JPS6220182B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel organic compounds. More specifically, it relates to dimethylaminoalkyl-3',4'-dihaloanilide (formula), its pharmaceutically acceptable acid addition salts, the uses of compounds of the formula and their salts, and their synthesis. The new compound and its production method are shown below. as well as In the formula, A is −(CH ₂ ) ₂ −, −(CH ₂ ) ₃ −,

【formula】

[Formula] and

selected from the group consisting of: Ao' is -(CH ₂ ) ₄ or -(CH ₂ ) ₅ -: X is bromine or chlorine; X' is chlorine, bromine or iodine; R is ethyl or vinyl; . A more preferred end product of this synthesis is a compound of formula A. In the formula, A is −(CH ₂ ) ₂ −, −(CH ₂ ) ₃ −, −(CH) ₄
−, −(CH ₂ ) ₅ −,

【formula】

[Formula] and

selected from the group consisting of [Formula], and X is bromine or chlorine. The most preferred compounds of the invention are those of formula B. In the formula, A' is ethylene or trimethylene. A compound of similar structure is shown in US Pat. No. 3,016,281, but this patented compound is an analgesic. In contrast, the compounds of the present invention are antidepressants. US Pat. No. 3,573,320 discloses, but does not claim, an antidepressant of the formula: In the formula, B is oxygen or sulfur, and R ₂ is

[Formula] (where n is 2 or 3; R ₄ is H or alkyl or

[Formula] is morpholino, piperidino, pyrrolidino or piperazino. ), R ₃ is alkyl, aryl, etc. US Pat. No. 3,234,276 and French Patent No. 2,073,286 (Chemical Abstracts 77, 88108) also claim related products, but with different uses. None of the above references mention the novel antidepressants of the present invention. The method of the present invention involves heating 1 molar equivalent of 3,4-dihaloaniline (1) with about 1/2 to 1 molar equivalent of dimethylaminoalkyl halide to form a compound (excess compound is generated in this reaction). (becomes a base for accepting hydrogen halides). It consists of acylating the compounds, for example with propionic or acrylic acid chlorides or bromides or with propionic anhydride in the presence of a base, to obtain the corresponding compounds. The method of the present invention involves heating one molar equivalent of 3,4-dihaloaniline with about one molar equivalent of N.N-dimethylaminohalobutylamide or -valeramide to form a compound, which is then reduced with a metal hydride. and acylating the compound to produce the compound. Such metal hydrides include lithium aluminum hydride, sodium cyanoborohydride, borane, diborane. The present invention also includes pharmaceutically acceptable acid addition salts of compounds of formula (including formulas A and B).
These salts include hydrochloride, hydrobromide, sulfate,
malate, maleate, tartrate, lactate,
citrate, cyclohexane sulfamate,
These include methanesulfonate salts, etc., which are made by reacting a compound of the formula with a stoichiometric amount of acid in an aqueous or ethereal solution and finally evaporating the solvent. The present invention also encompasses the use of a compound of the above formula or a salt thereof as a pharmaceutical preparation for the treatment of endogenous and/or exogenous depression. The novel compounds of formula were tested for their antidepressant activity by the standard test set forth below. The main action of antidepressants is to restore normal functioning in depressed people. It must be carefully distinguished from psychostimulants such as amphetamine, which cause excessive excitement in normal individuals. Many different methods have been used to measure antidepressant activity. These methods generally include:
Antagonism to sedatives such as reserpine or tetrabenazine or a synergistic increase in the toxicity of certain compounds (e.g. yohimbine or 3,4-dihydroxyphenylalanine) or the efficacy of new compounds with other known antidepressants. This includes comparisons of Although no single test can determine whether a new compound is an antidepressant, the contours revealed in a variety of tests establish the presence of antidepressant activity. Some of these tests are listed below. Antidepressant activity test A. Antagonism to hypothermia induced by oxotremorine (1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone) 4 male Carworth Farm (CF ₁ ) in each group Mouse (18−22
g) Inject test compound in 0.25% methylcellulose solution intraperitoneally to 15.25 cm x 28 cm x
They were placed in 12.7 cm plastic cages. After 30 minutes, oxotremorine hydrochloride is injected subcutaneously at 1 mg/Kg, after which the mice are placed in a refrigerator maintained at 19°C. A control group of mice injected with oxotremorine alone was also placed in a similar refrigerator. Thirty minutes after administration of oxotremorine, intraperitoneal temperature was measured using a thermistor probe. If the body temperature was higher than twice the standard deviation of the body temperature of the control group to which oxotremorine was administered alone, the compound was considered to have antagonized oxotremorine. Active compounds were retested using multiple dose levels with logarithmic intervals of 0.3.
The ED ₅₀ (50% effective dose) was calculated using the Spearman and Karber method (Finney, DF, Statistical Method).
in Biological Assay, Hafner Publ.Co., N.
Y., p. 524 (1952)). B. Enhancement of apomorphine sucking behavior Mice injected subcutaneously with 20 mg/Kg or more of apomorphine were observed for their sucking response to paper at the bottom of the cage in relation to the dose. Low doses of apomorphine (10 mg/Kg, subcutaneous) elicited this response only when mice were pretreated with antidepressants or stimulants. Groups of 4 albino mice (CF ₁ , 18-22 g each) were injected intraperitoneally with the test compound in 0.25% methylcellulose. After 1 hour, apomorphine hydrochloride 10mg/
Kg subcutaneously injected. The mice were then placed in a plastic box (10 cm x 10 cm x 12.7 cm) and observed for normal sucking and licking behavior after 30 minutes. ED ₅₀ was determined as in the oxotremorine antagonism test described above. C. Enhancement of Yohimbine Toxicity in Aggregated Mice Groups of 4 18-22 g albino CF ₁ mice were injected intraperitoneally with the test compound in 0.25% methylcellulose 30 minutes before administering 220 mg/Kg yohimbine HCl intraperitoneally. . Each group of mice was then placed in a plastic box (15.25 cm x 28 cm x
12.7 cm) and placed in a room at 30°C. It is considered active when at least 3 out of 4 mice die after 2 hours of collection. The active compound was tested again at doses reduced by logarithmic intervals of 0.3 and the number of deaths was used to calculate the ED ₅₀ by the method of the oxotremorine antagonistic test. In the above tests A to C, the test compounds shown in the table below were used to obtain the results shown in the table. Table of conventional compounds Compounds of the invention

[Table] Conclusion: The compounds of the present invention have dramatically stronger antidepressant activity than conventional compounds.
