IL46387A - 3-phenoxa-3-phenylpropylamine derivatives - Google Patents

Description

The present invention relates to novel 3-aryloxy-3-phenylpropylamines and acid addition salts thereof, useful as psychotropic agents, particularly a anti-depressants .

Tertiary 2-phenoxy-2-phenylethylamines constitute the subject matter of U.S. Patent 3,106,564. The compounds are said to be useful pharmacological agents exhibiting activity on the central nervous system including useful application as analeptic agents without significant effect on respiration. The compounds are also said to have a high order of activity as antihistaminic and anticholinergic agents. Several tertiary 3-phenoxy-3-phenylpropylamines and quaternary ammonium compounds are disclosed in J. Pharmaceutical Society , Ja an , 93 508-519 ,. 1144-53, 1154-61 (1973) . The compounds are said to be mydriatic agents .

Secondary and primary 3-aryloxy-3-phenylpropy1-amines have hot hitherto been known.

This invention provides »novel 3-aryloxy-3-phenylpropylamines of the formula I wherein en or methyl; R^ and R^ are halo, tri fluoromethy1 , C2~C^ alkyi, C^-C^ alkoxy or C3-C1j alkenyl; and n and m are 0, 1 or 2 with the limitation that both n and m are not 0 when both R^ are methyl and both R are hydrogen; and acid addition salts thereof formed with pharmaceutically-acceptable acids.

In the above formula and when they are halo* C2~C4 alk l, C^-C^ alkyloxy or C3~C4 alkenyl represent; illustratively, he following atoms or groups: fluoro, chloro, bromo, iodo, ethyl, isopropyl, n-propyl, h-butyl; isobutyl, sec. -butyl , t-butyl, methoxy, ethoxy, n-propoxy > isopropoxy, allyl, methallyl, or crotyl. Compounds illustrative of the scope of this invention include the following: 3- (p_-isopropoxyphenoxy ) -3-pheny Ipropy lamine methanesulfpnate Ν,Ν-dimethyl 3-(3' , 4 ' -dimethoxyphenoxy) -3-pheny1-propylamine p-hydroxybenzoate 3- (p-t-buty lphenoxy ) -3-phenyIpropy lamine glutarate 3-(2' , ' -dichlorophenoxy) -3-pheny 1-2-methylpropyi-aminecitrate ,N-dimethy 1 3- (m-anisyloxy ) -3-pheny1-1-methy1-propylamine maleate Ν,Ν-dimethyl 3-(2' , 4 ' -dif.luorophenoxy) -3-pheny 1-propylamine 2 , 4-dinitrobenzoate 3- (o-ethylphenoxy ) -3-phenylpropylamine dihydrogen phosphate N-methyl 3- (2 ' -chloro-4 ' -isopropylphenoxy) -3-phenyl-2-methylpropylamine maleate N,N-dimethyl 3- ( 2 ' -ethyl-4 ' -fluorophenoxy ) -3-phenylpropylamine succinate Ν,Ν-dimethyl 3- (o-isopropoxyphenoxy ) -3-phehyl-propylamine phenylacetate N ,N-dimethyl 3- (o-bromophenoxy) -3-phenyl-propyl-amine 3-phenyIpropionate N-methyl 3- (p-iodophenoxy ) -3-pheny1-propylamine propiolate N-methyl 3- ( 3-n-propylphenoxy ) -3-pheny1-propylamine decanoate.

Also included within the scope of this invention are the pharmaceutically-acceptable salts of the amine bases represented by the above formula formed with non-toxic acids; These acid addition salts include salts derived from in-organic acids such as: hydrochloric acidr nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid hydriodic acid, nitrous acid, or phosphorous acid, as well as salts of non-toxic organic acids including aliphatic mono and dicarboxylases , pheny1-substituted aikanoates, hydroxy alkanoates and alkanedioates , aromatic acids, aliphatic arid aromatic sulfonic acids. Such pharmaceutically-acceptable salts thus include: sulfate, pyrosuifate, bisulfate, sulfite, bisulfite, nitrate, phosphate, mono-hydrogenphosphate , dihydrogenphosphate , metaphosphate , pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, iso- butyrate, caprate, heptanoate , propiolate , oxalate, malonate > succinate, suberate, sebacate , f umarate , maleate, butyne-1,4-dioate , hexyne-1 , 6-dioate , benzoate , chlorobenzoate > methyl-benzoate, dinitrobenzoate , hydroxybenzoate , methoxybenzoate phthalate, terephthalate , benzenesulf onates , toluenesulfon-ate, chlorobenzenesulf onate , xy lenesulfonate , phenylacetate , phenylpropionate , phenylbutyrate , citrate, lactate, 3-hydroxy-butyrate, glycollate, malate , tartrate, methanesulfonate , propanesulfonates , naphthalene-l-sulf onate , naphthalene-2-sulfonate, or mandelate.

The compounds of this invention in the form of their free bases are high boiling oils, but white crystalline solids in the form of their acid addition salts. The compounds can be prepared in several ways . A particularly useful procedure for preparing compounds represented by the above formula (in which both groups are methyl) involves the reduction of 3-dimethylaminopropiophenone produced by a Mannich reaction to yield Ν,Ν-dimethyl 3-phenyl-3-hydroxypropy lamine . Replace-ment of the hydroxyl group with a halogen, such as chlorine, ■ yields the corresponding Ν,Ν-dime thy 1 3-phenyl-3-chloropro-pyiamine. Reaction of this chloro compound with a suitably substituted phenol, as for example o-methoxy phenol (gliiacol) , * produces a compound of this invention in which both R^ groups are methyl. Treatment of the N,N-dimethyl compound with cyanogenbromide serves to replace one N-methyl group with a cyano group. Hydrolysis of the resulting compound with base yields a compound of this invention in which only one R^ group on the nitrogen is methyl. For exam le, treatment of N, -dimethyl 3- (o-anisyloxy ) -S-^phehylpropy lamine with cyanogen bromide followed by alkaline hydrolysis of the -cyanb compound yields directly N-methyl 3- (o-anisyloxy ) -3-pheny1-propylamine [N-methyl 3- (o-methoxyphenoxy) -3-phenylpropyl-amihe] .

