GB1566693A

GB1566693A - Naphthyridines

Info

Publication number: GB1566693A
Application number: GB16780/78A
Authority: GB
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1977-05-02
Filing date: 1978-04-27
Publication date: 1980-05-08
Also published as: IT1107210B; LU79551A1; IE46874B1; SE7804318L; FR2389624A1; DK166478A; IT7849081A0; DE2818290A1; FR2389624B1; CH634320A5; BE866544A; IE780862L; JPS6115875B2; NL7804168A; JPS53136000A

Abstract

Novel naphthyridines, which possess a 3-amino-2-OR-propoxy substituent, have the following formulae <IMAGE> in which R<2> and Z are defined in claim 1. The novel compounds can be used in pharmaceutical preparations for producing a beta -adrenergic blockage or for treating hypertension.

Description

(54) NAPHTHYRIDINES (71) We, MERCK & CO. INC., a corporation duly organized and existing under the laws of the State of New Jersey, United States of America, of Rahway, New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- N-heteromonocyclic 3-amino-2-hydroxypropoxy substituted compounds having A-adrenergic blocking activity are known (U.S. 4,000,282; South African 74/01070). Mono-N-heterobicyclic 3-amino-2-hydroxypropoxy substituted compounds exhibiting A-adrenergic blocking effectiveness are also known [Crowther et al., J. Med. Chem. 15, 260266 (1972)].

The present invention is based on the discovery of certain novel di-N heterobicyclic compounds, namely 3-amino-2-OR-propoxynaphthyridines. which have p-adrenergic blocking activity and antihypertensive activity of immediate onset.

The present invention provides compounds of formula

and pharmaceutically acceptable salts thereof, in which Z is -CH2-CHOR- CH2NHR1 where R is hydrogen or C2~12 acyl and R1 is C,~12 alkyl, and R2 is a hydrogen, chlorine, bromine or fluorine atom or a cyano, amino, nitro, trifluoromethyl, carboxy, (C1-6 alkoxy)carbonyl, (C6-12 carbocyclic aryloxy)carbonyl, C16 alkylthio, C18 alkylsulfinyl, C16 alkylsulfonyl, carbamoyl, (C1-6 alkyl)carbamoyl, di(C1~6 alkyl)carbamoyl, piperidinocarbonyl, 1piperazinylcarbonyl, 4-methyl-l -piperazinylcarbonyl or morpholinocarbonyl radical.

The numbers within the naphthyridine formulae I--VI indicate the ring positions.

The pharmaceutically acceptable salts are the acid-addition salts of naphthyridine free base. Suitable acids may be organic or inorganic. 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 and oleic acid, and non-carboxylic acids such as isethionic acid. Examples of useful inorganic acids are the hydrogen halides HCI, HBr and HI, phosphoric acid and sulfuric acid. The hydrohalide salts, especially the hydrochlorides and the maleates, especially the hydrogen maleate, are preferred.

R may be hydrogen or C2~12 acryl. The C2~,2 acyl groups include alkanoyl groups such as acetyl, pivaloyl, dodecanoyl, hexanoyl and succinoyl, and carbocyclic aroyl groups such as benzoyl, 1- or 2-naphthoyl, p-methylbenzoyl and p-phenylbenzoyl. The C26 alkanoyl and benzoyl groups are preferred acyl groups.

Hydrogen is a most preferred R group.

R1 is preferably C16 alkyl. The C1-12 alkyl groups are exemplified by methyl, dodecyl, hexyl, 2-ethylhexyl, isopropyl, sec-butyl and heptyl. The C34 branchedchain alkyl R1 groups are especially preferred, with t-butyl being most suitable.

Among values of R2 are -COOCH3, -COOC6H13, -COOCH(CH3)2, -COOC2H5, C6H5XOC, p-CH3-C6H5--OOCC-, C6H5-C6H5--OOC-, C 10H8- OOC-, -CON(CH3)2, -CON(C6H13)2, -CONHC2H5, -CON (sec.biityl)2, CH3-S-, C6H13-S-, (CH3)3C-S-, (CH3)2CH-SO-, CH3-SO2-, C2H5- SO2, C6H13--SO--, C5H11-SO- and sec.butyl-SO-2. CN is the preferred value of R2.

