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WO2004029068A1 - Derives comprenant des sterols et/ou des stanols et des classes specifiques d'agents anti-inflammatoires, et utilisation desdits derives pour le traitement ou la prevention de maladies cardiovasculaires - Google Patents

Derives comprenant des sterols et/ou des stanols et des classes specifiques d'agents anti-inflammatoires, et utilisation desdits derives pour le traitement ou la prevention de maladies cardiovasculaires Download PDF

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Publication number
WO2004029068A1
WO2004029068A1 PCT/CA2003/001412 CA0301412W WO2004029068A1 WO 2004029068 A1 WO2004029068 A1 WO 2004029068A1 CA 0301412 W CA0301412 W CA 0301412W WO 2004029068 A1 WO2004029068 A1 WO 2004029068A1
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Prior art keywords
compound
group
acid
acids
inflammation
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James P. Kutney
P. Haydn Pritchard
Yangbing Ding
Kishor M. Wasan
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Forbes Medi-Tech Inc
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Forbes Medi-Tech Inc
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Priority claimed from US10/255,558 external-priority patent/US20040236125A1/en
Application filed by Forbes Medi-Tech Inc filed Critical Forbes Medi-Tech Inc
Priority to AU2003266885A priority Critical patent/AU2003266885A1/en
Priority to JP2004538597A priority patent/JP2006503840A/ja
Priority to EP03747766A priority patent/EP1556406A1/fr
Priority to CA002499817A priority patent/CA2499817A1/fr
Priority to BR0314700-2A priority patent/BR0314700A/pt
Publication of WO2004029068A1 publication Critical patent/WO2004029068A1/fr
Anticipated expiration legal-status Critical
Priority to NO20051932A priority patent/NO20051932L/no
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

Definitions

  • Atherosclerosis is a degenerative process resulting from an interplay of inherited (genetic) factors and environmental factors such as diet and lifestyle.
  • CVD cardiovascular disease
  • Studies to date suggest that cholesterol may play a role in atherosclerosis by forming atherosclerotic plaques in blood vessels, ultimately cutting off blood supply to the heart muscle or alternatively to the brain or limbs, depending on the location of the plaque in the arterial tree (1,2).
  • Overviews have indicated that a 1% reduction in a person's total serum cholesterol yields a 2% reduction in risk of a coronary artery event (3).
  • a 10% decrease in average serum cholesterol (e.g. from 6.0 mmol/L to 5.3 mmol/L) may result in the prevention of 100,000 deaths in the United States annually (4).
  • Phytosterols have received a great deal of attention due to their ability to decrease serum cholesterol levels when fed to a number of mammalian species, including humans. While the precise mechanism of action remains largely unknown, the relationship between cholesterol and phytosterols is apparently due in part to the similarities between the respective chemical structures (the differences occurring in the side chains of the molecules). It is assumed that phytosterols displace cholesterol from the micellar phase and thereby reduce its absorption or possibly compete with receptor and/or carrier sites in the cholesterol absorption process.
  • Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG 2 , PGH 2 and PGE 2 , and have been a common target of anti-inflammatory drug discovery.
  • NSAID's common non- steroidal anti-inflammatory drugs
  • use of high doses of most common NSAID's can produce severe side effects, including life-threatening ulcers, that limit their therapeutic potential.
  • corticosteroids An alternative to NSAID's is the use of corticosteroids, which also produce severe adverse effects, especially when long-term therapy is involved.
  • COX-1 is a constitutive isoform found in blood vessels, stomach, and kidney while COX-2 is induced in settings of inflammation by cytokines and inflammatory mediators.
  • PGG 2 /PHG 2 cyclooxygenase products differ from tissue to tissue depending on the particular PGG 2 /PHG 2 metabolizing enzymatic activities present.
  • Arachidonic acid also can be converted via 12-lipoxygenase to 12-HPETE and 12-HETE or via the 5-lipoxygenase pathway to a variety of leukotrienes.
  • Aspirin and other NSAIDS inhibit the cyclooxygenase enzyme and prostaglandin production; they do not inhibit lipoxygenase pathways and hence, do not suppress leukotriene production.
