DD266351A5 - PROCESS FOR PREPARING (+) - 1-ISOPROPYLAMINO-3- [O- (PYRROL-1-YL) -PHONOXY] -2-PROPANOL - Google Patents

Abstract

The invention relates to a process for the preparation of () -1-isopropylamino-3- & 0- (pyrrol-1-yl) -phenoxy! -2-propanol and its salts. The production takes place z. In such a way as to separate racemic 1-isopropylamino-3- & 0- (pyrrol-1-yl) -phenoxy-2-propanol or a salt thereof into the () -enantiomer. Further variants of the method are described. The compounds of the invention are used in pharmaceutical preparations for the treatment of anxiety. Likewise provided by the invention is the use of the racemic 1-isopropylamino-3- & 0- (pyrrol-1-yl) -phenoxy! -2-propanol or a pharmaceutically acceptable, non-toxic salt thereof and pharmaceutical compositions containing such an active ingredient for the treatment of anxiety ,

Description

Characteristic of the known state of the art

No. 2,109,313, inter alia, describes racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxyl-2-propanol. The substances disclosed in this reference can be used as beta-receptor blockers, some with anti-inflammatory properties. These properties were noted in the Pargylln reserpine antagonism test. In this test model the inhibition of unmotivated hyperactivity caused by test substances is determined, which occurs as a result of pharmacogenetically induced noradrenaline release. Inhibition of the hyperactivity thus produced occurs at higher dosages, i. In the same dose range as exhibited by beta-receptor-blocking events. As daily drug dosing, about 30 bjs 240 mg were suggested when tablets were administered.

Object of the invention

The compounds according to the invention have pronounced anxiolytic properties. In addition, the (+ (• enantiomeric nootropic and antidopressive effect.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of (+) - 1-l8opropylamlno-3- | o- (pyrrol-1-yl) -phenoxy) · 2-propanol and its salts available.

Surprisingly, it has now been found that (+) - 1-leopropyl-amlno-3- | o- (pyrrol-1-yl) -phenoxy) -2-propanol in free form or in the form of a pharmaceutically acceptable non-toxic salt is not relevant ß-blocking, but has pronounced anxiolytic properties. In addition, the (+) enantiomer exhibits nootropic and antidepressant activities, and thus the object of the invention is (+ 1-1 -leopropylamino-3- [o- (pyrrol-1-yl) -phenoxy) -2-propanol or a salt, in particular a pharmaceutically acceptable, non-toxic saliva thereof.

Pharmaceutically usable salts of the respective active ingredient are its pharmaceutically acceptable acid addition salts, for example with strong inorganic acids, such as mineral acids, with sulfamic acids, such as Cycloniederalkyleulfamlnsäuren with strong organic carboxylic acids, such as Niedoralkancarbonsäuren, optionally unsaturated dicarboxylic acids or substituted by hydroxy and / or oxo Niedoralkancarbonsäuren, or Sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, for example the corresponding sulfate, phosphate, hydrohalide, such as hydrochloride or hydrobromide, cyclohexylsulfamate, acetate, malonate, oxalate, malelnate, fumarate, citrate, tartrate, pyruvate and sulfonate, in particular methane sulfonate, also benzene or p-toluenesulfonate. A preferred pharmaceutically acceptable salt of the (+) enantiomer is the corresponding fumarate, while the racemate is preferably used as the hydrochloride. Unless defined otherwise, substructures denoted by "lower" are preferably to be understood as meaning those containing up to and including 7, especially up to and including 4 carbon atoms (C atoms) Form and in the form of its pharmaceutically acceptable salts are understood above and below by the free compound or its pharmaceutically acceptable salts meaningful and appropriate, if appropriate, also the corresponding pharmaceutically acceptable salts or the free compound.

The active ingredient according to the invention can also be present in the form of its hydrates or other pharmaceutically acceptable solvents, for example those which are used for the crystallization of the corresponding active ingredient which is present in solid form.

The characteristic anxiolytic profile of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol results, for example, from the results of Geller-Tostes, (J. Geller, Psyc. iopharmacologia, 3, p. 374ff. (1962)) in which rats are exposed to a foot-shock induced conflict situation proves (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] - 2-propanol as a strong anxiolytic. In this test, the feet of the experimental animals are periodically subjected to electric shock when operating a food release lever. Normally, the reaction to punishment is suppressed only when high doses of anxlolytic drugs are administered. In a group of rats receiving a dose of 3mg / kp p.o. of (+ 1-1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy-2-propanol react as early as about 80% of the experimental animals with a marked increase in HebelbedienungshSumigkeit during the shock phase.

