DE1944755C3 - Fatty acid amides, processes for their production and their use for the production of foods enriched with these fatty acid amides - Google Patents

Description

in which R is a saturated or unsaturated, unbranched or branched aliphatic hydrocarbon ^{radical with 15 to 25 carbon atoms and R 1 is} a Ci-C ₄ -AlCyI- or a phenyl (Ci-C4-alkyl) radical and R ^{2 is} a 2-, Represents 3- or 4-pyridyl or a 2-thienyl group.

2. Process for the preparation of the compounds according to claim 1, characterized in that one either

(a) a fatty acid of the general form! Il

R — COOH (II)

in which R has the meaning given in claim 1, or its acid halide, its lower alkyl ester or its glyceride or

(b) an acid hydride of the general formula III

RCO

(HD

R'CO

in which R 'has the same meaning as R or an alkyl or alkoxy radical with 1 to 4 Represents carbon atoms with an amine of the general formula IV

R ² (IV)

R ¹ -CH

NH ₂

40

in which R ¹ and R ^{2 are} those specified in claim 1

Have meaning
condensed in a manner known per se.

3. Use of the fatty acid amides according to claim 1 for the preparation of fatty acid amides with these fortified foods.

R -CO-NH-CH

(D

R ²

■ C4-ä! Kyi) radical and R ^{2 is} a 2-, 3- or

IVJ.

Atherosclerosis is an adult disease People for whom there has not yet been a satisfactory therapy. Despite numerous investigations, the The cause of the arteriosclerosis is not yet known. It was found, however, that an essential The histopathological sign of arteriosclerosis is the deposition of lipids in the blood. Accordingly were you? Researches have been directed towards the disturbance of fatty acid metabolism and it has been elevated Particular attention is paid to the level of cholesterol in the blood.

A number of experimental and clinical facts have been reported to support the relationship between atherosclerosis and high blood cholesterol levels Show. Thus, the development of medicinal preparations for reducing blood cholesterol levels and has been considered particularly important for the prevention of atherosclerosis.

Considerable efforts have already been made to develop such medicinal preparations for reduction of blood cholesterol developed, and a Number of compounds have not been clinically proven, but none of these compounds have been found to be completely satisfactory. Some of these compounds are quite effective, yet they produce significant side effects, and other compounds have insufficient effects so that they are in large doses must be administered.

A group of compounds currently in practical use for lowering blood cholesterol are the unsaturated fatty acids, especially linoleic acid. Linoleic acid is characterized by its harmlessness to humans, its effect is however not very high, uncertain and indefinite. Accordingly, high doses are required to to achieve a significant reduction in blood cholesterol levels.

The fatty acid amides of the invention have a much greater effect in lowering the Cholesterol levels in the blood, and they are also practically non-toxic.

The invention also relates to a process for the preparation of the new fatty acid amides, which is characterized in that either
(a) a fatty acid of the general formula II

The invention relates to fatty acid amides in general Formula I.

R ¹

which represents a 2-thienyl group.

It has been found that the fatty acid amides of the invention are valuable drugs because they have the ^ lower the level of holesterin in the blood.

R-COOH

dl)

in which R has the above meaning, or its acid halide, its lower alkyl ester or a glyceride or
(b) an acid anhydride of the general formula III

55 RCO

RCO

(HI)

ι the R is a saturated or unsaturated, n-branched or branched aliphatic carbon / asserstoffrest with 15 to 25 carbon atoms ledeutet, R ^{1 is} a Ci-Ct-alkyl or a phenylene R 'has the same meaning as R or an alkyl or alkoxy radical with 1 to 4 carbon atoms, with an amine of the general formula IV

R ¹ -CH-R ² (IV)

NH ₂

in which R ¹ and R ^{2 have} the above meaning, condensed in a manner known per se.

• oils for the fatty acids of the general formula ^B Ü! L ^{Pie of} their reactive derivatives and the '. Ate are listed below, jlycenu. P _elts acids can z. B. palmitic acid,

^AlS - ^g ^ ,, rp isostearic acid, arachidic acid, behen-; ^Steann n! Noceric acid, pentacosanoic acid or 1! ^Acid ncSure can be used.

