NO145098B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE ISOINDOLIN DERIVATIVES - Google Patents

Description

Process for the production of new, therapeutically effective phenylalkylamines.

The invention relates to a process for the production of new phenylalkylamines which excel in their analgesic properties

properties.

It was found that phenylalkylamines

with the general formula

in which R1 means a hydrogen atom, a low-molecular alkyl group or benzyl group, R2 means an alkyl group with 2-4 carbon atoms, R;1 means a pentyl or cyclopentyl group, and R4 and R, alkyl groups with 1-4 carbon atoms or together with the central carbon atom means members of a saturated ring system with 5-6 carbon atoms, as well as salts thereof have valuable therapeutic properties, especially analgesic action, and that one obtains these compounds as an amine with the general formula

where Rj — R:) has the indicated meaning,

either

a) is reduced with activated hydrogen i

presence of a ketone of the general formula

in which R,, means an alkyl group with 1-4 carbon atoms and R7 means a saturated or unsaturated hydrocarbon residue with up to 4 carbon atoms, or in which R,, and R7 together with the central carbon atom means members of a saturated ring system with 5-6 carbon atoms, or b) reacted with an ester of the general formula in which R4 and Rn have the indicated meaning, and X means an inorganic or organic acid residue, if desired with the aid of acid-residue decomposing agents, or c) heated with an alcohol of the general formula

wherein R 4 and Rs have the indicated meaning,

and if desired when in the process products the substituent Ri means an al-

cooling group, this is cleaved off according to the usual methods, or if R, means a hydrogen atom, the hydroxy group is transferred in the alkoxy group, or if R, means the benzyl group, the benzyl residue is cleaved off by catalytic hydrogenation, and further, if desired, the formed basic compounds are transferred with inorganic or organic acids in the corresponding addition salts.

For the preparation of the process products, the reaction of an amine of the general formula II with a ketone of the general formula III is particularly well suited.

The alkyl radicals R2, R4 and Rr can be the same or different, linear or branched. Mention may be made, for example, of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and secondary butyl residues.

As amines can be used, for example: 2-(3'-hydroxy-phenyl)-2-pentyl-(3") -

butylamine-(1), 2-(3'-hydroxy-phenyl)-2-pentyl-(3")-

pentylamine-(l),

2-(3'-hydroxy-phenyl)-2-pentyl-(3")-

3-methyl-butylamine-(1),

2-(3'-hydroxy-phenyl)-2-pentyl-(3")-

3-methyl-pentylamine-(l),

2-(3'-methoxy-phenyl)-2-pentyl-(3")-

butylamine-(l),

2-(3'-methoxy-phenyl)-2-pentyl-(3")-

pentylamine-(l),

2-(3'-methoxy-phenyl)-2-pentyl-(3")-

3-methyl-butylamine-(1),

2-(3'-methoxy-phenyl)-2-pentyl-(3")-

3 -methyl-pentylamine-(1),

2-(3'-ethoxy-phenyl)-2-pentyl-(3")-

butylamine-(l),

2-(3'-ethoxy-phenyl)-2-pentyl-(3")-

Pentylamine-(1), 2-(3'-ethoxy-phenyl)-2-pentyl-(3")-

3-methyl-butylamine-(1),

2-(3'-ethoxy-phenyl)-2-pentyl-(3")-

3-methyl-pentylamine-(1),

2 - (3' -hydroxy -phenyl) -2 -cyclopentyl -

butylamine-(l),

2-(3'-hydroxy-phenyl)-2-cyclopentyl-pentylamine-(1), 2-(3'-hydroxy-phenyl)-2-cyclopentyl-3-methyl-butylamine-(1),

2-(3'-hydroxy-phenyl)-2-cyclopentyl-3-methyl-pentylamine (1),

2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(l), 2-(3'-methoxy-phenyl)-2-cyclopentyl-pentylamine-(l),

2-(3'-methoxy-phenyl)-2-cyclopentyl-3-methyl-butylamine-(1),

2-(3'-methoxy-phenyl)-2-cyclopentyl-3-methyl-pentylamine-(1),

2-(3'-ethoxy-phenyl)-2-cyclopentyl-butylamine-(1),

2-(3'-ethoxy-phenyl)-2-cyclopentyl-pentylamine-(1),

2-(3'-ethoxy-phenyl)-2-cyclopentyl-3-methyl-butylamine-(1),

2-(3'-ethoxy-phenyl)-2-cyclopentyl-3-methyl-pentylamine - (1),

2-(3'-benzyloxy-phenyl)-2-cyclopentyl-butylamine-(1),

2-(3'-benzyloxy-phenyl)-2-cyclopentyl-pentylamine-(1),

2-(3'-benzyloxy-phenyl)-2-cyclopentyl-3-methyl-butylamine-(1) and

2-(3'-Benzyloxy-phenyl)-2-cyclopentyl-3-methyl-1-pentylamine-(1).

