CS264269B2 - 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 novel condensed derivatives of an as-triazine of the " Zwitterionts " type, to a process for their preparation and to pharmaceutical preparations containing them.

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

Θ

where

R 1 is phenyl optionally substituted with one halogen atom,

R2 represents a hydrogen atom or a halogen atom;

X is hydrogen or halogen.

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

Of the compounds of formula I, those wherein X is hydrogen are preferred. Further preferred are those compounds of formula (I) wherein R 1 is phenyl optionally substituted at the 4-position with a halogen atom, preferably 4-chlorophenyl.

A particularly preferred representative compound of formula I is S-chloro-1- [beta] -chlorophenyl-1,4-dihydro-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)

where

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

R 1, R 2 and X are as defined above, reduce and the dihydric compound thus obtained is treated, optionally without intermediate isolation, with bases.

¹ A ~ is a suitable inorganic or organic anion such as a halide anion such as chloride, bromide or iodide anion or chlorstanový Me thansulfonátový, ethanesulfonate or p-toluenesulfonate anion, etc.

In the process according to the invention, the compounds of the formula I are prepared by reduction of a compound of the formula II, and the product thus formed is treated, optionally without intermediate isolation, with bases. The reduction can advantageously be carried out by catalytic hydrogenation. The catalyst used may be palladium, platinum oxide or ruthenium, and the catalyst may optionally be supported. The catalytic hydrogenation can optionally be carried out in a buffer-containing system. A mixture of sodium acetate and acetic acid is preferably used for this purpose. The hydrogenation can be carried out at ambient or elevated temperature and at atmospheric or elevated pressure. The product obtained is optionally treated with a base without intermediate insulation. As the base, for example, an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate or alkoxide can be used.

The starting materials of the formula II are known from DOS No. 3 12B 386.

The novel compounds of formula (I) may be formulated into pharmaceutical preparations which contain as active ingredient at least one compound of formula (I) in association with suitable inert, solid or liquid pharmaceutical carriers. These preparations can be prepared by methods conventional 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 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 (eg sodium citrate, calcium carbonate, calcium calcium phosphate, etc.).

Aqueous suspensions and elixirs suitable for o264269

Oral administration may further include flavors, colorants, emulsifiers, diluents (e.g., water, ethanol, propylene glycol or glycerol, etc.).

The parenteral compositions may contain pharmaceutically acceptable solvents (e.g., 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 isotonic Aqueous solutions are particularly suitable for intravenous, intramuscular (or intraperitoneal administration). Sterile aqueous solutions are prepared by known methods.

The daily dosage of the active ingredient of the formula I can vary within wide limits and is dependent 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 CFLP strain mice weighing 18-122 g. The test compound is administered orally and the animals are monitored for 7 days. In each dose group tested, there are half males and half females. The animals are housed in a 39 X 12 X 12 cm plastic cage on the cut waste paper at room temperature. [tap water "ad Iibitum." Toxicity data is determined by the Litchfield-Wilcoxon 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 E 1000 ^ Amitriptyline preferential 225 [Compound D 600

12. Antagonism against tetraben-azine ptosi in mice and rats p.o.

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

The results are evaluated as follows:

On the basis of all measured values, the mean pt l is calculated in each group and the deviation from the mean value of the control group is expressed as a percentage (inhibition). The ED 50 values are calculated from the data thus obtained.

The results are summarized in Table II.

(Table II (Tetrabenazine ptosis antagonism in mice and rats)

Test compound Mice

ED 50 mg / kg Ther. Index (Compound · E20.00 (Reference Compound D3.2Amitriptyline12.00)

3. Antagonism against reserpine ptosis in p.o.

Each animal from a group of 10 mice is administered subcutaneously with 6 mg / kg reserpine and is then orally challenged after 60 minutes with an ED 50 mg / kg rat.

5008.1

1885.6

1911.50 Compound. Animals exhibiting pto-si were 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 against reserpine ptosis in mice

Test compound ED 50 mg / kg

40.0 over 120 65.0

Ther. index compound E reference compound D Amitriptyline

250.0 below 5.0

3.45

4. Antagonism to reserpine ptosi in rats p.o.

Each animal of 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 test with ptosi (Test 2).

The results are summarized in Table IV.

Table IV

Antagonism to reserpine ptosi in rats

Test Compound ED 50 mg / kg Compound E 30 Reference Compound D 60

Amitriptyline about 140

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 given a sublethal dose of 20 mg / kg yohimbine (intraperitoneally). Dead animals are counted after 1 and 24 hours. The results are summarized in Table V.

