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WO2012154554A1 - Dérivés de triterpène d'acide gras et leurs utilisations - Google Patents

Dérivés de triterpène d'acide gras et leurs utilisations Download PDF

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Publication number
WO2012154554A1
WO2012154554A1 PCT/US2012/036504 US2012036504W WO2012154554A1 WO 2012154554 A1 WO2012154554 A1 WO 2012154554A1 US 2012036504 W US2012036504 W US 2012036504W WO 2012154554 A1 WO2012154554 A1 WO 2012154554A1
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Prior art keywords
alkyl
disease
independently
compound
heptamethyl
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English (en)
Inventor
Amal Ting
Jill C. Milne
Michael R. Jirousek
Jean E. Bemis
Chi B. Vu
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Astria Therapeutics Inc
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Catabasis Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid

Definitions

  • the invention relates to fatty acid triterpene derivatives; compositions comprising an effective amount of a fatty acid triterpene derivative; and methods for treating or preventing a metabolic disease comprising the administration of an effective amount of a fatty acid triterpene derivative.
  • Oily cold water fish such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids, with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids.
  • Omega-3 fatty acids have previously been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose, and insulin metabolism have been shown to improve in overweight hypertensive subjects through treatment with omega-3 fatty acids.
  • Omega-3 fatty acids have also been shown to decrease triglycerides and to reduce the risk for sudden death caused by cardiac arrhythmias in addition to improve mortality in patients at risk of a cardiovascular event. Omega-3 fatty acids have also been taken as dietary supplements part of therapy used to treat dyslipidemia, and anti-inflammatory properties. A higher intake of omega-3 fatty acids lower levels of circulating TNF-a and IL-6, two of the cytokines that are markedly increased during inflammation processes (Chapkin et al, Prostaglandins, Leukot Essent Fatty Acids 2009, 81, p. 187-191; Duda et al, Cardiovasc Res 2009, 84, p. 33-41).
  • omega-3 fatty acids have also been shown to increase levels of the well-characterized anti-inflammatory cytokine IL-10 (Bradley et al, Obesity (Silver Spring) 2008, 16, p. 938-944). More recently, DHA has been shown to attenuate kidney disease and prolong the lifespan of autoimmune lupus-prone mice (Halade et al, J. Immunology 2010, 184, p. 5280-6). Studies have shown that DHA could potentially suppress glomerulonephritis because of its ability to lower LPS-mediated increase in serum IL-18 as well as its ability to dampen LPS-mediated PI3K, Akt and NF- ⁇ activation in the kidney.
  • Both DHA and EPA are characterized as long chain fatty acids (aliphatic portion between 12-22 carbons).
  • Medium chain fatty acids are characterized as those having the aliphatic portion between 6-12 carbons.
  • Lipoic acid is a medium chain fatty acid found naturally in the body. It plays many important roles such as free radical scavenger, chelator to heavy metals and signal transduction mediator in various inflammatory and metabolic pathways, including the NF- ⁇ pathway (Shay, K. P. et al. Biochim. Biophys. Acta 2009, 1790, 1149-1160). Lipoic acid has been found to be useful in a number of chronic diseases that are associated with oxidative stress (for a review see Smith, A. R. et al Curr. Med. Chem.
  • Lipoic acid has now been evaluated in the clinic for the treatment of diabetes (Morcos, M. et al Diabetes Res. Clin. Pract. 2001, 52, p. 175-183) and diabetic neuropathy (Mijnhout, G. S. et al Neth. J. Med. 2010, 110, p. 158-162). Lipoic acid has also been found to be potentially useful in treating cardiovascular diseases (Ghibu, S. et al, J. Cardiovasc. Pharmacol. 2009, 54, p. 391-8), Alzheimer's disease (Maczurek, A. et al, Adv. Drug Deliv. Rev. 2008, 60, p. 1463-70) and multiple sclerosis (Yadav, V. Multiple Sclerosis
  • the pentacyclic triterpenes belong to a diverse class of naturally occurring and synthetically-modified derivatives with a broad range of biological activity, as reviewed recently by Yadav et al in Toxins (Basel) 2010, 2(10), p. 2428-2466.
  • Corosolic acid for instance, is a triterpene that has been used in dietary supplement as a glucose-lowering agent and insulin mimetic (Sivakumar et al Biotechnol. J. 2009, 4, p. 1704-11; Takagi et al Biomed.
  • Betulinic acid is a naturally occurring triterpene which has been found to have anti-retroviral, anti-malarial, anti-inflammatory (Yogeeswari et al Current
  • R' can be H, CN, C0 2 H, CONH 2 or CHO
  • R" can be C0 2 H or C0 2 Me.
