DE2706038A1 - NEW PIPERIDINE BASED THERAPEUTICS - Google Patents

Description

NEW THSSAPEUSIKA ON PI? EHIDIIi3A3IS

DIE EÄFIxTDüriG refers to new, therapeutically usable Derivatives of piperidine, their methods of preparation and pharmaceuticals in which they are contained.

According to the invention, new piperidine derivatives are the compounds of the general formula:

R ³

CONH- (CH ₂ ) _χ C N-CH-W-IT

(where R stands for a lower alkoxy or a lower one

1 2

Alkenyloxy group; H and R, which may be the same or different can, each stand for a hydrogen or halogen atom, a Sulfonamide, amino, lower alkylamino, lower dialkylaniino, lower alkylsulfonyl or lower alkylsulfonamide group, or a lower acylamino group in which the acyl portion of a carboxylic acid, which can also be halogen-substituted, v / ie e.g. trifluoroacetic acid, (preferably an alkanoylainino group), - the halogen atom or the group which is symbolized by R, are in the 3- or 4-position of the phenyl ring (preferably in the 4-position), with the condition,

1 2

that R and R cannot both be a hydrogen atom; Br stands for a hydrogen atom or a lower alkyl, lower alkenyl or phenyl group, or a cycloalkyl or a Cjrcloallcenylgruppe with 3 to 7 carbon atoms in the ring; R ⁴ "stands for its cycloal2 <yl group with 3 to 7 carbon

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Substance atoms in ring, optionally as follows: ei-t ⁷ Id. T an alkyl group with 1 to 3 carbon atoms or a hydroxy (lower) alkyl or. Alkenyl group or i
Group of formulas:

Alkenyl group or R represents an adamantyl group or a

or

in which R and R both represent a hydrogen atom or a diethyl group, or a grouping of the formulas (2) or (5) with a double bond between two of the carbon atoms of the cyclohexyl ring; χ is zero or 1 and W stands for a single bond or a lower alkylene (e.g. -CHp- or -CHpCH ₂ -) or lower alkenylene (e.g. -CE = CH- or -CK ₂ -CHsCH-) group, with the condition that if V / is a single bond, R must be a group other than cycloalkenyl) and their pharmaceutically acceptable acid addition salts, quaternary ammonium derivatives and IT oxides. Preferably χ is zero and W is a single bond.

The term "low", as used in this context on the groups alkoxy, alkenyloxy, alkyl, acyl, alkanoyl, Alkenyl, alkylene and alkenylene means that the ! Each group contains a maximum of 6 carbon atoms. aside from that can be the cycloalkenyl group within the definition R ^ have one, zv / ei or three double bonds, as indicated by the respective Number of carbon atoms in the ring is determined.

Preferred compounds of the general formula (1) are those of the more specified formula:

³ '

CONH (N-CH-R (4)

709833/0 9.9 A - 3 -

(therein R ¹ stands for a lower alkoxy (preferably methoxy or Etiio: cy) or allyloxy group, E atelic iur a './asserstoffaton or an amino, lower alkylamino (preferably Kethylamino), di (-iodi) all : ylanino- (preferably dimethylamino-) or lower acylaiaino- (preferably lower alkanoylamino-, z, B.
Acetamide or irifluoroacetamide) group, II represents a halogen (preferably chlorine or bromine) atom or an amino, sulfonamide or alkylsulfonyl (preferably methylsulfonyl) group ^
A- ⁵ 'stands for a "..' hydrogen atom or a lower alkyl (preferably methyl) group and R ⁴ " stands for a cycloalkyl group, optionally substituted by an alkyl group having 1 to 3 carbon atoms (preferably methyl) and their pharmaceutically acceptable acid addition salts.

Of exceptional importance are L ^T - (1-cyclohexylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide, N- (1 cyclohexylmethylpiperid-4-yl) -2-methoxy-4-amino- 5-bromobenzamide, N- (1-cyclohexylmethylpiperid-4-yl) -2-iIιethoxy-4-methylamino-5-chlorobenzamide, N- (1-cyclohexylmethylpiperid-4-yl) -2-allyloxy-4-amino-5- chlorobenzamide and N- (I-cyelohexylmethylpiperid-4-yl) -2-ethoxy-4-amino-5-chlorobenzamide, and their pharmaceutically acceptable acid addition salts.

According to one embodiment of the invention, the piperidine derivatives of the general formula (1) prepared in a process in which a reactive derivative of benzoic acid according to the general Formula:

(5)

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ORIGINAL INSPECTED

(where R, R and R \ * ie are previously defined) with a Piperidine derivative of the general formula:

R ³

- (CH ₂ ) ₂ C N-CH-WR ^

(where the various symbols are as previously defined) is implemented. The realrtiven derivatives of the benzoic acid mentioned can be a halide (preferably chloride), an alkyl ester (preferably ethyl ester), anhydrides or a mixed one Anhydride, the H-imidazolamides or acid azides.

The reaction is preferably carried out in an inert organic solvent, see 3. Benzene, toluene, chloroform, tetrahydrofuran or dioxane at a temperature between -5 ° and 12O ⁰ C carried out.

