FI61484C - PROCEDURE FOR FRAMSTATION OF Z-3- (4-BROMOPHENYL) -N-METHYL-3- (3-PYRIDYL) -ALLYLAMINE WITH ANTIDEPRESSIVE OCH - Google Patents

Description

I. Γβ1 .... WHEN PUBLISHING, „. Λ Λ Μ (11) UTLÄGGNINGSSKRI FT 614 84 C (45) Patonibl obtained 10 GG 19-2 ^ ^ (51) Kv.lk?/lnt.CI.^ C 07 D 213/38 ENGLISH I - Fl N LAN D ( 21) P »t * nttlh« k «mu * - P» t * nMn * öknlng 753260 (22) Hakamispkivi - Antdkningtdig 19 · 11 · 75 ^ ^ (23) Alkupiivt - GlMghattdag 19.11.75 (41) Tullut Julkltaktl - Blivlt offantHg 22.05.76

Patent and Registration Office / 44) Date of issue: 30 82

Patent and registration authorities Arnokin utlagd och utl.tkrlftan publkarad (32) (33) (31) Pyydetty etuoikeus-Bogird priorltet 21.11.7l

Sweden-Sweden (SE) 7I1I622-6 (71) Astra Läkemedel Ab, S-151 85 Södertälje, Sweden-Sverige (SE) (72) Per Arvid Emil Carlsson, Gothenburg, Bernt Sigfrid Emanuel Camma 1 m, Södertälje, Svante Bertil Ross , Södertälje, Carl Bengt Johan Ulff, Södertälje, Sweden-Sweden (SE) (7l) Berggren Oy Ab (51) Method Z-3- (1-bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine, for the manufacture of an antidepressant and anxiety-relieving effect - Förfarande för framställning av Z-3- (1-bromophen1) -N-methyl-3- ~ (3-pyridyl) -allylamine with antidepressant and anesthetic network

The present invention relates to a process for the preparation of Z-3- (1-bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine having antidepressant and anxiety-relieving effect, or a pharmaceutically acceptable salt thereof.

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

The most widely used antidepressants in clinical use are tricyclic tertiary amines, such as imipramine, having the structural formula ^ 1 ^^ OH,

CH0CH "CH0-N

2 2 2 n.

CH.

3 and amitriptyline of structural formula 2,61484 ^ ch3

Secondary amines such as desipramine having the structural formula CXJT) I / CHOCHOCH-N.

2 2 2 \ ch3 and nortriptyline of structural formula CH3 are used somewhat less. 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 antidepressant 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 a compound of the formula C = CHCH2n '/ r \ /, have an antidepressant effect, cf. J.Med. Chem. IU, 161-14 (1971). For compounds of formula 3 61484 'chch2ch2n.

R 1 Y CH 3 wherein X is chlorine or bromine and R is hydrogen or methyl has been described as having antidepressant activity, cf. U.S. Patent No. 3,423,510, however, these compounds also have a strong antihistamine effect. It is also known from the literature that the formula

Br ^ "I

CH ^ ^ c = chch2n ^

U

has an antidepressant effect in animal experiments, cf. Belgian Patent No. 781,105.

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.

11 61484

According to the invention there is provided a process for Z-3- (b-bromophenyl) -N-methyl-3- (3-pyridyl) -allylamine having antidepressant and anxiety relieving activity and having the formula λ Br c \ txr

Il

CHCH "N

^ ch3 or a pharmaceutically acceptable salt thereof.

The compounds of this invention may be administered in the form of a free base or 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 invention 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 salts 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. Usually, the amount of active ingredient in the pharmaceutical preparation is 0.1 to 95% by weight, especially 0.5 to 20% by weight in the case of injectable preparations and 2 to 50% by weight of the preparations for oral administration.

To produce pharmaceutical preparations containing a compound of formula (I) in unit dosage form, the compound selected for oral administration may be mixed with a solid powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starches such as potato starch or amylopectin, gelatin with 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 (bead-shaped closed capsules) consisting of gelatin and, for example, glycerol, or for the preparation of similar tablets, the active ingredient can be mixed with a 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 gelatin.

