CH635585A5 - N-Phenyl-N-(4-piperidinyl)amides, processes for their preparation, and a pharmaceutical composition which contains these compounds - Google Patents

Description

The invention relates to new N-phenyl-N- (4-piperidinyl) amides with a (4,5-dihydro-4-R-5-oxo-1H-tetrazol-1-yl) alkyl or (4 , 5-Dihydro-4-R-5-thioxo-1H-tetrazol-1-yl) -alkyl-substituents in the 1-position of the piperidine nucleus, process for the preparation of these compounds and pharmaceutical compositions with analgesic activity which have at least one active ingredient contain new compound or a pharmaceutically acceptable acid addition salt thereof.

In US-PS 3998834 various analgesically active N-phenyl-N- (4-piperidinyl) amides are described. These compounds differ from the compounds according to the invention essentially in the type of (4,5-dihydro-4-R-5-oxo-1H-tetrazol-1-yl) alkyl or (4,5-dihydro-4 -R-5 - thioxo-1H-tetrazol-1-yl) alkyl radicals in the 1-position of the piperidine nucleus.

The invention relates to N-phenyl-N- (4-piperidinyl) amides of the general formula I.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

635 585

4th

R-N ^ N-CH- (CH,) -CH-

\ / N = N

R

(I)

in which R represents a hydrogen atom or a lower alkyl, C3-C6-cycloalkyl- lower alkenyl, lower alkynyl, lower-alkoxy-lower alkyl, aryl or aryl-lower alkyl radical,

R1 represents a hydrogen atom or an aryl or lower alkyl radical,

R2 is a hydrogen atom or a lower alkyl radical, R3 is a lower alkoxycarbonyl, lower alkoxymethyl

or lower alkylcarbonyl radical,

R4 represents a lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy or arylmethyl radical,

R5 is a hydrogen atom or a lower alkyl radical,

R6 represents a hydrogen or halogen atom, a trifluoromethyl group or a lower alkyl or lower alkoxy radical,

Z is an oxygen or sulfur atom and n has the value 0 or 1, the abovementioned aryl radicals being substituted by phenyl, thienyl, pyridinyl or by 1 or 2 substituents from the series consisting of halogen atoms, trifluoromethyl groups, lower alkyl or lower alkoxy radicals Are phenyl groups, as well as their acid addition salts.

The term “lower alkyl group” includes straight-chain and branched alkyl groups with 1 to 6 carbon atoms, such as the methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl or hexyl group. The term “cycloalkyl radical” encompasses cycloalkyl radicals having 3 to 6 carbon atoms, such as the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group. “Lower alkenyl residues” are preferably understood to mean alkenyl residues with 3 to 6 carbon atoms, such as the 2-propenyl, 2-butenyl, 3-pentenyl and 2-hexenyl groups. The term “lower alkynyl group” includes in particular alkynyl groups with 3 to 6 carbon atoms, such as the 2-propynyl and 2-butynyl groups.

Compounds of formula IA

R-N ^ TT-CK-fCH,) -Ch'-N \ / | 2 a I

N == N R1 i2

(III)

where either X 'is a hydrogen atom and X is a radical of the general formula IV

-CH- (CH2) n-CH-Y R1 R2

(IV)

20 are or X is a hydrogen atom and X1 is a radical of the general formula V

Y-CH- (CH2) n-CH-i!

R1 R2

(V)

30th

and Y represents a reactive ester residue in an inert organic solvent in the presence of a base and any compounds obtained are converted into the corresponding salts.

(IA)

wherein the substituents are described above and acid addition salts of these compounds according to the invention are prepared by using a compound of general formula II

0

11

\ /

it = X

(Ii)

In compounds of formula V, Y is preferably halogen, such as chlorine, bromine or iodine, or a sulfonyloxy group, e.g. Methylsulfonyloxy or 4-methylphenylsulfonyloxy. The implementation is carried out in particular at an elevated temperature.

The reaction of (II) with (III) can be carried out as a conventional N-alkylation. The reaction is preferably carried out in a suitable organic solvent which is inert to the reaction, e.g. an aromatic hydrocarbon such as benzene, methylbenzene or dimethylbenzene, a lower alkanol such as methanol, ethanol, 2-propanol or 1-butanol, a ketone such as 4-methyl-2-pen-tanone, an ether such as 1 , 4-dioxane or diethyl ether, N, N-dimethylformamide or nitrobenzene. 45 The reaction mixture can be mixed with a suitable base, e.g. an alkali metal carbonate or hydrogen carbonate or an organic base such as N, N-diethylethane amine or N- (l-methylethyl) -2-propanamine are added to capture the acid released during the reaction. In some cases it is also advisable to add an iodide, preferably an alkali metal iodide. Slightly elevated temperatures can advantageously be used to increase the reaction rate. In some cases, especially if one of the radicals R1 or R2 is a methyl group and the other a 55 hydrogen atom, a partial rearrangement can occur during the reaction, so that a mixture of positional isomers is formed in which R1 is a methyl group and R2 Hydrogen atom or conversely R1 are a hydrogen atom and R2 is a methyl group. These positional isomers can be separated from one another in the usual way, e.g. by selective crystallization from a suitable solvent system or by column chromatography.

Another process according to the invention for the preparation of the new compounds of the formula IA is based on the N- 5 acylation of compounds of the formula with an N-phenyl-N- (4-piperidinyl) -amide of the general formula III

5

635 585

B-N-S -CH- (CHJ -CH-N

\ / I 2 n I 'N = N I |

R E

(VI)

wherein the substituents are defined above.

The N-acylation can be carried out in a conventional manner, e.g. by reacting (VI) with a suitable acyl halide: R4-CO halogen, e.g. a lower alkylcarbonyl halide, a cycloalkylcarbonylhalide, an arylacetylhalide or a lower alkylcarboxylic acid halide, according to known methods. If R4 is a cycloalkyl or lower alkyl radical, the acylation can also be carried out using an anhydride derived from the acid: R4COOH.

New N-phenyl-N- (4-piperidinyl) amides of the general formula

1

R5

(IB)

-R

iu,

are prepared according to the invention by preparing a compound of the formula IA and then reacting it with a sulfurizing agent while stirring and heating the reactants in an inert organic solvent and, if appropriate, converting the compounds obtained into the corresponding salts. P2S5 is preferred as the sulfurizing agent.

