DE3314196A1 - Heterocyclyl ethers - Google Patents

Abstract

Compounds of the formula <IMAGE> in which Ar denotes a mono- or bicyclic, carbocyclic or heterocyclic aryl radical bonded to a group Het via a ring carbon atom, Het denotes an azaphenylene radical bonded to the group Ar via a ring carbon atom and to the oxygen atom via a ring carbon atom, and alk denotes alkylene having 2-5 carbon atoms, the nitrogen atom and the oxygen atom being separated from one another by at least two carbon atoms, and R1 and R2 independently of one another each represent hydrogen or lower alkyl, or together represent lower alkylene, oxa-lower alkylene, thia-lower alkylene, aza-lower alkylene or N-lower alkylaza-lower alkylene, and N-oxides and salts of such compounds, process for their preparation, pharmaceutical preparations which contain the novel compounds and their use as blockers of adrenergic beta -receptors for the treatment of high blood pressure, angina pectoris, hypertrophic cardiomyopathies and cardiac arrhythmias.

Description

Heterocyclic ethers

The invention relates to new heterocyclyl ethers, methods for their manufacture, pharmaceutical preparations containing such compounds, and their use for the manufacture of pharmaceutical preparations, or as pharmacological active connections.

The invention relates to new compounds of the formula where Ar is a mono- or bicyclic, carbocyclic or heterocyclic aryl radical bonded to a group Het via a ring carbon atom, Het denotes an azaphenylene radical bonded to the group Ar via a ring carbon atom and to the oxygen atom via a ring carbon atom, and alkalkylene with 2-5 carbon atoms, wherein the nitrogen atom and the oxygen atom are separated from one another by at least two carbon atoms, and R1 and R2 independently of one another each represent hydrogen or lower alkyl, or together represent lower alkylene, oxane-lower alkylene, thian-lower alkylene, aza-lower alkylene or N-lower alkylazane-lower alkylene.

The subject of the invention also includes N-oxides of heterocycles as well as salts of compounds of the formula I.

The residue Ar is a monocyclic aromatic hydrocarbon residue, i.e. phenyl, but can also be a bicyclic aromatic Hydrocarbon residue, i.e. 1- or 2-naphthyl or partially saturated naphthyl such as 1,2,3,4-tetrahydro-5-naphthyl mean. As a mono- or bicyclic heteroaryl, Ar represents a ring carbon atom linked to the azaphenylene radical Het, an oxygen, sulfur or nitrogen atom and optionally containing 1-3 additional nitrogen atoms as ring members Rest, preferably with 5 or 6 ring members, which is at least partially saturated and in this case can be substituted by oxo, being in a bicyclic heterocyclic radical the second ring can be a fused benzo ring, and means in particular pyridyl, e.g. 2-, 3- or 4-pyridyl, or dihydro-oxo-pyridinyl e.g. 1,6-dihydro-6-oxo-2-pyridinyl, pyridazinyl, e.g. 3-pyridazinyl, pyrazinyl, e.g., 2-pyrazinyl, pyrimidinyl, e.g., 2-, 4- or 5-pyrimidinyl, or dihydro-oxo-pyrimidinyl e.g.

3,4-dihydro-4-oxo-2-pyrimidinyl, furyl e.g. 2- or 3-furyl, pyrryl e.g. 2- or 3-pyrryl, thienyl e.g. 2- or 3-thienyl, oxazolyl e.g.

2- or 4-oxazolyl, thiazolyl, e.g. 2-, 4- or 5-thiazolyl, thiadiazolyl e.g. 1,2,4-thiadiazol-3- or -5-yl or 1,2,5-thiadiazol-3-yl, imidazolyl e.g. Imidazol-2- or -4-yl, pyrazolyl e.g. 3- or 4-pyrazolyl, triazolyl e.g. 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, tetrazolyl such as tetrazol-5-yl, also indolyl e.g. indol-4-yl, Quinovinyl, e.g. 2-quinolinyl, isoquinolinyl, e.g. l-isoquinolinyl, benzimidazolyl, e.g. 2-benzimidazolyl, benzofuranyl, e.g. 4- or 5-benzofuranyl, benzthiophene e.g. 4- or 5-benzthiophene, or naphthyridinyl e.g. 1,8-naphthyridin-2-yl substituents a carbocyclic or heterocyclic aryl radical, in the latter case primarily a ring carbon atom, but also a secondary ring nitrogen atom may be substituted, and such substituents one or more times, preferably can be present at most fourfold are, for example, optionally substituted aliphatic hydrocarbon radicals, such as optionally substituted Lower alkyl, e.g. lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, such as hydroxy-lower alkyl, lower alkoxy-lower alkyl or halo-lower alkyl, or optionally substituted, such as acylated amino-lower alkyl, such as lower alkanoylamino-lower alkyl or lower alkoxycarbonylamino lower alkyl, or lower alkenyl or lower alkynyl, optionally etherified or esterified hydroxy or mercapto, such as hydroxy, optionally, e.g. by aryl, by optionally etherified or esterified Hydroxy or mercapto or lower alkoxy substituted by acyl, e.g. lower alkoxy, Phenyl lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, lower alkylthio lower alkoxy Halo-lower alkoxy or lower alkanoyl-lower alkoxy or lower alkenyloxy, lower alkynyloxy, Lower alkylthio or halogen, acyl, e.g. lower alkanoyl, optionally esterified Carboxy such as carboxy or lower alkoxycarbonyl, amidated carboxyl e.g. substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl, Cyano, nitro or optionally substituted, such as acylated amino, e.g. lower alkanoylamino, Lower alkoxycarbonylamino, lower alkylsulfonylamino, optionally substituted Ureido, also amino, N-lower alkylamino or N, N-di-lower alkylamino, also lower alkylsulfonyl. Substituents of a heterocyclic aryl radical Ar are also optionally substituted by lower alkyl9 lower alkoxy, halo-lower alkyl, carbamoyl or cyano Aryls, in particular phenyl, or aroyl, in particular benzoyl, or optionally, e.g. as indicated, substituted heterocyclic aryl radicals, e.g. those mentioned, those on a ring carbon atom or a ring nitrogen atom of the to be substituted heterocyclic aryl radical are bonded.

Divalent substituents in one of the group Ar corresponding monocyclic, carbocyclic, aromatic hydrocarbon, e.g., phenyl, or in a monocyclic Heteroaryl radical, e.g. imidazole, which are bonded to two ring carbon atoms Lower alkylene or lower alkenylene.

In connection with the present description with "low" The radicals and compounds indicated preferably contain up to 7 and primarily up to 4 carbon atoms.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl or tert-butyl; substituted lower alkyl is particularly appropriate Methyl or 1- or 2-ethyl.

Lower alkenyl is e.g. vinyl, allyl, 2- or 3-methallyl or 3, 3-dimethylallyl.

Lower alkynyl is, in particular, propargyl.

Lower alkoxy is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy, while phenyl lower alkoxy e.g.

Benzyloxy or 1- or 2-phenylethoxy, lower alkenyloxy e.g. allyloxy, 2- or 3-methallyloxy or 3,3-dimethylallyloxy and lower alkinyloxy in particular Represents propargyloxy.

Lower alkylthio is, for example, methylthio, ethylthio, n-propylthio or Isopropylthio.

Lower alkylsulfonyl is, for example, methylsulfonyl or ethylsulfonyl.

Halogen is preferably halogen of atomic number up to 35, i.

Fluorine, chlorine or bromine.

Lower alkanoyl is, for example, acetyl, propionyl or butyryl.

Lower alkoxycarbonyl is, for example, methoxycarbonyl or ethoxycarbonyl.

Optionally substituted carbamoyl is, for example, carbamoyl, or N-lower alkyl- or N, N-di-lower alkylcarbamoyl, such as N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl or N, N-diethylcarbamoyl.

Lower alkanoylamino is, for example, acetylamino or propionylamino, lower alkoxycarbonylamino is e.g. Nethoxycarbonylamino or Aethoxycarbonylamino.

Lower alkylsulfonylamino is, for example, methylsulfonylamino or ethylsulfonylamino.

Optionally substituted ureido is e.g. ureido or 3-lower alkyl or 3-cycloalkyl ureido, in which cycloalkyl has e.g. 5-7 ring members, e.g. 3-methyl ureido, 3-ethylureido or 3-cyclohexylureido.

N-lower alkylamino and N, N-di-lower alkylamino are e.g. methylamino, Ethylamino, dimethylamino or diethylamino.

Hydroxy lower alkyl is preferably hydroxymethyl or 1- and in primarily 2-hydroxyethyl.

Lower alkoxy lower alkyl is preferably lower alkoxymethyl or 1- and primarily 2-lower alkoxyethyl, e.g. methoxymethyl, ethoxymethyl, 2-methoxyethyl or 2-ethoxyethyl.

Halo-lower alkyl is preferably halomethyl, e.g., trifluoromethyl.

Lower alkanoylamino lower alkyl is, in particular, lower alkanoylaminomethyl or 1- and primarily 2-lower alkanoylamino-ethyl, e.g. acetylaminomethyl, 2-acetylaminoethyl or 2-propionylaminoethyl.

Lower alkoxycarbonylamino-lower alkyl is, in particular, lower alkoxycarbonylaminometl-zyl, or 1- and primarily 2-lower alkoxycarbonylamino-ethyl, e.g. methoxycarbonylaminomethyl, 2-methoxycarbonylamino-ethyl or 2-ethoxycarbonylamino-ethyl.

Lower alkoxy-lower alkoxy includes lower alkoxymethoxy or 1- and in particular 2-lower alkoxy-ethoxy, e.g. ethoxymethoxy, 2-methoxy-ethoxy or 2-ethoxy-ethoxy.

Lower alkylthio-lower alkoxy is, in particular, lower alkylthiomethoxy or 1- and primarily 2-lower alkylthioethoxy, e.g.

2-methylthio-ethoxy or 2-ethylthio-ethoxy.

Halo-lower alkoxy is in particular 2-haloethoxy, e.g.

2-chloroethoxy.

Lower alkanoyl lower alkoxy is e.g. lower alkanoyl methoxy or 1- or 2-lower alkanoyl ethoxy, e.g., acetyl methoxy.

Lower alkylsulfonyl is, for example, methylsulfonyl or ethylsulfonyl.

Lower alkylene as a substituent of a carbocyclic aryl radical Ar is for example 1,3-propylene or 1,4-butylene, while lower alkenylene is e.g.

1,3-prop-1-enylene, 1,4-but-1-enylene or 1,3-butadienylene. A Such a radical forms together with a phenyl radical Ar, for example, an optionally substituted, via an aromatic ring carbon atom substituted indanyl, 1,2,3,4-tetrahydronaphthyl, Naphthyl or indenyl group, while e.g. with a monocyclic heteroaryl group, such as one of the above, e.g. imidazole, for example a 1,6-dihydrocyclopenta [d] imidazole, a 4,5,6,7-tetrahydrobenzimidazole or benzimidazole group is formed.

Substituents in a monocyclic heterocyclic aryl radical Ar, e.g. those mentioned, such as pyridyl, pyrimidinyl, furyl, pyrryl, thienyl, thiadiazolyl, Indolyl, quinolyl, imidazolyl or benzimidazolyl are furthermore optionally, e.g. as indicated, substituted monocyclic heteroaryl radicals, e.g., those as indicated.

In this sense substituted Ar radicals are, for example, pyridylphenyl, such as lower alkyl such as (methyl-2-pyridyl) -phenyl, (cyano-2-pyridyl) -phenyl, pyrimidinyl-phenyl such as (2-pyrimidinyl) -phenyl or (hydroxy-2-pyrimidinyl) -phenyl, furyl-phenyl e.g. Lower alkoxy such as methoxy furyl (2) phenyl, pyrryl phenyl such as pyrrol-2-yl or -3-yl-phenyl, e.g. halo-lower alkyl-, such as triEluoromethyl-pyr rol-2-yl or -3-yl-phenyl, Imidazolyl-phenyl e.g. halo-lower alkyl such as trifluoromethylimidazol-2-yl-phenyl, Imidazolyl-furyl e.g.

