DE2818290A1 - NEW NAPHTHYRIDINE - Google Patents

Description

PR.-ING. WALTER ABITZ DR. DIETER F. MORF (ο _{Poitfach8eoioe} , _{8OOOMÜnchen8e} DIPL.-PHYS. M. GRITSCHNEDER Postal address

Pienzanauerstrafie phone 68 32 22

Patent attorneys Telegrams: Chemindus Munich

Tel: (O) 523892

15964

MERCK & CO., INC. Rahway, New Jersey 07065, V.St.A.

New naphthyridines

809845/0817

The invention relates to new naphthyridines with a 3-amino-2-OR-propoxy substituent. The compounds have ß-adrenergic blocking and immediate antihypertensive Activity.

The invention relates to new 3-amino-2-OR-propoxy-substituted naphthyridines with useful pharmacological activity.

N-heteromonocyclic 3-amino-2-hydroxypropoxy-substituted Compounds with β-adrenergic blocking activity are known (US Patent 4,000,282; South African PS 74/01070). Mono-N-heterobicyclic 3-Amino-2-hydroxypropoxy-substituted compounds that have ß-adrenergic blocking activity show are known [Crovrther et al, J.Med.Chem. Jj ?, 260-266 (1972)].

There were now new di-N-heterobicyclic compounds, viz 3-Amino-2-0R-propoxynaphthyridines, found. These compounds show β-adrenergic blocking activity and an immediate onset antihypertensive activity.

The invention relates to 3-substituted naphthyridine compounds Amino-2-OR-propoxy substituents and their pharmaceutical use.

The invention relates to naphthyridine compounds of the formulas

IV

809845/0817

28 IB290

II

or

III

VI

and their pharmaceutically acceptable salts, wherein

Z is —CH ₂ —CHOR — CH ₂ NHR ₁ , where R is hydrogen or C ₂ -C ₁₂ acyl and R _{1 is} C ₁ -C ₁₂ alkYl,

and R ₂ H, Cl, Br, F, -CN, -NH ₂ , CF ₃ , NO ₂ , -COOR ₃ , where

R _{3 represents} H, C ₁ -Cg -AlkYl or Cg-C ₁₂ -carbocyclic

Aryl stands,

where R ^ and Rc »when separated for H or C ₁ -Cg-AIkYl and, when connected, for -CHp""νCHp /« t "* CHp t -CHp-CHp-0-CHp-CHp , -CHp-CHp-NH-CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₂ -CH ₂ -, -C ₁ -Cx - alkylthio, -C.-C / r-Alkylsulfinyl or -C ^ -C ^ -Alkylsul-

IO IO ID

fonyl means.

809845/0817

15 964 <J.

The numbers within the naphthyridine formulas I-VI give the Ring positions.

The pharmaceutically acceptable salts are the acid addition salts of the naphthyridine free base. Suitable acids include organic as well as inorganic acids. Examples of useful organic acids are carboxylic acids such as acetic acid, pamoic acid, Maleic acid, succinic acid, citric acid, tartaric acid, oxalic acid, malic acid, pivalic acid, heptanoic acid, lauric acid, Propanoic acid, pelargonic acid, oleic acid and others, and the non-carboxylic acids, like isethionic acid. Examples of useful inorganic acids are the hydrohalic acids, e.g. HCl, HBr, HJ, Phosphoric acid, sulfuric acid, etc. The hydrohalide salts, in particular the hydrochlorides and maleic acid salts, especially hydrogen maleate, are preferred.

R may represent hydrogen or C ₂ _ ₁₂ acyl For ^{re-ded. The C-2} i2 ^"acyl" groups include alkanoyl groups such as acetyl, pivaloyl, dodecanoyl, hexanoyl, succinoyl, among others, and carbocyclic aroyl groups such as benzoyl, 1- or 2-naphthoyl, p-methylbenzoyl, p-phenylbenzoyl, etc. The C ₂ - Cg alkanoyl and benzoyl groups are preferred acyl groups. Hydrogen is the most preferred R group.

The Rj substituent includes Cj-C ^ -alkyl groups and preferably the Cj-Cg-alkyl groups. Examples of alkyl groups are methyl, C ₁₂ H ₂₅ , hexyl, 2-ethylhexyl, isopropyl, sec-butyl, heptyl, etc. C, Λ-branched alkyl groups are more _{preferred as R 1} groups, with the t-butyl group being the most preferred group is.

