CS268676B2 - Method of as-triazine's new fussed 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

(57) A process for the preparation of novel condensed as-triazine derivatives of the general formula (I) wherein R1 is a phenyl group which is optionally substituted by one halogen atom. B 2 is hydrogen, phenyl or C 1 -C 4 alkyl, and Z is but-1,3-dienyl or a group of formula (a), characterized by. A compound of formula II wherein A is an anion derived from an inorganic or strong organic acid and R1, R2 and Z are as defined above is reacted with an aqueous solution of an inorganic base. The compounds of the formula I are pharmacologically active and in particular have an antidepressant and antiarrhythmic effect.

CM kO ckO

CO kO

CM

WHAT

CS 268 676 B2

The present invention relates to novel condensed derivatives of the as-triazine type Zwitterions *, to a process for their preparation and to pharmaceutical compositions containing them.

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

Wherein βχ is phenyl optionally substituted with one halogen atom, R ₂ is hydrogen, phenyl or C 1 -C 4 alkyl and

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

As used herein, a straight or branched chain alkyl group (e.g., methyl, ethyl, η-propyl, isopropyl, tert-butyl, etc.) The term halogen includes fluorine, chlorine, bromine and iodine atoms. .......

Among the compounds of formula (I), those in which R ^ represents 4-halogen, preferably 4-chlorophenyl or unsubstituted phenyl, are preferred.

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, R ₂ and 2 have the abovementioned meanings,

HU 268 676 В2 reacts in aqueous base solution ·

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

In the process of the invention, compounds of formula I are prepared by reacting a compound of formula II with an aqueous solution of a base, preferably an inorganic base. For this purpose an alkali or alkaline earth metal carbonate or hydroxide may be used. organic solvent partially miscible with water (for example in an alkanol, aromatic hydrocarbon, ether or ester) · The reaction may preferably be carried out at ambient temperature ·

The compound of formula (I) may optionally be separated into its isomers by methods known per se.

The starting materials of the formula II are compounds known from DOS No. 3,128,386.

The novel compounds of formula (I) may be formulated into pharmaceutical compositions containing at least one compound of formula (I) as an active ingredient in association with 8 suitable inert solid or liquid pharmaceutical carriers. These pharmaceutical compositions may be prepared by processes in the pharmaceutical industry per se known · Formulations may be solid (eg tablets, capsules, pills, coated pills, dragees), semi-solid (ie ointments) or liquid (eg solutions, suspensions, emulsions) · Can be finalized to a form suitable for oral or parenteral administration ·

The 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 sweetening or other excipients (e.g. starch, preferably potato starch), binders (e.g. polyvinylpyrrolidone, gelatin). ), lubricants (eg magnesium stearate, sodium lauryl sulfate or talc) or other additives (eg sodium citrate, calcium carbonate, calcium phosphate, etc.) · Aqueous suspensions and elixirs suitable for oral administration may further contain flavoring, coloring, emulsifying, diluent ( water, ethanol, propylene glycol or glycerol, etc.).

Parenteral compositions may contain pharmaceutically acceptable solvents (for example, sesame oil, ground oil, aqueous propylene glycol, dimethylformamide, etc.) or water, if 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). The aqueous solutions are particularly suitable for intravenous, intramuscular or intraperitoneal administration. The sterile aqueous solutions are prepared in a manner known per se. The daily dose of the effective formula I kit may vary within wide limits and depends on several factors, notably the effectiveness of the additive 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 plastic cage on shredded waste paper at room temperature. · Mice receive standard food and tap water ad libitum. Toxicity data is determined by the Bitchfield-Wilcoxon method. ·

Test compounds are administered in the form of aqueous suspensions prepared using

0.5 carboxymethylcellulose.

на 268 676 31

Table I

Toxicity in mice

test compound LD ^ q mg / kg ρ · ο · Compound A 50 Amitriptyline 225 Reference Compound D 600

2) Antagonism to tetrabenazine ptosi in mice and rats p.o.

Groups of 10 mice were dosed orally with test compound, followed by intraperitoneal administration of 50 mg / kg tetrabenazine after 30 minutes and counting animals showing ptosis (eyelid dropping) after 30, 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% (inhxbice).

The results are summarized in Table II.

Table II

Tetrabenazine ptosi antagonism in mice and rats

test compound liyái ^ed 50 mg / kg Ther · index Rats ED ₅₀ mg / kg Compound A 1.0 100 ALIGN! 10.6 Reference Compound D - 3,2 188 5.6. Amitriptyline 12.0 19 Dec 11.50

3) Antagonism to reserpine ptosi in mice, p.o ·

Each animal from a group of 10 mice was injected subcutaneously with 6 mg / kg of reserpine and then orally administered the test compound after 60 minutes · Animals showing ptosi were counted after 60 and 120 minutes · Evaluation of results was performed as described in the previous ptosi test (test) No. 2) · The results are summarized in the following Table III · ·

268σ 268 676 В2 'Table III

Antagonism against reserpine ptosis in mice

test compound BDjq mg / kg Ther · index Compound A 5 ° 20 May Reference Compound D over 120 below 5.0 Amitriptyline 65 3.45

4) Antagonism against reserpine ptosi in rats, p.o.

Each animal of the 10 rats is injected subcutaneously with 2.5 mg / kg of reserpine and then orally administered the test compound after 60 minutes · Animals showing ptosi until the effect subsides · Evaluation of results is performed as described in the previous ptosi test ( test 2).

The results are summarized in Table IV below.