  • the present invention provides, in one aspect, novel derivatives comprising sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, including salts of these derivatives, and having one or more of the following formulae:
  • R is a sterol or stanol moiety
  • the present invention provides, in another aspect, a composition
  • a composition comprising at least one sterol and/or stanol and at least one an NSAID selected from salicylic acids and arylalkanoic acids.
  • the present invention also comprises processes of preparing the novel derivatives having the above noted formulae.
  • the present invention further comprises a pharmaceutical composition for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, having one or more of the above noted formulae, and a pharmaceutically acceptable carrier therefor.
  • a pharmaceutical composition for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids
  • the present invention further comprises a pharmaceutical composition for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, and for treating and reducing inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and with surgical procedures which comprises one or more sterols and/or stanols and one or more NSAIDs selected from salicylic acids and arylalkanoic acids, and a pharmaceutically acceptable carrier therefor.
  • the present invention further provides foods, beverages and nutraceuticals supplemented with derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, or compositions thereof having one or more of the above noted formulae.
  • the present invention further provides a method for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, and for treating and reducing inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises administering to an animal, a non-toxic and therapeutically effective amount of one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, having one or more of the above noted formulae.
  • the present invention further provides a method for treating or preventing CVD and its underlying conditions including, without limitation, atherosclerosis, hypercholesterolemia, hyperlipidemia, hypertension, thrombosis, coronary artery disease, inflammation including coronary plaque inflammation, bacterial-induced inflammation, viral induced inflammation and inflammation associated with acute pain and surgical procedures which comprises administering to an animal, a non-toxic and therapeutically effective amount of a composition comprising one or more sterols and/or stanols and one or more NSAIDs selected from salicylic acids and arylalkanoic acids.
  • the derivatives and compositions of the present invention exhibit superior activity in both for treating or preventing CVD and its underlying conditions, particularly hyperlipidemia, and treating conditions having inflammation as a part of their aetiology or presentation. There may be an additive or svnerqistic therapeutic effect, in both of these respects. Equally importantly, it is believed that when the salicylic acids and/or arylalkanoic acids are either derivatized with the sterol/stanol component as described herein, or merely co-adminstered with sterols/stanols in composition, a lower dosage of the selected NSAID may be required to achieve the desired therapeutic effects. This is important due to the documented long-term adverse effects of the administration of many anti-inflammatory agents such as NSAIDs of which the salicylic acids and arylalkanoic acids form part. These effects and other significant advantages will become apparent herein below.
  • Figure 2 is a schematic showing the formation of another derivative of the present invention, acetoxyphytostanyl salicylates by reaction of activated phytostanyl chloride with the carboxylate group of the salicylic acid component;
  • Figure 3 is a bar graph showing the inhibition of cholesterol absorption by one of the derivatives of the present invention.
  • Figure 4 is a bar graph showing percent inhibition of COX-1 in the presence of one of the derivatives of the present invention "FDC-2-4".
  • SC-560 is an inhibitor of COX-1 with an IC50 of 10 nM.
  • FDC-2-4 is treated with PL/C (PL+) and untreated with PL/C (PL-).
  • PL only groups are only treated with PL/C alone (no drug).
  • Data presented as percentage inhibition of mean absorbance compared to 100% activity ⁇ standard error, n 3. * indicates p ⁇ 0.05 vs. 0.45 mM ASA;
  • Figure 5 is a bar graph showing percent inhibition of COX-2 in the presence of one of the derivatives of the present invention "FDC-2-4".
  • DuP-697 is an inhibitor of COX-2 with an IC50 of 50 nM.
  • FDC-2-4 is treated with PL/C (PL+) and untreated with PL/C (PL-).
  • PL only groups are only treated with PL/C alone (no drug).
  • Data presented as percentage inhibition of mean absorbance compared to 100% activity ⁇ standard error, n 3. * indicates p ⁇ 0.05 vs. 0.45 mM ASA;
  • Figure 6 is a digital image of a 1mL aqueous solution containing 4mg of one compound of the present invention called FDC 2-4 and 120mg of polysorbate 80, against a black background;
  • Figure 7 is transmission electron microscope image of an aqueous solution containing FDC-2-4 (4mg/ml) and polysorbate 80 (120mg/ml), possibly showing micelles;
  • Figure 8 is a graph showing the particle size distribution of a 4mg/ml FDC 2-4 aqueous solution with 120mg/ml polysorbate 80;
  • Figure 9 is a graph showing the particle size distribution of a 120mg/ml polysorbate 80 solution (control).
