Ursolic acid morpholine salt and diethanolamine salt

Abstract

The present invention provides ursolic acid diethanolamine salts and morpholine salts, as well as compositions containing the salts and methods of using the salts.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 558,004, filed September 13, 2017, and U.S. Publication No. 62 / 649,938, filed March 29, 2018, the entire contents of each of which are incorporated herein by reference. [Technical field]

[0002] The present invention provides novel ursolic acid diethanolamine and morpholine salts that exhibit superior efficacy and properties, as well as compositions containing and methods of using the salts. [Background technology]

[0003] Ursolic acid is a pentacyclic triterpene acid. The range of biological effects of ursolic acid is discussed in WO 2011 / 146768 and WO 2012 / 170546. At the molecular level, among other effects, ursolic acid inhibits the STAT3 activation pathway, reduces expression of matrix metalloproteinase-9 via the glucocorticoid receptor, inhibits protein tyrosine phosphatases, acts as an insulin mimetic, activates PPARs, inhibits NF-kB transcription factors, translocates hormone-sensitive lipase to stimulate lipolysis, and inhibits the hepatic polyol pathway. Summary of the Invention

[0004] Briefly, the present invention provides novel diethanolamine and morpholine salts, and related compositions and methods, which exhibit superior properties, including effects on skeletal muscle, compared to ursolic acid itself and other ursolic acid salts.

[0005] Certain embodiments of ursolic acid salts (i.e., compositions comprising the salts) and methods of using the salts currently disclosed have several features, no single one of which is responsible for their desirable attributes. Without limiting the scope of ursolic acid salts (i.e., compositions comprising the salts) and methods of using the salts as defined by the claims below, their more prominent features will be briefly described. After reviewing this discussion, and especially after reading the section of this specification entitled "Detailed Description of the Invention", one will appreciate how the features of the various embodiments disclosed herein provide many advantages over the current state of the art. For example, embodiments of the present invention provide unexpectedly superior properties compared to, for example, natural ursolic acid and other ursolic acid salts, including, for example, efficacy in stimulating skeletal muscle hypertrophy, increased lean muscle mass, reduced fat mass, increased skeletal muscle fiber size, reduced fat cell size, reduced obesity and / or blood glucose levels, improved glucose tolerance, and the like.

[0006] In a first aspect, the present invention provides an ursolic acid salt selected from an ursolic acid diethanolamine salt and an ursolic acid morpholine salt.

[0007] In a second aspect, the present invention provides a composition comprising an ursolic acid salt selected from ursolic acid diethanolamine salt and ursolic acid morpholine salt, and an additional agent.

[0008] In a third aspect, the present invention provides a method for: In the subject, (i) increasing skeletal muscle mass; (ii) treating skeletal muscle atrophy; (iii) treating sarcopenia; (iv) treating cachexia; (v) increasing strength; (vi) Treating frailty; (vii) improving athletic performance; (viii) Treating fatigue; (ix) promoting muscle growth; (x) promoting normal muscle function; (xi) improving muscle function; (xii) promoting muscle health; (xiii) promoting healthy aging of muscle; (xiv) increasing energy expenditure; (xv) increasing the ratio of skeletal muscle to fat; (xvi) reducing fat; (xvii) treating obesity; (xviii) Treating diabetes; (xix) Lowering blood sugar levels; (xx) treating prediabetes; (xxi) Treating metabolic syndrome; (xxii) treating insulin resistance; (xxiii) reducing plasma cholesterol; (xxiv) treating hypercholesterolemia; (xxv) reducing plasma triglycerides; (xxvi) Treating hypertriglyceridemia; (xxvii) promoting healthy metabolism; (xxviii) promoting metabolic health; (xxix) Treating hypertension; (xxx) Treating atherosclerosis; (xxxi) treating myocardial ischemia; (xxxii) Treating myocardial infarction; (xxxiii) treating cardiomyopathy; (xxxiv) treating cardiac arrhythmias; (xxxv) treating nonalcoholic fatty liver disease (NAFLD); (xxxvi) treating liver fibrosis; (xxxvii) treating liver disorders; (xxxviii) treating lung injury; (xxxix) Treating gastric ulcers; (xl) Treating nephropathy; (xli) promoting bone formation; (xlii) promoting normal bone structure; (xliii) promoting bone health; (xliv) Treating osteoporosis; (xlv) Treating cerebral ischemia; (xlvi) Treating cerebral hemorrhage; (xlvii) Treating stroke; (xlviii) Treating traumatic brain injury; (xlix) Treating dementia; (l) Treating Alzheimer's disease; (li) Treating memory loss; (lii) Treating cognitive impairment; (liii) promoting normal cognitive function; (liv) Treating anxiety; (lv) Treating depression; (lvi) reducing inflammation; (lvii) Treating arthritis; (lviii) Treating skin ulcers; (lix) Treating skin wounds; (lx) promoting wound healing; (lxi) Treating dry skin; (lxii) Treating rough skin; (lxiii) Treating skin scars; (lxiv) Treating skin wrinkles; (lxv) reducing the undesirable effects of aging; (lxvi) Treating cancer; (lxvii) inhibiting tumor growth; (lxviii) treating tumor metastasis; (lxix) Treating tumor angiogenesis; (lxx) Increasing tumor cell apoptosis; (lxxi) reducing protein oxidation; (lxxii) reducing lipid oxidation; (lxxiii) Reducing DNA oxidation; (lxxiv) Reducing RNA oxidation; (lxxv) reducing the oxidation of cellular molecules; (lxxvi) Reducing DNA damage; (lxxvii) Treating bacterial infections; (lxxviii) reducing bacterial growth; (lxxix) Treating fungal infections; (lxxx) Reducing fungal growth; (lxxxi) Treating viral infections; (lxxxii) Treating protozoal infections; (lxxxiii) treating nematode infections; or (lxxxiv) treating a condition, pathology, or disease disorder mediated by activation of transcription factor 4 (ATF4); The method includes administering to the subject an ursolic acid salt selected from ursolic acid diethanolamine salt and ursolic acid morpholine salt, or a composition comprising an ursolic acid salt.

