DE3426152A1 - Secondary hydroxy compounds - Google Patents

Abstract

Secondary hydroxy compounds of the formula <IMAGE> in which Ar denotes a mono- or bicyclic, carbocyclic aryl radical or a heterocyclic aryl radical bonded via a ring carbon atom to a phenylene radical Ph, Ph denotes a phenylene radical 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 alkyl aza-lower alkylene, their N-oxides or salts of compounds of this type, a 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 arrhythmial.

Description

Secondary hydroxy compounds

The invention relates to new secondary hydroxy compounds, Process for their production, 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 a heterocyclic aryl radical bonded to a phenylene radical Ph via a ring carbon atom, Ph is a phenylene radical and alkalkylene with 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, 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 nitrogenous Heterocycles and salts of compounds of the formula I.

The residue Ar is a monocyclic aromatic hydrocarbon residue, d.ll. Phenyl, but can also be a bicyclic aromatic hydrocarbon radical, i.e. 1- or 2-naphthyl or partially saturated Naphthyl, like Mean 1,2,3,4-tetrahydro-5-naphthyl. As a mono- or bicyclic heteroaryl Ar is connected to the phenylene radical Ph via a ring carbon atom, an oxygen, Sulfur or nitrogen atom and optionally 1-3 additional nitrogen atoms as ring members containing radical, preferably with 5 or 6 ring members, the can be at least partially saturated and in this case substituted by oxo, where in a bicyclic heterocyclic radical the second ring is a fused-on ring Can be 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, furthermore indolyl, e.g. indol-4-yl, quinolinyl, 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 of a carbocyclic or heterocyclic aryl radical Ar, in the latter case primarily a ring carbon atom, but also a secondary ring nitrogen atom may be substituted, and such substituents can be present one or more times, preferably at most four times, are e.g. 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., through aryl, through optionally etherified or esterified hydroxy or mercapto or substituted by acyl Lower alkoxy, 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 alkinyloxy, lower alkylthio or halogen, acyl, e.g. Lower alkanoyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxyl, e.g. optionally 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-Diniederalkylamino, also lower alkylsulfonyl substituents of a heterocyclic Aryl radicals are Ar, also optionally by lower alkyl, lower alkoxy, halo-lower alkyl, Carbamoyl or cyano substituted aryl, especially phenyl, or aroyl, especially Benzoyl, or optionally substituted heterocyclic, e.g., as indicated Aryl radicals, e.g. those mentioned, attached to a ring carbon atom or a ring nitrogen atom of the heterocyclic aryl radical to be substituted are bound.

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, bonded to two ring carbon atoms are lower alkylene or lower alkenylene.

The 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, for example, 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 Represents lower alkinyloxy in particular 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, for example, methoxycarbonylamino or ethoxycarbonylamino.

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 primarily Line 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-acetylamino-ethyl or 2-propionylamino-methyl.

Lower alkoxycarbonylamino lower alkyl is, in particular, lower alkoxycarbonylaminomethyl, 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. methoxymethoxy, 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-methylthioethoxy or 2-ethylthio-ethoxy.

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

Lower alkanoyl-lower alkoxy is, for example, 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-l-enylene or 1,3-butadienylene. A such a radical forms together with a phenyl radical Ar e.g. an optionally substituted, Indanyl, 1,2,3,4-tetrahydronaphthyl, substituted via an aromatic ring carbon atom 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 also optionally, e.g., as indicated, substituted monocyclic heteroaryl radicals e.g. specified.

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 trifluoromethylpyrrol-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, pyrrylfuryl 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-thienyl) -imidazolyl, Thiazolylimidazolyl e.g. halogen- such as chlorothiazol-2-yl-imidazolyl or 1,2,5-thiadiazol-3-yl-imidazolyl.

A phenylene radical Ph is 1,2-, 1,3- or especially a 1,4-phenylene radical, which can be substituted 1 to 3 times. Substituents are mainly lower alkyl, like methyl, lower alkoxy like methoxy, Halogen e.g. chlorine, halo-lower alkyl e.g. trifluormenyl, possibly functionally modified carboxy, such as carboxy ' Lower alkoxycarbonyl, e.g., methoxycarbonyl, carbamoyl. N-lower alkylcarbamoyl such as N-methylcarbamoyl, N, N-di-lower alkylcarbamoyl such as N, N-dimethylcarbamoyl, lower alkanoyl e.g. acetyl, or cyano, also nitro.

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 from compounds in which Ar is at least mono- or bicyclic heteroaryl containing a tertiary nitrogen atom, e.g. Pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, quinolinyl, pyrazolyl, Represents triazolyl, tetrazolyl, thiazolyl or thiadiazolyl.

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 hydrogen halide 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, Propion, amber, glycol, milk, apple, wine, lemon, maleic, ilydroxymalein, Pyruvic, fumaric, benzoin, 4-aminobenzoic, anthranil, 4-elydroxybenzoic, salicylic, Embon, methanesulfone, ethanesulfone, 2-hydroxyethanesulfone, ethylene sulfone, toluenesulfone, Naphthalenesulfonic or sulfanilic acid, or with other acidic organic substances, like 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 Trials in standard test procedures. So the new compounds show an inhibition tachycardia induced by isoproterenol in isolated guinea pig hearts according to Langendorff in a concentration range from about 0.01 mmol / liter to about louMol / liter, when the dog is awake and trained, as well as when the cat is anesthetized 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 arterial Blood pressure on the anesthetized cat, while the bradycardia effect on the anesthetized Cat at doses from 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 compounds bonded to the phenylene radical Ph 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, Cyan 'nitro and / or optionally substituted, such as acylated amino, e.g. Amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino, Are lower alkylsulfonylamino, ureido, 3-lower alkylureido or 3-cycloalkylureido, and also substituents of heterocyclic aryl Ar optionally as indicated, substituted phenyl or benzoyl or optionally, as indicated, substituted represent monocyclic heteroaryl, Ph optionally, as indicated, substituted 1,3- or 1,4-phenylene and alk is an alkylene radical having 2 to 4 carbon atoms represents, wherein the nitrogen atom and the oxygen atom by 2 or 3 carbon atoms are separated from one another and 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 in which Ar is an optionally substituted carbocyclic or ring carbon atom bonded to the phenylene radical Ph, 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 alkylamines, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylsulfonylamino, optionally substituted by lower alkyl, lower alkoxy, halogen, halo-lower alkyl, nitro or cyano Phenyl or benzoyl, or optionally, as indicated, substituted monocyclic, an oxygen or nitrogen atom and optionally 1-3 further nitrogen atoms containing heteroaryl, Ph optionally by lower alkyl, lower alkoxy, Is halo-lower alkyl, halogen or cyano-substituted 1,4-phenylene, and alk denotes an alkylene radical having 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom, are separated from each other by 2 to 3 carbon atoms and R1 and R2 represent hydrogen or lower alkyl or together with the nitrogen atom of the amide group form pyrrolidino, piperidino or morpholino, or their N-oxides and salts, especially acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts thereof.

The invention relates in particular to compounds of the formula I in which Ar is an optionally substituted phenyl radical, or one via a ring carbon atom bonded to the phenylene radical Ph, an oxygen, sulfur or nitrogen atom and optionally containing 1 to 3 additional nitrogen atoms as ring members means monocyclic heteroaryl radical with 5 to 6 ring members, the at least may be partially saturated and in this case substituted by oxo, with substituents optionally substituted lower alkyl, e.g. lower alkyl, hydroxy lower alkyl, Halo-lower alkyl or lower alkenyl, optionally etherified or esterified Hydroxy, e.g. hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, halo-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, 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, or optionally, as indicated, substituted monocyclic, an oxygen or nitrogen atom and optionally 1 to 3 further nitrogen atoms containing heteroaryl, Ph optionally 1,4-phenylene substituted by lower alkyl, lower alkoxy, halogen or cyano represents, alk is an alkylene radical having 2 to 4 carbon atoms, where the Nitrogen atom and the oxygen atom by 2 to 3 carbon atoms from each other are separated, and R1 and R2 are hydrogen or lower alkyl or together form pyrrolidino or morpholino with the nitrogen atom of the amide group, or their N-oxides and salts, especially acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts thereof.

The invention relates in particular to compounds of the formula I in which Ar is an optionally substituted phenyl radical, or one via a ring carbon atom bonded to the phenylene radical Ph, an oxygen, sulfur or nitrogen atom and optionally containing 1 to 2 additional nitrogen atoms as ring members means monocyclic heteroaryl radical with 5 to 6 ring members, or at least one partially saturated oxo-heteroaryl radical with 5-6 ring members and 1-2 nitrogen atoms represents as ring members, with substituents optionally substituted lower alkyl, e.g. lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, optionally etherified or esterified hydroxy, e.g. hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, Lower alkylthio or halogen, acyl e.g.

Lower alkanoyl, optionally esterified carboxy such as carboxy or Lower alkoxycarbonyl, carbamoyl, cyano, optionally substituted, such as acylated Amino, e.g. amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, Lower alkoxycarbonylamino, lower alkylsulfonylamino, or optionally, as indicated, substituted monocyclic, an oxygen or nitrogen atom and optionally denote 1 to 2 further nitrogen atoms containing heteroaryl, Ph optionally substituted by lower alkyl, lower alkoxy, halogen or cyano Is 1,4-phenylene, alk is an alkylene radical having 2 to 3 carbon atoms, wherein the nitrogen atom and the oxygen atom are separated by 2 to 3 carbon atoms from each other are separated, and R1 and R2 are hydrogen or lower alkyl or together form morpholino with the nitrogen atom of the amide group, or their N-oxides and Salts, especially acid addition salts, especially pharmaceutically acceptable, non-toxic ones Acid addition salts thereof.