  • Figure 10 is the structure of one of the preferred compounds of the present invention, "FDC 2-4". PREFERRED EMBODIMENTS OF THE INVENTION
  • stanol refers to saturated or hydrogenated sterols including all natural or synthesized forms and derivatives thereof, and isomers. It is to be understood that modifications to the sterols and stanols i.e. to include side chains also falls within the purview of this invention. For example, the purview of this invention clearly includes 24 beta-ethylchlostanol, 24-alpha-ethyl-22-dehydrocholstanol. It is also to be understood that, when in doubt throughout the specification, and unless otherwise specified, the term “sterol” encompasses both sterol and stanol.
  • arylethanoic (arylacetic) acid compounds such as acemetacin, amfenac sodium, bendazac, glucametacin, oxametacin;
  • arylbutanoic (arylbutyric) acid compounds such as bumadizon, butibufen, fenbufen, and xenbucin;
  • salicylic acid as used herein is intended to encompass: • salicylic acid compounds such as acetylsalicylic acid (ASA), aluminium ASA, sodium ASA, ASA glycolates, salicylic acid, salicylic acid glycolates, salicins, salicortin, tremulacin, acetaminosalol; balsalazide, benorylate, gentisic acid, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, naphthyl salicylate,olsalazine, parsalimide, phenyl salicylate, salicylsulfuric acid, choline magnesium trisalicylate, and other salts, diflunisal, etersalate, fosfosal, salol, salsalate, salacetamide, salicylsalicylic acid, sulfasalazine, o
  • Naturally derived salicylates may be extracted, for example, from the bark of Salix alba, S. prupurea L, S. fragilis L. (also known as willow, a deciduous shrub) by techniques which are known and available in the art.
  • the NSAID is a salicylic acid derivative, more preferably, ASA or one of its' derivatives.
  • the derivatives are formed between salicylic acid compounds and the sterol/stanol moiety and have one of the following structures:
  • R H or CH 3 and R1, R2, R3, R4, R5 are selected, independently, from the group consisting of OH, acetyl, halogen (CI, Br, I, or F) and an alkyl moiety having from 1-5 carbon atoms;
  • R H or CH 3 and R1 , R2, R3, R4, R5 are independently selected from the group consisting of OH, acetyl, halogen (CI, Br, l,or F) and an alkyl moiety having from 1 -5 carbon atoms;
  • R1, R2, R3, R4, R5 are independently selected from the group consisting of OH, acetyl, halogen (CI, Br, I, or F) and an alkyl moiety having from 1-5 carbon atoms; and
  • R1, R2, R3, R4, R5 are independently selected from the group consisting of OH, acetyl, halogen (CI, Br, l,or F) and an alkyl moiety having from 1-5 carbon atoms.
  • the derivative of the present invention is selected from the group consisting of phytostanyl acetylsalicylates, phytostanyl salicylates , acetoxyphytostanyl acetylsalicylates, acetoxyphytostanyl salicylates, acetoxyphytostanyl acetate, cholestanyl salicylates, acetoxycholestanyl salicylates, and acetoxyphytostanyl aminosalicylates as represented by the following formulae:
  • novel structures comprising sterols and/or stanols and the selected anti-inflammatory agent can be formed.
  • the selected sterol or stanol (or halophosphate, halocarbonate or halo-oxalate derivatives thereof) and the anti-inflammatory agent are mixed together under reaction conditions to permit condensation of the "acid" moiety with the "alcohol” (phytosterol).
  • reaction conditions are the same as those used in other common esterification reactions in which the acid chloride formed from the acid component and the alcohol component are allowed to react directly or in the presence of a suitable acid catalyst such as mineral acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid.
  • organic solvents generally employed in such esterification reactions are ethers such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents and the temperatures can vary from room to elevated temperatures depending on the reactivity of the reactants undergoing the reaction.
