FI64353B - FOERFARANDE FOER FRAMSTAELLNING AV E-3- (4-BROMOPHENYL) -N-METHYL-3- (3-PYRIDYL) -ALLYLAMINE TILL ANVAENDNING SOM LAEKEMEDEL - Google Patents

Description

64353

Process for the preparation of E-3- (i-bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine for use as a medicament

The present invention relates to a process for the preparation of E-3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) allylamine having antidepressant and antidepressant scavenging, or a pharmaceutically acceptable salt thereof.

Depressive disorders have been treated with better or less success with many different compounds.

The most widely used antifreeze agents in clinical use are tricyclic tertiary amines, such as imi-pramine of structural formula 1 / CH3

CH2CH2CH2-N

CH- and amitriptyline of structural formula 'Wchch2ch2-n

Secondary amines, such as desipramine, having the structural formula

i H

ch2ch2c ^ -n ^ CH 3 and nortripty1 M n 1 a of structural formula 2 64353 / Η

CHCH0CH-, N

\ ch3 is used to reduce some. However, these compounds have side effects that are undesirable in therapeutic use, such as orthostatism, anticholinergic effects and, above all, arrhythmia, i. cardiac arrhythmic effect when administered at high doses in elderly patients. In addition, all the mentioned substances have the disadvantage that the anti-nasal effect only begins after a few weeks of treatment. In addition, it is known from the literature that certain 1,1-diphenyl-3-aminoprop-1-enes, such as

C = CH-CH? N

The compound of formula q / x '"> has an antidepressant effect, cf. J. Med. Chem. 14, 161-4 (1971). The compounds of formula x CHCHOCH-N / 2 2 \ ^ CH3 n wherein X is chlorine or bromine, and tt is hydrogen or methyl is described to have antidoprosis ivist.'i effect, vrl · LL-pa- 3 64353 exam 3,423,510, however, these compounds also have a strong antihistamine effect.

Br 2 CH 3

C = CHCH "N

The compound according to CH3 has an antidepressant effect in animal experiments, cf. Belgian Patent No. 781105.

Many different types of depressive disorder are known in medicine. Depressed patients respond differently to different antidepressants used clinically. Most of these agents inhibit the binding of noradrenaline to neurons and some of them further inhibit the binding of 5-hydroxytryptamine. Inhibition of 5-hydroxytryptamine binding is believed to be the mechanism by which some of these antidepressants cause improvement in mood. In addition to the absolute value of inhibiting the binding of 5-hydroxytryptamine or noradrenaline, there is great interest in the selectivity that determines which of these two amines binds.

It is a general object of the present invention to provide a novel compound having good antidepressant activity. It is a further object of the invention to provide a compound having an antidepressant effect and having only minor side effects, especially arrhythmias. Another object is to prepare a compound having therapeutic activity against anxiety. Other objects of the invention will become apparent from the following description.

According to the invention there is provided a process for E-3- (4-bromophenyl) -4,4353 N-methyl-3- (3-pyridyl) allylamine having antidepressant and anxiety relieving activity and having the formula

O XX

! i H

1 '/

C HCH-N

X'ch3 or a pharmaceutically acceptable salt thereof.

Due to the absence of free rotation of the double bond, the compound of formula I may exist in different stereoisomeric forms, i. as cis-trans isomers or according to the IUP ^ C nomenclature (J. Org. Chem. 3-5, 2849-2867, September 1970) in E-form and Z-form. The compound can be used therapeutically as a mixture of geometric isomers or in pure E or Z form. Pure geometric isomers can be prepared from a mixture of isomers, from an isomerically pure starting material or directly by stereoselective synthesis.

The compounds of formula I may be administered as a medicament in the form of a free base or in the form of a salt thereof with a non-toxic acid. Some typical examples of these salts are hydrobromide, hydrochloride, phosphate, sulfate, sulfamate, lactate, acetate, citrate, tartrate, malate and maleate.

Pharmaceutical preparations

In clinical use, the compounds of the present formula I are normally administered orally, rectally or by injection in the form of pharmaceutical preparations containing the active ingredient either as the free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. one of the above, together with a pharmaceutically acceptable carrier. Thus, when referring to a novel compound of the present invention, this means both the free amine base and the acid addition salt of the free base, unless the context in which such terms are used, e.g., a particular example, is inappropriate for such broad meaning. The carrier may be a solid, semi-solid, or liquid diluent or capsule. These pharmaceutical preparations form a further aspect of this invention. The amount of active ingredient in the pharmaceutical preparation is usually 0.1 to 95% by weight, in particular 0.5 to 20% by weight in preparations for injection and 2 to 50% by weight in preparations for oral administration.

For the preparation of pharmaceutical preparations containing a compound of formula I in unit dosage form for oral use, the compound may be mixed with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch or Amy-lopectin, with magnesium stearate, calcium stearate or polyethylene glycol waxes, and then compressed into tablets. If it is desired to prepare coated tablets, the cores prepared as described above may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatin, talc or titanium oxide. Alternatively, the tablet may be coated with a varnish dissolved in a volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active ingredients and tablets containing different amounts of active compound.

For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatin and, for example, glycerol, or for the preparation of similar tablets, the active ingredient can be mixed with vegetable oil. Hard gelatine capsules may contain granules of the active ingredient together with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine derivatives.

