CS196397B2 - Process for preparing 3-aryloxy-3-phenylpropylamines - Google Patents

Description

The present invention relates to a process for the preparation of novel 3-aryloxy-3-phenylpropylamines and their acid salts which are useful as psychotics; opioids, in particular as antidepressants.

Tertiary 2-phenoxy-2-phenylethylanines are the subject of U.S. Patent No. 3106,564. The compounds are useful pharmacological agents with central nervous system activity, including utility as analeptic agents without significant respiratory effect. The compounds also have a high effect as antihistaminic and anticholinergic agents. Some tertiary 3-phenoxy-3-phenylpropylamines and quaternary ammonium compounds are disclosed in the Pharmaceutical Society, Japan, 93, 508-519, 1144-53, 1154-61 (1973). These compounds have a mydriatic effect.

Secondary and primary 3-aryloxy-3-phenylpropylamines are not yet known.

The present invention relates to a process for the preparation of the novel 3-aryloxy-3-phenylpropylamines of formula (I)

wherein R 2 and R 2 are each independently hydrogen or methyl, R 3 is halogenphenyl, trifluoromethyl; alkyl of 2 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms, or C 1 -C 4 alkyl and m is 0 or 1, and salts thereof with pharmaceutically acceptable acids. The process of the present invention is characterized in that the 3-chloro-1- (substituted phenoxy) -phenylpropane of the formula

198397

wherein R 2, R * 2, R 5 and m are as defined above, reacted with sodium azide and then reduced with sodium borohydride and optionally formed with a pharmaceutically acceptable acid.

In the above formula R 5 is halogen, C 2 -C 4 alkyl, C 1 -C 3 alkoxy or C 3 -C 4 alkenyl, for example, the following atoms or groups: fluorine, chlorine, bromine, iodine, ethyl, isopropyl , n-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, methoxy, ethoxy, n-propoxyl, isopropoxyl, allyl, methallyl or crotyl. Compounds within the scope of the present invention are, for example:

3- (p-isopropoxyphenoxy) -3-phenylpropylamine methanesulfonate;

3- (p-t-butylphenoxy) -3-phenylpropylamine glutarate,

3- (o-ethylphenoxy) -3-phenylpropylamine dihydrogen phosphate,

Also included within the scope of the present invention are pharmaceutically acceptable amine salts of the above formula with non-toxic acids. These salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, as well as salts with non-toxic organic acids including aliphatic monocarboxylic and long carboxylic acids, phenyl substituted with phenyl. alkanoic acids, hydroxyalkanoic acids and hydroxyalkanedicarboxylic acids, aromatic acids, aliphatic sulfonic acids and aromatic sulfonic acids. Such pharmaceutically acceptable salts include:

sulphates, pyrosulphates, bisulphates, sulphides, bisulphides, nitrates, phosphates, pyrophosphates, dihydrogenophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanonates, caprylates, acrylates, formatesates, propanoates, isobutyrates, , oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthonates, benzenesulfonates, benzenesulfonates, benzenesulfonates , chlorobenzenesulfonates, xylene sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, malate, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates or mandelates.

The compounds of the present invention are high boiling oils when they are in the form of the free base but in the form of acid salts are white crystalline solids. The compounds can be prepared in several ways.

In one method, 1-phenyl-3-chloropropane is reacted with a halogenating agent such as N-bromosuccinimide to give the corresponding 1-phenyl-1-bromo-3-chloropropane. Selective replacement of the bromine atom by treatment with a phenol sodium salt such as sodium o-methoxyphenol (quajqkol) yields 3196397

With chloro-1- (1-methoxyphenoxy) -1-phenylpropane also referred to as 3-chloro-1- (o-anisyloxy} -1-phenylpropane). Reaction of the 3-chloro derivative thus formed with sodium azide affords the corresponding 3-azido-1- (o-anisyloxy) -1-phenylpropane. Reduction of the azide with a metal-organic reducing agent such as sodium borohydride affords the desired primary amine. Alternatively, the chloro compound can be reacted directly with an excess of ammonia in a high pressure reactor to form a primary amine.

Compounds wherein the R 2 groups are methyl are prepared from the corresponding starting compounds.

