SE447380B - PROCEDURE FOR PREPARING 3-SUBSTITUTED TETRAHYDRO-1,2,4-TRIAZINES - Google Patents

Description

447 380 and B are independently naphthyl, 1,3-benzodioxol-5-yl, phenyl or substituted phenyl having one or two moieties selected from the group consisting of lower alkyl, lower alkoxy, halogen and naphthyl, with the proviso that A cannot be phenyl when B is phenyl or naphthyl. These new compounds have been shown to have both antidepressant and anti-anxiety activity in; internal administration to a mammal. The term "psychoactive agent" as used herein refers to a compound having both anti-anxiety and antidepressant properties.

Pharmaceutically acceptable salts of the novel 3- (1,2-diarylethyl) -1,4,5,6-tetahydro-1,2,4-triazines prepared according to the invention relate to non-toxic acid addition salts of the compounds, which anions are relatively harmless to animals at the dosages giving good psychoactive activity, whereby the beneficial effects of the free bases are not destroyed by side effects attributed to the anions. Pharmaceutically acceptable salts include those derived from mineral acids such as hydrochloric acid, 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 and similar.

A particularly suitable class of the compounds of the invention comprises those of formula I, wherein m is 0, n is 1, R is hydrogen, one of A and B represents substituted phenyl and the other represents phenyl or substituted phenyl , wherein the substituents on the phenyl ring are selected from lower alkyl, lower alkoxy and halogen and the pharmaceutically acceptable salts thereof.

Various substituted 1,4,5,6-tetrahydro-1,2,4-triazines are disclosed in U.S. Pat. No. 3,471,486 having antidepressant properties. The compound 3- (1,2-diphenylethyl) -1,4,5,6-tetahydrol-1,2,4-triazine has been described in the literature as an antidepressant in the Journal of Medicinal Chemistry, La, 257 (1969). This compound has been tested for anti-anxiety activity and found to be substantially inactive. The compounds are generally prepared by reacting a aminoester hydrohalide, dissolved in glacial acetic acid, methanol or ethanol, with a 2-aminoalkydrazine. This method of preparation of the compounds is cumbersome and gives poor yields, whereby the overall procedure becomes economical for commercial production.

Known substituted 2-imidazolines have been synthesized by cyclization of a diamine with a nitrile in the presence of elemental sulfur.

Nippon Kagaku Zasshi- l968, 89 (8), 780 (Chem. Abs. 70: l9883q).

The novel process for the preparation of 3-substituted tetrahydro-1,2,4-triazine according to the invention can be illustrated as follows: R E B- (CH 2) n \ \\\\\ I _ H: \ '- c +: 2 -cH2-r: -r ~ n + 2 + CH CN A- (CH2) n sulfur or transition metal salt V pm HIR "N f NJ /, CH \\ (men (ß fl gm I | AB wherein m, n, R , A and B have the specified meaning.

The reaction of the nitrile with 2-aminoethylhydrazine can be carried out in a suitable solvent, usually a high-boiling alcohol, but the reaction can also be carried out in the absence of a solvent, by simply mixing the reactants together with a catalytic 447,380 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 manufactured in large batches, it is often desirable to use a certain amount of a solvent to lower the viscosity of the reactants to facilitate mixing. The term "catalytic amount" as used herein refers to the amount of transition metal salt or elemental sulfur required to convert equimolar amounts of hydrazine and 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 suitable because it is readily available and leaves the reaction mass, leaving only trace amounts in the final product.

As mentioned, sulfur proved to be the most suitable catalyst for carrying out the process according to the invention. The reaction is usually carried out at a temperature of 70 DEG-100 DEG C., especially 85-95 ° C. Lower temperatures can be used, but the reaction rate will be lower. Temperatures above about 120 ° C cause the hydrazine / sulfur complex to evaporate and leave the reaction mixture, leading to reduced yields and the formation of impurities.

The various nitrile intermediates are prepared according to known methods described in the literature. See, e.g., Synthesis 441-456, August 1973; J. Org. Chem. 36, 2948 (1971) and Tetrahedron Letters No. 14, pp. 1509-1511 (1966). The 2-aminoethylhydrazines are also prepared according to literature methods.

The tetrahydrotriazine products obtained according to the invention can be easily converted to the hydrohalide salts, possibly by acidification with a preselected hydrogen halide.

The compounds of formula I, wherein R is methyl or acetyl, can also be easily obtained from the corresponding N-unsubstituted compounds by customary methylation or acetylation.

