CS217261B1 - Cinnamylpiperazine Derivatives and Their Pigments - Google Patents

Abstract

The invention relates to novel 1-cinnamyl-4-(aminoacetyl)piperazine derivatives and their salts, in whose molecules the amine group is formed by aniline, pre-aniline and 4-hydroxy(or pre-phenyl)-4-arylpiperidine residues, wherein the aryl may be substituted by a chlorine, fluorine or trifluoromethylene atom. The substances according to the invention are non-narcotic analgesics which have similar efficacy to eminephenazene in pain induction tests by mechanical or chemical irritation. The substances according to the invention can be prepared from the known 1-cinnamylpiperazine by acylation with chloroacetyl chloride and subsequent substitution reactions of the obtained 1-cinnamyl-4-(chloroacetyl)piperazine with aniline or 4-hydroxy-4-arylpiperidine; the synthesis can be completed by optional acylation of the free hydroxy group or the NH group of the pre-. pieeylchleriiem.

Description

This invention relates to certain cinnamylpiperazine derivatives of the general formula I

(I) wherein R ¹ denotes phenyl and R ² represents a hydrogen atom or propionyl,

WR R is substituted piptrialyl of general sub-formula II

is a hydrogen, chlorine or fluorine atom, and their pharmaceutically acceptable salts with inorganic or organic acids.

The compounds of formula I and their salts are non-narcotic analgesics which have a similar degree of activity to aminaphenazene in mechanical and chemical analgesia tests; at the same time, the needle does not have side effects. These properties make them useful as pharmaceuticals. The properties of the substances according to the invention can be illustrated by these specific data.

1-Cinnamyl-4- [trans- (propionanilido) acetyl] piperazine hydrochloride is very toxic. Its acute toxicity in mice is expressed as mean death at the oral dose, <sc · 1 β / kg. The oral dose of 183 mg / kg is the median effective dose of the compound in the mechanical analgesia test in mice (push). In the chemical analgesia test (irritation by intraperitoneal administration of acetic acid in mice), the BD q q is 74 74 mg / kg p · · .; in this teat, the new substance is more effective than aminophenazone (ΕΕ ^ θ = 104 mg / kg p. ·.).

1-Cinnamyl-4- (4-phanyl-4-hydroxypiperidinoacetyl) piperazine dihydrochloride has an LB of about 0.6 g / kg p.o. For oral counting, ED50 is 205 mg / kg in the mschanical analgesia test and 113 mg / kg in the chemical analgesia test.

1-Cinnamyl-4- [4- (4-fluorophenyl) -4-hydroxpiperidinoacetyl] piperazine bihydrochloride has an oral LB ^ qu mouse of approximately 0.5 g / kg. In the chemical analgesia test, oral ^ED 50 is 62 mg / kg, so that the substance is almost twice as effective as aminophenazone.

1-Cinnamyl-4- (4-phenyl-4-propionoxypiperidinoacetyl) piperazine dimaleinate has oral LE 4 qu mice also of approx. 0.5 g / kg. In the chemical analgesia test, the aforesaid is λΒΒ ^and 153 mg / kg.

The processes for the preparation of the compounds according to the invention are described in the examples. They are based on the known 1-cinnamylpiperazine (T. Irikura et al., J. Med. Chem. II. 801, 1968). which is first converted by reaction with chloroacetyl chloride in chlereferm at room temperature to the chloroacetyl derivative hydrochloride of formula III

-CH = CHCH ₂ W hCOCH ₂ Cl (III),

By stamping with a solution of sodium hydrogen carbonate, crystalline base III is obtained, which is reacted in the crude state with amines. So, for example, it reacts with aniline in? boiling benzene gives the corresponding anilinaacetyl derivative. Reactions of the chloroacetyl derivative of formula III and 4-phenylpiperidin-4-elem (P.A.J.Janssen et al., J. Med. Pharm. Chem. 1, zul, 1959;

Belg. 577.977; U.S. Pat. 2,973,363; Briton. 881.893), 4- (4-fluorophenyl) piperidin-4-6-one (Holland, login 65/10107; Chem. Abdtr., 65, 7154, 1966) and 4- (4-chloro-3-yl), rif lue rmethy Heny 1) piperidia-4-eleR, (K. Sindelar and Cell. The compounds of formula (I), the attribute of which exhibits an additional OH or NH group, can be prepared by the action of prapianyl chloride to produce the corresponding propene esters or N-propionylderivatives, which are also subject of the invention.

The compounds of formula (I) are basic in nature and provide acid neutralization salts, some of which crystallize and are suitable for re-pharmacological testing and for the preparation of attractive farms. The identity of all the substances mentioned below was ensured both by analyzes and by all types of common spectra (UF, IR, Ή-ΝΜΗ, mass).

Example 1 1- (Anilineacetyl) -4-cinnamylpiperazine

A mixture of 2.5 g of 1-chloroacetyl-4-cinnamylpiperosine, 3.5 ml of aniline and 5 ml of benzene is heated under reflux for 2 hours and left to stand overnight at room temperature. The precipitated product hydrochloride was filtered, quenched with 50 ml of 10% sodium hydroxide solution and the base was isolated by extraction with benzene. Workup of the extract yielded 2.2 g (73%) of the product melting at 142-144 ° C. After crystallization. from benzene melts the analytical sample at 144-146 ° C.