The reaction is usually carried out with stirring and heating the reactants, in an organic solvent inert to the reaction, e.g. an aromatic hydrocarbon such as benzene, methylbenzene or dimethylbenzene.

Compounds of formula (I) in which R is a hydrogen atom are preferably obtained from corresponding compounds (I) in which R is a phenylmethyl group by conventional debenzylation, e.g. by catalytic hydrogenation with a suitable catalyst such as palladium on activated carbon.

In the production processes described above and below, the products isolated from the reaction mixture can, if appropriate, be further purified in the customary manner.

Different compounds of formula (I) have one or more asymmetric carbon atoms and therefore exist in different stereochemically isomeric forms. In particular when R1 or R2 are not hydrogen atoms, the carbon atoms to which they are attached are asymmetrical. Further asymmetric carbon atoms can be present in the lower alkyl radicals R, R3 and R4.

Although mixtures of these stereochemical isomers, e.g. racemic mixtures are obtained, these mixtures can be separated into the stereochemically pure isomeric forms in a conventional manner, e.g. by salt formation with optical isomers of asymmetric acids and selective crystallization of the salts obtained. The stereochemically isomeric forms of the compounds of formula (I) are also the subject of the invention.

Because of their basic properties, the compounds of formula (I) can be converted into acid addition salts, preferably pharmaceutically acceptable salts, by treating them with a suitable acid, e.g. an inorganic 5-acid, such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or an organic acid such as acetic, propionic, hydroxyacetic, 2-hydroxypropionic, 2-oxo-propionic, malonic -, amber, maleic, fumaric, 2-hydroxy-10 amber, 2,3-dihydroxy amber, 2-hydroxy-l, 2,3-propane-tricarbon-, benzoe, 3-phenyl-2- propen, -hydroxybenzene-vinegar, methanesulfone, ethanesulfone, benzenesulfone, 4-methyl-benzenesulfone, cyclohexanesulfamine, -hydroxybenzoic or 4-amino-2-hydroxybenzoic acid. Conversely, the salts 15 can be converted into the free bases by treatment with an alkali base.

The starting compounds of formula (II) in which X is a hydrogen atom (II-a) can be prepared by reacting a suitable isocyanate of formula (VII) or an acyl chloride 20 of formula (VII ') with sodium azide in the presence of aluminum chloride in a suitable one organic solvents, preferably an ether, such as tetrahydrofuran, can be prepared:

25 R = N = C = 0 (VIS

or NaN- / A1C1 «fi

J J ^ ^ -N JtfH

-> R-

R — C

THF

Cl (VII)

N = - N

(Il-a)

40 The reaction is preferably carried out by stirring and heating the reactants in a solvent for several hours. If an acyl chloride of the formula (VIP) is used as reactant, at least 2 molar equivalents of the azide must be used, with the use of a larger excess being generally preferred.

Starting compounds of the formula (II) in which X is a radical of the formula IV (II-b) can be prepared by introducing this radical into corresponding compounds (II-a) by known methods.

50 The following process steps are generally used to prepare the starting compounds (II-b):

a) reacting a suitable compound (II-a) with a haloalkanol of the general formula VIII

Halogen-CH- (CH2) n-CH-OH F I

R1 R2

(VIII) '

by conventional N-alkylation methods and so b) subsequent transfer of the hydroxyl group of the intermediate product of the general formula IX obtained

tf-CH- (CH2) -CH-OH

R

I.

E:

(IX)

635 585

6

into a reactive ester group using conventional methods for the preparation of reactive esters from the corresponding alcohols.

(IX)

O

Formation of the <1

► CHa) n-CK-Y (Il-b)

reactive ester i

Halides can be obtained by reacting (IX) with a halogenating agent, e.g. with sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus penta-bromide or phosphoryl chloride. If the reactive ester is an iodide, it is preferably produced from the corresponding chloride or bromide by exchange for iodine. Reactive sulfonate esters, e.g. Methanesulfonates and 4-methyl-benzenesulfonates are usually prepared by reacting the alcohol with a suitable sulfonyl halide, e.g. with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride.

In the case of compounds (II-b) in which Y is a chlorine atom (II-b-1), the chloroalkyl chain can also be introduced by reacting a suitable compound (Il-a) with a suitable bromochloroalkane derivative of the formula ( X) converted to a corresponding compound (II-b-1) by customary N-alkylation processes.

(Il-a) + ■ Br-ÇH- (CH2) n-ÇH-CI>

Alkylation of a piperidine derivative of the formula (III-a) with a haloalkanol of the formula (XII) and subsequent conversion of the hydroxyl group of the resulting intermediate of the formula (XIII) in the manner described above into a reactive ester group.

R5 r3

HOÇH- (CH) -CH-halogen hnY R

11 '\ A-c-a4

E

1

R

(XII)

'R (Ill-a)

20th

HIGH- (CH2) n -CH-N

E '

TT

(XIII)

f

È

V

Formation of the reactive ester, 5

(X)

Y-CH- (CH2) n-CH-N

(CH2) n-CH-Cl

E

R

E

(III-b)

(II-b-1) 40

Intermediates of formula (XIII) in which n the starting compounds (II-b-1), in which R has no water value 0, are obtained, for example also by reacting (III-a) atom of matter and not a phenyl group, can also be achieved by an appropriately substituted oxirane of the formula XIV

Introduction of the radical R into a precursor of the formula XI

45

0

N-CH- (CH0) -CH-Cl

\ / i L

O

(XI)

50

ch i

R1

ch

É2

(XIV)

getting produced. R is usually introduced by reacting (XI) with a suitable reactive ester: RY by customary N-alkylation processes, where R has the meaning given above, but is not a hydrogen atom or a phenyl group. If Y in the compound RY is an iodine atom, the chlorine substituent of (XI) can be replaced by iodine during the reaction, especially when using excess iodide for alkylation. The preparation of the precursor (XI) is e.g. in Tetrahedron, vol. 31, p. 765 (1975), where compounds of the formula (XI) are mentioned in which R1 and R2 are both hydrogen atoms and n has the value 1.

The starting compounds of formula (III) in which X1 is a hydrogen atom (III-a) can be prepared by the method of U.S. Patent 3,998,834.

