NO149775B - ANALOGY PROCEDURE FOR THE PREPARATION OF PHENYL-PYRIDYLAMINE DERIVATIVES WITH ANTIDEPRESSIVE EFFECT - Google Patents

Description

The present invention relates to an analogue method for the production of new phenyl-pyridylamine derivatives with antidepressant action.

Morbid depressive states have been treated with more or less success with various substances. The anti-depressants that have the greatest clinical prevalence are tricyclic tertiary amines such as imipramine with the structural formula: and amitriptyline with the formula:

Secondary amines such as desipramine with structural formula:

and nortriptyline with formula: is used to a somewhat lesser extent. However, these compounds have side effects that are undesirable in connection with therapeutic use, such as orthostatic action, anti-cholinergic action and, above all, arrhythmogenic action, i.e. cardiac arrhythmia, which is particularly troublesome when larger doses are administered to elderly patients. Furthermore, all mentioned substances have the disadvantage that the anti-depressant effect only occurs after a few weeks of treatment. Furthermore, it is known from the literature that certain 1,1-diphenyl-3-aminoprop-l-enes, such as e.g. the compound with formula:

has antidepressant effect, see J. Med. Chem. 14, 161-4, (1971).

Compounds with formula:

where X denotes chlorine or bromine and R denotes hydrogen and methyl, is described as having an antidepressant effect in US patent 3,423-510, these substances, however, also have a strong anti-histamine effect. It is also known from the literature that a compound of formula: has an anti-depressant effect on animals, see Belgian patent 781,105. In Proe. Int. Solvent Extr. Conf. 1974 no. 3 page 2173-2181 there is an account of separation experiments in which the mono- and dimethylamine with the formula

where R is H or CH^, are separated. Furthermore, it is explained

separation experiments in which cis- and trans-isomers of the compound with the above formula where R is CH^ are separated. While the compound where R is CH 2 has known therapeutic action, no medical applicability for the compound where R is H has been previously known. Furthermore, its cis- and trans-isomers have not been previously described at all. In comparison experiments, it has been shown that the pure cis and trans isomers of the compound where R is H have superior selectivity in inhibiting the uptake of serotonin and noradrenaline respectively in the central nervous system.

In clinical practice, different types of depression are known. Depressed patients react in different ways to the different anti-depressants used for treatment. Most of these compounds inhibit the neuronal uptake of noradrenaline and some of them also inhibit the uptake of 5-hydroxytryptamine. It is assumed that inhibition of the uptake of 5-hydroxytryptamine is the mechanism behind the mood-enhancing properties found in some of these anti-depressants. In addition to the absolute inhibition level for the uptake of either 5-hydroxytryptamine or norepinephrine, the selectivity with respect to the uptake of these two amines is of great interest.

That is the main purpose of the present invention

to provide an analogue method for the production of new compounds with good antidepressant action, and which only give rise to minor side effects, particularly arrhythmic effects.' Likewise, nerve-sedating effects are associated with compounds produced according to the invention.

According to the present invention, therapeutically active compounds are produced in Z-form and E-form and with the formula:

or a pharmaceutically acceptable salt thereof.

Due to the lack of free rotation at the double bond in the above compound, it can exist in different stereoisomeric forms, i.e. in cis-trans isomers or according to the UIPAC nomenclature (J. Org. Chem. 3_5, 2849-2867 , Sept. 1970) in an E form and a Z form. The compound can be used therapeutically as. a mixture of geometric isomers or in pure E or Z form. The pure geometric isomers that are produced from isomer mixtures from isomeric starting materials or directly by stereoselective synthesis.

The compound produced according to the invention can be administered as a free base or a salt thereof with non-toxic acids. Typical examples of such salts are hydrobromides, hydrochlorides, phosphates, sulphates, sulfamates, lactates, acetates, citrates, tartrates, maleates and malates.

