NO170525B - DISPENSER CONTAINER FOR PASTAS CONTAINING TASTE OIL AND WHICH HAVE A MULTILAYER STRUCTURE INCLUDING A BACKGROUND OF FLUORED POLYETHYL - Google Patents

Description

Analog production method for the production of a serum lipid-lowering compound

"The present invention relates to a process for the production of a serum lipid complex compound • which also has vasodilating properties.

In view of the fact that there is -still more and more -which suggests that a too high serum lipid concentration is correlated with basic pathogenic mechanisms -and symptoms -of several diseases, such as vascular diseases, diabetes and hyperthyroidism, lowering serum lipid is -concentration important in the treatment of such diseases.

The lowering of the serum lipid concentration can be achieved by inhibiting lipid mobilization, e.g. by reducing the net release of lipids into the circulation in the form of free fatty acids from tagged triglycerides in adipose tissue.

It has now been found that the compound with the formula;

and therapeutically acceptable salts thereof, have vasodilator properties and are particularly valuable in lowering excessively high serum lipid concentrations.

The known unsubstituted analog 3-pyridine methanol, although used as a serum lipid-lowering compound and also as a vasodilator, is known to be associated with certain imperfections with respect to duration of activity and degree of efficacy. It has now unexpectedly been found that 5-fluoro-substituted 3-pyridine ethanol is more powerful, effective and has a longer duration of activity than the unsubstituted analogue compound.

By the term "therapeutically acceptable salts" is meant acid addition salts which are physiologically innocuous when administered in a dose and at an interval (ie, frequency of administration) effective for the indicated therapeutic use of the compound from which the salt is derived. Typical therapeutically acceptable addition salts of compounds of formula I include salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric or sulfuric acid, organic acids such as acetic acid, glycolic acid, lactic acid, levulinic acid, citric acid, fumaric acid, maleic acid, succinic acid, tartaric acid, benzoic acid and sulfonic acids, such as methanesulfonic acid and sulfamic acid.

The compounds of formula I are obtained by reduction of a compound of the formula:

or a salt thereof, where X is a chlorocarbonyl-, alkoxycarbonyl-, thiol-O

ii

ester (-C-S-alkyl) or a cyano group, by means of known methods used for the reduction of the unsubstituted analogue compounds, e.g. by catalytic hydrogenation and reduction with a complex metal hydride to form a compound of formula I, and, in those cases where a therapeutically acceptable salt is desired, reaction of the compound of formula I with the appropriate acid.

According to a preferred embodiment, a compound of formula II, where X is an alkoxycarhonyl group with at most 5 carbon atoms, is reduced by means of complex metal hydrides, such as sodium or potassium borohydride and lithium aluminum hydride. In cases where potassium or sodium borohydride is used as -reducing agent, the reaction can be carried out in such solvents as methanol, ethanol, water or mixtures thereof. When lithium aluminum hydride is used as reducing agent, the reaction is preferably carried out in inert solvents such as diethyl ether and tetrahydrofuran.

The compounds used as starting materials can be prepared according to known methods.

In clinical practice, the compound produced according to the invention will normally be administered orally or by injection in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a therapeutically acceptable acid addition salt, e.g. 1 form of the hydrochloride, hydrosulphate or the like, together with a pharmaceutically acceptable carrier. General or special indications <4> of the newly produced compound are consequently intended to include both the free base and the acid addition salts of the free base unless the context in which such indications are used, e.g. in special examples, is inconsistent with the general meaning. The carrier may be a solid, semi-solid or liquid diluent or an ingestible capsule.

The active ingredient will usually make up between 10 and 95% by weight of the preparation, and in particular between 0.5 and 20% by weight for preparations for injection and between 2 and 50% by weight for preparations suitable for oral administration.

The invention is illustrated by the following examples. Example I. Starting compounds for the production of pyridine methanols.

