KR800001009B1 - Process for the preparation of aryloxy phenyl-propylamines - Google Patents

Abstract

Title compd.(I; R2 = H or methyl; R3 and R4 are halogen, trifluoromethyl, C2-4 alkyl, C1-3 alkoxy or C3-4 alkenyl; n and m are 0-2) and its acid salts, useful as antidepressant agent, were prepd. by reaction of N, N-dimethyl-3-phenyl-3-hal opropylamine(II) and phenols(III). Thus, 29.8g N,N-dimethyl-3-phenyl-3-chloropropylamine hydrochloride and a soln. of 50g p-trifluoromethylphenol, 12g sodium hydroxide and 400ml MeOH were reacted and refluxed for 5 days to give N,N-dimethyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.

Description

Method for producing aryloxyphenylpropyl amines

The present invention relates to 3-artyoxy-3-phenylpropylamines of the following formula (I) and acid addition salts thereof which are effective as antipsychotics, in particular antidepressants.

R ₂ in the structural formula is each hydrogen or methyl,

R ₃ and R ₄ are halo, trifluoromethyl, alkyl of 2 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms or alkenyl of 3 to 4 carbon atoms,

n and m are 0, 1 or 2.

Provided that when both R ₂ are hydrogen n and m are not zero.

U.S. Patent No. 3,106,564 describes tertiary 2-phenoxy-2-phenylethyl amines. This compound is a useful pharmaceutical agent that acts on the central nervous system and is useful as a stimulant without disturbing breathing. The compound also has a high activity as an antihistamine and a clean inhibitor. Some tertiary 3-phenoxy-3-phenylpropylamines and quaternary ammonium compounds are described in Japanese Pharmaceutical Journal, 93, 508-519, 1144-53, 1154-61 (1 (1973)). But secondary and tertiary 3-aryloxy-3-phenylpropyl-amines are not yet known.

According to the present invention, N, N-dimethyl 3-phenyl-3-halo-propylamine of the following formula (II) is reacted with a phenol of the formula (III) to prepare a compound of formula (I) and acid addition salts thereof.

Wherein R ₃ , R ₄ , m and n are as defined above.

Examples of the compound obtained according to the present invention are as follows.

N, N-dimethyl-3- (3 ′, 4′-dimethoxyphenoxy) -3-phenylpropylamine-hydroxybenzoate

N, N-dimethyl-3- (m-anisyloxy) -3-phenyl-1-methylpropylamine maleate

N, N-dimethyl 3- (2 ', 4'-difluorophenoxy) -3-phenylpropylamine 2,4-dinitrobenzoate

N, N-dimethyl 3- (2'-ethyl-4'-fluorophenoxy) -3-phenyl propylamine succinate

N, N-dimethyl 3- (0-isopropoxyphenoxy) -3-phenylpropylamine phenylacetate

N, N-dimethyl 3- (0-bromophenoxy) -3-phenylpropylamine-phenylpropionate

Pharmaceutically nontoxic salts obtained by reacting amine bases of the structural formula with nontoxic acids are also within the scope of the present invention. These acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonate, naphthalene-2-sulfonate or mandelate.

The organic base form of the compound of the present invention is a high boiling oil phase, but acid addition salts thereof are white crystalline solids. These compounds can be obtained by various methods. Particularly useful methods for the preparation of compounds of formula (I) (wherein R ₁ are all methyl) are N, N-dimethyl 3-phenyl-3-hydroxy by reducing β-dimethylaminopropion obtained by the Mannich reaction. It is a method of obtaining propylamine. Substituting the hydroxyl group with a halogen such as chlorine gives the corresponding N, N-dimethyl-3-phenyl-3-chloropropylamine. This chloro compound is reacted with a suitably substituted phenol such as 0-methoxyphenol (guiacle) to obtain a compound of formula (I) wherein R ₁ is methyl.

Compounds in which the R ₂ group attached to the α-position carbon atom of the nitrogen atom is methyl can be obtained by reacting phenyl 2′-propenyl ketone with dimethylamine [J. Am. Chem. Soc. 75, 4460 (1953). The pinone is reduced with the resulting 3-dimethylaminorobutyne to give N, N-dimethyl 3-hydroxy-1-methyl-3-phenyl propylamine. The hydroxyl group is substituted with chlorine and then the chloro compound is reacted with the sodium salt of a suitably substituted phenol to obtain the N, N-dimethyl derivative of the present invention having α methyl group in propylamine.

