Capsaicin as a physical performance aid

Abstract

The present invention relates to synthetic capsaicin, its tautomers, or salts for enhancing physical performance and / or reducing or delaying mechanical fatigue. More specifically, the present invention provides compositions comprising synthetic capsaicin of formula (I) provided as a sports dietary supplement, and the use of capsaicin compounds or compositions for improving training performance, accelerating recovery, and / or reducing or delaying mechanical fatigue. Furthermore, the present invention provides compositions comprising capsaicin for use in the treatment of diseases or indications related to physical weakness or energy deficiency, as well as methods for using the compounds and compositions.

Description

Technical Field

[0001] The present invention relates to synthetic capsaicin and compositions containing such capsaicin for enhancing the physical performance of a subject and / or reducing or delaying mechanical fatigue. More particularly, the present invention provides a composition containing synthetic capsaicin of formula (I) provided as a sports diet supplement, the use of a compound or composition for improving the training performance of a subject, promoting the acceleration of recovery and / or reducing or delaying mechanical fatigue. Further provided are compositions containing capsaicin for use in the treatment of diseases or conditions associated with physical weakness or energy deficiency, and methods for using the compounds and compositions.

Background Art

[0002] Sports supplements are common ergogenic aids among athletes, aimed at maximizing performance in sports tasks. Recent sports nutrition research has focused on the discovery of new bioactive compounds that may be able to improve high-intensity training in various aspects. Thus, research related to the effects of capsinoids in resistance training has grown in recent years, as shown by de Freitas et al., Acute Capsaicin Supplementation Improves Resistance Training Performance in Trained Men. J Strength Cond Res. 2018; 3:2227-2232. Capsinoids are a group of compounds naturally found in hot peppers, characterized by their vanilloid structure. Capsaicin (8-methyl-N-vanillyl-trans-6-nonenamide), found in the placental tissue of the fruit of the Capsicum genus, has emerged as the main and most abundant capsinoid with therapeutic and physical performance relevance.

[0003] As a transient receptor vanilloid 1 (TRPV1) agonist, a plausible resistance-training ergogenic mechanism underlying capsaicin is the increase in calcium released by the sarcoplasmic reticulum and its thermoanalgesic effect. Therefore, in high-intensity tasks, afferent nerve fibers III and IV are associated with peripheral and central fatigue. These small-diameter myoafferent nerves contribute to sensory responses during movement that can lead to discomfort, increased perceived exertion (RPE), and neuromuscular fatigue. Since these fibers directly or indirectly reduce motor neuron firing and motor unit recruitment, their TRPV1 content (primarily in group IV afferent nerves) has been proposed as a physical performance target. On the other hand, while capsaicin's TRPV1 activity may be related to its characteristic spiciness, encapsulated capsaicin does not have an immediate spiciness. However, a previous study, Opheim MN and Rankin JW. Effect of Capsaicin Supplementation on Repeated Sprinting Performance. J Strength Cond Res. 2012;26:319-26, reported intestinal discomfort after high-dose oral encapsulated capsaicin supplementation (25.8 mg).

[0004] To date, capsaicinoid supplementation for sports performance has been tested under oral capsaicin supplementation; see Jimenez-Martinez P. et al., Effects of oral capsaicinoids and capsinoids supplementation on resistance and high intensity interval training: A systematic review of randomized controlled trials. J HumSportExer. 2022. Purified acute (i.e., 45 minutes prior to exercise) oral capsaicin supplementation resulted in improved performance in upper and lower limb resistance training tasks. Thus, de Freitas et al., in a double-blind, randomized, placebo-controlled trial, showed that acute 12 mg capsaicin supplementation significantly increased the number of repetitions to failure and total lifted mass, and reduced generalized perceived exertion-observed (RPE-OB) in squat exercises with an unmatched volume design. In contrast, lower doses of purified capsaicin (i.e., 1.2 mg in gummy form) did not show significant differences in total torque during isokinetic knee extension or fatigue index in randomized, double-blind, controlled trials, as demonstrated by Cross BL et al., Effect of a Commercially Available Low-Dose Capsaicin Supplement on Knee Extensor Contractile Function. 2020;7. Furthermore, while velocity-based training has been proposed as an objective method for resistance training by reflecting the state of the neuromuscular system that generates force in response to load, the only study, da Silva BVC et al., Acute Supplementation with Capsaicin Enhances Upper-Limb Performance in Male Jiu-Jitsu Athletes. Sports. 2022;10:120, demonstrated the effect of capsaicin on velocity variables in resistance training.Furthermore, studies addressing the effects of capsaicinoids on velocity-related performance have reported only on upper limb movements and not at all on lower limb activity (i.e., squats), see da Silva and Jimenez-Martinez P.

[0005] Therefore, there is a need for alternative compounds and compositions for use as sports supplements, and for positively influencing the target sports performance and / or reducing or delaying mechanical fatigue. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] European Patent 1670310B1 [Non-patent literature]

[0007] [Non-Patent Document 1] de Freitas et al., Acute Capsaicin Supplementation Improves Resistance Training Performance in Trained Men. J Strength Cond Res. 2018; 32:2227~32 [Non-Patent Document 2] Opheim MN, Rankin JW. Effect of Capsaicin Supplementation on Repeated Sprinting Performance. J Strength Cond Res. 2012;26:319~26 [Non-Patent Document 3] Jimenez-Martinez P. et al., Effects of oral capsaicinoids and capsinoids supplementation on resistance and high intensity interval training: A systematic review of randomized controlled trials. J HumSportExer. 2022 [Non-Patent Document 4] Cross BL et al., Effect of a Commercially Available Low-Dose Capsaicin Supplement on Knee Extensor Contractile Function. 2020;7 [Non-Patent Document 5] da Silva BVC et al., Acute Supplementation with Capsaicin Enhances Upper-Limb Performance in Male Jiu-Jitsu Athletes. Sports. 2022;10:120 [Non-Patent Document 6] EFSA Panel on Nutrition, Novel Foods and Food Allergens (EFSA NDA Panel), Turck D et al., Safety of phenylcapsaicin as a novel food pursuant to Regulation (EU) 2015 / 2283. EFSA J [Internet]. 2019. [Non-Patent Document 7] www.randomizer.org [Brief explanation of the drawing]

[0008] [Figure 1]This graph shows the results from Example 1, a study evaluating the ergogenic effect of phenylcapsaicin (PC), displaying individual (point) and average (bar) values ​​for (a) RPE-OB, generalized subjective exercise intensity, (b) RPE-AM, subjective exercise intensity of active muscles, and (c) PRS, subjective recovery status, for three different supplementation conditions. [Figure 2] This graph shows the results from Example 2, a study evaluating the ergogenic effect of phenylcapsaicin (PC), showing (a) pre- and post-test CMJ levels and CMJ 24 hours after testing, (b) the percentage difference of CMJ before and after testing, and (c) the individual (point) and average (bar) values ​​of the percentage difference of CMJ before and 24 hours after testing for three different supplementation conditions. [Figure 3] This graph shows the mean propulsion velocity (MPV) in individual and intra-set comparisons of phenylcapsaicin (PC) under different supplementation conditions (PLA, HD, LD) in Example 2. [Overview of the project] [Means for solving the problem]

[0009] The inventors have discovered that a group of synthetic capsaicins have ergogenic effects, and that supplementation with such capsaicins before physical exercise can enhance performance, accelerate post-exercise recovery, and reduce or delay mechanical fatigue.

[0010] The present invention provides compositions comprising a compound of formula (I) or its tautomers or salts for enhancing the physical performance of a subject, accelerating recovery, and / or reducing or delaying mechanical fatigue.

[0011] [ka]

[0012] (wherein R is alkyl, trifluoromethyl, cycloalkyl, phenyl, or halogen, and when the substituent R contains a carbon chain, it is linear or branched and is alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, aminoalkylthio, arylthio, cyano, cycloalkyl, cycloalkenyl, halo, hydroxy, oxo, nitro, or trifluoromethyl, optionally further substituted).

[0013] In another aspect, the present invention provides a composition provided in a unit dosage form of, for example, 0.5 to 4.0 mg of a compound of formula (I), formulated as a sports diet supplement containing the compound of formula (I).

