CA1302421C - 3-aryloxy-3-substituted propanamines - Google Patents

Abstract

Abstract of the Disclosure The present invention provides 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine.

Description

X-7042 ~1 This invention relates to novel 3-aryloxy-3-substituted propanamines, and to their use in inhibiting serotonin and norepinephrine uptake.
During the past decade, the relationship between monoamine uptake and a variety of diseases and conditions has been appreciated and investigated.
For example, the hydrochloride salt of fluoxetine (dl-N-methyl y-[4-(trifluoromethyl)phenoxy]benzenepropan-amine) is A selective and spe~ific serotonin (5~hydroxy~
tryptamine~ uptake inhibitor presently undergoing clinical evaluation for.the treatment of depression, anxiety, appetite suppression, and other disorders.
Similarly, tomoxetine hydrochloride ((-)-N-~methyl-y-(2-methylphenoxy)benzenepropanamine hydrochloride) is a selectiv~ and specific inhibitor of norepinephrine uptake being investigated clinically for its antidepres-sant activity. These compounds are among many taught in ~0U.S. Patents Nw~rs 4,018,895, 4,194,009, and 4,~14,081 as being potent but selective blockers of the uptake of one particular monoamine inhibitor.
. The present invention provides novel 3-aryloxy-3 substituted propanamines which are potent inhi~itors of both serotonin and norepinephrine uptake.

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X~70~2 -2-According to the present invention there is provided a compound of the formula Rl -CHCH2 CH2 NR2 1~3 Ar wherein:
0 Rl iS C5-C7 cycloalkyl, thienyl, halothienyl, (Cl-C4 alkyl~thienyl, furanyl, pyridyl or thiazolyl;

7_~ Rm Ar is ~ ~ or ~ _ R ~
each of R2 and R3 independently is hyd~ogen or methyl;
each R4 independently is halo, Cl-C~ alkyl, Cl-C3 alkoxy or trifluoromethyl;
each R5 independently is halo, Cl-C~ alkyl or trifluoromethyl;
m is 0, 1 or 2;
n is 0 or 1; and the pharmaceutically acceptable acid addi-tion salts thereof.
The in~ention also provides pharmaceutical formulations comprising a compound of the above formula ~-7042 ~3~

and a pharmaceutically acceptable carrier, diluent or excipient therefor.
A further embodiment of the invention are methods for selec-tively inhibiting the uptake of serotonin and norepinephrine, as well as for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin and norepinephrine in m~nals including obesity, depression, alcoholism, pain, loss of memory, anxiety, smoking, and the like, employing a compound of the invention.
In the above formula, the term Cl-C4 alkyl represents a straight or branched alkyl chain bearing from one to our carbon atoms. Typical Cl-C~ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-bu-tyl, isobutyl, sec.-butyl and t-butyl.
Cl-C3 Alkoxy represents methoxy, ethoxy, n-propoxy or isopropoxy.
Halo represents fluoro, chloro, bromo or iodo.
When Ar is naphthalenyl, it can be either l-naphthalenyl or 2-naphthalenyl.
When Rl is thienyl, it can be either ?-thienyl or 3-thienyl; when Rl is furanyl, it can be either 2-furanyl or 3-furanyl; when Rl is pyridyl, it can be either 2-pyridyl, 3-pyridyl or 4-pyridyl; when Rl is thiazolyl, it can be either 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

(Cl-C4 Al~yl)thienyl represents a thienyl ring monosubstituted with a Cl-C4 alkyl substituent. Typic 1 ( Cl -C4 alkyl)thienyl groups include 4-methyl-2-thienyl, 3-ethyl~2-thienyl, 2-methyl-3~thienyl, 4--propyl-3~thienyl, 5-n~butyl-2-thienyl, 4-methyl-3-thienyl, 3-methyl 2-thienyl, and the like.
Halothienyl represents a thienyl rlng mono-substituted with a halo substituent. Typical halo-thienyl groups include 3-chloro-2-thienyl, 4-bromo-3-thienyl, 2-iodo-3-thienyl, 5iodo-3-thienyl, 4-fluoro 2-thienyl, 2-bromo 3-thienyl, 4-chloro-2-thienyl and the like.
While all of the compounds of the present invention are believed to inhibit the uptake of serotonin and norepinephrine in mammals, there are certain o~
these compounds which are preferred for such uses.
Preferably, R1 is halothienyl, ~Cl-C~ alkyl)thienyl and especially ~hienyl. Fuxther, one of R2 and R3 is hydrogen and ~he other is methyl. It is also preferred that those compounds wherein both R2 and R3 are other than methyl are preferred for inhibiting the uptake of norepinephrine in mammals. Other prefer~ed aspects of the present invention will be noted hereinafter~
The compounds of the present invention possess an asymmetric carbon represented by the carbon atom labeled "C" in the following formula:

R1-C~CH2CE2NR2R3 O
Ar h X-704~ _5_ As such, the compounds can exist as the individual stereoisomers as well as the racemic mixture. Accord-ingly, the compounds of the present invention will include not only ~he dl-racemates, but also their re-spective optically active d- and l-isomers.
As pointed out above, the invention includes the pharmaceutically acceptable acid addition salts of the compounds defined by the above formula. Since the compounds of this invention are amines, they are basic in nature and accordingly react with any num~er of inor-ganic and organic acids to form pharmaceutically accept-able acid addition salts. Since the free amines of the invention are typically oils at room temperature, it is preferable to convert the free amines to their corre-sponding pharmaceutically acceptable acid addition salts,which are routinely solid at room temparature, for ease of handling. Acids commonly employed to form such salts i~clude inorganic acids ~uch as hydrochloric, hydro-bromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methane-sulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acid~. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenpho~phate, metaphosphate, pyrophos-phate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malo~ate, succinate, suberate, sebacate, fumarate, maleate, ~3~

butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chloro-ben~oate, methylbenzoate, dinitrobenzoate, hydro~y-benzoate, metho~y~enzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetat.e~ phenylpro-pionate, phenylbutyrate, citrate, lactate, ~-hydroxy butyrate, glycollate, maleate, tartrate, methanesul-fonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts.
Preferred pharmaceutically acceptable acid additlon salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, a~d especially those formed with organic acids such as oxalic acid and maleic acid.
The ~ollowing compounds further illustrate compounds contemplated within the ~cope of the presen-t invention:
N-Methyl-3~ naphthalenyloxy)-3~(3-thienyl)-propanami~e phosphate N-Methyl-3-~2~naphthalenyloxy)-3-(cyclohe~yl)-propanami~e citrate N,N-Di~ethyl-3-(4-chloro-1-naphthalenyloxy)-3-(3-furanyl)propanamine hydrochloride N-Methyl-3-(S-methyl-2-naphthalenyloxy)-3-~2-thiazolyl)propanamine hydrobromide N-Methyl-3-[3-(trifluoromethyl)-1-naphthalenyl-oxy]-3-(3-methyl-2-thienyl)propanamine oxalate N-Methyl-3-(6-iodo-1-naphthalenyloxy)-3-~4-pyridyl)propanamine maleate N,N-Dimethyl 3~ naphthal~nylo~y) 3 (cyclo heptyl)propanamine formate N,N-Dimethyl-3-(2-naphthalenyloxy)-3-(2-pyridyl)~
propanamine N-Methyl-3~ naphthalenyloxy)-3-(2-furanyl)-propanamine sulfate S N-Methyl-3-(4-methyl-1-naphthalenyloxy)-3-(4-thiazolyl)propanamine oxalate N-Methyl-3~(2-naphthalenyloxy)-3-(2-thienyl)-propanamine hydrochloride N,N-Dimethyl-3-(6-iodo-2-naphthalenyloxy)-3-~4-10 bromo-3-thienyl )propanamine malonate N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(3-pyridyl)-propanamine hydroiodide N,N-Dimethyl-3-(4~methyl-2-naphthalenyloxy)-3-(3-furanyl)propanamine maleate N-Methyl-3-(2-naphthalenyloxy)-3-(cyclohexyl)-propanamine caprate N-Methyl-3-(6-_-propyl-1-naph~halenyloxy~-3-(3-i60propyl-2-thien~l)prop~namine citrate N,N-Dimethyl-3-(2-methyl~1-naphthalenylo~y)-3-(4-thiazolyl)propanamine monohydrogen phosphate 3~ Naphthalenyloxy)-3-(5-ethyl-3-thienyl)-propanamine succinate 3-[3-(Trifluoromethyl)-l-naphthalenyl-oxy]-3 (pyridyl)propanamine acetate N-Methyl~3-(6-methyl-1-naphthalenyl-3-(4-chloro-2-thienyl)propanamine tartrate 3 (2-Naphthalenyloxy)-3-(cyclopentyl )propananine N-~ethyl-3-(4-n-butyl-1-naphthalenyloxy) 3-(3-~uranyl)propan~mine methanesulonate :~3~

3-(2-Chloro-1-naphthalenyloxy) 3-(5-thiazolyl)-propanamine oxalate N-Methyl-3~ naphthalenyloxy~-3-(3-furanyl)-propanamine tartrate N,N-Dimethyl-3-(phenoxy3-3-(2-furanyl)-propanamine oxalate N,N-Dime~hyl-3-[4-(trifluoromethyl3phenoxy]-3-(cyclohexyl)propanamine hydrochloxide N-Me~hyl-3-(4-methylphenoxy)-3-(4-chloro~2-thienyl)propanamine propionate N-Methyl-3-(phenoxy)-3-(3-pyridyl)propanamine oxalate 3-[2-Chloro-4-(tri1uoromethyl)phenoxy]-~3-~-thienyl)propanamine N,N-Dimethyl-3-(3-methoxyphenoxy)-3-(3-bromo-2-thienyl)propanamine citrate - N-Methyl-3-(4-bromophenoxy~-3-(4-thiazolyl)-propan~mine maleate N,N-Dimeth~1-3-(2-ethylphenoxy~-3-(5-methyl 3-thienyl)propanamine N-Methyl-3-(2-bromophenoxy)-3-(3-thienyl)-propanamine succinate N-Methyl-3-(2,6-dimethylphenoxy)-3-(3~methyl-2-thienyl)propanamine acetate 3-~3-(Trifluoromethyl~phenoxy]-3-~3-furanyl)-propanamine oxalate N-Methyl-3-(2,5-dichlorophenoxy)-3 (cyclo-pentyl~propanamine 3-[4-(Trifluoromethyl)phenoxy]-3-~2-thiazolyl)propanamine ~3~ 3~

N-Methyl 3-~phenoxy)-3-(5-methyl-2-thienyl)-propanamine citrate 3-~4-Methylphenoxy) 3-(4-pyridyl)propanamine hydrochloride N,N-Dlmethyl-3-(3-methyl-5-bromophenoxy)-3 (3-thienyl)propanamine N-Me~hyl-3-(3-n-propylphenoxy)-3-(2-thienyl)-propanamine hydrochloride N-Methyl-3-~phenoxy~-3-(3thienyl)propanamine phosphate N-Methyl-3-(4-methoxyphenoxy) 3-~cycloheptyl)-propanamine citrate 3-(2-Chlorophenoxy)-3-(S-thiazolyl)propanamine propionate 3-[2-Chloro-4-(tri1uoromethyl)phenoxy]-3-(3-thienyl)propanamine oxalate 3-~Phenoxy)-3-(4-methyl-2-thienyl)propanamine N,N-Dimethyl-3-(4-ethylphenoxy)-3-(3-pyridyl)-propanamine maleate N,N-Dimethyl-3~[4-~trifluoromethyl)phenoxy~-3-(2-pyridyi)propanamine The compounds of the present invention may be prepared by procedures well known to those of ordinaxy skill in the art. The compounds are preferably synthe-sized by treating an hydroxy intermediate with an alkali metal hydride to form the corresponding alkali metal salt~ which is then reacted with an appropriate compound containing a good leaving group to provide the corre-~ 3 ~
~042 -10~

sponding 3-aryloxy-3-substituted propanamine of the invention. This reaction may be represented by the fol-lowing scheme:

MH
~l-CHCH2CH2NR2Pc3 ~ Rl~CHC'~2CH2NR2R3 X t ~ Ar Y-Ar wherein M is an alkali metal, R1, R2, R3 and Ar are as defined above, and one of X and Y is hydroxy and the other is a good leaving group such as p-toluenesulfonyl, methanesulfonyl, triphenylphosphine oxide, halo and the like. Preferably X is hydroxy and Y is halo. The alkali metal,hydride may be replaced by other bases strong enough to generate t~e anion.
The present invention, therefore~ in another aspect, resides in a process for preparing a compound o~
the formula (I):

Rl-CaC~2C~2NR2R3 (I) O
Ar ~herein:
R1 is C5-C7 ~ycl~alkyl, thienyl, halothienyl, ~C1 -C4 alkyl)thie~yl~, fu~anyl, pyrldyl or thiazolyl;
/~=~yR m Ar is ~ or t R8~f ~
n ,~..;.

-lOa~

each of R2 and R3 independently is hydrogen or methyl;
each Rd independently is halo, C~-C~ alkyl, Cl-C~ alkoxy or trifluorome~yl;
5each R5 independe~tly is halo, Cl-C~ alkyl or tIifluoro~ethyl;
m is 0, 1 or 2;
is 0 or 1, ~r a pharmaceutically acceptable acid addi-tion 6alt ~hereof which compri~es:
(~) reacti~g a compound of formula:
R1-CHCH2C~2NR2R3 X
with a reagent of formula Y-Ar, wherein R1, R2, R3 and I5 Ar are a~ de~ined above and OnQ o~ X and Y i~
hydro~y and the other is a good leaving group, in ~he pres~nce of a base strong enough to generate the anion of ~he hy~roxy containing compounds; or ~B) khe demethylation of a compound of Formula (I) wherein both of R2 and R3 are methyl so as to provide a compound of Formula (I) in which one of R2 and R3 is hydrogen and the other is methyl;
(C) reaction (A) or (B~ b~ing optionally followed, if necessary, by salification to form a pharmaceuti~ally acceptable acld addition salt;
and in the event that an enantiomerically pure product, viz. an enantiomerically pure form of the compound of formula (I), is desired, preparing ~aid enantiomerically pure product by the reaction of the re~pective enanticmerically pure reactants a~ defined above, or by e~fecting resolution of a racemi~ mixture of said compound of ~ormula (I) to the desired enantiomerically pure form thereof.