The starting compounds of the formula (III) in which X1 is a radical of the formula (V) (III-b) can be prepared by customary N-

In the formula (XIV) if one of the radicals R1 or R2 is a methyl group and the other is a hydrogen atom, essentially an intermediate (XIII) is obtained in which the 55 methyl substituent in the ^ position with respect to the piperidine nitrogen stands. Intermediates of formula (XIII), in which R1 is a phenyl group and n has the value 0, and processes for their preparation are described in US Pat. No. 3,998,834.

60 The reaction of (XIV) with (III-a) is preferably carried out by stirring and heating the reactants in a suitable organic solvent, e.g. an aromatic hydrocarbon such as benzene, methylbenzene or dimethylbenzene, a halogenated hydrocarbon such as dichloromethane or trichloromethane, or a lower alkanol such as methanol, ethanol or 2-propanol, preferably in a mixture of an aromatic hydrocarbon and a lower alkanol. The reaction can be carried out by adding an appropriate one

7

635 585

Acid e.g. an alkali metal carbonate or bicarbonate can be accelerated.

Starting compounds of the formula (III-b) in which Y is a chlorine atom (III-b-1) can also be prepared directly by reacting a compound (III-a) with a bromochloroalkane of the formula (XV) by similar methods implemented as described above in the preparation of starting compounds (II-b-1) from compounds (II-a).

R "

Cl ~ ÇH- (CH2) n-ÇH-3r + (Ill-a) (XV)

K1 R2

Cl-ÇH- (CH2) n-ÇH-N Y "0

^ f NH

(XVI)

(III-b-1)

The starting compounds of the formula (VI) are generally prepared by reacting a reactive ester of the formula (II) in which R is a radical of the formula (IV) with a 4-piperidinamine of the general formula XVI

implemented by methods similar to those described above for the preparation of compounds (I-a) from compounds (II) and (III).

The 4-piperidin-15 amines of the formula (XVI) used as starting compounds can also be prepared by the process of US Pat. No. 3,998,834.

The remaining starting compounds in the individual processes described above are known and can be prepared by known literature processes.

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties. In particular, they are effective morphine-like analgesics and can be used to combat pain in warm-blooded animals.

25 The analgesic properties clearly result from the results of the rat tail test, which is described in “Arzneimittel-Forschung”, vol. 13, p. 502 (1963) and vol. 21, p. 862 (1971). In Table I below, the LEDs, i.e. the minimum dose 30 (mg / kg) required for a 100% effect when given intravenously and the duration of action (min) at the stated dose.

Table I

/ R3

E- \ ö ~? H- (CHaV | H \ Y ff

N = N I 1 i; 2 JÎ-C-R4

CH- (CH2) "- CH

r | | R3 R4 base or salt LED duration of action,

R1 R2 mg / kg s.c. min ch3

ch2-ch2

cooch3

c2h5

(cooh) 2

0.16

39

c2h5

ch2-ch2

COOCH3

c2h5

11/2 (cooh) 2

0.16

19th

nC3H7

ch2-ch2

COOCH3

c2h5

(cooh) 2

0.16

11

iC3H7

ch2-ch2

COOCH3

c2h5

(cooh) 2

2.5

41

ch2-ch2

COOCH3

c2h5

(cooh) 2

2.5

18th

nCsHn ch2-ch2

COOCH3

c2h5 _

(cooh) 2

2.5

20th

ÇLch2.ch2

ch2-ch2

COOCH3

c2H5

(cooh) 2

<0.63

150

©

ch2-ch2

COOCH3

c2h5

(cooh) 2

Sow 10

45

ch3

ch2-ch2

ch2och3

c2h5

(cooh) 2

0.16

31

C2H5

ch2-ch2

ch2och3

C2H5

hci.h2o

0.08

17th

ÌC3H7

ch2-ch2

ch2och3

c2h5

hno3.h2o

0.63

12

c2h5

ch2-ch (ch3)

ch2och3

c2h5

hno3

0.16

13

c6h5

ch2-ch (ch3)

ch2och3

C2Hs hno3

10th

14

c2h5

ch2-ch2-ch2

ch2och3

c2h5

hc1.1 / 2h20

2.5

14

365 585

In preferred compounds of formula (I), R is a lower alkyl radical. These preferred compounds are potent, short-acting analgesics that offer particular advantages in the short-term control of acute severe pain, e.g. in anesthesia.

Because of their analgesic effect, the compounds according to the invention can be formulated into various pharmaceutical forms of administration. The medicaments of the invention contain an analgesically effective amount of the compounds according to the invention in the form of the free base or a pharmaceutically acceptable acid addition salt as active ingredient in combination with conventional carriers, the nature of which depends on the dosage form. The drugs are preferably formulated into dosage units, e.g. are suitable for oral, rectal or parenteral administration. For the preparation of oral dosage forms e.g. Common pharmaceutical media are used, such as water, glycols, oils or alcohols in the case of liquid oral preparations, e.g. Suspensions, syrups, elixirs or solutions, or solid carriers such as starch, sugar, kaolin, lubricants, binders and release agents in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units that are usually made using solid pharmaceutical carriers. Parenteral administration forms usually contain at least a large part of sterile water as a carrier, but other components, e.g. Solubilizers to be included. Injection solutions can e.g. with saline, glucose solution or a mixture of saline and glucose solutions as a carrier. Injectable suspensions can be made using suitable liquid carriers, suspending agents, etc. Since the acid addition salts have increased water solubility compared to the free bases, they are more suitable for the preparation of aqueous preparations.

The pharmaceutical compositions of the invention are preferably formulated into dosage units to facilitate administration and uniformity of dosage. Dosage units are understood to be physically separate units, each of which, in combination with the required pharmaceutical carrier, contain a sufficient amount of active ingredient in order to achieve the desired therapeutic effect. Examples of these dosage units are tablets (including notched or coated tablets), capsules, pills, powder preparations, waffles, injection solutions or suspensions, drop solutions and corresponding multiple preparations.

For preventive or therapeutic pain relief in warm-blooded animals, the active compounds according to the invention can be administered within wide dosage limits, depending on the circumstances of the individual case. A dose of about 0.01 to 1 mg / kg administered once or several times has generally been found to be effective.

