WO2019052629A1

WO2019052629A1 - Lipids with odd number of carbon atoms and their use as pharmaceutical composition or nutritional supplement

Info

Publication number: WO2019052629A1
Application number: PCT/EP2017/072849
Authority: WO
Inventors: Yuhong DONG
Original assignee: Sunregen Healthcare AG
Current assignee: Sunregen Healthcare AG
Priority date: 2017-09-12
Filing date: 2017-09-12
Publication date: 2019-03-21
Anticipated expiration: 2020-03-12
Also published as: BR112020004023A2; PH12020500511A1; EA202090566A1; IL273069A

Abstract

The present invention relates to the use of lipids bearing fatty acids with an odd number of carbon atoms as pharmaceuticals or nutritional supplement. In particular, such lipids are used in the treatment and/or prevention of neurodegenerative diseases, optic and retinal degenerative diseases, demyelinating diseases, neuromuscular disorders and muscular dystrophy, stroke, brain or spinal cord nerve injury, amyloid related diseases, but also a functional food or food supplement for anti-aging or life-span prolongation and brain function improvement for human and/or animals.

Description

LIPIDS WITH ODD NUMBER OF CARBON ATOMS AND THEIR USE AS PHARMACEUTICAL COMPOSITION OR NUTRITIONAL SUPPLEMENT

FIELD OF THE INVENTION

The present invention relates to lipids and their use as pharmaceutical composition or nutritional supplement. In particular, the invention provides novel use of lipids bearing fatty acids with an odd number of carbon atoms, particularly tripentadecanoin, that exhibit potent neuroprotective, anti-apoptotic, neuro-rescuing, and axon-outgrowth effects, which are useful as pharmaceuticals or nutritional supplement for the treatment and/or prevention of neurodegenerative diseases, optic and retinal degenerative diseases, demyelinating diseases, neuromuscular disorders and muscular dystrophy, stroke, brain or spinal cord nerve injury, amyloid related diseases, but also a functional food or food supplement for anti-aging or life-span prolongation and brain function improvement for human.

BACKGROUND OF THE INVENTION Hundreds of millions of people worldwide are affected by neurological disorders. Neurological disorders include diseases of the central and peripheral nervous system. In other words, the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscles.

The current invention is related to the treatment of different neurological diseases and associated chronic diseases as detailed as below:

A. Neurodegenerative diseases

Neurodegenerative disease is the umbrella disease term for the progressive loss of structure or function of neurons, including death of neurons. The damage or death of neurons lead to a gradual deterioration of the functions controlled by the affected part of the nervous system. The selected group of neurodegenerative disorders include Alzheimer's Disease (AD), Parkinson's disease (PD), Huntington's diseases (HD), Amyotrophic Lateral Sclerosis (ALS), Dementia, dementia with Lewy bodies (DB), frontotemporal dementia (FTD), Creutzfeldt- Jakob disease (CJD), and brain atrophy.

Most neurodegenerative diseases are also classified as proteinopathies as they are associated with the aggregation of misfolded proteins during aging process. Protein misfolding and aggregation is a major histopathologic hallmark of neurodegenerative diseases. A major histopathologic focus in all the neurodegenerative diseases is now on small protein aggregates termed oligomers. These aggregates may be the toxic species of β-amyloid, a-synuclein, prions, etc. Disposition of β-amyloid is the major component of senile plaques in Alzheimer's disease and strongly implicated in the pathogenesis of AD; tau protein is the main component of neurofibrillary tangles implicated in the pathogenesis of AD; a-synuclein can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, and is strongly implicated in the pathogenesis of PD and DLB; prion is the main component of prion diseases and transmissible spongiform encephalopathies and is strongly associated with spongiform encephalopathy (Creutzfeldt- Jakob disease).

Apoptosis, or programmed cell death, plays an important role in both physiologic and pathologic conditions. There is mounting evidence for an increased rate of apoptotic cell death in a variety of acute and chronic neurological diseases including neurodegenerative disease. Apoptosis is characterized by neuronal shrinkage, chromatin condensation, and DNA fragmentation, whereas necrotic cell death is associated with cytoplasmic and mitochondrial swelling followed by dissolution of the cell membrane. Evidence of DNA fragmentation has been found in several degenerative neurologic disorders, including AD, HD and ALS. There is no effective treatment targeting the original causes of neurodegenerative diseases.

Dementia is defined as an acquired deterioration in cognitive abilities with memory loss as the most common symptoms. It is estimated that there are globally 35.6 million people with dementia - AD is the most common cause of dementia, accounting for 60-70% of all patients (WHO Online Q&A, February 2014). The strongest risk factor for dementia is increasing age. AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Increasing evidence suggests that soluble amyloid species called oligomers may cause cellular dysfunction and represent the early toxic molecule in AD. There are neuritic plaques containing β-amyloid (Αβ). Αβ is a protein of 39^2 amino acids that is derived proteolytically from a larger transmembrane protein, amyloid precursor protein (APP), when APP is cleaved by and secretases. Moreover, none of the molecules currently available efficiently target the underlying causative pathophysiological processes of the disease.

Parkinson's disease is a degenerative disorder of the central nervous system. It results from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown. Parkinson's disease is the second most common neurodegenerative disorder and manifests as bradykinesia, rigidity, resting tremor and posture instability. PD affects approximately 7 million people globally and 1 million people in the United States. The number of new cases per year of PD is between 8 and 18 per 100,000 persons-year. Levodopa has been the most widely used treatment for over 30 years but with very limited efficacy. Investigations on neuroprotection are at the forefront of PD research.

Huntington's Disease (HD) causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices. The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder. There is no treatment for HD. Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, is a rapidly progressive, invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles. The disease belongs to a group of disorders known as motor neuron diseases, which are characterized by the gradual degeneration and death of motor neurons. Management of ALS attempts to relieve symptoms and extend life expectancy. Riluzole has been found to modestly improve survival by several months. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. In vitro and cell line experimental evidence suggests that SOD1 , TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein aggregates can act as seeds to trigger the aggregation of native counterparts. Many evidences support the prion-like properties of major ALS-associated proteins and the possible therapeutic strategies for ALS based on a prion-like mechanism were discussed. (Grad, Leslie I.; et al. Neurobiology of Disease. 2015;77: 257-265.)

B. Retinal and optical nerve degenerative diseases B-l . Optic nerve degenerative diseases

Optic atrophy is a condition that affects the optic nerve, which carries impulses from the eye to the brain. Optic atrophy results from damage to the optic nerve from many kinds of pathologies. The condition can cause problems with vision, including blindness, glaucoma, stroke of the optic nerve, known as anterior ischemic optic neuropathy; tumor that is pressing on the optic nerve; optic neuritis, an inflammation of the optic nerve caused by multiple sclerosis; a hereditary condition known as Leber's hereditary optic neuropathy (LHON).

Optic neuritis (ON) is inflammation of the optic nerve that can cause partial or complete vision loss. The optic nerve comprises axons that emerge from the retina of the eye and carry visual information to the primary visual nuclei, most of which is relayed to the occipital cortex of the brain to be processed into vision. Inflammation of the optic nerve causes loss of vision, usually because of the swelling and destruction of the myelin sheath covering the optic nerve. Direct axonal damage may also play a role in nerve destruction. Dominant Optic Atrophy (DO A) is neuro -ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. The prevalence of the disease varies from 1/10000 to 1/30000 in the rest of the world.

B-2. Retinal degenerative diseases

Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. It is one of the most common causes of irreversible blindness affecting nearly 50 million individuals globally. Degenerative processes in the ageing retina and brain show striking similarities, and offers scope for identifying novel targets as well as pathogenic mechanisms. Amyloid beta, which builds up in Alzheimer's disease brains, is one the proteins accumulating in AMD, which is one of the reasons AMD is sometimes called "Alzheimer's of the eye" or "Alzheimer's of the retina". At present, the majority of AMD patients have no effective treatment.

Glaucoma, a major cause of blindness worldwide, is commonly linked to raised intraocular pressure (IOP). The precise means by which IOP may lead to the irreversible destruction of retinal ganglion cells (RGCs) is far from clear. The principal step leading to irreversible loss of vision in glaucoma is RGC apoptosis. Αβ has been reported to be implicated in the development of RGC apoptosis in glaucoma, with evidence of increased expression of Αβ in RGCs in experimental glaucoma and decreased vitreous Αβ levels (consistent with retinal Αβ deposition) in patients with glaucoma. Strong evidence from an animal model of glaucoma supporting the involvement of Αβ in glaucoma-induced apoptosis of RGCs and show that the use of agents targeting multiple phases of the Αβ pathway raises the possibility of a neuroprotective approach to the treatment of glaucoma. (Guo L, et al. Targeting amyloid-β in glaucoma treatment. Proc Natl Acad Sci U S A. 2007;104 (33): 13444-13449.) Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes severe vision impairment due to the progressive degeneration of the rod photoreceptor cells in the retina. The progressive rod degeneration is later followed by abnormalities in the adjacent retinal pigment epithelium (RPE) and the deterioration of cone photoreceptor cells. Patients in the early stages of RP first notice compromised peripheral and dim light vision due to the decline of the rod photoreceptors inherited, and finally blindness. It is estimated that 1.5 million people worldwide 1/4,000 are currently affected. There is no cure for retinitis pigmentosa.

C. Demyelinating neurological disorders The group of demyelinating neurological disorders include adrenoleukodystrophy, multiple sclerosis (MS), optical neuritis, acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillian-Barre syndrome (GBS), encephalitis caused by or related to Zika virus, neuromyelitis optica ( MO), acute disseminated encephalomyelitis, acute necrotizing hemorrhagic encephalitis, concentric sclerosis, diffuse sclerosis, metachromatic leukodystrophy, ball-like cell leukodystrophy, spongy degeneration of the central nervous system, Perry-plum disease, Alexander disease, radiation injury leukoencephalopathy, hypoxic leukoencephalopathy, periventricular leukomalacia disease, arteriosclerotic cortex under encephalopathy, progressive multifocal leukoencephalopathy, and central pontine myelinolysis syndrome. C- 1. Adrenoleukodystrophy

Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy, ALD, X-ALD, Siemerling-Creutzfeldt disease or bronze Schilder disease) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by the relevant enzymes not functioning properly, which then causes damage to the myelin sheathes of the nerves, resulting in seizures and hyperactivity. Other symptoms include problems with speaking, listening and understanding verbal instructions. ALD is the most common peroxisomal inborn error of metabolism, with an incidence estimated between 1 : 18,000 and 1 :50,000. Initial attempts at dietary therapy in ALD involved restricting the intake of very-long chain fatty acids (VLCFA), however it did not impact the levels of VLCFA in plasma and other body tissues. The parents of Lorenzo Odone, a boy with ALD, spearheaded efforts to develop a dietary treatment to slow the progression of the disease. They developed a mixture of unsaturated fatty acids (glycerol trioleate and glyceryl trierucate in a 4:1 ratio), known as Lorenzo's oil that inhibits elongation of saturated fatty acids in the body. Supplementation with Lorenzo's oil has been found to normalize the VLCFA concentrations in the body, although its effectiveness at treating the cerebral manifestations of the disease is still controversial and unproven. Trials with Lorenzo's oil have shown that it does not stop the neurological degradation in symptomatic patients, nor does it improve adrenal function.