The piperidine derivatives of the general formula (6) in which χ is zero can be prepared by reducing the corresponding piperid-4-one oxime with lithium aluminum hydride in Presence of diethyl ether or tetrahydrofuran, or dissolved by reductive amination of the corresponding piperid-4-ones in an organic solvent, e.g. an alcohol with up to 6 carbon atoms, in the presence of Raney nickel or Platinum as a catalyst. The piperidine derivatives of the general formula (6), in which R is a cyclohexadienyl-

group _t can be derived from the corresponding phenyl derivatives dieeer formula wherein R ^. represents a phenyl group produced by reduction with lithium in the presence of liquid ammonia or a lower alkylamine. The piperidine derivatives of the general formula (6), in which χ is 1,

* 709833 / (Γ9! Η '

can be prepared by known reductive methods, by starting from the corresponding 4-cyanopiperidines.

Halides of benzoic acids of the general formula (6) v / ground in the reaction dei. * Satire with thionyl chloride or a Phosphorus halide in the presence of an inert organic solvent, such as benzene, toluene or a halogenated hydrocarbon. The mixed anhydrides of benzoic acids of the general formula (6) can be represented by the reaction of the acid with, for example, an alkyl chloroformate in the presence of an organic nitrogenous base, e.g. triethylamine, in an inert organic solvent, e.g. Tetrahydrofuran or methylene chloride, at a temperature between -20 ° and + 25 ° C. The esters and anhydrides of benzoic acids of the formula (5), which are used as starting substances in the process described above, can, exactly such as the Il-imidazolaraide and the acid azides, known by Methods are made from the benzoic acids.

According to a further embodiment of the invention, the piperidine derivatives of the general formula (1) can also be prepared by the direct reaction of a benzoic acid of the general formula (5) uit a piperidine derivative of the general formula (6) in the presence of a suitable dehydrating agent. Such agents are silicon tetrachloride, mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, Ν, Ν ¹ -dicyclohexyl-carbodiimide, thionyl chloride, sulfur trioxide in dimethyl sulfoxide, toluene-p-sulfonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. The reaction is carried out at a temperature between 20 ° and ItO ⁰ C in an inert organic solvent, for example methylene chloride, acetone, pyridine, ethyl acetate or dioxane.

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During the representation of those compounds of the general formula (1) in which the symbols R and / or R for an amino group, after the process described above it is sometimes recommended to use the amino group (s) of the acid of the general formula (5) and its derivatives to protect before starting the reaction with the piperidine derivative of the general Pormel (6) performs. In this case, an N-acyl derivative of the amino-substituted benzoic acid of the general Pormel (5) prepared, wherein the protective acyl group is preferably acetyl, chloroacetyl, trifluoroacetyl or phthalimide is. After the reaction between the II-acylated compound of general formula (5) or one of its reactive derivatives with the piperidine derivative of general formula (6) is obtained corresponding H-acyl derivative of the compound of the general formula (1); this is then an acidic or alkaline one

Subjected to hydrolysis and thus gives the corresponding compound of the general formula (1), in which R and / or R for a Amino group. The Acid Hydrolysis of the K-acylated Compound takes place by heating with a hydrochloric acid solution, preferably at the boiling point of the reaction mixture, while the alkaline hydrolysis is preferably carried out at room temperature with sodium or potassium hydroxide in a water / alcohol solution v / ird.

The piperidine derivatives of the general formula '1) have as one of their basic pharmacological properties the ability to combat the effects of dopamines or dopaminergic agents of endogenous or exogenous origin. she have pronounced activities that can be considered beneficial in the treatment of gastrointestinal and cerebral Functional disorders in mammals, including humans.

_ ₇ _ 709833/0994

It has also been shown to be capable of loss of appetite bring about. Their characteristic property int the opposite effect to the effects of the dopaninergic ! • litteis, aponorphine, in animals, local ana3tlietic activity and the 2ahigke.it, cause catatonia in rats and houses. As a result, they can be useful in the treatment of nausea and vomiting of various origins and as neuroleptic and soothing smocks. They can be used to treat nausea and vomiting as a result of gastrointestinal problems Diseases, congestive heart failure, postoperative conditions etc., as well as other gastrointestinal diseases v / ie z.3. Dyspepsia, flatulence, biliary regurgitations, eiatus hernia, Peptic ulcer, hindflux aeropathy, gastritis, duodenitis and Biliary congestion, as well as a variety of conditions that affect the central nervous system such as 3. acute and chronic Psychosis, manic psychosis, schizophrenia, serious behavioral disorders and non-melancholic and depression Iligraine. They can also be used in the treatment of obesity and the associated states are used when the administration of an appetite suppressant is justified.

Piperidine derivatives can be used for therapeutic purposes of the general formula (1) are used in the form of their non-toxic pharmaceutically acceptable inorganic or organic salts v / earth, e.g. as sulfates, hydrogen halides, phosphates,

"4 lower alkanesulfonates, arylsulfonates, as salts of aliphatic ο

"* Mono-, di- or tri-basic acids with 1 to 20 carbons atoms that have one or more double bonds, an aryl nucleus ***

ο or other functional groups v / ie hydroxy, amino or keto «Ο

* Can own £; Salts of aromatic acids, their more aromatic Nucleus is optionally substituted with hydroxy, lower alkoxy, amino, mono- or di (lower) alkylamino and sulfonamide groups.

