MXPA97008031A - Salts of 3-phenyl-1,4-dialkyl-1,2,4-triazolio and its use as antidepresi - Google Patents

Abstract

This invention relates to the treatment of depression by the administration of novel salts of 3- (Rn-phenyl) -1,4-dialkyl-1,2,4-triazolium of the formula (I), wherein R is halogen, trifluoromethyl lower alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, n is zero, 1 to 2, and R 1 and R 4 independently represent lower alkyl of 1 to 3 carbon atoms, and A represents a pharmaceutically acceptable anion

Description

SALTS OF 3-FENIL-1.4-DIALOUIL-l, 2.4-TRIAZOLIO AND ITS USE AS ANTIDEPRESSANTS This invention relates to novel 3-phenyl-1,4-dialkyl-1,2,4-triazolium salts and their use as antidepressants. In a more specific manner, this invention relates to novel triazolium salts of the formula I, and to their use as pharmaceutical agents for the treatment of depression. wherein: represents halogen, trifluoromethyl, lower alkyl of 1 to 4 carbon atoms and lower alkoxy of 1 to 4 carbon atoms; n represents 0, 1, or 2; ? and R 4 independently represent lower alkyl of 1 to 3 carbon atoms; and A ~ represents a pharmaceutically acceptable anion.

ANTECEDENTS OF L? INVENTION In the prior art it has been reported that 3- and 5-aryltriazole derivatives have a wide variety of pharmacological activities. For example, it is known that 5-aryl-2,4-dialkyl-3H-1,2,4-triazole-3-thiones have activity against depression, as claimed in the Patents of the United States of North America. US 4,775,688, and US 4,775,689, against thrombocytosis, as claimed in U.S. Patent No. US 4,847,276, against the symptoms of Wernicke-Korsakoff syndrome, as claimed in the U.S. Patent Number US 5,100,906, against Alzheimer's disease, as claimed in U.S. Patent Number US 5,236,942, and for improving memory and knowledge, as claimed in U.S. Patent Number US 5,331,002. The use of 5-phenyl-1,2,4-triazole-3-thione as an antisecretory agent is disclosed in U.S. Patent No. US 4,230,715. It is known that 5-aryl-1,2,4-triazol-3-one derivatives have activity against attack disorders, as claimed in US Pat. Nos. 4,966,909, and 4,946,856, and Neurodegeneration treatment due to embolism, as claimed in the pending United States Patent Application Serial Number 494,049. The 3-phenyl-3-thioalkyl, thioalkenyl, alkoxy, and hydroxy-triazole derivatives are described as anticoccidial agents in Japanese Patent Number Kokai 50-63119. It is known that the 3-aryl-5-thioalkyl, alkylsulfinyl-, and alkylsulfonyl-4H-1,2,4-triazole derivatives have activity against convulsive attacks, as claimed in the U.S. Patent Number US 5,143,933, against anxiety, as claimed in United States Patent Number US 4,981,863, against muscular spasms and muscle tension, as claimed in United States Patent Number US 4,900,743, and against hyperreflexia due to spinal trauma, as claimed in United States Patent Number US 5,158,968. Mhasalkar et al. (J. Med. Chem 14 (3), 260-262 (1971)) evaluated a series of 3-phenyltriazoles for hypoglycemic activity, and noted that the level of activity varied substantially when the substituents were changed over the positions 4 and 5 of the triazole ring and on the benzene ring. In contrast, it is not reported that the 3-aryltriazolium salts known in the prior art have a beneficial pharmacological activity. For example, triazolium dyes are disclosed in the German Patent Number Offenegung 3,314,659, assigned to VEB Filfabrik olfen, and in an article by Alberti (Ann Chim. (Rome) (1975), 65 (5-6), 305-14 ). French Patent Number 1,481,761, assigned to Badische Anilin, discloses triazolium salts useful as plant protection agents. United States Patent Number US 4,414,221, assigned to FBC Ltd., includes triazolium salts in a genus of o-halophenyl substituted N-heterocyclic compounds useful as pesticides against mites and insects.

