Nicotinamide mononucleotide derivatives and their use in the treatment and prevention of toxicity induced by antitumor drugs

Abstract

The present invention relates to nicotinamide mononucleotide derivatives of formula (I) for use in the treatment and / or prevention of toxicity induced by antineoplastic drugs. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) for use in the treatment and / or prevention of toxicity induced by antineoplastic drugs.

Description

TECHNICAL FIELD

[0001] The present invention relates to nicotinamide mononucleotide derivative compounds for use in the treatment and / or prevention of toxicity induced by antineoplastic drugs. BACKGROUND

[0003] Drug-induced toxicities, such as cardiotoxicity, nephrotoxicity, neurotoxicity, hematotoxicity or hepatotoxicity, are a major cause of compounds withdrawal in preclinical and clinical development.

[0004] Notably, almost 10% of drugs have been withdrawn worldwide in the past four decades because of cardiovascular safety issues, such as rofecoxib, tegaserod and sibutramine, despite the tremendous efforts made to reveal cardiotoxicity in the preclinical phase of pharmaceutical product development, cardiotoxicity still leads to safety issues, mainly because of the lack of sufficient understanding of the mechanisms of cardiotoxicity.

[0005] While all therapeutic drug classes have unanticipated toxicities, drugs for long-term administration, such as neuro / psychiatric drugs and anticancer chemotherapy drugs, are of major concern because the toxicity can only manifest itself after long-term accumulation of the drug or its metabolites.

[0006] In particular, drug-induced cardiotoxicity, usually in the form of myocardial dysfunction that can progress to heart failure, is a major adverse effect of some common traditional antineoplastic drugs, such as anthracyclines, cyclophosphamide, fluorouracil (5-FU) and taxanes, as well as newer drugs, such as the biological monoclonal antibodies, such as trastuzumab, bevacizumab and nivolumab; the tyrosine kinase inhibitors, such as sunitinib and nilotinib; the antiretroviral drugs, such as zidovudine; the antidiabetic drugs, such as rosiglitazone; and some recreational drugs, such as alcohol, cocaine, methamphetamine, ecstasy and synthetic cannabinoids.

[0007] Currently, more than one-third of the population is affected by cancer in their lifetime, which, together with cardiovascular diseases, is the two main causes of death in developed countries. Due to the progress in cancer drug therapy, the 10-year overall cancer survival rate for the 20 most common malignancies is 50%, and it is estimated that 33% of long-term cancer survivors die from heart disease.

[0008] Anthracycline-induced cardiotoxicity, in particular doxorubicin (DOX)-induced cardiomyopathy, is considered an extremely serious adverse effect of tumor therapy.

[0009] Doxorubicin is one of the most widely used drugs for the treatment of cancer in adults and children. DOX-induced cardiotoxicity has several manifestations, ranging from asymptomatic electrocardiogram (ECG) changes to decompensated cardiomyopathy characterized by a decrease in left ventricular ejection fraction. These cardiotoxic events can be classified into three types according to their clinical presentation: (1) acute, occurring during treatment or immediately after treatment; (2) early-onset chronic progressive cardiotoxicity, occurring within 1 year after exposure to chemotherapy; and (3) late-onset chronic progressive cardiotoxicity, occurring 1 year or more after the end of treatment.

[0010] Many studies have explored the pathophysiology and mechanisms of doxorubicin-induced cardiotoxicity, however the exact mechanisms remain unclear, although it is likely to be multifactorial.

[0011] Mitochondrial damage and apparent ROS production are considered to be the main causes of cardiotoxicity. However, the use of ROS inhibitors to treat DOX cardiomyopathy has not been successful, and there is currently no effective therapy to treat established DOX cardiomyopathy.

[0012] To date, standard management during anthracycline-based chemotherapy involves pre-treatment assessment of cardiac function, monitoring for potential cardiotoxicity during treatment, and long-term follow-up after the end of chemotherapy.

[0013] Several regimens have been proposed to improve or treat doxorubicin-induced / drug-induced cardiotoxicity, including the use of epirubicin instead of doxorubicin; the simultaneous use of antioxidants and iron chelators dexamethasone, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, ranolazine, metformin and hydroxymethylglutaryl coenzyme A reductase inhibitors; the use of self-nanoemulsifying formulations of antioxidants such as quercetin, coenzyme Q10, pyrroloquinoline quinone, vitamin E, and carnitine.

[0014] However, the effectiveness of these drugs varies from patient to patient and the observed clinical presentation, further studies are needed to assess whether the observed beneficial effects on cardiac function are maintained over the years.

[0015] Therefore, there is an urgent need for effective and safe preventive and / or therapeutic treatment of drug-induced toxicity, in particular antineoplastic drug-induced toxicity.

[0016] Therefore, it is an object of the present application to provide safe preventive and / or therapeutic treatment by providing nicotinamide mononucleotides of formula 001 and derivatives thereof for the treatment and / or prevention of antineoplastic drug-induced toxicity, in particular antineoplastic drug-induced cardiotoxicity.

[0017] The applicant has surprisingly found that the nicotinamide mononucleotide derivative according to the application is an effective agent for the treatment and / or prevention of cardiotoxicity induced by antitumor drugs, in particular doxorubicin-induced cardiotoxicity, and is well tolerated. SUMMARY

[0018] The present application thus relates to a compound of formula (I),

[0019]

[0020] or a pharmaceutically acceptable salt or solvate thereof;

[0021] wherein:

[0022] X is selected from O, CH2, S, Se, CHF, CF2and C=CH2;

[0023] R1is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; wherein R is selected from H and (C1-C8)alkyl;

[0024] R2, R3, R4and R5are independently selected from H, halogen, azido, cyano, hydroxyl, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl and OR; wherein R is selected from H, (C1-C 12 )alkyl, -C(O)(C1-C 12 )alkyl, -C(O)NH(C1-C 12 )alkyl, -C(O)O(C1-C 12 )alkyl, -C(O)aryl, -C(O)(C1-C 12 )alkyl-(C5-C 12 )aryl, -C(O)NH(C1-C 12 )alkyl-(C5-C 12 )aryl, -C(O)O(C1-C 12 )alkyl-(C5-C 12 )aryl and -C(O)CHR AA NH2; wherein R AA is a side chain selected from proteinogenic amino acids;

[0025] R6is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; wherein R is selected from H and (C1-C8)alkyl;

[0026] R7is selected from H, P(O)R9R 10 , P(S)R9R 10 and

[0027] wherein:

[0028] R9and R 10 are independently selected from OH, OR 11 , NR 13 R 14 , (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

[0029] (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C5-C 12 )aryl-(C1-C8)alkyl, (C1-C8)alkyl-(C5-C 12 )aryl, (C1-C8)heteroalkyl, (C3-C8)heterocycloalkyl, (C5-C 12 )heteroaryl and NHCR α R α’ C(O)OR 12 ; wherein:

[0030] -R 11 is selected from (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C1-C 10 )alkyl-(C5-C 12 )

[0031] aryl, substituted (C5-C 12 )aryl, (C1-C 10 )heteroalkyl, (C1-C 10 )haloalkyl,

[0032] -(CH2) m C(O)(C1-C 15 )alkyl, -(CH2) m OC(O)(C1-C 15 )alkyl, -(CH2) m OC(O)O(C1-C 15 )alkyl, -(CH2) m SC(O)(C1-C 15 )alkyl, -(CH2) m C(O)O(C1-C 15 )alkyl, -(CH2) m C(O)O(C1-C15 )alkyl-(C5-C 12 )aryl; wherein m is an integer selected from 1 to 8; and -P(O)(OH)OP(O)(OH)2; and the internal or external counterion;

[0033] -R 12 is selected from the group consisting of hydrogen, (C1-C 10 )alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C 10 )haloalkyl, (C3-C 10 )cycloalkyl, (C3-C 10 )heterocycloalkyl, (C5-C 12 )aryl, (C1-C4)alkyl-(C5-C 12 )aryl, and (C5-C 12 )heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or two groups selected from halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy, and cyano;

