Nicotinamide dinucleotide derivatives and uses thereof

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 , R 12 , R 13 , R 14 , Y1, Y2, M, (i) and (ii) are as defined in the claims, a process for preparing a compound of formula (I) and its use as a therapeutic compound.

Description

Technical Field

[0001] The present invention relates to novel nicotinamide dinucleotide derivatives, including their pharmaceutically acceptable salts and / or solvates, methods for preparing these compounds and their use as therapeutic compounds. Background Art

[0002] At least five physiological mechanisms have been proposed to explain referred pain: (1) excessive nociceptive pain, (2) neuropathic pain, (3) sympathetic nerve activity, (4) idiopathic pain, and (5) psychogenic pain.

[0003] Excessive nociceptive pain is the most common mechanism and is caused by tissue damage resulting in excessive pain impulses transmitted by the intact nervous system. It results in localized pain in a non-neural topography with an inflammatory or mechanical schedule.

[0004] It can also originate from the viscera. Then it seems to be less localized, deep, and sometimes accompanied by nausea and vomiting.

[0005] With little understanding of its mechanisms, visceral pain represents a major clinical problem and a common reason for both men and women to seek medical treatment. Visceral pain is experienced by 40% of the population and 28% of cancer patients suffer from pain due to intra-abdominal metastases or treatment. The recent growth in interest among researchers and clinicians in pain originating from visceral organs reflects an important paradigm shift in the understanding of the extent and impact of visceral pain disorders.

[0006] It is well known that visceral hypersensitivity can be triggered by (1) sensitization of primary sensory afferents innervating the viscera, (2) overexcitation of ascending spinal neurons that receive synaptic input from the viscera (central sensitization), and (3) dysregulation of descending pathways that regulate nociceptive transmission in the spinal cord.

[0007] Although medical advances have allowed for the proper diagnosis and treatment of acute pain associated with infection and disease, many chronic pain syndromes remain a challenge for clinicians. This visceral chronic pain is observed in multifaceted and poorly understood functional bowel disorders (e.g., noncardiac chest pain, chronic idiopathic dyspepsia, functional abdominal pain, irritable bowel syndrome; IBS, Crohn's disease) and chronic pelvic pain (e.g., chronic interstitial cystitis, painful bladder syndrome, or endometriosis).

[0008] Functional bowel disorders and chronic pelvic pain represent unexplained symptoms without an easily identifiable infectious, anatomic, or metabolic basis, yet it is known that visceral pain may be triggered by agents that cause visceral inflammation.

[0009] For example, cyclophosphamide, an alkylating agent widely used in malignant and various inflammatory diseases, is known to exert toxic effects on the bladder wall through its major toxic metabolite, acrolein, leading to acute hemorrhagic cystitis (HC). In addition to acute hemorrhagic cystitis, bladder complications include bladder fibrosis and bladder cancer.

[0010] Several channels are important for visceral pain: transient receptor potential vanilloid receptor 1 (TRPV-1), ASIC3 channels, and sodium channels (NaV), especially those that are resistant to tetrodotoxin (NAV1.7, NAV 1.8, and NAV 1.9), and calcium channels. Certain receptors downregulate pain: gamma-aminobutyric acid-B (GABA-B) channels, kappa and mu opioid receptors, and somatostatin receptors. These channels and receptors are potential targets for novel analgesics to treat visceral pain.

[0011] In most clinical trials, somatic and nociceptive pain are included as visceral pain; therefore, it is difficult to determine the appropriate drug choice for the visceral pain phenotype. The fact that there are some differences in neurotransmission, neurotransmitters, channels, and receptors between somatic and visceral pain suggests that there may actually be real differences in the response to analgesics. For example, the use of strong opioids to treat inflammatory bowel disease is associated with higher morbidity and mortality, which has not been reported for various types of somatic pain. In a similar manner, certain nonsteroidal anti-inflammatory drugs have been associated with worse outcomes in inflammatory bowel disease but not in somatic pain. On the other hand, octreotide improves symptoms of colic and ileus more than anticholinergics; strong opioids may actually worsen colic.

[0012] Therefore, there remains a need for effective methods to treat visceral pain, including somatic pain and nociceptive pain.

[0013] The object of the present invention is to provide novel nicotinamide dinucleotide derivatives for use in the treatment of visceral pain. Unexpectedly, the applicants found that the nicotinamide dinucleotide derivatives of the present invention are well tolerated and show significant anti-nociceptive activity in a CYP-induced cystitis model. Summary of the invention

[0014] Therefore, the present invention relates to compounds of formula I

[0015]

[0016] or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

[0017] - X1 and X2 are independently selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0018] -R1 and R 13independently selected from H, azido, cyano, C1 to C8 alkyl, C1 to C8 thioalkyl, C1 to C8 heteroalkyl, and OR, wherein R is selected from H and C1 to C8 alkyl;

[0019] -R2, R3, R4, R5, R9, R 10 , R 11 , R 12 independently selected from H, halogen, azido, cyano, hydroxyl, C1 to C12 alkyl, C1 to C12 thioalkyl, C1 to C12 heteroalkyl, C1-C12 haloalkyl, and OR, wherein R is selected from H, C1 to C12 alkyl, C(O)(C1 to C12)alkyl, C(O)NH(C1 to C12)alkyl, C(O)O(C1 to C12)alkyl, C(O)aryl, C(O)(C1 to C12)alkylaryl, C(O)NH(C1 to C12)alkylaryl, C(O)O(C1 to C12)alkylaryl, or C(O)CHR AA NH2, where R AA selected from the side chains of proteinogenic amino acids;

[0020] - R6 and R8 are independently selected from H, azido, cyano, C1 to C8 alkyl and OR; wherein R is selected from H and C1 to C8 alkyl;

[0021] -R7 and R 14 independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N3 and halogen, wherein R and R' are each independently selected from H, C1 to C8 alkyl, (C1 to C8) alkylaryl;

[0022] - Y1 and Y2 are independently selected from CH, CH2, C(CH3)2 or CCH3;

[0023] -M is selected from H or a suitable counterion;

[0024] - represents a single bond or a double bond depending on Y1 and Y2; and

[0025] - It depends on R1 and R 13 The α anomer or the β anomer of the position.

[0026] The present invention also relates to compounds of formula I as described above for use as medicaments.

[0027] According to one embodiment, M is an internal counterion or an external counterion.

[0028] According to one embodiment, X1 and X2 each independently represent oxygen.

[0029] According to one embodiment, R7 and R14 Each independently represents NH2.

[0030] According to one embodiment, R1 and / or R 13 Each independently represents hydrogen.

[0031] According to one embodiment, R6 and / or R8 each independently represent hydrogen.

[0032] According to one embodiment, R3, R4, R 10 , R 11 are identical and each represents hydrogen.

[0033] According to one embodiment, R2, R5, R9 and R 12 are the same and each represents a hydroxyl group.

[0034] According to one embodiment, Y1 and Y2 each independently represent CH.

[0035] According to one embodiment, Y1 and Y2 each independently represent CH2.

[0036] According to one embodiment, the compounds according to the invention are selected from compounds of formula IA to formula IF:

[0037]

[0038] According to one embodiment, the compound is of Formula IA, Formula IB or Formula IC.

[0039] The present invention also relates to compounds of formula I'

[0040]

[0041] or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

[0042] - X1 and X2 are independently selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0043] -R1 and R 13 independently selected from H, azido, cyano, C1 to C8 alkyl, C1 to C8 thioalkyl, C1 to C8 heteroalkyl, and OR; wherein R is selected from H and C1 to C8 alkyl;

[0044] -R2, R3, R4, R5, R9, R 10 , R 11 , R 12independently selected from H, halogen, azido, cyano, hydroxyl, C1 to C12 alkyl, C1 to C12 thioalkyl, C1 to C12 heteroalkyl, C1-C12 haloalkyl, and OR; wherein R is selected from H, C1 to C12 alkyl, C(O)(C1 to C12)alkyl, C(O)NH(C1 to C12)alkyl, C(O)O(C1 to C12)alkyl, C(O)aryl, C(O)(C1 to C12)alkylaryl, C(O)NH(C1 to C12)alkylaryl, C(O)O(C1 to C12)alkylaryl, or C(O)CHR AA NH2, where R AA is a side chain selected from proteinogenic amino acids;

[0045] - R6 and R8 are independently selected from H, azido, cyano, C1 to C8 alkyl and OR; wherein R is selected from H and C1 to C8 alkyl;

[0046] -R7 and R 14 independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N3 and halogen; wherein R and R' are each independently selected from H, C1 to C8 alkyl, (C1 to C8) alkylaryl;

[0047] - Y1 and Y2 are independently selected from CH, CH2, C(CH3)2 or CCH3;

[0048] -M is selected from H or a suitable counterion;

[0049] - represents a single bond or a double bond depending on Y1 and Y2; and

[0050] - It depends on R1 and R 13 The position of the α anomer or the β anomer,

[0051] Provided that when X1 and X2 are oxygen; R1, R3, R4, R6, R8, R 10 , R 11 and R 13 is hydrogen; R2, R5, R9 and R 12 is a hydroxyl group; R7 and R 14 is NH2; and Y1 and Y2 are independently selected from CH or CH2,

[0052] At least one of represents an α anomer.

[0053] The present invention also relates to a pharmaceutical composition comprising at least one compound for use according to the present invention or at least one compound according to the present invention and at least one pharmaceutically acceptable carrier.

[0054] The invention also relates to a food composition comprising at least one compound for use according to the invention or at least one compound according to the invention and at least one acceptable carrier and / or diluent.

[0055] The invention also relates to a cosmetic composition comprising at least one compound for use according to the invention or at least one compound according to the invention and at least one acceptable carrier and / or diluent.

[0056] According to one embodiment, the compounds for use according to the invention or the compounds according to the invention are used for the treatment of pain.

[0057] According to one embodiment, the compounds for use according to the invention or the compounds according to the invention are used for the treatment of anti-tumor induced cardiotoxicity or sickle cell disease.

[0058] The present invention also relates to a method for preparing a compound of formula I or formula I', comprising the following steps:

[0059] 1) Monophosphorylation of a compound of formula X,

[0060]

[0061] in:

[0062] X1, R1, R2, R3, R4, R5, R6, R7, Y1, and As defined in formula I or I',

[0063] To obtain a compound of formula XI,

[0064]

[0065] in:

[0066] X1, R1, R2, R3, R4, R5, R6, R7, Y1, and As defined in formula I or I';

[0067] 2) hydrolyzing the compound of formula XI obtained in step 1) to obtain a compound of formula XII

[0068]

[0069] in:

[0070] X1, R1, R2, R3, R4, R5, R6, R7, Y1, and As defined in formula I or I';

[0071] 3) reacting the compound of formula XII obtained in step 2) with the compound of formula XIII obtained as described in step 1),

[0072]

[0073] in:

[0074] X2, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 、Y2、 and As defined in formula I or I',

[0075] To obtain a compound of formula I or formula I'.

[0076] According to one embodiment, the method further comprises a step of reducing the compound of formula I or the compound of formula I' obtained in step 3) to obtain the compound of formula I or the compound of formula I' wherein Y1 and Y2 each independently represent CH2.

[0077] definition

[0078] In the present invention, the following terms have the following meanings.

[0079] Unless otherwise indicated, nomenclature of substituents not specifically defined herein is derived by naming the terminal functionality followed by the adjacent functionality toward the point of attachment.

[0080] - "Alkyl" by itself or as part of another substituent refers to a hydrocarbon radical of the formula CnH2n+1, wherein n is a number greater than 1 or equal to 1. Typically, the alkyl radicals of the present invention contain 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 2 carbon atoms. Alkyl radicals may be straight-chain or branched and may be substituted as indicated herein.

[0081] Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and its isomers (e.g. n-pentyl, isopentyl), hexyl and its isomers (e.g. n-hexyl, isohexyl), heptyl and its isomers (e.g. n-heptyl, isoheptyl), octyl and its isomers (e.g. n-octyl, isooctyl), nonyl and its isomers (e.g. n-nonyl, isononyl), decyl and its isomers (e.g. n-decyl, isodecyl), undecyl and its isomers, dodecyl and its isomers. Preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Cx to Cy-alkyl refers to an alkyl group containing x to y carbon atoms.

[0082] - "Alkoxy" refers to an alkyl group as defined above, which is attached to another moiety through an oxygen atom. Examples of alkoxy groups include methoxy, isopropoxy, ethoxy, tert-butoxy, and the like. The alkoxy group may be optionally substituted with one or more than one substituent. The alkoxy groups included in the compounds of the present invention may be optionally substituted with solubilizing groups.

[0083] - "Aryl" as used herein refers to a polyunsaturated aromatic hydrocarbon radical having a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently linked, typically containing 5 to 12 atoms; preferably 6 to 10, at least one of which is aromatic. The aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems listed herein. Examples of aryl groups include phenyl, biphenyl, biphenylene, 5- or 6-tetrahydronaphthyl, naphthalen-1- or -2-yl, 4-, 5-, 6-, or 7-indenyl, 1-, 2-, 3-, 4-, or 5-acenaphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1- or 2-pentadienyl, 4- or 5-indanyl, 5-, 6-, 7-, or 8-tetrahydronaphthyl, 1, 2, 3, 4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4-, or 5-pyrenyl.

[0084] - "Alkylaryl" refers to an aryl group substituted by an alkyl group: alkyl-aryl-.

[0085] - "Amino acid" refers to an alpha-aminocarboxylic acid, ie a molecule comprising a carboxylic acid function and an amine function located alpha to the carboxylic acid group, such as a proteinogenic amino acid or a non-proteinogenic amino acid, such as 2-aminoisobutyric acid.

[0086] - "Proteinogenic amino acid" refers to an amino acid that is incorporated into proteins in an organism during the process of ribosome translation of messenger RNA, namely alanine (ALA), arginine (ARG), asparagine (ASN), aspartic acid (ASP), cysteine ​​(CYS), glutamic acid (GLU), glutamine (GLN), glycine (GLY), histidine (HIS), isoleucine (ILE), leucine (LEU), lysine (LYS), methionine (MET), phenylalanine (PHE), proline (PRO), pyrrolysine (PYL), selenocysteine ​​(SEL), serine (SER), threonine (THR), tryptophan (TRP), tyrosine (TYR) or valine (VAL).

[0087] - "Halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine and chlorine.

[0088] - "Haloalkyl", alone or in combination, refers to an alkyl group having the meaning defined above, wherein one or more than one hydrogen is replaced by a halogen group as defined above. Examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. x至y -Haloalkyl and Cx-alkyl to Cy-alkyl refer to alkyl groups containing x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl, trifluoromethyl.

[0089] - "heteroalkyl" refers to an alkyl group as defined above in which one or more carbon atoms are replaced by heteroatoms selected from oxygen, nitrogen and sulfur atoms. In a heteroalkyl group, heteroatoms are bonded only to carbon atoms along the alkyl chain, i.e. each heteroatom is separated from any other heteroatom by at least one carbon atom. However, the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. A heteroalkyl group is bonded to another group or molecule only via a carbon atom, i.e. the bonding atom is not selected from the heteroatoms contained in the heteroalkyl group.

[0090] - "Pharmaceutically acceptable salts" include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphtholate, 2-naphthalenesulfonic acid, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine penicillin, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine, and zinc salts. Hemisalts of acids and bases may also be formed, such as hemisulphates and hemicalcium salts. Preferably, pharmaceutically acceptable salts include hydrochlorides / chlorides, hydrobromides / bromides, bisulfates / sulfates, nitrates, citrates, and acetates.

[0091] Pharmaceutically acceptable salts can be prepared by one or more of the following methods:

[0092] (i) by reacting the compound with a desired acid;

[0093] (ii) by reacting the compound with a desired base;

[0094] (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic precursor such as a lactone or lactam using the required acid; or

[0095] (iv) converting one salt of a compound into another by reaction with a suitable acid or passing through a suitable ion exchange column.

[0096] All of these reactions are usually carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to nearly non-ionized.

