NEW PSYCHOSTIMULANT AGENT

Abstract: Pharmaceutical composition comprising as active ingredient a compound of general Formula (I), wherein R<1> stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; phenyl alkyl having 7 to 10 carbon atoms; phenyl; or cycloalkyl comprising 3 to 8 carbon atoms; R<2> stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms, alkyl comprising 1 to 8 carbon atoms substituted by halogen, hydroxy, alkoxy having 1 to 4 carbon atoms or by one or two phenyl groups; phenyl; or cycloalkyl having 3 to 8 carbon atoms, with the proviso that groups R<1> and R<2> together contain at least three carbon atoms. The invention also relates to a process for the preparation of compounds of the general Formula (I) by methods known per se. The compounds of the general Formula (I) are psychostimulants having a new spectrum of effect which can be used in therapy for increasing psychical activity (learning and retention) and for treating clinical patterns of depression and deficites of learning and retention like in Alzheimer's disease, and are void of side effects (e.g. due to catecholamine release) of known stimulants.

Description: _ _ NEW PSYCHOSTIMULANT AGENT This invention relates to pharmaceutical compositions stimulating the central nervous system and having a new spectrum of activity, new phenyl alkyl amine derivatives which can be -used as active ingredient in said pharmaceutical compositions, a process for the preparation of the ' said active ingreαients and pharmaceutical compositions and the use of the said new phenyl alkyl amine derivatives and pharmaceutical com¬ positions comprising the same for stimulating the central nervous system. The pharmaceutical compositions of the present invention exhibit their activity in the organism mainly by inhibiting the nεuronal uptake of biogenic amines. It is known that the most ipocrtaπt dose-deoeπdant affect of zr.e so-called indirectly act:-.:: sympathomimεtic amines celcngiπg chemically to the clβss of rreπyl-alkylamines e.g. the endogenous phenyl ethylamiπe (PEA) 3-._ tyramiπe/ resides in tπe release of cate ' cholamines - first of all that of ncradrsπaline - from tr.e plas atic stores of the neurons. Other non-endogenous αheπyi alkyl amines (e.g. amphetamine and -netampnetamine) possess similar properties. Voreover, the πoracreπaline releasing effect and - depending on the dose - " that of other transmitter amines (e.g. sεrotoniπe) is strong and long lasting for .retabolic reasons. r'etamphetamine, also inhibits the neurcπal uptake of iπcirectly acti ~ g endogeπic syrrpathomimetic amines to a significant extent, but this effect is completely supressed by noradrenaliπe release uncer in vivo conditions. The present invention is basso on the reeogπition that in the class of phenyl alkylamines a suitable modification of the chεπical structure can completely ei iπatε the known charac- teristic and dominant effect of the said compound group - namely the effect inducing the outflow of transmitter amines - and, on the other hand, it can strengthen a hitherto subordinated effect of the said compound group (namely the inhibition of πeuronal uptake of sympathomi etic amines) in a selective manner. Thus stimulants having a new spectrum of activity can be- obtained. According to the present invention there are provided biologically active phenyl alkylamines of the general Formula I, salts thereof, processes for the preparation of the said cαm- αouπds, pharmaceutical compositions comprising as active ingredi¬ ent the said compounds or salts thereof and the. use of the said cαrπocunds or pharmaceutical compositions comprising the same. In the present specification the substitueπt definition of the general Formulae is as follows: , ? - stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; phenyl alkyl having- 7 to 10 carbon atoms; ohεnyl; or cycloalkyl comprising 3 to 3 carbon atoms; ^ stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; alkyl comprising 1 to 8 carbon atoms substituted by halogen, nycroxy, alkoxy having 1 to 4 carbon atoms or by one cr two p enyl groups; phenyl; or cycloalkyl having 3 to 6 careen atoms, with the proviso that groups R^- and R^ together contain at least three carbon atoms ; R- stands for straight or braπcned chain alkyl comprising 2 to 8 carbon atoms; phenyl alkyl having 7 to 10 carbon atoms; pnenyl; or cycloalkyl comprising 3 to 8 carbon atoms; and R " stands for straight or. braπcnεd chain alkyl comprising 1 to 8 carbon atoms; alkyl having- 1 to 8 carbon atoms substituted by πalogen, hydroxy, alkoxy having 1 to 4 carbon atoms or by one or two phenyl groups; phenyl; or cycloalkyl having 3 to 8 carbon atoms; provided that R- 5 and R* together contain at least 5 carbon atoms; with the proviso that if R- 3 stands for methyl, R^ is other than benzyl; and with the further proviso that if R- 5 stands for ethyl, R 4 is other than isobutyl. A and B stand for groups which are capable of forming a -NH-R 2 group when reacting with each other