An alternate preparation of the compounds of this invention is as follows: 3-Chloropropylbenzene is reacted with a positive haiogenating agent such N-bromosuccinimide to yield the corresponding 3-chloro-l-bromopropylbenzene . Selective replacement of the bromo atom with the sodium salt of a phenol, as for example, the sodium salt of o-methoxyphenol (guiacol) yields a 3-chloro-l- (1-me thoxyphenoxy ) -propylbenzene [also named as 3-chloro-l- (o-anisyloxy ) propylbenzene] . Reaction of the 3-chloro derivative thus produced with methylamine or dimethylamine yields the desired N-methyl or N,N-dimethyl 3- (o-anisyloxy ) -3-phenyl-propylamine.

Compounds in which both groups attached to the nitrogen in the above formula are hydrogen can be prepared from an intermediate produced in the previous preparation such as, for illustrative purposes, 3-chloro-l- (o-ahisyloxy) -propylbenzene prepared by the reaction of 3-chioro-l-bromo-behzene and sodium guiacol. This chloro compound is reacted with sodium azide to give the corresponding 3-azido-i- (o-anisyloXy) -propylbenzene . Reduction of the azide group with a metallo-organic reducing agent such as sodium borohydride yields the desired primary amine. Alternatively, the chloro compound can be reacted directly with a large excess of ammonia in a high pressure reactor to give the primary amine .

Compounds in which the R group on the carbon atom alpha to the nitrogen is methyl can be prepared by reacting phenyl 2 * -propenyl ketone with dimethy lamine [See J . Am. Chenu Soc . , 75 , 4460 (1953 ) ] . The resulting 3-dimethy lami o-butyrophenone . is reduced to yield the Ν , Ν-dimethyl 3-hydroxy- 1-methyl- 3-pheny lpropy lamine . Replacement of the hydroxyl with chlorine followed by reaction of the ch loro-compound with the sodium salt of a suitably . substituted phenol yields the Ν , Ν-dime thyl derivatives of this invention bearing an alpha methyl group on the propylamine backbone of the molecule . Production of the corresponding N-methyl derivative can be accomplished by the aforementioned reaction sequence utili zing cyanogen bromide . The N-methyl derivative can in turn be converted to the corresponding primary amine (in which both R^ groups on the nitrogen are hydrogen) by oxidation in neutral permanganate . Compounds in which the group attached to the 0-carbon atom is methyl are prepared by a Mannich reaction involving propiophenone formaldehyde and dime thy lamine . The resulting ketone , a a-methyi-3-dimethylaminopropiophenone , is subjected to the same reduction procedure as before to yield a hydroxy compound . Replacement of the hydroxyl with chlorine followed by reaction of the chloro compound with the sodium salt of a phenol yields a dimethyl amine compound of this invention . Conversion of the dime thy lamine to the corresponding monomethyl and primary amines is carried out as before .

Those compounds in which the R2 group attached to either the a or 3-carbon is methyl have two asymmetric carbon atoms , the carbon carrying the 2 methyl and the γ-carbon carrying the phenoxy and phenyl groups . Thus , such com ounds exist in four diastereomeric forms occurrin as two racemic pairs, the less soluble pair being designated a-dl form and the more soluble the 0-dl form. Each racemate can be resolved into its individual d and 1 isomers by methods well known in the art, particularly, by forming salts with optically active acids and separating the salts by crystallization.

This invention is further illustrated by the following specific examples: Example 1* Preparation of N-methyl 3- (p-trifluoromethy lphenoxy ) -3-pheny l ropy1amine' and of N,N-dimethyl 3- (p-trifluoromethy1-phenoxy) - 3-phenylpropy1amine About 600 g. of 0-dimethylaminopropiophenohe hydrochloride were converted to the corresponding ftee base by the action of 1.5N aqueous sodium hydroxide. The liberated free base was taken up in ether, the ether layer separated and dried, and the ether removed therefrom ih vacuo. The residual oil comprising 0-dimethylamino-propiophenone was dissolved in two liters of tetrahydrofuran,> and the resulting solution added in dropwise fashion with stirring to a solution of four moles of diborane in four liters of tetrahydrofuran. The reaction mixture was stirred overnight at room temperature. An additional mole of diborane ih one liter of tetrahydrofuran was added, and the reaction mixture stirred again overnight at room temperature. Next, two liters of aqueous hydrochloric acid were added to decompose any excess diborane present. The tetrahydrofuran was removed by evaporation. The acidic solution was extracted twice with one liter portions of benzene, arid the benzene extracts were discarded. The acidic solution was then made basic with an excess of 5N aqueous sodium hydroxide. The basic solution was extracted three times with two liter portions of benzene. The benzene extracts ere separated and combined, and the combined extracts washed with a saturated aqueous sodium chloride and then dried. Evaporation of the solvent in vacuo yields 442 g. of Ν,Ν-dimeth l 3-phenyl- 3-hydroxypropylamine .

A solution containing 442 g. of N,N-dimethyl 3-pheny1-3-hydroxypropylamine in 5 1. of chloroform was saturated with dry gaseous hydrogen chloride. 400 ml. of thionyl chloride were then added to the chloroform solution at a rate sufficient to maintain reflux. The solution was refluxed an additional 5 hours. Evaporation of the chloroform and other volatile constituents n vacuo yielded Ν,Ν-dimethyl 3-pheny1-3-chloropropylamine hydrochloride which was collected by filtration, and the filter cake washed twice with 1500 ml. portions of acetone. The washed crystals weighed about 500 g. and malted at 181-3°C; with decomposition. An additional 30 g. of compound were obtained from the acetone wash by standard crystallization procedures. The structure of the above compound was verified by NMR and titration.

A solution of 50 g. p-trifluorome thylpheriol , 12 g. of solid sodium hydroxide and 400 ml. of methanol Was placed in a one liter round-bottom flask equipped with magnetic stirrer, condenser and drying tube. The reaction mixture was stirred until the sodium hydroxide had dissolved. Next 29.8 g. of Ν,Ν-dimethyl 3-pheny1-3-chloropropylamine hydrochloride were added. The resulting reaction mixture was refluxed for about 5 da s and then cooled. The methanol was then removed by evaporation, and the resulting residue taken up in a mixture of ether and 5N aqueous sodium hydroxide.

The ether layer was separated and washed twice with 5N aqueous sodium hydroxide and three times with water. The ether layer was dried, and the ether removed by evaporation in vacuo to yield as a residue N,N-dimethyl 3- (p-trifluoro-methylphenoxy) -3-phenylpropylamine .

