NL8702533A - (+) - 1-ISOPROPYLAMINO-3-0- (PYRROOL-1-YL) -PENOXY-2-PROPANOL OR A SALT THEREOF, A PROCESS FOR THE PRODUCTION OF THE PROPANOL DERIVATIVE AND ITS SALTS AND THE PHARMACEUTICAL PREPARATIONS THEREOF. - Google Patents

Description

"*" J? Ν.0. 34773 1 (+) - 1-isopropylamino-3-to- (pyrrol-1-yl) -phenoxy] -2-propanol or a salt thereof, a process for preparing the propanol derivative and its salts, and pharmaceutical preparations containing these compounds contain »__ 5

The present invention relates to (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl} -phenoxy] -2-propanol and its salts, the use and preparation as well as pharmaceutical preparations containing these active The subject of the invention is also the use of the racemic (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutically applicable non toxic salt thereof and pharmaceutical preparations containing such an active ingredient for the treatment of anxiety states.

German Patent Application No. 2,409,313, which discloses, inter alia, racemic (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol. The materials disclosed in this reference can be used as g-receptor blockers, in part with anti-arousal properties. These properties were determined in the pargyline reserpine antagonism test. In this test model, the inhibition of unmotivated hyperactivity caused by the test substances, which occurs as a result of pharmacogen-induced norepinephrine effusion, is determined. The inhibition of the hyperactivity thus effected occurs at higher dosages, i.e. in the same dose range, in which blocking properties appear at β-receptors. About 30 to 240 mg have been proposed as the daily dose of active substance when tablets are administered.

What is surprising now is that (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol in free form or in the form of a pharmaceutically applicable, non-toxic salt does not relevant β-blocking-30 has the, however, pronounced anxiolytic properties. In addition, the (+) enantiomer has nootropic and antidepressant activities.

The object of the invention is thus (+) - 1-isopropylamino-3- [o- (pyr-rool-1-yl) -phenoxy] -2-propanol or a salt, in particular a pharmaceutically usable, non-toxic salt thereof.

Pharmaceutically applicable salts of the active substance in question are their pharmaceutically applicable acid addition salts, for example with strong inorganic acids with sulfamic acids, such as cycTo-lower alkyl sulfamic acids, with strong organic carboxylic acids, such as lower alkane carboxylic acid, optionally unsaturated dicarboxylic acids and by hydroxy and / or 40 oxo-substituted lower alkanoic acids, or with sulfonic acids, such as lower 870 2 53 3 2 alkane or optionally substituted benzenesulfonic acids, for example the corresponding sulfate, phosphate, hydrogen halide, such as hydrogen chloride or hydrogen bromide, cyclohexyl sulfamate, acetate, malonate oxalate, maleate, fumarate, citrate, tartrate, pyruvate as-5 sulfonate, especially methanesulfonate, further benzene or p-toluenesulfonate. A preferred pharmaceutically applicable salt of the (+) - enantiomer is the corresponding fumarate, the racemate being preferably used as hydrogen chloride. Partial structures denoted by "small", in so far as not defined differently, should preferably be understood to mean those containing up to 7, in particular up to 4, carbon atoms.

Owing to the close relationship between the active substance in question in free form and in the form of its pharmaceutically applicable salts, the above and below under free compound resp. their pharmaceutically usable salts make sense and expedient, optionally also the corresponding pharmaceutically usable salts, respectively. the free connection to be understood.

The active substance concerned which can be used according to the invention can also be in the form of its hydrates and include other pharmaceutically safe solvents, for example those which are used for the crystallization of the corresponding active substance which is in solid form. .

For example, the characteristic anxiolytic profile of (+) - 1-isopropylami-25-no-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol is shown in the results of the Geller test, [J. Geiler, Psychopharmacologia, 3, p. 374 ff. (1962)], where rats are exposed to a foot shock-induced conflict situation, (+) - 1-isopropylamino-3- [o- (pyrrole-1-yl) -phenoxy -2-propanol as a strong anxiolytic indicates 30. In this test, the feet of the test animals are periodically exposed to electric shock when a food release siphon is operated. Normally, only when high doses of anxiolytics are administered, the response to the punishment is suppressed. A group of rats which have received a dose of (+) - 1-isopropyl-35 amino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol from 3 mg / kg po already reacts from about 80% of the test animals with a marked increase in the helvel operating frequency during the shock phase.