[0097] - "Pharmaceutically acceptable" means approved by a regulatory agency or listed in a recognized pharmacopoeia for use in animals, more preferably in humans. It can be a material that is biologically or otherwise non-unwelcome, i.e., the material can be administered to an individual without causing any adverse biological effect or interacting in a deleterious manner with any component of the composition in which it is contained.

[0098] - "Solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more than one pharmaceutically acceptable solvent molecules, such as ethanol.

[0099] -The term "substituent" or "substituted" refers to the replacement of a hydrogen radical on a compound or group by any desired group that is substantially stable to the reaction conditions in an unprotected form or when protected with a protecting group. Examples of preferred substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen, alkyl, or aryl, hydroxy, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, and solubilizing groups, -NRR', -NR-CO-R', -CONRR', -SONRR' groups as defined above, wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl as defined above.

[0100] - In this article, bonds from asymmetric carbons can be represented by solid wedges or Dashed Wedge or Zigzag describe. DETAILED DESCRIPTION

[0101] Compound

[0102] The present invention relates to a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof:

[0103]

[0104] in

[0105] - X1 and X2 are independently selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0106] -R1 and R 13 independently selected from H, azido, cyano, C1 to C8 alkyl, C1 to C8 thioalkyl, C1 to C8 heteroalkyl, and OR; wherein R is selected from H and C1 to C8 alkyl;

[0107] -R2, R3, R4, R5, R9, R 10 , R 11 , R 12 independently selected from H, halogen, azido, cyano, hydroxyl, C1 to C12 alkyl, C1 to C12 thioalkyl, C1 to C12 heteroalkyl, C1-C12 haloalkyl, and OR, wherein R is selected from H, C1 to C12 alkyl, C(O)(C1 to C12)alkyl, C(O)NH(C1 to C12)alkyl, C(O)O(C1 to C12)alkyl, C(O)aryl, C(O)(C1 to C12)alkylaryl, C(O)NH(C1 to C12)alkylaryl, C(O)O(C1 to C12)alkylaryl, or C(O)CHR AA NH2, where R AA is a side chain selected from proteinogenic amino acids;

[0108] - R6 and R8 are independently selected from H, azido, cyano, C1 to C8 alkyl and OR; wherein R is selected from H and C1 to C8 alkyl;

[0109] -R7 and R 14 independently selected from H, OR, NHR, NRR', NH-NHR, SH, CN, N3 and halogen, wherein R and R' are each independently selected from H, C1 to C8 alkyl, (C1 to C8) alkylaryl;

[0110] - Y1 and Y2 are independently selected from CH, CH2, C(CH3)2 or CCH3;

[0111] -M is selected from H or a suitable counterion;

[0112] - represents a single bond or a double bond depending on Y1 and Y2; and

[0113] - It depends on R1 and R 13 The α anomer or the β anomer of the position.

[0114] According to one embodiment, M is an internal counterion or an external counterion.

[0115] According to an embodiment, preferred compounds of formula I are those wherein X1 and X2 are independently selected from O, CH2, S.

[0116] According to one embodiment, R7 and R 14 are independently selected from H, OR, NHR and NRR', wherein R and R' are independently selected from H, C1 to C8 alkyl, (C1 to C8) alkylaryl. According to one embodiment, R7 and R 14 is NHR, wherein R is selected from H, C1 to C8 alkyl, (C1 to C8) alkylaryl.

[0117] According to one embodiment, R2, R3, R4, R5, R9, R 10 , R 11 , R 12 are independently selected from H, halogen, hydroxyl, C1 to C12 alkyl and OR, wherein R is as described above. According to a preferred embodiment, R2, R3, R4, R5, R9, R 10 , R 11 , R 12 are independently selected from H, hydroxyl and OR, wherein R is as described above.

[0118] According to an embodiment, preferred compounds of formula I are those wherein R2, R3, R4, R5, R9, R 10 , R 11 , R 12 Those compounds independently selected from H and OH.

[0119] According to one embodiment, R2 and R3 are identical.According to one embodiment, R2 and R3 are identical and each represents OH.According to one embodiment, R2 and R3 are identical and each represents hydrogen.

[0120] According to a preferred embodiment, R2 and R3 are different. According to a preferred embodiment, R2 is hydrogen and R3 is OH. According to a more preferred embodiment, R2 is OH and R3 is hydrogen.

[0121] According to one embodiment, R4 and R5 are identical. According to one embodiment, R4 and R5 are identical and each represents OH. According to one embodiment, R4 and R5 are identical and each represents hydrogen.

[0122] According to a preferred embodiment, R4 and R5 are different. According to a preferred embodiment, R4 is OH and R5 is hydrogen. According to a more preferred embodiment, R4 is hydrogen and R5 is OH.

[0123] According to one embodiment, R3 and R4 are identical.According to one embodiment, R3 and R4 are identical and each represents OH.According to one embodiment, R3 and R4 are identical and each represents hydrogen.

[0124] According to a preferred embodiment, R3 and R4 are different. According to a preferred embodiment, R3 is OH and R4 is hydrogen. According to a more preferred embodiment, R3 is hydrogen and R4 is OH.

[0125] According to one embodiment, R2 and R5 are different. According to one embodiment, R2 is hydrogen and R5 is OH. According to one embodiment, R2 is OH and R5 is hydrogen.

[0126] According to a preferred embodiment, R2 and R5 are identical. According to a preferred embodiment, R2 and R5 are identical and each represents hydrogen. According to a more preferred embodiment, R2 and R5 are identical and each represents OH.

[0127] According to one embodiment, R9 and R 10 According to one embodiment, R9 and R 10 are identical and each represents OH. According to one embodiment, R9 and R 10 are identical and each represents hydrogen.

[0128] According to a preferred embodiment, R9 and R 10 According to a preferred embodiment, R9 is hydrogen, R 10 According to a more preferred embodiment, R9 is OH, R 10 It's hydrogen.

[0129] According to one embodiment, R 11 and R 12 According to one embodiment, R 11 and R 12 are identical and each represents OH. According to one embodiment, R 11 and R 12 are identical and each represents hydrogen.

[0130] According to a preferred embodiment, R 11 and R 12 According to a preferred embodiment, R 11 Yes OH, R 12 According to a more preferred embodiment, R 11 is hydrogen, R 12 It's OH.

[0131] According to one embodiment, R 10 and R 11According to one embodiment, R 10 is hydrogen, R 11 According to one embodiment, R 10 Yes OH, R 11 It's hydrogen.

[0132] According to a preferred embodiment, R 10 and R 11 According to a preferred embodiment, R 10 and R 11 are identical and each represents OH. According to a more preferred embodiment, R 10 and R 11 are identical and each represents hydrogen.

[0133] According to one embodiment, R9 and R 12 According to one embodiment, R9 is hydrogen, R 12 According to one embodiment, R9 is OH, R 12 It's hydrogen.

[0134] According to a preferred embodiment, R9 and R 12 According to a preferred embodiment, R9 and R 12 are identical and each represents hydrogen. According to a more preferred embodiment, R9 and R 12 are the same and each represents OH.

[0135] According to one embodiment, Y1 is CH. According to one embodiment, Y1 is CH2.

[0136] According to one embodiment, Y2 is CH. According to one embodiment, Y2 is CH2.

[0137] According to one embodiment, X1 and X2 are different and are selected from the group as described above. According to one embodiment, X1 and X2 are the same and are selected from the group as described above.

[0138] According to an embodiment, preferred compounds of the general formula I are those in which X1 and X2 each independently represent oxygen.

[0139] According to an embodiment, preferred compounds of the general formula I are those in which X1 and X2 are identical and each represent oxygen.

[0140] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula II:

[0141]

[0142] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 、Y1、Y2、M、 and As mentioned above.

[0143] According to one embodiment, R7 and R 14 are different and are selected from the group as described above. According to one embodiment, R7 and R 14 are the same and are selected from the group as described above.

[0144] According to an embodiment, a preferred compound of formula I is one in which R7 and R 14 Each independently represents those compounds of NH2.

[0145] According to an embodiment, a preferred compound of formula I is one in which R7 and R 14 Those compounds which are the same and each represent NH2.

[0146] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula III:

[0147]

[0148] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R1, R2, R3, R4, R5, R6, R8, R9, R 10 , R 11 , R 12 , R 13 、Y1、Y2、M、 and As mentioned above.

[0149] According to one embodiment, R1 and R 13 are different and are selected from the group as described above. According to one embodiment, R1 and R 13 are identical and are selected from the group as described above.

[0150] According to an embodiment, a preferred compound of formula I is one in which R1 and R 13 Those compounds each independently represent hydrogen.

[0151] According to an embodiment, a preferred compound of formula I is one in which R1 and R 13 Those compounds which are identical and each represent hydrogen.

[0152] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula IV:

[0153]

[0154] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 、Y1、Y2、M、 and As mentioned above.

[0155] According to one embodiment, R6 and R8 are different and are selected from the group as described above. According to one embodiment, R6 and R8 are identical and are selected from the group as described above.

[0156] According to an embodiment, preferred compounds of the general formula I are those in which R6 and R8 each independently represent hydrogen.

[0157] According to an embodiment, preferred compounds of the general formula I are those in which R6 and R8 are identical and each represent hydrogen.

[0158] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula V:

[0159]

[0160] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R2, R3, R4, R5, R9, R 10 , R 11 , R 12 、Y1、Y2、M、 and As mentioned above.

[0161] According to one embodiment, R3, R4, R 10 and R 11 are different and are selected from the group as described above. According to one embodiment, R3, R4, R 10 and R 11 The same and selected from the group as described above.

[0162] According to an embodiment, the preferred compound of formula I is wherein R3, R4, R 10 and R 11 Those compounds each independently represent hydrogen.

[0163] According to an embodiment, the preferred compound of formula I is wherein R3, R4, R 10 , R 11Those compounds which are identical and each represent hydrogen.

[0164] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula VI:

[0165]

[0166] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R2, R5, R9, R 12 、Y1、Y2、M、 and As mentioned above.

[0167] According to one embodiment, R2, R5, R9 and R 12 are different and are selected from the group as described above. According to one embodiment, R2, R5, R9 and R 12 The same and selected from the group as described above.

[0168] According to an embodiment, a preferred compound of formula I is one in which R2, R5, R9 and R 12 Each independently represents those compounds of OH.

[0169] According to an embodiment, preferred compounds of formula I are those wherein R2, R5, R9, R 12 Those compounds which are identical and each represent OH.

[0170] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula VII:

[0171]

[0172] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: Y1, Y2, M, and As mentioned above.

[0173] According to one embodiment, Y1 and Y2 are different. According to a preferred embodiment, Y1 and Y2 are identical.

[0174] According to an embodiment, preferred compounds of the general formula I are those wherein Y1 and Y2 each independently represent CH.

[0175] According to an embodiment, preferred compounds of the general formula I are those wherein Y1 and Y2 are identical and each represent CH.

[0176] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula VIII:

[0177]

[0178] or a pharmaceutically acceptable salt and / or solvate thereof, wherein M and As mentioned above.

[0179] According to an embodiment, preferred compounds of the general formula I are those wherein Y1 and Y2 each independently represent CH2.

[0180] According to an embodiment, preferred compounds of the general formula I are those wherein Y1 and Y2 are identical and each represent CH2.

[0181] According to a preferred embodiment, among the compounds of formula I, the present invention relates to compounds having the following formula IX:

[0182]

[0183] or a pharmaceutically acceptable salt and / or solvate thereof, wherein M and As mentioned above.

[0184] According to one embodiment, preferred compounds of the present invention are Compounds IA to IF, listed in Table 1:

[0185] Table 1

[0186]

[0187]

[0188] According to one embodiment, preferred compounds of the present invention are compounds of Formula IA to Formula IC.

[0189] According to one embodiment, the preferred compound of the present invention is the compound of formula IA.

[0190] According to one embodiment, the preferred compound of the present invention is the compound of formula IB.

[0191] According to one embodiment, preferred compounds of the present invention are compounds of formula IC.

[0192] According to another embodiment, the preferred compounds of the present invention are compounds of formula ID.

[0193] According to another embodiment, a preferred compound of the present invention is a compound of formula IE.

[0194] According to another embodiment, a preferred compound of the present invention is a compound of formula IF.

[0195] The present invention also relates to a compound of formula I' or a pharmaceutically acceptable salt and / or solvate thereof:

[0196]

[0197] Among them, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 、Y1、Y2、M、 and As described above for compounds of formula I,

[0198] Provided that when X1 and X2 are oxygen; R1, R3, R4, R6, R8, R 10 , R 11 and R 13 is hydrogen; R2, R5, R9 and R 12 is a hydroxyl group; R7 and R 14 is NH2; and Y1 and Y2 are independently selected from CH or CH2,

[0199] At least one of represents an α anomer.

[0200] According to the present invention, M can be an internal counterion or an external counterion.

[0201] In this particular embodiment, the following compounds are excluded from Formula I':

[0202]

[0203] method

[0204] In another aspect, the present invention relates to a process for preparing a compound of formula I or a compound of formula I' as described above.

[0205] In particular, compounds of Formula I or Formula I' disclosed herein can be prepared from substrates X to XIII as described below. One of ordinary skill in the art will appreciate that these schemes are in no way limiting and that changes in detail may be made without departing from the spirit and scope of the invention.

[0206] According to one embodiment, the present invention relates to a process for preparing the compound of formula I or the compound of formula I' as described above.

[0207] The method first involves monophosphorylating a compound of formula X in the presence of phosphorus oxychloride in a trialkyl phosphate to obtain a dichlorophosphate compound XI,

[0208]

[0209] Among them, X1, R1, R2, R3, R4, R5, R6, R7, Y1, and As described herein for Formula I or I'.

[0210] In the second step, the dichlorophosphate XI obtained in the first step is hydrolyzed to obtain a phosphate compound of formula XII,

[0211]

[0212] Among them, X1, R1, R2, R3, R4, R5, R6, R7, Y1, M, and As described herein for Formula I or Formula I'.

[0213] Then, the phosphate compound of formula XII obtained in the second step is reacted with the dichlorophosphate compound of formula XIII obtained as described in the first step,

[0214]

[0215] Among them, X2, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 、Y2、 and as described herein for a compound of formula I or a compound of formula I' to obtain a compound of formula I or a compound of formula I' as described herein.

[0216] According to one embodiment, the method of the present invention further comprises the step of reducing the compound of formula I or the compound of formula I' using various methods known to those skilled in the art to obtain the compound of formula I or the compound of formula I', wherein Y1 and Y2 are the same and each represents CH2 and wherein X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 、Y1、Y2、M、 and As described herein for Formula I or Formula I'.

[0217] According to another embodiment, the compound of formula X is synthesized using various methods known to those skilled in the art. According to one embodiment, the compound of formula X is synthesized in two steps, first reacting a pentose of formula XIV with a nitrogen-containing derivative of formula XV, wherein R1, R1, R2, R3, R4, R5, R6, R7, Y1 and R are as described herein for formula I or I' to obtain a compound of formula X-1, followed by selective deprotection to obtain a compound of formula X.

[0218]

[0219] Among them, X1, R1, R2, R3, R4, R5, R6, R7, Y1, and As described herein for Formula I or Formula I', and R is a protecting group.

[0220] According to one embodiment, R is a suitable protecting group known to those skilled in the art. Examples of suitable protecting groups include triarylmethyl and / or silyl. Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl and 4,4',4"-trimethoxytrityl. Non-limiting examples of silyl include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.

[0221] According to one embodiment, any hydroxyl group attached to the pentose ring is protected by a suitable protecting group known to those skilled in the art.

[0222] The selection and exchange of protecting groups is within the skill of those skilled in the art.Any protecting group may also be removed by methods known in the art, for example, with an acid (eg, an inorganic or organic acid), a base, or a fluoride source.

[0223] According to a preferred embodiment, the nitrogen-containing derivative of formula XV is added to pentose XIV by a coupling reaction in the presence of a Lewis acid to obtain a compound of formula X1. Non-limiting examples of suitable Lewis acids include TMSOTf, BF3, OEt2, TiCl4 and FeCl3.

