sulfonyl group, further an alkoxycarbonyl group having 1 to 6, preferably 1 to 4 carbon atoms in the alkyl moiety, cyano or a hydroxyl group, and optionally either R ⁵ and R ⁶ when attached to adjacent carbon atoms, or R ⁸ and R ⁸ when attached at adjacent carbon atoms together with the atoms to which they are attached th wherein a fused or 6-membered cartocyclic or _0- heterocyclic ring containing, as heteroatom, oxygen, nitrogen or sulfur, optionally substituted by one or more of the abovementioned substituents,

R is as defined above an optionally substituted aryl or heteroaryl or cycloalkyl radical of 5 to 7 carbon atoms, the heteroaryl radical containing as the heteroatom oxygen, nitrogen or sulfur, each of S ¹ , R ² , R ³ R ⁹ being hydrogen or an alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, the dotted line represents an optional bond, n represents 0 or 1,

X is oxygen = O, sulfur = S, or imino = NH, and

Y is -O- or a direct bond, q

wherein when Ar is unsubstituted phenyl and R is hydrogen, then Y is -O-.

Examples of the substituted amino group 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, preferably 1 to 4 carbon atoms in the alkyl moiety, or a sulfonylamino group , for example, alkylsulfonamido having 1 to 6, preferably 1 to 4, carbon atoms or dialkylsulfonylamino having 1 to 6, preferably 1 to 4, carbon atoms in each alkyl moiety.

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

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

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

Examples of haloalkyl groups are chloroethyl and trifluoromethyl.

Examples of alkoxycarbonyl groups are methoxycarbonyl and ethoxycarbonyl.

Preferred halogen substituents are chlorine and bromine.

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

R ⁵ R ⁵

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

8

Examples of Ar groups wherein Q is -GR-GR- are groups of formulas

Examples of groups in the meaning of the symbol Ar, wherein Q represents a group -N = CR 0 of the formulas, are groups

r ^{nX 8} / -

N ^ R ⁸

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

234947

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-bromo-pyrid-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, 2,3-diethylphenyl, 3-methyl-4-vinylphenyl, 2,4-dichloropyrid-6-yl or 3,4-dimethylpyrid-6-yl.

Examples of Ar when a phenyl radical having an unfused five- or six-membered carbocyclic or heterocyclic ring are naphth-1-yl, naphth-2-yl, benzoO, 4] dioxan-6-yl, 3,4-methylenedioxyphenyl, 1, 2,3,4-tetrahydronaphth-6-yl,

A 1,4-dihydronaphth-6-yl, benzofb] thiophen-6-yl, indol-6-yl, benzo [b] furan-6-yl, quinol-6-yl or quinol-5-yl residue.

Examples of the meaning of Ar when a pyridyl radical having an unfused five- or six-membered carbocyclic or heterooylcyclic ring are quinol-4-yl, quinol-2-yl, 5,6,7,8-tetrahydroquinol-4-yl or 5,6,7 , 8-tetrahydroquinolin-2-yl. Examples of such groups when substituted on an unfused ring are the 6-methoxynaphth-2-yl, 7-methoxyetaphth-2-yl and 4-methylnaphth-2-yl radicals. Preferred Ar heterocyclic groups with non-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 substituents such as methyl (e.g. 4-methyl), ethyl, propyl, nitro (such as 3- or 4). -nitro), hydroxy (e.g. 4-hydroxy), methoxy, ethoxy, fluoro, bromo, or chloro (e.g.

3,4-dichloro). Heteroaryl radicals R are 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 as described above for the phenyl radical Ar.

Preferred meanings of Ar are phenyl substituted by one or more C 2 -C 6 alkyl or alkoxy groups, for example 4-ethyl phenyl,

A 3,4-dimethylphenyl or 3,4-dimethoxyphenyl radical, a longer phenyl radical with an unfused five- or six-membered carbooylic ring, such as a naphth-1-yl and naphth-2-yl radical, which radicals are optionally substituted by at least one alkyl group having 1 from 1 to 6, preferably 1 to 4, carbon atoms, alkoxy of 1 to 6, preferably up to 4, carbon atoms, halogen, nitro, trifluoromethyl, amino, alkylamino of 1 to 6, preferably 1 to 4, carbon atoms (e.g. methylamino) , C1-C6, preferably C1-C4 dialkylamino in each of the alkyl moieties (e.g., dimethylamino) or cyano.