In clinical practice, the compounds produced according to the invention will usually be given orally, rectally or by injection, in the form of pharmaceutical preparations containing the active ingredient either as a free base or as a pharmaceutically usable non-toxic acid addition salt, e.g. as a salt of the above type in connection with pharmaceutical carriers. Designations relating to new compounds produced according to the present invention shall thus include both the free amine base and the acid addition salts of the free bases unless the context indicates otherwise. The carrier may be a solid, semi-solid or liquid diluent, or a capsule. Generally, the active substances will make up 0.1 - 95% by weight of the preparation, more particularly between 0.5 and 20% by weight for injection forms and 2-50% by weight in preparations suitable for oral administration.

For the production of pharmaceutical preparations containing the compound according to the invention, as dosage units for oral use, the selected compound can be mixed with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol wax, and pressed into tablets. If coated tablets are desired, the cores prepared as above can be coated with concentrated sugar solutions which may possibly contain gum arabic, gelatin, talc or titanium dioxide. Optionally, the tablets can be coated with a varnish dissolved in a volatile organic solvent or a mixture of such. Dyes can be added to the coatings to easily distinguish between tablets containing different active substances or different dosage amounts.

For the production of soft gelatin capsules (bead-shaped closed capsules) containing gelatin and e.g. glycerol or similar closed capsules, the active substance can be mixed with a vegetable oil. Hard gelatin capsules may contain granules of active substance combined with solid, powdered carriers such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal use can be produced in the form of suppositories containing the active substance mixed with a neutral fatty acid base or gelatin rectal capsules containing the active substance mixed with vegetable oil or paraffin oil.

Liquid preparations for oral use can take the form of syrups or suspensions, e.g. solutions containing 0.2 - 20% by weight of active substance, the rest being sugar, and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain dyes, flavourings, saccharin and carboxymethyl cellulose as a thickening agent.

Solutions for parenteral use by injection can be made as aqueous solutions of water-soluble pharmaceutical salts of the active compound, preferably in a concentration of 0.5 - 10% by weight. These solutions can also contain stabilizers and/or buffers and can advantageously be shaped as dosage unit ampoules.

Suitable daily doses of compounds prepared according to the invention for therapeutic use are 25 - 250 mg orally, preferably 50 - 150 mg, and 5 - 50 mg, preferably 10 - 30 mg parenterally.

A preparation in the form of dosage units for oral use may contain 10 - 50 and preferably 10 - 25 mg of active substance per dosage unit.

The preferred compound which is prepared according to the method of the invention is the Z-isomer with the formula:

Preferably, salts are prepared from the compounds in question.

The compound with formula I is prepared according to the invention by the following methods,

a) Dehydration of a compound of formula:

to a compound of formula I. Dehydration of the starting material can e.g. happen by treating with sulfuric acid and heating the reaction mixture. Dehydration of the starting material can also be carried out by other types of acid catalysis, e.g. by means of hydrochloric acid, HC1, phosphoric acid, H^PO^, potassium hydrogen sulphate, KHSO^, or oxalic acid, (C00H)2. Other dehydration methods for the starting material for the preparation of a compound of formula I are dehydration with phosphorus oxychloride, POCl-j, in pyridine, and with thionyl chloride, SOC12> in pyridine. Catalytic dehydration of the starting material can also be used. Dehydration takes place in this case at a temperature of approx. 300 - 500°C with a catalyst such as kaolin or aluminum oxide. b) Alkylation of monomethylamine with a compound of formula:

where Y denotes a leaving group, for the preparation of a

compound of formula I.

Illustrative examples of Y are halogens such as Cl, Br and J or sulfonates such as methanesulfonate, toluenesulfonate and benzenesulfonate.

c) Introduction of a methyl group in a manner known per se in a compound of formula:

for the preparation of a compound of formula I.

d) Hydrolysis of an acyl or sulfonyl compound with formula: where Z denotes an acyl or sulfonyl group, to a compound of formula I, either directly or via an intermediate of formula:

Examples of Z are acetyl, benzoyl, methanesulfonyl, benzoylmethanesulfonyl and toluenesulfonyl.

The compounds obtained according to the methods

a) - d) are isolated as pure Z-isomer and E-isomer and optionally transferred to a pharmaceutically acceptable salt.

For the preparation of compounds of formula I, it has been shown that hitherto unknown and new intermediates can be valuable. For the preparation of compounds of formula I according to method a), the compound is used:

as starting material.