Compounds in which the R ₂ group attached to either α or β carbon is methyl have two sub-carbon atoms, that is, a carbon atom having R ₂ methyl and two γ-carbon atoms having phenoxy and phenyl groups. Therefore, these compounds exist as two racemates of four porous isomers, α-dl type with low solubility and β-dl type with high solubility. Each racemate can be isolated into d and l isomers, respectively, by forming salts with known methods, in particular optically active acids, and then separating the salts by crystallization.

The following examples specifically illustrate the present invention.

Example 1

N, N-dimethyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine

About 600 g of β-dimethylaminopropiophenone hydrochloride is reacted with 1.5N sodium hydroxide solution to convert to the corresponding freebase. This free base is taken up in ether, the ether layer is separated, dried and the ether is removed in vacuo.

The residual oil containing β-dimethylaminopropiophenone is dissolved in 2 l of tetrahydrofuran and the resulting solution is added dropwise with stirring to a 4 mole diborane solution in 4 l of terahydrofuran. The reaction mixture is stirred overnight at room temperature, then 1 additional diborane solution in tetrahydrofuran is added and the reaction mixture is stirred again at room temperature overnight. 2 l of hydrochloric acid is then added to decompose the diborane present in excess. Tetrahydrofuran is evaporated off, the acidic solution is extracted twice with 1 l of benzene and the benzene extract is decanted. The acidic solution is made basic with an excess of 5N sodium hydroxide solution, and the basic solvent is extracted three times with 2 l of benzene. The benzene extract is separated, combined, washed with saturated sodium chloride solution and dried. The solvent is evaporated in vacuo to give 442 g of N, N-dimethyl-3-phenyl-3-hydroxypropylamine.

A solution containing 442 g of N, N-dimethyl-3-phenyl-3-hydroxypropylamine in 5 l of chloroform is saturated with anhydrous hydrogen chloride gas. 400 ml of thionylchloride is added to this chloroform solution at an appropriate rate to maintain reflux. The solution was refluxed for another 5 hours, and then N, N-dimethyl 3-phenyl 3-chloropropylamine hydrochloride obtained by vacuum evaporation of chloroform and other volatile components was collected by filtration, and the foil was washed twice with 1,500 ml of acetone.

The washed crystals are about 500 g and dissolve at 181 to 183 ° C. (decompose). According to the standard crystallization method, 30 g of the compound is further obtained from the acetone washing solution. The structure of this compound was confirmed by NMR and titration.

A solution of 50 g of p-trifluoromethylphenol, 12 g of solid sodium hydroxide, and 400 ml of methanol is placed in 1 L of round bottom plaques equipped with a magnetic stirrer, a content yarn and a drying tube. The reaction mixture is stirred until the sodium hydroxide is dissolved and 29,8 g of N, N-dimethyl-3-phenyl-3-chloropropylamine hydrochloride are added. The reaction mixture obtained is refluxed for about 5 days and then cooled. Methanol is evaporated to raise and the residue is treated with ether and 5N sodium hydroxide solution mixture, the ether layer is separated and washed twice with water twice with 5N sodium hydroxide solution. The ether layer is dehydrated and the ether is evaporated and removed in vacuo to afford N, N-dimethyl 3- (p-trifluoromethylphenoxy) -3-phenylpropylamine.

This free base is converted into the corresponding oxalate salt by dissolving 32 g of amine in ethyl acetate and adding a solution of 9 g of oxalic acid in ethyl acetate. Recrystallization with ethyl acetate gives N, N-dimethyl-3-p-trifluoro methylphenoxy-3-phenylpropylamine oxalate. Melting Point: 177 to 119 ° C (Decomposition)

Elemental analysis

Calculated Value: 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

The following N, N-dimethyl 3-substituted phenoxy-3-phenylpropylamines are obtained according to the above method.

N, N-dimethyl-3- (0-chlorophenoxy) -3-phenylpropyl amine maleate, melting point 88-90 ° C. (ethylacetate-cyclohexane solvent mixture)

Elemental Analysis: Calculation: C, 62.14, H, 5.96, N, 3.45, Cl, 8.73

Found: C, 61.94, H, 5.67, N, 3.68, Cl, 8.92

N, N-dimethyl 3- (0-trifluoromethylphenoxy) -3-phenyl propylamine P-toluene-sulfonate Melting point: 134-136 degreeC (ethyl acetate)

Elemental analysis: Calculated value: C, 60.59, H, 5.70, N, 2.83, F, 11.50 S, 6.47

Found: C, 60.36, H, 5.52, N, 3.12, F, 11.80 S, 6.66

N, N-dimethyl 3-phenyl-3- (m-methoxyphenoxy) propyl amine oxalate, melting point 125-128 ° C.