Dosage units for rectal administration may be prepared in the form of suppositories containing the active ingredient in admixture with a neutral fatty base, or in the form of gelatin rectal capsules in which the active ingredient is mixed with vegetable oil or paraffin.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing from about 0.2% to about 20% by weight of the active ingredient described herein, the remainder consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent.

Injectable preparations for parenteral use may be prepared from a water-soluble pharmaceutically acceptable salt of the active ingredient, preferably in concentrations of about 0.5% to about 10% by weight. These solutions may also contain stabilizers and / or buffering agents and are preferably packaged in various dosage unit ampoules.

Suitable daily doses of a compound prepared by the method of the invention for therapeutic treatment are 25 to 250 mg in an oral dose, preferably 50 to 150 mg, and 5 to 50 mg in a parenteral dose, preferably 10 to 30 mg. A dosage unit for oral administration may contain 10 to 50 mg, preferably 10 to 25 mg of active ingredient per dosage unit.

By the process of the invention, compound 7 64353 is preferably prepared in the form of a salt and used as such. The compound of formula I is prepared by a) dehydration of 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine of formula ... Br O xr HO CH2CH2NHCH3 The dehydration of the starting material can be carried out, for example, by treating the reaction mixture with sulfuric acid and heating. The dehydration of the starting material can also be performed using other types of acid catalysis, such as hydrochloric acid, HCl, phosphoric acid, H 3 PO 4, potassium hydrogen sulfate, KHSO 4, or oxalic acid, (COOH) 2 /. Other methods for dehydrating the starting material to form a compound of formula I include dehydration using phosphorus oxychloride, POCl 3, in pyridine, and dehydration with thionyl chloride, SOCl 2 in pyridine. Catalytic dehydration of the starting material can also be used. The dehydration is in this case carried out at temperatures of about 300-500 ° C using a catalyst such as kaolin or alumina, h) by alkylation of monomethylamine with a 3- (4-bromophenyl) -3- (3-pyridyl) allyl derivative of the formula XBr '

II

CH-CH, -Y

to form a compound of formula I, wherein in formula Y represents a leaving group.

Examples of the meaning of Y are halogens, such as chlorine, 64353 bromine and iodine, or sulfonates, such as methanesulfonate, toluenesulfonate and benzenesulfonate, c) by introducing a methyl group into 3- (4-bromophenyl) -3- (3-pyridyl) allylamine. L · i I! CHCH 2 NH 2 to form a compound of formula I, d) treating under hydrolysing conditions an acyl or sulfonyl compound of formula 3- (4-bromo-phenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) -propylamine rr

^ CT

X'NVvCH2CH2-N-CH3-Z

wherein Z is an acyl or sulfonyl group to form a compound of formula I, either directly or via an unsaturated acyl or sulfonyl compound, after which the compound obtained by any of a) to d) is optionally converted / separated into the pure E-isomer and optionally converted as a pharmaceutically acceptable salt.

The following examples further illustrate the invention.

Example 1, {method b) ^ / x ✓ Br n. / x / Br i h l II ~ 2) —-----> i ij il

N 'NH2CH 3 N

'' '^ CH-CH-OH 1' 2 2 CHCH2NHCH3

II

64353 1- (4-Bromophenyl) -1- (3-pyridyl) -1,3-propanediol (7.2 g, 0.023 mol) was dissolved in dry acetone (70 mL). Hydrogen bromide was bubbled through the solution and the solvent was removed in vacuo. Methylene chloride (50 mL) and phosphorus tribromide (6.4 g, 0.047 mol) were added to the residue, and the mixture was 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 was dissolved in ether (25 ml) and water (25 ml). The pH of the mixture was adjusted to 9.0 with ammonia and the layers were separated. A second portion of water was added to the ether layer, and the pH was adjusted to 2.1 liters with HCl. The aqueous phase was treated with activated carbon, then basified with ammonia and extracted with ether. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residual base was dissolved in ether (40 ml), and the solution was cooled in an ice bath. An ethereal solution of hydrogen chloride was added dropwise to the solution to give a slightly yellowish precipitate. The precipitate was filtered, washed with ether and dried in vacuo. 3- (4-Bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine hydrochloride was obtained. Yield 43% - 5p. 138-144 ° C.

Example 2, (Method a) [3- (4-Bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine crude product (prepared 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 was heated at 110 ° C for 10 minutes. The mixture was then cooled, poured onto crushed ice, basified by the addition of 30% NaOH and extracted with ether. Evaporation gave 4.9 g of a semi-crystalline residue. 150 ml of acetone were added and the solution was clarified by filtration. 0.9 g (0.01 mol) of oxalic acid was dissolved in 25 ml of acetone, and the solution 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 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) allylamine oxalate as white crystals. Sp. 180-208 ° C, the N.MR spectrum shows a vinyl proton as a double triplet at 6.1-6.4 ppm, indicating the mixture of E and Z isomers in question.

Isolation of the Z-isomer: Crystallized 3 times from ethanol to give 0.5 g of material, m.p. 202-205 ° C. The NMR spectrum shows the vinyl proton as a single triplet, J = 3.4 Hz, with the position indicating that the compound is the Z isomer.

