NO754088L - - Google Patents

Description

Procedure for the preparation of new substituted pyridines..

The present invention relates to the preparation of new 2-(3-t-butyl- or isopropylamino-2-hydroxypropoxy)-3-cyano-pyridines and their pharmaceutically acceptable salts. These pyridines are vasodilators with anti-hypertensive activity with rapid and lasting action and a reduced tendency to cause unwanted tachycardia. They are also (3-adrenergic blocking agents .

Hypertension in humans and other animals can be treated with various chemical agents. One such class of agents is known as (3-adrenergic blocking agents or (3-blockers). Although this class of agents may have anti-hypertensive activity, the onset of this activity is generally gradual. The structure and activity of (3-blockers is generally discussed in "ClinicalPharmacology and Therapeutics" 10, 252, 306 (1969). Cyanosubstituted carbocyclic and heterocyclic a ryi-(3-adrenergic blocking agents are discussed in Belgian Patent 707,050 and Netherlands Patent 69,07700. Cyanosubstituted heteroaryl-(3 -adrenergic blocking agents are also discussed in German patent 2./+06.930.

Another class of anti-hypertensive agents is the vaso-dilators. However, vasodilators usually cause unwanted tachycha rdia.

In one embodiment of the present invention, compounds with the formula are produced:

wherein R is isopropyl or t-butyl, and pharmaceutically acceptable. salts thereof. A preferred substituted pyridine is 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine and its pharmaceutical good-

absorbable salts.

The substituted pyridines produced according to the invention include all the optically isomeric forms, i.e. mixtures of the enantiomers, e.g. racemates, as well as the individual enantiomers. These individual enantiomers are usually designated according to the optical rotation they cause, with (+) and (-), (L) and (D), (1) and (d) or combinations of these symbols. The symbols (S) and (R) denote respectively sinister and rectus, and denote the absolute spatial configuration of the enantiomer.

According to the invention, the pyridines can be prepared by any convenient method.

Such a method involves coupling a 2-halo-3-cyanopyridine with a suitably substituted oxazolidine and hydrolysis of the resulting reaction product. This procedure is illustrated by the following reaction equations:

where R is t-butyl or isopropyl, M is an alkali metal, either potassium or sodium, and r can be hydrogen or the residue of a suitable aldehyde

e.g. arylaldehyde such as benzaldehyde,

naphthaldehyde or the like, or alkanal such as acetaldehyde butyraldehyde. and the like. The method of primarily illing'of 3XaZ°lldiner where M is the ^drogen, is described in US patent 3 718 647

and 3,657,237. The alkali metal salt of the oxazolidine is prepared in a conventional manner by reacting the corresponding hydroxymethyl-oxazolidine with an appropriate amount of base, such as potassium hydroxide, sodium hydroxide, sodium methoxyide or the like. However, this reaction A can also be carried out with in situ formation of the alkali meta11-oxazolidine salt of formula III by reacting the oxazolidine:

with the pyridine of formula II in the presence of a strong base such as an alkali metal alkoxide [e.g. K-O-C-(CH^ ) ^ ] or- hydroxide (e.g. NaOH) or sodium hydride.

The coupling reaction can be carried out at temperatures from approx.

0° to approx. 100°C. A temperature range from 10° to approx. 50°C is preferred. The reaction is generally carried out in a solvent. Any suitable solvent can be used, and examples of useful solvents are dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, C-^-C^-alkanols

and such. The hydrolysis is carried out using conventional acid hydrolysis reagents and methods, e.g. treatment with a solution of strong mineral acid such as hydrochloric or sulfuric acid.

The coupling reaction is generally carried out at atmospheric pressure. Higher pressures can be used if desired.

When the racemic oxazolidine (formula III or V) is used as a reactant, the product of formula I is obtained as a racemate. The racemate can be separated into its individual enantiomers by conventional resolution methods.

By using a single optical isomer of the oxazolidine of formula IV or V in the above reactions, the product of formula I can be obtained directly as a single enantiomer. If the S-isomer of the oxazolidine is thus used, the product obtained will be the S-isomer. This constitutes a convenient way for the direct preparation of individual isomers of the present pyridines.