Elemental Analysis: Calculation: C, 63.99, H, 6.91, N, 3.73

Found: C, 63.93, H, 6.90, N, 3.59

N, N-dimethyl 3-phenyl-3- (0-allylphenoxy) propylamine oxalate, melting point 159 to 161 ° C

Elemental Analysis: Calculation: C, 68.55, H, 7.05, N, 3.63

Found: C, 68.67, H, 7.15, N, 3.83

N N-dimethyl 3- (3-phenyl- (P-chlorophenoxy) propylamine oxalate, melting point 139 to 141 ° C

Elemental Analysis: Calculation: C, 60.08, H, 5.84, N, 3.69, Cl, 9.33

Found: C, 60.34, H, 5.95, N, 3.88, Cl, 9.61

N, N-dimethyl 3- (0-methoxyphenoxy) -3-phenylpropyl amine maleate, melting point 98-103 캜

Elemental Analysis: Calculation: 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-phenylpropyl amine maleate, melting point 101-104 ° C

Elemental Analysis: Calculation: C, 65.82, H, 6.78, N, 3.49

Found: C, 65.96, H, 6.50, N, 3.68

N, N-dimethyl 3- (0-bromophenoxy) -3-phenylpropyl amine oxalate, melting point 144-146 ° C

Elemental Analysis: Calculation: C, 53.79, H, 5.23, N, 3.30, Br, 18.85

Found: C, 53.84, H, 5.52, N, 3.38, Br, 18.86

N, N-dimethyl 3-phenyl-3- (m-trifluoromethylphenoxy) propylamine oxalate, melting point 163 to 165 ° C

Elemental Analysis: Calculation: C, 58.11, H, 5.36, N, 3.39, F, 13.79

Found: C, 57.89, H, 5.26, N, 3.41, F, 13.69

N, N-dimethyl 3-phenyl-3- (0-t-butylphenoxy) -propyl amine oxalate, melting point 146-149 ° C.

Elemental Analysis: Calculation: C, 68.88, H, 7.78, N, 3.49

Found: C, 68.56, H, 8.04, N, 3.69

N, N-dimethyl 3 (0-ethylphenoxy) -3-phenylpropyl amine oxalate, melting point 152-154 캜

Elemental Analysis: Calculation: C, 67.54, H, 7.29, N, 3.75

Found: C, 67.33, H, 7.05, N, 3.98

N, N-dimethyl 3- (0-isopropoxyphenoxy) -3-phenylpropylamine oxalate, melting point 139 to 142 ° C

Elemental Analysis: Calculation: C, 68.20, H, 7.54, N, 3.61

Found: C, 68.50, H, 7.82, N, 3.85

N, N-dimethyl 3- (P-fluorophenoxy) -3-phenylpropylamine maleate, melting point 103 to 108 ° C

Elemental Analysis: Calculation: C, 64.77, H, 6.21, N, 3.60

Found: C, 64.79, H, 6.50, N, 3.82

N, N-dimethyl 3 (-chlorophenoxy) -3-phenylpropylamine oxalate, melting point 150-152 degreeC (isopropanol)

Elemental Analysis: Calculation: C, 60.08, H, 5.87, N, 3.69, Cl, 9.33

Found: C, 59.90, H, 6.08, N, 3.42, Cl, 9.60

N, N, -dimethyl 3- (0-fluorophenoxy) -3-phenylpropylamine hydrochloride, melting point 166-168 ° C. (acetone-cyclohexane)

Elemental analysis: Calculated value: 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

α-dl-N, N-dimethyl-3-phenoxy-3-phenyl-1-methylpropylamine oxalate, melting point 113 to 116 ° C

Elemental Segment: Calculation: C, 66.84, H, 7.01, N, 3.90

Found: C, 67.03, H, 7.20, N, 4.13

N, N-dimethyl 3-phenoxy-3-phenyl-2-methylpropylamine oxalate, melting point 130-134 ° C

Elemental Analysis: Calculation: C, 66.89, H, 7.01, N, 3.90

Found: C, 66.59, H, 7.08, N, 3.96

N, N-dimethyl 3 (0-ethoxyphenoxy) -3-phenylpropylamine oxalate, melting point 101-104 캜

Elemental Analysis: Calculation: C, 64.77, H, 6.99, N, 3.60

Found: C, 65.05, H, 7.00, N, 3.88

β-dl-N, N-dimethyl-3-phenoxy-3-phenyl-1-methylpropylamine oxalate, melting point 131 to 133 ° C

Elemental Analysis: Calculation: C, 66.89, H, 7.01, N, 3.90

Found: C, 66.64, H, 7.00, N, 3.77

Example 2

Preparation of Salts

Salts of free bases other than hydrochloride, maleate and oxalate obtained according to example 1 are obtained by dissolving the free base in ether and adding 1 equivalent of a suitable non-toxic acid to the ether. The obtained salts, such as acetate and benzoate salts, are insoluble in ether and can be separated by filtration. Another method is to dissolve the amine base in ethanol and add 1 equivalent of acid to the ethanol solution. The salts obtained in this case are dissolved in the reaction mixture and the solvent is separated by evaporation under vacuum. Salts obtainable according to the above methods include sulfate, hydrobromide, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, methanesulfonate, succinate, tartrate, citrate, benzoate and p-toluene sulfonate. have.