Thus, according to the invention, 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4-triazine has been prepared in experimental development studies on both a small laboratory scale and on a large production scale, and the obtained results are compiled. in the following.

The compound 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4-triaz: is conveniently prepared by a two-step synthesis, the second step being the novel process of the invention. In the first step, the intermediate 2,3-diphenylpropionitrile is produced by a phase transfer catalysis reaction comprising benzyl cyanide and benzyl chloride in the presence of sodium hydroxide in water. Reactics 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 give s- (i, z-aiphenylethyl) -1,4,4,5-s-tetrahyaro-1,2-triazine.

The triazine can be easily converted to the hydrohalide salt, optionally by acidification with a preselected hydrogen halide. As mentioned, the novel substituted 3-diarylethyl tetrahydro-1,2,4-triazine compounds having anti-anxiety activity are easily prepared according to the same general procedure.

The anti-anxiety and antidepressant properties of the novel substituted 3-diarylethyl tetrahydro-triazines prepared according to the invention were confirmed by pharmacological tests.

Compounds with anti-anxiety properties block the stress-induced increase in serum corticosteroid levels. See British Medical Journal, 1971 (2), pp. 310-313. Corticosteroid levels in stressed male rats pretreated with 20 mg / kg of the active compound administered by intraperitoneal injection were compared with corticosteroid levels in stressed male rats pretreated with physiological saline. 3 ml of blood was collected by cardiac puncture after methoxyflurane anesthesia. After coagulation, the blood was centrifuged to separate the serum for use in the corticosteroid assay. The assay is performed by adding 5 ml of methylene chloride to 300 μl of the serum sample and vortexing the sample for 15-20 seconds. The samples were centrifuged at 41 x g for about 5 minutes. The fat layer was removed by aspiration and 3 ml of the methylene chloride fraction was transferred to a clean tube. This sample was charged with 3 ml of fluorescent reagent (25% ethanol and 75% concentrated sulfuric acid) and vortexed for 5 seconds. Fluorescence evolution was complete within 20 minutes and was read on a Perkin-Elmerég Model 204 fluorometer at an encoder wavelength of 470 mu and an analyzer wavelength of 530 mu. This analysis determines free cortisol and corticosterone. The corticosteroid values were calculated as follows: corticosteroid (ug%) = fluorescence of agitation - fluorescence of blind predation x 25 ng% fluorescence of standard - fluorescence of blind samples Using said procedure, it was found that the compounds of the invention have anti-anxiety activity. The results are shown in Table II. Values below 100% are an indication of activity. 447 380 6 The antidepressant effect was detected using the Reserpin ptosis test. Groups of 4 mice were administered 30 mg / kg of 3- (1,2-diarylethyl) -1,4,5,6-tetrahydro-1,2,4-triazine compounds by intraperitoneal injection via an aqueous vehicle. A similar group of mice were used as controls and injected with the vehicle only. After 30 minutes, both groups of mice were injected subcutaneously with 2.5 mg / kg reserpine.

The administration of reserpine to the control mice resulted in a classic development of symptoms, which began with drip from the eyelids and later culminated in a general depression with decreased spontaneous motor activity and reduced propensity to respond to auditory and tactical 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 0 or 100%. The percentage protection for each compound is given in Table I. 447 380 7 Table: Compound% inhibition of reserpine ptosis Serum corticosteroid example no. level ug% 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 Physiological O 100 saline solution It appears from Table I that the compounds of Examples 13, 14, 21, 22 and 26 are particularly active as anti-anxiety agents. The other compounds shown in the table are less active than the compounds from Examples 13, 14, 21, 22 and 26, but also provide significant activity as anti-anxiety agents. In addition to having the above anti-anxiety properties, the following compounds were found to be highly active as antidepressants and they are referred to as such as psychoactive agents, i.e. agents with both anti-anxiety and antidepressant properties: 3- [2- (4-chlorophenyl) -1-phenylethyl] -1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 14); 3- [1- (4-methylphenyl) -2-phenylethyl] -1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 16); 3- [2- (2,6-dichlorophenyl) -1-phenylethyl] -1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride (Example 23). 447 380 The invention is further illustrated by the following examples, in which the stated temperatures refer to degrees Celsius.

