JPS6146471B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to aminoalicyclic amides that have medicinal effects in the central nervous system. More particularly, the present invention provides cis and/or trans N-(2-aminocycloheptyl)-N-alkanoylanilide compounds or pharmaceutically suitable salts thereof, which compounds have high central nervous system (CNS) Found to have antidepressant effects. Thus, these compounds, when formulated into useful pharmaceutical compositions and administered in appropriate dosages and modes of administration, are useful as antidepressants.

WGStoll etc. are Helvetica Chemica Acta,
Vol.34, (1951), pp1937-1943 N-[2
-dimethylamino)cyclohexyl]aniline and its N-(2-hydroxycyclohexyl)
Although it discloses a process for its preparation from aniline and suggests that this compound has antihistamine action, it does not say anything about the compound of the invention or its use as an antidepressant.

JW Lewis et al. “The Reactions of Aromatic
Nitroso−compounds With Enamines.Part.
The Reaction of Nitrosobenzene With 1−
morpholin-1-cyclohe-Xene” (J.Chem.Soc. (London) (1972), Perkins
Transactions I, Part, pp2521-2524) discloses N-(2-morpholin-1-ylcyclohexyl)phenylhydroxylamine and its hydrochloric acid addition salt, and the alkanoylanilide of the present invention or its properties as an antidepressant. Nothing is disclosed or suggested.

JW Lewis et al. “Chemistry and Biological
Activity of N-Substituted Hydroxylamines”
Paper entitled (J.Pharmaceutical Sciences,
December, 1974, Vol.63, No.12, pp.1951−
(1953) disclosed some N-arylhydroxylamines such as N-[2-(N-pyrrolidinyl)cyclohexyl]-N-phenylhydroxylamine, but these compounds had useful CNS properties. do not. In this paper, [2-(N
The diuretic effect of alcohols such as -pyrrolidinyl)cyclohexyl]-(4-methoxyphenyl)methanol has been discussed, and it is said that acetylation of this alcohol causes a CNS depressant effect. This paper also describes propionyl chloride and N-[2-(N-piperidinyl)-1.1-
dimethylethyl]-N-phenylhydroxylamine to produce an N-chloro compound,
It is also disclosed that this is then converted into a mixture of chlorinated aniline derivatives. However, this article does not teach either the compounds disclosed herein, their method of preparation, or their anti-inhibitory effects.

U.S. Pat. No. 3,510,492 to Szmuszkoricz discloses and claims several 2-anilino- and 2-anilinomethylcycloalkylamines useful as antidiabetic agents when administered in low doses to lower blood sugar. There is. The structural formulas described in column 2 of this patent generally suggest some of the compounds of the formulas of the pharmaceutical formulations and methods of use of this invention as intermediates in the reaction with 2-anilinocycloalkylamine as the final product. ing. However, it does not disclose the actual utility of the final product from the structure and the compounds claimed herein.

The object of this invention is to identify some novel N-
(2-Aminocycloheptyl)alkanoylanilide.

Other objects, aspects, and advantages of the invention will be apparent from the following description and claims.

In summary, this invention describes several cis and trans N-(2-
Pharmaceutical formulations of aminocycloheptyl)-N-alkanoylanilide and pharmaceutically suitable salts thereof are provided: [wherein the wavy line at the 1-position of the cycloheptyl ring represents the cis and trans configuration with respect to the substituents at the 1- and 2-positions of the cycloheptyl ring; R, R ₁ and
R ₂ is each C ₁ to C ₃ -alkyl; Y and Z are each halogen with atomic number 9 to 35 and are present in the 3 and 4 positions or in the 3 and 5 positions. ] Compounds suitable for this use are trans-
3,4-dichloro-N-[2-(dimethylamino)
cycloheptyl]propionanilide. The present invention encompasses these compounds (), which are novel in themselves, and their acid addition salts, especially their pharmaceutically suitable salts. These compounds are useful in suitable pharmaceutical dosage unit form for administration to humans at doses of 4 to 400 mg per day as part of the treatment of depressive conditions. In the standard laboratory animals used to measure these properties, these compounds exhibit rapid antidepressant activity, and the preferred compounds also exhibit antidepressant activity in standard laboratory tests. It is less toxic than the depressant imipramine and has a longer duration of activity in experimental animals.
Because these compounds have the above-mentioned properties, they may be administered in small doses and/or with long intervals (e.g., once a day) to obtain the desired antidepressant response.
It would be useful to administer

Sometimes, the above-mentioned compound or acid addition salt thereof in crystalline state is isolated as a solvate, ie, physically associated with a discrete amount of a solvent, such as water, ethanol, and the like. Since the solvent can be removed without appreciably changing the chemical properties, these solvates are included in the compounds of this invention.

