US3551462A

US3551462A - N-substituted amides of natural fatty acids

Info

Publication number: US3551462A
Application number: US450534A
Authority: US
Inventors: Takashi Seki; Katsuyuki Toki; Hiroshi Nakatani; Yoshio Suzuki; Hideaki Fukushima; Yoshio Nawashiro
Original assignee: Sumitomo Chemical Co Ltd
Current assignee: Sumitomo Chemical Co Ltd
Priority date: 1964-04-28
Filing date: 1965-04-23
Publication date: 1970-12-29
Anticipated expiration: 1987-12-29
Also published as: FR4939M; US3741999A; CH474478A; GB1051286A; NL6505431A; FR1602617A; NL130295C; BE663071A; SE334602B; DE1493049B1

Abstract

Novel N- alpha -(C1-C4)alkyl-benzyl natural fatty acid amides of the formula WHEREIN R1 is a fatty acid residue of a naturally occurring oil such as safflower oil etc., and R2 is alkyl of 1-4 carbon atoms having excellent blood cholesterol lowering effects are provided.

Description

United States Patent .0

3,551,462 N-SUBSTITUTED AMIDES OF NATURAL FATTY ACIDS Takashi Seki, Toyonaka, Katsuyuki Toki, Nishinomiya,

Hiroshi Nakatani, Toyonaka, Yoshio Suzuki, Amagasaki, Hideaki Fukushima, Takatsuki, and Yoshio Nawashiro, Moriguchi, Japan, assignors to Sumitomo Chemical Co., Ltd., Osaka, Japan No Drawing. Filed Apr. 23, 1965, Ser. No. 450,534 Claims priority, application Japan, Apr. 28, 1964, 39/24,061; May 20, 1964, 39/28,284; June 8, 1964, 39/32,324; Aug. 28, 1964, 39/49,073; Sept. 1, 1964, 39/ 49,812; Sept. 5, 1964, 39/ 50,947

Int. Cl. C09f 7/00 US. Cl. 260-404 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula R CR wherein R is a natural fatty acid residue, and R is R is alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, alkylaryl, hydroxyaryl, alkoxyaryl, halogenoaryl, halogenoalkylaryl, alkoxyhalogenoaryl, halogenoalkylhalogenoaryl, aralkyl, alkylaralkyl,- hydroxyaralkyl or alkoxyaralkyl having not more than 36 carbon atoms, R is H or an R radical, and R is bivalent alkylene, oxygen-interrupted bivalent alkylene or oxygen-interrupted bivalent :alkenylene, R having not more than 7 carbon atoms, are excellently suitable for use as agents for reducing elevated cholesterol level in the blood.

The present invention relates to a novel type of cho esterol-lowering agents. More particularly, it relates to agents which are useful for the reduction of the elevated blood cholesterol level.

Atherosclerosis is one of the problems in the adult diseases, which have not come to a satisfactory solution. Although the cause of atherosclerosis has not yet been brought to light in spite of the discussions in the academic world, it has broadly been recognized that one of the most significant histopathological manifestations of atherosclerosis is the deposition of lipids in the blood vessels. Accordingly, the researchers have been directed to the disturbed metabolism of lipids, and attention has been paid to the extraodinarily elevated level of cholesterol in the blood.

A number of experimental and clinical facts have been reported which point out the relationship between atherosclerosis and elevated blood cholesterol level. Hence, the development of agents to reduce elevated blood cholesterol level is one of the most important keys for precaution against or prevention of atherosclerosis.

Concentrated efforts have heretofore been made for the development of such agents for lowering cholesterol, not a few compounds have been tested clinically, but none of them are satisfactory. Some of the cholesterol-lowering agents are fairly excellent in their effectiveness but are inevitably bound hp with harmful side effects which are ice not negligible, and the others are insufiicient in their effectiveness, namely needing administration in abundant doses.

The sole group of compouds practically employed nowadays for the purpose comprises unsaturated fatty acids, especially linoleic acid. The reason why linoleic acid is employed is in its safety or harmlessness to the human body. As regards the effectiveness, however, it is not so high and is uncertain and indefinite. Accordingly, administration in abundant doses is necessary to realize at least appreciable efficacy as cholesterol-lowering agents.

Duly recognizing the disadvantages of the agents to reduce the blood cholesterol level, heretofore proposed and employed, and in order to meet the demand for novel superior agents, we have conducted broad researches as to variety of compounds, and have previously found that N-substituted octadecadienoic acid amide compounds especially N-substituted linoleic acid amide, fulfill the re-' quirements and made patent application in this regard.

The present invention is based on the discovery that natural fatty acid amide derivatives are as effective as linoleic acid amide derivatives concerning the lowering of cholesterol level in blood and the natural fatty acid amide of the present invention is far advantageous from the commercial view point. Such specific biological properties of the natural fatty acid amide derivatives have never been reported before the present invention.

Thus, an object of the present invention is to provide novel type of cholesterol-lowering agents having superior effectiveness which may be used to reduce the elevated level of cholesterol in the blood, without appreciable toxicities during the course of long administration, as compared with the known agents, with low cost and advantageously in commercial point of view. Other objects and advantages would be apparent from the following descriptions.

In order to accomplish these objects the present invention provides a novel group of N-substituted natural fatty acid amides represented by the following general formula:

wherein R stands for a natural fatty acid residue, R is a member selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aryl, alkylaryl, hydroxyaryl, alkoxyaryl, halogenoaryl, halogenoalkylaryl, alkoxyhalogenoaryl, halogenoalkylhalogenoaryl, aralkyl, alkylaralkyl, hydroxyaralkyl and alkoxyaralkyl having not more than 36 total carbon atoms, and R is a member selected from the group consisting of hydrogen atom and the radicals described with respect to R Speaking of the biological activity, the present natural fatty acid amides are superior to the cholesterol-lowering agent and preventing agent of atherosclerosis now commonly employed concerning the cholesterol lowering effect, which was tested by using experimental animals such as mouse, rat and rabbit. In other Words, the natural fatty acid amides of the present invention do not possess abominable toxicity and side effect even when continuously administered for a long period of time to mouse and rat.

For the production of the present natural fatty acid amides, any of the processes known for the amide preparation from oil, its hydrolyzate or functional derivatives of the acid and an amine may be employed.

For example (1) a natural fat is hydrolyzed and the resulting fatty acid is reacted directly with an amine of the formula R H (R is a substituted amino radical as defined before) in the presence of a dehydrating agent such as a disubstituted carbodiimide compound, in an aqueous or organic solvent, (2) a natural fat is hydrolyzed and the resulting fatty acid is converted to fatty acid chloride (Organic Synthesis, vol. 37, p. 66), and the resulting chloride is contacted with at least equimolar amount of the amine in the presence of a basic condensing agent, and (3) a natural oil or lower alkyl esters of natural fatty acid is directly reacted with the amine in the presence or absence of solvent and in the presence of or absence of condensing agent, this is the simplest method.

