USOO8198324B2

(12) United States Patent (10) Patent No.: US 8,198.324 B2 Fortin (45) Date of Patent: Jun. 12, 2012

(54) COMPOSITIONS COMPRISING Rubinstein, L.V., "Comparison of InVitro Anticancer-DrugScreen POLYUNSATURATED FATTY ACID ing Data Generated with a Tetrazolium Assay Versus a Protein Assay MONOGLYCERDES ORDERVATIVES Against a Diverse Panel of Human Tumor Cell Lines”. JNatl Cancer Inst, Jul. 4, 1990, 1113-1118, vol. 82, No. 13. THEREOF AND USES THEREOF Skehan, P. “New Colorimetric Cytotoxicity Assay for Anticancer DrugScreening”. JNatl Cancer Inst, Jul. 4, 1990, 1107-1112, vol.82. (75) Inventor: Samuel Fortin, Ste-Luce (CA) No. 13. Rose, D.P. “Omega-3 fatty acids as cancer chemopreventive agents'. (73) Assignee: Centre de Recherche sur les Phamarcology & Therapeutics, 1999, 217-244, 83. Biotechnologies Marines, Rimouski Ohta et al., “Action of a New Mammalian DNA Polymerase Inhibitor, (CA) Sulfoquinovosyldiacylglycerol'. Biol. Pharm. Bull., 1999, 111-116 22(2). (*) Notice: Subject to any disclaimer, the term of this Pacetti et al., “High performance liquid chromatography-tandem patent is extended or adjusted under 35 mass spectrometry of phospholipid molecular species in eggs from hens fed diets enriched in seal blubber oil'. Journal of Chromatog U.S.C. 154(b) by 387 days. raphy A, 2005, 66-73, 1097. Watanabe et al., “n-3 Polyunsaturated fatty acid (PUFA) deficiency (21) Appl. No.: 12/536,519 elevates and n-3 pufa enrichment reduces brain 2-arachidonoylglycerol level in mice'. Department of Clinical Appli (22) Filed: Aug. 6, 2009 cation. Institute of Natural Medicine, Toyama Medical and Pharma ceutical University, Prostaglandins, Leukotrienes and Essential Fatty (65) Prior Publication Data Acids 69 (2003) 51-59. US 2010/O196496 A1 Aug. 5, 2010 Schaafet al., “Polyunsaturated Monoglycerides and a Pregnadiene in Defensive Glands of the Water Beetle Agabus affinis”, University of Bayreuth, Department of Animal Ecology II, Lipids vol. 35. No. 5 Related U.S. Application Data (2000), pp. 543-550. (63) Continuation-in-part of application No. Schaafet al., “Polyunsaturated monoglycerides and a pregnadiene in PCT/CA2008/000530, filed on Mar. 19, 2008. defensive glands of the water beetle Agabus affinis”. Department of Aimal Ecology II, University of Bayreuth, Bayreuth, Germany. (60) Provisional application No. 60/895,795, filed on Mar. Lipids (2000), 35(5), 543-550. 20, 2007. Vandevoorde et al. Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of (51) Int. Cl. 1-arachidonoylglycerol with monoacyglycerol lipase abd fatty acid A6 IK3I/22 (2006.01) amide hydrolase. Department of Pharmacology and Clinical A6 IK3I/20 (2006.01) Neuroscience, Umea University, Umea, Swed. Biochemical and Bio physical Research Communications (2005), 337(1), 104-109. Pub (52) U.S. Cl...... 514/549; 514/558: 514/559; 514/560 lisher: Elsevier. (58) Field of Classification Search ...... 514/549, Akoh, Casimir C. Lipase-catalyzed synthesis of partial glyceride. 514/558,559, 560 Dep. Food Sci. Technol. Univ. Georgia, Athens, GA, USA. See application file for complete search history. Biotechnoloy Letters (1993), 15(9), 949-954. An English abstract of JP2000044588. Yagi et al. Novel (56) References Cited monoacylglycosyl monoacylglycerols for Surfactants. (Agency of Industrial Sciences and Technology, Japan) Jpn. Kokai Tokkyo Koho U.S. PATENT DOCUMENTS (2000), 7 pp. CODEN. 6,180,671 B1 1/2001 Freedman et al. Rosu et al., “Enzymic synthesis of glycerides from DHA-enriched 6,552,081 B1 4/2003 Freedman et al. PUFAethyl ester by glycerolysis under vacuum”. Graduate school of 7,138.431 B1 1 1/2006 Chilton Bio- and Agro-Sciences, Laboratory of Molecular Biotechnology, 7,981,915 B2 7, 2011 Freedman Nagoya University, Nagoya Japan. Journal of Molecular Catalysis B. 2002fO188024 A1 12/2002 Chilton et al. Enzymatic (1988), 4(4), 191-198. 2004/0214799 A1 10, 2004 Mukai et al. 2009, 0291 102 A1 11/2009 Fortin (Continued) 2009,0292019 A1 11/2009 Fortin 2010, 0160261 A1 6, 2010 Fortin FOREIGN PATENT DOCUMENTS Primary Examiner — Kevin E Weddington WO O2O64166 8, 2002 (74) Attorney, Agent, or Firm — Bereskin & Parr WO O2O89787 11, 2002 LLP/S.E.N.C.R.L., s.r.l. WO 020964.08 12/2002 WO 2004O24136 3, 2004 WO 2004O64716 8, 2004 (57) ABSTRACT WO 2006, 117668 11, 2006 WO 2008O36353 3, 2008 There are provided various compounds and compositions comprising polyunsaturated fatty acid monoglycerides and OTHER PUBLICATIONS derivatives thereof. These compounds and compositions can Aggarwal et al., Chapter 10, Curcumin-Biologican and medicinal be useful as cancer chemopreventive agents. They can also be Properties, 2007, Medicinal and Aromatic Plants—Industrical Pro useful for enhancing solubility of various active agents and files, Turmeric, 45,297-368. enhancing their bioavailability. Monks, A., “Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines”. JNatl Cancer Inst, Jun. 5, 1991, 757-766, vol. 83, No. 11. 29 Claims, 9 Drawing Sheets US 8,198.324 B2 Page 2

OTHER PUBLICATIONS An English Abstract of JP 02131418 of Okazaki et al., "Comparison of Enhanced and Routine Methods for Measuring Ambient Low Yamane et al. “Mutiple intensified performance of an enzyme-cata Level Sulfur Dioxide”. (Sansei Pharmaceutical Co., Ltd., Japan.) lyzed reaction in organic medium'. Laboratory of Molecular Jpn. Kokai Tokkyo Koho (1980), 7 pp. Biotechnology Graduates School of Bio- and Agro-Sciences, An abstract of Myrdal et al., “Solubilization of Drugs in Aqueous Nagoya University, Nagoya, Japan. Annals of the New York Acad Media' Department of pharmacy Practice and Science, College of emy of Sciences (1988), 864 (Enzyme Engineering XIV), 171-179. Pharmacy, The University of Arizona, Encyclopedia of pharmaceu Ando et al., “Reinvestigation of positional distribution of fatty acids tical technology, published on Oct. 2, 2006. in docosahexaenoic acid-rich fish oil triacyl-sn-glycerols'. Depar An abstract of Rohan et al., “Dietary factors and survival from breast ment of Marine Bioresources Chemnistry, Faculty of Fisheries, Hok cancer', National Cancer Institute of Canada (NCIC) Epidemiology kaido Universit, Hakodate, Japan. Lipids (2000), 35(5), 579-582. Unit, University of Toronto, Nutr Cancer 1993.20(2) 167-77. Kawashima et al., “Enzymatic synthesis of high-purity structured Kafrawy et al., “Docosahexaenoic acid in phosphatidylcholine medi lipids with caprylic acid at 1.3-positions and polyunsaturated fatty ates cytotoxacity more effectively than other (O-3 and (O-6 fatty acid at 2-positin”. Sonoda Wowen's Junior College, Hyogo, Japan. acids'. Department of Biology, Indiana University, Cancer Letters Journal of the American Oil Chemists' Society (2001) 78(6), 611 132(1998) 23-29. 616. Kawashima et al., “Inhibition of Rat Liver Microsomal Desaturases Watanabe et al. “n-3 Polyunsaturated fatty acid (PUFA) deficiency by Curcumin and Related Compounds'. Biosci. Biotech. Biochem. elevates and n-3 PUFA enrichment reduces brain 60(1), pp. 108-110, 1996. 2-arachidonoyglycerol level in mice' Institute of Natural Medicine, Shimizu et al., “Sesamin Is a Potent and Specific Inhibitor of A5 Department of Clinical Application, Toyama Medical and Pharma Desaturase in Polyunsaturated Fatty Acid Biosynthesis”. LIPIDS. ceutical University, Toyama, Japan. Prostaglandins Leukotrienes and vol. 26, No. 7, pp. 512-516, 1991. Essential Fatty Acids (2003), 69(1), 51-59. Nakano et al., “Inhibitory Effects of Capsaicinoids on Fatty Acid Watanabe et al., “Chemical signals involved in larval metamorphosis Desaturation in a Rat Liver Cell Line'. Biosci. Biotech. Biochem. in Hydroides Ezoensis(Serpulidae; Polychaeta). Part II: isolation and 65(8), pp. 1859-1863, 2001. identification of a new monoacyl Glycerol from adult tube clumps as Kawashima et al., “ and Inhibit Fatty Acid a metamorphosis-including Substance'. Department of Applied Bio Desaturases in Rat Liver Microsomes’, Biosci. Biotech. Biochem. logical Chemistry, Faculty of Agricultur, Shizuoka University, 60(10), pp. 1672-1676, 1996. Shizuoka, Japan. Journal of Marine Biotechnology (1998), 61(1), Kawashima et al., “Inhibitory effects of alkyl gallate and its deriva 11-15. tives on fatty acid desaturation'. Biochimica et Biophysica Acta A partial English translation of Tanaka et al., Preparative separation 1299, pp. 34-38, 1996. of acylglycerol by cebtrifugal partition chromatography (CPC). Chau et al., “Monoglyceride and diglyceride lipases from human Tsukuba Res. Lab., Nippon Oil and Fats Co., Ltd., Tsukuba, Japan. platelet microsomes”. Biochimica et Biophysical Acta, 963, pp. 436 Yukagaku (1992), 41(1), 23-7. 444, 1998. Feng Li et al., "Biosynthesis of Docosahexaenoate-Containing Beharry et al., "Long-term docosahexaenoic acid therapy in a Glycerolipid Molecular Species in the Retina” Journal of Molecular congenic murine model of cystic fibrosis'. Am J Physiol Gastrointest Neuroscience (2001), vol. 16, 206-214. Liver Physiol 292:G839-G848, Nov. 9, 2006. An English abstract of JP7149786 of Yazama et al., C. R. Martin et al., “The safety and efficacy of oral docosahexaenoic “Glyceroglycolipid and Carcinogenic Promoter Inhibitor', pub acid Supplementation for the treatment of primary Sclerosing lished on Jun. 13, 1995. cholangitis—a pilot study”. Aliment Pharmacol Ther, Nov.30, 2011; Zerouga et al., “Synthesis of a Novel Phosphatidylcholine Conju 35:255-265. gated to Docosahexaenoic Acid and Methotrexate that Inhibits Cell Freedman et al., “Fatty acids in cystic fibrosis”. Curr Opin Pulm Med Proliferation' Anti-Cancer Drugs (2002), 13, pp. 301-311. 2000, 6:530-532. U.S. Patent Jun. 12, 2012 Sheet 1 of 9 US 8,198.324 B2

In vitro assay of composition 1 On human lung cancer cell line (A549) 120

In vitro assay of purified Curcumin On human lung cancer cell line (A549) 120 100 U.S. Patent Jun. 12, 2012 Sheet 2 of 9 US 8,198.324 B2

In vitro assay of a mixture comprising Composition 1 and purified Curcumin On human lung cancer cell line (A549)

-201Etoposide sugm 25 ugm (25 ugm 625 ugm 33 gmi Sugim Vehicule the

In vitro assay of COmposition 1 On human prostate cancer cell line (PC3) 100

80

60

40

Etoposide 100 ugm 50 ugm 25 ugm 125 ugm 6.25 ugml 313 ugml Vehicule FEF 4. U.S. Patent Jun. 12, 2012 Sheet 3 of 9 US 8,198.324 B2

In vitro assay of purified Curcumin On human prostate cancer cell line(PC3) 100

Etoposide 100 ugm 30 ugm 25 ugm (25 ugm 6.25 ugm 313 ugml Vehicule Fr.

