AMPK Activators (CBDA) and SGLT2 Inhibitors for Metabolic Health

Abstract

The composition includes a first compound having general formula I and a second compound for use in synergistic activation of AMPK. Methods of using the composition in synergistic activation of AMPK are also provided.

Description

[Background technology]

[0001]

[0001] The present disclosure relates generally to compositions and methods for improving metabolic health. Specifically, the present disclosure relates to a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, or CBNA) with a sodium-glucose cotransporter 2 (SGLT2) inhibitor to improve metabolic health. For example, a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, or CBNA) with a SGLT2 inhibitor synergistically activates AMPK and improves metabolic health.

[0002] AMP-activated protein kinase (AMPK) is an evolutionarily conserved master regulator of energy homeostasis that coordinates metabolic pathways aimed at balancing nutrient supply with energy demand. AMPK is considered to be an important drug target to combat the epidemic of metabolic disorders such as obesity, type 2 diabetes, and cardiovascular disease.

[0003]

[0003] AMPK activity is found in all tissues, including liver, kidney, muscle, lung, and brain (PMID:10698692). Structurally, AMPK is a heterotrimeric complex consisting of a catalytic subunit (α) and two regulatory subunits (β and γ). The AMPK complex is evolutionarily conserved and can also be found in yeast and plants. Mammalian AMPK is composed of different isoforms of subunits: α1, α2, β1, β2, γ1, γ2, and γ3 (PMID:11746230), resulting in 12 possible heterotrimeric combinations. The α2 isoform is found primarily in skeletal and cardiac muscle AMPK, while both the α1 and α2 isoforms are found in liver AMPK. On the other hand, for example in adipose and T cells, the α1 isoform of AMPK predominates (PMID:16818670, PMID15878856).

[0004]

[0004] Despite the continuous and intensive efforts in the pharmaceutical industry, there are no direct AMPK activators available for treating metabolic disorders. Several synthetic AMPK activators have been identified / developed. However, the activators either have no or low oral availability (PMID:16753576, PMID:24900234), or have off-target side effects, as chronic and strong AMPK activation can cause increased glycogen content and hypertrophy in the heart (PMID:11827995).

[0005]

[0005] Finding natural bioactive molecules that moderately activate AMPK with a defined mechanism of action, particularly in muscle, liver, and kidney, is likely to provide exercise-mimetic effects and help maintain / improve metabolic health.

[0006] There are many natural compounds / extracts that have been shown to indirectly stimulate AMPK (most likely through inhibition of mitochondrial respiration) and are known to have some metabolic health benefits. However, it is very difficult to determine whether these metabolic effects are mediated by AMPK, and furthermore, there are concerns regarding side effects / toxic effects such as cellular or mitochondrial poisoning.

[0007]

[0007] Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are non-insulin-dependent oral hypoglycemic drugs used by clinicians to treat type 2 diabetes. Since 2013, four SGLT2 inhibitors have been approved by the Food and Drug Administration: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.

[0008]

[0008] SGLT2 inhibitors are a class of prescription drugs approved by the FDA to lower blood sugar in adults with type 2 diabetes in combination with diet and exercise. Drugs in the SGLT2 inhibitor category include canagliflozin, dapagliflozin, and empagliflozin. These drugs are available as single-ingredient products and in combination with other diabetes drugs such as metformin. SGLT2 inhibitors allow the kidneys to remove sugar from the body through urine, lowering blood sugar.

[0009]

[0009] There is a clear unmet need for novel compositions of combinations of AMP-activated protein kinase (AMPK) activators (e.g., CBDA, CBGA, or CBNA) with sodium-glucose cotransporter 2 (SGLT2) inhibitors to improve metabolic health. There is a need in the art for combinations of AMP-activated protein kinase (AMPK) activators (e.g., CBDA, CBGA, or CBNA) with sodium-glucose cotransporter 2 (SGLT2) inhibitors to synergistically activate AMPK and thus improve metabolic health.

[0010] [Summary of the Invention]

[0010] The present disclosure includes the recognition that administering a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, or CBNA) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor to a subject to synergistically activate AMPK represents a breakthrough for improving metabolic health. Indeed, the method of administering a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, or CBNA) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor disclosed herein to a subject resulted in improved performance of activated AMPK compared to administering an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, or CBNA) or a sodium-glucose cotransporter 2 (SGLT2) inhibitor alone. [Brief description of the drawings]

[0011] [Figure 1A] A set of graphs showing glucose clearance in zebrafish according to certain embodiments of the present invention. Figure 1A shows that the combination of CBD and Dapa (SGLT2 inhibitor) improves glucose clearance in zebrafish compared to CBD alone and Dapa alone. Figure 1B shows that the combination of CBDA and Dapa (SGLT2 inhibitor) improves glucose clearance in zebrafish compared to CBDA alone and Dapa alone. [Figure 1B] A set of graphs showing glucose clearance in zebrafish according to certain embodiments of the present invention. Figure 1A shows that the combination of CBD and Dapa (SGLT2 inhibitor) improves glucose clearance in zebrafish compared to CBD alone and Dapa alone. Figure 1B shows that the combination of CBDA and Dapa (SGLT2 inhibitor) improves glucose clearance in zebrafish compared to CBDA alone and Dapa alone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012]

[0012] Definition

[0013] Some definitions are provided below. However, definitions may be found in the "Embodiments" section below, and the heading "Definitions" above does not imply that such disclosure in the "Embodiments" section is not a definition.

[0013]

[0014] All percentages stated herein are by total weight of the composition unless otherwise indicated. As used herein, "about," "approximately," and "substantially" are understood to refer to numbers within a certain range of numerical values, for example, within the range of -10% to +10% of the referenced number, preferably within the range of -5% to +5% of the referenced number, more preferably within the range of -1% to +1% of the referenced number, and most preferably within the range of -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers or fractions within the range. Furthermore, these numerical ranges should be interpreted as supporting claims directed to any number or subset of numbers within the range. For example, a disclosure of 1 to 10 should be interpreted as corresponding to ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0014]

[0015] As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "a component" or "the component" includes two or more components.

[0015]

[0016] The terms "comprise", "comprises", and "comprising" should be interpreted as inclusive rather than exclusive. Similarly, the terms "include", "including", and "or" should all be interpreted as inclusive unless such interpretation is clearly prevented by the context. However, the compositions disclosed herein may not include elements not specifically disclosed herein. Thus, disclosure of an embodiment using the term "comprising" includes disclosure of an embodiment "consisting essentially of" the specified components, and an embodiment "consisting of" the specified components.

[0016]

[0017] The term "and / or" used in the context of "X and / or Y" shall be interpreted as "X" or "Y" or "X and Y." Similarly, "at least one of X or Y" shall be interpreted as "X" or "Y" or "X and Y." For example, "at least one dithionite or a functionally equivalent reducing agent" shall be interpreted as "dithionite" or "a functionally equivalent reducing agent" or "both dithionite and a functionally equivalent reducing agent."

[0017]

[0018] As used herein, the terms "examples" and "such as," especially when followed by a list of terms, are merely exemplary and illustrative and should not be considered as exclusive or inclusive. As used herein, a condition "associated with" or "linked with" another condition means that the conditions occur simultaneously, preferably that the conditions are caused by the same underlying condition, and most preferably that one of the specified conditions is caused by the other specified condition.

[0018]

[0019] The term "cannabidiol acid" or "CBDA" as used herein refers to 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid, CAS number 1244-58-2. Such compound is also called 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-6-pentylbenzoic acid, 2,4-dihydroxy-3-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-6-pentyl-(1R-trans)benzoic acid, 3-p-mentha-1,8-dien-3-yl-6-pentyl-β-resorcylic acid, cannabidiol carboxylic acid, or cannabinoid CBDA. Such compounds have the formula:

[0019] [ka]

[0020]

[0020] As used herein, the term "resorcylic acid" refers to a type of dihydroxybenzoic acid. In one embodiment, resorcylic acid may include 3,5-dihydroxybenzoic acid (α-resorcylic acid), 2,4-dihydroxybenzoic acid (β-resorcylic acid), or 2,6-dihydroxybenzoic acid (γ-resorcylic acid), or any of their derivatives.

[0021]

[0021] The term "cannabidiol" or "CBD" as used herein refers to 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. This compound is also called 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol, 2-p-mentha-1,8-dien-3-yl-5-pentyl-trans-(-)-resorcinol, 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-(1R-trans)-1,3-benzenediol, Epidiolex, GWP42003P, or Epidiolex. Such compounds have the formula: [ka]

[0022]

[0022] The term "cannabigerolic acid" or "CBGA" as used herein refers to the acidic form of cannabigerol (CBG). Such compounds are dihydroxybenzoic and olivetolic acids with the hydrogen at the 3-position replaced by a geranyl group. Such compounds are the biosynthetic precursors of delta-9-tetrahydrocannabinol, the major psychoactive component of the Cannabis plant. Such compounds are also members of the diterpenoid, polyketide, resorcinol and phytocannabinoid classes. Such compounds are derived from olivetolic acid. Such compounds are the conjugate acids of cannabigerolate. Such compounds have the formula: [ka]

[0023]

[0023] As used herein, the term "cannabinolic acid" or "CBNA" refers to 1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxylic acid. Such a compound is also called 1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-2-carboxylic acid, 1-hydroxy-6,6,9-trimethyl-3-pentylbenzo[c]chromene-2-carboxylic acid, or 1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-dibenzo(b,d)pyran-2-carboxylic acid. Such a compound has the formula: [ka]

[0024]

[0024] In one embodiment, the first compound of the present invention comprises CBNA or a derivative or analog thereof. WO 2021 / 105075 discloses examples of CBNA derivatives or analogs.

[0025]

[0025] As used herein, the term "5'-adenosine monophosphate-activated protein kinase", "AMP-activated protein kinase", or "AMPK" refers to a heterotrimeric kinase composed of a catalytic alpha subunit and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors intracellular energy status. AMPK is activated in response to cellular metabolic stress. AMPK also phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxybeta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating the de novo biosynthesis of fatty acids and cholesterol, as well as other proteins involved in metabolism. AMPK and its role as an energy sensor have been reviewed in various publications, which are incorporated by reference, including Kemp et al (Trends Biochem. Sci. 1999 24:22-5), Hardie et al (Bioessays. 2001 23:1112-9), Musi et al (Curr. Drug Targets Immune Endocr. Metabol. Disord. 2002 2:119-27), Musi et al (Biochem. Soc. Trans. 2003 31:191-5) and Hardie (Endocrinology. 2003 144:5179-83) and Aschenbach (Sports Med. 2004 34:91-103).

[0026]

[0026] AMPK is a central regulator of energy homeostasis, which regulates metabolic pathways and thus balances nutrient supply and energy demand. Due to the favorable physiological outcomes that AMPK activation brings to metabolism, AMPK has been considered an important therapeutic target for controlling human diseases, including metabolic syndrome and cancer. AMP-activated protein kinase (AMPK), a cellular energy sensor, is activated in response to various conditions that deplete intracellular energy, such as nutrient starvation (especially glucose), hypoxia, and exposure to toxins that inhibit mitochondrial respiratory chain complexes. AMPK is a serine / threonine protein kinase complex consisting of catalytic subunits α-subunits (α1 and α2), scaffolding subunits β-subunits (β1 and β2), and regulatory subunits γ-subunits (γ1, γ2, and γ3).

[0027]

[0027] As used herein, the term "AMPK activation" refers to the phosphorylation state of AMPK or the phosphorylation state of a direct target of AMPK. AMPK can be activated by modulation of proteins upstream of AMPK (e.g., adiponectin receptor, leptin receptor, α-adrenergic receptor, insulin receptor, etc.) or by AMPK itself. AMPK activation can also be assessed by assaying AMPK itself or downstream targets of AMPK.

[0028]

[0028] As used herein, the term "AMP-activated protein kinase activator" or "AMPK activator" refers to any compound or substance that activates AMP-activated protein kinase (AMPK). For example, a European patent application entitled "SUBSTITUTED RESORCYLIC ACID COMPOUNDS AS AMPK ACTIVATOR, COMPOSITIONS, METHODS AND USES THEREOF" (EP Application No. 20205952.3) describes compounds that directly bind to AMPK via an ADaM (allosteric drug and metabolite) site formed at the interface between the AMPKα and AMPKβ subunits. These compounds are from a class of substituted resorcylic acids and directly activate AMPK in cells.

[0029]

[0029] The AMPK activator may be a direct AMPK activator or an indirect AMPK activator. In one embodiment, the AMPK activator is a direct AMPK activator. In one embodiment, the AMPK activator is an indirect AMPK activator.

[0030]

[0030] In one embodiment, AMPK activators may have potential as novel therapeutic agents for these diseases. In one embodiment, one type of AMPK activator is a small molecule that mimics intracellular AMP.

[0031] In one embodiment, the AMPK activator is cannabidiolic acid (CAS number 1244-58-2), CBDA, CBGA, CBNA, or any of their derivatives. In one embodiment, the derivative is any of the compounds having the general formula I:

[0032] In one embodiment, the AMPK activator is cannabidiol, CBDA, CBGA, CBNA, or any of their derivatives. In one embodiment, the derivative is any of the compounds having the general formula I:

[0033]

[0033] The term "sodium-glucose cotransporter 2 inhibitor" or "SGLT2 inhibitor" as used herein refers to a compound or substance that exhibits an inhibitory effect on SGLT2 (sodium-sugar carboxy-2), in particular human SGLT2. The hSGLT2 inhibitory effect is measured as IC50, preferably below 1000 nM, more preferably below 100 nM, most preferably below 50 nM. The IC50 value of SGLT2 inhibitors is typically above 0.01 nM, or even above 0.1 nM. The inhibitory effect on hSGLT2 can be measured by methods known in the literature, in particular by the methods described in WO 2005 / 092877 or WO 2007 / 093610 (pages 23 / 24) (hereby incorporated by reference). The term "SGLT2 inhibitor" also includes pharma- ceutically acceptable salts, hydrates and solvates, including the respective crystalline forms.

[0034]

[0034] In one embodiment, the SGLT2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, remogliflozin, sergliflozin, phlorizin and derivatives thereof.