The invention relates in particular to compounds of the formula I in which Ar is an optionally substituted, via a ring carbon atom to the phenylene radical Ph bonded, a sulfur or a nitrogen atom and optionally 1 to 2 additional nitrogen atoms as ring members containing heteroaryl radical with 5 to 6 ring members, e.g. imidazolyl, pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, Indolyl or pyridyl, or a dihydro-oxo-heteroaryl radical with 1-2 nitrogen atoms as ring members, e.g. dihydro-6-oxo-2-pyridinyl or dihydro-4-oxo-2-pyrimidinyl represents, where substituents are lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, Hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, lower alkylthio, halogen, lower alkanoyl, Carboxy, lower alkoxycarbonyl, cyano, carbamoyl, amino, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylsulfonylamino, Ph optionally by lower alkyl or halogen is substituted 1,4-phenylene, alk is an alkylene radical having 2 to 3 carbon atoms means, wherein the nitrogen atom and the oxygen atom through 2 to 3 carbon atoms are separated from one another, and R1 and R2 each represent hydrogen, or their N-oxides and salts, especially acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts thereof.

The invention relates in particular to compounds of the formula 1 in which Ar optionally substituted, via a ring carbon atom to the phenylene radical Ph bonded imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl or dihydro-oxo-2-pyridinyl, for example 1,2-dihydro-2-oxopyridin-6-yl with substituents lower alkyl, e.g. Methyl, hydroxy-lower alkyl, e.g., 2-hydroxyethyl, halo-lower alkyl, e.g.

Trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkoxy-lower alkoxy, e.g. 2-methoxy-ethoxy, halogen, e.g. chlorine, lower alkanoyl e.g. acetyl, lower alkoxycarbonyl e.g. ethoxycarbonyl, carbamoyl, lower alkanoylamino e.g. acetylamino, lower alkoxycarbonylamino e.g. methoxycarbonylamino, lower alkylsulfonylamino, e.g.

Methylsulfonylamino, Ph is 1,4-phenylene, alk is an alkylene radical with 2 to 3 carbon atoms, wherein the nitrogen atom and the oxygen atom are separated from one another by 2 carbon atoms, and R1 and R2 each represent hydrogen stand, or their N-oxides and salts, especially acid addition salts, above all 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 adding a compound of the formula with a compound of the formula wherein one of the groups Z1 and Z2 represents a reactive esterified hydroxy group and the other represents the primary amino group, and X1 represents hydroxy, or wherein X1 and Z1 together represent the epoxy group and Z2 represents the primary amino group, Ar, Ph, and alk above Have meaning, and, if desired, converting a compound obtained into another compound of the formula I, and / or, if desired, a free compound obtained into an N-oxide or a salt or a solid N-oxide 6the salt into a converts free compound or its N-oxide, and / or, if desired, separates a racemate mixture obtained into the racemates or a racemate obtained into the optical antipodes.

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 acid, especially a strong organic sulfonic acid such as a aliphatic or aromatic sulfonic acid, e.g.

Methanesulfonic acid, 4-methylbenzenesulfonic acid or 4-bromobenzenesulfonic 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, wherein one, especially when using a starting material with a reactive one esterified hydroxyl group, advantageously in the presence of a basic agent, such as an inorganic base such as an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent such as one Alkali metal lower alkanolate, and / or an excess of the basic reactant and usually in the presence, but optionally also in the absence of a solvent or Solvent mixture and, if necessary, with cooling or heating, e.g. in a temperature range of about -200C to about +150 "C, in an open or closed Vessel and / or in an inert gas atmosphere, e.g. in a nitrogen atmosphere, is working.

Starting materials of the formulas II or III are known or can be found in can be produced in a manner known per se. So you can go to the production of a raw material of the formula II a compound of the formula Ar-Ph-H, wherein optionally present Amino or hydroxyl groups through a protecting group, e.g. one of those described below, can be protected with a haloacetyl halide, e.g. chloroacetyl chloride, in the presence of a suitable Lewis acid, e.g. aluminum chloride, according to the Friedel-Crafts method haloacetylate on a carbon atom of the radical -Ph-H and in the form obtainable in this way Ar-Ph-haloacetyl compound, e.g. by treatment with a suitable hydride reducing agent, reduce the carbonyl to the carbinol group; if desired, one can use a halogen Zl e.g. by treating with ammonia, or a suitable derivative thereof, such as hexamethylenetetramine, and decomposition of the compound obtained with dilute mineral acid, or by Reaction with an alkali metal salt of phthalimide and cleavage of the obtained Convert N-phthalimide compound, e.g. with hydrazine, into the primary amino group Z1. Starting materials of the formula II, in which X1 and Z1 together denote epoxy, can e.g. by cyclizing a compound of the formula II in which X1 is hydroxy or acyloxy, for example lower alkanoyloxy, e.g. acetyloxy and Z1 a reactive esterified hydroxyl group, represent chlorine or methanesulfonyloxy by means of alkaline reagents, e.g. in the event that X1 is hydroxy is, by means of a mixture of dilute sodium hydroxide solution and tetrabutylammonium chloride in a suitable solvent, e.g. methylene chloride, or in the event that X1 is e.g. acetyloxy, by means of a Alkali alcoholate, such as sodium methylate in methanol, can be obtained.

Starting materials of the formula II, in which X1 and Z1 together represent the eposy group and any amino or hydroxyl groups present are protected by a protective group, for example as indicated below, can be obtained by reacting in a compound of the formula Ar-Ph-CH = CH2 (IIa), the -CH = CH2 group by introducing the epoxy group into the group converts, for example by reacting with a peroxy compound, such as hydrogen peroxide, or an organic peracid, such as

an optionally substituted, such as halogenated, aliphatic or aromatic peracid, e.g. peracetic acid or trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid, in an anhydrous solvent such as chloroform. This implementation is carried out in the usual way.

Starting materials of the formula III can, for example, by reacting a hydroxysalicylamide with a dihaloalkane corresponding to the meaning of alk, for example a chlorobromo or dibromoalkane in the presence of an alkaline condensing agent such as a Alkali carbonate, and, if desired, replacement of the remaining halogen Z2 in the manner indicated above for Z1 by the primary amino group. These Reactions are carried out in the customary manner, with the amino or hydroxyl groups standing protecting groups simultaneously or subsequently, e.g. as described below, be split off.

The compounds of the formula I can also be prepared by converting into a compound of the formula wherein Ar has the meaning of Ar or is a radical Ar which is substituted by 1 to 2 groups which can be converted into hydroxy and / or amino, X2, X3 and X4 are each hydrogen or a substituent which can be replaced by hydrogen, and X5 is R1 , or X2 and X3 and / or X4 and X5 together denote a divalent radical which can be replaced by two hydrogen atoms, with the proviso that at least one of the radicals X2, X3 and X4 is different from hydrogen, or at least Arl denotes a radical Ar which is through in each case 1 to 2 groups convertible into hydroxy and / or amino is substituted, or at least X2 and X3 together or X4 and X5 together represent a divalent radical which can be replaced by two hydrogen atoms, Ph and R2 have the above meanings, or in a salt thereof, the X2>X3> or X4 other than hydrogen, or X2 and X3 together or X4 and X5 together replaced by hydrogen, and / or substituted Hy present in a radical Arl Converted hydroxy and / or amino into free hydroxy and / or amino, and if desired, carries out the additional process steps mentioned after the first process.

The cleavage of groups2, X3 or X4 or each of X2 and X3 or X4 and X5 together and any protective groups present in a radical Arl of hydroxy and / or amino substituents is by means of solvolysis, such as hydrolysis, Alcoholysis, aminolysis or acidolysis, or by means of reduction including hydrogenolysis performed.

Particularly suitable cleavable groups X3 and X or hydroxy-4 and / or Amino protective groups in a radical Ar can primarily be split off by hydrogenolysis a-Aryl-lower alkyl groups, such as an optionally substituted l-polyphenyl or 1-phenyl-lower alkyl group, wherein substituents, especially des Phenyl moiety, e.g., lower alkyl, such as methyl, or lower alkoxy, such as thethoxy can, and primarily benzyl. Groups X3 and in particular X2 and X4 as well as Hydroxy and / or amino protective groups in a radical Arl can also be solvolytic, such as hydrolytic or acidolytic, also reductive, including hydrogenolytic cleavable radicals, in particular corresponding acyl radicals such as the acyl radical of an organic Carboxylic acid, for example lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, also the Acyl radical of a half ester of carbonic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, Ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-Trichloräthoxyearbonyl or 2-Jodäthoxycarbonyl, optionally substituted l-phenyl-lower alkoxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further optionally substituted l-Polyphenyl lower alkyl groups, in which substituents, primarily of the phenyl part, e.g. have the meaning given above, and are primarily trityl.