The naphthyridine compounds have one chiral center which confers optical activity. The optical isomers are designated conventionally as L and D, l and d, + or -, or S and R, or by combinations of these symbols. Where the formula or compound name herein carries no specific designation, the formula or name includes the individual isomers, the mixtures thereof and racemates.

Preferred naphthyridines are those having the -OZ group in a position ortho to a ring nitrogen. In especially preferred naphthyridines, the R2 substituent is also ortho to the -OZ group.

Particularly preferred naphthyridines are those of Formulae I, II and III. More particularly preferred are these naphthyridines in which the -OZ group is ortho to the N atom, and especially where the R2 group is ortho to the -OZ group.

Especially preferred naphthyridines have the formulae: or particularly

It is preferred that, R2 be cyano and Z -CH2-CHOH-CH2-NR1 where R, is C16 alkyl, with C3-C4 branched alkyl as a preferred group and t-butyl being especially preferred.

While the naphthyridines include all optical isomers and mixtures, the Sisomer form is preferred.

The naphthyridines of the present invention can be prepared by any convenient process.

One such process involves the coupling of a halonaphthyridine with a suitable substituted oxazolidine and hydrolyzing the reaction product obtained. This process is illustrated by the following set of reaction equations:

R halo X halo E R' Base R2 N R2 < Hydrolyse t34 O - C H O-CH2-CH-CHiR1 WAR1 OH Y R, H R' LX V Halo may be Cl, Br and I, with Cl being preferred. M is an alkali metal, preferably potassium or sodium. R2 is hydrogen or alkyl or aryl residue of any suitable aldehyde

e.g. a C6 12 arylaldehyde, such as benzaldehyde, naphthaldehyde, m-NO2benzaldehyde, p-phenylbenzaldehyde or tolualdehyde, furfural or a C2-C12 alkanal such as acetaldehyde, butyraldehyde,

or 2-ethylhexanol. The process for preparing oxazolidines where M is hydrogen (and related coupling reaction) is disclosed in U.S. 3,718,447 and U.S. 3,657,237.

The alkali metal salt of the oxazolidine is prepared in a conventional manner by reaction of the corresponding hydroxymethyloxazolidine with an appropriate amount of an alkali base reactant. However, this reaction is more conveniently carried out with in-situ formation of the alkali metal oxazolidine salt (Formula VIII) by reacting the oxazolidine

with the Formula VII naphthyridine in the presence of a suitable base such as K2CO3, an alkali metal alkoxide [e.g. K-O-C-CH3)3i, sodium hydride, an organolithium e.g. phenyllithium or n-butyllithium; or lithium diisopropylamide.

The coupling reaction can be carried out at temperatures ranging from 0 to 100 C. A temperature range of 10 to 500C is preferred. The reaction is generally carried out in a solvent. Any suitable solvent may be used. Examples of useful solvents are dioxane, toluene, tetrahydrofuran, dimethylformamide, toluene, dimethylsulfoxide, hexamethylphosphoramide, tert. butanol, acetone and alkanols.

The hydrolysis is carried out using conventional acid hydrolysis reagent and techniques e.g. treatment with a solution of any suitable acid such as CH3COOH, HCI or H2SO4. The hydrolysis product can be directly obtained as the salt of the acid used for the hydrolysis. Ordinarily, the product is recovered as the free base after conventional neutralization of the salt.

The coupling reaction is ordinarily carried out at atmospheric pressure.

Higher pressures may be used if desired.

When a racemic oxazolidine (Formula VII or X) is used as a reactant, the product is obtained as a racemate. The racemate may be separated into its individual enantiomers by conventional resolution techniques.

When R' in the oxazolidine (e.g. Formulae VIII, IX or X) is other than hydrogen, in addition to the chiral center at oxazolidine position 5 there is a second chiral center at position 2. However, whenever the oxazolidine is designated as e.g.

(S), (R) or (R,S), this designation refers only to the optical configuration around the carbon atom at the 5 position.

By using a single optical isomer of the Formula VII or X oxazolidine in the above reactions, the naphthyridine product may be obtained directly as a single enantiomer. Thus, if the S-isomer of the oxazolidine is used, then the product obtained will be the S-isomer. This provides a convenient way for directly preparing individual isomers of the present naphthyridines.