The free base was converted to the corresponding oxalate salt by dissolving 32 g. of the amine in ethyl acetate to which was added a solution of 9 g. of oxalic acid also in ethyl acetate. ,N-dimethyl-3-p-trifluoromethylphenoxy- 3-phenylpropy lamine oxalate thus formed melted at 117-119 °C. with decomposition after recrys tallization from ethyl acetate. Analysis calc: C, 58.11; H, 3.36; N, 3.39; F, 13.79; Found: C, 58.19; H, 3.49; N, 3.59; F, 13.85.

A solution containing 8.1 g. of cyanogen bromide in 500 ml. benzene and 50 ml. of toluene was placed in a one liter three-neck round-bottom flask equipped with thermometer, addition funnel, drying tube and inlet tube for nitrogen. The solution was cooled to about 5°C. with stirring, and nitrogen gas was bubbled thru the solution.

Next, a solution of 12.146 g. of N,N-dimethyl 3- (p-trifluorb-methylphenoxy) -3-phenylpropylamine dissolved in 40 ml. of benzene was added in drbpwise fashion. The temperature of the reaction mixture was allowed to rise slowly to room temperature, at which temperature stirring was continued overnight while still maintaining a nitrogen atmosphere.

IbO ml. of benzene were added. The reaction mixture was washed twice with water, once with 2N aqueous sulfuric acid and then with water until neutral. The organic layer was dried, and the solvents removed therefrom by evaporation in vacuo to yield about 9.5 g. of an oil comprising N-methyl-N-cyano 3- (p-trifluoromethylphenoxy) -3-pheny1-propylamine . , A solution of 100 g. potassium hydroxide, 85 ml. water, 400 ml. ethylene glycol and 9.50 g. of N-meth 1-N-cyano 3- (p-trifluoromethylphenoxy) -3-propylamine was prepared in a one liter three-neck, round-bottom flask equipped with magnetic stirrer and condenser. The reaction mixture was heated to refluxing temperature (130°C.) for 20 hours, and was then cooled. 500 ml. of water were added. The reaction mixture was extracted with three 500 ml. portions of ether. The ether extracts were combined, and the combined extracts washed with water. The water wash was discarded. The ether solution was next contacted with 2N aqueous hydrochloric acid. The acidic aqueous layer was separated. A second aqueous acidic extract with 2N hydrochloric acid was made followed by three aqueous extracts and an extract With saturated aqueous sodium chloride. The aqueous layers were all combined and made basic with 5N aqueous sodium hydroxide.

N-methyl 3- (p-trifluoromethylphenoxy ) -3-phenylpiropylamine , formed in the above reaction, was insoluble in the basic solution and separated. The amine was extracted into ether. Two further ether extractions were carried out. The ether extracts were combined, and the combined extracts washed With saturated aqueous sodium chloride and then dried.

Evaporation of the ether in vacuo yielded about 6.3 g. of N-methyl 3- (p-trifluorometh lphenoxy) -3-phenylpropyiamine . The amine free base was converted to the corresponding oxalate sale by the method set forth above. N-methyl 3- (p-trifluoro- methyIphenoxy) -3-phenylpropylamine oxalate thus prepared melted at 179-182°C. with decomposition after recrystaili za-tioh from an ethyl acetate-methanol solvent mixture. Analysis calc: C, 57.14; H , 5.05; N, 3.51; F, 14.27; Found; C, 57.43; H 5.30; , 3.79; F , 14.24.

The amine free base was also converted to the maieate salt.

The following Ν,Ν-dimethyl or N-methyl 3-sub-stituted phenoxy- 3-phenylpropylamines were prepared by the above procedures .

N,N-dimethyl 3- (o-chlorophenoxy) -3-phenylpropy1-amine maieate which melted at 88-90°C. after recrystailizatioh from an ethyl acetate-cyclohexane solvent mixture. Analysis calc: C, 62.14; H, 5.96; N, 3.45; Cl, 8.73; Found; C, 61.94 H > 5.67; , 3.68; Cl , 8.92;.

N ,N-dimethyl 3- (o-trifluoromethyIphenoxy) -3-phenylpropy1amine p_-toiuene-sulfonate which melted at 134-6°C. after irecrystallization from ethyl aeetate. Analysis calc; C, 60.59; H, 5.70; N , 2.83; F, 11.50; S, 6.47; Found; C, 60.36, H, 5.52; , 3.12; F, 11.80; S, 6.66.

N-methyl 3-phenyl-3- (m-chlorophenoxy) propylamine oxalate: melting point=177-9°C. Analysis calc; C, 59.10; H; 5.51; N, 3.83; Clf 9.69; Found; C, 58.89; H, 5.45; N, 4^07; Cl, 9.24.

N,N-dime hyl 3-phenyl-3- (m-methox phenoxyj propy1-amine oxalate: melting point=125-8°C. Analysis calc: 63.99; H, 6.91, N, 3.73; Found: C, 63.93; H; 6.90; 3.59.

N,N-dimethyl 3-phenyl-3- (o-allyIphenoxy) prbpylamihe oxalate : melting point = 159-161°C. Analysis calc: 68.55; H, 7.06; , 3.63; Found; C, 68.67; H, 7.15; N, 3.83.

N ,N-dimethyl 3-phenyl-3- (£-chlorophenoxy) propylamine oxalate: melting point = 139-141°C. Analysis calc: C; 60.08; H, 5.84; N, 3.69; CI, 9.33; Found; C, 60.34> H> 5.95; N, 3.88; CI, 9.61.

N,N-dimethyl 3- (o-me thoxyphenoxy )- 3-phenylpropy 1-amine maleate: m.p. = 98-103°C. Analysis calc: C,■ 65.82; H, 6.78; N, 3.49; Found; C, 65.83; H, 6.52; N, 3.63; N,N-dimethyl 3- (p_-methoxyphenoxy) -3-phenylpropy1-amine maleate: m.p. = 101-104°C. Analysis calc: C, 65.82; H, 6.78; N, 3.49; Found; C, 65.96; H, 6.50; N, 3.68.

N-methyl 3- (£-fluorophenoxy ) -3-phenylpropy lamine maleate: m.p. = 112.5-119°C. Analysis calc: C, 63.99; H> 5.91; N, 3.73; Found; C, 63.77; H, 6.19; N, 3.90.

N-methyl 3- ( _-methoxyphenoxy ) -3-phenylpropylamine maleate: m.p. = 128.5-135°C. Analysis calc: C> 65.10; H> 6.50; N> 3.62; Found; C, 64.94, H, 6.54; N, 3.67.

N,N-dimethyl 3- (o-bromophenoxy) -3-phenylpropylaniine oxalate: melting point = 144-6°C. Analysis calc; C; 53.79 5.23; N, 3.30; Br, 18.86; Found, C, 53.84; H, 5.52; N, 3.38; Br, 18.86.

