US3576830A - Amides containing sulfur - Google Patents

Abstract

NEW COMPOUND HAVING CHOLESTEROL LOWERING ACTIVITY. THE COMPOUND HAS THE FORMULA,

R-CO-NH-R''

WHEREIN R IS C13-C25 BRANCHED OR STRAIGHT SATURATED OR UNSATURATED ALIPHATIC GROUP HAVING OH OR NOT, AND R'' IS

-PHENYLENE-S-CH3, -PHENYLENE-S-C2H5, -PHENYLENE-SH,

-PHENYLENE-SN(-I)-C3H7 OR -PHENYLENE-SN(-I)-C4H9

THE COMPOUND IS PREPARED, FOR EXAMPLE, BY REACTING A FATTY ACID RCOOH WITH AN AMINE

NH2-R''

Description

United States Patent Int. Cl. 'C08h9/02, 3/00 US. Cl. 260-4025 2 Claims ABSTRACT OF THE DISCLOSURE New compound having cholesterol lowering activity. The compound has the formula,

RCON/ wherein R is C -C branched or straight saturated or unsaturated aliphatic group having OH or not, and R is The compound is prepared, for example, by reacting a fatty acid RCOOH with an amine 1 RI HN/ The present invention relates to cholesterol-lowering agents. More particularly, it relates to agents which are useful for the lowering of elevated levels of cholesterol'in the blood.

Atherosclerosis, which is a form of simple intimal arteriosclerosis, is an adult disease for which there is no known satisfactory cure. Although the cause of atherosclerosis is not yet known, in spite of discussions in the academic world, it has broadly been recognised that one of the most significant histopathological manifestations of atherosclerosis is the deposition of lipids in the blood. Accordingly, research has been directed to the disturbed metabolism of lipids, and attenuation has been given to the extraordinarily elevated level of cholesterol in the blood.

A number of experimental and clinical facts have been reported which indicate the relationship between atherosclerosis and elevated blood cholesterol level. Hence, the development of agents to reduce the elevated blood cholesterol level is extremely important for the prevention of atherosclerosis.

Concentrated efforts have heretofore been made for the development of such agents for lowering chloresterol and 3,576,830 Patented Apr. 27, 1971 a number of compounds have been tested clinically, but none of them have proved to be completely satisfactory. Some are fairly effective but produce harmful side effects which are not negligible, and others have indaequate effectivenes, so that they require tobe administered in large doses.

A group of compounds practically employed nowadays for the above purpose comprises unsaturated fatty acids, especially linoleic acid. The reason why linoleic acid is employed is because of its harmlessness to the human body. However, its eifectivenes is not very high and it is uncertain and indefinite. Accordingly, large doses are required to obtain at least appreciable efficacy as a cholesterol-lowering agent.

We have found a group of compounds which are elfective as cholesterol-lowering agents and are substantially non-toxic.

In accordance with this invention there is provided a cholesterol-lowering agent comprising an N-substituted fatty acid amide having the formula,

RI RCON/ H wherein R is a C -C branched or straight, saturated or unsaturated, synthetic or natural aliphatic chain having or not having OH group. Examples of RCO are the residues of following fatty acids, in the case of saturated acids, myristic acid, palmitic acid, stearic acid, isostearic acid, arachidic acid, behemic acid, lignoceric acid, cerotic acid and montanic acid; and in the case of unsaturated acids, residues of tsuzuic acid, physetoleic acid myristoleic acid, zoomaric acid, palmitoleic acid, petroselinic acid, oleic acid, elaidic' acid, vaccentic acid, gadoleic acid, erucic acid, brasidic acid, selachloeic acid, linoleic acid, linolenic acid, eleostearic acid, ricinoleic acid, parinaric acid, arachidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, decosapentaenoic acid, hemp-seed oil fatty acid, linseed oil fatty acid, perilla oil fatty acid, styrax oil fatty acid, oiticia oil fatty acid, kaya oil fatty acid, walnut oil fatty acid, poppy-seed oil fatty acid, safflower oil fatty acid, water melon-seed oil fatty acid, soybean oil fatty acid, sunflower oil fatty acid, rice bran oil fatty acid, pumpkin-seed oil fatty acid, kaoliang oil fatty acid, sesame oil fatty acid, corn oil fatty acid, rape oil fatty acid, cottonseed oil fatty acid, olive oil fatty acid, cashew oil fatty acid, tsubaki oil fatty acid, ergot oil fatty acid, castor oil fatty acid, peanut oil fatty acid, palm oil fatty acid, palm kernel oil fatty acid, coconut oil fatty acid, beef tallow fatty acid, lard fatty acid, bone oil fatty acid, horse fat fatty acid, locust oil fatty acid, crystalis oil fatty acid, shark oil fatty acid, cuttlefish oil fatty acid, sardine oil fatty acid, horse-mackerel oil fatty acid, mackerel oil fatty acid, saury pike oil fatty acid, herring oil fatty acid, saurel oil fatty acid, cod oil fatty acid, trout oil fatty acid, gray mullet oil fatty acid, tunny oil fatty acid, menuke oil fatty acid, menhaden oil fatty acid, fiatfish oil fatty acid, eel oil fatty acid, various kinds of whole oil fatty acid, body oil fatty acid, skin oil fatty acid, head oil fatty acid, liver oil fatty acid, residual oil fatty acid and egg oil fatty acid and the like vegitable, land or marine animal oils. In addition on thereto, double bond position isomers or stereoisomers thereof may also be used.