Preferably n is zero, R is hydrogen or methyl and R is hydrogen. The preferred meaning of X is oxygen.

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

Preferably, Y is a direct bond.

Preferred compounds produced by the process of the invention are

1-Benzoyl-3-01- (naphth-2-ylmethyl) piperid-4-yl] urea, 1-Banzoyl-3-01- (naphth-1-ylinethyl) piperidin-4-yl] urea,

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

-benzoyl-3-0- (5,6,7,8-tetrahydro-naphth-2-ylmethyl) piperid-4-yl] -urea, 1-benzoyl-3-fl- (3,4-dimethylbenzyl) piperid-4 -yl3 urea

1-Benzoyl-3- [1- (indan-5-ylmethyl) piperid-4-yl] urea,

-benzoyl-3-l- (1- (naphth-2-yl) ethyl) piperid-4-yl] urea 1-benzoyl-1-3-1- (4-ethylbenzyl) piperidin-4-yl] urea,

Examples of acid addition salts are those compounds which are prepared using inorganic and organic acids, in particular 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, malomate, and formate.

The compounds of formula (1) produced by the method of the invention were tested for psychotropic activity, which was 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 four 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, all animals were injected intraperitoneally with 20 mg / kg of p-chloramphetamine. The groups of mice are then immediately transferred to rectangular cages of plastic material equipped with an activity monitor. The physical activity of the animals is recorded for 10 to 30 minutes after ingestion of p-chloramphetamine. This procedure is repeated three more times so that four groups of mice are used in each experiment and each activity monitor is used alternately in all experiments. The inhibition of p-chloramphetamine-induced hyperactivity is calculated according to

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

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

Compounds, rendering! inhibition greater than 50% are considered to be particularly significant. In this test, these compounds were found to be particularly effective;

p-chloramphetamine-induced hyperactivity inhibition compound (%) t-benzoyl-31-benzoyl-31-benzoyl-31-benzoyl-31-benzoyl-3,11-benzoyl-31-benzoyl-3,11-benzoyl-3,1- (naphth-2- ylmethyl) piperid-4-yl] urea. 1- (4-isopropylbenzyl) piperid-4-yl] urea 1- (5,6,7,8-tetrahydro dronap-2-ylmethyl) -1- (naphth-1-ylmethyl) piperid-4-yl 1- (3,4-dimethylbenzyl) piperid-4-yl] urea 1- (indan-5-ylmethyl) piperid-4-yl] urea 1- (1-naphthyl) piperidin-4-yl] urea 1- (2-ylethyl) piperid-4-yl] urea

N- (4-ethylbenzyl) piperid-4-yl] urea

67.5

56.4 49

69.4

68.9 59.3 71.7

72.9

73.5

The ability of the compounds of formula I produced by the method of the invention to inhibit the uptake of 5-hydroxytryptaroin by a brain tissue preparation was tested by this procedure.

The effect of test compound on neuronal uptake of 5-hydroxytryptamine by cortex preparation prepared from rat brain is determined by the method described by Snyder, Green and Hendley in the article. 164. pp. 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-O- (naphth-2-ylmethyl) pi- was found to be particularly effective. perid-4-yl] urea, which had 8.8-fold greater potency compared to imipramine (imipramine potency = 1.0).

In vivo, the inhibition of 5-hydroxytryptamine uptake caused by the compounds produced by the method of the invention was determined by a method comprising 5-hydroxy-L-tryptophan-induced behavioral syndrome in experimental animals. Mice treated with a large dose of 5-hydroxy-L-tryptophan exhibit a behavioral syndrome consisting of tremors, hind paw abduction, lateral tilt of the head, and tramping of the front paws. In addition to these symptoms, rats also exhibit head twitches 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 that does not itself 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.

