DE2606393A1 - 3-PHENYL-SEC-BUTYLAMINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The invention relates to new 3-phenyl-sec-butylamine derivatives and processes for their preparation as well as new intermediates which for the preparation of the 3-phenyl-sec-butylamine derivatives are useful. The invention also relates to the manufacture of pharmaceuticals Preparations containing the 3-phenyl-sec-butylamine derivatives and methods for their pharmacological use.

Depressive illnesses have been treated with various compounds with more or less success. There were many types

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chemical substances used, and among these amphetamine of the formula

^CH 3

: h ₂ -ch-nh ₂

CO

The euphoretic effect and the risk of getting used to and however, becoming dependent on this drug severely limited the use of amphetamine in therapy.

The medicinal uses of amphetamine are primary today limited to the treatment of narcolepsy and asthenic conditions in the elderly.

It has been found that by appropriate modification of the Amphetamine molecule reduces the euphoric or centrally stimulating effect of the substance or completely abolishes it can be. The pharmacological profile of the compounds according to of the invention provides potential value for the compounds as antidepressant agents and as a new type of anti-anxiety agent.

The compounds according to the invention have the general formula

CH

CH ₀ CH-CH-NH.
ι X ^{2 2}

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or are their pharmaceutically acceptable salts, where in

1 2

of the formula R and R are identical or different and are each Hydrogen atoms, low molecular weight alkyl groups or halogen atoms mean, R a low molecular weight alkyl group or a Benzyl group means, R a hydrogen atom, a low molecular weight Denotes an alkyl group or a benzyl group, where R

and / or R is a low molecular weight alkyl group or a halogen

3 4
atom is when R and R represent a methyl group.

1 2

R and R can be in any free position on the phenyl nucleus stand.

Illustrative examples of radicals according to the above definitions are, as low molecular weight alkyl groups, methyl, ethyl and n-propyl and isopropyl and, as halogen atoms, chlorine, bromine, iodine and fluorine. The term "low molecular weight alkyl group" is used here Understood alkyl groups with 1 to 5 carbon atoms.

»
The new compounds of the invention can be used therapeutically as racemic mixtures of the (+) and (-) forms obtained by synthesis. However, these mixtures can also be separated into the corresponding optically active modifications, which can be used in the same way in therapy. The compounds according to the invention can be administered in the form of the free bases or their salts with non-toxic acids. Some typical examples of these salts are the hydrobromides, hydrochlorides, phosphates, sulphates, citrates and tartrots.

In clinical practice the compounds according to the present invention are used Invention usually orally, rectally, or by injection

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tion administered in the form of pharmaceutical preparations containing the active ingredient either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, such as hydrochloride, hydrobromide, lactate, acetate, sulfate, Sulfamate and the like, in association with a pharmaceutically acceptable carrier material. If so here of the new compounds of the invention in general or specifically, are thus both the free amine bases and the acid additxon salts of the free bases meant, unless the accompanying text in which such expressions are used, as in the specific examples, is incompatible with this broad meaning. The carrier material can be a solid, be semi-solid or liquid diluent or a capsule. These pharmaceutical preparations make another one Aspect of the invention. Usually the active substance constitutes 0.1 to 99% by weight of the preparation, more specifically 0.5 to 20% by weight for preparations for injection and 2 to 50% by weight for preparations suitable for oral administration are.

To pharmaceutical preparations containing a compound according to the invention may contain, in the form of dosage units for oral administration, the selected compound with a solid, powdery carrier material, such as lactose, sucrose, sorbitol, mannitol, starches, such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin and a lubricant such as magnesium stearate, calcium stearate, Polyethylene glycol waxes and the like are mixed and then compressed into tablets. If coated tablets or dra-

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gees are required, the tablet cores prepared and described above can be mixed with a concentrated sugar solution are coated, which can contain, for example, gum arabic, gelatin, talc, titanium dioxide or the like. Instead of this the tablets can also be mixed with a volatile organic solvent or mixture of organic solvents V / ground the dissolved lacquer. Coloring agents can be added to these coatings to easily between tablets with different active substances or different To be able to differentiate amounts of the active compound.