Halo-lower alkyl such as (trifluoromethyl) imidazol-2-yl-furyl, pyrimidinyl-furyl such as hydroxy-2-pyrimidinyl-furyl, pyrryl-furyl e.g. halogen- such as chloropyrrol-3-yl-furyl, Thienyl-furyl e.g.

Lower alkyl such as methyl-2-thienyl-furyl, thiadiazolyl-furyl e.g.

1,2,4-thiadiazol-3-yl-furyl, indolyl-furyl such as lower alkoxy- e.g.

4-methoxyindol-2-yl-furyl, benzimidazolyl-furyl, e.g. lower alkyl such as 4-methylbenzimidazol-2-yl-furyl, triazolyl-furyl such as 1,2,4-triazol-3-yl-furyl, tetrazolyl-furyl such as tetrazol-5-yl-furyl, pyrazolyl-furyl such as pyrazol-3-yl- or 4-yl-furyl, quinolinyl-furyl e.g.

Lower alkoxy such as methoxy-2-quinolinyl-furyl, thienyl-imidazolyl e.g.

Lower alkoxy such as (methoxy-2-thienyl or 3-thieny »+ imidazolyl, thiazolylimidazolyl e.g. halo- such as chlorothiazol-2-yl-imidazolyl or 1,2,5-thiadiazol-3-yl-imidazo2yl.

An azaphenylene radical Het is, for example, a mono- or diazaphenylene radical, for example one of the formulas wherein the group Ar on the one hand and the oxygen atom of the side chain on the other hand be bonded to any ring carbon atoms and accordingly in a monoazaphenylene radical Ia in 2,3-, 2,4-, 2,6- and especially in 2,5-position, incine diazaphenylene radical Ib in Can be 2,3-, 2,6- and especially in the 2,5-position to each other.

Alkylene alk can be straight-chain or branched and is e.g.

1,2-ethylene, 1,2-, 2,3- or 1,3-propylene, 1,4- or 2,4-butylene, 2-methyl-2,4-butylene, or l, l-dimethylethylene.

Together with the nitrogen atom of the amide group, R1 and R2 are as Lower alkylene, for example, l-aziridinyl, l-azetidinyl, pyrrolidino, piperidino, Hexahydro-1H-azepin-1-yl, as oxane-lower alkylene e.g.

Morpholino, as thiane lower alkylene, e.g. thiomorpholino, as optionally N-lower alkylated aza lower alkylene e.g. N-lower alkyl such as N-methyl-1-piperazinyl or hexahydro-1H-1,4-diazepin-1-yl.

The aliphatic side chain can contain the salicylamide residue in any Position, preferably in the para position to the carbamoyl group, especially in the para position to the hydroxyl group.

N-oxides are derived on the one hand from those compounds in which Ar is mono- or bicyclic containing at least one tertiary nitrogen atom Heteroaryl, e.g. pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, quinolinyl, Represents pyrazolyl, triazolyl, tetrazolyl, thiazolyl or thiadiazolyl. on the other hand the azaphenylene radical Het is also capable of binding N-oxides.

The new compounds can be in the form of their salts, such as their acid addition salts and primarily their pharmaceutically acceptable non-toxic acid addition salts are present. Suitable salts are, for example, those with inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid or hydrobromic acid, sulfuric acid, or phosphoric acid, or with organic acids such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, Amber-, Glycol, milk, apple, wine, lemon, male, Hydroxymalein, pyruvine, Ftmar, benzoin, 4-aminobenzoe, anthranil, 4-hydroxybenzoene, Salicyl-, Embon-, FIcthansulfon-, Aethansulfon-, 2-Hydroxyäthansulfon-, Aethylenesulfon-, Toluenesulfonic, naphthalenesulfonic or sulfanilic acid, or with other acidic organic acids Substances such as ascorbic acid.

The new compounds of the formula I have valuable pharmacological properties Properties. In particular, they act in a specific way on ß-adrenergic receptors. The common property of this effect is their affinity for these receptors which are based on a lack of or very little self-stimulating effect expressed as a pure blockage. Accordingly, the new compounds show blocking effects on ß-adrenergic receptors with clearly preferential inhibition of cardiac receptors. As an additional effect, the new compounds also show a stimulation of dopaminergic Receptors and a bradycarde effect.

This information is based on the results of corresponding pharmacological Try using the usual test procedure. So the new compounds show an inhibition of tachycardia induced by isoproterenol: in the isolated guinea pig heart according to Langendorff in a concentration range from about 0.003 r mol / liter to about 0.3 lu MoL / liter, with the awake, trained dog as well as with the anesthetized cat at a dose range of from about 0.01 mg / kg to about 1 mg / kg after intravenous administration. Those in the conscious dog after parenteral administration of doses from about 0.01 mg / kg to about Emetic effects occurring at 1 mg / kg can be inhibited by dopamine antagonists.

The new compounds act in a dose range of about 0.03 mg / kg to about 1 mg / kg after intravenous administration a lowering of the artial Blood pressure on the anesthetized cat, while the bradycardia effect on the anesthetized Cat canned of about 0.001 mg / kg to about 0.1 mg / kg after intravenous Administration occurs.

Because of these properties, the new compounds can act as p-receptor blockers with or without cardioselectivity for the treatment of high blood pressure, angina pectoris, hypertrophic cardiomyopathies and arrhythmias can be used.

The compounds of the formula I can also be used as valuable intermediates for the preparation of other valuable, especially pharmaceutically active compounds be used.

The invention relates in particular to compounds of the formula I in which Ar is an optionally substituted mono- or bicyclic, carbocyclic or heterocyclic heterocyclic ones bonded to the azaphenylene radical Het via a ring carbon atom Represents aryl radical with 5-6 ring members, which is at least partially saturated and in in this case can be substituted by oxo, with substituents optionally substituted lower alkyl, e.g. lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, Halo-lower alkyl, lower alkanoylamino-lower alkyl, lower alkoxycarbonylamino-lower alkyl, or lower alkenyl, lower alkynyl, optionally etherified or esterified hydroxy or mercapto, e.g. hydroxy, lower alkoxy, hydroxy-lower alkoxy, phenyl-lower alkoxy, Lower alkoxy-lower alkoxy, lower alkylthio-lower alkoxy, halo-lower alkoxy, lower alkanoyl-lower alkoxy, Lower alkenyloxy, lower alkinyloxy, lower alkylthio, lower alkylsulfonyl, or Halogen, acyl, e.g. lower alkanoyl, optionally esterified carboxy such as carboxy, or lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl or N, N-di-lower alkyl-carbamoyl, Cyano, nitro and / or optionally substituted, such as acylated amino, e.g. amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino , Lower alkylsulfonylamino, ureido, 3-lower alkylureido or 3-cycloalkylureido and also heterocyclic aryl substituents Ar optionally how indicated, substituted phenyl or benzoyl or optionally, as indicated, represent substituted monocyclic heteroaryl, llet one via a ring carbon atom bonded to the group Ar and via a ring carbon atom to the oxygen atom Represents azaphenylene radical, and alk represents an alkylene radical having 2 to 4 carbon atoms means, wherein the nitrogen atom and the oxygen atom by 2 or 3 carbon atoms are separated from one another, R1 and R2 have the meaning given under the formula I. have, but are preferably hydrogen or lower alkyl, or together with the nitrogen atom of the amide group morpholino or alkylenamino with 5 to 6 ring members form, such as pyrrolidino or piperidino, or their N-oxides and salts, in particular Acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts, of that.

The invention very particularly relates to compounds of the formula I, wherein Ar is an optionally substituted carbocyclic or ring carbon atom bound to the azaphenylene radical Het, an oxygen, sulfur or nitrogen atom and optionally containing 1 to 3 additional nitrogen atoms as ring members Represents heteroaryl radical with 5-6 ring members which is at least partially saturated and in this case may be substituted by oxo, and substituents optionally substituted lower alkyl, e.g. lower alkyl, hydroxy lower alkyl, halo lower alkyl, or lower alkenyl, optionally etherified or esterified hydroxy or mercapto, e.g. hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkoxy-lower alkoxy, halogen-lower alkoxy, Lower alkenyloxy, lower alkinyloxy, lower alkylthio, lower alkylsulfonyl, or halogen, Acyl, e.g. lower alkanoyl, optionally esterified carboxy such as carboxy or Lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkyl-carbamoyl, Cyano, nitro, optionally substituted such as acylated amino, e.g.

Amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, Lower alkoxycarbonylamino, lower alkylsulfonylamino, optionally by Substituted lower alkyl, lower alkoxy, halogen, halo-lower alkyl, nitro or cyano Phenyl or benzoyl, and also substituents of heterocyclic aryl Ar, if appropriate, as indicated, substituted monocyclic, oxygen or nitrogen atom and optionally mean heteroaryl containing 1-3 further nitrogen atoms, Het one through a ring carbon atom to the group Ar and through a ring carbon atom represents azaphenylene radical bonded to the oxygen atom, and alk represents an alkylene radical with 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom are separated from one another by 2 to 3 carbon atoms, R1 and R2 for hydrogen or lower alkyl or together with the nitrogen atom of the amide group pyrrolidino, Form piperidino or morpholino, or their N-oxides and salts, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts thereof.

The invention relates specifically to the compounds mentioned in the examples of the formula I, or their N-oxides and salts, in particular acid addition salts, in primarily pharmaceutically acceptable, non-toxic acid addition salts thereof.

The new compounds of the formula I are prepared in a manner known per se. They can be obtained, for example, by using a compound of the formula wherein Ar1 represents the radical Ar or a radical containing at least one functional group in protected form, X2, X3 and X4 each represent hydrogen or a hydrogen-replaceable substituent, X5 represents R1 or a hydrogen-replaceable substituent, or X2 and X3 and / or X4 and X5 together represent a divalent radical which can be replaced by two hydrogen atoms, and / or any functional groups present in the radical Ar are optionally present in protected form, with the proviso that at least one of the radicals X2, X3, X4 or X5 of Hydrogen is different, or at least Ar is a radical Ar which contains at least one functional grouping in protected form, or at least X2 and X3 together or X4 and X5 together represent a divalent radical which can be replaced by two hydrogen atoms, or in a salt thereof, those of Hydrogen different groups X2, X3, X4 or X5 or X2 and X 3 together and / or X4 and X5 together are replaced by hydrogen atoms, and / or in a radical Arl splitting off the protective groups bonded to one or more functional groups and replacing them with hydrogen, and, if desired, converting a compound obtainable in this way into another compound of the formula I converts and / or, if desired, a free compound obtained or an N-oxide thereof into a salt or a salt obtained into a free compound or an N-oxide, and / or, if desired, a mixture of isomers obtained into the isomers or separating a racemate obtained into the antipodes.

Protected functional groups in a radical Ar are e.g.

protected hydroxyl, amino or mercapto groups, also one as Ring member in a heteroaryl residue Ar standing protected group -NH-, whereby protecting groups represent groups which can be split off and which can be replaced by hydrogen.

The splitting off of the groups X2, X3 or X4 or each of X2 and X3 and / or X4 and X5 together, as well as the functional groups in a radical Ar, e.g. protective groups containing hydroxyl and / or amino groups is obtained by means of solvolysis, such as hydrolysis or alcoholysis or acidolysis, or by means of reduction, inclusive Hydrogenolysis made.

A particularly suitable, removable group X3 or X4, or a Hydroxy or amino protective group in a radical Arl is primarily a hydrogenolytic one removable a-aryl lower alkyl group, such as an optionally substituted l-polyphenyl lower alkyl or l-phenyl-lower alkyl group, e.g. benzhydryl or trityl, in which substituents, especially the phenyl moiety, e.g. lower alkyl such as methyl, or lower alkoxy such as Methoxy, can be, and primarily benzyl.

A group X3 and in particular X2 and X4 as well as hydroxy and / or Amino protective groups in a radical Ar can also be solvolytic or hydrolytic or acidolytically, furthermore one which can be split off reductively, including hydrogenolytically Radical, in particular a corresponding acyl radical, such as the acyl radical of an organic one Carboxylic acid, e.g.

Lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, and also the acyl radical a half-ester of carbonic acid, such as lower alkoxycarbonyl, e.g. methoxynarbonyl, Ethoxy carbonyl or tert-butyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-Trichloräthoxycarbonyl or 2-Jodäthoxycarbonyl, optionally substituted l-phenyl-lower alkoxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further one optionally substituted 1-polyphenyl-lower alkyl group, e.g.

as indicated above and are primarily trityl.

A splittable one formed by X2 and X3 or X4 and X5 together The remainder is primarily a hydrolytically cleavable group, such as lower alkylidene, e.g. isopropylidene, or optionally substituted l-phenyl-lower alkylidene, wherein substituents, especially of the phenyl part, e.g. lower alkyl or lower alkoxy and especially benzylidene, or cycloalkylidene, e.g., cyclopentylidene or cyclohexylidene, furthermore for X and X3 together the carbonyl group.

Starting materials which can be used in the form of salts are primarily Line in the form of acid addition salts, e.g. with mineral acids, as well as with organic Acids used.

Hydrogenolytically cleavable radicals X2, X3, X4 and / or X5, in particular optionally substituted l-pbenyl lower alkyl groups, also suitable acyl groups, such as optionally substituted l-phenyl-lower alkoxycarbonyl, as well as by the Groups X2 and X3 and also X4 and X5 formed together, optionally substituted l-phenyl lower alkylidene groups, as well as hydroxy and / or amino protecting groups of this type can be obtained by treating with catalytically activated Hydrogen, for example with hydrogen in the presence of a catalyst such as a suitable one Noble metal catalyst, e.g.

Palladium or platinum are split off.

Groups X2, X3, X4 and / or X5 which can be split off hydrolytically, such as acyl radicals of organic carboxylic acids, e.g. lower alkanoyl, and of semi-esters of carbonic acid, e.g. lower alkoxycarbonyl, further e.g.

Trityl residues, as well as through the residues X2 and X3 and / or X and X5 to-4 together formed lower alkylidene, l-phenyl-lower alkylidene or cycloalkylidene groups, as well as in a radical Ar on functional groups, such as on hydroxyl, mercapto, amino and / or protecting groups on a group -NH- as a ring member of a heteroaryl radical Ar Depending on the nature of such residues, this type can be treated with water under acidic conditions or basic conditions, e.g. in the presence of a mineral acid such as hydrogen chloride or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate or an amine, such as isopropylamine, are split off.

Residues X2, X3, X4 and / or X5 and / or an can be split off acidolytically functional groups, such as those mentioned, e.g. on hydroxy, mercapto or amino standing protecting groups in a radical Ar1 are in particular certain Acyl residues of half-esters of carbonic acid, e.g.

tert-lower alkoxy carbonyl or optionally substituted diphenylmethoxycarbonyl radicals, furthermore also a tert-lower alkyl radical; such residues can e.g. by treating with suitable strong organic carboxylic acids, such as optionally by halogen, especially fluorine, substituted lower alkanoic acids, primarily with Trifluoroacetic acid (if necessary, in the presence of an activating agent such as Anisole), as well as with formic acid.

Among radicals X2, X3, X4 and / or X5 and / or which can be split off reductively on functional groups, such as those mentioned, e.g. on hydroxyl and / or amino Protective groups in a radical Arl are also understood to mean those groups which, when Treatment with a chemical reducing agent (especially a reducing agent Metal or a reducing metal compound). Such leftovers are in particular 2-halo-lower alkoxycarbonyl or rylmethoycarbonyl, e.g. when treating with a reducing heavy metal such as zinc, or with a reducing heavy metal 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 split off from water.

Protective groups which are present in a radical Ar functional, z. B. hydroxyl and / or amino groups correspond to those mentioned above and can be split off by means of the methods described and can be replaced by hydrogen Groups, with such groups in the course of the procedure described simultaneously split off with other groups or subsequently in a separate procedural measure will.

The above reactions are usually carried out in the presence of a solvent, or solvent mixture carried out, with suitable Respondents at the same time can also function as such, and, if necessary, with cooling or heating, e.g. in an open or closed vessel and / or in the atmosphere an inert gas such as nitrogen.

The starting materials of the formula II can be prepared in a customary manner, for example by reacting a compound of the formula with a compound of the formula wherein Xo has the meaning given above for X2, and one of the groups Y1 and Y2 for a reactive esterified hydroxyl group, for example

Halogen, such as chlorine or bromine, and the other for the group of the formula -NH (X3), or in which X20 and Y1 represent the direct bond-3 1 and Y2 represents the group of the formula -NH (X), in which X3 has in each case -3 because the above meaning produce. The above reactions are carried out in a manner known per se.

Starting materials of the formula IIa, in which X20 is hydrogen or acyloxy, for example lower alkanoyl, e.g. acetyl, and Y1 is a reactive, esterified hydroxyl group, For example, chlorine or methanesulfonyloxyl can be prepared using alkaline reagents convert into compounds of the formula IIa in which X20 and Y1 represent the direct bond. This conversion is e.g. for the case that X2 is hydrogen, e.g. by means of a mixture of dilute alkali, such as sodium hydroxide, and tetrabutylammonium chloride in a suitable solvent, such as methylene chloride, or in the event that that X20 is acetyl, e.g. by means of an alkali lower alkanolate, about sodium ethylate in methanol, carried out in the usual manner.

If e.g. Y1 or Y2 is a reactive, esterified hydroxyl group, E.g. chlorine, one works in the presence of a basic agent, such as a Alkali or alkaline earth carbonate, such as potassium or calcium carbonate, or an alkali or alkaline earth hydroxide, such as sodium or calcium hydroxide, conveniently in Presence of a suitable solvent, such as a lower alkanol such as ethanol, or an alkanone such as acetone.

You can also, for example, by reacting a compound of the formula with a carbonyl compound of the formula wherein alk represents an alkylidene radical corresponding to the radical alk, and at least one of the radicals X2, X4 or X4 and X5 together represents one of the specified protecting groups, or at least Arl represents a radical Ar in which at least one functional group is present in protected form, formed Schiff ' cal base with a reducing agent, for example a borohydride, such as sodium borohydride, reduce to the compound of formula II. The reduction can also take place by means of activated hydrogen, for example hydrogen in the presence of a hydrogenation catalyst, for example a platinum-on-carbon catalyst.

Carbonyl compounds of the formula (IId) in turn can be obtained by reacting a compound of the formula or a salt thereof with a compound of the formula (O = alk) -Hal (IIf), in which alk1 has the above meaning, Hal stands for halogen and such a compound is, for example, a halo ketone, for example chloroacetone, can be obtained in the customary manner.

Starting materials of the formula IIc for their part are, for example, in a customary manner by reacting an epoxide of the formula accessible with ammonia. Epoxides of the formula IIf, in turn, can be prepared by reacting a compound of the formula Arl-Het-Z (IIg), in which Z is a nucleophilically removable group, for example halogen, for example chlorine, with a compound of the formula Vm explained below and the procedure described there can be obtained.

The new compounds of the formula I can also be obtained by adding a compound of the formula with a compound of the formula or a salt thereof, in which one of the groups Z1 and Z2 is a reactive esterified hydroxy group and the other is the primary amino group, and Xl is hydroxy, or in which X1 and Z1 together are the epoxy group and Z2 is the primary amino group, and Ar , Het, alk, R1 and R2 have the above meanings, and, if desired, carry out the additional process steps.

A reactive esterified hydroxyl group Z1 or Z2 is one by a strong acid, especially a strong inorganic acid such as a hydrohalic acid, in particular chloric, bromic or hydroiodic acid, or sulfuric acid, or a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, e.g. methanesulphonic acid, 4-methylphenylsulphonic acid or 4-bromophenylsulphonic acid, esterified hydroxyl group, and is primarily halogen, e.g. chlorine, bromine or Iodine, or aliphatic or aromatic substituted sulfonyloxy, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The above reaction is carried out in a manner known per se, being, especially when using a starting material with a reactive esterified hydroxyl 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 alkali metal lower alkanolate, and / or an excess of the basic reactant and usually in the presence of a solvent or solvent mixture and, if necessary, with cooling or heating, e.g. in a temperature range from about -20 ° C to about +150 "C, in an open or closed vessel and / or in an inert gas atmosphere, e.g. in a nitrogen atmosphere.

Starting materials of the formula III can be prepared in a manner known per se will. So these can be obtained by e.g.

a compound of the formula Ar - Het - Z (liga), in which Z is a nucleophilically removable group, with a compound of the formula or a corresponding cyclic compound of the formula converts, in which Y is the group of the formula denotes wherein R6 and R7 are each hydrogen or lower alkyl, e.g.

Is methyl, or the group of the formula IIId is optionally substituted l-Phenylniederaikyliden, in which substituents, in particular of the phenyl part, for example lower alkyl, lower alkoxy or halogen, and especially for benzylidene or cycloalkylidene, e.g.

Cyclopentylidene or cyclohexylidene, or the group Y the Group - (C = O) - (IIIe), the groups X2 and X3, are different from hydrogen and groups removable by, for example, hydrolysis or hydrogenolysis, e.g., as above described, for example, lower alkanoyl, such as acetyl, or benzoyl, represent the reaction product hydrolyzed and existing protective groups e.g. by means of hydrolysis, for example in the course of hydrolysis of an oxazolidine or oxazolidinone ring, described below, or split off by means of hydrogenolysis.

A nucleophilically removable group æ is, for example, a halogen atom, such as Chlorine, bromine or iodine, a nitro, lower alkylsulfonyloxy such as methylsulfonyloxy, Lower alkylsulfonyl, such as methylsulfonyl, lower alkylsulfinyl, such as methylsulfinyl, Lower alkoxy, such as methoxy or ethoxy, or an ammonium group, such as the trimethyl or triethylammonium group.

The implementation of a compound of the formula IlIa with such a of the formula IIIb or IIIc is expediently carried out in the presence of a basic one By means of, for example, an alkali metal such as sodium or a metal hydride, e.g. an alkali metal hydride such as sodium hydride. The hydrolysis of a reaction product obtained is carried out by means of water, optionally in the presence of acidic agents, e.g. a mineral acid, such as hydrochloric acid or sulfuric acid, made, the acid Hydrolysis in particular in the case of reaction products with a group of the formula IIId is used, with any protective groups present being split off at the same time and can be replaced by hydrogen, while reaction products with a Group Y of the formula IIIe advantageously in the presence of alkaline substances Substances, e.g.

strong bases such as alkali hydroxides e.g. sodium hydroxide it may be useful to use a higher boiling solvent, e.g. Butanol, to use. In this way a starting material of the formula is obtained III, wherein X1 is hydroxy and Z1 is amino.

Compounds of the formula IIIa, in turn, are obtainable by in a compound of the formula R3 - et - Z (eleven), wherein R3 is one to form a mono- or bicyclic heteroaryl radicals Ar capable, optionally protective groups containing substituents represents the mono- or bicyclic heteroaryl group Ar forms and any protecting groups present simultaneously or subsequently split off and replaced by hydrogen.

Thus, compounds of the formula purple, in which Ar has the meaning given has, and e.g. an imidazolyl, benzimidazolyl, pyrrolyl, indolyl, pyrazolyl, Thiazolyl, thiadiazolyl, pyrimidinyl or triazolyl radical means from a compound the formulailif analogous to that for the formation of a corresponding heteroaryl radical Ar in a compound of formula VIII described methods in the usual way can be obtained.

Starting materials of the formula IV, in which Z2 is halogen, can e.g. by reacting a hydroxysalicylamide with one of the meaning of alk corresponding Dihaloalkane, for example a chlorobromo- or diromolcan in the presence of an alkaline one Condensing agent such as an alkali carbonate. From this can e.g. by reaction with hexame thy len tetr amine and decomposition of the formed Adduct with an aqueous mineral acid, e.g., dilute hydrochloric acid, is a starting material of formula III, wherein Z2 is primary amino. These implementations will be made in the usual way.