Furthermore, the compound of the present invention caused no deaths in mice and rats at doses higher than 200 mg/Kg.
Thus, an effective dose for use as an antidepressant
Since there is no toxicity even at about 100 times the amount, the LD ₅₀ of the compound of the present invention is so large that it cannot be specifically measured, and it is considered that there is no point in measuring it. The compounds described in the examples below have been tested and found to have activity equal to or greater than commercially available antidepressants such as imipramine hydrochloride. Pharmaceutical forms of the compounds of formula and their salts contemplated by this invention include formulations for oral, parenteral and rectal use, such as tablets, powder sachets, casseroles, dragees, capsules, Solutions, suspensions, sterile injections, suppositories, bougies, etc. Suitable diluents or carriers, such as carbohydrates, lactose, sucrose, mannitol, proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose, etc., are used as carriers or coatings. Water or oils such as coconut oil, sesame oil, safflower oil, cottonseed oil and peanut oil are used to prepare solutions or suspensions of the active drug. Artificial sweeteners, colors and flavors may also be added. Compounds of formula (including A and B) and their pharmaceutically acceptable acid addition salts are used in dosages of 0.01 to 2 mg/Kg, depending on the type of compound and the weight, age and condition of the patient. .
Preferably a dosage of 0.05 to 1 mg/Kg is used to alleviate depression in a patient, in the form of an oral or injectable formulation as described above. Treatment of depression in humans depends on the weight, age, and condition of the patient and the type of compound in the formula used.
Dosage units containing 1.0 to 30 mg are given 1 to 4 times a day. These dosage units may be given orally, by subcutaneous, intravenous, or intramuscular injection, or by rectal administration. The starting compounds of the invention are the known 3,4-dihaloanilines, where halo is chloro or bromo.
Similarly, the reactants chloro- or bromo-dimethylaminoalkanes are well known to those skilled in the art. In order to carry out the manufacturing method of the present invention, specific 3-4-
Dihaloaniline 1 is heated in the presence of a particular halo-1(N-dimethylamino)alkane or acid addition salt thereof and a base, with or without a solvent or suspending agent, to form the compound. In a preferred embodiment of the invention, 1 to 2 molar equivalents of 3,4-dihaloaniline are used per molar equivalent of halodialkylaminoalkane, either as a free amine base or as a hydrochloride. If used as a salt, additional base is additionally required to liberate the free base. If aniline is used in excess, aniline is used as this additional base. Inorganic bases such as sodium or potassium bicarbonate or sodium or potassium carbonate may also be used as additional bases. If a solvent is used, it is preferably one that refluxes above 85°C. For example, toluene, xylene, trimethylbenzene, ethylbenzene, dioxane can be used as solvent or suspending agent. The reaction is carried out at a temperature between 100°C and the boiling point of the solvent or suspending agent. Under these conditions, the reaction time is 1-5 days. After the reaction is complete, the product () is N・N-dimethyl-
The N'-(3,4-dihalophenyl)alkanediamine is recovered by any suitable method. For example, the diamine is extracted as a base with a water-immiscible organic solvent, such as ether, benzene, toluene, or as a salt, such as a hydrochloride, into an acidic aqueous phase. The compounds are purified by appropriate methods such as repeated extractions or chromatography and recrystallization. It is also available as a salt, eg the hydrochloride. The compounds are acylated in conventional manner. That is, the compound can be converted into a corresponding acid halide (propionyl-, acryloyl-chloride or bromide) or an acid anhydride (e.g. propionic anhydride).
react with. When using acid halides, triethylamine, methyldiethylamine,
Preferably, a base such as N-methylpiperidine and the like is used therewith. The reaction proceeds with an acid halide, a base or an acid anhydride, and usually a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane, etc. Reaction time is 1-8 hours at room temperature. When using propionic anhydride, 2 to 24 hours at 75 to 100°C (steam bath) is required. After completion of the reaction, the compound is isolated as a free base or as an acid addition salt by adding acid to the mixture and extracting with water. The product is further purified by crystallization, additive extraction or chromatography. The crystalline compound or its acid addition salt physically associates with a separated amount of a solvent such as water or ethanol to form a solvate and is separated.
It can therefore be removed without changing the chemical entity. The following examples are illustrative of the products, methods of manufacture, and uses of the invention, but are not to be construed as limiting. Example 1 N-N-dimethyl-N'-(3,4-dichlorophenyl)-ethylenediamine and its dihydrochloride 3,4-dichloroaniline (71.7 g, 0.44 mol) and 1-chloro-2-dimethylamino A solution of ethane (23.8 g, 0.22 mol) (obtained by neutralizing and distilling its hydrochloride salt) is heated on a steam bath for 72 hours. This mixture was mixed with a 20% aqueous solution of sodium hydroxide (200%
ml) and extracted with ether. The extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium and evaporated. 3,4-dichloroaniline and the product N,N-dimethyl- by distillation under reduced pressure.
50.6g mixture of N'-(3,4-dichlorophenyl)ethylenediamine (boiling point 128-135°/0.1mm)
get. This mixture is chromatographed on 500 g of silica gel and the fractions are eluted with 1000 ml of chloroform. Fraction 1-11 is 44.6g of 3.4-
Contains dichloroaniline. Furthermore, when eluted with 3000ml of 20% methanol in chloroform solution, 4.4
g of N.N-dimethyl-N'-(3,4-dichlorophenyl)ethylenediamine are obtained as an oil. N.N-dimethyl-N'-(3,4-dichlorophenyl)ethylenediamine hydrochloride was obtained by reacting with excess ether hydrogen chloride, and recrystallized from methanol-ether to give 4.2 g.