In particular, marked anxiolytic effects when administering the active substance in social conflict situations in 40 rhesus monkeys were observed. The experimental basis for this 870253 3 3 s social conflict test analogous to J. Jaekel in Biological Psychiatry (Forschungsergebnisse), W. Kemp (Hrsg), Springer Verlag, Heidelberg, 1986, is the hierarchical order in Rhesus monkeys. The relative rank status of an animal is a determining factor for mutual communication, for example for aggression or mutual social fleas. Normally, animals of low rank status are suppressed by higher-ranking fellow members of the group. These oppressed animals withdraw into social isolation and fearfully avoid any social contact. Repeated administrations of active substance in doses of 0.2 mg / kg 10 p.o. in groups of 5 resp. 7 monkeys significantly reduce the fearful behavioral pattern of the respective monkeys, which are ranked lowest. They also actively engaged in social contacts and became care partners, although they had never been care partners before. These effects are considered clear anxiolysis.

In experimental models in rhesus monkeys as well as in rats, an additional nootropic and antidepressant action component could be identified.

For example, (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol in a double blind study in rhesus monkeys against placebo in the "Del ayed-Matching-to -Sample-Test "(time-delayed-choice-by-sample) according to the HF method Harlow et al., J. Comp. Physiol. Psychol. 53, 113-121 (1960) e.g. at 1 mg / kg p.o. a markedly increased success rate in the deficit range. This means that time delay in seconds, after which monkey has a discrimination success of <75% 25. In addition, the delay times for the shortage trajectory could be increased by an average of 20 seconds. After these nootropic effects, antidepressant properties could also be observed in this test. The Rhesus monkeys clearly showed motivation and incentive increases, because their interest in the stated tasks and their willingness to cooperate increased markedly.

The nootropic antidepressant activity components could also be manifested in rat studies. For example, in a complicated deep labyrinth analogous to the model of J.B. Watson, Animal Education, Contrib. Psychol. Lab. Univ. Chicago, 4, 5-122 (1903), as a result of a smaller error rate, a marked improvement in the orientation performance of the rats has been observed (nootropic action). On motivation resp. spur-increasing effects indicate the rats' markedly shorter maturities from start to reward, compared to placebo, suggesting antidepressant properties of the active substance. Further, 870253 3 * 4 set contains (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol in rats in the Screening model of S. Bischoff et al. ,

Europ. J. of Pharmacology 104, 173-176 (1984), in vivo dose-dependent increases in% -spiperone binding of stratial dopaminergic receptors.

Therefore, (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol has a pronounced and specific anxiolytic profile, because it reduces, for example, aggressive behavior and in particular to an improvement of positive social behavior. In addition, 10 (+) enantiomer is nootropic and antidepressant. Accordingly, (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutically usable, non-toxic salt thereof may be used in the treatment of anxiety, especially generalized (chronic) anxiety states, panic disorders, obsessive compulsive behavior and 15 phobias, such as social phobias, neophobia (fear of the new) and agoraphobia (claustrophobia), in the treatment of dementias of any kind, eg Alzheimer's disease and age-related and traumatic deficits in learning and memory, as well as in the treatment of depression.

A further subject of the invention is therefore the use of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutically applicable, non-toxic salt for the treatment of anxiety states, of demension of any type and of depressions and the preparation of pharmaceutical preparations for the treatment of anxiety states, of dementias of any type and of depressions.

A further subject of the invention are processes for the preparation of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol and salts thereof, which can be carried out in a manner known per se and are characterized, for example, by splitting a) racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a salt thereof into the (+) enantiomer, or b ) an enantiomer of formula 1, wherein on the one hand X 1 and together represent -O- or, on the other hand, represents Χχ hydroxy and reactively esterified hydroxy, in particular halogen or sulfonyloxy, reacts with isopropylamine, or c) the (R) -enantiomer of formula 2 hydrolyses, or d) of the (R) -enantiomeric compound of formula 3, wherein Sch represents a group conventionally used for protecting amino groups, cleaves the protecting group, or 40 e) starting from the (R) -enantiomer of formula 4 , the 870253 3 l * 5 pyrrole-l-yl ring builds up and / or obtained free (+) - l-isopropylamino-3 ~ £ o- (pyrro ol-1-yl) -phenoxy] -2-propanol in a salt or convert an obtained salt of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol converts the free enantiomer.

The conversions described above and hereinafter in the variants are carried out in a manner known per se, e.g. in the absence or conventionally in the presence of a suitable solvent or diluent or a mixture thereof, with cooling, at room temperature or under heating as required, e.g. in a temperature range from about -10 ° to the boiling temperature of the reaction medium, preferably from about -10 ° to about 150 ° C, and if required, in a closed container, under pressure, in an atmosphere of a inert gas and / or operates under anhydrous conditions.

The starting material of formulas 1, 2 and 3 mentioned above and hereinafter, which was developed for the preparation of the compound according to the invention and its salts, is partly known or can also be carried out by methods known per se, for example analogous to the process variants described above are prepared.

Starting materials with a basic center can, for example, be in the form of acid addition salts, for example with the acids mentioned above in connection with salts of the compound according to the invention.

