IL27338A - N-pyridyl amides of aliphatic carboxylic acids and their preparation - Google Patents

Description

New N-pyridyl amides of aliphatic carboxylic acide and their preparation J.B. GlIGY A.G- J. R. GEIGY A. G. BASEL 21 4-2334* The present invention concerns processes for the production of new amides of aliphatic carboxylic acids, these amides as new substances as well as medicaments which contain them and the use thereof.

Amides of the general formula I wherein R-^-CO-represents the acyl radical of an alkanoic acid or alkenoic acid having 15 - 22 carbon atoms, R2 represents a halogen atom, a low alkyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, alkanoylamino or alkoxycarbonyl group, and R^ represents hydrogen or a low alkyl radical, have not been known hitherto.

Surprisingly, it has now been found that such compounds and their addition salts with inorganic and organic acids have valuable pharmacological properties. In particular they have antiviral and tumour inhibiting properties; also the favourable relationship of the significantly active to the maximal tolerated dosages is remarkable. The antiviral activity could be determined, e.g. in the mouse on subcutaneous and oral administration against Herpes simplex virus, influenza-A virus, Columbia SK virus and Louping ill virus (encephalitis virus in sheep) : the tumour inhibiting action could be determined in pharmacological tests on subcutaneous and oral administration to the mouse against transplanted Ehrlich carcinoma, induced methyl cholanthrene sarcoma, dimethyl benzanthracene carcinoma of the skin and spontaneous tumours and on the same administration to the rat against transplanted Yoshida sarcoma and induced dimethyl benzanthracene mammary carcinoma. The animal tests, characterise the compounds of general formula I as suitable for the treatment of virus diseases such as Herpes simplex, Herpes zoster, influenza, encephalitis and others as well as for the treatment of neoplasia.

In the compounds of general formula I, R^-CO- is, for example, the acyl radical of pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanic acid (arachidic acid) , heneicosanic acid, docosanoic acid (behenic acid) , 2-methyl-tetradecanoic acid, 2-ethyl-tetrade-canoic acid, 2-methyl-hexadecanoic acid, 2- (n-butyl) -tetra-decanoic acid, 2- (n-pentyl) -tetradecanoic acid, 2-ethyl-octa-decanoic acid, 2-methyl-eicosanic acid, hexadecenoic acids such as cis-9-hexadecenoic acid (palmitoleic acid) , heptadecenoic acids such as cis-9-heptadeceno.i.c.. acid, octadecenoic acids such as oleic acid, elaidic acid, cis-6-, -8-, -10-, and -11- octadecenoic acid, 9-nonadecenoic acid, iecosanic acids, heneicosanic acids, docosenoic acids such as cis-13-docosenoic acid 2-allyl-dodecanoic acid, 2-allyl-tridecanoic acid, 2-allyl-tetradecanoic acid and 2- (n-heptyl) -12-tridecenoic acid.

The substituent R2 is, e.g. chlorine, fluorine, bromine, iodine, a methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert. butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-hexoxy, allyloxy, ( 1-methyl-allyloxy) , ( 2-methyl-allyloxy) , methylthio, ethylthio, isopropylthio , n- utylthio , allylthio, formamido , acetamido, methoxycarbonyl , ethoxycarbonyl , n-propoxycarbonyl , isopropoxycarbonyl , n-butoxycarbonyl , isobutoxycarbonyl , tert. butoxycarbonyl group.

Low alkyl radicals R^ are exemplified by those listed for Rg. T^^¾-e»e-:_^t-^ •erf--t?OmjKHg>d-s--e-f--fehe--genoral -ik»pm»-?ar-■_·.

