CS200208B2 - Method of preparing alkylene-dioxy-piperazine derivatives - Google Patents

Description

The invention relates to a process for the preparation of alkylenedioxypiperazine derivatives.

It is known that life-threatening ventricular disorders of the heart rhythm, and coronary heart disease often occur in a narrow temporal context or causally related to each other. F. Nager et al. Schweiz. copper. Wscher. 102. 1836-1851 (197217.

The drugs available for the treatment of these diseases either act only against cardiac arrhythmia (e.g. lidocaine) or only in coronary disorders (e.g. nitroglycerin).

The present invention is a process for preparing a formula I derivative of alkylendioxypiperazinových ^R 3 -O-

(I) where

R 1 represents a hydrogen atom or a diphenylmethyl radical in which the phenyl group may be replaced by a halogen atom,

Hg represents a hydrogen atom or a (C 1 -C 5) -alkyl radical, is a methylene or ethylene group, and their physiologically tolerated acid salts, characterized in that the compound of formula (II) (II) is of the general formula II.

CH ₃

l-R.

‘1

R, where R, and Rg ^is as defined above, is reacted. If R @ ₁ and / or R @ 8 in the compounds thus obtained are hydrogen, optionally ee introduce substituents on the nitrogen atom and optionally convert the obtained compounds into physiologically tolerable salts by means of acids.

The invention also relates to medicaments which contain the compounds of the formula I or their salts with physiologically tolerated acids. Suitable physiologically tolerable acids are, inter alia: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, citric acid, tartaric acid, lactic acid, diamidosulfonic acid.

The reaction of the 3,4-dihydroxybenzyl compounds to the corresponding alkylenedioxybenzyl compounds ee is carried out in an aprotic solvent such as dimethylformamide, hexamethylphosphoric triamide and sulfolane. Dimethylsulfoxide is particularly preferred. Suitable alkylating agents are halogenated hydrocarbons, such as 1,2-dihalogenethane and dihalogenethane. It is recommended to work in the presence of a basic condensing agent such as an alkali metal hydroxide and carbonate. The addition of copper powder is preferred. The reaction temperature is between 40 and 150 ° C.

The same reaction can also be carried out by phase transition catalysis in aromatic hydrocarbons such as benzene, toluene and xylene, or cyclic ethers such as tetrahydrofuran and dioxane. Suitable catalysts are quaternary alkyl ammonium halides with longer alkyl radicals. The reaction is carried out at a temperature of 20 to 100 ° C, preferably with dibromomethane or 1,2-dibromomethane in the presence of basic condensing agents such as alkali metal hydroxides.

Alliylation of the piperazine ring system with substituted or unsubstituted diphenylmethyl halides occurs specifically at the 1-position nitrogen. Bromides and chlorides are preferably used as halides, preferably aromatic hydrocarbons such as benzene, toluene and xylene or low boiling ketones such as acetone, methyl ethyl ketone, diisobutyl ketone. Also preferred is, for example, dimethylformamide and hexamethylphosphoric triamide; the temperature is preferably between 25 and 130 ° C. It is recommended to add a basic condensing agent such as tertiary organic bases or an alkali metal carbonate such as potassium or sodium carbonate

The alkylation to the nitrogen atom in the 4-position can be carried out in an analogous manner. However, when using alkyl chlorides or alkyl bromides, addition of sodium iodide or potassium iodide and a slight overpressure of 0.147 to 0.98 MPa are recommended.

Further, it is possible to acylate the piperazine ring system with acyl halides, anhydrides or esters at the 4-position nitrogen atom and reduce the acylation products in aliphatic or cyclic ethers, such as diethyl ether, dioxane or tetrahydrofuran, using complex hydrides to the corresponding alkyl derivatives.

