GB1576579A - 3-substituted 1,2,4-triazines and their preparation - Google Patents

Abstract

A nitrile is reacted with a 2-aminoethylhydrazine in the presence of transition metal salts or of elemental sulphur as catalyst. The new 3-diarylethyl-tetrahydro-1,2,4-triazines thus obtained, of formula <IMAGE> in which m = 0, n = 1, R is a hydrogen atom or a methyl or acetyl group, R1 is a hydrogen atom or a methyl group, A and B independently represent a naphthyl, 1,3-benzodioxol-5-yl or phenyl group or a phenyl group substituted by one or two fragments chosen from the following: lower alkyl, lower alkoxy, halo and naphthyl, provided that A is not a phenyl group when B is a phenyl or naphthyl group, and their pharmaceutically acceptable salts can be used as anxiolytic medicaments.

Description

(54) 3-SUBSTITUTED 1,2,4-TRIAZINES AND THEIR PREPARATION (71) We, THE DOW CHEMICAL COMPANY, a corporation organised and existing under the laws of the State of Delaware, United States of America, of Midland, County of Midland, State of Michigan, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a general process for preparing 3 - substituted tetrahydro - 1,2,4 - triazines, to novel compounds of this type and to pharmaceutical compositions comprising these novel compounds.

Various substituted 1,4,5,6 - tetrahydro - 1,2,4 - triazines are described as having anti-depressant properties in U.S. Patent Specification No. 3,471,486. 3 (1,2 - diphenylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazine is described as an antidepressant in Journal of Medical Chemistry, 12, 257 (1969). This compound has been tested for anti-anxiety activity and found to be essentially inactive.

In general, tetrahydrotriazines have been prepared by reacting an imino ester hydrohalide dissolved in glacial acetic acid, methanol or ethanol with a 2 aminoalkylhydrazine. This preparation is tedious and gives poor yields, making the overall procedure uneconomical for commercial production.

In related art, substituted 2 - imidazolines have been synthesised by the cyclization of a diamine with a nitrile in the presence of elemental sulphur; see Nippon Kagaku Zasshi (1968), 89 (8), 780 (Chem. Abs. 70:19983q).

According to the present invention, a process for preparing a 3 - substituted tetrahydro - 1,2,4 - triazine comprises reacting a nitrile with an optionally substituted 2 - aminoethylhydrazine in the presence of a catalyst selected from transition metal salts and elemental sulfur. The process is particularly useful in preparing tetrahydrotriazines of formula I:

wherein m is zero or one; n is zero or:one; either R is hydrogen or methyl and R, is hydrogen or R is hydrogen, methyl or acetyl and R1 is methyl; and A and B are the same or different and are each hydrogen, C14 alkyl, naphthyl, 1,3 - benzodioxol 5 - yl or optionally substituted phenyl in which any substituents are selected from halogen, C13 alkyl, C13 alkoxy, nitro, naphthyl and pyridyl.

The process of the invention for preparing the compounds of formula I comprises reacting a 2 - aminoethylhydrazine of the formula R'NH-CH2-CH2-NR;-NH2 with a nitrile of the formula A-(CH2)nCH(CNHCH2)rnB wherein m, n, A and B are as defined above and R' and R1 are each hydrogen or methyl, in the presence of a catalyst selected from transition metal salts and elemental sulfur, to obtain a compound of formula I in which R and R1 are each hydrogen or methyl; and, if desired, either methylating (in conventional manner) a compound of formula I in which R and/or R1 is hydrogen to obtain a compound of formula I in which R and R1 are each methyl, or acetylating (in conventional manner) a compound of formula I-in which R is hydrogen and R1 is methyl to obtain a compound of formula I in which R is acetyl and R1 is methyl.