Within the scope of the above and below process description, reactive esterified hydroxy, unless defined differently, means in particular esterified hydroxy with a strongly inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonylo * y, e.g. fluorosulfonyloxy, optionally, e.g. halogen-substituted C1-C7 alkanesulfonyloxy, e.g. methane or trifluoromethyl-thanesulfonyloxy, C3-C7 cycloalkanesulfonyloxy, e.g. cyclohexane-sulfonyloxy, or optionally e.g. (4-C7 alkyl or halo-substituted benzenesulfonyloxy), for example p-bromophenyl or p-toluenesulfonyl oxy.

Arylmethyl, such as mono-, di- or triphenylmethyl, primarily benzyl, is particularly suitable as the protecting group for amino Sch.

If, for example, bases are used in the above and the conversions described below, unless otherwise stated, for example, alkali metal hydroxides, hydrides, amldenes, -alkano-870253 3 6 * *, -carbonates, -triphenylmethylides, -di- C1-C7 alkalamides, -amino-C1-C7 alkyl amides or C1-C7 alkyl amides, -amino-C; pC7 alkyl amides or -C1-C7 alkyl silylamides, naphthalenes, C1-C7 alkyl amines, basic heterocycles, ammonium hydroxide and carbocyclic amines. For example, lithium hydroxide, sodium hydroxide, hydride, amide, ethanolate, potassium tert-butoxide, carbonate, lithium triphenylmethylide, diisopropylamide, potassium 3- (aminopropyl) -amide, -bis- (trimethylsilyl) amide, dimethylaminonaphthalene, di- or triethyl amine, pyridine, benzyltrim-10-thylammonium hydroxide, 1,5-diaza-bicyclo [4.3.0] non-5-ene (DBN) as well as 1,8-diaza-bicyclo [5.4. 0.] undec-7-een (DBU).

Depending on the choice of starting material, the aforementioned process variants can be carried out in such a way that the synthesis in question proceeds enantioselectively, i.e. one of the possible enantiomers exclusively or. can be obtained predominantly. Variant a):

Racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol can be decomposed in the optical antipodes by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, using appropriate microorganisms, by cleavage with specific immobilized enzymes, through the formation of inclusion compounds, eg using chiral crown ethers, in which only an enantiomer is complexed, or by conversion to diastereomeric salts, e.g.

By reacting the basic racemate with an optically active acid, such as a carboxylic acid, e.g. almond, tartaric or malic acid, or sulfonic acid, e.g. camphor sulfonic acid, and separation of the diastereomeric mixture obtained in this way, for example because of their different solubilities, into the diastereomers from which the desired enantiomer can be released by the action of suitable agents. Variant b):

If X2 of the formula 1 stand for -0- then the corresponding (R) -enantiomer is used. The conversion of this enantiomer is preferably carried out with an excess of isopropylamine.

The (S) -enantiomeric form is used for the reaction of the compound of the formula 1, wherein X 2 preferably represents halogen, such as chlorine or bromine, further sulphonyloxy, and X 1 is hydroxy. The conversion of such an enantiomer of the formula I into the enantiomer according to the invention can take place, for example, in the presence of 40 of the aforementioned organic bases, but in the first 8702 53 3 * 7 place, however, an excess of isopropylamine is used.

Variant c):

The hydrolysis of the (R) -enantiomer of the formula II can take place in particular in the presence of a base, primarily by alkaline hydrolysis, e.g. in the presence of an alkali metal hydroxide, such as sodium hydroxide.

Variant d):

The cleavage of the group protecting the amino group, Sch, from the (R) -enatiomer compound of formula 3 takes place in a manner known per se. For example, benzyl can be cleaved off by catalytic hydrogenation.

As hydrogenation catalysts, e.g. elements of the 5th subgroup of the periodic table of elements or derivatives thereof, such as palladium, platinum, platinum oxide, rutheonium, rhodium, tris (triphenylphosphine) rhodium (I) halide, e.g. chloride, or Raney nickel, optionally on a support material such as activated carbon, alkali metal carbonate or. sulfate or a silica gel have been deposited. Palladium is used as the preferred catalyst.

Variant e): The construction of the pyrrole ring starting from the compound of formula 4 takes place in a manner known per se. For example, the compound of formula 4 with a 2,5-di-lower alkoxytetrahydrofuran, e.g. 2,5-dimethoxy-tetrahydrofuran, advantageously in the presence of an acid, e.g. acetic acid, and under heating, e.g. at the reflux temperature of the reaction medium.

Salts of the compound of the invention can be prepared in a manner known per se. For example, corresponding acid addition salts are obtained by treatment with an acid or a suitable ion exchange reagent. Salts can be converted into the free compounds in the usual manner, acid addition salts, e.g. by treatment with an appropriate basic agent.