[0224] According to a specific embodiment, the present invention relates to the preparation of a compound of formula VIII,

[0225]

[0226] or a pharmaceutically acceptable salt and / or solvate thereof.

[0227] In the first step, nicotinamide of formula XV is added to ribose tetraacetate XIV by a coupling reaction in the presence of a Lewis acid to give a compound of formula X-1:

[0228]

[0229] In the second step, the compound of formula X-1 is subjected to ammoniation treatment to obtain a compound of formula X:

[0230]

[0231] In the third step, the compound of formula X is monophosphorylated in the presence of phosphorus oxychloride in a trialkyl phosphate to give the dichlorophosphate compound XI,

[0232]

[0233] In the fourth step, the dichlorophosphate compound XI obtained in the third step is partially hydrolyzed to obtain a phosphate compound of formula XII:

[0234]

[0235] In the fifth step, the phosphate compound of formula XII obtained in the fourth step is then reacted with the dichlorophosphate compound of formula XI obtained as described in the third step to obtain the compound of formula VIII.

[0236] According to another embodiment, the present invention is directed to the preparation of compounds of formula IX,

[0237]

[0238] or a pharmaceutically acceptable salt and / or solvate thereof.

[0239] According to one embodiment, the compound of formula IX is obtained from a compound of formula VIII previously synthesized as described above.

[0240] In this embodiment, the compound of formula IX is obtained by reducing the compound of formula VIII using a suitable reducing agent known to those skilled in the art to give the compound of formula IX.

[0241] use

[0242] The present invention also relates to a compound of formula I or a compound of formula I' for use as a medicament.

[0243] According to one embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of a disease or disorder.

[0244] According to one embodiment, the disease or disorder is selected from age-related disorders, infectious or parasitic diseases, tumors, cancer, immune system diseases, blood and organ diseases, endocrine diseases, nutritional diseases and metabolic diseases, mental development disorders, behavioral development disorders and neurodevelopmental disorders, sleep-wake disorders, nervous system diseases, visual system diseases, ear and mastoid diseases, circulatory system diseases, vascular diseases, cardiomyopathy, respiratory system diseases, digestive system diseases, skin and subcutaneous cell tissue diseases, musculoskeletal system or connective tissue diseases, genitourinary system diseases, diseases related to sexual health, pregnancy, childbirth and puerperium, certain diseases originating from the perinatal period, developmental abnormalities, congenital malformations and chromosomal abnormalities, symptoms, signs and abnormal results of clinical and laboratory examinations, consequences of trauma, poisoning and some other external causes, external causes of morbidity and mortality, changes in the biological clock, kidney disorders, mitochondrial diseases, diseases or syndromes.

[0245] According to another embodiment, the present invention relates to compounds of formula I or compounds of formula I' for use in the treatment of age-related disorders, infectious or parasitic diseases, tumors, cancer, immune system diseases, blood and organ diseases, endocrine diseases, nutritional diseases and metabolic diseases, mental development disorders, behavioral development disorders and neurodevelopmental disorders, sleep-wake disorders, nervous system diseases, visual system diseases, ear and mastoid diseases, circulatory system diseases, vascular diseases, cardiomyopathy, respiratory system diseases, digestive system diseases, skin and subcutaneous cell tissue diseases, musculoskeletal system or connective tissue diseases, genitourinary system diseases, diseases related to sexual health, pregnancy, childbirth and puerperium, certain diseases originating from the perinatal period, developmental abnormalities, congenital malformations and chromosomal abnormalities, symptoms, signs and abnormal results of clinical and laboratory tests, consequences of trauma, poisoning and some other external causes, external causes of morbidity and mortality, changes in the biological clock, kidney disorders, mitochondrial diseases, diseases or syndromes.

[0246] According to one embodiment, the invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of age-related disorders.

[0247] Non-limiting examples of age-related disorders include lifespan, cellular senescence, progeria, frailty, osteoporosis, Werner syndrome, muscular dystrophy.

[0248] According to one embodiment, the invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of infectious or parasitic diseases.

[0249] According to one embodiment, the infectious or parasitic disease is infectious gastroenteritis or colitis.

[0250] Non-limiting examples of infectious gastroenteritis or colitis include:

[0251] - For example, bacterial intestinal infections such as cholera, intestinal infections caused by other Vibrio species, intestinal infections caused by Shigella, intestinal infections caused by Escherichia coli, intestinal infections caused by Clostridium difficile, intestinal infections caused by Yersinia enterocolitica, gastroenteritis caused by Campylobacter, typhoid fever, paratyphoid fever, infections caused by other Salmonella, other specific bacterial intestinal infections or non-specific bacterial intestinal infections;

[0252] - Bacterial foodborne poisoning, such as foodborne staphylococcal poisoning, botulism food poisoning, foodborne Clostridium perfringens poisoning, foodborne Bacillus cereus poisoning, other specific bacterial foodborne poisoning or non-specific bacterial foodborne poisoning;

[0253] - Viral enteric infections, such as adenovirus enteritis, astrovirus enteritis, rotavirus enteritis, norovirus enteritis, cytomegalovirus enteritis, other specific viral enteric infections or non-specific enteric infections;

[0254] - Protozoal intestinal infections such as those caused by Balantidia spp., giardiasis, cryptosporidiosis, isosporiasis, sarcocystis, blastocystis hominis, amebiasis, other specific protozoal intestinal infections, non-specific protozoal intestinal infections, or gastroenteritis or colitis without a clear source of infection.

[0255] According to one embodiment, the infectious or parasitic disease is primarily a sexually transmitted infection.

[0256] Non-limiting examples of infections that are primarily sexually transmitted include:

[0257] -Syphilis such as congenital syphilis, early syphilis, late syphilis, non-specific early or late latent syphilis;

[0258] - Gonorrhea infection such as gonococcal urogenital infection, gonococcal pelvic peritonitis, gonococcal infection at other sites, disseminated gonococcal infection, or nonspecific gonococcal infection;

[0259] - Sexually transmitted infections caused by Chlamydia, such as Chlamydial lymphogranuloma, non-ulcerative sexually transmitted Chlamydial infection, other specific Chlamydial sexually transmitted infections, nonspecific Chlamydial sexually transmitted infections, chancroid, granuloma inguinale, trichomoniasis, sexually transmitted infections, anogenital herpes simplex infection, anogenital warts, other specific primarily sexually transmitted infections, or nonspecific primarily sexually transmitted infections.

[0260] According to one embodiment, the infectious or parasitic disease is a bacterial infection.

[0261] Non-limiting examples of bacterial infections include:

[0262] - bacterial diseases such as actinomycosis, bartonellosis, pertussis, tetanus, obstetric tetanus, neonatal tetanus, gas gangrene, diphtheria, Brazilian purpura fever, Legionnaires' disease, listeriosis, nocardiosis, meningococcal disease, yaws, pinta, endemic non-venereal syphilis, Lyme (Borrelia) disease, necrotizing dental caries, or relapsing fever;

[0263] - Mycobacterial diseases, such as respiratory tuberculosis, nervous system tuberculosis, tuberculosis of other systems and organs, miliary tuberculosis, latent tuberculosis, leprosy, infections caused by nontuberculous mycobacteria, other specific mycobacterial diseases, or nonspecific mycobacterial diseases.

[0264] - Staphylococcal or streptococcal diseases, such as acute rheumatic fever without cardiac involvement, acute rheumatic fever with cardiac involvement, rheumatic chorea, scarlet fever, streptococcal pharyngitis, toxic shock syndrome, meningitis caused by streptococci, meningitis caused by staphylococci, other specific staphylococcal or streptococcal diseases, staphylococcal or streptococcal diseases;

[0265] - bacterial diseases of zoonotic origin, such as rat-bite fever, leptospirosis, glanders, plague, tularemia, brucellosis, erysipelas, anthrax, cat-scratch disease, pasteurellosis or extraintestinal yersiniosis;

[0266] - Diseases caused by Chlamydia such as Chlamydial conjunctivitis, Chlamydial peritonitis, infections caused by Chlamydia psittaci or Chlamydia trachomatis;

[0267] - Rickettsial diseases, such as typhus, spotted fever, rickettsial pox, Q fever, campylobacteriosis, melioidosis, actinomycosis, non-purulent bacterial infections of the skin

[0268] According to one embodiment, the infectious or parasitic disease is a viral infection.

[0269] Non-limiting examples of viral infections include:

[0270] - Viral diseases, such as human immunodeficiency virus (HIV), dengue virus, parotitis, infectious mononucleosis, cytomegalovirus disease, epidemic myalgia, viral conjunctivitis, viral myocarditis, viral hemorrhagic fever, adenovirus infection, enterovirus infection, coronavirus infection, parvovirus infection, influenza virus or viral hepatitis, adenovirus, human T-lymphotropic virus-1 (HTLV-1), Ebola virus;

[0271] - Animal-borne viral diseases such as filovirus disease, arenavirus disease, hantavirus disease, henipavirus encephalitis, Middle East respiratory syndrome, or severe acute respiratory syndrome;

[0272] - Arboviral fevers, such as Chikungunya virus disease, Colorado tick fever, Aryan fever, Oropouche virus disease, Rift Valley fever, sand fly fever, West Nile virus infection, yellow fever, Zika virus disease, Crimean-Congo hemorrhagic fever, Omsk hemorrhagic fever, Kaisanu Forest disease, Alkhurma hemorrhagic fever, Ross River disease, or fever with thrombocytopenia syndrome;

[0273] - infections caused by poxviruses, such as smallpox, monkeypox, cowpox, buffalopox, sheeppox, or molluscum contagiosum;

[0274] - Human papillomavirus infection of the skin or mucous membranes, such as common warts, flat warts, labial or oral warts or proliferation of wart viruses in immunodeficient states;

[0275] - Varicella zoster virus infection, such as chickenpox, herpes zoster, herpes simplex infection, roseola infantum, rubella, measles, erythema infectiosum, or picornavirus infections occurring in the skin or mucous membranes.

[0276] According to one embodiment, the infectious or parasitic disease is a parasitic disease.

[0277] Non-limiting examples of parasitic diseases include:

[0278] - malaria, such as malaria caused by Plasmodium falciparum, malaria caused by Plasmodium vivax, malaria caused by Plasmodium malariae, malaria caused by Plasmodium ovale, other parasitologically confirmed malaria or malaria not parasitologically confirmed;

[0279] - Non-intestinal protozoan diseases, such as Acanthamoebiasis, African trypanosomiasis, babesiosis, American trypanosomiasis, leishmaniasis, Naegleria mebiasis, rhinosporidiosis, toxoplasmosis, or microsporidiosis;

[0280] - diseases caused by nematodes, such as angiostrongylus, anisakiasis, ascariasis, capillariasis, dracunculiasis, enterobiasis, filariasis, gnathostomiasis, hookworm disease, esophagostomiasis, onchocerciasis, strongyloidiasis, tracheorrhea, toxocariasis, trichinosis, trichostrongylosis, whipworm disease, or hookworm disease;

[0281] - Diseases caused by tapeworms, such as cysticercosis, diphyllobothrium, dipylidiasis, echinococcosis, hymenolepiasis, sparganosis, or taeniasis

[0282] - diseases caused by trematodes, such as liver flukes, diplococci, fascioliasis, fascioliasis, opisthorchiasis, paragonimiasis, schistosomiasis, sparganosis and sparganosis or helminthiasis;

[0283] - External parasite bites such as lice, myiasis, leechosis, pediculosis, scabies, tungiasis, bedbug itch or mite bites.

[0284] According to one embodiment, the infectious or parasitic disease is a fungal disease.

[0285] Non-limiting examples of fungal diseases include: aspergillosis, frog dung mold, blastomycosis, candidiasis, chromoblastomycosis, coccidioidomycosis, mold disease, cryptococcosis, dermatophytosis, mycetoma, histoplasmosis, keloidal blastomycosis, mucormycosis, non-dermatophyte superficial cutaneous fungi, paracoccidioidomycosis, phaeohyphomycosis, pneumocystis, sedosporosis, sporotrichosis, talaromycosis, or emmonidiosis.

[0286] According to one embodiment, the present invention relates to the compound of formula I or the compound of formula I' as described above for use in treating or preventing tumors.

[0287] Non-limiting examples of tumors include: brain or central nervous system tumors, hematopoietic or lymphoid tissue tumors, malignant tumors, malignant tumors of the lip, oral cavity or pharynx, malignant tumors of the digestive organs, malignant tumors of the middle ear, respiratory tract or thoracic organs, malignant tumors of the skin, malignant tumors of the peripheral nerves or autonomic nervous system, malignant tumors of the peripheral nerves or autonomic nervous system, malignant tumors of the breast, malignant tumors of the female reproductive organs, malignant tumors of the male reproductive organs, malignant tumors of the urinary tract, malignant tumors of the eye or ocular adnexa, malignant tumors of the endocrine glands, metastases of malignant tumors, tumors in situ, benign tumors, benign stromal tumors, benign non-stromal tumors, benign tumors of the respiratory tract and thoracic organs, benign skin tumors.

[0288] According to another embodiment, the present invention relates to the compound of formula I or the compound of formula I' as described above for use in treating or preventing tumors.

[0289] Non-limiting examples of cancer include: cancer metastasis, brain cancer, kidney cancer, breast cancer, prostate cancer, testicular cancer, ovarian cancer, lymphoma, leukemia, pancreatic cancer, platinum-based chemotherapy-induced ototoxicity, colon cancer, large intestine cancer, skin cancer, lung cancer, laryngeal cancer, side effects of cancer chemotherapy.

[0290] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' as described above for use in the treatment or prevention of immune system diseases.

[0291] Non-limiting examples of immune system diseases include: primary immunodeficiency, lupus, lupus erythematosus, systemic lupus erythematosus, idiopathic inflammatory myopathy, vasculitis, antiphospholipid syndrome, alopecia, ankylosing spondylitis, spondyloarthritis, allergy, allergic reaction, scleroderma, Crohn's disease, antiphospholipid antibody syndrome, Guillain-Barre syndrome, Lambert-Eaton syndrome, myasthenia gravis, Goodpasture's syndrome or multiple sclerosis, neutrophil number disorder, neutrophil function disorder, eosinophilia, eosinophilia, monocyte count decreased disorder, monocyte count increased disorder, acquired lymphocytopenia, acquired lymphocytosis, sarcoidosis, polyclonal hypergammaglobulinemia, cryoglobulinemia, immune reconstitution inflammatory syndrome, graft versus host disease, thymic disease.

[0292] According to one embodiment, the invention relates to compounds of formula I or compounds of formula I' for use in the treatment or prevention of blood and organ diseases.

[0293] Non-limiting examples of blood and organ diseases include: diseases related to platelet aggregation, coagulation disorders, blood inflammation, inherited thrombocytopenia, inherited leukemia syndrome, thrombotic disorders, thromboembolism, thrombophilia associated with antithrombin III deficiency, myeloproliferative disorders, disseminated intravascular coagulation, coagulation disorders, thrombotic thrombocytopenic purpura, drug-induced thrombocytopenia, dysfibrinogenemia, protein C deficiency, protein S deficiency, activated protein C resistance, fibrinolytic disorders, sickle cell disease, sickle cell nutritional or metabolic anemia, hemolytic anemia, pure red cell aplasia, erythrocytosis, sepsis, erythropoiesis or iron homeostasis.

[0294] According to another embodiment, the present invention relates to compounds of formula I or compounds of formula I' for use in the treatment or prevention of endocrine, nutritional and metabolic diseases.