Detailed Description of the Invention It has been found that the 3-phenyltriazolium salts of the formula I display activity as antidepressants without showing other characteristic activities of the known 3- or 5-aryltriazole derivatives. The 3- (3-fluorophenyl) -1,4-dimethyl-1,2,4-triazolium ion has been identified in the urine of test animals as a metabolite of 5- (3-fluorophenyl) -2, 4- dimethyl-3H-l, 2,4-triazole-3-thione, a compound known to have antidepressant activity, as well as activity in tests that indicate protection from neurodegeneration that results in the symptoms of Wernicke-Korsakoff syndrome and of Alzheimer's disease. However, it has been discovered in pharmacological tests, that a salt of 3- (3-fluorophenyl) -1,4-triazolium shows a selective activity against depression without a concomitant activity against neurodegeneration, or test activity for other effects Pharmacological effects of related triazole derivatives. In formula I, the phenyl moiety can be a fraction of unsubstituted or mono-substituted phenyl, where n is 1, with the substituent group R located at any of the ortho, meta, or para positions, or a moiety of disubstituted phenyl wherein n is 2, and the substituent groups may be the same or different, and may be attached at any of positions 2,3; 2.4; 2.5; 2.6; 3,4; and 3.5. As used herein, halogen represents chloro, fluoro, bromo, or iodo. When the phenyl ring is substituted by alkyl of 1 to 4 carbon atoms or by alkoxy of 1 to 4 carbon atoms, the alkyl fraction can be straight or branched. When the phenyl ring is substituted, the substituent group is preferably halogen, with more fluorine being preferred. Preferably, R1 and R4 represent methyl, but can independently represent any straight or branched alkyl group of 1 to 3 carbon atoms. For convenience, formula I has been plotted herein with the positive charge on the nitrogen atom at position 1 of the triazole ring. However, it is well known that, in a ring system such as the 1,4-dialkyl-1,2,4-triazolium system of the formula I, the positive charge is not located at a particular nitrogen atom, but rather that is dispersed over the conjugate ring system. Formula I should not be construed as limited to compounds charged to the nitrogen atom 1. Instead, formula I covers all compounds having the defined skeleton and substituent groups, and having a positive charge, either the charge is located on one of the nitrogen or carbon atoms of the ring skeleton, or is delocalized around the ring system. The antidepressant properties of the claimed compounds and their relative potencies can be easily determined using conventional laboratory methodology. When compared with other agents clinically known as useful as antidepressants, ordinary practitioners in this field can easily assert the dosage regimen. For example, antidepressant activity is indicated by the test test for the prevention of reserpine-induced ptosis in mice. In this test, individual heavy mouse test groups are housed in wire mesh cages, and the test compound or vehicle is administered. At a later selected time, reserpine is administered as a solution of 0.2 milligram / milliliter in dilute acetic acid, in a dose of 2 milligrams / kilogram intravenously in a vein of the tail. In each test, the animals are examined individually in a Plexiglas® cylinder 90 minutes later. The prevention or delay in ptosis is considered significant if the closing of both eyes on average is less than 50 percent after observing for 30 seconds. The ED50 for the prevention of ptosis is defined as the dose of the test compound that significantly prevents ptosis in 50% of the test animals. In these tests, the imipramine has an ED50 of 4.89 milligrams / kilogram (using a pre-treatment time of 60 minutes), while the hydrosulfate of 3- (4-chlorophenyl) -1,4-dimethyl-1,2,4-triazolium, the most active compound of formula I tested, has an ED50 of 0.09 milligrams / kilogram under the same conditions. Another test used to evaluate antidepressant activity is the test for antagonism for hypothermia induced by RO 4-1284 *. (* Niemegeers, Carlos, J.E. "Antagonism of Reserpine - Like Activity", edited by S. Fielding and Lal, published by Futura, pages 73-98). In this test, groups of male mice are weighted and individually housed in wire mesh cages. The rectal temperature of each mouse is recorded, and then the test compound or the vehicle is administered, at a selected time later, Ro 4-1284, prepared as a 2 mg / milliliter solution in distilled water, is administered in a dose of 20 milligrams / kilogram intraperitoneally. The mice are then placed in a cold room (2.2 ° C) for 30 minutes, and then returned to room temperature for 30 minutes. At this time (60 minutes after the administration of Ro 4-1284) the rectal temperature of each mouse is recorded again. Under these conditions, Ro 4-1284 causes a drop in rectal temperature from 10 ° C to 12 ° C. The final temperatures of the control groups of 10 mice treated with Ro 4-1284 from a number of experiments, combine to form a "historical control" of 100 mice. This control is periodically updated by replacing the oldest data. Any animal treated with a drug that has a final temperature (after Ro 4-1284) that is greater than the average + 2 S.D. of the historical control of Ro 4-1284, it is considered to exhibit a significant antagonism to the hypothermic effect of Ro 4-1284. The ED50 for antagonism is defined as the dose of the test compound that significantly antagonizes hypothermia with Ro 4-1284 in 50 percent of the test animals. Using a pre-treatment time of 60 minutes, and these criteria for the evaluation of the effects, it was discovered that desipramine has an ED50 of 0.1 milligrams / kilogram intraperitoneally; imipramine, an ED50 of 1.8 milligrams / kilogram intraperitoneally; the catrón, an ED50 of 0.7 milligrams / kilogram intraperitoneally; and 3- (3-chlorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate, the active co-testosterone of formula I tested, an ED 50 of 0.34 milligrams / kilogram intraperitoneally. The results of testing a number of compounds of formula I for the effects summarized above, as well as their LD 50, are summarized in Table I.

