CS250580B1 - N-(piperazinoacyl) and 4-cyclopentylaniline's n-(piperazinoalkyl)derivatives and their salts - Google Patents

Description

The invention relates to N- (piperazinoacyl) - and N- (piperazinoalkyl) 4-cyclopentylaniline derivatives of the general formula I

(0 in which

R is hydrogen, ethyl or propionyl,

R ^{* 1} is hydrogen or isobutyl,

R ² is methyl, 2-hydroxyethyl or 2-propionoxyethyl,

X is CO or CH 2 and n is 0, 1 or 2, and their salts with pharmacologically acceptable inorganic or organic acids.

The compounds of formula I and their salts are characterized by several types of biological activity for which their use as pharmaceuticals is contemplated. These include, in particular, locally anesthetic activity (use for local anesthesia in small surgical procedures), mild spasmolytic activity of the anticholinergic type and considerable spasmolytic activity of musculotropic type (use in painful smooth muscle spasms, especially gastrointestinal and urogeninal tract, analgesic use of non-opiate pains of various origins without the risk of addiction) and antimicrobial activity in vitro (chemotherapy of bacterial and fungal infections) The following are a few of the compounds of the invention with specific data on their effects, which have been found in both in vivo and in vitro tests .

N- (4-Cyclopentylphenylphenyl) -2- (4-methylpiperazino) acetamide was tested as dihydrochloride.

LD50 - 150 mg / kg iv Locally anesthetic ú250580 dumbbells in infiltration anesthesia test (concentration in% which causes complete anesthesia in 50% of guinea pigs; for procaine, EC = 1 percent): 0.1 to 0.5% (the substance is therefore more effective than procaine).

N- (4-Cyclopentylphenyl) -2- [4- (2-hydroxyethyl) piperazino] acetamide was tested as the dihydrochloride. LD 50 = 175 mg / kg i.v. Local anesthetic effect in infiltration anesthesia test, EC = 0.1 to 0.5%.

N- (4-Cyclopentylphenyl) -3- (4-methylpiperazino) propionamide was tested as the dihydrochloride LD 50 = 150 mg / kg iv Spasmolytic (anticholinergic) effect (concentration in µg / ml causing a 50% decrease in acetylcholine contractions of isolated rat duodenum); for atropine, EC = 0.05 µg / ml: 1 to 10 µg / ml Spasmolytic (muscotropic) effect (concentration in µg / ml causing a 50% decrease in isolated rat duodenum barium chloride contractions; for papaverine, EC = 5 [mu] g / ml): 10 [mu] g / ml, the substance is therefore similar to papaverine.

N- (4-Cyclopentylphenyl) -3- (4- (2-hydroxyethyl) piperazino) propionamide was tested as dihydrochloride LD50 - 150 mg / kg iv Local anesthetic effect in infiltration anesthesia test, EC = 0.1 to 0.5 %.

N- (4-Cyclopentylphenyl) -N- [3- (4- (2-hydroxyethyl) piperazino) propyl] propionamide was tested as the dihydrochloride. LD 50 = 75 mg / / kg i.v. Local anesthetic effect in infiltration anesthesia test, EC = 0.1 to 0.5%. Local anesthetic effect in corneal anesthesia test (% concentration that induces complete corneal anesthesia in 50% of rabbits; for trimecaine, EC = 1%): 0.1 to 0.5%; the substance is therefore more potent than procaine than trimecaine.

N- (4-Cyclopentylphenyl) -N- [3- (4- / 2-propionoxyethyl / piperazino) propyl] propionamide was tested as the dihydrochloride monohydrate. LD 50 = 62.5 mg / kg i.v. Local anesthetic effect in corneal anesthesia test, ED = 0.1 to 0.5%. Spasmolytic (muscotropic) effect, EC = 1 to 10 µg / ml.

N- (4-Cyclopentylphenyl) -N- [4- (4-methylpiperazino) butyl] propionamide was tested as dihydrochloride hemihydrate. LD 50 = 56.3 milligrams / kg i.v. Local anesthetic effect in infiltration anesthesia assay, EC = 0.1 to 0.5%; in the corneal anesthesia test, EC = - 0.1 to 0.5%. Spasmolytic (muscotropic) effect, EC = 10 µg / ml.