  • the process to form the ester derivative comprises "protecting" the hydroxyl groups of the anti-inflammatory or derivatives thereof as esters (for example, as acetate esters) or ethers (for example, methyl ethers) and then condensing the protected anti-inflammatory agent with the reactive sterol/stanol (or its halophosphate, halocarbonate or halo-oxalate) under suitable reaction conditions.
  • ester/stanol or its halophosphate, halocarbonate or halo-oxalate
  • condensation reactions are conducted in an organic solvent such as diethyl ether, tetrahydrofuran, or benzene, toluene or similar aromatic solvents.
  • the reaction temperatures may vary from low (-15°C) to elevated temperatures.
  • Figure 1 is a schematic showing the formation of the "protected" anti-inflammatory agent (acetylsalicylic acid chloride) and the phytostanol in a condensation reaction yielding one of novel derivatives of the present invention.
  • the overall formation of the desired ester may be achieved by the creation of an activated chloride in the stanyl or steryl component which is subsequently reacted with the carboxylic acid or carboxylate unit of the anti-inflammatory agent.
  • a carboxy "linker" between the anti-inflammatory agent and the steryl/stanyl component may comprise preferably from 1-5 carbon atoms.
  • monochloroacetic acid was reacted with a stanol mixture to achieve the stanyl monochloroacetic ester.
  • the present invention encompasses the biologically acceptable metal, alkali earth metal, or alkali metal salts of the disclosed derivatives. These salts are generally more water soluble than the corresponding parent compounds and therefore their efficacy and evaluation both in vitro and in vivo is improved.
  • Salt formation of the derivatives of the present invention can be readily performed by treatment of any parent compound containing a phenolic OH group with a series of bases (for example, sodium methoxide or other metal alkoxides) to produce the corresponding alkali metal salts.
  • bases for example, sodium methoxide or other metal alkoxides
  • Other metal salts of calcium, magnesium, manganese, copper, zinc, and the like can be generated by reacting the parent with suitable metal alkoxides.
  • FDC 2-4 is the structure as shown in Figure 10 and is a stanol derivative (mixture of sitostanol and campestanol attached to ASA. It is a preferred compound in accordance with the present invention.
  • the present invention provides a method for:
  • CVD cardiovascular disease
  • cardiovascular disease cardiovascular disease
  • cardiovascular disease cardiovascular disease
  • cardiovascular disease cardiovascular disease
  • cardiovascular disease cardiovascular disease
  • cardiovascular disease cardiovascular disease
  • composition comprising one or more sterols or stanols and at least one NSAID selected from salicylic acids and arylalkanoic acids or one or more derivatives of sterols and/or stanols and an NSAID selected from salicylic acids and arylalkanoic acids, having one or more of the following formulae:
  • R is a sterol or stanol moiety
  • the selected solubility enhancing agent have a hydrophilic/lipophilic balance ("HLB") of 12 or greater.
  • HLB hydrophilic/lipophilic balance
  • the selected solubility enhancing agent have an HLB of 8 or less.
  • the HLB scale represents the relative solubilizing power of a molecule vis-a-vis its lipophilic tendencies i.e. a relative ratio of polar and non-polar groups in the molecule.
  • one or more of the compounds of the present invention are mixed with a selected solubility enhancing agent, preferably polysorbate-80;
  • an organic solvent preferably chloroform, is added at or about room temperature and mixed;
  • the compounds and compositions of the present invention may be administered through foods, beverages and nutraceuticals, including, without limitation, the following:
  • Fat-Based Products such as margarines, spreads, mayonnaise, shortenings, cooking and frying oils and dressings;
  • Confectioneries such as chocolate, candies, chewing gum, desserts, non-dairy toppings (for example Cool WhipTM), sorbets, icings and other fillings;
  • the stanol mixture (2g, campestanol: 36.4%w/w; sitostanol: 62.3%w/w) and pyridine (10ml) was added, and the mixture was then stirred overnight at room temperature.
  • the red solution was poured into water (100ml), filtered, the solid was collected, (2.1g).
  • the crude product was loaded on a silica gel column (100ml), eluted with petroleum (30-50°C):EtOAc (100:3) to yield a white powder, (1.5g, yield 55%).