N-methyl 3-pheny1-3- (o-allylphenoxy) ropylamine oxalate: melting point = 144-147°C (dec). Analysis calc: C; 67.91; H, 6.78; N, 3.77; Found; C, 67.90; H, 6.85· N, 3.96. Ν,Ν-dimethyl 3-phenyl-3- (m-trifluorometh lphenoxy) propylamine oxalate: melting point = 163-5°C. Analysis calc.; C, 58.11; H, 5.36; N, 3.39; F, 13.79; Found; C* 57.89? tii 5.26; N, 3.41, F, 13.69.

,N-dimethy 1 3-phenyl-3- (o-t-butylphenoxy ) propylamine oxalate: melting point = 146-9°C. Analysis calc; C, 68.88; H, 7.78; N, 3.49; Found; C, 68.56; H, 8.04; N, 3.69 N-methyl 3-phenyl-3- (p_-fluorophenoxy ) propylamine oxalate: melting point = 159=161°C. Analysis calc; C; 61.88; H, 5.77; N, 4.01; F, 5.44; Found; C, 61.66; H, 5.90; N, 3.72, F, 5.70.

• N-methyl 3-phenyl-3- (o-me thox'yphenoxy ) propylamine hydrochloride: melting point = 105-8°C. (recrystallized from' ethyl acetate) ; Analysis calc ; C, 66.33, H, 7.20; N( 4.55, CI, 11.52; Found; C, 66.16; H, 7.36; N, 4.41; Cl , 11.48.

N-methyl 3-phenyl- 3- (o-fluorophenoxy ) propylamine oxalate, melting point = 148-50°C. Analysis calc : C, 61.88; H, 5.77; N, 4.01; F, 5.44; Found; C, 61.83; H, 5.97; N, 4.14; F, 5.65.

N-methyl 3-phenyl-3- (m-methoxyphenoxy ) propylamine oxalate; melting point = 140-3°C. Analysis calc: C, 63.15; H, 6.42; N, 3.88; Found; C , 62.91 ; H , 6.40 ; N , .17.

N,N-dimethyi 3- (o-ethylphenoxy ) -3-phenylpropy lamirie oxalate: melting point = 152-4°C. Analysis calc: C, 67.54; H, 7.29, N, 3.75; Found; C, 67.33; H, 7.05, N, 3.98.

N ,N-dimethyl 3- (o-isopropoxyphenoxy ) -3-phenylpr6pyl-amine oxalate: melting point = 139-142°C. Analysis calc; C, 68.20; H, 7.54; N, 3.61; Found, C, 68.50; H, 7.82, N, 3.85.

N-methyl 3-phenyl- (p_-chlorophenoxy) propylamine oxalate: melting point = 163-5°C. Analysis calc; C, 59.10; H, 5.51; N, 3.83; Cl, 9.69; Found; C, 59.33; H, 5.58; N, 4.07; Cl 9.45.

N ,N-dimethyl 3- (p_-fluorophenoxy ) -3-phenylpropylamine maleate : melting point = 103-8°C. Analysis calc: C, 64.77; H, 6.21; N, 3.60; Found: C, 64.79; H, 6.50; N, 3.82.

N,N-dimethyl 3- (m-chlorophenoxy) -3-phenyIpropylamine oxalate: melting point = 150-2°C. (recrystallizatioh from isopropanol) Analysis calc: C, 60.08; H, 5.87; N, 3.69; CI, 9.33; Found: C, 59.90 ; II, 6.08; N, 3.42; Cl, 9.60. Ν,Ν-dimethyl 3- (o-fluorophenoxy)- 3-phehyIpropylamine hydrochloride: melting point = 166-8°C. (from acetone-cyclohexane) Analysis calc: C, 65.91; H, 6.83; N, 4.52; Cl> 11.99; F, 6.13; Found: C, 65.78; H, 6.82; N, 4.78; Cl, 11.70; F , 5.99.

N-methyl 3-phenoxy- 3-pheny1-2-methyIpropylamine oxalate: melting point = 158-160°C. (from isopropanol) Analysis calc: C, 66.07; H, 6.71; N, 4.06; Found: C, 66.12; H, 6.72; N, 4.26 N-methyl 3-phenoxy- 3-pheny1-1-methyIpropylamine oxalate: melting point = 80-100°C. with decomposition (from ethyl acetate) Analysis calc: C, 66.07; H, 6.7l; * 4.06; Found: C, 65.85; H , 6.45, N, 4.20. a-dl-N ,N-dimethy1-3-phehoxy- 3-pheny1-1-methyIpropy1-amine oxalate: melting point = 113-16°C. Analysis calc: C, 66.84; H, 7.01; N, 3.90; Found: C, 67.03; H, 7.20; N, 4.13 Ν,Ν-dimethyl 3-phenoxy- 3-pheny1-2-methyIpropy1-airiine oxalate: melting point = 130=4°C. Analysis calc.: C, 66.89; H, 7.01; N, 3.90; Found: C, 66.59; H; 7.08; N, 3.96; N-methyl 3- (m-fluorophenoxy) -3-phenylpropylaniine oxalate: melting point = 177-9°C. Analysis calc.: C, 61.87; H , 5.77; N, 4.01; F, 5.44; Found: C, 62.07, H, 6.02, N, 4.23 5.23.

,N-dimethyl 3- (o-ethoxyphenoxy ) -3-phenylpropy1amihe oxalate: melting point = 101-4°C. Analysis calc. : C, 64.77^ ti, 6.99, , 3.60; Found: C, 65.05; H, 7.00; N, 3.88. 3-dl-N ,N-dimethy1-3-phenoxy- 3-pheny1-1-methyl-propylamine oxalate: melting point = 131-33°C. Analysis dale: C, 66.89 ; H, 7.01; N, 3.90; Found: C, 66.64; U} 7.00; N , 3.77.

Example 2 Preparation of N-methyl 3- (o-methoxyphenoxy) -3-phehylprop 1-aitiine hydrochloride.