[0035] In one embodiment, SGLT2 inhibitors may comprise a class of FDA-approved prescription drugs for lowering blood glucose in combination with diet and exercise in adults with type 2 diabetes. Medications in the SGLT2 inhibitor class may include canagliflozin, dapagliflozin, and empagliflozin. These compounds are available as single-ingredient products and in combination with other diabetes medications, such as metformin. SGLT2 inhibitors allow the kidneys to remove sugar from the body through urine, lowering blood glucose.

[0036]

[0036] Curr Opin Endocrinol Diabetes Obes. 2017 Feb;24(1):73-79.doi;10.1097 / MED to Hsia et al provide a list of compounds that are SGLT2 inhibitors.

[0037]

[0037] As used herein, the term "active ingredient" refers to any AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA or CBNA) and / or SGLT2 inhibitor according to the present invention.

[0038]

[0038] As used herein, the term "nutritional composition" or "nutritional supplement" refers to a nutritional product that provides an individual with nutrients that the individual may not otherwise be able to consume in sufficient amounts. For example, the nutritional composition or nutritional supplement of the present invention may include vitamins, minerals, fiber, fatty acids, or amino acids. The nutritional composition or nutritional supplement of the present invention may be provided, for example, in the form of a pill, tablet, lozenge, chewable capsule or tablet, tablet or capsule, or a powder supplement that can be dissolved in water or sprinkled on food, for example.

[0039]

[0039] In one embodiment, the nutritional composition or dietary supplement of the present invention may provide selected nutrients, but not a significant portion of the overall nutritional needs of a subject. Typically, the nutritional composition or dietary supplement of the present invention does not represent more than 0.1%, 1%, 5%, 10%, or 20% of the daily energy needs of a subject. The nutritional composition or dietary supplement of the present invention may be used in any subject, such as a pregnant subject, for example, as a maternal supplement.

[0040]

[0040] As used herein, an "effective amount" or a "pharmaceutical effective amount" is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or more generally, alleviates symptoms, manages the progression of a disease, or provides a nutritional, physiological, or medical benefit to an individual. The relative terms "promote," "improve," "increase," "enhance," and the like refer to the effect of a composition comprising an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, or CBNA) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor as disclosed herein relative to an otherwise identical composition lacking an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, or CBNA) and / or a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

[0041]

[0041] The term "unit dosage form" as used herein refers to a physically discrete unit suitable as a unit of administration to human and animal subjects, each unit containing a predetermined amount of the nutritional composition disclosed herein in an amount sufficient to produce the desired effect, preferably together with a pharma- ceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage form depend on the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host. In one embodiment, the unit dosage form may be a predetermined amount of powder in a sachet.

[0042]

[0042] As used herein, the term "nutritional product" refers to any product that can be used to provide nutrition to a subject. Typically, a nutritional product contains a protein source, a carbohydrate source, and a lipid source.

[0043]

[0043] As used herein, the term "food product" refers to any type of product that may be safely consumed by humans or animals. Such food products may be in solid, semi-solid, or liquid form and may contain one or more nutrients, foods, or dietary supplements. For example, food products may further contain the following nutrients and micronutrients: a protein source, a lipid source, a carbohydrate source, vitamins, and minerals. Food products may also contain antioxidants, stabilizers (if provided in solid form) or emulsifiers (if provided in liquid form).

[0044]

[0044] As used herein, the term "functional food product" refers to a food product that provides an individual with additional health-promoting or disease-preventing functions.

[0045]

[0045] As used herein, the term "healthy aging product" refers to a product that provides an individual with additional health-promoting or disease-preventing functions associated with healthy aging.

[0046]

[0046] The term "dairy product" as used herein refers to food products made from milk or milk fractions of animals such as cows, goats, sheep, yaks, horses, camels, and other mammals. Examples of dairy products are low fat milk (e.g., 0.1%, 0.5% or 1.5% fat), nonfat milk, milk powder, whole milk, whole milk products, butter, buttermilk, buttermilk products, skim milk, skim milk products, high milkfat products, condensed milk, creme fraiche, cheese, ice cream, and confectionery products, probiotic beverages or probiotic yogurt type beverages.

[0047]

[0047] As used herein, the term "dairy substitute product" refers to a product that is similar to a dairy product, but is made without the use of milk.

[0048]

[0048] As used herein, the term "milk" is defined by Codex Alimentarius as the normal mammary secretion of a lactating animal, obtained by one or more milkings, and intended for consumption as liquid milk or for further processing, without additions or extractions.

[0049]

[0049] As used herein, the term "beverage product" refers to a nutritional product in liquid or semi-liquid form that can be safely consumed by an individual.

[0050]

[0050] As used herein, the term "diet product" refers to a food product that has limited and / or reduced calorie content.

[0051]

[0051] The term "pet food product" as used herein refers to a nutritional product intended for consumption by pets. Pet or companion animals referred to in this specification should be understood as animals selected from dogs, cats, birds, fish, rodents, such as mice, rats, etc.

[0052]

[0052] As used herein, an "effective amount" is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or, more generally, alleviates symptoms, manages the progression of a disease, or provides a nutritional, physiological or medical benefit to the individual.

[0053] All components of the composition can be mixed together or the composition can be provided in the form of a kit of parts, in which components or groups of components are provided separately. These separate compositions can be intended to be taken separately or together.

[0054]

[0054] The description of simple chains such as methyl, pentyl, and dodecyl are known to those skilled in the art. For example, methyl is an alkyl derived from methane, -CH3, which contains one carbon atom to which three hydrogen atoms are attached. Pentyl has the chemical formula -CH 11 Dodecyl is a 5-carbon alkyl functional group (substituent) having the chemical formula -C 12 H 25 It is a 12-carbon alkyl functional group (substituent) having the formula:

[0055] In all structures, the dots represent the insertion points of the chains on the aromatic rings.

[0056] For example, in Markush structure A, when R2 is 3-methyl-2-buten-1-yl (1h), it corresponds to structure B. [ka]

[0057]

[0057] As used herein, the term "C5 isoprenoid" refers to the following substituents: 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl(3,3-dimethylallyl). (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p). [ka]

[0058] As used herein, the term "C 10"Isoprenoid" refers to the following substituents: 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)- 3,7-Dimethyl-2,6-octadien-1-yl(geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl(neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl(lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o). [ka]

[0059] As used herein, the term "C 15 "Isoprenoid" refers to the following substituents: 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). [ka]

[0060] As used herein, the term "C 20 "Isoprenoid" refers to the following substituents: 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b). [ka]

[0061]

[0061] As used herein, the term "alkyl" refers to a branched or unbranched saturated hydrocarbon chain having 1 to 20 carbon atoms, or 1 to 15 carbon atoms, or 1 to 10 carbon atoms, or 1 to 7 carbon atoms, or 1 to 5 carbon atoms, or 1 to 3 carbon atoms. The alkyl chain may be cyclic, in which case it is known as a "cycloalkyl" group.

[0062]

[0062] Non-limiting examples of branched or unbranched alkyl chains include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, nonyl, decyl, undecyl, tetradecyl, pentadecyl, heptadecyl, and eicosyl.

[0063]

[0063] Non-limiting examples of cycloalkyl chains include 5-methyl-2-(1-methylethyl)cyclohexyl (2o).

[0064] The term "substituted alkyl" refers to the following: 1) alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy. An alkyl chain as defined above having 1, 2, 3, 4 or 5 substituents (in some embodiments 1, 2 or 3 substituents) selected from the group consisting of cycloalkyl, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, and -S(O)2-heteroaryl. Unless otherwise constrained by definition, all substituents are optionally selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) n R [In the formula, R is alkyl, aryl or heteroaryl, and n is 0, 1, or 2; one of the oxygen substituents of the alkyl chain can be attached by a single bond to two adjacent carbon atoms of the same alkyl chain to form an epoxy group, i.e., a three-membered epoxide ring. Non-limiting examples of alkyl chains substituted with hydroxy, alkoxy, and / or acyloxy groups or containing epoxy groups include 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 8-hydroxy-3,7-dimethyloctyl (2b), hydroxylmethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 12-hydroxytridecyl (5e), ​​12-hydroxytridecyl (5f), 12-hydroxytridecyl (5g), 12-hydroxytridecyl (5h), 12-hydroxytridecyl (5i), 12-hydroxytridecyl (5j ... Examples of the hydroxytridecyl compounds include 5d, 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), and 2-(acetyloxy)tridecyl (5p). [ka] Non-limiting examples of alkyl chains substituted with aryl / aryloxy groups include benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e). [ka] Non-limiting examples of alkyl chains substituted with aryl / aryloxy and hydroxy groups include 2-hydroxy-2-phenylethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b). [ka] A non-limiting example of an alkyl chain substituted with a heterocyclyl group includes (tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a). [ka] Or, 2) Oxygen, Sulfur, and NR [In the formula, R is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl. All substituents are optionally selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)R. [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 3) an alkyl chain as defined above that has 1, 2, 3, 4, or 5 substituents as defined above and is further interrupted by 1 to 5 atoms (e.g., 1, 2, 3, 4, or 5 atoms) as defined above; Or, 4) An alkyl chain as defined above in which one or more of the methylene groups is replaced by a carbonyl group to give an oxo group. Non-limiting examples of alkyl chains in which one or more methylene groups are replaced with a carbonyl group include 3-methyl-2-oxobutyl (1g), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 2-oxotridecyl (9g). [ka] Or, 5) An alkyl chain as defined above, in which one of the methylene groups is replaced by a carbonyl group to give an oxo group and which has 1, 2, 3, 4, or 5 substituents as defined above, or which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms), or which has 1, 2, 3, 4, or 5 substituents as defined above and is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms). Non-limiting examples of alkyl chains in which one of the methylene groups is replaced by a carbonyl group to give an oxo group and have a hydroxy substituent include 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b). [ka] Non-limiting examples of aryl / aryloxy substituted alkyl chains in which one of the methylene groups is replaced by a carbonyl group to give an oxo group include 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxo-2-phenylethyl (11b). [ka]

[0065]

[0065] As used herein, the term "alkenyl" refers to an alkyl chain, as defined above, of the type in which two atoms of the alkyl chain form a double bond that is not part of an aromatic group. That is, the alkenyl chain contains the pattern RC(R)=C(R)-R, where in one embodiment R refers to the remainder of the alkenyl chain and may be the same or different. The alkenyl moiety may be branched, straight chained, or cyclic (in which case the moiety is also referred to as a "cycloalkenyl" group).

[0066] The term "substituted alkenyl" refers to the following: 1) alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy an alkenyl chain as defined above having 1, 2, 3, 4 or 5 substituents (in some embodiments 1, 2 or 3 substituents) selected from the group consisting of: -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, and -S(O)2-heteroaryl; unless otherwise constrained by a definition, all substituents are optionally selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)nR [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; One of the oxygen substituents of an alkenyl chain can be attached by single bonds to two adjacent carbon atoms of the same alkenyl chain to form an epoxy group, i.e., a three-membered epoxide ring. Or, 2) Oxygen, Sulfur, and NR [In the formula, R is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl. All substituents are optionally selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)R. [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 3) an alkenyl chain as defined above that has 1, 2, 3, 4, or 5 substituents as defined above and is further interrupted by 1 to 5 atoms (e.g., 1, 2, 3, 4, or 5 atoms) as defined above; Or, 4) An alkenyl chain as defined above in which one or more of the methylene groups is replaced by a carbonyl group to give an oxo group. Or, 5) An alkenyl chain as defined above, in which one of the methylene groups is replaced by a carbonyl group to give an oxo group and which has 1, 2, 3, 4, or 5 substituents as defined above, or which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms), or which has 1, 2, 3, 4, or 5 substituents as defined above and is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms).

[0067]

[0067] Non-limiting examples of alkenyl chains include 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), and 10-heptadecen-1-yl (12g). [ka]

[0068]

[0068] Non-limiting examples of alkenyl chains substituted with hydroxy groups and / or acyloxy groups, or alkenyl chains containing epoxy groups include 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2 ... hydroxy-3-methyl-3-buten-1-yl (1o), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), and 10-(acetyloxy)-8-pentadecenyl (13a). [ka]

[0069] A non-limiting example of an alkenyl chain substituted with an aryl group is 2-phenylethenyl (14a). [ka]

[0070] A non-limiting example of an alkenyl chain in which one of the methylenes is replaced with an oxo group is 1-hydroxymethylene-2-oxopropyl (15a). [ka]

[0071]

[0071] As used herein, the term "alkynyl" refers to an alkyl chain according to the above definition, of the type in which two atoms of the alkyl chain form a triple bond. That is, an alkynyl chain has the pattern [ka] In one embodiment, R refers to the remainder of the alkynyl chain, which may be the same or different. Non-limiting examples of alkynyl chains include: [ka] The "R" portion of the alkynyl moiety may be branched, straight chain, or cyclic. The alkynyl chain may be optionally substituted.

[0072] The term "substituted alkynyl" refers to: 1) alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy an alkynyl chain as defined above having 1, 2, 3, 4 or 5 substituents (in some embodiments 1, 2 or 3 substituents) selected from the group consisting of: -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, and -S(O)2-heteroaryl; unless otherwise constrained by a definition, all substituents are optionally selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)nR [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; One of the oxygen substituents of an alkynyl chain can be attached by single bonds to two adjacent carbon atoms of the same alkynyl chain to form an epoxy group, i.e., a three-membered epoxide ring. Or, 2) Oxygen, Sulfur, and NR [In the formula, R is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl. All substituents are optionally selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)R. [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 3) an alkynyl chain as defined above that has 1, 2, 3, 4, or 5 substituents as defined above and is further interrupted by 1 to 5 atoms (e.g., 1, 2, 3, 4, or 5 atoms) as defined above; Or, 4) An alkynyl chain as defined above in which one or more of the methylene groups is replaced by a carbonyl group to give an oxo group. Or, 5) An alkynyl chain as defined above, in which one of the methylene groups is replaced by a carbonyl group to give an oxo group and which has 1, 2, 3, 4, or 5 substituents as defined above, or which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms), or which has 1, 2, 3, 4, or 5 substituents as defined above and is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms).

[0073]

[0073] As used herein, the term "polyalkenyl" refers to a chain in which two or more pairs of atoms in an alkyl chain form a double bond that is not part of an aromatic group. That is, the polyalkenyl chain contains 2 to 8 R-C(R)=C(R)-R patterns, where in one embodiment, R refers to the remainder of the alkenyl chain and may be the same or different. The polyalkenyl portion may be branched or linear.