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This reaction is carried out by combining approximately eguimolar guantities to a slight excess of ~he alkali metal hydride with the alcohol to provide the corresponding alkali metal salt. $ypical alkali metal hydrides include sodium hydride and potassium hydride. The compou~d is the~ reacted with an equimolar quantity to slight excess of the compound having the good leaving group. The reaction is conducted in a suitable aprotic solvent such as N,N-dimethylacetamide and related solvents. The reaction is substantially complete after about 10 minutes to about 24 hours when conducted at a temperature in the range of about 25C to about 150C. More preferably, ~he reaction mixture will be complete within about 30 minutes to about 6 hours when conducted at a temperature in the range of about 75C to about 125C. The product may be isolated by standard conditions as well. Typically, the mixture is S diluted with water and extracted with a water immiscible organic solvent uch as diethyl ether, ethyl acetate, chloroorm and the like. The organic extracts are typically combined and dried. Following evapor~tion of the organic solvent the isolated residue may be further purified, if desired, by standard techniques such as crystalli2ation from common solvents, or chromatography over solid supports such as silica gel or alumina.
The compounds of the present invention wherein one of R2 and R3 is hydrogen and the other is methyl are preferably prepared by demethylating the corresponding N,N-dimethylpropanamine. Preferably, a reagent such as phenyl chloroformate or trichloroethyl chloroformate i5 reacted with the N,N-dime~hylpropanamine to provide the correspondi~g intermediate, which is then hydrQlyzed in base to provide the corresponding N-methylpropanamine.
As ~oted above, the optically active isomers of the racemates of the invention are also considered part of ~his invention. 5uch optically active isomers may be prepared from ~heir respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out in the presence of a re~olving agent, by chromatography or by repeated crystallization. Parti~u larly useful resolving agents include dibenzoyl-d- and -l-tartaric acids and the like.

~ 3 The compounds employed as starting materials in the synthesis of the compounds of the invention are also prepared by standard procedurec;. Preferably, standard Mannich reaction conditions are employed to synthesize the corresponding Mannich Base from the appro-priate ketone, formaldehyde and dimethylamine, which is then reduced with a hydride reducing agent, such as sodium borohydride, employing standard reduction condi-tions. The analogs containing the leaving group are also prepared by known procedures or are commercially available from various organic laboratories.
The pharmaceutically acceptable acid addition salts of the invent.ion are typically ormed by reacting a 3-aryloxy-3-substitu-ted propanamine of the invention with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene, and the salt normally precipitates out of solution within about one hour to 10 days, and can be isolated by filtration.
The following Examples further illustrate the compounds of the present invention and methods for their synthesis. The Examples are not intended to be limiting to the scope of the invention in any respect and should not be so construed.

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Example 1 N,N-Dimethyl-3~ naphthalenyloxy)~3-(2-thi enyl)propanamine o~alate A. 3-Dimethylamino-1-(2-thienyl)-1-propanone hydrochloride A mixture of 2-acetylthiophene (63.1 g, 0.5 mol), dimethylamine hydrochloride (53.0 g, 0.65 mol), paraformaldehyde (19.8 g, 0.22 mol), and 12N hydro-chloric acid (1 ml) in ethanol (80 ml) was refluxed for one and one-half hours~ The solution was diluted with ethanol (100 ml) and acetone (500 ml). The solution was chilled overnight and the resulting solid was collected by ~iltration to yield 75.0 y (73%) of 3-dimethylamino-1-(2-~hie~yl)-1-propanone hydrochioxide as a colorless crystalline solid. mp = 182C-184C

Analysis calculated for CgH14ClNOS
Theory: C, 49.20; ~, 6.42; N, 6.37;
Found: C, 49.40; H, 6.21; ~, 6.09.

B. a-[2-(Dimethylamino)ethyl]-2-~hiophene methanol To a solution of 3-dimethylamino-1-(2-thienyl)-1-propano~e hydrochloride (70.0 g, 0.34 mol) in 840 ml of methanol and 420 ml of water at about 0C was added 5N sodium hydro~ide until the solution was slightly basic. To ~he resultiug solution was added sodium boro-hydride (12.9 g., 0.34 mol) in portions. The mixture was allowed to warm to room temperature overnight. The methanol was removed in vacuo and the remaining solution was diluted with water. The solution was extracted with diethyl ether, and the solution was washed with a satu-S rated sodium chloride solu~ion , dried over anhydroussodium sulfate and concentrated ln vacuo to provide 56.7 g of colorless crystals. Recrystallization of the crystals from hexane~ gave 49.24 g (78%~ of the title compound as colorless crystals. mp = 72C 74C
Analysis calculated for CgH15NOS
Theory: C, 58.34; H, 8.16; N, 7.56;
Found: C, 58.62; H, 8.29; N, 7.68.

C. ~-[2~(Dimethylamino)ethyl]-2-thiophene me~hanol (2.0 g~ 0.011 mol) was added in portions to a solution of 60% sodium hydride (463 mg, 0.012 mol) in 100 ml of dimethylacetamide. The resulting mixture was heated at 70C for 20 minutes. l~Fluoronaphthalene (1.27 ml, 0.012 m) was added dropwise to the mixtuxe and the resulting solution was heated at 110C or 60 min-utes. The reaction mixture was diluted with water and extracted twice with diethyl ether. The extracts were combined, washed with water followed by a saturated sodium chloride solution, dried ovex anhydrous sodium aulfate and concentrated under reduced pressure to yield 3.2 g of an oil. Crystallization of the oil as the oxalate salt from ethyl acetate/methanol yielded 3.28 g ~75.6%~ of N,N-dimethyl-3-~1-naphthalenyloxy)-3-(2-thienyl)propa~amine oxalate as a white solid.mp = 148C-148.5C

~3~3~

Analysis calculated for C2lH23NO55 Theory: C, 62.83; ~, 5.77; N, 3.49;
Found : C, 62.70; ~, 5.88; N, 3.26.

Example 2 N-Methyl~3~ naphthalenyloxy)-3-(2-thienyl)-propanamine oxalate Phenyl chloroformate (794 ~1, 0.0063 mol) was added dropwise to a refluxing solution of N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (1.79 g, 0.0058 mol) in 100 ml of toluene. The resulting solu-tion was refluxed one and one half hours and cool~d to room temperature. The solution was washed (2.~N sodium hydroxide, water, lN hydrochloric acid, brine), dried over anhydrous sodium sulfate a~d concentrated in vacuo to give 2.4 g of the crude carbamat~. 5N Sodium hydroxide (11.5 ml, 0.058 mol) ~as added to a solution of the carbamate ~2.4 g, 0.0058 mole) in propylene glyco~ (100 ml). The mi~ture was heated at 110C for 75 minutes. ~he reaction mixture was diluted wi~h water and e~txacted with diethyl ether. The organic phase was washed with wat~r and then wi~h a saturated sodium chloride solution, dried over anhydrous ~odium sulfate, and ~on-centrated under vacuum to yield 1.5 g of an oil. Crys-tallization of the oil as the oxalat~ salt from ethyl acetate/m~thanol gave 920 mg ~41.3%] o~ the ~itle com-pound as a whit~ powder. mp - 136C-138.5C

P~ .
., ~3~2~

Analysis calculated for C2oH2lNO5S
Theory: C, 62.00; H, 5.46; N, 3.62;
Found: C, 62.21; H, 5.72; N, ~.57.