[0295] Non-limiting examples of endocrine diseases include:

[0296] - disorders of the thyroid gland or thyroid hormone system, such as hypothyroidism, nontoxic goiter, thyrotoxicosis, thyroiditis, calcitonin excess, thyroid hormone resistance in general, or euthyroid syndrome;

[0297] - Diabetes mellitus, such as type 1 diabetes, type 2 diabetes, or diabetes associated with malnutrition;

[0298] - Impairments of glucose regulation or pancreatic endocrine disorders, such as intermediate hyperglycemia, hypoglycemia without associated diabetes, excessive glucagon secretion, abnormal gastrin secretion, insulin resistance syndrome, persistent hyperinsulinemic hypoglycemia in infancy;

[0299] -Diseases of the parathyroid glands or parathyroid hormone system, such as hypoparathyroidism, hyperparathyroidism;

[0300] - Pituitary hormone system diseases, such as hyperpituitarism and hypopituitarism;

[0301] - disorders of the adrenal glands or adrenal hormone system, such as Cushing's syndrome, adrenal reproductive disorders, hyperaldosteronism, hypoaldosteronism, adrenal insufficiency, or adrenal medullary hyperfunction;

[0302] - Gonadal hormone system disorders, such as ovarian dysfunction, testicular dysfunction, or testosterone-related disorders,

[0303] - Pubertal disorders, such as those due to estrogen resistance, delayed puberty, or peripheral precocious puberty;

[0304] - Polyglandular dysfunction, such as autoimmune polyendocrine disease or polyglandular hyperfunction.

[0305] Non-limiting examples of nutritional diseases include:

[0306] - nutritional deficiencies such as underweight infants, children or adolescents, wasting in infants, children or adolescents, acute malnutrition in infants, stunting in infants, children or adolescents, underweight adults, vitamin A deficiency, vitamin C deficiency, vitamin D deficiency, vitamin E deficiency, vitamin K deficiency, vitamin B1 deficiency, vitamin B2 deficiency, vitamin B3 deficiency, vitamin B6 deficiency, folic acid deficiency, vitamin B12 deficiency, biotin deficiency, pantothenic acid deficiency, choline deficiency or mineral deficiencies;

[0307] - Sequelae of malnutrition;

[0308] - Overweight, obesity or specific nutritional excess, such as overweight or obesity, overweight or local obesity, obesity, dietary obesity, hormone-related obesity, obesity associated with drug administration, obesity-related inflammation, vitamin excess or mineral excess.

[0309] Non-limiting examples of metabolic disorders include:

[0310] - Inborn errors of metabolism, such as inborn errors of amino acid or other organic acid metabolism, inborn errors of carbohydrate metabolism, inborn errors of lipid metabolism, inborn errors of energy metabolism, inborn errors of glycosylation or other specific protein modification, inborn errors of purine, pyrimidine, or nucleotide metabolism, lysosomal diseases, peroxisomal diseases, inborn errors of porphyrin or heme metabolism, inborn errors of neurotransmitter metabolism, alpha-1-antitrypsin deficiency;

[0311] - Metabolite absorption or transport disorders, such as amino acid absorption or transport disorders, carbohydrate absorption or transport disorders, lipid absorption or transport disorders, vitamin or non-protein cofactor absorption or transport disorders, or mineral absorption or transport disorders;

[0312] - Fluid, electrolyte, or acid-base disorders, such as volume depletion, hyperosmolar or hypernatremia, hypoosmolar or hyponatremia, acidosis, alkalosis, mixed acid-base disorders, hyperkalemia, hypokalemia, or fluid overload;

[0313] - Lipid disorders, such as dyslipidemia / dyslipogenesis, hypercholesterolemia, hyperlipidemia, Gaucher disease, HDL hypocholesterolemia, LDL hypercholesterolemia, HLD noncholesterolemia, hypertriglyceridemia, Niemann-Pick disease, gangliosidosis (including Tay-Sachs disease), leukodystrophy, mucopolysaccharidosis, mucopolysaccharidosis, lipodystrophy, beta-oxidation defect, HIV-induced lipodystrophy, lipid storage myopathy.

[0314] - Other metabolic disorders, such as amyloidosis, tumor lysis syndrome, prediabetic state, diabetes insipidus, optic atrophy, deafness (DID-MOAD), diabetes mellitus and deafness (DMDF), impaired glucose tolerance, insulin resistance, diabetes-related diseases or disorders, high blood glucose levels, high blood cholesterol, hyperglycemia, homocystinuria, metabolic syndrome and syndrome X, glycoprotein storage diseases, Luft's disease, CPT1 deficiency, CPT2 deficiency, hyperinsulinemia.

[0315] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' as described above for use in the treatment or prevention of psychiatric, behavioral and neurodevelopmental disorders.

[0316] Non-limiting examples of psychiatric, behavioral and neurodevelopmental disorders include: schizophrenia, catatonia, behavioral and autism spectrum disorders, such as Asperger's syndrome, autism, autism or attention deficit hyperactivity disorder (ADHD); mood disorders, such as bipolar disorder, depressive disorders, anxiety or fear-related disorders, obsessive-compulsive disorder or related disorders, disorders specifically related to stress, dissociative disorders, feeding or eating disorders, elimination disorders, physical complaints, distorted body image, low self-esteem; disorders due to drug use or addictive behavior, impulse control disorders, destructive behavior or antisocial disorders; neurocognitive disorders, such as dementia; mental or behavioral disorders related to pregnancy, childbirth or the puerperium.

[0317] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' as described above for use in the treatment or prevention of a neurological disease.

[0318] Non-limiting examples of nervous system diseases include: inflammatory diseases of the central nervous system, such as bacterial meningitis, meningitis in bacterial diseases, meningitis in infectious diseases, encephalitis, myelitis, encephalomyelitis, intracranial and intraspinal abscesses and granulomas, intracranial intraspinal venous inflammation, thrombophlebitis and sequelae of inflammatory diseases of the central nervous system; systemic atrophy mainly affecting the central nervous system, such as Huntington's disease, hereditary ataxia, spinal muscular atrophy and related syndromes, systemic atrophy mainly affecting the central nervous system and post-poliomyelitis syndrome; extrapyramidal and movement disorders, such as Parkinson's disease, multiple system atrophy; other nervous system diseases Degenerative diseases of the central nervous system, such as Alzheimer's disease; demyelinating diseases of the central nervous system, such as multiple sclerosis, acute disseminated demyelinating disease; paroxysmal and epileptic disorders, such as epilepsy, status epilepticus, migraine, transient ischemic attacks and related syndromes, cerebrovascular syndromes in cerebrovascular diseases; polyneuropathies and other disorders of the peripheral nervous system, such as hereditary and idiopathic neuropathies, inflammatory polyneuropathies and myoneural junction and muscle diseases; essential tremor (ET), ataxia, catatonia, epilepsy, neuroleptic malignant syndrome, chorea, chorea gravidarum (chorea of ​​pregnancy), acanthocytic chorea, corticobasal ganglia Degeneration, dystonia, ischemic stroke, mental retardation, neuroacanthocytosis, Pelizeus-Merzbacher disease, X-linked spastic paraplegia, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), striatonigral degeneration, Shy-Dreyfus syndrome, sporadic olivopontocerebellar atrophy, Creutzfeldt-Jakob encephalopathy, myelodysplasia, dementia, myoclonus, and deafness (AMDF), Cockayne syndrome (Neill-Dingwall syndrome), Friedreich's ataxia, Alpers disease, neuropathy, chemotherapy-induced neuropathy, diabetes-induced neuropathy amyotrophic lateral sclerosis (ALS) , primary lateral sclerosis, dementia with Lewy bodies, Wolfram syndrome, cerebral edema, Rett syndrome, maternally inherited Leigh disease, intractable epilepsy, progressive myoclonic epilepsy (PME), dyslexia with descent in infection, cerebral palsy with descent in infection, uridine-responsive neurological syndrome (URNS), myoclonic epilepsy and psychomotor regression (MERM), familial bilateral striatal necrosis (FBSN), stroke, striatonigral degeneration, tardive dyskinesia, progressive Charcot-Marie-Tooth disease, post-traumatic head injury, spinal cord injury, familial migraine, peripheral neuropathy, tardive ulnar nerve palsy, encephalomyelitis, creatinine deficiency.

[0319] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of sleep-wake disorders.

[0320] Non-limiting examples of sleep-wake disorders include: insomnia disorder, hypersomnia disorder, sleep-related breathing disorder, circadian rhythm sleep-wake disorder, sleep-related movement disorder, parasomnia disorder.

[0321] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of visual system diseases.

[0322] Non-limiting examples of visual system diseases include: disorders of the eye adnexa or orbit, such as eyelid or periocular area disorders, tear apparatus disorders, orbital disorders; eyeball disorders, such as conjunctival disorders, corneal disorders, anterior chamber disorders, anterior uveal disorders, pupillary dysfunction, lens disorders, scleral disorders, choroidal disorders, retinal disorders or vitreous disorders; disorders of the visual pathway or center; glaucoma or suspected glaucoma, retinal degeneration, age-related macular degeneration (AMD), retinitis pigmentosa (RP), rod and cone dystrophy, Leber's congenital amaurosis (LCA), cataract (ocular neuritis), progressive external ophthalmoplegia, Stargardt's disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, retinal hemorrhage, glaucoma, strabismus, esotropia, exotropia, hyperopia, myopia, astigmatism, anisometropia, presbyopia, uveitis, conjunctivitis, photoreceptor cell degeneration after retinal detachment, or optic neuropathy.

[0323] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of ear and mastoid diseases.

[0324] Non-limiting examples of ear and mastoid diseases include: infectious diseases of the external ear, otitis externa, such as non-infectious inflammation of the external ear, non-inflammatory disorders of the external ear; diseases of the middle ear or mastoid, such as otitis media, non-suppurative otitis media, suppurative otitis media; diseases of the inner ear, such as acute vestibular syndrome, paroxysmal vestibular syndrome, chronic vestibular syndrome, otosclerosis, vestibular dysfunction, labyrinthine fistula, labyrinthine dysfunction, effects of noise on the inner ear; disorders of hearing impairment, such as congenital hearing impairment, such as acquired hearing impairment, deafness, hearing loss, ototoxic hearing loss, sensorineural hearing loss (SNHL), presbycusis, sudden idiopathic hearing loss, hereditary hearing loss, auditory synaptic disease or neuropathy; ear pain or ear effusion, degenerative or vascular disease of the ear, auditory nerve disease or ear atrophy.

[0325] According to another embodiment, the present invention relates to compounds of formula I or compounds of formula I' for use in the treatment and / or prevention of circulatory system diseases.

[0326] Non-limiting examples of circulatory system diseases include cardiac hypertrophy, Wolff-Parkinson-White syndrome, atrial fibrillation, idiopathic ischemia / reperfusion, myocardial infarction, myocarditis, angina pectoris and unstable angina pectoris, cardiovascular disease, hypertensive disease, idiopathic hypotension, orthostatic hypotension, acute or chronic acute ischemic heart disease, coronary artery disease, cor pulmonale or pulmonary circulation disease, such as pulmonary thromboembolism or pulmonary hypertension; acute, chronic or constrictive pericarditis, cardiac tamponade, hemopericardium, pericardial effusion; acute or subacute endocarditis; mitral valve disease, aortic valve disease, tricuspid valve disease, pulmonary valve disease; arrhythmia, heart failure, such as congestive heart failure, congestive heart failure, left ventricular heart failure, high output syndrome, right heart failure, biventricular failure, arterial or arteriole disease, Brugada syndrome, heart failure with preserved ejection fraction; venous disease; lymphatic or lymph node disorders; postoperative disorders of the circulatory system; septic shock.

[0327] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of vascular diseases.

[0328] Non-limiting examples of vascular disease include: atherosclerotic disease, aortic atherosclerosis, coronary atherosclerosis, carotid atherosclerosis, cerebrovascular atherosclerosis, renal atherosclerosis, iliac atherosclerosis, femoral atherosclerosis, popliteal atherosclerosis, retinal arteriolar atherosclerosis, glomerular arteriolar atherosclerosis, neurovascular atherosclerosis, cardiac arteriolar atherosclerosis, ocular capillary bed atherosclerosis, renal atherosclerosis, cardiac and central and peripheral nervous system atherosclerosis, restenotic atherosclerosis (e.g., following coronary intervention), abnormal high and low density cholesterol, atherosclerosis, endothelial dysfunction, hypertension, deep vein thrombosis, large vessel disease, perivascular disease, vascular remodeling, giant cell arteritis, polyarteritis nodosa, vasculitis.

[0329] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' as defined above for use in the treatment and / or prevention of cardiotoxicity.

[0330] Non-limiting examples of cardiotoxicity include: idiopathic cardiotoxicity, metabolic cardiotoxicity, alcoholic cardiotoxicity, drug-induced cardiotoxicity, ischemic cardiotoxicity, hypertensive cardiotoxicity, maternally inherited hypertrophic cardiotoxicity (MHCM), maternally inherited cardiotoxicity, maternal cardiotoxicity, fatal infantilecardiotoxicity Plus, MELAS-associated cardiotoxicity, or Barth syndrome.

[0331] According to another embodiment, the present invention relates to compounds of formula I or compounds of formula I' for use in the treatment and / or prevention of respiratory diseases.

[0332] Non-limiting examples of respiratory diseases include:

[0333] - Upper respiratory tract disorders such as acute nasopharyngitis, acute sinusitis, acute pharyngitis, acute tonsillitis, acute pharyngitis, acute laryngitis or tracheitis, acute obstructive laryngitis or epiglottitis, vasomotor or allergic rhinitis, chronic rhinitis, nasopharyngitis or pharyngitis, chronic sinusitis, silent sinus syndrome, nasal or sinus cysts or mucoceles, deviated nasal septum, hypertrophy of the turbinates, chronic diseases of the tonsils or adenoids, chronic laryngitis or laryngotracheitis, diseases of the vocal cords or larynx, nasal polyps, upper respiratory tract abscesses;

[0334] -Lower respiratory tract diseases, such as bronchitis, emphysema, chronic obstructive pulmonary disease, asthma, bronchiectasis, cystic fibrosis, chronic bronchiolitis, tracheobronchitis;

[0335] - Pulmonary disorders, such as pulmonary embolism, pulmonary hypertension, cystic fibrosis, asthma, respiratory tract infection, lung infection, bronchitis, emphysema;

[0336] - Pulmonary infections, such as pneumonia, post-influenza pneumonia, acute bronchiolitis, acute or chronic bronchitis, lung or mediastinal abscess, empyema, idiopathic pulmonary fibrosis, acute lung injury, sarcoidosis;

[0337] - Lung diseases caused by external factors, such as pneumoconiosis, pneumonia caused by organic dust, allergic pneumonitis, pneumonia caused by solids and liquids, radiation pneumonitis, aspiration syndrome, airway diseases caused by specific organic dusts, respiratory diseases due to inhalation of chemicals, gases, fumes or vapors, COPD (chronic obstructive pulmonary disease);

[0338] - Respiratory diseases that primarily affect the lung interstitium, such as acute respiratory distress syndrome, pulmonary edema, pulmonary eosinophilia, idiopathic interstitial pneumonia, specific primary interstitial lung disease of infancy or childhood, interstitial lung disease associated with systemic disease, alveolar microlithiasis, lymphangioleiomyomatosis;

[0339] - Pleural, diaphragmatic or mediastinal disorders, such as pleural plaques, pneumothorax, mediastinal disease, diaphragmatic disorders, chylous effusions, fibrothorax, hemothorax, pleural effusions, respiratory failure;

[0340] - Postoperative disorders of the respiratory system, such as tracheostomy dysfunction, postoperative chronic pulmonary insufficiency, postoperative subglottic stenosis, postoperative tracheal stenosis, and transfusion-related acute lung injury.

[0341] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of digestive system diseases.

