WO2004039771A1 - Composes de diallyldisulfure presentant une activite antilipidemique et antioxydante - Google Patents

Composes de diallyldisulfure presentant une activite antilipidemique et antioxydante Download PDF

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WO2004039771A1
WO2004039771A1 PCT/IN2003/000250 IN0300250W WO2004039771A1 WO 2004039771 A1 WO2004039771 A1 WO 2004039771A1 IN 0300250 W IN0300250 W IN 0300250W WO 2004039771 A1 WO2004039771 A1 WO 2004039771A1
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diallyldisulphide
pharmaceutically acceptable
formula
cooh
compound
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PCT/IN2003/000250
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English (en)
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Manisha Tiwari
Meenakshi Sharma
Ramesh Chandra
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Department Of Science And Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/16—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
    • C07C321/20—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
    • C07C323/02—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/07—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/29—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings

Definitions

  • the present invention relates to a novel diallyldisulphide analogues of general formula I exhibiting antilipidemic and antioxidant activity and pharmaceutical compositions containing these analogues.
  • the invention also provides a process of preparation of such analogues and the pharmaceutical composition containing such analogues.
  • the novel diallyldisulphide compound is represented by
  • R C 6 H
  • X H, CI, Br, F, CF 3 , CH 3 , CN,
  • Garlic is known for its medicinal and nutritional values for a very long time. Among the various potential therapeutic applications of garlic, its antilipidemic effects has been well demonstrated in studies of humans and animals [C.C.Gardner et.al, Atherosclerosis 154, 213-220, (2001); Liu et.al, Lipids 35, 197-203, (2000) and L.A. Simons et.al, Atherosclerosis 113, 219-225, (1995)]. Allicin (diallylthiosulfinate) is reported to be one of the most active constituents of garlic. Due to its unstable nature, allicin disallows its chemical modification to achieve a potent analogues.
  • Allicin readily undergoes transformation to a volatile diallyldisulphide.
  • the precursor of allicin, i.e. Alliin is known to be effective in treating hepatic diseases and fatigue. [Nagai Katsuji, Pat No. JP 56127312].
  • the main object of the invention is to provide a novel diallyldisulphide analogues exhibiting antilipidemic and antioxidant activity.
  • Another object is to provide pharmaceutical compositions containing novel diallyldisulphide compounds.
  • Yet another object of the invention is to provide an effective and economical process for the preparation of novel diallyldisulphide compounds.
  • the present invention relates to novel diallyldisulphide analogues of general formula (I), exhibiting antilipidemic and antioxidant activity.
  • the invention relates to novel active diallyldisulphide analogues which are represented by general formula I as shown hereinbelow:
  • diallyldisulphide derivatives are:
  • R C 6 H 5 ; CeH-NO ⁇ ); C 6 H 3 (NO 2 ) 2 (2,4); C-H-COOH ⁇ ); C 6 H 4 CN(4); C 6 H 3 (COOH) 2 (2,4); C 6 H 3 (CN) 2 (2,4); C 6 H 2 (NO 2 ) 3 (2,4,6); C 6 H 3 NO 2 (4)COOH(2);
  • the novel diallyldisulphide compound and its analogues are found to be less toxic than known drugs and exhibit activity equipment to or greater than known drugs.
  • the process for the preparation of diallyldisulphide compounds comprises the steps of:
  • step (c) drying the organic layer over anhydrous sodium sulphate and evaporating the organic layer to yield bis(2-hydroxyethyl)bisulphide, (d) treating the compound of step (c) under stirring with hydrohalogenic acid and cone, sulphuric acid at an ambient temperature ???? for 15 to 30 hours followed by heating for 2 to 4 hours in a steam bath,
  • step (e) separating the upper layer of step (d), washing with 10 % aqueous alkali carbonate solution, drying the organic layer over anhydrous sodium sulphate and evaporating the organic layer to yield bis (2-bromoethyl) disulphide,
  • step (f) reacting the product of step (e) with triaryl phosphine in dry dimethyl formamide at reflux temperature for 4-6 hours,
