CS234043B2 - Method of piperidine derivatives making - Google Patents

Abstract

The present invention relates to a process for the preparation of new piperidine derivatives, in particular piperidinoureas, thiocarpins and guanidines, which exhibit pharmaceutical efficacy, especially psychotropic activity in standard pharmacological tests, and may be perspectively useful as antidespresant. 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 compounds prepared by the process of the invention, which compounds may be described in general Formula I

Description

The present invention relates to a process for the production of novel piperidine derivatives, in particular piperidineureas, thioureas and guanidines, which exhibit pharmaceutical efficacy, in particular psychotropic efficacy in standard pharmacological tests and can be used as an antidespresant 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 encompasses 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 broken line represents an optional bond,

234043 2

Ar is a ring radical of formula (Ia)

where

Q is oxygen, sulfur, the group -CR 1 = CR ⁸ - or -N = CR ⁸ - or -N = N-, and each of R 1, R ³ , R ⁸ , and R ^{6 is the} same; and R ⁸ 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 carbon atoms, nitro, haloalkyl of 1 to b, preferably 1 to 4 carbon atoms, amino optionally substituted by one or two alkyl groups of 1 to 6 carbon atoms, acyl group of 2 to 7 carbon atoms or sulfonyl, furthermore alkoxycarbonyl having 1 to 6, preferably 1 to 4, carbon atoms in the alkoxy moiety, cyano or hydroxy, and optionally either R ⁴ and R ³ when attached to adjacent carbon atoms, or R ⁸ and R ⁸ are when attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, also means an unfused five- or six-membered carbocyclic or heterocyclic ring containing as the heteroatom an oxygen, nitrogen or sulfur, optionally substituted with one or more of the above substituents,

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

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

X is O = S, S = S, or -NH,

Y is -O- or a direct bond and

Z represents a carbonyl group -CO- or a methylene group -CH 2 -, wherein when Ar represents an unsubstituted phenyl radical and R 1 represents hydrogen, then Y represents oxygen -O-, or when Z represents a methyl group -CH 2 - and Ar represents optionally a substituted phenyl or pyridyl residue, then R is hydrogen.

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

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

Examples of alkylamino and dialkylamino are methylamino, ethylamino, di-ethylamino, 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 where Q is oxygen or sulfur are radicals of the formulas

in particular furan-2-yl, thiophen-2-yl, runz [b] furan-3-yl, benzo [b] thiophen-3-yl. Examples of Ar where Q is -C 1 J = GR - are

Examples of Ar, wherein Q is -N = ^CR8 -, are n®

R ·

.8

R®

FÍ

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

, R

.6

When Ar is a monosubstituted phenyl or pyridyl radical, it may be, for example, 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.

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 2,4-dimethylpyrid-6-yl.

Examples of Ar when this represents a phenyl radical having an unfused five or six membered carboeyl or heterocyclic ring are the naphth-1-yl radical, the naphth-2-yl radical, the benzo [1,4] dioxan-6-yl radical, 4-methylenedioxyphenyl, 1,2,3,4-tetrahydronaphth-6-yl, 1,4-dihydro-naphth-6-yl, benzobenzothiophen-6-yl, indol-6-yl, benzo [b] furan-6-yl, quinol-6-yl, and quinol-5-yl.

Examples of the meaning of Ar when a pyridyl radical having an unfused five- or six-membered carboeyl or heterocyclic 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 radical, the 7-methoxynaphth-2-yl radical and the 4-methylnaphth-2-yl radical. Preferred Ar heterocyclic groups with non-fused heterocyclic rings contain, as heteroatom or heteroetoms, oxygen, nitrogen or sulfur.

Examples of R groups are aryl radicals such as a phenyl radical which may be optionally substituted, for example, with uvedenými ¹ * substituents, j _and k being, 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, fluoro, bromo or chloro (e.g. 3,4-dichloro) R heteroaryl radicals include thienyl (e.g. a thien-2-yl) residue, a furyl (e.g. fur-2-yl) residue, and a pyridyl (e.g. pyrid-2-yl) residue, which residues are optionally substituted as described above for the phenyl radical Ar.