Starting materials of the formula IV, in which Z2 is halogen, can also be obtained by reacting a phenol of the formula or an alkali salt, for example the sodium salt, with carbon dioxide under the conditions of the Kolbe synthesis to form the correspondingly substituted salicylic acid, and its conversion, for example via the acid chloride, which is usually obtained by means of thionyl chloride, into the substituted salicylamide corresponding to the radicals R1 and R2 in a manner known per se can be obtained.

The new compounds can also be obtained by looking at a compound of the formula wherein X6 is a reducible group of the formula - CII = N - olk - (Va) or - C112 - N = alk2 - (Vb), where alk2 is an alkylylidene radical corresponding to the radical alk, the group X6 to the group of the formula - Cl {2 - NH - alk- (Vc) reduced, if necessary, any protective groups not participating in the reaction, attached to functional groups, cleaved off simultaneously or subsequently and replaced by hydrogen, and, if desired, carries out the additional process steps. Protective groups of protected functional groups, for example those of the type mentioned above, such as protected hydroxyl and / or amino groups, are primarily groups that can be split off hydrogenolytically, for example an a-aryl-lower alkyl group, such as an optionally substituted l-phenyl-lower alkyl group, in which substituents, such as the phenyl radical , e.g.

Lower alkoxy, such as methoxy, and especially benzyl, such protective groups in the course of the process described simultaneously or subsequently split off in a separate procedural measure.

Starting materials of the formula V with a group X6 of the formula Vb can also be in the isomeric form of ring tautomers of the formula wherein alk3 corresponds to the meaning of alk2 or represents an alkylidene group, and the oxygen and nitrogen atoms of the ring are bonded to the same carbon atoms.

An alkyl-ylidene group alk2 is, for example, methine or ethyl-ylidene, while an alkylidene group alk2 represents e.g. methylene, ethylidene or l-methyl-ethylidene.

The reduction of the nitrogen-carbon double bond in starting materials of the formula V, which contain a group Va or Vb as X6, to form a nitrogen-carbon single bond of the group Vc, in a manner known per se, for example by treating with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, e.g. a nickel, platinum or palladium catalyst, with hydrogenolytic Removable protective groups are split off and replaced by hydrogen at the same time; or you work with a suitable hydride reducing agent, such as an alkali metal borohydride, e.g. sodium borohydride. When using a hydride reducing agent, oxygen acyl residues of carboxylic acids, such as acetic acid, bound as protective groups, be split off in the same operation.

A starting material of the formula V can be prepared in a manner known per se, if appropriate in situ, ie under the conditions of the process described. So you can get a compound of the formula with an amine of the formula where functional groups, for example hydroxyl groups, optionally, for example

as described, in a protected form, to a starting product of the formula V are reacted with the group X6 of the formula Va.

By reacting a compound of the formula with a carbonyl compound of the formula wherein alk has the meaning given under the formula IIf, and where functional groups not involved in the reaction, for example hydroxyl groups, are optionally present in protected form, for example as described, starting materials of the formula V can be obtained.

Oxo compounds of the formula Vi, in turn, are obtained, for example, by reacting a compound of the formula or a salt thereof with a haloalkanone compound of the formula IIf explained above, for example chloroacetone, in the presence of an alkaline condensing agent, for example potassium carbonate, or an organic base, such as triethylamine.

Amines of the formula Vh are in turn made, for example, by reacting a compound of the formula obtained with ammonia in the usual way.

Epoxides of the formula V1 in turn can be prepared by reacting a compound of the formula IIIa explained above with a compound of the formula wherein X2 is a protective group which can be split off by hydrolysis, for example

as described above, for example lower alkanoyl, such as is acetyl, or the two groups X2 together are lower alkylidene, eg isopropylidene or benzylidene, to form a compound of the formula converts this by means of hydrolysis, for example in an acidic medium, for example by means of a mineral acid such as hydrochloric acid, into the corresponding glycerol ether, converts this with an ortho-ester, for example triethyl orthoacetate and trimethylchlorosilane, and from the reaction product by the action of a base, e.g. a tetra-lower alkylammonium base, about tetrabutylammonium hydroxide, an epoxide of the formula V1.

The new compounds of formula I can also be obtained or a reactive derivative of such a carboxylic acid, in which functional groups not participating in the reaction are optionally protected by protective groups which can be split off by means of aminolysis or ammonolysis and can be replaced by hydrogen, with a compound of the formula HNR 1R2 (VIa), and at the same time splits off any protective groups that may be present and replaced by hydrogen, and, if desired, performing the additional process steps.

Protecting groups of protected functional groups, e.g.

those of the type mentioned, such as those attached to hydroxyl and / or amino groups Protective groups are residues that can be split off aminolytically and in particular ammonolytically, e.g. acyl residues of organic carboxylic acids, e.g.

Aroyl, such as benzoyl, or lower alkanoyl, such as acetyl.

Reactive derivatives of the carboxylic acids defined in formula VI are e.g. acid anhydrides, especially mixed acid anhydrides, e.g. the halides, like the chlorides or bromides, also the azides or those with carboxylic acids, for example Lower alkanecarboxylic acids, such as acetic acid or propionic acid, lower alkoxyalkanecarboxylic acids like 2-methoxyacetic acid. Reactive derivatives of carboxylic acids of the formula VI are also in particular esters, for example lower alkyl, such as methyl or tert-butyl esters with aryl lower alkanols, for example optionally with lower alkyl, e.g. methyl or Lower alkoxy e.g. methoxy, substituted benzyl alcohol, or phenols, which may optionally are activated by suitable substituents, e.g. by halogen, such as 4-halogen, such as 4-chloro, lower alkoxy, for example 4-lower alkoxy such as 4-methoxy, 4-nitro or 2,4-dinitro, such as 4-chlorophenol, 2,3,4,5,6-pentachlorophenol, 4-methoxyphenyl, 4-nitro or 2,4-Dinitrophenol, also with cycloalkanols, such as cyclopentanol or cyclohexanol, which may optionally be substituted by lower alkyl, e.g., methyl. the Implementation is known per se, usually in the presence of an inert Solvent, and in a temperature range of about -10 "to +1500 in one carried out in a closed vessel.

The starting materials of the formula VI can be obtained in a manner known per se by adding a compound of the formula (III), in which X1 and Z1 together represent the epoxy group, with an amino compound or a reactive derivative of such a carboxylic acid, e.g.

as described under formula VI, implemented.

You can also react by reacting a compound of the formula Vh explained above with a carbonyl compound of the formula or a reactive carboxylic acid derivative thereof, for example as described under formula VI, in which alk has the meaning given under formula IIf, reduce the Schiff base formed with a borohydride, for example sodium borohydride. The reduction can also be carried out by means of activated hydrogen in the presence of a hydrogenation catalyst, for example a platinum-on-carbon catalyst.

Carbonyl compounds of the formula (VIc) in turn can be prepared by reacting a compound of the formula or a reactive carboxylic acid derivative thereof, for example as described under formula VI, with a compound of the formula lif described above, for example chloroacetone, in the presence of an alkaline agent such as potassium carbonate or an organic base such as triethylamine. In these reactions, functional groups that are not involved, for example hydroxyl groups, if appropriate in protected form, for example as described, are present. These reactions are carried out in a manner known per se.

The new compounds of the formula I can also be obtained by converting into a compound of the formula wherein functional groups not participating in the reaction are protected by protective groups which can be split off by means of hydrolysis and can be replaced by hydrogen, which are split off under the conditions of the process and replaced by hydrogen, converts the -CN group into the -CONli2 group by hydrolysis, and at the same time splitting off any protective groups present and replacing them with hydrogen, and, if desired, carrying out the additional process steps.

The above reactions are carried out in a manner known per se. The hydrolysis is carried out in a basic or, advantageously, in an acidic medium, especially in the presence of concentrated aqueous mineral acid, such as conc. Hydrochloric acid, and if necessary, with cooling or heating, e.g. in a temperature range from about 0 to 60 °, preferably from about 40-50 °, in an open or closed Vessel and / or in an inert gas atmosphere, e.g. in a nitrogen atmosphere carried out.

The starting materials of the formula VII can be prepared, for example, by reacting a compound of the formula III explained above with a compound wherein one of the groups Zl and Z2 represents a reactive esterified hydroxyl group and the other represents the primary amino group, and X1 represents hydroxy, or wherein kl and Zl together represent the epoxy group and Z2 represents the primary amino group, and Ar, Het, alk, Rl and R2 have the above meaning. Reactive esterified hydroxyl groups Z1 and Z2 are preferably halogen, in particular chlorine, bromine or iodine. If Z1 or Z2 represent a reactive esterified hydroxyl group, the reaction is advantageously carried out in the presence of a basic agent in a manner known per se.

The compound VIIa in turn can by the action of acetic anhydride can be obtained on the oxime corresponding to the cyanide. This is conveniently done by refluxing. The oxime can in turn be derived from the corresponding Aldehyde by boiling with Hydroxylamill hydrochloride in the presence of alcoholic Soda solution can be produced under reflux. The corresponding aldehyde in turn can be obtained by reacting 2,4-dihydroxybenzaldehyde with a (t, SF-dihalo-lower alkane, are preferably prepared in the presence of a basic agent. But you can also in an analogous manner a hydroxysalicylonitrile, e.g. 2,4-dihydroxybenzonitrile [Chem. Ber. 24, 3657 (1891)] or 2,5-dihydroxybenzonitrile [Helv. Chim. Act 30, 149, 153 (1947)] with a non-geminal dihalo-lower alkane to form a compound implement the formula VIIa.

The new compounds of the formula I, in which Ar represents a mono- or bicyclic heteroaryl radical, can also be obtained by reacting in a compound of the formula wherein hydroxy groups and / or the amino group are protected by protective groups, and R3 represents a substituent capable of forming a mono- or bicyclic heteroaryl radical Ar, which forms mono- or bicyclic heteroaryl group Ar, splitting off any protective groups present at the same time and replacing them with hydrogen, and if desired to carry out the additional process steps mentioned above. Protective groups are, for example, acyl, such as Niederalkanoyl.wie Acetyl, which are split off under the process conditions used to form the heteroaryl radical Ar and replaced by hydrogen.

Thus, for the preparation of a compound of the formula I in which Ar is an imidazolyl radical which is substituted, for example in the 2-position by the group Het, a compound of the formula VIII in which R3 is the formyl group, in the customary manner with a 1,2 -Dicarbonyl.verbirldlll) g of the formula in which R4 and / or R5 are each hydrogen or a radical substituting the heteroaryl group, for example as described above, in the presence of ammonia or with a monooximino compound corresponding to the formula VIIIa. Depending on the nature of the radical R4 and / or R5, the compound of the formula VIIIa can be used as such or it can be formed in situ in the reaction mixture from a suitable precursor. Suitable precursors for this are, for example, acyloins, which are derived from hydroxyacetone, and are, for example, l-lower alkanoyloxy, such as l-acetyloxyacetone or l, l-dihalo, such as, for example, 1,1-dibromoacetone, which is optionally converted into 1 and / or 3-position is substituted by the group R4 and / or R5. Further precursors are those in which the carbonyl compound of the formula VIIIa is present in a modified form, for example as an acetal, for example as a dimethyl acetal, as a hydrate or as a bisulfite addition compound. From such precursors, in the case of the acyloins, such as the l-acetyloxyacetone mentioned, in the presence of a copper (II) salt, e.g. copper (II) acetate, or in the case of the l, l-dihaloacetone derivatives, by treatment with hydrolyzing agents, preferably weak alkalis, e.g.

Sodium acetate, or in the case of the acetals or bisulfite addition compounds with aqueous acids, the compound of formula VIIIa can be obtained in situ. on in this way, compounds of the formula I are obtained in which the group Het is in a 2-position, a group R4 and / or R5 in each case the 4- or 5-position of the imidazole residue formed substitute.

To prepare compounds of the formula I in which an imidazole radical Ar is substituted, for example in the 4-position by the group Het, one can, for example, by reacting a compound of the formula VIII in which R3 represents the group (VIIIb) is obtained with a compound of the formula (VIIIc), and ammonia. The groups of formula VIIIb or VIIIc can also be present in a functionally modified form, for example as acetals, such as dimethylacetals, as hydrates or as bisulfite addition compounds, from which the free compounds are formed in situ by treatment with aqueous acids and then reacted further in the same reaction batch . These reactions are carried out in a customary manner, for example in the presence of a solvent or solvent mixture, and, if necessary, with cooling or heating, for example in a temperature range from about -309 to about + 150 ° C., if necessary in a closed vessel and / or in an inert gas atmosphere, for example under nitrogen.

