FI56378C - PROFESSIONAL FORM OF THERAPEUTIC ACTIVATION OF 1- (4-BROMOPHENYL) -1-PYRIDYL-3-DIMETHYLAMINO-PROP-1-ENDERIVAT - Google Patents

Description

Ιτ_ιΊ »ΓΤΐ ΓΒΐ NOTICE ς CO 7« JSBTtk (11) UTLÄCCNINCSSKRIFT 30J / Ö C ¢ 45) Patent granted 10 01 1930 Patent aieddelat ^ '(51) Kv.lk.' / Lnt.a. * c 07 D 213/38 FINLAND —FINLAND (21) P »tenttlh» k * mus - PatontaraBIcnlng 858/72 (22) Hakamiiptlvi - AnsBknlngsdtg 28.03 * 72 (23) Primary Cloud — Giltlghotsdag 28.03.72 (41) Become Public - Bllvtt offm2ll 29

Patent · And registrar-administered · (44) Date of issue and date of publication. -

Patent · och reglateratyrelaen Ameiun utiagd och uti.skrift «n pubiicarad 28.09.79 (32) (33) (31) fy / dotty etuoikeus —Begird prloritet 2 8.0 ^. 71

Sweden-Sweden (SE) 5 ^ 96/71 (71) AB Hässle, Fack, S- ^ 02 20 Gothenburg 5 »Sweden-Sweden (SE) (72) Peder Bernhard Berntsson, Västra Frölunda, Per Arvid Emil Carlsson, Gothenburg, Hans Rudolf Corrodi, Askim, Sweden-Sweden (SE) (7 * 0 Berggren Oy Ab (5 * 0 Process for the preparation of therapeutically active 1- (1 + -bromophenyl) -1-pyridyl-3-dimethylamino-prop-1-ene derivatives The present invention relates to a process for the treatment of therapeutically active 1- (4-bromophenyl) -1-pyridyl-3-dimethylamino-propionic acid 1- (U-bromophenyl) -1-pyridyl-3-dimethylamino-prop-1-enders. for the preparation of 1-ene derivatives.

The most clinically widely used antidepressants are tricyclic tertiary amines such as imipramine with the structural formula 07X5 CH2CH2CH2 - ^ • ch3 and amitriptyline with the structural formula / ch3

chch2ch2n <^ II

^ CH3 2 56376

Secondary amines such as desipramine having the structural formula

III

CH CH..CH N 'CT

CH ά ^ CH3 and nortriptyline having the structural formula

OyQ

CHCH2CH2N- ^ "CH3 is used somewhat less. However, all of these substances have unfavorable side effects when used therapeutically, such as orthostatism, anticholinergic activity and, above all, arrhythmogenic or cardiac arrhythmic effect when administered at higher doses to older patients. also cause pain in a number of depressed patients, and all of these substances have the disadvantage that their antidepressant effect does not appear until a few weeks of treatment, and this late-onset effect must be due to the fact that all of these substances have low antidepressant efficacy. It is further known from the literature that certain 1'-diphenyl-4-amino-prop-1-enes, such as a compound of the formula

C Ä CHCHyN CT

d ^ CH,

QT

has an antidepressant effect, see J.Med.Chem. 14 lbl-lb4 (1971J · It has also been reported in the literature that compounds of formula 3 56376

CHCH0CH0N VI

ζΤ '"t, J

wherein X is chlorine or bromine and R is hydrogen or methyl has antihistamine and antidepressant activity, see U.S. Patent 3,423,510. A compound of formula VI wherein X is bromine and R is methyl is represented by bromopheniramine in Table 1 below. However, both the compounds of compound V above and the compounds of compound VI have the dangerous side effect of causing pain conditions and also orthostatism.

The main object of the present invention is to prepare new compounds having a good antidepressant effect. It is a further object of the invention to provide antidepressant active compounds which do not cause orthostatism, anticholinergic effects or cardiac arrhythmias. Other objects of the invention will become apparent from the following description.

According to the present invention, it has surprisingly been found that compounds of the formula

Br - / N

R 2 CH 3

c = CHCH.N ^ VII

cr -> wherein the pyridyl group is attached in the ortho, meta or para position to an adjacent carbon atom and R is hydrogen or bromine and their therapeutically suitable acid addition salts are in contrast to the most clinically used tricyclic agents such as imipramine, desipramine, amitriptyline and nortriptyl as well as, in contrast to compounds known from the literature such as the compounds of formulas V and VI, highly antidepressant, depressant agents which do not cause the most disturbing side effects such as pain, orthostatism and cardiac arrhythmias.

11 56378 ττ. . . . .. · «of the compounds of the invention

Illustrative examples * · of you are: „,, Code number

Structural formula

Br_H 102/09 ^ C = CHCHON.

ςχ

'-CX

^ C = CHCH2N ^

(X

Rt »H 100/011 ^ CS5 0 = ΟΗΟΗ, Ν ^" OH,

Br _H 99/88

Br -kJL / CH3

J> C = CHCHpN

o: = xi

= CHCH N

N <! I ^

Of the compounds according to the invention, the preferred compounds are the code numbers H 102/09> H 102/10 and H 100/04.

These compounds are prepared according to the invention by removing water from a compound of formula 5 563/8

Br -

——Ch3 IX

R C —CH ~ CH0N ^ '\> H ^ CH3 y to give a compound of formula "~ ίΊ R —- (¾ x C = CHCH2N' ^ ^ ch3

The compound of formula IX can be dehydrated, for example, with concentrated sulfuric acid and by heating the reaction mixture to a high temperature, approximately 165-175 ° C. The dehydration of the compound of formula IX can also be carried out by other types of acid catalysis, such as, for example, hydrochloric acid, HCl, phosphoric acid, H 2 PO 4, potassium hydrogen sulphate, KHSO 4, or oxalic acid, (CO 2 H 2 O 2). Other methods for removing water from a compound of formula IX to give a compound of formula X include dehydration with phosphorus oxychloride, POCl 3, in pyridine, and dehydration with thionyl chloride, SOCl 2, in pyridine.

