IL27336A - N-pyridyl amides of aliphatic carboxylic acids and their production - Google Patents

Description

Hew N-pyri&yl aiaidee of aliphatic J. R. GEIGY A.G. BASEL 21 4-23.32* The present invention concerns processes for the production of new amides of aliphatic carboxylic acids, these amides as new substances and the medicaments containing them and the use of the latter.

Amides of general formula I wherein R-^-CO represents the acyl radical of an alkanoic acid, alkenoic acid or of alkapolyene acid having 6-14 carbon atoms, R2 represents a halogen atom, ' a low alkyl, alkoxy, al- kenyloxy, 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 antiviral and tumour inhibiting activity ; also the favourable relation 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, particularly influenza-A PR 8 virus, and influenza B-Lee- Columbia S virus virus/and Louping ill virus (virus of sheep encephalitis) and 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 subcutaneous and oral administration to the rat against transplanted Yoshida sarcoma and induced dimethyl benzanthracene mammary carcinoma. The tests on animals 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 I, R-^-CO- is, e.g. the acyl radical of a straight chain alkanoic acid such as hexanoic acid, hep-tanoic acid, octanoic acid, nonanoic acid, decanoic acid, un-decanoic acid, dodecanoic acid, tridecanoic acid or tetrade-canoic acid ; the acyl radical of a straight chain alkenoic or alkapolyene acid such as sorbic acid, 2-octenoic acid, 2-nonenoic acid, 2-decenoic acid, 2-undecenoic acid, 10-un-decenoic acid, 2-dodecenoic acid, 2-tridecenoic acid, 2-tetra-decenoic acid or 2, 4, 6, 8-decatetraenoic acid ; the acyl radical of a branched chain alkanoic acid such as 2-ethyl butyric acid, 3, 3-dimethyl^butyric acid, 2-ethyl pentanoic acid, 2-ethyl-4-methyl-pentanoic acid, 2-ethyl hexanoic acid, 2,2-diethyl butyric acid, 3, 3, 5-trimethyl hexanoic acid, 3, 5, 5-trimethyl hexanoic acid, 2-n-butyl hexanoic acid, 2-ethyl decanoic acid or 2-ethyl dodecanoic acid, or the acyl radical of a branched chain alkenoic acid or alkapolyene acid such as 2-allyl-4-pentenoic acid, 3-ethyl-2-hexenoic acid, 2- (1-methyl-allyl) -pentenoic acid, 3-me thyl-2-nonenoic acid, 3-methyl-2-undecenoic acid or 3-methyl-2-tridecenoic acid.

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

Low alkyl radicals R^ are exemplified by those listed for ϊ^.. £k«-g©fie#a4-£«#md^-i-^^^ αςΐΜ ααΗ &-θί-^«¾βίβ4-4, Η¾Η*1·&---ί-τ 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 ^ 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 presence of a carbodiimide such as dicyclohexyl carbodi-imide, in an inert solvent such as tetrahydrof ran. Low alkyl esters, e.g. the methyl or ethyl ester, of acids of the general formula II and also the amides yield 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 trie.thylamine, pyridine or s-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 triethylamine, in an inert organic solvent, filtration of the hydrohalide formed and reaction of 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-imidazol .-ides 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 are mentioned as reactive functional derivatives of compounds of general formula III which can be reacted direct with acids of the general formula IT. These are heated with the acids o'f general formula II until the equimolar amount of carbon dioxide 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 inert organic solvents- In addition, for example N-chlorocar- bonyl 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 abc vent 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 amides of general formula I.

Other reactive functional derivatives of compounds of general formula III are, for example, the N-trime thylsilyl derivatives, among others, e.g. ethyl trimethylsilyl amino-pyridine carboxylates (ϊ^ = COC^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 organic solvents to form N-trimethylsilyl 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 N, ' -dipyridyl carbodiimide s substituted in the two pyridine rings corresponding to the definition of R2. These can be obtained, e.g. by heating the corresponding, substituted N, N' -dipyridyl thioureas with lead-(II) oxide in anhydrous toluene while gradually distilling off the solvent. On heating the carbodiimide s mentioned with acids of general formula II in a stream of carbon dioxide at tempera° are formed.

