IL27346A - Preparation of the 6,7-dinicotinate of 4-methyl esculetol starting from nicotinic acid anhydride - Google Patents

Description

C O H E N Z E D S P I S B A C H PATENT ATTORNEYS LEVONTIN T E A V V P A T E N T S D E S I G N S O R D I N A N C E SPECIFICATION Ax HEREBY DECLARE the nature this invention and in what manner the same is to be performed The present as its new derivatives of nicotinic acid as as a process of preparing these More the invention has as new of nicotinic acid of the general formula in which om the group constitute by hydrogen and the and propyl radicals the new derivatives of nicotinic acid of formula I have useful pharmacological These which dinicotinate of stands out a and hypocholesterolemie activity which clearly dif erentiates them from other1 known derivatives of nicotinic Nicotinic acid has a known vitaminic activity and a direct vasodilator it at high dosages a action clarifying action on the this property has bee used since until it is starting from the lowest a v effect especially affecting the region of a pur is the face and It is accompanied by and a burning is why the therapeutic use of this been Various esters of nicotinic acid have been therapeutic such ethyl or tetrahydro these are essentially the corresponding has also been recommended a new derivatives of nicotinic which are the subject of the represent the substances having a action to a degree a least to that of but devoid of any he vasodilator effect on by an intense both laboratory animals and in separation new derivatives represent a realized the between the lipotropic and the peripheral dilating nicotinic disappearance of a parallel effect seems to be due to the esteri of the acid by a certain type phenolic probable that in the organism the molecule of the is degraded such a way that the separation the of acid limited to the class of nicotinic esters constitute the of the present since the on the a strong vasodilator It would to the nicotinic acid with a phenolic molecule or a hindrance such as is the case in presence of an radical in the 4 position of derivatives of nicotinic acid which a e the of the present invention used of arterial arthritis of the lower the disturbances txeatmeat of of metabolism and the treatment of ia lore blood the amount of and the amount of effective which is always may vary from to per day an Even at this high no peripheral dilation phenomenon has been invention also has as an objective a process the of the new derivatives of nicotinic acid eneral process which is of the characterized by the fact according to nicotinic acid or a functional derivative a ol of the latter is made to react with a a and the of the is Among these known the action of nicotinic acid in the presence of an acid in the presence of a dehydrating agent such carbodiimlde or ethoxyacetylene a the action of nicotinic anhydride on in the presence of triethylamine or a the action of nicotinic acid chloride on a basic agent in the presence of a such or The following examples illustrate the Invention without in any way limiting Example 1 Preparation of the 6 of 4methylesculetol starting from nicotinic Into 128 of g of nicotinic g of in are with while bringing to cm3 of triethylamine are added and reflux is maintained for three the and evaporated to dryness under g of crude product recovered which product is purified by recrystallization 11 g of are 6 of occurs in the form of colorless soluble in acetic and slightly soluble in alcohols and insoluble in Its melting on a block is Infra red spectrum disappearance of the hydroxyl band 300 is by Analysis Found as is this compound has not been described in the Preparation of the of starting from nicotinic acid To 20 g of nicotinic acid are added 58 cm3 of thionyl while stirring and cooling at about The mixture is then warmed during a period of one hour to the reflux temperature of thionyl The excess of the thionyl chloride Is eliminatedjthen by evaporation under The hydrochloride of nicotinic acid chloride formed is introduced into 200 cm3 of 47 of ded we as a sus ension of 12 of in 80 of The is heated at reflux for three After the mixture is water then with sodium carbonate and finally with The material is dried and evaporated of crude product are received which product purified g of the of are and the product is identical the product obtained in The derivatives of nicotinic the of the present may be presented in the form coated cachets and The pharmaceutical such as coated and suppositories are prepared according to the usua Pharmacological Study Determination of the toxicity in an acute experiment The lethal doses were determined on mice according to the method Dragstedt and Lang by the administration of the of in suspension in an aqueous solution of gum arable The following were obtained intraperltoneally 1 2 orally 3 Activity according to the technique of Jacobs and 1117 Male of the Wistar strain weighing to g were to fast for 24 The suspended in a gum were administered o dosages of by oesophageal The blood triglyceride teste were carried out at 4 8 and 16 after administration of the product being The glycerides In the blood testing for each two animals dose results represent the average of five that is ten animals per d The ollowing results were As is dinicotinate esculetol at equal a more marked action than that of nicotinic and its action is of The action of dinicotinate on the amount of blood cholesterol was determined according to the method of Grigaut by ale of the ar strain weighing 160 to 180 were made to fast for 24 The roducts bein a suspension of gum was administered by oesophageal hours the the collected th wa The following results were Investigation of the vasodilate possible variations of r to the effects the product being by per at constant ia the A in in hind are quarter and an action on the carotid pressure is observed in the vasodila dinicotinate in a suspension in p opyleneglycol was injected in dosages 2 mg and 5 e control animals received only The results were as mm Investigation of the peripheral vasodilator fhe peripheral vasodilator effect studied on the pig appearance reddening of the Using fasting nicotinic and ol dinicotinate administered per in increasing doses of from 10 to 100 the time required for the of were a nicotinic acid leads to an immediate reddening of the of the highest causes no immediate The an activity of c aa experimental arthritis induced cm3 of a sterile lin suspension in physiological serum was administered to rats in the joint of the product being in a suspension The volume of leg was measured eight f seventy two hours after The results obtained are shown in the following were ed hypercholeste had a blood cholesterol rate greater than g per dinicotinate was administered one at a daily of A significant n the cholesterol blood level was varying 20 and withou vasodilation the face being patient having a and also a coronary before treatment the followin biological blood Triglycerides g per liter ol 20 g per liter After three weeks of treatment wi dose o constants returned to g per 2 liter gxample of preparation 6f tlaylea g lactose 40 Bice starch 140 g Colloidal silica 80 g Corn starch g 1 7 g Magnesium stearate 2 In an successively introduced as the the rice starch and 75 g of colloidal ffhen these substances were g s and a the and magnesium This powder was then on a AFNOR very fine sieve and compressed each tablets weighing about insufficientOCRQuality

Claims (1)

1. HAVING NOW particularly described and ascertained the nature of our said invention and in what manner same is to be we declare that what we claim The derivatives of nicotinic acid of the general ormula in which R is selected in the group constituted by hydrogen and methyl and propyl Process for the preparation of compounds according to Claim characterized by the fact that nicotinic acid or a functional derivative of it is reacted with a where R is selected from the group constituted by hydrogen and and propyl and the desired corresponding of is A process according to Claim characterized by the fact that nicotinic acid is used in the presence of an acid A process according to Claim characterized by the fact that nicotinic acid is used in the presence of a dehydrating A process according to Claim characterized by is anhydride and the reaction is effected in the presence of a basic o the fact that the functional derivative of nicotinic acid reaction is nicotinic acid chloride and the in the of a s c a for the preparation of 6 characterized by the fact that nicotinic anhydride ie reacted with in the presence Therapeutic compositions comprising a compound according to Claim 1 and a pharmaceutical therapeutic comprising a pharmaceutical THIS 26th day of insufficientOCRQuality