2-hydroxypropylamino-alkyl-benzimidazoly-5-yl derivatives and their use in the treatment of heart disease

Abstract

The invention relates to new 2-hydroxy-n-propylamines of the formulaR.sub.1 --O--CH.sub.2 --CHOH--CH.sub.2 --NH--A--R.sub.2 (I)whereinR.sub.1, R.sub.2 and A are defined as in claim 1, the tautomers, enantiomers and acid addition salts thereof, particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof with inorganic or organic acids, which have valuable pharmacological properties, more particularly a simultaneous cardiotonic and .beta.-blocking activity, and the use thereof as pharmaceutical compositions and processes for preparing them.

Description

The present invention relates to 2-hydroxy-n-propylamines of the formula

R.sub.1 --O--CH.sub.2 --CHOH--CH.sub.2 --NH--A--R.sub.2 (I) the tautomers, the enantiomers and acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof with inorganic or organic acids, the use thereof and processes for preparing them.

The above compounds have valuable pharmacological properties, particularly a simultaneous cardiotonic and .beta.-blocking activity.

In the above formula I

R.sub.1 represents a naphthyl group, a 3,4-dihydro-2-hydroxyquinolinyl group bound via the phenyl ring, a phenyl group substituted by a C.sub.1-5 alkylsulphonyloxy or by an allyl, allyloxy, cyano or aminocarbonylmethyl group, a phenyl group substituted by a C.sub.1-3 alkyl group, wherein the alkyl moiety is substituted in the 1-, 2- or 3-position by an alkoxy, cycloalkyloxy, cycloalkylmethoxy, 2-alkoxyethoxy, 2-cycloalkyloxyethoxy, 2-cycloalkylmethoxy-ethoxy or 2-phenoxyethoxy group, wherein the alkoxy moiety may contain from 1 to 6 carbon atoms and the cycloalkyl or cycloalkyloxy part may contain 3 to 6 carbon atoms, or a phenyl group disubstituted by a C.sub.1-3 alkyl group and by a halogen atom, A represents a straight-chained C.sub.2-4 alkylene group optionally substituted by one or two C.sub.1-3 alkyl groups and R.sub.2 represents a group of formula ##STR1## wherein R.sub.3 represents a hydrogen atom or a C.sub.1-3 alkyl group, R.sub.4 and R.sub.5 each represent a hydrogen atom or together represent another carbon-carbon bond and B represents a group of the formula ##STR2## wherein R.sub.6 represents a C.sub.1-3 alkyl group or a hydrogen or halogen atom, Y.sub.1 represents a bond, an oxygen atom, a sulphonyl group or an --NH--CO--CH.sub.2 group wherein the CH.sub.2 moiety is attached to the phenyl nucleus, X.sub.1 represents a nitrogen atom or a methyne group optionally substituted by a hydroxy group or by a C.sub.1-3 alkyl group, X.sub.2 represents an oxygen atom or an imino group and Y.sub.2 represents a bond or an imino group.

As examples of the definitions for the groups given hereinbefore:

R may represent a 1-naphthyl, 2-napthyl, 3,4-dihydro-2-hydroxy-quinolin-5-yl, 3,4-dihydro-2-hydroxy-quinolin-6-yl, 3,4-dihydro-2-hydroxy-quinolin-7-yl, 3,4-dihydro-2-hydroxy-quinolin-8-yl, 4-methylsulphonyloxy-phenyl, 4-ethylsulphonyloxy-phenyl, 4-n-propylsulphonyloxy-phenyl, 4-isopropylsulphonyloxy-phenyl, 4-n-butylsulphonyloxyphenyl, 4-n-pentylsulphonyloxy-phenyl, 4-isobutylsulphonyloxy-phenyl, 4-tert.pentylsulphonyloxyphenyl, 2-allyl-phenyl, 4-allyl-phenyl, 2-allyloxy-phenyl, 4-allyloxy-phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyano-phenyl, 2-aminocarbonylmethyl-phenyl, 3-aminocarbonylmethyl-phenyl, 4-aminocarbonylmethylphenyl, 4-(methoxymethyl)phenyl, 4-(ethoxymethyl)phenyl, 4-(n-propoxymethyl)phenyl, 4-(isopropoxymethyl)phenyl, 4-(cyclopropyloxymethyl)phenyl, 4-(n-butyloxymethyl)phenyl, 4-((2-methyl-n-propoxy)methyl)phenyl, 4-(n-pentyloxymethyl)-phenyl, 4-(n-hexyloxymethyl)phenyl, 4-(cyclopropylmethoxy-methyl)phenyl, 4-(cyclobutyloxymethyl)phenyl, 4-(cyclobutylmethoxy-methyl)phenyl, 4-(cyclopentyloxy-methyl)phenyl, 4-(cyclopentylmethoxymethyl)phenyl, 4-(cyclohexyloxymethyl)phenyl, 4-(cyclohexylmethoxymethyl)-phenyl, 4-(2-methoxyethyl)phenyl, 4-(2-ethoxyethyl)-phenyl, 4-(2-n-propoxyethyl)phenyl, 4-(2-isopropoxy-ethyl)phenyl, 4-(2-n-butoxy-ethyl)phenyl, 4-(2-(2-methyl-n-propoxy)ethyl)phenyl, 4-(2-n-pentyloxyethyl)-phenyl, 4-(2-n-hexyloxyethyl)phenyl, 4-(2-cyclopropyloxy-ethyl)phenyl, 4-(2-cyclopropylmethoxy-ethyl)phenyl, 4-(2-cyclobutyloxyethyl)phenyl, 4-(2-cyclobutylmethoxy-ethyl)phenyl, 4-(2-cyclopentyloxy-ethyl)phenyl, 4-(2-cyclopentylmethoxyethyl)phenyl, 4-(2-cyclohexyloxy-ethyl)phenyl, 4-(2-cyclohexylmethoxy-ethyl)phenyl, 4-(3-methoxypropyl)phenyl, 4-(3-ethoxy-propyl)phenyl, 4-(3-n-propoxypropyl)phenyl, 4-(3-isopropoxypropyl)phenyl, 4-(3-n-butoxypropyl)phenyl, 4-(3-(2-methyl-n-propoxy)propyl)phenyl, 4-(3-n-pentyloxypropyl)phenyl, 4-(3-n-hexyloxypropyl)phenyl, 4-(3-cyclopropyloxypropyl)phenyl, 4-(3-cyclopropylmethoxy-propyl), 4-(3-cyclobutyloxy-propyl)phenyl, 4-(3-cyclobutylmethoxypropyl)phenyl, 4-(3-cyclopentyloxy-propyl)phenyl, 4-(3-cyclopentylmethoxy-propyl)phenyl, 4-(3-cyclohexyloxypropyl)phenyl, 4-(3-cyclohexylmethoxy-propyl)phenyl, 4-((2-methoxyethoxy)methyl)phenyl, 4-((2-ethoxyethoxy)methyl)phenyl, 4-((2-n-propoxyethoxy)methyl)phenyl, 4-((2-isopropoxyethoxy)methyl)phenyl, 4-((2-n-butoxyethoxy)methyl)phenyl, 4-((2-(2-methyl-n-propoxy)ethoxy)methyl)phenyl, 4-((2-n-pentyloxyethoxy)methyl)phenyl, 4-((2-n-hexyloxyethoxy)methyl)phenyl, 4-((2-cyclopropyloxyethoxy)methyl)phenyl, 4-((2-cyclopropylmethoxy-ethoxy)methyl)phenyl, 4-((2-cyclobutyloxyethoxy)-methyl)phenyl, 4-(( 2-cyclobutylmethoxy-ethoxy)methyl)-phenyl, 4-((2-cyclopentyloxyethoxy)methyl)phenyl, 4-((2-cyclopentylmethoxyethoxy)methyl)phenyl, 4-((2-cyclohexyloxyethoxy)methyl)phenyl, 4-((2-cyclohexylmethoxy-ethoxy)methyl)phenyl, 4-(2-(2-methoxyethoxy)-ethyl)phenyl, 4-(2-(2-ethoxyethoxy)ethyl)phenyl, 4-(2-(2-n-propoxyethoxy)ethyl)phenyl, 4-(2-(2-isopropoxyethoxy)ethyl)phenyl, 4-(2-(2-n-butoxyethoxy)ethyl)phenyl, 4-(2-(2-(2-methyl-n-propoxy)ethoxy)ethyl)phenyl, 4-(2-(2-n-pentyloxyethoxy)ethyl)phenyl, 4-(2-(2-n-hexyloxyethoxy)ethyl)phenyl, 4-(2-(2-cyclopropyloxyethoxy)-ethyl)phenyl, 4-(2-(2-cyclopropylmethoxyethoxy)ethyl)-phenyl, 4-(2-(2-cyclobutyloxyethoxy)ethyl)phenyl, 4-(2-(2-cyclobutylmethoxyethoxy)ethyl)phenyl, 4-(2-(2-cyclopentyloxyethoxy)ethyl)phenyl, 4-(2-(2-cyclopentylmethoxyethoxy)ethyl)phenyl, 4-(2-(2-cyclohexyloxyethoxy)ethyl)phenyl, 4-(2-(2-cyclohexylmethoxyethoxy)ethyl)phenyl, 4-(3-(2-methoxyethoxy)propyl)phenyl, 4-(3-(2-ethoxyethoxy)propyl)phenyl, 4-(3-(2-n-propoxyethoxy)propyl)phenyl, 4-(3-(2-isopropoxyethoxy)propyl)phenyl, 4-(3-(2-n-butoxyethoxy)propyl)phenyl, 4-(3-(2-(2-methyl-n-propoxy)ethoxy)propyl)phenyl, 4-(3-(2-n-pentyloxyethoxy)propyl)phenyl, 4-(3-(2-n-hexyloxyethoxy)-propyl)phenyl, 4-(3-(2-cyclopropyloxyethoxy)propyl)phenyl, 4-(3-(2-cyclopropylmethoxyethoxy)propyl)phenyl, 4-(3-(2-cyclobutyloxyethoxy)propyl)phenyl, 4-(3-(2-cyclobutylmethoxyethoxy)propyl)phenyl, 4-(3-(2-cyclopentyloxy-ethoxy)propyl)phenyl, 4-(3-(2-cyclopentylmethoxyethoxy)-propyl)phenyl, 4-(3-(2-cyclohexyloxyethoxy)propyl)phenyl, 4-(3-(2-cyclohexylmethoxyethoxy)propyl)phenyl, 4-((2-phenoxyethoxy)methyl)phenyl, 4-(2-(2-phenoxyethoxy)ethyl)phenyl, 4-(3-(2-phenoxyethoxy)propyl)phenyl, 2-chloro-3-methyl-phenyl, 2-chloro-4-methyl-phenyl, 2-chloro-5-methyl-phenyl, 2-chloro-6-methyl-phenyl, 3-chloro-2-methyl-phenyl, 3-chloro-4-methyl-phenyl, 3-chloro-5-methyl-phenyl, 3-chloro-6-methyl-phenyl, 4-chloro-2-methyl-phenyl, 4-chloro-3-methyl-phenyl, 2-fluoro-3-methyl-phenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 2-fluoro-6-methyl-phenyl, 3-fluoro-2-methyl-phenyl, 3-fluoro-4-methyl-phenyl, 3-fluoro-5-methyl-phenyl, 3-fluoro-6-methyl-phenyl, 4-fluoro-2-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 2-bromo-3-methyl-phenyl, 2-bromo-4-methyl-phenyl, 2-bromo-5-methyl-phenyl, 2-bromo-6-methyl-phenyl, 3-bromo-2-methyl-phenyl, 3-bromo-4-methyl-phenyl, 3-bromo-5-methyl-phenyl, 3-bromo-6-methyl-phenyl, 4-bromo-2-methyl-phenyl or 4-bromo-3-methyl-phenyl group, A may represent an ethylene, n-propylene, n-butylene, .alpha.-methyl-ethylene, .alpha.-methyl-n-propylene, .alpha.-methyl-n-butylene, .alpha.,.alpha.-dimethyl-ethylene, .alpha.,.alpha.-dimethyl-n-propylene, .alpha.,.alpha.-dimethyl-n-butylene, .alpha.,.alpha.-diethylethylene, .alpha.,.alpha.-diethyl-n-propylene, .alpha.,.alpha.-diethyl-n-butylene, .alpha.-methyl-.alpha.-ethyl-ethylene, .alpha.-methyl-.alpha.-ethyl-n-propylene, .alpha.-methyl-.alpha.-ethyl-n-butylene, .alpha.-methyl-.alpha.-n-propyl-ethylene, .alpha.-methyl-.alpha.-n-propyl-n-propylene or .alpha.-ethyl-.alpha.-n-propyl-n-propylene group and R.sub.2 may represent a 3-(3(2H)-pyridazinon-6-yl)phenoxy, 4-(3-(2H)-pyridazinon-6-yl)phenoxy, 3-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenoxy, 3-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenoxy, 3-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenyl, 3-(4,5-dihydro-5-isopropyl-(3(2H)-pyridazinon-6-yl)phenoxy, 4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenoxy, 4-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenoxy, 4-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenoxy, 4-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-3-(3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-4-(3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-3-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-3-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-3-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-3-(4,5-dihydro-5-isopropyl-3 (2H)-pyridazinon-6-yl)phenoxy, 2-methyl-4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-4-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-4-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-methyl-4-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-chloro-4-(3(2H)-pyridazinon-6-yl)phenoxy, 2-chloro-4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenoxy, 2-chloro-4-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-chloro-4-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenoxy, 2-chloro-4-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)phenoxy, 5-(3(2H)-pyridazinon-6-yl)-benzoxazol-(2)-imino, 5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)benzoxazol-(2)-imino, 5-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)benzoxazol-(2)-imino, 5-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)benzoxazol-(2)-imino, 5-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)benzoxazol-(2)-imino, 5-(3(2H)-pyridazinon-6-yl)benzimidazol-1-yl, 5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)benzimidazol-1-yl, 5-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)benzimidazol-1-yl, 5-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)benzimidazol-1-yl, 5-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)-benzimidazol-1-yl, 5-(3(2H)-pyridazinon-6-yl)-benzimidazol-2-yl, 5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-benzimidazol-2-yl, 5-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)benzimidazol-2-yl, 5-(4,5-dihydro-5-ethyl- 3(2H)-pyridazinon-6-yl)benzimidazol-2-yl, 5-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)benzimidazol-2-yl, 5-(3(2H)-pyridazinon-6-yl)-2-methyl-benzimidazol-1-yl, 5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-2-methylbenzimidazol-1-yl, 5-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)-2-methyl-benzimidazol-1-yl, 5-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)-2-methylbenzimidazol-1-yl, 5-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)-2-methyl-benzimidazol-1-yl, 5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)-2-hydroxy-benzimidazol-1-yl, 5-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)-2-hydroxy-benzimidazol-1-yl, 5-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)-2-hydroxy-benzimidazol-1-yl, 5-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)-2-hydroxy-benzimidazol-1-yl, 5-(3(2H)-pyridazinon-6-yl)benztriazol-1-yl, 5-(4,5-dihydro-3(2H)-pyridazinon-6-yl)benztriazol-1-yl, 5-(4,5-dihydro-5-methyl-3 (2H)-pyridazinon-6-yl)benztriazol-1-yl, 5-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)benztriazol-1-yl, 5-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)benztriazol-1-yl, 4-(3(2H)-pyridazinon-6-yl)phenylsulphonyl, 4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenylsulphonyl, 4-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenylsulphonyl, 4-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenylsulphonyl, 4-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)phenylsulphonyl, 4-(3(2H)-pyridazinon-6-yl)phenyl, 4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenyl, 4-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenyl, 4-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenyl, 4-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)phenyl, 4-(3-(2H)-pyridazinon-6-yl)phenylmethylcarbonylamino, 4-(4,5-dihydro-3(2H)-pyridazinon-6-yl)phenylmethylcarbonylamino, 4-(4,5-dihydro-5-methyl-3(2H)-pyridazinon-6-yl)phenylmethylcarbonylamino, 4-(4,5-dihydro-5-ethyl-3(2H)-pyridazinon-6-yl)phenylmethylcarbonylamino or 4-(4,5-dihydro-5-isopropyl-3(2H)-pyridazinon-6-yl)phenylmethylcarbonylamino group.