C-2. Multiple sclerosis

The total estimated number of people diagnosed with multiple sclerosis (MS) is approximately 1.3 million globally. MS is a debilitating, and disabling neurological disease characterized by multifocal destruction of myelin in central nervous system. Due to demyelination of myelin sheath of axons in white matter of central nervous system, myelin is damaged or destroyed, and the nerve impulses get slower or do not transmit at all, leading to disrupted communication between the brain and other parts of the body. Axonal damage occurs in every newly formed MS lesion, and cumulative axonal loss is the major cause of progressive and irreversible neurologic disability in MS. As many as 70% of axons are lost from the lateral corticospinal (e.g., motor) tracts in patients with advanced paraparesis from MS, and longitudinal MRI studies suggest there is progressive axonal loss over time within established, inactive lesions.

C-3. Other demyelinated diseases Other demyelinated diseases include Acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillian-Barre syndrome (GBS), encephalitis caused by or related to Zika virus, neuromyelitis optica ( MO), acute disseminated encephalomyelitis, acute necrotizing hemorrhagic encephalitis, concentric sclerosis, diffuse sclerosis, metachromatic leukodystrophy, ball-like cell leukodystrophy, spongy degeneration of the central nervous system, Perry-plum disease, Alexander disease, radiation injury leukoencephalopathy, hypoxic leukoencephalopathy, periventricular leukomalacia disease, arteriosclerotic cortex under encephalopathy, progressive multifocal leukoencephalopathy, and central pontine myelinolysis syndrome.

D. Neuromuscular disorders and muscular dystrophy

Neuromuscular disease encompasses many diseases, disorders or conditions that impair the functioning of the muscles, either directly, or indirectly, being pathologies of nerves, muscle or neuromuscular junctions. Spinal muscular atrophies are disorders of lower motor neuron while amyotrophic lateral sclerosis is a mixed upper and lower motor neuron condition. Myasthenia gravis and Lambert-Eaton syndrome are examples of neuromuscular junction disorders. There is no cure for the treatment of these neuromuscular disorders. Current treatments are mostly symptomatic treatment and with modest efficacy. Muscular dystrophy (MD) is a group of muscle diseases that results in increasing weakening and breakdown of skeletal muscles over time. The disorders differ in which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. The most common type is Duchenne muscular dystrophy (DMD) which typically affects males beginning around the age of four. Other types include Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Many people eventually become unable to walk. Some types are also associated with problems in other organs. Charcot-Marie-Tooth disease (CMT), named after the three doctors who first identified it, is one of the most common inherited nerve disorders. CMT affects an estimated 1 in 2,500 people in the United States and 2.6 million people worldwide, although experts believe the number could be much higher.

Currently, there is no cure for muscular dystrophy.

E. Stroke, brain injury or spinal cord nerve injury, cranial nerve disorders, or seizures Stroke or cerebrovascular accident is defined as an acute focal or global neurological deficit caused by neuronal cell death associated with cerebral ischemia. The cause of neuronal death is due to lack of oxygen and glucose, loss of ATP, excitotoxicity of glutamate, oxidative stress, etc. Neuroprotective treatment is an increasingly recognized strategy in stroke that assists clinicians in reducing stroke mortality rates and improving the quality of life of survivors.

A brain injury is any injury occurring in the brain. Brain injuries can be classified along several dimensions. Primary and secondary brain injury are ways to classify the injury processes that occur in brain injury, while focal and diffuse brain injury are ways to classify the extent or location of injury in the brain. Brain injuries have far-reaching and varied consequences due to the nature of the brain as the main source of bodily control. Patients commonly experience issues with memory. This can be issues with either long or short-term memories depending on the location and severity of the injury. Memory can improve through rehabilitation but in some cases the damage can be permanent. A spinal cord injury (SCI) is damage to the spinal cord that causes changes in its function, either temporary or permanent. These changes translate into loss of muscle function, sensation, or autonomic function in parts of the body served by the spinal cord below the level of the lesion.

Cranial nerve disease is an impaired functioning of any one of the twelve cranial nerves that emerge directly from the brain (including the brainstem), including the olfactory nerve (I), the optic nerve (II), oculomotor nerve (III), trochlear nerve (IV), trigeminal nerve (V), abducens nerve (VI), facial nerve (VII), vestibulocochlear nerve (VIII), glossopharyngeal nerve (IX), vagus nerve (X), accessory nerve (XI), and hypoglossal nerve (XII).

There is no cure for the treatment of these cranial nerve disorders. Current treatments are mostly symptomatic treatment and with modest efficacy.

Epilepsy is a group of neurological diseases characterized by epileptic seizures. About 1% of people worldwide (65 million) have epilepsy, and nearly 80% of cases occur in developing countries. In seizures, a group of neurons begin firing in an abnormal, excessive, and synchronized manner. This results in a wave of depolarization known as a paroxysmal depolarizing shift. Factors around the neuron include synaptic plasticity and ion concentrations are potential pathological mechanism. Current treatments are mostly symptomatic treatment. F. Amyloid deposit related diseases

Amyloid deposit related diseases are selected from the group consisting of diabetes, cardiac amyloidosis, primary amyloidosis, familial amyloidosis, senile systemic amyloidosis (SSA), secondary amyloidosis, and haemodialysis-associated amyloidosis.

Amyloidosis is a group of related diseases in which a protein called amyloid builds up in one or many organs— typically the kidney, heart, central nervous system (CNS), and/or liver— and interferes with organ function, eventually leading to organ failure. Primary amyloidosis (AL, amyloid light chain) is associated with a clonal plasma cell disease and the immunoglobulin light chains made by the abnormal plasma cells. AL also occurs in amyloidosis associated with multiple myeloma. Familial amyloidosis (AF) is associated with a genetic abnormality that can be inherited. AF causes the liver to make an abnormal form of a protein called transthyretin.

Secondary amyloidosis (AA) is associated with inflammation and elevated levels of serum amyloid A caused by inflammation.

G. Anti-aging or life-span prolongation Maximum life span for humans, (or, maximum reported age at death or MRAD) is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. Currently there is no effective methods to prolong human life-span.

H. Brain functions Basic brain functions include vision, memory, learning, imaging, judgment, reading, perception, thinking and creating etc. Different people may have different levels of intellectual quotient (IQ). There is still a lot of undiscovered area about how brain works and the human brain functions are not fully developed. How to further develop the brain functions in human is an underdeveloped area in neuroscience.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a medicament for the treatment and the prophylaxis of neurological diseases in humans, but also in animals. These diseases include neurodegenerative diseases, optic or retinal degenerative diseases, demyelinating diseases, neuromuscular disorders and muscular dystrophy, stroke, brain or spinal cord nerve injury, cranial nerve disorders, or seizures, amyloid deposit related diseases. It is further an object of the present invention to provide a functional food or nutrition supplement for humans and animals, e.g. for anti-aging, life-span prolongation or improving brain functions.

The present invention is based on the surprising findings that lipids bearing fatty acids with an odd number of carbon atoms can be used for treating and/or prevention of diseases and disorders of the central nervous system.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 relates to Example I-l and shows neuroprotective effects of tripentadecanoin (added alone or 48 hours before ΑβΟ treatment) based on cell viability evaluated with MTT; FIG. 2 relates to Example I-l and shows neuroprotective effects of tripentadecano in- microscopic images of neurons;

FIG. 3 relates to Example 1-2 and shows axon outgrowth effects of tripentadecanoin;

FIG. 4 relates to Example 1-3 and shows neuroprotective, anti-apoptotic and neuro- rescuing effects of tripentadecanoin in mouse primary neuron models when added concomitantly or 3, 6 hours after ΑβΟ treatment; FIGs. 5a to 5c relate to Example 1-4 and show neuroprotective, anti-apoptotic and neuro- rescuing effects of tripentadecanoin in human induced pluripotent stem cells (iPSCs) when added concomitantly or 3, 6 hours after ΑβΟ treatment;

FIGs. 6a to 6i relate to Example 1-5 and show neuroprotective, anti-apoptotic and neuro- rescuing effects of tripentadecanoin in multiple toxins treated mouse primary neuron models when added at 3 hours after toxin treatment;

FIG. 7 relates to Example 1-6 and shows neuroprotective effects of different fatty acids with odd number of carbons in ΑβΟ treated mouse primary neuron models - when added at 48 hours before ΑβΟ treatment; FIG. 8 relates to Example 1-7 and shows neuroprotective effects of tripentadecanoin in camptothecin treated mouse primary neurons- when added at 48 hours before camptothecin treatment;

FIGs. 9a to 9d relate to Example 1-8 and show effects of tripentadecanoin in age-induced protein aggregates in Saccharomyces cerevisiae; DETAILED DESCRIPTION OF THE INVENTION

I. General Definitions

"Treat" or "treating" means any treatment, including, but not limited to, alleviating symptoms of a disease, disorder or condition, elimination the causation of a disease, disorder or condition on either on a temporary or permanent basis; or slowing, reducing, or inhibiting an ongoing pathological process in an asymptomatic individual.

"Preventing" and/or "prophylaxis" refers to inhibiting the initial onset of a pathologic process, such that that pathologic process that could eventually lead to development of symptoms never develops (i.e., preventing the development of a disease, disorder, or condition in a prophylactic manner). "Therapeutically effective amount" means an amount of a compound that is effective in treating and/or preventing a particular disorder or condition.

"Pharmaceutically acceptable carrier" is a non-toxic solvent, dispersant, excipient, or other material used in formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject or patient.

"Functional food" refers to a food given an additional function (often one related to health- promotion or disease prevention) by adding new ingredients or enriching existing ingredients. The term may also apply to traits purposely bred into existing edible plants, such as purple or gold potatoes having enriched anthocyanin or carotenoid contents, respectively. Functional foods may be "designed to have physiological benefits and/or reduce the risk of chronic disease beyond basic nutritional functions, and may be similar in appearance to conventional food and consumed as part of a regular diet" (US Department of Agriculture, Agricultural Research Service, AgResearch Magazine. November 2014; US Department of Agriculture, Agricultural Research Service. July 2010) The term "pharmaceutically acceptable salt" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example "Handbook of Pharmaceutical Salts. Properties, Selection and Use", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co- crystals", Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

As used herein, "rescue" means returning or rejuvenating the current pathological structure, state, condition or function of human body to a previous younger or better structure, state, condition or function status.

As used herein, "regenerating" means regrowing new tissues to replace lost or injured tissues or function of human body. (1) In a first embodiment, the present invention relates to a compound of the formula (I)

(I) wherein R¹, R² and R³ are independently selected from H or -C(0)R⁴, wherein R⁴ is

- (C8-C2o)alkyl, which is optionally mono-, di- or trisubstituted with OH, NH₂,

NHCH₃, N(CH₃)₂, F or CI; or

(C₈-C₂o)alkenyl, bearing 1 , 2 or 3 double bonds;

whereby at least one of R¹ , R² and R³ is -C(0)R⁴ with R⁴ being (C8-C20) alkyl with an even number of carbon atoms;

or a pharmaceutically acceptable salt thereof, for the use as a medicament for human and/or animals.

