Compositions comprising polyunsaturated fatty acid monoglycerides or derivatives thereof and uses thereof

Abstract

There are provided various compounds and compositions comprising polyunsaturated fatty acid monoglycerides and derivatives thereof. These compounds and compositions can be useful as cancer chemopreventive agents. They can also be useful for enhancing solubility of various active agents and enhancing their bioavailability.

1 . A composition comprising at least one active agent and at least one compound chosen from compounds of formulae (I), (II), (III), and (IV): 
       
         
           
           
               
               
           
         
         wherein 
         in formula (I):
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents —H, —C(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C3-C22 alkenyl, or —C3-C22 alkynyl, 
 
         in formula (II):
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C3-C22 alkenyl, or —C3-C22 alkynyl, 
 
         in formula (III)
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  is chosen from —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, and R 2  is chosen from —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, or 
 R 1  is chosen from —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, and R 2  is chosen from —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, 
 
         in formula (IV)
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  is chosen from —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, and R 2  is chosen from —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, or 
 R 1  is chosen from —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, and R 2  is chosen from —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —C1-C22 (oxy)alkyl, —C1-C22 alkyl, —C1-C22 (hydroxy)alkyl, —C1-C22 (amino)alkyl, —C1-C22 (halo)alkyl, —C3-C22 alkenyl, and —C3-C22 alkynyl, 
 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The composition of  claim 1 , wherein said at least one active agent is an active agent belonging to a therapeutic chosen from therapeutic class Analgesic, anesthetic, anti-Alzheimer's, anti-asthma agent, anti-Parkinsonism, antiallergic, antianginal, antiarrhythmic, antiarthritic, antiasthmatic, antibacterial, antibiotic, anticancer, anticoagulant, antidepressant, antidiabetic, antiemetic, antiepileptic, antifungal, antiglaucoma, anti-gout, antihistamine, antihyperprolactinemia, antihypertensive, antiinflammatory, antimigraine, anti-neoplastic, antiobesity, antiparasitic, anti-protozoal, anti-phyretics, antipsoriatic, antipsychotic, antithrombotic, antiulcer, antiviral, anxiolytic, benign prostatic hypertrophy, bronchodilator, calcium metabolism, cardiotonic, cardiovascular agent, chelator & antidote, chemopreventive agent, contraception, diuretic, dopaminergic agent, gastrointestinal agent, gastroprokinetic, hematopoiesis, hemophilia, hormone, hormone replacement therapy, hypnotic, hypocholesterolemic, hypolipidemic, immunomodulator, immunostimulant, immunosuppressant, lipid regulating agent, male sexual dysfunction, multiple sclerosis, muscle relaxant, neuroleptic, nootropic, osteoporosis, phytoestrogen, platelet aggregation inhibitor, prostaglandin, radioenhencer for radiotherapy, relaxant and stimulant, respiratory distress syndrome, urinary incontinence, vasodilator, vitamin/nutritional, vulnerary and xanthine 
     
     
         3 . The composition of  claim 1 , wherein said at least one active agent is a at least one lipid or an hydrolysate thereof. 
     
     
         4 . The composition of  claim 3 , wherein said at least one active agent is said at least one lipid that is at least one fatty acid, an ester thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The composition of  claim 4 , wheein said at least one lipid is a C1-C6 ester of said at least one fatty acid. 
     
     
         6 . The composition of  claim 4 , wherein said at least one lipid is an ethyl ester of said at least one fatty acid. 
     
     
         7 . The composition of  claim 6 , wherein said at least one fatty acid is chosen from eicosapentaenoic acid, ω3-docosapentaenoic acid, ω6-docosapentaenoic acid, and docosahexaenoic acid. 
     
     
         8 . The composition of  claim 1 , wherein said at least one active agent is at least one lipid chosen from a polyunsaturated fatty acid, a pharmaceutically acceptable salt thereof, an ester thereof, and mixtures thereof. 
     