The resulting amine oxalate was converted to the corresponding hydrochloride via the free base. Recrystallization from acetonitrile containing some percent water gave a compound melting at 161-165 ° C. Elemental analysis showed it to be the dihydrochloride of formula C15H15BrN2 '2 HCl * H2O' Isolation of the E-isomer: Stock solutions obtained from the isolation of the Z-isomer containing both isomers in an E: Z ratio of about 60:40 were used. The oxalate of this amine mixture was crystallized 3 times from acetonitrile containing 15% water to give a material melting at 198-201 ° C. According to the NMR spectrum, this substance was the E-isomer.

64353

Example 3, (method c) O Cf - O nr "-

Vv./vJ

CH CH

CH- L · I 2 ψ2 NH2 NHCCCF3

Br _ Br lJj - * Γ "| c xc

Il Cl! <JH2 {b2 NCH, NHCH-

N, 3-Amino-1- (4-bromophenyl) -1- (3-pyridyl) -prop-1-ene (0.58 g, mixture of isomers) in ether (10 ml) was added ethyl fluoroacetate (0.43 g). in ether (5 mL) at room temperature. After 1.5 hours, the solution was extracted with ether which, after evaporation, gave the trifluoroacetamide amide derivative as an oil. This oil was dissolved in dimethylformamide (DMF, 25 mL, dried over CaH 2). Sodium hydroxide (0.1 g, 50% oil emulsion) in nitrogen gas was added and the mixture was stirred at room temperature for 4 hours. Methyl iodide (0.3 g) in DMF (10 ml) was added and stirring was continued for a further 1.5 hours. The mixture was diluted with water and extracted with ether. After evaporation to dryness, the residual oil, which was a methylated trifluoroacetamide amide derivative, was dissolved in ethanol (30 ml) containing sodium hydroxide (5 ml, 10M) and the mixture was refluxed for 50 minutes. Completion of the hydrolysis was observed by thin layer chromatography. It was then diluted with water, extracted with ether 11a, extracted with Cotter's extract with hydrochloric acid, calibrated with granular chloride and evaporated to dryness to give methylated abine as an oil (0.3). The oxalate was doped with isopropyl alcohol and recrystallized from methanol, m.p. 185 ° C. In the NMR spectrum of the product, a peak could be observed for the methyl group (6 ^ 2.4, consistent with the reference substance) in the region that is empty in the spectrum of the primary amine. In the range of about 6 = 6.2, a double triplet was observed, indicating that the compound consists of a mixture of isomers.

Example 4, (method d)

Step 1 a xr - ox / r

H S

^ C \ C1-CH2 h CH3NCH2 h 10 CF3

A mixture of methyl trifluoroacetamide sodium was prepared by stirring a mixture of 0.06 g (0.002 mol) of 80% sodium hydroxide and 0.25 g (0.002 mol) of CF 2 CONHCH 2 in DMF ether (10 ml, 1: 1) for 1 hour. time at room temperature. A solution of 0.61 g (0.002 mol) of Z-3- (4-bromophenyl) -3- (3-pyridyl) allyl chloride in the above solvent (5 ml) was added. After stirring for 2 hours at room temperature, water was slowly added and the reaction mixture was extracted with ether. The combined etherases 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 to dryness gave 0.5 g of N-methyl-N-trifluoroacetyl-3- (4-bromophenyl) -3- (3-pyridyl) -propenylamine as an oil. The product was identified by thin layer chromatography on two systems. The Rf value observed was 0.23 when isopropyl ether containing 5>, methanol and 0.47 when ethyl acetate was used. In both cases, commercially available coated sheets of the brand Merck Silica Gel F254 were used. A characteristic peak at 6 = 3.0 ppm was observed in the NMR spectrum (deutero-chloroform). A carbonyl band at 1680 cm-1 was observed in the IR spectrum.

Step 2

- * Ux XJ

! l c "ch3nch ^ XH ch, nc <CX ^ l 3i 2 COCF3 h

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

Pharmacological experiments

It is not possible to experimentally induce depressive states in laboratory animals. A biochemical-pharmacological test must be used to assess the possible antidepressant effect of new substances. One such method that appears to provide a good indication of the potential antidepressant efficacy of a test substance is described in Europ. J. Pharmacol. 17, 107, 1972.

This method measures the reduction in binding of β-C-5-hydroxytryptamine (β-5-HT) and β-noradrenaline (3H-NA) to mouse brain fragments after in vivo and in vitro administration of the test substance.

14 64353 14 3 Inhibition of C-5-HT and H-NA binding in vitro and in vivo

The test substances were administered to the animals intraperitoneally half an hour before the animals were sacrificed. The midbrain was retrieved, sliced, and incubated in a mixture of 0.2 14 3 nmoles of C-5-HT, 0.2 nmoles of H-NA, and 11 μmoles of glucose in 2 ml of Krebs-Henseleit buffer, pH 7. , 4, 100 mg per brain pieces. The incubation time was 5 minutes, followed by 5 minutes of pre-incubation before the addition of labeled amines. The pieces were dissolved in Soluene and the bound amounts of radioactive amine were measured with a liquid scintillation counter. Doses that caused a 50% 14.3 reduction in (ED 2) active binding of C5-HT and H-NA were determined graphically from dose-response curves. Active binding is therefore defined as part of radioactive binding that is prevented by high cocaine levels.

In the in vitro method, fragments of mouse midbrain were preincubated for 5 minutes in a solution of test compound and then incubated as described above.

