CS264267B2 - Method of as-triazine's new condensed derivatives preparation - Google Patents

Abstract

Amphoteric triazine cpds. of formula (I) and their isomers are new: R1 = 1-10C alkyl, 3-6C cycloalkyl, phenyl, naphthyl or phen (1-4C) alkyl (the last 3 opt. ring-substd. by 1 or more halo, NO2, CF3, NH2, OH, and/or 1-4C alkyl or alkoxy); R2 = H, halo, OH, oxo, 1-4C alkyl or alkoxy, or phenyl or naphthyl (both opt. substd. as above); R3 = H, OH or 1-4C alkoxy; Z = beta-1,3-dienyl or a gp. (a) or (b); X = H or halo. Pref. Z = gp. (b); X = H; R1 = phenyl, opt. 4-halo(esp. chloro)substd.

Description

The present invention relates to n-condensed derivatives of the " Zwitterionts " -triazine derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

In particular, the invention relates to novel compounds of formula I

where

R 1 is phenyl which is substituted with one halogen atom,

R 2 is hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is C 1 -C 4 alkoxy.

The term "C 1 -C 4 alkyl" as used herein refers to a straight or branched chain alkyl group (e.g., methyl, ethyl, η-propyl, isopropyl, tert-butyl, etc.). ).

The term "C 1 -C 4 alkoxy" is used to denote straight or branched alkoxy (such as methoxy, ethoxy, isopropoxy, etc.).

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

Among the compounds of formula I, those in which R 1 is 4-chlorophenyl are preferred. Preferably R3 is methoxy.

A particularly preferred representative compound of Formula I is 1- (4-chlorophenyl) -1-methoxy-as-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide.

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

R 1 and R 2 are as defined above, reacted with a C 1 -C 4 metal alkoxide.

A represents a suitable inorganic or organic anion, for example a halide anion such as:

chloride, bromide or iodide anion, or perchlorate, methanesulfonate, ethanesulfonate or p-toluenesulfonate anion, etc.

In the process for the preparation of the compounds of the formula I according to the invention, the compounds of the formula II are reacted with a C1 -C4 metal alkoxide. The metal alkoxide is preferably an alkali metal or alkaline earth metal alkoxide, for example sodium or potassium alkoxide.

The reaction may be carried out in a solvent forming the anion with the desired alkoxide. The alkanol corresponding to the alkoxide used is preferably used as the reaction medium. It is also possible to use a solid alkoxide in conjunction with an anhydrous solvent which is capable of dissolving the alkoxide and which serves as the reaction medium (e.g. an ether such as tetrahydrofuran, dioxane or diethyl ether; or an aromatic hydrocarbon such as benzene or toluene). The alkoxide may be used in an equimolar amount or in a slight excess. The reaction may be carried out at a temperature of 0 to 100 ° C and preferably at room temperature.

The starting materials of formula (II) are those known from DOS No. 3,128,386.

The novel compounds of formula (I) may be formulated into pharmaceutical compositions containing as active ingredient at least one compound of formula (I) in association with suitable inert solid or liquid pharmaceutical carriers.

These pharmaceutical compositions can be prepared by methods well known in the pharmaceutical industry. The means may be:

solids (e.g. tablets, capsules, pills, coated pills, dragees), semisolids (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 where

A represents an anion derived from an inorganic or strong organic acid and

suitable for oral administration may include:

sweeteners and / or other excipients (e.g. starch, preferably potato starch), binders (e.g. ipolyvinylpyrrolidone, gelatin), lubricants (e.g. magnesium stearate, sodium lauryl sulfate or talc), or other additives (e.g. sodium citrate, calcium carbonate, calcium phosphate, etc,).

Aqueous suspensions and elixirs suitable for oral administration may further contain flavors, colorants, emulsifiers, diluents (e.g. water, ethanol, propylene glycol or glycerol, etc.).

Parenteral compositions may contain pharmaceutically acceptable solvents (for example, sesame oil, peanut oil, aqueous propylene glycol, dimethylformamide, etc.) or water, if water-soluble active ingredients are used. Aqueous solutions may be buffered with a suitable buffer solution or may be isotonicized with a suitable 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 carried out on male and female white-and-white CFLP strain mice weighing 18-22 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. Animals are housed in a 39 X 12 X 12 cm plastic cage on shredded waste paper at room temperature. Mice receive standard food and tap water ad libitum. Toxicity data is determined by the Litchfield-Wilcoxoin method.

Test compounds are administered in the form of aqueous suspensions prepared using 0.5% carboxymethylcellulose.

Table I

Toxicity in mice

Tested LD 50 mg / kg compound after. compound В 420 Amitriptyline reference 225 Compound D 600

2. Antagonism to tetrabenazine ptosi in mice and rats p.o.

Groups of 10 mice were orally administered the test compound, followed by intraperitoneal administration of 50 mg / kg tetrabenazine after 30 minutes, and animals showing ptosi (eyelid drop) were counted after 30, 60, 90 and 120 minutes in each group.

The results are evaluated as follows:

On the basis of all 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.

The results are summarized in Table II.

Tetrabenazine ptosi antagonism in mice and rats

Test compound (Mice

ED 50 mg / kg Compound V.25 Reference Compound D3.2

Amitriptyline12,00

3. Antagonism against reserpine ptosis in mice, p.o.

Each animal of the group of 10 mice is administered subcutaneously with 6 mg / kg of reserpine and is then orally administered the Ther after 60 minutes. rats index

ED 50 mg / kg

16800.6

1885.6

1911.50 Compound. Animals showing ptosi are counted after 60 and 120 minutes. The results are evaluated as described in the previous ptosi test (Test 2). The results are summarized in Table III below.

