IE43129B1 - 3-phenyl-sec-butylamine derivatives - Google Patents

Abstract

3-Phenyl-sec-butylamine derivatives of the formula I in which R<1> and R<2>, which are identical or different, are hydrogen, an alkyl group with 1 to 5 carbon atoms or a halogen atom, R<3> is an alkyl group with 1 to 5 carbon atoms or the benzyl group, R<4> is hydrogen, an alkyl group with 1 to 5 carbon atoms or the benzyl group, where R<1> and/or R<2> are an alkyl group with 1 to 5 carbon atoms or a halogen atom when R<3> and R<4> are the methyl group, are valuable antidepressants which have a lower euphoric or central stimulant effect than amphetamine; they are also valuable agents for eliminating anxiety states. They are prepared by reducing a compound of the formula II in which A is -CH2-CH2- or -CH=CH-.

Description

This invention relates to new 3-phenyl-secbutylamine derivatives and to methods for their preparation ‘as well as to new intermediates useful for the preparation of the 3-phenyl-sec-butylamine derivatives The invention also relates to the preparation of pharmaceutical preparations Containing the 3-phenyl-secbutylamine derivatives and to the methods for their pharmacological use.

Depressive disorders have been treated with 10 various compounds with varying success. Many types of chemical substances have been used, among these amphetamine with the structure However, the euphoria and the risk of dependence have .5 to a great extent restricted the use of amphetamine in therapy.

The medical use of amphetamine is nowadays mainly restricted to the treatment of narcolepsy and asthenic states in aged people.

It has now boon found according to the present invention that by a proper modification of tho amphetamine molecule the euphoric or central stimulant effect of the substance can be diminished or completely abolished. The pharmacological profile of the compounds of the invention suggests a potential value of the compounds as antidepressants and also as a new type of anxiolytics.

Tiie present invention provides compounds of the formula and pharmaceutically acceptable salts thereof, in which 1 2 formula R and R are the same or different and each represents a hydrogen atom, a lower alkyl group or a halogen atom, R represents a lower alkyl group or a benzyl group, and R^ represents a hydrogen atom, a lower alkyl group or a benzyl 1 2 group, provided that R and/or R represents a lower alkyl group or a halogen atom when R3 and r'1 both represent a methyl group. 2 R and R may be situated at any free position on the phenyl nucleus.

Illustrative examples of radicals included in the above definitions are lower alkyl group: methyl, ethyl, n-propyl and isopropyl halogen atom: chlorine, bromine, iodine and fluorine.

The expression lower alkyl group in this specification means alkyl groups with 1 to 5 carbon atoms, inclusive. - 3 13129 The new compounds of this invention may he used therapeutically as the racemic mixtures of (+)- and (-)forms, which are obtained by synthesis. They may also be resolved into, the corresponding optically active isomers 5 which, likewise, may be used in therapy. The compounds of this invention may be administered in the form of free bases or their salts with non-toxic acids. Examples of these salts are the hydrobromide, hydrochloride, phosphate, sulphate, citrate and. tartrate.

In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, sulphate or sulphamate in association with a pharmaceutically acceptable carrier. Accordingly, terms relating to the novel compounds of this invention whether generically or specifically are intended to include 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. in the specific Examples would be inconsistent with the broad concept. The carrier may for example, be a solid, seffii-solid or liquid diluent or capsule. These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will constitute 0.1 to 99% by weight of the preparation, more specifically 0.5 to 20% by weight for preparations intended for injection and 2 to 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for - 4 30 3129 oral application, the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, com starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol waxes, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum or titanium dioxide. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to distinguish between tablets containing different active substances or different amounts of the active compound.

For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatine and for example, glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatine capsules may contain granulates of the active substance in combination with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.

Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil. 3129 Liquid preparations for oral application may be in the form of syrups or suspensions for example, solutions containing from 0.2% to 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol. Optionally, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.

Solutions for parenteral application by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from 0.5% to 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

Suitable peroral doses of the compounds of the invention are 2 to 20 mg, preferably 5 to 15 mg given 1 to 3 times a day, preferably 2 times a day.

Preferred compounds of the invention have the formula in which R^ is methyl or halogen, particularly chlorine.