A reaction mixture consisting of 1000 g. of 3-chlbropropylbenzene , 1500 g. of N-bromosuccinimide > 5 g. of benzoyl peroxide and 6 1. of carbon tetrachloride were placed in a 12 1. 3-neck, round-bottom flask equipped with stirrer and condenser. The reaction mixture was stirred and heated until an exothermic reaction began. The heat source was then removed, and the irefluxing, of reaction mixture controlled by external cooling. After the reaction had been completed as hbted by the disappearance of the N-bromosuccihimide , the reaction mixture was cooled and crystalline sUccihimide collected by filtration. The succihimide filter cake was washed with carbon tetrachloride. The combined filtrate and wash was concentrated in vacuo. The residue comprising 3-chlorb-l-bromopropylbenzene obtained in the above reaction Was showri by a NMR to be the desired material and as used Without further purification. The yield was essentially quantitative .

Next* a solution of sodium gUaiacol (o-me hbxy-pheribl) was prepared by dissolving 156 g. of sodium hydroxide arid 485.6 g. of guaiacbl in 2.5 1. of ethanol. The ethanol was removed by evaporation ii vacuo , benzene added, and the benzene also removed by evaporation in vacuo . This process was repeated several times in order to dry completely the sodium guaiacol. The sodium guaiacol obtained by the above procedure was dissolved in approximately 3 1. of dimethy1-siilfoxide. The solution was cooled to about 20°C. 3-Chlorc— i-bromopropylbenzene was added thereto in dropwise fashion over a period of 3/4 hour while the reaction temperature was maintained at about 25°C. The reaction mixture was allowed to stir at room temperature overnight and was then poured onto ice. The resulting aqueous layer was extracted with four 2 1. portions of hexane. The hexane extracts were washed with water and dried. Removal of the hexane in vacuo yielded as a residue 3-chloro-l- (o-methoxyphenoxy) propylbenzene. The compound was distilled in vacuo. 3-Chibro-l- (o-raethoxyphenoxy ) ropylbenzene thus purified distilled in the rarige 135-145°C. (.03 tofr) . The structure of the compound was verified by N R.

A reaction mixture consisting of 200 nil* of methyl-amine, 225 ml. of methanol and 75 g.. of 3-chloro-l- (o-methoxy phehoxy) propylbenzene was heated in an autoclave for 12 hours at 140°C. The reaction mixture was cooled, and the solvent was removed by evaporation. The semisolid residue was mixed ith concentrated aqueous sodium hydroxide. The resulting mixture was extracted several times with ether. N-methyl 3- (o-methoxyphenox ) -3-phenylpropylamine , formed in the above reaction, was insoluble in the alkaline solution and Was extracted therefrom with ether. The ether extracts were combined, and the combined extracts washed with water and dried. The ether was removed therefrom in vacuo leaving the amine as a dark colored residue. The residue was dissolved in ether and 1 equivalent of oxalic acid in methanol added slowly. N-methyl 3- (o-methoxyphenoxy) -3-phen lpropylamine oxalate formed an insoluble precipitate which was collected by filtration, and the filter cake washed with ether and dried. N-methyl 3- (o-methoxyphenoxy) -3-pheny lpropylamine oxalate melted at 150-152°C. The NMR spectrum of the compound was consistent with the expected structure.

■N-methyl 3- (o-methoxyphenoxy) -3-pheny-.propylamine oxalate was dissolved in a minimum quantity of water with heating, and concentrated aqueous sodium hydroxide added.

After cooling, the alkaline solution was extracted several times with ether. The combined ether extracts were washed with water and dried, and the ether removed therefrom in vacuo. N-methyl 3 (o-methoxyphenoxy) -3-phenylpropylamine free base thus isolated was dissolved in ether, and the ether solution saturated with dry gaseous hydrogen chloride. N-methyl 3 (o-methoxyphenoxy ) -3-phenyJ.propylamine hydrochloride thus formed was recrystallized from ethyl acetate containing a small amount of methanol. N-methyl 3- (o-methbxy-phenoxy) -3-phenylpropylamine hydrochloride thus prepared and purified melted at 129-131°C.

Exam le 3 Preparation of 3- (o-methoxyphenoxy ) -3-phenylpropylamine .

A solution of 2.6 g. of sodium azide in 10 ml. of water was placed in a 100 ml. three-neck, round-bottom flask equipped with stirrer, condenser and thermometer. A second solution containing 2.76 g. of 3-chloro-l- (o-methoxyphenoxy) propylbenzene (as provided by the procedure of Exam le 2) in 30 nil. of dimethylformamide was added to the sodium azide solution, and the resulting mixture heated at 95°C. overnight. The reaction mixture was cooled, diluted with water and extracted three times with ether. The ether extracts were combined, the combined extracts were washed five times with water followed by a saturated aqueous sodium chloride wash, and were then dried. Evaporation of the ether in vacuo yielded a colorless liquid comprising 3-azido-l- (o-methoxy-phenoxy) propylbenzene . Forty-one grams of this latter compound were dissolved in 350 ml. of isopropanol. The resulting solution was placed in a 1 1. round-bottom flask equipped with magnetic stirrer condenser and drying tube.

Fifteen and two-tenths grams of 96% sodium borohydride in the solid form were added to the azide solution. The resulting mixture was heating to refluxing temperature overnight and then cooled. The alcohol was evaporated therefroiti in vacuo . About 1.5 1. of water were added, and the resulting aqueous mixture acidified cautiously with 2N aqueous hydrochloric acid. 3- (o-methoxyphenoxy ) -3-phenylpropylamihe produced in the above reaction was soluble in the aqueous acidic layer as the hydrochloride salt. The acidic aqueous layer was extracted three times with ether, and the ether extracts saved to recover unreacted starting material. The acidic layer was then made basic with 5N aqueous sodium hydroxide. The primary amine, being insoluble in base, separated and was extracted into ether. The ether layer was separated, and the aqueous alkaline layer extracted twice more with ether. The ether extracts were combined, and the combined layers washed with a saturated aqueous sodium chloride solution. Evaporation of the ether in vacuo yielded about 17 g. of 3- (o-methoxyphenoxy ) -3-phenylpropylamine which was converted to the oxalate salt by the procedure of Example 1. 3- (o-methoxyphenoxy) -3-phenylpropylamine oxalate thus prepared melted at 118-121°C. after recrystallization from an ethyl ace tate-cyclohexane solvent mixture. The oxalate salt was converted to the hydrochloride salt by forming the free base in ether solution and then saturating the ether solution with gaseous hydrogen chloride. The hydrochloride salt melted at 77-8°C. Analysis calc. : C, 65.91; H, 6.86; , 4.77; CI, 12.07; Found: C, 65.13; H 7.12; N , 4.61; Cl, 12.21.