234047 8

a) Mouse test to determine dose-response

Groups of twelve (two subgroups of six) female mice (weighing between 18 and 22 g) were used at each dose, each group being kept separately in a separate pen for the duration of the experiment. Mice are dosed orally with either test compound or vehicle (0.5% HPMC) and then, after 30 minutes intraperitoneally a threshold dose (80 mg / kg) of 5-hydroxy-L-tryptophan, and placed in 30 cm diameter perspex cylindrical containers. .

After an additional 20 minutes, mice are monitored for 5 minutes to determine whether or not the described syndrome is present.

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

(b) Rat test to determine dose-response

Groups of six male rats (50 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- was administered. tryptophan. A linear regression analysis of the results is performed and the value ΕΒ ^ θ is calculated.

The results obtained for 1-benzoyl-3- ( ^{na: t-} 2-ylmethyl) piperid-4-ylurea and for the antidepressant clomipramine are as follows:

compound ED ^ q values for the potentialization of 5-hydroxy-L-trypto- fanem u. mice (mg / kg p.o.) rats (mg / kg i.p.) 1-Benzoyl-3-O '(naphth-2-ylmethyl) piperid-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 VI

Ar-Y-CHR ⁹ - (CHR ² ) _n -Ny-NR ¹ CXNHR ³ (VI), wherein

Ar, X, X, her phi ^1, R ^2, R ³ to R ⁹ are as defined above, is acylated with an acylating agent containing the group -COR wherein R is as defined above, or with an alkoxy group attached to the compound of formula I is dealkylated to form an hydroxyl group, or the nitro group attached 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 acylanino group, and optionally the base of formula 1 obtained is converted into an acid addition salt or quaternary an ammonium salt, or an acid addition salt of a compound of formula I is converted into the free base.

Examples of acylating agents are reactive derivatives of acids of the formula RCOOH, such as acid halides (e.g. chloride or bromide) and anhydrides and activated esters, as used in peptide chemistry. Other acylation procedures are also known, for example those using coupling agents such as carbodiimides (e.g. dicyclohexylcarbodiimide),

Compounds of formula (VI) may be prepared by hydrolyzing compounds of formula (I) obtainable as described in U.S. Pat. No. 234043.

As mentioned above, after obtaining a compound of formula I having a reactive group as a substituent, it can be converted by a known method into a compound of formula I having a different group. Further, the base of the formula I obtained can be converted into an acid addition salt or a quaternary ammonium salt by known methods, or the free base can be liberated from the acid addition salt of a compound of the formula I.

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

The invention also provides pharmaceutical compositions comprising as active ingredient a compound of formula I as described above. The active compound may optionally be finely divided. In addition to the active ingredient, these compositions also comprise a pharmaceutically acceptable carrier. Any suitable known carrier can be used to prepare the pharmaceutical compositions. In such compositions, the carrier may be a solid, a liquid, or a mixture of a solid and a liquid. In solid form, the compositions 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, binder or tablet disintegrant; 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 appropriate proportions with a carrier having the necessary binding properties, and the resulting mixture is compressed into a tablet of the desired shape and size. The powders and tablets preferably contain 5 to 99%, in particular 10 to 80%, of the active ingredient.

Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low wax and cocoa butter. The term composition 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 associated therewith. The same is true when using wafers.

Sterile liquid compositions include sterile solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier such as sterile water, a sterile organic solvent, or a mixture thereof. A liquid carrier suitable for parenteral injection is preferred.

If the active ingredient is sufficiently soluble, it can be dissolved in normal saline as a carrier; if it is too poorly soluble for this purpose, it can often be dissolved in a suitable organic solvent, for example an aqueous solution of propylene glycol or polyethylene glycol. In general, an aqueous solution of propylene glycol containing glycol in a concentration by weight of 10 to 75% is suitable. In other instances, the composition may be prepared by dispersing the fine powdered active ingredient in an aqueous solution of starch or sodium carboxymethylloolysis, optionally in a suitable oil, for example a peanut 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.

