FI75823C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA 1-PHENYL-AS-TRIAZINO / 6,1-A / ISOKINOLINIUM- OCH 1-PHENYLPYRIDO / 2,1-F / -AS-TRIAZINIUM DERIVATIVES. - Google Patents

Description

75823

Process for the preparation of therapeutically useful 1-phenyl-as-triazino [6,1-a] isoquinolinium and 1-phenylpyrido [2,1 - (?) - as-triazinium derivatives 5 Partitioned from application 812254

Patent 73215.

The invention relates to a process for the preparation of new condensed astriazinium derivatives.

1- (4H) -oxopyrido ε 2,1-β-as-triazinium salts with the 3-position of the phenyl ring substituted are described in Chem. Lett. 1976, 5, p. 413-414, and J. Org. Chem. 42, 3 (1977), ss. 443 - 448.

1-Methoxy-3-phenylpyrodo [2,1-f] -az-triazinium bromides having 4 methoxycarbonyl-15 substituents on the phenyl ring are described in Liebigs Ann.

Chem. (1977), ss. 1421-1428 and 1718-1724. These known compounds have not been reported to have biological activity.

The invention relates to a process for the preparation of therapeutically useful astriazinium derivatives of the formula x-s + V. R3

'N J

-K; I - ~ R1 wherein Z is a group of formula 1 (b) (a) 2 75823 R1 is hydrogen or halogen, is hydrogen or C1-6-alkyl and X- is a physiologically acceptable anion, preferably chloride, bromide, perchlorate or p-toluenesulfonate.

The process according to the invention is characterized in that a) a compound of the formula + ^ nh9 f '

10 Z. Il VI

Wherein R 1, Z and X are as defined above, is reacted in the presence of a dehydrating agent with an amide of formula

h2n-co-r3 VII

20 wherein R 2 is as defined above, and the compound thus formed has the formula + ^ nh9 / --- M / ^

25 f N

Z

V --- x 'C = N-CO-R3 wherein Z, R1, R1 and X are as defined above, cyclized, or 75823

b) a compound of formula / '- "N

5 VJ

Wherein Z, and denote the same as above, is reacted with an O-substituted hydroxylamine, such as O- (p-toluenesulfonyl) hydroxylamine, and the resulting compound of formula V is cyclized without isolating it from the reaction mixture and preferably in the presence of a dehydrating agent, and if desired the anion X in the obtained compound of formula I is replaced by another anion X-.

The term "alkyl" means a straight or branched saturated aliphatic hydrocarbon group.

The term "halogen" means fluorine, chlorine, bromine and iodine.

X- is preferably chloride, bromide, perchlorate or p-toluenesulfonate, but X may be any pharmaceutically acceptable anion.

Particularly preferred compounds of formula I are 1- (4-chlorophenyl) pyrido [2,1-f] -az-triazinium salts, preferably bromide or perchlorate, and 1-phenylpyrido [2,1-f] triazinium salts, preferably bromide or perchlorate.

Particularly preferred pharmaceutical properties are 1- (4-chlorophenyl) -as-triazino-5,1-α-isoquinolium salts, especially bromide.

4 75823

The cyclization of a compound of formula V in the process of the invention can be carried out by heating a compound of formula V in the presence of a dehydrating agent. The reaction temperature is preferably 60 to 110 ° C. Phosphorus halide (e.g. phosphorus oxychloride or phosphorus pentachloride), polyphosphoric acid or dicyclohexylcarbodiimide, in particular phosphorus oxychloride, are preferably used as dehydrating agents.

Compounds of formula V are prepared in process variant a) by reacting an oxo compound of formula VI with an imide of formula VII. The reaction can be carried out in a solvent in the presence of a dehydrating agent at 20 to 60 ° C. Preferably, the same dehydrating agents are used as listed above for the cyclization of the compound of formula V. Suitable reaction medium is any solvent inert under the reaction conditions, for example, halogenated hydrocarbons (such as chloroform, carbon tetrachloride, chlorobenzene, etc.). Aromatic hydrocarbons (e.g. xylene, toluene, benzene, etc.), dialkylamines (e.g. dimethylformamide), dialkyl sulfoxides (e.g. dimethyl sulfoxide, etc.), cyclic ethers (e.g. tetrahydrofuran, dioxane, etc.), aliphatic ethers (e.g. diethyl ether, etc.), other hydrocarbons (e.g. hexane, benzine, etc.), aceto-nitrile, or mixtures of these solvents.