[0009] These and other features and advantages of the present invention will become apparent from the following detailed description of the various aspects of the invention taken in conjunction with the appended claims and the accompanying drawings. [Brief description of the drawings]

[0010] The invention will now be described in conjunction with the following drawings, as follows:

[0011] 1A and 1B are photomicrographs of quadriceps skeletal muscle fibers from control and test mice, respectively, after 7 weeks of ad libitum consumption of either standard chow (control) or standard chow supplemented with 0.059% ursolic acid-morpholine salt.

[0012] 2A and 2B are photomicrographs of adipocytes in the retroperitoneal fat pads of control and test mice, respectively, after 7 weeks of ad libitum consumption of either standard chow (control) or standard chow supplemented with 0.059% ursolic acid-morpholine salt.

[0013] FIG. 3 is a chart showing glucose tolerance test results of control and test mice after 8 weeks of ad libitum access to a high-fat diet (control) or a high-fat diet supplemented with 0.059% ursolic acid-morpholine salt.

[0014] 4 is a graph showing the results of the glucose tolerance test.

[0015] Aspects of the invention and certain features, advantages, and details of the invention are described more fully below. Descriptions of well-known materials, equipment, processing techniques, and the like are omitted so as not to unnecessarily obscure the invention with detailed descriptions.

[0016] In a first aspect, the present invention provides an ursolic acid salt selected from an ursolic acid diethanolamine salt and an ursolic acid morpholine salt.

[0017] The ursolic acid salts of the present invention can be synthesized by techniques known in the art. The starting materials of the compounds of the present invention are commercially available or can be synthesized themselves using reagents and techniques known in the art. Non-limiting synthetic embodiments are described herein.

[0018] The formula below: [ka] Ursolic acid, having the formula: is commercially available and is present in a variety of plants from which it can be extracted (e.g., apple, basil, bilberry, cranberry, elderflower, peppermint, rosemary, lavender, oregano, thyme, hawthorn, and prune).

[0019] In one embodiment, the ursolic acid salt of the present invention has the following formula: [ka] is ursolic acid diethanolamine salt having the formula:

[0020] In one embodiment, the ursolic acid salt of the present invention has the following formula: [ka] It is a morpholine salt of ursolic acid having the formula:

[0021] In a second aspect, the present invention provides a composition comprising an ursolic acid salt selected from an ursolic acid diethanolamine salt and an ursolic acid morpholine salt, and an additional agent.

[0022] The additional agent is a component that is present in the composition in addition to ursolic acid salt.Those skilled in the art are familiar with the various types of additional agents that may be included in the composition.For example, in one non-limiting embodiment, the additional agent includes excipients, binders, diluents, carriers, other delivery vehicles or systems, fillers, salts, buffers, preservatives, antioxidants, stabilizers, sweeteners, or flavoring agents.

[0023] In some embodiments, the additional agent is a physiologically acceptable agent. As used herein, a physiologically acceptable agent is an agent that does not exhibit significant toxicity at the doses for which it is intended. The term physiologically acceptable agent includes generally regarded as safe (GRAS) substances. GRAS substances are listed by the Food and Drug Administration in the Code of Federal Regulations (CFR) at 21 CFR 182 and 21 CFR 184. The August 2017 editions of 21 CFR 182 and 21 CFR 184 are incorporated herein by reference. The term physiologically acceptable agent also includes pharma- ceutically acceptable agents.

[0024] As used herein, the term "pharmaceutical acceptable" means a component that is suitable for use in contact with the tissues of a subject (e.g., a human or other animal) without undue toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0025] In some embodiments, the compositions of the invention are formulated for pharmaceutical use (i.e., are "pharmaceutical compositions"). A pharmaceutical composition contains a pharma- ceutically acceptable carrier, adjuvant, or vehicle that is "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof in amounts typically used in pharmaceuticals.

[0026] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphoric acid), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0027] In some embodiments, the composition is a pharmaceutical composition, a nutritional composition, a food composition, or a dietary supplement.

[0028] In some embodiments, the composition is in the form of or includes a non-naturally occurring oral delivery vehicle, which does not include naturally occurring vehicles such as plants or fruits, and includes, but is not limited to, capsules, pills, tablets, cachets, syrups, foods, and beverages.