The R ₂ substituent includes hydrogen, Cl, Br, CF ₅ , NO ₂ , P, -CN, -NH ₂ , the carboxy group and its ester and amide derivatives, the C ₁ -., Cg-alkyl-thio-, - sulfonyl and sulfonyl groups and their derivatives. The ester groups are Cj-Cg-alkyl esters, e.g. -COOCH ₃ , -COOC ₆ H ₁₅ , -COOCH (CH ₅ ) ₂ , -COOC ₂ H ₅ and others, and C ₅ -C ₁₂ -

809845/0817

15964 W

Aryl esters, preferably carbocyclic aryl, for example g ₅ P-CH ₃ -C ₆ H ₅ -OOC-, C ₆ H ₅ -C ₆ H ₅ -OOC-, C ₁₀ H ₈ -OOC-, etc. The amide groups include -CONHp, C ₁ -C ₆ -substituted amide groups, such as -CON (CH,) ₂ , -CON (C ₆ H ₁₅ ) ₂ , -CONHC ₂ H ₅ , -CON (sec-butyl) ₂ and others, and heterocyclic carbonyl groups such as 0 OO

nFS, -C-NSNH (or -CH ₃ ) and -C-NSJ3. The ^ -Cg

Examples of thio, sulfinyl and sulfonyl groups are CH ₃ -S-, C ₆ H ₁₃ -S-, (CH ₃ J ₃ CS-, (CH ₃ ) ₂ CH-SO-, CH ₃ -SO ₂ -, C ₂ H ₅ -SO ₂ -, C ₆ H ₁₃ -SO-, C ₅ H ₁₁ -SO-, sec-butyl-SO ₂ - and others. Of the R ₂ groups, CN is preferred.

The naphthyridine compounds have a chiral center that gives them optical activity. The optical isomers are referred to in the usual way with L and D, 1 and d, + and -, S and R or a combination of these symbols. If the Formula or the name of the compounds listed in the present application is not a specific designation carries, the formula or the name includes the individual isomers, their mixtures and racemates.

Preferred naphthyridines are those which contain an -OZ group in a position ortho to a ring nitrogen. In the case of the more preferred naphthyridines, the R ₂ substituent is also ortho to the -OZ group.

Particularly preferred naphthyridines are those of the formulas I, II and III. Particularly preferred are those naphthyrins in which the -OZ group is ortho to the N atom, and in particular those in which the R ₂ group is ortho to the -OZ group.

Particularly preferred naphthyridines have the formulas

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15964

or

More preferred naphthyridines have the formulas

In the case of the most preferred naphthyridines, Rp is cyano and Z is -CH ₂ -CHOH-CH ₂ -NR ₁ , where R _{1 is} C ₁ -Cg -AllCyI, with C ^ -C ^ -branched alkyl being a preferred group and t- Butyl are the most preferred group.

809845/0817

The naphthyridines include all optical isomers and their mixtures, but the S-isomer is preferred.

The naphthyridines according to the invention can according to any one suitable processes can be produced.

In such a process, the halonaphthyiidine is used
coupled to a suitable substituted oxazolidine and the resulting reaction product is hydrolyzed. The procedure is represented by the following scheme from reaction equations:

alo

MO-CH

base

Hydrolysis'

VII

VIII

O-CH,

IX i

Halo can be Cl, Br and I, with Cl being preferred. M is an alkali metal, preferably potassium or sodium. R ₂ represents hydrogen or the alkyl or aryl radical of any

suitable aldehyde R'-C ζ

, for example a Cg-C ^ ₂ arylaldehyde, such as

809845/0817

Benzaldehyde, naphthaldehyde, m-NC ^ -benzaldehyde, p-phenylbenzaldehyde, tolualdehyde, etc., furfural or Cg-C ₁ , p-alkanyl, such as

Acetaldehyde, butyraldehyde, C ₁₁ H _0x C ^, 2-ethylhexanol, among others

-π ο \ _H

The process for the preparation of oxazolidines wherein M is hydrogen (and the related coupling reaction) is described in and to U.S. Patents 3,718,447 and 3,657,237 References are referred to expressly. The alkali metal salt of oxazolidine is prepared by a method known per se by reacting the corresponding hydroxymethyl oxazolidine with a suitable amount of alkaline basic reactant manufactured. However, this reaction becomes more convenient with in situ formation of the alkali metal oxazolidine salt (Formula VIII) by reacting the oxazolidine

with the naphthyridine of the formula VII in the presence of a suitable Base such as KgCO ,, an alkali metal alkoxide [e.g. K-O-CfCIT) I sodium hydride, an organolithium, e.g. phenyllithium, n-butyllithium, lithium diisopropylamide, and others.