N- (4-Cyclopentylphenyl) -N- (4- (4- (2-hydroxyethyl / piperazino) butyl) propionamide) was tested as dihydrochloride monohydrate LD50 - 100 mg / kg iv Local anesthetic effect in infiltration anesthesia test, EC = = 0.1 to 0.5%.

N- (4-Cyclopentylphenyl) -2- (4-methylpiperazino) -4-methylvaleramide was tested as dihydrochloride hemihydrate. LD 50 = 27.5 milligrams / kg i.v. Local anesthetic effect in infiltration anesthesia test, EC = 0.1 to 0.5%; in the corneal anesthesia test, EC = 0.1 to 0.5%. Spasmolytic (anticholinergic) effect, EC = 1 to 10 µg / ml; spasmolytic (musculotropic) effect, EC = -1 to 10 µg / ml.

N- (4-Cyclopentylphenyl) -2- [4- (2-hydroxyethyl] piperazino] -4-methylvaleramide was tested as dihydrochloride hemihydrate LD50 = 37.5 mg / kg iv Local anesthetic effect in infiltration anesthesia test, EC = = 0.1 to 0.5% Spasmolytic (anticholinergic effect, EC = 1 to 10, µg / ml; spasmolytic (musculotropic) effect, EC = 1 to 10 µg / ml.

N- (4-Cyclopentylphenyl) -N- [2- (4-methylpiperazino) -4-methylpentyl] propionamide was tested as succinate. LD 50 = 1500 mg / kg po Analgesic efficacy in mice using chemical stimulation (intraperitoneal acetic acid), D 50 = 2.4 mg / kg po (for morphine, D 50 = 0.24 mg / kg po, for meperidine, D 50 = 3.1 mg / kg po); the substance is more effective than meperidine in this test.

N- (4-Cyclopentylphenyl) -N- [2- (4- (2-hydroxyethyl) piperazino) ethyl] propionamide was tested as the dihydrochloride. LD 50 = 100 mg / kg i.v. Analgesic efficacy in mice in the "peritoneal" test, D 50 is less than 10 mg / kg p.o.

N- (4-Cyclopentylphenyl) -N- [4- (4- (2-propionoxyethyl) piperazino) butyl] propionamide was tested as dihydrochloride dihydrate. Analgesic efficacy in mice in the "peritoneal" test, D 50 = 17.2 mg / kg p.o.

N- [4- (4-Methylpiperazino) butyl] -4-cyclopentylaniline was tested as trihydrochloride. In vitro antimicrobial activity (minimum inhibitory concentrations in <µg / ml given): Streptoooccus / ha-haemolyticus, 100; Pseudomonas aeruginosa 100; Mycobacterium tuberculosis, 25; Saccharomyces pasterianus, 50; Trichophyton mantagrophytes, 50.

N- [4- (4- / 2-Hydroxyethyl / piperazino) butyl] -4-cyclopentylaniline was tested as trihydrochloride hemihydrate. In vitro antimicrobial activity: Streptococcus / ha-haemolyticus, 100; Pseudomonas aeruginosa 100; Mycobacterium tuberculosis, 100; Saccharomyces pasterianus, 50; Trichophyton mentagrophytes, 50.

N- [2- (4-Methylpiperazino) -4-methylpentyl] -4-cyclopentylaniline has been tested as sesquimaleinate sesquihydrate.In vitro antimicrobial activity: Streptoccocus β-haemolyticus, 12.5; Streptoccocus faecalis, 50; Staphylococus pyogenes aurees Mycobacterium tuberculosis, 6.25; Saccharomyces pasterianus, 50; Trichophyton mentagrophytes, 25.

N- [2- (4- / 2-Hydroxyethyl / piperazino) -4-methylpentyl] -4-cyclopentylaniline was tested as sesquimaleinate sesquihydrate. In vitro antimicrobial activity: Streptococcus β-haemolyticus, 25; Streptococcus faecalis 50; Staphylococcus pyogenes aureus, 25; Pseudomonas aeruginosa 100; Mycobacterlum tuberculosis, 12.5; Saccharomyces pasterianus, 50; Trichophyton mentagrophytes, 25.