[0074]

[0074] Non-limiting examples of polyalkenyl chains include 3-methyl-1,3-butadienyl (1p), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl(geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl(neryl) (2i), 5-methyl-2-(1-methylethenyl)-2-cyclohexen-1-yl (2j), 5-methyl-2-(1-methylethenyl)-2-cyclohexen-1-yl (2k ...). (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b), and 8,11-heptadecadien-1-yl (16a). [ka]

[0075]

[0075] The polyalkenyl moiety containing two double bonds may be cyclic (in which case the moiety is also referred to as a "cyclodialkenyl" group). Non-limiting examples of cyclodialkenyl groups include cyclopentadiene and cyclohexadiene groups. The polyalkenyl chain may be optionally substituted.

[0076] As used herein, the term "substituted polyalkenyl" refers to: 1) alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, A polyalkenyl chain as defined above having 1, 2, 3, 4 or 5 substituents (in some embodiments 1, 2 or 3 substituents) selected from the group consisting of heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, and -S(O)2-heteroaryl. Unless otherwise constrained by definition, all substituents are optionally selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) n R [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; One of the oxygen substituents of the polyalkenyl chain can be attached by single bonds to two adjacent carbon atoms of the same polyalkenyl chain to form an epoxy group, i.e., a three-membered epoxide ring. One of the oxygen substituents of the polyalkenyl chain can form a five-membered aromatic ring with four carbon atoms of the same chain, resulting in a furan ring. Or, 2) Oxygen, Sulfur, and NR [In the formula, R is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl. All substituents are optionally selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) n R [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 3) a polyalkenyl chain as defined above, which has 1, 2, 3, 4, or 5 substituents as defined above and which is further interrupted by 1 to 5 atoms (e.g., 1, 2, 3, 4, or 5 atoms) as defined above; Or, 4) A polyalkenyl chain as defined above in which one or more of the methylene groups are replaced by a carbonyl group to give an oxo group. Or, 5) A polyalkenyl chain as defined above, in which one of the methylene groups is replaced by a carbonyl group to give an oxo group and which has 1, 2, 3, 4, or 5 substituents as defined above, or which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms), or which has 1, 2, 3, 4, or 5 substituents as defined above and which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms).

[0077]

[0077] Non-limiting examples of polyalkenyl chains substituted with hydroxy groups or containing furan rings include 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methyl-1-propen-1-yl)-3-furanyl]-2-hexen-1-yl (3d).

[0078]

[0078] Non-limiting examples of linear or cyclic polyalkenyl chains in which one of the methylene groups is replaced by a carbonyl group to give an oxo group include 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c). [ka]

[0079] A non-limiting example of a polyalkenyl chain substituted with an aryloxy group is 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a). [ka]

[0080] The term polyalkynyl refers to a chain in which two or more pairs of atoms in an alkyl chain form a triple bond. That is, a polyalkynyl chain is a chain having 2 to 8 [ka] In one embodiment, R refers to the remainder of the alkynyl chain, which may be the same or different. Non-limiting examples of polyalkynyl chains include: [ka] The "R" portion of the polyalkynyl moiety may be branched, linear, or cyclic.

[0081] As used herein, the term "substituted polyalkynyl" refers to: 1) alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, A polyalkynyl chain as defined above having 1, 2, 3, 4 or 5 substituents (in some embodiments 1, 2 or 3 substituents) selected from the group consisting of heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, and -S(O)2-heteroaryl. Unless otherwise constrained by definition, all substituents are optionally selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)nR. [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 2) Oxygen, Sulfur, and NR [In the formula, R is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl. All substituents are optionally selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) n R [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 3) a polyalkynyl chain as defined above, which has 1, 2, 3, 4, or 5 substituents as defined above and which is further interrupted by 1 to 5 atoms (e.g., 1, 2, 3, 4, or 5 atoms) as defined above; Or, 4) A polyalkynyl chain as defined above in which one or more of the methylene groups are replaced by a carbonyl group to give an oxo group. Or, 5) A polyalkynyl chain as defined above, in which one of the methylene groups is replaced by a carbonyl group to give an oxo group and which has 1, 2, 3, 4, or 5 substituents as defined above, or which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms), or which has 1, 2, 3, 4, or 5 substituents as defined above and which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms).

[0082]

[0082] As used herein, the term "polyunsaturated" refers to a chain in which at least one pair of atoms in the alkyl chain forms a double bond and one pair of atoms in the alkyl chain forms a triple bond. That is, a polyunsaturated chain is one in which R-C(R)=C(R)-R and [ka] In one embodiment, R refers to the remainder of the polyunsaturated chain and may be the same or different, and the total number of unsaturated bonds may vary from 2 to 8. Non-limiting examples of this type of polyunsaturated chain include: [ka] The "R" portion of the polyunsaturated moiety may be branched, linear, or cyclic.

[0083] As used herein, the term "substituted polyunsaturated" refers to: 1) alkyl; alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy A polyunsaturated chain as defined above having 1, 2, 3, 4 or 5 substituents (in some embodiments 1, 2 or 3 substituents) selected from the group consisting of: -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl, and -S(O)2-heteroaryl. Unless otherwise constrained by definition, all substituents are optionally selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) n R [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 2) Oxygen, Sulfur, and NR [In the formula, R is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl. All substituents are optionally selected from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)R. [In the formula, R is alkyl, aryl, or heteroaryl, and n is 0, 1, or 2; Or, 3) a polyunsaturated chain as defined above that has 1, 2, 3, 4, or 5 substituents as defined above and is further interrupted by 1 to 5 atoms (e.g., 1, 2, 3, 4, or 5 atoms) as defined above; Or, 4) Polyunsaturated chains as defined above in which one or more of the methylene groups are replaced by a carbonyl group to give an oxo group. Or, 5) A polyunsaturated chain as defined above, in which one of the methylene groups is replaced by a carbonyl group to give an oxo group and which has 1, 2, 3, 4, or 5 substituents as defined above, or which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms), or which has 1, 2, 3, 4, or 5 substituents as defined above and which is interrupted by 1 to 5 atoms as defined above (e.g., 1, 2, 3, 4, or 5 atoms).

[0084]

[0084] The term "ring" as used herein refers to any structure that is closed by a covalent bond. Rings include, for example, carbocycles (e.g., aryl and cycloalkyl), heterocycles (e.g., heteroaryl and non-aromatic heterocycles), aromatic (e.g., aryl and heteroaryl), and non-aromatic (e.g., cycloalkyl and non-aromatic heterocycles). A ring may be optionally substituted. A ring may form part of a ring system. As used herein, the term "ring system" refers to two or more rings, and in one embodiment, two or more rings are fused. As used herein, the term "fused" refers to a structure in which two or more rings share one or more bonds.

[0085]

[0085] As used herein, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0086]

[0086] As used herein, the term "glycoside" refers to a compound in which at least one sugar is linked to another functional group via a glycosidic bond. Typically, a glycoside chain may contain from 1 to 4 sugar units.

[0087]

[0087] As used herein, the term "glycosidic bond" refers to a bond formed between a hemiacetal or hemiketal group of a sugar and a chemical group of a compound. The chemical group can be -OH (O-glycoside), or -CR1R2R3 (C-glycoside).

[0088]

[0088] The terms "acylated O-glycoside" and "acylated C-glycoside" refer to compounds in which at least one hydroxyl of the glycosidic chain is esterified with an organic acid. Typical examples of organic acids may include acetic acid, substituted benzoic acids, cinnamic acids (caffeic acid, ferulic acid, p-coumaric acid), and / or phenylpropanoic acid (dihydrocaffeic acid).

[0089]

[0089] The terms "sulfated O-glycoside" and "sulfated C-glycoside" refer to compounds in which at least one hydroxyl of the glycoside chain is esterified with sulfuric acid.

[0090]

[0090] As used herein, the term "methylenedioxy" refers to a functional group having the structural formula RO-CH2-O-R' and which is linked to the remainder of the molecule by two chemical bonds.

[0091]

[0091] As used herein, the term "analog" refers to a compound that has a similar structure to a compound, but differs from the compound with respect to certain constituents. As used herein, the term "derivative" refers to any compound that can be imagined or actually synthesized to result from a parent compound by replacing one or more atoms with another atom or group of atoms.

[0092]

[0092] It is understood that, according to certain embodiments, the compound of the present invention or a composition thereof may be a nutraceutical composition, a pharmaceutical composition, a functional food, a functional nutritional product, a medical food, a medical nutritional product, or a dietary supplement.

[0093]

[0093] The term "nutraceutical" combines the words "nutrition" and "pharmaceutical." They are foods or food products that provide health and medical benefits, including the prevention and treatment of a condition, disorder, or disease. Dietary supplements are commonly sold in the form of medicines that are not normally associated with food, and are products isolated or purified from food. Dietary supplements have been demonstrated to have physiological benefits or provide protection against a condition, disorder, or disease. Such products can range from isolated nutrients, dietary supplements, and special diets to genetically modified foods, herbal products, and processed foods such as cereals, soups, and beverages.

[0094]

[0094] The term "nutraceutical" as used herein means useful in both the nutritional and pharmaceutical fields of use. Thus, the novel nutraceutical composition can be used as a nutritional supplement to food and beverages, as well as a pharmaceutical preparation for enteral or parenteral administration, which can be a solid preparation such as a capsule or tablet, or a liquid preparation such as a solution or suspension.

[0095]

[0095] The nutritional supplement compositions according to the present invention may further contain protective hydrocolloids (gums, proteins, modified starches, etc.), binders, film formers, encapsulants / encapsulants, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, taste masking agents, bulking agents, jellifying agents, gel forming agents, antioxidants and antimicrobial agents.

[0096]

[0096] Additionally, multivitamin and mineral supplements can be added to the nutritional supplement composition of the present invention to provide adequate amounts of essential nutrients that are lacking in some diets. Multivitamin and mineral supplements can also be useful in disease prevention and prevention of nutritional deficiencies and malnutrition due to lifestyle patterns.

[0097]

[0097] The nutritional compositions of the invention may be in any galenic form suitable for administration to the body, in particular in any form conventionally used for oral administration, for example in solid forms such as food or feed, food or feed premixes, fortified food or feed, tablets, pills, granules, dragees, capsules and effervescent preparations (such as powders and tablets), or in liquid forms such as solutions, emulsions or suspensions (for example as beverages, pastes and oily suspensions). Pastes may be incorporated into hard or soft shell capsules, where the capsules are characterized for example by a matrix of gelatin (fish, porcine, poultry, bovine), plant proteins or lignin sulfonates. Examples of other application forms are forms for transdermal, parenteral or injectable administration. The nutritional and pharmaceutical compositions may be in the form of controlled (delayed) release formulations.

[0098]

[0098] Beverages include non-alcoholic and alcoholic beverages, as well as liquid preparations added to drinking water and liquid foods. Non-alcoholic beverages are, for example, soft drinks, sports drinks, fruit juices, tea, and milk-based drinks. Liquid foods are, for example, soups and dairy products. The nutritional supplement composition containing the compounds of the present invention may be added to soft drinks, energy bars, or candies.

[0099]

[0099] When the nutritional composition is a pharmaceutical preparation and the composition further contains a pharma- ceutically acceptable excipient, diluent or adjuvant, standard techniques may be used for its formulation, for example as disclosed in Remington's Pharmaceutical Sciences, 20th edition Williams & Wilkins, PA, USA. For oral administration, it is preferred to use tablets and capsules, which contain a suitable binder (e.g., gelatin or polyvinylpyrrolidone), a suitable filler (e.g., lactose or starch), a suitable lubricant (e.g., magnesium stearate), and optionally further additives.

[0100]

[0100] As used herein, the terms "functional food", "functional nutritional product", "medical food" or "medical nutritional product" refer to any health food that claims to have health-promoting or disease-preventing properties beyond the basic function of providing nutrients. The general category of functional foods includes processed foods or foods that have been enriched with health-promoting additives, such as "vitamin-fortified" products.

[0101]

[0101] The terms "food," "food product," and "food composition" or "diet food" refer to a product or composition intended for ingestion by an individual, such as a human, and providing at least one nutrient to such an individual. The compositions of the present disclosure, including the many embodiments described herein, may comprise, consist of, or essentially comprise the elements disclosed herein, as well as any additional or optional ingredients, components, or elements described or not described herein that are useful in the diet.

[0102] Dietary supplements, also known as food supplements or nutraceuticals, are preparations intended to supplement the diet and provide nutrients such as vitamins, minerals, fiber, fatty acids, or amino acids that may be deficient or not consumed in sufficient amounts in an individual's diet. Some countries define dietary supplements as foods, while others define them as drugs or natural health products. Dietary supplements containing vitamins or nutrients minerals are included as a category of food in the Codex Alimentarius, a collection of internationally recognized standards, codes of practice, guidelines, and other recommendations on food, food production, and food safety. Codex Alimentarius standards are developed by the Codex Alimentarius Commission, an organization sponsored by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO).

[0103]

[0103] Animal compositions include food compositions, animal treats (e.g., biscuits), and / or dietary supplements to provide the necessary dietary requirements for an animal. The compositions may be dry compositions (e.g., kibble), semi-moist compositions, wet compositions, or any mixture thereof. In one embodiment, the composition is a dietary supplement such as a gravy, drinking water, beverage, yogurt, powder, granule, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or other suitable delivery form. The dietary supplement may contain high concentrations of UFAs and NORCs, as well as B vitamins and antioxidants. This allows such dietary supplements to be administered to animals in small amounts or can be diluted before administration to the animal. The dietary supplement may need to be or can be mixed with water or other diluents before administration to the animal.

[0104]

[0104] A "pet food" or "pet treat composition" comprises about 15% to about 50% crude protein. The crude protein material may comprise vegetable proteins such as soybean meal, soy protein concentrate, corn gluten meal, wheat gluten, cottonseed, and peanut meal, or animal proteins such as casein, albumin, and meat proteins. Examples of meat proteins useful herein include pork, lamb, horse, poultry, fish, and mixtures thereof. The composition may further comprise about 5% to about 40% fat. The composition may further comprise a carbohydrate source. The composition may comprise about 15% to about 60% carbohydrate. Examples of such carbohydrates include grains or cereals such as rice, corn, milo, sorghum, alfalfa, barley, soybean, canola, oats, wheat, and mixtures thereof. The composition may also optionally comprise other ingredients such as dried whey and other dairy by-products.

