JPS6241227B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following formula In the formula, A represents phenyl, naphthyl, or phenyl substituted with one or two groups selected from the group consisting of a halogen atom and lower alkyl, and B represents phenyl, 1,3-benzodioxole-
5-yl, or phenyl substituted with one group selected from the group consisting of lower alkyl and lower alkoxy, provided that when B represents phenyl, A cannot represent phenyl. 3-substituted-tetrahydro-1.
The present invention relates to 2,4-triazines and pharmaceutically acceptable salts thereof, processes for their production, and pharmaceutical compositions containing the novel compounds. According to the present invention, the 3-substituted-tetrahydro-1,2,4-triazine of the above formula () is of the formula where A and B have the meanings given above, a nitrile of the formula _H2N - _CH2 -CH2- _NH - _NH2 and a catalytic amount of a transition metal salt or element It can be prepared by a novel process consisting of reaction in the presence of sulfur and optionally converting the product into a pharmaceutically acceptable salt. As used herein, "lower alkyl" and "lower alkoxy" are groups having 1 to 3 carbon atoms. It has been found that novel compounds of formula () above have both antidepressant and anti-instability activity when administered internally to mammals.
As used herein, "psychoactive agent"
The term "agent" refers to a compound that has both anxiolytic and antidepressant properties. The present invention also provides novel 3-(1・2-
(diarylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine, as used herein. The word “urushio” is
refers to a non-toxic acid addition salt of the compound, the ion of which is administered in a manner consistent with good psychoactive effects, such that the beneficial effects of the free base are not compromised by side effects based on the anion. It is relatively non-toxic to animals in amounts. Pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid and sulfuric acid, and salts such as lactic, maleic, succinic, fumaric, glutaric, citric, malic, p-toluenesulfonic, methane Those derived from organic acids such as sulfonic acid and tartaric acid are included. U.S. Pat. No. 3,471,486 describes various substituted 1,4,5,6-tetrahydro-1,2,4-triazines as having antidepressant properties. Literature [Journal of Medical
Chemistry, 12 , 257 (1969)] describes the compound 3-
(1,2-diphenylethyl)-1,4,5,6-
Tetrahydro-1,2,4-triazine has been described as an antidepressant. This compound was tested for anxiolytic activity and was found to be essentially inactive. Generally, the compounds are prepared by reacting an iminoester hydrohalide salt dissolved in glacial acetic acid, methanol or ethanol with a 2-aminoalkylhydrazine. This method of preparing the compound is tedious and gives only poor yields, making the whole process uneconomical for industrial production. In a related field, substituted 2-imidazolines have been synthesized by cyclization of diamines with nitriles in the presence of elemental sulfur [Nippon Kagaku Zasshi 1968, 89(8), 780 (Chem. Abs. .70:
19983q)]. 3-Substituted-tetrahydro-1 according to the invention
The new process for the production of 2,4-triazines can be expressed as follows: The reaction of the nitrile with 2-aminoethylhydrazine can be carried out in a suitable solvent system, usually a high boiling alcohol, but the reaction can be carried out in the absence of a solvent with a catalytic amount of a transition metal salt or an elemental salt. It can also be done by simply mixing the reactants together with the sulfur. The reaction usually proceeds more rapidly in the absence of a solvent, but when manufacturing in large batches some solvent is often used to reduce the viscosity of the reactants and facilitate mixing. It is desirable to do so. 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 is released from the reactants leaving only trace amounts in the final product. As mentioned above, sulfur has been found to be a suitable catalyst in carrying out the process that is the subject of the invention. This reaction is generally carried out at a temperature of 70-100°C, preferably 85-95°C. Lower temperatures can also be used, but the reaction rate will be reduced. Temperatures higher than about 120° C. cause the hydrazine/sulfur complex to evaporate out of the reaction mixture and result in reduced yield and formation of impurities. Various nitrile intermediates can be produced by known methods described in the literature [e.g.
Synthesis441-456, August 1973; J.Org.Chem.
36 , 2948 (1971), and Tetrahedron
See Letters, No. 14, 1509-1511 (1966)]. Part 2
-Aminoethylhydrazine can also be prepared by literature methods. The tetrahydro-triazine product obtained by the above reaction can optionally be acidified with a preselected hydrogen halide.
Can be easily converted to hydrohalides. In the course of experimental development studies of the present invention, 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1.
A 2,4-triazine was prepared, which is summarized below. Compound, 3-(1,2-diphenylethyl)-
1,4,5,6-tetrahydro-1,2,4-triazine can be most conveniently prepared by a two-step synthesis, the second step of which is the novel process that is the subject of the present invention. It is. In the first step, by a phase transfer catalytic reaction involving benzyl cyanide and benzyl chloride in the presence of aqueous sodium hydroxide, the intermediate,
2,3-diphenylpropionitrile is produced. General reactions of this type are well described in the literature. In the second step, 3-(1,2-diphenylethyl)-1,4.