The compounds of the formula I according to the invention can be prepared from the following N- (4-cyclopentylphenyl) -haloalkanecarboxamides:

N- (4-cyclopentylphenyl) chloroacetamide,

N- (4-cyclopentylphenyl) -N-ethylchloroacetamide,

N- (4-cyclopentylphenyl) -3-chloropropionamide,

N- (4-cyclopentylphenyl) -4-chlorobutyramide and N- (4-cyclopentylphenyl) -2-bromo-4-methylvaleramide;

the preparation of these compounds has been described (Vejdělek Z. et al., Collect. Czech. Chem. Commun. 48, 156, 1983). Reacting these halogen derivatives with 1-methylpiperazine and l- (2-hydroxyethyl) piperazine can be obtained from the amides of formula I (X = ICO, R = H or C2H5, ^R2 is methyl or 2-hydroxyethyl). By reducing these amides, the corresponding amines of formula β (X ™ = C'H 2) can be obtained. Acylation of these amines with propionyl chloride results in propionamides of formula I (R = - COC 2 H 5) and, when the starting amines are 2-hydroxyethylpiperazine derivatives, the resulting propionamides are simultaneously propionic esters [I, R ² = 2-propionoxyethyl]. Boiling with ethanol in the presence of sodium ethoxide occurs ethanolyse these amide-esters to produce respective aminoalkoholamidů (I, R = COC2H5, R ² - = CH2CH2OH). The details of the preparation of all these compounds are given in the examples, but are not intended to limit the invention to the methods set forth in the examples. All compounds of formula I are basic in nature; bases are partly crystalline, partly oily. By acid neutralization, all bases provide crystalline salts, of which the hydrochlorides and maleate compounds have proven best for their good crystallization properties, water solubility, and suitability for pharmacological tests. All of the compounds of Formula I described are novel; their identity was ensured by analyzes and, in part, by spectral methods.

Example 1

N- (4-Cyclopentylphenyl) -2- (4-methylpiperazino) acetamide

To a solution of 11.0 g of N- (4-cyclopentylphenyl) chloroacetamide in 70 ml of benzene was added 10.0 g of 1-methylplperazine, and the stirred mixture was refluxed for 6 hours and allowed to stand overnight. The precipitated 1-methylpiperazine hydrochloride is filtered off with suction, washed with benzene, the filtrate is washed with water, dried over sodium sulphate and evaporated in vacuo; 11.9 g (86%) of an oily base which crystallizes on standing, m.p. 70-71 ° C (hexane). Neutralization with hydrogen chloride in ethanol gives the dihydrochloride which crystallizes in fine plates from aqueous ethanol and melts at 204-205 ° C (south at 180-190 ° C).

Example 2

N- (4-Cyclopentylphenyl) -2- [4- (2-hydroxyethyl) piperazino] acetamide

Analogously, 21.0 g of N- (4-cyclopentylphenyl) chloroacetamide is reacted with 26.0 g of 1- (2-hydroxyethyl) piperazine in 140 ml of boiling benzene and the reaction mixture is worked up analogously to give 29.3 g of crude oily base, m.p. 81 ^DEG- 82 ^DEG C. (benzene-hexane), neutralization with hydrogen chloride in ethanol affords crystalline dihydrochloride, m.p. 194 DEG-195 DEG C. (95% ethanol).

Example 3

N- (4-Cyclopentylphenyl) -N-ethyl-2- (4-methylpiperazino) acetamide

As in the previous cases, 17.1 g of N- (4-cyclopentylphenyl) -N-ethylchloroacetamide were reacted with 13.5 g of 1-methylpiperazine in 120 ml of boiling benzene. After standing overnight, the benzene layer was separated by decantation from the precipitated hygroscopic 1-methylpiperazine hydrochloride, washed with water, and the base was extracted into a solution of 30 ml of hydrochloric acid in 300 ml of water. The precipitated solid is filtered off, the filtrate is basified with 20% sodium hydroxide solution and the oily base is isolated by extraction with a mixture of benzene and ether; 17.3 g (82 percent). By neutralization with maleic acid in a mixture of ethanol and ether, it is converted to crystalline bis (hydrogen maleate), m.p. 158-159 ° C (ethanol).

Example 4

N- (4-Cyclopentylphenyl) -3- (4-methylpiperazino) proplonamide

As in Example 1, 11.7 g of N- (4-cyclopentylphenyl) -3-chloropropionamide are reacted with 10.0 g of 1-methylpiperazine in 70 ml of boiling benzene (boiling 9 h) to give 13.0 g of analogous work-up. (89%) of an oily base which crystallizes from a mixture of benzene and hexane, mp 122-123 [deg.] C. Neutralization with hydrogen chloride in ethanol affords crystalline dihydrochloride, mp 221-222 [deg.] C (95% ethanol).