In particular, significant anxiolytic effects were observed when the drug was administered in social conflict situations in rhesus monkeys. The experimental basis for this social conflict test analogous to J. Jaekel in Biological Psychiatry (research results), W. Kemp (ed.), Springer Verlag, Heidelberg, 1986, is the hierarchical ranking attached

Rhesus monkeys. The relative Rankstotuu of an animal is the determining factor for intorindividuelle communication, z. For aggression or mutual social cleaning. Normally, animals with low rank status are suppressed by higher group members. These repressed animals retreat into social isolation and anxiously avoid any social contact. Repeated Drug Administration Doses of 0.2 mg / kg po in groups of 5 and 7 monkeys, respectively, resulted in a significant reduction in the anxiety behavior patterns of the respective monkeys, which are ranked lowest. Likewise, they actively took up social contacts and became partners in caring, even though they had never been caregivers before. These effects are unseen as marked anxiolyso. In test models on rhesus monkeys as well as on rats, an additional nootropic and anti-infective component could be detected. Thus, (+) - 1-leopropylamino-3- [o- (pyrrol-1-yl) -phenoxy) -2-propanol in a double-blind study in rhesus monkeys versus placebo in the "delayed-match-to-sample" test According to the methodology of HF Harlow et al., J.Comp.Pyelol.Psychol., 53, 131-121 (1960), for example, with 1 mg / kg po, a significantly increased success rate in the deficit range means that Zeitverzöge ^r ung in seconds after which a monkey has a Dlskriminationserfolg of <76%. Furthermore, the Verzögerungsztilten for the deficit area to an average of 20 seconds could be increased. in addition to these nootropic effects and antidepressant properties were observed in dlosem test. the rhesus monkeys namely showed clear increases in motivation and motivation, and their interest in the tasks assigned and their willingness to work together increased significantly.

The nootropic or t ntidepressive Wirkungskompononte could also be manifested in studies with rats. For example, in a complete low-labyrinth analogous to the model of JB Watson, Animal Education, Contrib. Psychol. Lab. Univ. Chicago, 4, Ί-112 (1903) noted a significant improvement in the orientation performance of rats due to a lower error rate (nootropic effect). In response to motivational or drive-enhancing effects, the significantly shorter runtimes of the rats compared to placebotieren from the start to the rewarded target, which suggests antidepressive Elgensc'iaften the active subtle.

Further, (+ 1-1 -lsopropyln-methyl-3- [o- (pyrrol-1-yl) -phenyl) -2-propanol on rats in the screening model of S. Bischoff et al., Europ. J. of Pharmacology 104,173 -176 (1984), in vivo dose-dependent elevations of ³ H-splperone influx of stratial dopamine receptors.

Thus, (+) - 1-inopropylamino-3- | o- (p -rol-1-yl) -phenoxy) -2-propanol has a pronounced and specific anxiolytic profile as it reduces, for example, aggressive stooping and, most importantly, to an improvement in positive social behavior. Furthermore, this (f!) Enantiomer is clearly nootropic and antidepressant Accordingly, (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) phenox]] - 2-propanol or a pharmaceutically acceptable, non-toxic salt of which in the treatment of anxiety, in particular of generalized (chronic) anxiety, panic disorders, obsessive compulsive behavior and prioblen, such as social phobias, neophobia (fear of new) and agoraphobia (claustrophobia), in the treatment of domentia of any kind, eg. Alzheimer's disease and age-related and traumatic learning and memory deficits, as well as in the treatment of depression.

Another object of the invention is thus the use of (+ M-isopropylamino-3- | o- (pyrrol-1-yl) phenoxy] -2-propanol or a pharmaceutically acceptable, non-toxic salt for the treatment of anxiety, of thorns of any kind and depression and the manufacture of pharmaceutical preparations for the treatment of anxiety, all types of dementia and depression.

Another object of the invention are processes for the preparation of (+) - 1-isopropylamino-3- | o- (pyrrol-1-yl) -phenox "l" propanol and its salts, which can be carried out in a conventional manner and z. B. characterized in that one

a) racemic 1-l8propylamino-3- (o- (pyrroM-yl) -phenoxy] -2-propanol or a salt thereof In which (+ (- enantiomer separates, or

b) an enantiomer of the formula

^s _N _i ¹ J (I),

0-CH ₂ -CH-CH ₂

wherein on the one hand X ₁ and X ₂ together are -O- or on the other hand X, hydroxy and X ₂ reactive esterified hydroxy, especially halogen or sulfonyloxy, is reacted with isopropylamine, or c) the (R) -antantomers of the formula

-s Λ, κ

(I) -CH ₂ -CH-CH ₂ hydrollsiert, or

d) of the (R) -enantiomeric compound of the formula

• CXI · ·

L> ~ v · o "

0-CH ₃ -CH-CHa-N-CH (CH ₃ ) ₃ h

in which Sch represents a group used for the protection of amino groups, the protective group is split off, or e) starting from the (R) -antantomer of the formula

♦ ·

Y? ^H

0-CH ₂ -CH-CH ₃ -NH-CH (CHa) ₃

building the pyrrol-1-yl-ring, and / or, available free (+) - 1-leopropylarno-3- (o- (pyrrol-1-yl) -phenoxyj-2-propanol converted into a salt or an available salt of (+) - 1-isopropylamino-3-IO- (pyrrol-1-yl) -phenoxy) -2-propanol converted to the free enantiomer.