(6.2%) of N・N-dimethyl-N′-(3,4-dichlorophenyl)ethylenediamine (melting point 151~
153℃). Analysis (C ₁₀ H ₁₄ Cl ₂ N ₂・2HCl・1/2CH ₃ OH) Calculated value
C, 39.25; H, 5.63; Cl, 44.03; N, 8.70 Actual value
C, 39.58; H, 5.51; Cl, 44.03; N, 9.06 This methanol solvate dihydrochloride was heated at 80°C in vacuo.
Heating at for 72 hours yields the pure, unsolvated dihydrochloride salt. The dihydrochloride salt was treated with aqueous sodium carbonate until approximately neutral, and the mixture was then extracted twice with ether and the ether was evaporated to give the free base, N.N-dimethyl-N'-(3 -4-dichlorophenyl)ethylenediamine is obtained. Example 2 N-[2-(dimethylamino)ethyl]-3'.
4'-Dichloropropionanilide and its maleate salt Triethylamine (2.84 g, 0.028 mol) and N.N-dimethyl-N'-(3,4-dichlorophenyl)ethylenediamine (3.26 g, 0.024 mol)
Propionyl chloride (2.60 g, 0.028 mole) is added over 30 minutes to a solution of and dissolved in 100 ml of methylene chloride. After 4 hours, 100 ml of a saturated aqueous solution of sodium bicarbonate is added. The organic layer is washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to give a yellow oil.
The maleic acid addition salt is obtained by reaction with maleic acid (1.62 g, 0.014 mol) in ethanol-ether followed by recrystallization from ether-water. Analysis (C ₁₃ H ₁₈ Cl ₂ N ₂ O・C ₄ H ₄ O ₄ ) Calculated value
C, 50.39; H, 5.47; Cl, 17.50; N, 6.91 Actual value
C, 50.15; H, 5.46; Cl, 17.56; N, 6.82 The maleate salt is treated with aqueous sodium hydroxide, the mixture is extracted with ether, and the ether layer is then evaporated to yield the free base, N- [(2
-dimethylamino)ethyl]-3',4'-dichloropropionanilide is obtained. Treatment of this free base with hydrogen chloride in ether yields N-[(2-dimethylamino)ethyl]-3'.
The hydrochloride of 4'-dichloropropionanilide is obtained. Example 3 N,N-dimethyl-N'-(3,4-dichlorophenyl)trimethylene-1,3-diamine and its dihydrochloride 3,4-dichloroaniline (60.8 g, 0.38 mol), 1-chloro A mixture of -3-dimethylaminopropane hydrochloride (39.5 g, 0.25 mol) and sodium carbonate (53.0 g, 0.50 mol) in toluene (250 ml) is refluxed for 72 hours. Add water, wash the organic layer with water, and extract with 10% hydrochloric acid. Wash the acidic layer with ether, make basic with 40% sodium hydroxide, and extract with ether. The ether is washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The crude oil was chromatographed on 100 g of silica gel in a glass funnel, eluted three times with 250 ml of chloroform, then
Elute with 700ml methanol. Evaporation of methanol yields 5.1 g of N.N-dimethyl-N'-(3.4
-dichlorophenyl)trimethylene-1,3-diamine is obtained as a brown oil. The hydrochloride salt is obtained by treatment with excess ethereal hydrogen chloride and recrystallized from methanol-ether to yield 5.1 g of N.
N-dimethyl-N'-(3,4-dichlorophenyl)trimethylene-1,3-diamine dihydrochloride (melting point 182-183 DEG C.) is obtained. Analysis (as C ₁₁ H ₁₈ Cl ₂ N ₂・2HCl) Calculated value
C, 41.27; H, 5.67; Cl, 44.31; N, 8.75 Actual value
C, 41.63; H, 5.74; Cl, 43.92; N, 8.73 Example 4 N-[3-dimethylamino)propyl]-3'.
4'-Dichloropropionanilide and its hydrochloride N,N-dimethyl-N'-(3,4-dichlorophenyl)trimethylene-1,3-diamine (3.70
g, 0.015 mol) and propionic anhydride (20 ml) on a steam bath overnight. Add water (100ml),
Continue heating for 30 minutes. Cool this mixture and 20%
Make basic with aqueous sodium hydroxide solution and extract with ether. The ethereal layer is washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a yellow oil. The hydrochloride was obtained by treatment with excess ethereal hydrogen chloride and then recrystallization from methanol-ether, yielding 3.3 g of N-[(3-dimethylamino)propyl]-3',4'-dichloropropionanilide hydrochloride. generate. Analysis (C ₁₄ H ₂₀ Cl ₂ N ₂ O・HCl) Calculated value
C, 49.50; H, 6.23; Cl, 31.31; N, 8.25 Actual value
C, 49.59; H, 6.31; Cl, 31.61; N, 8.52 When this hydrochloride is treated with aqueous sodium hydroxide, extracted with ether, and the ether is evaporated,
The free base N-[(3-dimethylamino)propyl]-3'.4'-dichloropropionanilide is obtained. Example 5 N′-(3,4-dichlorophenyl)-N・N・
1-trimethyl-ethylenediamine and N'-
(3,4-dichlorophenyl)-N.N.2-trimethylethylenediamine 16.2 g of 3,4-dichloroaniline, 39.6 g
A mixture of (0.25 mol) 2-chloro-1-dimethylaminopropane hydrochloride, 26.5 g (0.25 mol) sodium carbonate and 21.1 g (0.25 mol) sodium bicarbonate in 200 ml toluene was steam bathed for 72 hours. Heat on top. Then 250 ml of water was added, the organic layer was separated and then evaporated in vacuo to N′-(3.