15 64353

Cl, l G · ί οι · Η; C tp I ™ HO, g> \ -. (N rH L «CO LD ro 0 -n 05 | rP O O CM CP CM X3 -U> ° -Η ί I Ή I — I * 0 Lfl Τ 'I A ^ 0 c a g • P -P W g’

* H 0 I

0} \ l o i C M -

·· Jj I

<-h; Z> ο j co 1 m g ^ in in oo ίγ> h o DCUC -p --- ro -h k I cn ί — ί o - = r co c c ί ™ 0 G c

-p QJ, I

g g u, \ 0 -H · P g -H; 35 tjl ί 0 + J O 3 P 0> \ ΓΜ> i P O -H 0 Ui U) Pi -P> o * h CNJOOlOCnj On 00 LfO · Ρ P3 -P Ln'dni-HrHO ^ fO 'iN: 0

G v to cfi C D H 1 ^ Λ \ Ή X

-P C \ ffi -H K g X

C Ή / \ On Ο ^ ί 05 3 5 // Λ \ / 3 o! X O \ / Z K M | 0} C X - / CM I -P, o \ o CO \ iB m -H i <DM \ υ [> olLomrHcnr ^^ icA oo OM 35 \ KU i-og ^ - ro & £ D <D r) -r) CU 35 ooocm ih md o

«CöC y H hh \ G

D M / -H

D O G, _ / -H -H -p -p

D CO) f / Λ D D D -P

<5 4-> // \\ * H Ή -P Ή Ή -P -m -U

E-t cd CD \ / -P + J M -P M P M CL) • n Γ5 \ _ / P P O 4-> O P O 4- 'f — l' - ^ 05 ct3 ro · -! cr; —I r5 —l en

C icj Ή 05 05 Λ! 05 X 05 X O

-H Qh O f "! F”) O iP O · Ρ O ““ “f C 0 05 05 M 05 M 05 M 0 • pc w | to w ό en x> en Ό p • HO) X Λ>, >>, Λ!> Gi—, oo χ o χ o χ 05 O e, 1-t> Ή · en -M Mi -p X 05 Q) [

0 <D! CP

MC g t en AC

DO) O i O CM CM W! K] U \> i M en a) -h x * p i — i j en t — i

1 -H O

en X O

<1> I g -μ o5 0 en m -h \ • H Cl, e D ΓΟ ΓΟ -H -H i — i X k k g -H o> · Ä K K a K U O -H g. i — i ^ - ^ - J 0 O r 4J dj

I -P i — l f — I

0 O -M e — I

g -H 0) O

D ac en ex: p o x

: 0> 1 p <l) X O

C C Cl C

CC -P -P -PC

PO O tn Oi 05 tn e e -p

! X -P CD

: O oi ex: - -.

I X .y H> 1 rp IN! 16 64353

As can be seen from the table, the compound of formula I has a strong inhibitory effect on the binding of neurons to 5-hydroxytryptamine and noradrenaline. The Z-form of the compound has a stronger inhibitory effect on 5-HT binding in vivo than any of the known compounds tested.

It is also found from the table that the E-isomer 11a of the compound of formula I has a better in vitro selectivity for the inhibition of noradrenaline binding in a mouse brain assay than the corresponding known N, N-dimethyl compound. The effect of both compounds on both 5-hydroxytryotamine and noradrenaline is weak when administered to mice in vivo, making it difficult to assess selectivity. This weak effect can be explained by the special metabolic behavior of the mouse, towards these compounds. However, superior selectivity has been confirmed by an experiment with mouse brain synaptosomes, which gave the following results.

Inhibition of binding EC_q ^, μM

5-HT NA

Known dimethyl compound, E-form 0.65 1.2

New monomethyl compound, E-form 0.60 0.015

In addition, the Z-form of the compound of formula I tested as the hydrochloride has a stronger inhibitor of 5-HT binding in vitro than any of the previously known compounds tested. (The difference between the oxalate and the hydrochloride is believed to be due to the fact that the hydrochloride was prepared from the oxalate to give the purer Z isomer). Form E of a compound of the invention primarily inhibits noradrenaline binding. Inhibition of the neuronal binding of 5-hydroxytryptamine and noradrenaline makes the compound of the invention a valuable antidepressant. Likewise, the compound of the invention is useful as an analgesic.

The use of E-3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine as an antidepressant and an anti-inflammatory drug is contraindicated. site därav.

Depression distillation is associated with the whole or the same Frara-Gäng med flera olika föreningar.

The antidepressant medication, which may be used in clinical trials, is a tricyclic tertiary amine or an amine-derivative, with the structural form I / CH3 CH2ch2ch2-n ^ CH3 and amitriptyline with the structural form T / CH3 CHCH2CH2-N "

-J

Secondary amine desipramine with structural form 2 2 2 \

VcH3 and nortriptyline in structural form

B

CHCH0CH0N ^ 2 2 \ c „3 is 64353 and the face is utilized. All of these substances have been shown to be effective against therapeutic orthostatic effects, anticholinergic effects, and framför allt arvtmi, dvs. The use of these substances has been shown to have antidepressant effects after treatment. The mixture is converted to 1,1-diphenyl-3-aminoprop-1-energy in the form of the formulation / CH3 ^ C = CHCH2N ^ 3

har en antidepressant effect, se J- Med. Chem. 14 161-4 (1971). Exemption from form X

R

^^ CHCH2CH2N ^. 'CH,

When X is chlorine or bromine or R, or an antidepressant effect, the U.S. Pat. No. 3,423,510 discloses the use of an antihistamine effect. The present invention is described as having a formulation with the form of an anti-depressant effect, Belgian Patent No. 781 105. The inherent medical scanner has been shown to be depressive. Deprimerade patienter reagerar pä olika vis till de kliniskt använda olika antidepressionsläkemedlen. The fixture is derived from the addition of 5-hydroxytryptamine to noradrenaline and neurons and from the addition of 5-hydroxytryptamine. The inhibition of the 5-hydroxytryptamine moiety is a mechanism that can be used to treat antidepressant medications in a stable manner. In this case, the absolute value of the inhibition of the 5-hydrotryptamine or noradrenaline button is selective and the best of these can be found in the present invention.

