Blood Pressure

Quinoxalinyloxy-amino-propanol compounds with blood pressure lowering and .beta.-blocking properties, their use and pharmaceutical compositions containing them

Blood Pressure Abstract
An aminopropanol compound of the formula wherein R.sub.1 and R.sub.2 are individually selected from hydrogen and lower alkyl; or R.sub.1 and R.sub.2 together represent an alkylene radical; R.sub.3 is hydrogen or acyl; A is one of the following structures ##STR2## wherein R.sub.4 is hydrogen or lower alkyl optionally substituted by hydroxyl halogen and lower alkylthio; and R.sub.5 and R.sub.6 are individually selected from lower alkyl; B is alkylamino which optionally carries a phenyl and a phenoxy radical optionally substituted by at at least one of halogen, hydroxyl or lower alkyl, lower acyl, lower alkylthio, acylamino, aminocarbonyl, lower alkoxy, lower alkenyloxy, phenoxy, lower alkenyl, lower alkylsulphonyl, lower alkylsulphinyl or haloalkyl; or B is an aryl- or heteroaryloxymethylpiperidine radical optionally substituted by at least one of halogen hydroxyl or lower alkyl, hydroxyl alkyl or carboxamido alkyl, or by lower alkoxy, lower acyl, amino, carboxamido, lower alkylcarbonylamido or lower alkylsulphonylamino; and the pharmacologically acceptable salts thereof, are outstandingly effective beta blockers and blood-pressure depressants.

Blood Pressure Claims
What is claimed is:

1. An aminopropanol compound of the formula ##STR21## wherein R.sub.1 and R.sub.2 are individually selected from hydrogen and lower alkyl; or

R.sub.1 and R.sub.2 together represent an alkylene radical of between 2 and 4 carbon atoms;

R.sub.3 is hydrogen or acyl in the form of an acid residue of an hydrocarbon aliphatic carboxylic acid containing 2 to 6 carbon atoms, an aromatic carboxylic acid or of an aromatic carboxylic acid substituted with up to two substituents selected from halogen, lower alkyl or lower alkoxy radicals;

R.sub.4 is hydrogen or lower alkyl optionally including one substituent selected from hydroxyl, halogen or lower alkylthio; and

B is alkylamino which optionally carries on the alkyl moiety a phenyl and/or a phenoxy radical optionally substituted by one of halogen, hydroxyl, lower alkyl, lower acyl, lower alkylthio, acylamino, aminocarbonyl, lower alkoxy, lower alkenyloxy, phenoxy, lower alkenyl, lower alkylsulphonyl, lower alkylsulphinyl or haloalkyl; or

B is a phenyl-, naphthyl-, pyridyl-, pyrimidyl-, or benzimidazolinyl-oxymethylpiperidine radical, optionally substituted by at least one of halogen, hydroxyl or lower alkyl, hydroxyl alkyl or carboxyamido alkyl, or by lower alkoxy, lower acyl, amino, carboxamido, lower alkanecarboxamido or lower alkylsulphonylamino; wherein the acyl radicals or acyl moieties in either B definition are in the form of an acid residue of an hydrocarbon aliphatic carboxylic acid containing 2 to 6 carbon atoms, an aromatic carboxylic acid or of an aromatic carboxylic acid substituted with up to two substituents selected from halogen, lower alkyl or lower alkoxy radicals, the piperidine radical in each case being fixed to the propanol chain by its nitrogen atom;

and the pharmacologically acceptable salts thereof.

2. A pharmaceutical composition with blood pressure lowering and .beta.-blocking properties comprising a pharmaceutically acceptable carrier and, in effective amount, an aminopropanol compound as claimed in claim 1.

3. A method of treating an afflicted subject for high blood pressure, angina pectoris or circulatory diseases by blood pressure lowering and beta-blocking, which comprises administering to the subject a pharmacologically effective amount of a pharmaceutical composition as claimed in claim 2.

4. Aminopropanol compound as claimed in claim 1 wherein B is phenyloxymethylpiperidine or naphthyloxymethylpiperidine.
Patent Information Search Body

Blood Pressure Description
This invention relates to new aminopropanol compounds, to pharmaceutical compositions containing them, and to methods of combating cardiac and circulatory insufficiencies.

