7-hyrdroxyfrullanolide its analogs for prevention control and treatment of metabolic disorders

Abstract

The invention discloses biologically active ingredient(s) selected from 7-hydroxyfrullanolide, its analogs, the ex-tract(s) and fraction(s) standardized to 7-hydroxyfrullanolide or its analogs or both or mixtures thereof or their composition(s) for the prevention, control and treatment of one or more obesity, overweight, metabolic syndrome, diabetes and other metabolic disorders or for producing lean body mass in a warm blooded animal in need thereof.

1 . Biologically active ingredient(s) comprising at least one component selected from 7-hydroxyfrullanolide, its analog(s); extract(s) and fraction(s) containing 7-hydroxyfrullanolide or its analog(s) or both; or mixtures thereof for the prevention, control and/or treatment of one or more metabolic disorders. 
     
     
         2 . A biologically active composition comprising at least one component selected from the list comprising 7-hydroxyfrullanolide, its analog(s); the extract(s) or fraction(s) containing 7-hydroxyfrullanolide/its analog(s) or both; or mixture(s) thereof as an active in combination with one or more ingredients selected from other biologically active components derived from plants, animals and microorganisms; pharmaceutically or dietetically acceptable active ingredients, vitamins, aminoacids, minerals, vehicles, carriers and diluents or mixtures thereof for the prevention, control and/or treatment of one or more metabolic disorders. 
     
     
         3 . The biologically active ingredient or their composition according to  claim 1 , wherein said metabolic disorders comprise obesity, over weight, diabetes, arteriosclerosis, cardiovascular diseases, hypertension, hypercholesteremia, hyperlipidemia, triglyceridemia, metabolic syndrome, endothelial dysfunction and other metabolic disorders. 
     
     
         4 . The biologically active ingredient(s) or their composition according to  claim 1 , for the amelioration of the expression/production of one or more biological marker proteins related to metabolic disorders. 
     
     
         5 . The biologically active ingredient(s) or their composition according to  claim 4 , wherein said biological marker proteins comprise Peroxisome proliferator-activated receptor gamma (PPARγ), Adipose Differentiation Related Protein (ADRP), adipocyte CD36, Macrophage CD36, Monocyte Chemotactic protein (MCP-1), Oxidized LDL (Ox-LDL), adipocyte fatty-acid-binding protein (aP2/FABP4/A-FABP), beta-3 Adrenergic Receptor (β3AR), Perilipin, Adiponectin, Protein tyrosine phosphatase-1B (PTP-1B), Matrix Metalloproteinase-1 (MMP-1), Matrix Metalloproteinase-3 (MMP-3), and Matrix Metalloproteinase-13 (MMP-13). 
     
     
         6 . The biologically active ingredient(s) or their composition according to  claim 1 , wherein the analog(s) of 7-hydroxyfrullanolide comprises of the compound(s) represented by the general formula I given below; 
       
         
           
           
               
               
           
         
         Wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from hydrogen, hydroxy, halogen, —OOR 12 , alkoxy, —OC(O)R 12  and C(O)R 12 ; optionally R 1  and R 2  are taken together to form a ketone (═O). 
         The tricyclic ring system consists of one or two or three double bonds. 
         Optionally R 2  and R 3  together form a double bond; 
         Optionally R 3  and R 4  together form a double bond; 
         Optionally R 3  and R 5  together form a double bond; 
         Optionally R 5  and R 6  together form a double bond; 
         Optionally R 8  and R 9  together form a double bond; 
         Further optionally R 3  and R 5  together form an epoxide ring
 R 7  is selected from hydrogen, hydroxy, halogen, alkoxy and —OC(O)R 12 ; R 8  is selected from hydrogen, hydroxy, halogen, alkoxy, —OC(O)R 12 , —C(O)R 12  and NR 13 R 14 ; R 9  is selected from hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heterocyclyl, halogen, —OC(O)R 12 , —C(O)R 12 , azido and —NR 13 R 14 , —S(O) m R 15 , —OS(O) m R 15 ; wherein m is 0, 1 or 2; 
 R 10  and R 11  are each independently selected from hydrogen, alkyl, halogen, OR 16 , —NH R 12  and SR 12 ; wherein R 16  is selected from hydrogen, alkyl and C(O)R 12  or R 10  and R 11  together form one of ketone (═O), thioketone (S), imine (NH) and selenoketone (Se); 
 R 12  is selected from hydrogen and alkyl; 
 R 13  and R 14  are each independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heterocyclyl, —C(O)R 12  and —C(S)NHR 12 ; or R 13  and R 14  together with the N atom to which they are bonded, to form a 5-, 6-, or 7-membered heterocyclic ring, optionally having one or more additional heteroatoms selected from O, N, S and Se; 
 R 15  is selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl 
 X is selected from O, NH, S and Se 
 