Those compounds wherein the R 2 group attached to either or or the 3 carbon atom is methyl have two asymmetric carbon atoms, a non-saline carbon atom. methyl and γ carbon atoms bearing phenoxy and phenyl groups. Thus, these compounds can exist in four diastereomeric forms occurring as two racemic pairs, the less soluble pair being designated as the α-dl form and more soluble as the β-dl form. Each racemate can be resolved into the individual d and 1 isomers in a known manner, in particular by forming salts with optically active acids and separating the salts by crystallization.

The present invention is illustrated by the following examples.

Example i

Preparation of 3- (O-methoxyphenoxy) -3-phenylpropylamine.

A solution of 2.6 g of sodium azide in 10 ml of water is placed in a 10 ml three-necked round-bottom flask equipped with a stirrer, a condenser and a thermometer. A second solution containing 2.76 g of 3-chloro-1- (o-methoxyphenoxy) -1-phenylpropane in 30 ml of dimethylformamide was added to the azide solution. The mixture was heated at 95 ° C overnight. The reaction mixture was cooled, diluted with water and extracted three times with ether. The ethereal extracts were combined, the combined extracts were washed five times with water and then saturated aqueous sodium chloride solution and then dried. Evaporation of the ether in vacuo afforded a colorless liquid consisting of 3-azido-1- (o-methoxyphenoxy) -1-phenylpropane. 41 g of this compound are dissolved in 350 ml of isopropanol. The resulting solution was placed in a 1 liter round flask equipped with a magnetic stirrer, reflux condenser and drying tube. Then 15.2 g of 96% solid sodium borohydride are added to the azide solution. The resulting mixture was heated to boiling overnight and allowed to cool. The alcohol is then evaporated from the solution in vacuo. About 1.5 liters of water are added and the resulting aqueous mixture is carefully acidified with a 2N aqueous hydrochloric acid solution. The 3- (o-methoxyphenoxy) -3-phenylpropylamine formed by the above reaction was dissolved in the aqueous acidic phase as the hydrochloride, the aqueous acidic phase was extracted three times with ether to remove unreacted starting material and basified with 5N aqueous sodium hydroxide solution. The amine, which is insoluble in the alkaline solution, is separated and extracted into ether, the ether phase is separated and the aqueous-alkaline phase is extracted twice more with ether, the ether extracts are combined and the combined phases are washed with a saturated aqueous solution of sodium chloride. in vacuo, 17 g of 3- (o-methoxyphenoxy) -3-phenylpropylamine are obtained, which is converted to the oxalate according to the procedure of Example 1, 3- (o-methoxyphenoxy) -3-phenylpropylamine oxalate, prepared in this way, m.p. 121 DEG C. after crystallization from a mixture of ethyl acetate and cyclohexane, the oxalate is then converted to the hydrochloride by forming the free base in an ethereal solution and and the saturation of the ether solution with hydrogen chloride gas. 77-78 ° C.

Analysis calculated:

C 65.91, H 6.86, N 4.77, Cl 12.07,

See VLW

C, 65.13; H, 7.12; N, 4.61; Cl, 12.21.

3 * (p-Trifluoromethylphenoxy) -3-phenylpropylamine oxalate was prepared as described above, m.p. 162-164 ° C. The oxalate is converted to the hydrochloride by forming the free base, extracting the free base into ether, and then saturating the ethereal solution of the free base with hydrogen chloride gas. The hydrochloride has mp 130 to 133 ⁱⁿ C.

Analysis calculated:

C 57.93, H 5.17, N 4.22, Cl 10.69,

F 17.18, found:

C 57.66, H 5.08, N 4.09, Cl 11.15,

F, 16.66.

3-Phenoxy-3-phenylpropylamine, m.p. mp 173 ° C.

Analysis calculated:

C 64.34, H 6.04, N 4.41, found:

C 64.49, H 5.80, N 4.67.