17 g of a mixture of N'-(3,4-dichlorophenyl)-N.N.2-trimethylethylenediamine was obtained. It also contains unreacted starting material. Example 6 N-[(2-dimethylamino-1-methyl)ethyl]-3',4'-dichloropropionanilide and its hydrochloride The mixture obtained in Example 5 and 50 ml of propionic anhydride were placed on a steam bath. Heat for 18 hours. then 400
Add ml of water and continue heating for 1 hour. The mixture is then made basic with 40% aqueous sodium hydroxide, extracted with 500 ml of ether, the extract is washed with 200 ml of water and then extracted again with 200 ml of 10% aqueous hydrochloric acid. This second extract was washed with 250 ml of ether, made basic with 40% aqueous sodium hydroxide, extracted with ether, and this ether extract
Wash with 100 ml of saturated sodium chloride solution. The extract is then dried over anhydrous magnesium sulphate and evaporated. The remaining oil is chromatographed on 500 g of silica gel, eluting with ethyl acetate. Evaporation of fractions 91-180 yields 6.5 g of yellow oil. This oil is the free base N-[(2
-dimethylamino-1-methyl)ethyl]-3′・
4'-dichloroanilide. This oil was treated with excess ethereal hydrogen chloride and the precipitated salt was dissolved in methanol-ether (1/
When recrystallized twice with 10-vol/vol), 5.6 g
(16% of N-[(2-dimethylamino-1-methyl)ethyl]-3',4'-dichloropropionanilide hydrochloride (melting point 196° to 197°C) is obtained. Analysis (C ₁₄ H ₁₀ N ₂ Cl ₂ O・HCl−H ₂ O) Calculated value C, 47.10; H, 5.87; N, 7.84 Actual value C, 47.45; H, 5.99; N, 7.91 Example 7 N-[(2-dimethylamino- 2-Methyl)ethyl]-3',4'-dichloropropionanilide In Example 6, after the elution of the free base was completed, the chromatographic column was further washed with ethyl acetate.
Elute with methanol (9:1). Fractions of 500 ml each are obtained. Fractions 5-8 were combined and evaporated to give 2.2 g of a yellow oil, which was N-
[(2-dimethylamino-2-methyl)ethyl]-
3',4'-dichloropropionanilide. Mix this product with 1g of oxalic acid and 20ml of methanol.
Treat with a solution in 200 ml of ether. Next, when recrystallized with methanol-ether, 2.3g
(6%) of N-[(2-dimethylamino-2-methyl)ethyl]-3'.4'-dichloropropionanilide oxalate (melting point 183 DEG C.) is obtained. Analysis (C ₁₄ H ₂₀ N ₂ Cl ₂ O・C ₂ H ₂ O ₄ ) Calculated value
C, 48.86; H, 5.64; N, 7.12; Cl, 18.03 Actual value
C, 49.04; H, 5.63; N, 7.31; Cl, 18.30 Treatment of the oxalate with aqueous sodium hydroxide, extraction of the aqueous mixture with ether, and treatment of the ether solution with hydrogen chloride gas yields N-[ (2
-dimethylamino-2-methyl)ethyl]-3′・
The hydrochloride of 4'-dichloropropionanilide is obtained. Example 8 N-[(3-dimethylamino-2-methyl)propyl]-3',4'-dichloropropionanilide (A) N'-(3,4-dichlorophenyl)-N.
N.2-trimethylpropane-1.3-diamine 43 g (0.75 mol) of 1-chloro-2-methyl-3-(dimethylamino)propane hydrochloride,
25ml of 40% sodium hydroxide solution in ether
Heat with 250ml of mixed liquid. 16 g (0.10 mol) of 3,4-dichloroaniline are added to this mixture. The ether is distilled off and the mixture is heated on a steam bath for 72 hours. The mixture is then treated with 200 ml of 20% aqueous sodium hydroxide solution, treated on a steam bath for 1 hour and extracted with 250 ml of ether. The extract is dried over anhydrous magnesium sulfate and evaporated to give an oil. The black oil is filtered through 200 g of silica and eluted with methylene chloride until no more material is eluted. When the filtered material is evaporated, N-(3,4-dichlorophenyl)-
N.N.2-trimethylpropane-1.3-diamine is obtained as an orange oil. (B) N-[(3-dimethylamino-2-methyl)propyl]-3',4'-dichloropropionanilide The orange oil of Example 8A was treated with 25 ml of propionic anhydride and dried on a steam bath. Heat for 20 hours. Then 100 ml of water are added to the reaction mixture. The mixture is then made basic with 40% aqueous sodium hydroxide solution and extracted with 250 ml of ether. The extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated to give the base N-[(3-dimethylamino-2-methyl)propyl]-3'·4'-dichloropropionanilide. . This free base is converted to its hydrochloride salt upon treatment with excess ethereal hydrogen chloride. This compound was mixed with methanol-ether (1/
12, volume/volume) and recrystallizes with 2.8 g (8
%) of N-[(3-dimethylamino-2-methyl)propyl]-3',4'-dichloropropionanilide hydrochloride (melting point 209 DEG -210 DEG C.). Analysis (C ₁₅ H ₂₂ N ₂ Cl ₂ O・HCl) Calculated value
C, 50.93; H, 6.55; N, 7.92; Cl, 30.07 Actual value
C, 51.16; H, 6.51; N, 8.10; Cl, 30.07 Example 9 N-[(2-dimethylamino)ethyl]-3'.
4'-Dibromopropionanilide By the method of Example 1, a mixture of 3,4-dibromoaniline and 1-chloro-2-dimethylaminoethane was heated at 90 to 100°C for 72 hours, and N.N.
-dimethyl-N'-(3,4-dibromophenyl)
Ethylenediamine was obtained. By the method of Example 2, N.N-dimethyl-
When propionyl chloride is added to a solution of N'-(3,4-dibromophenyl)ethylenediamine and triethylamine, N-[(2-dimethylamino)ethyl]-3',4'-dibromopropionanilide is obtained. Example 10 N-[3-(dimethylamino)propyl]-3'.
4'-Dibromopropionanilide When a mixture of 3,4-dibromoaniline and 1-chloro-3-dimethylaminopropane is heated at 90-100°C for 72 hours according to the method of Example 1,
N.N-dimethyl-N'-(3.4-dibromophenyl)trimethylene-1.3-diamine is obtained. By the method of Example 2, N.N-dimethyl-
When propionyl chloride is added to a solution of N'-(3,4-dibromophenyl)trimethylene-1,3-diamine and trimethylamine, N-[3-(dimethylamino)propyl]-3',4'-dibromopropion Anilide is obtained. Example 11 N-[2-(dimethylamino)ethyl]-3'.
4'-Dichloroacrylanilide Heating 3,4-dichloroaniline; 1-chloro-2-dimethylaminoethane hydrochloride and sodium bicarbonate according to the method of Example 1 gives N.N.