They can also be used in pharmaceutically acceptable quaternary form Ammonium salts are used as they are in the reaction of the Piperidine derivatives of the general formula (1) with lower alkyl halides or sulfates arise, or in the form of oxidized derivatives, in which the oxygen to the nitrogen atom des Piperidine nucleus is bound, namely the N-oxides.

The pharmaceutically acceptable acid addition salts, quaternary ammonium salts and Η-oxides of the piperidine derivatives general formula (1) can be prepared by generally known methods.

The invention also extends to pharmaceuticals, the active ingredient of which is at least one piperidine derivative general formula (1) or one of its non-toxic pharmaceutically acceptable acid addition salts, quaternary. Ammonium derivatives or! '! - oxides contain i3t, in connection with a pharmaceutical acceptable carrier or diluent. The mixtures are preferably brought into a form suitable for oral, topical, percutaneous or parenteral administration is suitable.

The pharmaceutically acceptable carriers or diluents which are combined with the active compound or compounds to form the mixtures of this invention are well known per se and the choice of particular excipient depends, inter alia, on the method of administration. The mixtures of this invention are preferably adapted for administration per ps . In this case, the mixtures can be brought into the forms of tablets, capsules, troches or effervescent granules, or into liquid preparations such as, for example, mixtures, elixirs, syrups or suspensions, all of which contain one or more compounds of the invention; such preparations can be produced by generally known methods.

709833/0994

The diluents that can be used in making the mixtures include liquids and solids Diluents compatible with the active ingredients, if desired together with coloring or aromatic Agents. The tablets or capsules should expediently contain between 0.1 and 20 mg of the active component or an equivalent Amount of an acid addition salt or quaternary ammonium or H-oxide derivative thereof.

For oral administration, the liquid mixtures should be in the form of solutions or suspensions. The solutions may be aqueous solutions of a salt or other derivative of the active compound in association with, e.g. Sucrose, like that that a syrup is produced. The suspensions can be one in water contain insoluble active compound or one of its acid addition salts or quaternary ammonium or H-oxide derivatives in './water, susanraen with a suspending agent and a flavoring agent.

The mixtures' for parenteral injection can be made from the water-soluble salts are prepared, v / which are freeze-dried may or may not be and which can be dissolved in water or a suitable liquid for parenteral injection.

Another aspect of the invention is that the compounds for oral, in suitable cases also parenteral use with other active anti-acid and anti-UU agents (except anticholinergic agents) can be mixed.

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The following reference example ■ and the other examples illustrate the preparation of the piperidine derivatives of the general formula (1).

REI ¹ EXAMPLE OF EXAMPLE

(a) A solution of ^1-Cj-4-r clohexylinethylpiperid onoxiri (37.8 g; 0.18 Hol) in anhydrous diethyl ether (250 ml) was added portionwise to a suspension of LithiumaluminiumhydricL g (H, 04; 0.36 I -Iol) in anhydrous diethyl ether (200 ml) was added. After the addition was complete, the resulting mixture was heated to the boiling point and refluxed at this temperature for 12 hours, during the subsequent careful cooling, water (14 ml), i5 /> (v // v) aqueous sodium hydroxide solution ( 14 ml) and V / ater (42 ml) added. The mixture was filtered, the ethereal solution dried (ITa ₀ SO.) And the solvent removed in vacuo. The product 1-cyclohexylmethyl-4-aminopiperidine (31 g) was isolated as a viscous liquid, boiling point 105-110 ° C / 0, 3 mm Hg.

In a similar way, proceeding from suitable oximes, also manufactured:

i-Cyclopentylmethyl-4-aninopiperidine, b.p. SO ° -92 ° C / O, 45 mm Eg; i-cyclobutylmethyl-4-aminopiperidine, b.p. 70 ° -71 ° O / O, 0.5 mm Hg; 1- (1-Adamantylmethyl) -4-aminopiperidine, P: 76 ° -79 ° C and 1- (4-Hethylcyclohexylmethyl) -4-aminopiperidine, Bp. 127 ° -i30 ° C / 4 mm Hg.

(b) A solution of 1-Gyclohexylmethylpiperid-4-one (65 gi 0.33 mol) in a saturated solution of ammonia in ethanol (350 ml) was at 75 ⁰ C and under 13 atmospheres for 3.5 hours in the presence of Raney Nickel (6.5 g) hydrogenated. After the mixture had cooled, the catalyst was filtered off and the solvent was distilled off in vacuo. The residue was saturated with a

" ¹¹ " 709833/0994

Solution of hydrogen chloride in ethanol "treated, the insoluble dihydrochloride filtered off, treated with an aqueous sodium hydroxide solution and extracted with chloroform. The organic phase was dried (Ha ₂ SO.) And the solvent removed in vacuo, so 1-Cyclohe: cylmethyl-4 -aminopiperidine (45.5 g) obtained as a viscous liquid, boiling point 1G5 ° -110 ° C / 0.3 mm Hg.