Preferred compounds of the above formula are those wherein

R.sub.1 represents a naphthyl, 3,4-dihydro-2-hydroxy-quinolin-5-yl, allylphenyl, allyloxyphenyl, cyanophenyl, aminocarbonylmethyl-phenyl or chloro-methylphenyl group, an alkylsulphonyloxyphenyl group with 1 to 4 carbon atoms in the alkyl moiety or a phenyl group substituted in the 4-position by a 2-alkoxyethyl, 2-cycloalkylmethoxy-ethyl, 2-alkoxy-ethoxymethyl, 2-cycloalkyloxy-ethoxymethyl, 2-cycloalkylmethoxy-ethoxymethyl or 2-phenoxy-ethoxymethyl group, wherein the alkoxy moiety may contain 1 to 4 carbon atoms and the cycloalkyl or cycloalkyloxy part may contain 3 or 4 carbon atoms, A represents a C.sub.2-4 n-alkylene group optionally mono- or disubstituted by a methyl group in the .alpha.-position with respect to the adjacent nitrogen atom and R.sub.2 represents a group of the formula ##STR3## wherein R.sub.3 represents a hydrogen atom or a methyl group, R.sub.4 and R.sub.5 each represent a hydrogen atom or together represent another carbon-carbon bond and B represents a group of the formula ##STR4## wherein R.sub.6 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl group, Y represents a bond, an oxygen atom or an --NH--CO--CH.sub.2 -- group, the --CH.sub.2 -- moiety being attached to the phenyl nucleus, X.sub.1 represents a nitrogen atom or a methyne group optionally substituted by a hydroxy or methyl group, X.sub.2 represents an oxygen atom or an imino group and Y.sub.2 represents a bond or an imino group, the tautomers, enantiomers and acid addition salts thereof.

Particularly preferred compounds of formula I above are however those wherein

R.sub.1 represents a naphthyl, 3,4-dihydro-2-hydroxy-quinolin-5-yl, allylphenyl, allyloxyphenyl or chloro-methylphenyl group or a phenyl group substituted in the 4-position by a 2-alkoxyethyl, 2-cycloalkylmethoxyethyl, 2-alkoxyethoxymethyl, 2-cycloalkyloxyethoxymethyl, 2-cycloalkylmethoxyethoxymethyl or 2-phenoxyethoxymethyl group, wherein the alkoxy moiety may contain 1 to 3 carbon atoms and the cycloalkyl or cycloalkyloxy moiety may contain 3 or 4 carbon atoms, A represents a C.sub.2-4 n-alkylene group optionally disubstituted by methyl groups in the .alpha.-position with respect to the adjacent nitrogen atom and R.sub.2 represents a group of the formula ##STR5## wherein R.sub.3 represents a hydrogen atom or a methyl group, R.sub.4 and R.sub.5 each represent a hydrogen atom or together represent another carbon-carbon bond and B represents a group of formula ##STR6## wherein R.sub.6 represents a methyl group or a hydrogen or chlorine atom, Y.sub.1 represents an oxygen atom, X.sub.1 represents a methyne group, X.sub.2 represents an oxygen atom or an imino group and Y.sub.2 represents a bond or an imino group, the tautomers, enantiomers and acid addition salts thereof.

According to the invention the compounds of formula I are obtained by reacting a compound of formula

R.sub.1 --O--CH.sub.2 --CHOH--CH.sub.2 --Z (II) (wherein R.sub.1 is as hereinbefore defined and Z represents a nucleophilic leaving group such as a halogen atom or a sulphonic acid ester group, e.g. a chlorine, bromine or iodine atom or a methylsulphonyloxy or p-toluenesulphonyloxy group, or Z together with the hydrogen atom of the adjacent hydroxy group represents an oxygen-carbon bond) with an amine of formula NH.sub.2 --A--R.sub.2 (III) wherein A and R.sub.2 are as hereinbefore defined.

The reaction is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxan, benzene, toluene, dimethylformamide or dimethylsulphoxide, optionally in the presence of an acid binding agent such as triethylamine or pyridine, which may simultaneously be used as solvent, at temperatures between 0.degree. and 100.degree. C., but preferably at temperatures between 25.degree. and 80.degree. C.

As the compounds of formula I have at least one chiral centre, they may be resolved by conventional methods into their diastereoisomers, for example by column chromatography, and into their enantiomers, for example by column chromatography on a chiral phase or by crystallisation with optically active acids, e.g. with D- or L-monomethyl tartaric acid, D- or L-diacetyl tartaric acid, D- or L-tartaric acid, D- or L-lactic acid or D- or L-camphoric acid.

Furthermore, the compounds of formula I obtained may if desired be converted into the acid addition salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of such acids include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic acid.

The compounds of formulae II and III used as starting materials are obtained using methods known from the literature.

Thus, for example, a compound of formula II is obtained by reacting a corresponding phenol with a corresponding epihalohydrin or with a 2-hydroxypropane substituted appropriately in the 1- and 3-positions.

A compound of formula III is obtained by cleavage of an amine of formula III protected by a suitable protecting group, the starting compound required being obtained either by reacting a corresponding 4-oxobutyric acid with hydrazine, by reacting a corresponding 2-methylthio-benzoxazole (see EP-A-34743) with a corresponding amine or by alkylation of a corresponding phenol, thiophenol, benzimidazole or benzotriazole, the thio compound thus obtained subsequently being converted into the corresponding sulphone by oxidation.

As already mentioned hereinbefore, the new 2-hydroxy-n-propylamines of formula I, the tautomers, enantiomers and physiologically acceptable acid addition salts thereof have valuable pharmacological properties, particularly a simultaneous cardiotonic and .beta.-blocking activity.

The following compounds, for example:

A=6-[1-[2-[3-(4-(2-cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone, B=6-[1-[2-[3-(4-(2-cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone, C=6-[4-[2-[3-(4-(2-cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone, D=6-[4-[2-[3-(4-(2-cyclopropylmethoxyethyl)phenoxy)-2-hydroxy-propylamino]ethoxy]phenyl]-3(2H)-pyridazinone, E=6-[4-[2-[3-(4-(2-cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone, F=6-[4-[2-[3-(4-((2-isopropoxyethoxy)methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone, G=6-[4-[2-[3-(4-(2-isopropoxyethoxymethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-3(2H)-pyridazinone, H=6-[1-[3-[3-(4-(2-isobutoxyethyl)phenoxy)-2-hydroxypropylamino]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone, I=6-[1-[2-[3-(4-(2-isobutoxyethyl)phenoxy)-2-hydroxypropylamino]-2,2-dimethyl-ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone, K=6-[4-[3-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]propoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone, L=6-[4-[2-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone, M=6-[4-[2-[3-(4-(2-cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone, N=6-[4-[2-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone, O=6-[4-[3-[3-(4-(2-cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone, P=6-[4-[3-[3-(4-(2-cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone and Q=6-[4-[2-[3-(4-(2-isopropoxyethoxy-methyl)phenoxy)-2-hydroxy-propylamino]ethoxy]-3-methyl-phenyl]-3(2H)-pyridazinone were investigated for their biological properties as follows:

1. Affinity for .beta.-adreno recectors

The inhibitory effect on the binding of .sup.3 H-CGP 12177 was tested on receptor preparations from rat hearts (.beta..sub.1) and rat lungs (.beta..sub.2). The binding assay was carried out with some modifications according to the method of Dammgen et al. (Drug. Res. 35: 383-390 (1985)). The incubation mixture contained aliquots of the membrane preparation in Tris buffer, increasing concentrations of the potential antagonist as well as 200 pM .sup.3 H-CGP 12177. The bound and free radioligands were separated after the incubation period by rapid filtration through glass fibre filters. The filter-bound radioactivity was determined in a .beta. counter with a counting yield of about 52%. The non-specific binding was determined in the presence of 10.sup.-5 M propranolol.

