CS259533B2 - Method of as-triazine's condensed derivatives preparation - Google Patents

Abstract

Process for preparing condensed derivatives of an as-triazine of formula I wherein fRi is phenyl optionally substituted with one halogen atom, Z 'is buta, 1,3-dienyl or the group of formula (a) and Ά "represents an anion pharmaceutically acceptable. inorganic or an organic acid. In the method the procedure is such that the compound is general of formula II wherein R 1, Z and A "are as defined above importance with the orthoformate of the formula III wherein R 5 represents an alkyl group having 1 to 4 carbon atoms, whereupon; in the thus obtained formimino ether of formula IV, wherein R 1, R 5, Z and A-m as defined above, is quenched with ammonia the ring and the compound thus obtained of formula (I) is optionally an anion A "exchanges for another A- anion. General compounds Formula I exhibits useful pharmacological properties, especially antiarrhythmic and antidepressant * 1 effect.

Description

A process for the preparation of fused as-triazine derivatives of formula I wherein R 1 is phenyl optionally substituted by one 'halogen atom, Z' is buta-1,3,3-dienyl or (a) and Ά 'is an anion derived from a pharmaceutically acceptable compound. inorganic or organic acids. The process is carried out by reacting a compound of formula (II) wherein R 1, Z and A are as defined above with an orthoformate of formula (III) wherein R 5 is C 1 -C 4 alkyl. the formimino ether of formula IV, wherein R 1, R 5, Z and A ^{- is} as defined above, is closed by reaction with ammonia and in the compound of formula I thus obtained optionally anion A is replaced by another anion A ^- . Compounds of formula I exhibit useful properties Ťarmakologické particular antiarrhytmický and antidepressantní ^{* 1} effect.

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 formula I

where

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.

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

Preferably R 1 is 4-chlorophenyl or phenyl.

Particularly preferred representative compounds of 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) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium chloride.

A ^- may 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)

AND,

A ® wherein R 1, Z and A ^- are as defined above, reacted with an orthoformate of formula III

HC (OR 5) 3 (ΙΠ) where

R 5 is C 1 -C 4 alkyl, then the formimino ether (IV) thus formed

(IV) where

R 1, R 5, Z and A - are as defined above, closed by reaction with ammonia and in the compound of formula I thus obtained optionally anion A is replaced by another anion A ^- .

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

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

The formimino ether (IV) thus obtained is reacted with ammonia, preferably ammonia gas. The reaction can be advantageously carried out in an inert organic solvent, in particular a lower alkanol (e.g. ethanol). The reaction is carried out at ambient temperature, usually at 15 to 35 ° C. Ammonia can advantageously be used in equimolar or moderate amounts. a few percent surplus.

If desired, anion A ^- from another anion A ^- can be exchanged in the compounds of formula I obtained. The processes are carried out in a manner known per se. Thus, for example, a compound of formula I containing an anion A ^- chloride anion can be converted to the corresponding compound of formula I containing an anion A ^- perchlorate by reaction with perchloric acid. Compounds of formula I containing an A ^- bro259533 mid 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, is ethanesulfonate can be prepared by reacting a compound of formula I wherein A 'is another anion (e.g., bromide anion) with ethanesulfonic acid.

The starting materials of the formula II are disclosed in DOS 3 128 128 and the starting materials of the formula III are commercially available compounds.

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 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 made into 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., vinylpyrrolidone, gelatin), lubricants (e.g., magnesium stearate, sodium lauryl sulfate or talc) or other ingredients (e.g. sodium citrate). , calcium carbonate, middle calcium phosphate, etc.). Aqueous suspensions and elixirs suitable for oral administration may further contain flavoring agents, coloring agents, emulsifying agents, 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 when 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 intraperitivaleal 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 the CFLP strain 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 from the libitum. Toxicity data is determined by the Lichtfield-Wilcoxon method.

Test compounds are administered in the form of aqueous solutions.

The results are summarized in Table I.

Table I

Toxicity in mice

Test compound LD 50 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 except that the observation period is 14 days and the animals are housed in cages of 30 X 39 X 12 cm in five pieces.

The results are summarized in Table II.

T and b u 1 k and II

Toxicity in rats

Test compound LD 50 mg / kg p.o.

compound A 1300 compound B about 1100 compound C about 1030

3. Antagonism against tetrabenzine ptosi in mice and rats, p. O.

Groups of 10 mice were dosed orally with test compound, after which they were intraperitoneally administered with 50 mg / kg tetrabenazine after 30 minutes, and animals showing ptosi (eyelid dropping) were counted after 36, 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 III.

Table III

Antagonism to tetrabenzine ptosi in mice and rats

Test compound

Mice

Rats

ED50 mg / kg Ther. index ED 50 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 Dec 11.5 46 4. Antagonism against reserpine ptosi na compound. The animals showing are counted rats, p. o. ptosi until fade effect. Evaluation results carried out in the manner specified in Each animal of the groups of 10 rats with sub- prior to the test with ptosi (test 3). cutaneously administered 2.5 mg / kg reserpine and then The results are summarized in the following after 60 minutes he orally administers the test Table IV. Table IV Antagonism against reserpine ptosi in rats Test compound Rats ED 50 mg / kg Ther. index Compound A 14 92.8 Compound B 28 39.3 Compound C 21 49.0 Reference Compound D ca. 60 16.7

amitriptyline about 140

3.6

5. 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. 5 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 results are summarized in Table V.

Table V

Antiarrhythmic effect on 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 produce a uniform, long-term pressure increase of 2.66 to 4 kPa.