Exam~le 3 N, ~-Dimethyl-3-(1-naphthalenyloxy)-3-(5-methyl 2-thienyl)propanamine oxalate A. 3-Dimethylamino-l-(5-methyl-2-thienyl~-1 propanone hydrochloride The title compound was prepared according to the general procedure outlined in Example 1 employing lS 2~acetyl-5-methylthiophene as the starting material to provide 31.3 g (37.4%) of a yellow powder following crystallization from acetone. mp = 145C-147C

Analysis calculated for CloHl6ClNOS
Theory: C, 51.38; ~, 6.90; N, 5.99;
Found : C, 51.53; ~, 6.82, N, 5.66.

B. a-[2-(Dimethylamino)ethyl]-5-methyl-2-thiophene methanol According to the general procedure set forth in Example 1 using 3-dimethylamino-1-(5-methyl-2-thienyl)-1-propanone hydrochloride as ~he starting material.
The title compound was obtained (50.9%) as an opaque crystalli~e solid was synthesized. mp = 66.5C-68C

~3~3Z~
~70~2 -17-Analysis calculated for C1oH1?NOS
Theory: C, 60.26; H, 8.60; N, 7.03;
Found: C, 60.49; H, 8.58; N, 6.9]..

C. According to the procedure.set forth in Example 1, using ~-[2-~dimethylamino)ethyl~-5-methyl-2-thiophene methanol as the starting material N,N dimethyl-3-(1-naphthalenylo~y)=3-(5-methyl-2-thienyl)propanami~e was prepared. The crude material was chromatographed over silica gel (eluent-methylene chloride/methanol) to yield 1.4 g (25.5~) of an oil. Crystallization from ethyl acetate/methanol of a small portion of the oil as the oxalate salt gave the title compound as yellow crystals. ~p = 151C
Analysis calculated for C22E25NO5S
Theory: C, 63.59; H, 6.06; N, 3.37;
Found: C, 63.36; ~, 5.84; N, 3.33.

Exam~e 4 N,N~Dimethyl-3~(1 naphthalenyloxy)-3-~3-methyl-2-thienyl)propanamine oxalate A. 3-Dimethylamino-1-(3-methyl-2-thienyl)-l-propanone hydrochloride The title compound w~s prepared according to the general procedure set forth in Example 1 using 2-acetyl-3-methylthiophene as the starting material.

The crude material was crystallized from acetone to provide 43.4 g (60.7%) of the title compound as a white powder. mp = 157C-158C

S Analysis calculated for CloHl6ClNOS
Theory: C, 51.38; H, 6.90; N, 5.99;
Found: c, 51.63; H, 7.14; N, 5.82.

B. ~-[2-(Dimethylamino)ethyl]-3-methyl-2-thiophene methanol The title compound was prepared from 3-dimet:hyl-amino-1-(3-methyl-2-thienyl)-1-propanone hydrochloride according to the yeneral procedure of Example 1. Crys-tallization from hexanes yielded 11.38 g (53.7%) of an op~que crystalline solid. mp = 41.5C-42.5C.

Analysis. calculated for C10~17NOS
- Theory: C, 60.26; H, 8.60; N, 7.03;
Found: C, 60.80; H, 8.33; N, 6.56.

C. Crude N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(3-methyl-2-thienyl~propanamine, prepared according to the general procedure outlined in Example 1, was chromatographed over silica gel (eluent-methylene chloride/methanol) to yield 10.4 g ~74.3%) of an oil.
The oil was converted to the oxalate salt and crystal-lized from ethyl acetate/m~thanol to give a white powder. mp = 140C-141C

Analysis calculated for C22H25N05S
Theory: C, 63.59; H, 6.06; N, 3.37;Found: C, 63.85; H, 6.07; N, 3.49.

Example 5 N,N-Dimethyl-3~ naphthalenyloxy)-3-(5-chloro-2-thienyl)propanamine oxalate - A. 3-Dime~hylamino-1-(5-chloro-2-thienyl)-1-propanone hydrochloride The title compound was prepared according to the general procedure of Example 1 using 2 acetyl-5-chlorothiophene as the starting material. Crystalliza-tion from acetone gave 14.55 g ~36.9%). mp = 170C-171C

Analysis calculated for C9H13Cl2NOS
Theory: C, 42.53; ~, 5.16; N, 5.51;
Found: C, 42.00; H, 5.23; M, 6.50 B. ~-[2-(Dimethylamino)ethyl] 5-chloro-2 thiophene methanol Three grams of the title compound were prepared from 3-dimethylamino-1-(5-chloro-2 thienyl)-l-propanone hydrochloride according to the general procedure of E~ample 1 following cryst~llization from hexanes (38.6%).
~p _ 76~-77C

~3X:~2~

Analysis calculated fo~ CgH14ClNOS
Theory: C, 49.20; H, 6.42; N, 6.37;
Found: C, 47.3?; H, 6.o5; N, 6.40.

C. N,N-Dimethyl-3-(1-naphtha].enyloxy)-3-(5-chloro-2-thienyl)propanamine was prepared from a-[2-(dimethylamino)ethyl]-5-chloro-2-thiophene methanol according to the general procedure of Example 1. The crude product was chromatographed over silica gel employ-ing methylene chloride/methanol/ammonium hydroxide as the eluent to yield 320 mg (5.5%) of an oil. Crystal-lization of the oil as the oxalate salt from ethyl acetate/methanol gave a brown solid. mp = 134C-135C

hnalysis calculated for C21~22ClNO5S
Theory: C, 57.86; H, 5.09; N, 3.21;
Found: C, 57.73; ~, 5.35; N, 3.30.

Exam~le 6 N,N-Dimethyl-3-[4-(trifluoromethyl)-1-naphthalenyloxy]-3-(2-thienyl)propanamine oxalate According to the procedure set forth in Exam-ple 1 using 4-trifluoromethyl-1-fluoronaphthalene as a starting ma~erial, 1.7 g (66.9%) of the title compound as a tan solid was prepared following crystallization from ethyl acetate/methanol. mp = 146C-147C

,~nalysi~ calculated for C22~22F3NO5S
Theory: C, 56~28; H, 4.72; N, 2.98;
Found : C, 56.04; H, 4.65; N, 3.23.

2~

N-Methyl-3-[4-(trifluorome~hyl)-l-naphtha-lenylo~yl-3~(2-thienyl)propanamlne o~alate According to the procedure set forth in Example 2 N,N-dimethyl-3-[4-(trifluoromethyl)-1-naph-thalenyloxy]-3-(2-~hienyl)propanamine oxalate was converted to the title compound. Crystallization from e~hyl acetate/methanol gave 430 mg (33.8%) of a tan powder. mp = 154C-156C

Analysis calculated or C20H20F3N05S
Theory: C, 55.38; H, 4.43; N, 3.08;
Found: C, 55.63; H, 4.55; N, 3.27.