A splittable one formed by X2 and X3 and / or X4 and X5 together The remainder is primarily a hydrogenolytically cleavable divalent group, such as optionally substituted l-phenyl lower alkylidene, in which substituents, in particular of the phenyl moiety, e.g., lower alkyl or lower alkoxy, and in particular Benzylidene, as well as solvolytically, in particular hydrolytically cleavable groups, such as Lower alkylidene, e.g. methylene or isopropylidene, or l-phenyl-lower alkylidene, its phenyl moiety, if appropriate, by lower alkyl, such as methyl, or lower alkoxy, such as methoxy, especially benzylidene, or cycloalkylidene, e.g.

Cyclopentylidene or cyclohexylidene.

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 and / or X4, in particular Optionally substituted 1-zenyl-lower alcohol groups, and also suitable ones Acyl groups, such as optionally substituted l-phenyl-lower alkoxycarbonyl, and optionally substituted ones formed together by the groups X2 and X3 and also X4 and X5 l-phenyl lower alkylidene groups, as well as hydroxy and / or hydroxyl groups present in a radical Arl Amino protecting groups of this type can be treated with catalytically activated Hydrogen, e.g. with hydrogen in the presence of a nickel catalyst such as Raney nickel, or a suitable noble metal catalyst can be split off.

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

Trityl residues, as well as by the residues X2 and X3 and / or X4 and X5 together formed lower alkylidene, l-phenyl-lower alkylidene or cycloalkylidene groups, as well as Hydroxy and / or amino protective groups of this type present in a radical Arl can depending on the nature of such residues by treating with water under acidic or basic Conditions, e.g. in the presence of a mineral acid such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate or one Amines such as isopropylamine are split off.

By aminolysis, for example, as protecting groups of hydroxyl groups acyl radicals present and in particular lower alkylidene formed by X 4 and X5 together, l-Phenyl lower alkylidene or cycloalkylidene groups, such as the l-methylethylidene group are split off, for example by reacting with ammonia or, especially in Case of the aforementioned divalent protective groups, with primary amines, such as e.g. Isopropylamine or benzylamine, in a suitable cation medium such as isopropanol or dioxane. as primary amine can also be a starting material Formula II for the first-mentioned production process for the compounds of the formula I act. Therefore, when implementing compounds, one obtains the below given formula IVa, in which X4 and X5 together are one of the aforementioned divalent Protective groups, such as isopropylidene mean, with twice the molar amount of corresponding starting materials of the formula II with elimination of the from X4 and X5 Protective group formed directly end products of the formula I, while said protective group remains in place and the corresponding starting material of the formula IV arises if as an agent which binds hydrogen halide instead of an excess of the compound of formula II or IVa e.g. certain inorganic bases, such as alkali metal carbonates, used.

Residues Xz, X3 and / or X4 and / or hydroxyl and / or which can be split off acidolytically Amino protective groups in a residue Ar are, in particular, certain acyl residues of half-esters of carbonic acid, such as tert.-lower alkoxycarbonyl or optionally substituted Diphenylmethoxycarbonyl radicals, also the tert-butyl radical; such leftovers can by treating with suitable strong organic carboxylic acids, such as optionally lower alkanecarboxylic acids substituted by halogen, in particular fluorine, in the first place Line with trifluoroacetic acid (if necessary, in the presence of an activating agent, such as anisole), as well as be split off with formic acid.

Among radicals X2, X3 and / or X4 and / or hydroxy- and / or amino protective groups in a radical Arl are also understood to mean those groups when treated with a chemical reducing agent (especially with a reducing metal or a reducing metal compound) are split off. Such radicals are in particular 2-halo-lower alkoxycarbonyl or arylmethoxycarbonyl, e.g. when treating with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, like 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 optionally present in a radical Arl Hydroxy and / or amino groups are, correspond to the aforementioned and means the methods described, which can be split off and replaced by hydrogen, such groups in the course of the procedure described concurrently with others Groups or subsequently split off in a separate procedural measure.

The above reactions are usually carried out in the presence of a solvent, or solvent mixture carried out, with suitable reactants simultaneously 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 of a Inert gas, e.g. nitrogen.

The starting materials of the formula IV can be obtained in a manner known per se by reacting, for example, a compound of the formula Arl-Ph-H with a haloacetyl halide, for example chloroacetyl chloride, in the presence of a suitable Lewis acid, for example aluminum chloride, by the Friedel-Crafts process , the carbonyl group in the thus obtained or otherwise conventionally obtained Ar-Ph-haloacetyl compound, for example by means of sodium borohydride, reduced to the carbinol group and the compound obtained with an amine of the formula in which X3 has the meaning given, and X4 or X4 and X5 together are different from hydrogen.

Starting materials of the formula IV are also by implementing a Compound of the formula II explained above with a compound of the formula IVa accessible. These conversions are carried out in a manner known per se.

You can also, for example, by reacting a compound of the formula with a carbonyl compound of the formula where R denotes an alkyl group corresponding to the alkylene group alk and containing a carbonyl group separated from the oxygen atom by at least one carbon atom, and X4, or X4 and X5 together denote one of the stated protecting groups, Schiffs base formed with a borohydride, such as sodium borohydride, for the compound of the formula IV to reduce. 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.

Amines of the formula IVb in which X2 represents hydrogen or a group which can be split off by means of reduction, including hydrogenolysis and can be replaced by hydrogen, can be obtained, for example, by reacting a compound of the formula wherein X1 and Z1 have the meaning given under the formula (II), are prepared with ammonia or an amine containing an amine, for example benzylamine, which can be split off by means of reduction including hydrogenolysis, for example as indicated, and can be replaced by hydrogen.

Carbonyl compounds of the formula (IVc) can be prepared by reacting a compound of the formula with a compound of the formula R-Hal (VIf), in which R has the above meaning, and a compound (IVf) is, for example, a halo ketone, for example chloroacetone, can be obtained in a customary manner.

Compounds of the formula can also be obtained from the abovementioned compounds of the formula (IVe) by reaction with non-geminal, in particular vicinal, dihalo-lower alkanes, especially dibromo- or bromo-chloro-lower alkanes in which Hal stands for bromine or chlorine, and R2 alk, X4 and X5 have the meaning given above, produce and react these with compounds of the formula IVb to form starting materials of the formula IV, whereby, as already mentioned, end products of the formula I are optionally formed directly .

The nine compounds of the formula I can also be obtained by converting into a compound of the formula where X6 is a reducible group of the formulas -CH = N-alk- (Va), or -CH2-N = alkl- (Vb) or -c (= x7) -N (X8) -alk- (Vc) or

-CH2-N (X8) -C (= X7) -alk2- (Vd) or a group 7 2 -CH2-N (X8) -alk- (Ve), where alkl stands for the alkyl-ylidene radical corresponding to a radical alk and alk2 one shortened by a methylene group bonded to the nitrogen atom Radical corresponds to alk, X7 the oxo or thioxo radical and X8 hydrogen or one of the following the conditions for the reduction of X6 and / or Y by hydrogen Represents a radical and Y represents a radical of the formula -CO- (Vf) or -CH (OX8) - (Vg), in which X8 has the meaning given above, Ar2 corresponds to a radical Ar, but optionally instead of one or two hydroxyl and / or amino in each case one or two groups -OX8, and / or -N (X8) -, in which X8 is the above Has meaning, carries, Ph, R1 and R2 have the above meanings, where X6 is always a reducible group Va to Vd and / or Y is a carbonyl group Vf, this (group (s) and in the same operation those groups other than hydrogen X8 is mixed with hydrogen, and, if desired, the additional ones afterwards to carry out the process steps mentioned in the first process.

A hydrogenolytically cleavable group X8 is primarily one a-aryl-lower alkyl group, such as an optionally substituted l-penzene-lower alkyl group, wherein substituents can be, for example, lower alkoxy such as methoxy, and very particularly Benzyl.

Protective groups which are optionally substituted on the radical Ar2 Hydroxy and / or amino groups correspond to those mentioned above for X8 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.

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 alk corresponds to the meaning of alkl and the oxygen and 3 nitrogen atoms of the ring are bonded to the same carbon atom.

An alkyl-ylidene group alk is e.g. l-ethyl-2-ylidene or 2-methyl-l-ethyl-2-ylidene, while an alkylidene or alkylene group alk2 e.g. methylene, ethylidene or l-methylethylidene or is ethylene, l-methylethylene or trimethylene.

The reduction of the nitrogen-carbon double bond in starting materials of the formula V, which contain a group Va or Vb as X6, while Ar2, Y and X8 have the meaning given under the formula V (or in the isomeric compounds formula Vh of the oxygen-carbon-nitrogen bond) to the nitrogen Carbon single bond can in a manner known per se, e.g.

by treating with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogen catalyst, e.g. in the nickel, platinum or palladium catalyst, take place, wherein groups X8 which can be split off hydrogenolytically are split off and at the same time be replaced by hydrogen; or you work with a suitable hydride reducing agent, such as an alkali metal borohydride, e.g.

Sodium borohydride. In all cases, group Va or Vb also, if present, reduce a carbonyl radical Y to the hydroxymethylene radical, and when using hydride reducing agents, oxygen-bound agents can also be used Acyl residues of carboxylic acids, such as acetic acid, are present as residues X8 and in the same Work step are split off.

The reduction of the carbonyl group Y in starting materials of the general Formula V, which contain a group Ve as radical X6, while Ar and X are those under formula V can have the meaning given, 2 8 in the above for the reduction of the groups Va and Vb take place indicated manner, again in the catalytic hydrogenation corresponding residues X8 can be split off hydrogenolytically.

