CS222663B2 - Method of making the new n-aryl-n-/4-piperidyl/-arylacetamide - Google Patents

Abstract

N-Aryl-N-(4-piperidinyl)arylacetamides of the formula <IMAGE> and their salts with acids, the substituents in the formula being defined in Claim 1, are prepared. These compounds are obtained by acylating corresponding piperidine derivatives with an arylacetyl halide. The resulting compounds can be used for the drug therapy of cardiac arrhythmias.

Description

Process for the preparation of the novel N-aayl-N- (piperidyl) aryaaceaaeides of the general formula I <X ^X , (I)

N - CO — СНч — Ar l ^Z

Ar te is carried out according to the invention by te acylating a compound of formula VI

Ar (VI) arylactylhaorone free formula (VII)

NO. 1

Halogen-C-Cl ₂ -Ar 1 '(VI) in a suitable inert organic solvent, preferably in the presence of a blend, whereupon it optionally prepares it with physiologically harmless addition salts of the final acid reaction products.

The compounds of formula (I) and their physiologically acceptable acid addition salts have remarkable antiarrhythmic properties and are therefore useful as medicaments for normalizing the irregular heartbeat.

The invention relates to processes for the preparation of N-aryl-N- (4-piperidyl) arylacetamides.

Some N-aryl-N- (4-piperazines) are known in the art, and many such compounds can be found in therapeutic sources such as e.g. , U.S. Patent No. 3,164,600 and C.A, 77, 34, 349a (1972).

The antiarrhythmic compounds produced by the process of the invention differ, inter alia, from such known compounds by the nature of the arylacetamide group attached at the 4-position of the piperidine core.

The novel N-aryl-N- (4-piperidyl) arylacetools produced by the process of the invention are characterized by the general formula I

Ar (I) in which

Ar is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, cyclopropylmethyl or propejinyl, represents phenyl, mono- or disubstituted phenyl, pyrtdyl or 2-prrimidinyl, each substituent in said mono - or the disubsubstituted phenyl group is independently selected from the group consisting of halogen and a C 1 -C 6 -alkyl group, meaning a phenyl group, a mono- or di-substituted phenyl group or a thienyl group, each substituent in said mono- or disubstituted phenyl group being independently selected from the group consisting of (halogen-containing, methyl and methoxy), is hydrogen or C1-C2-alkyloxy (1-aryl).

The invention also includes physiologically non-acidic acid addition salts derived from compounds of formula I.

In the general formula, the ^C 1 ^-C 10 -alkyl group for L includes straight and branched chain residues such as, for example, methyl, ethyl, 1-methyl-ethyl, propyl, 1-methylpropyl, butyl, 2-methylbutyl, 1H-dimethylethyl, pentyl , password, heptyl, decyl / like alkyl groups.

For Ar and X, the C 1 -C 6 -alkyl group includes a methyl / ethyl group, the C 1 -C 8 -cycloalkyl group refers to cyclic hydrocarbon radicals having 5 to 6 carbon atoms, ie, cyclopentyl / cyclohexyl groups and halogen is a generic term for halogens having an atomic hmoonoot of less than 127, i.e. fluorine, chlorine, bromine and iodine.

The process for the preparation of the compounds of the formula I according to the invention consists in acylating a compound of the formula VI in which:

Ar (Vt)

L, Ar and X mm (as defined above), (ethyl) cetyl and O-thenooro (VII)

Halogen-C-CH 2 -Ar (VI) wherein

Ar ¹ is as defined above, in a suitable reaction-inert organic solvent, preferably in the presence of a base, whereupon physiologically acceptable acid addition salts of the final reaction products are optionally prepared.

The acylation of the compound of formula VI is carried out by known N-acylation methods, for example by stirring and refluxing a mixture of the reactants under reflux in a suitable inert organic solvent, preferably in the presence of a suitable base. Suitable solvents that can be used include, for example, aromatic hydrocarbons such as benzene, toluene and xylene and halogenated hydrocarbons such as trichloromethane. Suitable bases are, for example, alkali metal carbonates and bicarbonates, alkali metal amides such as sodium amide, and organic bases such as pyridine and N, N-diethyleneamine.

The compounds of the formula I prepared according to the invention can be converted into physiologically acceptable acid addition salts by reaction with suitable acids, for example an inorganic acid such as a hydrohalic acid such as hydrochloric or hydrobromic acid and the like, sulfuric, nitric, phosphoric and the like. or with an organic acid such as acetic, propanoic, 2-hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z) -2-butenedioic, (E) -2-butenedioic, 2-hydroxybutanedioic, 2 , 3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic, alpha-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-aminobenzoic -2-hydroxybenzoate Vou _T and the like acids. Conversely, the salt may be converted into the free base by treatment with bases.

The starting compounds for the process according to the invention of the general formula VI in which X represents a hydrogen atom (VI-а) are readily prepared from the starting compound of the following general formula ΙΙ-a by first deprotecting P in a conventional manner to give N-aryl-4- of the piperidine amine of the above formula (IX) and then introducing the L-substituent. These reactions are illustrated by the scheme:

removal of P

IAr introduction of L

I Ar

Ar (II-8l) (XI) (VI-a)

In addition to L in the compounds of formula VI, a methyl group (VI-a-1) can be obtained directly by reduction of a compound of formula ΙΙ-a in which P represents up to a C8-alkoxycarbonyl group (II-a-2) by a suitable reducing an agent such as lithium aluminum hydride. These reactions are further illustrated by the scheme:

LiAIH ₄ ° ^η 3- € Χ

Г

Ar (VI-a-2)

The starting compounds for the process according to the invention of the general formula VI, in which X represents a Oj to C8-alkyloxycarbonyl group, are prepared preferably by introducing an L-group into a compound of formula XIX which can be obtained from a compound of formula II-b-1 according to the scheme:

hydrogen Pd on coal

(Ш)

The compounds of formula I and their physiologically acceptable salts have excellent antiarrhythmic properties and as such are useful in normalizing the irregular heartbeat.