The starting material can be prepared according to the following reaction scheme:

In the reaction scheme, Y has the previously indicated meaning and denotes a lower alkyl group with 1-5 C atoms, preferably ethyl. The reduction in the last step preferably takes place with a hydride reagent.

In the production of compounds with formula I according to method b) substances with the formula are used:

where Y is a leaving group, as starting material. This starting material can be prepared according to the reaction scheme

In the reaction scheme above, Y and R have the previously stated meanings. The reduction in the first step takes place advantageously with LiAlH^. The last step is preferably carried out with ?Br^ which means that the leaving group Y is Br.

The same starting material where the leaving group is halogen can also be produced by the following reaction scheme:

where Y' denotes a halogen such as Cl, Br or iodine. The allyl halogenation takes place with a suitable halogenating agent such as halosuccinimide. For the preparation of compounds according to method c) the starting material is used

This compound can be prepared according to similar methods as method a), b) and d) above. There are also other methods for producing starting materials, e.g. according to the following reaction scheme:

In the following, examples of the production of intermediate products are discussed.

Example A

Step 1.

A mixture of 4-bromophenyl-3-pyridyl ketone (CA 66, 3712Sh (1967), 50 g, 0.19 mol) and activated zinc (20 g) in benzene (100 ml) was heated under reflux. Ethyl bromoacetate (56 g, 0.35 mol) dissolved in benzene (50 mL) was slowly added over 30 min. A new portion of zinc (50 g) was added and the mixture refluxed for 14 hours. After cooling and filtering, benzene (300 ml) was added to the filtrate, which was washed 3 times with 10% aqueous acetic acid solution.

Ethyl ether (200 ml) was added and the solution acidified with 10% hydrochloric acid. The precipitate was filtered off, washed with ether and dried. Yield: 75%, m.p. 168 - 175°C.

Step 2

The base (9.5 g = 0.027 mol) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)propanoate hydrochloride (Step 1) was prepared and dissolved in ethyl ether (50 mL). The solution was added dropwise to an ice-cooled mixture of lithium aluminum hydride (1.0 g, 0.027 mol) and ethyl ether (150 mL). The reaction mixture was refluxed for 5 hours, cooled and a saturated sodium sulfate solution added until a white precipitate formed. This was filtered off and the filtrate evaporated. The residue was crystallized from chloroform. 1-(4-Bromophenyl)-1-(3-pyridyl)-1,3-propanediol was obtained, yield 39%, m.p. 130 - 132°C.

Example B

Step 1

3~( 4- bromophenyl)- 3- hydroxy- N- methyl- 3-( 3- pyridyl)- propionamide

19.4 g (0.05 mol) ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)propanoate, 200 ml of a 40% strength solution of methylamine in water and 30 ml of absolute ethanol were stirred for 24 hours at room temperature. The precipitate was filtered off and recrystallized from isopropyl alcohol to give 13.2 g (79%) of amide. Sm.p. 188 - 191°C. The formula C1^H-L^BrN2O2 was confirmed by elemental analysis.

(Elementary analyzes in the present application were carried out for all elements in the relevant compounds and lie within +_ k% of the theoretical values where nothing else is stated).

Step 2

3-"(4- broynf enyl l- 3- hydroxy- N- methyl- 3-( pyridyl)- propylamine

To 1.0 g (3.1 mmol) 3~(4-bromophenyl)-3-hydroxy-N-methyl-3-(3-pyridyl)-propionamide and 0.8 g (0.02 mol) sodium borohydride in 60 ml of dry tetrahydrofuran at 0°C and under N2, was added dropwise over the course of 20 min. 4.6 g (0.03 mol) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred overnight at room temperature and carefully hydrolyzed with water. Alkalization with 2M NaOH and extraction with ether gave after evaporation 0.9 g of semi-crystalline residue. Recrystallization from ether-petroleum ether gave 0.2 g (23%) amine, m.p. 8l-88°C.