Example 5

N- (4-Cyclopentylphenyl) -3- (4- (2-hydroxyethyl) piperazino] propionamide

As above, reaction of 23.4 g of N- (4-cyclopentylphenyl) -3-chloropropionamide with 26.0 g of 1- (2-hydroxyethyl) piperazine in 120 ml of boiling benzene (8 hours) was performed. 4 g (95%) of an oily base crystallized from benzene / hexane and melted at 119-120 ° C. Neutralization with hydrogen chloride in ethanol and addition of ether gave the dihydrochloride which crystallized from 90% ethanol and melted at 223-225 ° C. .

Example 6

N- (4-Cyclopentylphenyl) -2- (4-methylpiperazino) -4-methylvaleramide

Reaction of 20.3 g of N- (4-cyclopentylphenyl) -2-bromo-4-methylvaleramide with 13.0 g of 1-methylpiperazine in 120 ml of benzene (7 h var) gives 18.6 g (87%) of an oily base, which crystallizes from a mixture of benzene and hexane and melts at 93-94 ° C. Neutralization with hydrogen chloride in ethanol and addition of ether gave the dihydrochloride, which crystallized from a mixture of 90% ethanol and ether as the hemihydrate and melted at 218-220 ° C (south at 200-210 degrees Celsius).

Example 7

N- (4-Cyclopentylphenyl) -2- (4- (2-hydroxyethyl) piperazino) -4-methylvaleramide

As in the previous examples, 20.0 g of N- (4-cyclopentylphenyl) -2-bromo-4-methylvaleramide are reacted with 17.0 g of 1- (2-hydroxyethyl) piperazine in 120 ml of benzene (boiling for 7 h). 16.5 g (72%) of an oily base were obtained by neutralization with hydrogen chloride in ethanol and addition of ether to give the dihydrochloride which crystallized from 95% ethanol as the hemihydrate, mp 228-230 ° C ( (at 200 to 205 ° C).

Example 8

N- (4-Cyclopentyl) -4- (4- (2-hydroxyethyl) piperazino] butyramide

To a solution of N- (4-cyclopentylphenyl) -4-chlorobutyramide (19.1 g) in toluene (150 ml) was added 1- (2-hydroxyethyl) piperazine (19.5 g) and the mixture was refluxed under stirring for 16 hours. After cooling, it is diluted with benzene, washed thoroughly with water, dried and evaporated under reduced pressure. The residue is dissolved in 50 ml of ethanol, the solution is neutralized and slightly acidified with hydrogen chloride and evaporated again in vacuo. The crude hydrochloride was dissolved in 130 ml of water, filtered with charcoal, basified with aqueous ammonia and allowed to stand overnight at 4 ° C. Filtration gave 10.2 g (40%) of the desired crystalline base, m.p. 99-100 ° C (benzene-hexane). Neutralization with hydrogen chloride in ethanol gave the dihydrochloride, which crystallized from 96% ethanol and melted at 222-223 ° C.

Example 9

N- (4-Cyclopentylphenyl) -4- (4-methylpiperazino) butyramide

As in the previous example, 10.6 g of N- (4-cyclopentylphenyl) -4-chlorobutyramide was reacted with 9.0 g of 1-methylpiperazine in 80 ml of boiling toluene (boiling for 16 h). Analogous work-up gave 5.40 g (41%) of a base which crystallized from a mixture of benzene and hexane and melted at 82-83 ° C.

Example 10

2- (4- (3- (4-Cyclopentylanilino / propyl) piperazino) ethanol

A solution of 22.0 g of N- (4-cyclopentylphenyl) -3- [4- (2-hydroxyethylpiperazino) -propionamide (Example 5) in 150 ml of benzene (prepared with heating and then cooled) is slowly added to the stirred A suspension of 8.0 g of lithium aluminum hydride in 100 ml of ether and refluxed for 5 hours, cooled, quenched by the slow addition of 32 ml of 20% sodium hydroxide solution with stirring, the precipitate formed is filtered off after 30 minutes, washed with benzene and 18.9 g (90%), mp 75-76 ° C (benzene-hexane), neutralized with hydrogen chloride in ethanol to give the trihydrochloride, which crystallizes from ethanol containing hydrogen chloride and melts at 231 ° C. up to 232 ° C.

