US3741999A - N-substituted amides of natural fatty acids - Google Patents

N-substituted amides of natural fatty acids Download PDF

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US3741999A
US3741999A US00071205A US3741999DA US3741999A US 3741999 A US3741999 A US 3741999A US 00071205 A US00071205 A US 00071205A US 3741999D A US3741999D A US 3741999DA US 3741999 A US3741999 A US 3741999A
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oil
fatty acid
acid residue
natural
alkyl
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T Seki
K Toki
H Fukushima
Y Nawashiro
H Nakatani
Y Suzuki
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Sumitomo Chemical Co Ltd
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    • 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

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  • N-SUBSTITUTED AMIDES OF NATURAL FATTY ACIDS I Inventors: Takashi Seki, Toyonaka;,Katsuyuki I (Told, Nishinomiya; Hiroshi Nakatani, Toyonaka; Yoshlo Suzuki, Amagasaki; Hideaki Fukushima, Takatsuki; Yoshio Nawasltiro,
  • This invention relates to novel anti-atherosclerosis agents. More particularly, the invention pertains to novel N-substituted natural fatty acid amide derivatives which are useful for lowering the elevated levels of cholesterol or lipids.
  • Atherosclerosis is an adult disease for which there is no known satisfactory cure. Although the cause for atherosclerosis is not yet known in spite of discussions in the academic circles, it has broadly been recognized that one of the most significant histo-pathological manifestations of atherosclerosis is the deposition of cholesterol or lipids in the blood. v
  • the present inventors have found a group of novel compounds which are effective as cholesterol-lowering agents and which are substantially non-toxic.
  • the present invention provides novel N-a-alkyl-benzyl natural fatty acid amides of the formula wherein R is a fatty acid residue ofa naturally occurring oil, said fatty acid having an iodine value of at least 50, and R is C -C alkyl, provided that in case the oil is sesame oil, safflower oil, soybean oil or cuttlefish oil, R is C -C, alkyl.
  • fatty acid residue of a naturally occurring oil refers to fatty acid residues of fatty acids which are present in naturally occurring oils.
  • the naturally occurring oils include vegetable oils, animal oils, etc., such as sesame oil, safflower oil, cuttlefish oil, linseed oil, soybean oil, sunflower oil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil, residual oil (liver oil from which vitamin A has been removed), perilla oil and menuke oil, the preferred examples being safflower oil, linseed oil, soybean oil, corn oil, cottonseed oil, sunflower oil, cuttlefish and sardine oil.
  • a natural oil is hydrolyzed and the resultant natural directly with an amine of the formula (R is as defined before) in the presence of adehydrating agent such as a disubstituted carbodiimide compound, in an aqueous or organic solvent.
  • adehydrating agent such as a disubstituted carbodiimide compound
  • disubstituted carbodiimide compounds are as follows: dialkylcarbodiimides such as diisopropylcarbodiimide and the like: dicycloalkyl carbodiimides such as dicyclohexylcarbodiimides and the like; and diaryl carbodiimides such as diphenylcarbodiimides, dibenzylcarbodiimides and the like.
  • dialkylcarbodiimides such as diisopropylcarbodiimide and the like
  • dicycloalkyl carbodiimides such as dicyclohexylcarbodiimides and the like
  • diaryl carbodiimides such as diphenylcarbodiimides, dibenzylcarbodiimides and the like.
  • carbodiimides other than those specifically mentioned can be employed without any trouble.
  • condensation reaction between a hydrolyzed natural oil and an amine using a carbodiimide proceeds smoothly at room temperature, but when the reaction is vigorously exothermic, if necessary, it may be allowed to cool.
  • organic solvents can be employed as solvent.
  • organic solvents are as follows: ethers such as diethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate, ethyl acetate, and butyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogeno alkanes such as chloroform, carbon tetrachloride and ethylene dichloride; and hydrocarbon solvents such as cyclohexane, n-hexane, petroleum ether', gasoline, benzene and toluene. They are employed alone or in the formv of a mixture thereof in optional proportions.