Instead of alkenoic or alkapolyene acids having 6-14 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 aminopyridines or nuclear substituted alkylamino pyridines of general formula III or with reactive derivatives thereof and the amides of polybromine fatty acids immediately obtained which have 6-14 carbon atoms and an even number of bromine atoms can be debrominated.

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 performed, 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 or alkapolyene 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 pyridylamides of dibromo-or polybromoalkanolc 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. λ 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 wherein is a low alkanoylamino group can also be produced by reacting amides of the general formula IV, wherein R-^-CO- and R^ 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 acylatihg 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 pro-tection 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 the acid addition salts which have already been mentioned above 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 disulphonic 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 5Ό 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 30% 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 tabletsor dragee (sugar coated tablet) cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, tal-cum 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 administration a supposito ies 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, intramuscular 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 solution, 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 g of active substance, e.g. N- ( 5-methyl-2-pyridyl ) -dodecanamide , are mixed with 175.80 g of lactose and 169.70 g of potato starch, the mixture is moistened with an alcoholic solution 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-(5-methyl-2-pyridyl)-sorbamide, 175.90 g of lactose and the alcoholic solution of 10 g of stearic acid. After drying, the granulate is mixed with 50.60 g of colloi' 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 dyestuff and 1.5 g of titanium dioxide and dried. The dragees obtained each weigh 140 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 are given in degrees Centigrade, EXAMPLE 1 7.6 (0.05 mol) of 5-amino-2-propoxy-pyridine are dissolved in 20 ml of pyridine. While stirring and cooling with ice water, 10.15 g (0.05 mol) of 10-undecenoyl chloride are added dropwise within 10 minutes and the mixture is stirr for another 2 hours at room temperature. The reaction mixture is then poured into 200 ml of ice water, extracted three time with 100 ml of chloroform and the chloroform solutionsare washed neutral with water. The combined chloroform solutions are dried with sodium sulphate and evaporated to dryness. The residue is recrystallised from benzene/petroleum ether whereupon N-(6-propoxy-3-pyridyl) -10-undecenamide is obtained, M.P. 64°.

To prepare the hydrochloride, the above amide is dissolved in a little methanol, an excess of ethereal hydrochloric acid is added and the precipitated hydrochloride is filtered off. After recrystallisation from methanol/ether, it melts at 159°.

The following compounds, e.g. are produced in an analogous way : a) N- ('5-bromo-2-pyridyl ) -10-undecenamide M.P. 74° ; b) N-(5-chloro-2-pyridyl) -10-undecenamide M.P. 67° ; c) N-( 5-methyl-2-pyridyl)-10-undecenamide M.P. 67° ; d) N- ( 6-allylthio-3-pyridyl ) -10-undecenamide hydrochloride M.P. 153° .

EXAMPLE 2 7.0 g (0.0404 mol) of 2-amino-5-bromopyridine are dissolved in 50 ml of pyridine. 8.21 g (0.0404 mol) of 10-un-decenoyl chloride 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. The reaction mixture is poured into 250 ml of ice water and the precipitated N-(5-bromo-2-pyridyl) -10-undecenamide is recrystalllsed from methanol, M.P. 74°.