^ω ι neesaturated fatty acids can, for. ! B. Palmito, - in-Toomarinsäure, oleic acid, Petroselin acid, elaidic, w ^ _af-censäure Gadoleinsäure, erucic ^acid> -j- _{n <:} änre selacholeic, linoleic, linolenic ^{B. raS} rünoelaidic acid, ricinoleic acid, eleosteanic acid, acid, w_ ^ -linolenic acid, eicosatetraenoic acid,

or arachidonic acid is used

“- .. niele for the reactive derivatives are the c- Vhaloeenide, acid anhydrides, mixed Sädre- ^S tdride dS lower aryl esters and glycerides of the - named saturated and unsaturated fatty acids. • Niele of usable natural oils and fats hemp oil, linseed oil, perilla oil, oiticica, kaya oil, ~ u / _a in, ißöL poppy seed oil, safflower oil, watermelon seed oil, c thohnenöl, sunflower oil, rice bran oil, Kürb.s- ^ ^J - Kaoiiangöl, sesame oil, corn oil, Rapeseed oil, tree

Oil Olive Oil, Cashew, tsubaki, Mother "peanut oil, palm oil, palm kernel oil, coconut Ug, lard, bone oil, horse fat, Chrysalisöl, Haifischtranöl, Tintenfischkl SardinenöuThunfischöl, mackerel oil, saury-Λΐ HerinKöl, cod oil, trout oil, mullet oil, i JnSS menhaden oil, Eel oil, flatfish oil, the various snaps on whale oil. Liver oil and residual oil.

n7r Alkvh-est R ¹ is an unbranched or branched alkyl «* with 1 to 4 carbon atoms. Examples of the phenyl ₍ C1-C4-alkyl) radical R · are the benzyl, phenylethyl, phenylpropyl and phenylbutyl groups.

The conditions applied in the process of the invention nurse α r alüremeinen formula IV may be prepared by known MeÄTSgestellt; see J. Amer. Chem. Soc. MA S 477 and 50 (1928), p. 2484; ]. Org. Chem. 23, 0 M95ksi989 or 24 (1959), p.1936.

The fatty acid amides of the invention can be prepared by the following processes: ^ Implementation of the fatty acid with the nurse in the presence or absence of a water-releasing

₍₂₎ SÜSiSti «fatty acid ester or glyceride ¹ 'with the amine in the presence or absence

(3) By ten fine fatty acid halide with the

(4) Formation of an acid anhydride or mixed Acid anhydride with the Amm.

The above procedures are explained in detail below

■ τ

and used again in the reaction. Using of a dehydrating agent, the starting compounds are used either in equimolar amounts or one of them is used in excess. The output connections are in a solvent such as benzene, toluene, xylene, or carbon tetrachloride, and the solution is mil a dehydrating agent such as sulfuric acid, potassium hydrogen sulfate, phenolsulfonic acid, p-toluenesulfonic acid, p-Toluenesulfonyl chloride or an acidic one or basic ion exchangers, such as Amberlite IRA-400, IR-50 or IR-120, or Amberlyst 15, 21, 26 or 27, offset. The reaction mixture is then refluxed for 10 to 200 hours, the , water of reaction formed during the reaction is preferably separated off. After completion of the implementation the dehydrating agent is removed or neutralized and then the solvent and unreacted starting compounds separated when using a disubstituted carbodiimide as dehydrating agent, the reaction can be terminated in a short time at a low temperature. Examples of usable carbodiimides are diphenylcarbodiimide, Diisopropylcarbodiimide and dicyclohexylcarbodiimide. The most common is dicyclohexylcarbodiimide In this case, the fatty acid, the amine and the disubstituted carbodiimide are each used in dissolved in an inert solvent Examples of suitable solvents are diethyl ether, dioxane, Tetrahydrofuran, petroleum ether, ligroin, kerosene, n-hexane, Cyclohexane, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform and carbon tetrachloride. The three solutions are then mixed together with stirring at room temperature or below The reaction is complete within a few minutes. However, the reaction mixture is usually left to stand for a few hours at room temperature. the urea compound formed is then filtered off and the fatty acid amide is recovered from the filtrate. the Urea compound is converted back to the disubstituted carbodiimide for reuse.