The route compounds also include the pharmaceutically acceptable salts thereof. new pyridines. These salts are generally salts of the pyridines of formula I and organic or inorganic acids. ■ These salts are prepared by treating the pyridine with a suitable amount of a useful acid, usually in a suitable solvent. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid. oxalic acid and the like, and useful inorganic acids are hydrogen halide acids such as HC1, HBr and HI, sulfuric acid, phosphoric acid and the like.

The procedural prohibitions have a double effect. They are-(1) vasodilators with anti-hypertensive activity with rapid and

prolonged action and reduced propensity to cause tachycardia, and (2) [3-adrenergic blocking agents. This anti-hypertensive activity is believed to be the result of peripheral vaso-dilatation via a mechanism not directly associated with (3-adrenergic blockade. The present pyridines thus provide (a) an advantage over common vasodilators as vasodilator treatment usually leads to an unwanted tachycardia response , and (b) an advantage over the usual (3-adrenergic blocking agent in having an immediate and considerable anti-hypertensive effect.

This rapid onset anti-hypertensive activity is determined by administering (orally) a representative pyridine of formula I to spontaneously hypertensive (SH) rats and measuring the effect on blood pressure. A representative substituted pyridine, (S)-2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, was shown to rapidly lower the SH rat's blood pressure.

The (3-adrenergic blocking activity of the methods is determined by measuring the ability of a representative pyridine to block isoproterenol-induced β-adrenergic stimulant effects such as heart rate increase, hypotension and bronchodilation, in animals. A representative pyridine, (S)-2-(3- t-butylamino-2-hydroxy-propoxy)-3-cyanopyridine hydrochloride, was administered intravenously and was found to act as a β-adrenergic blocking agent in this test.

The present pyridine's ability to lower blood pressure,

in a SH rat, rapid and of extended duration, indicates that the present pyridines and their salts are useful for the treatment of hypertension in humans. Likewise, the observed β-adrenergic blocking activity of these pyridines indicates that they are useful in humans as β-adrenergic blocking agents.

For use as antihypertensive and/or β-adrenergic blocking agents, the compounds of the method may be administered orally, by inhalation, by suppository, or parenterally, i.e., intravenously, intraperitoneally, etc., and in any appropriate dosage form. The compounds may be used. in a form (1) for oral administration, i.e. as tablets in combination with other compositional ingredients (diluents or carriers) commonly used, such as talc, vegetable oils, polyols, benzyl alcohol, starches, gelatin and the like, 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, or (3) as an aerosol, or (4) ) as a suppository. The ratio between active ingredient (method compound) and preparation ingredients will vary since the dosage form creates be it.

The amount of Dbs for the process compounds can be varied from approx. 0.01 rag to approx. 50 mg per kg animal body weight per day. Daily doses varying from approx. 0.04 to approx. 2.5 mg/kg is preferred, since approx. 0.08 to approx. 1.25 mg/kg is a more preferred range.' Oral administration is preferred. Either single or multiple daily doses can be administered depending on the unit dose.

The following examples illustrate pharmaceutical preparations containing the pyridines which are prepared according to the invention. Conventional methods are used for the production of these preparations.

Capsule composition Injectable solution

Liquid suspension

The following examples illustrate the preparation of a representative pyridine of formula I. All parts and percentages are by weight unless otherwise specifically stated.

Example 1

( S )- 2- f 3- t- butylamino- 2- hydroxypropoxy)- 3- cyanopyridine hydrochloride

To 7 g (0.03 mol) (S)-2-phenyl-3-t-butyl-5-hydroxymethyl-oxazolidine in 35 ml N,N-dimethylformamide (DMF) is added 1.3 g (0.03 mol) nat r iumh yd r id (57% dispersion in mineral oil). This mixture is heated for 5 minutes over steam and then stirred for 15 minutes at room temperature. 4.1 g (0.03 mol) of 2-chloro-3-cyanopyridine in 20 ml of DMF are then added, and the resulting reaction mixture is stirred for 4 hours at room temperature. Water is then added, and an oil separates. This oil is extracted with 3 x 25 ml of chloroform. This chloroform extract is dried over sodium sulfate and evaporated under reduced pressure (20 mm) over steam to give the product, (S)-2-phenyl-3-t-butyl-5-(3-cyano-2-pyridyloxymethyl)-oxazolidine, like an oil. This oil is suspended in 50 ml IN hydrochloric acid, heated for 5 minutes over steam and then stirred for 15 minutes at room temperature. The solution obtained is then extracted with 2 x 25 ml of diethyl ether. The extracted aqueous layer is made alkaline by the addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with 3 x 25 ml of ethyl acetate, and the ethyl acetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then evaporated under reduced pressure

pressure (20 mm) over steam, whereby an oil is obtained. This oil is chromatographed on aluminum oxide. The chromatographic fractions are evaporated, whereby an oil is obtained which is dissolved in diethyl ether.