Ethy. l- 5-fluoronicotinate. 5-Fluoronicotinic acid X U 3.6 g) was boiled under reflux for 4 hours with 550 ml of thionyl chloride. Excess thionyl chloride was then evaporated and to the hydrochloride of the acid chloride thus obtained 420 ml of absolute ethanol was slowly added at room temperature. The mixture, which soon became homogeneous, was refluxed for 2 hours. Profit

-ethanal Jåle was evaporated and the solid residue was treated with excess saturated sodium bicarbonate solution. The resulting mixture was extracted three times with ether and the ether solution dried over anhydrous sodium sulfate. -Evaporation of the solvent and distillation of

the residue in vacuo gave 10.9 g of an almost colorless liquid, (bp. 92°-94<c>C/ 13 mm Hg.' n^5 .= 1.4820) in

Example II. S-fluoro-^-pyridinemethanol.

To a stirred solution of ethyl 5-fluoronicotinate (54.1 g) in 270 ml of methanol, calumboric acid (53.9 g) was added with cooling over 1 hour. The mixture was stirred for 30 minutes at room temperature and then boiled under reflux for 6 hours. The solution was stirred overnight at room temperature and most of the solvent was evaporated. The residue was dissolved in 300 ml of water and then extracted for 1 hour with five ether portions of 100 ml each. The ether solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to give 38 g of a yellow oil. 'XJ

The oil was distilled in vacuum and this gave 29. él g colorless desired product boiling point 83°-a5°C/0.05-0-01 mm. Hg. The hydrochloride. melts (after repeated cross-extraction from ethanol) at 162°C.

Analyzes: Found: C 4-4.19; H 4.59in M 8.70; F 11.42; Cl 21.52%;

Calculated for CgH NOFClr C 44.05; H 4.32; N 8.56; F 11.61; Cl 21.68%. Example III. 5- fluoro- 3- pyridinemethanol.

To a stirred ice-cooled solution of lithium aluminum hydride (14.4 g) in 530 ml of anhydrous ether, a previously cooled solution of ethyl 5-fluoronicotinate (54.3 g) in 370 ml of anhydrous ether was added over 1.5 hours at a reaction temperature of at most 6° C. The mixture was stirred with cooling for 30 minutes and then 72 mL of a sodium sulfate solution in water (5 mL/g) was slowly added with stirring and cooling. The mixture was filtered and the solid washed with ether. The combined ether solutions were dried, filtered and the solvent evaporated giving 36.6 g of a red oil. This was converted to the hydrochloride, which after repeated recrystallizations from ethanol melts at 162° C. The product was found to be identical to that prepared according to Example II.

Example IV. 5- fluoro- 3- pyridinemethanol.

The starting compound 5-fluoro-3-cyanopyridine, m.p. 53C'-54.5°C, was prepared by dehydration of the known compound 5-fluoro-nicotinamide with phosphorus pentoxide.

5-Fluoro-3-cyanopyridine (1.50 g) was dissolved in a mixture of 2.5 ml of concentrated hydrochloric acid and 25 ml of water and hydrogenated at atmospheric pressure at room temperature over 10% Pd/C (0.40 g). After 8 hours, 535 ml of hydrogen had been consumed. The hydrogenation was interrupted for 1 3 days and

16,406 r

then a further hydrogenation was carried out for 1 hour over a further amount of 10% Pd/C (0.30 g). A total amount of 600 ml of hydrogen was consumed. The catalyst was filtered off and washed with water. The combined filtrate and washings were concentrated to a volume of 25 ml, made alkaline by addition of solid sodium bicarbonate and extracted five times with 40 ml of butyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to give an oily residue, which was converted to a hydrochloride salt. This product, which was colorless, weighed 1.42 g and had an IR spectrum identical to that obtained for the product of Example II.

Example V. 5-fluoro-5-pyridinemethanol.

5-Fluoronicotinic acid (3.00 g) was refluxed for 4 hours with 30 ml of thionyl chloride and excess thionyl chloride was evaporated in vacuo. The 5-fluoronicotinic acid chloride thus obtained was dissolved in 30 ml of diglyme and treated with stirring with sodium borohydride (2.40 g), first for 15 minutes at 35°C and then for 30 minutes at 80°C. The mixture was poured onto ice and gently acidified with dilute aqueous hydrochloric acid. The aqueous solution was washed with two portions of ether and its volume reduced in vacuo to approx. 50 ml. It was then made alkaline with aqueous ammonia and extracted with five portions of chloroform. The chloroform solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to give an oily product which was converted -to a hydrochloride salt. The dry salt weighed 1.35 g and had an IR spectrum identical to that obtained from the product prepared according to Example II.