  • Nrf2 is a transcription factor that is responsible for the induction of a number of important antioxidants and detoxification enzymes that protect mammalian cells against reactive oxygen/nitrogen species and electrophiles. Induction of anti-oxidant systems in the kidney has previously been shown to be beneficial in models of hypertension, renal dysfunction and renal failure (Botros et al, Kidney International 2005, 68, p. 2745-2755; Pradhan et al, Am. J.
  • Bardoxolone methyl is currently being evaluated in Phase 2 trials for the treatment of moderate to severe chronic kidney disease (CKD) in type 2 diabetic patients. After a six-month treatment with bardoxolone, an improvement in renal function can be observed, as measured by the estimated glomerular filtration rate, creatinine, blood urea nigrogen (BUN), phosphorus, uric acid and magnesium (Sherwyn et al, oral presentation at the American Diabetes Association Annual Scientific Meeting, June 6, 2009, Abstract no. 112-OR).
  • the invention is based in part on the discovery of Fatty Acid Triterpene Derivatives and their demonstrated effects in achieving improved treatment that cannot be achieved by administering a triterpene or fatty acids alone or in combination.
  • the Fatty Acid Triterpene Derivatives are designed to be stable in the plasma.
  • the individual components i.e. fatty acid, triterpene derivative
  • These novel compounds are useful in the treatment or prevention of metabolic disorders including diabetic nephropathy, chronic kidney disease (CKD), atherosclerosis, dyslipidemia, coronary heart disease, hypercholesterolemia, Type 2 diabetes, elevated cholesterol, metabolic syndrome and cardiovascular disease.
  • autoimmune diseases such as rheumatoid arthritis, cystic fibrosis, inflammatory bowel diseases (including colitis and Crohn's disease) and neurodegenerative diseases such as multiple sclerosis, Parkinson's disease and Alzheimer's disease.
  • neurodegenerative diseases such as multiple sclerosis, Parkinson's disease and Alzheimer's disease.
  • the compounds described herein are also useful in treating psoriasis, and the like.
  • a molecular conjugate which comprises a triterpene covalently linked to a fatty acid, wherein the fatty acid is selected from the group consisting of omega-3 fatty acids and fatty acids that are metabolized in vivo to omega-3 fatty acids, and the conjugate is capable of hydrolysis to produce free triterpene and free fatty acid.
  • Wi and W 2 are each independently null, O, S, NH, NR, or Wi and W 2 can be taken together can form an imidazolidine or piperazine group; each a, b, c, and d is independently -H, -D, -CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(0)OR, -O-Z, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; each n, o, p, and q is independently 0, 1, or 2; each L is independently null, -0-, C(O) ,-S-, -S(O)-, -S(0)2-, -S-S-, (Cl-C6alkyl) , - (C3-C6cycloalkyl)-, a heterocycle, a heteroaryl,
  • each R 6 is independently -H, -D, -C 1 -C4 alkyl, -halogen, cyano, oxo, thiooxo, -OH, -C(0)Ci-C 4 alkyl, -O-aryl, -O-benzyl, -OC(0)Ci-C 4 alkyl, -C1-C3 alkene, -C1-C3 alkyne, -C(0)Ci-C 4 alkyl, -NH 2 , -NH(Ci-C 3 alkyl), -N(Ci-C 3 alkyl) 2 , -NH(C(0)Ci-C 3 alkyl), -N(C(0)Ci-C 3 alkyl) 2 , -SH, -S(C C 3 alkyl),
  • each Ri and R 2 is independently -H, -D, -C 1 -C4 alkyl, -halogen, -OH, -C(0)Ci-C 4 alkyl, -O-aryl, -O-benzyl, -OC(0)Ci-C 4 alkyl, -C1-C3 alkene, -C1-C3 alkyne, -C(0)Ci-C 4 alkyl, -NH 2 , -NH(Ci-C 3 alkyl), -N(Ci-C 3 alkyl) 2 , -NH(C(0)Ci-C 3 alkyl), -N(C(0)Ci-C 3 alkyl) 2 , -SH, -S(C C 3 alkyl), -S(0)C C 3 alkyl, -S(0)C C 3 alkyl,
  • any one or more of H may be substituted with a deuterium. It is also understood in Formula I that a methyl substituent can be substituted with a Ci-C 6 alkyl.
  • compositions comprising at least one fatty acid triterpene derivative.