To produce the new amides of general formula I, an acid of the general formula II R1 - CO - OH (II) wherein R-^-CO- has the meaning given above, or a reactive functional derivative of such an acid, is reacted with a nuclear substituted aminopyridine or nuclear substituted alkylamino-pyridine of the general formula III wherein R2 and R^ have the meanings given above, or with a reactive functional derivative thereof. To perform this process, for example, an acid of the general formula II is reacted with a compound of the general' formula III; this is done in the re nce of bodiimi h - esters, e.g. the methyl or ethyl ester, of acids df the general formula II and also the amides yield ·. i the correspondingly substituted amides of general formula I on heating with compounds of general formula III.

Other suitable reactive functional derivatives of acids of the general formula II are the halides and anhydrides in particular the mixed anhydrides with carbonic acid semi esters. These functional derivatives are reacted with a compound of the general formula III preferably in the presence of an acid binding agent, e.g. a strong tertiary organic base such as tri-ethylamine, pyridine, or p-collidine, which, in excess, can also serve as reaction medium, or the reaction is performed, in the presence of an excess of the reaction component of general formula III in the presence or absence of an inert organic solvent such as benzene, tetrahydrofuran or dimethyl formamide.

The reaction of acid halides with suitable tertiary' organic bases, particularly tr iethylamine , in an inert organic solvent, filtration of the hydrohalide formed and reaction of the ketene or ketene dimer present in the solution with the desired compound of general formula III is mentioned as a modification of the reaction of acid halides with compounds of the general formula III in the presence of acid binding agents.

Activated esters of acids of general formula II are, e.g. their p-nitrophenyl ester and cyanomethyl ester, which can be reacted with compounds of general formula III in inert organic solvents, if necessary while heating. The 1-imidazolides of the acids mentioned are reacted under similar conditions with compounds of general formula III.

The isocyanates and isothiocyanates derived from compounds of the general formula III having a hydrogen atom as R^ are mentioned as reactive functional derivatives of compounds of general formula III which can be reacted direct with acids of the general formula II. These are heated with the acids of general formula II until the equimolar amount of carbon flioxide or carbon oxysulphide has been liberated.

The reactions with isocyanates and isothiocyanates can be performed in the presence or absence of an inert organic solvent having a sufficiently high boiling point or range.

Instead of isocyanates, also components thereof can be used, i.e. in particular the azides of pyridine carboxylic acids substituted corresponding to the definition of can be reacted with acids of general formula II while heating in suitable organic inert^solvents. In addition for example, N-chloro-carbonyl derivatives of compounds of general formula III, in particular of such compounds of general formula III having a low alkyl radical R^, are reacted with salts, e.g. alkali metal salts, of acids of general formula II in the presence or absence of inert organic solvents and the reaction mixtures are heated until the equimolar amount of carbon dioxide has been liberated from the carboxylic acid-carbamic acid anhydrides primarily formed. Also, sulphurous acid monoalkyl ester amides and phosphorous acid-o-phenylene diester amides can be derived from compounds of the general formula III having a low alkyl radical as R^. These ester amides, on being reacted with acids of general formula II in organic solvents such as pyridine, dioxane or dimethyl formamide or benzene, yield the desired Other reactive functional derivatives of compounds of the general formula III are, for example, the N-trimethylsilyl derivatives, among others, e.g. ethyltrimethylsilyl aminopyridi-ne carboxylates (I^ = COOC^H^) which can be obtained by reacting these amines with trimethylsilyl chloride in inert, anhydrous, organic solvents. These N-trimethylsilyl derivatives can be reacted with reactive functional derivatives of acids of the general formula II in inert solvents to form N-tr imethylsilyl derivatives of amides of general formula I, from which the desired amides are formed by decomposing with water or low alkanols.

Another type of reactive derivatives of compounds of general formula III are the , 1 -dipyridyl carbodiimides substituted in the two pyridine rings corresponding to the defini-tion of R2- These can be obtained, e.g. by heating the corresponding, substituted ,N ' -dipyr idyl thioureas with lead-(II) oxide in anhydrous toluene while gradually distilling off the solvent. On heating the carbodiimides mentioned with acids of general formula II in a stream of carbon dioxide at tempera-tures of about 200° C, the desired amides of general formula I are formed.