or comprise said group; X stands for halogen or a sulfoπic acid ester group. According to a further aspect of the present invention there is provided a process for the preparation of compounds of the general Formula I and salts thereof which comprises re¬ acting a compound of the general Formula II with a compound of the general Formula III (in which Formulae R-*- and R 2 are as stated above and A and B stand for groups which are either capable of forming a -NH-R 2 group when reacting with each other or comprise the* said group) 'and thereafter if desired con¬ verting the compound of the general Formula I into a salt formed with an organic or inorganic acid and/or setting free a compound of the general Formula I from a salt and if desired finishing a compound of the general Formula I or a salt thereof in the form of a pharmaceutical composition by methods known per se. Thus the compounds of the general Formula I can be prεared by reacting a ketone of the general Formula IV with an amiπe of the general Formula V and reducing the ketimine intermediate formed without or after isolation. The reduction can be carried out by methods known per se, e.g. by catalytic hydrogeπation (preferably in the presence of a palladium or Raney-πikkel catalyst) or by using a complex metal hydride (e.g. sodium hydrido borate) or with the aid of a conventional chemical reducing agent (e.g. sodium dithioπite or amalgamated aluminium) . According to a further form of realization of the process of the present invention a compound of the general Formula VII is reacted with an alkylating agent of the general Formula VI, or an amine of the general Formula V is alkylatεd with a compond of the general Formula VIII. The said reactions can preferably be carried out in the presence of an acid binding agent. For this purpose an excess of the amine starting material may serve or an organic or inorganic base (e.g. triethyl amine or potassium carbonate) or a basic ion-exchanging resin can be used. The compounds of the general Formula XI can be prepared by ethylatiπg a compound of the general Formula VII by reacting the same with formaldehyde and formic acid. Th compounds of the general Formula I prepared by the process of the present invention are in the free base form lipoid-soluble oily substances which can be - if desired - con¬ verted into crystalline water-soluble salts. Salt formation can be carried out by using pharmaceutically acceptable inorganic or organic acids (e.g. hydrochloric acid, hydrobrαmic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, maleic acid etc). The compounds of the general Formula I can be set free from the acid addition salts by conventional methods. The compounds of the general Formula I and biologically acceptable acid addition salts thereof can be used as active ingredient in the preparation of human pharmaceutical compo¬ sition. According to a further aspect of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of the general Formula I or a pharmaceutically acceptable acid addition salt theref. According to a still further aspect of the present invention there is provided a process for the preparation of pharmaceutical compositions which comprises admixing a compound of the general Formula I or a pharmaceutically acceptable acid addition salt thereof with suitable inert pharmaceutical carriers. The said pharmaceutical compositions can be prepared by known methods of pharmaceutical- industry. The active ingredient can be finished in the conventional dosage forms (eg. tablets, pills, coated pills, dragees, capsules, injections etc). The said pharmaceutical compositions can comprise usual carriers, additives, sliding agents, fillers, auxiliary agents etc. The compounds of the general Formula I significantly inhibit the tyramiπe-inducsd noradreπaliπe release from the plas atic pores cf neurons by inhibiting the tyramine uptake. As opposed to known phenyl alkyla ines the compounds of the general Formula I do not exhibit a nciradrεπaline releasing effect. At the same time the compounds of the general Formula I strongly inhibit the neuronal uptake of noradreπaliπe and dopamine, considerably . increase the catecholaminergic activity, but - contrary to amphetamine and metamphεtamiπs - do not in¬ fluence serotoπergic activity even if administered at high doses. The compounds of tne general Formula I are stimulants of tπe central . πervcus system which show a stimulating effect in learning and anticeprassive pharmacological tests, increase ~otility and metabolism only to a moderate extent, exert no considerable aπorectic effect and are but sligπtly toxic. Contrary to a main group of known psychoeπergetic agents, the compounds of the general Formula I are void of MAO inhibiting activity and are - coπcεrπiπg their mechanism of activity and chemical structure - considerably different from known tricyclic antidepressants too. It can be declared on the basis of the aforesaid that the phenyl alkylamiπes of the general Formula I constitute