Naphthyridines of the present invention in which R is other than hydrogen are conveniently prepared by treating the corresponding compound where R is hydrogen with an appropriate acylating agent such as an acyl halide, e.g.

undecanoyl chloride, pivaloyl chloride, benzoylchloride or p-methoxybenzoyl chloride, or an acid anhydride e.g. acetic anhydride. The reaction is illustrated by the following equation:

The compounds of the present invention also include the pharmaceutically acceptable salts of the novel naphthyridines. These salts are conveniently prepared e.g. by treating the naphthyridine with an appropriate amount of a useful acid.

generally in a suitable solvent.

Additional processes for preparing naphthyridines with certain other substituents are illustrated by the following equation sequences. Conventional reaction conditions are involved. The desired other substituent is underlined.

Sequence 1

CN CONY, Ng OZ Hrdrotysis > MNOZ Hyd Hydrolysis COOR3 COOH NX * < OZ Sequence 2

U COOR, C1-N(C2H5)2 (4,oz \ HN(C2H5)2 'k,oz > 1 atm J-CH, HNN-CH m/ 0 İNN'CH3 > 1 atm Oz The naphthyridines having an alkylsulfinyl or alkylsulfonyl substituent are prepared by oxidizing the corresponding C1-C6 alkylthio containing compound.

Any suitable oxidizing agent, e.g. H2O2, may be used. The following equation illustrates the reaction

Certain naphthyridine intermediate compounds are prepared using processes illustrated by the following reaction sequences, using conventional procedures and reagents.

Sequence A

Sequence B

< hydrolyse > ( cco2H CI SF4 /HF X Cl Sequence C

Sequence X (CtorBr) XN J6, oH halogenating L, 9 N N AOH agent ) 9 N AN OH POCt3/PCt5 X I C Compounds of the present invention have been found to possess antihypertensive activity of rapid onset and also to be ,3-adrenergic blocking agents. This antihypertensive activity is believed to be the result of peripheral vasodilation via a mechanism not directly related to ,B-adrenergic blockade. One advantage the present naphthyridines have over ordinary p-adrenergic agents is that the antihypertensive effect is immediate and generally of extended duration.

This rapid onset antihypertensive activity is determined by administering a reresentative compound of the present invention to spontaneously hypertensive (SH) rats and measuring the effect on blood pressure. Using this test method a representative naphthyridine was found to have this antihypertensive activity of immediate onset when administered orally.

The p-adrenergic blocking activity of the present naphthyridines is determined by measuring the ability of a representative compound to block isoproterenol induced p-adrenergic stimulant effects such as heart rate increase, hypertension and bronchodilation, in vivo. A representative naphthyridine was demonstrated to have ,B-adrenergic blocking activity, using this in-vivo test procedure.

The ability of the present naphthyridines to rapidly reduce blood pressure in an SH rat indicates that the present compounds are useful to treat hypertension in humans. Likewise, the observed p-adrenergic blocking activity of these compounds indicates that they are useful in humans as p-adrenergic blocking agents to therapeutically treat cardiovascular conditions such as angina pectoris and arrhythmia.

For use as antihypertensives and/or p-adrenergic blocking agents, the compounds of the present invention can be administered orally or parenterally, e.g.

intravenously or, intraperitoneally, and in any suitable dosage form. The compounds may be offered in a form (1) for oral administration e.g. as tablets in combination with other compounding ingredients (diluents or carriers) customarily used such as talc, vegetable oils, polyols, benzyl alcohols, starches and glycerine, or dissolved, dispersed or emulsified in a suitable liquid carrier-or in capsules or encapsulated in a suitable encapsulating material; or (2) for parenteral administration, dissolved, dispersed, or emulsified in a suitable liquid carrier or diluent. The ratio of active ingredient (present naphthyridine) to compounding ingredient(s) will vary as the dosage form and pharmacelogical effect requires.

Conventional procedures are used to prepare the pharmaceutical formulations.

The daily dosage level for the present compounds may be varied from 0.02 mg to 50 mg per kilogram of body weight. Daily doses ranging from 0.05 to 25 mg/kg are preferred, with 0.1 to 15 mg/l:g being a particularly preferred range. Oral administration is preferred. Either single or multiple daily doses may be administered depending on unit dosage.

Thus, another embodiment of this invention is a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention.

The following examples illustrate the preparation of representative naphthyridines of the present invention. All parts are by weight unless otherwise noted. The abbreviation "m" means "mole". All temperatures are in "C. Some intermediate compounds useful in preparing the present naphthyridines are disclosed in Hawes et al., J. Med. Chem. 16, 849-853 (1973).