Preferably these compounds are of their dihydrochloride salt. prepared and used in the form The compounds of the present invention may, for 25 example be prepared by one of the following methods: Reduction of a compound of the formula II wherein r\ R2, R3 and R^ are as previously defined, and A is or -CH=CH- to form a compound of the formula I.

The reduction can suitably be effected by catalytic hydrogenation, using a metal catalyst such as Raney nickel or palladium on charcoal. The reaction is conducted in a suitable solvent e.g. methanol or acetic acid preferably in the presence of a mineral acid. If the reaction mixture becomes sluggish, additional catalyst may be introduced thereinto. When no more hydrogen is absorbed the catalyst is removed by filtration, and the filtrate is concentrated. The residue is recrystallized from a suitable solvent.

B. Heating a ketone of the formula CHn ch2-ch2-c-owherein R , R , RJ and R4 are as previously defined with formamide, ammonium formate or formamide and formic acid according to the Leuckart reaction to form a compound of - 7 43139 the formula I. In case the product obtained is a N-formyl derivative of the amine, hydrolysis will yield the compound of the formula I.

C. Reductive amination of a ketone of the formula CH ,1 ch2-ch2-c=o wherein R3-, R2, R3 and d are as previously defined with ammonia in the presence of a catalyst (e.g. a metal catalyst) to form a compound of the formula I.

D. Direct halogenation of a compound of the formula wherein R3 and R^ are as previously defined and either R3- or 2 R or both are hydrogen, to form a compound of the formula 12 I wherein R or R or both are a halogen atom.

Por the preparation of the compounds of the formula X it has been found that a compound of the formula CH.

II 43123 in which A is -CH2CH2- or -CH=CH- and R^, R2, Rg and R^ are as defined in formula I is a valuable starting material.

The preparation of the oxime of formula II is 5 suitably effected by treating a ketone of the formula wherein A, R1, R2, R3 and R^ are as defined above, with a hydroxylamine salt according to known procedures. The reaction is suitably performed at elevated temperatures in a suitable solvent, e.g. ethanol or acetic acid and preferably in the presence of sodium acetate.

The ketones of the formula III are suitably prepared as outlined below: The formylation of the substituted aniline according to the Vilsmeyer-Haack reaction gives in a first step the corresponding aldehyde. The formylation is effected by using a mixture of dimethylformamide and phosphorus oxychloride^ Alternatively the preparation is achieved by using a mixture of phosphorus tribromide and dimethylformamide (see Acta Pharm.Suecica 7., 87, 1970).

The procedure involving the condensation of the aldehyde with acetone in a second step gives the intermediate benzylidenoacetqne. The condensation is performed in a suitable solvent or with excess of acetone, in the presence of a base e.g. sodium hydroxide. in a third step the benzylideneacetone is subjected to catalytic hydrogenation to yield a 4-phenyl15 2-butanone. The catalytic hydrogenation is performed using a metal catalyst such as platinum. The reaction is conducted, in a suitable solvent, e.g. ethyl acetate and ethanol.

The following Examples serve to illustrate the invention.

Preparation of - starting materials Experiment 1. 4-Dimethvlamino-2-chlorobenzalacetone oxime (a) 4-Dimethylamino-2-chlorobenzylideneacetone To a-solution of 50 g of 2-chloro-4~dimethylamino25 benzaldehyde in 200 ml of acetone was added dropwise 75 ml of 10% NaOH solution. The mixture was stirred overnight at room temperature and then poured on 1.5 1 of iced water. The resulting precipitate was collected by suction filtration and air-dried.

Yield 62.5 g. M.p. 70 to 75°C. Recrystallization from dimethylformamide-water yields 39.5 g. (65%). M.p. 80 to 81°C. -10 43139 Analysis. Calculated for C^IL^CINO: C C/+.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 mole) of 4-dimethylamino-2-chlorobenzalacetone, 18 g of CII^COONa · 3H2O and 7.2 g hydroxylamine hydrochloride in 250 ml of abs. ethanol was refluxed for 4 hours. The mixture was then poured in 1 litre of iced water. The resulting precipitate was collected by suction filtration 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 17.5 g (73%). Calculated equivalent weight 238.73. Found equivalent weight 239.

Analysis. Calculated for C-^H^^OCl: C 60.37, H 6.33, N 11.73, O 6.70, Cl 14.85. Found: C 60.3, H 6.37, N 11.5, 6.98, Cl 15.1.

