JPH0257544B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel piperidine derivatives, methods for their production, and pharmaceutical compositions containing them. More particularly, the present invention relates to piperidinoureas and thioureas which have pharmaceutical activity, particularly psychoactive activity, in standard pharmacological tests and have potential for use as antidepressants. In general, the compounds of the invention are specific inhibitors of 5-hydroxytryptamine reuptake in vitro and in vivo, and are also useful in other therapeutic applications where pharmacological properties of this type are beneficial. Compounds of the invention have the formula [In the formula, a dotted line indicates the presence of a bond if necessary, and Ar represents a phenyl, naphthyl, pyridyl, benzofuranyl, quinolyl, indanyl, tetrahydronaphthyl or benzodioxanyl group, and these groups are halogen, lower Alkyl, alkenyl having 2 to 6 carbon atoms, lower alkoxy, _NO2 , _NH2 , halolower alkyl,
hydroxy lower alkyl, amino lower alkyl,
Mono- or di-lower alkylamino, lower alkylcarbonylamino, ureido, lower alkylsulfonamide, di-lower alkylsulfonamino, lower alkoxycarbonyl, cyano,
It may be substituted with one or more substituents selected from CONH ₂ and hydroxy, and this Ar group is bonded to Y via an aromatic ring, and R is phenyl, pyridyl, furanyl, or a thienyl group, each of which may be substituted with one or more of the substituents listed above for Ar, R ¹ , R ³
and R ⁹ are each hydrogen or a lower alkyl group, n is 0 or 1, X is =O or =S, Y is -O- or a direct bond, and Z is -CO- or -CH ₂ -, provided that (i) when Ar is unsubstituted phenyl and R ⁹ is hydrogen, Y is -O-, and (ii) Z is
represents CH ₂ and Ar may be substituted,
When representing phenyl or pyridyl, R ¹ is hydrogen], as well as acid addition salts and quaternary ammonium salts thereof. The term "lower" used in connection with alkyl or alkoxy groups means such groups having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. "Substituted amino" includes alkyl or dialkylamino, acylamino such as lower alkylcarbonylamino, ureido or sulfonylamino such as lower alkylsulfonamide or di-lower alkylsulfonylamino. Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, t-butyl,
Neopentyl, n-hexyl and the like can be mentioned. Examples of lower alkoxy groups include methoxy, ethoxy, isopropoxy, butoxy and hexoxy. Examples of cycloalkyl groups include cyclohexyl and cyclopentyl. The word "hydroxy lower alkyl" has HO
It includes a group represented by (CH ₂ ) _n - (wherein m is 1 to 4). For example hydroxymethyl or hydroxyethyl. Examples of lower alkylamino and di-lower alkylamino groups include MeNH-, EtNH-, dimethylamino, isopropylamino and butylamino. Examples of lower alkenyl groups include vinyl, propenyl, butenyl (1) and butenyl (2). Examples of halo-lower alkyl groups include chloroethyl and trifluoromethyl. The term "aminoalkyl" refers to the group _NH2 ( _CH2 ) _n- , where m is from 1 to 4, such as aminomethyl, aminoethyl. Examples of lower alkoxycarbonyl groups are methoxy and ethoxycarbonyl. Preferred halogen substituents are chlorine and bromine. Examples of groups Ar in which Q is O or S are:

【formula】

【formula】

【formula】

[Formula] In particular, furan-2-yl, thiophen-2-yl, benzo[b]furan-3-yl and benzo[b]thiophen-3-yl. Q is −CR ⁷ =
An example of Ar which is CR ⁸ is