[0029] In some embodiments, the compositions are in the form of one or more of: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; poultices (compresses); pastes; powders; dressings; creams; bandages; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject; suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0030] In a third aspect, the present invention provides a method for: In the subject, (i) increasing skeletal muscle mass; (ii) treating skeletal muscle atrophy; (iii) treating sarcopenia; (iv) treating cachexia; (v) increasing strength; (vi) Treating frailty; (vii) improving athletic performance; (viii) Treating fatigue; (ix) promoting muscle growth; (x) promoting normal muscle function; (xi) improving muscle function; (xii) promoting muscle health; (xiii) promoting healthy aging of muscle; (xiv) increasing energy expenditure; (xv) increasing the ratio of skeletal muscle to fat; (xvi) reducing fat; (xvii) treating obesity; (xviii) Treating diabetes; (xix) Lowering blood sugar levels; (xx) treating prediabetes; (xxi) Treating metabolic syndrome; (xxii) treating insulin resistance; (xxiii) reducing plasma cholesterol; (xxiv) treating hypercholesterolemia; (xxv) reducing plasma triglycerides; (xxvi) Treating hypertriglyceridemia; (xxvii) promoting healthy metabolism; (xxviii) promoting metabolic health; (xxix) Treating hypertension; (xxx) Treating atherosclerosis; (xxxi) treating myocardial ischemia; (xxxii) Treating myocardial infarction; (xxxiii) treating cardiomyopathy; (xxxiv) treating cardiac arrhythmias; (xxxv) treating nonalcoholic fatty liver disease (NAFLD); (xxxvi) treating liver fibrosis; (xxxvii) treating liver disorders; (xxxviii) treating lung injury; (xxxix) Treating gastric ulcers; (xl) Treating nephropathy; (xli) promoting bone formation; (xlii) promoting normal bone structure; (xliii) promoting bone health; (xliv) Treating osteoporosis; (xlv) Treating cerebral ischemia; (xlvi) Treating cerebral hemorrhage; (xlvii) Treating stroke; (xlviii) Treating traumatic brain injury; (xlix) Treating dementia; (l) Treating Alzheimer's disease; (li) Treating memory loss; (lii) Treating cognitive impairment; (liii) promoting normal cognitive function; (liv) Treating anxiety; (lv) Treating depression; (lvi) reducing inflammation; (lvii) Treating arthritis; (lviii) Treating skin ulcers; (lix) Treating skin wounds; (lx) promoting wound healing; (lxi) Treating dry skin; (lxii) Treating rough skin; (lxiii) Treating skin scars; (lxiv) Treating skin wrinkles; (lxv) reducing the undesirable effects of aging; (lxvi) Treating cancer; (lxvii) inhibiting tumor growth; (lxviii) treating tumor metastasis; (lxix) Treating tumor angiogenesis; (lxx) Increasing tumor cell apoptosis; (lxxi) reducing protein oxidation; (lxxii) reducing lipid oxidation; (lxxiii) Reducing DNA oxidation; (lxxiv) Reducing RNA oxidation; (lxxv) reducing the oxidation of cellular molecules; (lxxvi) Reducing DNA damage; (lxxvii) Treating bacterial infections; (lxxviii) reducing bacterial growth; (lxxix) Treating fungal infections; (lxxx) Reducing fungal growth; (lxxxi) Treating viral infections; (lxxxii) Treating protozoal infections; (lxxxiii) treating nematode infections; or (lxxxiv) treating a condition, pathology, or disease disorder mediated by activation of transcription factor 4 (ATF4); The method includes administering to the subject an effective amount of an ursolic acid salt selected from ursolic acid diethanolamine salt and ursolic acid morpholine salt, or a composition comprising an ursolic acid salt.

[0031] The various uses described in the preceding paragraphs are described with respect to ursolic acid itself in the following references, the disclosures of which are incorporated herein by reference in their entireties: 1. Wozniak, L., Skapska, S., and Marszalek, K. (2015) Ursolic Acid--A Pentacyclic Triterpenoid with a Wide Spectrum of Pharmacological Activities. Molecules20, 20614-20641 2. Liu, J. (2005) Oleanolic acid and ursolic acid: research perspectives. J Ethnopharmacol 100, 92-94 3. Sultana, N. (2011) Clinically useful anticancer, antitumor, and antiwrinkle agent, ursolic acid and related derivatives as medicinally important natural product. J Enzyme Inhib Med Chem 26, 616-642 4. Liu, J. (1995) Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 49, 57-68 5. Shanmugam, MK, Dai, X., Kumar, AP, Tan, BK, Sethi, G., and Bishayee, A. (2013) Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies. Biochem Pharmacol 85, 1579-1587 6. Kashyap, D., Tuli, H. S., and Sharma, A. K. (2016) Ursolic acid (UA): A metabolite with promising therapeutic potential. Life Sci146, 201-213 7. Lopez-Hortas, L., Perez-Larran, P., Gonzalez-Munoz, M. J., Falque, E., and Dominguez, H. (2018) Recent developments on the extraction and application of ursolic acid. A review. Food Res Int 103, 130-149 8. Pironi, A. M., de Araujo, P. R., Fernandes, M. A., Salgado, H. R. N., and Chorilli, M. (2018) Characteristics, Biological Properties and Analytical Methods of Ursolic Acid: A Review. Crit Rev Anal Chem 48, 86-93 9. Cargnin, S. T., and Gnoatto, S. B. (2017) Ursolic acid from apple pomace and traditional plants: A valuable triterpenoid with functional properties. Food Chem 220, 477-489 10. Lee, S. U., Park, S. J., Kwak, H. B., Oh, J., Min, Y. K., and Kim, S. H. (2008) Anabolic activity of ursolic acid in bone: Stimulating osteoblast differentiation in vitro and inducing new bone formation in vivo. Pharmacol Res 58, 290-296 11. Lu, J., Zheng, Y. L., Wu, D. M., Luo, L., Sun, D. X., and Shan, Q. (2007) Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Biochem Pharmacol 74, 1078-1090 12. Wang, X. T., Gong, Y., Zhou, B., Yang, J. J., Cheng, Y., Zhao, J. G., and Qi, M. Y. (2018) Ursolic acid ameliorates oxidative stress, inflammation and fibrosis in diabetic cardiomyopathy rats. Biomed Pharmacother 97, 1461-1467 13. Zhou, Y., Li, J. S., Zhang, X., Wu, Y. J., Huang, K., and Zheng, L. (2010) Ursolic acid inhibits early lesions of diabetic nephropathy. Int J Mol Med 26, 565-570 14. Ling, C., Jinping, L., Xia, L., and Renyong, Y. (2013) Ursolic Acid provides kidney protection in diabetic rats. Curr Ther Res Clin Exp 75, 59-63 15. Ding, H., Wang, H., Zhu, L., and Wei, W. (2017) Ursolic Acid Ameliorates Early Brain Injury After Experimental Traumatic Brain Injury in Mice by Activating the Nrf2 Pathway. Neurochem Res 42, 337-346 16. Ma, J. Q., Ding, J., Zhang, L., and Liu, C. M. (2015) Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2 / ARE pathway. Clin Res Hepatol Gastroenterol 39, 188-197 17. Zhang, T., Su, J., Wang, K., Zhu, T., and Li, X. (2014) Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage. Neurosci Lett 579, 12-17 18. Hwang, T. L., Shen, H. I., Liu, F. C., Tsai, H. I., Wu, Y. C., Chang, F. R., and Yu, H. P. (2014) Ursolic acid inhibits superoxide production in activated neutrophils and attenuates trauma-hemorrhage shock-induced organ injury in rats. PLoS One 9, e111365 19. Martinez-Abundis, E., Mendez-Del Villar, M., Perez-Rubio, K. G., Zuniga, L. Y., Cortez-Navarrete, M., Ramirez-Rodriguez, A., and Gonzalez-Ortiz, M. (2016) Novel nutraceutic therapies for the treatment of metabolic syndrome. World J Diabetes 7, 142-152 20. Somova, L. O., Nadar, A., Rammanan, P., and Shode, F. O. (2003) Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine10, 115-121 21. Somova, L. I., Shode, F. O., Ramnanan, P., and Nadar, A. (2003) Antihypertensive, antiatherosclerotic and antioxidant activity of triterpenoids isolated from Olea europaea, subspecies africana leaves. J Ethnopharmacol 84, 299-305