Example C

Step 1

3-( 4- bromophenyl)- 3~ hydroxy- 3-( 3- pyridyl) propionamide

0.8 g (2.5 mmol) ethyl 3~(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate, 50 ml aqueous ammonia and 10 ml absolute ethanol were stirred at room temperature for 24 hours . The white precipitate was filtered off and recrystallized from isopropyl alcohol to give 0.45 g (56%) product with m.p. 213-214°C. The formula C^H-^BrN^ was confirmed by elemental analysis. C (calculated): 52.4,

C (found): 51.9-

Step 2

3-( 4- bromophenyl)- 3- hydroxy- 3-( 3- pyridyl)- propylamine

To 1.0 g (3.1 mmol) 3"(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionamide and 0.8 g (0.02 mol) sodium borohydride in 60 ml dry tetrahydrofuran at 0°C and under N2, 4.6 g (0.03 mol) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran was added dropwise over 20 min. The mixture was stirred for 48 h at room temperature and carefully hydrolyzed with water. Alkalization with 2 M NaOH and extraction with ether gave after evaporation a semi-crystalline residue.Recrystallization from ether-petroleum ether gave 0.6 g (63 i) of amine, mp 95-H5°C, NMR spectrum (COCl^): 2HC 2.4, 1-CH2)m: 2H(3.0, 2-CH2)m: 3H(3.6, -0H, "NH2)b : 6H(7.1-8.0 ArH)m: 2H (8.6) m.

Step 3

3-(4-bromophenyl)-3-(3-pyridyl)-allylamine

The crude product of 3-(4-bromophenyl)-3-hydroxy-3~(3-pyridyl)propylamine (from 0.4 g of 3-(4-bromophenyl)-3-hydroxy-3~pyridyl)-propionamide) was under stirring was added to 50 ml of acetic anhydride and 0.25 ml of concentrated sulfuric acid, and the mixture was heated at 130°C for 45 minutes. It was then cooled, poured onto crushed ice, alkalized with 30% NaOH and extracted with ether. Evaporation gave 0.36 g of oil. After hydrolysis with 15 ml of concentrated hydrochloric acid for 4 hours, 0.25 g of an oil was obtained. Thin layer chromatography showed two spots with Rf = 0.1 and 0.8. Column chromatography on silica gel with methanol as eluent gave 0.06 g of the fastest fraction and 0.19 g of the slowest, which was the amine. The oxalate of this compound was prepared. It was crystallized from ethanol, m.p. 153.5-155.5°C.

The NMR spectrum shows the vinyl proton as a double triplet at 6.1-6.5 ppm, indicating a 1:1 isomeric ratio.

The formula C-^H-^B^ . 1 H2O was confirmed by elemental analysis.

The oxalate was further purified by crystallization from a mixture of equal volumes of methanol and isopropyl alcohol and once from pure methanol. One got a connection with sm.p. 160-162°C. The NMR spectrum showed that this was the Z isomer.

Example D

Step 1

3-( 4- bromophenyl)- 3- hydroxy- 3-( 3- pyridyl)- propionitrile

A mixture of 6.5 g (0.16 mol) of acetonitrile and 50 ml of dry tetrahydrofuran (THF) was slowly added under a ^-atmosphere to a mixture of 100 ml of 1.5 M n-butyllithium in hexane and 50 ml of dry THF at -50°C. After stirring for 35 min. a solution of 36.5 g (0.14 mol) of 4-bromophenyl-3-pyridyl ketone in 250 ml of dry THF was added at -50°C. The temperature was kept at -70°C for 15 min., then the reaction mixture became viscous and it was allowed to warm to room temperature. The product was poured into a stirred mixture of 500 g of ice-water and 500 ml of methylene chloride. The layers were separated and the aqueous layer extracted with 2x200 mL CH 2 Cl 2 . The combined organic layers were washed with water and dried. The solvent was evaporated to give 39.7 g of an oily compound. The oil was dissolved in 550 ml of hot i-PrOH and a solution of 35 ml of 4M HCl ether (0.14 mol) in 100 ml of i-PrOH was added. After cooling, 34.6 g (74%) of hydrochloride of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)propionitrile were obtained, m.p. 15 8-161°C. Step 2