Dosage units for rectal administration may be prepared in the form of suppositories containing the active ingredient in admixture with a neutral lipid excipient, 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 carboxymethylselulobob as a thickening agent.

6 61484

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 buffers and are preferably packaged in various unit dose ampoules.

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

The process of the invention preferably prepares the compound in the form of a salt and uses it 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 the formula .

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 2 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, POC17, in pyridine, and dehydration with thionyl chloride, SOCl2, in pyridine. Catalytic dehydration of the starting material can also be used. The dehydration in this case is carried out at temperatures of about 300-500 ° C using a catalyst such as kaolin or alumina, b) by alkylation of monomethylamine with a 3- (4-bromophenyl) -3- (3-pyridyl) allyl derivative having formula

Br if

CHCH 2-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, bromine and iodine, or sulfonates, such as methanesulfonate, toluenesulfonate and benzenesulfonate, c) by introducing a methyl group into 3- (N-bromophenyl) -3- (3-pyridyl) allylamine. <* x ex

C

II

chch2nh2 to form a compound of formula I, d) by treating, under hydrolysing conditions, an acyl or sulfonyl compound of the formula ULcajj with 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine

H6 ^ X'CH2CH2-NCH, -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 one of methods a) to c) is optionally converted / separated into the pure Z isomer and optionally converted pharmaceutically ,. acceptable salt.

8 61484

The following examples further illustrate the invention.

Example 1, (method b). Br] _) Br

Π rr Οι. XX

2, nh2ch3 isAcAk HO ^ ^ CH „CH„ OH CHCH-NHCH-, kk k 1- (4-bromophenyl) -1- (3-pyridyl) -1,3-propanediol (7.2 g, 0.023 mol) was dissolved to 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 basified 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 L 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%. Sp. 138-L44 ° C.

Example 2, (method a)

Br. br

h2s04 _ XX] XXX

Ά AJ - AJ

O S

HO CH 2 CH 2 NHCH 2 CHCH 3 NHCH 9 61484 3- (4-Bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine crude (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-bromo-phenyl) -N-methyl-3- (3-pyridyl) -dayylamine oxalate as white crystals. Sp. 180-208 ° C, the NMR spectrum shows a vinyl proton as a double triplet at 6.1-6.4 ppm, indicating a mixture of the 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 a few percent water gave a compound melting at 116-165 ° C. Elemental analysis showed it to be the dihydrochloride of formula C, ΕΗη, -BrN ~ · 2 HCl · H „0.

15 15 2 2

..I

10 61 484

Example 3 (method c) r ^ i ^ VBr

Il 'I -> I I I j - 5 »11 il CH 1 U i I 2 ™ 2 NH2 NHCOCF ^ H i ^ rBr—. n rrBr A ^ N "c /

I! B

(j: h fH

ethyl 2 fluoroacetate was added to ether (10 ml) in ether (10 ml) to ethyl 2 fluoroacetate (0.5 ml, isomeric mixture) in ether (10 ml). (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 determined by thin layer chromatography. It was then diluted with water, extracted with ether, extracted with ether extracts with hydrochloric acid, basified, extracted with methylene chloride and evaporated to dryness to give the methylated amine as an oil (0.36 g). The oxalate was precipitated with isopropyl alcohol and recrystallized from methanol, mp ~ 185 ° C.

In the NMR spectrum of the product, a peak for the methyl group (6 ~ 2.4, consistent with the reference substance) could be observed in the region of 11,61484 blank 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 \ c / v \ c /

tl M

/ ‘X Xc’

C1-CH- H CH, NCHO X

2 31 2 COCF3

A sodium salt of methyl trifluoroacetamide 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). atmosphere for one hour at room temperature. A solution of 0.6 g (0.002 mol) of Z-3- (4-bromo-phenyl) -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 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 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 observed R f 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 sheets of Merck Silica Gel ^ 254 were used. A characteristic peak at 6 = 3.0 ppm was observed in the NMR spectrum (deutero-chloroform). In the IR spectrum, a carbonyl band was observed at 168Ο cm 12 61 484

Step 2

^ 11 i NaOH 'I I I

\ / ^ C X

0 II

H c

CH, NCh ', XH CHNCl2H

i | 2 I

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. l65-175 ° 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.

