IE46246B1 - 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 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

This invention relates to a general process Tor 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 - diphenyl ethyl) 1,4,5,6 - tetrahydro - 1,2,4 - triazine is described as an antidepressant in Journal of Medical Chemistry, 12, 257 (1369).

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 - aminoethyl hydrazine 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: 'N-R, R-N.

CH 1 («ίη ^m A B wherein m is zero or one; £ is zero or one; either R is hydrogen or methyl and R^ 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, Chalky!, naphthyl, 1,3benzodioxol - 5 - yl or optionally substituted phenyl in which any substituents are selected from halogen, Cp3 alkyl, Cp3 alkoxy, nitro, naphthyl and pyridyl.

The process of the invention for preparing the compounds of formula I comprises reacting a 2 - ami noethyl hydrazine of the formula R'NH — CHg —CH2—NRij — NH^ with a nitrile of the formula A-(CH2)n- CH(CN) - (CH2)m— B wherein m , n_, A and B are as defined above and R1 and R^' 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 R^ are each hydrogen or methyl; and, if desired, either methylating (in conventional manner) a compound of formula I in which R and/or R^ is hydrogen to obtain a compound of formula I in which R and R^ are each methyl, .or acetyl ati ng (in conventional manner) a compound of formula I in which R is hydrogen and R^ is methyl to obtain a compound of formula I in which R is acetyl and R^ 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, £ is 1, either R is hydrogen or methyl and R.| is hydrogen or R is hydrogen, methyl or acetyl and R-j is methyl, A and B independently represent naphthyl, 1,320 benzodioxol - 5 - yl, phenyl or phenyl substituted once or twice by substituents independently selected from alley!, 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 6 2 4c 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 nontoxic 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, £ - toluenesulfonic, rnethanesulfonic or tartaric acid.

A preferred group of novel compounds of this invention comprises those compounds of formula I wherein m is zero, ji is 1, R and R1 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 C^_3 alkyl, C^_3 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 Λ6246 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 100°C with from 85 to 95°C being preferred. Lower temperature are operable but the rate of reaction is slowed down. Temperatures above about 120°C 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 441-455 August 1973: J. Org. Chem. 36, 2948 (1971), and Tetrahedron Letters No. 14, pp. 1509-1511 (1966). Also the 2 - ami noethyl hydrazines 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- di phenyl ethyl) - 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 10 di phenyl propionitrile 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 - di phenyl propionitrile and 2 - ami noethyl hydrazine are cyclized in the presence of sulfur to yield the 3 - (1,2 diphenyl ethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazine. The tri azine 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 20 tetrahydro - 1,2,4 - triazine compounds endowed with anti-anxiety activity are readily prepared by the same general process disclosed before.