The pharmaceutical composition is preferably 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 be in the form of a sachet containing a certain amount of composition, for example, sachet powders or vials or ampoules. The unit dose may be formulated in a capsule, cachet, or tablet, or it may be the appropriate number of any of these packaged forms. The amount of active ingredient per unit dose of the composition may vary or be adjusted in the range of 5 mg or less to 500 mg or more as appropriate and effective. The pharmaceutical compositions also include the compounds produced by the method of the invention alone without a carrier, wherein the compounds are in unit dosage form.

The amount of compound employed will depend on the compound administered, the intensity and nature of the depression, and the animal being treated. In large animals (about 70 kg body weight), the oral dose and preferably is in the range of about 5 to 75 mg, especially in the range of about 10 to about 25 mg, every 4 hours or as needed. For parenteral administration, the dose is preferably in the range of from about 2 to about 35 mg, as needed. Ideal treatment should be initiated at lower doses, followed by increased doses until the desired antidepressant effect is achieved.

The invention is illustrated by the following examples.

He did

- (4-Methoxybenzoyl) -3-0- (naphth-2-yimethyl) piperid-4-yl] urea

1-Benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea prepared by reaction of 4-araino-1- (naphth-2-ylmethyl) piperidine with benzoyl isocyanate is hydrolyzed by heating in 2N solution sodium hydroxide at reflux to give Q1- (naphth-2-ylmethyl) piperid-4-yl-urea. This compound is acylated by treatment with 4-methoxybenzoyl chloride in toluene in the presence of pyridine to give the title compound, m.p. hydrochloride quarter hydrate, 193-193.5 ° C.

Example 2

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

1.4 g of 1-methyl-3-Q1- (n-naphth-2-ylmethyl) piperid-4-yl] urea, prepared by reacting 4-amino-1- (naphth-2-ylmethyl) piperidine with methyl isocyanate, is added in 30 ml. Toluene was acylated using 0.92 g of benzoyl chloride in the presence of 0.6 g of pyridine to give the title compound, m.p. 164-166 ° C.

Analysis for ^C 25 ^H 27 ^M 3 ° 2 · ^HCl * ^{1/2 H} 2 ° calculated: C 67.18 H 6.54 N 9.40% found: C 67.37 H 6.58 N 9.45%

Examples 3 to 35

Using the procedure described in Example 1, reaction of the corresponding compound of formula VI with benzoyl chloride affords the following compounds of formula Is

EXAMPLE 1 Compound

1-Henzoyl-3- [1- (2- (naphth-1-yloxy) ethyl) piperid-4-yl] urea (m.p. 226-229 ° C)

1-Benzoyl-3-0 (3,4-dichlorobenzyl) piperid-4-yl] urea (m.p. hydrochloride wire, 244-245 ° C)

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

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

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

1-Benzoyl-3-0 (5,6,7,8-tetrahydro-naphth-2-ylmethyl) -piperid-4-yl] -urea (m.p. 233-235 ° C)

1-Benzoyl-3-0- (4-ethylbenzyl) piperid-4-yl] urea (m.p. hydrochloride, 234-236 ° C)

1-Benzoyl-3- [β (3,4-dibromobenzyl) piperidin-4-yl] urea (m.p. hydrochloride, 228-223 ° C)

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

1-benzoyl-3- [j (4-n-propoxybenzyl) piperidin-4-yl3 ^m ° thiourea (m.p. hydrochloride in the range of 232 to 234 ° C)

1-Benzoyl - [] 1- (2- (naphth-2-oxy / ethyl) piperid-4-yl) urea (m.p. 215 DEG-21 DEG C.)