In vitro assay of a mixture Comprising Composition and purified Curcumin On human prostate cancer cell line (PC3) 100 80 60 40 20 Eose sign sign (sign sign sign sign vice Fr. Ei U.S. Patent Jun. 12, 2012 Sheet 4 of 9 US 8,198.324 B2

In vitro assay of composition 1 On human Colon cancer cell line (HCT-15) 120 100

Etoposide tough 50 ugm 25 ugm 125 ugm 6.25 ugml 313 ugml Vehicule Fr. 7

In vitro assay of purified Curcumin On human Colon cancer cell line (HCT-15) 120 100

Etoposide 100 ugm sign 25 ugm 125 ugm 6.25 ugml 313 ugml Vehicule Fr.EFE7 U.S. Patent Jun. 12, 2012 Sheet 5 Of 9 US 8,198.324 B2

In vitro assay of a mixture Comprising composition 1 and purified Curcumin On human Colon cancer cell line (HCT15) 120 100 80

Eose sign sign rigin sign ign sign vetoe Fre,

Curcuminoids solubility

U.S. Patent Jun. 12, 2012 Sheet 6 of 9 US 8,198.324 B2

Change in plasma docosahexaenoic acid (DHA) concentration 11,00% 10,00% res 8,00%70% H S 6.00% -O-Fish Oil 5.00% -- Composition 4,00%30%|| --S 2,00% 1,00% 0.00% O 200 400 600 800 1000 1200 1400 1600 Time (min) Fr. 77 U.S. Patent US 8,198.324 B2

N

WHO % U.S. Patent Jun. 12, 2012 Sheet 8 of 9 US 8,198.324 B2

ETT–EE-ET

WO % U.S. Patent Jun. 12, 2012 Sheet 9 Of 9 US 8,198.324 B2

N (u/5u 00 S1) uunoun)+ CuOSOduoo (u/fu 00 S1) uunono (u/fu 00 Sc) uOSOduoo (u/5u 00 S1) euoZeeuexeO

(u/5u 00 S1) %. OSNO (OS) uuunoun)+ uOSOduo) (O Sal) uuunoun) (OS) uOSOduoo

(OS) %. OSNO US 8,198.324 B2 1. 2 COMPOSITIONS COMPRISING -continued POLYUNSATURATED FATTY ACID II MONOGLYCERDES ORDERVATIVES

THEREOF AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS III

The present application is a continuation-in-part of PCT 10 international patent application No. PCT/CA2008/000530 filed on Mar. 19, 2008, which claims priority on U.S. provi sional application No. 60/895,795 filed on Mar. 20, 2007. These applications are incorporated herein by reference in IV their entirety. 15

FIELD OF THE DISCLOSURE

The present disclosure relates to the field of medicinal chemistry. More particularly, it relates to polyunsaturated fatty acid monoglyceride compounds and derivatives thereof. wherein It also relates to compositions which comprise such com X is O, NH, or S: pounds. There is also provided a method for enhancing the 25 X is O, NH, or S: bioavailability of an active agent and a method for enhancing X is O, NH, or S; solubility of such an active agent. R and R. each independently represents —H. —C(O) NH, —S(O)NH2. —S(O)NH2. —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 BACKGROUND OF THE DISCLOSURE 30 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alk enyl, - C3-C22 alkynyl, —(C3-C7) cycloalkyl unsub The primary targets for any dosage formulation is to deliver stituted or Substituted with at least one substituent cho the necessary concentration of an active drug to the site of sen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 action to elicit the desired therapeutic response and to main C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl, tain an effective concentration of the drug for a sufficient 35 —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, period to achieve efficacious treatment. Oral administration is three- to seven-membered non-aromatic heterocycle generally preferred but is frequently dependent upon the bio unsubstituted or substituted with at least one substituent availability of the active form of the drug, i.e., the rate and chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and extent that the active form of the drug appears from the dosage —C2-C22 alkynyl, five- to seven-membered aromatic form in the systemic circulation. Bioavailability is affected by 40 heterocycle unsubstituted or substituted with at least one the drug's physical chemical properties. Such as pKa, water substituent chosen from —C1-C22 alkyl, —C2-C22 solubility, oil solubility and stability, as well as its absorption, alkenyl, and —C2-C22 alkynyl, -(CH)amino acid distribution, metabolism and excretion. It is well known that wherein the amino acid is connected through its alpha water insoluble drugs are not generally available for absorp carbon atom, -(CH2), peptide wherein the peptide is tion through intestinal lumin and oil insoluble drugs are gen 45 connected through the alpha carbon atom of one of its amino acids, —CHORs, —C(O)Rs, —C(O)ORs, erally unable to pass across intestine cell membranes into —C(O)NRs. -P(O)(OR), -S(O)NHRs, -SOR, systemic circulation (S. H. Yalkowsky, "DRUGS AND THE —S(O)2Rs, -arylP(O)(ORs), a Sugar, or a Sugar phos PHARMACEUTICAL SCIENCES: TECHNIQUES OF phate SOLUBILIZATION OF DRUGS. Marcel Dekker, Inc., Vol. 50 or R and R2 are joined together so as to form a five- to 12, 1981). Proper formulations can improve the bioavailabil seven-membered non-aromatic heterocycle unsubstituted or ity of a drug. substituted with at least one substituent chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phos SUMMARY OF THE DISCLOSURE phate, Sulfate carbonyl group, or a thiocarbonylimine; 55 Rs is —H. —C1-C22 alkyl, —(C3-C7) cycloalkyl, - C1 C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 alkenyl, —C2 According to one aspect there are provided compounds of C22 alkynyl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, formulas (I), (II), (III), and (IV): —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, —C1 C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7) cycloalkyl 60 unsubstituted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C-C22 alkynyl, a three- to seven-membered non-aromatic hetero cycle unsubstituted or substituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2 65 C22 alkynyl, a three- to seven-membered aromatic hetero cycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2 US 8,198.324 B2 3 4 C22 alkynyl, a —(CH)amino acid wherein the amino acid is -continued connected to the compound through its alpha carbon atom, a XII

—(CH), peptide wherein the peptide is connected to the O compound through the alpha carbon atom of one of its amino acids, a Sugar or a Sugar phosphate; and 5 n is an integer having a value of 0, 1, 2, 3, or 4. and pharmaceutically acceptable salts thereof. According to another aspect there are provided compounds of formulas (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), 10 (XIII), (XIV) or (XV):