【formula】

[Formula] (i.e. R ⁴ and R ⁵ are

【formula】),

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

There is a [formula]. When Q is −N=CR ⁸ −, an example of Ar is

【formula】

【formula】

[expression] and

【formula】 There is. As an example when Q is -N=N-,

[expression] and

There is [Formula]. In the case of monosubstituted phenyl or pyridyl, the group
Ar is, for example, 4-t-butylphenyl, 4-cumenyl, 4-n-butoxyphenyl, 4-nitrophenyl, 4-dimethylaminophenyl, 3-vinylphenyl, 3-methylpyridinyl (2), 4-methylpyridinyl (2), 4- Methylpyridinyl (3), 4
-chloropyridinyl (2), 2-methylpyridinyl (4)
or 2-bromopyridinyl (4). In the case of polysubstituted phenyl or pyridyl, examples of the group Ar include 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-dichloropyridinyl (6), 2,4-dimethylpyridinyl (6). In the case of phenyl with a fused 5- or 6-membered carbocycle or heterocycle, examples of Ar are naphthyl (1), naphthyl (2), benz[1,4]dioxanyl (6), 3,4-methylenedioxy Phenyl, 1,2,3,4-tetrahydronaphthyl (6),
Mention may be made of 1,4-dihydronaphthyl (6), benz[b]thiophenyl (6), indolyl (6), benz[b]furanyl (6), quinolyl (6) and quinolyl (5). In the case of pyridyl with fused 5- or 6-membered carbocycles or heterocycles, examples of Ar are quinolyl (4), quinolyl (2), 5,6,7,8-tetrahydroquinolyl (4) or 5,6 , 7,8-tetrahydroquinolyl (2). Examples of cases where the condensed ring has a substituent include 6-methoxynaphthyl (2), 7-methoxynaphthyl (2) and 4-
Mention may be made of methylnaphthyl (2). Preferred fused heterocyclic Ar rings have oxygen, nitrogen or sulfur as heterocyclic ring atoms. The radical R in the case of an aryl group may include the substituents mentioned for R ⁴ such as methyl (e.g. 4-methyl), ethyl, propyl, nitro (e.g. 3-methyl), ethyl, propyl, nitro (e.g.
- or 4-nitro), hydroxy (e.g. 4-hydroxy), methoxy, ethoxy, fluorine,
Phenyl optionally substituted with bromine or chlorine (eg 3,4-dichloro). When R is a heteroaryl group, thienyl (such as thienyl (2), furyl such as furyl (2) and pyridyl such as pyridyl (2) Preferably Ar is a phenyl group substituted with one or more alkyl or alkoxy groups having two or more carbon atoms, such as 4-ethylphenyl, 3,4-dimethylphenyl, 3,
4-dimethoxyphenyl, phenyl with fused 5- or 6-membered carbocycles, such as naphthyl (1), naphthyl (2); such radicals include lower alkyl, lower alkoxy, halogen, nitro, trifluoromethyl, amino, It may also be substituted with lower alkylamino (eg methylamino), di-lower alkylamino (eg dimethylamino) and cyano. Preferably n is 0, R ⁹ is hydrogen or methyl, and R ¹ is hydrogen. Preferred X is oxygen. Preferable Z is -CO-, R is phenyl or 4
Phenyl substituted with lower alkoxy, such as methoxy, in position. Preferably, Y is a direct bond. When Z is _-CH2- , R is preferably methyl. Preferred compounds of the invention are 1-benzoyl-
3-[1-(naphthyl(2)methyl)piperidyl(4)]urea, 1-benzoyl-3-[1-(naphthyl(1)methyl)piperidyl(4)]urea, 1-benzoyl-3-
[1-[4-isopropylbenzyl)pyridinyl]
(4)] Urea, 1-benzoyl-3-[1-(5,6,
7,8-tetrahydronaphthyl(2)methyl)pyridinyl(4)]urea, 1-benzoyl-3-[1-(3,
4-dimethylbenzyl)piperidyl(4)]urea, 1
-benzoyl-3-[1-(indanyl(5)methyl)
piperidyl (4)] urea, 1-benzoyl-3-[1
-(1-naphthyl(2))ethyl)piperidyl(4)urea and 1-benzoyl-3-[1-(4-ethylbenzyl)piperidyl(4)]urea. Examples of acid addition salts include salts formed from organic and inorganic acids, especially pharmaceutically acceptable acid addition salts;
For example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, sulfonic acids (e.g. methanesulfonic acid and p-toluenesulfonic acid), acetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, malonic acid. and salts formed from formic acid. The compound of formula was tested for its psychoactive effects by blocking p-chloroamphetamine (pCA)-induced hyperactivity and inhibiting 5-hydroxytryptamine (5-HT) uptake in brain slices. The following test method was used to test the ability to inhibit p-chloroamphetamine-induced hyperactivity. Groups of 4 female mice (20-24 g) are administered, 3 groups are administered the test compound (50 mg/Kg orally), and the 4th group is given only the required amount of vehicle. After 30 minutes, animals were given 20 mg p-chloroamphetamine (pCA)/
Kg is administered intraperitoneally. Mice in groups were immediately placed into square plastic cages in an activity recorder.
Record locomotor activity over a period of 10-30 min after pCA administration. This procedure is repeated three more times, using four groups of mice for each treatment, so that each recorder is used for all treatments in turn. The inhibition of pCA-induced hyperlocomotion is calculated using the following formula: C-T/C x 100% (where C = average motor activity of the control group 10-30 minutes after pCA administration, T = average motor activity of the treated group 10-30 minutes after pCA administration) This test is 5- It is used for in vivo screening of hydroxytryptamine reuptake blocking effect. Compounds exhibiting greater than 50% inhibition are considered to be of particular interest. The results of this test are shown in the table below: Table Test compound example number % inhibition of pCA-induced hyperactivity 1 67.5% 2 56.4% 3 49.0% 4 57.5% 5 59.0% 6 68.9% 9 37.0% 10 24.9% 14 69.4/73.5% 15 72.9% 16 32.5% 18 33.5% 19 21.0% 20 59.3% 21 71.7% 22 32.7% 24 21.3% 25 35.8% 27 44.9% 29 20.7% 30 35.7% 33 37.4% 34 30. 4% 36 40.9% 37 52.6% 38 53.2 % 40 58.2% 41 67.0% 42 50.6% 43 39.2% 44 44.6% 45 82.2% 47 49.0% b) 49 55.5% 52 55.2% b) Measured at a dose of 30 mg/Kg. Regarding the compound represented by the formula of the present invention, 5-hydroxytryptamine (5-
HT) Uptake blocking ability was tested. (A) Purified rat brain cortical synaptosomes (P ₂ B) from 8-10 male albino rats (body weight 190-250 g) are used as test subjects. Stun the rat and then kill it by decapitation. The brain is rapidly removed and the cortex substantially free of the striatum and midbrain is dissected. The tissue is then gently homogenized in 0.32M sucrose (10 strokes at 840 rpm). This homogenate at a concentration of 10% (wt/vol) in 0.32 M sucrose was centrifuged for 10 minutes at an average centrifugal force of 1000Xg, the supernatant was separated by decanting and centrifuged for 20 minutes at an average centrifugal force of 10000Xg. and obtain a crude mitochondrial pellet (P ₂ ). This fraction was resuspended in 0.32M sucrose (3-4 ml) by manual homogenization, 0.8M sucrose (10 ml),
