CH479586A - Process for the production of new nicotinic acid derivatives and their salts - Google Patents

Description

  

  Process for the production of new nicotinic acid derivatives and their salts The invention relates to a process for the production of new nicotinic acid derivatives of the formula:
EMI0001.0000
    in which R is CF, groups, halogen atoms or lower alkyl radicals, which can be identical or different from one another, R is a hydroxyl group and n is an integer from 1 to 3 , and pharmaceutically acceptable salts of these compounds. The compounds of the formula I can be converted into corresponding compounds by esterification or amidation in which R 1 is a lower alkoxy, di-lower alkylamino alkoxy, lower alkylamino or di-lower alkylamino group.

    



  The compounds defined above form water-soluble acid addition salts. Because these compounds are therapeutically useful, medically acceptable acid addition salts formed with pharmaceutically acceptable acids are preferred. These addition salts can be formed with both organic and inorganic acids, e.g. B. with hydrochloric acid, nitric acid, citric acid, maleic acid, fumaric acid, succinic acid, sulfuric acid, acids of phosphorus and tartaric acid.



  The nicotinic acid derivatives defined above also form salts with metals, e.g. B. alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, barium and calcium, or with aluminum.



  The free bases of the compounds defined above are generally crystalline solids and are at least somewhat soluble in common organic solvents and in water.



  The compounds defined above are physiologically active and therefore suitable for pharmaceutical purposes. They have been shown to provide particular benefits as hypotonics or anti-inflammatory drugs, non-addictive analgesics, and diuretics in warm blooded blood.



  It has been found that the compounds defined above are active analgesics that act as antagonists of phenyl-p-quinone (PPQ) convulsive syndrome. The compounds are modified according to the method described by E. Siegmund et al., Proc. Soc. Exptl. Biol. Med. 95, p. 729 (1957), tested method described. The test is briefly described below: The test compound is administered orally to 2 mice 30 minutes before the intraperitoneal injection of 1 mg / kg phenyl-p-quinone. Fifteen minutes later, the mice are observed for 3 minutes and the total number of typical seizures in both animals is counted and recorded.

   The mean number of seizures that occurred in 21 pairs of control animals who were orally administered 2% strength was <B> 29. </B> When the incidence of convulsions was <B> 18 <in this compound test / B> or less is decreased, the compound is considered active in the PPQ test, otherwise it is eliminated. These compounds have anti-inflammatory activity, as demonstrated by a test in which the reduction in edema produced by injection of a 1% solution of carageenin into the paws of rats is examined.



  These compounds have also been shown to have diuretic effects in rats and dogs. For example, the diuretic properties of adult rats were determined using the following method: Adult male rats weighing between 180 and <B> 300 g </B> (2 rats per <B> cage) </ Normal fluid intake was permitted prior to the examination. A single dose of 400 micrograms of the test compound was administered orally in 0.5 ml of a 2% aqueous starch suspension. Other animals in 4 cages with 2 rats per cage served as controls. The control animals were given only the starch suspension.

   After the administration, the test animals were placed in metabolism cages. The amount of urine excreted was determined after 5 hours. The measured urine values were then corrected to take into account the different weights of the individual animals. The urine samples taken after <B> 5 </B> hours of the control animals and the treated rats were examined for sodium and chloride content.



  The compounds of the formula <B> 1 </B> are prepared according to the invention by adding a compound of the formula:
EMI0002.0004
    with a compound of the general formula -.
EMI0002.0005
    in which R and n are as defined above, to a compound of the formula:
EMI0002.0006
    in which R and n are as defined above, and this is oxidized to the compound of formula I and decarboxylated.



  A particular embodiment of the method according to the invention consists in that by heating 4-chloroquinoline (11) with 4 - (α, α, α-trifluoro- m-toluidine) (IIIa) 4- ( α, α, α-trifluoro-m-toluidino) -quinoline (IVa). Oxidation of (IVa) gives 4 - (α, α, α-tri-fluoro-m-toluidino) -quinolinic acid (V), which gives 4 - (α, α, α-tri-fluoro- m-toluidino) nicotinic acid (VI) is decarboxylated.
EMI0002.0015
    The 4-aryl nicotinic acids described above can be converted into related derivatives.