       
     
     
         7 - 8 . (canceled) 
     
     
         9 . The biologically active ingredient(s) or their composition according to  claim 1 , wherein the analogs of 7-hydroxyfrullanolide are natural analogs selected from the group consisting of 11α,13-dihydro-3α,7α-dihydroxy-4,5-epoxy-6β,7-eudesmanolide; 11α,13-dihydro-7α-acetoxy-3β-hydroxy-6β,7-eudesm-4-enolide; 3-keto-β-eudesmol; 11α,13-dihydro-3α,7α-dihydroxyeudesm-4-en-6α,12-olide; 11α,13-dihydro-3α,7α-dihydroxyfrullanolide; 11α, 13-dihydro-7α,13-dihydroxyfrullanolide; 11α, 13-dihydro-7α-hydroxy-13-methaoxyfrullanolide; 2α, 7α-dihydroxy-4-en-11,13-dihydroeudesm-6,12-olide; 2α-hydroxycostic acid; 3-keto-7α-hydroxyeudesm-4-en-6,12-elide (cryptomeridiol); 4-epicryptomeridiol; sphaeranthanolide; 2a-hydroxysphaerantholide; 2α-acetoxysphaerantholide; 2α,7α-dihydroxysphaerantholide; 2α-acetoxy-7α-hydroxysphaerantholide; 2α-acetoxy-5α-hydroxyisosphaerantholide; eudesmanolide dimer (compound-2); 5aR,9aR,9bR)-decahydro-9a-hydroperoxy-3a-hydroxy-5a-methyl-3,9-dimethylenenaphtho[1,2-b]furan-2(9bH)-one (compound-3); (3aS,5aR,9bR)-3,3a,4,5,5a,6,7,8-octahydro-3,5a,9-trimethylnaphtho[1,2-b]furan-2(9bH)-one (compound-4); (R)-5,5a,6,7-tetrahydro-3,5a,9-trimethylnaphtho[1,2-b]furan-2(4H)-one (compound-5), (3R,3aR,5aR,9bS)-3,3a,4,5,5a,6,7,8-octahydro-3a-hydroxy-3-(methoxymethyl)-5a, 9-dimethylnaphtho[1,2-b]furan-2(9bH)-one (compound-6); 2-((3R,8aR)-1,2,3,7,8,8a-hexahydro-5,8a-dimethylnaphthalen-3-yl)acrylic acid (compound-7); (3aR,5aR,9bS)-3-((6-amino-9H-purin-9-yl)methyl)-3,3a,4, octahydro-3a-hydroxy-5a, 9-dimethylnaphtho[1,2-b]furan-2 (9bH)-one (compound-8); (3R,3aR,5aR,8R,9bS)-8-((2R,3S,4R,5R)-tetrahydro-3,4,5-trihydroxy-6-(hydroxymethyl)-2H-pyran-2-yloxy)-3,3a,4,5,5a,6,7,8-octahydro-3a-hydroxy-3,5a,9-trimethylnaphtho[1,2-b]furan-2(9bH)-one (compound-9) and mixtures thereof. 
     