Particularly suitable for reducing compounds of the formula V with a group of the formula Vc or Vd and the meanings defined under the formula V of Ar2 and Y are hydride reducing agents such as sodium borohydride or diborane.

The reduction takes place at the same time as the reduction of a group Vc or Vd a carbonyl group Y, if this is present, and the splitting off of oxygen bonded acyl residues of carboxylic acids, such as acetic acid, as residues X8. on the other hand is by restricting the amount of reducing agent and appropriately choosing the reducing conditions to ensure that the aromatically bound carboxamide group is not reduced will. Grouping the formulas Vc and Vd, where X7 is each one Thioxo group means, are by reductive desulfurization, e.g. by treating with a hydrogenation catalyst, such as Raney nickel, in the Cruppicrung dc formula -CH2-NH-alk- converted. The above reduction reactions are carried out in a manner known per se, usually in the presence of an inert solvent and, if necessary, under Cooling or heating, e.g. in a temperature range from about -20 "to about +1500, and / or in a closed vessel under pressure and / or in an inert gas, e.g. nitrogen atmosphere.

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. For example, a compound of the formula Ar2-Ph-H (Vi) can be acetylated with an acetic acid halide or anhydride in the presence of a Lewis acid and the acetyl group in the intermediate product obtained can then be converted into the glyoxyloyl group, for example by treatment with a suitable oxidizing agent such as selenium dioxide. Such a glyoxyl compound, or, if desired, a suitable derivative thereof, for example an acetal, can then be mixed with an amine of the formula to be converted to a starting product of the formula V with the group X6 of the formula Va, in which Y represents the carbonyl group. A compound of the formula (Vi) can also be haloacetylated with a haloacetyl halide, for example chloroacetyl chloride, in the presence of a suitable Lewis acid, for example aluminum chloride, by the Friedel-Crafts method to give the corresponding Ar2-Ph-chloroacetyl compound, in one or the other Haloacetyl compounds usually obtainable by treatment with a suitable hydride reducing agent reduce the carbonyl to the carbinol group, and the halogen atom by treating with ammonia or a suitable derivative thereof, such as hexamethylenetetramine, and decomposition of the reaction product formed with dilute acid, such as aqueous hydrochloric acid, into the primary amino group convert, after which you get an intermediate of the formula receives. Amines of the formula Vk, in turn, are obtained, for example, by reacting a compound of the formula in which X1 and Z1 have the meanings given under formula II, with ammonia, or, if Z1 is a reactive, esterified hydroxyl group, e.g. chlorine, and X1 is hydroxy, with hexamethylenetetramine and subsequent reaction of the adduct obtained with dilute mineral acid, e.g. aqueous hydrochloric acid, or with phthalimide potassium and subsequent cleavage of the phthaloyl group using hydrazine hydrate.

Amines of the formula Vk can also be obtained by reacting an aldehyde of the formula Ar2Ph-CHO (Vm) or a suitable derivative thereof, such as an acetal, e.g.

of dimethyl acetal, or a bisulfite addition compound, with a suitable organosilicon cyanide compound, for example a tri-lower alkyl, for example trimethylsilyl cyanide, in the usual manner in the presence of a catalyst such as zinc iodide to give a compound of the formula and their conversion by means of a suitable reducing agent, for example a light metal hydride, for example lithium aluminum hydride, in a solvent, for which an ethereal liquid, for example diethyl ether or tetrahydrofuran, is usually used, into a compound of the formula Vk.

By reacting an intermediate of the formula Vk with a carbonyl compound of the formula one can get to starting materials of the formula V with a group X6 of the formula (Vb). A modification of this reaction consists in that in a compound of the formula II in which X1 is hydroxy and Z1 is halogen, the halogen atom, instead of being exchanged for the primary amino group by treatment with ammonia, etc., by reaction with an l-aryl-lower alkylamine , e.g.

Benzylamine or a di- (1-aryl-lower alkyl) -amine e.g. dibenzylamine against the corresponding l-aryl-lower alkylamino or di- (laryl-lower alkyl) -amino group exchanges and the compound obtained, for example the corresponding dibenzylamino compound, with the oxo compound of formula Vo under the reducing conditions of the process implements. The reducing agent used here is in primarily catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst or a mixture thereof, such as a palladium and / or platinum catalyst.

Under such reaction conditions, they are cleavable by hydrogenolysis Groups X, e.g. benzyl groups, split off, the carbonyl groups that may be present to the carbinol group and at the same time the nitrogen-carbon double bond to corresponding nitrogen-carbon single bond is reduced.

In turn, oxo compounds of the formula Vo are obtained, for example, by reacting a dihydroxy compound of the formula with a haloalkanone compound of the formula R-Hal (IVf) explained above, for example chloroacetone, in the presence of an alkaline condensing agent such as potassium carbonate, or an organic base such as triethylamine.

Starting products of the formula V with a group X6 of the formula Vc or Vd can be prepared in a manner known per se, for example by adding a formyl compound of the formula Ar2-Ph-CHO (Vq) reacts with hydrogen cyanide and in the cyanohydrin intermediate thus obtainable the cyano group is hydrolyzed to the carboxyl group, e.g. under acidic conditions. The so Ar2 -2-hydroxyacetic acid obtained is then in the presence of a suitable condensing agent, for example a carbodiimide such as dicyclohexylcarbodiimide with an amine of the formula (Vj) implemented. after which a starting material of the formula V with the group X6 of Formula (Vc) is obtained.

Furthermore, by reacting a compound of the formula Vk with a compound of the formula wherein Hal stands for halogen and in particular for chlorine, a starting material of the formula (V) with the group X6 of the formula (Vd) is obtained. The chlorine in the above-mentioned Ar2-Ph-chloroacetyl compound can also be exchanged for the primary amino group, for example by reaction with hexamethylenetetramine, and a compound thus obtained can be reacted with a halogen compound of the formula Vr. In a starting product of the formula V obtained in this way with a group X6 of the formula Vd and in which Y represents the carbonyl group, the carbonyl group can be reduced to the carbamoyl group and the aliphatically bonded carbamoyl group to the group of the formula -CH2-N-alk- at the same time -H , for example by means of a hydride reducing agent, in particular diborane.

The new compounds of the formula I can also be obtained by adding a compound of the formula where Ar3 has the meaning of Ar, or represents a radical Ar which is substituted by 1 to 2 which can be converted into hydroxyl and / or amino by means of aminolysis or ammonolysis and / or by groups of the formula -COOH, Xg is hydrogen or by means of aminolysis or ammonolysis means removable group, and Ph and alk have the above meanings, or a reactive derivative of one of the carboxylic acids defined in formula VI, with a compound of the formula RNR1R2 (VII) and at the same time any existing, convertible by aminolysis or ammonolysis into hydroxyl and / or amino Residues converted into hydroxyl and / or amino, and / or any radicals Xg present are cleaved off and mixed with hydrogen, and, if desired, the additional process steps mentioned after the first process are carried out. Residues which can be converted hydrolytically and in particular by aminolysis or ammonolysis into hydroxyl and / or amino or radicals Xg which can be split off in this way are acyl radicals of organic carboxylic acids, for example aryl, such as benzoyl, or lower alkanoyl, such as acetyl.

Reactive derivatives of the carboxylic acids defined in formula VI are e.g. the halides, such as the chlorides or bromides, also the azides, as well as Acid anhydrides, especially mixed acid anhydrides with e.g. lower alkanecarboxylic acids, such as acetic acid or propionic acid, lower alkoxyalkanecarboxylic acids such as 2-methoxyacetic acid. Reactive derivatives of carboxylic acids of the formula VI are in particular esters, e.g. with lower alkanols such as methanol, ethanol, isopropanol, tert-butanol, and more 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, 4-methoxyphenol, 4-nitro- or 2,4-dinitrophenol, furthermore Esters with cycloalkanols, such as cyclopentanol or cyclohexanol, which optionally may be substituted by lower alkyl, e.g., methyl. The implementation is in in a manner known per se, usually in the presence of an inert solvent, E.g. in a temperature range of about -10 "to +50" C in a closed (; efäss carried out.

The starting materials of the formula VI can be obtained in a manner known per se by brominating a compound of the formula Ar3-Ph-COCH3 and reducing the carbonyl group in the so erhnltonon Ar3-ph-halogen acetyl compound to the carbinol group, for example by means of diborane and the compound obtained with an amine of the formula wherein X9 has the meaning given, or a reactive derivative thereof, converts. The Ar -Ph-haloacetyl-3 compound can also be reacted with the amine of the formula VIa and the carbonyl group can subsequently be converted into the carbinol group.

For the preparation of starting materials of the formula VI you can also use the reaction of a compound of the formula with a carbonyl compound of the formula where R corresponds to the alkyl radical corresponding to an alkylene radical alk and containing a carbonyl group, ie corresponds to an oxoalkyl radical, reduce the Schiff's base formed with a borohydride, for example sodium borohydride.

The reduction can also be carried out using activated hydrogen in the presence a hydrogenation catalyst, e.g. a platinum-on-carbon catalyst.