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

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 extracted, sliced 14 and incubated in a mixture of 0.2 nmol C-5-HT, 0.2 nmol H-NA and 11 glucol in 2 ml Krebs-Henseleit buffer, pH 7.4, per 100 mg of brain pieces. The incubation time was 5 minutes, followed by pre-incubation before the addition of the labeled amine. 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% reduction (ED 2) in the active binding of 1 H-C-5-HT and N-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.

13 61484

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

14 61484

. I

c.

0j · γη I ° I ™

3 "rj · Η OJ I — I CO IP

4->> OH O O CT \ VO

O LH O rH rH a 0 3 Q g / s. Λ 4-3 · Η (¾ § '* H \ co o 3 3 .. .p <· Η S i> c oo 1 LT1 · E m i_n - = r o

1 — J— '3 00 3 A A A A

IP -H W ^ <\ | rH -ΐΤ O

O] c Φ 34 3 3

• H <D * H

• H C

x: · η bo ε 44 3 3 p.

Φ 40 Ο · Η

Φ 3> 1 — I c \ J

3 O -H O «3 .p> 0 0 co ir \ co lp

4-3 · Η LP E H 1 — I -¾- OJ

3 co 3 Q 3 rH

Ο -H £ 4 P

43 3 • H ·

cn Eh O

JO, ip ffi 3 3 CQ K I 4-3>, • H \ CC O IP -H w

3 \ - v / I> 0 „LT \ r — I t- ΓΡ * H

• H If Vc \ / 0 LP E aa aa ax) • H // \\ 2 ^ rC03 00 rH 0 χ OH \ / (\ jHHHn jh «CÖ \ - / ffi a) 04« 1 \ Ο · Η * H · Η 03 \ EC T3X3TS 3 μ-l Cl) 3 Ö - Ο · Η -Η · Η · Η ·· 0 3 Ή / 40333 -6¾

<OO _ / -P O O O

EhoJ-ΗΑΛ Cfl rH 1 — I rH CO

3 Φ // \\ cti 34 04 rP

0 3 \ / «3 rH O O O

3 O \ - U rH cö 3 3 3 3

3 ^ O co ό! OS Ό -H

«13 3 .14> s >> Ph -H

hh w ooox: 40 c o 3 Φ • H 3 -p

3 Φ -H CO

• H 4-3 3 O

H CO Φ rH

Era φ 3 ra rH E 3 • H ra O 04 00 00 co a co E4, H * d o, ° 3 .3

3 Φ .d -H

XS -r-D Φ d> 5 o 3 ra ho -3> CO 3 3; 1 · Η · Η p, ^ LP Cd * 3 ΓΡ * H .f—)

o K ε rH

> H K Ϊ) K O -H O

- '-' 1 3

4-3 1 — I

Φ O

CO 1 — i

•B

ra ra

E4 rH

3 rH

ε φ co 3 -P -P x

• O Φ 4-3 Φ .O

3 Φ 3 Φ 3 3 4-3 + s -P 3 • h co cd co ra

CO · Η 3 -H

V. , r xxi CO., LTD

'Φ 43 3 £ r- ^ M i »Ei> 3 oj i is 614 84

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 compound has a stronger inhibitory effect on the binding of 5 "HT in vivo than any previously known compound tested.

With a compound of formula (I) which. tested as the hydrochloride, is also 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). Inhibition of the neuronal binding of 5-hydroxytryptamine and noradrenaline may make a compound of the invention a valuable antidepressant. Likewise, the compound of the invention may be useful as an analgesic.

OF

16 61 484 For the preparation of a compound for the preparation of Z-3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine with an antidepressant such as a pharmaceutical agent, if acceptable site därav.

Depression distillation is accompanied by damage to the whole or the other part of the body.

