WO1984004302A1 - Substituted picolinic acids, processes for their preparation, their use and medicaments containing them - Google Patents

Abstract

Substituted picolinic acids of the general formula (I), wherein R1 denotes alkyl with 1 to 7 carbon atoms - but not butyl if R2 and R3 denote alkyl and X denotes NH -, cycloalkylalkyl with 3 to 7 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, R2 denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms and R3 denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms, or R2 and R3 together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, morpholino, piperidino, hexahydroazepino, or 1-piperazinyl which is substituted in the 4-position by R4, R4 denotes hydrogen, alkyl with 1 to 4 carbon atoms, phenyl, benzyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, A denotes straight-chain or branched alkylene with 1 to 5 carbon atoms and X denotes O (oxygen) or NH, and the acid addition salts of these compounds, R1, R2 and R3 not simultaneously denoting alkyl if X represents O (oxygen) and A represents ethylene, are new compounds with a hypotensive activity. Processes for the preparation of these compounds are described.

Description

Substituted picolinic acids, processes for their preparation, their use and medicaments containing them

Field of the invention

The invention relates to substituted picolinic acids, processes for their preparation, their use and medicaments containing them.

The compounds according to the invention are used in the pharmaceutical industry as intermedia es and for the preparation of medicaments. Known prior art

German Offenlegungsschrift DE-OS 2,306,671 describes di- and tri-substituted picolinic acid derivatives and thiopicolinic acid derivatives as dopamine β-hydroxylase inhibitors having an antihypertensive action. U.S. Patents USP 4,044,140 and USP 4,127,662 describe triphenylmethyl-substituted picolinic acid derivatives which are said to be used as anti-acne agents. Japanese P releasing Published Application 50-130,770 clear (halogeno) butyl-substituted picolinic acid amides, which are said to have a hypotensive action. Russian Patent Specification SU 598,892 describes an n-butyl-picolinic acid amide, which is said to be used as an antiarrhythmic agent. British Patent GB 1,037,380 claims pyridinecar- boxylic acid derivatives which are said to be used in pharmaceutical products.

A class of new substituted picolinic acids which have been neither ment i oned in nor suggested by the above publications has now been synthesized. It has further- more been found that these substituted picolinic acids have interesting and particularly advantageous pharmacological properties. Summary of the invention

whereinThe invention relates to substituted picolinic acids of the general formula I

wherein

R ¹ denotes alkyl with 1 to 7 carbon atoms - but not butyl if R ² and R ³ denote alkyl and X denotes NH -, cycloaIkylaIkyl with 3 to 7 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms,

R ² denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms and R ³ denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms, or

R ² and R ³ together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, morpholino, piperidino, hexahydroazepino, or 1- piperazinyl which is substituted in the 4-position by R ⁴ ,

R ⁴ denotes hydrogen, alkyl with 1 to 4 carbon atoms, phenyl, benzyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms,

A refers to the chain or branched alkylene with 1 to 5 carbon atoms and X denotes O (oxygen) or NH, and the acid addition salts of these compounds, R ¹ , R ² and R ³ not simultaneously denoting alkyl if X represents O (oxygen) and A represents ethylene.

Alkyl radicals can be straight-chain (for example methyl, ethyl, propyl, pentyl, hexyl and heptyl) or branched (for example isopropyl, isobutyl, sec.-butyl, tert.-butyl, neopentyl, 3-methylbutyl or 3,3 -dimethylbutyl).

Cycloalkyl radicals in the cycloalkylalkyl groups are the cyclopropyl, cyclobutyl, cycloheptyl and, in particular, the cyclopentyl and cyclohexyl radical. Alkylene radicals in the cycloalkylalkyl groups are the tetramethylene, trimethylene, ethylene and, in particular, the methylene radical. A preferred cycloalkylalkyl radical is the cyclohexylmethyl radical.

In the context of the invention, halogen atoms are the fluorine, chlorine and bromine atom. Examples of alkoxy groups are the butoxy, propoxy and, in particular, the ethoxy and methoxy group.

Examples of alkenyl radicals which may be mentioned are the allyl, 2-methallyl and 1-butenyl radical. Examples of alkylene groups which may be mentioned are the methylene, ethylmethylene, propylene, tetramethylene, pentamethylene and, in particular, the trimethylene and ethylene group.

Possible salts are all the acid addition salts. Pharmacologically acceptable salts of the inorganic and organic acids customarily used in galenics may be mentioned in particular. Pharmacologically unacceptable salts, which, for example, may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes which are known to the expert. Examples of such suitable salts are acid addition salts which are readily or even sparingly soluble in water, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate (2- (4-hydroxybenzoyl ) -benzoate), propionate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4,4'-diamino stilbene-2,2'-disulfonate), embonate (1,1'-methylene-bis-2-hydroxy-3-naphthoate), metembonate, stearate, tosylate (p-toluenesulfonate), 2-hydroxy-3-naphthoate, 3 -hydroxy- 2-naphthoate and mesylate (methanesulfonate), and furthermore salts with bumetanide (3- (butylamino) -4-phenoxy-5-sulfamoyl-benzoic acid), furosemide (4-chlσro-N-furfuryl-5-sulfamoylanthranilic acid ), azosemide [2-chloro-5- (1Htetrazol-5-yl) -N ⁴ -2-thenylsulfanilamide], galosemide [N- [4- (3-trifluoromethylanilino) -3-pyridylsulfonyl] propionamide], besunide (4th -benzyl-3- (butylamino) -5-sulfamoyl-benzoic acid), piretanide (4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid), etacrynic acid ([2,3-dichloro-4 - (2-methylenebutyryl) phenoxy] acetic acid), tienilic acid ([2,3-dichloro-4- (2-thenoyl) phenoxy] - acetic acid) and 4-chloro-3-sulfamoyl-benzoic acid. Compounds of the general formula I wherein R ¹ denotes alkyl with 1 to 7 carbon atoms - but not butyl if

R ² and R ³ denote alkyl and X represents NH -, R ² denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms and R ³ has one of the meanings of R ² , or R ² and R ³ together , and including the nitrogen atom to which they are bonded, denote pyrrolidino, morpholino, piperidino, hexahydroazepino, or 1-piperazinyl which is substituted in the 4-position by R ⁴ , R ⁴ denotes hydrogen, alkyl with 1 to 4 carbon atoms, phenyl, benzyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, A denotes straight-chain or branched alkylene with 1 to 5 carbon atoms and X denotes O (oxygen) or NH, and the acid addition salts of these compounds, R ² and R ³ not simultaneously denoting alkyl when X represents O (oxygen) and A represents ethylene, form an embodiment (embodiment a) of the invention.

