Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09F—NATURAL RESINS; FRENCH POLISH; DRYING-OILS; OIL DRYING AGENTS, i.e. SICCATIVES; TURPENTINE
  • C09F5/00—Obtaining drying-oils

Definitions

• R is a natural fatty acid residue
• 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
• R is bivalent alkylene, oxygen-interrupted bivalent alkylene or oxygen-interrupted bivalent :alkenylene, R having not more than 7 carbon atoms, are excellently suitable
• 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.
• 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.
• the sole group of compouds practically employed nowadays for the purpose comprises unsaturated fatty acids, especially linoleic acid.
• linoleic acid is employed is in its safety or harmlessness to the human body.
• the effectiveness 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.
• 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.
• 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.
• 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
• R is a member selected from the group consisting of hydrogen atom and the radicals described with respect to R
• 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.
• the natural fatty acid amides are superior to
• 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.
• 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.
• 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
• 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.
• 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,
• 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.
• 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.
• 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.
• 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.
• auxiliary agent of condensation In case of the acid halide method, basic compounds are employed in case of necessity as an auxiliary agent of condensation.
• 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.
• 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.
• solvents employed in this method are water; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, esters such as methyl acetate
• reaction temperature 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.
• 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
• 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.
• 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.
• 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.
• an inactive gas such as nitrogen, helium and the like
• conjugated double bond isomer are partially obtained.
• the present invention confirmed that saturated and isomerized fatty acid amides affect on the human body no undesirable effect.
• 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.
• 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 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.--
• A means cyclohexylamine 2.
• B means o-toluidine 3.
• the fatty acids attached with the mark are used after removing saturated fatty acid.
• 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.
• the acid chloride attached with is that from which saturated fatty acids have beeupreviously removed with urea.
• the acid chloride attached is that from which saturated fatty acids have been previously removed by lithium salt methods.
• 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.
• 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.
• 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.
• the oil attached with is treated after hydrolysis with lead salts to remove saturated fatty acids.
• the oil attached with is treated aiter hydrolysis with urea to remove saturated fatty acids.
• the oil attached with is after hydrolysis recrystallized to remove saturated fatty acids.
• 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.
• 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.
• 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 extracted ether layer is washed successively with 5% hydrochloric acid and water, and dried over anhydrous sodium sulfate.
• 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.
• reaction mix- Product Auxiliary agent Temp. B.P. Oil Amine for condensation Solvent .lhour C./mm. Hg
• 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,
• 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 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 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 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.
• 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.
• 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.
• 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.

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• 0
  • NL NL130295D patent/NL130295C/xx active
  • GB GB1051286D patent/GB1051286A/en active Active
• 1965
  • 1965-04-23 US US450534A patent/US3551462A/en not_active Expired - Lifetime
  • 1965-04-23 SE SE05367/65A patent/SE334602B/xx unknown
  • 1965-04-27 BE BE663071D patent/BE663071A/xx unknown
  • 1965-04-27 FR FR14875A patent/FR4939M/fr not_active Expired
  • 1965-04-28 CH CH587865A patent/CH474478A/de not_active IP Right Cessation
  • 1965-04-28 NL NL6505431A patent/NL6505431A/xx unknown
  • 1965-07-12 FR FR1602617D patent/FR1602617A/fr not_active Expired
  • 1965-08-28 DE DE19651493049 patent/DE1493049B1/de not_active Withdrawn
• 1970
  • 1970-09-10 US US00071205A patent/US3741999A/en not_active Expired - Lifetime

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