     
         10 . The biologically active ingredient(s) or their composition according to  claim 1 , wherein the analogs of 7-hydroxyfrullanolide are synthetic/semi-synthetic analogs selected from the group consisting of (3aR,5aR,9bS)-3,3a,4,5,5a,6,7,8-octahydro-3a,8-dihydroxy-5a,9-dimethyl-3-methylene naphtho[1,2-b]furan-2(9bH)-one (compound-10); 5aS,9bS)-3a,4,5,5a,6,7-hexahydro-3a-hydroxy-5a,9-dimethyl-3-methylene naphtho[1,2-b]furan-2,8(3H,9bH)-dione (compound-11); (R)-2,4,5,5a,6,7-hexahydro-5a,9-dimethyl-2-oxonaphtho[1,2-b]furan-3-carbaldehyde (compound-12); 4,5-epoxy-7-hydroxyfrullanolide (compound-13); (R)-3-(bromomethyl)-5,5a,6,7-tetrahydro-5a,9-dimethylnaphtho[1,2-b]furan-2(4H)-one (compound-14; (3aR,5aR,9bS)-3,3a,4,5,5a,6,7,8-octa hydro-3a-hydroxy-3,5a, 9-trimethylnaphtho[1,2-b]furan-2(9bH)-one (compound-15); (2E)-(3aR,5aR,9bS)-2,3,3a,4,5,5a,6,7,8,9b decahydro-3a-hydroxy-3,5a,9-trimethyl-2-oxonaphtho[1,2-b]furan-8-yl 3-(2,5-dimethoxyphenypacrylate (compound-16); (3aR,5aR,9bS)-3,3a,4,5,5a,6,7,8-octahydro-3a-hydroxy-5a,9-dimethyl-3-(morpholinomethyl)naphtho[1,2-b]furan 2(9bH)-one (compound-17); (3aR,5aR,9bS)-3,3a,4,5,5a,6,7,8-octahydro-3a,8-dihydroxy-5a, 9-dimethyl-3-(morpholinomethyl)naphtho[1,2-b]furan-2(9bH)-one (compound-18); (3aR,5aR,9bS)-3,3a,4,5,5a,6,7,8-octahydro-3a-hydroxy-5a,9 dimethyl-3-((piperidin-1-yl)methyl)naphtho[1,2-b]furan-2(9bH)-one (compound-19); (5aR)-5,5a,6,7,8,9-hexahydro-9-hydroxy-5a,9-dimethyl-3-((piperidin-1-yl)methyl)naphtho[1,2-b]furan-2(4H)-one (compound-20); (3aR,5aR,9bS)-3-((4H-1,2,4-triazol-4-yl)methyl)-3,3a,4,5,5a,6,7,8-octahydro-3a-hydroxy-5a,9-dimethylnaphtho furan-2 (9bH)-one (compound-21), (3aR,5aR,9bS)-3,3a, 4,5,5a,6,7,8-octahydro-3a hydroxy-5a,9-dimethyl-3-((piperazin-1-yl)methyl)naphtho[1,2-b]furan-2(9bH)-one (compound-22) and piperazine bis-7-hydroxyfrullanolide (compound-23) as substantially depicted in figure X by structures 12 through 25. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . The biologically active ingredient(s) comprising at least one component selected from 7-hydroxyfrullanolide, its analog(s); extract(s) and fraction(s) containing 7-hydroxyfrullanolide or its analog(s) or both; or mixtures thereof according to  claim 1 , wherein the said extracts and fractions contain 7-hydroxyfrullanolide or its analog(s) or mixtures thereof in the range of 0.001% to 100%, preferably 0.01 to 99%. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The biologically active composition according to  claim 2 , wherein the other biologically active components used for making the compositions comprise extract(s), fraction(s), active compound(s), phytochemical(s) or powder(s) derived from plant(s), animal(s) or microorganisms having one or more health benefits selected from but not limited to anti-diabetic activity, anti-hyperlipidemic activity, anti-obesity activity, anti-hypertensive activity, anti-platelet aggregation activity, anti-infective activity, anti-atherosclerotic activity, anti-inflammatory activity, anti-oxidant activity and bio-enhancing activity. 
     
     
         17 . The biologically active ingredient(s) or their compositions according to  claim 1 , can be optionally combined with bio-availability enhancing agents selected from but not limited to extract(s), fraction(s), pure compound(s) derived from  Piper nigrum  or  Piper longum  or  Stevia rebaudiana.    
     
     
         18 . The biologically active ingredient(s) or their compositions according to  claim 1 , wherein the 7-hydroxyfrullanolide, its analogs; extracts and fractions containing 7-hydroxyfrullanolide or its analogs or mixtures thereof are derived from  Sphaeranthus indicus , wherein said extract(s) or active fraction(s) or active compound(s) or phytochemicals or mixtures thereof are derived from at least one of the plant parts selected from leaves, flower heads, fruits, stem, bark, root, whole plant or mixtures thereof, preferably flower heads. 
     