[0342] Non-limiting examples of digestive system disorders include:

[0343] - Diseases or disorders of the orofacial complex, such as disorders of the lips, oral mucosa, tongue, salivary glands, cysts in the oral cavity or cervical region of the face, certain specific jaw diseases, disorders of tooth development or eruption, diseases of the hard tissues of the teeth, pulp or periapical tissues, gum disease, periodontal disease, sensory disorders affecting the orofacial complex;

[0344] -Esophageal diseases, such as acquired esophageal anatomical changes, esophageal motility disorders, gastroesophageal reflux disease, esophageal columnar metaplasia, esophagitis, esophageal ulcers, and esophageal vascular disorders;

[0345] - Gastric diseases, such as acquired gastric anatomical changes, gastroduodenal motility or secretion disorders, gastritis, gastric vascular disorders, gastric polyps;

[0346] - Duodenal diseases, such as acquired duodenal anatomic changes, duodenitis, duodenal vascular disorders, duodenal polyps;

[0347] - Intestinal diseases, such as irritable bowel syndrome, inflammatory bowel disease, neurogenic intestinal dysfunction, chronic intestinal pseudo-obstruction with myopathy and ophthalmoplegia, Crohn's disease, colitis, ulcerative colitis, necrotizing enterocolitis, diarrhea, celiac disease, motility disorders, diverticular disease;

[0348] - Liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic hepatic steatosis (NASH), liver fibrosis, cirrhosis, alcoholic liver disease, drug-induced toxic liver disease, autoimmune liver disease, hepatitis steatosis, alcoholic hepatitis, infectious liver disease, fulminant hepatitis, acute liver failure, hepatorenal syndrome, jaundice, hepatic vasculitis, cirrhosis, hemochromatosis, Wilson's disease;

[0349] - Gallbladder or bile duct disease, such as gallstones, cholecystitis, cholangitis;

[0350] - Pancreatic disease, such as pancreatic cystic disease, acute, chronic, autoimmune, or obstructive pancreatitis;

[0351] -Peritoneal diseases, such as peritonitis;

[0352] - Ischemic intestinal vascular disorder, such as acute intestinal vascular disorder or chronic intestinal vascular disorder.

[0353] According to another embodiment, the present invention relates to compounds of formula I or compounds of formula I' for use in the treatment and / or prevention of diseases of the skin and subcutaneous cell tissue.

[0354] Non-limiting examples of skin and subcutaneous cell tissue diseases include: viral rashes, skin diseases, dermatitis (including irritant contact dermatitis and allergic contact dermatitis), natural skin aging, wrinkles, liver spots / chloasma, skin inflammation, sunburn, atopic dermatitis, atopic eczema, seborrheic dermatitis, seborrheic keratosis, lichen simplex, lipid eczema, actinic keratosis, skin atrophy, keratosis disorders (including eczema), epidermolysis bullosa (including penguin), exfoliative dermatitis, seborrheic dermatitis, erythema (erythema multiforme and erythema nodosum), damage caused by the sun or other light sources, discoid lupus erythematosus, dermatomyositis, lichen planus, lichen sclerosis, morphea, psoriasis, lichenoid dermatosis, pityriasis rubra pilaris, small plaque psoriasis, skin cancer, wounds and burns (1st, 2nd and 3rd degree burns and / or thermal, chemical or electrical burns), transplant rejection, xeroderma pigmentosum, alopecia, hair pigmentation, pemphigus, pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, dermatitis herpetiformis acne, skin aging, urticaria, angioedema, cholinergic urticaria and related conditions, urticarial reaction or angioedema syndrome, idiopathic angioedema, acute febrile neutrophilic dermatosis, pyoderma gangrenosum, erythema nodosum, genetic syndromes affecting the skin, simplex epidermolysis bullosa, junctional, dystrophic or syndromic epidermolysis bullosa, pruritus, prurigo, mucocutaneous or cutaneous pain syndrome, neuropathic skin lesions, Burning foot syndrome, ichthyosis, diffuse epidermal hyperkeratosis and acanthosis, keratosis pilaris, peeling skin, dry or fatty skin, palmoplantar keratosis, follicular keratosis, acquired hypermelanosis, acquired melanotic macules or nevi, endogenous non-melanin pigmentation, acquired hypopigmentation disorders, alopecia, hirsutism, hirsutism and hirsutism syndrome, acquired hair shaft disorders, acne, inflammatory disorders acneiformis, rosacea and related disorders, sebaceous gland disorders, hyperhidrosis, hypohidrosis, prickly heat, acquired poikiloderma, keloid or hypertrophic scars, superficial fibroma, perforating dermatosis, necrotizing granulomatous dermatosis, dermal dendritic cells, benign lymphocytic infiltration of the skin, cutaneous lymphocytoma, panniculitis, lipoatrophy or lipodystrophy , acquired skin vascular malformations, purpura or bruises caused by coagulation disorders, traumatic purpura, vasculitis or capillaritis involving the skin, livedoid vasculopathy, ischemic skin ulcers, venous eczema of the lower limbs, vasodilation of the extremities, vasoconstriction of the extremities, flushing disorders, local skin disorders of the scalp, contact dermatitis of the external ear, anal pruritus, anal or perianal skin infections, perianal inflammatory skin diseases, sacrococcygeal pilonidal disease, neonatal viral skin infections, neonatal purulent skin infections, neonatal fungal skin infections, infantile skin diseases, exanthematous drug eruptions, drug-induced urticaria, angioedema and allergic reactions, lichenoid drug eruptions, Stevens-Johnson syndrome and drug-induced toxic epidermal necrolysis, drug-induced erythroderma, clothing syndrome, fixed drug eruptions,Drug-induced acne or acneiform reactions, other specific drug eruptions, nonspecific drug eruptions, drug-induced skin pigmentation abnormalities, drug-induced skin diseases caused by drug therapy, drug-induced hair abnormalities, drug-induced nail abnormalities, drug-induced oral diseases, drug-induced photosensitivity, skin diseases associated with specific classes of drugs, local adverse skin reactions to applied drugs, adverse skin reactions to herbal medicines, homeopathy or other alternative therapies, pressure sores, skin diseases caused by friction or mechanical stress, skin diseases caused by foreign bodies, heat-induced erythema, photoaging of the skin, allergic contact dermatitis, photoallergic contact dermatitis, irritant contact dermatitis, allergic contact urticaria, protein contact dermatitis, allergic contact sensitization, phototoxic dermatitis, skin reactions to poisonous or toxic animals, skin cysts, skin tags or polyps, actinic keratoses and other discrete epidermal dysplasias, skin diseases that may indicate cutaneous lymphoma, histiocytosis, paraneoplastic syndromes involving the skin.

[0355] According to another embodiment, the invention relates to compounds of formula I or compounds of formula I' for use in the treatment and / or prevention of diseases of the musculoskeletal system or of connective tissue.

[0356] Non-limiting examples of diseases of the musculoskeletal system or connective tissue include: osteoarthritis, infection-related arthropathy, inflammatory arthropathy such as rheumatoid arthritis, psoriatic arthritis or polymyalgia rheumatica; spondylolisthesis, spinal stenosis, spondylolisthesis, spinal inflammation, spondylosis, spondyloarthritis, synovitis, SAPHO syndrome, muscle disorders, synovial or tendon disorders, bone disease, osteomalacia, cachexia, muscular dystrophy, Duchenne muscular dystrophy, Becker's Muscular dystrophy, tardive myopathy, congenital muscular dystrophy, maternal myopathy, myopathy, sarcopenia, vitiligo myopathy, Emery-Dreyfus muscular dystrophy, facioscapulohumeral humoral muscular dystrophy, hyaline myopathy, limb-girdle myopathy, muscle sodium channel disorders, myotonic chondrodystrophy, myotubular myopathy, Nema body disease, oculopharyngeal muscular dystrophy, spinal muscular atrophy, fibromyalgia, steroid myopathy, muscle weakness and atrophy, gout, degenerative joint disease, joint inflammation, Marfan syndrome.

[0357] According to another embodiment, the present invention relates to compounds of formula I or compounds of formula I' for use in the treatment and / or prevention of urogenital system diseases.

[0358] Non-limiting examples of urogenital diseases include: female reproductive tract disorders such as vulvitis, uterine inflammatory disease, vaginitis, Bartholin gland disease, cervicitis, female pelvic inflammatory disease, pelvic peritoneal adhesions, salpingitis and oophoritis, endometriosis, adenomyosis, dyspareunia, acquired abnormalities, abnormal uterine or vaginal bleeding, such as menstrual irregularities; reproductive disorders, such as miscarriage, eclampsia or pre-eclampsia, pregnancy, infertility, menopausal infertility, male infertility, female infertility, irregular ovulation, chemotherapy-induced menopause; female genital skin diseases; male genital skin diseases; prostate diseases, such as prostatic hyperplasia, hydrocele or spermatocele, orchitis or epididymitis; inflammatory disorders of the male reproductive organs ; Vascular disorders of the male reproductive system; Breast disorders, such as benign breast disease, inflammatory mastopathy, and breast hypertrophy; Glomerular diseases, such as nephritic syndrome, nephrotic syndrome, persistent proteinuria or proteinuria; Tubulointerstitial diseases, such as acute tubulointerstitial nephritis, acute pyelonephritis, acute tubular necrosis, acute renal papillary necrosis, tubulointerstitial nephritis, chronic tubulointerstitial nephritis, obstructive or reflux nephropathy, nephrocalcinosis, pyonephrosis, and renal or perinephric abscess; Renal failure; Urolithiasis, urethritis, and urethral syndrome; Urethral stricture; Cystic or dysplastic kidney disease; Cystitis; Gallstones; Cholecystitis; Cholelithiasis; Neurogenic bladder dysfunction; Postoperative diseases of the genitourinary system.

[0359] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of diseases related to sexual health.

[0360] Non-limiting examples of disorders related to sexual health include: sexual dysfunction, such as hypoactive sexual desire disorder, sexual arousal disorder, orgasmic dysfunction, ejaculation dysfunction; sexual pain disorder; or gender incongruence.

[0361] According to another embodiment, the invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of diseases associated with pregnancy, childbirth and the puerperium.

[0362] Non-limiting examples of pregnancy, delivery, and the puerperium include: pregnancy loss; edema, proteinuria, hypertension during pregnancy, delivery, or the puerperium; obstetric hemorrhage; maternal disorders primarily related to pregnancy; maternal care related to fetal, amniotic, or possible delivery problems; delivery or delivery complications; complications primarily related to the puerperium.

[0363] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of certain diseases originating from the perinatal period.

[0364] Non-limiting examples of certain diseases that originate in the perinatal period include: fetus or neonate affected by maternal factors or complications of pregnancy, labor or delivery; neonatal diseases related to gestational timing or fetal growth; birth injuries; fetal or neonatal infections; hemorrhagic or blood system diseases of the fetus or neonate; neurological diseases specific to the perinatal or neonatal period; respiratory diseases specific to the perinatal or neonatal period; cardiovascular diseases existing in the perinatal or neonatal period; temporary endocrine or metabolic disorders specific to the fetus or neonate; urogenital system disorders specific to the perinatal or neonatal period; disorders involving the fetal or neonatal skin; skin disorders related to premature infants; postpartum iatrogenic skin injuries; neonatal temperature regulation disorders; certain disorders that originate in the perinatal period.

[0365] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of alterations in the biological clock.

[0366] Non-limiting examples of alterations in the circadian clock include: travel to or across one or more time zones, circadian rhythms, shift changes, night shift work, changes in medical condition (pregnancy or medication), improper eating cycles or times, fasting cycles, hyperglycemia, hypoglycemia, insomnia, advanced or delayed sleep phase syndrome, inconsistent sleep or wake cycles, and improved wakefulness in patients with narcolepsy or hypersomnia.

[0367] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' as defined above for use in the treatment and / or prevention of renal disorders.

[0368] Non-limiting examples of renal disorders include: renal failure, renal ischemia / reperfusion injury (IRI), glomerulonephritis, lupus nephritis, nephropathy, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, Bartter's syndrome, renal tubular acidosis.

[0369] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of mitochondrial diseases.

[0370] Non-limiting examples of mitochondrial diseases include: chronic progressive external ophthalmoplegia (KSS), myoclonic epilepsy with ragged red fiber syndrome, Fukuhara syndrome (MERFF), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), hereditary optic neuropathy, Leigh encephalopathy, Pearson's disease, lactic acidosis, fatal infantile mitochondrial myopathy (LIMM), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy, mitochondrial myopathy, mitochondrial cytopathy, mitochondrial encephalopathy, multiple mitochondrial DNA deletion syndrome, mitochondrial DNA depletion syndrome, Pearson's medullary pancreas syndrome, multisystem mitochondrial disorders (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy), maternally inherited deafness or aminoglycoside-induced deafness, myoneurogenic gastrointestinal encephalopathy, carnitine acylcarnitine transferase deficiency, carnitine deficiency, complex 1, 2, 3, 4, 5 deficiency.

[0371] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of a disease.

[0372] Non-limiting examples of diseases include: indigestion, fatigue, sleep disorders, mouth ulcers, lethargy, energy deficiency, pellagra, gastrointestinal reflux (GER), premenstrual syndrome, menstrual cramps, cyclical vomiting syndrome during infection, exercise intolerance, stress incontinence, chronic fatigue syndrome, stress, stress resistance, hot flashes, radiation or toxin-derived side effects, amino acid deficiency, transplantation, cell survival under hypoxia, coenzyme Q10 deficiency, weight gain, obstructive sleep apnea, transplant rejection, endotoxic shock, exotoxin poisoning, or chemotherapy fatigue.

[0373] According to another embodiment, the invention relates to a compound of formula I or a compound of formula I' for use in the treatment and / or prevention of syndromes.

[0374] Non-limiting examples of syndromes include: epilepsy, stroke, optic atrophy and cognitive decline (ESOC), myopathy and external ophthalmoplegia, neuropathy, gastrointestinal, encephalopathy (MNGIE), neurogenic myasthenia, neuropathy, ataxia and retinitis pigmentosa (NARP), sudden infant death syndrome, acquired immune deficiency syndrome (AIDS), MARIAHS syndrome (mitochondrial ataxia, recurrent infections, aphasia, hypouricemia / hypomyelination, seizures and dicarboxylic aciduria), glutarate type 2 deficiency / long-chain acyl-CoA dehydrogenase deficiency (DMAD), autoimmune polyglandular disease, acute respiratory distress syndrome, Sjögren's syndrome, granulocyte transfusion-related syndrome, Kearns-Sayre syndrome, Raynaud's syndrome.

[0375] According to a preferred embodiment, the present invention relates to compounds of formula I or compounds of formula I' for use in the treatment of degenerative diseases and neurodegenerative diseases.

[0376] Non-limiting examples of degenerative diseases and neurodegenerative diseases include: corticobasal syndrome, motor neuron disease, systemic atrophy primarily affecting the central nervous system, Tay-Sachs disease, transmissible spongiform encephalopathy, ataxia-telangiectasia, autosomal dominant cerebellar ataxia, autosomal recessive Charcot-Sagnac spastic ataxia, Baggio-Ginari syndrome, Batten disease, cell cycle hypothesis of Alzheimer's disease, Cohen syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, estrogen and neurodegenerative diseases, RAN translation, fatal insomnia, fragile X-associated tremor / ataxia syndrome, frontotemporal lobe associated with chromosome 17 Dementia and Parkinson's disease, hereditary motor and sensory neuropathy with proximal dominance, infantile Refsum disease, Kufor-Rakeb syndrome, Kufs disease, ataxia, Lyme disease, Machado-Joseph disease, mental retardation and microcephaly with pontine and cerebellar dysgenesis, mitochondrial-associated membrane, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, occupational exposure to Lyme disease, pontocerebellar dysgenesis, protein aggregation, pyruvate dehydrogenase deficiency, Sandhoff disease, spinocerebellar ataxia, subacute combined degeneration of the spinal cord, subacute sclerosing panencephalitis, tabes dorsalis, toxic encephalopathy, toxic leukoencephalopathy, quaggaxinus neuronal degeneration, wiggly hedgehog syndrome.

[0377] According to a more preferred embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment of pain, preferably nociceptive pain, more preferably in the treatment of visceral pain.

[0378] According to one embodiment, the compounds used according to the invention or the compounds according to the invention act on nociception. According to one embodiment, the compounds used according to the invention or the compounds according to the invention act on muscle pain. According to one embodiment, the compounds used according to the invention or the compounds according to the invention act on ligament pain. According to one embodiment, the compounds used according to the invention or the compounds according to the invention act on tendon pain. According to one embodiment, the compounds used according to the invention or the compounds according to the invention act on joint pain, for example knee pain, back pain, shoulder pain, neck pain, elbow pain, wrist pain, hip pain, ankle pain.

[0379] According to one embodiment, pain is a symptom or complication associated with a disease or disorder as described above.

