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WO1999034794A1 - Procedes de traitement de la dyslipidemie diabetique au moyen de tocotrienols - Google Patents

Procedes de traitement de la dyslipidemie diabetique au moyen de tocotrienols Download PDF

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Publication number
WO1999034794A1
WO1999034794A1 PCT/US1999/000596 US9900596W WO9934794A1 WO 1999034794 A1 WO1999034794 A1 WO 1999034794A1 US 9900596 W US9900596 W US 9900596W WO 9934794 A1 WO9934794 A1 WO 9934794A1
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WIPO (PCT)
Prior art keywords
tocotrienol
tocotrienols
composition comprises
group
patient
Prior art date
Application number
PCT/US1999/000596
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English (en)
Inventor
Ronald H. Lane
Frederick H. Schneider
Original Assignee
Lipogenics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lipogenics, Inc. filed Critical Lipogenics, Inc.
Priority to AU21126/99A priority Critical patent/AU2112699A/en
Priority to EP99901429A priority patent/EP1047419A1/fr
Priority to CA002318218A priority patent/CA2318218A1/fr
Publication of WO1999034794A1 publication Critical patent/WO1999034794A1/fr

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E

Definitions

  • This invention relates to the treatment of diabetic dyslipidemia using tocotrienols. Specifically, this invention relates to the use of individual tocotrienols (such as P 25 tocotrienol), mixtures of tocotrienols and mixtures of one or more tocotrienols with other substances (such as the TRF 25 mixture). The methods of this invention are particularly well suited for treating diabetic dyslipidemia in Type 2 diabetic patients.
  • Blocking the oxidative action of glucose responsible for diabetic vascular dysfunction has been validated as one approach to reduce the occurrence of diabetic complications.
  • aldose reductase inhibitors have been shown to prevent or reduce different components of vascular dysfunction, cataract formation, neuropathy and nephropathy in animal model. Encouraging results have also been observed in diabetic patients in the prevention of neuropathy and retinopathy using aldose reductase inhibitors.
  • glycation inhibitors such as aminoguanidine
  • antioxidants such as vitamin E, vitamin C and alpha lipoic acid
  • antiplatelet agents such as aspirin and ticlopidine
  • the present invention satisfies the need for therapeutic agents effective in the treatment of diabetic dyslipidemia. Specifically this invention provides methods for treating diabetic dyslipidemia comprising the step of administering to a diabetic patient an effective amount of a tocotrienol, a mixture of tocotrienols or a mixture of one or more tocotrienols with other substances.
  • Figures 1A and IB show the effects of ⁇ -tocotrienol (GT301) on superoxide production in human peripheral blood neutrophils.
  • composition refers to a preparation for administration via any acceptable route known to those of ordinary skill in the art. Such routes include, but are not limited to oral, parenteral, transdermal, intravenous or topical administration. “Composition” encompasses pharmaceutical compositions as well as dietary supplements, foodstuffs, food additives and the like.
  • Patient' refers to a warm-blooded mammal and preferably, a human.
  • P 18 tocotrienol refers to a tocotrienol having the formula
  • P.,. tocotrienol and P ]8 are trademarks of Bionutrics, Inc. (Phoenix, Arizona).
  • P 21 tocotrienol refers to the compound 3,4-dihydro-2-methyl-2-(4,8,12- trimethyltrideca-3'(E), 7'(E), 11 '-trienyl)-2H-benzopyran-6-ol. This specific tocotrienol has been referred to as "tocotrienol” in some of the published literature cited herein.
  • P 25 tocotrienol refers to the tocotrienol 3,4-dihydro-2-(4,8,12-trimethyltrideca- 3'(E),7'(E), 1 l"-trienyl)-2H-l-benzopyran-6-ol) which has the formula:
  • P 25 tocotrienol and P 25 are trademarks of Bionutrics, Inc. (Phoenix, Arizona).
