DE2705949A1 - NEW PIPERIDINE BASED THERAPEUTICS - Google Patents

Description

Claudius w * mtä ^ PIPERIDIIiBASIS HERAPEUTICS

^^ / y b j 4 Si

THE INVENTION relates to new, therapeutically useful derivatives of piperidine, their method of preparation and Pharinaka in which they are included.

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

( N-CH-WR *

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

1 2

Alkenyloxy group; R and R, which may be the same or different can, each stand for a hydrogen or halogen atom, a sulfonamide, amino, lower alkylamino, lower dialkylamino, lower alkylsulfonyl or lower alkylsulfonamide group, or a lower acylamino group in which the acyl part is derived from a carboxylic acid which is also halogen-substituted such as trifluoroacetic acid, (preferably an alkanoylamino group), - the halogen atom or the group 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; 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 stands for a cycloalkenyl group with 3 to 7 carbon

- 2 - 709834/1008

Substance atoms in the ring, optionally substituted with an alkyl group having 1 to 3 carbon atoms or a hydroxy (lower) alkyl or alkenyl group; χ is zero or 1, and W stands for a single bond or a lower alkylene (e.g. -CH ₂ - or -CH ₂ CH ₂ -) or lower alkenylene- (e.g. -CH = CH- or -CH ₂ -CH =) CH-) group) as well as their pharmaceutically acceptable acid addition salts, quaternary ammonium derivatives and N-oxides. Preferably χ is zero and W is a single bond.

The term "low" as it is used in this context is based 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

• Ζ Α

the cycloalkenyl group within the definitions R ^ and R ^ "can have one, two or three double bonds, which is determined by the respective number of carbon atoms in the ring. Possible cycloalkenyl groups are, for example, cyclopentenyl, cyclohexenyl and cycloheptenyl with one double bond, cyclohexadienyl ( preferably cyclohexa-1,4-dienyl optionally substituted with an alkyl group having 1 to 3 carbon atoms) and cycloheptatrienyl.

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

ONH ί Ν -CH-R * '

(2)

709834/1008

_M. 2? 0b9A9

(therein R ¹ stands for a lower alkoxy (preferably kethoxy or A "tho: cy) or allyl oxy group, R stands for a to ffatom or an amino, lower alkylamino (preferably methylamines), di (Niodrig) alkylamino (preferably dirnethylaniino) or lower acylanino (preferably lower allcanoylamino, e.g.

O f

Acetamid.- or trifluoroacetamide) group, R stands for a halogen (preferably chlorine or bromine) atom or an amino, sulfonamide or alkylsulionyl (preferably methylsulfonyl) group, R- ⁵ stands for an hydrogen atom or a lower alkyl (preferably methyl) group and R ⁴ "stands for a cycloalkenyl, group optionally substituted by an alkyl group with 1 to 3 carbon atoms (preferably methyl)) and their pharmaceutical

table acceptable acid addition salts. !

Such connections are of exceptional importance

of the general formula (2), in which R ^ stands for the cyclohexa-1,4-dienyl group -./ optionally substituted with a methyl group and, in particular, for HO-cyclohexa-I ', 4'-dienylmethylpip3rid-4-yl ) -2-metho :: y-4 - am.ino-5-chlorobenzamide, II- (1-0yclohe; ca-1 ', 4'-diene5 * lmethylpiperid-4-yl) -2-metho: cy- 4-methylamino-5-chlorobenzamide, K- (1-Cyclohe: ca-1'4 ^l -dienylmethylpiperid-4-yl) -2-methoxy-4-acetamid-5-chlorobenzamide and H- (1 - (4-methylcyclohexa -1,4-dienyl) methylpiperid-4-yl) -2-nethoxy-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:

/ VCOOH (3)

A = C

^R 70.9 834/100 ^

ORIGINAL INSPECTED

(wherein R, R and R are as previously defined) with a Piperidine derivative of the general formula:

/ -λ

ν - CH W R * (4)

^r3

CHW *

(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 methyl esters), anhydrides or a mixed anhydride, the II-imidazole amides or acid azides.

The reaction is "preferably in an inert organic solvent, Z.3. Benzene, toluene, chloroform, tetrahydrofuran or dioxane at a temperature between -5 ° and 120 · ⁰ C.