The resulting compounds of formula V may be isolated or cyclized in the same reaction mixture in which they were formed.

When the reaction between compounds of formulas VI and VII is carried out at a lower temperature, generally at 20-60 ° C, the compounds of formula V are immediately cyclized to give compounds of formula I directly.

In process variant b) compounds of formula V are prepared by reacting a compound of formula VIII with an O-substituted hydroxylamine. As the O-substituted hydroxylamine, O- (p-toluenesulfonyl) hydroxylamine is preferably used. Reaction I! 5 75823 is carried out at room temperature or by heating in an organic solvent. The same solvents listed above can be used as the reaction medium. This reaction is carried out with gentle heating over a long period of time, and the compounds of formula V cyclize spontaneously and are not isolated in between. Cyclization can be accelerated by the use of dehydrating agents. Suitable dehydrating agents are listed above.

Compounds of formula VIII may be prepared by reacting a compound of formula IX

OF

z li

x— * X. IX

^ C = NH

The imide of R1 reacts with the formula

r3-cooh X

20 with a carboxylic acid or a reactive derivative thereof, optionally in the presence of an acid scavenger. The reactive derivative of formula X is preferably the corresponding acid halide (e.g. chloride or bromide), acid anhydride, mixed anhydride, ester or imidazole. The reaction is carried out at 0 to 120 ° C, preferably at about room temperature. Inorganic bases (e.g. alkali metal hydroxides, alkali metal carbonates or alkali metal bicarbonates (such as sodium or potassium carbonate or bicarbonate), or organic bases (e.g. triethylamine, trimethylamine, pyridine), pyridine can be used as the acid scavenger. carried out in the presence of an acid scavenger, the compounds of formula VIII can be isolated.

The reaction described above is generally carried out using equivalent amounts of reactants or a small excess of another reactant, and the reactants are preferably dissolved or suspended in a suitable solvent; reaction 6 75823 is optionally carried out in the presence of a dehydrating agent and an acid scavenger at a suitable temperature. When the reaction is complete, the product usually separates from the reaction mixture. Isolation of the product is performed by conventional methods (e.g., filtration or centrifugation). If desired, the product can be cleaned.

In the compound of formula I, the anion X may, if desired, be replaced by another anion X. The reaction is carried out by reacting a compound of formula I with an acid or salt containing the desired anion. Perchlorates of formula I are prepared by reacting a compound of formula I containing another anion (e.g. p-toluenesulfonyl anion) with hydrochloric acid.

The ketimines of formula IX used as starting materials can be prepared by the method described in Compt. Rend. 258, 12, (1964), pp. 3323; and ketone sources of formula VI in Liebigs Ann. Chem. (1976), ss. 1351-1366. Other starting materials are known compounds.

The compounds of formula I have valuable pharmaceutical properties and can be used in therapy.

The therapeutic effect of the compounds of formula I has been demonstrated by the experiments described below. The following compounds were used in the experiments:

Compound A: 1-phenylpyrido [2,1-a] triazinium bromide Compound B: 1- (4-chlorophenyl) pyrido [2,1-a] triazinium bromide Compound C: 1- (4-chlorophenyl) -as -triazino / 6,1-ay-isoquinolinium bromide it 7 75823 A. Acute toxicity a. Mouse

The acute toxicity of the novel compounds of the invention was determined in 5 CFLP strain mice of either sex (weight 18-24 g). The compound was administered orally to animals at 20 ml / kg. After treatment, the animals were observed for 4 days. Toxicity was determined graphically, the results are shown in Table Ia.

10

Table Ia

Test compound LD50 m <3 / k9 ρ · ° · 15 A 1400 B 900 C 600

Amitriptyline_225_ 20 b. Rat

Acute toxicity was also determined in Wistar rats. Animals were orally administered a 0.5% suspension of test compound in carboxymethylcellulose solution. The test results are shown in Table Ib.

8 75823

Table Ib

Test compound LD50 m <3 / k <3 Ρ · ο.