Catalytic dewatering of a compound of formula IX may also be used. The dewatering is in this case carried out at a temperature of 300-500 ° C using kaolin, aluminum or alumina as catalyst, such as AlgOy

The starting material of formula IX may be prepared optionally, for example by administering a compound of formula XI ΒΓΥΊ ^ 01i3

-CCHpCHpN 'XI

R II

0 -5

react with a pyridyl lithium compound of formula XII

6 56378

_ Li XII

in which formulas R is as defined above and the lithium atom is attached in the ortho, meta or para position to the pyridine ring.

The end products of the invention may exist in E and Z forms according to the IUPAC nomenclature, and the therapeutic effect cannot be unambiguously read only in the account of the other form, but to a greater or lesser extent it can be credited to the account of one or both forms.

When used clinically, the compounds of the invention are normally administered orally, rectally or by injection, as a pharmaceutical preparation containing the active ingredient in the form of a free base or a pharmaceutically acceptable salt thereof, such as hydrochloride, lactate, acetate, oxalate or the like together with a pharmaceutically acceptable carrier. be a solid, semi-solid or liquid diluent or an oral capsule.

The preparation usually contains 0.1-95% by weight of active ingredient, for example 0.5-20% in preparations for injection and 0.1-50% in preparations for oral administration.

When pharmaceutical preparations are presented in unit dosage form for oral administration and contain a compound of the invention in the form of the free base or a pharmaceutically acceptable salt thereof, the active ingredient may be mixed with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, starch, potato starch, potato starch cellulose derivative or gelatin. The mixture may also contain a cream such as magnesium or calcium stearate or a wax called Carbowax ® or other polyethylene glycol waxes, and the mixture is compressed to form the core of the tablets or granules. When drug granules are desired, the compressed core may be coated, for example, with a concentrated sugar solution which may contain gum arabic, talc and / or titanium dioxide, or alternatively with a varnish dissolved in volatile organic solvents or mixtures of organic solvents. Dyestuffs can be added to these coatings, for example in order to distinguish between preparations containing different amounts of active substance. When preparing soft gelatin capsules (bead-shaped closed capsules) made of gelatin and, for example, glycerin, or other similar closed capsules, the active ingredient can be mixed with Carbowax®. Hard gelatine capsules may contain granules of the active ingredient and a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, grain starch or amylopectin, a cellulose derivative or gelatin and may also contain magnesium or stearate. Dosage units for rectal administration may be in the form of suppositories containing the active ingredient in admixture with a neutral base fat, or in rectal capsules of gelatin containing the active ingredient in admixture with Carbowax ® or other polyethylene glycol wax.

Liquid preparations for oral use may be in the form of syrups or suspensions, for example, solutions containing from about 0.1 to about 20% by weight of active ingredient, sugar and a mixture of ethanol, water, glycerin, propylene glycol and the optional flavor, saccharin. and / or carboxymethylcellulose as a dispersant.

Formulations for parenteral injection may contain a water-soluble, pharmaceutically acceptable salt of the active ingredient in aqueous solution, preferably in a concentration of 0.5-10%> optionally also a stabilizing agent and / or a buffering agent in aqueous solution. Dosage units of the solution may be conveniently placed in ampoules.

A suitable daily dose of the compounds of the invention in therapeutic treatment is 5-500 mg, preferably 50-250 mg, when administered orally, and 1-100 mg, preferably 10-50 mg, when administered parenterally.

Biological effect

It is not possible to experimentally induce depressive states in experimental animals. Therefore, biochemical-pharmacological test methods must be used to assess the potential antidepressant effect of new substances. A test method has been developed which appears to give results on the antidepressant effect of a compound which coincide with a clinically described effect; this method is described in European Journal of Pharmacology 5,367-373 (I969) and European Journal of Pharmacology 5,357-366 (1969). This test method investigates the ability of a compound to inhibit the release of noradrenaline into the brain and heart due to the injection of 4, α-dimethyl-m-tyramine and the ability of the compound to inhibit the release of 5-hydroxy-tryptamine into the brain due to the injection of 4-methyl-α-ethyl-m-tyramine. . The substances that prevent the release of noradrenaline into the brain and heart are, above all, secondary amines of the desipramine and nortriptyline type, which have the dangerous side effect of causing pain. Inhibition of noradrenaline release in the brain and heart by these compounds is also likely to induce orthostatism. The truly depressant effect of some substance appears to be related to the inhibition of 5 ′ ′ hydroxytryptamine release. As shown below, it has surprisingly been found that the compounds of the invention have a strong inhibitory effect on the release of 5-hydroxytryptamine caused by 4-methyl-α-ethyl-m-tyramine, whereas the compounds are completely absent or have only a very poor ability to inhibit release of noradrenaline caused by 4-α-dimethyl-m-tyramine. In addition, the compounds of the invention differ from all tricyclic antidepressants used heretofore in that they have a much lower cardiac arrhythmic effect than previously used tricyclic agents. Although compounds of the type described in Journal of Medicinal Chemistry 14 161-164 (1971) have an antidepressant effect, this antidepressant effect is weak compared to the compounds of the invention, and these known compounds of the above compound V are also capable of considerable prevent

The depletion of noradrenaline in the brain and heart by 4-α-dimethyl-m-tyramine, which in humans leads to the said undesired side effects, pain and probably also orthostatism. The compounds of Compound VI disclosed in U.S. Patent No. 3,423,510 are described as antihistamines and antidepressants. The compound bromopheniframine of formula XIII

9 56378 ΒΓ '> γ ^ ^ CH3 CHCH? CH? NC ^ XI11 cr' appears to have a strong inhibitory effect on the release of 5-hydroxytryptamine, but this compound also largely inhibits the release of noradrenaline by 4-α-dimethyl-m-tyramine. , which in humans leads to unwanted side effects such as pain and orthostatism.

The following is a pharmacological comparison between the compounds of the invention and previously used tricyclic antidepressants and the compounds described in the literature.