  • the invention also includes pharmaceutical compositions that comprise an effective amount of a fatty acid triterpene derivative and a pharmaceutically acceptable carrier.
  • the compositions are useful for treating or preventing diabetic nephropathy, chronic kidney disease (CKD) or a metabolic disease.
  • the invention includes a fatty acid triterpene derivative provided as a pharmaceutically acceptable prodrug, a hydrate, a salt, enantiomer, stereoisomer, or mixtures thereof.
  • Metabolic diseases are a wide variety of medical disorders that interfere with a subject's metabolism. Metabolism is the process a subject's body uses to transform food into energy. Metabolism in a subject with a metabolic disease is disrupted in some way. The fatty acid triterpene derivatives possess the ability to treat or prevent metabolic diseases.
  • the fatty acid triterpene derivatives have been designed to bring together triterpene and omega-3 fatty acids into a single molecular conjugate.
  • the activity of the fatty acid triterpene derivatives is substantially greater than the sum of the individual components of the molecular conjugate, suggesting that the activity induced by the fatty acid triterpene derivatives is synergistic.
  • fatty acid triterpene derivatives includes any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the fatty acid triterpene derivatives described herein.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted.
  • C 1 -C 3 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-3 carbon atoms.
  • Examples of a C 1 -C 3 alkyl group include, but are not limited to, methyl, ethyl, propyl and isopropyl.
  • C 1 -C 4 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms.
  • Examples of a C 1 -C 4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.
  • C 1 -C5 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-5 carbon atoms.
  • Examples of a C 1 -C5 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
  • Ci-C 6 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms.
  • Examples of a Ci-C 6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.
  • cycloalkyl refers to a cyclic hydrocarbon containing 3-6 carbon atoms.
  • examples of a cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • any of the substitutable hydrogens on an alkyl or cycloalkyl can be substituted with halogen, C 1 -C 3 alkyl, hydroxyl, alkoxy and cyano groups.
  • heterocycle refers to a cyclic hydrocarbon containing 3- 6 atoms wherein at least one of the atoms is an O, N, or S.
  • heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane.
  • heteroaryl refers to a monocyclic or bicyclic ring structure having 5 to 12 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g. N, O or S and wherein one or more rings of the bicyclic ring structure is aromatic.
  • heteroaryl are pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, xanthenes and dihydroindole. It is understood that any of the substitutable hydrogens on a heteroaryl can be substituted with halogen, C1-C3 alkyl, hydroxyl, alkoxy and cyano groups.
  • any one of the side chains of the naturally occurring amino acids means a side chain of any one of the following amino acids: Isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine, Histidine and Tyrosine.
  • fatty acid as used herein means an omega-3 fatty acid and fatty acids that are metabolized in vivo to omega-3 fatty acids.
  • Non-limiting examples of fatty acids are a//-cz ' s-7,10,13-hexadecatrienoic acid, a-linolenic acid (ALA or all-cis-9, 12,15- octadecatrienoic acid), stearidonic acid (STD or a/7-cz ' s-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-cis- 11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA or a//-cz ' s-8,l l,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA or all-cis- 5,8,11, 14, 17-eicoico
  • triterpene refers to a pentacyclic triterpene derivative such as, for example, but not limited to, bardoxolone, corosolic acid, betulinic acid, maslinic acid, moronic acid, oleanoic acid, glycyrrhetic acid, ursolic acid, boswellic acid, avicins, celastrol, pristimerin, PA-457 and any derivatives thereof.
  • a "subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus, and the terms “subject” and “patient” are used interchangeably herein.
  • the invention also includes pharmaceutical compositions comprising an effective amount of a fatty acid triterpene derivative and a pharmaceutically acceptable carrier.
  • the invention includes a fatty acid triterpene derivative provided as a pharmaceutically acceptable prodrug, hydrate, salt, such as a pharmaceutically acceptable salt, enantiomers, stereoisomers, or mixtures thereof.
  • Representative "pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 - disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, la
  • metabolic disease refers to disorders, diseases and syndromes involving dyslipidemia, and the terms metabolic disorder, metabolic disease, and metabolic syndrome are used interchangeably herein.
  • an "effective amount" when used in connection with a fatty acid triterpene derivative is an amount effective for treating or preventing a metabolic disease.
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • treating refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • prodrug means a compound which is convertible in vivo by metabolic means ⁇ e.g., by hydrolysis) to a fatty acid triterpene derivative.