In the compounds of the above formula, C1- _C3 -alkyl means methyl, ethyl, n-propyl and isopropyl; halogen _with an atomic number of 9 to 35 means fluorine, chlorine and bromine.

Preferred compounds of this invention are of the trans configuration.

A preferred group of the above compounds are those in which R is ethyl.

Examples of acid addition salts, including pharmaceutically suitable salts of the above formulas, are hydrochloric acid, methanesulfonic acid, pamoic acid, hydrochloric acid, sulfuric acid, acetic acid, cyclohexane sulfamic acid, p-toluenesulfonic acid, succinic acid,
Salts of β-naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, lactic acid and oxalic acid.

The use of these new compounds in pharmaceutical antidepressant formulations is to incorporate them into conventional pharmaceutical compositions such as tablets, powders, capsules and solutions or suspensions in suitable solvents or suspension vehicles. Oral dosage forms, and parenteral dosage forms such as dry powders in sterile sealed containers, which should be mixed with a sterile solvent immediately prior to administration, and sterile solutions or suspensions in water or other suitable solvents or suspending agents. When formulated or formulated, they can be combined with a pharmaceutical carrier to provide a convenient means for administering to a patient an amount effective to alleviate depression. Generally, the daily dosage of a compound of formula or a pharmaceutically suitable salt thereof will be from about 4 mg to about 400 mg, preferably from 50 to 200 mg, the amount being administered depending on the potency of the compound of formula, the condition being treated and the weight of the patient. and other factors related to the patient's physician.

The compound of the formula is (a) the compound of the following formula (wherein R ₁ , R ₂ , Y and Z are as defined above) and a mixture of anhydrides of the appropriate organic carboxylic acids of the formula R-COOH on a steam bath or at an equivalent temperature for a sufficient period of time. (b) an excess of aqueous medium sufficient to decompose the anhydride to form an N-acylated product of formula (where R is as defined above and Q is oxygen); In addition to the reaction mixture of (a), (c)
(d) adding a sufficient amount of alkali metal hydroxide or its equivalent to neutralize the excess acid present in the reaction mixture of (b) and render the mixture basic; () is extracted with a water-immiscible organic liquid solvent such as diethyl ester, an ethereal solvent such as tetrahydrofuran (THF) or dioxane, or chloroform, carbon tetrachloride, methylene chloride, ethylene dichloride, etc., and (e) N- The organic liquid phase containing the acylated product () is separated from the aqueous phase, and (f) the organic liquid phase is usually washed one or more times with sodium chloride solution, sodium bicarbonate solution or water to remove the soluble compounds in these aqueous media. The corresponding N-acylated compound ( ) from the organic liquid phase. Further purification can be achieved by forming the acid salt of this N-acylated amide product ( ) and then recrystallizing the amide salt from a suitable solvent or solvent mixture.

Compounds of these formulas are prepared by adding (a) a solution of a suitable carboxylic acid halide R-C(O)-X, where R is as defined above and X is chlorine or bromine, to a diamine (). and a tertiary amine, the tertiary amine forming a tertiary amine hydrochloride or bromo salt in the mixture, such as a C ₁ to C ₄ -trialkylamine, such as trimethylamine, Triethylamine, tributylamine, or pyridine, lutidine, N/N
- Dimethylaniline, etc., is added to a cooled mixture (-5° to +10°C) of an organic liquid solvent for the mixture, such as diethyl ether,
In an ethereal solvent such as THF, dioxane, etc., the mixture is added with stirring until the corresponding N-acylated compound () is formed; (b) an aqueous alkali metal bicarbonate solution is added to the reaction mixture of (a) above; , (c) separating the aqueous phase from the organic liquid phase, (d) washing the organic liquid phase with an aqueous washing liquid as described above, (e) drying the organic phase, and (f) the resulting organic liquid mixture. It can also be produced by recovering the N-acylated compound () from. The N-acylated amide compound () can be further purified by formation of an acid addition salt, such as a hydrochloric acid addition salt or a maleic acid addition salt, and recrystallization of the amide salt from a suitable solvent or solvent mixture.