The antidepressant medication, wherein the fat is used in clinical trials, is a tricyclic tertiary amino acid imipramine, with the structural form / CH3 CH0CH-CH ~ - N 2 2 2 \ x ch3 and amitriptyline with the structural form ^ CH3

CH ~ CH ~ N

ch3

Secondary amine to desipramine with structural form CH ~ CH0CHoN ^ 2 l λ \ ^ CH3 and nortriptyl with structural form

XcH3 17 61 4 8 4 används i nägot mindre utsträckning. All of these substances have been shown to be effective in the treatment of orthostatics, anticholinergic effects, and framför allt arrhythmias, dvs. hjärtarytmiframkallande effekt vid administration i högre doser account äldre patienter. The use of such 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 C - CHCH2N2.

Xcn3 has an antidepressant effect, see J. Med. Chem. 14 161-164 (1971). Föreningar med formeln r ^ chch9ch9n ^ sy 'Nch3

CJ

whether X is chlorine or bromine or methyl is methylated to a high antidepressant effect, see U.S. Pat. In addition, the antidepressant effect of the formulation of Tl V \ .ch3 <Z = CHCH-N ^ 0 / har antidepressant effect is contraindicated, Belgian Patent No. 781 105. In the present case, medical devices have been shown to be depressive. Deprimerade patienter reagerar pä olika vis account de kliniskt använda olika antidepressionsläkemedlen. The fixture is based on the uptake of noradrenaline and neurons and is 61484 and the uptake of 5-hydroxytryptamine. The use of 5-hydroxytryptamine uptake is a mechanism that can be used to treat antidepressant medications in the first instance. In this regard, the use of 5-hydrotryptamine or noradrene-linupptage is selectively selective with the best possible interest.

That interest in the use of anti-depressant drugs has the potential to have an antidepressant effect. In addition, the use of anti-depressant drugs and the development of antidepressant effects and the use of such agents are particularly effective. The effect of the therapeutic effect on the therapeutic effect is not severe. Exemption from the rules of the Treaty on the basis of which the aid is granted.

The reaction is preferably carried out for the preparation of Z-3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine with antidepressant and anti-inflammatory effects, in which form

Oh fjf

Il

CHCH

\ ch3 eller farmaceutiskt acceptabelt site därav.

For the purposes of Formula (I), the administrators may use the form or the same as the said form. Vissa typiska exempel pädana salter is hydrobromide, hydrochloride, phosphate, sulphate, sulphamate, lactate, acetate, citrate, tartrate, malate and maleate.

Pharmaceutical products

In the case of clinical administration, the competent authority for the administration of the drug is normally orally, rectally or by genomic injection, in the form of a pharmaceutical formulation of an active ingredient in the form of a pharmaceutical or other acceptable form of pharmacy, tillsammans med en farmaceutiskt acceptabel bärare. Säledes avses 61484 19 med en ny förening enligt denna uppfinning Bade en fri aminbas och den fria basens syraadditionssalter, undantaget da sanunan-hanget, där dessa termer används, t.ex. ett visst exempel, icke faller inom denna vida definition. Bäraren kan vara ett fast, halvfast eller flytande utspädningsmedel eller en kapsel. The active ingredient is present in the form of 0.1 to 95% by weight of a pharmaceutical preparation, in particular 0.5 to 20% of the active ingredient in the form of an injection and in addition to 0.1 to 50% in the case of an oral formulation. .

For use in the manufacture of pharmaceutical preparations in the form of oral dosage enhancers for oral administration in accordance with the provisions of this Regulation, the active ingredient may be formulated with the active ingredient in a pharmaceutically acceptable form. . lactose, sackaros, sorbitol, mannitol, starch or potassium starch, or amylopectin, cellulose or gelatin and silage, magnesium stearate or calcium stearate or polyethylene glycol extractor and press tablets. For the purposes of this Regulation, the reference number of the headform shall be as set out in point (s) above the t.ex. gum arabicum, gelatin, talc and / or titanium dioxide. Alternatively, the tablet may be leached with organic organic solids or bleached organic solids. The account was set up by dessa täcklager t.ex. For the purposes of this Regulation, the other parties were involved in the assets.

For the production of a gelatin capsule (pearl capsule 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, sackaros, sorbitol, mannitol, starch (i.e. potassium starch, maize starch or amylopectin), cellulose adsorbent or gelatin.