The piperidine derivatives of the general formula (4) in which χ is zero can be prepared by reducing the corresponding piperid-4-one oximes with lithium aluminum hydride in the presence of diethyl ether or tetrahydrofuran, or by reductive amination of the corresponding piperid-4-ones dissolved in one organic solvent, for example 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 (4), in which R ^ and / or R ⁴ stand for a cyclohexadienyl group, can be prepared from the corresponding phenyl derivatives of this formula-in which R ^ and / or R stand for a phenyl group by reduction with lithium in the presence of liquid ammonia or a lower alkylamine. The piperidine derivatives of the general formula (4), in defl <w gUitb \ ς \ _f

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270594S

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

Halides of the benzoic acids of the general formula (3) are prepared in the reaction of the acid 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 the benzoic acids of the general formula (3) can be prepared by the reaction of the acid with, for example, an alkyl chloroformate in the presence of an organic, nitrogenous base, for example triethylamine, in an inert organic solvent, for example tetrahydrofuran or methylene chloride, at one temperature between -20 ° and + 25 ⁰ C. The esters and anhydrides of the benzoic acids of the formula (5), which are used as starting substances in the process described above, can, just like the N-imidazolamides and the acid azides, by known methods from the Benzoic acids are produced.

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 (3) with a piperidine derivative of the general formula (4) in the presence of a suitable one Dehydrating agent. Such agents are silicon tetrachloride, mono-, di- or trialkyl-silyl chloride, titanium tetrachloride, N, N ^f -dicyclohexyl-carbodiimide, thionyl chloride, sulfur trioxide in dimethylsulfoxide, toluene-ja-sulfonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. The reaction is conducted at a temperature between 20 ° and 110 ⁰ C in an inert organic solvent such as methylene chloride, acetone, pyridine, ethyl acetate or dioxane.

_ ₆ _ 709834/1009

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 (3) and its derivatives to protect before starting the reaction with the piperidine derivative of the general Formula (4) carries out. In this case, an N-acyl derivative of the amino-substituted benzoic acid of the general Formula (3) prepared, wherein the protective acyl group is preferably acetyl, chloroacetyl, trifluoroacetyl or phthalimide is. After the reaction between the N-acylated compound of the general formula (3) or one of its reactive derivatives with the piperidine derivative of the general formula (4) gives the corresponding N-acyl derivative of the compound of the general formula (1); this is then subjected to acidic or alkaline hydrolysis and thus gives the corresponding compound of the general formula (1), in which R and / or R stands for an amino group. The acid hydrolysis of the N-acylated compound takes place by heating with a hydrochloric acid solution, preferably at the boiling point of the reaction mixture, while the alkaline hydrolysis preferably at room temperature with sodium or potassium hydroxide in a water / alcohol solution.

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 Mammalian dysfunctions, including humans.

_ ₇ _ 709834/1008

270b949

They have also been shown to be able to induce loss of appetite. Their characteristic property is the opposite effect to the effects of the dopaminergic agent, aponorphine, in animals, local anesthetic activity and the ability to produce catatonia in rats and houses. As a result, they can be useful in the treatment of nausea and vomiting of various origins, as well as neuroleptic and soothing gowns. They can be used for the treatment of nausea and vomiting as a result of gastrointestinal diseases, congestive heart failure, postoperative conditions etc., as well as other gastrointestinal diseases such as dyspepsia, flatulence, biliary regurgitations, hiatal hernia, gastric ulcer, reflux aeropathy, gastritis, duodenitis and biliary stasis A variety of conditions affecting the central nervous system such as acute and chronic psychosis, manic psychosis, schizophrenia, serious behavioral disorders and non-melancholic depression and migraines. They can also be used in the treatment of obesity and related conditions when the administration of an appetite suppressant is warranted.

For therapeutic purposes, the piperidine derivatives of the general formula (1) in the form of their non-toxic pharmaceutically reasonable inorganic or organic salts are used, e.g. as sulfates, hydrogen halides, phosphates,

*** lower alkanesulfonates, aryl sulfonates, as salts of aliphatic ο

^ monobasic or tri-basic acids with 1 to 20 carbons

.p- atoms which have one or more double bonds, an aryl nucleus ^.
- »or other functional groups such as hydroxy, amino or keto

° 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 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 is attached to the nitrogen atom of the Piperidine nucleus is bound, namely the N-oxides.