The reactions described above and below in the variants are carried out in a manner known per se, for example in the usual or customary manner in the presence of a suitable solvent or diluent or a mixture thereof, where rrmn, as required, with cooling, at room temperature or below Admit men, ζ. S. In a temperature range of about -10 ° to Siedetempuratur of the reaction medium, preferably from about -10 ° to about 15O ⁰ C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and / or under anhydrous conditions is working.

The above and below listed starting material of the formula I, II and III, which was developed for the preparation of the compound of the invention and its salts, is known in part or can also by known methods, for. B. analogously to the process variants described above, are produced.

Starting materials with a basic center can, for. Example, in the form of Säuruaddltiunssalzen, for example, with the above listed in connection with salts of the compound of the invention acids. In the context of the process description above and below means reactive esterified hydroxy, unless otherwise defined, in particular esterified with a strong inorganic acid or organic sulfonic acid hydroxy, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, z. For example, fluoroulfonyloxy, optionally, z. B. substituted by halogen, substituted Ci-C ₇ -Alkansulfonyloxy, z. Methane or trifluoromethanesulfonyloxy, C ₃ -C ₇ cycloalkanesulfonyloxy, e.g. B. cyclohexanesulfonyloxy, or optionally, for. B. by C ₁ -C ₇ alkyl or halogen, substituted benzenesulfonyloxy, z. For example, p-bromophenyl or p-toluenesulfonyloxy.

Arylmethyl, such as mono-, di- or triphenylmethyl, in the first place benzyl, is suitable in particular as amino-protecting group Sch.

If, for example, bases are used in the reactions described above and in the following, for example alkali metal hydroxides, hydrides, amides, alkoxides, carbonates, triphenylmethylidene, di-C, -C ₇ , are used, unless stated otherwise. Alkylamlde, -amino-C, -C ₇ -alkylamides or -C, -C ₇ -alkylsilylamide, naphthalenamine, C, -C ₇ -alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines in question. Examples which may be mentioned are lithium hydroxide, sodium hydroxide, hydride, amide, ethylate, potassium tert-butylate, carbonate, lithium tri-phenylmethylidene, diisopropylamide, kallm-3- (aminopropyl) amide, bis (temethylsilyl) amide, dimethylaminonaphthalene, Di- or triethylamine, pyridine, Benzyltrlme'hylammonlumhydroxld, 1,5-diazabicyclo (4.3.0 | non-5-ene (DBN) and 1,8-Dlaza-bicyclo [5.4.0] undec-7-ene ( Depending on the choice of the starting material, the above process variants can be conducted in such a way that the respective synthesis proceeds enantioselectively, ie one of the possible enantiomers can be obtained exclusively or predominantly

Option A):

Racemic 1-isopropylamino-3-pyrol-1-yl) -phenoxy) -2-propanol can be decomposed by known methods into the optical antipodes, for example by Umkristallisatlon from an optically active solvent, chromatography on chlralen adsorbents, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of Eirischlußverbindungen, z. Using chiral crown ethers, where only c is complexed in enantiomer, or by conversion to diastereomeric salts, e.g. By reacting the basic racemate with an optically active acid such as carboxylic acid, e.g. As almond, tartaric or malic acid, odor sulfonic acid, eg. B. camphorsulfonic acid, and separation of the diastereomeric mixture obtained on this catfish, z. Due to their different solubility in the diastereomers from which the desired enantiomer can be released by the action of suitable means.

Variant b):

When Xi and X ₂ of formula I are -O-, the corresponding (R) -enantiomer is used. The implementation of this enantiomer

is preferably carried out with an excess of isopropylamine.

For the reaction of the compound of the formula I in which X _{2 is} preferably halogen, such as chlorine or bromine, furthermore sulphonyloxy,

and Xi is hydroxy, the (S) -enantiomeric form is used. The conversion of such enantiomoron dui formula I into the enantiomer according to the invention can be carried out, for example, in the presence of one of the abovementioned analogous bases, but in the first place an excess of isopropylamine is used.

Variant c):

The hydrolysis of the (R) -enantiomer of the formula II can be carried out in particular in the presence of a base, Ir. first line through

alkaline hydrolysis, e.g. B. in the presence of an alkali metal hydroxides, such as sodium hydroxide

Variant d):

The cleavage of Amlnoechutzgruppe Sch from the (R) -enantlomeren compound of formula III is carried out in per se known Welso. So z. B. Benzyl Sch are split off by catalytic ^ hydrogenation. As hydrogenation catalysts come z. B. elements of the VIII. Subgroup of the Periodic Table of the Elements or their Derivatives such as palladium, platinum, platinum oxide, ruthenium, rhodium, tris-triphenylphosphine-rhodolum-1-halo, e.g.

Chloride, or Raney nickel, which are optionally supported on a support material, such as activated carbon, alkali metal carbonate or sulfate or a silica gel. Palladium is used as the preferred catalyst.

