CS259533B2 - Processes for the preparation of fused as-triazine derivatives - Google Patents

Abstract

A process for the preparation of condensed derivatives of a-triazine of the general formula I, where fRi represents a phenyl group, which is optionally substituted by one halogen atom, Z 'represents a buta41,3-dienyl group or a group of formula (a) and A" represents an anion derived from a pharmaceutically acceptable inorganic or organic acid. The process proceeds as follows: a compound of the general formula II, where Ri, Z and A" have the above-mentioned meaning, is reacted with an orthoformate of the general formula III, where Rs represents an alkyl group with 1 to 4 carbon atoms, after which the formiminoether of the general formula IV thus obtained, where Ri, Rs, Z and A- have the above-mentioned meaning, is closed by reaction with ammonia and in the compound of the general formula I thus obtained, the anion A" is optionally exchanged for another anion A-. The compounds of the general formula I exhibit useful pharmacological properties. properties, especially antiarrhythmic and antidepressant* 1 effects.

Description

A method for preparing condensed derivatives of a-triazine of the general formula I, where fRi represents a phenyl group, which is optionally substituted by one halogen atom, Z represents a buta41,3-dienyl group or a group of formula (a) and A represents an anion derived from a pharmaceutically acceptable inorganic or organic acid. The method proceeds as follows: a compound of the general formula II, where Ri, Z and A have the above-mentioned meaning, is reacted with an orthoformate of the general formula III, where Rs represents an alkyl group with 1 to 4 carbon atoms, after which the formiminoether of the general formula IV, where Ri, Rs, Z and ^A have the above-mentioned meaning, is closed by reaction with ammonia and in the compound of the general formula I thus obtained, the anion A is optionally exchanged for another anion A ^- . The compounds of the general formula I exhibit useful pharmacological properties, especially antiarrhythmic and antidepressant ^{* 1} effect.

The invention relates to pharmaceutically effective novel condensed derivatives of as-triazine, a process for their preparation and pharmaceutical preparations containing them.

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

where

R 1 represents a phenyl group which is optionally substituted with one halogen atom,

Z represents a buta-1,3-dienyl group or a group of formula (a) (a) and

A represents an anion derived from a pharmaceutically acceptable inorganic or strong organic acid.

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

R 1 preferably represents a 4-chlorophenyl group or a phenyl group.

Particularly preferred representative compounds of general formula I are the following derivatives:

1-(4-chlorophenyl)-1-hydroxy-1,2-dihydro-as-triazino [6,1-a]isoquinolinium methanesulfonate and

1-(4-Chlorophenyl j -1-hydroxy-1,2-dihydro-as-triazino[6,1-a]isoquinolinium chloride.

A ^- can mean any pharmaceutically acceptable inorganic or organic anion (such as chloride, bromide, iodide, perchlorate, methanesulfonate, ethanesulfonate anion, etc.).

The subject of the invention is a process for preparing compounds of general formula I, which is characterized in that the compound of general formula II is

AND,

A® where R1, Z and A ^- have the meanings given above, is reacted with an orthoformate of the general formula III

HC(OR5)3 (ΙΠ) where

Rs represents an alkyl group with 1 to 4 carbon atoms, after which in the thus formed formiminoether of general formula IV

(IV) where

Ri, Rs, Z and A~ have the above-mentioned meaning, the ring is closed by reaction with ammonia and in the compound of general formula I thus obtained, the anion A is optionally exchanged for another anion A ^- .

According to the invention, the compounds of the general formula I are prepared by reacting the compound of the general formula II with the orthoformate of the general formula III and treating the thus obtained formiminoether of the general formula IV with ammonia.

As orthoformates of the general formula III, methyl or ethyl esters are preferably used. The reaction of the compounds of the general formulas II and III can be carried out in an inert solvent, for example a nitrile (such as acetonitrile) or in an aromatic hydrocarbon (such as benzene or toluene). An excess of the starting compound of the general formula III can also play the role of the reaction medium. The reaction can be carried out under heating, preferably at the boiling point of the reaction mixture.

The formiminoether of the general formula IV thus obtained is reacted with ammonia, preferably with gaseous ammonia. The reaction can be advantageously carried out in an inert organic solvent, in particular in a lower alkanol (for example ethanol). The reaction takes place at ambient temperature, usually at a temperature of 15 to 35 °C. Ammonia can be advantageously used in an equimolar amount or in a slight excess of a few percent.