Instead of alkenoic acids having 15 - 22 carbon atoms embraced by general formula II or instead of reactive functional derivatives thereof, if desired, the saturated bromine addition products of those acids or reactive functional derivatives thereof can be reacted with nuclear substituted amino-pyridines or nuclear substituted alkylamino pyridines of general formula III or with reactive derivatives thereof and The reactive functional derivatives of both reaction components and also the reaction conditions for the amide formation, are substantially those given for the direct production of compounds of general formula I. The debromination is per-formed, for example, by boiling the intermediate products with zinc in ethanol. This two step process for the production of compounds of general formula I appears to be more complicated than the single step process first mentioned. It can be of advantage, however, if amides of those alkenoic acids are to be produced which are difficult to purify, e.g. wherein it is difficult to separate isomers and/or homologues. In such cases, an optional purification, e.g. crystallisation, can be performed in the step of the bromine addition products of the acids or if the substituted pyr idylamides of dibromo-alkanoic acids obtained with such bromine addition products can be better purified, e.g. recrystallised, than the end substances containing no bromine in the acyl radical. When the latter is the case, then bromine can be added to an alkenoic amide of the general formula I obtained by the first process mentioned, -which can also be regarded as a purifying operation - the addition product can be purified by crystallisation or by another usual process and, finally, debrominated.

Finally, amides of the general formula I wheren R2 is a low alkanoylamino group can also be produced by reacting amides of the general formula IV (IV) wherein R-^-CO- and R3 have the meanings given in formula I, with a compound introducing a low alkanoyl radical. The alka-noylation, e.g. acetylation, is performed by known methods, e.g. by reacting with a low alkanoic acid halide or anhydride at room temperature or moderately raised temperatures. If necessary, the reaction is performed in the presence of an acid binding agent such as pyridine, which is simultaneously the reaction medium, or in the presence of an alkali carbonate in an inert organic solvent or in the presence of sodium hydroxide solution in a two-phase, organic aqueous system.

Starting materials of the general formula IV can be obtained, for example, by reduction of corresponding nitro-pyridyl amides. These can be produced in their turn, e.g. by acylating amino-nitro-pyridines analogously to the process first mentioned for production of compounds of 'general formula I.

If a protecting group which is usual in peptide synthesis is first introduced into the amino-nitro-pyridines mentioned, then the nitro group is reduced, the acyl radical R-^-CO- is introduced analogously to the first process mentioned for the production of compounds of general formula I and then the protecting group is split off, then starting materials of the general formula IV in which the amide group and amino group have , changed places are obtained from the same amino-nitro-pyridines.

Compounds of general formula I are converted into the urea adducts already mentioned, e.g. by adding a solution of urea in methanol to a compound of general formula I and isolating the adduct precipitated.

The conversion of compounds of general formula I into can be performed in the usual way. Acids suitable for salt formation are: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane disul-phonic acid, β-hydroxyethane sulphonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.

Suitable daily dosages of amides of general formula I and their salts for the treatment of virus diseases and neoplasia lie between 100 mg and 3000 mg for adult humans of normal weight and, within this range, generally the dosage on parenteral administration is lower than that on oral administration. The daily dosages mentioned are administered advantageously in dosage units of 50 to 500 mg of active substance but also corresponding amounts of forms for administration not made up into single dosages can be administered, e.g. syrups, sprays, aerosols, powders and ointments.

Dosage units for oral administration preferably contain between 10% and 90% of an amide of general formula I or a pharmaceutically acceptable salt thereof as active ingredient. They are produced by mixing the active substance with, e.g., solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights, and the mixture is pressed into tablets or dragee (sugar coated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between different dosages of active ingredient.

Examples of dosage units for rectal administra ion are suppositories which consist of a combination of an amide of general formula I or a suitable, pharmaceutically acceptable salt thereof with a neutral fatty foundation, or also gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycols of suitable molecular weight.