Similarly, were also made:

i-Cycloheptylmethyl ^ -aminopiperidine, b.p. 1O1 ° -1O2 ° C / O, 15 mm Hg and i-Cyclobutylmethyl-4-aminopiperidine, b.p. 70 ° 71 ° C / O, 0.5 mm Hg.

3 EXAMPLE 1

Triethylamine (5.6 ml; 0.04 mol) and ethyl chloroformate (3.84 al; 0.04 mol) were successively with stirring to a suspension of 2-methoxy-4-ariino-5-chlorobenzoic acid (8 g; 0, 04 mol) in anhydrous tetrahydrofuran (300ml) was added while the temperature was kept at -5 ° to -1O ⁰ C. After stirring at this temperature for 30 minutes, a solution of 1 -Cyclohe: iylmeth \ ri-4 aminopiperidine (7.85 g "0.04 mol) is added in anhydrous tetrahydrofuran (50 ml); the temperature was kept for one hour at -5 ° to -10 ⁰ C and then stored overnight at room temperature. The solvent was then removed in vacuo, the residue was poured into water, extracted with chloroform and the organic phase was washed with water. The chloroform solution was dried (ITa-SO.) And the solvent removed in vacuo; the resulting solid was treated with a mixture of methanol and diethyl ether to give H- (1-cyclohexylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide (8 g). *

The hydrochloride was prepared by adding a saturated solution of hydrogen chloride in ethanol to a solution the base in ethanol. The precipitate was recrystallized from ethanol and gave a white solid, F: 225 ° -227 ° C (decomp.).

_ ₁₂ _ 709833/099 *

In a similar way were also made:

N- (1-Cyclopentylmethylpiperid-4-yl) -2-ethoxy-4-amino-5-chlorobenzamide hydrochloride, F: 226-227 ° C; N- (KJyclobutylnethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloride, F: 240 ° -242 ° C; N- (1 - (1 -Adamantyl) methylpiperid-4-yl) ^ -methoxy ^ -amino-S-chlorobenzanide hydrochloride, F: 259-260 ° C; N- (1-Cycloheptyl2nethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobensamide hydrochloride, F: 218-220 ° C; N- (1 -Cy clohexylmethylpiperid ^ -yl) -2-yne thoxy-4 ~ amino-5-bromobenzamide hydrochloride, F: 229-230 ° C; N- (i-Cyclohe2cylniethylpiperid-4-yl) -2-methoxy-4-AcetaEiid-5-Chlorbenzaniidhydrochloridnonohydrat, F: 219 ° -221 ° U; N- (i-CyclohexylEtethylpiperid-4-yl) -2-inetho: ^ jr-5-chlorobenzaiide hydrochloride, F: 231-233 ° C; N- (i-Cyclohexylniethylpiperid-4-yl) -2-Eiethoxy-5-sulfonaniid-benzanide hydrochloride, F: 237-238 ° C; N- (1-Cyclohexylnethylpiperid-4-yl) -2-siethoxy-4-trifluoroacetanide-5-chlorobenzaniidhydrochloride, F: 218 ° -22O ° C (dec.) T N- (i-Cyclohe: cylniethylpiperid-4-yl) -2-niethoxy-5-methylsulfonylbenzainide hydr ο chloride, F: 216-218 ° C (decomp.); U- (1- (4-liethylcyclohexyl) methylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloride, F: 229-230 ° C; N- (1- (1-Cyclohexyl) äthylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamidohydrochloride, F: 225-227 ° C; N- (1-Cyclohe: cylnethylpiperid-4-yl) -2-etho27-4-acetamid-5-chlorobenzamide, its fuaarat melts at 189 ° -191 ° C; N- (1 -Cyclohexylmethylpiperid-4-yll-2-ethoxy-4-ainino-5-chlorobenzamidohydrochloride, F: 242-243 ° C;

- 13 -

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N- (1-Cyclche :: ylinethylpipericL-4-yl) -2-rietho3q7'- ^z i-, 5-d.iaminbenaamiddiiiydr ο chloride, 3 ?: 270 ° -272 ° C (decomp.);

Ii- (1 -Cycloheiicyimethylpiperid ^ -yl) -2-methoxy-4-dimethylamino-5-chlorobenzamide, its pumate melts at 181-183 ° C; If- (1-Cyclo} ie: c3 '"methylpiperid-4-yl) -2-iaeth.oxy-4-methylamino-5-chlorobenzamide, its pumarat melts at 216 ° -218 ° G and N- (1-Cycloiie: cyliuethylpiperid-4-yl) -2-allyloxy-4-amino-5-chlorobenzamide hydrochloride, P: 212-214 ° C.

The above mentioned fumarates of individual piperidine derivatives were made in a process which is described in the following example 9 for the preparation of the fumarate of N- (1-Cycloliexylmethylpiperiu-4-yl) -2-metho :: y-4-ainino-5-chlorobenzamide described v; ird.