A saturated solution of ethanolic hydrogen chloride is added to this ether solution until solid separation is substantially complete. The separated semi-solid substance is recrystallized from isopropanol/ether (ether added to isopropanol to the boiling point), whereby 1 g of (S)-2-(3-t-butylamino-2-hydroxy-propoxy)-3-cyanopyridine hydrochloride is obtained as melts at l6l - l63°c.

Although in example 1 the S-isomer of the pyridine salt is prepared, the racemate is primarily illed by use of the racemic (S/R)-oxazolidine reactant, and the R-isomer is prepared by using the R-oxazolidine reactant.

The free amine is obtained from the salt of Example 1 by any conventional method, e.g. by treating the salt with a base (eg sodium hydroxide) in solution and extracting the free amine therefrom.

Using the method in example 1, (S)-2-(3-isopropylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride is prepared by using the corresponding N-isopropyl-oxazolidine instead of the N-t-butyl-oxazolidine.

Other methods for producing the pyridines according to the invention include reactions which are described below.

In each of the illustrative equations, R is t-butyl and isopropyl groups.

where X is halogen, especially chlorine, bromine and iodine, or aryl- or alkylsulfonyloxy, such as C-^-C-^O-alkylsulfonyloxy, methylsulfonyloxy, phenylsulfonyloxy, -C^-alkyl-phenylsulfonyloxy, p-methylphenylsulfonyloxy, naphthylsulfonyloxy or the like . In the preferred method, a reactant is used where X is halogen, preferably bromine or chlorine.

Reaction B is generally carried out in the presence of a basic condensing agent such as an alkali metal carbonate such as sodium carbonate or potassium carbonate, or the reaction may be carried out in excess of the RNH 2 reactant. The reaction temperature may vary. A comfortable temperature range is from room temperature to approx. 100°C. The reaction is conveniently carried out at atmospheric pressure, although overpressure can be used. The product obtained from reaction B is generally a racemic mixture, and can be separated into its individual enantiomers. by conventional cleavage methods.

where X is as indicated above under reaction B.

Reaction C is carried out under the same general conditions

as reaction B.

The product obtained from reaction C is usually a racemic mixture which can be separated into its individual enantiomers by common resolution methods.

Reaction D is advantageously carried out in excess of the amine reactant (RNF^). Temperatures up to the reflux temperature can be used. A particularly useful reaction temperature is from room temperature to approx. 100°C. The reaction is conveniently carried out at atmospheric pressure.

The product from reaction D is usually a racemic mixture, and can be separated into its enantiomers using known cleavage methods.

any suitable mild dehydrating agent may be used. One such agent is trifluoroacetic anhydride in pyridine

and such. Typical dehydration reaction conditions are satisfactory.

In reaction E, the optical isomeric properties of the product will

in general be those for the reactant (4). Thus, e.g. The S-reactant (4) gives an S-product.

where halo is bromine, chlorine or iodine.

Reaction F is carried out in the presence of a strong base such as an alkali metal alkoxide, e.g. K-O-t-butyl, NaOCH 3„, a hydroxide e.g. NaOH, KOH or NaH. The reaction is preferably carried out in solution. Any suitable solvent can be used as aprotic solvents, e.g. dimethylformamide, dimethyl sulfoxide and the like, or lower alkanols, e.g. methanol, t-butanol and the like. The reaction is conveniently carried out at room temperature, although temperatures from about. 0°C to the return temperature for. the system can be used. The reaction is usually carried out at atmospheric pressure, but overpressure can also be used.

The optical isomer configuration of the final product in reaction F will be that of reactant (6), e.g. if reactant (6) is an R,S mixture, the product will be an R,S mixture.

where halo is chlorine, bromine or iodine.