3-( 4- bromophenyl)- 3- hydroxy- 3-( 3- pyridyl)- propylamine

17.2 g (0.056 mol) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionitrile was dissolved in 175 ml of THF and diluted with 200 ml of ether. The solution was cooled to -35°C and 4.0 g (0.112 mol) LiAlH 2 was added portionwise under N 2 atmosphere. The mixture was kept at 0°C for 2 hours and at 15°C for 2 hours. 20 ml solution of saturated Na 2 SO 1 was slowly added. After 30 min. the mixture was filtered and the inorganic salts washed with 2 x 100 ml of ether. The filtrate was collected and the solvent evaporated to 14.7 g of oil. It was diluted with 500 ml of hot i-PrOH and 4.3 g (0.048 mol) of oxalic acid in 300 ml of hot i-PrOH was added dropwise. After cooling overnight, 11.8 g of crystals formed with m.p. 98-105°C. An analytical sample of the free amine had m.p. 118-120°C crystallized from in PrOH. Yield: 51%.

Step 3

3-(4-bromophenyl)~3~(3-pyridyl)-allylamine

To 0.80 g (0.002 mol) oxalate of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propylamine was added 6 ml of 70 µg of H 2 SO 3 for 35 min. Ice-water was added, then 30 ml of 30% NaOH and the mixture was extracted with 3x 100 ml of ether. Drying and evaporation of the solvent gave 0.62 g of oil. It was dissolved in 10 ml of hot ethanol and a hot solution of 0.20 g of oxalic acid in 5 ml of ethanol was added. On cooling, 0.49 g of crystals were collected.

NMR showed that the product was a mixture of E and Z isomers of 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine as in Example C, step 3-

Example 1 (method b)

1-(4-Bromophenyl)-1-(3-pyridyl)-1,3-propanediol (prepared according to Example A, 7.2 g = 0.023 mol) was dissolved in dry acetone (70 mL). Hydrogen bromide was bubbled through the solution and the solvent evaporated in vacuo. Methylene chloride (50 mL) and phosphorus tribromide (6.4 g - 0.047 mol) were added to the residue and the mixture refluxed for 14 hours, poured onto ice and made alkaline with sodium carbonate. Methanol (50 ml) was added

to the organic phase and the solution was evaporated in vacuo at 30°C to 30 ml. The solution was heated with monomethylamine (14 g = 0.47 mol) in an autoclave at 110°C for 15 hours. After cooling, the solvent was evaporated and the residue dissolved in ether (25 ml) and water (25 ml). The pH of the mixture was adjusted to 9.0 with ammonia and the layers separated. More water was added to the ether layer and the pH adjusted to 2.1 with HCl. The water phase was treated with charcoal and made alkaline with ammonia and extracted with ether. The organic phase was dried with sodium sulfate and evaporated in vacuo. The evaporation residue base was dissolved in ether (40 ml) and cooled in an ice bath. Hydrochloric acid was added dropwise in ether and a pale yellow precipitate was obtained. The precipitate was filtered off, washed with ether and dried in vacuo. The hydrochloride of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine was obtained. Yield: 43%, m.p. 138-144°C. The Z-isomer and the E-isomer were obtained in the same way as described in Example 2.

Example 2 (method a)

The crude product of 3~(4-bromophenyl)-3~hydroxy-N-methyl-3-(3-pyridyl)-propylamine (prepared as in Example B from 5.0 g of 3-(4-bromophenyl)-3-hydroxy- N-methyl-3-pyridyl-propionamide) was added with stirring to 50% sulfuric acid (50 ml) and the mixture heated at 110°C for 10 minutes. The mixture was then cooled, poured into crushed ice, alkalized by the addition of 30% NaOH and extracted with ether. Evaporation gave 4.9 g of semi-crystalline residue. 150 ml of acetone was added and the solution clarified by filtration. 0.9 g (0.01 mol) of oxalic acid dissolved in 25 ml of acetone was added dropwise to the filtrate. The white precipitate was collected and recrystallized from 350 ml of isopropyl alcohol to give 1.7 g of white crystals consisting of the oxalate of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine, m.p. l80-208°C. The NMR spectrum shows the vinyl proton as a double triplet at 6.1-6.4 ppm, indicating a mixture of E and Z isomers.