If desired, the anion A ^- in the obtained compounds of the general formula I can be replaced by another anion A ^- . In this case, the procedure is known per se. For example, a compound of the general formula I containing the chloride anion as the anion A ^- can be converted into the corresponding compound of the general formula I containing the perchlorate anion as A ^- by reaction with perchloric acid. Compounds of the general formula I containing the bromide anion as A ^- can be prepared from compounds of the general formula I containing another anion, for example the 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 (for example, bromide anion) with ethanesulfonic acid.

The starting materials of general formula II are disclosed in DOS No. 3,128,388 and the starting materials of general formula III are commercially available compounds.

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

Pharmaceutical compositions may contain carriers. These carriers may be solid carriers, fillers, sterile aqueous solutions or non-toxic organic solvents. Tablets suitable for oral administration may contain sweeteners 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 citrate, calcium carbonate, dicalcium 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 formulations may contain pharmaceutically acceptable solvents (e.g., 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 isotonized with a suitable liquid diluent (e.g., saline or glucose solution). Aqueous solutions are particularly suitable for intravenous, intramuscular, or intraperitoneal administration. Sterile aqueous solutions are prepared by methods known per se.

The daily dose of the active ingredient of the general formula I may vary within wide limits and depends on several factors, in particular on the potency of the active ingredient used, the route of administration and the condition of the patient.

The pharmaceutical efficacy of the compounds of general formula I is demonstrated by the following tests:

1. Acute toxicity in mice

The test is performed on male and female CFLP white mice weighing 18 to 22 g. The test compound is administered orally and the animals are observed for 7 days. In each dose group, half are male and half are female. The animals are housed in a 39 X 12 X 12 cm plastic cage on shredded waste paper at room temperature. The mice are given a standard diet and tap water ad libitum. Toxicity data are determined by the Lichtfield-Wilcoxon method.

The test compounds are administered in the form of aqueous solutions.

The results are summarized in Table I.

Table I

Toxicity in mice

Test compound LD50 mg/kg p. o.

compound A 410 compound B 560 compound C 590

Reference compound D 600

Amitriptyline 225

2. Acute toxicity, in rats

The test described in paragraph 1 is repeated with the only difference that the observation period is 14 days and the animals are kept in cages measuring 30 X 39 X 12 cm, five at a time.

The results are summarized in Table II.

T a b l e 1 k a II

Toxicity in rats

Test compound LD50 mg/kg p. o.

compound A 1,300 compound B about 1,100 compound C about 1,030

3. Antagonism to tetrabenzene ptosis in mice and rats, p. o.

Groups of 10 mice are orally administered the test compound, followed by intraperitoneal administration of 50 mg/kg tetrabenazine 30 minutes later, and animals in each group showing ptosis (drooping eyelids) are counted after 36, 60, 90 and 120 minutes.

The results are evaluated as follows: based on all measured data, the average ptosis is calculated in each group and the deviation from the average value of the control group is expressed in % (inhibition). ED50 values are calculated from the data thus obtained. The results are summarized in Table III.

Table III

Antagonism to tetrabenzene ptosis in mice and rats

Test compound

Mice

Rats

ED50 mg/kg Ther. index EDso mg/kg Ther. index compound A 0.3 1367 0.3 4,333 compound B 0.3 1867 1.0 1100 compound C 2.9 203 4.5 191 Reference compound D 3.2 188 5.6 179 Amitriptyline 12.0 19 11.5 46 4. Antagonism to reserpine ptosis on compound. Are animals showing rats, p. o. but until disappearance effect. Evaluation results are is carried out in the manner specified in Each animal in groups of 10 rats was given a sub- previous exam with ptosis (test 3). 2.5 mg/kg of reserpine is administered subcutaneously and then The results are summarized below. he will be given the test substance orally after 60 minutes relating to Table IV. Table IV Antagonism to reserpine ptosis in rats Test compound Rats ED50 mg/kg Ther. index compound A 14 92.8 compound B 28 39.3 compound C 21 49.0 Reference compound D about 60 16.7

amitriptyline about 140

3.6

5. Antiarrhythmic effect in rats

The test is performed using a modified method according to Marmo et al. The test animals are anesthetized with ethylurethane (1.2 g/kg i. p.). The animals are given aconitine intravenously in the form of an injection at a dose of 75 µg/kg. 5 minutes after the administration of aconitine, ECG changes are monitored in standard lead II. The observed changes are rated on a scale from 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 results are summarized in Table V.

Table V

Antiarrhythmic effect in rats Test compound

i.v.

compound A 0.9 compound B 1.6

Lidocaine 4.0

6. Effect on blood pressure

When administered intravenously to anesthetized cats, the test compounds induce a uniform, long-term increase in pressure of 2.66 to 4 kPa.