Of the above acids, the natural fatty acid residues may be, if desired, in the form of unsaturated fatty acid residues which have been freed from saturated acid portions according to a suitable method such as, for example, cooling method, urea method, recrystallization method, metal salt method, distillation method or the like.

Next, R' in the aforesaid Formula I are as follows.

SICH: SICHa SIC H -Q 3 S C H Sn, 1C3H Q 8'11, lCaHy Sln, i, tC4Hn S11, 1, t C 4119 For the production of the present N-substituted acid amides may be used any of the processes known for the preparation of acid amides.

For example, (1) a fatty acid of the formula, is made RCOOH to react directly with an amine of the formula,

in the presence of a basic condensing agent, (3) a lower alkyl ester or glyceride of a fatty acid of the formula, RCOOH is made to react directly with the amine of the formula,

R! HN/ in the presence or absence of a solvent and condensing agent or (4) a mixed acid anhydride of a fatty acid of the formula, RCOOH, having the formula,

RCO

wherein R" is an alkyl or hologenoalkyl having 1 to 4 carbons, is made to react with the amine of the formula,

in the presence of a basic condensing catalyst, in the above (1) to (4) processes the R and R is the same meanings as defined before. The processes (1) to (4) will be more fully explained below.

(1) (a) There have already been various researches wherein dicyclohexyl carbodiimide is used in synthesizing polypeptide. But there has never been a report that an amide is synthesized by using such higher fatty acid to produce an antiatherosclerosis agent, and therefore the process of the present invention is significant. Especially, the process of the present invention can be said to be very advantageous because of the fact that the desired product is readily isolated by filtering and separating the urea precipitated when the reaction has been completed, without any special operation and that the said urea can be used again after being regenerated by such treatment as dehydration.

For the di-substituted carbodiimide to be used in the process of the present invention, there may be exemplified dicyclohexylcarbodiimide, diisopropylcarbodiimide, diphenylcarbodiimide and any other dialkyl-, dicyclalkylor di-substituted phenyl-carbodiimide. Any of them is equally useful in the process of the present invention.

In carrying out the process, a fatty acid, a corresponding amide and di-substituted carbodiimide, for example, are separately dissolved in an organic solvent, for example, such aromatic hydrocarbon organic solvent as benzene or toluene, such hydrocarbon solvent as n-hexane, cycloalkane, petroleum ether or gasoline, such ether solvent as dioxane, ether or tetrahydrofuran or such alkyl halide solvent as chloroform, ethylene dichloride or carbon tetrachloride or such ester solvent as methyl, ethyl propyl or butylacetate. These solutions are mixed at once at the room temperature or under cooling when heat generation is severe so as to be of about 1 in the mol ratio, and the mixture is stirred as required and is then allowed to stand at the room temperature for about 3 to 24 hours, whereupon the corresponding urea which is a by-product of the reaction will be precipitated. After the precipitate is filtered off, the desired product will be able to be obtained from the filtrate. Further, the excess di-substituted carbodiimide may be decomposed with acetic acid or the like as required.

The recovered urea is dehydrated and the resulting carbodiimide is usable again for the main reaction.

(b) The above-mentioned fatty acid and amine are dissolved in a suitable solvent such as, benzene, toluene, xylene, chloroform or carbon tetrachloride and the like. To the solution is added sulfuric acid, phenolsulfonic acid, p-toluenesulfonic acid, p-toluenesulfonylchloride, or an acidic or basic ion-exchange resin, e.g. IRA400, IR- 50 or IR-l20 or Amberlist 15, 21, 26 or 27 as a dehydrating agent. Subsequently, the solution is heated using a water separator to separate and remove the water generated. Thereafter, the solvent is removed and the resultant is purified, whereby a desired product can be obtained in a high yield and in a simple manner. Alternatively, the desired object of the present process may sufficiently be achieved by merely heating the solution in the presence of a dehydrating agent, using as the solvent a tertiary organic amine such as pyridine, picoline or lutidine, besides the above-mentioned solvent.

(c) Thermal dehydration process.-The aforesaid fatty acid and amine are heated at about -300 C. for several hours to several ten hours, if necessary in the presence of an acid catalyst such as boric acid, whereby a desired product is obtained. In this case, water generated may be removed out of the reaction system or the reaction can carry out in an autoclave to maintain the higher temperature.