  • Boc and BOC are tert-butoxycarbonyl
  • Boc 2 0 is di-tert-butyl dicarbonate
  • BSA bovine serum albumin
  • CDI is 1 , ⁇ -carbonyldiimidazole
  • DCC is N,N-dicyclohexylcarbodiimide
  • DIEA is N,N-diisopropylethylamine
  • DMAP is 4-dimethylaminopyridine
  • DMEM is Dulbecco's Modified Eagle Medium
  • DMF is N,N-dimethylformamide
  • DOSS sodium dioctyl sulfosuccinate
  • EDC and EDCI are l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • ELISA is enzyme-linked immunosorbent assay
  • EtOAc is ethyl acetate
  • FBS fetal bovine serum albumin
  • CDI is 1
  • the present invention provides a molecular conjugate which comprises a triterpene and a fatty acid covalently linked, wherein the fatty acid is selected from the group consisting of omega-3 fatty acids and fatty acids that are metabolized in vivo to omega-3 fatty acids, wherein the conjugate comprises at least one amide and the conjugate is capable of hydrolysis to produce free triterpene and free fatty acid.
  • the fatty acid is selected from the group consisting of all- cz ' s-7,10,13-hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid, tetracosahexaenoic acid and lipoic acid.
  • the fatty acid is selected from eicosapentaenoic acid, docosahexaenoic acid and lipoic acid.
  • the hydrolysis is enzymatic.
  • the present invention provides fatty acid triterpene derivatives according to Formula I:
  • G is
  • G is
  • G is [0052] In some embodiments, G is
  • G is
  • G is
  • G is
  • G is
  • G is [0058] In some embodiments, G is
  • G is
  • G is
  • G is
  • G is
  • one Z is
  • one Z is
  • one Z is
  • one Z is
  • one Z is
  • one Z is
  • one Z is and v is 1.
  • one Z is and v is 2. [0071] In some embodiments, one Z is and v is 6.
  • one Z is and s is 3.
  • one Z is and s is 5.
  • one Z is and s is 6. [0075] In other embodiments, Z is and t is 1
  • Z is and t is 1.
  • Wi is NH.
  • W 2 is NH
  • Wi is O.
  • W 2 is O.
  • Wi is null.
  • W 2 is null.
  • Wi and W 2 are each NH.
  • Wi and W 2 are each null.
  • Wi is O and W 2 is NH.
  • Wi and W 2 are each NR, and R is CH 3
  • m is 0.
  • m is 1.
  • n is 2.
  • L is -S- or -S-S-. [0091] In some embodiments, L is -0-.
  • L is -C(O)-.
  • L is heteroaryl
  • L is heterocycle
  • L is N
  • L is N
  • L is N
  • L is N
  • L is [0100] In some embodiments, L is
  • L is ( 2)m * wherein m is 2. In some embodiments, L is
  • L is In some embodiments, L is
  • L is
  • L is
  • L is
  • one of n, o, p, and q is 1.
  • two of n, o, p, and q are each 1.
  • n, o, p, and q are each 1.
  • n, o, p, and q are each 1.
  • one d is C(0)OR.
  • r is 2 and s is 6.
  • r is 3 and s is 5.
  • t is 1.
  • w is 0 [CHI - 1 CAN'T FIND A "w” IN FORMULA I].
  • w is 1 [CHI - 1 CAN'T FIND A "w” IN FORMULA I].
  • Wi and W 2 are each NH, m is 0, n, and o are each 1, and p and q are each 0. [0121] In some embodiments, W 1 and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is O.
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is
  • Wi and W 2 are each NH, m is 1 , n, o, p, and q are each 1 , and L is -S-S-.
  • Wi and W 2 are each NH, m is 1 , n and o are each 0, p and q are each 1 , and L is
  • Wi and W 2 are each NH, m is 1, k is O, n and o are each 0, p and q are each 1 , and L is
  • Wi and W 2 are each NH, m is 1, n and o are each 1 , p and q are each 0, and L is [0127] In some embodiments, Wi and W 2 are each NH, m is 1, k is 0, n is 1, o, p and q are each 0, and L is
  • Wi and W 2 are each NH, m is 1, n, o, and p are each 0, and q is 1 , and L is
  • Wi and W 2 are each NH, m is 1, k is 1, n, o, and p are each 1 , and L is
  • Wi and W 2 are each NH, m is 1, n is 1, and o, p, and q are each 0, and L is In some embodiments, Wi and W 2 are each NH, m is 1, k is 1, o, p, and q are each 0, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is In some embodiments, Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is
  • Wi and W 2 are each NH, m is 0, k is 1, o and p are each 1, and q is 0.