     
         9 . The composition of  claim 8 , wherein said at least one lipid is an ester that is a monoglyceride, a diglyceride, or a triglyceride of said polyunsaturated fatty acid. 
     
     
         10 . The composition of  claim 1 , wherein said at least one active agent is at least one lipophilic active agent. 
     
     
         11 . The composition of  claim 10 , wherein said at least one lipophilic active agent is a C12-C22 fatty acid, an ester thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The composition of  claim 10 , wherein said at least one lipophilic active agent is a C12-C22 polyunsaturated fatty acid or an ester thereof. 
     
     
         13 . The composition of  claim 10 , wherein said at least one lipophilic active agent is a C1-C6 ester of a C12-C22 polyunsaturated fatty acid. 
     
     
         14 . The composition of  claim 10 , wherein said at least one lipophilic active agent is an ethyl ester of a C12-C22 polyunsaturated fatty acid. 
     
     
         15 . The composition of  claim 1 , wherein said at least one compound is chosen from: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The composition of  claim 3 , wherein said at least one active agent is at least one lipid chosen from arachidonic acid, ω3-arachidonic acid, alpha-linolenic acid, conjugated linoleic acid, linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, stearidonic acid, eicosapentaenoic acid, ω3-docosapentaenoic acid, ω6-docosapentaenoic acid, docosahexaenoic acid, C1-C6 esters thereof monoglycerides thereof, diglycerides thereof, triglycerides thereof, phospholipids thereof, and salts thereof. 
     
     
         17 . The composition of  claim 1 , wherein said at least one active agent is chosen from compounds of formulae (I), (II), (III), and (IV). 
     
     
         18 . The composition of  claim 1 , wherein said at least one active agent is a at least one natural product or natural product crude extract chosen from a vegetable, mussels, shrimps, fish, seal, microalgae, krill, a crustacean; an hydrolysate from a vegetable oil, mussels oil, shrimps oil, fish oil, seal oil, microalgae oil, krill oil, a crustacean oil; and a protein hydrolysate from vegetable, animal or marine source. 
     
     
         19 . The composition of  claim 1 , wherein said at least one active agent is at least one natural product or natural product crude extract chosen from alfalfa, aloe, angelica, arnica, aristolochic acid,  artemisia , astaxanthin, ashwaganda,  astragalus , avens, beta-carotene, bilberry, birch, black cohosh, black horehound, blessed thistle, biotin, boldo, burdock, calcium,  calendula , California poppy, caraway, cascara sagrada, catnip, cayenne, chaste tree fruit, chondroitin sulphate, copper, cramp bark, cranberry, dandelion, dang gui, devil's claw, echinacea, echinacea purpurea, echinacea pallida, eleuthero, evening primrose oil, european linden, european pennyroyal, fenugreek, feverfew, figwort, flax, folate, frankincense, garlic, gentian, ginger, ginkgo, globe artichoke, glucosamine, goldenseal, green tea, ground ivy, hawthorn, heal-all, hops, horse chestnut, horseradish, hyssop, illicium verum, juniper, licorice, linden, lungwort, lutein, melatonin, milk thistle, mugwort, niacin, pantothenic acid, peppermint, reishi mushroom, riboflavin, rosemary, saw palmetto, scullcap, selenium, schisandra, stinging nettle, St. John's wort,  thuja , thyme, tomato, turmeric, valerian, willow bark, witch hazel and zeaxanthin. 
     