The following compounds, for example, are produced analogously : a) N- [5 -iodo-2-pyridyl) -10-undecenamide M. P. 84°; b) N- :e -ethoxy-3-pyridyl ) -10-undecenamide M. P. 67° c) N- -butoxy-3-pyridyl) -10-undecenamide M. P. 62° d) N- [6 -allyloxy-3-pyridyl) -10-undecenamide M. P. 62° e) N-( [6 -ethylthio-3-pyridyl ) -10-undecenamide M. P. 64° f) N- [5 -ethoxycarbon l-2-pyridyl)-iD-undecenamide M. P. 74° g) N-(( acetamido-3-pyridyl ) -10-undecenamide M. P. 152° h) N- 6 -propoxy-3-pyridyl )-octanamide M. P. 78° i) N- '6 -propoxy-3-pyridyl ) -nonanamide M. P. 65° j) N- [6 -propoxy-3-pyridyl) -decanamide M. P. 70° k) N- [6 -propoxy-3-pyridyl) -undecanamide M. P. 77° 1) N- [5 -chloro-2-pyridyl) -dodecanamide M. P. 91° m) N- 4 -methyl-2-pyridyl) -dodecanamide M. P. 52° n) N- [5 -methyl-2-pyridyl) -dodecanamide M. P. 79° o) N- [6 -propoxy-3-pyridyl) -dodecanamide M. P. 83° P) N-< -propoxy-3-pyridyl ) -tridecanamide M. P. 84° q N-(6-propoxy-3-pyridyl) -tetradecanamide M.P. 85° r N-(5-ethoxycarbonyl-2-pyrldyl) -tetradecanamide M.P. 79° s N-( 6-propoxy-3-pyridyl) -2-nonenamlde M.P. 84° t N- ( 5-bromo-2-pyridyl ) -sorbamide M.P. 154°; u N-(5-methyl-2-pyridyl) -sorbamide M.P. 151° ; V N-(5-methyl-2-pyridyl) -2-allyl-3-methyl-4-pentanamide hydrochloride, M.P. 121° w N- (6-acetylamino-3-pyridyl) -sorbamide, M.P. 238° X N-(6-allyloxy-3-pyridyl) -undecanairide M.P. 68° y N-(5-ethoxycarbonyl-2-pyridyl) -sorbamide M.P. 162° z N-(5-ethoxycarbonyl-2-pyridyl)-3, 5, 5-trimethyl- hexanamide M.P. 82° ; aa N-(6-acetylamino-3-pyridyl)-3-ethyl-2-hexanamide M.P. 162°; bb N- ( 5-chloro-2-pyridyl ) -3-ethyl-2-hexenamide hydrochloride , M.P. 136° ·, cc N-(5-methyl-2-pyridyl)-2-ethyl-hexanamide 22° : 1,5185 dd N-(6-acetylamino-3-pyridyl)-tridecanamide M.P. 162° ; ee N-methyl-N- (5~methyl-2-pyridyl) -10-undecenamide 210 : 1,5095 ff N-( -methyl -2 -pyridyl) -sorbamide, M.P. 210° ; gg N-( 4-methyl-2-pyridyl Λ -3, 5, -trimethyl-hexanamide M.P. 53°; hh) N-(4-methyl-2-pyridyl) -10-undecenamide M.P. 38° j EXAMPLE 3 7.6 g (0.05 mol) of 5-amino-2-propoxy-pyridine are dissolved in 20 ml of chloroform. While stirring and coolin with ice water, 5.48 g (0.025 mol) of dodecanoyl chloride are ,2k added dropwise within 10 minutes and the mixture is stirred for another 2 hours at room temperature. The reaction mixture is poured into 200 ml of ice water and extracted three times with 100 ml of chloroform. The combined chloroform solutions are washed neutral with water, dried with sodium sulphate and concentrated to dryness. The residue is recrystallised from methanol, whereupon N- ( b-propoxy-3-pyridyl ) -dodecanamide is obtained, M.P. 83°.

EXAMPLE 4 3.69 g (0.02 mol) of 10-undecenoic acid and 2,02 g (0.02 mol) of triethylamine are dissolved in 100 ml of tetrahydrofuran and the solution is cooled to -15°. While stirring well, 2.15 g (0.02 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 3.08 g (0.02 mol) of 6-aminonicotinic acid ethyl ester in 20 ml of tetrahydrofuran is added at -18° to -12° to the solution formed of the mixed anhydride of 10-undecenoic acid and carbonic acid monoethyl ester. The mixture is stirred for 1 hour at -10° and, freezing mixture after removal of the Aooiiftg, for another 12 hours at room temperature. The precipitated triethylamine hydrochloride is filtered off under suction, the filtrate is evaporated and the N-(5-ethoxycarbonyl-2-pyridyl) -10-undecenamide is recrystallised from methanol, M.P. 74°.