  • Preferred tocotrienols for use in the methods of this invention are those which are naturally occurring. These naturally occurring tocotrienols may be conveniently isolated from biological materials or synthesized from commercially available starting material. Preferably, the tocotrienols for use in the methods of this invention are obtained from biological materials that have been stabilized and extracted, such as by the processes described in PCT publication WO 91/17985 (the entire disclosure of which is hereby incorporated by reference). Examples of preferred biological materials, tocotrienols and methods for obtaining tocotrienols synthetically and from biological materials are referred to in co-owned US patent 5,591,772 and PCT publication WO 91/17985 (the entire disclosures of which are hereby incorporated by reference). Preferred biological materials from which the tocotrienols of this invention may be obtained include stabilized brans and especially, stabilized rice bran.
  • R j and R 3 are each independently selected from the group consisting of H, halogen, OH, OCH 3 and C r C 6 branched or unbranched alkyl (preferably, H, halogen and C,- C 3 branched or unbranched alkyl and more preferably, H and methyl); 1 ⁇ is a hydrogen donor group selected from the group consisting of OH, NHR 8 , CO 2 Y, C(R g ) 2 CO 2 H and C r C g branched or unbranched alkyl substituted with OH, NHR 8 , CH 2 Y or C(R g ) 2 CO 2 H (preferably, OH and C,-C 3 branched or unbranched alkyl substituted with OH and more preferably, OH);
  • R 6 is selected from the group consisting of H and C j -C 6 branched or unbranched alkyl
  • R is selected from the group consisting of isoprenoid and isoprenoid-like side chains, and more preferably from the group consisting of side chains of formulas (a)-(c):
  • each R ]0 is independently selected from the group consisting of H, NH 2 and C r C 6 branched or unbranched alkyl and R u is selected from the group consisting of H, C,-C 6 branched or unbranched alkyl, CH 2 OH, CO 2 H and OH (preferably, R, is a side chain of formula (a), wherein R 10 and R ⁇ are each independently is selected from the group consisting of H and C j -C 3 branched or unbranched alkyl and more preferably, H and methyl); each R 8 and R ⁇ , is independently selected from the group consisting of H and C,-C 6 branched or unbranched alkyl (preferably, H and C j -C 3 branched or unbranched alkyl and more preferably, H and methyl);
  • Y is H or and C j -C lg branched or unbranched alkyl (preferably H and C j -C 6 branched or unbranched alkyl and more preferably, H and C1-C4 branched or unbranched alkyl);
  • Z is selected from the group consisting of H, halogen, OH, CH 2 OH, CH 3 , OCH 3 and
  • COCH 3 (preferably H and CH 3 ); n is an integer selected from the group consisting of 0, 1, 2, 3 and 4 (preferably 0 and l); and m is an integer selected from the group consisting of 1-30 (preferably 1-20, more preferably 3-10 and most preferably, 3-7).
  • More preferred tocotrienols of this invention include P 21 tocotrienol, ⁇ - tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, P lg tocotrienol and P 25 tocotrienol.
  • This invention expressly encompasses the prodrug form of tocotrienols. Upon administration to a patient, such a prodrug undergoes biotransformation to their active form.
  • Prodrugs include the esterified form of the tocotrienols used in this invention which comprise a carboxylic acid functionality.
  • the tocotrienols for use in the methods of this invention may be in their isomerically pure form or be present as mixtures of isomers.
  • the tocotrienols of this invention may exist as the d- or 1-isomer or the d,l-racemic mixture.
  • the naturally occurring isomer (usually the d-isomer) and the d,l-racemic mixture are preferred.
  • TRF refers to a tocotrienol rich fraction obtained by the stabilization and extraction of a biological source.
  • TRF typically contains varying amounts of P 21 tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol and ⁇ -tocotrienol and may also contain quantities of the newly discovered tocotrienols, P ]g tocotrienol and P 25 tocotrienol.
  • TRF will be comprise at least about 50% to about 90% tocotrienols w/w (preferably, at least about 60% to about 90% and more preferably, at least about 70% to about 90%).
  • TRF 25 refers to a TRF comprising a significant weight percentage of P 25 tocotrienol.
  • TRF 25 comprises at least about 5% P 25 , more preferably, at least about 10% P 25 , and even more preferably, at least about 15% P 25 w/w.
  • An example of the preparation of a specific TRF 25 is set forth in A. A. Qureshi et al., Nutr. Biochem.. 8, pp. 290-98 (1997).
  • TRF 25 is a preferred component of the compositions and methods described herein.