5,6-tetrahydro-1,2,4-triazine is produced. The triazine is optionally
It can be easily converted to a hydrohalide salt by acidification using a pre-selected hydrogen halide. As mentioned above, novel substituted-3-diarylethyl-tetrahydro-1,2,4-triazine compounds with anxiolytic activity can be readily prepared by general methods similar to those described above. Novel substituted-3-diarylethyl- of the present invention
The anxiolytic and antidepressant activity of tetrahydro-triazines can be demonstrated using pharmacological experiments. Compounds exhibiting anxiolytic properties block stress-induced increases in serum corticosteroid concentrations [British Medical Journal, 1971(2), 310-313]
reference〕. Corticosteroid concentrations in stressed male rats pretreated with 20 mg/Kg of active compound administered by intraperitoneal injection were compared with those in stressed male rats pretreated with saline. compared with corticosteroid concentrations. Blood (3
ml) was collected. After clotting, the blood is centrifuged and
Serum was separated for use in corticosteroid analysis. The analysis was performed by adding 5 ml of methylene chloride to a 300 micron serum sample and then vortexing the sample for 15-20 seconds.
The sample was then centrifuged at 41 xg for approximately 5 minutes.
The lipid layer was removed by suction and 3 ml of the methylene chloride fraction was transferred to a clean tube. For this sample, 3
After adding ml of fluorescent reagent (25% ethanol and 75% concentrated sulfuric acid), it was vortexed for 5 seconds. Development of fluorescence was complete within 20 minutes and was detected using a Perkin-Elmer fluorometer at an exciter wavelength of 470 mμ and an analyzer wavelength of 530 mμ.
Measured by Model 204. This assay measures free cortisol and corticosterone. Corticosteroid values were calculated as follows: Corticosteroid (μg%) = Sample fluorescence − Blank fluorescence / Standard fluorescence − Blank fluorescence × 25 μg% By using the method described above, Compounds of the invention have been shown to have anxiolytic activity. The results are shown in the table below. Values lower than 100% are indicative of activity. The reserpine ptosis test (reserpine ptosis test)
ptosis test). Groups of four mice were treated with 30 mg/Kg of 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-1, by intraperitoneal injection with an aqueous vehicle.
A 2,4-triazine compound was administered. A similar group of mice used as controls were injected with vehicle only. After 30 minutes, both groups of mice were injected subcutaneously with 2.5 mg/Kg reserpine. Administration of reserpine to control mice
A typical progression of symptoms that begins with drooping of the eyelids and later culminates in generalized depression with decreased spontaneous motility and decreased responsiveness to auditory and tactile stimuli. Brought. Animals injected with the triazine compound were graded 45 minutes later based on the following criteria: 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 shown in the table.

TABLE From the table it can be seen that the compounds of Examples 1, 2, 9, 10 and 14 are particularly active as anxiolytic agents. Other compounds shown in the table are generally
Although the activity is lower than that of the compounds of Examples 1, 2, 9, 10 and 14, it still shows remarkable activity as an anxiolytic agent. In addition to the anxiolytic properties already mentioned, the compounds listed below have also been found to be highly active as antidepressants and are thus considered psychoactive agents, i.e. drugs with both anxiolytic and antidepressant properties. Particularly preferred: 3-[2-(4-chlorophenyl)-1-phenylethyl]-1.4.5.6-tetrahydro-
1,2,4-triazine-hydrochloride (Example 2); 3-[1-(4-methylphenyl)-2-phenylethyl]-1,4,5,6-tetrahydro-
1,2,4-triazine-hydrochloride (Example 4); 3-[2-(2,6-dichlorophenyl)-1-
phenylethyl]-1,4,5,6-tetrahydro-1,2,4-triazine-hydrochloride (Example
11). The invention further provides a method for treating anxiety in animals, particularly mammals, by administering to the animal an effective anxiolytic amount of one or more novel compounds of the invention. and pharmaceutical compositions. As used herein, the term "effective anxiolytic amount" refers to the amount of one or more compounds administered to an animal to reduce central nervous system anxiety. An effective anxiolytic amount will depend on, for example, the size, type, age and condition of the animal being treated, the particular compound or compounds of the invention used, the method and frequency of administration, and the degree of anxiety involved. , the timing of compound administration before and after the provision of food and beverages, etc. The term "effective psychoactive amount" refers to the amount of one or more compounds administered to an animal to reduce central nervous system depression and anxiety. In practicing the methods of the invention, one or more compounds of the invention are introduced into the bloodstream of a mammal by an effective route for introducing an effective anxiolytic amount of the compound into the mammal's bloodstream. Administer internally to a mammal. Administration may be by parenteral methods, such as intravenous, intraperitoneal, subcutaneous or intramuscular injection, or by oral administration to the gastrointestinal tract, for example to introduce the compound into the blood via the gastrointestinal tract. This can be done either by introduction. The compounds of the invention are orally effective and generally have a relatively high ratio of toxic to effective doses when administered orally, thus making this method preferred. Generally, the active compound will be administered in dosages of about 0.2 to about 40 mg/Kg of body weight, with about 0.5 to about 5 mg/Kg being preferred. Higher dosages may be used, for example, when administering the compound orally in a timed release, dosoge form. In the case of a mammal suffering from central nervous system anxiety, ie exhibiting signs of anxiety, it is preferred to repeat the administration of the anxiolytic amount of the compound at predetermined intervals. Generally, it is desirable to administer individual dosages at the lowest anxiolytic amount that provides the desired persistence consistent with a suitable dosing schedule. In practicing the methods of the invention, it is preferred to formulate the active ingredient into a composition comprising a pharmaceutical carrier and about 0.001% to about 95% by weight of the compound.