  • the natural fatty acid, the amine and the disubstituted carbodiimide compound, at least one of which 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 stirred as necessary.
  • To the reaction mixture is added a small portion of acetic acid to decompose theexcess carbodiimide and the urea derivative formed is filtered off to yield the fatty acid amide in the filtrate.
  • a natural oil is reacted with an amine of the aforesaid formula. That is, about l mol. of the oil and l to equivalent mols of the amine are mixed in the absence or presence of solvents, e.g.
  • alcohols such as methanol, ethanol or the like, aromatic hydrocarbones such as benzene, toluene, xylene or the like, halogenoalk-anes such as methylenechloride, chloroform, carbon tetrachlorideor the like, alkenes or alkanes such as petroleum ether, benzine, gasoline, ligroin or cyclohexane, and ethers such as tetrahydrofuran, dioxane and the like, or a mixture thereof, and the mixture is subjected to reaction in the absence or presence of a catalytic amount, or equimolar amount to the amine, or.
  • aromatic hydrocarbones such as benzene, toluene, xylene or the like
  • halogenoalk-anes such as methylenechloride, chloroform, carbon tetrachlorideor the like
  • alkenes or alkanes such as petroleum ether,
  • an auxiliary condensation agent such as an alcoholate oran alkali metal, i.e. lithium methylate, lithium ethylate, sodium methylate, sodium ethylate, potassium-t-butylate and the like, or acidic auxili rx agents, i.e. p-to'lue'nes'ulfonic acid and the like, to
  • the alcohol formed may be removed from the reaction system.
  • a 2004221005 the like to prevent production of undesirable by- 53 ""U ml igfifijg'gf I products and colormg, to yield the ob ective product, 21 'n-C lh a 200-210/0.o4 which can be subjected to a fractional distillation and 15 I: -2 3 Z 32%: Z88: recrystallization method using a petroleum hydrocare 24 1 igh a 19s-2
  • lf alkali alcoholate is used is 'r. 5833:3823; as an auxiliary a ent, conju ated double bond isomers 2'8 i-CJI, b 19a-219/o.o2
  • a l88-220/0.05 R1 r 90 can, a 1s9 221/0.os g; 1 cm, a, 1s9-221/o.0s -C1 1 a 192-222/0.o4 .93 i-cl-l a 192'-220/0.04'
  • N-a-alkylbenzyl natural fatty acid amides of the present invention have excellentcholesterol lowering effects.
  • the effectiveness of the present amides are set forth-as shown in the following test examples.
  • mice were fed on a special diet which was supplemented with cholesterol and bile acids. Blood cholesterol level of the mice had been elevated to 3 to 6 times the normal level. Each amide compound was well mixed to the specifical diet in 1 percent administration and fed orally to the mice for 10 days. At each dose level, 10 or 20 mice were used and serum total cholesterol levels of the blood serum were measured at the end of the experimental period.
  • the extremely low toxicities of the instant amides are also an aspect of the present invention.
  • the cholesterol-lowering agent in this invention may be orally administered.
  • the amount orally administered is 0.1 g. 20 g. per day for a human adult, preferably 0.5 g. 5 g. per day, and the administration may be continued for l-5 months, usually for about 3 months.
  • the amide can be orally administered to a human adult in an amount of 2.0 g. per day for about 3 months.
  • the cholesterol-lowering agent may be employed in any suitable form which is conventional for oral administration. Thus, it may be encased in a capsule, in liquid form, in tabletform, or in powder form.
  • the active compound may be used as such, without being mixed with a carrier, or mixed with or impregnated in a suitable solid carrier, or it may be mixed with a liquid carrier such as an edible oil, preferably those containing linoleic acid. It is also possible to use a mixture of two or more of the acid amides of the invention. It may also be used as mixed with linoleic acid.
  • the content of the acid amide of the composition varies depending upon the kind of carrier used, and the content is adjusted so that the amide is administered to a patient within the indicated dosage range.