Following the above procedure, 3- (p_-trifluoromethy1-phenoxy) -3-phenylpropylamine oxalate was prepared: melting point =.162-164°C. The oxalate salt was converted to the hydrochloride salt by forming the free base, extracting the free base into ether and then saturating an ether solution of the free base with gaseous hydrogen chloride. The hydrochloride salt melted at 130-133°C. Analysis calc: C, 57.93; H, 5.17; N 4.22; Cl , 10.69; F, 17.18; Found: C, 5.66; H , ft 5.08; N, 4.09; Cl, 11.15; F, 16.66.

Example 4 Preparation of 3-phenoxy-3-phenylpropylamine .

Eight grams of 3-phenoxy-3-phenylpropylchloride provided by the procedure of Example 2 were heated with 150 iril. of liquid ammonia in a high pressure reactor at 100°C. for 20 hours. The volatile constituents of the reaction mixture Were evaporated, and the residue, comprising, 3-phenoxy-3-phenylpropylamine formed in the above reaction, was dissolved in ethanol and the volatile constituents again removed by evaporation. The resulting residue was dissolved in a mixture of ether and 5N aqueous sodium hydroxide. The ether layer was separated, and the alkaline aqueous layer extracted three mbre times with ether. The ether extracts were combined, and th# combined extracts washed with water. The ether layer Was next extracted twice with 2N aqueous hydrochloric acid, the primary amine passing into the acidic layer. The acidic extracts were combined and made basic by the addition of an excess of 5N aqueous sodium hydroxide. The primary amine, being insoluble in the basic solution, separated and was extracted into ether. The ether extract was separated, and the basic solution extracted twice more with ether. The ether extracts were combined, the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the ether in vacuo yielded 3-phenoxy-3-phenylpropylamine as an oil. The oxalate salt of the primary amine was prepared by the procedure of Example 1 and melted at 170-173°C. Analysis calc^ : C, 64.34; H, 6.04; N, 4.41; Found: C, 64.49; H, 5.80; N, 4.67.

Example 5 .Preparation bf Salts.

Salts of the free bases of this invention, other than the hydrochloride, maleate and oxalate salts Whose preparation is illustrated in Examples 1-4, are prepared by dissolving the free base in ether and adding an equivalent of a suitable on-toxic acid, also in ether. The salts thus formed, as for example the acetate and benzoate salts, are insoluble ih ether and can be isolated by filtration. Alternatively, the amine base can be dissolved in ethanoi and a equivalent of the acid added as an ethanolic solution. In this instance, since the salts thus formed are soluble in the reaction mixture, they are isolated by evaporation of the solvent in vacuo. Salts which can be formed by the above procedure include the sulfate, hydrobromide , phosphate, hydrogen ;> phosphate, dihydrogen phosphate, acetate, methenesulfonate , succinate, tartrate, citrate, benzoate, and £- oluene sulfonate salts .

As indications of their psychotropic activity, the compounds of this invention have been found to block the uptake of various physiologically active monoamines . This blockade is shown both in vitro with radioactive labelled compounds to determine the amount of monoamine uptake by synapto-somes from rat brain, and in vivo by a variety of methods.

Among the physiologically active monoamines whose uptake is blocked by the compounds of this invention are included serotonin, norepinephrine and dopamine ( 3 , 4-dihydroxyphenyl-ethylamine) . While all of the compounds of this invention block the Uptake of monoamines, certain of them possess a unique selectivity in that they block the uptake of one of the monoamines to a far greater exteht than they do the uptake of the other two. Tables 1 and 2 which follow set forth the results of some of the in vitro determinations of the blockage of monoamine uptake by the compounds of this invention. In the tables, column 1 gives the R substitueht on the 3-phenylpropylamine and columns 2-4, the concentration in micrograms per ml. that blocks the uptake of a particular amine by 50 percent for the amines—norephinephrine , serotonin, and dopamine. At the head of each column is given the concentration of the particular monoamine used in the experiment.

TABLE 1 -CH-CH2-CH2-N(CH- Concentration in meg. /ml. that blocks 50% of amine uptake Norepine- R phrine Serotonin Dopamine 0 0.48 yM 0.1 yM 0.2 μΗ -fluorophenyl 15 .01 • 6 p-chloropheny 1 3 .03 1. 3 m-me thoxyphenyl 2 .08 • 5 m- tri f1uoromethy1 8 .18 >100. phenyl o-bromophenyl -- .1 5 m-ch loropheny1 02 .15 2 p-trifluoro- 70 .16 >100 methylphenyl o-ch loropheny1 45 .2 ' . 2 o-ethylpheny 1 >100 3.5 >100 o-isopropy 1- 1. 5 >100 >100 pheny 1 o-t-butylpheny 1 1. 5 40 >100 o-a1ly lpheny 1 1 .8 50 o-trifluoro- 70 .16 >100 methylpheny 1 o-anisyl 3 2.6 20 p-anisyl 7 1 3. 6 o-ethoxyphenyl 3 6 >100 o-fluoropheny 1 05 .3 35 p-fluoropheny1 >100 1 e- 45 2 , 4-difluoropheny 1 2 .3 10 TABLE 2 -CH-CH. -CH2-NH-CH3 6H5 Concentration in meg. /ml. blocks 50% of amine uptak Norepine- R phrine Serotonin Dopamine 0.48 μΜ 0.1 yM 0.2 μΜ p-trifluoro- 20 .06 >100 methylphenyl m-chlorophen 1 .07 .15 50 phenyl .12 .25 1 o-allylphehy1 .5 1 >100 o-trifluoro- 6.0 2.5 >100 meth lphenyl o-anisy1 .06 .3 .6 m-anisyl .15 4.5 .45 p-anisyl .16 .01 -■ o-fluorophenyl .1 3.5 10 m-fluorophehy1 .05 .8 4 p-fluorophenyl 2 1 .25 p-chlorophenyl .8 .2 >100 2 ,4-difluoro- >100 4.5. >100 phenyl One demonstration of the in vivo effect of the compounds of this invention in blocking serotonin uptake was made indirectly by the following experiment, based on a previous experiment of Meek et al. Biochem. Pharmacol., 20 707 (1971) who found that inhibitors of serotonin uptake prevent the depletion of brain serotonin caused by the injection of 4-chloromethamphetamine . in our procedure, ah amount of 4-chloroamphetamine known to deplete the birain serotonin level about 50 percent was injected into rats. Following this injection, the protecting drug was injected at a dose of 15 mg./kg. of rat-weight intraperi toneally and determinations of brain serotonin levels were carried out 4 hours later. In Table 3 which follows, column 1 gives the name of the drug employed, and column 2, the brain serotonin levels in mcg./g. of brain tissue.