EXAMPLE 5 1.84 g (0.01 mol) of 10-undecenoic acid and 2.79 g (0.01 mol) of 2-amino-5-bromopyridine are dissolved in 50 ml of tetrahydro uran . A solution of 2.08 g (0.01 mol) of N, N' -dicyclohexyl carbodiimide in 50 ml of tetrahydrofuran is added dropwise while stirring at ^10p. After stirring for 1 hour at -10° and for 4 hours at. room temperature, the precipitated N, N1 -dicyclohexyl urea is filtered off under suction and washed with tetrahydrofuran. The filtrate is concentrated and the N- ( -bromo-2-pyridyl ) -10-undecenamide is recrystallised from methanol, M.P. 74°.

EXAMPLE 6 2.14 g (0.01 mol) of 10-undecenoic acid ethyl ester and 1.08 g (0.01 mol) of 6-amino-3-picoline are heated under a stream of nitrogen and while stirring well for 4 hours at 230°. After cooling, the crude N- ( 5-methyl-2-pyridyl ) -10-undecenamide is recrystallised from methanol, M.P. 66.5°.

EXAMPLE 7 A solution of 2.08 g (0.01 mol) of N, N' -dicyclo-hexyl carbodiimide in 50 ml tetrahydrofuran is added dropwise at -10° to a stirred solution of 1.84 g (0.01 mol) of 10-undecenoic acid and 1.4 g (0.01 mol) of p-nitrophenol in 50 ml of tetrahydrofuran. After stirring for 1 hour at -10° and for 4 hours at room temperature, the precipitated N, N' -dicyclo-hexyl urea is filtered off under suction and washed with tetrahydrofuran and the filtrate is concentrated. 3.06 g (0.01 mol) of the 10-undecenoic acid-p-nitrophenyl ester which remains as residue are left to stand for 4 days with 10.8 g (0.1 mol) of 6-amino-3-picoline in 50 ml of chloroform, After evaporating off the solvent, the crude product is purified by chromatography through a column. The product is identical with the N-(5-methyl-2-pyridyl) -10-undecenamide produced according to example 6.

EXAMPLE 8 2.22 g (0.022 mol) of triethylamine are dissolved in 50 ml of anhydrous ether. While stirring and cooling with ice water, 2 g (0.01 mol) of 10-undecenoyl chloride dissolved in 20 ml of anhydrous ether are added dropwise within 5 minutes. Then 1.73 g (0.01 mol) of 2-amino-5-bromopyridine dissolved in 50 ml of ethyl acetate are added dropwise within 10 minutes and the mixture is stirred for another 2 hours.

The precipitated triethylamine hydrochloride is filtered off under suction and washed with ethyl acetate. On working up the filtrate analogously to example 1, N- ( 5-bromo-2-pyridyl) -10-undecenamide is obtained, M.P. 74°.

EXAMPLE 9 2.22 g (0.01 mol) of 2-amino-5-iodopyridine are dissolved in 30 ml of dimethyl formamide and 1.01 g (0.01 mol) of triethylamine . While stirring and cooling with ice water, 1.86 g (0.01 mol) of trimethyl silyl chloride dissolved in 10 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, 1.11 g (0.011 mol) of triethylamine and then 2.0 g (0.01 mol) of 10-undecenoyl chloride, dissolved in 10 ml of dimethyl formamide, are added dropwise to the solution obtained of 2-trimethyl silylamino-5-iodopyridine , whereupon the mixture is stirred for another 2 hours. The reaction mixture is poured into 300 ml of ice water, the precipitated product is filtered off under suction, dried under high vacuum (4 hours at 40°) and recrystallised from methanol. The N- (5-iodo-2-pyridyl) -10-undecenamide obtained melts at 84°, (cf. example 2).

