CS264333B2 - Preparation method of new condensated as- triazine derivatives - 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 fused Zwitterionts astriazine derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

In particular, the invention relates to compounds of formula I

(I) where

is phenyl optionally substituted with one halogen atom and is C1-C4alkoxy.

The term C 1 -C 4 alkoxy is used to denote straight or branched chain alkoxy groups (such as methoxy, ethoxy, isopropoxy, etc.). The term halogen includes fluorine, chlorine, bromine and iodine atoms.

Among the compounds of formula (I), those in which R @ 1 is phenyl optionally substituted in the 4-position by halogen, in particular 4-chlorophenyl, are preferred. R ₃ preferably represents methoxy.

A particularly preferred representative compound of formula (I) is 1- (4-chlorophenyl) -1-methoxy-as-triazino [a, 1-a] isoquinolin-5-ium-2- (1H) -ide.

The present invention provides a process for the preparation of compounds of formula (I) which is characterized by alkylating a compound of formula (II)

(II) wherein R1 is as defined above.

The alkylation in the process according to the invention can be carried out by methods known per se. An alkyl halide or dialkyl sulfate can be used as the alkylating agent. The alkylation may preferably be carried out in the presence of a base (for example an alkali metal hydroxide or alkoxide). The alkylating agent may be used in equimolar amounts or in a slight excess. The reaction may be carried out at a temperature ranging from 0 ° C to room temperature.

The starting materials of general formula (II) are described in parallel U.S. Pat. No. 264,269.

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 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 (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, carbonate) calcium, calcium phosphate, etc.). Aqueous suspensions and elixirs suitable for oral administration may further contain flavoring agents, coloring agents, 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. 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 method 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 39x12x12 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 suspensions prepared using 0.5% carboxymethylcellulose.

Table I

Toxicity in mice

Test compound

LD ₅₀ mg / kg po

Compound В 420 Amitriptyline 225 Reference Compound D 600

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 tetrabenzine was administered intraperitoneally 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.

Table II

Antagonism to tetrabenazine ptos.i in mice and rats

Test compound ED ₅₀ mg / kg mice Ther. index Rats ED ₅₀ mg / kg compound В 0.25 1 680 0.6 Reference Compound D 3.2 188 5.6 Amitriptyline 12.00 19 Dec 11.50

3. Antagonism against reserpine ptosis in mice, p.o.

Each animal of the group of 10 mice is administered subcutaneously with 6 mg / kg of reserpine and then orally administered the test compound after 60 minutes. Animals showing ptosi are 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 Ther. index compound В 1.5 280.0 Reference Compound D over 120 below 5.0 Amitriptyline 65.0 3.45

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

Each animal of the group 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 ptosi test (test 2).

The results are summarized in the following Table IV.

Table IV

Antagonism to reserpine ptosi in rats

Test compound ^ED 50 ^{ιη <} / ^ 9

compound В 34 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 injected intraperitoneally with a 20 ml / kg sublethal dose of yohimbine. Dead animals are counted after 1 and 24 hours. The results are summarized in Table V.

Table V

Potentiation of yohimbine toxicity

Test compound ^ed ₅ q mg / kg Ther. index compound В 1,2 350 Amitriptyline 12.5 18

6. Antiarrhythmic effect in rats

The test is carried out by the modified method of Marmo et al. Test animals were anesthetized with ethyl urethane (1.2 g / kg i.p.). As an injection, animals are injected intravenously with aconitine at a dose of 75 µg / kg. Five minutes after the administration of aconitin, ECG changes on the standard lead II are monitored. The observed changes are scored from 0 to 5. The test compound is administered either intravenously two minutes prior to 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 Inhibition%

compound В 1 mg / kg 44.3 Lidocaine 4 mg / kg 23.4

7. Antitremorin effect in mice

Mice are i.p. administration of 20 mg / kg tremorine and after 45 minutes the characteristic tremor is registered. Test compounds were administered orally 1 hour prior to administration of tremorine. The results are summarized in Table VII.

Table VII

Antitremorin effect in mice

Test compound ED ₅₀ (mg / kg) Ther. index compound В 40 10.5 Reference Compound D inactive -

The following compounds were used for testing:

Compound в = 1- (4-chlorophenyl) -1-methoxy-as-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide,

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

Amitriptyline = N, N-dimethyl-3- [dibenzo [a, d] -cycloheptadien-5-ylidene] propylamine

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

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 No. 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 3,128. 386, which is manifested in that the compounds of general 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 up 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.

He did

Preparation of 1- (4-chlorophenyl) -1-methoxy-as-triazino [6,1-a] isoquinolin-5-ium-2- (1H) -ide

To a solution of 4.1 g (0.01 mol) of 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino [b, 1-a] isoquinolinium perchlorate in 10 ml of ethanol was added 16 ml of 1N aqueous sodium hydroxide solution, and then 1.25 g (0.01 mol) of dimethyl sulfate is added at a temperature below 15 ° C. 2.9 g of the desired compound are obtained, corresponding to a yield of 90%, m.p. 158-159 ° C.

Example 2

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

4.03 g (0.01 mol) of 1- (4-fluorophenyl) -1-hydroxy-1,2-dihydro-as-triazino- [6,1a] -isoquinolinium ethanesulfate are treated with 16 ml of hydroxide solution in 15 ml of ethanol. of sodium 1 mol / l, and then 1.26 g (0.01 mol) of dimethyl sulfate are added at 15 ° C. 2.7 g of the title compound precipitated. Yield 88%, mp 160-162 ° C.

Example 3

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

The reaction is carried out as described in Example 2. Starting from 3.74 g (0.01 mol) of 1-phenyl-1-hydroxy-1,2-dihydro-as-triazino [6,1a] -isoquinolinium perchlorate to give 2.4 g of the title compound. Yield 84%, mp 152-154 ° C.

Claims (2)

1. A process for the preparation of novel condensed as-triazine derivatives of the general formula I (I) wherein ^R 1 is phenyl optionally substituted with one halogen atom and. ^R 3 C 1 -C 4 alkoxy characterized by alkylating a compound of formula II (II) wherein R 1 is as defined in formula (I). 2. A process according to claim 1 wherein the alkylating agent is an alkyl halide or dialkyl sulfate.