EXAMPLE I A. 2-Hydroxy-3-cyano- 1 ,8-naphthyridine A mixture of 2-aminonicotinaldehyde (2.44 g, 0.02 m), ethyl a-cyanoacetate (4.52 g, 0.04 m), absolute ethanol (50 ml) and piperidine (0.5 ml) is stirred under reflux. After 1 hour, the solution is cooled to 040C. The yellow solid is filtered and dried to yield 2.5 g (73Vn) of 2-hydroxy-3-cyano-l,8-naphthyridines, m.p.

300"C.

B. 2-Chloro-3-cyano-1,8-naphthyridine A mixture of phosphorus pentachloride (12.2 g, 0.059 m), phosphorus oxychloride (44 ml), and 2-hydroxy-3-cyano-1,8-naphthyridine (2.3 g, 0.013 m) is stirred under reflux. After 1 hour, the excess of phosphorus oxychloride is distilled off under reduced pressure (2030 mm). The residue is treated with ice and solution neutralized with solid Na2CO3. The aqueous solution is extracted with CHCI3 (3x100 ml). The organic extracts are dried over Na2SO4, filtered and concentrated to dryness. The residue is sublimed at 140--1500C at 0.3 mm to yield 1.2 g (810/n) of 2-chloro-3-cyano-1,8-naphthyridine, m.p. 273"C.

C. (S) 3-Cyano-2-(3-tert. butylamino-2-hydroxypropoxy)- 1 ,8-naphthyridine Into a dry flask under N2 is placed (S)-2-phenyl-3-tert. butylamino-5hydroxymethyloxazolidine (2.4 g, 0.01 m) dimethylformamide (15 ml) and NaH (50% mineral oil 0.5 g, .01 m) and the mixture heated for 5 minutes on a steam bath.

After cooling to room temperature, 2-chloro-3-cyano- 1 ,8-naphthyridine (1.89 g, 0.01 m) is added and the solution is stirred at room temperature. After stirring overnight, the mixture is poured into H2O (200 ml), and extracted with ether (4x 100 ml). The organic layer is washed with H2O (2x50 ml) and cold IN HCI (2x 100 ml).

The acid layer is poured into NaOAc.3H2O (17 g, 0.2 m) and the solution stirred at room temperature. After 5 hours, the solution is extracted with ether (2x75 ml).

The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHCI3 (3x 100 ml). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is crystallized from CH3CN to yield 0.85 g (20%) of (S) 3cyano-2-(3-tert.-butylamino-2-hydroxypropoxy)- 1 ,8-naphthyridine, m.p. 1 52-30C.

By using 2-chloro-3-cyano- I ,6-naphthyridine in place of the 2-chloro-3-cyano 1,8 naphthyridine in Example 1, step C, (S) 3-cyano-2-(3-tert. butylamino-2 hydroxypropoxy)- I ,6-naphthyridine is obtained.

EXAMPLE 2 (S) 3-Cyano-2-(3-tert. butylamino-2-hydroxypropoxy)- 1 ,6-naphthyridine Dihydrochloride Into a dry flask under N2 is placed (S) 2-phenyl-3-tert. butylamino-5hydroxymethyloxazolidine (4 g, 0.07 m), DMF (25 ml), and NaH (50 ,/" mineral oil 0.85 g, 0.018 m) and heated on a steam bath for 5 minutes. After cooling to room temperature, 2-chloro-3-cyano-l,6-naphthyridine (3.3 g, 0.017 m) is added and the mixture stirred at room temperature. After stirring overnight, the mixture is poured into H2O (200 ml) and extracted with ether (4x 100 ml). The organic layer is washed with H2O (2x50 ml), and cold 1N HCI (2x100 ml). The acid layer is poured in NaOAc.3H2O (27 g, 0.2 m) and the solution is extracted with ether (2x75 ml). The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHIC1, (3x 100 ml). The aqueous layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product eluted with CHIC13 saturated with aqueous NH2. The crude product is crystallized from methanolic HCI and isopropanol (IPA) to yield 0.32 g. (5 /n) of (S) 3-cyano-2(3-tert.

butylamino-2-hydroxypropoxy)- 1 ,6-naphthyridine dihydrochloride, m.p. 215 170C.