The methyl group can also be introduced at the 4-position nitrogen atom by reacting the piperazines in a suitable solvent, such as aromatic hydrocarbons or chlorinated hydrocarbons, in the presence of a base, preferably triethylamine, at a low temperature of 8 with a formic halide ester. The acylation product thus obtained can be very easily reduced by complex hydrides in a known manner.

Reaction with acylation! with piperazinones. Reducing the CO-group at the 2-position also reduces the acyl residue at the 4-position and converts the ee to an alkyl group.

The piperazine derivatives can further be hydroxyalkylated at the 4-position nitrogen atom with alkylene oxides. The solvent used is a 2: 1 mixture of low-boiling alcohols and aromatic hydrocarbons, preferably methanol and benzene. The reaction is preferably carried out at a temperature of 25 to 80 ° C and a pressure of 0.294 to 0.490 UPa.

In these reactions on the nitrogen atom 4, the nitrogen atom 1 must either be substituted with a radical R or protected with a protecting group which is later cleaved again, otherwise the nitrogen reaction 1 would have the same reaction as the nitrogen atom 4.

The novel compounds have good antiarrhythmic effects. In addition, it has been shown to counteract the tapering effect of Ca-ions in blood vessels at low doses. They are therefore particularly suitable for the treatment of coronary heart disease and associated cardiac disorders.

Furthermore, the novel compounds inhibit the effects of numerous biogenic amines and other vasoconstrictor vasoconstrictors, so that they can be used to treat vascular diseases such as high blood pressure, peripheral and cerebral disorders of blood circulation.

Table 1

Batch A B C

Substance (molar) histamine adrenaline calcium Sherotonin AND IO ' ⁷ -41% -83% -30% -40% II io- ⁷ -27% -58% -26% -27% III 10 ⁷ -43 # -56% -16% -6 # IV IO ⁷ -12% -65% -20% -50% Vincamin io- ⁶ -5 » +6% +3 » ⁰ * Peribedil io- ⁶ -4% +9% -2 » +3% Pentoxy- fyllin io- ⁶ + 1% -5% -2% +3 »

I (L) -1-Diphenylmethyl-3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine

XI »(L) -1-diphenylaethyl-3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine

III '(L) -1- (p, p'-difluorophenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine

IV (L) -1- (p-fluorophenylphenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine.

Table 1 shows how strongly the test substance is suppressed at the indicated dose at the perforated rabbit ear flow induced by histamine (1.5.10 moles) or adrenaline (3.10 ”moles) / method according to: Aust. J. exp. Biol. copper. Sci. Fafa, 739 (1968)]. Column B shows to what extent the contraction induced by 5.10 ⁴ moles is suppressed. with calcium chlo200206 solution on aortic strips in calcium depleted rats and depolarized potassium / method according to: Brit. J. Pharmac. 2 $. 549 (19691) - column C contains the appropriate values for serotonin antagonism, which was measured on aortic lanes in Krebs-Henseleit solution

The values show how strongly the test substances are inhibited by the contraction induced by aerotonin (10 µmoles).

Furthermore, the novel compounds have good antiarrhythmic effects, which are determined by determining the functional refractive time on the isolated right atrium of the guinea pig according to the Goric Zerov method. J. Pharm. Exp. Ther. 148. 100 (1965) / - Table II shows the results thus obtained. RF means increasing the refractive time in percent.

Table II

Substance Dose (molar) RP AND 10 “ ⁵ 47 II ⁵ ' ⁵ 49 III , 0 ⁵ 28 IV 10 ⁵ 55 vincamin 10-5 21 piribedil , 0-5 4 pentoxyfyllin ΙΟ ^-5 0

I-IV see Table I

The novel compounds are therefore suitable for the treatment of vascular diseases such as peripheral and cerebral disorders of blood circulation. Further, they may use, for their calcium-entagonistic properties and refractive time-prolonging effects, to treat coronary heart disease and related heart rhythm disorders.