The starting materials can be produced in a manner known per se will.

For example, compounds of the formula VIII in which R3 represents the formyl group or the group of the formula VIIIb can be converted by reacting a compound of the formula wherein the formyl group corresponding to the radical R3 or the group of the formula VIIIb preferably in protected form, for example as an acetal, such as dimethyl acetal, as a hydrate or as a bisulfite addition compound, for example

those formed with sodium sulfite, are present with a compound of the formula for example with 5- (2-aminoethoxy) salicylamide obtained. An intermediate product formed here from the formyl group or the group of the formula VIIIb and a compound of the formula VIIIe, for example a Schiff base, is then hydrolyzed, for example with acidic agents such as a mineral acid, for example aqueous hydrochloric acid, after which the compound of the formula VIII is obtained.

Instead of the reaction described, a compound of the formula IIIf in which Z, for example, is halogen, for example chlorine, and the group R3 is the formyl group or the group of the formula VIIIb and is preferably in protected form, for example in acetal form, can also be used an oxazolidine compound of the formula convert, wherein Y is the group of the formula where R6 and R7 are each hydrogen, or the group of the formula VIILg is optionally substituted l-phenyl-lower alkylidene, where substituents, in particular of the phenyl moiety, can be, for example, lower alkyl or lower alkoxy, and in particular benzylidene or cycloalkylidene, e.g. cyclopentylidene or cyclohexylidene, or the Group Y is the carbonyl group represent, and the compound of formula obtained hydrolyze. The hydrolysis of a compound of the formula VIIIi is carried out by means of water, optionally in the presence of acidic agents, such as a mineral acid such as hydrochloric acid or sulfuric acid, the acidic hydrolysis being used in particular for compounds of the formula VIIIi with a group of the formula VIIIg, whereby at the same time optionally present protective groups can be split off and replaced by hydrogen. Compounds of the formula VIIIi with a group Y of the formula VIIIh are advantageously hydrolyzed in the presence of alkaline substances, for example strong bases such as alkali metal hydroxides, for example sodium hydroxide, it being possible to use a higher-boiling solvent, for example butanol. Any protective groups present can be split off simultaneously or subsequently in an acidic medium, for example as described.

These conversions are carried out in a manner known per se.

For example, a compound of the formula IIIf is used with a those of formula VIIIf in the presence of a basic agent, e.g.

Sodium hydride to.

Compounds of the formula VIIIf, in turn, in which Y denotes the radical of the formula VIIIg, can be prepared from a compound of the formula by reaction with an oxo compound of the formula such as formaldehyde or benzaldehyde, or their reactive derivatives, for example the acetals, such as the dimethylacetals, are obtained in the customary manner, while compounds of the formula VIlIf, in which Y represent the remainder of the formula VIIIh, are obtained by the action of phosgene on a compound of the formula VIIIk , in which the primary hydroxyl group is in protected, for example esterified, form, are accessible in a known manner, the protective group then being split off, for example by means of hydrolysis, and replaced by hydrogen.

Starting materials of the formula VlIIf are also, for example, by reacting a compound of the formula with a connection wherein Z3 is a reactive esterified hydroxyl group, roughly as defined above, for example halogen, such as chlorine or bromine, is accessible in the usual manner, preferably in the presence of an alkaline condensing agent, for example potassium carbonate, and in the absence of water, with any protecting groups present simultaneously or subsequently split off and replaced by hydrogen.

A compound of the formula I in which Ar is the thiazolyl radical which is substituted, for example in the 2-position by the group Het, can be obtained by, for example, a compound of the formula VIII in which R3 is the group of the formula means with a compound of the formula in which Hal represents halogen, for example chlorine and in particular bromine, and R4 and / or R5 each represents hydrogen or a radical which substitutes the heteroaryl group, for example as described above.

Depending on the nature of the remainder R4 and / or R5, a connection can be made Formula IXb in the form of its derivatives, e.g. the acetals, such as the diethyl acetals, or the a, ß-dihalo, such as a, ß-dibromoethyl ether, e.g.

α, ß-Dibromoethyl methyl ether, or the α, ß-Dihalogen-, such as α, ß-Dichloräthylacetale use. Instead of a carbonyl compound of the formula IXb, an epoxide of the formula can also be used where Hal is halogen, for example chlorine, use for the reaction described.

To prepare compounds of the formula I in which Ar is a thiazolyl radical substituted in the 4- or 5-position by the group Het, one can, for example, use a compound of the formula VIII in which R3 is the group of the formula or of the formula is, and the carbonyl group is optionally in the form of, for example acetal, in which tial in each case represents halogen, for example chlorine or bromine, and R4 and R have the above meanings, with a compound of the formula realize. These reactions are carried out in a manner known per se, for example in the presence of a suitable solvent, for example a lower alkanol such as ethanol, or an ethereal liquid such as dioxane, optionally at an elevated temperature and optionally in the presence of a basic agent, e.g. a metal such as alkali or alkaline earth salt of a weak acid such as carbonic acid or acetic acid, e.g.

Magnesium carbonate or sodium acetate, and if necessary, all in one closed vessel and / or in an inert gas atmosphere, e.g. under nitrogen carried out.

The starting materials can be produced by known methods. So you can have a compound of formula VIII with the group the group N r C - by reaction with hydrogen sulfide in a suitable, for example a basic organic solvent, such as

Convert pyridine or triethylamine or mixtures thereof into group IXa.

Starting materials of the formula IXg in turn can be obtained by adding a compound of the formula with a compound of the formula VIIIe explained above, for example with 5- (2-aminoethoxy) salicylamide, to form a compound of the formula IXg.

Starting materials of the formula IXh, for their part, are, for example, by reaction a compound of the formula N = C - Het - Z (Ixi), where Z is above Has meaning, and for example halogen, such as chlorine, with a compound of the formula Vm and analogous to the procedural measures described there below are accessible.

Starting materials of the formula VIII, in which R3 represents a group of the formula IXd or IXe, can be obtained, for example, by reacting a compound of the formula or the formula where Hal stands for halogen and in particular for chlorine or bromine, and Z has the meaning given under formula purple, and is, for example, chlorine, reacts with an optionally protective group-containing compound of formula VIIIf, hydrolyzes the reaction product and splits off any protective groups that may be present and replaces them with hydrogen replaced. This reaction is conveniently carried out in the presence of a basic agent, such as an alkali metal or an alkali metal hydride or lower alkoxide, such as sodium, sodium hydride or

Sodium methoxide usually in the presence of a solvent or Solvent mixture.

The hydrolysis is carried out in a customary manner by means of water, if appropriate with the addition of acidic substances, such as a mineral acid, e.g. hydrochloric acid, or a base such as an alkali or alkaline earth metal hydroxide such as sodium hydroxide or calcium hydroxide.

A compound of the formula I in which Ar is a pyrimidinyl radical which, for example, is substituted in the 4 (6) position by the group Het, can be obtained by e.g. B. a compound of formula VIII, wherein R3 is the group of formula represents in which the carbonyl group (s) are optionally in a protected, for example acetalized, form, for example as dimethylacetal, or as a bisulfite addition compound, for example with sodium bisulfite, with a compound of the formula wherein R4 and R5 have the above meanings.

This reaction is carried out in the usual way and preferably under acidic Conditions, e.g. in the presence of an acidic reacting agent such as ammonium chloride, performed.

The starting materials can be obtained by methods known per se will.

For example, a starting material of the formula VIII with the group Xa as R3 can be prepared by adding a compound of the formula with preferably protected, for example as described, acetalized carboxaldehyde group with epichlorohydrin in the presence of a base, for example

an organic amine, for example pyridine or collidine, to give a corresponding compound of the formula converts, from this the adduct obtained by reaction with elexamethylenetetramine in the usual way by decomposition by means of aqueous mineral acid, for example dilute sulfuric acid. into a corresponding compound of the formula which is then reacted with a compound of the formula VIIIn explained above in an analogous manner, for example as described there, and after converting the optionally protected carboxaldehyde group into the free carboxaldehyde group, for example by means of acidic agents such as aqueous mineral acid, e.g. dilute sulfuric acid leads to a starting material of the formula VIII with the group Xa as R3. These conversions are carried out in a manner known per se.

To prepare compounds of the formula I in which Ar is a pyrimidinyl radical which is substituted, for example, in the 2-position by the group Het, one can use, for example, a compound of the formula VIII in which R3 is the group of the formula means with a compound of the formula R4 - CO - CH2 - CO - R5 (Xg)> in which the carbonyl group (s) are optionally present in protected, for example acetalized, form, for example as dimethylacetals, and R4 and R5 have the meanings given . This reaction is carried out in a manner known per se, for example under acidic conditions, for example as described, for example in the presence of ammonium chloride.

The starting materials can be prepared by methods known per se will. For example, a compound of formula VIII with group Xf can be used as R3 obtained by, for example, a compound of the formula (IXg) explained above in the corresponding imidoesters, e.g.

by saturating an absolute ethanol solution of such a compound with hydrogen chloride, and converted therefrom by reaction with anhydrous ammonia a compound of the formula VIII containing the group XE as R3, preferably in In the form of a salt, for example with a strong acid, e.g. as a hydrochloride, and any protective groups present are removed simultaneously or subsequently and replaced by hydrogen.

The new compounds of the formula I can also be obtained by adding a compound of the formula Ar - Het - OH (XI) in which Z3 stands for a reactive, esterified hydroxyl group and X1 is hydroxyl, or in which Z3 and X1 together denote the epoxy group, or with a corresponding ring-closed compound of the formula wherein R1, R2 and alk have the meaning given, and X8 is hydrogen or a group which can be split off under the conditions of the process and is capable of forming the ether bond with the hydroxyl group of a compound of the formula VI, and, if desired, the group thereafter the first method carries out the procedural steps described. Groups X8 which can be split off and are capable of forming the ether bond are, for example, aryl-lower alkyl groups, in which aryl stands for naphthyl, for example l-naphthyl, and in particular for phenyl, which is optionally substituted by lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl and / or nitro is. Groups X8 defined in the above sense are accordingly in particular benzyl, furthermore lower alkoxymethyl, for example methoxymethyl.

A reactive esterified hydroxy group Z3 is one through a strong acid, especially a strong inorganic acid such as a hydrohalic acid, in particular chloric, bromic or hydroiodic acid, or sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid such as a aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, esterified hydroxyl group, and primarily represents Halogen, e.g. chlorine, bromine or iodine, or aliphatic or aromatic substituted Sulfonyloxy, e.g. ethylsulfonyloxy or 4-methylphenylsulfonyloxy.

The implementation of a compound of the formula XI with one of the Formula via is carried out in a manner known per se, whereby one, especially in Use of a starting material of the formula XI with a reactive esterified Hydroxy group, advantageously in the presence of a basic agent such as a inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent, such as an alkali metal lower alkanolate, and / or an excess of the basic reactant works. The connection of the formula XI can also be present as a salt, for example as an alkali salt, e.g. as a sodium salt.

The reaction of a compound of the formula XI with a compound of the formula XII is usually carried out in the presence of a basic catalyst, such as an alkali hydroxide such as potassium hydroxide or an organic base such as Triethylamine, or an acidic catalyst such as trifluoroacetic acid.

These reactions are carried out in a manner known per se and usually in the presence of a solvent or solvent mixture and, if necessary, with cooling or heating, e.g. in a temperature range from about +200 to about +2000, preferably from about +100 to about +1800 in an open or closed Vessel and / or in an inert gas atmosphere, e.g. in a nitrogen atmosphere, carried out.

Starting materials of the formula XI can be obtained in a customary manner by for example, in a compound of the formula R3 - Het - OH (XIb) in which R3 has the formula below VIII has given meaning, the group R3 in the manner described there in converts a heterocycle Ar.

