US3576830A - Amides containing sulfur - Google Patents

Amides containing sulfur Download PDF

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Publication number
US3576830A
US3576830A US658634A US3576830DA US3576830A US 3576830 A US3576830 A US 3576830A US 658634 A US658634 A US 658634A US 3576830D A US3576830D A US 3576830DA US 3576830 A US3576830 A US 3576830A
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United States
Prior art keywords
acid
oil
fatty acid
oil fatty
amine
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US658634A
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English (en)
Inventor
Toshitsugu Fukumaru
Noritaka Hamma
Hiroshi Nakatani
Hideaki Fukushima
Katsuyuki Toki
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines

Definitions

  • 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.
  • 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 group of compounds practically employed nowadays for the above purpose comprises unsaturated fatty acids, especially linoleic acid.
  • linoleic acid is employed because of its harmlessness to the human body.
  • 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.
  • a cholesterol-lowering agent comprising an N-substituted fatty acid amide having the formula
  • R is a C -C branched or straight, saturated or unsaturated, synthetic or natural aliphatic chain having or not having OH group.
  • 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, arachi
  • 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.
  • 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
  • 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.
  • a fatty acid of the formula is made RCOOH to react directly with an amine of the formula
  • R" is an alkyl or hologenoalkyl having 1 to 4 carbons, is made to react with the amine of the formula
  • di-substituted carbodiimide 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.
  • a fatty acid, a corresponding amide and di-substituted carbodiimide 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.
  • 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 tetrachlor
  • the recovered urea is dehydrated and the resulting carbodiimide is usable again for the main reaction.
  • 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.
  • 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.
  • 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.
  • organic ketone as acetone, methylethyl ketone or methylisobutyl ketone
  • ester as methyl acetate, ethyl acetate, propy
  • 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.
  • 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.
  • organic solvent-soluble tertiary amines such as trimethylamine, triethylamine, dimethylaniline, diethylaniline and pyridine and the like are desirably used.
  • inorganic bases such as potassium carbonate and sodium carbonate, or basic ion exchange resins may also be used.
  • 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.
  • R is the same meanings as identified above.
  • Examples of the said lower alkyl haloformate in- I clude chloroformate.
  • 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.
  • 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.
  • N-substituted acidam1de compounds according to the present invention ⁇ 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.
  • 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.
  • R Mackerel oil fatty acid residue.
  • R Safilower oil fatty acid residue.
  • R Sardine oil fatty acid residue.
  • R Isostearic acid residue.
  • 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,
  • 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).
  • 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.
  • Acid halide X Amine moiety Assistant vent; C. Hg Amide structure 82 Soybean oil acid 017-8 HzNSH g 188-213 0. 05 Soybean cii CONH-Q-SH N 83 Safliower oil acid 017-8 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.
  • 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.
  • 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).
  • herring oil acid 157 Saurel oil Same as above 200 72 188-213/0. 06
  • 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.
  • 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,
  • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Fats And Perfumes (AREA)
US658634A 1966-08-12 1967-08-07 Amides containing sulfur Expired - Lifetime US3576830A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP5317066 1966-08-12
JP67567 1966-12-27
JP67467 1966-12-27
JP56867 1966-12-28
JP4355167 1967-07-05
JP4355267 1967-07-05

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US (1) US3576830A (de)
BE (1) BE702623A (de)
CH (1) CH508607A (de)
DE (1) DE1618935A1 (de)
FI (1) FI47882C (de)
FR (2) FR7586M (de)
GB (1) GB1201631A (de)
NL (1) NL6711100A (de)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6426365B1 (en) 1997-02-12 2002-07-30 Japan Tobacco Inc. CETP activity inhibitors
US20040225018A1 (en) * 2003-03-17 2004-11-11 Japan Tobacco Inc. Pharmaceutical compositions of CETP inhibitors
US20040242683A1 (en) * 2003-03-17 2004-12-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl] amino)phenyl] 2-methylpropanethioate
US20050020668A1 (en) * 2003-05-02 2005-01-27 Japan Tobacco Inc. Combination comprising S-[2-([[1-(2-ethylbutyl)cyclohexyl] carbonyl]amino)phenyl] 2-methylpropanethioate and an HMG CoA reductase inhibitor
US20050059810A1 (en) * 2002-08-30 2005-03-17 Japan Tobacco Inc Dibenzylamine compound and medicinal use thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1268082A (en) * 1969-08-08 1972-03-22 Orsymonde Improvements in or relating to bis-(carboxy-alkylene-thio)-decanes
DE3064904D1 (en) * 1979-06-13 1983-10-27 Nat Res Dev A process for electrochemical additions to alkenes

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6753346B2 (en) 1997-02-12 2004-06-22 Japan Tobacco Inc. CETP activity inhibitor
US9000045B2 (en) 1997-02-12 2015-04-07 Japan Tobacco Inc. CETP activity inhibitors
US20040229957A1 (en) * 1997-02-12 2004-11-18 Japan Tobacco Inc. CETP activity inhibitors
US6426365B1 (en) 1997-02-12 2002-07-30 Japan Tobacco Inc. CETP activity inhibitors
US7271196B2 (en) 1997-02-12 2007-09-18 Japan Tabacco Inc. CETP activity inhibitors
US20100197736A1 (en) * 1997-02-12 2010-08-05 Japan Tobacco Inc. Cetp activity inhibitors
US20080027109A1 (en) * 1997-02-12 2008-01-31 Japan Tobacco Inc. CETP Activity Inhibitors
US20080146620A1 (en) * 2002-08-30 2008-06-19 Japan Tobacco Inc. Dibenzylamine Compounds and Pharmaceutical Use Thereof
US7807701B2 (en) 2002-08-30 2010-10-05 Japan Tobacco Inc. Dibenzylamine compounds and pharmaceutical use thereof
US20050059810A1 (en) * 2002-08-30 2005-03-17 Japan Tobacco Inc Dibenzylamine compound and medicinal use thereof
US7332514B2 (en) 2002-08-30 2008-02-19 Japan Tobacco Inc. Dibenzylamine compound and medicinal use thereof
US20040242683A1 (en) * 2003-03-17 2004-12-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl] amino)phenyl] 2-methylpropanethioate
US20080045599A1 (en) * 2003-03-17 2008-02-21 Japan Tobacco Inc. Method for Increasing the Bioavailability of the Active Form of S-[2-([[1-(2-Ethylbutyl)Cyclohexyl]Carbonyl] Amino)Phenyl] 2-Methylpropanethioate
US7276536B2 (en) 2003-03-17 2007-10-02 Japan Tobacco Inc. Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate
US20040225018A1 (en) * 2003-03-17 2004-11-11 Japan Tobacco Inc. Pharmaceutical compositions of CETP inhibitors
US20050020668A1 (en) * 2003-05-02 2005-01-27 Japan Tobacco Inc. Combination comprising S-[2-([[1-(2-ethylbutyl)cyclohexyl] carbonyl]amino)phenyl] 2-methylpropanethioate and an HMG CoA reductase inhibitor

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Publication number Publication date
CH508607A (de) 1971-06-15
GB1201631A (en) 1970-08-12
NL6711100A (de) 1968-02-13
DE1618935A1 (de) 1971-09-16
FR1565354A (de) 1969-05-02
FI47882B (de) 1974-01-02
BE702623A (de) 1968-02-12
FR7586M (de) 1970-01-12
FI47882C (fi) 1974-04-10

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