  • TRF 25 is a trademark of Bionutrics, Inc. (Phoenix, Arizona).
  • This invention provides a method for treating diabetic dyslipidemia in a diabetic patient comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a tocotrienol, a mixture of tocotrienols or a combination of one or more tocotrienols with one or more additional substances.
  • the "diabetic patient” is a patient with the symptoms of Type 2 diabetes mellitus (non-insulin dependent diabetes).
  • “Therapeutically effective amount” refers to an amount sufficient to reduce the levels of triglycerides, total cholesterol and/or LDL-cholesterol in a diabetic patient.
  • a therapeutically effective amount of a composition according to this invention will reduce the levels of one or more of these serum factors by at least about the following percentages: total cholesterol reduced by at least about 10%, preferably, by at least about 15% and more preferably, by at least 20%; triglycerides reduced by at least about 3%, more preferably, by at least about 5% and more preferably, by at least about 10%; and LDL-cholesterol levels reduced by at least about 10%, preferably, by at least about 15% and more preferably, by at least 20%.
  • “Therapeutically acceptable means” refer to means effective to impart a therapeutic effect.
  • the methods described herein may be used alone or in conjunction with conventional therapeutic methods for treating diabetic complications (such as those described above).
  • the methods of this invention may be used together with methods for treating hyperglycemia.
  • Such therapies attack the underlying causes of diabetic complications on at least two levels by reducing high glucose levels (with their attendant oxidant activity) and simultaneously reducing high levels of lipids (the oxidative target).
  • tocotrienols are useful in treating diabetic dyslipidemia due to their unique lipid lowering properties. Tocotrienols reduce total cholesterol, LDL-cholesterol and triglyceride levels in diabetic patients. Furthermore, tocotrienols target several additional mechanisms leading to the complications caused in part by diabetic dyslipidemia. For example, the tocotrienols of this invention inhibit the production of free arachidonic acid (a major mediator of inflammatory response). This inhibition is believed to occur by either the inhibition of phospholipase A 2 or alternatively, through the increase in corticosterone levels in the blood.
  • Phospholipase A 2 cleaves at C-2 of phosphate head groups, resulting in the release of free arachidonic acid. Free arachidonic acid can then be converted to a variety of biologically important molecules, such as prostaglandins and thromboxanes (via the cyclooxygenase pathway) and the leukotrienes (via the lipoxygenase pathway). These factors are associated with the increased level of glucose and triglycerides observed in diabetic dyslipidemic patients.
  • tocotrienols inhibit the production of a variety of cytokines (including TNF, IL-1 and growth factors). These cytokines contribute to the proliferation of smooth muscle and propagation of the inflammatory response partially responsible for the development of atherosclerosis and other diabetic complications associated with dyslipidemia. Furthermore, tocotrienols reduce the levels of superoxide production. Superoxide and nitric oxide react to form peroxynitrite, which is a causative factor in arterial atherosclerosis. By reducing superoxide and cytokine production, tocotrienols reduce the cell proliferation, chemotaxis, inflammation and endothelial damage that also play a role in atherosclerosis and other complications associated with diabetic dyslipidemia.
  • compositions of this invention are prepared by combining one or more tocotrienols with an acceptable carrier.
  • the carrier must be pharmaceutically acceptable (i.e., a carrier which is non- toxic to the patient at the administered level and which does not destroy the activity of the active component of the composition).
  • Acceptable carriers, including pharmaceutically acceptable carriers, are well known to those of ordinary skill in the art.
  • compositions of this invention may be used or administered by any therapeutically acceptable means to a patient in need of treatment for diabetic dyslipidemia.