Ett huvudSndamäl med den föreliggande uppfinningen Sr att ästad-komma nya föreningar med god antidepressiv efekt. In addition to the action of anti-depressant effects and the action of anti-depressant effects, it is particularly effective in arthropodic effects. In the case of Sndamalet Sr, framstSlla en förening med therapeutisk efekt mot ängest, Ytter-ligare Sndamäl med merffinningen kommer att upbarbar and den up-jande beskrivningen.

Preferably, the addition of an E-3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine with antidepressant and long-acting effects is effective.

chch9n ^ z X

ch3 eller pharmaceutiskt acceptabelt sait dSrav.

In addition to the rotation and duplication of the formulation, it exists in the form of a former stereoisomer, which is a cis-trans isomer or an IUPAC nomenclature (J. Org. Chem. 3J>, 2849-2867, September 1970). in E-form and Z-form. Föreningen kan användas therapeutiskt som en blandning av de geo-metriska isomercrna eller e ren E- eller Z-forma. The Rena is a geomorphic isomercrane that can be found in the isomeric bands, and that 20 6 4 3 5 3 isomeric-rent utgängsmaterial eller direkt med en stereoselektiv synthes.

For example, the administration may be in the form of a salt or a salt of a medium. Vissa typiska exempel pädana salter is hydrobromide, hydrochloride, phosphate, sulphate, sulphamate, lactate, acetate, citrate, tartrate, malate and maleate.

Pharmacological medicine. _________- - -. --.-

In the case of clinical administration, the administration of the active substance in the form of orally, rectally or by genomic injection, in the form of a pharmaceutical formulation with active pharmaceutical ingredients and in the form of a pharmaceutically acceptable formulation, in addition to the right en farmaceutiskt acceptabel bärare. Saledes avses med ny ny förening enligt upn ^ Inning Bade en fri aminbas och den fria basens syraadditionsaiter, undantaget da sammanhanget, där dessa termer används, t.ex et visst exempel, icke faller inom denna vida definition. Bäraren kan vara ett fast, halvfast eller flytande utspädningsmedel eller en kapsel. This pharmaceutical practice is based on the most important aspects of research. The active ingredient is present in an amount of 0.1 to 95% by weight of a pharmaceutical preparation, 0.5 to 20% in the form of an injection for injection and 2 to 50% of an addition to the oral administration.

For use in the manufacture of pharmaceutical preparations in the form of dosage enhancers for oral administration, the active ingredient may be formulated in the form of a pharmaceutically acceptable salt with a fast-acting formulation. ex. lactose, sackose, sorbitol, mannitol, starch or potassium starch, or amylopectin, cellulose or gelatin and silage, magnesium or calcium or stearate or polyethylene glycol extractant and pressed tablets. Qm beläggda tabletter önskas kan kärnorna som framställts pä ovan beskrivet sätt täckas med concentrerad sockerlösning som kan innehälla t.ex. gum arabic cum, gelatin, talc and titanium dioxide. Alternatively, the Latvian leaflets with the lack of organic matter may be used! 21 64353 lösningsrnedel eller blandningar av organiciska lösningsmedel. Färgäranen kan set up an account with dessa tacklager t.ex. for the purposes of the present case, the owner was involved in the assets.

For the production of a gelatin capsule (pearl capsule), the gelatin capsule and t.ex. glycerin, or a liquid tablet, which is an active substance in a medium.

The gelatin capsule may contain granules of the active substance in the form of a powdered form of lactose, sackose, sorbitol, mannitol, starch (e.g. potatisstarch, maize-starch or anylopectin), cellulose-containing or gelatin.

Dosers for the rectification of the active substance in the form of suppositories may be used as assets and blends. In neutral fats, or rectal capsules of gelatin are used as active ingredients in the bleaching of a medium or paraffin.

The oral preparation for oral administration can be in the form of a syringe or a suspension, e.g. The solution is preferably from 0.2 to 20% by weight of active substance, which is the best salt in the mixture and enriched in ethanol, water, glycerin and propylene glycol. In this case, the mixture can be treated with soda ash and / or carboxyethylcellulose as a desperation medium.

For parenteral administration, genomic injection can be carried out in combination with a water-based pharmaceutical formulation with an active substance in a concentration of 0.5 to 10% by weight. In this case, it is possible to stabilize the components and / or buffer substances in the water and to prepare the package in the form of an ampouler.

The preferred dosage form is preferably 25 to 250 mg for oral administration, preferably 50 to 150 mg, and 5 to 50 mg for parenteral administration, preferably 10 to 30 mg. For oral administration, 10 to 50 mg, preferably 10 to 25 mc of active ingredient per dose may be administered.