(2) In a further embodiment, the present invention relates to embodiment (1), wherein R¹, R and R are independently selected from H or -C(0)R , wherein R is

(C₈-C₂o)alkyl, which is optionally mono-, di- or trisubstituted with OH, F or CI; or - (C₈-C₂o)alkenyl, bearing 1 , 2 or 3 double bonds;

whereby at least one of R¹ , R² and R³ is -C(0)R⁴ with R⁴ being (C₈-C₂₀) alkyl with an even number of carbon atoms.

(3) In a further embodiment, the present invention relates to embodiment (1) or (2), wherein R¹, R² and R³ are independently selected from H or -C(0)R⁴, wherein R⁴ is

- (C₈-C₂o)alkyl, which is optionally mono-, di- or trisubstituted with OH, F or CI; whereby at least one of R¹, R² and R³ is -C(0)R⁴ with R⁴ being (C₈-C₂₀) alkyl with an even number of carbon atoms.

(4) In a further embodiment, the present invention relates to any one of embodiments (1) to (3), wherein R¹, R² and R³ are independently selected from H or -C(0)R⁴, wherein R⁴ is - (C₈-C₂o)alkyl, which is optionally mono-, di- or trisubstituted with OH or F; or

(C₈-C₂o)alkenyl, bearing 1 , 2 or 3 double bonds; whereby at least one of R¹ , R² and R³ is -C(0)R⁴ with R⁴ being (C₈-C20) alkyl with an even number of carbon atoms.

(5) In a further embodiment, the present invention relates to any one of embodiments (1) to (4), wherein R¹, R² and R³ are independently selected from H or -C(0)R⁴, wherein R⁴ is - (C₈-C2o) lkyl, which is optionally mono-, di- or trisubstituted with OH or F; or whereby at least one of R¹ , R² and R³ is -C(0)R⁴ with R⁴ being (C₈-C20) alkyl with an even number of carbon atoms.

(6) In a further embodiment, the present invention relates to any one of embodiments (1) to (5), wherein R¹, R² and R³ are independently selected from H or -C(0)R⁴, wherein R⁴ is - (C₈-C2o) lkyl, which is optionally mono-, di- or trisubstituted with F; or

(C₈-C2o)alkenyl, bearing 1 , 2 or 3 double bonds;

whereby at least one of R¹ , R² and R³ is -C(0)R⁴ with R⁴ being (C₈-C20) alkyl with an even number of carbon atoms.

(7) In a further embodiment, the present invention relates to any one of embodiments (1) to (6), wherein R¹, R² and R³ are independently selected from H or -C(0)R⁴, wherein R⁴ is

(C₈-C2o) lkyl, which is optionally mono-, di- or trisubstituted with F;

whereby at least one of R¹ , R² and R³ is -C(0)R⁴ with R⁴ being (C₈-C20) alkyl with an even number of carbon atoms. (8) In a further embodiment, the present invention relates to any one of embodiments (1) to (7),

wherein R¹, R² and R³ are independently selected from H and at least one -C(0)R⁴, wherein R⁴ is (C₈-C20) alkyl with an even number of carbon atoms.

(9) In a further embodiment, the present invention relates to any one of embodiments (1) to (8), wherein R¹, R² and R³ are independently selected from -C(0)R⁴ with R⁴ being (Cs- C20) alkyl with an even number of carbon atoms. (10) In a further embodiment, the present invention relates to any one of embodiments (1) to (9), wherein R⁴ is H or -C(0)R⁴ with R⁴ being Ci₂-alkyl, Ci₄-alkyl, Cie-alkyl, Cis-alkyl, or C₂₀-alkyl, whereby not all R¹, R² and R³ are H at the same time.

(11) In one embodiment of (10), one of R¹, R² and R³ is H and the others are -C(0)R⁴ with R⁴ being C₁₂-alkyl, C₁₄-alkyl, Ci₆-alkyl, Cis-alkyl or C₂₀-alkyl.

(12) In one embodiment of (10), two of R¹, R² and R³ are H and the other is -C(0)R⁴ with R⁴ being C₁₂-alkyl, C₁₄-alkyl, Ci₆-alkyl, Cis-alkyl or C₂₀-alkyl.

(13) In one embodiment of (10), R 1 , R2 and R 3 are independently from each other -C(0)R⁴ with R⁴ being Ci₂-alkyl, C_H-alkyl, Cie-alkyl, Cis-alkyl or C₂₀-alkyl. It is to be understood, that each of the alkyls of R⁴ can be combined with each other of the alkyls. In

1 2 3 · 4 1 2 3 particular, all R , R and R can be the same kind of -C(0)R . Preferably, R , R and R are either independently from each other or all together -C(0)R⁴ with R⁴ being Cn-alkyl or Ci₆-alkyl.

(14) In a particularly preferred embodiment, the present invention relates to a compound of formula (I), wherein R⁴ is -C(0)Ci₄-alkyl, i.e. a compound of formula (I) wherein R¹, R² and R³ are all -C(0)Ci₄-alkyl. The compound of this embodiment is the same as tripentadecanoin described below. The chemical name of tripentadecanoin, is also known as 1,2,3-Propanetriyl tripentadecanoate, 1,2,3-propanetriyl tripentadecanoate, or 1 ,2,3- tripentadecanoylglycerol. (15) In another embodiment, the present invention relates to a compound of formula (I), wherein one of R¹, R² and R³ is H and the others are -C(0)Ci₄-alkyl.

(16) In another embodiment, the present invention relates to a compound of formula (I), wherein two of R¹, R² and R³ is H and the third one is -C(0)Ci₄-alkyl.

(17) In a further embodiment, the invention relates to metabolites or prodrugs of the compound according to embodiments (10) to (16), namely to the carboxylic acids

HOC(0)Ci₂-alkyl, HOC(0)Ci₄-alkyl, HOC(0)Ci₆-alkyl, HOC(0)Ci₈-alkyl and HOC(0)C2o-alkyl. In particular, the invention relates to metabolites or prodrugs of the compound according to embodiment (14), namely to HOC(0)Ci4-alkyl.

(18) It is to be understood that all embodiments (1) to (17) relate to the described compounds or, where applicable a pharmaceutically acceptable salt thereof, for the use as a medicament for human, wherein the treatment dosage is 1 mg/day to 1000 mg/day.

(19) One embodiment of the invention relates to the compound according to any one of embodiments (1) to (17) for the use as a medicament for human, wherein the treatment dosage is from 1 mg/day to 1000 mg/day of the compound of formula (I). The lower limits of the treatment dosage are for instance 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day or 200 mg/ day. The upper limits are for instance 1000 mg/day, 900 mg/day, 800 mg/day, 750 mg/day, 700 mg/day, 600 mg/day, 500 mg/day, 400 mg/day, 300 mg/day, or 250 mg/day. It is to be understood that each upper limit can be combined with each lower limit. For instance, the dosage may be from 1 mg/day to 900 mg/day, or from 5 mg/day to 800 mg/day, or from 5 mg/day to 750 mg/day.

In one embodiment, the invention relates to the compound according to any one of embodiments (1) to (17) for the use as a medicament for animals, wherein the treatment dosage is from 1 mg/kg/day to 100 mg/kg/day.

In one embodiment, the given doses apply in particular to the compound according to any one of embodiments (8) to (17), particularly to embodiment (14).

(20) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of neurodegenerative diseases, retinal or optic nerve degenerative diseases, demyelinating diseases, neuromuscular disorders and muscular dystrophy, stroke, brain or spinal cord nerve injury, cranial nerve disorders, or seizures, amyloid deposit related diseases; and for the use of anti-aging or life-span prolongation and improving brain function. (21) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of neurodegenerative diseases which are selected from the group consisting of Amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and brain atrophy.

(22) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of optic and retinal degenerative diseases which are selected from the group consisting of optical atrophy, Leber's hereditary optic neuropathy (LHON), Dominant Optic Atrophy (DOA), age-related macular degeneration, glaucoma and retinitis pigmentosa.

(23) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of demyelinating diseases which are selected from the group consisting of adrenoleukodystrophy, multiple sclerosis, optical neuritis, Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Guillian-Barre syndrome, encephalitis caused by or related to Zika virus, cranial nerve palsy, neuromyelitis optica ( MO), acute disseminated encephalomyelitis, acute necrotizing hemorrhagic encephalitis, concentric sclerosis, diffuse sclerosis, metachromatic leukodystrophy, ball-like cell leukodystrophy, spongy degeneration of the central nervous system, Perry-plum disease, Alexander disease, radiation injury leukoencephalopathy, hypoxic leukoencephalopathy, periventricular leukomalacia disease, arteriosclerotic cortex under encephalopathy, progressive multifocal leukoencephalopathy, and central pontine myelinolysis syndrome. In particular, for the use in the treatment and/or prevention of multiple sclerosis, optical neuritis, Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Guillian-Barre syndrome, encephalitis caused by or related to Zika virus, cranial nerve palsy, and neuromyelitis optica (NMO).

(24) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of neuromuscular disorders and muscular dsytrophy diseases which are selected from the group consisting of myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, Charcot-Marie-Tooth disease (CMT). In particular for the use in the treatment and/or prevention of Duchenne muscular dystrophy and Charcot-Marie-Tooth disease (CMT)

(25) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of neurological injury related diseases or mixed neurological diseases selected from the group consisting of stroke, acute or chronic brain injury or spinal cord or nerve injury, cranial nerve disorders and seizures.

(26) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of amyloid deposit related diseases which are selected from the group consisting of diabetes, cardiac amyloidosis, primary amyloidosis, familial amyloidosis, senile systemic amyloidosis (SSA), secondary amyloidosis, and haemodialysis-associated amyloidosis.

(27) A further embodiment of the invention relates to any one of the compounds described in embodiments (1) to (17), for the use in the treatment and/or prevention of diseases or disorders of the central nervous system. (28) It is to be understood that all embodiments (1) to (17) relate to the described compounds or, where applicable a pharmaceutically acceptable salt thereof, for the use as a medicament for human, wherein the treatment dosage is 1 mg/day to 1000 mg/day.

(29) The compound of the formula (I) according to any one of embodiments (1) to (17) for the use in the treatment and/or prevention of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), dementia, and Creutzfeldt- Jakob disease, wherein the treatment dosage is from 1 mg/day to 1000 mg/day. (30) One embodiment of the invention relates to the compound according to any one of embodiments (1) to (17) for the use as a medicament for human according to any one of embodiments (20) to (27) and (29), wherein the treatment dosage is from 1 mg/day to 1000 mg/day of the compound of formula (I). The lower limits of the treatment dosage are for instance 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day or 200 mg/ day. The upper limits are for instance 1000 mg/day, 900 mg/day, 800 mg/day, 750 mg/day, 700 mg/day, 600 mg/day, 500 mg/day, 400 mg/day, 300 mg/day, or 250 mg/day. It is to be understood that each upper limit can be combined with each lower limit. For instance, the dosage may be from 1 mg/day to 900 mg/day, or from 5 mg/day to 800 mg/day, or from 5 mg/day to 750 mg/day.