(2) Conversion of a lower alkyl ester of fatty acid or a corresponding fatty acid glyceride with the amine. The alkyl radical in the fatty acid alkyl ester contains 1 to 5 carbon atoms.

The starting compounds are used in equimolar amounts, or one of the compounds is used in excess. The mixture is ^{heated to 100 to 250 °} C., as much of the alcohol released as possible being separated off. The reaction is complete within about 50 hours to several days. Optionally, a solvent such as toluene or xylene can be used in this reaction. In most cases, however, a solvent is not required. The reaction cell can be shortened by using catalytic amounts of a base such as lithium, sodium or potassium, sodium methylate, sodium ethyl, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, or an acidic condensing agent such as sodium hydrogen sulfate or boric acid. (3) Reaction of a fatty acid halide with the

In this reaction, the amine in water or is s in a water-containing solvent such as acetone, dioxane or tetrahydrofuran, dispersed in the obtained dispersion, the fatty acid halide at 0 to 30 ⁰ C in the presence is a base such as sodium hydrogen

droxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, gradually introduced. You can also use the amine in an inert organic solvent such as acetone, methyl ethyl ketone, Methyl isobutyl ketone, diethyl ether, dioxane, s tetrahydrofuran, petroleum ether, ligroin, kerosene, benzene, Toluene, xylene, chloroform or carbon tetrachloride, in the presence of a base such as sodium carbonate, Potassium carbonate, sodium hydroxide, potassium hydroxide, or a tertiary amine such as trimethylamine, triethylamine, dimethylaniline, diethylaniline, pyridine or Lutidine, and gradually add the fatty acid halide to this solution at 0 to 20 ° C. If necessary the reaction mixture is then heated. This process gives very good yields.

(4) Reaction of an anhydride of the fatty acid with the amine.

A solution of the fatty acid anhydride in an inert solvent gradually becomes that at 0 to 100 ° C Given amine or a solution of the amine in an inert solvent. If necessary, the reaction mixture can The formed in the reaction are heated until the reaction is complete Fatty acid and the unreacted fatty acid anhydride can be isolated for reuse. at Use of a mixed acid anhydride from the fatty acid and a lower alkyl formate, the reaction of a fatty acid of the general formula II with z. B. obtained ethyl chloroformate is, the reaction can be carried out in a very short time and at a low temperature. Such mixed acid anhydrides are often used for the production of peptides and can e.g. B. after that in J. Ame '. Chem. 74 (1952), p. 676 described method are produced.

Toluene, xylene, η-hexane, cyclohexane, petroleum ether, ligroin, kerosene, diethyl ether, dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, chloroform or carbon tetrachloride can be used as solvents in the reaction described above. The reaction is within 20 to 30 minutes to 2 hours completed the solution of the mixed acid anhydride in the organic solvent with the amine at temperatures of - mixing 20 to +20 ⁰ C. Usually, is allowed to stand the reaction mixture at room temperature overnight, the reaction to complete.

The fatty acid amides of the invention produce a large reduction in blood cholesterol levels. this is evident from the comparison tests below. Compounds of the Invention and Known Compounds that lower cholesterol are included in feed, each containing 1% cholesterol and contains 0.5% of a bile acid salt. Mice are fed with this feed for K) days On the 11th day the cholesterol in the serum and in the liver is determined. The total amount of serum and liver cholesterol per 100 g of body weight of each mouse is calculated, and the percentage change in cholesterol value is calculated according to the following equation:

Change (%) = 1 -

Value of the treated group
Control group value

χ 100.

The percentage change in cholesterol caused by the compounds is in Table I compiled. All of the compounds of the invention show a much greater reduction of cholesterol than the known compounds / i-sitosterol and linoleic acid, despite the fact that they were used in lesser amounts.