Separate into layers using a sucrose concentration gradient consisting of 1.2M sucrose (12 ml) and 3.0M sucrose (5 ml). This is then done using an upright rotor,
With an average centrifugal force of 201000Xg, 2.5×10 ¹⁰ rad ² /S
Centrifuge for approximately 35 minutes. This purified synaptosome ( _P2B ) was collected from the 0.8M/1.2M interface and its volume was increased to 50-60 ml with 0.32M sucrose.
Make it. The synaptosomes were then subjected to an average centrifugal force of 97000Xg in a pendulum rotor.
Centrifuge for 30 minutes. The resulting pellet is resuspended in 0.32M sucrose (2 ml/g raw tissue) by manual homogenization. Throughout these operations, tissues and synaptosomes
It is essential to maintain the temperature at 0.4°C. Synaptosomes must be used within a 3 hour preparation period. This synaptosome suspension (2.5 ~
A 100u sample of 3.0mg protein/ml was heated at 37°C.
Add to the incubation medium (900u) which has been pre-incubated for 5 minutes at . This incubation medium has a final concentration of (
¹⁴ C)-5-hydroxytryptamine (10 ^-7 M),
NaCl (136mM), KCl (5mM), _MgCl2
(1.2mM), _CaCl2 (2.5mM), glucose (10mM), ascorbate (1mM), Tris
(20mM). HCl the pH of this medium
(appropriate amount) and aerated with pure oxygen for 30 minutes. The test compound can be present in 4 to 6 concentrations empirically, but typically ranges from 10 ^{-9 M} to 10 ^-6 M of active compound. Reaction at 37℃
The uptake lasted for 4 minutes with 2.4 ml of incubation medium (less radioactive label).
and then rapidly filtered under reduced pressure through a 0.45 μm pore size cellulose ester filter. Radioactivity retained on the filter is removed using Instagel (10ml) (Packard
The results obtained are then converted to dpm by liquid scintillation counting. Nonspecific binding and passive accumulation of 5-hydroxytryptamine
accumulation) is corrected by measuring uptake in sodium-free medium.
The % uptake inhibition is calculated from the following formula: 1 - sample dpm - background dpm/control dpm - background dpm x 100% where the background dpm corresponds to that accumulated in the sodium-free medium. . The data obtained is plotted as % inhibition versus log5-HT concentration to determine the 5-HT uptake.
Determine the concentration that inhibits 50% (IC ₅₀ ). The assay is performed in triplicate using 2 or 3 subjects, with background measurements randomly interspersed. The results obtained are shown in the table below. References: EGGray and VP Whittaker, J. Anat 96 , pp. 79-88 (1962): “The
isolation of nerve endings from brain：An
electron microscopic study of cells
fragments derived by homogenization and
The compound represented by the formula "centrifugation." can also be used in Method B below.
Accordingly, the ability to inhibit 5-hydroxytryptamine (5-HT) uptake in brain slices was tested. (B) Effects of test compounds on neuron uptake of 5-hydroxytryptamine into cerebral cortical slices prepared from rat brain.
The method reported by Green and Hendley [J.Pharm.exP.Therap. 164 , 90-102 (1968),
Kinetics of H ³ −norepinephrine
accumulation into slices from different
regions of the rat brain.] Concentration-response curves are obtained for test and standard compounds. The potency of the test compound is expressed as a ratio to that of imipramine. The efficacy ratio of the test compound is expressed as 5HT uptake 50% inhibition imipramine molar concentration/5HT uptake 50% inhibition test compound molar concentration. Compounds that do not give 50% inhibition are considered inactive. The results obtained are also shown in the table below. Table 5 - Concentration of test compound to inhibit HT uptake by 50% Method A Method B Example number IC ₅₀ nM IC ₅₀ nM 1 11 3 3400 6 110 10 410 11 1800 14 42 20 360 21 50 33 560 45 660 46 26 52 250 51 ₊₊₊ 97 +++: This data is based on 1-benzoyl-3
-[1-(naphthyl(2)methyl)-3,4-dehydropiperidyl(4)]urea (compound described in Example 51)
It is related to. In the above test, 1-benzoyl-3-[1
-(Naphthyl(2)methyl)piperidyl(4)]urea (compound of Example 1) was particularly active, showing a potency ratio of 8.8 (imipramine=1.0). in of the compound of the present invention
Inhibition of 5-HT uptake in vivo was also demonstrated using 5-hydroxy-L-tryptophan (5-HTP)-induced behavioral symptoms. 5-
Mice given high doses of HTP showed tremors,
Behavioral symptoms consist of hindlimb external rotation, temporal weaving, and forefoot treading. In addition to these symptoms, rats also exhibit head twitching and circling behavior. After the experiment, if a mouse showed at least 3 of these symptoms and a rat showed 4 of these symptoms, it was considered to have these symptoms. This symptom does not appear when animals are administered low doses of 5-HTP, and only appears with pretreatment with inhibitors of 5-HT uptake. Therefore, this test can be used as an indicator of 5-HT uptake inhibition in vivo. a) Dose/response study in mice Groups of 12 female mice (18-22g) (6
Two small groups of animals were used for testing one dose, and each group was kept in a separate cage for the duration of the experiment. Mice were dosed orally with either test compound or vehicle (0.5% HPMC) and 30 minutes later received a threshold dose of 5-HTP (80 mg/Kg, ip) and placed in a perspex cylinder (12″ diameter). After an additional 20 minutes, the mice are observed for 5 minutes to check for symptoms.The dose that causes symptoms in 50% of the mice is determined by the method of Litchfield and Wilcoxon [J.
Pharm. Exp. Ther. 96 , 99-113 (1949)]. b) Dose/response study in rats Groups of 6 male rats (150 g) were treated with HPMC.
A test compound suspended in water was administered. 5 after 30 minutes
− HTP (70 mg/Kg, ip) was administered for 20 days after administration.
The number of symptoms per animal was recorded from minutes to 35 minutes. Perform a linear regression analysis of the results, and from this
Asked for _ED50 . The results for 1-benzoyl-3-[1-(naphthyl(2)methyl)piperidyl(4)]urea (A) and the antidepressant clomipramine are as follows.

