NO159529B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVITY 3-SUBSTITUTED TETRAHYDRO-1,2,4, TRIAZINES. - Google Patents

Description

The present invention relates to the production of new 3-substituted tetrahydro-1,2,4-triazines with anti-anxiety and anti-depression activity and with the formula:

where R is hydrogen, methyl or acetyl, F^ is hydrogen or methyl, and A and B independently of each other are naphthyl,

1,3-benzodioxol-5-yl, phenyl or phenyl which may be substituted by one or two of the groups C-^-C^ alkyl,

<"1~C3 α-Loxy, halogen and naphthyl, under the condition that A cannot be phenyl when B is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof.

These new compounds have been shown to have both anxiety-

and anti-depressant activity when administered internally to mammals.. As the term "psychoactive agent" is

used in the present context, means a compound with properties that counteract both anxiety and depression.

The invention also includes the preparation of pharmaceutically acceptable salts of the new 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazines, and the term "pharmaceutically acceptable salts" refers to non- toxic acid addition salts of the compounds, and where the anions are relatively harmless to mammals in the doses used when a good psychoactive effect is achieved, so that the beneficial effect of the free bases is not damaged by side effects caused by the anions. Pharmaceutically acceptable salts include those prepared from mineral acids such as hydrochloric acid and sulfuric acid, and from organic acids such as lactic acid, maleic acid, succinic acid, fumaric acid, glutaric acid, citric acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid and

tartaric acid, etc.

A preferred group of new compounds of formula (I) comprises those where R and R-^ are hydrogen, and where one of the symbols A and B represents substituted phenyl while the other represents phenyl or substituted phenyl where the substituents are selected from C^C -^ alkoxy and halogen,

as well as pharmaceutically acceptable salts thereof.

Various substituted 1,4,5,6-tetrahydro-1,2,4-triazines with antidepressant properties are described in US patent no. 3,471,486. v

The compound 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine is described in the literature as an anti-depressant, in Journal of Medical Chemistry, 12, 257, ( 1969). This compound has been tested for anti-nervous activity and has been found to be essentially inactive. The compounds described above have been prepared by reacting an imino ester hydrohalide dissolved in glacial acetic acid, methanol or ethanol with a 2-aminoalkyl hydrazine. This method is labor-intensive and gives a poor yield and is thus uneconomical for commercial use.

In the literature, it is described how synthesized 2-imidazolines can be prepared by a ring closure of a diamine with a nitrile in the presence of elemental sulphur. Nippon Kagaku Zasshi 1968, 89 (8), 780 (Chem. Abs. 70:19983q).

According to the present invention, the compounds of formula (I) are prepared by reacting a 2-aminoethylhydrazine compound with the formula: and a nitrile compound with the formula:

wherein R and R 1 are hydrogen or methyl, and A and B have the above meaning, in the presence of a catalytic amount of a transition metal salt or elemental sulfur and, in which case a compound of formula (I) is obtained wherein R and/or B.^ is hydrogen, then said compound can be converted into the corresponding compound with formula (I)

where R is methyl or acetyl, and R 1 is methyl, by usual methylation or acetylation methods, and, if desired, conversion of a compound thus obtained into a pharmaceutically acceptable salt thereof.

The reaction between the nitrile and the 2-aminoethylhydrazine compound can be carried out in a suitable solvent system, usually a high-boiling alcohol, but the reaction can also be carried out in the absence of a solvent by mixing only the reactants and a catalytic amount of a transition metal salt or elemental sulphur. The reaction usually occurs faster in the absence of solvent, but when the product is prepared in large portions, it is also often desirable to use some solvent to lower the viscosity of the reactants so that mixing is facilitated. As used herein, the term "catalytic amount" denotes an amount of a transition metal salt or elemental sulfur sufficient to convert equimolar amounts of the hydrazine and nitrile to the desired 1,2,4-triazine product. Transition metal salts such as ferric chloride and zinc acetate give satisfactory results. Elemental sulfur is particularly preferred because it is readily available and escapes from the reaction mass so that only trace amounts of sulfur are found in the final product. Sulfur is thus the preferred catalyst in the present invention. The reaction is carried out at temperatures from 70 to 100°C, preferably at 85-95°C. Lower temperatures can be used, but then the reaction is slower. Temperatures above 120°C cause the hydrazine/sulphur complex to evaporate from the reaction mixture and lead to a reduced yield and the formation of large amounts of impurities.

The various nitrile intermediates can be prepared by known methods, as described in the literature. See e.g. Synthesis 441-456, August 1973; J. Org. Chem. 36, 2948 (1971), and Tetrahedron Letters No. 14, pages 1509-1511 (1966). 2-aminohydrazines can also be prepared using known methods. The produced tetrahydrotriazine products can easily be converted into hydrohalide salts if this is desired, by acidifying a preselected hydrohalide.