The novel 3 - substituted - tetrahydro - triazine compounds in accordance with the invention are substituted 3 - (1,2 - diarylethyl) - 1,4,5,6 - tetrahydro 1,2,4 - triazines of formula I wherein m is zero, n is 1, either R is hydrogen or methyl and R, is hydrogen or R is hydrogen, methyl or acetyl and R, is methyl, A and B independently represent naphthyl, 1,3 - benzodioxol - 5 - yl, phenyl or phenyl substituted once or twice by substituents independently selected from C13 alkyl, C13 alkoxy, halo and naphthyl with the proviso that A cannot be phenyl when B is phenyl or naphthyl. These novel compounds have been found to have both anti-depressant and anti-anxiety activity when administered internally to a mammal. As used in this specification, the phrase "phychoactive agent" refers to a compound having both anti-anxiety and anti-depressant properties.

The invention also includes the pharmaceutically acceptable salts of the novel 3 - (1,2 - diarylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazines of the present invention. As used in this specification, the phrase "pharmaceutically acceptable salts" refers to non-toxic acid addition salts of the compounds, the anions of which are relatively innocuous to animals at dosages consistent with good psychoactive activity so that the beneficial effects of the free base are not vitiated by the side effects ascribable to the anions. Pharmaceutically acceptable salts include those derived from mineral acids such as hydrochloric and sulfuric and from organic acids such as lactic, maleic, succinic, fumaric, glutaric, citric, malic, ptoluenesulfonic, methanesulfonic or tartaric acid.

A preferred group of novel compounds of this invention comprises those compounds of formula I wherein m is zero, n is 1, R and R, are hydrogen, one of A and B represents substituted phenyl and the other represents phenyl or substituted phenyl wherein the substituents on the phenyl groups are selected from C13 alkyl, C13 alkoxy and halogen, and the pharmaceutically acceptable salts thereof.

In conducting the process of this invention, the reaction of the nitrile with the 2 - aminoethylhydrazine 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 solvent by simply mixing the reactants together with a catalytic amount of a transition metal salt or elemental sulfur. The reaction usually proceeds more rapidly in the absence of solvent, but when the product is made in large batches, it is often desirable to use some solvent to lower the viscosity of the reactants to facilitate mixing. As used herein, the term "catalytic amount" refers to the amount of transition metal salt or elemental sulfur required to convert equimolar amounts of the hydrazine and the nitrile to the 1,2,4 - triazine product. The transition metal salts ferric chloride and zinc acetate were found to give satisfactory results.

Elemental sulfur is particularly preferred because of its ready availability, and it evolves out of the reaction mass leaving only trace amounts in the final product.

The reaction is generally carried out at a temperature of from 70 to 1000C with from 85 to 950C being preferred. Lower temperatures are operable but the rate of reaction is slowed down. Temperatures above about 1200C cause the hydrazine/sulfur complex to vaporize out of the reaction mixture and lead to decreased yields and the formation of impurities.

The various nitrile intermediates are prepared by known procedures described in the literature. See for instance Synthesis 441--456 August 1973; J. Org. Chem.

36, 2948 (1971), and Tetrahedron Letters No. 14, pp. 1509-1511(1966). Also the 2 - aminoethylhydrazines are prepared according to literature methods.

The tetrahydro - triazine products obtained through the reaction described above may be readily converted to the hydrohalide salts, if desired, by acidification with a pre-selected hydrohalide.

As an embodiment of the invention, production of 3 - (1,2 - diphenylethyl) 1,4,5,6 - tetrahydro - 1,2,4 - triazine in experimental developmental studies in both small laboratory and large production size batches has been carried out and is summarized below.

The compound 3 - (1,2 - diphenylethyl)- 1,4,5,6 - tetrahydro - 1,2,4 - triazine is most conveniently prepared by two step synthesis, the second step being an embodiment of the novel process of this invention. In the first step, the intermediate 2,3 - diphenylpropionitrile is produced by a phase transfer catalysis reaction involving benzyl cyanide and benzyl chloride in the presence of aqueous sodium hydroxide. Reactions of this general type are well documented in the literature. In the second step, the 2,3 - diphenylpropionitrile and 2 aminoethylhydrazine are cyclized in the presence of sulfur to yield the 3 - (1,2 diphenylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazine. The triazine readily may be converted to the hydrohalide salt if desired by acidification with a pre-selected hydrohalide.