Compounds of the general formula I wherein R ¹ denotes cycloalkylalkyl with 3 to 7 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, R ² denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms, R ³ has one of the meanings of R ² , A denotes straight- chain or branched alkylene with 1 to 5 carbon atoms and X denotes O (oxygen) or NH, and the acid addition salts of these compounds, form a further embodiment (embodiment b) of the invention. Compounds of the general formula I wherein R ² denotes cycloalkylalkyl with 3 to 7 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to three substitutes from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, R ² and R ³ together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, morpholino, piperidino, hexahydroazepi no, or 1- piperazinyl which is substituted in the 4-position by R ⁴ , R ⁴ denotes hydrogen, alkyl with 1 to 4 carbon atoms, phenyl, benzyl or substituted phenyl with up to three substitutes from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, A denotes straight-chain or branched alkylene with 1 to 5 carbon atoms and X denotes O (oxygen) or NH, and the acid addition salts of these compounds, form another embodiment (embodiment c) of the invention .

Preferred compounds of embodiment a are those of the general formula I *

(I *)

wherein

wherein

R ¹ * denotes alkyl with 1 to 5 carbon atoms (but not butyl if R ² * and R ³ * denote methyl or ethyl and X represents NH),

R ² * denotes methyl or ethyl and

R ³ * denotes methyl or ethyl, or R ² * and R ³ * together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, piperidino, or 1-piperazinyl which is substituted in the 4-position by R ⁴ * ,

R ⁴ * denotes phenyl, or phenyl which is substituted by methoxy or ethoxy,

A * denotes ethylene or trimethylene and X * denotes O (oxygen) or NH, and the acid addition salts of these compounds, R ² * and R ³ * not denoting methyl or ethyl when X * represents O (oxygen) and A * represents ethylene.

Preferred compounds of embodiment b are those of the general formula I **

wherein

R ¹ ** denotes cycloalkylalkyl with 5 or 6 carbon atoms in the cycloalkyl part and 1 or 2 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to two substituents from the group comprising chlorine, methoxy and ethoxy,

R ² ** denotes methyl or ethyl,

R ³ ** denotes methyl or ethyl,

A ** denotes ethylene or trimethylene and

X ** denotes O (oxygen) or NH, and the acid addition salts of these compounds.

Preferred com ounds I ** are those in which A ** denotes trimethylene, X ** denotes NH and R ¹ **, R ² ** and R ³ ** have the abovement ion.ed meanings, and the pharmacologically acceptable acid addition salts of these compounds. Particularly preferred compounds I ** are those in which R ¹ ** denotes cyclohexylmethyl, phenyl or 4-chlorophenyl, R ² ** and R ³ ** denote methyl or ethyl, A ** represents trimethylene and X ** represents NH, and the pharmacologically acceptable acid addition salts of these compounds.

Preferred compounds of embodiment c are those of the general formula I ***

wherein R ^{1 ***} denotes cycloalkylalkyl with 5 or 6 carbon atoms in the cycloalkyl part and 1 or 2 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to two substituents from the group comprising chlorine, methoxy and ethoxy, R ^{2 ***} and R ^{3 ***} together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, piperidino, or 1-piperazinyl which is substituted in the 4-position by R ^{4 ***} , R ^{4 ** *} denotes hydrogen, methyl, phenyl or phenyl which is substituted by methoxy or ethoxy,

A *** denotes ethylene or trimethylene and X *** denotes O (oxygen) or NH, and the acid addition salts of these compounds.

Preferred compounds I *** are those in which A *** denotes trimethylene, X *** denotes NH and R ^{4 ***,} R ^{2 ***,} R ³ *** and R ⁴ *** have the abovementioned meanings, and the pharmacologically acceptable acid addition salts of these compounds.

Particularly preferred compounds I *** are those in which R ¹ *** denotes cyclohexylmethyl, phenyl or 4-chlorophenyl, R ² *** and R ³ *** together, and including the nitrogen atom to which they are bonded, denote piperidino, or 1-piperazinyl which is substituted in the 4-position by R ⁴ ***, R ⁴ *** denotes 2-methoxy- or 2-ethoxy-substituted phenyl, A *** represents trimethylene and X *** represents NH, and the pharmacologically acceptable acid addition salts of these compounds.