The dosage form for rectal administration can be in the form of a suppository with the active substance in a bleaching medium with neutral fats, or a rectal capsule with a gelatin in which the active substance is bleached with a neutral flour or paraffin.

20 61 484

The oral preparation for oral administration can be in the form of a syringe or a suspension, e.g. The total amount of the active compound is 0.1 - 20% by weight of active substance. The active substance is varnished with ethanol, water, glycerin and propylene glycol. In this case, the mixture is treated with a solid, sacharin and / or carboxymethylcellulose with a desperation medium.

For parenteral administration, the genomic injection can be formulated in a water-borne and pharmaceutically acceptable pharmaceutical salt with an active substance in a concentration of 0.5 to 10% by weight. In this case, it is possible to use a stable stabilizing medium and / or buffer substrates and watering and de-packing the dosage form in the ampouler.

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

For example, the above-mentioned frameworks are used in the form of salt and anchovies.

The genome of the compound of formula (I) thus comprises a) dehydrated 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) propylamine CH2-CH2N · ^ \ ch3

Dehydration of the uterine growth can be obtained from t.ex. genomic behavior and uptake of the reaction reaction in the environment. Dehydration with other materials can be used to give a syrup catalyst, chlorosulfur, HCl, phosphorus, H 2 PO 4, potassium sulphate, KHSO 4, or oxalic acid, (COOH) 2 Form I (I) is dehydrated in the genome of phosphorus oxychloride, POCl 3 in pyridine and dehydrated in thionyl chloride, SOCl 2 in pyridine. Catalytic dehydration of the raw materials can be used. In this case, the dehydration reaction is carried out at a temperature of about 300-500 ° C with the addition of a catalyst such as Kaolin or alumina, the formula

CHCH 2-y

the group has a group account for the purposes of Formula I.

Exempel days Y can be taken up in halogen, chlorine, bromine and iodine, or sulfonates, methanesulfonates, toluenesulfonates and benzenesulfonates, c) methyl groups which are substituted by 3- (4-bromophenyl) -3 - (3-pyridyl) -allylamine enligt formeln

Br c

II

Ch (2-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) -propylamine is used as a compound for the preparation of 3- (4-bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyl) -propylamine. ^ ^ Br

Ok / r / c \

HO CH2CH2-NCH3-Z

* O * 22 61 484 for the use of acyl or sulphonyl groups for the preparation of compounds of formula I in the form of an acyl or sulphonyl group, which may be used as a form of treatment (a) to (d) / isolates the Z-isomer and, if appropriate, accounts for a pharmaceutically acceptable site.

The aid is granted for the production of fungi.

Example 1 (form b) H 2 O 2 CH 2 CH 2 OH CHCH 2 NHCH 3 1- (4-bromophenyl) -1- (3-pyridyl) -1,3-propanediol (7.2 g, 0.023 mol) was taken up in acetone (70 ml). The bromide leddes genom lösningen, och lösningsmedlet avlägsnades i vakuum. Methylene chloride (50 mL) and phosphorus tribromide (6.4 g, 0.047 mol) were added to the mixture, and the mixture was stirred at room temperature for 14 minutes, and the residue was quenched with alkaline sodium carbonate. Methanol was added to the organic phase (50 mL) and the solution was stirred under vacuum 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 temperature separated. In addition, the pH was adjusted to ether, and the pH was adjusted to 2.1 with HCl. Vatenfasen behandlades med aktivt koi, gjordes därefter alkalisk med ammoniak och extraherades med ether.

The organic phase is pierced with sodium sulfate and induced by vacuum. The mixture is taken up in ether (40 ml) and stirred at room temperature. In addition to the chlorine exchange rate, the colors are reduced to a maximum level. Apply filtration, cooling with ether and piercing under vacuum. Hydrochloric acid 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine hydrochloride. Vinst 43%. Smp. 138-144 ° C.