-dimethyl-N'-(3,4-dichlorophenyl)
Ethylenediamine is obtained. When this diamine is heated with acryloyl chloride in the presence of triethylamine in the same manner as in Example 2, the corresponding N-[2-(dimethylamino)ethyl]
-3',4'-dichloroacrylanilide is obtained. Treatment of this anilide with hydrogen chloride in ether gives the corresponding N-[2-(dimethylamino)ethyl]-3'.4'-dichloroacrylanilide hydrochloride. Example 12 When 3,4-dibromoaniline, 1-chloro-2-methyl-3-dimethylaminopropane hydrochloride and sodium hydroxide are heated by the method of Example 8A, N'-(3,4- dibromophenyl)
-N・N・2-trimethylpropylene-1・3-
Diamine is obtained. When this diamine is heated with propionyl chloride in the presence of triethylamine in the same manner as in Example 2, the corresponding N-[(3-dimethylamine-2-methylpropyl]-3',4'-dibromopropionanilide) is obtained. Treatment of the anilide with hydrogen chloride in ether gives the corresponding N-[3-(dimethylamino-2-
methyl)propyl]-3',4'-dibromopropionanilide hydrochloride is obtained. Example 13 N-[(3-dimethylamino-2-methyl)propyl]-3',4'-dibromoacrylanilide 3,4-dibromoaniline, 1-chloro-2- Heating methyl-3-dimethylaminopropane hydrochloride, sodium carbonate and sodium bicarbonate in toluene gives N-
(3.4-dibromophenyl)-N.N.2-trimethylpropane-1.3-diamine is obtained. When this diamine is heated with acryloyl chloride in the presence of triethylamine as in Example 2, the corresponding N-[(3-dimethylamino-2-methyl)-propyl]-3'.4'-dibromoacrylanilide is obtained. Treatment of this anilide with hydrogen chloride in ether gives the corresponding N-[(3-dimethylamino-2-methyl)propyl]-3'.4'-dibromoacrylanilide hydrochloride. Example 14 N-[3-(dimethylamino)propyl]-3'.
4'-Dichloroacrylanilide When 3,4-dichloroaniline, 1-chloro-3-dimethylaminopropane hydrochloride and sodium carbonate are heated in toluene by the method of Example 3, N.N-dimethyl-N '-(3,4-dichlorophenyl)propylene-1,3-diamine is obtained. When this diamine is heated with acryloyl chloride in the presence of triethylamine as in Example 2, the corresponding N-[(3-dimethylamino)propyl]-3'.4'-dichloroacrylanilide is obtained. Treatment of this anilide with hydrogen chloride in ether gives the corresponding N-[(3-dimethylamino)propyl]-3'.4'-dichloroacrylanilide hydrochloride. Example 15 N′-(3,4-dibromophenyl)-N・N・
1-trimethylethylenediamine and N'-
(3,4-dibromophenyl)-N·N·2-trimethylethylenediamine 3,4-dibromoaniline, 2-chloro-1-dimethylaminopropane hydrochloride, sodium carbonate and sodium bicarbonate according to the method of Example 5. is heated in toluene for 72 hours on a steam bath. After adding water to this mixture, the organic layer is separated and evaporated, resulting in N-(3,4-dibromophenyl)-N.
N・1-trimethylethylenediamine and N-
A mixture with (3.4-dibromophenyl)-N.N.2-trimethylethylenediamine is obtained. Example 16 N-[(2-dimethylamino-1-methyl)ethyl]-3',4'-dichloroacrylanilide and its hydrochloride;
2-Methyl)ethyl]-3',4'-dichloroacrylanilide and its hydrochloride By the method of Example 6, the mixture of compounds obtained in Example 5 was treated with acryloyl chloride in the presence of triethylamine, Then add water, make basic with sodium hydroxide and extract with ether. Wash the ether extract with water and extract with 10% hydrochloric acid. Wash this hydrochloric acid extract with ether,
The ether is discarded, the aqueous solution is made basic with sodium hydroxide and extracted with ether. The ether solution was washed, evaporated and chromatographed on silica gel with ethyl acetate.
[(2-dimethylamino-1-methyl)ethyl]-
3′,4′-dichloroacrylanilide is obtained. When this compound is treated with ether hydrogen chloride,
N-[(2-dimethylamino-1-methyl)ethyl]-3,4-dichloroacrylanilide is obtained. Further extraction of the silica gel column with ethyl acetate yielded N-[(2-dimethylamino-2-methyl)ethyl]-3',4'-dichloroacrylanilide, which upon treatment with an ethereal solution of hydrogen chloride Converts to hydrochloride. Example 17 N-[(2-dimethylamino-1-methyl)ethyl]-3',4'-dibromopropionanilide and its hydrochloride; and N-[(2-dimethylamino-2-methyl)ethyl]- 3',4'-Dibromopropionanilide and its hydrochloride A mixture of the compounds obtained in Example 15 was treated with propionic anhydride according to the method of Example 6, then water was added and the mixture was basified with sodium hydroxide. and extract with ether. This ether extract is washed with water and extracted with 10% hydrochloric acid. The hydrochloric acid extract is washed with ether, the ether is discarded, the aqueous solution is made basic with sodium hydroxide and extracted with ether. The ether solution was washed, evaporated and chromatographed on silica gel with ethyl acetate to yield N[(2-dimethylamino-1-methyl)-ethyl]-3',4'-dibromopropionanilide. obtain. When this compound is treated with ether hydrogen chloride,
N-[(2-dimethylamino-1-methyl)ethyl]-3'.4'-dibromopropionanilide hydrochloride is obtained. Next, when the silica gel column was extracted with ethyl acetate-methanol, N-[(2-dimethylamino-2
-methyl)ethyl]-3',4'-dibromopropionanilide, which on treatment with an ethereal solution of hydrogen chloride converts into its hydrochloride. Example 18 N-[(2-dimethylamino-1-methyl)ethyl]-3',4'-dibromoacrylanilide and its hydrochloride; N-[(2-dimethylamino-2-