  • Intralipid is a sterile non-pyrogenic fat emulsion prepared for administration as a source of calories and essential fatty acids. It is made up of 10% Soybean Oil (refined natural product consisting of a mixture of neutral triglycerides and unsaturated fatty acids), 1.2% egg yolk phospholipids, 2.25% glycerin and water. In addition sodium hydroxide was added to adjust the pH so that the final product pH is 8.0; pH range is 6.0 to 8.9. The major components fatty acids are linoleic (50%), oleic (26%), palmitic (10%), linolenic (9%) and stearic (3.5%). Each animal received 20mg/kg body weight test substance dissolved in water or other appropriate solvent. The same final volume of the vehicle was administered to rats in the control group.
  • Soybean Oil refined natural product consisting of a mixture of neutral triglycerides and unsaturated fatty acids
  • egg yolk phospholipids 2.25% glycerin and water
  • Plasma samples were collected 10 hours after oral gavage by cardiac puncture and plasma prepared by centrifugation at 40C and 4,000 rpm for 15 minutes. Plasma samples were analyzed for [3H] cholesterol by radioactivity and the effectiveness of novel sterol/stanol compounds reported as a percentage of inhibition of cholesterol absorption compared to controls.
  • FIG. 3 shows a comparison between the FDC-2-4 and control groups as compared to another effective cholesterol absorption inhibitor (an ascorbate ester) called VP4.
  • VP4 another effective cholesterol absorption inhibitor
  • pancreatic lipase/colipase- treated acetoxyphytostanyl salicylate derivative of the present invention (which is designated as "FDC-2-4"), can inhibit cyclooxygenase (COX) activity.
  • FDC-2-4 was treated with a 1 :1 ratio of porcine pancreatic lipase and colipase (PL/C).
  • Inhibition of cyclooxygenase was determined using a colorimetric (ovine) COX inhibitor screening assay. The conversion of arachidonic acid to prostaglandin H 2 was monitored by a colorimetric reaction.
  • PL/C-treated FDC-2-4 was constituted in 0, 0.45, 4.5- ⁇ M concentrations in a 1 ⁇ M hematin/0.1 M Tris-HCI, pH 8.0, buffer. Reaction was initiated by adding 100- ⁇ M arachidonic acid and 100- ⁇ M tetramethyl-p-phenylenediamine (TMPD — the colourimetric substrate). The optical density of the colored product was determined at 620 nm. Acetylsalicylate was used as a positive control in all experiments.
  • Pancreatic lipase/Colipase treatment The enzymatic reaction was carried out in a final volume of 50 mL assay buffer (30 mM Tris-HCI, pH 8.0, ⁇ .0 mM CaCI2, 4 mM taurodeoxycholate), 0.312 mM triolein, in the absence or presence of FDC-2-4. The solution was vortexed for 2 min. and sonicated for 5 min. before adding 2.5 mg porcine pancreatic lipase and 2.5 mg porcine colipase. The reaction was incubated at room temperature for 2 hours.
  • Inhibition of Cyclooxygenase was determined using a colorimetric (ovine) COX inhibitor screening assay (Cayman Chemicals). The conversion of arachidonic acid to prostaglandin H2 was monitored by a colorimetric reaction. COX was exposed to the inhibitors for 5 minutes. Reaction was initiated by adding 100- ⁇ M arachidonic acid and 100- ⁇ M tetramethyl-p-phenylenediamine (TMPD— the colourimetric substrate). The optical density of the colored product was determined at 620 nm 5 minutes after initiation.
  • TMPD tetramethyl-p-phenylenediamine
  • PL/C-treated FDC-2-4 was constituted in 0, 0.45, 4.5- ⁇ M concentrations in a 1 ⁇ M hematin/0.1 M Tris-HCI, pH 8.0, buffer.
  • PL/C- treated FDC-2-4 was compared with non-PL/C-treated FDC-2-4 and control (no FDC-2-4 added) in determining COX inhibition.
  • Acetylsalicylate (ASA) was used as a positive control in all experiments.
  • ASA Statistical Analysis on all treatment groups were done using ANOVA and Tukey Posthoc tests .
  • EXAMPLE 9 Forming the water insoluble FDC-2-4 (phytostanyl analogue having a chemical designation of phytostanyl-O-acetylsalicyloxyacetates and a molecular weight of 631.66g/mol) into a 4mg/ml to 8mg/ml aqueous solution using a solubility enhancing agent.