  • pharmaceutical compositions of this invention may be administered orally, topically, transdermally, parenterally, intravenously or by inhalation. These compositions may be formulated so as to impart a time-released benefit.
  • Oral compositions may take the form of tablets, capsules, caplets, emulsions, liposomes, suspensions, powders and the like.
  • Topical compositions include, but are not limited to, gels, lotions and creams.
  • Parenteral compositions take the form of sterile solutions and emulsions and the like.
  • Intravenous compositions include, but are not limited to sterile solutions. The preferred routes of administration is oral or transdermal administration.
  • Dosage levels and requirements are well-recognized in the art and may be chosen by those of ordinary skill in the art from publicly available sources. Typically, dosage levels will range between about 0.1 and about 5000 mg of tocotrienol or mixture of tocotrienols per dose. Multiple doses may be required over a period of time to obtain maximum benefit. For example, a patient may receive oral or transdermal administration of between about 0.1 and about 1000 mg/day for a period of several days to several weeks or more. Specific dosage and treatment regimens will depend upon factors such as the patient's overall health status, the severity and course of the patient's disorder or disposition thereto and the judgment of the treating physician. Higher or lower doses may be employed as needed.
  • Tocotrienols and mixtures thereof may be used in combination with conventional therapeutics in the methods described herein.
  • the conventional therapeutics may be administered separately from the tocotrienols and mixtures thereof, or they may be formulated together in a single dosage form.
  • Such combination therapy may advantageously utilize lower dosages of those conventional therapies and reduce or avoid possible toxicity incurred when those agents are used as monotherapies.
  • the tocotrienols used in the methods of this invention may be administered with conventional antioxidants such as those of the vitamin E, vitamin C and lipoic acid (preferably alpha lipoic acid) classes, aldose reductase inhibitors, glycation inhibitors (such as aminoguanidine), anti-platelet agents (such as aspirin and ticlopidine), bile acid sequestrants, such as Cholestyramine and Colestipol; fibric acid derivatives, such as Clofibrate, Gamfibrozil, Bezafibrate, Fenofibrate and Ciprofibrate; HMGR inhibitors such as statins (including but not limited to Lovastatin, Mevastatin, Pravastatin, Simvastatin and SRI-62320; Probucol; Nicotinic Acid and its derivatives and conjugates such as Nicotinamide-N-oxide, 6- OH Nicotinamide, NAD, N-methyl-2-pyridine-8-carboxamide, N-Methyl-
  • the tocotrienols used in the methods of this invention may be administered with conventional antidiabetes drugs.
  • conventional antidiabetes drugs include biguanides (such as Glucophage (metformin hydrochloride)), glucosidase inhibitors (such as Precose (acarbose)), sulfonylureas (such as Amaryl (glimepiride), DiaBeta (glyburide), Diabinese (chlo ropamide), Glucotrol and Glucotrol XL (glypizide), Glynase (glypizide), and Micronase (glypizide)) and insulin (including natural and recombinant forms, insulin zinc, isophane insulin and human, bovine or procine forms).
  • biguanides such as Glucophage (metformin hydrochloride)
  • glucosidase inhibitors such as Precose (acarbose)
  • Protocol I Dry Heat Stabilization
  • Protocol II Dry Heat followeded By Wet Heat Stabilization Dry Heat Stage: Protocol I
  • Protocol III Drying/Cooling Procedure The wet heat stabilized product of protocol II (15% moisture) was discharged onto aluminum trays and placed in a tray oven at 101.1 °C until the moisture content was 8- 10% (approximately 1.5 hrs). The trays were then placed on tray racks and allowed to cool at ambient temperature (approximately 20°C). Protocol IV: Oil Extraction
  • Protocol V Dewaxing
  • Example 1 The effects of tocotrienols (in the form of the TRF mixture and individual tocotrienols) on plasma levels of thromboxane B 2 and platelet factor 4 in chickens were determined. These levels are known to correlate with the levels of inflammatory cytokines. The serum levels of triglycerides and glucose were also measured.