methyl)ethyl]-3',4'-dibromoacrylanilide and its hydrochloride The mixture of the compound obtained in Example 15 was treated with acryloyl chloride and triethylamine according to the method of Example 6, and then water was added. and the mixture is made basic with sodium hydroxide and extracted with ether. Wash this ether extract with water and give 10%
Extract with hydrochloric acid. The hydrochloric acid extract is then washed with ether, the ether is discarded, and the aqueous solution is made basic with sodium hydroxide and extracted with ether. The ether solution was washed, evaporated and chromatographed on silica gel with ethyl acetate to reveal N-[(2-dimethylamino-1-methyl)-ethyl]-3',4'-dibromoacrylate. Anilide is obtained. When this compound is treated with ether hydrogen chloride,
N-[(2-dimethylamino-1-methyl)ethyl]-3'.4'-dibromoacrylanilide hydrochloride is obtained. When this silica gel column was further extracted with ethyl acetate-methanol, N-[(2-dimethylamino-
2-Methyl)ethyl]-3'.4'-dibromoacrylanilide is obtained, which is converted to its hydrochloride by means of an ethereal solution of hydrogen chloride. Example 19 N-(3',4'-dichlorophenyl)-N-[5-
(dimethylamino)pentyl]propionamide and its hydrochloride 57.6g (1.28mol) of dimethylamine in 500ml
Cool the solution in ether in an ice bath. A solution of 50.0 g (0.32 mol) of 5-chlorovaleryl chloride in 50 ml of ether is added dropwise over 30 minutes, and then 100 ml of water is slowly added. The organic layer was separated, washed with 100 ml of saturated aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and evaporated to give 41.5 g (79%) of 5-chlorovaleryl-N.N-dimethylamide to a yellow Obtained as an oil. Add this oil to 3,4-dichloroaniline40.5
(0.25 mol) and a suspension of 1.0 g of potassium iodide in 250 ml of dimethylformamide and heated to reflux for 16 hours. Then add this mixture
Pour into a mixture of 1500 ml water and 100 ml 20% aqueous sodium hydroxide solution (1600 ml, pH approx. 8). The precipitate formed was collected by filtration, washed with water, and recrystallized twice with ether, yielding 16.7 gg (23%) of 5-
(3'.4'-dichloroanilino)-N.N-dimethyl-valeramide (melting point 114 DEG C.) is obtained. Analysis (C ₁₃ H ₁₈ N ₂ Cl ₂ O) Calculated value
C, 53.99; H, 6.27; N, 9.69; Cl, 24.52 Actual value
C, 53.65; H, 6.28; N, 9.45; Cl, 14.41 14.5 g (0.05 mol) of 5-(3'·4'-dichloroanilino)-N·N-dimethylvaleramide -5
Add 200 ml of a solution of borane (0.20 mol) in 200 ml of tetrahydrofuran to the solution cooled to 200 ml of tetrahydrofuran. The mixture is kept at room temperature overnight and then refluxed on a steam bath for 2.5 hours, resulting in a milky suspension. Slowly add 100 ml of 6N hydrochloric acid aqueous solution to this suspension. about
The boiling (nitrogen gas) will stop after 30 minutes. This mixture is then distilled to remove tetrahydrofuran,
The remaining aqueous solution is washed with 200 ml of ether, then made basic with 100 ml of 40% aqueous sodium hydroxide solution and extracted with 300 ml of ether. The ether extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, yielding 12.9 g (94
%) of N-(3′・4′-dichlorophenyl)-N′・
N'-dimethyl-1,5-pentanediamine is obtained as a yellow oil. This oil was converted to the hydrochloride with hydrogen chloride in ether, yielding 0.8 g (63%) of N-(3',4'-dichlorophenyl)N',N'-dimethyl-1,5-pentadiamine hydrochloride. is generated. It melts (with decomposition) at 183°C. Analysis C ₁₃ H ₂₀ N ₂ Cl ₂ 2HCl Calculated value
C, 44.84; H, 6.37; N, 8.05; Cl, 40.74 Actual value
C, 44.96; H, 6.27; N, 8.04; Cl, 41.22 Oily N-(3,4-dichlorophenyl)-
N'.N'-dimethyl-1,5-pentanediamine (11.9 g, 0.043 mol) and 80 ml of propionic anhydride are heated on a steam bath overnight. 250ml of this mixture
Add water and continue heating for 30 minutes. The mixture obtained is made basic with 150 ml of 40% aqueous sodium hydroxide solution and extracted with 200 ml of ether. The ether extract was washed with 100 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give N-(3'·4'-dichlorophenyl)-N-
(5-Dimethylaminopentyl)propionamide is obtained as a yellow oil. When this was treated with oxalic acid dissolved in a mixture of 50 ml of methanol and 50 ml of ethanol, N-(3'.
The oxalate salt of 4'-dichlorophenyl)-N-(5-dimethylaminopentyl)propionamide is formed. This oxalate salt has a melting point of 166-167°C. Analysis C ₁₆ H ₂₄ Cl ₂ N ₂ O・C ₂ H ₂ O ₄ Calculated value
C, 51.31; H, 6.22; N, 6.65; Cl, 16.83 Actual value
C, 51.74; H, 6.24; N, 6.64; Cl, 17.14 Similar to Example 7, the oxalate is converted to the hydrochloride. Example 20 N-(3″・4′-dichlorophenyl)-N-(4-
Dimethylaminobutyl) propionamide and its hydrochloride 30 g (0.2 mol) of N.N-dimethyl-4-chlorobutyramide [J. Falbe et al., Chem. Ber. 97
2544 (1964)], 32.4 g (0.2 mol) of 3,4-dichloroaniline and 1 g of potassium iodide at 250
ml of dimethylformamide and reflux for 17 hours. Reaction product with sodium hydroxide 20%
Make basic by dissolving 100ml of the aqueous solution in 1500ml of water. The precipitate is collected by filtration, washed with 500 ml of ether and then dissolved in 500 ml of methanol. After concentrating to 200 ml, 13.5 g of solid are obtained.