Example 11

N- [2- (4-Methylpiperazino) ethyl] -4-cyclopentylaniline

As in the previous case, 6.0 grams of N- (4-cyclopentylphenyl) -2- (4-methylpiperazino) acetamide (Example 1) was reduced in 50 mL of benzene with 2.5 g of lithium aluminum hydride in 50 mL of ether to give 5.8 g. g of a crude oily base which, by neutralization with hydrogen chloride in ethanol, gives 7/50 g of trihydro2 sosoa chloride, mp 224 DEG-226 DEG C. (ethanol containing hydrogen chloride).

Example 12

2- (4- (2- / 4-Cyclopentylanilino / ethyl) piperazino) ethanol

As in the previous cases, 22.0 g of N- (4-cyclopentylphenyl) -2- (4- (2-hydroxyethyl) piperazino] acetamide (Example 2) is reduced in 150 ml of benzene with 7.0 g of lithium aluminum hydride in 100 ml of ether. 19.4 g (93%) of an oily base are obtained, which is neutralized with hydrogen chloride in ethanol to give the dihydrochloride, mp 213-214% (aqueous ethanol).

Example 1 a d 13

N-Ethyl-N- [2- (4-ethylpiperazino) ethyl] -4-cyclopentylaniline

As in the previous examples, it is reduced

6.1 g of N- (4-cyclopentylphenyl) -N-ethyl-2- (4-methylpiperazino) acetamide (Example 3) in 50 ml of benzene using 2.5 g of lithium aluminum hydride in 50 ml of ether. 5.70 g of an oily base are obtained which, by neutralization with hydrogen chloride in a mixture of ethanol and ether, yields 6.90 g of trihydrochloride, m.p. 215-217% (ethanol-ether containing hydrogen chloride).

Example 14

N- [3- (4-Methylpiperazino) propyl] -4-cyclopentylaniline

As in the previous examples, 7.0 g of N- (4-cyclopentylphenyl) -3- (4-methylpiperazino) propionamide (Example 4) was reduced in 50 ml of benzene with 3.0 g of lithium aluminum hydride in 50 ml of ether to give 6.7 g. oily base which, by neutralization with hydrogen chloride in ethanol and addition of ether, gave 8.3 g (91%) of the trihydrochloride, mp 243-245% (aqueous ethanol-ether containing hydrogen chloride).

Example 15

N- [4- (4-Methylpiperazinyl) butyl] -4-cyclopentylaniline

As in the previous examples, it is reduced

5.2 g of N- (4-cyclopentylphenyl) -4- (4-methylpiperazino) butyramide (Example 9) in 70 ml of benzene with 2.0 g of lithium aluminum hydride in 30 ml of ether to give 5.0 g of an oily base which is neutralized with hydrogen chloride in ethanol-ether mixture yields 60 g of trihydrochloride, mp 215-216% (95% ethanol containing hydrogen chloride).

Example 16

2- (4- (4- / 4-Cyclopentylanilino / butyl) piperazino) ethanol

As in the previous examples, 8.7 g of N- (4-cyclopentylphenyl) -4- (4- (2-hydroxyethyl) piperazino] butyramide (Example 8) is reduced in 60 ml of benzene with 3.5 g of lithium aluminum hydride in 50 ml. ether to give 8.5 g of an oily base which was neutralized with hydrogen chloride in ethanol / ether to give the trihydrochloride (9.8 g) crystallized from 95% ethanol containing hydrogen chloride as the liemihydrate, mp 223-224%.

Example 17

N- [2- (4-Methylpiperazino) -4-methylpentyl] -4-cyclopentylaniline

As in the previous examples, 11.6 g of N- (4-cyclopentylphenyl) -2- (4-methylpiperazino) -4-methylvaleramide (Example 6) was reduced in 75 ml of benzene with 3.6 g of lithium aluminum hydride in 50 ml of ether. 10.6 g (95%) of an oily base are obtained, which is neutralized with maleic acid in a mixture of ethanol and ether. A sesquimoleinate is obtained which crystallizes with 1.5 molecules of water (sesquihydrate), m.p. 168-169% (95% ethanol-ether).