Embodiments b and c are preferable to embodiment a Examples which may be mentioned of representatives of the compounds according to the invention are: 3- diethylaminopropyl 5-n-propylpyridine-2-carboxylate, 5-ethyIpyridine-2-carboxylic acid (5-dimethylaminopentyl ) - amides, 5-n-hexy lpyridine-2-carboxylic acid (2-diethylaminoethyl) amide, 5-isopropy lpyridine-2-carboxylic acid (3-dimethylaminobutyl) amide, 5-n-butylpyridine-2-carboxylic acid (3-piperidinopropyl) amide, 5-n-hexylpyridine-2-carboxylic acid (2-pyrrolidinoethyl) amide, 5-morpholinopentyl 5-ethyIpyridine-2-carboxylate, 5-methylpyridine-2-carboxylic acid (2-piperidinobutyl) amide, 3-diethylaminopropyl 5-cyclopentyImethyIpyridine-2-carboxylate, 5- (2-cyclohexylethyl) -pyridine-2-carboxylic acid (4-dimethylaminobutyl) amide, 5-cycloheptylmethyIpyridine-2-carboxylic acid (3-diethylaminopropyl) amide, 2 -diisopropylaminoethyl 5- (3-cyclobutylpropyl) -pyridine-2-carboxylate, 5-cyclopropyimethylpyridine-2-carboxylic acid (3-pyrroli dinopropyl) amide, 5-cyclohexylmethylpyridine-2-carboxylic acid (3- [4- (2-methylphenyl) piperazin-1-yl] propyl) amide, 5- (2-cyclopentylethyl) pyridine-2-carboxylic acid [3 - (4-phenylpiperazin-1-yl) propyl] amide, 5-cyclohexytmethylpyridine-2-carboxylic acid (4- [4- (2-methoxyphenyl) piperazin-1-yl] butyl) amide, 5- (3- cyclobutyipropyl) pyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amide, 5- (4-chlorophenyl) pyridine-2-carboxylic acid (4- diethylaminobutyl) amides, 5- (2,4-dichlorophenyl) pyridine-2-carboxylic acid (3-dimethylaminopropyl) amide, 4-diisopropylaminobutyl 5- (4-hydroxyphenyl) pyridine-2-carboxylate, 5- (4-ethoxyphenyl) pyridine- 2-carboxylic acid (2-diethylaminopropyl) amide, 5- (2,4-dichlorophenyl) pyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl -_-propyl) amide , 5- (4-chlorophenyl) pyridine-2-carboxylic acid [3- (4-methylpiperazin-1-yl) propyl lamide, 5-phenylipyridine-2-carboxylic acid (4- [4- (2nd -methoxyphenyl) piperazin-1-yl -] - butyl) - amide, 5- (4-hydroxyphenyl) -pyridine-2-carboxylic acid (3- (4- (2-methylphenyl) piperazin-1-yl] -propyl) amide and 5- (2,4,6-trichlorophenyl) pyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl-3-propyl) amide, and in particular 5-cyclohexyimethylpyridine -2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amide, 5- (4-chlorophenyl) pyridine-2-carboxylic acid (3-diethylaminopropyl) amide, 5 - (4-chlorophenyl) pyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperaz in-1-yl) -propyl) - amide and 5-phenylpyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) -piperazin-1-yl] -propyl) amide, and the acid addition salts of these compounds.

Where compounds "of the (general) formula I" are referred to in the description which follows, this expression comprises (or represents) the compounds of executing a, b and c, the compounds I *, I ** and I *** , their preferred and particularly preferred representatives and the compounds mentioned expressis verbis; this expression moreover includes the acid addition salts of these compounds. The invention furthermore relates to a process for the preparation of substituted picolinic acids of the general formula I, which comprises reacting picolinic acid derivatives of the general formula II

(II)

w i t h a mi n es of th e gene ra l f o rmu l a I I I

witha mi n es of th e gene ra lfo rmu la III

(III)

and, if desired, then converting the products into the acid addition salts, the radicals Y and Z being chosen so that the desired member X is formed, and R ¹ , R ² , R ³ ,

A and X have the subscription ioned meanings.

The expert is familiar, on the basis of his expert knowledge, with which radicals Y and Z must be chosen. The following list gives a summary of suitable radicals Y and Z for the desired X:

X - O (oxygen) a) Y = OH, Z = OH (esterification) b) Y = halogen, Z = OH c) Y = OR '(R' is, for example, methyl or ethyl), Z = OH ( transesterification) d) Y = 0 ^θ (salt of a picolinic acid derivative), Z = a leaving group (for example halogen, such as bromine or chlorine) (alkylation) X = NH e) Y = OH, Z = NH ₂ f ) Y = halogen, Z = NH ₂ g) Y - OR '(R' is, for example, methyl or ethyl), Z = NH ₂ h) Y = -O-CO-OR '(R * is, for example , methyl or ethyl),

Z = NH ₂ The reaction according to a) is carried out analogously to conventional esterification reactions, preferably in an anhydrous solvent (for example dichloroethane, toluene, benzene or dioxane), under acid catalysis (mineral acid or acid ion exchanger), at temperatures between 50 and 150 ° C, at the boiling point of the solvent used, and using a water separator or a water-absorbing molecular sieve.

The reaction according to b) is carried carried out in an inert, anhydrous solvent (for example acetonitrile, dichloroethane, tetrahydrofuran or benzene), an acid bromide or chloride preferably being used as the acid halide. The reaction is carried out with simultaneous cooling or with slight heating, but preferably at room temperature, depending on the reactivity of the alcohol used. The reaction is carried out with the addition of an acid-binding agent (for example an amine, such as triethylamine), or with an excess of compound III.

The transesterification reaction according to c) is preferably carried out under base catalysis, for example by addition of catalytic amounts of sodium, in inert high-boiling solvents (for example xylene) or with- out a solvent, at temperatures between 50 and 180 ° C.

The alkylation reaction according to d) is carried out either as a one-phase reaction (direct reaction of the picolinic acid salt with the alkylating agent) or as a two-phase reaction with addition of a phase transfer catalyst (use of the free acid and a suitable base).

The amide formation reaction according to e) is carried out by heating (preferably to 50 to 100 ° C) the corresponding acid and the amine in inert anhydrous solvents (such as, for example, tetrahydrofuran, dioxane or toluene), preferably in the presence of a water binding agent (for example a carbodiimide).

The reaction according to f) can be carried out analogously to the reaction described under b). The reaction according to g) is carried carried out as described for c), without the addition of a solvent, at elevated temperature and if necessary under base catalysis. The reaction with the mixed anhydride according to h) is preferably carried out in anhydrous solvents (for example in methylene chloride, chloroform or dioxane) at temperatures between 0 ° and 50 ° C, preferably at room temperature. Instead of a mixed anhydride, it is, of course, also possible to use the pure anhydride of the corresponding picolinic acid.

