CS259531B2 - Method of as-triazine's condensed derivatives preparation - Google Patents

Abstract

A process for the preparation of fused as-triazine derivatives of the general formula I wherein R 1 is phenyl optionally substituted by one or two halogen atoms, R 1 is hydrogen or C 1 -C 4 alkyl, Z is buta-1,3; a dienyl group or a group of formula (a) or (bj, and A 'represents an anion derived from a pharmaceutically acceptable inorganic or strong organic acid in which the compound of formula II wherein R 1, Z and A- are as defined above is reacted with a compound of formula III wherein R 2 is as defined above, in the presence of a dehydrating agent, and then treating the reaction mixture with water and optionally converting the anion A to another anion A "in the compound of formula (I). pharmacologically effective and have an especially antiarrhythmic and antidepressant effect.

Description

The invention relates to pharmaceutically active novel fused as-triazine derivatives, to a process for their preparation and to pharmaceutical preparations containing them.

In particular, the invention relates to novel fused as-triazine derivatives of formula 1

(') where

R 1 is phenyl optionally substituted with one or two halogen atoms,

R 2 is hydrogen or C 1 -C 4 alkyl,

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

and

A - is the anion of a pharmaceutically acceptable inorganic acid or a strong organic acid.

The term "C 1 -C 4 alkyl" as used herein refers to a straight or branched C 1 -C 4 alkyl group such as methyl, ethyl, η-propyl, isopropyl The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

Preferred compounds of formula I are those wherein Z is a group of formula (b). R 1 is preferably phenyl optionally substituted with halogen, especially 4-chlorophenyl. Preferably R2 is hydrogen.

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

1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino (6,1-a) isoquinolinium methanesulfonate,

1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino (6,1-aisoquinolinium chloride).

A ^- can be any pharmaceutically acceptable inorganic or organic anion, such as chloride, bromide, iodide, perchlorate, methanesulfonate or 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)

wherein R 1, Z and A ^- are as defined above, reacted with a compound of formula III

NH 2 - CO - R 2 (ΠΙ) wherein R 2 is as defined above, in the presence of a dehydrating agent, then treated with water and optionally anion A ^{- is} exchanged for another anion A ^- in the compound of formula I thus obtained.

The reaction of the compounds of formulas II and III is carried out in the presence of a dehydrating agent. For this purpose it is preferable to use Lewis acids, for example titanium tetrachloride, aluminum chloride, boron trifluoride, etc. or phosphorus oxychloride. The reaction may be carried out at a temperature in the range of from 50 to 120 ° C, preferably at a temperature of from 80 to 90 ° C. As reaction medium inert organic solvents, for example halogenated hydrocarbons (for example chloroform, chlorobenzene, etc.), aromatic hydrocarbons (for example benzene, toluene or xylene), dialkylamides (for example dimethylformamide), cyclic ethers or acetonitrile can be used. An excess of the liquid acid amide of formula V (e.g. formamide) may also serve as the reaction medium. The resulting reaction mixture is then treated with water.

If desired, in resulting compounds of formula I to exchange the anion A ^- for another anion A ". The processes are carried out in a manner known per se. Thus, for example, a compound of formula I containing an anion A ^- chloride anion can be converted to the corresponding compound of formula I containing an anion A ^- perchlorate anion by reaction with perchloric acid.

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WITH

Compounds of formula I containing a bromide anion as A 'can be prepared from compounds of formula I containing another anion, for example perchlorate anion, by reaction with tetrabutylammonium bromide.

A compound of formula I wherein A represents an ethanesulfonate, can be prepared by reacting a compound of formula I wherein A is another anion, for example a bromide anion, with ethanesulfonic acid.

The starting materials of the formula II are disclosed in DOS 3 128 386 and the starting materials of the formula III are commercially available compounds.

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 pharmaceutically acceptable 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 ingredients (e.g. sodium citrate, carbonate) calcium suspensions, middle 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 isotonized with a suitable buffer. Aqueous solutions are particularly suitable for intravenous, intramuscular or intraperitoneal administration, and sterile aqueous solutions are prepared by known methods.

