Boehringer Mannheim Gmbh

Helmut Michel

Wolfgang Bartsch

Herbert Simon

Wolfgang Kampe

Roland Ofenloch

Walter-Gunar Friebe

Klaus Strein

Fritz Wiedemann

Michael Schultz

Gisbert Sponer

Wolfgang Schaumann

Karl Dietmann

Carl H Ross

Egon Roesch

Wolfgang Weckerle

Klaus Marzenell

The invention concerns nitric acid esters of cyclohexanol of formula I ##STR1## in which A signifies a valency bond or a C.sub.1 -C.sub.6 -alkylene chain and B the group --NR.sup.1 --CO--Z, --NR.sup.1 --SO.sub.2 --Z or --CO--NR.sup.2 --Z, whereby R.sup.1 signifies hydrogen or a C.sub.1 -C.sub.6 -alkyl alkyl group R.sup.2 hydrogen, a hydroxyl, hydroxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl or C.sub.2 -C.sub.6 -alkynyl group and Z signifies hydrogen a C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl or C.sub.2 -C.sub.6 -alkynyl group which may optionally be substituted for the case that B is an --NR.sup.1 --CO--Z group, Z can also signify a C.sub.1 -C.sub.6 -alkoxy group.

Nitric acid esters of cyclohexanol derivatives

The present invention provides anti-angina pharmaceutical compositions containing at least one compound of the formula: ##STR1## wherein n is 1 or 2, R is a hydrogen atom or an H--(C.sub.1 -C.sub.8)-alkylene, hydroxy-(C.sub.1 -C.sub.8)-alkylene, R.sup.1 R.sup.2 N--(C.sub.1 -C.sub.8)-alkylene, R.sup.1 R.sup.2 N--(C.sub.1 -C.sub.8)-alkylene-CO--, R.sup.1 R.sup.2 N--CO--NR.sup.3 --(C.sub.1 -C.sub.8)-alkylene or R.sup.1 R.sup.2 N--CO-- radical, A is a valency bond or an --NR.sup.4 --CO-- or --CO-- NR.sup.4 -- radical, R.sup.4 is a hydrogen atom or a straight-chained or branched, saturated or unsaturated or cyclic alkyl radical containing up to 6 carbon atoms and B is a valency bond or a straight-chained or branched alkylene chain containing up to 8 carbon atoms, in which a --CH.sub.2 -- group can be replaced by a cycloalkylene radical containing 3 to 7 carbon atoms.

Cyclic azaaliphatic compounds with a nitroxy function, processes for the

The present invention provides pharmaceutical compositions effective against angina-like heart and circulatory diseases containing at least one nitroxyalkylamine derivative of the general formula: ##STR1## wherein R.sub.1 is a hydrogen atom, a lower-alkyl radical, a C.sub.3 -C.sub.8 -cycloalkyl or C.sub.3 -C.sub.8 -cycloalkenyl radical, an aminocarbonyl, C.sub.1 -C.sub.6 -mono- or di-alkylaminocarbonyl radical, R.sup.2 is a hydrogen atom, a lower-alkyl radical or a C.sub.3 -C.sub.8 -cycloalkyl or cycloalkenyl radical or R.sup.2, together with R.sup.1 and the nitrogen atom to which they are attached, form a heteroaliphatic ring containing up to 6 carbon atoms, A is a valency bond or a straight-chained or branched lower-alkylene radical, in which a --CH.sub.2 -- group can be replaced by a cycloalkylene radical, B is a lower-alkylene radical, in which a --CH.sub.2 -- group can be replaced by a cycloalkylene radical and X is an --NR.sup.3 --CO-- or --CO--NR.sup.3 -- radical, in which R.sup.3 is a hydrogen atom or a lower-alkyl radical, when X is an --NR.sup.3 --CO-- radical, R.sup.3, together with the nitrogen atom and a carbon atom of the group A, bridge a heterocyclic ring containing 4 to 6 carbon atoms or R.sup.3, together with R.sup.2, A and the two nitrogen atoms, bridge a heterocyclic ring containing 3 to 5 carbon atoms; and the optically-active forms and physiologically acceptable salts thereof.