As noted above, the novel substituted - 3 - diarylethyl - tetrahydro - 1,2,4 triazine compounds endowed with antianxiety activity are readily prepared by the same general process disclosed before.

The following Examples illustrate the invention.

Example 1 Preparation of 3 - (1,2 - Diphenylethyl) - 1,4,5,6 - Tetrahydro - 1,2,4 - Triazine Monohydrochloride Step one: A reaction vessel consisting of a 2 liter round bottom flask fitted with a mechanical stirrer, thermometer, nitrogen inlet and reflux condenser was charged with 585 g (574 ml; 5.0 moles) of benzyl cyanide, 250 ml of 50 /" sodium hydroxide and 12.5 g (0.055 mole; 4.4 mole%) of benzyltriethylammonium chloride. While maintaining the temperature at about 50"C in a cool water bath, 224.4 g (1.77 mole) of benzyl chloride was slowly added dropwise over a period of about one hour. The reaction mass was stirred for an additional one hour after which 400 ml of deionized water was added to dissolve the sodium chloride and caused a separation of the aqueous and organic layers. In this step, if an emulsion formed, methylene chloride was added. The organic layer was distilled to separate the 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 two: The nitrile intermediate prepared in step one (35.0 g, 0.169 mole) was heated under nitrogen with 0.379 gram (0.012 gram-atom, 7 mole/") of sulfur to about 70"C in a 100 ml round bottom flask until the sulfur dissolved (about 2 hours). The reaction vessel was charged with 25.4 grams (0.338 moles; 2 equiv.) of 2 - aminoethylhydrazine. The temperature was increased to about 100"C and held for about five hours.

The reaction mass was cooled to about 50"C after which 75 ml of toluene was added followed by extraction with 75 ml of water. Absolute alcohol (35 ml) was added and the mixture refluxed while hydrogen chloride was bubbled into flask.

The 3 - (1,2 - diphenylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazine monohydrochloride crystallized out and was then filtered off and washed with a 90/10 toluene/ethanol mixture. The product was dried in vacuo. Elemental analysis, X-ray crystallography, NMR, and mass spectrophotometry were used to confirm the structure.

Using the general procedure outlined above, a number of related compounds can be prepared having the general structure

wherein k is the integer 1 or 2. These compounds are shown in Table I.

TABLE I Compound Example Number R R' 2 CH3 H H 3 H H 4-OCH3 4 H 4-NO2 H 5 H 3,4-di OCH3 H 6 H 2-pyridyl H 7 H 4-pyridyl H 8 H 2-naphthyl 2-naphthyl 9 H H 2-naphthyl- 10 H H l-naphthyl 11 H l-naphthyl H In addition to the compounds listed above, compounds which do not fit the general formula of Table II can be prepared using the process of the invention.

Such compounds include: 1,4,5,6 - tetrahydro - 3 - (2 - naphthylmethyl) - 1,2,4 - triazine monohydrochloride, and 3 - [2 - -(p - chlorophenyl)- 1 - (p - tolylsulfonyl)ethyl] - 1,4,5,6 - tetrahydro - 1,2,4 - triazine.

Example 12 Using essentially the same procedures outlined above, two batches containing 25.5 kg and 26.5 kg of 3 - (1,2 - diphenylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 triazine monohydrochloride were produced. The crude yield was found to be 65.1 /" and 70.0, respectively. Following recrystallization from ethanol the yield of purified product was 42.5% and 53.1 /", respectively.

It was found that the sulfur catalyst could be added directly to the melted nitrile without the lengthy heating needed to dissolve the sulfur in step two of the reaction. Thus overall batch time was significantly reduced from that of Example 1 above Example 13 Preparation of 3 - [2 - (p - Fluorophenyl)- 1 - Phenylethyli - 1,4,5,6 Tetrahydro - 1,2,4 - Triazine Monohydrochloride A mixture containing 5.0 grams of 1 - phenyl - 2 - (p fluoropheiiyl)propionitrile and 0.5 grams of elemental sulfur was placed in a 50 ml round-bottomed flask equipped with a condenser, magnetic stirrer and maintained under a nitrogen atmosphere. A minimal amount of 2 - methoxyethanol (5 ml) was added and the mixture was heated at 900C for 2 hours to dissolve the sulfur. To the heated solution, 3.3 grams of 2 - aminoethylhydrazine was slowly injected, and the resultant blue-green reaction mass was heated at 900C for 18 hours.