Preferred meanings of Ar are a phenyl radical substituted with at least one C 2 -C 6 alkyl or alkoxy group, for example 4-ethylphenyl,

A 3,4-dimethylphenyl or 3,4-dimethoxyphenyl radical; a phenyl radical having an unfused five- or six-membered carbocyclic ring, for example a naphth-1-yl and a naphth-2-yl radical, the radicals of which are optionally substituted by at least one alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, 1 to 6, preferably 1 to 4, carbon atoms, halogen, nitro, trifluoromethyl, amino, alkylamino (e.g., methylamino), dialkylamino (e.g., dimethylamino) of 1 to 6, preferably 1 to 4, carbon atoms in each alkyl moiety; or cyano.

of

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

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

Preferably, Y is a direct bond.

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

Preferred compounds produced 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- [1- (4-isopropylbenzyl) piperid-4-yl] urea,

-benzoyl-3-p - (5,6,7,8-tetr8hydroneft-2-ylmethyl) piperid-4-yl] urea,

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

-benzoyl-3- [i -indan-5-ylmethyl) 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 prepared from the use of 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 psyohotropic activity, which was evaluated for their ability to inhibit p-chloramphetamine-induced hyperactivity and / or their ability to inhibit 5-hydroxytryptamine uptake in thin brain preparations.

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

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

where

C represents the mean activity of the control groups at 10 to 30 minutes after administration of parachloramphetamine a

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

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

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

Compound

Inhibition of p-chloramphetamine-induced hyperactivity (%)

1-Benzoyl-3- [j- (naphth-2-ylmethyl) piperid-4-yl] urea 67.5% i-Benzoyl-3- [j- (naphth-1-ylmethyl) piperid-4 -yl] urea 56.4% .benzoyl-3- [1- (4-isopropylbenzyl) piperid-4-yl [urea 49%] -benzoyl-3- [1,5,6,7,8-tetrahydro] -urea -napht-2-ylmethyl) piperidin-4-yl] urea 69.4% 73.5%

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

1-Benzoyl-3- [1- (indan-5-ylmethyl) piperid-4-yl] urea 59.3%

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

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

The ability of a compound of formula I to inhibit the uptake of 5-hydroxytryptamine by brain tissue preparations was tested as follows:

The effect of the compound on the neuronal uptake of 5-hydroxytryptamine by cortex preparations prepared from rat brain is determined by the method described by Snyder, Green and Hendley. Kinetics of H? -Norepinephrine accumulation of brain tissue preparations from various parts of rat brain (J. Pharm. Exp. 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:

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

Compounds which do not achieve 50% inhibition are considered ineffective

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

In vivo, the inhibition of 5-hydroxytryptamine uptake induced by the compounds 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 twitching and circular head movements.

In the experiments described below, it was assumed that this syndrome is present when at least 3 of these symptoms occur in mice and 4 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 inhibition of 5-hydroxytryptamine uptake in vivo.

a) Dose-dependency test in mice

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

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

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

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

(b) Dose-dependency test in rats

Groups of 6 male rats (150 g) are palliated with the test compound suspended in HPMC. After 30 minutes, 5-hydroxy-L-tryptophan (70 mg / kg) is administered intraperitoneally and the number of symptoms in 1 rat is determined between 20 and 35 minutes after 5-hydroxy-L-tryptophan. A linear regression analysis of the results is performed and ED 50 is calculated.

The results found for 1-benzoyl-3 - ['- (naphth-2-ylmethyl) piperid-4-yl3urea and for the antidepressant (clomipramine) are as follows:

Compound Εβ ^ θ values for the potentialization of 5-hydroxy-L-tryptamine-induced syndrome in mice (mg / kg p.o.) rats (mg / kg i.p.) 1-Benzoyl-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 the compounds of the formula I or of their acid addition salts or of their quaternary ammonium salts is characterized in that:

(II), wherein the dashed line R, r ’, R,, X and Z are as defined in formula I, is reacted with a compound of formula III

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

9

Ar, Y, H, R and n are as defined in 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 in the presence of a base or by heating in an inert solvent, and optionally the alkoxy group bound to a compound of formula I is dealkylated or a nitro group bound to a compound of formula I is reduced to form an amino group, or an amino group bound to a compound of formula I is acylated to form an acylamino group, and optionally the base of formula I obtained is converted into an acid addition salt or quaternary ammonium a salt, or an acid addition salt of a compound of formula I is converted into the free base.