The coupling reaction can be carried out at temperatures ranging from about 0 to about 100 ° C. A temperature range from about 10 to about 50 ° C is preferred. The reaction is suitably carried out in a solvent. Any suitable solvent can be used. Examples of suitable solvents are dioxane, toluene, tetrahydrofuran, Dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, tert-butanol, acetone, alkanols, etc. The hydrolysis is carried out using a common acidic hydrolysis reagent and more common

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Process, e.g. treatment with a solution of any suitable acid such as CH, COOH, HCl or H ₂ SO ^, performed. The hydrolysis product can be obtained directly as the salt of the acid used in the hydrolysis. The product is normally obtained as the free base after the neutralization of the salt, which is known per se.

The DI © coupling reaction is normally carried out at atmospheric pressure. Higher pressures can be used if necessary will.

When a racemic oxazolidine (Formula VII or X) is the reactant is used, the product obtained is a racemate. The racemate can be broken down into the individual enantiomers split-off processes known per se are separated.

If R ¹ in the oxazolidine (for example formula VIII, IX or X) has a meaning other than hydrogen, a second chiral center is present at the 2-position in addition to the chiral center at the oxazolidine position. However, when the oxazolidine is referred to as, for example, (S), (R) or (R, S), that designation refers only to the optical configuration around the carbon atom in the 5-position.

Using a single optical isomer of the oxazolidine of formula VII or X in the above reactions, the naphthyridine product can be obtained directly as the only enantiomer will. Therefore, if the S-isomer of the oxazolidine is used, the product obtained will be the S-isomer. this makes possible an expedient route for the direct preparation of individual isomers of the naphthyridines according to the invention.

The naphthyridines according to the invention, in which R has a different meaning as hydrogen are expedient by treating the corresponding compound in which R is hydrogen

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means with a suitable acylating agent, such as acyl halide, e.g. undecanoyl chloride, pivaloyl chloride, benzoyl chloride, p-methoxybenzoyl chloride, an anhydride, e.g. acetic anhydride, manufactured among others. The reaction is explained by the following equations:

O CH ₃ -C-Cl

The compounds of the invention also include the pharmaceutically acceptable salts of the new naphthyridines. These Salts are useful e.g. B. by treating the naphthyridine with a suitable amount of a useful acid, generally in a suitable solvent.

Further process for the preparation of naphthyridines ^ with certain other substituents are represented by the following reaction equations. Reaction conditions known per se are used. The other substituent desired is underlined.

809845/0817

15964 Scheme 1

/ fc

hydrolysis

COOR,

Scheme 2

COOR,

atm

1 atm

CONH.

Hydrolysis COOH

-CH.

The naphthyridines having an alkylsulfinyl or alkylsulfonyl substituent are prepared by oxidation of the corresponding C 1 -C 6 -alkylthio-containing compound. Any suitable oxidizing agent, for example H ₂ O ₂ *, can be used. the
the following equation explains the reaction:

SOC ₃ H ₇ (or

- 10 -

809845/0817

Certain naphifoyridine intermediates are tinter use obtained by the process shown in the following reaction scheme. Conventional procedures and reagents are used.

Scheme A

HNO ₂ / H ₂ SO ₄

pci ₅ / poci ₃

NaNO ₂ / H
Cu CN

Sn Cl ₂ ZHCl γ

- 11 -

809845/0817

15964 Scheme B

Scheme C

hydrolysis

Cl

SFj / HF

Cl

Cl

NaNO ₂ ZH

HBF./EtO

^^ NaNO ₂ / H

J NaSr-CH-

Scheme D.