The antiarrhythmic effect of the compounds of the invention is illustrated by the following experiment in dogs: The test is performed under neuroleptanalgesia (1 ml phenanthyl per 10 kg body weight (0.4 mg / ml) and droperodol (20 mg / ml)). 16 hours after ligation of the anterior descending branch of the left coronary artery, dogs exhibit multifocal ventricular arrhythmia.

Test compounds were administered intravenously after a control period of 30 minutes, using the following criteria for evaluation:

no effect + reduction of premature pulse rate and increase of normal pulse rate by at least 30% compared to control value.

++ Reduce premature heart rate and increase normal heart rate by at least 50% compared to control value.

+++ normalization of cardiac rhythm or reduction of premature pulse rate and increase of normal pulse rate by at least 75% compared to control value.

The results obtained in this experiment are given in Tables I and II below. The compounds disclosed herein are not intended to limit the invention not only to the listed substances, but only to demonstrate the antiarrhythmic properties of all compounds within the scope of Formula I.

Table I

L Ar Ar ¹ Base or salt Antiarrhythmic effect in dogs 2.5 mg / kg 5 mg / kg -ch ₃ 4-Cl-C ₆ H ₄ ^C 6 ^H 5 base ++ - “ ^C 2 ^H 5 4-Cl-C ₆ H ₄ ^C 6 ^H 5 HCl +++ -nC ₃ H _? 4-Cl-C ₆ H ₄ ^C 6 ^H 5 HCl - +++ -iCjH, 4-Cl-C ₆ H ₄ ^C 6 ^H 5 HCl ++ +++ -nC ₄ H ₉ 4-Cl-C ₆ H ₄ ^C 6 ^H 5 HCl ++ ++ -CH-CH 3 -CH 2 f ^{2 3} CH ₃ 4-Cl-C ₆ H ₄ ^C 6 ^H 5 HCl 0 ++ ~ ^nC 6 ^H 13 4-Cl _4-CGH ^C 6 ^H 5 HCl 0 +++ -CH ₂ <] 4-Cl-C ₆ H ₄ ^C 6 ^H 5 HCl ++ +++

continuation of Table

L Ar Ar ¹ Base or salt Antiarrhythmic effect in dogs 2.5 m ^ kg 5 mg / kg Ό 4-Cl-C ₆ H ₅ С _б Нб base + ++ -iC ₃ H ₇ 4-FC ₆ H ₃ ^С 6 ^Н6 base + ++ -iC ₃ H ₇ S-Cl- ^С бНб. base ++ - ³ -Cl · ^^ С _б Нб HCl + ++ - ^iC 3 ^H7 4-Cl-C _b H ₄ 4-F- ^C ₆ H ⁴ HCl ++ ++ -1C ₃ ^H7 4-С1-С _б Н4 N-Cl-Cl base +++ - ^IC3I 3 4-Cl-C6H4 3-Cl-C6H4 base ++ +++ -iC ₃ H ₇ 4-С) .- ^ СбН4 4-С. ^ С _б Н4 base + ++ -Cl3H7 4-С1- ^ СбН4 3,4- (С.) ₂ ^ С ₆ Н3 base ++ +++ -1C3H7 4-С1- ^ СбН4 4-ВГ-С6Н4 base + ++ - ^iC3H ? 4- ^С 1- ^СбН4 3-с ^н г ^с 6 ^ин ₄ HCl '+ ++ - ^CC A 4-Cl-C6H4 4- ^СН3 ' ^С 6 ^Н 4 HCl ++ ++ ^-iC3H ? 4-Cl-C6H4 3-ССН3-С6Н3 base ++ +++ -i ^ ⁷ 2,6 - (<С.) _{Г -СбНз} 4-0.-0 ^ 4 base ++ - - ^ ⁷ 3,4 (С1) ₂ -С ₆ Нз СбНб HCl + +++ - ^iC3H ? 3,4- (С1) ₂ -СбНз 4-С1-С6Н ₄ HCl + ++ - ^с л 4-В ^ -С _б Н4 СбНб base ++ ++ - ^iC3 » ⁷ 2,6- (СНз) ₂ -СбНз ^С Л HCl ++ ++ ^{-I C 3 H 7} 2-С1,6-СН3-СН3 СбНб HCl ++ - -XC3H7 2, б- (СНз) ₂ -С ₆ Нз 4-С1-С6Н4 HCl ++ +++ <] 4-Cl-C6H4 4-FC ₆ ^H ₃ base ++ ++ -and ⁴ -С1-С _б ^Н4 4-С1-С6Н ₄ base + ++ 0 4-С1-С ₆ Н4 3- ^СН _Г ^С б ^Н4 base + ‘+++ Ό 4-С1-С _б Н4 4- ^СН3 - ^С 6 ^Н 4 HCl ++ ++ 4] 4-С1-СбН ₄ 3-ССН3-С6Н3 base ++ - * ^C 2 ^H 5 4-Cl-C6H4 4-FC ₆ H ₃ base + +++ - ^C 2 ^H 5 4-C1O ^^ Нд 3- ^СН3 - ^С6Н ₄ base ++ +++ -c ₂ h ₅ 4-С1-С6Н4 4-С3-С ₆ Н ₄ base + ++ ^C 2 ^H 5 ⁴ - ^С 1- ^С ₆ Н ⁴ 3-ocH 3 -C ₆ H ₄ base +, +++ -CzHj 2,6- (СН ₃ ) ₂ -СбН3 ^СбНб base ++ ++ -ПС3Н7 2, й-СН ₃ ) ₂ -СбН3 СбНб (CCOH) ₂ ++ +++