[Table] The present invention also provides a method for preparing a compound of formula or an acid addition salt or quaternary ammonium salt thereof. Generally, compounds of the formula can be synthesized from suitable starting materials by known reactions. That is, the first method of preparing a compound of formula (wherein the dotted line, R, R ^{1 ,} R ^{3 ,} _Z and () [wherein Ar, Y, n, R ² and R ⁹ are the same as defined above, W is a group that is easily removed, such as a halogen such as chlorine, bromine or iodine, an organic sulfonyloxy group such as tosyloxy, mesyloxy group, or the formula -OSO ₂ OR (wherein R is W
There is a method of reacting with a compound represented by -A-, that is, a sulfate. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine. Also,
The reaction can also be carried out with heating in the presence of an inert solvent such as toluene. A second general method for preparing compounds in which X is O or S and R ₃ is hydrogen is the formula (wherein Ar, Y, R ¹ , R ² , R ⁹ and n are as defined above), a compound of the formula R-Z-N=C=X (wherein R and Z is the same as defined in
There is a method of reacting with a compound represented by (X is O or S). This type of reaction takes place at room temperature. The starting material, which is R ¹ hydrogen in the formula, can be prepared by the method described in GB 1345872.
Starting materials in which R ¹ is lower alkyl may be used to alkylate corresponding compounds in which R ¹ is hydrogen or as described in British Patent No. 1345872.
It can be produced by a method similar to that described in No. An alternative method of preparing a compound of formula is to prepare a compound of formula There is a method of reacting the product with a compound represented by the formula (wherein R, R ³ , Z and X are the same as defined above) to optionally convert the product into an acid addition salt. Although this method may be carried out without a solvent, it is usually carried out by heating the reaction materials in the presence of a suitable inert organic solvent such as toluene, pyridine, xylene, chlorobenzene, dimethylformamide or dioxane. In many cases, it is convenient to boil the reaction materials in a solvent at reflux until the reaction is complete. For example, high yields of 80-90% can be obtained. Preferably, the solvent has a boiling point higher than 100°C. It is preferable to use equimolar amounts of the reaction raw materials. As a method for producing a compound of the formula in which Z is -CO-, the formula ( ^{wherein the} dotted line, ^{Ar ,} There is a method of acylation. Examples of acylating agents include reactive derivatives of acids of the formula RCOOH, such as acid halides (eg chloride, bromide) and acid anhydrides or activated esters, and derivatives used in peptide chemistry. Other acylation methods are well known in the art and include the use of coupling agents such as carbodiimides, such as dicyclohexylcarbodiimide. Compounds of the formula can also be prepared by hydrolysis of compounds in which Z is -CO-. Compounds of the formula also include the formula or Compounds of ^the formula ⁽ wherein ^{Z ,} It can also be produced by reducing . For example, when X=O, catalytic hydrogenation, for example in the presence of a Raney nickel or platinum catalyst, provides a piperidine compound of formula. This reduction can also be carried out by the method described in British Patent No. 1542137. Reduction processes of this type use alkali metal borohydrides in secondary alcohols having 3 to 5 carbon atoms, such as isopropanol. Alternatively, the compound of the formula can be reduced with an alkali metal borohydride in methanol to obtain the dehydropiperidine compound of the formula. Furthermore, as a method for producing a compound of the formula Ar-Y-CHR ⁹ -(CHR ² ) _o -OH () (wherein Ar, Y, n, R ² and R ⁹ are the same as defined above) ) is reacted with a compound of the formula (X=O) in the presence of a catalyst, for example a nickel catalyst such as Raney nickel. A compound of formula X=O or =NH in the formula (wherein the dotted line, Ar, Y, R, R ¹ , R ² , R ³ , R ⁹ and B are the same as defined above, n is 1, and R ¹⁰ is an organic quaternized group. It can also be obtained by treating the corresponding compound under mild conditions that do not affect other parts of the molecule, such as groups that can be removed by hydrolysis. For example, when R ¹⁰ is an arylmethyl group such as benzyl, hydrogenolysis using a suitable catalyst such as palladium black, platinum or nickel catalyst under standard conditions provides compounds of formula. How to carry out this reaction is described in British Patent No. 1399608.
Suitable solvents are alkanols such as methanol. The starting material of formula XI is a compound of the above formula (wherein R ¹⁰ , R ³ , R ¹ and R are the same as defined above, and X is =O or =NH). Compounds in which Y is -O- also include
Formula XII (In the formula, hal represents halogen, dotted line, R, R ¹ ,
R ² , R ³ , R ⁹ , n, X and Z are the same as defined above). It can be produced by reacting with a compound.
This reaction is advantageously carried out by heating the reaction materials in an inert solvent such as dimethyl sulfoxide in the presence of a base such as sodium hydride. Preferred hals are bromine or chlorine. Furthermore, compounds in which X is NH and there is no dotted line have the formula (wherein R and R ³ are the same as defined above)
A compound represented by can be produced by reacting with a compound of the above formula. This reaction can be carried out by heating in an insoluble solvent such as toluene. Once a compound having a reactive substituent in the formula is obtained, this compound can be converted into other compounds of the formula by known methods.
For example, when Ar is a group having a lower alkoxy or aryl lower alkoxy group on the aromatic ring, a compound in which Ar has a hydroxy substituent can be obtained by dealkylation. When Ar is a group having a nitro group on the aromatic ring, the nitro group can be converted to an amino group by reduction, for example, catalytic hydrogenation. This amino group can be acylated. After the above operations, the acid addition salt can be added to the free base or vice versa. Quaternization of the tertiary nitrogen of the piperidine ring can also be carried out as an optional step after the above-described operations using, for example, alkyl or aryl lower alkyl halides such as methyl iodide, benzyl chloride. The starting materials used in the above-mentioned process can be prepared by known methods or by analogous methods. For example, a compound with X=O in the formula has the formula The corresponding compounds of the formula can be prepared by reduction using, for example, catalytic hydrogenation. A compound in which R ³ is H and X is O or S can be produced by reacting 4-aminopyridine with a compound represented by the formula RZNCX. Z is -CO-