  • step (g) cooling the reaction mixtures of step (f) to room temperature and diluting with hexane to yield the required phosphonium bromide salt of bis (2- homothyl) disulphide, (h) treating the compound of step (g) with a benzaldehye or substituted benzaldehyde derivative in the presence of alkali metal alkoxide in the corresponding alcohol at reflux temperature for 15 to 30 hours, and (i) pouring the reaction mixture of step (h) onto ice and the precipitated solid is filtered, washed and dried to yield the corresponding final diallyldisulphide analogue and if desired, converting the analogues into their pharmaceutically acceptable salts.
  • the stirring in step (c) is carried out at an ambient temperature for 24 hours followed by heating for 3 hours.
  • the benzaldehyde used in step (h) is unsubstituted or substituted with suitable funcational group selected from cyano, carboxyl, nitro, trifluoromethyl, amino, methoxyl. or combination thereof.
  • the diallyldisulphide analogue is as active and two times less toxic than the standard drug.
  • the protective effective dose of the diallyldisulphide analogue is 20 mg/kg of body weight for antilipidemic activity and 20 mg/kg of body weight for antioxidant activity.
  • the acceptable additives are selected from the group of nutrients which are pharmaceutically acceptable carrier.
  • the novel diallyldisulphide analogues may be used in the form of tablets, capsules, syrup, powder, ointment, injectable, etc.
  • the diallyldisulphide analogue may be administered through routes such as oral, nasal intravenous, intra-peritoneal, intramuscular, etc.
  • the effective dose of diallyldisulphide analogues may be in the range of 20 mg/kg of body weight.
  • novel pharmaceutically acceptable salts comprising the novel diallyldisulphide analogues, said salts may be hydrochloride, hydrobromide, maleate, citrate, sodium or potassium, etc.
  • LiOEt Lithium ethoxide
  • 50ml of ethanol were taken in a dry round bottom flask.
  • the flask was flushed with Argon gas 0.779g (ImM) of the phosphonium salt (IV) in 10ml of super dry ethanol was added to the Lithium ethoxide formed by the addition of lithium in superdry ethanol 0.37g (25mM) p-nitrobenzaldehyde dissolved in 5ml of superdry ethanol and 3ml of THF was added to the reaction mixture.
  • the reaction mixture was refluxed with stirring for 24hours.
  • the reaction mixture was poured into ice, the final compound (V) precipitated out.
  • the compound was filterted and dried.
  • LiOEt Lithium ethoxide
  • 50mM 0.0174g of Lithium ethoxide (LiOEt) (25mM) and 50ml of ethanol were taken in a dry round bottom flask.
  • the flask was flushed with Argon gas 0.779g (ImM) of the phosphonium salt (IV) in 10ml of super dry ethanol was added to the Lithium ethoxide formed by the addition of lithium in superdry ethanol 0.6g (50mM) p-aminobenzaldehyde was dissolved in 5ml of superdry ethanol and 3ml of THF was added to the reaction mixture.
  • the reaction mixture was refluxed with stirring for 24hours. After completion, the reaction mixture was concentrated under vacuum.
  • LiOEt Lithium ethoxide
  • 50mM 0.0174g of Lithium ethoxide (LiOEt) (25mM) and 50ml of ethanol were taken in a dry round bottom flask.
  • the flask was flushed with Argon gas 0.779g (ImM) of the phosphonium salt (IV) in 10ml of super dry ethanol was added to the Lithium ethoxide formed by the addition of lithium in superdry ethanol 0.68g (50mM)
  • p- methoxybenzaldehyde was dissolved in 5ml of superdry ethanol.
  • the reaction mixture was concentrated under vacuum.
  • the residue was dissolved in water and extracted with chloroform (2 X 50ml).
  • the organic layer was dried over anhydrous Na 2 SO 4 and cone, under reduced pressure.
  • Example IV Conversion of compound IV of example I to phenyl substituted diallyldisulfide (VIII).
  • BIOLOGICAL ACTIVITY Antilipidemic activity assay Data pertaining to this activity is depicted in Table I.
  • GROUP-1 Orally administered equivalent amount of saline, treated as control.
  • GROUP-2 20mg/kg.b.wt of the Diallyl thiosulphinate fraction of garlic (Allicin extract) was orally administered for 5days.
  • GROUP-3 20mg/Kg.b.wt of Lovastatin was orally administered to the rats.
  • GROUP-6 20mg/Kg.b.wt of Bis [4-methoxy-phenyl allyl] disulphide was orally administered.
  • Rats 150-200g were divided into eight groups. Five rats in each group.
  • GROUP-8 Orally administered equivalent amount of saline, treated as control GROUP-9 Rats were fed with 5% cholesterol in their diet for one week.
  • GROUP- 11 Rats were fed with 5% cholesterol in diet for one week, along with the oral administration of Lovastatin (20mg/Kg.b.wt.).
  • GROUP-12 Rats were fed with 5% cholesterol in diet for one week, along with the oral administration of Bis[4-nitro phenyl allyl] "disulphide (20mg/Kg.b.wt.).