7. Other effects

In addition to the above-mentioned effects, compounds of general formula I also exhibited spasmolytic, local anesthetic, analgesic, and antipyretic effects.

p. o. Ther. index

40 32.5 30 27.5 120 therapeutic index cannot be calculated from these data; no activity

tic, anti-inflammatory and tranquilizing-sedative properties. Some compounds of general formula I also exhibit tremorin-antagonistic effects.

Anti-inflammatory effect in rats

1% carrageenan is injected into the plantar surface of the hind paw of a rat weighing 150 to 180 g. The volume of the paw is measured using a plethysmometer before and 3 hours after the administration of the irritant agent. 1 hour before the administration of the irritant agent, the animals are given the test compound or only the vehicle (control experiment). Due to the different solubility, the surfactant Tween 80 is used as an auxiliary agent.

The results are summarized in Table VI.

Table VI

Anti-inflammatory effect in rats

Test compound Inhibitory effect

ED50 mg/kg

Thermal index

Compound A 24.5 53.1

Reference compound D cannot be determined, — no effect phenylbutazone about 90.0 5.3

Antitremorine effect in mice. The test compounds are administered orally 1 hour before the administration of tremorine. The results are summarized in Table Vii.

Table VII

Antitremorine effect in mice

Test compound Antitremorine effect Ther. index

ED50 mg/kg

Compound B 6 93.3

Reference compound D ineffective —

The following compounds were used for testing:

compound A =

1-(4-chlorophenyl)-1-hydroxy-1,2-dihydro-as-triazino [6,1-a]isoquinolinium methanesulfonate compound B —

1-{4-Chlorophenyl-1-hydroxy-1,2-dihydro-as-triazino[6,1-a]isoquinolinium chloride compound C =

1-(4-chlorophenyl j -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide

Reference compound D —

1-(4-Chlorophenyl)-as-triazino[6,1-a] isoquinolinium bromide (DOS No. 3 128 386]

Amitriptyline —

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

Lidocaine — and diethylamino-2,6-dimethylacetanilide

Phenylbutazone

4-Butyl-1,2-diphenyl-3,5-pyrazolidinedione.

It can be summarized that the novel compounds of the invention exhibit excellent antidepressant and antiarrhythmic effects. The efficacy of the compounds of general formula I is an order of magnitude higher than the efficacy of the most potent compound disclosed in DOS No. 3,128,385, both in terms of absolute dose and therapeutic index in the tetrabenzene antagonism test in mice and rats.

In the activity test in the case of reserpine ptosis, the efficacy of the new compounds according to the invention is 2 to 6X higher than the efficacy of the reference compound D. In addition to this surprising and unpredictable increase in efficacy, the spectrum of efficacy of the compounds of general formula I also differs qualitatively from the spectrum of efficacy of the compounds published in DOS No. 3,128,386, which is manifested in the fact that the compounds of general formula I have highly favorable tranquilizing, analgesic, spasmolytic, anti-inflammatory and antitremorine effects from a therapeutic point of view.

As already mentioned, the daily dose of the compounds of formula I can vary within wide limits and depends on various factors of the case. For illustration, it can be stated that the average daily oral dose of the compounds of formula I is about 5 to 150 mg, which can be increased in severe cases up to 300 mg. The daily parenteral dose can be about 5 to 50 mg.

Further details relating to the invention are given in the following examples.

2595Ž3 embodiments. The examples are for illustrative purposes only and do not limit the scope of the invention in any way.

Example 1

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

3.5 g (0.008 mol) of 1-(4-chlorobenzoyl)-2- [N-(ethoxyiminoformyl) isoquinolinium perchlorate are treated with ammonia in 30 ml of ethanol, after which the solvent is removed. The crystalline residue is dissolved in ethanol containing 5% water and the solution is mixed with 5 ml of 70% perchloric acid. The product is extracted with nitromethane and the solvent is removed. 1.64 g of the desired compound are obtained, yield 50%, melting point: 239-240 °C.

The starting material can be prepared as follows:

A mixture of 4.55 g (0.010 mol) of 2-amino-1-(4-chlorobenzoyl)isoquinolinium tosylate, 4.45 g (0.030 mol) of ethyl orthoformate and acetonitrile is heated to boiling for 1 hour. The reaction mixture is cooled and the product is precipitated by addition of ether. 4.4 g of 1-(4-chlorobenzoyl)-2- [ N - (ethoxyiminoformyl) ] isoquinolinium tosylate are obtained. The yield is 86%, melting point: 183-184 °C.