Examples of the natural oils mentioned herein are as follows: as a vegetable oil, hempseed oil, linseed oil, perilla oil, oiticica oil, kaya oil, walnut oil, poppyseed oil, safflower oil, water melon oil, soybean oil, sunflower oil, rice bran oil, pumpkin oil, kaoliang oil, sesame oil, corn oil, rape oil, cottonseed oil, olive oil, cashew oil, tsubaki oil, ergot oil, castor oil, peanut oil, palm oil, palm kernel oil, coconut oil, and the like oils; as an animal oil, beef tallow, lard, bone oil, horse fat, locust oil, crysalis oil, shark oil, cuttlefish oil, sardine oil, fiatfish oil, horse mackerel oil, mackerel oil, saury pike oil, herring oil, cod oil, trout oil, grey mullet oil, tunny oil, menuke oil, menhaden oil, eel oil, various kinds of whale oils and the like oils or residual oils of land or marine animals, without distinction of origin, for example, body oil, skin oil, head oil, liver oil or egg oil thereof.

In case of a dehydration condensation method using disubstituted carboxiimides, and dehydrogen halide condensation method through acid halide, these oils are hydrolyzed by suitable methods, for example, using a mixture of an alkaline hydroxide and an alcohol, water, acetone or other solvents, these solvents being used alone or as a mixture, thereby to yield a mixture of fatty acids.

The resulting fatty acids are employed for the synthesis of their amides without or after removing most of saturated fatty acids simply and with good efficiency by Winterizing method, urea method, recrystallization method, metal salt method, distillation method or other methods.

In case of an acid halide method, the fatty acids are converted without any trouble in good yield according to the methods using thionyl chloride, phosgene, dimethylformamide and the like, which have been investigated by many investigators. If necessary, it is possible to use bromides or iodides instead of chloride, but not important.

Typical amines of the formula R H (R is as defined before) employed in the present invention are as follows: it is not necessary to say that it is proved by the present inventors to be able to employ other amines, as far as they are primary or secondary amines, without any trouble in proceeding of the present invention, as monoor dialkylamines, such lower alkylamines as monoor dimethylamine, monoor diethylamine, monoor di-nor i-propylamine, and monoor di-n-, ior t-butylamine and such higher alkylamines as monoor didodecylamine, monoor dipalmitylamine and monoor distearylamine; as monoor dialkenylamines, such amines as mono or diallylamine, monoor dioleylamine, monoor dilinoleylamine and monoor dilinolenylamine; as cycloalkylamines or their derivatives, such amines as cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methyl-, N-ethyl-, N-n or i-propyl or N-n, i-, t-butylcyclopentylamine, N- methylor N-ethylcyclohexylamine, N-methyl-, N-ethyl-,

N-nor i-propyl or N-n,i,t-butylcycloheptylamine, N- cyclohexylor N-phenyl-N-cyclohexylamine; lower alkylcycloalkylamine substituted by one or more of methyl ethyl, nor i-propyl or n-, ior t-butyl radical in at least an ortho, meta or para position, hydroxycyclohexylamine substituted by one or more of hydroxy radicals in at least a 2, 3, or 4 position and cycloalkylamine, substituted by one or more of lower alkyl and hydroxy radical at least a 2, 3 or 4 position, lower alkoxycycloalkylamine substituted by methoxy, ethoxy or other alkoxy radicals in at least a 2, 3 or 4 position; as aromatic amines, for example, aniline, diphenylamine, benzylamine, lower alkylaniline substituted by one or more methyl, ethyl, n-, i-propyl and n,i,t-butyl radicals in at least an ortho, meta or para position, N-methylor N-ethyl-amine, hydroxyaniline substituted by one or more hydroxy radicals in at least an ortho, meta or para position, lower alkoxyaniline substituted by one or more of methoxy or ethoxy, n-, i-propoxy, 11-, i-, t-butoxy radical in at least an ortho, meta or para position, halogenoaniline substituted by one or more of fluorine, chlorine, bromine or iodine atom in at least an ortho, meta or para position, trifiuoromethylaniline substituted by one or more of trifluoromethyl radicals in at least an ortho, meta or para position, aniline substituted by one or more of lower alkyl, hydroxy, halogen, lower alkoxy or trifluoromethyl radicals, such as 2,4,6- trimethylaniline and fiuorotoludines, dibenzylamine, lower alkylbenzylamine such as a-methylbenzylamine, u-ethylbenzylamine, a-n,i-propyl, a-n,i,t-butyl and the like, lower alkylbenzylamine substituted by methyl, ethyl, propyl, butyl or other lower alkyl radicals, lower alkoxybenzylamine substituted by methoxy, ethoxy, n-, i-propoxy, n-, i-, t-butoxy or other lower alkoxy radicals in at least an ortho, meta, or para position, hydroxybenzylamine substituted in at least an ortho, meta or para position, and benzylamines substituted by one or more of lower alkyl, lower alkoxy or hydroxy radicals.

In case of the carboxiimide method, the di-substituted carhoxiimide having the following general formula, R N=C=NR wherein R represents a member selected from the group consisting of alkyl, phenyl, cycloalkyl and aralkyl radicals, is employed as condensation agents, thereby to yield fatty acid amides in good yield.

Typical examples of di-substituted carbodiimide are as follows: as dialkylcarbodiimides di-isopropylcarbodiimide and the like, as dicycloalkyl carbodiimides dicyclohexylcarbodiimides and the like, and as diaryl carbodiimides diphenylcarbodiimides, dibenzylcarbodiimides and the like. It is not necessary to say that carbodiimides other than those above-mentioned are employed without any trouble.

The condensation reaction between a hydrolyzed natural fats and an amine using a carbodiimide is well proceeded at room temperature, but when the reaction is vigorously exothermic, if necessary, it may be allowed to cool.

Water and almost all of organic solvents can be employed as a solvent.

They are: ethers such as diethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate, ethyl acetate, ethyl acetate and butyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogenoalkanes such as chloroform, carbon tetrachloride and ethylene dichloride; hydrocarbonic solvents such as cyclohexane, n-hexane, petroleum ether, gasoline, benzene and toluene; and water.

They are employed alone or in the form of a mixture thereof in optional proportion.

The reaction procedure is as follows: The natural fatty acid, the amine and the di-substituted carbodiimide mentioned above, at least one of them is dissolved in a solvent, are mixed at room temperature or under cooling, if required, and the mixture is allowed to stand for 3 to 24 hours while being sitrred at need. T o the reaction mixture is added a small portion of acetic acid to decompose the excess carbodiimide and formed urea derivative is filtered olf thereby to yield fatty acid amides in the filtrate.

