• 专利附录
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    • 专利摘要:
    The invention relates to new condensed as-triazine derivatives of the general formula (I) <IMAGE> (I) wherein Z represents a buta-1,3-dienyl group or a group of the formula (a), (b), (c) or (d) <IMAGE> <IMAGE> R1 denotes a C1-10 alkyl group, an oxo group or a C6-10 aryl or C6-10 aryl-(C1-3 alkyl) group optionally substituted by one or more identical or different substituents selected from the group consisting of amino, nitro, C1-6 alkyl, C1-6 alkoxy, hydroxy and halogen, R2 stands for hydrogen, C1-10 alkyl or amino, R3 represents hydrogen, C1-10 alkyl or C6-10 aryl or C6-10 aryl-(C1-3 alkyl) optionally substituted by one or more identical or different substituents selected from the group consisting of nitro, amino, C1-6 alkyl, C1-6 alkoxy, hydroxy and halogen, X- denotes an anion, and n is 0 or 1, with the proviso that if n is O, R1 is other than an oxo group and R1' and R2' form together a double bond, and with the further provisos that if n is 1, R1 represents an oxo group and the symbols R1' and R2' are not present, and if Z is a buta-1,3-dienyl group and R1 denotes an oxo group, R3 is other than unsubstituted phenyl. The new compounds of the general formula (I) can be prepared by cyclizing the compounds of the general formula (II) or (V), wherein R1, Z, R3 and X- have the above defined meanings, R4 is a leaving group and R7 represents hydrogen or C1-10 alkyl. The new compounds of the general formula (I) possess a valuable antidepressant effect and can advantageously be used in the therapy.
    公开号:SU1041545A1
    申请号:SU813334949
    申请日:1981-09-10
    公开日:1983-09-15
    发明作者:Батори Шандор；Хайош Дьердь；Мешшмер Андраш；Бенко Пал；Паллош Ласло；Петец Луиза；Грассер Каталин；Кошоцки Иболиа；Тончев Ева
    申请人:Эдьт Дьедьсерведьесети Дьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    cl
    4 SL The invention relates to the forked derivatives of e S-triaine, namely to compounds of the formula </ BR> where Z is 1,3-butadienyl 1,3-residue R is phenyl, 4-chlorophenylyl or 2 is a group of the formula R-4 is chlorophenyl-, showing antidepressant activity, and who can find their attachment in medical practice. Salts of 1 (4H) -oxirpyrido (2 1-) -a5-triazini are known, containing 3 as the substituent phenyl residue 1. However, there are no data in the literature about the presence of pharmaceutical activity in these compounds. Amitriptyline 5 (3-dimethylaminopropylidene j-1O, 11-dihydrodibenzocyclohepten with antidepressant activity 2 is known. However, this compound has a relatively low therapeutic index. The purpose of the invention is to find new compounds with antidepressant activity and arsenic enhancing effects. on living organisms. The present goal is achieved by obtaining new derivatives of (5-triazine formulas t t) that exhibit a1-depressive properties. The proposed compounds are obtained by reacting paratoluo 1-amino-2-benzoylpyridinium sulfonate or 1-amino-2 (4-chlorobenoyl pyridini or 2-amino-1- (4-chlorobenzoyl) -isbquinolini with formamide in the presence of phosphorus oxychloride.) M me r 1. Preparation of 1-feNylpyrido 2,1-f} -c perchlorate (5-triazine.,., ... .-. - to a solution of 0.18 g of 0.5. Mole of 1-amino-2-6-benzoylpyridinium para-toluenesulfonate and 5 ml of formamide was added with stirring 3.35 g (22 mol) of phosphorus oxychloride. After 30 min, the reaction mixture was poured onto ice, the reaction was carried out with 1m of 70% perchloric acid, and after that the extraction was carried out Thane. After removing the solution, 120 mg of the title compound is obtained. The yield is 80%. M.p. 259-260 ..,. Calculated,%: N 13.66; C1 11.52. Found, -%: N 13.62; C1 11.52. 1-Phenylpyrido G2.1-c-5-triazine perchlorate is dissolved in acetonitrile and treated with triethylamine hydrobromide. I Thus, the above compound is converted to methyl 1-phenylpyrido 2, 1-f-a5-triazine. M.p. 271-272С. The starting material is obtained as follows. A solution of 1.04 g (5.5 mol of 0- (para-toluenesulfonyl) -hydroxylamine in 20 ml of dichloromethane) is added to a solution of 1 g (5.5 mol) of 2-benzoylpyridine in 10 ml of dichloromethane. After 2 h, the reaction mixture is added diethyl ether. As a result, 1.5 g (74%) of 1-amino-2 para-toluenesulfonate 1-benzoylpyridinium is obtained, mp 1446147 ° C. Calculated,%: N 7, 56; 5 8.66. Found ,%: N 7.66 5 8.73. Example 2. Preparation of 1- (4-chlorophenyl -) o (5-triazino 1, 6-b isoquinolini perchlorate. 100 mg (about 23 mol) para-toluenesulfonate 2-amino- 3- {4-hls benzoyl-isoquinolini is suspended in 1.5 ml of phosphorus oxychloride. After about 5 ml of formamide, the reaction mixture is stirred for 30 minutes at which time the reaction mixture is poured into ice-cold water and treated with perchloric acid to give 54 mg of the title compound. The yield of the product is 62%. .203-204c.f | Calculated,%: N 10.71. Found,%: N 10.48. The starting material was prepared as follows: To a mixture of 0.62 g (26 mol) of magnesium chips and 8 ml of anhydrous diethyl an ether solution of 5.0 g (26. mole) of 4-chlorobromobenzene is added dropwise to the ether. The resulting Grignard solution is mixed with 3.1 g (20 mol) of 3-cyano-isoquinoline and the reaction mixture is stirred at room temperature for 1 hour. The Grignard complex is destroyed by the addition of an aqueous solution of ammonium chloride, the solvent is distilled off and the residue is recrystallized from ethyl alcohol. 