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

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

1-Benzoyl-3-] 1- (4-methyl-3-nitrobenzyl) piperid-4-yl] urea (m.p. 232-234 ° C)

1-Benzoyl-3-O- (3-bromo-4-methylbenzyl) piperid-4-yl] urea

1-Benzoyl-3-O- (quinol-4-ylmethyl) -piperidin-4-yl] -quinoline and (melting point of sesquihydrochloride in the range of 211 to 213 ° C) 1-benzoyl-3-O- (quinol- 2-yimethyl) piperid-4-yl] urea (m.p. dihydrochloride, 213-215 ° C)

1-Benzoyl-3-C1- (3,5-dimethylbenzyl) piperid-4-yl] urea (m.p. 248-252 ° C)

1-benzoyl-3-0 ^- (2, 4-dimethylbenzyl) piperidin-4-yl] urea (mp čtvrthydrátu hydrochloride in the range of 230 to 232 ° C)

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

234047 12

Example. compound

1-benzoyl-3-0 ^- (3-iodobenzyl) piperid-4-yl] urea (mp hydrochloride in the range of 217 to 219 ° C)

1-Benzoyl-3-O- (pyrid-4-ylmethyl) -piper-4-ylurea (m.p. dihydrochloride, 236-238 ° C)

1-Benzoyl-3-0- (3-trifluoromethylbenzyl) -piperid-4-yl] urea (m.p. hydrochloride at 241-243 ° C)

1-Benzoyl-3-O- (4-methoxycarbonylbenzyl) piperid-4-yl] urea (m.p. 247-249 ° C)

1-Benzoyl-3-O- (6-methylnaphth-2-yl-ethyl) piperid-4-yl] -urea (m.p. hydrochloride melting range 250-253 ° C)

1-Benzoyl-3-O- (1- (benzofuran-2-yl) ethyl) piperid-4-yl] urea (m.p. 148-149 ° C)

1-O- (5-azetamido-2-hydroxybenzyl) piperid-4-yl] -3-benzoylurea (m.p. 3/4 hydrochloride hydrate, 230-232 ° C) t-benzoyl-3-O- (naphtha) -2-ylmethyl) piperid-4-yl] thiourea (melting point of the monohydrochloride quarter hydrate in the range of 212 to 214 ° C)

1-Benzoyl-3-O- (naphth-1-ylmethyl) piperid-4-yl] urea (melting point of the hydrochloride wire in the range of 185-186 ° C)

1-Benzoyl-3-O- (4-isopropylbenzyl) piperidin-4-yl] urea (melting point of the hydrochloride hydrate in the range of 240-242 ° C)

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

3-Benzoyl-1-O- (1,4-benzodioxan-6-ylmethyl) piperid-4-yl] urea * (m.p. hydrochloride quartrate hydrate in the range 231-235 ° C)

1-benzoyl-3-C1- (3,4-dimethylbenzyl) piperidin-4-yl] urea and (m.p. hydrochloride quarter hydrate in the range of 239-240 ° C)

Example 36

1-O- (naphth-2-ylmethyl) piperid-4-yl-3- (then-2-oyl) urea

Following the procedure described in Example 1, 4-ureido-1- (naphth-2-ylmethyl) piperidine and 2-thenoyl chloride were reacted to give the title compound. This was recrystallized from ethanol, converted to the hydrochloride in ethanol using ethanolic hydrogen chloride solution, and the resulting hydrochloride was recrystallized from ethanol. The melting point of the hydrochloride is in the range 217-219 ° C.

Examples 37 to 40

Using the procedure described in Example 1, 4-ureido-1- (naphth-2-ylmethyl) piperidine is reacted with each of the compounds selected from the group consisting of:

3,4-dimethylbenzoyl chloride,

4-trifluoromethylbenzoylbroraid,

4-nitrobenzoyl chloride and isonicotinoyl chloride to give the following compounds:

> 3

Example No. Compound

1- (3,4-Dimethylbenzoyl) -3- (1- [1- (2-ylmethyl) piperidin-4-yl] urea (m.p. hydrochloride quarter hydrate in the range of 223 to 226 ° C)

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

1-O- (naphth-2-ylmethyl) piperid-4-yl] -3- (4-nitrobenzoyl) urea (m.p. 264-265 ° C)