In case of the acid halide method, basic compounds are employed in case of necessity as an auxiliary agent of condensation. Typical examples of the auxiliary agent are hydroxide, carbonate or bicarbonate of alkali metal such as lithium, sodium or potassium, or those of alkali earth metal such as calcium or barium; tertiary amines such as pyridine, picoline, lutidine, trimethylamine, triethylamine, dimethylaniline or diethylaniline. An excess amount of reactant amines may also be used as the auxiliary agent.

-It is possible to recover and thereafter to employ the amines above-mentioned and excess amount of reactant amines in the present method. Typical examples of solvents employed in this method are water; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, esters such as methyl acetate, ethyl acetate, propyl acetate or butyl acetate; hydrocarbonic solvents such as nhexane, cyclohexane, benzene and toluene; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenoalkanes such as dichloroethylene, chloroform and carbon tetrachloride; and tertiary amines such as dimethylformamide, pyridine, trimethylamine or the other tertiary amines, or a mixture thereof in optional proportion.

Though the reaction temperature, of course, generally depends on the employed solvent, it is within a temperature range of from 20 C. to near the boiling point of the solvent. The reaction is preferably carried on in an atmosphere of such an inactive gas as nitrogen, helium and the like. Thus, the amide derivatives of the objective products are obtained under relatively mild conditions in high yields and simplicity without oxidation of the reactant.

In case of the direct reaction of the natural oil or lower alkyl ester of natural fatty acid and the amine the reaction method for producing the amide derivatives is as follows: That is, about 1 mol of the said oils and l to 100 equivalent mols of the said amines are mixed in the absence or presence of solvents such alcohols as methanol, ethanol or the like, such aromatic hydrocarbons as benzene, toluene, xylene or the like, such halogenoalkanes as methylenechloride, chloroform, carbon tetrachloride or the like, and such alkenes or alkanes as petroleum ether, benzene, gasoline, ligroin or cyclohexane, such ethers as tetrahyrofuran, dioxane and the like, or a mixture thereof, and the mixture is subjected to the reaction in the absence or presence of catalyst amount or equimolar amount to the amine of an auxiliary agent of condensation, such as alkoholate of alkali metal, i.e. lithium methylate, lithium ethylate, sodium methylate, sodium ethylate, potassium-t-butylate and the like, or acidic auxil iary agents, i.e. p-toluenesulfonic acid and the like, thereby to yield the amide derivat ves. In this reaction, a formal alcohol may be removed from the reaction system.

It is a matter of course that even absence of any solvents and any auxiliary agents can sufliciently accomplish the purpose.

In case of using amines having lower boiling point, if necessary, an autoclave may be employed 'but in case of another amines the reaction mixture is stirred under atmospheric pressure while being heated at need, thereby easily to yield the objective amide.

In carrying out the reaction, a mixture of respective substance is stirred at a suitable temperature of between room'temperature and 400 C. for about 3 hours to a month.

If necessary, the reaction is carried on in an atmosphere of an inactive gas such as nitrogen, helium and the like to prevent from producing undesirable byproducts and coloring, thereby to yield the objective product, which is, at need, subjected to a fractional distillation, recrystallization using a petroleum hydrocarbon, acetone or the like or urea method to remove saturated fatty acid amides. If alkali alcoholate is used as an auxiliary agent, conjugated double bond isomer are partially obtained. However, the present invention confirmed that saturated and isomerized fatty acid amides affect on the human body no undesirable effect.

The process of the invention is described in more detail with reference to the following examples, which are however to be construed for the purpose of illustration and not of the limitation.

EXAMPLE 1 Ten grams of safilower oil fatty acid, from which saturated fatty acids have been roughly removed by treating with urea, 10 -g. of oleylamine and 9 g. of diisopropylcarbodiimide are treated in benzene in a similar way as in Example 1, to yield 10 g. of N-oleyl safflower oil fatty acid amide, which is semi solid and can not be distilled.

EXAMPLE 3 Ten grams of soybean oil fatty acid, from which saturated fatty acids have been roughly removed by low temperature recrystallization method using acetone, 5 g. of allylamine and 9 g. of diphenylcarbodiimide are treated in tetrahydrofuran in a similar way as in Example 1, to yield 8.1 g. of N-allyl soybean oil fatty acid amide, B.P. 190-208" C./0.04 mm. Hg.

EXAMPLE 4 Ten grams of rice bran oil fatty acid, 5 g. of cyclopentylamine and 9 g. of dicyclohexylcarbodiimide are treated in chloroform in similar way as in Example 1 to yield 7.9 g. of N-cyclopentyl rice bran oil fatty acid amide, B.P. 202224 C./0.02 mm. Hg.

EXAMPLE 5 Ten grams of hydrolysed product of sunflower oil, 5 g. of cyclohexylamine and 9 g. of dibenzylcarbodiimide are reacted in carbon tetrachloride to yield 8.1 g. of N-cyclo hexyl sunflower oil fatty acid amide, B.P. 20l-22l C./ 0.03 mm. Hg.

EXAMPLE 6 Ten grams of sesame oil fatty acid, from which saturated fatty acids have been roughly removed by using lead acetate, 5 g. of 4-methylcyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 9.0 g. of N-4-methylcyclohexyl sesame oil fatty acid amide, B.P. 200-215" C./0.04 mm. Hg.

EXAMPLE 7 Ten grams of sesame oil fatty acid, 5 g. of B-methylcyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 8.2 g. of N-3-methylcyclohexyl sesame oil fatty acid amide, B.P. ZOO-221 C./ 0.03 mm. Hg.

EXAMPLE 8 Corn oil is ester-exchanged with methanol and the product is distilled in vacuo and the fraction boiling at -150 C./0.05 mm. Hg. is collected, whereby methyl ester of the saturated fatty acids are roughly removed. Ten grams of the hydrolysate fatty acids are roughly removed. Ten grams of the hydrolysate of this fraction, 5 g. of Z-methylcyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 8.3 g. of

N-Z-methylcyclohexyl corn oil fatty acid amide, B.P. 198- 213 C./0.03 mm. Hg.

EXAMPLE 9 Ten grams of hydrolyzed product of rape oil, g. of 2-ethylcyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 9.0 g. of N-2-ethy1- cyclohexyl rape oil fatty acid amide, B.P. 188-205 C./ 0.02 mm. Hg.

EXAMPLE 10 Ten grams of cottonseed oil fatty acid, 5 g. of 3-isopropylcyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in dioxane to yield 8.8 g. of N-3-isopropylcyclohexyl cottonseed oil fatty acid amide, B.P. 196- 213 C./0.03 mm. Hg.

EXAMPLE 11 Ten grams of olive oil fatty acid, 5 g. of 2-hydroxycyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in dichloroethane to yield 9.3 g. of N-Z-hydroxycyclohexyl olive oil fatty acid amide, B.P. 193-209 C./ 0.02 mm. Hg.