[0380] According to one embodiment, pain is a symptom or complication associated with antineoplastic drug-induced cardiotoxicity.

[0381] According to one embodiment, pain is a symptom or complication associated with sickle cell disease.

[0382] According to one embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use in the treatment of drug-induced cardiotoxicity, more preferably in the treatment of antineoplastic drug-induced cardiotoxicity.

[0383] According to one embodiment, the invention relates to a compound of formula I or a compound of formula I' for use in the treatment of sickle cell disease.

[0384] According to another embodiment, the invention relates to a compound of formula I or a compound of formula I' for use as a food supplement.

[0385] According to a preferred embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use as a food supplement to prevent cellular aging by increasing the NAD+ rate in the body.

[0386] According to another embodiment, the present invention relates to a compound of formula I or a compound of formula I' for use as a cosmetic ingredient.

[0387] In another embodiment, the invention relates to a food composition comprising at least one compound according to formula I or a compound of formula I' or a salt or solvate thereof, and at least one carrier and / or diluent.

[0388] In another embodiment, the present invention relates to a cosmetic composition comprising at least one compound according to formula I or a compound of formula I' or a salt or solvate thereof, and at least one carrier and / or diluent.

[0389] In another embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant. The present invention also includes a pharmaceutical composition containing, in addition to at least one compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof as an active ingredient, additional therapeutic agents and / or active ingredients.

[0390] The compounds of the present invention can be used as monotherapy or combination therapy for subjects in need of therapeutic and / or prophylactic treatment. Thus, according to a first embodiment, the compounds used in the present invention are administered to a subject without any other active ingredient. Thus, according to a second embodiment, the compounds used in the present invention are administered to a subject in combination with at least one additional active ingredient, such as an active ingredient as described above.

[0391] In one embodiment, the compound is administered to a subject sequentially, simultaneously, and / or separately with other active ingredients described herein.

[0392] Preferably, the subject in need of therapeutic and / or prophylactic treatment is a warm-blooded animal, more preferably a human. According to one embodiment, the subject is a male. According to one embodiment, the subject is a female.

[0393] According to one embodiment, the subject is an adult, i.e., over the age of 18. According to one embodiment, the subject is a child, i.e., under the age of 18. According to one embodiment, the subject is an infant, i.e., older than one month and younger than two years. According to one embodiment, the subject is a newborn, i.e., from birth to less than one month old.

[0394] According to a preferred embodiment, the subject is older than 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 years old. In one embodiment, the subject is older than 65, 70, 75, 80, 85, 90 or 95 years old.

[0395] According to another embodiment, the subject is less than 20, 15, 10 or 5 years old. In one embodiment, the subject is less than 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 years old.

[0396] The present invention also relates to the use of the compound or pharmaceutical composition as described above as a medicine.

[0397] The present invention also relates to the use of a compound or a pharmaceutical composition as described above for the treatment and / or prevention of a disease or disorder as described above.

[0398] The present invention also relates to a method for treating and / or preventing the diseases or disorders described above, comprising administering to a subject in need thereof an effective amount of at least one compound or pharmaceutical composition described above.

[0399] The present invention also relates to the use of the compound or pharmaceutical composition as described above in the preparation of a drug.

[0400] The present invention also relates to the use of the compound or pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing the diseases or disorders as described above.

[0401] By way of non-limiting example, such formulations may be in a form suitable for oral administration, parenteral administration (e.g. by intravenous, intramuscular or subcutaneous injection or intravenous infusion), topical administration (including ophthalmic), administration by inhalation, administration by skin patch, administration by implant, administration by suppository. The skilled person is aware of such suitable administration forms, which may be solid, semisolid or liquid, depending on the mode of administration and the methods and carriers, diluents and excipients used for their preparation; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0402] Some preferred but non-limiting examples of such formulations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions for administration as a bolus and / or for continuous administration, and sterile packaged powders (which are usually reconstituted prior to use), which may be formulated with carriers, excipients and diluents suitable for such formulations, such as lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginates, xanthan gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyridone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl and propylparaben, talc, magnesium stearate, edible oils, vegetable oils and mineral oils, or suitable mixtures thereof. The preparation may optionally contain other substances commonly used in pharmaceutical preparations, such as lubricants, wetting agents, emulsifiers and suspending agents, dispersants, deslagging agents, bulking agents, fillers, preservatives, sweeteners, flavoring agents, flow regulators, release agents, etc. The composition can also be formulated to provide rapid, sustained or delayed release of the active compound contained therein.

[0403] The pharmaceutical preparations of the present invention are preferably in unit dosage form and may be suitably packaged in, for example, boxes, blisters, vials, bottles, sachets, ampoules or any other suitable single-dose or multi-dose holders or containers (which may be appropriately labeled); optionally with one or more leaflets containing product information and / or instructions for use.

[0404] In another embodiment, the medicament of the present invention contains, in addition to at least one compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof as an active ingredient, another therapeutic agent and / or active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

[0405] Figure 1 A and Figure 1 Panel C is a graph showing the basal nociceptive thresholds of all experimental groups.

[0406] Figure 1 B and Figure 1 D in FIG. 5 is a graph showing the basal nociception scores of all experimental groups.

[0407] Figure 2 A in Figure 2 is a graph showing the nociceptive thresholds of CYP-induced visceral pain at 2, 4, and 6 hours compared to basal values ​​within the vehicle group. Both parameters were subjected to Friedman's test or one-way ANOVA and two-way repeated measures ANOVA with Dunn's or Dunnett's post hoc test relative to basal values, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001.

[0408] Figure 2 B is a graph showing the nociception scores of CYP-induced visceral pain at 2, 4 and 6 hours compared with basal values ​​within the vehicle group. Both parameters were subjected to Friedman's test or one-way ANOVA and two-way repeated measures ANOVA with Dunn or Dunnett post hoc test relative to basal values, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001.

[0409] Figure 3 A in FIG. 1 is a graph showing the effects of NMN, prodrug A, and prodrug B on the nociceptive threshold of CYP-induced allodynia at 2 hours.

[0410] Figure 3 B is a graph showing the effects of NMN, prodrug A, and prodrug B on the nociceptive threshold of CYP-induced allodynia at 4 hours.

[0411] Figure 3 C in Figure 3 is a graph showing the change in nociceptive threshold 6 hours after administration of Compound IB and IC. Two-way repeated measures ANOVA and Sidak's multiple comparison test were performed, p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001 relative to the vehicle group.

[0412] Figure 4 It is shown that in 2 hours ( Figure 4 A) and 4 hours ( Figure 4 B) Graph showing the effect of NMN on CYP-induced visceral pain (nociception score). Two-way repeated measures ANOVA, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001.

[0413] Figure 5 It is shown that in 2 hours ( Figure 5 A) and 4 hours ( Figure 5 B) Graph of the effect of prodrug A on CYP-induced visceral pain (nociception score). Two-way repeated measures ANOVA, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001.

[0414] Figure 6 It is shown that in 2 hours ( Figure 6 A) and 4 hours ( Figure 6 B) Graph showing the effect of prodrug B on CYP-induced visceral pain (nociception score). Two-way repeated measures ANOVA, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001.

[0415] Figure 7 It is shown that in 2 hours ( Figure 7 A), 4 hours ( Figure 7 B) and 6 hours ( Figure 7 C) Graph showing the effect of Compound IB on CYP-induced visceral pain (nociception score). Two-way repeated measures ANOVA, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001.

[0416] Figure 8 It is shown that in 2 hours ( Figure 8 A), 4 hours ( Figure 8 B) and 6 hours ( Figure 8 C) Graph showing the effect of compound IC on CYP-induced visceral pain (nociception score). Two-way repeated measures ANOVA, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001.

[0417] Fig. 9 is a histogram showing the survival of treated and untreated mice 5 days after DOX (20 mg / kg) or vehicle induction. ##p<0.01: Fisher's test for Dox mice treated with vehicle relative to control mice, £p<0.05, £p<0.01: Fisher's test for Dox mice treated with vehicle relative to Dox mice treated with NMN analogs.

[0418] Fig.10Figure A shows the body weight changes of mice treated with NMN, Compound IB and IC (180 mg / kg) or vehicle before (light gray symbols) and 5 days after (dark gray symbols) injection of saline solution or DOX (20 mg / kg). £££p<0.001: Two-way ANOVA followed by Bonferroni post hoc test was performed on the body weight before Dox injection relative to the body weight 5 days after Dox injection.

[0419] Fig.10 B in FIG. 1 is a histogram showing body weight gain, calculated as follows: BW on the day of sacrifice minus BW before injection with or without DOX (20 mg / kg) in mice treated with NMN, Compound IB and IC (180 mg / kg) or vehicle. ***p<0.001: Mann-Whitney test for Dox mice treated with vehicle relative to control mice, $$p<0.01, $$$p<0.001: One-way ANOVA followed by post hoc Dunnett's test for Dox mice treated with vehicle relative to Dox mice treated with NMN analogs.

[0420] Fig.11 Figure 2 shows the left ventricular (LV) end-diastolic phase ( Fig.11 A) and end-systolic volume ( Fig.11 B) and ejection fraction ( Fig.11 **p<0.01, ***p<0.001: Mann-Whitney test for Dox mice treated with vehicle relative to control mice, $p<0.05, $$$p<0.001: Kruskal-Wallis test followed by post hoc Dunn's test for Dox mice treated with vehicle relative to Dox mice treated with NMN analogs.

[0421] Fig.12 Figure 2 shows the left ventricular end-diastolic and end-systolic diameters (respectively) 5 days after injection of saline solution or DOX (20 mg / kg) Fig.12 A and Fig.12 B in), shorten the score ( Fig.12 C) and heart rate ( Fig.12 **p<0.01, ***p<0.001: t-test or Mann-Whitney test for Dox mice treated with vehicle relative to control mice, $$$p<0.001: One-way ANOVA, post hoc Dunnett's test or Kruskal-Wallis test, post hoc Dunn's test for Dox mice treated with vehicle relative to Dox mice treated with NMN analogs (180 mg / kg) or vehicle.

[0422] Fig.13 Figure 5 shows the left ventricular anterior wall thickness during systole and diastole 5 days after injection of saline solution or DOX (20 mg / kg) Fig.13 A and Fig.13 B) and left ventricular posterior wall thickness during systole and diastole ( Fig.13 C and Fig.13 Histogram of D). *p<0.05, **p<0.01: Mann-Whitney test of Dox mice treated with vehicle relative to control mice.

[0423] Fig.14 Figure 2 shows the heart weight 5 days after injection of saline solution or DOX (20 mg / kg) Fig.14 A) and heart weight normalized to tibia length ( Fig.14 ***p<0.001: t-test of Dox mice treated with vehicle versus control mice.

[0424] Fig.15 Figure 2 shows the concentration of LDH (U / L, Fig.15 A) and LDH (fold change, Fig.15 **p<0.01: Mann-Whitney test for Dox mice treated with vehicle relative to control mice; $p<0.05: Kruskal-Wallis test for Dox mice treated with vehicle relative to Dox mice treated with NMN analog (180 mg / kg) or vehicle.

[0425] Fig.16 is a histogram showing the ability of NMN to prevent SS RBC sickling under 1% O2. Nonparametric one-way ANOVA followed by Kruskal-Wallis test: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0426] Fig.17 is a histogram showing the ability of Compound IB to prevent SS RBC sickling under 1% O2. Nonparametric one-way ANOVA followed by Kruskal-Wallis test: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0427] Fig.18is a histogram showing the ability of Compound IC to prevent SS RBC sickling under 1% O2. Nonparametric one-way ANOVA followed by Kruskal-Wallis test: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0428] Example

[0429] The present invention is further illustrated by the following examples.

[0430] Example 1: Synthesis of the compounds of the present invention

[0431] Materials and methods

[0432] All materials were obtained from commercial suppliers and used without further purification. Thin layer chromatography was performed on TLC plastic sheets of silica gel 60 F254 from Merck (layer thickness 0.2 mm). Column chromatography purification was performed on silica gel 60 (70-230 mesh ASTM, Merck). Melting points were determined on a digital melting point apparatus (Electrothermal IA8103) and were uncorrected or on a Kofler bench type WME (Wagner & Munz). IR, 1 H. 19 F and 13 C NMR spectroscopy confirmed the structures of all compounds. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer, and NMR spectra were recorded on a BRUKER AC 300 or 400 spectrometer using CDCl3, CD3CN, D2O or DMSO-d6 as solvents. 1 H spectrum range 300MHz or 400MHz, 13 C spectral range 75MHz or 100MHz and 19 F spectrum range recorded at 282MHz or 377MHz. (i) 1 The chemical shift (δ) of H is expressed in parts per million relative to the signal of CHCl3 (δ 7.27), (ii) 13 The chemical shift (δ) of C is expressed in parts per million relative to the signal of CDCl3 (δ 77.2), (iii) 19Chemical shifts (δ) of F are expressed in parts per million relative to the signal of CFCl3 (internal standard) (δ0). Chemical shifts are expressed in ppm and peak multiplicities are assigned as follows: s, singlet; br s, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; quint, quintet; m, multiplet. High-resolution mass spectra (HRMS) were obtained from the "Service Central d'analyze de Solaize" (Centre Nationale de la Recherche Scientifique) and recorded on a Waters spectrometer using electrospray ionization-TOF (ESI-TOF).

[0433] General Experimental Procedure

[0434] Step-1 Synthesis of compounds of formula XI

[0435] The compound of formula XIV (1.0 equivalent) is dissolved in dichloromethane. Nicotinamide (1.50 equivalent) and TMSOTf (1.55 equivalent) of formula XV are added at room temperature. The reaction mixture is heated to reflux and stirred until the reaction is complete. The mixture is cooled to room temperature and filtered. The filtrate is concentrated to dryness to obtain the crude NR tetraacetate of formula X-1.

[0436] Step 2 Synthesis of the compound of formula X

[0437] The crude NR tetraacetate of formula X-1 was dissolved in methanol and cooled to -10°C. A 4.6 M methanolic ammonia solution (3.0 eq.) was added at -10°C and the mixture was stirred at this temperature until the reaction was complete. Dowex HCR (H + ) until pH = 6 to 7. The reaction mixture is warmed to 0°C and filtered. The resin is washed with a mixture of methanol and acetonitrile. The filtrate is concentrated to dryness. The residue is dissolved in acetonitrile and concentrated to dryness. The residue is dissolved in acetonitrile to obtain a crude NR triflate solution of formula X.

[0438] Step 3 Synthesis of the compound of formula XI

[0439] The crude NR triflate in acetonitrile solution was diluted with trimethyl phosphate (10.0 eq.). Acetonitrile was distilled under vacuum and the mixture was cooled to -10°C. Phosphorus oxychloride (4.0 eq.) was added at -10°C and the mixture was stirred at -10°C until the reaction was complete.

[0440] Step 4 and Step 5: Synthesis of compounds of Formula IA

[0441] The mixture was hydrolyzed by adding a 50 / 50 mixture of acetonitrile and water, followed by the addition of tert-butyl methyl ether. The mixture was filtered and the solid was dissolved in water. The aqueous solution was neutralized by the addition of sodium bicarbonate and extracted with dichloromethane. The aqueous layer was concentrated to dryness to give a crude mixture of NMN and di-NMN of Formula IA.

[0442] Isolation of di-NMN of Formula IA:

[0443] NMN of Formula IA and di-NMN were separated by purification by elution with water on Dowex 50wx8. The fractions containing di-NMN were concentrated to dryness. The residue was purified by silica gel (gradient isopropanol / water) column chromatography. The pure fractions were mixed and concentrated. The residue was freeze-dried to give di-NMN as a beige solid.