The reaction mass was quenched by the addition of 30 ml of toluene, transferred to a separatory funnel, and an additional 70 ml of toluene added.

The toluene was washed with water and 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 to give the 3 - [2 - (p fluorophenyl) - 1 - phenylethyl] - 1,4,5,6 - tetrahydro - 1,2,4 - triazine monohydrochloride as a precipitate. The crude product was dried under vacuum and recrystallized from isopropanol. The salt was found to have a melting point of 220--222"C.

Elemental analysis showed carbon 63.95%, hydrogen 6.02% and nitrogen 13.09% as compared to theoretical values of carbon 63.84%, hydrogen 5.79% and nitrogen 13.14%.

Using essentially the same procedure outlined in Example 13 above a number of other 3 - (1,2 - diarylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazine monohydrochlorides of formula I were prepared, in which m is zero, n is one and R and R1 are each hydrogen. The compounds are described in Table II below: TABLE II Example No. A B Melting Point "C 14 p-chlorophenyl phenyl 212-213 15 p-fluorophenyl p-methoxyphenyl 145-147 16 phenyl p-tolyl 217-219 17 m-tolyl phenyl 184-186 18 p-tolyl phenyl 141-143 19 m-chlorophenyl phenyl 144-146 20 phenyl m-tolyl 177-178.5 21 phenyl 1,3-benzodioxol-5-yl 95-98 22 3,4-dimethylphenyl phenyl 211-213 23 2,6-dichlorophenyl phenyl 135-138 24 3,4-dichlorophenyl phenyl 22W225 25 1-naphthyl phenyl 248-249 26 2-naphthyl phenyl 219-220 27 m-fluorophenyl phenyl 233-235 In addition to the compounds shown in Table III, two compounds were prepared having substitutions on the triazine ring. These compounds are: Example 28: 3 - [2 - (p - chlorophenyl) - 1 - phenylethyl] - 1,4,5,6 tetrahydro - 1 - methyl - 1,2,4 - triazine monohydrochloride.

Example 29: 4 - acetyl - 3 - (1,2 - diphenylethyl) - 1,4,5,6 - tetrahydro - 1 methyl - 1,2,4 - triazine monohydrochloride.

The anti-anxiety and anti-depressant properties of the novel substituted - 3 diarylethyl - tetrahydro - triazines of this invention have been tested by experiment.

Compounds exhibiting anti-anxiety properties block the stress-induced rise of serum corticosteroid levels. See British Medical Journal, 1971 (2), p. 310313. The corticosteroid levels of stressed male rats pretreated with 20 mg/kg of the active compound given by intraperitoneal injection were compared to coerticosteroid levels of stressed male rats pretreated with saline. Blood (3 ml) was collected by means of cardiac puncture after methoxyflurane anesthesia. Following clotting, the blood was centrifuged to separate the serum for use in the corticosteroid analysis.

The analysis was carried out by adding 5 ml of methylene chloride to 300 y1 of the serum sample and vortexing the sample for 15-20 seconds. The samples were then centrifugated at 41 xg for about 5 minutes. The lipid layer was removed by aspiration and 3 ml of the methylene chloride fraction was transferred to a clean tube. To this sample, 3 ml of fluorescence reagent (25% ethanol and 75% concentrated sulfuric acid) was added and vortexed for 5 seconds. Fluorescence development was complete in 20 minutes and was read on a Perkin-Elmer fluorometer Model 204 at an exciter wavelength of 470 my and an analyzer wavelength of 530 my. This assay measures free cortisol and corticosterone. The corticosteroid values were calculated as follows: C=25(FspFb)/(FstFb) wherein C is the amount of cortiosteroid (yg), and F,0, F,t and Fb are the fluorescences of the sample, standard and blank, respectively.