[0034] -R 13 and R 14 are independently selected from the group consisting of H, (C1-C8)alkyl, and (C1-C8)alkyl-(C5-C 12 )aryl; and

[0035] -R α and R α’ are independently selected from the group consisting of hydrogen, (C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 )alkynyl, (C3-C 10 )cycloalkyl, (C1-C 10 )thioalkyl, (C1-C 10 )hydroxyalkyl, (C1-C 10 )alkyl-(C5-C 12 )aryl, (C5-C 12 )aryl, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein said aryl is optionally substituted with a group selected from hydroxy, (C1-C 10 )alkyl, (C1-C6)alkoxy, halogen, nitro, and cyano; or

[0036] R9and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, wherein -R9-R 10- represents -O-CH2-CH2-CHR-O-; wherein R is selected from hydrogen, (C5-C6) aryl and (C5-C6) heteroaryl; wherein said aryl or heteroaryl is optionally substituted by one or two groups selected from halogen, trifluoromethyl, (C1-C6) alkyl, (C1-C6) alkoxy and cyano;

[0037] X' is selected from O, CH2, S, Se, CHF, CF2and C=CH2;

[0038] R 1’ is selected from H, azido, cyano, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) heteroalkyl and OR; wherein R is selected from H and (C1-C8) alkyl;

[0039] R 2’ , R 3’ , R 4’ and R 5’ are independently selected from H, halogen, azido, cyano, hydroxyl, (C1-C 12 ) alkyl, (C1-C 12 ) thioalkyl, (C1-C 12 ) heteroalkyl, (C1-C 12 ) haloalkyl and OR; wherein R is selected from H, (C1-C 12 ) alkyl, -C(O)(C1-C 12 ) alkyl, -C(O)NH(C1-C 12 ) alkyl, -C(O)O(C1-C 12 ) alkyl, -C(O)aryl, -C(O)(C1-C 12 ) alkyl-(C5-C 12 ) aryl, -C(O)NH(C1-C 12 ) alkyl-(C5-C 12 ) aryl, -C(O)O(C1-C 12 ) alkyl-(C5-C 12 ) aryl and -C(O)CHR AA NH2; wherein R AA is a side chain selected from proteinogenic amino acids;

[0040] R 6’ is selected from H, azido, cyano, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) heteroalkyl and OR; wherein R is selected from H and (C1-C8) alkyl;

[0041] R 8’ is selected from H, OR, NR 15’ R 16’ , NH-NHR 15’SH, CN, N3, and halogen; wherein R is selected from the group consisting of H and (Ci-C8)alkyl, R 15’ and R 16’ are independently selected from the group consisting of H, (Ci-C8)alkyl, (Ci-C8)alkyl-(C5-C 12 )aromatic-CHR AA’ CO2H, wherein R AA’ is a side chain selected from the group consisting of proteinogenic or non-proteinogenic amino acids;

[0042] Y' is selected from the group consisting of CH, CH2, CHCH3, C(CH3)2, and CCH3;

[0043] n is an integer selected from the group consisting of 1 to 3;

[0044] represents a point of attachment;

[0045] depending on Y', represents a single or double bond; and

[0046] depending on the position of R 1’ , represents an alpha or beta anomer;

[0047] R8is selected from the group consisting of H, OR, NR 15 R 16 , NH-NHR 15 , SH, CN, N3, and halogen; wherein R is selected from the group consisting of H and (Ci-C8)alkyl, R 15 and R 16 are independently selected from the group consisting of H, (Ci-C8)alkyl, and (Ci-C8)alkyl-(C5-C 12 )aromatic-CHR AA CO2H, wherein R AA is a side chain selected from the group consisting of proteinogenic or non-proteinogenic amino acids;

[0048] Y is selected from the group consisting of CH, CH2, CHCH3, C(CH3)2, and CCH3;

[0049] depending on Y, represents a single or double bond; and

[0050] depending on the position of R1, represents an alpha or beta anomer,

[0051] for the treatment of an antineoplastic drug-induced toxicity, preferably wherein the toxicity is selected from the group consisting of cardiotoxicity, nephrotoxicity, neurotoxicity, hematotoxicity, hepatotoxicity, lymphotoxicity, gastrointestinal toxicity, dermal toxicity, ototoxicity, reproductive toxicity, skeletal toxicity, genotoxicity, and urotoxicity; more preferably wherein the toxicity is selected from the group consisting of cardiotoxicity, nephrotoxicity, hematotoxicity, hepatotoxicity, lymphotoxicity, gastrointestinal toxicity, dermal toxicity, reproductive toxicity, skeletal toxicity, genotoxicity, and urotoxicity.

[0052] According to one embodiment, X represents oxygen.

[0053] According to one embodiment, R1and R6are identical and represent hydrogen.

[0054] According to one embodiment, R3and R4are identical and represent hydrogen.

[0055] According to one embodiment, R2and R5are identical and represent OH.

[0056] According to one embodiment, Y is selected from CH and CH2.

[0057] According to one embodiment, R7is selected from H, P(O)R9R 10 and

[0058] wherein

[0059] R9and R 10 as described above;

[0060] X’ is oxygen;

[0061] R 1’ and R 6’ each represent hydrogen;

[0062] R 2’ , R 3’ , R 4’ and R 5’ are independently selected from hydrogen and OH;

[0063] R 8’ is NH2;

[0064] Y’ is selected from CH and CH2;

[0065] n is equal to 2;

[0066] represents a point of attachment;

[0067] depending on Y’, represents a single or double bond; and

[0068] depending on R 1’the position of the asterisk indicates the alpha or beta anomer.

[0069] According to one embodiment, R8 is NH2.

[0070] According to one embodiment, the compound for use according to the application is selected from compounds 001 to 014:

[0071]

[0072]

[0073]

[0074] and the pharmaceutically acceptable salts and solvates thereof.

[0075] According to one embodiment, the toxicity is induced by an antineoplastic drug selected from the group consisting of anthracyclines, alkylating agents, taxanes, antimetabolites, biological response modifiers, histone deacetylase inhibitors, hormonal drugs, vinca alkaloids, topoisomerase inhibitors, monoclonal antibodies, tyrosine kinase inhibitors, and mixtures thereof.

[0076] According to one embodiment, the toxicity is induced by an anthracycline selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, bleomycin, mitomycin, mitoxantrone, porthyrin and valrubicin.

[0077] According to one embodiment, the toxicity is induced by doxorubicin.

[0078] According to one embodiment, the toxicity is a cardiotoxicity selected from the group consisting of heart failure, left ventricular failure, myocardial ischemia, myocardial infarction, QT interval prolongation, torsades de pointes, arrhythmia, pericarditis, myocarditis, bradycardia, hypertension and thromboembolic events.

[0079] The present application also relates to a pharmaceutical composition for the treatment of toxicity, comprising at least one compound for use according to the application and at least one pharmaceutically acceptable carrier.

[0080] According to one embodiment, the pharmaceutical composition for use comprises, in addition to at least one of the above-mentioned compounds for use, at least one active ingredient selected from natural extracts, antitumor agents, antidepressants, antiretrovirals, beta blockers, antidiabetics, diuretics, antihypertensives, antiarrhythmics, CNS stimulants, antimalarials, immunosuppressants, antifungals, cytokines, interferons, androgens, adrenergic stimulants, neuromodulators, COX inhibitors, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ranolazine, metformin, mineralocorticoid receptor antagonists, hydroxymethylglutaryl coenzyme A reductase inhibitors, self-nanoemulsifying formulations of antioxidants such as quercetin, coenzyme Q10, vitamin E, L-carnitine, steroids, cyclosporine, mycophenolate mofetil, anti-TNF such as infliximab or etanercept, anti-Il 1 such as Sraninka, anti-PGF such as gleevec, anti-CD20 such as rituximab, myriocin, PTEN modulators, narigenin, pyrroloquinoline quinone, urolithin.

[0081] Definitions

[0082] The following definitions and explanations are intended to apply to the terms used in the present application, including the specification and claims.