As ketones with formula III, the following compounds can be used, for example: Acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone, methyl vinyl ketone, isopropylideneacetone (mesityl oxide), cyclopentanone, cyclohexanone.

The amines of formula II which can be used as starting materials can advantageously be prepared by hydrogenation of the corresponding substituted cyanides in the presence of catalysts from the 8th group of the periodic table. The cyanides, in turn, are available from the corresponding substituted benzyl cyanides by reaction with sodium amide and alkyl-respective cyclopentyl halides in a water-immiscible solvent.

The reduction of an amine with the general formula II in the presence of a ketone with the general formula III can, for example, take place catalytically with the help of metals from the 8th group of the periodic table, preferably with palladium catalysts. The turnover can vary within wide limits and can be adapted to any circumstances. For example, you can work in the presence of an excess of ketones, which then simultaneously serve as a solvent. The conversion is suitably carried out at temperatures up to 50° C and at lower (1.1 ato) or higher hydrogen overpressure (up to 50 ato). The excess ketone is not hydrogenated to carbinol in this process and can be recovered. However, one can also work without using an excess of ketones and use another suitable solvent, for example methanol. Instead of palladium, nickel catalysts (Raney nickel) can also be used. Similarly, one can also reduce with nascent hydrogen, for example aluminum amalgam and alcohol, sodium amalgam, lithium aluminum hydride or sodium borohydride. The reduction can also be carried out electrolytically.

According to a further advantageous embodiment of the method according to the invention, amines of formula II can be reacted with esters of inorganic or organic acids of formula IV. As such can be used, for example: Isopropyl iodide, secondary butyl bromide, 3-bromopentane, 2-bromo-3-methyl-butane, 2-bromo-4-methyl-pentane, cyclopentyl bromide, cyclohexyl bromide, p-toluenesulfonic acid isopropyl ester , diisopropyl sulfate.

The reaction conveniently takes place by heating the components in a suitable solvent, for example in ethanol, isopropanol, benzene, toluene or xylol at temperatures between 80-130° C. The duration of the heating depends on the temperature and the reactivity of the ester components and is usually between one and twenty hours. To capture the acid formed, the amine of formula II is appropriately added in a one to several times molar excess and a water-immiscible solvent is used in which the amine salt formed during the reaction is insoluble. Instead of excess amine, however, other basic compounds can also be used to trap the acids formed, for example sodium bicarbonate, anhydrous sodium carbonate or tertiary amines such as triethylamine or diethylaniline. The reaction can also be carried out without a solvent by heating the two components at temperatures between 80 and 130° C, using the amine in double molar excess appropriately.

A further embodiment consists in heating amines of formula II with alcohols of formula V in the presence of Raney nickel for a longer time at temperatures between 100° C and 120° C. The duration of the heating depends on the structure of the starting material used and is usually between five past fifteen hours.

For the production of the process products in whose formula the substituent Rs means a hydrogen atom, the corresponding alkoxy or benzyloxy compound is suitably prepared first according to one of the specified methods. The alkoxy compound can then be converted in the usual way, for example by heating with hydrogen chloride, hydrogen bromide, aluminum chloride or pyridine hydrochloride, into the corresponding hydroxy compounds. If benzyloxy compounds, for example 2-(3'-benzyloxy-phenyl)-2-cyclopentyl-butylamine-(1), are used as starting materials for the production of the process products, then the reaction can either be carried out in one or two work steps.

For example, you introduce the rest

into a compound of formula I by hydrogenating an amine of formula II together with a ketone of formula III in the presence of palladium as catalysts, then the benzyl group is split off in the same procedure. However, the rest are introduced

according to other methods, for example by reacting an amine of formula II with an ester of formula IV, the benzyloxy group is first retained and can, if desired, provide a further work step, for example catalytically split off with the help of noble metal numbers from the periodic table 8 .group as catalysts.

