GB2197315A - Anti-anxiety propanolamine derivatives - Google Patents

Description

1 GB2197315A 1

SPECIFICATION

Therapeutic compositions and use thereof 1 The present invention relates to the (+)-enantiomer of 1-isopropylamino-3[o-(pyrrol-1-yl)phenoxy]-2-propanol and salts thereof, to the use and preparation thereof and to pharmaceutical compositions containing said compound and to the preparation thereof. The invention further relates to the use of racemic 1-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2-propanol, or a pharmaceutically acceptable non-toxic salt thereof, and to pharmaceutical compositions containing such a compound for the treatment of anxiety states.

Racemic 1-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2-propanoI is disclosed in German Offenlegungsschrift 2 409 313. The compounds disclosed in this publication can be used as fl-receptor blockers, some of which have antianxiety properties. These properties were observed in the pargylin-reserpine antagonism test. This test model is used to determine the inhibition effected by test compounds of unmotivated hyperactivity which occurs as a consequence of the pharma- cogenically induced release of noradrenaline. The inhibition of this induced hyperactivity occurs at higher doses, i.e. in the same dosage range in which fl-receptor blocking properties are observed. The proposed daily dosage for the administration of tablets is in the range from about 30 to 240 mg. 20 Surprisingly, it has now been found that (+)-lisopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2-pro- 20 panol in the free form or in the form of a pharmaceutically acceptable non-toxic salt possesses marked anxioloytic, but no relevant fl-blocking, properties. In addition, the (+)-enantiomer has nootropic and antidepressant properties. Accordingly, the present invention relates to (+)-l-isopropylamino-3-[o(pyrrol-1-yl)phenoxy]-2- propanol or a salt thereof, especially a pharmaceutically acceptable non- toxic salt thereof.

Pharmaceutically acceptable salts of the respective compound are the pharmaceutically accept able acid addition salts thereof, for example with strong inorganic acids such as mineral acids, with sulfamic acids such as cyclo-lower alkylsulfamic acids, with strong organic carboxylic acids such as lower alkanecarboxylic acids, unsaturated or saturated dicarboxylic acids or lower alkane carboxylic acids which are substituted by hydroxy and/or oxo, or with sulfonic acids such as lower alkanesulfonic acids or unsubstituted or substituted benzenesulfonic acids, and are for example the corresponding sulfate, phosphate, hydrohalide such as hydrochloride or hydrobrom ide, cyclohexylsulfa mate, acetate, malonate, oxalate, maleate, fumarate, citrate, tartrate, pyruvate, and sulfonate, especially methanesulfonate, as well as benzenesulfonate or p-toluenesulfonate. A preferred pharmaceutically acceptable salt of the (+)-enantiomer is the corresponding fumarate, whereas the racernate is preferably used in the form of the hydrochloride. Unless otherwise indicated, moieties qualified by the term "lower" will be understood as meaning those containing up to 7 carbon atoms inclusive, preferably up to 4 carbon atoms inclusive.

Because of the close relationship between the respective active ingredient in the free form and in the form of its pharmaceutically acceptable salts, the references made throughout this specifi- 40 cation to the free compound and the pharmaceutically acceptable salts thereof also apply by analogy to the corresponding pharmaceutically acceptable salts and the free compound.

The compound eligible for use in the practice of this invention can also be in the form of its hydrates or may contain other pharmaceutically acceptable solvents in its crystal structure, for example those which are used for crystallising the active ingredient which is in solid form. 45 The characteristic anxiolytic profile of (+)-l-isopropylamino-3-[o(pyrrol-1-yl)phenoxy]-2-propa- nol is shown for example by the results of the Geller test [J. Geller, Psychopharmacologia, 3, p.

374 et seq. (1962)]. In this test, in which rats are subjected to a conflict situation induced by electroshocks administered to the feet, (+)-l-isopropylamino-3-[o-(pyrrol- 1-yl)-phenoxy]-2-propa- nol is shown to be a potent anxiolytic agent. In this test, electroshocks are periodically adminis- 50 tered to the feet of the test animals when activating a lever for releasing food. Normally the reaction to punishment is suppressed only on the administration of high doses of anxiolytic agents. In a group of rats to which a dose from 3 mg/kg of (+)-l- isopropylamino-3-[o (pyrrolyl)phenoxyl-2-propanol is administered p.o., 80% of the test animals react with a marked increase in the frequency with which the lever is activated during the shock phase.

In particular, significant anxiolytic effects have been observed by administering the active.

ingredient to Rhesus monkeys in social conflict situations. The experimental basis of this social conflict test according to J. Jaekel in Biologische Psychiatrie (research results), ed. W. Kemp, Springer-Verlag, Heidelberg, 1986, is the hierarchical order of precedence of Rhesus monkeys.

The relative social status of an animal is the determining factor in inter-individual communication, 60 e.g. aggression or reciprocal social grooming. Normally animals of low status are oppressed by members of the group further up the social scale. These oppressed animals withdraw into social isolation and timidly avoid any social contact. Repeated administration of the active indredient in doses of 0.2 mg/kg p.o. to groups of five and seven monkeys resulted in a significant reduction of the anxious behaviour pattern of those monkeys on the lowest rung of the social ladder. They 65 2 GB2197315A 2 also actively engaged in contact and participated in grooming, although they had previously never been partners in grooming. These effects are regarded as marked anxiolysis.