[0083] When describing the compounds of the present application, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

[0084] The nomenclature of substituents not specifically defined herein is accomplished by naming the adjacent functional group first, followed by the terminal portion of the functional group, unless otherwise specified. For example, the substituent "arylalkyl" means -(aryl)-(alkyl).

[0085] In the present application, the following terms have the following meanings:

[0086] The term "alkyl" by itself or as part of another substituent means an alkyl radical of the formula C n H 2n+1Rn-Cx-Cy-alkyl, wherein n is a number greater than or equal to 1. Generally, the alkyl groups of the present application contain from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 2 carbon atoms. The alkyl groups can be straight-chained or branched. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-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, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. Branched saturated alkyl groups include, but are not limited to: isopropyl, sec-butyl, isobutyl, t-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl.

[0087] Cx-Cy-alkyl refers to an alkyl group containing from x to y carbon atoms.

[0088] When the suffix "ene" ("alkylene") is used in connection with an alkyl group, it means an alkyl group as defined herein having two single bonds as the point of attachment to the other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethyl ethylene, and 1,2-dimethyl ethylene.

[0089] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon group, which can be straight-chain or branched, containing one or more carbon-carbon double bonds. Suitable alkenyl groups contain 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms. Examples of alkenyl groups are ethenyl, 2- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and the like.

[0090] As used herein, the term "alkynyl" refers to a class of monovalent unsaturated hydrocarbon groups, wherein the unsaturation is due to the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically and preferably have the same number of carbon atoms as the alkyl groups described above. Non-limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, and the like.

[0091] As used herein, the term "alkoxy" refers to any group -O-alkyl, wherein alkyl is as defined above. Suitable alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0092] As used herein, the term "amino acid" refers to an alpha-amino carboxylic acid, i.e., a molecule containing a carboxylic acid functional group and an amine functional group located alpha to the carboxylic acid functional group, such as a proteinogenic or non-proteinogenic amino acid.

[0093] As used herein, the term "aryl" refers to a polyunsaturated, aromatic hydrocarbon group having a single ring (i.e., phenyl) or two rings fused together (i.e., naphthyl), or a polycyclic ring system (i.e., anthracenyl), typically containing 5 to 12 atoms; preferably, 6 to 10 atoms, more preferably 6 atoms, wherein at least one ring is aromatic. The aromatic ring(s) can optionally contain one to two other rings fused to it (cycloalkyl, heterocyclyl, or heteroaryl). Aryl is also intended to include partially hydrogenated derivatives of the carbon ring systems listed herein. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, naphth-1-yl, naphth-2-yl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1-acenyl, 2-acenyl, 3-acenyl, 4-acenyl, 5-acenyl, 3-acephenyl, 4-acephenyl, 5-acephenyl, 1-menthyl, 2-menthyl, 4- isomenthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl, 8- tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-pyrenyl, 2-pyrenyl, 3-pyrenyl, 4-pyrenyl, or 5-pyrenyl.

[0094] The term "cycloalkyl" as used herein refers to cyclic alkyl, cyclic alkenyl or cyclic alkynyl, i.e. monovalent saturated or unsaturated hydrocarbon radicals having one or two cyclic structures. Cycloalkyl includes mono- or bicyclic hydrocarbon radicals. Cycloalkyl can contain 3 or more than 3 carbon atoms in the ring, typically 3 to 10, more preferably 3 to 8, even more preferably 3 to 6 carbon atoms according to the present application. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, particularly preferred is cyclopropyl.

[0095] The term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine and chlorine.

[0096] The term "haloalkyl", alone or as part of another group, refers to an alkyl radical having the above-mentioned meaning wherein one or more than one hydrogen atom is replaced by a halogen as defined above. Non-limiting examples of haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. Cx-Cy-haloalkyl is a haloalkyl group containing x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

[0097] The term "heteroalkyl" refers to an alkyl group as defined above wherein one or more than one carbon atom is replaced by a heteroatom selected from oxygen, nitrogen and sulfur atoms. In heteroalkyl groups, the heteroatoms are only linked 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 can optionally be oxidized, the nitrogen heteroatoms can optionally be quaternized. Heteroalkyl groups are only bound to other groups or molecules via carbon atoms, i.e. the binding atoms are not selected from the heteroatoms comprised in the heteroalkyl group.

[0098] When at least one carbon atom in an aromatic group is replaced by a heteroatom, the resulting ring is referred to herein as a heteroaromatic ring.

[0099] The term "heteroaromatic" as used herein by itself or as part of another group refers to, but is not limited to, an aromatic ring containing 5 to 12 carbon atoms or a ring system containing 1 to 2 rings which are fused together or covalently linked, typically containing 5 to 6 atoms; wherein at least one is aromatic, one or more than one carbon atom in one or more than one of these rings is replaced by an oxygen, nitrogen and / or sulfur atom, wherein the nitrogen and sulfur heteroatoms can optionally be oxidized, the nitrogen heteroatoms can optionally be quaternized. Such a ring can be fused to an aromatic, cycloalkyl, heteroaromatic or heterocyclyl ring. Non-limiting examples of such heteroaromatic groups include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, oxazolyl, isothiazolyl, triazolyl, oxazolyl, isothiazolyl, triazolyl, Triazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl Azinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]phenylthiol, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazo[l,5-a]pyridyl, indoleyl, indoleazinyl, isoindoleyl, benzofuranyl, isobenzofuranyl, benzobenzenthiol, isobenzobenzenthiol, indoleyl, benzimidazolyl, 1,3-benzo[ azole group, 1,2-benzisyl azole group, 2,1-benzisyl Azolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzo[] diazolyl, 2,1,3-benzo[ Diazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridyl, purine, imidazo[l,2-a]pyridyl, 6-oxopyridin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxopyridin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxy, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinazolinyl phyll group.

[0100] When at least one carbon atom in a cycloalkyl group is replaced by a heteroatom, the resulting ring is referred to herein as a "heterocyclic alkyl" or "heterocyclic group".

[0101] As used herein, the terms “heterocyclic group,” “heterocyclic alkyl group,” or “heterocycle,” whether used alone or as part of another group, refer to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3- to 7-membered monocyclic ring, a 7- to 11-membered bicyclic ring, or containing a total of 3 to 10 ring atoms) having at least one heteroatom in at least one carbon-containing ring. Each ring of the heterocyclic group containing a heteroatom may have one, two, three, or four heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Any carbon atom of the heterocyclic group may be substituted with an oxygen (e.g., piperidinone, pyrrolidone). If the valence allows, the heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system. The rings of a polycyclic heterocycle may be fused, bridged, and / or linked by one or more spirocyclic atoms. Non-limiting exemplary heterocyclic groups include oxoheterobutyl, piperidinyl, azaheterobutyl, 2-imidazolinyl, pyrazolyl, imidazolinyl, and isoheterobutyl. zoline group azolealkyl, isopropyl Alzolyl, thiazolyl, isothiazolyl, piperidinyl, 3H-indolyl, indololinyl, isoindololinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxopentyl, 1,4-dioxohexyl, 2,5- Dioxoimidazolyl, 2-oxopiperidinyl, 2-oxopyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanecycloyl, 1,4-thiazolinyl Alkyl, 1H-pyrrolazinyl, tetrahydro-1,1-dioxophenylthioyl, N-formylpiperazinyl, and morpholino-4-yl.

[0102] The term "haloalkyl" refers to an alkyl group having the above meaning, in which one or more hydrogen atoms are replaced by the -OH moiety.

[0103] The term "thioalkyl" refers to an alkyl group having the above meaning, in which one or more hydrogen atoms are replaced by the -SH moiety.

[0104] As used herein, the term "non-protein amino acid" refers to an amino acid that is not naturally encoded or found in the genetic code of an organism. Non-limiting examples of non-protein amino acids include ornithine, citrulline, arginine succinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomucosinate, δ-aminolevulinic acid, β-alanine, cystathionine, γ-aminobutyric acid, DOPA, 5-hydroxytryptophan, D-serine, amaminine, α-aminobutyric acid, 2-aminoisobutyric acid, D-leucine, D-valine, D-alanine, or D-glutamic acid.