[0444] 31 P RMN: δ (ppm, ref. 85% H3PO4: 0ppm dans D2O) = -11.72; 1 H RMN:δ(ppm, ref. TMS:0ppm dans D2O)=4.20(ddd,J H-H =11.9,3.5,2.4Hz,2H),4,35(ddd,J H-H =11.9,3.9,2.2Hz,2H),4.43(dd,J H-H =5,0,2.6Hz,2H),4.53(t,J H-H =5.0Hz,2H),4.59(m,2H),6.16(d,J H-H =5.4Hz,2H),8.26(dd,J H-H =8.1,6.3Hz,2H),8.93(d,J H-H =8.1Hz,2H),9.25(d,J H-H =6.2Hz,2H),9.41(s,2H); 13 C RMN: δ (ppm, refer to TMS: 0ppm dans D2O)=64.84(CH2),70.73(CH),77.52(CH),87.11(CH),99.88(CH),128.65(CH),133.89(Cq),139.84( CH), 142.54(CH), 146.04(CH), 165.64(Cq); MS (ES+): m / z=122.8[Mnicotinamide+H]+, 650.8[M+H]+.

[0445] Synthesis of compounds of formula IB

[0446] Phosphoryl chloride (3.0 eq.) was added to trimethyl phosphate (20.0 eq.) at -5°C. β-NR chloride (1.0 eq.) was added in portions at -5°C and the reaction mixture was stirred overnight at -5°C. Morpholine (3.0 eq.) was added dropwise at -10 / 0°C and the mixture was stirred for 2 to 3 hours. α-NMN (1.0 eq.) was then added in portions at -5°C and the reaction mixture was stirred overnight at -5°C. Hydrolysis was carried out by adding water (5 vol.) dropwise at -10 / 0°C and the mixture was stirred at 10°C to 15°C until complete homogenization. The reaction mixture was then extracted with dichloromethane (6*10 vol.) and eluted through Purolite A600E formate form resin to neutralize the aqueous phase (neutralize the theoretical amount of HCl from POCl3). The eluate was then concentrated in vacuo at 45 / 50°C to obtain a crude product containing α,β-diNMN of formula IB. Wash with water Dowex 50wx8100-200 mesh H + Forming resin, allowing some impurities to be removed. Fractions containing compound IB were combined and concentrated under vacuum at 45°C to 50°C. The crude product was purified by preparative chromatography, Luna Polar RP 10 μm was the stationary phase, and eluted with 10 mM NaH2PO4 aqueous solution. The pure fractions were combined and washed with water on Purolite C100EH H + Form resin elution (need to Na + Completely exchanged for H + amount), and then eluted on Purolite A600E acetate resin (requires H2PO4 - The eluate was concentrated in vacuo and the residue was freeze-dried to give Compound IB as a white solid.

[0447] 31 P RMN: δ (ppm, ref. 85% H3PO4: 0 ppm dans D2O) = -11.87, -11.69, -11.46, -11.29; 1HRMN: δ (ppm, refer to TMS: 0ppm dans D2O)=4.10(ddd,J=11.1,6.1,3.1Hz,1H),4.15-4.25(m,2H),4.36(ddd,J=12.2,4.4,2.4Hz,1H),4.40(dd,J=4. 9,2.4Hz,1H),4.44(dd,J=5.0,2.7Hz,1H),4.53(t,J=5.0Hz,1H),4.5(m,1H),4.85(m,1H),4.92(t,J=5.3Hz,1H ),6.15(d,J=5.5Hz,1H),6.51(d,J=5.7Hz,1H),8.14(dd,J=8.0,6.3Hz,1H),8.26(dd,J=8.1,6.3Hz,1H),8.88( d,J=8.1Hz,1H),8.92(d,J=8.1Hz,1H),9.02(d,J=6.3Hz,1H),9.24(s,1H),9.26(d,J=6.4Hz,1H),9.40(s,1H); 13 C RMN: δ (ppm, refer to TMS: 0ppm dans D2O)=64.83,64.87(CH2),65.30,65.35(CH2),70.65(CH),70.74(CH),71.92( CH),77.51(CH),87.03,87.10(CH),87.19,87.26(CH),96.57(CH),99.83(CH), 126.89(CH),128.54(CH),132.44(Cq),133.81(Cq),139.85(CH),140.92(CH), 142.50(CH),143.49(CH),145.06(CH),145.97(CH),165.64(Cq),165.88(Cq);

[0448] MS (ES+): m / z=122.8[Mnicotinamide+H]+, 650.9[M+H]+.

[0449] Synthesis of compounds of formula IC

[0450] Phosphorus oxychloride (3.0 equiv.) was added to trimethyl phosphate (20.0 equiv.) at -5 °C.

[0451] α-NR chloride (1.0 equiv) was added in portions at -5°C and the reaction mixture was stirred at -5°C overnight. Morpholine (3.0 equiv) was added dropwise at -10 / 0°C and the mixture was stirred for 2 to 3 hours. α-NMN (1.0 equiv) was then added in portions at -5°C and the reaction mixture was stirred at -5°C overnight. Hydrolysis was performed by adding water (5 volumes) dropwise at -10 / 0°C and stirring the mixture at 10°C to 15°C until complete homogenization. The reaction mixture was then extracted with dichloromethane (6*10 volumes) and eluted through Purolite A600E formate form resin to neutralize the aqueous phase (neutralize the theoretical amount of HCl from POCl3). The eluate was then concentrated in vacuo at 45 / 50°C to obtain a crude product of α,β-diNMN containing formula IC. Dowex50wx8 100-200 mesh H was eluted with water. + Form resin, allowing some impurities to be removed. Fractions containing compound IC were combined and concentrated under vacuum at 45°C to 50°C. The crude product was purified by preparative chromatography, Luna Polar RP 10 μm was the stationary phase, and eluted with 10 mM aqueous NaH2PO4. The pure fractions were combined and washed with water on Purolite C100EH H + Form resin elution (need to Na + Completely exchanged for H + amount), and then eluted on Purolite A600E acetate resin (requires H2PO4 - The eluate was concentrated in vacuo and the residue was freeze-dried to give Compound IC as a white solid.

[0452] 31 P RMN: δ (ppm, ref. 85% H3PO4: 0 ppm dans D2O) = -11.40; 1 H RMN: δ (ppm, refer to TMS: 0ppm dans D2O)=4.14(ddd,J=11.4,3.4,2.8Hz,2H),4.23(ddd,J=11.6,3.3,2.8Hz,2H),4.44(dd,J=4.8,2.3Hz,2H),4.88(m,2H),4.96( t,J=5.3Hz,2H),6.54(d,J=5.7Hz,2H),8.15(dd,J=8.1,6.2Hz,2H),8.89(d,J=8.1Hz,2H),9.05(d,J=6.3Hz,2H),9.26(s,2H); 13C RMN: δ (ppm, refer to TMS: 0ppm dans D2O)=65.37(CH2),70.70(CH),71.95(CH),87.30(CH),96.62(CH),126.91(CH),132.45(Cq),140.94( CH), 143.52(CH), 145.07(CH), 165.90(Cq); MS (ES+): m / z=122.7[Mnicotinamide+H]+, 650.8[M+H]+.

[0453] Example 2: Effect of compounds of the present invention on acute cyclophosphamide (CYP)-induced dysregulation in female Sprague-Dawlev rats Evaluation in a Cystitis Model

[0454] The aim of this study was to evaluate the effects of oral administration of nicotinamide mononucleoside (NMN), prodrug A (α-NMN) and prodrug B (Compound IA), Compound IB and IC at a dose of 500 mg / kg on visceral pain in an acute cyclophosphamide (CYP)-induced cystitis model in female Sprague-Dawley rats.

[0455] I. Materials and Methods

[0456] animal

[0457] Female Sprague-Dawley rats, 7 weeks postpartum

[0458] Drug treatment

[0459] -NMN: 500mg / kg

[0460] - Prodrug A: 500 mg / kg

[0461] -Prodrug B (Compound IA): 500 mg / kg

[0462] -Compound IB: 500 mg / kg

[0463] -Compound IC; 500 mg / kg

[0464] -Carrier: distilled water

[0465] -Route of administration: Oral, 5 mg / kg

[0466] -Dosage frequency: once on D0, 15 minutes before intraperitoneal injection of CYP (ip).

[0467] CYP-induced acute cystitis

[0468] CYP was injected intraperitoneally at 150 mg / kg in a final volume of 5 mg / kg in normal saline.

[0469] Mechanical stimulation using von Frey filaments

[0470] - Rats were placed in individual plexiglass boxes with wire mesh floors and allowed to acclimate to the box for at least 30 minutes before any testing began.

[0471] - Eight von Frey fibers were used with increasing forces of 1 g, 2 g, 4 g, 6 g, 8 g, 10 g, 15 g and 26 g.

[0472] - Each calibrated fiber was applied 3 times in the lower abdominal area close to the bladder.

[0473] Scoring of each nociceptive behavior applied

[0474] - Rating 0 = No response

[0475] - Score 1 = Abdominal contraction

[0476] - Rating 2 = Trampling or changing position

[0477] - Score 2 = wincing or abdominal flexion or licking of the area stimulated with the von Frey fibers.

[0478] For each rat, the results are expressed as:

[0479] -Nociception threshold: the first von Frey force that is perceived as painful (score > 1)

[0480] =>Lower threshold=allodynia

[0481] - Nociception score: Percentage of maximum response for each filament (total = 9 for 3 mixed applications)

[0482] => Systemic pain response

[0483] Experimental Group:

[0484] Table 2

[0485] Group treat injection n 1 Vehicle (5mL / kg) CYP 6 2 NMN (500mg / kg) CYP 6 3 Prodrug A (500 mg / kg) CYP 6 4 Prodrug B (500 mg / kg) CYP 6 5 Compound IB (500 mg / kg) CYP 6 6 Compound IC (500 mg / kg) CYP 6

[0486] II. Results and Discussion

[0487] 1. Basal nociception parameters of all experimental groups (before CYP injection)

[0488] The results show that Figure 1 A in Figure 1 B in Figure 1 C and Figure 1 D) Basal nociceptive responses were similar between all experimental groups (before CYP injection).

[0489] 2. CYP-induced visceral pain at 2 and 4 hours after injection (compared with baseline values ​​in the vehicle group)

[0490] The results showed that compared with the basal response, CYP (150 mg / kg, intraperitoneal injection) induced a significant decrease in the nociceptive threshold at 2 hours, 4 hours and 6 hours ( Figure 2 A) and nociception scores increased significantly ( Figure 2 B).

[0491] 3. Effects of NMN, prodrug A, prodrug B, compound IB and compound IC on CYP-induced allodynia Effect of nociception threshold

[0492] The results showed that compared with vehicle:

[0493] -NMN (500 mg / kg, oral) at +2 hours ( Figure 3 A) and +4 hours ( Figure 3 B) resulted in a slight increase in nociceptive thresholds, with the effect at +4 h just above the statistical significance limit (p = 0.063),

[0494] - Prodrug A (500 mg / kg, p.o.) resulted in no significant increase in nociceptive threshold at +2 hours ( Figure 3 A), and increased significantly at +4 hours ( Figure 3 B) in

[0495] - Prodrug B (500 mg / kg, p.o.) resulted in a significant increase in nociceptive threshold at +4 hours ( Figure 3 B).

[0496] - Compound IB (500 mg / kg, p.o.) caused a significant increase in nociceptive threshold at +6 hours after CYP induction ( Figure 3 C).

[0497] -Compound IC (500 mg / kg, p.o.) caused a significant increase in nociceptive threshold at +6 hours after CYP induction ( Figure 3 C).

[0498] 4. Effects of NMN, prodrug A, prodrug B, compound IB and compound IC on CYP-induced visceral pain Response (nociception score)

[0499] The results showed that compared with vehicle:

[0500] -NMN (500 mg / kg, oral) resulted in a decrease in nociception scores at +2 hours ( Figure 4 A) and +4 hours ( Figure 4 The B) in the figure decreases significantly.

[0501] - Prodrug A (500 mg / kg, p.o.) resulted in nociception scores at +2 hours ( Figure 5A) and +4 hours ( Figure 5 B) in the figure, and only reaches statistical level at +4 hours.

[0502] - Prodrug B (500 mg / kg, p.o.) resulted in a significant decrease in nociception scores at +4 hours ( Figure 6 B) (no effect observed at +2 hours ( Figure 6 A)) in

[0503] -Compound IB (500 mg / kg, p.o.) resulted in nociception scores at +2 hours ( Figure 7 A in), +4 hours ( Figure 7 B) and +6 hours ( Figure 7 C) decreased significantly,

[0504] -Compound IC (500 mg / kg, p.o.) resulted in nociception scores at +2 hours ( Figure 8 A in), +4 hours ( Figure 8 B) and +6 hours ( Figure 8 C) decreased significantly.

[0505] 5. Summary of results

[0506] Basal nociceptive responses were similar between all experimental groups (before CYP injection).

[0507] Compared with the basal response, the effects of CYP (150 mg / kg, ip) at 2 and 4 hours were characterized as follows:

[0508] -Nociceptive thresholds decreased significantly at +2, +4 and +6 hours,

[0509] -Nociception scores increased significantly at +2, +4 and +6 hours.

[0510] Compared to vehicle, the effects of NMN (500 mg / kg, p.o.) in CYP-injected rats resulted in:

[0511] - a slight increase in nociceptive thresholds at +2 and +4 hours, with the effect just above the statistical significance limit for +4 hours (p=0.063),

[0512] -Nociception scores decreased significantly at +2 and +4 hours.

[0513] The effects of prodrug A (500 mg / kg, p.o.) in CYP-injected rats were characterized as follows compared to vehicle:

[0514] - Increased nociceptive thresholds at +2 and +4 hours, reaching significance at +4 hours,

[0515] -Nociception scores decreased at +2 and +4 hours, reaching significance at +4 hours.

[0516] The effects of prodrug B (500 mg / kg, p.o.) in CYP-injected rats resulted in:

[0517] - +4 hours nociceptive threshold significantly increased,

[0518] -+4 hours nociception scores decreased significantly.

[0519] The effects of Compound IB (500 mg / kg, po) compared to vehicle in CYP-injected rats resulted in:

[0520] -Nociception scores decreased significantly at +2, +4 and +6 hours.

[0521] -Nociceptive threshold increased significantly 6 hours after CYP injection.

[0522] Compared to vehicle, the effects of Compound IC (500 mg / kg, po) in CYP-injected rats resulted in:

[0523] -Nociception scores decreased significantly at +2, +4 and +6 hours,

[0524] -Nociceptive threshold increased significantly 6 hours after CYP injection.

[0525] III. Conclusion

[0526] The model was validated by a single intraperitoneal injection of CYP (150 mg / kg) to induce visceral pain at 2, 4, and 6 hours after injection.

[0527] A single oral treatment with NMN (500 mg / kg) reduced CYP-induced visceral pain at both evaluation time points (+2 h and +4 h), with a higher level of significance at +4 h.

[0528] Prodrug A (500 mg / kg, p.o.) reduced CYP-induced visceral pain at both evaluation time points (+2 hours and +4 hours), with significance being achieved at +4 hours.

[0529] In CYP-injected rats, oral treatment with prodrug B (Compound IA) (500 mg / kg, po) produced significant antinociceptive activity at +4 hours.

[0530] In CYP-injected rats, oral treatment with compounds IB and IC (500 mg / kg, p.o.) showed significant antinociceptive activity at three evaluation time points: +2 h, +4 h, and +6 h.

[0531] Example 3: Evaluation of compounds of the invention in a doxorubicin-induced cardiotoxicity model

[0532] The aim of this study was to evaluate the effects of 180 mg / kg intraperitoneal administration of nicotinamide mononucleotide (NMN), compound IB, and compound IC on the progression of doxorubicin-induced cardiotoxicity.

[0533] I. Materials and Methods

[0534] Material

[0535] animal:

[0536] 76 male mice, 8 weeks old when arriving, were obtained from Janvier Labs, Le Genest St Isle, 53941 St Berthevin, France. Each animal was identified with an electronic chip. Each cage was numbered. Animals were uniquely numbered according to animal number / cage and number of cages, and group names and mouse numbers were named respectively.

[0537] The matching cards used to identify the cages in which the experimental animals were kept contained the following information: experiment name, experiment number, and cage number.

[0538] method

[0539] 1. Preparation of formulations

[0540] NMN powder, Compound IB and Compound IC (180 mg / kg) were dissolved in vehicle (solutions were used for up to 1 day at room temperature). Fresh samples were prepared for each administration every day except weekends (solutions were prepared on Saturday and used on Saturday and Sunday).