   For example, the ester methyl 4 - (α, α, α-trifluoro-m-toluidino) nicotinate (VII) can be prepared by treating 4 - (α, α, α-trifluoro-m -toluidino) nicotinic acid (VI) can be produced with methanol and sulfuric acid. Treatment of (VII) with ammonia provides 4- (α, α, α-trifluoro-m-toluidino) -nicotinamide (VIII). Treatment of VII with dimethylamine gives N, N-dimethyl-4 - (α, α, α-trifluoro-m-toluidino) nicotinamide (IX).

   Treatment of sodium 4 - (α, α, α-trifluoro-m-toluidino) nicotinate (X) with f-dimethylaminoethyl chloride gives dimethylaminoethyl-4 - (α, α, α- trifluoro-m-toluidino) nicotinate (XI).
EMI0003.0000
    The compounds defined above can be used as active ingredients of preparations for administration in the form of dosage units, such as. B. tablets, Pil len, capsules, powders, granules, sterile parenteral solutions or suspensions, solutions or suspensions for oral use and the like, are administered. The effective dosage can vary depending on the warm-blooded animals from 100 mg to 200 mg / kg.



  The following examples illustrate the invention without restricting it.



  <I>Example<B>1</B> </I> a) A mixture of 2.0 g of 4-chloro-3-picoline and 8 ml of α, α, α-trifluoro-m-toluidine becomes Heated to 150 ° C. for 1 hour. After cooling the mixture, it is diluted with ether, the ethereal layer is washed with 3N hydrochloric acid and evaporated to give 4 - (α, α, α-trifluoro-m-toluidino) -3-picoline. This product is dissolved in 15 ml of sulfuric acid and a solution of <B> 5 g </B> sodium dichromate in 15 ml of sulfuric acid is added dropwise at such a rate that the temperature is 45 to <B> 50 </B> 'C. is held. When the addition is complete, pour the green syrup onto crushed ice and leave to stand overnight.

   The filtered off crude 4- (α, α, α-trifluoro-m-toluidino) -nicotinic acid is purified by recrystallization from methanol and gives a product of <B> R = 268 </B> to <B> 271 < / B> IC.



  b) A mixture of 2.0 g of 4-chloroquinoline and 8 ml of α, α, α-trfluoro-m-toluidine is heated to 150 ° C. for 1 hour. After cooling, the mixture is diluted with chloroform, washed with 3N hydrochloric acid and evaporated. The 4 - (α, α, α-trifluoro-m-toluidino) -quinoline obtained is suspended in 20 ml of sulfuric acid at 170 ° C. and treated with 6 g of manganese dioxide. After cooling, water is added and 4- (α, α, α-trifluoro-m-toluidino) -quinolinic acid is filtered off. This product is suspended in cyclohexanol and refluxed for <B> 6 </B> hours.

   After evaporation of the solvent, the resulting crude 4 - (α, α, α-trifluoro-m-toluidino) nicotinic acid is recrystallized from methanol to give a colorless solid with a melting point of 268 Cleaned to <B> 270 </B> 'C.



  <I> Example 2 </I> Sodium 4 - (?,?,? -Trifluoro-m-toluldino) nicotinate A solution of 1.41 g of 4 - (?,?,? - Trifluoro-m-toluidino) nicotinic acid in 50 ml of 0.10 N sodium hydroxide is evaporated to a creamy white paste. This. dissolve in ethanol, filter and concentrate until crystallization occurs. After filtration, 400 mg of sodium 4 - (α, α, α-trifluoro-m-toluidino) nicotinate are obtained as a white water-soluble powder with a temperature above 400 ° C.

    <I>Example<B>3</B> </I> N- (2-dimethylaminoethyl) -4 - (α, α, α-trifluoro-m-toluldino) nicotinate A mixture of 2.74 g of sodium 4 - (α, α, α-trifluoro-m-toluidino) nicotinate and 1.05 g of 2-chloro-N, N-dimethylethylamine in 30 ml of ethanol are stirred for 24 hours at room temperature . The mixture is filtered and the filtrate is concentrated under reduced pressure. The N- (2-dimethylaminoethyl) -4 - (α, α, α-trifluoro-m-toluidino) nicotinate formed is recrystallized from methanol / petroleum ether.