Compounds of the formula or in which R ³ is lower alkyl can be prepared by alkylation (eg, with an alkali metal hydride and an alkyl halide) of corresponding compounds in the formula in which R ³ is hydrogen. Compounds of the formula can be prepared by reacting compounds of the formula in which W is halogen, especially bromine, with compounds of the formula. Two general methods for producing the starting materials of the formula are shown below. In the above reaction, if necessary, reactive substituents may be protected during the reaction and removed in subsequent steps. For example, an amino substituent can be protected with a benzyloxycarbonyl group that can be removed using H ₂ /Pd after the reaction. Dehydropiperidine compounds of the formula (in which a double bond is present) are also useful as intermediates in the preparation of piperidine compounds of the formula since the double bond can be removed by reduction. Since the acylurea compound of the formula can be hydrolyzed to the urea of the formula and reacylated, it is also useful as an intermediate for producing other acylurea compounds of the formula. The present invention also provides pharmaceutical compositions containing a compound of the above formula as an active ingredient. The active ingredient may be finely divided if desired. In addition to the active ingredient, the composition also includes a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used in preparing pharmaceutical compositions. In compositions of this type, the carrier can be solid, liquid, or a mixture of solid and liquid. Solid dosage form compositions include powders, tablets and capsules. Solid carriers include flavors, lubricants,
One or more substances can be used that act as solubilizers, suspending agents, binders or disintegrants. Encapsulating materials can also be used. In powder forms, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. For tablets, the active ingredient is mixed with a carrier having the necessary binding properties in appropriate proportions and compressed into the desired shape and size. Powders and tablets contain 5-99% active ingredient, preferably 10-80%. Suitable solid supports include magnesium carbonate,
Magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,
Mention may be made of gum tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes and cocoa butter. The term composition also includes formulations of the active ingredient with an encapsulating agent as a carrier, ie, formulations in which the active ingredient (alone or in combination with a carrier) is surrounded by the carrier. It also includes cashew. Sterile liquid dosage compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.
The active ingredient is dissolved or suspended in a sterile pharmaceutically acceptable liquid carrier such as sterile water, sterile organic solvent, or a mixture of both. Liquid carriers are suitable for parenteral injection. If the active ingredient has sufficient solubility, it is dissolved in physiological saline as a carrier. If sufficient solubility is not present, it can often be dissolved in a suitable organic solvent such as propylene glycol or aqueous polyethylene glycol. Aqueous propylene glycol solutions containing 10 to 75% by weight of glycol are generally suitable. The composition may also be prepared by dispersing the micronized active ingredient in an aqueous solution of starch or sodium carboxymethyl cellulose or in a suitable oil such as peanut oil. Liquid pharmaceutical compositions that are sterile solutions or suspensions can be used for intramuscular, intraperitoneal, or subcutaneous injection. In many cases, the compounds are effective for oral administration and can be administered orally in liquid or solid composition forms. Preferred pharmaceutical compositions are in unit dosage form. In this type of dosage form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, eg, a powder pack or a vial or an ampoule, containing a specified quantity of the composition. The unit dosage form can be a capsule, cachet, or tablet itself, or it can be the appropriate number thereof in packaged form. The amount of active ingredient in a unit dose composition may be up to 5 mg or less depending on the specific requirements and the potency of the active ingredient.
Adjust to 500 mg or more as appropriate. In the present invention, the compounds are not combined with carriers. Also included are unit dosage forms of the compound itself. The present invention also encompasses a method for alleviating depression in a warm-blooded animal suffering from depression, which comprises administering to the animal an effective amount of a compound of the above formula. The amount of compound used will vary depending on the type of compound used, the severity and nature of the depression, and the type of animal being treated. Large animals (weighing approximately 70
The dose for oral administration per kg) is preferably from about 5 mg to about 75 mg, particularly preferably from about 10 mg to about 25 mg, every 4 hours or as required. In the case of parenteral administration, the amount is preferably about 2 mg to about 35 mg, if necessary.
The ideal treatment would be to start with a low dose and increase the dose until the desired antidepressant effect is achieved. Furthermore, the present invention provides chemical intermediates of compounds of the formula, ie compounds of the above-mentioned formula, in which R ³ is hydrogen, and compounds of the above-mentioned formula. Next, the present invention will be explained in more detail with reference to the following examples. Example 1 1-benzoyl-3-[1-(naphthyl(2)methyl)piperidine(4)]urea 4-benzoylureidopiperidine (1.28g,
0.005 mol), 2-(bromomethyl)naphthalene (1.1 g, 0.005 mol) and triethylamine (0.6 g, 0.006 mol) in dimethylformamide (25
cm ³ ) and stirred at room temperature for 23 hours. Add water;
The precipitated solid was filtered and thoroughly washed with water. The solid was suspended in warm ethanol, acidified with ethanolic hydrochloric acid, and then heated until all solids were dissolved.
The title compound crystallized. As hydrochloride hemihydrate
1.6g was obtained. Melting point 232-234℃, elemental analysis:
C ₂₄ H ₂₅ N ₃ O ₂・HCl1/2H ₂ O, C66.58,
H6.29, N9.70%, analysis value C66.57, H6.43, N9.45
% Example 2 1-benzoyl-3-[1-naphthyl(1)methyl)
Piperidyl (4) Urea 1-chloromethylnaphthalene (0.88 g, 0.005 mol), 4-benzoylureidopiperidine (1.28 g, 0.005 mol) and triethylamine (0.6 g) were taken in dimethylformamide (25 cm ³ );
Stirred at room temperature for 24 hours. Water was added and the precipitated solid was filtered. The solid was suspended in isopropyl alcohol and acidified with ethanolic hydrochloric acid. The title compound was filtered and dried. 1.2 g of hydrochloride hemihydrate was obtained. Melting point 185-186℃, elemental analysis:
Calculated value C66.58 as C ₂₄ H ₂₅ N ₃ O ₂・HCl1/2H ₂ O,
H6.29, N9.70%, analysis value C66.19, H6.52, N9.72