a psycho- pharmacoπe group of a new mechanism of effect, being suitable for increasing psychical activity (learning, memory storing) and for the medical treatment of clinical patterns of depression as well as diseases with significant learning and memory deficits like Alzheimer's disease, presumably without exhibiting the side- effects of known stimulants which cause catecholamiπe release. Acording to a still further aspect of the present invention there is orcvided a method of treatment which comprises treating healthy or ill humans with a oharmacεutical compositicn containing an effective amount of a compound of the general Formula I or a pharmaceutically accεotacle acid addition salt tπsrscf. The preferred daily dose amounts tc from about 10 mg to aoout 150 mg, particularly to aocut 30 mg. The pharmaceutical compositions may be administered prεfsraoly orally, parentεrally or ay the subliπguar route. Due to their low tαxicity tie ccmDcuπds of the general Formula I can also be used in paediatrics, in a suitable trans— calculated dose. The -uitaDie veterinary cose amounts to 2-8 mg/ ' kg. Tnε compounds of tne general Formula IX form a sub-gro--p of the compounds of the general Formula I cεing new and πe'.sr disclosed in prior art. Examples without limiting the scocs of protection to tr.e said Examples. Chemical examples Example 1 To a solution of 16.2 g (0.1 mole) of beπzyl-propyl- ketoπe in 200 ml of methaπol 23.6 g (0.4 mole) of isαpropyl amine and 6 g of a 5 H palladium/charcoal catalyst are added and the reaction mixture is hydrogeπated under a pressure of 7-10 atm. under shaking. After the uptake of the calculated amount of hydrogen the reaction mixtrurε is filtered, the filtrate is evaporated and the residue dissolved in ethaπol comprising hydrochloric acid. The mixture is evaporated. The residual N-iso- propyl-l-pheπyl-2-peπtylamine-hydrochloride can be purified by recrystallizatioπ. Mp.: 136-139 °C. Example 2 To a solution of 16.2 g (0.1 mole) of beπzyl-propyl- kεtαne in 30 ml of methaπol a solution of 7.5 g (0.1 mole) of 3- propaπol-a iπe and 20 ml of methaπol is added. The mixture is allowed to stand, whereupon 1.9 g of sodium hydrido borate are added, the reaction mixture is allowed again to stand and then eveporated. The residue is taken up in water, extracted with ben¬ zene, the benzene solution is dried and evaporated. The residual crude N-(3-hydroxypropyl)-l-phenyl-2-peπtylamiπe is purified by distillation in vacua. Bp.: 100-110 °C/0.5 Hgmm, Π 20 Q = 1.5173. An etheral solution of the above base is acidified to pH 2 by adding an etheral oxalic acid solution. The precipitated oxalate is filtered and dried. Mp.: 144-146 °C (ethyl-acetate). Example 3 To a solution of 19.62 g (0.1 mole) of deoxy beπzoine in 130 ml methanol 7.B g (0.13 mole) pf n-propyl-amine and after standing for some hours 3.7B g (0.1 mole) of sodium hydrido borate are added. The reaction mixture is allowed to stand and thereafter evaporated. The residue is taken up in water and extracted with benzene. The benzene solution is acidified with 10 h hydrochloric acid under stirring. The precipitated crystalline N-propyl-l,2-dipheπyl-ethylamiπe-hydrochloride is filtered and dried. Mp. : 229-231 °C (ethanol-ether). Example 4 11.0 g (Q.06B mole) of beπzyl-propyl-ketoπe are dissolved in 110 ml of benzene, whereupon 8.0 g (0.135 mole) of π_-propyl- amine and 22.6 g (0.2 mole) of anhydrous calciium chloride are added to the solution. The reaction mixture is stirsd at 40-50 °C for 6 hours, then filtered and evaporated. The crude ketimiπe thus obtained is dissolved in 120 ml of methaπol, whereupon 6.4 g (.17 mole) of sodium hydrido borate are added. The reaction mixture Is allowed to stand , whereupon it is poured into 500 ml of water and extracted five times with 100 ml of benzene each. The benzene solution is dried and evaporated. The crude N-prαpyl- -l-phenyl-2-pentylamiπe thus obtained is purified by distillation in vacuo. B.p.: 112-120 °C/7 Hgmm, π 20 0 = 1.5030. The ethyl acetate solution of the above base is acidified by adding ethaπol containing hydrochloric acid. The precipitated hydrochloride is purified and dried. Mp.: 122-124 α C (ethanol- ether) . Example 5 14.82 g (0.1 mole) of benzyl-ethyl-ketoπe are dissolved in 100 ml of 96 ethanol. To the solution 12.12 g (0.1 mole) of 2-pheπyl-ethylamine are added, the mixture is stirred for half an hour, whereupon 3.5 g of amalgamated aluminium foils are added under stirring. The reaction mixture is stirred at 55 °C for 20 hours, filtered and evaporated. The crude N-(2-ρheπyl-ethyl)-l- pheπyl-2-butyl-amiπe thus obtained is purified by distillation in vacuo. Bp. : 171-173 °C/1 Hgmm, π 20 0 = 1.5471. 14.5 g of the above base are dissolved in 14.5 ml of an¬ hydrous ethaπol and the solution is acidified to pH 2 by adding ethaπol containing hydrochloric acid. To the clear solution 800 ml of ether are added in portions. The solution is cooled and the precipitated hydrochloride is filtered and dried. Mp.: 127-131 °C .