C 1000

Amitriptyline_530_ B. Tetrabenazine Antagonism a. Mice

Groups of 10-20 mice were used in the experiment. The control group was given 0.9% sodium chloride solution at 20 ml / kg. After 30 minutes, the animals were administered 50 mg / kg tetrabenazine. The number of animals with ptosis was counted at 30, 60, 90, and 120 minutes after tetrabenazine administration. The results were added together and the inhibitory effect was calculated compared to the result obtained with the control group. The results are shown in Table Ha.

20 Table Ha

Test compound ED, n mg / kg p.o. Therapeutic - - index LP50 / ED50 25 A 30 46.7 B 14.0 64.2 C 3.2 187.5

Amitriptyline_12_18.75_ 1

Il b. Rotta

The same experiment was performed on rats. The results are shown in Table Hb.

9 75823

Table Hb

Test compound Tetrabenate - Blade - Reserpine - Terazine - ethinopathic ethanol arthritis agonism index co-antagonistic (ptosis) - nism index 5 ED50 mg / kg - - C 5.6 178.6 40.0 25.0

Amitriptyline 11.5_46.1_40.0_13.25 10 C. Enhancement of the toxic effect of yohimbine in mice

The experiments were performed according to Quinton1 et al. by the method described. The test compound was administered orally to animals at 20 ml / kg 0.5 hours before the administration of a standard dose of yohimbine. The results are shown in Table-15 in Figure III.

Table III

Test compound ΕΟςη p.o. Therapeutic - - index 20 LD5q / EP50 A 66.0 21.2 B 50.0 18.0 C_3_j_5_171.4_ 1

As can be seen from the results shown in the tables above, the novel compounds of the invention have a significantly better antidepressant effect than the commercial, very good antidepressant amitriptyline.

10 75823

The invention is illustrated by the following examples. Example 1 To a solution of 1-phenylpyrido [2,1-f] -as-triazinium perchlorate or 1-amino-2-benzoylpyridinium p-toluenesulfonate (0.8 g, 0.5 mmol) in 50 mL of formamide is added. 3.35 g (22 mmol) of phosphorus oxychloride The reaction mixture is allowed to stand for 1 hour, then poured onto ice, 1 ml of 70% perchloric acid is added and the mixture is extracted with nitromethane and the extract is evaporated to give 120 mg (80%). ) of the desired product, mp 259-260 [deg.] C. Analysis, calculated: N 13.66% Cl 11.52% obtained: N 13.62% Cl 11.52% The compound obtained above is converted into 1-phenylpyrido-E2, 1- [7-as-triazinium bromide (m.p. 271-272 ° C) as described in the second paragraph of Example 4. The starting material is prepared as follows: To a solution of 2- (benzoylpyridine (1 g, 5.5 mmol) in 10 mL of dichloromethane is added O- A solution of (p-toluenesulfonyl) hydroxylamine (1.04 g, 5.5 mmol) in 20 mL of dichloromethane was allowed to stand for 2 hours, then ether was added to give 1.5 g (74 g). %) 1-amino-2-benzoylpyridinium p-toluene sulfonate, m.p. 146-147 ° C.

Analysis calculated: N 7.56% S 8.66% obtained: N 7.66% S 8.73%

Example 2 Preparation of 1-phenyl-3-methylpyrido [2,1-f] -as-triazinium perchlorate

To a solution of phenyl-2-pyridyl- (N-acetyl) ketimine (0.3 g, 1.34 mmol) in dichloromethane was added a solution of O- (p-toluenesulfonyl) hydroxylamine (0.25 g, 1.34 mmol) in 20 mL. dichloroethane, and the reaction mixture is stirred at room temperature for 2 hours. Treating

II

n 75823 reaction mixture as in Example 1 gives 0.21 g (46.6%) of 1-phenyl-3-methylpyrido [2,1-f] as-triazinium perchlorate, m.p. 261-262 ° C.

Analysis calculated: N 13.06% Cl 11.02% δ obtained: ti 13.02% Cl 11.05% The starting material is prepared as follows: To a solution of phenyl-2-pyridylketimine (1.5 g, 8.25 mmol) in 7 ml In benzene, 0.34 g (8.3 mmol) of triethylamine and 0.65 g (8.35 mmol) of acetyl chloride are added.