[0105] The term "protein amino acid" as used in this article refers to the amino acids incorporated into proteins during the translation of messenger RNA by ribosomes in organisms, 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), pyrrolidone (PYL), selenocysteine ​​(SEL), serine (SER), threonine (THR), tryptophan (TRP), tyrosine (TYR), or valine (VAL).

[0106] As used herein, the term "prodrug" refers to a pharmacologically acceptable derivative of a compound of formula (I), such as an ester whose in vivo biotransformation yields an active pharmaceutical ingredient. Prodrugs are characterized by increased bioavailability and are readily metabolized in vivo into the active compound. For the purposes of this invention, suitable prodrugs include aminophosphates, HepDirect, (S)-acyl-2-thioethyl esters (SATE), carboxylic esters, particularly alkyl esters, aromatic esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters.

[0107] The term "substituent" or "substituted" refers to the replacement of a hydrogen group on a compound or group with any desired group that is substantially stable under reaction conditions, either in its unprotected form or protected by a protecting group. Examples of preferred substituents include, but are not limited to: halogens (chlorine, iodine, bromine, or fluorine) as described above, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, nitro, mercapto, thioether, imino, cyano, amino, phosphonic acid, phosphine, carboxyl, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, oxy (-O), haloalkyl (e.g., trifluoromethyl), monocyclic or fused or non-fused polycyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), monocyclic or fused or non-fused polycyclic heterocyclic groups (e.g., pyrrolyl, piperidinyl, piperazine, morpholinyl, or thiazinyl), monocyclic or fused or non-fused polycyclic aromatic or heteroaromatic groups (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, phenylthio, imidazolyl). azole group, iso Azolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridineyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzobenzenethio, or benzofuranyl), amino (primary, secondary, or tertiary), CO2CH3, CONH2, OCH2CONH2, NH2, SO2NH2, OCHF2, CF3, OCF3, and these groups may optionally be substituted with fused ring structures or bridging groups, such as -OCH2O-. These substituents may optionally be further substituted with substituents selected from such groups. In some embodiments, the term "substituent" or the adjective "substituted" refers to a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aromatic, heteroaromatic, aromatic alkyl, heteroaromatic alkyl, haloalkyl, -C(O)NR 17 R 18 -NR 19 C(O)R 20 Halogen, -OR 19 , cyano, nitro, haloalkoxy, -C(O)R 19 -NR 17 R 18 -SR19 -C(O)OR 19 -OC(O)R 19 -NR 19 C(O)NR 17 R 18 -OC(O)NR 17 R 18 -NR 19 C(O)OR 20 -S(O) r R 19 -NR 19 S(O) r R 20 -OS(O) r R 20 S(O) r NR 17 R 18 -O, -S, and -N-R 19 wherein r is 1 or 2; R 17 and R 18 are each independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or R 17 and R 18 together with the nitrogen to which they are attached are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R 19 and R 20 are each independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

[0108] The bond to an asymmetric carbon can be represented here by a solid triangle a dashed triangle or a wavy line .

[0109] The term "active ingredient" refers to a molecule or substance which, when administered to a subject, can slow down or prevent the development, aggravation or worsening of one or more symptoms of a disease, or disorder; relieve symptoms of a disease or disorder; cure a disease or disorder. According to one embodiment, the therapeutic ingredient is a natural or synthetic small molecule. According to another embodiment, the therapeutic ingredient is a biological molecule, such as an oligonucleotide, siRNA, miRNA, DNA fragment, aptamer, antibody, etc.

[0110] The term "administering" refers to providing an active agent or active ingredient to a patient in need of treatment of a condition, symptom or disease, either alone or as part of a pharmaceutically acceptable composition.

[0111] The term "drug" refers to any substance that, when administered to a subject, causes a physiological or psychological change in the subject. In the context of the present application, "drug" includes both medical drugs ("medicinal drugs" or "active ingredients") and non-medical drugs, such as recreational drugs (e.g. psychoactive drugs).

[0112] By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition are compatible with each other and not deleterious to the patient.

[0113] The term "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" or "drug carrier" refers to an inert medium or carrier used as a solvent or diluent for the pharmaceutical active ingredient, in which the active ingredient is formulated and / or administered, and which does not produce an adverse, allergic or other reaction when administered to an animal, preferably a human. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other similar ingredients. For human administration, the formulation must meet the standards of sterility, general safety and purity required by regulatory agencies such as the FDA or EMA. For the purposes of the present application, "pharmaceutically acceptable excipient" includes all pharmaceutically acceptable excipients as well as all pharmaceutically acceptable carriers, diluents and / or adjuvants.

[0114] The term "pharmaceutically acceptable salt" includes both acid and base salts. Suitable acid addition salts are formed from acids which form nontoxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, borate, camsylate, citrate, cyclamate, diacetate, edisylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobenzoe, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts.

[0115] Suitable base salts are formed from bases which form nontoxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)-ethanol, diethanolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0116] Acid and base half-salts can also be formed, for example, hemi-sulfate and hemi-calcium salts.

[0117] Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by one or more of the following methods:

[0118] (i) reacting a compound of formula (I) with the desired acid;

[0119] (ii) reacting a compound of formula (I) with the desired base;

[0120] (iii) by removing a protecting group which is labile to acid or base from a suitable precursor of a compound of formula (I), or by ring opening a suitable cyclic precursor, for example a lactone or lactam, using the desired acid; and / or

[0121] (iv) converting one salt of a compound of formula (I) to another by reaction with a suitable acid or by treatment with a suitable ion exchange column.

[0122] All these reactions are typically carried out in solution. The salts can be precipitated from solution by addition of a poor solvent or by co-evaporation with toluene, the product can be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionisation of the salts will vary from completely ionised to almost non-ionised.

[0123] Although in general, with respect to the salts of the compounds of the present application, pharmaceutically acceptable salts are preferred, it should be noted that the present application in its broadest sense also encompasses non-pharmaceutically acceptable salts, which can be useful, for example, in the isolation and / or purification of the compounds of the present application. For example, salts formed with optically active acids or bases can be useful to form diastereomeric salts, which can facilitate the separation of optical isomers of the compounds of formula (I) as described above.

[0124] The term "solvate" as used herein means a molecular complex comprising a compound of the present application and containing a stoichiometric or sub-stoichiometric amount of one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term "hydrate" means a solvate when the solvent is water.

[0125] The term "human" means a subject of either sex at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).

[0126] The term "subject" means a mammal, preferably a human. According to the present application, the subject is a mammal, preferably a human, who suffers from and / or is susceptible to develop an antineoplastic drug-induced toxicity. In one embodiment, the subject is a "patient", i.e. a mammal, preferably a human, who is awaiting to receive or is receiving medical care, or who has been / is / will be the object of a medical procedure, or who is being monitored for the development of an antineoplastic drug-induced toxicity.

[0127] The term "therapeutically effective amount" (or more simply "effective amount") as used herein means the amount of an active agent or active ingredient which is aimed at preventing, reducing, alleviating or slowing down (mitigating) one or more symptoms of an antineoplastic drug-induced toxicity, without causing significant negative or adverse side effects to the subject in need of treatment.

[0128] The term "treatment" as used herein means a therapeutic treatment, or a prophylactic treatment, or a therapeutic treatment and a prophylactic treatment, wherein the goal is to prevent, reduce, alleviate and / or slow down (mitigate) a drug-induced toxicity, in particular one or more symptoms of an antineoplastic drug-induced toxicity, in a subject in need of treatment. In one embodiment, "treatment" means a therapeutic treatment. In another embodiment, "treatment" means a prophylactic treatment. In another embodiment, "treatment" means a prophylactic treatment and a therapeutic treatment.

