DD141926A6 - PROCESS FOR THE PREPARATION OF NEW METHODS OF HYDROXYBENZODIHETEROCYCLES - Google Patents

Description

Process for the preparation of etherified Hydroxybenzodiheterocyc len __ _ · ' .

Field of application of the invention

The invention relates to processes for the preparation of novel etherified Hydroxybenzodiheterocyclen according to DD-PS 129 444 »

These compounds having long-lasting beta-receptor blocking activity are used as drugs.

Characteristic of the known technical solutions

From DD-PS 129 444 a process for the preparation of etherified Hydroxybenzodiheterocyclen known

Aim of the invention;

The aim of the invention is to provide an improved, simple and economical process for the preparation of new etherified Hydroxybenzodiheterocyclen with additional cardiostimulatory efficacy <>

The invention has for its object to produce suitable starting compounds and suitable reaction conditions for the preparation of new etherified Hydroxibenzodiheterocyclen with the desired properties »

According to the invention, etherified hydroxybenzodiheterocyclenej, in particular compounds of the formula

HO

O-alk-NH-OHg-CH-CHg-O

(D

where alk is vicinal alkylene having 2-3 carbon atoms and their acid addition salts ©

denη the compounds of formula I is vicinales alkylen alk 1- or 2-Methyläthyl ~ en and before all em.Äthylen «'

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Acid addition salts of compounds of the formula I are in particular pharmaceutically acceptable, non-toxic acid addition salts with suitable inorganic acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acid, or with suitable organic aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, Acetic, propionic, succinic, glycolic, lactic, succinic, tartaric, citric, maleic, fumaric, pyruvic, benzoic, anthranilic, 4-hydroxybenzoic, salicylic, phenylacetic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, 4-chlorobenzenesulfonic, toluenesulfonic, Naphthalene sulfonic acid, sulfanilic acid or cyclohexylamine sulfonic acid, or other acidic organic substances, such as ascorbic acid.

As a result of the close relationship between the new compounds in free form and in the form of their acid addition salts, the free salts and salts are to be understood as meaningful and expedient, if appropriate, also the corresponding salts or free compounds. The new compounds may be in the form of racemates or antipodes.

The novel compounds have valuable pharmacological properties, in particular strong and long-lasting beta-receptor blocking effects, as determined by appropriate pharmacological approaches {see, e.g. Meier et al., Arzneimittelforschung, Bd. J2O., P. 1890 (1970). Thus, the new compounds show a 50% inhibition of isoproterenol tachycardia in isolated guinea pig hearts (according Langendorff) in concentrations of about 0.001 to 0.003 üg / ml and a

50% inhibition of isoproterenol tachycardia or vasodilatation in the anesthetized cat in pens from about 0.001 to 0.003 mg / kg or about 0.01 to 0.1 mg / kg when given intravenously. The new compounds thus belong to the class of cardioselective β-receptor blockers, ie they preferentially inhibit the cardiac effects of isoproterenol over the vascular ones. The new compounds can be used as beta-blockers, for example in the treatment of cardiac arrhythmias (arrhythmias) and coronary heart diseases such as angina pectoris, as well as hypotensive agents in the treatment of hypertension. In addition, the compounds still have a cardiostimulatory activity, which can be detected, for example, in the isolated atrium of the guinea pig as an increase in heart rate in a concentration range of about 0.01 to about 1 jig / ml . This quality of action can also be demonstrated in the anesthetized, respein-pretreated cat also in the form of an increase in heart rate in a dose range of about 0.0003 to about 0.3 mg / kg iv. Compounds with such cardio-stimulating activity affect cardiac function less than substances that do not possess these additional properties.

The compounds also show alpha receptor blocking properties which range from about 0.03 to about 0.3 μg / ml, e.g. on the isolated mesenteric bed of the rat as an inhibition of norepinephrine-induced vasoconstriction or on the isolated vas deferens of the rat as inhibition of norepinephrine-induced contraction. Furthermore, the compounds have a prolonged antihypertensive effect on the anesthetized cat in the dose range of 0.03 to 3 mg / kg i.v. on. By means of these components of action, for example, a blood pressure-lowering effect can be promoted.

210909 -4- Berlin, ά; 5 · 7 · 1979

AP C 07 D / 210 909 55 001 11

In particular, compounds of the formula I are prepared in which alk represents the ethylene radical, and pharmaceutically acceptable acid addition salts of such compounds,. , ''

According to the invention, the following compounds of the formula I described in the examples are prepared in the first place, as well as pharmaceutically acceptable acid addition salts of these compounds:

4 ~ [3 · * - Γ ² * "(4-hydroxyphenoxy) ethylaminoJ -2-hydroxypropoxy] benzimidazole 2 ~ on and

4 "jy" ^ 2- (2-Hy droxyphenoxy) ethylamino] - 2-hydroxypr opoxyjbenzimidazol ~ 2 ~ on. "

The novel compounds of the present invention can be prepared in a manner known per se.