Table 1

connection

Linoleoyl - «- (2-thienyl) ethylamide

Structural formula

C _n H ₃₁ CONHCH _{NC /}

CH ₃ % in feed change,%

0.2

-48

Isostearoyl- «- (2-thienyl) -ethyIamide

JC ₁₇ H ₃₅ CONHCH \ _p . CH, 0.2

-49

Linolenoyl - ^ - (2-lhienyl) ethylamide

C ₁₇ H ₂₉ CONHCH-A ₈ ; CH ₃ 0.2

-44

Linoleoyl-ix- (2-thienyl) -phenethylamide

CH ₂ 0.2

-77

continuation

connection Structural formula

% in feed change. %

ci- (2-thienyl) phenethylamide of safflower oil

Linoleoyl - «- (2-pyridyl) benzylamide Oleoyl ft- (3-pyridyl) benzylamide Linoleoyl-ft- {3-pyridyl) benzylamide Safflower Oil-CONHCH C "H ₃ iCONHCH

C ₁₇ H "CONHCH

C ₁₇ H ₃₁ CONHCH

0.2

0.2

0.2

0.2

-73

-48

-58

-60

Oleoyl-a- {2-pyridyl) benzylamide

Linoleoyl - «- (4-pyridyl) benzylamide

α- (4-pyridyl) -benzylamide from whale oil

Blind test

Whale oil-CONHCH

/? - Sistosterin LinoMure 0.2

-45

0.2

0.2

1.0 1.0

-56

-47

+

+

The fatty acid amides of the invention are used orally in therapy and in daily doses of about 0.1 to 10 g administered Usually the active ingredients for oral administration are mixed with pharmacologically acceptable excipients. The fatty acid amides of the 6s Invention can also be used for the preparation of foods enriched with these fatty acid amides.

Examples of foods that can be fortified with the fatty acid amides of the invention are Dairy products such as butter, margarine, cheese, cream, ice cream, skimmed milk, dry milk and whole milk. Animal and vegetable edible oils are also suitable for enrichment, such as oils for frying, salad oils, Mayonnaise and lard, breakfast cereals and similar foods, wheat flour,

Bread, crackers and biscuits, confectionery such as chocolate, Chewing gum and candies, and meat products such as sausages and ham.

Because of their low toxicity, the fatty acid amides of the invention can be incorporated into foods in a wide range of amounts. The salary of fatty acid amides in the food should depend on the frequency of consumption of the food. So z. B. cream and similar products that are used less frequently, a larger one Content of fatty acid amides, while e.g. wheat flour products that are consumed in larger quantities have a lower content of fatty acid amides. In general, the fortified foods about 0.1 to about 80 weight percent fatty acid amide. The maximum daily dose is preferably about 10 g of the fatty acid amide contained in the food

For the production of the foods enriched with the fatty acid amides, other common additives can be used, such as natural and synthetic emulsifiers for food, e.g. Lecithin, sorbitan, cane sugar esters, fatty acid monoglycerides, antioxidants for food, such as butylated hydroxyanysol, tocopherols, propyl gallate, nor-dihydroguajaretic acid, colorings, flavorings, hosts and water.

For the enrichment of z. B. Margarine are solid fats such as beef tallow, lard or hydrogenated oils, e.g. B. hardened corn oil, with liquid oils, such as Soybean oil, peanut oil, cottonseed oil or safflower oil, mixed in a mixer in such a way that a product with a suitable melting point is obtained. This mixture is at least one fatty acid amide of the general formula I in the required amount and a dye, an aqueous sodium chloride solution, an emulsifier and an antioxidant incorporated The mixture obtained is at a temperature slightly higher than that Melting point of the mixture, stirred vigorously and then rapidly cooled.

Since the fatty acid amides of general formula I are very soluble in fats, they can oil through edible oils simply stirring in, if necessary with slight heating, can be easily incorporated.

The addition of the fatty acid amides of the general formula I to powdery food, such as Wheat flour and rice flour, can be done in a mill or in a mixer. Possibly the fatty acid amides can be in the form of a solution in an inert organic solvent such as ethanol, or added to a vegetable oil.

Fortified bread, fortified crackers, and biscuits can be made from fortified wheat flour or buckwheat flour in a conventional manner. Fortified cereals, e.g. Wheat or rice can be prepared by coating with a fatty acid amide of the invention or by mixing the grain with the fatty acid amides. Furthermore, the fatty acid amides of the invention can be kneaded with wheat flour, cellulose acetate, gum arabic or rice flour and then shaped into the desired shape. These products can then be mixed with untreated rice.