For the production of soft gelatine capsules (pearl-shaped closed Capsules), which consist of gelatin and, for example, glycerin ^ or for the production of similar closed ones Capsules, the active substance can be mixed with a vegetable oil. Hard gelatin capsules can be granules of the active Substance in combination with solid, powdery carrier materials such as lactose, sucrose, sorbitol, mannitol, starches (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.

Dosage units for rectal administration can be prepared in the form of suppositories containing the active substance in admixture with a neutral fat base, or they can be made in the form of gelatin rectal capsules that contain the active substance mixed with vegetable oil or paraffin oil. ;

Liquid preparations for oral administration may be in the form of syrups or suspensions, such as

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Solutions containing from about 0.2 to about 20% by weight of the active substance described herein, with the remainder being made up of Sugar and a mixture of ethanol, water, glycerine and propylene glycol. If necessary, such liquid Preparations containing coloring agents, flavoring agents, saccharin and carboxymethyl cellulose as thickening agents.

Solutions for parenteral administration by injection can be considered as aqueous solutions of a water-soluble pharmaceutically acceptable Salt of the active substance, preferably in a concentration of about 0.5 to 10% by weight. These solutions may also contain stabilizing agents and / or buffering agents, and conveniently in ampoules of various kinds Dosage units are filled.

Useful peroral doses of the compounds according to the invention are from 2 to 20 mg, preferably from 5 to 15 mg, 1 to 3 times administered daily, preferably twice a day.

The preferred compound of the invention has the formula

CH ₂ -CH ₂ -CH-NH ₂
Cl

Preferably, the compounds according to the invention in the Form of their dihydrochloride salts are made and used.

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The following methods are used to prepare the compounds according to the invention:

A. Reduction of a compound of the general formula

CH

I ³

A-C = N-GH

(II)

12 3 4
wherein R, R, R and R have the above meaning and A is the group -CH ₂ CH ₃ - or -CH = CH-, with formation of a compound of the general formula I.

The reduction can be carried out by catalytic hydrogenation using a metal catalyst such as Raney nickel or palladium on activated carbon. The reaction takes place in a suitable solvent, such as methanol or acetic acid, preferably in the presence of a mineral acid. If the reaction mixture becomes sluggish, further catalyst can be added will. When no more hydrogen is absorbed, the catalyst is removed by filtration and that Concentrated filtrate. The residue is recrystallized from a suitable solvent.

B. Heating a ketone of the general formula

CH-

CH ₂ -CH ₂ -C = O

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12 3 4 in which R, R, R and R are as defined above, with formamide, Ammonium formate or formamide and formic acid according to the Leuckart reaction forming a compound of the general formula In the event that the product obtained is an N-formyl derivative of the amine, hydrolysis gives the compound of the formula

C. Reductive amination of a ketone of the general formula

CH_

CH ₀ -CH ₀ -C = O

12 3 4

wherein R, R, R and R have the above meaning, with ammonia in the presence of a catalyst (such as a metal catalyst) to form a compound of the general formula

D. Direct halogenation of a compound of the general formula

CFL

I ³

CH ₀ CH ^ CH-I R ¹

NH,

3 4

wherein R ^and R have the above meaning and either R or

R or both represent hydrogen atoms, forming one

1

Compound of the general formula I in which R and R are both halogen atoms mean.

Intermediate products are also within the scope of the invention of the general formula II

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(H)

1 2 where A is the group -CH ₂ CH ₃ - or -CH = CH-, R and R

are the same or different and each have low molecular weight hydrogen atoms Alkyl groups or halogen atoms mean, R means one

4 is a low molecular weight alkyl group or a benzyl group, R a hydrogen atom, a low molecular weight alkyl group or

1 2

denotes a benzyl group, where R and / or R is a low molecular weight Mean alkyl group or a halogen atom when R

and R represent a methyl group. These compounds of the formula II are valuable starting materials for the preparation of the compounds of formula I.