Table III

Antagonism to reserpine ptosis in mice

Test compound

ED 50 mg / kg

Ther. index compound В reference compound Amitriptyline

1,5 over 120

280.0 below 5.0

3.45

4. Antagonism against reserpine ptosi in rats, p.o.

Each animal of the groups 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 (test number 2).

The results are summarized in Table IV below.

5. Potentiating the toxicity of yohimbine in mice

The tests are carried out using the Quinton method. Groups of 10 mice each receive the test compound. After one hour, the animals are injected intraperitoneally with a 20 ml / kg sublethal dose of yohimbine. Dead animals are counted after 1 and 24 hours. The results are summarized in Table V.

Table IV

Antagonism to reserpine ptosi in rats

ED 50 mg / kg

Test compound Compound В 34

Reference Compound D Amitriptyline 60 about 140

Table V

Potentiation of yohimbine toxicity

Test compound

ED 50 mg / kg

Ther. index compound В Amitriptyline

1,2

12.5

3'50

6. Antiarrhythmic effect in rats

The test is carried out by the modified method of Marmo et al. Test animals are anesthetized with ethylurethane (1.2 g / kg,

i.p.J. 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. Observed changes are scored from 0 to

5. The test compound is administered either intravenously two minutes before the administration of aconitine or orally one hour before the administration of aconitine.

The results are summarized in Table VI.

Table VI

Test compound Dose Inhibition% compound В Lidocaine 1 mg / kg 44.3 4 mg / kg 23.4

7. Antitremorin effect in mice

Mice are administered i.p. with 20 mg / kg tremotime and after 45 minutes the characteristic tremor is registered. Test compounds were administered orally 1 hour prior to administration of tremorine. The results are summarized in Table VII.

Table VII

Antitremorin effect in mice

Test compound ED50 mg / kg Ther. index compound В 40 10, ^l 5 reference compound D inactive -

The following compounds were used for testing:

Compound VI = 1- (4-chlorophenyl) -1-methoxy-as-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide

Reference Compound D = 1- (4-chlorophenyl) -as-triazino [6,1-a] isoquinolinium bromide (Example 5, DOS No. 3 128 386)

Amitriptyline = N, N-dimethyl-3- [dibenzo (a, d) -cycloheptadien-5-ylidene] propylamine

Lidocaine = α-diethylamino-2,6-dimethylacetanilide.

In summary, the novel compounds of the present invention exhibit excellent antidepressant and antiarrhythmic effects. The potency of the compounds of formula I is of the order of magnitude greater than that of the most potent compound disclosed in DOS 3,128,386, both in absolute dose and therapeutic index in the tetrabenazine antagonist assay in mice and rats.

In the activity test for reserpine ptose, the activity of the novel compounds of the invention is substantially higher than that of reference compound D. In addition to this surprising and unpredictable increase in activity, the activity spectrum of the compounds of formula I also differs qualitatively from that disclosed in DOS 3,128. 386, which is reflected in the fact that the compounds of the formula I have highly favorable transquillization, ainalgesic, locally anesthetic and antitremorine effects from a therapeutic point of view.

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 dose of the compounds of formula I is about 5 to 150 mg, 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-ethoxy-3-chloro-as-triazinoyl 6,1-a] isoquinolin-5-ium-2- (1H) -ide

To a solution of 1- (4-chlorophenyl) -3-chloro-as-triazino [5,1a] isoquinolinium perchlorate (5 g, 0.012 mol) in ethanol (50 ml) was added sodium ethoxide solution containing 0.012 mol of sodium while cooling. There separated 3.2 g of the desired compound as yellow crystals, yield 72%, mp 283-284 ° C ^Q

Example 2

Preparation of 1- (4-chlorophenyl) -1-methoxy-as-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide

1- (4-chlorophenyl) -as-triazino [6,1-a] isoquinolinium perchlorate was reacted with sodium methoxide in an analogous manner to that described in Example 1. The title compound was obtained in 83% yield, m.p. 158 to 159 ° C.

Example 3

Preparation of 1- (4-fluorophenyl) -1-ethoxy-as-triazino (6,1-a) -isoquinoline-5-ium-2- (1H) -ide

3.85 g (0.01 mol) of 1- (4-fluorophenyl) -as-triazino [6,1-a] isoquinolinium ethanesulfonate are dissolved in 50 ml of ethanol and sodium ethoxide solution containing 0.012 mol of sodium is added under cooling. 3.0 g of the title compound precipitated. Yield: 90%, m.p. 158-159 ° C.

Example 4

Preparation of 1- (4-chlorophenyl) -1-methoxy-3-methyl-as-triazino- (6,1-a) -isoquinolin-5-ium-2 (1H) -ide

To a solution of 3.4 g (0.01 mol) of 1- (4-chlorophenyl) -3-methyl-as-triazino- (6,1-a) -isoquinolinium chloride in 50 ml of methanol, a sodium methoxide solution containing 0.012 mol of sodium. 3.1 g of the title compound precipitated. Yield: 91%, m.p. 276-278 ° C.

Claims (3)

A process for the preparation of novel condensed as-triazine derivatives of the general formula I wherein R 1 is phenyl which is substituted with one halogen atom, R 2 is hydrogen, halogen or C 1 -C 4 alkyl; R 3 is C 1 -C 4 alkoxy, characterized in that the compound of formula (II) wherein: A ^- represents an anion derived from an inorganic or strong organic acid and R 1 and R 2 are as defined above, reacted with a C 1 -C 4 metal alkoxide. 2. The process according to claim 1, wherein the reaction is carried out in an alkanol corresponding to the alkoxide used. Process according to claim 1, characterized in that the reaction is carried out using a solid alkali metal alkoxide in an anhydrous medium, preferably in an ether or an aromatic hydrocarbon.