This is 4-(3'.4'-dichloroanilino)-N.N-dimethylbutyramide with a melting point of 154-155°C. Analysis C ₁₂ H ₁₆ Cl ₂ N ₂ O Calculated value C, 52.37;
H, 5.86; N, 10.18; Cl, 25.77 Actual value C, 52.73;
H, 5.99; N, 10.04; Cl, 25.40 4-(3′·4′-dichloroanilino)-N·N-dimethylbutyramide was reduced with borane in tetrahydrofuran by the method of Example 24, N-
(3',4'-dichlorophenyl)-N,N'-dimethylbutane-1,4-diamine is obtained as an oil. The hydrochloride salt obtained by treating this oil with hydrogen chloride in ether has a melting point of 200-201°C. Analysis C ₁₂ H ₁₈ N ₂ Cl ₂・2HCl (334.14) Calculated value
C, 43.13; H, 6.03; N, 8.39; Cl, 42.45 Actual value
C, 43.62; H, 6.15; N, 8.91; Cl, 42.07
When heated with ml of propionic anhydride, N-
(3'.4'-Dichlorophenyl)-N-(4-dimethylaminobutyl)propionamide is obtained as an oil. Treatment of this oil with hydrogen chloride in ether yielded 7.3 g (63%) of N-(3',4'-dichlorophenyl)-N-(4-dimethylamino)butylpropionamide hydrochloride. , which has a melting point of 162~
It is 163℃. Analysis C ₁₅ H ₂₂ N ₂ Cl ₂ O・HCl Calculated value
C, 50.73; H, 6.55; N, 7.92; Cl, 30.07 Actual value
C, 51.02; H, 6.58; N, 8.11; Cl, 30.54 Other compounds of the formula can be obtained by the method of the examples above. Representative compounds thus produced are shown below. N-[(2-dimethylamino)ethyl]-3'・4'-
Dibromoacryl-anilide; N-[(3-dimethylamino)propyl]-3'.
4'-dibromoacrylanilide;N-[(3-dimethylamino-2-methyl)propyl]-3',4'-di-chloropropionanilide; N-[(3-dimethylamino-2-methyl)propyl] -3',4'-di-chloroacrylanilide; Treatment of these amino compounds or the amino compounds of the examples with a calculated stoichiometric amount of a pharmaceutically acceptable acid results in the formation of a pharmaceutically acceptable form of these amines. Addition salts of acidic acids are obtained. Such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, lactate, malate, maleate, succinate, tartrate, and citric acid. salts, benzenesulfonates, methanesulfonates, sulfamates, etc. Example 21 From the following ingredients and blending amounts, 2.5 mg of N-[3
1000 oral two-piece hard capsules containing -(dimethylamino)propyl]-3',4'-dichloropropionanilide hydrochloride are produced. Ingredient blend amount N-[3-(dimethylamino)propyl]-3'.
4'-Dichloropropionanilide hydrochloride 2.5g Lactose 150g Cornstarch 25g Talc 20g Magnesium stearate 2.0g The above materials are thoroughly mixed and then placed into capsules in the usual manner. One to two capsules are administered every four hours to alleviate depression in a person. Similarly, capsules containing 5, 10, 15, 20, 25 or 30 mg of active substance are obtained in a similar manner. Example 22 1000 oral tablets each containing 25 mg of N-[3-(dimethylamino)propyl]-3',4'-dichloropropionanilide hydrochloride are manufactured from the following ingredients and formulations: . Ingredient blending amount N-[3-(dimethylaminopropyl]-3'/4'-
Dichloropropionanilide hydrochloride 25g Lactose 125g Cornstarch 65g Magnesium stearate 2.5g Light liquid paraffin 3g Mix each ingredient thoroughly. This is broken up by pressing through a No. 16 sieve, and the resulting granules are then compressed into tablets. Each tablet contains 25 mg of N-[3-(dimethylamino)propyl]-3',4'-dichloropropionanilide hydrochloride. The above tablets are used to treat depression in adults, 1 to 3 times a day.
It is used by orally administering one tablet at a time. Example 23 Oral Syrup An aqueous suspension for oral use containing 10 g of N-[2-(dimethylaminoethyl]-3',4'-dichloropropionanilide hydrochloride) per 5 ml unit from the following ingredients and formulations: 1000ml is produced.Ingredients N-[2-dimethylamino)ethyl]-3',4' - dichloropropionanilide hydrochloride 2g Citric acid 2g Benzoic acid 1g Sucrose 700g Gum tragacanth 5g Lemon oil 2ml Deionized water Disperse 1000ml citric acid, benzoic acid, sucrose, gum tragacanth and lemon oil in enough water to make 850ml solution. N-[2-dimethylamino)ethyl]-
Add 3',4'-dichloropropionanilide hydrochloride to the syrup with stirring until uniformly dispersed. Add enough water to make 1000ml. The composition thus prepared is used in the treatment of depression in adults by administering one teaspoonful four times a day. Example 24 Parenteral solution 25 mg of N-
A sterile aqueous solution for intramuscular use is prepared containing [3-(dimethylamino)propyl]-3',4'-dichloropropionanilide hydrochloride. Ingredient blend amount N-[3-(dimethylamino)propyl]-3'.
4'-Dichloropropionanilide hydrochloride 25g Lidocaine hydrochloride 4g Methylparaben 2.5g Propylparaben 0.17g In water for injection 1000ml Dissolve the above ingredients in water and sterilize the solution by filtration. Place this sterile solution in a bottle and seal. Example 25 Rectal suppositories Each weighs 2.0 g and contains 5 mg of N-[(2-
dimethylamino-1-methyl)-ethyl]-3′・
Suppositories containing 4′-dichloropropionanilide
1000 pieces are made from the following ingredients and amounts. Component blend amount N-[(2-dimethylamino-1-methyl)ethyl]-3',4'-dichloropropionanilide 5g Propylene glycol 162.5g 2000g in polyethylene glycol 4000 N-[(2-dimethylamino-1 -Methyl)ethyl]-3',4'-dichloropropionanilide hydrochloride is added to the propylene glycol and the mixture is bubbled until the powder is fine and uniformly dispersed. Melt polyethylene glycol 4000 and slowly add the propylene glycol dispersion while stirring. Transfer this suspension to an uncooled mold at 40°C.
