NO762996L - - Google Patents

Description

Chemical compounds for use as starting material

in the production of new substituted pyridines.. •

The present invention relates to the production of new 2-(3-t-butyl- or isopropylamino-2-hydroxypropoxy)-3-eyano-pyridines and their pharmaceutically acceptable salts. These pyridines are vasodilators with anti-hypertensive activity with rapid and lasting action and 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 β-blockers is generally discussed in "Clinical Pharmacology and Therapeutics" 10, 252, 30.6 (1969). Cyanosubstituted ca rbocyclic and heterocyclic α-β-adrenergic blocking agents are discussed in Belgian Patent 707,050 et seq. -landish patent 69.07700 Cyano-substituted heteroaryl-|3-adrenergic blocking agents are also discussed in German patent 2./+06.930.

Another class of anti-hypertensive agents are the vaso-dilators. However, vasodilators usually cause unwanted tachycardia.

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-butyl-• amino-2-hydroxypropoxy)-3-cyanopyridine and its pharmaceutical good-

Sl

absorbable salts.

The substituted pyridines which are prepared 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 benza ldehyde,'*

naphthaldehyde or the like, or alkanol such as acetaldehyde butyraldehyde and the like. The procedure for the preparation of oxazolidines where M is hydrogen 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 a suitable amount of base, such as potassium hydroxide, sodium hydroxide, sodium methoxyd or the like. However, this reaction A can also be carried out with in situ formation of the alkali meta 11-oxazolidine salt of formula III by reacting the oxazolidine:

with the pyridine of formula II in the presence of one strong base such as an alkali metal alkoxide [e.g. K-O-C-(CH^)3]or hydroxide (eg 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 dissolution chamber. 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 process for the compounds also includes the pharmaceutically acceptable salts of the 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 an appropriate amount of a useful acid, generally 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 HCl, HBr and HI, sulfuric acid, phosphoric acid and the like.

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

prolonged action and reduced tendency to cause tachycardia, and (2) (3-adrenergic blocking agents. This anti

hypertensive activity is assumed to be the result of peripheral vasodilation via a mechanism that is not directly connected with (3-adrenergic blockade. Present pyridines thus provide (a) an advantage over ordinary vasodilators as vasodilator treatment usually leads to an unwanted tachycardia response, and (b ) an advantage over the usual (3-adrenergic blocking agent by 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 measure 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 one representative pyridine to block isoproterenol-induced (3-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 shown to act as a β-adrenergic blocking agent by

this sample.

The ability of the present pyridine to lower blood pressure, in a SH rat, rapidly and with extended duration, indicates that the present pyridines and their salts are useful for the treatment of hypertension in humans. Likewise, it indicates the observed

(3-adrenergic blocking, activity of these pyridines that they are useful in humans as (3-adrenergic blocking agents.

For use as antihypertensive and/or β-adrenergic blocking agents, the subject compounds may be administered orally, by inhalation, by suppository, or parenterally, i.e., intravenously, intraperitoneally, etc., and in any suitable 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 alcohols, 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 as the dosage form requires it.

The dosage amount for the process compounds can vary from approx. 0.01 mg to approx. 5b mg per kg animal body weight per day. Daily doses varying from approx. 0.04 to approx. 2.5 mg/kg feed is given, with 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 preparation of these preparations. Tablet composition Capsule composition

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-( 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 1.39 (0.03 mol) nat rium hydr id (57% dispersion in mineral oil). This mixture is heated for 5 minutes over steam and then stirred for 15 minutes at room temperature. 4,19 (0.03 mol) 2-chloro-3-cyanopyridine in 20 ml of DMF is 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: get the product, . (S)-2-phenyl-3-t-butyl-5-(3-cyano-2-pyridyloxymethyl)-oxazolidine, as 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 sulphate. The dried ethyl acetate solution is then evaporated under reduced 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 is prepared from the pyridine salt, the racemate is prepared using the racemic (S/R)-oxazolidine reactant, and the R-isomer is prepared 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-isoprop<y>lamino-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 C₁-C₂O-alkylsulfonyloxy, methylsulfonyloxy, phenylsulfonyloxy, -C₉-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 can be carried out in an excess of RNH — the 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 resolution methods.

Reaction C

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 that can be separated into its individual enantiomers by common resolution methods.

Reaction D

Reaction D is advantageously carried out in excess of the amine reactant (RNH^). 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.

React ion . E

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

will generally be those for the reactant (4)-Thus, e.g. The S-reactant (4 ) give 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^, 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 approx. 0°C. until 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 (11) 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 3 , 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 3.09 (0.015 mol) 2-(3-amino-2-hydroxypropoxy)-3-cyanopyridine and 1.2 g (0.01 mol) isopropyl bromide in 50 ml of ethanol is added 2.5 g (0.02 mol) potassium carbonate. 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 •

To 1.8 g (0.01 mol) of 2-(2,3-epoxypropoxy)-3-cyanopyridine is added 10 ml of t-butylamine. The reaction mixture is refluxed 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-butylaraino-2-hydroxypropoxy)-3-cyanopyridine is purified by recrystallization.

Example 5

To a solution of 1.2 g (0.006 mol) of trifluoroacetic anhydride in 10 ml of pyridine is added 0.4 g (0.0015 mol) of 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 l6. hours at room temperature. The alkaline suspension is extracted with chloroform. The chloroform extract is dried over sodium sulphate and evaporated under reduced pressure (25 mm) at 50°C. The residue is chromatographed on

neutral aluminum oxide, whereby 2-(3-t-but<y>lamino^-hydroxypropoxy )-3-cyanopyridine is obtained.

Example 6

A solution of 1.4 g (0.01 mol) 2-chloro-3-cyanopyridine °9 1.5.g (0.005 mol) 2,2'-methylene-bis-3-t-butylamino-1,2- propane-diol in 15 ml of dimethylformamide is 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) of 3-t-butylamino-1,2-dihydroxypropane in 10 ml. dimethylformamide, 0.42 g (0.01 mol) of 56.8% sodium hydride is added. After stirring for 0.5 hours at room temperature, the solution is cooled to 0°C, and 1,4.9 (0.01 mol) 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 g (0.01 mol) 2-(3-t-butylamino-2-hydroxypropoxy)-3-hydroxyiminomethylpyridine. The reaction 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-propanoe.

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-cyanopyridine.

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 (6)

1. Chemical compounds for use as starting material in the production of therapeutically active compounds with the general formula: wherein R is isopropyl or t-butyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that they are covered by the general formula: where R is as stated above, and R"*" is hydrogen or the remainder of a alkyl or aryl aldehyde. 2. Connections according to claim 1, characterized in that they have .S-isomer configuration. 3. Compounds according to claim 1 or 2, characterized in that R is isopropyl.. k-. Compounds according to claim 1 or 2, characterized in that R- is t-butyl. 5. Connections according to requirement k, ' i characterized in that R is phenyl. 6. Procedure for the preparation of compounds according to claims 1 - 5 with the general formula: where R is isopropyl or t-butyl, and R"*" is hydrogen or the residue ■ of an alkyl or aryl aldehyde, characterized in that a pyridine with the formula: is reacted with an oxazolidine with the formula: where R and R"*" are as above, and M is an alkali metal.