IL30910A - Naphthyl isopropylamine derivatives and process for the preparation thereof - Google Patents

Description

naphthyl isopropylamine derivatives and prooess for the preparation thereof TBRMEKEK GYARA This invention relates to new isopropylamino derivatives and methods for preparing the More particularly it is cerned with new methods for the preparation and pharmaceutical compositions containing Several derivatives of isopropylamine substituted carbon by an aromatic ring possess useful therapeutical properties Potent The and isopropylamine and salts thereof are described however as compounds having very weak pharmaceutical It is also disclosed in literature that said compounds not be used practically in Acta In zing these articles the molecule is nated as and the compounds are reported to have toxic In a more recen publication however France the psychotropic effect of been The present provides new isopropylamine derivatives of the general formula and acid addition salts thereof with inorganic or organic acids of a quite different spectrum of The new compounds formula I are enhance the coronary flow and The salts of the compounds of the formula I are acid addition salts formed with inorganic phosphoric and the like and organic acids formic tartaric malonic and the like According to a further feature of the present vention there are provided processes for the preparation the formula I and salts which react with a compound of the general formula III 6 According to one embodiment of method compounds of the general formula are reacted compounds of the general formula X 1 4 wherein R and have the meaning and stands for halogen or a sulphonic acid ester The compounds of the formula may be preferably the corresponding or alkinyl bromides or but the corresponding and may be used as Accordingly in formula the symbol X represents preferably iodine or a sulphonyl or or compounds containing two halogen groups are the halogenated products may be readily such compounds A in which the group is The reaction is carried out conveniently at a temperature in the range of optionally in the presence of an organic Accordi compounds of the are reacted with compounds of the formula 2 R VI 1 2 3 in which formulae R R R and X have the same meaning The reaction may be carried out preferably in the presence of an Inorganic bases or or organic bases as or may be used for this One proceed preferably by using an excess of the amine of the formula VI which acts also as The reaction is accomplished preferably in the presence of an organic According to a still further embodiment of process a ketone of the general formula 0 are witfi of the Formula under subsequent or simultaneous which R R have meaning stated The reductive may be provided b catalytic hydrogenation or If the reaction is carried out by means of catalytic it is preferred to use or platinum Nascent hydrogen may be developped preferably complex as or or activated The condensation may be carried out advantageously in an organic alcohols as or in ethers such ahydrofuran The reaction may be accomplished conveniently at a temperature between and the boiling point of the particularly at If reduction carried out after one may by the by the optionally the formed in an organic nt as ethanol or and said intermediate It is preferred ever to carry out reduction in the same solvent as b The reduction may also be carried out in the presence of a Nascent hydrogen may also developped using activated aluminium or comple or The reac may be worked up by methods known may be if desired by catalytic Said unsaturated derivatives may also be reacted with or halogens to yield the halog n or Compounds containing a ma be converted into the reacting a halogenating agent according to methods known r The unsaturated compounds may be saturated erabl by catalytic hydrogenatlon in the presence a pal or On accomplishing n conditions be used that the of the should be If palladium as catalyst it preferable to apply the starting material in the form of a mineral may be carried out preferably in a polar solvent such as hydrogenatlon may be partial complete The compounds of the Formula are of basic character and may be converted into pharmaceutically suitable The base may be set free from the thereof or a may be converted into other ceutically preferable The may carried out by methods known per by adding an amount of the acid to the o base in an organic For mineral acids as hydrochloric sulphuric phosphoric a o organic act formic acetic malonic may