A trans-diamine starting compound () of the formula (In the formula, R ₁ , R ₂ , Y and Z are as defined above.) is 1,2-cycloheptenoxide (
a) is reacted with selected HNR ₁ R ₂ in water to produce trans-2-aminocyclopentanol of formula b, The amino-alcohol (b) is treated with sodium hydride and then with methanesulfonyl chloride to produce the recovered mesylate of the formula, (In the formula, Ms represents a CH ₃ SO ₂ − group.) This reaction mixture was mixed with a selected substituted aniline of the formula It can be produced by treating with diamine () to produce diamine (). An example of this method will be described later.

Examples of carboxylic anhydrides that can be used to prepare the compounds of this invention are acetic anhydride, propionic anhydride, isobutyric anhydride, n-butyric anhydride, cyclopropanecarboxylic anhydride, acrylic anhydride, and the like. The preferred anhydride is propionic anhydride. Examples of carboxylic acid halides are acetic acid chloride or bromide, propionic acid chloride or bromide, acrylic acid chloride or bromide, cyclohexanecarbonyl chloride or bromide, n- and isobutyric acid chloride or bromide, cyclopropane carbonyl chloride or bromide, ethyl formate, methoxyacetic acid Such as chloride or bromide. Generally, the most potent antidepressant compounds are prepared from compounds with an N-propionyl moiety, so it is preferred that R is ethyl in compounds of formula.

Preparation of cisaminoamide compounds of the invention: JW Lewis et al., J.Pharm.Sci., 63, 1951 using 1-dialkylaminocyclopentenes (enamines) and nitrosoaryls as starting compounds.
(1974) to the corresponding cycloheptenenamine to give cis-1,2-diaminocycloheptane, followed by reaction with carboxylic acid anhydride or carboxylic acid halide as described above to give the amino-amide product. Obtainable.

A preferred method for use in this invention is to react cycloheptenoxide with aniline in the presence of a strong acid to obtain a compound of formula: This is subsequently reacted with a carboxylic anhydride and then with a base to isolate a compound of formula:

Oxidation of this alcohol results in a compound of formula XI, Reaction of this with a primary or secondary amine and a reducing agent such as sodium cyanoborohydride gives the compound of formula:

(In the formula, R ₂ is not C ₃ -C ₆ (allyl position) alkenyl.) The cis and trans mixture of the resulting compound was physically separated by column chromatography on silica gel to obtain the cis isomer of the following formula: Can be isolated.

(wherein R, R ₁ , R ₂ , Y and Z are as defined above.) If desired, compounds of the formula of this invention can be resolved into d- and l-enantiomers, respectively, by known methods. . In this case, the optical splitting is performed by at least two separate experiments. The resolving agent by way of route is also optically active camphorsulfonic acid, bis-
Resolution of commercially available amines (bases) such as p-toluoyltartaric acid, tartaric acid and diacetyltartaric acid (e.g. Organic Syntheses, Coll. V., p. 392 (1973))
Any known resolving agent commonly used for (resolution of R-(+) and S-(-)-α-phenylethylamine with (+)-tartaric acid) may be used.

By a first method of resolving compounds of this invention, for example, one of the aminoamide compounds is reacted with an optically active acid (such as those described above) to determine its optical activity by reacting with standard methods in the isomer resolution art. Can be converted into diastereomeric salts.
These diastereomeric salts can then be separated by conventional methods such as fractional crystallization. Diastereomeric salts have different crystalline properties, which is advantageous for this separation. Neutralization of each diastereomeric salt with aqueous base can yield the corresponding optically active isomer of the free aminoamide, which can then be separately converted to the desired acid addition salt as described above.

The second method is preferred for some compounds of this invention, according to which the cis- or trans-1,2-alicyclic asymmetrically substituted diamines are treated with a resolving agent, crystallized, separated, and Resolving each resolved diamine starting compound into its d- and l-isomers by regeneration of trans-d-diamine, trans-l-diamine, or cis-d-diamine and cis-l-diamine, respectively; cis- or trans-d- or l by reaction with the desired carboxylic acid anhydride or halide.
- Compounds of the formula can be made into the respective d- and l-isomers by forming the compounds, which can then be converted into the desired pharmaceutically suitable acid addition salts by the methods described above.

If the acid addition salt used to extract the compound of formula from the reaction mixture is not pharmaceutically suitable, the free aminoamide base () is prepared from the acid addition salt and then converted to the pharmaceutically suitable salt by known methods. Can be converted.