  • GROUP-13 Rats were fed with 5% cholesterol in diet for one week, along with the oral administration of Bis[4-amino phenyl allyl] "disulphide (20mg/Kg.b.wt).
  • GROUP- 14 Rats were fed with 5% cholesterol in diet for one week, along with the oral administration of Bis [4-methoxy phenyl allyl] disulphide (20mg/Kg.b.wt.).
  • GROUP-15 Rats were fed with 5% cholesterol in diet for one week, along with the oral administration of Bis[phenyl allyl] "disulphide (20mg/Kg.b.wt.)
  • Tissue preparation At the end of the experimental period, after overnight starvation animals were anesthetized using chloroform. Blood was drawn from retroorbital sinus using capillary tubes, into dried test tubes, which were kept at an angle of 45° for ten minutes at room temperature and then for an hour at 4°C. After that the blood was centrifuged at 800 x g for 10 min. to get serum separated from cellular clot. The animals were immediately dissected to remove their tissues, which were washed in ice-cold saline (0.85% NaCl), and extraneous material was removed.
  • HMG-CoA reductase activity was determined by the method of Venugopala Rao et al (1975). Equal volumes of the 10% tissue homogenate (i.e. lg of tissue/lOml of saline arsenate sol.) and diluted perchloric acid (50ml of HCIO ⁇ of water) were mixed. This was allowed to stand for 5 min. and centrifuged (600g, 10 min.).
  • TLC Thin Layer Chromatography
  • the glyceride was saponified with 0.5 ml of 0.1 N Alcoholic KOH at 70°C for 20 minutes. 200 ⁇ l of 0.4 N H 2 SO was added and placed in boiling water bath for 10-15 min. After that 50 ⁇ l of 0.05 N sodium metaperiodate was added. Excess NalO was neutralized with 0.1 ml of 0.5 M NaAsO 2 . A brown coloration developed after the addition of 5 ml of 0.108% chromotropic acid in 50% H SO 4 . Again heated in boiling water bath for 30-40 minutes. Then the samples were cooled and 3 ml of distilled water were added. Readings were taken at 570 nm. Ref.: VanHandel, E. and Zilversmit, D.B., J. Lab. Clin. Invest. 50,152 (1957). Antioxidant acitvity assay: Data pertaining to this activity is depicted in Table II. 6e. Reduced glutathione
  • Reduced glutathione was determined by the method of Jollow et al (1974). 1.00 ml of Post Mitochondrial Supernatant (PMS) obtained after centrifugation at 10,000 x g. was precipitated with 1.0 ml of sulfosalicylic acid (4%). The samples were kept at 4°C for at least one hour and then subjected to centrifugation at 1200xg for 15 minutes at 4°C.
  • PMS Post Mitochondrial Supernatant
  • the assay mixture contained 0.1 ml of filtered aliquot, 2.7 ml phosphate buffer (0.1 M, pH 7.4) and 0.2 ml DTNB [5.5"-Dithiobis(2-nitro-bezoic acid)] (40 mg/10 ml of phosphate buffer, 0.1 M, pH 7.4) in a total volume of 3.0 ml.
  • the yellow color developed was read immediately at 412 nm. Ref.: Jollow J.D., Mitchell R.J., Zampaglione N, and Gillette R.J; Pharmacology, 11, 151- 169 (1974).
  • Glutathione reductase activity was assayed by the method of Carlberg and Mannervik (1975) as modified by Mohandas et al (1984).
  • the assay system consisted of 1.65 ml phosphate buffer (0.1 M, pH 7.6), 0.1 ml NADPH (0.1 mM), 0.1 ml EDTA(0.5 mM), 0.05 ml oxidized glutathione (1 mM) and 0.1 ml PMS (10% w/v) in a total volume of 2.0 ml.
  • Glutathione reductase activity was calculated in terms of NADPH oxidized/min/mg protein using molar extinction coefficient of 6.22 x lO ⁇ M ⁇ cm "1 . Ref.: Carlberg J, and Mannervik B., J. Biol. Chem. 250, 14, 5475-5480 (1975). 6g. Catalase activity
  • Catalase activity was assayed by the the method of Claiborne (1985).
  • the assay mixture consisted of 1.95 ml phosphate buffer (0.05 m,pH 7.0), 1.0 ml hydrogen peroxide (0.019M), and 0.05 ml PM (10% w/v) in a total volume of 3.0 ml. Changes in absorbance were recorded at 240 nm. Catalase activity was calculated in terms of nmol H 2 O 2 consumed/min/mg protein.
  • Lipid Peroxidation level was measured by the method of Yagi et.al. 0.05ml of the blood was taken in 1.0 ml of physiological saline and centrifuged at 800g for lOmin. 0.5ml of supernatant (0.02ml of serum) was added in 0.5ml of 10% phosphotungstic acid and mixed. After standing at room temperature for 5min, the mixture was centrifuged at 800g for lOmin.The sediment was suspended in 4.0ml of distilled water, and 1.0ml of TBA reagent was added. The reaction mixture was heated for 60min.at 95° in an oil bath. After cooling with tap water, 5.0 ml of n-butanol was added and the mixture was shaken vigorously. After centrifugation at 800g for 15min, the n-butanol layer was taken for fluorometrically measured at 553nm with 515nm excitation. Tetraethoxypropane was used as standard.
  • Wistar rats (administered 5% cholesterol in their diet)