Depending on the working method resp. the reaction conditions allow the compounds of the invention to be obtained with salt-forming, in particular basic properties, in free form or preferably in the form of salts.

The starting material mentioned in the process variants is partly known or known. can be prepared in a manner known per se.

The preparation of racemise 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol is described, for example, in German Patent Application No. 2,409,313 laid open to public inspection.

870 2 53 3 * 8

The compound of formula 1, wherein X 1 and X represent £ -O-, can be prepared, for example, by starting from (R) -2,2-dimethyl-1,3-dioxolane-4-methanol-p-toluenesulfonate and with an alkali metal salt of 2- (pyrrole-1-yl) -phenol to the (S) -2,2-di-5 methyl-4- [o- (pyrrol-1-yl) -phenoxy] -methyl -1, 3-dioxolane turnover.

After acid hydrolysis, formation of the tosylate and subsequent treatment with one of the aforementioned bases, e.g. sodium ethanate, the (R) -1,2-epoxy-3- [o- (pyrrol-1-yl) -phenoxy] -propane of formula 1 is accessible. The diol obtainable after acid hydrolysis of the (S) -2,2-dimethyl-4-10 ([o- (pyrrol-1-yl) -phenoxy] -methyl-1,3-dioxolane, ie a compound of formula 1, wherein Xj and X2 represent a hydroxy, can advantageously also be converted by reaction with an orthoester, eg with the trimethyl ester of orthoacetic acid, into the corresponding cyclic orthoester form, the ring opening of which, eg

With trimethylchlorosilane, and subsequent cyclization of the chlorhydrin thus obtained with a base, e.g. sodium hydroxide to give the corresponding compound of formula 1, wherein X 1 and X 2 together form -O-.

The compound of formula 2 can e.g. prepared by using 20 (R) -3-sopropylamino-4- (p-toluenesulfonyloxymethyl) oxazoli di-2-one with o- (pyrrole) -1-yl) -phenol in the presence of a base, e.g. sodium hydride, and a solvent, e.g. DMF, turnover.

For the preparation of a compound of the formula 3, it is possible, for example, to start from (R) -1,2-epoxy-3- [o- (pyrrol-1-yl) -phenoxy] -propane and this with an appropriately protected isopropylamine, e.g. Convert N-benzyl isopropylamine.

For the preparation of the compounds of the formula IV, it is possible, for example, to start from 2-nitrophenol, first condense it with (S) -glycidol and then treat it with isopropylamine. In the next reaction step, the nitro group, e.g. by catalytic hydrogenation in the presence of a hydrogenation catalyst, e.g. Pd / C Raney nickel, until the amino group are reduced.

In the preparation of the respective starting compounds, as a result of an exchange of substituents associated with a priority exchange, the designation of the configuration may change, even if no stereochemical changes take place directly at the center of chirality. However, the enantioselective synthesis is always carried out in such a way that those enantiomeric starting materials are prepared which lead directly to the enantiomers according to the invention.

Furthermore, racemic starting material in the appropriate required form 87 0 2 53 3 J-9 can be cleaved by a conventional racemate cleavage.

Furthermore, it was surprisingly found that the racemate 1-isopro-pylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol and suitable pharmaceutically usable, non-toxic salts thereof in addition to the β-block- 5 quays have associated actions as an additional active ingredient, having marked anxiolytic activities. These axiolytic properties already occur at dosages in which no β-receptor inhibitory effects yet occur. Thus, 1-isopropylamino-3- [o- (pyrrho-yi) -phenoxy] -2-propanol has the additional property of normalizing, respectively, anxiety-induced hy-peractivity. convert inhibited behavior in anxiety to incentive increase and accordingly also has an "anti-anxiety effect".

For example, the characteristic anxiolytic profile of 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol is evidenced by the inhibition of the hyperactivity of rats kept in isolation measured by their locomotor and exploratory behavior, achieving maximum effects at a dose of 0.01-0.1 mg / kg po [analogous to the methodology of R. Weinstock et al., Psychopharmacoïogia 30, 24 ff (1973). In contrast, in the case of propranolol, the hyperactivity of isolated rats 20 was maximally inhibited at a dose of 3.0 mg / kg p.o.

Also in the Geller test described above, 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol appears to be a strong anxiolytic. In a group of 29 rats, which received a dose of 20 mg / kg po of 25 l-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol, 50% of the test animals with a marked increase in the lever actuation frequency during the shock phase, the increase in individual animals being 300%. In this foot shock test, a dose of 20 mg / kg propranolol p.o. in rats did not result in a notable change in behavior.

