CS259541B2 - Method of as-triazine's condensed derivatives preparation - Google Patents

Abstract

Process for preparing condensed derivatives of the as-triazine of formula I wherein Rt is 4-chlorophenyl- or 4-fluorophenyl, R 2 is hydrogen or monohalophenyl, R 5 is alkyl with 1 to 4 carbon atoms, Z represents buta-1,3-dienyl or a group formula (a) and A- represents an anion derived from an inorganic or strong organic acid. This method is performed so that it is a compound of formula II wherein R 1, R 2, Z and A " with an alkali metal alkoxide containing 1 to 4 carbon atoms and the like the compound of formula I obtained is obtained alternatively the anion A- exchanges for another anion AND". The compounds of formula (I) exhibit particularly useful pharmacological properties antiarrhythmic and antidepressant effect.

Description

The invention relates to pharmaceutically active novel fused as-triazine derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

In particular, the invention relates to novel fused as-triazine derivatives of the general formula I

© A Θ (i) where

R 1 is 4-chlorophenyl or 4-fluorophenyl,

R ₂ represents hydrogen or monohalogenfenylskupinu,

R ₃ is C 1-4 alkyl,

Z is buta-1,3-dienyl or a group of formula aj

A 'represents an anion derived from an inorganic or strong organic acid.

The term "alkyl" as used herein refers to a straight or branched chain alkyl group (for example, methyl, ethyl, η-propyl, isopropyl, tert-butyl, etc.). "Are fluorine, chlorine, bromine and iodine atoms.

Preferred compounds of formula (I) are those in which R 1 is 4-chlorophenyl and R ₂ is hydrogen.

It can be any pharmaceutically acceptable inorganic or organic anion (such as chloride, bromide, iodide, perchlorate, methanesulfonate, ethanesulfonate anion, etc.).

The present invention provides a process for the preparation of compounds of formula (I), characterized in that the compound of formula (II)

(I!) Where

R _b, R ₂ , Z and A are as defined above, reacted with a C 1 -C 4 alkali metal alkoxide, and in the compound of formula (I) thus obtained, optionally anion A 'is exchanged for another anion A.

Accordingly, the compounds of formula (I) are prepared by reacting a compound of formula (II) with an alkali metal alkoxide containing from 1 to 4 carbon atoms. Sodium or potassium alkoxide is preferably used.

Any inert organic solvent in which the alkali metal alkoxide is soluble can be used as the reaction medium. Preferably, the reaction is carried out in an alkanol corresponding to the alkali metal alkoxide used. Thus, when sodium methoxide is used, methanol can be used as the reaction medium. The alkali metal alkoxide can be used in an equimolar amount or in an excess of 10 to 100%. The reaction may preferably be carried out at a temperature of 10 to 100 ^and C.

If desired, the anion A 'can also be exchanged for another anion A' in the compounds of the formula I obtained. This is done by methods known per se. Thus, for example, a compound of formula I containing an anion A containing a chloride anion can be converted to the corresponding compound of formula I containing a perchlorate anion by reaction with perchloric acid. Compounds of formula I containing as an N-bromide anion can be prepared from compounds of formula I containing another anion, for example perchlorate anion, by reaction with tetrabutylammonium bromide.

A compound of formula I wherein A represents ethanesulfonate can be prepared by reacting a compound of formula I wherein A^- represents another anion (e.g. bromide anion J with ethanesulfonic acid.

The starting compounds of the formula II are known (DOS 3 128 386).

239541

The novel compounds of formula (I) may be formulated into pharmaceutical compositions containing as active ingredient at least one compound of formula (I), or an isomer thereof, in association with suitable inert solid or liquid pharmaceutical carriers. These pharmaceutical compositions can be prepared by methods known in the pharmaceutical industry. The compositions may be solid (e.g. tablets, capsules, pills, coated pills, dragees), semi-solid (i.e. ointments) or liquid (e.g. solutions, suspensions, emulsions). They may be finalized to a form suitable for oral or parenteral administration.

The pharmaceutical compositions may contain carriers. These carriers can be solid carriers, fillers, sterile aqueous solutions or non-toxic organic solvents. Tablets suitable for oral administration may contain sweetening and / or other excipients (e.g. starch, preferably potato starch), binders (e.g. polyvinylpyrrolidone, gelatin), lubricants (e.g. magnesium stearate, sodium lauryl sulfate or talc) or other additives (e.g. sodium tartrate, calcium carbonate, medium calcium phosphate, etc.).

Aqueous suspensions and elixirs suitable for oral administration may further contain flavoring agents, coloring agents, emulsifying agents, diluents (for example, water, ethanol, propylene glycol or glycerol, etc.).

The parenteral compositions may contain pharmaceutically acceptable solvents (for example, sesame oil, peanut oil, aqueous propylene glycol, dimethylformamide, etc.) or water when water-soluble active ingredients are used. a liquid diluent (e.g., sodium chloride or glucose solution).

Aqueous solutions are particularly suitable for intravenous, intramuscular or intraperitoneal administration. Sterile aqueous solutions are prepared by known methods.

The daily dose of the active ingredient of the formula I can vary within wide limits and depends on several factors, in particular the effectiveness of the active ingredient used, the mode of administration and the condition of the patient.

The pharmaceutical activity of the compounds of formula I is demonstrated by the following tests.