Pharmaceutical compositions containing nitroxyalkylamines, novel

The present invention provides anti-angina pharmaceutical compositions containing at least one compound of the formula: ##STR1## wherein n is 1 or 2, R is a hydrogen atom or an H-(C.sub.1 -C.sub.8)-alkylene, hydroxy-(C.sub.1 -C.sub.8)-alkylene, R.sup.1 R.sup.2 N-(C.sub.1 -C.sub.8)-alkylene, R.sup.1 R.sup.2 N-(C.sub.1 -C.sub.8)-alkylene-CO--, R.sup.1 R.sup.2 N-CO-NR.sup.3 -(C.sub.1 -C.sub.8)-alkylene or R.sup.1 R.sup.2 N-CO-- radical, A is a valency bond or an --NR.sup.4 --CO-- or --CO--NR.sup.4 -- radical, R.sup.4 is a hydrogen atom or a straight-chained or branched, saturated or unsaturated of cyclic alkyl radical containing up to 6 carbon atoms and B is a valency bond or a straight-chained or branched alkylene chain containing up to 8 carbon atoms, in which a --CH.sub.2 -- group can be replaced by a cycloalkylene radical containing 3 to 7 carbon atoms.

The present invention provides compounds of the general formula: ##STR1## wherein Ar is a substituted or unsubstituted aromatic or heteroaromatic radical, A is a straight-chained or branched alkylene chain containing up to 8 carbon atoms, a --CH.sub.2 -- group of which can be replaced by a cycloalkylene radical containing 3 to 7 carbon atoms, B is a straight-chained mono- or bicyclic, optionally branched, saturated or unsaturated alkylene chain containing up to 12 carbon atoms, a --CH.sub.2 -- group of which can be replaced by a cycloalkylene radical containing 3 to 7 carbon atoms and/or up to two --CH.sub.2 -- groups of which can be replaced by an oxygen or a sulphur atom or by an --S(.dbd.O) or --S(.dbd.O).sub.2 group, X is a valency bond, an oxygen atom or an --NR.sup.1 group, in which R.sup.1 is a hydrogen atom or a straight-chained or branched, saturated or unsaturated alkyl or nitroxyalkyl radical containing up to 6 carbon atoms or R.sup.1, together with the nitrogen atom of the --NR.sup.1 -- group and a --CH.sub.2 -- group of the chain B, can form a heteroaliphatic ring containing 4 to 6 carbon atoms and n is 1, 2 or 3; and the physiologically acceptable salts thereof. The present invention also provides processes for the preparation of these compounds and pharmaceutical compositions containing them. Furthermore, the present invention is concerned with the use of these compounds for the treatment and/or prophylaxis of heart and circulatory diseases.

Aminopropanol derivatives, processes for the preparation thereof, the

The present invention provides oxindole derivatives of the formula: ##STR1## wherein the various substituents are defined hereinbelow. The above compounds display nitrate-like as well as .beta.-blocking actions.

Beta-blocking oxindole derivatives

The present invention provides a process for the preparation of 4-hydroxyindole derivatives of the general formula: ##STR1## in which R.sub.1 is a hydrogen atom or an alkyl radical containing up to 6 carbon atoms and R.sub.2 is a hydrogen atom or an alkyl radical containing up to 6 carbon atoms, wherein a compound of the general formula: ##STR2## in which R.sub.2 has the same meaning as above, is reacted with a compound of the general formula:

4-oxo-4,5,6,7-Tetrahydroindole derivatives

The present invention provides new aminopropanol derivatives of the general formula: ##STR1## wherein A is a direct bond, a straight-chained or branched alkylene chain containing up to 3 carbon atoms or a --CO--CH.sub.2 -- group; X is a direct bond or a carbonyl group; B is a straight-chained or branched, saturated or unsaturated alkylene chain containing up to 12 carbon atoms, in which one or two --CH.sub.2 -- groups can also be replaced by a saturated or unsaturated alkylene ring containing 3 to 7 carbon atoms and/or by an oxygen or sulphur atom or an --S(.dbd.O)-- or --S(.dbd.O).sub.2 -- group, n is 1, 2 or 3; R.sub.1 is a hydrogen atom or a straight-chained or branched, saturated or unsaturated alkyl radical containing up to 6 carbon atoms or a --B--(ONO.sub.2).sub.n group, in which B and n have the same meanings as above, or when A is a --CO--CH.sub.2 -- group and X is a direct bond, R.sub.1 together with the nitrogen atom and a carbon atom of chain B can represent a heteroaliphatic ring containing 2 to 7 carbon atoms; R.sub.2 is a hydrogen or halogen atom or a cyano, hydroxyl, amino, nitro, carboxyl, carbamoyl, ureido or sulphamoyl group or an alkyl, alkoxy, alkylamino, alkylthio, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino or alkylaminocarbonylamino radical; and R.sub.3 is an alkyl or nitroxyalkyl radical containing 3 to 8 carbon atoms; and the physiologically acceptable salts thereof. The present invention also provides processes for the preparation of these aminopropanol derivatives and pharmaceutical compositions containing them, as well as intermediates for the preparation of the new aminopropanol derivatives.

Nitroxy amino propanols for treating heart and circulatory diseases

Process for the preparation of indole derivatives

The present invention provides indolin-2-one derivatives of the general formula: ##STR1## wherein R.sub.1 is a C.sub.1 -C.sub.6 alkyl radical or a radical of the general formula: ##STR2## in which A is a straight-chained or branched C.sub.2 -C.sub.4 alkylene radical and Z is an oxygen or sulphur atom, R.sub.2 and R.sub.3, which can be the same or different, are hydrogen or halogen atoms, hydroxyl groups, C.sub.2 -C.sub.6 alkanoyl radicals, C.sub.2 -C.sub.4 alkenyl radicals, C.sub.2 -C.sub.4 alkynyl radicals, C.sub.1 -C.sub.6 alkyl radicals, C.sub.1 -C.sub.6 alkoxy radicals, C.sub.2 -C.sub.4 alkenyloxy radicals, C.sub.2 -C.sub.4 alkynyloxy radicals, C.sub.1 -C.sub.6 alkylthio radicals, C.sub.2 -C.sub.6 alkanoylamido radicals or radicals of the general formula: ##STR3## in which R.sub.4 and R.sub.5, which can be the same or different, are hydrogen atoms, C.sub.1 -C.sub.6 alkyl radicals or C.sub.3 -C.sub.10 cycloalkyl radicals or R.sub.4 and R.sub.5 together represent a C.sub.2 -C.sub.8 alkylene radical optionally interrupted by an oxygen or sulphur atom or by an &gt;N-R.sub.6 group, in which R.sub.6 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl radical, X is a hydrogen atom, Y is a hydrogen atom or a group of the general formula ##STR4## in which Q is a hydrogen atom or, together with X, can also represent a bond and R.sub.7 is a heterocyclic radical which is optionally substituted one or more times by hydroxyl or C.sub.1 -C.sub.6 alkyl or is a phenyl radical which is optionally substituted one or more times by halogen, hydroxyl, mercapto, carboxyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulphinyl, C.sub.1 14 C.sub.6 alkylsulphonyl, C.sub.2 -C.sub.6 alkanoylamido, C.sub.1 -C.sub.6 alkylsulphonylamido, methylenedioxy, nitro, cyano or amino, with the proviso that R.sub.1 cannot be a C.sub.1 -C.sub.6 alkyl radical when X and Y are both hydrogen atoms; as well as the pharmacologically acceptable salts thereof. The present invention also provides intermediates of the general formula: ##STR5## in which R.sub.7 is a heterocyclic radical which is optionally substituted one or more times by hydroxy or C.sub.1 -C.sub.6 alkyl or is a phenyl radical which is optionally substituted one or more times by hydroxyl, halogen, mercapto, carboxyl, C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 14 C.sub.6 alkylsulphinyl, cyano C.sub.1 -C.sub.6 alkylsulphonyl, C.sub.2 -C.sub.6 alkanoylamido, C.sub.1 -C.sub.6 alkylsulphonylamido, nitro amino or methylenedioxy. Furthermore, the invention provides processes for the preparation of the above indolin-2-one derivatives and the above intermediates, as well as pharmaceutical compositions containing the above indolin-2-one derivatives.