Compounds of the formula VIb for their part are, for example, by reacting a compound of the formula where X1 and Z1 together are epoxy, or X1 is hydroxy and Zl is a reactive esterified hydroxy group, e.g. halogen, such as chlorine, with ammonia, or, if X1 is hydroxy and Z1 is e.g. chlorine, with hexamethylenetetramine and decomposition of the adduct formed with dilute mineral acid, such as dilute hydrochloric acid, available, where starting materials of the formula VId can be prepared analogously to the process described for the preparation of starting materials of the formula II.

Carbonyl compounds of the formula (VIc), in turn, can be obtained by reacting a compound of the formula with a compound of the formula R-Hal (IVf), in which Hal is halogen, in particular chlorine, can be obtained in a manner known per se. The new compounds of the formula I in which R1 and R2 are each hydrogen can also be obtained by in a compound of the formula in which one or both hydroxyl groups and / or hydroxyl and / or amino groups present in the Ar radical are optionally protected by groups which can be split off by hydrolysis and can be replaced by hydrogen and which are split off under the conditions of the process and replaced by hydrogen, or optionally in the Ar radical the group -CN, is present together with the mentioned protected hydroxyl and / or amino groups, the groups -CN by hydrolysis into the group -CONH2 and at the same time optionally protected hydroxyl and / or amino groups into free hydroxyl and / or amino groups, and, if desired, carrying out the additional process steps mentioned after the first process.

The starting materials of the formula VII can be prepared in a customary manner by adding a compound of the formula with a compound of the formula where Hal stands for chlorine, bromine or iodine. The reaction is advantageously carried out in a manner known per se in the presence of a basic agent.

Starting materials of the formula (VIIa) in turn, wherein Ar and Ph above Have meaning are by reacting a compound of the formula (II) in which X1 and Z1 together denote the epoxy group, with ammonia, or when X1 is hydroxy and Z1 as a reactive esterified hydroxyl group means e.g. halogen, such as chlorine, e.g. with hexamethylenetetramine and subsequent conversion of the obtained adduct with dilute mineral acid, such as dilute hydrochloric acid.

Starting materials of the formula (VII) can also be prepared in the usual way, for example by halogenating, for example brominating, a compound of the formula Ar-Ph-COCH3 (VIIc), for example using bromine in an inert solvent, such as chloroform, in the Ar thus obtained -Ph-haloacetyl, for example -bromoacetyl compound, the halogen replaced by the amino group, for example by reacting with hexamethylenetetramine in a solvent, such as a chlorinated hydrocarbon such as chloroform, and decomposition of the adduct obtained with dilute mineral acid, such as hydrochloric acid, in the obtained compound of the formula Ar-Ph-CO-CH2-NH2 (VIId) the carbonyl group to the carbinol group, for example by means of diborane> reduced and the resulting compound of the formula with a compound of the formula VIIb explained above in the manner indicated there.

A compound of the formula VIIb, in turn, can be obtained by the action of Acetic anhydride can be obtained on the oxime corresponding to the cyanide. this happens conveniently by refluxing. The oxime, in turn, can come from the corresponding aldehyde by boiling with hydroxylamine hydrochloride in the presence of alcoholic sodium carbonate solution can be prepared under reflux.

The corresponding aldehyde in turn can be obtained by reacting 2,4-dihydroxybenzaldehyde with an α, ß-, α, # - or α, # - dihalo-lower alkane, preferably in the presence of a basic agent. You can also use analog Type a hydroxysalicylonitrile, for example 2,4-dihydroxybenzonitrile [Chem. Ber. 24, 3657 (1891)] or the 2,5-dihydroxybenzonitrile [Helv. Chim. Acta 30, 149, 153 (1947)] with a non-geminal dihalo-lower alkane to form a compound implement the formula VIIb.

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 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 the mono- or bicyclic heteroaryl group Ar, splits off any protective groups present simultaneously or subsequently and replaces them with hydrogen, and, if desired, performing the additional process steps mentioned above. Protective groups are, for example, acyl, such as lower alkanol, such as 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 substituted group Ph, a compound of the formula VIII in which R3 is the formal group, in the customary manner with a l, 2-dicarbonyl compound of the formula in which R4 and / or R5 each represent hydrogen or a radical which substitutes the hetercaryl 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

l, l-dibromoacetone, which optionally in the 1 and / or 3-position is substituted by the group R4 and / or R5. Further preliminary stages are those in which the carbonyl compound of formula VIIIa in modified form, e.g. as Acetal, for example as dimethyl acetal, as a hydrate or as a bisulfite addition compound, is present. In the case of acyloins, such as the aforementioned l-acetyloxyacetone, 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 compounds of the formula VIIIa are obtained in situ. In this way, compounds of the formula I are obtained in which the substituted group Ph a 2-position, a group R4 and / or R5 in each case the 4- or 5-position of the Substitute the imidazole residue formed.

To prepare compounds of the formula I in which an imidazole radical Ar is substituted, for example in the 4-position by the substituted group Ph, one can, for example, by reacting a compound of the formula VIII in which R3 represents the group (VIIIb) represents, with a compound of the formula (VIIIc) and ammonia obtained. The groups of the 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 of about -300 to about +150 "C, if necessary in a closed vessel and / or in an inert gas atmosphere, e.g. under nitrogen, carried out.

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

Compounds of the formula VIII in which R3 represents the formyl group or the group of the formula VIIIb can thus be converted into a compound of the formula in which the formyl group corresponding to the radical R3 or the group of the formula VIIIb are preferably in protected form, for example as an acetal, such as dimethylacetal, as a hydrate or as a bisulfite addition compound, for example that formed with sodium sulfite, with a compound of the formula for example with 5- (2-aminoethoxy) salicylamide obtained. An intermediate product also formed here from the formyl group or the group of the formula VIIIb and a compound of the formula VIIIe, eg

a Schiff base is then hydrolyzed, e.g. with acidic Agents such as a mineral acid, e.g., aqueous hydrochloric acid, after which the compound of formula VIII is obtained.

Starting materials of the formula VIIId, in turn, are derived from one explained above Compound of the formula IIa by means of epoxidation, for example as described there, for example obtainable with a peroxy compound such as hydrogen peroxide or m-chlorobenzoperic acid, wherein a group R3, as indicated, preferably in protected, e.g. acetalized Form, for example as dimethyl acetal, or as a bisulfite addition compound, for example with Sodium bisulfite, is present and, after the epoxidation has ended, the protective groups are split off. These conversions are carried out in the usual way.

A compound of the formula I in which Ar is the thiazolyl radical which is substituted, for example in the 2-position by the substituted group Ph, 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 radical R4 and / or R5, a compound of the formula VIIIg'in the form of its derivatives, for example the acetals, such as diethyl acetals, or α, β-dihalo such as α, β-dibromoethyl methyl ether, or the a, ß-dihalogen, such as α, ß-Dichloräthylacetate use. Instead of a carbonyl compound of the formula VIIIg, an epoxide of the formula can also be used in which Hal is halogen, for example chlorine, use for the reaction described.

To prepare compounds of the formula I in which Ar represents a thiazolyl radical substituted in the 4- or 5-position by the substituted group Ph, a compound of the formula VIII in which R3 is the group of the formula or the formula is, and the carbonyl group optionally in protected, e.g.

Acetal form, in which Hal each 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 known in a manner, for example

in the presence of a suitable solvent, e.g. a lower alkanol, such as ethanol, or an ethereal liquid such as dioxane, if necessary 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, in a 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 behave a compound of formula VIII with group VIIIf as R3 by being in a compound of formula the group N = C- by reaction with hydrogen sulfide in a suitable, for example a basic organic solvent, such as

Pyridine or triethylamine or mixtures thereof, in group VIIIf convert.

Starting materials of the formula VIIIm 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 - (# - aminoethoxy) salicylamide.

Starting materials of the formula VIII, in which R3 represents a group of the formula VIIIi or VIIIk, can be obtained, for example, by reacting a compound of the formula or the formula where Hal is halogen and in particular chlorine or bromine, with a compound of the formula VIIIe explained above, for example with 5- (2-aminoethoxy) salicylamide.

Starting materials of the formulas VIIIo or VIIIp are in turn derived in a customary manner from a compound of the formula wherein hydroxy or amino groups R or R5 in protected, for example

4 R5 as described above, in a-aryl-lower alkylated, such as benzylated, or lower alkanoylated, e.g. acetylated form, by means of epoxidation, e.g. by means of a peroxy compound such as hydrogen peroxide, or a peracid, such as peracetic acid, and subsequent splitting off of existing protective groups accessible.

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

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

4 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 VIIIs as R3 can be prepared by adding a compound of the formula with preferably protected, for example as described, acetalized carboxaldehyde group with a compound of the formula VIIIe explained above, for example with 5- (2-aminoethoxy) salicylamide, reacted in the usual way, and optionally a protected carboxaldehyde group in the free carboxaldehyde group, for example by means of acidic agents , such as aqueous mineral acid, for example dilute sulfuric acid.

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 substituted group Ph, 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-C0-CH2-C0-R5 (VIIIw) 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 VIIIv can be used as R3 behave by, for example, a compound of the formula VIIIm explained above in the corresponding imidoester, e.g. by saturating an absolute ethanol Solution of such a compound with hydrogen chloride, converts and from it through Reaction with anhydrous ammonia a compound containing group VIIIv as R3 of formula VIII, preferably in the form of a salt, e.g. as the hydrochloride, and splitting off any protective groups present simultaneously or subsequently and replaced by hydrogen.