Reaction G is carried out in the presence of a strong base as described for reaction F. The pressure, temperature and solution reaction parameters are generally the same as those described above for reaction F.

The optical isomeric configuration of reactant (8) is generally transferred to the product. For example, an R-reactant (8) will thus give an R-product.

Any suitable mild dehydrating agent can be used such as acetic anhydride and the like. Conventional dehydration reaction conditions are used.

The product from reaction H will have the same optical isomer properties as reactant (9)■

where Y is halogen, especially chlorine, bromine or iodine, alkyl- or aryl-sulfonyloxy such as phenylsulfonyloxy, -C 8 -alkylphenylsulfonyloxy, p-methylphenylsulfonyloxy, naphthylsulfonyloxy, -C₉Q-alkylsulfonyloxy, methylsulfonyloxy, decylsulfonyloxy and the like.

Reaction I is carried out in the presence of a strong base, in a solvent, and reaction temperatures and pressures are used as described for reaction F.

The optical isomer configuration for reactant (H) is generally transferred to the product.

The base, solvent and reaction pressures and temperatures used for reaction J are essentially the same as described for reaction F.

The product from reaction J will usually be a racemic mixture, which can optionally be cleaved using conventional cleavage methods.

where halo is bromine, chlorine or iodine.

Various reagents can be used to give the group CN~'. An example of such a reagent is CuCN in dimethylformamide. Reaction K can be carried out in any conventional solvent such as dimethylformamide, quinoline, xylene and the like. Temperatures varying from 100°C to the reflux temperature are conveniently used. Atmospheric pressure is generally sufficient for carrying out the reaction.

The product from reaction K will have the isomeric properties of the reactant (11).

The reducing agent used in reaction L can be a chemical reducing agent such as NaBH"^, aluminum alkoxide or the like, or a microbial reducing agent such as a bacterial reductase, e.g. E. coli, an actinomycetal reductase, e.g. S. coelicolor or

a fungal reductase, e.g. C. lunata. The chemical reduction is generally carried out in a solvent such as an aprotic solvent, e.g. dimethylformamide, hexamethylphosphoramide or the like, or a lower alkanol, e.g. methanol, isopropanol or the like. Conventional temperature and pressure reaction conditions can be used.

The microbial reaction is carried out by preparing a culture of the chosen organism and then exposing the reactant (12), generally in the form of a salt, to the action of the culture under suitable conditions, and finally recovering the desired product in a conventional manner.

The product from reaction L is generally a racemic mixture.

In the following are representative examples of the methods described above, such as reactions B - L.

Example 2

10 ml of t-butylamine is added to 2-(3-bromo-hydroxypropoxy)-3-cyanopyridine. The reaction mixture is heated for 4 hours under reflux, and excess t-butylamine is recovered under reduced pressure (25 mm). The residue formed is dissolved in ether, filtered,

and ethanolic hydrochloric acid is added until precipitation is complete. The formed hydrochloride salt of 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine is purified by recrystallization.

Example 3

To 3jO g (0.015 mol) 2-(3~amino-2-hydroxypropoxy)-3-cyanopyridine and 1.2 g (0.01 mol) isopropyl bromide in 50 ml ethanol, 2.5 g (0.02 mol) potassium carbonate is added . The reaction mixture is allowed to stand for 5 days at room temperature. After filtration, the solution is evaporated under reduced pressure (25 mm) at 50°C. The residue is chromatographed on neutral aluminum oxide, whereby 2-(3-isopropylamino-2-hydroxypropoxy)-3-cyanopyridine is obtained.

Example 4~

10 ml of t-butylamine is added to 1.8 g (0.01 mol) of 2-(2,3-epoxypropoxy)-3-cyanopyridine. The reaction mixture is boiled under stirring for 4 hours. Excess t-butylamine is removed under reduced pressure (25 mm) at 50°C. The residue is dissolved in ether, and ethanolic hydrochloric acid is added until precipitation is complete. The formed hydrochloride salt of 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine is purified by recrystallization.