EXAMPLE 2

A solution of 2-iietho: cy-4-a.cetamid-5-chlorobenzoyl chloride (14, 4 g "0.055 koi) was added slowly in methyl ethyl ketone (100 ml) at a temperature between 0 ° and 5 ⁰ C. The mixture was stirred at the same temperature for one hour and then for 4 hours at room temperature. The solid precipitate was filtered off, washed with methyl ethyl ketone, recrystallized from an ethanol / water mixture and gave IT- (1-cyclohexylmethylpiperid-4-yl) -2-methoxy-4-ac _# etanide-5-chlorobenzamide hydrochloride nonohydrate ( 21 g), P: 219-221 ° C.

The following was also produced in a similar manner:

N- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-4-trifluoroacetamide-5-chlorobenzamidohydrochloride, P: 218-220 ° C (dec.).

EXAMPLE 3

A mixture of N- (iC! Yclohexylmethylpiperid-4-yl) -2-metho: qy-4-acetamid-5-chlorobenzamidh3 ^r hydrochloride monohydrate (10 g; 0.02 mol), concentrated hydrochloric acid (6 ml) and '.' / water (20 ml)

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was refluxed for 1.5 hours. The batch was then made alkaline with sodium hydroxide and extracted with chloroform. The organic solution was dried (ITa ₂ SO ₄ ) and the solvent was removed in vacuo and, after recrystallization from ethanol 1- (1-cyclohexylinethylpiperid-4-yl) -2-methoxy-4-ainino-5- chlorobenzamide (7.1 g), P: 213-215 ° C.

By treatment with a saturated solution of hydrogen chloride in ethanol the base was converted into its hydrochloride. The solid substance obtained melted at 225 ° -227 ° C. (decomp.).

EXAMPLE 4

A mixture of N- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-4-trifluoroacetamide-5-chlorobensamide (8.1 g; 0.017 Hol), ethanol (25 nil), v / water (15 nil) and 8 η sodium hydroxide solution (25 ml) was stirred for 12 hours at room temperature. After dilution with water, the mixture was extracted with chloroform, the chloroform _{solution was dried (Na 2} SO ^) and the solvent was removed in vacuo; 30 was obtained II- (1-cyclohexylmethylpiperid-4-yl) -2-methoxy-4- ~ amino-5-chlorobenzamide (5 g). The base was converted into the hydrochloride by treatment with a saturated solution of hydrogen chloride in ethanol; this melted at 225 ° -227 ° C (decomp.).

EXAMPLE 5

A mixture of Hethyl ^ -methoxy ^ -acetamide-S-chlorobenzoate (25.7 g; 0.1 mol), xylene (80 ml), 1-cyclohexymethyl-4-aminopiperidine (21.6 g; 0.11 mol) and aluminum isopropoxide (5 g) were heated to boiling point while the methanol formed constantly distilled off after the theoretical amount of methanol had been removed, the xylene was distilled off and the residue was dissolved in 2N hydrochloric acid (200 ml). The aqueous solution was made alkaline with a sodium hydroxide solution, with

709833/0994

- 15 -

Extracted chloroform and evaporated the chloroform phase to dryness; thus became N- (1-Cyclohexylraethylpiperid-4-yl) -2-methoxy-4-acetylamide-5-chlorobenzanide (27 g) obtained. Its hydrochloride was prepared according to the method described in Example 1, F: 219 ° -221 ° C.

EXAMPLE 6

Njll'-dicyclohexylcarbodiinide (10.3 g> 0.05 mol) and i-cyclohexylmethyl-4-aminopiperidine (8.8 g; 0.05 mol) successively to a solution of 2-methoxy-4-acetamid-5-chlorobenzoic acid (12.1 g; 0.05 hol) in methylene chloride (250 nl) was added. After the mixture was stirred overnight, the insoluble Ν, Ν'-dicyclohexylurea was filtered off, the Solution washed with water, dried (üTapSO.) And the solvent removed in vacuo. The residue was crystallized and converting the product to the hydrochloride; 14.2 g of N- (1-cyclohexylmethylpiperid-4-yl) -2-rtethoxy-4-acetamide-5-chlorobenzaldehydrochloride monohydrate were obtained received, F: 219-221 C.

EXAMPLE 7

To a warm solution of 1T- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-4-acetamid-5-chlorobenzamide (10 g; 0.025 mol) in diethyl ether (300 ml) was a solution of methyl iodide (1.8 al; 0.033 mol) in diethyl ether (25 ml) was added. The mixture was stirred at room temperature for one hour and then Heated to reflux for 2 hours. An additional amount of methyl iodide (1 g; 0.0023 mol) was added and heating of the Mixing continued at reflux for a further 3 hours. The mixture was then evaporated in vacuo and the residue from a Mixture of diethyl ether-ethanol recrystallized; so v / urde N- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-4-acetamid-5-chlorobenzaniic.- methyl iodide (10.5 g) obtained, P: 209-211 ° C.