Ampoules for parenteral, particularly intravenous, intra muscular or subcutaneous administration contain a water soluble pharmaceutically acceptable salt of an amide of general formula I in a concentration of, preferably, 0.5 - 10%, in aqueous solu tion, optionally together with suitable stabilising agents and buffer substances.

Other forms for administration, particularly for the treatment of virus infections of the respiratory tract, are syrups and also aerosols and, for local treatment of virus diseases, ointments and powders. All these' forms for administration can be prepared by using the carriers, diluents and additives usual for this purpose.

One example each for the production of tablets and dragees is given below: a) 250 mg of active substance, e.g. N- ( 5-chloro-2-py idyl) -oleamide are mixed with 175.80 g of lactose and 169.70 g of tion of 10 g of stearic acid and granulated through a sieve. After drying, 160 g of potato starch, 200 g of talcum, 2.50 g of magnesium stearate and 32 g of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing 100 mg and containing 25 mg of active substance. The tablets can be grooved if desired for better adaptation of the dosage. b) A granulate is produced from 250 g of active substance, e.g. N-( -chloro-2-pyridyl) -oleamide , 175.90 g of lactose and the alcoholic solution of 10 g of stearic acid. After drying, the granulate is mixed with 56.60 g of colloidal silicon dioxide, 165 g of talcum, 20 g of potato starch and 2.50 g of magnesium stearate, and the mixture is pressed into 10,000 dragee cores. These are then coated with a concentrated syrup made from 502.28 g of crystallised saccharose, 200 g of talcum, 6 g of shellac, 10 g of gum arabic, 0.22 g of dye stuff and 1, g of titanium dioxide and dried. The dragees obtained each weigh 150 mg and contain 25 mg of active substance.

The following examples illustrate the production of the new compounds of general formula I but they in no way limit the scope of the invention. The temperatures aren given in degrees Centigrade.

Example 1 2.57 g (0.02 mol) of 2-amino-5-chloropyridine and 2.22 g (0.022 mol) of triethylamine are dissolved in 100 ml of benzene. 6 g (0.02 mol) of oleoyl chloride dissolved in 30 ml of benzene are added dropwise within 10 minutes while stirring and cooling wit ice water, and the mixture is stirred for another 2 hours at room temperature. The precipitated triethylamine hydrochloride is filtered off under suction and washed with hot benzene. After adding a stabiliser [0.5 per mil dodecyl gallate, 0.5 per mil (D ,L) - -tocopherol] , the filtrate is concentrated and the crude product (7.8 g) is dissolved in low boiling petroleum ether (40-60°) and chromatographed on a column of 300 g of aluminium oxide (Grade III, according to Brockmann) . The fractions eluted with petroleum ether (40-60°), petroleum ether/benzene and benzene are tested by thin layer chromatography (according to Stahl, Silicagel G, solvent: acetone/hex-ane 1:4, development: phosphorus molybdic acid 20% in alcohol, Rf value of N- ( 5-chloro-2-pyr idyl) -oleamide : 0.7).

The fractions containing pure N- ( -chloro-2-pyridyl) -oleamid'e are purified and concentrated, M.P. 43°.

Fractions which contain the product with impurities are purified, concentrated and again chromatographed (Alox III, 150 g) . As described above, the fractions containing pure N-( 5-chloro-2-pyridyl) -oleamide ; are identified, combined and concentrated. The purification by chromatography may be-replaced by recrystallisation from methanol.

The following compounds, for example, are produced analogously : a) N-(5-methyl-2-pyridyl) -oleamide, M.P. 18°; ° b) N- ( 4-methyl-2-pyridyl) -oleamide , :1.5155; c) N-( 5-bromo-2-pyridyl) -oleamide , M.P. 48°; d) N-(5-iodo-2-pyridyl)-oleamide, M.P. 57°.