Method e): The construction of the pyrrole ring, starting from the preaction of the formula IV, takes place in a manner known per se. That's the way to do it

for example, the compound of formula IV with a 2,5-Dinieaeralkoxytetrahydrofuran, z. B. 2,6-Dlmethoxy-tetrn'iydrofuran, advantageously in the presence of an acid, for. As acetic acid, and with heating, for. B. at reflux temperature of the reaction medium, implement.

Salts of the preliminary preparation according to the invention can be prepared in a manner known per se. This is how you get, for example

corresponding acid addition salts by treatment with an acid or a suitable ion exchange reagent. Salts can be converted in the usual way into the free compounds, Säuroadditlonssalze z. R. by treating with a suitable basic agent.

Jo by procedure or Rer.ktionsbedingungen can the compounds of the invention with salt-forming, In particular basic properties, in free form or preferably in the form of salts can be obtained. The output matorlal listed in the process variants is in part known or can be produced in catfish known per se. The preparation of racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy) -2-p-opanol is e.g. In DE-OS No. 2,209,313

described.

The compound of the formula I in which X) and Xj are -O- can be prepared, for example, by reacting e.g. B. from

(R) -2,2-dimethyl-1, S-dloxolan ^ -methanol p-toluenesulfonate starting with an alkali metal salt of 2- (pyrrol-1-yl) -phenyl to (S) -2,2- ^r viHiethyl 4 - {(o- (pyrrole-T-yl) -phenoxy] -methyl} -1,3-dloxolane.

After (ahydrolysis, formation of the tosylate and subsequent treatment with any of the above bases, e.g. Natri ', methylate, the (R) -1,2-epoxy-3- (o- (pyrrol-1-yl) -phenoxy) propane of Formol I is accessible. This after acid hydrolysis

of the (S) -2,2-dimethyl-4 - {[o- (pyrrol-1-yl) -phenoxy] -methyl} -1,3-dloxolane obtainable DIoI, ie fine compound of formula I, wherein X) and H ₂ hydroxy may advantageously also be obtained by reaction with an orthoester, eg

Orthoesslgsfturetrlmethylester be converted into the corresponding cyclic Orthoesterform whose ring opening, z. B. Trimethylchlorosilane, and subsequent cyclization of the thus obtainable chlorohydrin with a base, for. B. sodium hydroxide, for

corresponding compound of formula I wherein Xt and X ₂ together form -O-.

The compound of formula II is z. B. preparable by reacting (R) -3-isopropylamino-4- (p-toluenesulfonyloxymethyl) -oxazolidin-2 ·

on with o- (pyrrole-1-yD-phenol in the presence of a base, e.g., sodium hydride, and a solvent, e.g., DMF.

For example, (R) -1,2-epoxy-3- [o- (pyrrol-1-yl) -phenoxy) -propane can be used to prepare a compound of formula III

go out and this with appropriately protected Isopropylamln, 7. B. N-benzyl Isopropylamln, implement.

For the preparation of the compound of formula IV can be emanated, for example, from 2-nitropnenol, this first with

(S) -glycidol condense and then with Isoproj. to treat idmln. In the next reaction step, the nitro group, for example by catalytic hydrogenation in the presence of a hydrogenation catalyst, for. As Pd / C or Raney Niokel, to

Amino group can be reduced. In the preparation of the respective starting compounds, as a result of a substituent change associated with a Priority changes the designation of the configuration, even if no stereochemical changes directly on the Chiralltätszentrum take place. However, the enantioselective synthesis is always carried out so that those enantiomeric Starting materials are prepared which lead directly to the enantiomer of the invention. Furthermore, racemic Starting material to be separated in the entsewchende required form by conventional resolution. Furthermore, it was surprisingly found that the racemate 1 • isopropylamino-3- [o- (pyrrol-1-yl) phenoxy] -2-propanol and

corresponding Pharmnzeutisch usable, ntchttoxischs salts thereof in addition to those associated with the ß-blockade

Effects as an additional component of activity has pronounced anxiolytic activities. This anxiolytic Properties are well prepared at dosages where beta-receptor-inhibiting effects are still absent.

1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy-2-propanol thus has the additional property of inducing anxiety

To normalize hyparactivity or inhibited behavior occurring in anxiety states in an increase in drive

accordingly, and accordingly also has an "anti-long-term effect".

The characteristic anxiolytic profile of 1-isopropylamino-3- (o- (pyrrol-1-yl) -phenoxy) -2-propanol is given by way of example

from the inhibition of hyperactivity of rats kept in isolation as measured by their locomotor and exploratory fetus, with maximum effects at a dose of 0.01-0.1 mg / kg p. o. be achieved (analogous to the

Methodology of R. Weinstock et al., Psychopharmacologia 30, 241 ff. [1973]). The hyperactivity of isolated rats

on the other hand, in the case of propranolol it was possible to administer it only at a dose of 0.3 mg / kg p.o. maximum inhibited.