[0105]

[0105] As used herein, the term "diabetes" includes insulin-dependent diabetes mellitus (i.e., IDDM, also known as type 1 diabetes), non-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as type 2 diabetes), and borderline diabetes. Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type 2 diabetes often occurs with normal or even high insulin levels and is thought to be the result of a loss of appropriate response to insulin in tissues. This condition is called "insulin resistance." Most type 2 diabetes patients are also overweight or obese. One of the criteria for diagnosing diabetes is fasting plasma glucose concentration. A diabetic subject has a fasting plasma glucose concentration of 126 mg / dL or greater. A borderline diabetic subject is one who is suffering from borderline diabetes. A subject with pre-diabetes is one who has impaired fasting glycemia (fasting plasma glucose concentration ≥ 100 mg / dL and < 126 mg / dL); or impaired glucose tolerance (2-hour plasma glucose concentration ≥ 140 mg / dL and < 200 mg / dL); or insulin resistance, and is therefore at increased risk of developing diabetes. Prevention of type 2 diabetes includes treatment of pre-diabetes.

[0106]

[0106] As used herein, the term "dyslipidemia" encompasses abnormalities of any lipid fraction and specific lipoprotein abnormalities. For example, dyslipidemia refers to elevated plasma cholesterol and / or elevated triglycerides and / or elevated free fatty acids and / or low high density lipoprotein (HDL) and / or high low density lipoprotein (LDL) and / or high very low density lipoprotein (VLDL) levels. Dyslipidemia may contribute to the development of symptomatic vascular disease, including, for example, atherosclerosis and ultimately coronary heart disease. Dyslipidemia may or may not be associated with diabetes.

[0107]

[0107] As used herein, the term "metabolic disorder" encompasses any abnormal chemical and enzymatic reactions due to environmental and genetic factors (environmental factors include physical activity, nutrition) that disrupt normal metabolism and result in excess or deficiency of a particular substance and dysfunction of energy homeostasis. Non-limiting examples of metabolic disorders include diabetes, dyslipidemia, hypertension, overweight, obesity, and any combination thereof.

[0108]

[0108] As used herein, the term "AMPK-related disease" includes pathological or genomic pathological conditions in which activation of AMPK has a beneficial effect on health. Examples of such diseases or conditions include obesity, diabetes, metabolic syndrome, acute inflammatory lung injury, heart disease, reperfusion ischemia, cancer, aging, retinal degeneration, cardiac hypertrophy, nonalcoholic fatty liver disease, hypertension, albuminuria, sporadic Alzheimer's disease, muscular dystrophy, and osteoarthritis. In addition, the term "AMPK-related condition" includes conditions associated with primary "AMPK-related disease" and improved by activation of AMPK. For example, diabetic nephropathy (Salotto et al. (2017) J. Pharma and Expt Thera. 361:303-311) or diabetic neuropathy are "AMPK-related conditions" that may be associated with the "AMPK-related disease" of diabetes.

[0109]

[0109] As used herein, the term "prevention" or "preventing" refers to the reduction of the risk and / or severity of a condition, disorder, or disease.

[0110]

[0110] As used herein, the terms "treatment," "treating," "treat," "alleviate," and "alleviate" include both preventative or prophylactic treatments (treatments that prevent and / or delay the onset of a targeted pathological condition or disorder) and curative, therapeutic, or disease-modifying treatments, including, for example, therapeutic measures for curing, delaying, alleviating symptoms, and / or halting the progression of a diagnosed pathological condition or disorder, as well as treatment of patients at risk of having a disease or suspected of having a disease, and patients who are unwell or diagnosed as suffering from a disease or medical condition. The terms do not necessarily imply that a subject is treated to the point of complete cure. These terms also refer to the maintenance and / or promotion of health in a subject who is not suffering from a disease but is susceptible to an ill-health condition. These terms are also intended to include the synergism or potentiation of one or more primary preventative or therapeutic measures. The terms "treatment," "treat," "alleviate," and "alleviate" are further intended to include treatment of a disease or condition or for the prophylaxis or prevention of a disease or condition. Treatment may be patient-related or physician-related.

[0111]

[0111] Obesity, an excess of body fat relative to lean body mass, is a very common chronic disease in modern society. Obesity is not only socially stigmatized, but is also associated with a shortened life span and a number of medical problems, including adverse mental development, coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia, and some cancers (see, e.g., Nishina, et al., Metab. 43:554-558, 1994; Grundy and Barnett, Dis. Mon. 36:641-731, 1990; Rissanen, et al., British Medical Journal, 301:835-837, 1990).

[0112]

[0112] As used herein, the term "obesity-related disease" refers to a disease or condition in which excess body weight or a high "body mass index (BMI)" contributes to the progression or suppression of the disease or condition. Representative examples of obesity-related diseases include, but are not limited to, diabetes, diabetic complications, insulin sensitivity, polycystic ovarian disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, weight gain, inflammatory diseases, gastrointestinal diseases, angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, and vascular dementia. See Harrison's Principles of Internal Medicine, 13th Ed., McGraw Hill Companies Inc., New York (1994). Non-limiting examples of inflammatory conditions include diseases of the digestive tract (ulcerative colitis, Crohn's disease, pancreatitis, gastritis, benign digestive tumors, digestive polyps, hereditary polyposis syndromes, colon cancer, rectal cancer, gastric cancer, and digestive ulcer disease), angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, cerebrovascular dementia, immune diseases, and cancer in general.

[0113]

[0113] As used herein, the terms "subject", "individual" or "patient" refer to any animal, including a human, that can benefit from one or more of the compounds, compositions or methods disclosed herein. Generally, a subject is a human or an animal that is a bird, cow, dog, horse, cat, goat, wolf, murine, ovine or porcine. As used herein, the term "companion animal" refers to any animal that is kept in captivity, including, but not limited to, cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, horses, cows, goats, sheep, donkeys, pigs, and the like. Preferably, the subject is a human or a companion animal, such as a dog or cat. The term "elderly" in the human context means an age of at least 60 years, preferably greater than 63 years, more preferably greater than 65 years, and most preferably greater than 70 years. The term "elderly" in the human context means an age of at least 45 years, preferably greater than 50 years, more preferably greater than 55 years, including geriatric subjects. In the case of other animals, "elderly individuals" refer to animals that have exceeded 50% of the average lifespan of their respective species and / or lineages within a species. An animal is considered "elderly" if it has exceeded 66% of the average expected lifespan, preferably greater than 75% of the average expected lifespan, and more preferably greater than 80% of the average expected lifespan. An elderly cat or dog is at least about 7 years old.

[0114]

[0114] In one embodiment, the term "subject" as used herein refers to a mammal. Mammals include, but are not limited to, rodents, aquatic mammals, domestic animals (such as dogs and cats), livestock (such as sheep, pigs, cows and horses), and humans. In one embodiment, the mammal may be a cat, a dog, or a human. The human may be a female, such as a female attempting to become pregnant or who is pregnant. In one embodiment of the present invention, the subject is a mammal selected from the group consisting of a cat, a dog, and a human. For example, the subject may be an elderly human.

[0115]

[0115] As used herein, the term "empagliflozin" refers to an antidiabetic drug (sold under the trade name Jardiance, among others) used to improve glucose control in people with type 2 diabetes, to reduce the risk of cardiovascular death in adults with type 2 diabetes and a history of cardiovascular disease, to reduce the risk of death and hospitalization in people with heart failure and low ejection fraction, and to reduce the risk of cardiovascular death and hospitalization due to heart failure in adults. Empagliflozin can be prescribed instead of metformin and has advantages over sulfonylureas. Empagliflozin may be used with other medications such as metformin or insulin. Empagliflozin may not be recommended for type 1 diabetes. Empagliflozin is an inhibitor of sodium-glucose cotransporter 2 (SGLT2) and acts by increasing the amount of sugar excreted in the urine. The IUPAC name of empagliflozin is (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol.

[0116]

[0116] As used herein, the term "canagliflozin" refers to a drug used to treat type 2 diabetes (sold, among others, under the trade name Invokana). In type 2 diabetes, canagliflozin is a third-line drug, tried after metformin is the first-line drug. Canagliflozin is used in conjunction with exercise and diet. Canagliflozin is not recommended in type 1 diabetes. Canagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Canagliflozin works by increasing the amount of glucose excreted in the urine. The IUPAC name for canagliflozin is (2S,3R,4R,5S,6R)-2-{3-[5-[4-fluoro-phenyl]-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

[0117]

[0117] As used herein, the term "dapagliflozin" or "Dapa" refers to a drug used to treat type 2 diabetes (sold under the trade names Farxiga (US) and Forxiga (EU), among others). Dapagliflozin is also used to treat adults with certain types of heart failure and chronic kidney disease. Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which works by removing sugar from the body through urine. The IUPAC name for dapagliflozin is (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

[0118]

[0118] As used herein, the term "ertugliflozin" refers to a drug (sold under the trade name Steglatro) for the treatment of type 2 diabetes. Ertugliflozin is a sodium / glucose cotransporter 2 (SGLT2) inhibitor and belongs to the class of drugs known as gliflozins. The IUPAC name for ertugliflozin is (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol.

[0119]

[0119] The term "phlorizin" as used herein refers to a dihydrochalcone and glucoside of phloretin. A white solid, samples often appear yellow due to impurities, have a sweet taste, and contain four molecules of water in the crystals. Above 200°C, it decomposes to form rufin. Phlorizin is poorly soluble in ether and cold water, but soluble in ethanol and hot water. Phlorizin hydrolyzes to phloretin and glucose on prolonged exposure to aqueous solutions. The IUPAC name for phlorizin is 1-(2,4-dihydroxy-6-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}phenyl)-3-(4-hydroxyphenyl)propan-1-one. It is also called isosalipurposide.

[0120]

[0120] Embodiment

[0121] composition

[0122] One aspect of the present disclosure is a composition comprising a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, CBNA, or a derivative or analog thereof) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor to synergistically activate AMPK and improve metabolic health (e.g., treating or preventing a metabolic disorder or an obesity-related disease).

[0123] Applicants have surprisingly found that administering to a subject in need a composition comprising a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, CBNA, or a derivative or analog thereof) and a sodium-glucose cotransporter-2 (SGLT2) inhibitor results in improved performance of activated AMPK compared to administering either the AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, CBNA, or a derivative or analog thereof) or the sodium-glucose cotransporter-2 (SGLT2) inhibitor alone, thereby synergistically activating AMPK to improve metabolic health. For example, Applicant has surprisingly found that administering to a subject a composition comprising a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, CBNA, or a derivative or analog thereof) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor can result in an overall improvement in glucose clearance of at least 1% in the subject, as compared to administering either the AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, CBNA, or a derivative or analog thereof) or the sodium-glucose cotransporter 2 (SGLT2) inhibitor alone. Further, Applicant has surprisingly found that administering to a subject a composition comprising a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor can result in an overall improvement in glucose clearance of at least 1% in the subject, as compared to the combined effect on glucose clearance of the AMP-activated protein kinase (AMPK) activator (e.g., CBDA, CBGA, CBNA, or a derivative or analog thereof) and the sodium-glucose cotransporter 2 (SGLT2) inhibitor.

[0121]

[0124] In one aspect, the present disclosure relates to a composition for use in activating AMPK in a subject, comprising a first compound and a second compound.The subject is a mammal, such as a cat, a dog, or a human.In one embodiment, the subject is a female human or a male human.In a preferred embodiment, the subject is an elderly female human or an elderly male human.

[0122]

[0125] In one embodiment, the first compound is an AMP-activated protein kinase (AMPK) activator or a derivative thereof. In one embodiment, the second compound is a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a derivative thereof.

[0123]

[0126] In one embodiment, the first compound is a direct AMP-activated protein kinase (AMPK) activator or a derivative thereof. In one embodiment, the second compound is a sodium-glucose cotransporter 2 (SGLT2) inhibitor selected from the group consisting of dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, remogliflozin, sergliflozin, phlorizin, and derivatives thereof.

[0124]

[0127] In one embodiment, the first compound is a substituted resorcylic acid as a direct AMP-activated protein kinase (AMPK) activator or a derivative thereof. In one embodiment, the second compound is a sodium-glucose cotransporter 2 (SGLT2) inhibitor selected from the group consisting of dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, remogliflozin, sergliflozin, phlorizin, and derivatives thereof.

[0125]

[0128] In one embodiment, a composition for use in activating AMPK comprises a first compound and a second compound, the first compound having the general formula I: [ka] [wherein R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate; R2 is OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary, or tertiary alcohol; ketone; aldehyde; ester; primary, secondary, or tertiary amine; primary or secondary amide; cyano; nitro; sulfonate; sulfate; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R4 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen atom which is Cl, I, or F; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; cyano; nitro; a sulfonate; a sulfate; an optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R5 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary or tertiary alcohol; ketone; aldehyde; ester; secondary or tertiary amine; primary or secondary amide; cyano; nitro; sulfonate; sulfate; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 polyalkynyl; optionally, the OCH groups can cyclize with adjacent OH groups to form methylenedioxy bridges; or a derivative or analog thereof, The composition, wherein the second compound is a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

[0126]

[0129] In one embodiment, the sodium-glucose cotransporter 2 (SGLT2) inhibitor is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin.

[0127]

[0130] In one embodiment, the sodium-glucose cotransporter 2 (SGLT2) inhibitor is selected from the group consisting of empagliflozin, canagliflozin, phlorizin, and dapagliflozin.

[0128]

[0131] In one embodiment, the sodium-glucose cotransporter 2 (SGLT2) inhibitor comprises dapagliflozin.

[0129]

[0132] In one embodiment, the sodium-glucose cotransporter 2 (SGLT2) inhibitor is dapagliflozin.

[0130]

[0133] In one embodiment, the sodium-glucose cotransporter 2 (SGLT2) inhibitor is phlorizin.

[0131]

[0134] In one embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; or sulfated O-glycoside; R2 is OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary or tertiary alcohol; ketone; aldehyde; ester; primary, secondary or tertiary amine; primary or secondary amide; cyano; nitro; or sulfonate; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 10 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R4 is H; OH; OCH; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen atom that is Cl, I, or F; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; or a sulfonate; an optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R5 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary or tertiary alcohol; ketone; aldehyde; ester; secondary or tertiary amine; primary or secondary amide; cyano; nitro; or sulfonate; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 polyalkynyl; optionally, the OCH3 groups can be cyclized with adjacent OH groups to form methylenedioxy bridges; or a derivative or analog thereof.