Acid addition salts are obtained by dissolving the free base in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a Iow-molecular aliphatic alcohol (ethanol or isopropanol) containing the desired acid or to which the desired acid is subsequently added.

The salts are isolated by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or evaporation of the solvent.

The salts obtained can be converted into the free bases by treatment with alkali, for example with aqueous sodium bicarbonate, and the bases can in turn be converted into acid addition salts. Pharmacologically unacceptable acid addition salts can in this way be converted into pharmacologically acceptable acid addition salts.

The starting compounds II and III are either known, or they can be prepared by known processes. Compounds II, II *, II ** or II *** and III, III *,

III ** or III *** in which the substituents and symbols R ¹ ,

R ² , R ³ and A, R ¹ *, R ² *, and A *, R ¹ **, R ² **, R ^{3 **} and

A ** and R ^{1 ***} , R ^{2 ***} , R ^{3 ***} and A *** have the above- mentioned meanings, the members X, X *, X ** or X *** being formed by suitable radicals Y and Z, which have the above- mentioned meanings, are used as starting substances for the preparation of the compounds of embodiments a, b and c or their preferred representatives I *, I ** and I ***.

The examples which follow illustrate the invention in more detail, without limiting it. m.p. represents "melting point" and b.p. represents "boiling point". Examples of carrying out the invention

1. 2-Diethylaminoethyl 5-n-butylpyridine-2-carboxylate a) 20 ml of thionyl chloride are poured over 5 g of 5-n-butylpyridine-2-carboxylic acid, with external cooling, and the mixture is left to stand overnight . The suspension is evaporated in vacuo, the dark residue is taken up in 50 ml of acetonitrile and the mixture is added dropwise to a solution of 9 g of 2-diethylaminoethanol in 20 ml of acetonitrile. The mixture is stirred at room temperature for 6 hours and is then evaporated in vacuo. The semi-solid residue is taken up in 100 ml of 2 N hydrochloric acid and the mixture is extracted with 3 100 ml portions of chloroform. The aqueous phase is then adjusted to pH 9 with 2 N sodium hydroxide solution and the oil which separates out is extracted with 3 100 ml portions of chloroform. The combined chloroform phases are dried over calcined calcium carbonate and evaporated in vacuo. The brown oil which remains is subjected to bulb tube distillation. The title compound distills at 150 ° c / 0.015 mm Hg (2 Pa) as a slightly yellowish oil. Yield: 3.8 g (53%). b) 5.0 g of methyl 5-n-butylpyridine-2-carboxylate are heated to 130 ° C with 9.1 g of 2-diethylaminoethanol and 100 mg of sodium in an oilbath for 2 hours. The mixture is then evaporated in vacuo and further treatment is carried out as described under a). After distillation, 4.0 g (56%) of the title compound are obtained. c) 5.0 g of 5-n-butylpyridine-2-carboxylic acid are heated under reflux with 4.4 g of 2-diethylaminoethanol hydrochloride and 1 g of p-toluenesulfonic acid in 50 ml of 1,2-dichloroethane in a round-bottomed flask . with a Thielepape head for 12 hours. The molecular sieve in the head removes the water formed. When the reaction has ended, the contents of the flask are cooled, 2 N hydrochloric acid is added and the dichloroethane phase is stripped off. The aqueous solution, containing hydrochloric acid, is worked up as described under a). 3.2 g (44%) of the title compound are obtained. 2. 3-Dimethylaminopropyl 5-n-butylpyridine-2-carboxylate

5.0 g of 5-n-butylpyridine-2-carboxylic acid are stirred vigorously with 8.8 g of tetrabutylammonium bisulfate and 5 g of 3-dimethylaminopropyl chloride hydrochloride in a mixture of 100 ml of 2 N sodium hydroxide solution and 100 ml of methylene chloride at 30 ° C for 8 hours. The methylene chloride phase is then separated off, dried over potassium carbonate and evaporated in vacuo. The brownish oil which remains is distilled in a bulb tube, the title compound being obtained at 150 ° C / 0.01 mm Hg (1.33 Pa) as a slightly yellowish oil in a yield of 2.0 g (29%). 3. 3- [4- (2-methoxyphenyl) piperazin-1-yl) propyl) 5-n-butylpyridine-2-carboxylates

1.3 g of methyl 5-n-butylpyridine-2-carboxylate and 1.7 g of 1- (3-hydroxypropyl) -4- (2-methoxyphenyl) - piperazine are stirred at 140 ° C, with addition of 100 mg of sodium, for 16 hours, methanol slowly being distilled off. The black-brown mass is chromatographed on neutral silica gel using chloroform / methanol 98: 2, for purification. After evaporation of the appropriate fractions, 0.8 g (27%) of the title compound is obtained as a light brown oil. 4. 2-Dimethylaminoethyl 5-phenylpyridine-2-carboxylate

5.0 g of methyl 5-phenylpyridine-2-carboxylate are heated with 10 ml of 2-dimethy laminoethanol and about 100 mg of sodium to 50 ° C for 3 hours and to 100 ° C for a further 2 hours. The reaction mixture is then evaporated in vacuo and the dark brown residue is chromatographed as described in Example 3. 0.8 g of the title compound is obtained as a light, yellowish-brown oil. 5. 3-Diethylamino propyl 5-phenylpyridine-2-carboxylate

2.4 g (33%) of the title compound are obtained as a brownish oil from 5.0 g of methyl 5-phenylpyridine-2-carboxylate and 9.3 g of 3-diethylaminopropanol by the procedure described in Example 1 b, after bulb tube dis- tillation at 200 ° C / 0.15 mm Hg (20 Pa).