The compound last mentioned is converted into the hydrochloride by dissolving 0.48 g (0.001 mol) of N-(5-iodo-2- pyridyl) -oleamide · in 10 ml of methanol and adding 12 ml of IN ethereal hydrochloric acid solution. The reaction mixture is evaporated to dryness and the N-( 5-iodo-2-pyridyl) ole- 0 amide hydrochloride is recrystallised from methanol, M.P. 1450. ° e) N-(5-chloro-2-pyridyl) -N-methyl-oleamide, nD : 1.5099} f) N-( 5-methoxycarbonyl-2-pyridyl) -oleamide , M.P. 67°^, g) N-(6-allyloxy-3-pyridyl) -oleamide, M.P. 51°; h) N-(6-acetamido-3-pyridyl) -oleamide , M.P. 132°', i) N-( 6-propoxy-3-pyridyl) -oleamide , M.P. 44°', j) N-(6-allylthio-3-pyridyl) -oleamide, M.P. 37°'; k) N-(6-butylthio-3-pyridyl)-oleamide, M.P. 32°; Example 2 0 7.7 g CO.05 mol) of 6-acetamido-3-aminopyr idine are dissolved in 20 ml of pyridine. 13.7 g (0.05 mol) of hexadecanoyl chloride dissolved in 40 ml of ethyl acetate are added dropwise within 10 minutes while stirring and cooling with ice water and the mixture is stirred for another 2 hours at room temperature. 5 The reaction mixture is poured into 200 ml of ice water and , , extracted three times with 100 ml of ethyl acetate each time.

The combined ethyl acetate solutions are washed neutral with water, dried with sodium sulphate and evaporated to dryness.

The residue is recrystallised from methanol whereupon N-(6-acetamido-3-pyridyl) -hexadecanamide is obtained, M.P. 162°.

The following compounds, for example, are produced in an analogous way: a) N- (6-acetamido-3-pyridyl) -octadecanamide , M.P. 161°; b) N- (6-acetamido-3-pyridyl) -docosanamide , M.P. 153°; c) N- ( 5-methyl-2-pyridyl) -octadecanamide , M.P. 74°; d) N-(5-methyl-2-pyridyl)-eicosanamide, M.P. 84°; e) N- ( 5-chloro-2-pyridyl) -hexadecanamide , M.P. 94°; f) N- ( 5-chloro-2-pyr idyl) -octadecanamide , M.P. 94°; hydrochloride, M.P. 158° (produced analogously to last paragraph of example 1) g) N-.( 5-ethoxycarbonyl-2-pyridyl) -octadecanamide ; h) N- ( 5-methyl-2-pyr idyl) -2-butyl-tetradecanamide , M.P. 76°; i) N- (6-propoxy-2-pyridyl) -octadecanamide , M.P. 87°; j) N-methyl-N- ( 5-methyl-2-pyridyl) -octadecanamide , M.P. 57°; k) N-(4-methyl-2-pyridyl)-stearamide, M.P. 62°; 1) N-( 5-methyl-2-pyridyl) -hexadecanamide , M.P. 78°.

Example 3 .8 g (0.1 mol) of 6-amino-3-picolihe are dissolved in 50 ml of ethyl acetate. While stirring and cooling with ice water, 15.1 g (0.05 mol) of octadecanoyl chloride dissolved in 20 ml of ethyl acetate are added dropwise within 10 minutes and the mixture is stirred for another 2 hours at room temper-ture. The reaction mixture is worked up analogously to example 2 and the reaction product is recrystallised. The N-(5-methyl-2-pyridyl) -octadecanamide obtained melts at 74°.