Halogenation ^ - medium 7

X (Cl

or Br)

The compounds according to the invention show an antihypertensive one Rapid onset activity, and they are also beta-adrenergic blocking agents. It is believed that this antihypertensive activity is due to peripheral vasodilation via a mechanism that is not direct is related to ß-adrenergic block. An advantage of the naphthyridines according to the invention over conventional ones ß-adrenergic means is that the antihypertensive effect sets in immediately and in general one has extended duration.

This rapid onset of antihypertensive activity is achieved by administering an exemplary compound of the invention on spontaneously hypertonic (SH) rats and measuring the effect on blood pressure. Using this Test procedure it is found that an exemplary compound of the invention has this antihypertensive activity with immediate onset for oral administration.

The ß-adrenergic blocking activity of the naphthyridines according to the invention is determined by the ability of a exemplary compound measures the ß-adrenergic stimulatory effect induced by isoproterenol, such as increase to block the heart rate, negative pressure, and bronchodilation, in vivo. It has been shown that an exemplary naphthyridine exhibits β-adrenergic blocking activity using this in vivo test method.

The ability of the naphthyridines of the invention to rapidly reduce blood pressure in an SH rat shows that the compounds of the invention are useful for treating hypertension in humans. Similarly leaves the observed ß-adrenergic blocking activity of these compounds suggests that they may be useful in humans as ß-adrenergic blocking agents for the therapeutic treatment of cardiovascular conditions, such as angina, arrhythmia, etc., are useful.

809845/0

For use as antihypertensive agents and / or ß-adrenergic blocking agents, the inventive Compounds administered orally or parenterally, i.e. intravenously, intraperitoneally, etc., in any suitable dosage form will. The compounds can be presented in a form (1) for oral administration, e.g., tablets along with other processing ingredients (diluents or carriers) commonly used such as Talc, vegetable oils, polyols, benzyl alcohol, starches, glycerine i.a., or dissolved, dispersed or emulsified in a suitable liquid carrier, or in capsules or encapsulated in a suitable encapsulation material; or (2) for parenteral administration, dissolved, dispersed or emulsified in a suitable liquid carrier or diluent. The ratio of active ingredient (inventive naphthyridine) becomes processing ingredient (s) according to the dosage form and the required pharmacological effect vary. Known methods can be used for the production of the pharmaceutical preparations.

The daily dose level for the compounds of the invention can be from about 0.02 mg to about 50 mg / kg of body weight vary. Daily dose levels in the range of about 0.05 to about 25 mg / kg are preferred, with about 0.1 to about 15 mg / kg is a more preferred range. Oral administration is preferred. Depending on the unit dose, can be simple or multiple daily doses are administered.

The invention also relates to pharmaceutical preparations, which contain a therapeutically effective amount of a compound according to the invention.

The following examples illustrate the preparation of the inventive Naphthyridines. All parts are expressed by weight unless otherwise specified. All tempera-

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doors are indicated ^{in 0 C.} Some intermediates suitable for the preparation of the naphthyridines according to the invention are described by Hawes et al, J. Med. Chem., 16, 849-853 (1973).

example 1

A. 2-Hydroxy-3-cvano-1.8-naphthvridine

A mixture of 2.44 g (0.02 mol) of 2-aminonicotinaldehyde, 4.52 g (0.04 mol) of ethyl a-cyanoacetate, 50 ml of absolute ethanol and 0.5 ml of piperidine is stirred under reflux. After 1 h, the solution is cooled ^{to 0 to 4 ° C.} The yellow solid is filtered off and dried; 2.5 g (73%) of 2-hydroxy-3-cyano-1,8-naphthyridine are obtained; M.p. 300 ° C.