The leaving group for the meaning of V 1 may be, for example, chlorine, bromine or iodine, an organic sulfonyloxy group, for example a tosyloxy group, a mesyloxy group, or a radical of the formula -OSOgOR where R is Ar - Y - CHic - (CHR) _n - sulphate.

When V1 is a leaving group, the reaction of the compound of formula II with the compounds of 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 such as toluene.

A process according to the invention for the preparation of a compound of the formula (I), comprising:

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

9,

Ar, Y, K, Ran, as previously described, are reacted with a compound of formula II wherein X is 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, it can be converted by known methods into other compounds of formula I. For example, when Ar is a group having an alkoxy or arylalkoxy group having from 1 to 6 on the aromatic ring, preferably from 1 to 4 carbon atoms in the alkoxy moiety, the corresponding compound of formula I may be prepared by dealkylation, wherein a hydroxyl group is attached to the Ar group. When Ar is a nitro radical on the aromatic ring, the nitro radical can be converted to an amino radical by reduction (e.g., catalytic hydrogenation). Such amino groups may be acylated.

The above processes may also include converting the acid addition salt into the free base or vice versa. The quaternization of the tertiary nitrogen of the piperidine ring may be included as 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 and the like. benzyl chloride.

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

V-RN ¹ CXNHZR (XIV), for example by catalytic hydrogenation. Compounds of formula XIV wherein H is hydrogen and X is oxygen or sulfur may be prepared by reacting 4-aminopyridine with a compound of formula RZNCX. Compounds of formula I or XIV wherein Z is -CO and R ³ is C 1 -C 6 alkyl, preferably C 4 -C 4 alkyl may be prepared by eluting an appropriate compound of formula I or XIV wherein R ³ is hydrogen (e.g. using alkali metal hydride and alkyl halides).

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

K 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 reactions described above, the reactive groups contained as substituents may be blocked and later released again. For example, the amino group may be protected with a benzyloxycarbonyl group, which may then be removed after completion. The reaction was carried out using hydrogen with a palladium catalyst. 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 in the preparation of other acylurea 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 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 the pharmaceutical compositions. In such compositions, the carrier may be a solid, a liquid, or a mixture of a solid and a liquid. Solid form preparations 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 tablet 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 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. Tablet powders preferably contain γ 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, sodium carboxymethyl cellulose, low melting wax and cocoa butter. The term resource. it also encompasses the formulation of the active ingredient with the encapsulating material as the carrier so that the composition is in the form of a capsule in which the active ingredient (with or without the carrier) is surrounded by the carrier that is 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, 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 insoluble 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 propylene glycol solution containing glycol in an amount of 10 to 75% by weight is suitable. In other cases, the composition may be prepared by dispersing the fine powdered active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose, or 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 therefore be administered in the form of a liquid or solid composition.

The pharmaceutical composition is preferably in the form of a dosage unit. In such form, the composition may be subdivided into smaller dosage units containing appropriate quantities of the active ingredients; the unit dose may take the form of a package containing a certain amount of the composition, for example, packaged 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 in a 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 for the active ingredient. The pharmaceutical compositions also include said compounds alone without a carrier, wherein the compounds are in unit dosage form.

1

The amount of compound used will depend upon the compound administered, the severity and nature of the depression, and the animal being treated. In large animals (about 70 kg body weight), the oral dose is preferably in the range of about 5 to 73 mg, especially in the range of 10 to 23 mg every four hours, or as needed. When perenteral! administration, the dose is preferably in the range of 2 to 35 mg as needed. Ideal treatment should be initiated with lower doses, followed by dose escalation until the desired antidepressant effect is achieved.

The invention is illustrated by the following examples.

Example 1

1-Benzoyl-3- Q1- (naphth-2-ylmethyl) piperidin-1-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 precipitated solid precipitate is filtered off and washed thoroughly with water. The solid obtained is suspended in hot ethanol, 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 as the hydrochloride hemihydrate, m.p. mp 234 ° C. Yield 1.6 g.

Analysis for. ^C 24 ^H 25 ^N 3 ° ^{2'HG 1} * ^{1/2 H} 2 ° calculated: 66.58% G, 6.29% H, 9.70% N;

Found:% C, 66.57;% H, 6.43;% N, 9.45.