Example 5

To a solution of 1.2 g (0.006 mol) trifluoroacetic anhydride in 10 ml pyridine is added 0.4 g (0.0015 mol) 3-carbamoyl-2-(3-t-butylamino-2-hydroxypropoxy)-pyridine. The reaction mixture is heated for 4 hours under reflux and then evaporated under reduced pressure (25 mm) at 50°C. The residue is suspended in 10 ml of saturated aqueous sodium carbonate solution and stirred for 16 hours at room temperature. The alkaline suspension is extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated under reduced pressure (25 mm) at 50°C. The residue is chromatographed on neutral aluminum oxide, whereby 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine is obtained.

Example 6

A solution of 1.4 g (0.01 mol). 2-chloro-3-cyanopyridine

and 1.5 g (0.005 mol) of 2,2'-methylene-bis-3-t-butylamino-1,2-propane-diol in 15 ml of dimethylformamide are cooled to 0°C. 0.21 g (0.005 mol 56.8% sodium hydride) is added to the solution. The reaction mixture is stirred at 0 - 5°C until testing with phenolphthalein paper shows the absence of a strong base. Another portion of 0.21 g (0.005 mol) of 56.8% sodium hydride is added. After 1 hour, 30 ml of 4N hydrochloric acid is added, and the mixture is extracted with ether.

The aqueous layer is boiled under reflux, cooled and brought to pH 9 with concentrated ammonium hydroxide and extracted with methylene chloride. The extract is dried and evaporated, whereby 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine is obtained.

Example 7

To a solution of 1.47 g (0.01 mol) 3-t-butylamino-1,2-dihydroxypropane in 10 ml of dimethylformamide, add 0.42 g

(0.01 mol) 56.8% sodium hydride. After stirring for 0.5 hours at room temperature, the solution is cooled to 0°C, and 1.4 g

(0.01 mol) of 2-chloro-3-cyanopyridine in 5 ml of dimethylformamide is added. After stirring for 2 hours at 0°C, the solution is allowed to warm to room temperature. After stirring for 2 hours at room temperature, 50 ml of water is added, and the mixture is extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated under reduced pressure (25 mm) at 40°C, whereby 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine is obtained.

Example 8

To 10 ml of acetic anhydride is added 2,7 9-(0.01 mol) 2-(3-t-butylamino-2-hydroxypropoxy)-3-hydroxyiminomethylpyridine. The rex ion mixture is slowly heated to reflux and. kept under reflux for 1 hour. After cooling, the mixture is poured into 50 ml of water and stirred until the excess of acetic anhydride is split. The mixture is extracted with chloroform and washed with water and aqueous sodium bicarbonate solution. The organic extract is dried and evaporated. The residue is dissolved in 25 ml of ethanol, and 25 ml of 10% aqueous sodium hydroxide is added. The solution is stirred at room temperature for 17 hours. After evaporation to 25 ml under reduced pressure (25 mm) at 50°C, 50 ml of water is added, and the mixture is extracted with chloroform. The organic extract is dried and evaporated, whereby 2-(3-t-butylamino-2-hydroxy-propoxy)-3-cyanopyridine is obtained. -

Example 9

A solution of 3-t-butylamino-2,3-dihydroxypropane in pyridine is treated with p-toluenesulfonyl chloride at 0°C. After stirring for 0.5 hours, the solution is allowed to warm to room temperature and poured into water. The solution is treated with potassium carbonate and extracted with chloroform. The chloroform extract is evaporated in vacuo at 50°C, whereby 1-toluenesulfonyloxy-3-

t-butylamino-2-propanol.

Sodium hydride is added to 3-cyano-2-hydroxypyridine in dimethylformamide. After stirring at room temperature for 0.5 hours, 1-toluenesulfonyloxy-3-t-butylamino-2-propanol is added. Stirring is continued for 3 hours, water is added, and the mixture is extracted with chloroform. Evaporation of the chloroform extract gives 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyano<p>pyridine.

Example 10

Sodium hydride is added to a solution of 3-cyano-2-hydroxypyridine in dimethylformamide. After stirring for 0.5 hours at room temperature, 1,2-epoxy-3-t-butylaminopropane in dimethylformamide is added dropwise at 0°C. The solution is allowed to warm to room temperature, and stirring is continued for 4 hours. Water is added and the mixture is extracted with chloroform. The chloroform extract is dried over sodium sulphate and evaporated, whereby 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine is obtained.