[0129] The term "toxicity" means a condition that causes damage to the body, such as cardiotoxicity, nephrotoxicity, neurotoxicity, hematotoxicity, hepatotoxicity, lymphotoxicity, gastrointestinal toxicity, dermal toxicity, metabolic toxicity, ototoxicity, reproductive toxicity, skeletal toxicity, genotoxicity and urotoxicity. According to the present application, the toxicity can be caused, for example, by a direct or indirect influence of a molecule or a substance on an organ, a tissue or a system, such as a drug, alcohol or a heavy metal. For example, the toxicity can also be caused by at least one disease or disorder.

[0130] The term "cardiotoxicity" refers to a condition leading to cardiac muscle damage, such as heart failure, left ventricular failure, myocardial ischemia, myocardial infarction, QT interval prolongation, torsades de pointes, arrhythmia, pericarditis, myocarditis, bradycardia, hypertension and thromboembolic events. According to the present application, cardiotoxicity can be caused, for example, by a direct or indirect effect of a molecule or substance on the heart, such as a drug, alcohol or heavy metals. For example, cardiotoxicity can also be caused by at least one disease or disorder. If severe, cardiotoxicity can lead to cardiomyopathy.

[0131] DETAILED DESCRIPTION

[0132] The present application thus relates to the use of a nicotinamide mononucleotide derivative for the treatment of an antineoplastic drug-induced toxicity, preferably wherein the toxicity is selected from the group consisting of cardiotoxicity, nephrotoxicity, hematotoxicity, hepatotoxicity, lymphotoxicity, gastrointestinal toxicity, dermotoxicity, reprotoxicity, osteotoxicity, genotoxicity and urotoxicity. In particular, the present application relates to the use of a nicotinamide mononucleotide derivative for the treatment of an antineoplastic drug-induced toxicity in a subject in need thereof.

[0133] Nicotinamide mononucleotide derivatives

[0134] In one embodiment, the nicotinamide mononucleotide derivative of the present application is a compound of formula (I)

[0135]

[0136] or a pharmaceutically acceptable salt or solvate thereof;

[0137] wherein:

[0138] X is selected from the group consisting of O, CH2, S, Se, CHF, CF2and C=CH2;

[0139] R1is selected from the group consisting of H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; wherein R is selected from the group consisting of H and (C1-C8)alkyl;

[0140] R2, R3, R4and R5are independently selected from the group consisting of H, halogen, azido, cyano, hydroxyl, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl and OR; wherein R is selected from the group consisting of H, (C1-C 12 )alkyl, -C(O)(C1-C 12 )alkyl, -C(O)NH(C1-C 12 )alkyl, -C(O)O(C1-C12 alkyl, -C(O)aryl, -C(O)(C1-C 12 alkyl-(C5-C 12 aryl, -C(O)NH(C1-C 12 alkyl-(C5-C 12 aryl, -C(O)O(C1-C 12 alkyl-(C5-C 12 aryl, and -C(O)CHR AA NH2; wherein R AA is selected from the side chains of the proteinogenic amino acids;

[0141] R6is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl, and OR; wherein R is selected from H and (C1-C8)alkyl;

[0142] R7is selected from H, P(O)R9R 10 , P(S)R9R 10 , and

[0143] wherein:

[0144] R9and R 10 are independently selected from OH, OR 11 , NR 13 R 14 , (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C5-C 12 )aryl-(C1-C8)alkyl, (C1-C8)alkyl-(C5-C 12 )aryl, (C1-C8)heteroalkyl, (C3-C8)heterocycloalkyl, (C5-C 12 )heteroaryl, and NHCR α R α’ C(O)OR 12 ; wherein:

[0145] -R 11 is selected from (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C1-C 10 )alkyl-(C5-C 12 )aryl, substituted (C5-C 12 )aryl, (C1-C 10 )heteroalkyl, (C1-C 10haloalkyl, -(CH2) m C(O)(C1-C 15 )alkyl, -(CH2) m OC(O)(C1-C 15 )alkyl, -(CH2) m OC(O)O(C1-C 15 )alkyl, -(CH2) m SC(O)(C1-C 15 )alkyl, -(CH2) m C(O)O(C1-C 15 )alkyl, -(CH2) m C(O)O(C1-C 15 )alkyl, -(C5-C 12 )aryl; wherein m is an integer selected from 1 to 8; and -P(O)(OH)OP(O)(OH)2; and the internal or external counterion;

[0146] -R 12 is selected from hydrogen, (C1-C 10 )alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C 10 )haloalkyl, (C3-C 10 )cycloalkyl, (C3-C 10 )heterocycloalkyl, (C5-C 12 )aryl, (C1-C4)alkyl-(C5-C 12 )aryl, and (C5-C 12 )heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or two groups selected from halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy, and cyano;

[0147] -R 13 and R 14 are independently selected from H, (C1-C8)alkyl, and (C1-C8)alkyl-(C5-C 12 )aryl; and

[0148] -R α and R α’ are independently selected from hydrogen, (C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 )alkynyl, (C3-C 10 )cycloalkyl, (C1-C 10 )thioalkyl, (C1-C 10 )hydroxyalkyl, (C1-C 10 )alkyl-(C5-C 12)alkyl, (C1-C6)alkoxy, halogen, nitro and cyano; or 12 )aryl, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from the group consisting of proteinogenic or non-proteinogenic amino acids; wherein said aryl is optionally substituted with one or two groups selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, nitro and cyano; or 10 )alkyl, (C1-C6)alkoxy, halogen, nitro and cyano; or

[0149] R9and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, wherein -R9-R 10 represents -O-CH2-CH2-CHR-O-; wherein R is selected from the group consisting of hydrogen, (C5-C6)aryl and (C5-C6)heteroaryl; wherein said aryl or heteroaryl is optionally substituted with one or two groups selected from the group consisting of halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano;

[0150] X' is selected from the group consisting of O, CH2, S, Se, CHF, CF2and C=CH2;

[0151] R 1’ is selected from the group consisting of H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; wherein R is selected from the group consisting of H and (C1-C8)alkyl;

[0152] R 2’ , R 3’ , R 4’ and R 5’ are independently selected from the group consisting of H, halogen, azido, cyano, hydroxy, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl and OR; wherein R is selected from the group consisting of H, (C1-C 12 )alkyl, -C(O)(C1-C 12 )alkyl, -C(O)NH(C1-C 12 )alkyl, -C(O)O(C1-C 12 )alkyl, -C(O)aryl, -C(O)(C1-C 12 )alkyl-(C5-C 12 )aryl, -C(O)NH(C1-C 12 )alkyl-(C5-C 12 )aryl, -C(O)O(C1-C 12 )alkyl-(C5-C 12 )aryl and -C(O)CHRAA NH2; where R AA It is a side chain selected from amino acids in proteins;

[0153] R 6’ It is selected from H, azide, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; wherein R is selected from H and (C1-C8)alkyl;

[0154] R 8’ Selected from H, OR, NR 15’ R 16’ NH-NHR 15’ , SH, CN, N3 and halogens; where R is selected from H and (C1-C8) alkyl groups, R 15’ and R 16’ Independently selected from H, (C1-C8)alkyl, (C1-C8)alkyl-(C5-C 12 Aromatic groups and -CHR AA’ CO2H, where R AA’ It is a side chain selected from protein amino acids or non-protein amino acids;

[0155] Y' is selected from CH, CH2, CHCH3, C(CH3)2, and CCH3;

[0156] n is an integer selected from 1 to 3;

[0157] Indicates the connection point;

[0158] Depending on Y', it indicates a single or double bond; and

[0159] Depends on R 1’ The position indicates whether it is an α-angioma or a β-angioma;

[0160] R8 is selected from H, OR, and NR. 15 R 16 NH-NHR 15 , SH, CN, N3 and halogens; where R is selected from H and (C1-C8) alkyl groups, R 15 and R 16 Independently selected from H, (C1-C8)alkyl, (C1-C8)alkyl-aryl, and -CHR AA CO2H, where R AA It is a side chain selected from protein amino acids or non-protein amino acids;

[0161] Y is selected from CH, CH2, CHCH3, C(CH3)2, and CCH3;

[0162] represents a single or double bond depending on Y; and

[0163] represents an alpha or beta anomer depending on the position of R1.