be According to a feature of our there are provided compositions comprising at least of the Formula or a salt thereof active ingredient in admixture with inert pharmaceutical carriers or The compounds of the Formula can be used in therapy first of all as psychostimulant The particular advantage of the compounds according to the present invention reaides in the fact that they influence the motility only in a very small extent or even not at all Some compounds o Formula the exhibit an advantageous effect on circulation and enhance also the coronary The pharmaceutical according to the present invention may be finished in solid coated or liquid form emulsions and injectable The compositions may be administered parenterally or The compositions contain inert pharmaceutical which may be of organic or inorganic The compositions can be sterilised and may optionally contain further additives such stabilizing emulsifyin wetting In addition to the compound of Formula the compositions may also contain further therapeutically active The pharmaceutical compositions may be prepared by known methods of pharmaceutical industry by admixing the active ingredient with suitable inert pharmaceutically acceptable solid or liquid carriers or Further details of our process are to be found the It is however by no means intended to the scope of the invention to the Example g of are dissolved 200 m ethanol g of benzylamine and ml of water are added and the is stirred at for abou 3 g of ground aluminium foils activated with mercuric chloride are added constant The stirred for The residual and the aluminium oxide formed are dissolved in about ml of whereupon the solution is allowed to settle and he ethanol distilled whereupon the product is extracted the aqueous solution with The benzene phase is separated and the solvent distilled Thus g of oily are The base is dissolved in and solution la saturated with dry gaseous The crude ia from From the further amounts of the product can be obtained The toxicity of the product is in The product exhibits a significant psychostimulant effect hay been determined in the usual way by the modified r The antagonistic effect of the product has been tested n experiments against 10 of and 5 of It has that alone does not influence the rl of nervous even dose determined by the modified The product antagonises significantly of Tetrabenazine in a dose o In said dose the product also antagonised the effect of reaerpine but in a The obtained are in the following Dose Irritability Perishing between in units in and measuring 0 Product 10 0 20 Product 30 0 1 10 lh 10 66 Te 10 Product 20 10 Product 30 40 Reserpine 5 4h 75 4h 40 Reserpine 5 4 30 80 Example g of are dissolved in 100 ml of anhydroua ethanol whereupon g are added and the is stand at is then kept at C for 2 hours and at C for 2 The are Prom the further product can be toxicity of the product to in According to the modified product considerable psychostimulant The product exhibits in rata already after 60 a considerable inhibiting effect both in liver and The been tested by administering the product capitating the animals 16 minutes after making preparations from the mitochondrium of liver brain and finally measuring the The results trated in the following Compound Dose Activation in of oontrol brain mitochondrium ium Product 25 Product 50 insufficientOCRQuality

Claims (1)

1. CLAIMS 1. Comp and their acid addition salts with Inorganic or organio acids, . — ' wherein R1 is hydrogen or an alkyl group of 1 to 4 carbon atoms, ; 2 ■ - R is an alkyl group of 1-18 carbon atoms optionally, substituted by a hydroxy group, a phenylalkyl group, a phenyl gxoap optionally ; substituted by a chlorine atom, a cycloalkyl group, an alkenyl group, an alkinyl group or an amino group substituted by a carbalkoxy gipoup; 3 1 R is hydrogeni or an alkoxy group, provided that, when R is hydrogen 2 R cannot be methyl. 2 2. Compounds of the formula I in Claim 1, wherein R is an alkyl group containing 2-8 carbon atoms j a phenyl alkyl grou containing 1-3 carbon atoms in the alkyl moiety -^ew^;, an alkenyl group containing 2-8 carbon atoms or a cycloalkyl group containing 4-8 carbon atoms. 3. 1-Haphthyl^2^penzylamino¾propan©. 4. l-Naphthyl-2-(Lsopropylamino)propahei.. 5· l-Haphthyl-2-(Oropyiamino!propane.- 6. l-Naphthyl-2-<butylamino^ropane. 7· l-Naphthyl-2<)entylamino¾)rppane. 8. l-Naphthyl-2-[(2 '-hydroxyethyl)-omino Opane . 9· l-Naphthyl-2-(hexylaminopropane. 10. l-Naphthyl-2-(cycl0hexylamino)propane. 