  • Wi and W 2 are each NH, m is 0, n, o, p, and q are each 1. In some embodiments, Wi and W 2 are each NH, m is 0, n and o are each 1 , p and q are each 0, and each a is CH 3 .
  • Wi and W 2 are each NH, m is 0, n and o are each 1 , p and q are each 0, and each b is CH 3 . [0138] In some embodiments, Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, R 3 is H, and L is xV .
  • Wi and W 2 are each NH, m is 1, n, p and q are each 1, and o is 2, R 3 is H, and L is xV .
  • Wi and W 2 are each NH, m is 1, n, o, p are each 1, and q is 2, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is
  • Wi and W 2 are each NH, m is 1, n and p are each 1, and o and q are each 0, and L is -C(O)-.
  • Wi and W 2 are each NH, m is 1, n and p are each 1, and o, and q are each 0, and L is 4-N' R [0144] In some embodiments, Wi and W 2 are each NH, m is 1, n, o, p, q are each 1, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p , and q are each 1, h is 1 , and L is
  • Wi and W 2 are each NH, m is 1, n, o, p , and q are each 1, and L is-S-.
  • Wi and W 2 are each NH, m is 1, n, o, p are each 0, q is 1, one d is -CH 3 , and L is
  • Wi and W 2 are each NH, m is 2, n, o, p, and q are each 0, one L is
  • m is 0, n, o, p, and q are each 0, and Wi and W 2 are taken together to form an optionally substituted piperazine group.
  • m is 1, n, o, p, and q are each 0, W t and W 2 are each null, and L is
  • m is 1, n and p are each 1, o and q are each 0, Wi and W 2 are each NH, and L is C3-C6 cycloalkyl.
  • m is 1, n is 1, o, p, and q are each 0, Wi and W 2 are each NH, and L is C3-C6 cycloalkyl.
  • m is 1 , n, o, p, are each 0, q is 1 , Wi and W 2 are each NH, and L is C3-C6 cycloalkyl.
  • m is 1, n, o, p, and q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1, n, o, p, and q are each 0, Wi is null, W 2 is NH, and
  • m is 1, n, o, p, and q are each 0, Wi is NH, W 2 is null, and
  • L is [0157] In some embodiments, m is 1, n, o, p, and q are each 0, Wi is null, W 2 is NH, and L is
  • m is 1, n is 1, o, p, and q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1, n, o, p, are each 0, q is 1, Wi is null, W 2 is NH, and
  • m is 1, n, o, p, and q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1, n, o, p, and q are each 0, Wi is null, W 2 is NH, and L is
  • m is 1, n is 1, o, p, and q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1, n, o, p, are each 0, q is 1, Wi is null, W 2 is NH, and L is
  • m is 1, n is 1, o, p, and q are each 0, Wi is NH, W 2 is null,
  • m is 1, n, o, p, are each 0, q is 1, Wi is null, W 2 is NH, and
  • m is 1, n, o, p, q are each 0, Wi and W 2 is null, and L is [0167] In some embodiments, m is 1, n, o, p, q are each 0, Wi and W 2 is null, and L is
  • m is 1, n, o, p, q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1, n, o, p, q are each 0, Wi is null, W 2 is NH, and L is
  • m is 1, n, o, p, are each 0, q is 1, Wi and W 2 are each and NH, is null, L is
  • m is 1, n, o, p, are each 0, q is 1, Wi and W 2 are each NH, is null, and L is a heteroaryl.
  • r is 2
  • s is 6
  • t is 1.
  • r is 3, s is 5 and t is 1.
  • any one or more of H may be substituted with a deuterium. It is also understood in Formula I that a methyl substituent can be substituted with a Ci-C 6 alkyl. [0175] In other illustrative embodiments, compounds of Formula I are as set forth below:
  • Also provided in the invention is a method for inhibiting, preventing, or treating inflammation or an inflammatory disease in a subject.
  • the inflammation can be associated with an inflammatory disease or a disease where inflammation contributes to the disease.
  • Inflammatory diseases can arise where there is an inflammation of the body tissue. These include local inflammatory responses and systemic inflammation. Examples of such diseases include, but are not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al, J. Mol. Cell Cardiol. 1999, 31, p.