Chloroimipramine and N-desme thy limipramine were employed as controls since Meek et al . (loc. cit.) had previously . shown that these drugs were capable of preventing the depletion of brain serotonin by 4-chloromethamphetamine * TABLE 3 Name of drug Brain serotonin level in mcg./g none 0.33 + .02 N -me thy 1 3- (£-trif luoro- 0.69 + .02 methylphenoxy ) -3-phehylpropylamine oxalate chioroimipramine 0.45 + .03 desmethylimipramine 0.44 + .03 saline con-trol 0.70 + .02 As can be seen from Table 3, N-methyl 3- (p_-tri- fluoromethylphenoxy) -3-phenylpropylamine as the oxalate salt prevented the depletion of serotonin caused by the injection of -chloroamphetamine and brain levels of serotonin were indistinguishable from those of the control rats to whom no drugs were given. The corresponding tertiary and primary amine derivatives, Ν,Ν-dimethyl 3- (p_-trifluoromethylphenoxy) -3-^phenylpropylamine oxalate and 3- (p-trifluoromethylphenoxy) -3-phenylpropylamine oxalate gave similar results. The secondary amine also prevented the depletion of serotonin in the brain occasioned by the administration of a-ethyl-4-methy1-m-tyramine but not the depletion of norepinephrine.

The tricyclic antidepressant drugs presently being marketed inhibit the uptake of monoamines by brain neurons most of them being more effective in inhibiting the uptake of riorephinephrine . Many of the compounds of this invention behave similarly in that they block norephinephrine uptake more effectively than they do serotonin uptake. Exceptions are the aforementioned p-trifluoromethy1 derivatives, the dimethylamino, monomethylamino and unsubsti tuted amine derivatives being far more effective in inhibiting serotonin uptake than in inhibiting norepinephrine uptake. Thus, although the compounds of this invention clearly have potential as anti-depressant compounds, it is apparent that N-methyl 3- (p_-trifluoromethylphehyloxy) -3-phenyIprbpylamine and its tertiary and primary amine analogs will have a different type of anti-depressant action from the presently marketed drugs. The compounds may also find use in the treatment of schizophrenia according to the hypothesis of Wyatt 7 112 1972 who were able to roduce id to moderate improvement in 6 of 7 chronic undifferentiated schizophrenic patients by the oral administration of 1-5-hydroxytryptophane , a serotonin precursor.

In addition to their usefulness as psychotropic agents , the above compounds may also find use in treating disorders of sleep, sexual performance, appetite, muscular function, and pituitary function. All of these physiologic functions have been shown to be subject to influence by brain serotoninergic neural systems.

In another aspect of their action as psychotropic drugs, specifically as antidepressants, the compounds of this invention show activity in antagonizing hypothermia induced by the injection of apomorphine and also in antagonizing the central effects of tremorine and oxotremorine , including hypothermia. In addition, the compounds are effective in reversing reserpine hypothermia, but are less effective in preventing reserpine hypothemia. In this regard * the mono-methylamines of this invention above are in general more active in antagonizing or reversing hypothermia than aire their dimethylamino analogs.

The apomorphine hypothermia antagonism test is carried out as follows: mice are injected with a dose of apbmorphine known to reduce body temperature approximately 4°C. The compound under test is injected 1/2 hour before the injection of the apomorphine and the temperatures measured 1/2 hour after injection. The degree of antagonism is expressed as a percent reduction (as compared with controls^ of the temperature decrease produced by the injection of the apomorphine. The reserpine hypothermia reversal test i3 carried out as follows: groups of mice are injected with reserpine and 16.5 hours later are injected intraperitoneally with graded doses of the drug, a different dose level being given to each group of mice. Temperatures are measured at 1 hour after injection of the drug under test and again the effectiveness of the drug is expressed as a percentage decrease in the hypothermia induced by the injection of reserpine as compared with the control group. In the tables which follow, Table 4 gives the results in the apomorphine antagonism and reserpine reversal hypothermia tests for the secondary amines of this invention. In the table, the first column gives the substituent attached to the oxygen atom at the 3 position of the propylamine chain; columns 2 to 4 the percent antagonism against apoirtorphine hypothermia at dose levels of 0.3, 1 and 3 mg./kgi and columns 5-7 the percent reversal of reserpine hypothermia at the same dose levels. Table 5 gives similar information for the , dimethylamino compounds of this invention.

TABLE 4 R-O-CH-CH. ■CH2-NH-CH3 έ6Η5 ' phenyl 16 36 86 7 27 36 o-allyIpheny1 19 29 120 — 11 29 o-trifluoromethylphenyl — 13 28 — 9 8 p-trifluoroniethyIpheny1 — 11 25 — 10 2 ,4-di fluorophenyl 20 53 64 13 17 27 o-anisyl 47 101 121 17 55 58 m-anisyl 15 15 71 8 21 21 p-ariisyl 0 31 45 12 23 20 o-fluoropheny1 13 57 87 10 8 34 hi-fluoropheny1 28 53 89 13 12 19 p-fluoropheny 1 7 19 66 7 39 32 m-chlorophenyl 11 58 136 — 12 38 p-chloropheny1 32 29 37 9 23 Ce H s Percent Antagonism Apomorphine Reser Pre- 30 min. Post- Dosage in mg./kg. .3 1 3 10 .3 1 o-ethyIpheny1 20 74 17 o-isopropylpheny1 3 17 39 65 12 20 o-allyIpheny1 11 67 o-1rif1uoromethy1pheny1 21 32 55 p-trifluoromethyIpheny1 24 2 , 4-difluorophenyl 26 55 98 23 11 o-anisyl 11 30 61 17 m-anisyl -'12 -7 -5 -1 p-anisyl 25 o-ethoxyphenyl 13 76 o-fluorophenyl -10 11 31 -1 m-fluorophe y1 24 41 p-fluorophenyl 26 63 116 14 10 o-chlorophenyl -10 -17 57 3 m-chloropheny1 0 13 66 9 p-chlorophenyl 7 43 85 5 o-bromophenyl 19 40 47 Reversal of reserpine hypothermia and antagonism of apomorphine hypothermia are pharmacologic tests in which a number of marketed antidepressants drugs, in particular ; imipramine, amitriptyline , nortriptyline and desmethyl-imipramine , are active . One of the compounds of this invention , -methy1-3- (o-methoxyphenoxy) -3-phenylpropylamirie has been found to be an apomorphine and reserpine hypothermia antagonist or reversant having an activity of the same order of magnitude as the aforementioned marketed antidepressant drugs. This compound, when its effect is measured 60 minutes after injection of the apomorphine, at a 10 mg./kg. dose gives 100 percent reduction of hypothermia, as do imipramine and amitriptyline . Similarly the same drug is extremely effective in reversing the effects of reserpine hypothermia and compares favorable in this regard with the same four marketed antidepressant compounds, giving a similar degree of reversal of hypothermia measured at 60 and 120 minutes; In manifesting their psychotropic action, the compounds of this invention also affect the behavior of animals trained in a variety of operant behavior schedules; Again, the activity of compounds of this invention in this type of test parallels that of known antidepressant drugs * particularly desmethyliraipramine . For example, N-meth 1 3-(o-riiethoxyphenoxy) -3-propylamine increased response rates of pigeons in a fixed-ratio, fixed interval schedule arid there was a persistence of this effect lasting for moire than 24 hours. A similar effect w^.s obtained with desmetiiyiiniipraniine although it is possible that the persistence encountered was the result of training under the influence of the drug, in Sidman avoidance usin s uirrel monke s the res onse of the monkeys increased at a dose level of 5 mg. kq. with N-methyl 3- (o-methoxyphenoxy) -3-phenylpropylamine . Similarly, in monkeys on a multiple fixed-ratio fixed-interval schedule, responses were reduced at dose levels of 2.5 or 5 mg./kg. of the drug. With pigeons trained under an adjusting ratio schedule, the drugs of this invention affect behavior in the same way as does the marketed antidepressant, desmethylimi-pramine (DMI) . In this test, drugs with this type of activity do not markedly affect the response rate but pausing is decreased, as reflected in an increased response per reinforcement. N-methyl 3- (o-methoxyphenoxy ) -3-phenylprop lamine , however, gave a significant percent increase in the ratio of responses to reinforcements at dose levels one- fourth of that required by DMI to produce a similar increase. The above results are consistent with anti-depressant action.