[0032] In certain embodiments, the ursolic acid salts described herein are useful, among other things, for the same conditions as ursolic acid itself.

[0033] As used herein, the term "subject" refers to an animal that is the target of administration. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human animal. In some embodiments, the subject is a non-rodent animal. In some embodiments, the subject is a non-human animal and / or a non-rodent animal. In some embodiments, the subject is a vertebrate and / or an amphibian. In some embodiments, the subject is a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, a hamster, a ferret, a fish, a bird, or a rodent. In some embodiments, the subject is a human or a livestock animal. In some embodiments, the subject is a domesticated animal, such as a domesticated fish, a domesticated crustacean, or a domesticated mollusc. In some embodiments, the livestock is poultry. In some embodiments, the poultry is selected from chicken, turkey, duck, and goose. In some embodiments, the livestock is a livestock animal. In some embodiments, the livestock animals are selected from pigs, cows, horses, goats, bison, and sheep. In some embodiments, the livestock animals include rodents. In other embodiments, the livestock animals are free of some or all rodents. In some embodiments, the livestock animals are free of mice and rats.

[0034] As used herein, the term "treatment" and its variations (e.g., "treat") refers to the management (e.g., medical management) of a patient / subject with the intent to cure, ameliorate, stabilize, or forestall a disease, pathological condition, or disorder. This term includes administering to a subject a compound and / or composition of the present invention for the purpose of curing, heal, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting a disease state, condition, or disorder, a symptom (for a disease state, condition, or disorder), or a tendency toward a disease state, condition, or disorder. The term "treatment" and its various forms include use for aesthetic and self-improvement purposes. For example, such uses include, but are not limited to, administration of the disclosed compounds in dietary supplements, medicinal foods, energy bars, energy drinks, and supplements (e.g., multivitamins). The term includes active treatments (i.e., treatments specifically directed to ameliorating a disease, condition, or disorder), and also includes causal treatments (i.e., treatments directed to eliminating the cause of the associated disease, condition, or disorder). Additionally, the term includes palliative treatments (i.e., treatments designed to relieve symptoms rather than cure the disease, condition, or disorder), preventative treatments (i.e., treatments aimed at minimizing or partially or completely inhibiting the onset of the associated disease, condition, or disorder), and supportive treatments (i.e., treatments employed to supplement another specific therapy directed to ameliorating the associated disease, condition, or disorder). In various embodiments, the term includes any treatment for a subject, and further includes the following: (i) to prevent disease from occurring in subjects who are susceptible to the disease but have not yet been diagnosed as having it; (ii) inhibiting the disease (i.e. preventing its onset); or (iii) alleviating the disease (i.e. causing regression of the disease). The term further includes preventing or inhibiting the onset, recurrence, or progression of a disease state, condition, or disorder disclosed herein, as well as ameliorating and / or reducing the occurrence of symptoms of a disease state, condition, or disorder.

[0035] The therapeutic methods and uses of the ursolic acid salts of the present invention typically include administering an effective amount (e.g., a therapeutically effective amount) of the salt to a subject in need thereof. As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including an amount of a compound that, when administered to a subject to treat a disorder, is sufficient to effect treatment of such disorder. An effective amount may vary depending on the compound, the disorder and its severity, as well as the age, weight, etc., of the subject being treated. An effective amount may be one or more doses (e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint). An effective amount may be considered to be administered in an effective amount if, in conjunction with one or more other agents, a desired or useful result may be or is achieved. A subject in need of treatment includes a subject at risk in need of treatment. As used herein, a subject "at risk" is a subject at risk of developing the condition or disorder to be treated. This can be indicated, for example, by one or more risk factors, which are measurable parameters that correlate with the development of a condition or disorder and are known in the art.