The new aminopropanol derivatives according to the present invention are compounds of the formula ##STR3## wherein R.sub.1 and R.sub.2, which can be the same or different, are hydrogen atoms or lower alkyl radicals or together represent an alkylene radical;

R.sub.3 is a hydrogen atom or an acyl radical;

A is one of the following structural elements ##STR4## wherein R.sub.4 is a hydrogen atom or lower alkyl radical which is optionally substituted by halogen, hydroxyl, phenyl or alklylthio; and

R.sub.5 and R.sub.6, which can be the same or different, are lower alkyl radicals, and

B is an alkylamino radical which can carry a phenyl and/or phenoxy radical, which can be substituted one or more times by halogen, hydroxyl, lower alkyl, lower acyl, lower alkylthio, acylamino, aminocarbonyl, lower alkoxy, lower alkenyloxy, phenoxy, lower alkenyl, lower alkylsulphonyl, lower alkylsulphinyl or haloalkyl, or is an aryl- or heteroaryloxymethylpiperidine radical which can be substituted one or more times by halogen, hydroxyl or lower alkyl, which can bear a hydroxyl or carboxamido substituent, a lower alkoxy, lower acyl, amino, carboxamido, lower alkylcarbonylamido or lower alkylsulphonylamino radical; and the pharmacologically acceptable salts thereof.

Compounds of general formula (I) contain an asymmetric carbon atom and can, therefore, be present in optically-active form or as a racemic mixture. The present invention includes not only the racemic forms but also the optical isomers.

The alkylamino radicals in the definition of B are derived from lower alkylamines containing up to 6 carbon atoms and preferably 2 to 4 carbon atoms, preferred amines including isopropylamine, tert.-butylamine, sec.-butylamine and substituted and unsubstituted phenyl- and phenoxyethylamine and -propylamine.

The acyl radicals which are possibly represented by R.sub.3 can be acid residues of straight-chained and branched aliphatic carboxylic acids containing 2 to 6 carbon atoms or of aromatic carboxylic acids optionally substituted by halogen atoms or by lower alkyl or lower alkoxy radicals. Preferred acyl radicals include the acetyl, pivaloyl and benzoyl radicals.

The lower alkyl and alkoxy radicals which occur in the definitions of the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and B can be straight-chained or branched and contain up to 6 and preferably up to 4 carbon atoms, preferred radicals of this kind including the methyl, methoxy, ethoxy and propoxy radicals.

The alkylene radical which can be formed by the substituents R.sub.1 and R.sub.2 together can contain 2 to 4 carbon atoms and is preferably in the ortho position.

The term halogen means, according to the present invention fluorine, chlorine, bromine or iodine, fluorine, chlorine and bromine being preferred.

By an aryl or heteroaryl radical in the definition of substituent B, there is to be understood a carbocyclic or heterocyclic monocyclic or bicyclic radical, for example a phenyl, naphthyl, pyridyl, pyrimidyl or benzimidazolinyl radical, the phenyl, pyridyl and benzimidazolinyl radicals being especially preferred.

The compounds of general formula (I), as well as their pharmacologically acceptable salts, inhibit adrenergic .beta.-receptors and, at the same time, lower the blood pressure to a great extent. Therefore, they are suitable for the treatment and prophylaxis of cardiac and circulatory diseases.

It is known that aminopropanols of similar structure have similar actions. However, by the introduction of the new heterocyclic phenol components, a surprising improvement of the quality of action is achieved.

The new compounds of general formula (I) according to the present invention can be prepared, for example, by one of the following methods:

(a) reaction of a compound of the general formula: ##STR5## with a compound of the general formula:

H--B (III),

in which R.sub.1, R.sub.2, A and B have the same meanings as above, V represents a reactive residue and U stands for the group ##STR6## E being a hydrogen atom or an acyl radical or, together with V, forming a single bond, and, if U is the group ##STR7## subsequent reduction of the product obtained; or

(b) reaction of a compound of the general formula: ##STR8## with a compound of the general formula:

V--CH.sub.2 --U--CH.sub.2 --B (V),

in which R.sub.1, R.sub.2, A, B, U and V have the same meanings as above, and, if U is the group ##STR9## subsequent reduction of the product obtained; or

(c) when A stands for the grouping ##STR10## reaction of a compound of the general formula: ##STR11## with a compound of the general formula: ##STR12## in which R.sub.1, R.sub.2, R.sub.3 and B have the same meanings as above and R.sub.7 is a hydrogen atom or a lower alkyl radical; or

(d) when A stands for the grouping ##STR13## reaction of a compound of general formula (VI) with acetylenedicarboxylic acid; or

(e) when A stands for the grouping ##STR14## reaction of a compound of the general formula (VI) with a compound of the general formula: ##STR15## in which R.sub.4 and R.sub.7 have the same meanings as above, X.sub.1 is a halogen atom and X.sub.2 is a hydrogen atom or X.sub.1 and X.sub.2 together represent an oxygen atom, and, when X.sub.2 is a hydrogen atom, subsequent oxidation; or

(f) when A stands for the grouping ##STR16## in which R.sub.4, R.sub.5 and R.sub.6 have the same meanings as above, reduction and cyclisation of a compound of the general formula: ##STR17## in which R.sub.1, R.sub.2, R.sub.3, R.sub.7 and B have the same meanings as above and R.sub.8 is a hydrogen atom or R.sub.5 and R.sub.9 is R.sub.4 or R.sub.6, and, when R.sub.8 is a hydrogen atom, subsequent oxidation; or

(g) when A stands for the grouping ##STR18## in which R.sub.4, R.sub.5 and R.sub.6 have the same meanings as above, reduction and cyclisation of a compound of the general formula: ##STR19## in which R.sub.1, R.sub.2, R.sub.3, R.sub.8, R.sub.9 and B have the same meanings as above and Y is a reactive group and, when R.sub.8 is a hydrogen atom, subsequent oxidation; whereafter, if desired, a compound of general formula (I), in which R.sub.3 is a hydrogen atom, is acylated or a substituent in B is, if desired, converted into a different substituent B, protective groups possibly present are removed and the compound obtained of general formula (I) is, if desired, converted into a pharmacologically acceptable salt.