On the other hand, if, according to one of the above-mentioned embodiments, process products are obtained in whose formula R means a hydrogen atom, the hydroxy group can be transferred by alkylation in the usual way, for example with dimethyl sulfate or diethyl sulfate in alkaline solution, in the methoxy or ethoxy group.

The process products can be converted into the corresponding acid addition salts by treatment with inorganic or organic acids. For example, the following physiologically tolerable acids can be used for salt formation: Inorganic acids such as hydrohalic acid, especially hydrochloric and bromic acid, sulfuric acid, phosphoric acid, amide osulphonic acid, and organic acids such as acetic acid, propionic acid, oxalic acid, malic acid, succinic acid, lactic acid, maleic acid, fumaric acid, sorbic acid, citric acid, aceturic acid, aspartic acid, p-amino-benzoic acid, salicylic acid and ethylenediamine-tetraacetic acid.

The analgesic effect of the new method products can, for example, be demonstrated by the burning beam method according to Wolff, Hardy, Goodell, J. Clin. Inv. 19, 659

(1940) on mice. According to this experimental device, the reaction time to thermal irritation before and after subcutaneous application of the preparations was investigated in groups of mice. This technique was modified to the extent that, in an all-or-none procedure, certain criteria were used to determine the percentage of animals that respond positively to the stimulus. Thus, very precise dose-effect relationships could be found. For N-sec-butyl-2-(3'-hydroxyphenyl)-2-cyclopentyl-butylamine-(1)-hydrochloride, the smallest effective quantity (dosis effec-tiva minima 50) of 0, 85 mg/kg. By way of comparison, the smallest effective amount of the known 2-dimethylamino-4,4-diphenylheptanone (5) hydrochloride by subcutaneous application amounts to 1.5 mg/kg. The preparation thus proved, by subcutaneous application, to be twice as effective as the known 2-dimethylamino-4,4-diphenyl-heptanone (5) hydrochloride.

The said compound shows a clear sedative effect on mice which have been agitated by subcutaneous application of 1-phenyl-2-methylamino-propane hydrochloride by the method according to Ther (Deutsche Apo-theker Zeitung 1953, p. 292).

Similarly, according to the research method proposed by Ther, Vogel and Werner (Arzneimittelforschung 9, 351 (1959) ) on golden hamsters as well as according to the method of Vogel and Ther (Arzneimittelforschung 10, 806 (1960) ) on cotton roots a clear sedative neuroleptic effect is established.

The toxicity studies showed that the process products can be considered completely harmless. Thus, for example, N-sec. Butyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine-(1)-hydrochloride dose lethalis 50 in mice in case of intravenous injection 30 mg/kg, in case of subcutaneous injection 250 mg/kg and in case oral application 900 mg/kg. When examined for chronic toxicity, it was 900 mg/kg with peroral application. In an examination of chronic toxicity, 10 mg/kg was tolerated when the same compound was administered orally to dogs for 28 days without pathological phenomena in the clinical picture and in autopsy findings.

Also in clinical investigations, an N-sec.butyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine-(1)-hydrochloride already shows a clear analgesic effect at a dosage of 2-4 mg.

The method products can be used as pain relievers both in free form and in the form of their addition salts with physiologically tolerable acids, possibly in admixture with suitable solid or liquid pharmaceutical carriers such as water, plant oils, starch, milk sugar or talc, possibly with auxiliaries such as stabilizers, preservatives - and emulsifiers. Preferred pharmaceutical preparation forms are solutions or suspensions for injection, tablets, dragees, capsules and suppositories.

For parenteral use, a dosage of 1 to 20 mg can be used, for oral use a dosage of 5 to 50 mg.

From German patent no. 1,058,063 it is known that diphenylethylamine compounds have

analgesic effect. While the known compounds are, however, of a potency such as 1-methyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester, the products produced by the method according to the invention are analgesics that achieve the potency of 2-dimethylamino-4 ,4-diphenylheptanone-5-hydrochloride (methadone) and also surpasses this (from Liebig's Annalen der Chemie, volume 561 (1948), page 79 it appears that methadone has at least the 5-fold analgesic potency of pethidine). The following table shows the values obtained by the burning beam method according to Wolff, Hardy and Goodell on mice for the smallest amount of twitching of some process products compared to methadone.

Example 1.

N-sec.-butyl-2-(3'- methoxy-phenyl)-

2-pentyl-(3")-butylamine-(1).