In test models carried out with Rhesus monkeys and rats, an additional nootropic and anticlepressant activity has also been observed. Thus in a double-blind study made with Rhesus monkeys, (+)-l-isopropylamino-3-[o-(pyrrol-1-yi)-phenoxy]-2-propanol, when administered in a dose of e.g. 1 mg/kg p.o. in the delayed matchingto-sample test in accordance with the method of H.F. Harlow et al., J. Comp. Physiol. Psychol. 53, 113-121 (1960), brought about a significantly enhanced success rate in the deficiency range compared woith results obtained with placebo. The deficiency range is the delay in seconds after which a monkey successfully overcomes discrimination by <75 %. In addition, the delay of the deficiency range was in- 10 creased by an average of 20 seconds. Besides these nootropic effects, antidepressant properties were also observed in this test. The Rhesus monkeys exhibited a marked increase in motivation and initiative, as their interest in the tasks given them and their readiness to participate increased siginificantly.

The nootropic and antidepressant activity was also observed in tests carried out on rats. Thus 15 in a complicated underground maze in accordance with the test model of J. B. Watson, Animal Education, Contrib. Psychol. Lab. Univ. Chicago, 4, 5- 122 (1903), a marked improvement of the rats' sense of orientation (nootropic activity) as a consequence of fewer errors was observed. As compared with the results obtained with animals treated with placebo, the significantly shorter times taken by the rats from start to rewarded finish indicate enhancement of motivation 20 and initiative and thus point to antidepressant properties of the active ingredient. Furthermore, in the screening test model of S. Bischoff et al. , Europ. J. of Pharmacology 104, 173-176 (1984), (+)-l-isopropylamino-3[o-(pyrrol-1-yi)-phenoxy]-2-propanoI induces in rats in vivo dosedependent increases of 3H-spiperone binding of stratial clopamine receptors. 25 Accordingly, (+)- 1 -iso pro pyla m i no-3 -[o- (pyrrol- 1 yl)-phenoxyl-2-pro pa nol has a pronounced and 25 specific anxiolytic profile, as for example it reduces aggressive behaviour and results in particular in an enhancement of positive social behaviour. This (+)enantiomer also has pronounced nootropic and antidepressant properties. Hence, (+)-l-isopropylamino-3-[o-(pyrrol-1-yl)phenoxyl-2propanol, or a pharmaceutically acceptable non-toxic salt thereof, can be used for the treatment of anxiety states, especially of generalised (chronic) anxiety states, panic disorders, obsessive compulsive behaviour, and phobias such as social phobias, neophobia (fear of the new) and agoraphobia (fear of open spaces), for the treatment of dementias of all kinds, e.g. of Alzheimer's disease, and of learning deficiency and impairment of memory resulting from age and trauma, as well as for the treatment of depressions. 35 Accordingly, the present invention relates to the use of (+)-l-isopropylamino-3-[o-(l-pyrrolyl)- 35 phenoxy]-2-propanol, or a pharmaceutically acceptable non-toxic salt thereof, for the treatment of anxiety states, clementias of all kinds and of depressions, and for the preparation of pharmaceutical compositions for the treatment of anxiety states, dementias of all kinds and of depressions. The present invention further relates to processes for the preparation of (+)-l-isopropylamino3-[o-pyrrol-1-yl)-phenoxy]-2-propanoI and salts thereof, which can be carried out in a manner known per se and comprise e.g.

a) resolving racemic 1-isopropylamino-[o-(pyrrol-1-yl)phenoxy]-2-propanol, or a salt thereof, into the (+) -ena ntio meter; or b) reacting an enantiometer of formula 0 DN 2 D-CH2- CH-CH2 wherein X, and X2 are, on the one hand, together -C- or, on the other hand, X, is hydroxy and X2 is reactive esterified hydroxy, preferably halogen or sulfonyloxy, with isopropylamine; or 55 c) hydrolysing the (R)-enantiomer of formula 3 GB2197315A 3 DNJ 1 or 0 N-CH(CH)2 CH2 (11) d) removing the protective group from the (R)-enantiomer of formula - 1 CN-q OH 1 0 - CH2 -G H -CH2 -N- CH(CH3)2 Cn wherein Sch is a group customarily employed for protecting amino groups; or 25 e) starting from the (11)-enantiomer of formula H2N-Jl, OH 1 O-CH -CH-CH2-NH-CH(CH)2 2 3 (IV) forming the pyrrol-1-yl ring, and/or converting free (+)-l-isopropylamino- 3-[o-(pyrrol-1-yl)-phe35 noxy]-2-propanol into a salt or converting a salt of (+)-l-isopropylamino- 3-[o-(pyrrol-1-yl)-phe- noxy]-2-propanol into the free enantiomer.

The reactions in the process variants described above and subsequently are conducted in a manner known per se, e.g. in the absence, or normally in the presence, of a suitable solvent or diluent or mixture thereof, and, as required, with cooling, at room temperature or with heating, 40 e.g. in the temperature range from about - 1 O'C to the boiling temperature of the reaction medium, preferably in the range from about - 10" to + 150'C and, if necessary, in a closed reactor under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

Some of the starting materials of formulae 1, 11 and III which have been developed for the synthesis of the compound of the invention and salts thereof are known or can also be obtained 45 by methods which are known per se, e.g. in accordance with the process variants described above.