______________________________________ IC.sub.50 (nM)Substance .beta..sub.1 .beta..sub.2______________________________________A 26 940B 34 2300C 29 1200D 22 1000E 15 1100F 24 7200G 53 4400H 10 19I 12 65K 10 350L 7.6 600M 0.5 100N 2.6 520O 59 66P 6.0 220Q 2.0 210______________________________________

Cardiotonic effect with antiadrenergic activity

Guinea-pigs (Dunkin-Hartley-Pirbright, male, 450-600 g) were anaesthetised with hexobarbital-sodium (150 mg/kg i.p.). After the animals had become unconscious, a tracheal cannula was inserted and the animals were pitched (van Meel, J. Pharmacol. Methods 31 (1): 1-11 (1985)). The animals were then immediately artificially respirated using a breathing pump. The left ventricular pressure (LVP) was measured with a Millar PR-249 catheter-tip manometer inserted into the left ventricle through the left carotid artery. This pressure signal was differentiated electronically (LV-dP/dtmax) and used as a parameter for inotropia. The arterial blood pressure was recorded by a cannula in the right carotid artery using a Bell & Howell pressure recorder. The heart rate was also measured. The substances were administered through a cannula in the jugular vein.

The test substances were administered to three animals cumulatively in four doses (0.1 to 3 mg/kg) and the effects on blood pressure, heart rate and LV-dP/dtmax were measured. Three minutes after the last dose of the test substance, isoprenalin was administered intravenously in increasing doses. In this way, a cumulative dose-activity correlation was obtained for isoprenalin in the presence of the test substance. The parameters measured were the increase in heart rate and the LV-dP/dtmax. These dose-activity curves were compared with standard curves for isoprenalin without the test substances. The shift to the right of the dose-activity curves for isoprenalin brought about by the test substances were determined graphically and corresponding pA2 values for the test substances were calculated. (see Tenakin in "Pharmacologic Analysis of Drug Receptor Interaction", Rawen Press 1987, pages 211-212).

The Table shows the effects of the test substances after a dose of 3 mg/kg i.v. on the LV-dP/dtmax and heart rate and the calculated pA2 values for the test substances as against the inotropic (pA2 inotropia) and heart rate-increasing (pA2 heart rate) activity of isoprenalin.

The Table which follows contains the averages from 2 to 3 tests:

______________________________________ Effect on Effects on heart rateSub- LV-dP/dtmax in beats pA2 pA2stance % increase per minute inotropia heart rate______________________________________A +50 -23 6.30 8.20B +51 -47 6.83 6.95C +25 -51 6.76 7.22D +51 -49 6.67 7.24E +49 -71 6.19 7.23F +37 -94 7.14 6.96G +38 -36 6.32 6.38H +10 -90 8.28 >9.0I +58 -59 7.17 7.89K +11 -121 6.56 7.52L +66 -51 6.23 6.77M +51 -64 7.05 8.20N +34 -94 7.34 8.34O +38 -116 6.44 7.70P +69 -61 5.31 6.45______________________________________

The compounds mentioned above show no negative inotropic effects up to a dosage of 4.4 mg/kg i.v., nor were any cardiac rhythm disorders observed. The new compounds are therefore well tolerated in therapeutic doses.

In view of their pharmacological properties the new compounds and the physiologically acceptable acid addition salts thereof are suitable for the treatment of myocardial ischaemia (angina), for treating cardiac insufficiency, for preventing the progression of cardiac insufficiency after myocardial infarct and for treating hypertension.

The dosage required to achieve such an effect will conveniently be 20 to 100 mg, preferably 30 to 75 mg, for intravenous administration, and 50 to 200 mg, preferably 75 to 150 mg, for oral administration, taken once or twice daily. For this purpose, the compounds prepared according to the invention, optionally combined with other active substances, may be formulated together with one or more inert conventional carriers and/or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, into the usual galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The Examples which follow are intended to illustrate the invention:

EXAMPLE I

1-(1-Naphthyloxy)-2,3-epoxypropane

14.1 g (100 mmol) of 1-naphthol and 11.2 g (100 mmol) of potassium tert.butoxide are dissolved at 50.degree. C. in 50 ml of dimethylsulphoxide. Then, at ambient temperature, 15.0 g (110 mmol) of epibromohydrin are added dropwise, with stirring, and the mixture gradually warms up to about 50.degree. C. After two hours, 200 ml of water are added and the mixture is extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate and evaporated down. The crude product thus obtained is purified by vacuum distillation

(b.p..sub.0.1 mm : 108.degree.-110.degree. C.).

Yield: 16.1 g (80% of theory).

The following epoxides are obtained analogously:

1-(4-aminocarbonylmethyl-phenoxy)-2,3-epoxypropane R.sub.F value: 0.68 (silica gel, dichloromethane/methanol=9:1).

Melting point: 172.degree.-173.degree. C.

(3,4-dihydroquinolin-2-on-5-yl)-2,3-epoxy-1-propylether R.sub.F value: 0.66 (silica gel, dichloromethane/methanol=9:1).

1-(2-allyloxy-phenoxy)-2,3-epoxypropane R.sub.F value: 0.88 (silica gel, dichloromethane).

1-(2-cyano-phenoxy)-2,3-epoxypropane R.sub.F value: 0.86 (silica gel, dichloromethane/methanol=9:1).

1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane R.sub.F value: 0.85 (silica gel, dichloromethane).

1-(2-allyl-phenoxy)-2,3-epoxypropane R.sub.F value: 0.92 (silica gel, dichloromethane).

1-[4-(2-cyclobutylmethoxy-ethyl)phenoxy]-2,3-epoxypropane R.sub.F value: 0.43 (silica gel, dichloromethane/methanol=50:1).

1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane R.sub.F value: 0.62 (silica gel, dichloromethane/methanol=19:1).

1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane R.sub.F value: 0.31 (silica gel, dichloromethane).

1-(4-methanesulphonyloxy-phenoxy)-2,3-epoxypropane R.sub.F value: 0.66 (silica gel, dichloromethane/ethanol=50:1).

1-(4-butanesulphonyloxy-phenoxy)-2,3-epoxypropane R.sub.F value: 0.42 (silica gel, dichloromethane/ethanol=50:1).

1-(4-isopropanesulphonyloxy-phenoxy)-2,3-epoxypropane R.sub.F value: 0.38 (silica gel, dichloromethane/ethanol=50:1).

1-(4-(2-isopropoxyethoxy)methyl-phenoxy)-2,3-epoxypropane R.sub.F value: 0.68 (silica gel, dichloromethane/ethanol=19:1).

1-[4-(2-phenoxyethoxymethyl)phenoxy]-2,3-epoxypropane R.sub.f value: 0.70 (silica gel, dichloromethane/ethanol=19:1).

1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane R.sub.f value: 0.69 (silica gel, dichloromethane/ethanol=19:1). 1-[4-(2-methoxyethoxy-methyl)phenoxy]-2,3-epoxypropane R.sub.f value: 0.78 (silica gel, dichloromethane/methanol=30:1).

EXAMPLE II

6-[4-(3-Phthalimidopropylsulphonyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

34 g (78.2 mmol) of methyl 4-oxo-4-[4-(3-phthalimidopropylsulphonyl)phenyl]butyrate are refluxed for two hours in a solution of 6 ml (120 mmol) of hydrazine hydrate (99%) in 350 ml of glacial acetic acid. Then the mixture is poured onto 2.5 liters of ice water, the product precipitated is suction filtered and dried in a circulating air dryer at 80.degree. C.

Yield: 96.5% of theory.

Melting point: 205.degree.-207.degree. C.

EXAMPLE III

6-[1-(2-Acetylaminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone

14.2 g (49.4 mmol) of 6-(3-amino-4-acetylaminoethylaminophenyl)-3(2H)-pyridazinone are refluxed for one hour in 60 ml of formic acid. Then the excess formic acid is distilled off in vacuo, the residue is mixed with 50 ml of ice water and then adjusted to pH 8-9 with concentrated ammonia solution. The product precipitated is suction filtered, washed with about 50 ml of cold water, then with 50 ml of ether and dried.

Yield: 54% of theory.

Melting point: >250.degree. C.

EXAMPLE IV

6-[1-(2-Acetaminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

To a solution of 580 mg (2.0 mmol) of 6-(3-amino-4-acetylaminoethylamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone in 50 ml of dimethylformamide, 325 mg (2.0 mmol) of carbonyldiimidazole are added at 50.degree. C. After 45 minutes at 50.degree. C. the mixture is evaporated to dryness and the residue is mixed with 10 ml of water. The product precipitated is suction filtered, washed with 5 ml of water and dried.

Yield: 79% of theory.

Melting point: >250.degree. C.

EXAMPLE V

6-[1-(2-Acetaminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

15.98 g (55.3 mmol) of 6-(3-amino-4-acetaminoethylamino-phenyl)-4,5-dihydro-3(2H)-pyridazinone are dissolved in 300 ml of 2N sulphuric acid, then cooled to 2.degree.-5.degree. C. and a solution of 4.2 g (61 mmol) of sodium nitrite in 70 ml of water is slowly added dropwise with stirring. After about one hour the cooling bath is removed and the mixture is stirred for a further hour at ambient temperature. The solids precipitated are suction filtered, stirred into 100 ml of a 5% sodium bicarbonate solution and suction filtered again after 10 minutes.

Yield: 49% of theory.

Melting point: 255.degree.-257.degree. C.

EXAMPLE VI

5-Methyl-6-[2-(2-phthalimidoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

120 g (286 mmol) of 5-methyl-6-[3-amino-4-(2-phthalimidopropionylamido)phenyl]-4,5-dihydro-3(2H)-pyridazinone are refluxed for one hour in 1.2 liters of glacial acetic acid. The mixture is then stirred into 1 liter of water and the impurities precipitated are filtered off. Then the filtrate is evaporated to dryness using a rotary evaporator and the solid residue is triturated with 200 ml of 2N ammonia solution. Then the solid material is suction filtered and recrystallised from methanol.

Yield: 71% of theory.

Melting point: 148.degree.-150.degree. C.

EXAMPLE VII

5-Methyl-6-[2-(4-aminobutylamino)benzoxazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

4.1 g (15.0 mmol) of 5-methyl-6-(2-methylthiobenzoxazol-5-yl)-4,5-dihydro-3(2H)-pyridazinone and 15 ml of 1,4-diaminobutane are heated to 60.degree. C. for 45 minutes, then stirred into 200 ml of water and left to crystallise at ambient temperature. After about 30 minutes the product is suction filtered, washed with about 50 ml of water and dried at 60.degree. C. in a circulating air dryer.

Yield: 89% of theory.

Melting point: 184.degree.-187.degree. C.

EXAMPLE VIII

6-[4-((2-tert.Butoxycarbonylamino)ethylaminocarbonylmethyl)-phenyl]-4,5-dihydro-3(2H)-pyridazinone

2.3 g (10.0 mmol) of 6-(4-carboxymethyl-phenyl)-4,5-dihydro-3(2H)-pyridazinone are dissolved in 30 ml of dimethylformamide, 1.8 g (11.0 mmol) of carbonyldiimidazole are added and the mixture is stirred for 30 minutes at ambient temperature. Then 1.2 g (7.3 mmol) of 2-tert.butoxycarbonylaminoethylamine are added and the mixture is stirred for a further hour. The reaction mixture is then stirred into about 1 liter of water and left to crystallise overnight. The product precipitated is suction filtered, washed with about 30 ml of water and dried in a circulating air dryer.

Yield: 52% of theory.

Melting point: 226.degree.-228.degree. C.