Compounds of formula (I) where is methyl, and R is hydrogen, methyl or acetyl, can be easily prepared from the corresponding N-substituted compounds by ordinary methylation or acetylation. The production of 3-(1,2-diphenyl-ethyl)-1,4,5,6-tetrahydro-1,2,4-triazine was carried out both with experimental studies in the laboratory and in a larger production series with large portions.

The compound 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine can conveniently be prepared by first providing the intermediate product 2,3-diphenylpropionitrile by a so-called phase transition catalysis reaction involving benzyl cyanide and benzyl chloride in the presence of aqueous sodium hydroxide. Reactions of this type are well described in the literature. Next, said 2,3-diphenylpropionitrile and 2-aminoethylethylhydrazine are ring-closed in the presence of sulphur, whereby 3-(1,2-diphenylethyl) is obtained. -1,4,5,6-tetrahydro-1,2,4-triazine. The triazine can easily be converted to the hydrohalide salt if this is desired by acidification with a preselected hydrohalide. As mentioned above, the new substituted 3-diarylethyl-tetrahydro-1,2,4-triazine compounds can be easily prepared by the same type of process. The anti-anxiety and antidepressant properties of the new substituted 3-diarylethyl-tetrahydro-1,2,4-triazines according to the present invention were proven by means of pharmacological experiments.

Compounds that have anti-anxiety properties,

will block a stress-induced elevation of the serum corticosteroid level, cf. British Medical Journal, 1971 (2), pages 310-313. Corticosteroid levels in stressed male rats pretreated with 20 mg/kg of the active compound given by intraperitoneal injection were compared with corticosteroid levels in stressed male rats pretreated with saline. 3 ml of blood was collected using a methoxyflurane anaesthetic. After coagulation, the blood was centrifuged to separate

the serum used in the analysis for corticosteroids. The assay was performed by adding 5 ml of methylene chloride to 300 µl of the serum sample and stirring it for 15-20 seconds.

The samples were then centrifuged at 41 xg for 5 minutes. Lipid stock was removed by aspiration, and 3 ml of the methylene chloride fraction was transferred to a clean tube. This sample was then added to 3 ml of fluorescence reagent (25% ethanol and 75% concentrated sulfuric acid) and stirred for 5 seconds. Fluorescence development was complete within 20 minutes and was read in a Perkin-Elmer (<R>) fluorometer model 204 204 at an excitation wavelength of 470 mu and an analysis wavelength of 530 mu. This test measures free cortisol and corticosterone. The corticosteroid value was calculated as follows:

By using this method, it was found that compounds produced according to the present invention had activity that counteracted nervousness. The results are shown in Table II below. Values below 100% indicate activity. The antidepressant effect was shown using the Reserpin ptosis test. Groups of four mice were added

30 mg/kg body weight of the 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine compounds by intraperitoneal injection via an aqueous liquid. A similar group of mice was the control group and was only injected with the aqueous liquid. After 30 minutes, both groups were injected subcutaneously with 2.5 mg/kg resperine. The administration of resperine to the control group resulted in a classic development of symptoms that began with the eyelids (ptosis) beginning to droop and later culminated in a general depression with decreased spontaneous motor activity and decreased response to both sound and sensory stimuli. Animals injected with the triazine compound were graded after 45 minutes on the following basis: no ptosis = 0, partial ptosis = 1, complete ptosis = 2. Complete protection against reserpine-induced ptosis gives a value of zero or 100%. Percent protection for each of the compounds is given in Table 1.

It appears from table 1 that the compounds from the examples

4, 5, 12, 13 and 17 are particularly active as remedies for nervousness. The other compounds in the table are somewhat less active than the compounds mentioned, but show significant activity as anti-nervous agents. In addition to this property, the following compounds were also found to be very active as antidepressants, and as such are particularly preferred as psychoactive agents, i.e.

as agents with both properties against nervousness and depression: 3-(2-(4-chlorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 5);

3-(1-(4-methylphenyl)-2-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 7);

3-(2-(2,6-Dichlorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 14).

In the treatment of anxiety in mammals, an effective amount of a compound of formula (I) which counteracts anxiety is administered. An effective amount that counteracts anxiety is understood to mean an amount of one or more compounds that will counteract anxiety in the central nervous system.

The following examples illustrate the connection.