In particular, remarkable anxiolytic effects when administering the active agent in social conflict situation in rhesus monkeys in Jaekel's social conflict trial described above could be observed. Repeated administrations of active substance in 35 doses of 0.1-0.3 mg / kg po in groups of 7 monkeys resulted in a marked reduction in the monkey's anxious behavioral pattern, which were ranked lowest and increased of social contacts. They also actively contacted and became care partners, although they had never been care partners before. These effects were observed both in groups with high level 870253 3 - -¾ 10 in social contacts and in groups with few care relationships. After administration of 0.3-3.0 mg / kg p.o.oxprenolol, no increase in social contact with low-ranking monkeys was observed in the behavioral pattern of the rhesus monkeys. At a dose of 0.5-10.0 mg / kg p.o. propranolol, the social contacts of the rhesus monkeys with low rank status were relatively little affected. Unsurprisingly, this marked anxiolytic profile was not found with the standard receptor blockers oxprenolol and with beta-receptor blocking doses to a much lesser extent with propranolol. In contrast, the racemate has this effect in non-β-blocking doses.

The active substance to be used according to the invention is furthermore a powerful selective antagonist of the presynaptic serotonin-1B-receptor (5-ΗΤ1Β), while propranolol and oxprenolol act less selectively, because they also work with the post-synaptic 5-HT. receptor.

Thus, the aforementioned pharmacological studies document that 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol has remarkable anxiolytic activity and that it also manifests itself at 20 low doses and therefore differentiation between anxiolytic and β-receptor inhibitory activity.

It is therefore surprising that the anxiolytic profile of this active substance is also very pronounced even at doses which do not block beta-blocking, as well as in the animal model and in humans. The latter confirm studies in stationary patients.

Based on a three-center double-blind study with more than 100 stationary patients, it may be surprising that, when a daily dose of 2 mg po was administered, remarkable, at least as potent, anxiolytic effects were achieved when a daily dose of 2 mg po dose of 4 mg po of the active substance to be used according to the invention.

Furthermore, it was determined that, for example at low daily doses, such as 2 mg and 4 mg p.o., no cardiovascular effects have occurred, i.e. no β-blockade has been observed. The corresponding is to be expected when using the (+) enantiomer.

Accordingly, the treatment of anxiety states in humans may preferably take place at non-β receptor blocking doses. This means on the one hand a higher selectivity in the therapy, on the other hand a considerable reduction of side effects, which can be brought about by high doses of active substance, can also be expected, 670253 3π.

Accordingly, 1-isopropylamino-3-Co- (pyrrol-1-yl) -phenoxy-2-propanol or a pharmaceutically applicable, non-toxic salt thereof can be used in the treatment of anxiety conditions, in particular generalized ( chronic) anxiety states, panic disorders, obsessive compulsive behavior and phobias, such as social phobias, neophobia (fear of the new) and agoraphobia (claustrophobia).

In the aforementioned test arrangements according to H.F. Harlow et al. And J.B. At the dosages used, Watson was unable to make strong evidence regarding nootropic and antidepressant properties of racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol.

A further subject of the invention is therefore the use of 1-isopropylannno-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutically applicable, non-toxic salt for the treatment of anxiety states and for the preparation of pharmaceutical preparations for the treatment of anxiety states.

The present invention also relates to pharmaceutical preparations which, as active substance (+) - 1-isopropylamino-3- [o- (pyr-20-rool-1-yl) -phenoxy] -2-propanol, which are contained in pure resp. in essentially pure form, or containing a pharmaceutically usable toxic salt thereof, also pharmaceutical preparations intended for the treatment of anxiety, containing racemic 1-isopropylamino-3-Co- (pyrrole-1-yl) -phenoxy] -2-propanol or pharmaceutically usable, non-toxic salt thereof, as well as processes for the preparation of such pharmaceutical preparations.

The pharmaceutical preparations according to the invention, which contain a compound proposed for use according to the invention or a pharmaceutically acceptable salt thereof, are such for enteral, such as oral, further rectal, and parenteral administration to warm-blooded animals, the pharmacologically active substance being or is present together with a pharmaceutically usable carrier material.

The new pharmaceutical preparations contain, for example, a therapeutic, e.g. anxiolytic resp. nootropic as well as depressant effect-inducing amount, such as from about 0.5%, preferably from 1.0%, of the active ingredient. Pharmaceutical preparations according to the invention for the enteral resp. parenteral administration are e.g. those in dosage unit forms, such as dragees, tablets, capsules or suppositories, furthermore ampoules. These are prepared in a manner known per se, for example, by means of conventional mixing, granulating, dragier, solution or lyophilization methods. For example, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, optionally granulating a mixture obtained, and mixing the mixture, respectively. granules, if desired or necessary, processed into tablets or dragee cores after the addition of suitable auxiliary substances.