EXAMPLE 10 1.62 g (0.01 mol) of 1 , 1 ' -carbonyl diimidazole are added at room temperature to 1.84 g (0.01 mol) of 10-un-decenoic acid dissolved in 25 ml of anhydrous tetrahydrofuran. On completion of the development of carbon dioxide, 1.56 g (0.01 mol} of 3-amino-6-ethylthiopyridine dissolved in 20 ml of anhydrous tetrahydrof ran are added to the solution obtained of l-(lO-undecenoyl) -imidazole and the reaction mixture is refluxed for 10 minutes. The residue obtained after evaporating off the tetrahydrofuran is taken up in 50 ml of ether and extracted three times with 50 ml of water. The ethereal solution is concentrated and the N- (6-ethylthio-3-pyridyl) -10-undecenamide is recrystallised from methanol M.P. 64°.

EXAMPLE" 11 3.71 g (0.01 mol) of N- ( 6-amino-3-pyridyl ) -10-undece oic acid amide in 20 ml of pyridine and 10 ml of acetan hydride are left to stand for 12 hours at room temperature. The reaction mixture is poured onto 150 g of ice and the crystals of N- ( 6-acetylamino-3-pyridyl) -10-undecenamide which precipitate are filtered off under suction and recrystallised from methanol, M'.P. 152° (cf. example 2 g) .

EXAMPLE 12 a) 1.52 g (0.01 mol) of b-amino-3-propoxy-pyridine and 1.1 g (0.011 mol) of triethylamine are dissolved in 50 ml of chloroform. While stirring and cooling with ice water, 3,63 g (0.01 mol) of 10 , 11-dibromoundecanoyl ■ 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 rs washed with water 3 times, evaporated to dryness and the N-(6-propoxy 3-pyridyl) -10, 11-dibromoundecanamide is recrystallised from methanol. M..P, 83°. b) 4.78 g (0.01 mol) of N- ( 6-propoxy-3-pyridyl) -10, 11-dibromo-undecanamide are dissolved in 5 ml of abs. ethanol, 5 g of activated zinc dust are added under an at-τ mosphere of nitrogen and the mixture is refluxed for 1 hour. After cooling, the zinc is removed by filtration, the solution is evaporated to dryness and the N- ( 6-propoxy-3-pyridyl ) -10-undecanamide which remains is recrystallised from methanol, EXAMPLE 13 a) 2.75 g (0.01 mol) of N-( 5-amino-2-pyridyl) - 10-undecenamide are left to stand for 12 hours at room temperature in 5 ml of pyridine and 5 ml of acetanhydride . The reaction product is poured onto 100 g of ice and the crystals of N-(5-acetylamino-2-pyridyl)-10-undecenamide formed are filtered off under suction and recrystallised from methanol, M.P. 149°. b) N-( 5-amino-2-pyridyl) -10-undecenamide can be produced as follows : .56' g (0.04 mol) of 2 -amino-5-nitropyridine are dissolved in 30 ml of pyridine. While stirring and cooling (ice water), 8.12 g (0.04 mol) of 10-undecenoyl chloride are added dropwise and the mixture is stirred for 6 hours at room temperature. The reaction mixture is poured onto ice and the crystals of N-(5-nitro-2-pyridyl)-10-undecenamide which are formed are recrystallised from methanol, M.P. 74°. -v 3.05 g (0.01 mol) of N-( 5-nitro-2-pyridyl) -10-undecenamide are dissolved in a mixture of 30 ml of water, 6 ml of dioxane and 6 ml of methanol. 10 g of iron powder are added and the mixture is stirred for 30 minutes at 90-93° under an atmosphere of nitrogen. The reaction mixture is then filtered while hot and the filtrate is evaporated to dryness. The N-(5-amino-2-pyridyl) -10-undecenamide is recrystallised from methanol, K. P. 82°.