  • a compound of the formula wherein R is a fatty acid residue of a naturally occurring oil selected from the group consisting of sesame oil, safflower oil, cuttlefish oil, linseed oil, soybean oil, sunflower oil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil, residual oil, perilla oil and menuke oil, and
  • R is an alkyl group containing l-4 carbon atoms, with the proviso that when R, is a fatty acid residue of sesame oil, safflower oil, soybean oil or cuttlefish oil, R, is an alkyl group containing 2-4 carbon atoms.
  • R is a fatty acid residue of safflower oil, linseed oil, soybean oil, cuttlefish oil or sardine oil.
  • R is a fatty acid residue of linseed oil, sunflower oil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil, residual oil, perilla oil or menuke oil, and R, is methyl.
  • R is a fatty acid residue of sesame oil, safflower oil, soybean oil or cuttlefish oil and R, is alkyl of 2-4 carbon atoms.
  • R is a fatty acid residue of safflower oil and R, is alkyl of 2-4 carbon atoms.

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  • Pharmacology & Pharmacy (AREA)
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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 1 1 1 1 3,741,999 14 1 June 26, 1973 Seki 'et al.
N-SUBSTITUTED AMIDES OF NATURAL FATTY ACIDS I Inventors: Takashi Seki, Toyonaka;,Katsuyuki I (Told, Nishinomiya; Hiroshi Nakatani, Toyonaka; Yoshlo Suzuki, Amagasaki; Hideaki Fukushima, Takatsuki; Yoshio Nawasltiro,
Moriguchi, all of Japan Assignee: Sumitomq Cliemicaltlm, Lt'rL,
Higashi-ku, Qsaigaalapan; Filed: 'se 1.10,1 97o-.
Appl. No.: 71,205"
Related US. Application Data Continuation-impart of Ser. No. 450,534, April 23,
1965, Pat. No. 3,551,462. I
Foreign Application Priority, Data Field of Search 260/404; 424/320,
[56] R rer nees Cited I UNITED STATES PATENTS 3,193,458 7/1965 Shapiro et a1 424/320 2,978,381 4/1961 Freedman et al 424/106 OTHER PUBLICATIONS Andre et al., d-Ricinoleates of a-phenethylamine V 7 etc); (1932) CA 26 pp. 2702-2703 (1932). Hashim et al., Effect of Mixed Fat Formula Feeding etc.; (1959) CA53 p. 7338 (1959).
I Primary Examiner-Lewis Gotts Assistant Examiner-G. l-lollrah Attorney-Wenderoth, Lind and Ponack [571 ABSTRACT Novel Nea-(C -Coalkyl-benzyl natural fatty acid amides of the formula wherein R is a fatty acid residue of a naturally occurring oil such as saffloweroil etc., and R is alkyl of 1-4 carbon atoms having excellent blood cholesterol lowering effects are provided.
5 Claims, No Drauiings This application is a continuation-in-part of Ser. No. 450,534, filed Apr. 23, 3,551,462.
This invention relates to novel anti-atherosclerosis agents. More particularly, the invention pertains to novel N-substituted natural fatty acid amide derivatives which are useful for lowering the elevated levels of cholesterol or lipids.
Atherosclerosis is an adult disease for which there is no known satisfactory cure. Although the cause for atherosclerosis is not yet known in spite of discussions in the academic circles, it has broadly been recognized that one of the most significant histo-pathological manifestations of atherosclerosis is the deposition of cholesterol or lipids in the blood. v
A number of experimental and clinical facts have been reported, which indicate that the reduction of the elevated blood cholesterol or lipid level is considered extremely important for the prevention of atherosclerosis.
The present inventors have found a group of novel compounds which are effective as cholesterol-lowering agents and which are substantially non-toxic.
An object of the presentinvention is to provide N- substituted natural fatty acid amide derivatives usable as anti-atherosclerosis agents having prominent effects and extremely high-admissibility.
Other objects and merits of the invention will be apparent from the following description.
In order to accomplish these objects, the present invention provides novel N-a-alkyl-benzyl natural fatty acid amides of the formula wherein R is a fatty acid residue ofa naturally occurring oil, said fatty acid having an iodine value of at least 50, and R is C -C alkyl, provided that in case the oil is sesame oil, safflower oil, soybean oil or cuttlefish oil, R is C -C, alkyl.