Since the fatty acid amides of the invention are odorless and tasteless, the taste of the fortified food is unchanged Alkalis are stable to hydrolysis.
The examples illustrate the invention.

example 1

A solution of 2.1 g of triethylamine and 3.8 g of a- (2-pyridyl) benzylamine in 70 ml of diethyl ether at 15 to 2O ⁰ C dropwise and while stirring 4 g

ίο Linoleoyl chloride added The mixture is 2 hours stirred at room temperature, then left to stand for 15 hours and then under reflux for 2 hours boiled and stirred. After cooling, the reaction mixture is washed with water, aqueous sodium carbonate

sodium solution and washed again with water, then dried over sodium sulfate and then evaporated The residue is purified by chromatography on a silica gel column. As a solvent is a mixture of benzene and chloroform is used.

After the solvent has evaporated, 73 g (79% of theory) of linoleoyl- <x- (2-pyridyl) benzylamide; n " = 1.5330.

Example 2

In a flask a mixture of 14 g oleic acid and 12 g <x (3-pyridyl) benzylamine was heated in a nitrogen stream 45 hours at 160 ⁰ C and stirred. At the same time, the water formed during the reaction is distilled off. The reaction mixture is chromatographed

Purified phisch on silica gel with a solvent mixture of benzene and chloroform. After the solvent has been completely distilled off, 15.4 g (71% of theory) 01eoyl - «- (3-pyridyl) · benzylamide remain; n " = 1.5323.

Example 3

A mixture of 7 g isostearic acid, 4 g «- (2-Thie nyi) -äthyiamine and 0.2 g of p-toluenesulfonic acid in 50 m Xylene is refluxed for 40 hours, wöbe

distill off the water formed during the reaction! will. When the reaction is complete, the reaction 50 ml of diethyl ether are added to the mixture and dilute hydrochloric acid, water and aqueous sodium carbonate are used natlösung and washed again with water. Danad

■ 45 the solution is dried over sodium sulfate Da; Solvent is completely distilled off. 7.2 g (73% of theory) of isostearoyl- <x- (2-thienyl) -ethy / amide remain; for D ³ = 1.5099.

B is ρ ie 1 4
A solution of 1.3 g of linolenic acid in 30 m of diethyl ether is added a solution of 0.8 g '- (2-thie nyl) ethylamine and 1.2 g Dicyclohcxylcarbodiimid it 20 ml of diethyl ether at 0 ⁰ C was added The erhaltcm

S5 mixture is stirred for 15 hours. Then 5 m Glacial acetic acid is added, the mixture obtained is left to stand for 2 stunts and then filtered. The filtrate is mixed dilute hydrochloric acid, water, aqueous sodium carbonate solution and washed again with water unc

then dried over sodium sulfate The solvent is completely removed by distillation. B. 1.5 g (83% of theory) linolenoyl - «- (2nd thienyl) ethylamide; π? - 1.5082.

f »5 Example 5

A mixture of 15 g of linoleic acid methyl ester and 15 { '- (2-thienyl) -phenäthylamin is 70 hours call 15O ⁰ C heated, said arising in the implementation "

Methanol is distilled off. After cooling, the reaction product is mixed with 100 ml of benzene, which Benzene solution washed with dilute hydrochloric acid, aqueous sodium carbonate solution and water and dried over sodium sulfate. The reaction product is purified by chromatography on silica gel. The Solvent is completely distilled off. 193 g (84% of theory) of linoleoyl- «- (2-thienyl) -phenethylamide remain behind from 41 to 42 ° C.

Example 6

IO

A mixture of 20 g whale oil and 25 g <% - (4-pyridyl) benzylamine is heated to 150 ° C. for 80 hours. After cooling, 100 ml of diethyl ether are added to the reaction product, the ether solution is washed with aqueous sodium carbonate solution and water and dried over sodium sulfate. The solvent is then completely distilled off. The reaction product is purified by chromatography on silica gel. A mixture of benzene and chloroform is used as the solvent. The solvent is then completely distilled off. 24 g of a product with a refractive index n " of 1.5396 remain. Elemental analysis shows 79.07% C, 632% H and 15.02% N The IR absorption spectrum shows a band at 3260 cm- '(NH) and a band at 1650 cm-' (CON), from which it follows that the reaction product is the whale oil fatty acid amide of the amine used.