7. Other effects

In addition to the above effects, spasmolytic, locally anesthetic, analgeED50 mg / kg were also observed with the compounds of Formula I

P. Ther. index

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

toxic, anti-inflammatory and tranquilizing sedative properties. Certain compounds of formula I also exhibit tremorin-antagonistic activity.

Anti-inflammatory effect in rats

1% carragenine is injected into the plantar surface of the hind paw of a rat weighing 150-180 g. Using a plethysmometer, the paw volume was measured before and 3 hours after the irritant was administered, 1 hour before the irritant was given, the animals were dosed with test compound or vehicle only (control). Due to the different solubilities, Tween 80 surfactants are used as adjuvants.

The results are summarized in Table VI.

Table VI

Anti-inflammatory effect in rats

Test compound Inhibitory effect

ED50 mg / kg

Ther. index

Compound A 24.5 53.1

Reference compound D could not be determined. - No effect of phenylbutazone of about 90.0 5.3

Antitremorin effect on mice characteristic shaking. Test compounds were administered orally 1 hour before administration to the subjects. I.p. 20 mg / kg morphine tremorine was administered. The results are summarized in and, after 45 minutes, the induced chart Vii is determined.

Table VII

Antitremorin effect in mice

Test compound Antitremorin effect Ther. index

ED 50 mg / kg

Compound B 6 93.3

Reference compound D inactive -

The following compounds were used for testing:

Compound A =

1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium ethanesulfonate Compound B -

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

1- (4-chlorophenyl) -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.

In summary, the novel compounds of the present invention exhibit excellent antidepressant and antiarrhythmic effects. The efficacy of the compounds of formula I is of the order of magnitude higher than that of the most potent compound disclosed in DOS No. 3,128,385, both in absolute dose and therapeutic index in the tetrabenzin antagonistic test in mice and rats.

In the activity test for reserpine ptose, the activity of the novel compounds of the invention is 2 to 6X 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 those disclosed in DOS. No. 3,128,386, which is characterized in that the compounds of formula I have highly beneficial, transient, analgesic, spasmolytic, anti-inflammatory and antitremorinic effects from a therapeutic standpoint.

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 mg, which in severe cases may be increased to 300 mg. The daily parenteral dose may be about 5 to 50 mg.

Further details of the invention are given in the following examples

2595Ž3 design. 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-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] is treated with ammonia in 30 ml of ethanol and the solvent is removed. The crystalline residue was dissolved in ethanol containing 5% water and treated with 5 ml of 70% perchloric acid. The product was extracted with nitromethane and the solvent was removed. 1.64 g of the desired compound are obtained, yield 50%, m.p. 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 was heated at reflux for 1 hour. The reaction mixture was cooled and the product was precipitated by addition of ether. 4.4 g of 1- (4-chlorobenzoyl) -2- [N- (ethoxyiminoformyl)] isoquinolinium tosylate are obtained. Yield 86%, mp 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 period of time and then the excess thionyl chloride is distilled off. Ether was added to the residue. 1.7 g of yellow 1- (4-chlorobenzoyl) -2- [N- (ethoxyiminoformyl) isoquinolinium chloride are obtained, yield 90%, m.p. 158-160 [deg.] C. After recrystallization from acetonitrile, 1.4 g are obtained. Yield 74%, m.p. 167-169 ° C.

g (0.006 mol) of the above product was dissolved in ethanol and 5 ml of 70% perchloric acid was added. The precipitated crystals are filtered off. 2.3 g of crystalline 1- (4-chlorobenzoyl) -2- [N- (ethoxyiminoformyl) isoquinolinium hydrochloride are obtained. Yield 90%, mp 224-225 ° C (from acetonitrile / ether).

Example 2

Preparation of 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino (6,1-aisoquinolinium ethanesulfonate)

3.55 g (0.0081 mol) of 1- (4-chlorophenyl) -1H-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide was reacted with 2.22 g (0, Moles of ethanesulfonic acid in 50 ml of acetonitrile. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. After cooling, 3.3 g of the desired compound are obtained, which precipitates in the form of prismatic crystals. Yield 86%, mp 187-188 ° C.

Example 3 1-phenyl-1-hydroxy-1,2-dihydroas-triazino [6,1-a] isocliinolinium perchlorate

4.04 g (0.01 mol) of 1-benzoyl-2- [N- (ethoxyiminoformyl) -1-isoquinolinium perchlorate in 35 ml of ethanol are treated with ammonia gas. The solvent was removed and the crystalline residue was dissolved in ethanol containing 5% water. 7 ml of 70% perchloric acid was added to the resulting solution. The product was extracted with nitromethane and the solvent was distilled off from the extract. Thus, 1.9 g of the title compound are obtained. Yield: 50%; mp 245-246 ° C.

Example 4

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

3.84 g (0.008 mol) of 1- [4-chlorobenzoyl) -2- [N- (methoxyiminoformyl)] isoquinolinium tosylate in 30 ml of ethanol are treated with ammonia gas. The solvent was removed and the crystalline mixture was dissolved in 50 ml of acetonitrile. To this was added ethanesulfonic acid (2.22 g, 0.022 mol). The reaction mixture was evaporated. The residue was dissolved in ethyl acetate and the resulting solution was cooled. 2.4 g of the title compound are obtained. Yield: 57%; mp 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 are treated with ammonia gas and then the solvent is removed. The crystalline residue was dissolved in ethanol containing 5% water and 5 ml of 70% perchloric acid was added. The product was extracted with nitromethane and the solvent was distilled off from the extract. 2.1 g of the title compound are obtained. Yield: 65%; mp 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.