[0014] In yet another aspect, the present invention relates to the use of a compound of formula (I) for enhancing physical performance during exercise and / or reducing or delaying mechanical fatigue of a subject, wherein the compound is administered to the subject before exercise or the like. The compound of formula (I) may be used in a composition.

[0015] In yet another aspect, the present invention relates to a composition comprising a compound of formula (I) for use in the treatment of a subject suffering from or recovering from a disease or condition associated with physical weakness or energy deficiency such as chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME) or ME / CFS.

Mode for Carrying Out the Invention

[0016] Unless otherwise defined, all technical terms, notations and other scientific or technical terms used herein are intended to have the meaning generally understood by those skilled in the art to which the present invention pertains. In some cases, terms having a generally understood meaning are defined herein for the sake of clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is generally understood in the art.

[0017] There is a need for a nutritional composition that can improve high-intensity training and enhance mechanical performance, such as having a beneficial effect on training performance, perceived exercise intensity, muscle damage, proteolysis, perceived fatigue, and recovery after training, etc.

[0018] In recent years, synthetic analogs containing phenylcapsaicin (PC) have emerged as a valid alternative to traditional oral purified capsaicin supplementation. See EFSA Panel on Nutrition, Novel Foods and Food Allergens (EFSA NDA Panel), Turck D et al., Safety of phenylcapsaicin as a novel food pursuant to Regulation (EU) 2015 / 2283. EFSA J [Internet]. 2019 [cited September 14, 2022].

[0019] The applicant of the present application has surprisingly found that certain synthetically produced capsaicin analogs containing phenylcapsaicin can have a positive effect on the sports performance of a subject and can promote the acceleration of recovery after exercise, including reducing or delaying mechanical fatigue.

[0020] Therefore, the present invention relates to a synthetic compound and a composition containing the compound that are safe and effective for maintaining or enhancing sports performance in mammals in general, particularly in human subjects. The compound or composition can be advantageously used alone in a human subject or in combination with any diet and / or therapy for supporting, restoring or enhancing training performance and endurance. Therefore, the present invention as a whole relates to a composition effective for maintaining or enhancing physical performance in a human subject.

[0021] The composition of the present invention comprises at least one compound of formula (I)

[0022]

Chemical formula

[0023] (wherein R is alkyl, trifluoromethyl, cycloalkyl, phenyl, or halogen), or a tautomer thereof or a salt thereof.

[0024] If the substituent R comprises a carbon chain, it may be linear or branched and optionally further substituted with alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, aminoalkylthio, arylthio, cyano, cycloalkyl, cycloalkenyl, halo, hydroxy, oxo, nitro, or trifluoromethyl.

[0025] If R contains a carbon chain, the carbon chain may preferably be alkyl. The carbon chain may have a length of 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. More preferably, R may be isopropyl, C4 alkyl, or preferably phenyl. Therefore, compounds in which R is phenyl are called phenylcapsaicin.

[0026] In one embodiment, the compound of formula I is selected from the group consisting of methyl capsaicin, ethyl capsaicin, propyl capsaicin, butyl capsaicin, and phenyl capsaicin. In one embodiment, the compound is phenyl capsaicin.

[0027] Thus, the compound of formula (I) is called R-capsaicin. It is important to note the structural differences between capsaicin, a chili pepper analog, and R-capsaicin. First, capsaicin contains a double bond instead of the triple bond present in R-capsaicin. Therefore, the suffixes -in and -yn are different. Thus, the substituent R is not a substituent at the end of the capsaicin molecule, but a substituent at the end of an analog that may have different properties from capsaicin. The applicant's European Patent 1 670 310 B1 discloses how R-capsaicin can be synthesized and produced, and thus avoids the limitations and drawbacks of extracting the compound from natural products and raw materials.

[0028] Accordingly, the present invention provides a compound of formula (I), a composition containing the same, and its use as an ergogenic aid, thereby enhancing physical performance, stamina, and / or reducing subjective fatigue.

[0029] The compositions of the present invention can be advantageously used to enhance physical performance, accelerate recovery, and / or reduce or delay mechanical fatigue. In one embodiment, the present invention provides a compound of formula (I) for enhancing physical performance and / or reducing or delaying mechanical fatigue. Alternatively, the use of a compound of formula (I) for enhancing the physical performance of a subject, accelerating recovery, and / or reducing or delaying mechanical fatigue is provided, wherein the compound is administered to the subject. Preferably, the compound of formula (I) is contained in a composition formulated for administration to a human subject.

[0030] This invention is based in part on findings from research conducted by the applicant. Two such studies, detailed in Examples 1 and 2, provide an evaluation of the ergogenic effects of two different doses of phenylcapsaicin. Velocity-based training has been proposed as an objective method to resistance training by reflecting the state of the neuromuscular system that generates force in response to a load, but the only previous study by da Silva BVC et al. drew out the effect of capsaicin on velocity variables in resistance training. Furthermore, as mentioned, the effect of capsaicinoids on velocity-derived performance has only been reported for upper limb exercises and not at all for lower limb activity (i.e., squat exercises). Variables of acute muscle injury, proteolysis, and recovery have not been previously measured after capsaicin supplementation. Since strenuous exercise can acutely and chronically increase metabolic, biochemical, and neuromuscular fatigue, it may also be relevant to investigate the biochemical, sensory, and neuromuscular effects of capsaicin and capsaicinoids on these topics. Therefore, the objective of this study was to investigate the effects of synthetic capsaicin on lower limb performance, metabolic response to exercise, acute biochemical muscle injury and protein breakdown, generalized perceived exercise intensity (RPE-OB), perceived exercise intensity of active muscles, and perceived recovery in resistance-trained men during speed-based controlled squat exercises.

[0031] The study provides evidence-supported ergogenic effects of phenylcapsaicin. More specifically, Example 1 supports the fact that the compound of Formula I, when administered before exercise, can enhance performance, reduce muscle damage, reduce protein breakdown, and decrease perceived exertion and recovery time. Example 2 supports the fact that the compound of Formula I, when administered before exercise, can exert a positive effect on mechanical dynamic performance, increase neural activity during dynamic resistance training, and reduce acute mechanical fatigue. Phenylencapsaicin intake may also be considered an anti-fatigue ergogenic aid, and post-exercise mechanical fatigue may be delayed.

[0032] Exercises that can enhance performance are typically physical training, particularly intense physical activities such as high-intensity training, resistance training, speed-based training, high-volume training, dynamic resistance training, or interval training.

[0033] Capsaicin of formula I and compositions containing it enhance physical performance by affecting, or manifesting as, one or more of the following: Resistance training performance: For example, improving performance measured in squat exercises, velocity-load assessment, and maximum repetitions (RM), such as the number of repetitions before failure to lift, total lifted mass, force, or power generation; Mechanical and dynamic performance: For example, isometric and / or dynamic performance, such as force generation, velocity-derived performance as a velocity variable like the speed of movement, reduction of movement speed, and positive effects on the distance of movement, as measured in squat exercises, countermovement jumps (CMJ), and isometric squats. Muscle damage: Reduces biomedical muscle damage by measuring aspartate aminotransferase (AST) levels in the subject's blood, for example, as lower post-training AST levels, such as 24 hours after training, compared to a subject who took a placebo; Metabolic response: for example, by reducing post-test lactate blood levels, which may be measured as a metabolic indicator of exercise intensity; Protein breakdown: For example, by lowering the level of urea in the blood as a measure of systemic protein breakdown. Neuromuscular fatigue: Average propulsion power, average propulsion force, and velocity decrease may be measured, for example, as indicators of neuromuscular fatigue in squat exercises. Neuronal excitability and recovery; improving recovery outcomes, shortening recovery time, especially mechanical recovery outcomes. It reduces subjective fatigue by influencing neuromuscular activity, delaying the effects of training on neuromuscular fatigue, and mitigating acute and / or post-exercise mechanical fatigue.

[0034] Therefore, the use of a compound of Formula I or a composition containing the same has a positive effect on any of the following: resistance training performance or mechanical dynamic performance, muscle injury, metabolic response, proteolysis, neuromuscular fatigue, neuronal excitability, or neuromuscular activity, including enhancing physical performance and accelerating recovery and / or reducing recovery time.

[0035] More specifically, the following in vivo parameters may be affected: • Lactate level: An indicator of metabolic stress and exercise intensity. • Urea levels: Reflect protein breakdown and muscle metabolism. • Aspartate aminotransferase (AST) levels: Used as a marker for muscle injury and post-exercise recovery.