B e i s ρ i e 1 7

A mixture of 24 g of oleic anhydride and 25 g of <x- (2-pyridyl) benzylamine is gradually heated with stirring and finally stirred at 120 ° C. for 4 hours. After cooling, the reaction mixture is treated with diethyl ether, the solution is washed with aqueous sodium carbonate solution and with water and dried over sodium sulfate. The solvent is then distilled off. Subsequently, the reaction product is purified by chromatography on silica gel with a solvent mixture of benzene and chloroform 14.8 g (75% of theory) oleoyl-a- (2-pyridyl) -benzylannide; n ' _D ' = 1.5330.

Example 8

A solution of 21 g of linoleic acid and 7.7 g of triethylamine in 150 ml of toluene is added dropwise at -7 ° C and with stirring with 8.4 g of ethyl chloroformate After stirring for 30 minutes, a solution of 153 g of α- (2-thienyl) phenethylamine in 70 ml of toluene is added dropped in at -5 to -7 ° C. The reaction mixture is 20 minutes at this temperature and then Stirred for 2 hours at room temperature. After standing for 15 hours, the reaction mixture is with dilute hydrochloric acid, water, aqueous sodium carbonate solution and washed again with water, over Sodium sulfate dried and evaporated. 23 g (66% of theory) of crystalline linoleoyl-a- (2-thienyl) -phenethylamide remain from 41 to 42 ° C.

Example 9

A mixture of 10 g safflower oil and 17 g «- (2-thienyl) -phenäthyla: min is heated to 150 ° C in a stream of nitrogen for 85 hours 100 ml of diethyl ether are added to the product. The ether solution becomes more aqueous with dilute hydrochloric acid, water Sodium carbonate solution and washed again with water, dried over sodium sulfate and then evaporated. The reaction product is then chromatographed on silica gel with a solvent mixture purified from petroleum ether and benzene. After the solvent has completely evaporated 21.5 g of a semi-solid substance remain. Elemental analysis gives 77.07% C, 9.52% H, 3.01% N and 6.72% S. The infrared absorption spectrum showed a band at 3260 cm- '(NH) and at 1640 cm-' (CON). It follows that the product is the safflower oil fatty acid amide of the amine used

Example 10

A solution of 23 g of triethylamine and 3.4 g α- (2-Thienyl) ethylamine in 100 ml of diethyl ether is added dropwise at 15 to 20 ° C. with stirring with 8 g Linoleoyl chloride is added. The mixture is stirred for 4 hours at room temperature, then for 15 hours left to stand and then refluxed for 2 hours. After cooling, the reaction mixture is with dilute hydrochloric acid, water, aqueous sodium carbonate solution and again with water washed, dried over sodium sulfate and then evaporated. Finally, the last traces of the Solvent distilled off at 80 "C / 0.1 Torr. 9.0 g (81% of theory) of linoleoyl -« - (2-thienyl) ethylamide; n!> ' - 1.5067.

Example 11

A solution of 2.1 g of triethylamine and 4.0 g of x- (3-pyridyl) benzylamine in 60 ml of diethyl ether is added dropwise and with stirring with 7.1 g of linoleoyl chloride over 1 hour at 20 to 25 ° C. The reaction mixture is worked up as in Example 1. 6.2 g (64% of theory) of linoleoyl - «- (3-pyridyl) benzyamide are obtained; n "- 1.5357.

Example 13

A mixture of 1.5 g of triethylamine and 3.0 g «- (4-Pyridyl) benzylamine in 50 ml of diethyl ether is added dropwise within 40 minutes at 20 to 25 ° C unc 5.4 g of linoleoyl chloride are added while stirring. Since the reaction mixture is prepared according to the example! 1 worked up 5.0 g (69% of theory) of liroleoyl- <x- {4-pyri are obtained dyl) benzylamide; η "« 1.5323.

Claims (1)

Patent claims: 1. Fatty acid amides of the general formula I R ¹ R -CO-NH-CH (D R ²