CS226459B1 - Symmetrically 1,4-di-substituted piperazine derivatives and dihydrochlorides thereof - Google Patents

Description

The invention relates to symmetrically 1,4-di substituted piperazine derivatives of the general formula I,

ArOCH ₂ COX (CH ₂ ) _n (CH ₂ ) _n XCOCH ₂ OAr (I) wherein Ar represents 2,4,5-trichlorophenyl, 2,4,6-trimethylphenyl or 4-bromo-3,5-dimethylphenyl ,

X represents an oxygen atom or an NH group and n is 2 or 3, and their dihydrochlorides.

The compounds of the formula I and their dihydrochlorides are characterized by pharmacological effects which make them potential drugs relating in particular to cardiovascular diseases. When administered orally to experimental animals, they lower blood pressure and induce peripheral blood vessel dilatation, so that they can be considered as drugs against hypertension and peripheral blood flow disorders. In addition, some of them have mild centrally depressed effects, manifested by potentiation of thiopental sleep and hypothermal effects. Some also act locally anesthetically and spasmolytically. The following are specific cases of individual active substances:

1,4-Bis / 3- (2,4,5-trichlorophenoxyacetoxy) propyl / piperazine was tested as the dihydrochloride. Its acute oral toxicity in mice LD ^ q = 2000 mg / kg. At an oral dose of 300 mg / kg, the substance slightly lowers the blood pressure of normotensive rats. It is only at doses higher than 300 mg / kg p.o. that it exhibits a depressant effect in mice (it decreases spontaneous locomotor activity).

22Ó45S

1,4-Bla / 3- (2,4,6-triaethylphenoxyacatoxy) propyl / piperazine was also tested as dihydroehloride. Acute Toxitis in Mice · LDjq = 350 mg / kg p. O. At an oral dose of 70 mg / kg, the substance exhibits a peripherally vasodilatory effect assessed by raising the temperature of the guinea pig ear.

1,4-Bis / 3- (2,4,5-trichlorophenoxyacetamido) propyl / piperazine was tested in the form of dihydrate dihydrochloride. Its acute toxicity in mice (LD ^ q) on oral administration is greater than

2.5 g / kg. At an oral dose of 300 mg / kg, it causes a significant decrease in blood pressure in normotensive rats. At the same dose, it significantly increases the duration of sleep in mice induced by a standard dose of thiopental; while slightly lowering the body temperature of the mice in rectal measurement.

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1,4-Bis / 3- (2,4,6-trimethylphenoxyacetamido) propyl / piperazine was tested as the dihydrate dihydrochloride. This substance is well soluble in water, allowing parenteral administration. Acute toxicity in mice by intravenous administration. LD 50 = 50 mg / kg. At intravenous doses, mg / kg significantly reduced the blood pressure of normotensive rats. At a dose of 10 mg / kg i.v., my peripherally vasodilatory effect was assessed by increasing the temperature of the guinea pig ear. In the form of a 1% aqueous solution, my locally anesthetic effect in the corneal anesthesia test in the rabbit eye.

At concentrations of 1-10 µg / ml, it exhibits spasmolytic activity against both acetylcholine and barium chloride contractions of isolated rat duodenum.

Compounds of formula I may be obtained by the action of compounds of formula II,

ArOCH2COR (II) wherein Ar is the same as in Formula I and R is Cl or OCH3, to the piperazine derivatives of formula III,

III (0Η ₂ ) _η θ (0Η ₂ ) _η ΧΗ (III) in which X and _{n are the} same as in formula I. In the case where the end products are eateres (I, X = θ '), it is preferable to use chloride reactions of acids (II. R = Cl) with amino alcohols III (X = θ ') in dimethylformamide at 100 ° C. In this way, dihydrochlorides of the desired diesters are obtained directly. In the preparation of diamines of formula I (X = NH), on the other hand, it is preferable to use the reactions of esters of formula II (R = OCH3) with amines III (X = NH) in boiling ethanol. Approximately two molecules of said esters II are used per amine molecule of formula III. The final products of the invention are novel.

F*'

Among the intermediates are the new methyl esters of 2,4,5-trichlorophenoxyacetic acid, 2,4,6-trimethylphenoxyacetic acid, 4-bromo-3,5-dimethylphenoxyacetic acid and longer 2,4,6-trimethylphenoxy acetic acid chloride, the preparation of which is described in the examples. .

The compounds of formula III are generally known and have been prepared according to the following literature sources: 1,4-bis (2-hydroxyethyl) piperazine (Gold-Aubert P., Locher A., Helv. Chira. Acta 42.