[0036] In one embodiment, the use of a compound of formula I or a composition containing the same results in one or more of the following effects on the blood of a subject: a decrease in the level of aspartate aminotransferase (AST), a decrease in the level of urea, or a decrease in the level of lactate, thereby enhancing physical performance during exercise and / or reducing or delaying mechanical fatigue after exercise. As detailed in Examples 1 and 2, supplementation with two different doses of the compound phenylcapsaicin before exercise resulted in a decrease in the blood levels of AST, urea, and lactate of the subject after exercise, thereby enhancing physical performance.

[0037] The discovery of these previously unknown properties of the compound of formula I, which result in the novel technical effects described above, clearly represents a valuable and inventive contribution to the art.

[0038] In one embodiment, the effect manifests as a reduction in the perceived exertion of the active muscle, an increase in mechanical performance, or a reduction in muscle damage or protein breakdown. Furthermore, the effect may manifest as an increase in velocity, force and / or power generation, particularly as an increase in velocity, measured, for example, as mean propulsion velocity (MPV). In one embodiment, the performance improvement takes the form of an improvement in force and / or power generation.

[0039] In relation to the first study, Example 1, we hypothesized that capsaicin of formula I might exert a dose-response positive effect on speed performance and perceived exertion (RPE), and this was indeed found. However, an accompanying increase in perceived fatigue, protein breakdown, and muscle damage due to the increased physical performance after supplementation was also anticipated. With higher doses, it was anticipated that recovery impairment, as well as higher muscle and protein damage, would be even more pronounced. Surprisingly, the results of the study suggest that high-dose (2.5 mg) phenylcapsaicin supplementation taken 45 minutes before exercise can indeed increase performance, but can also reduce muscle damage (decreased AST), reduce protein breakdown (decreased urea), and reduce peripheral perceived exertion, demonstrating a mechanical anti-fatigue effect on trained subjects. Using perceived recovery status to make subjective fatigue and recovery assessments, as shown in Figure 1c), the compound of formula I can also promote accelerated post-exercise recovery. Therefore, these new findings are valuable, at least because capsaicinoids have never been evaluated before in relation to muscle damage, protein breakdown, and peripheral fatigue.

[0040] The human subjects according to the present invention may be healthy and physically active individuals, or conversely, individuals suffering from or recovering from a disease. In this context, “healthy and physically active individuals” means human subjects with good physical health, i.e., individuals who have physical functions that do not deviate significantly from their peak, but do not significantly deviate from their peak, which affects the individual’s overall physical, mental, and social well-being, particularly processes related to bodily function and musculoskeletal activity, and who perform tasks normally. In a preferred embodiment, a healthy and physically active individual is a human subject who has regular periods of intense physical activity requiring significant energy expenditure, such as an athlete or other subject who exercises to improve their physical performance. The use of a compound of formula (I) or a composition containing the same can help such individuals repair, maintain, and / or enhance physical performance, and / or reduce or delay the perceived fatigue of exercise. The state of fatigue induced by exercise performance is a temporary physiological state caused by natural circumstances and can be eliminated by mere rest. Simple training is generally known to delay the perception of fatigue. The use of compounds of formula (1) results in enhanced performance during exercise and / or a reduction or delay of fatigue, which is a physiological state caused by natural circumstances. Therefore, the preferred use of compounds of formula (1) is non-therapeutic.

[0041] In one embodiment, the human subject according to the present invention is an individual suffering from or recovering from a disease, or having signs associated with an acute or chronic medical condition related to physical weakness or energy deficiency. An example of a related disease is chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME) or ME / CFS. In one embodiment, the condition is asthenia. CFS is a complex condition characterized by persistent and debilitating fatigue that does not improve with rest and may be aggravated by physical or mental exertion. Patients with CFS / ME often experience a variety of symptoms, including muscle pain, sleep disturbances, cognitive impairment, and post-exertional fatigue, which is an exacerbation of symptoms after physical or mental activity. Currently, there is no specific medicine that can cure CFS / ME, but some treatments may help alleviate symptoms and improve quality of life. For medical treatment, compositions comprising at least one compound of formula (I) for use in the treatment of diseases selected from the group consisting of chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), and ME / CFS, which are administered to subjects suffering from or recovering from the disease.

[0042] One possible approach to help patients with CFS / ME is to improve their physical performance and recovery. In one embodiment of the present invention, the composition of the present invention is for subjects having CFS. Generally, treatment can be achieved by using pharmaceuticals that target metabolic pathways in the body. For example, some pharmaceuticals used to treat metabolic disorders such as type 2 diabetes or mitochondrial disorders have been shown to improve physical performance and recovery in some patients. One such pharmaceutical is metformin, which is commonly used to treat type 2 diabetes. Metformin works by reducing the amount of glucose produced by the liver and improving insulin sensitivity, resulting in improved energy metabolism. Some studies have shown that metformin improves physical performance in healthy individuals and in humans with metabolic disorders. Another pharmaceutical that may be helpful for patients with CFS / ME is coenzyme Q10 (CoQ10). CoQ10 is a naturally occurring substance that plays a vital role in energy production in the body. Studies have shown that CoQ10 supplementation can improve physical performance and reduce symptoms in patients with metabolic disorders, and some evidence suggests that it may also be beneficial for patients with CFS / ME. In addition, pharmaceuticals that improve mitochondrial function, such as nicotinamide adenine dinucleotide (NAD+) precursors, may also be beneficial for patients with CFS / ME. NAD+ plays a crucial role in energy production in the body and is involved in many metabolic pathways. Some studies have shown that NAD+ precursors can improve mitochondrial function and physical performance in healthy individuals and humans with metabolic disorders. Pharmaceuticals that improve physical performance and recovery, such as the compositions of the present invention, may be expected to improve symptoms and quality of life in patients with CFS / ME.

[0043] The compound of formula (I) may be included in the composition at concentrations that produce the disclosed effects. The concentrations of the compound of formula (I), provided by parts per million (ppm), are, for example, 1 to 500 ppm, 5 to 250 ppm, 10 to 100 ppm, 10 to 75 ppm, 10 to 50 ppm, 5 to 50 ppm, and 1 to 50 ppm, but are not limited to these. Selecting an appropriate amount to be incorporated into the composition is a routine task. Those skilled in the art can do so without undue burden. In one embodiment, the composition of the present invention contains the compound of formula I, for example phenylcapsaicin, at a concentration of 70.0 to 100 wt%, for example 90.0 to 100 wt%, preferably 97.0 to 100% of the composition. In the study of Example 1, a composition containing 98 wt% phenylcapsaicin was used.

[0044] The composition may further contain one or more of any conventionally acceptable excipients and / or carriers, such as solvents, fillers, diluents, binders, lubricants, viscosity modifiers, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, buffers, pH adjusters, absorption retarders, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, auxiliary agents, sweeteners, fragrances, and colorants. Conventional formulation techniques known in the art, such as conventional mixing, dissolution, suspension, granulation, sugar coating, polishing, emulsification, encapsulation, sealing, or pressurization processes, may be used to formulate the composition.

[0045] In one embodiment, the composition includes, for example, an excipient for encapsulating capsaicin. For example, the compound of formula I may be encapsulated so as to be provided in the form of microencapsulated capsaicin, using, for example, an encapsulation material, such as cellulose and / or a lipid excipient, as a primary vesicle. Microencapsulation may result in less irritation, less gastrointestinal mucosal irritation, and potentially higher bioavailability. For example, the composition is provided in the form of an encapsulated compound of formula I, containing the excipient at a concentration of 0 to 3.0 wt%, for example, 0.5 to 2.0 wt%.

[0046] The compositions of the present invention may be formulated as supplements or, depending on the use and recipient, as pharmaceutical compositions. These formulations contain effective amounts of the essential components of the compositions of the present invention in appropriate molar ratios. The formulations can be prepared according to standard rules and procedures established in the corresponding art. The supplements include, but are not limited to, at least one of dietary supplements, nutritional supplements, dietary supplements, commercial supplements, and / or pharmaceutical-grade supplements.