Starting materials with basic centre can be obtained e.g. in the form of acid addition saltsl' for example with the acids cited above in connection with salts of the compound of this invention.

Within the scope of this description, reactive esterified hydroxy - unless otherwise specified - will be understood as meaning hydroxy which is esterified with a strong inorganic acid or organic sulfonic acid, and is e.g. halogen such as chlorine, bromine or iodine, sulfonyloxy such as hydroxysulfonyloxy, e.g. fluorosulfonyloxy, C,-C,alkanesulfonyloxy which is unsubstituted or substituted e.g. by halogen, e.g. methanesulfonyloxy or trifluormethanesulfonyloxy, C,-C,cycloal kanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or benzenesulfonyloxy which is unsubstituted or substituted by C,-C,alkyl or halogen, e.g. p-bromophenylsulfonyloxy or ptosyloxy.

A preferred amino protective group Sch is arylmethyl such as mono-, di- or triphenylmethyl, and is most preferably benzyl.

If, for example, bases are employed in the above described reactions, then these are typically - unless otherwise indicated - hydroxides, hydrides, amides, alkanolates, carbonates, triphenylme thylides, di-C,-Calkylamides, ami no-C, -C,a Ikyla m ides or C,-C,al kylsilylam ides of alkali metals, naphthaleneamines, Cl-C7alkylamines, basic heterocycles, ammonium hydroxides as well as car bocyclic amines. Exemplary of such bases are: lithium hydroxide, sodium hydroxide, sodium hydride, sodium amide, sodium ethylate, potassium tert-butylate, sodium carbonate, lithium tri phenylmethylimide, lithium diisopropylamide, potassium 3(aminopropyl)amide, potassium bis(tri- 4 GB2197315A 4 m ethyl silyl) a mide, climethylaminonaphthalene, cliethylamine or triethylamine, pyridine, benzyltrimethylammonium hydroxide, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0)undec-7-ene (DBU).

Depending on the choice of starting material, the above process variants can be carried out such that the respective synthesis proceeds selectively with respect to the enantiomer, i.e. one of the possible enantiomers can be obtained exclusively or predominantly.

Variant a): Racemic 1-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-propanoI can be resolved by known methods into the optical antipodes, for example by recrystallisation from an optively active solvent, chromatography over a chiral absorbent, with the aid of suitable microorganisms, 10 by cleavage with the specific immobilised enzymes, via the formation of inclusion compounds, e.g. using chiral crown ethers such that only one enantiomer is complexed, or by conversion into salts of diastereoisomers, e.g. by reaction of the basic racernate with an optically active acid such as a carboxylic acid, e.g. mandelic acid, tartaric acid or malic acid, a sulfonic acid such as camphorsulfonic acid, and separation of the mixture of diastereoisomers so obtained, e.g. on 15 the basis of their different solubilities, into the diasteroisomers from which the desired enan- tiomer can be isolated by treatment with a suitable agent. Variant b): If X, and X2 in formula 1 are -0-, the appropriate (R)-enantiomer is used. The reaction of this enantiomer is preferably carried out with an excess of isopropylamine. The (S)-enantiomer is used for the reaction of the compound of formula 1, wherein X2 is 20 preferably halogen such as chlorine or bromine, and also sulfonyloxy, and X, is hydroxy. The conversion of such an enantiomer of formula 1 into the enantiomer of the invention can be effected for example in the presence of one of the above mentioned inorganic bases; but most preferably the conversion is carried out with an excess of isopropylamine. Variant c): The hydrolysis of the (R)-enantiomer of formula 11 can be effected in particular in 25 the presence of a base, most particularly by alkaline hydrolysis, e.g. in the presence of an alkali 25 metal hydroxide such as aqueous sodium hydroxide. Variant d): The removal of the amino protective group Sch from the (R)enantiomer of formula Ill is effected in a manner known per se. Thus, for example, the benzyl protective group Sch can be removed by catalytic hydrogenation.

Examples of suitable hydrogenation catalysts are elements of subgroup Vill of the Periodic Table such as palladium, platinum, platinum oxide, ruthenium, rhodium, tri s (tri phenyl phos phine) rhodium(]) halide, e.g. tris(triphenylphosphi ne) rhodium (1) chloride, or Raney nickel, which catalysts may be applied to a carrier such as activated carbon, an alkali metal carbonate or alkali metal sulfate, or a silica gel. The preferred catalyst is palladium.

Variant e): The formation of the pyrrole ring, starting from the compound of formula IV, is effected in a manner known per se. Thus, for example, the compound of formula IV can be reacted with a 2,5-cli-lower alkoxytetrahydrofuran, e.g. 2,5- dimethoxytetrahydrofuran, conveni ently in the presence of an acid, e.g. acetic acid, and with heating, e.g. to the of the reaction medium.

Salts of the compound of this invention can be prepared in a manner known per se. Thus, for 40 example, corresponding acid addition salts are obtained by treatment with an acid or with a suitable ion exchange reagent. Salts can be converted in customary manner into the free compounds: acid addition salts, for example, by treatment with a suitable base.

Depending on the mode of synthesis or on the reaction conditions, the compounds of the invention having salt-forming, especially basic properties, can be obtained in the free form or 45 preferably in the form of salts.