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Abstract

L'invention concerne un nouveau dérivé de diallyldisulfure représenté par la formule (I ) : R-CH = CH - CH2-S-S-CH2-CH = CH-R, ainsi que ses sels pharmaceutiquement acceptables. Dans ladite formule (I) : R=C6HnXp[lorsque n = 3 à 5, p = 2 à 0; X=H, Cl, Br, F, CF3, CH3, CN, COOH, NO2, NH2, OH, OCmH2m+1(m = 1 à 8)]
PCT/IN2003/000250 2001-11-15 2003-07-24 Composes de diallyldisulfure presentant une activite antilipidemique et antioxydante WO2004039771A1 (fr)

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IN1155DE2001 2001-11-15
IN1154DE2001 2001-11-15
IN1154/DEL/2001 2002-10-31
IN1155/DEL/2001 2002-10-31

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006027711A3 (fr) * 2004-08-26 2007-03-15 Nicholas Piramal India Ltd Promedicaments contenant de nouveaux lieurs bio-clivables
US7932294B2 (en) 2004-08-26 2011-04-26 Apparao Satyam Prodrugs containing novel bio-cleavable linkers
WO2017081314A1 (fr) 2015-11-12 2017-05-18 L'oreal Colorant direct cationique comprenant une chaîne aliphatique et portant une fonction de disulfure/thiol/thiol protégé pour colorer des fibres de kératine
US11096880B2 (en) 2017-06-16 2021-08-24 L'oreal Process for dyeing keratin fibres using at least one direct dye and at least one disulfide, thiol or protected-thiol fluorescent dye
US11278482B2 (en) 2017-06-16 2022-03-22 L'oreal Process for dyeing keratin materials using at least one blue, purple or green dye and at least one disulfide, thiol or protected thiol fluorescent dye

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. SENDL ET AL, ATHEROSCLEROSIS, vol. 94, no. 1, 1992, pages 79 - 85, XP001091358 *
E. WEBER ET AL, JUSTUS LIEBIGS ANNALEN DER CHEMIE, no. 5, 1976, pages 891 - 915, XP008026395 *
J. DRABOWICZ ET AL, SYNTHESIS, no. 1, 1980, pages 32 - 34, XP008026792 *
K.R. PRABHU ET AL, J. ORG. CHEM., vol. 60, no. 22, 1995, pages 7142 - 7143, XP002266364 *
W. XIAO ET AL, PHOSPHOROUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, no. 116, 1996, pages 211 - 216, XP001091359 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006027711A3 (fr) * 2004-08-26 2007-03-15 Nicholas Piramal India Ltd Promedicaments contenant de nouveaux lieurs bio-clivables
JP2008510795A (ja) * 2004-08-26 2008-04-10 アッパラオ・サティアム 新規バイオ開裂性リンカー
US7932294B2 (en) 2004-08-26 2011-04-26 Apparao Satyam Prodrugs containing novel bio-cleavable linkers
EP2266623A3 (fr) * 2004-08-26 2011-10-12 Piramal Life Sciences Limited Promédicaments contenant de nouveaux liens bio-clivables
EP2075011A3 (fr) * 2004-08-26 2012-02-29 Piramal Life Sciences Limited Promédicaments contenant des liens disulfures bio-clivables
US8349901B2 (en) 2004-08-26 2013-01-08 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US8354455B2 (en) 2004-08-26 2013-01-15 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US8357723B2 (en) 2004-08-26 2013-01-22 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
WO2017081314A1 (fr) 2015-11-12 2017-05-18 L'oreal Colorant direct cationique comprenant une chaîne aliphatique et portant une fonction de disulfure/thiol/thiol protégé pour colorer des fibres de kératine
US11096880B2 (en) 2017-06-16 2021-08-24 L'oreal Process for dyeing keratin fibres using at least one direct dye and at least one disulfide, thiol or protected-thiol fluorescent dye
US11278482B2 (en) 2017-06-16 2022-03-22 L'oreal Process for dyeing keratin materials using at least one blue, purple or green dye and at least one disulfide, thiol or protected thiol fluorescent dye

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