EXAMPLE 12 Ten grams of castor oil fatty acid, 5 g. of 3-hydroxycyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 6.3 g. of N-3-hydroxycyclohexyl castor oil fatty acid amide, B.P. 195-215 C./0.05 mm. Hg.

EXAMPLE 13 Ten grams of peanut oil fatty acid, from which saturated fatty acids have been previously removed by treating with urea, 5 g. of 2-propylcyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in methyl acetate to yield 7.9 g. of N-2-pr0pylcyclohexyl peanut oil fatty acid amide, B.P. 200-219 C./0.06 mm. Hg.

EXAMPLE 14 Ten grams of fish liver oil fatty acid, 5 g. of N-methyl- N-cyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 10.3 g. of N-methyl-N- cyclohexyl fish liver oil fatty acid amide, B.P. 203-215 C./0.02 mm. Hg.

EXAMPLE 15 Ten grams of chrysalid oil fatty acid, 5 g. of cycloheptylarnine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 8.0 g. of N-cycloheptyl chrysalis oil fatty acid amide, B.P. 203-217 C./0.03 mm. Hg.

EXAMPLE 16 Ten grams of shark oil fatty acid, 5 g. of pyrrolidine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 8.3 g. of N-tetramethylene shark oil fatty acid amide, B.P. ZOO-223 C/0.03 mm. Hg.

EXAMPLE 17 Ten grams of cuttlefish oil fatty acid, 5 g. of morpholine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 8.2 g. of cuttlefish oil fatty acid amide derivative having the formula of RiCON O B.P. 199-216 C./0.03 mm. Hg.

EXAMPLE 19 Ten grams of cuttlefish oil fatty acid, from which saturated fatty acids are roughly removed by treating with 8 urea, 5 g. of hexamethyleneimine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 8.0 g. of N-hexamethyleneimino cuttlefish oil fatty acid amide, B.P. 200-218" C./0.02 mm. Hg.

EXAMPLE 20 Ten grams of sardine oil fatty acid, 5 g. of m-toluidine and 9 g. of dicyclohexylcarbodiimide are treated in benzene to yield 7.9 g. of N-m-tolyl sardine oil fatty acid amide, B.P. 197-223" C./0.02 mm. Hg.

EXAMPLE 21 Ten grams of mackerel oil fatty acid, 5 g. of aniline and 9 g. of dicyclohexylcarbodiimide are treated in ether to yield 9.1 g. of N-phenyl mackerel oil fatty acid amide, B.P. 195-203 C./0.03 mm. Hg.

EXAMPLE 22 Ten grams of mackerel oil fatty acid, 5 g. of 2,4,6-trimethylaniline and 9 g. of dicyclohexylcarbodiimide are treated in ether to yield 10 g. of N-2,4,6-trimethylphenyl mackerel oil fatty acid amide, B.P. 197-219 C./ 0.03 mm. Hg.

- EXAMPLE 23 Ten grams of saury pike oil fatty acid, 5 g. of p-fiuoroaniline and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 11 g. of N-p-fluorophenyl saury pike oil fatty acid amide, B.P. 202218 C./0.03 mm. Hg.

EXAMPLE 24 Ten grams of herring oil fatty acid, 5 g. of m-trifiuoromethylaniline and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield N-m-trifiuoromethylphenyl herring oil fatty acid amide, B.P. 200-215 C./ 0.02 mm. Hg.

EXAMPLE 25 Ten grams of whale oil fatty acid, 5 g. of o-anisidine and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 8.3 g. of N-o-methoxyphcnyl whale oil fatty acid amide, B.P. 2092l9 C./0.03 mm. Hg.

EXAMPLE 26 Ten grams of whale oil fatty acid, 5 g. of m-anisidine and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 9.2 g. of N-m-methoxyphenyl Whale oil fatty acid amide, B.P. 207220 C./0.03 mm. Hg.

EXAMPLE 27 Ten grams of sperm head oil fatty acid, 5 g. of p-t-butylaniline and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 9.3 g. of N-p-t-butylphenyl sperm head oil fatty acid amide, B.P. 194-209 C./0.03 mm. Hg.

EXAMPLE 28 Ten grams of sperm blubber oil fatty acid, 5 g. of phydroxyaniline and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 9.5 g. of N-p-hydroxyphenyl sperm blubber oil fatty acid amide, B.P. 201-219 C./ 0.03 mm. Hg.

EXAMPLE 29 Ten grams of razorback oil fatty acid, 5 g. of diphenylamine and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 9.3 g. of N,N-diphenyl razorback oil fatty acid amide, B.P. 209223 C./0.03 mm. Hg.

EXAMPLE 30 Ten grams of fish liver oil fatty acid, 5 g. of N-methylaniline and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 9.4 g. of N-methyl-N-phenyl fish liver oil fatty acid amide, B.P. 200-214 C./0.03 mm. Hg.

EXAMPLE 31 Ten grams of fish liver oil fatty acid, 5 g. of N-methylcyclohexylamine and 9 g. of dicyclohexylcarbodiimide are treated in ethyl ether to yield 10.3 g. of N-methyl-N- 9 cyclohexyl fish liver oil fatty acid amide, B.P. 203-215 C./0.02 mm. Hg.--

Y Y In similar way as in Examples 1 to 31, the following results are obtained.

are dissolved in 50 ml. of benzene and the mixture is allowed to stand overnight at room temperature. Acetic acid is added thereto decompose the excess amount of dicyclohexylcarbodiimide and the mixture is filtered to B.P. M.P. Fatty acid Amine C./mm. Hg C. m)

Example:

32 Cuttlefish oil fatty acid A 200-204/0 04 as (in B 210-21s 0.04 a4 an v A 208-216/0. 04 35 do B 208-218/0. 03 36 Shark oil fatty aeid A 200-205/0.04 37 do B 205-215/0.04 as p p, do. A 200-218/0. 04 3Q 1 do p B 206-218/0. 04 i no"! 1.5000 40 Whale oil fatty acid A 200-211/0. 03 49-51 on 1.4774 41 do B 194-210/0. 03 7-49 1113 1.4866 &2 do! A 200-218/0. 03 no 1.4800 43 Whale oil fatty acid B 193-216/0. 03 H1325 1.4952 44 Linseed oil fatty acid A 200-218/0. 03 50-53 11 1.4888 45 r y do B 204-220/0. 03 47-49 71113 1.5037 4s e035 A 200-218/0. o3 mew 1.4934 47 do. B 211218/0.07 1141 1.5080 48....-., Rape oil fatty acid A 198-213/0. 04 46-50 49 do B 190-223/0. 05 44-50 50 do r A 198-218/0. 07 D 3 1.4830 51 B 208218/0.07 "D25 1.4952 52 Soybean oil fatty acid A 188-211/0. 02 43-45 53 do B 209-220/0. 07 5254 54 do A 188-192/0. 05 no 1.4828 5s B 180-213/0. 01 H024 1 5004 56---, Com oil fatty aeid--.- A 197213/0. 09 57 do B 200-209 0. 0e as I do. A 182208/0.03 m do, B 195-213/(L03 110 1.5019 60 u--- Cottonseed oil fatty acid...,...,--. A 172-184/0. 03 49-50 61 do B 197-203 0. 03 48-49 62 do. A 185-193/0. 02 no 1 4851 as I y I do B 193209/0. 08 71/13 1 5001 640", Beef tallow fatty acid C 200-221/0. 02 40-50 65 Lard fatty acid -L--- D 203-225/0. 02 47-53 NOTE;

1. A means cyclohexylamine 2. B means o-toluidine 3. C means p-ethoxyaniline D means N-ethylaniline E AMPLE 66 In similar way as in Example 66, the following results are obtained.