Example 1

Preparation of 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride Step 1: A reaction vessel consisting of a 2-liter round-bottomed flask equipped with a mechanical stirrer, thermometer , nitrogen inlet and reflux condenser, were added 585 g (574 ml; 5.0 mol) of benzyl cyanide, 250 ml of 50% sodium hydroxide solution and 12.5 g (0.055 mol; 4.4 mol%) of benzyltriethylammonium chloride. While maintaining the temperature at about 500 in a cold water bath, 224.4 g (1.77 moles) of benzyl chloride were slowly added dropwise over a period of about one hour. The reaction mass was stirred for a further hour, after which 400 ml of deionized water were added to dissolve the sodium chloride and separate the aqueous and organic layers.

If at this stage an emulsion is formed, methylene chloride is added. The organic layer was distilled to separate 2,3-diphenylpropionitri from the other reactants and impurities. The identity of this compound was confirmed by elemental analysis, NMR, IR and mass spectrophotometry data.

Step 2: 35.0 g (0.69 mol) of the nitrile intermediate obtained according to step 1 was heated under nitrogen together with 0.379 g (0.012 gram atom, 7 mol%) of sulfur to about 700 in a 100 ml -circular flask, until sulfur dissolved (approximately 2 hours). The reaction vessel was charged with 25.4 g (0.338 mol, 2 equivalents) of 2-aminoethylhydrazine. The temperature was raised to about 1000 and maintained for about 5 hours.

The reaction mass was cooled to about 500, after which 75 ml of toluene were added and extracted with 75 ml of water. 35 ml of absolute alcohol was added and the mixture was refluxed while hydrogen chloride was bubbled through the flask. The 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride crystallized out and was filtered off, after which it was washed with a 90/10 mixture of toluene / ethanol. The product was dried in vacuo.

Elemental analysis, X-ray crystallography, NMR and mass spectrophotometry were used to confirm the structure.

Using said general method, a number of related compounds of the general formula 447 380 "n" RN \\ íQ N (R 1) k CH 2 \ cH 2 // wherein k is the number 1 or 2 are prepared. These compounds are summarized in Table II .HC1 Eëë§ll_šl Compound melting point example no. RR 'R "' ° c 2 CH3 HH - 3 HH 4-OCH3 178-180 4 H 4-NO2 H - 5 H 3, 4-diOCH3 H 191-192 6 H 2-pyridyl H - 7 H 4-pyridyl H - 8 H 2-naphthyl 2-naphthyl - 9 HH 2-naphthyl - 10 HH 1-naphthyl - 11 H 1 -naphthyl H - In addition to the aforementioned compounds, compounds which do not fall into the general formula II are prepared using the process of the invention These compounds include: 1,4,5,6-tetrahydro-3- (2-naphthylenylmethyl) -1,2,4-triazine monohydrochloride and 3- [2- (4-chlorophenyl) -1 - [(4- methylphenyl) -sulfonyl] ethyl] -1,4,5,6-tetrahydro-1,2,4-triazine.

Example 12.

Said procedures were essentially repeated, preparing two batches containing 25.5 kg and 26.5 kg of 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,2-triazine monohydrochloride . The crude yield was found to be 65.1 resp. 70.0%. After recrystallization from ethanol, the yield of purified product was 42.5% resp. 53.1%. It was found that the sulfur catalyst could be added directly to the molten nitrile without prolonged heating to dissolve the sulfur in step 2 of the reaction. The total operating time was significantly reduced compared to, for example, 1 above.

Exemgel l3.

Preparation of 3- [3- (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 -fluorophenylpropionitrile and 0.5 g of elemental sulfur were immersed in a 50 ml round bottom flask equipped with a condenser, magnetic stirrer and maintained under a nitrogen atmosphere.

The minimum amount of 2-methoxyethanol (5 ml) was added and the mixture was heated for 2 hours at 90 ° to dissolve the sulfur. The heated solution was slowly added to 3.3 g of 2-aminoethylhydrazine and the resulting blue-green reaction mass was heated for 18 hours at 900 DEG C. The reaction mass was quenched by the addition of 30 ml of toluene, transferred to a separatory funnel and another 70 ml of toluene was added.

The toluene was washed with water and saturated sodium chloride solution.

The organic layer was separated, dried over sodium sulfate and filtered. Dry hydrogen chloride gas was bubbled through the toluene solution to give 3- [2- (4-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 22 ° -222 °.