(2) The reaction for condensing an organic amine with an acid halide is also known. However, so far as we know, there has been no report on the production of antiatherosclerosis agents by utilizing this process. We have found that, by using this process, an amide derivative which is useful as an antiatherosclerosis agent can be obtained at a favorable yield under a mild nonoxidative condition.

Even when an excess of such basic condensing agent as such caustic alkali as caustic lithium soda or potash, such alkaline earth hydroxide as calcium or barium hydroxide, such alkali carbonate as lithium, sodium or potassium carbonate, such alkaline earth carbonate as calcium or barium carbonate, such tertiary amine as trimethylamine, dimethylaniline, pyridine, picoline, anion exchange resin or an excess of the starting amine or any of the above mentioned amines is used, the object of the invention will be able to be attained.

As for this solvent in this reaction, is used water, such organic ketone as acetone, methylethyl ketone or methylisobutyl ketone, such ester as methyl acetate, ethyl acetate, propyl acetate or butyl acetate, such other as ethyl ether, propyl ether, tetrahydrofuran or dioxane, such hydrocarbon solvent as n-hexane, cyclohexane, benzene or toluene, such alkyl halide as ethylene dichloride, chloroform or carbon tetrachloride, such tertiary amine as dimethyl formamide, pyridine or picoline or any of the starting material amines as alone or as properly mixed.

Any temperature from the freezing point up to near the boiling point of the solvent used can be applied for the reaction. Further, it is desirable that the reaction is conducted in a stream of such inert gas as nitrogen or helium.

(3) Process using glycerides.The aforesaid oil glyceride and an equimolar amount of an amine are mixed with a basic catalyst such as, sodium methylate, sodium ethylate, potassium butylate, potassium hydroxide or sodium hydroxide and the like, or with an acidic catalyst such as ammonium chloride or boric acid and the like, and the mixture is heated at about 50300 C. for 30 minutes to several ten hours to obtain a desired product. Even in the absence of the basic or acidic catalyst, the desired product canbe obtained in a favorable yield when the amine is used in excess. In this case, the object can be achieved either in the presence or absence of an inert organic solvent.

(b) Process using esters.An ester of the aforesaid fatty acid or of a fatty acid mixture obtained from the aforesaid oils or fats is mixed with an amine, and the mixture is heated at about 100-300 C. for 30 minutes to several ten hours either in the presence or absence of the above-mentioned basic or acidic catalyst and of an inert solvent, whereby the object of the present process can be achieved. In this case, an alcohol formed may be removed out of the reaction system or an autoclave may be used.

The reactions of both processes (a) and (b) mentioned above should be done in an inert gas such as nitrogen to inhibit the formation of peroxides, coloring matters and the like undesirable by-products.

(4) The reaction of mixed anhydride method which is carried out at a low temperature is substantially complete at about 0 C. Unsaturated fatty acid derivatives, in particular, are unstable substances which, under certain conditions undergo oxidation, polymerization, position or geometrical isomerization and the like due to heat and air. Therefore, the process for producing unsaturated fatty acid amide derivatives according to the present invention, which is a low temperature reaction, has found a great significance to attain excellent results.

The solvents employed in the present reaction include eher, dioxane, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, benzene, toluene, xylene, acetone and methylisobutylketone. As the basic materials, organic solvent-soluble tertiary amines such as trimethylamine, triethylamine, dimethylaniline, diethylaniline and pyridine and the like are desirably used. In some cases, however, inorganic bases, such as potassium carbonate and sodium carbonate, or basic ion exchange resins may also be used.

In order to prepare said mixed acid anhydride, lower alkyl haloformate having 1 to 4 carbon atoms in the lower alkyl group is reacted with a fatty acid of the formula, RCOOH wherein R is the same meanings as identified above. Examples of the said lower alkyl haloformate in- I clude chloroformate.

The chloroformates to be employed are methyl chloroformate, ethyl chloroformate, and butyl chloroformate, and the like.

The effectiveness of the compounds was tested by using mice fed on a specific diet which was enriched with cholesterol and bile acids. The blood cholesterol level of the mice had been raised to 3 to 6 times as high as the normal level. The amide compound as well was mixed with the specific diet in an amount of 1%, and continuously administered orally for 8 to 12 days. Then the total cholesterol value in the blood serum of the animals was evaluated. During the tests, unfavourable side effects, such as the prevention of body weight gain and others, were not observed. It is noted that the stated compound is superior to linoleic acid Moreover, in the linoleic acid-administered group, ineffective cases were sometimes observed due to the individual difference of the animals, and the effectiveness varied considerably even in the same individual animal. While, it should be emphasised that no such phenomena were observed in the linoleamide-administered group.