The term "pharmaceutical carrier" means a carrier that is useful in formulating pharmacologically active compositions for internal administration to animals and is practically non-toxic and non-sensitizing under the conditions of use. Refers to known pharmaceutical excipients. Suitable pharmaceutical carriers are known and can be found in various literature [e.g. Remington's Pharmaceutical
Science, 13th edition, Martine (Ed.) Mack
Publishing Co., Easton Pa (1965)]. The composition can be formulated into tablets, capsules, dragees,
Troches, elixirs, syrups, emulsions, dispersions, wettable and foamable powders, sterile injectable compositions which can be prepared by known methods and of the particular type desired. It may contain suitable excipients known to be useful in the manufacture of products. Dosage units adapted for oral administration, such as tablets, capsules, dragees, elixirs, syrups, etc., are suitable and the active compound is formulated in conventional time-release capsule or tablet formulations. can do. Suitable compositions include, for example, isotonic saline solution, Ringer's Injection USP and Lactated Ringer's USP
in a pharmaceutical carrier suitable for injection, such as
Includes sterile injectable solutions containing from 0.001 to 10% by weight of the compound. The following examples serve to further clarify the invention and to illustrate some preferred embodiments of the invention; however, these examples are not intended to limit the scope of the invention. It should not be interpreted. Reference example 3-(1,2-diphenyl)-1,4,5,6-
Preparation of tetrahydro-1,2,4-triazine-hydrochloride Step 1: 585 g (574 ml; 5.0 mol. )
of benzyl cyanide, 250 ml of 50% sodium hydroxide and 12.5 g (0.055 mol; 4.4 mol %)
of benzyltriethylammonium chloride was added. 224.4 g (1.77 mol) of benzyl chloride was slowly added dropwise over a period of about 1 hour while maintaining the temperature at about 50° C. in a cooling bath. After the reaction mass was stirred for an additional hour, 400 ml of deionized water was added to dissolve the sodium chloride and cause separation of the aqueous and organic phases. If an emulsion still formed at this stage, methylene chloride was added. By distilling the organic phase,
2,3-diphenylpropionitrile was separated from other reactants and impurities. The compound was identified by elemental analysis, NMP, IR and mass spectrometry. Step 2: The nitrile intermediate prepared in Step 1 (35.0 g, 0.169 mol) was dissolved in 0.379 g (0.012 g atoms, 7 mol) in nitrogen in a 100 ml round bottom flask.
mol %) of sulfur at about 70° C. until the sulfur was dissolved (about 2 hours). in this reactor
25.4 g (0.338 mol; 2 equivalents) of 2-aminoethylhydrazine was added. The temperature was raised to 100°C and maintained for approximately 5 hours. After cooling this reaction material to about 50℃, 75ml
of toluene was added and then extracted with 75 ml of water. Absolute alcohol (35ml) was added and the mixture was brought to reflux while bubbling hydrogen chloride into the flask. Crystallized 3-(1,2-diphenylethyl)-
1,4,5,6-tetrahydro-1,2,4-
After filtering off the triazine-hydrochloride, it was washed with a 90/10 toluene/ethanol mixture. The product was dried in vacuo. The structure was confirmed using elemental analysis, X-ray crystallography, NMR and mass spectrometry. Example 1 Preparation of 3-[2-(4-fluorophenyl)-1-phenylethyl]-1,4,5,6-tetrahydro-1,2,4-triazine-hydrochloride 5.0 g of 1-phenyl- A mixture containing 2-p-fluorophenylpropionitrile and 0.5 g of elemental sulfur was placed in a 50 ml round bottom flask equipped with a condenser, magnetic stirrer and kept under nitrogen atmosphere. Minimum amount of 2-methoxyethanol (5
ml) was added and the mixture was heated at 90° C. for 2 hours to dissolve the sulfur. Add 3.3g to this heated solution.