% Example 3 1-benzoyl-3-[1-(4-isopropylbenzyl)piperidyl (4)] urea 4-isopropylbenzyl chloride (0.84 g,
0.005 mol), 4-benzoylureidopiperidine (1.28 g, 0.005 mol) and triethylamine (0.6 g) in dimethylformamide (25 cm ³ );
Stirred at room temperature for 24 hours. Water was added and the precipitated solid was filtered off. The solid was suspended in isopropyl alcohol and acidified with ethanolic hydrochloric acid. The title compound was filtered and dried. 1.2 g of hydrochloride-hydrate was obtained. Melting point 240-242℃, elemental analysis:
Calculated value C65.01 as C ₂₃ H ₂₉ N ₃ O ₂・HCl1/2H ₂ O,
H7.35, N9.89%, analysis value C65.24, H7.66, N9.67
% Example 4 1-benzoyl-3-[1-(6-methoxynaphthyl(2)methyl)piperidyl(4)]urea 6-methoxynaphthyl(2)methanol (0.94g,
0.005 mol) was taken up in dry benzene (10 cm ³ ) and refluxed with thionyl chloride (3 cm ³ ) for 3 hours. The solvent was evaporated and the residue was treated with benzene (3x) and evaporated. 4-Benzoylureidopiperidine (1.28 g, 0.005 mol), triethylamine (1.5 g, 0.015 mol) and dimethylformamide (25 cm ³ ) were added to the residue and the reaction mixture was stirred at 50° C. for 2 hours. The solution was filtered and then diluted with water. The precipitated solid was washed with water and dissolved in chloroform, and the chloroform extract was washed with water and dried (MgSO ₄ ). The solid obtained by evaporation was suspended in ethanol, acidified with ethanolic hydrochloric acid, and heated until all solids were dissolved. Upon cooling, the title compound crystallized. After filtering and drying, 1.3 g of hydrochloride hemihydrate was obtained. Melting _point 243-244℃, elemental _analysis : Calculated value as _C25H27N3O3・_HCl・1/ _2H2O
C64.85, H6.31, N9.07%, analysis value C64.59,
H6.40, N8.90% Example 5 3-benzoyl-1-[1-(1,4-benzidioxan-6-ylmethyl)piperidyl (4)] urea 1,4-benzidioxan-6-ylmethanol (1.55 g, 9.34 mmol) and thionyl chloride (1.7 g, 14.29 mmol) were refluxed in sodium dry diethyl ether (30 cm ³ ) for 3 hours, then the solvent and excess thionyl chloride were evaporated. The residue was dissolved in toluene (20 cm ³ ), thionyl chloride (1.7 g, 14.29 mmol) was added and the solution was heated and stirred at 80° C. for 3 hours. To the residue obtained by evaporation of the solvent were added 4-benzoylureidopiperidine (2.0 g, 8.1 mmol) and triethylamine (1.09 g, 10 mmol) and refluxed in isopropyl alcohol overnight. The isopropyl alcohol was evaporated and the residue was triturated in water. The water was decanted and the residue was crystallized from isopropyl alcohol (1.64g). The base was suspended in refluxing isopropyl alcohol, ethanolic hydrochloric acid was added, and the mixture was filtered. The liquid was cooled to 5° C. overnight and the title compound was collected and dried. 1.46 g of hydrochloride quarter hydrate was obtained. Melting point 231-235℃, elemental analysis:
Calculated value as C ₂₂ H ₂₅ N ₃ O ₄・HCl・1/4H ₂ O
C60.55, H6.12, N9.63%, analysis value C60.74,
H6.27, N9.38% Example 6 1-benzoyl-3-[1-(3,4-dimethylbenzyl)piperidyl(4)] urea 3,4-dimethylbenzyl alcohol (0.68g,
0.005 mol) was taken in dry benzene (10 cm ³ ), thionyl chloride (3 cm ³ ) was added, and the mixture was refluxed for 3 hours. The solvent was evaporated and the residue was treated with benzene (3 times) and evaporated. 4-Benzoylureidopiperidine (1.28 g, 0.05 mol), triethylamine (1.5 g, 0.015 mol) and dimethylformamide (25 cm ³ ) were added to the residue and the reaction mixture was heated at 50°C for 2 hours.
Stir for hours. The solution was filtered and diluted with water. The precipitated solid was filtered, dissolved in chloroform, washed thoroughly with water, dried (MgSO ₄ ) and evaporated to give a solid. Suspension of the solid in ethanol and acidification with ethanolic hydrochloric acid yields the title compound; recrystallization from ethanol yields the hydrochloride salt 1/4
The hydrate exhibited a melting point of 239-240°C. Elemental analysis:
Calculated value as C ₂₂ H ₂₇ N ₃ O ₂・HCl・1/4H ₂ O
C65.01, H7.07, N10.34%, analysis value C64.62,
H7.05, N10.15% Example 7 1-benzoyl-3-[1-(3-aminobenzyl)piperidyl (4)] urea 1-benzoyl-3-[1-(3-nitrobenzyl)piperidyl (4) ] 4.47 g of urea (from Example 13) was hydrogenated with 5% Pd/C (0.5 g) at room temperature and 1 atm until no more hydrogen was absorbed. The catalyst was filtered and the liquid was evaporated. Dissolve the residue in water,
It was made basic with 0.880 ammonia. The precipitated solid was filtered, washed thoroughly with water, dried, treated with activated charcoal and evaporated to give 1.9 g of the title compound. Recrystallization from ethanolic hydrochloric acid gave the dihydrochloride-hydrate. Melting point 194-195°C Example 8 1-benzoyl-3-[1-(3-dimethanesulfonylaminobenzyl)piperidyl (4)] urea The product of Example 7 (1.69 g) and triethylamine (0.5 g) were dissolved in chloroform (10 cm ³ ) Methanesulfonyl chloride (0.55g) was added at room temperature while stirring. After the addition was complete, the solution was stirred for 3 hours, then washed with water, dried and evaporated. The residue was leached in ethanol under reflux. The product was suspended in ethanol, acidified with ethanolic hydrochloric acid, heated for 5 minutes, cooled and the hydrochloride salt of the title compound was collected. _Yield 0.5g, melting point _189-191 ℃, elemental analysis: Calculated value as _C22H28N4O6S2・_HCl・1/ _2H2O : C47.69, H5.46 _, N10.11%, analysis value C47 .56,
H5.25, N9.74% Examples 9-35 Using the method of Example 1, 4-benzoylureidopiperidine was reacted with a suitable compound in which W is chlorine or bromine to obtain compounds of the following formulas: . Example number Compound 9 1-benzoyl-3-[1-(2-(naphthyl(1)oxy)ethyl)piperidyl(4)]urea (hydrochloride/quarter hydrate melting point = 226
~229℃) 10 1-benzoyl-3-[1-(3,4-dichlorobenzyl)piperidyl (4)] urea (hydrochloride/half hydrate melting point = 244-245
℃) 11 1-benzoyl-3-[1-(4-t-butylbenzyl)piperidyl (4)] urea (hydrochloride/quarter hydrate melting point = 202-204℃) 12 1-benzoyl-3 -[1-(4-n-butoxybenzyl)piperidyl (4)] urea (hydrochloride, hemihydrate melting point = 214-217
℃) 13 1-benzoyl-3-[1-(3-nitrobenzyl)piperidyl (4)] urea (hydrochloride,
Melting point of quarter hydrate = 255-257℃) 14 1-benzoyl-3-[1-(5,6,7,
8-tetrahydronaphthyl(2)methyl)piperidyl(4)]urea (melting point of hydrochloride = 233
~5℃) 15 1-benzoyl-3-[1-(4-ethylbenzyl)piperidyl (4)] urea (melting point of hydrochloride = 234-236℃) 16 1-benzoyl-3-[1-(3, 4-dibromobenzylpiperidyl (4)] urea (melting point of hydrochloride = 228-230℃) 17 1-benzoyl-3-[1-(2,5-dimethylbenzyl)piperidyl (4)] urea (melting point of hydrochloride =231~232℃) 18 1-benzoyl-3-[1-(1-n-propoxybenzyl)piperidyl (4)] urea (melting point of hydrochloride = 232~234℃) 19 1-benzoyl-[1-[ 2-(naphthoxy
(2)) Ethyl]piperidyl(4)]urea (melting point of hydrochloride = 215-218℃) 20 1-benzoyl-3-[1-(indanyl(5)
methyl)piperidyl(4)]urea (melting point of hydrochloride = 253-6℃) 21 1-benzoyl-3-[1-(1-naphthyl)