Example VI. 5- fluoro- 3- pyridinemethanol.

The starting compound S-benzyl 5-fluoro-3-pyridinecarbothioate with a melting point of 42° - 44°C was prepared by reacting 5-fluoronicotinoyl chloride with benzyl mercaptan.

S-benzyl 5-fluoropyridine carbothioate (1.00 g) was stirred for 3 hours at room temperature; with freshly produced Raney nickel (W 4, 10 g)

in 70 ml of ethanol. The metal was filtered off and thoroughly washed with ethanol. The combined filtrate and washing solutions were added in a small excess. shot of hydrogen chloride in ether. Evaporation of the solvent in vacuo gave the hydrochloride salt which was washed with ether and air dried. The colorless product weighed 0.43 g and had an IR spectrum identical to that of the product of Example II.

Pharmacological trials. ■ . *

The compound prepared according to the present invention was examined with regard to lowering the concentration of free fatty acids in the serum of dogs according to the method described by Carlson £>g Liljedahl in Acta Med. Seand. 1963, 173, 7-87-791, and by Bergstrom, Carlson and Oro in Acta Physiol. Scand. 1964, -60, 170-180. In this method, the compound is examined on a model in a stress situation where it is known that norepinephrine-stimulated lipid mobilization occurs. Anesthetized dogs were given continuous infusions of noradrenaline in a constant amount. After 60 minutes of infusion, a solution of the test compound was injected intravenously. Arterial blood samples were taken, the blood was immediately centrifuged and the plasma extracted for determination of free fatty acids according to Dole, J. Clin. Invest. 1, 1956, 35, 150, as modified by Trout et al. J. Lipid.Res., 1960, 1, 199. The effect of each compound was judged from the relative lowering a, calculated as a percentage of the total rise in concentration of free fatty acids in the serum induced by the norepinephrine infusion, and from the total duration b (minutes) of more than a 50 lowering of the concentration of free fatty acids in the serum. The test results at a dosage level of 25 mg/kg are classified according to the following scheme:

Nicotinic acid was used as a reference (effect = + +).

The effects for the compound of formula I are given in Table I.

In an analogous experiment, the quantitative effect + + • was obtained for 3-pyridinemethanol. The resorption of 5-fluoro-3-pyridinemethanol in dog serum was also studied. 200 mg of the compound was administered orally to the dog in the form of a tablet or capsule. The amount of the compound was analyzed as the corresponding nicotinic acid derivative (the metabolism of these acids is very rapid) at various times according to Hughes, D.E. and Williamson, D.H., Biochem. J. 55 (1953), 851. A comparison was made with the unsubstituted analogous compound. The maximum resorption and duration (given as time after administration when the serum concentration had decreased to 25% of the maximum concentration) for the compound of formula I is given in Table II.

5-Fluoro-3-pyridinemethanol prepared according to the present invention has a low toxicity. Thus, the toxicity in mice by intraperitoneal administration of the compound of formula I, >_ 2 g/kg body weight is given as LD,_n.

The compound 5-fluoro-3-pyridinemethanol was also investigated for its vasodilating properties. Changes in the peripheral blood flow in a cat's hind leg were measured in the following way: The blood from the femoral artery was led into a loop of a polyethylene tube which was inserted into the artery. The blood flow through the loop was regulated using a metering pump. Arterial pressure was measured immediately after the pump. This feature is therefore dependent on the pump current and the resistance in front of the pump. If the current is kept constant, the pressure changes will thus reflect the peripheral resistance.

Intra-arterial injections of 5-fluoro-3-pyridinemethanol (0.1% solution in isotonic sodium chloride solution, 1 mg compound/minute) produced a 23% decrease in vascular resistance.

Claims (1)

Analogous process for the preparation of a compound which inhibits serum lipid mobilization and which has the formula: as well as therapeutically acceptable salts thereof, characterized in that a compound with the formula: where X is a chlorocarbonyl, alkoxycarbonyl, thiol ester (-C-S-alkyl) or a cyano group, is reduced, after which the compound thus obtained is, if desired, converted into a therapeutically acceptable salt by reaction with the appropriate acid..