The daily dose of the active ingredient of the formula (I) may vary within wide limits and depends on several factors, in particular the activity 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 grams. 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 compound LD 50 / mg / kg p.o.

compound A 410 compound B 560 compound C 590 reference compound D 600

Amitryptylin 225

(a) 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 LD 50 mg / kg p.o.

compound A 1300 compound B about 1100 compound C about 1033

3. Antagonism against 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 III.

Table III

Antagonism to tetrabenazine ptosi in mice and rats

Test Compound Rat Mice

ED50 mg / kg Ther. index ED50 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 against reserpine ptosi in rats, p. O.

Each animal of the groups of 10 rats was injected subcutaneously with 2.5 mg / kg of reserpine and then orally administered the test compound after 60 minutes. The animals showing are counted

1 367 0.3 4 333 1867 1.0 1100 203 4,5 191 188 5.6 179 19 Dec 11.5 46 ptosi until the fading effect. Evaluation results carried out in the manner specified in

prior to the ptosi test (test 3). The results are summarized in Table IV below.

Table IV

Antagonism against reserpine ptosi in rats

Test compound Rats

ED50 mg / kg Ther. index compound A 14 compound B 28 compound C 21 reference compound D about 60

Amitriptyline about 140

5. Antiarrhythmic effect on 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 of 75 µg / kg of aconitine intravenously.

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 intrave, legally 2 minutes before the administration of aconitine or orally 1 hour before the administration of aconitine.

The results are summarized in Table V.

Table V

Antiarrhythmic effect on rats

Test compound ED50 mg / kg i.v. Rats p. Ther. index Compound A 0.9 40 32.5 Compound B 1.6 30 27.5 Lidocaine 4.0 (23.4 O / o) 120 (3.5%) The therapeutic index cannot be calculated from this data; no activity

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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, spasmolytic, locally anesthetic, analgesic, anti-inflammatory and tranquilizing sedative properties have also been observed with the compounds of formula (I). Certain compounds of formula I also exhibit tremorin-antagonistic activity.

Anti-inflammatory effect in rats

Into the plantar surface of the hind paws of the weights. 150 to 180 g are injected with 1% carragenine. Using a plethysmometer, the paw volume was measured before and 3 hours after the irritant was administered. Animals are dosed with test compound or vehicle (control) for 1 hour prior to administration of the irritant. Due to the different solubilities, Tween 80 surfactants are used as adjuvants.

The results are summarized in Table VI.

Table VI

Anti-inflammatory effect in rats

Test compound Inhibitory effect ED 50 mg / kg Ther. index Compound A 24.5 53.1 Reference Compound D Can not determine any effect - phenylbutazone about 90.0 5.3

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

Tables 1 to VII

Antitremorin effect in mice

Test compound Antitremorin effect Ther. index

ED 50 mg / kg

Compound B 6 93.3

Ref. compound D inactive -

The following Lidocaine compounds were used for the assay: N-diethylamino-2,6-dimethylacetanilide compound A = 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium ethanesulfonate 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 [6,1-a] isoquinolinium bromide Reference Compound D =

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

Amitriptyline =

N, N-dimethyl-3- (dibenzo [a, dicycloheptadien-5-ylidene) propylamine

Phenylbutazone -

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

In summary, the novel compounds of the present invention exhibit excellent anti-depressant 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 the fact that the compounds of general formula

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They also have highly favorable transient, analgesic, spasmolytic, anti-inflammatory and antitremorinic effects from a therapeutic standpoint.

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 1-phenyl-1-hydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium perchlorate

A mixture of 10 g (0.024 mol) of 2-amino 1-henzoylisoquinolinium tosylate, 30 ml of formamide and 15 ml of phosphorus oxychloride is heated to 80-90 ° C. The reaction mixture was cooled, diluted with water and 10 ml of 70% perchloric acid was added. Thus 4.8 g of the title compound are obtained, yield 55%, m.p. 245-246 ° C (after recrystallization from acetonitrile / water).