The following Examples illustrate the invention. ,46246 Example 1 Preparation of 3-(1,2- Di phenyl ethyl) - 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 mi of 50% sodium hydroxide and 12.5 g (0.055 mole; 4.4 mo1e%) of benzyl triethylammonium 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 - di phenyl propionitrile 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, 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. <46246 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 - di phenyl ethyl) - 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 (R')k- wherein k is the integer 1 or 2. These compounds are shown in Table 1. 6 2 4 6 TABLE 1 Compound Example Number R R' R 2 ch3 H H 3 H H 4-OCHj 4 H 4-N02 H 5 H 3,4-di OCHg H 6 H 2-pyric(yl H 7 H 4-pyridyl H 8 H 2-naphthyl 2-naphthyl 9 H H 2-naphthyl 10 H H 1-naphthyl 11 H 1-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- naphthyl methyl) - 1,2,4 triazine monohydrochloride, and 3 E? ~ (E chlorophenyl) - 1 - (2 - tolylsulfonyl)ethylj 1,4,5,6 - tetrahydro - 1,2,4 - triazine. 4624 8 Example 12 Using essentially the same procedures outlined above, two batches containing 25.5 kg and 26.5 kg of 3 - (1,2 di phenylethyl) - 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 - (j> - Fluorophenyl) - 1 - Phenylethyf] - 1>4,5,6 - Tetrahydro - 1,2,4 - Triazine Monohydrochloride A mixture containing 5.0 grams of 1 - phenyl -2(j> - fluorophenyl)propionitrile and 0.5 gram 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 90°C for 2 hours to dissolve the sulfur. To the heated solution, 3.3 grams of 2 - ami noethyl hydrazine was slowly injected, and the resultant blue-green reaction mass was heated at 90°C for 18 hours. 6 2 4 6 The reaction mass v/as 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 5 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- (£- 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 v/ere prepared in which m is zero, £ is one and R and R^ are each hydrogen. The compounds are described in Table II below: 6 2 4 TABLE II Example No. A B Melting Point θθ 14 £-chlorophenyl phenyl 212-213 15 ja-fluorophenyl ^-methoxyphenyl 145-147 5 16 phenyl £-tolyl 217-219 17 m-tolyl phenyl 184-186 18 £-toly1 phenyl 141-143 19 m-chlorophenyl phenyl 144-146 20 phenyl m-tolyl 177-178.5 10 21 phenyl 1,3-benzodioxol5-yl 95-98 22 3,4-dimethylphenyl phenyl 211-213 23 2,6-dichlorophenyl phenyl 135-138 24 3,4-dichlorophenyl phenyl 224-225 25 1-naphthyl phenyl 248-249 15 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 tri azine ring. These compounds are: 20 Example 28: 3 - [l· - (£ - chlorophenyl) - 1 - phenyl ethyl] - 1,4,5,6 - tetrahydro - 1 - methyl - 1,2,4 - tri azine monohydrochloride. Example 29: 4 - acetyl - 3 - (1,2 - diphenyl ethyl) - 1,4,5,6 - tetrahydro - 1 - methyl - 1,2,4 - triazine monohydrochloride. 6 2 4 6 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 stress5 induced rise of serum corticosteroid levels. See British Medical Journal, 1971 (2), P. 310-313. 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 μΐ of the serum sample and vortexing the sample for -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, 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 mu and an analyzer wavelength of 530 my. This assay measures free cortisol and corticosterone. The corticosteroid values were calculated as follows: C = 25(FSp - FbV

Claims (15)

1. A process for preparing a 3 - substituted - tetrahydro 1,2,4 - triazine which comprises reacting a nitrile with an optionally substituted 2 - ami noethylhydrazine in the presence 5 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 10 or methyl and R^ is hydrogen or R is hydrogen, methyl or acetyl and R 1 is methyl; and A and B are the same or different and are each hydrogen, alkyl, naphthyl, 1,3 - benzodioxol - 5 - yl or 4 6 2 4 6' optionally substituted phenyl in which any substituents are selected from alkyl, C^_ 2 alkoXy, halogen, nitro, naphthyl and pyridyl, which comprises reacting a 2 - aminoethylhydrazine of the formula 0 R ΉΝ'- CH 2 - CH 2 - NR-j - NIL, with a nitrile of the formula A ~ (CH 2 )~ CH(CN) _(CH 2 ) m — B wherein m, n, A and B are as defined above and R‘ and Rj are each hydrogen or methyl, in the presence of a catalyst selected from 10 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 R^ 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 15 which R is hydrogen and R^ is methyl to obtain a compound of formula I in which R is acetyl and R-j 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, C]_4 alkyl of optionally substituted phenyl as defined in Claim 2. 20 4. A process according to Claim 3 wherein R is hydrogen, m is zero, ji is one and A and B are the same or different and are each optionally substituted phenyl as defined in Claim 2.

4. -6 2 4 6

5. A process according to Claim 4 wherein 2,3 - diphenylpropionitrile is reacted with 2-- ami noethyl hydrazine to obtain 3 - (1,2 - di phenylethyl) - 1,4,5,6 - tetrahydro - 1,2,4 - triazine.

6. A process for preparing 3 - (1,2 - di phenylethyl) - 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 - di phenyl propionitrile 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 - diphenyl ethyl) - 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, ji 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 C^-j alkyl, Cp 3 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 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 C^_g alkyl, C^_ 2 alkoxy and halogen. 5

13. 3 - - (jo - chlorophenyl) - 1 - phenylethylj - 1,4,5,6 tetrahydro - 1,2,4 - triazine or a pharmaceutically acceptable salt thereof.

14. 3 - 0 - (£ - tolyl - 2 - phenylethyCJ- 1,4,5,6 - tetrahydro 1,2,4 - triazine or a pharmaceutically acceptable salt thereof. 10 15. 3 - - (2,6 - dichlorophenyl) - 1 - phenyl ethyl 3 - 1,4,5,6 - tetrahydro - 1,2,4 - triazine or a pharmaceutically acceptable salt thereof. 16. A process according to Claim 2 wherein m, ri, A and B are as defined in Claim 10.

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