B. 2-chloro-3-cyano-1 »8-naphthyridine

A mixture of 12.2 g (0.059 mol) of phosphorus pentachloride, 44 ml of phosphorus oxychloride and 2.3 g (0.013 mol) of 2-hydroxy-3-cyano-1,8-naphthyridine is stirred under reflux. After 1 hour, excess phosphorus oxychloride is distilled off under reduced pressure (20 to 30 mm). The residue is treated with ice and the solution is _{neutralized with solid Na 2} CO ^. The aqueous solution is extracted with 3 × 100 ml CHCl _5. The organic extracts are _{dried over Na 2} SO ^, filtered and concentrated to dryness. The residue is sublimed at 140 to 150 ^° C. and 0.3 mm; 1.2 g (81%) of 2-chloro-3-cyano-1,8-naphthyridine are obtained; M.p. 273 ^° C

C. (S) -3-Cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -1,8- naphthyridine

To a dry flask is added under N ₂ 2.4 g (0.01 mol) of (S) -2-Phenyl-3-tert-butylamino-5-hydroxymethyloxazolidin, 15 ml dimethylformamide and 0.5 g (0.01 Mol; 50% mineral oil) NaH and heat the mixture on a steam bath for 5 min. After cooling to room temperature, 1.89 g (0.01 mol) of 2-chloro-3-cyano-1,8-naphthyridine are added and the solution becomes

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stirred at room temperature. After stirring overnight, the mixture is poured into 200 ml of water and extracted with 4 × 100 ml of ether. The organic layer is washed with 2 × 50 ml of water and then washed with 2 × 100 ml of cold 1N HCl. The acidic layer is poured into 17 g (0.2 mol) of NaOAc.3H ₂ O and the solution is stirred at room temperature. After 5 h, the solution is extracted with 2 × 75 ml of ether. The aqueous layer is _{neutralized with saturated Na 2} CO. * And extracted with 3 x 100 ml CHCl 2. The organic layer is _{dried over Na 2} SO 4, filtered and concentrated to dryness. The residue is crystallized from CH ^ CN; 0.85 g (20%) are obtained. (S) -3-cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -1,8-naphthyridine; Mp. 152 to 153 ⁰ C.

Using 2-chloro-3-cyano-1,6-naphthyridine instead of 2-chloro-3-cyano-1,8-naphthyridine in Example 1, stage C, (S) -3-cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -1,6-naphthyridine is obtained.

Example 2

(S) -3-Cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -1,6- naphthyridine dihydrochloride

To a dry flask is added under N ₂ 4 g (0.07 mol) of (S) -2-Phenyl-3-tert, butylamino-hydroxymethyloxazolidin-5, 25 ml DMF and 0.85 g (0.018 mol) of NaH ( 50% mineral oil) and heated for 5 minutes on a steam bath. After cooling to room temperature, 3.3 g (0.017 mol) of 2-chloro-3-cyano-1,6-naphthyridine are added and the mixture is stirred at room temperature. After stirring overnight, the mixture is poured into 200 ml of water and extracted with 4 × 100 ml of ether. The organic layer is washed with 2 × 50 ml of water and 2 × 100 ml of cold 1N HCl. The acidic layer is poured into 27 g (0.2 mol) of NaOAc.3H ₂ O and the solution is extracted with 2 × 75 ml of ether. The aqueous layer is saturated Na ₂ CO, neutralized and extracted with 3 × 100 ml CHCl- *. The watery one

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Layer is _{dried over Na 2} SO ^, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product is eluted with CHCl · *, saturated with aqueous NH ,,. The crude product is crystallized from methanolic HCl and isopropanol (IPA); 0.32 g (5%) of (S) -3-cyano-2- (3-tert-butylamino-Z-hydroxypropoxy) -1,6-naphthyridine dihydrochloride are obtained; Fp. 215 Ms 217 ⁰ C.

Using (R, S) -2-methyl-3-isopropylamino-5-hydroxymethyloxazolidine instead of (S) -2-phenyl-3-tert-butylamino-5-hydroxymethyloxazolidine in Example 2, the dihydrochloride of (R, S) -3-cyano-2- (3-isopropylamino-2-hydroxypropoxy) -1,6-naphthyridine is obtained.

Example 3

(S) -1- (3-tert-Butylamino-2-hydroxypropoxy) -2,7-naphthyridine hydrogen maleate salt