[0036] In some embodiments, the subject has been identified as in need of treatment for a condition or disorder or has been diagnosed with a condition or disorder prior to administering a salt of the invention to the subject. In some embodiments, the subject has not been diagnosed with a condition or disorder prior to administering a salt of the invention to the subject. In some embodiments, the subject has not been diagnosed with cancer or diabetes. In other embodiments, the subject may have been diagnosed with a condition or disorder, such as cancer or diabetes.

[0037] As used herein, the term "diagnosed" means that a person has been physically examined by a person skilled in the art (e.g., a physician) and found to have a condition that can be diagnosed or treated by the ursolates, compositions, or methods / uses of the invention disclosed herein. For example, "diagnosed with a muscle wasting disorder" means that a person has been physically examined by a person skilled in the art (e.g., a physician) and found to have a condition that can be diagnosed or treated by a compound or composition that can promote muscle health, promote normal muscle function, and / or promote healthy aging muscle. As a further example, "diagnosed as needing to promote muscle health" means that a person has been physically examined by a person skilled in the art (e.g., a physician) and found to have a condition characterized by muscle wasting or other disease, where promoting muscle health, promoting normal muscle function, and / or promoting healthy aging muscle is beneficial to the subject. Such a diagnosis may be for a disorder (e.g., muscle wasting) as discussed herein.

[0038] As used herein, the term "identified as needing treatment for a condition or disorder" and the like refers to selecting a subject based on the need for treatment for the disorder. For example, a subject is identified as needing treatment for a disorder (e.g., a disorder associated with muscle atrophy) based on an initial diagnosis by a person skilled in the art, and then receives treatment for the disorder. As another example, a subject intended for consumption (e.g., fish, livestock production, etc.) is identified as needing treatment, for example, to increase muscle mass, to increase the average amount of meat that can be obtained per animal.

[0039] In one embodiment, the ursolate salts of the present invention are administered at a dosage ranging from about 0.001 to about 500 mg / kg of subject body weight (e.g., 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0. 27,0.28,0.29,0.30,0.31,0.32,0.33,0.34,0.35,0.36,0.37,0.38,0.39,0.40,0.41,0.42,0.43,0.44,0.45,0.46,0.47,0.48,0.49,0.50,0.51,0 .52,0.53,0.54,0.55,0.56,0.57,0.58,0.59,0.60,0.61,0.62,0.63,0.64,0.65,0.66,0.67,0.68,0.69,0.70,0.71,0.72,0.73,0.74,0.75,0.76,0 .77,0.78,0.79,0.80,0.81,0.82,0.83,0.84,0.85,0.86,0.87,0.88,0.89,0.90,0.91,0.92,0.93,0.94,0.95,0.96,0.97,0.98,0.99,1.0,1.1,1. 2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3 ,4.4,4.5,4.6,4.7,4.8,4.9,5.0,5.1,5.2,5.3,5.4,5.5,5.6,5.7,5.8,5.9,6.0,6.1,6.2,6.3,6.4,6.5,6.6,6.7,6.8,6.9,7.0,7.1,7.2,7.3,7.4, 7.5,7.6,7.7,7.8,7.9,8.0,8.1,8.2,8.3,8.4,8.5,8.6,8.7,8.8,8.9,9.0,9.1,9.2,9.3,9.4,9.5,9.6,9.7,9.8,9.9,10.0,10.1,10.2,10.3,10.4,10.5,10.6,10.7,10.8,10.9,11.0,11.1,11.2,11.3,11.4,11.5,11.6,11.7,11.8,11.9,12.0,12.1,12.2,12.3,12.4,12.5,12.6,12.7,12.8,12.9,13.0,13.1,13.2,13.3,13.4,13.5,13.6,13.7,13.8,13.9,14.0,14.1,14.2,14.3,14.4,14.5,14.6,14.7,14.8,14.9,15.0,16.1,16.2,16.3,16.4,16.5,16.6,16.7,16.8,16.9,17.0,17.1,17.2,17.3,17.4,17.5,17.6,17.7,17.8,17.9,18.0,18.1,18.2,18.3,18.4,18.5,18.6,18.7,18.8,18.9,19.0,19.1,19.2,19.3,19.4,19.5,19.6,19.7,19.8,19.9,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,4 68, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, or 500 mg / kg), including any and all ranges and subranges therein (e.g., 0.001 to 100 mg / kg, 0.01 to 75 mg / kg, 0.05 to 20 mg / kg, 0.1 to 10 mg / kg, etc.).

[0040] In one embodiment, the ursolic acid salt of the present invention is administered in an amount of 1 to 2,000 mg. (For example, 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 ,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,12 0,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151 ,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182 ,183,184,185,186187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,2 14,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,24 5,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415416,417,418,419,420,421,422,423,424,425,426,427,428,429,430431432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470471,472,473,474,475,476,477,478,479,480,481,482,483,484,485,486,487,488,489,490,491,492,493,494,495,496,497,498,499,500,1000,1010,1020,1030,1040,1050,1060,1070,1080,1090,1100,1110,1120,1130,1140,1150,1160,1170,1180,1190,1200,1210,1220,1230,1240,1250,1260,1270,1280,1290,1300,1310,1320,1330,1340,1350,1360,1370,1380,13901400,1410,1420,1430,1440,1450,1460,1470,1480,1490,1500,1510,1520,1530,1540,1550,1560,1570,1580,1590,1600,1610 ,1620,1630,1640,1650,1660,1670,1680,1690,1700,1710,1720,1730,1740,1750,1760,1770,1780,1790,1800,1810,1820,1830,1840,1850,1860,1870,1880,1890,1900,1910,1920,1930,1940,1950,1960,1970,1980,1990, or 2000 mg). It is understood that this range includes any and all ranges and subranges therein (e.g., 20-1900 mg, 50-1800 mg, 75-1700 mg, 100-1600 mg, etc.), and thus, in some embodiments where the ursolate salt is administered in a composition, the composition comprises such an amount of the compound.