Exam~le 8 N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(3-thienyl)propanamine oxalate A. 3-Dim~thylamino-1 (3-thienyl)-1-propanone hydrochloride The title compound was prepared according to the procedure of Example 1 using 3-acetylthiophene as a starting material. Crystallization from acetone gave 73.9 g (84.9%~ of a tan powder. mp = 143C-145C

Analy~is calculated for CgH14ClNOS
Theory: C, 49.20; H, 6.42; N, 6.37;
Found: C, 46.27; ~, 6~11; N, 7.00.

~3~

B. ~[2~(Dimethylamino~ethyl] 3-thiophene me~hanol The title compound was prepared according to the procedure in Example 1 using 3-dimethylamino-1-(3-thienyl~ propanone hydrochlorlde as a starting material. Crystallization from diethyl ether/hexane gave 29.0 g (47.7%~ of the title compound as a solid.
mp = 63C-65C
Analysis calculated for CgH1sNOS
Theory: C, 58.34; E, 8.16; N, 7.56;
Found: C, 58.34; H, 8.17; N, 7.72.

C. N,N-Dimethyl-3-(1-naphthalenyloxy)-3~(3-thienyl)propanamine oxalate was prepared according to the procedure of E~ample 1 using ~ [2-(dimethyl-ami~o)~thyl3-3-thiophene methanol as a starting mate-rial. Crystallization from ethyl acetate/methanol gave 5.88 g (69.8%) of a white powder. mp = 164C-165C

Analysis calculated or C21H23NO5S
Theory: C, 62.83; ~, 5.77; N, 3.49;
Found: C, 63.12; H, 6.01; N, 3.51.

N-Methyl-3~ naphthalenyloxy)-3-(3-thlenyl~-propanamine oxalate s The title compound was prepared according to the proceduxe of Example 2 from N,N-dimethyl-3~ naph-thal~nyloxy)-3-(3-thienyl)propanami~e. Crystallization from ethyl acetate/methanol gave 2.97 g (63.6%) of a white powder. mp = 148C-150C

Analysis calculated for C~oH2lNO5S
Theory: C, 62.00; ~, 5.~6; N, 3.62;
Found: C, 62.23; H, 5.59; N, 3.85.
Example 10 N,N-Dimethyl-3-(4 chloro-1-naphthalenyloxy)-3;~2 thienyl)propan~nine oxalate To a stirred mixture of 4-chloro-1-naphthol (5.36 g, 0.03 mol), ~-[2-(dimethylamino)ethyl]-2-thio-phene methanol (5.56 g, 0.03 mol), triphenylphosphine (7.87 g, 0.03 mol) and 75 ml of tetrahydrofuran under a nitrogen atmosphere was added 4.8 ml ~0.03 mol) of diethylazodicarboxylate dropwise. Occasional cooling wa~ needed to keep the temperature of the reaction mix-ture below about 30C. The resulting solutian was stirrad at room t~mperature overnight. The volatile constituents were evaporated under vacuum. The residue ~3~

was diluted with water and the mixture was basified with 5N sodium hydroxide. The mixture was extracted with diethyl ether, and the organic extracts were washed with water and dried over anhydrous sodium sulfate. Evapora-tion of the diethyl ether and preparative HPLC of theresidue using a silica column with a methylene chlorlde/-methanol mixture as eluant yielded 3 7 g (36% yield) of the puxe free base as an oil. The oxalate salt was prepared from the above free base by treating an ethyl acetate solution of the free base with oxalic acid. The resulting precipitate was recrystalli~ed from ethanol to afford colorless crystals. mp = 155C dec.

Analysis calculated for C2lH22ClNO5S
Theory: C, 57.86; H, 5.09; N, 3.21;
Found: C, 57.66; H, 4.94; N, 3.12.

N-Methyl-3-(4-chloro-1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate To a stirred solution of N,N-dimethyl-3-(4-chloro-1-naphthalenyloxy)-3-(2-thienyl)propanamine (2.81 g, 8.12 mmol) and 20 ml of toluene heated at 85C was add~d dropwise trichloroethyl chloroformate (1.89 g, 8.93 mmol). The stirring was continued at 85C for three hours, and ~he resulting solution was cooled in an ice bath. To the mi~ture was added 0.13 ml of 98% formic acid followed by 0.28 ml of triethylamine.

The mixture was stirred at room temperature for 30 min-utes. The mixture was poured into water and the result-ing mixture was extracted with diethyl ether. The organic extracts were washed successively with a satu-rated sodium chloride solution, a 2N hydrochloric acidsolution and a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate.
The volatile constituents wexe evaporated under vacuum to yield 3.83 g (92% yield) of the crude carbamate as an oil. To a solution of the crude carbamate in 10.0 ml of DMF was added 98% formic acid (0.69 g., 14.9 mmol). The reaction solution was cooled to about 15C under a n:Ltro-gen atmosphere. Zinc dust (1.22 g, 18.7 mmol) was next added in portions over a 30 minute period. The mixture was stirred at about 15C for one hour and then over-night at room temperature. The reaction mixture was filtered through a sintered glass funnel and the fil-trate was diluted with water. The acidic solution was made basic with excess cold ammonium hydro~ide and then extracted with diethyl ether. The organic extracts were washed with water followed by a saturated sodium chlo-ride solution. The organic phase was dried OVeL anhy-drous sodium sulfa-te and evaporated under vacuum. The residue was purified by preparative HPLC using a silica gel column with a methylene chloride/methanol/a~monium hydroxide 5100:5:1, v:v:v) mixture as eluant to give - 1.26 g (51% yield) of the free base as an oil.
The oxalate salt was prepared from the free base by treating an ethyl acetate solution of the free base with oxalic acid. The resulting precipitate was :IL3~

X-704~ -26-crystallized from methanol to afford colorless crystals.
mp = 182C dec.

Analysis calculated for C20H20ClNOsS
Theory: C, 56.94; H, 4.78; N, 3.32;
Found: C, 57.22; H, 4.54; N, 3.48.

ExamPle 12 N,N-Dimethyl~3-~4-methyl-1-naphthalenyloxy)-3-~2-thienyl)propanamine oxalate N,N-Dimethyl-3-(4-methyl-1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate was prepared in 21%
yield by the general procedure described in~Example 10.
The oxalate salt was made and crystallized from ethanol to afford the title compou~d as colorless crystals.
mp = 151C dec.

. 20 Analysis calculated for C22H2sNsS
Theory: C, 63.59; H, 6.06; N, 3.37;
Found: C, 63.29; ~, 6.02; N, 3.23.

Example 13 N-Methyl-3-(4-methyl-1-naphthalenyloxy)-3-(2-thienyl)propanamine maleate The free base of the title compound was prepared in 44% yield by the procedure described above in Example 11. The maleate salt was prepared from the free ~ase by treating an ethyl acetate solution of the free base with maleic acid. The resulting precipitate was recrystallized from ethanol to afford colorless crystals. mp = 174C dec.

Analysis calculated for C23H25NOsS
Theory: C, 64.62; H, 5.89; H, 3.28;
Found: C, 64.49; H, 5.71; N, 3.48.

The following compounds were prepared accord-ing to the general procedures outlined in Examples 1 and 2 above.