Indolin-2-one derivatives preparation thereof and intermediates for the

The present invention provides heteroaryloxypropanolamines and pharmaceutical compositions containing them, for combating, and for the prophylaxis of, cardiac and circulatory diseases. The heteroaryloxypropanolamines of the present invention are of the general formula: ##STR1## wherein A is a bi- or tricyclic heteroaromatic radical, which is optionally partly hydrogenated, X is a straight-chained or branched alkylene chain containing 2 to 6 carbon atoms, R.sub.1 and R.sub.2, which can be the same or different, are hydrogen atoms or lower alkyl or benzyl radicals, R.sub.3, R.sub.4 and R.sub.5, which can be the same or different, are hydrogen atoms or lower alkyl, benzyl, formyl, lower alkanoyl, cyano, hydroxymethyl, lower alkoxycarbonyl or carbamoyl radicals or the divalent substituents sulfur or oxygen and R.sub.6, R.sub.7 and R.sub.8, which can be the same or different, are hydrogen or halogen atoms, lower alkyl, nitro, amino, lower alkylthio or lower alkoxy radicals or R.sub.6 and R.sub.7 together represent an optionally unsaturated trimethylene chain; and the pharmacologically acceptable salts thereof. The present invention also provides processes for the preparation of these compounds, as well as pharmaceutical compositions containing them.

Indazoloxypropanolamine derivatives and use in combating, and for the

The present invention provides aminopropanol derivatives of the general formula: ##STR1## wherein R.sub.1 is a hydrogen atom or a lower alkanoyl or an aroyl radical, R.sub.2 is a lower alkyl radical or a radical of the general formula: ##STR2## wherein X is a valency bond, a methylene group or an oxygen or sulphur atom, Ar is a monocyclic, carbo- or heterocyclic aryl radical, R.sub.6 and R.sub.7, which can be the same or different, are hydrogen atoms or lower alkyl radicals, R.sub.8 and R.sub.9, which can be the same or different, are hydrogen or halogen atoms, hydroxyl groups, lower alkanoyl radicals, alkenyl radicals, alkynyl radicals, alkyl radicals, lower alkoxy radicals, aralkoxy radicals, alkenyloxy radicals, alkynyloxy radicals, lower alkylthio radicals, aminocarbonyl radicals, aminosulphonyl radicals or acylamino radicals; or R.sub.2 is a 1,4-benzodioxan-2-ylmethyl radical, R'.sub.2 is a hydrogen atom or a benzyl radical, R.sub.3 is a carboxyl group or a lower alkoxycarbonyl, aminocarbonyl, cyano, oximinomethyl, formyl, hydroxymethyl or lower alkoxycarbimidoyl radical, R.sub.4 is a hydrogen atom or a lower alkyl radical or a --CH.sub.2 --O--R.sub.1 radical, R.sub.1 having the same meaning as above, and R.sub.5 is a hydrogen atom or a lower alkyl radical; the optionally-active forms and racemates thereof and the pharmacologically acceptable salts thereof. The present invention also provides processes for the preparation of these compounds and pharmaceutical compositions containing them. Furthermore, the present invention is concerned with the use of these compounds for the prophylaxis and treatment of heart and circulatory diseases.

3-Cyano-indoles as cardioselective agents

The present invention provides indole derivatives of the general formula: ##STR1## wherein R.sub.1 is a hydrogen atom, an aralkyl radical or a radical of the general formula: ##STR2## in which B is a reactive group or, together with R.sub.5, represents a valency bond, and R.sub.5 is a hydrogen atom or an aliphatic or aromatic acyl radical, R.sub.2 is a hydrogen atom or a lower alkyl radical, R.sub.3 is a hydrogen atom, a methyl radical or a --CH.sub.2 --O--R.sub.5 radical, R.sub.5 having the same meaning as above, and R.sub.4 is an aminocarbonyl, cyano, oximinomethyl, formyl, hydroxymethyl or lower alkoxycarbimidoyl radical, with the proviso that R.sub.1 is not an aralkyl radical when R.sub.4 is a formyl radical. The present invention also provides processes for the preparation of these compounds. Furthermore, the present invention is concerned with the use of these compounds for the preparation of compounds with a heart and circulatory activity.