By using (R,S) 2-methyl-3-isopropylamino-5-hydroxymethyloxazolidine in place of the (S) 2-phenyl-3-tert. butylamino-5-hydroxymethyloxazolidine in Example 2, the dihydrochloride of (R,S) 3-cyano-2-(3-isopropylamino-2 hydroxypropoxy)lz6-naphthyridine is obtained.

EXAMPLE 3 (S) 1 -(3-tert. B utylamino-2-hydroxypropoxy)-2,7-naphthyridine Hydrogen Maleate Salt Into a dry flask under N2 is placed (S)-2-phenyl-3-tert. butylamino-5hydroxymethyloxazolidine (2.5 g, 0.01 m), tert. butanol (50 ml), potassium tert.

butoxide (1.3 g, 0.011 m) and l-chloro-2,7-naphthyridine (1.67 g, 0.01 ml) and heated at 400C with stirring. After 15 hours, the solution is concentrated to dryness.

Acetic acid (7.2 g, 0.12 m) and H2O (120 ml) are added to the residue and the solution stirred at room temperature. After 5 hours, the solution is extracted with ether (2x100 ml). The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHIC13 (3x 100 ml). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product eluted with 20% MeOH-CHCl3. The crude product is crystallized with maleic acid in IPA to yield 0.4 g (10 /") of (S) l-(3-tert. butylamino-2hydroxypropoxy)-2,7-naphthyridine hydrogen maleate salt, m.p. 177--90C.

WHAT WE CLAIM IS: 1. Compounds having the formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. dryness. The residue is crystallized from CH3CN to yield 0.85 g (20%) of (S) 3cyano-2-(3-tert.-butylamino-2-hydroxypropoxy)- 1 ,8-naphthyridine, m.p. 1 52-30C. By using 2-chloro-3-cyano- I ,6-naphthyridine in place of the 2-chloro-3-cyano 1,8 naphthyridine in Example 1, step C, (S) 3-cyano-2-(3-tert. butylamino-2 hydroxypropoxy)- I ,6-naphthyridine is obtained. EXAMPLE 2 (S) 3-Cyano-2-(3-tert. butylamino-2-hydroxypropoxy)- 1 ,6-naphthyridine Dihydrochloride Into a dry flask under N2 is placed (S) 2-phenyl-3-tert. butylamino-5hydroxymethyloxazolidine (4 g, 0.07 m), DMF (25 ml), and NaH (50 ,/" mineral oil 0.85 g, 0.018 m) and heated on a steam bath for 5 minutes. After cooling to room temperature, 2-chloro-3-cyano-l,6-naphthyridine (3.3 g, 0.017 m) is added and the mixture stirred at room temperature. After stirring overnight, the mixture is poured into H2O (200 ml) and extracted with ether (4x 100 ml). The organic layer is washed with H2O (2x50 ml), and cold 1N HCI (2x100 ml). The acid layer is poured in NaOAc.3H2O (27 g, 0.2 m) and the solution is extracted with ether (2x75 ml). The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHIC1, (3x 100 ml). The aqueous layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product eluted with CHIC13 saturated with aqueous NH2. The crude product is crystallized from methanolic HCI and isopropanol (IPA) to yield 0.32 g. (5 /n) of (S) 3-cyano-2(3-tert. butylamino-2-hydroxypropoxy)- 1 ,6-naphthyridine dihydrochloride, m.p. 215 170C. By using (R,S) 2-methyl-3-isopropylamino-5-hydroxymethyloxazolidine in place of the (S) 2-phenyl-3-tert. butylamino-5-hydroxymethyloxazolidine in Example 2, the dihydrochloride of (R,S) 3-cyano-2-(3-isopropylamino-2 hydroxypropoxy)lz6-naphthyridine is obtained. EXAMPLE 3 (S) 1 -(3-tert. B utylamino-2-hydroxypropoxy)-2,7-naphthyridine Hydrogen Maleate Salt Into a dry flask under N2 is placed (S)-2-phenyl-3-tert. butylamino-5hydroxymethyloxazolidine (2.5 g, 0.01 m), tert. butanol (50 ml), potassium tert. butoxide (1.3 g, 0.011 m) and l-chloro-2,7-naphthyridine (1.67 g, 0.01 ml) and heated at 400C with stirring. After 15 hours, the solution is concentrated to dryness. Acetic acid (7.2 g, 0.12 m) and H2O (120 ml) are added to the residue and the solution stirred at room temperature. After 5 hours, the solution is extracted with ether (2x100 ml). The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHIC13 (3x 100 ml). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product eluted with 20% MeOH-CHCl3. The crude product is crystallized with maleic acid in IPA to yield 0.4 g (10 /") of (S) l-(3-tert. butylamino-2hydroxypropoxy)-2,7-naphthyridine hydrogen maleate salt, m.p. 177--90C. WHAT WE CLAIM IS:

1. Compounds having the formula

and pharmaceutically acceptable salts thereof, in which Z is -CH2-CHOR-CH2-NHR1 where R is hydrogen or C2~12 acyl and R1 is C,~12 alkyl, and R2 is a hydrogen, chlorine, bromine or fluorine atom or a cyano, amino, nitro, trifluoromethyl, carboxy, (C~8 alkoxy)carbonyl, (C6~12 carbocyclic aryloxy)carbonyl, C16 alkylthio, C16 alkylsulfinyl, C18 alkylsulfonyl, carbamoyl, (C1~6 alkyl)carbamoyl, di(C1 6 alkyl)carbamoyl, piperidinocarbonyl, 1piperazinylcarbonyl, 4-methyl- 1 -piperazinylcarbonyl or morpholinocarbonyl radical.

2. A compound as claimed in Claim 1 in which R is hydrogen.

3. A compound as claimed in Claim 2 in which -OZ is in a position ortho to an N atom.

4. A compound as claimed in Claim 3 in which R2 is ortho to the -OZ group.

5. A compound as claimed in Claim 1 having the formula

in which Z and R2 are as defined in Claim 1.

6. A compound as claimed in Claim 5 in which R is hydrogen.

7. A compound as claimed in Claim 6 in which R1 is C24 branched alkyl.

8. A compound as claimed in Claim 7 in which R1 is t-butyl.

9. A compound as claimed in Claim 8 having the S-isomer configuration.

10. A compound as claimed in Claim 5 having the formula

in which R, R1 and R2 are as defined in Claim 1.

II. A compound as claimed in Claim 10 in which R is H, R1 is C24 branched alkyl and R2 is -CN.

12. A compound as claimed in Claim 11 in which R, is t-butyl.

13. A compound as claimed in Claim 12 having the S-isomer configuration.

14. A compound as claimed in Claim 5 having the formula

in which R, R, and R2 are as defined in Claim 1.

15. A compound as claimed in Claim 14 in which R is hydrogen, R, is C3~,4 branched alkyl and R, is -CN.

16. A compound as claimed in Claim 15 in which R, is t-butyl.

17. A compound as claimed in Claim 16 having the S-isome; configuration.

18. A compound as claimed in Claim 5 having the formula

in which Z is as defined in Claim 1.

19. A compound as claimed in Claim 18 in which R is H.

20. A compound as claimed in Claim 19 in which R1 is t-butyl.

21. A compound having the formula set forth in Claim 1 in which Z is an oxazolidine group of the formula

where R1 is C112 alkyl and R' is H, C112 alkyl or C6~12 aryl, and R2 is as defined in Claim 1.

22. A process for preparing compounds of Claim 1 in which R is H that comprises hydrolysis of a compound having the formula

where R2 is defined as in Claim I and Z' is an oxazolidine group of the formula

where R1 is C112 alkyl and R' is H, C1~,2 alkyl or C6~12 aryl.

23. A process for preparing a compound as claimed in Claim 1 in which R is C2~12 acyl, that comprises acylating the corresponding compound in which R is H.

24. A process for preparing a compound as claimed in Claim 1 substantially as hereinbefore defined in any one of the Examples.

25. A compound as claimed in Claim I when prepared by a process as claimed in Claim 22, 23 or 24.

26. A pharmaceutical composition useful for effecting ,B-adrenergic blockade or treating hypertension containing an effective amount of a compound as claimed in Claim 1 and one or more compounding ingredients.

27. A composition as claimed in Claim 26 in which the said compound is a compound as claimed in any one of Claims 2 to 20 and 25.

28. A composition as claimed in Claim 26 or 27 in orally administrable form.

29. A composition as claimed in Claim 26 or 27 in parenterally administrable form.

30. A composition as claimed in Claim 28 in the form of a tablet or capsule.

31. A composition as claimed in Claim 29 in the form of a solution, dispersion or emulsion.