of 2-aminoethylhydrazine was gradually injected,
The resulting blue-green reaction mass was heated at 90° C. for 18 hours. The reaction mass was cooled by the addition of 30 ml of toluene, transferred to a separatory funnel, and an additional 70 ml of toluene was added. The toluene was washed with water and saturated sodium chloride solution. The organic phase was separated, dried over sodium sulfate and filtered. Dry hydrogen chloride gas was bubbled into the toluene solution to precipitate 3-[2-(4-fluorophenyl)-1-phenylethyl]-1,4,5,6-tetrahydro-
This gave 1,2,4-triazine-hydrochloride. The crude material was dried under vacuum and then recrystallized from isopropanol. The salt was found to have a melting point of 220-222°C. Elemental analysis shows 63.84% of theoretical carbon and 5.79% of hydrogen.
%, carbon 63.95%, hydrogen compared to nitrogen 13.14%
6.02%, nitrogen 13.09%. Using essentially the same method as outlined in Example 1 above, the general formula Numerous other 3-(1,2-diarylethyl)-1,4,5,6-tetrahydro-
1,2,4-triazine was produced. These compounds are shown in the table below:

[Table] Nil

[Table] Phenyl

[Table] Enil

Claims (1)

[Claims] 1 formula In the formula, A represents phenyl, naphthyl, or phenyl substituted with one or two groups selected from the group consisting of a halogen atom and lower alkyl, and B represents phenyl, 1,3-benzodioxole-
3 represents phenyl substituted with 5-yl, or one group selected from the group consisting of lower alkyl and lower alkoxy, provided that when B represents phenyl, A cannot represent phenyl. -Substituted-tetrahydro-1, 2, 4
- triazines and pharmaceutically acceptable salts thereof. 2 3-[2-(4-chlorophenyl)-1-phenylethyl]-1,4,5,6-tetrahydro-
The compound according to claim 1, which is 1,2,4-triazine and a pharmaceutically acceptable salt thereof. 3 3-[1-(4-methylphenyl)-2-phenylethyl]-1,4,5,6-tetrahydro-
The compound according to claim 1, which is 1,2,4-triazine and a pharmaceutically acceptable salt thereof. 4 3-[2-(2,6-dichlorophenyl)-1
-phenylethyl]-1,4,5,6-tetrahydro-1,2,4-triazine and a pharmaceutically acceptable salt thereof. 5 formula In the formula, A represents phenyl, naphthyl, or phenyl substituted with one or two groups selected from the group consisting of a halogen atom and lower alkyl, and B represents phenyl, 1,3-benzodioxole-
5-yl, or phenyl substituted with one group selected from the group consisting of lower alkyl and lower alkoxy, provided that when B represents phenyl, A cannot represent phenyl. is reacted with 2-aminoethylhydrazine of the formula H ₂ N-CH ₂ -CH ₂ -NH-NH ₂ in the presence of a catalytic amount of a transition metal salt or elemental sulfur, optionally converting the product into a pharmaceutical preparation. A formula characterized by the conversion into an acceptable salt of 3-substituted-tetrahydro-1,2,4, where A and B have the above-mentioned meanings
- A process for producing triazines and pharmaceutically acceptable salts thereof. 6. The process according to claim 5, wherein the reaction between 2-aminoethylhydrazine and the nitrile is carried out at a temperature of 70 to 100°C. 7 formula In the formula, A represents phenyl, naphthyl, or phenyl substituted with one or two groups selected from the group consisting of a halogen atom and lower alkyl, and B represents phenyl, 1,3-benzodioxole-
3 represents phenyl substituted with 5-yl, or one group selected from the group consisting of lower alkyl and lower alkoxy, provided that when B represents phenyl, A cannot represent phenyl. -Substituted-tetrahydro-1, 2, 4
- A psychoactive agent characterized by containing a triazine or a pharmaceutically acceptable salt thereof as an active ingredient. 8 3-[2-(4-chlorophenyl)-1-phenylethyl]-1,4,5,6-tetrahydro-
The psychoactive agent according to claim 7, which contains 1,2,4-triazine or a pharmaceutically acceptable salt thereof as an active ingredient. 9 3-[1-(4-methylphenyl)-2-phenylethyl]-1,4,5,6-tetrahydro-
The psychoactive agent according to claim 7, which contains 1,2,4-triazine or a pharmaceutically acceptable salt thereof as an active ingredient. 10 3-[(2,6-dichlorophenyl)-1-
8. The psychoactive agent according to claim 7, which contains as active ingredients 1,4,5,6-tetrahydro-1,2,4-triazine (phenylethyl)-1,2,4-triazine and a pharmaceutically acceptable salt thereof.