30910/3 - 27 - with a compound of formula III in which E is a halogen atom or a sulphonic acid ester grou * 21. A process as claimed in Claim 20 wherei the compound, of general formula, III Is an alkyl, alkenyl or alkynyl chloride, bromide or iodide or the corresponding methanesulphohate, , toluenesulphonate or benaenesulphonate. 22. A process as claimed in Claim 20 or 21 wherein the eVr action is performed at a temperature in the range 10~120°C. 23. A process as claimed i any of Claims 20 to 22 wherein the reaction is performed in the presence of an organic solvent . 24. A process as claimed in Claim 23 wherein the organic solvent is a hydrocarbon, alcohol, ether or tertiary amine, 25· A process as claimed in an of Claim 20 to 24 wherein ; the reaction is performed in the presence of an acid-binding agent 26. A process as claimed in Claim 25* herein the acid-binding agent is triethylamine, N-e hylplperidine , an alkali metal hydroxide or carbonate or an alkaline-earth metal hydroxide. 27. A process as claimed in Claim 20 which comprises using the amine of general formula II in an excess of 1-1.5 moles, whereby it acts as solvent and acid-binding agent. ' 28. A process as claimed in Claim 19 which comprises reacting a compound of general formula II in whic B is a grou of formula , R i -NH 30910/3 - 28 - wherein R is hydrogen or has ¾D same meaning as R , except that it cannot be an amino group substituted with oarbolkoxy group and R has the same meaning as R , with simultaneous or subsequent reduction. · 29. A process as claimed in Claim 28 wherein the reduction is effected with catalytic hydrogenation or with, ascent hydrogen. 30. A process as claimed in Claim 29 wherein hydrogenation is effected in the presence of a platinum, Raney nickel or palladium catalyst. 31· A process as claimed in Claim 29 wherein nascent hydrogen is produced by means of complex metal hydrides, activated aluminium in alkaline or acidic media, or by alkali soluble metals. 32i A process for the preparation of compounds of general formula I in Glaim 1 which comprises reacting a compound of the general formula wherein X represents a halogen atom or a sulphonio acid ester group, with an amine of the general formula R1 m 1 - 2 vi passing gaseous acetylene into this solution in the presence of a copper compound. 40. A process as claimed in Claim 39 wherein the high "boiling point ether is d butyl ether or dioxane, 41. A process as claimed in Claim 39 or 40 which comprises using 1.5-3 molea of paraformaldehyde and 0.05-0.1 mole of copper compound per mole of 1-naphthylisopropylmethylamine. 42. A process as claimed in any of Claims 39 to 41 which comprises using cuprous acetylide, cuprous chloride or other cuprous salt as the copper compound. 43· A process as claimed in any of Claims 39 to 42 whic comprises heating the reaction mixture to a temperature in the range 50°C - 110°C. 44· A process for the preparation of compounds of general formula I in Claim 1 which comprises reducing a compound of general formula 3 wherein R is as hereinbefore defined, and Y represents a hydroxy group and a hydrogen atom, a halogen and a hydrogen atom, or a carbonyl oxygen atom in order to remove the hydroxy group, halogen atom or oxo group. 45. A process for the preparation of acid addition salts of the com ounds of the eneral fo mula I in Claim 1 which com rises - 31 - reacting the compound, prepared according to any of Claims 19 to 44» with an organic or inorganic acid. 46. A process as claimed in Claim 45 which comprises using formic, acetic, tartaric, lactic, malonic, hydrochloric, hydrobromic, sulphuric or phosphoric acid in the salt formation. 47. .Processes for the preparation of compounds of the general formula I in Claim 1, substantially as herein described with reference to the Examples. 48. Compounds of the general formula I in Claim 1 and their acid addition salts, whenever prepared by a process as claimed in any of Claims 19 to 44 and 47. 49· Pharmaceutical compositions containing as active ingredient at least one compound of the general formula I in Claim 1, or an acid addition salt Hereof,1 in admixture with suitable inert pharmaceutical carriers or excipients. 50. Pharmaceutical compositions ae claimed in Claim 49 containing as active ingredient at least one compound as claimed in any of Claims 2 to 10 or an acid addition salt thereof. 51. Compositions as claimed in Claim 49 or Claim 50 in the form of tablets, coated pills, suppositories, capsules, solutions, emulsions or injectable preparations. RTNERS