Example 18

2- (4- (1- (4-Cyclopentylanilino) -4-methyl-2-pentyl) piperazino) -ethanol

Similar to the previous examples, reduction of 11.5 g of N- (4-cyclopentylphenyl) -2- (4- (2-hydroxyethyl) piperazino] -4-methylvaleramide (Example 7) in 70 ml of benzene is carried out with 4.0 g of hydride of lithium aluminum in 50 mL of ether gave 9.50 g (86%) of an oily base which was neutralized with maleic acid in a mixture of ethanol and ether to give a crystalline sesquimaleinate sesquihydrate, mp 160-161% (95% ethanol-ether). 19 Dec

N- (4-Cyclopentylphenyl) -N- [4- (4-methylpiperazino) butyl] propionamide

To a stirred mixture of 4.8 g of N- [4- (4-methylpiperazino) butyl] -4-cyclopentylaniline (Example 15), 25 ml of chloroform and 4.3 g of potassium carbonate was added dropwise over 25 min. solution of 1.7 g of propionyl chloride in 20 ml of chloroform and the mixture was refluxed for 2.5 h. After cooling, it is washed several times with water, dried over sodium sulphate and evaporated. 5.3 g (93%) of an oily base are obtained. This was dissolved in 80 ml of ether and added

25058Q a small excess of a solution of hydrogen chloride in ethanol. The precipitated dihydrochloride crystallizes from 98% ethanol as a hemihydrate, mp 211-213 ° C.

Example 20

N- (4-Cyclopentylphenyl) -N- [2- (4-methylpiperazino) -4-methylpentyl] propionamide

As in the previous example, 7.9 g of N- [2- (4-methylpiperazino) -4-methylpentyl] -4-cyclopentylaniline (Example 17) are reacted with 2.35 g of propionyl chloride in 60 ml of chloroform in the presence of 3.5 g of potassium carbonate. 9.0 g of an oily base are obtained which, by neutralization with maleic acid in a mixture of ethanol and ether, gives 9.6 g of the maleate, m.p. 139 DEG-140 DEG C. (ethanol-ether).

Example 21

N- (4-Cyclopentylphenyl) -N- [2- (4- / 2-propionoxyethyl / piperazino) ethyl] propionamide

As in the previous examples, 17.0 g of 2- [4- (2- / 4-cyclopentylanilino / ethyl) piperazino] ethanol (Example 12) are reacted with 11.0 g of propionyl chloride in 120 ml of chloroform in the presence of 15 g of potassium carbonate . 18.5 g (81%) of the desired oily base are obtained, which is neutralized with hydrogen chloride in ethanol. Addition of ether precipitates the dihydrochloride, which crystallizes from a 95% ethanol / ether mixture as a monohydrate, m.p. 172-173 ° C.

Example 22

N- (4-Cyclopentylphenyl) -N- [3- (4- (2-propionoxyethyl) piperazino) propyl] propionamide

Similar to the previous examples, 13.5 g of 2- [4- (3- (4-cyclopentylanilimo / propyl) piperazino] ethanol (Example 10) were reacted with 8.3 g of propionyl chloride in 110 ml of chloroform in the presence of 11.5 g potassium carbonate. 16.2 g (90%) of the desired oily base are obtained. Neutralization with hydrogen chloride in ethanol and addition of ether precipitates the dihydrochloride, which crystallizes from a 95% ethanol / ether mixture as a monohydrate, m.p. 177-178.

Example 23

N- (4-Cyclopentylphenyl) -N- [4- (4- (2-propionoxyethyl / piperazino) butyl] propionamide

As in the previous examples, 9.0 g of 2- [4- (4- (4-cyclopentylanilino / butyl) piperazino] ethanol Example 16) are reacted with 4.75 g of propionyl chloride in 70 ml of chloroform in the presence of 6.5 g potassium carbonate. 10.0 g of a crude oily base are obtained, which is neutralized with hydrogen chloride in ethanol. By addition of ether, 10.8 g of the dihydrochloride precipitate, which crystallizes from a mixture of 95% ethanol and ether as the dihydrate, m.p. 170-171 ° C.