Also in the above-described Geller test, 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy) -2-propanol proves to be

strong anxiolytic. One of a group of 29 rats given a dose of 20 mg / kg p.o. of 1-isopropylam! n-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol, already 50% of the experimental animals react with a marked increase in the

Lever handling frequency during the shock phase, with an increase of 300% in individual animals. In this Footshock test resulted in a dosage of 20mg / kg propanolol p. o. in rats no significant behavioral change. In particular, significant anxolytic effects have been shown when administering the drug in social conflict situations Rhesus monkeys In the social conflict test described above, according to Jaekel. Repeated active ingredient in canned cans

from 0.1-0.3 mg / kg p.o. in groups of 7 monkeys resulted in a significant reduction of the anxious behavioral pattern of the

Monkeys ranked lowest in rank order and social contacts increase. Likewise, they took

actively got in touch and became partners with Pflegan, even though they had never been caregivers before. These effects were observed in both high-level groups of soybean contacts and groups with little nursing partnerships.

After administration of 0.3-3.0 mg / kg p.o. Oxprenolol could not increase the behavior of rhesus monkeys Social contacts of monkeys with low ranking are observed. At a dose of 0.5-10.0 mg / kg p. o. Propranolol

The social contacts of rhesus monkeys with low rank status were relatively little affected. As expected, dloso-dominated anxlolytic profile was not detected in the standard beta-receptor blockers oxprenolol and in propranolol to a much lesser extent only at beta-receptor-blocking dopants. In contrast, the racemate has this effect on ß-blocking acting dosages.

The Active Ingredient to be Used According to the Invention Is Still a Potent Selective Antagonist of Presynaptic Serotonin

1 B receptor (5-HTi b)> while propranolol and oxprenolol are less or less selective as they also react with the post-synaptic 5-HT, _A receptor.

The above-mentioned pharmacological studies thus document that 1-isopropylamino-3- | o-! Pyrrole-1

yl) -phenoxy] -2-propanol has a significant anxiolytic activity, and this manifests itself even at low dosages and thus a clear differentiation between anxiolytic and beta-receptor inhibitory activity occurs.

So surprising is the fact that the anxiolytlsche profile of this drug even in non-betarezeptorenblockierenden

effective doses in both the animal model as well as in humans extremely. is imprinted. Confirm the latter

Investigations on inpatients. Due to a drug-blind double-blind study involving more than 100 inpatients, it is considered surprising

when administering a daily dose of 2 mg p.o. significant, at least as potent, anxiolytic effects were achieved as when administering a daily dose of 4 mg p. o. The inventively used drug.

It has also been found that, for example, at low daily doses, such as 2 mg and 4 mg p. o "no cardiovascular effects

have occurred, d. H. no ß-blockade was detected. The same is to be expected when using dos (+) enantlomors.

The treatment of anxiety in humans may accordingly be preferred in the case of long-term receptor blocking Dosages done. This means on the one hand a higher selectivity in the therapy, on the other hand i.M thereby also one

Considerable reduction of side effects that can be caused by high doses of active ingredient.

Accordingly, 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy) -fc-propanol or a pharmaceutically acceptable,

non-toxic salt thereof in the treatment of anxiety, particularly generalized (chronic) / - ^y nstzuetänden, panic disorders, obsessive compulsive behavior and phobias such as social phobia, neophobia (fear

I 'euem) and agoraphobic (claustrophobia). In the above-mentioned test arrangements according to H.F. Harlow et al. and J. B. Watson were able to use the Dosages no aussagefa ¹ & Saints observations regarding nootropic and antidepressant properties of racemic

1-isopropylamino-3- (o- (pyrrol-1-yl) -phenoxy] -2-propanol.

Another object of the invention is therefore the use of 1-isopropylarr> ino-3- (o- (pyrrol-1-yl) -phenoxy) -2-propanol

or a pharmaceutically acceptable non-toxic salt for the treatment of anxiety disorders and for the preparation of pharmaceutical preparations for the treatment of anxiety.

The present invention also relates to pharmaceutical compositions containing as active ingredient (+) - 1-isopropylamino-3- | o- (pyrrol-1-yl) -

phenoxy] -2-propanol, which is in pure form or in a pure form, or a pharmaceutically acceptable non-toxic salt thereof, as well as pharmaceutical preparations for the treatment of anxiety, containing racemic 1-isopropylamino-3- (o - (pyrrol-1-yl) phenoxy) -2-propai: ol or a pharmaceutically acceptable, nichttoxlscheu salt thereof, as well as processes for the preparation of such more pharmaceutical preparations.

In the case of the pharmaceutical preparations according to the invention which are proposed for use according to the invention Containing a compound or a pharmaceutically acceptable salt thereof are those for enteral, such as oral,

further, rectal, and parenteral administration to warm-blooded animals, wherein the pharmacologically active ingredient is contained alone or together with a pharmaceutically acceptable carrier material.

The new pharmaceutical preparations contain z. B. a therapeutic, z. B. anxlolytiscnen or nootropic as well

antidepressant effect-producing amount, such as from about 0.5%, preferably from 1.0%, of the active ingredient. Egg pharmaceutical preparations for enteral or parenteral administration are e.g. B. those in dosage unit forms, such as

Dragees, tablets, capsules or suppositories, and ampoules. These are in a conventional manner, for. B. by means

conventional mixing, granulating, coating, solution or lyophilization process. Thus, man-pharmaceutical preparations for oral use may be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture as obtained, and, if desired or necessary, processing the mixture into tablets or dragee cores, if desired or necessary.