The novel compounds and their salts can be administered orally and parenterally. The daily dose is between 0.1 and 3.0 mg / kg for intravenous or intramuscular administration and between 0.5 and 10 mg / kg for oral dose. Known galenic forms such as tablets, dragees, capsules and solutions are suitable for administration.

Preparation of starting materials

AND.

Reaction of 3,4-dihydroxyphenyl-alpha-alanine methyl ester with benzyl bromide in methyl ethyl ketone under reflux gives N-benzyl-3,4- (dibenzyloxyphenyl) -alpha-alanine methyl ester (tt HCl = 170 ° C), which forms cold with aqueous formaldehyde solution and potassium cyanide N-benzyl-N-cyanomethyl-3,4-dibenzyloxyphenyl-alpha-alanine methyl ester (mp = 107 ° C). It is then obtained by hydrogenation using Hg / Raney nickel under pressure of 3-methyl-3- (3,4-dibenzyloxyphenyl) -4-benzylpiperazinone- (2) (mp = 55 ° C) from which it is obtained with concentrated acid hydrogen bromide at room temperature 3-methyl-3- (3,4-dihydroxybenzyl) -4-benzylpiperazinone- (2) -hydrobromide (mp = 16-163 ° C).

B.

From (D) -3-methyl-3- (3,4-dihydroxybenzyl) -4-benzylpiperazinone- (2) (cf. A), it is obtained by reaction with benzyl bromide in acetone and in the presence of potassium carbonate (D) -3- methyl-35

- (3,4-Dibenzyloxybenzyl) -4-benzylpiperazinone- (2). When this compound is reacted with sodium hydride and then with diphenylmethyl bromide in dimethylformamide, (D-1-diphenylmethyl-3-methyl-3- (3,4-dibenzyloxybenzyl) -4-benzylpiperazinone- (2) is formed, from which they can be cleaved by hydrogenation using a palladium / hydrogen benzyl group.

From the dihydroxybenzyl compound thus obtained, glacial acetic acid (HCl) (D) -1-diphenylmethyl-3-methyl-3- (3,4-diacetoxybenzyl) -piperazinone (2) is obtained by reaction with acetyl chloride. When this compound is reacted with methyl iodide and then lithium aluminum hydride, (D) -1-diphenylmethyl-3-methyl-3- (3,4-dihydroxybenzyl) -4-methylpiperazine (8a) is formed. HCl ⁼ -76 to 178 ° C (ethanol) ^{/ alpha /} 334 nm ^{H 1} > ² °

By analogy, the corresponding (L) -compound is obtained, mp = 175-177 ° C (ethanol) ^{/ alpha /} n4nm = -> ² °

He did

9.5 g of (D) -1-diphenylmethyl-3-methyl-3- (3,4-dihydroxybenzyl) -4-methylpiperazine dihydrochloride (Ba) are suspended under nitrogen in 100 ml of toluene-tetrahydrofuran (1: 1) mixture. and 0.1 g of tributylbenzylammonium bromide a, 1 g of 50% sodium hydroxide solution are added.

The mixture was stirred for 20 minutes. 4.5 g of dibromoethane in 20 ml of toluene-tetrahydrofuran (1: 1) are then added dropwise over 10 minutes. After stirring at 45 ° C for 20 minutes, 4.5 g of dibromoethane are added. After a further 60 hours, the reaction solution is concentrated, dissolved in 100 ml of toluene, washed with water until the halogen disappears, dried and evaporated to dryness in vacuo.

The residue was dissolved in 75 ml of diisopropyl ether, filtered and isopropanolic hydrochloric acid was added to the filtrate. The precipitate formed is filtered off and dried under vacuum at 40 ° C. 8.1 g (80.6 ') of (D) -1-diphenylmethyl-3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine dihydrochloride are obtained,

mp = 215-2.7 ° C (isopropanol), [α] D -15.6 ° (free base, c = 1, methanol).

Accordingly, the L-enantiomer is also obtained as the dihydrochloride, m.p. > 2.4 DEG-215 DEG C. [.alpha.] D @ 15 +15.6 DEG (c = 1, methanol).