Example 1

Preparation of 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1, 2, 4-triazln monohydrochloride

Step 1: A reaction vessel consisting of a 2-liter round-bottomed flask equipped with a mechanical stirrer, thermometer, nitrogen supply tube, and reflux condenser was charged with 585 g (574 mL; 5.0 mol) of benzyl cyanide, 250 mL of 50% sodium hydroxide, and 12.5 g

(0.055 mol; 4.4 mol%) benzyltriethylammonium chloride. While the temperature was kept at approx. 50°C, 224.4 g (1.77 mol) of benzyl chloride were added dropwise over the course of 1 hour. The reaction mass was stirred for a further 1 hour, after which 400 ml of deionized water was added to dissolve the sodium chloride and obtain a separation of the aqueous and organic layers. If an emulsion formed at this stage, ethylene chloride was added. The organic layer was distilled to separate 2,3-diphenylpropionitrile from the other reactants and impurities. The identity of the compound was confirmed by elemental analysis, NMR, IR and mass spectrophotometry data.

Step 2: The nitrile intermediate prepared in Step 1 (35.0 g: 0.169 mol) was heated under nitrogen with 0.379 g (0.012 gram atom, 7 mol %) of sulfur from ca. 70°C in a 100 ml round bottom flask until the sulfur was dissolved, which took approx. 2 hours. To the reaction vessel was then added 25.4 g (0.338 mol; 2 equiv.) of 2-aminoethylhydrazine. The temperature was raised to approx. 100°C and held here for approx. 5 hours.

The reaction mass was cooled to approx. 50°C, after which 75 ml of toluene was added and the whole was extracted with 75 ml of water. 35 ml of absolute alcohol was added, and the mixture boiled under reflux while hydrogen chloride was bubbled through the mass.

The 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride produced was crystallized and filtered off and then washed with a 90/100 toluene/ethanol mixture. The product was then dried in vacuum. Elemental analysis, X-ray crystallography, NMR and mass spectrophotometry were used to confirm the structure.

Examples 2 and 3

Using the same method as stated above, the following examples were produced, which have the general structure:

where k is 1 or 2. These compounds are shown in the table

II.

Example 4

Preparation of 3-(2-(4-fluorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride

A mixture containing 5.0 g of 1-phenyl-2-p-fluoromethyl-propionitrile and 0.5 g of elemental sulfur was placed in a 50 ml round bottom flask equipped with a condenser, magnetic stirrer and maintained under a nitrogen atmosphere. A minimal amount of 5 ml of 2-methoxyethanol was added and the mixture held at 90°C for 2 hours to dissolve the sulphur. A heated solution was slowly injected with 3.3 g of 2-aminoethylhydrazine, and the resulting blue-green reaction mass was held at 90°C for 18 hours. The mass was then cooled by adding 30 ml of toluene, transferred to a rinsing funnel, after which a further 70 ml of toluene was added.

The toluene was washed with water and a saturated sodium chloride solution. The organic layer was separated, dried with sodium sulfate and filtered. Dry hydrogen chloride gas was bubbled into the toluene solution, and 3-(2-(4-fluorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride was obtained. This crude product was dried under vacuum and recrystallized from isopropanol. The salt had a melting point of 220-222°C.

Elemental analysis showed carbon 63.95%, hydrogen 6.0 2% and nitrogen 13.09%, compared to the theoretical values of 63.84%, hydrogen 5.79% and nitrogen 13.14%.

- Example 5-18

By using the same procedure as stated in example 4, a number of other 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazines with the following general formula were prepared:

These compounds are listed in Table III.

In addition to the compounds shown in Table III, two compounds with substitutions on the triazine ring were also prepared. These compounds were the following: Example 19

3-(2-(4-chlorophenyl)-1-phenylethyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine monohydrochloride, m.p. 212-213°C.

Example 20

4-Acetyl-3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine monohydrochloride, oil.

Claims (1)

Analogous process for the preparation of 3-substituted tetrahydro-1,2,4-triazines with anti-anxiety and anti-depressant activity and with the formula: where R is hydrogen, methyl or acetyl, R 1 is hydrogen or methyl, and A and B independently of each other are naphthyl, 1,3-benzodioxol-5-yl, phenyl or phenyl which may be substituted with one or two of the groups C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen and naphthyl, with the proviso that A cannot be phenyl when B is phenyl or naphthyl, as well as pharmaceutically acceptable salts thereof, characterized by reacting a 2-aminoethylhydrazine compound with the formula: and a nitrile compound of the formula: wherein R and R^ are hydrogen or methyl, and A and B are as defined above, in the presence of a catalytic amount of a transition metal salt or elemental sulfur and, in which case a compound of formula I is obtained, wherein R and/or R.^ is hydrogen, then said compound can optionally be converted into a corresponding compound of formula I where R is methyl or acetyl, and R^ is methyl, by usual methylation or acylation methods, and, if desired, conversion of a thus obtained compound into a pharmaceutically acceptable salt thereof.