So germ you get the new compounds Z ₀ B ₆ , if you have a compound of the formula

X ₁ - CH ₂ - CH - CH ₂ 0H

with a compound of the formula

0-alk-X ₃ (III)

in which one of the groups X- and X ^ represents a reactive esterified hydroxy group and the other

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represents the primary amino group, and X "represents hydroxy, or wherein X, and X ₂ together denote the epoxy group, and X" is the primary amino group, and, if desired, a resulting free compound in a salt or a obtained Salt is converted into a free compound, and / or, if desired, a resulting racemate separates into the antipodes.

A reactive esterified hydroxy group X, or Χ "is one, by a strong acid, in particular a strong inorganic acid such as a hydrohalic acid, especially hydrochloric, hydrobromic or hydroiodic acid, or sulfuric acid, or a strong organic acid, in particular a strong organic Sulfonic acid, such as an aliphatic or aromatic sulfonic acid, eg Methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, esterified hydroxy group, and is primarily halogen, e.g. Chlorine, bromine or iodine, or aliphatically or aromatically substituted sulphonyloxy, e.g. Methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The above reaction is carried out in a manner known per se, wherein, especially when using a starting material having a reactive esterified hydroxy group, advantageously in the presence of a basic agent, such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent such as an Alkalimeta 11 lower alkanolate, and / or an excess of the basic reactant and usually in the presence of a solvent or solvent mixture and, if necessary, cooling or heating, e.g. in a temperature range of about -20 ° to about + 150 °, in an open or closed vessel and / or in an inert gas atmosphere.

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phase, e.g. in a nitrogen atmosphere, works.

The starting materials of the formula II 'can be prepared in a manner known per se, for example by converting the phenolic hydroxyl group into the allyloxy group in 4-hydroxybenzimidazol-2-one or in an optionally monocyclic precursor thereof and converting these into the desired group of the formula X, -CH ₂ -CH (X ₂ ) -CH ₂ -O- (Ha). Thus, for example, in a 3-hydroxyphthalic acid lower alkyl ester, the phenolic hydroxy group can be converted into an allyloxy group by treatment with an allyl halide, eg bromide, in the presence of a suitable base, such as an alkali metal, eg potassium carbonate, the 3-allyloxy group. Release phthalic acid from the ester by hydrolysis, for example by treatment with an alkali metal hydroxide, and, for example, by treatment with acetic anhydride, into the corresponding anhydride. By modified Curtius'sehen degradation of the thus obtainable 3-allyloxy-phthalsäureanbydrids, for example by treatment with a suitable Azidverbindung, such as a Triniederalkylsilylazid, in particular trimethylsilyl, is obtained after subsequent hydrolysis, the 4-allyloxybenzimidazol-2-one. The allyl group is converted, for example, by oxidation with hydrogen peroxide or a suitable inorganic or organic peracid, for example 3-chloroperbenzoic acid, into the desired 2,3-epoxypropyl group; this can be converted to a 2-hydroxy-3- <reactive-hydroxy) -propyl group by treating the appropriate compound with a suitable strong acid such as a hydrohalic acid.

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Another method for the preparation of compounds of formula I is that in a compound of formula

f \

HO

O-alk = N-CH ₀ -CH-CH ₀ -O z Zi

O (IV)

where alk represents the alkylylidene radical corresponding to a vicinal alkylene radical alk, reduces the grouping of the formula -alk = N - (IVa) to the grouping of the formula · -alk-NH- (IVb) and, if desired, carries out the additional process steps.

The above reductive conversion of a radical of the formula IVa into the desired moiety of the formula IVb can be carried out in a manner known per se, with suitable reducing agents being, in particular, lower metal hydride reducing agents such as alkali metal borohydrides, e.g. Sodium borohydrides, as well as alkali metal cyanoborohydrides, e.g. Sodium cyanoborohydride, or borohydrides, e.g. Diborane, further catalytically activated hydrogen, e.g. Hydrogen in the presence of a heavy metal catalyst, e.g. Raney nickel, platinum oxide or palladium.

The above reductions are carried out in a manner known per se, usually in the presence of an inert solvent and, if necessary, with cooling or heating, e.g. in a temperature range of about -20 ° to about -1-150 °, and / or in a closed vessel under pressure and / or in an inert gas, e.g. Nitrogen atmosphere,

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leads.