Experiment 2. 4-Dimethylamino-2-methylbenzylideneacetone oxime (a) 4-Dimethylamino-2-methylbenzylideneacetone To a solution of 32.7 g of 4-dimethylamino-2methylbenzaldehyde in 135 ml of acetone was added dropwise while stirring 49 ml of 10% NaOH solution. The mixture was stirred overnight at room temperature and then poured into 1,5 1 of iced water. The resulting precipitate was collected by filtration, washed with ice water and airdried.

Yield: 38.6 g (95%). M.p. 65 to 75°C.

Recrystallization from ligroin-ethanol yielded 22.4 g. of the product (55%). M.p. 77 to 79°C.

Analysis. Calculated for C13H NO: 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-methylbenzylideneacetone oxime A mixture of 4.1 g of 4-dimethylamino-2-methylbenzylideneacetone, 1.44 g of hydroxylamine hydrochloride and 3.72 g of sodium acetate trihydrate in 50 ml of ethanol was refluxed for 7 h. Hie mixture was then poured into 1 litre of iced water. The resulting precipitate was filtered off and dried.

Yield: 2.8 g (64%). M.p. 155 to 157°C.

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

Analysis. Calculated for α^Ιί^θΝ^Ο: C 71.58, H 8.31, N 12.84, O 7.33. Found: C 71.20, H 8.25, N 12.6, 0 7.7.

Experiment 3. 4-(4-Dimeth-ylamino-o-totyl)-2-butanone A solution of 10.15 g of 4-dimethylamino~2methylbenzylideneacetone 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 residual oil was distilled at 114 to 123°/0.3 mm, yielding 7.1 g (69%) of the compound.

Neut. equiv. (determined by potentiometric titration with perchloric acid in acetic acid). Calc. Cj^H^gNO: 205.30. Found 205.

Experiment 4. 4-{Dimethylamino-o-totyl)-2-bUtanone oxime A mixture of 8.24 g of 4-(dimethylamino-o-totyl)butanone, 2.88 g of hydroxylamine hydrochloride and 7.44 g - 12 43129 of sodium acetate trihydrate in 100 ml of ethanol was refluxed for 5 hr. The mixture was then poured into 1 litre of iced water and left overnight at 0°C. The resulting precipitate was filtered off and dried.

Yield: 4.9 g (56%). M.p. 83 to 90°C.

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

Analysis. Calculated for ci3H20N2^: C ^0-87, H 9.15, N 12.72, 0 7.26.

Found: C 70.87, H 9.3, N 12.4, O 7.0.

Preparation of end compounds Example 1. 4-(3-Aminobutyl)-3-chloro-N,N-dimethylaniline dihydrochloride. Method A.

A solution of 4.8 g (0.02 mole) of 4-dimethylamino2-chlorobenzalacetone oxime in 150 ml of acetic acid and 4 ml of concentrated HCl was hydrogenated with t^/Pd-C 5% at room temperature and normal pressure. The consumption of H2 stopped at 900 ml (2.5 hours). The catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from ethanol-ether. M.p. 200 to 202°C. (decomposition). Yield 1.2 g (20%). The product was recrystallized from ethanol-isopropylether. M.p. 204 to 205°C (decomposition). Yield 0.8 g. A further recrystallization yielded 0.5 g of the product. M.p. 206 to 207°C (decomposition).

Analysis. Calculated for C^H-^gCl^ · 2HC1: C 48.09, H 7.06, Cl- 23.66, Cl+Cl- 35.49, W 9.35.

Found: C 48.2, II 7.77, Cl- 23.4, Cl+Cl- 34.9, H 9.14.

Example 2. 4-(3-Aminobutyl)-H,N-dimethyl-m-toluidine dihydrochloride. Method A, A solution of 10.92 g of 4-dimethylamino-2- 13 3129 methylbenzylideneacetone oxime in 200 ml of acetic acid and 8 ml of concentrated hydrochloric acid was hydrogenated in presence of 2 g Pd-C 10% at room temperature and normal pressure. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 200 ml of water and the solution was extracted with ether and evaporated. The residue was recrystallized from aqueous ethanol-isopropylether.

Yield: 6.7 g (48%). M.p. 220.5 to 222.5°C.

A further recrystallization yielded 3.6 g of the product melting at 227 to 228°C.