[0047] In one embodiment, the present invention provides a novel composition comprising a compound of formula I disclosed above, for example, in the form of a sports diet supplement. The composition may be formulated as a powder, granules, tablets, capsules, aerosol inhalation preparation, or as a drink or beverage. In one embodiment, the composition is a nutritional supplement. The composition in the form of a powder or granules may be further included in or used in food such as a drink or bar. In one embodiment, the composition is formulated in the form of a sports food or sports beverage such as a sports drink, energy drink, sports bar, or energy bar. In one embodiment, the composition is formulated as a sports diet supplement.

[0048] Furthermore, in addition to the compound of formula (I), the composition may further contain one or more components that act synergistically with the compound of formula (I), such as phenylcapsaicin, in order to enhance its effects on physical performance and recovery. In one embodiment, one or more components are selected from the group consisting of adaptogens, amino acids, antioxidants, electrolytes, energy boosters, and creatine.

[0049] More specific examples of ingredients that may be included in the composition are as follows: Adaptogen: Rhodiola rosea or ashwagandha, which can help improve endurance and recovery. Amino acids: Specifically, branched-chain amino acids (BCAAs) or L-arginine, which support muscle recovery and nitric oxide production. Antioxidants: Compounds such as vitamins C and E, or quercetin, that reduce oxidative stress and support recovery. Electrolytes: Potassium, magnesium, and sodium for hydration and muscle function. Energy Booster: Natural caffeine derived from green tea or guarana for increased energy and concentration. Creatine: Enhances the ability of compositions to improve physical performance, muscle strength, and recovery.

[0050] In one embodiment, the composition is a nutritional supplement such as a sports diet supplement, comprising a compound of formula (I) and further comprising one or more components selected from the group consisting of adaptogens, amino acids, antioxidants, electrolytes, energy boosters, and creatine.

[0051] Preferably, the route of administration is oral, sublingual, inhaled, intestinal, and / or rectal. More preferably, the route of administration is oral. The advantage of oral administration is its low level of invasiveness, causing less stress to the subject than more invasive routes of administration such as parenteral administration. In some embodiments, the compound of formula (I) or a composition containing the same is administered orally. In some embodiments, it is administered with or before a meal. The compound or composition may be formulated as appropriate, preferably for oral administration, or for inhalation instead.

[0052] The applicant found that administering capsaicin of formula (I) in a tolerable and safe dose prior to physical activity had a positive effect on the subject's performance. This is in comparison to previous studies using natural capsaicin (8-methyl-N-vanillyl-trans-6-nonenamide), such as the study by de Freitas et al., which showed limited effects despite the use of high doses of 12 mg.

[0053] Therefore, the advantage of the composition is the reduction in the amount of active substance required to achieve the desired results compared to the amount required in the absence of the composition.

[0054] The compound or composition is administered to the subject in an effective dose according to the present invention. As used herein, the term “effective dose” means the amount of the compound according to the present invention that is effective in producing the desired effect on performance. The effective dose may vary depending on the route of administration and dosage form. The appropriate dose may depend on the compound used, the stage of the condition, the patient’s age and weight, etc., and can be routinely determined by those skilled in the art according to principles well known in the art. A suitable daily dose of the compound according to the present invention may be in the range of about 0.01 mg / kg body weight to 1.0 mg / kg body weight. For example, in some embodiments, the daily dose may be 0.01 to 0.1 mg / kg body weight, e.g., 0.01 to 0.05 mg / kg body weight, e.g., 0.03 to 0.08 mg / kg body weight, e.g., 0.05 to 0.1 mg / kg body weight. In other embodiments, the daily dose may be 0.05 to 0.5 mg / kg body weight, e.g., 0.05 to 0.02 mg / kg body weight, e.g., 0.08 to 0.5 mg / kg body weight. In yet another embodiment, the daily dose, or single dose used in conjunction with exercise, may be 0.5 mg to 4.0 mg, for example, 0.625 mg or 2.5 mg. In one embodiment, the compound of formula I is provided in a composition presented as a single dose unit of the compound of formula I, for example, containing 0.5 to 4.0 mg of the compound of formula I, for example, 0.5 mg, 0.625 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, or 4.0 mg of the compound of formula I.

[0055] For optimal effect, the compound of formula I or a composition containing it should be administered to the subject before physical activity, and not too far in advance. In one embodiment, the subject should be administered the compound or composition up to 60 minutes before exercise, for example, 10 to 60 minutes before exercise, most preferably 30 to 50 minutes before exercise. In one embodiment, the subject ingests the compound or composition by oral ingestion or the like. Subsequent exercise performance is enhanced compared to the subject's physical performance during physical exercise in the absence of administration of compound I.

[0056] In another aspect, the present invention provides the use of a composition comprising a compound of formula (I) disclosed above in a human subject, thereby enhancing physical performance during exercise and / or reducing or delaying mechanical fatigue, wherein the composition is administered to the subject before exercise.

[0057] In yet another aspect, the present invention provides a method for non-therapeutic enhancement of the physical performance of a subject and / or reduction or delay of mechanical fatigue, wherein a composition comprising a compound of formula (I) is administered before exercise.

[0058] In yet another embodiment, the present invention provides compositions comprising at least one compound of formula (I) for use in the medical treatment of subjects suffering from or recovering from a disease or indication related to physical weakness or energy deficiency, such as chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), or ME / CFS, wherein use comprises the step of administering a compound of formula (I) or a composition comprising a compound of formula (I) to a subject. Alternatively, for non-therapeutic use, compositions of the present invention may be advantageously used, for example, by subjects recovering from a disease or condition, or by subjects affected by physical injury or environmental or physiological stressors. In one embodiment, use is for the treatment of asthenia, for example, to improve the symptoms and quality of life of a subject having any of these indications by improving physical performance, recovery, or reducing or delaying fatigue. In one embodiment, use is for preventing or reducing asthenia. Similarly, the present invention provides a method for treating subjects suffering from or recovering from a disease or indication related to physical weakness or energy deficiency, such as chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME) or ME / CFS, or asthenia, the use of which enhances performance and / or reduces or delays mechanical fatigue, and a composition comprising a compound of formula (I) is administered to the subject.

[0059] Those skilled in the art are familiar with how to produce and manufacture suitable compositions in accordance with Good Manufacturing Practices (GMP). Those skilled in the art can handle standard processes for producing stable formulations and compositions.

[0060] In the context of one embodiment, for example, embodiments and features described in relation to a compound of formula (I) or a composition containing the same apply to other embodiments of the present invention in terms of use or method thereof. Accordingly, the variants and active substance options and combinations of the compound disclosed in one embodiment also apply to other embodiments.

[0061] The present invention is not limited to the embodiments and examples shown. While various embodiments of the Disclosure are described herein, it will be obvious to those skilled in the art that such embodiments are provided merely as examples. Numerous modifications and changes, as well as variations and substitutions, to the embodiments described herein will be apparent to those skilled in the art without departing from the Disclosure. It should be understood that various alternatives to the embodiments described herein may be used in the practice of the Disclosure.

[0062] It should be understood that all embodiments of this disclosure may be optionally combined with any one or more of the other embodiments described herein.

[0063] It should be understood that each component, compound, particle, or parameter disclosed herein is disclosed for use alone or in combination with one or more other components, compounds, or parameters disclosed herein. Each quantity / value or range of each component, compound, or parameter disclosed herein is also disclosed in combination with any other quantity / value or range of each component, compound, or parameter disclosed herein; therefore, it should be further understood that any combination of quantities / values ​​or ranges of two or more components, compounds, or parameters disclosed herein is also disclosed in combination with each other for the purposes of this description. All features and combinations of such features described herein are included within the scope of the invention, provided that the features are not mutually inconsistent. [Examples]

[0064] Abbreviation AM active muscles AST (Aspartate Aminotransferase) CMJ Countermovement Jump EMG (Electromyography) Test MIF (Maximum Isometric Strength) MDF Central Frequency MPF average propulsion force MPP (Average Propulsion Power) MPV average propulsion speed OB whole body PC Phenylencapsaicin PLA placebo PRS (Perceived Recovery Status) RFD force rise rate RMS (Root Mean Square) RM (Maximum Repetitions) RPE Perceived exertion intensity VL speed reduction VLA (Vastus Lateralis) VM (Vastus Medialis)

[0065] (Example 1) Evaluation of the effects of phenylcapsaicin on resistance training performance, muscle damage, protein breakdown, metabolic response, perceived exercise intensity, and recovery. Randomized, triple-blind, placebo-controlled, crossover trial. Introduction The objective of this study was to evaluate the ergogenic effects of phenylcapsaicin (PC), including its effects on resistance training performance, muscle injury, and metabolic response. Therefore, the effects of different doses of PC on lower limb performance, metabolic response to exercise, acute biochemical muscle injury and proteolysis, generalized perceived exercise intensity (RPE-OB) and active muscle perceived exercise intensity (RPE-AM), and perceived recovery in resistance-trained men. More specifically, the objective of this study was to investigate the effects of low-dose (LD) 0.625 mg and high-dose (HD) phenylcapsaicin (PC) compared to placebo (PLA) on full squat speed performance, active muscle (AM) and generalized (OB) perceived exercise intensity (RPE), muscle injury, proteolysis, metabolic response, and 24-hour recovery.