Example 4 8.4 g (0.03 mol) of oleic acid and 3.03 g (0.03 mol) of triethylamine are dissolved in 100 ml of tetrahydrofuran and the solution is cooled to -15°. While stirring, 3.23 g (0.03 mol) of ethyl chloroformate dissolved in 20 ml of tetrahydrofuran are added dropwise, during which addition the temperature should not rise above -10°. After stirring for 15 minutes at -10°, a solution of 3.24 g' (0.03 mol) of 6-amino-3-picoline in 20 ml of tetrahydrofuran is added at -8° to -12° to the solution obtained of the mixed anhydride of oleic acid and carbonic acid monoethyl ester. The mixture is stirred for 1 hour at -10° and, after removal of the cooling for another 12 hours at room temperature. The precipitated tri-methylamine hydrochloride is filtered off under suction and washed with hot benzene. The crude product is purified by chromatography on a column analogously to example 1. The N-(5-methyl-2-pyridyl) -oleamide melts at 18°.

Example 5 11.2 g (0.04 mol) of oleic acid and 4.32 g (0.04 mol) of 2-amino-4-picoline are dissolved in 100 ml of tetrahydrofuran. A solution of 8.24 g (0.04 mol) of Ν,Ν'-dicyclohexyl carbodiimide in 50 ml of tetrahydrofuran are added dropwise at -10° while stirring. After stirring for 1 hour at -10° and 4 hours at room temperature, the precipitated Ν,Ν'- dicyclohexyl urea is filtered off under suction, washed with tetrahydrofuran and the filtrate is concentrated. The crude product is purified by column chromatography analogously to Example 6 3.08 g (0.01 mol) of oleic acid ethyl ester and 1.28 g (0.01 mol) of 2-amino-5-chloropyridine are heated for 2 hours at 200° under a stream of nitrogen while stirring vigorously. After cooling, the crude product is purified by column chromatography analogously to example 1. The. product is identical with the N-(5-chloro-2-pyridyl) -oleamide produced according to example 1, M.P. 43°.

Example 7 a) A solution of 8.24 g (0.04 mol) of Ν,Ν'τάΐ-cyclohexyl carbodiimide in 50 ml of tetrahydrofuran is added dropwise at -103 stirring to a solution of 11.2 g (0.04 mol) of oleic acid and 5.6 g (0.04 mol) of p-nitrophenol in 100 ml of tetrahydrofuran. After stirring for 1 hour at -10° and 4 hours at room temperature, the precipitated Ν,Ν' -dicyclo-hexyl urea is filtered off under suction, washed with tetra-hydrofuran and concentrated. The oleic acid-p-nitrophenyl ester obtained melts at 37°. b) 4.01 g (0.01 mol) of oleic acid-p-nitrophenyl ester and 10.8 g (0.1 mol) of 6-amino-3-picoline are left to stand in 50 ml of chloroform for 4 days. After evaporation of the solvent, the crude product is purified by column chromatography analogously to example 1. The product is identical with the N-(5-methyl-2-pyridyl)-oleamide produced according to example 1.

Example 8 .4 g (0.05 mol) of 6-amino-3-picoline are dissolved in 100 ml of dimethyl formamide and 5.05 g (0.05 mol) of triethylamine . While stirring and cooling with ice water, 5.43 g (0.05 mol) of trimethylsilyl chloride dissolved in ml of dimethyl formamide are added dropwise within 10 minutes, and the mixture is stirred for another 2 hours at room temperature. While stirring and cooling with ice water, 5.55 g (0.055 mol) of triethylamine and then 15.0 g (0.05 mol) of oleoyl chloride, dissolved in 30 ml of dimethyl formamide, are added dropwise to the solution of 6-trime thylsilylamino-3-picoline so obtained and the mixture is stirred for another 2 hours. The reaction mixture is poured onto 800 ml of ice water, the oil which separates is removed and dried under high vacuum (4 hours at 40°). The oil is then dissolved in 100 ml of petroleum ether and chromatographed on 300 g of aluminium oxide (Activity Grade III, according to Brockmann) . The fractions eluted with petroleum ether/benzene and benzene are tested by thin layer chromatography (according to Stahl, Silicagel G, solvent chloroform/methanol 20:1, development : phosphorus molybdic acid 20% in ethanol) . The fractions containing pure N- ( 5-methyl-2-pyridyl) -oleamide are combined and concentrated (cf. example 1).