6. 2- [4-phenylpiperazin-1-yl] ethyl 5-phenylpyridine-2-carboxylates

0.6 g of the title compound of m.p. 150 ° C is obtained from 5.0 g of methyl 5-phenylpyridine-2-carboxylate and 13.8 g of 1- (2-hydroxyethyl) -4-phenylipiperazine in 25 ml of xylene by the procedure described in Example 3, after chromatographic purification and crystallization from petroleum spirit (bp 50-70 ° C).

7. 5-n-butylpyridine-2-carboxylic acid (2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl) amide a) 4.66 g of 5-n-butylpyridine-2- carboxylic acid are stirred at room temperature in 50 ml of anhydrous tetrahydrofuran with 5.9 g of dicyclohexylcarbodiimide for 1 hour. After addition of 6.71 g of 1- (2-aminoethyl) -4- (2- methoxyphenyl) -piperazine, dissolved in 30 ml of tetrahydrofuran, the reaction mixture is stirred at room temperature for a further hour and is then heated to the boiling point under reflux for 1 hour. The reaction solution is allowed to cool and is evaporated in vacuo and the residue is taken up in 2 N hydrochloric acid. The dicyclohexylurea which remains is filtered off and the filtrate is extracted with 3 100 ml portions of chloroform. The aqueous phase is separated off and adjusted to pH 8-9 with potassium carbonate and the phase which separates out is extracted with chloroform. The combined extracts are dried over potassium carbonate siccative and evaporated in vacuo. The residue is chromatographed on neutral silica gel using chloroform / methanol 9: 1. After the fractions have been evaporated, the oily amide is taken up in a little acetone, 20 ml of methanolic hydrochloric acid are added and the mixture is freed from the solvent in vacuo. After the residue has been dried over potassium hydroxide at 90 ° C in vacuo, 11.2 g (83%) of the title compound are obtained as the trihydrochloride of mp 210 ° C. b) 5.0 g of methyl 5-n-butylpyridine-2-carboxylate and 12.2 g of 1- (2-aminoethyl) -4- (2-methoxyphenyl) - piperazine are stirred at 140 ° C for 2 hours. After the reaction mixture has cooled, it is dissolved in acetone, excess methanolic hydrochloric acid is added and the mixture is evaporated. The salt which remains is extracted by boiling several times with acetone and is dissolved in water and extracted with 3 30 ml portions of methylene chloride. The aqueous phase is brought to pH 9-10 with 2 N sodium hydroxide solution and extracted exhaustively with methylene chloride. After the solvent has been stripped off, the oily residue is distilled in a bulb tube at 260 ° C / 0.15 mm Hg (20 Pa). 6.2 g (85%) of the title compound are obtained as an almost colorless oil. 8. 5-n-Butylpyridine-2-carboxylic acid (3-diethylaminopropyl) amide

20 ml of thionyl chloride are poured over 5.0 g of 5-n-butyIpyridine-2-carboxylic acid, with external cooling, and the mixture is left to stand overnight. The reaction mixture is evaporated in vacuo, the dark residue is taken up in chloroform and the mixture is added dropwise to a solution of 6.7 g of 3-diethylaminopropylamine in 20 ml of chloroform. The mixture is stirred at 40 ° C for 3 hours and, after cooling, is extracted with 2 N sodium hydroxide solution. The chloroform phase is dried over potassium carbonate and evaporated. The oily residue is distilled in a bulb tube at 170 ° C / 0.01 mm Hg (1.33 Pa) and 4.2 g (56%) of the title compound are obtained as a yellowish oil.

9. 5-n-Butylpyridine-2-carboxylic acid (2-dimethylaminoethyl) amide

5.4 g of 5-n-butylpyridine-2-carboxylic acid are dissolved in 60 ml of methylene chloride with 3 g of triethylamine. 3.3 g of ethyl chlorocarbonate are added dropwise, with ice-cooling, the mixture is stirred at room temperature for 15 minutes, 3.4 g of 2- dimethylaminoethylamine are added and the mixture is stirred at room temperature for a further 30 minutes. The methylene chloride solution is then extracted by shaking with 2 N hydrochloric acid; the hydrochloric acid phase is rendered alkaline with 2 N sodium hydroxide solution and extracted again with methylene chloride. The combined organic extracts are extracted with water, dried over potassium carbonate and concent rated. After distillation of the residue in a bulb tube at 150 ° C / 0.01 mm Hg (1.33 Pa), 4.9 g (66%) of the title compound are obtained as a slightly yellowish oil. 10. 5-Phenylpyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amide

5.0 g of methyl 5-phenylpyridine-2-carboxylate and 10 g of 1- (3-aminopropyl) -4- (2-methoxyphenyl) piperazine are stirred at 140 ° C for 1.5 hours. After cooling, the reaction mixture is taken up in a little chloroform and is purified by chromatography on neutral silica gel using chloroform / methanol 95: 5. After the appropriate fractions have been evaporated, the residue is crystallized from petroleum spirit (bp 50-70 ° C) / ethyl acetate 9: 1. 3 g (30%) of the title compound of mp 132-134 ° C are obtained.

11. 5-Phenylpyridine-2-carboxylic acid (3-dimethylamino-propyl) -amide 5.0 g of methyl 5-phenylpyridine-2-carboxylate are stirred in 20 ml of 3-dimethylaminopropylamine at 70 ° C for 3 hours. All the volatile constituents are stripped off in vacuo, the residue is taken up in chloroform and the mixture is chromatographed on neutral silica gel using chloroform / methanol 9: 1. The appropriate fractions are collected and concentrated and the residue is distilled in a bulb tube at 210 ° C / 0.1 mm Hg (13.3 Pa). 3.8 g (57%) of the title compound are obtained as a yellowish oil. The following pyridine-2-carboxylic acid amides are obtained from correspondingly substituted methyl pyridine-2-carboxylates and amines by the procedure described in Example 11:

12. 5-Phenylpyridine-2-carboxylic acid (2-piperidinoethyl) amide

From methyl 5-phenylpyridine-2-carboxylate and 2-piperidinoethylamine. M.p. 72-76 ° C; yield: 44%.