156 1959). 1,4-bis (3-hydroxypropyl) piperazine (Gardner, J.H., Snyder, J.H., J.Amer. Chem. Soc. 55 3,823, 1933). 1,4-bis (3-aminopropyl) piperezine (Behr LC et al., J. Amer. Chem. Soc. 8, 1296, 1946): Protiva M. et al., Collet. Czech. Chem. Commun. 42 No. 3,628, 1977). The identity of all new substances was ensured by analyzes and spectra.

Example 1

1,4-Bi / 2- (2,4,5-1-chlorophenoxyacetoxy) ethyl / p razin.

To a stirred solution of 2.38 g of 1,4-bis (2-hydroxyethyl) piperazine in 20 ml of dimethylformamide was added dropwise a solution of 7.5 g of 2,4,5-trichlorophenoxyacetic acid chloride (Hill CK et al., J) at 60 ° C. Amer. Chem. Soc., 21, 257 (1949) in 20 ml of dimethylformamide. The mixture was stirred at 100 ° C for 5 h.

Upon standing overnight and cooling, the hydrochloride of the desired product crystallizes; crystallization is accelerated by addition of 40 ml of ether. A total of 7.0 g (71%) of crystalline dihydrochloride is obtained, which melts at 2.2-2.4 ° C after recrystallization from aqueous ethanol.

Example 2

1,4-Bis / 2- (2,4,6-trimethylphenoxyacetoxy) ethyl / piperazine.

As in the previous example, 10.6 g of 2,4,6-trimethylphenoxyacetic acid chloride are reacted with 4-bis (2-hydroxyethyl) piperazine in 55 ml of dimethylformamide. 6.9 g of the desired dihydrochloride are obtained, which crystallizes from 96% ethanol and melts at 201-203 ° C.

The starting 2,4,6-trimethylphenoxyacetic acid chloride is a novel substance and can be prepared from the known 2,4,6-trimethylphenoxyacetic acid (Steinkopf Vi., Hopner T., J. Prakt. Chem. Chem.

(2 / 113. 137, 1926) as follows:

A mixture of 20.6 g of 2,4,6-trimethylphenoxyacetic acid, 50 ml of benzene and 31.5 ml of thionyl chloride is refluxed for 5 hours and then evaporated under reduced pressure. The residue is distilled under vacuum; 17.3 g (77%) of a product boiling at 139 ° C / 1.6 kPa are obtained. The distillate crystallizes on standing and the product melts at 61-62.5 ° C.

Example 3

1,4-bis / 3- (2,4,5-trichlorophenoxyacetoxy) propyl / piperazine.

Analogously to Examples 1 and 2, 8.2 g of 2,4,5-trichlorophenoxyacetic acid chloride (reference to Example 1) are reacted with 3.0 g of 1,4-bis (3-hydroxypropyl) piperazine in 40 ml. dimethylformamide. 7.3 g (65%) of crystalline dihydrochloride of the desired compound are obtained, which crystallizes from aqueous ethanol and melts at 205 DEG-210 DEG.

Example 4

1,4- bis [3- (2,4,6-trimethylphenoxyacetoxy) propyl] pi perazine.

Similar to Examples 1-3, 10.6 g of 2,4,6-trimethylphenoxyacetic acid chloride (prepared as described in Example 2) are reacted with 5.5 g of 1,4-bis (3-hydroxypropyl) piperazine in 55 ml. dimethylformamide. 11.8 g (75%) of the desired dihydrochloride are obtained, which crystallizes from 98% ethanol and melts at 204-205.5 ° C.

Example 5

1,4-Bis (3- (2,4,5-trichlorophenoxyacetamido) propyl / piperazine).

A mixture of 17.0 g of 2,4,5-trichlorophenoxyacetic acid methyl ester, 6.0 g of 1,4-bis (3-aminopropyl) piperazine and 25 ml of ethanol is stirred and refluxed for 24 h. On standing overnight, 18.8 g (88%) of the base crystallized out, which crystallized from a mixture of ethanol and benzene and melted at 164-166 ° C. Neutralizing the solution of the base in ethanol with ethereal hydrogen chloride gives the dihydrochloride dihydrate, which crystallizes from aqueous ethanol and melts at 2.6-219 ° C.