Starting materials of the formula XIa, in which Z3 is a reactive esterified hydroxyl group, for example chlorine, and X1 represents hydroxyl, are obtained by reacting an amine with an optionally protected hydroxyl group of the formula accessible with epichlorohydrin in the usual way, while a starting material of the formula, in which Z3 and X1 together represent the epoxy group, from an amine of the formula XIc with epichlorohydrin in the presence of a basic agent, for example an alkali or alkaline earth metal hydroxide or carbonate, such as sodium hydroxide or - carbonate, or calcium hydroxide or carbonate can be obtained. A protected hydroxy group is, for example, one by means of reduction including hydrogenolysis, for example an a-aryl lower alkyl group, such as an optionally substituted l-phenyl lower alkyl group, for example a benzyl group, or a group which can be split off by means of hydrolysis and replaceable by hydrogen, e.g. a Acyl group such as lower alkanoyl group such as acetyl group, substituted hydroxyl group. Such protective groups are cleaved off by means of reduction, including hydrogenolysis, or hydrolysis, in the customary manner, simultaneously or in a separate reaction step, for example as described, and replaced by hydrogen.

Starting materials of the formula XII can be prepared in a manner known per se by reacting a compound of the formula in which the two hydroxyl groups can preferably be present in reactive, esterified form, for example as halogen, such as chlorine, or as sulfonyloxy such as methanesulfonyloxy group, and X8 is preferably different from hydrogen and, for example, as described, can represent an optionally substituted benzyl group, with a compound of the formula in which R1, R2 and alk have the meanings given, are obtained.

These reactions are usually in a solvent or Solvent mixture and, if necessary, with cooling or heating, e.g. in one Temperature range from about -20 ° to about + 1500C, preferably from about + 60 ° to about +100 "C, in an open or closed vessel and / or in an inert gas atmosphere such as a nitrogen atmosphere. Provides in a starting material of the formula XII obtained in this way, the group X8 is optionally for example, as described, represents a substituted benzyl group, this can be e.g. catalytically activated hydrogen, e.g. hydrogen in the presence of a noble metal catalyst, like a palladium-on-carbon catalyst, split off in the usual way and through Hydrogen can be replaced, with a starting material of the formula XII, wherein X8 is hydrogen is obtained.

The reactions described above can optionally be carried out simultaneously or one after the other, furthermore in any order. If required, they take place in the presence of diluents, condensing agents and / or catalytically active agents, at reduced or increased temperature, in the closed Vessel under pressure and / or in an inert gas atmosphere.

In choosing the appropriate method of manufacture above of compounds of the formula I, care must be taken that existing substituents, primarily the residues Ar, are not converted or split off, if such Conversions or spin-offs are not desired. So in particular can be functional modified carboxyl groups, such as esterified or amidated carboxyl groups, as well as Cyano groups, as substituents of the radicals Ar during solvolysis, in particular hydrolysis, also be involved in the reaction in the case of reductions and are converted. On the other hand, simultaneous conversions of substituents may be desirable; e.g., unsaturated substituents such as lower alkenyl can be used under the conditions a reduction process used according to the invention, e.g. to lower alkyl will.

In compounds obtained, one can, within the definition of the Compounds of the formula I compounds obtained in a customary manner according to the process convert into other end products, e.g. by changing suitable substituents, introduces or splits off.

Free carboxyl groups in the radicals Ar can be added in the usual way esterify, for example by reacting with an appropriate alcohol, advantageous in the presence of an acid such as a mineral acid, e.g. sulfuric acid or hydrochloric acid, or in the presence of a water-binding agent such as dicyclohexylcarbodiimide, or by reacting with an appropriate diazo compound, e.g.

Diazomethane. The esterification can also be carried out by reacting a salt, preferably an alkali metal salt of the acid with a reactive esterified one Alcohol, for example a corresponding halide such as chloride.

Free carboxyl groups can be amidated in the usual way, for example by reaction with ammonia, or with a primary or secondary amine, advantageous in the presence of a water-binding agent such as dicyclohexylcarbodiimide, or by Conversion of the carboxyl group into a halocarbonyl, e.g. chlorocarbonyl group, and subsequent reaction with ammonia or with a primary or secondary Amine.

In compounds that contain an esterified carboxyl group, can these in the usual way, e.g. by hydrolysis, preferably in the presence of strong Bases such as an alkali metal hydroxide e.g.

Sodium or potassium hydroxide, or strong acids, e.g. a strong one Mineral acid such as a hydrohalic acid e.g. hydrochloric acid or Sulfuric acid, can be converted into a free carboxyl group.

In compounds with an esterified carboxyl group as a substituent this can be done in the usual way, e.g. by ammonolysis or aminolysis with ammonia or a primary or secondary amine converted into the corresponding carbamoyl group will.

Compounds having a carbamoyl group and other than hydrogen Residues R1 and R2 can be removed in the usual way, e.g. by the action of dehydrating agents Agents such as phosphorus pentoxide, phosphorus oxychloride or trifluoroacetic anhydride, preferably at higher temperatures, dehydrated to the corresponding cyano compounds will.

In compounds with an esterified carboxyl group as a substituent and preferably radicals R1 and R2 other than hydrogen, the esterified Carboxyl group in a conventional manner, e.g.

by the action of an organic aluminum compound, such as one Di-lower alkyl aluminum amide compound, e.g. diethyl aluminum amide, into a cyano group being transformed.

Compounds with radicals R1 and R2 other than hydrogen, which contain a cyan substituent can be used in a conventional manner, e.g.

in the presence of concentrated aqueous mineral acids or alkali metal hydroxides, hydrolyzed to the corresponding carbamoyl or directly to the carboxyl compounds will.

Compounds with a cyano group as a substituent can be used in conventional Way, e.g. by adding alcohols in the presence of an anhydrous acid, such as hydrogen chloride, and subsequent hydrolysis of the imidoester formed alcoholysed to the corresponding compounds with esterified carboxyl groups will.

In compounds of the formula I in which Ar represents the group -NH- as a ring member contains, you can do this by introducing a substituent, e.g. an optionally substituted lower alkyl group such as methyl or benzyl, on usual Manner, e.g. using an appropriate reactive esterified alcohol, such as a corresponding halide, e.g. chloride or bromide, or a diazoalkane, e.g. diazomethane, convert into compounds of the formula I in which Ar is a contains tertiary amino group as a ring member.

Compounds in which Ar is at least one tertiary nitrogen atom Ring member contains, or a tertiary nitrogen atom present in the group Het can in the usual way by treating with a peroxy compound such as hydrogen peroxide, or an acid derivative thereof such as peracetic acid or m-chloroperbenzoic acid in N-oxides are converted.

Compounds that are present as N-oxides can be known per se Way into the non-N-oxidized compounds, e.g. by means of reducing acting agents, such as sulphurous acid, or phosphorus oxychloride, or above all by means of hydrogen in the presence of a hydrogenation catalyst, e.g. a noble metal catalyst, like platinum or palladium, also Raney nickel.

In compounds that have a lower alkylthio, e.g. methylthio group, can be desulphurized by treatment with suitable acting agents, e.g. Raney nickel, in a suitable solvent, e.g. dioxane, the lower alkylthio group is split off and replaced by hydrogen.

As with the creation process, it must also be carried out of the additional steps, care should be taken to avoid undesirable side reactions, which may result in the conversion of additional groupings, will not occur.

The reactions described above can optionally be carried out simultaneously or one after the other, furthermore in any order. If required, they take place in the presence of diluents, condensing agents and / or catalytically active agents, at reduced or increased temperature, in the closed Vessel under pressure and / or in an inert gas atmosphere.

Depending on the process conditions and starting materials, one obtains the new compounds in free form or in the likewise encompassed by the invention Form of their salts, the new compounds or salts thereof also as hemi-, Mono-, sesqui- or polyhydrates thereof can be present. Acid addition salts of the new Compounds can in a manner known per se, for example by treating with basic Agents such as alkali metal hydroxides, carbonates or hydrogen carbonates or ion exchangers, are converted into the free connections.

On the other hand, obtained free bases with organic or inorganic Acids, e.g. with the acids mentioned, form acid addition salts, with their Manufacture in particular those acids are used, which lead to the formation of pharmaceutically acceptable, non-toxic salts are suitable.

These or other salts, especially acid addition salts of the new ones Compounds such as oxalates or perchlorates can also be used to purify the obtained Free bases are used by converting the free bases into salts, separating them off and cleans, and in turn releases the bases from the salts.

The new compounds can depending on the choice of starting materials and modes of operation, as optical antipodes or racemates, or if they are at least contain two asymmetric carbon atoms, also exist as mixtures of racemates. The starting materials can also be used as certain optical antipodes.

Racemic mixtures obtained can be based on the physico-chemical Differences in diastereoisomers in a known manner, e.g.

by chromatography and / or fractional crystallization into which two stereoisomeric (diastereomeric) racemates are separated.

Obtained racemates can be according to methods known per se in disassemble the antipodes, e.g. by recrystallization from an optically active solvent, by treating with suitable microorganisms or by reacting with a, with the racemic compound salt-forming optically active substance, in particular Acids, and separating the salt mixture obtained in this way, e.g. due to of different solubilities, in the diastereomeric salts that make up the free Antipodes can be released by the action of suitable means. Particularly Common, optically active acids are e.g. the D- and L-forms of tartaric acid, Di-O, O '- (p-Toluoyl) -tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, Aspartic acid or quinic acid. It is advantageous to isolate the effective ren of the two Antipodes.

The invention also relates to those embodiments of the method, after which one of one at some stage of the process as an intermediate available connection goes out and carries out the missing procedural steps, or the process is terminated at any stage, or in which one starting material forms under the reaction conditions, or in which a reaction component optionally present in the form of their salts.

It is expedient to use for the implementation of the invention Reactions are those starting materials that belong to the groups specifically mentioned at the beginning of end products and especially those specifically described or highlighted Lead end materials.

The starting materials are known or, if they are new, can according to methods known per se, as described above, e.g. analogously to the examples, can be obtained. New starting materials are used to carry out those described above Procedures have been specially developed and are also an object of the Invention. The invention also relates to novel intermediates obtainable in accordance with the process.

The new compounds can be used, for example, in the form of pharmaceutical preparations Find use, which is a pharmacologically effective amount of the active ingredient, optionally contain together with pharmaceutically acceptable carriers, which are suitable for enteral, e.g.

oral or parenteral administration are suitable, and inorganic or can be organic, solid or liquid. How to use tablets or gelatin capsules, which the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, Mannitol, sorbitol, cellulose and / or glycerine and / or lubricants, e.g. silica, Talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or Polyethylene glycol. Tablets can also contain binders, e.g. Magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methyl cellulose, Sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, Disintegrants, e.g. starches, agar, alginic acid or a salt thereof such as sodium alginate, and / or effervescent mixes, or adsorbents, dyes, flavorings and Contains sweeteners. You can also use the new pharmacologically active compounds use in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, this e.g. in the case of lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. mannitol, prepared before use will can. The pharmaceutical preparations can be sterilized his and / or auxiliaries, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, Solubilizers, salts to regulate the osmotic pressure and / or buffers contain. The present pharmaceutical preparations, plus others if desired may contain pharmacologically active substances, are in a known manner, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1% to 100%, especially from about 1% to about 50%, lyophilisates up to 100% of the active ingredient.

The dosage can depend on various factors, such as the method of application, Species, age and / or individual condition depend. So they are in every day one or more total doses to be administered, preferably at most 4 individual doses when administered orally to warm-blooded animals weighing about 70 kg, between about 0.1 g and about 0.6 g.

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

Example 1: A mixture of 13.5 g of crude 1-amino-3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol and 6.4 g of 6- (2-bromoethoxy) -2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one melted in a bath preheated to 1300 and the melt for 40 minutes at 120-130 ° touched. The resin formed after cooling is boiled with 60 ml of ethyl acetate, until a suspension is formed. This is mixed with 30 ml of water and stirred. The 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol crystalline, which after the suction and recrystallization from methanol the Shows m.p. 191-193 °.