The pharmaceutically acceptable acid addition salts, quaternary ammonium salts and N-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 N-oxides, in conjunction 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 give 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 orally . 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.

7038 34/1008 - 9 -

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 Ken, ~ e of an acid addition salt or quaternary Contain ammonium or N-oxide derivatives 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 contain a water-insoluble active compound or one of its acid addition salts or quaternary ammonium or N-oxide derivatives in water, together with a suspending agent and a flavoring agent.

The mixtures for parenteral injection can be made from the water-soluble salts, which may or may not be freeze-dried, and those in water or a suitable liquid for parenteral injection.

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

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270b949

The following reference example and the other examples illustrate the preparation of the piperidine compounds of these Invention.

REFERENCE EXAMPLE

A solution of lithium (5 g »0.7 mol) in liquid Ammonia (250 ml) was added portionwise to another solution of 1-benzyl-4-α-amino piperidine (50 g; 0.264 mol) in anhydrous Diethyl ether (100 ml) added. After stirring for 30 min, absolute ethanol (180 ml) was gradually added, the solvent im The vacuum is drawn off and the residue is taken up in water. The aqueous solution was extracted with diethyl ether, the organic Phase dried, distilled in vacuo and gave 1-cyclohexa-1 ', 4'-dienylmethyl-4-aminopiperidine (48 g), b.p. 117-118 ° C / 0.5 mm Hg «In a similar» / ice were also produced:

1- (4-diethylcyclohexa-1 ', 4'-dienyl) -4-aainopiperidine, Bp 104-106 ° C / 0.07 mm Hg;

1-0-Cyclohexa-i, 4'-dienyl-ethyl) -4-aminopiperidine, Bp. 1O3-1O5 ° C / O, 08 mm Hg and

1-cyclohexen-3-ylmethyl-4-aminopiperidine, bp. 101-103 ⁰ C / 0.05 mm Hg.

EXAMPLE 1

Triethylamine (7.0 ml; 0.05 hol) and ethyl chloroformate

^ (4.8ml; 0.05 mol) were successively with stirring to a

<o Suspension of 2-methoxy-4-amino-5-chlorobenzoic acid (10.1 g;

^ 0.05 mol) in v / water-free tetrahydrofuran (300 ml), _ * while the temperature was kept at -5 ° to -10 ⁰ C. After ο

o had been stirred at this temperature for 30 minutes co

a solution of 1-cyclohexa-1 ', 4'-dienylmethyl-4-aminopiperidine (9.6 g; 0.05 mol) in v / anhydrous tetrahydrofuran (50 ml) added;

- 11 -

the temperature was kept at -5 ° to -1O ⁰ C for one hour and then the reaction mixture was kept 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 Ciilorofonösung was drummet (HagSO.) And the solvent removed in vacuo; the resulting plague substance was treated with a mixture of methanol and diethyl ether to give N- (1-cyclohexa-1 ^f , 4 ^l -dienylmethylpiperid-4-yl) -2-methoxy-4-amirio-5-chlorobenzamide (12.2 g ).

The hydrochloride monohydrate was prepared by adding a saturated solution of hydrogen chloride in ethanol to a solution of the base in ethanol. The precipitate was recrystallized from ethanol to give a white Pestsubstanz, P: 226 ° - 227 ⁰ C (dec.).

In a similar way were also produced:

N- (1-Cyclohexa-1 ', 4'-dienylmethylpiperid-4-yl) -2-methoxy-5-methylsulfonylbenzamide hydrochloride, F: 209 ° -211 ° C (dec.);

N- (1-Cyclohexa-1 ·, 4'-dienylmethylpiperid-4-yl) -2-methoxy-5-chl orbenzamidiiydr ο chloride, P: 231-233 ° C;

N- (1 -cyclohexa-1 ', 4 .'- dienylinethylpiperid-4-yl) -2-methoxy-4-amino-5-brombenzamidhydrochlorid, P: 215 ⁰ C (dec ·);

N- (1-Cyclohexa-1 ', 4 ^l -dienylmethylpiperid-4-yl) -2-methoxy-5-sulfonamidobenzamide hydride chloride, P: 230-231 ° C (decomp.);