22 6 4 3 53

For the purposes of this Regulation, the provisions of this Regulation shall apply in such a way as to ensure that the requirements are met.

For the purposes of the general formula I a) dehydrated 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine

Br c.

HO "^ ^ CH2CH2NHCH3

Dehydration of the starting material can be found in t.ex. genomic behavior and uptake of the reaction reaction with svavel-syra. Dehydration with other materials can be used to give a syrup catalyst, chlorosulfur, HClf, phosphorus, H3PO4, potassium sulphate, KHSO4, or oxalic acid, for example, a method for dehydrating by the addition of phosphorus oxychloride, POCl 2 pyridine and dehydration with thionyl chloride, SOCl 2 and pyridine. ) alkyl monomethylamine with 3- (4-bromophenyl) -3- (3-pyridyl) allyl derivatives

br

^ fY

^ C: tl

CHCH 2-y

the group is grouped in the form of a copy of Form I.

Exempel days Y can be substituted with halogen, chlorine, bromine and iodine, or sulfonates, methanesulfonates, toluenesulfonates and benzenesulfonates, 23 6 4 3 5 3 c) methyl of 3- (4-bromophenyl) -3- (3 -pyridy1) -ally1-air.in ^ ΒΓ CHCH ^ NHt ^ 2 is a compound of the same formula as in D, or d) is used under hydrolysis to give an acyl or sulfonyl derivative of 3- (4-bromophenyl) -3-hydroxy- N-methyl-3- (3-pyridyl) -propylamine enligt formeln

Br n jy

HO '//////' 'XvCH2CH2-NCH3-Z

with regard to acyl or sulphonyl groups in the form of an acyl or sulphonyl form I may be directly or through the acyl or sulphonyl group, which may be used as a sub-form (a) to (d) isomer och eventuvert överförs account et farmaceutiskt acceptabelt sait därav.

The exhortation of the aid is limited.

Exempt 1 (förfarande b)

HO CH0CH0OH H

2 CHCH-NHCH., 1- (4-Bromophenyl) -1- (3-pyridyl) -1,3-propanediol (7.2 g, 0.023 mL) was added dropwise to acetone (70 mL). genomic solutions, och is determined by vacuum. Methylene chloride (50 ml) and phosphorus tribromide (6.4 g, 0.047 mol) are added, and 24 6 4 3 5 3 of a mixture of 14 ml of ethyl acetate are added, which is then treated with sodium carbonate. Methanol was added to the organic phase (50 mL) and the solution was removed in vacuo at 30 ° C to a volume of 30 mL. The solution was stirred with monomethylamine (14 g, 0.47 mol) in an autoclave at 110 ° C for 15 minutes. The mixture was quenched with ether and water (25 mL) and water (25 mL). The pH was adjusted with ammonia to a value of 9.0 and the mixture separated. In this case, water was added to the ether phase, and the pH was adjusted to 2.1 with HCl. Vatenfasen behandlades med aktivt koi, gjordes därefter alkaiisk med ammoniak och a extrahera-des med eter. The organic phase is pierced with sodium sulfate and induced by vacuum. The residue is taken up in ether (40 ml) and stirred at room temperature. Tili lösningen till-sattes droppvis klorväteeterlösnina, varviä erhölls en svagt gul avfällning. Avfällningen filtrerades, tvättades med eter och torkades i vacuum. Yields 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine hydrochloride. Vinst 43%. Smp. 138-144 ° C.

Exempt 2 (for example)

Br Br

o XX

HO · ^ XnCH2CH-NHCH3 II

CHCH2NFCHO 3- (4-Bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine (framoyl 5.0 g of 3- (4-bromophenyl) -3-hydroxy-N-methyl - (3-pyridyl) propionamide) is obtained under 50% purity (50 ml) and stirred at 110 ° C for 10 minutes. After distillation and cooling to dryness, the basic genome is then concentrated to 30% with NaOH and extraction with ether, 150 ml of acetone and filtration. 0.9 g (0.01 mol) of oxalic acid are taken up in 25 ml of acetone and the solution is added dropwise to the filtrate. The mixture is then stirred and 350 ml of isopropyl alcohol are obtained, and 1.7 g of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine oxalate are obtained as Vita crystals. Smp. 180-208 ° C, NMR spectroscopy of vinyl proton on a double triplet in the range of 0.1-6.4 ppm, vigorously bleached with E- and 7-isomers.

25

Isolation of the Z-isomers: In the crystallization from ethanol to give three genes, color is obtained 0.5 g of product, m.p. 202-205 ° C. The NMR spectrum was determined on vinyl proton using an triplet, J = 3.4 Hz, and the residue was obtained in the form of the Z-isomers.

The aminoxalate is isolated to give the hydrochloride via water. The genomic crystallization from acetonitrile is carried out at about 1 to 16 ° C. Substantial analysis was performed to give the dihydrochloride in the form of C15HlcBrN2 * 2HCl-H2O.

Isolation of the E-isomer: Moderlut frän isoleringen av Z-isomeren användes, innehällande bäda isomererna i förhällandet E: Z ca 60:40. Oxalate in the form of crystals of 3 g of acetonitrile is obtained at a rate of 15% of water, the color being reduced to 198-201 ° C. The NMR spectrum is then shown on the alsters of the E-isomers.