The fatty acids attached with the mark are used after removing saturated fatty acid.

separate the decomposed product off. Then the filtrate is washed successively with 5% hydrochloric acid, 5% sodium carbonate aqueous solution and Water, and dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue is distilled in vacuo to yield 12. g. of N-a-methylbenzyl soybean oil fatty acid amide, BR 200- 203 C./ 0.04 mm. Hg., n 1.4844.

a se mente Fatty acid Amine Solvent (timid; B ilo=N-B Example No.: 0 8

67 Soybean oil fatty acid Ll. NH2' Benzene 192-208/0. 03 i I I 00113 68 Sesame oil fatty acid NH2- .do 178199/0.02 -CH2 69-; Linseed oil fatty acid; blHrO-OCH; Ethylether 184-210/0. o3 -C r ?H 70 Safllovver 011 fatty aeid NHzCHz-Q Benzene 200204/0.03

; CH: 71 Sunflower oil fatty acid NH2CH2 do 201-205/0.03 i-Pro- Footnotes at end of table.

R" in the dlsubstituted curbodiimide B.P. of the formula Fatty acid Amine Solvent C./mm, Hg RN=C=NR Example No.:

72 Bran oilfatty acid NHaCHz-CH; Ethylethcr 191-204/0.03 3

73 Corn oil fatty acid NH(CH2) Benzene 17B-200/0.04

OCH;

......... Cottonseed oil fatty acid NH2CH2 Tetrahydrofurau 199-210/0.03 -C 5 Cuttlefish oil fatty acid NH2CHz -0 CH Dichloroethylene. 187-219/0.05 i-Pro- 76 Chrysalis oil fatty acid NHzGHz-Q Benzene 191206/0.03

17 Sardine oil fatty acid NH.C -00.H. Dichloroethylene.. 113-21510. o5 -C 7s Cod oilfatty acid NHz-OOCH: Tetrahydrofuran.... lea-20910.04 Q

79 Whale oil fatty acid 5 NH2CHzOH Ethyl ether 185198/0.02

1 The fatty acid attached with is used after roughly removing saturatodjatty acids with the urea method. 3 The fatty acid attached with is used after removing saturated fatty acids with the acetone-recrystallization method. a The fatty acid attached with is u ed after roughly removing saturated fatty acids with the distillation method.

EXAMPLE 80 Ten grams of linseed oil fatty acid chloride is dropped into 40 ml. of methyl isobutyl ketone solution containing 4.5 g. of monoethylamine and 5 g. of potassium carbonate at a temperature of C. while being vigorously stirred. The reaction mixture is allowed to stand overnight and stirred for 2 hours at a temperature of 40 0, followed by filtration to remove the precipitate. The filtrate is evaporated, and the residue is dissolved in ethyl ether, washed successively with hydrochloric acid, aqueous 5% sodium carbonate solution and Water, dried over anhydrous sodium sulfate and evaporated to remove ether. The product thus obtained is distilled in vacuo, thereby to yield 9.8 g. of N-ethyl linseed oil fatty acid amide, B.P. ZOO-213 C./0.05 mm. Hg.

EXAMPLE 81 Ten grams of rice bran oil fatty acid chloride, from which saturated fatty acids have been nearly removed with urea, is dropped into 30 ml. of benzene solution containing 5 g. of allylamine and 6 g. of trimethylamine at a temperature of 10 C. The reaction mixture is treated in similar way as in Example 80. The obtained benzene layer is washed successively with 5% hydrochloric acid, aqueous 5% sodium carbonate solution and Water, and dried and evaporated to remove benzene, thereby to yield 9.3 g. of N-allyl rice bran oil fatty acid amide, B.P. 190214 C./0.03 mm. Hg.

EXAMPLE 82 Ten grams of soybean oil fatty acid chloride is dropped into a mixture of 10 g. of oleylamine and ml. of pyridine at a temperature of 0 C. The reaction mixture is treated in similar way as in Exam-pie 80. The crystals thus obtained are subjected to recrystallization with petroleum ether or acetone, thereby to yield semi-solid N-oleyl soybean oil fatty acid amide.

EXAMPLE 83 Ten grams of safiiower oil fatty acid chloride is dropped into ml. of acetone solution containing 5 g. of cyclopentylamine and 5 g. of potassium carbonate at a temperature of 5 C. The reaction mixture is treated in similar way as in Example 80, thereby to yield 10.1 g. of N-cyclopentyl safflower oil fatty acid amide, B.P. 202-224 C./ 0.02 mm. Hg. If necessary, it is possible to remove saturated amides from the product obtained above by recrystallization from petroleum ether or acetone.

EXAMPLE 84 Ten grams of sunflower oil fatty acid chloride is dropped into 50 ml. of acetone solution containing 3 g. of cyclohexylamine and 2 g. of potassium hydroxide at a temperature of 0 C. The reaction mixture is treated in similar way as in Example 80, thereby to yield 10.3 g. of N-cyclohexyl sunflower oil fatty acid amide, B.P. 200- 218 C./0.03 mm. Hg.

EXAMPLE 85 Ten grams of sesame oil fatty acid bromide, from which saturated fatty acids have been previously removed with lead acetate, is dropped into 40 ml. of tetrahydrofuran solution containing 4 g. of 4-methylcyclohexyiamine and 2 g. of trimethylamine at a temperature of 0 C. The reaction mixture is treated in similar way as in Example 80, thereby to yield 10.5 g. of N-4-methylcyclohexyl sesame oil fatty acid amide, B.P. 203218 C./ 0.03 mm. Hg.

EXAMPLE 86 Corn oil is transesterized with methanol and the resulting methyl ester is fractionated to obtain a fraction of -150 C./0.05 mm. Hg, which is almost freed from the ester of saturated fatty acids and the fraction is hydrolyzed and chlorinated, thereby to obtain the acid chloride. Ten grams of the acid chloride is treated in methyl acetate with 4 g. of 3-methylcyclohexylamine and 4 g. of sodium carbonate to yield 10.2 g. of N-3-methylcyclohexyl corn oil fatty acid amide, B.P. 193-209 C./ 0.03 mm. Hg.