(31) A further embodiment of the invention relates to any one of the compounds described in embodiments (8) to (17), for the use in the treatment and/or prevention of the diseases and conditions of embodiments (20) to (27) and (29), wherein the treatment dosage is as defined in embodiment (28) or (30). A particularly preferred embodiment of the invention relates to any one of the compounds described in embodiment (14), for the use in the treatment and/or prevention of the diseases and conditions of embodiments (20) to (27) and (29), wherein the treatment dosage is as defined in embodiment (28) or (30).

(32) A further embodiment of the invention relates to a pharmaceutical composition as such and in particular for the use in the treatment and/or prevention of the diseases and conditions of any one of embodiments (20) to (27) and (29), wherein the composition contains the compound of any one of embodiments (1) to (17) and a pharmaceutically acceptable carrier. Preferably, the composition contains the compound of any one of embodiments (8) to (17), in particular embodiment (14). The pharmaceutical composition may be used for human and/or animals.

(33) In a further embodiment, the pharmaceutical composition, in particular for human, according to embodiment (32) contains the compound of any one of embodiments (1) to (17) in an amount of 1 mg/day to 1000 mg/day. The lower limits are for instance 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day or 200 mg/ day. The upper limits are for instance 1000 mg/day, 900 mg/day, 800 mg/day, 750 mg/day, 700 mg/day, 600 mg/day, 500 mg/day, 400 mg/day, 300 mg/day, or 250 mg/day. It is to be understood that each upper limit can be combined with each lower limit. For instance, the dosage may be from 1 mg/day to 900 mg/day, or from 5 mg/day to 800 mg/day, or from 5 mg/day to 750 mg/day. This pharmaceutical composition is preferably for human.

In a further embodiment, the pharmaceutical composition for animals contains the compound of any one of embodiments (1) to (17) in an amount of 1 mg/kg/day to 100 mg/kg/day.

(34) In one embodiment, the pharmaceutical composition of embodiment (32) or (33) relates to formulations containing the active ingredient preferably in an amount as indicated embodiment (19), (28) or (30), and can be prepared in any form, such as oral dosage form (powder, tablet, capsule, soft capsule, aqueous medicine, syrup, elixirs pill, powder, sachet, granule), or topical preparation (cream, ointment, lotion, gel, balm, patch, paste, spray solution, aerosol and the like), or injectable preparation (solution, suspension, emulsion). Such formulations may be used for human and/or animals. In one embodiment, the formulations apply in particular to the compound according to any one of embodiments (8) to (17), particularly to embodiment (14). (35) A further embodiment of the invention relates to the use of the compound according to any one of embodiments (1) to (17) for the manufacture of a medicament for the treatment and/or prevention of the diseases and conditions of any one of embodiments (20) to (27) and (29). It is to be understood that all embodiments relating to the compounds of embodiments (1) to (17) for the use as medicament as such or for the treatment and/or prevention of the diseases given in embodiments (20) to (27) and (29) are disclosed and may be reformulated as use of the compound(s) for the manufacture of a medicament for the treatment and/or prevention of the disclosed diseases and conditions. The medicament may be used for human and/or animals. Preferably, the compound according to any one of embodiments (1) to (17), particularly of embodiments (8) to (17), preferably of embodiment (14) is comprised in the medicament in the amount as described in embodiments (19), (28), (30) and (33). Moreover, the medicament may be formulated as described in embodiment (34).

(36) A further embodiment of the invention relates to a method for treating and/or preventing the diseases and conditions of any one of embodiments (20) to (27) and (29), comprising administering to a patient an effective amount of the compound according to any one of embodiments (1) to (17). Thereby, the "effective amount" is as described above. In particular, the effective amount is as described in embodiments (19), (28) (30) and (33). It is to be understood that all embodiments relating to the compounds of embodiments (1) to (17) for the use as medicament as such or for the treatment and/or prevention of the diseases given in embodiments (20) to (27) and (29) are disclosed and may be reformulated in the respective method for treating and/or prevention format. The doses are the same as disclosed for example in embodiment (19), (28), (30) or (33). Moreover, the treatment and/or prevention can be performed with a medicament formulated as described in embodiment (34). Such method may be used for human and/or animals.

Preferably, the compound according to any one of embodiments (1) to (17), particularly of embodiments (8) to (17), preferably of embodiment (14) is comprised in the amount as described in embodiments (19), (28) (30) or (33). Moreover, the compound may be formulated as described in embodiment (34). (37) A further embodiment of the invention relates to the use of the compound according to any one of embodiments (1) to (17) as functional food or food supplement for human and/or animals. A functional food or food supplement in this sense is a food or food supplement that has physiological benefits and/or reduces the risk of the diseases and disorders of embodiments (20) to (27) and (29). A functional food or food supplement can be consumed as a part of a regular diet.

(38) A further embodiment of the invention relates to the use of any one of the compounds described in embodiments (1) to (17), for humans and animals for anti-aging, life-span prolongation or improving brain functions. (39) A further embodiment of the invention relates to the use according to embodiment (37), wherein the functional food or the food supplement is for humans and animals for anti-aging, life-span prolongation or improving brain functions.

(40) A further embodiment of the invention relates to the use of the compound according to any one of embodiments (1) to (17) as functional food or food supplement for human and/or animals, wherein the functional food or food supplement is for improving brain functions including vision, memory, learning, imaging, judgement, reading, perception, thinking, creating, elevating intellectual quotient (IQ).

(41) A further embodiment of the invention relates to the use of the compound according to any one of embodiments (1) to (17) as functional food or food supplement for human and/or animals, wherein the functional food is for neurodegenerative diseases, retinal or optic nerve degenerative diseases, demyelinated diseases, neuromuscular disorders and muscular dystrophy, stroke, brain or spinal cord nerve injury, amyloid deposit related diseases.

(42) A further embodiment of the invention relates to the use of the compound according to any one of embodiments (1) to (17) as functional food or food supplement for human and/or animals for specific diseases and conditions, wherein the diseases and conditions are those recited in embodiments (20) to (27) and (29). (43) A further embodiment of the invention relates to any one of the compounds described in embodiments (8) to (17), as functional food or food supplement for human and/or animal according to embodiments (37) to (42).

A particularly preferred embodiment of the invention relates to the compound described in embodiment (14), as functional food or food supplement for human and/or animal according to embodiments (37) to (42).

In one embodiment, the compound relates to any one of the compounds described in embodiments (8) to (17), particularly to embodiment (14).

(44) A further embodiment of the invention relates to the use of the compound according to any one of embodiments (1) to (17) as functional food or food supplement for human, wherein the dosage is from 1 μg (microgram)/day to 50 mg/day. In a further embodiment, the dosage is from 1 μg (micro gram)/day to 20 mg/day. The lower limits are for instance 1 μg (micro gram)/day, 2 μg (microgram)/day, 3 μg (microgram)/day, 4 μg (micro gram)/day, 5 μg (microgram)/day, 7 μg (microgram)/day, 10 μg (microgram)/day, 20 μg (microgram)/day, 25 μg (microgram)/day, 50 μg (microgram)/day, 100 μg (microgram) /day, 200 μg (microgram) /day, 300 μg (microgram) /day, 400 μg (microgram) /day or 500 μg (microgram) /day. The upper limits are for instance 50 mg/day, 40 mg/day, 30 mg/day, 20 mg/day, 10 mg/day, 5 mg/day, 3 mg/day, 2 mg/day, 1 mg/day, 900 μg (microgram) /day. It is to be understood that each upper limit can be combined with each lower limit. In one embodiment, the dosage is from 1 μg (microgram)/day to 20 mg/day. In another embodiment, the dosage is from 1 μg (microgram)/day to 900 μg (microgram) /day.

A further embodiment of the invention relates to the use of the compound according to any one of embodiments (1) to (17) as functional food or food supplement for animals, wherein the dosage is from 1 mg/kg /day to lOOmg/kg/day. In one embodiment, the given doses apply in particular to the compound according to any one of embodiments (8) to (17), particularly to embodiment (14). (45) A further embodiment of the invention relates to the preparation of a compound of formula (I) according to any one of embodiments (1) to (17) by esterification of glycerol with a fatty acid of the formula (II) HOC(0)R⁴, wherein R⁴ is independently from each other

- (C5-C20) alkyl, which is optionally mono-, di- or trisubstituted with OH, NH₂, NHCH3, N(CH₃)₂, F or CI; or

(C5-C₂₀) alkenyl, bearing 1, 2 or 3 double bonds;

whereby at least one of H0C(0)R⁴ bears an R being (C₆-C₂₀) alkyl with an even number of carbon atoms. Esterification of glycerol is known to the skilled person. For example, esterification can be acid-catalysed, for instance with methanolic HC1, methanolic H₂SO₄, boron-trifiouride as an example of a Lewis acid and other acidic catalysts. Moreover, esters can be obtained via activated fatty acids, such as acid halides, fatty acid anhydrides, imidazolides and with other well-known coupling reagents like DCC ( ,Ν'-Dicyclohexylcarbodiimid) or EDC (1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide).

Moreover, protecting group strategies can be used in order to specifically esterify a desired position with a desired fatty acid. Appropriate protecting groups can form 5- or 6- membered 1,2-diols, such as the reaction of glycerol with benzaldehyde, leading to a 1 ,3- benzylidene derivative, or the formation of a 1 ,2-acetonide with acetone. 1,2-Diols may also be protected as their cyclic carbonates, which can be prepared with phosgene (COCl₂), or triphosgene (CC1₃0C(0)0CC1₃). Protecting group strategies are known to the skilled person, for instance from "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley- Interscience, 1999. Protecting groups are also used to protect amino groups or hydroxy groups bound to the alkyl groups of the fatty acids during esterification. (46) A further embodiment of the invention relates to the preparation of the compound according to embodiment (14) by esterification of glycerol with pentadecanoic acid.

In summary, the present invention can also be formulated as follows:

(i) Use of a compound of the formula (I)

(I)

wherein R¹, R² and R³ are independently selected from H or -C(0)R⁴, wherein R⁴ is

(C₈-C₂₀) alkyl, which is optionally mono-, di- or trisubstituted with OH, NH₂, NHCH3, N(CH₃)₂, F or CI; or

(C₈-C₂₀) alkenyl, bearing 1, 2 or 3 double bonds;

whereby at least one of R¹, R² and R³ is -C(0)R⁴ with R⁴ being (C8-C20) alkyl with an even number of carbon atoms;

or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for humans and/ 0 r animals .

(ii) The use of the compound of the formula (I) according to (i), wherein R¹, R² and R³ are independently selected from H and at least one -C(0)R⁴, wherein R is (C₈-C₂₀) alkyl with an even number of carbon atoms.