The phrase fatty acid residue of a naturally occurring oil refers to fatty acid residues of fatty acids which are present in naturally occurring oils. Examples of the naturally occurring oils include vegetable oils, animal oils, etc., such as sesame oil, safflower oil, cuttlefish oil, linseed oil, soybean oil, sunflower oil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil, residual oil (liver oil from which vitamin A has been removed), perilla oil and menuke oil, the preferred examples being safflower oil, linseed oil, soybean oil, corn oil, cottonseed oil, sunflower oil, cuttlefish and sardine oil.
The processes for the production of the N-substituted natural fatty acid amides of the present inventon natu rally vary, for example, depending upon the nature of R, and R and the origin of the acid moiety of the amfatty acid is reacted 1965, now US. Pat. No. 5
ides. Owing to their great number it is not possible tqi,
describe all of them in detail, which is in any case un-- necessary since they are all based on conventional or ganic chemistry processes. However, details of typical.
and suitable processes are given below.
A natural oil is hydrolyzed and the resultant natural directly with an amine of the formula (R is as defined before) in the presence of adehydrating agent such as a disubstituted carbodiimide compound, in an aqueous or organic solvent.
Typical examples of disubstituted carbodiimide compounds are as follows: dialkylcarbodiimides such as diisopropylcarbodiimide and the like: dicycloalkyl carbodiimides such as dicyclohexylcarbodiimides and the like; and diaryl carbodiimides such as diphenylcarbodiimides, dibenzylcarbodiimides and the like. Of course, carbodiimides other than those specifically mentioned can be employed without any trouble.
The condensation reaction between a hydrolyzed natural oil and an amine using a carbodiimide proceeds smoothly at room temperature, but when the reaction is vigorously exothermic, if necessary, it may be allowed to cool.
Water and substantially all organic solvents can be employed as solvent. Examples of organic solvents are as follows: ethers such as diethyl ether, tetrahydrofuran and dioxane; esters such as methyl acetate, ethyl acetate, and butyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogeno alkanes such as chloroform, carbon tetrachloride and ethylene dichloride; and hydrocarbon solvents such as cyclohexane, n-hexane, petroleum ether', gasoline, benzene and toluene. They are employed alone or in the formv of a mixture thereof in optional proportions.
The reaction procedure is as follows:
The natural fatty acid, the amine and the disubstituted carbodiimide compound, at least one of which 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 stirred as necessary. To the reaction mixture is added a small portion of acetic acid to decompose theexcess carbodiimide and the urea derivative formed is filtered off to yield the fatty acid amide in the filtrate.
Alternatively, a natural oil is reacted with an amine of the aforesaid formula. That is, about l mol. of the oil and l to equivalent mols of the amine are mixed in the absence or presence of solvents, e.g. alcohols such as methanol, ethanol or the like, aromatic hydrocarbones such as benzene, toluene, xylene or the like, halogenoalk-anes such as methylenechloride, chloroform, carbon tetrachlorideor the like, alkenes or alkanes such as petroleum ether, benzine, gasoline, ligroin or cyclohexane, and ethers such as tetrahydrofuran, dioxane and the like, or a mixture thereof, and the mixture is subjected to reaction in the absence or presence of a catalytic amount, or equimolar amount to the amine, or. an auxiliary condensation agent, such as an alcoholate oran alkali metal, i.e. lithium methylate, lithium ethylate, sodium methylate, sodium ethylate, potassium-t-butylate and the like, or acidic auxili rx agents, i.e. p-to'lue'nes'ulfonic acid and the like, to
yield. the amide derivatives. In this reaction, the alcohol formed may be removed from the reaction system.