Example 2

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

A mixture of 5 g (0.013 mol) of 2-amino-1- (p-chlorobenzoyl) isoquinolinium perchlorate, 8 ml of titanium tetrachloride and 40 ml of formamide is heated at 90-100 ° C for one hour and then 10 ml of water are added. When precipitation of the crystals began, a solution of 5 g of sodium perchlorate and 10 ml of water was added. 3.0 g of the desired compound are obtained, yield 50%, mp 238-239 ° C (from acetonitrile-water).

Example 3

Preparation of 4- (4-chlorophenyl) 4-hydroxy-3,4-dihydro-as-triazino [1,6-a] quinolinium perchlorate

A mixture of 5 g (0.011 mol) of 1-amino-2- (4-chlorobenzoyl) quinolinium tosylate, 30 ml of formamide and 20 ml of phosphorus oxychloride is heated at 90 DEG C. for one hour. Perchloric acid was obtained

3.3 g of the title compound, yield 73%, m.p. 293-294 ° C (after crystallization from a mixture of nitromethane and ether).

Example 4

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

3.55 g (0.0081 mol) of 1- (4-chlorophenyl) -1-liydroxy-1,2-dihydro-as-triazino [6,1-a] isoquinolinium bromide was reacted with 2.22 g (0.0022 mole of ethanesulfonic acid in 50 ml of acetonitrile, the reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate and cooled to give 3.3 g (86%) of the title compound which precipitates as prismatic crystals, m.p. 188 [deg.] C.

Example 5

Preparation of 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydropyrido [2,1-f] -as-triazinium perchlorate

The procedure described in Example 2 was followed except that 11 g (0.027 mol) of 2-amino-2- (4-chlorobenzoyl) pyridinium tosylate was used as the starting material (yield: 79.5%, mp 254-255 degrees). Celsius (from acetonitrile).

Example 6

4-Phenyl-4 hydroxy-2-methyl-3,4-dihydropyrido [2,1- f] -as-triazinium perchlorate g (0.01 mol) of 1-amino-2-benzoylpyridinium perchlorate was stirred at 170 DEG C. for 3 hours. ° C with 6 ml (0.01 mol) of acetamide in 50 g of polyphosphoric acid. The reaction mixture is poured onto ice, the solution is saturated with sodium perchlorate, the precipitate is filtered off, washed with water and recrystallized from acetonitrile-water. 1.0 g of product is obtained. Yield: 31%; mp 289-271 ° C. Example 7

4-phenyl-4-hydroxy-2-methyl-3,4-dihydropyrido [2,1- f] -as-triazinium bromide g (0.025 mol) 4-phenyl-4-hydroxy-2-methyl-3,4- of dihydropyrido [2,1-b] -as-triazinium perchlorate was stirred with 12 g (0.037 mol) of tetrabutylammonium bromide in 80 ml of acetonitrile for three hours. The precipitated crystals are filtered off and washed with acetonitrile. 5.8 g of product are obtained. Yield: 77%, m.p. 246-248 ° C.

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of a fused as-triazine derivative of the general formula (I) of a ganic acid or a strong organic acid, characterized in that the compound of the general formula (II) P, i? where R 1 is phenyl optionally substituted with one or two halogen atoms, R 2 is hydrogen or C 1 -C 4 alkyl, Z is buta-1,3-dienyl or a group of formula (a) or (b) A is an anion of a pharmaceutically acceptable anion where R1, Z and A are as defined above, reacted with a compound of formula III In the presence of a dehydrating agent, the reaction mixture is treated with water and optionally the anion A 'in the compound of the formula I thus obtained is exchanged for another anion A ^- . 2. The process according to claim 1, wherein the dehydrating agent is a Lewis acid, preferably titanium tetrachloride, aluminum chloride or boron trifluoride or phosphorus oxychloride. 3. The process of claims 1 and 2, starting from the compounds defined in claim 1 to give 1- (4-chlorophenyl) -1-hydroxy-1,2-dihydro-as-triazine [6,1- a] Isoquinolinium methanesulfonate or chloride.