Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• phenylalkylamines of the general Formula I in which R represents hydrogen, an alkyl group having from 1 to 4 carbon atoms or the benzyl group, R represents an alkyl group having from 2 to 4 carbon atoms, R represents a pentyl group or a cylclopentyl group and R and R represent an alkyl group having from 1 to 4 carbon atoms or, together with the combining carbon atom, members of a saturated carbocycle having from 5 to 6 carbon atoms, possess valuable therapeutical properties, particularly analgesic action and that said compounds may be obtained by (a) The reaction of an amine of the general Formula wherein R R have the meanings given above, with a ketone of the general Formula III (III) R. IV
• R, and R have the meanings given above and X represents an inorganic or organic acid residue, if desired, by means of an agent splitting off the acid residue;
• the most advantageous method of preparation of the products according to the invention is to react amines of the general Formula II with ketones of the Formula III.
• the alkyl radicals R R and R may be. the same or different and may be straight chained or branched. There may be mentioned, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec. butyl radicals.
• amines there may be used, for example:
• ketone of the Formula III there may be used, for example, the following compounds: acetone, methylethylketone, methylpropyl-ketone, methylbutyl-ketone, met-lb ylisopropyl-ketone, methylisobutyl-ketone, diethyl-ketone, dipropyl-ketone, methylvinyl-ketone, isopropylidene-acetone (rnesityloxide), cyclopentanone or cyclo-hexanone.
• the amines of the Formula II to be used as starting substances are advantageously prepared by hydrogenation of the correspondingly substituted cyanides in the presence of catalysts of the 8th group of the Mendeleff Periodic System.
• the cyanides may be prepared by reacting the correspondingly substituted benzyl-cyanides with sodium amide and alkyl or cyclopentyl halides in a solvent 1mmiscible with water.
• the reduction of an amine of the general Formula II in the presence of a ketone of the general Formula III may, for example, be effected catalytically with the use of metals of the 8th group of the Mendeleff Periodic System, preferably with palladium catalysts.
• the reaction may be varied in wide limits and may be adapted to special conditions. It can, for example, be carried out in the presence of an excess amount of ketone simultaneously serving as solvent.
• the reaction is preferably effected at a temperature up to 50 C. and under a pressure of hydrogen of 50 atmospheres. When operating accordthe presence of an excess amount of ketone simultaneing to this method, the excess ketone is not hydrogenated to yield the corresponding carbinol and may be recovered.
• nickel catalysts Raney nickel
• the reduction may furthermore, be carried out by electrolysis.
• the amines of the Formula II may be reacted with the esters of inorganic or organic acids of the Formula IV.
• esters of inorganic or organic acids of the Formula IV There may be used for example, isopropyliodide, sec.butyl-bromide, 3-bromopentane, 2-bromo-3-methylbutane, 2-bromo-4-Inethyl-pentane, cyclopentyl-bromide, cyclohexyl-bromide, p-toluenesulfonic acid isoprop-yl-ester, or di-isopropyl-sulfate.
• the reaction is preferably performed by heating the reactants in an appropriate solvent, for example, ethanol, isopropanol, benzene, toluene or xylene, at temperatures between 80 and 130 C.
• the heating period depends on the temperature and the reactivity of the ester component and usually amounts to 1 to 20 hours.
• the amine of the Formula II may be used in an excess of one to several times the molar quantity, and a solvent immiscible with water, in which the amine salt formed during the reaction is insoluble, may be used.
• the acids formed there may also be used instead of the excess amine other basic compounds, for example, sodium bicarbonate, anhydrous sodium carbonate or tertiary amines, such as triethylamine or diethylaniline.
• the reaction may also be carried out without using solvents by heating both reaction components to temperatures between 80 and 130 C., the use of the amine in a bimolar excess being advantageous.
• Another method of preparing the compounds of the invention consists in heating amines of the Formula II with alcohols of the Formula V in the presence of Raney nickel for a prolonged period of time at temperatures between 100 C. and 120 C.
• the heating period depends on the structure of the starting substances used and is generally between 5 and hours.
• the substituent R represents a hydrogen atom
• the alkoxy compounds may then be converted in the usual manner, for example by heating with hydrogen chloride, hydrogen bromide, .aluminum chloride or pyridinhydrochloride into the corresponding hydroxy compounds.
• benzyloxy compounds are used as starting substances, for example 2-(3-benzyloxy-phenyl)-2-cyclopentyl-butylamine-(l), the reaction can be carried out in one or two stages of operation.
• the radical R4 is introduced according to other methods, for example, by reacting an amine of the Formula II with an ester of the Formula IV, the benzyloxy group is not affected and if desiredcan be split oil in a further step of this reaction, for example, by means of noble metals of the 8th group of the Mendeleff Periodic System as catalysts.
• the hydroxy group can be converted into the methoxy or ethoxy group by ethylation in the usual manner, for example with dimethylsulfate or diethylsulfate in an alkaline solution,
• the products of the present invention can be converted into the corresponding acid addition salts by treatment with inorganic or organic acids.
• inorganic acids for example a hydrohalic acid, particularly hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, amido-sulfo acid, and organic acids such as acetic acid, propionic acid, oxalic acid, malic acid, succinic acid, lactic acid, maleic acid, furmaric acid, sorbic acid, citric acid, aceturic acid aspartic acid, p-amino-benzoic acid, salicylic acid and ethylenediamine-tetracetic acid.