Example 9 1.62 g (0.01 mol) of 1 , 11 -carbonyl-diimidazole are added at room temperature to 2.82 g (0.01 mol) of oleic acid dissolved in 25 ml of anhydrous tetrahydrofuran, On completion of the carbon dioxide development, 1.29 g (0.01 mol) of 2-amino-5-choropyridine dissolved in 20 ml of anhydrous tetrahydrofuran are added to the solution formed of 1-oleoyl imidazole and the reaction mixture is refluxed for 10 minutes. The residue obtained after evapo-ration of the tetrahydrofuran is taken up in 50 ml of ether and extracted three times with 50 ml of water each time. The ethereal solution is concentrated and the N-(5-chloro-2-pyridyl) oleamide is purified by column chromatography analogously to example 1, M.P. 40°.

Example 10 2.81 g (0.01 mol) of oleamide and 1.75 g (0.01 mol) of 2-amino-5-bromopyridine are heated, while stirring in a stream of nitrogen, for 2 hours at 220°. After cooling, the N-(5-bromo-2-pyridyl)-oleamideJ.. is purified by column chromatography analogously to example 1, M.P. 48°.

Example 11 a) 1.28 g (0.01 mol) of 2-amino-5-ch]oropyridine and 1.1 g (0.011 mol) of triethylamine are dissolved in 50 ml of chloroform. While stirring and cooling with ice water, 6.18 g (0.01 mol) of 9 , 10-dibromo-octadecanoyl chloride dissolved in 35 ml of chloroform, are added dropwise within 10 minutes and the mixture is stirred for another 2 hours at room temperature. The chloroform solution is washed with water three times and evaporated to dryness and the N-(5-chloro-^-pyridyl) -9 , 10-dibromo-octadecanamide is recrystal-lised from methanol, M'.P. 72°. b) 0.690 g (0.001 mol) of N-( -chloro-2-pyridyl ) -9, 10-dibromo-octadecanamide are dissolved in 5 ml of anhydrous ethanol. 0.9 g of activated zinc dust are added under an atmosphere of nitrogen and the mixture is refluxed for 1 hour. After cooling, the zinc is removed by filtration and washed with 100 ml of ether free from peroxide. The filtrate is extracted 4 times with 100 ml of water each time, the organic phase is dried over sodium sulphate, concentrated and the N-'( 5-chloro-2-pyridyl) -oleamide is recrystallised from methanol, M.P. 44°.

Example 12 3.93 g (0.01 mol) of N- ( -chloro-2-pyridyl) -oleamide are dissolved in 30 ml of chloroform. While stirring and cooling with a solution of ice and sodium chloride 1.6 g (0.01 mol) of bromine are added dropwise within 1 hour and the mixture is stirred for another 2 hours at room temperature. The chloroform solution is concentrated to dryness (at 30°) and the N-( 5-chloro-2-pyridyl ) -9, 10-dibromo-octa-decanamide is recrystallised from methanol, M.P. 72°.

Debromination to form N-( 5-chloro-2-pyridyl) -oleamide is performed according to example 11 b) .

Example 13 3.75 g (0.01 mol) of N- ( 6-amino-3-pyridyl) -octadecanamide are left to stand in 20 ml of pyridine and 10 ml of acetanhydride for 12 hours at room temperature; The reaction product is poured onto 150 g of ice and 6 3 the precipitated crystals of N-( 5/-acetamido-^-pyridyl) -octadecanamide are filtered off under suction and recrystallised from methanol, M.P. 161°.

Claims (4)

1. HAYIHG HOW particularly described and ascertained "the nature of our -said invention and in what manner the same is to be performed, we declare that what we claim is: 1. New amides of aliphatic carboxylic acids of the general formula I wherein R-^-CO- represents the acyl radical of an alkanoic acid or alkenoic acid having 15-22 carbon atoms R2 represents a halogen atom, a low alkyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, alkanoyl- amino or alkoxycarbonyl group, and R^ represents hydrogen or a low alkyl radical, and their addition salts with inorganic and organic acids.