(iii) The use of the compound of the formula (I) according to (i) or (ii), wherein R¹, R² and R³ are independently selected from -C(0)R⁴ with R⁴ being (C8-C20) alkyl with an even number of carbon atoms. (iv) The use of the compound of the formula (I) according to (i) or (ii), wherein one or two of R¹, R² and R³ are H and the other(s) is/are -C(0)R⁴ with R⁴ being Ci₂-alkyl, C_H- alkyl, Ci6-alkyl, Cis-alkyl or C₂o-alkyl.

(v) The use of the compound of the formula (I) according to any one of (i) to (iii), wherein R¹, R², and R³ are -C(0)R⁴ with R⁴ being Ci₄-alkyl.

(vi) A metabolite or prodrug of the compound of formula (I) according to (iv), wherein the metabolite or prodrug is HOC(0)Ci₂-alkyl, HOC(0)Ci₄-alkyl, HOC(0)Ci₆-alkyl, HOC(0)Ci8-alkyl or HOC(0)C2o-alkyl for the manufacture of a medicament for humans and/or animals.

(vii) The use of the compound of the formula (I) according to any one of (i) to (vi) for the manufacture of a medicament for the treatment and/or prevention of neurodegenerative diseases, retinal or optic nerve degenerative diseases, demyelinating diseases, neuromuscular disorders and muscular dystrophy, stroke, brain or spinal cord nerve injury, cranial nerve disorders, or seizures, amyloid deposit related diseases, and for the use of anti-aging or life-span prolongation and improving brain function.

(viii) The use of the compound of the formula (I) according to any one of (i) to (vi)for the manufacture of a medicament for the treatment and/or prevention of neurodegenerative diseases which are selected from the group consisting of, Amyotrophic lateral sclerosis (ALS), Dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and brain atrophy.

(ix) The use of the compound of the formula (I) according to any one of (i) to (vi) for the manufacture of a medicament for the treatment and/or prevention of retinal and optic degenerative diseases which are selected from the group consisting of optical atrophy, Leber's hereditary optic neuropathy (LHON), Dominant Optic Atrophy (DOA) and age- related macular degeneration, glaucoma and retinitis pigmentosa,

(x) The use of the compound of the formula (I) according to any one of (i) to (vi)for the manufacture of a medicament for the treatment and/or prevention of demyelinating diseases which are selected from the group consisting of adrenoleukodystrophy, multiple sclerosis, optical neuritis, Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Guillian-Barre syndrome, encephalitis caused by or related to Zika virus, cranial nerve palsy, neuromyelitis optica ( MO), acute disseminated encephalomyelitis, acute necrotizing hemorrhagic encephalitis, concentric sclerosis, diffuse sclerosis, metachromatic leukodystrophy, ball-like cell leukodystrophy, spongy degeneration of the central nervous system, Perry-plum disease, Alexander disease, radiation injury leukoencephalopathy, hypoxic leukoencephalopathy, periventricular leukomalacia disease, arteriosclerotic cortex under encephalopathy, progressive multifocal leukoencephalopathy, and central pontine myelinolysis syndrome. (xi) The use of the compound of the formula (I) according to any one of (i) to (vi)for the manufacture of a medicament for the treatment and/or prevention of neuromuscular disorders and muscular dsytrophy diseases which are selected from the group consisting of myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, Charcot-Marie-Tooth disease (CMT).

(xii) The use of the compound of the formula (I) according to any one of (i) to (vi)for the manufacture of a medicament for the treatment and/or prevention of neurological injury related diseases or mixed neurological diseases selected from the group consisting of acute or chronic brain injury or spinal cord nerve injury, cranial nerve disorders and seizures.

(xiii) The use of the compound of the formula (I) according to any one of (i) to (vi) for the manufacture of a medicament for the treatment and/or prevention of amyloid deposit related diseases which are selected from the group consisting of diabetes, cardiac amyloidosis, primary amyloidosis, familial amyloidosis, senile systemic amyloidosis (SSA), secondary amyloidosis, and haemodialysis-associated amyloidosis.

(xiv) The use of the compound of the formula (I) according to any one of (i) to (vi) for the manufacture of a medicament for the treatment and/or prevention of the diseases and conditions of (vii) to (xiii), wherein the compound is contained in a dosage from 1 mg/day to 1000 mg/day.

(xv) The use of the compound of the formula (I) according to any one of (i) to (vi) for the manufacture of a medicament for the treatment and/or prevention of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), dementia, and Creutzfeldt- Jakob disease, wherein the compound is contained in a dosage from 1 mg/day to 1000 mg/day.

(xvi) The compound of the formula (I) according to any one of (i) to (vi) for the use as a medicament for animals, wherein the treatment dosage is 1 mg/kg/day to lOOmg/kg/day.

(xvii) A pharmaceutical composition for the use in the treatment and/or prevention of the diseases and conditions of (vii) to (xiii) and (xv), wherein the composition contains the compound of claims 1 to 6 and a pharmaceutically acceptable carrier.

(xviii) A compound of the formula (I) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, for the use as a medicament for human and/or animals. (xix) The compound of the formula (I) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, for the use as a medicament for the treatment and/or prevention of the diseases and conditions according to any one of (vii) to (xiii) and (xv). (xx) A method for treating and/or preventing of the diseases and conditions of (vii) to (xiii) and (xv), comprising administering to a patient an effective amount of the compound according to any one of (i) to (vi).

(xxi) Use of the compound according to any one of (i) to (vi) as functional food or food supplement for human and/or animal.

(xxii) Use according to (xxi) for human, wherein the dosage of the compound is from 1 μg (microgram)/day to 50 mg/day. (xxiii) Use according to (xxi) for animals, wherein the dosage of the compound is from 1 mg/kg /day to lOOmg/kg/day.

Conclusion Surprisingly, the inventors have found that the administration of lipids bearing fatty acids with odd number of carbon atoms have presented neuroprotective effects. Tripentadecanoin presented a strong effect on preventing and/or clearing the age-induced protein aggregation during normal yeast ageing. The results from the Camptothecin model suggest that tripentadecanoin may play a significant protective role at the gene level. A functional food containing tripentadecanoin was particularly efficacious in the volunteers of patients with incurable diseases, showing very potent neuroprotective, anti-apoptotic, neuro-rescuing, and neuro-regenerative effects, accordingly it has potential to be used as a medicament and/or functional food for the treatment and/or prevention of neurodegenerative diseases and other chronic diseases. FIG. 1 relates to Example 1-1 - neuroprotective effects of tripentadecanoin (added alone or 48 hours before ΑβΟ treatment) based on cell viability evaluated with MTT

Mouse primary cortical neurons were pre-incubated for 48h with vehicle, 0.05 μΜ DHA (used as positive control) or different concentrations of tripentadecanoin. Then, cortical neurons were treated for 24 h with vehicle (FIG. 1 left) or 1 μΜ ΑβΟ (FIG. 2 right) and cell viability was determined using the MTT assay (n=3 determinations per condition, 1 independent experiment). Data are represented as % of vehicle control (Mean±SD).

FIG. 2 relates to Example 1-1 - neuroprotective effects of tripentadecanoin- microscopic images of neurons

Left: vehicle control added for 48 hours, then adding ΑβΟ control for 24 hours; Right: tripentadecanoin at 320nM added for 48 hours, then adding ΑβΟ for 24 hours

FIG. 3 relates to Example 1-2 - axon growth effects of tripentadecanoin Mouse primary cortical neurons were pre-incubated for 48h with vehicle, 60nM sAPPa (used as positive control) or different concentrations of tripentadecanoin. Then, cortical neurons were treated for 24 h with vehicle. Data are represented as % of vehicle control (MeaniSD). FIG. 4 relates to Example 1-3 - neuroprotective, anti-apoptotic and neuro-rescuing effects of tripentadecanoin in mouse primary neuron models when added concomitantly or 3, 6 hours after ΑβΟ treatment

Mouse primary cortical neurons were treated at 0 h (TO) with vehicle or 1 μΜ ΑβΟ. Different concentrations of tripentadecanoin or HNG (0.1 μΜ, used as positive control) were added concomitantly to ΑβΟ at 0 h (TO), 3 h (T3) or 6 h (T6) after ΑβΟ. Then, cortical neurons were incubated for 24 h and cell viability was determined using the MTT assay (n=3 determinations per condition, 1 independent experiment). Data are represented as % of vehicle control (Mean± SD).

FIG. 5 (FIGs. 5a, 5b and 5 c) relates to Example 1-4 - neuroprotective, anti-apoptotic and neuro-rescuing effects of tripentadecanoin in human induced pluripotent stem cells (iPSCs) when added concomitantly or 3, 6 hours after ΑβΟ treatment iPSCs were treated at 0 h (TO) with vehicle or 1 μΜ ΑβΟ. Different concentrations of tripentadecanoin or 0.1 μΜ HNG (used as positive control) were added concomitantly to ΑβΟ at 0 h (TO), 3 h (T3) or 6 h (T6) after ΑβΟ. Then, were incubated for 24 h and cell viability was determined using the NSE ELISA assay (n=6 determinations per condition, 1 independent experiment). Data are represented as % of vehicle control (Meant SD).

FIG. 6 (FIGs. 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i) relates to Example 1-5 - neuroprotective, anti-apoptotic and neuro-rescuing effects of tripentadecanoin in multiple toxins treated mouse primary neuron models when added at 3 hours after Toxin treatment Cortical neurons were treated at 0 h (TO) with vehicle or multiple neuron toxins. Different concentrations of tripentadecanoin or 0.1 μΜ HNG (0.1 μΜ, used as positive control) were added at 3 h (T3) after toxins treatment. Then, cortical neurons were incubated for 24 h and cell viability was determined using the MTT assay (n=3 determinations per condition, 1 independent experiment). Data are represented as % of vehicle control (Mean±SD).

FIG. 7 relates to Example 1-6 - neuroprotective effects of different fatty acids with odd number of carbons in ΑβΟ treated mouse primary neuron models - when added at 48 hours before ΑβΟ treatment

Mouse primary cortical neurons were incubated with vehicle or 1 μΜ ΑβΟ in the absence or presence of different fatty acids with odd number of carbons at 1 μΜ) for 48 hours. Then ΑβΟ (ΙμΜ Αβ1-42 oligomers) or vehicle were added for 24 h. ΑβΟ-induced neurotoxicity was evaluated using MTT assay. Data are represented as % of vehicle control (MeaniSD).

FIG. 8 relates to Example 1-7 - neuroprotective effects of tripentadecanoin in camptothecin treated mouse primary neurons- when added at 48 hours before camptothecin treatment

Mouse primary neurons were incubated with vehicle or toxins in the absence or presence of different concentrations of tripentadecanoin added 48 hours before toxin's challenge. After the addition of toxins, cells were further incubated for 24 h.