(2)) Ethyl)piperidyl (4)] Urea (Melting point of hydrochloride = 172-4℃) 22 1-benzoyl-3-[1-(4-methyl-
3-nitrobenzyl)piperidine (4)] urea (melting point of hydrochloride = 232-234°C) 23 1-benzoyl-3-[1-3-bromo-4-methylbenzyl)piperidyl (4)] urea 24 1-benzoyl -3-[1-(quinolyl(4)methyl)piperidyl(4)]urea (melting point of 1 1/2 hydrochloride = 211-213℃) 25 1-benzoyl-3-[1-(quinolyl(2)methyl) ) piperidyl (4)] urea (melting point of dihydrochloric acid = 213-215℃) 26 1-benzoyl-3-[1-(3,5-dimethylbenzyl)piperidyl (4)] urea (hydrochloride, 1/4 water Melting point of Japanese product = 248-252
℃) 27 1-benzoyl-3-[1-(2,4-dimethylbenzyl)piperidyl (4)] urea (hydrochloride, quarter hydrate, melting point 230-232℃) 28 1-benzoyl-3- [1-(3-bromobenzyl)piperidyl(4)] Urea (hydrochloride,
Melting point of quarter hydrate = 222-224℃) 29 1-benzoyl-3-[1-(3-iodobenzyl)piperidyl (4)) urea (Melting point of hydrochloride = 217-219℃) 30 1- Benzoyl-3-[1-(pyridyl(4)methyl)piperidyl(4)]urea (melting point of dihydrochloride = 236-238°C) 31 1-benzoyl-3-[1-(3-trifluoromethylbenzyl) Piperidyl (4)] Urea (Melting point of hydrochloride = 241-243°C) 32 1-benzoyl-3-[1-(4-methoxycarbonylbenzyl)piperidyl (4)] Urea (Melting point of hydrochloride = 247-249°C ) 33 1-benzoyl-3-[1-(6-methylnaphthyl(2)methyl)piperidyl(4)]urea (hydrochloride, 1/2 hydrate melting point = 250~
253°C) 34 1-benzoyl-3-[1-(1-benzofuranyl(2)]ethyl)piperidyl(4)]urea (melting point of hydrochloride = 148-149°C) 35 1-[1-(5-acetamide) -2-hydroxybenzyl)piperidyl (4)]-3-benzoyl urea (hydrochloride, 3/4 hydrate melting point = 230-232°C) Example 36 1-benzoyl-3-[1-(naphthyl (2) 4-Amino-1-(naphthyl(2)methyl)piperidine (1.0 g, 0.0042 mol) and benzoyl isothiocyanate (0.69 g, 0.0042 mol) were taken in toluene (120 cm ³ ) and heated to room temperature. The mixture was stirred for 6 hours. The solvent was evaporated and the gum was dissolved in isopropyl alcohol and acidified with ethanolic hydrochloric acid. The solvent was evaporated and the residue was dissolved in ethyl acetate. The title compound crystallized and was filtered and dried to give the monohydrochloride quarter hydrate having a melting point of 212-214°C. Example 37 1-[1-(naphthyl(2)methyl)piperidyl(4)]
-3-(Thenoyl(2))urea 4-amino-1-(naphthyl(2)methyl)piperidine (1.0 g, 0.0047 mol) and 1-(Thenoyl(2))
Urea (0.65g, 0.0042mol) in pyridine ( ^5cm3 )
and refluxed for 9.5 hours. The solvent was evaporated, water was added, and the precipitated title compound was filtered and washed thoroughly with water. This is recrystallized from ethanol, converted to hydrochloride with ethanolic hydrochloric acid in ethanol, and recrystallized from ethanol.
0.5g was obtained. Example 38-41 Similarly to Example 37, 4-amino-1-(naphthyl
(2) Methyl) piperidine is reacted with each of the following ureas, 3,4-dimethylbenzoyl urea, 3-trifluoromethylbenzoyl urea, 4-nitrobenzoyl urea, and 1-(pyridoyl(4)) urea to obtain the following compounds. It will be done. Example number Compound 38 1-(3,4-dimethylbenzoyl)-3-
[1-(naphthyl(2)methyl)piperidyl
(4)] Urea (hydrochloride/quarter hydrate melting point = 223-226℃ 39 1-(1-(naphthyl(2)methyl)piperidyl)
(4)]-3-(3-trifluoromethylbenzoyl)urea (melting point 251-253℃) 40 1-[1-(naphthyl(2)methyl)piperidyl
(4)]-3-(4-nitrobenzoyl)urea (melting point of hydrochloride = 264-5℃) 41 (1-(pyridoyl(4))-3-[1-(naphthyl(2)methyl)piperidyl( 4)〕Urea (melting point
254-255℃) Example 42 1-(4-methoxybenzoyl)-3-[1-(naphthyl(2)methyl)piperidyl(4)] urea 1-benzoyl-3-[1-(naphthyl(2)methyl) Piperidyl (4)] urea (prepared according to Example 1 and hydrolyzed by refluxing in 2N sodium hydroxide gives [1-(naphthyl(2)methyl)piperidyl (4)]
Urea (melting point 183-5°C) is obtained. product 4
-Reaction with methoxybenzoyl chloride gives the title compound. The hydrochloride quarter hydrate has a melting point of 193-193.5°C. Examples 43-44 Reacting 2-bromomethylnaphthalene with a compound of the formula 4-benzylureidopiperidine 4-(p-fluorobenzoyl)ureidopiperidine in a similar manner to Example 1 gives a compound of the formula . Example number Compound 43 1-benzyl-3-[1-(naphthyl(2)methyl)piperidyl(4)] urea (hydrochloride 1/
Melting point of tetrahydrate = 243-247℃ (decomposition) 44 1-(p-fluorobenzoyl)-3-[1
-(naphthyl(2)methyl)piperidyl(4)]
Urea (hydrochloride/quarter hydrate melting point =
Example 45-50 In the same manner as in Example 1, 1,4-benzoylureidopiperidine was converted into the following compounds: 2-(naphthyl(2))ethyl tosylate 6-cyanonaphthyl(2)methyl Bromide 6-fluoronaphthyl(2) methyl bromide 6-bromonaphthyl(2) methyl bromide 1-(naphthyl(2))propyl chloride Reaction with di(naphthyl(2)methyl) sulfate gives the following compounds. Example number Compound 45 1-benzoyl-3-[1-(2-[naphthyl(2)]ethyl)piperidyl(4)]urea (melting point of hydrochloride = 230-232°C) 46 1-benzoyl- 3-[1-(6-cyanonaphthyl(2)methyl)piperidyl(4)]urea (melting point of hydrochloride hemihydrate = 264-266°C) 47 1-benzoyl-3-[1-(6-fluoro Naphthyl(2)methyl)piperidyl(4)] Urea [Hydrochloride/hemihydrate melting point = 215-220℃
and 246-249℃ (multiple melting point)] 48 1-benzoyl-3-[1-(6-bromonaphthyl(2)methyl)piperidyl (4)] urea (hydrochloride/hydrate melting point = 235-247℃ 49 1-benzoyl-3-[1-[1-(naphthyl(2))propyl]piperidyl(4)]urea (hydrochloride, 3/4 hydrate melting point = 222~
224°C 50 1-benzoyl-3-[1-(naphthyl(2)methyl)piperidyl(4)]urea (melting point of hydrochloride hemihydrate = 232° to 234°C) Example 51 1-benzoyl-3-[ 1-(Naphthyl(2)methyl)piperidyl(4)]Urea Heating 2-bromomethylnaphthalene with 4-benzoylureidopiperidine in acetonitrile solvent produces 1-benzoyl-3-[1-(naphthyl(2)).
methyl)-4-piperidinium]urea bromide is obtained. Reduction of this compound by refluxing with sodium borohydride in isopropyl alcohol solvent affords the title compound. Melting point of hydrochloride hemihydrate = 232-234°C Also, 1-benzoyl-3-[1-(naphthyl(2)
Reduction of methyl)-4-piperidinium]urea bromide with sodium borohydride in methanol solvent yields 1-benzoyl-3-[1-(naphthyl
(2) Methyl)-3,4-dehydropiperidyl (4)] urea is obtained (melting point of quarter hydrate = 191-193
℃). Reduction of this compound by refluxing with sodium borohydride in isopropyl alcohol gives the title compound. Example 52 1-Benzoyl-1-methyl-3-[1-(naphthyl(2)methyl)piperidyl(4)]urea 1-Methyl-3-[1-(naphthyl(2)methyl)piperidyl(4)]urea (1.4 g) (prepared by reacting 4-amino-1-(naphthyl(2)methyl)piperidine with methyl isocyanate) in toluene (30 cm ³ ).
Acylation using benzoyl chloride (0.92 g) in the presence of pyridine (0.6 g) gives the title compound. Melting point of hydrochloride hemihydrate = 164-166
°C, elemental analysis: _C67.18 , _H6.54 , N9.40%, analytical value as _C25H27N3O2・_HCl・1/ _2H2O
C67.37, H6.58, N9.45% Example 53 1-benzoyl-3-methyl-3-[1-(naphthyl(2)methyl)piperidyl(4)]urea In the same manner as in Example 37, 4- Methylamino-1-
Reaction of (naphthyl(2)methyl)piperidine with benzoylurea gives the title compound.