N- (1-Cyclohexa-1 ', 4'-dienylmethylpiperid-4-yl) -2-methoxy-4-acetamide-S-chlorobenzamide hydrochloride monohydrate, P: 193-195 ° C;

N- (1- (4-I'othylcyclohexa-1,4-dienyl) methylpiperid-4-yl) -2-methoxy ^ -anino-S-chlorobenzamide hydrochloride, P: 246-248 ° C (dec.);

70983A / 1008

NOd-Cyclohexa-i «, 4'-dienylethyl) piperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide _{hydrochloride f} F: 241 ° -242 ° C (decomp.);

N-Ci-d-cyclohexa-i _'f 4'-dienyläthyl) piperid-4-yl) -2-ethoxy-4-acetamide-5-chlor'beiizaciid, its fumarate melts at 171 ° -173 ° C;

N-Ci-d-Cyclohexa-i », 4'-dienylethyl) piperid-4-yl) -2-ethoxy-4-amino-5-chlorobenzamide hydrochloride, F: 264-266 ° C;

N- (1 -Cyclohexa-1 ' _J 4'-dienylmethylpiperid-4-yl) -2-ynetho ^ -4,5-diaminobenzamide dihydrochloride monohydrate, m.p .: 240-242 ° C;

N- (1-cyclohexa-1 _'t 4'-dienylinethylpiperid-4-yl) -2-niethoxy-4-dtmethylainino-5-chlorobenzamide, its fumarate melts at 167 ° -169 ° C;

N- (1-cyclohexa-1 ·, 4 ^x dienylmethylpiperid-4-yl) -2-methoxy-4-methylamino-5-chlorobenziaide, its pumate melts at 2 ° 3 ° -205 ° C;

N-Ci-Cyclohexa-I ', 4'-dienylriethylpiperid-4-yl) -2-allylo: cy-4-amino-5-chlorobenzamide hydrochloride, P: 180-182 ° C;

N- (1 -Cyclohexa-1 ', 4' -dienylmethylpiperid-4-yl) -2-etho: cy-4- - amino-S-chlorobenzamide hydrochloride, P: 247 ° -249 ° C;

N- (1-Cyclohexa-1 ', 4' -dienylmethylpiperid-4-yl) -2-etho:>: y-4-acetamid-5-chlorobenzamide, its pumate melts at 173 ° -175 ° C, and

IT- (1 -Cyclohexen-3 '-ylmethylpiperid-4-yl) -2-metho3py-4-amino-5-chlorobenzamide, P: 189 ° -191 ° C.

The above-mentioned piperidine derivatives were obtained by adding fumaric acid to a hot ethanolic solution the amount of acid added was essentially equimolecular to the given piperidine base; the hot mixture was stirred until completely dissolved and upon subsequent cooling of the solution this crystallized Pumarat from

709834/1008 - 13 -

EXAMPLE 2

To a poor solution of N- (1-cyclohexen-3 ^l -ylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide (3.5 g; 0.0093 mol) in acetone (75 ml) a solution of methyl iodide (2.63 g; 0.0185 mol) in acetone (25 ml) was slowly added. The mixture was stirred at room temperature for 12 hours and then refluxed for an additional 4 hours. The mixture was then concentrated to a small volume in vacuo, the residue filtered off to give li- (1-cyclohexen-3 ^l -ylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide methyl iodide (4 g), F: 231 ° -233 ° G (decomp.), After recrystallization from an ethanol-water mixture.

The following examples illustrate the pharmaceutical compositions according to this invention as well as theirs Production method:

EXAMPLE 3

100,000 tablets each with 2 mg N- (1-Cyclohexa-1, 4'-dienylmethylpiperid-4-yl) - ^ - methoxy ^ -amino-S-chlorobenzamide hydrochloride monoh * "drat were prepared from the following approach: N- (1-cyclohexa-1 ', 4'-dienylmethylpiperid-4-yl) -2-me thoxy-4-amino-5-chlorobenzamidhydrο chloridmonohydrate 200 g

microcrystalline cellulose 1870 g

Lactose, spray-dried 9880 g

Carboxymethyl starch 430 g

Sodium stearyl fumarate 60 g

colloidal silicon dioxide 60 g

- 14 -

709834/1008

270b949

Procedure; ^m **

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 60 seconds.