Elemental analysis showed carbon 63.95%, hydrogen 6.02%, nitrogen 13.09%, compared to the theoretical values for carbon 63.84%, hydrogen 5.79% and nitrogen 13.14 a. I Using mainly In the same procedure as described in Example 13, a number of other 3- (1,2-diarylethyl) -1,2,5,6-tetra-1,2,4-triazines of the general formula N ..: \ ~ 447 380 ll The compounds are listed in Table III: Example no. AB Melting point, OC 14 p-chlorophenyl phenyl 212-213 p-fluorophenyl p-methoxyphenyl 145-147 16 phenyl p-methylphenyl 217-219 17 m-methylphenyl phenyl 184-186 18 p-methylphenyl phenyl 141-143 19 m-chlorophenyl phenyl 144-146 20 phenyl m-methylphenyl 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 224-225 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 having substituents on the triazine ring were prepared. These compounds are Exemgel 28. 3- [2- (4-chlorophenyl) -1-phenylethyl] -1,4,5,6-tetrahydro-1-methyl-1,2,2-triazine monohydrochloride2 mp 212-213 ° C.

Example Gel 29. 4-Acetyl-3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1-methyl-1,2,2-triazine monohydrochloride; Oil.

Claims (7)

447380 PATENT CLAIMS A process for the preparation of a 3-substituted-tetrahydro-1,2,4-triazine of the formula: wherein in waxy R represents hydrogen, methyl or acetyl, m and n are independently 0 or 1 and A and B independently represent naphthyl, 1,3-benzodioxol-5-yl, phenyl or lower alkyl, lower alkoxy, halogen, nitro, naphthyl or pyridyl substituted phenyl, characterized in that a -2-aminoethylhydrazine of the formula : RHII HN-CH 2 CH 2 -N ~ NH 2 wherein R is as defined above, is reacted with a nitrile of the formula: A- (CH 2) n - \ C \ B - (CH 2 GK 2 H CN wherein A, B, m and n has the meaning given above, in the presence of a calorific amount of olomentary sulfur, at a temperature not exceeding about 120 ° C, and that when a compound of formula I is desired, wherein R is methyl or acetyl, this is prepared by methylation or acetylation of corresponding compound of formula I wherein R is hydrogen 447 380 Furfuran fl e according to claim 1, characterized in that the 2-aminoethylhydrazine has the formula: RH SN-CH 2 CH 2 -N ~ NH 2 and the nitrile has the formula: A- (cH 2) n, CH-CN m 5, wherein m and n are independently 0 or 1, R is hydrogen or methyl, A and B are independently phenyl or halogen, lower alkyl, lower alkoxy, nitro, naphthyl or pyridyl substituted phenyl. 3. A process according to claim 2, characterized in that R is hydrogen, m is 0, n is 1, A and B are phenyl or with lower alkyl, lower alkoxy, halogen, nitro, naphthyl or pyridyl substituted phenyl. A process according to claim 1 for the preparation of a novel anti-anxiety compound of the formula: NH RN, fN CH (lazy \ (cH2) mns AB wherein m is 0, n is 1, R is hydrogen, methyl or acetyl, A. and B independently, naphthyl, 1,3-benzodioxol-5-yl, phenyl 447 380 or phenyl is substituted with one or two moieties selected from lower alkyl, lower alkoxy, halogen or naphthyl, with the proviso that A is not phenyl when B is phenyl or naphthyl, and pharmaceutically acceptable salts thereof, characterized in that a 2-aminoethylhydrazine of the formula: RHII HN ~ CH2CH2 ~ N-NH2 ä f * / öbh a nitrile of the formula: A- (cn2) n \ CH-CN B- (CH2) / m wherein R is hydrogen or methyl and A and B have the meaning given above, in the presence of a catalytic amount of elemental sulfur and that, when a compound of formula I is desired, wherein R is methyl or acetyl this is prepared by methylation or acetylation of the corresponding compound of formula I, wherein R is hydrogen. 5. A process according to claim 4, characterized in that R is hydrogen, one of A and B is lower alkyl, lower alkoxy or halogen substituted phenyl and the other is phenyl or lower alkyl, lower alkoxy or halogen substituted phenyl. 6. A process according to claim 3, characterized in that the nitrile 2,3-diphenylpropionitrile is reacted with 2-aminoethylhydrazine. Process according to one of Claims 1 to 6, characterized in that the reaction between the 2-aminoethylhydrazine and the nitrile is carried out at a temperature of between 70 and 100 ° C.