The reaction mixture is allowed to stand at room temperature, then the triethylammonium chloride and solvent are removed. 1.4 g (75.5%) of phenyl-2-pyridyl- (N-acetyl) ketimine are obtained, m.p. 35-86 ° C (from ether).

Analysis calculated: N 12.49% Found: N 12.50%

Example 3 Preparation of 1- (4-chlorophenyl) -az-triazino [β, 6-b] isoquinolinium perchlorate___ 100 mg (0.23 mol) of 2-amino-3- (4-chlorobenzoyl) -20 isoquinolinium p-toluenesulfonate are suspended in 1.5 to 1 ml of phosphorus oxychloride, 0.5 ml of formamide is added to the suspension and the mixture is stirred at 80 ° C for 30 minutes. The mixture is poured into ice water, perchloric acid is added to give 54 mg (62%) of the desired compound, 25 m.p. 203-204 ° C.

Analysis calculated: N 10.71% obtained: N 10.48% The starting material is prepared as follows:

To a mixture of metallic magnesium (0.62 g, 26 mmol) and 30 anhydrous ether (8 mL) is added dropwise an ether solution of 4-chlorobromobenzene (5.0 g, 26 mmol). To the resulting Grignard solution is stirred 3.1 g (20 mmol) of 3-cyano-isoquinoline, and the reaction mixture is stirred at room temperature for 1 hour. The Grignard complex 35 is decomposed with ammonium chloride solution, the solvent is distilled off, and the residue is crystallized from ethanol to give 3.2 g (60%) of 3- (4-chlorobenzoyl) isoquinolinimine, 12,752,23 m.p. 151-152 ° C.

Analysis calculated: N 10.50% Found: N 10.38%

The ketimine obtained above is treated with 20 ml of 5% concentrated hydrochloric acid, the reaction mixture is made alkaline with sodium hydroxide and the solvent is distilled off to give 3.1 g (95%) of 3- (4-chlorobenzoyl) isoquinoline, m.p. 126-127 ° C.

Analysis calculated: N 5.24% Found: N 5.19% 5 g (19 nunol) of 3- (4-chlorobenzoyl) isoquinoline are dissolved in 10 ml of dichloromethane, 4 g (22 mmol) of O- (p toluenesulfonyl) hydroxylamine, and the mixture is allowed to stand for one hour. 6 g (73%) of 2-amino-3- (4-chlorobenzoyl) isoquinolinium p-toluenesulphonate are obtained, m.p. 201-202 ° C.

Analysis calculated: S 7.05% obtained: S 7.15%

Example 4 Preparation of 1- (4-chlorophenyl) -α-triazino [6,1-a] isoquinolinium bromide

Following the procedure of Example 1, using 2-amino-1- (4-chlorobenzoyl) isoquinolinium p-25 toluenesulfonate instead of 1-amino-2-benzoylpyridinium p-toluenesulfonate, 1- (4-chlorophenyl) is obtained in 70% yield. -as-triazino [6,1-a] isoquinolinium perchlorate, m.p. 243-244 ° C (from acetonitrile).

6.9 g (17.5 mmol) of the title compound are dissolved in acetonitrile and reacted with triethyl ammonium bromide (5.5 g, 30 mmol). 4.1 g (62.6%) of the desired compound are obtained, m.p. 271-272 ° C.

Analysis calculated: N 11.28% Cl 19.03% obtained: N 11.18% Cl 18.98%

II

13 75823 The starting material is prepared as follows: To a solution of 1-cyano-isoquinoline (3.1 g, 20 mmol) in anhydrous ether is added Grignard reagent prepared from 5.75 g (30 mmol) of 4-chlorobromobenzene 5 and 0.735 g (30 mmol) of magnesium? · The reaction mixture is allowed to stand overnight, then the complex is decomposed with ammonium chloride solution and 20% sulfuric acid is added to the mixture. After standing for 2 hours, the mixture is neutralized, the ether phase is separated off and evaporated to give 4.1 g (76.7%) of 1- (4-chlorobenzoyl) isoquinoline, m.p. 100-101 ° C.