23 614 8 4

Exempt 2 (for example)

Br f! m.p. 3-Hydroxy-N-methyl- (3-pyridyl) propionamide) is added under 50% purity (50 ml) and bleached at 110 ° C for 10 minutes. After leaving the mixture and halides at the bottom, the alkaline genome is adjusted to 30% NaOH and extracts with ether. 150 ml of acetone are added and the mixture is filtered. 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 stirred in 350 ml of isopropyl alcohol to give 1.7 g of 3- (4-bromophenyl) -N-methyl-3- (3-pyridyl) -allamine oxalate as Vita crystals. Smp. 180-208 ° C, NMR spectra of vinyl protons commercially available in a double triplet at 6.1-6.4 ppm, in the presence of bleaching of E and Z isomers.

Isolation of the Z-isomers: In the case of 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 was carried out at a rate of 16% to 165 ° C. Substantial analysis was performed to give the dihydrochloride in the form of C 1 H 2 N 2 BrN 3 * H 2 O 2 H 2 O.

24 6 1 484

Exempel 3 (for c)> o ^ xx

CH (JH

{H2 fH2 NH2 NHCOCF3

Br Br

CH CH

I I

CH, CH, I 2 I 2 NCH3 nhch3 cocf3

3-Amino-1- (4-bromophenyl) -1- (3-pyridyl) -prop-1-ene (0.58 g, isomeric bleaching) 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 (2 M) of salt, extracts of basic bases and extracts of ether are then carried out to give a trifluoroacetamide derivative. Dissolve 1 dimethylformamide (DMF, 25 ml, ca. Ca 2) in the oil. Methyl iodide (0.3 g) in DMF (10 ml) was added and the mixture was stirred for 1.5 hours. Blandnings are prepared with water and extra ether. After uptake of the essential oil, the methyl trifluoroacetamide derivative was added, and ethanol (30 ml) was added with sodium hydroxide (5 ml, 10 M) and stirred at room temperature for 50 minutes. Medium flash chromatography is performed to complete the hydrolysis. After working up with water, extraction with ether and extraction with ether extracts with salt syrup, alkalization, extraction with methylene chloride and induction of methylation with some oil (0.36 g). Oxalate is added to isopropyl alcohol and crystalline serum from methanol. Mp. '^ 185 ° C. The NMR spectrum is shown to be on top of the methyl group (δ2.4, overturned with reference substances) and to be found in the primary spectrum. I omrmet omkring = 6,2 erhölls en dubbel triplett som visur attöreningen utgjordes av isomerblandning.

25 61484

Exempt 4 (for others)

Steg 1 arr-> asxr

C1-CH2 h CH3ljICH2 H

COCF3

Sodium salt of methyl trifluoroacetamide is added to the genome after removal 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 hour at room temperature. 0.61 g (0.002 mol) of Z-3- (4-bromophenyl) -3- (3-pyridyl) allyl chloride are then added in 5 ml of the same solution. After 2 hours at room temperature, the water is stirred at room temperature and the reaction is carried out with ether. In the case of ether-containing skakades with 0.5 M saltsy, the aqueous phase is reduced to alkaline and extraherades with methylene chloride. 0.5 g of N-methyl-N-trifluoroacetyl-3- (4-bromophenyl) -3- (3-pyridyl) -propenyl-amine is obtained. Denna character series medelst tunnskiktskroma-tografi i tvä skilda system. The R-color was obtained as 0.23 parts of isopropyl ether in 5% methanol and 0.47 parts of ethyl acetate. The NMR spectrum of the Merck Silica Gel F254 'NMR spectrum in the form of deuterochlorochloride has a characteristic peak of <5 = 3.0 ppm. The IR spectrum shows a carbon band at 1680 cm -1.

Steg 2

br

i ^ j] (Ύ NaOH> fjl f J

CH3? CH2 H CH.NCH, NH

COCF3

To a solution of 0.4 g (0.001 mol) of trifluoroacetamides in 10 ml of ethanol is added 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 isopropyl alcohol are crystallized from oxalate. Crystallization from methanol (5 ml 95%) 61484 26 g 0.3 g (75%) of 1- (4-bromophenyl) -3-methylamino-1- (3-pyridyl) -prop-1-ene, m.p. 165-175 ° C.