Claims (1)

[Claims] 1 formula [In the formula, a dotted line indicates the presence of a bond if necessary, and Ar represents a phenyl, naphthyl, pyridyl, benzofuranyl, quinolyl, indanyl, tetrahydronaphthyl or benzodioxanyl group, and these groups are halogen, lower Alkyl, alkenyl having 2 to 6 carbon atoms, lower alkoxy, _NO2 , _NH2 , halolower alkyl,
hydroxy lower alkyl, amino lower alkyl,
Mono- or di-lower alkylamino, lower alkylcarbonylamino, ureido, lower alkylsulfonamide, di-lower alkylsulfonamino, lower alkoxycarbonyl, cyano,
optionally substituted with one or more substituents selected from CONH ₂ and hydroxy, and this Ar group is bonded to Y via an aromatic ring,
R is a phenyl, pyridyl, furanyl, or thienyl group, each of these groups optionally substituted with one or more of the substituents listed above for Ar, and R ¹ , R ³ and R ⁹ are each hydrogen or a lower alkyl group, n is 0 or 1, X is =O or =S, Y is -O- or a direct bond, and Z is -CO- or _-CH2- , However, if (i) Ar is unsubstituted phenyl and R ⁹ is hydrogen,
Y is -O-, and (ii) when Z represents _CH2 and Ar represents optionally substituted phenyl or pyridyl, ^R1 is hydrogen, and its acid addition salts and quaternary ammonium salts. 2 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-tetrahydronaphth-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; 1-benzoyl-3-[1-(4-ethylbenzyl)piperid-4-yl]urea; 3-benzoyl-1-[1-( 1,4-benzodioxan-6-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(2-[naphtho-1-
yloxy]ethyl)piperid-4-yl]urea; 1-benzoyl-3-[1-(3,4-dibromobenzyl)piperid-4-yl]urea; 1-benzoyl-3-[1-(4-n - a compound selected from propoxybenzyl)piperid-4-yl]urea and 1-benzoyl-3-[1-(3-amino-4-methylbenzyl)piperid-4-yl]urea or pharmaceutically compatible thereof; A compound according to claim 1 which is an acid addition salt or a quaternary ammonium salt.