(ethanol-ether). Example 6 To a solution of 21.03 g (0.1 mole) of 1,3-diphenyl- acεtαne in 140 ml of 96 % ethanol 11.8 g (0.2 mole) of rv- propyla iπe are added, the mixture is stirred for an hour, whereupon 3.5 g of amalgamated aluminium foils are added. The reaction mixture is stirred at 55 °C for 20 hours, filtered and evaporated. The residue is dissolved in benzene and acidified under stirring with 10 h hydrochloric acid. The precipitated crystalline N-propyl-1,3-dipheπyl-2-propylamiπe-hydrochloride is filtered and dried. Mp.: 174-176 °C (ethanol-ether). Example 7 To a solution of 29.6 g (0.2 mole) of benzyl-ethyl-ketoπe in 200 ml of 96 % ethanol 34 ml (0.5 mole) of propyl amine are added, the mixture is stirred for an hour, whereupon 6.75 g of amalgamated aluminium foils are added. The reaction mixture is stirred at 55 °C for 5 hours,, whereupon 60 ml of a 40 sodium hydroxide solution are added under stirring. The mixture is filtered and the filtrate is evaporated. The residue is taken up in benzene, washed with water and extracted with 150 ml of 10 % hydroxhloric acid. The acidic solution is made alkaline with a 40 % sodium hydroxide solution, extracted with benzene, the benzene solution is dried and evaporated. The residual N-prαpyl-1-phenyl- -2-butyl-amine is purified by distillation in vacuo. Bp.: 84-8B °C/0.5 Hgπrn, n 20 D = 1.4956. The above base is dissolved in ether and the solution is acidified by adding ethanol containing hydrochloric acid. The precipitated crystalline hydrochloride is filtered and dried, mp.: 98-100 °C (ethyl-acetate). Example B To a solution of 16.34 g (0.2 mole) of ethyl amine hydro¬ chloride in 90 ml of 96 % ethanol a solution of B g of sodium hydroxide and B ml of water is added dropwise. To the suspension thus obtained 13.42 g (0.1 mole) of benzyl methyl ketone are added under cooling, the mixture is stirred for an hour, whereupon 3.45 g of amalgamated aluminium foils are added. The reaction mixture is stirred at 40 °C for B hours,, then filtered and evaporated. The residue Is taken up in benzene and evaporated again. The crude product is dissolved in 14 ml of 96 % ethanol and acidified to pH 1 by adding ethaπol containing hydro¬ chloric acid. To the solution 100 ml of ether are added. The precipitated crystalline N-ethyl-l-phenyl-2-propylamine-hydrα- chloride is filtered and dried. Mp.: 148-149 °C (ethanol-ether). Example 9 To a solution of 67.5 g (0.5 mole) of l-pheπyl-2-propyl- a iπe in 340 ml of benzene 17.0 g (0.074 mole) of 2-methoxyethyl- tosylate (3. Org. Chem. 9_, 235 /1944/) are added. The reaction mixture is heated to boiling for 3 hours, and evaporated. The residue is taken up in benzene, extracted with 100 ml of a 10 % sodium hydroxide solution and washed with 700 ml of water. The benzene phase is dried and evaporated. The residual crude N-(2 -methoxyethyl)-l-phenyl-2-propyl-amiπe is purified by distilla¬ tion in vacuo. B.p.: 94-102 °C/8 Hg m, π 20 D = 1.5012. The etheral solution of the above base is acidified with ethanol containing hydrochloric acid. The precipitated crystalline hydrochloride is filtered and dried. M.p.: 115- 118 α C (acetone). Example 10 A mixture of 5 g of N-(3-hydroxypropyl)-l-phenyl-2- propyl-amine (prepared according to Example 2) and 20 ml of con¬ centrated hydrobromic acid is heated to boiling for 5 hours. The reaction mixture is evaporated and the residue is dehydrated three times with 25 ml of benzene each. The crude N-(3-bromo- propyl)-l-phenyl-2-prαpylamine-hydrobromide thus obtained is purified by recrystallizatiαn from ethyl acetate. M.p.: 94-96 °C. Examples 11-20 The following compounds enumerated in Table 1 are prepared in an aπaloguous manner to Examples 1-10. Tabl e 1 E x ample .20 0 B . p . P ecryst . No . ϋ Acid used M Λ C/Hcjmin for salt solvent transformation 11 C 2 H 5 C 2 H 5 HC1 145-147 ethanol-ether 12 C 2 H 5 C 6 H 11 137-140/1 1,5160 HC1 202-203 acetone-ethan 13 C 3 H 7 CH. 47-50/15 1,4203 HC1 125.5 ethanol-ether 14 C 4 H 9 C 3 H ? HC1 7B-B0 ethyl-acetate 15 C 4 H 9 CH(CH 3 )CH 2 C 6 H_ HC1 174-176 ethyl-acetate 16 C 6 H 13 C 3 H ? 118-126/0,2 (COQH), 118-120 ^-propanol 17 CH, C 6 H 5 176-180/9 HC1 155-157 ethanol-ether IB CM- (CH 2 ) 2 Br HBr 148-150 acetonitrile 19 Cll. C 4 H 9 -i 63-66/0,2 1,4915 HC1 128-130 acetone 20 CH- C 6 11 112-113/0,3 1,5178 HC1 216-218 ethanol-ether Iπ the following Examples the preparation of pharma¬ ceutical compositions comprising as active ingredient a compound of the general Formula I or IX, respectively, is described. As active ingredient the product of Example 4 is used, but any other compound of the general Formula I or IX may be applied as well. Example 21 Hard gelatine capsules having the following composition are prepared: Component Amount, mg/capsule N-propyl-l-phenyl-2-pentyl- amine-hydrochloride 30.0 Maize starch 67.0 Avicel 50.0 Lactose 50.0 Polyvinyl pyrrolidoπe 1.0 Talc 2.0 Total weight 200.0 The capsules are prepared as follows (for 1000 capsules) 30.0 g of the