DE2844427A1 - Antiparkinson 3-hydroxy-phenethyl:amine derivs. - N-substd. by a butyl or 1-methyl-3-phenyl-propyl group - Google Patents

Abstract

New 3-(2-aminoethyl)styrene derivs. are cpds. of formula (I) and their salts. In (I), R1 is n-butyl or 1-methyl-3-phenyl-propyl; and R2 is H or n-propyl. Pref. R1 is 1-methyl-3-phenylpropyl, R2 is H, and R1 is n-butyl, R2 is n-propyl. (I) are dopaminergic cpds. useful as antiparkinsonism agents. They readily cross the blood-brain barrier, but are highly specific for the dopamine receptor. Because of their specific dopaminergic action, (I) are also useful as prolactin inhibitors and, possibly, antidepressants.

Description

3- (p-Amino-ethyl) -phenols, their production and the like

Preparations containing compounds The invention relates to new 3- (0-amino-ethyl) -phenols of the general formula: where R1 is n-butyl or 1-methyl-3-phenyl-propyl and R2 is hydrogen or n-propyl, and their pharmacologically acceptable salts.

Some examples of pharmacologically acceptable salts are the hydrochloride, Hydrobromide, sulfate, acetate, mesylate, tartrate, maleate, succinate, adipate.

The new compounds are characterized in particular by a very good effect against Parkinson's disease.

The compounds of the invention have been found to be particularly effective proven: 5-9 - (1-methyl-3-phenyl-propyl) amino-ethyl-2-phenol and 3- [ß- (n-butyl-n-propyl) amino-ethyl] -phenol and their pharmacologically acceptable salts.

Parkinson's disease is a degenerative decrease dopaminergic neurons in the basal ganglia. The result is a deficiency at the natural neurotransmitter 1) opamine, whereupon the symptoms: tremor, rigor and akinesia are to be traced back.

Try to address this deficiency in neurotransmitters through exogenous intake from Fixing dopamine was unsuccessful because dopamine does not cross the blood-brain barrier exceeds.

With the replacement of dopamine with the amino acid L-Dopa, a means was created found that absorbed by active transport into the brain, there to dopamine is decarboxylated and as a result a more or less pronounced one Compensation of all symptoms of illness, e.g. tremor, rigor and akinesia, leads, but often causes severe gastrointestinal and cardiovascular side effects.

Through the combination with exclusively peripheral decarboxylase inhibitors We have succeeded in partially alleviating these side effects, but not in reversing them. The centrally caused side effects (e.g. dyskinesia) are not alleviated by this. Further disorders are those in the central nervous system from the large amount of dopamine required the resulting metabolites.

It is also disadvantageous that I-Dopa facilitates the transport of the other amino acids (e.g. the serotonin precursor: tryptophan) is hindered by the blood-brain barrier.

The advantages of the compounds of the invention are that they have far better pharmacokinetics than I-Dopa because they are more permeable to the brain and can therefore be dosed considerably lower than l-Dopa. aside from that they do not block the transport systems for the essential amino acids, as the Uptake of the compounds of the invention into the brain occurs by passive diffusion.

Another advantage of the compounds of the invention is that they have a greater selectivity than i-dopa and dopamine. The natural one Transmitter dopamine has an a-, a p- and a specific dopaminergic effect, of which for the therapy of Parkinson's disease only the specifically dopaminergic Effect is desired. As a result of these three modes of action is at pharmacotherapy with l-dopa using ubiquitous decarboxylases dopamine increased in the brain not only in the basal ganglia, but also in other brain areas formed and takes effect there on the one hand through its direct a- and P-effect and on the other hand as a precursor of norepinephrine into the brain functions. in the In contrast, the compounds of the invention act equally, although they are also similar distribute over the brain, but practically only a specific dopaminergic effect only on the brain structures provided with specific dopaminergic receptors.

Because of this specific dopaminergic effect, the compounds Also suitable as a prolactin inhibitor and possibly also as an antidepressant.

3- (2-Dipropylamino-ethyl) -phenol is already from the literature known (Geißler, II. E., Arch. Pharm. 310, 749 (1977).

However, the activity of the compound is in particular the 3-Wp- Far inferior to (n-butyl-n-propyl) -amino-ethylj-phenol.

The invention also relates to a process for the preparation of the 3- (p-maino-ethyl) -phenols of the general formula I, which is characterized in that a) an amine of the general formula: in which R1 and R2 have the meaning given above, either with a phenylacetic acid halide of the general formula: in the R eire easily removable protective group and Hal mean chlorine, bromine or iodine, converted to acid amide, which is then reduced, or with a 3- (ß-halo-amino-ethyl) -phenol derivative of the general formula: in which R and Hal have the meaning given above, reacts and splits off the protective group R from the amine obtained, or b) a 3- (ß-amino-ethyl) -phenol derivative of the general formula: in which R has the meaning given above, is subjected to a reductive alkylation with benzyl acetone and the protective group R is split off from the amine obtained, or c) a 3- (ß-amino-ethyl) -phenol derivative of the general formula: in which R and R2 have the meaning given above, either subjected to a reductive alkylation with propionaldehyde or with an alkyl halide of the general formula: Hal R1 (VII) in which R1 and Hal have the meaning given above, then the protective group R is removed and the 3- (ß-amino-et'nyl) -phenols obtained in this way are, if desired, converted into their salts with pharmacologically acceptable acids.