EXAMPLE IX

6-[4-((2-Aminoethyl)aminocarbonylmethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

A mixture of 6.8 g (18 mmol) of 6-[4-((2-tert.butoxycarbonylaminoethyl)aminocarbonylmethyl)phenyl]4,5-dihydro-3(2H)-pyridazinone, 25 ml of ethanol and 50 ml of 2N hydrochloric acid is refluxed for about 2 minutes, then the ethanol is distilled off, the aqueous solution is made alkaline with concentrated ammonia solution and finally the precipitate is suction filtered. This product is purified by chromatography on 200 g of silica gel (eluant: dichloromethane/methanol/ammonia=70:30:1).

Yield: 69% of theory.

Melting point: 193.degree.-196.degree. C.

EXAMPLE X

6-[1-(2-Aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone

8.0 g (26.0 mmol) of 6-[1-(2-acetylaminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone are refluxed for 4 hours in 80 ml of 5N sodium hydroxide solution. After cooling the mixture is adjusted to pH 8-9 with concentrated hydrochloric acid, the product precipitated is suction filtered and dried in a vacuum drying cupboard. The crude product obtained is used again without any further purification.

Yield: 99% of theory, amorphous.

EXAMPLE XI

6-[4-(3-Aminopropylsulphonyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

30.0 g (70.7 mmol) of 6-[4-(3-phthalimidopropylsulphonyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone are stirred vigorously for two hours at ambient temperature in a mixture of 200 ml of toluene and 300 ml of 40% aqueous methylamine solution. Then the solid matter precipitated is suction filtered, washed successively with 100 ml of water, 50 ml of acetone and 50 ml of diethylether and then dried over phosphorus pentoxide in a vacuum drying cupboard.

Yield: 20.2 g (97% of theory).

Melting point: from 100.degree. C. (decomp.).

EXAMPLE XII

6-[4-(2-Aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone

To a mixture of 24.7 g (0.1 mol) of 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone in 600 ml of glacial acetic acid and 9.8 g (0.1 mol) of concentrated sulphuric acid, 19.2 g (0.12 mol) of bromine dissolved in 20 ml of glacial acetic acid are slowly added dropwise, with stirring. After stirring for 1 hour at 70.degree. C. the mixture is cooled, stirred for a further 12 hours at 20.degree. C., then the yellow precipitate is suction filtered and washed with acetone. In order to liberate the base it is suspended in 500 ml of water and made alkaline with concentrated ammonia. The product precipitated is suction filtered and dried.

Yield: 20.5 g (84% of theory), amorphous.

R.sub.f value: 0.30 (silica gel, dichloromethane/ethanol=9:1).

C.sub.13 H.sub.15 N.sub.3 O.sub.2 (245.28).

______________________________________Calculated: C 63.66 H 6.16 N 17.13Found: 63.83 6.01 17.05______________________________________

EXAMPLE 1

6-[4-[2-[3-(4-(2-Cyclopropylmethoxyethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-3(2H)-pyridazinone

A solution of 1.5 g (6 mmol) of 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 1.2 g (5 mmol) of 6-[4-(2-aminoethoxy)phenyl-3(2H)-pyridazinone in 100 ml of absolute ethanol is refluxed for seven hours. The mixture is then evaporated to dryness and the crude product thus obtained is purified by chromatography over 200 g of silica gel (dichloromethane/methanol=9:1).

Yield: 950 mg (39.6% of theory).

Melting point: 134.degree.-135.degree. C.

C.sub.27 H.sub.33 N.sub.3 O.sub.5 (479.58).

______________________________________Calculated: C 67.62 H 6.94 N 8.76Found: 67.46 6.94 8.58______________________________________

EXAMPLE 2

6-[4-[2-[3-(4-(2-Isopropoxyethoxymethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-3(2H)-pyridazinone.

Melting point: 106.degree.-108.degree. C.

C.sub.27 H.sub.35 N.sub.3 O.sub.6 (497.6).

______________________________________Calculated: C 65.17 H 7.09 N 8.44Found: 64.95 7.03 8.44______________________________________

EXAMPLE 3

6-[4-[2-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 24% of theory.

Melting point: 119.degree.-120.degree. C.

C.sub.28 H.sub.39 N.sub.3 O.sub.5 (497.6).

______________________________________Calculated: C 67.58 H 7.90 N 8.44Found: 67.56 7.88 8.64______________________________________

EXAMPLE 4

6-[4-[2-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6- [4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 20% of theory.

Melting point: 98.degree.-99.degree. C.

C.sub.28 H.sub.37 N.sub.3 O.sub.5 (495.6).

______________________________________Calculated: C 67.86 H 7.53 N 8.48Found: 67.83 7.61 8.55______________________________________

EXAMPLE 5

6-[4-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 16% of theory.

Melting point: 95.degree.-96.degree. C.

C.sub.28 H.sub.39 N.sub.3 O.sub.6 (513.6).

______________________________________Calculated: C 65.48 H 7.65 N 8.18Found: 65.31 7.75 8.24______________________________________

EXAMPLE 6

6-[4-[3-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 7% of theory.

Melting point: 142.degree.-145.degree. C.

C.sub.29 H.sub.39 N.sub.3 O.sub.5 (509.6).

______________________________________Calculated: C 68.35 H 7.71 N 8.24Found: 68.13 7.62 8.10______________________________________

EXAMPLE 7

6-[4-[3-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 21% of theory.

Melting point: 149.degree.-152.degree. C.

C.sub.30 H.sub.41 N.sub.3 O.sub.5 (523.7).

______________________________________Calculated: C 68.81 H 7.89 N 8.02Found: 68.72 7.71 7.73______________________________________

EXAMPLE 8

6-[4-[3-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 18% of theory.

Melting point: 145.degree.-147.degree. C.

C.sub.29 H.sub.41 N.sub.3 O.sub.5 (511.7).

______________________________________Calculated: C 68.08 H 8.08 N 8.21Found: 67.82 8.20 8.19______________________________________

EXAMPLE 9

6-[4-[3-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 21% of theory, amorphous.

C.sub.29 H.sub.41 N.sub.3 O.sub.6 (527.7).

______________________________________Calculated: C 66.01 H 7.83 N 7.96Found: 65.88 7.89 7.78______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.18 (d,6H); 2.13 (m,2H); 2.21 (s,3H); 2.56 (t,2H); 2.97 (m,6H); 3.60 (m,5H); 3.90-4.90 (m,5H); 4.50 (s,2H); 6.88 (m,3H); 7.27 (m,2H); 7.50 (m,2H) ppm.

EXAMPLE 10

6-[4-[3-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 25% of theory.

Melting point: 120.degree.-122.degree. C.

C.sub.29 H.sub.38 ClN.sub.3 O.sub.5 (544.1).

______________________________________Calculated: C 64.02 H 7.04 N 7.72 Cl 6.52Found: 63.88 6.87 7.82 6.82______________________________________

EXAMPLE 11

6-[4-[3-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 33% of theory.

Melting point: 118.degree.-120.degree. C.

C.sub.28 H.sub.36 ClN.sub.3 O.sub.5 (530.1).

______________________________________Calculated: C 63.44 H 6.85 N 7.93 Cl 6.69Found: 63.34 6.83 7.95 6.91______________________________________

EXAMPLE 12

6-[4-[3-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]propoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 15% of theory.

Melting point: 187.degree.-189.degree. C.

C.sub.28 H.sub.38 ClN.sub.3 O.sub.6 .times.HCL (584.6).

______________________________________Calculated: C 57.52 H 6.72 N 7.19 Cl 12.13Found: 57.44 6.59 7.14 12.16______________________________________

EXAMPLE 13

6-[4-[2-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 27% of theory.

Melting point: 128.degree.-130.degree. C.

C.sub.28 H.sub.36 ClN.sub.3 O.sub.5 (530.1).

______________________________________Calculated: C 63.44 H 6.85 N 7.93 Cl 6.69Found: 63.52 6.71 8.02 6.89______________________________________

EXAMPLE 14

6-[4-[2-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 33% of theory.

Melting point: 127.degree.-129.degree. C.

C.sub.27 H.sub.36 ClN.sub.3 O.sub.5 (518.1).

______________________________________Calculated: C 62.59 H 7.00 N 8.11 Cl 6.84Found: 62.46 7.02 8.14 7.06______________________________________

EXAMPLE 15

6-[4-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 19% of theory.

Melting point: 96.degree.-99.degree. C.

C.sub.27 H.sub.36 ClN.sub.3 O.sub.6 (534.1).

______________________________________Calculated: C 60.71 H 6.79 N 7.87 Cl 6.64Found: 60.59 6.90 8.10 6.45______________________________________

EXAMPLE 16

6-[4-[2-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 34% of theory, amorphous.

C.sub.26 H.sub.29 N.sub.3 O.sub.4 (447.5).

______________________________________Calculated: C 69.78 H 6.53 N 9.39Found: 69.54 6.44 9.35______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.42 (dd,1H); 2.71 (dd,1H); 2.9-3.2 (m,4H); 3.3-3.45 (m,1H); 4.1-4.4 (m,6H); 6.8-7.0 (m,3H); 7.3-7.6 (m,4H); 7.65-7.85 (m,3H); 8.25 (m,1H) ppm.

EXAMPLE 17

6-[4-[2-[3-(2-Chloro-5-methyl-phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 37% of theory, amorphous.

C.sub.23 H.sub.28 ClN.sub.3 O.sub.4 (445.9).

______________________________________Calculated: C 61.95 H 6.33 N 9.42 Cl 7.95Found: 61.84 6.39 9.45 7.96______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.31 (s,3H); 2.40 (dd,1H); 2.70 (dd, 1H); 2.85-3.20 (m,4H); 3.86 (m,1H); 3.95-4.20 (m,5H); 6.75 (m,2H); 6.95 (d,2H); 7.20 (d,1H); 7.70 (d,2H) ppm.

EXAMPLE 18

6-[4-[2-[3-(2-Cyano-phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-cyano- phenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 23% of theory, amorphous.

C.sub.23 H.sub.26 N.sub.4 O.sub.4 (422.5).

______________________________________Calculated: C 65.39 H 6.20 N 13.26Found: 65.28 6.32 13.13______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.42 (dd,1H); 2.72 (dd,1H); 2.85-3.15 (m,4H); 3.37 (m,1H); 4.05-4.25 (m,5H); 6.90-7.10 (m,4H); 7.90-7.80 (m,4H) ppm.

EXAMPLE 19

6-[4-[2-[3-(2-Allyloxy-phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 39% of theory, amorphous.

C.sub.25 H.sub.31 N.sub.3 O.sub.5 (453.5).

______________________________________Calculated: C 66.21 H 6.89 N 9.26Found: 65.92 7.00 9.17______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.42 (dd,1H); 2.72 (dd,1H); 2.90 (m,2H); 3.10 (t,2H); 3.38 (m,1H); 3.95-4.20 (m,5H); 4.60 (m,2H) 5.25-5.50 (m,2H); 6.10 (m,1H); 6.90-7.00 (m,6H); 7.70 (d,2H) ppm.

EXAMPLE 20

6-[4-[2-[3-(3,4-Dihydro-2-hydroxy-quinolin-5-yloxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 32% of theory, amorphous.

C.sub.25 H.sub.30 N.sub.4 O.sub.5 (466.5).

______________________________________Calculated: C 64.36 H 6.48 N 12.01Found: 64.12 6.61 11.85______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.23 (d,3H); 2.38-3.40 (m,11H); 3.95-4.20 (m,5H); 6.48 (d,1H); 6.60 (d,1H); 6.93 (d,2H); 7.11 (t,1H); 7.70 (d,2H) ppm.

EXAMPLE 21

6-[4-[2-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 27% of theory.

Melting point: 116.degree.-117.degree. C.

C.sub.28 H.sub.37 N.sub.3 O.sub.5 (495.6).

______________________________________Calculated: C 67.86 H 7.53 N 8.48Found: 67.69 7.51 8.44______________________________________

EXAMPLE 22

6-[4-[2-[3-(4-((2-Isopropoxyethoxy)methyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-((2-isopropoxyethoxy)methyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 25% of theory.