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 taken up in 25 ml of dimethylformamide. The mixture was stirred at room temperature for 24 hours.

Water is then added and the precipitate formed is filtered off. The solid obtained is suspended in isopropanol and acidified with ethanolic hydrogen chloride solution. The title compound is filtered off and dried; it is obtained as the hydrochloride hemihydrate, m.p. 185-186 ° C. Yield 1.2 g.

Analysis for ^C 24 ^H 25 ^N 3 ° 2 * ^ 2θ calculated: 66.58% C, 6.29% H, 9.70% N;

Found:% C, 66.19;% H, 6.52;% N, 9.72.

Example 3

-benzoyl-3- [1- (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 isopropanol and acidified with ethanolic hydrogen chloride solution. The title compound precipitates, which is filtered off and dried. It is obtained in the form of the hydrochloride hemihydrate, m.p. 240-242 ° C. Yield 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% N i Found: 65.24% C, 7.66% H, 9.67% N.

Example 4

1-Benzoyl-3- [1- (6-methoxy-naphth-2-yl-methyl) -piperid-4-yl] -urea

0.94 g (0.005 mol) of 6-methoxynaphth-2-yl-methanol in 10 ml of anhydrous benzene was refluxed with 3 ml of thionyl chloride for 3 hours. The solvent was evaporated and the residue was treated three times with benzene and evaporated. 1.28 g (0.005 mol) of 4-benzoylureidopiperidine, 1.5 g (0.015 mol) of triethylamine and 25 ml of dimethylforraamide were added to the residue, and the resulting reaction mixture was stirred at 50 ° C for 2 hours. The solution was filtered and diluted with water. The precipitated solid precipitate was washed with water, dissolved in chloroform, and the chloroform extract was washed with water, then dried over magnesium sulfate. Evaporation gave a solid which was suspended in ethanol, acidified with ethanolic hydrogen chloride solution and heated until all solid was dissolved. On cooling, the title compound crystallizes, which is filtered off and dried. Obtained as the hydrochloride hemihydrate, m.p. 243-244 ° C. Yield 1.3 g.

Analysis for ^C 25 ^H 27 ^N 3 ° 3 ^{'HC1' 1} ^ ² ° ^H 2 Calculated: 64.85% C, 6.31% H, 9.07% N;

Found:% C, 64.59;% H, 6.40;% N, 8.90.

Example 5

3-Benzoyl-1- [1- (1,4-benzodioxan-1-ylmethyl) piperid-4-yl3-urea

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

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

The resulting base was suspended in isopropyl alcohol, ethanolic hydrogen chloride solution was added, and the mixture was filtered. The filtrate was cooled to 5 ° C overnight to give the title compound which was isolated and dried. The hydrochloride quaternate of the title compound of melting point 23 DEG-235 DEG C. is obtained. Yield 1.46 g.

Analysis for C ₂ ^H 25 ^N 2 ° 3 * ^HC1 4 ^{'1/4 H} 2 ° Calculated: C 60.55%, H 6.12 56 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-yl-3-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 evaporated and the residue was treated three times with benzene and evaporated. 1.28 g (0.05 mol) of 4-benzoylureidopiperidine, 1.5 g (0.015 mol) of triethylamine and 25 ml of dimethylformamide were added to the evaporation residue, and the resulting reaction mixture was stirred at 50 ° C for 2 hours. The solution was filtered and the filtrate was diluted with water. The precipitated solid precipitate 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 was suspended in ethanol and acidified with ethanolic HCl to give the title compound which was isolated as the hydrochloride quaternate as a crystalline quarter hydrate, m.p. 239-240 ° C.

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

Found:% C, 64.62;% H, 7.05;% N, 10.15.

Example 7

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

4.47 g of 1-benzoyl-3- [1- (3-nitrobenzyl) piperid-4-yl] urea from Example 13 was hydrogenated at atmospheric pressure at room temperature using 0.5 g of a 5% activated carbon catalyst. % palladium, as long as hydrogen is absorbed. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and basified with 0.880 ammonia solution. The precipitated solid was filtered, washed well with water, dried, treated with charcoal and evaporated to give 1.9 g of the title compound. After recrystallization from an ethanolic solution of hydrogen chloride, it is obtained as the dihydrochloride monohydrate, m.p. 194-195 ° C.