  • the following feeding conditions were used: Each group of six chickens (6-week old female white leghorn chickens) was administered a chick mash control diet or a control diet containing one or more additives. The amount of feed consumed by all groups was comparable to the control group. The feeding period was 4 weeks. The birds were fasted for a period of 14 hours prior to sacrifice (at 0800 hours).
  • the chicken mash control diet contained the following ingredients:
  • Results are reported as mean ⁇ standard deviation. Percentages of control are reported in parentheses. The following results were obtained
  • Example 2 The effects of tocotrienols (in the form of the TRF mixture and individual tocotrienols) on plasma levels of thromboxane B 2 and platelet factor 4 in swine were determined. These levels are known to correlate with the levels of inflammatory cytokines. The serum levels of glucose and triglycerides was also measured. The following feeding conditions were used:
  • Each group of three swine (5-month old swine carrying Lpd 5 and Lpu 1 mutant alleles) were administered a control diet or a control diet supplemented with one or more additives. After a 12 hour fast, plasma samples were taken at 42 days from the start of the feeding period.
  • the swine control diet contained the following ingredients:
  • the mineral mixture contained per kg feed: zinc sulfate • H 2 O, 110 mg; manganese sulfate • 5H 2 O, 70 mg; ferric citrate • H 2 O, 500 mg; copper sulfate •
  • the vitamin mixture contained per kg feed: vitamin A, 1,500 units; vitamin D 3 , 400 units; vitamin E, 10 units; riboflavin, 3.6 mg; calcium panthothenate, 10 mg; niacin, 25 mg; pyridoxine HCl, 3 mg; folacin, 0.55 mg; biotin, 0.15 mg; vitamin B 12 , 0.01 mg; and vitamin K,, 0.55 mg.
  • Results are reported as mean ⁇ standard deviation. Percentages of control are reported in parentheses. The following results were obtained:
  • Example 3 The effects of ⁇ -tocotrienol on the release of superoxide in human peripheral blood neutrophils were determined. Neutrophils are an extracellular source of oxygen free radicals and, together with nitric oxide, form peroxynitrite (responsible for endothelial damage). Activated neutrophils attach to endothelial tissue, where they release the potent toxin, superoxide. Superoxide amplifies the inflammatory response and impairs local blood circulation.
  • the neutrophils tested were isolated by density centrifugation on Ficoll- Hypaque gradients using conventional methods (see E. Serbinova et al., Free Rad.
  • the amount of released superoxide was reduced from 19.7 nmole (5x10 5 cells/hour) in the control to 8.0 and 0.0 nmole at ⁇ -tocotrienol concentrations of 10 "6 and 10 "5 , respectively.
  • mice are markedly hyperglycemic, hyperinsulinemic and insulin resistant, while demonstrating moderate hyperphagia and obesity.
  • genetically obese mice are markedly obese and hyperphagic while demonstrating less hyperglycemia, hyperinsulinism and insulin resistance.
  • mice are fed a normal protein control diet (NPCD) or NPCD supplemented with between about 5 and about 100 ppm of tocotrienols and tocotrienols mixtures (such as P, g , P 25 and TRF 25 ).
  • NPCD normal protein control diet
  • a typical NPCD consists of casein (vitamin-free) 27%, starch 58%, corn oil 10%, mineral mixture 4% and vitamin mixture 1% (see Examples 1 and 2 above for composition of mineral and vitamin mixtures).
  • the mice are housed in wire cages under artificial illumination from 0600 to 1800 hours during each 24 hour period.
  • the mice are fed ad libitum and are weighed every two weeks. The serum and urine glucose levels are determined at the beginning of each experiment and after two weeks during the treatments.
  • mice are fasted on the 52 nd day for 36 hours and then refed on the 54 th day until the end of the experiment (58 day period). The mice are then sacrificed and the following measurements are taken: body weight gain, feed consumption, feed efficiency, serum and urine glucose levels, plasma glucose levels, serum triglyceride levels, fatty acid synthetase and maleic enzyme activities in the cytosolic fraction of the liver. While we have described a number of embodiments of this invention, it is apparent that our basic constructions may be altered to provide other embodiments which utilize the compositions and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific embodiments that have been presented hereinabove.