continuation of Table

. L Ar Ar ¹ Base or salt Antiarrhythmic effect in dogs 2.5 mg / kg 5 mg / kg -1C ₃ H ₇ ^C 6 ^H 5 з-сн ₃ -с ₆ ин ₄ HCl +++ - -Ό ^C 6 ^H 5 ^C 6 ^H 5 base ++ +++ -Ό ^C 6 ^H 5 3-ci-c ₆ h ₄ base +++ - -Ώ ^C 6 ^H 5 4-Cl-C ₆ H ₄ base + +++ ^C 6 ^H 5 3-ci-c ₆ h ₄ HCl ++ ♦ ++ ^C 2 ^H 5 4-Cl-C ₆ H ₄ 13 HCl 0 ++ -nCl 2 Hy 4-Cl-C ₆ H ₄ 13 , HCl + ++ -CH ₂ -CH = CH. ₂ 4-Cl-C ₆ H ₄ 13 HCl 0 ++ -nC ₃ H ₇ 2,6- (CH ₃ ) ₂ -C ₆ H ₃ 13 (C00H) ₂ ++ ++ -iC ₃ H ₇ ^C 6 ^H 5 (COOH) ₂ + +++ <1 ^C 6 ^H 5 13 base +++ - -1C ₃ H _? 4-Cl-C ₆ H ₄ 13 HCl ++ +++ -iCjl 2,6- (CH ₃ ) ₂ -C ₆ H ₃ 13 HCl ++ ♦ +

continuation of Table

Base or salt

2.5 mg / kg 5 mg / kg

Ar

Aitiarythmic effect in dogs

-C 1 H ^y

-cy ^; 7 <]

-Ώ ^ 7 ^-1C r ^{7 -1C} 3 ^H 7 <]

M

C6H5 base ++ ++

3-Cl-C6H4

4-Cl-C ₆ H ₄

C ^6H5

4-Cl-C6H4

3- ^C Hr ^C 6 H ₄

C6H5

З-С1-С6Н3

4-Cl-C ₆ H ₄

3- ^{CH 3 -C} 6 ^H 4

3-C 6 H ₄ Cl-based base (C00H) ₂ Base Base Base Base Base Base Base

HCl. 1/2 HgO base

HOOCCH = CHCOOH з-сн _г с _б н ₄

H 4-Cl-C6H4 C6H5 HCl H 2-Cl- _C6 H4 <^ 5 base H 4- ^ 64 4-F-C 6 H 4 base

+++ ++ ++ ++ ++ ++ ++ ++ ++

+++ ++ ++ +++ ++ ++ ++ ++ ++ +++ ++ +++ ++ ++ ++ Table I continued

L Ar Ar ' Base or salt Anti arrhythmic effect in dogs 2.5 mg / kg 5 mg / kg H 4-Cl-C ₆ H ₄ з- (осн ₃ ) -с ₆ и ₄ base + ++ (+) H 4-Cl-C ₆ H ₄ 2-Cl-C ₆ H ₄ base + ++ (+)

Table II

L X Ar ¹ Base or salt Antiarrhythmic effect in dogs 2.5 mg / kg 5 mg / kg O COOCH ₃ 3-Cl-C ₆ H ₄ base + ++ [> COOC ₂ H ₅ 3-Cl-C ₆ H ₄ HOOC-CH = CH-COOH + ++ [> COOC ₂ H ₅ 4-Cl-C ₆ H ₄ HOOC-CH = CH-COOH 0 ++ O COOC ₂ H ₅ 3-ch ₃ -c ₆ h ₄ HOOC-CH = H-COOH ++ +++ -1C ₃ H ₇ CH ₂ -OCH ₃ ^C 6 ^H 5 HCl ++ ++ (+)

The following examples illustrate the invention but do not limit it. Unless otherwise indicated, all parts herein are by weight.

Example 1

To a stirred mixture of 58 parts of 4 - [[4-chlorophenyl / amino] -1-piperidinecarboxylic acid ethyl ester in 240 parts of benzene was added dropwise a solution of 46.2 g of benzeneacetyl chloride in 80 parts of benzene at a temperature ranging from 40 to 70 ° C. After completion of the dropwise addition, the reaction mixture was stirred and refluxed for 6 hours and 15 minutes. The reaction mixture was then cooled and filtered. The filtrate was washed repeatedly with water, sodium bicarbonate solution and water, then dried and evaporated in vacuo. The residue is crystallized from 1,1'-oxybisethane to give 47 parts of [N- (4-chlorophenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylic acid ethyl ester. Melting point: 108 ° C.

