DK152755B - METHOD FOR PREPARING 3-SUBSTITUTED TETRAHYDRO-1,2,4-TRIAZINES OR PHARMACEUTICAL ACCEPTABLE SALTS - Google Patents

Description

DK 152755B

The present invention relates to a particular process for the preparation of 3-substituted tetrahydro-1,2,4-triazines having the general formula of formula I as set forth in claim 1, wherein R, R, A, B, m and n -5 ne meanings. The method according to the invention is characterized by the characteristic part of claim 1.

Some of the compounds prepared by the process of the invention are novel, namely, 3- (1,2-diarylethyl) -1,4,5,6-tetrahydro-1,2,4-triazines of the general formula I, wherein m is zero, n is 1, R is hydrogen or in methyl, R is hydrogen or methyl, and A and B are independently naphthyl, 1,3-benzodioxol-5-yl, phenyl or substituted phenyl with one or two parts selected from lower alkyl, lower alkoxy, halogen and naphthyl, with the proviso that A cannot be phenyl when B is phenyl or naphthyl. These novel compounds have been shown to have both anti-depressant and anxiety-relieving effects when administered internally to a mammal. In the present specification and claims, the term "psychoactive agent" will refer to a compound 20 which has both anxiety-relieving and antidepressant properties.

The invention also relates to the preparation of pharmaceutically acceptable salts of the disclosed novel 3- (1,2-diaryl-ethyl) -1, 4,5,6-tetrahydro-1,2,4-triazines and in the present description and in the claims indicate the term "pharmaceutically acceptable salts" of the non-toxic acid addition salts of the compounds, whose anions are relatively harmless to animals at doses corresponding to a good psychoactive effect so that the beneficial effects of the free base are not distorted by the side effects attributable to the anions. Pharmaceutically acceptable salts include those derived from mineral acids such as hydrochloric and sulfuric acids 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 the like.

A preferred group of the present novel compounds comprises those of the general formula I wherein m is zero, n is 1, R and R 3 are hydrogen and one of groups A and B is a substituted phenyl group and the other is a phenyl group 2

DK 152755 B

or a substituted phenyl group wherein the substituents on the phenyl groups are selected from lower alkyl, lower alkoxy and halogen, and pharmaceutically acceptable salts thereof.

Both in US Patent No. 3,428,635 and in Journ.

5 Med. Chem. 12, 257-260 (1969) discloses a process for preparing a 1,4,5,6-tetrahydrotriazine using a nitrile. In addition, the known process uses an ε-hydroxyalkylhydrazine of formula 2 1

10 IT R

3 1 '

R — C — C — N — R

in 1 OH H NH 2 while using the method of the invention a 2-aminoethylhydrazine of the formula

R R

• i I

HN-CH2-CH2-N-NH 2

This implies a difference in the reaction mechanism, so that by the known process, 1,4,5,6-tetrahydrotriazines where the nitrogen atom in the 4-position is substituted cannot be directly produced, while in the process of the present invention both 4-unsubstituted - and 4-substituted tetrahydrotriazines. In addition, concentrated sulfuric acid, the toxicity of which is well known, is used in the known process, while the process of the present invention requires only the presence of a catalytic amount of sulfur or a transition metal salt. Thus, the new process avoids the use of concentrated sulfuric acid, which is especially important when working on an industrial scale. Finally, it should be mentioned that in the process of the present invention, yields which are at least approx. twice the size of the prior art.

35 U.S. Patent Nos. 3,497,509 and 3,471,486 disclose a process for preparing a 1,4,5,6-t.

DK 152755 B

3 trahydrotriazine by reacting a 3-aminoalkylhydrazine with a lower alkylimino ester hydrohalide of formula 4

R -C

5 O-lower alkyl, HX

This method, in comparison with the method of the present invention, is slow and produces poor yields, making it uneconomical for commercial production. The compounds of U.S. Patent No. 3,471,486 may be used in the treatment of mammalian depressions, whereas, for example, the compound 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4- triazine hydrochloride, known from the aforementioned patent, is inactive as an anti-anxiety agent, although it is highly active as an antidepressant.

2-Imidazolines substituted in a related manner have been synthesized by cyclizing a diamine with a nitrile in the presence of elemental sulfur. Nippon Ka-gaku Zasshi 1968, 89 (8) 780 (Chem. Abs. 70: 19983q.).

The process of the invention can be reproduced in the following way: R R1

I I

HN-CH 2 CH 2 -N-NH 2

+ CH-CN

A- (CH2) n

Sulfur or transitions t a1s alt n-r1 30 I i

R-N ^^ N

CH

/ \ (C? 2> n «= 2> *

35 1 I

A B

DK 152755B

4 of the reaction scheme, m, n, R, r \ A and B have the meanings previously stated.