[0066] Materials and methods Twenty-five healthy men (age = 21.00 ± 2.15 years, weight = 76.54 ± 9.50 kg, height = 176.39 ± 7.47 cm, weight-normalized 1RM squat maximum lifting mass [1RM] = 1.66 ± 0.22 kg) voluntarily enrolled to participate in this randomized, triple-blind, placebo-controlled, crossover trial.

[0067] All participants were resistance-trained men with at least two years of experience (range = 2-5 years). Prior to the first session, all participants had completed other studies in which squat tests were performed within the preceding six months. All participants underwent squat strength and anthropometric measurements (i.e., weight and height) one week before the start of the study. Exclusion criteria included cardiovascular, neurological, physical, and / or metabolic disorders that could impair primary outcomes.

[0068] Participants visited the laboratory twice a week for the total study duration of three weeks. Therefore, participants undertook a main session and a 24-hour reminder session for each of the three supplementary conditions. Each condition included six capillary blood draws, a warm-up, a full squat test protocol, and a 24-hour recovery and muscle injury reminder session. To ensure blinding, supplements and placebos were encapsulated and number-labeled by an unrelated third-party researcher (i.e., not involved in the study) (Life Pro Nutrition Industries, Madrid, Spain). The packaging and capsules were indistinguishable, and their contents were only revealed after statistical analysis was performed by a blinded, uninvolved researcher.

[0069] Acute oral administration for each randomization condition was performed 45 minutes before the physical examination in the first session of each week. Under the supervision of the researchers, participants were asked to freely select one capsule from a numbered package. Participants were only permitted to consume the selected capsule with water.

[0070] Replenishment: The capsules contained either a low dose of 0.625 mg of PC (LD), a high dose of 2.5 mg of PC (HD) (Axivite, Malmo, Sweden), or a placebo (PLA) consisting of maltodextrin and excipients. The PC and PLA were identical in appearance, taste, and odor. According to the EFSA, both doses are considered within the safe range suggested by its expert panel.

[0071] Blood test: Blood samples were extracted and analyzed at four different times each week. Before the start of each main session, baseline capillary lactate, serum urea, and aspartate aminotransferase (AST) samples were collected from the fingertips of each participant's index finger. The timelines for each biomarker in this study were selected for their appropriateness and reproducibility, in accordance with previous data. Lactate Pro 2LT-1730 (Arkray, Japan, Kyoto) was used for lactate measurement as it has been previously shown to be reliable across the entire physiological range of 1.0–18.00 mmol. Post-test lactate was examined 90 seconds after the final squat, which was set as a metabolic indicator of exercise intensity. Urea and AST were tested in 28.5–31.5 μl blood samples using automated reflectivity photometry (Reflotron, Roche, Boheringer Mannhein, Germany) as measures of whole-body protein degradation and muscle damage, respectively. For the determination of urea and AST, heparinized capillaries, pipettes, and manufacturer's reagent paper were used immediately after each extraction. Therefore, post-test extractions and analyses were performed 40 minutes after the last squat set for urea and before initiating the 24-hour reminder session for AST.

[0072] Resistance Training Protocol A full squat resistance protocol was performed to address the mechanical response to acute oral polypeptide supplementation 40 minutes after the intake of the assigned weekly condition in the first session and after blood tests in both sessions. Prior to the start of the study, each participant undertook an initial test of increasing load for individual determination of estimated 1-RM and load-velocity relationship in full squat exercises. The load-velocity relationship was established after measuring the mean propulsion velocity (MPV) for each repetition on a Smith machine without a counterweight mechanism (Multipower Fitness Line, Peroga, Murcia, Spain). MPV was measured directly with a linear velocity transducer (T-Force System, Ergotech, Murcia, Spain) mounted vertically on the barbell. MPV values ​​were obtained as fastest, average, and slowest for three sets, as well as fastest for a warm-up set.

[0073] Full squat protocol The full squat protocol consisted of 3 sets of 8 repetitions at 70% RM per day. Based on the warm-up sets and individual load-velocity relationships, the 70% RM load was consistently established for each participant. This RM percentage was chosen because it could potentially involve high effort without submaximal considerations (i.e., not reaching muscle failure) for the selected repetitions. Furthermore, the actual relative intensity was progressively increased as the absolute load was fixed while performing the same repetitions for each set. Since MPV and the resulting percentage of velocity decrease (%VL) are indicators of neuromuscular fatigue, two repetitions at a 60% RM load were performed 3 minutes and 24 hours after the final set of the 3x8 protocol. Velocity values ​​were treated as the slowest, average, and fastest obtained for each set. The average and maximum velocity decrease percentages were also reported.

[0074] Assessment of perceived exercise intensity and perceived recovery status (PRS): Subjective fatigue and recovery were assessed using the Subjective Recovery Score (PRS), RPE-OB, and the RPE (RPE-AM) scale for active muscles. PRS, RPE-AM, and RPE-OB are subjective recovery and fatigue diagrams with a fixed cutoff point between 0 and 10. In PRS, subjective recovery was defined as ranging from "very insufficient recovery / extreme fatigue" (value 0) to "very sufficient recovery / very energetic" (value 10). PRS was explained and evaluated before the start of the 24-hour follow-up for each condition. Fatigue was assessed using RPE-AM and RPE-OB immediately after each 3x8 set. The RPE scale was explained after 60% RM loading and before the 3x8% protocol. Maximum subjective exertion was defined as a value of 10, corresponding to exhaustion, and no exertion as a value of 0. RPE-AM was defined as the local subjective exertion of the quadriceps, and RPE-OB as the traditional global subjective exertion of the whole body. Both validated scales were printed, allowing participants to visualize each one as needed.

[0075] statistical analysis Data are presented as mean and standard deviation (mean ± SD). Normal distribution (Shapiro-Wilk test) and homogeneity of variance (Rubyne test) were tested for each variable (p>0.05). Two-way repeated measures ANOVA (condition × time) was used to investigate the effects of time-series interventions (LD, HD, PLA) on the magnitude of each dependent biochemical and perceptual variable. Bonferroni post-hoc comparisons were performed where ANOVA significance was reached. Mass and velocity analyses were compared using one-way repeated measures ANOVA. Greenhouse-Geyser correction was applied when Mauchly's sphericity test was significant (p ≤ 0.05). Cohen effect size (ES) with 95% confidence intervals was calculated, and the magnitude of the difference was evaluated using the following scales: negligible (<0.20), small (0.20–0.49), moderate (0.50–0.79), and large (≧0.80)

[31] . For examining nonparametric data, Friedman and Wilcoxon were used instead. Statistical analysis was performed using the SPSS software package (IBM SPSS version 25.0, Chicago, IL, USA). Statistical significance was set at p ≤ 0.05.

[0076] Results and Discussion: Blood Test Two-way repeated-measures ANOVA reported significant differences in absolute values ​​of lactate and urea against time (pre-post comparison) (F=269.62, p<0.001), but did not report significant differences for condition (F=1.49, p=0.23) or condition × time interaction (F=0.94, p=0.34) (Table 1). For AST, the Friedman test revealed no significant difference between conditions in baseline values ​​(p=0.771), showing similar baseline levels.

[0077] However, a significant difference between the conditions was found in post-aspartate aminotransferase (AST) levels (p=0.029) (Table 1). The post-hoc Wilcoxon test revealed significantly higher post-AST levels compared to PLA compared to HD (p=0.021). The Friedman test revealed significant differences between the conditions in the percentage change in urea levels (p=0.042). The post-hoc Wilcoxon test revealed significantly higher percentage changes compared to LD compared to PLA (p=0.026) and compared to HD (p=0.037).