[0132]

[0135] In one embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; or acylated O-glycoside; R2 is OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary or tertiary alcohol; ketone; aldehyde; ester; primary, secondary or tertiary amine; primary or secondary amide; cyano; or nitro; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C 10 ~C 20 alkenyl; optionally substituted and / or optionally branched C 10 ~C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R4 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen atom that is Cl, I, or F; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; or a nitro; an optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R5 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary or tertiary alcohol; ketone; aldehyde; ester; secondary or tertiary amine; primary or secondary amide; cyano; or nitro; optionally branched C1-C 20 Alkyl; optionally branched C2-C 20 Alkenyl; optionally branched C4-C 20 Polyalkenyl; optionally branched C2-C 20 Alkynyl or optionally branched C4-C 20 polyalkynyl; optionally, the OCH3 groups can be cyclized with adjacent OH groups to form methylenedioxy bridges; or a derivative or analog thereof.

[0133]

[0136] In another embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; or acylated O-glycoside; R2 is OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary alcohol, secondary alcohol, or tertiary alcohol; ketone; aldehyde; or ester; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R4 is H; OH; OCH; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen atom, Cl, I, or F; a primary alcohol, a secondary alcohol, or a tertiary alcohol; a ketone; an aldehyde; or an ester; an optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 is polyalkynyl; R5 is H; OH; OCH; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary alcohol, secondary alcohol, or tertiary alcohol; ketone; aldehyde; or ester; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 Alkenyl; optionally substituted and / or optionally branched C4-C 20 Polyalkenyl; optionally substituted and / or optionally branched C-C 20 Alkynyl or optionally substituted and / or optionally branched C4-C 20 polyalkynyl; optionally, the OCH3 groups can be cyclized with adjacent OH groups to form methylenedioxy bridges; or a derivative or analog thereof.

[0134]

[0137] In another embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate; R2 is CH3, OH; O-glycoside; C-glycoside; sulfated O-glycoside; sulfated C-glycoside; chlorine; CHO (aldehyde); sulfate; optionally substituted and / or optionally branched C2-C 15 alkenyl; or optionally substituted and / or optionally branched C4-C 15 is a polyalkenyl; R4 is H; CH3, OH; OCH3; chlorine, or a 3,3-dimethylallyl chain (1h); R5 is H; optionally substituted and / or optionally branched C1-C 20 Alkyl; optionally substituted and / or optionally branched C-C 20 alkenyl; or optionally substituted and / or optionally branched C4-C 20 polyalkenyl; optionally, the OCH3 groups can cyclize with adjacent OH groups to form methylenedioxy bridges]; or derivatives or analogs thereof.

[0135]

[0138] In one embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate; R2 is OH; OCH3; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogen; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; primary, secondary, or tertiary amines; primary or secondary amides; cyano; nitro; sulfonates; sulfates; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy- C5 isoprenoid chains selected from the group consisting of si-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p);3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-Hydroxy-3,7-dimethyloctyl (2b), 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-Dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-Methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-Hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-Dimethyl-2,6-octyl C selected from the group consisting of dien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); 10 Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methyl-1-propen-1-yl)-3-furanyl]-2-hexen-1-yl (3d). 15 Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) 20 Isoprenoid chain; methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (12a), 1-hydroxy-2-oxopropyl (12b), 1-hydroxy-2-oxopropyl (13a), 1-hydroxy-2-oxopropyl (13b), 1-hydroxy-2-oxopropyl (14a), 1-hydroxy-2-oxopropyl (14b), 1-hydroxy-2-oxopropyl (15a), 1-hydroxy-2-oxopropyl (15b), 1-hydroxy-2-oxopropyl (16a), 1-hydroxy-2-oxopropyl (16b), 1-hydroxy-2-oxopropyl (17a), 1-hydroxy-2-oxopropyl (17b), 1-hydroxy-2-oxopropyl (17c), 1-hydroxy-2-oxopropyl (17d), 1-hydroxy-2-oxopropyl (17e), 1-hydroxy-2-oxopropyl (17f ...f), 1-hydroxy-2-oxopropyl (17f), 1-hydroxy-2 (Substituted) alkyl chains selected from the group consisting of so-2-phenylethyl (11b); (Substituted) alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen atom Cl, I, or F; primary, secondary, or tertiary alcohol; ketone; aldehyde; ester; primary, secondary, or tertiary amine; primary or secondary amide; cyano; nitro; sulfonate; sulfate; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2 , 3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p);3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-Hydroxy-3,7-dimethyloctyl (2b), 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-Dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-Methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-Hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-Dimethyl-2,6-octyl C selected from the group consisting of dien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); 10 Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). 15 Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) 20 Isoprenoid chain; methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl acetyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a) , 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2- oxo-2-phenylethyl (11b); substituted alkyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R5 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary, or tertiary alcohol; ketone; aldehyde; ester; secondary or tertiary amine; primary or secondary amide; cyano; nitro; sulfonate; sulfate; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3 -methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p);3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-Hydroxy-3,7-dimethyloctyl (2b), 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-Dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-Methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-Hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-Dimethyl-2,6-octyl C selected from the group consisting of dien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); 10 Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). 15 Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) 20 Isoprenoid chain; methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (12a), 1-hydroxy-2-oxopropyl (12b), 1-hydroxy-2-oxopropyl (13a), 1-hydroxy-2-oxopropyl (13b), 1-hydroxy-2-oxopropyl (14a), 1-hydroxy-2-oxopropyl (14b), 1-hydroxy-2-oxopropyl (15a), 1-hydroxy-2-oxopropyl (15b), 1-hydroxy-2-oxopropyl (16a), 1-hydroxy-2-oxopropyl (16b), 1-hydroxy-2-oxopropyl (17a), 1-hydroxy-2-oxopropyl (17b), 1-hydroxy-2-oxopropyl (17c), 1-hydroxy-2-oxopropyl (17d), 1-hydroxy-2-oxopropyl (17e), 1-hydroxy-2-oxopropyl (17f ...f), 1-hydroxy-2-oxopropyl (17f), 1-hydroxy-2 (Substituted) alkyl chains selected from the group consisting of so-2-phenylethyl (11b); (Substituted) alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); optionally, the OCH3 groups can cyclize with adjacent OH groups to form methylenedioxy bridges; or a derivative or analog thereof;

[0136]

[0139] In another embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate; R2 is OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary, or tertiary alcohol; ketone; aldehyde; ester; sulfate; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p);3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-Hydroxy-3,7-dimethyloctyl (2b), 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-Dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-Methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-Hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-Dimethyl-2,6-octyl C selected from the group consisting of dien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); 10 Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). 15 Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) 20 Isoprenoid chain; methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl acetyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a ), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2 -oxo-2-phenylethyl (11b); substituted alkyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a (substituted) polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen atom Cl, I, or F; primary alcohol, secondary alcohol, or tertiary alcohol; ketone; aldehyde; ester; sulfate; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl -2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p);3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-Hydroxy-3,7-dimethyloctyl (2b), 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-Dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-Methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-Hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-Dimethyl-2,6-octyl C selected from the group consisting of dien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); 10 Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). 15 Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) 20 Isoprenoid chain; methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (12a), 1-hydroxy-2-oxopropyl (12b), 1-hydroxy-2-oxopropyl (13a), 1-hydroxy-2-oxopropyl (13b), 1-hydroxy-2-oxopropyl (14a), 1-hydroxy-2-oxopropyl (14b), 1-hydroxy-2-oxopropyl (15a), 1-hydroxy-2-oxopropyl (15b), 1-hydroxy-2-oxopropyl (16a), 1-hydroxy-2-oxopropyl (16b), 1-hydroxy-2-oxopropyl (17a), 1-hydroxy-2-oxopropyl (17b), 1-hydroxy-2-oxopropyl (17c), 1-hydroxy-2-oxopropyl (17d), 1-hydroxy-2-oxopropyl (17e), 1-hydroxy-2-oxopropyl (17f ...f), 1-hydroxy-2-oxopropyl (17f), 1-hydroxy-2 (Substituted) alkyl chains selected from the group consisting of so-2-phenylethyl (11b); (Substituted) alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a (substituted) polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R5 is H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary, or tertiary alcohol; ketone; aldehyde; ester; sulfate; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyric acid (1g), 4-hydroxy-3-methylbutyl (1h), 4-hydroxy-3-methylbutyl (1i), 4-hydroxy-3-methylbutyl (1j ... C5 isoprenoid chains selected from the group consisting of 1g, 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p);3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-Hydroxy-3,7-dimethyloctyl (2b), 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-Dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-Methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-Hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-Dimethyl-2,6-octyl C selected from the group consisting of dien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); 10 Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). 15 Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) 20 Isoprenoid chain; methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl acetyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a) , 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2- (Substituted) alkyl chains selected from the group consisting of oxo-2-phenylethyl (11b); substituted alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); optionally, the OCH3 groups can cyclize with adjacent OH groups to form methylenedioxy bridges; or a derivative or analog thereof;

[0137]

[0140] In another embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate; R2 is CH3, OH; O-glycosides; C-glycosides; sulfated O-glycosides; sulfated C-glycosides; chlorine; CHO (aldehyde); sulfate; 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl C5 isoprenoid chain selected from the group consisting of 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl)-1,3-butadienyl] (2e), [3-methyl-3-(4-methyl)-1,3-butadienyl] (2f), [3-methyl-3-(4-methyl)-1,3-butadienyl] (2g), [3-methyl-3-(4-methyl)-1,3-butadienyl] (2h), [3-methyl-3-(4-methyl)-1,3-butadienyl] (2i), [3-methyl-3-(4-methyl)-1,3-butadienyl] (2j), [3-methyl-3-(4-methyl)-1,3-butadienyl] (2k ... -3-penten-1-yl)-2-oxiranyl]methyl(geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl(geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl(neryl) (2i), 5-methyl-2-(1-methylethenyl)-2-pyrrolidone (geranyl 2,3-epoxide) (2f), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (geranyl 2,3-epoxide) (2g), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (geranyl 2,3-epoxide) (2h), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (geranyl 2,3-epoxide) (2i ... C10 isoprenoid chains selected from the group consisting of 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o);C selected from the group consisting of (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methyl-1-propen-1-yl)-3-furanyl]-2-hexen-1-yl (3d); 15 an isoprenoid chain; or a (substituted) polyalkenyl chain selected from the group consisting of 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is H; CH3, OH; OCH3; chlorine, or a 3,3-dimethylallyl chain (1h); R5 is H; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl(3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1 -dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p);3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-Hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5 -Methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), C10 isoprenoid chain selected from the group consisting of hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); C selected from the group consisting of trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d); 15 Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) 20 Isoprenoid chain; methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (12a), 1-hydroxy-2-oxopropyl (12b), 1-hydroxy-2-oxopropyl (13a), 1-hydroxy-2-oxopropyl (13b), 1-hydroxy-2-oxopropyl (14a), 1-hydroxy-2-oxopropyl (14b), 1-hydroxy-2-oxopropyl (15a), 1-hydroxy-2-oxopropyl (15b), 1-hydroxy-2-oxopropyl (16a), 1-hydroxy-2-oxopropyl (16b), 1-hydroxy-2-oxopropyl (17a), 1-hydroxy-2-oxopropyl (17b), 1-hydroxy-2-oxopropyl (17c), 1-hydroxy-2-oxopropyl (17d), 1-hydroxy-2-oxopropyl (17e), 1-hydroxy-2-oxopropyl (17f ...f), 1-hydroxy-2-oxopropyl (17f), 1-hydroxy-2 a (substituted) alkyl chain selected from the group consisting of iso-2-phenylethyl (11b); a (substituted) alkenyl chain which is one of the following representative examples: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a (substituted) polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); optionally, the OCH3 group can cyclize with the adjacent OH group to form a methylenedioxy bridge]; or a derivative or analogue thereof;

[0138]

[0141] In one embodiment, the first compound has the general formula I: [ka] [In the formula, R2 is hydrogen and R4 is not hydrogen]; or a derivative or analog thereof.

[0139]

[0142] In one embodiment, the first compound has the general formula I: [ka] [In the formula, R2 is hydrogen and R5 is not hydrogen]; or a derivative or analog thereof.

[0140]

[0143] In one embodiment, the first compound has the general formula I: [ka] [In the formula, R1 and R3 are each independently OH; OCH3; O-glycoside; or sulfate; R2 is H; 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h); or (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h); R4 is H; R5 is pentyl; benzyl (6a); 2-phenethyl (6b); or phenylethenyl (14a)], or a derivative or analogue thereof.

[0141]

[0144] In one embodiment, the first compound has the general formula I: [ka] [In the formula, R1 is OH; O-glycoside; or sulfate; R2 is H; [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl(geranyl 2,3-epoxide) (2e); 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g); (2E)-3,7-dimethyl-2,6-octadien-1-yl(geranyl) (2h); (2Z)-3,7-dimethyl-2,6-octadien-1-yl(neryl) (2i); or 5-methyl-2-(1-methylethyl)cyclohexyl (2o); R3 is OH; OCH3; O-glycoside; or sulfate; R4 is H; R5 is CH3; n-propyl, n-butyl, or pentyl; or a derivative or analog thereof.

[0142]

[0145] In one embodiment, the first compound of general formula I is cannabidiolic acid (CAS number 1244-48-2) or a derivative or analogue thereof.

[0143]

[0146] In one embodiment, the first compound is CBDA, CBGA, CBNA, or a derivative or analog thereof.

[0144]

[0147] In one embodiment, the first compound is CBGA, CBNA, or a derivative or analog thereof.

[0145]

[0148] In one embodiment, the first compound is CBGA or a derivative or analog thereof.

[0146]

[0149] In one embodiment, the first compound is CBNA or a derivative or analog thereof.

[0147]

[0150] In one embodiment, a composition for use in activating AMPK comprises a first compound, which is cannabidiolic acid (CAS number 1244-58-2) or a derivative or analogue thereof, as an AMP-activated protein kinase (AMPK) activator, and a second compound, which is a sodium-glucose co-transporter 2 (SGLT2) inhibitor or a derivative or analogue thereof.