X is O, NH, or S: X is O, NH, or S: X is O, NH, or S; R and R each independently represents —H. —C(O) NH = S(O)NH2. —S(O)NH2. —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (ami no)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, —C3 C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted or substi tuted with at least one substituent chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, three- to seven-membered non-aromatic het erocycle unsubstituted or substituted with at least one sub stituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic hetero cycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 alkynyl, -(CH2)amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH), peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH2ORs, —C(O)R. —C(O)CR = C(O)NR, -P(O)(OR), S(O)NHRs, —SORs, —S(O)Rs, -arylP(O)(ORs), a Sugar, or a Sugar phosphate, or R and R are joined together so as to form a five- to seven-membered non-aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1 -OH C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, a phos p-R phate, Sulfate carbonyl group, or a thiocarbonylimine; o o o *-Qub Rs is —H. —C1-C22 alkyl, —(C3-C7) cycloalkyl, - C1 65 C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 alkenyl, —C2 o o O C22 alkynyl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, US 8,198.324 B2 5 6 C22 alkoxy, —C1-C22 (amino)alkyl, a —(C3-C7) cycloalkyl According to another aspect, there is provided a method for unsubstituted or substituted with at least one substituent cho chemopreventing cancer comprising administering to a Sub sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 ject an effective amount of at least one compound or compo alkynyl, a three- to seven-membered non-aromatic hetero sition as previously defined. Sucha cancer can be lung cancer, cycle unsubstituted or substituted at least one substituent prostate cancer, breast cancer, or colon cancer. chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2 According to another aspect, there is provided a method for C22 alkynyl, a three- to seven-membered aromatic hetero reducing tumor growth in a Subject comprising administering cycle unsubstituted or substituted with at least one substituent to the Subject an effective amount of at least one compound or chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2 composition as previously defined. C22 alkynyl, a —(CH)amino acid wherein the amino acid is 10 According to another aspect there is provided a method for connected to the compound through its alpha carbon atom, a treating cancer (for example breast cancer, lung cancer, pros —(CH), peptide wherein the peptide is connected to the tate cancer, colon cancer) comprising administering to the compound through the alpha carbon atom of one of its amino subject in need thereof an effective amount of at least one acids, a Sugar or a Sugar phosphate; and 15 compound chosen from compounds of formulas I, II, III, IV, n is an integer having a value of 0, 1, 2, 3, or 4: V,VI,VII, VIII, IX, X, XI, XII, XIII, XIV, and XV. and pharmaceutically acceptable salts thereof. According to another aspect there is provided a method for The previously mentioned compounds can be used sepa treating cancer (for example breast cancer, lung cancer, pros rately or in a mixture (or composition) of at least two of them tate cancer, colon cancer) comprising administering to the (for example 2, 3, 4, 5 or 6 of them). Thus, the present subject in need thereof an effective amount of at least one disclosure also includes compositions comprising at last two active agent and an effective amount of at least one compound compounds of the present disclosure, of the present disclosure. For example, a composition com According to another aspect, there is provided a composi prising an effective amount of the at least one active agent and tion comprising at least one compound chosen from com an effective amount of at least one compound of the present pounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, 25 disclosure can be administered. Alternatively, the effective XII, XIII, XIV, and XV; and at least one active agent. amount of the at least one active agent and the effective According to another aspect, there is provided a method for amount of the at least one compound can be administered solubilizing a lipophilic active agent. The method comprises separately. For example, the active agent can be curcumin. mixing the lipophilic active agent with at least one compound According to another aspect there is provided a method for chosen from compounds of formulas I, II, III, IV, V, VI, VII, 30 inhibiting tumor growth, inhibiting tumor cell proliferation, VIII, IX, X, XI, XII, XIII, XIV, and XV. The method can or reducing tumor growth, in vitro or in Vivo, comprising further comprise mixing a lipid with the at least one com administering an effective amount of at least one active agent pound and the lipophilic active agent. and an effective amount of at least one compound of the According to another aspect, there is provided a method for present disclosure. For example, a composition comprising enhancing the solubility of at least one active agent in a lipid 35 an effective amount of the at least one active agent and an or a lipid formulation. The method comprises mixing the at effective amount of at least one compound of the present least one active agent, and at least one compound chosen from disclosure can be administered. Alternatively, the effective compounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, amount of the at least one active agent and the effective XI, XII, XIII, XIV, and XV. The method can comprise mixing amount of the at least one compound can be administered together the at least one active agent and the at least one 40 separately. compound so as to obtain a composition and then, mixing the According to another aspect, there is provided a method for lipid and the composition or the method can comprise mixing enhancing bioavailability of at least one active agent. The together the lipid and the at least one compound so as to method comprises mixing the at least one active agent with at obtain a composition and then, mixing the at least one active least one compound of the present disclosure. agent and the composition. For example, the lipid can be 45 According to another aspect, there is provided a method for chosen from compounds of formulas I, II, III, IV, V, VI, VII, enhancing bioavailability of at least one active agent. The VIII, IX, X, XI, XII, XIII, XIV, and XV or the lipid formula method comprises adminitering to a Subject an effective tion can comprise at least one compound chosen from com amount of the at least one active agent and an effective pounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, amount of at least one compound of the present disclosure. XII, XIII, XIV, and XV. 50 For example, a composition comprising an effective amount According to another aspect, there is provided a method for of the at least one active agent and an effective amount of at enhancing bioavailability of at least one active agent. The least one compound of the present disclosure can be admin method comprises mixing the at least one active agent with at istered. Alternatively, the effective amount of the at least one least one compound chosen from compounds of formulas I. active agent and the effective amount of the at least one II, III, IV, V,VI,VII, VIII, IX, X, XI, XII, XIII, XIV, and XV. 55 compound can be administered separately. For example, the compounds and compositions of the According to another aspect, there is provided a method for present disclosure can be used for treating cancer (for enhancing bioavailability of at least one lipophilic active example breast cancer, lung cancer, prostate cancer, colon agent, natural product or natural crude extract. The method cancer). comprises adminitering to a Subject an effective amount of For example, the compounds and compositions of the 60 the at least one lipophilic active agent, natural product or present disclosure can be used for enhancing bioavailability natural crude extract and an effective amount of at least one of at least one active agent. compound of the present disclosure. For example, a compo According to another aspect, there is provided a method for sition comprising an effective amount of the at least one inhibiting tumor growth, inhibiting tumor cell proliferation, lipophilic active agent, natural product or natural crude or reducing tumor growth, in vitro or in vivo. The method 65 extract and an effective amount of the at least one compound comprises contacting the tumor with an effective amount of at of the present disclosure can be administered. Alternatively, least one compound or composition as previously described. the effective amount of the at least one lipophilic active agent, US 8,198.324 B2 7 8 natural product or natural crude extract and the effective FIG. 6 represents an in vitro assay of a composition accord amount of the at least one compound can be administered ing to another example, wherein the assay was carried out on separately. PC3 human cancer cell line; According to another aspect, there is provided a method for FIG.7 represents an in vitro assay of a composition accord enhancing bioavailability of at least one active agent present ing to another example, wherein the assay was carried out on in at least one oil. The method comprises adminitering to a HCT-15 human cancer cell line; Subject an effective amount of the at least one oil and an FIG.8 represents an in vitro assay of a composition accord effective amount of at least one compound of the present ing to another example, wherein the assay was carried out on disclosure. For example, a composition comprising an effec HCT-15 human cancer cell line; tive amount of the at least one oil and an effective amount of 10 FIG.9 represents an in vitro assay of a composition accord at least one compound of the present disclosure can be admin ing to another example, wherein the assay was carried out on istered. Alternatively, the effective amount of the at least one HCT-15 human cancer cell line; oil and the effective amount of the at least one compound can FIG. 10 represents a comparative solubility study of bis be administered separately. 15 demethoxycurcumin, demetoxycurcumin, curcumin and It was found that the compounds and compositions previ total curcuminoids in two different solvents which are a fish ously mentioned can be useful as bioavailability enhancers of oil and a composition according to another example: various types of active agents. FIG. 11 represents a comparative in vivo absorption study It was also found that the compounds and compositions of two different formulations containing docosahexaenoic previously mentioned can enhance the solubility of an active acid (DHA) which are a fish oil and a composition according agent Such as a lipophillic active agent. It was observed that to another example; active agents can be more easily solubilized in the compounds FIG. 12 represents a comparative human absorption cross and compositions previously defined than in the usual lipids over study of two different compositions containing docosa or lipid formulations. Thus, the active agents that need to be hexaenoic acid (DHA) which are a fish oil and a composition dissolved in a lipid or a lipid formulation can be dissolved in 25 according to another example: the compounds or compositions as those previously defined FIG. 13 represents a comparative human absorption cross instead than in other conventional lipids or lipid formulations. over study of two different compositions containing omega-3 Alternatively, such active agents can be mixed with at least docosapentaenoic acid (DPAC)3) which are a fish oil and a one compound or composition as previously defined in order composition according to another example; and to obtain another composition and then the other composition 30 FIG. 14 represents an in vitro assay of a composition can be dissolved in a lipid or a lipid formulation. In such a according to an example, wherein the assay was carried out on case, the overall solubility of the active agent in the lipid or human THP-1 monocyte cell. lipid formulation is enhanced. According to another aspect, there is provided a method for DETAILED DESCRIPTION OF THE treating an inflammatory disease comprising administering to 35 DISCLOSURE a subject in need thereof an effective amount of at least one Further features and advantages of the previously-men active agent and an effective amount of at least one compound tioned compounds will become more readily apparent from of the present disclosure. For example, a composition com the following description of non-limiting examples. prising an effective amount of the at least one active agent and 40 The compounds and compositions of the present disclosure an effective amount of at least one compound of the present can also be effective so as to enhance solubility of various disclosure can be administered. Alternatively, the effective active agents. They can also be used as a emulsifier alone, amount of the at least one active agent and the effective emulsifier in a self-emulsifying drug delivery systems amount of the at least one compound can be administered (SEDDS), self-microemulsifying drug delivery systems separately. 45 (SMEDDS) and selfemulsifying oil formulations (SEOF) for improved oral delivery of a lipophilic active agent, natural BRIEF DESCRIPTION OF THE FIGURES product or natural crude extract. They can also be used in combination with a 1-monoglyceride, 2-monoglyceride, 1.2- Further features and advantages will become more readily diglyceride, 1,3-diglyceride, triglyceride, free fatty acid, apparent from the following description of specific embodi 50 phospholipid and pharmaceutically acceptable salts thereof. ments as illustrated by way of examples in the appended For example, they can also be used in combination with figures wherein: Vegetable oil, fish oil, Seal oil, microalgae oil, krill oil and FIG.1 represents an in vitro assay of a composition accord crustacean oil (ex. shrimp oil). According to another example, ing to an example, wherein the assay was carried out on A549 they can also be used in combination with oil hydrolysate human cancer cell line; 55 from vegetable oil, fish oil, Seal oil, microalgae oil, krill oil FIG.2 represents an in vitro assay of a composition accord and crustacean oil (ex. shrimp oil). According to another ing to another example, wherein the assay was carried out on example they can be used in combination with proteins A549 human cancer cell line; hydrolysate from vegetable, animal and marine source. FIG.3 represents an in vitro assay of a composition accord Moreover, they can also be used to form micelle or liposome ing to another example, wherein the assay was carried out on 60 for a drug delivery system. A549 human cancer cell line; According to another example, the active agent can be a FIG.4 represents an in vitro assay of a composition accord lipid oran hydrolysate thereof, or a protein oran hydrolysate ing to another example, wherein the assay was carried out on thereof. PC3 human cancer cell line; According to another example, the active agent can be FIG.5 represents an in vitro assay of a composition accord 65 chosen from a fatty acid, a salt thereof, an ester thereof (for ing to another example, wherein the assay was carried out on example a monoglyceride, a diglyceride, or a triglyceride), PC3 human cancer cell line; and mixtures thereof. US 8,198.324 B2 10 According to another example, the active agent can be a Zoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefu fatty acid or a derivative thereof (for example an C1-C6 ester Zonam Sodium, clarithromycin, dalfopristin, dirithromycin, (C1-C6 being the amount of carbon atoms in the “alcohol doripenem, ertapenem Sodium, acistrate, flo portion of the ester) of a fatty acid such as an ethyl ester) or a moxefsodium, flurithromycin ethylsuccinate, fropenam, imi pharmaceutically acceptable salt thereof. penem/cilastatin, lenampicillin HCl, loracarbef, meropenem, According to another example, the active agent can be a moxalactam disodium, panipenem/betamipron, quinupristin, polyunsaturated fatty acid chosen from arachidonic acid, rifabutin, rifamixin, rifapentine, , rokitamycin, (D3-arachidonic acid, alpha-linolenic acid, conjugated roXithromycin, Sultamycillin tosylate, taZobactam Sodium, linoleic acid, linoleic acid, gamma-linolenic acid, dihomo telithromycin, temocillin disodium, tigecycline, balafloxa gamma-linolenic acid, Stearidonic acid, eicosapentaenoic 10 cin, ciprofloxacin, enoxacin, fleroxacin, gatilfloxacin, gemi acid, (O3-docosapentaenoic acid, (D6-docosapentaenoic acid, floxacin mesilate, grepafloxacin, levofloxacin, lineZolid, docosahexaenoic acid, monoglycerides thereof, diglycerides lomefloxacin, moxifloxacin HCl, nadifloxacin, norfloxacin, thereof, triglycerides thereof, phospholipids thereof, and salts ofloxacin, paZufloxacin, pefloxacin meSylate, prulifloxacin, thereof. rufloxacin hydrochloride, sparfloxacin, taurolidine, tema According to another example, the active agent can be a 15 floxacin hydrochloride, toSufloxacin, trovafloxacin mesylate, compound chosen from compounds previously defined. rodimoprin, ACWY mening.occal PS vaccine, MCV-4, h According to another example, the active agent can be influenzae b vaccine, h influenzae b vaccine, meningitis b chosen from any of the following therapeutic class: analgesic, vaccine, meningococcal vaccine, oral cholera vaccine, pneu anesthetic, anti-Alzheimer's, anti-asthma agent, anti-Parkin mococcal vaccine, and Vi polysaccharide typhoid vaccine Sonism, antiallergic, antianginal, antiarrhythmic, antiar According to another example, the active agent can be an thritic, antiasthmatic, antibacterial, antibiotic, anticancer, agent. The antifungal agent can be, for example, anticoagulant, antidepressant, antidiabetic, antiemetic, anti chosen from interferon gamma-nl, anidulafungin, caspofun epileptic, antifungal, antiglaucoma, anti-gout, antihistamine, gin acetate, micafungin sodium, amorolfine hydrochloride, antihyperprolactinemia, antihypertensive, antiinflammatory, butoconazole, ciclopirox, olamine, cloconazole HCl, eber antimigraine, anti-neoplastic, antiobesity, antiparasitic, anti 25 conazole, fenticonazole nitrate, fluconazole, flutrimazole, protozoal, anti-phyretics, antipsoriatic, antipsychotic, anti fosfluconazole, itraconazole, , lanoconazole, thrombotic, antiulcer, antiviral, anxiolytic, benign prostatic luliconazole, naftifine HCl, neticonazole HCl, oxiconazole hypertrophy, bronchodilator, calcium metabolism, cardio nitrate, posaconazole, Sertaconazole nitrate, Sulconazole tonic, cardiovascular agent, chelator & antidote, chemopre nitrate, Gyno, tioconazole, Voriconazole, buten ventive agent, contraception, diuretic, dopaminergic agent, 30 afine hydrochloride, liranaftate, and terbinafine hydrochlo gastrointestinal agent, gastroprokinetic, hematopoiesis, ride hemophilia, hormone, hormone replacement therapy, hyp According to another example, the active agent can be an notic, hypocholesterolemic, hypolipidemic, immunomodula antiviral agent. Non-limitative examples of antiviral agents tor, immunostimulant, immunosuppressant, lipid regulating are: immunoglobulin intravenous, interferon alfa, interferon agent, male sexual dysfunction, multiple Sclerosis, muscle 35 alfa-2b, interferon alfa-n3, interferon alfacon-1, interferon relaxant, neuroleptic, nootropic, osteoporosis, phytoestro beta, palivizumab, peginterferon alfa-2a, peginterferon alfa gen, platelet aggregation inhibitor, prostaglandin, radioen 2b, resp syncytial virus IG, thymalfasin, interferon alfa-n1. hencer for radiotherapy, relaxant and stimulant, respiratory enfuVirtide, Zanamivir, delavirdine mesylate, , fos distress syndrome, urinary incontinence, vasodilator, Vita carnet Sodium, imiquimod, , propagermanium, min/nutritional, Vulnerary and Xanthine. Active agents 40 rimantadine HCl, oseltamivir, abacavir Sulfate, acyclovir, belonging to these classes can be used in the previously adefovir dipivoxil, cidofovir, didanosine, emitricitabine, ente mentioned compositions. cavir, eperVudine, famciclovir, ganciclovir, inosine pranobex, According to one example, the active agent can be a lamivudine, penciclovir, Sorivudine, stavudine, tenofovir chemopreventive agent. The chemopreventive agent can be, disoproxil fumarate, Valaciclovir HCl, Valganciclovir, Zalcit for example, chosen from 13-cis-retinoic acid, 9-cis retinoic 45 abine, Zidovudine, amprenavir, atazanavir, darunavir, acid, anetholtrithione, arZoxifene hydrochloride, aspirin, fomivirsen Sodium, fosamprenevir, Sulfate, lopi bexarotene, biaxin (clarithromycin), budesonid, calcium, navir, neflinavir mesylate, , saquinavir mesylate, celecoxib, curcumin, DFMO, DHEA (Dehydroepiandroster tipranavir, MR vaccine, anti-Hep B immunoglobulin, attenu one), fenretinide, indole-3-carbinol, 1-perillyl alcohol, lyco ated chickenpox vaccine, hepatitis A and B vaccine, hepatitis pene, oltipraz, phenethyl isothiocyanate (PEITC), piroxicam, 50 B vaccine, hepatitis a vaccine, inact hepatitis a, influenza raloxifen, selenium, Soy isoflavones, Sulindac, tamoxifen, vaccine, influenza virus (live), rotavirus vaccine, rubella vac 4-hydroxy-tamoxifen, citrate, tea polyphenols, ursodiol, Vita cine, varicella virus vaccine, and Zoster vaccine live. min D and analogs, and Zileuton. According to another example, the active agent can be an According to another example, the active agent can be an antiparasitic agent. Non-limitative examples of antiparasitic antibacterial agent. Non-limitative examples of antibacterial 55 agents are: , ivermectin, arteether, artemether, agents are RV-11, carumonam, daptomycin, fosfomycin artenusate, eflornithine HCl, mefloquine HCl, albendazole, trometamol, isepamicin, micronomicin Sulfate, miokamycin, halofantrine, lumefantrine, quinfamide, atovaquone, mupirocin, netilimicin Sulfate, teicoplanin, apalcillin Sodium, bulaquine/chloroquine, and trichomonas vaccine arbekacin, aspoxicillin, astromycin Sulfate, azithromycin, According to another example, the active agent can be an aztreonam, biapenem, cefbuperaZone sodium, cefcapene piv 60 anticancer agent. Non-limitative examples of anticancer oxil, cefdinir, cefditoren pivoxil, cefepime, cefetamet pivoxil agents are H-101, aldesleukin, alemtuzumab, bevacizumab, HCl, cefixime, cefinenoxime