To a dry flask is added under N ₂ 2.5 g (0.01 mol) of (S) -2-Phenyl-3-tert-butylamino-5-hydroxymethyloxazolidin, 50 ml of tert-butanol, 1.3 g ( 0.011 mole) of potassium tert-butoxide and 1.67 g (0.01 mole-chloro-2,7-naphthyridine 1 and heated with stirring at 40 ⁰ C. After 15 h), the solution concentrated to dryness. 7.2 g (0.12 mol) of acetic acid and 120 ml of water are added to the residue and the solution is stirred at room temperature. After 5 h, the solution is extracted with 2 × 100 ml of ether. The aqueous layer is _{neutralized with saturated Na 2} CO * and extracted with 3 × 100 ml CHCl. The organic layer is dried over Na ₂ SO. dried, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product is eluted _{with 20% MeOH-CHCl 3.} The crude product is crystallized with maleic acid in IPA; 0.4 g (10%) of (S) -1- (3-tert-butylamino-2-hydroxypropoxy) -2,7-naphthyridine hydrogen maleate salt is obtained; Pp. 177-179 ° C.
End of description. y ^

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Claims (22)

DR.-ING. WALTER ABITZ DR. DIETER F. MORF DIPL.-PHYS. M. GRITSCHNEDER Patentanwälte Munich, Postal Address Postfach 860109, 80OO Munich Pienzenaueratraße 28 Telephone 983323 Telegrams: Chemlndus Munich Telex: (OJ 533993 Merck & Co., Inc. 15964 patent claims 1. Compounds of the formula OZ, OZ or and their pharmaceutically acceptable salts, wherein 809845/0317 ORIGINAL INSPECTED and 15964 * Z is -CH ₂ -CHORO-CH ₂ -NHR ₁ , wherein
R is hydrogen or C ₂ -C ₁₂ acyl and
R _{1 is} C ₁ -C ₁₂ -alkYl, R ₂ H, Cl, Br, F, CN, -NH ₂ , NO ₂ , CF ₅ , -COOR ^, wherein
R ^ for H, C ₁ -Cg -AlkYl or Cg-C ₁₂ -carbocyclic Aryl stands;
Rg, in which R ₅ and Rg, when separated, represent H or
C ₁ -Cg-AIkYl and, when connected, for
-CH ₂ - (CH ₂ ) ^ - CH ₂ , - CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -NH-CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₂ -CH ₂ ;
-CI -C / r-alkylthio, -C, -Cc-alkylsulfinyl or -C ^ -C ^ -alkylsulfo- IO IO IO means nyl. 2. Compounds according to claim 1, characterized in that that R stands for H. 3. Compounds according to claim 2, characterized in that -OZ is in a position ortho to an N atom. 4. Compounds according to claim 3 »characterized in that R _{2 is} ortho to the -OZ group. 5. Compounds according to claim 1, characterized in that they have the formula OZ, or own. 6. Compounds according to claim 5, characterized in that R is hydrogen. 809845/0817 15964 3 7. Compounds according to claim 6, characterized in that R _{1 represents} C ^ -C ^ -branched alkyl. 8. Compounds according to claim 7, characterized in that R _{1 is} t-butyl. 9. Compounds according to claim 8, characterized in that they have S-isomer configuration. 10. Compounds according to claim 5, characterized in that they have the formula own. 11. Compounds according to claim 10, characterized in that R is H, R _{1 is} C ₃ -C ₄ -AlkYl and R _{2 is} -CN. 12. Compounds according to claim 11, characterized in that R _{1 is} t-butyl. 13. Compounds according to claim 12, characterized in that that they have S-isomer configuration. 14. Compounds according to claim 5 _r characterized in that they have the formula own. 809845/0817 15964 ^ 15. Compounds according to claim 14, characterized in that R is hydrogen, R _{1 is} C ₃ ^ -alkyl and R _{2 is} -CN. 16. Compounds according to claim 15, characterized in that R _{1 is} t-butyl. 17. Compounds according to claim 16, characterized in that they have the S-isomer configuration. 18. Compounds according to claim 5, characterized in that they have the formula own. 19. Compounds according to claim 18, characterized in that that R stands for H. 20. Compounds according to claim 19, characterized in that R _{1 is} t-butyl. 21. Compounds of the formula according to claim 1, characterized in that that Z is an oxazolidine group of the formula -CH • ο ι Γ * O N-R. means where R _{1 is} Cj-C ^ -alkyl and R »is H,
Alkyl or Cg-C ₁₂ aryl. 809845/0817 15964 ⁵ 22. Pharmaceutical preparation used for the creation of a ß-adrenergic block or for the treatment of Is suitable for hypertension characterized in that it contains an effective amount of a compound according to claim 1. - 5 809845/0817