Pharmacological tests

It is not possible to experiment with force depression in the field. For example, a possible antidepressant effect may be present in the biochemical-pharmacological test method for influenza. One hundred test methods are used to reduce the antidepressant effects of steroids in clinical trials and to treat them in Europe. J. Pharmacol. 17 ^, 107, 1972.

14 The test method for the preparation of C-5-- 14 3 3 hydroxytryptamine (C-5-HT) and H-noradrenaline (H-NA) and other fragments of moss after in vivo and in vitro administration the substance.

14 3

Inhibition of up to C5HT and H-NA in vitro and in vivo Test substances are administered intraperitoneally and in vivo. Mellanjärnan togs, scars and incubates and incubated with bleaching equivalents of 0.2 nmol C-5-HT, 0.2 nmol 3 H-NA and 11 μmol glucose in 2 ml Krebs-Henseleitufuft, pH 7.4, per 100 mg hjärnbitar. Incubation for 5 minutes, after 5 minutes of incubation in the wet area.

Bitarna upplöstes i Soluene och mängden upptagna radioactive aminer bestämdes med vätskescintillator. The dosage was 14 to 50% min (ED 2 q) and the active label was added to the C-5-HT and HNA graphs on a dose-response curve. An active label defines a radioactive label that inhibits the cocaine salt.

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

27,614 84 ft

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Claims (1)

As shown in the table, the compound of formula (I) has a potent inhibitory effect on the uptake of 5-hydroxytryptamine and norepinephrine into neurons. The compounds exhibit more potent inhibition of 5-HT uptake in vivo than any of the other known compounds tested. In addition, the compound of formula (I), which was tested as hydrochloride, has a stronger inhibition of 5-HT uptake in vitro than any other of the previously known compounds tested. (The difference between the oxalate and the hydrochloride would probably be due to the fact that the hydrochloride was prepared from the oxalate to give a purer Z-isomer). The inhibition of the uptake of 5-hydroxytryptamine and norepinephrine into neurons can give the compound of the invention value as an antidepressant. Likewise, the compound of the invention may be useful as a meadow suppressant. Patenttivaatimus Menetelmä lääkeaineena käytettävän Z-3- (4-bromophenylyl) -N-methylyl-3- (3-pyridyyli) -allyyliamiinine, yolk on kaava 3- (4-Bromophenyl) -3-hydroxy-N-methyl-3- (3-pyridyyl) propylaminoamina, juliocaava OH [CH2-CH2N / CH3 61484 29 b) monomethylethylamino alkyloidane 3- (3-bromophenyl) -3- (3-pyri-dyyli) -allyylijohdannaisella, jolla on kaava. Br i ^ ji j ^ T II CHCH2-Y jossa Y on lohkaistavissa oleva ryhmä, kaavan I mukaisen yhdisteen muodostamiseksi, c) 3 - (3 BrCH CHCH2NH2 viedään sinänsä tunnetulla tavalla methylyliryhmä kaavan In mukaisen yhdisteen muodostamiseksi, tai d) 3 ~ (k-bromophenylyl) -3-hydroxy-N-methylyl-3- (3-pyridyylmethyl) propylmethyl ,, jolla on kaava / C \ HO CH2CH2-NCH3-Z jossa kaavassa Z on asyylitai sulfonyyliryhmä, käsitellään hydrolysoivissa olosuhteissa, jolloin muodostuu kaavan - d) saatu yhdiste mahdollisesti muutetaan / erotetaan puhtaaksi Z-isomee-riksi ja mahdollisesti muutetaan pharmaseuttisesti hyväksyttäväksi suolakseen. a. Process for the preparation of Z-3 - (3-bromophenyl) -N-methyl-3- (3-pyridyl) -allyl-amine for use in drugs of the form In II / H CHCHON a pharmaceutically acceptable site thereof, characterized by a) dehydrating 3- (4-bromophenyl) -2-hydroxy-N-methyl-3- (3-pyridyl) propylamine. BrH ΠΓ c 1 H OH I CH 2 -CH 2 N 2 CH 2 wherein Y is a cleavable group to form a compound of formula I, c) before a methyl group in a manner known per se in 3- (3-bromo-phenyl) -3- (3-pyridyl) -allylamine of the formula