HCl, cefiminox, sodium, cefo celmoleukin, cetuximab, denileukin, diftitox, interferon dizime Sodium, cefonicid sodium, cefoperaZone sodium, alfa2a, interferon alfa2b, interferon gamma-1a, interleukin-2, ceforanide, cefoselis, cefotetan disodium, cefotiam HCl, mobenakin, pegaspargase, rituximab, tasonermin, teceleu cefoZopran HCl, cefpimizole, ce?piramide Sodium, cef 65 kin, to situmomab, trastuzumab, aclarubicin, actinomycin D, pirome sulfate, cefpodoxime proxetil, cefprozil, cefsoludin angiotensin II, arglabin, asparaginase, bleomycin, carzino sodium, ceftazidime, cefteram pivoxil, ceftibuten, cefti philin, chromomycin A3, daunomycin, doxorubicin, leucov US 8,198.324 B2 11 12 orin, masoprocol, mithramycin, mitomycin C, neocarzinosta hound, blessed thistle, biotin, boldo, burdock, calcium, cal tin, , palictaxel nanoparticles, pentostatin, endula, California poppy, caraway, Cascara Sagrada, catnip, peplomycin, Sarkomycin, Solamargine (aka BEC), StreptoZo cayenne, chaste tree fruit, chondroitin Sulphate, copper, cin pre-, taxotere, testosterone pre-, vinblastine, Vincristine, cramp bark, cranberry, dandelion, dang gui, devil's claw, alitretinoin, amrubicin HCl, belotecan hydrocholoride, calus echinacea, echinacea purpurea, echinacea pallida, eleuth terone, cladribine, cytarabine ocfosfate, , doc ero, evening primrose oil, european linden, european penny etaxel, dromostanolone, elliptinium acetate, epirubicin HCl, royal, fenugreek, feverfew, figwort, flax, folate, frankincense, estramustine, ethinyl estradiol pre-, toposide, exemestane, garlic, gentian, ginger, ginkgo, globe artichoke, glucosamine, fluoxymesterone pre-, formestane, foSfestrol pre-, fulves goldenseal, green tea, ground ivy, hawthorn, heal-all, hops, trant, gemtuzumab, oZogamicin, goserelin acetate, hexyl 10 horse chestnut, horseradish, hyssop, illicium verum, juniper, aminolevulinate, histrelin, hydroxyprogesterone pre-, idaru licorice, linden, lungwort, lutein, melatonin, milk thistle, bicin hydrochloride, irinotecan hydrochloride, leuprolide, mugwort, niacin, pantothenic acid, peppermint, reishi mush medroxyprogesterone acetate, megesterol acetate, methyl room, riboflavin, rosemary, saw palmetto, Scullcap, selenium, , methyltestosterone, miltefosine, mitobronitol, schisandra, stinging nettle, St. John’s wort, thuja, thyme, nadrolone phenylpropionate, norethindrone acetate pre-, 15 tomato, turmeric, Valerian, willow bark, witch hazel or Zeax pirarubicin, prednisolone pre-, prednisone pre-, teniposide, anthin. testolactone, topotecan HCl, triamcinolone, triptorelin, val According to another example, the active agent can be rubicin, vapreotide acetate, Vindesine, Vinorelbine, Zinostatin curcumin, artemisinin, astaxanthin, lutein, or zeaxanthin. stimalamer, amsacrine, arsenic trioxide, bisantrene hydro According to another example the active agent can be a chloride, busulfan, carboplatin, carmustine (BCNU), turmeric crude extract or purified extract from turmeric crude chlorambucil, chlortrianisene pre-, cis-diamminedichloro extract, an artemisia crude extract or purified extract from platinum, , dacarbazine, diethylstilbestrol artemisia crude extract, green lipped mussels crude extractor pre-, flutamide, fotemustine, heptaplatin/SK-2053R, hexam purified extract from green lipped mussels crude extract, a ethylmelamine, hydroxyurea, ifosfamide, lenalidomide, crude extract or purified extract of a microalgae. levamisole pre-, lobaplatin, lomustine (CCNU), lonidamine, 25 According to another example the active agent can be a mechlorethanamine, melphalan, mitotane, medaplatin, niluta Haematococcus pluvialis microalgae crude extract or puri mide, nimustine hydrochloride pre-, oxaliplatin, pamidr fied extract from Haematococcus pluvialis microalgae crude onate, pipobroman, porfimer Sodium, procarbazine, ranimus eXtract. tine, razoxane pre-, Semustine (MCCNU) pre-, Sobuzoxane, The person skilled in the art would be able to identify, Sorafenib mesylate, thiotepa, triethylenemelamine pre-, 30 among the active agents previously described, those that can Zoledronic acid, anastroZole, bicalutamide, bortezomib, be considered as lipophillic active agents. camostat mesylate, dasatinib, erlotinib hydrochloride, fadro According to another example, the at least one compound Zole HCl, gefitinib, imatinib mesilate, letrozole, nafoxidine present in an oil can be a fatty acid or a derivative thereof (for pre-, Sunitinib maleate, tamoxifen, toremifene, aminoglute example an C1-C6 ester (C1-C6 being the amount of carbon thimide, azacytidine pre-, apecitabine, carmofur, clofarabine, 35 atoms in the “alcohol portion of the ester) of a fatty acid such cytosine arabinoside, decitabine, doxifluridine, enocitabine, as an ethyl ester) or a pharmaceutically acceptable salt floxuridine, fludarabine phosphate, fluorouracil, forafur, thereof. gemcitabine HCl, mercaptopurine, methotrexate, mitox According to another example, the oil can be a vegetable antrone HCl, nelarabine, thioguanine, uracil mustard, oil (such as flaxseed oil, pumpkinseed oil, canola oil, soybean abarelix, bexarotene, pemetrexed, raltitrexed, tamibarotene, 40 oil, or walnut oil), fish oil (such as cod liver oil, salmon oil, temozolomide, bcg live, and melanoma theraccine tuna oil, shark oil, pelagic fishes oil, or sardine oil), seal oil, According to another example, the active agent can be an microalgae oil, krill oil, crustacean oil (for example shrimps antidiabetic agent. Non-limitative examples of antidiabetic oil), mussels oil (for example green lipped mussels oil), or agents are biphasic porcine insulin, hu neutral insulin, human mixtures thereof. insulin Zn suspension, human insulin Zinc suspension, human 45 The Sugar can be chosen from 5-carbon Sugars and 6-car neutral insulin, insulin aspart, insulin aspart/IA protamine, bon Sugars. Non-limiting examples of 5-carbon Sugar include insulin determir, insulin glargine, insulin glulisine, insulin ribose, arabinose, Xylose, and lyxose. Non-limiting examples lispro, isophane insulin, mecasermin, oral insulin, porcine of 6-carbon Sugar include glucose, galactose, mannose, isophane insulin, porcine neutral insulin, pulmonary insulin, allose, gulose, idose, talose, and altrose. soluble insulin, Voglibose, acarbose, extenatide, miglitol, 50 The Sugarphosphate can be chosen from monosaccharides triproamylin acetate, glimepiride, mitiglinide calcium (such as mannose-6-phosphate, glucose-6-phosphate, galac hydrate, pioglitaZone, repaglinide, epalrestat, rosiglitaZone tose-6-phosphate, mannose-1-phosphate, glucose-1-phos maleate, tolrestat, , and nateglinide phate and galactose-1-phosphate), disaccharides (such as According to another example, the active agent can be a 6-O-phosphoryl-a-D-mannopyranosyl-(1-2)-D-mannopyra natural product or natural product crude extract chosen from 55 nose, 6-0-phosphoryl-a-D-mannopyranosyl-(1-3)-mannopy a vegetable, mussels (for example, green lipped mussels), ranose, 6-O-phosphoryl-a-D-mannopyranosyl-(1-6)-D-man shrimps, fish, Seal, microalgaee, krill, a crustacean; an nopyranose), trisaccharides (such as 6-O-phosphoryl-a-D- hydrolysate from vegetable oil, fish oil, seal oil, microalgae mannopyranosyl-(1-2)-D-mannopyranosyl-(1-2)-D- oil, krill oil or crustacean oil, a vegetable oil, mussels oil (for mannopyranose), and higher linear or branched example green lipped mussels oil), shrimps oil, fish oil, seal 60 oligosaccharides (such as pentamannose-6-phosphate). oil, microalgae oil, krill oil, a crustacean oil; and a proteins The amino acid can be chosen from alanine, arginine, hydrolysate from vegetable, animal or marine source. asparagine, aspartic acid, cysteine, glutamine, glutamic acid, According to another example, the active agent can be ana glycine, isoleucine, leucine, lysine, methionine, phenylala natural product or natural product crude extract, which can nine, proline, serine, threonine, tryptophan, tyrosine, and be, for example, alfalfa, aloe, angelica, arnica, aristolochic 65 Valine. acid, artemisia, astaxanthin, ashwaganda, astragalus, avens, The peptide can be chosen from any possible combination beta-carotene, bilberry, birch, black cohosh, black hore of the amino acids previously described. US 8,198.324 B2 13 14 The compounds and compositions previously defined can atoms for linoleic acid (18:2); and between the 9th and 10th, be in a mixture with a vegetable oil (such as flaxseed oil, 12th and 13th, and 15th and 16th for alpha-linolenic acid pumpkinseed oil, canola oil, soybean oil, or walnut oil) a (18:3)). marine oil (such as algae oil, seal oil, krill oil, crustacean oil, “PUFAs' can be classified into two major families (de or fish oil (for example cod liver oil, Salmon oil, tuna oil, shark pending on the position (n) of the first double bond nearest the oil, pelagic fishes oil, or sardine oil), or an hydrolysate. methyl end of the fatty acid carbon chain). Thus, the The term “aryl as used herein refers to a cyclic or poly "Iomega-6 fatty acids' omega-6 or n-6) have the first unsat cyclic aromatic ring. For example, the aryl group can be urated double bond six carbon atoms from the omega (me phenyl or napthyl. thyl) end of the molecule and additionally have a total of two The expression “aromatic heterocycle' as used herein 10 or more double bonds, with each Subsequent unsaturation refers to an aromatic cyclic or fused polycyclic ring system occurring 3 additional carbon atoms toward the carboxyl end having at least one heteroatom selected from the group con of the molecule. In contrast, the "Iomega-3 fatty acids' sisting of N, O, S and P. Non-limitative examples include (omega-3 or n-3) have the first unsaturated double bond heteroaryl groups are furyl, thienyl, pyridyl, quinolinyl, iso three carbonatoms away from the omega end of the molecule 15 and additionally have a total of three or more double bonds, quinolinyl, indolyl, isoindolyl, triazolyl pyrrolyl, tetrazolyl, with each Subsequent unsaturation occurring 3 additional imidazolyl pyrazolyl, oxazolyl, thiazolyl, benzofuranyl. carbon atoms toward the carboxyl end of the molecule. benzothiophenyl, carbazolyl, benzoxazolyl pyrimidinyl, The expression “inflammatory disease(s)' as used herein benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridi refers to all of the acute or chronic inflammatory diseases nyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on. associated with the excessive release of cytokines, and com The expression “non-aromatic heterocycle includes non plication thereof. The expression "chronic inflammatory dis aromatic rings or ring systems that contain at least one ring ease(s) refers to all diseases that induce tissue injury or having at least one hetero atom (such as nitrogen, oxygen, induce continuous inflammation due to hyperactivity and the Sulfur orphosphorus). This term includes, in a non-limitative excessive release of cytokines, and complication thereof. In manner all of the fully saturated and partially unsaturated 25 particular, the inflammatory diseases to which the com derivatives of the above mentioned aromatic heterocycles pounds and compositions of the present disclosure can be groups. Examples of non-aromatic heterocycle groups applied are not limited to, but include inflammatory bowel include, in a non-limitative manner, pyrrolidinyl, tetrahydro disease Such as Crohn's disease and ulcerative colitis, perito furanyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazi nitis, osteomyelitis, cellulitis, meningitis, cerebritis, pancre nyl, thiazolidinyl, isothiazolidinyl, and imidazolidinyl. 30 atitis, trauma-inducing shock, bronchial asthma, allergic rhinitis, cystic fibrosis, cerebral apoplexy, acute bronchitis, The term "crude extract” refers to an unpurified extract. chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, Such an extract can be obtained, for example, by means of a osteoarthritis, gout, spinal arthropathy, ankylosing spondyli supercritical fluid extract (for example carbon dioxide or an tis, Reiter's syndrome, psoriatic arthropathy, enteropathic alkane), by using a solvent as ethanol, methanol, isopropanol, 35 spondylitis, juvenile arthropathy, juvenile ankylosing acetone or water, or by hydrodistillation. spondylitis, reactive arthropathy, infectious arthritis, post The expression “lipophilic active agent” as used herein infectious arthritis, gonococcalarthritis, tuberculous arthritis, refers to an active agent which has an affinity for, or capability viral arthritis, fungal arthritis, syphilitic arthritis, Lyme dis of dissolving in, lipids; i.e., non-water soluble oils, fats, Ste ease, arthritis associated with vasculitis syndrome, pol rols, triglycerides and the like. 40 yarteritis nodosa, hypersensitivity vasculitis, Wegener's The term “lipid as used herein refers to as any fat-soluble granulomatosis, polymyalgia rheumatica, giant cell arteritis, (lipophilic), molecules. Such as fats, fat-like Substances, oils calcium crystal deposition arthropathy, pseudogout, non (such as animal oil, marine oil or vegetable oil), waxes, sterols joint rheumatism, bursitis, tenosynovitis, epicondylitis (ten (such as cholesterol, ergosterol, sitosterol, Stigmasterol, fat nis elbow), neuropathic joint disease (charcot joint), hemar soluble vitamins (such as vitamins A, D, E and K), fatty acids, 45 throsic, Henoch-Schonlein purpura, hypertrophic esters thereof, and various derivatives thereof such as osteoarthropathy, multicentric reticulohistiocytoma, scolio monoglycerides, diglycerides, triglycerides, phospholipids, sis, hemochromoatosis, meniscocytosis, other hemoglobin glycolipids, and cerebrosides. opathy, hyperlipoproteinemia, hypogammaglobulinaemia, The term “fatty acid(s) as used herein refers to long chain familial mediterranean fever, Gerhardt Disease, systemic aliphatic acids (alkanoic acids) of varying chain lengths, from 50 lupus erythematosus, relapsing fever, psoriasis, multiple scle about C12 to C22 (although both longer and shorter chain rosis, sepsis (septicemia), septic shock, acute respiratory dis length acids are known). For example, the predominant chain tress syndrome, multiple organ dysfunction syndrome, lengths are about C16 to about C22. The structure of a fatty chronic obstructive pulmonary disease, rheumatic arthritis, acid is represented by a simple notation system of “X:Y”. acute lung injury, bronchopulmonary dysplasia and so on. where X is the total number of carbon (C) atoms and Y is the 55 The expression “effective amount of a compound of the number of double bonds. present disclosure or of a composition of the present disclo Generally, fatty acids are classified as Saturated or unsat Sure is a quantity Sufficient to, when administered to the urated. The term “saturated fatty acids’ refers to those fatty Subject, including a mammal, for example a human, effect acids that have no “double bonds' between their carbon back beneficial or desired results, including clinical results, and, as bone. In contrast, “unsaturated fatty acids' are cis-isomers 60 such, an “effective amount” or synonym thereto depends that have “double bonds' along their carbon backbones. upon the context in which it is being applied. For example, in "Monounsaturated fatty acids have only one “double bond' the context of treating cancer, for example, it is an amount of along the carbon backbone (e.g., usually between the 9th and the compound sufficient to achieve such treatment of the 10th carbonatom as for palmitoleic acid (16:1) and oleic acid cancer as compared to the response obtained without admin (18:1)), while “polyunsaturated fatty acids” (or “PUFAs) 65 istration of the compound. The amount of a given compound have at least two double bonds along the carbon backbone of the present disclosure that will correspond to an effective (e.g., between the 9th and 10th, and 12th and 13th carbon amount will vary depending upon various factors, such as the US 8,198.324 B2 15 16 given drug or compound, the pharmaceutical formulation, the The formation of a desired compound salt is achieved using route of administration, the type of disease or disorder, the standard techniques. For example, the neutral compound is identity of the subject or host being treated, and the like, but treated with an acid or base in a suitable solvent and the can nevertheless be routinely determined by one skilled in the formed salt is isolated by filtration, extraction or any other art. Also, as used herein, an “effective amount of a com 5 suitable method. pound of the present disclosure is an amount which inhibits, Suppresses or reduces a cancer (e.g., as determined by clinical Compounds of the present disclosure include radiolabeled symptoms or the amount of cancerous cells) in a Subject as forms, for example, compounds labeled by incorporation compared to a control. The same definition of “effective within the structure H, H, C, N, or a radioactive halogen amount also applies when the compounds of the present 10 such as I. A radiolabeled compound of the compounds of disclosure are used for inhibiting tumor growth, inhibiting the present disclosure may be prepared using standard meth tumor cell proliferation, reducing tumor growth, or enhanc ods known in the art. ing bioavailability of an active agent, or treating an inflam As used herein, and as well understood in the art, “treat matory disease. ment” or “treating is an approach for obtaining beneficial or The term “subject’ as used herein includes all members of 15 desired results, including clinical results. Beneficial or the animal kingdom including human. According to one desired clinical results can include, but are not limited to, embodiment, the Subject is a human. The expression “pharmaceutically acceptable” means alleviation or amelioration of one or more symptoms or con compatible with the treatment of subjects Such as animals or ditions, diminishment of extent of disease, stabilized (i.e. not humans. worsening) state of disease, preventing spread of disease, The expression “pharmaceutically acceptable salt' means delay or slowing of disease progression, amelioration or pal an acid addition salt or basic addition salt which is suitable for liation of the disease state, and remission (whether partial or or compatible with the treatment of subjects Such as animals total), whether detectable or undetectable. “Treatment” or or humans. “treating can also mean prolonging Survival as compared to The expression “pharmaceutically acceptable acid addi 25 expected Survival if not receiving treatment. tion salt as used herein means any non-toxic organic or In understanding the scope of the present disclosure, the inorganic salt of any compound of the present disclosure, or term "comprising and its derivatives, as used herein, are any of its intermediates. Illustrative inorganic acids which intended to be open ended terms that specify the presence of form suitable salts include hydrochloric, hydrobromic, sulfu the stated features, elements, components, groups, integers, ric and phosphoric acids, as well as metal salts such as sodium 30 and/or steps, but do not exclude the presence of other unstated monohydrogen orthophosphate and potassium hydrogen Sul features, elements, components, groups, integers and/or fate. Illustrative organic acids that form suitable salts include steps. The foregoing also applies to words having similar mono-, di-, and tricarboxylic acids such as glycolic, lactic, meanings Such as the terms, “including”, “having and their pyruvic, malonic, Succinic, glutaric, fumaric, malic, tartaric, derivatives. citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and 35 The compounds and compositions described in the present salicylic acids, as well as Sulfonic acids such as p-toluene disclosure can be useful for chemoprevention of cancer, treat sulfonic and methanesulfonic acids. Either the mono or di ing cancer, inhibiting tumor growth, reducing tumor growth acid salts can be formed, and Such salts may exist in either a the prevention or treatment of cardiovascular disease, the hydrated, Solvated or Substantially anhydrous form. In gen prevention or treatment of neurodegenerative diseases, the eral, the acid addition salts of the compounds of the present 40 disclosure are more soluble in water and various hydrophilic prevention or treatment of inflammation or of an inflamma organic solvents, and generally demonstrate higher melting tory disease, the prevention or treatment of age-related eye points in comparison to their free base forms. The selection of disease. the appropriate salt will be known to one skilled in the art. The compounds and compositions described in the present Other non-pharmaceutically acceptable salts, e.g. oxalates, 45 disclosure can also be useful for in a self-emulsifying drug may be used, for example, in the isolation of the compounds delivery systems (SEDDS), a self-microemulsifying drug of the present disclosure, for laboratory use, or for Subsequent delivery systems (SMEDDS) or a selfemulsifying oil formu conversion to a pharmaceutically acceptable acid addition lations (SEOF). They can also be used for oral delivery of salt. In embodiments of the present disclosure, the pharma lipophilic drugs, natural product or natural crude extract, as ceutically acceptable acid addition salt is the hydrochloride 50 an oral bioavailability enhancer of docosahexaenoic acid, salt. (O3-docosapentaenoic acid, ()6-docosapentaenoic acid or The term “pharmaceutically acceptable basic addition salt” eicosapentaenoic acid, or for preparing a micelle or liposome as used herein means any non-toxic organic or inorganic base for a drug delivery system. addition salt of any acid compound of the disclosure, or any of For example, the compounds previously defined can be of its intermediates. Acidic compounds of the disclosure that 55 formulas: may form a basic addition salt include, for example, where R is COH. Illustrative inorganic bases which form suitable salts include lithium, Sodium, potassium, calcium, magne sium or barium hydroxide. Illustrative organic bases which form Suitable salts include aliphatic, alicyclic or aromatic 60 organic amines Such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. Other non pharmaceutically acceptable basic addition salts, may be used, for example, in the isolation of the compounds of the 65 disclosure, for laboratory use, or for Subsequent conversion to a pharmaceutically acceptable acid addition salt. US 8,198.324 B2 17 18 -continued -continued