\nother significant effect of the N-substituted acidam1de compounds according to the present invention is to prevent the deposition of cholesterol and fat in the liver, which occurs in animals fed on a diet rich in cholesterol. It seems that the linoleamide compounds improve the declined lipid-metabolism function of the liver. This effectiveess is also favourable, in view of the fact that the emtabolism of lipid mainly relies upon the function of the liver.

, In the administration of linoleic acid, such effectiveness is never observed. The results are shown in Table 1.

The extremely low toxicities of the present linoleamide compounds are illustrated in Table 2, in which the acute Loxigities of some of the present compounds in mice are ste Material mg. percent; man/ g.

Control Linolelc acld R 0 ONH-Q-S on, 200 1, 750

s 0H, RwoNH-Q 209 1, 420

R 0 ONE-Q 199 1, 520

I s 02H,

S 03111 R 0 0 NH@ 187 1, 400

R 0 ONH-Q-S 01H. 190 1, 520

R 0 ONE-Q 222 1, 600

R 0 ONE-@811 209 1, 750

R 0 ONE-Q 212 1, 520

See Notes at end of Table 2.

R =Mackerel oil fatty acid residue. R =Safilower oil fatty acid residue. R =Sardine oil fatty acid residue. R =Isostearic acid residue.

All the products involved in the present invention are novel compounds unknown to the literature.

As is seen from Table 2, no fatal case and no significant toxic symptoms were observed even in such large doses (per os) as 0.5 g. per g., namely 50 g./kg. of the body Weight. Also, no significant toxic symptoms, or fatal cases, were observed when the amides in amounts of 1%, 0.5%

8 Iventional for oral administration. Thus, it may be en cased in a capsule, or it may be 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 an edible oil,

' preferably those contaning linoleic acid. It is also possible to use a mixture of two or more of the N-substituted amides of the invention. It may also be used as mixed with linoleic acid.

The present invention shall now be explained in detail with reference to the following examples which are giwen only for illustration and not for limitation of the invention in any way.

EXAMPLE 1 In ml. of toluene 28 g. of linoleic acid and 12.9 g. of p-aminothioanisole were dissolved. To the solution was added a solution of 21 g. of dicyclohexyl carbodiimide in 20 ml. of toluene, and the mixed solution was allowed to stand overnight. The deposited crystals were removed by filtration, and the filtrate was washed successively with dilute alkali, dilute acid and water, and dried over anhydrous sodium sulfate and was then concentrated to obtain 28.3 g. of a desired product, M.P. 5860 C. (acetone).

Elementary analysis-Calculated (percent): C, 74.81; H, 9.72; N, 3.49. Found (percent): C, 74.82; H, 9.98; N, 3.28.

EXAMPLES 2-9 Reactions were effected in the same manner as in Example 1 to obtain the results as shown in the following table:

0, percent H, percent N, percent Example .P., No. Acid Amine C. Calcd Found Calcd Found Calcd Found 2 Safliower oll acid.. NHT'QS CH 58-70 3 Llnolelc acid NHz- 60-64 75. 52 75.38 10.02 10.39 3. 26 3.17

S C3H1 4 Linolenle acld..-.- NIL-@s 0,115 62-65 76.19 76.06 9.75 10.00 3.17 3.08

5 Mackerel 5115510.. NHz-Q 48-65 l S CH3 C3111 6 Cuttlefish oil acid. NEE-Q 43-57 7 Corn 011 acid NHz- 60-67 s Sardine 5115610--- NHz-QS C 11 40-60 9 Linolelc acid NHrQ-SH (1) 74. 38 74.44 9.62 9. 53 3.61 3.60

1 13.1. 200-205 o./0.05 mm.

or 0.2% in the diet were administered to mice everyday EXAMPLE 10 In ml. of toluene 28 g. of linoleic acid and 12.9 g. of p-aminothioanisole were dissolved. The'solution was incorporated with 0.1 g. of p-toluenesulfonic acid and was then boiled for 16 hours using a water separator. The reaction mixture was washed successively with alkali, acid and water, was dried and concentrated and was then recrystallized from acetone to obtain 27.9 g. of a desired product, M.P. 58-60 C.