The reaction between the nitrile and the 2-aminoethylhydrazine can be carried out in a suitable solvent system, usually in a high boiling alcohol, but the reaction can also be carried out in the absence of solvent by simply mixing the reactants 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 prepared in large portions it is often desirable to use some solvent to reduce the viscosity of the reactants to facilitate mixing. In this specification, the term catalytic amount refers to the amount of transition metal salt or elemental sulfur required to convert equimolar amounts of the 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 preferred because of its easy accessibility and it is released from the reaction mass leaving only trace amounts in the final product.

As mentioned above, sulfur has been found to be a preferred catalyst in carrying out the process of the present invention. The reaction is usually carried out at a temperature between 70 and 100 ° C, preferably from 85 to 95 ° C. It is possible to work at lower temperatures, but the reaction rate is reduced. Temperatures above approx. 120 ° C causes the hydrazine / sulfur complex to evaporate out of the reaction mixture and lead to reduced yields and the formation of impurities.

The various nitrile intermediates are prepared by known methods described in the literature. See, e.g., Synthesis 30 441-456, August 1973, J. Org. Chem. 36, 2948 (1971) and Tetrahedron

Letters No. 14, pages 1509-1511 (1966). Also, the 2-aminoethyl hydrazines are prepared according to methods described in the literature.

The tetrahydrotriazine products obtained by the above

o C

written process can, if desired, be readily converted into hydrohalide salts by acidification with a pre-selected hydrohalide *

Compounds of formula I wherein R 1 is methyl and R 5 is 5

DK 152755B

hydrogen or methyl can also be readily recovered from the corresponding N-unsubstituted compounds by ordinary methylation procedures.

As an embodiment of the invention, preparation 5 of 3- (1,2-diphenylethyl) -1 / 4 / 5,6-tetrahydro-1,2,4-triazine has been carried out in experimental development studies both in small laboratory batches and in large batches. production portions, and the results obtained hereby are summarized below.

The compound 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4,4-triazine is most conveniently prepared by a two-step synthesis, the last step of which is the process of the present invention. In the first step, the intermediate 2,3-diphenylpropionitrile is prepared 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, 2,3-diphenylpropionitrile and 2-aminoethylhydrazine are cyclized in the presence of sulfur to form 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4-triazine. If desired, the triazine can be readily converted to the hydrogen halide salt by acidification with a pre-selected hydrogen halide.

As mentioned above, by the same general procedure described above, the novel substituted 3-diarylethyl-tetrahydro-1,2,4-triazine compounds 25 which have an anxiolytic effect can be readily prepared.

The anxiolytic and antidepressant properties of the novel novel substituted 3-diaryl-ethyl-tetrahydro-triazines were demonstrated by pharmacological tests.

Compounds with anxiety-reducing properties block the stress-induced increase in serum corticosteroid levels. See British Medical Journal, 1971 (2), pages 310-313. corticosteroid levels in stressed male rats pretreated with 20 mg / kg of the active compound administered by intra-traperitoneal injection were compared to corticosteroid levels in stressed male rats pretreated with saline. 3 ml of blood was collected by cardiac puncture following methoxyflurane anesthesia. After solidification, the blood was centrifuged to separate 6

DK 152755 B

le serum for use in the corticosteroid assay.

The assay was performed by adding 5 ml of methylene chloride to 300 μΐ of the serum sample and vortexing the sample for 15-20 seconds. The samples were then centrifuged at 41 x g for approx. 5 minutes-5 hours. The lipid layer was removed by aspiration and 3 ml of the methylene chloride fraction was transferred to a clean tube. To this sample was added 3 ml of fluorescence reagent (25% ethanol and 75% concentrated sulfuric acid) and stirred for 5 seconds. The fluorescence induction was completed in 20 minutes and read on a 10 Perkin-Elmer ^ fluorometer model 204 at an impact wavelength of 470 mu and an assay wavelength of 530 ιημ. This test measures free cortisol and corticosterol. The corticosteroid values were calculated as follows: 15 corticosteroid (µg%) = sample fluorescence - blank test fluorescence_ x 2s standard sample fluorescence - blank test fluorescence 20

Using the method described above, the compounds of the invention were found to have anti-anxiety effects. The results are shown in Table I below. Values below 100% are indicative of effect.

The antidepressant effect was tested by the reser-pin-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 using a aqueous carrier. A similar group of mice that served as control animals were injected with the carrier only. After 30 minutes, both groups of mice received 2.5 mg / kg reserpine injected subcutaneously. The administration of reserpine to the control mice produced a classic progression of symptoms beginning with lowering of the eyelids (ptosis) and later culminating in a depression that is widespread throughout the organism with diminished spontaneous motor activity and diminished response to auditory and touch stimuli. The animals injected with the triazine compound were grafted after 45 minutes

DK 152755B

pigeonholed 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 percent protection for each of the compounds is shown in Table I.