The starting materials of the formula IV can be obtained in a manner known per se, by adding e.g. Treated 4- (2,3-epoxypropyloxy) benzimidazol-2-one with ammonia and the thus obtainable (3-amino-2-hydroxy-propyloxy) benzimidazol-2-one with a Carbony! Connection of the formula

-aIk ₀ = O (V)

wherein alk has the meaning given above, implements.

In this case, the preparation of the starting material of the formula IV can take place simultaneously with its conversion into the desired compound of the formula I. If the reaction of the amino compound with the carbonyl compound of the formula V is carried out in the presence of a suitable reducing agent, e.g. in the presence of catalytically activated hydrogen or, preferably, a hydride reducing agent, e.g. Sodium cyanoborohydride performs.

The novel compounds of the formula I can also be obtained when in a compound of the formula

ff\ _C ~ alk-N - CH₉ - CH - CH₉ X = / J,, Ν (VI)

wherein at least one of the groups X, X _r, and X - represents a replaceable by hydrogen group and the other

represents hydrogen or a group which can be replaced by hydrogen, ₃ and X, and X ₁ - together also represent a cleavable radical which can be replaced by two hydrogen atoms connected to the oxygen or nitrogen atom, or in a salt thereof the radicals other than hydrogen X /, X _c and X ^ by hydrogen

4 5 ο

replaced, and if desired, the additional process steps durchfuhrt.

The cleavage of the groups X, and / or X ₁ - and / or X, - is carried out by solvolysis or reduction. In this case, in the abovementioned starting materials of the formula VI, X is preferably a hydrogen-displaceable group, while _X.sup.c and X.sup.b are primarily hydrogen.

A particularly suitable cleavable group X is primarily a hydrogenolytically cleavable cc-aryl-lower alkyl group, such as an optionally substituted 1-phenyl-lower alkyl group, wherein substituents, especially the phenyl moiety, e.g. Lower alkyl, such as methyl or tert-butyl, hydroxy, lower alkoxy, such as methoxy, halo, e.g. Chlorine or bromine, and / or nitro, and especially benzyl. A group X / can also be a solvolytic, such as hydrolytic or acidolytic, furthermore a reductive, including hydrogenolytically, cleavable radical, in particular a corresponding acyl radical, such as the acyl radical of an organic carboxylic acid, e.g. Lower alkanoyl such as acetyl, or aroyl such as benzoyl, further the acyl radical of a monoester of carbonic acid such as lower alkoxycarbonyl, e.g. Methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1 -benzenyl-lower alkoxycarbonyl, e.g. Benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl ^ e.g. Phenacylo-xycarbonyT, or the

210909

Acyl radical of an organic sulfonic acid, such as an aromatic sulfonic acid, primarily an optionally substituted phenylsulfuryl radical, wherein substituents e.g. have the meaning given for the above 1-Phenylniederalkylrest, and in particular 4-methylphenylsulfonyl, further an optionally substituted 1-polyphenyl-lower alkyl group, wherein substituents, primarily of the phenyl moiety, e.g. have the meaning given above, and represent trityl in the first place.

Hydrogen-displaceable groups X ₅ and / or X, - are preferably also hydrogenolytically cleavable groups, such as one of the above, optionally substituted 1-phenyl-lower alkyl groups and benzyl in the first place. They may furthermore also be one of the solvolytic, including alcoholic, or reductively cleavable acyl groups mentioned for the group X /, furthermore an optionally substituted aliphatic or araliphatic hydrocarbon radical poly-branched on the linking carbon atom, such as tert-lower alkyl, eg tert-butyl, or Be trityl.

A cleavable radical formed by X, and X ₁ - together is primarily a hydrogenolytically cleavable group, such as optionally substituted 1-phenyl-lower alkylidene, wherein substituents, for example lower alkyl, such as tert-butyl, hydroxy, lower alkoxy, halogen and or nitro, and in particular benzylidene, as well as solvolytic, in particular hydrolytically cleavable groups, such as lower alkylidene, for example methylene or isopropylidene, or cycloalkylidene, for example cyclohexylidene. Another group formed by the groups X, and X ₁ - together is the diacyl radical of carbonic acid or thiocarbonic acid, ie the carbonyl or thiocarbony group.

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 - 11 -

Starting materials useful in the form of salts are primarily in the form of acid addition salts, especially corresponding salts with inorganic acids, e.g. Mineral acids, as well as with organic acids used.

Hydrogenolytically cleavable radicals X / and / or X ₁ -, and / or X ^, in particular optionally substituted 1-Pbenylniederalkylgruppen, further also suitable acyl groups, such as optionally substituted 1-Phenylniederalkoxycarbonyl, and by the groups X, and X ₅ together formed, if appropriate substituted 1-phenyl-lower alkylidene groups can be cleaved by treatment with catalytically activated hydrogen, for example with hydrogen in the presence of a nickel catalyst, such as Raney nickel, or a suitable noble metal catalyst.