Melting point: 102.degree.-105.degree. C.

C.sub.27 H.sub.37 N.sub.3 O.sub.6 (499.6).

______________________________________Calculated: C 64.91 H 7.46 N 8.41Found: 64.89 7.64 8.46______________________________________

EXAMPLE 23

6-[4-[2-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 37% of theory.

Melting point: 121.degree.-122.degree. C.

C.sub.27 H.sub.35 N.sub.3 O.sub.5 (481.6).

______________________________________Calculated: C 67.34 H 7.33 N 8.73Found: 67.13 7.34 8.59______________________________________

EXAMPLE 24

6-[4-[3-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]propoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 19% of theory.

Melting point: from 113.degree. C. (sintering).

C.sub.28 H.sub.37 N.sub.3 O.sub.5 (495.6).

______________________________________Calculated: C 67.86 H 7.53 N 8.48Found: 67.85 7.44 8.29______________________________________

EXAMPLE 25

6-[3-[2-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 36% of theory, amorphous.

C.sub.26 H.sub.29 N.sub.3 O.sub.4 (447.5).

______________________________________CalcuIated: C 69.78 H 6.53 N 9.39Found: 69.58 6.55 9.33______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.42 (dd,1H); 2.70 (dd,1H), 2.90-3.40 (m,5H); 4.00-4.35 (m,5H); 6.85 (dd,1H); 6.98 (m,1H); 7.30-7.55 (m,7H); 7.80 (dd,1H); 8.35 (dd,1H) ppm.

EXAMPLE 26

6-[3-[2-[3-(2-Cyano-phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 27% of theory, amorphous.

C.sub.23 H.sub.26 N.sub.4 O.sub.4 (422.5).

______________________________________Calculated: C 65.39 H 6.20 N 13.26Found: 65.12 6.11 13.09______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.24 (d,3H); 2.40-3.40 (m,7H); 4.05-4.55 (m,5H); 7.00 (m,3H); 7.25-7.40 (m,3H); 7.45-7.60 (m,2H) ppm.

EXAMPLE 27

6-[3-[2-[3-(3,4-Dihydro-2-hydroxy-quinolin-5-yloxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 43% of theory, amorphous.

C.sub.25 H.sub.30 N.sub.4 O.sub.5 (466.5).

______________________________________Calculated: C 64.36 H 6.48 N 12.01Found: 64.35 6.57 11.78______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.40-3.40 (m,10H); 3.95-4.20 (m,5H); 6.50 (d,1H); 6.60 (d,1H); 6.98 (m,1H); 7.11 (t,1H); 7.30-7.42 (m,3H) ppm.

EXAMPLE 28

6-[3-[2-[3-(2-Chloro-5-methyl-phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 22% of theory, amorphous.

C.sub.23 H.sub.28 ClN.sub.3 O.sub.4 (445.9)

______________________________________Calculated: C 61.95 H 6.33 N 9.42 Cl 7.95Found: 61.78 6.21 9.33 8.03______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.31 (s,3H); 2.35-3.40 (m,7H); 4.00-4.25 (m,5H); 6.75 (m,2H); 6.99 (m,1H); 7.20 (d,1H); 7.33 (m,3H) ppm.

EXAMPLE 29

6-[3-[2-[3-(2-Allyloxy-phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 33% of theory, amorphous.

C.sub.25 N.sub.31 N.sub.3 O.sub.5 (453.5).

______________________________________Calculated: C 66.21 H 6.89 N 9.26Found: 66.05 6.98 9.11______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.22 (d,3H); 2.35-3.40 (m,7H); 3.95-4.20 (m,5H); 4.56 (m,2H); 5.20-5.50 (m,2H); 5.95-6.20 (m,1H); 6.80-7.00 (m,5H); 7.20-7.40 (m,3H) ppm.

EXAMPLE 30

6-[3-[2-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 25% of theory.

Melting point: 102.degree.-104.degree. C.

C.sub.27 H.sub.35 N.sub.3 O.sub.5 (481.6).

______________________________________Calculated: C 67.34 H 7.33 N 8.73Found: 67.15 7.21 8.77______________________________________

EXAMPLE 31

6-[3-[2-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 14% of theory.

Melting point: 109.degree.-110.degree. C.

C.sub.27 H.sub.37 N.sub.3 O.sub.5 (483.6).

______________________________________Calculated: C 67.06 H 7.71 N 8.69Found: 66.86 7.54 8.64______________________________________

EXAMPLE 32

6-[3-[2-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 19% of theory.

Melting point: 102.degree.-103.degree. C.

C.sub.28 H.sub.37 N.sub.3 O.sub.5 (495.6).

______________________________________Calculated: C 67.86 H 7.53 N 8.48Found: 67.60 7.38 8.32______________________________________

EXAMPLE 33

6-[3-[3-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]propoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(3-aminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 12% of theory.

Melting point: 182.degree.-183.degree. C.

C.sub.28 H.sub.37 N.sub.3 O.sub.5 (495.6).

______________________________________Calculated: C 67.86 H 7.53 N 8.48Found: 67.57 7.49 8.40______________________________________

EXAMPLE 34

6-[2-[4-[3-(2-Cyano-phenoxy)-2-hydroxypropylamino]butylamino]benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(4-aminobutylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 42% of theory, amorphous.

C.sub.26 H.sub.30 N.sub.6 O.sub.4 (490.6).

______________________________________Calculated: C 63.65 H 6.16 N 17.13Found: 63.76 6.18 16.98______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.25 (d,3H); 1.60-1.90 (m,4H); 2.45 (dd,1H); 2.65-3.10 (m,7H); 3.30-3.60 (m,3H); 4.05-4.30 (m,3H); 6.45-7.30 (m,3H); 7.40-7.60 (m,3H); 7.76 (s,1H) ppm.

EXAMPLE 35

6-[2-[4-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]butylamino]benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[2-(4-aminobutylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 41% of theory, amorphous.

C.sub.29 H.sub.33 N.sub.5 O.sub.4 (515.6).

______________________________________Calculated: C 67.55 H 6.45 N 13.58Found: 67.42 6.22 13.33______________________________________ .delta.=1.22 (d,3H); 1.62-1.40 (m,4H); 2.40 (dd,1H); 2.60-3.10 (m,5H); 3.31 (m,1H); 3.49 (t,2H); 4.12-4.40 (m,3H); 6.82 (dd,1H); 7.17-7.53 (m,6H); 7.70-7.84 (m,2H); 8.23 (dd,1H) ppm.

EXAMPLE 36

6-[2-[3-[3-(2-Cyano-phenoxy)-2-hydroxypropylamino]propylamino]benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(3-aminopropylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 47% of theory, amorphous.

C.sub.25 H.sub.28 N.sub.6 O.sub.4 (476.5).

______________________________________Calculated: C 63.01 H 5.92 N 17.64Found: 62.89 5.81 17.49______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.24 (d,3H); 1.84-2.00 (m,2H); 2.45 (dd,1H); 2.65-3.05 (m,7H); 3.38 (m,1H); 3.66 (t,2H); 4.10-4.30 (m,3H); 7.00 (m,2H); 7.20 (d,1H); 7.38-7.60 (m,3H); 7.88 (s,1H) ppm.

EXAMPLE 37

6-[2-[3-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]propylamino]benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[2-(3-aminopropylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 22% of theory, amorphous.

C.sub.28 H.sub.31 N.sub.5 O.sub.4 (501.6).

______________________________________Calculated: C 67.05 H 6.23 N 13.96Found: 66.91 6.11 14.12______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.24 (d,3H); 1.92 (m,2H); 2.40 (dd,1H); 2.62-3.05 (m,5H); 3.36 (m,1H); 3.55 (t,2H); 4.10-4.40 (m,3H); 6.85 (dd,1H); 7.18-7.53 (m,6H); 7.80 (m,2H); 8.20 (dd,1H) ppm.

EXAMPLE 38

6-[2-[2-[3-(2-Cyano-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 18% of theory.

Melting point: 183.degree.-184.degree. C.

C.sub.23 H.sub.24 N.sub.6 O.sub.3 (432.5).

______________________________________Calculated: C 63.88 H 5.59 N 19.43Found: 63.70 5.45 19.40______________________________________

EXAMPLE 39

6-[2-[2-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]ethyl]-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 22% of theory.

Melting point: 203.degree.-204.degree. C.

C.sub.26 H.sub.27 N.sub.5 O.sub.3 (457.5).

______________________________________Calculated: C 68.25 H 5.95 N 15.31Found: 68.10 5.88 15.48______________________________________

EXAMPLE 40

6-[2-[2-[3-(2-Chloro-5-methyl-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 20% of theory.

Melting point: 182.degree.-183.degree. C.

C.sub.23 H.sub.26 ClN.sub.5 O.sub.3 (455.9).

______________________________________Calculated: C 60.59 H 5.75 N 15.36 Cl 7.78Found: 60.49 5.75 15.62 8.03______________________________________

EXAMPLE 41

6-[2-[2-[3-(2-Allyloxy-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 9% of theory.

Melting point: 172.degree.-173.degree. C.

C.sub.25 H.sub.29 N.sub.5 O.sub.4 (463.5).

______________________________________Calculated: C 64.78 H 6.31 N 15.11Found: 64.72 6.38 15.20______________________________________

EXAMPLE 42

6-[2-[2-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-[2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 9% of theory, amorphous. R.sub.f value: 0.47 (silica gel, dichloromethane/methanol/ammonia=80:20:0.5).

C.sub.28 1H.sub.37 N.sub.5 O.sub.4 (507.6).

______________________________________Calculated: C 66.25 H 7.35 N 13.80Found: 65.92 7.19 13.99______________________________________

EXAMPLE 43

6-[2-[2-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 30% of theory, amorphous.

C.sub.27 H.sub.29 N.sub.5 O.sub.3 (471.6).

______________________________________Calculated: C 68.77 H 6.20 N 14.85Found: 68.57 6.18 14.64______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.13 (d,3H); 2.28 (dd,1H); 2.65-3.20 (m,7H); 3.47 (m,1H); 4.05-4.20 (m,3H); 6.91 (dd,1H); 7.35-7.56 (m,5H); 7.70 (dd,1H); 7.80-7.90 (m,2H); 8.27 (m,1H) ppm.

EXAMPLE 44

6-[2-[2-[3-(4-Aminocarbonylmethyl-phenoxy)-2hydroxypropylamino]-ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-aminocarbonylmethylphenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-(3(2H)-pyridazinone.

Yield: 12% of theory, amorphous.

C.sub.25 H.sub.30 N.sub.6 O.sub.4 (478.6).

______________________________________Calculated: C 62.75 H 6.32 N 17.56Found: 62.73 6.23 17.33______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.14 (d,3H); 2.28 (dd,1H); 2.60-2.83 (m,3H); 3.02 (m,4H); 3.30 (m,2H); 3.48 (m,1H); 3.80-4.00 (m,3H); 6.84 (d,2H); 7.18 (m,2H); 7.50 (d,1H); 7.69 (dd,1H); 7.89 (d,1H) ppm.

EXAMPLE 45

6-[2-[2-[3-(3,4-Dihydro-2-hydroxy-quinolin-5-yloxy)-2-hydroxypropylamino]-ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(3,4-dihydro-2-hydroxy-quinolin-5-yloxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 19% of theory.

Melting point: from 130.degree. C. (sintering).

C.sub.26 H.sub.30 N.sub.6 O.sub.4 (490.6).

______________________________________Calculated: C 63.66 H 6.16 N 17.13Found: 63.49 6.29 16.82______________________________________

EXAMPLE 46

6-[2-[2-[3-(2-Allyloxy-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 39% of theory, amorphous.

C.sub.26 H.sub.31 N.sub.5 O.sub.4 (477.6).