Example 11

Cuprocyanide is added to a solution of 2-(3-t-butylamino-2-hydroxypropoxy)-3-bromopyridine in dimethylformamide. The solution is heated for 10 hours under reflux and evaporated to dryness in vacuo. The residue is triturated with ethanol and filtered. The ethanol solution is evaporated in vacuo, whereby 2-(3-t-butylamino-2-hydroxypropoxy)-3-cyanopyridine is obtained.

Example 12

Sodium borohydride is added to a solution of 2-(3,-t-butylamino-2-oxopropoxy)-3-cyanopyridine in ethanol. After stirring for 3 hours at room temperature, water is added. After evaporation to half the volume, in a vacuum, the mixture is extracted with chloroform. Evaporation of the chloroform extract gives 2-(3-t-butylamino-2-hydroxy-propoxy)-3-cyanopyridine.

The cyanopyridines where R is isopropyl are prepared by using the corresponding isopropyl-substituted reactants instead of the t-butyl reactants in the method according to examples 2 - 12.

The salts obtained in examples 2 and 4 can be transferred to the free bases by conventional neutralization, if desired. Moreover, the free base products obtained in the other examples can be converted to the acid salts by treatment with any suitable acid

as previously mentioned.

When the product obtained is an R,S racemate, it can be separated into its individual enantiomers using conventional resolution methods. In some cases, the R- or S-enantiomer can be prepared directly using the relevant R- or S-isomer reactant.

Claims (12)

1. Analogy method for the preparation of therapeutically active compounds with the general formula: where R is isopropyl or t-butyl, and pharmaceutically acceptable acid addition salts thereof, characterized by ata) a compound with the formula:. where R1 is hydrogen or the residue of an alkyl or aryl aldehyde, is hydrolysed, or b) a compound of the formula: where X is halogen or aryl or alkylsulfonyloxy, is reacted with RNH2' using a basic condensing agent, or c) a compound of the formula: is reacted with (CH^ ^CH-X using a basic condensing agent, ord) a compound with the formula: is reacted with RNH^ , where R is as indicated above, or e) a compound with the general formula: 0 II where Y is -C-NH^ or -CH=NOH , is dehydrated. using a mild dehydrating agent, or f) a compound of the formula: is reacted with a compound with the formula: where R is as indicated above, in the presence of a strong base, or g) a compound of the formula: is reacted with a compound with the formula: where R is as indicated above, in the presence of a strong base, or h) a compound of the formula: is reacted with a compound with the formula: where Z is halogen or alkyl- or arylsulfonyloxy, in the presence of a strong base, ori) a compound of the general formula: where R is as indicated above, is reacted with a CN~ emitting reagent, orj) a compound with the general formula: where R is as above, is reduced by a suitable chemical or microbial reducing agent, and, if desired, the salt of a compound of formula I is prepared by treating a compound obtained by methods a) - j) with a pharmaceutically acceptable acid in a manner known per se. 2. Method according to claim 1, characterized in that the R-isomer is used as starting material. 3. Method according to claim 1, characterized in that the S-isomer is used as starting material. 4. Process according to claims 1-3, characterized in that a starting material is used where R is t-butyl. 5. Method according to claims 1-4, characterized in that the hydrochloride is prepared. 6. Procedure for the preparation of compounds with the general formula: where R is isopropyl or t-butyl, and pharmaceutically acceptable acid addition salts thereof, characterized by ata) a pyridine with the formula: is reacted with an oxazolidine with the formula: where R is as stated above, M is an alkyl a 11, and R is hydrogen, C 1 -C 8 alkyl or phenyl, and b) the reaction product from a) is hydrolysed. 7. Process according to claim 6, characterized in that an oxazolidine is used where M is sodium, R is t-butyl, and R 1 is phenyl. 8. Procedure, according to claim 6, characterized in that a reactant 2) is used which is the R-isomer. 9. Method according to claim 6, characterized in that a reactant 2) is used which is the S-isomer. 10. Method according to claim 9, characterized in that a reactant 2) is used where R is t-butyl. 11. Procedure for the preparation of compounds with the general formula: where R is isopropyl or t-butyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound with the formula: where R is as stated above, and R^ is hydrogen or an aldehyde residue, is hydrolyzed. 12. Method according to claim 11, characterized in that a starting material is used where R is t-butyl. 13- Method according to claim 11 or 12, characterized in that a starting material which is the S-isomer is used.