Starting 1- (chloroacetyl) -4-cinnamylpiperazine is a novel material and is prepared as follows: To a stirred solution of 14.3 g of 1-cinnamylpiperazine in 90 ml of chloroform is added dropwise 8.0 g of chloroacetyl chloride over 20 minutes at 5-10 ° C. The mixture was stirred for 3 hours at room temperature and allowed to stand for 48 hours. The precipitated product hydrochloride (17.0 g, 78%) was filtered and recrystallized from ehlereferm; mp 174-177 ° C (flashing at 111 ° C and re-solidification). Decomposition of the hydrochloride with a saturated solution of sodium hydrogen carbonate and extraction with benzene gave a crude solid base with a melting point of 98 already 104 ° C, which was used without further purification.

Example 2 1-Cinnamyl-4 - [(N-prepienanilide) acetyl] piperazine

To a solution of 6.2 g of 1- (anilineacetyl) -4-cinnamylpiperazine in a mixture of 100 ml of benzene and 10 ml of chloroform is added dropwise a solution of 1.75 g of prepienylchloride in 10 ml of benzene with stirring at 30 ° C. The mixture was boiled under reflux for 2 hours. After cooling, the precipitated crude hydrochloride was filtered, quenched with aqueous ammonia and the crude base was isolated by extraction with benzene. Purify by chromatography on 130 g of alumina (neutral, activity II). 5.7 g (79%) of a heugenic tallow base are obtained. Neutralization of the base solution in acetone with hydrogen chloride in ether afforded the hydrochloride melting at 210-215 ° C (ethanol). Neutralization of the base with maleic acid in ethanol yields hyargen maleate, m.p. 146 DEG-148 DEG C. (ethanal).

Example 3 1-Cinnamyl-4- (U-hydroxy-4-phenylpiperidium) acetyl] -piperazine

4.9 g of 4-phenylpiperidia-4-rel in 50 ml of chlereferm were added to the stirred residue and 7.2 g of 1- (chleracetyl) -4-cimnamylpiperazim in 30 ml of chlereferm were added dropwise over 30 minutes.

The mixture was boiled for 4 minutes under reflux, concentrated in vacuo, the residue was resolved with 100 ml of 10% sodium hydroxide solution and extracted with chloroform. Workup of the extract yielded 7.2 g (67%) of the product melting at 135-140 ° C. Recrystallization from a mixture of ethamel and ether gave the analytical product and m.p. 137.5-139.5%. The base can be converted by neutralization with a chlorohydrogen to both menehydrochloride melting at 225.5-227 ° C under decomposition (ethanol-ether) and dihydrochloride which crystallizes from a mixture of 97% ethanol and ether as menehydrate, mp 254-255 ° C.

Example 4 1-Cinnamyl-4- (4-fluorophenyl) -4-hydrexypiperidine / acetylpiperazine

To a residue of 5.45 g of 4- (4-fluorophenyl) piperidine-4-el in 50 ml of chlerephrene, a solution of 7.7 g of 1- (chcleracetyl) -4-cinnamylpiperazine in 45 ml of chlereferm is added and the mixture is pretreated as as described in Example 3. 9.1 g (75%) of the crystalline base are obtained. Some crystallization from acetone melts at 145.5 to 147%. Neutralization reactions can produce the following selenium: bis (hydrogengenealeinate) -enhydrate, m.p. 94-97 (ethanol-ether); m.p. 243 DEG-245.5 DEG C. with decomposition (95% ethanol).

Example 5 1-Cinnumyl-4-Z4-halo-3-trifluoromethylphenyl) -4-hydroxy-piperidine / acetylpiperazine

Reaction of 2.3 g of 4- (4-ehler-3-trifluoromethylphenyl) piperidin-4-el and 2.4 g of 1- (ehleracetyl) -4-cinnamylpiperazine in 25 ml of boiling chlereferm gives, as in the previous examples, 2.6 g (54%) of the crude base, which crystallizes from benzene and melts at 156-158 ° C. Neutralization with maleic acid yields bie (hydegen maleate) and melting point 151 DEG-154 DEG C. (aoetene ether).

Example 6 1-Ciananyl-4 - [(4-phenyl-4-prepienexypiperidiae) acetyl] piperazine

To a residue of 5.2 g of 1-cinnaayl-4 - [(4-hydroxy-4-phenylpiperidine) -acetyl] piperazine and 1.0 g of triethylamine in 25 ml of chlereferm, 2.5 g of prepienylahleride are added dropwise with stirring and external cooling. The mixture is stirred for 6 h at room temperature, allowed to stand over somewhat, then shaken and 150 ml of saturated potassium carbonate effluent and extracted with chloroform. The extract was washed with water, dried (MgSO4) and evaporated. The residue is chromatographed on sleupei with 250 g of alumina. Elution with benzene, to which ae adds 25% of chlereferm, yields 2.8 g (48%) of the hemegenic elevevite base. Neutralization of maleic acid in acetone gave bis (hydragenmaleinate) with a melting point of 184-186 ^and C (ethanol).

Claims (1)

Cinnamyl-piperazine derivatives of the formula (I): ch = chch _2. N noch ₂ nk ¹ r ² (I), 12 wherein R is phenyl and R is hydrogen or propionyl, or wherein the whole of NR 1 R ² is substituted piperidyl of the general formula II (II), Υχ / wherein R ^J is hydrogen or propionyl; R * jo voaíku atom or trifluoromethyl and Ir qt ", hydrogen, chlorine or fluorine, and their pharmaceutically nezáv.ané sowed with inorganic or organic acids.