Hydrolytically cleavable groups X, and / or X, -, and / or X ^ J as acyl radicals of organic carboxylic acids, eg lower alkanoyl, and half esters of carbonic acid, eg lower alkoxycarbonyl, furthermore trityl radicals, and by the radicals X, and X ₅ together formed Depending on the nature of such radicals, lower alkylidene groups or carbonyl groups can be cleaved off by treatment with water under acidic and / or basic conditions, for example in the presence of a mineral acid, such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonates.

Acidolytically cleavable radicals are, in particular, certain acyl radicals of half-esters of carbonic acid, such as e.g. tert.-Niederalkoxycarbonyl, or optionally substituted Diphenylmethoxycarbonylreste, and also tert - lower alkyl radicals X <- and / or X ^, they can by treatment with

2 1 0909 -

suitable strong organic carboxylic acids, such as optionally substituted by halogen, in particular fluorine, substituted lower alkanecarboxylic acids, primarily with Trifluoressigsäurey if necessary, in the presence of an activating agent such as anisole, as well as with formic acid.

By reductively cleavable radicals X, and / or X, - and / or X / - are also understood those groups which, when treated with a chemical reducing agent ^ in particular. with a reducing metal or a reducing metal compound. Such radicals are especially 2-halo-lower alkoxycarbonyl or aroylmethoxycarbonyl, e.g. upon treatment with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, such as a chromium (II) salt, e.g. chloride or acetate, usually in the presence of an organic carboxylic acid, such as formic acid or acetic acid, and can be cleaved from water. Reductively cleavable arylsulfonyl radicals, especially those primarily representing the radical X, may be e.g. when treating with an alkali metal, e.g. Lithium or sodium, be replaced by ammonia or by electrolytic reduction by hydrogen,

The above reactions are carried out in a manner known per se, usually in the presence of a solvent or solvent mixture, it being possible for suitable reactants to function simultaneously as such and, if necessary, under cooling or heating, e.g. in a temperature range of about -20 ° to about + 150 °, in an open or closed vessel and / or in the atmosphere of an inert gas, e.g. Nitrogen.

The starting materials of the formula VI can be prepared in a manner known per se, e.g. by treating a compound of the formula

xy o

X ° ₇ - CH ₂ - CH - CH ₂ - OH

C = O (VII)

with a compound of the formula

X ₆ is -O

O-alk-X ° ₈ (VIII)

where X °, - the above for X ₁ . and one of the groups X ° ₇ and X ° p represents a reactive esterified hydroxy group, and the other represents the group of the formula -NH (X,), wherein X has the meaning given above, with the proviso that at least one of the groups X, X, X ₅ and X, - is different from hydrogen, or in which X °, - and X ⁰ ^ together form a bond and X ° g is the group of the formula -NH (X,), where X is different from hydrogen. The above reactions are carried out in a manner known per se.

The novel compounds of the present invention can also be obtained when starting from a compound of the formula

2 "1 09 0

XJ

OaIk-NH-CH ₂ -CH-CH ₂ -O

^H0 "- (Κ),

wherein Xq and X, ~ are radicals which are cleavable to form the carbonyl group connected in the compounds of formula I with the two nitrogen atoms, or in a salt thereof, the radicals Xq and X, _Q split off to form the carbonyl group, and, if desired , which performs additional process steps.

The starting material of formula IX in the form of an acid addition salt is e.g. that with a mineral acid.

Usually one of the radicals Xg and X represents hydrogen, while the other represents the acyl radical of a carbonic acid derivative, such as a corresponding ester, halides or amide and e.g. is lower alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, or halocarbonyl such as chlorocarbonyl or aminocarbonyl.

The reaction is carried out in the absence or presence of a suitable solvent or diluent, such as an optionally substituted, eg chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as benzene, and, if necessary, under cooling or heating, for example in a temperature range from about 0 ° to about 100 °, in a closed vessel and / or in an inert gas, eg nitrogen atmosphere. Optionally, and preferably when one of Xq or X-, _Q

1 0909 - is -

Aminocarbonyl_, the reaction is conducted in the presence of a basic condensing agent, such as a metal alcoholate, such as an alkali metal alkoxide, e.g. Sodium ethylate in a solvent, such as a lower alkanol, such as ethanol by. In this case, it is expedient to work in a temperature range of about 0-150 °, preferably of 10-120 °.