It is a matter of course that the reaction will proceed I: :ggjggfg'gg even in the absence of solvents and auxiliary agents. 4 3 199.2 3/0:o5 In case of using amines having a lower boiling point, 2 1: ggg-gigg-g: if necessary, an autoclave may be employed, but in case 7 "mo", 5 1 going/:04 of other amines the reaction mixture is stirred under 8 I 1 -01", b l 2l atmospheric pressure while being heated as necessary, g {gijfijgfij thereby easily yielding the objective amide. 11 J i-Cfl-l. b 199-212/0..o4 In carrying out the reaction. the mixture of reactants b zos'nolo'os l3 Cuttlefish Oll C,H, a 200209/0.05 1s strrred at a suitable temperature of between room 14 a woq g opy temperature and 400C for about 3 hours to a month. lO :2 I: '93 {33-5} 8-8; If necessary, the reaction is carried on in an atmol7 u Z in sphere of an inactive gas such as nitrogen, helium and l8 -61". a 2004221005 the like to prevent production of undesirable by- 53 ""U ml igfifijg'gf I products and colormg, to yield the ob ective product, 21 'n-C lh a 200-210/0.o4 which can be subjected to a fractional distillation and 15 I: -2 3 Z 32%: Z88: recrystallization method using a petroleum hydrocare 24 1 igh a 19s-2|4/o. o4 bon, acetone or the like, or the urea method, to remove 5 g t"- 201424/0-03 saturated fatty acid amides. lf alkali alcoholate is used is 'r. 5833:3823; as an auxiliary a ent, conju ated double bond isomers 2'8 i-CJI, b 19a-219/o.o2
8 8 .1 are partially obtamed. However, the present inventors 20 i3 'g'n' g ggigyg'gi confirmed that saturated andisomerized fatty acid am- 31 min: b 205-22510105 ides cause no undesirable effect on the human body. I ff" g lgg'g flg-gg The process for the production of the amides of the 4 u 1 g g i g 1nvent1on 1s descnbed 1n more detail wrth reference to 35 I n rb 2l -05 the following examples, which are however to be conis v gxgmggg .strued for the purpose of illustration only and not as 38 t-CJL b 200-22l/0.05= 39 corn. oil cl-r. b 200-21 110.03 l1m1t1ng the mventron. 4Q b imam/Q05. 41- n-clll, b 202-21s/o. 03 EXAMPLES l-l22 I s 2o0 -213/0.0s 43 a n-C 11 b 200-2l4/0.06 General procedure I 4 1 min: b 201-2l4/0.05 a. A natural 01] 1s hydrolyzed 1n 1N solut1on of so- 45 v y t-Cr b /0.05 dium hydroxide in methanol and the resulting natural is f y g fggjtggfig fatty acid is treated with urea and methanol to remove 4s n-cnt, b 192-299/aos the saturated fatty. acid. :3 I: g 1 :ggjt lggggg Ten grams of the thus obtained natural fatty acid, an 3 5| a b waltz/0106 a-a lkylbenzylamme and d1cyclohexylcarbod11m1de are. I t-tgt b g l -5538.8: dissolved in benzene and the mixture is allowed to 54 2 3 1 1 stand overnight at room temperature. Acetic acid. is 55 v n -C:1H1 I M-20410.03. added thereto to decompose the excess amount oldicyis :gn" ggg'gfijg'gg 01 1 1 1 I I, 1 clohex-ylcarbodumrde and the m1xture 1s filtered to sep- V 58 i-c u. a 20492141003 arate off the decomposed product. Then the filtrate is. 23 1 62" fig'ggzg'gg I nu I washed successively w1th5 percent hydrochlorrc ac d, 61 pg g Z [grams/(m5vv 5 percent sod1um carbonate aqueous, solution and wag5 -g:|=it a :gg-ggglggg.