Exempel 3 (förfarande c) -Br ^ / Br -> CXcXX - * 1 n

CH CH

I I

CH, CH- I 1 I 2 NH2 nhcocf3

br

Η H

CH (JH

CH- CH- I 2 I 2 NCH- NHCH- I 3 3 COCF3

3-Amino-1- (4-bromophenyl) -1- (3-pyridyl) -prop-1-ene (0.58 g, isomeric) in ether (10 ml) was added to ethyl trifluoroacetate (0.43 g) in ether. (5 ml) at room temperature, after 1.5 hours of extraction with a solution of (2 M) salts, extracts with a base of 26 64353 and extracts with ethers after extraction of the trifluoroacetamide derivative. The oil was taken up in dimethylformamide (DMF, 25 mL, pierced over Cal · ^). Sodium hydroxide (0.1 g of a 50% oil emulsion) is added under high pressure and bleaching at room temperature for 4 minutes. Methyl iodide (0.3 g) in DMF (10 ml) was added dropwise and the reaction mixture was stirred for 1.5 h. Blandnings are prepared with water and extra ether. After uptake of the resulting oil, which was then methylated with trifluoroacetamide, ethanol (30 ml) was added sodium hydroxide (5 ml, 10 M) under reflux for 50 minutes. Medium flash chromatography is performed to complete the hydrolysis. The water is extracted with water, extraction with ether and extraction with ether extracts with salt syrup, alkalization, extraction with methylene chloride and induction of methylation with oil (0.36 g). Oxalate is added to isopropyl alcohol and crystalline serum from methanol. Smp. <^ 185 ° C. The NMR spectrum is shown to be on top of the methyl group (5, 2.4, overhead with reference substances) and to show the primary spectrum. In this case, a total of 6 = 6.2 is observed and the double triplet is viscous to the isomeric state.

Exempt 4 (for others)

Steg 1 _. Br _

Ol ct - * n rr - * ASA1 X \ / c \ cl CH2 H CH- ^ CH ^ h COCF3

Sodium salt from methyltrifluoroacetamide in the form of 0.06 g (0.002 mol) of 80% sodium hydride and 0.25 g (0.002 mol) of CF3CONHCH3 in 10 ml of DMF-ether (1: 1) under N2-atmosphere 1 temperature at room temperature. 0.61 g (0.002 mol) of Z-3- (4-bromophenyl) -3- (3-pyridyl) allyl chloride are added in 5 ml of the same solution. After 2 hours at room temperature, water is added and the reaction is carried out with ether. The combined ethers- ll 27 6 4 3 5 3 are prepared with 0.5 M salt syrup, and the water is preferably alkaline and extra cold with methylene chloride. 0.5 g of N-methyl-N-trifluoroacetyl-3- (4-bromophenyl) -3- (3-pyridyl) -propenylamine is obtained as an oil. The characters in the characteristic series are characterized by chromatographic chromatography. The R-color was obtained as 0.23 parts of isopropyl ether in 5% methanol and 0.47 parts of ethyl acetate.

The mercury of the Merck Silica Gel, 254 'NMR spectrum of deuterochlorochloroform was shown to be in the form of δ = 3.0 ppm. The IR spectrum showed a carbonyl band of 1680 cm

Steg 2

Br ... Br a XT ^ Crxr s 2 / \ / \

CHINCH, H CHINCH- H

3 | 2 -31 λ C0CF3 h

To this was added 0.4 g (0.001 mol) of trifluoroacetamide in 10 ml of ethanol to give 0.2 ml (0.002 mol) of 10 M NaOH and a mixture of 1.5 ml at room temperature. 0.38 g (0.003 mol) of oxalic acid dihydrate and 10 ml of iso-propyl alcohol are crystallized from this solution. Crystallization from methanol (5 ml 95%) gave 0.3 g (75%) of 1- (4-bromophenyl) -3-methylamino-1- (3-pyridyl) prop-1-ene, m.p. 165-175 ° C.

Pharmacological sprays

It is not possible to experiment with force depression in the field. For example, an antidepressant effect may be present in the form of a biochemical-pharmacological text method for influenza. There are hundreds of test methods that have been used to reduce the antidepressant effect of stammer or over-the-counter clinical effects of the use and use in Europe. J. Pharmacol. 17, 107, 1972.

14 28 6 4 3 5 3 I use the test method for the preparation of uptake of C-5- 14 3 3 hydroxytryptamine (C-5-HT) and H-noradrenaline (H-NA) and its moiety after in vivo and in in vitro administration of test substances.

14 3

Inhibition of uptake of C ~ -5HT and H-NA in vitro and in vivo Test substances are administered intraperitoneally and in vivo. The reaction is carried out with the aid of incubation and incubation with 0.2 nmol C-5-HT, 3 0.2 nmol H-NA and 11 μmol glucose in 2 ml Krebs-Henseleitufuft, pH 7.4, per 100 mg hjärnbitar. The incubator can be incubated for 5 minutes, and the incubator for 5 minutes. Bitarna upplöstes i Soluene ®, och mängden upptagna radioactive aminer bestämdes med vätskescintillator. The dosage is up to 50% min (ED 2 q) and the active label is selected from the group consisting of a radioactive label to inhibit the presence of cocaine. .

The in vitro formulation is performed with the addition of a batch of 5 minutes and the test substance is incubated and the incubation is set up.

29 64353

G. I

r-i!