EXAMPLE 4

100,000 capsules each containing 1 mg of N- (1-Cyclohexa-1 ', 4 ¹ -dienylmethylpiperid-4-yl) ^ -methoxyM-amino-S-chlorobenzamide hydrochloride monohydrate were prepared from the following approach: N- (1-Cyclohexa-1' , 4 ^l -dienylmethylpiperid-4-yl) -2-methoxy ^ -anino-S-chlorobenzamide hydrochloride monohydrate 100 g

Lactose 9000 g

Sodium Lauryl Sulphate 370 g

Grain starch 8000 g

Alpintalkum 53Og

Procedure:

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

EXAMPLE 5

10,000 suppositories each with 5 mg of N- (1-cyclohexa-1 ', 4 ¹ -dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate were prepared from the following approach:

N-O-Cyclohexa-I, 4'-dienylmethylpiperid-4-yl) -2-methoxy 1-4 -amino-S-chlorobenzamide hydrochloride monohydrate 50 g

Theobroma oil 19,950 g

709834/1008 - 15 -

Procedure; ^ 3

The theobroma oil was melted and the N- (1-cyclohexa-1% 4 ^l -dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamido chloride monohydrate was suspended in it. The mixture was then poured into appropriate suppository molds, making 2.0 g suppositories.

EXAMPLE 6

50,000 ampoules each containing 2 mg of N- (1-cyclohexa-1 ·, 4'-dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloriamonohadrate were prepared from the following approach: N- (1 -Cyclohe :: a-1 ', 4'-dienylmethylpiperid-4-yl) -2-methoxy ^ -amino - ^ - chlorbenzaaidhydrochlorid-

monohydrate 100 g

Sodium chloride 500 g

Injection grade water s.cfc. 100 liters

Procedure;

The N- (1-cyclohexa-1 ', 4'-dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate and the sodium chloride in about 80 liters with gentle heating Dissolved in water. The solution was made up to 100 liters with water, passed through a bacteria filter and in known procedure filled in 2 ml glass ampoules. The solution for injection can be prepared under sterile conditions take place. But it is also possible to work under normal conditions and then heat sterilization with the filled ampoules to subjugate.

EXAMPLE 7

1,000 bottles of 150 ml each with 75 mg of N- (1-cyclohexa-1 ·, 4 ^I -dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate were prepared according to the following approach

manufactured: 709834/1008

- 16 -

β *

N- (1-Cyclohexa-1 ·, 4 * -dienylmethylpiperid-4-yl) -2-methoxy 1-4 -amino-S-chlorobenzamide hydrochloride monohydrate 75 g

Sorbitol 70,000 g

Sorbic acid 125 g Citric acid 125 g

distilled water s.q. 150 liters

Flavor q.s.

Procedure:

The N- (1-cyclohexa-1 *, 4 * -dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate and the Sorbic acid was dissolved in 100 liters of water and then the sorbitol, citric acid and flavoring were stirred until added to the solution · The mixture was diluted to 150 liters and distributed on the bottles "

Mixtures similar to those described in Examples 3 to 3 can be prepared if one is considered active Constituents other piperidine derivatives of the general formula (1) than N- (1-cyclohexa-1 ·, 4 * -dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide are used; e.g. other products accordingly of the formula mentioned in Example 1.

The piperidine derivatives of the general formula (4) are new compounds and as such represent a further embodiment of the invention.

-17- 709834/1008

Claims (40)