[0148]

[0151] In one embodiment, a composition for use in activating AMPK comprises a first compound as an AMP-activated protein kinase (AMPK) activator, which is cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analogue thereof, and a second compound as a sodium-glucose cotransporter 2 (SGLT2) inhibitor selected from the group consisting of dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, remogliflozin, sergliflozin, phlorizin and derivatives thereof.

[0149]

[0152] In one embodiment, a composition for use in activating AMPK comprises a first compound as an AMP-activated protein kinase (AMPK) activator, which is cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analogue thereof, and a second compound as a sodium-glucose cotransporter 2 (SGLT2) inhibitor selected from the group consisting of dapagliflozin, canagliflozin, phlorizin and empagliflozin and derivatives thereof.

[0150]

[0153] In one embodiment, a composition for use in activating AMPK comprises a first compound as an AMP-activated protein kinase (AMPK) activator, which is cannabidiolic acid (CAS number 1244-558-2), CBGA, CBNA, or a derivative or analogue thereof, and a second compound as a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which is at least one of dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, remogliflozin, sergliflozin, phlorizin, and derivatives thereof.

[0151]

[0154] In one embodiment, a composition for use in activating AMPK comprises a first compound, cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analogue thereof, as an AMP-activated protein kinase (AMPK) activator, and a second compound, comprising dapagliflozin or a derivative thereof, as a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

[0152]

[0155] In a preferred embodiment, a composition for use in activating AMPK comprises a first compound as an AMP-activated protein kinase (AMPK) activator, which is cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analogue thereof, and a second compound as a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which is dapagliflozin, or a derivative or analogue thereof.

[0153]

[0156] The first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and the second compound (e.g., an SGLT2 inhibitor such as dapagliflozin, phlorizin, or a derivative or analog thereof) of the composition for use in activating AMPK can be administered in any pharma- ceutical effective amount according to the present invention. Typically, the pharma-ceutical effective amount will depend on the type, age, size, health, lifestyle, and / or genetic traits of the subject. The pharma-ceutical effective amount may be divided into several small amounts and administered throughout the day, so that the total daily intake is an effective amount. A person skilled in the art will be able to suggest the appropriate amount of the first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and the second compound (e.g., an SGLT2 inhibitor such as dapagliflozin, or a derivative or analog thereof) to be taken per day.

[0154]

[0157] In one embodiment, the compositions of the present invention may have an acute effect observed in less than one month. Additionally or alternatively, the compositions may have a long-term effect, and thus various embodiments are administered to an individual for a period of at least one month; preferably at least two months, more preferably at least three, four, five or six months, and most preferably at least one year. During this period, the compositions may be administered to an individual at least one day per week, preferably at least two days per week, more preferably at least three, four, five or six days per week, and most preferably seven days per week. The compositions may be administered in a single dose once per day, or in multiple divided doses per day. In one embodiment, the single dose is about 100 mg or more. In one embodiment, the single dose is about 1000 mg or less. In one embodiment, the single dose is about 100 mg to about 1000 mg.

[0155]

[0158] In one embodiment, the first compound of the present invention (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) is administered at a daily dose of about 1 mg to about 10,000 mg, about 5 mg to about 5,000 mg, about 10 mg to about 2,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 2,000 mg, about 50 mg to about 1,500 mg, about 100 mg, or about 2,000 mg per day. The composition may be provided in an amount of about 1 to about 1000 mg per daily dose, about 150 mg to about 900 mg per daily dose, about 200 mg to about 800 mg per daily dose, about 250 mg to about 750 mg per daily dose, about 300 mg to about 700 mg per daily dose, about 350 mg to about 650 mg per daily dose, about 400 mg to about 600 mg per daily dose, about 450 mg to about 550 mg per daily dose, preferably about 500 mg per daily dose.

[0156]

[0159] In one embodiment, the second compound of the invention (e.g., an SGLT2 inhibitor such as dapagliflozin, phlorizin, or a derivative or analog thereof) is provided in an amount of about 1 mg to about 2000 mg per daily dose, about 50 mg to about 1500 mg per daily dose, or about 100 mg to about 1000 mg per daily dose.

[0157]

[0160] In one embodiment, the second compound of the present invention (e.g., an SGLT2 inhibitor such as dapagliflozin or a derivative or analog thereof) is administered in a daily dose of about 1.1 mg to about 40 mg, about 1.4 mg to about 38.8 mg, about 1.7 mg to about 37.6 mg, about 2.0 mg to about 36.4 mg, about 2.3 mg to about 35.2 mg, or about 2.5 mg to about 36.4 mg. about 2.6 mg to about 34 mg, about 2.9 mg to about 32.8 mg per daily dose, about 3.2 mg to about 31.6 mg per daily dose, about 3.5 mg to about 30.4 mg per daily dose, about 3.8 mg to about 29.2 mg per daily dose, about 4.1 mg to about 28 mg per daily dose, about 4.4 mg to about 26.8 mg per daily dose, about 4.7 mg to about 25.6 mg per daily dose, about 5.0 mg to about 6.5 mg per daily dose, about 6.5 mg to about 7.5 mg per daily dose, about 7.5 mg to about 8.5 mg per daily dose, about 8.5 mg to about 9.5 mg per daily dose, about 9.5 mg to about 10.5 mg per daily dose, about 10.5 mg to about 11.5 mg per daily dose, about 11.5 mg to about 12.5 mg per daily dose, about 12.5 mg to about 13.5 mg per daily dose, about 13.5 mg to about 14.5 mg per daily dose, about 14.5 mg to about 15.5 mg per daily dose, about 15.5 mg to about 16.5 mg per daily dose, about 16.5 mg to about 17.5 mg per daily dose, about 17.5 mg to about 18.5 mg per daily dose, about 18.5 mg to about 19.5 mg per daily dose, about 18.5 mg to about 20.5 mg per daily dose, about 18.5 mg to about 21.5 mg per daily dose, about 18.5 mg to about 22.5 mg per daily dose, about 18.5 mg to about 23.5 mg per daily dose, about 18.5 mg to about 24.5 mg per daily dose, about 18.5 mg to about 25.5 mg per daily dose, about 1 about 24.4 mg, about 5.3 mg to about 23.2 mg per daily dose, about 5.8 mg to about 22 mg per daily dose, about 6.1 mg to about 20.8 mg per daily dose, about 6.4 mg to about 19.6 mg per daily dose, about 6.7 mg to about 18.4 mg per daily dose, about 7.0 mg to about 17.2 mg per daily dose, about 7.3 mg to about 16 mg per daily dose, about 7.6 mg to about 14.8 mg per daily dose g, about 7.9 mg to about 13.6 mg per daily dose, about 8.2 mg to about 12.4 mg per daily dose, about 8.5 mg to about 11.2 mg per daily dose, about 8.8 mg to about 6 mg per daily dose, about 9.1 mg to about 11.0 mg per daily dose, about 9.4 mg to about 10.8 mg per daily dose, about 9.7 mg to about 10.4 mg per daily dose, preferably about 10 mg per daily dose.

[0158]

[0161] In one embodiment, a composition for use in activating AMPK comprising both a first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS No. 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) in an amount of about 100 mg to about 1000 mg per daily dose, preferably about 500 mg per daily dose, and a second compound (e.g., an SGLT2 inhibitor such as dapagliflozin or a derivative or analog thereof) in an amount of about 1.1 mg to about 40 mg per daily dose, preferably about 10 mg per daily dose. In a preferred embodiment, a nutritional composition or dietary supplement comprising both a first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analogue thereof) in an amount of about 100 mg to 1000 mg per daily dose, and a second compound (e.g., an SGLT2 inhibitor such as dapagliflozin or a derivative or analogue thereof) in an amount of about 10 mg per daily dose.

[0159]

[0162] In another embodiment, a nutritional composition or dietary supplement comprising both a first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) in an amount of about 100 mg per daily dose, and a second compound (e.g., an SGLT2 inhibitor such as dapagliflozin or a derivative or analog thereof) in an amount of about 10 mg per daily dose.

[0160]

[0163] In another embodiment, a nutritional composition or dietary supplement comprising both a first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) in an amount of about 200 mg per daily dose, and a second compound (e.g., an SGLT2 inhibitor such as dapagliflozin or a derivative or analog thereof) in an amount of about 10 mg per daily dose.

[0161]

[0164] In another embodiment, a nutritional composition or dietary supplement comprising both a first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) in an amount of about 300 mg per daily dose, and a second compound (e.g., an SGLT2 inhibitor such as dapagliflozin or a derivative or analog thereof) in an amount of about 10 mg per daily dose.

[0162]

[0165] In another embodiment, a nutritional composition or dietary supplement comprising both a first compound (e.g., an AMPK activator such as cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) in an amount of about 400 mg per daily dose, and a second compound (e.g., an SGLT2 inhibitor such as dapagliflozin or a derivative or analog thereof) in an amount of about 10 mg per daily dose.

[0163]

[0166] In one embodiment, a composition comprising a first compound, cannabidiolic acid (CAS No. 1244-58-2), CBGA, CBNA, or a derivative or analog thereof, as an AMP-activated protein kinase (AMPK) activator, and a second compound, comprising dapagliflozin or a derivative thereof, as a sodium-glucose cotransporter 2 (SGLT2) inhibitor, may be used as a nutritional composition or dietary supplement. For example, a composition comprising a first compound (e.g., cannabidiolic acid (CAS No. 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin or a derivative thereof) may be beneficial to a human subject (such as an elderly adult or a patient in need of improved metabolic health) to synergistically activate AMPK, thus improving the metabolic health of the subject.

[0164]

[0167] In one embodiment, a composition comprising a first compound (e.g., cannabidiolic acid (CAS No. 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may be used for daily supplemental administration or for routine administration. For example, a composition comprising a first compound (e.g., cannabidiolic acid (CAS No. 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, or a derivative thereof) may be administered to an older adult or a patient in need of improved metabolic health. In one embodiment, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may be administered to a human subject having obesity, type 2 diabetes, a metabolic disease such as cardiovascular disease, or an obesity-related disease such as diabetic complications, insulin sensitivity, polycystic ovarian disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, weight gain, inflammatory disease, gastrointestinal disease, angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, and vascular dementia.

[0165]

[0168] In some embodiments, a composition comprising a first compound (e.g., cannabidiolic acid (CAS No. 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may further comprise at least one of an excipient, a diluent, or a carrier. In one embodiment, the first compound (e.g., cannabidiolic acid (CAS No. 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and the second compound (e.g., dapagliflozin or a derivative thereof) may be dissolved or suspended in a diluent or carrier.

[0166]

[0169] In some embodiments, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may further comprise an excipient. Exemplary excipients may be those described in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).

[0167]

[0170] Non-limiting examples of suitable excipients include buffers, preservatives, stabilizers, binders, compression agents, lubricants, chelating agents, dispersion enhancers, disintegrants, flavoring agents, sweetening agents, and coloring agents.

[0168]

[0171] In some embodiments, the excipient may be a buffer.Non-limiting examples of suitable buffers include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.As buffers, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, and calcium salts or combinations thereof may be used in the pharmaceutical composition.

[0169]

[0172] In some embodiments, the excipient may include a preservative. Non-limiting examples of suitable preservatives include antioxidants (e.g., α-tocopherol and ascorbate) and antimicrobial agents (e.g., parabens, chlorobutanol, and phenol). Antioxidants may further include, but are not limited to, EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium sulfite, p-aminobenzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol, and N-acetylcysteine. In some examples, the preservative may include validamycin A, TL-3, sodium orthovanadate, sodium fluoride, N-α-tosyl-Phe-chloromethylketone, N-α-tosyl-Lys-chloromethylketone, aprotinin, phenylmethylsulfonyl fluoride, diisopropylfluorophosphate, kinase inhibitors, phosphatase inhibitors, caspase inhibitors, granzyme inhibitors, cell adhesion inhibitors, cell division inhibitors, cell cycle inhibitors, lipid signaling inhibitors, protease inhibitors, reducing agents, alkylating agents, antibacterial agents, oxidase inhibitors, or other inhibitors.

[0170]

[0173] In one embodiment, the composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may further comprise a binder. Non-limiting examples of suitable binders include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, polyvinyl alcohol, C12-C18 fatty acid alcohol, polyethylene glycol, polyol, sugar, oligosaccharide, and combinations thereof.

[0171]

[0174] In one embodiment, the binder may be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG; waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol, and water or combinations thereof.

[0172]

[0175] In some embodiments, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may further comprise a lubricant as an excipient. Non-limiting examples of suitable lubricants can include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. Lubricants that can be used in the pharmaceutical composition can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate, etc.), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oils, leucine, polyethylene glycol (PEG), metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc or combinations thereof.

[0173]

[0176] In some embodiments, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may further comprise a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include high HLB emulsifier surfactants such as starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, refined wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose.

[0174]

[0177] In some embodiments, the composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may further comprise a disintegrant as an excipient. In some embodiments, the disintegrant may be a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays such as bentonite, microcrystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, carob, karaya, pesitin, and tragacanth. In some embodiments, the disintegrant may be an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[0175]

[0178] In some embodiments, the excipient may include a flavoring agent. The flavoring agent incorporated in the outer layer may be selected from synthetic flavor oils and flavor aromatic compounds; natural oils; extracts from plants, leaves, flowers, and fruits; and combinations thereof. In some embodiments, the flavoring agent may be selected from the group consisting of cinnamon oil; wintergreen oil; peppermint oil; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oils, such as lemon oil, orange oil, grape oil, and grapefruit oil; and fruit essences, including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0176]

[0179] In some embodiments, the excipient may include a sweetener. Non-limiting examples of suitable sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts, such as sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (stevioside); chloro derivatives of sucrose, such as sucralose; and sugar alcohols, such as sorbitol, mannitol, syritol, etc.

[0177]

[0180] In some embodiments, the composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may comprise a colorant. Non-limiting examples of suitable colorants may include Food, Drug and Cosmetic Colorants (FD&C), Drug and Cosmetic Colorants (D&C), and External Drug and Cosmetic Colorants (Ext. D&C). The colorants may be used as dyes or their corresponding lakes.

[0178]

[0181] In some embodiments, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may include a diluent. Non-limiting examples of diluents can include water, glycerol, methanol, ethanol, and other similar biocompatible diluents. In some embodiments, the diluent may be an aqueous acid, such as acetic acid, citric acid, maleic acid, hydrochloric acid, phosphoric acid, nitric acid, or sulfuric acid. In some embodiments, the diluent may be used to titrate the pH of the compound to a pH, such as physiological pH, to produce the above salts. In other cases, the diluent may be selected from the group comprising: alkali metal carbonates such as calcium carbonate; alkali metal phosphates such as calcium phosphate; alkali metal sulfates such as calcium sulfate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, kaolin, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and / or anhydrates, hydrates and / or pharma- ceutically acceptable derivatives thereof, or combinations thereof.