US 8,198.324 B2 19 20

-continued -continued

10

15

25 EXAMPLE 1. Preparation of Monoglyceride 1

O

XCluO 3 -as Lipase from Candida antartica

Acidic resin --- EtOH

Docosapentaenoic acid ethyl ester (compound 2) (10 g) and compound 3 (6 g) were mixed together and heated at a -continued

60 temperature of 60°C. The enzyme (100 mg) was added and the reaction mixture was stirred at 60°C. under vacuum (18 mbar) or under nitrogen bubbling for 5 h. The reaction mix ture was filtered and the enzyme was washed with ethanol 95% (20 ml). The acidic resin (500mg) or organic acid was added to the ethanol solution and heated to reflux for 18h. The resin was removed by filtration and the ethanol was evapo rated in vacuo. The resulting crude product was dissolved in US 8,198.324 B2 21 22 a mixture of hexanes/ethyl acetate 90:10 (10 ml) and silica gel Pure compounds 5 and 6 (see below) have also been suc (40 g) was added. The slurry was put on a fritted funnel and cessfully prepared by following the same procedure. eluted with hexanes/ethyl acetate 90:10 (150 ml) to remove EXAMPLE 2 unreacted starting material. A second elution with ethyl acetate (300 ml) give, after evaporation in vacuo, the pure 5 Preparation of a Composition (Composition 1) compound 1 (8.7 g) was tested in vitro on the cell viability Comprising Various Monoglycerides (Compounds 1, assay and in an in vivo Xenograft tumor model. 5 and 6)

Lipase from Candida antartica

Acidic resin Ho EtOH

10 US 8,198.324 B2 23 24

-continued

Composition 1 comprising compounds 1, 5 and 6 was dye sulforhodamine B (SRB). The detection of luminescence, prepared according to the same procedure as previously emitted by SRB, is completed by a microplate reader. This described in Example 1. The starting material was a mixture method of detection is based upon works published by Monks of compounds 2, 7, and 8 at respectively (10%, 80%, and 30 et al., in Journal of the National Cancer Institute vol. 82 no. 13 10%). This starting material composition was sold by the (1991) p. 757, Skehan et al. in Journal of the National Cancer Company CRODATM Chemical Europe Ltd. under the name Institute vol. 82 no. 13 (1990) p. 1107 and Rubinstein et al. in INCROMEGATM DHA 700 E SR. Thus, the obtained com Journal of the National Cancer Institute vol. 82 no. 13 (1990) position 1 contains 10% of compound 1,80% of compound 5. p. 1113. The amount of luminescence is directly proportional and 10% of compound 6. 35 to the number of living cells in culture. EXAMPLE 3 Cancer cells were grown in T-75 flask (Falcon) containing 20 ml of appropriate culture medium, subcultured twice a Freshly purified curcumin (10 mg) was dissolved in week at 37° C., 5% CO, 95% air and 100% relative humidity DMSO (1 ml). Five consecutive dilutions with a equal volume 40 and maintained at low passage number (5 to 20), following of DMSO was performed. PBS was added to the six stock manufacturer recommendations. The cell lines used were solutions to a final volume of 1% DMSO for the in vitro assay. A-549 (human lung carcinoma), HCT-15 (human colon Precipitation occur at high concentration of curcumin. To adenocarcinoma), BT-549 (human breast ductal carcinoma) Solve the problem, curcumin (5 mg) was dissolve in a com and PC3 (human prostate adenocarcinoma). Cells were position 1 (5 mg) and DMSO (1 ml) was added. Five con 45 trypsinized using 0.25% trypsine (w/v)/0.53 mM EDTA solu secutive dilutions with a equal volume of DMSO was per tion (Hyclone), counted and plated at densities between 1000 formed. PBS was added to the six stock solutions to a final and 3000 cells per well in flat bottom 96-well clear plates volume of 1% DMSO for the in vitro assay. (Becton Dickinson) in 100 ul of appropriate culture medium The cell viability assay is performed to measure the relative supplemented with fetal bovine serum (Hyclone). Culture cell viability status of cancer cells upon exposure to test 50 plates were incubated at 37° C., 5% CO, 95% air and 100% compounds in comparison to a positive control (etoposide) relative humidity for 72 hours. At 20-30% of cell confluence, and a negative control (vehicule). Adherent cells growing in 80 ul of appropriate culture medium was added to each well. 96-well plates are exposed to test compounds for 3 days (72 20 ul of either a solution of test compounds in 6 difference hours). Four cancer cell lines including lung, colon, prostate concentration, drug for positive controls (at concentration of and breast types are used since these types of cancer possess 55 29 mg/ml) or solvent (vehicle or water) for negative controls high incidence in human. Test compounds (composition 1 were added on top of the 180 ul of culture medium to obtain comprising compounds 1, 5 and 6) as well as positive and a final Volume of 200 ul. Background plate containing the negative controls were tested in parallel on the same culture same volume of medium without cells were included in each plate. All conditions are tested in triplicate. Apoptotic agents experiment. Microplates containing cells and test compounds Such as etoposide or epigallo-catechin-gallate are used as 60 were incubated at 37°C., 5% CO, 95% air and 100% relative positive controls to kill cells whereas the solvent (dimethyl humidity for 72 hours. One microplate for each cell line were Sulfoxide and water) is used as negative controls for basal fixed as described below. These four microplates represented determination. Inhibition of 50% of cell growth compared to basal growth at time Zero. After incubation time of 72 hours, basal condition is the lower limit indicating a positive bio cells were fixed with 50 ul of cold (4°C.) 50% (w/v) trichlo logical response 65 roacetic acid (TCA) added to the top of 200 ul of culture (considered as a hit). After the incubation time, total pro medium. These microplates contained conditions of growth tein content is quantified following staining with the anionic control and test growth. Microplates were left 60 minutes at US 8,198.324 B2 25 26 4°C. and subsequently wash five times with 200 ul of deion and the 50% growth inhibition concentration of same purified ized water. Microplates were left to dry at room temperature curcumin formulated in composition 1 is around 3.13 Lug/ml. for at least 24 hours. All microplates were fixed with 100 ul of a more than 20 times improvement of potency. cold 0.4% (w/v) SRB dissolved in 1% acetic acid solution in FIG. 7 represents the in vitro cell viability assay of six water added to each well containing cells and left at room 5 different concentrations of composition 1 on HCT-15 human temperature for 10 minutes. Unbound SRB was removed with colon cancer cell line. The positive control etoposide at 294 successive washes (five times) with 200 ul of cold 1% acetic ug/ml shows 100% growth inhibition. The 50% growth inhi acid solution in water. All microplates were left to dry at room bition is around 75 lug/ml of the tested composition. temperature for at least 24 hours. Bound SRB to proteins was FIG. 8 represents the in vitro cell viability assay of six solubilised with the addition of 100 ul of 10 mM cold unbuf 10 different concentrations of purified curcumin on HCT-15 fered Tris-base solution (pH 10.5). Microplates were left on a human colon cancer cell line. The positive control etoposide plate shaker for 5 minutes. Absorbance was read at 515 nm. at 294 g/ml shows 100% growth inhibition. The 50% growth using a 96-well plate Multiskan Spectrum luminescence inhibition is around 100 ug/ml of curcumin. reader (Thermo Electron Corporation). Data analysis was FIG. 9 represents the in vitro cell viability assay of six performed using Excel 2003 and SigmaPlot 8.0 or GraphPad 15 different concentrations of purified curcumin formulated Prism 3.02 software. Percent growth inhibition was calcu with composition 1 on HCT-15 human colon cancer cell line. lated using the absorbance measurements Growth at time The positive control etoposide at 294 ug/ml shows 100% Zero (To), growth control (C) plus the test growth at the drug growth inhibition. The 50% growth inhibition is around 12.5 concentrations tested (T,) as follows: (T-T)/(C-T)x100. ug/ml of the tested composition. The results obtained are shown in FIGS. 1 to 9. Purified curcumin formulated in composition 1 decreases FIG. 1 represents the in vitro cell viability assay of six significantly the concentration needed to reach the 50% different concentrations of composition 1 on A-549 human growth inhibition of HCT-15 human colon cancer cell line lung cancer cell line. The positive control etoposide at 294 (see FIG.9) as compared to purified curcumin (see FIG. 8) or ug/ml shows 100% growth inhibition. The 50% growth inhi composition 1 alone (see FIG. 7). The 50% growth inhibition bition is around 25 g/ml of the tested composition. 25 concentration of purified curcumin alone is around 100 ug/ml FIG. 2 represents the in vitro cell viability assay of six and the 50% growth inhibition concentration of same purified different concentrations of purified curcumin on A-549 curcumin formulated in composition 1 is around 6.25 ug/ml. human lung cancer cell line. The positive control etoposide at a more than 15 times improvement of potency. 294 g/ml shows 100% growth inhibition. The 50% growth inhibition is around 100 ug/ml of curcumin 30 EXAMPLE 4 FIG. 3 represents the in vitro cell viability assay of six different concentrations of purified curcumin formulated In order to determine the solubility of various compounds with composition 1 on A-549 human lung cancer cell line. in a fish oil as compared to their solubility in composition 1. The positive control etoposide at 294 ug/ml shows 100% a first sample of turmeric oleoresin (100 mg) obtained from growth inhibition. The 50% growth inhibition is around 6.25 35 ethanol extraction was stirred at room temperature in a fish oil ug/ml of the tested composition. (1.0 g) for 30 minutes. Then, another sample of turmeric Purified curcumin formulated in composition 1 decreases oleoresin (100 mg) (also obtained from ethanol extraction) significantly the concentration needed to reach the 50% was stirred at room temperature in composition 1 (1.0 g) for growth inhibition of A-549 human lung cancer cell line (see 30 minutes. Both resulting Suspensions were centrifuged at FIG. 3) as compared to purified curcumin (see FIG. 2) or 40 12 000 RPM for 5 minutes and 10 ul of each supernatant was composition 1 alone (see FIG. 1). The 50% growth inhibition dissolved in DMSO and further dilution was made to meet the concentration of purified curcumin alone is around 100 ug/ml linearity range of HPLC/MS method for the quantification of and the 50% growth inhibition concentration of same purified curcuminoids (0.001 ug/ml to 0.1 ug/ml). The comparative curcumin formulated in composition 1 is around 3.13 g/ml. results obtained concerning the solubility of some compo a more than 30 times improvement of potency. 45 nents of the turmeric oleoresin extract (bis-demethoxycur FIG. 4 represents the in vitro cell viability assay of six cumin, demetoxycurcumin, curcumin and total curcumi different concentrations of composition 1 on PC-3 human noids) in the fish oil and in the composition 1 are shown in prostate cancer cell line. The positive controletoposide at 294 FIG 10. ug/ml shows 100% growth inhibition. The 50% growth inhi As it can be seen in FIG. 10, composition 1 permits to bition is around 50 lug/ml of the tested composition. 50 enhance the solubility of various active agents (bis FIG. 5 represents the in vitro cell viability assay of six demethoxycurcumin, demetoxycurcumin, curcumin and different concentrations of purified curcumin on PC-3 human total curcuminoids) in a lipid or lipid formulation. It can be prostate cancer cell line. The positive controletoposide at 294 clearly seen from FIG. 10 that such active agents have a ug/ml shows 100% growth inhibition. The 50% growth inhi greater Solubility in a lipid formulation consisting of compo bition is around 75 g/ml of curcumin. 55 sition 1 than in a lipid formulation consisting of a fish oil. As FIG. 6 represents the in vitro cell viability assay of six it can be seen, the active agents are about 3 to 4 times more different concentrations of purified curcumin formulated soluble in composition 1 than in a fish oil. It can thus also be with composition 1 on PC-3 human prostate cancer cell line. seen the that such a composition is effective for solubilizing The positive control etoposide at 294 ug/ml shows 100% lipophilic active agents. growth inhibition. The 50% growth inhibition is around 6.25 60 ug/ml of the tested composition. EXAMPLE 5 Purified curcumin formulated in composition 1 decreases significantly the concentration needed to reach the 50% The relative in vivo bioavailability of two different formu growth inhibition of PC-3 human prostate cancer cell line (see lations containing docosahexaenoic acid which are a fish oil FIG. 6) as compared to purified curcumin (see FIG. 5) or 65 and composition 1 was determined by a pharmacokinetic composition 1 alone (see FIG. 4). The 50% growth inhibition study. Upon arrival in the animal facility, the male Sprague concentration of purified curcumin alone is around 75 ug/ml Dawley rats were marked for identification and weighed. The US 8,198.324 B2 27 28 animals were acclimatized for 1 week before commencing soluble in composition 1 than in a fish oil. It can thus also be the study. On the day of the study, shortly before dosing, the seen the that such a composition is effective for solubilizing animals were re-weighed and placed into experimental lipophilic active agents. groups based on a distribution of weight. Animals received As it can be seen in FIG. 11, composition 1 permits to food and water ad libitum except during the pharmacokinetic 5 enhance the bioavailability of docosahexaenoic acid as com study (from overnight to Bleed Time 480 minutes). The ani pared to a fish oil. The relative bioavailability of docosa mals were not deprived of food overnight from Bleed Time hexaenoic acid from composition 1 compared to a fish oil 480 to 1440 minutes since the length of the pharmacokinetic calculated from time 0 to time 1440 min. is 4.48 and when the study was 24 hours. The compound dosing solutions were calculation is made from time 0 to infinity, the relative bio administered orally as a single slow bolus (over approxi 10 availability of docosahexaenoic acid from composition 1 mately 15 seconds) according to standard procedures for compared to a fish oil is 50.31. Such a study thus clearly administration of Solution by gavage: the animal was firmly shows that the compounds and compositions of the present restrained; a bulb-tipped gastric gavage needle of 18 G was disclosure are useful for enhancing bioavailability of an passed through the side of the mouth and was moved forward 15 active agent. toward the esophagus. The dosing solutions were dosed orally at 3 g/kg by adjusting the dose Volume (3 mL/kg) according to EXAMPLE 6 the body weight of each animal and the density of the com pound-1 g/mL). Blood samples were collected prior to com The relative human bioavailability of two different com pound administration and at different time points following positions (composition 2 and a fish oil) containing docosa administration. Blood samples (200 ul) from each animal hexaenoic acid (DHA) and omega-3 docosapentaenoic acid were collected by veinipuncture, under isoflurane anaesthesia (DPACO3) has been determined. according to the following standard operating procedure for blood collection via the jugular vein: animals were placed in a Supine position on a slanted board to allow the head to be 25 lower than the lower extremities. The upper extremities were extended at a 90° angle and the neck extended and turned gently towards the site of blood collection. A 22-gauge 1" needle was inserted underneath the clavicle while aspirating. For plasma preparation, blood samples were placed into 30 tubes containing EDTA, mixed gently to assure anticoagula tion and put on ice. Plasma separation was performed follow ing centrifugation of the blood samples. Plasma was trans ferred into a tube and stored at -80° C. pending shipment for 35 analysis. The pellet was kept in the initial tube containing docosahexaenoic acid EDTA and stored at -80° C. pending shipment. The results of this study are shown in FIG. 11. FIG. 11 shows the change in plasma docosahexaenoic acid The fish oil comprises compounds 2 and 7 in about a 1:8 concentration of composition 1 compared to a fish oil upon 40 ratio (11% of 2 and 89% of 7): time over a 1440 minutes study. The relative bioavailability of docosahexaenoic acid from composition 1 compared to docosahexaenoic acid from fish oil is calculated with the formula: 45