Example 8

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

While stirring at room temperature, to a solution of 1.69 g of the product of Example 7 and 0.5 g of triethylamine in 10 ml of chloroform is added 0.55 g of methanesulfonyl chloride. After the addition was complete, the solution was 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, acidified with ethanolic hydrogen chloride solution, heated for 5 minutes, cooled and the title compound hydrochloride is filtered off.

Yield 0.5 g, mp 189-191 ° C.

Analysis calculated for: C, 47.69; H, 5.46; K, 10.11;

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

Examples 9 to 35

Following the procedure described in Example 1, the following compounds of formula I are prepared by reacting the corresponding compound of formula III where ff is chlorine or bromine with 4-benzoylureidopiperidine:

Example #

Compound

1-Benzoyl-3-0- (2-Oiaphth-1-yl-oxy-ethyl) -piperid-4-ylamine urea (hydrochloride quaternate, m.p. 226-229 ° C),

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

11-Benzoyl-3-O- (4-tert-butylbenzyl) piperid-4-yl-3-urea (hydrochloride quatrate, m.p. 202-204 ° C),

2 1-benzoyl-3- [1- (4-n-butoxybenzyl) piperid-4-yl] urea (hydrochloride hemihydrate, m.p. 214-217 ° C),

3 1-benzoyl-3-O- (3-nitrobenzyl) piperid-4-yl] -urea (hydrochloride quatrate, m.p. 255-257 ° C),

4-1-benzoyl-3- (5,6,7,8-tetrahydronaphth-2-ylmethyl) piperid-4-yl] urea (hydrochloride, m.p. 233-235 ° C),

5 1-benzoyl-1-3-O- (4-ethylbenzyl) piperid-4-yl] urea (hydrochloride, m.p. 234-236 ° C),

1-benzoyl-3-O- (3,4-dibromobenzyl) piperid-4-yl] urea (m.p. 228-230 ° C),

1-benzoyl-1-3-O- (2,5-dimethylbenzyl) piperid-4-yl] urea (hydrochloride, m.p. 23-232 ° C),

1-Benzoyl-3-01- (4-n-propoxybenzyl) piperid-4-yl] urea (hydrochloride, m.p. 232-234 ° C),

1-Benzoyl-3-O- [2- (n-naphth-2-oxy) ethyl] piperid-4-yl; Urea (hydrochloride, m.p. 215-218 ° C)

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

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

1-benzoyl-3-O- (4-methyl-3-nitrobenzyl) piperid-4-yl] urea (hydrochloride, m.p. 232-234 ° C), 1-benzoyl-3-Q- (3 -bromo-4-methylbenzyl) piperid-4-yl urea,

1-benzoyl-3-O- (quinol-4-ylmethyl) piperid-4-ylurea (sesquihydrochloride, m.p. 211-213 ° C),

1-Benzoyl-3-O- (quinol-2-yl-methyl) -piperid-4-ylurea (dihydrochloride, m.p. 213-2 ° C),

1-benzoyl-3-O- (3,5-dimethylbenzyl) piperid-4-yl] urea (hydrochloride quatrate, m.p. 248-252 ° C),

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

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

Example # Compound 29 1-Benzoyl-3- [1- (3-iodobenzyl) piperid-4-yl] -urea (hydrochloride, m.p. 217-219 ° C), 30 1-benzoyl-3-O- (pyrid-4-ylmethyl) piperid-4-yl] urea (dihydro chloride, m.p. 236-238 ° C), 3 ’ 1 1-benzoyl-3-O- (3-trifluoromethylbenzyl) piperid-4-yl] urea (hydrochloride, m.p. 241-243 ° C), 32 1-Benzoyl-3- [1- (4-methoxycarbonylbenzyl) piperid-4-yl] urea (hydro- ³³ chloride, m.p. 247-249 ° C), 1-Benzoyl-3-O- (6-methylnaphth-2-ylmethyl) piperid-4-yl] urea (hydrochloride hemihydrate, m.p. 250-253 ° C), 34 1-Benzoyl-3- (1- [benzofuran-2-yl] ethyl) piperid-4-yl | Urea (melting point hydrochloride, 148-149 ° C) 35 1- O - (5-Acetamido-2-hydroxybenzyl) piperid-4-yl] -3-benzoylurea (3/4 hydrochloride hydrate, m.p. 230-232 ° C).