The starting materials can be produced in the following way: a) A solution of 88 g of 6-chloro-3-pyridinecarboxaldehyde in 1.6 liters of methanol becomes with 300 ml of water, 200 g of ammonium acetate and 310 ml of conc. aqueous ammonia added. 184 g of 1,1-dibromo-3,3,3-trifluoroacetone are added dropwise to this suspension with stirring over the course of 20 minutes.

The reaction mixture is stirred at room temperature for 15-20 hours and then the methanol was evaporated off under reduced pressure. By extraction with Ethyl acetate and evaporation of the organic phase gives a crude product which after recrystallization from ethyl acetate-cyclohexane, pure 2- (6-chloro-pyridin-3-yl) -4-trifluoromethylimidazole of m.p. 205-207 °.

b) A solution of 63.6 g of 2- (6-chloropyridin-3-yl) -4-trifluoromethylimidazole in 180 ml of dimethylformamide is mixed with 93 g of powdered, dry potassium carbonate stirred for 1 hour at room temperature.

73.3 g of methyl iodide are then added dropwise at 0-5 ° with stirring and the suspension is stirred for a further 20 hours at 0-5 °. 400 ml Added dropwise water and stirred for 2-3 hours. The precipitated crystals will be suctioned off, dried in vacuo at 50 ° and put 2- (6-chloropyridin-3-yl) -1-methyl-4-trifluoromethyl-imidazole from m.p. 96-100 °.

c) A solution of 27.2 g of 3-benzyl-5-hydroxymethyl-2-phenyl-1,3-oxazolidine in 300 ml of 1,2-dimethoxyethane is added in portions with stirring with 4.2 g of sodium hydride suspension (55% in mineral oil) and the suspension for 2 hours at 40-50 ° internal temperature stirred. Thereupon 24.0 g of 2- (6-chloro-pyridin-3-yl) -l-methyl-4-trifluoromethyl-imidazole are added added and the reaction mixture refluxed for 15 hours. be on this 250 ml 2-n. Hydrochloric acid was added and the reaction mixture was left to stand for 10-15 hours. After evaporation of the solvent, the residue is between 200 ml of water and 200 ml of ether distributed, the ether phase separated, the water phase with conc. Sodium hydroxide solution made alkaline and extracted with ethyl acetate. By evaporation the ethyl acetate solution gives crude l-benzylamino-3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol as an oil which, after column chromatography over silica gel and elution with a mixture Chloroform-methanol 95: 5 crystallized and after recrystallization from ether the Shows m.p. 90-91 °.

d) A solution of 11 g of the compound obtained in 150 ml of methanol is in the presence of 2 g of palladium-on-carbon catalyst (5%) until uptake the calculated amount of hydrogen hydrogenated under normal conditions. After filtration and evaporation of the solution gives crude l-amino-3- [5- (l-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol as oil, which is further processed as such.

Example 2: 0.55 g of 5- (2-aminoethoxy) salicylamide are dissolved in 20 ml of isopropanol dissolved, the solution with 1.0 g of 2- [6- (2,3-epoxy-propoxy) -pyridin-3-yl] -l-methyl-4-trifluoromethyl-imidazole added and the mixture heated under reflux for 5 hours. The one after the evaporation of The residue obtained isopropanol is made from as little methanol as possible recrystallized. Another recrystallization from methanol gives l- [2- (3-Carbamoy 1-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-4-triEluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol from m.p. 191-193 °.

The starting materials can be produced in the following ways: a) A suspension of 2.4 g of sodium hydride (55% in mineral oil) in 100 ml of 1,2-dimethoxyethane 10.0 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane are slowly added with stirring. The suspension is stirred for a further 2 hours at a bath temperature of 40-50 °, with one Solution emerges.

13.1 g of 2- (6-chloro-pyridin-3-yl) -l-methyl-4-trifluoromethyl-imidazole are then added and the mixture is stirred under reflux for 4-5 hours. The reaction mixture is evaporated and washed with a little cyclohexane by decanting. The residue is dissolved in ethyl acetate, the solution washed with a little cold water, the organic Phase dried and evaporated, after which crude 2,2-dimethyl-4- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxymethyl] -1,3-dioxolane of m.p. 108-115 °, which is further processed as such.

b) 5.6 g of 2,2-dimethyl-4- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxymethyl] -1,3-dioxolane are dissolved in 30 ml of hot methanol, with 30 ml of l-n. Hydrochloric acid added and the Solution left for 3-5 hours. The solution is evaporated to 20 ml, each with 10 ml of ethyl acetate washed twice and with conc. Sodium hydroxide solution made alkaline. By saturating the solution with sodium chloride and extracting with dichloromethane (3 times with 100 ml each) one obtains the one corresponding to the starting material used Glycerin ether, which is mixed with 35 ml of triethyl orthoacetate and 5 drops of trifluoroacetic acid added and stirred for 1.5 hours at room temperature. The one after evaporation The residue obtained is dissolved in 50 ml of dichloromethane and the solution after addition of 3 ml of trimethylchlorosilane for 2 hours Stirred at 20-30 °. the volatile components are evaporated, the evaporation residue is dissolved in 50 ml dichloromethane dissolved and the solution after adding 30 ml 2-. Sodium hydroxide solution and 0.5 g of tetrabutylammonium hydrogen sulfate Stirred vigorously overnight.

The organic phase is separated off, washed with 20 ml of water, dried over magnesium sulfate and evaporated. By chromatography of the residue on 100 g of silica gel and elution with a 95: 5 mixture of Ohioroform-methanol one 2- [6- (2,3-epoxy-propoxy) -pyridin-3-yl] -l-methyl-4-trifluoromethyl-imidazole as Oil that solidifies in crystalline form and melts at 72-75 ° (sinters from 70 °).

Example 3: A mixture of 3.7 g of 1-amino-3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyrazin-2-yloxy] -2-propanol and 1.75 g of bromoethoxy) -2, 3-dihydro-2, 2-dimethyl-4H-1,3-benzoxazin-4-one melted analogously to Example 1 and then held the melt at 1300 for 30 minutes. After cooling, the melt is dissolved in hot ethyl acetate. Out of the solution the product gradually crystallizes out. By dissolving the raw product in a lot Methanol and concentration of the solution until crystallization gives carbamoyl-4-hydroxyphenoxy) -ethylamino] -3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyrazin-2-yloxy] - 2-propanol from m.p. 2100 to 2110.

The starting material can be made in the following ways: a) One Mixture of 74 g of 5-chloro-pyrazine-carboxylic acid and 150 ml of thionyl chloride is 3 hours heated to reflux and then evaporated in vacuo. The residue is dissolved in toluene dissolved and evaporated again.

The crude acid chloride thus obtained is dissolved in 50 ml of dioxane and with ice cooling at 10 ° to 20 ° to a solution of 56 g of sodium borohydride in 900 ml of water dripped. The reaction mixture is after the dropping Stirred for 1 hour at 100, saturated with sodium chloride and with conc. Potash lye on pH 10 brought. By extraction with ethyl acetate, drying the organic phase 5-chloro-pyrazine-methanol is obtained over sodium sulfate and evaporation of the solvent as a yellow oil that gradually solidifies in crystalline form. It can be processed raw will.

b) A solution of 49 g of 5-chloro-pyrazine methanol in 430 ml of 1,2-dimethoxyethane is heated to the boil in a 2.5 liter flask equipped with a stirrer and reflux condenser. After removing the heating bath, 275 g of manganese dioxide are added in one portion. After the vigorous reaction has subsided, the reaction mixture is under for a further 1 hour Stirred at reflux. After filtering off and evaporating the filtrate, one obtains an oil, which after recrystallization from cyclohexane 5-chloro-pyrazinecarboxaldehyde from m.p. 500 to 53 "results.

c) 21.1 g of 5-chloro-pyrazinecarboxaldehyde are dissolved in 370 ml of methanol and with 72 ml of water, 72 ml of conc. Ammonia and 15 g ammonium acetate are added. In 40.0 g of 1,1-dibromo-3,3,3-trifluoroacetone are added dropwise to this reaction mixture without cooling to. The reaction mixture is stirred for 20 hours at room temperature and then analogously Example la) worked up. 2- (5-chloro-pyrazin-2-yl) -4-trifluoromethyl-imidazole is obtained in this way from m.p. 2500 to 252 ° (from ethyl acetate).

d) Methylation of the compound mentioned under c) analogously to the example 1 b) gives after chromatography on silica gel and elution with dichloromethane that 2- (5-chloro-pyrazin-2-yl) -l-methyl-4-trifluorimidazole of m.p. 1150 to 1160. Avg The elution can also be continued with the corresponding 5-trifluoromethyl isomer isolate from m.p. 980 to 1030.

e) A solution of 16.5 g of 3-benzyl-5-hydroxymethyl-2-phenyl-1,3-oxazolidine in 150 ml of 1,2-dimethoxyethane is first mixed with 2.55 g of sodium hydride -Dispersion (55% in mineral oil) and then with 14.6 g of 2- (5-chloro-pyrazin-2-yl) -1-methyl-4-tri Fluoromethyl-imidazole implemented and worked up analogously to Example 1c). You get so 1-Benzylamino-3- [5- (f-methyl-4-trifluoromethyl-imidazol-2-yl) -pyrazin-2-yloxy] -2-propanol with a melting point of 1100 to 1179 as a crude product which is debenzylated without further purification.

f) 17.7 g of the compound obtained are dissolved in 180 ml of methanol and the solution is debenzylated in the presence of 6 g of Pd-C (5%) analogously to Example 1d). Filtration and evaporation of the methanol give a complex mixture (14 g), from which by chromatography on silica gel (1.3 kg) and elution with a mixture of chloroform-methanol conc. Ammonia (40: 10: 1) fractions are isolated first, the 3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyrazin-2-ylamino] -1,2-propanediol contain.

The required starting material is isolated from the following fractions 1-Amino-3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyrazin-2-yloxy] -2-propanol from m.p. 1340 to 1350 (from isopropanol).

Example 4: Analogous to those described in the previous examples Proceedings can, starting from the corresponding starting materials, the following Compounds of the formula I, their N-oxides or salts, in particular pharmaceutical acceptable, non-toxic acid addition salts can be prepared.

a) 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (l-methylimidazol-2-yl) pyridin-2-yloxy] -2-propanol; b) 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1,4,5-trimethyl-imidazol-2-yl) -pyridin-2-yloxy] - 2-propanol; c) 1- [2- (3-Carbamoy1-4-hydroxyphenonxy) ethylamino] -3- [5- (1-n-butyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy ] -2-propanol; d) 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-3-methylthio-1H-1,2,4-triazol-5-yl) pyridine -2-yloxy] -2-propanol.

e) 1- [2- (3-Carbamoyl-4-1lydroxyphenoxy) ethylamino] -3- [5- (1-methyl-3-methylsulfonyl-1H-1,2,4-triazol-5-yl) pyridin-2-yloxy] -2-propanol; f) 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-3-methylsulfonyl-1H-1,2,4-triazol-5-yl) -pyrazin-2-yloxy] -2-propanol; g) 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) -1-methylethylamino] -3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy ] -2-propanol; h) 1- [2- (4-carbamoyl-3-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] - 2-propanol.

Example 5: tablets containing 20 mg of active substance prepared in the usual way in the following composition: Composition 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-4- (trifluoromethyl) -lH-imidazole-2 -yl) -pyridin-2-yloxy] -2-propanol 20 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg Magncsium stearate 1 mg 145 mg Preparation: 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) -ethylamino] -3- [5- (1-methyl-4- (trifluoromethyl) -lH-imidazol-2-yl ) pyridin-2-yloxy] -2-propanol will with part of the wheat starch, with lactose and colloidal Silica mixed and the mixture forced through a sieve. Another part the wheat starch is gelatinized with 5 times the amount of water on the water bath and knead the powder mixture with this paste until it is slightly plastic Mass has arisen.

The plastic mass is passed through a sieve with a mesh size of approx. 3 mm pressed, dried and the dry granules obtained again through a sieve driven. The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture pressed into tablets weighing 145 mg with a score line.