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Reae- Reac- Exampie tion tion B.P., Mm. N0. Acid moiety Amine moiety time temp. C. Hg Amide structure 44 Soybean oil ecid..... HzN-Q-S H 1 20 110 188-211 0. 06 Soybean oil ONH-Q-S H 45 Safiiiower oil acid Same as above 20 170 190-209 0. Safiiower oil 0 ONH-Q- s H SH 611 I 46 Sesame 011 acid HzN- 170 196-210 0. 05 Sesame oil CONE-Q v s H I 47 Castor oil acid Same as above 20 170 195-208 0.06 Castor oil CONE-Q 4s Cottonseed oil acid H2NS 11 20 170 200-213 0. 06 Cottonseed oil 0 ONHS H 49 Rice bran oil acid Same as above 20 165 193-208 0. 05 Rice bran 011 C ONH-S H 50 Sunflower oil acid ..d0 20 165 198-211 0. 04 Sunflower oil 0 ONH-Q-S H 51 Linseed oil acid -.do 20 170 .195-208 0. 03 Linseed oil 0 ONHS E an I s11 I I 52 Corn 011 acid EN-Q 20 160 196-217 0. 05 Corn 011 CONE-Q 53 Rapeseed oil acid HzN-Q 20 170 196-216 0. 05 Rape seed oil CONE-Q I SH SH 54 Olive oil acid HzN-Q-S H 20 170 199-219 0. 04 Olive oil 0 ONHQ- s H 55 Cuttlefish oil acid Same as above 20 188-219 0. 05 Cuttlefish oil 0 ONH-Q-S H SH SH I I 56 Sardine oil acid HzN-Q 20 194-217 0.05 Sardine oil OONHQ 57 Mackerel 011 acid Hus-Q-sn 18 170 166-217 0. 06 Mackerel 011 CONHSH 58 Saury pike oii acid Same as above 18 193-211 0.07 Saury pike oil C ON H-Q-S H 59 Herring oil acid HzN-Q 20 175 184-213 0. 06 Herring oil OONH@ SH H 60 Saurel oil acid HzNQ-S H 20 170 188-218 0.05 Seurel 011 o ONH--S H SH SH l I 61 God 011 acid H2N" 20 170 -216 0. 07 God oil CONE-Q 62.....'.. Tunny oil acid HzN-Q-S H 18 170 188-208 0. 05 Tunny oil 0 ONH-Q-S H sn s11 I 1 I 63 Menhaden oil acid HEN-Q 1B 170 100-210 0.05 eiiheden oil CONE-Q j 64 Fletfish 011 acid HzN-Q-S H 20 170 196-213 0. 06 Fietfish oil 0 ONH-Q-s H; 65 Meiiuke oil acid HzN-Q 16 170 196-218 0. 06 Menuke oil CONE-Q I I s11 I SH 1 66 Whale 011 acid HzN-Q-SH 20 165 188-215 0. 05 Whale oil CONE-@811 i 67 Residual oil acid Same as above 20 160 193-218 0. 06 Residual oil GONH-S 1 Boric acid.

19 Example 75 In 50 ml. of anhydrous ether, 29.9 g. of linoleic acid chloride was dissolved. The solution was added dropwise to a mixture of 13.5 g. of o-aminothiophenol, 7 g. of trimethylamine and 100 ml. of anhydrous ether under cooling and stirring at 0-5 C. After the addition, the reac- H, 9.62; N, 3.61. Found (percent): C, 74.57; H, 9.82; N, 3.44.

Examples 76-106 Reactions were done in the same manner as in Example to obtain the results as shown in the preceding table in which:

tion mixture was boiled for 2 hours to complete the reac- Solvents tion. The ether solution was washed successively with a: Ether f: Benzene acid, alkali and water, dried and concentrated, and the b: Dioxane g: Toluene residue was distilled to obtain 32 g. of a desired product, 10 c: Tetrahydrofuran h: Chloroform B.P. 200-209 C./ 0.03 mm. Hg. (1: Acetone i: Dimethylformamide Elementary analysis.-Calculated (percent): C, 74.38; c: Methylisobutylketone k: Water Example 601- B .P. Mm. No. Acid halide X Amine moiety Assistant vent; C. Hg Amide structure 82 Soybean oil acid 01..... HzNSH g 188-213 0. 05 Soybean cii CONH-Q-SH N 83 Safliower oil acid 01..... Same as above N(OHc) h 192-211 0. 05 Safliower oil CONE-@411 sH SH 84 Sesame cii acid 01 rim-Q K2003 e 195-210 0. 04 Sesame oil CONE-Q SH 85 Castor oil acid 01 Same as above K2003 e 195-209 0. 05 Castor oil 0 ONE-G SH SH so Cottonseed cii acid 01. H N- KOH e, k 2011213 0.06 Cottonseed cii CONE-Q 87 Rice bran oil acid 01-.-- HrNSH K 0 0, 0 193-208 0. 06 Rice bran cii o ONE-@SH 88 Sunflower oil acid 01..-. Same as above g 198-213 0. 06 Sunflower oil 0 ONE-@513.