Two determinations were made, and listed separately.

In common with other compounds showing activity in the above assays, the compounds of this invention have pharmacological effects generally attributed to antidepressants, and therefore, the compounds of this invention elevate the mood of the patients eiferating from depreetion, and consequently, it will have an end-use application for the treatment of patients suffering from endogenous depression, a term used interchangeably with psychotic or involutional depression. In this use, the compound (I) will exercise a relatively fast action establishment, and will have a prolonged duration of activity. In general, the compounds are expected to exert their antidepreematory effect at a dose level of approximately 0.25 to 25 milligrams / kilogram of body weight per day, although, for example, the degree of disease severity, the age of the patient, and other factors determined by the diagnosing that aeieta, will influence the exact course and the appropriate dosage regimen for each patient. In general, the doses parenterally administered are approximately 1/4 to 1/2 that of the dose orally administered. For oral administration, compounds can be formulated into solid or liquid preparations, such as capsules, pills, tablets, troches, powders, solutions, euepeneionee or emulsions. The solid unit dosage forms may be a capsule, which may be of the ordinary gelatin type containing, for example, lubricant and an inert filler, such as lactose, sucrose, or corn starch. In another embodiment, the compounds of the general formula I can be formed into tablets with conventional tablet bases such as lactose, sucrose, and corn starch, in combination with binders, taille as acacia, corn starch, or gelatin, disintegrating agents. such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. For parenteral administration, the compounds can be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier, which can be a sterile liquid such as water, alcohols, oils, and other acceptable organic solvents. , with or without the addition of a pharmaceutically acceptable surfactant or other auxiliaries. The illustrative oils that can be used in eetae are petroleum, animal, vegetale, or synthetic origin preparations, for example, peanut oil, soy bean oil, and mineral oil. In general, preferred liquid carriers are water, serum, aqueous dextrose and related sugar solvents, ethanol and glycols such as propylene glycol or polyethylene glycol, or 2-pyrrolidone, particularly for injectable solutions. The compounds can be administered in the form of a depot injection or an implant preparation, which can be formulated in such a way as to allow a sustained release of the active ingredient. The active ingredient can be compressed into granules or small cylinders, and can be implanted subcutaneously or intramuscularly as depot injections or implants. The implants may employ an inert material, such as biodegradable polymers or silicone eintéticae, for example Silastic®, a silicone rubber manufactured by the Dow-Corning Corporation. As is true in many classes of compounds generally suitable for any particular pharmacological activity having a therapeutic end use application, certain subgeneric groups and certain specific members of the class are preferred, because of their overall therapeutic index and their biochemical and pharmacological profile. In this case, the preferred compounds are those where the group R is located? and R4 are methyl, and esae wherein the R substituent is fluorine or chlorine. Compounds are also preferred where the anion A ~ is the hydrosulfate anion. The compounds are preferably prepared with 3- (3-fluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate and 3- (4-chlorophenyl) -1, -dimethyl-1,2,4- hydrosulfate. triazolium. The compounds of the formula I ee can be easily prepared using processes and procedures analogously known in the art, as seen in the following reaction scheme.