2. New amides of aliphatic carboxylic acids of the general formula la wherein R^-CO- is defined as in claim 1, and R2 represents a halogen atom, a low alkyl or alkanoylamino group of at most 4 carbon atoms and their acid addition salts with inorganic or organic acids, 3.' N-(5-chloro-2-pyridyl)-oleamide as well as its addition salts with inorganic or organic acids. 4. N-( 6-acetamido-3-pyridyl) -hexadecanamide as well as its addition salts with inorganic or organic acids. 6 5. N-( -acetamido-3-pyridyl) -octadecanamide as well as its addition salts with inorganic or organic acids. 6. N-( 6-acetamido-3-pyridyl) -docosanamide as well as its addition salts with inorganic or organic acids'. 7. N-( 5-methyl-2-pyridyl ) -eicocanamide as well as its addition salts with inorganic or organic acids. 8. N-(5-methyl-2-pyridyl) -hexadecanamide as well as its addition salts with inorganic or organic acids. 9. Process for the production of new amides of aliphatic carboxylic acids corresponding to the general formula I wherein R^-CO- represents the acyl radical of an alkanoic acid or alkenoic acid having 15-22 carbon atoms, R2 represents a halogen atom, a low alkyl, alkoxy, alkenyloxy, alkylthio, alkenylthio, alkanoyl- amino or alkoxycarbonyl group, and 1 R^ represents hydrogen or a low alkyl radical, and their addition salts with inorganic and organic acids, characterised by reacting an acid of general formula II R± - CO - OH (II) wherein R-^-CO- has the meaning given above, or a reactive functional derivative of such an acid, with a nuclear substituted aminopyridine or nuclear substituted alkylaminopyridine of the general formula III wherein R2 and R^ have the meanings given above, or with a reactive functional derivative thereof, and if desired, adding bromine to an alkenoic acid amide of general formula I obtained, purifying the addition product by crystallisation or another usual process and then debrominating, and/or, if desired, converting a compound obtained of the general for- mula I into an addition salt with an inorganic or organic acid. —24··* .275382 1©. Modification of the p ocess according to Claim 9, characterised in that, instead of as alkenole acid hav¾af 15*22 earbea atoms embraced 'by general foraala II in €laiJ» 9# or instead of a. reactive functional de va ve of eueia, an acid,, the saturated bromine addition .product of Jaie -acid or a reactive fuctional derivative thereof is reacted with a. nuclear substituted tsilnepyridine or with nuclear substituted alkyla!ftinepyridiiae of the general oMula til de ined in Claim 9 or with a reaetive functional derivative thereof' atnd the amide- of iibreaiide f tty acid having 15*22 -carbon atone liiiediately obtained is defeToalnated. in the It&otrti eaniier an4f if desired,, a compound obtained f general fermula ,1.is can* verted into an addition ' salt with an' inorganic or organic acid. 11. i process for the production of amides of foimsla Ϊ is Olaiia 1( in which it,, is an alka oylasilBO group., characterise!, by reacting a side of the general fomula . If: wherein. S^--0©- and have- the ¾«te meaning' m in 'Claim 1, with a compound .introducing a low aikaaoyl radical and, if desired.,, . converting' a compound, obtained, of gemeisal forjastla, I into an additio salt with an inorganic or organic acid., 12. New amides of aliphatic carboxylic acids of the general formula I as defined in claim 1, substantially as herein described with reference to and as illustrated in any of the foregoing examples. 1

3. Process according to claim 9, substantially as herein described with reference to and as illustrated in any of the foregoing examples. 1

4. Pharmaceutical compositions containing as active ingredient at least one compound of formula I, defined in claim 1, together with at least one pharmaceutically acceptable carrier. F a 1966