1. Inhibitory effect on 5-hydroxytryptamine release by 4-methyl-α-ethyl-m-tyramine 1.1 Rats

The test substance is injected intraperitoneally into the rat. After 30 minutes, 50 mg / kg of 4-methyl-α-ethyl-m-tyramine is injected intraperitoneally. After two hours, the animal is sacrificed and the amount of 5-hydroxytryptamine in the brain is measured. Animals treated with the test substance only or with 4-methyl-α-ethyl-m-tyramine only, as well as animals not treated at all, are used for the control. The percentage inhibition of 5-hydroxytryptamine release is given by the following formula:% inhibition = - ^ ~ - · 100 A = amount of 5-hydroxytryptamine (ng / g) in the brain after administration of the test substance and 4-methyl-α-ethyl-m-tyramine B = Amount of 5-hydroxytryptamine (ng / g) in the brain after administration of 4-methyl-α-ethyl-m-tyramine C = amount of 5-hydroxytryptamine (ng / g) in the brain after administration of the test substance.

The effective dose that inhibits the 50% release of 5-hydroxytryptamine (ED 2 q) is calculated by regression analysis. The test results are shown in Table 1.

J ° 563/8 1.2 Mice

The test substance is injected intraperitoneally into the mouse. After 30 minutes, 100 mg / kg of 4-methyl-α-m-tyramine is injected intraperitoneally. After 90 minutes, the test substance is administered again, this time half the initial dose, and after 30 minutes, 4-methyl-α-ethyl-m-tyramine (100 mg / kg) is administered. Two hours later, the animals are sacrificed and the amount of 3-hydroxytryptamine in the brain is measured.

Percent inhibition of 3-hydroxytryptamine release and EDijQ are determined in the same way as in 1.1. The method is described in detail in the European Journal of Pharmacology b, 337-3bb (1969) · The test results are given in Table 1 below.

2. Inhibitory effect on noradrenaline release by 4, α-dimethyl-m-tyramine

The test substance is injected intraperitoneally (10 mg / kg) into mice. After 30 minutes, 4, α-dimethyl-m-tyramine (12.3 mg / kg) is administered. After 90 minutes, half of the initial dose (b mg / kg) of the test substance is administered to the animals, and 30 minutes later, 4, α-dimethyl-m-tyramine (12.5 mg / kg) is administered. After 2 hours, the animals are sacrificed and the amount of noradrenal in the brain and heart is measured. Animals treated exclusively with the test substance or exclusively 4, α-dimethyl-m-tyramine and animals not treated at all are used for the control.

The percentage inhibition of noradrenal discharge is determined according to the following formula

A - B

percent inhibition = --100 A = amount of noradrenaline (ng / g) in the brain or heart after administration of the test substance and 4, α-dimethyl-m-tyramine.

B = amount of noradrenaline (ng / g) in the brain or heart after administration of 4, α-dimethyl-m-tyramine.

C = amount of noradrenaline (ng / g) in the brain or heart after administration of the test substance.

The test results are shown in Table 1.

3. Cardiac arrhythmia effect

The test substance solution is infused continuously, slowly, into nembutal-anesthetized rats and the electrocardiogram of the animals is monitored. After some time, an irregularity appears in the heart rhythm, which gets worse and worse and eventually leads to ventricular fibrillation, causing the animals to die. The magnitude of the accumulated dose required to cause ventricular fibrillation is given in Table 1.

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> -H 3 · Η cO 3 Cd p p p 3 3 3 · γ-3 ro co co

p> bO-H PC P P P

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g 3> 5-3 CO ro 3 P P P

ro p ro ^ a-π ro co to p 3 co ro o g ρφφο ^ γ o m m o o la σι ia proroi333 = ro oppph cm cm <m ph

ro rop 3 -H Ό -H P M 3 A

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ro pro> ι g m g 3 E

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>> S · Η P · Η 3 H | · 3 H | p · Η -H CO

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12 56378

As can be seen from the test values in Table 1, the compounds according to the invention have a strong inhibitory effect on the release of 5-hydroxytryptamine caused by 4-methyl-α-ethyl-m-tyramine compared to the reference substances, while the compounds according to the invention have an effect on 4, α-dimethyl-m-tyramine. tyramine-induced noradrenaline release is weak. The dose in mg / kg body weight intra-peritoneally that causes ventricular fibrillation with continuous infusion is also considerably higher with the compounds tested according to the invention than with the reference substances, which means that the compounds according to the invention have a rather weaker cardiac arrhythmic effect than the reference substances.

The preparation of the compounds of the present invention is illustrated by the following examples.

Example 1. Preparation of (E) - and (Z) -3- (4'-bromophenyl--3- (2'-pyridyl) -dimethylallylamine dihydrochloride

br

CH 2 -H 2 O'H

Ö: - CHpCHpN cT 2-> 9 ~ cC

CH, .- / CH0-N (CH,) '2HCl -> X <->

Rr, H 100/04

X

97- 1- (4'-bromophenyl) -3- (N, N-dimethylamino) -1- (2''-pyridyl) -propanol (CH2N (CH3) 2 * 2HCl) / 96) is dissolved in 300 ml of 85% H 2 O 2 and heated at 170 ° C for 10 minutes. The reaction mixture is then poured into a vessel containing 1 liter of water and made alkaline with 10 N NaOH and extracted into ether (2 x 250 ml), the ether extract is dried, treated with activated carbon and evaporated to dryness. The product obtained is dissolved in 250 ml of ether and dry hydrogen chloride is introduced into the solution. The precipitate formed is filtered off and recrystallized from ethanol (99.5%). Yield 40 g of (E) -3 '(N' - bromophenyl) -3- (2 '' - pyridyl) -dimethylallylamine dihydrochloride (H 100/04). Sp. 195 ° C.

13 56378

The mother liquor obtained on crystallization is evaporated to dryness, the residue is dissolved in acetone. After 24 hours, the precipitate formed is filtered off. Yield 15 g of (Z) -3- (4'-bromophenyl) -3- (2''-pyridyl) -dimethylallylamine dihydrochloride (H 100/03). Sp. 160 ° C. The starting material, 1- (4'-bromophenyl) -3- (N, N-dimethylamino) -1- (2''-pyridyl) propanol, is prepared as follows: O.