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EXAMPLE 8

A 30% hydrogen peroxide solution (6 ml) was added to a solution of K- (1-cyclohexylmethylpiperid-4-yl) -2-methoxy ^ -acetainide-S-chlorobenzamide (10 gj 0.023 hol) in glacial acetic acid (50 ril) . The mixture vrurde 8 hours heated to a temperature between 70 ° and 80 ⁰ C. The solvent was then evaporated in vacuo; K- (1-Cyclohexylmethylpiperid-4-Z / 'l) -2-metho: iy-4-acetamide-5-chlorobenzamide-i \ -oxide was thus obtained as a viscous liquid. Hach recrystallization from a mixture of acetone and diethyl ether resulted in 7.3 g of the Η-oxide, I ^- : 2O6 ° -2O8 ° G.

EXAMPLE i 9

To a hot solution of N- (1-cyclohexylmethylpiperid-4-yl) -2-metlioxy-4-amino-5-chlorobenzamide Fumaric acid (1.7 g; 0.014 mol) was added (5 gi 0.013 hol) in ethanol (30 ml). The hot mixture was stirred until completely dissolved. After cooling, the fumarate of 1T- (1-cyclohexylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide crystallized from: Yield 6.3 g, mp: 229 ° -23 ° C

The following examples illustrate the pharmaceutical Compositions according to this invention and their methods of manufacture:

EXAMPLE 10

100,000 tablets each with 2mg N- (1-Cyclohexylmethylpiperid ~ 4-yl) -2-methoxy-4-amino ~ 5-chlorobenzamidohydrochloride were produced from the following approach:
N- (1-Oyclohexylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloride 200 g

microcrystalline cellulose 1870 g

Lactose, spray dried 9880 g

Carboxymethyl starch 430 g

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Sodium stearyl iunarate. ; 60 g

colloidal silicon dioxide 60 g

Procedure ;

All powders were passed through a 0.6 mm mesh sieve happened. The powders were then mixed for 20 minutes in a suitable mixer and using 6 mm disks and, flat ground punches compressed into 125 mg tablets. The disintegration time of the tablets was approximately 60 seconds.

EXAMPLE 11 ·. ·. '

100,000 capsules nif jev / eils 1 mg li-O-cyclohexylinethyl-

■ *

piperid-4-yl) -2-methoxj ^r -4-amino-5-chlorobenzamide hydro chloride were prepared from the following approach: N- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-

4-amino-5-chlorobenzanide hydrochloride 100 g

Lactose 9000 g

Sodium aurysulfate 370 g

Grain starch 8000 g

Alpintalkum 530 g

Procedure:

The above ingredients were sifted through a 40 mesh screen, then mixed and processed in a suitable mixer 100,000 gelatin capsules (180 mg) distributed.

EXAMPLE 12

10,000 suppositories with 5 mg each of N- (1-Cyclohexylmethylpiperid-4-yl) -2-metho: jy-4-amino-5-chlorobenzamide hydrochloride were prepared as follows:
N- (1 -Cyclohe: cylmethylpiperid-4-yl) -2-methoxy-

4-aminc— S-chlorobenzamide hydrochloride. . 50 g

Theobrona oil '. . 19950 g

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Procedure: 9, £

The theobrorea oil was melted and the N- (1-Cyclohe: ^ ylmethylpiperid-4-yl) -2-riethoxi '- 4-ai! Iino ~ 5-chlorobenzamide hydrochloride suspended in it. The mixture was then put into suitable supermarket molds poured resulting in 2.0 g suppositories.

EXAMPLE 15

50,000 ampoules each with 2 mg of 1T- (1-Cyciohexylmethylpiperid-4-yl) -2-methoxy-4-anino-5-chlorobenzanide hydrochloride v / are prepared from the following approach: N- (1-Cyclohe: cylnethylpiperid-4-yl) -2-Kiethoxy-4-amino-5-chlorobenzamide hydrochloride 100 g

Sodium chloride 500 g

V / ater of injection quality see q. 100 liters

Procedure ;

K- (1-cyclohexylmethylpiperid-4-yl) -2-methoxy-4-aiaino-5-chlorobenzamyl hydrochloride and the sodium chloride were dissolved in about 80 liters of v / water with gentle heating. the The solution was diluted with 1 / water to 100 liters, passed through a bacteria retention filter and in a known manner filled in 2 ml glass ampoules. The injection solution can be prepared under sterile conditions. 3s is but it is also possible to work under normal conditions and then subject the filled ampoules to hot sterilization.

EXAMPLE 14

1,000 bottles of 150 ml each with 75 mg of iI- (1-Cyclohexylmethylpip3rid-4-yl) -2-niethoxy-4-amino-5-chlorobenzamide hydrochloride were prepared as follows: N- (1-Cyclohe ^ ylnethyIpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzaniide hydrochloride 75 g

Sorbitol 70000

. 19th 709833/0994

Sorbic acid % 125 g

Citric acid 125 g

distilled water see q. . 1 50 liters

Flavoring agent. ;; q..s.