Analogously, (D) -1-diphenylmethyl-3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine is obtained as a glassy solidified [alpha] -15.7 ° (c = 1, methanol) (L). ) -diphenylmethyl-3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin [.alpha.] D @ 20 = + 15.8 DEG (c = 1, methanol) (D) -1-diphenylmethyl -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-ethylpiperazine as a glassy solidified [alpha] β 9.1 ° (c, methanol) (L) -1-diphenylmethyl-3-methyl-3- (3,4-ethylenedioxybenzyl) -4-ethylpiperazine as a glassy solidified resin / alpha / β ° + 9.2 ° (c = 1, methanol) (D) -1-diphenylmethyl-3-methyl-3- (3,4 -ethylenedioxybenzyl) -4-n-propylpiperazine as a glassy solidified [alpha] -5.3 ° (c = 1, methanol) (L) -1-diphenylmethyl-3-methyl-3- (3,4-ethylenedioxybenzyl) ) -4-n-propylpiperazine as a glassy solidified resin / alpha /? 0 + 5.4 ° (c -1, methanol)

1- (p-chlorophenyl-phenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine dihydrochloride

mp = 223-225 ° C (ethanol) (D) -1- (p-chlorophenylphenylmethyl) -3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin (alpha) | ° = · -15 , 7 ° (c = 1, methanol) (L) -1- (p-chlorophenylphenylmethyl) -3-methyl-3- (314-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin (alpha) | ° = + 15.5 ° (c 1, methanol) (D) -1- (p, p'-dichlorodiphenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin (alpha) p ° = -15.1 ° (c = 1, methanol) (L) -1- (p, p'-dichlorodiphenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified [.alpha.] D @ 20 = + 15.3 DEG (c, methanol), - (p-fluorophenylphenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine mp 189-191 ° C (ethanol) (D) -1- (p-fluorophenylphenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin (alpha) β ° -14.0 ° (c 1, methanol) (L) -1- (p-fluorophenylphenylmethyl) -3-methyl-3- (3,4-ethylenedioxybene) zyl) -4-methylpiperazine as a glassy solidified resin / alpha / j ⁰ = + 14.1 ° (c = 1, methanol)

- (p, p'-Difluorodiphenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine dihydrochloride

mp 224-226 ° C (methanol) (D) -1- (p, p'-difluorophenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin (alpha) | -13.6 ° (o = 1, methanol) (L) -1- (p, p'-difluorodiphenylmethyl) -3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin / alpha / p ° »+ 13.5 ° (e-1, methanol)

1-Diphenylmethyl-3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazinedihydrochloride hydrate

mp 195-198 ° C (ethanol) (D) -1-diphenylmethyl-5-methyl-5- (3,4-methylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin (alpha) -20 ° -20, 0 ° (c - 1, methanol) (L) -1-diphenylmethyl-3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin / alpha / p = +19.8 (c 1 (methanol) (D) -1-Diphanylmethyl-3-methyl-3- (3,4-methylenedioxybenzyl) -4-ethylpiperazine as a glassy solidified resin [.alpha.] D @ 20 = -12.4 DEG (c = 1, methanol) (L) -1-diphenylmethyl-3-methyl-3- (3,4-methylenedioxybenzyl) -4-ethylpiperazine / elf / ^ ^{0 and} + 12.2 ° (c = 1, methanol) (D) -1-diphenylmethyl -3-methyl-3- (3,4-methylenedioxybenzyl) -4-n-propylpiperazine / [alpha] D = -8.1 (c = 1, methanol) (L) -1-diphenylmethyl-3-methyl- 3-Methyl-3- (3,4-methylenedioxybenzyl) -4-n-propylpiperazine / [alpha] D = + 8.0 [deg.] (C = 1, methanol)