Isolation of the Z-isomer: After recrystallization

0.5 g of substance was obtained 3 times from ethanol. Sm.p. 202-205°C. The NMR spectrum shows the vinyl proton as a single triplet with

J= 3.4 Hz and in a position showing that the compound is the Z-isomer.

The amino oxalate produced was transferred to the corresponding hydrochloride via the free base. Recrystallization from acetonitrile containing a few percent water gave a compound melting at 161-165°C. Elemental analysis showed that the compound was a dihydrochloride with the composition C^^H^^BrN2.2HC1.H^O.

Isolation of the E-isomer: The mother liquor from isolation

of the Z-isomer, containing both isomers in a ratio of approx. 60:40 resp. E and Z isomers, were used. The oxalate of this amine mixture was recrystallized 3 times from acetonitrile containing 15% water to give a compound melting at 198-201°C. According to the NMR spectrum, this compound was the E isomer.

Example 3 1-(4-bromophenyl)-3-methylamino-1-(3-pyridyl)-prop-1-ene

(method c)

To 3-amino-1-(4-bromophenyl)-1-(3-pyridyl)-prop-1-ene (0.58 g, mixture of isomers) in ether (10 mL) was added ethyl trifluoroacetate (0.43 g) in ether (5 ml) at room temperature. After 1.5 hours the solution was extracted with dilute 2M hydrochloric acid, the extract was made basic and extracted with ether which after evaporation gave the trifluoroacetamide derivative in the form of an oil. This oil was dissolved in dimethylformamide (DMF, 25 ml, dried over CaH 2 ). Sodium hydroxide (0.1 g 50% oil emulsion) was added under nitrogen gas and the mixture stirred at room temperature for 4 hours. Methyl iodide (0.3 g) in DMF (10 mL) was added and stirring continued for an additional 1.5 h under N 2 . The mixture was diluted with water and extracted with ether. After evaporation, the residual oil consisting of the methylated trifluoroacetamide derivative was dissolved in ethanol (30 ml) containing sodium hydroxide (5 ml, 10 M) and the mixture was refluxed for 50 min. By means of thin-layer chromatography, it was ascertained that the hydrolysis was then complete. Dilution with water, extraction with ether and extraction of the ether extract with hydrochloric acid, alkalization, extraction with methylene chloride and evaporation gave the methylated amine as an oil (0.36 g). The oxalate was precipitated from isopropyl alcohol and recrystallized from methanol. Sm.p. » 185°C. The NMR spectrum shows a peak for the methyl group

(6~ 2.4, in agreement with the reference substance) in a region which is empty in the spectrum of the primary amine. In the region around 6 =6.2, a double triplet was obtained, which shows that the compound consisted of a mixture of isomers. The Z-isomer and the E-isomer were obtained as described in Example 2.

Example 4 1-(4-bromophenyl)-3-methylamino-1-(3-pyridiyl)prop-1-ene

(method d)

Step 1

The sodium salt of methylfluoroacetamide was prepared by stirring a mixture of 0.06 g (0.002 mol) 80% sodium hydride and 0.25 g (0.002 mol) CF3C0NHCH3 in 10 ml of DMF-ether (1:1) under ^-atmosphere in i hour at room temperature. A solution of 0.61 g (0.002 mol) Z-3-(4-bromophenyl)-3-(3-pyridyl)-allyl chloride in 5 ml of the same solvent was added. After stirring for 2 hours at room temperature, water was slowly added and the reaction mixture was extracted with ether. The combined ether phases were shaken with 0.5 M hydrochloric acid, the aqueous phase was made slightly alkaline and extracted with methylene chloride. Drying and evaporation of the solvent gave 0.5 g of N-methyl-N-trifluoroacetyl-3-(4-bromophenyl)-3-(3-pyridyl)propenylamine as an oil. This was characterized using thin-layer chromatography in two separate systems. The observed Rf value was 0.23 when isopropyl ether containing 5% methanol was used and 0.47 when ethyl acetate was used. In both cases, commercially available coated plates of the "Merck Silica Gel F254" type were used - the NMR spectrum in deutero-chloroform had a characteristic peak at 6 3.0 ppm. The IR spectrum had a carbonyl band at 1680 cm-1.