[0078] [Table 1]

[0079] Resistance training and operating speed One-way repeated-measures ANOVA reported no significant difference between conditions regarding mass (F=0.171, p=0.843). On the other hand, one-way repeated-measures ANOVA for operating speed performance revealed significant effects on the fastest speed, fastest speed, average speed, and maximum speed reduction at 60% load (p range = <0.001~0.05) (Table 2).

[0080] Post-hoc Bonferroni measurements reported significant differences between LD and PLA for 60% fastest velocity (p=0.05) and between LD and HD for set fastest velocity (p=0.009). Post-hoc Bonferroni comparisons revealed a significant difference between HD and LD for maximum velocity reduction (p=0.008), which was nearly achieved between HD and PLA for mean velocity variables (p=0.06). The magnitude of the differences between the different conditions ranged from negligible to large (Table 3).

[0081] [Table 2]

[0082] [Table 3]

[0083] Assessment of perceived exertion (RPE) and perceived recovery status (PRS). A two-way repeated-measures ANOVA for RPE-OB reported a significant difference with respect to time (F=49.00, p<0.001), but not significant differences with respect to condition (F=2.77, p=0.07) or condition-time interaction (F=1.339, p=0.261) (Table 1).

[0084] The Bonferroni post-hoc analysis did not reveal any significant differences. For RPE-AM (local RPE in the quadriceps), significant differences were reached for both condition (F=9.19, p<0.001) and time (F=36.154, p<0.001), but not for condition × time interaction (F=0.553, p=0.697). The Bonferroni post-hoc analysis showed significant differences for all time comparisons (p range = <0.001~0.002) and for comparisons between PLA and HD (p=0.004) and HD and LD (p=0.016). On the other hand, the one-way repeated-measures ANOVA did not find any difference between conditions for PRS (F=0.698, p=0.463). The results, descriptive values ​​as mean ± SD, and individual variability are shown in Figure 1. This figure includes graphs a), b), and c) for different supplementation conditions (PLA, HD, LD). (a) RPE-OB, whole body perceived exercise intensity; (b) RPE-AM, perceived exertion of active muscles, (c) PRS, subjective recovery status Individual (point) and average (bar) values. PC, phenylcapsaicin; S1 / 2 / 3, set 1 / 2 / 3 (* p ANOVA ≤ 0.05; # p Bonferroni ≤ 0.05).

[0085] In summary, high-dose phenylcapsaicin (HD) yielded significant differences compared to LD and PLA in perceived exercise intensity (RPE-AM) of the active muscle, aspartate aminotransferase (AST), % urea change, and mean propulsion velocity (MPV) and maximum velocity reduction at the slowest repetition. Post-hoc analyses revealed significant differences between HD and PLA for AST, % urea change, RPE-AM, and maximum velocity reduction; between HD and LD for % urea change; and between PLA and LD for % urea change and 60% fastest velocity. LD elicited faster repetitions compared to HD (p ≤ 0.05). The magnitude of the differences between conditions ranged from negligible to large. Therefore, phenylcapsaicin can have a favorable effect on performance, perceived exercise intensity (RPE-AM) of the active muscle, muscle damage, protein breakdown, and recovery status compared to placebo.

[0086] A plausible mechanism linking force application, muscle damage, protein breakdown, and peripheral perceived exercise intensity can explain the ergogenic effect of PC on resistance squat exercises. This ergogenic effect may only appear after reaching the “dose” threshold. In summary, the findings from this study suggest that a 2.5 mg dose of PC yields a reasonable ergogenic effect on sports performance, muscle damage, protein breakdown, and peripheral perceived exercise intensity compared to PLA and the lower dose of 0.625 mg. Furthermore, a 0.625 mg dose of PC may be able to enhance low-fatigue mechanical performance compared to PLA.

[0087] conclusion The results of this study suggest that high-dose (2.5 mg) phenylcapsaicin supplementation administered 45 minutes prior to exercise can improve squat performance and reduce muscle damage, protein breakdown, and perceived exertion in the peripheral quadriceps in trained subjects, compared to low-dose (0.625 mg) and placebo. Key findings included that high-dose phenylcapsaicin (HD) reduced perceived exertion in active muscles, RPE-AM, enhanced mechanical performance, and showed a lower percentage change in muscle damage and protein breakdown compared to placebo (PLA) and low-dose phenylcapsaicin (LD).

[0088] On the other hand, low-dose phenylcapsaicin (LD, 0.625 mg) was effective in inducing significant differences in the fastest repetitions (i.e., less intense repetitions) of both loads compared to HD and PLA. Low doses can enhance mechanical performance in low-fatigue tasks, but not when exercise is performed at near-exhaustion.

[0089] In summary, the ergogenic effect of phenylcapsaicin on performance was examined for both hemodynamic (HD) and, partially, leprosy (LD). Furthermore, HD was effective in reducing muscle damage and protein degradation. Therefore, the results of this study confirm the valid ergogenic effect of phenylcapsaicin.

[0090] (Example 2) Evaluation of the effects of phenylcapsaicin on neuromuscular activity and mechanical performance in dynamic and isometric exercises. Randomized, triple-blind, crossover, placebo-controlled trial. Introduction The objective of this study was to investigate the effects of phenylcapsaicin (PC) supplementation on mechanical performance and neuromuscular activity. Mechanical performance was assessed during dynamic full squats, countermovement jumps (CMJs), and isometric squats. Neuromuscular fatigue after resistance training was examined by calculating the difference in mechanical performance as a reliable variable, such as a decrease in height or linear velocity in load-matched countermovement jumps (CMJs).

[0091] Therefore, the objective of this study was to investigate the effects of two different doses of phenylcapsaicin (PC, LD, and HD) on isometric and dynamic performance, neuronal excitability, fatigue, and recovery throughout the CMJ and full squat exercise. To this end, a randomized, triple-blind, placebo-controlled crossover trial with two sessions per condition was conducted. It was hypothesized that PC could rapidly increase velocity, force and power generation, neuronal excitability, and CMJ height during the squat exercise. However, due to the performance improvement, adverse effects on higher fatigue and mechanical recovery in post-test measurements were also anticipated.

[0092] Materials and methods Experimental methods for addressing the problem This study was designed as a randomized, triple-blind, crossover, placebo-controlled trial. Participants completed three experimental conditions, each consisting of a main session and a 24-hour second session. Each session was performed at the same individual time of day under stable environmental conditions (22–24°C and 55% humidity). Two weeks prior to the start of the study, participants underwent anthropometric measurements (weight and height), 1RM in squats, and load-velocity relationship tests. For the next three weeks, participants were randomly assigned either placebo (PLA) or a low (LD) or high (HD) dose of PC before the first weekly session. Participants then warmed up and performed the CMJ and squat tests. In the second session, participants did not consume any of the conditions. Therefore, after warming up, participants were immediately evaluated again for the CMJ and squat tests. Electromyographic (EMG) results were recorded for each session while participants performed the squat tests.

[0093] subject Twenty-five healthy men (age = 21.69 ± 3.65 years, weight = 77.43 ± 9.09 kg, height = 176.74 ± 7.20 cm, maximum squat mass [1RM] = 125.62 ± 21.01 kg, RM normalized to body weight = 1.64 ± 0.22 kg) with at least two years of experience in resistance training were recruited for this study. Participants with any cardiovascular, muscular, neurological, and / or metabolic disorder were immediately excluded. After participants were informed of the purpose, procedures, and potential risks of the study, they voluntarily signed an informed consent form. This study was approved by the Research Ethics Committee of Pablo of Olavide University in accordance with the doctrines of the Declaration of Helsinki. Each condition was established within the safety range proposed by the European Food Safety Authority (EFSA) expert panel (10).

[0094] Participants were asked not to take stimulants (e.g., caffeine) or other ergogenic aids before each session, not to engage in strenuous physical activity, and not to alter their diet two days prior to the test. During the three-week study, two participants dropped out; one due to injury and the other due to missing the final session.