active ingredient are homogenized with 67.0 g of maize starch, 50 g of Avicel and 50 g of lactose. The homogeneous powder mixture is granulated with an alcoholic polyvinyl pyrrolidoπe solution on a sieve No. 18, dried and re- granulated on a sieve No. 24. After re-graπulation the talc is added and the granules thus obtained are filled into "Snap fit No. 1" - capsules either manually or on a machine. The capsules are made free of dust, polished and packed. Example 22 Suppositories having the following composition are prepared: Component Amount, mg/suppository N-propyl-l-phenyl-2- peπtylamiπe-hydrochloride 25.0 Massa Estariπum R C (1) 2975.0 Total weight 3000.0 The suppositories are prepared as follows (for 1000 suppositories): 2975 g of Massa Estarinurrr C are weighed in a duplicator adjusted to 39-40 Q C and melt. To the melt suppository mass 25 g of the active ingredient are added and stirred until it is completely dissolved (about 5-10 minutes). From the melt suppositories weighing 3.0 g are casted. After cooling the excess of the suppository mass is removed. The rεady-for-use suppositories are removed from the form and packed. (1) = Adeps solidus hartfett DAB (Dyπamit Nobel) Example 23 Dragees (coated pills) having the following composition are prepared: Component Amount mg/dragee core N-propyl-1-phenyl- -2- peπtylamiπe-hydrochloride 30 Maize starch 51 Lactose 82 Luviscol VA64 4 Steariπe 4 Avicel 25 Talc 4 Total weight : 200 The dragee core is prepared as follows: The active ingredient, the maize starch and the lactose are homogenized (mixture I). The Luviscol and steariπe are dis¬ solved in isopropaπol (solution II). The homogeneous powder mixture (I) is granulated with the isopropanol solution (II). The granules are driεd and rε- graπulated on a sieve No. 16. The Avicel and talc are added and homogenized. Dragee cores are prepared by using a convex dye having a diameter of 10 mm. The dragee core thus obtained can be coated with a syrup or film layer by conventional methods (e.g. E. Paπdula, G. Takacs. Industrial Pharmacy /Ipari Gydgysze- reszet/, Mediciπa, Budapest /1964/; H.A. Liebermaπ, L.Lachmaπn: Pharmaceutical dosage forms, Marcel Dekkar, Inc. N.Y. /1982/) Example 24 Tablets having the following composition are prepared: CαmDoπent Ai Tiount, mg/tablet N-propyl-l-phenyl-2- pentylamine-hydrochloride 30 Maize starch 29 Lactose 24 Maize starch 9 Gelatine alba 3 Talc 3 Magnesium stearate 2 Total weight: 100 The tablets are prepared as follows: The active ingredient, maize starch and lactose are sieved and homogenized, whereupon the mixture is granulated with an about 5 % aqueous gelatine solution. The granules are dried to a moisture content of 2 % and re-granulated on a sieve No. 18. To the granules as external phase the remaining part of maize starch, talc and magnesium stearate are added and from the mixture tablets are pressed by using a dye having a diameter of 8 mm. Example 5 Ampoules having the following composition are prepared: Component Amount N-propyl-l-phenyl-2- peπtylamiπe-hydrochloride 30.0 mg Sodium chloride 8.9 g Ammonium hydroxide solution 1.7 % q .3. Distilled water pro injection ad 1.00 ml The ampouls are prepared as folows (for 1000 a pouls). 30.0 g of the active ingredient and 8.9 g of sodium chloride are dissolved in 800 ml of distilled water suitable for injection purpQses. The pH of the solution is adjusted to 3.0- 8.0 by adding a 1.7 % ammonium hydroxide solution. The solution is filled up to 1000.0 ml with distilled water suitable for injection purposes. The microorganism content of the solution is decreased by means of bacteria filtration before filling to ampouls and sterilization. The filtered solution is immidiately filled into suitable ampouls which are thεπ sealed. The ampouls are sterilized. Further manufacture is carried out by conventional methods of pharmaceutical industry. II. Biological Examples II/l. Determination of noradrenaliπe releasing effect in cats (in vivo) The condition of the nictitating membrane of an anesthetized cat is continuously registered by the aid of an auxotoπic writing lever kymograph. Releases of πoradreπaliπe induce contractions of the the nictitating membrane in a oose- depeπdεπt manner. The i.p. administration PEA induces contrac¬ tions of the nictitating membrane which is transient in nature. Amphetamine and metamphetamiπe, however, cause contraction of long duration. In the above test the compounds of the general Formula I do not cause any contraction. (Method: 3.Knoll: ohαamine Oxic ' ase and Its Inhibition (Eds Wolstenπclme and Knight), Elsevier, 1976, page ' 131). II/2. Determination of αsvcπcsti ulaπt effect in rats a/ Modified jumping test ... Knoll and B. Knoll: Arch. Inc. °harmacodyn. J S, 200 (196^/). In this test small .ocsεs of amphεta inε (up ' o 1-2 - i g c) imprαvε while larer ccses cf amphetamine (aoαve 3 ""g '' v_) deteriorate learning and retention in a dαse-dspencenτ manner. The compounds of the general Formula I give rise to " an improvement of nεrformance at a αosε of 0.5-15 mg/ g in a ccse- cspenceπt ~ _..