FIG. 9 (FIG. 9a, 9b, 9c, and 9d) relates to Example 1-8 - The effects of tripentadecanoin extracts in age-induced protein aggregates in Saccharomyces cerevisiae FIG. 9a: Representative images of a young cell, or old cells untreated or treated with tripentadecanoin (30 μΜ). Upper panels are maximum projection of z-series stacks of cells stained with fluorescent brightener 28 and imaged in the DAPI channel to reveal bud scars. Lower panel are single focal planes images of the same cells that express Hspl04-GFP and imaged in the GFP channel. Arrow point at an Hspl04-GFP focus. FIG. 9b: Quantification of age of old cells obtained in all conditions tested. Young cells obtained through an exponentially growing culture had an average age of 0.383 ±0.5952. The number of cells analyzed varied from 73 to 342. FIG. 9c: Percentage of cells with an Hspl04-GFP focus. Cells were imaged with the same illumination conditions. All old cells imaged were included (between 75 and 94 cells). All focal planes were examined. Mean±SD. P values are adjusted p values from an ANOVA comparing to vehicle only.

FIG. 9d: Average fluorescence intensity of Hspl04-GFP in the cell as a proxy for Hspl04- GFP concentration. Mean±SD. P values are adjusted p values obtained from ANOVA comparing to vehicle only.

EXPERIMENTAL PART ABBREVIATIONS AND DEFINITIONS

ΑβΟ Amyloid-β Oligomers

DHA Docosahexaenoic acid

HNG Humanin

iPSC(s) Induced Pluripotent Stem Cell(s)

MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide

NSE Neuron specific enolase

ELISA Enzyme-linked immunosorbent assay sAPPa Secreted amyloid precursor protein-a SD Standard Deviation

tripentadecanoin CAS No.: 7370-46-9

The chemical formula is C48H92O6, named herein as tripentadecanoin, also known as 1,2,3- Propanetriyl tripentadecanoate, 1 ,2,3-propanetriyl tripentadecanoate, or 1 ,2,3- tripentadecanoylglycerol. The molecular weight is 765.24 g/mol (see embodiment (14)).

EXAMPLES (I) OF CELLULAR EXPERIMENTS EXAMPLE 1-1

The effects of tripentadecanoin in mouse primary neuron models when added 48 hours prior to ΑβΟ treatment

The aim of this study is to determine whether tripentadecanoin might rescue neuronal death in in vitro neuron models. For that purpose, the neuro -protective effects of tripentadecanoin at six concentrations were investigated using mouse primary cortical neurons challenged with Αβ1-42 oligomers (ΑβΟ). β-Amyloid peptide triggers a variety of pathological changes finally leading to neuronal dysfunction and degeneration in multiple neurological diseases including AD (Deshpande et al. The Journal of Neuroscience, 2006; 26(22):6011- 6018).

Cortical neurons from embryonic day 16-17 are prepared from C57BL6/J mouse fetuses. In brief, dissociated cortical cells were plated (50.000 cells/well) in 48-well plates pre- coated with 1.5 μg/mL polyornithine (Sigma). Cells were cultured in a chemically defined Dulbecco's modified eagle's/F12 medium free of serum and supplemented with hormones, proteins and salts. Cultures were kept at 35°C in a humidified 6% C0₂ atmosphere. Mouse cortical neurons were exposed for 24 h to 1.0 μΜ ΑβΟ after a 48-h pre-incubation with vehicle or different concentrations of tripentadecanoin. The ΑβΟ-induced neurotoxicity was evaluated using the MTT assay.

As expected, the incubation of cortical neurons with 1.0 μΜ ΑβΟ for 24h resulted in a decreased cell viability by 48.6±1.4%. DHA (0.05 μΜ, positive control) reduced ΑβΟ- induced neuronal death with a remaining cell viability of 82.0±2.6% of control. These control data demonstrate that: i) as expected, DHA protected neurons, and ii) cells challenged with ΑβΟ could be successfully prevented by DHA pre -treatment, verifying the test system. Neurons were pre-incubated with different concentrations of tripentadecanoin for 48h and thereafter treated for 24h with ΙμΜ ΑβΟ. The results were that in the presence of different concentrations of tripentadecanoin resulted in dose-dependent neuroprotective effect (FIG. 1 right and FIG. 2). The maximal neuroprotective effect was 100% at a dilution of the suspension corresponding to 320 nM (cell viability of 11 1.9±1.5%). The EC50 effect is expected around 66 nM.

When neurons pre-incubated for 48 h with different concentrations of tripentadecanoin only, showed a trend for a higher cell viability of up to 116.6±3.7% at InM of tripentadecanoin (FIG. 1 left). Please note the tripentadecanoin was not fully soluble in stock solutions.

In conclusion, the data suggest that tripentadecanoin offer a strong protection toward ΑβΟ- induced neurotoxicity. A neuronal-growth-stimulating effect of tripentadecanoin is observed. EXAMPLE 1-2

The effects of tripentadecanoin of axonal growth in mouse primary neuron models

The aim of this study is to test the neurotrophic effects of different concentrations of tripentadecanoin in mouse primary cortical neurons.

Cortical neurons from embryonic day 16-17 are prepared from C57B16/J mouse fetuses, as described in Example 1-1. After 96-h incubation, axonal length is recorded. Briefly, cells were washed with ice-cold PBS and fixed with cold methanol. Following fixation, cells are immunolabelled using a specific antibody detecting total MAP2 protein. Antibodies to MAP2 are excellent markers on neuronal cells, their axons and neuronal dendrites. For quantification of axonal length, six independent images of labelled cells are captured using an inverted microscope. Pictures of cells are analyzed using Neuron-J software and axonal length is recorded manually. A minimum of 100 independent neurons are treated. The data are expressed as mean axonal length (expressed in μηι) (Mean±SD). Statistical differences between vehicle -treated cells and cells treated with compounds are determined using a t- test. As expected, sAPPa (positive control) strongly stimulated neuronal axon outgrowth of 264.63±157.51 μιη vs. vehicle control of 165.96±90.18 μιη (p<0.0001); while tripentadecanoin strongly stimulated neuronal axon outgrowth of 304.27±149.60 μηι at a concentration of Ι ΟΟΟΟηΜ vs. vehicle control (p<0.0001 vs. vehicle control); 199.93±101.17 μιη at a concentration of ΙΟΟΟηΜ vs. vehicle control (p<0.05 vs. vehicle control). (FIG. 3) In summary, tripentadecanoin has demonstrated significant axonal growth effects and neurotrophic effects in mouse primary neuron models.

EXAMPLE 1-3

The effects of tripentadecanoin in mouse primary neuron models when added

concomitantly with ΑβΟ or 3, and 6 hours after ΑβΟ treatment The aim of this study is to determine whether tripentadecanoin might present neuroprotective, anti-apoptotic and neuro -res cuing effects in in vitro ΑβΟ induced neuron death models. For that purpose, the neuro-protective effects of tripentadecanoin at six concentrations were investigated using mouse primary cortical neurons challenged with Αβ1 -42 oligomers (ΑβΟ). Compounds were added at different time points (concomitantly TO with ΑβΟ and T3, or T6 after ΑβΟ) with the aim to identify rescuing effects or anti- apoptotic effects.

Cortical neurons from embryonic day 16-17 are prepared from C57B16/J mouse fetuses, as described in Example 1-1.

Mouse cortical neurons were exposed for 24 h to 1.0 μΜ ΑβΟ. The ΑβΟ-induced neurotoxicity was evaluated using the MTT assay. As expected, the incubation of cortical neurons with 1.0 μΜ ΑβΟ for 24 h resulted in a decreased cell viability by 50.9±2.0%, 51.3±2.0% and 51.7±4.2 % for plates 1 , 2 and 3 respectively. (FIG. 4)

As expected, humanin peptide (FING, S 14G variant of humanin peptide, positive control) added at TO strongly reduced ΑβΟ-induced neuronal death with a remaining cell viability of 91.6 ± 2.1 % of control (FIG. 4). When added 3 or 6 h after ΑβΟ, HNG did not prevent cell death in agreement with historical data. These control data demonstrate that: as expected, HNG protects neuronal cells only when added concomitantly to ΑβΟ, verifying the test system.

Neurons were treated with different concentrations of tripentadecanoin added concomitantly to ΑβΟ (TO), 3 h after ΑβΟ (T3), or 6 h after ΑβΟ (T6). The results were: in all experimental conditions (i.e. TO, T3 and T6), tripentadecanoin showed dose-dependent neuroprotective effects. For a concentration of 1000 nM, tripentadecanoin prevented ΑβΟ- induced cell death when added concomitantly to ΑβΟ (viability of 94.5±4.6%). Moreover, tripentadecanoin protected from ΑβΟ-induced cell death when added 3 h after ΑβΟ at concentrations of 320 and 1000 nM (viability of 65.3±2.6% and 76.6±2.9%, respectively) and when added 6 h after ΑβΟ at a concentration of 1000 nM (viability of 62.4±3.5%). (FIG. 4)

The percentage of neuroprotection and anti-apoptosis effects was defined as: (neuron viability of tripentadecanoin group - neuron viability of toxin treated group) / (100 - neuron viability of toxin treated group) x 100%. The % of neuroprotection and anti- apoptotic effects of tripentadecanoin at ΙΟΟΟηΜ is 88.7%, 52.0%, 22.3%, at TO, T3, or T6, respectively. (FIG. 4)

In summary, the data suggest that tripentadecanoin offer a strong neuroprotective, anti- apoptotic and neuro-rescuing effects toward ΑβΟ-induced neurotoxicity. Tripentadecanoin discriminate from humanin that it was more potent than humanin to rescue ΑβΟ-induced neuronal death.

EXAMPLE 1-4

The effects of tripentadecanoin in ΑβΟ treated human induced pluripotent stem cells (iPSC) when added concomitantly or 3 and 6 hours after ΑβΟ treatment

To determine whether tripentadecanoin might rescue neuronal death in human iPSC- derived neurons challenged with Αβ1-42 oligomers (ΑβΟ). In this cellular model, ΑβΟ induce a dramatic neuronal death that could be monitored by the level of neuronal specific enolase ( SE) using a specific ELISA assay. Tripentadecanoin will be added at different time points (concomitantly and after ΑβΟ) with the aim to identify rescuing effects.

Cells (HIP-Neuronal progenitors, GlobalStem, Cat#GSC-4312, Lot#20010260) are plated in 96-well plates at a density of 60.000 cells per well and culture. Before experiments, cells are matured for five weeks and kept at 37°C in a humidified 5% C0₂ atmosphere.

Cells are incubated with vehicle or 1 μΜ ΑβΟ in the absence or presence of different concentrations (i.e. 10, 100, 1000 and 10000 nM) of tripentadecanoin added concomitantly to ΑβΟ (TO), 3 h after ΑβΟ (T3), or 6 h after ΑβΟ (T6). Cells are incubated for 24h in a final volume of 100 μL per well. For positive control, cells are treated similarly in the presence of 0.1 μΜ HNG (i.e. S14G variant of humanin peptide). In addition, neuronal loss is monitored using the detection of neuronal specific enolase (NSE) by ELISA assay according to supplier's recommendations (CloneCloud, Cat#SEA537Hu). A total of three data points per experimental condition will be generated here.

Human iPSC were exposed for 24 h to 1.0 μΜ ΑβΟ. The ΑβΟ-induced neurotoxicity was evaluated using the NSE assay. As expected, the incubation of neurons with 1 ,0 μΜ ΑβΟ for 24 h resulted in a decreased cell viability of 49.7±5.5%, 37.5±3.0% and 46.9±1.9 % for plates 1 , 2 and 3 respectively.