The respective starting materials employed in the above process variants are either known or can be obtained in a manner known per se.

The preparation of racemic 1-isopropylamino-3-[o-(pyrrol-l-yi)-phenoxy]-2propanoI is described e.g. in German Offenlegungsschrift 2 409 313.

The compound of formula 1, wherein X, and X, are -0-, can be prepared for example by starting from (R)-2,2-dimethyl-1,3-dioxolane-4-methanol-ptoluenesuifonate, which is reacted with an alkali metal salt of 2-(pyrrol1 -yi) phenol to (S)-2,2-dimethyi-4- {[o-pyrrol-l-yi)phenoxy]methyl1,3-dioxolane. After acid hydrolysis, formation of the tosylate and subsequent treatment with one of the above mentioned bases, e.g. sodium ethylate, the (R)-1,2-epoxy- 3-[[o-pyrrol-l-yl)phe- 55 noxy]-propane of formula 1 is obtained. The diol obtainable after acid hydrolysis of (S)-2,2 dimethy]-4-[o-pyrrol-l-yl)phenoxy]methyll-1,3-dioxolane, i.e. a compound of formula 1, wherein X, and X2 are hydroxy, can also conveniently be converted by reaction with an orthoester, e.g.

trimethyl orthoacetate, into the corresponding cyclic orthoester form, the ring opening of which, e.g. with trimethylsilyl chlorsilane and subsequent cyclisation of the resultant chlorohydrin with a 60 base, e.g. aqueous sodium hydroxide, leads to the corresponding compound of formula 1, wherein X, and X2 together are -0-.

The compound of formula 11 can be prepared e.g. by reacting (R)-3isopropylamino-4-(p-tosy loxymethyl)oxazolidin-2-one with o-(pyrrol-l-yl)-phenol in the presence of a base, e.g. sodium hydride, and a solvent, e.g. dimethylformamide.

reflux temperature GB2197315A 5 The compound of formula III can be prepared for example by starting from (R)-1,2-epoxy-3-[o(pyrrol-1-yl)phenoxy]propane, which is reacted with suitably protected isopropylamine, e.g. Nbenzylisopropylamine.

The compound of formula IV can be prepared for example by first condensing 2-nitrophenol with (S)-glycidol and subsequently treating the condensate with isopropylamine. In the next reaction step, the nitro group can be reduced to the amino group, for example by catalytic hydrogenation in the presence of a hydrogenation catalyst, e.g. Pd/C or Raney nickel.

In the preparation of the respective starting compounds, the designation of the configuration can change owing to a change of substituent linked to a change in priority, even if no stereoche- mical changes take place direct at the centre of chirality. However, the enantiorner-selective 10 synthesis is carried out in each case such that those starting enantiomers are prepared that lead direct to the enantiomers of the invention. Further, racemic starting material can be resolved into the appropriate necessary form by conventional racernate cleavage.

The further surprising observation has been made that racemic 1isopropylamino-3-[o-(pyrrol-l- yl)phenoxyl-2-propanol and suitable pharmaceutically acceptable non-toxic salts thereof possess, together with the fl-receptor blockade activity, as additional property, a pronounced anxiolytic activity which takes effect even at doses that do not induce any P- receptor blockade activity. 1 lsopropylamino-3-[pyrrol-1-yl)phenoxy]-2-propanoI thus possesses the additional property of nor malising anxiety-induced hyperactivity and of transforming inhibited behaviour resulting from anxiety states into an increased output of behaviour, so that it also has an antianxiety effect. 20 The characteristic anxiolytic profile of 1-isopropylamino-3-[o-(pyrrol-1- yl)phenoxyl-2-propanoI is shown e.g. by the inhibition of hyperactivity in rats which are kept in isolation, and is deter mined from their locomotor and exploratory behaviour, the best effects being obtained at a dosage of 0.01 to 0.1 mg/kg p.o. [in accordance with the method described by R. Weinstock et aL, Psychopharmacologia 30, 241 et seq. (1973)]. When propranolol was administered, however, maximum inhibition of the hyperactivity of rats kept in isolation was only achieved at a dose of 0.3 mg/kg p.o. 1-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2- propanoI has also been found to be a potent anxiolytic agent in the above described Geller test. In a group of 29 rats to which a dose of 20 mg/kg of 1-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2- propanoI is adminis tered p.o., 50 % of the test animals react with a marked increase in the frequency with which 30 the lever is activated during the shock phase, the increase amounting to 300 % in individual animals. In this feet shock test, a dose of 20 mg/kg of propranolol adminstered to rats p.o. did not lead to any significant change in behaviour.

In particular, significant anxiolytic effects have been observed by administering the active ingredient to Rhesus monkeys in social conflict situations in the above described social conflict test according to Jackel. Repeated administration of the active ingredient in doses of 0.1 to 0.3 mg/kg p.o. to groups of seven monkeys resulted in a significant reduction of the anxious behaviour pattern of the monkeys on the lowest rung of the social ladder, and to an increase in social contacts. The monkeys also actively engaged in contact and participated in grooming, although they had previously never been partners in grooming. These effects were observed in 40 groups exhibiting a high level of social contact as well as in groups with few grooming partnerships. No increase in the social contacts of monkeys of inferior status was observed in the behaviour pattern of the Rhesus monkeys after administration of 0.3-3. 0 mg/kg p.o.. of oxprenolol.-A dose of 0.5-10.0 mg/kg p.o. of propranolol had relatively little influence on the social contacts of Rhesus monkeys of inferior status. As was to be expected, when the standard fl-receptor blockers, oxprenolol and propranolol, were administered, this pronounced anxiolytic profile was not found in the case of oxprenolol and was observed to a very much lesser degree in the case of propranolol and only at doses effecting fl- receptor blockade. By comparison, the racernate produced this effect when administered in doses that do not effect flreceptor blockade.