Using the procedure described above, the compounds of the prsent invention were shown to have anti-anxiety activity. The results are shown in Table III below.

Values below 100% are indicative of activity.

The anti-depressant effect was proved by means of Reserpine ptosis test.

Groups of four mice were administered 30 mg/kg of the 3 - (1,2 - diarylethyl) 1,4,5,6 - tetrahydro - 1,2,4 - triazine compounds by intraperitoneal injection via an aqueous carrier. A similar group of mice serving as controls were iniected only with the carrier. After 30 minutes, both groups of mice were injected subcutaneously with 2.5 mg/kg of reserpine. The administration of reserpine to the -control mice resulted in a classical progression of symptoms beginning with a drooping of the eyelids (ptosis) and later culminating in a generalized depression with decreased spontaneous motor activity and decreased responsiveness to auditory and tactile stimuli. Animals injected with the triazine compound were graded after 45 minutes on the following basis: no ptosis=0, partial ptosis complete ptosis=2. Complete protection against reserpine-induced ptosis gives a value of0 or 100%. The percent protection for each of the compounds is given in Table I.

TABLE III % Inhibition of Serum Corticosteroid Compound Example No. Reserpine Ptosis Levels Mg % 13 63 25 14 88 13 15 38 82 16 38 67 17 25 32 18 50 62 19 88 75 20 38 52 21 50 33 22 25 33 23 88 39 24 63 79 25 13 72 26 42 39 27 25 62 28 50 77 29 13 77 Saline control 0 100 It will be seen from Table III that the compounds of Examples 13, 14, 21, 22 and 26 are especially active as anti-anxiety agents. The other compounds shown in the Table, while generally less active than the compounds of Examples 13, 14, 21, 22 and 26, also display significant activity as anti-anxiety agents. In addition to the anti-anxiety properties already noted, the compounds of Examples 14, 16 and 23 were also found to be highly active as anti-depressants and as such are especially preferred as psychoactive agents, i.e. agents having both anti-anxiety and antidepressant properties.

According to the present invention, a pharmaceutical composition comprises a novel compound of formula I in association with a pharmaceutically acceptable carrier.

The novel compounds of this invention can be used to treat anxiety in animals, and especially mammals, by administering an effective anti-anxiety amount of one or more of the compounds to the animal, internally into the blood stream. The "effective anti-anxiety amount" will be sufficient to alleviate central nervous system anxiety. This amount depends on various known factors, such as the size, type, age and condition of the animal to be treated, the particular compound or compounds of the invention employed, the route and frequency of administration, the degree of anxiety involved, and the time the compound is administered relative to prior and subsequent presentation of food and liquids. Administration can be carried out either by a parenteral route such as intravenous, intraperitoneal, subcutaneous or intramuscular injection, or by introduction into the gastrointestinal tract by oral administration, for example, to introduce the compound in to the blood via the gastrointestinal tract. The compounds are orally effective, and generally have a higher ratio of toxic dose to effective dose when orally administered, and this route is preferred.

Generally, the active compounds are administered at a dosage of from 0.2 to 40 mg/kg of body weight with from 0.5-to 5 mg/kg being preferred. Higher dosage rates may be employed, for example, when the compound is administered orally'fin a timed release dosage form. In the case of mammals suffering from central nervous system anxiety, i.e. exhibiting symptoms of anxiety, administration of an antianxiety amount of the compound is preferably repeated at predetermined intervals.

It is generally desirable to administer the individual dosages at the lowest antianxiety amount which provides the desired continuity consonant with a convenient dosing schedule.

In practising the method of the invention, the active ingredient is preferably incorporated in a composition comprising a pharmaceutical carrier and from about 0.001 to about 95 percent by weight of the compound. The phrase "pharmaceutical carrier" refers to known pharmaceutical excipients useful in formulating pharmacologically-active compositions for internal administration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use.