REACTION SCHEME (A) RNHNH2 + R4NCS .So light > R NHC-NRX-NH2 II III IV where R- ^ R n and R eon as defined above. In Paeo A, the preparation of the thiophemicarbazides (IV) is easily effected by the reaction of hydrazine with an isothiocyanate (III), contacting the reactants in a suitable solvent. The reaction is very fast and can be carried out from 0 ° C to room temperature. Although the reaction proceeds rapidly, the mixture can be left for up to 24 hours without a significant decrease in yields. Reflux conditions may be used, but are not preferred. Almost all the solvents can be used (with the exception of water and organic acids). Anhydrous alcohols (preferably ethanol or methanol) are preferred, although dimethyl formamide (DMF), CHC13, tetrahydrofuran (THF), and Et20 may also be used. Lae hydrazinae and the isothiocyanates normally required are commercially available, but can be prepared by known techniques. In Step B, the thiosemicarbazidae of benzoyl solidituidae (VI) ee can be prepared by reacting the thioe icarbazidae (IV) with a benzoyl chloride Rn-substituted (V) in an aprotic solvent such as pyridine, CHC13, THF, or similar. The acylation proceeds most easily from 0 ° C to room temperature for periods of 3 to 24 hours, although high temperatures (e.g., reflux temperatures) may be employed. Again, acid halides (V) are generally commercially available, but can also be prepared from the corresponding acids that are generally commercially available.

In Step C, the substituted benzoyl thiosemicarbazide (VI) is subjected to a cyclization reaction, which is effected by heating the compounds (VI) in an aqueous base, for example sodium dicarbonate or sodium hydroxide. . Alcoholic bases can be used, but in general they are less desirable. The reaction is conducted at about the reflux temperature of the solvent, preferably from about 65 ° C to 100 ° C. In practice, it is not necessary to purify lae tioeemicarbazidae (VI) for use in Paeo C, such that it inclued the 1: 1 mixtures with pyridine hydrochloride, produced as a by-product when pyridine is used as a solvent in Step B, can be used. In Step D, the triazolethione (VII) is suspended in acetic acid, and a solution of 6 to 10 equivalents of nitric acid in acetic acid is added. The reaction mixture becomes a black solution, and immediately releases N02 gas. The mixture is refluxed for 10 to 60 minutes, cooled slightly, and poured into ether with stirring. After stirring for 1 to 6 hours, the resulting triazolium hydroheulfate crietaline eal of formula I is filtered under suction, washed with ether or other organic liquid where the triazolium salt is insoluble, and dry, preferably low. a high vacuum. The salts of hydrosulfate of formula I prepared by this method are analytically pure without the need for recrietalization. Alternatively, the triazolethiae of the formula VII can be dissolved in glacial acetic acid, and reacted with HBF4 and hydrogen peroxide according to the general method of H.G.O. Becker et al. (J. Prakt, Chem. 330 (3), 325-337 (1988)), to form a triazolium tetrafluoroborate salt of the formula I. The hydroeulfate salts of the formula I are particularly suitable for administration pharmaceutical The triazolium derivatives of the formula I can also be administered as salts, wherein A "is any other pharmaceutically acceptable anion, the chloride salt being particularly suitable. The saltse wherein A" is a pharmaceutically acceptable anion different from tetrafluoroborate hydroeulfate. , can be easily prepared by using exchange techniques of known anionee. The following specific examples will be to illustrate the preparation of the compounds of this invention, although it does not mean that the scope of the exemplified compounds is limiting.

Preparation of R1-R-substituted Tiosemicarbazides EXAMPLE 1 2.4-Dimethylthiosemicarbazide To a stirred solution of methylhydrazine (16.0 milliliters, 3.00 x 10"1 mol), and dry screened ethanol (50 milliliters), a solution of isothiocyanate was added dropwise. methyl (22.0 grams, 3.00 x 10-1 moles) and dry screened ethanol (30 milliliters) The reaction was exothermic and gently refluxed as the isothiocyanate was added in. Soon a precipitate formed.