The compound eligible for use in the practice of this invention is also a potent selective antagonist of the presynaptic serotonin-113 receptor (5HT,,), whereas propranolol and oxprenolol exhibit a less selective activity, as they react also with the post-synaptic, 5-HT1A receptor.

The pharmacological investigations discussed above thus demonstrate that 1-isopropylamino-3- [o-(pyrrol-1-yl)phenoxy]-2-propanoI exhibits a significant anxiolytic activity, and also that this activity is clearly observed at lower doses and that there is accordingly a marked distinction between anxiolytic activity and fl-receptor blockade.

It is therefore a surprising fact that the anxiolytic profile of this compound is very marked even when administered to animals as well as humans in doses that do not effect fl-receptor block- ade. Tests carried out on inpatients confirm this finding.

A double-blind study carried out with more than 100 inpatients in three centres has produced the surprising result that administration of a daily dose of 2 mg p.o. of the compound eligible for use in the practice of this invention produced significant anxiolytic effects that were at least just as potent as those achieved by administration of a daily dose of 4 mg p.o. of the same compound.

6 GB2197315A 6 It was further observed that no cardiovascular effects were induced at low daily doses such as 2 mg and 4 mg p.o., i.e. no fl-receptor blockade was found. A corresponding result is to be expected when using the (+)-enantiomer.

Thus the treatment of anxiety states in humans can preferably be carried out at doses that do not effect fl-receptor, on blockade. This means, on the one hand, higher selectivity in therapy, 5 and the other, that consequently a substantial reduction of side-effects caused by high dosage may be expected.

Accordingly, 1-isopropylamino-3-[o-(pyrrol-1-yl)phenoxyl-2-propanol, or a pharmaceutically ac ceptable non-toxic salt thereof, can be used for the treatment of anxiety states, especially of generalised (chronic) anxiety states, panic disorders, obsessive compulsive behaviour, and pho- 10 bias such as social phobias, neophobia (fear of the new) and agoraphobia (fear of open spaces).

In the above described test procedures according to H.F. Harlow et al. and J.B. Watson, it was not possible, at the doses administered, to make any explicit observations with respect to nootropic and antidepressant properties of racemic 1 -iso pro pyla m i no- 3-[o-(pyrrol- 1 -yl) phenoxy]-2 propanol.

Accordingly, the present invention also relates to the use of 1isopropylamino-3-[o-(pyrrol-l- yl)phenoxyl-2-propanol, or a pharmaceutically acceptable non-toxic salt thereof, for the treatment of anxiety states and for the preparation of pharmaceutical compositions for the treatment of anxiety states.

The present invention also relates to pharmaceutical compositions which contain, as active ingredient, (+)-l-isopropylamino-3-fo-(pyrrol-1-yl)phenoxy]-2-propanol, which is in pure or substantially pure form, or a pharmaceutically acceptable non-toxic salt thereof, and to specific pharmaceutical compositions for the treatment of anxiety states, which compositions contain racemic 1-isopropylamino-3-[o-(pyrrol-1-yl)-phenoxy]2-propanoI or a pharmaceutically acceptable non-toxic salt thereof, as well as to processes for the preparation of such compositions.

The pharmaceutical compositions which contain the compound eligible for use in the practice of this invention, or a pharmaceutically acceptable non-toxic salt thereof, are those for oral, rectal and parenteral administration to warm-blooded animals, the pharmocological active ingredi ent being present alone or together with a pharmaceutically suitable carrier.

The novel pharmaceutical compositions contain e.g. a therapeutic amount, for example an 30 amount that produces an anxiolytic, nootropic and antidepressant effect, such as from about 0.5 %, preferably from 1.0 %, of the active ingredient. Pharmaceutical compositions for enteral or parental administration are e.g. those in dosage unit forms such as drag6es, tablets, capsules or suppositories, as well as ampoules. These pharmaceutical compositions are prepared in a man- ner known per se, for example by conventional mixing, granulating, confectioning, dissolving or 35 lyophilising methods. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture and processing the mixture or granulate, if desired or necessary after the addition of suitable excipients, to tablets or drag6e cores.

Suitable carriers are in particular fillers such as sugar, for example lactose, saccharose, manni- 40 tol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium biphosphate, and also binders such as starch pastes, e.g. maize, corn, rice or potato starch, gelatin, tragacanth, methyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, disin tegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Excipients are in particular glidants and lubricants, for example silica, talcum, stearic acid or salts thereof such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Drag6e cores areprovided with suitable coatings which can be resistant to gastric juices, using inter alia concentrated sugar solutions which may contain gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and/or 50 titanium dioxide, shellac solutions in suitable organic solvents or mixtures of solvents or, for the 50 preparation of coatings which are resistant to gastric juices, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to the tablets or drag6e coatings, for example to identify or indicate different doses of active ingredient.