Example 14 (+)-N-Methyl-3-(i-naphthalenyloxy)-3-(2-thienyl)-propanamine maleate, mp = 118C-122C

[~]589 = ~82 [~]365 = +391 at C=1 in methanol Analysis calculated for C2~23NO5S
Theory: C, 63.90; H, 5.61; N, 3.39; S, 7.75;
Found: C, 63.78; H, 5.44; N, 3.35; S, 7.64.
Example 15 N~Methyl~3~ naphthalenyloxy)-3-cyclohexyl-propanamine oxalate, mp = 184C-185C
Analysis calculated for C22E2gN05 Theory: C, 68.20; ~, 7.54; N, 3.61;
Found: C, 68.36; ~, 7.30; N, 3.45.

~l3~
X-7042 ~28-Example 16 N-Methyl-3~ naphthalenyloxy)-3 (2-thiaæolyl)-propanamine oxalate, mp = 183C-185C

Analysis calculated for C1gH20N205S
Theory: C, 58.75; H, 5.19; N, 7.2:L;
Found: C, 59.02; H, 4.94; N, 7.47.

Example 17 N,N-Dimethyl-3-[4-(trifluoromethyl)phenoxy]-3-(2-ur~nyl)propanamine oxalate, mp = 144 5C 145.5C
~5 Analysis calculated for C18H20F3N06 Theoxy: C, 53.60; H, 5.00i ~, 3.47;
Found: C, 53.83; H, 5.22; N, 3.23.
.
20Exampl 18 N,N-Dimethyl-3-[4-(trifluoromethyl)phenoxy]-3-(2-thienyl)propan~mine oxalate, mp = 130C-131.5C

25Analysis calculated for C1~20F3NO5S
Theory: C, 51.55; H, 4.81; N, 3.34;
Found: C, 51.25; H, 4.91; N, 3.55.

~3~Z~

Example 19 N, N-Dimethyl - 3 - [ 4- ~ tri f luoromethyl)phenoxy]-3-(3-thienyl)propanamine oxalate, mp = 124C-125C

Analysis calculated or Cl8H~oF3NO5S
Theory: C, 51.SS; H, 4.81; N, 3.34;
Found: C, 51.35; H, 4.68; N, 3.39.

Example_20 N-Methyl-3-[4-( tri fluoromethyl)phenoxy]-3 -(2-~hienylJpropanamine oxalate, mp = 167C-168C dec.

Analysis calculated for Cl7Hl8F3NO5S
Theory: C, 50.37; H, 4.48; N, 3.46;
Found: C, 50.40; H, 4.66; N, 3.72.

ExamFle 21 N,N-Dimethyl-3-[4-~trifluoromethyl)phenoxy~-3-~2-furanyl)propanamine, oil Ana~ysis calculated for Cl 6H18F3N2 Theory: C, 61.34; H, 5.79; N, 4.47;
Found: C, 61.07; H, 5.82; N, 4.68.

Example 22 N-Methyl-3-[4-(trifluoromethyl)phenoxy]-3 (3-thienyl)propanamine oxalate, mp = 181C-182C
s Analysis calculated for C17Hi8F3NOsS
Theory: C, 50.37; H, 4.48; N, 3.46;
Found: C, 50.49; H, 4.42; N, 3.67.

E ample 23 N-Met~lyl-3-~4-(trifluoromethyl)phenoxy]-3-(2-furanyl)propanamine oxalate, mp = 98C~102C dec.

Analysis calculated for Cl7H18F3NO6 Theory: C, 52.45; H, 4.66; N, 3.60;
Found: C, 52.52; H, 4.45; N, 3.80.

Example 24 N,N-Dimethyl-3-(4-methylphenoxy)-3-(2 thienyl)-propanamine oxalate, mp = 132.5C-133.5C
.

Analysis calculated for C18H23NO5S
Theory: C, 5g.16; H, 6.34; N, 3.83;
Found: C, 59.06; H, 6.12; N, 4.11.

~3~

Exam~le 25 N,N-Dimethyl-3-~4-chlorophenoxy)-3-t2-thienyl)-propanamine oxalate, mp = 118~C-119C
s Analysis calculated for C17H20ClNOsS
Theory: C, 52.95; H, 5.22; N, 3.63;
Found: C, 52.85; H, 5.22; N, 3.48.

10Ex~nple 26 N-Me~hyl-3-(4-methylphenoxy)-3-(2-thienyl)-propan~nine oxalate, mp = 152C-153C

Analysis calculated for C17H2lNOsS
Theoxy: C, 58.10; H, 6.02; N, 3.99;
Found: C, 58.05; H, 6.04; N, 3.72.

N-Methyl-3-(4-chlorophenoxy)-3-(2-thienyl)-pxopanamine oxalate, mp = 126C-129C

Analysis calculated for C16H18ClNOsS
25Theory: C, 51.68; H, 4.88; N, 3.77;
Found: C, 51.60; ~, 5.01; N, 3.52.

~3~)2~A~

N-Methyl-3-(4-methoxyphenoxy)~3-(2-thienyl)-propanamine oxalate, mp - 140C-143C

Analysis calculated for Cl7H2lMO6S
Theory: C, 55.57; H, 5.76; N, 3.81;
Found: C, 55.31; H, 5.55; N, 4.06.

1 0 _~

N,N-Dimethyl-3-(4-methoxyphenoxy)-3-(2-thienyl)propanamine oxalate, mp = 110C-111.5C

Analysis calculated for C18H23N06S
Theory: C, 56.68; H, 6.0ai N, 3.67;
Found: C, 56.43i H, 5.85; N, 3.81.

Example 30 N,N-Dimethyl-3-(1-naphthalenyloxy)-3-~2-furanyl~propanamine oxalate, mp = 153C-155.5C

Analysis calculated for C21H~3NO6 Theory: C, 65.44; H, 6.02; N, 3.63;
Found: C, 65.21; H, 5.75; N, 3.,8.

~-7042 ~33~

- Exam~le 31 N-Methyl-3-(1-naphthalenyloxy)-3-~2-f~ranyl)-propanamine oxalate, mp - 145C-146C

Analysis calculated for C20H21NO6 Theory: C, 64.68; H, 5.70; N, 3.77;
Found: C, 64.79; H, 5.51; N, 3.95.

Example 32 N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thiazolyl)propanamine oxalate, mp = 190C-191C dec.

Analysis calculated for C20H22N2OsS
Theory: C, 59.69; H, 5.51; N, 6.96;
Found: C, 59.99; ~, 5.80; N, 7.01.

Example 33 2~
N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(cyclo-hexyl)propanamine oxalate, mp = 167C-169C

Analysis calculated for C23X31NO5 Theory: C, 68.80; H, 7.78; N, 3.49;
Found: C, 68.53; H, 7.53; N, 3.54.

~L3 X-7042 _34l Example 34 N-Methyl-3- L4- ( trifluoromethyl)phenoxy]-3-(cyclohexyl)propanamine oxalate, mp = 212C-213C

Analysis calculated for C1s~26F3Ns Theory: C, 56.29; H, 6.46; N, 3.45;
Found- C, 56.19; H, 6.37; N, 3.32.

10Example 35 N,N-Dimethyl-3-[4-(trifluoromethyl)phenoxy]-3-(cyclohexyl)propanamine oxalate, mp = 159C-160C

15Analysis calculated Eor C20~28F3N05 Theory: C, 57.27; H, 6.73; M, 3.34;
Found: C, 57.49; ~, 6.61; N, 3.20.