[0179]

[0182] In some embodiments, the composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may comprise a surfactant. The surfactant may be selected from, but is not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols (PEGs), polyoxyethylene castor oil derivatives, sodium docusate, quaternary ammonium compounds, amino acids such as L-leucine, sugar esters of fatty acids, glycerides of fatty acids, or combinations thereof.

[0180]

[0183] The composition may be administered by any method recognized by those skilled in the art. For example, the first compound of the present invention (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or derivatives or analogs thereof) and the second compound (e.g., dapagliflozin, phlorizin, or derivatives thereof), or the composition thereof, is preferably administered by oral administration. In some embodiments, the first compound of the present invention (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or derivatives or analogs thereof) and the second compound (e.g., dapagliflozin, phlorizin, or derivatives thereof), or compositions thereof, may be administered intravenously, topically, parenterally, intraperitoneally, intramuscularly, intrathecally, intralesional, intracranial, intranasal, intraocular, intracardiac, intravitreal, intraosseous, intracerebral, intraarterial, intraarticular, intradermal, transdermal, transmucosal, sublingual, enteral, sublabial, insufflation, suppository, inhalation, and subcutaneously.

[0181]

[0184] In one embodiment, the composition of the present invention may have an acute effect observed in less than one month. Additionally or alternatively, the composition may have a long-term effect, and in various embodiments, the composition is administered (e.g., by oral administration) to an individual for a period of at least one month, preferably at least two months, more preferably at least three, four, five or six months, and most preferably at least one year. During this period, the composition may be administered to an individual at least one day per week, preferably at least two days per week, more preferably at least three, four, five or six days per week, and most preferably seven days per week. The composition may be administered in a single dose once per day, or in multiple divided doses per day. In one embodiment, the single dose is about 100 mg or more. In one embodiment, the single dose is about 1000 mg or less. In one embodiment, the single dose is about 100 mg to about 1000 mg.

[0182]

[0185] In one embodiment, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may be in liquid form or solid form (e.g., a solid dosage form).

[0183]

[0186] In some embodiments, the solid dosage form of the composition for oral administration may include capsules, tablets, caplets, pills, troches, lozenges, powders, and granules. In one embodiment, the first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or derivatives or analogs thereof) and the second compound (e.g., dapagliflozin, phlorizin, or derivatives thereof) of the composition are in two separate solid dosage forms.

[0184]

[0187] In one embodiment, the first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and the second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) of the composition are in the same solid dosage form.

[0185]

[0188] For example, the capsule may include a core material comprising a composition including a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and / or a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) and a shell wall encapsulating the core material. In some embodiments, the core material may comprise at least one of a solid, a liquid, and an emulsion. In some embodiments, the shell wall material may comprise at least one of a soft gelatin, a hard gelatin, and a polymer. Suitable polymers include, but are not limited to, cellulose-based polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, and sodium carboxymethylcellulose; acrylic acid polymers and copolymers, such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ammoniomethyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate (e.g., copolymers sold under the trade name "Eudragit"); vinyl polymers and copolymers, such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; and shellac (purified lac). In some embodiments, at least one polymer can function as a taste masking agent.

[0186]

[0189] In some embodiments, tablets, pills, and the like may be compressed, multi-compressed, multi-layered, and / or coated. For example, the coating may be single or multiple. In some embodiments, the coating material (i.e., including compositions including a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or derivatives or analogs thereof) and / or a second compound (e.g., dapagliflozin, phlorizin, or derivatives thereof)) may include at least one of sugars, polysaccharides, and glycoproteins extracted from at least one of plants, fungi, and microorganisms. Non-limiting examples may include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextran, maltodextrin, cyclodextrin, inulin, pectin, mannan, gum arabic, locust bean gum, mesquite gum, guar gum, karaya gum, ghatti gum, tragacanth gum, funori, carrageenan, agar, alginate, chitosan, or gellan gum. In some embodiments, the coating material may include a protein. In some embodiments, the coating material may include at least one of a fat and / or an oil. In some embodiments, at least one of the fat and / or oil may be high temperature melting. In some embodiments, at least one of the fat and / or oil may be hydrogenated or partially hydrogenated. In some embodiments, at least one of the fat and / or oil may be plant derived. In some embodiments, at least one of the fats and / or oils may include at least one of glycerides, free fatty acids, and fatty acid esters. In some embodiments, the coating material may include at least one edible wax. The edible wax may be of animal, insect, or vegetable origin. Non-limiting examples include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills may additionally be prepared with enteric coatings.

[0187]

[0190] Liquid formulations of the composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or derivatives or analogs thereof) and / or a second compound (e.g., dapagliflozin, phlorizin, or derivatives thereof) may include syrups (e.g., oral formulations), intravenous formulations, intranasal formulations, ophthalmic formulations (e.g., for treating eye infections), otic formulations (e.g., for treating ear infections), ointments, creams, aerosols, and the like. In some cases, combinations of various formulations may be administered. In some embodiments, tablets, pills, and the like may be formulated for an extended release profile. In some embodiments, the composition may be formulated to increase shelf stability when stored in a closed container under standard ambient conditions.

[0188]

[0191] Each component in the compositions of the present invention may be used in any amount effective to achieve the objectives of the present invention (i.e., increasing the subject's breast milk micronutrient levels after the subject gives birth). For example, one of skill in the art will be able to determine appropriate dosages depending on the age, size and health of each specific subject, the lifestyle of that subject, and the genetic makeup of that subject.

[0189]

[0192] In one embodiment, the amount used in this application is the amount per daily dose.The amount of each component can be used as disclosed, or can be changed (e.g., increased or decreased) according to the age, physique and health condition of each specific subject, the lifestyle of the subject, and the genetic traits of the subject.In one embodiment, the nutritional composition or dietary supplement of the present invention can be administered periodically, for example, twice a day, once a day, once every two days, or once a week.

[0190]

[0193] In one embodiment, the composition of the present invention may be in any form suitable for administration of all ingredients, for example, the composition of the present invention may be in the form of a powdered nutritional composition to be reconstituted in milk or water, a food, a beverage, a nutritional supplement or a nutraceutical.

[0191]

[0194] When the composition of the present invention is in the form of a powder nutritional composition to be reconstituted with milk or water, the nutritional composition or dietary supplement may preferably comprise a protein source, a carbohydrate source and a lipid source, preferably together with lecithin. The composition may also comprise soy lecithin and / or a bulking agent. The protein source may be dry milk or dry skim milk. As a carbohydrate source, sucrose and / or maltodextrin may be used. The lipid source may be vegetable oil. The formulation may also alternatively or additionally contain glucose syrup, milk fat, magnesium citrate, choline salts and esters, prebiotic fibers, and / or ascorbyl palmitate. Flavoring compounds such as cocoa powder or honey may be added to provide taste variations.

[0192]

[0195] In another aspect, the composition of the present invention may be a product selected from the group consisting of a nutritional product, a functional food product, a healthy aging product, a dairy product, a dairy alternative product, a beverage product, a dietary product, and a pet food product.

[0193]

[0196] In one embodiment, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may be used to treat or prevent a condition, disorder, or disease associated with type 2 diabetes, non-alcoholic fatty liver disease, and / or obesity in a subject.

[0194]

[0197] In one embodiment, the condition may be a metabolic disorder such as obesity, type 2 diabetes, cardiovascular disease, or an obesity-related disease such as diabetic complications, insulin sensitivity, polycystic ovarian disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, weight gain, inflammatory disease, gastrointestinal disease, angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, and vascular dementia.

[0195]

[0198] In another embodiment, a composition comprising a first compound (e.g., cannabidiolic acid (CAS number 1244-58-2), CBGA, CBNA, or a derivative or analog thereof) and a second compound (e.g., dapagliflozin, phlorizin, or a derivative thereof) may be used to treat or prevent a condition selected from the group consisting of obesity, type 2 diabetes, cardiovascular disease, diabetic complications, insulin sensitivity, polycystic ovarian disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, weight gain, inflammatory disease, gastrointestinal disease, angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, and vascular dementia.

[0196]

[0199] method

[0200] Another aspect of the present disclosure is a method of improving metabolic health (e.g., treating or preventing a metabolic disorder or an obesity-related disease) by synergistically activating AMPK. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

[0197]

[0201] In one embodiment, the method of improving metabolic health comprises treating or preventing a metabolic disorder. In one embodiment, the metabolic disorder comprises obesity, type 2 diabetes, cardiovascular disease. In one embodiment, the metabolic disorder is selected from the group consisting of obesity, type 2 diabetes, and cardiovascular disease.

[0198]

[0202] In another embodiment, the method of improving metabolic health comprises treating or preventing an obesity-related disease. In one embodiment, the obesity-related disease comprises diabetic complications, insulin sensitivity, polycystic ovarian disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, weight gain, inflammatory diseases, gastrointestinal diseases, angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, and vascular dementia. In one embodiment, the obesity-related disease is selected from the group consisting of diabetic complications, insulin sensitivity, polycystic ovarian disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, weight gain, inflammatory diseases, gastrointestinal diseases, angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, and vascular dementia.

[0199]

[0203] In one embodiment, the disclosure is a method of treating or preventing a condition selected from the group consisting of obesity, type 2 diabetes, cardiovascular disease, diabetic complications, insulin sensitivity, polycystic ovarian disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, weight gain, inflammatory disease, gastrointestinal disease, angina pectoris, myocardial infarction, sequelae of angina pectoris or myocardial infarction, senile dementia, and vascular dementia.

[0200]

[0204] In another embodiment, the disclosure is a method of treating or preventing type 2 diabetes, non-alcoholic fatty liver disease, and / or obesity related conditions, disorders, or diseases in a subject by activating AMPK.

[0201]

[0205] As disclosed above, the method includes administering to a subject in need thereof a composition comprising a combination of an AMP-activated protein kinase (AMPK) activator (e.g., CBDA) and a sodium-glucose cotransporter 2 (SGLT2) inhibitor to activate AMPK.

[0202]

[0206] In one embodiment, the first compound of general formula I is cannabidiolic acid, CAS number 1244-58-2, and the second compound is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, phlorizin and ertugliflozin.

[0203]

[0207] In one embodiment, the first compound is CBDA, CBGA or CBNA and the second compound is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, phlorizin and ertugliflozin.

[0204]

[0208] In one embodiment, the second compound is selected from the group consisting of empagliflozin, canagliflozin and dapagliflozin.

[0205]

[0209] In one embodiment, the second compound comprises dapagliflozin.

[0206]

[0210] In one embodiment, the second compound is dapagliflozin.

[0207]

[0211] In one embodiment, the second compound is phlorizin.

[0208]

[0212] In one embodiment, the first compound is CBDA, CBGA or CBNA and the second compound is phlorizin.

[0209]

[0213] In one embodiment, the first compound of general formula I is cannabidiolic acid, CAS number 1244-58-2, and the second compound is dapagliflozin.

[0210]

[0214] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising a combination of a first compound, cannabidiolic acid (CAS number 1244-58-2), and a second compound, dapagliflozin, to activate AMPK.

[0211]

[0215] In one embodiment, activation of AMPK is by either a direct or an indirect activation mechanism.

[0212]

[0216] In one embodiment, activation of AMPK is by a direct activation mechanism.

[0213]

[0217] In one embodiment, activation of AMPK occurs in any tissue of a subject that is associated with a condition, disorder, or disease.

[0214]

[0218] In one embodiment, the activation of AMPK is in muscle tissue, liver tissue, and / or kidney tissue.

[0215]

[0219] In one embodiment, the activation of AMPK is in activated AMPK comprising an α2 subunit, a β1 subunit, and a γ1 subunit.

[0216]

[0220] In one embodiment, the first compound is obtained from a plant or plant extract.

[0217]

[0221] As shown in Example 1 and Figure 1, subjects were administered a composition containing about 1 μM or about 0.5 μM CBD or CBDA and about 1 μM Dapa. Example 1, Figure 1A shows that the combination of CBD and Dapa (SGLT-2 inhibitor) improves glucose clearance in zebrafish compared to CBD alone and Dapa alone. Figure 1B shows that the combination of CBDA and Dapa (SGLT-2 inhibitor) improves glucose clearance in zebrafish compared to CBDA alone and Dapa alone.

[0218]

[0222] In one embodiment, the compositions of the invention provide an effect of at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 102%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 120%, 121%, 122%, 130%, 131%, 132%, 143 %, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52 %, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, and 80% increases.

[0219]

[0223] In one embodiment, the increase in glucose clearance may persist for up to 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 36 months, or 48 months. EXAMPLES

[0220]

[0225] Example 1.

[0226] FIG. 1 (FIG. 1A and FIG. 1B) are a pair of graphs showing glucose clearance in zebrafish according to certain embodiments of the present invention. FIG. 1A shows that a combination of CBD and Dapa (an SGLT-2 inhibitor) improves glucose clearance in zebrafish compared to CBD alone and Dapa alone. FIG. 1B shows that a combination of CBDA and Dapa (an SGLT-2 inhibitor) improves glucose clearance in zebrafish compared to CBDA alone and Dapa alone.