The examples illustrate the invention. All parts are by weight unless otherwise stated.

example 1

A stirred mixture of 14.2 parts of ethyl isocyanate, 29.2 parts of sodium azide and 135 parts of anhydrous tetrahydrofuran is mixed with a solution of 39 parts of aluminum chloride in 225 parts of anhydrous tetrahydrofuran. Stirring is continued overnight at reflux temperature. The reaction mixture is then cooled and acidified with 6N hydrochloric acid. The product obtained by evaporation to dryness is extracted four times with 2-propanol, after which the combined extracts are dried, filtered and evaporated. The residue is dried overnight, 18

Parts (65%) of l-ethyl-1, 4-dihydro-5H-tetrazol-5-one are obtained.

Example 2

The following compounds are prepared according to the procedure of Example 1 using equivalent amounts of cyclohexyl isocyanate or 2-propyl isocyanate: 1-cyclohexyl-1,4-dihydro-5H-tetrazol-5-one and 1,4-dihydro-1- (l-methylethyl) -5H-tetrazol-5-one as a residue.

Example 3

990 parts of tetrahydrofuran, which are cooled in an ice bath, are mixed in batches with 156 parts of aluminum chloride, whereupon the mixture is stirred vigorously until all the solids are dissolved. The solution is then quickly added to a stirred suspension of 208 parts of sodium azide in 225 parts of tetrahydrofuran and stirred at reflux temperature for a further 1 hour. After cooling to room temperature, a solution of 54 parts of butanoyl chloride in 225 parts of tetrahydrofuran is added dropwise at a temperature below 30 ° C. The mixture is slowly heated to reflux temperature and stirred overnight at this temperature. With simultaneous cooling, the reaction mixture is then acidified with 800 parts of 6N hydrochloric acid and the solvent is evaporated off. The residue is stirred in sodium hydrogen carbonate solution and trichloromethane is added. The layers are then separated, the aqueous phase is acidified with concentrated hydrochloric acid and the solvent is evaporated off. The residue is stirred in 2-propanone, whereupon the precipitate is filtered off and the filtrate is evaporated. 32 parts of 1,4-dihydro-l-propyl-5H-tetrazol-5-one are obtained as a residue.

Example 4

Following the procedure of Example 3, the following compounds are prepared using equivalent amounts of suitable acyl chlorides: 1- (1,1-dimethylethyl) -1,4-dihydro-5H-tetrazol-5-one as residue;

1,4-dihydro-l-pentyl-5H-tetrazol-5-one; 1,4-dihydro-1- (2-phenylethyl) -5H-tetrazol-5-one as a solid residue;

1,4-dihydro-1- (phenylmethyl) -5H-tetrazol-5-one; Mp 152 ° C; and l-cyclopropyl-l, 4-dihydro-5H-tetrazol-5-one; F. 128 ° C.

Example 5

A mixture of 22 parts l-ethyl-l, 4-dihydro-5H-tetra-zol-5-one, 45 parts l-bromo-2-chloroethane, 26 parts sodium carbonate, 0.3 parts potassium iodide and 240 parts 4 -Methyl - 2-pentanone is stirred with a water separator under reflux overnight. The reaction mixture is then cooled, water is added and the layers are separated. The aqueous phase is extracted three times with dichloromethane, whereupon the combined organic phases are dried, filtered and evaporated. The residue is chromatographed on silica gel with trichloromethane as the eluent. The pure fractions are collected and the eluent is evaporated, giving 28.4 parts (80%) of 1- (2-chloroethyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one as a residue .

Example 6

Following the procedure of Example 5 using equivalent amounts of suitable 1,4-dihydro-5H-tetrazole-5-ones or suitable bromochloroalkanes, the following 1 - (chloroalkyl) -l, 4-dihydro-5H-tetrazole-5 -one received as a backlog:

l- (2-chloroethyl) -l, 4-dihydro-4-propyl-5H-tetrazol-5-one;

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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635 585

1 - (2-chloroethyl) -1,4-dihydro-4- (1-methylethyl) -5H-tetrazole - 5-one;

1 - (2-chloroethyl) -4- (l, 1-dimethylethyl) -l, 4-dihydro-5H-tetrazole - 5-one;

1 - (2-chloroethyl) -1,4-dihydro-4-pentyl-5H-tetrazol-5-one;

1- (2-chloroethyI) -4-cyclohexyI-l, 4-dihydro-5H-tetrazol-5-one; 1 - (2-chloroethyl) -1,4-dihydro-4- (2-phenylethyl) -5H-tetrazole-

-5-on;

1 - (3-chloropropyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one; 1 - (2-chloroethyl) -1,4-dihydro-4- (phenylmethyl) -5H-tetrazole - 5-one and

1 - (2-chloroethyl) -4-cyclopropyl-l, 4-dihydro-5H-tetrazol-5-one. Example 7

A mixture of 49 parts methyl iodide, 10.5 parts l- (2-chloroethyl) -l, 4-dihydro-5H-tetrazol-5-one, 15 parts sodium carbonate, 0.2 parts potassium iodide and 240 parts 4- Methyl-2-pentanone is stirred with a water separator under reflux overnight. The reaction mixture is then cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with dichloromethane, whereupon the combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography on silica gel with trichloromethane as the eluent. The pure fractions are collected and the eluent is evaporated, 15 parts (85%) of 1,4-dihydro-1- (2-iodoethy]) - 4-methyl-5H-tetrazol-5-one being obtained as a residue .

Example 8

A mixture of 19.6 parts of [2- (2-thienyl) ethyl] -4-methyl-benzenesulfonate, 10 parts of l- (2-chloroethyl) -l, 4-dihydro-5H - tetrazol-5-one, 10 parts of sodium carbonate and 90 parts of N, N-dimethylformamide are stirred at 70 ° C. overnight. The reaction mixture is then cooled, 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column chromatography on silica gel with trichloromethane / petroleum ether (volume ratio 70:30) as the eluent. By collecting the pure fractions and evaporating the eluent, 15 parts (46.5%) of l- (2-chloroethyl) -l, 4-dihydro-4- [2- (2-thie-nyl) -ethyl] -5H are obtained -tetrazol-5-one as residue.