Example 24

N- (4-Cyclopentylphenyl) -N- [2- (4- (2-propionoxyethyl) piperazino) -4-methylpentyl] propionamide

As in the previous examples, 9.1 g of 2- [4- (1- (4-cyclopentylanilimo) -4-methyl-2-pentyl) piperazino] ethanol (Example 18) are reacted with 5.0 g of propionyl chloride in 70 ml. chloroform in the presence of 68 g of potassium carbonate. 10.9 g (92%) of an oily base are obtained, which is neutralized with maleic acid in ethanol. Addition of ether precipitates (hydrogen maleate), which crystallizes from a mixture of 96% ethanol and ether as the monohydrate, mp 88-89 ° C.

Example 25

N- (4-Cyclopentylphenyl) -N- [3- (4- (2-hydroxyethyl) piperazino) propyl] propionamide

To a solution of sodium ethoxide prepared from 70 ml of absolute ethanol and 0.4 g of sodium is added a solution of 8.3 g of N- (4-cyclopentylphenyl) -N- [3- (4- / 2-propionoxyethyl / piperazino) propyl of propionamide (Example 22) in 30 ml of ethanol and the mixture was allowed to stand at room temperature for 24 hours. Addition of a calculated amount of a solution of hydrogen chloride in ethanol precipitates sodium chloride, which is filtered off. The filtrate was evaporated under reduced pressure, the residue was dissolved in chloroform, washed with water, dried and evaporated. The residue (7.25 g) is the desired oily base which is dissolved in 20 ml of ethanol and the solution is neutralized with a solution of hydrogen chloride in 10 ml of ethanol. Evaporation under reduced pressure gave a solid salt which was dissolved in boiling ethanol (20 ml), cooled and slowly treated with ether (100 ml). After standing for 2 hours, 7.60 g (88%) of the dihydrochloride, m.p.

Example 26

N- (4-Cyclopentylphenyl) -N- [2- (4- (2-hydroxyethyl) piperazino) ethyl] propionamide

Similar to the previous example, 9.5 g of N- (4-cyclopentylphenyl) -N- [2- (4- / 2-propionoxyethyl / piperazino) ethyl] propionamide (Example 21) in ethanol (110 ml) in ethanol in the presence of sodium ethoxide from ethanol were carried out. 0.5 g of sodium. 8.25 g of an oily base are obtained which, by neutralization with hydrogen chloride in ethanol and addition of ether, yields 7.7 g of dihydrochloride, m.p. 157 DEG-159 DEG C. (ethanol-ether).

Example 27

N- (4-Cyclopentylphenyl) -N- [4- (4- (2-hydroxyethyl) piperazino) butyl] propionamide

As in the previous examples, ethanol (5.0 g) of N- (4-cyclopentylphenyl) -N- [4- (4- (2-propionoxyethyl / piperazino) butyl] propionamide (Example 23) in ethanol (65 ml) containing sodium ethoxide from ethanol was carried out. 0.25 g of sodium The crude base obtained is dissolved in ethanol, neutralized with a solution of hydrogen chloride in ethanol and evaporated in vacuo, the residue is dissolved in 10 ml of hot 96% ethanol and 5.1 g of dihydrochloride monohydrate are added by addition of 80 ml of ether. mp 145-146 ° C (96% ethanol-ether).

Example 28

N- (4-Cyclopentylphenyl) -N- [2- (472-hydroxyethyl / piperazino) -4-methylpentyl] propionamide

Similar to the previous examples, 6.0 g of N- (4-cyclopentylphenyl) -N- [2- (4- (2-propionoxyethyl) piperazino] -4-methylpentyl] propionamide (Example 24) in ethanol (65 ml) were performed in ethanol with The presence of sodium ethoxide from 0.28 g of sodium yielded 5.4 g of an oily base which was neutralized with maleic acid in 96% ethanol and added ether to precipitate the maleate hemihydrate, mp 69-72 ° C (96% ethanol-ether).

Claims (1)

N- (Piperazinoacyl) - and N- (piperazinoalkyl) 4-cyclopentylaniline derivatives of formula (I) Λ // N-X-CH (CH 2) p. / - \, N ŇR '\ ™ / CO in which R is hydrogen, ethyl or propionyl, R ¹ is hydrogen or isobutyl, R ^a is methyl, 2-hydroxyethyl or 2-propionoxyethyl, X is CO or CH 2 and n is 0, 1 or 2, and their salts with pharmacologically acceptable inorganic or organic acids.