Examples 36-39 Following a procedure similar to that described in Example 1, 2-bromomethylnaphthalene was reacted with the following compounds:

4- (3,4-dimethylbenzoyl) ureidopiperidine,

4- (3-trifluoromethylbenzoyl) ureidopiperidine,

4- (4-nitrobenzoyl) ureidopiperidine a

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

Example # Compound 36 1- (3,4-Dimethylbenzoyl) -3-O- (naphth-2-ylmethyl) piperid-4-yl] urea, m.p. 223 DEG-226 DEG C .; 37 1 -0- (naphth-2-yl-methyl) ^-piperazine, id-4-yl-3- (3-trifluoromethylbenzoyl) urea having a melting point in the range 251-253 ° C, 38 1-O- (naphth-2-ylmethyl) piperid-4-yl] -3- (4-nitrobenzoyl) urea (hydrochloride, m.p. 264-265 ° C), 39 1- (pyrid-4-oyl) -3-O- (naphth-2-ylmethyl) piperid-4-yl] urea, m.p.

Examples 40 to 4 '

In a manner analogous to that described in Example 1, 2-bromoethyl naphthalene is reacted with the following compounds of formula II:

4-benzylureidopiperidine,

4- (p-fluorobenzoyl) ureidopiperidine to give the following compounds of Formula I:

Example no.

Compound

1-Benzyl-1-3-O- (naphth-2-yl-methyl) -piperid-4-yl [urea (hydrochloride quatrate, m.p. 243-247 ° C (dec.)),

1- (p-fluorobenzoyl) -3- [1- (naphth-2-yl-methyl) piperid-4-yl] urea (hydrochloride quatrate, m.p. 242-245 ° C (dec.)).

Examples 42 to 50

In a manner analogous to that described in Example 1, 4-benzoyl-ureidopiperidine was reacted with the following compounds:

2- (Naphth-2-yl) ethyl tosylate

6-cyanonaphth-2-ylmethyl bromide,

6-fluoro-naphth-2-yl-methyl bromide,

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

6-chloromethylquinoxaline,

3-chloromethylcinnoline,

6-chloromethylisoquinoline to give the following compounds:

Example No. Compound

1-benzoyl-3-O- (2- [β-thiophen-2-yl] ethyl) piperid-4-yl] urea (hydrochloride, m.p. 230-232 ° C),

1-Benzoyl-3-O- (6-cyanonaphth-2-yl-methyl) -piperid-4-yl] -urea (hydrochloride hemihydrate, m.p. 264-266 ° C),

1-Benzoyl-3-0- (6-fluoro-naphth-2-ylmethyl) -piperid-4-yl] -urea,

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

1-Benzoyl-3- [1H - (naphth-2-yl) propyl] piperidin-4-yl] urea,

1-benzoyl-3-O- (naphth-2-ylmethyl) piperid-4-yl] urea (hydrochloride hemihydrate, m.p. 232-234 ° C),

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

Example δ. Compound 1-Benzoyl-3-ij - (cinnolin-3-yl-methyl) -piperid-4-yl-urea,

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

Examples 51 to 56

In a manner similar to that of Example 1, 2-bronmethylnaphthalene is reacted with the following compounds:

4-benzoylthioureidopiperidine,

4- (thien-2-yl) ureidopiperidine,

1-Benzoyl-1-methyl-3- (piperid-4-yl) urea

1-Benzyl-3-methyl-3- (piperid-4-yl) urea

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

Example no

Compound

1-Benzoyl-3- [1- (naphth-2-ylmethyl) piperid-4-yl] thiourea (m.p. hydrochloride quarter hydrate in the range 212-214 ° C)

1- [1- (Naphth-2-ylmethyl) piperid-4-yl] -3- (then-2-oyl) urea (hydrochloride, m.p. 217-219 ° C)

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

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

1-Benzoyl-3-E '- (naphth-2-yl-methyl) -piperid-4-yl] guanidine (m.p. dihydrochloride quarter hydrate ranging from 260 to 262 ° C)

1-benzoyl-3-0- ^{(naphth 't} ~ ^{2-yl 1} - ^{| net y1)} -3,4-dehydropiperid-4-yl] urea (mp čtvrthydrátu in the range 191-193 ° 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.