Suitable carriers are in particular fillers, such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch, using corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or polyvinyl pyrrolidone, if desired, such as disintegrants the above starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow, control and lubricant agents, e.g. silicic acid, talc, stearic acid and its salts, such as magnesium or potassium stearate and / or polyethylene glycol. Dragee cores are provided with suitable coatings, which may be gastro-resistant, including concentrated sugar solutions, which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium oxides, lacquer solutions in suitable organic solvents or solvent mixtures or, for the manufacture of gastric juice resistant coatings, using solutions of suitable cellulose preparations, such as acetyl cellulose phosphate or hydroxypropyl methyl cellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. are added for the identification or for the labeling of different doses of active substance.

Further orally applicable pharmaceutical preparations are gelatin plug capsules such as soft closed gelatin capsules and a plasticizer such as glycerol or sorbitol. The insertion capsules can contain the active substance in the form of a granulate, e.g. mixed with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In active capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

Pharmaceutical preparations which can be used rectally are e.g. suppo-40 sitoria, which consist of a combination of the active substance with 670253 3 13 a base mass for suppositories. As a suppository mass, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, rectal gelatin capsules can also be used, which contain a combination of the active substance with a base mass substance. As a base mass substance, e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons are eligible.

For parenteral administration, primarily aqueous solutions of an active substance in water-soluble form, e.g. a water-soluble salt, further active substance suspensions, such as suitable oil-containing injections, using suitable lipophilic solvents or carriers, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity enhancers, e.g. sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also contain stabilizers.

Another subject of the invention is a process for the preparation of suitable pharmaceutical preparations, e.g. for the treatment of anxiety states, characterized in that (+) - 1-isopropylamino-3- [o- (pyrrole-1-yl} -pheno] -2-propanol or the corresponding racemate or a pharmaceutically usable, non-toxic salt thereof, optionally processed into suitable compositions while mixing with conventional auxiliaries and carriers.

The dosage of the active substance concerned depends on the type of warm blood, the age and the individual condition as well as the mode of application. Suitable pharmaceutical preparations are preferably administered once a day.

In humans, e.g. daily doses of less than 40 mg p.o. In particular, daily doses of from about 10 to 0.5 mg, preferably 10 to about 4 mg, but primarily 3.5 to 0.5 mg, especially 2 mg, p.o. are administered. Daily doses of 4 and 10, respectively, are to avoid cardiovascular events due to β-receptor blocking effects. 3.5 to 0.5 mg, primarily 2 mg, p.o. recommended.

The following examples illustrate the invention described above and are intended to illustrate the provision of a typical application form, but by no means to represent the only embodiments and application forms. Moreover, the invention should not be limited in any way by the examples.

40 Temperatures are indicated in degrees Celsius.

870253 3

* '"K

14

Preparation example I

27.4 g (100 mmol) of racemic l-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol and 16.7 g (110 mmol) 1 - (+) - mandelic acid are added in 143 ml water dissolved and allowed to crystallize overnight. The crystals are aspirated and recrystallized several times from as little water as possible until the melting point is 122-123 ° C and a sample of the liberated base has an optical rotation of [(x3q0: + 12 ± 1 ° (c »5¾ in methanol).

There is thus obtained (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-10 propanol as salt of (+) - mandelic acid, the purity of the enantiomer being given by ^ C-NMR as ¾99¾ was determined (90 MHz, CDCl3). The base is then liberated with aqueous sodium hydroxide and extracted with ethyl acetate.

Preparation Example II 15 Preparation of the neutral fumarate 6.4 g (23 mmol) crude (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol and 1.45 g (12, 5 mmol) of fumaric acid are dissolved in 45 ml of isopropyl alcohol by heating. After cooling, neutral (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol fumarate crystallizes with a mp. from 165-166 °, [a] D: + 19.4 ± 0.2 ° (c = 5.4¾ in water).

Preparation Example III

Advantageously, it is also possible to start from a product for the separation of enantiomers, the one enantiomer, e.g. the (+) enantiomer 25 is already enriched.

For example, e.g. from the racemic (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol with (-) - mandelic acid, preferably the (-) - enantiomer. By alkalizing by means of sodium hydroxide the base (+) - enantiomer enriched base can be isolated from the mother liquor and converted with (+) - mandelic acid to the pure (+) - enantiomer (analogous to example I).

Preparation Example IV

A solution of 9.8 g (0.045 mol) (R) -1,2-epoxy-3- [o- (pyrrol-1-yl) -phenoxy] -propane and 26.9 g (0.455 mol) isopropylamine in 100 ml of iso-35 propyl alcohol is stored at room temperature for 15 hours. Evaporation of the volatile constituents gives crude (R) -1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol as a yellowish oil, which has a rotation [α] 3: + 11.8 ° ± 0.2 ° has [c = 5¾ in methanol].