  • inflammatory diseases of the joints including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, chronic obstructive airway disease, and cystic fibrosis; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; chronic kidney disease (CKD) including focal segmented glomerulosclerosis, nephrotic syndrome, reflux uropathy or polycystic kidney disease; IgA nephropathy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and
  • Metabolic disease such as type II diabetes mellitus; the prevention of type I diabetes; dyslipidemia; hypertriglyceridemia; diabetic complications, including, but not limited to glaucoma, retinopathy, macula edema, nephropathy, such as microalbuminuria and progressive diabetic nephropathy, polyneuropathy, diabetic neuropathy, atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemichyperosmolar coma, mononeuropathies, autonomic neuropathy, joint problems, and a skin or mucous membrane complication, such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorum; immune-complex vasculitis, systemic lupus erythematosus; inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that can have significant inflammatory components,
  • the inflammatory disease can also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to proinflammatory cytokines, e.g., shock associated with proinflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
  • Other disorders include depression, obesity, allergic diseases, acute cardiovascular events, arrhythmia, prevention of sudden death.
  • muscle wasting diseases such as Muscular Dystrophy including but not limited to Duchenne's Muscular Dystrophy, Becker Muscular Dystrophy, Emery- Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Myotonic Dystrophy, Oculopharyngeal Muscular Dystrophy, Distal Muscular Dystrophy, Congential Muscular Dystrophy, Spinal Muscular Atrophy, and Spinal Bulbar Muscular Dystrophy.
  • Muscular Dystrophy including but not limited to Duchenne's Muscular Dystrophy, Becker Muscular Dystrophy, Emery- Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Myotonic Dystrophy, Oculopharyngeal Muscular Dystrophy, Distal Muscular Dystrophy, Con
  • fatty acid triterpene conjugate diseases that can be treated with fatty acid triterpene conjugate include inflammatory myopathies such as dermatomositis, inclusion body myositis, and polymyositis, and cancer cachexia. Also inflammation that results from surgery and trauma can be treated with a Fatty Acid Triterpene Derivative.
  • the compounds described herein are also useful in treating a variety of cancer such as carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiople myeloma, seminoma, and cancer of the bladder, blood, bone, brain, breast, central nervous system, colon, endometrium, esophagus, genitourinary tract, head, larynx, liver, lung, neck, ovary, pancreas, prostate, testicle, spleen, small intestine, large intestine or stomach.
  • cancer such as carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiople myeloma, seminoma
  • cancer of the bladder blood, bone, brain, breast, central nervous system, colon, endometrium, esophagus, genitourinary tract, head, larynx, liver, lung, neck, ovary
  • Fatty Acid Triterpene Derivatives include fatty liver disease, non-alcoholic fatty liver disease, NASH (non-alcoholic steatohepatitis), Sarcopenia, Sjogren syndrome, Myasthenia gravis, and xerophthalmia.
  • Also provided in the invention is a method for inhibiting, preventing, or treating a metabolic disease, or symptoms of a metabolic disease, in a subject.
  • disorders include, but are not limited to atherosclerosis, dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmias, low HDL levels, high LDL levels, sudden death, stable angina, coronary heart disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, stroke, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, intermittent claudication, hyperphosphatemia, carotid atherosclerosis, peripheral arterial disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease, arterial occlusive diseases, cerebral arteriosclerosis, cerebrovascular disorders, myocardial ischemia, polycystic ovary
  • the subject is administered an effective amount of a fatty acid triterpene derivative.
  • the invention also includes pharmaceutical compositions useful for treating or preventing a metabolic disease, or for inhibiting a metabolic disease, or more than one of these activities.
  • the compositions can be suitable for internal use and comprise an effective amount of a fatty acid triterpene derivative and a pharmaceutically acceptable carrier.
  • the fatty acid triterpene derivatives are especially useful in that they demonstrate very low peripheral toxicity or no peripheral toxicity.
  • the fatty acid triterpene derivatives can each be administered in amounts that are sufficient to treat or prevent a metabolic disease or prevent the development thereof in subjects.
  • Administration of the fatty acid triterpene derivatives can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a fatty acid triterpene derivative and a pharmaceutically acceptable carrier, such as: a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega- 3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the fatty acid triterpene derivative is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the fatty acid triterpene derivatives.
  • the fatty acid triterpene derivatives can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the fatty acid triterpene derivatives can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564, the contents of which are herein incorporated by reference in their entirety.
  • Fatty acid triterpene derivatives can also be delivered by the use of monoclonal antibodies as individual carriers to which the fatty acid triterpene derivatives are coupled.
  • the fatty acid triterpene derivatives can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysme substituted with palmitoyl residues.
  • fatty acid triterpene derivatives can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • fatty acid triterpene derivatives are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1 % to about 90 %, from about 10 % to about 90 %, or from about 30 % to about 90 % of the fatty acid triterpene derivative by weight or volume.