ιπsr. Thus tπe ew compounds are devoid of tne performance deteriorating effect characteristic of high doses of amphetamine due to an activation of the serotonergic system (doses above 10 mg/kg are considered to be very high). b/ Shuttle-box text (Method: B.Knoll, J. Knoll: Pol. _. Pharmacol. Pharm. 34.. 17-23 /1982/) According to this test the daily administration of 1 mg/kg s.c. dose of amphetamine significantly increases the acquizitiαn of a conditioned reaction and its retention during the five days of observation. The increase ' of performance is however accompanied by a disproportionately high intersignal re¬ action. The effect of higher amphetamine doses (5-10 mg/kg) can not be even evaluated in the shuttle-oox because of an extremely nigh general otility increasing effect. The daily administration of 0.5 τ.g./kg of the compound according to Example 4 gives rise to a significant increase of performance over the control without signs of increased general motility. Compound according to Example 4 increased learning and retentions from the very first day αuring the complete test- period, even when administered in an sxtremε high daily dose of 15 mg/kg. ..hersas the performance cf these animals is unusually efficient, the increase cf the intersignal reactions can be deemed as moderate, when ta.- ng into consideration t e extremely high performance. Animals treated with a σosε of 15 mg/kg of τne compound according -to Example 4 completely maintain the αerformancε acquired at the end of the one-week learning period even for 6 weeks after the termination of the treatment. According to the said tests the compounds of the present invention bring about an extremely high learning per¬ formance increasing effect, the said effect being very strong and broad but corresponding to an other mechanism than the activity of amphetamine. II/3 Determination of antagonism of tetrabeπazine-iπduced depression, in learning test, on rats a/ Jumping test. Method: 3. Knoll, B. Knoll: Arzπeimittel For- schung 8_, 339 (1958), 9_, 633 (1959). The solid conditioned reflex acquired on the jumping test can not be inhibited even with high doses of the compounds of the general Formula I (e.g. with a dose of 15 mg/kg of compound according to Example 7). The reflex can be completely inhibited only with high doses of tetrabenazine (5 mg/kg) while the depressive effect of tetrabenazine can be entirely antagonized by a dose of 15 mg/kg of the compound according to Example 7. b/ Shuttle-box test Method: B. Knoll, 3. Knoll: Pol. 3. Pharmacol. Pharm. 34, 17- 23 (1982). According to this test depression caused by tetrabenazine can be antagonized by the compounds of the geπεral Formula I. In Table 3 the numerical values of the series of test carried out by using the compound according to Example 7 are disclosed. Similar results are obtained when using the compounds according to Examples 4 and 14. Table 3 C = control (physiological sodium chloride solution, s.c, daily, N = 12); T = 0.5 mg/kg of tetrabenazine, s.c, daily N = 12; V = 0.5 mg/kg of tetrabenazine + 10 mg/kg of compound according to Example 7, s.c, daily, N = 12. Learning Response to stimulus F+ f+ f- IR 1st day C 29.67 51.67 18.67 9.25 £ 6.31 £ 6.62 £ 7.96 £ 2.39 T 9.58 31.25 59.17 10.25 £ 3.74 £ 9.20 £11.68 £ 2.45 V 34.60 49.80 16.40 10.50 - £ 7.00 £ 7.08 £ 10.18 £ 2.05 nd day c 53.33 25.25 21.42 11.00 £ 9.87 £ 6.01 £ 10.84 £ 2.51 T 8.50 30.75 60.75 8.33 ±3.68 £ 9.81 £ 11.81 £ 2.34 V 62.20 21.00 16.80 14.70 £ 11.39 £ 7.17 £ 11.45 £ 5.27 rd day c 58.25 31.17 10.58 13.33 £ 10.43 £ 8.35 £ 6.46 £ 4.00 T 11.42 15.83 72.75 4.67 £ 4.94 £ 6.14 £ 11.10 £ 1.23 V 69.20 9.80 21.00 21.30 £ 11.65 £ 3.17 £ 12.51 £ 7.50 th day c 66.00 28.83 5.17 13.25 + 8.97 + 8.14 + 4.09 + 5.80 T 9.8 17.83 73.08 4.50 £ 4.02 £ 6.81 £ 10.63 £ 1.31 V 64.90 17.70 17.40 14.30 £ 10.92 £ 5.21 £ 11.66 £ 5.06 th day c 72.25 23.33 4.52 12.83 £ 7.60 £ 6.62 £ 3.60 £ 4.06 T 17.67 12.58 69.75 6.92 £ a.lo £ 4.03 £ 11.64 £ 1.90 V 76.10 8.50 15.40 16.80 £ 11.29 £ 2.33 £ 10.31 £ 5.78 F+ = H of animals showing a conditioned reaction f+ = % of animals responding to uπconditionεd stimulus, f- = % of animals which do not respond even to unconditioned stimulus, IR = number of iπtersigπal reactions. II/4. Determination of effect exεrted on motility, on rats The test is carried out in a - Shuttle-box without introducing current and light. Tne number of spontaneous passings over from side of the oox to the other is rεgistereø and su arizεc by the apparatus for . an observation peri-ad of 30 minutes. The test Is carried out en groups comprising 112 CFY rats of ooth =exes weighing 130-2C0 each. The test compound of the general o mula I is accsd o ior tc the test suπcutanεcusiy, togetπer wit tetrabeπszi-ε and cε-sπethyl-imioramiπe (Dϊ ' .I) reference comcends, respectively. ccor ing to this test the cc couπds of Examples 3 and 7 ■ do -ct increase motility in a dc-se of 13 mg/kg, wnile