______________________________________Calculated: C 65.39 H 6.54 N 14.66Found: 65.21 6.66 14.66______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=1.27 (d,3H); 2.46 (dd,1H); 2.70-3.20 (m,8H); 3.48 (m,1H); 4.00 (m,2H); 4.18 (m,2H); 4.58 (dt,2H); 5.25-5.47 (m,2H); 5.95-6.16 (m,1H); 6.92 (s,4H); 7.50 (m,1H); 7.71 (dd,1H); 7.89 (d,1H) ppm.

EXAMPLE 47

6-[2-[2-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H -pyridazinone-dihydrochloride

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 15% of theory.

Melting point: 194.degree.-96.degree. C.

C.sub.30 H.sub.39 N.sub.5 O.sub.4 .times.2 HCl (606.6).

______________________________________Calculated: C 59.40 H 6.81 N 11.55 Cl 11.69Found: 59.23 6.78 11.62 11.79______________________________________

EXAMPLE 48

6-[2-[2-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 13% of theory, amorphous.

C.sub.29 H.sub.39 N.sub.5 O.sub.4 (521.7).

______________________________________Calculated: C 66.77 H 7.54 N 13.43Found: 66.59 7.58 13.69______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=0.83 (d,6H); 1.13 (d,3H); 1.7S (m,1H); 2.29 (dd,1H); 2.68-2.80 (m,3H); 3.10-3.20 (m,3H); 3.28(m,2H); 3.99(m,2H); 4.20 (m,1H); 6.89 ) (d,2H); 7.18 (d,2H); 7.45 (d,1H); 7.71(d,1H); 7.90 (s,1H) ppm.

EXAMPLE 49

6-[2-[2-[3-(2-Allyl-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-allylphenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)- pyridazinone.

Yield: 14% of theory, amorphous.

C.sub.26 H.sub.31 N.sub.5 O.sub.3 (461.6).

______________________________________Calculated: C 67.65 H 6.77 N 15.18Found: 67.44 6.59 15.09______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.13 (d,3H); 2.27 (dd,1H); 2.65-2.90 (m,3H); 3.07 (m,4H); 3.34 (dd,2H); 3.48 (m,1H); 3.90-4.05 (m,3H); 4.93-5.11 (m,2H); 5.85-6.07 (m,1H); 6.80-6.97 (m,2H); 7.05-7.20 (m,2H): 7.48 (d,1H): 7.63 (dd,1H): 7.83 (d,1H) ppm.

EXAMPLE 50

6-[2-[3-(2-Chloro-5-methyl-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 33% of theory, amorphous.

C.sub.24 H.sub.28 ClN.sub.5 O.sub.3 (470.0).

______________________________________Calculated: C 61.29 H 6.00 N 14.89 Cl 7.54Found: 61.00 5.87 14.55 7.55______________________________________ .sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.13 (d,3H); 2.26 (s,3H); 2.26 (dd,1H); 2.65-2.96 (m,3H); 3.00-3.19 (m,4H); 3.48 (m,1H); 4.00 (m,3H); 6.74 (dd,1H); 6.94 (d,1H); 7.23 (d,1H); 7.49 (d,1H); 7.69 (dd,1H); 7.88 (d,1H) ppm.

EXAMPLE 51

6-2-[2-[3-(2-Cyano-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-cyano- phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)- benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 29% of theory, amorphous. C.sub.24 H.sub.26 N.sub.6 O.sub.3 (446.5).

______________________________________Calculated: C 64.56 H 5.87 N 18.82Found: 64.43 5.81 18.59______________________________________ .sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.12 (d,3H); 2.24 (dd,1H); 2.60-2.85 (m,3H); 2.90-3.10 (m,4H); 3.35-3.55 (m,1H); 3.92 (m,1H); 4.02-4.18 (m,2H); 7.08 (t,1H); 7.21 (d,1H); 7.47 (d,1H); 7.55-7.74 (m,3H); 7.83 (d,1H) ppm.

EXAMPLE 52

6-[2-[3-(3-(Naphthyl-1-oxy)-2-hydroxypropylamino)propyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[2-(3-aminopropyl)-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 32% of theory, amorphous.

C.sub.28 H.sub.31 N.sub.5 O.sub.3 (485.6).

______________________________________Calculated: C 69.26 H 6.44 N 14.42Found: 69.10 6.21 14.07______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.11 (d,3H); 2.05 (m,2H); 2.22 (dd,1H); 2.70 (dd,1H); 2.80-3.10 (m,6H); 3.35-3.55 (m,1H); 4.05-4.26 (m,3H); 6.95 (dd,1H); 7.35-7.55 (m,5H); 7.65 (dd,1H); 7.85 (m,2H); 8.23 (dd,1H) ppm.

EXAMPLE 53

6-[2-[2-(3-(2-Cyano-phenoxy)-2-hydroxypropylamino)ethyl]benzimidazol-5-yl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.

Yield: 19% of theory.

Melting point: 188.degree.-189.degree. C.

C.sub.23 H.sub.22 N.sub.6 O.sub.3 (430.5).

______________________________________Calculated: C 64.17 H 5.15 N 19.52Found: 63.92 5.14 19.62______________________________________

EXAMPLE 54

6-[2-[2-(3-(Naphthyl-1-oxy)-2-hydroxypropylamino)ethyl]benzimidazol-5-yl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.

Yield: 11% of theory,

Melting point: 196.degree.-197.degree. C.

C.sub.26 H.sub.25 N.sub.5 O.sub.3 (455.5).

______________________________________Calculated: C 68.56 H 5.53 N 15.37Found: 68.46 5.36 15.41______________________________________

EXAMPLE 55

6-[1-[2-[3-(4-(2-Isobutoxy-ethyl)-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

Yield: 18% of theory.

Melting point: from 75.degree. C. (sintering).

R.sub.f value: 0.63 (silica gel, dichloromethane/methanol/ammonia =80:20:0.5).

C.sub.29 H.sub.39 N.sub.5 O.sub.4 (521.6).

______________________________________Calculated: C 66.77 H 7.54 N 13.43Found: 66.51 7.33 13.10______________________________________

EXAMPLE 56

6-[1-[2-[3-(4-(2-Isobutoxy-ethyl)-phenoxy)-2-hydroxypropylamino]-ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.

Yield: 22% of theory.

Melting point: 120.degree.-122.degree. C.

C.sub.28 H.sub.37 N.sub.5 O.sub.4 (507.6).

______________________________________Calculated: C 66.25 H 7.35 N 13.80Found: 66.08 7.32 13.94______________________________________

EXAMPLE 57

6-[1-[2-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 28% of theory.

Melting point: 150.degree.-151.degree. C.

C.sub.28 H.sub.35 N.sub.5 O.sub.4 (505.6).

______________________________________Calculated: C 66.51 H 6.98 N 13.85Found: 66.30 7.04 13.84______________________________________

EXAMPLE 58

6-[1-[2-[3-(4-n-Butylsulphonyloxy-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-n-butylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 7% of theory, amorphous.

R.sub.f value: 0.24 (silica gel, dichloromethane/ethanol =80:20).

C.sub.26 H.sub.33 N.sub.6 O.sub.6 S (543.7).

______________________________________Calculated: C 57.44 H 6.12 N 12.88 S 5.90Found: 57.39 6.23 13.03 5.74______________________________________

EXAMPLE 59

6-[1-[2-[3-(4-Methylsulphonyloxy-phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-methylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 23% of theory, amorphous.

C.sub.23 H.sub.27 N.sub.5 O.sub.6 S (501.5).

______________________________________Calculated: C 55.08 H 5.43 N 13.96 S 6.39Found: 54.90 5.46 14.20 6.54______________________________________

.sup.1 H-NMR spectrum (CDCl.sub.3 /CD.sub.3 OD): .delta.=2.58-2.90 (m,4H), 3.03-3.20 (m,3H); 3.15 (s,3H); 3.45-3.65 (m,1H); 3.85-4.10 (m,3H); 4.38 (t,2H); 6.88 (dt,2H); 7.19 (dt,2H); 7.50 (d,1H); 7.85 (dd,1H); 8.04 (d,1H); 8.10 (s,1H) ppm.

EXAMPLE 60

6-[1-[2-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 13% of theory.

Melting point: from 125.degree. C. (sintering).

C.sub.29 H.sub.37 N.sub.5 O.sub.4 (519.6).

______________________________________Calculated: C 67.03 H 7.18 N 13.48Found: 66.81 6.94 13.47______________________________________

EXAMPLE 61

6-[1-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone-dihydrochloride

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 13% of theory.

Melting point: from 200.degree. C. (sintering).

C.sub.28 H.sub.37 N.sub.5 O.sub.5 .times. 2 HCl (596.5).

______________________________________Calculated: C 56.38 H 6.59 N 11.74 Cl 11.89Found: 56.19 6.56 12.00 11.72______________________________________

EXAMPLE 62

6-[1-[3-[3-(4-(2-Isobutoxyethyl)phenoxy)-2hydroxypropylamino]propyl]benzimidazol-5-yl]-4,5-dihydro-3-(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(3-aminopropyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 32% of theory.

Melting point: 132.degree.-134.degree. C.

C.sub.29 H.sub.39 N.sub.5 O.sub.4 (521.67).

______________________________________Calculated: C 66.77 H 7.54 N 13.43Found: 66.69 7.51 13.41______________________________________

EXAMPLE 63

6-[1-[2-[3-(4-(2-Isobutoxyethyl)phenoxy)-2-hydroxypropylamino]-2,2-dimethyl-ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-amino-2,2-dimethylethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 11% of theory.

Melting point: 130.degree.-132.degree. C.

______________________________________Calculated: C 67.26 H 7.71 N 13.07Found: 66.96 7.56 13.41______________________________________

EXAMPLE 64

6-[1-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]-2,2-dimethyl-ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-amino-2,2-dimethyl-ethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 9% of theory, amorphous.

R.sub.f value: 0.55 (silica gel, dichloromethane/methanol/ammonia =80:20:0.5).

C.sub.30 H.sub.41 N.sub.5 O.sub.5 (551.7).

______________________________________Calculated: C 65.31 H 7.49 N 12.70Found: 65.11 7.29 12.57______________________________________

EXAMPLE 65

6-[1-[2-[3-(4-(2-Isobutoxyethyl)phenoxy)-2-hydroxypropylamino]ethyl]-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 28% of theory.

Melting point: 198.degree.-200.degree. C.

C.sub.29 H.sub.39 N.sub.5 O.sub.4 (521.7).

______________________________________Calculated: C 66.77 H 7.54 N 13.43Found: 66.56 7.53 13.30______________________________________

EXAMPLE 66

6-[1-[2-[3-(4-Isopropylsulphonyloxy-phenoxy)-2-hydroxypropylamino]ethyl]-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-isopropylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 31% of theory.

Melting point: 176.degree.-178.degree. C.

C.sub.26 H.sub.33 N.sub.5 O.sub.6 S (543.7).

______________________________________Calculated: C 57.44 H 6.12 N 12.88Found: 57.34 6.07 12.70______________________________________

EXAMPLE 67

6-[1-[2-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.

Yield: 21% of theory.

Melting point: 188.degree.-190.degree. C.

C.sub.29 H.sub.37 N.sub.5 O.sub.4 (519.7).

______________________________________Calculated: C 62.68 H 7.44 N 12.60Found: 62.59 7.31 12.42______________________________________

EXAMPLE 68

6-[1-[3-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]propyl]-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(3-aminopropyl) -2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 6% of theory, amorphous.

R.sub.f value: 0.56 (silica gel, dichloromethane/methanol/ammonia =80:20:0.5).

C.sub.30 H.sub.41 N.sub.5 O.sub.4 (535.7).

______________________________________Calculated: C 67.26 H 7.72 N 13.08Found: 67.11 7.53 13.00______________________________________

EXAMPLE 69

6-[1-[2-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2- isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 17% of theory.

Melting point: from 110.degree. C. (sintering).

C.sub.28 H.sub.37 N.sub.5 O.sub.5 (523.6).

______________________________________Calculated: C 64.22 H 7.12 N 13.38Found: 63.91 6.99 13.44______________________________________

EXAMPLE 70

6-[1-[2-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 13% of theory, amorphous.