Example 36 N-Methyl-3~ naphthalenyloxy)-3-(3--pyridyl)-propanamine oxalate, mp = 98C dec.

Analysis calculated for C21H22N2O5 25Theory: C, 65.96; H, 5.80; N, 7.33,~
Found: C, 64.27; H, 5.67; N, 7.01.

~3~3Z,f~

X-7042 -35_ ExamE~e 37 N,N-Dimethyl~3-(1-naphthalenyloxy)-3-(3-pyridyl)propanamine oxalate, mp = 176C-178C

Analysis calculated for C22H2~N205 Theory: C, 66.65; H, 6.10; N, 7.07;
Found: C, 66.53; ~, 6.36; ~, 6.41.

10Example 38 ~ N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate, mp = 133C-134C

Analysis calculated for C20H21NsS
Theory: C, 62.00; H, 5.46; N, 3.62;
- Found: C, 62.03; H, 5.51; N, 3.87.

Example 39 ~ N-methyl-3-(1-naphthalenyloxy)-3-(2~thienyl)-propanamine oxalate, mp = 138C-138.5C

Analysis calculated for C2~H21N05S
25Theory: C, 62.00; H, 5.46; N, 3.62;
Found: C, 61.72, H, 5.32; N, 3.82.

As noted above, the compounds of this in~en-tion axe useful for inhibiting the uptake of serotonin.
Therefore, another embodiment of the present invention ~3~

is a method for inhibiting serotonin uptake in mammals which comprises administering to a mammal requiring increased neurotransmission of serotonin a pharmaceu~
tically effective amount of a compound of the invention.
Compounds of the invention al~o have the ability to inhibit the uptake of norepinephrine. As such, yet another embodiment of this invention is a method for inhibiting norepinephrine uptake in mammals which comprises administering to a mammal requiring increased neurotransmission of norepinephrine a pharma-ceutically effective amount of a compound of the invention.
The term "pharmaceutically effective amount", as used herein, represents an amount of a compouncl of the invention which is capable of inhibiting serotonin or norepinephrine uptake. The particular dose of com-pound administered according to this invantion will of course be determined by the particular circumstances sur-rounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar consideratio~s. The compounds can be admi~istered by a variety of routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes. The compounds of the invention unexpectedly inhibit the uptake of not only serotonin but also norepinephrine in mammals. It is a special feature of the compounds that they have good oral bioa~ailability without losing their substan-tial potent inhibiting effect of serotonin and norepi-nephrine uptake inhibiting effect. It is also a special feature of the compounds of ~he present invention in ~3~

X-70~2 -37-that they have been found to demonstrate a low degree of toxicity to mammals. A typical daily dose will ~ontain from about O .01 mg/kg to about 20 mg/kg of the active compound of this invention. Preferred daily d~ses will be about 0.05 to about 10 mg/kg, ideally about 0.1 to about 5 mg/kg.
A variety of physiologic functions have been shown to be subject to influence by brain serotoninergic and norepinephrinergic neural systems. As such, the compounds of the present invention are believed to have the ability to treat a variety of disorders in mammals associated with these neural systems such as obesity, depression, alcoholism, pain, loss of memory, anxiety and smoking. Therefore, the present invention also provides methods of treating the above disorders at rates set forth above for inhibiting serotonin and norepinephrine uptake in mammals.
The following experiment was conducted to demonstrate the ability of the compounds of the present invention to inhibit the uptake of serotonin and norepinephrine. This general procedure is set forth by Wong et al., in Vrug Devel Pment Research 6:397-403 ~1985).
Male Sprague-Dawley rats (110~15a g) from ~arlan Industries (Cumberland, IN) were fed a1'Purina Chow"ad libitum for at least 3 days before being used in the studies. Rats were killed by decapitation. Whole brains were re~oved and dissected. Cerebral cortex was homogenized i~ 9 volumes of a ~edium containing 0.32 M
su~ro~ and 10 mM glucose. Crude synaptosomal prepara-tions were isolated after differential centrifugation at * Trademark ,, , ., !

2~

1,000 g for lO min. and 17,000 g for 28 min. The final pellets were su~pended in the same medlum and kept in ice until use within the same day.
Synaptosomal uptake of 3~-serotonin~3H-5-5 hydroxytryptamine, 3H~5HT ) and 14 C-Q-norepinephrine 1 4C~NE ) was determined as follows. Cortical synaptosomes (equivalent to 1 mg of protein) were incubated at 37C
for 5 min in 1 ml o Krebs-bicarbonate medium containing also 10 mM glucose, 0.1 mM iproniazid, 1 mM ascorbic acid, 0.17 mM EDTA, 50nM 3H-5~T and lO0 nM l~C-NE. The reaction mixture was immediately diluted with 2 ml of ice-chilled Kre~s-bicarbonate buffer and filtered under vacuum with a cell harvester (Brandel, Gaithersburg, MD). Filters were rinsed twice with approximately 5 ml of ice-chilled 0.9% saline and were transferred to a counting vial containin~ 1~ ml o scintillation ~luid (PCS, Amersham, Arlington Heights, IL). Radioactivity was measured by a liguid scintillation spectrophotometer.
Accumulation of 3H-5H~ and 1 4C-NE at 4C represented the background and was subtracted from all samples.
The results of the evaluation of various com-pounds of the present invention are set forth below in Table I. In the Table, columns 1-4 identify the struc ture o the compounds evaluated when taken with the formula set forth in the headiny; colum~ 5 identi~ies ~he salt form, if any, of the compound evaluated; and columns 6 and 7 provide the concentration o~ the test compound at lO-9M ~nM) needed to inhibit 50% of serotoni~
~5~T3 or norepinephrine, respectively, and is indicated 30 in the Table as IC50. The numbers in parentheses represent percent inhibition at 1000 nM.

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The compounds of the present invention are preferably formulated prior to administration. Th~re-fore, yet another embodimellt of the presen~ invention is a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient therefor.
The present pharmaceutical fonmulations are prepared by known procedures using well known and readily available ingredients. In making the composi tions of the present invention, the active i~gredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other con-tainer.
When the carrier serves as a diluent, it may be a solid, semisolid or li~uid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspen-sions, emulsions, solutions, syrups, aerosol ~as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
Some examples of suitable carriers, excipi-ents, and diluents include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacan~h, gelatin, calcium silicate, microcrystalline cellulose, pol~vinylpyrroli-done, cellulQse, water syrup, methyl cellulose, methyl-and propylhydroxybenzoates, talc, magnesium stea~ate and ~a3~

mineral oil. The formulations can additionally lnclude lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions of the lnvention may be formulated so as to provide quick, sustained or delayed release of the active ingredient: after adminis-tration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage fonm, each dosage containing from about 5 to about 500 mg, more usually about 25 to about 300 mg, of the active ingredient. The term "unit dosage formt' refers to physically discrete units suitable as unita:ry dosages for human subjects and ~ther mammals, each unit containing a predetermined quantity of active material calcula-ted to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
The following formulation examples are illus-trative only and are not intended to limit the scope of the invention in any way.