  • the dosage regimen utilizing the fatty acid triterpene derivative is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular fatty acid triterpene derivative employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Effective dosage amounts of the present invention when used for the indicated effects, range from about 20 mg to about 5,000 mg of the fatty acid triterpene derivative per day.
  • Compositions for in vivo or in vitro use can contain about 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the fatty acid triterpene derivative.
  • the compositions are in the form of a tablet that can be scored.
  • Effective plasma levels of the fatty acid triterpene derivative can range from about 5 ng/mL to 5,000 ng/mL.
  • Appropriate dosages of the fatty acid triterpene derivatives can be determined as set forth in Goodman, L. S.; Gilman, A. The Pharmacological Basis of Therapeutics, 5th ed.; MacMillan: New York, 1975, pp. 201-226.
  • Fatty acid triterpene derivatives can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, fatty acid triterpene derivatives can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen.
  • Topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of the fatty acid triterpene derivative ranges from about 0.1 % to about 15 %, w/w or w/v.
  • the mono-BOC protected amine of the Formula B can be obtained from commercial sources or prepared according to the procedures outlined in Krapcho et al, Synthetic Communications 1990, 20, p. 2559-2564.
  • Compound A (prepared according to the procedures outlined in Honda et al, J. Med. Chem. 2000, 43, p. 4233-4246) can be amidated with the amine B using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by deprotection of the BOC group with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane to produce the coupled compound C.
  • a coupling reagent such as DCC, CDI, EDC
  • a tertiary amine base and/or catalyst e.g., DMAP
  • the acylated amine of the Formula F can be prepared using the procedures outlined in Andruszkiewicz et al, Synthetic Communications, 2008, 38, p. 905-913.
  • Compound A can be amidated with the amine F using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by deprotection of the BOC group with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane to produce the coupled compound G.
  • Activation of compound G with a coupling agent such as HATU in the presence of an amine such as DIEA followed by addition of a fatty acid of Formula D affords compounds of the formula H.
  • Activation of compound J with a coupling agent such as HATU in the presence of an amine such as DIEA followed by addition of a fatty acid of Formula D affords compounds of the formula K.
  • Hydrolysis of the ester under basic conditions such as NaOH or LiOH produces the corresponding acid, which can be coupled with glycidyl to afford compounds of the Formula L.
  • the amine M can be prepared according to the procedures outlined in Dahan et al, J. Org. Chem. 2007, 72, p. 2289-2296.
  • Compound A can be coupled with the amine M using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by deprotection of the BOC group with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane to produce the coupled compound N.
  • Activation of compound N with a coupling agent such as HATU in the presence of an amine such as DIEA followed by addition of a fatty acid of Formula D affords compounds of the formula O.
  • Compound A can be amidated with the commercially available amine P using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, to afford compound Q.
  • the BOC group in compound Q can be removed with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane and the resulting amine can be coupled with a fatty acid of Formula D using a coupling agent such as HATU in the presence of an amine such as DIEA to afford compounds of the Formula R.
  • the sulfur group in formula Q can be oxidized to the corresponding sulfoxide or sulfone using an oxidizing agent such as H 2 0 2 or oxone.
  • the amine T can be prepared from the commercially available diamine according to the procedures outlined in Dahan et al, J. Org. Chem. 2007, 72, p. 2289-2296.
  • Compound A can be amidated with the amine T using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, to afford compound U.
  • the BOC group of compound U can be removed with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane and the resulting amine can be coupled with a fatty acid of Formula D using HATU in the presence of an amine such as DIEA to afford compounds of the Formula V.
  • the hydroxyl group in compound U can be further acylated or converted to an amino group by standard mesylation chemistry followed by displacement with sodium azide and hydrogenation over a catalyst such as Palladium on carbon.
  • the amine can be further acylated or alkylated, followed by the removal of the BOC group.
  • the resulting amine can be coupled with a fatty acid of the Formula D to afford compounds of the formula W.
  • Compound A can be amidated with the commercially available amine X using a coupling reagent such as DCC, CDI, EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP to afford compound Y.
  • a coupling reagent such as DCC, CDI, EDC
  • a tertiary amine base and/or catalyst e.g., DMAP
  • the BOC group in compound Y can be removed with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane.
  • the resulting amine can be coupled with a fatty acid of the Formula D using a coupling agent such as HATU in the presence of an amine such as DIEA to afford compounds of the Formula Z.
  • Compound A can be amidated with the commercially available cysteine methyl ester using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, to afford compound AA.