89 Linseed 011 acid 01.. do fl me g 193-214 0. 05 Linseed oil GONH-Q-SH SH SH I 90 Corn 011 acid 01 rim-Q NaOH b, k 195-208 o. 05 Corn 011 CONE-Q 91 Rapeseed oil acid 01-. adv- 3 K20 03 c, 1: 198-218 0. 0s Rapeseed oil 0 ONE- 3 SH SH 92 Olive oil acid 01 HzN-QSH K10 03 e 198-214 0. 04 Olive oil CONE-@511 93 Cuttlefish oil acid CL..- Same as above NaC 03 0 188-221 0. 04 Cuttlefish 011 C ONE-Q-SH s H SIH 94 Sardine oil acid 01 HzN-Q N(Et); a 193-218 0. 05 sardine oil CONE-Q 95 Mackerel oil acid 01..... H1NSH 1] 188-219 0. 05 Mackerel oil GONE-@811 96 saiir pike 011 acid 01... same as above Same g 19cm 0. 05 Saury pike oil 0 ONH-Q-SH 97 Herring 011 acid 01 HzN-Q KOH d 121-214 o. 05 Herring oil CONE-Q l 1 SH SH 98 saurei oil acid 01 H2NSH N(CHi)a g 183-219 0.06 Saurel oil CONHSH Example 801- B.P., Mm. N 0. Acid halide X Amine moiety Assistant vent C. Hg Amide structure SH v v 99 Cod oil acid 01 EN-Q NaOH d, 1: 19am 0. 06 God oil CONE-Q 10o Tunny oil acid 01 lam-@411 NaOH -c,k 187-209 V 0. 05 Tunny oil CONHSH s H s H 101 Menhaden oil acid 01.... ENG KOH b, k 191211 0.04 Menhaden oil CONE-Q 102 Flat fish oil 01 HzN-Q-SH I 1 195-215 0.06 Flat fish oil ONH-Q-SH 103 Menuke oii acid 01 Has-Q Same a 195-218 o. Mennke 011 o ONE-Q 104 Whale oil acid 01 rim-Q43 do I 189-217 0. 04 Whale 011 o ONE-@8121 105 Residual 011 acid Cl Same as above ..do g 200-221 0. 04 Residual oil 0 ONH-Q-SH 106 Samower oil acid 01 do IRA-400 b, k 200-218 0. 04 Safliiower oil 0 ONH-Q-SH Example 107 A mixture of 8.8 g. of safllower oil and 5.9 g. of paminothioanisole was heated at 160 C. for 50 hours to obtain 10.3 g. of a desired product, M.P. 5973 C.

(acetone).

Examples 108-112 Reactions were effected in the same manner as in Example 107 to obtain the results as shown in the following table:

Example 113 A mixture of 8.8 g. of safflower oil, 4.7 g. of o-anilineethylthioether and 0.2 g. of sodium methylate was heated at 130 C. for 3 hours. The reaction mixture was dissolved in ether, and the solution was washed successively with dilute acid, dilute alkali and water and then dried and concentrated to obtain 8.9 g. of a desired product, MP.

48 -62 C. (acetone).

Examples 114-117 Reactions were done in the same manner as in Example 113 to obtain the results as shown in the following table:

fi f Glyeeride Amine 10s Linseed oil NHQ-SOEfi 3846 109 Sunflower oil-....- NEE-Q 52451 110 Sesame oil NHzQ-SCzH;

111 Olive oil Same as above 61-69 112 Sardine oil NHz-Q-SCiHi 46-59 The fatty acid residues of amides obtained in the above reactions are isomers mainly having conjugated double bonds. Example 1 18 A mixture of 29.4 g. of methyl linoleate and 19.3 g.

49-63 of p-aminothioanisole was heated at 160 C. for 60 hours to obtain 32.1 g. of a desired product, M.P. 59-62. C. (acetone).

Elementary analysis.Ca1culated (percent): C, 74.81; H, 9.72; N, 3.49. Found (percent): C, 74.66; H, 9.91; N,

Examples 119-127 H a v. -1.

Reactions were done in the same manner as in Example 118 to obtain the results as shown in the following table:

0, percent H, percent N, percent Oaled Found Calc'd Found Oalcd Found Example M. No. Ester M: methyl Amine 119 Llnoleic acid M--- NHz@S CH 58-60 74. 81 74. 66 9. 72 9. 82 3. 49 3. 21

120 Linolenic acid M- Nile-Q8 131 4850 75. 87 75. 71 9. 60 9. 77 3. 27 3. 09

121 Oleic acid M NHz-@S CH 60-64 75. 18 75. 01 9.87 9. 94 3. 37 3. 21

(3211 8 122 Safliower oil M Nib-Q 48-62 sc m H 123 Saurel 011M NHz-Q 42-58 124 Mackerel oi1M.-.. NHz- 46-66 S OH;

I 125 Cuttlefish oll NH -Q 43-59 126 Sardine oilM NHz-S 04m 48-62 127 Soybean oil NHz-QS 0311, 52-66 Example 128 The fatty acid residues obtained in the above reactions A mixture of 29.4 g of methyl 1i noleate 129 of are mainly isomers having conjugated double bonds.

p-arninothioanisole and 0.5 g. of sodium methylate was Example 132 heated at 130 C. for 3 hours. Thereafter, 31.0 g. of a s' d roduct was obtaine the same anner as 1 21351 315113, M.P. 5860 0? 21mm m E FF l l lfmleate i 18 Elementary analysis.-Calculated (percent): C, 74.81; 'amhne was heated Wlth stlmng at 160 for 90 H, 972; N, 3.49 Found (percent): C, 7471; H, N, hours and the residue was distilled to obtain 35.9 g. of a 3 4 desired product, B.P. 194-206 C./0.05 mm. Hg.