Starting materials of the formula IX can be prepared in a manner known per se and, if appropriate, in situ . Thus, it is possible to obtain preferred starting materials by, for example, converting the phenolic hydroxy group into the allyloxy group in the presence of a base, for example potassium carbonate, in the 2,3-dinitrophenol by treatment of the intermediate with Hydrogen peroxide, for example in the presence of potassium bicarbonate, or with a suitable inorganic or organic percarboxylic acid, for example 3-chloro-perbenzoic acid, in the 2,3-epoxy-propyloxyr group and these, for example by treating the intermediate with an amine of the formula

S_ 0-aIk-NH ₀ (IHa)

A = /

HO

into the corresponding substituted 3-amino-2-hydroxypropyloxy group. "The two nitro groups, e.g. by treatment with catalytically activated hydrogen, reduced to the amino groups. By reacting with a suitably reactive carbonic acid derivative, e.g. a corresponding ester, such as a dilower alkyl carbonate, e.g. Dimethyl or diethyl carbonate, a mixed anhydride such as carbon dioxide dihalide,

2 1 090

For example, phosgene, or an amide, such as urea or Ν, Ν'-carborryldiimidazole, to obtain a preferred starting material, which is preferably formed only in situ and directly converted into a compound of formula I.

The novel compounds of the formula I can also be obtained by reacting in a compound of the formula

OH X ₁ , - CH- CH ₀ - 0

11 z

^Η0 - ο

wherein X ,, one of the radicals of the formulas - a Ik- NH- (C = X. ₂ ) - - (C = X ₁₁ ) - (Xa) or -alk _a ~ (C = X ₁₂ ) -NH-CH ₂ - (Xb), where alk represents a methylene or ethylidene group and X, ~ represents the oxo or thioxo radical, the group of the formula X.sup.-, -. "to the rest of the formula

-alk-NH-CH ₂ - (XI)

reduces and, if desired, performs the additional process steps. Particularly suitable for the reduction of groups Xa and Xb, which _; corresponding to an oxo radical Xi ₂ 'contain a carbamoyl moiety, light metal hydride reducing agents such as alkali metal aluminum hydrides, eg lithium aluminum hydrides which are particularly suitable for the reduction of carbamoyl groups, or alkali metal borohydrides, eg sodium cyanoborohydride, or borohydrides, eg diborane.

Groupings of formulas (Xa) and (Xb) wherein X, "each represents a thioxo radical, are prepared by reductive desulfurization, e.g. by treating with one

Hydrogenation catalyst, such as Raney nickel converted into the grouping of formula (XI).

The above reduction reactions are carried out in a manner known per se, usually in the presence of an inert solvent and, if necessary, under cooling or heating, e.g. in a temperature range of about -20 ° C to about + 150 ° C, and / or in a closed vessel under pressure and / or in an inert gas, e.g. Nitrogen atmosphere, performed.

Starting materials of the formula (X) can be prepared by reacting amino compounds of the formula

OH H ₂ N - CH ₂ - CH - CH ₂ - 0 _{to H χ}

wherein the hydroxy group optionally in protected, e.g. may be in esterified or suitably etherified form with carboxylic acid compounds of the formula

5L \> - O-älk -C ^ "" Oh or their (XIII) HC = / ^ Has, wherein a Ik above meaning reaction-

suitable derivatives wherein the phenolic hydroxy group is optionally protected, such as the halides, e.g. the chlorides, or by reaction of amino compounds of the formula

2 1 0909 -i8-

fL \ - O - alk - NH ₂ (XIV)

HO

wherein the hydroxy group is optionally protected with the carboxylic acid of the formula

HO OH

\ ι . C-CH-CH ₀ -O

C = O

wherein the hydroxy group is optionally in slotted, e.g. may be present in esterified or suitably etherified form, or their reactive functional derivatives are obtained. In an intermediate with one or two slit hydroxy groups, these are or are converted into the free form. The above reactions are carried out in a manner known per se.

Depending on the process conditions and starting materials, the novel compounds are obtained in free form or in the form of their acid addition salts also encompassed by the invention, wherein the new compounds or salts thereof may also be present as hemi, mono, sesquic or polyhydric thereof. Acid addition salts of the novel compounds can be prepared in a manner known per se, e.g. by treatment with basic agents, such as alkali metal hydroxides, carbonates or bicarbonates, or ion exchangers are converted into the free compounds. On the other hand, obtained free compounds can be obtained in a manner known per se, e.g. by

2 1Ό909 - is -

Treating with organic or inorganic acids, such as the acids mentioned above, acid addition salts, wherein in particular those acids are used for the production, which are suitable for the formation of pharmaceutically acceptable salts.

These or other acid addition salts of the novel compounds, e.g. Picrates or perchlorates can also be used to purify the resulting free bases by converting the free compounds into salts, separating and purifying them, and in turn forming the free compounds from the salts.

The new compounds may be present as optical antipodes or racemates, depending on the choice of starting materials and procedures.