  • the commercially available maleimide derivative BB can be coupled with a fatty acid of the Formula D using a coupling agent such as HATU or EDCI to afford compounds of the Formula CC.
  • Compound AA can be coupled to compounds of the Formula CC in a solvent such as acetonitrile to afford compounds of the Formula DD.
  • the commercially available amino acid esters EE can be coupled with a fatty acid of the Formula D using a coupling agent such as EDCI or HATU, followed by alkaline hydrolysis of the methyl ester to afford compounds of the Formula FF.
  • Compounds of the Formula FF can be coupled with the commercially available BOC-amino acid derivatives GG using a coupling agent such as EDCI or HATU.
  • the BOC group can be removed by treatment with acids such as TFA or HCl to afford compounds of the Formula HH which can then be coupled with compound A to afford compounds of the Formula II.
  • RAW264.7 macrophages are seeded at a density of 100,000 cells/well in a 96-well plate in DMEM supplemented with 10% FBS and Penn/strep. 16 hours later, medium is aspirated and replaced with 90uL/well of serum- free DMEM.
  • a fatty acid triterpene derivative, DHA and EPA are brought up in 100% EtOH to a concentration of lOOmM and then diluted 1 : 100 in 100% FBS for a 20x stock solution consisting of ImM compound and 1% EtOH.
  • the fatty acid triterpene derivative 20x stock solutions are diluted 1 :2 in FBS supplemented with 1% EtOH for a 500uM lOx stock solution, whereas equal volumes of the DHA and EPA 20x stock solutions are mixed to create a lOx stock solution containing 500 ⁇ each of DHA and EPA.
  • the lOx stock solutions are then serially diluted 1 :2 in FBS supplemented with 1% EtOH and ⁇ ⁇ , of each dilution is added to the RAW246.7 cells to generate final concentrations of 50, 25, 12.5, 6.25, 3.12 and 1.6 ⁇ .
  • mice Female Sprague-Dawley rats (8 weeks old, with an average weight of 150 g) are used for the study. Diabetes is induced by a single tail vein injection of streptozotocin (STZ) in 0.1 mol/L sodium citrate buffer, pH 4.5. Diabetes is then confirmed by measuring blood glucose levels at two and three days after the STZ treatment. Diabetic animals are classified as those with plasma glucose higher than 16 nmol/L. The diabetic animals are then divided into the vehicle control group and the treatment group (each group having 12 animals). All animals are housed individually with a light dark cycle of 12 hours each, with animals having free access to food and water.
  • STZ streptozotocin
  • diabetic animals are treated with 3 IU of ultralente insulin three times per week in the afternoon (at approximately 3 to 4 pm).
  • the dose of insulin is increased to 5 IU at week 15.
  • Animals are dosed with the vehicle or the fatty acid triterpene derivative over a 28 week period (Examples of vehicles that can be used include combinations of solvents such as polyethylene glycol and propyleneglycol, lipids such as glycerol monooleate and soybean oil, and surfactants such as polysorbate 80 and cremophor EL).
  • solvents such as polyethylene glycol and propyleneglycol
  • lipids such as glycerol monooleate and soybean oil
  • surfactants such as polysorbate 80 and cremophor EL.
  • Progression of renal disease can be assessed by monthly measurements of urinary albumin and plasma creatinine concentrations.
  • Urinary albumin can be quantified by a competitive ELISA assay according to the protocols outlined in Degenhardt et al, Kidney International 2002, 61, p. 939-950.
  • Plasma creatinine concentrations can be measured by the Jaffe picric acid procedure, using the standard kit from Sigma (Sigma cat # 555-A).
  • Statistical analyses can be performed using SigmaStat for Windows VI .00.
  • P values can be calculated by non-parametric Mann- Whitney Rank Sum analysis.
  • dyslipidemia can also be assessed by measuring plasma triglycerides and total cholesterol.
  • Plasma lipids can be measured by enzymatic, colorimetric, end-point assays using standardized, commercially available kits.
  • Total cholesterol can be analyzed using the Sigma kit (cat # 352) and triglycerides can be analyzed by the Sigma kit (cat # 37, GOP Grinder).

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Abstract

L'invention concerne des dérivés de triterpène d'acide gras ; des compositions comprenant une quantité efficace d'un dérivé de triterpène d'acide gras ; et des procédés pour traiter ou prévenir une maladie métabolique comprenant l'administration d'une quantité efficace d'un dérivé de triterpène d'acide gras.
PCT/US2012/036504 2011-05-06 2012-05-04 Dérivés de triterpène d'acide gras et leurs utilisations Ceased WO2012154554A1 (fr)

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