[0041] In some embodiments, the ursolate is administered in an amount greater than 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg. EXAMPLES

[0042] The present invention is illustrated, but not limited, by reference to specific embodiments described in the following examples. Sample Preparation – Ursolic Acid Diethanolamine Salt [ka]

[0043] Ursolic acid (1.0450 g) and diethanolamine (208.6 mg) were dissolved in THF:MeOH (10:1), allowed to stand, then concentrated and dried to give ursolic acid diethanolamine salt (965.0 mg) as a white solid, which was used as ursolic acid diethanolamine salt in the following studies. Sample preparation – ursolic acid morpholine salt [ka]

[0044] Ursolic acid (1.0715 g) was dissolved in 20 mL of THF. Morpholine (224 mg) was added and stirred for 1.5 hours. 8 mL of hexane was added, resulting in a cloudy homogeneous solution. The salt was stirred at room temperature for 12 hours. No significant amount of salt was formed. The solution was concentrated in vacuum and the stirred residue gave a white powder, which was isolated by filtration and dried in vacuum to give ursolic acid morpholine salt (867.1 mg). This product was used as ursolic acid morpholine salt in the following studies.

[0045] Comparative study of grip strength for ursolic acid and its salts Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum feed on either standard chow (control) or standard chow supplemented with 0.050% ursolic acid, 0.200% ursolic acid, or one of its ursolic acid salts (ursolic acid-ethanolamine salt; ursolic acid-tris(hydroxymethyl)aminomethane salt (hereafter referred to as ursolic acid-"tris" salt); ursolic acid-lysine salt; ursolic acid-diethanolamine salt; ursolic acid-morpholine salt; or ursolic acid-piperazine salt). Ursolic acid-diethanolamine salt and ursolic acid-morpholine salt were prepared as described above. Ursolic acid is commercially available and was used as the starting material for the manufacture of other ursolic acid salts following techniques similar to those described above and known in the art. The dose of ursolate was molar-matched to either 0.050% ursolic acid (i.e., 0.057% ursolic acid-ethanolamine salt, 0.063% ursolic acid-tris salt, 0.066% ursolic acid-lysine salt, 0.059% ursolic acid-morpholine salt, 0.059% ursolic acid-piperazine salt) or 0.048% ursolic acid (i.e., 0.060% ursolic acid-diethanolamine salt). Grip strength was measured in vivo after the mice consumed these diets for 6 weeks. The results are shown in Table 1 below. Data are the mean ± SEM from 12 mice per cohort. **P<0.01 by one-way ANOVA with Dunnett's post-test. [Table 1]

[0046] As evidenced by the data from Table 1, not all salts of ursolic acid show a statistically significant improvement in grip strength. In fact, many may be less effective than the free acid at the same dose. Ursolic acid-diethanolamine salt and ursolic acid-morpholine salt were unexpectedly more potent and effective than ursolic acid itself and other ursolic acid salts.

[0047] Ursolic acid-morpholine salt - Grip strength, body weight and composition, and skeletal muscle fiber testing Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum consume either standard chow (control) or standard chow supplemented with 0.059% ursolic acid-morpholine salt. After the mice consumed these chow diets for 7 weeks in vivo, grip strength was measured in vivo, mice were weighed, body composition was assessed by NMR, and quadriceps muscles were dissected for histological analysis of skeletal muscle fiber cross-sectional diameter. Results are shown in Table 2 below. Body weight data, grip strength data, and NMR data (lean mass, fat mass, % lean, and % fat) are means ± SEM from 14-15 mice per cohort. Muscle fiber diameter data are means ± SEM from over 4200 muscle fibers per diet. *P<0.05; **P<0.01; ***P<0.001. [Table 2]

[0048] The data in Table 2 demonstrate that ursolic acid-morpholine salt stimulated skeletal muscle hypertrophy, increased lean body mass, and decreased fat mass.

[0049] Ursolic acid-morpholine salt-Skeletal muscle fiber size test Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum eat either standard chow (control) or standard chow supplemented with 0.059% ursolic acid-morpholine salt. After the mice consumed these diets for 7 weeks, quadriceps muscles were dissected, fixed, sectioned, stained with hematoxylin and eosin, and photomicrographed. Figure 1A is a photomicrograph of quadriceps skeletal muscle fibers in the control group. Figure 1B is a photomicrograph of quadriceps skeletal muscle fibers in the ursolic acid-morpholine salt group. Comparison of Figure 1A and Figure 1B shows that ursolic acid-morpholine salt increased skeletal muscle fiber size.

[0050] Ursolic acid-morpholine salt-adipocyte size test Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum eat either standard chow (control) or standard chow supplemented with 0.059% ursolic acid-morpholine salt. After the mice consumed these diets for 7 weeks, retroperitoneal fat pads were dissected, fixed, sectioned, stained with hematoxylin and eosin, and photographed under a microscope. Figure 2A is a micrograph of adipocytes in a retroperitoneal fat pad from the control group. Figure 2B is a micrograph of adipocytes in a retroperitoneal fat pad from the ursolic acid-morpholine salt group. Comparison of Figures 2A and 2B shows that ursolic acid-morpholine salt reduced adipocyte size.