The reactions are carried out in a customary manner.

In choosing the appropriate above method for making Compounds of the formula I must be ensured that existing substituents, primarily the residues Ar, are not converted or split off, if such Conversions or

Spin-offs are not welcome. So in particular can be functional modified carboxyl groups, as well as cyano groups, as substituents of the radicals Ar during solvolysis, especially hydrolysis, and also during reductions in the Reaction to be involved and transformed. On the other hand, simultaneous Conversions of substituents may be desired; e.g. unsaturated substituents, such as lower alkenyl, under the conditions of a reduction process used according to the invention, e.g. to lower alkyl.

In the compounds obtained, one can, within the scope of the definition of the compounds of the formula I in the usual manner according to the process obtained compounds into others Transfer end products, e.g. by modifying suitable substituents, introducing or split 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 a corresponding 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 1 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, to the corresponding cyano compounds be de-hydrated.

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, the contain a cyan substituent can in the usual manner, for example in the presence of concentrated aqueous mineral acid or alkali metal hydroxides, to the corresponding carbamoyl or hydrolyzed directly to the carboxyl compounds.

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 in a conventional 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 containing can in the usual way by treating with one Peroxy compound such as hydrogen peroxide or an acid derivative thereof such as peracetic acid or m-chloroperbenzoic acid, can be converted into N-oxides.

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.

\ he in the manufacturing process must also be used in the implementation of the Additional steps ensure that 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, 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 of which may exist. 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 into which free compounds are converted. on the other hand can obtained free bases with organic or inorganic acids, e.g. with the acids mentioned, form acid addition salts, in particular for their preparation such 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 the diastereoisomers in a known manner, e.g. by chromatography and / or fractional crystallization, into the two stereoisomers (diastereomers) Racemates are resolved.

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 repositioning with an optically active substance which forms salts with the racemic compound, in particular acids, and separating the salt mixture thus obtained, e.g. due to different solubilities, in the diastereomeric salts from which the free antipodes can be released by the action of suitable means. Optically active acids that are particularly common are e.g. the D- and L-forms of Tartaric acid, di-O, O '- (p-toluoyl) -tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, Glutamic acid, aspartic acid, or quinic acid. It is advantageous to isolate the more effective one 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 is in the form of their salts.

It is expedient to use for the implementation of the invention Reactions of those starting materials belonging to the groups mentioned above of end products and especially those specifically described or highlighted Lead end materials.

The starting materials are known or, if they are new, can be checked 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 the Active substance, optionally 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 salt thereof, such as magnesium or Calcium stearate and / or polyethylene glycol. Tablets can also Binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, 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 mixtures, or Contain adsorbents, colorings, flavorings and sweeteners. Further you can get the new pharmacologically active compounds in the form of parenteral use preparations that can be administered or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g. with lyophilized preparations that contain the active substance alone or together with a carrier material, e.g.

Mannitol, contained, can be prepared before use. The pharmaceutical Preparations can be sterilized and / or auxiliary materials, e.g. preservatives, stabilizers, Wetting and / or emulsifying agents, solubilizers, salts to regulate the osmotic pressure and / or buffer included. The present pharmaceutical Preparations which, if desired, contain other pharmacologically active substances can be used in a manner known per se, e.g.

by means of conventional mixing, granulating, coating, dissolving or Lyophilization processes made and contained from about 0.1% to 100%, in particular 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 solution of 11.1 g of crude a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] benzylaminomethyl] -4- [l-methyl-4- (trifluoromethyl) imidazole- 2-yl] benzyl alcohol in 110 ml of methanol, after adding 1 g of palladium-on-carbon catalyst (5%) hydrogenated until the calculated amount of hydrogen is absorbed. The resulting suspension is diluted with 200 ml of dioxane, heated to reflux, through a glass fiber filter filtered and the filtrate freed from the solvent on a rotary evaporator Recrystallization of the residue from methanol gives the a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) - ethyl] aminomethyl] -4- [1-methyl-4- (trifluoromethyl) imidazol-2-yl] benzyl alcohol.

By chromatography of the mother liquor residue on silica gel with the Eluent chloroform / methanol / ammonia 40: 10: 1 can use a further amount of this compound be won.

The base is then dissolved in warm methanol with one equivalent Methanesulfonic acid added, the resulting solution on the rotary evaporator from Freed solvent and the residue from a mixture of acetonitrile and ethyl acetate recrystallized, the α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- [1-methyl-4- (trifluoromethyl) -imidazol-2-yl] -benzyl alcohol methanesulfonate of m.p. 166-168 ° is obtained.

The starting material can be prepared as follows: a) A solution of 13.1 g of 4-cyanobenzaldehyde and 16.0 g of ammonium acetate in a mixture of 100 ml of water, 500 ml of methanol and 100 ml of concentrated ammonia solution are adjusted to 0 to 5 " chilled. With stirring, at this temperature in the course of 15 minutes 27.0 g 1,1-dibromo-3,3,3-trifluoroacetone were added dropwise. The reaction mixture is then stirred at room temperature for 5 hours, the solvent largely on a rotary evaporator removed and the residue partitioned between water and ethyl acetate.

The organic phase is separated off, dried and evaporated. Crystallization of the residue from ethyl acetate / hexane gives 4- (4-trifluoromethyl-imidazol-2-yl) -benzonitrile with a melting point of 204 bis. 2060 ..

b) A solution of 8.9 g of 4- (4-trifluoromethyl-imidazol-2-yl) -benzonitrile in 100 ml of dimethylformamide is cooled to 0 °, in portions with 1.96 g of sodium hydride dispersion (55%) are added and the mixture is then stirred in an ice bath for 2 hours. After that, 2.92 ml of methyl iodide were added and the solution was then added for 18 hours at room temperature touched. The dimethylformamide is on a rotary evaporator at a bath temperature of 70 "removed and the residue partitioned between water and ethyl acetate. The organic phase is separated off, dried over sodium sulfate and the solvent freed and the residue recrystallized from diisopropyl ether, the 4- (l-methyl-4-trifluoromethyl-imidazol-2-yl) -benzonitrile from m.p. 100 to 1010 is obtained.

c) A solution of 41.4 g of 4- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -benzonitrile in 600 ml of toluene is added dropwise with 180 ml of a Diisobutylaluminum hydride solution (20% in toluene) was added. The reaction is carried out by thin layer chromatography followed and, if necessary, again added diisobutylaluminum hydride solution. After the starting material has completely disappeared in the thin layer chromatogram is, is under Ice cooling one after the other first 80 ml of methanol, then a mixture of 80 ml of methanol and 40 ml of water and finally 330 ml of 20 % sulfuric acid was added dropwise. The two-phase reaction mixture is on a rotary evaporator concentrated to a small volume and then with ethyl acetate and Ice water added. The organic phase is separated off, the water phase twice more extracted with ethyl acetate and the combined organic phases Dry over sodium sulfate evaporated on a rotary evaporator. The one left behind Crude 4- (l-methyl-4-trifluoromethylimidazol-2-yl) -benzaldehyde is used right in the next Level used.

d) 0.48 g of sodium hydride dispersion are washed with petroleum ether and the remaining sodium hydride is mixed with 12 ml of dimethyl sulfoxide. Under Then 2.53 g of trimethylsulfoxonium iodide are stirred in portions after 30 minutes a solution of 2.54 g of crude 4- (1-methyl-4-trifluoromethyl-imidazol-2-yl) -henzaldehyde added in 12.5 ml of dimethyl sulfoxide. After a further 15 minutes, the temperature is raised to 60 °, then the reaction mixture is cooled and added to 200 ml of ice water. The water phase is extracted three times with Seither, the combined organic phases over sodium sulfate dried and freed from solvent on a rotary evaporator. The leftover yellow oil is chromatographed on silica gel with an ethyl acetate / hexane mixture 1: 1. 4- (1-Methyl-4-trifluoromethylimidazol-2-yl) -styrene oxide is obtained from the main fractions as a pale yellowish oil, which is used directly in the next stage.

e) A solution of 5.9 g of 4- (1-methyl-4- (trifluoromethyl) imidazol-2-yl) styrene oxide and 5.7 g of 5- [2- (N-benzyl-amino) -ethoxy] -salicylamide in 120 ml of isopropanol is during Stirred under reflux for 120 hours.

After filtration through activated charcoal, the solvent is evaporated on a rotary evaporator removed, the crude a- [N- [2- (3-carbamoyl-4-hydroxy -phenoxy) -ethyl] -benzylaminomethyl] -4- [1-methyl-4- (trifluoromethyl) -imidazol-2-yl] -benzyl alcohol obtained as foam, which is used directly in the next stage.

Example 2: A solution of 2.2 g of crude a- [N-t2- (3-carbamoyl-4-hydroxyphenoxy) -ethyl] -benzylaminomethyl] -4- (1-methyl-imidazol-2-yl) -benzyl alcohol in 10 ml of methanol, after adding 0.2 g of palladium on carbon catalyst (5%) hydrogenated until the calculated amount of hydrogen is absorbed. The resulting suspension is diluted with methanol and filtered through a glass fiber filter. After removal of the solvent, the residue on silica gel with the mobile phase chloroform / methanol / ammonia 350: 50: 1 chromatographed. The main fractions are recovered after recrystallization α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (1-methyl-imidazol-2-yl) -benzyl alcohol from methanol / isopropanol from m.p. 117-120 °.