Example 2

Method of Example 1 and using the appropriate equivalent amount of an appropriate ethyl 4-arylamino-1-pipericiOnkarbuxylové and suitable arylacetylchluridu instead etyletteru Selin k ^{y y} ^ [/ ^ - ^ сНогГегц ашСо] -L-piperiiHk rboxyLové and benoθnoac ^ ^e y ^y ch ^h ori ^d u used in the above example, te prepared:

II ch ₃ -ch ₂ -oc-

H

O

II,

NC-CH3-Ar ¹

Ar

Ar --- Melting point 2,6- (CH ₃₎ 2 -C ₆ H ₃ 2-thienyl 94.5 Noc: 2 ° C 4-Cl-C5H4 2-thitoyl 98 ^, 5 Noc: 2 ° C 4-01- ^ 4-Cl-C ₆ H ₄ 127.5 Noc: 2 ° C 4-Cl-C ₆ H ₄ 4- ^ch 3- ^c 6 ^h ₄ 112.5 Noc: 2 ° C 2-Cl- _C6 H4 c ₆ h ₅ 123 ^ Noc: 2 ° C 2-Cl, 6-CH ₃ -C ₆ H ₃ c ₆ h ₅ • 114 ^ Noc: 2 ° C 4-FC ₆ ^H3 CgH ₅ 82.0 Noc: 2 ° C 3,4- (Cl) 2 -C ₆ H ₃ C ₆ H ₅ 115 ^ Noc: 2 ° C 3-01- ^ C ₆ H ₅ 92.0 Noc: 2 ° C 4-01- ^ 4-F- ^C _fi ^H4 109.0 Noc: 2 ° C 4-C.- _C6 H4 3- ^{CH 3 -C} 6 ^H 4 121.5 Noc: 2 ° C 4-Br-C ₆ H ₄ C6H5 114Д Noc: 2 ° C 4-Cl-C 6 H ⁴ _3- OCH ₃ -C ₆ H ₄ 121.2 Noc: 2 ° C 4-Cl ^4-CGH 2-Cl-C ₆ H ₄ 139.3 Noc: 2 ° C 4-Cl _4-CGH 3-Cl-C ₆ H ₄ 142.7 Noc: 2 ° C 2-Cl, 6-CH ₃ -C ₆ H ₃ 4- ^{C 1 -C} 6 ^H 4 95.6 Noc: 2 ° C 4-C.-C ₆ H ₄ 2,6- (CH 3) ₂ -C ₆ H ₃ 120.4 Noc: 2 ° C 3,4- (Cl) 2-C ₈ H ₃ 4-Cl-C ₆ H ₄ 136 ^ Noc: 2 ° C 2,5- (CL) gC ₆ H ₃ 4-Cl-C ₆ H ₄ D7 ^, 0 Noc: 2 ° C 2,6- (Cl) ₂ -C ₆ H ₃ 4-Cl-C ₆ H ₄ 140 ^ Noc: 2 ° C

Example 3

К a stirred solution of 8 (HLU et ^y tyseliny ester of 4- ^{[[(2, t} ime ^and б- yl ^{tu f l)} aainoJ-1-p ^p ρptiiiokarboxylové in 4 parts of pyridine and 80 parts of benzene was added dropwise a solution of 7.7 parts of Benzenactyl chloride in 40 ml of benzene After completion of the dropwise addition, the reaction safe was returned to reflux and stirred at this temperature for 3 hours 45 minutes.

The reaction mixture was cooled and filtered. The benzene phase is washed with water and then with sodium bicarbonate solution and water. Evaporation gave an oily residue which solidified on trituration with ^p se ^ ^d to 5 ^{d, Lu} et ^yl ester 4 - [(N / 2 б ^а di-ee ^y lfθI ^about Уlí ^-

-N- (phenylecetyl) amino-1-piperidinecarboxylic acid. Melting point: 106 ° C.

Example 4

To a stirred solution of ¹⁵ parts of 4 - [(4-chlorophenyl) amino-1-piperidin-1 H-boxylic acid ethyl ester, 5,4 parts of Ν, Ν-diethylenettenamine and 160 parts of benzene, and 11.07 parts of 4-n-methoxybenzenac ^c butyl chloride ^thereof toplotě ^{32 u} at ⁴⁰ ° C National Coordinator. ^p ^ PRIK completion of the reaction mixture was stirred n boiled under reflux for 3 hours. The reaction mixture was cooled and filtered. The filtrate was washed repeatedly with water, sodium bicarbonate and water, filtered and evaporated in vacuo. The oily residue was crystallized from a mixture of 56 parts of 11-hexybenzoate and 40 parts of hexane. The crude solid was oddiltruje and recrystallized from a mixture of benzene and 1,1 '-oxybisethane, yielding ³ and ^{t d} I ^ ^ly etyestoru ^SEH-4 - [N- ^{(4-c h} lor ⁱ e ⁿ yl) -N- / ^(4-n metoxyfet T) ^e yl ACE / imino-piperldinkarbox ⁰ -1 ^{y é} hunting. Melting point: P7 ° C.

Example 5

A mixture of 4.5 parts of N- (1-cyclopentyl-4-piperidyl) -2-pyrimidnyphaimine, 3.4 parts of 3-methylbenzeneacetyl chloride, 2 parts of NaH2O4 in sodium and 180 parts of dimethylbenzene is stirred and boiled under stirring. A further 9 parts of 3-hydroxybenzylethyl chloride are added dropwise. After completion of the addition, stirring and refluxing is continued for '67 hours. The reaction mixture was cooled, water was added and the layers were separated. The orgard phase is extracted with dilute hydrochloric acid solution. The combined aqueous phases were washed with benzene and basified with dilute sodium hydroxide solution while cooling in an ice bath. The product was extracted twice with trichomeomeney. The combined extracts were dried, filtered and filtered. The residue is converted into the oxalate salt in 2-propanol. Iittrací salt was obtained and crystallized twice: first from - ethanol then mmeanolu, yielding 1 part F ^ avelmu 'N- (1-cykloppetyll4 pPpeerdyl) -3-Уθeyl- ^N - ^(2-p riyidtnyl ^{y) e} tzntnacntayi ^d u. Toning temperature: 204 ° C.