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

Examples 41 to 45

Following the procedure described in Example 1, benzoyl chloride is reacted with each of the following compounds:

4-ureido-1-02- (naphth-2-yl) ethyl] piperidine,

4-urido-1-O-cyanonapht-2-ylinethyl] piperidine,

4-ureido-1-O-fluoro-2-ylmethyl] piperidine,

4-Fluoro-1- (6-bromonaphth-2-ylmethyl)] piperidine a

4-ureido-1- (3- (naphth-2-yl) propyl) piperidine to give the following compounds:

Example #

compound

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

1-Benzoyl-3-O- (6-cyano-naphth-2-ylmethyl) piperidin-4-yl] urea (m.p. hydrochloride wire in the range 264-266 ° C)

1-Benzoyl-3-01- (6-fluoro-naphth-2-ylmethyl) -piperid-4-yl] -urea

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

1-Benzoyl-3-O- (1- (naphth-2-yl) -propyl) piperidin-4-yl] urea

Example 46

-benzoyl-3-methyl-3-yl- (naphth-2-ylmethyl) piperid-4-yl urea

Following the procedure described in Example 1, 3-methyl-3-01- (naphth-2-ylmethyl) piperid-4-yl] urea was reacted; with benzoyl chloride to give the title compound, m.p. hydrochloride wire, 207-209 ° C.

Example 47

1-Benzoyl-3-O- (naphth-2-ylmethyl) -3,4-dehydropiperid-4-yl] urea

Following the procedure described in Example 1, 3-O- (naphth-2-ylmethyl) -3,4-dehydropiperid-4-yl] urea is reacted with benzoyl chloride to give the title compound, the quarter of which melts in the range of 191-193 ° C. .

Claims (12)