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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)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le traitement de la dyslipidémie diabétique au moyen de tocotriénols. De façon spécifique, cette invention concerne l'utilisation de tocotriénols individuels (par exemple le tocotriénol P25), de mélanges de tocotriénols et de mélanges d'un ou de plusieurs tocotriénols avec d'autres substances (par exemple le mélange TRF25). Les procédés selon l'invention sont particulièrement adaptés au traitement de la dyslipidémie diabétique chez des patients souffrant du diabète du type 2.
PCT/US1999/000596 1998-01-12 1999-01-11 Procedes de traitement de la dyslipidemie diabetique au moyen de tocotrienols WO1999034794A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU21126/99A AU2112699A (en) 1998-01-12 1999-01-11 Methods for treating diabetic dyslipidemia using tocotrienols
EP99901429A EP1047419A1 (fr) 1998-01-12 1999-01-11 Procedes de traitement de la dyslipidemie diabetique au moyen de tocotrienols
CA002318218A CA2318218A1 (fr) 1998-01-12 1999-01-11 Procedes de traitement de la dyslipidemie diabetique au moyen de tocotrienols

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US598798A 1998-01-12 1998-01-12
US09/005,987 1998-01-12

Publications (1)

Publication Number Publication Date
WO1999034794A1 true WO1999034794A1 (fr) 1999-07-15

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EP (1) EP1047419A1 (fr)
AU (1) AU2112699A (fr)
CA (1) CA2318218A1 (fr)
WO (1) WO1999034794A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7399784B2 (en) * 2002-11-26 2008-07-15 Children's Hospital & Research Center At Oakland Tocopherol and tocotrienol anti-obesity medicaments
CN106916133A (zh) * 2017-01-18 2017-07-04 东北大学 一种具有抑制ptp1b活性的间苯三酚衍生物及其制备方法、应用
CN111574486A (zh) * 2020-05-22 2020-08-25 中国科学院南海海洋研究所 香叶基三羟基色酮及其在制备肝x受体激动剂中的应用
CN116354916A (zh) * 2021-12-27 2023-06-30 深圳大学 具有改善胰岛素抵抗作用的化合物或其药学上可接受的盐及其制备方法和应用

Citations (2)

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US4492706A (en) * 1983-08-01 1985-01-08 American Home Products Corporation Method of lowering lipid levels
US5591772A (en) * 1991-11-22 1997-01-07 Lipogenics, Inc. Tocotrienols and tocotrienol-like compounds and methods for their use

Patent Citations (2)

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US4492706A (en) * 1983-08-01 1985-01-08 American Home Products Corporation Method of lowering lipid levels
US5591772A (en) * 1991-11-22 1997-01-07 Lipogenics, Inc. Tocotrienols and tocotrienol-like compounds and methods for their use

Non-Patent Citations (1)

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Title
CHEMICAL ABSTRACTS, 1 January 1900, Columbus, Ohio, US; abstract no. 92-209097, XP002918473 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7399784B2 (en) * 2002-11-26 2008-07-15 Children's Hospital & Research Center At Oakland Tocopherol and tocotrienol anti-obesity medicaments
CN106916133A (zh) * 2017-01-18 2017-07-04 东北大学 一种具有抑制ptp1b活性的间苯三酚衍生物及其制备方法、应用
CN111574486A (zh) * 2020-05-22 2020-08-25 中国科学院南海海洋研究所 香叶基三羟基色酮及其在制备肝x受体激动剂中的应用
CN111574486B (zh) * 2020-05-22 2022-04-26 中国科学院南海海洋研究所 香叶基三羟基色酮及其在制备肝x受体激动剂中的应用
CN116354916A (zh) * 2021-12-27 2023-06-30 深圳大学 具有改善胰岛素抵抗作用的化合物或其药学上可接受的盐及其制备方法和应用
CN116354916B (zh) * 2021-12-27 2024-07-19 深圳大学 具有改善胰岛素抵抗作用的化合物或其药学上可接受的盐及其制备方法和应用

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CA2318218A1 (fr) 1999-07-15
AU2112699A (en) 1999-07-26

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