30 g of 2-(3'-methoxy-phenyl)-2-pentyl-(3")-butylamine-(1) and 150 g of methyl ethyl ketone are hydrogenated in the presence of palladium as a catalyst at 50° C until complete hydrogen uptake. After separation of catalyst and distilling off the excess methyl ethyl ketone gives N-sec-butyl-2-(3'-methoxy-phenyl)-2-pentyl-(3")-butylamine-(1) in quantitative yield. The corresponding fumaric acid salt melts at 107° C.

The starting material 2-(3'-methoxy-phenyl)-2-pentyl-(3")-butylamine-(1) with a boiling point at 3 mm hg 148-152° C is obtained by hydrogenation of (3-methoxy- phenyl)-ethyl-pentyl-(3')-acetonitrile (boiling point at 6 mm hg 148-150° C) which can be prepared from (3-methoxy-phenyl)-ethyl-acetonitrile by reaction with sodium amide and 3-bromo- pentane.

Example 2.

N- sec. butyl-2-(3'-hydroxy-phenyl)-

2-pentyl-(3")-butylamine-(1).

By heating N-sec-butyl-2-(3'-methoxy-phenyl)-2-pentyl-(3")-butylamine-(l) with 48% hydrobromic acid under reflux for eight hours, the methyl group is split off. You get in quantitative yield N-sec.butyl-2-(3'-hydroxy-phenyl)-2-pentyl-(3")-butylamine-(1) which forms a fumarate with melting point 167° C.

Example 3.

N-isopropyl-2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(1).

a) 20 g of 2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(1) are hydrated in 100 g of acetone

corresponding to the regulation stated in Example 1. N-isopropyl-2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(1) whose hydrochloride melts at 145° C is obtained in quantitative yield.

b) The same compound is obtained by heating 2-['-methoxy-phenyl)-2-cyclopentyl-butylamine- (1) for 15 hours with

excess isopropanol and a lot of Raney nickel at 100° C. c) The same compound is obtained by heating 2-(3'-methoxy-phenyl)-2-cyclopentyl-butyl-amine-(l) with 1 mol of diisopropyl sulfate for 3 hours at 100°C.

Example 4.

N- sec. butyl-2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(1).

a) 300 g of 2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine- (1) is hydrogenated in 750 g of methyl ethyl ketone corresponding to the regulation stated in example 1. N-sec.butyl is obtained in quantitative yield -2-^'-methoxy-phenyl)-2-cyclopentyl-butylamine- (1) if

hydrochloride melts at 185°C.

b) The same compound is obtained when 2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(1) is hydrogenated with methyl vinyl ketone and palladium as catalyst at 50° C to complete hydrogen absorption. The starting material 2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(1) with a boiling point at 5 mm hg 174 —176° C is obtained by hydrogenation of (3-methoxy-phenyl)-ethyl- cyclopentyl acetonitrile (boiling point at 3 mm hg 154-156° C) which can be prepared from (3-methoxy-phenyl)-ethyl acetonitrile by reaction with sodium amide and cyclopentyl bromide.

Example 5— 9.

Following the procedure stated in example 1, the following compounds were formed from 2-(3'-methoxy-phenyl)-2-cyclopentyl-butyl-amine- (1) by hydrogenation with ketones: 5) With methylisopropyl ketone N-[3" -methyl-butyl-(2")] -2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(1), hydrochloride-

its melting point 131° C.

6) With methylpropyl ketone N-pentyl-(2")-

2-(3'-methoxy-phenyl)-2-cyclopentyl-

butylamine-(1), the melting point of the hydrochloride 200° C. 7) With diethyl ketone N-pentyl-(3")-2-(3'-methoxy-phenyl-2-cyclopentyl-butylamine-

(1), the melting point of the hydrochloride 155° C.

8) With cyclopentanone N-cyclopentyl-2-(3'-methoxy-phenyl)-2-cyclopentyl-butylamine-(l), melting point of the hydrochloride 230° C. 9) With cyclohexanone N-cyclohexyl-2-(3'-methoxy enyl)-2-cyclopentyl-butylamine - (1) -hydrochloride melting point 195° C.

Examples 10-16.

During 8 hours of heating of those in the

examples 3 to 9 described 3-methoxyfor-

bonds with 48% hydrobromic acid under reflux, the methyl groups are split off to form the corresponding hydroxyphenyl derivatives. In this way, the follow-

manufacturing process products

easy:

10) N-isopropyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine-(1), hydrochloride

its melting point 206° C.

Ila) N-sec.butyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine-(1), hydrochloride

its melting point 178° C.