1) Acute toxicity in mice

The test is performed on male and female white mice of strain 18 to CFLP

g. The test compound is administered orally and the animals are monitored for 7 days. There are half males and half females in each dose-tested group. The animals are housed in a plastic cage measuring 39, <12 x 12 cm on a shredded waste paper at room temperature. Mice receive standard food and tap water ad libitum. Toxicity data is determined by the Litchfield-Wilcoxon method.

Test compounds are administered in the form of aqueous solutions.

2) Antagonism to tetrabezine ptosi in mice and rats, p. O.

Groups of 10 mice were orally administered the test compound, after which 50 mg / kg tetrabenzine was administered intraperitoneally after 30 minutes, and animals showing ptosi (eyelid dropping) were counted in each group after 30, 60, 90 and 120 minutes.

The results are evaluated as follows: on the basis of all the measured data, the mean ptose is calculated in each group and the deviation from the mean value of the control group is expressed in% (inhibition. ED ₅₀ values are calculated from the data thus obtained.

3) Antagonism against reserpine ptosi in rats, p. O.

Each animal of the group of 10 rats was injected subcutaneously with 2.5 mg / kg of reserpine and then orally administered the test compound after 60 minutes. Animals showing ptosi until counting are counted. The results are evaluated as described in the previous ptosi test.

4) Antiarrhythmic effect on rats

The test is carried out by the modified method of Marmo et al. Test animals are anesthetized with ethyl urethane (1.2 g / kg i.p.). The animals are injected intravenously with aconitine at a dose of 75 µg / kg. Five minutes after the administration of aconitin, ECG changes on the standard lead II are monitored. The observed changes are scored on a scale of 0 to 5. The test compound is administered either intravenously 2 minutes before the administration of aconitine or orally 1 hour before the administration of aconitine.

The following table shows data relating to the efficacy of 1- (4-chlorophenyl) -1-methoxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium chloride. The testing was carried out according to the methods described above.

Table

LD ₅₀ about 500 mg / kg after ED ₅₀ mg / kg after 1.0 ED ₅₀ mg / kg after 1.4 ED ₅₀ mg / kg after 9.0

ED ₅₀ mg / kg p · o. 12.0 EC50 0.18 below 0.5 mg / kg

Acute toxicity in mice Antagonism against tetrabenazine ptosis in mice

Antagonism against tetrabenazine ptosi in rats Antagonism against reserpine ptosi in mice

Antagonism against reserpine ptosis in rats Local anesthetic effect Antiarrhythmic effect against aconitic arrhythmia in rats

The above results show that the above-mentioned methoxy derivative has excellent central nervous system activity (as an antidepressant) and is also suitable as antiarrhythmic agents and as a local anesthetic.

Analogous reactions also show ^one of the other compounds of Formula I.

As mentioned above, the daily dose of the compounds of formula I can vary within wide limits and depends on various factors of the case. By way of illustration, the average daily oral dose of the compounds of Formula I is about 5 to 150 milligrams, which in severe cases may be increased to 300 mg. The daily parenteral dose may be about 5 to 50 mg.

Further details relating to the invention are given in the following examples. The examples are illustrative only and do not limit the scope of the invention in any way.

Example 1

Preparation of 1- (4-chlorophenyl) -1-methoxy-1,2-dihydro-as-triazino [6,1-a] isoquinoline perchlorate

To 3.91 g (0.01 mole) of 1- (4-chlorophenyl) -as-triazino [6,1- and isoquinolinium perchlorate is added methanol containing 0.02 mole of sodium methoxide. The yield is 83%, m.p. 158-159 ° C.

Example 2

1- (4-Fluorophenyl) -1-methoxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium ethanesulfonate

385 g (0.01 mol) of 1- (4-fluorophenyl) -as-triazino] 6,1-a] isoquinolinium ethanesulfonate are added methanol containing 0.02 mol of sodium methoxide and then the product is added by adding 2,2 g (0.022 mol) of ethanesulfonic acid precipitates, yield: 78%, mp: 144-146 ° C.

Example 3

4- (4-chlorophenyl) -4-methoxy-3,4-dihydropyrido [2,1-f] -as-triazinium perchlorate

To 5.5 g (0.013 mol) of 4- (4-chlorophenyl) pyrido [2,1-f] -as-triazinium perchlorate is added methanol containing 0.03 mol of sodium methoxide and then the product is precipitated by the addition of 12 ml of 7% aqueous perchloric acid. Yield: 81%, mp: 162-164 ° C.

Claims (2)

Process for the preparation of fused as-triazine derivatives of the general formula I H OF THE INVENTION a A @ - represents an anion derived from an inorganic or strong organic acid, characterized in that the compound of the formula (II) wherein R 1 is 4-chlorophenyl or 4-fluorophenyl, R ₂ is hydrogen, or monohalo-phenyl, R ₃ is C 1-4 alkyl, Z is buta-1,3-dienyl or a group of formula (a) (A 1 H) wherein R _H, R ₂ , T and A are as defined above, reacted with an alkali metal alkoxide having 1 to 4 carbon atoms, and in the compound of formula I thus obtained optionally anion A ^{- is} exchanged for another anion A '. 2. The process according to claim 1, wherein the reaction medium is an alkanol corresponding to the alkali metal alkoxide used.