Br - <y — cch2ch2n (ch3) 2 _______ f * HO ^ C - CH2CH2N (CH3) 2 To 50 g of n-butyllithium dissolved in 0.5 liter of dry ether is added at -40 ° C 23.7 g of 2 bromopyridine as quickly as possible without raising the temperature. After the addition is complete, stir for a further 30 minutes. 1.5 liters of dry ether are then added, followed by 197 g of ω-dimethylamino-4'-bromopropiophenone so that the temperature does not exceed -40 ° C. Cooling is stopped and the mixture is stirred overnight, after which the reaction mixture is poured onto ice with dilute HCl, the mixture is washed with a small amount of methylene chloride. The aqueous phase is then made alkaline and extracted with ether, the extract dried and evaporated to dryness. The residue is recrystallized from petroleum ether (40 ° C). Yield 9b g of 1- (4'-bromophenyl) -3- (N, N-dimethylamino) -1- (2''-pyridyl) propanol. Sp. b5 ° C. Example 2 Preparation of 3- (4, -bromophenyl) -3 '(3''-pyridyl) -dimethylallylamine dihydrochloride 3.6 g of 1- (4'-bromophenyl) -3- (N, N-dimethylamino) -1- (31-Pyridyl) -propanol is dissolved in 15 ml of 05% H2SO4 and heated at 170 ° C for 10 minutes. The reaction mixture is poured into a vessel of 60 ml of water and made alkaline with 10 N NaOH, extracted with 2 x 25 ml of ether. The ether extract is dried over i2a2SO4, treated with activated carbon and evaporated to dryness. The residue is dissolved in 25 ml of acetone and an equivalent amount of oxalic acid dissolved in 25 ml of acetone is added.

η 56378

The resulting precipitate is filtered, dissolved in 50 ml of water and basified with 10 N NaOH and extracted with 2 x 25 ml of ether. The ether solution is dried over Na 2 SO 4, filtered and then dry hydrogen chloride is passed. The precipitate formed is filtered off. Yield 1.2 g of 3- (4'-bromophenyl) -3- (3''-pyridyl) -dimethylallylamine dihydrochloride (H 102/09). Sp. 193 ° C.

The starting material, 1- (4'-bromophenyl) -N, N-dimethylamino) -1- (3'-pyridyl) -propanol, is prepared as follows: To 9 g of butyllithium in 200 ml of dry ether is added -40 At 20 ° C 20 g of 3-bromopyridine as rapidly as possible without raising the temperature. After the addition is complete, stirring is continued for another 30 minutes. 32.5 g of 1-dimethylamino-4'-bromopropiophenone are then added so that the temperature does not rise above -40 ° C. Cooling is stopped and the reaction mixture is stirred overnight, then poured onto ice with dilute HCl, washed with ether and extracted with 20 ml of methylene chloride. The methylene chloride extract is dried and evaporated. The crystals are dissolved in water, which is made alkaline with Na2CO3 solution, extracted with ether, dried and evaporated and recrystallized from a mixture of isopropyl ether and petroleum ether (1: 1). Yield 4 g of 1- (4'-bromophenyl) -3'- (N, N-dimethylamino) -1- (3''-pyridyl) propanol. Sp. 67 ° C.

Example 3 Preparation of 3- (4'-bromophenyl) -3- (4'-pyridyl) -dimethyl-allylamine dihydrochloride 3 g of 1- (4'-bromophenyl) -3- (N, N-dimethylamino) -1- : (4'-Pyridyl) -propanol is dissolved in any 85% I 2 SO 4 and heated at 170 ° C for 15 minutes. The reaction mixture is then poured onto ice water, which is made alkaline with 10 N NaOH and extracted into ether. The ether phase is dried and dry hydrogen chloride is introduced into the solution. The precipitate obtained is filtered off and recrystallized so that it is dissolved in ethanol and mixed with acetone. Yield 1.4 g of 3- (4'-chromophenyl) -3-01'-pyridyl) -dimethylallylamine dihydrochloride, m.p. 190 ° C. (H 102/10).

The starting material, 1- (4'-bromophenyl) -3- (N, N-dimethylamino) -1- (4''-pyridyl) propanol, is prepared as follows: To 10 g of n-butyllithium in 250 ml: dry ether, 17.7 g of 4-bromopyridine are added at -40 [deg.] C. as quickly as possible without raising the temperature, after which the mixture is stirred for a further 30 minutes. 28.7 g of m-dimethylamino-4'-bromopropiophenone are added so that the temperature does not rise above -40 ° C.

66378 Cooling is stopped and the reaction mixture is stirred overnight, then poured onto ice with dilute HCl. The aqueous phase is washed with methylene chloride, then made alkaline with 10 N NaOH and extracted into ether. The ether teriphasic phase is dried over Na 2 SO 4, treated with charcoal and evaporated. The residue was recrystallized from diisopropyl ether. Yield 3 g of 1- (4-bromophenyl) -3- (N, N-dimethylamino) -1- (4''-pyridyl) propanol. Sp. 120 ° C.

At a level analogous to Examples 1-3, 3- (3 ', β'-dichromophenyl) -3- (2 "-pyridyl) -dimethyl-allylamine dihydrochloride (H 99/88) with a mp of 136 ° C was prepared. .

For example, uptake of the active compound 1- (4-bromophenyl) -1-pyridyl-3-dimethylamino-prop-1-enders occurs.

The antidepressant medication, which has been shown to be clinically relevant to the tricyclic tertiary amino imipramine,

Jh2ch2ch2 _ n- ^ CH3 I

CH, and amitriptyline with structural form ^ CJCJO ^ 'ch3

raCH2CH2N II

^ CHj

Secondary amine to desipramine with structural form 16 66378 Ιΐχ CH, CH ~ CH ~ N X ± single ά ά 0 '\ ch3 and nortriptyl with structural form

cT ^ IV

ά ^ ch3 användes i nägotmindre utsträckning. These substances have been shown to be effective in the treatment of orthostatics, anticholinergic effects, and all the effects of the arrhythmia-rhythmic rhythm effect in the administration of the patient. The second amino acid is desipramine and nortriptyl has the effect of depressing the patient. Dessutom upp-. visar alla de nämnda substantanserna den nackdelen att den Antide-oppressive effects inträder först efter nägra veckors behandling. The effect of the intrinsic effect may be limited to the presence of antidepressant activity. In this case, the literature contains 1,1,1-diphenyl-3-aminoprop-1-energy in the form of a compound with the formula JC == CHCHON C y 0 - with an antidepressant effect, see J. Med. Chem. _14 l6l-l64 (1971) · I literary in the context of the form "Ok.