As expected, humanin peptide (HNG, positive control) added at TO strongly reduced ΑβΟ- induced neuronal death with a neuron viability of 85.3±5.6% of control. When added 3 or 6 h after ΑβΟ, HNG did not prevent cell death. These control data demonstrate that: i) as expected, HNG protects neuronal cells only when added concomitantly to ΑβΟ, and ii) cells challenged with ΑβΟ can be successfully rescued, verifying the test system. (FIG. 5)

IPSCs were treated with different concentrations of tripentadecanoin added concomitantly to ΑβΟ (TO), 3 h after ΑβΟ (T3), or 6 h after ΑβΟ (T6). The results were as follows: tripentadecanoin in all experimental conditions (i.e. TO, T3 and T6), showed dose- dependent neuroprotective, neuro-rescuing and anti-apoptotic effects. For a concentration of 10000 nM, tripentadecanoin prevented ΑβΟ-induced cell death when added concomitantly to ΑβΟ (cell viability of 76.7±2.7%). Tripentadecanoin protected from ΑβΟ-induced cell death when added 3 h after ΑβΟ at concentrations of 10000 nM (cell viability of 94.2±7.1%) and when added 6 h after ΑβΟ at a concentration of 10000 nM (cell viability of 88.8±1.3%). The % of neuroprotection and anti-apoptotic effects of tripentadecanoin at 10000 nM is 53.7%, 90.8%, 78.9%, at TO, T3, or T6, respectively. (FIG. 5)

In conclusion, the data suggest that tripentadecanoin offers a strong protection, neuro- rescuing and anti-apoptotic effect toward ΑβΟ-induced neurotoxicity in human neurons derived from iPSC. Tripentadecanoin discriminates from humanin as it was more potent than humanin to inhibit ΑβΟ-induced toxicity in this cellular model. EXAMPLE 1-5

The effects of tripentadecanoin in multiple neuron toxins treated mouse primary neuron models - when added at 3 hours after toxins treatment

To determine whether tripentadecanoin might rescue neuronal death in multiple toxin stressed in vitro models. The neuro-protective effects of different concentrations of tripentadecanoin was investigated using mouse primary cortical neurons challenged with different types toxins. Tripentadecanoin was added three hours (T3) after toxins with the aim to identify rescuing effects. Cell viability was investigated using the MTT assay after a 24-h incubation of cells with toxins.

Stable oligomeric or fibrillar preparations are prepared according to historical protocols. The source of the different toxins is as follow:

• Αβ1 -42 and Αβ25-35 from Bachem (ref H1368 and HI 192, respectively).

• Human Tau (2N4R) protein from Evotec.

· Human a-synuclein from r-Peptide (ref 0101008603).

• Amylin from Bachem (ref H-7905.1000) • Prion Protein Π8-135 from Bachem (ref H-4206, respectively).

All treatments are done in triplicates in 48-well plates at DIV 6/7. Cells were incubated with vehicle or toxins (at the indicated final concentrations) in the absence or presence of different concentrations of tripentadecanoin (100, 1000, 10000 nM) added 3 h after toxins (T3). Cells were incubated for 24 h in a final volume of 140 μL· per well.

The positives control (added at T3) used was 0.1 μΜ HNG (S 14G variant of humanin peptide) as a well-known antiapoptotic peptide.

Cells were incubated for 24h before monitoring cell viability using the MTT assay. Briefly, cells were incubated at 35°C for 1 h with MTT (Sigma, Cat #M2128-10G, Lot # MKBH7489V). For that purpose, 14 nL of 5 mg/mL MTT (solubilized in PBS) are added in each well. After incubation, medium was removed and cells were lyzed with 150 μL· DMSO for 10 minutes and protected from light. After complete solubilization of formazan, absorbance at 570 nm is recorded using a Spectrophotometer BMG Labtech Fluostar Omega. The percentage of neuroprotection and anti-apoptosis effects was defined as: (neuron viability of tripentadecanoin group - neuron viability of toxin treated group) / (100 - neuron viability of toxin treated group) x 100%.

• Tripentadecanoin showed anti-apoptotic and neuroprotective effects against Αβ1-42 fibrils (22.3% at ΙΟΟΟΟηΜ) (FIG. 6a) and Αβ25-35 fibrils (32.1% at ΙΟΟΟΟηΜ) (FIG. 6b).

• Tripentadecanoin showed anti-apoptotic and neuroprotective effects against human tau oligomer-induced toxicity (46.8% at 10000 nM) (FIG. 6c) and tau fibril-induced toxicity (23.1% at 10000 nM) (FIG. 6d).

• Tripentadecanoin showed anti-apoptotic and neuroprotective effects against human alpha-synuclein oligomer-induced toxicity (FIG. 6e) (45.8% at ΙΟΟΟΟηΜ) and against alpha-synuclein fibrils (FIG. 6f) (34.0% at ΙΟΟΟΟηΜ). • Tripentadecanoin showed anti-apoptotic and neuroprotective effects against human amylin in both oligomers (30.8%, 37.3% at 1000, 10000 nM, respectively) (FIG. 6g) and fibrils assays (45.3%, 52.6% at 1000, ΙΟΟΟΟηΜ, respectively) (FIG. 6h).

• Tripentadecanoin showed anti-apoptotic and neuroprotective effects against prion oligomer-induced toxicity (23.5%, 53.8%, respectively at 10000 nM) (FIG. 6i).

In conclusion, the data suggest that tripentadecanoin offers a strong protective, neuro- rescuing and anti-apoptotic effect toward Αβ1-42 fibrils-, Αβ25-35 fibrils-, human tau oligomer-, human tau fibrils-, human alpha-synuclein oligomer-, alpha-synuclein fibrils-, human amylin oligomers-, human amylin fibrils- and prion oligomers-induced neurotoxicity in mouse primary cortex neurons. Tripentadecanoin discriminates from humanin as it is more potent than humanin to inhibit multiple toxins-induced neuron deaths in these cellular models.

EXAMPLE 1-6

The effects of Different Fatty Acids with Odd Number of Carbons in ΑβΟ treated mouse primary neuron models - when added at 48 hours before ΑβΟ treatment

The aim of this study was to test if there was any difference in the neuro-protective effects of fatty acids containing odd number of carbons using mouse primary cortical neurons challenged with ΑβΟ. Compounds were added 48 hours before treatment with 1 μΜ ΑβΟ, with the aim to identify preventing effects. Cell viability was investigated using the MTT assay after a 24-h incubation of cells with ΑβΟ.

Cortical neurons from embryonic day 16-17 were prepared from C57B16/J mouse fetuses, as described in Example I- 1.

All treatments were done in triplicates in 48 -well plates. Cells were incubated with vehicle or 1 μΜ ΑβΟ in the absence or presence of different lipids at the indicated final concentrations) added at 48 hours before ΑβΟ. Cells were incubated with ΑβΟ for 24 h in a final volume of 140 μL· per well. For positive controls, cells are treated similarly (48 hours before ΑβΟ) in the presence of 0.05 μΜ DHA.

Following ΑβΟ-treatment, cell viability was measured using the MTT assay. Briefly, cells were incubated at 35°C for 1 h with MTT (Sigma, Cat #M2128-10G, Lot # MKBH7489V). For that purpose, 14 of 5 mg/mL MTT (solubilized in PBS) were added in each well. After incubation, medium was removed and cells were lyzed with 150 μL· DMSO for 10 minutes and protected from light. After complete solubilization of formazan, absorbance at 570 nm was recorded.

Mouse primary cortical neurons were exposed for 24 h to vehicle or ΙμΜ Αβ1-42 oligomers. ΑβΟ-induced neurotoxicity was evaluated using MTT assay. As expected, the incubation of cells with ΑβΟ for 24 h resulted in a decreased viability of 59.9±1.7% of control. (FIG. 7)

As expected, the preincubation of cells with 50 nM DHA prevented ΑβΟ-induced cell death. Indeed, primary neurons preincubated with 50 nM DHA for 48 h and challenged with 1 μΜ ΑβΟ exhibited a remaining cell viability of 90.9±3.1 % of control.

In summary, the 48-h preincubation of cells with lipids with odd number of carbons GG05, GG07 or GG09 resulted in a dose independent neuroprotective effects at 0.01 and 0.1 μΜ, but lost neuroprotective effect at ΙμΜ (FIG. 7).

The names and codes of selected fatty acids were listed as follows:

Compound code Name No. of Neuroprotection Neuroprotection in the test carbons (0.0 ΙμΜ) (0.1 μΜ)

GG05 Pentadecanoic acid 15 21.9% 14.0%

GG07 Heptadecanoic acid 17 27.4% 21.4%

GG09 Nonadecanoic acid 19 31.2% 25.9%

EXAMPLE 1-7

The effects of tripentadecanoin in Camptothecin treated mouse primary neuron models - when added at 48 hours before Camptothecin treatment The neuro -protective effects of different concentrations of tripentadecanoin was investigated using mouse primary cortical neurons challenged with camptothecin, which is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I (topo I).

Camptothecin is obtained from Sigma, (ref C991 1 - (S)-(+)-Camptothecin).

Mouse primary neurons were incubated with vehicle or toxins in the absence or presence of different concentrations of tripentadecanoin added 48 hours before toxin's challenge. After the addition of 1 μΜ camptothecin, cells were further incubated for 24 h in a final volume of 140 μL per well.

As expected, the incubation of cells with 1 μΜ camptothecin for 24 h resulted in a decreased cell viability of 57.7±1.6% of control. When preincubated for 48h before camptothecin-treatment, tripentadecanoin induced a dose-dependent neuroprotection (bell- shape curve), with a maximal effect at doses of 10 and 100 nM, with a cell viability of 73.5±1.5% and 73.4±5.9% of control, respectively. The neuroprotective and anti-apoptotic effects of tripentadecanoin at ΙΟηΜ, ΙΟΟηΜ are 37.3%, 37.2%, respectively. (FIG. 8)

In conclusion, the data suggest that tripentadecanoin offers protection toward neuronal death induced by camptothecin.

EXAMPLE 1-8 The effects of tripentadecanoin on age-induced protein aggregates in Saccharomyces cerevisiae

Background: In most organisms, aging is associated with the accumulation of damaged and misfolded proteins. Pioneering studies from the group of Thomas Nystrom identified that this is also the case in budding yeast (Aguilaniu, et al. 2003 14;299(5613): 1751-3). Carbonylated proteins accumulate in replicative old mother yeast cells. Interestingly, these carbonylated proteins recruit the protein disaggregase Hspl04. Hspl04 is an hexameric ATPases Associated with diverse cellular Activities (AAA+) protein and translocase (Sweeny EA, Shorter J. J Mol Biol. 2016;428(9 PtB): 1870-85). Hspl04 couples ATP hydrolysis to disassembly and reactivation of proteins trapped in soluble preamyloid oligomers, disordered protein aggregates, and stable amyloid or prion conformers. HSP104 is endogenously generated due to aggregation of mis-folded proteins in old cells.