Claims (17)

HAVIMC- NOW particularly described and ascertained the " nature of our said invention and in what manner the same is to b •A. performed, we declare that what we claim is

1. New amides of aliphatic carboxylic acids corresponding to the general formula I wherein 'R -CO- represents the acyl radical of an alkanoic acid, alkenoic acid or of an alkapolyene acid having 6-14 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 corresponding to the general formul la wherein R-^-CO- is defined as in claim 1, and R2 represents a low alkyl, alkoxy or alkanoylamino group of at most 4 carbon atoms and their addition salts with inorganic and organic acids.

3. N-( 5-methyl-2-pyridyl) -dodecanamide as well as its addition salts with inorganic and organic acids.

4. N-(6-propoxy-3-pyridyl) -2-nonenamide as well as its addition salts with inorganic or organic acids.

5. N-( 5-ethoxycarbonyl-2-pyridyl) -tetradecanamide as well as its addition salts with inorganic or organic acids.

6. N-(4-methyl-2-pyridyl) -dodecanamide as well as its addition salts with inorganic or organic acids.

7. N- ( 5-methyl-2-pyridyl) -10-undecenamide as well as its addition salts with inorganic or organic acids.

8. N- (6-acetylamino-3-pyridyl) -sorbamide as well as its addition salts with inorganic or organic acids.

9. N- ( 5-methyl-2-pyridyl) -sorbamide as well as its addition salts with inorganic or organic acids.

10. N- ( 6-propoxy-3-pyridyl) -octanamide as' well as its addition salts with inorganic or organic acids.

11. N-(6-butoxy-3-pyridyl)-lQ*-undecenamide as well as its addition salts with inorganic or organic acids.

12. Process for the production of new amides of aliphatic carboxylic acids corresponding to the general formula wherein R-, -CO- represents the acyl radical of an alkanoic ac alkenoic acid or of an alkapolyene acid having 6-14 carbon atoms, ■R, represents a halogen atom, a low alkyl, alkoxy alkenyloxy, alkylthio, alkenylthio, alkanoyl- amino or alkoxycarbonyl group, and R 3 represents hydrogen or a low alkyl radical, and their addition salts with inorganic and organic acids as characterised by reacting 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 with a nuclear substitu ted aminopyridine or nuclear substituted alkylaminopyrldine the general formula III wherein Rg and R^ have the meanings given above, or with a reactive functional derivative thereof and, if desired, adding amide bromine to an alkenoic acid/or alkapolyene acid , amide obtained of the general formula I, purifying the addition .product by. crystallisation or another usual process and then debrominating and/or, if desired, converting a compound obtained of the general formula I into a addition salt with an inorganic or · organic acid. " '

13. Modification of the process according to claim 12, characterised in that, instead of an alkenoic acid or alkapolyene acid having 6-1 carbon atoms defined in general formula II in claim l^or instead of a reactive functional derivative thereof, the saturated bromine addition product of this acid or a reactive functional, derivative- thereof is reacted with " a nuclear substituted aminopyridine or nuclear substituted alkylaminopyridine of the general formula III de-' fined in claim 1 or with- a reactive functional derivative- there of and the amide of a polybromihe fatty acid, having 6-14 carbon atoms and an even number of bromine atoms, immediately obtained is debrominated in the usual way and, if desired, a compound of general formula I obtained is converted into an addition salt with an inorganic or organic acid;

14. Process for the production of new amides of formula I in .Claim 1 and their addition salts with inorganic and organic acids, characterised · y reacting an amide of the general formula IV wherein R^-CO- and have the meanings given in claim 12, with a compound introducing a low alkanoyl radical and, if desired, , converting a compound obtained of the general formula I into an addition salt with an inorganic or organic acid

15. 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.

16. Process according to claim 12, substantially as herein described with reference to and as illustrated in any of the foregoing examples.

17. 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 Dated this 26th day of January, 1967 Fo/ja/29.12.66