13. 5-Phenylpyridine-2-carboxylic acid (2-diethylaminoethyl) -amide From methyl 5-phenylpyridine-2-carboxylate and

2-diethylaminoethylamine. B.p. (bulb tube): 190 ° C / 0.1 mm Hg (13.3 Pa); m.p. 47-53 ° C; yield: 20%.

14. 5- (3,4-dichlorophenyl) pyridine-2-carboxylic acid (2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl) amide from methyl 5- (3,4- dichlorophenyl) pyridine-2-carboxylate and 2- [4- (2-methoxyphenyl) piperazin-1-yl] ethylamine. M.p. 104 ° C; yield: 40%.

15. 5- (4-Chlorophenyl) pyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amide from methyl 5- (4-chlorophenyl) pyridine -2-carboxylate and 3- [4- (2-methoxyphenyl) piperazin-1-yl] propylamine. Mp 143 ° C; yield: 83%. 16. 5- (4-Chlorophenyl) pyridine-2-carboxylic acid (3-diethylaminopropyl) amides

From methyl 5- (4-chlorophenyl) pyridine-2-carboxylate and 3-diethylaminopropylamine. M.p. 79 ° C (x 1.5 HCl); yield: 15%.

17. 5-Cyclohexylmethylpyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amide

From methyl 5-cyclohexylimethylpyridine-2-carboxylate and 3- [4- (2-methoxyphenyl) piperazin-1-yl) propyl amine. M.p. 186 ° C (x HCl); yield: 82%.

18. 5- (3,4-Dimethoxyphenyl) pyridine-2-carboxylic acid (3-piperidinopropyl) amides

From methyl 5- (3,4-dimethoxyphenyl) pyridine-2-carboxylate and 3-piperidinopropylamine. M.p. 89 ° C; yield: 77%.

19. 5-Cyclohexylmethylpyridine-2-carboxylic acid (3- [4- (2-ethoxyphenyl) piperazin-1-yl] propyl) amides

From methyl 5-cyclohexylmethylpyridine-2-carboxylate and 3- [4- (2-ethoxyphenyl) piperazin-1-yI] propylamine. Mp 80 ° C (x HCL x H ₂ O); yield: 58%.

20. 5-Cyclohexyimethylpyridine-2-carboxylic acid (3-dimethylaminopropyl) amide

From methyl 5-cyclohexylmethylpyridine-2-carboxylate and 3-dimethylaminopropylamine. Slightly yellowish oil; yield: 62%.

21. 5-Cyclohexyimethylpyridine-2-carboxylic acid (3-piperidinopropyl) amide

From methyl 5-cyclohexylimethylpyridine-2-carboxylate and 3-piperidinopropylamine. M.p. 77 ° C; yield: 64%. 22. 5- (3,4-Dimethoxyphenyl) pyridine-2-carboxylic acid

(3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amides From methyl 6- (3,4-dimethoxyphenyl) pyridine-2-carboxylates and 3- [4- (2-methoxyphenyl ) -piperazin-1-yI] - propylamine. M.p. 143 ° C; yield: 59%. 23. 5- (3,4-Dimethoxyphenyl) pyridine-2-carboxylic acid (3-dimethylaminopropyl) amides

From methyl 5- (3,4-dimethoxyphenyl) pyridine-2-carboxylate and 3-dimethylaminopropylamine. Mp 111 ° C; yield: 72%. 24. 5-Cycl oh e xyImethylpyridine-2-carboxylic acid (3-pyrrolidinopropyl) amide

From methyl 5-cyclohexylmethylpyridine-2-carboxylate and 3-pyrrolidinopropylamine. Slightly yellowish oil; yield: 61%.

25. 5- (3,4-Dimethoxyphenyl) pyridine-2-carboxylic acid (3-pyrrolidinopropyl) amides

From methyl 5- (3,4-dimethoxyphenyl) pyridine-2-carboxylate and 3-pyrrolidinopropylamine. M.p. 102-104 ° C; yield: 67%. Commercial usefulness

The substituted picolinic acids of the general formula I according to the invention have valuable pharmacological properties, which render them commercially useful; in particular, they cause a lasting lowering in blood pressure, as can be seen from investigations on conscious, genetically hypertonic rats, in which they prove to be superior to known picolinic acid derivatives, such as, for example, 5-butyl-2- pyridinecarboxylic acid (INN: fusaric acid) or 5-butyl-2-pyridinecarboxylic acid amide (INN: bupicomide). The compounds according to the invention also inhibit electrically induced tachycardia, and moreover display an interesting α ₁ -adrenolytic action.

The excellent activity of the compounds of the general formula I according to the invention enables them to be used in human medicine, possible indications being, in particular, primary (essential) and secondary hypertensions of all degrees of severity.

The invention thus furthermore relates to a method of treating mammals suffering from one of the abovicted diseases. The method is characterized in that a therapeutically active and pharmacologically acceptable amount of one or more compounds of the general formula I is administered to the sick mammal. The invention also relates to the compounds of the formula I for use in the treatment of hypertension.

The invention moreover relates to the use of compounds of the formula I in the preparation of medicaments used for combating hypertension. The invention furthermore relates to medicaments containing one or more compounds of the general formula I.

The medicaments are prepared by processes which are known per se and with which the expert is familiar. As medicaments, the pharmacologically active compounds (= active ingredients) according to the invention are used either as such or, preferably, in combination with suitable pharmaceutical auxiliaries, in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions.

The expert is familiar, on the basis of his expert knowledge, with which auxiliaries are suitable for the desired medicament formulations. Besides solvents, gelling agents, ointment bases, suppository bases, tableting auxiliaries and other active compound excipients, it is also possible to use, for example, antioxidants, dispersing agents, emulsifiers, anti-foaming agents, flavor correctants, preservatives, solubilizing agents or colorants. The active compounds can be administered orally or parenterally, oral and intravenous administration being preferred.