Objective: To understand the effects of tripentadecanoin on the formation and maintenance of age-induced protein aggregates in budding yeast system were tested.

Methods: In old yeast cells, age induced protein aggregates recruit a specific set of chaperones and co-chaperones and hence can be easily visualized at the microscope. Hspl04 expressed endogenously as a fusion to the green fluorescent protein tag (Hspl04- GFP) form a focus in these cells. (FIG. 9a)

To test an effect on the formation of age-induced Hspl04-GFP foci, old cells were obtained and cultivated in the presence of tripentadecanoin (1 μΜ, 10 μΜ and 30 μΜ), ethanol (0.3%, vehicle only) or in the absence of any treatment. Untreated young cells were obtained through a simple exponential growth.

Age was determined by staining bud scars with fluorescent brightener 28. In all conditions, old cells had a similar age distribution with an average age of 10 generations (n>73 cells). (FIG. 9b)

Most of the old cells untreated or treated with vehicle only contained one Hspl04-GFP focus (68.2±3.7% and 58.7±10.6% of the cells respectively). Treatment of cells with tripentadecanoin at either 10 μΜ or 30 μΜ significantly reduced the proportion of cells with a Hspl04-GFP focus (37.5±6.0% and 34.3±13.7%, respectively, P<0.001). Treatment with tripentadecanoin at 1 μΜ reduced the proportion of cells with a Hspl04-GFP focus, however this reduction was not statistically significant (46.2±4.8%, P>0.05). Since Hspl04 belongs to the arsenal of proteins that counteract and channel protein aggregates to a single protein deposit, the concentration of Hspl04-GFP in old cells in all conditions was measured. The intensity of Hspl04-GFP was much higher in old cells than in young cells. However, tripentadecanoin reduced the extent of this increase suggesting that Hspl04-GFP was less concentrated in cells exposed to these compounds. Hspl04-GFP intensity is higher at lower tripentadecanoin concentration (1 and ΙΟμΜ) compared to the highest concentration tested (30μΜ), correlating with the effect of these treatments on the percentage of cells that have an Hspl04-GFP focus. (FIG. 9d)

In conclusion, tripentadecanoin presented a strong effect on preventing and/or clearing the age-induced protein aggregation during normal yeast ageing.

EXAMPLES (II) OF FUNCTIONAL FOOD

Tripentadecanoin is a natural lipid. The patients described in examples II suffered from incurable diseases without any efficient treatment have voluntarily requested the functional food which containing tripentadecanoin.

EXAMPLE II- 1

This case refers to a male patient at 48 years old. He was diagnosed with primary Parkinson's Diseases for 9 years with shaking, rigidity, slowness of movement, and difficulty with walking. He was treated with levodopa, and trihexyphenidyl for eight years with initial effects but lost effects gradually. Three years ago, he was placed with microelectrodes for deep brain stimulation to reduce motor symptoms as the drugs were ineffective. He still presented with symptoms of abnormal shaking in feet, rigidity, slowness of movement, and difficulty with walking. He ate a form of function food containing tripentadecanoin about lOmg/day. After about one week, his abnormal shaking in feet improved for about 2 weeks. Then he discontinued due to some reasons, afterwards, he re-started for another half month and his symptoms improvement again.

EXAMPLE II-2

This case refers to a male patient at his 49 years old. He was diagnosed as cerebellar atrophy with limb spasm and was paralyzed on bed in need of a 24-hour nursing assistance. He could not smile or speak, could not communicate with others. When people talked with him, he had no facial expressions. He ate a form of functional food containing tripentadecanoin at about lOmg/day. After about one month, he started to smile, and had facial expressions on his face and even tended to speak when people were talking with him. EXAMPLE II-3

This case refers to a male patient with date of birth 22-Sep-1959. In Dec-2015, he had severe spinal bones fractures in his thoracic and lumbar spines due to an accidental fall from a 10-meter high building. At that time, he could not walk, could not sit, was paralyzed on bed, lost feelings in his lower legs and had severe pains in lumbar area. After about 6 months, he had a bit improvement and could sit for about 1 hour/time, however other symptoms persisted. His CT showed a diagnosis of "complex burst type compression fracture of the superior end plate of the Ti l vertebral body with fracture line extending to the posterior cortex as well as avulsed fracture of the anterior cortex with approximately 40-50% decreases in height with retropulsion of bony material into the spinal canal stenosis, especially at the T10-T11 disc level."

He ate a form of functional food containing tripentadecanoin about 20 mg/day. On Day 1 , he felt a stream of heat in his whole spinal area (especially lumbar area) after taking tripentadecanoin. For about 10 days, he had great improvement in the following symptoms: 1) remaining lumbar pains reduced to 40% of the pains before taking tripentadecanoin; 2) he could sit for up to 2 hours / time compared to only 1 hour / time before taking tripentadecanoin. In addition, he often felt a warm stream in his spinal area and his lower legs had less spasms than before.

Claims

1. A compound of the formula (I)

- (C8-C20) alkyl, which is optionally mono-, di- or trisubstituted with OH, NH₂, NHCH₃, N(CH₃)₂, F or CI; or

- (C₈-C₂₀) alkenyl, bearing 1, 2 or 3 double bonds;

whereby at least one of R¹, R² and R³ is -C(0)R⁴ with R⁴ being (C₈-C₂₀) alkyl with an even number of carbon atoms;

2. The compound of the formula (I) according to claim 1 , wherein R¹, R² and R³ are independently selected from H and at least one -C(0)R⁴, wherein R is (C₈-C₂₀) alkyl with an even number of carbon atoms for the use as a medicament for human and/or animals.

3. The compound of the formula (I) according to claim 1 or 2, wherein R¹, R² and R³ are independently selected from -C(0)R⁴ with R⁴ being (C8-C20) alkyl with an even number of carbon atoms; for the use as a medicament for human and/or animals.

4. The compound of the formula (I) according to claim 1 or 2, wherein one or two of R¹, R² and R³ are H and the other(s) is/are -C(0)R⁴ with R⁴ being C₁₂-alkyl, C₁₄-alkyl, C₁₆- alkyl, Cis-alkyl, or C₂o-alkyl for the use as a medicament for human and/or animals.

5. The compound of the formula (I) according to any one of claim 1 to 3, wherein R¹, R², and R³ are -C(0)R⁴ with R⁴ being Ci₄-alkyl for the use as a medicament for human and/or animals.

6. A metabolite or prodrug of the compound of formula (I) according to claim 4, wherein the metabolite or prodrug is HOC(0)Ci₂-alkyl, HOC(0)Ci₄-alkyl, HOC(0)Ci₆- alkyl, HOC(0)Ci8-alkyl or HOC(0)C2o-alkyl for the use as a medicament for human and/or animals.

7. The compound of the formula (I) according to any one of claims 1 to 6, for the use in the treatment and/or prevention of neurodegenerative diseases, retinal or optic nerve degenerative diseases, demyelinating diseases, neuromuscular disorders and muscular dystrophy, stroke, brain or spinal cord nerve injury, cranial nerve disorders, or seizures, amyloid deposit related diseases, and for the use of anti-aging or life-span prolongation and improving brain function.

8. The compound of the formula (I) according to any one of claims 1 to 6, for the use in the treatment and/or prevention of neurodegenerative diseases which are selected from the group consisting of Amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and brain atrophy.

9. The compound of the formula (I) according to any one of claims 1 to 6, for the use in the treatment and/or prevention of optic and retinal degenerative diseases which are selected from the group consisting of optical atrophy, Leber's hereditary optic neuropathy (LHON), Dominant Optic Atrophy (DOA), age-related macular degeneration, glaucoma and retinitis pigmentosa.

10. The compound of the formula (I) according to any one of claims 1 to 6, for the use in the treatment and/or prevention of demyelinating diseases which are selected from the group consisting of adrenoleukodystrophy, multiple sclerosis, optical neuritis, Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Chronic Inflammatory

Demyelinating Polyneuropathy (CIDP), Guillian-Barre syndrome, encephalitis caused by or related to Zika virus, cranial nerve palsy, neuromyelitis optica (NMO), acute disseminated encephalomyelitis, acute necrotizing hemorrhagic encephalitis, concentric sclerosis, diffuse sclerosis, metachromatic leukodystrophy, ball-like cell leukodystrophy, spongy degeneration of the central nervous system, adrenal leukodystrophy, Perry-plum disease, Alexander disease, radiation injury leukoencephalopathy, hypoxic

leukoencephalopathy, periventricular leukomalacia disease, arteriosclerotic cortex under encephalopathy, progressive multifocal leukoencephalopathy, and central pontine myelinolysis syndrome.

1 1. The compound of the formula (I) according to any one of claims 1 to 6, for the use in the treatment and/or prevention of neuromuscular disorders and muscular dsytrophy which are selected from the group consisting of myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, Charcot-Marie-Tooth disease (CMT).

12. The compound of the formula (I) according to any one of claims 1 to 6, for the use in the treatment and/or prevention of neurological injury related diseases or mixed neurological diseases selected from the group consisting of stroke, acute or chronic brain injury or spinal cord nerve injury, cranial nerve disorders and seizures.

13. The compound of the formula (I) according to any one of claims 1 to 6, for the use in the treatment and/or prevention of amyloid deposit related diseases which are selected from the group consisting of diabetes, cardiac amyloidosis, primary amyloidosis, familial amyloidosis, senile systemic amyloidosis (SSA), secondary amyloidosis, and

haemodialysis-associated amyloidosis.

14. The compound of the formula (I) according to any one of claims 1 to 6 for the use in the treatment and/or prevention of the diseases and conditions of claims 7 to 13, wherein the treatment dosage is from 1 mg/day to 1000 mg/day.

15. The compound of the formula (I) according to any one of claims 1 to 6 for the use in the treatment and/or prevention of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), dementia, and Creutzfeldt- Jakob disease, wherein the treatment dosage is from 1 mg/day to 1000 mg/day.

16. The compound of the formula (I) according to any one of claims 1 to 6 for the use as a medicament for animals, wherein the treatment dosage is from 1 mg kg /day to lOOmg/kg/day.

17. A pharmaceutical composition for the use in the treatment and/or prevention of the diseases and conditions of claims 7 to 13 and 15, wherein the composition contains the compound of the formula (I) of claims 1 to 6 and a pharmaceutically acceptable carrier.

18. Use of the compound of the formula (I) according to any one of claims 1 to 6, for the manufacture of a medicament for the treatment and/or prevention of the diseases and conditions of claims 7 to 13 and 15.

19. A method for treating and/or preventing of the diseases and conditions of claims 7 to 13 and 15, comprising administering to a patient an effective amount of the compound of the formula (I) according to any one of claims 1 to 6.

20. Use of the compound of the formula (I) according to any one of claims 1 to 6 as functional food or food supplement for human and/or animal.

21. Use of the compound of the formula (I) according to any one of claims 1 to 6 as functional food or food supplement for human, wherein the dosage is from 1 μg

(microgram)/day to 50 mg/day.

22. Use of the compound of the formula (I) according to any one of claims 1 to 6 as functional food or food supplement for animals, wherein the dosage is from 1 mg/kg /day to lOOmg/kg/day.