After stirring overnight, the reaction was cooled in an ice bath. Then the precipitate was collected by filtration, washed with a little cold isopropanol, and dried by eduction, yielding a colorless solid: 26.7 grams (75 percent). This material was crietalized doe vecee from water, and doe vecee from iopropanol, yielding small, colorless needles: 14.7 grams (41 percent), m.p. 135-137 ° C.

Preparation of l- (Rn-benzoyl) -ltRd-substituted thiosemicarbazides EXAMPLE 2 2,4-Dimethyl-1- (3-fluorobenzoyl) thiosemicarbazide To a stirred solution at room temperature 2,4-dimethylthiosemicarbazide (5.96 grams, 50.0 milliols) and pyridine (100 milliliters) were added dropwise 3-fluorobenzoyl chloride (7.93 grams, 50.0 millimoles). After stirring overnight, the reaction mixture was evaporated at reduced pressure. The concentrate was formed in a pan with water, and the one that did not die was collected by filtration. Crystallization of this material from ethanol gave the desired product as colorless needles, m.p. 202-205 ° C.

Preparation of Intermediate Triazole-3-thiones EXAMPLE 3 2.4-Dihydro-2,4-dimethyl-5- (3-fluorophenyl) -3H-1.2.4-triazole-3-thione 3, 4 -dimet i 1-1- ( 3-fluorobenzoyl) thiosemicarbazide (11.1 grams, 46.0 milli olee) and 1 molar aqueous eodium dicarbonate (460 milliliter, 0.460 mole), and heated to reflux. After refluxing for 5 hours, the reaction was allowed to cool to room temperature. After stirring overnight, the reaction was placed in a freezer for several hours. Then the precipitate was collected by filtration. Crystallization from isopropanol gave the desired product as colorless needles matt, m.p. 126-128 ° C. In a similar manner, using a variety of substituted benzoyl chlorides and a variety of 4-substituted thioemicarbazides to replace the reagents of Examples 1 to 3, and following conventionally the technique of the mieme, the following compounds are easily prepared.

Preparation of 3-phenyl-1,4-dialkyltriazolium salts EXAMPLE 4 3- (3-Fluorophenyl) -1,4-dimethyl-2,4-triazolium hydrosulfate 2,4-dihydro-2,4-dimethyl-5 was suspended - (3-fluorophenyl) -3H-1, 2,4-triazole-3-thione (3.00 grams, 13.4 millimoles) in glacial acetic acid (5 milliliters). The suspension was stirred, and a solution of concentrated nitric acid (7.25 grams, 81 mmol) and glacial acetic acid (25 milliliters) was added in one portion. The reaction was heated to reflux. After refluxing for 20 minutes, the reaction was allowed to cool, at which time it was poured into stirred anhydrous ether (600 milliliters). The resulting yellowish oil was crystallized, and after 2 hours, the desired product was isolated by filtration as yellowish green crystals, m.p. 106-107 ° C. In a similar manner, using an appropriate triazole-3-tione intermediary in the procedure of Example 4, the following compounds are readily prepared.

R4

Claims (47)