The 2,4,5-trichlorophenoxyacetic acid methyl ester used is a novel substance and is prepared from the known 2,4,5-trichlorophenoxyacetic acid (Pokorny R., J. Amer. Chem. Soc. 63, 1 768,

1951: Galat A., J. Amer. Chem. Soc. 74, 3,890 (1952) as follows:

To a stirred mixture of 51 g 2,4,5-trichlorophenoxyacetic acid, 600 ml acetone, 60 ml water and 26.6 g dimethylsulfate, 29 g potassium carbonate are added in small portions at reflux. The mixture is boiled for an additional 8 h and allowed to stand overnight. The precipitated solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was combined with the filtered solids, stirred with 250 ml of 5% sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried over sodium sulfate and evaporated. 36.6 g (68%) of the crude ester are obtained, which is recrystallized from 230 ml of methanol; it then melts at 91-92 ° C.

Example 6

1,4-Bis [3- (2,4,6-trimethylphenoxyacetamido) propyl] pi perazine.

As in the previous example, 11.5g of 2,4,6-trimethylphenoxyacetic acid methyl ester was reacted with 5.0g of 1,4-β-(3-aminopropyl) piperazine in 15ml of ethanol. After 24 h, the mixture is diluted with 30 ml of ethanol, the solution is filtered with carboraffin, dried over magnesium sulfate and the filtrate is slightly acidified with ethereal hydrogen chloride. On standing, 11.0 g (71 ®) of the dihydrochloride monohydrate of the desired product precipitated, which crystallized from a mixture of 85 ® ethanol and ether and melted at 206-208 ° C.

The starting 2,4,6-trimethylphenoxyacetic acid methyl ester is a novel substance and is prepared from the known 2,4,6-trimethylphenoxyacetic acid (Steinkopf W. and Hopner T., cited) analogously to Example 5 for a similar acid ester 2,4,5-trichlorophenoxy acetic acid, i.e. by reacting 29 g of 2,4,6-trimethylphenoxyacetic acid with 28.5 g of dimethyl sulfate and 32 g of potassium carbonate in a mixture of 375 ml of acetone and 50 ml of water. It is obtained in a yield of 21 g (68 ®) as an oil boiling at 135-138 ° C / 1.3 kPa.

Example 7

1,4-Bis / 3- (4-bromo-3,5-dimethylphenoxyacetamido) propyl / piperazine.

Similar to Example 5, 13 g of 4-bromo-3,5-dimethyl-phenoxyacetic acid methyl ester is reacted with 4.0 g of 1,4-bis (3-aminopropyl) piperazine in a mixture of 25 ml of ethanol and 10 ml of dimethylformamide. On standing and cooling, 6.0 g of the desired base precipitated, which crystallized from ethanol and in a pure state and melted at 185.5 ° C. Neutralizing the solution of the base in a mixture of ethanol and dimethylformamide with ethereal hydrogen chloride gives the dihydrochloride melting at 209.5-210.5 ° C.

The starting 4-bromo-3,5-dimethylphenoxy-acetic acid methyl ester is new and is prepared from the known 4-bromo-3,5-dimethylphenol (Auwers K. v. Borsche E., Ber. Deut. Chem. Ges. 48. 1698, 1915; Reid VI, U.S. Patent 2,719,851), as follows:

A stirred solution of 4-bromo-3,5-dimethylphenol (20.1 g) and sodium hydroxide (11.2 g) in water (40 ml) was heated to 90 ° C and a solution of chloroacetic acid (13.2 g) in 20 ml was added dropwise over 1 h. water. The mixture is stirred for 4 hours in a 105 ° C bath, the melt is diluted with 50 ml of hot water, stirred for 1 hour at 80 ° C and, after cooling, the precipitated sodium 4-bromo-3,5-dimethylphenoxyacetate is filtered off with suction and dried; 26.6 g (95 ®), m.p. above 250 ° C. A mixture of 20 g of this salt, 200 ml of methanol and 20 g of dimethyl sulfate was refluxed for 10 h and evaporated in vacuo. The residue was partitioned by shaking between 250 ml of chloroform and 100 ml of 2.5 Μ-NaOH, the chloroform solution was dried over magnesium sulfate and evaporated. The residual oil is purified by distillation (b.p. 128 ° C / 70 Pa) and the distillate crystallizes on standing; 11.0 g (58 ° C), mp 62-65 ° C (aqueous methanol).

Claims (1)

Symmetrically 1,4-disubstituted piperazine derivatives of formula (I), ArOCH ₂ COX (CH ₂ ) _Q ( _N ) (CHg) _n XCOCH _and OAr (I) wherein Ar is 2,4,5-trichlorophenyl, 2,4,6-trimethylphenyl or 4-bromo-3,5-dimethylphenyl X represents an oxygen atom or an NH group and n is 2 or 3, and their dihydrochlorides.