Obtained racemates can be broken down into antipodes by methods known per se, for example by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with a optically active compound which forms a salt with the racemic compound, in particular a corresponding acid. and separating the salt mixture thus obtained, for example due to different solubilities, into the diastereomeric salts from which the free antipodes can be released by the action of suitable means. Particularly common as optically active acids are, for example, the D and L forms of tartaric acid, bis-O, O ^f - (p-toluoyl) tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Advantageously, one isolates the more effective of the two antipodes.

2 1 09 0 9 - 2o

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or in which a starting material is formed under the reaction conditions, or in which a reaction component is optionally present in the form of their salts.

It is expedient to use starting materials which lead to the groups of end-products which have been particularly mentioned above and in particular to the end-products which have been specially described or highlighted, for carrying out the reactions according to the invention.

The starting materials are known or, if they are new, may be prepared according to known metstocks, e.g. as described above. New starting materials also form an object of the invention. The invention also relates to Zwischenprodtikte available according to the method.

The new compounds may e.g. find use in the form of pharmaceutical preparations containing a pharmacologically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable for enteral, e.g. oral or parenteral administration. Thus, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets may also contain binders, e.g. Magnesiumalüminiumsilikat,

2 1 09Oy - 21 - Berlin, de 5.7.1979. AP C 07 D / 210 909

55 001 11

Starches, such as maize, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, itfatrium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, eg _c. , Starches, agar, alginic acid or a salt thereof, such as IT sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. In addition, the novel pharmacologically active compounds may be used in the form of parenterally administered preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these being ₀ O B _e for lyophilized preparations containing the active substance alone or together with contain a carrier material, such ^ B »mannitol, can be prepared before use * the pharmaceutical preparations can be sterilized and / or HilfBstoffej Z ₉ B * Konservier" stabilizers, wetting agents and / or emulsifiers, solubilisers, salts for regulating the οsmotischen pressure and / or buffers contained the present pharmaceutical preparations which, if, which may contain further pharmacologically active substances desired to be in a known \ 7eise, B z _e ", by means of conventional mixing, granulating, coating, solution ~ or lyophilization process, prepared and contained by about 0 , 1 % to 100 % _f, in particular from about 1 % to about 50 % ₉ lyophilizates up to 100 % of the active substance _o

The dosage may depend on various factors, such as the mode of administration and the individual condition. The daily doses for oral administration are between about 1 mg and about 15 mg for warm-blooded animals weighing about 70 kg ₀

The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade.

2 1 090 9 -22-

example 1

To a suspension of 22.4 g of 4- (3-amino-2-hydroxypropoxy) benzimidazol-2-one and 21.2 g of sodium carbonate in 100 ml of dioxane, which is stirred under reflux under a nitrogen atmosphere, is allowed to Over the course of 30 hours, a solution of 22 g of 4-hydroxyphenoxyethyl bromide in 200 ml of dioxane is added dropwise. The mixture is allowed to react for 5 hours, filtered with suction from the inorganic salts, the filtrate is concentrated under reduced pressure, the remaining OeI is taken up in acetone and treated with an ethereal hydrogen chloride solution. This gives the 4- [3- [2- (4-hydroxyphenoxy) ethylamino] -2-hydroxypropoxy] benzimidazole-2-one hydrochloride, which melts at 206-208 °.

Example 2

5.2 g of 4- [3 ~ (N -encyl-N- [2- (4-benzyloxy) -phenoxy-ethyl-amino]

2 ~ hydroxypropoxyJ-benzimidazol-2-one are hydrogenated in 200 ml of ethanol over 0.5 g of 57o-palladium-on-carbon catalyst at 20-25 ° under atmospheric pressure. After completion of the hydrogen uptake, the catalyst is filtered off with suction, and the filtrate is evaporated. From the resulting Eindampfrlickstand is dissolved in an acetone-methanol mixture by addition of ethereal hydrogen chloride solution

2 1 09 0 9 - 23 -

In the usual way the hydrochloride prepares. This gives the 4- [3- [2- (4-hydroxyphenoxy) ethylamino] -2-hydroxypropoxy] benzimidazol-2-one hydrochloride, which melts at 206-208 °.

The starting material can be prepared as follows:

A mixture of 3.09 g of 4- (2,3-epoxypropoxy) benzimidazol-2-one, 4.99 g of benzylaminoethoxyphenyl-4-benzyl ether

and 50 ml of isopropanol is heated to boiling for 2 hours with stirring and reflux. A clear solution is obtained, which is evaporated under reduced pressure. The residue gives 4- [3- (N-benzyl-N- [2- (4-benzyloxy-phenoxy) -ethyl] -amino] -2-hydroxypropoxy] -benzimidazole-2 from an ethyl acetate-ether mixture -on, which melts at 108 - 109 °.