The oxime II is produced by treating a General formula ketones

(III)

12 3 4
wherein A, R, R, R and R have the above meaning, with a Hydroxylaminealζ according to methods known per se. The reaction takes place at elevated temperatures in a suitable solution

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medium, such as ethanol or acetic acid, and preferably in the presence of sodium acetate.

The ketones of formula III are produced as follows:

CHO

POCl.

DMF

CH COCH ₃

CH

CH = CH-C = O

CH

CH ₂ CH ₂ -C = I

The formylation of substituted aniline according to the Vilsmeyer-Haack reaction yields the corresponding aldehyde in a first stage. The formylation is carried out using a mixture of dimethylformamide and phosphorus oxychloride. Instead of this the production can also be carried out using a mixture of phosphorus tribromide and dimethylformamide (Acta Pharm. Suecica 7, page 87, 1970).

The process including condensation of the aldehyde with acetone in a second step gives the intermediate benzylidene acetone. The condensation takes place in a suitable solvent or with an excess of acetone in the presence a base such as sodium hydroxide.

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In a third stage, the benzylidene acetone becomes a catalytic one Subjected to hydrogenation, forming a 4-phenyl-2-butanone. The catalytic hydrogenation is carried out using a metal catalyst such as platinum. The reaction is carried out in a suitable solvent, such as ethyl acetate and ethanol, carried out.

The following examples serve to further illustrate the invention.

Production of raw materials example 1

4-Dimethylamino-2-chlorobenzalacetone oxime a) 4-Dimethylamino-2-chlorobenzylidene acetone 50 ml of a 10% sodium hydroxide solution were added dropwise to a solution of 50 g of 2-chloro-4-dimethylaminobenzaldehyde in 200 ml of acetone. The mixture was stirred at room temperature overnight and then poured onto 1.5 l of ice water. The resulting precipitate was filtered off with suction and dried in air. Yield 62.5 g, mp = 70 to 75 ° C. Recrystallization from dimethylformamide / water gave 39.5 g (65%). F. = 80 to 81 ° C.

Analysis for CH ₁

Calculated: C 64.43, H 6.31, Cl 15.85, N 6.25, 0 7.15 Found: C 64.3, H 6.20, Cl 16.1, N 6.07, 0.7 , 26

b) 4- Dimethylamino-2-chlorobenzylideneacetone oxime A mixture of 22.4 g (0.1 mol) of 4-dimethylamino-2-chlorobenzalacetone, 18 g of CH ₃ COONa. 3H ₂ O and 7.2 g of hydroxylamine hydrochloride in 250 ml of absolute ethanol were refluxed for 4 hours. The mixture was then poured into 1 liter of ice water. Of the

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The resulting precipitate was filtered off with suction and washed with water. M.p. = 160 to 166 ° C. Yield 26.5 g. After recrystallization from ethanol the product melted at 170 to 171/5 -C. Yield 17.5g (73%). Calculated equivalent weight 238.73. Equivalent weight found 239.

Analysis for C ₂ H ₅ N ₂ OC1:

Calculated: C 60.37, H 6.33, N 11.73, 0 6.70, Cl 14.85 Found: C 60.3, H 6.37, N 11.5, 0.6.98, Cl 15.1

Example 2

4-dimethylamino-2-methylbenzylidene acetone oxime

a) 4-Dimethylamino-2-methylbenzylidene acetone

To a solution of 32.7 g of 4-dimethylamino-2-methylbenzaldehyde 49 ml of 10% sodium hydroxide solution in 135 ml of acetone were added dropwise with stirring. The mixture was at overnight Stirred at room temperature and then poured into 1.5 l of ice water. The resulting precipitate was filtered off and washed with ice water and air dried. Yield 38.6 g (95%), m.p. = 65 to 75 ° C.

Recrystallization from ligroin-ethanol gave 22.4 g of the product (55%), m.p. = 77 to 79 ° C.