CP (M

O X, '> \' -— * CM r — f LTO 00 LO ΓΟ

C <-r-t> - '1 r — I O O CNJ CT rs! VD

Ϊ3> O O; I 1—1 '—1 Λ ~ e i λ 5 rn -h a p> O ΓΤ3 O | P 5-1 i n CT. -P i

“CS -H; ^ CD

C + J> O i LT) LO (X) «-.- HO

cl, m e j H> - v - v

~ CLCCJ2jftNMOCNCCO

^ D -H u \ | C, i 'c! G 1 ε. ·,

<ö -h I

•B

Ϊ E-ι D- j

P p X o M

Z m jr LO> ^ ™ o

CT, V ^ i> o o «n oo m cn σ, αοιη C

U \ y U LO £! ΓΟ -H -H O TfC ^ CN -r-,

'P> -V \ / ^ C D 3 i Ή Λ Ή P

> 2 AV H> H w I

- * s w / * g: i u | 3 £ \ a ^ ij! • 31 -P .C y ——P> 4 - >> o i in u ~> rH in Γ '^ - ιγο cr eO G w / q, m g

E "1 · S * 55 A = ~ \ GCUSloOOCN r-l 10 O

13 -o / \ ο -h ω <*>> V /)

^ v I τ3 ό XS PO

, I -H -P -H

? h) P P P «g £ j c o o

"P C I f — I I — 1 f—. Γ — J

p P; -P + J, χ .p, V -P, X: 0 ph: c ro o ro o <o o -c

P 3 +> | rH P, Η P -P P P

'£ Ϊ rH (0 Π5 TJ 3 Ό (0 "C O

-e c co | x κ>, χ> - x> -, 5, en iCOiCOPoox:

P! tT -P

0)! c ε! -h tr o CNNiWM & a, κ CD i ne! \ • H: C Ή

3 CO

i — r ή ε e λ ε 3 • H ro v

C P

cu ·, a, r-i

p j CD ro -H O

= o, a a ε fr. a uu-h

| V '^ "e (D

-P K

I P LO O

I C> T5 CU TO

! tr G o tr -p

! C G tr C P

| -h e C -P -ro: 0 I C -h f0 C O U-r

'; 1). C Ό (D

I p, —1 C CP

: 0 C -rJ: ro: 0 -

i COP! C P, -. T'J

30 6 4 3 5 3 These frameworks in the form of a compound I and kraftig inhiberand network are ρ uptake of 5-hydroxytryptamine and norepinephrine in neurons. Z-forms of the compound can be used to inhibit the in vivo use of the 5-HT label and then the test is performed in this way.

In this case, the E-isomers of the compounds of formula I are used in vitro to selectively inhibit the uptake of the noradrenaline in the form of a mixture of Ν, Ν-dimethyl derivatives. In vivo administration to all of the effects of 5-hydroxytryptamine on norepinephrine has been shown to increase the selectivity. These effects can be achieved with a specific metabolic effect. the selectivity of the emitters is determined by the number of synaptosomers in the ratios above the data of EC50 ^ uM for uptagsinhibering

5-HT NA

Känd dimethylförening, E-form 0.65 1.2

Ny monoir.etylförening, E-fcrm 0.60 0.015

The Z-form is further prepared according to the formula I, which is a test for the hydrochloride, and the in vitro incorporation of the 5-HT insert is carried out in vitro and then the test is carried out. (oxalates and hydrochlorides may be added, the hydrochlorides of the oxalates being varied and the Z-isomer). E-fcrmen av föreningen enligt uppfinningen in-hiberar i interesudsak upptaget av noradrenalin. Inhibition of up to 5-hydroxytryptamine and norepinephrine in neurons can be used as an antidepressant. Liquidation may be carried out at the same time.

Claims (3)

A process for the use of E-3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine of the formula n iYBr Vk 1 X C x H 11 / CHCHO To prepare CH 2 or a pharmaceutically acceptable salt thereof, characterized in that a) 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine of formula o, ry "is dehydrated b) to form a compound of formula I, b) the monomethylamine is alkylated with a 3- (4-bromophenyl) -3- (3-pyridyl) allyl derivative of the formula n CH 2 CH 2 Cl 2 -Y wherein Y is a cleavable group to form a compound of formula I, c) 3- (4-bromophenyl) -3- (3-pyridyl) -allylamine of formula 64353 Br c 2 CHCH 2 NH 2 is introduced in a manner known per se into a methyl group of formula To form a compound of formula I, or d) an acyl or sulfonyl compound of 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine of the formula ^ Br N HO 'CH2CH2-NCH3- Z wherein Z is an acyl or sulfonyl group is treated under hydrolysing conditions to give a compound of formula I either directly or via an unsaturated acyl or sulfonyl compound, after which the compound obtained by one of the methods a) to d) is optionally converted / separated into the pure E-isomer and optionally converted into a pharmaceutically acceptable salt. il 33 6 4 3 5 3 For the preparation of E-3- (4-bromophenyl) -X-nety-1-3- (3-pyridyl) -allylamin account is described as a source of this compound. The CHCH2N3 or pharmacologically acceptable site is described as a) dehydrated 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) -propylamine. b) alkyleric monomethylamine with 3- (4-bromophenyl) -3- (3-pyricyl) -allylated derivatives of the formulation of O2T-CH2-CH2N2CH3 Or. 3-pyridyl) -allamine enligt formeln