In similar way as in Examples 80 to 85, the following results are obtained.

.iauxiliay agent or con e sa- Acid chloride Amine tion n Solvent CJmnfIig Example No.2 v

87 Rape oil fatty acid chloride.-. 2-ethylcyclohexylamine K2003 Acetone 190-206/0.03 88 cgt gsg at y ac d 3ethy1cyc1o exy1am1n' e".-. NazCOs Methylethylketone 193-210/0,03

o l e. 89 olive oil fatty acid chloride--- Z-hydroxycyclohexylamine Pyridine Pyridine-. 193-210/0.o3

/CH, 90 Castor oil fatty acid ch1oride.. 3-hydroxycyclohexylamine N-CH; Ethyl ether 190-214/0.

CHI

91 Peanutoilfatty acidchloride 2-propylcyciohexylamine N-CzHs n-Hexane 201-219/0,05

92 oi ysal oi atty acid Cycloheptylamine K200 Methyl isobutyl ketone.. 201-22o 0 04 on 93 Shark oil fatty acid chloride.-. Pyrrolidine Pyrrolidiue Toluene 200-220/o,o3 94 .....do2.. Pipendrne.-- 11200 cetone 189-218/0.02 95-; cugt lefigh 011 fatty acid Morpholme K2003 Methyl isobutyl ketone 200-313/0 03 c on e. 96 cu t t lef s h gil fatty acid Hexamcthyleneimine K20 0a. Methyl isobutyl ketone. 200-217/0, 03

c on e. 97 Mackereloilfattyacidchloride. Aniline Aniline Ethyl ether 198209/0,03

/CH3 9s Horse ngickerel oil fatty acid 2,4,6-trimethylaniline N-GHS Cyclohexane 19s-211/0 03 c on e.

99.- Herring oil fatty acid chloride. Benzylamine. Beuzylamine 199-220/0. 04 God oil fatty acid chloride-...- p-Fluoroaniline K 00 2032l9/0. O4 10 Herring oil fatty acid chloride. m-Trifluoromethylaniline 200-213/0. 02 10 saiilrly pke 011 fatty acid N-methylcyclohexylamine.. 198-221/0. 03

c on e. 103 Coilllresglual oil fatty acid Diphenylamine Diphenylamine Toluene 205-219/0.03

c on e.

' /CH3 104 Sang; pile oil fatty acid 2-chloro-5-triiiuoromethylaniline N-CHa .-do 200-215/0, 05

c on e.

105 Saulrly pilke oil fatty acid p-t-Butylaniline- NazCOa Acetone-water 194-215/0. 05

c on e. 106 Whale oil fatty acid chloride.-. o-Anisidine..... K2003 Methylisobutyl ketone. 203288/0. 03 107.-. o mm-Anisidine-... 2C0; 202220/0.03 108--. ---do p 2003 -do. 203-219/0.03 109 pgr m l ead 011 fatty acid N-methylamlme 200; .....do 100-223/0. 03

c on e. 110 Spelrim lzilubber oil fatty acid o-Toluidiue K2005 Methyl ethyl ketone 201-218/0. 03

c on e. 111 Sardine oil fatty acid chloridem-Toluidine rn-Toluidine Benzene 200-216/0. 03 112 Fislllillivgr oil fatty acid o-Chloroaniline KOH Acetone-water 200-215/0. 03

c on e. 113 Cod oil fatty acid chloridem-Chloroaniline KOH .do 195-208/0. 03 114... o p-Bromoaniline. KOH .d 195-210/0.03 115 FlSIIIIIIlYSI' oil fatty acid 3,4dichloroaniline K2CO3 \.cetone 180200/0. 03

c on e. 116 Fislhllivgr oil fatty acid 3,5dichl0roanilino K2C0a Acetone 189-208/0. 03

c on e. 117 coglresiiiual oil fatty acid o-Hydroxyaniline K26 03 .....do 228/0. 02

c or e. 118 Corn oil fatty acid chloridem. 2-mcthoxy-5-chloroaniline K2003 ...do 200-214/0. 03

1 The acid chloride attached with is that from which saturated fatty acids have beeupreviously removed with urea. 2 The acid chloride attached is that from which saturated fatty acids have been previously removed by lithium salt methods.

EXAMPLE 1 l 9 Soybean oil is hydrolyzed in sodium hydroxide methanol under boiling for 1 hour to obtain the fatty acids, which are treated once with urea in methanol to remove saturated fatty acids roughly and treated with thionyl chloride, thereby to obtain soybean oil fatty acid chloride.

Ten grams of thus obtained soybean oil fatty acid chloride is dropped into a benzene solution containing acid amide, B.P. 178-189 C./0.03 mm. Hg, I.V. 125.8. (I.V. means iodine value.)

EXAMPLE 120 Safiiower oil is transesterified with methanol and the methyl ester is distilled, thereby to obtain the methyl ester of safllower oil, hydrolyzed and chlorinated, thereby to obtain safilower oil fatty acid chloride. Ten grams of thus obtained safllower oil fatty acid chloride is dissolved in 20 ml. of tetrahydrofuran and the solution is dropped into a mixture of 6 g. of m-methylbenzylamine, .5 g. of sodium carbonate and 50 ml. of methyl isobutyl ketone at a temperature of 0 C. to 3 C. while being stirred. The reaction mixture is treated in similar way as in Example 119, thereby to obtain 12.1 g. of N-m-methylbenzyl safilower oil fatty acid amide, B.P. 200208 C./0.02 mm. Hg, I.V. 123.5.

In similar way as in Examples 119 and 120, the following results are obtained.

Auxiliary agent for B.P. Oil Amine Solvent condensation C./mm. Hg

Example No.:

(i) CH 121 Corn 011 N1r2C Acetone K200i 188204/0.04

/CH 122 Linseed oil NHiC -ocin Benzene N-CH; 192206/0.05

02135 123 Cottonseed oil NHz-O-OCzIfi Tetrahydroi'uran N\ 192-190/006 C II 124 Cuttlefish on NH |JH Benzene NHzCH- 201-216/0.03

CH3 CH;

125 Rice bran oil NH(CH2) Toluene NH( CHZQ) 178-196/0. 02

126 Chrysalis oil NH2CH2 Methyl isobutyl ketone K200 169193/0. 01

127 God 011 NHZCHP -CH3 do K 191-203/0. 02

CZHB

128 Sharkwil NH2CH2- Benzene N-CzH 190200/0.02

/CH; 129 Sardine oil NHzCHz-O 0H3 Acetone N\ 190-20310. 03

130 Cod residual oil NHzCHz- Pyridine Pyridine 188206I0.03

CH 131 Whale oil NHzCH2- Benzene Pyridine 178211/0.02

132 Plaice oil NHzCHz-Q-OCzHr Pyridine Pyridine 181-205/0.03

1 The oil attached with is treated after hydrolysis with lead salts to remove saturated fatty acids. 2 The oil attached with is treated aiter hydrolysis with urea to remove saturated fatty acids. 3 The oil attached with is after hydrolysis recrystallized to remove saturated fatty acids.