Analysis. Calculated for C^H N2 · 2HC1: C 55.91, H 8.66, N 10.03, Cl 25.39. Found C 55.6, II 8.6, N 9.8, Cl 25.0, Example 3. 4-(3-Aminobutyl)-N,N-dimethyl-m-toluidine dihydrochloride. Method B.

A solution of 8.21 g of 4-(4-dimethylamino-otolyl)-2-butanone in 15.2 g of formamide was heated at 200°C for 20 h. After the addition of 25 ml of 30% NaOH solution ' the mixture was refluxed.for 12 h. An equal volume of water was added and the solution was extracted with ether. The ether layer was separated and extracted with 2 N hydrochloric acid. The extracts were alkalized with sodium hydroxide solution and extracted with ether. The ether layer was separatedj dried with sodium sulphate and evaporated. The residue was distilled at about 150°/0.6 mm yielding 2.05 g of the crude base. The product was treated with anhydrous hydrogen chloride in ether and the resulting crude, semicrystalline hydrochloride salt was recrystallized twice from aqueous ethanol-isopropylether.

Yield: 1.5 g (13%). M.p. 219.5 to 223°C. “14 Pharmacological tests It is not possible by experimental means to induce depressions in laboratory animals. In order to evaluate a possible antidepressive effect of new substances biochemical-pharmacological test methods must be resorted to. One such method, which seems to give a good indication of the potential antidepressive effects of the test substances, is described in Europ. J. Pharmacol. 17, 107, 1972. This method involves the measurement of the potentiation of the syndromes produced by 5-hydroxytryptophan (5-HTP) in a laboratory animal.

The lack of euphoric effects, that is lack of central stimulatory activity, is tested by measuring the motor activity in mice after administration of the test substance.

Potential anxiolytic activity is tested by measuring the antiaggressivity in isolated mice after administration of the test substance. In this test not amphetamine but valium - a well-known anxiolytic substance is used as a reference.

-HTP response potentiation test Inhibition of the uptake of 5-HT potentiates the effects of administered 5-hydroxytryptophan (5-HTP) probably by increasing the amount of 5-HT at the receptor. Three mice are given the test drugs one hour (or 4, 24 hours) before dl-5-HTP, 90 mg/kg i.v. 5-HTP alone gives only a weak behavioural syndrome but in pretreated mice there is seen a characteristic behavioural syndrome, which comes within five minutes.: tremor, lordosis, abduction of the hindlegs, head-twitches.

The absence or presence of each respective 13139 syndrome is scored in groups of ten mice. The compound was administered in at least five doses and the quantal responses were analysed by probit analysis and ED^q determined according to the method of Litchfield and Wilcoxon.

Motor activity in mice The exploratory activity of mice was recorded ih a locomotion cage in which the movements Were counted each time the animals cross-circuit an electrical current in the bottom plate. The activity was recorded for ten minutes one hour after the administration of the drug.

The animals were tested individually. Groups of six mice were used and the mice were only used once. The activity was expressed in per cent of the activity of control groups run simultaneously. The compounds were administered in at least four doses. The increase (+) or decrease (-) of the activity compared to control groups was determined from log dose response curves.

Aggressive behaviour in mice Male mice kept isolated for 3 weeks or longer develop an aggressive behaviour when caged together. The method used follows that of Valzelli et al. (Europ. J. Pharmacol. 2, 144, 1967); with the exception that 2 mice were tested on each other. The aggressiveness Was scored during a 5 min. test according to the following schedule; O the animals show ro interest in each other except occasional nosing frequent vigorous nosing and tail rattling, the animals assume a fighting position and occasionally attack each other - no more than 3 to 4 times in the 5 min. period 312 9 tail rattling, powerful attacks - no more than 10 times in the test period the animals follow their partners, attacking and biting for most of the time 100 attacks over the entire period.

Controls administered with the solvent were tested. The repeated testing had no influence on the aggressiveness. The animals were used for several experiments but with intervals of at least one week.

Groups of 10 mice were used.

EDgg is the dose which reduces the aggressiveness score by 50%.