Example 6: Tablets containing 1 mg of active substance are in the following composition prepared in the usual way: Composition: 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) -ethylamine ° ~ 3 ~ f5- (l-methyl-4- (trifluoromethyl) -lH-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol 1 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg magnesium stearate 1 mg 126 mg Preparation: l- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (l-methyl-4- (trifluoromethyl) -lH-imidazol-2-yl) - pyridin-2-yloxy] -2-propanol is made with part of the wheat starch, with lactose and colloidal silica mixed and the mixture forced through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture kneaded with this paste until a weakly plastic mass is formed.

The plastic mass is passed through a sieve with a mesh size of approx. 3 mm pressed, dried and the dry granules obtained again through a sieve driven. The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture pressed into tablets weighing 145 mg with a score line.

Example 7: Capsules containing 11 mg of active substance are like is prepared in the usual way: Composition: 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) -ethylamino] -3- [5- (1-methyl-4- (trifluoromethyl) -lH-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol 2500 mg talc 200 mg colloidal silica 50 mg Manufacture: The active substance is intimately mixed with talc and colloidal silica, the mixture through a Sieve with 0.5 mm mesh size driven and this in portions of 11 mg filled in hard gelatine capsules of suitable size.

Example 8: 3.62 g of 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl- (4-trifluoromethyl) -iH-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol are added of 100.0 ml of O, 10-n. Hydrochloric acid to volume with 18,000 ml of distilled water dissolved by 18100 ml.

The sterilized solution is filled into ampoules of 5.0 ml, in which 1 mg of active ingredient are included.

Example 9 Instead of that in Examples 4 to 7 as the active substance The compound used can also include the following compounds of the formula I, or their pharmaceutically acceptable, non-toxic Acid addition salts are used as active ingredients in tablets, coated tablets, capsules, ampoule solutions, etc.: 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (l-methylimidazol-2-yl) pyridin-2-yloxy] -2-propanol, 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1,4,5-trimethyl-imidazol-2-yl) -pyridin-2-yloxy] -2- propanol; 1- [2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (ln-butyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] - 2-propanol, 1- [2- (3-carbamoyl-4-hydroxyphenoxy) -ethylaminol-3- [5- (1-methyl-3-methylthio-1H-1,2,4-triazol-5-yl) -pyridine- 2-yloxy 2-propanol, 1- [2-C3-Carbamoy1-4-hydroxyphenoxy) -ethylamino] -3- [5- (1-methyl-3-methylsulfonyl-1H-1,2,4-triazol-5-yl ) -pyridin-2-yloxy] -2-propanol, 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-3-methylsulfonyl-1H-1,2,4-triazol-5-yl) pyrazine -2-yloxy] 2-propanol, 1- [2- (3-carbamoyl-4-hydroxyphenoxy) -l-methylethylamino] -3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2 -yloxyj-2-propanol, 1- [2- (4-Carbamoyl-3-hydroxyphenoxy) ethylamino] -3- [5- (1 methyl-4-trifluoromethyl-imidazol-2-yl) -pyridin-2-yloxy] -2-propanol .

Claims (10)

Claims 1. Heterocyclyl ethers of the formula wherein Ar is a mono- or bicyclic, carbocyclic or heterocyclic aryl radical bonded to a group Het via a ring carbon atom, fletein denotes an azaphenylene radical bonded to the group Ar via a ring carbon atom and to the oxygen atom via a ring carbon atom, and alkalkylene with 2-5 carbon atoms, where the The nitrogen atom and the oxygen atom are separated from one another by at least two carbon atoms, and R1 and R2 independently of one another each represent hydrogen or lower alkyl, or together represent lower alkylene, oxane-lower alkylene, thian-lower alkylene, aza-lower alkylene or lower alkylazane-lower alkylene. 2 compounds of the formula I in which Ar is an optionally substituted one mono- or bicyclic, carbocyclic or via a ring carbon atom to the Azaphenylene radical Het is a bonded heterocyclic aryl radical with 5-6 ring members, which is at least partially saturated and in this case substituted by oxo can, where substituents are optionally substituted lower alkyl, e.g. lower alkyl, Hydroxy-lower alkyl, lower alkoxy-lower alkyl, halo-lower alkyl, lower alkanoylamino-lower alkyl, Lower alkoxycarbonylamino lower alkyl, or lower alkenyl, lower alkynyl, optionally etherified or esterified hydroxy or mercapto, e.g. hydroxy, lower alkoxy, Hydroxy-lower alkoxy, phenyl-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylthio-lower alkoxy, Halo-lower alkoxy, lower alkanoyl-lower alkoxy, lower alkenyloxy, lower alkinyloxy, Lower alkylthio, lower alkylsulfonyl, or halogen, acyl e.g. lower alkanoyl, optionally esterified carboxy such as carboxy or lower alkoxycarbonyl, carbamoyl, N-lower alkyl -carbamoyl or N, N-di-lower alkyl-carbamoyl, cyano, nitro and / or optionally substituted, such as acylated amino, e.g. amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, Lower alkoxycarbonylamino, lower alkylsulfonylamino, ureido, 3-lower alkylureido or 3-cycloalkylureido, and also substituents on heterocyclic aryl Ar optionally, as indicated, substituted phenyl or benzoyl or optionally, as indicated, represent substituted monocyclic heteroaryl, Het one above a ring carbon atom to the group Ar and via a ring carbon atom to the Represents an oxygen atom bonded azaphenylene radical, and alk represents an alkylene radical with 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom are separated from one another by 2 or 3 carbon atoms, R1 and R2 are those under formula I have given meaning, but preferably for hydrogen or lower alkyl stand, or together with the nitrogen atom of the amide group morpholino or alkylenamino with 5 to 6 ring members, such as pyrrolidino or piperidino. 3. Compounds of the formula I in which Ar is an optionally substituted one carbocyclic or bonded to the azaphenylene radical Het via a ring carbon atom, an oxygen, sulfur or nitrogen atom and optionally 1 to 3 additional ones Heteroaryl radical containing nitrogen atoms as ring members and having 5-6 ring members represents which is at least partially saturated and substituted in this case by oxo may be, and substituents optionally substituted lower alkyl, e.g. lower alkyl, Hydroxy-lower alkyl, halo-lower alkyl, or lower alkenyl, optionally etherified or esterified hydroxy or mercapto, e.g. hydroxy, lower alkoxy, phenyl-lower alkoxy, Lower alkoxy-lower alkoxy, halo-lower alkoxy, lower alkenyloxy, lower alkynyloxy, Lower alkylthio, lower alkylsulfonyl, or halogen, acyl e.g. lower alkanoyl, optionally esterified carboxy like, Carboxy or lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkyl-carbamoyl, cyano, nitro, optionally substituted, such as acylated amino, e.g. amine, N-lower alkylamino, N, N-di-lower alkylamino, Lower alkanoylamino, lower alkoxycarbonylamino, lower alkylsulfonylamino, optionally substituted by lower alkyl, lower alkoxy, halogen, halo-lower alkyl, nitro or cyano Phenyl or benzoyl, and also substituents of heterocyclic aryl Ar, if appropriate, as indicated, substituted monocyclic, oxygen or nitrogen atom and optionally mean heteroaryl containing 1-3 further nitrogen atoms, Het one through a ring carbon atom to the group Ar and through a ring carbon atom represents azaphenylene radical bonded to the oxygen atom, and alk represents an alkylene radical with 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom are separated from one another by 2 to 3 carbon atoms, R1 and R2 for hydrogen or lower alkyl or together with the nitrogen atom of the amide group pyrrolidino, Form piperidino or morpholino. 4. 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-y 1) -pyridin-2-yloxy] -2-propanol. 5. 1- [2- (3-Carbamoyl-4-hydroxyphenoxy) ethylamino] -3- [5- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -pyrazin-2-yloxy1-2 -propanol. 6 N-oxides of compounds of claims 1-5. 7 Pharmaceutically acceptable, non-toxic acid addition salts of Compounds of claims 1-6. 8. Pharmaceutical preparations containing a compound of the formula I. 9. Compounds of formula 1 as agents for combating high blood pressure, of angina pectoris, hypertrophic cardiomyopathies and cardiac arrhythmias. 10. Process for the preparation of heterocyclyl ethers of the formula where Ar is a mono- or bicyclic, carbocyclic or heterocyclic aryl radical bonded to a group Het via a ring carbon atom, Het denotes an azaphenylene radical bonded to the group Ar via a ring carbon atom and to the oxygen atom via a ring carbon atom, and alkalkylene with 2-5 carbon atoms, wherein the nitrogen atom and the oxygen atom are separated from each other by at least two carbon atoms, and R1 and R independently represent 1 2 each hydrogen or lower alkyl, or together lower alkylene, oxane lower alkylene, thian lower alkylene, aza lower alkylene or N-lower alkylazane lower alkylene, characterized in that a) in a compound of the formula wherein Arl represents the radical Ar or a radical containing at least one functional group in protected form, X2, X3 and X4 each represent hydrogen or a substituent which can be replaced by hydrogen, X5 represents R1 or a substituent which can be replaced by hydrogen, or X2 and X3 and / or X4 and X5 together represent a divalent radical that can be replaced by two hydrogen atoms, and / or any functional groups present in the radical Arl are optionally present in protected form, with the proviso that at least one of the radicals X2, X3, X4 or X5 is different from hydrogen, or at least Ar1 is a radical Ar which contains at least one functional grouping in protected form, or at least X2 and X together or X4 and X5 together represent a divalent radical which can be replaced by two hydrogen atoms, or in a salt thereof, the groups other than hydrogen X2, X3, X4 or X5 or X2 and X3 together and / or X4 and X5 together are replaced by hydrogen atoms, and / or in a radical Ar1 splitting off the protective groups bonded to one or more functional groups and replacing them with hydrogen, or b) a compound of the formula with a compound of the formula or a salt thereof in which one of the groups Z1 and Z2 is a reactive esterified hydroxy group and the other is the primary amino group and X1 is hydroxy, or in which X1 and Z1 together are the epoxy group and Z2 is the primary amino group, and Ar , Het, alk, R1 and R2 have the above meaning, or c) in a compound of the formula wherein X is a reducible group of the formula 6 - CH = N - alk - (Va) or - CH2 - N = alk2 - (Vb), where alk2 is an alkylidene radical corresponding to the alk radical, the group X6 to the group of the formula - CH2 - NH - alk - (Vc) reduced or d) a compound of the formula or a reactive derivative of such a carboxylic acid, in which functional groups not participating in the reaction are optionally protected by protective groups which can be split off by means of aminolysis or ammonolysis and can be replaced by hydrogen, is reacted with a compound of the formula HNR R (VIa) 12, and at the same time splitting off any protective groups that may be present and replaced by hydrogen, or e) in a compound of the formula wherein functional groups not participating in the reaction are optionally protected by protective groups which can be split off by means of hydrolysis and can be replaced by hydrogen, which are split off under the conditions of the process and replaced by hydrogen, converts the -CN group into the -CONH2 group by hydrolysis, and at the same time splitting off any protective groups present and replacing them with hydrogen, or f) in a compound of the formula wherein hydroxyl groups and / or the amino group are protected by protective groups, and R3 represents a substituent capable of forming a mono- or bicyclic heteroaryl radical Ar, which forms mono- or bicyclic heteroaryl group Ar, splits off any protective groups present at the same time and replaces them with hydrogen, or protective groups present removed simultaneously or subsequently and replaced by hydrogen, or g) a compound of the formula Ar - Het - OH (xI) with a compound of the formula in which Z3 stands for a reactive, esterified hydroxyl group and X1 is hydroxyl, or in which Z3 and X1 together denote the epoxy group, or with a corresponding ring-closed compound of the formula in which R1, R2 and alk have the meaning given, and X8 is hydrogen or a group which can be split off under the conditions of the process and is capable of forming the ether bond with the hydroxyl group of a compound of the formula XI, and, if desired, one obtainable in this way The compound is converted into another compound of the formula I and / or, if desired, a free compound obtained or an N-oxide thereof is converted into a salt or a salt obtained is converted into a free compound or an N-oxide thereof, and / or, if it is desirable to separate a mixture of isomers obtained into the isomers or a racemate obtained into the antipodes.