In general, it has proved advantageous in human medicine to administer the active compound or compounds, when these are given orally, in a daily dose of about

0.01 to about 50, preferably 0.1 to 20 and in particular 0.5 to 10 mg / kg of body weight, if appropriate in the form of several, preferably 1 to 4, individual administrations to achieve the desired result. In the case of parenteral, for example intravenous, treatment, similar dosages can be used. For determining proper dosage by incrementally increasing the doses, a lower dose is administered at the start of the treatment and this is slowly increased to a higher dose. After the desired lowering of blood pressure has been achieved, a lower dose is returned to again.

The optimum dosage and mode of administration of the active compounds required in each particular case can easily be determined by any expert, on the basis of his expert knowledge. If the substituted picolinic acids according to the invention and / or their acid addition salts are to be used for the treatment of hypertension, the pharmaceutical formulations may also contain one or more other pharmacologically active members of other groups of medicaments, such as other anti- hypertensive agents, β - receptor blockers, diuretics, saluretics, alkaloids and the like, such as dihydralazine, propranolol, labetalol, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, reserpine, dihydroergoamine, Rwolfau, Rauau and thewolf Like.

T h e a c t i ve c o mpounds can be formulated, for example, in the following manner: a) Tablets with an active compound content of 20 mg

10.81 kg of 5-cyclohexyimethylpyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) - amide hydrochloride, 50.0 g of calcium sulfate dihydrate, 31.0 kg of maize starch and 3.0 kg of polyvinylpyrrolidone are moistened with 20 liters of water and the mixture is granulated through a sieve of 1.25 mm mesh width. The granules are dried in a fluidized bed dryer down to a relative moisture content of 50-60%, and 8.0 g of sodium carboxymethylellulose, 2.0 kg of talc and 1.0 kg of magnesium stearate are then added. The finished granules are pressed to tablets weighing 200 mg and 8 mm in diameter. b) Ampoules with an active compound content of 22.5 mg 1,502 kg of 5- (4-chlorophenyl) pyridine-2-carboxylic acid (3-diethylaminopropyl) -amide fumarate are dissolved in 80 liters of doubly distilled water, and 4,337 kg of mannitol are added. The solution is made up to 100 kg with doubly distilled water, sterile-filtered over a filter and filled into 2 ml ampoules. c) 25,000 delayed release capsules with an active compound content of 30 mg

8.9 kg of 5- (4-chlorophenyl) pyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amide hydrochloride and 3.1 kg of hydroxypropyl isomethylellulose are dissolved in a mixture of 16 ethanol and 24 liters of water. 1.1 kg of talc are suspended in this solution. 16 kg of sugar pellets are sprayed with this solution of active compound in a fluidized bed apparatus. The resulting pellets of active compound are sprayed, in the same apparatus, with a solution of 0.6 kg of ethyl cellulose, 0.3 kg of hydroxypropyl methyl cellulose and 0.12 kg of stearic acid in 14.8 liters of methylene chloride and 4.0 liters of 96% strength ethanol. After the coated pellets of active compound have dried, they are filled into size 4 hard gelatin capsules.

Pharmacology

To determine the anti-hypertensive action, the given doses of the compounds listed below are administered once daily, by means of a stomach tube, to in each case 6 rats (strain SHR / N / Ibm / Bm, ♂, 250-350 g ) with high blood pressure of genetic origin (RR> 180 mm Hg) on four successive days. The blood pressure is measured in each case 2 and 6 hours after administration of the substance.

The blood pressure is measured in a heat chamber at 36 ° C, in order to achieve better blood circulation in the tail artery. For this, the animals are placed in perforated plate cages and the measurements are made 20 - 40 minutes after the start of warming up. To measure the systolic arterial pressure, an annular cuff with an inflatable rubber membrane, for stopping the blood circulation, and an annular piezo crystal recorder, for recording the pulse waves, are pushed onto the tail. When the flow of blood in the tail artery has been stopped, the cuff pressure is reduced continuously. The recurrence of the pulse waves when reducing the cuff pressure is recognized automatically as systolic blood pressure and printed out accordingly (Bühler, R. et al .: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. (Eds.), Schattauer Verlag, Stuttgart, New York, 1982, P.410-413).

The pulse signals and pressure course are plotted graphically for evaluation.

To accustom them to the measuring operation, the animals are trained for 14 days before testing of the substance. In the second week of training, blood pressure pre-values are recorded. Groups of animals receiving the substance are tested against a control group.

For determining the inhibition of electrically induced tachycardia, the method of Kobinger and Pichler is used

(Kobinger, W. and Pichler, l .: Investigation into different types of post- and presynaptic α-adrenoceptors at cardiovascular sites in rats. Eur. J. Pharmacol. 65, 393-402, 1980).

For determining the α ₁ -adrenolytic action, the model according to Arunlakshana and Schild is used (Arunlakshana, 0. and Schild, HO: Some quantitative uses of drug antagonists. Brit. J. Pharmacol. 14, 48, 1959).

The toxicity studies are carried out on female NMRI mice (body weight: 22 - 26 g). The animals (5 animals per dose) receive food and water ad libitum. Various doses of the substances are administered orally. The observation period is 14 days. The LD ₅₀ , that is to say the dose at which 50% of the animals die, is determined graphically from the dose / effect curve.