Suitable pharmaceutical carriers are known and disclosed in texts such as Remington's Pharmaceutical Sciences, Thirteenth Ed., Martine (Ed.) Mack Publishing Co., Easton, Pa. (1965). The compositions can be prepared by known techniques for the preparation of tablets, capsules, lozenges, troches, elixirs, syrups, emulsions, dispersions, wettable and effervescent powders, sterile injectable compositions, and can contain suitable excipients known to be useful in the preparation of the particular type of composition desired.

Dosage units adaptable to oral administration, such as tablets, capsules and lozenges, and elixirs and syrups in encapsulated form, are preferred and the active compound can be formulated in conventional timed release capsule or tablet formulations.

Preferred compositions include sterile injectable solutions containing from 0.001 to 10 percent by weight of the compound in a pharmaceutical carrier suitable for injection, such as isotonic saline solution, Ringer's injection USP, and lactated Ringer's USP.

WHAT WE CLAIM IS: 1. A process for preparing a 3 - substituted - tetrahydro - 1,2,4 - triazine which comprises reacting a nitrile with an optionally substituted 2aminoethylhydrazine in the presence of a catalyst selected from transition metal salts and elemental sulphur.

2. A process for preparing a compound of the formula

wherein m is zero or one; n is zero or one; either R is hydrogen or methyl and R1 is hydrogen or R is hydrogen, methyl or acetyl and R, is methyl; and A and B are the same or different and are each hydrogen, C14 alkyl, naphthyl, 1,3 - benzodioxol 5 - yl or optionally substituted phenyl in which any substituents are selected from C12 alkyl, C13 alkoxy, halogen, nitro, naphthyl and pyridyl, which comprises reacting a 2 - aminoethylhydrazine of the formula R'HN-CH2-CH2-NR;-NH2 with a nitrile of the formula A(CH2)nCH(CN)(CH2)rnB wherein m, n, A and B are as defined above and R' and R; are each hydrogen or methyl, in the presence of a catalyst selected from transition metal salts and elemental sulphur, to obtain a compound of formula I in which R and R, are each

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (17)

**WARNING** start of CLMS field may overlap end of DESC **. rates may be employed, for example, when the compound is administered orally'fin a timed release dosage form. In the case of mammals suffering from central nervous system anxiety, i.e. exhibiting symptoms of anxiety, administration of an antianxiety amount of the compound is preferably repeated at predetermined intervals. It is generally desirable to administer the individual dosages at the lowest antianxiety amount which provides the desired continuity consonant with a convenient dosing schedule. In practising the method of the invention, the active ingredient is preferably incorporated in a composition comprising a pharmaceutical carrier and from about 0.001 to about 95 percent by weight of the compound. The phrase "pharmaceutical carrier" refers to known pharmaceutical excipients useful in formulating pharmacologically-active compositions for internal administration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use. Suitable pharmaceutical carriers are known and disclosed in texts such as Remington's Pharmaceutical Sciences, Thirteenth Ed., Martine (Ed.) Mack Publishing Co., Easton, Pa. (1965). The compositions can be prepared by known techniques for the preparation of tablets, capsules, lozenges, troches, elixirs, syrups, emulsions, dispersions, wettable and effervescent powders, sterile injectable compositions, and can contain suitable excipients known to be useful in the preparation of the particular type of composition desired. Dosage units adaptable to oral administration, such as tablets, capsules and lozenges, and elixirs and syrups in encapsulated form, are preferred and the active compound can be formulated in conventional timed release capsule or tablet formulations. Preferred compositions include sterile injectable solutions containing from 0.001 to 10 percent by weight of the compound in a pharmaceutical carrier suitable for injection, such as isotonic saline solution, Ringer's injection USP, and lactated Ringer's USP. WHAT WE CLAIM IS:

1. A process for preparing a 3 - substituted - tetrahydro - 1,2,4 - triazine which comprises reacting a nitrile with an optionally substituted 2aminoethylhydrazine in the presence of a catalyst selected from transition metal salts and elemental sulphur.