Examples 129-131 Elementary analysis.-Calculated (percent): C, 74.38; Reactions were done in the same manner as in Example H, 9-62; Found (P C, 7444; N,

128 to obtain the results as shown in the following table: H 3.54.

| 13o Corn oil NH2 NaOCH 58-70 131 God 011 NHrQ-SCzH; NaO can, Toluene... 36-50 3, 57 6,830 26 Examples 133-162 Reactions were done in the same manner as in Example 132 to obtain the results as shown in the following table:

B.P. Reaction Reaction 0.! 0, percent H, percent N, percent Ex. temp., time, mm. No. Acid moiety Amine moiety Assistant 0. hr. Hg Calcd Found Calcd Found Oalc'd Found 140 60 74. 38 74. 19 9. 62 9. 58 3. 61 3. 49 133.-.. Methyl 1lnoleate. NH2

134 do NHz--S H 150 60 74. 38 74. 22 9. 62 9. 3. 61 3. 64

l 135.-" Methyl oleate Nm 160 so 73. 99 73.88 10. 09 9. 95 3.60 3.69

I 136-... Methyl isostearate..- NET-Q KotBu 160 5 73. 11 73. 21 10. 55 10.56 3. 58 3. 57

137 d0 NHz-Q NaO CH; 160 I 8 73. 11 73. 21 10. 55 10. 49 3. 58 3.

138 do NHz S H 160 73. 11 73. 20 10. 55 10. 50 3. 58 3. 62

13a.-- Methyl lin0lenate NEH-Q 150 70 74.76 74.67 9.15 9.08 3.63 3.60

l 140.--. Ethyl ester of linman-Q 150 70 seed oil acid.

s H 141. Methyl ester of NH2@ Bone acid- 180 20 safiiower oil acid.

142.--- Safllower 0il NH2- 180 60 Reac- Reaction tion B.P., Example temp., time, CJmrn. N 0. Acid moiety Amine moiety Assistant 0. hr. Hg

143 Saflilower oil NHPQfis H 180 so 144 Methyl ester of soy- Same as above 170 58 199-205/0. 04

been oil acid.

145 Sunflower 011 Nib-Q 170 58 191-215 0. 05

l H S 146 Castor oil Same as above 160 195-213/0. 4

147 Methyl ester of rape- NHz-SH 88 200-212/0. 05

seed oil acid.

148 Cottonseed oil Same as above 60 200-216/0. 06

149 Methyl ester of olive NHFQ 160 60 196208/0.06

oil acid.

Reac- Reaction tion B.P., Example temp., time, C.,mm. No. Acid moiety Amine moiety Assistant 0. hr. Hg

15o Peanut 011 NHz-Q-SH 180 60 195-207 o.os

151 Locust oil NHFQ 20o 52 199-211 11. 07'

152 Crysalis oil NET-Q 200 52 194-214 (106 l as srr

I 153 Shark oil NH2 180 78 196-213/0.06

154 Methyl ester of Same as above 170 72 195-208/0. 07

sardine oil acid.

155 Mackerel oil do 170 000-199/0. 06

SH 156 Methyl ester of NHz- 165 198-222/0.

herring oil acid. 157 Saurel oil Same as above 200 72 188-213/0. 06

I 158 Cod oil NET-Q 140 60 1s2-2o9 o.o5

159 Gray mullet oil NHFQ 145 60 184214l0.06

l SH

I 160 Menhaden 011 man-Q 160 72 1s7-21s o.0s

161 Flatfish 511 NHz-SH 180 72 186-216/0. 05

SH 162 Residual oil NH 200 72 1s4-215 o.03

Example 163 Elementary analysis.--Calculated (percent): C, 74.38; 55 H, 9.62; N, 3.61. Found (percent): C, 74.47; H, 9.61;

To a solution of 14 g. of linoleic acid and 5.5 g. of triethyiamine in 100 cc. of tetrahydrofuran, 5.9 g. of ethyl chloroformate was added dropwise with stirring at to -5 C. After the dropwise addition, the further stirring was continued at -5 C. for additional minutes, and then 6.5 g. of O-SH-aniline was added dropwise at 5 C. Thereafter, the cooling of the reaction system was ceased and the stirring was continued until the temperature was elevated to room temperature. Subsequently, the temperature was gradually elevated and at C., the reaction liquid was stirred for 20 minutes. After cooling the reaction liquid, tetrahydrofuran was removed by distillation under reduced pressure. The residue was dissolved in ether, and the solution was washed successively with cold dilute hydrochloric acid, cold aqueous sodium carbonate and water, and dried over anhydrous sodium carbonate.