[0164] In one embodiment, in formula (I):

[0165] X is selected from O, CH2, S, Se, CHF, CF2, and C=CH2;

[0166] R1is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl, and OR; wherein R is selected from H and (C1-C8)alkyl;

[0167] R2, R3, R4, and R5are independently selected from H, halogen, azido, cyano, hydroxyl, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl, and OR; wherein R is selected from H, (C1-C 12 )alkyl, -C(O)(C1-C 12 )alkyl, -C(O)NH(C1-C 12 )alkyl, -C(O)O(C1-C 12 )alkyl, -C(O)aryl, -C(O)(C1-C 12 )alkylaryl, -C(O)NH(C1-C 12 )alkyl-(C5-C 12 )aryl, -C(O)O(C1-C 12 )alkyl-(C5-C 12 )aryl, and -C(O)CHR AA NH2; wherein R AA is a side chain selected from proteinogenic amino acids;

[0168] R6is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl, and OR; wherein R is selected from H and (C1-C8)alkyl;

[0169] R7is selected from H, P(O)R9R 10 , P(S)R9R 10 , and

[0170] wherein:

[0171] R9and R 10 are independently selected from OH, OR 11, NHR 13 , NR 13 R 14 , (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C5-C 12 )aryl-(C1-C8)alkyl, (C1-C8)alkyl-(C5-C 12 )aryl, (C1-C8)heteroalkyl, (C3-C8)heterocycloalkyl, (C5-C 12 )heteroaryl, and NHCR α R α’ C(O)R 12 ; wherein:

[0172] -R 11 is selected from the group consisting of (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C1-C 10 )alkyl-(C5-C 12 )aryl, substituted (C5-C 12 )aryl, (C1-C 10 )heteroalkyl, (C1-C 10 )haloalkyl, -(CH2) m C(O)(C1-C 15 )alkyl, -(CH2) m OC(O)(C1-C 15 )alkyl, -(CH2) m OC(O)O(C1-C 15 )alkyl, -(CH2) m SC(O)(C1-C 15 )alkyl, -(CH2) m C(O)O(C1-C 15 )alkyl, -(CH2) m C(O)O(C1-C 15 )alkylaryl; wherein m is an integer selected from 1 to 8; and -P(O)(OH)OP(O)(OH)2; and an inner or outer anion;

[0173] -R 12 is selected from the group consisting of hydrogen, (C1-C 10 )alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C 10 )haloalkyl, (C3-C 10 )cycloalkyl, (C3-C 10Heterocyclic alkyl groups, (C5-C 12 Aromatic group, (C1-C4)alkyl-(C5 ... 12 Aromatic groups and (C5-C) 12 ( ) heteroaromatic group; wherein the aromatic group or heteroaromatic group is optionally substituted by one or two groups selected from halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano;

[0174] -R 13 and R 14 Independently selected from H, (C1-C8)alkyl and (C1-C8)alkyl-(C5-C 12 Aromatic group;

[0175] -R α and R α’ Independently selected from hydrogen, (C1-C 10 )alkyl, (C2-C 10 )alkenyl, (C2-C 10 ) ynyl group, (C3-C 10 )cycloalkyl, (C1-C 10 )thioalkyl, (C1-C 10 )hydroxyalkyl, (C1-C 10 )alkyl-(C5-C 12 Aromatic group, (C5-C 12 Aromatic group, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and side chain selected from protein amino acids or non-protein amino acids; wherein the aromatic group is optionally selected from hydroxyl, C1-C 10 Substitution of alkyl, C1-C6 alkoxy, halogen, nitro, and cyano groups; or

[0176] R9 and R 10 Together with the phosphorus atom it is attached to, it forms a 6-membered ring, where -R9-R 10 - represents -CH2-CH2-CHR- or -O-CH2-CH2-CHR-O-; wherein R is selected from hydrogen, (C5-C6) aryl and (C5-C6) heteroaryl; wherein the aryl or heteroaryl group is optionally substituted by one or two groups selected from halogen, trifluoromethyl, (C1-C6) alkyl, (C1-C6) alkoxy and cyano;

[0177] X' is selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0178] R 1’R is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl, and OR; wherein R is selected from H and (C1-C8)alkyl;

[0179] R 2’ , R 3’ , R 4’ , and R 5’ are independently selected from H, halogen, azido, cyano, hydroxyl, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl, and OR; wherein R is selected from H, (C1-C 12 )alkyl, -C(O)(C1-C 12 )alkyl, -C(O)NH(C1-C 12 )alkyl, -C(O)O(C1-C 12 )alkyl, -C(O)aryl, -C(O)(C1-C 12 )alkylaryl, -C(O)NH(C1-C 12 )alkyl-(C5-C 12 )aryl, -C(O)O(C1-C 12 )alkyl-(C5-C 12 )aryl, and -C(O)CHR AA NH2; wherein R AA is a side chain selected from proteinogenic amino acids;

[0180] R 6’ is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl, and OR; wherein R is selected from H and (C1-C8)alkyl;

[0181] R 8’ is selected from H, OR, NHR 15’ , NR 15’ R 16’ , NH-NHR 15’ , SH, CN, N3, and halogen; wherein R 15’ and R 16’ are independently selected from H, (C1-C8)alkyl, (C1-C8)alkyl-aryl;

[0182] Y' is selected from CH, CH2, C(CH3)2, and CCH3;

[0183] n is an integer selected from 1 to 3;

[0184] Y' represents a single or double bond; and

[0185] R1 depends on the position of R and represents an alpha or beta anomer; 1’

[0186] R8 is selected from the group consisting of H, OR, NHR 15 , NR 15 R 16 , NH-NHR 15 , SH, CN, N3, and halogen; wherein R 15 and R 16 are independently selected from the group consisting of H, C1-C8 alkyl, and C1-C8 alkyl- aryl;

[0187] Y is selected from the group consisting of CH, CH2, C(CH3)2, and CCH3;

[0188] Y' represents a single or double bond; and

[0189] R1 depends on the position of R and represents an alpha or beta anomer.

[0190] The nicotinamide mononucleotide derivative of the present application can comprise one or more charged atoms. In particular, when a phosphate group is present it can carry one or more charges, preferably one or more negative charges. Furthermore, when a nitrogen atom of the pyridine moiety of the nicotinamide group is quaternized, this nitrogen atom can carry a positive charge. The skilled person will recognize that the presence of one or more charged atoms in the nicotinamide mononucleotide derivative of the present application depends on the conditions, in particular the pH conditions.

[0191] According to one embodiment, X is selected from the group consisting of O, CH2, and S. In one embodiment, X is oxygen.

[0192] According to one embodiment, R1 is selected from the group consisting of hydrogen and OH. In one embodiment, R1 is hydrogen. In one embodiment, R1 is OH.

[0193] According to one embodiment, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C 12 alkyl, and OR; wherein R is as described above. In a preferred embodiment, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, hydroxyl, and OR; wherein R is as described above. In a more preferred embodiment, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen and OH.

[0194] According to one embodiment, R2 and R3 are the same. In one embodiment, R2 and R3 are the same and represent OH. In one embodiment, R2 and R3 are the same and represent hydrogen.​

[0195] According to one embodiment, R2and R3are different. In a preferred embodiment, R2is hydrogen and R3is OH. In a more preferred embodiment, R2is OH and R3is hydrogen.

[0196] According to one embodiment, R4and R5are the same. In one embodiment, R4and R5are the same and represent OH. In one embodiment, R4and R5are the same and represent hydrogen.

[0197] According to one embodiment, R4and R5are different. In a preferred embodiment, R4is OH and R5is hydrogen. In a more preferred embodiment, R4is hydrogen and R5is OH.

[0198] According to one embodiment, R3and R4are different. In one embodiment, R3is OH and R4is hydrogen. In one embodiment, R3is hydrogen and R4is OH.

[0199] According to one embodiment, R3and R4are the same. In a preferred embodiment, R3and R4are the same and represent OH. In a more preferred embodiment, R3and R4are the same and represent hydrogen.