[0541] 2. Doxorubicin-induced cardiotoxicity

[0542] Cardiotoxicity was induced by a single intraperitoneal injection of doxorubicin (DOX) at 20 mg / kg. Doxorubicin was prepared at 2 mg / mL and the administration volume was 10 mL / kg.

[0543] Mortality was followed throughout the experimental period.

[0544] 3. Experimental Group

[0545] Team Description:

[0546] Group 1: Vehicle (ip)

[0547] Group 2: Doxorubicin (20 mg / kg)

[0548] Group 3: Doxorubicin (20 mg / kg) + test compound 180 mg / kg (NMN)

[0549] Group 4: Doxorubicin (20 mg / kg) + test compound 180 mg / kg (Compound IB)

[0550] Group 5: Doxorubicin (20 mg / kg) + test compound 180 mg / kg (Compound IC)

[0551] Group Assignment:

[0552] Each group involved 14 to 24 mice.

[0553] The test and control animal groups were maintained under identical conditions in accordance with nonclinical laboratory study regulations. The expected study duration was 11 days.

[0554] 4. Induced with doxorubicin

[0555] On D0, mice were injected with DOX (20 mg / kg) by intraperitoneal route.

[0556] 5. treat

[0557] Treatment with NMN, Compound IB, and Compound IC was performed once a day starting 5 days before DOX injection, from D-5 to D0.

[0558] Mice were treated with NMN, Compound IB, and Compound IC by intraperitoneal injection 30 min before DOX injection.

[0559] Mice were treated with NMN, Compound IB, and Compound IC by intraperitoneal injection once daily during the experimental period (D0 to D5). The last injection occurred 24 hours before sacrifice.

[0560] 6. Body weight, survival rate and clinical examination

[0561] Body weight assessments were performed at inclusion and on D5.

[0562] The survival rate was recorded every day until the end of the experiment (D5).

[0563] 7. Blood collection

[0564] Retro-orbital bleeding was performed at inclusion and 1 and 5 days after infection with DOX to assess biomarkers (LDH and creatinine).

[0565] 8. Organ collection

[0566] On D5, hearts and tibiae were harvested.

[0567] 9. Echocardiography to assess heart function

[0568] Echocardiography (ECG) was performed in anesthetized (isoflurane 1.5-2%) animals 5 days after doxorubicin injection using noninvasive two-dimensional echocardiography (VF16-5 probe, Siemens, Acuson NX3 Elite). After removing chest hair, digital images of the heart were obtained in parasternal long-axis and short-axis views.

[0569] The following heart functions are assessed during an ECG:

[0570] - Left ventricular (LV) end-systolic and end-diastolic internal dimensions;

[0571] - left ventricular end-systolic and end-diastolic volumes,

[0572] - shorten the score;

[0573] - Ejection fraction;

[0574] - Heart rate; and

[0575] - Anterior and posterior wall thickness during diastole and systole.

[0576] II. Results and Discussion

[0577] 1. Survival rate

[0578] Fig. 9 Shown are the survival rates of mice induced or not with DOX (20 mg / kg) 5 days after doxorubicin injection.

[0579] DOX mice were treated with NMN, Compound IB and Compound IC (180 mg / kg) or vehicle.

[0580] like Fig. 9 As shown, nearly 50% of the doxorubicin mice treated with vehicle died before the end of the experimental protocol.

[0581] NMN treatment tended to improve survival (78% survival), but did not reach statistical significance. However, treatment with Compound IB or Compound IC significantly improved survival (98% and 100% survival, respectively) compared to the untreated group (50% survival).

[0582] 2. weight

[0583] Fig.10Panel A shows the body weight changes of mice treated with NMN, Compound IB and Compound IC (180 mg / kg) or vehicle before (light gray symbols) and 5 days after (dark gray symbols) injection of saline solution or DOX (20 mg / kg).

[0584] Fig.10 Panel B shows the body weight gain calculated as follows: body weight on the day of sacrifice minus body weight before injection.

[0585] Surviving vehicle-treated mice exhibited major signs of distress associated with a robust loss of body weight (-4.2 ± 0.5 g). NMN, Compound IB, and Compound IC significantly reduced the body weight loss observed after doxorubicin administration (p<0.01, p<0.001, p<0.001, respectively).

[0586] 3. Heart function

[0587] 3.1. Left ventricular end-diastolic / systolic volumes and ejection fraction

[0588] Fig.11 Figure 5 shows the left ventricular (LV) end-diastolic (D) values ​​of the cells treated with or without NMN, Compound IB, and Compound IC 5 days after saline solution or DOX (20 mg / kg) injection. Fig.11 A), end-systolic volume ( Fig.11 B) and ejection fraction ( Fig.11 C).

[0589] like Fig.11 As shown in Figure B, compared with the control group, doxorubicin induced a significant increase in LV end-systolic volume, while end-diastolic volume ( Fig.11 A) in the figure showed no difference, resulting in a significant decrease in ejection fraction (38.9±1.3% in the adriamycin vehicle group vs. 64.8±0.6% in the control mice) ( Fig.11 C).

[0590] Compared to untreated DOX animals, NMN, Compound IB, and Compound IC reduced end-systolic LV ( Fig.11 In B) volume, statistical significance (p<0.05) was observed for compound IB.

[0591] Compared to DOX-induced animals receiving vehicle, ejection fraction was significantly improved after treatment with NMN, Compound IB, and IC, with NMN-treated DOX mice being 56.9 ± 0.6% (p < 0.05), Compound IC-treated DOX mice being 58.2 ± 0.5% (p < 0.001), and Compound IC-treated DOX mice being 60.0 ± 0.6% (p < 0.001) ( Fig.11 C).

[0592] 3.2. Left ventricular end-diastolic / end-systolic diameter, fractional shortening, and heart rate

[0593] Fig.12 The left ventricular end-diastolic and end-systolic diameters (respectively) 5 days after injection of saline solution or DOX (20 mg / kg) are shown. Fig.12 A and Fig.12 B in), shorten the score ( Fig.12 C) and heart rate ( Fig.12 D).

[0594] As shown in the figure, in doxorubicin-treated mice, LV internal diameter increased significantly during systole ( Fig.12 B), while there was no significant difference in diastole ( Fig.12 A), resulting in a decrease in fractional shortening (33.5 ± 0.4% vs. 43.2 ± 0.5% in control mice) ( Fig.12 C). Treatment with NMN, Compound IB and Compound IC significantly improved the shortening fraction to approximately 38% (p<0.001 for the three groups).

[0595] In addition, doxorubicin significantly reduced heart rate ( Fig.12 D) (365.1±23.9bpm and 525.6±19.8bpm, respectively). Treatment with NMN, Compound IB and Compound IC resulted in an increase in heart rate, with Compound IB significantly improving this parameter (470.1±18.8bpm (p<0.001)).

[0596] 3.3. Anterior and posterior wall thickness of the left ventricle during systole and diastole

[0597] Fig.13 The systolic and diastolic left ventricular anterior wall thickness ( Fig.13 A and Fig.13 B) and left ventricular posterior wall thickness during systole and diastole ( Fig.13 C and Fig.13 D).

[0598] Doxorubicin significantly reduced anterior and posterior wall thickness during systole but had no significant effect during diastole, and all treatments had significant effects.

[0599] Treatment with Compound NMN, Compound IB, and Compound IC (180 mg / kg) in DOX mice resulted in non-significant increases in anterior and posterior wall thickness during systole.

[0600] 4. Heart weight

[0601] Fig.14 The heart weight ( Fig.14 A) and heart weight normalized to tibia length ( Fig.14 B).

[0602] DOX mice were treated with Compound NMN, Compound IB, and Compound IC (180 mg / kg) or vehicle.

[0603] like Fig.14 A and Fig.14 As shown in B, doxorubicin significantly reduced heart weight compared to control mice (102.3 ± 4.6 mg vs. 128.9 ± 3.3 mg, respectively). Treatment with Compound IB and Compound IC tended to increase heart weight compared to DOX vehicle mice, but did not reach significance. Similar results were obtained when heart weight was normalized to tibia length.

[0604] 5. Biomarker Assessment

[0605] Fig.15 The LDH concentration (U / L, Fig.15 A) and LDH (fold change, Fig.15 B).

[0606] DOX mice were treated with Compound NMN, Compound IB, and Compound IC (180 mg / kg) or vehicle.

[0607] Plasma LDH (lactate dehydrogenase) was measured 5 days after doxorubicin injection. Fig.15 A and Fig.15 As shown in Figure B, doxorubicin induced a 3-fold increase in LDH release compared to the control group. NMN treatment reduced LDH release by more than 35%, but did not reach statistical significance. However, treatment with Compound IB and Compound IC resulted in a significant decrease in LDH levels by 50% to 55% (p<0.05).

[0608] III. Conclusion

[0609] Overall, the results suggest that doxorubicin induces cardiac dysfunction characterized by impaired myocardial contractility and cardiac filling, as well as cellular cardiac damage. Doxorubicin also causes high mortality and strong weight loss.

[0610] NMN, Compound IB, and Compound IC treatment significantly improved survival, body weight loss, and prevented cardiac function deterioration as shown by the effects of treatment on ejection fraction, fractional shortening, and heart rate.

[0611] Example 4: Evaluation of compounds of the invention in experimental models of sickle cell disease

[0612] The aim of this study was to evaluate the effects of nicotinamide mononucleotide (NMN), Compound IB, and Compound IC at a dose of 185 mg / kg injected intraperitoneally as modulators of red blood cell sickle cell disease and their potential role in treating sickle cell disease in SCD mice.

[0613] Ⅰ. Materials and methods

[0614] Material

[0615] animal:

[0616] Townes S / S mice with a 129 / B6 mixed genetic background.

[0617] method

[0618] 1. Preparation of formulations

[0619] NMN powder, Compound IB and Compound IC (185 mg / kg) were dissolved in vehicle (solutions were used for up to 1 day at room temperature). Fresh samples were prepared for each administration every day except weekends (solutions were prepared on Saturday and used on Saturday and Sunday).

[0620] 2. sickle cell

[0621] In Townes S / S mice, the mouse α and β globin gene loci are deleted and replaced with human α and β globin. When carrying two copies of the βS allele, the mice develop the human sickle cell disease phenotype, with sickle-shaped red blood cells visible in blood smears.

[0622] 3. Experimental Group

[0623] Team Description:

[0624] Group I: Vehicle (ip injection)

[0625] Group II: NMN (185 mg / kg)

[0626] Group III: L Compound IB (185 mg / kg)

[0627] Group IV: Compound IC (185 mg / kg)

[0628] 4. treat

[0629] Mice were treated with NMN, Compound IB, and Compound IC once daily by intraperitoneal injection during all experimental periods (D0 to D15). The last injection occurred 24 hours before sacrifice.

[0630] 5. Blood collection

[0631] Retro-orbital blood sampling was performed on D0 and D5, D10 and D15 inclusive, via facial vein bleeding.

[0632] 6. in vitro

[0633] The collected erythrocytes were placed under hypoxia (1% O2) for 30 minutes to induce sickling cells. The percentage of sickled cells was then assessed.

[0634] II. Results and Discussion

[0635] 1. Erythrocyte sickling under hypoxic conditions in vitro

[0636] Fig.16 , Fig.17 and Fig.18 Shows NMN ( Fig.16 )、Compound IB( Fig.17 ) and compound IC( Fig.18 ) Ability to prevent sickling of SS RBCs at 1% O2.

[0637] SS RBCs from treated mice were collected at D0, D5, D10, and D15 and placed in a hypoxic chamber (1% O2) for 30 minutes. The percentage of sickled erythrocytes at each time point was then assessed using Compound NMN, Compound IB, and Compound IC.

[0638] The results show that using

[0639] -After NMN (185 mg / kg, intraperitoneal injection) was treated for 15 days, the percentage of sickle cells decreased significantly from 40% at D0 (p<0.001) to less than 10% ( Fig.16 );

[0640] - After 15 days of treatment with Compound IB (185 mg / kg, intraperitoneal injection), the percentage of sickle cells decreased significantly from 32% at DO to less than 15% (p<0.0001). Fig.17 );

[0641] - After 15 days of treatment with compound IC (185 mg / kg, intraperitoneal injection), the percentage of sickle cells decreased significantly (p<0.001) from 31% at DO to below 20% ( Fig.18 );

[0642] III. Conclusion

[0643] These results indicate that NMN, Compound IB, and Compound IC prevent SS RBC sickling under hypoxic conditions.

Claims

1. Use of a compound in the preparation of a medicament for treating pain, anti-tumor induced cardiotoxicity or sickle cell disease, wherein the compound is a compound of formula I or a pharmaceutically acceptable salt thereof, in: -X1 and X2 each independently represent oxygen; -R1 and R 13 each independently represents hydrogen; -R3, R4, R 10 , R 11 are identical and each represents hydrogen; -R2, R5, R9 and R 12 are identical and each represents a hydroxyl group; - R6 and R8 each independently represent hydrogen; -R7 and R 14 are identical and each represents NH2; -Y1 and Y2 are independently selected from CH and CH2; -M is selected from H or a suitable counterion; - represents a single bond or a double bond depending on Y1 and Y2; and - It depends on R1 and R 13 The α anomer or the β anomer of the position.

2. The method according to claim 1, wherein Y1 and Y2 each independently represent CH.

3. The use according to claim 1, wherein Y1 and Y2 each independently represent CH2.

4. The use according to claim 1, wherein the compound is selected from the compounds of formula IA to formula IF:

5. The use according to claim 1, wherein the compound is a compound of formula IA, formula IB or formula IC.

6. A compound of formula I' or a pharmaceutically acceptable salt thereof, wherein: -X1 and X2 each independently represent oxygen; -R1 and R 13 each independently represents hydrogen; -R3, R4, R 10 , R 11 are identical and each represents hydrogen; -R2, R5, R9 and R 12 are identical and each represents a hydroxyl group; - R6 and R8 each independently represent hydrogen; -R7 and R 14 are identical and each represents NH2; -Y1 and Y2 are independently selected from CH and CH2; -M is selected from H or a suitable counterion; - represents a single bond or a double bond depending on Y1 and Y2; and - It depends on R1 and R 13 The position of the α anomer or the β anomer, The condition is At least one of represents an α anomer.

7. The compound according to claim 6, wherein Y1 and Y2 each independently represent CH.

8. The compound according to claim 6, wherein Y1 and Y2 each independently represent CH2.

9. The compound according to claim 6, wherein the compound is selected from the group consisting of compounds of Formula IB, Formula IC, Formula IE and Formula IF:

10. The compound according to claim 6, wherein the compound is a compound of formula IB or formula IC.

11. A pharmaceutical composition comprising at least one compound of formula I' as defined in claim 6, and at least one pharmaceutically acceptable carrier.

12. A food composition comprising at least one compound of formula I' as defined in claim 6, and at least one acceptable carrier and / or diluent.

13. A cosmetic composition comprising at least one compound of formula I' as defined in claim 6, and at least one acceptable carrier and / or diluent.

14. A method for preparing a compound of formula I as defined in claim 1 or a compound of formula I' according to claim 6, comprising the following steps: 1) monophosphorylating the compound of formula X, in: X1, R1, R2, R3, R4, R5, R6, R7, Y1, As defined in claim 1, To obtain a compound of formula XI, in: X1, R1, R2, R3, R4, R5, R6, R7, Y1, As defined in claim 1; 2) hydrolyzing the compound of formula XI obtained in step 1) to obtain a compound of formula XII in: X1, R1, R2, R3, R4, R5, R6, R7, Y1, As defined in claim 1; 3) reacting the compound of formula XII obtained in step 2) with the compound of formula XIII obtained as described in step 1), in: X2, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 、Y2、 As defined in claim 1; To obtain the compound of formula I or the compound of formula I' after hydrolysis.

15. The method according to claim 14, further comprising the step of reducing the compound of formula I or the compound of formula I' obtained in step 3) to obtain the compound of formula I or the compound of formula I' wherein Y1 and Y2 each independently represent CH2.

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