[0095] Refilling procedure The supplements and placebos were prepared and packaged by researchers at an unrelated facility (Life Pro Nutrition Industries, Madrid, Spain). To ensure blinding, each package was coded with a number from 1 to 3. The packages and capsules were identical in appearance, color, and taste, and their contents were only revealed after statistical analysis was completed. The composition of the capsules was: Maltodextrin containing a red pigment and placebo (PLA) as an excipient. 2.5 mg high-dose (HD) PC (Axivite, Malmo, Sweden), or It contained one of the low-dose (LD) PCs at 0.625 mg.

[0096] Randomization and crossover were performed two weeks prior to the start of the study. To reduce potential bias, a third-party researcher assigned participants to each condition using the Research Randomizer website (www.randomizer.org). Each participant consumed one condition per week for the entire three-week study. Participants took either the PC dose or placebo 45 minutes before their first exercise session. Researchers encouraged participants to freely select a capsule from the packaging of their assigned condition each day. Capsules were taken with water under the supervision of at least one researcher.

[0097] Electromyography (EMG) Prior to EMG recording, each subject was shaved and marked with a black oil-based marker to ensure consistency in electrode position between conditions (30). Surface EMG electrodes were placed on the vastus medialis (VM) and vastus lateralis (VLA) muscles of the right leg. EMG signals were evaluated for 60% and 70% maximum repetition (RM) sets and isometric tests in both sessions. EMG signals were continuously recorded using a bipolar, parallel-bar surface electromyography wireless Trigno® sensor. Baseline noise was established at <5 μV peak-to-peak, and the sampling rate was 1926 Hz. The EMG system was set with an inter-electrode distance of 10 mm, a common-mode rejection ratio >80 dB, and a bandwidth filter between 20–450 Hz ± 10% (Delsys Inc., MA, USA). Data were saved using EMG works Acquisition software (Delsys Inc., MA, USA). For each measurement, the median frequency (MDF) and root mean square (RMS) were calculated individually for the VM and VLA as indicators of excitatory muscle activity. All measured results were recorded for each individual repetition (with a 500-millisecond sliding window with a 499-millisecond overlap) and averaged for further analysis of dynamic and isometric tests. To ensure inter-condition reliability, the data were normalized to the maximum daily value of the first isometric signal. Therefore, EMG values ​​are expressed as a percentage of the maximum daily value obtained.

[0098] Resistance Training Protocol Warm-up A standardized warm-up was performed 30 minutes after capsule ingestion in the first session and immediately upon the subjects' arrival in the laboratory in the second session. All subjects were tested for EMG marks before the warm-up. The warm-up consisted of (I) 5 minutes of continuous submaximal running at 9 km / h-1, (II) 3 sets of 10 repetitions of bodyweight squats, 3 progressive CMJs, (III) 2 maximal CMJ repetitions, and 3 sets of 2 repetitions of full squat exercises at 40%, 50%, and 60% of 1RM. A fixed 2-minute rest period was observed between full squat sets.

[0099] Countermovement Jump (CMJ) Test CMJ height was determined using an infrared timing system (OptojumpNext, Microgate, Bolzano, Italy) (31). Participants were instructed to perform the CMJ with both hands on their hips and elbows extended during the eccentric and concentric phases. Thus, the CMJ method was established as 90° knee flexion followed by a maximum vertical jump. For each trial, landing required being in a standing position with the knees not bent until the movement was complete. For each measurement, participants were asked to perform two trials separated by 10 seconds, and the average value was calculated for further analysis. If the CMJ difference between trials exceeded 2 cm, a third measurement was required, and the two closest values ​​were averaged. The CMJ test was performed twice: before a specific squat warm-up in both sessions and after the last 70% RM set in the first session.

[0100] Isometric squat test To investigate the effect of PC on maximum isometric force (MIF) and rate of force rise (RFDmax), isometric squat tests were performed with the knees flexed at 90° (180° = fully extended). Three isometric tests were performed for each condition: (I) 2 minutes before and (II) 3 minutes after the 70% RM set in the first session, and (III) 2 minutes after the 60% RM set in the second session. For this purpose, an 80 x 80-cm dynamometric platform (FP-500, Ergotech, Murcia, Spain) was attached to a Smith machine with customizable height support. Participants were instructed to press their feet as hard as possible against the platform floor after the cue "On your marks, ready, go!". Participants were asked to perform two 5-second trials with a 1-minute rest between each test. External forces for each trial were collected at a sampling rate of 1000 Hz and processed using specific software (T-Force System, Ergotech, Murcia, Spain). For RFDmax determination, the maximum slope in the force-time curve at 20-millisecond intervals was selected. Furthermore, since the RFD data was represented by different distinguishable time differences, RFD was calculated at intervals of 0-50, 0-100, 0-150, 0-200, and 0-400 milliseconds. The RFD and MIF results were both averaged for further analysis.

[0101] Dynamic Squat Protocol For dynamic squat evaluation, the final set of squat warm-up (1x2x60%RM), three sets of 8 repetitions at 70%RM, and another 1x2x60%RM after 60%RM load were recorded during the first session of each condition. In the second session, subjects were asked to perform a third 1x2x60%RM as a baseline for comparing mechanical fatigue over time. Average propulsion velocity (MPV), average propulsion force (MPF), average propulsion power (MPP) values, and velocity decrease values ​​were obtained from a force platform synchronized with a linear velocity transducer (T-Force System, Ergotech, Murcia, Spain) mounted vertically on the barbell. Individual force-load relationships were calculated on the first visit to always fit the percentage of actual RM load. To ensure the effect of the relatively increasing exertion over time, rest between sets was fixed at 2 minutes.

[0102] statistical analysis Sample size calculations were performed using G*POWER software (Heinrich-Heine-Universitat Dusseldorf, Germany) with an alpha value of 0.05. Based on the total volume of squat exercise in previous studies, the power was fixed at 0.80 and the effect size at 0.60 (14). At least 21 subjects were required for this study.

[0103] Data are presented as mean and standard deviation (mean ± SD). The normal distribution and homovariance of the variables were tested using the Shapiro-Wilk and Rubine tests, respectively (p>0.05). Two-way repeated measures ANOVA (condition × time), along with Bonferroni post-hoc analysis, was used to investigate the effects of interventions (LD, HD, PLA) over time on the magnitude of each dependent variable. Total volume loadings were compared using one-way repeated measures ANOVA. For nonparametric data, the Friedman-Wilcoxon test was used instead. If Mauchly's sphericity test was significant (p≦0.05), the Greenhouse-Geyser correction was applied. Statistical analysis was performed using the SPSS software package (IBM SPSS version 25.0, Chicago, IL, USA). Statistical significance was established at p≦0.05.

[0104] result EMG The descriptive values ​​and statistical comparisons of EMG results are presented in Table 4 below. Two-way repeated-measures ANOVA revealed significant differences over time in 60% load RMS for VLA and VM, isometric MDF for VLA and VM, 60% load MDF VLA, and training MDF VLA (p range = <0.001 to 0.05). On the other hand, significant differences were reported for 60% load RMS VLA and training RMS for VLA and VM relative to the conditions (p range = 0.039 to 0.05). Post-hoc Bonferroni showed a significant difference between PLA and LD for 60% load RMS VLA (p = 0.05). Furthermore, a significant difference was found between HD and LD for training RMS VM (p = 0.045).

[0105] [Table 4A]

[0106] [Table 4B]

[0107] [Table 4C]

[0108] Countermovement Jump Test The Friedman test revealed significant differences between conditions in CMJ height at post-hoc (p=0.002) and 24-hour post-hoc (p=0.003) intervals. The post-hoc Wilcoxon test for post-hoc CMJ values ​​showed significant differences compared to HD compared to both PLA (p=0.009) and LD (p=0.004). However, significant differences were found when comparing HD and PLA (p=0.02) and LD and PLA (p=0.019) for 24-hour post-hoc CMJ values. Furthermore, significant differences were found between conditions for the percentage change in CMJ from baseline to post-hoc (p=0.04), although the post-hoc analysis did not reach statistical significance. Figure 2 shows the descriptive values ​​as mean ± SD for CMJ comparisons and the individual variability. This figure includes graphs a), b), and c), showing (a) pre- and post-test CMJ height and CMJ 24 hours after testing, (b) percentage difference of CMJ before and after testing, and (c) individual (point) and mean (bar) values ​​of the percentage difference of CMJ before and 24 hours after testing (* p ANOVA ≤ 0.05; # p Bonferroni ≤ 0.05).