     
         19 . The biologically active ingredient(s) or their compositions according to  claim 2 , wherein, the pharmaceutically or dietetically acceptable excipients, vehicles and carriers comprise surfactants, binders, diluents, disintegrators, lubricants, preservatives, stabilizers, buffers, suspensions and drug delivery systems. 
     
     
         20 . The biologically active ingredient(s) or their compositions according to  claim 19 , wherein the pharmaceutically or dietetically acceptable excipients, carriers and diluents comprise glucose, fructose, sucrose, maltose, yellow dextrin, white dextrin, aerosil, microcrystalline cellulose, calcium stearate, magnesium stearate, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-alpha-tocopherol, glycerin, propylene glycol, glycerin fatty ester, poly glycerin fatty ester, sucrose fatty ester, sorbitan fatty ester, propylene glycol fatty ester, acacia, carrageenan, casein, gelatin, pectin, agar, vitamin B group, nicotinamide, calcium pantothenate, amino acids, calcium salts, pigments, flavors, preservatives, distilled water, saline, aqueous glucose solution, alcohol, propylene glycol and polyethylene glycol, various animal and vegetable oils, white soft paraffin, paraffin and wax. 
     
     
         21 . The biologically active ingredient(s) or its composition(s) according to  claim 1 , wherein said ingredient(s) or composition(s) is administered orally, topically, parenterally or by inhalation to a subject or mammal or warm blooded animal in need thereof. 
     
     
         22 . (canceled) 
     
     
         23 . The biologically active ingredient(s) or its composition(s) according to  claim 1 , wherein said ingredient(s) or composition(s) can be formulated as oral agents such as tablets, soft capsule, hard capsule, soft gel capsules, pills, granules, powders, emulsions, suspensions, syrups, pellets, food, beverages, concentrated shots, drops and the like; and parenteral agents such as injections, intravenous drip and the like; suppositories; and transdermal agents such as patches, topical creams and gel; ophthalmic agents; nasal agents; and food or beverages. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . Use of biologically active ingredient or its composition(s) according to  claim 1  for prevention, control and/or treatment of one or more diseases or conditions including but not limited to obesity, diabetes, hypertension, arteriosclerosis, cardiovascular diseases, neurological disorders, Alzheimer's, cognitive disorders, oxidative stress, skin disorders, aging of the skin, UV irradiated damage, hypercholesterolemia, hyperlipidemia, triglyceridemia, immune deficiency, metabolic syndrome, for bringing about weight loss effectively, for producing lean body mass, for using during weight loss program as well as for other metabolic disorders. 
     
     
         27 . A method of preventing/controlling/treating one or more metabolic disorders selected from obesity, over weight, diabetes, arteriosclerosis, cardiovascular diseases, hypertension, hypercholesterolemia, hyperlipidemia, triglyceridemia, metabolic syndrome, endothelial dysfunction and other metabolic disorders in a mammal or warm blooded animal in need thereof, wherein the method comprises administering to mammal or warm blooded animal a therapeutically effective amount of at least one biologically active ingredient or its composition(s) according to  claim 1 . 
     
     
         28 . A method of promoting lipolysis and/or inhibiting adipogenesis in a subject or mammal or warm blooded animal in need thereof comprising administering to said subject or mammal or warm blooded animal a therapeutically effective quantity of at least one biologically active ingredient or its composition(s) according to  claim 1 . 
     
     
         29 . A method of amelioration of the expression or production of at least one biological marker selected from PPAR-γ, C-reactive protein (CRP), Adipose Differentiation Related Protein (ADRP), adipocyte CD36, macrophage CD36, Monocyte Chemotactic protein (MCP-1), Oxidized LDL, Adipocyte Fatty-acid-Binding Protein (aP2/FABP4/A-FABP), Beta-3 adrenergic receptor (β3-AR), adiponectin, Perilipin, Protein tyrosine phosphatase 1B (PTP 1B), Matrix Metalloproteinase-1 (MMP-1), Matrix Metalloproteinase-3 (MMP-3) and Matrix Metalloproteinase-13 (MMP-13) in a subject or mammal or warm blooded animal in need thereof, wherein the method comprises administering to the subject or mammal or warm blooded animal at least one biologically active ingredient or its composition(s) according to  claim 1 .