Suitable carriers are in particular fillers, such as sugars, for. Lactose, sucrose, mannitol or sorbitol, Collulins and / or calcium phosphates, e.g. Tricalcium phosphate or cetilcium hydrogen phosphate, furthermore binder,

such as starch gums, using corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, if desired, disintegrants such as the above-mentioned starches, further carboxymethylstarch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof like sodium alginate. Aids are in the first place

Flow regulators and lubricants, e.g. As silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate,

and / or polyethylene glycol, dragee cores are provided with suitable, optionally gastric juice-resistant coatings, which u. a. concentrated sugar solutions, which may be Arabic gum, talc, polyvinylpyrrolidone,

Polyethylene glycol and / or titanium dioxide, Lacklösungon in suitable organic solvents or Lösungsmitlgemgems or, for the production of gastric juice-resistant coatings, solutions of suitable Cellulose preparations such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate used. The tablets or Dragoe coatings may contain dyes or pigments, e.g. B. for identification or identification of various Drug cans, to be attached. Other oral pharmaceuticals include gelatin capsules and soft, closed capsules Gelatin and oil softeners such as glycerine or sorbitol. The capsules may contain the active ingredient in the form of granules,

z "in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers., In soft capsules, the active ingredient is preferably in suitable liquids,

such as fatty oils, paraffin oil or liquid polyethylene glycols, dissolved or suspended, stabilizers may also be added.

As rectally applicable pharmaceutical preparations come z. B. Supposltorlen into consideration, which consists of a combination of Active ingredients consist of a suppository base. As Supposltorienmasse z. Natural or synthetic Triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkenols. Furthermore, also Qolatine Rek'alkapsoln

used, which contain a combination of the active ingredients with a basic mass. As a base material, e.g. liquid triglycerides, polyethylene glycols or Paraffinkohlenwassorfstoffo in question.

For pnrenteralen administration are primarily aqueous solutions of an active ingredient in water-soluble form, z. B.

a water-soluble salt, furthermore suspensions of the active substance, such as corresponding oily injection pensions, wherein

suitable solvents or vehicles such as fatty oils, e.g. As sesame oil, or synthetic fatty acid esters, z. As ethyl oleate or triglycerides used or aqueous injection suspensions, which vlskoeltätserhöhende substances, eg. As sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also contain stabilizers.

The invention further relates to a process for the preparation of corresponding pharmaceutical preparations, for. B.

for the treatment of anxiety, which is characterized in that in a conventional manner (+) - 1 -lsopropylamino-3- (o- (pyrrol-1-yl) -phenoxy) -2-propanol or the corresponding racemate or a pharmaceutically acceptable, non-toxic

Salt thereof, if appropriate, admixed with customary auxiliaries and excipients to corresponding preparations. The dosage of the respective active substance depends on the warm-blooded species, the age and the individual condition as well as the Application catfish. Corresponding pharmaceutical preparations are preferably administered once a day. For example, daily doses of less than or equal to 40mg p. o. Be used. In particular, be Daily doses of about 10 to 0.5 mg, for example about 10 to 4 mg, in the first i.inin but 3.6 to 0.5 mg, more preferably

2 mg, p. o. administered. To reduce cardiovascular events attributable to beta-receptor blocking effects, daily doses of 4 and 3.5 to 0.5 mg, respectively, 2 mg, p.o. recommended.

The following examples illustrate the invention described above and are intended to provide a typical Explain the form of application, but in no way represent the only embodiments and application forms. In addition, the should Be limited by the Beisplelo in scope in any way. Temperatures are given in degrees centigrade. embodiments Manufacturing sheet 1;

27.4 g (10 μmol) racemic 1-isopropylamino-3- (o- (pyrrol-1-yl) -phenoxy-2-propanol and 16.7 g (11OmMoI) L - (+) ·

Mandelic acid are dissolved in 143 ml of water, allowed to crystallize overnight. The crystals are sucked off and

Recrystallized several times from water if possible until the mp. 122-123 ⁰ C and a pattern of the liberated base has an optical rotation of (a] J °: +12 ± 1 ⁰ C (c = 5% in methanol).

This gives (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy) -2-propanol as the salt of (+ (- mandelic acid, whose Enantiomeric purity was determined by ¹³ C-NMR as & 99% (90 MHz ₁ CDCl ₃ ). The oasis is then liberated with aqueous sodium hydroxide solution and extracted with ethyl acetate. Manufacturing label 2: Production of the neutral fumarate

6.4g (23mM) of crude (+) - 1-isopropylamino-3- (o- (pyrrol-1-yl) -phenoxy] -2-propanol and 1.45g (12.6mM) fumaric acid are dissolved in 45ml of isopropanol by heating .. After cooling, crystallises dissolved neutral (+) - 1-lsopropylamlno-3- | o- (pyrrol-1-yl) -phenoxy-2-propariol fumarate, mp 165-166 ⁰ C, (a] J ^0: + 19.4 ± 0.2 ⁰ C (c = 5.4% in water).