Finally, the compounds of this invention do not have significant antiserotonin , antihistaminic and ahticholinergic effects when tested in isolated muso-le strips using routine laboratory procedures. Again, there was a difference between N-methyl 3- (o-methoxyphenoxy) -3-phenylpropylamine as compared with desmethyliniipramine , which latter compound was 150 times more potent as an antihistaminic and anticholinergic agent and three times more potent as an antiserotonin agent, in anesthetized cats, intravenous injection of amitriptyline and other marketed tricyclic antidepressants causes a widening of the QRS complex of the electrocardiogram, indicating a delay in intraventricular conduction. 3- (o-Methoxyphenoxy) -3-phenylprop 1-amine affects the electrocardiogram similarly, but at far higher doses than are found with the aforementioned marketed antidepressants .

In testing humans suffering from various psychoses having a depressive, component, the compounds of this invention can be given orally or pairenterally . In either instance, it is preferred to use an acid addition salt of the compound formed with a pharmaceutically-acceptable non-toxic acid. For purposes of oral administration, the salt can be mixed with standard pharmaceutical excipients and placed in telescoping gelatin capsules. Similarly, the compound can be mixed with starch, binders, etc. and formulated into tablets, which tablets may be scored for ease of divided dosage administration. For parenteral administration, a water soluble salt of the compound of this invention; which salt is pharmaceutically-acceptable, is dissolved in an isotonic solution and administered intramuscularly, intravenously or subcutaneous ly . For chronic administration, the oral pharmaceutical forms are naturally preferred. The dose level should vary from 1 to 50 mg./dose given from 1 to 4 times a day with a total daily dosage of 1 to 200 mg. /day/human .

Claims (12)

What is claimed is :

1. Compounds of the formula 1 wherein each and is independently hydrogen or methyl; and R^ are halo, trifluoromethyl , C^-C^ alkyl, C^-C alkoxy or C^-C^ alkenyl; and n and m are 0, 1, or 2, with the limitation that both n and m are not 0 when both R^ are methyl and both R2 are hydrogen; and acid addition salts . thereof formed with pharmaceutically-acceptable acids.

2. A compound according to claim 1 wherein ^ is trifluoromethyl , allyl, methoxy, chloro, or fluoro; ^ is hydrogen or fluoro; and at least one R^ is methyl; and acid addition salts thereof formed with pharmaceutically acceptable acids.

3. A compound according to claims 1 or 2, said compound being N-methyl 3- (p_-trifluoromethylphenoxy) -3-phenylpropylamine , and acid addition salts thereof formed with pharmaceutically-acceptable acids .

4. A compound according to any of claims 1 to 3 , said compound being N-methyl 3- (p_-trifluoromethylphenoxy) -3-phenylpropylamine hydrochloride.

5. A compound according to claims ί or 2,■ said compound being N-methyl 3- (o-methoxyphenoxy) -3-phehylpropyi-amine , and acid addition salts thereof formed with pharmaceutically-acceptable acids .

6. A compound according to any of claims 1, 2, or 5, said compound being N-methyl 3- (o-methoxyphenoxy) - 3-phenylpropylamine hydrochloride.

7. A compound according to claims 1 or 2 , said compound being N-methyl 3- ( 2 , 4-difluorophenoxy) -3-phenylpropylamine.

8. A compound according to claims 1 or 2, said compound being N-methyl 3- (m-fluorophenoxy ) -3-phenylpropyl- amine oxalate.

9. A compound according to claim 1 said compound being 3- (p_-trifluoromethylphenoxy ) -3-phenylpropylamine and acid addition salts thereof formed with pharmaceutically acceptable acids. X-3821 36

10. A process for preparing compounds of the formula wherein R^, R2 , R^, and R^ are as defined in claim 1, which comprises reacting a N,N-dimethyl-3-phenyl-3-halopropylamine with a "phenol; and if desired demethy lating the dimethylamine so obtained to provide the corresponding monbmethy1amine compound; or reacting a 3-chloro-l- (subs tituted-phenoxy) - propyl benzene With an amine of the formula HN. or R with sodium azide followed by reduction with sodium boro- hydride; and if desired forming an acid addition salt with a pharmaceutically-acceptable acid.

11. X-3821 37 Compounds of the formula wherein R^, R2 , R3, and are as defined in claim 1, substantially as hereinbefore described with particular reference to the examples.

12. A process for preparing compounds of the formula wherein F^, 2 , 3, and R^ are as "defined in claim 1, substantially as hereinbefore described with particular reference to the examples.