.CHCH5CH9N \

^ «3 VI

O '17 56378 from X to chlorine or from Brom to R or from methyl, including antihistaminic effect and antidepressant effect, see U.S. Patent No. 3,423,510. Formulation of Formula VI from Brine and methyl bromopheniramine in Table 1. Säväl de föreningar som föreningen V ovan som de föreningar som illus-treras av föreningen VI ovan har emellertid den allvarliga bieffek-ten att vara ängestframkallande ocv även ortostatismframkallande.

That interest in the use of anti-depressant agents is not limited to the antidepressant effect. In addition, the anti-depressant effect of orthostatism, anti-cholinergic effect, or arrhythmic effect can be exacerbated by antidepressant effects. Exemption from the rules of the rules of the Treaty and the application of this Regulation.

For the purposes of this Regulation, the relevant measures shall be taken in accordance with the procedure laid down in

Br tl

R ^ CH

= CHCH2N2 VII

CT is a pyridyl group which is ortho-, meta-, or para-rectifying to an anthropogenic group and to a substituent R is an arthropod to a bromine and therapeutically acceptable therapeutic agent, to which skill is used in the practice of the clinical trial, amethriptyline and nortriptyline, in addition to the ability to use the form of an anti-depressant, in addition to the form of an anti-depressant drug, er.

Illustrative exceptions to the above guidelines are as follows:

Strukturformel Kodnummer

Br -H 102/09 • νΛ C = CHCH.N ^ cr

OF

66378 BC

Strukturformel Kodnummer

Br-H 102/10 c = OHCH 2 N 2 CH 3 r V 2 H 3

Br-H 10 ° / 1 * CH, C = CHCHpN ^ 0 "

Br-H 99/88

Br --- CH3. c = chch2n rr ^ ^ ch3 V1 B ^ ri

fejr - ^ CH

^ C = CHCHoN _ -1 cr

However, the application of this Regulation is subject to the conditions of H 102/09, H 102/10, and H 100/04.

These frameworks have been used for uptake of the genome for the purposes of the form.

_C — CH, CH, N IX

° H ^ 0H3 19 563/8 to the image of the formulation

^ C = CHCH2N X

CX

The dehydration of the compounds of formula IX can be carried out with the aid of a concentrated mixture and the reaction of the reaction mixture at a temperature of 165 to 175 ° C. Dehydration of the compounds of formula IX can be carried out by means of a syrup catalyst, including chlorides, HCl, phosphorus, H 2 PO 4, potassium wax sulphate, KHSO 4, or oxalic acid, (COOH) 2 for the preparation of formula IX with the formation of the formula X for the dehydration with phosphorus oxychloride, POCl 3, pyridine; as well as dehydration with thionyl chloride, SO 2 Cl 2, and pyridine. The catalytic dehydration process of formula IX can be performed. The dehydration is carried out at a temperature of 300 to 500 ° C with a catalyst such as Kaolin, Aluminum, or alumina with an Al 2 O 2 catalyst.

Utility materials with formula IX in the form of p4 val-fritt sätt exempelvis genom reaction with the formulation

Br Π

R-VJ-CCH2CH2N2 XI

0 CH3 is a pyridyl-lithium formulation with a form of _ Li XII 1 a single form of R is an angular betydelse and lithium atoms in the ortho-, meta-, or para-stellating p4 pyridinkärnan.

20 56378

In particular, the addition of the E-form and the Z-form to the IUPAC nomenclature, and to the therapeutic effect of the active substance in the form of an active substance, may be carried out in the form of an orthopedic form. .

In the clinical administration, the administration of the active substance in the form of an oral, rectal or genomic injection, in the form of a pharmaceutical preparation in the form of an active pharmaceutical ingredient or in the form of a pharmaceutically acceptable site of action, liquid products with an acceptable pharmaceutical form which can be used as fast, cheap or free of charge or in the form of capsules.

For example, active substances are used in the form of 0.1-95 times the dose, in addition to 0.5 ~ 20% of the solution for injection and 0.1-50% of the product for oral administration.

For pharmaceutical formulations in the form of oral dosage forms for oral administration and for use in the form of a pharmaceutically acceptable pharmaceutical form, the active ingredient may be in the form of a fast powder formulation, ex-lactate, saccharine, starch sdsom potatissträrkelse, corn starch or amylopectin, to cellulosaderate or gelatin. Blandningen kan ocksd innehdlla smörjmedel säsom magnesium- or calcium stearate eller et ett Carbo-wax 'S' eller andra polyethylene glycol extractor and presses account for the preparation of tablets or dragdkärnor. In the case of solid organic matter, it can be used as a concentrate for the production of gum arabicum, or octane or titanium dioxide or as an alternative to the lack of organic matter in the bleaching process or in the bleaching process. Färgämnen kan sättas accounts dessa täcklager t ex för att skilja mellan beredningar som innehdller olika mängder av den aktiva substantansen. For the production of a gelatin capsule (pearl capsule), gelatin and ex glycerin are preferred, or a liquid capsule, which is an active substance in a mixture of Carbowax ®. The gelatin capsule can be granulated with the active substance in powder form in the form of lactose, saccharose, sorbitol, mannitol, starch or exylate, or cellulose starch or magnesium oxide. The dosage form for rectal administration can be in the form of a suppository with an active substance and a bleaching agent which is neutral neutral, or a rectal capsule with a gelatin for the active substance bleaching with Carbowax or a polyethylene glycol.

The oral preparation for oral administration can be in the form of a syringe or a suspension, e.g. The active ingredients are selected from the group consisting of 0.1-20 wt. # Aktiv substancens, socker och en en blandning av ethanol, vatten, glycerin, propylene glycol and valfritt smakämne, sackarin och / eller carboxymethylcellulosa som dispersionsmedel.

For parenteral administration, the genomic injection can be formulated into a water-rich pharmaceutical formulation with an active substance in a concentration of 0.5-10% and a stabilization medium and / or buffer-free formulation. The dosage unit can be filled with an ampouler.