[0200] According to one embodiment, R2and R5are different. In one embodiment, R2is hydrogen and R5is OH. In one embodiment, R2is OH and R5is hydrogen.

[0201] According to one embodiment, R2and R5are the same. In a preferred embodiment, R2and R5are the same and represent hydrogen. In a more preferred embodiment, R2and R5are the same and represent OH.

[0202] According to one embodiment, R6is selected from hydrogen and OH. In one embodiment, R6is OH. In a preferred embodiment, R6is hydrogen.

[0203] According to one embodiment, R1and R6are each independently selected from hydrogen and OH. According to one embodiment, R1and R6are both hydrogen atoms.

[0204] According to one embodiment, R7is selected from hydrogen, P(O)R9R10and

[0205] According to one embodiment, R7is hydrogen.

[0206] According to one embodiment, R7is P(O)R9R 10 ; wherein R9and R 10 As described above. In a preferred embodiment, R7is P(O)(OH)2.

[0207] According to one embodiment, R7is wherein R 1’ , R 2’ , R 3’ , R 4’ , R 5’ , R 6’ , R 8’ , R9, X’, Y’, n, and as described above for the compounds of formula (I).

[0208] According to a preferred embodiment, R7is wherein:

[0209] X’ is selected from O, CH2and S, preferably X’ is O;

[0210] R 1’ is selected from hydrogen and OH, preferably R 1’ is hydrogen;

[0211] R 2’ , R 3’ , R 4’ and R 5’ are independently selected from hydrogen, halogen, hydroxyl, (Ci-C 12 )alkyl and OR; wherein R is as described above, preferably R 2’ , R 3’ , R 4’ and R 5’ are independently selected from hydrogen, hydroxyl and OR; wherein R is as described above, more preferably R 2’ , R 3’ , R 4’ and R 5’ are independently selected from hydrogen and OH;

[0212] R 6’ is selected from hydrogen and OH, preferably R 6’ is hydrogen;

[0213] R 8’ is selected from H, OR and NR 15’ R 16’ ; wherein R 15’ and R 16’ are as described above, preferably R 8’ is NHR 15’ ; wherein R 15’ is as described above, more preferably R 8’ is NH2;

[0214] Y’ is selected from CH and CH2;

[0215] n is an integer selected from 1 to 3;

[0216] represents a point of attachment;

[0217] represents a single or double bond, depending on Y';

[0218] represents an alpha or beta anomer, depending on the position of R 1’ .

[0219] According to one embodiment, in formula (I),

[0220] R7is

[0221] X and X' are independently selected from O, CH2and S, preferably X and X' are O;

[0222] R1and R 1’ are independently selected from hydrogen and OH, preferably R1and R 1’ are hydrogen;

[0223] R2, R3, R4, R5, R 2’ , R 3’ , R 4’ and R 5’ are independently selected from hydrogen, halogen, hydroxyl, (Ci-C 12 )alkyl and OR; wherein R is as described above, preferably R2, R3, R4, R5, R 2’ , R 3’ , R 4’ and R 5’ are independently selected from hydrogen, hydroxyl and OR; wherein R is as described above, more preferably R2, R3, R4, R5, R 2’ , R 3’ , R 4’ and R 5’ are independently selected from hydrogen and OH;

[0224] R6and R 6’ are independently selected from hydrogen and OH, preferably R6and R 6’ are hydrogen;

[0225] R8and R 8’ are independently selected from H, OR and NR 15’ R 16’ ; wherein R 15’ and R 16’ are as described above, preferably R8and R 8’ are NHR 15’ ; wherein R 15’ is as described above, more preferably R8and R 8’is NH2;

[0226] Y and Y' are independently selected from CH and CH2;

[0227] n is an integer selected from 1 to 3;

[0228] represents a point of attachment;

[0229] depends on Y and Y' and represents a single or double bond; and

[0230] depends on the position of R1and R 1’ and represents an alpha or beta anomer.

[0231] According to one embodiment, n is 1. According to one embodiment, n is 2. According to one embodiment, n is 3.

[0232] According to one embodiment, R8is selected from H, OR and NR 15 NR 16 ; wherein R 15 and R 16 are as described above. In a preferred embodiment, R8is NHR 15 ; wherein R 15 are as described above. In one embodiment, R8is NH2.

[0233] According to one embodiment, Y is CH or CH2. In one embodiment, Y is CH. In one embodiment, Y is CH2.

[0234] According to a preferred embodiment, the nicotinamide mononucleotide derivative used in the present application is a compound of general formula (II):

[0235]

[0236] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, X, Y, and are as described above for the compound of formula (I).

[0237] According to one embodiment, a preferred compound of general formula (II) is a compound of formula (II-1):

[0238]

[0239] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, Y, and As described above for the compounds of formula (I).

[0240] According to one embodiment, preferred compounds of general formula (II) are compounds of formula (II-2):

[0241]

[0242] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R3, R4, R5, R6, R8, Y, and As described above for the compounds of formula (I).

[0243] According to one embodiment, preferred compounds of general formula (II) are compounds of formula (II-3):

[0244]

[0245] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R5, R6, R8, Y, and As described above for the compounds of formula (I).

[0246] According to one embodiment, preferred compounds of general formula (II) are compounds of formula (II-4):

[0247]

[0248] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R8, Y, and As described above for the compounds of formula (I).

[0249] According to one embodiment, preferred compounds of general formula (II) are compounds of formula (II-5):

[0250]

[0251] or a pharmaceutically acceptable salt or solvate thereof; wherein R8, Y, and As described above for the compounds of formula (I).

[0252] According to one embodiment, preferred compounds of general formula (II) are compounds of formula (II-6):

[0253]

[0254] or a pharmaceutically acceptable salt or solvate thereof; wherein Y, and As described above for the compounds of formula (I).

[0255] According to one embodiment, preferred compounds of general formula (II) are compounds of formula (II-7):

[0256]

[0257] or a pharmaceutically acceptable salt or solvate thereof; wherein as described above for the compounds of formula (I).

[0258] According to a preferred embodiment, the present application relates to compounds of general formula (II-8):

[0259]

[0260] or a pharmaceutically acceptable salt or solvate thereof; wherein as described above for the compounds of formula (I).

[0261] According to another preferred embodiment, the nicotinamide mononucleotide derivative used in the present application is a compound of general formula (III):

[0262]

[0263] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, X, Y, and as described above for the compounds of formula (I).

[0264] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-1):

[0265]

[0266] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, Y, and as described above for the compounds of formula (I).

[0267] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-2):

[0268]

[0269] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R3, R4, R5, R6, R8, Y, and as described above for the compounds of formula (I).

[0270] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-3):

[0271]

[0272] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R5, R6, R8, Y, and as described above for compounds of formula (I).

[0273] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-4):

[0274]

[0275] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R8, Y, and as described above for compounds of formula (I).

[0276] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-5):

[0277]

[0278] or a pharmaceutically acceptable salt or solvate thereof; wherein R8, Y, and as described above for compounds of formula (I).

[0279] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-6):

[0280]

[0281] or a pharmaceutically acceptable salt or solvate thereof; wherein Y, and as described above for compounds of formula (I).

[0282] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-7):

[0283]

[0284] or a pharmaceutically acceptable salt or solvate thereof; wherein as described above for compounds of formula (I).

[0285] According to one embodiment, preferred compounds of general formula (III) are compounds of formula (III-8):

[0286]

[0287] or a pharmaceutically acceptable salt or solvate thereof; wherein as described above for the compounds of formula (I).

[0288] According to another preferred embodiment, the nicotinamide mononucleotide derivative used in the present application is a compound of general formula (IV):

[0289]

[0290] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R 1’ , R2, R 2’ , R3, R 3’ , R4, R 4’ , R5, R 5’ , R6, R 6’ , R8, R 8’、 X, X’, Y, Y’, and as described above for the compounds of formula (I).