[0109] Isometric squat test Table 5 presents the descriptive values ​​and statistical comparisons of isometric mechanical results. Two-way repeated measures ANOVA did not reveal any significant differences in results for time (p range = 0.06 to 0.78), condition (p range = 0.19 to 0.97), or condition × time interaction (p range = 0.09 to 0.89).

[0110] [Table 5A]

[0111] [Table 5B]

[0112] Dynamic Squat Protocol One-way repeated-measures ANOVA did not report any significant difference between conditions for total lifted mass (F=1.087, p=0.346). On the other hand, two-way repeated-measures ANOVA for motion velocity performance revealed significant effects with respect to time (p=<0.001) and condition (p range=0.02~0.24), but not with respect to condition × time interaction (p range=0.74~0.90) (Table 6). Post-hoc Bonferroni analysis for time analysis revealed significant differences between sets 1 and 2 for all performance (p range=<0.001~0.007). However, between sets 1 and 3, the Bonferroni post-hoc analysis only reported a significant difference for mean MPV (p<0.001). For comparisons between sets 2 and 3, all motion velocity performance showed significant differences (p range=<0.001~0.036). Individual intra-set analyses revealed significant differences in replicates 13, 15, 16, 17, 23, and 24 (p range = 0.027 to 0.04). Post-hoc Bonferroni analyses, as shown in Figure 3, which illustrates mean propulsion velocity (MPV) in intra-set comparisons of individual replicates and replicates over time for different supplementation conditions (PLA, HD, LD) (* p ANOVA ≤ 0.05; # p Bonferroni ≤ 0.05), reported differences between HD and PLA in replicate 23 and between HD and LD in replicates 15 and 16 (p range = 0.03 to 0.04).

[0113] [Table 6A]

[0114] [Table 6B]

[0115] [Table 6C]

[0116] The aim of this study was to investigate the neuromuscular and mechanical responses to capsaicinoid supplementation during dynamic and isometric exercise for the first time. The main finding of this study was that, compared to placebo (PLA) and high-dose PC, low-dose PC could modulate the excitability of muscle motor units (i.e., RMS) during dynamic squat exercise, particularly in the vastus lateralis (VLA) and vastus medialis (VM), but not during isometric squat exercise. Furthermore, significant differences were evident in mean propulsion velocity (MPV) and % velocity reduction in dynamic or isometric tests, but not in any other mechanical performance variables such as force and power. However, the HD condition showed higher values ​​in post- and 24-post-stage countermovement jumps (CMJ) compared to placebo and lower doses. Positive effects were reported for velocity (MPV), individual repetitions, and mechanical recovery performance. Dose-response relationships were not established between different PC doses and nerve output. Therefore, PC supplementation, particularly at high doses, may reduce acute mechanical fatigue and reasonably post-24 mechanical fatigue. These effects on fatigue performance cannot be mediated by traditional neural mechanisms proposed in previous literature.

[0117] In summary, compared to each other and PLA, acute oral low dose (LD; 0.625 mg) of PC can increase neural activity during dynamic resistance training, while high dose (HD; 2.5 mg) can reduce acute mechanical fatigue (i.e., less CMJ height reduction and higher MPV values). Therefore, PC may be a valuable tool for high-volume resistance training workouts.

[0118] This study provides valuable insights into capsaicinoid supplementation. Acute phenylcapsaicin intake can be considered an anti-fatigue ergogenic aid (2.5 mg) for dynamic resistance training sessions when more than one exercise is performed. Consistently, mechanical fatigue after submaximal exercise can be delayed by the compositions of the present invention.

[0119] reference:

[0120] (Example 3) (Prediction): Alternative compound for formula (I) To demonstrate that the present invention is applicable to various compounds of formula (I), several compounds may be prepared and their ergogenic effects investigated.

[0121] The following compounds of the present invention may be synthesized and tested, for example: methyl capsaicin, ethyl capsaicin, propyl capsaicin, and butyl capsaicin.

[0122] The proposed compounds described above may be studied as appropriate, for example, as shown in Example 1 or 2 for phenylcapsaicin, to evaluate their potential as ergogenic aids.

Claims

1. Compounds of formula (I) for enhancing the physical performance of a subject, accelerating recovery, and / or reducing or delaying mechanical fatigue. 【Chemistry 1】 (wherein R is alkyl, trifluoromethyl, cycloalkyl, phenyl, or halogen, and if substituent R includes a carbon chain, it is linear or branched and optionally further substituted with alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, aminoalkylthio, arylthiol, cyano, cycloalkyl, cycloalkenyl, halo, hydroxy, oxo, nitro, or trifluoromethyl), or the use of its tautomers or salts, The compound is administered to the target; use.

2. Use of the compound according to claim 1, wherein R of the compound comprises a chain with a length of 1 to 6 carbon atoms, more preferably R is an alkyl group with a length of 1 to 4 carbon atoms, or R is a phenyl group.

3. Use of the compound according to claim 1 or 2, wherein R of the compound is phenyl.

4. Use of the compound according to any one of claims 1 to 3, wherein the administration is by oral ingestion.

5. Use of the compound according to any one of claims 1 to 4, wherein the compound is included in a composition formulated for administration to a human subject.

6. Use of the compound according to any one of claims 1 to 5 in an amount effective for lowering the levels of aspartate aminotransferase (AST), urea, or lactate in the blood of the subject, thereby enhancing physical performance during exercise, accelerating recovery, and / or reducing or delaying post-exercise mechanical fatigue.

7. Use of the compound according to any one of claims 1 to 6 for enhancing physical performance, which positively affects any of the following: resistance training performance, mechanical dynamic performance, muscle injury, metabolic response, proteolysis, neuromuscular fatigue, neuronal excitability, or neuromuscular activity.

8. Use of the compound according to any one of claims 1 to 7 for a mechanical anti-fatigue effect on a target.

9. Use of the compound according to any one of claims 1 to 8, wherein the compound is administered to a subject who is suffering from or recovering from physical weakness, energy deficiency, or asthenia.

10. Use of the compound according to any one of claims 1 to 9, wherein the compound is administered to the subject before exercise.

11. Provided in unit dosage forms containing 0.5 to 4.0 mg of the compound of formula I, Compound of formula (I) 【Chemistry 2】 (wherein R is alkyl, trifluoromethyl, cycloalkyl, phenyl, or halogen, and if substituent R includes a carbon chain, it is linear or branched and optionally further substituted with alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, aminoalkylthio, arylthio, cyano, cycloalkyl, cycloalkenyl, halo, hydroxy, oxo, nitro, or trifluoromethyl), or tautomers or salts thereof, and One or more components selected from the group consisting of adaptogens, amino acids, antioxidants, electrolytes, energy boosters, and creatine. A sports diet supplement composition containing the following:

12. The composition according to claim 11, which is formulated as a powder, granules, tablets, capsules, aerosol inhalation preparation, beverage, or food such as a bar.

13. The composition according to claim 11 or 12, wherein R of the compound comprises a chain with a length of 1 to 6 carbon atoms, more preferably R is an alkyl group with a length of 1 to 4 carbon atoms, or R is a phenyl group.

14. The ingredients are, Adaptogens selected from Rhodiola rosea and Ashwagandha Amino acids selected from branched-chain amino acids (BCAAs) and L-arginine, Antioxidants selected from vitamins C and E and compounds such as quercetin, Electrolytes selected from potassium, magnesium, and sodium, Energy booster selected from caffeine and guarana, and creatine A composition according to any one of claims 11 to 13, wherein one or more of the above.

15. A composition according to any one of claims 11 to 13, comprising the ingredient caffeine.

16. For use in the treatment of chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), or ME / CFS, at least one compound of formula (I) 【Transformation 3】 A composition comprising (wherein R is alkyl, trifluoromethyl, cycloalkyl, phenyl, or halogen, and if substituent R includes a carbon chain, it is linear or branched and optionally further substituted with alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, aminoalkylthio, arylthio, cyano, cycloalkyl, cycloalkenyl, halo, hydroxy, oxo, nitro, or trifluoromethyl), or a tautomer thereof or a salt thereof, A composition to be administered to a subject who is suffering from or recovering from a disease.

17. The composition for use according to claim 16, wherein R of the compound comprises a chain of 1 to 6 carbon atoms, more preferably R is an alkyl group of 1 to 4 carbon atoms, or R is a phenyl group.

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