Claims

1. A composition for activating AMPK, the composition comprising: A first compound; and a second compound, The first compound has the general formula I: 【Chemistry 1】 [In the formula, R1 and R3 each independently represent OH, OCH ３ , O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside, acylated O-glycoside, sulfated O-glycoside, or sulfate; R2 is OH, OCH ３ , O-glycosides, C-glycosides, acylated O-glycosides, acylated C-glycosides, sulfated O-glycosides, sulfated C-glycosides, halogens, primary, secondary or tertiary alcohols, ketones, aldehydes, esters, primary, secondary or tertiary amines, primary or secondary amides, cyano, nitro, sulfonates, sulfates, optionally substituted and / or optionally branched C １ ~C ２０ Alkyl, optionally substituted and / or optionally branched C ２ ~C ２０ Alkenyl, optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl, optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ is polyalkynyl; R4 is H, OH, OCH ３ , O-glycosides, C-glycosides, acylated O-glycosides, acylated C-glycosides, sulfated O-glycosides, sulfated C-glycosides, halogen atoms that are Cl, I, or F, primary, secondary, or tertiary alcohols, ketones, aldehydes, esters, primary, secondary, or tertiary amines, primary or secondary amides, cyano, nitro, sulfonates, sulfates, optionally substituted and / or optionally branched C1-C20 alkyl, optionally substituted and / or optionally branched C ２ ~C ２０ Alkenyl, optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl, optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ is polyalkynyl; R5 is H, OH, OCH ３ , O-glycosides, C-glycosides, acylated O-glycosides, acylated C-glycosides, sulfated O-glycosides, sulfated C-glycosides, halogens, primary, secondary or tertiary alcohols, ketones, aldehydes, esters, secondary or tertiary amines, primary or secondary amides, cyano, nitro, sulfonates, sulfates, optionally substituted and / or optionally branched C １ ~C ２０ Alkyl, optionally substituted and / or optionally branched C ２ ~C ２０ Alkenyl, optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl, optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ polyalkynyl, optionally OCH ３ The group can cyclize with adjacent OH groups to form a methylenedioxy bridge; or a derivative or analogue thereof; or the first compound is cannabigerolic acid (CBGA) or cannabinolic acid (CBNA); The composition, wherein the second compound is a sodium glucose cotransporter 2 (SGLT2) inhibitor.

2. 2. The composition of claim 1, wherein the sodium glucose cotransporter 2 (SGLT2) inhibitor is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, phlorizin, and mixtures thereof.

3. 2. The composition of claim 1, wherein the sodium glucose cotransporter 2 (SGLT2) inhibitor is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, and mixtures thereof.

4. 2. The composition of claim 1, wherein the sodium glucose cotransporter 2 (SGLT2) inhibitor comprises dapagliflozin.

5. 2. The composition of claim 1, wherein the sodium glucose cotransporter 2 (SGLT2) inhibitor is dapagliflozin.

6. The first compound has the general formula I: 【Chemistry 2】 [In the formula, R1 and R3 each independently represent OH; OCH ３ O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; or sulfated O-glycoside; R2 is OH; OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; primary, secondary, or tertiary amines; primary or secondary amides; cyano; nitro; or sulfonates; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; optionally substituted and / or optionally branched C ４ ~C １０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ is polyalkynyl; R4 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogen atoms Cl, I, or F; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; primary, secondary, or tertiary amines; primary or secondary amides; cyano; nitro; or sulfonates; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ is polyalkynyl; R5 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; secondary or tertiary amines; primary or secondary amides; cyano; nitro; or sulfonates; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ polyalkynyl; optionally, OCH ３ The group can cyclize with adjacent OH groups to form a methylenedioxy bridge; or a derivative or analog thereof.

7. The first compound has the general formula I: 【Chemistry 3】 [In the formula, R1 and R3 each independently represent OH; OCH ３ O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; or an acylated O-glycoside; R2 is OH; OCH; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; halogen; primary, secondary, or tertiary alcohol; ketone; aldehyde; ester; primary, secondary, or tertiary amine; primary or secondary amide; cyano; or nitro; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C １０ ~C ２０ alkenyl; optionally substituted and / or optionally branched C １０ ~C ２０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkynyl, or optionally substituted and / or optionally branched C4 to C20 polyalkynyl; R4 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogen atoms Cl, I, or F; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; primary, secondary, or tertiary amines; primary or secondary amides; cyano; or nitro; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ is polyalkynyl; R5 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; secondary or tertiary amines; primary or secondary amides; cyano; or nitro; optionally branched C １ ~C ２０ Alkyl; optionally branched C ２ ~C ２０ alkenyl; optionally branched C ４ ~C ２０ Polyalkenyl; optionally branched C ２ ~C ２０ Alkynyl or optionally branched C ４ ~C ２０ polyalkynyl; optionally, the OCH3 groups can cyclize with adjacent OH groups to form methylenedioxy bridges; or a derivative or analog thereof.

8. The first compound has the general formula I: 【Chemistry 4】 [In the formula, R1 and R3 each independently represent OH; OCH ３ O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; or an acylated O-glycoside; R2 is OH; OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; or esters; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ is polyalkynyl; R4 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogen atoms Cl, I, or F; primary alcohols, secondary alcohols, or tertiary alcohols; ketones; aldehydes; or esters; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ is polyalkynyl; R5 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; or esters; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; optionally substituted and / or optionally branched C ４ ~C ２０ Polyalkenyl; optionally substituted and / or optionally branched C ２ ~C ２０ Alkynyl or optionally substituted and / or optionally branched C ４ ~C ２０ polyalkynyl; optionally, OCH ３ The group can cyclize with adjacent OH groups to form a methylenedioxy bridge; or a derivative or analog thereof.

9. The first compound has the general formula I: 【Chemistry 5】 [In the formula, R1 and R3 each independently represent OH; OCH ３ O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate, R2 is CH ３ , OH; O-glycosides; C-glycosides; sulfated O-glycosides; sulfated C-glycosides; chlorine; CHO (aldehyde); sulfate; optionally substituted and / or optionally branched C ２ ~C １５ alkenyl; or optionally substituted and / or optionally branched C ４ ~C １５ is polyalkenyl; R4 is H; CH ３ , OH;OCH ３ chlorine, or a 3,3-dimethylallyl chain (1h); R5 is H; optionally substituted and / or optionally branched C １ ~C ２０ Alkyl; optionally substituted and / or optionally branched C ２ ~C ２０ alkenyl; or optionally substituted and / or optionally branched C ４ ~C ２０ polyalkenyl; optionally, OCH ３ The group can cyclize with adjacent OH groups to form a methylenedioxy bridge; or a derivative or analog thereof.

10. The first compound has the general formula I: 【Chemistry 6】 [In the formula, R1 and R3 each independently represent OH; OCH ３ O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate, R2 is OH; OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; primary, secondary, or tertiary amines; primary or secondary amides; cyano; nitro; sulfonates; sulfates; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy C selected from the group consisting of 1f, 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2, C selected from the group consisting of 6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadien-1-yl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o). １０ Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methyl-1-propen-1-yl)-3-furanyl]-2-hexen-1-yl (3d). １５ Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) ２０ Isoprenoid chain: methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (Substituted) alkyl chains selected from the group consisting of so-2-phenylethyl (11b); (Substituted) alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogen atoms Cl, I, or F; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; primary, secondary, or tertiary amines; primary or secondary amides; cyano; nitro; sulfonates; sulfates; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2, C selected from the group consisting of 3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2, C selected from the group consisting of 6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadien-1-yl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o). １０ Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). １５ Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) ２０ Isoprenoid chain: methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a). , 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2- oxo-2-phenylethyl (11b); substituted alkyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R5 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; secondary or tertiary amines; primary or secondary amides; cyano; nitro; sulfonates; sulfates; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3- C selected from the group consisting of methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2, C selected from the group consisting of 6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadien-1-yl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o). １０ Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). １５ Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) ２０ Isoprenoid chain: methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (Substituted) alkyl chains selected from the group consisting of so-2-phenylethyl (11b); (Substituted) alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); optionally, OCH; ３ The group can cyclize with adjacent OH groups to form a methylenedioxy bridge; or a derivative or analog thereof.

11. The first compound has the general formula I: 【Chemistry 7】 [In the formula, R1 and R3 each independently represent OH; OCH ３ O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate, R2 is OH; OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; sulfates; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2, C selected from the group consisting of 6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadien-1-yl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o). １０ Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). １５ Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) ２０ Isoprenoid chain: methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a ), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2 -oxo-2-phenylethyl (11b); substituted alkyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a (substituted) polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogen atoms Cl, I, or F; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; sulfates; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2, C selected from the group consisting of 6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadien-1-yl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o). １０ Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). １５ Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) ２０ Isoprenoid chain: methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (Substituted) alkyl chains selected from the group consisting of so-2-phenylethyl (11b); (Substituted) alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a (substituted) polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R5 is H;OH;OCH ３ ; O-glycosides; C-glycosides; acylated O-glycosides; acylated C-glycosides; sulfated O-glycosides; sulfated C-glycosides; halogens; primary, secondary, or tertiary alcohols; ketones; aldehydes; esters; sulfates; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2, C selected from the group consisting of 6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadien-1-yl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o). １０ Isoprenoid chain; C selected from the group consisting of 3,7,11-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). １５ Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) ２０ Isoprenoid chain: methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a). , 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2- (Substituted) alkyl chains selected from the group consisting of oxo-2-phenylethyl (11b); substituted alkenyl chains selected from the group consisting of ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a substituted polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); optionally, the OCH3 group can cyclize with the adjacent OH group to form a methylenedioxy bridge; or a derivative or analog thereof.

12. The first compound has the general formula I: 【Chemistry 8】 [In the formula, R1 and R3 are each independently OH; OCH ３ O-aliphatic saturated acyl or O-aliphatic unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; or sulfate, R2 is CH ３ , OH; O-glycosides; C-glycosides; sulfated O-glycosides; sulfated C-glycosides; chlorine; CHO (aldehyde); sulfate; C selected from the group consisting of 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3, C10 isoprenoid chain selected from the group consisting of 7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); C10 isoprenoid chain selected from the group consisting of (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), 3-methyl-6-[5-(2-methyl-1-propen-1-yl)-3-furanyl]-2-hexen-1-yl (3d) １５ an isoprenoid chain; or a (substituted) polyalkenyl chain selected from the group consisting of 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is H; CH3, OH; OCH ３ chlorine, or a 3,3-dimethylallyl chain (1h); R5 is H; 3-methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl(epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl C selected from the group consisting of 1,1-dimethylallyl (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p). ５ Isoprenoid chain; 3,7-dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-oct-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5- Hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j ), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), 5-methyl-2-(1-methylethyl)cyclohexyl (2o); C selected from the group consisting of 1-trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d). １５ Isoprenoid chain; C selected from the group consisting of 3,7,11,15-tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b) ２０ Isoprenoid chain: methyl, ethyl, propyl, butyl, pentyl, heptyl, nonylundecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), ​​2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylethyl (7a), 2-Hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxopropyl (Substituted) alkyl chains selected from the group consisting of so-2-phenylethyl (11b); (substituted) alkenyl chains which are one of the following representative examples: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), 1-hydroxymethylene-2-oxopropyl (15a);or a (substituted) polyalkenyl chain selected from the group consisting of 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); optionally, OCH; ３ The group can cyclize with adjacent OH groups to form a methylenedioxy bridge; or a derivative or analog thereof.

13. The first compound has the general formula I: 【Chemistry 9】 [In the formula, R2 is hydrogen and R4 is not hydrogen.

14. The first compound has the general formula I: 【Chemistry 10】 [In the formula, R2 is hydrogen and R5 is not hydrogen; or a derivative or analogue thereof.

15. The first compound has the general formula I: 【Chemistry 11】 [In the formula, R1 and R3 each independently represent OH; OCH ３ ; O-glycosides; or sulfates; R2 is H; 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h); or (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h); R4 is H; R5 is pentyl; benzyl (6a); 2-phenethyl (6b); or phenylethenyl (14a); or a derivative or analog thereof.

16. The first compound has the general formula I: 【Chemistry 12】 [In the formula, R1 is OH; O-glycoside; or sulfate; R2 is H; [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl(geranyl 2,3-epoxide) (2e); 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g); (2E)-3,7-dimethyl-2,6-octadien-1-yl(geranyl) (2h); (2Z)-3,7-dimethyl-2,6-octadien-1-yl(neryl) (2i); or 5-methyl-2-(1-methylethyl)cyclohexyl (2o); R3 is OH; OCH3; O-glycoside; or sulfate; R4 is H; R5 is CH3; n-propyl, n-butyl, or pentyl; or a derivative or analog thereof.

17. The composition according to any one of claims 1 to 16, wherein the first compound of general formula I is cannabidiolic acid, CAS number 1244-58-2.

18. 20. A compound according to any one of claims 1 to 17 for use in the treatment or prevention of type 2 diabetes, non-alcoholic fatty liver disease, and / or obesity related conditions, disorders or diseases in a subject.

19. The composition according to any one of claims 1 to 18, wherein the activation of AMPK is via a direct activation mechanism.

20. The composition according to any one of claims 1 to 18, wherein the activation of AMPK is in muscle tissue, liver tissue, and / or kidney tissue.

21. The composition according to any one of claims 1 to 18, wherein the activated AMPK is AMPK comprising an α2 subunit, a β1 subunit, and a γ1 subunit.

22. The composition of any one of claims 1 to 21, wherein the first compound is obtained from a plant or a plant extract.

23. 23. A composition according to any one of claims 1 to 22 for use in the preparation of a medicament for the treatment or prevention of a condition, disorder or disease responsive to AMPK activation.

24. A composition according to any one of claims 1 to 23 for use in activating AMPK.

25. The composition of any one of claims 1 to 24, wherein the composition is a food, beverage, or dietary supplement.

26. The composition of any one of claims 1 to 24, wherein the composition further comprises a pharma- ceutically acceptable carrier.

27. The composition according to any one of claims 24 to 26, wherein said compound of general formula I is compound 1, cannabidiolic acid, CAS number 1244-58-2.

28. 28. The composition according to any one of claims 1 to 27, wherein the composition is a pharmaceutical composition comprising a therapeutically effective amount of the first compound of general formula I or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient, a therapeutically effective amount of the second compound as an active ingredient, and a pharma- ceutically acceptable carrier, for use in activating AMPK.

29. 29. An in vitro method of activating AMPK comprising contacting AMPK with a composition according to any one of claims 1 to 28.

30. 29. A method of treating or preventing type 2 diabetes, non-alcoholic fatty liver disease, and / or obesity related conditions, disorders, or diseases comprising administering a composition according to any one of claims 1 to 28.

31. 31. The method of claim 30, wherein the first compound of general formula I is cannabidiolic acid, CAS number 1244-58-2, CBGA or CBNA, and the second compound is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, phlorizin and mixtures thereof.

32. 32. The method of claim 31 , wherein the second compound is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, and mixtures thereof.

33. 32. The method of claim 31 , wherein the second compound comprises dapagliflozin.

34. 32. The method of claim 31 , wherein the second compound is dapagliflozin.

35. 31. The method of claim 30, wherein the first compound of general formula I is cannabidiolic acid, CAS number 1244-58-2, and the second compound is dapagliflozin.

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