A process for the preparation of piperidine derivatives of the general formula I wherein Ar-Y-CriS ⁹ - (CHR ² ) -N R ^J , I NR CXNCOR Ar is a ring moiety of formula Ia (Ia) wherein Q is oxygen, sulfur, the group -CR 1 = CR ⁸ -, -N = CR ⁸ - or -N = N-, and each of R ¹ , R 2 and R ⁸ , as well as R ⁶ , R ⁸ and R ⁸ ; and R ⁸ , if present, is hydrogen, halogen or alkyl of 1 to 6, preferably 1 to 4 carbon atoms, alkenyl of 2 to 6, preferably 2 to 4 carbon atoms, alkoxy of 1 to 6, preferably 1 to 4 carbon atoms, haloalkyl of 1 to 6, preferably 1 to 4 carbon atoms, nitro, amino optionally substituted by one or two: alkyl groups of 1 to 6, preferably 1 to 4 carbon atoms, acyl having 2 to 7 carbon atoms or a sulfonyl group, furthermore an alkoxycarbonyl group having 1 to 6, preferably 1 to 4, carbon atoms in the alkoxy moiety, a cyano group or a hydroxyl group, and optionally either L 1 and R 2 when attached to adjacent atoms or R ⁸ and R ⁸ , when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, also represent a fused five- or six-membered carbocyclic or heterocyclic ring oxygen, sulfur or nitrogen heteroatom optionally substituted by 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 oxygen, nitrogen or sulfur as heteroatoms, each of R, R, R and R being hydrogen or an alkyl group having 1 to 6, preferably 1 to 4, carbon atoms, n being 0 or 1, X is oxygen = U, sulfur = S or imino = NH, Y represents oxygen-O- or a direct bond, and the dotted line represents an optional bond, q wherein when Ar is an unsubstituted phenyl radical and R is hydrogen, Y is oxygen-O-, as well as their acid addition salts or their quaternary ammonium salts, characterized in that the compound of formula VI Ar- Ϊ- CHH ⁹ - (CHR ² ) _n ~ N 3— NR ¹ CXNHR ³ (VI), wherein N, Ar, X, Y, R, R, R and 3 are as defined above, acylated with an acylating agent containing a -COR group wherein R is as defined above, and optionally the alkoxy group bound to the compound of formula I is dealkylated to form a hydroxyl group, or a thread bonded to a compound of formula I is reduced to form an amino group, or an amino group bonded to a compound of formula I is acylated to form the above acylamino group, and optionally the base of formula I obtained is converted into an 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 compound of formula (I) is acylated 12 3 9 VI, wherein Y, JJ, X, R, R and R ⁷ have the meaning mentioned above and Ar is phenyl substituted with one or more radicals from the group consisting of alkyl of 1 to 6, preferably 1 to 4 carbon atoms, halogen or an alkoxy group having 1 to 6, preferably 1 to 4, carbon atoms or naphthyl, benzofuranyl, benzothiophenyl, tetrahydronaphthyl, indanyl, benzodioxanyl, quinolinyl, isoquinolinyl, cinnolyl or 4- (5-, 6- or 7-indolyl) groups, each is optionally substituted by at least one of halogen, alkyl of 2 to 6, preferably 1 to 4 carbon atoms, alkoxy of 1 to 6, preferably 1 to 4 carbon atoms, and cyano, using an acylating agent containing a COR group wherein R is as defined above. 3. Method according to claim 1 or 2, characterized in that a compound of formula VI wherein Ar, X, R \ R ^2, R ³ and R ⁹ are as defined in claim 1, Y is a direct bond, n represents zero and dashed line is not present. 4. A process according to any one of claims 1 to 3, wherein the compound of general formula is acylated Wherein n, Ar, X, X, R, R, R, and R are as defined in item 1, using an acylating agent containing a COR group wherein R is phenyl, a phenyl group substituted with at least one residue from the group comprising halogen, lower alkyl of 1 to 6, preferably 1 to 4 carbon atoms, alkoxy of 1 to 6, preferably 1 to 4 carbon atoms, hydroxy or nitro, further thienyl or pyridyl. 5. A process according to claim 1 for the preparation of 1-benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] urea, characterized in that 4-ureido-1- (naphth-2-ylmethyl) urea is obtained. Piperidine was reacted with benzoyl chloride. 6. A process according to claim 1 for the preparation of 1-benzoyl-3- (1-naphth-1-ylmethyl) piperid-4-ylurea, characterized in that 4-ureido-1- (naphth-1-ylmethyl) is used. piperidine was reacted with benzoyl chloride. 7. Method according to claim 1 for the production of 1-benzoyl-3-RI (4-isopropylbenzyl) ^{piperidin-4-H} y37J guilt ° C, characterized in that a 4-ureido-1- (4-isopropylbenzyl) piperidine is reacted with benzoyl chloride. 8. The process of item 1 for the preparation of 1-benzoyl-3-O '- (5,6,7,8-tetrahydro-naphth-2-ylmethyl) piperid-4-yl] urea, characterized in that 4- ureido-1- (5,6,7,8-tetrahydro-naphth-2-ylmethyl) piperidine was reacted with benzoyl chloride. 9. The process of item 1 for the preparation of 1-benzoyl-3- [1- (3,4-dimethylbenzyl) piperid-4-yl] urea, characterized in that 4-ureido-1- (3,4-dimethylbenzyl) piperidine is allowed to react. react with benzoyl chloride. 10. The process of item 1 for the preparation of 1-benzoyl-3-E - (indan-5-ylmethyl) piperid-4-yl] urea, characterized in that 4-ureido-1- (indan-5-ylmethyl) is used. The piperidine is reacted with benzoyl chloride. 11. The process of item 1 for the preparation of 1-benzoyl-3- [1-01- (naphth-2-yl) ethyl] piperidin-4-yl] urea, characterized in that 4-ureido-1- (naphth-2) is -ylethyl) piperidine is reacted with benzoyl chloride. 12. The method of item 1 for the preparation of 1-benzoyl-3-O '- (4-ethylbenzyl) piperid-4-yl] urea, characterized in that 4-ureido-1- (4-ethylbenzyl) piperidine is reacted 3 with benzoyl chloride.