PATSILT APPLICATIONS Jy piperidine derivatives of the general formula: £ y CONH- (CH ₂ J _x ( N-CH-WI (D (where R stands for a lower alkoxy or a lower one 1 2
Alkenyloxy group; R and R, which can be the same or different, each stand for a hydrogen or halogen atom, a sulfonamide, amino, lower alkylamino, lower dialkylamino, lower alkylsulfonyl or lower alkylsulfonamide group, or a lower acylamino group in which the Acyl moiety is derived from a carboxylic acid, the halogen atom or the group symbolized by R Bind, are in 3- or 4- 1 2 Position of the phenyl ring with the proviso 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 cycloalkyl group. a cycloalkenyl group having 3 to 7 carbon atoms in the ring; R ^ stands for a cycloalkenyl group with 3 to 7 carbon atoms in the ring, '• / optionally substituted with an alkyl group with 1 to 3 carbon atoms or one. Hydroxy (lower) alkyl or alkenyl groups; χ is zero or 1, and W stands for a single bond or a lower alkylene or lower alkenylene group) and their pharmaceutically acceptable acid addition salts, quaternary ammonium derivatives and H-oxides. 709834/1003 - 18 - ORIGINAL INSPECTED 2. Piperidine derivatives according to claim 1, wherein χ is zero and W is a single bond. _r 3. Piperidine derivatives according to claim 1 or 2, in which R is a Kalosenatora or a group as described in Claim 1 is specified, appended to the 4-position of the Phenyl ring. 4. piperidine derivatives according to claim 1, 2 or 3, in which IT "represents the cyclohexa-1,4-dienyl group, optionally substituted with an alkyl group of 1 to 3 carbon atoms. 5. Piperidine derivatives of the general formula: ^r3 ' _C0NII -JjJ _CH ^ ' (2) (where R ¹ stands for a lower alkoxy or allyloxy group, R stands for a hydrogen atom or an amino, lower Alkylamino, di (lower) alfcylamino or a lower acyl amino group, R stands for a halogen atom or an amino, • ζ ι Sulphonamide or lower alkylsulphonyl group, R ^ represents / I a hydrogen atom or a lower alkyl group and R ^ ^- stands for a cycloalkenyl group, optionally substituted with an alkyl group having 1 to 3 carbon atoms) and pharmaceutically acceptable acid addition salts thereof. - 1 ^ 09834/1008 6. piperidine derivatives according to claim 4 _f wherein R ¹ -if a lower alkoxy group- represents methoxy or ethoxy; R (i) - if a lower alkylanino group- for methylamino, (ii) -v / enn a 2i (lower) alkylamino group- for dimethyiamino or (iii) -if a lower acylamino group- for one Oil lower allcanoylamino group; R (i) -if a halogen atom- for Cilor or 3rom or (ii) -v / enn a lower alkyl- ■ z ι sulfonylgruppe- stands for methylsulfonyl-; R ^ -v / enn a low At Alkylgruppe- stands for methyl and R ^ for a cycloalkenyl group is optionally substituted with a methyl group, and their pharmaceutically acceptable acid addition salts. 7. piperidine derivatives according to claim 5 or 6, in which R stands for the acetamide or the trifluoroacetamide group. 8. Piperidine derivatives according to claim 5, 6 or Ί, in which R ^ represents the cyclohexa-1,4-dienyl group, optionally substituted with a methyl group. 9 · piperidine derivatives according to claim 1, in which R. represents a cyclopentenyl, cyclohexadienyl or cycloheptenyl group, or represents a cyclohexenyl group which is optionally substituted in the 4-position with an alkyl group having 1 to 3 carbon atoms or a hydroxy (lower) alkyl or a lower alkenyl group; W stands for a - (CH ₂ ) - group, where y is zero or an integer between 1 and 5. 10. U- (1-Cyclohexa-1 ', 4'-dienylmethylpiperid-4-yl) -2-methoxy-4-ataino-5-chlorobenzamide 70983W1008 - 20 - 27059Ά9 11. N- (1-Cyclohexa-1 ^t , 4 ^t -dienylmethylpiperid-4-yl) -2-methoxy-4-acetamid-5-chlorobenzamide 12. N- (1- (4-Methylcyclohexa-1,4-dienyl) methylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide. 13. N- (1-Cyclohexa-1 «, 4'-dienylEiethylpiperid-4-yl) -2-methoxy-5-methylsulfonylbenzamide # 14. U-Ci-Cyclohexa-I • _f 4 ^t -dienylmethylpiperid-4yl) -2-methoxy-5-clilorbenzainidi 15.N-Ci-Cyclohexa-i '^' - dienylmethylpiperid ^ -yl) ^ - methoxy-4-amino-5-bromobenzamide. 