Further pharmaceutical compositions for oral administration are dryfilled capsules made of gelatin and also soft sealed capsules consisting of gelatin and a plasticiser such as glycerol or sorbitol. The dry-filled capsules can contain the active ingredient in the form of granules, for example in admixture with fillers such as lactose, binders such as starches, and/or glidants such as talcum or magnesium stearate, and optionally stabilisers. In soft capsules, the active ingredi- ent is preferably dissolved or suspended in a suitable liquid, such as a fatty oil, paraffin oil or a 60 liquid polyethylene glycol, to which a stabiliser can also be added.

Suitable pharmaceutical compositions for rectal administration are e.g. suppositories, which consist of a combination of the active ingredient with a suppository base. Examples of suitable suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene gly cols and higher alkanols. It is also possible to use gelatin rectal capsules which contain a 65 7 GB2197315A 7 combination of the active ingredient with a base material. Suitable base materials are e.g. liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.

Particularly suitable dosage forms for parenteral administration are aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, for which there are used suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain substances which increase the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally also stabilisers.

The invention further relates to a process for the preparation of pharmaceutical compositions. 10 for the treatment of anxiety states, which comprises processing, in a manner known per se, 1isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2- propanol, or a pharmaceutically acceptable non-toxic salt thereof, together with optional conventional excipients and carriers, to suitable dosage forms.

The dosage of the active ingredient will depend on the species of warmblooded animals, the 15 age and individual condition of the patient, and on the mode of administration. Suitable pharma ceutical compositions will preferably be administered once daily.

Thus, for example, daily doses of less than 40 mg can can be administered p.o. to humans. It is preferred to administer daily doses of c. 10 to 0.5 mg, for example c. 10 to 4 mg. However, to avoid cardiovascular symptoms resulting from fl-receptor blockade, it is advisable to admin- 20 ister daily doses of 3.5 to 0.5 mg and, most preferably, 2 mg, p.o.

The following Examples will serve to illustrate the invention and also the preparation of a typical dosage form, but without implying any restriction to the individual methods employed and dosage forms obtained. The Examples are furthermore not intended to limit the scope of the invention in any way.

Temperatures are given in degrees Centigrade.

Preparatory Examples Example 1: 27.4 g (100 mmols) of racemic 1-isopropylamino-3-[o-(pyrrol-l- yi)-phenoxy]-2-propa- no] and 16.7 g (110 mmols) of L-(+)-mandelic acid are dissolved in 143 mi of water and the 30 solution is left to stand overnight to crystallise. The crystals are collected by suction filtration and recrystallised repeatedly from the smallest possible amount of water until the melting point is 122- 1 23'C and a sample of the isolated base has an optical rotation of [C1120:+ 12 1 ' (c = 5 D % in methanol). The (+)-enantiomer of 1-isopropylamino-3-[o-(pyrrol-l-yi)- phenoxy]-2-propanol is obtained in the form of the salt of (+)-mandelic acid in a purity of 99 % determined by 13C-NiVIR 35 (90 MHz, CDC13).

The base is subsequently isolated with aqueous sodium hydroxide and extracted with ethyl acetate.

Example 2: Preparation of the neutral fumarate 6.4 9 (23 mmols) of crude (+)-1-isopropylamino-3-[o-(pyrrol-l-yi)- phenoxy]-2-propanol and 1.45 9 (12.5 mmols) of fumaric acid are dissolved in 45 mi of isopropanol with heating. Neutral (+)-1-isopropylamino-3-[o(pyrrol-l-yi)-phenoxy]-2-propanol fumarate crystallises from the cooled solution. Melting point: 16W-166'C; [a120:+19.4 0.2' (c=5.4 % in water).

D Example 3: To separate the enantiomers, it is also convenient to start from a product which is already enriched with the one enantiomer, e.g. the (+)-enantiomer.

Thus, for example, the (+enantiomer preferably crystallises e.g. from racemic 1-isopropylam ino-3-[o-(pyrrol-l-yi)-phenoxy]-2-propanol with (+mandelic acid. The base enriched with (+) enantiomer can be isolated from the mother liquor after alkalising with aqueous sodium hydrox- 50 ide and converted into the pure (+)-enantiomer with (+)-mandelic acid (as in Example 1).

Example 4: A solution of 9.8 9 (0.045 mole) of (R)-1,2-epoxy-3-[o-(pyrroll-yi)-phenoxy]propane and 26.9 9 (0.455 mole) of isopropylamine is left to stand for 15 hours at room temperature.

After evaporation of the volatile constituents, crude (R)-1isopropylamino-3-[o-(pyrrol-l-yi)-phe- 55 noxy]-2-propanol is obtained as a yellowish oil which has an optical rotation of a20:+111.8 0.2' (c=5 % in methanol).

]D A neutral fumarate with a melting point of 16WC is obtained (recrystallisation from isopropa nol); [a]20:+19.0 0.2' (c=5 % in water).