When the process is carried out, the compounds of the formulas III and VI, preference is given in which the protecting group R is the phenolic OH group is a lower alkyl, preferably methyl or benzyl. If R is lower alkyl, if the cleavage takes place by ether cleavage with hydrohalic acid, R is benzyl, the cleavage takes place by reductive ether cleavage.

The registration is to be explained in more detail by the following examples. However, no restriction can be derived from this.

Example 1 3- [2- (1-Methyl-3-phenylpropyl) -amino-ethyl] -phenol 10 mmol (1.51 g) 2- (3-methoxyphenyl) ethylamine are dissolved in 10 ml of methanol with 5 ml of benzyl acetone and 1 g of palladium / activated carbon 10: Z0 reductive under a hydrogen pressure of 10 atm alkylated, converted into the hydrobromide by adding 1.4 ml HBr / glacial acetic acid, precipitated by petroleum ether and recrystallized from ethanol / ether / petroleum ether.

The ether cleavage to 3-C2- (1-methyl-3-phenylpropyl) -aminoethyl7-phenol hydrobromide is in 20 ml nitrogen-gassed, 47%, aqueous hydrobromic acid within passed through for 24 hours at 90 ° C.

The crystallization takes place from ethanol / ether, whereby one is colorless Crystals with a melting point of 1480C are obtained.

Yield: 85% of theory

IR maxima at 690, 780, 1150, 1480, 1585, 2830, 3270 cm 1.

Example 2 3- (2-butyl-propylamino-ethyl) -phenol 10 mmol (2.74 g) 3-methoxy-1- (2-propylamino-ethyl) -benzene-H; srdrobromide let one in 30 ml of dimethylformamide with 30 mmol (4.15 g) potassium carbonate and 20 mmol (2.14 ml) 1-bromopropane react for 24 hours at 50 ° C., add 60 ml of water, shake the resulting 2- (3-methoxyphenyl) -1- (butyl-propylamino) -ethane with ether from, adds 1.4 ml of HBr / glacial acetic acid (40%) and leaves the hydrobromide formed from ethanol / ether crystallize.

The ether cleavage to 3- (2-butyl-propylamino-ethyl) -phenol is in 20 ml nitrogen-gassed, 47%, aqueous hydrobromic acid within Carried out at 90 ° C for 24 hours.

The crystallization takes place from ethyl acetate, whereby one is colorless Needles with a melting point of 8800 are obtained.

Yield: 68% of theory

IR maxima at 695, 790, 1150, 1270, 1480, 1585, 1610, 2650, 2720, 3240 cm-1.

Claims (1)

Claims 1) 3- (ß-amino-ethyl) -phenols of the general formula: wherein R¹ is n-butyl or 1-methyl-3-phenyl-propyl and R2 is hydrogen or n-propyl, and their pharmacologically acceptable salts. 2) 3- [ß- (1-methyl-3-phenyl-propyl) -amino-ethyl] -phenol and its pharmacologically acceptable salts 3) 3- [ß- (n-butyl-n-propyl) -amino-ethyl] -phenol and its pharmacologically acceptable salts. 4) Process for the preparation of 3- (ß-amino-ethyl) -phenols of the general formula: in which R1 is n-butyl or 1-methyl-3-phenyl-propyl and R2 is hydrogen or u-propyl, and the pharmacologically acceptable salts thereof, characterized in that a) an amine of the general formula: in which R1 and R2 have the meaning given above, either with a phenylacetic acid halide of the general formula: in which R is an easily removable protective group and Hal is chlorine, bromine or iodine, is converted to the acid amide, which is then reduced, or with a 3- (p-halo-amino-ethyl) -phenol derivative of the general formula: in which R and Hal have the meaning given above, reacts and splits off the protective group R from the amine obtained, or b) a 3- (p-amino-ethyl) -phenol derivative of the general formula: in which R has the meaning given above, subjects it to a reductive alkylation with benzyl acetone and splits off the protective group R from the amine obtained, or c) a 3- (p-amino-ethyl) -phenol derivative of the general formula: in which R and R2 have the meaning given above, either subjected to reductive alkylation with propionaldehyde or with an alkyl halide of the general formula: Hal 21 (VII) in which R1 and Hal have the meaning given above, then the protective group R is removed and the 3- (P-amino-ethyl) -phenols thus obtained are, if desired, converted into their salts with pharmacologically acceptable acids. 5) Pharmaceutical preparations, especially against the effectiveness Have Parkinson's disease and, as active ingredient, a compound according to claim 1, excipients and / or contain carriers.