R.sub.f value: 0.56 (silica gel, dichloromethane/methanol/ammonia =80:20:0.5).

C.sub.28 H.sub.35 N.sub.5 O.sub.5 (521.6).

______________________________________Calculated: C 64.47 H 6.76 N 13.43Found: 64.31 6.39 13.55______________________________________

EXAMPLE 71

6-[1-[2-[3-(4-Isopropylsulphonyloxy-phenoxy)-2-hydroxypropylamino]ethyl]-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-isopropylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 18% of theory, amorphous

C.sub.25 H.sub.31 N.sub.5 O.sub.7 S (545.6).

______________________________________Calculated: C 55.03 H 5.73 N 12.84 S 5.88Found: 54.83 5.44 12.29 5.89______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.42 (d,6H); 2.42 (t,2H); 2.55-2.97 (m,6H); 3.66 (m,1H); 3.74-3.96 (m,5H); 6.93 (d,2H); 7.13-7.25 (m,3H); 7.27-7.43 (m,2H) ppm.

EXAMPLE 72

6-[1-[2-[3-(4-(2-Isobutoxyethyl)phenoxy)-2-hydroxypropyl-amino]ethyl]benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 19% of theory, amorphous.

C.sub.27 H.sub.36 N.sub.6 O.sub.4 (508.6).

______________________________________Calculated: C 63.76 H 7.13 N 16.53Found: 63.59 7.13 16.44______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=0.83 (d,6H); 1.77 (m,1H), 2.55-2.80 (m,4H); 3.03- 3.18 (m,7H); 3.50 (t,2H); 3.75 (m,4H); 4.78 (m,2H); 6.73 (d,2H); 7.10 (d,2H); 7.90 (d,1H); 8.06 (dd,1H); 8.31 (d,1H) ppm.

EXAMPLE 73

6-[1-[2-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6- [1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 17% of theory.

Melting point: 157.degree.-158.degree. C.

C.sub.28 H.sub.36 N.sub.6 O.sub.4 (520.6).

______________________________________Calculated: C 64.60 H 6.97 N 16.14Found: 64.50 7.04 16.22______________________________________

EXAMPLE 74

6-[1-[2-[3-(4-Methylsulphonyloxy-phenoxy)-2-hydroxypropylamino]ethyl]benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-methylsulphonyloxy-phenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.

Yield: 23% of theory.

Melting point: 156.degree.-158.degree. C.

C.sub.22 H.sub.26 N.sub.6 O.sub.6 S (502.6).

______________________________________Calculated: C 52.58 H 5.21 N 16.72 S 6.38Found: 52.30 5.22 16.85 6.45______________________________________

EXAMPLE 75

6-[1-[2-[3-(4-n-Butylsulphonyloxy-phenoxy)-2-hydroxypropylamino]ethyl]benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-(4-n-butylsulphonyloxyphenoxy)-2,3-epoxypropane and 6-[1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 8% of theory, amorphous.

R.sub.f value: 0.49 (silica gel, dichloromethane/ethanol =9:1).

C.sub.25 H.sub.32 N.sub.6 O.sub.6 S (544.6).

______________________________________Calculated: C 55.13 H 5.92 N 15.43 S 5.89Found: 54.99 5.51 15.30 6.02______________________________________

EXAMPLE 76

6-[1-[2-[3-(4-(2-Isobutoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.

Yield: 8% of theory, amorphous.

C.sub.28 H.sub.35 N.sub.5 O.sub.4 (505.6).

______________________________________Calculated: C 64.23 H 7.12 N 13.37Found: 64.07 7.29 13.14______________________________________ .sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=0.80 (d,6H); 1.76 (m,1H); 2.53-2.70 (m,4H); 2.92-3.18 (m,4H); 3.39-3.55 (t,2H); 3.66-3.87 (m,3H); 4.25-4.43 (m,2H); 6.63-7.18 (m,5H); 7.67-7.83 (m,2H); 8.04-8.19 (m,2H); 8.28 (s,1H) ppm.

EXAMPLE 77

6-[1-[2-[3-(4-(2-Cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.

Yield: 18% of theory.

Melting point: 115.degree.-117.degree. C.

C.sub.26 H.sub.33 N.sub.5 O.sub.4 (503.6)

______________________________________Calculated: C 66.78 H 6.61 N 13.91Found: 66.77 6.41 13.74______________________________________

EXAMPLE 78

6-[1-[2-[3-(4-(2-Cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.

Yield: 13% of theory, amorphous.

C.sub.29 H.sub.35 N.sub.5 O.sub.4 (517.6).

______________________________________Calculated: C 67.29 H 6.82 N 13.53Found: 67.00 6.71 13.52______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=1.60-2.04 (m,7H); 2.38-2.55 (m,2H); 2.71 (t,2H); 3.32 (t,2H); 3.51 (t,2H); 3.93-4.05 (m,2H); 4.27-4.46 (m,3H); 4.54 (t,2H); 6.82 (d,2H); 7.00-7.18 (m,3H); 7.73 (d,1H); 7.86 (dd,1H); 8.11 (d,1H); 8.20 (d,1H); 8.30 (s,1H) ppm.

EXAMPLE 79

6-[4-[3-[3-(4-(2-Isobutoxyethyl)phenoxy)-2-hydroxypropylamino]propylsulphonyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2isobutoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl]phenyl]-3(2H)-pyridazinone.

Yield: 24% of theory.

Melting point: 129.degree.-131.degree. C.

C.sub.28 H.sub.39 N.sub.3 O.sub.6 S (545.7).

______________________________________Calculated: C 61.63 H 7.20 N 7.70 S 5.88Found: 61.43 6.95 7.53 6.07______________________________________

EXAMPLE 80

6-[4-[3-[3-(4-(2-Cyclopropylmethoxyethyl)phenoxy)-2-hydroxypropylamino]propylsulphonyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl)phenyl]-3(2H)-pyridazinone.

Yield: 24% of theory.

Melting point: 128.degree.-130.degree. C.

C.sub.28 H.sub.37 N.sub.3 O.sub.6 S (543.69).

______________________________________Calculated: C 61.86 H 6.86 N 7.73 S 5.90Found: 61.75 7.09 7.60 6.06______________________________________

EXAMPLE 81

6-[4-[3-[3-(4-(2-Isopropoxyethoxymethyl)phenoxy)-2-hydroxypropylamino]propylsulphonyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl)phenyl]-3(2H)-pyridazinone.

Yield: 23% of theory.

Melting point: 108.degree.-110.degree. C.

C.sub.28 H.sub.39 N.sub.3 O.sub.7 S (561.7).

______________________________________Calculated: C 59.87 H 7.00 N 7.48 S 5.71Found: 59.76 6.81 7.56 5.99______________________________________

EXAMPLE 82

6-[4-[2-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]ethyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone-hydrochloride

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 33% of theory.

Melting point: 177.degree.-180.degree. C.

C.sub.25 H.sub.27 N.sub.3 O.sub.3 .times.HCl (454.0).

______________________________________Calculated: C 66.14 H 6.22 N 9.26 S 7.81Found: 65.99 6.21 9.35 7.76______________________________________

EXAMPLE 83

6-[4-[2-[3-(4-(2-Cyclobutylmethoxyethyl)phenoxy)-2-hydroxypropylamino]ethyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 24% of theory.

Melting point: from 119.degree. C. (sintering).

C.sub.28 H.sub.37 N.sub.3 O.sub.4 (479.6).

______________________________________Calculated: C 70.12 H 7.78 N 8.76Found: 69.94 7.79 8.67______________________________________

EXAMPLE 84

6-[4-[2-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]ethyl]phenyl]-3(2H)-pyridazinone-hydrochloride

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-3(2H)-pyridazinone.

Yield: 16% of theory.

Melting point: 219.degree.-222.degree. C.

C.sub.25 H.sub.25 N.sub.3 O.sub.3 .times.HCl (452.0).

______________________________________Calculated: C 66.43 H 5.80 N 9.30 Cl 7.84Found: 66.42 5.97 9.30 8.01______________________________________

EXAMPLE 85

6-[4-[2-[3-(4-(2-Cyclobutylmethoxyethyl)phenoxy)-2-hydroxypropylamino]ethyl]phenyl]-3(2H)-pyridazinone

Prepared analoqously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethyl)phenyl]-3(2H)-pyridazinone.

Yield: 10% of theory.

Melting point: 119.degree.-121.degree. C.

C.sub.28 H.sub.35 N.sub.3 O.sub.4 (477.6).

______________________________________Calculated: C 70.42 H 7.39 N 8.80Found: 70.31 7.39 8.76______________________________________

EXAMPLE 86

6-[4-[2-[3-(Naphthyl-1-oxy)-2-hydroxypropylamino]-ethylaminocarbonylmethyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone-hydrochloride

Prepared analogously to Example 1 from 1-(naphthyl-1-oxy)-2,3-epoxypropane and 6-[4-((2-aminoethyl)aminocarbonylmethyl)phenyl]-3(2H)-pyridazinone.

Yield: 12% of theory, amorphous.

C.sub.27 H.sub.30 N.sub.4 O.sub.4 .times.HCl (511.1).

______________________________________Calculated: C 63.45 H 6.11 N 10.96 Cl 6.94Found: 63.60 6.25 10.75 7.03______________________________________

.sup.1 H-NMR spectrum (d.sub.6 -DMSO/CD.sub.3 OD): .delta.=2.40-2.55 (m,2H); 2.88-3.57 (m,9H); 4.08-4.22 (m,3H); 4.32 (m,1H); 6.98 (dd,1H); 7.29-7.73 (m,8H); 7.83-7.91 (m,1H); 8.22-8.35 (m,1H) ppm.

EXAMPLE 87

6-[4-[2-[3-(4-(2-Cyclobutylmethoxyethyl)phenoxy)-2-hydroxypropylamino]ethylaminocarbonylmethyl]phenyl]-4,5-dihydro-3(2H)-pyridazinone-hydrochloride

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-((2-aminoethyl)aminocarbonylmethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone.

Yield: 12% of theory.

Melting point: 214.degree.-216.degree. C.

C.sub.30 H.sub.40 N.sub.4 O.sub.5 .times.HCl (573.1).

______________________________________Calculated: C 62.87 H 7.21 N 9.78Found: 62.75 7.03 9.77______________________________________

EXAMPLE 88

6-[3-[2-[3-(4-(2-Cyclobutylmethoxyethyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-3(2H)-pyridazinone.

Yield: 11% of theory.

Melting point: 111.degree.-112.degree. C.

C.sub.28 H.sub.35 N.sub.3 O.sub.5 (493.6).

______________________________________Calculated: C 68.13 H 7.15 N 8.51Found: 67.95 7.10 8.50______________________________________

EXAMPLE 89

6-[4-[2-[3-(4-(2-Isopropoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-methyl-phenyl]-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone.

Yield: 35% of theory.

Melting point: 121.degree.-122.degree. C.

C.sub.28 H.sub.37 N.sub.3 O.sub.6 (511.6).

______________________________________Calculated: C 65.73 H 7.29 N 8.21Found: 65.51 7.14 8.10______________________________________

EXAMPLE 90

6-[4-[2-[3-(4-(2-Phenoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-phenoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.

Yield: 28% of theory.

Melting point: 95.degree.-97.degree. C.

C.sub.30 H.sub.34 ClN.sub.3 O.sub.6 (568.10).

______________________________________Calculated: C 63.43 H 6.03 N 7.40 Cl 6.24Found: 63.35 5.97 7.44 6.44______________________________________

EXAMPLE 91

6-[4-[2-[3-(4-(2-Phenoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-phenoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.

Yield: 26% of theory.

Melting point: 85.degree.-87.degree. C.

C.sub.31 H.sub.37 N.sub.3 O.sub.6 (547.70).

______________________________________Calculated: C 67.98 H 6.81 N 7.67Found: 67.89 7.01 7.81______________________________________

EXAMPLE 92

6-[4-[2-[3-(4-(2-n-Butyloxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.

Yield: 28% of theory.