Example 3

In a distillation apparatus, a suspension of 22.4 g of 4- (3-amino-2-hydroxypropoxy) -benzimidazol-2-one and 20 g of 4-hydroxyphenoxyacetic acid methyl ester in 200 ml of xylene is heated to boiling with stirring, taking care that the Temperature in the distillation head does not rise above 100 °. During this process, the methanol liberated during the reaction slowly distils over. After 24 hours, the temperature is increased so that the

210909.

Xylene distilled over. The distillation residue, the 4- [3- [2- (4-hydroxyphenoxy) -acetamido] -2-hydroxypropoxy] -benzimidazole-2-one, is dissolved in absolute tetrahydrofuran and added slowly to a stirred suspension of 7.6 g of lithium aluminum hydride 200 ml of absolute tetrahydrofuran was added dropwise. Subsequently, the reaction mixture is heated for a further 5 hours with stirring and reflux, then cooled to ⁰ and the residue is decomposed by dropwise addition of 80 ml of 12-n. Hydrochloric acid at a temperature of 0-5 °. Then 70 g of Seignette salt are introduced and the reaction mixture is adjusted to pH 9-10 by addition of concentrated ammonia solution. The reaction solution is now present as a two-phase mixture. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure. The remaining, crude 4- [3- [2- (4-hydroxy-phenoxy) ethylamino] -2-hydroxypropoxy] -benzimidazol-2-one provides the hydrochloride with hydrochloric acid, which after recrystallization from acetone at 206-208 ° melts.

The starting 4- (3-amino-2-hydroxypropoxy) benzimidazol-2-one can be prepared as follows:

a) 3.3 g of 4- (2,3-epoxypropoxy) -benzimidazol-2-one and 11.8 g of benzylamine are heated in 80 ml of isopropanol for 5 hours under reflux to boiling. Then, under reduced pressure, the solvent, together with the excess!

benzylamine distilled off and the remaining OeI dried at 90 ° / 0.001 torr for 2 hours. It consists of 4- (3-benzylamino-2-hydroxy-propoxy) -benzimidazol-2-one, which is obtained from water in crystals which melt after drying at 60 ° / l Torr for 18 hours at 203-205 ° ,

The hydrochloride melts at 231-232 ° with decomposition.

b) A solution of 15.5 g of 4- (3-benzylamino-2-hydroxypropoxy) benzimidazol-2-one in 160 ml of methanol is treated with 1.6 g of 5% palladium-on-carbon catalyst and until Recording the calculated amount of hydrogen hydrogenated. After filtration of the catalyst and distilling off the solvent to give the 4- (3-amino-2-hydroxypropoxy) benzimidazol-2-one, which melts after recrystallization from ethanol at 188-190 °.

The hydrochloride melts at 232-239 °.

Example 4

9.5 g of 4- [3- [N-benzyl-N- [2-benzyloxyphenoxy] ethyl] amino] -2-hydroxypropoxy-benzimidazol-2-one are added with the addition of 18 ml of 1-n. methanolic hydrochloric acid dissolved in 100 ml of methanol and then hydrogenated over 1.0 g of 5% palladium on carbon catalyst at 20-25 ° under atmospheric pressure. After completion of the hydrogen uptake dilute with methanol-water mixture (.1: 1, v / v) until the precipitated product is dissolved. Then the catalyst is filtered off and then the filtrate pin. From rlnrn prhp 1 tnn ^ -n fin

2 1 09 0 9 - 26 -

After evaporation from hot water, the residue obtained in vacuo gives the 4- [3- [2- (2-hydroxyphenoxy) -ethylamino] -2-hydroxypropoxy] -benzimidazol-2-one hydrochloride, which melts at 256-257 °.

The starting material can be prepared as follows:

A mixture of 6.86 g of 4- [2,3-epoxypropoxy] benzimidazol-2-one, 11.1 g of benzylaminoethoxyphenyl-2-benzyl ether and 150 ml of isopropanol is heated to boiling for 3 hours with stirring and reflux. Then the solvent is distilled off under reduced pressure and the residue taken up in hot methanol. On cooling, the crystallized 4- [3- [N-benzyl-N- (2-benzyloxyphenoxy) ethyl] -aiaino] -2-hydroxypropoxy] benzimidazol-2-one, which melts bei_152-153 ⁰

 Example 5

Tablets containing 0.002 g of 4- [3- [2- (4-hydroxyphenoxy) ethylamino] -2-hydroxy-propoxy] -benzimidazol-2-one hydrochloride are prepared as follows:

Composition (for 1000 tablets):

4- [3 - [2- (4-hydroxyphenoxy) -ethylamino] -2-hydroxy

propoxy) benzimidazole-2-one hydrochloride 2.00 g

Lactose 35.00 g

Corn starch · * 50.00 g

Colloidal silica 6.00 g

Talc 6.00 g

Magnesium Stearate 3- »00 S Water q.s.