D The starting epoxide can be prepared by methods described in the literature.

a) (S)-2,2-dimethyi-4-1[o-pyrrol-l-yi)-phenoxylmethyll-1,3-dioxolane of m. p. 57-58C [ recrystal lisation from petroleum ether; [a120:+24.0 0.2' (c=5 % in methanol)] is obtained from o-(pyrrol D l-yl)phenol and (R)-2,2-di methyl- 1,3-dioxola ne-4-methanol-p- toluenesuifonate in the presence of sodium hydride in dimethylformamide.

b) Hydrolysis of the compound obtained in q) in 80 % acetic acid for 30 minutes at WC 65 8 GB2197315A 8 gives (R)-3-[o-pyrrol-1-yl)phenoxy]-propane-1,2-dioI of m.p. 95-96'C (recrystallisation from ether); [a]20:+1.6 (c=5.5 % in methanol).

D c) The diol obtained in b) is reacted with trimethyl orthoacetate, using trifluoroacetic acid as catalyst, to give (2 R/S,4S)-2-methoxy-2-methyl-41[o-(pyrrol-1-yl)phenoxy]methyll-1,3-dioxolane, 5 which is further used in the crude form.

d) The crude orthoester obtained in c) is converted by the method of M.S. Newman et al., J. Org. Chem. 1978, 38, 4203, with trimethylchlorosilane into the chlorohydrin derivative, which gives (R)-1,2-epoxy-3-[o-(pyrrol1-yl)phenoxylpropane with 2N aqueous sodium hydroxide. The crude product is purified by flash chromatography over silica gel (elution with toluene). The resultant colourless oil has an optical rotation of [a]20: -25.8' 0.2'; [a]205:-81.6' (c=5.3 % in 10 D 36 methanol).

Formulation Examples Example 1: Film-coated dragees containing neutral (+)-1-isopropylamino-3- [o-(pyrrol-l-yi)phe- 15 noxy]-2-propanol fumarate or racemic 1-isopropylamino-3-[o-pyrrol-l- yi)phenoxy]-2-propanol hydrochloride as active ingredient.

Composition:

Core:

active ingredient silica aerogel (AeroslIA200) cellulose (AvicelPH 102) lactose, cryst. magnesium starch sodium carboxymethyl starch Coating.

hydroxypropyl methyl cellulose (Cellulose-HP-M-603) glyceryl WIethylene glycoloxy stearate 1,.1 - (CremophorARH 40) iron oxide, red. talcum (PH) tiranitim dioxide (PH) Total weight 0. 5 mg 2. 5 mg 36. 0 mg 180.0 mg 1.5 mg 19.5 mg 240.0 mg 3. 30 mg 0.15 mg 0.19 mg 2.93 mg 0. 43 mg 7.0 mg 247.0 mg Example 2: Film-coated dragees containing neutral (+)-1-isopropylamino-3- [o-pyrrol-l-yi)phenoxy]- 2-propanol fumarate or racemic 1-isopropylamino-3-[o-pyrrol-l-yl)phenoxy]- 2-propanol hydrochlo55 ride as an active ingredient.

v 9 GB2197315A 9 Composition:

Core.

active ingredient 2. 0 Tng 5 silica aerogel (Aerosil 200) 2.5 mg cellulose (Avicel PH 102) 36.0 mg lactose, cryst, 180.0 mg 10 inagnesium stearate 1.5 mg sodium carboxylmethyl starch 18.0 mg 240.0 mg Coating: 20 hydroxypropyl metbyl cellulose (Cellulose-HP-M-603) 3.3 mg glyceryl polyethylene glycoloxy stearate (CremophoT RH 40) 0.2 mg 25 iron oxide, red. 0.2 mg talcum (PH) 2.9 mg titanium dioxide 0.4 mg 30 7. 0 mg total weight 247.0 mg 35 Example 3: Film-coated dragees containing neutral (+)-1-isopropylamino-3- [o-(pyrrol-l-yi)phenoxy]-2-propanol fumarate or racemic 1-isopropylamino- 3-[o-(pyrrol-l-yi)phenoxy]-2-propanoI hydrochloride as active ingredient.

m GB2197315A 10 Composition Core.

active ingredient 4.0 mg 5 silica aerogel (Aerosil 200) 2.5 Tng cellulo8e (Avicel PH 102) 36.0 mg 10 lactose, cryst. 180.0 mg magnesium stearate 1.5 mg sodium carboxylmetbyl starch 16.0 mg 15 240.0 mg Coating: 20 bydroxypropyl metbyl cellulose (Cellulose-HP-M-603) 3.3 mg glyceryl polyethylene glycoloxy stearate (Cremophor RH 40) 0.2 mg 25 iron oxide, red. 0.2 mg talcum (PH) 2.9 mg titanium dioxide 0.4 mg 30 7. 0 mg total 'eight 247.0 mg 35 Example 4: Film-coated dragees containing neutral (+)-1-isopropylamino-3- [o-(pyrrol-l-yi)phenoxy]-2-propanol fumarate or racemic 1-isopropylamino- 3-[o-(pyrrol-l-yi)phenoxy]-2-propanol hydrochloride as active ingredient.

11 GB2197315A 11 Composition:

Core: 5 active ingredient 10.0 mg silica aerogel (Aerosil 200) 2.5 mg cellulose (Avicel PH 102) 34.0 mg 10 lactose, cryst. 174.0 mg magnesium stearate 1.5 mg sodium carboxy1methyl starch 18.0 mg 15 240.0 mg Coatng:

hydroxvpropyl methyl cellulose 20 (Cellulose-HP-M-603) 3.3 mg glyceryl polyethylene glycoloxy stearate (Cremophor RH 40) 0.2 mg 25 iron oxide, red. 0.2 mg talcum (PH) 2.9 mg titanium dioxide 0.4 mg 30 7. 0 mg total weight 247.0 mg Preparation:

The ingredients of the core are mixed and the homogeneous mixture is compressed to tablets.

