CS264265B2 - Process for the preparation of fused α-triazine derivatives - Google Patents

Abstract

A method for preparing condensed as-triazine derivatives of the general formula I, wherein Ri represents a phenyl group optionally substituted by one halogen atom, R3 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, Z represents a buta-1,3-dienyl group or a group of formula (a) and A- represents an anion derived from a pharmaceutically acceptable inorganic or strong organic acid, by reacting a compound of the general formula II, wherein Ri, R3 and Z have the above-mentioned meaning, with an acid of the general formula III, wherein A has the above-mentioned meaning, and in the compound of the general formula I thus obtained, the anion A~ is optionally exchanged for another anion A". Compounds of the general formula I exhibit useful pharmacological properties, in particular antiarrhythmic and antidepressant effects.

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 formula I

R, 0

Ri

Θ (I) where

R1, R3 and Z are as defined above, and do not react with an acid of formula III wherein

R 1 is phenyl optionally substituted with one halogen atom,

R3 is hydrogen or (C1-C4) -alkyl,

Z is but-a-1,3-dienyl -or-the formula (a)

fa.) a

A ^- represents -anion derived from pharmaceutically acceptable Inorganic or force-no organic acid.

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, i-sopropyl, tert-butyl, etc. The term halogen refers to the fluorine, chlorine, bromine and iodine atoms.

Preferred compounds of formula I are those wherein R 3 is preferably hydrogen.

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

1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-astiazino [6,1- and isoquinolinium methanesulfonate, 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazinof 6,1-a] isoquinolinium chloride.

A 'may be any pharmaceutically acceptable inorganic or organic anion (e.g., 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)

H — A, (III) where - -....................

A is as defined above, and in the compound of formula (I) thus obtained, anion A 'is optionally replaced with another anion A'.

In the process of the invention, the compound of formula II is reacted with an acid of formula III. Preferably, an acid of the formula III is used which contains the desired anion A ^- . The acids of the formula III are used in equimolar amounts or in a slight excess. The reaction medium used is preferably inert organic solvents in which the acid of formula III is sufficiently soluble. Preferably, the reaction is carried out in a lower -alk-ainol (e.g. methanol or ethanol). The reaction takes place at ambient temperature, but it can also be carried out with gentle heating.

If desired, anion A ^- for another anion A ^- can also be exchanged in the compounds of formula I obtained. The processes are carried out in a manner known per se. T-AK, for example, a compound of Formula I containing, as the anion A ^- the chloride anion can be converted to the corresponding compound of formula I comprising as A ^- perchlorate oinio-n by reaction with perchloric acid. Compounds of formula I containing an A-bromide-anion can be prepared from compounds of formula I containing another anion, for example perchlorate anion, by reaction with tetrabutyl-ammonium bromide.

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

The starting materials of formula (II) are new and are described in U.S. Pat. No. 264,262.

The novel compounds of formula (I) may be formulated into pharmaceutical compositions containing at least one compound of formula (I) as the active ingredient

Also in conjunction 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) other 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 include:

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, 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 when water-soluble active ingredients are used. The 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 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 ad libitum. Toxicity data is determined by the Litchfield-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 LD50 mg / kg compound p.o.

compound A 410 compound Β 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.

Table II

Toxicity in rats

Test compound Compound A Compound B Compound C

LD 50 mg / kg ρ, ο.

300 about 1,100 about 1,030

3. Antagonism to tetrabenazine ptosi in mice and rats, p.o.

Groups of 10 mice were orally administered the test compound, after which 50 mg / kg of tetrabenazine was intraperitoneally administered 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 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 these data. The results are summarized in the table

III.

Table III

Antagonism to tetrabenazine ptosl in mice and rats Mice

Test compound ED 50 mg / kg Ther. index compound A 0.3 compound B 0.3 compound C 2.9 reference compound D 3.2

Amitriptyline 12.0

4. Antagonism to reserpine ipitosl in rats, p.o.

Each animal of the group of 10 rats was injected subcutaneously with 2.5 mg / kg of reserpine and then administered orally after 60 minutes.

ED 50 mg / kg Ther. index

367 0.3 4,333

867 1.0 1,100

203 4.5 191

188 5.6 179

11.5 46 Compound. Animals showing ptosi until counting are counted. The results are evaluated as described in the previous ptosi test (test 3).

The results are summarized in Table IV below.

Table IV

Reserpine ptosol antagonism in rats Test compound

ED 50 mg / kg

Rats

Ther. index about 60 about 140 compound A compound B compound C reference compound D Amitriptyline

5. Ainitiarrhythmic effect on rats

The test is carried out by the modified method of Marmo et al. The test animals were anesthetized with ethyl urethane (1.2 g / kg i.p.) as an injection of 75 mg / kg of aconitine intravenously to the animals.

Antiarrhythmic effect on rats Test compound

i. v.

Compound A 0.9 Compound B 1.6

Lidocaine 4.0 (23.4%)

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, they have also been observed with the compounds of formula (I)

92.8 39.3 49.0 16.7

3.6

ECG on standard terminal II. The observed changes are scored on a scale of 0 to 5. The test compound is administered either initially intravenously 2 minutes before the administration of aconitine or orally 1 hour before the administration of aconitine.

The results are summarized in Table V.