Procedure;

The l) - (i-Cyclohe: qylinethylpiperid-4-yl) -2-methoxy-4-3-nino-5-chlorobenzanide hydrochloride and the sorbic acid were dissolved in 100 liters ΐ / water and then the sorbitol, the citric acid and de: Flavor added. The mixture was diluted to 150 liters and distributed on the bottles.

Similar rules to those in Examples 10 to 14 can be prepared if other piperidine derivatives of the general formula (1) are used as active ingredients as l • T- (1-Cyclohejcylmethylpiperid-4-yl) -2-methoxy-4-arlino-5-chlorbenaainid begins; z.3. other products according to the porn, those mentioned in Examples 1, 2, and 5 to 8 are mentioned.

The piperidine derivatives of the general formula (6) are new connections and as such represent a further Ausfülirungsform of the invention.

- 20 -

709833/0994

Claims (40)

PATENT CLAIMS CONH- (CH ₂ ) _x (where R stands for a lower alkoxy or a lower one 1 2
Allcenyloxy group; R and R, which can be the same or different, each stand for a hydrogen or halogen atom, a sulfonamide, amino, lower alkylaciino, lower dialkylanino, lower alkylsulfonyl or lower alkylsulfonaaid group, or a lower acylam.no group, in which the acyl part is derived from a carboxylic acid, the halogenatos or the Group, which ^{are symbolized by R 1} , 3tehen in 3-.odor 4- 1 2 Position of the phenyl ring with the condition that R and R cannot both be hydrogen atoms .; R stands for a hydrogen atom or a lower alkyl, lower alkenyl or phenyl group, or a cycloalkyl or a cycloalkenyl group with 3 to 7 carbon atoms in the ring; R represents a cycloalkyl group having 3 to 7 carbon atoms in the ring, optionally substituted with an alkyl group having 1 to 3 carbon atoms or one. Hydroxy (r.lower) alkyl or alkenyl group or R stands for an adamantric group or a group of the formula? (2) or - 21 - (3) 709833/0994 ORlGlNAtHNSPECTED wherein R and R both stand for a hydrogen atom or a methyl group, or a grouping of the form (2) or (3) with a double bond between two of the carbon atoms of the cyclohexyl ring j χ is zero or 1 and W stands for a simple or a lower alkylene or a lower alkenylene group with the proviso that when V / is a single bond ? <? must be a group other than cycloalkenyl) and their pharmaceutically acceptable acid addition salts, quaternary ammonium derivatives and N-oxides. 2. piperidine derivatives according to claim 1, wherein χ is the same is zero and V / stands for a single bond. 3. Piperidine derivatives according to claim 1 or 2, in which R represents a halogen atom or a group as in Claim 1 is specified appended to the 4-position of the phenyl ring. 4. Piperidine derivatives of the general formula: R ³ ' / - \ I i— -4 N-CH- CONH - -i. N-CH-R ^H. (4) (where R ¹ stands for a lower alkoxy or allyloxy group, R stands for a hydrogen atom or an Aiaino, lower Alkylamino, di (lower) alkylamino or a lower acyl 2 « amino group, R stands for a Halogenatoia or an amino, sulphonamide or lower alkylsulphonyl group, R ^ stands for a V / as3 3rstoffatoa or a lower alkyl group and R ^ stands for a cycloalkyl group:, optionally substituted with an alkyl group having 1 to 3 carbon atoms ) and pharmaceutically acceptable acid addition salts thereof · 709833/0994 - 22 - 5. Piperidine derivatives according to claim 4, wherein R ¹ -if a lower alkoxy group- is Hethoxy- or Ethoxy-; R (iy - if a lower alkylamino group- for methylamido, 'Ii) -v / enn a DiCniedriGOalkylamino group- for dimethylamino or (iii) -v / enn a lower acylamino group- for a Ot * lower alkanoylanino group; R (i) -v / enn a halogen atom- for (tilor or bromine or (ii) -v / enn a lower alkylsulfonyl group for Methyl sulfonyl-; R ^ -v / enn a low / I Alkylgruppe- stands for He thy 1 and A * stands for a Gycloalbri _rU pp _e , alternatively substituted with a Hethy 1 group, and their pharmaceutically acceptable acid addition salts. 6. piperidine derivatives according to claim 4 or 5, in which R 'stands for the acetamide or the! Drifluoroacetaaidgruppe. 7. Piperidine derivatives according to claim 1, in which R represents a cyclobutyl, cyclopentyl, oycloheptyl or adaniantyl group, or represents a cyclohexyl group which is alternatively substituted in the 4-position by an alkyl group having 1 to 3 carbon atoms or a hydroxy (lower) alkyl or lower alkylene group, and V / is a group - (CHp) _v - in which V _{1 is} zero or an integer between 1 and 5. 8. H- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide. 9. N- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-4-acetamid-5-chlorobenzamide. 