EXAMPLE 133 Ten grams of linseed oil and g. of methylamine are stirred in an autoclave at room temperature for 240 hours.

After the reaction is over, the reaction mixture is poured into a mixture of 1 N hydrochloric acid and ice, and subjected to extraction with ethyl ether.

The ether layer is washed successively with 5% hydrochloric acid, 5% sodium carbonate aqueous solution and water, and then dried over sodium sulfate. Upon evaporation of ether, the residue is subjected to fractional distillation in vacuo, thereby to yield 8.9 g. of N-methyl linseed oil fatty acid amide, B.P. 178-190" C./0.03 mm. Hg, LR. 1,650 cm. (LR. means wave number of the infrared absorption spectrum.)

EXAMPLE 134 Twenty grams of linseed oil and 10 g. of cyclohexylamine are stirred in an atmosphere of nitrogen for 70 hours at a temperature of 145 C. to 150 C. while being heated. After the reaction is over, the reaction mixture is poured into a mixture of 1 N hydrochloric acid and ice, and subjected to extraction with ethyl ether. The ether layer is washed successively with 5% hydrochloric acid, 5% sodium carbonate aqueous solution and water, and dried over anhydrous sodium sulfate.

Upon evaporation of ethyl ether, the residue is sub jected to careful fractional distillation, thereby to yield 18.2 g. of N-cyclohexyl linseed oil fatty acid amide, B.P. 195208 C./0.03 mm. Hg.

EXAMPLE Ten grams of safiiower oil and 5 g. of o-toluidirie are added into a solution of 50 ml. of anhydrous benzene and sodium mcthylate which is prepared from 1 g. of sodium, and the mixture is stirred in an atmosphere of nitrogen for 5 hours under boiling, and then the reaction mixture is carefully poured into a mixture of 1 N hydrochloric acid and ice.

The solution is treated in similar way in Example 133 or 134, thereby to yield 8.1 g. of N-Z-methylphenyl saffiower oil fatty acid amide, B.P. 183-215 C./ 0.03 mm. Hg.

This product is dissolved in petroleum ether and subjected to recrystallization to remove impurities, thereby to yield the product having iodine value of 130.2.

1 7 EXAMPLE 136 Ten grams of soybean oil and g. of piperidiue are stirred in an autoclave for 50 hours at a temperature of 200 C.

The reaction mixture is treated in similar Way as in Example 133, thereby to yield 7.3 g. of N-pentamethylene soybean oil fatty acid amide, B.P. 176213 C./0.03 mm. Hg.

EXAMPLE 137 Ten grams of rice bran oil and g. of 2,4,6-trimethylaniline and sodium methylate which is prepared from 1.3 g. of sodium, are stirred in toluene for about 5 hours under boiling, while the formed methanol is continuously removed from the reaction system with rectification column. The reaction mixture is treated in similar way as in Example 133, thereby to yield 9.2 g. of N-2,4,6-trimethylphenyl rice bran oil fatty acid amide, B.P. 181- 204 C./0.02 mm. Hg.

EXAMPLE 138 Ten grams of safflower oil and 8 g. of allylamine are stirred in an autoclave for 60 hours at a temperature of 100 C.

The reaction mixture is treated in similar way as in Example 133, thereby to yield 6.9 g. of N-allyl safilower oil fatty acid amide, B.P. 185199 C./0.02 mm. Hg.

In similar way as in Examples 133 to 138, the following results are obtained.

The extracted ether layer is washed successively with 5% hydrochloric acid and water, and dried over anhydrous sodium sulfate.

Upon evaporation of ether, the residue is subjected to distillation, thereby to yield 23 g. of N-4-methoxycyclohexyl cottenseed oil fatty acid amide, B.P. 189-203" C./0.03 mm. Hg. 11 1.4838.

EXAMPLE 173 acetone to yield the product having M.P. C. to 34 C., I.V. 135.

EXAMPLE 174 Twenty grams of corn oil and 20 g. of diben zylamine 25 are dissolved in 100 ml. of toluene and 5.5 g. of sodium methylate is added thereto.

The solution is stirred at a temperature of 90 C. to 100 C. 'for about 7 hours, While the formed methanol is removed from reaction system. Then the reaction mix- Product Auxiliary agent Temp. B.P., Oil Amine for condensation Solvent .lhour C./mm. Hg

Example No.:

139 Linseed oil Diethylamine 180-194/0. 07 140 safflower 011.... Palmitylamine.-. 141.-. ..d0 Oleylamine 142 Soybean 011.. Allylamine 03 143 sunflower oil. Cye1openty1am1ne 189-206/0. 03 Rice bran oil- Z-methylcyclohexylam 200213/0. 03 Sesame oil. 3-ethylcyclohexylamine 193-214/0. 03 Corn 011..-. N-methylcyclohexylamine. KO tCiEle 199-219/0. 04 147.-. Rape oil 2-hydr0xycyclohexylamine 190212/0. 03 148-.. Cottonseed oil 2,6-d'm1ethylcyclohexylarnine.. p-Toluene 191-221/0. 03

' sulfonic acid.

Tsubaki 011 2-isopropyleyclohexylamine 190-217/0. 03 Castor oil- 4-hydroxycyclohexylamine 187-209/0. 04 Peanut 011...- Pyrrolidine 197-203/0. 07 Chrysalis oil Hexmethyleneimina. 195-206/0. 06 Shark oil N-methylaniline 205-219/0. 07 154.-. Cuttlefish oil Dlphenylamine. 201-220/(). 03 155.. Sardine oil. 4-t-butylamiline 200-213 /0. 03 156 Mackerel oil.. 2-chloro-6-methylaniline.. 195-206/0. 04 Saury pike oi 2-methoxy-5-eh1oroaniline 189-203/0. 02 Herring oil..- 3,4-dichloroaniline 193212/0. 02 Horse mackerel oil o-Chloroaniline.. 190-203/0. 04 God oil p-Brom0ani1ine 192209/0. 03 God liver oil o-Hydroxyaniline 194-211/0 03 God residual oil m-Anisidine 199-208/0 02 M enhaden oil o-Anisidine p-Fluoroaniline m-Toluidiue Mackerel 0 2-rnethyl-4-fiuoroaniline. 168... Saury pike oil Djallylamine 178-191/0. 03 169... Whale oil p-Anisidine 193209/(). 03 170 do Cycloheptylaminc o do 189-207/0.