Example 2

Preparation of salts

The salts of the free bases of the present invention, other than the hydrochlorides and oxalates, the preparation of which is shown in Example 1, are prepared by purging the free base in ether and adding an equivalent of a suitable non-toxic acid, also in ether. The salts thus formed, such as acetates and benzoates, are insoluble in ether and can be isolated by filtration. Alternatively, the ammonium base can be dissolved in ethanol and an equivalent of the acid in an ethanolic solution is added. In this case, since the salts thus formed are soluble in the reaction mixture, they can be isolated by evaporating the solvent under vacuum. Salts which may be formed as described above are sulfates, hydrobromides, phosphates, hydrogenphosphates, dihydrogenophosphates, acetates, methanesulfonates, subkinates, tartrates, citrates, benzoates and p-toluenesulfonates.

As an indication of psychotropic activity, the compounds of the present invention have been found to block the elevation of various physiologically active monoamines. This blockade is demonstrated both in vitro using radiolabelled compounds to determine the amount of increase in monoamines of symptom from rat turkey and in vivo using various methods. Physiologically active monoamines whose increase is blocked by the compounds of the present invention include serotonin and norepinephrine. While all of the compounds of the present invention block the elevation of monoamines, some of them exhibit excellent selectivity as they block the elevation of one of the monoamines far more than the other two. Table 1 summarizes the results of some in vitro assays to block monoamine increases by the compounds of the present invention. In Table 1, the R-substituent of 3-phenylpropylamine is shown and columns 2-4 show the concentration in µg per ml of 1 ml, which blocks a 50% increase in the amine, for example, norepinephrine and serotonin amines. The title of each column shows the concentration of the monoamines used in the experiment.

Table 1

R-O-CH-CH2-CH2-NH2

C6H5. mcg / ml concentration that blocks a 50% increase in the amine

P ^: Serotin. Norepinephrin

0,1 μΜ 0,48 μΜ phenyl o-methoxyphenyl p-trifluoromethylphenyl

When tested in humans with various psychoses having a depressive component, the compounds of the present invention may be administered orally or parenterally. In both cases, it is preferred to use salts of the compounds formed with a pharmaceutically acceptable non-toxic acid. For the purpose of oral administration, the salts may be mixed with standard pharmaceutical carriers to form gelatin capsules. Similarly, the compounds can be blended with starch, binders, and the like to form tablets with a notch for ease of separation.

0.88

0.23

0.60 0.97

16.6 l, for smaller doses. For parenteral administration, a water-soluble salt of a compound of the present invention that is pharmaceutically acceptable may be dissolved in an isotonic solution and administered intramuscularly, intravenously or subcutaneously. For chronic applications, oral pharmaceutical forms are naturally preferred. The dosage level ranges from 1 to 50 mg / dose 1 to 4 times daily, with the total daily human dose being from 1 to 200 mg / day.

Claims (4)

A process for the preparation of 3-aroloxy-3-phenylpropylamines of the general formula IA ^{/ H} H (I) wherein R a and R 2 'are independently hydrogen or methyl, R 3 is halogen, trifluoromethyl, C 2 -C 4 alkyl, C 1 -C 3 alkoxy or C 3 -C 4 alkenyl and m is Or their salts with pharmaceutically acceptable acids, characterized in that 3-chloro- (1-substituted-phenoxy) -1-phenylpropane of the formula I is reacted O-CH-CR-CH-CL wherein R 2, R 2, R 3 and m are as defined above with sodium azide and then sodium borohydride reduction is performed and optionally a salt with a pharmaceutically acceptable acid is prepared. 2. A process according to claim 1 for the preparation of 3- (p-trifluoromethylphenoxy) -3-phenylpropylamine, characterized in that 3-chloro-1- (p-trifluoromethylphenoxy) -1-phenylpropane is reacted with sodium azide and then reduction with sodium borohydride. ¹ 3. A process according to claim 1 for the preparation of 3- (o-methoxyphenoxy) -3-phenylpropylamine, characterized in that 3-chloro-1- (o-methoxyphenoxy) -1-phenylpropane is reacted with sodium azide and then treated with sodium azide. carry out the reduction with sodium borohydride. and 4. A process according to claim 1 for the preparation of 3-phenoxy-3-phenylprophylamine, characterized in that 3-chloro-1-phenoxy-1-phenylpropane is reacted with sodium azide and then reduced with sodium borohydride.