Table IV

Antagonism to reserpine ptosi in rats test compound

Compound A 40 Reference Compound D 60 Amitriptyline about 140

5) Potentiating the toxicity of yohimbine in mice

The tests are performed by a Quinton mathod. Groups of 10 mice each receive the test compound. After one hour, the animals are injected intraperitoneally with a sublethal dose of 20 ml / kg yohimbine. Dead animals are counted after one and 24 hours. The results are summarized in Table V.

Table V

Potency of yohimbine toxicity test compound ED ^ Ther · index compound A 15.0 66.7

Amitriptyline

12.5 ни 268 676 В2

6) Antiarrhythmic effect in rats

The test is carried out using a modified method according to Marmo et al. Test animals are anesthetized with ethyl urethane (1.2 g / kg, i.p.). In the form of injection, animals are injected intravenously with aconitin at a dose of 75 µg / kg. Five minutes after aconitine administration, ECG changes on standard lead II are monitored · Observed changes are graded from 0 to 5 · Test compound is administered either intravenously two minutes before aconitine administration or orally one hour before aconitine administration ·

The results are summarized in Table VI ·

Table VI

test compound Dose Inhibice% Compound A 1 mg / kg 35.0 Lidocaine 4 mg / kg 23.4 7) Antithremorin effect in mice Mice are i.p. administration of 20 mg / kg tremorine and after 45 minutes the characteristic tremor is registered. Test compounds are administered orally one hour prior to administration of tremorine. The results are summarized in Table VII. Taboo 1 and VII Antitremorin effect in mice test compound ED / mg mg / kg Ther. index Compound A 50 20 May Reference Compound D inactive -

The following compounds were used for testing: Compound A = 4-phenyl-4-hydroxy-as-triazino-l, 6-a] quinolin-11-ium-3- (4H) -ide Reference Compound D = 1- (4-chlorophenyl) - aa-tria zinoLl is -α-isoquinolinium bromide (Example 5, DOS No. 3 128 386)

Amitriptyline = N, N-dimethyl-3-L-dibenzot α, d] -cycloheptadien-5-ylidenlpropylamine Lidocaine = diethylamino-2,6-dimethylacetanilide.

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 higher than that of the most potent compound disclosed in DOS 3 128 386, both in absolute dose and therapeutic index in the tetrabenazine antagonist assay in mice and rats. ’

In the activity test for reserpine ptose, the activity of the novel compounds of the invention is substantially 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.

ни 268 676 В2 б · 3 128 386, which is manifested in that the compounds of formula X have highly therapeutically beneficial tranquillizing, analgesic, locally anesthetic and antitremorinic effects ·

As already mentioned, the daily dose of the compounds of the 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 the formula I is about 5 to 150 mg. increased daily up to 300 mg · daily parenteral dose may be about 5 to 50 mg ·

Further details of 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 4-phenyl-4-hydroxy-as-triazinorium, 6-a3-quinolin-11-ium-3- (4H) -ide

11 ml of 4% aqueous sodium hydroxide solution are added to a solution of 3.6 g (0.01 mol) of 4-phenyl-a-triazinoCl, 6-alquinolinium perchloride in ethanol. 2.5 g of the desired compound precipitates, corresponding to a yield of 91 temperature. mp 137-138 ° C.

Example 2

Preparation of 1,3-diphenyl-1-hydroxypyrido [2,1-f] as-triazin-5-ium-2- (1H) -ide

The procedure of Example 1 is followed except that 1,3-diphenylpyridor2,11] -as-triazinium perchlorate is used as the starting material and the reaction is carried out in a reaction medium consisting of acetonitrile instead of ethanol. mp: 168-169 ° C.

Example 3 1-phenyl-1-hydroxy-3-methylpyrido [2,1-f] -as-triazin-5-ium-2 (1H) -ide

To a solution of 3.0 g (0.01 mol) of 1-phenyl-3-methylpyrido [2,1-b] -as-triazinium perchlorate in acetonitrile is added 11 ml of a 4% aqueous sodium hydroxide solution. . Yield 87%, mp 166-168 ° C.

Example 4 1-phenyl-1-dydroxy-3- t -butylpyrido [2,1-f] -as-triazin-5-ium-2 (1H) -ide

To a solution of 3.6 ml (0.01 mole) of 1-phenyl-3- t -butylpyridoyl-1,1H-triazinium perchlorate in acetonitrile was added 11 ml of a 4% aqueous sodium hydroxide solution. 2.6 g of the title compound are obtained. Yield: 92%, mp 170-172 ° C.

Example 5

4- (4-Fluorophenyl) -4-hydroxy-as-triazino- [1,6-a] quinolin-11-ium-3 (4H) -ide

To a solution of 3.75 g (0.01 mol) of 4- (4-fluorophenyl) -α-triazino- [1,6-a] quinolinium perchlorate in ethanol was added 11 ml of a 4% aqueous sodium hydroxide solution. 2.5 g of the title compound precipitated. Yield: 88%, mp 142-144 ° C.

SUBJECT OF THE INVENTION

Claims (2)

A process for the preparation of novel condensed as-triazine derivatives of the general formula I (I) 268 268 676 V2 wherein By is a phenyl group which is optionally substituted with one halogen atom, R ₂ represents hydrogen, phenyl or alkyl containing 1 to 4 carbon atoms and represents a buta-1,3-dienylskupinu or a group of formula (a) (a), characterized in that a compound of general formula II wherein. A represents an anion derived from an inorganic or strong organic acid and Sp R ₂ and Z are as defined above, react with an aqueous solution of an inorganic base · 2. A process according to claim 1, wherein the inorganic base is an alkali metal hydroxide.