The tablets are coated with lacquer prepared from the indicated components, which are in turn 40 e.g. dissolved or suspended in water.

1 Compositions having a different content of active ingredient can be prepared in a manner corresponding to that described in Formulation Examples, which compositions can contain the (+)-enantiomer or racernate also in the free form or in the form of another pharmaceutically acceptable non-toxic salt.

Claims (18)

1. (+)-l-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2-propanoI or a salt thereof.

2. A pharmaceutically acceptable non-toxic salt of (+)-l-isopropylamino-3[o-pyrrol-1-yl)phe- noxy]-2-propanol.

3. (+)-l-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2-propanof or a salt thereof, for use in a 50 therapeutic method of treating the human or animal body.

4. A pharmaceutically acceptable non-toxic salt of (+)-l-isopropylamino-3[o-(pyrrol-1-yl)phe- noxy]-2-propanol for use in a therapeutic method of treating the human or animal body.

5. A process for the preparation of (+)-l-isopropylamino-3-fo-(pyrrol-1yl)phenoxy]-2-propanoI or a salt thereof, which comprises a) resolving racemic 1-isopropylamino-[o-pyrrol-1-yl)phenoxy]-2-propanol, or a salt thereof, into the (+)-enantiomer; or b) reacting an enantiomer of formula 12 GB2197315A 12 5DN-9 1 2 1 1 -CH2- CH-CH2 (1) wherein X, and X2 are, on the one hand, together -0- or, on the other, X, is hydroxy and X2 is 10 reactive esterified hydroxy, halogen or sulfonyloxy, with isopropylamine; or c) hydrolysing the (R)-enantiomer of formula or 0 11 ,- C, 11 0 N-CH(CH3)2 1 1 -CH2-UH-CH2 (11) d) removing the protective group from the (R)-enantiomer of formula - 1 E-N-9 OH 1 O-CH2-UH-CH2-N-CH(CH_?)2 1 Sch wherein Sch is a group customarily employed for protecting amino groups; or e) starting from the (R)-enantiomer of formula H2N-1. 1 O-CH2-CH-CH2-NH-CH(CH)2 (,v) 3 forming the pyrrol-1-yl ring, and/or converting free (+)-l-isopropylamino- 3-[o-(pyrrol-1-yl)-phenoxy]-2-propanol into a salt or converting a salt of (+)-l-isopropylamino3-[o-(pyrrol-1-yl)-phe- noxy]-2-propanol into the free enantiomer.

6. A pharmaceutical composition containing as active ingredient (+)-lisopropylamino-3-[o- 50 (pyrrol-1-yl)-2-propanol or a pharmaceutically acceptable non-toxic salt thereof.

7. A pharmaceutical composition according to claim 6 for the treatment of anxiety states, containing as active ingredient (+)-l-isopropylamino-3-[o-(pyrrol-1- yl)phenoxy]-2-propanoI or a pharmaceutically acceptable non-toxic salt thereof.

8. A pharmaceutical composition according to either claim 6 or claim 7, wherein the active 55 ingredient is the furnarate of (+)-l-isopropylamino-3-[o-(pyrrol-1- yl)phenoxyl-2-propanol.

9. A pharmaceutical composition according to any one of claims 6 to 8, for oral administra tion of the active ingredient in a daily dose of less than 40 mg.

10. A pharmaceutical composition according to claim 9 wherein the daily dose is 10 to 0.5 mg.

11. A pharmaceutical composition according to claim 10 wherein the daily dose is from 3.5 to 0.5 mg.

12. Use of (+)-l-isopropylamino-3-[o-(pyrrol-1-yl)phenoxyl-2-propanoI or of a pharmaceutically acceptable non-toxic salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety states.

13 GB2197315A 13 13. A pharmaceutical composition for the treatment of anxiety states containing, as active ingredient, 1-isopropylamino-3-[o-(pyrrol-1- yl)phenoxy]-2-propanoI or a pharmaceutically acceptable non-toxic salt thereof.

14. A pharmaceutical composition according to claim 13 which contains the hydrochloride of 5 1-isopropylamino-3-[o-(pyrrol-1-yl)phenoxy]-2-propanoI as active ingredient.

15. A pharmaceutical composition according to either claim 13 or claim 14 for oral administration of the active ingredient in a daily dose of less than 40 mg.

16. A pharmaceutical composition according to claim 15 wherein the daily dose is from 3.5 to 0.5 mg.

17. A pharmaceutical composition as described in any of formulation Examples 1 to 4. 10

18. Use of 1-isopropylamino-3-[o-(pyrrol-1-yl)-phenoxy]-2-propanoI or a pharmaceutically acceptable non-toxic salt thereof for the preparation of a pharmaceutical composition as claimed in any of claims 13 to 15.

Published 1988 at The Patent Office, State House, 66/71 High Holborn, London WC1R 4TP. Further copies may be obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Burgess & Son (Abingdon) Ltd. Con. 1/87.