  • FDC-2-4 and the solubility enhancing agent being tested were dissolved using a suitable organic solvent; heat was applied if necessary. The organic solvent was removed by nitrogen evaporation and water was added to the test tubes. The mixtures were visually inspected for cloudiness or particles. The formulation developed was characterized using light microscopy, particle size measurement, zeta potential measurement, and transmission electron microscopy.
  • the nitrogen evaporator was turned on and the temperature was set for 65°C (without nitrogen air - the nitrogen evaporator was initially used as a hot water bath). 2.
  • Four mg of FDC 2-4 was measured into 16 x 100mm test tubes. In the same test tubes, 120mg of Tween 80 was measured out using a glass pipette.
  • the parafilm was removed from the test tubes, the temperature of the nitrogen evaporator was reduced to 60°C, and the nitrogen air was turned on. The pressure of the nitrogen air was initially about 7 psi for about 30 minutes to ensure that none of the solution splattered out. After about 30 minutes, the psi was increased to 15-20. The samples were left in the nitrogen evaporator for a total of about 2.5 hours.
  • Figure 6 shows a digital image of a 1mL aqueous solution containing 4mg of FDC 2- 4 and 120mg of polysorbate 80, against a black background showing a clear solution.

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Abstract

La présente invention concerne, dans un aspect, de nouveaux dérivés, qui contiennent des stérols et/ou des stanols, ainsi qu'un AINS sélectionné dans le groupe constitué par des acides salicyliques et des acides arylalcanoïques, y compris des sels desdits dérivés; et présentent une ou plusieurs des formules suivantes: a) R2-(CH2)n-CO-OR; b) R2-R; c) R2-CO-CO-OR; d) la formule (I), dans lesquelles R est un fragment de stérol ou de stanol; R2 est dérivé de l'acide salicylique ou de l'acide arylalcanoïque; et n=1-5. L'invention concerne également des compositions pharmaceutiques contenant un ou plusieurs de ces nouveaux dérivés; des méthodes de traitement ou de prévention de maladies cardiovasculaires ou de leurs affections sous-jacentes, y compris, mais pas exclusivement, l'athérosclérose, l'hypercholestérolémie, l'hyperlipidémie, l'hypertension, la thrombose, la coronaropathie; ou des méthodes de traitement et de réduction des inflammations, y compris l'inflammation des plaques coronaires, l'inflammation d'origine bactérienne, l'inflammation d'origine virale ou l'inflammation associée à la douleur aiguë ou à des interventions chirurgicales. Ces méthodes consistent à administrer à un animal, en particulier un être humain, une quantité non toxique, thérapeutiquement efficace d'un ou de plusieurs de ces composés, ou un sel biologiquement acceptable de ces composés.
PCT/CA2003/001412 2002-09-25 2003-09-25 Derives comprenant des sterols et/ou des stanols et des classes specifiques d'agents anti-inflammatoires, et utilisation desdits derives pour le traitement ou la prevention de maladies cardiovasculaires Ceased WO2004029068A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU2003266885A AU2003266885A1 (en) 2002-09-25 2003-09-25 Derivatives comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease
JP2004538597A JP2006503840A (ja) 2002-09-25 2003-09-25 ステロール及び／又はスタノール及び抗炎症剤の特定の種類を含有する新規構造体及び組成物、並びに、心血管疾患、その根底にある高脂血症を含む病気、及び原因又は症状の一部として炎症を有する他の障害の治療又は予防におけるそれらの使用
EP03747766A EP1556406A1 (fr) 2002-09-25 2003-09-25 Derives comprenant des sterols et/ou des stanols et des classes specifiques d'agents anti-inflammatoires, et utilisation desdits derives pour le traitement ou la prevention de maladies cardiovasculaires