Table V

Potentiation of yohimbine toxicity

Test compound Compound E

Amitriptyline

ED 50 mg / kg

10.0

12, '5

Ther. index

100 ALIGN!

6. Antiarrhythmic effect in rats

The test is carried out by a modified method of Marmo et al. The test animals were anesthetized with ethyl urethane (1.2 g per kilogram i.p.) injected as an intravenous dose of aconitine at 75 </ g / kg.

II. The observed changes are scored on a scale of 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

Compound E 1 mg / kg

Lidocaine 4 mg / kg

Inhibition (° / o)

40.0

23.4

The following compounds were used for testing:

Compound E =

3-chloro-1- (p-chlorophenyl) -1,2-dihydro-as-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide;

reference compound D =

1- (4-chlorophenyl) ras-triazino [6,1-a] isoquinolinium bromide (Example 5, DOS No. 3,128,386);

Amitriptyline =

N, N-dimethyl-3- (dibenzo [a, d] cycloheptadien-5-ylide) n-propylamine;

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

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

In the activity test for reserpine ptose, the efficacy of the novel compounds of the present invention is significantly higher than that of reference compound D. In addition to this, in contrast to the efficacy spectrum of the compounds of formula I, the efficacy spectrum also differs from that of surprising and unpredictable increases. The compounds of formula I have highly therapeutically beneficial tranquilizing, analgesic, locally anesthetic and antitremorinic effects.

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 3-chloro-1- (p-chlorophenyl) -1,2-dihydro-, α-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide

1.5 g (0.004 mol) of 3-chloro-1- (p-chlorophenyl) -as-triazino [6,1-iisoquinolinium perchlorate are hydrogenated in a mixture of 0.34 g (0.0041 mol) of sodium acetate and 30 µl of acid acetic acid in the presence of 0.05 g of palladium on carbon catalyst as one equivalent of hydrogen. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 5 ml of acetonitrile and 1 ml of 70% perchloric acid was added. The precipitated product is filtered off and dissolved in ethanol. The pH of the solution is adjusted to 9 with 10% sodium hydroxide solution and then 10 ml of water are added. 0.13 g of the desired compound is obtained in the form of crystals. Yield 30%, mp 110-113 ° C (from dichloromethane / petroleum ether).

Example 2

Preparation of 3-chloro-1-phenyl-1,2-dihydro-as-triazino [6,1-a] isoquinolin-5-ium-2 (1H) -ide

1.56 g (0.004 mol) of 3-chloro-1-phenyl-as-triazolo [6,1-a] isoquinolinium perchlorate is reacted in a mixture of 0.34 g (0.0041 mol) of sodium acetate and 30 ml of acetic acid in The presence of 0.05 g of palladium on the bottom, as a catalyst, is reacted with an equivalent amount of hydrogen. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 5 mL of acetonitrile. 1 ml of 70% perchloric acid is added and the resulting precipitate is filtered off and dissolved in ethanol. The pH of the solution is adjusted to 9 with 10% sodium hydroxide solution and then 10 ml of water are added. Thus, 1.02 g of the title compound are obtained. Yield 35%, mp 113-115 ° C.

Example 3

Preparation of 1- (4-fluorophenyl) -1,2-dihydro-10-chloro-as-triazine- [6,1-aisoquinolin-5-ium-2- (1H) -ide

The procedure described in the previous example was followed except that starting from 1.64 g (0.004 mol); 1- (4-Fluorophenyl) -10-chloro-as-triazino [6,1- and isoquinolinium perchlorate. 0.9 g of the title compound precipitated. Yield 30%, mp 115-117 ° C.

Claims (3)

A process for the preparation of novel condensed as-triazine derivatives of the general formula I wherein R 1 is phenyl optionally substituted with one halogen atom, R2 represents a hydrogen atom or a halogen atom; X is hydrogen or halogen, characterized in that the compound of formula (II): wherein: A ^- represents an anion derived from an inorganic or strong organic acid and R 1, R 2 and X are as defined above, reduced and the dihydro compound thus obtained is treated, optionally without intermediate isolation, with bases. 2. The process according to claim 1, wherein the reduction is carried out by catalytic hydrogenation. 3. Process according to claim 2, characterized in that the palladium catalyst is used in a damped environment, preferably in the presence of sodium acetate and acetic acid.