- (p-chlorophenyl-phenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine dihydro chloride

mp = 193 ° C (isopropanol) (D) -1- (p-chlorophenylphenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin / alpha / p ° * - 21.0 ° (c = 1, methanol) (L) -1- (p-chlorophenylphenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl-4-methylpiperazine) as a glassy solidified resin (alpha) ? D = + 20.8 ° (c = 1, methanol) (D) -1- (ρ, p'-dichlorodiphenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin [.alpha.] D @ 20 -19.3 DEG (c = 1, methanol) (L) -1- (r, p'-dichlorodiphenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine as glassy solidified [alpha] + - 19.5 ° (c = 1, methanol) (D) -1- (p-fluorophenylphenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4 methylpiperazine as a glassy solidified resin / alpha / jj ⁰ -22.4 DEG (c = 1, methanol) (L) -1 - (p-fluorophenyl-phenylmethyl-ethyl) -3-methyl-3- (3,4-methylenedioxybenzyl ) -methylpiperazine as glassy solidified resin / alpha / j) ⁰ '+ 22.5 ° (c = 1, metha nol)

200208 8

- (P, P'-difluorophenylmethyl) -3- (3,4-methylenedioxybenzyl) -4-methylpiperazine dihydrochloride as hydrate

mp 201 ° C (isopropanol) (D) -1- (p, p'-difluorophenylmethyl) -3- (3,4-methylenedioxybanzyl) -4-methylpiparazine as a glassy solidified resin / alpha / p® "-20,4 ° (e = 1, methanol) (L) -1- (p, p'-difluorophenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine as a glassy solidified resin / alpha / p® = + 20.6 ° (c 1, methanol)

Example 2

Tablets of the following composition are compressed in a conventional manner on a tabletting machine:

200 mg (L) -1-diphenylmethyl-3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine; 150 mg corn starch, 13.5 mg gelatine, 45 mg milk sugar, 22.5 mg talku, 2.25 mg aerosil® (chemically pure silica in submicroscopically fine dispersion); and 6.75 mg Potato Starch (as 6% sebum). Ex lad 3

In the usual manner ae prepare dragees of the following composition:

100 ALIGN! mg (L) -1- (p-fluorophenylphenylmethyl) -3-methyl-3- (3,4-methylenedioxybenzyl) -4-methylpiperazine, 170 mg fillers and , 60 mg dražovací mass,

The filler consists of 9 parts corn starch, 3 parts milk sugar and 1 part luviscol® Va 64 (vinyl pyrrolidone vinyl acetate copolymer 60:40, cf. Pharm. Ind. 1962, 586). The solder mass consists of 5 parts of cane sugar, 2 parts of corn starch, 3 parts of calcium carbonate and 1 part of talc. The dragees thus prepared are then coated with a gastric-resistant coating.

Example 4 g of (L) -1-diphenylmethyl-3-methyl-3- (3,4-ethylenedioxybenzyl) -4-methylpiperazine diaminodosulfonate was dissolved in 5 liters of water. The solution was adjusted to pH 3.5 with 0.1 N sodium acetate and isotonic with sodium chloride. The sterling is then filled into 2 ml ampoules.

Claims (1)

A process for the preparation of alkylenedioxypiperezine derivatives of the general formula I -B, Ί R. (I) where R 1 represents a hydrogen atom or a diphenylmethyl radical in which the phenyl group may be replaced by a halogen atom, R 8 represents a hydrogen atom or a C 1 -C 5 alkyl radical, is a methylene or ethylene group, and their physiologically tolerated acid salts, characterized in that the compound of formula II HIM HIM R. (II) where R 1 and Rg ^m hjí výěe hereinbefore defined, is reacted with alkylendihalogenidem having 1-2 carbon atoms and if R and / or R in the thus obtained compounds is hydrogen or substituent is introduced on the nitrogen atom and the substance obtained is optionally converted into physiologically snáěenlivé salts with acids.