ED 50 mg / kg

after. Ther. index

32.5

27.5

The therapeutic index (3.5 ° / o) cannot be calculated from these data; no activity spasmolytic, locally anesthetic, analgesic, 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. One hour prior to the irritant administration, animals are dosed with test compound or vehicle only (Table VI Trolley J. Due to the different solubility, Tween 80 surfactants are used as adjuvants.

The results are summarized in Table VI.

Anti-inflammatory effect in rats

Test compound

Inhibitory effect of ED 50 mg / kg

Ther. index compound A 24.5 53.1 reference compound D cannot be determined, no effect - phenylbutazoin about 90.0 5.3

Antitremorlnni effect on mice rakteiristic tremor. Test compounds were administered orally 1 hour prior to administration to the subjects. I. The results are summarized after 45 min.

Table VII

Antitremorin effect in mice

Test compound Antitremorin effect Ther. index

ED 50 mg / kg Compound B Reference Compound D Inactive

93.3

The following compounds were used for testing:

compound A = 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1a] isoquinolinium methanesulfonate 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 [6,1a] isoquinolinium bromide reference compound D = 1- (4-chlorophenyl) -as-triazino- [6,1-a] isoquinolinium bromide (DOS No. 3 128 386)

Table

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

Lidocaine = α-diethylamino-2,6-dimethylacetanilide

Phenylbutazone = 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione.

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

Acute toxicity in mice Antagonism against tetrabenazine ptosis in mice Antagonism against tetrabenazine ptosis in rats Antagonism against reserpine ptosis in mice Antagonism against reseirpine ptosis in rats Local anesthetic effect Antiarrhythmic effect against aconitic arrhythmia in rats

LD 50 of about 500 mg / kg

ED 50 mg / kg p.o.

ED 50 mg / kg

ED 50 mg / kg

ED 50 mg / kg EC 50

p. o,

1.0

1.4

9.0

12.0

0.18 below 0.5 mg / kg (The above results show that the above methoxy derivative has excellent central nervous system activity (as an antidepressant) and is also useful as an antiarrhythmic agent and as a local anaesthetic.

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 No. 3,128,385, both in absolute dose and therapeutic index in the tetrabenzin antagonist assay in mice and rats.

In the activity test for reserpine ptose, the activity of the novel compounds of the invention is 2 to 6 times 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 No. 3,128,386, which is manifested in that the compounds of formula I have highly beneficial, transient, analgesic, spasmolytic, anti-inflammatory and antitremorinic 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 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 purenteral 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-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium chloride

To a solution of 3.1 g (0.01 mol) of 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-aisoquinolin-5-ium-2- (1H) 11 ml of hydrochloric acid (1 mol) were added at room temperature and after half an hour the product was precipitated by the addition of water to give 3 g of the title compound (87%), mp 227-228 ° C.

Example 2

Preparation of 1- (4-chlorophenyl) -1-methoxy-1,2-dihydrin-as-triazino [6,1-a] isoquinolinium chloride

The procedure of Example 1 was followed except that 3.23 g (0.01 mol) of 1- (4-chlorophenyl) -1-methoxy-as-triazino [6,1a] isoquinolin-5-ium was used. -2- (1H) -ide. Yield 85%, mp 158-160 ° C.

Example 3

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

3.55 g (0.0081 mol) of 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide was reacted with 2.22 g ( 0.0-022 mol) 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 is obtained, which precipitates in the form of prismatic crystals. Yield 86%, mp 187-188 ° C.

Example 4

1- (4-chlorfe.nyl) ^C l-hydroxy-l, 2-dihydro opyrido [2,1-f] -as-triaziniumperchlorát

To 2.6 g (0.01 mol) of 1- (4-chlorophenyl) -1-hydroxypyrido [2,1-f] -as-triazine- (S) -ium-2- (1H). The reaction mixture was treated with 11 ml of 1M hydrochloric acid in 15 ml of ethanol at room temperature. After stirring briefly, the mixture was diluted with water and 6 ml of 70% perchloric acid was added. 2.1 g of the title compound are obtained. Yield: 59%, mp 254-255 ° C. EXAMPLE 5 1-Phenyl-1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinlumperchlorate

2.74 g (0.01 mol) of 1-phenyl-1-hydroxy-as-triazolo [6,1-a] isoquinolin-5-ium-2- (1H) -ide are treated at room temperature with 11 ml of 1M hydrochloric acid in 15 ml of ethanol. The reaction mixture was stirred for half an hour, then diluted with water and 6 mL of 70% perchloric acid was added. 2.6 g of the title compound are obtained. Yield: 70%, mp 245-246 ° C.

Claims (2)

SUBJECT OF THE INVENTION Process for the preparation of fused as-triazine derivatives of the general formula I Θ (I) where R 1 is phenyl optionally substituted with one halogen atom, R 3 is hydrogen or C 1 -C 4 alkyl, Z is buta-1,3-dienyl or a group of formula (aa and a) ^_ iA represents an anion derived from a pharmaceutically acceptable inorganic or strong organic acids, characterized in that a compound of formula II © ofoecného wherein R 1, R 3 and Z are as defined above, reacted with an acid of formula III H-A (III) wherein A has the meaning given above, and thus> obtained compound of formula I or anion A ^- is exchanged for another anion AND". 2. The process of claim 1, wherein said compound is said to form 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazine [6,1a] isoquinolinium methanesulfonate; or -chloride.