[0051] Ursolic acid-morpholine salt-obesity and blood sugar testing Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum consume either a high-fat diet (control) or a high-fat diet supplemented with 0.059% ursolic acid-morpholine salt. Just prior to initiating these diets, mice were weighed and body composition analysis was performed by NMR. After the mice had been on the diets for 9 weeks, body weight and body composition were reassessed, retroperitoneal and epididymal fat pads were dissected and weighed, and fasting blood glucose was measured. Results are shown in Table 3 below. Data are mean ± SEM of 15 mice per cohort. *P<0.05; **P<0.01. [Table 3]

[0052] The data in Table 3 demonstrate, inter alia, that ursolic acid-morpholine salt reduced obesity in diet-induced obese mice.

[0053] Ursolic acid-morpholine salt-glucose tolerance test Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum access either high-fat chow (control) or high-fat chow supplemented with 0.059% ursolic acid-morpholine salt. After the mice had been on the diet for 8 weeks, they were fasted for 6 hours and subjected to a glucose tolerance test. The results are shown in Figure 3, which is a graph showing the glucose tolerance test. Data are the mean ± SEM of 15 mice per cohort. As can be seen from Figure 3, the area under the curve (AUC) of mice treated with ursolic acid-morpholine salt (31,383 ± 1,869) was significantly lower than the AUC of control mice (37,122 ± 1,339; P < 0.01), indicating that ursolic acid-morpholine salt significantly improved glucose tolerance (i.e., reduced glucose tolerance).

[0054] Ursolic acid-diethanolamine salt-body weight and composition test Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum consume either standard chow (control), standard chow supplemented with 0.060% ursolic acid-diethanolamine salt, or standard chow supplemented with 0.180% ursolic acid-diethanolamine salt. After the mice consumed these diets for 7 weeks, they were weighed and body composition was assessed by NMR. The results are shown in Table 4 below. Data are the mean ± SEM of 15 mice per cohort. *P<0.05. [Table 4]

[0055] The data in Table 4 demonstrate that ursolic acid-diethanolamine salt increases lean mass and decreases fat mass.

[0056] Head-to-head comparison of ursolic acid-morpholine salt with a molar-matched dose of ursolic acid in diet-induced obesity Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum consume either high-fat chow (control), high-fat chow supplemented with 0.050% ursolic acid, or high-fat chow supplemented with a molar-matched dose of ursolic acid-morpholine salt (0.059%). Just prior to initiating these diets, mice were weighed and subjected to body composition analysis by NMR. After mice had been on the diets for 8 weeks, body weight and body composition were reassessed, retroperitoneal and epididymal fat pads were dissected and weighed, and skeletal muscles (tibialis anterior, gastrocnemius, soleus, quadriceps, and triceps) were dissected and weighed. For each mouse, the total weight of dissected skeletal muscles (combined weight of tibialis anterior, gastrocnemius, abdominal, soleus, quadriceps, and triceps) was normalized to final body weight. Data are means ± SEM from 10 mice per cohort. Different letters indicate statistically significant differences (P<0.05 by one-way ANOVA with Tukey's post-hoc test). Results are summarized in Table 5. [Table 5]

[0057] Head-to-head comparison of ursolic acid-morpholine salt with a molar-matched dose of ursolic acid in glucose loading-induced obesity Weight-matched cohorts of 8-week-old male C57BL / 6 mice were randomized to ad libitum access to either high-fat chow (control), high-fat chow supplemented with 0.050% ursolic acid, or high-fat chow supplemented with a molar-matched dose of ursolic acid-morpholine salt (0.059%). After the mice had been on the diet for 7 weeks, they were fasted for 6 hours and subjected to a glucose tolerance test. The results are shown in Figure 4. Figure 4 is a graph showing the glucose tolerance test results. Data are the mean ± SEM from 10 mice per cohort. Fasting blood glucose in mice treated with ursolic acid-morpholine salt (140.6 ± 7.8 mg / dL) was significantly lower than that in mice treated with ursolic acid (166.3 ± 3.7; P < 0.01). Furthermore, the area under the curve (AUC) for mice treated with ursolic acid-morpholine salt (32,606 ± 2,471) was significantly lower than the AUC for mice treated with ursolic acid (40,585 ± 1,357; P < 0.01), indicating that ursolic acid-morpholine salt significantly reduced glucose tolerance compared with a molar-matched dose of ursolic acid.

[0058] As used herein, the terms "comprise" (and all forms thereof, such as "comprises" and "comprising"), "have" (and all forms thereof, such as "has" and "having"), "include" (and all forms thereof, such as "includes" and "including"), "contain" (and all forms thereof, such as "contains" and "containing"), and other grammatical variations are open linking verbs. As a result, a method or composition that "comprises," "has," "includes," or "contains" one or more steps or elements includes, but is not limited to, having, one or more of those steps or elements. Similarly, a method step or element in a sentence that "comprises," "has," "includes," or "contains" one or more features may possess one or more of those features, but is not limited to having only those one or more features.

[0059] As used herein, the terms "comprising," "has," "including," "containing," and other grammatical variations thereof, encompass the terms "consisting of" and "consisting essentially of."

[0060] As used herein, the term "consisting essentially of" or grammatical variations thereof is intended to specify the stated features, integers, steps, or components, but does not exclude the addition of one or more additional features, integers, steps, components, or groups thereof, provided that the additional features, integers, steps, components, or groups thereof do not materially alter the basic and novel characteristics of the claimed composition or method.