Analysis for C ₃ H NO:

Calculated: C 76.81, H 8.43, N 6.89, 0 7.87 Found: C 76.6, H 8.37, N 6.76, 0 8.02

b) 4-dimethylamino-2-methylbenzylidene acetone oxime

A mixture of 4.1 g of 4-dimethylamino-2-methylbenzylidene acetone, 1.44 g of hydroxylamine hydrochloride and 3.72 g of sodium acetate

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trihydrate in 50 ml of ethanol was refluxed for 7 hours. The mixture was then poured into 1 liter of ice water. The resulting precipitate was filtered off and dried. Yield 2.8 g (64%), F. = 155 to 157 C.

After recrystallization from aqueous ethanol, the product melted at 155 to 156.5 ° C. Yield 2.6 g (60%).

Analysis for C ₁₃ H ₁₃ N ₂ O:

Calculated: C 71.58, H 8.31, N 12.84, 0 7.33 Found: C 71.20, H 8.25, N 12.6, 0 7.7

Example 3

4- (4-dimethylamino-o-tolyl) -2-butanone

A solution of 10.15 g of 4-dimethylamino-2-methylbenzylidene acetone in 250 ml of ethyl acetate was hydrogenated in the presence of 0.42 g of platinum dioxide at room temperature and normal pressure. The catalyst was filtered off and the filtrate was evaporated. The oily residue was distilled at 114 to 123 ° C / 0.3 mm and yielded 7.1 g (69%) of the compound.

Neutralization equivalent (determined by potentiometric titration with perchloric acid in acetic acid) calculated for C ₁₃ H ₁₉ NO: 205.30, found 205.

Example 4

4- (Dimethylamino-o-tolyi) -2-butanone oxime A mixture of 8.24 g of 4- (dimethylamino-o-tolyl) -2-butanone, 2.88 g of hydroxylamine hydrochloride and 7.44 g of sodium acetate trihydrate in 100 ml of ethanol was added Heated under reflux for 5 hours. The mixture was then poured into 1 liter of ice water and overnight

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left at O C. The resulting precipitate was filtered off and dried. Yield 4.9 g (56%), m.p. = 83 to 90 ° C.

After recrystallization from aqueous ethanol, the product melted at 87 to 89 ° C. Yield 3.6 g.

Analysis for ^c i3 ^H ₂ o ^N 2 ^O:

Calculated: C 70.87, H 9.15, N 12.72.0.7.26 Found: C 70.87, H 9.3, N 12.4, 0 7.0

Manufacture of final products Example 5

4- (3-aminobutyl) - ^ - chloro-NyN-dimethylaniline dihydrochloride Method a

A solution of 4.8 g (0.02 moles) of 4-01 Acetone oxime in 150 ml of acetic acid and 4 ml of concentrated HCl were treated with H ^ / Pd-C (5%) at room temperature and normal pressure hydrogenated. The consumption of hydrogen stopped at 900 ml (2.5 hours). The catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from ethanol-ether. F. = 200 to 202 ° C (with decomposition). Yield 1.2g (20%). The product was recrystallized from ethanol isopropyl ether. F. = 204 to 205 ° C (with decomposition). Yield 0.8g. One further recrystallization gave 0.5 g of the product. F. = 206 to 207 ° C (with decomposition).

Analysis for CH ₁₉ ClN ₂ . 2HCl:

Calculated: C 48.09, H 7.06, Cl "23.66, Cl + Cl" 35.49, N 9.35 Found: C 48.2, H 7.77, Cl "23.4, Cl + Cl" 34.9, N 9.14

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Example 6

4- (3-Aminobuty 1) -N, N-dimethyl-iu-toluidine dihydrochloride Method a

A solution of 10.92 g of ^ dimethylamino - ^ - methylbenzylidene acetone oxime in 200 ml of acetic acid and 8 ml of concentrated hydrochloric acid was in the presence of 2 g of Pd-C (10%) at room temperature and normal pressure hydrogenated. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 200 ml of water dissolved, and the solution was extracted with ether and evaporated. The residue was obtained from aqueous ethanol-isopropyl ether recrystallized. Yield 6.7 g (48%), m.p. = 220.5 to 222.5 ° C.