The starting material can be prepared as follows: a) A solution of 39.3 g of 4-cyanobenzaldehyde, 193.2 g of sodium acetate and 232 g of glyoxal in one Mixture of 1 liter of methanol and 740 ml of ammonia solution for 60 minutes stirred at room temperature.

The reaction mixture is diluted with 3 liters of water and 4 times with Ethyl acetate extracted, the organic phase then washed over Dried sodium sulfate and freed from solvent on a rotary evaporator. Of the The residue is chromatographed on silica gel with chloroform / methanol 20: 1. the end 2- (4-Cyanophenyl) imidazole can be added to the main fractions after crystallization from ethyl acetate from m.p.> 200 ° can be obtained.

b) Analogous to the procedures described in Examples lb) -e) Finally, the α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] benzylaminomethyl] -4- (1-methyl-imidazole-2) is obtained from 2- (4-cyanophenyl) imidazole -yl) -benzyl alcohol, which is obtained as a raw product and further processed as such.

Example 3: A solution of 5.4 g of 4- (1-methyl-4- (trifluoromethyl) imidazol-2-yl) styrene oxide and 4 g of 5- (2-aminoethoxy) salicylamide in 100 ml of isopropanol is added for 120 hours stirred under reflux.

After filtering through activated charcoal, the filtrate is evaporated on a rotary evaporator and the residue recrystallizes from methanol, after which α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- [1-methyl-4- (trifluoromethyl) imidazole- 2-yl] benzyl alcohol obtained whose methanesulfonate after recrystallization from a mixture of acetonitrile and ethyl acetate shows m.p. 166-1680.

Example 4: Analogous to those described in the previous examples The following compounds can work based on the corresponding starting materials of formula I, their N-oxides or salts, in particular pharmaceutically acceptable, non-toxic acid addition salts are prepared: a) a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (1,4, 5-trimethyl-imidazol-2-yl) benzyl alcohol; b) a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (tr ifluoromethyl-thiazol - 2-yl) benzyl alcohol; c) a- [N- [2- (3-Carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (1-methyl-3-methylthio-1H-1,2,4-triazole-5 -yl) -benzyl alcohol; d) a- [N- [2- (3-Carbamoy1-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (1,2-dihydro-1-methyl-2-oxo-pyridin-6-yl ) -benzyl alcohol; e) a- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) ethyl] aminomethyl] -4- (1-methyl-4 - (trifluoromethyl) imidazol-2-yl) benzyl alcohol; f) cx-N- [2- (3-carbamoyl-4-hydroxyphenoxy) -l-methyl-ethyl] -aminomethyl] -4- (1-methyl-4- (trifluoromethyl) -imidazol-2-yl) -benzyl alcohol.

Example 5: tablets containing 20 mg of active substance produced in the usual way in the following composition: Composition: α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- [1-methyl-4- (trifluoromethyl) imidazol-2-yl] methanesulfonate L mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg magnesium stearate 1 mg 145 mg Preparation: α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- [1-methyl-4- (trifluoromethyl) imidazol-2-yl] benzyl alcohol methanesulfonate 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 made with 5 times the amount of water gelatinized on the water bath and kneaded the powder mixture with this paste, until a weakly 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. On top of this are the remaining wheat starch, talc and magnesium stearate mixed in and the mixture pressed into tablets of 145 mg weight with a break notch.

Example 6: Tablets containing 1 mg of active substance are in the following composition prepared in the usual way: Composition: a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ~ ethyl] aminomethyl] -4- [l-methyl-4 '(trifluoromethyl) -imidazole- 2-yl] methanesulfonate 1 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg Magnesium stearate 1 mg 126 mg Preparation: (1- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- [imethyl-4- (trifluoromethyl) imidazol-2-yl ] benzyl alcohol methanesulfonate 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. On top of this are the remaining wheat starch, talc and magnesium stearate mixed in and the mixture pressed into tablets of 145 mg weight with a break notch.

Example 7: Capsules containing 10 mg of active substance are like is made in the usual way: Composition: a-EN- [2- (3-Carbamoyl-4-hydroxyphenoxy) -ethyl] -aminomethyl] -4- [1-methyl-4- (trifluoromethyl) -imidazol-2-yl] -benzyl alcohol-methane -sulfonate 7500 mg talc 200 mg colloidal silica 50 mg Manufacture: The active one Substance is intimately mixed with talc and colloidal silica, the mixture driven through a sieve with 0.5 mm mesh size and this in portions of each 11 mg filled into hard gelatine capsules of a suitable size.

Example 8: A sterile solution of 5.0 g of a- [N- [2- (3-carbamoyl-4-hydroxyphenoxyethyl] aminomethyl] -4- [methyl-4- (trifluoromethyl) -imidazole-2 -yl] benzyl alcohol methanesulfonate in 5000 ml of distilled water is filled into 5 ml ampoules, the 5 ml Solution contain 5 mg of active ingredient.

Example 9: 3.62 g of cx- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- [1-methyl- (4-trifluoromethyl) -imidazole-2- yl] benzyl alcohol are with the addition of 100.0 ml 0.10-n. Hydrochloric acid with 18,000 ml of distilled water dissolved to a volume of 18100 ml. The sterilized solution is in ampoules à 5.0 ml filled with 1 mg of active ingredient.

Example 10: Instead of that in Examples 5 to 9 as the active substance The compound used can also include the following compounds of the formula I, their N-oxides or pharmaceutically acceptable, non-toxic acid addition salts as active ingredients in tablets, coated tablets, capsules, ampoule solutions etc. are used: a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (1-methyl-imidazole-2- yl) benzyl alcohol, a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy ) -äthyl] -aminomethyl] -4- (1,4,5-trimethyl-imidazol-2-yl) -benzyl alcohol, α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] -. iminomethyl] -4 ~ (trifluoromethyl-thiazol-2-yl) -benzyl alcohol; α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (1-methyl-3-methylthio-1H-1,2,4-triazol-5-yl ) benzyl alcohol, α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (1,2-dihydro-1-methyl-2-oxo-pyridin-6-yl) - benzyl alcohol, cx- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) ethyl] aminomethyl] -4- (l-methyl-4- (trifluoromethyl) imidazol-2-yl) benzyl alcohol, α- [N- [2- (3-carbamoyl-4-hydroxy-pllenoxy) -l-methyl-ethyl] -aminomethyl] -4- (l-methyl-4- (trifluoromethyl) -imidazol-2-yl) - benzyl alcohol.

Claims (18)