     
         20 . A composition comprising at least one compound chosen from compounds of formulae (I), (II), (III), and (IV): 
       
         
           
           
               
               
           
         
         wherein 
         in formula (I):
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate 
 or R 1  and R 2  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-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C1-C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
         in formula (II):
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate 
 or R 1  and R 2  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-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C1-C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
         in formula (III)
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents, —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate, 
 or R 1  and R 2  are joined together so as to form a five- to seven-membered non-aromatic heterocycle comprising at least one hetero atom chosen from nitrogen, oxygen, and sulfur, said heterocyle being unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C1-C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
         in formula (IV)
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents, —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate, 
 or R 1  and R 2  are joined together so as to form a five- to seven-membered non-aromatic heterocycle comprising at least one hetero atom chosen from nitrogen, oxygen, and sulfur, said heterocyle being unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C1-C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
       
       or a pharmaceutically acceptable salt thereof:
 and 
 
       at least one active agent chosen from at least one natural product or natural product crude extract chosen from alfalfa, aloe, angelica, arnica, aristolochic acid,  artemisia , astaxanthin, ashwaganda,  astragalus , avens, beta-carotene, bilberry, birch, black cohosh, black horehound, blessed thistle, biotin, boldo, burdock, calcium,  calendula , California poppy, caraway, cascara sagrada, catnip, cayenne, chaste tree fruit, chondroitin sulphate, copper, cramp bark, cranberry, dandelion, dang gui, devil's claw, echinacea, echinacea purpurea, echinacea pallida, eleuthero, evening primrose oil, european linden, european pennyroyal, fenugreek, feverfew, figwort, flax, folate, frankincense, garlic, gentian, ginger, ginkgo, globe artichoke, glucosamine, goldenseal, green tea, ground ivy, hawthorn, heal-all, hops, horse chestnut, horseradish, hyssop, illicium verum, juniper, licorice, linden, lungwort, lutein, melatonin, milk thistle, mugwort, niacin, pantothenic acid, peppermint, reishi mushroom, riboflavin, rosemary, saw palmetto, scullcap, selenium, schisandra, stinging nettle, St. John's wort,  thuja , thyme, tomato, turmeric, valerian, willow bark, witch hazel, zeaxanthin, and mixtures thereof. 
     
     
         21 . A method of using at least one compound of formula (I), (II), (III), or (IV): 
       
         
           
           
               
               
           
         
         wherein 
         in formula (I):
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate 
 or R 1  and R 2  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-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C 1 -C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
         in formula (II):
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate or R 1  and R 2  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-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C1-C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
         in formula (III)
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents, —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate, 
 or R 1  and R 2  are joined together so as to form a five- to seven-membered non-aromatic heterocycle comprising at least one hetero atom chosen from nitrogen, oxygen, and sulfur, said heterocyle being unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C1-C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
         in formula (IV)
 X 1  is O, NH, or S; 
 X 2  is O, NH, or S; 
 X 3  is O, NH, or S; 
 R 1  and R 2  each independently represents, —H, —C(O)NH 2 , —S(O)NH 2 , —S(O) 2 NH 2 , —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)cycloalkyl unsubstituted or substituted 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 heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, —(CH 2 ) n amino acid wherein the amino acid is connected through its alpha carbon atom, —(CH 2 ) n peptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, —CH 2 OR 5 , —C(O)OR 5 , —C(O)NR 5 , —P(O)(OR 5 ) 2 , —S(O) 2 NHR 5 , —SOR 5 , —S(O) 2 R 5 , -arylP(O)(OR 5 ) 2 , a sugar, or a sugar phosphate, 
 or R 1  and R 2  are joined together so as to form a five- to seven-membered non-aromatic heterocycle comprising at least one hetero atom chosen from nitrogen, oxygen, and sulfur, said heterocyle being unsubstituted or substituted with at least one substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine; 
 R 5  is —H, —C1-C22 alkyl, —(C3-C7)cycloalkyl, —C1-C22 (halo)alkyl, —C6-C12 aryl, —C2-C22 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 unsubstituted or substituted with at least one substituent chosen 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 substituent chosen from —C1-C22 alkyl, —C2-C22 alkenyl, and —C2-C22 alkynyl, a —(CH 2 ) n amino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a —(CH 2 ) n peptide wherein the peptide is connected to the compound through the alpha carbon atom 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, 
 
       
       said method comprising solubilizing at least one active agent in said at least one compound of formula (I), (II), (III), or (IV).