Formulation 1 Hard gelatin capsules are prepared using the following ingredients:

Quantity ~+)-N-methyl-3~ naphthalenyloxy~-3-(2-thienyl)propanami~e maleate 250 starch, dried 200 magnesium stearate 10 Total 460 mg X-7042 ~50-The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

. Formulation 2 A tablet is prepared using the ingredients below:

Quantity ~m~/tablet~
N,N-dimethyl-3-~1-naphthalenyloxy)-3-(5-chloro-2-thienyl)propanarnine oxalate 250 cellulose, microcrystalline 400 silicon dioxide, fumed 10 stearic acid 5 _ Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg.
Formulation 3 An aerosol solution is prepared containing the following components:
~5 Weight %
3~ naphthalenyloxy)-3~(2-thiazoyl)-propanamine hydrochloride 0.25 ethanol 29.75 Propellant 22 (chlorodifluorome~hane) 70.00 Total 100.00 ~3~

X-7042 -51~

The active compound i5 mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30C. and transferred to a f:illing device.
The re~lired amount is then fed to a stainless steel c~ntainer and diluted with ~he remainder of the propel lant. The valve units are than fitted to the container.

Formulation 4 - 10 Tablets each containing 60 mg of activ@
ingredient are made as follows:

N,N-dimethyl-3-[4-(trifluoromethyl)phen-oxy]-3-(3-thienyl)propanamine oxalate 60 mg 15 starch 45 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone (as 10% solution in water) 4 mg sodium carboxymethyl starch . 4.5 mg 20 magnesium stearate OO5 mg talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so pro-duced are dried ~t 50C and passed through a No. 1~ mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 ~3e~

mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

FormuLation 5 Capsules ea~h containing 80 mg of medicament are made a~ follows:

N,N-dimethyl-3-[4~(trifluoromethyl)phenoxy]~
3-(2-furanyl)propanamine hydrobromide80 starch 59 mg microcrystalline cellulose 59 mg magnesiwn stearate 2 m~
15 Total . 200 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.

Formulation 6 Suppositories each containing 225 mg of active 25 ingredient may be made as follows:

N-methyl-3-(2-naphthalenyloxy)-3-(2-thienyl)propanamine maleate225 mg saturated atty acid glycerides2,000 mg 30 Total 2,225 mg ~3~`~ 2~
~-7042 ~53~

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. ~he mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to c~ol.

Formulation 7 Suspensions each containing 5Q mg of medica-ment pPr 5 ml dose are made as follows:

N,N-dimethyl-3-(4~chlorophenoxy) 3-(2-thie~yl)propanamine succinate 50 mg 15 sodium carboxymethyl cellulose 50 mg syrup 1.25 ml benzoic acid solution 0.10 ml flavor q.v.
color q.v.
20 purified water to total 5 ml The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient watex is then added to produce the required volume.

~3~

Forrnulation 8 An intravenous formulation may be prepared as follows:
N-methyl-3-(1-naphthalenyloxy)-3-(3-methyl-~-thienyl)propanamine acetate 100 mg isotonic saline 1000 ml The solution of the above ingredients is administered intravenously at a rate of 1 ml per minute to a subject suffering from depression.

Claims (23)

1. A process for preparing a compound of the formula (I):
wherein:
R1 is C5-C7 cycloalkyl, thienyl, halothienyl, (C1-C4 alkyl)thienyl, furanyl, pyridyl or thiazolyl;
each of R2 and R3 independently is hydrogen or methyl;
each R4 independently is halo, C1-C4 alkyl, C1-C3 alkoxy or trifluoromethyl;
each R5 independently is halo, C1-C4 alkyl or trifluoromethyl;
m is 0, 1 or 2;
n is 0 or 1; or a pharmaceutically acceptable acid addition salt thereof; which comprises:

(A) reacting a compound of formula:
with a reagent of formula Y-Ar, wherein R1, R2, R3 and Ar are as defined above and one of X and Y is hydroxy and the other is a good leaving group, in the presence of a base strong enough to generate the anion of the hydroxy containing compounds; or (B) the demethylation of a compound of Formula (I) wherein both of R2 and R3 are methyl so as to provide a compound of Formula (I) in which one of R2 and R3 is hydrogen and the other is methyl;
(C) reaction (A) or (B) being optionally followed, if necessary, by salification to form a pharmaceutically acceptable acid addition salt;
and in the event that an enantiomerically pure product, viz. an enantiomerically pure form of the compound of formula (I), is desired, preparing said enantiomerically pure product by the reaction of the respective enantiomerically pure reactants as defined above, or by effecting resolution of a racemic mixture of said compound of formula (I) to the desired enantiomerically pure form thereof.

2. A process of Claim 1 wherein Ar is

3. A process of Claim 1 wherein R1 is thienyl.

4. A process according to any one of Claims 1-3 wherein one of R2 and R3 is hydrogen and the other is methyl.

5. A process according to Claim 1 which comprises reacting phenyl chloroformate with N,N-dimethyl-3-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, to form a carbamate intermediate and then subjecting said carbamate intermediate so formed to hydrolysis in the presence of a base, thereby to produce N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine;
and where desired, forming a pharmaceutically acceptable acid addition salt thereof; and further where desired, preparing an enantiomerically pure form of said N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine or of a pharmaceutically acceptable acid addition salt thereof.

6. A process according to Claim 5 wherein the (+) stereoisomer of N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine or of a pharmaceutically acceptable acid addition salt thereof is prepared.

7. A process according to Claim 6 wherein (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine maleate is prepared.

8. A compound of formula I as defined in Claim 1, whenever prepared by a process according to Claim 1.

9. N-Methyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine, or a pharmaceutically acceptable salt thereof, whenever prepared by a process according to Claim 5.

10. A compound of the formula (I):
wherein:
R1 is C5-C7 cycloalkyl, thienyl, halothienyl, (C1-C4 alkyl)thienyl, furanyl, pyridyl or thiazolyl;
each of R2 and R3 independently is hydrogen or methyl;
each R4 independently is halo, C1-C4 alkyl, C1-C3 alkoxy or trifluoromethyl;
each R5 independently is halo, C1-C4 alkyl or trifluoromethyl;
m is 0, 1 or 2;
n is 0 or 1; or a pharmaceutically acceptable acid addition salt thereof.

11. A compound of Claim 10 wherein Ar is

12. A compound of Claim 10 wherein R1 is thienyl.

13. A compound of any one of Claims 10-12 wherein one of R2 and R3 is hydrogen and the other is methyl.

14. N-Methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamide, or a pharmaceutically acceptable acid addition salt thereof.

15. The compound of Claim 14 which is the (+)-stereoisomer.

16. (+)-N-Methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine maleate.

17. A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound of formula (I) as defined in Claim 10, or of a pharmaceutically acceptable acid addition salt thereof, in association with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

18. A pharmaceutical composition according to Claim 17 wherein Ar is

19. A pharmaceutical formulation according to Claim 17 wherein R1 is thienyl.

20. A pharmaceutical formulation according to any one of Claims 17,18 or 19 wherein one of R2 and R3 is hydrogen and the other is methyl.

21. A pharmaceutical composition according to Claim 17 wherein said compound is N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propanamine, or a pharmaceutically acceptable acid addition salt thereof.

22. The pharmaceutical composition of Claim 21 wherein said compound is in the form of the (+)-stereoisomer.

23. A pharmaceutical composition according to Claim 21 wherein said compound is (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine maleate.