Claims: 1. Secondary hydroxy compounds of the formula where Ar is a mono- or bicyclic, carbocyclic or a heterocyclic aryl radical bonded to a phenylene radical Ph via a ring carbon atom, Ph is a phenylene radical and alkalkylene with 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, oxane-lower alkylene, thian-lower alkylene, aza-lower alkylene or N-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 Phenylene radical Ph represents 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, Cyan. Nitro and / or optionally bubstiLuieess such as acylated hmino, e.g. amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino, Are lower alkylsulfonylamino, ureido, 3-lower alkylureido or 3-cycloalkylureido, and also substituents of heterocyclic aryl Ar optionally as indicated, substituted phenyl or benzoyl or optionally, as indicated, substituted represent monocyclic heteroaryl, Ph optionally, as indicated, substituted Is 1,2- or 1,4-phenylene, and alk is an alkylene radical having 2 to 4 carbon atoms represents, wherein the nitrogen atom and the oxygen atom by 2 or 3 carbon atoms are separated from one another and R1 and -R2 have the meaning given under 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. 3. Compounds of the formula I in which Ar is an optionally substituted one carbocyclic or bonded to the phenylene radical Ph 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 such as, carboxy or lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkyl-carbamoyl, Cyan, nitro, optionally substituted, such as acylated amino, e.g. amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, Niederalkoxyearbonylamino, Niederalkoxysulfonylamino, optionally by lower alkyl, Lower alkoxy, halogen, halo-lower alkyl, nitro or cyano substituted phenyl or benzoyl, or optionally, as indicated, substituted monocyclic, an oxygen or nitrogen atom and optionally 1-3 further nitrogen atoms containing heteroaryl, Ph optionally by lower alkyl, lower alkoxy, Is halo-lower alkyl, halogen or cyano-substituted 1,4-phenylene, and alk denotes an alkylene radical having 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom is separated from each other by 2 to 3 carbon atoms and R1 and R2 represent hydrogen or lower alkyl or together with the nitrogen atom of the amide group form pyrrolidino, piperidino or morpholino. 4. Compounds of the formula I in which Ar is an optionally substituted one Phenyl radical, or one bonded to the phenylene radical Ph via a ring carbon atom, an oxygen, sulfur or nitrogen atom and optionally 1 to 3 additional ones Monocyclic heteroaryl radical containing nitrogen atoms as ring members with 5 up to 6 ring members means that is at least partially saturated and in this case may be substituted by oxo, with substituents optionally substituted Lower alkyl, e.g. lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, or lower alkenyl, optionally etherified or esterified hydroxy, e.g. hydroxy, 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, such as carboxy or lower alkoxycarbonyl, 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, or optionally, as indicated, substituted monocyclic, a Oxygen or nitrogen atom and optionally 1 to 3 further nitrogen atoms containing heteroaryl, Ph optionally by lower alkyl, lower alkoxy, 1,4-phenylene substituted by halogen or cyano, 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, and R1 and R2 are hydrogen or lower alkyl or pyrrolidino together with the nitrogen atom of the amide group or form orpholino. 5. Compounds of the formula I in which Ar is an optionally substituted one Phenyl radical, or one bonded to the phenylene radical Ph via a ring carbon atom, an oxygen, sulfur or nitrogen atom and optionally 1 to 2 additional ones Monocyclic heteroaryl radical containing nitrogen atoms as ring members with 5 means up to 6 ring members, or an at least partially saturated oxo-heteroaryl radical with 5-6 ring members and 1-2 nitrogen atoms as ring members, with substitutents optionally substituted lower alkyl, e.g. lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, optionally etherified or esterified hydroxy, e.g. hydroxy, lower alkoxy, Lower alkoxy lower alkoxy, lower alkylthio or halogen, acyl, e.g. lower alkanoyl, optionally esterified carboxy such as carboxy or lower alkoxycarbonyl, carbamoyl, Cyano, optionally substituted such as acylated amino, e.g. Amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, Lower alkoxycarbonylamino, lower alkylsulfonylamino, or optionally, as indicated, substituted monocyclic, an oxygen or nitrogen atom and optionally Mean 1 to 2 further nitrogen atoms containing heteroaryl, Ph optionally is 1,4-phenylene substituted by lower alkyl, lower alkoxy, halogen or cyano, alk denotes an alkylene radical having 2 to 3 carbon atoms, the nitrogen atom and the oxygen atom separated from each other by 2 to 3 carbon atoms are, and R1 and R2 represent hydrogen or lower alkyl or together with the nitrogen atom of the amide group form morpholino. 6. Compounds of formula 1, wherein Ar is an optionally substituted, bonded to the phenylene radical Ph via a ring carbon atom, a sulfur or one nitrogen atom and optionally 1 to 2 additional nitrogen atoms as ring members containing heteroaryl radical with 5 to 6 ring members, e.g. imidazolyl, pyrazolyl, Triazolyl, thiazolyl, thiadiazolyl, indolyl or pyridyl, or a dihydro-oxo-heteroaryl radical with 1-2 nitrogen atoms as ring members, e.g. tihydro-6-oxo-2-pyridinyl or dihydro-4-oxo-2-pyrimidinyl represents, where substituents are lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, Hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, lower alkylthio, halogen, lower alkanoyl, Carboxy, lower alkoxycarbonyl, cyano, carbamoyl, amino, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylsulfonylamino, Ph optionally by lower alkyl or halogen is substituted 1,4-phenylene, alk is an alkylene radical having 2 to 3 carbon atoms means, wherein the nitrogen atom and the oxygen atom through 2 to 3 carbon atoms are separated from one another, and R1 and R2 each represent hydrogen. 7. Compounds of the formula I in which Ar is optionally substituted, Imidazolyl, pyrazolyl bonded to the phenylene radical Ph via a ring carbon atom, Triazolyl, thiazolyl, pyridyl or dihydrooxo-2-pyridinyl, e.g., 1,2-dihydro-3-oxo-pyridin-6-yl denotes, where substituents are lower alkyl, e.g. methyl, hydroxy-lower alkyl, e.g. 2-hydroxyethyl, halo-lower alkyl, e.g. trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkoxy-lower alkoxy, e.g. 2-methoxy-ethoxy, halogen, e.g. chlorine, Lower alkanoyl e.g. Acetyl, lower alkoxycarbonyl, e.g. ethoxycarbonyl, carbamoyl, lower alkanoylamino e.g. acetylamino, lower alkoxycarbonylamino e.g. ulethoxyearbonyAamino, lower alkylsulfonylamino, e.g. methylsulfonylamino, Ph is 1,4-phenylene, alk is an alkylene radical having 2 to 3 carbon atoms, wobci the nitrogen atom and the oxygen atom by 2 carbon atoms from each other are separated, and R1 and R2 each represent hydrogen. 8. α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- [1-methyl-4- (trifluoromethyl) imidazol-2-ylI-benzyl alcohol. 9. α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (l-methyl-imidazol-2-yl) -benzyl alcohol. 10. N-oxides of compounds of claims 1-9. 11. Salts of compounds of claims 1-10. 12. Pharmaceutically acceptable, non-toxic acid addition salts of compounds of claims 1-10. 13. Pharmaceutical preparations containing a compound of the formula 1. 14. Compounds of formula I for use in a process for therapeutic treatment of the human or animal body. 15. Compounds of the formula I as agents for combating high blood pressure, of angina pectoris, hypertrophic cardiomyopathies and cardiac arrhythmias. 16. Use of compounds of the formula I for the preparation of pharmaceutical Preparations. 17. Process for the preparation of secondary hydroxy compounds of the formula where Ar is a mono- or bigyclic, carbocyclic or a heterocyclic aryl radical 'Ph bonded to a phenylene radical Ph via a ring carbon atom and alkalkylene with 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, oxane-lower alkylene, thian-lower alkylene, aza-lower alkylene or N-lower alkylazane-lower alkylene, their N-oxides or salts thereof, characterized in that a compound of the formula with a compound of the formula wherein one of the groups Z1 and Z2 represents a reactive esterified hydroxy group and the other represents the primary amino group, and X1 represents hydroxy, or wherein X1 and Z1 together represent the epoxy group and Z2 represents the primary amino group, Ar, Ph, and alk above Have meaning, converts, or b) in a compound of the formula where hrl has the meaning of Ar or a radical Ar which is substituted by 1 to 2 groups which can be converted into hydroxyl and / or amino, X2, X3 and X4 each denote hydrogen or a substituent which can be replaced by hydrogen, and X5 denotes R1 , or X2 and X3 and / or X4 and X5 together denote a divalent radical which can be replaced by two hydrogen atoms, with the proviso that at least one of the radicals X2, X3 and X4 is different from hydrogen, or at least Arl denotes a radical Ar which is through in each case 1 to 2 groups convertible into hydroxy and / or amino is substituted, or at least X2 and X3 together or X4 and X5 together represent a divalent radical which can be replaced by two hydrogen atoms, Ph and R2 have the above meanings, or in a salt thereof, the X2, X3, or X4 other than hydrogen, or X2 and X3 together or X4 and X5 together are replaced by hydrogen, and / or substituted Hy present in a radical Ar Hydroxy and / or amino converted into free hydroxy and / or amino, or c) in a compound of the formula where X6 is a reducible group of the formulas -CH = N-alk- (Va), or -CH2-N = alk1- (vb) 2 1 or -C (= X7) -N (X8) -alk- (Vc) respectively. -CH2-N (X8) -C (= X7) -alk2- (vd) or a group -CH2-N (X8) -alk- (Ve), where alk stands for the alkyl-ylidene radical corresponding to an alk radical and alk2 corresponds to a radical alk shortened by a methylene group bonded to the nitrogen atom, X7 represents the oxo or thioxo radical and X8 represents hydrogen or a radical which can be replaced by hydrogen under the conditions for the reduction of X6 and / or Y and Y represents a radical of the formula - CO- (Vf) or -CH (OX8) - (Vg), in which X8 has the meaning given above, Ar2 corresponds to a radical Ar, but optionally one or two groups instead of one or two hydroxyl and / or amino in each case - OX8, and / or -N (X8) -, in which X8 has the meaning given above, Ph, R1 and R2 have the above meanings, where X6 is always a reducible group Va to Vd and / or Y is a carbonyl group Vf, this group (s) is reduced and, in the same operation, the groups X8 other than hydrogen are replaced by hydrogen , or d) a compound of the formula wherein Ar has the meaning of Ar, or represents a radical Ar, 3 which is substituted by 1 to 2 by means of aminolysis or ammonolysis in hydroxyl and / or amino and / or by groups of the formula -COOH, Xg is hydrogen or by means of aminolysis or Ammonolysis is a removable group, and Ph and alk have the above meanings, or a reactive derivative of one of the carboxylic acids defined in formula VI, with a compound of the formula HNR1R2 (VII) and at the same time any existing, by means of aminolysis or ammonolysis into hydroxyl and / or amino convertible radicals are converted into hydroxyl and / or amino, and / or any radicals Xg present are split off and replaced by hydrogen, or e) a compound of the formula in which one or both hydroxyl groups and / or hydroxyl and / or amino groups present in the Ar radical are optionally protected by groups which can be split off by hydrolysis and can be replaced by hydrogen and which are split off under the conditions of the process and replaced by hydrogen, or optionally in the Ar radical the group -CN, is present together with the mentioned protected hydroxyl and / or amino groups, the groups -CN by hydrolysis into the group -CONH2 and at the same time optionally protected hydroxyl and / or amino groups into free hydroxyl and / or amino groups, or f) in a compound of the formula in which hydroxyl groups and / or the amino group are protected by protective groups, and R3 represents a substitute Pn capable of forming a mono- or bicyclic heteroaryl radical Ar, which forms mono- or bicyclic heteroaryl group Ar, splits off any protective groups present simultaneously or subsequently and replaces them with hydrogen, and , if desired, converting a compound obtained into another compound of the formula I, and / or, if desired, converting a free compound obtained into an N-oxide or a salt or an N-oxide or salt obtained into a free compound or its N Oxide converted, and / or, if desired, a racemate mixture obtained into the racemates or a racemate obtained into the optical antipodes separates. 18. The compounds obtainable by the process of claim 17.