In the tables which follow, the compounds investigated are given serial numbers, which are allocated as follows:

Serial No. Name of compound 1 5-Butyl-2-pyridinecarboxylic acid (fusaric acid) 2 5-Butyl-2-pyridinecarboxylic acid amide

(bupicomid)

3 3-dimethylaminopropyl 5-n-butylpyridine-2-carboxylate 4 3-diethylaminopropyl 5-phenylpyridine-2-carboxylate 5 5-phenylpyridine-2-carboxylic acid (3- [4- (2-methoxyphenyl) piperazin-1-yl ] -propyl) -amide 6 5-phenylpyridine-2-carboxylic acid (3-dimethylaminopropyl) amide 7 5-phenylpyridine-2-carboxylic acid (2-diethylaminoethyl) amide

8 5- (4-chlorophenyl) pyridine-2-carboxylic acid

(3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amide 9 5- (4-chlorophenyl) pyridine-2-carboxylic acid

(3-diethylaminopropyl) amides

10 5-Cyclohexylmethylpyridine-2-carboxylic acid

(3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl) amides

11 5-CyclohexyImethylpyridine-2-carboxylic acid

(3- [4- (2-ethoxyphenyl) piperazin-1-yl] propyl) amides

12 5-CyclohexyImethylpyridine-2-carboxylic acid

(3-piperidinopropyl) amides Table I shows the percentage lowering in blood pressure following oral administration to rats and the lethal effect following oral administration to mice for representatives of the compounds according to the invention. Table I

% changes in blood pressure (BP) in genetically hypertonic rats following a single daily peroral administration on four successive days (N = 6 / dose) and the toxicity (peroral; LD _{5 0} in mice (N = 5 / dose).

Table II which follows shows the therapeutic activity (Th.W.) of the compounds listed in Table I. The therapeutic activity is the quotient of the maximum percentage change in blood pressure BP and the dose administered (μmoles/kg), in each case the mean value of this quotient being given, for the dosages shown in Table I. Table II

Table II which follows shows the therapeutic activity (Th.W.) of the compounds listed in Table I. The therapeutic activity is the quotient of the maximum percentage change in blood pressure BP and the dose administered (μmoles / kg), in each case the mean value of this quotient being given, for the dosages shown in Table I. Table II

Therapeutic activity (Th.W.) calculated from the maximum percentage change in blood pressure (BP) and the dose administered.

Table III shows the therapeutic index, with the standardizat ion Th.W. fusaric acid = 1, for the days shown in Table II. The mean of the 2 hour and 6 hour value on the Ist and 4th day were taken here. Table III

Therapeutic index (Th.I.), with the standardization Th.W. fusaric acid = 1.

Claims

P atent C laims 1. Compounds of the general formula I (I)

wherein R ¹ denotes alkyl with 1 to 7 carbon atoms - but not butyl if R ² and R ³ denote alkyl and X denotes NH -, cycloalkylalkyl with 3 to 7 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, R ² denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms and R ³ denotes alkyl with 1 to 4 carbon atoms or alkenyl with 3 to 5 carbon atoms, or R ² and R ³ together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, morpholino, piperidino, hexahydroazepino, or 1- piperazinyl which is substituted in the 4-position by R ⁴ , R ⁴ denotes hydrogen, alkyl with 1 to 4 carbon atoms, phenyl, benzyl or substituted phenyl with up to three substituents from the group comprising halogen, hydroxyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, A denotes straight-chain or branched alkylene with 1 to 5 carbon atoms and X denotes O (oxygen) or NH, and the acid addition salts of these compounds, R ¹ , R ² and R ³ not simultaneously denoting alkyl if X represents O (oxygen) and A represents ethylene. 2. Compounds of the general formula I * (I *)

wherein R ¹ * denotes alkyl with 1 to 5 carbon atoms (but not butyl if R ² * and R ³ * denote methyl or ethyl and X represents NH), R ² * denotes methyl or ethyl and R ³ * denotes methyl or ethyl, or R ² * and R ³ * together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, piperidino, or 1-piperazinyl which is substituted in the 4-position by R ⁴ *, R ⁴ * denotes phenyl, or phenyl which is substituted by methoxy or ethoxy, A * denotes ethylene or trimethylene and X * denotes O (oxygen) or NH, and the acid addition salts of these compounds, R ² * and R ³ * not denoting methyl or ethyl when X * represents O (oxygen) and A * represents ethylene. 3. Compounds of the general formula I ** (I **)

wherein R ¹ ** denotes cycloalkylalkyl with 5 or 6 carbon atoms in the cycloalkyl part and 1 or 2 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to two substituents from the group comprising chlorine, methoxy and ethoxy, R ² ** denotes methyl or ethyl, R ³ ** denotes methyl or ethyl, A ** denotes ethylene or trimethylene and X ** denotes O (oxygen) or NH, and the acid addition salts of these compounds. 4. Compounds of the general formula I *** (I ***)

wh e re in R ¹ *** denotes cycloalkylalkyl with 5 or 6 carbon atoms in the cycloalkyl part and 1 or 2 carbon atoms in the alkylene part, phenyl or substituted phenyl with up to two substituents from the group comprising chlorine, methoxy and ethoxy, R ² * ** and R ³ *** together, and including the nitrogen atom to which they are bonded, denote pyrrolidino, piperidino, or 1-piperazinyl which is substituted in the 4-position by R ⁴ ***, R ⁴ *** denotes hydrogen, methyl, phenyl or phenyl which is substituted by methoxy or ethoxy, A *** denotes ethylene or trimethylene and X *** denotes O (oxygen) or NH, and the acid addition salts of these compounds. 5. Process for the preparation of compounds of the formula I according to Claim 1, which comprises reacting picolinic acid derivatives of the general formula II (II)

with amines of the general formula III (III)

and, if desired, then converting the products into the acid addition salts, the radicals Y and Z being chosen so that the member X is formed, and R ¹ , R ² , R ³ , A and X have the meanings given in Claim 1 . 6. Compounds according to one or more of Claims 1, 2, 3 or 4 for use in the treatment of high blood pressure, 7. Medicaments containing one or more compounds according to one or more of Claims 1, 2, 3 or 4 and / or their pharmacologically acceptable acid addition salts.