Example 9

4.5 parts of sulfinyl chloride are added dropwise with a mixture of 13 parts of N- [l- (2-hydroxy-2-phenylethyl) -4 - (methoxymethyl) -4-piperidinyl] -M-phenylpropanamide hydrochloride and 260 parts Dichloromethane added. The mixture is then stirred under reflux for a few hours, then cooled and the solvent is evaporated off. The backlog is in

2-propanone was added, whereupon the mixture was filtered and the filtrate was treated with activated carbon. After the activated carbon has been filtered off, the filtrate is evaporated, the residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, the product is filtered off and dried, 9.2 parts (61.7%) of N- [1- (2-chloro-2-phenylethyl) -4- (methoxy-methyl) -4-piperidinyl] -N-phenylpropanamide monohydrochloride;

F. 145.3 ° C can be obtained.

Example 10

A mixture of 35 parts of 2-methyloxirane, 83 parts of N- [4 - (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide, 25 parts of sodium hydrogen carbonate, 450 parts of benzene and 80 parts of methanol is stirred under reflux overnight. The reaction mixture is then evaporated and the residue is taken up in water. The product is extracted with trichloromethane, after which the extract is dried, filtered and evaporated. The residue is converted into the hydrochloride in 2-propanol, which is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, whereby 41.5 parts (37%) of N- [l- (2nd -Hydroxypropyl) -4- (methoxy-methyl) -4-piperidinyl] -N-phenylpropanamide monohydrochloride.

14 parts of sulfinyl chloride are stirred and a dropwise solution of 37 parts of N- [l- (2-hydroxypropyl) -4 - (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide mono-hydrochloride in 360 parts of dichloromethane is added. The mixture is then stirred at reflux overnight, the reaction mixture is then evaporated and the residue is suspended in 2-propanone. Filtering and drying the product gives 31.5 parts (85%) of N- [l- (2-chloropropyl) -4 - (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide monohydrochloride.

Example 11

A mixture of 1.8 parts of 1- (2-chloro-4-ethyl-1, 4-di-hydro-5H-tetrazol-5-one, 3.45 parts of N- [4- (methoxymethyl) -4 --piperidinyI] -N-phenylpropanamide, 5 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2-pentanone are stirred under reflux overnight with a water separator, the reaction mixture is poured into water and the layers separated. The organic phase is dried, filtered and evaporated, the residue is then purified by column chromatography on silica gel with trichloromethane / methanol (volume ratio 97: 3) as the eluent, the pure fractions are collected and the eluent is evaporated off 2-Propanone is converted into the hydrochloride, which is filtered off and crystallized from 2-propanone, 1.5 parts (33.3%) of N-îl- [2 - (4-ethyl-4,5-dihydro-5- oxo-lH-tetrazol-l-yl) ethyl] -4- (meth-oxymethyl) -4-piperidinyl] -N-phenyIpropanamide monohydrochloride monohydrate, mp 140.8 ° C.

Example 12

Following the procedure of Example 11, using equivalent amounts of suitable starting compounds and treating the free bases with suitable acids, the following compounds are prepared as acid addition salts:

N- [1- [2- (4,5-Dihydro-5-oxo-4-propyl-1H-tetrazol-1-yl) ethyl] - 4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide -oxa-lat (1: 2) monohydrate; M. 103.8 ° C;

N- [l-! 2- [4,5-Dihydro- (l-methylethyl) -5-oxo-lH-tetrazol-l-yl] - ethyl] -4- (methoxymethyl) -4-piperidinyl] -N -phenylpropane amide mononitrate monohydrate; M. 104.5 ° C; 1- [2-! 4,5-Dihydro-5-oxo-4- [2- (2-thienyl) ethyl] -1H-tetrazoI-1-yl] ethyl] -4 - [(1-oxopropyl ) -phenylamino] -4-piperidine-carbonic acid methyl ester oxalate (1: 1); M. 162.9 ° C; N- [l- [3- (4-ethyl-4,5-dihydro-5-oxo-lH-tetrazol-l-yl) propyl] - 4- (methoxymethyl) -4-piperidinyli-N-phenylpropanamide- hydrochloride hemihydrate; Mp 182 ° C; and N- [l-] 2- [4,5-dihydro-5-oxo-4- (phenylmethyl) -lH-tetrazol-l-yl] ethyl] -4- (methoxymethyl) -4-piperidinyl] -N -phenylpropanamide oxalate (1: 1); M. 166.4 ° C.

Example 13

A mixture of 3.6 parts of 1- (2-chloroethyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 6.4 parts of 4- [N- (l-oxopropyl) -N --phenylamino] -4-piperidinecarboxylic acid methyl ester hydrochloride, 4 parts of sodium carbonate, 0.1 part of potassium iodide and 240 parts of 4-methyl-2-pentanone are stirred with a water separator under reflux overnight. The reaction mixture is then cooled and poured into water. The organic phase is separated off, dried, filtered and evaporated, whereupon the residue is purified by column chromatography

5

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65

635 585

10th

Clean silica gel with trichloromethane / methanol (volume ratio 97: 3) as eluent. The residue obtained by collecting the pure fractions and evaporating the eluent is converted into 2-propanone in the oxalate, which is filtered off and dried, and 1.5 parts (13%) of l- [2- (4 - ethyl-4, 5-dihydro-5-oxo-lH-tetrazol-l-yl) ethyl] -4 - [(l-oxo-propyl) phenylamino] -4-piperidinecarboxylic acid methyl ester oxa lat (2: 3); Mp 158.9 ° C.

Example 14

The following oxalates are prepared according to the procedure of Example 13 using equivalent amounts of suitable starting compounds: 1- [2- (4,5-dihydro-5-oxo-4-propyl-1H-tetrazol-1-yl) ethyl] - 4 - [(l-oxopropyl) phenylamino] -4-piperidinecarboxylic acid methyl ester oxalate (1: 1); M. 168.4 ° C;

l-i2- [4,5-Dihydro-4- (l-methylethyl) -5-oxo-lH-tetrazol-l-yl] - ethylj-4 - [(l-oxopropyl) phenylamino] -4-piperidinecarboxylic acid methyl ester oxalate (1: 1); M. 184.2 ° C;

l-: 2- [4- (l, dimethylethyl) -4,5-dihydro-5-oxo-lH-tetrazoI-l-yl] - ethyl] -4 - [(l-oxopropyl) phenylamino] -4 -piperidinecarboxylic acid methyl ester oxalate (1: 1); M. 168.1 ° C;

1- [2- (4,5-Dihydro-5-oxo-4-pentyl-lH-tetrazoI-l-yl) ethyl] -4 - [(l - oxopropyl) phenylamino] -4-piperidinecarboxylic acid methyl ester oxalate (1: 1); F. 153.5 ° C;