Table Pharmacological effects Compound Potentiation of 1 2 3 4 5-HTP R R R R ED50 mgAg i.p. Motor activity Antiaggressive behaviour in mice EDg0 mg/kg i.p. + 0 = increase = decrease = no effect Valium 2.5 Amphetamine >5 +++ X p-Aminoamphetamine 11.5 5-10 p-Chloroamphetamine 0.8 ++ 0.3 H 3-C1 CH3 CH3 1.6 0 3.4 H 3-CH, CH, CH, 2.0 3 3 3 x not tested, due to interference with motor activity. 312 9 As can be seen from the test values of the Table, the tested substance of the invention differs considerably in activity from amphetamine both qualitatively and quantitatively. In contrast to amphetamine the tested compound of the invention strongly potentiates the 5-HTP response. Furthermore the tested compound lacks the central stimulation which is pronounced after amphetamine and p-chloroamphetamine administration. Thus the potential antidepressive activity as indicated by the potentiation of 5-HTP and the lack of central stimulatory activity may give the compounds of this invention value as potential antidepressive agents.

The tested compound of the invention antagonizes the aggressive behaviour of male mice which have been kept isolated for one month or more. The Compound is almost as active as Valium in this test which may indicate that the compound may have, therapeutic value as an anxiolytic compound.

Claims (15)

1. CLAIMS:1. A compound of formula: 1 2 in which R and R are the same or different and each 5 represents hydrogen, lower alkyl or halogen, R represents A lower alkyl or benzyl, and R represents hydrogen, 1 2 lower alkyl or benzyl, provided that R and/or R 3 A represents lower alkyl or halogen when R J and κ both represent methyl; or a pharmaceutically acceptable salt 10 thereof.

2. A compound according to claim 1, of formula: CH 3 ch 3 in which R 3- is methyl or halogen; or a pharmaceutically 15 acceptable salt thereof. 19 13129 A compound according to claim 1, of formula; / \ CH 3 CH 3 or a pharmaceutically acceptable salt thereof.

3. 4. A compound according to any one of claims

4. 5 1 to 3 in the form of a substantially pure stereoisomer. 5. 4-(3-Aminobutyl)-3-chloro-N,N-dimethylaniline dihydrochloride.

5. 6. 4-(3-Aminobutyl)-N,N-dimethyl-m-toluidine dihydrochloride . .0 7. A process for the preparation of a compound according to claim 1, which comprises reducing a compound of formula: 4 3129 12 3 4 wherein R , R , R and R are as defined in claim 1, and A is-CH 2 CH£ or -CH=CH~. 8. A process for the preparation of a compound according to claim 1, which comprises heating a ketone of 5 formula:

6. 7 H 3 rF ^r^ wherein r 1 , r^, r/ anc j R 4 are as £ n c i a i m i ( with formamide, ammonium formate or formamide and formic acid, optionally via a N-formyl derivative of the amine.

7. 10 9. A process for the preparation of a compound - according to claim 1, which comprises reductively aminating a compound of formula: N p?/ X 4 12 3 4 wherein R , R , R and R are as defined in claim 1, 15 with ammonia in the presence of a catalyst. - 21 4 312 9 10. A process for the preparation of a compound according 3 4 to claim 1, m which R and R are as defined in claim 1 and 1 2 R or R or both arc halogen, which comprises halogenating a compound of formula: or R or both are hydrogen.

8. 11. A process according to any one of claims 7 to 10, wherein the compound of formula I is converted into a pharmaceutically acceptable salt thereof and/or converted into a substantially pure stereoisomer thereof.

9. 12. A process according to any one of claims 7 to 11, substantially as hereinbefore described.

10. 13. A process according to claim 7 substantially as described in Example 1 or 2.

11. 14. A process according to claim 8 substantially as described in Example 3.

12. 15. A compound of formula I according to claim 1, whenever prepared by a process as claimed in any one of claims 7 to 14.

13. 16. A pharmaceutical preparation which comprises as active ingredient a therapeutically effective amount of at least one 4 3129 compound of formula I as claimed in any one of claims 1 to 6 and 15, in association with a pharmaceutically acceptable carrier.

14. 17. A pharmaceutical preparation according to claim 16, substantially as hereinbefore described.

15. 18. A method for the treatment of depression or alleviation of anxiety in mammals excluding humans, which comprises administering to a host suffering from such ailment a therapeutically acceptable amount of a compound of formula I as claimed in any one of claims 1 to 6 and 15, or a pharmaceutical preparation as claimed in claim 16 or 17.