IL25939A

IL25939A - Nicotinic acid esters and method for producing same

Info

Publication number: IL25939A
Application number: IL6625939A
Authority: IL
Original assignee: Bofors Ab
Priority date: 1965-04-22
Filing date: 1966-06-09
Publication date: 1970-06-17
Also published as: SE323679B; FI47187C; DK112237B; GB1080128A; BR6680462D0; FR5624M; ES328732A1; BE682920A; DE1645915A1; FI47187B; NO121496B; CH468383A; AT263010B

Description

C O H E N Z E D E K & S P I S B A C H R EG D. PATENT ATTO R N EYS 24, LEVONTIN ST ., P. O. B. 1169 T E L - A V I 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 NEW NI COTI NI C ACID ESTERS AND METHOD FOR PRODUCING SAME AKTIfBOIAGFT BOIOBS, a Swedish Aktiebolaget of Bofora, Sweden, O HEREBY DECLARE the nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement: Tranola ion of Owed .Ta . Appl .

No.8215/1963— Method of Producing Now Nicotinic Acid Eatcro.

Inventors: Do af Ekensteam and Ooran Olaeson The present invention relates to ^-i^tt*iM-^ii-^« iKiki^ii*@' esters of nicotinic acid and polyvalent alcohol with the general formula : and to a method of producing same, in which formula and R2 together signify an oxygen atom or R-^ a lower alkyl group with one or two carbon atoms and R2 a hydroxy-methyl group. According to this structure description, three different esters can be obtained, viz. of the diol dihydroxy acetone (DHOA) and of the triols trimethylol ethane (TME) or trimethylol propane (TMP).

The esters in question have the following structural formula; Dihydroxy acetone dinicotinate * la - Trimethylol ethane trinicotinate (B) ,1-Trimethylol propane trinicotinate (c) The new esters are characterized by good resorption and a rapid increase of the periferal blood flow in the same way as is characteristic of sodium nicotinate. Sodium nicotinate gives a very great increase of the periferal blood flow which, however, is of short duration, and is accompanied by a very pronounced flush, with unpleasant irritating effects in the skin organ, caused by the momentary great increase of blood in the blood organ. The new compounds are also resorbed comparatively rapidly, but are stored up to a great extent in the fat tissue and other organs, from where, successively, owing to hydrolysis, biologically active nicotinic acid is emitted. The esters in question have less side effects than those characteristic for sodium nicotinate.

The effect on the blood vessels and the duration of the three new esters, which is rather similar, can possibly be graduated with consideration to the duration: B > C > A A further, considerable advantage of the new esters according to the invention, compared with other polyvalent alkanol esters, is their comparatively good solubility in water, as salts of a neutral reaction, which permits parenteral use.

The new esters are produced through the ordinary esterificaticn methods which, in themselves, are known, but most appropriately through a reaction between nicotinic acid chloride and the correspond ingjpolyol in the presence of a hydrochloric acid absorbent (tertiary amine) or through a reaction between a halogenide of the corresponding polyol and a salt of nicotinic acid.

The invention is described in more detail . through the following examples: Example 1. flask In a 1000 ml reaction s&fcMafc, 58. g of sodium nicotinate is dissolved in 400 g of dimethyl formamide, after which 25-6 g of 1, 3-dichloro-acetone is dropped in rapidly, while stirring. The solution is heated, with continued stirring, to 100°C, which temperature is maintained for 1 hour. Thereafter, the reaction which mixture is cooled, and the product thea crystallize^ is filtered By off. Threwgh- suspension in water, filtering off and washing, the salt formed the reaction is separated f. The raw product, 1, 3-dihydroxy acetone dinicotinate, is dissolved from 600 g of boiling 70 % ethanol, while being treated with active carbon. After cooling, the dinicotinate is crystallized, in the form of almost colourless crystals, with a melting point of 17 - 5 - 175 « 0°C. More of the product can be recovered from the mother liquids. The total yield is 44 g (75#) · Example 2 . 1 , 1 , 1- 26 . 8 g of trimethylol propane is mixed in a 500 ml reaction fl sk jpeA^pt, and dissolved in 142 g of dried pyridine, while stirring, after which 160 g of nicotinic acid chloride is added in portions at a temperature of 30°C. The reaction mixture is thereafter heated for 5 hours at 100°C, with continued stirring. After the reaction the contents of the apparatus is poured into 2000 g of ice water (60% ice and K0% water), and a dark brown, somewhat e smeary precipitatioa is obtained. The precipitatisft- is dissolved after separation in 200 g of boiling benzene. After cooling, the reaction product is precipitated as yellow crystals from the benzene with 150 g of ligroin. The crystals have a melting point of Q carbon 77 - 79 C. They are dissolved in ethyl alcohol and .jiaxiicin. treated .wilh^ Through the addition of water and slow stirring of the filtrate, very pale yellow crystals are obtained, with a melting point of 78 - 79°C. A re-crystallization of acetone-nitrile ligroin ether wAth. the proportions of 1 : 3 : 1 gives an entirely colourless final o in product, with a melting point of 80 - 8l C, -i&fc. a yield of 61 g (68#) .

Example 3 » 1 ,1 , 1- As example 2 , but 23 - 5 g of/trimethylol ethane is used instead of 26 . 8 g of trimethylol propane. The 1 , 1 , 1-yield is 62 g ( 73$) of trimethylol ethane trini-cotinate with a melting point of 9¾- 95°C.

Example .

The following data were determined for Compound As a. The LDJJQ = 10 , 000 mg/kg. p.o. (mite). b. The compound has a good vasodilatory activity when used in a dosage in the range of 10 mg/kg (guinea pig). c. In a dosage of about 16 mg/kg and after 3 minutes after administration, a reduction of 70$ of the contents of free fatty acids in plasma of rats was attained.

Pharmaceutical compositions containing the novel compounds according to the present invention can be prepared in a conventional manner.

Claims

WHAT IS CLAIMED ISt

1. Esters of nicotinic acid and a polyvalent alcohol of the general formula CH - OH in which formula R^ and Rg together signify an oxygen atom or R^ a lover alkyl group with one or two carbon atoms and Rg a hydroxy-methyl group, having the formulas: Dihydroxy acetone dinicotinate (A)« ,1, 1-Trimethylol ethane trinleotinate (B): P.A. 25939/1 ,1,1-Trimethylol propane trinicotinate (C)i as de ined in

2. * Method of producing new nicotinic acid esters, characterized in that nicotinic acid or nicotinic acid derivatives are made to react with a polyvalent alcohol with the general formulas in which formula R^ and R2 together signify an oxygen atom or a lower alkyl group with one or two carbon atoms and Rg a hydroxy-niethy1 group or derivative of said alcohol and possibly in the presence of a hydrochloric acid absorbent tertiary amine if the nicotinic acid derivative is consists of a chloride, the following three compounds then being formed* P.A. 25939/1 Dihydroxy acetone dinlcotinate (A)» l»l»l-TrimeH¾rlol ethane trinicotinate (B)» ,1,1-Trimethylol propane trinicotinate (c ) :

3. Method for producing novel esters of nicotinic acid and polyvalent alcohols as defined in Claim 1, substantially as hereinbefore described and with P.A. 25939/1

4. Esters of Nicotinic acid and polyvalent alcohols, as defined in Claim 1, whenever obtained by a process as claimed in Claim 2 or 3· 5· Pharmaceutical compositions, containing an ester of nicotinic acid and a polyvalent alcohol as claimed in Claim 1» as active ingredient.