The preferred dosage form for use in therapeutic administration is 5-500 mg for oral administration, preferably 50-250 mg, and 1-100 mg for parenteral administration, preferably 10-50 mg.

Biological effects

In this case, it is possible to experimentally force the de-pressioner in the field. For example, the anti-depressant effect may be a significant substance in a biochemical-pharmacological test method in influenza. The test method is based on the use of antidepressant effects in combination with clinically relevant clinical effects and in particular in the European Journal of Pharmacology 5 367-373 (1969) and the European Journal of Pharmacology 5 357-366 (1969) · A test method for the preparation of a blocker for the preparation of noradrenaline in a mixture and for the injection of 4, α-dimethyl-m-tyramine, and for the preparation of a blocker for the preparation of 5-hydroxytryptamine In addition to the injection of 4-methyl-α-ethyl-m-tyramine. Substance with blocker noradre-nalinuttömningen i hjärna och hjärta är framför allt sekara aminer av nitrogen nitrogen desipramine and nortriptylin vilka har den all-varliga bieffekten att leda account ängest. Blocking of noradrena-linuttömningen i hjärna och hjärta som orsakas av dessa föreningar 22 5 6 3 7 8 framkallar sannolikt ocksä orthostatism. The effects of depression on the substance can be reduced by the use of 5-hydroxytryptamine blockers. However, all of these barrels can be used as a barrier to a barrier effect of the 5-hydroxytryptamine. inducers of 4-methyl-α-ethyl-m-tyramine, Medan förening-Arnas förmäga att blockera den uttömning av noradrenalin som induceras av 4-a-dimethyl1-m-tyramine helt saknas eller är mycket svag. The present invention is based on the presence of tricyclic antidepressants in the genome of the tricyclic antidepressant effect of the tricyclic antidepressant effect. For example, the antidepressant effect is described in the Journal of Medicinal Chemistry l4_ 161-164 (1971), which has the antidepressant effect and has been shown to have the effect of increasing the effect of the invention, and the present invention is illustrated. If the compound is blocked with 4-α-dimethyl-1-m-tyramine - the induction of norepinephrine utilization in the environment and the activity of these compounds occurs in the presence of orthostatic disease. The invention is contemplated in U.S. Patent Nos. 3,235,1010 and illustrates a contemplation of the antihistamines and antidepressants. Formed from bromopheniramine, with the formulation

O

If the blocking effect of the 5-hydroxytryptamine is used, it can be used as a blocker and then the 4-α-dimethyl-m-tyramine-inducer of norepinephrine can be removed, with a strong effect on the ointment.

The pharmacological action is contemplated by the use of a tricyclic antidepressant in the form of a single and conventional formulation.

23 5 6 3 7 8 1. Blocker effect of t-methyl-α-ethyl-m-tyramine-inducer 5-hydroxytryptamine extraction ____ 1.1 Rattor

These substances are tested by intraperitoneal injection. 50 mg / kg of 4-methyl-α-ethyl-m-tyranine intraperitoneally is injected for 30 minutes. These compounds were treated with 5-hydroxytryptamine and the best. Djur som behandlas enbart med test substance, resp. enbart med ^ -methyl-α-ethyl-m-tyramine is added to the controller. The percentage of the 5-hydroxytryptamine utilization is best followed by the formulation

A - B

% hämning = - '100

C - B

A = game (ng / g) 5-hydroxytryptamine and other administration after test administration och-methyl-α-ethyl-m-tyramine B = game (ng / g) 5-hydroxytryptamine after administration 4-methyl-a -ethyl-m-tyramine C = game (ng / g) 5-hydroxytryptamine and then after administration of the test substance.

Effective dosage of 5-hydroxytryptamine utilization at 50% (SD ^ 0) was determined by genomic regression analysis of the sedan. Test results are shown in Table 1 below.

1.2 Möss

These substances are injected intraperitoneally into the head. 30 mg / kg of 4-methyl-α-m-tyramine intraperitoneally is injected for 30 minutes. For 90 minutes, 4-methyl-α-ethyl-m-tyramine (100 mg / kg) was administered to the test substance, and the mixture was administered at a rate of 30 minutes. Ytterligare 2 timmar senare dödas djuren och mängden 5-hydroxitryptamin i hjärnan bestämmes.

The percentage of 5-hydroxytryptamine utilized and EDc; 0 is best measured under 1.1. The method described in the European Journal of Pharmacology 5, 357-366 (1969) · Test results are shown in Table 1 below.

2. Blocker effect of 4, α-dimethyl-m-tyramine-inducible noradrenaline excipient ___

These substances were injected intraperitoneally at daytime (10 mg / kg). For 4 minutes, 4, α-dimethyl-1-m-Tyra-min (12.5 mg / kg) was administered. For 90 minutes, the administration of halogenated test substance (5 mg / kg) was administered and 30 minutes of administration of 9, α-dimethyl-m-tyramine (12.5 mg / kg). Ytterligare 2 timmar senare dödas djuren och mängden noradrenalin i hjärna och hjärta 24 56378 bestämmes. Djur soin behandlas enbart med testsubstans resp. enbart med 4, α-dimethyl-iT! -tyramine samt obehandlade djur används som kor.troller.

The percentage of normal to normal use is best achieved after the form

A - E

% hämning = - · 100 C - 3 A = game (ng / g) noradrenaline i hjärna, resp. hjärta efter administration av testubstans och 4, α-dimety1-m-Tyra-min.

B = game (ng / g) noradrenaline i hjärna resp. hjärta efter administration av 4, α-dimethyl-m-tyramine.

C = game (ng / g) noradrenaline i hjärna resp. hjärta efter administration av testsubstans.

Test results are shown in Table 1 below.

3 · Effect of rhythmic diffraction

In the case of test substances, a constant infarct is shown on the basis of an electrocardiogram observer. After that, all of these upright or so-called light blades are all engraved and slurryed to the center of the air conditioner. These batteries are also shown in the table in Table 1 below.