Ψ 27 -

The 4- [3- {2- (4-hydroxyphenoxy) ethylnate] -2-hydroxypropoxy-benzimidazol-2-one hydrochloride is mixed with the milk sugar, a portion of the corn starch and colloidal silica, and the mixture is forced through a sieve , Another part of the cornstarch will be. gelatinized with five times the amount of water on the water bath and the powder mixture kneaded with this paste until a weak plastic mass is formed. This is pressed through a sieve of about 3 mm mesh size, dried and the dry granules are again driven through a sieve. Then the remaining corn starch, the talc and the magnesium stearate are mixed in and the resulting mixture is compressed into tablets of 0.100 g weight (with score).

In an analogous manner, other compounds of formula I or their pharmaceutically acceptable non-toxic acid addition salts, e.g. the 4- [3- [2- (2-hydroxyphenoxy) '- ethylamino] -2-hydroxy-propoxy] -benzimidazol-2-one hydrochloride can be used as active ingredients in the tablets described.

Claims (4)

Invention sanction. - 1 © 90 9 - ³¹ * "Berlin, d.5.7.1979 AP C 07 D / 210 909 55 001 11 indicates or produces pharmaceutically acceptable acid addition salts of such compounds. " 1 »Process for the preparation of etherified Hydroxybenzodiheterocyclen of the formula alk-HH-CH HO (D according to DP · -.; · · 129 444, in which alk is vicinal alkylene having 2-3 carbon atoms, and their acid addition salts, characterized in that a) a compound of the formula CH ₀ ~ C = O (II) with a compound of the formula alk-X. implements, wherein one of the groups and X (III) a reactionary represents the esterified hydroxy group and the other represents the primary amino group, and X "represents hydroxy, or wherein X and X _? together denote the epoxy group and X ^ is the primary amino group, or Berlin, d.5.o7o 1979 AP C 07 D / 210 909 55 001 11 b) in a compound of the formula , 0-alk _o = U- HO = 0 (IV) where alk is the alkylidene radical corresponding to a vicinal alkylene radical alk, the grouping of the formula -alk = H - (IVa) to Gn
-alk-HH- (IVb) reduced, or Formula -alk = H - (IVa) for grouping the formula - c) in a compound of the formula O-alk-1T-CH ₂ -CH 0 ι CH- CH (VI) wherein at least one of the groups X ^, X ₁ - and Xr represents a hydrogen-displaceable group and the. other represent hydrogen or a group which can be replaced by hydrogen, and X.sup.1 and X.sup. together also form a cleavable radical which can be replaced by two hydrogen atoms connected to the oxygen or nitrogen atom, or in a salt thereof the radicals X which are different from hydrogen ^, X, - and Xg replaced by hydrogen, or d) in a compound of the formula - 30 - Berlin, d.5.7.1979 AP C 07 D / 210 909 55 001 11 HO -CH-C • CH ^, - HO (IX), Xq wherein X ₁ and Q represent radicals which are äbspaltbar to form the joined in the compounds of formula I with the two nitrogen atoms carbonyl, or a salt thereof is split off in the radicals Xq Xq and under, the formation of the carbonyl group, or e) in a compound of the formula OH 0 - X ₁₁ «CH - CH ₂ - 0 0 (X) where X _{11 is} one of the radicals of the formulas -alk-IJH <- (C =X ₁₂ ') - - (C =X ₁₁ ) - (Xa) or ^ aIk- (C =X ₁ ") -HH-CH ₀ - (Xb) "represents" where alk is a methylene or ethylidene group egg and X _{12 represents} the oxo or thioxo radical, the group of the formula X ₁₁ to the rest of the formula -alk-NH-OHg- (XI). reduced, and if desired, a resulting free compound converted into a salt or a salt obtained in a free compound, and / or, if desired, a resulting racemate separated into the antipodes » 2 »Process according to item 1, characterized in that compounds of the formula I ₅ in which alk is the ethylene radical Method according to item 1, characterized in that the 4 ~ [_3 "JJ2- (4-hydroxyphenoxy) -ethylaminq] -2-hydroxypropoxy] -benzimidazol-2-one or pharmaceutically acceptable acid addition salts thereof were prepared Method according to item 1, characterized in that the 4- [3-] "2- (2-hydroxyphenpoxy) -ethylamino J-2-hydroxy-3-propoxy-benzimidazol-2-one or pharmaceutically acceptable acid addition salts thereof were prepared 5ο embodiment of the method according to item 1, characterized by "starting from an available at any stage of the process as an intermediate compound and performs the missing process steps, or that one forms a starting material under the reaction conditions, or that a Ileaktionskomponente optionally in the form of Salt is present »