2.6 g (0.05 mol) of the above product are dissolved in 30 ml of thionyl chloride, the solution is heated to boiling for a short time and then the excess thionyl chloride is distilled off. Ether is added to the residue. 1.7 g of yellow 1-(4-chlorobenzoyl)-2-[N-(ethoxyiminoformyl]isoquinolinium chloride are obtained. The yield is 90%, melting point: 158-160 °C. After recrystallization from acetonitrile, 1.4 g of yellowish needle-like crystals are obtained. Yield 74%, melting point: 167-169 °C.

g (0.006 mol) of the above product is dissolved in ethanol and 5 milliliters of 70% perchloric acid are added. The precipitated crystals are filtered off. 2.3 g of crystalline 1-(4-chlorobenzoyl)-2-[N-(ethoxyiminoformyl)] isoquinolinium perchlorate are thus obtained. The yield is 90%, melting point 224-225 °C (from a mixture of acetonitrile and ether).

Example 2

Preparation of 1-(4-chlorophenyl)-1-hydroxy-1,2-dihydro-as-triazino(6,1-a j isoquinolinium methanesulfonate

3.55 g (0.0081 mol) of 1-(4-chlorophenyl)-1·-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide are reacted with 2.22 g (0.0022 mol) of ethanesulfonic acid in 50 ml of acetonitrile. The reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate. After cooling, 3.3 g of the desired compound is obtained, which precipitates in the form of prismatic crystals. The yield is 86%, melting point 187-188 °C.

Example 3 1-Phenyl-1-hydroxy-1,2-dihydroas-triazino[6,1-a]isoquinolinium perchlorate

4.04 g (0.01 mol) of l-benzoyl-2-[N-(ethoxyiminoformyl)]-isoquinolinium perchlorate in 35 ml of ethanol is treated with gaseous ammonia. The solvent is removed and the crystalline residue is dissolved in ethanol containing 5% water. To the resulting solution is added 7 ml of 70% perchloric acid. The product is extracted with nitromethane and the solvent is distilled off from the extract. 1.9 g of the title compound is obtained. Yield: 50%; melting point 245-246 °C.

Example 4

1-(4-Chlorophenyl-1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium methanesulfonate

3.84 g (0.008 mol) of 1-[4-chlorobenzoyl)-2- [N-(methoxyiminoformyl)]-isoquinolinium tosylate in 30 ml of ethanol was treated with gaseous ammonia. The solvent was removed and the crystalline mixture was dissolved in 50 ml of acetonitrile. 2.22 g (0.022 mol) of ethanesulfonic acid was added to the resulting solution. The reaction mixture was then evaporated. The residue was dissolved in ethyl acetate and the resulting solution was cooled. 2.4 g of the title compound were obtained. Yield: 57%; melting point: 187-188 °C.

Example 5

4-(4-Chlorophenyl)-4 hydroxy-3,4-dihydropyrido[2,1-f]-as-triazinium perchlorate

4.05 g (0.01 mol) of 1-[N-(ethoxyiminoformyl))-2-(4-chlorobenzoyl)-pyridinium tosylate in 40 ml of ethanol is treated with ammonia gas and then the solvent is removed. The crystalline residue is dissolved in ethanol containing 5% water and 5 ml of 70% perchloric acid is added to the solution. The product is extracted with nitromethane and the solvent is distilled off from the extract. 2.1 g of the title compound is obtained. Yield: 65%; melting point: 254-255 °C (from acetonitrile).

Claims (3)

FIELD OF THE INVENTION A process for the preparation of a fused as-triazine derivative of the general formula I wherein R 1, Z and A ^- are as defined above, is reacted with an orthoformate of the general formula III. HC (OR5) 3 III I ( in. Z, (l) where R 5 is C 1 -C 4 alkyl, then in the thus formed formimino ether of formula IV wherein: R 1 is phenyl optionally substituted with one halogen atom, Z is buta-1,3-dienyl or a group of formula (a) (A) and A ^- represents an anion derived from a pharmaceutically acceptable inorganic or strong organic acid. characterized in that the compound of formula (II) R 1, R 5, Z and A "are as defined above, are closed by reaction with ammonia, and in the compound of formula (I) thus obtained, optionally anion A" is replaced by another anion A ". 2. The process of claim 1 wherein the reaction of the formimino ether of formula IV and ammonia is carried out in an inert organic solvent. 3. A process according to any one of Claims 1 to 2, which comprises starting from the compounds defined in item 1 to give 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazine [6,1-a] isoquinolinium methanesulfonate. or -chloride.