1- [2- (4-Cyclohexyl-4,5-dihydro-5-oxo-lH-tetrazol-l-yl) ethyl] -4 - [(l-oxopropyl) phenylamino] -4-piperidinecarboxylic acid, methyl ester oxalate (1: 1); Mp 173 ° C;

l-; 2- [4,5-Dihydro-5-oxo-4- (2-phenylethyl) -lH-tetrazol-l-yl] - ethylj-4 - [(l-oxopropyl) phenylamino] -4- piperidinecarboxylic acid methyl ester oxalate (2: 3); M. 162.2 ° C; l-: 2- [4,5-Dihydro-5-oxo-4- (phenylmethyl) -lH-tetrazol-l-yl] - ethylj-4 - [(l-oxopropyl) phenylamino] -4-piperidinecarboxylic acid- methyl ester oxalate (1: 1); M. 191.7 ° C;

1- [2- (4-Cyclopropyl) -4,5-dihydro-5-oxo-lH-tetrazol-l-yl) ethyl] - 4 - [(l-oxopropyl) phenylamino] -4-piperidinecarboxylic acid - ethyl ester oxalate (2: 3) hemihydrate; M. 155.9 ° C, and l- [2- (4-ethyl-4,5-dihydro-5-oxo-lH-tetrazol-l-yl) ethyl] -4 - (phenylamino) -4- methyl piperidinecarboxylate oxalate (2: 3); F. 172 ° C.

Example 15

A mixture of 2.55 parts of 1,4-dihydro-1- (2-iodoethyl) -4-methyl-5H-tetrazol-5-one, 3.45 parts of N- [4- (methoxymethyl) -4- piperidinyl] -N-phenylpropanamide, 2 parts of sodium carbonate, 0.2 part of potassium iodide and 160 parts of 4-methyl-2-penta-non is stirred with a water separator under reflux overnight. The reaction mixture is then cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with dichloromethane, whereupon the combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography on silica gel with trichloromethane / methanol (volume ratio 97: 3) as the eluent. The pure fractions are collected and the eluent is evaporated, whereupon the residue is converted into 2-propanone in the oxalate, which is filtered off and crystallized from 2-propanone. 2.1 parts (42%) of N-II- [2- (4,5-dihydro-4-methyl-5-oxo - 1H-tetrazol-1-yl) ethyl] -4- (methoxymethyl) -4-piperidinyl3-N-phenylpropanamide oxalate (1: 1); M. 155.9 ° C.

Example 16

Following the procedure of Example 15, 1- [2- (4,5-di-hydro-4-methyl-5-oxo-1H-tetrazol-1-yl) ethyl-4 - [(1-oxopropyl) - phenylamino] -4-piperidinecarboxylic acid methyl ester oxalate (1: 1); M. 185.9 ° C; prepared by reacting 1,4-dihydro-1- (2-iodoethyl) -4-methyl-5H-tetrazol-5-one with 4 - [(1- oxopropyl) phenylamino] -4-piperidinecarboxylic acid methyl ester.

Example 17

A mixture of 3 parts of l-ethyl-1,4-dihydro-5H-tetrazol-5-one, 9.4 parts of N- [l- (2-chloropropyl) -4- (methoxymethyl) -4: -piperidinyl] -N-phenylpropanamide, 2.5 parts of sodium carbonate, 2.5 parts of N, N-diethylethamine and 90 parts of N, N-dimethylformamide is stirred at 70 ° C. overnight. The reaction mixture is then cooled, 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated, whereupon the residue is purified twice by column chromatography on silica gel, the first time with trichloromethane / methanol (volume ratio 97: 3) and then with ethyl acetate / ethanol (volume ratio 99: 1) as eluent. The residue obtained by collecting the pure fractions and evaporating the eluent is converted to the hydrochloride in 2-propanone and 2,2'-oxybispropane, which is filtered off and dried, and 2.1 parts (18%) of N- [l- [ 2- (4-ethyl-4,5-dihydro-5-oxo-1 H-tetrazol-1-yl) -1-methylethyl] -4- (methoxymethyl) -4-piperidinyl3-N-phenylpropanamide monohydrochloride; F. 185.4 ° C.

Example 18

A mixture of 1.2 parts of l-ethyl-l, 4-dihydro-5H-tetra-zol-5-one, 3.9 parts of N- [l- (2-chloropropyl) -4- (methoxymethyl) - 4 -piperidinyl] -N-phenylpropanamide monohydrochloride, 2 parts of sodium carbonate, 0.1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred with a water separator under reflux overnight. The reaction mixture is then cooled, poured into water and the layers are separated. The organic phase is dried, filtered and evaporated, whereupon the residue is purified by column chromatography on silica gel with trichloromethane / methanol (volume ratio 99: 1) as the eluent, the residue obtained by collecting the pure fractions and evaporating the eluent is dissolved in 2-propanone in the nitrate is transferred, which is filtered off and crystallized twice, first from 2,2'-oxybispropane and 2-propanone and then from 2-propanone. This gives 1.5 parts (30%) of N- [l- [2- (4 - ethyl-4,5-dihydro-5-oxo-1 H-tetrazol-l-yl) -l-methylethyl] -4 - (methoxymethyl) -4-piperidinyl3-N-phenylpropanamide mono-nitrate; M. 146.6 ° C.

Example 19

Following the procedure of Example 18, N- [1- [2- (4,5-di-hydro-5-oxo-4-phenyl-1H-tetrazol-1-yl) -l-methylethyl] -4- (meth -oxymethyl) -4-piperidinyl] -N-phenylpropanamide mononitrate; F. 151.2 ° C, by reacting 1,4-dihydro-l-phenyl-5H - tetrazol-5-one with N- [l- (2-chloropropyl) -4- (methoxymethyl) -4-- piperidinyl] -N-phenylpropanamide monohydrochloride.

Example 20

A mixture of 3 parts of l-ethyl-l, 4-dihydro-5H-tetrazol-5-one, 8 parts of N- [l- (2-chloro-2-phenylethyl) -4- (methoxy-methyl) -4 -piperidinyl] -N-phenylpropanamide, 0.2 part of potassium iodide, 5 parts of sodium carbonate and 135 parts of N, N-dimethylformamide is stirred at 70 ° C. overnight. The reaction mixture is then cooled to room temperature and 150 parts of water are added. The product is extracted three times with methylbenzene, after which the combined extracts are dried, filtered and evaporated. The solid residue is purified by column chromatography on silica gel with trichloromethane / methanol (volume ratio 97: 3) as the eluent. The residue obtained by collecting the pure fractions and evaporating the eluent is crystallized from petroleum ether / 2,2'-oxybispropane. Filtration and drying of the product gives 5.7 parts (65%) of N- {1 - [2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) -2 -phenylethyl] -

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635 585

-4- (methoxymethyl) -4-piperidinyl) -N-phenylpropanamide; F. 125.7 ° C.