V and Y in compounds of general formulae (II), (V) and (X) stand for all residues which can be nucleophilically substituted, such residues including, for example, halogen atoms, preferably bromine and chlorine atoms, and sulphonic acid ester groups.

The processes according to the present invention are preferably carried out in a solvent which is inert under the reaction conditions, for example, water, ethanol, dioxan or dimethylformamide, optionally in the presence an acid-binding agent. The reactions can also be carried out, after mixing the reaction components, without the use of a solvent. The reactions are carried out by leaving the reaction mixture to stand at ambient temperature or by heating, possibly under an atmosphere of a protective gas.

The reaction of compounds of general formula (IV) with compounds of general formula (V) according to process (b) is preferably carried out with the exclusion of oxygen and in the presence of an acid acceptor. However, it is also possible to use alkali metal salts of the hydroxy compounds of general formula (IV).

The reduction of the group ##STR20## which is possibly to be carried out can take place by catalytic hydrogenation with a noble metal or nickel catalyst or by means of a complex metal hydride, for example sodium borohydride. Reductions such as are necessary for processes (f) and (g) are preferably carried out with catalytically-activated hydrogen.

Process (f) is preferably carried out under the conditions of hydrogenation; cyclisation can take place with the addition of acid.

The cyclisation according to process (g) takes place with the addition of bases, for example triethylamine or potassium carbonate.

Oxidations which are of importance for processes (e), (f) and (g) are preferably carried out with air, hydrogen peroxide in an alkaline medium or potassium permanganate.

Some of the compounds of general formula (VI) are known (see Federal Republic of Germany Patent Specification No. 27 37 630.3) and those which are not known can be prepared analogously to the processes described therein.

Compounds of general formula (IV) are either known or can be prepared from known phenols analogously to processes (c), (d), (e), (f) or (g).

Compounds of general formula (X) are new and can be obtained from the appropriate 2-nitroanilines by reaction with 2-halocarboxylic acid chlorides.

The subsequent acylation of compounds of general formula (I), in which OR.sub.3 is a hydroxyl group, possibly to be carried out can take place in the usual manner by reaction with a reactive acid derivative, for example an acid halide, acid azide or acid anhydride, possibly in the presence of an acid-binding agent, for example pyridine, in a solvent, for example acetone, benzene or dimethylformamide, or also in excess acid.

The subsequent conversion of a substituent in B can be, for example, the conversion of an amino group into an alkylcarbonylamino or alkylsulphonylamido radical. These reactions also take place according to known methods with conventional acylation agents, for example carboxylic acid anhydrides, carboxylic acid chlorides or alkylsulphonic acid chlorides.

As protective groups which may possibly be necessary, there can, in principle, be used all protective groups employed for the intermediate protection of amino or hydroxyl groups which can easily be split off again. The benzyl radical is preferred which, after the reaction according to one of the described processes, can be split off hydrogenolytically in known manner.

The compounds of general formula (I) according to the present invention can be obtained in the form of a racemic mixture. The separation of the racemate into the optically-active forms can be carried out by known methods via the diastereomeric salts with active acids, for example tartaric acid, malic acid or camphor-sulphonic acid.

Under the reaction conditions of the described processes, the new compounds of general formula (I) are preponderantly obtained as acid-addition salts, for example as hydrochlorides, and can be readily converted into the free bases according to known methods.

For the conversion of the compounds of general formula (I) into their pharmacologically acceptable salts, they are reacted, preferably in an organic solvent, with an equivalent amount of an inorganic or organic acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, citric acid or maleic acid.

The present invention also provides pharmaceutical compositions containing at least one of the new compounds in admixture with a solid or liquid pharmaceutical diluent or carrier.

For the preparation of pharmaceutical compositions, the compounds (I) are mixed in known manner with suitable pharmaceutical carrier substances, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example olive oil.

The new compounds (I) according to the present invention and the salts thereof can be administered enterally or parenterally in liquid or solid form. As injection medium, it is preferred to use water which can contain the usual additives for injection solutions, such as stabilising agents, solubilising agents or buffers. Additives of this kind include, for example, tartrate and citrate buffers, ethanol, complex formers (such as ethylenediamine-tetraacetic acid and the nontoxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening agents.