Analysis calculated: N 6.44% Found: N 6.46%

The 1- (4-chlorobenzoyl) isoquinolin-15 prepared above is reacted with O- (p-toluenesulfonyl) hydroxylamine as described in Example 1, paragraph 3 to give 2-amino-1- (4) in 88.5% yield. -chlorobenzoyl) isoquinolinium p-toluenesulfonate, m.p. 189-190 ° C (from mitomethane / ether).

Analysis calculated: N 6.16% Cl 7.79% Found: N 6.18% Cl 7.56%

Example 5 Preparation of 1- (4-chlorophenyl) pyrido [2,1-f] -as-triazinium perchlorate Following the procedure of Example 1 starting from 1-amino-2- (4-chlorobenzoyl) pyridinium p-toluenesulfonate, the desired compound 79 is obtained. , In 5% yield. Sp. 249-250 ° C.

Analysis calculated: N 12.28% Cl 20.73% 30 Found: N 12.23% Cl 20.45%

The compound obtained above is converted into 1- (4-chlorophenyl) pyrido [2,1-f] -az-triazinium bromide by the method described in Example 4, paragraph &.

The starting material is prepared as described in Example 1, paragraph 23 by using 2- (4-chlorobenzoyl) pyridine instead of 14,752,223 instead of 2-benzoylpyridine. 1-Amino-2- (4-chlorobenzoyl) pyridinium p-toluenesulfonate is obtained in 89% yield, m.p. 151-152 ° C.

Example 6 Preparation of 4- (4-chlorophenyl) -α-triazino-1,6-α-quinolinium perchlorate-1-amino-2- (4-chlorobenzoyl) quinolinium p-toluenesulfonate (0.5 g, 1 , 1 mmol), formamide (3 ml) and phosphorus oxychloride (2 ml) are stirred at 90 ° C for 10 hours. The mixture is then poured into water, treated with perchloric acid and the separated product filtered off to give 0.33 g (77%) of the title compound, m.p. 193-194 ° C.

Analysis calculated: N 10.71% Found: N 10.52%.

The starting material is prepared as follows: 15.4 g (0.1 mol) of 2-cyanoquinoline are dissolved in 200 ml of anhydrous ether and Grignard reagent (prepared from 2.5 g (0.13 mol) of 4-chloro 20 of benzene and 3.16 g (0.13 mol) of magnesium). The reaction mixture is allowed to stand overnight, then poured into a mixture of ammonium bromide (15 g) and ice, acidified with sulfuric acid and the organic phase is separated. Evaporation of the ether and crystallization of the residue from ethanol gives 24 g (89%) of 2- (4-chlorobenzoyl) quinoline, m.p. 130-131 ° C.

Analysis, calculated: N 5.23% Found: N 5.21%.

1.43 g (0.53 mmol) of 2- (4-chlorobenzoyl) quino-30 dissolved in 20 ml of dichloromethane are reacted at 20 ° C with O- (p-toluenesulfonyl) hydroxylamine (1 g, 0, 53 mmol). The separated product is filtered to give 1.4 g (58%) of 1-amino-2- (4-chlorobenzoyl-quinoxalinium sulfonate, mp 219-220 ° C.

35 Analysis, calculated: N 6.16% Found: N 6.08%.

Il

Claims (1)

5 H2N-CO-R3 VII wherein R1 is as defined above and the compound thus formed has the formula 10 R 1 and X 2 are as defined above, cyclized, or b) a compound of formula Z 1 C 3 -C 0 -r 3 is wherein Z, R 1 and R 2 are as defined above, is reacted with an O-substituted hydroxylamine, such as 3 O- (p-toluenesulfonyl) hydroxylamine, and the resulting compound of formula V is cyclized isolated from the reaction mixture and preferably in the presence of a dehydrating agent, and optionally replaced in the resulting compound of formula I. anion X with another anion X. 17 75823 For the preparation of therapeutically active compounds 1-phenyl-as-triazino-6,1-α-isoquinolium and 5'-phenylpyrido [N, l] -as-trazinium derivatives of formula I and CJ - ** 15 color A group of formula 20 or 25 / b (b) (d) is halogen, halo, C 1-4 alkyl and X "is physiologically modified anion, chlorides, bromides, perchlorate or p-toluenesulfonate, 30 kännetecknat därav, att man a) omsätter en förening med formeln, NH ~ 1 Γ = \ * 1 - vi c ° vvx