1. CLAIMS 1. A compound of the formula: wherein: R is halogen, trifluoromethyl, lower alkyl of 1 to 4 carbon atoms or lower alkoxy of 1 to 4 carbon atoms; n is 0, 1, or 2; R x and R 4 independently represent lower alkyl of 1 to 3 carbon atoms; and A "represents a pharmaceutically acceptable anion. 2. A compound of claim 1, wherein R is halogen. 3. A compound of claim 2, wherein R is fluorine. 4. A compound of claim 2, wherein R ee chloro. 5. A compound of claim 1, wherein n is one. 6. A compound of claim 1, wherein n is two. 7. A compound of claim 1, wherein R-L and R4 are each methyl. 8. A compound of claim 7, wherein R is fluorine and n is one. 9. A compound of claim 1, wherein Add a hydro-sulfate anion. 10. A composition of claim 1, wherein 3- (3-fluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydroeulfate consists of this compound. 11. A composition of claim 1, this compound being 3- (2-fluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate. 12. A compound of claim 1, with 3- (2,6-difluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate compound being eete. 13. A compound of claim 1, this compound being 3- (4-chlorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate. 14. A composition of claim 1, said compound being 3- (4-bromophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate. 15. A composition of claim 1, said composition being 3- (3-fluoro-2-methoxyphenyl) -1,4-dimethyl-1,2,4-triazolium hydroeulfate. 16. A method for the treatment of depression, which comprises administering to a patient in need, an effective dose of a compound of the formula: 4 wherein: R is halogen, trifluoromethyl, lower alkyl of 1 to 4 carbon atoms or lower alkoxy of 1 to 4 carbon atoms; n ee 0, 1, or 2; R1 and R4 independently independently represent lower alkyl of 1 to 3 carbon atoms; and A ~ represents a pharmaceutically acceptable anion. 17. A method according to claim 16, wherein R is halogen. 18. A method according to claim 17, wherein R ee fluorine. 19. A method according to claim 17, wherein R is chloro. 20. A method according to claim 16, wherein n is one. 21. A method according to claim 16, wherein n is two. 22. A method according to claim 16, wherein R2 and R4 are each methyl. 23. A method according to claim 22, wherein R is fluorine and n is one. 24. A method according to claim 16, wherein A "is a hydrosulfate anion 25. A method according to claim 16, this compound being 3- (3-fluorophenyl) -1,4-dimethyl hydro- sulfate. -1, 2, 4-triazolium 26. A method according to claim 16, this compound being 3- (2-fluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate. The method according to claim 16, wherein said compound is 3- (2,6-difluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrochloride 28. A method according to claim 16, said compound 3- (4-chlorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate 29. A method according to claim 16, wherein this 3- (4-bromophenyl) -1 hydrosulfate compound is added, 4-dimethyl-1,2,4-triazolium 30. A method according to claim 16, this compound being 3- (3-fluoro-2-methoxyphenyl) -1,4-dimethyl-1,2, hydrosulfate. 4-triazolium 31. A composition farm aceutical, which comprises a compound of the formula: wherein: R is halogen, trifluoromethyl, lower alkyl of 1 to 4 carbon atoms or lower alkoxy of 1 to 4 carbon atoms; n ee 0, 1, or 2; R? and R4 independently repreferably lower alkyl of 1 to 3 carbon atoms; and A ~ represents a pharmaceutically acceptable anion; and a pharmaceutically acceptable vehicle. 32. A composition according to claim 31, wherein R is halogen. 33. A composition according to claim 32, wherein R is fluorine. 34. A composition according to claim 32, wherein R is chloro. 35. A composition according to claim 31, wherein n ee one. 36. A composition according to claim 31, wherein n is doe. 37. A composition according to claim 31, wherein Rx and R4 are each methyl. 38. A composition according to claim 37, wherein R is fluorine and n ee one. 39. A composition according to claim 30, wherein A "is a hydrosulfate anion 40. A composition according to claim 30, wherein 3- (3-fluorophenyl) -1,4-dimethyl hydroeulfate is comprised. -1, 2, 4-triazolium, 41. A composition according to claim 30, wherein three (2-fluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydroeulfate is added. Composition according to claim 30, said compound being 3- (2,6-difluorophenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulphate. 43. A composition according to claim 30, said compound being 3- (4-chlorophenyl) -1,4-dimethyl-1,2,4-triazolium hydroeulfate. 44. A composition according to claim 30, this compound being 3- (4-bro-ofenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate. 45. A composition according to claim 30, said compound being 3- (3-fluoro-2-methoxyphenyl) -1,4-dimethyl-1,2,4-triazolium hydrosulfate. 46. The use in the manufacture of a medicament, of a compound of the formula: wherein: R is halogen, trifluoromethyl, lower alkyl 1 to 4 carbon atoms or lower alkoxy of 1 to 4 carbon atoms; n is 0, 1, or 2; Ri and R4 independently represent lower alkyl of 1 to 3 carbon atoms; and A "represents a pharmaceutically acceptable anion. 47. The use in the manufacture of a medicament for the treatment of depression, of a compound of the formula: wherein: R is halogen, trifluoromethyl, lower alkyl of 1 to 4 carbon atoms or lower alkoxy of 1 to 4 carbon atom; n ee 0, 1, or 2; R? and R 4 independently represent lower alkyl of 1 to 3 carbon atoms; and A "represents a pharmaceutically acceptable anion.