TABLE I

Compound prepared% inhibition of serum corticosteroid according to Example No. reserpine ptosis levels yg% _ 13 63 25 10 14 88 13 15 38 82 16 38 67 17 25 32 18 50 62 15 19 88 75 20 38 52 21 50 33 22 25 33 23 88 39 20 24 63 79 25 13 72 26 42 39 27 25 62 28 50 77 2 5 29 13 77

Saline (control) 0 100 30

It can be seen from Table I that the compounds of Examples 13, 14, 21, 22 and 26 are particularly active as anti-anxiety agents. Although the other compounds shown in the table are less active than the compounds of Examples 13, 14, 21, 22 and 26, they also show a significant effect as anti-anxiety agents. In addition to the anti-anxiety e-35 properties already mentioned, the following compounds also proved to be highly active as antidepressants and as such, they are

DK 152755B

8 are therefore particularly preferred as psychoactive agents, i.e. agents that have 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).

10

Example 1 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 bottom flask fitted with a mechanical stirrer, thermometer , nitrogen introduction and reflux condenser were charged with 585 g (574 ml, 5.0 mole) of benzyl cyanide, 250 ml of 50% sodium hydroxide and 12.5 g (0.055 mole, 4.4 mole%) of benzyl triethyl ethyl ammonium chloride. While the temperature was kept at approx. At 50 ° C in a cold water bath, 224.4 g (1.77 mole) of benzyl chloride was slowly added dropwise over a period of approx. and 20 hours. The reaction mass was stirred for an additional hour, after which 4QQ ml of deionized water was added to dissolve the sodium chloride and a separation of the aqueous and organic layer was induced. If an emulsion formed in this step, 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 established by elemental analysis and by nuclear magnetic resonance, infrared and mass spectrophotometric results.

Step Two: 35.0 g (0.169 mol) of the nitrile intermediate produced in Step 1 was heated under nitrogen with 0.379 g (0.012 gram atom, 7 mol%) of sulfur to ca. 70 ° C in a 100 ml round bottom flask until the sulfur dissolves (about 2 hours). The reaction vessel was filled with 25.4 g (0.338 mol, 2 equivalents) of 2-aminoethylhydrazine.

The temperature was raised to approx. 100 ° C and held there for approx. 5 hours.

35 o

The reaction mass was cooled to ca. 50 C and then 75 ml of toluene was added followed by extraction with 75 ml of water '

DK 152755B

9

35 ml of absolute alcohol was added and the mixture was refluxed while bubbling hydrogen chloride into the flask.

The 3- (1,2-diphenylethyl) -1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride was crystallized and filtered off and then washed with a mixture of toluene and ethanol in the ratio of 90%. 10th The product was dried under vacuum. Elemental analysis, X-ray crystallography, nuclear magnetic resonance spectrum and mass spectrophotometry are used to confirm the structure.

Using the general procedure described above, a number of related compounds of the general formula were prepared. 1, HCl r-n ^ n 15 / “Vn ch2 fe— * 20 where k is an integer 1 or 2. These compounds are shown in Table II.

TABLE II

Example No. R R 'R "

2 CH3 Η H

3 HH 4-OCH3

30 4 H 4-N ° 2 H

5 H 3,4-di-OCH 3 H

6 H 2-Pyridyl H

7 H 4-Pyridyl H

8 H 2-Naphthyl 2-Naphthyl 35 9 Η H 2-Naphthyl 10 HH 1-Naphthyl

11 H 1-naphthyl H

10

DK 152755 B

In addition to the compounds shown above, compounds which do not have the general formula of Table II were prepared using the process of the invention. Compounds include: 1,4,5,6-tetrahydro-3- (naphthalenylmethyl) -1,2,4-triazine monohydrochloride and 3- (2- (4-chlorophenyl) -1 - ((methylphenyl) - sulfonyl) ethyl) -1,4,5,6-tetrahydroxy-dro-1,2,4-triazine.

Example 12 10

Using essentially the same procedure as indicated above, two portions containing 25.5 kg and 26.5 kg of 3- (1,2-diphenylethyl) -1, 4,5, 6-tetrahydro-1,2,4- triazine monohydrochloride. The crude yield was found to be 65.1% and 70.0%, respectively. After recrystallization from ethanol, the yield of the purified product was 42.5% and 53.1%, respectively.

It was found that the sulfur catalyst could be added directly to the molten nitrile without the need for prolonged heating to dissolve the sulfur in step two of the reaction. Thus, the overall serving time was substantially reduced from that given in Example 1.