. I ia ter, and dried over anhydrous sodium. sulfate Upon 4 u i 8 93,408,005 evaporanon of the solvent, the. residue 15 d1st1lled 1n; 65. i-CJ'I, a l922,09/0.06
66. t-C 1-1 a; 1994191005 vacuo to y1eld N (1 alkylbenzyl natural 01] fatty acid 67 flamh 0 6 by mums/0.02 am1de. I 68. cm. b 185-208/003 b. A natural c1]: and an a-alkylbenzylamine are mixed g3 I: 2 Pigs 8'8; and stirred in an atmosphere of nitrogen ata tempera- 71 1. 3 b g a t ture of 135C to 140C for 40 hours. Then the reaction 5 1 i-CJ'I. b 1s9-2;l6/0.03 mixtureis distilled in vacuo to yield Ni-a-alltylbenzyl sardine 6 62" 8 igg'ggg'gg 1 1 1 il r natural o1l fatty ac1d'am1de. 7s C,H, b 1s4,-21s/o.o3 According to one of the procedures mentioned I: g n :ggfgigjg-gi above, the following ljl-a-alkylbenzyl natural oil fatty 7g I 'I b hi acrd amrdes are obtamed as shown In the followrn 79 t t. b l88-220/0-03 8 Table l 80 C4H11 b l94-225/0.06 I g; cod on (ca l89-220/0104 ,7, l88-2l8/0.03 TABLE 1 as can, b 190 2 10/0.oa
34 b l88-2l2/0.05 60 :2 Il-CJ'l b 192-21.4/0.o5 I i-CJ-h, b 195-2 1 610.06 117 t-CJ'I, b- 2034261005; 1t,-(;0-N11--C11- as menhaden oil x cm a l89-2l9/0.06 s9 cm. a l88-220/0.05 R1 r 90 can, a 1s9 221/0.os g; 1 cm, a, 1s9-221/o.0s -C1 1 a 192-222/0.o4 .93 i-cl-l a 192'-220/0.04' Example RI-CO- R2 Pro- BoilingPojnt 94 t-cili: a l98-224/0.04 No. (natural oil) cedure (C/mmHg) 95 whale-oil CH, 21. vl93--2l8/(1.05 i 96 Cm, a 19o-221/o.06 I sesame oil C 2H5 21 200-2 l0/0.05- 97 n-C fl, a l92 -2l 810.05
98 i-c ll; 'a 194-215/(104 99 n-ciHu a l992l8/0.04 100 i-C H a 200-2 l /0.03 101 t-CJHSI a 202-226/0.06 102 residual oil CH b 194-2 1 7/0.04 103 C2: b 192-220/0.03 104 n-CaH: b 194Zl7/0.04 105 iC:iH1 b l93-220/0.05 106 n-C4Ho b l97-222/0.05 107 i'CJH b l99-223/0.06 108 l-C4Hu b 200226/0.05 109 perilla oil C H l92208/0.05 1 l0 C H; a 190-210/0.05 1 ll n-C H a 190-21 1/0.05 1 12 i-C; H1 a 190213/0.06 113 n-CJ-i a 195215/0.05 1 14 i-CJ'ls a 1962l6/0.06 115 t-C H a 200-2 1 8/002 1 l6 menuke oil CH 8 l842l5/0.06 117 C 11, a 185-2 1 7/007 118 n-C H a 188-218/0.05 1 l9 i-C I-L- a 183-205/0.06 120 1'1'C4Hg a 190-21 1/0.05 121 i-C H a l91-2l2/0.06 122 l-CJ-i a 200222/0.03
As mentioned above, the N-a-alkylbenzyl natural fatty acid amides of the present invention have excellentcholesterol lowering effects. The effectiveness of the present amides are set forth-as shown in the following test examples.
TEST EXAMPLES ll 22 Cholesterol Lowering Effects on Mice Mice were fed on a special diet which was supplemented with cholesterol and bile acids. Blood cholesterol level of the mice had been elevated to 3 to 6 times the normal level. Each amide compound was well mixed to the specifical diet in 1 percent administration and fed orally to the mice for 10 days. At each dose level, 10 or 20 mice were used and serum total cholesterol levels of the blood serum were measured at the end of the experimental period. One group of mice, in
each set of experiment, was given the specifical diet without the test compound and served as control. Mean level of serum total cholesterol of the treated group was expressed as a per cent of that of the control group (blood cholesterol index).
Results are shown in the following Table 2.