It can be seen that it inhibits the absorption of various physiologically active monoamines as shown in the antipsychotic activity of the compounds obtained according to the present invention. This inhibition was shown in rat in vitro neuron junction cells, in vitro experiments of radioactive compounds to measure monoamine uptake, and in vivo experiments of various methods. Among the physiologically active monoamines whose absorption is inhibited by the compounds obtained according to the present invention are serotonin, norepinephrine and topamine (3,4-dihydroxyphenylethylamine). All of the compounds obtained according to the present invention inhibit the absorption of monoamines but some of them have the only selectivity that inhibits one absorption much more than inhibiting the other two absorption of monoamines.

Table 1 below shows the results of measuring inhibition of monoamine uptake by in vitro experiments of the compounds obtained according to the present invention. Column 1 in the table is a substituent on 3-phenylpropylamine, column 2-3 shows the concentration (mcg / ml) that inhibits the uptake of one special amine by 50% for amines, ie norepinephrine, dopamine and serotonin. . At the top of each column, the concentrations of the specific monoamines used in the experiments were noted.

TABLE 1

The in vivo effect of the compounds obtained according to the invention in inhibiting serotonin uptake was found to be a mech and co-investigator who discovered that inhibitors of serotonin uptake prevent the brain serotonin from being injected by injection of 4-chloro metaamphetamine. . Pharma. 20,707 (1971)] may be indirectly measured.

In the present invention, the rat is injected with a known amount of 4-chloro amphetamine, which can reduce the brain serotonin by about 50%, and then the concentration of the brain serotonin is measured 4 hours after the intraperitoneal injection of 15 mg / kg of rat inhibitor. It was. Column 1 in Table 2 is the name of the drug used, column 2 shows the brain serotonin concentration per gram of brain tissue in micrograms. Since chloroimipramine and N-desmethylimipramine have been reported by Mech et al. To inhibit brain serotonin consumption caused by 4-chloromethamphetamine, these drugs were used as reference drugs.

TABLE 2

As can be seen from Table 2, N-methyl 3 (p-trifluoromethylphenoxy) -3-phenylpropylamine as an oxalate salt inhibits the consumption of serotonin resulting from injection of 4-chloroamphetamine and Brain concentrations did not differ significantly from those of the control rats to those without any drug. Corresponding tertiary and primary amine derivatives, namely N, N-dimethyl 3 (p-trifluoro methylphenoxy) -3-phenylpropylamine oxalate and 3- (p-trifluoromethylphenoxy) -3 -Phenylpropylamine oxalate gave the same result. Secondary amines also inhibited the consumption of serotonin resulting from the administration of α-ethyl-4-methyl-m-titamin but did not inhibit the consumption of norepinephrine.

Tricyclic antidepressants currently on the market inhibit the uptake of monoamines by the brain nerve bundles, most of which are more effective in inhibiting uptake of norepinephrine. Most compounds obtained according to the present invention similarly inhibit norepinephrine uptake more effectively than serotonin uptake. The exceptions are that the p-trifluoromethyl derivatives, dimethylamino, monomethylamino and unsubstituted amine derivatives described above are more effective at inhibiting serotonin uptake than at norepinephrine uptake. Thus, the compounds obtained according to the invention are clearly effective as antidepressants but differ from the drugs currently marketed in N-methyl 3- (p-trifluoromethylphenyloxy) -3-phenylpropylamine and its tertiary and primary amines. It is certain that it will have a form of depression. The compound also collaborates with wyatt, who reported that six out of seven patients with chronic schizophrenia may have mild to moderate effects by oral administration of the serotonin precursor 1-5-hydroxy-tripropane. According to the hypothesis of the author (Science 177,1124 (1972)), it can be used to treat schizophrenia.

In addition to being used as psychotropic drugs, these compounds can be used to treat sleep disorders, sexual intercourse, anorexia, muscle dysfunction, and pituitary dysfunction. All of these physiological effects affect the nervous system affected by serotonin.