Herttellungsbelsplel 3: Advantageously, the enantiomeric resolution can also be based on a product in which the one enantiomer,

z. B. the (+ (- enantiomers, already enriched.

To crystallize z. B. from the racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol with (-! - Mandelic acid

preferably the (- (-. enantiomers by making alkaline with sodium hydroxide solution may be from the mother liquor attached to (+) - were isolated Enantiomerically enriched Base ¹ .η and (with (+ - mandelic acid (in the pure (+ - enantiomers are converted (analog Example 1 ).

Manufacturing label 4: A solution of 9.8 g (0.045 mol) of (R) -1,2-epoxy-3- [o- (pyrrol-1-yl) -phonoxy! -Propane and 26.9 g (0.455 mol) of isopropylamine in

100 ml of isopropanol are allowed to stand for 15 hours at room temperature. Evaporation of the volatiles gives crude (R) -1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol as a yellowish oil which is rotated [a] β ° +11, 8 ⁰ C ± 0.2 ° C has [c "· 5% in methanol !.

It forms a neutral fumarate of the mp. 165 ⁰ C (from isopropanol), (a) J ⁰ : + 19, O ⁰ C ± 0.2 ⁰ C (c = 5% in water). The starting epoxide can be prepared by methods described in the literature:

a) Auso (pyrrol-1-yl) -phonol and (R) -2,2-D! methyl-1,3-dioxolane-4-methanol p-toluenesulfonate is obtained by means of sodium hydride in DMF, the (S) -2 , 2-Dilethyl-1- {- (pyrrol-1-yl) -phenoxy-methyl) -1,3-dioxolane of the mp 57-58X (from petroleum ether,

Ia) J ⁰ : + 24, O ⁰ C ± 0.2 ° C (c = 5% in methanol).

b) Hydrolysis of the Vorbindung described in a) in 80% liger acetic acid for 30 minutes at 8O ⁰ C gives the (R) -3- · o · (pyrrol-1-yl) -phenoxy] -propane-1,2-dlol ., mp 95-96 ⁰ C (from ether) | a) £ °: + 1.6 ⁰ C (c = 5.6% in methanol).

c) The oiol described under b) is converted to (2R / S, 4S) -2-methoxy-2-methyl-4 - {[o- (pyrrol-1-yl) phenoxy] with trimethyl orthoacetate by trifluoroacetic acid catalysis. -methyl) -1,3-dloxolane, which is used raw welter

d) The crude cyclic orthoester described under c) is converted into the chlorohydrin derivative by reaction with 2-n. Sodium hydroxide gives the (R) -1,2-epoxy-3- | o- (pyrrol-1-y-o-phenoxyl-propah The crude product is purified by "flat" chromatography on silica gel (elution with toluene) colorless oil shows an optional rotation of [a] & ° - -25.8 ⁰ C ± 0.2 ⁰ C, & 81.6 "C (c - 6.3% in methanol).

Formullorungsbeliplel 1:

Filmdragoee containing the active ingredient neutral (+) - 1-isopropylamino-3- | o- (pyrrol-1'yl) -phenoxy] -2-propanol fumarate or racemic Ri-leopropylarnino-S-lo-lpyrrol-i-yD- phonoxyl ^ -propanolhydrochlorld

Composition: Core:

Active ingredient 0.6 mg

Silica airgel (Aerosil 200) 2.6 mg

Cellulose (Avlcel PH102) 36.0 mg

Lactose, krist. 1BJ, 0mg

Magnuaium starch 1.5 mg

Native carboxy methyl starch 19.6 mg

240.0 mg coating: hydroxypropyl methylcellulose (Cellulose-HP-M-TTK) 3.30 mg Glycerylpolyethylenglycoloxystearat (CremophorRK40) 0.16 mg Iron oxide, red. 0.19 mg Talcum (PH) 2.93 mg Titanium dioxide (PH) 0.43 mg 7.0 mg

Total weight 247.0 mg

Formulation banner 2:

Filmdragees containing as active ingredient neutral (+) - 1-isopropylamino-3- | o- (pyrrol-1-yl) -phenoxyl-2-propanol fumarate or

racemischesi-lsopropylamlno-S-yO-i.o-tpyrroM-phenoxyll-i-nol-prop' hydrochlorld

Composition: Core:

Active ingredient 2.0 mg

Sillca airgel (Aerosil 200) 2.5 mg

Cellulose (Avicel PH102) 36.0 mg

Lactose, krist. 180.0 mg

Magnesium starch 1.5 mg

Sodium carboxymethyl starch 18.0 mg

240.0 mg coating: hydroxypropyl methylcellulose (Cellulose-HP-M-603) 3.3 mg Glycerylpolyethylenglycoloxystearat (CremophorllH40) 0.2 mg Iron oxide, red. 0.2 mg Talcum (PH) 2.9 mg Titanium dioxide (PH) 0.4 mg 7.0 mg