Example 6

By the method of Example a5 and the use of equivalent mm mm ^ of the appropriate N-errl-4-pipenidylamine and suitable as starting compounds, the following compounds were obtained in the form of a base or in an acid addition salt form after treatment with a suitable acid:

O,

Ar

L Ar Ar ' Base or salt ..Melting point O ³ -pyridyl ^C 6 ^H 5 (E) -2-butenedioate 2U ^, 6 ° C O ³ -pyridyl 3-CH ³ -c ₆ H ₄ (E) -2-butenedioate 250.3 ° C D- 2-pyridyl 3-CL-e ₆ H ₄ (C00H) ₂ 205.9 ° C O 2-pyridyl 3-3-C ₆ H ₄ base 107.8 ° C 2-pyridyl 4-Cl-C ₆ H ₄ base 119.2 ° C O 2-pyridyl 2-thienyl base 129.4 ° C 2-pyridyl ^C 6 ^H 5 base 108.8 ° C d- 2-pyrimidinyl ^C 6 H ₅ (COOH) ₂ ^223, 5 ° C

continued table

L Ar Ar ¹ Base or salt Melting point (СНз) ₂ -СН- 3-pyridyl Сб ^Н 5 base 129.4 ° С (СН ₃ ) ₂ -СН- 3-pyridyl 4-С1-С _б Н ₄ base 117.7 ° С. (СНз ^ -СН-) 3-pyridyl 4-С1-С _б Н ₄ · base 1-46.6 ° С (СНз ^ -СН 3-pyridyl 2-thienyl base 126.7 ° С (СНз) 2-СН- 3-pyridyl 3-СН ₃ -С _б Н4 base 100 ° С (СНз ^ -СН-) 2-pyridyl 3-С1-С ₆ Н4 base 102.6 ° С (СНз ^ -СН-) 2-pyridyl Сб ^Н 5 base 72.1 ° С (СНз) 2-С ^^ 2-pyridyl 4-С1-С6Н4 base 83.3 ° С (СНз) 2-С ^^ 2-pyridyl 3 - ^ - ^ ⁴ (С00Н) ₂ 190.6 ° С (СНз ^ -СН-) 2-pyridyl 2-thlenyl (COOH) ₂ 196.1 ° С (СН ₃ ) ₂ -СН- 2-pyrimidinyl 4-С1-СбЙ4 (COOH) ₂ 195.7 ° С

Example 7

A mixture of 5 parts of alkyl Betylesteru ^Selin y 1 "(1-metyD-4- (FEIYA ^am i ⁿ o) -4-piperidyl] kcerboxylové, 24 parts of 4-chlorbtnz <fincefylchloridu, 4 parts of sodium carbonate and 180 parts of dimethylbenzene was stirred and heated The reaction mixture was cooled, washed with dilute sodium hydroxide solution and extracted with dilute hydrochloric acid: three layers were obtained.The oil and aqueous phase were combined and made alkaline with dilute sodium hydroxide solution. The extract is washed with water, dried, filtered and evaporated, the residue is taken up in 2-propanol to the cellic acid salt, and the salt is obtained by filtration and crystallized from a mixture of 2-propanol and 2,2-propanol. There was obtained 5 parts of S-velan (48%) methyl [N-chlorophenyl] phenyl-N-phenylamino-1- (1-methyl-ethyl-4-piperidicarboxylic acid) methylphosphoric acid, m.p. 154.2 °. Deň: 32 ° C.

rung d 8

Using the method of Example 7 and employing equivalent amounts of the appropriate 4-arylmino-4-piperidinecarbonyl salt and the appropriate methylcetyl chloride as starting material, the following compounds are obtained in the free base form or in acid addition salt form after treatment with the appropriate acid:

O

-R

-СН2-АГ ¹

L Ar ¹ (B) Base or salt Melting point (CH ₃ ) ₂ -CH- 3- ^СНз - ^С б ^Н 5 ^C 2 ^H 5 (COOH) 2 198.4 ° С (снз) ₁ -сн- c ₆ H ₅ С2Н5 (E) -2-butenedioate 168.5 ° С (СНз) 2-СН- 2-thienil С2Н5 (С0О1) ₂ 156.8 ° С (CH ₃ ) ₂ -CH- 4-С1-С ₆ Н ₄ c ₂ h ₅ НС1 191.5 ° С (CH ₃ ) ₂ -CH- 4-СН ₃ -С _б Н ₄ CH ₃ (С00Н) ₂ 170 ° С _(CH3) j-CH 3-С1-р. ₆ Н ₅ CH ₃ (С00Н) ₂ 152.2 ° С (СНз) 2-СН- С _{6 and 5} . CH ₃ (С00Н) ₂ 165.5 ° С (СНз) 2-СН- 2-thL.enil CH ₃ (COOH) 2 173.6 ° С O- 4-С1-С _б Н4 ^C 2 ^H 5 (E) -2-butenedioate 195.6 ° С from _{6 to 5} С2Н5 (E) -2-butenedioate 203.3 ° С 3-Cl-C ₆ H ₄ ^C 2 ^H 5 (E, .alpha.-butenedioate 207.8 ° С D- 3- ^CH 3 -C 6 ^H 4 C2H5 (EJ-α-butenedioate 188.1 ° С O C ₆ H ₅ СН ₃ (С00Н) ₂ 197.2 ° С 2-thienylX CH ₃ (С00Н) ₂ 166.4 ° С O 3-01- ^ ⁴ CH ₃ base 94 ° С O 3- ^Н 3- ^С 6 ^Н4 СН ₃ (С00Н> 2 189.5 ° С

Example 9.