In view of yet another action as a psychotropic drug, in particular as an antidepressant, the compounds obtained according to the invention show antagonism during hypothermia induced by apomorphine injection and antagonize the central action of tremoline and oxotremoline. The compound is also effective at restoring a decrease in body temperature abnormalities, but not so effective in inhibiting a temperature decrease in body temperature. As such, the monomethylamines according to the present invention are generally more effective than their dimethylamino compounds in antagonizing hypothermia or restoring them to their original state. Antagonistic tests in apomorphine hypothermia are carried out as follows. Mice are injected with an amount of known apomorphine that will lower the body temperature to about 4 ° C. Test compounds are injected 1/2 hour before apomorphine injection and the temperature is measured 1/2 hour after injection. The degree of antagonism is the degree of decrease in body temperature drop caused by apomorphine injection as compared to the control group. Regerpin hypothermic recovery test is performed as follows. Groups of mice injected with reserpin were injected intraperitoneally with different amounts of drug for each mouse after 16.5 hours. The temperature is measured 1 hour after the test injection and again the effect of the drug is shown as a% decrease in hypothermia by rezerpin injection compared to the control.

Table 4 is similar data for the dimethylamino compound obtained according to the present invention.

TABLE 4

The recovery of rezerpinin hypothermia and antagonism of apomorphine hypothermia is a pharmacological test that shows that antidepressants currently on the market, in particular imipramine, amitrifthilin, nortriptyline and des Methylimipramine is effective.

In demonstrating the psychotropic effects of these drugs, the compounds of the present invention also affect the behavior of animals trained according to various behavioral guidelines. In addition, this compound has the same effect as conventional antidepressants, especially desmethylimipramine, in this type of test. For example, administration of N-methyl-3 (0-methoxyphenoxy) -3-phenyl-propylamine at a constant rate, at regular intervals, increases the reaction rate of pigeons and continues for more than 24 hours. Persistence is maintained as a result of training under this medication, but similar effects are obtained with desmethylimipramine.

In the Sidman avoidance reaction with Squirrel monkey, the dose of 5 mg / kg N-methyl 3- (0-methoxyphenoxy) -3-phenylpropylamine increases the monkey's response but similarly If the drug is administered at 2.5 mg / kg or 5 mg / kg several times, at constant rates and at regular intervals, the response is reduced. In pigeons trained according to controlled rates, the drug affects behavior in the same way as the commercial antidepressant, desmethylimipramine (DMI). Drugs with this type of action in this test do not have a significant effect on the reaction rate, but as the response is stronger, the reflexes are less rested. However, N-methyl-3- (0-methoxyphenoxy) -3-phenylpropylamine significantly increases the rate of reaction at a quarter dose of the DMI dose which can be increased to the same extent. These results are consistent with the action of antidepressants.

Finally, the compounds of the present invention do not have strong antiserotonin action, antihistamine action, anticholinergic action as a result of testing the muscle extraction in a general experimental method. Compared with N-methyl 3- (0-methoxyphenoxy) -3-phenylpropylamine and desmethylimipramine, the latter has 150 times more potent antihistamine and anticolinergic action, and 3 times more antiserotonin action. More powerful

Intravenous injection of amitriptyline and other commercially available tricyclic antidepressants into anesthetized cats widens the QRS complex of the ECG, which may delay ventricular conduction. 3- (0-methoxyphenoxy) -3-phenylpropylamine has a similar action but occurs at much higher doses than commercial antidepressants.

In experiments of several psychotic patients with depression, the compounds of the present invention can be administered orally or parenterally. In both cases, it is recommended to use it as acid addition salts of non-toxic acids, which are academically possible. For oral administration, the salts can be mixed with standard pharmaceutical excipients and filled into gelatin capsules. Similarly, the compound is mixed with starch, binder, and the like to form a tablet, and the tablet is also used in a dose that facilitates divided administration. For parenteral administration, a soluble, soluble salt of the present compound is dissolved in isotonic solution and administered intramuscularly, intravenously or subcutaneously. Oral formulations are preferred for long-term administration. Dosage is administered once to 50mg once daily total dose 1 to 200mg 1 to 4 times a day.

Claims (1)

N-N-dimethyl 3-phenyl-3-halopropylamine of the following formula (II) is reacted with phenols of the following formula (III), and 3-aryloxy-3-phenylpropyl of the following formula (I) Process for preparing amine compound.

Wherein R ₂ is each hydrogen or methyl, R ₃ and R ₄ are halo, trifluoromethyl, alkyl of 2 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms or alkenyl of 3 to 4 carbon atoms, n And m is 0, 1 or 2. Provided that when R ₂ is both hydrogen, n and m are both nonzero.