CA002499817A CA2499817A1 (fr) 2002-09-25 2003-09-25 Derives comprenant des sterols et/ou des stanols et des classes specifiques d'agents anti-inflammatoires, et utilisation desdits derives pour le traitement ou la prevention de maladies cardiovasculaires
BR0314700-2A BR0314700A (pt) 2002-09-25 2003-09-25 Derivados que compreendem esteróis e/ou estanóis e classes especìficas de agentes antiinflamatórios e seu uso no tratamento ou prevenção de doença cardiovascular
NO20051932A NO20051932L (no) 2002-09-25 2005-04-20 Derivater omfattende steroler og/eller stanoler og spesifikke klasser av antiinflammatoriske midler og anvendelse derav ved behandling eller forebyggelse av kardiovaskulaer sykdom.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10/255,558 US20040236125A1 (en) 2002-09-25 2002-09-25 Novel structures and compositions comprising sterols and/or stanols and specific classes of anti-inflammatory agents and use thereof in treating or preventing cardiovascular disease, its underlying conditions including hyperlipidemia and other disorders having inflammation as part of their aetiology or presentation
US10/255,558 2002-09-25
US66484303A 2003-09-16 2003-09-16
US10/664,843 2003-09-16

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EP (1) EP1556406A1 (fr)
JP (1) JP2006503840A (fr)
KR (1) KR20050084572A (fr)
CN (1) CN1684971A (fr)
AU (1) AU2003266885A1 (fr)
BR (1) BR0314700A (fr)
CA (1) CA2499817A1 (fr)
NO (1) NO20051932L (fr)
RU (1) RU2005112247A (fr)
WO (1) WO2004029068A1 (fr)

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WO2005079743A1 (fr) * 2004-02-19 2005-09-01 Symrise Gmbh & Co. Kg Utilisation d'alcools 2-hydroxyphenyle et formulations cosmetiques ou therapeutiques contenant ces composes
US7811781B2 (en) 2005-07-06 2010-10-12 Btg International Limited Core 2 β(1,6)-acetylglycosaminyltransferase as diagnostic marker for atherosclerosis
US7906493B2 (en) 2003-12-22 2011-03-15 Btg International Limited Core 2 GlcNAc-T inhibitors
US7998943B2 (en) 2005-07-06 2011-08-16 Btg International Limited Core 2 GlcNAc-T inhibitors III
US8197794B2 (en) 2003-12-22 2012-06-12 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors

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ME02436B (fr) * 2012-05-10 2016-09-20 Beta Innov Dérivés de stérol, leur procédé de préparation, les compositions pharmaceutiques les contenant et leur utilisation pour le traitement du glioblastome multiple
CN104434927A (zh) * 2014-12-16 2015-03-25 吉林农业大学 丙二酸双环戊烷并多氢菲酯b在制备降血压药物中的应用
CN104530167B (zh) * 2014-12-16 2016-02-24 吉林农业大学 水杨酸环戊烷并多氢菲酯a及其提取方法和药物用途
CN111053741B (zh) * 2019-12-31 2021-09-28 江苏省中医院 一种用于治疗炎症性肠病的基于β-谷甾醇与5-ASA的口服多敏感胶束前药
CN114014905B (zh) * 2021-12-03 2023-07-21 浙江科技学院 靶向PPARγ的甘草次酸类衍生物及其制备方法和用途

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Publication number Priority date Publication date Assignee Title
US7906493B2 (en) 2003-12-22 2011-03-15 Btg International Limited Core 2 GlcNAc-T inhibitors
US8197794B2 (en) 2003-12-22 2012-06-12 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors
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US7811781B2 (en) 2005-07-06 2010-10-12 Btg International Limited Core 2 β(1,6)-acetylglycosaminyltransferase as diagnostic marker for atherosclerosis
US7998943B2 (en) 2005-07-06 2011-08-16 Btg International Limited Core 2 GlcNAc-T inhibitors III
US8609633B2 (en) 2005-07-06 2013-12-17 Ms Therapeutics Limited Core 2 GlcNAc-T inhibitors

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AU2003266885A1 (en) 2004-04-19
NO20051932L (no) 2005-04-20
BR0314700A (pt) 2005-07-26
EP1556406A1 (fr) 2005-07-27
JP2006503840A (ja) 2006-02-02
RU2005112247A (ru) 2006-01-20
CN1684971A (zh) 2005-10-19
KR20050084572A (ko) 2005-08-26
CA2499817A1 (fr) 2004-04-08

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