Enter it with The composition is allowed to cool and solidify, then removed from the mold and individually wrapped in suppository foil. Suppositories are used to relieve depression by inserting one suppository into the rectum four hours in advance. Example 26 Compositions are prepared in the same manner as in Examples 26 to 30 above, except that the active ingredient is replaced with equimolar amounts of each of the following compounds. N-[(2-dimethylamino-2-methyl)ethyl]-3', 4'-dichloropropionanilide;N-[(3-dimethylamino-2-methyl]propyl]-3',4'-dichloropropionAnilide;N-[(3-dimethylamino-2-methyl)propyl]-3',4'-dibromoacrylanilide;N-[(3-dimethylamino-1-methyl)propyl]-3',4'-Dibromoacrylanilide;N-[2-(dimethylamino)ethyl]-3'・4'-
Dibromopropionanilide;N-[3-(dimethylamino)propyl]-3'.
4'-dibromopropionanilide;N-[(2-dimethylamino-1-methyl)ethyl]-3',4'-dichloroacrylanilide; N-[(2-methylamino-2-methyl)ethyl]
-3′,4′-dichloroacrylanilide; and hydrochloride, hydrobromide, sulfate, tartrate, lactate, citrate, methanesulfonate, maleate, malate of each of the above bases Acid addition salts such as , sulfamates or similar salts.

Claims (1)

[Scope of Claims] 1 A compound represented by the formula or a pharmacologically acceptable acid addition salt thereof. (In the formula, A is -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄
-, -(CH ₂ ) ₅ -, [Formula] [Formula] and [Formula]; X represents chlorine or bromine; R represents ethyl or vinyl; ) 2 A compound according to claim 1 represented by formula A or a pharmacologically acceptable acid addition salt thereof. (In the formula, A is -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄
-, -(CH ₂ ) ₅ -, [Formula] [Formula] and [Formula]; X represents chlorine or bromine; ) 3 A compound according to claim 1 represented by formula B or a pharmacologically acceptable acid addition salt thereof. (In the formula, A' represents ethylene or trimethylene.) 4 A' is ethylene, so the compound is N-[2-(dimethylamino)ethyl]-3'・4'-
The compound according to claim 3, which is dichloropropionanilide. 5. The compound according to claim 4, which is a hydrochloride. 6 A' is trimethylene, so the compound is N-[3-(dimethylamino)propyl]-
The compound according to claim 3, which is 3',4'-dichloropropionanilide. 7. The compound according to claim 6, which is a hydrochloride. 8 A is a compound where A is [Formula] and X is chlorine, so the compound is N-[(2-dimethylamino-1-methyl)ethyl]-3'・4'-
The compound according to claim 2, which is dichloropropionanilide. 9. The compound according to claim 8, which is a hydrochloride. 10 A is [Formula] X is chlorine, so the compound is N-[(2-dimethylamino-2
-Methyl)ethyl]-3',4'-dichloropropionanilide. 11. The compound according to claim 10, which is a hydrochloride. 12 Claim 2, wherein A is [Formula] X is chlorine, and therefore the compound is N-[(3-dimethylamino-2-methyl)propyl]-3',4'-dichloropropionanilide Compounds described. 13. The compound according to claim 12, which is a hydrochloride. 14 Claim 2 in which A is tetramethylene, X is chlorine, and therefore the compound is N-(3',4'-dichlorophenyl)-N-(4-dimethylaminobutyl)propionamide. Compounds described in Section. 15. The compound according to claim 14, which is a hydrochloride. 16 Claim 2 in which A is pentamethylene, X is chlorine, and therefore the compound is N-(3',4'-dichlorophenyl)-N-(5-dimethylaminopentyl)propionamide. Compounds described in Section. 17. The compound according to claim 16, which is a hydrochloride. 18 Aniline of the following formula (wherein, X is chlorine or bromine) to a haloamino compound of the following formula (In the formula, Ao is −(CH ₂ ) ₂ −, −(CH ₂ ) ₃ −,
[Formula] is selected from the group consisting of [Formula] and [Formula], X' is chlorine, bromine or iodine), and the resulting diamine is treated with propionic anhydride or propionic acid chloride in the presence of a base. or bromide, or a compound of the following formula, characterized in that it is treated with an acylating agent selected from chloride or bromide of acrylic acid. (wherein Ao and X are the same as defined above, and R is ethyl or vinyl). 19. The method of claim 18, wherein the base used with the acylating agent is triethylamine. 20 Compound of the following formula (In the formula, Ao is −(CH ₂ ) ₂ −, −(CH ₂ ) ₃ −,
[Formula] [Formula] and [Formula] (where A compound of the following formula, characterized in that it is acylated with an acylating agent selected from the group consisting of bromides. (wherein Ao and X are the same as defined above, and R is ethyl or vinyl). 21 Aniline of the following formula (wherein X is chlorine or bromine) is a compound of the following formula (wherein n is 3 or 4 and X' represents chlorine, bromine or iodine) to obtain a compound of the following formula: (wherein X and n are as defined above) reducing a compound of this formula with a metal hydride to produce a compound of formula; (In the formula, Ao' represents -(CH ₂ ) ₄ - or -(CH ₂ ) ₅ -, and X is the same as defined above.) The compound of the formula is converted into propionic anhydride and propionic acid in the presence of a base. A compound of the following formula, characterized in that it is acylated with an acylating agent selected from the group consisting of the chloride or bromide of acrylic acid or the chloride or bromide of acrylic acid. (In the formula, Ao' and X are the same as defined above, and R
is ethyl or vinyl). 22 A compound of the following formula in a pharmacologically acceptable carrier and an antidepressant effective amount: (In the formula, A is -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄
-, -(CH ₂ ) ₅ -, [Formula] [Formula] and [Formula]; X represents chlorine or bromine; R represents ethyl or vinyl) or its pharmacologically acceptable An antidepressant pharmaceutical preparation containing an acid addition salt. 23 Compound of formula B (In the formula, A' represents ethylene or trimethylene)
or a pharmacologically acceptable acid addition salt thereof. 24 Claim 23 in dosage unit form
Pharmaceutical preparations as described in Section. 25. The preparation according to claim 23, wherein the active ingredient is N-[2-(dimethylamino)ethyl]-3',4'-dichloropropionanilide or a pharmacologically acceptable acid addition salt thereof. 26. The preparation according to claim 23, wherein the active ingredient is N-[3-(dimethylamino)propyl]-3',4'-dichloropropionanilide or a pharmacologically acceptable acid addition salt thereof.