compounds cf Ξxa-jles -, 6 and 14 co increase -ctillty in t.mε sure ccse. The motility inπioitiπg effect of I mg/kg of tetrabenazine is significantly antagonized oy a 2.5 mg/kg dose cf compound of Example 7 and completely antagonized already by a 1 mg/kg dose of cc- ound of Example 4. In tnis test D.,I is inhibitory by itself ratπer tr.an antagonistic against tstraceπaziπe ir.cuceα depression cf motility. II/5. Determination of the effect exerted on metabolism, in rats Method: B. Issekutz, B. Issekutz, Jr.: Naumyn. Schiedeberg 2 Arch Phar ac 306 (1942). In this test the compounds of the gneral Formula I in¬ crease metabolism in a significantly lower extent and for a shorter period of time than either amphetamine or 1-depreπyl. II/6. Determination of the effect exerted on food intake, in rats On well-fed satiated animals a 15 mg/kg p.o. or s.c. dose of the compound according to Example 7 does not change food intake (amphetamine exhibits an aπorectic effect already in a dose of 1 mg/kg). In a similar dose it does not influence the food intake of rats fasted for 96 hours, which could be completely inhibited by a 2-5 mg/kg dose of amphetamine for 3-4 hours. A 5 mg/kg dose of the compounds according to Examples 4 and 14 give rise to a decreasing effect being approximately identical with that of about 0.5 mg/kg of amphetamine, in the first hour. II/7. Determination of JH-πoradreπaiπe uptake in the nucleus free supernatant of rat cortex (in vivo) The cortex is homogenized in 0.32 M saccharose with a teflon potter, the cell nucleus is sedimeπted by cεntrifuging at 0 °C with 1000 g for 20 minutes; the supernatant thus obtained is used for the test. The intake is accomplished in a Krebs- Heiπseleit solution saturated with carbogeπ, in a final volume of 1 ml, at a ^H-πoradreπalinε concentration of S.IO-'-" moles. Pre-iπcubation and incubation are carried out at 37 °C for 5 minutes each. The reaction is stopped by adding 4 ml of ice-cold Krebs solution and the tissue is separatεd by GF/B filtration. Non-specific uptake is determined by using 10 " * M nisoxetine at 37 °C. The radioactivity of the GF/B filtεr-paper is determined by liquid scintillation ' measurement in a toluenε-PPO-POPOP- tritonε mixture. The results are summarized in Table 4. Taole 4 Co ocund IC 5n0-0-0 OKI . 1C -9 - 5xl0 "9 Compound accordi-m " to Example - 5xl0 ~ ° Compound according to Example 7 5x10 " ' . Compound according to Example I- IxlO -/ 1-ceoreπyl 7xl0 ~6 Determination of the copamineric activity increasing effect, cn isolated rat striatum orεoarations Met.ncc- Kerecseπ et al: Chromatography, the State of tne Art, Ettre) Akacεmiai Kiadό Budapest (15Ξ5) oace 195- 203. In ex M.α tests the animals are treatec s. c . for 3 weeks and the organ is removed 2 hours after administering the last injection. The results are summarized in Tables 5 and 6. = statistically significant Table 5 Change of the dopamiπe (DA) and DOPAC concentration of the bath of the organ, in vitro (pmole g__ min ___-) Test compound Dose DA DOPAC Control - 91 258 Example 7 0.3 214 x 172 x 1.0 366 x 190 x 3.0 290 x 331 x 10.0 477 x 537 x Table 6 Change of the dopamiπe (DA) and DOPAC concentration of the bath of the organ, ex vivo (pmole p l min ' l Test compound Daily dose DA DOPAC Control - 91 258 Example 7 0.25 257 x 222 5.0 189 .223 X _ statistically significant CT/HU87/00040 II/B . Acute toxicity (on rats) The results are summarized in Table 7. Table 7 Test compound ii..vv.. L LDD< 5 5π Q mmgg//kkgg p._o. Example No. s.c. 1 135 2 50 ^200 (0 H) 3 - 75 (0 %) x 4 2 277 ' 5 500 270 5 - 140 6 - ^150 (0 %) 7 4 400 1 14400 300 8 - 7200 (0 .) 9 - ^200 (0 %) 10 - ^200 (20 %) 11 46 195 12 - 160 13 18 175 14 - 110 15 16 25 x 16 - 50 (0 %) x 17 75 ?20Q 18 - >200 (0 %) 19 - >200 (0 %) 20 - >100 (20 %) X _ = a more concentrated solution can not be prepared. II/9 Inhibition of the πoradreπaliπe releasing effect of tyramine, on a rabbit pulmonary artery preparation (in vitro) Method: J. Knoll: 3. Neural. Traπsm. -V_ 111 (1978) The test comprises the following steps: 1/ Taking a control tyramine curve, in cumulative dosage (tyramine doses 1, 3, 8, 18 ug/ml). 2/ After washing for 20 minutes, a control tyramine curve is taken again. 3/ Equilibration with a single dose of thε tεst compound of the genεral Formula I for 30 inutεs. 4/ Taking a tyra iπε curve in the presence of the ' test compounds, as described in Par. 1). 5/ After washing for 20 minutes, a tyramine curve is taken again. The results are summarized in Table 3. Table-: Tεst compound IC^r ■ '•' ) r Examole No. 7.47x10 " ° 0.75 3.όoxic- 7 0.77 3 7.47x10-° 4 1.22xl0 _o 0. .77 5 i.ECxlO -7 0. .51 3. 4.51-xlC " ° r. , 62 i.AlxIQ- 5 C . . 7→ lu 5.75xlQ- ? C . II 1.59x10 " = Coπtiπuation of Table 8 Test Compound IC 5Q (M) r 2 Example No. 12 7.99xl0 -7 0.69 - 13 1.80x T 6 0.69 14 can not be given 15 3.46xlQ -6 0.96 16 5.01X10 "7 0.80 17 can not be given 18 can not be given 19 can not be given 20 1.87x1a -6 0.84