[0061] Where one or more ranges are recited throughout this specification, each range is intended to be a shorthand form of presenting information: the range will be understood to include each individual point within the range, as if each individual point were fully set forth herein.

[0062] While several aspects and embodiments of the present invention have been described and illustrated herein, alternative aspects and embodiments may be devised by those skilled in the art for accomplishing the same purposes, and it is therefore intended that this disclosure and the appended claims cover all such further and alternative aspects and embodiments that are within the true spirit and scope of the invention.

Claims

1. Ursolate, which is morpholine salt of ursolic acid.

2. A composition comprising the salt of claim 1 and an additional agent.

3. The composition of claim 2 comprising 25 to 1,500 mg of said salt.

4. The composition of claim 2 comprising 50 to 1,000 mg of said salt.

5. The composition of claim 2, wherein the additional agent comprises a physiologically acceptable carrier.

6. The composition of claim 2 , wherein the composition is a pharmaceutical composition, a nutritional composition, a food composition, or a dietary supplement.

7. The composition of claim 6 comprising 25 to 1,500 mg of said salt.

8. In non-human subjects, (i) increasing skeletal muscle mass; (ii) treating skeletal muscle atrophy; (iii) treating sarcopenia; (iv) treating cachexia; (v) increasing strength; (vi) treating frailty; (vii) improving athletic performance; (viii) treating fatigue; (ix) promoting muscle growth; (x) promoting normal muscle function; (xi) improving muscle function; (xii) promoting muscle health; (xiii) promoting healthy aging of muscle; (xiv) increasing energy expenditure; (xv) increasing the skeletal muscle to fat ratio; (xvi) reducing fat; (xvii) treating obesity; (xviii) treating diabetes; (xix) reducing blood glucose levels; (xx) treating prediabetes; (xxi) treating metabolic syndrome; (xxii) treating insulin resistance; (xxiii) reducing plasma cholesterol; (xxiv) treating hypercholesterolemia; (xxv) reducing plasma triglycerides; (xxvi) treating hypertriglyceridemia; (xxvii) promoting a healthy metabolism; (xxviii) promoting metabolic health; 1. A method for performing The method comprises administering to the subject an effective amount of the salt of claim 1.

9. 9. The method of claim 8, comprising administering to a subject a composition comprising 25 to 1,500 mg of the salt.

10. 10. The method of claim 9, wherein the subject is a non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, hamster, ferret, fish, bird, or rodent.

11. (i) increasing skeletal muscle mass; (ii) treating skeletal muscle atrophy; (iii) treating sarcopenia; (iv) treating cachexia; (v) increasing strength; (vi) treating frailty; (vii) improving athletic performance; (viii) treating fatigue; (ix) promoting muscle growth; (x) promoting normal muscle function; (xi) improving muscle function; (xii) promoting muscle health; (xiii) promoting healthy aging of muscle; (xiv) increasing energy expenditure; (xv) increasing the skeletal muscle to fat ratio; (xvi) reducing fat; (xvii) treating obesity; (xviii) treating diabetes; (xix) reducing blood glucose levels; (xx) treating prediabetes; (xxi) treating metabolic syndrome; (xxii) treating insulin resistance; (xxiii) reducing plasma cholesterol; (xxiv) treating hypercholesterolemia; (xxv) reducing plasma triglycerides; (xxvi) treating hypertriglyceridemia; (xxvii) promoting a healthy metabolism; (xxviii) promoting metabolic health; 2. Use of an effective amount of the salt of claim 1 in a non-human subject in need thereof.

12. In the subject, (i) increasing skeletal muscle mass; (ii) treating skeletal muscle atrophy; (iii) treating sarcopenia; (iv) treating cachexia; (v) increasing strength; (vi) treating frailty; (vii) improving athletic performance; (viii) treating fatigue; (ix) promoting muscle growth; (x) promoting normal muscle function; (xi) improving muscle function; (xii) promoting muscle health; (xiii) promoting healthy aging of muscle; (xiv) increasing energy expenditure; (xv) increasing the skeletal muscle to fat ratio; (xvi) reducing fat; (xvii) treating obesity; (xviii) treating diabetes; (xix) reducing blood glucose levels; (xx) treating prediabetes; (xxi) treating metabolic syndrome; (xxii) treating insulin resistance; (xxiii) reducing plasma cholesterol; (xxiv) treating hypercholesterolemia; (xxv) reducing plasma triglycerides; (xxvi) treating hypertriglyceridemia; (xxvii) promoting a healthy metabolism; (xxviii) promoting metabolic health; 2. Use of an effective amount of the salt of claim 1 for the manufacture of a medicament for treating

13. 2. The compound according to claim 1 , (i) increasing skeletal muscle mass; (ii) treating skeletal muscle atrophy; (iii) treating sarcopenia; (iv) treating cachexia; (v) increasing strength; (vi) treating frailty; (vii) improving athletic performance; (viii) treating fatigue; (ix) promoting muscle growth; (x) promoting normal muscle function; (xi) improving muscle function; (xii) promoting muscle health; (xiii) promoting healthy aging of muscle; (xiv) increasing energy expenditure; (xv) increasing the skeletal muscle to fat ratio; (xvi) reducing fat; (xvii) treating obesity; (xviii) treating diabetes; (xix) reducing blood glucose levels; (xx) treating prediabetes; (xxi) treating metabolic syndrome; (xxii) treating insulin resistance; (xxiii) reducing plasma cholesterol; (xxiv) treating hypercholesterolemia; (xxv) reducing plasma triglycerides; (xxvi) treating hypertriglyceridemia; (xxvii) promoting a healthy metabolism; (xxviii) promoting metabolic health; A pharmaceutical composition for

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