For use of a compound of the formula as an antidepressant, a selected compound of the formula (antidepressant active ingredient) is mixed with a suitable pharmaceutical diluent to form a pharmaceutical composition suitable for oral, parenteral and rectal administration. Dosage unit forms such as tablets, powder sachets, capsules, dragees, capsules, solutions, suspensions, sterile injections, suppositories, bougies, etc. are obtained. Suitable diluents or carriers, such as carbohydrates (lactose), proteins, lipids, calcium phosphate, corn starch, stearic acid, methylcellulose, etc., can be used for carrier or coating purposes. Solutions or suspensions of the active agent can be prepared using water and oils, such as coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil. Sweetening, coloring and flavoring agents can also be added. The efficacy of dosage unit forms for compounds of these formulas will vary from compound to compound and will depend on the physical properties of the compound of formulas or its pharmaceutically suitable salt, the weight and age of the individual patient, and the particular effect desired. Dependent.
Pharmaceutical dosage unit forms of these compounds are prepared as described above, each containing from about 4 to 400 mg of a compound of formula or a pharmaceutically suitable salt thereof. The amount of the compound of formula in a pharmaceutical dosage unit form is sufficient to reduce depression in the patient and is at a non-toxic dosage level.

The detailed processes and examples below further illustrate the preparation and use of the starting amine and target compounds of this invention. All temperatures in the examples are in degrees Celsius unless otherwise specified. Abbreviation
THF is tetrahydrofuran; NMR is nuclear magnetic resonance spectrum; IR is infrared spectrum; UV is ultraviolet spectrum; ether is diethyl ether;
NaOH represents sodium hydroxide; MgSO ₄ represents anhydrous magnesium sulfate; MeOH represents methanol.

Example 1 Trans-3,4-dichloro-N-[2-(dimethylamino)cycloheptyl]propionanilide and its maleate salt A Trans-2-dimethylaminocycloheptanol and its fumarate salt Cycloheptene oxide 89.09 g (0.80 mol) and 40% dimethylamine (275 ml, 2.4 mol)
The mixture was shaken for 24 hours at about 125° C. in a rocking pressure bomb. A brown solution was obtained. The reaction mixture was then saturated with about 50 g of potassium carbonate, forming two layers. 1 ml of 40% aqueous potassium hydroxide solution was added, the resulting mixture was extracted three times with ether, the ether layer was kept intact, dried over anhydrous magnesium sulfate, and then concentrated by evaporating the ether. Distill the residue to a boiling point of 98
゜~100゜/10mm Title Amino Alcohol 114.6
g (yield 91%) was obtained. NMR, IR and mass spectra were consistent with its manufacturing formula.

Crystals of the fumarate salt of the title amino alcohol were prepared and recrystallized from a mixture of methanol and ether to a melting point of 136°-137°C.

Elemental analysis value: C ₉ H ₁₉ NO (amino alcohol)
As: Calculated value: C, 68.74; H, 12.18; N, 8.91 Actual value: C, 68.48; H, 12.39; N, 8.53 B trans-N-[2-(dimethylamino)cycloheptyl]-3,4- Dichloroaniline and its oxalate salt 4.8 with 2-dimethylaminocycloheptan-1-ol (15.7 g, 0.10 mol) in 50 ml THF
A mixture of g (0.10 mol) of sodium hydride (50% dispersion) was heated on a steam bath for 1 hour and then cooled on ice. Methanesulfonyl chloride (11.5 g, 0.10 mol) in 25 ml THF was added over 30 minutes. Then 3,4-dichloroaniline (32.4 g, 0.20 mole) was added in one portion. this
The THF solvent was evaporated and the mixture was continued to be heated on a steam bath overnight. 200 ml of 20% aqueous sodium hydroxide solution was added and heating continued for 1 hour. This reaction mixture was extracted with 10% aqueous hydrochloric acid. The aqueous acid layer was washed with ether, basified with 40% aqueous sodium hydroxide and extracted with 250 ml of ether. The ether layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the ether was distilled off. The remaining oil is distilled to the boiling point.
17.3 g (57% yield) of the title amine of 170°-180°/0.3 mm were obtained.

The oxalate salt of the title amine is prepared from 5.2 g (0.057 mol) oxalic acid and the diamine prepared above in 25 ml.
of methanol and 200 ml of ether. 15.5 g of the oxalate salt of the title diamine, recrystallized from the same solvent mixture, melting point 153-154°C.
(yield 69%). NMR, IR, UV and mass spectra were consistent with the structural formula.