After removal of the ether, the residue was distilled in vacuo to obtain 13.9 g. of a desired product, B.P. 210- 215 C./0.02 mm. Hg, yield 64%.

Examples 164-198 In the same manner as in Example 163, 1 mole of a fatty acid and l1.1 moles of a basic substance are dissolved in 7-10 times the total amount of said materials of a solvent. To this solution, 1-1.1 moles of a chloroformate is added dropwise under stirring at -5 to '10 C. After the dropwise addition, the stirring is continued at said temperature for additional 10-30 minutes. Subsequently, 1-1.1 moles of an amine is added dropwise with stirring at said temperature. The reaction is substantially completed in about 10 minutes after the dropwise addition. In some cases, however, the temperature is elevated and the reaction liquid is stirred at room temperature and, if necessary, is heated to 40-50 C. Thereafter, the reaction liquid is subjected to ordinary treatments. According to the above procedures, the compounds shrivn in the following table can be obtained in 40-85% y1e s.

mm m 5 m g m mu db 2 2. AKHEV mw cw l. w 13%.... m HH Ow O WZ {132w 3 A $2 3 m .5 m 2. Q g m g E E 5. F35 21w 3 223 29 afi sfise E0 E0 w O MZ 2 220 a: mo a m a m E m a. Q s E a 5% i6- mo mz 6? 22 3 n:

. mm 8 33-5 EE m 3N E0 mz 3 2222 8T E 8 E0 mz mm 8 & oofi 22 0 mm Q MZ ......E%% 8% 2 2 3 Em m mo mz %BB 5 mm o: m: m; ii. 22E 8 2232 E EE e Eo E0 mz 2 2 85A s: mm 3 mm mm $2 2 3% 8 8822 8 fim "mo mz 8 52 5 m3" $2 3 2 2 2. :fi 8 2 852 s m :gssfi mo mm Q mZ 8 %H .2 we $2 2 2 mg 5 2 2232 fiafign se E6 52 2 6 22 2 8 i 3H 9 8 m3: 8 2 2 x 3 86 6830 E EEEQ EN mo mz 2 220 52 2 mm a; 3 $5 a; $4 858 5 223 5. 28 22 mo ETQ MZ $3 2 m: 8 a m; N: x x. m3 82:32 oo M s afi e fi z "mo mz 2 22 5 m: mm Eac POGO 959m 9060 am P930 mm EE\ 8:535 225 530m AH 3205 2. 3% @205 E04 02 BQEQH Qm .m o 6 Example Assistant Basic B.P., No. Acid moiety Amine moiety O11(zJooR Solvent substance C./mm. Hg

191 Mackerel oil acid NH 3 02H Tetrahydrofuran Trimethylamine 188-217/0. 05

192 Herring 011 acid C211 Benzene. do.

NH S H 193 Saurel oil acid Same as above CH3 Toluene dn- 189-220/0. 04

194 Cod oil acid $11 CH: .do Pyridine 178-218/0. 03

195 Gray mullet oil acid CH3 Chloroform Lutidine 195-219/0. 02

NHz-

l S H 196 Menhadcn oil acid CHa do. do-.. 179208/0. 04

197 Flatllsh oil acid CH3 Dioxane Picoline 200-21510. 05

NH S H 98 Residual oil acid Same as above CH3 Acetone Lutidine 187-209/0. 05

What We claim is:

wherein R is a saturated or unsaturated O -C aliphatic hydrocarbon chain which is unsubstituted or substituted by a hydroxy and R is SCH; SC H S-(normal or iso)C;H1

S-(normal, 150 or tertiary) 04H, or SH which comprises, reacting a fatty acid of the formula, RCOOH, with an amine of the formula,

at a temperature of 130-300 C.

2. A compound of the formula,

RCON/ wherein R is a saturated or unsaturated C -C aliphatic hydrocarbon chain which is unsubstituted or substituted by a hydroxy and R is SCHa S-(normal, iso or tertiary) 0411 or References Cited UNITED STATES PATENTS 4/1937 Felix 260402.5

FOREIGN PATENTS 6/1939 Great Britain 260620 LEON ZITVER, Primary Examiner N. P. MORGENSTERN, Assistant Examiner U.S. Cl. X.R. 424324 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent: No. 3,576,830 Dated April 27, 1971 Invent0r( Toshitsuqu FUKUMARU et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 10, after the first Japanese application, the remaining five other Japanese applications should be listed as follows:

-674/67 filed December 27, 1966; 675/67 filed December 27, 1966; 568/67 filed December 28, 1966 43551/67 filed July 5, 1967,- and 43552/67 filed July\ 5, 1967.

Signed and sealed this 7th day of March 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Atte sting Officer Commissioner of Patents