To a stirred mixture of 4.4 parts of 1- (1-methylethyl) -N-phenyl-4-piperidylminine, 5.3 parts of sodium carbonate and 180 parts of benzene was added 5 parts of benennactyl chloride. After dripping, stirring and refluxing are continued overnight. The reaction mixture was cooled, washed repeatedly with water and sodium hydroxide and again with water, dried, filtered and evaporated. The residue is converted to the hydrocchoride in a mixture of 2,2% -O-methyl-2-ananole. The resulting salt was filtered off and crystallized from a mixture of N, N-oxibispropane to give 2.5 parts.

N-El-methyl-H-III) - L-Гpdldyl] ^L -eifebn nθeiencneaamidhldrochlorLdu. Melting point: 184.4 ° C.

Example 10

Using the method of Example 9 and using equivalent amounts of the appropriate N-aryl-4-piperidylamine and the appropriate arylacetyl chloride as starting materials, the title compound is obtained as a base or as an acid addition salt after treatment with a suitable acid.

O c, ⁴ - 'NC-CH3-Ar'

Ar

L Ar. Ar ’ Base or salt Melting point (CH-Jg-CH- C ₆ ^H 5 3- ^ch ₃ -c ₆ h ₄ HCl 173.6 ° C (CH ₃ ) ₂ --CH ₂ - C ₆ ^H 5 3-Cl-C 6 H ₅ HCl 204.8 ⁰ <3 (CH ₃₎ 2 CH- c ₆ H ₅ 2-thienyl (E) -2-butenedioate 1613.1 ° C CH ₃ 2,6- (CH ₃ ) ₂ -C ₆ H ₃ Dl base 95.5 ° C 0H ₃ 4- ^C l- ^{C 6 H} ₄ base 115 ° c ^C 2 ^H 5 4-Cl-C 6 H ₄ 3-0CH 3 -C 6 H 4 base 90.7 ° C nC ^ y 2,6- (CH 3) ₂ -C ₆ H ₃ 2-thienyl (C00H) ₂ 153 [deg.] C ^nC 3 ^H 7 2,6- (CH ₃ ) ₂ -C ₆ H ₃ C6H5 (C00H) ₂ 161 ° C ch ₂ = ch-ch ₂ 4-Cl-C6H4 2-thienyl HCl 227.5 ° C O D- c ₆ h ₅ 4-Cl- _C6 H4 base 12 °, 1 ° C C6H5 ³ - ^CH 3 ^C 6 ^{H 4} (E) -2-butenedioate 161.3 ° C D- C6H5 2-thienyl base 119 ⁰ C O CgH, > -cl-c ₆ h ₄ base 121.8 ° C □> - C ₆ H ₅ ^C 6 H ₅ base 139.8 ⁰ C D- O 3-pyridyl 4-C1-C.H- base 149.9 ° C 3-pyridyl 3-Cl- _C6 H4 2 HCl. 1/2 HgO 236.6 ⁰ C O 3-pyridyl 2-thienyl base 159.8 ° C ^C 6 ^H 5 4-Cl-C6H4 HCl 265.8 ° C O ^c ó ^H ₅ 3-Cl- _C6 H4 HCl 255.4 ° C

Example 11

A suspension of 1.25 parts of sodium amide in 56 parts of benzene is stirred under a nitrogen atmosphere and heated to ⁴⁰ ° C. Then added dropwise ^to a ^p ZTO ^profiles 6 ^D I N-Ce-chloro-Orfei-D-toh-meeyletyl) -4-piperidinylamino in 56 parts of benzene. After the addition, the reaction mixture was stirred and refluxed for 16 hours 45 minutes. The mixture was cooled to 25 ° C and then 7.8 parts of 3-chlorobenzylethychloride in 88 parts of benzene were added. After stirring and refluxing for an additional 2 hours, the reaction mixture was cooled and 80 parts of water were added. The reaction mixture was acidified with dilute hydrochloric acid. The aqueous acidic phase was quenched with sodium hydroxide solution and the free base was extracted with ethyl acetate (100 ml). The extract was dried, filtered and evaporated. The solution is cooled to ^-10 ° C overnight, filtered from impurities and the filtrate is re-evaporated. The residue is dissolved in 120 parts of 1, (* - oxybis), clarified with charcoal, filtered and evaporated. ^ i. ^ t ^d consequential changes to ^the PARC ^ talus from hexane ^p s temperature - ¹⁰ ° C, ^C is IMZ získaáí ² 2 ^d d ^{LD 3, and} 4 ^h ic lor-N- (4-c ^h lot ^phenyl) -N- [1-. ¹ l dodeca ^{dl td} No. l) - i ^p i eri ^{d No.} yl] ^No eneenlcetacHďu. Melting Toni ^101.7 ° C.

Example 12

By the method of Example 11 and using the starting materials of the appropriate nitro piperidine amine and the appropriate arylacetyl chloride as starting materials, the following compounds were obtained in the form of a base or in the form of an acid addition salt after treatment with an appropriate acid.

4-Br ^tt l N- ^(4-n chloofee l) -] - [. 1-11metylčtyl) - ^- ip ^and č®iidyl beneenacetaíi ^{i e,} mp 118.1 ° C ^{4-Chloro -} - (2 ^O -cHmety ^ ery].) - ^- -TL - (1 -mýto those ^yl) M- ^ Perit 1] ^No bčnzennčc hydгothloti ea ^{md i,} mp 268.2 ° C ^- - ^{(^} ^ ^chtorlfen) - ^- - ⁽ -metytotyl ¹⁾ - ^- - ^f! - (tometydetyl ^ - ^ l ^ rityl] benzo · nnčcčald.d, mp 104.9 ° C.