40 It forms a neutral fumarate with a smp. of 165 ° (from isopro-870253 3 ér *> 15 pyl alcohol) Ea] g °: + 19.0 ° ± 0.2 ° (c = 5¾ in water).

The starting epoxide can be prepared according to methods described in the literature: a) From o- (pyrrol-1-yl) -phenol and (R) -2,2-dimethyl-1,3-dioxolane-4-me-5-thanol- p-toluenesulfonate is obtained by sodium hydride in DMF to obtain the (S) -2,2-dimethyl-4-j [o- (pyrrol-1-yl) -phenoxy] -methyl} -1,3-dioxolane with a mp . from 57-58 ° (from petroleum ether, [<x3q °: + 24.0 ° ± 0.2 ° (c * 5¾ in methanol).

b) Hydrolysis of the compound described under a) in 80% acetic acid 10 for 30 min at 80 ° gives the (R) -3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol -1,2-diol with a mp. of 95-96 ° (from ether), α a] D: + 1.6 (c = 5.5 in methanol).

c) The diol described under b) is converted to the (2 R / S, 15 4S) -2-methoxy-2-methyl-4 - ([0- (pyrrole-1) with the trimethyl ester of orthoacetic acid under catalysis with trifluoroacetic acid. -yl) phenoxy] -methyl] -1,3-dioxolane which is used impure further.

d) The impure cyclic orthoester described under c) is prepared according to M.S. Newman et al., J. Org. Chem. (1978), 38, 4203 with trimethyl-chlorosilane in the chlorohydrin derivative, which by reacting with 2-n sodium hydroxide the (R) -1,2-epoxy-3-Eo (pyrrol-1-yl) -phenoxy] -propane. The crude product is purified by "flaky" chromatography on silica gel (elution with toluene). The colorless oil thus obtained shows an optical rotation of Ca3 °: - 25.8 ± 0.2 °: [a] 20: - 81.6 ° (c = 5.3% fn methanol).

365

Formulation example A:

Film draeses, neutral active agent slide (+) - 1-isopropylamino-30 3- [o- (pyrrooT-1-yl) -phenoxy] -2-propanol fumarate or racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol hydrochloride.

870253 3

* 'V

16

Composition:

Core: active substance 0.5 mg 5 silica airgel (Aerosil 200) 2.5 mg cellulose (Avicel PH 102) 36.0 mg lactose, crystalline 180.0 mg magnesium stearate 1.5 mg sodium carboxymethyl starch 19.5 mg 10 240, 0 mg

Coating; hydroxypropylmethylcellulose (cell 1ulose-HP-M-603) 3.30 mg 15 glyceryl polyethylene glycol oxystearate (Cremophor RH 40) 0.15 mg iron oxide, reduced 0.19 mg talc (PH) 2.93 mg titanium dioxide (PH) 0.43 mg 20 7 mg

Total weight 247 mg

Formulation Example B: 25 Film dragees, which as active substance neutral (+) - 1-isopropylamino- 3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol fumarate or racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol hydrochloric acid.

30 Composition;

Core: Active substance 2.0 mg silica airgel (Aerosil 200) 2.5 mg cellulose (Avicel PH 102) 36.0 mg 35 lactose, crystalline 180.0 mg magnesium stearate 1.5 mg sodium carboxymethyl starch 18.0 mg 240.0 mg 8702 53 3 17

Coating: hydroxypropylmethylcellulose (Cellulose-HP-M-603) 3.3 mg glyceryl polyethylene glycol oxystearate 5 (Cremophor RH 40) 0.2 mg iron oxide, reduced 0.2 mg talc (PH) 2.9 mg titanium dioxide (PH) 0.4 mg 7 mg 10 ----------

Total weight 247 mg

Formulation example C:

Film draeses, which as active substance are neutral (+) - 1-isopropylamino-15 3-Co- (pyrrol-1-yl) -phenoxy] -2-propanol fumarate or racemic 1-isopropylamino-3- [o- ( pyrrol-1-yl) -phenoxy-2-propanol hydrochloride.

Composition: 20 Core: active substance 4.0 mg silica airgel (Aerosil 200) 2.5 mg cellulose (Avicel PH 102) 36.0 mg lactose, crystalline 180.0 mg 25 magnesium stearate 1.5 mg sodium carboxymethyl starch 16.0 mg 240.0 mg

Coating: 30 hydroxypropylmethylcellulose (Cellulose-HP-M-603) 3.3 mg glyceryl polyethylene glycol stearate (Cremophor RH 40) 0.2 mg iron oxide, reduced 0.2 mg talc (PH) 2.9 mg titanium dioxide (PH 0.4 mg 7 mg

Total weight 247.0 mg 8702 53 3

19 - V

18

Formulation example D:

Film draeses, which are active as neutral (+) - 1-isopropylamino- 3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol-fumarate or racemic 1-isopropylamino-3- [o- ( pyrrol-1-yl) -phenoxy] -2-propanol hydrochloride.