25 56378

-P

M H TS

• H rt -H>, —I> ro H

ft rt c c ai; o o o ε E -h? j <i ε m e; c -h 3 _ _ • c — ii— 'o— (rc> Ό Ό bO ω «MC CO CO rt C i EH -HH 40 jo • H xo li · Ρ roro ro · C-jp hOroa ^ C σ \ ohooo or a> π mt ddg £ tr .H rt rrt I — I -H CV CM ΓΟ JO r ~ - CO P +>

: θ rt ^ O

-p ro · -p ro -h> '-o —j -p ro cu rt co rt ro rt · *> o · rt o IM Ω -H> ei ccec rt £ i 40: 0 rt IIM 40 ap ε cc ro c> e:> 3 40 .p ω -h ro -h rt -h · rt CC OCr-t: oC> 0.40 401 i-HrtEECro-Crt-LooH cm Ή oo uo o> pt lo • hc 3 ic: rt o ft-c: rt H n- ro uo in or i> - h cm cm h

x -h «c rt ro £ -h a --o OH or -HOO 40001, C

ort ε-οΩΗχοο -CC> rtrt h d e: rt> 3 rt rt C C bO rt --o 40 jC c>. o c C C bo ro i rt rt o e -h o -h i ΰ lo rt cö I CC c rt

C igrtED ^ MM C

Ό o oirt: ooai £ 40CHHOH σ \ lp. o o ui w s m

rtC OHOJOO-PKlCrtHH CM H H LO H H

o. — f r> 3 rt 40 o c_i o rt --D

rt Ό a P O 3fc 0) H44 4C

o rt 0 c Ό rt

C O I

• PC 3 1 1 rt ie bo

CC H Ό C

H -H> 3 C -H Ο Ό Ό £ i jo -h i c o rt rt rt C rt I -H £ 40 40 40 m -H ε C X: o 40 ro ro>. £ i -h o 40 ocd rt rt o - = r o lo lo o o lo lo

40 rt rr £ P, 40 04040rHH CM CM CM H H

I C rt Ό C

£> 3> H> 3 I M --o --0 loo cti> 3-C C Ci rtrt

<—1 1 O 1 -H

> 3 £ rt i c g M

40 1 rt £ rt ε

d H no I rt) 40 LO CM LO

I> 3 O H rt a O ro n n * 3 40 o> 3 C> 3 lo ω ro r> i> lo o lo o - = r ro lo h

I rt I — i 40 φ sa CO: OCMH H CM CM H

Hgart040w e · λ

> 3-H

40 Ό rt i ^ i p Ö 40 (—I -H I 1 iic; i c o, c rr -rr 0) '> 3 O rt Ω 1 I I CL C 40 ° rt ° rt Ch <—te. — I i — i. i ft rt a a o> 3 rt> 3> 3 cm i p,

C CL, 40 c C ^ O I

404001 rtOrtrtrticw e; e; t) cm? -i £ '^! + - icl, h-h ^,

rt rt C I Q „-H H I O I E

P C nj M HiOIHC ^ -3 rt C

cpChhc i o i ^ i ft h h ocd -

rt rt H -H CCHCIOH> 3> 3 C CM

rt C C -H -H> 3-1 I I C> 3 O C 40 Cm CM

rtrtert -HESCEHrtCCrtrto rti rt) E C Hrtrtrtrt ^ ftrt-HCMS-o CCrtcO C> 3CC <hHCO <mEC-pCcm

H rt rt C H -H40pL-H £> 3rtCCrtOrC: rtHrTCOO

c c ft Sft-Hco4oa-cD, OHHie; i> -ooHc «

Hrtrt-ΗΌ rt-HErtcaj-HiH> 3e; LO '~' ^ ^ ^ 00 rii S (3 CC-HftXiSrtlOei-Pll cmocmcmo CDOO40 40 ft 40 a, g 1 -H 1 C 1 rt or- 'C 000 σ- \ JP OO> 3 ro -H -HOO ft-a H -HQ, ε - H rt 40 H, - |, —I cr \ rt1—1 '—1 C rt EE' — 1 C 1 1 «E il l> 3 1 rt HCCjDrtEH -PrteiOlHrOHrtHrOHrtlHooCCCCCCC; 56378 26

In this case, the test table in Table 1 is based on the test results and the corresponding reference substances in the blocking effect. The 5-hydroxytryptamine additive is treated with Ί-methyl-oi-ethyl-in-tyramine, which has the effect of further purifying up to 4, α-dimethyl-m-tyramine-ducerade noradrer.alin-uttömningen is lag. The dosage i mg / kg is calculated i.p. In the case of a constant pressure fusion, a constant infusion rate is used to determine the value of the reference value or the reference value of the reference value.

Framställning av föreningar enligten föreliggande uppfinningen ilustreras med feljande utföringseempempel.

Example 1. Preparation of (E) - and (Z) -3- (Ί'-bromophenyl) -3- (2 "-pyridyl) dimethylallylamine dihydrochloride 3r____ Br I ^ HO - - CH2CH2M ^ CH3 _H2 ° _c ^ .- k \ pu *. \ f \ 3 \ (~ J CH2-N (CH3) 2-2HCl)

-V Q

'2 nr, H 100/0 * xxCH 2 N (CH-5) 2-2CH 1 H 100/03 97 g 1- (Ί'-bromophenyl) -3- (N, Ν-dimethylamino) -1- (2 "- pyridyl) -propanol (H 9/96) was added in 300 ml of 85% and color at 170 ° C for 10 min.

Därefter uthälles reaktionsblandningen pä 1 1 watten som krs alkaliskt med 10 N NaOH och a extraheras med 2x250 ml ether soin torkas, behandlas ned Aktiv koi och indrives. The product was dissolved in 250 ml of ether and torr. Hey. The residue was purified by 11 times and 15 crystals of ethanol (09.5 7).

Jtbyte ΊΟ g (E) -5- (Ί'-bromophenyl) -3- (2 "-pyridy 1) -dimethyl v Lal I y J am i. Nd i.-hydrochloride. (H ΙΟΟ Mp 195 ° C.