A UCA : doSeB relative bioavailability= AUC dose, B 3. A.

The AUC (calculates area under the curve for concentra 50 tion vs. time data) is calculated using linear trapezoidal rule. The use of the linear trapezoidal rule as a method for approxi mating the area under a concentration-time curve is widely accepted. In this experiment, the doses are the same. The 55 Composition 2 comprises compounds 1 and 5 and fish oil calculated relative bioavailability of docosahexaenoic acid (comprising compounds 2 and 7 in about a 1:2 ratio. In other from composition 1 compared to a fish oil from time 0 to time words, composition 2 comprises (about) compounds 1 1440 min. is 4.48 and when the calculation is made from time (3.6%), 2 (7.4%), 5 (29.4%), and 7 (59.6%). 0 to infinity, the relative bioavailability is 50.31. As it can be seen in FIG. 10, composition 1 permits to 60 enhance the solubility of various active agents (bis demethoxycurcumin, demetoxycurcumin, curcumin and total curcuminoids) in a lipid or lipid formulation. It can be clearly seen from FIG. 10 that such active agents have a greater solubility in a lipid formulation consisting of compo 65 sition 1 than in a lipid formulation consisting of a fish oil. As it can be seen, the active agents are about 3 to 4 times more US 8,198.324 B2 29 30 accepted. In this experiment, the doses are the same. The -continued calculated relative bioavailability of docosahexaenoic acid from composition 2 compared to fish oil from time 0 to infinity is 3.72. Thus, when DHA is in the presence of com pounds 1 and/or 5, DHA is 3.72 times more bioavailable. For the relative bioavailability of DPAC)3, no significant absorp tion was found with fish oil, compared to an increase of more than 0.6% after 8 hours with composition 2. The relative bioavailability of compound 1 and compound 5 is calculated 10 with the same formula:

A UCA : doSeB relative bioavailability= AUC B. : dosedoSeA 15 The calculated relative bioavailability of compound 1 com pared to compound 5 from time 0 to infinity is 2.20. Thus, compound 1 is 2.2. times more bioavailable than compounds Composition 2 was prepared according to the same proce 5. dure as previously described in Example 2. The compounds and compositions of the present disclosure The relative human bioavailability of these two different can be used for enhancing bioavailability of an active agent. compositions (composition 2 and a fish oil) was determined For example, the active agent can be a fatty acidora derivative by a pilot cross-over study on one healthy Volunteer (male). thereof (for example an ester of a fatty acid). For example, the The volunteer fasted for 12 hours prior to the study. The 25 compounds of the present disclosure can be used for enhanc participant consumed fish oil (capsules) equivalent to 3.0 g of ing bioavailability of at least one compound present in a fish DHA and 375 mg of DPAC)3 as part of a breakfast. Controlled oil. For example, the compounds of the present disclosure can amount of boiled pasta was eaten after the 4h time point. An be used for enhancing bioavailability of the ethyl ester of EPA initial blood sample (400 ul) was collected using a lancet at a and/or DHA. fingertip into heparin tubes followed by samples at 1, 2, 3, 4, 30 5, 6, 7 and 8 hour after ingestion. Plasma was separated and EXAMPLE 7 immediately analysed for fatty acid composition. Fourteen days later (washout period), the procedure was repeated with Composition 3 (comprising compounds 1 and 5) at final composition 2 (capsules) equivalent to 3.0 g of DHA and 375 concentration of 10 ug/ml, curcumin (5 g/ml) and a 1:1 mg of DPA (03. 35 mixture of composition 3 (10 g/ml) and curcumin (5ug/ml) The results of this study are shown in FIGS. 12 and 13. in DMSO (1%) was used for the in vitro assay. Composition FIG. 12 shows the change in plasma docosahexaenoic acid 3 prepared according to the same procedure as previously (DHA) concentration of composition 2 compared to fish oil described in Example 2) upon time over an 8 hours study. The in vitro assay allows evaluation of the potential anti FIG. 13 shows the change in plasma omega-3 docosapen 40 inflammatory effects of compounds on the induced-release of taenoic acid (DPAC)3) concentration of composition 2 com pro-inflammatory mediator by monocyte cells. Typical pared to fish oil upon time over an 8 hours study. human monocyte THP-1 cells, involved in inflammatory pro In FIG. 12 the proportion of DHA in plasma (% DHA) cesses, are used in this assay. Measurement of pro-inflamma increased slowly only after 3 hours and reach a maximum of 4 tory mediator TNF-C. is performed by ELISA (manufactured less than 2% after 8 hours when fish oil was taken alone. With 5 by R&D Systems) with artificial induction of pro-inflamma composition 2, the DHA increased moderately right after the tory agents by LPS (E. Coli O55:B5) during 4 hours. Known ingestion and after 4 hours the DHA increased rapidly to anti-inflammatory agent dexametaZone was used as positive reach a plateau of more than 4.5% at 6 hours. After 8 hours the control. DHA variation is 4.5%. The results of this study are shown in FIG. 14. In FIG. 13 the proportion of DPAC)3 in plasma (%DPACO3) 50 In FIG. 14, no TNF-C. was measured when no LPS is added did not increase after 8 hours when fish oil was taken alone, to the monocyte THP-1 cells incubated with compounds or this mean that DPAC)3 was not absorbed in fish oil. With vehicle. With 100 ng/ml of LPS, 400 pg/ml of TNF-C. was composition 2, the DPAC)3 increased moderately right after measured with the vehicle. With positive control dexameta the ingestion to reach a plateau of 0.5% at 3 hours. After 8 Zone, only 125 pg/ml of TNF-C. was measured, showing the 55 anti-inflammatory effect of dexametazone. When composi hours the DPAC)3 variation was more than 0.6% tion 3 (10 ug/ml) was added, 275 pg/ml of TNF-C. was mea The relative bioavailability offatty acids from composition sured and 100 pg/ml of TNF-C. was measured when curcumin 2 compared to fish oil is calculated with the formula: (5 ug/ml) is added. When a mixture of composition 3 and curcumin was added, less than 50 pg/ml of TNF-C. was mea 60 Sured, showing a strong anti-inflammatory synergic effect. relative bioavailability= AAUC UCA : dosedoSeB While the compounds, compositions, methods and uses B. : doSeA thereof have been described in connection with specific embodiments thereof, it will be understood that they can be The AUC (calculates area under the curve for concentra further modified and this application is intended to cover any tion vs. time data) is calculated using linear trapezoidal rule. 65 variations, uses, or adaptations of the compounds, composi The use of the linear trapezoidal rule as a method for approxi tions, methods and uses thereof following, in general, the mating the area under a concentration-time curve is widely principles described in the present disclosure and including US 8,198.324 B2 31 32 Such departures from the present disclosure as come within —P(O)(ORs). —S(O)NHRs – SORs, S(O)Rs. known or customary practice within the art to which the —arylP(O)(ORs), a sugar, or a Sugar phosphate present disclosure pertains and as may be applied to the or R and R are joined together so as to form a five- to features hereinbefore set forth, and as follows in the scope of seven-membered non-aromatic heterocycle unsubsti the appended claims. 5 tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and What is claimed is: —C2-C22 alkynyl, a phosphate, Sulfate carbonyl 1. A method for enhancing bioavailability of at least one group, or a thiocarbonylimine; lipid, said method comprising administering to a subject an Rs is —H. —C-C22 alkyl, —(C3-C7) cycloalkyl, effective amount of said at least one lipid and an effective 10 —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 amount of at least one compound chosen from compounds of alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, formulae (I), (II), (III), and (IV): —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti 15 tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-membered non aromatic heterocycle unsubstituted or substituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one susbtituent chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 alkynyl, a —(CH)amino acid wherein the 25 amino acid is connected to the compound through its alpha carbon atom, a —(CH), peptide wherein the peptide is connected to the compound through the III alpha carbonatom of one of its amino acids, a Sugar or a Sugar phosphate; and 30 n is an integer having a value of 0, 1, 2, 3, or 4. in formula (II): X is O, NH, or S; X, is O, NH, or S, X is O, NH, or S: 35 R and Reach independently represents —H. —C(O) NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) 40 cycloalkyl unsubstituted or substituted with at least one substituent chosen from C1-C22 alkyl, —C2-C22 wherein alkenyl, and —C2-C22 alkynyl, - C6-C12 aryl, in formula (I): —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, X is O, NH, or S: —C8-C22 (aryl)alkynyl, three- to seven-membered X is O, NH, or S: 45 non-aromatic heterocycle unsubstituted or Substi X is O, NH, or S: tuted with at least one substituent chosen from —C1 R and Reach independently represents —H. —C(O) C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) five- to seven-membered aromatic heterocycle unsub alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, stituted or substituted with at least one substituent —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, 50 chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) —C2-C22 alkynyl, -(CH2)amino acid wherein the cycloalkyl unsubstituted or substituted with at least amino acid is connected through its alpha carbon one substituent chosen from C1-C22 alkyl, —C2-C22 atom, —(CH), peptide wherein the peptide is con alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, nected through the alpha carbon atom of one of its —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, 55 amino acids, —CHORs, —C(O)ORs, —C(O)NRs. —C8-C22 (aryl)alkynyl, three- to seven-membered —P(O)(ORs). —S(O)NHRs – SORs, S(O).Rs. non-aromatic heterocycle unsubstituted or Substi -arylP(O)(ORs), a Sugar, or a Sugar phosphate tuted with at least one substituent chosen from —C1 or R and R are joined together so as to form a five- to C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, seven-membered non-aromatic heterocycle unsubsti five- to seven-membered aromatic heterocycle unsub 60 tuted or substituted with at least one substituent cho stituted or substituted with at least one substituent sen from —C1-C22 alkyl, —C2-C22 alkenyl, and chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, Sulfate carbonyl —C2-C22 alkynyl, -(CH)amino acid wherein the group, or a thiocarbonylimine; amino acid is connected through its alpha carbon Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, atom, —(CH), peptide wherein the peptide is con 65 —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 nected through the alpha carbon atom of one of its alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, amino acids, —CHORs, —C(O)ORs, —C(O)NRs. —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, US 8,198.324 B2 33 34 —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti C22 alkynyl, a —(CH)amino acid wherein the tuted or substituted with at least one substituent cho amino acid is connected to the compound through its sen from —C1-C22 alkyl, —C2-C22 alkenyl, and alpha carbon atom, a —(CH), peptide wherein the —C2-C22 alkynyl, a three- to seven-membered non peptide is connected to the compound through the aromatic heterocycle unsubstituted or substituted at alpha carbonatom of one of its amino acids, a Sugar or least one substituent chosen from —C1-C22 alkyl, a Sugar phosphate; and —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to n is an integer having a value of 0, 1, 2, 3, or 4. seven-membered aromatic heterocycle unsubstituted in formula (IV) or substituted with at least one susbtituent chosen 10 X is O, NH, or S: from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 X is O, NH, or S: C22 alkynyl, a —(CH)amino acid wherein the X is O, NH, or S: amino acid is connected to the compound through its R and Reach independently represents, —H. —C(O) alpha carbon atom, a —(CH), peptide wherein the peptide is connected to the compound through the 15 alpha carbonatom of one of its amino acids, a Sugar or a Sugar phosphate; and n is an integer having a value of 0, 1, 2, 3, or 4. cycloalkyl unsubstituted or substituted with at least in formula (III) one substituent chosen from C1-C22 alkyl, —C2-C22 X is O, NH, or S: 2O alkenyl, and —C2-C22 alkynyl, - C6-C12 aryl, X, is O, NH, or S; —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, X is O, NH, or S: —C8-C22 (aryl)alkynyl, three- to seven-membered R and Reach independently represents, —H. —C(O) non-aromatic heterocycle unsubstituted or Substi tuted with at least one substituent chosen from —C1 alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, 25 C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, five- to seven-membered aromatic heterocycle unsub —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) stituted or substituted with at least one substituent cycloalkyl unsubstituted or substituted with at least chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and one substituent chosen from C1-C22 alkyl, —C2-C22 —C2-C22 alkynyl, -(CH2)amino acid wherein the alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, 30 amino acid is connected through its alpha carbon —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, atom, —(CH), peptide wherein the peptide is con —C8-C22 (aryl)alkynyl, three- to seven-membered nected through the alpha carbon atom of one of its non-aromatic heterocycle unsubstituted or Substi- amino acids, —CHORs, —C(O)ORs, —C(O)NRs, tuted with at least one substituent chosen from —C1- —P(O)(ORs). —S(O)NHRs – SORs, S(O)Rs. C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, 35 —arylP(O)(ORs), a sugar, or a Sugar phosphate, five- to seven-membered aromatic heterocycle unsub- or R and R are joined together so as to form a five- to stituted or substituted with at least one substituent seven-membered non-aromatic heterocycle compris chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and ing at least one hetero atom chosen from nitrogen, —C2-C22 alkynyl, -(CH2)amino acid wherein the oxygen, and Sulfur, said heterocyle being unsubsti amino acid is connected through its alpha carbon 40 tuted or substituted with at least one substituent cho atom, —(CH), peptide wherein the peptide is con- sen from —C1-C22 alkyl, —C2-C22 alkenyl, and nected through the alpha carbon atom of one of its —C2-C22 alkynyl, a phosphate, Sulfate carbonyl amino acids, —CHORs, —C(O)ORs, —C(O)NRs. group, or a thiocarbonylimine; —P(O)(ORs). —S(O)NHRs —SORs, S(O)Rs. Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, —arylP(O)(ORs), a Sugar, or a Sugar phosphate, 45 —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 or R and R are joined together so as to form a five- to alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, seven-membered non-aromatic heterocycle compris- —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, ing at least one hetero atom chosen from nitrogen, —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 oxygen, and Sulfur, said heterocyle being unsubsti- C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti tuted or substituted with at least one substituent cho- 50 tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, Sulfate carbonyl —C2-C22 alkynyl, a three- to seven-membered non group, or a thiocarbonylimine; aromatic heterocycle unsubstituted or substituted at Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, least one substituent chosen from —C1-C22 alkyl, —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 55 —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, seven-membered aromatic heterocycle unsubstituted —C8-C22–(aryl)alkenyl, —C8-C22 (aryl)alkynyl, or substituted with at least one susbtituent chosen —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1- from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti- C22 alkynyl, a —(CH)amino acid wherein the tuted or substituted with at least one substituent cho- 60 amino acid is connected to the compound through its sen from —C1-C22 alkyl, —C2-C22 alkenyl, and alpha carbon atom, a —(CH), peptide wherein the —C2-C22 alkynyl, a three- to seven-membered non peptide is connected to the compound through the aromatic heterocycle unsubstituted or substituted at alpha carbonatom of one of its amino acids, a Sugar or least one substituent chosen from —C1-C22 alkyl, a Sugar phosphate; and —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to 65 n is an integer having a value of 0, 1, 2, 3, or 4. seven-membered aromatic heterocycle unsubstituted 2. The method of claim 1, wherein a composition compris or substituted with at least one susbtituent chosen ing an effective amount of said at least one lipid and an US 8,198.324 B2 35 36 effective amount of at least one compound chosen from com 16. The method of claim 3, wherein said at least one com pounds of formulae (I), (II), (III), and(IV) is administered to pound is chosen from: said Subject.

3. The method of claim 1, wherein said at least one lipid is at least one fatty acid or an ester thereof. 4. The method of claim 3, wherein said lipid is a C1-C6 ester of said at least one fatty acid. 5. The method of claim3, wherein said at least one lipid is an ethyl ester of said at least one fatty acid. 10 6. The method of claim 5, wherein said at least one fatty acid is chosen from eicosapentaenoic acid, (D3-docosapen ~~ taenoic acid, (D6-docosapentaencic acid, and docosa hexaenoic acid. 15 7. The method of claim 1, wherein said at least one lipid is chosen from a polyunsaturated fatty acid, an ester thereof, and mixtures thereof. 8. The method of claim 7, wherein said ester is a monoglyc eride, a diglyceride, or a triglyceride of said polyunsaturated fatty acid. 9. The method of claim 1, wherein said at least one lipid is o O chosen from arachidonic acid, (D3-arachidonic acid, alpha linolenic acid, conjugatedlinoleic acid, linoleic acid, gamma 25 linolenic acid, dihomo-gamma-linolenic acid, Stearidonic acid, eicosapentaenoic acid, (D3-docosapentaenoic acid, 17. The method of claim 9, wherein said at least one com (D6-docosapentaenoic acid, docosahexaenoic acid, C1-C6 pound is chosen from: esters thereof, monoglycerides thereof, diglycerides thereof, triglycerides thereof, and phospholipids thereof. 30 10. The method of claim 1, wherein said at least one lipid is chosen from a vegetable oil, mussels oil, shrimps oil, fish oil, Seal oil, microalgae oil, krill oil, a crustacean oil and hydrolysates thereof. 35 11. The method of claim 1, wherein X is O, X is O, and X is a O. 12. The method of claim 11, wherein R and Reach inde pendently represents —H, —C1-C22 alkyl, —C3-C22 alk enyl, or—C3-C22 alkynyl. 40 13. The method of claim 11, wherein R is —H and R is —H. 14. The method of claim 13, wherein said at least one compound is a compound of formula (I) or (II). 45 15. The method of claim 1, wherein said at least one com pound is chosen from: O

50 18. The composition of claim 9, wherein said at least one compound is chosen from:

55

60

65 US 8,198.324 B2 37 38 19. The method of claim 15, wherein said at least one lipid C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, is: five- to seven-membered aromatic heterocycle unsub stituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, -(CH)amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH), peptide wherein the peptide is con nected through the alpha carbon atom of one of its amino acids, —CHORs, —C(O)ORs, —C(O)NRs. O 10 —P(O)(ORs). —S(O)NHRs – SORs, S(O)Rs. —arylP(O)(ORs), a sugar, or a Sugar phosphate or R and R are joined together so as to form a five- to seven-membered non-aromatic heterocycle unsubsti 15 tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and 20. A method for enhancing bioavailability of at least one —C2-C22 alkynyl, a phosphate, Sulfate carbonyl lipophilic active agent, said method comprising administer group, or a thiocarbonylimine; ing to a subject an effective amount of said at least one Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, lipophilic active agent and an effective amount of at least one —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 compound chosen from compounds of formulae (I), (II), (III), alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, and (IV): —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-membered non aromatic heterocycle unsubstituted or substituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one susbtituent chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 alkynyl, a —(CH)amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH), peptide wherein the III peptide is connected to the compound through the alpha carbonatom of one of its amino acids, a Sugar or a Sugar phosphate; and 40 n is an integer having a value of 0, 1, 2, 3, or 4. in formula (II): X is O, NH, or S; X is O, NH, or S: X is O, NH, or S: 45 R and Reach independently represents —H. —C(O) NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) 50 cycloalkyl unsubstituted or substituted with at least wherein one substituent chosen from C1-C22 alkyl, —C2-C22 in formula (I): alkenyl, and —C2-C22 alkynyl, - C6-C12 aryl, X is O, NH, or S: —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, X, is O, NH, or S; —C8-C22 (aryl)alkynyl, three- to seven-membered X is O, NH, or S: 55 non-aromatic heterocycle unsubstituted or Substi R and Reach independently represents —H. —C(O) tuted with at least one substituent chosen from —C1 NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, five- to seven-membered aromatic heterocycle unsub —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, stituted or substituted with at least one substituent —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) 60 chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and cycloalkyl unsubstituted or substituted with at least —C2-C22 alkynyl, -(CH)amino acid wherein the one substituent chosen from C1-C22 alkyl, —C2-C22 amino acid is connected through its alpha carbon alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, atom, —(CH), peptide wherein the peptide is con —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, nected through the alpha carbon atom of one of its —C8-C22 (aryl)alkynyl, three- to seven-membered 65 amino acids, —CHORs, —C(O)ORs, —C(O)NRs. non-aromatic heterocycle unsubstituted or Substi -P(O)(ORs), soNHRs, -SORs, -S(O).Rs. tuted with at least one substituent chosen from —C1 -arylP(O)(ORs), a Sugar, or a Sugar phosphate US 8,198.324 B2 39 40 or R and R are joined together so as to form a five- to —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 seven-membered non-aromatic heterocycle unsubsti C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti tuted or substituted with at least one substituent cho tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, Sulfate carbonyl —C2-C22 alkynyl, a three- to seven-membered non group, or a thiocarbonylimine; aromatic heterocycle unsubstituted or substituted at Rs is —H. —C-C22 alkyl, —(C3-C7) cycloalkyl, least one substituent chosen from —C1-C22 alkyl, —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, seven-membered aromatic heterocycle unsubstituted —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, 10 or substituted with at least one susbtituent chosen —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti C22 alkynyl, a —(CH)amino acid wherein the tuted or substituted with at least one substituent cho amino acid is connected to the compound through its sen from —C1-C22 alkyl, —C2-C22 alkenyl, and alpha carbon atom, a —(CH), peptide wherein the —C2-C22 alkynyl, a three- to seven-membered non 15 peptide is connected to the compound through the aromatic heterocycle unsubstituted or substituted at alpha carbonatom of one of its amino acids, a Sugar or least one substituent chosen from —C1-C22 alkyl, a Sugar phosphate; and —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to n is an integer having a value of 0, 1, 2, 3, or 4. seven-membered aromatic heterocycle unsubstituted in formula (IV) or substituted with at least one susbtituent chosen 20 X is O, NH, or S: from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 X, is O, NH, or S; C22 alkynyl, a —(CH)amino acid wherein the X is O, NH, or S: amino acid is connected to the compound through its R and Reach independently represents, —H. —C(O) alpha carbon atom, a —(CH), peptide wherein the peptide is connected to the compound through the 25 alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, alpha carbonatom of one of its amino acids, a Sugar or —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, a Sugar phosphate; and —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) n is an integer having a value of 0, 1, 2, 3, or 4. cycloalkyl unsubstituted or substituted with at least in formula (III) one substituent chosen from C1-C22 alkyl, —C2-C22 X is O, NH, or S; 30 alkenyl, and —C2-C22 alkynyl, - C6-C12 aryl, X is O, NH, or S: —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, X is O, NH, or S: —C8-C22 (aryl)alkynyl, three- to seven-membered R and Reach independently represents, —H. —C(O) non-aromatic heterocycle unsubstituted or Substi NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) tuted with at least one substituent chosen from —C1 alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, 35 C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, five- to seven-membered aromatic heterocycle unsub —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) stituted or substituted with at least one substituent cycloalkyl unsubstituted or substituted with at least chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and one substituent chosen from C1-C22 alkyl, —C2-C22 —C2-C22 alkynyl, -(CH2)amino acid wherein the alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, 40 amino acid is connected through its alpha carbon —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, atom, —(CH), peptide wherein the peptide is con —C8-C22 (aryl)alkynyl, three- to seven-membered nected through the alpha carbon atom of one of its non-aromatic heterocycle unsubstituted or Substi- amino acids, ORs, —C(O)ORs, —C(O)NRs. tuted with at least one substituent chosen from —C1- —P(O)(ORs). —S(O)NHRs – SORs, S(O)Rs. C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, 45 -arylP(O)(ORs), a Sugar, or a Sugar phosphate, five- to seven-membered aromatic heterocycle unsub- or R and R are joined together so as to form a five- to stituted or substituted with at least one substituent seven-membered non-aromatic heterocycle compris chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and ing at least one hetero atom chosen from nitrogen, —C2-C22 alkynyl, -(CH)amino acid wherein the oxygen, and Sulfur, said heterocyle being unsubsti amino acid is connected through its alpha carbon 50 tuted or substituted with at least one substituent cho atom, —(CH), peptide wherein the peptide is con- sen from —C1-C22 alkyl, —C2-C22 alkenyl, and nected through the alpha carbon atom of one of its —C2-C22 alkynyl, a phosphate, Sulfate carbonyl amino acids, —CHORs, —(C(O)ORs, —C(O)NRs. group, or a thiocarbonylimine; —P(O)(ORs). —S(O)NHRs – SORs, S(O).Rs. Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, arylP(O)(ORs), a Sugar, or a Sugar phosphate, 55 —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 or R and Rare joined together so as to form a five- to alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, seven-membered non-aromatic heterocycle compris- —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, ing at least one hetero atom chosen from nitrogen, —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 oxygen, and Sulfur, said heterocyle being unsubsti- C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti tuted or substituted with at least one substituent cho- 60 tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, Sulfate carbonyl —C2-C22 alkynyl, a three- to seven-membered non group, or a thiocarbonylimine; aromatic heterocycle unsubstituted or substituted at Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, least one substituent chosen from —C1-C22 alkyl, —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 65 —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, seven-membered aromatic heterocycle unsubstituted —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, or substituted with at least one susbtituent chosen US 8,198.324 B2 41 42 from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 -continued C22 alkynyl, a —(CH)amino acid wherein the III amino acid is connected to the compound through its alpha carbon atom, a —(CH), peptide wherein the peptide is connected to the compound through the 5 alpha carbonatom of one of its amino acids, a Sugar or a Sugar phosphate; and n is an integer having a value of 0, 1, 2, 3, or 4. IV 21. The method of claim 20, wherein said at least one lipophilic active agent is a C12-C22 fatty acid or an ester 10 thereof. 22. The method of claim 20, wherein said at least one lipophilic active agent is a C12-C22 polyunsaturated fatty acid or an ester thereof. 15 23. The method of claim 20, wherein said at least one wherein lipophilic active agent is a C1-C6 ester of a C12-C22 poly in formula (I): unsaturated fatty acid. X is O, NH, or S: 24. The method of claim 20, wherein said at least one X is O, NH, or S: lipophilic active agent is an ethyl ester of a C12-C22 polyun X is O, NH, or S: saturated fatty acid. R and Reach independently represents —H. —C(O) 25. The method of claim 22, wherein said at least one NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) compound is chosen from: alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, 25 —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) cycloalkyl unsubstituted or substituted with at least one substituent chosen from C1-C22 alkyl, —C2-C22 O~~ alkenyl, and —C2-C22 alkynyl, - C6-C12 aryl, OH —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, 30 —C8-C22 (aryl)alkynyl, three- to seven-membered non-aromatic heterocycle unsubstituted or Substi O tuted with at least one substituent chosen from —C1 ~~on C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, OH five- to seven-membered aromatic heterocycle unsub

O 35 stituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and O ~~ —C2-C22 alkynyl, -(CH2)amino acid wherein the OH amino acid is connected through its alpha carbon atom, —(CH), peptide wherein the peptide is con OH 40 nected through the alpha carbon atom of one of its amino acids, —CHORs, —C(O)ORs, —C(O)NRs. os---ol. -P(O)(ORs). —S(O)NHRs, -SORs, so).Rs. -arylP(O)(ORs), a Sugar, or a Sugar phosphate o O or R and R are joined together so as to form a five- to 45 seven-membered non-aromatic heterocycle unsubsti 26. A method for enhancing bioavailability of at least one tuted or substituted with at least one substituent cho fatty acid or an ester thereof, said method comprising admin sen from —C1-C22 alkyl, —C2-C22 alkenyl, and istering to a subject an effective amount of said at least one —C2-C22 alkynyl, a phosphate, Sulfate carbonyl fatty acid oran ester thereof and an effective amount of at least group, or a thiocarbonylimine; one compound chosen from compounds of formulae (I), (II), 50 Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 (III), and (IV): alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-membered non aromatic heterocycle unsubstituted or substituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one susbtituent chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 alkynyl, a —(CH)amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH), peptide wherein the US 8,198.324 B2 43 44 peptide is connected to the compound through the —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) alpha carbonatom of one of its amino acids, a Sugar or cycloalkyl unsubstituted or substituted with at least a Sugar phosphate; and one substituent chosen from C1-C22 alkyl, —C2-C22 n is an integer having a value of 0, 1, 2, 3, or 4. alkenyl, and —C2-C22 alkynyl, - C6-C12 aryl, in formula (II): —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, X is O, NH, or S: —C8-C22 (aryl)alkynyl, three- to seven-membered X, is O, NH, or S; non-aromatic heterocycle unsubstituted or Substi X is O, NH, or S: tuted with at least one substituent chosen from —C1 R and Reach independently represents —H. —C(O) C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) 10 five- to seven-membered aromatic heterocycle unsub alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, stituted or substituted with at least one substituent —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) —C2-C22 alkynyl, -(CH2)amino acid wherein the cycloalkyl unsubstituted or substituted with at least amino acid is connected through its alpha carbon one substituent chosen from C1-C22 alkyl, —C2-C22 15 atom, —(CH), peptide wherein the peptide is con alkenyl, and —C2-C22 alkynyl, —C6-C12 aryl, nected through the alpha carbon atom of one of its —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, amino acids, —CHORs, —C(O)ORs, —C(O)NRs. —C8-C22 (aryl)alkynyl, three- to seven-membered —P(O)(ORs), S(O)NHRs, —SORs, S(O)Rs. non-aromatic heterocycle unsubstituted or Substi -arylP(O)(ORs), a Sugar, or a Sugar phosphate, tuted with at least one substituent chosen from —C1 or R and R are joined together so as to form a five- to C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, seven-membered non-aromatic heterocycle compris five- to seven-membered aromatic heterocycle unsub ing at least one hetero atom chosen from nitrogen, stituted or substituted with at least one substituent oxygen, and Sulfur, said heterocyle being unsubsti chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and tuted or substituted with at least one substituent cho —C2-C22 alkynyl, -(CH2)amino acid wherein the 25 sen from —C1-C22 alkyl, —C2-C22 alkenyl, and amino acid is connected through its alpha carbon —C2-C22 alkynyl, a phosphate, Sulfate carbonyl atom, —(CH), peptide wherein the peptide is con group, or a thiocarbonylimine; nected through the alpha carbon atom of one of its Rs is —H. —C-C22 alkyl, —(C3-C7) cycloalkyl, amino acids, —CHORs, —C(O)ORs, —C(O)NRs. —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 —P(O)(ORs). —S(O)NHRs – SORs, S(O).Rs. 30 alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, -arylP(O)(ORs), a Sugar, or a Sugar phosphate —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, or R and Rare joined together so as to form a five- to —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 seven-membered non-aromatic heterocycle unsubsti C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti tuted or substituted with at least one substituent cho tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and 35 sen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, Sulfate carbonyl —C2-C22 alkynyl, a three- to seven-membered non group, or a thiocarbonylimine; aromatic heterocycle unsubstituted or substituted at Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, least one substituent chosen from —C1-C22 alkyl, —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to alkenyl, C2-C22 alkynyl, —C7-C22 (aryl)alkyl, 40 seven-membered aromatic heterocycle unsubstituted —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, or substituted with at least one susbtituent chosen —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti C22 alkynyl, a —(CH)amino acid wherein the tuted or substituted with at least one substituent cho amino acid is connected to the compound through its sen from —C1-C22 alkyl, —C2-C22 alkenyl, and 45 alpha carbon atom, a —(CH), peptide wherein the —C2-C22 alkynyl, a three- to seven-membered non peptide is connected to the compound through the aromatic heterocycle unsubstituted or substituted at alpha carbonatom of one of its amino acids, a Sugar or least one substituent chosen from —C1-C22 alkyl, a Sugar phosphate; and —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to n is an integer having a value of 0, 1, 2, 3, or 4. seven-membered aromatic heterocycle unsubstituted 50 in formula (IV) or substituted with at least one susbtituent chosen X is O, NH, or S: from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 X is O, NH, or S: C22 alkynyl, a —(CH)amino acid wherein the X is O, NH, or S: amino acid is connected to the compound through its R and Reach independently represents, —H. —C(O) alpha carbon atom, a —(CH), peptide wherein the 55 NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) peptide is connected to the compound through the alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, alpha carbonatom of one of its amino acids, a Sugar or —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, a Sugar phosphate; and —C3-C22 alkenyl, —C3-C22 alkynyl, —(C3-C7) n is an integer having a value of 0, 1, 2, 3, or 4. cycloalkyl unsubstituted or substituted with at least in formula (III) 60 one substituent chosen from C1-C22 alkyl, —C2-C22 X is O, NH, or S; alkenyl, and —C2-C22 alkynyl, - C6-C12 aryl, X is O, NH, or S: —C7-C22 (aryl)alkyl, —C8-C22 (aryl)alkenyl, X is O, NH, or S; —C8-C22 (aryl)alkynyl, three- to seven-membered R and Reach independently represents, -H, -C(O) non-aromatic heterocycle unsubstituted or Substi NH, -S(O)NH, -S(O)NH – C1-C22 (oxy) 65 tuted with at least one substituent chosen from —C1 alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, C22 alkyl, C2-C22 alkenyl, and —C2-C22 alkynyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, five- to seven-membered aromatic heterocycle unsub US 8,198.324 B2 45 46 stituted or substituted with at least one substituent peptide is connected to the compound through the chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and alpha carbonatom of one of its amino acids, a Sugar or —C2-C22 alkynyl, -(CH2)amino acid wherein the a Sugar phosphate; and amino acid is connected through its alpha carbon n is an integer having a value of 0, 1, 2, 3, or 4. atom, —(CH), peptide wherein the peptide is con- 5 27. The method of claim 26, wherein said ester is a C1-C6 nected through the alpha carbon atom of one of its ester, a monoglyceride, a diglyceride, a triglyceride, a phos amino acids, —CHORs, —C(O)ORs, —C(O)NRs, pholipid, a glycolipid, or a cerebroside. —P(O)(ORs). —S(O)NHRs —SORs, S(O)Rs. 28. The method of claim 27, wherein said at least one fatty -arylP(O)(ORs), a sugar, or a sugar phosphate, acid is a C12-C22 polyunsaturated fatty acid. or R and Rare joined together so as to form a five- to 10 29. The method of claim 28, wherein said at least one seven-membered non-aromatic heterocycle compris- compound is chosen from: ing at least one hetero atom chosen from nitrogen,

oxygen, and Sulfur, said heterocyle being unsubsti tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and 15 —C2-C22 alkynyl, a phosphate, Sulfate carbonyl group, or a thiocarbonylimine; Rs is —H, —C-C22 alkyl, —(C3-C7) cycloalkyl, —C1-C22 (halo)alkyl, - C6-C12 aryl, —C2-C22 alkenyl, —C2-C22 alkynyl, —C7-C22 (aryl)alkyl, 20 —C8-C22 (aryl)alkenyl, —C8-C22 (aryl)alkynyl, —C1-C22 (hydroxy)alkyl, - C1-C22 alkoxy, —C1 C22 (amino)alkyl, a —(C3-C7) cycloalkyl unsubsti tuted or substituted with at least one substituent cho sen from —C1-C22 alkyl, —C2-C22 alkenyl, and 25 —C2-C22 alkynyl, a three- to seven-membered non aromatic heterocycle unsubstituted or substituted at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle unsubstituted 30 or substituted with at least one susbtituent chosen from C1-C22 alkyl, —C2-C22 alkenyl, and —C2 C22 alkynyl, a —(CH)amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH), peptide wherein the k . . . .