Example 21

A mixture of 3 parts of l-ethyl-1, 4-dihydro-5H-tetrazol-5 -5-one, 9.4 parts of N- [l- (2-chloropropyl) -4- (methoxymethyl) -4 - piperidinyl ] -N-phenylpropanamide monohydrochloride, 25 parts of N, N-diethylethanolamine, 2.5 parts of sodium carbonate and 90 parts of N, N-dimethylformamide is stirred at 70 ° C. overnight. The reaction mixture is then cooled, 10 parts of 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated, whereupon the residue is purified twice by column chromatography on silica gel, the first time then using trichloromethane / methanol ('5 97: 3 by volume) and then using ethyl acetate / ethanol (99: 1 by volume) Eluent. The residue obtained by collecting the pure fractions and evaporating the eluent is converted into the hydrochloride in 2-propanone and 2,2'-oxybispropane, which is filtered off and dried, and 3.9 20 parts (33.4%) N -fl- [2- (4-ethyl-4,5-dihydro-5-oxo-lH-tetrazole-

25th

-l-yl) propyl] -4- (methoxymethyl) -4-piperidinyl] -N-phenylpro-panamide monohydrochloride; Mp 192.7 ° C.

Example 22

A mixture of 5.7 parts of l- [2- (4-ethyl-4,5-dihydro-5 - oxo-lH-tetrazol-l-yl) ethyl] -4- (phenylamino) -4-piperidine car- bonsäuremethyester, 1.9 parts of cyclopropanecarbonyl chloride, 2.7 parts of N, N-diethylethanolamine and 68 parts of methylbenzene is stirred under reflux overnight. The reaction mixture is then cooled, 100 parts of water are added and the layers are separated. The organic phase is dried, filtered and evaporated, whereupon the residue is purified by column chromatography on silica gel with trichloromethane / methanol (volume ratio 98: 2) as the eluent. The pure fractions are collected and treated with 1 part of oxalic acid. The resulting oxalate is filtered off and crystallized from 2-propanone / 2,2'-oxybispropane, 1.5 parts (1.5%) of 4 - [(cyclopropylcarbonyl) phenylamino] -l- [2- (4 - ethyl -4,5-dihydro-5-oxo-1 H-tetrazol-1-yl) ethyl] -4-piperidine-carboxylic acid methyl ester oxalate (2: 3); F. 181.5 ° C, can be obtained.

Example 23

The following compounds of the formula I are prepared according to the processes described above using suitable starting compounds:

H Z n R1 R2 R3 R4 R5 R6

h o

0

h h

cooch3

C2H5

h h

H

S

1

h h

COOCH3

c2h5

h h

H

0

0

h h

ch2och3

ch3

3-ch3

H

0

0

h h

cooc2h5

c2h5

h h

ch2 = ch-ch2

0

0

h h

COOC2H5

c2h5

h h

ch2 = ch-ch2

0

0

h h

coch3

C2H5

h h

ch = c-ch2

0

0

h h

cooc2h5

C2H5

h h

c2h5o-ch2ch2

0

0

h h

COOQjHJ

c2Hj h

H

4-Cl-C6h4

0

0

h h

COCH3

c2h5

h h

2-f-QH4

0

0

h h

coch3

c2h5

3-ch

4-c1

4-ch3-c6h4

0

0

h h

cooch3

C3H7

H

4-c1

2,4- (ch30) 2-c6h3

0

0

h h

ch2och3

C2H5

H

4-f

3- (cf3) -c6h4

0

0

H

H

COOC2H5

ch3

3-ch3

3-CF3

4-Cl-C6H4-CH2

0

0

H

H

COOCH3

>

H

H

2- (thienyl) ethyl

0

0

H

H

COOCH3

ch2-ch = ch2

H

H

2- (pyridinyl) ethyl

0

0

H

H

coch3

oc2h5

H

4-CH3

C2H5

S

1

H

H

CCOCH3

ch2-c6h5

H

4-OCH3

Claims (11)