A further recrystallization gave 3.6 g of the product with

a melting point of 227 to 228 C.

Analysis for C ₁₃ H ₂₂ N ₃ . 2HCl:

Calculated: C 55.91, H 8.66, N 10.03, Cl 25.39 Found: C 55.6, H 8.6, N 9.8, Cl 25.0

Example 7

4- (3-aminobutyl) -N, N-dimethyl-m-toluidine dihydrochloride Method B.

A solution of 8.21 g of 4- (4-dimethylamino-o-tolyl) -2-butanone in 15.2 g of formamide was heated to 200 ° C. for 20 hours. After adding 25 ml of 30% sodium hydroxide solution, the mixture became Heated under reflux for 12 hours. An equal volume of water was added and the solution was extracted with ether. The ether layer was separated off and extracted with 2 η hydrochloric acid. The extracts were made alkaline with sodium hydroxide solution and extracted with ether. The ether layer was separated with

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Dried sodium sulfate and evaporated. The residue was distilled at about 150 ° C / 0.6 mm to give 2.05 g of the crude Base. The product was treated with anhydrous hydrochloric acid in ether and the resulting crude semi-crystalline The hydrochloride salt was recrystallized twice from aqueous ethanol-isopropyl ether. Yield 1.5g (13%), m.p. = 2219.5 bis 223 ° C.

Pharmacological experiments

It is not possible to use experimental means in laboratory animals Induce depression. In order to evaluate a possible antidepressant effect of new substances, must biochemical-pharmacological test methods are used. Such a method that bodes well for potential The test substances seem to give antidepressant effects in Europ. J. Pharmacol. 17, page 107, 1972. This method consists of measuring the potentiation of those produced by 5-hydroxytryptophan (5-HTP} in a laboratory animal Syndromes.

The lack of euphoric effects, i.e. the lack of centrally stimulating effects Activity is determined by measuring the motor activity in mice after administration of the test substance.

Potential anxiolytic activity is measured by measuring anti-aggressiveness determined in isolated mice after administration of the test substance. This test is used as the reference substance not amphetamine, but Valium ^, a well-known anti-anxiety agent Substance, used.

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5-HTP potentiation test

Inhibiting the uptake of 5-HT potentiates the effects of administered 5-hydroxytryptophan (5-HTP) likely by increasing the amount of 5-HT at the receptor. Obtained three mice the test substances 1 hour (or 4 and 24 hours) before the administration of dl-5-HTP, 90 mg / kg intravenously. 5-HTP alone only gives a weak behavioral syndrome, but gets a characteristic behavioral syndrome that occurs within 5 minutes in pretreated mice: tremor, Lordosis, muscle movement of the hind legs, head wobbling.

The absence or presence of the syndrome in question is recorded in groups of 10 mice. The compound was administered in at least 5 doses, and that quantitative response was assessed by best analysis and EDj. - Determination according to the method of Litchfield and Wilcoxon analyzed.

Motor activity in mice

The exploratory activity in mice was recorded in a movement cage, in which the movements in each case then were counted when the animals completed an electrical circuit in the base plate. The activity was 10 minutes recorded for 1 hour after administration of the agent. The animals were tested individually. Groups of 6 mice were used and the mice were used only once. The activity was as a percentage of the activity and at the same time running control groups expressed. The compounds were administered in at least four positions. The increase (+)

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or decrease (-) in activity compared to control groups were determined from logarithmic dose response curves.

Aggressive behavior in mice ■

Male mice kept in isolation for three weeks or more develop aggressive behavior when together be locked in a cage. The method used follows that of Valzelli et al (Europ. J. Pharmacol. 2, Page 144, 1967), with the exception that two mice were tested at a time. The aggressiveness was during 5 minutes;

recorded according to the following scheme: i

O The animals show no interest in one another with the exception of;

casual sniffing. ·

25 Frequent, violent sniffing and swan-slapping, which I re take a fighting stance and intervene which occasionally, but not more than 3 to 4 times in

5 minutes.
50 Swan hit, violent attacks, but not more than

10 times in the test period.
75 The animals follow their partners, attacking them during the

most of the time and bite them.
100 attacks during the entire time.