Elemental analysis value: C ₁₅ H ₂₂ N ₂ Cl ₂・C ₂ H ₂ O ₄ Calculated value:
C, 52.15; H, 6.18; N, 7.16; Cl, 18.12 Actual value:
C, 52.25; H, 6.34; N, 6.98; Cl, 18.23 C trans-3,4-dichloro-N-[2-(dimethylamino)cycloheptyl]propionanilide and maleate salt Trans-N- in 100 ml of ether [2-(dimethylamino)cycloheptyl]-3,4-dichloroaniline (3.01 g, 0.01 mol) and
To an ice-cold solution of 2.02 g (0.02 mole) triethylamine was added 1.85 g (0.02 mole) propionyl chloride over 30 minutes. The reaction mixture was stirred at room temperature overnight. Then 100 ml of saturated aqueous sodium bicarbonate solution was added. The organic layer was washed with water, then saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated to a yellow oily residue of the title propionanilide. This oil was mixed with methanol (10ml) and ether (75ml).
ml) of maleic acid (11.6 g,
0.01 mol) was added. A crystalline precipitate formed which was recrystallized from the same solvent mixture as above to give 3.90
g title aminoanilide maleate (melting point
165° to 166°C, yield 82%). NMR,
IR, UV and mass spectra were consistent with the structural formula.

Elemental analysis value: C ₁₈ H ₂₈ N ₂ Cl ₂ O・C ₄ H ₄ O ₄ Calculated value:
C, 55.81; H, 6.39; N, 5.92; Cl, 14.98 Actual value:
C, 56.05; H, 6.46; N, 6.07; Cl, 15.16 For oral administration, either solid or liquid unit dosage forms are prepared. When producing solid compositions such as tablets, the compound of formula (1) may be added to talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, gum arabic,
It is mixed with conventional ingredients such as methylcellulose and similar materials that function as diluents or carriers for formulations. Wafers are manufactured similarly to tablets. They differ from tablets only in their shape and in the content of sucrose or other sweetening agents and flavorings. In one of these most simple embodiments, capsules, like tablets, are prepared by mixing the compound with an inert pharmaceutical diluent and filling the compound into a suitably sized hard gelatin capsule. Soft gelatin capsules are made by mechanically encapsulating a slurry of the compound and a suitable vegetable oil, light liquid paraffin, or other inert oil.

Liquid unit dosage forms for oral administration such as syrups, elixirs, and suspensions are prepared. A syrup can be prepared by dissolving the aqueous dosage form in an aqueous medium along with sugar, aromatic flavors and preservatives.
Elixirs are prepared by using an alcoholic (ethanol) solvent with a suitable sweetening agent such as sugar or saccharin, and aromatic flavoring agents.

Suspensions are prepared from water as a solvent along with suspending agents such as gum arabic, tragacanth, methylcellulose and the like.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle, water being preferred. Depending on the solvent and concentration used, the compound can be suspended or dissolved in the solvent. To prepare solutions, the compound is dissolved in Water for Injection, filled into suitable vials or ampoules, and sterilized before sealing.

Adjuvants such as local anesthetics, preservatives, and buffering agents are preferably dissolved in the vehicle. To increase stability, the composition can be frozen and vacuum applied to remove water after filling the vial. The lyophilized dry powder is then filled into vials and combined with a vial of water for injection for reconstitution into liquid form before use.

Parenteral suspensions are prepared in essentially the same manner, except that the compound is suspended in a solvent instead of being dissolved, and sterilization cannot be accomplished by accident. The compound is sterilized by exposure to ethylene oxide prior to suspension in a sterile solvent.

Preferably, a surfactant or wetting agent is included in the composition to promote uniform distribution of the compound.

As used herein, "rectal suppository" means a solid object that is inserted into the rectum. It melts or softens at body temperature and releases one or more pharmacologically or therapeutically active ingredients.

Pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and agents that increase the melting point.

Examples of bases or vehicles are, for example, cocoa milk fat (theobroma oil), glycerin-gelatin, carbo wax (polyoxyethylene glycol).
and suitable mixtures of mono-, di- and triglycerides of fatty acids. Combinations of various bases can also be used. Agents that increase the melting point of suppositories are, for example, spermaceti and waxes. Rectal suppositories can be manufactured either by compression or molding methods. The usual weight of rectal suppositories is 2.0 g.

Tablets and capsules for rectal administration are manufactured utilizing the same pharmaceutically acceptable materials and the same methods as formulations for oral administration.

Rectal suppositories, tablets or capsules may each be given in unit doses or in multiple doses, e.g.
Packaged in 6 or 12 pieces.