Composition:

Core: active substance 10.0 mg 10 silica airgel (Aerosil 200) 2.5 mg cellulose (Avicel PH 102) 34.0 mg lactose, crystalline 174.0 mg magnesium stearate 1.5 mg sodium carboxymethyl starch 18.0 mg 15 240, 0 mg

Coating: Hydroxypropylmethyl cell 1ulose (Cell 1ulose-HP-M-603) 3.3 mg 20 glycerylpolyethylene glycol oxystearate (Cremophor RH 40) 0.2 mg iron oxide, reduced 0.2 mg talc (PH) 2.9 mg titanium dioxide (PH) 0 .4 mg. 7.0 mg

Total weight 247.0 mg

Preparation method: The components of the core are mixed and the homogeneous mixture is pressed into tablets.

The tablets are coated with the lacquer, which consists of the described constituents, which again e.g. dissolved or suspended in water.

In an analogous manner as in the formulation examples A-D, compositions with different active ingredient content can be prepared, wherein the (+) enantiomer resp. the racemate can also be processed in free form or in the form of another pharmaceutically applicable, non-toxic salt.

8702 53 3

Claims (12)

1. (+) - 1-isopropylamino-3- [o- (pyrrol [1-yl) -phenoxy] -2-propanol or a salt »especially pharmaceutically usable, non-toxic salt thereof. 2. (+) - 1-isopropylamino-3-ro- (pyrrol-1-yl) -phenoxy] -2-propanol or a salt, in particular a pharmaceutically usable, non-toxic salt thereof, for use in a process for the therapeutic treatment of the human or animal body. 3. Process for the preparation of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol and its salts, characterized in that a) racemic 1-isopropylamino -3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a salt thereof splits into the (+) enantiomer, or b) an enantiomer of formula 1, wherein, on the one hand, X 1 and X 2 together - O- or alternatively represent Xj hydroxy and X2 reactive esterified hydroxy, especially halogen or sulfonyloxy, with isopropylamine conversion, or c) hydrolyzing the (R) enantiomer of formula 2, or d) of the (R) enantiomer compound of formula 3, wherein Sch represents a group used for the protection of amino groups, cleaves the protecting group, or e) builds the pyrrole-1-yl ring starting from the (R) -enantiomer of formula 4 and / or converting obtained free (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol into a salt or an obtained salt of 25 (+) - 1-isopropylamino- 3-Co- (pyrrole-1-yl) -phenoxy] Converts -2-propanol to the free enantiomer. 4. Pharmaceutical preparations containing as active substance (+ j-1-isopro-pylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutically usable, non-toxic salt thereof. Pharmaceutical preparations according to claim 4 for the treatment of anxiety states, which can be used as active ingredient (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutical, non-toxic salt thereof. Pharmaceutical preparations according to either of Claims 4 and 5, 35, characterized in that the active substance is the fumarate of (+) - 1-isopropylamino-3-Eo- (pyrrol-1-yl) -phenoxy] - 2-propanol is used. Pharmaceutical preparations according to any one of claims 4-6, characterized in that the active substance in daily doses of less than 40 mg po, in particular from about 10 to about 40, 0.5 mg po, in the first rather than 3.5 to 0.5 mg po. 870253 3 r '-v- 8. Use of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutically usable, non-toxic salt thereof, for the preparation of pharmaceutical preparations for the treatment of anxiety states. Pharmaceutical preparations for the treatment of anxiety, which contain as active substance 1-isopropylamino-3- [o- (pyrrol-1-yl} -fe-ηοίθΟ-2-propanol or a pharmaceutically usable, non-toxic salt thereof). Pharmaceutical preparations according to claim 9, characterized in that the hydrochloride of 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol is used as active substance. Pharmaceutical preparations according to claim 9 or 10, characterized in that the active substance is administered in daily doses of less than 40 mg p.o., primarily from 3.5 to 0.5 mg p.o. Use of 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a pharmaceutically usable, non-toxic salt thereof for the preparation of pharmaceutical preparations according to any one of claims 9 to 11 . ++++++++++ 870253 3 • T · ÏS ^ »· / \ ·« · · · I> \ A Urii, A. =. / \ o i> v! JL. Y o Vch (ch3) 2 Ó-CH2-CH — CH2 A y \ I> \ / 0H O-CH 2 -Ol-CH 2 —N-CH (CH3) 2 Sch 4 / \. HzN-i ^ Jè-CHa-IH-CHa-HH-ilHi CH3) a 870 2 53 3