Total weight 247.0 mg

Formulation banner 3:

Filmdragoes containing as active ingredient neutral (+) - 1-isopropylamino-3-lo- (pyrrol-1-yl) -phenoxy) -2-propanol fumarate or

racemischesi-isopropylamino-S-loi.pyrrol-i-YLJ-phenoxy-i-propanol hydrochloride

Composition: 4.0 mg Core: 2.6 mg active substance 36.0 mg Silica airgel (Aerosil 200) 180.0 mg Cellulose (Avicel PH 102) 1,6mg Lactose, krist. 16.0 mg magnesium strength 240.0 mg Natr '^ mcarboxy'methylstärke coating; 3.3 mg hydroxypropyl methylcellulose (Cellulose-HP-M-603) 0.2 mg Glycerylpolyethylonglycoloxystoarat 0.2 mg (CremophorRH40) 2.9 mg Iron oxide, red. 0.4 mg Talcum (PH) 7.0 mg Titanium dioxide (PH) 247.0 mg total weight

Formulation banner 4:

Filmdragoes containing as active ingredient neutral (+) - 1-isopropylamino-3- | o- (pyrrol-1-yl) phenoxy) -2-propanol fumarate or racemic 1-isopropylamino-3- [o (pyrrole-1) yl) -phonoxy] -2-propanol hydrochloride

Composition:

active substance

Silica airgel (Aerosil 200)

Cellulose (Avicel PH102)

Lactose, krist.

magnesium strength

Natrlumcarboxymethylstärke

10.0 mg

2.5 mg 34.0 mg

174.0 mg

1.6 mg 18.0 mg

240.0 mg coating: hydroxypropylmothylcelluloso (Cellulose-HP-M-603) 3.3 mg Glycerylpolyethylenglycoloxystoarat (CremophorRH40) 0.2 mg Elsenic oxide, red. 0.2 mg Talcum (PH) 2.9 mg Titanium dioxide (PH) 0.4 mg 7.0 mg

total weight

247.0 mg

Production catfish:

The constituents of the core are mixed and the homogeneous mixture is purified in tablets.

The tablets are coated with the paint, which consists of the described ingredients, which in turn z. B. were dissolved or suspended in water.

In a manner analogous to that described in Formulation Examples 1-4, compositions having different active substance content can be prepared, wherein the (+) - enantiomer or racemate can also be incorporated in free form or in the form of another pharmaceutically acceptable, non-toxic salts 3.

Claims (4)

1. A process for the preparation of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy) -2-propanol and its salts, and optionally the usual pharmaceutical application forms, characterized in that a) resolving racemic 1-isopropylamino-3- [o- (pyrrol-1-yl) -phenoxy] -2-propanol or a salt thereof into the (+! -enantiomer or b) an enantiomer of the formula DO - J ^ * χ χ Ο · I ι ¹ ι ² U-CH ₂ -CH-CH ₂ wherein, on the one hand X ₁ and X ₂ together are -O-stand or on the other hand, X ₁ hydroxyl and X _{2 is} reactive presterified hydroxy, especially halogen or sulfonyloxy, is reacted with isopropylamine, or
c) the (R) -antantimo of the formula r \ r ii ' 0 ^/ N-CH (CH ₃ ) ₂ I ³²
0-CH ₂ -CH-CH ₂ hydrolyzed, or
d) of the (R) -enantiomeric compound of the formula b -CH ₂ -CH-CH ₂ -N-CH (CH ₃ ) ₂ Sch wherein Sch is a group usually used 7 ¹ τι protection of amino groups, the protective group splits off, or
e) starting from the (R) -enantiomer of the formula (IV), builds up the pyrrol-1-yl ring, and / or salable free (+) - 1-isopropylamino-2- [o- (pyrrol-1-yD-phenoxy) -2-propanol, or an available salt of (H) -1-isopropylamino-3- [o (pyrrol-1-yl) -phenoxy) -2-propanol converted into the free enantiomer and optionally the compounds or a pharmaceutically acceptable non-toxic salt thereof with conventional excipients and carriers processed usual pharmaceutical application forms. 2. The method according to claim 1, characterized in that the pharmaceutically acceptable salt is the fumarate of (+) - 1-isopropyl-3- (o- (pyrrole) -phenoxy] -2-propanol. 3. The method of claim \ or 2, characterized gekonnzeichnet that the active ingredient in a daily dose of less than or equal 40mg po, particularly etvvo 10 to about 0.5 mg po, mainly 3.5 to 0.5 mg po, incorporated. 4. The method according to claim 3, characterized in that the active ingredient in a daily dose of 2 mg p.o. is incorporated. Field of application of the invention The invention relates to a process for the preparation of (+) - 1-isopropylamino-3- [o- (pyrrol-1-yl) phenoxy] -2-propanol and salts which find use in the pharmaceutical industry.