As used throughout this document, the term "unit dosage form" refers to physically discrete units suitable for single administration to humans and animals, each unit containing the necessary pharmaceutical diluent, carrier, or vehicle. They contain a predetermined amount of active substance calculated to produce the desired therapeutic effect. The description of the novel unit dosage form of the present invention is based on (a) the unique properties of the active substances and the particular effects achieved and (b) the nature of such use in humans and animals as detailed in this description. This is explained by and directly depends on the inherent limitations in the technology for the production of active substances. These two are aspects of the present invention. Examples of suitable unit dosage forms according to the invention are tablets, capsules, granules, suppositories, powder sachets, wafers, pills, casiers, teaspoonfuls,
Tablespoons, drops, ampoules, vials, separate combinations of the foregoing, and other dosage forms mentioned herein.

The amount of compound administered for treatment depends on the route of administration, age, weight and condition of the patient. The dosage schedule is about 4 to about 400 mg per day, preferably about 50 to about 200 mg, either all at once or divided into several doses. This dosage encompasses the effective dosage range for alleviating the depression for which the present composition is effective. The amount to be administered is about 0.08 to about 6 per kg of patient's body weight.
Calculated based on mg criteria. The compounds of the present invention are formulated with suitable pharmaceutical carriers into unit dosage forms that are convenient and effective for administration. In preferred experimental embodiments of the invention, unit dosages can contain amounts of 5, 10, 25, 30, 50, 100 and 200 mg of compound for systematic treatment. Sterile formulations of active ingredient contain 1% to 25% W/V for parenteral therapy. Dosages of compositions containing a compound of formula and one or more other active ingredients must be determined with respect to the actual dosage of each active ingredient.

In addition to administering a compound of formula 1 as the primary active ingredient in a composition for treating desired conditions as described herein, said compound may also be used in combination with other compounds such as aspirin, acetaminophen, PAC
(phenacetin-aspirin-caffeine) compounds, anti-inflammatory agents such as ibuprofen, perphenazine, amitriptylene hydrochloride,
It can be combined with anxiolytics such as chlordiazepoxide, alfrazolam, doxepin hydrochloride, etc.

Reference example 1 Trans-3,4-dichloro- as an active ingredient
10,000 tablets each containing 40 mg of N-[2-(dimethylamino)cycloheptyl]propionanilide were manufactured based on the following ingredient amounts.

Ingredient blending amount (g) Active ingredient compound 400 Dicalcium phosphate 1500 Methyl cellulose (15 cps. US Pharmacopeia) 60 Talc 150 Corn starch 200 Magnesium stearate 12 The active ingredient compound and dicalcium phosphate were thoroughly mixed. It was granulated with a 7.5% aqueous solution of methylcellulose, sieved through a No. 8 sieve, and carefully dried. The dried granules were sieved through a No. 12 sieve, thoroughly mixed with talc, starch, and magnesium stearate, and compressed into tablets.

The tablets thus obtained are effective in relieving depression in adults at a dosage of 1 to 2 tablets per day, depending on the age and weight of the patient.

Reference Example 2 Oral soft gelatin capsules each containing 20 mg of 3,4-dichloro-N-[2-(dimethylamino)cycloheptyl]propionanilide methanesulfonate were produced. The finely ground compound was first dispersed in corn oil to enable encapsulation of the active ingredient and then encapsulated in conventional manner. This capsule is effective in treating depression at a dosage of 1 to 2 capsules per day.

Reference Example 3 1000 tablets each containing 60 mg of 3,4-dichloro-N-[2-(N-pyrrolidinyl)cycloheptyl]propionanilide salt were manufactured from the following ingredients and blending amounts.

Ingredient content (g) 3,4-dichloro-N-[2-(N-pyrrolidinyl)cycloheptyl]propionanilide
60 Lactose 355 Microcrystalline cellulose (NF) 120 Starch 16 Magnesium stearate powder 4 All ingredients were sieved, mixed, and compressed into tablets. These tablets were effective in relieving depression.

Claims (1)

[Claims] 1 formula [wherein the wavy line at the 1-position of the cycloheptyl ring represents the cis and trans configuration with respect to the substituents at the 1- and 2-positions of the cycloheptyl ring; R, R ₁ and
R ₂ is each C ₁ to C ₃ -alkyl; Y and Z are each halogen with atomic number 9 to 35 and are present in the 3 and 4 positions or in the 3 and 5 positions. ] or its acid addition salt. 2. The compound according to claim 1, which is in the trans configuration. 3. The compound according to claim 1, which is in the cis configuration.