2. A process for preparing a compound of the formula

wherein m is zero or one; n is zero or one; either R is hydrogen or methyl and R1 is hydrogen or R is hydrogen, methyl or acetyl and R, is methyl; and A and B are the same or different and are each hydrogen, C14 alkyl, naphthyl, 1,3 - benzodioxol 5 - yl or optionally substituted phenyl in which any substituents are selected from C12 alkyl, C13 alkoxy, halogen, nitro, naphthyl and pyridyl, which comprises reacting a 2 - aminoethylhydrazine of the formula R'HN-CH2-CH2-NR;-NH2 with a nitrile of the formula A(CH2)nCH(CN)(CH2)rnB wherein m, n, A and B are as defined above and R' and R; are each hydrogen or methyl, in the presence of a catalyst selected from transition metal salts and elemental sulphur, to obtain a compound of formula I in which R and R, are each

hydrogen or methyl; and, if desired, either methylating a compound of formula I in which R and/or R1 is hydrogen to obtain a compound of formula I in which R and R, are each methyl, or acetylating a compound of formula I in which R is hydrogen and Rl is methyl to obtain a compound of formula I in which R is acetyl and R1 is methyl.

3. A process according to Claim 2 in which R, is hydrogen and A and B are the same or different and are each hydrogen, C14 alkyl or optionally substituted phenyl as defined in Claim 2.

4. A process according to Claim 3 wherein R is hydrogen, m is zero, n is one and A and B are the same or different and are each optionally substituted phenyl as defined in Claim 2.

5. A process according to Claim 4 wherein 2,3 - diphenylpropionitrile is reacted with 2 - aminoethylhydrazine to obtain 3 - (1,2 - diphenylethyl) - 1,4,5,6 tetrahydro - 1,2,4 - triazine.

6. A process for preparing 3 - (1,2 - diphenylethyl) - 1,4,5,6 - tetrahydro 1,2,4 - triazine which comprises (1) reacting benzyl cyanide with benzyl chloride in the presence of aqueous sodium hydroxide and (2) reacting the resultant 2,3 diphenylpropionitrile with 2 - aminoethylhydrazine in the presence of elemental sulphur as catalyst.

7. A process according to Claim 6 which further comprises the step of acidifying the 3 - (1,2 - diphenylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazine with a hydrohalide to produce a hydrohalide salt of the triazine.

8. A process according to any preceding claim wherein the reaction between the 2 - aminoethylhydrazine and the nitrile is carried out at a temperature between 70 and 100"C.

9. A process according to Claim 1 substantially as herein described with reference to any of the Examples.

10. A compound of formula I as defined in Claim 2 wherein m is zero, n is one, and A and B are the same or different and are each naphthyl, 1,3 - benzodioxol 5 - yl, phenyl or phenyl substituted once or twice by C13 alkyl, C13 alkoxy, naphthyl or halogen with the proviso that A is not phenyl when B is naphthyl or phenyl; or a pharmaceutically acceptable salt thereof.

11. A compound as claimed in Claim 10 wherein R and R1 are each hydrogen.

12. A compound as claimed in Claim 11 wherein one of A and B is substituted phenyl and the other is phenyl or substituted phenyl, and any substituents are selected from C13 alkyl, C13 alkoxy and halogen.

13. 3 - [2 - (p - chlorophenyl) - 1 - phenylethyl] - 1,4,5,6 - tetrahydro 1,2,4 - triazine or a pharmaceutically acceptable salt thereof.

14. 3 - [1 - (p - tolyl) - 2 - phenylethyl] - 1,4,5,6 - tetrahydro - 1,2,4 - triazine or a pharmaceutically acceptable salt thereof.

15. 3 - [2 - (2,6 - dichlorophenyl) - 1 - phenylethyl] - 1,4,5,6 - tetrahydro 1,2,4 - triazine or a pharmaceutically acceptable salt thereof.

16. A process according to Claim 2 wherein m, n, A and B are as defined in Claim 10.

17. A pharmaceutical composition comprising a compound as claimed in any of Claims 10 to 15 in association with a pharmaceutically acceptable carrier.