635 585 2. N-! 1 - [2- (4-Ethyl-4,5-dihydro-5-oxo-lH-tetrazol-l -yl) - ethyl] -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide and its acid addition salts as a connection according to claim 1. 2nd PATENT CLAIMS 1. N-phenyl-N- (4-piperidinyl) -amides of the general formula I 3rd 635 585 -CH- (CH-) -CH-N R-N T-C-R " in which R represents a hydrogen atom or a lower alkyl, C3-C6-cycloalkyl- lower alkenyl, lower alkynyl, lower-alkoxy-lower alkyl, aryl or aryl-lower alkyl radical, R1 represents a hydrogen atom or an aryl or lower alkyl radical, R2 is a hydrogen atom or a lower alkyl radical, R3 is a lower alkoxycarbonyl, lower alkoxymethyl or lower alkylcarbonyl radical, R4 represents a lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy or arylmethyl radical, R5 is a hydrogen atom or a lower alkyl radical, R6 represents a hydrogen or halogen atom, a trifluoromethyl group or a lower alkyl or lower alkoxy radical, and n the value 0 or 1, the above-mentioned aryl radicals being phenyl, thienyl, pyridinyl or phenyl groups substituted by 1 or 2 substituents from the series consisting of halogen atoms, trifluoromethyl groups, lower alkyl or lower alkoxy radicals, and their acid addition salts, characterized in that a compound of general formula VI R5 R-N '^ N-CH-CCHj -CH-NTY (VI) \ / I 2 n I WW correspondingly N-acylated and compounds obtained optionally converted into the corresponding salts. 3. l- [2- (4,5-Dihydro-4-methyl-5-oxo-lH-tetrazol-l-yl) - ethyl] -4 - [(l-oxopropyl) phenylamino] -4-piperidinecarboxylic acid methyl ester and its acid addition salts as a compound according to claim 1. 4. l- [2- (4-ethyl-4,5-dihydro-5-oxo-lH-tetrazol-l-yl) ethyl] - 4 - [(l-oxopropyl) phenylamino] -4-piperidinecarboxylic acid methyl -ester and its acid addition salts as a compound according to claim 1. 5 • R W N = N CH- (CH2) n- CH ■ ÓC in which R represents a hydrogen atom or a lower alkyl, C3-C6-cycloalkyl, lower alkenyl, lower alkynyl, lower-alkoxy-lower alkyl, aryl or aryl-lower alkyl radical, s R1 represents a hydrogen atom or an aryl or lower alkyl radical, R2 is a hydrogen atom or a lower alkyl radical, R3 represents a lower alkoxycarbonyl, lower alkoxymethyl or lower alkylcarbonyl radical, io R4 represents a lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy or arylmethyl radical, R5 is a hydrogen atom or a lower alkyl radical, R6 represents a hydrogen or halogen atom, a trifhiormethyl group or a lower alkyl or lower alkoxy radical, and n the value 0 or 1, the above-mentioned aryl radicals being phenyl, thienyl, pyridinyl or phenyl groups substituted by 1 or 2 substituents from the series consisting of halogen atoms, trifluoromethyl groups, lower 20 alkyl or lower alkoxy radicals, and their acid addition salts, characterized in that a compound of general formula II (II) N = N ) with an N-phenyl-N- (4-piperidinyl) -amide of the general formula III x1 (III) 45 where either X1 is a hydrogen atom and X is a radical of the general formula IV 50 -CH- (CN2) n-CH-Y I i R1 R2 (IV) or X is a hydrogen atom and X1 is a radical of the general formula V 55 Y-CH- (CH2) n-CH-R1 R2 (V) (IA) are and Y represents a reactive ester radical, in an inert organic solvent in the presence of a base to convert and optionally obtained compounds are converted into the corresponding salts. 5. 1 - [2- (4,5-Dihydro-5-oxo-4-propyl-1 H-tetrazol-1-yl) - ethyl] -4 - [(l-oxopropyl) phenylamino] -4- piperidinecarboxylic acid methyl ester and its acid addition salts as a compound according to claim 1. , 5th (I) in which R represents a hydrogen atom or a lower alkyl, C3-C6-cycloalkyl- lower alkenyl, lower alkynyl, lower-alkoxy-lower alkyl, aryl or aryl-lower alkyl radical, R R2 R3 R4 represents a hydrogen atom or an aryl or lower alkyl radical, is a hydrogen atom or a lower alkyl radical, represents a lower alkoxycarbonyl, lower alkoxymethyl or lower alkylcarbonyl radical, represents a lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy or arylmethyl radical, R5 is a hydrogen atom or a lower alkyl radical, R6 represents a hydrogen or halogen atom, a trifluoromethyl group or a lower alkyl or lower alkoxy radical, Z is an oxygen or sulfur atom and n has the value 0 or 1, the abovementioned aryl radicals being substituted by phenyl, thienyl, pyridinyl or by 1 or 2 substituents from the series consisting of halogen atoms, trifluoromethyl groups, lower alkyl or lower alkoxy radicals Are phenyl groups, and their acid addition salts. 6. N-; 1 - [(4,5-Dihydro-4-methyl-5-oxo-1 H-tetrazol-1-yl) - ethyl] -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide and its acid addition salts as A compound according to claim 1. 7. N-il- [2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) -l - methylethyl] -4- (methoxymethyl) -4-piperidinyl] - N-phenylpro-panamide and its acid addition salts as a compound according to claim 1. 8. Process for the preparation of new N-phenyl-N- (4-piperidinyl) amides of the general formula IA 9. Process for the preparation of new N-phenyl-N- (4-piperidinyl) amides of the general formula I 65 • R 10. Process for the preparation of new N-phenyl-N- (4-pipe-ridinyl) -amides of the general formula R5 3 S I R K "OC ff m N = N * 'i2 ^" 6 kXR in which R represents a hydrogen atom or a lower alkyl, C3-C6-cycloalkyl- lower alkenyl, lower alkynyl, lower-alkoxy-lower alkyl, aryl or aryl-lower alkyl radical, R1 represents a hydrogen atom or an aryl or lower alkyl radical, R2 is a hydrogen atom or a lower alkyl radical, R3 is a lower alkoxycarbonyl, lower alkoxymethyl or lower alkylcarbonyl radical, R4 represents a lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy or arylmethyl radical, R5 is a hydrogen atom or a lower alkyl radical, R6 is a hydrogen or halogen atom, a trifluoromethyl group or a lower alkyl or lower alkoxy radical, and n has the value 0 or 1, the above-mentioned aryl radicals phenyl, thienyl, pyridinyl or with 1 or 2 substituents from the series of halogen atoms, trifluoromethyl groups Alkyl or lower alkoxy radicals are substituted phenyl groups, characterized in that a compound of the formula IA is prepared by the process according to claim 9 and this is then reacted with a sulfurizing agent with stirring and heating of the reactants in an inert organic solvent, and any compounds obtained are also obtained converted into the corresponding salts. 11. Pharmaceutical composition with analgesic action, characterized in that it contains at least one new N-phenyl-N- (4-piperidinyl) -amide of the general formula I as active ingredient n -CH- (CH) -CH-N R-N -C-R * in which R represents a hydrogen atom or a lower alkyl, C3-C6-cycloalkyl- lower alkenyl, lower alkynyl, lower-alkoxy-lower alkyl, aryl or aryl-lower alkyl radical, R1 represents a hydrogen atom or an aryl or lower alkyl radical, R2 is a hydrogen atom or a lower alkyl radical, R3 is a lower alkoxycarbonyl, lower alkoxymethyl or lower alkylcarbonyl radical, R4 represents a lower alkyl, cycloalkyl, lower alkenyl, lower alkoxy or arylmethyl radical, R5 is a hydrogen atom or a lower alkyl radical, R6 represents a hydrogen or halogen atom, a trifluoromethyl group or a lower alkyl or lower alkoxy radical, Z is an oxygen or sulfur atom and n has the value 0 or 1, the abovementioned aryl radicals being substituted by phenyl, thienyl, pyridinyl or by 1 or 2 substituents from the series consisting of halogen atoms, trifluoromethyl groups, lower alkyl or lower alkoxy radicals Are phenyl groups, or contains a pharmaceutically acceptable acid addition salt thereof.