Melting point: 96.degree.-98.degree. C.

C.sub.29 H.sub.41 N.sub.3 O.sub.6 (527.70).

______________________________________Calculated: C 66.00 H 7.83 N 7.96Found: 65.88 7.95 7.80______________________________________

EXAMPLE 93

6-[4-[2-[3-(4-(2-n-Butyloxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-chloro-phenyl]-4,5-dihydro-3-(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.

Yield: 27% of theory.

Melting point: 108.degree.-110.degree. C.

C.sub.28 H.sub.38 ClN.sub.3 O.sub.6 (548.10).

______________________________________Calculated: C 61.36 H 6.99 N 7.67 Cl 6.47Found: 61.51 6.85 7.61 6.54______________________________________

EXAMPLE 94

6-[4-[2-[3-(4-(2-n-Butyloxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]phenyl]-4,5-dihydro-3-(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-3-(2H)-pyridazinone.

Yield: 30% of theory.

Melting point: 82.degree.-84.degree. C.

C.sub.28 H.sub.39 N.sub.3 O.sub.6 (513.60).

______________________________________Calculated: C 65.48 H 7.65 N 8.18Found: 65.31 7.74 8.16______________________________________

EXAMPLE 95

6-[4-[2-[3-(4-(2-Methoxyethoxy-methyl)phenoxy)-2-hydroxypropylamino]ethoxy]-3-methyl-phenyl]-3-(2H)-pyridazinone

Prepared analogously to Example 1 from 1-[4-(2-methoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-3(2H)-pyridazinone.

Yield: 32% of theory.

Melting point: 127.degree.-128.infin. C.

C.sub.26 H.sub.33 N.sub.3 O.sub.6 (483.55).

______________________________________Calculated: C 64.58 H 6.88 N 8.69Found: 64.42 6.7l 8.44______________________________________

In the pharmaceutical Examples which follow, any suitable compound of formula I can be used as the active substance, e.g. the compounds of the preceding Examples.

EXAMPLE 96

______________________________________Ampoules containing 100 mg of active substance per 5 ml______________________________________Active substance 100 mgMethyl glucamine 35 mgGlycofurol 1000 mgPolyethyleneglycol-polypropylene- 250 mgglycol block polymerWater for injections ad 5 ml______________________________________

Preparation

Methyl glucamine is dissolved in some of the water and the active substance is dissolved with stirring and heating. After the addition of the solvent the solution is made up to the required volume using water.

EXAMPLE 97

______________________________________Tablets containing 50 mg of active substance______________________________________Active substance 50.0 mgCalcium phosphate 70.0 mgLactose 40.0 mgCorn starch 35.0 mgPolyvinylpyrrolidone 3.5 mgMagnesium stearate 1.5 mg 200.0 mg______________________________________

Preparation

The active substance, CaHPO, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50.degree. C. in a circulating air dryer and screened again.

After the addition of the lubricant the granules are compressed in a tablet making machine.

EXAMPLE 98

______________________________________Coated tablets containing 50 mg of active substance______________________________________Active substance 50.0 mgLysine 25.0 mgLactose 60.0 mgCorn starch 34.0 mgGelatin 10.0 mgMagnesium stearate 1.0 mg 180.0 mg______________________________________

Preparation

The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying the granules are mixed with magnesium stearate and compressed to form cores. The cores thus produced are coated by known methods. Dyestuff may be added to the coating suspension or solution.

EXAMPLE 99

______________________________________Coated tablets containing 100 mg of active substance______________________________________Active substance 100.0 mgLysine 50.0 mgLactose 86.0 mgCorn starch 50.0 mgPolyvinylpyrrolidone 2.8 mgMicrocrystalline cellulose 60.0 mgMagnesium stearate 1.2 mg 350.0 mg______________________________________

Preparation

The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at 45.degree. C. After drying it is screened again and the magnesium stearate is added. This mixture is compressed to form cores.

The cores thus produced are coated by known methods. Dyestuffs may be added to the coating suspension or solution.

EXAMPLE 100

______________________________________Capsules containing 250 mg of active substance______________________________________Active substance 250.0 mgCorn starch 68.5 mgMagnesium stearate 1.5 mg 320.0 mg______________________________________

Preparation

The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.

EXAMPLE 101

______________________________________Oral suspension containing 50 mg of active substance per 5______________________________________mlActive substance 50.0 mgHydroxyethylcellulose 50.0 mgSorbic acid 5.0 mg70% sorbitol 600.0 mgGlycerol 200.0 mgFlavouring 15.0 mgWater ad 5.0 ml______________________________________

Preparation

Distilled water is heated to 70.degree. C. Hydroxyethylcellulose is dissolved therein with stirring. The solution is cooled to ambient temperature by the addition of sorbitol solution and glycerol.

At ambient temperature the sorbic acid, flavouring and active substance are added. To eliminate air from the suspension it is evacuated with stirring. One dose =50 mg is contained in 5.0 ml.

EXAMPLE 102

______________________________________Suppositories containing 100 mg of active substance______________________________________Active substance 100.0 mgSolid fat 1600.0 mg 1700.0 mg______________________________________

Preparation

The hard fat is melted. At 40.degree. C. the ground active substance is homogeneously dispersed in the melt. It is cooled to 38.degree. C. and poured into slightly chilled suppository moulds.

Claims

1. A 2-Hydroxy-n-propylamine of the formula

R.sub.1 --O--CH.sub.2 --CHOH--CH.sub.2 --NH--A--R.sub.2 (I)

wherein

R.sub.1 represents a naphthyl group, a phenyl group substituted by a C.sub.1-5 -alkylsulphonyloxy or by an allyl, allyloxy, cyano or aminocarbonylmethyl group, a phenyl group substituted by a C.sub.1-3 alkyl group, wherein the alkyl moiety is substituted in the 1-, 2- or 3-position by an alkoxy, cycloalkyloxy, cycloalkylmethoxy, 2-alkoxyethoxy, 2-cycloalkyloxyethoxy, 2- cycloalkylmethoxy-ethoxy or 2-phenoxyethoxy group, wherein the alkoxy moiety may have from 1 to 6 carbon atoms and the cycloalkyl or cycloalkyloxy part may have 3 to 6 carbon atoms, or a phenyl group disubstituted by a C.sub.1-3 alkyl group and by a halogen atom,

A represents a straight-chained C.sub.2-4 alkylene group optionally substituted by one or two C.sub.1-3 alkyl groups and

R.sub.2 represents a group of formula ##STR7## wherein R.sub.3 represents a hydrogen atom or a C.sub.1-3 alkyl group,

R.sub.4 and R.sub.5 each represents a hydrogen atom or together they represent another carbon-carbon bond and

B represents a group of formula ##STR8## wherein X.sub.1 represents a CH group optionally substituted by a hydroxy group or by a C.sub.1-3 alkyl group, and

Y.sub.2 represents a bond or an imino group,

or a pharmaceutically acceptable acid addition salt thereof.

2. A 2-hydroxy-n-propylamine of formula I according to claim 1, wherein

R.sub.1 represents a naphthyl, allylphenyl, allyloxyphenyl, cyanophenyl, aminocarbonyl-methylphenyl or chloro-methylphenyl group, an alkysulphonyloxyphenyl group with 1 to 4 carbon atoms in the alkyl moiety or a phenyl group substituted in the 4-position by a 2-alkoxyethyl, 2-cycloalkyl-methoxyethyl, 2-alkoxyethoxymethyl, 2-cycloalkyloxy-ethoxymethyl, 2-cycloalkylmethoxyethoxymethyl or 2-phenoxyethoxymethyl group, wherein the alkoxy moiety may have 1 to 4 carbon atoms and the cycloalkyl or cycloalkyloxy part may have 3 or 4 carbon atoms,

A represents a C.sub.2-4 n-alkylene group optionally mono- or disubstituted by a methyl group in the .alpha.-position with respect to the adjacent nitrogen atom and

R.sub.2 represents a group of the formula ##STR9## wherein R.sub.3 represents a hydrogen atom or a methyl group,

R.sub.4 and R.sub.5 each represent a hydrogen atom or together they represent another carbon-carbon bond and

B represents a group of the formula ##STR10## wherein X.sub.1 represents a CH group optionally substituted by a hydroxy or methyl group, and

Y.sub.2 represents a bond or an imino group,

or a pharmaceutically acceptable acid addition salt thereof.

3. A 2-hydroxy-n-propylamine of formula I according to claim 1, wherein

R.sub.1 represents a naphthyl, allylphenyl, allyloxyphenyl or chloro-methylphenyl group or a phenyl group substituted in the 4-position by a 2-alkoxyethyl, 2-cycloalkylmethoxyethyl, 2-alkoxyethoxymethyl, 2-cycloalkyloxyethoxymethyl, 2-cycloalkylmethoxyethoxymethyl or 2-phenoxyethoxymethyl group, wherein the alkoxy moiety may have 1 to 3 carbon atoms and the cycloalkyl or cycloalkyloxy moiety may have 3 or 4 carbon atoms,

A represents a C.sub.2-4 n-alkylene group optionally disubstituted by methyl groups in the .alpha.-position with respect to the adjacent nitrogen atom and

R.sub.2 represents a group of the formula ##STR11## wherein R.sub.3 represents a hydrogen atom or a methyl group,

R.sub.4 and R.sub.5 each represent a hydrogen atom or together they represent another carbon-carbon bond and

B represents a group of formula ##STR12## wherein X.sub.1 represents a CH group, and

Y.sub.2 represents a bond or an imino group,

or a pharmaceutically acceptable acid addition salt thereof.

4. A 2-hydroxy-n-propylamine of formula I according to claim 1, selected from the group consisting of:

6-[1-[2-[3-(4-(2-cyclobutylmethoxy-ethyl)phenoxy)-2-hydroxy-propylamino]ethyl]benzimidazol-5yl]-4,5-dihydro-3(2H)-pyridazinone,

6-[1-[2-[3-(4-(2-cyclopropylmethoxy-ethyl)phenoxy)-2-hydroxypropylamino]ethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone,

6-[1-[3-[3-(4-(2-isobutoxyethyl)phenoxy)-2-hydroxypropylamino]propyl]benzimidazol-5-yl]4,5-dihydro-3(2H)-pyridazinone,

6-[1-[2-[3-(4-(2-isobutoxyethyl)phenoxy)-2-hydroxypropylamino]-2,2-dimethylethyl]benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone,

and pharmaceutically acceptable salts thereof.

5. A compound of the formula I, in accordance with claim 3, wherein R.sub.1 represents a phenyl group substituted in the 4-position by a 2-alkoxyethyl, 2-cycloalkoxymethoxyethyl, 2-alkoxyethoxymethyl, 2-cycloalkyloxyethoxymethyl, 2-cycloalkylmethoxyethoxymethyl or 2-phenoxyethoxymethyl group, wherein the alkoxy moiety may have 1 to 3 carbon atoms and the cycloalkyl or cycloalkyloxy moiety may have 3 to 4 carbon atoms and

b represents a group of the formula ##STR13## or a pharmaceutically acceptable acid addition salt thereof.

6. A pharmaceutical composition suitable for the treatment of myocardial ischaemia (angina), cardiac insufficiency after myocardial infarct, or hypertension, comprising a therapeutic amount of a compound of formula I, according to claims 1, 2, 3, 4 or 5 and a pharmaceutically acceptable carrier.

7. A method for treating myocardial ischaemia which comprises administering to a warm blooded animal suffering from one of said conditions a therapeutic amount of a compound of formula I, as set forth in claims 1, 2, 3, 4, 5 or 6.

8. A method for treating cardiac insufficiency after myocardial infarct which comprises administering to a warm blooded animal suffering from one of said conditions a therapeutic amount of a compound of formula I, as set forth in claims 1, 2, 3, 4, 5, or 6.

9. A method for treating hypertension which comprises administering to a warm blooded animal suffering from one of said conditions a therapeutic amount of a compound of formula I, as set forth in claims 1, 2, 3, 4, 5 or 6.