Claims: What we claim is, 1/ Pharmaceutical composition comprising as active ingredient a compound of the gπeral Formula I /wherein Rl stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; phenyl alkyl having 7 to 10 carbon atoms; phenyl; or cycloalkyl comprising 3 to 8 carbon atoms; R 2 stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; alkyl comprising 1 to 8 carbon atoms substituted by halogen, hydroxy, alkoxy having 1 to 4 carbon atoms or by one or two phenyl groups; phenyl; or cycloalkyl having 3. to 8 carbon atoms, with the proviso that groups R^ and R 2 together contain at least three carbon atoms/ or a salt thereof optionally in admixture with suitable biologically inert carriers and/or auxiliary agents. 2/ Process for the preparation of compounds of the general Formula I (wherein R^ and R 2 are as stated in Claim 1) and salts thereof which comprises reacting a compound of the general Formula II with a compound of thε general Formula III (in which Formulae R-"- and R 2 are as stated above and A and B stand for groups which are εithεr capable of forming a -NH-R 2 group when reacting with each other or comprise the said group) and there¬ after if desired converting the compound of the general Formula I into a salt formed with an organic or inorganic acid and/or setting free compound of the general Formula I from a salt and if desired finishing a compound of the general Formula I or a salt thereof in the form of a pharmaceutical composition by methods known per se. 3/ Process according to Claim 2 which comprises reacting a ketone of the general Formula IV (wherein R-*- is as stated above) with an amine of the general Formula V (wherεin R 2 is as statεd above) and rεduciπg the ketimine intermediate formed without or after isolation. 4/ Process according to Claim 3 which comprises carrying out reduction by catalytic hydrogenation - preferably in the presεncε of a palladium or Raπey-nickel catalyst - or by using a complex metal hydride, sodium dithionite or amalgamated aluminium. 5/ Process according to Claim 2 which comprises reacting a compound of the general Formula VII (wherein R-"- is as stated above) with an alkylating agent of the general Formula VI (wherein X stands for halogen or a sulfoπic acid ester group and R 2 is as stated above), preferably in thε presence of an acid binding agent. 6./ Process according to Claim 2 which comprises reacting an amine of the gεπeral Formula V (wherεin R 2 is as stated above) with a compound of the general Formula VIII (wherein R-*- and X are as stated above), preferably in the presence of an acid binding agent. If Process according to Claim 5 or 6 which comprises using as acid binding agent an excess of the amine component or an organic or inorganic base or a basic ioπ-exchaπglπg resin. 8/ Procεss according to Claim 2 for the preparation of a compound of the general Formula XI (wherein R-*- is as stated above) which comprises rnethylating an amine of the general Formula VII (wherein R-"- is as stated above) by reacting with formaldehyde and formic acid. 9/ Process according to Claim 2 for the preparation of salts of the compounds of the general Formula I which comprises reacting a compound of the geπεral Formula I with an organic or inorganic acid, preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid or maleic acid. 10/ Compounds of the general Formula IX and salts thereof (wherein R- 5 stands for straight or branched chain alkyl comprising 2 to 8 carbon atoms; phenyl alkyl having 7 to 10 carbon atoms; phenyl; or cycloalkyl ' comprising 3 to 8 carbon atoms; and R* stands for straight or branched chain alkyl comprising 1 to 8 carbon atoms; alkyl having 1 to 8 carbon atoms substituted by halogen, hydroxy, alkoxy having 1 to 4 carbon atoms or by one or two phenyl groups; phenyl; or cycloalkyl having 3 to 8 carbon atoms; provided that and R* togethεr contain at least 5 carbon atoms; and with the proviso that if R- stands for methyl, R 4 is other than benzyl; and with the further proviso that if R- stands for ethyl, R* is other than isobutyl. 11/ N-propyl-l-phenyl-2-peπtylamine and acid addition salts thereof. 12/ N-proρyl-l-pheπyl-2-butylamine and acid addition salts thereof. 13/ N-propyl-l-phenyl-2-hexylamine and acid addition salts thereof. 14/ Method for treatment of learning deficiency of ill or healthy humans - eg. in case of senility or Alzheimer disease - or for stimulating clinical pattern of symptoms of depression and for increasing learinig ability which comprises administering at least one compound of the general Formula I or a biologically acceptable salt thereof in an efficient amount, preferably In a daily oral dose of 10-150 mg.

Inventors: BERGMANN JANOS, KNOLL JOZSEF, MOZSOLITS KAROLY, SIMAY ANTAL, SOMFAI EVA, SZINNYEI EVA, TOEROEK ZOLTAN, BERGMANN, JANOS, KNOLL, JOZSEF, MOZSOLITS, KAROLY, SIMAY, ANTAL, SOMFAI, EVA, SZINNYEI, EVA, TOEROEK, ZOLTAN
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT
Application year: 1987
Main classification: A61K31
IPC codes: A61K31, A61P25, C07C211