Example 13 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-fluorophenyl-propionitrile and 0.5 g of elemental sulfur was placed in a 50 ml round bottom flask equipped with a capacitor, magnetic stirrer and maintained under a nitrogen atmosphere. A minimal amount of 2-methoxyethanol (5 ml) was added and the mixture was heated to 90 ° C for two hours to dissolve the sulfur. To the heated solution was slowly injected 3.3 g of 2-aminoethylhydrazine and the resulting blue-green reaction mass heated to 90 ° C for 18 hours.

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

11

DK 152755B

The toluene was washed with water and saturated sodium chloride solution. The organic layer was separated and dried over sodium sulfate and filtered. Dry hydrogen chloride gas is bubbled into the toluene solution to form the 3- (2- (4-fluorophenyl) -1-phenylethyl) -5,1,5,6,6-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.

Calculated: C 63.84 H 5.79 and N 13.14 Found: C 63.95 H 6.02 and N 13.09%.

0

Using essentially the same procedure as described in Example 13, other 3 - (: 1,2-diaryl-ethyl) -1,4,5,6-tetrahydro-1,2,4-triazines of the general formula were prepared. 15 pT ^ j I ΗΠ

NH

20 '/ CH \ CH2 b

A

The compounds are described in Table III below:

DK 152755 B

12

TABLE III

Example No. A_ B_ Melting point ° C

14 p-chlorophenyl phenyl 212-213 5 15 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- 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 15 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 in the triazine ring were prepared. These compounds are: Example 28 3- (2- (4-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.

35

Claims (7)

A process for the preparation of a 3-substituted tetrahydro-1,2,4-triazine of the general formula 5 fV RV TI CH / \ (CH-) (CH2) in λ n 12 m AB 10 where m and n is independently zero or 1, R is hydrogen or methyl, R is hydrogen or methyl and A and B are independently naphthyl, 1,3-benzodioxol-5-yl, phenyl, substituted phenyl, the substituents 15 on the phenyl ring can be selected from halogen, alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms, nitro, naphthyl and pyridyl, or an acid addition salt thereof, characterized in that at a temperature of 70-100 ° C a nitrile is reacted with the general formula 20 A- (CH2) 2 n___ CH-CN B- (CH2) 2 m 25 wherein A, B, n and m have the above meanings, with a 2-aminoethylhydrazine of the general formula RR in I HNCH2-CH2-N-NH2 wherein R and R have the above meanings, in the presence of a catalytic amount of a transition metal salt or elemental sulfur, after which the compound obtained the desired is converted to an acid addition salt thereof and isolated. DK 152755B Process according to claim 1, characterized in that the 2-aminoethylhydrazine has the formula R R in ( A process according to claim 2, characterized in that R and R are hydrogen, m is zero, n is 1, A is phenyl or substituted phenyl, and B is phenyl or substituted phenyl. Process according to claim 3, characterized in that 2,3-diphenylpropionitrile is reacted with 2-aminoethylhydrazine. The method of claim 1 for the preparation of a novel anti-anxiety compound of general formula i-1. Wherein R is zero, n is 1, R is hydrogen or methyl, R is hydrogen or methyl, A and B are naphthyl independently, benzodioxol-5-yl, phenyl or substituted phenyl, substituted with one or two substituents selected from alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms, halogen and naphthyl, with the proviso that A cannot be phenyl when B is phenyl or naphthyl, or pharmaceutically acceptable salts thereof, characterized by reacting a 2-amino-10-ethylhydrazine of the formula RRII hn-ch2-ch2-n-nh2 with a nitrile of the formula A- (CH9) 1 n "___" CH-CN B- (CEL) 2m in which formulas R is hydrogen or methyl, R is hydrogen or methyl and A and B have the meanings given above. HN-CH 2 -CH 2 -N-NH 2 and the nitrile has the formula A- (CHO) 2 n 10 µl CH-CN B- (CHO) 2 m where m and n are independently zero or 1, R is hydrogen or methyl, R is hydrogen, A and B are independently phenyl or substituted phenyl, the substituents on the phenyl group is selected from halogen, alkyl having 1-3 carbon atoms, alkoxy having 1-3 carbon atoms, nitro, naphthyl and pyridyl. 6. A process according to claim 5, characterized in that R and R are hydrogen and that one of groups A and B is a substituted phenyl group and the other is phenyl or substituted phenyl, wherein the substituents of the phenyl ring is selected from alkyl having 1-3 carbon atoms, alkoxy having 1-3 carbon atoms and halogen. Process according to any one of the preceding claims, characterized in that the reaction between the 2-aminoethylhydrazine and the nitrile is carried out at a temperature between 85 and 95 ° C. 35