3-Cyano indoles as intermediates for cardioselective compounds

The present invention provides heterocyclic oxypropanol derivatives of the general formula: ##STR1## wherein R.sub.1 is a hydrogen atom or a lower alkyl, aralkyl or lower alkanoyl radical, R.sub.2 and R.sub.3, which can be the same or different, are hydrogen atoms or lower alkyl, hydroxyalkyl, alkoxycarbonyl or alkanoyloxyalkyl radicals or together represent an alkylene radical, R.sub.4 is a hydrogen atom or a lower alkanoyl radical or an aroyl radical, R.sub.5 is a hydrogen atom or a lower alkyl radical or an aralkyl radical, R.sub.6 is a hydrogen atom or a lower alkyl radical, R.sub.7 is a hydrogen atom, a hydroxyl group or a lower alkyl radical, Z is a valency bond, a methylene radical or an oxygen or sulphur atom, Ar is a carbocyclic aryl radical or a pyridyl radical, R.sub.8, R.sub.9 and R.sub.10, which can be the same or different, are hydrogen or halogen atoms, hydroxyl groups, lower alkanoyl radicals, lower alkyl radicals, lower alkenyl radicals, lower alkoxy radicals, aralkoxy radicals, allyloxy radicals, lower alkylthio radicals, aminocarbonyl radicals, aminosulphonyl radicals or lower alkanoylamino radicals or R.sub.8 and R.sub.9 together represent a lower alkylenedioxy radical or R.sub.7 and R.sub.8 together represent a --CH.sub.2 --O-- radical and A is --X.sub.1 --Y.sub.1, in which X.sub.1 is a methylene or --NR.sub.11 -- radical, R.sub.11 being a hydrogen atom or a lower alkyl radical, and Y.sub.1 is a methylene radical or .dbd.C.dbd.Q, Q being an oxygen or sulphur atom; or A is --X.sub.2 .dbd.Y.sub.2 --, in which X.sub.2 and Y.sub.2, which can be the same or different and signify nitrogen atoms or .dbd.C(R.sub.12)-- groups, R.sub.12 being a hydrogen atom or a lower alkyl or an alkoxycarbonyl radical, and when --X.sub.2 .dbd.Y.sub.2 -- represents a --CH.dbd.N-- group and R.sub.1 is an alkyl or aralkyl radical, because of the ability of indazole to tautomerise, this can also be localized on the nitrogen atom represented by Y.sub.2, with the proviso that Y.sub.1 or Y.sub.2 is joined to .dbd.N--R.sub.1 in general formula (I), and, when Q is an oxygen atom or --X.sub.2 .dbd.Y.sub.2 -- represents --CR.sub.12 .dbd.CR.sub.12 -- and Z is a valency bond or when --X.sub.1 --Y.sub.1 -- represents ##STR2## and Z is an oxygen atom or a valency bond, either the two symbols R.sub.2 and R.sub.3 do not simultaneously represent hydrogen atoms or R.sub.7 and R.sub.8 together must form a --CH.sub.2 --O-- radical; and the pharmacologically acceptable salts thereof. The present invention also provides processes for the preparation of these compounds and pharmaceutical compositions containing them. Furthermore, the present invention is concerned with the use of these compounds for the treatment of cardiac and circulatory diseases.

Heterocyclic oxypropanolamine compounds and pharmaceutical compositions

A piperidinopropyl derivative of the formula ##STR1## in which R.sub.1 and R.sub.2 each independently is hydrogen or a lower alkyl radical, or together are an alkylene radical,

Growing community of inventors

Mannheim, Germany

Helmut Michel