• inorganic acids for example a hydrohalic acid, particularly hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, amido-sulfo acid
• organic acids such as acetic acid, propionic acid, oxalic acid, malic acid, succinic acid, lactic acid, maleic acid, furmaric acid, sorbic
• mice The analgesic activity of the new products of the invention was demonstrated in mice according to the method of Wolfi, Hardy, Goodell, J. Clin. Inv. 19, 659 (1940).
• the preparation was administered subcutaneously or orally to a number of mice and the period of time in which the animals reacted to the thermal irritation was examined prior to and after administration of the products.
• This method was modified in such a way that by a process of all or nothing certain criteria were used in order to ascertain the percentage of animals showing positive response in the test. Thus, relatively exact relations of the eli ective doses could be found.
• the lowest ettective dose (dosis etfectiva minima 50) of 0.85 milligram/kilogram was ascertained for the N -sec.butyl-2- 3 '-hydroxy-phenyl -2-cyc1opentyl-butylamine-(l)-hydrochloride according to this method.
• the lowest elfective dose of the latter substance amounts to 1.5 milligrams/kilogram on subcutaneous administration.
• mice the lethal dose 50 for N-sec.butyl- 2-(3-hydroxy-phenyl)-2 cyclopentyl butylamine-(l)- hydrochloride is 30 milligrams/kilogram in the case of intraveneous injection, 250 milligrams/kilogram in the case of subcutaneous injection and 900 miligrams/kilogram in the case of oral administration.
• Long-term toxicity tests showed that the compound when administered orally to dogs for 28 days in a dose of milligrams/kilogram was tolerated without causing pathologic symptoms in the clinical picture and in post mortem examinations.
• hydrochloride revealed a marked analgesic action when administered in a dose of 2 to 4 milligrams.
• the products of the present invention can be applied either in form of the free amines or in the form of their addition salts with physiologically tolerable acids as analgesic medicaments, if desired, in admixture with suitable solid or liquid pharmaceutical carriers such as water, vegetable oils, starch, lactose or talcum, if desired, with auxiliary agents such as stabilizing, preserving and emulsifying agents.
• suitable solid or liquid pharmaceutical carriers such as water, vegetable oils, starch, lactose or talcum, if desired, with auxiliary agents such as stabilizing, preserving and emulsifying agents.
• the compounds are preferably administered in the form of solutions or suspensions for injections, and of tablets, clragees, capsules and suppositories.
• a dose of 1 to mg. may be taken into consideration and for oral administra tion a dose of 5 to 50 milligrams.
• the 2- 3 -methoxy-phenyl -2-pentyl- 3 -butylamine- (1), boiling point 148152 C. serving as starting sub stance was obtained by hydrogenation of (3-methoxyphenyl) -ethylpentyl- 3 -acetonitrile (boiling point 148-150 C.) prepared by reacting (3-methoxy-phenyl)- ethyl-acetonitrile with sodium amide and 3-bromopentane.
• N-isopr0pyl-2 (3-meth0xy-phenyl) -2-cycl0pentylbutylamine-(1) (a) 20 grams of 2-(3-methoxy-phenyl)-2-cyclopentylbutylamine-(1) were hydrogenated in 100 grams of acetone according to the prescriptions given in Example 1. The N-isopropyl-2-(3'-methoxy-phenyl)-2 cyclopentylbutyl-amine-(l) was obtained in a quantitative yield. Its hydrochloride melted at 145 C.
• N -sec.butyl-2- (3 '-methoxy-phenyl -2-cycI0pentylbutylamine-(1) (a) 300 grams of 2-(3'-methoxy-phenyl)-2-cyclopentylbutylamine (1) were hydrogenated in 750 grams of methylethylketone according to the prescriptions given in Example 1.
• the N-sec.butyl-2-(3'-methoxy-phenyl)-2- cyclopentyl-butylamine-( 1) was obtained in a quantitative yield. Its hydrochloride melted at C.
• N-sec.butyl-2-(3'-cthoxy-phenyl)-2 cyclopentylbutylamine-(1) was obtained by causing diethylsulfate in alkaline solution to act on N-secbutyl-Z-(3'-hydroxyphenyl)-2-cyclopentyl-butylamine(1) obtained according to Example 11.
• phenylalkylamines of the general Formula I in which R is selected from the group consisting of hydrogen, an alkyl group having from 1 to 4 carbon atoms and the benzyl group, R represents an alkyl group having from 2 to 4 carbon atoms, R is selected from the group consisting of a pentyl group and a cyclopentyl group, and R and R are selected from the group consisting of an alkyl group having from 1 to 4 carbon atoms and, together with the combining carbon atom, members of a saturated carbocycle having from 5 to 6 carbon atoms, and (2) addition salts of said compounds with physiologically compatible acids.
• N-secbutyl-Z-(3'-hydroXy-phenyl) 2 pentyl-(3)- butylamine- 1 3.
• N-isopropyl-Z-(3'-hydroxyphenyl) 2 cyclopentylbutylamine- 1 5.
• N-sec.butyl-2-(3'-hydroxy-phenyl) 2 cyclopentylbutylamine- 1 6.
• N-pentyl-(3")-2-(3-hydroxy-phenyl) 2 cyclopentyl-butylamine- 1) 7.

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• 1961
  • 1961-07-19 DE DEF34467A patent/DE1164399B/de active Pending
• 1962
  • 1962-07-17 US US210538A patent/US3225098A/en not_active Expired - Lifetime
  • 1962-07-19 GB GB27898/62A patent/GB1008639A/en not_active Expired
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