10. IT- (1-cyclohexylmethylpiperid-4-yl) -2-methoxy-4-trifluoroacetamide-5-chlorobenzamide. 709833/0994 - 23 - 2706033 i 11. N- (1-C7clohexylmethylpiperid-4-yl) -2-ethoxy-4-anino-5-chlorob enzainide 12. N- (1-Cyclopentylmethylpiperid-4-yl) -2-methoxy-4-ainino-5-chlorobenzamide. 13. N- (1 -Cyclobutyline-ethyl-piperid-4-yl) -2-methoxy-4-aiaino-5-chlorobenzanide. 14. N- (1 - (1-Aaaiaantyl) methylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzaaiide _# 15. N- (1-Cycloheptylraethylpiperid-4-yl) -2-methoxy-4-amine-5-chlorobenzamide 16. N- (1w-Cyolohexylmethylpiperid-4-yl) -2-methoxy-4-amino - 5-brosib enzamid 17. N- (1 -Cycloiiexylriiethylpiperid-4-yl) -2-methox3 "- 5-chlorobenzamide 18. N- (1-Cyclohexylmethyl-piperid-4-yl) -2-methoxy-5-sulfonanide acid. 19. N- (1-Cyclohe: - ^ nieth.ylpiperid-4-yl) -2-ynethoxy-5-yne t hy 1 sul f ony Ib enz ani d. 20. N- (1- (4-Methylcyclohexyl) methylpiperid-4-yl) -2-metho :: y-4-amino-5-chlorobenzamide. 21. N- (1- (1-Cyclohexylethyl) piperid-4-yl) -2-methoxy-4-amirio-5-chlorobenzeneide. 22. N- (1-Cyclohexyl-methylpiperid-4-yl) -2-ethoxy-4-acetateiaid-5-chlorobenzamide. 23. II- (1-Cyclohexylmethylpiperid-4-yl) -2-methoxy-4,5-dianiine benzaiide. 24. N- (1 -Cyclohexylniethylpiperid-4-yl) -2-metho: c5 ^r -4-dimethylamino-5-chlorobenzamide 25. N- (1 -Cyclohexylaiethylpiperid-4-yl) -2-nieth.oxy- 4-methylaaino-5-chlorobenzamide. ■ 709833/0994 - 24 - vT 26. N-Ci-Cyclohexylmethylpiporid- ^ yl) -2-allyloxy- 4.-amino-5-chlorobenzamide. 27. Pharmaceutically acceptable acid addition salts of each compound according to claims 8 to 26. 28. Pharmaceutically acceptable quaternary ammonium derivatives of each compound according to claims 8 to 26. 29. The K-oxides of each compound according to claim 8 to 26. 30. A process for the preparation of a piperidine derivative3 according to claim 1 characterized by the reaction of a reactive benzoic acid derivative of the general formula: ΌΟΗ 1 ο (v / orin R, R and R are as defined in claim 1) with one Piperidine derivative of the general formula: R ³ - / Y-CH-W-R ^ H ₂ N- (CH ₅ )
2 2 in which the various symbols are defined in claim 1. 31. Sin display method according to claim 30, in which the reactive benzoic acid derivative is a halide, an alkyl ester, anhydride, a mixed anhydride or the N-iinidazolamide bzv /. the acid azide .is. 709833/0994 - 25 - 32. Sin preparation method according to claim 30 or 31, in which the reaction in an inert organic solvent at a temperature between -5 ° and 12u ° C is carried out. 33. Sine modification of the representation process according to Claim 50, in which the benzoic acid of the general formula (5) reacted with the piperidine derivative of the general formula (6) in the presence of a dehydration agent. 34.Sin representations according to claim 33, in which the dehydrating agent is silicon tetrachloride Mono-, di- or trialkyl allyl chloride, titanium tetrachloride, NjIT'-dicyclohexyl-carbodiimide, thionyl chloride, sulfur trioxide in dimethyl sulfoxide, toluene-iosulfonyl chloride, acetone dimethyl acetal or is a polymeric dehydrating agent. 35. A display method according to claim 33 or 34, wherein the reaction in an inert organic solvent at a temperature zv / een 20 ° and 110 ⁰ C performed v / ill. 36., A process for the preparation of a piperidine derivative, according to Claim 1 specified in the general formula, as well as its acid addition salt, quaternary ammonium derivative or Η-oxide, as essentially described above, with particular reference to Examples 1 to 9. 709833/0994 - 26 - 37 · Pharmaceuticals as their active constituent at least one of the piperidine derivatives according to claim 1 to 26, or a non-toxic, pharmaceutically acceptable acid addition salt, quaternary ammonium derivative or N-oxide thereof is contained in Association with a pharmaceutically acceptable carrier or dilution smi 11 e1. 38. Pharmaceuticals according to claim 37, as described in the preceding are particularly described, with particular reference to Examples 10-14. 39. Piperidine derivatives of the general formula: R ³ H ₂ N- (CH ₂ ^ wherein R, R, χ and W are as defined in claim 1. 40. i-Cyclohexylmethyl-4-aminopiperidine, 1-cyclopentyl methyl-4-aminopiperidine, 1-cyclobutylmethyl-4-aminopiperiäin, 1- (1-Adamantylmethyl) -4-aminopiperidine, 1- (4-Ethylcyclohexyl methyl) -4-aminopiperidine and 1-cycloheptylmethyl-4-aminopiperidine. - 27 - 709833/0994