1 The reaction is proceeded in an autoclave. Z Impossible to distil.

EXAMPLE 171 Twenty grams of linseed oil and 10 g. of 2-methoxycyclohexylamine are mixed and stirred in an atmosphere of nitrogen at a temperature of 135 C. to 140 C. for hours. Then the reaction mixture is distilled in vacuo, thereby to yield 25 g. of N-Z-methoxycyclohexyl linseed oil fatty acid amide, B.P. 200-209 C./0.02 mm. Hg,

) LR. 1650 cm.-

EXAMPLE 172 ture is treated in similar Way as in Example 172 thereby to yield 20 g. of N,N-dibenzyl corn oil fatty acid amide, B.P. 190-212 C./0.02 mm. Hg.

EXAMPLE 175 Twenty grams of sesame oil and 10 g. of a-methyh benzylamine are treated in similar way as in Example 171, thereby to yield 23 g. of N-a-methylbenzyl sesame oil fatty acid amide, B.P. 188211 C./0.02 mm. Hg.

EXAMPLE 176 Twenty grams of sunflower oil and 10 g. of o-methylbenzylamine are treated in similar Way as in Example 171, thereby to yield 23 g. of N-o-methylbenzyl sunflower oil fatty acid amide, B.P. 188-210 C./0.03 mm. Hg.

EXAMPLE 177 Twenty grams of cuttlefish oil and m-methylbenzylamine are treated in similar way as in Example 171,

19 thereby to yield 21 g. of N-m-methylbenzyl cuttlefish oil fatty acid amide, B.P. 191-223 C./0.03 mm. Hg, 11 1.5130.

EXAMPLE 178 Twenty grams of shark oil and 10 g. of p-methyl benzylamine are treated in similar way as in Example 171, thereby to yield 23 g. of N-p-methylbenzyl shark oil fatty acid aimde, B.P. 195-216 C./0.03 mm. Hg.

EXAMPLE 179 Twenty grams of sardine oil and 10 g. of o-methoxybenzylamine are treated in similar way as in Example 171, thereby to yield 22 g. of N-o-methoxybenzyl sardine oil fatty acid amide, B.P. l99224 C./0.06 mm. Hg.

EXAMPLE 180 Twenty grams of whale oil and 10 g. of o-hydroxybenzylamine are treated in similar way as in Example 171, thereby to yield 23 g. of N-o-hydroxybenzyl whale oil fatty acid amide, B.P. 179-203 C./ 0.03 mm. Hg.

EXAMPLE 182 Twenty grams of flatfish oil and 10 g. of m-methoxycyclohexylamine are treated in similar way as in Example 171, thereby to yield 22 g. of N-m-methoxycyclohexyl flatfish oil fatty acid amide, B.P. 188211 C./ 0.03 mm. Hg.

EXAMPLE 183 A mixture of 10 g. of methyl ester of safflower oil fatty acid and g. of cyclohexylamine is treated in similar way as in Example 171, thereby to yield g. of N-cyclo- =hexyl safflower oil fatty acid amide, B.P. 1862l0 C./ 0.02 mm. Hg.

EXAMPLE 184 A mxture of 10 g. of methyl ester of cuttlefish oil fatty acid, from which saturated fatty acid has been roughly removed with urea and methanol, and 5 g. of a-methylbenzylamine is treated in similar way as in Example 171, thereby to yield 10 g. of N-(u-methylbenzyl) cuttlefish oilf'atty acid amide, B.P. 178-204 C./0.02 mm. Hg.

EXAMPLE 185 Blood cholesterol indexes (10 days) Fatty acid amide 1% 0. 2% derivatives of adminadmin- Example No. istered istered None Linoleie acid Blood cholesterol indexes (10 days) Fatty acid amide 1 0. 2 derivatives of admiZ admig Example N o. istered istered The effectiveness of these compounds were tested in mice which were fed a synthetic diet enriched with cholesterol and bile acids. The serum cholesterol level of the mice had been elevated 3 to 6 times the normal level. The natural fatty acid amide derivatives were well mixed in the synthetic diet in 1% or 0.2% amount, and fed ad libitum for a 10 day period. Then the total cholesterol value in the blood serum of the animals was determined. The value was calculated as a percentage of the serum cholesterol level of a simultaneous control group to obtain the blood cholesterol index.

The extremely low toxicities of the present fatty acid amide compounds, which are one of the features of the present invention, were confirmed by acute and chronic toxicity studies carried out on laboratory animals. As a result of the acute toxicity test, it was found that none of these compounds has any significant toxic effect on mice even when administered in such dosages as 50 g./kg. of the body weight. In the chronic toxicity test, no significant toxic eifect or mortality was observed when rats were placed on a commercial diet supplemented with N-cyclohexyl safliower oil fatty acid amide or N- cyclohexyl sardine oil fatty acid amide at levels of 2%, 1% or 0.5% for 6 months. There was no observed difference in body weight gain compared with that of the control group and no detectable change was found upon hematological and histological examination.

The cholesterol-lowering agent of this invention may be orally administered. Usually the oral dose is 0.1-20 g. per day, preferably 0.5-5 g. per day and the administration may be continued for 1-5 months, usually for about 3 months. The cholesterol-lowering agent may be in any suitable form 'which is conventional for oral administration. Thus, it may be encased in a capsule, in a liquid form, in a tablet form, or in a powder form.

In preparing the agents in these various forms, the active compound may be mixed with or impregnated in a suitable solid carrier, or it may be mixed with a liquid carrier such as edible oil, preferably those containing linoleic acid. It is also possible to use a mixture of two or more kinds of the N-substituted natural fatty acid amide of the invention.

What we claim is:

1. An N-substituted natural fatty acid amide represented by the formula References Cited UNITED STATES PATENTS 7/1939 Bousquet et a1. 260-294.7E 7/ 193,9 Bousquet 260-294.7E

22 3,248,396 4/1966 Shau et al. 260-2393 3,250,794 5/1966 Mod et a1 260239B 2,290,411 7/1942 De Groote et a1. 252341 3,426,025 2/1969 Smeltz 260-551 OTHER REFERENCES Andre et a1.: d-Ricinoleates of a-Phenylethylamine (1932), CA 26, pp. 2702-03. Hashim et al.: Effect of Mixed Fat Formula Feeding Etc. (1959), CA 53, p. 7338.

Ejsmont et a1.: The Influence of Diet on the Cholesterol Level Etc, (1960), CA 54, p. 25, 108.

Sumitomo Chem, N-Subs. Nat. Fat Acid Amides Etc. (1965), CA 64, pp. 14, 137-39.

Nakatani: The Eifect of N-Cyclohexyl Linoleamide Etc. (1966), CA 66, p. 53, 363; No. 53, 367u.

LEWIS GOTTS, Primary Examiner G. HOLLRAH, Assistant Examiner US. Cl. X.R.