  <I> Example 4 </I> Methyl-4 - (α, α, α-trifluoro-m-toluidino) nicotinate A solution of 5.1 g of 4 - (α, α, α - Trifluoro-m-toluidino) nicotinic acid in 40 ml of methanol and 7 ml of sulfuric acid is heated under reflux overnight. After cooling and dilution with water, the solution is neutralized with ammonium hydroxide and extracted with chloroform. The extract is washed with water, dried and concentrated, and the addition of n-hexane leads to the crystallization of yellow needles from F. 118 to 120 '. An analysis sample in the form of colorless needles from F. 121 to <B> 123 </B> \ C is obtained by sublimation.



  <I>Example<B>5</B> </I> 4 - (α, α, α-trifluoro-m-toluidino) -nicotinamide A solution of 1.47 methyl-4 - (α, α, α-trifluoro-m-toluidino) nicotinate and 20 ml ammonia in 80 ml ethanol are heated to <B><I>50 </I> </B> 'C for 80 hours in a steel autoclave. The residue, obtained on evaporation of the mixture to dryness under reduced pressure, upon crystallization from ethanol and water gives 4 - (α, α, α-trifluoro-m-toluidino) nicotinamide of F. <B> 237 </B> to <B> 239 </B> 'C.



  <I>Example<B>6</B> </I> N, N-Dimethyl-4 - (α, α, α-trifluoro-m-toluidino) -nicotinamide A solution of 1.33 methyl- 4 - (α, α, α, -trifluoro-m-toluidino) nicotinate and 14 ml of dimethylamine in 80 ml of ethanol are heated to 50 ° C for 8 hours in a steel autoclave. The residue obtained on concentrating the mixture to dryness is recrystallized from ether and yields N, N-dimethyl-4 - (α, α, α-trifluoro-m-toluidino) nicotinamide with a melting point of 125 to 127 'C.



  <I>Example<B>7</B> </I> N-Butyl-4 - (α, α, α-trifluoro-m-toluidino) -nicotinate A solution of 3.0 g of 4- ( α, α, α-Trifluoro-m-toluidino) nicotinic acid in 20 ml of n-butyl alcohol and 4 ml of sulfuric acid is refluxed for 16 hours, cooled and neutralized with ammonium hydroxide. The product is extracted with chloroform and the extract is washed with 10% sodium hydroxide solution and with water. After evaporation, the oil obtained is chromatographed on 150 Å silica gel. The eluate obtained with a mixture of ether and dichloromethane (3: 7) gives 1.5 - colorless crystals from 48 to 52 ° C. on evaporation.

   By recrystallizing the ester from an ether-n-hexane mixture cooled to -60 ', an analytically pure sample with a melting point of 44 to 46' is obtained. <I>Example<B>8</B> </I> 4 - (α, α, α-trifluoro-m-toluidino) -nicotinic acid hydrochloride In a suspension of 6-4 - (α, α; α-Trifluoro-m-toluidino) nicotinic acid in 500 ml of methanol is passed in a stream of hydrogen chloride gas until it dissolves. Evaporation of the solvent gives the hydrochloride from F. <B> 278 </B> to <B> 286 '; </B> ionic chlorine: calculated 11.1%, found 11.2%.

 

Claims (1)

<B> PATENT CLAIM </B> Process for the production of new nicotinic acid derivatives of the formula: EMI0004.0014 in which the substituents R, which may be the same or different from one another, are CF3 groups, halogen atoms or lower alkyl radicals, n is an integer from 1 to 3 and R is a hydroxyl group, and their pharmaceutically acceptable salts, characterized in that one compound of the formula: EMI0004.0015 with a compound of the formula: EMI0004.0016 in which R and n are as defined above, to a compound of the formula: EMI0004.0017 in which R and n are as defined above, and this is oxidized and decarboxylated to give the compound of formula 1. SUBClaims 1. Process according to patent claim, characterized in that the compounds obtained are converted by esterification into corresponding compounds in which R 1 denotes a lower alkoxy or di-lower alkylaminoalkoxy group. 2. The method according to claim, characterized in that the compounds obtained are converted by ami in corresponding compounds in which R is an amino, lower alkylamino or di-lower alkylamino group. Atimerkwig <I> des </I> Eidg. <I> Office for Intellectual Property: </I> If parts of the description do not match the definition of the invention given in the patent claim, it should be remembered that according to Art . <B> 51 </B> of the Patent Act, the claim is authoritative for the material scope of the patent.