16. N- (1-Cyclob.exa-1 ', 4'-dienylmethylpiperid-4-yl) -2-methoxy-5-sulfonamidobenzamide 17. N-Ci-Ci-cyclohexa-I ^l, 4'-dienyläthyl) piperid-4-7l) -2-methoxy-4-amino-5-chlorobenzamide. 18. N-Ci-Ci-Cyclohexa-I ', 4 ^f -dienylethyl) piperid-4-yl) -2-? Tlioxy-4-acetamid-5-clilorbenzami'd. 19. NOO-Cyclohexa-I ', 4 ^f -dienylethyl) piperid-4-yl) -2-ethoxy-4-amino-5-clilorbejizaiaid 20. N- (1-cyclohexa-1 ^l, 4 ^l -dienylmethylpiperid-4-yl) -2-methoxy-4,5-diaminbenzamid. - 21 - 709834/1008 270b9'49 21. N- (1-Cyclohexa-1 ·, 4 ^f -dienylmethylpiperid-4-yl) -2-methoxy-4-dimethylariino-5-chlorobenzene. 22. N- (1-Cyclohexa-1 », 4'-dienylmethylpiperid-4-yl) -2-methoxy-methylamino-S-chlorobenzamide. 23. N- (1-Cyclohexa-1 ', 4'-dienylmethylpiperid-4-yl) -2-allyloxy-4-amino-5-chlorobenzahide. 24. N-O-Cyclohexa-I, 4'-dienylmethylpiperid-4-yl) -2-ethoxy-4-amino-5-chlorobenzamide. 25. N- (1-Cyclohexa-1 ', 4 ^f -dienylnethylpiperid-4- ^ l) -2-ethoxy-4-acetanide-5-chlorobenzamide. 26. N- (1-Cyclohexen-3'-ylmethylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide. 27. Pharmaceutically acceptable acid addition salts
of each compound according to claims 10 to 26. 28. Pharmaceutically acceptable quaternary ammonium derivatives of each compound according to claims 10 to 26. 29. The N-oxides of each compound according to claim until 26. - 22 - 709834/1008 30. A process for the preparation of a piperidine derivative according to claim 1 characterized by the reaction of a reactive benzoic acid derivative of the general formula: R ² V 'V-COOH (3) (wherein R, R and R v / ie are defined in claim 1) with a Piperidine derivative of the general formula: J _x - / N-CH-W- R " R * wherein the various symbols are as defined in claim 1, 31. A method of preparation according to claim 30, wherein the reactive benzoic acid derivative is a halide Alkyl ester, anhydride, a mixed anhydride or the Ιϊ-imidazole amide bzv /. the acid azide is. 32. A display method according to claim 30 • or 31> in which the reaction takes place in an inert organic solvent at a temperature between -5 ° and 12U ⁰ C is carried out.
ο 33 · A modification of the representation method according to> ^ Claim 30, in which the benzoic acid of the general formula (3) ο with the piperidine derivative of the general formula (4) in Gegeno ° * wart a dehydrating agent is implemented. - 23 - 27Q5949 34. A method of preparation according to claim 33, wherein the dehydrogenating agent is silicon tetrachloride Mono-, di- or trialkylsilyl chloride, titanium tetrachloride, NjN'-dicyclohexyl-carbodiimide, thionyl chloride, sulfur trioxide in dimethyl sulfoxide, tolupl-j ^ sulfonyl chloride, acetone dimethyl acetal or is a polymeric dehydrating agent. 35. A display method according to claim 33 or 34t in which the reaction in an inert organic solvent at a temperature between 20 ° and 110 ⁰ C performed v / ill. 36. A process for the preparation of a piperidine derivative, specified according to claim 1 in the general formula, and its acid addition salt, quaternary ammonium derivative or N-oxide, as essentially described above, with special reference to example 1 37. Pharmaceuticals, as their active ingredient 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 diluent 38. Pharmaceuticals according to claim 37, as essentially described above, with particular reference to Examples 2 to 6. - 24 - 709834/1008 39 Piperidine derivatives of the general formula: H ₂ N- (CH ₂ ) _χ - / N-CH-WR * wherein R · ^, Ä, χ and W are as defined in claim 1. 40.1-Cyclohexa-1, 4'-dienylmethyl-4-aminopiperidine, 1- (4-Methylcyclohexa-i, 4-dienyl) methyl-4-aminopiperidine, 1- (1-Cyclohexa-1, 4'-dienylethyl) -4-aminopiperidine and 1-Cyclohexen-3'-ylmethyl-4-aminopiperidine. - 25 - 709834/1008