3.2 g of 3- (4-chlorobenzoyl) -isoquinolinimine are obtained. M.p. 151-152 ° C. The product yield was 60%. Calculated,%: N 10.50. Found: N 10.38. The ketimine prepared as described above is treated with 20 ml of concentrated hydrochloric acid. The reaction mixture is brought to an alkaline reaction by adding a solution of sodium hydroxide, after which the solvent is distilled off. This gives 3.1 g of 3-chloro benoyl) isoquinoline. The yield / product is 95%. M.p.126-127 ° C. Calculated,%: N 5., 24. Found,%: N 5.19. 5 g (19 mol) of 3- (4-chlorobenzoyl-isoquinoline is dissolved in 10 ml of dichloromethane. To the prepared solution add 4 g (22,. Mole O- (toluenesulfonyl) hydroxylamine. The reaction mixture is stirred for 1 hour at at room temperature. As a result, 6 g (73%) of the paralysis of shuolsul background von a 2-aminr-3- (4-chloro-benzoyl) -isoquinopini is obtained. mp., 201202 ° C. Calculated: %: S 7.15. Example 3. Preparation of methyl 1- (4-chlorophenyl-clS-tripiazino 6, l-aJ-isoxinapapini. The method is carried out as in Example 1, but with the difference that instead of 1-amino para-toluenesulfonate 2-benzoylpyridinium used an equimolar amount of para-toluenesulfone and 2-amino-1- (1.4-chlorobenzoyl J-isoquinol line, 1- (4-chlorophenyl J - 5-triazino b, 1-a-isoquinolini perchlorate is obtained in yield 70 %, Mp 243-244s (from acetonitrile). 6.9 g (17.5 mol) of the indicated cobalt are dissolved in acetonitrile and reacted with 5.5 g (30 mol) of triethylamine hydrobromide. obtain 4.1 g of the title compound. M.p. 271-272s. The product yield is 62.6%. Calculated,%: N 11.28; C1 19.03. Found,%: N 11.18; C1 18; 98. The original substance receive the following method. i To a solution of 3.1 g. (20. mol) of 1-dianoisoquinoline in anhydrous diethyl ether, Grignard reagent, 1, irradiated from 5.75 g (30 mol.) 4-hrsrbromobenzene and 0.735 g (30 mol. magnesium chips) was added. The reaction mixture is kept overnight, then the complex is destroyed by adding an aqueous solution of ammonium chloride, the mixture is acidified by adding 20% sulfuric acid and incubated for 2 hours. After neutralization, the ether phase is separated and the solvent is distilled off. the result is 4, 1 g of 1- (4-chlorobenzoyl) -isoquinrolin. T 76.7% T.pl.100. Calculated,%: N, 6.44; Found,%: N, 6.46. 1- (4-chlorobenzoyl-isoquinrline) obtained by the above method, is reacted with O- ( para-toluenesulfonyl-hydroxylamine similarly to Example 1. Para-toluenesulfonate 2-amino-1- (4-chlorobenzoyl) -isoquinoline is obtained in 88, -5% yield. So pl, 189-190 s (from a mixture of nitrbmethane and diethyl ether) Calculated,% : N 6.16; C1 7.79. Found,%: N 6.18; € 1 7.56. Example 4. Preparation of 1- (4-chlorophenyl) -pyrido perchlorate G2.1 - 3-aS-triazine . The method is carried out analogously to example 1, but with the difference that Para-toluenesulfonate 1-amino-2- (4-chlorobenzoyl) -pyridinium is used as the starting material. The result is the target compound with a yield of 79.5%. M.p. 249-250s. Calculated,%: N, 12.28; C1 20.73. Found,%: N 12.23; C1 20.45. The above compound, by analogy with that described in Example 3, is converted to methyl 1- (4-chlorophenyl) -pyrido 2, 1-l-aS-triazinium. M.p. 279280 ° C. , The starting material is obtained by analogy with the cp method of Example 1, but with the difference that an equimolar amount of 2- (4-chlorobenzoyl-pyridine) is used instead of 2-benzoylpyridine. As a result, 1-amino-2- (4-chlorobenzoyl - pyridinium with a yield of 89%. Tpl. 151-152® C. The core of the general formula (T) has valuable pharmaceutical properties and, especially due to their anti-suppressive activity, can be used for therapeutic purposes. The compounds of the general formula ( I) can be proved by test compounds. The following compounds were used in the tests: Compound A-bromide 1-phenylpyrido 2,1-f3-a5-triazinium, - Compound B-bromide 1- (4-chlorophenyl) pyrido 2,1-fJa5-triazinium ; Compound C-methyl 1- (4-chlorophenyl) -a S-triazino. b, l-aj-ispxKHINOLIIII Acute toxicity. Toxicity was determined on males and females albumens of the CFLP genus (weight 18-24 gJ. Investigated the compound was administered orally in a volume of 20 ml / kg. Symptoms were observed 4 days after administration. The results were evaluated graphically. Acute toxicity was also determined in rats. The test compound was administered orally in the form of a 0.5% suspension prepared with carboxymethylcellulose. The results are presented in table 1. Table 1
    权利要求:
    Claims (1)
    [1]
    Condensed Derivatives
    a5-triazine'formula ί
    AT '
    where 2 is a butadienyl 1,3-residue,
    P - phenyl, 4-chlorophenyl,
    or 2 - a group of formula P
    P-4-chlorophenyl,
    exhibiting antidepressant activity.
    511 1041545
    >
    1041545
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