Example 13

A mixture of 5 parts by weight of (phenylamine) -1- (phenylethyl) ^-4- piperidinecarboxylic acid and 600 parts of concentrated hydrochloric acid was refluxed for 16 hours. After cooling, the reaction mixture was concentrated in vacuo to a volume of 400 parts, then a precipitate formed which was filtered, washed with water and 2-propanone to give 43 parts of 4- (1-dimethylamino) -1- (trifluoromethyl) hydrochloride. Melting point: 261-263 ° C (decomp)

A mixture of 19 parts of 4- iihyirochltriiu (fendlníino) - (- (fenylíečyl) ^p --- pP erddiketrUxylové acid, 14.4 parts of sulfuric acid and 64 parts člnnoisl ·. · Was stirred and refluxed for 16 hours. Rozppuutědlo with dekannuje. burst the residue in water. _ voďi solution was basified with NH₄OH and extracted with íítylbčnzčnu and 2,2'-oxybispropane. the combined organic layers were SUEi magnesium sulfate, filtered and pm-l. the oily residue is rozpuutí ^{200 d h} ILEC ^2,2 ooxyb ^with ipoopnnu and to the solution ^p UVEE 13nmý chloride. Excluded Nu ^ hydrocciorid the Oddi-LT ^ is rubs 2 - ^ (^^ 10 ^ filtered again and was dried to give

11.5 parts of ethyl 4- (phenylamino) - (phenyl) -4-piperidinylbenzyl ester. Melting Toni ^{212 21} 4.4 ° C.

To a stirred and refluxed solution of 1.4 parts of ethyl 4- (phenylamino) -1- (phenylethyl) -4-piperidinecarboxylic acid ethyl ester in 640 parts of dry benzene was added dropwise a solution of 172 parts of ethyl-bi- (2-piperidinyl) Sodium difluoride in 70% benzene solution in 160 parts dry benzene.

^p is a strictly pokrajuje with stirring for ^{2 h} Odin 3 ⁰ minutes at te ^p lotto ⁸⁰ ° C. The aqueous mixture was cooled, poured into ice water, basified with sodium hydroxide solution and the product was extracted into benzene. The extract was washed twice with water, dried, fixed and filtered. The residue is taken up in 1-propanediol (1,1'-oxybisulfate) to 1: 1 (2-propanol). The salt is obtained by filtration, boiled in 2-propianol and after cooling the product oOdilltujč.

It is boiled again in acetonitrile and the salt is filtered again after cooling. The free bases are released in the usual manner. After extraction into 1,1'-oxybisethane, it is washed with water, dried and evaporated to give 56.6 parts of 4 '(itylamino) -O- (eenylmethyl) -4-piperidinylmethyl] as an oily residue.

To a solution of 32 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperphenyniethanol in 90 parts of benzene was added 0.2 parts of Ν, Ν, tre-triethylethylamine and 150 parts of 60% sodium hydroxide solution. With vigorous stirring, 10.9 parts of dimethylsulphide are added dropwise at a temperature below 30 ° C. After the addition, stirring is continued at room temperature first for 2 hours 30 minutes, then after the addition of a second sub-portion of 2.6 parts of the dimethylsulfate for 1 hour 30 minutes. The reaction mixture was cooled with ice water and 200 parts of water were added. The organic phase is subtracted and the aqueous phase is extracted into benzene. The organic phase combined was washed with water, dried, filtered and washed. The residue was purified by column chromatography on silica gel using a mixture of trechdomane and 3% ammonia saturated methanol as eluent. The pure fractions were collected and the eluent was evaporated to give 24.8 parts of 4- (yetoxymethyl) -N-phenyl-1- (phenylmethyl) -4-piperidine residue.

A mixture of 10 parts of 4- (yetoacetyl) -N-phenyl-1- (phenylyl) -4-piperiddylamine. and 200 parts of acetic acid are hydrogenated at atmospheric pressure and at room temperature with 2 parts of 10% catalyst on carbon. After the calculated hydrogen had been consumed, the catalyst was removed and the filtrate was evaporated. The oily residue was dissolved in water, cooled and basified with ammonium hydroxide. The product was extracted into trichloroethane. The extract was washed with water, dried, filtered and evaporated. The oily residue is purified by column chromatography. on silica gel using 90:10 ethanol / methanol saturated ammonia as eluent. The pure fraction was collected and the eluent was evaporated to give 4.5 parts of 4 - (((-? - (1) - (0-1) - N - ennl-4-aiatridyaine) as an oily residue).

A mixture of 10 parts of ^2- bromopropene, 9 parts of 4- (γ-ω-diethylacetamide)) ((~ f (tl-4-aiperiphenyl), 4.9 parts of Ν-^-Ο-γ-γ) was 72 parts of die, acet-dieethyaacetamide). After cooling, the resulting solution was diluted with water and diluted with water and the product was extracted into water and washed thoroughly with water and dried. The opartk was purified by column chromatography on silica gel, eluting with a 90:10 mixture of hexane and ethyl acetate as the eluent, and the pure fractions were precipitated and the eluent was evaporated. 5.7 parts (42.6%) of an oily residue of 4- (yloxycarbonyl) -1- (1-ylethylethyl) -N-phenyl-4-piperidinylatin are obtained.