Test R,-CO- R Blood Cholesterol Example No. (natural oil) index (71) Control (no drug) 1 100 linoleic acid 75-80 I sesame oil (I -H 40 2 n-C; H 38 3 i-C H; 34 4 n-C H 33 5 i-C H 37 6 t t-C H. 33 7 safflower oil C 11,, 38 8 n-C -,H,- 34 9 i-C -,H,- 35 10 n-C H, 36 l l i-C H 35 12 t-C H 34 I3 cuttlefish oil C H, 41 14 n-C;,H 33 I5 i-C H 34 I6 n-C H. 38 17 i-C H 39 linseed oil oil oil
1 l5 t-C,H, 38 H6 menuke oil CH, 38 1 17 c, 40 l 18 n-C,H, 32' 119 i-C,H, 39 120 n-CJ-l, 38 121 i-CJ-l, 39 122 t-C,H, as
The extremely low toxicities of the instant amides are also an aspect of the present invention.
The cholesterol-lowering agent in this invention may be orally administered. Usually the amount orally administered is 0.1 g. 20 g. per day for a human adult, preferably 0.5 g. 5 g. per day, and the administration may be continued for l-5 months, usually for about 3 months. For example, the amide can be orally administered to a human adult in an amount of 2.0 g. per day for about 3 months. The cholesterol-lowering agent may be employed in any suitable form which is conventional for oral administration. Thus, it may be encased in a capsule, in liquid form, in tabletform, or in powder form. In preparing the agents in these various forms, the active compound may be used as such, without being mixed with a carrier, or mixed with or impregnated in a suitable solid carrier, or it may be mixed with a liquid carrier such as an edible oil, preferably those containing linoleic acid. It is also possible to use a mixture of two or more of the acid amides of the invention. It may also be used as mixed with linoleic acid.
The content of the acid amide of the composition varies depending upon the kind of carrier used, and the content is adjusted so that the amide is administered to a patient within the indicated dosage range.
What is claimed is:
l. A compound of the formula wherein R, is a fatty acid residue of a naturally occurring oil selected from the group consisting of sesame oil, safflower oil, cuttlefish oil, linseed oil, soybean oil, sunflower oil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil, residual oil, perilla oil and menuke oil, and
R, is an alkyl group containing l-4 carbon atoms, with the proviso that when R, is a fatty acid residue of sesame oil, safflower oil, soybean oil or cuttlefish oil, R, is an alkyl group containing 2-4 carbon atoms. 2. A compound according to claim 1, wherein R, is a fatty acid residue of safflower oil, linseed oil, soybean oil, cuttlefish oil or sardine oil.
3. A compound according to claim 1', wherein R, is a fatty acid residue of linseed oil, sunflower oil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil, residual oil, perilla oil or menuke oil, and R, is methyl.
4. A compound according to claim 1, wherein R, is a fatty acid residue of sesame oil, safflower oil, soybean oil or cuttlefish oil and R, is alkyl of 2-4 carbon atoms. 5. A compound according to claim 1, wherein R is a fatty acid residue of safflower oil and R, is alkyl of 2-4 carbon atoms.
1 i II t i

Claims (4)

  1. 2. A compound according to claim 1, wherein R1 is a fatty acid residue of safflower oil, linseed oil, soybean oil, cuttlefish oil or sardine oil.
  2. 3. A compound according to claim 1, wherein R1 is a fatty acid residue of linseed oil, sunflower oil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil, residual oil, perilla oil or menuke oil, and R2 is methyl.
  3. 4. A compound according to claim 1, wherein R1 is a fatty acid residue of sesame oil, safflower oil, soybean oil or cuttlefish oil and R2 is alkyl of 2-4 carbon atoms.
  4. 5. A compound according to claim 1, wherein R1 is a fatty acid residue of safflower oil and R2 is alkyl of 2-4 carbon atoms.