Step 2

To a solution of 0.4 g (0.001 mol) of the obtained trifluoroacetamide in 10 ml of ethanol, 0.2 ml (0.002 mol) of 10M NaOH was added and the mixture was stirred for 1.5 hours at room temperature. The addition of 0.38 g (0.003 mol) of oxalic acid dihydrate in 10 ml of isopropyl alcohol gave crystals of the oxalate. Recrystallization from 5 mL of 95% methanol gave 0.3 g (76%) of 1-(4-bromophenyl)-3-methylamino-1-(3-pyridyl)-prop-1-ene, m.p. 165-175°C. The Z-isomer and the E-isomer were prepared as described in

example 2.

g) Pharmacological experiments

It is not possible experimentally to induce artificial ones

depression in experimental animals. In order to assess a possible antidepressant effect for new compounds, reference is made to biochemical-pharmacological test methods. Such a method which seems to give a good indication of potential anti-depressant effects of experimental compounds is described in Europ. J. Pharmacol. 17_,107p 1972.

The procedure consists in measuring the decrease in the uptake of <1>^C-5-hydroxytryptamine ("^C-5-HT) and ^H-noradrenaline (•^H-NA) in slice preparations from mouse brains after in vivo and in vitro -administration of the test compound l2 inhibition_of_extraction_of___C-5^ and in vivo

The test compound was given intraperitoneally 1/2 hour before the animals were killed. The mid-brain was taken out, prepared in ski-l il ^

ver and incubated in a mixture of 0.2 mol C-5-HT, 0.2 nmol H-NA and 11 umol glucose in 2 ml Krebs-Henseleit buffer, pH 7.4 per 100 mg slice preparations. The incubation time was 5 min. with 5 min. pre-incubation before the radioactively labeled amines were added. The discs were dissolved in the "Soluene" and the amount of radioactive amines that were taken up was measured by liquid scintillation. Doses that produced a 50% reduction in active uptake ( ED^-q ) for <12>|C-5-HT and <3>H-NA were determined graphically from dose-response curves. Active uptake is defined as the part of the radioactive uptake that is inhibited by a high concentration of cocaine.

In the in vitro method, mouse midbrain slices were pre-incubated for 5 min. with a solution of the test compound, and then incubated as described above.

As will be seen from the table, the compounds produced according to the invention are powerful inhibitors of the nerve uptake of 5-hydroxytryptamine and norepinephrine. The Z-form of the compound shows more potent inhibition of uptake of 5-HT in vivo than any of the known compounds investigated.

The Z-form of the compound prepared according to the invention and examined in the form of hydrochloride, is furthermore a more powerful inhibitor for the uptake of 5-HT in vitro than any of the previously known compounds. (The difference that appears between the effect of the oxalate and the hydrochloride is assumed to be due to the fact that the hydrochloride is prepared from the oxalate so that a purer Z-isomer was obtained. The E form of the compound produced according to the invention will mainly inhibit the uptake of norepinephrine. Inhibition of the nerve uptake of 5-hydroxytryptamine and noradrenaline that has been described can give the compounds value as antidepressants.They can also be used as nerve tranquilizers.

Claims (1)

Analogous method for the preparation of therapeutically active compounds in Z-form and E-form and with the formula: or a pharmaceutically acceptable salt thereof, characterized by a) dehydrating a compound with the formula: for forming a compound of formula I; b) alkylates monomethylamine with a compound of the formula: where Y is a leaving group, to obtain a compound according to formula I; c) introduces a methyl group in a manner known per se in a compound of the formula: for the formation of a compound of formula I, or d) treats under hydrolyzing conditions an acyl or sulfonyl compound of the formula: where Z is an acyl or sulfonyl group for the formation of a compound according to formula I either directly or via an unsaturated acyl or sulfonyl compound, after which the compound obtained according to methods a) - d) is isolated as pure Z-isomer and E- isomer and optionally transferred to a pharmaceutically acceptable salt.