To a stirred solution of 5.5 parts of 4- (yetoxtУmtylL-1- (1-myeojctyl) -N-4-feiyl pPpcrfjyřaшinž 5 · 6 parts of benzene was added dropwise a solution of 13.8 parts benieenřetylchlorifž benzene in 45 parts ^{of p} s ^p e ^I LD ²⁶ and ³² ° C. After the stončení ^ kraftujt in flicker therein tearing ^{p p} o ^d OBU ¹ hdiny ^p s ^p LDT TE ^{of 26} and ¹² ° ^C and ^p Otoya ^p o ^d o ^b in 3.6 hdiny when ^t e ^p lo ⁱ 38 and ⁵⁵ ° C. ^P for cooling the precipitated product by: ^ i ^, is and converted to lydrochlorid in 2-ardařnolu and 2-Flops (volume ratio 5: 1). salt After standing for 72 hours at room temperature, the precipitated product is washed with a small amount of ^2- alkanol and dried to give 1% by weight of ethanol. 0.05 parts of N- [4- (yetdximethyl) -1- (1-ethyl) hydrochloride was obtained, m.p. ² 49 ° C.

He said 14

By repeating the procedure of steps 1 to 4 of Example 13 using an equivalent amount of the lower alkylsulfate in step 5, the following meth products are prepared from the appropriate starting materials:

4- (γ-γ-ω-ω)) N- (3-methylphenyl) -1- (methylene-ethyl) -4-piperidinyl,

4- (eetootme t-a) -N- H-yet-tl-y (4-ienyameyl) -4-piase dyasein,

4- (ethoxymethyl) -N- ( ^2- oxo-thienyl) -1 (phenylmethyl-4-ai-trifluoromethyl), - (4 &lt; / RTI &gt; phenylethyl) -4-pi pereryl, - (ethoxymethyl-N-phenyl-1- (phenylethyl) -4-pi perfdyanyl) and

4- (ethoxymethyl) -N- (fluorophenyl) -1- (phenylmethyl) -4-piperidyl amine.

Example 15

Following the procedure of Example 7 step 7 and using equivalent amounts of the appropriate N-aryl-4- (lower alkoxymethyl) -1- (phenylmethyl) -4-plperidylamine and the appropriate arylacetyl chloride as starting compounds, the following intermediates were prepared:

N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl] -N-phenylbenzenation,

NL 4- (methoxymethyl) -1- (phenylmethyl) -4-piperidyl] -N- (3-methylphenyl) benzenesulfamide, N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidyl] -N- (4-methylphenyl) benzeneacetamide, N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidyl] -N- (2-methylphenyl) benzeneacetamide, N- ( 4-Fluorophenyl) -N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidyl] benzeneacetamide, N- [4- (ethoxymethyl) -1- (phenylmethyl) -4-piperidyl] -N-phenylbenzeneacetamide, N - [4- (ethoxymethyl) -1- (phenylmethyl) -4-piperidyl] -N- (4-fluorophenyl) benzeneacetamide, N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidyl] -N -phenyl-4-methylbenzeneacetamide d, N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidyl] -N-phenyl-4-methoxybenzeneacetamide and N- [4- (methoxymethyl) -Ir (phenylmethyl) - 4-piperidyl] -N-phenyl-2-thiophenacetemide.

Claims (4)

A process for the preparation of the novel N-aryl-N- (4-piperidyl) arylacetemides of the formula I, I Ar (I) in which L represents up to C 1-6 alkyl, up to C 8 -cycloalkyl, cyclopropylmethyl or propenyl, Ar represents a phenyl, mono- or disubstituted phenyl, pyrldyl or 2-pyrimidinyl group, wherein each substituent in said mono- or disubstituted phenyl group is independently selected from the group consisting of halogen and C1-6alkyl; to C2-alkyl, Ar 1 represents a phenyl, mono- or di-substituted phenyl or thienyl group, each substituent in said mono- or disubstituted group being independently selected from the group consisting of halogen, methyl and methoxy and X is hydrogen or Cl to a C 1-4 -alkyloxycarbonyl group, and their physiologically acceptable acid addition salts, characterized in that the compound of formula VI is acylated NH I, Ar (VI) wherein L, Ar and X> are as defined above, arylacetylhalogenidem formula VII (VII) ^kd e Ar ¹ has the abovementioned meaning, in inert organic solvent, preferably with přítomnosSi base and, if desired preparing a physiologically acceptable addition salts of the final acid reaction products. 2. Method of claim ¹ for the manufacture ciloofen NH ^) - ^-! - ^-! ^^ H-methylethyl piperidylJbenzenacetamidu and physiologically harmless sooi, vyznnauuící in that it comprises reacting N- (4-chltrfenyl) -N 2-Bromo-propanol (4-piperidyl) -butyramide, and optionally a physiologically acceptable acid addition salt is prepared from the reaction product. 3. A process according to claim 1 for the preparation of N- (4-chlorophthyl-N- (1-tert-444-pernyll) nitnacetamide) and its physiologically acceptable acid addition salt, which comprises reacting it with an acid. - (- chloroethyl) -N- (4βPeridyl) tenttaaceaamide with iodoethane, and optionally preparing a physiologically acceptable acid-addition salt from the action product, 4. A method according to claim 1 for the production of 3 "Chltr-N- (1-cyklthtxyl + 5-PI ^p eridyl) -N-Ethly) lnenznnacetamidu and its physiologically acceptable acid addition SOU with acids vyznaač ^ ICI said states to reacting 1-cyclotheyl-N-phthal-4-piperidyl amide with 3-chlorobenzoyl-naphthyl chloride, and optionally preparing a physiologically acceptable acid addition salt from the reaction product.