US00071205A 1964-04-28 1970-09-10 N-substituted amides of natural fatty acids Expired - Lifetime US3741999A (en)

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US4115587A (en) * 1976-02-04 1978-09-19 A. H. Robins Company, Inc. Fatty acid amides of norfenfluramine and compositions and methods thereof
US4194002A (en) * 1978-03-29 1980-03-18 Sandoz, Inc. Cholesterol ester-reducing amides of hexahydroindolinols
US4248893A (en) * 1978-12-30 1981-02-03 Sandoz, Inc. Arterial wall cholesterol ester reducing cyclopropanyl-bearing amides
US4544668A (en) * 1983-07-14 1985-10-01 The Procter & Gamble Company Compounds and compositions useful for producing analgesia
US4544669A (en) * 1983-07-14 1985-10-01 The Procter & Gamble Company Compounds and compositions useful for producing analgesia
US4980366A (en) * 1986-08-19 1990-12-25 Warner-Lambert Co. Amide, sulfonamide, urea, carbamate, thiocarbamate, and thiourea derivatives of 4'hydroxybenzylamine having anti-inflammatory and analgesic activity

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US3995059A (en) * 1966-10-04 1976-11-30 Sumitomo Chemical Company, Limited Pharmaceutical compositions containing fatty acid amide derivatives
US4229463A (en) * 1978-02-27 1980-10-21 Sandoz, Inc. Unsaturated fatty acid hydrazides
US4201785A (en) * 1978-02-27 1980-05-06 Sandoz Inc. Cyclopropanyl-bearing hydrazides
US4663353A (en) * 1979-03-06 1987-05-05 The United States Of America As Represented By The Secretary Of Agriculture Antibacterial fatty anilides
DE3276615D1 (en) * 1982-04-08 1987-07-30 Johnson & Johnson Prod Inc Topical acylaminophenols
US4751026A (en) * 1986-03-24 1988-06-14 Warner-Lambert Company Substituted anilides of oleic, linoleic, or linolenic acid as inhibitors of acyl-coa:cholesterol acyltransferase
FR2673625B1 (en) * 1991-03-08 1993-05-07 Adir NOVEL ACYLAMINOPHENOL DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

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US2978381A (en) * 1958-06-20 1961-04-04 Freedman Louis Process and composition for lowering blood serum cholesterol and chylomicron levels
US3193458A (en) * 1961-07-12 1965-07-06 Us Vitamin Pharm Corp Method of lowering blood cholesterol level

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US3219612A (en) * 1963-02-25 1965-11-23 Evald L Skau Vinyl chloride resins and butadiene rubbers with n-acyl derivatives of cyclic imines

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US2978381A (en) * 1958-06-20 1961-04-04 Freedman Louis Process and composition for lowering blood serum cholesterol and chylomicron levels
US3193458A (en) * 1961-07-12 1965-07-06 Us Vitamin Pharm Corp Method of lowering blood cholesterol level

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4115587A (en) * 1976-02-04 1978-09-19 A. H. Robins Company, Inc. Fatty acid amides of norfenfluramine and compositions and methods thereof
US4194002A (en) * 1978-03-29 1980-03-18 Sandoz, Inc. Cholesterol ester-reducing amides of hexahydroindolinols
US4248893A (en) * 1978-12-30 1981-02-03 Sandoz, Inc. Arterial wall cholesterol ester reducing cyclopropanyl-bearing amides
US4544668A (en) * 1983-07-14 1985-10-01 The Procter & Gamble Company Compounds and compositions useful for producing analgesia
US4544669A (en) * 1983-07-14 1985-10-01 The Procter & Gamble Company Compounds and compositions useful for producing analgesia
US4980366A (en) * 1986-08-19 1990-12-25 Warner-Lambert Co. Amide, sulfonamide, urea, carbamate, thiocarbamate, and thiourea derivatives of 4'hydroxybenzylamine having anti-inflammatory and analgesic activity

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US3551462A (en) 1970-12-29
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DE1493049B1 (en) 1971-09-30
CH474478A (en) 1969-06-30
SE334602B (en) 1971-05-03
GB1051286A (en)
NL6505431A (en) 1965-10-29
FR4939M (en) 1967-03-28
FR1602617A (en) 1971-01-04

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