CS264268B2 - 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 the " Zwitterionts " type triazine, to a process for their preparation and to pharmaceutical compositions containing them.

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

O

where

R 1 is phenyl optionally substituted with one halogen atom.

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

Among the compounds of formula (I), those in which R1 is 4-halophenyl, preferably 4-chlorophenyl or unsubstituted phenyl, are preferred. A particularly suitable representative compound of formula I is 1- (4-chlorophenyl) as-triazino [6,1-a] isoquinolin-5-im- (1H) -id-3-one.

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

where

A is an anion derived from an inorganic or strong organic acid,

R4 is C1-C6 alkyl,

R has the meaning given above, is reacted with a base derived from alkali or alkaline earth metal in an aqueous _(medium.

A represents a suitable inorganic or organic anion, such as a halide anion, for example a chloride, bromide or iodide anion, or a perchlorate, methanesulfonate, ethanesulfonate or p-toluenesulfonate anion, aitd.

In the process of the invention, the compound of formula (II) is reacted with an alkali metal or alkaline earth metal base. Preferably, weak bases are used, for example sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

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 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, emulsion suspensions). 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 contain sweetening and / or other excipients (for example starch, preferably potato starch), binders (for example polyvinylpyrrolidone, gelatin), lubricants (for example magnesium stearate, sodium lauryl sulfate or talc) or other additives (for example sodium citrate, calcium carbonate, middle calcium phosphate, etc. J. 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-264268 CFLP 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 or room temperature. Mice receive standard food and tap water ad libitum. Toxicity data was determined by the Lithfield-Wilcoxon method.

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

Table I

Toxicity in mice

2. 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 the data thus obtained.

The results are summarized in Table II.

Test compound LD 50 mg / .kg p.o. Compound C 2 000 Amitriptyline 22'5 Reference Compound D 600

Table II

Antagonism to tetrabenazine ptosi in mice

Test compound

Mice

ED 50 (mg / kg)

Ther. Index Compound C Reference Compound D amitriptyline

23,00

3.2

12.00

188

The following compounds were used for testing:

Compound C = 1- (4-chlorophenyl) -as-triazino (6,1-a) isoquinolin-5-ium- (1H) -id-3-one

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

Amitriptyline = N, N-di, ethyl-3- (dibenzo [a, d] cycloheptadien-5-ylidene) propyl The novel compounds of the present invention exhibit excellent anti-depressant and antiarrhythmic effects. No. 3,128,386, both with respect to the absolute dose and the therapeutic index in the tetrabenazine antagonist assay in mice.

The activity of the novel compounds prepared by the process of the invention is significantly 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. wherein the compounds of formula (I) have highly favorable transquillizing, analgesic, locally anesthetic and anti-tremorinic effects from a therapeutic standpoint.

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. 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) -as-triazino [6,1-a] isoquinolin-5-ium-2- (3Ή) Md-3-one

To a solution of 1 g (0.0022 mol of N-amino-isoquinolyl-4- (chlorophenyl) -N‘-ethoxycarbonylketiminperchlorate in acetonitrile) was added ml of a 10% aqueous solution of sodium carbonate.

0.5 g of the desired compound is obtained, corresponding to a yield of 74%, m.p. 310 DEG C. (dec.).

Example 2

Preparation of 1-phenyl-as-triazino- (6,1-a) -isoquinolin-5-ium-2H (1H) -id-3-one

To a solution of 4.2 g (0.01 mole of N-amino-1-isoquinolylphenyl-N'-ethoxycarbonylketiminperchlorate in acetonitrile) was added 10 mL of 10% sodium carbonate solution. The product precipitated after a short time to give 2.0 g of the title compound. Yield 73%, mp 300 ° C.

Example 3

Preparation of 1- (4-fluorophenyl) -as-triazino- [6,1-a] isoquinolin-5-ium-2- (1H) -id-3-one

4.4 g (0.01 mol) of N-amino-1-isoquinolyl (4-fluorophenyl) -1-N'-ethoxycarbonylketimine perchlorate were subjected to the reaction described in the previous example. 2.1 g of the title compound are obtained. Yield 72%, mp 305 DEG C. ^q

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of novel condensed as-triazine derivatives of the general formula I R 1 is phenyl optionally substituted with one halogen atom, characterized in that the compound of formula (II) A is an anion derived from an inorganic or strong organic acid, R4 is C1-C6 alkyl, R1 is as defined above, reacted with an alkali metal or alkaline earth metal base in an aqueous medium. 2. A process according to claim 1, wherein the alkali metal or alkaline earth metal base is sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.