Control animals were tested with the solvent administered, but repeated testing affected aggressiveness not. The animals were used in several experiments, but at least one week apart. There were Groups of 10 mice used.

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The ED ₁ - value is the dose that reduces aggressiveness by 50%. .

Tabel Pharmacological effects

link
1

R ² R ³

Valium
amphetamine
p-aminoamphetamine p-chloramphetamine

H 3-Cl CH ₃ CH ₃
H 3 -CH ₃ CH ₃ CH ₃

Motor activity

Potentiation vity, + = stiff anti-aggression

of 5-HTP irritation, - = averse behavior

ED50 / mg / kg, would take, 0 = none in mice

ip effect

11.5 0.8

1.6 2.0

ED _{5 0} mg / kg, ip 2.5

5-10 0.3 3.4

x) not tested due to motor disorder.

As can be seen from the test values in the table, the tested substance according to the invention differs in its activity essentially of amphetamine, both qualitatively and quantitatively. In contrast to amphetamine, the tested one potentiates Compound according to the invention strongly the 5-HTP response.

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In addition, the tested compound shows no central stimulation, which occurs strongly after amphetamine and p-chloramphetamine. So, the potential antidepressant activity that can arise by the potentiation of 5-HTP and the lack of a centrally stimulating activity shows the compounds according to the invention Lending value as a potential antidepressant agent.

The compound tested antagonizes the aggressive behavior of male mice kept in isolation for a month or more became. The compound is almost as effective as Valium in this test, which can indicate that the compound is therapeutic May have value as an anxiolytic or anxiolytic compound.

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Claims (6)

- 21 - Claims . j 3-phenyl-sec-butylamine derivatives of the general formula CH ₃
CH ₂ CH ₂ -CH-NH ₂ 1 2 where R and R are the same or different and mean hydrogen atoms, low molecular weight alkyl groups or halogen atoms 3
th, R is a low molecular weight alkyl group or a benzyl group and R denotes a hydrogen atom, a low molecular weight alkyl group or a benzyl group, where R and / or R means a low molecular weight alkyl group or a halogen atom 3 4 th when R and R are a methyl group, and their pharmaceutical compatible salts. 2. 3-phenyl-sec-butylamine derivatives according to claim 1 of the general formula CH 603837/0994 wherein R is a methyl group or a halogen atom, and their pharmaceutically acceptable salts. 3. 3-phenyl-sec-butylamine derivative of the formula and their pharmaceutically acceptable salts. 4. 3-phenyl-sec-butylamine derivatives according to claim 1 to 3 in the Form of an essentially pure stereoisomer. 5. Process for the preparation of 3-phenyl-sec-butylamine derivatives according to claim 1 to 4, characterized in that one a) a compound of the general formula CH, OH R. ₁ AC = NI wherein R ¹ , R ² , R ³ and R have the above meaning and A is the group -CH ₂ CH ₂ - or -CH = CH-, reduced or b) a ketone of the general formula 809837/099 CH, CH ₂ CH ₂ -CO ^ 1 O * 3 A wherein R, R, R and R have the above meaning, with Formamide, ammonium formate or formamide and formic acid, heated und.so, optionally via an N-formyl derivative of Amine, compounds of the formula I wins or c) a compound of the general formula CH 12 3 4 wherein R, R, R and R have the above meaning, with Reacts ammonia in the presence of a catalyst or d) a compound of the general formula R ' 609837/0994 3 4 1 wherein R and R have the above meaning and R and / or R are hydrogen atoms, forming a compound 1 2 Preparation of the formula I ₁ in which R and / or R are halogen atoms ", halogenated and optionally those obtained by one of methods a) to d) Converting compounds into their pharmaceutically acceptable salts and / or their substantially pure stereoisomers. 6. Medicaments containing at least one 3-phenyl-sec-butylamine derivative according to claim 1 to 4, preferably in connection with einarä ph ^ -τ :. ": ξ cu ti sch compatible carrier material. 609837/0994