11b) The same compound is also obtained when one hydrates 2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine-(1), which was dan-

net by demethylation of the corresponding methoxy compound with 48 percent bromine

hydrogen acid and forms a fumarate with a melting point of 150° C, with methyl ethyl ketone and palladium as a catalyst at 50° C. 12) N-[3"-methyl-butyl-(2")]-2-(3'-hydroxy-phenyl) -2-cyclopentyl-butylamine-

(1), the melting point of the hydrochloride 164° C.

13) N-pentyl-(2")-2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine- (1), hy-

the drochloride's melting point 212° C .

14) N-pentyl-(3")-2-(3'-hydroxy-

phenyl) -2-cyclopentyl-butylamine-(1), hy-

the melting point of the hydrochloride 184° C.

15) N-cyclopentyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine-(1), hy-

the melting point of the drochloride 209° C.

16) N-cyclohexyl-2-(3'-hydroxy-phenyl)-2-cyclo-pentyl-butylamine-(1), hy-

drochloride's melting point 236° C.

17) N-sec.butyl-2-(3'-ethoxy-phenyl)-2-cyclopentyl-butylamine-(1) is obtained by

impact of diethyl sulfate in alkaline up-

solution of N-sec.butyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-butylamine-(1), which is obtained according to example 11.

Example 18.

N- sec. butyl-2-(Z'-methoxy-phenyl)-2-cyclopentyl-pentylamine-(1).

16 g of 2-(3'-methoxy-phenyl)-2-cyclopentyl-pentylamine-(1) are hydrated in 150 g of methyl-

ethyl ketone corresponding to the regulation stated in example 1 and worked up. One obtains in quantitative yield N-sec.butyl-2-(3'-methoxy-phenyl)-2-cyclopentyl-pentyl-

amine-(l), whose hydrochloride melts at 127° C.

The starting material 2-(3'-methoxy-phenyl)-2-cyclopentyl-pentyl-

amine-(l), with boiling point at 5 mm hg 178-180° C is obtained by hydrogenation of (3-methoxy-phenyl)-propyl-cyclopentyl-

acetonitrile (boiling point at 5 mm hg 168—

170°C). The latter connection can produce

is produced by 3-methoxybenzyl cyanide, sodium

amide and propyl bromide and subsequent re-

reaction of the formed (3-methoxy-phenyl)-propyl-acetonitrile (boiling point at 5 mm hg 134-135° C) with sodium amide and cyclopentyl bromide.

Example 19.

N- sec. butyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-pentylamine-(1).

Upon 8-hour heating of N-sec.-butyl-2-(3'-methoxy-phenyl)-2-cyclopene-

tylamine-(l) with 48 percent hydrogen bromide

acid during reflux, the methyl group is split off

pretty. One gets in quantitative yield N-sec.-

butyl-2-(3'-hydroxy-phenyl)-2-cyclopentyl-pentylamine-(1), whose hydrochloride melts at 228°C.

Claims (1)

Process for the production of therapeutically effective phenylalkylamines with the general formula in which R. means a hydrogen atom, a low-molecular alkyl group or the benzyl group, R2 means an alkyl group with 2-4 carbon atoms, R. t means a pentyl or cyclopentyl group and R4 and R. mean alkyl groups with 1-4 carbon atoms or together with the central carbon atom means a member of a saturated ring system with 5-6 carbon atoms, as well as salts thereof, characterized in that an amine with the general formula wherein R, — R;1 has the indicated meaning, either a) is reduced with activated hydrogen in the presence of a ketone of the general formula in which R,, means an alkyl group with 1-4 carbon atoms and R7 means a saturated or unsaturated hydrocarbon residue with up to 4 carbon atoms, or in which R,, and R. together with the central carbon atom means a member of a saturated ring system with 5-6 carbon atoms, or b) is reacted with an ester of the general formula in which R 4 and RB have the indicated meaning and X represents an organic or inorganic acid residue, if desired by means of acid residue-releasing agents, or c) heated with an alcohol of the general formula in which R4 and Rr have the stated meaning, and if desired, when in the process products the substituent R means an alkyl group, this is cleaved off according to the usual methods, or if Rt means a hydrogen atom, the hydroxy group is transferred in the alkoxy group, or if R means the benzyl group, the benzyl residue is split off by catalytic hydrogenation, and further, if desired, the formed basic compounds are transferred with inorganic or organic acids in the corresponding addition salts.