27 56378

Moderluten frän omkristallisationen indrives, äterstoden loses i aceton. After 24 hours of filtration on the ground. 15 g of (Z) -3- (4'-bromophenyl) -3- (2 "-pyridyl) -dimethylallylamine hydrochloride (H 100/03) are obtained. M.p. 160 DEG C. Utgängsmaterialet, 1- (4 '- bromophenyl) -3- (N, N-dimethylamino) -1- (2 "-pyridyl) -propanol free of charge:

Br - ^ ^ - !: CH2CH2N (CH3) 2 ^ ΒΓ ^ HO - CH2CH2N (CH3) 2

50 g of n-butyllithium in 0.5 l of torr ether are set at -40 ° C

23.7 g of 2-bromopyridine are added after stirring at room temperature. After this time, the mixture is treated for 30 minutes. The residue is then treated with 1.5 l of ether and sediment to give 197 g of ω-dimethylamino-4'-bromopropiophenone at a temperature of -40 ° C. The reaction is carried out and the mixture is treated with various reactions and the reaction is carried out with HCl, which is then treated with methylene chloride. Därefter göres vattenfasen alkalik och a extraheras med eter, som thorkas och evaporers. The mixture is crystallized from petroleum ether at 40-60 ° C. 98 g of 1- (4'-Bromo-phenyl) -3- (N, N-dimethylamino) -1- (2M-pyridyl) -propanol are obtained. SMPT. 85 ° C.

Example 2. Framställning av 3- (4'-bromophenyl) -3- (3'-pyridyldimethylallylamine dihydrochloride) 3.6 g (4'-bromophenyl) -3- (N, N-dimethylamino) -1- (3'-Pyridyl) -propanol was added in 15 ml of 85% H 2 SO 4 at 170 ° C for 10 min. After reacting with 60 ml of water, the mixture is basified with 10 N NaOH, extracted with 2x25 ml of ether. Etern torkas med Na2S0lt, behandlas med aktivt koi och evaporeras. The solution was taken up in 25 ml of acetone and the equivalent of oxalic acid in 25 ml of acetone. The filtrate is filtered off, added to 50 ml of water with 10 N NaOH and extracted with 2x25 ml of ether. Eterlösningen torkas med Na ^ O ^ filterer varefter torr HCl inleds. The resulting filter. 1.2 g of 3- (4'-bromophenyl) -3- (3 '-pyridyl) -dimethylallylamine-28 563/8 hydrochloride (H 102/09) were added. SMPT. 193 ° C.

Material, 1- (4 "'- bromophenyl) -3- (N, Ν-dimethylamino) -1- (3" -pyridyl) -propanol, free of charge:

To 9 g of n-butyllithium in 200 ml of torr ether is adjusted to -40 ° C. 20 g of 3-bromopyridine are then added to the temperature-boiling mixture. After this time, the mixture is mixed for 30 minutes. 32.5 g of α-dimethylamino-4β-bromopropiophenone are then obtained and the temperature is stirred at -40 [deg.] C. The reaction mixture was stirred and mixed with water and the reaction mixture was treated with ether and extracts with 20 ml of methylene chloride. Methylenedichloride inoculated and evaporated. The crystals are dissolved in water to give an aqueous mixture of Na 2 CO 4, extracts with ether, concentrated and evaporated and crystallized from isopropyl ether and petroleum ether, 1: 1. 4 g of 1- (4'-bromophenyl) -3- (Ν, Ν-dimethylamino) -1- (3'-pyridyl) -propanol are obtained. SMPT. 67 ° C.

Example 3 · Preparation of 3- (4''-bromophenyl) -3- (4, '- pyridyl) -Dimethylallylamine dihydrochloride 3 g 1- (4'-bromophenyl) -3' (N, N-dimethylamino) -1- ( 4 "-Pyridyl) -propanol is taken up in 10 ml of 85% HgSO4 and stirred at 170 [deg.] C. for 15 minutes. The reaction mixture is then stirred after 10 minutes with 10% NaOH and extra ether with ether. 1.4 g of 3- (4'-bromophenyl) -3 "(4" -pyridyl) dimethylallylamine dihydrochloride are obtained, which are obtained by filtration and crystallization of the genome from ethanol and by the addition of acetone. 190 DEG C. (H 102/10)

A starting material, 1- (4'-bromophenyl) -3- (N, N-dimethylamino) -1- (4 "-pyridyl) propanol, fr.

10 g of n-butyllithium in 250 ml of torr ether are set at -40 ° C

17.7 g of 4-bromopyridine are added to the solid after stirring at room temperature for 30 minutes. 28.7 g of n-dimethylamino-4'-bromopropiophenone are added at a temperature of -40 ° C. Kylningen avbryts och blandningen omröres över natt värefter reaktionsblandningen uthälles pä is och utspädd HC1. The water phase is taken up in methylene chloride with a basic alkali containing 10 N NaOH and extra ether. The ether was stirred with Na 2 SO 4 (coles and evaporated). The mixture was crystallized from diisopropyl ether. 3 g of 1- (4-bromophenyl) -3- (N, N-dimethylamino) -1- (4 "-pyridyl) propanol were added. Mp 120 ° C.

The analogue is prepared in the form of a mixture of 3- (3'-2-dimethylphenyl) -3 "(2''-pyridyl) -dimethyl-allylamine dihydrochloride, (H 99/88), especially mp 136 ° C.

Claims (6)

29 56378 A process for the preparation of therapeutically active 1- (4-bromophenyl) -1-pyridyl-3-dimethylaminoprop-1-ene derivatives of the formula I r = OL ^> C = CHCH 2 N <TI fr s ^ and their therapeutically acceptable acid addition salts wherein the pyridyl group is attached in the ortho, meta or para position to an adjacent carbon atom and wherein R is H or Br, characterized in that the compound of formula I is formed by removing water from a compound of formula Br- ch3 \ C -CHOCH-N 11 fT 1 after which the compound thus obtained is, if desired, converted into a therapeutically suitable acid addition salt by means of a suitable acid. Process according to Claim 1, characterized in that R is hydrogen and the pyridyl group is attached in the meta position to an adjacent carbon atom. Process according to Claim 1 or 2, characterized in that the E-form of the compound I is separated. Process according to Claim 1 or 2, characterized in that the Z-form of the compound I is separated. A process for the preparation of therapeutically active 1- (4-bromophenyl) -1-pyridyl-3-dimethylamino-prop-1-enders with a formulation