[0291] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-1):

[0292]

[0293] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R 1’ , R2, R 2’ , R3, R 3’ , R4, R 4’ , R5, R 5’ , R6, R 6’ , R8, R 8’、 Y, Y’, and as described above for the compounds of formula (I).

[0294] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-2):

[0295]

[0296] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R 2’ , R3, R 3’ , R4, R 4’ , R5, R5’ R6, R 6’ R8, R 8’ Y, Y', and as described above for the compounds of formula (I).

[0297] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-3):

[0298]

[0299] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R 2’ R5, R 5’ R6, R 6’ R8, R 8’ Y, Y', and as described above for the compounds of formula (I).

[0300] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-4):

[0301]

[0302] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R 6’ R8, R 8’ Y, Y', and as described above for the compounds of formula (I).

[0303] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-5):

[0304]

[0305] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R 6’ R8, R 8’ Y, Y', and as described above for the compounds of formula (I).

[0306] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-6):

[0307]

[0308] or a pharmaceutically acceptable salt or solvate thereof; wherein Y, Y', and as described above for the compounds of formula (I).

[0309] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-7):

[0310]

[0311] or a pharmaceutically acceptable salt or solvate thereof; wherein as described above for the compounds of formula (I).

[0312] According to one embodiment, preferred compounds of general formula (IV) are compounds of formula (IV-8):

[0313]

[0314] or a pharmaceutically acceptable salt or solvate thereof; wherein as described above for the compounds of formula (I).

[0315] According to one embodiment, the nicotinamide mononucleotide derivative used in the present application is selected from the following compounds 001 to 014 in Table 1 and pharmaceutically acceptable salts or solvates thereof:

[0316] [Table 1]

[0317]

[0318]

[0319]

[0320] According to one embodiment, preferred nicotinamide mononucleotide derivatives are compounds 001 to 014, or pharmaceutically acceptable salts or solvates thereof.

[0321] According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 001, 002, 009, 010, and 011, or pharmaceutically acceptable salts or solvates thereof.

[0322] According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 001 and 002, or pharmaceutically acceptable salts or solvates thereof.

[0323] According to another embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 009, 010 and 011, or pharmaceutically acceptable salts or solvates thereof.

[0324] According to one embodiment, even more preferred nicotinamide mononucleotide derivatives are compounds 002, 010 and 011, or a pharmaceutically acceptable salt or solvate thereof.

[0325] All references to compounds of formula (I) and its subformulae include references to salts, solvates, polymeric complexes, liquid crystals thereof. All references to compounds of formula (I) and its subformulae include references to polymorphs and crystal habits thereof.

[0326] All references to compounds of formula (I) and its subformulae include references to pharmaceutically acceptable prodrugs thereof.

[0327] The nicotinamide mononucleotide derivatives used in the present application can be in the form of a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a nicotinamide mononucleotide derivative as defined above, and at least one pharmaceutically acceptable carrier.

[0328] Process

[0329] According to another aspect, the present application relates to a process for preparing a compound of formula (I) as described above.

[0330] In particular, compounds of formula (I) can be prepared from substrates A to E according to the methods described below. The skilled person will understand that these schemes are by no means limiting and that variations can be made without departing from the spirit and scope of the present application.

[0331] According to one embodiment, the process comprises in a first step monophosphorylation of a compound of formula (A) in the presence of phosphoryl chloride and a trialkyl phosphate to give a phosphorodichloridate of formula (B):

[0332]

[0333] wherein X, R1, R2, R3, R4, R5, R6, R8, Y, and as described above.

[0334] In a second step, the phosphorodichloridate of formula (B) is hydrolyzed to give a phosphate ester of formula (C).

[0335]

[0336] wherein X, R1, R2, R3, R4, R5, R6, R7, R8, Y, and as described above.

[0337] In another embodiment, when R7in formula (I) is The phosphate compound of formula (C) obtained in the second step is then reacted with the dichlorophosphate compound of formula (B’) obtained in the first step:

[0338]

[0339] wherein R 1’ , R 2’ , R 3’ , R 4’ , R 5’ , R 6’ , R 8’ , X’, Y’, and as described above for the compound of formula (I); followed by hydrolysis to obtain the compound of formula (I).

[0340] According to one embodiment, the compound of formula (A) is synthesized using various methods known to those skilled in the art.

[0341] According to one embodiment, the compound of formula (A) wherein Y is CH, is referred to as a compound of formula (A-a), is synthesized by reacting a pentose of formula (D) with a nitrogen derivative of formula (E) to obtain a compound of formula (A-1), followed by selective deprotection to obtain the compound of formula (A-a),

[0342]

[0343] wherein X, R1, R2, R3, R4, R5, R6, R8, Y, and as described above, and R is a protecting group.

[0344] According to one embodiment, R is a suitable protecting group known to those skilled in the art. In one embodiment, the protecting group is selected from triarylmethyl and silyl groups. Non-limiting examples of triarylmethyl groups include trityl, monomethoxytrityl, 4,4’-dimethoxytrityl, and 4,4’,4”-trimethoxytrityl. Non-limiting examples of silyl groups include trimethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl, triisopropylsilyloxymethyl, and [2-(trimethylsilyl)ethoxy]methyl.

[0345] According to one embodiment, any hydroxyl group attached to the pentose is protected by a suitable protecting group known to those skilled in the art.

[0346] The choice and exchange of protecting groups is the responsibility of the person skilled in the art. Protecting groups can also be removed by methods well known to those skilled in the art, for example with an acid (such as a mineral or organic acid), a base or a fluoride source.

[0347] According to a preferred embodiment, the azanucleoside of formula (E) is coupled with the pentose of formula (D) by a reaction in the presence of a Lewis acid to give a compound of formula (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF3, OEt2, TiCl4, and FeCl3.

[0348] According to one embodiment, the method of the application further comprises the step of reducing the compound of formula (A-a) by various methods well known to the person skilled in the art, to give a compound of formula (A-b) wherein Y is CH2, X, R1, R2, R3, R4, R5, R6, R8, Y, and as defined above.

[0349] According to a particular embodiment, the application relates to a method for preparing compounds 001, 003, 005, 007 and 009.

[0350] In a first step, the azanucleoside of formula (E-i) is coupled with the ribose tetraacetate of formula (D-i) by a coupling reaction in the presence of a Lewis acid to give a compound of formula (A-1-i):

[0351]

[0352] In a second step, the compound of formula (A-1-i) is subjected to an ammonia treatment to give compound 005:

[0353]

[0354] In a third step, the monophosphorylation of compound 005 in the presence of phosphoryl chloride and a trialkyl phosphate gives the phosphorodichloridate of formula (B-i):

[0355]

[0356] In a fourth step, the phosphorodichloridate of formula (B-i) is hydrolyzed to give compound 001:

[0357]

[0358] Alternatively, in a fifth step, the phosphate compound 001 obtained in the fourth step is reacted with the phosphorodichloridate compound of formula (B-i) obtained in the third step to give compound 009.

[0359] According to one embodiment, the step of reducing compound 005A-2 to give compound 007 is performed.

[0360] The compound of formula 007 is then monophosphorylated as described in the fourth step and hydrolyzed to compound 003.

[0361] The above described process for the preparation of compounds 001, 003, 005 and 007 can be easily adapted to the synthesis of compounds 002, 004, 006 and 008 by using the appropriate starting ribosyl tetraacetate of formula (D-ii):

[0362]

[0363] The above described process for the preparation of dimeric compound 009 can be easily adapted to the synthesis of dimeric compounds 010 to 014 by using the appropriate corresponding dichlorophosphates and phosphates intermediates.

[0364] Treatment of antitumor drug-induced toxicity

[0365] As mentioned above, the need for a treatment of drug-induced toxicity, in particular of anti-tumour drug-induced toxicity, is not yet fulfilled. It is therefore an object of the present application to provide a treatment of drug-induced toxicity, in particular of anti-tumour drug-induced toxicity, in a subject in need thereof. In particular, the present application relates to a nicotinamide mononucleotide derivative as defined above for use in the treatment of drug-induced toxicity, in particular of anti-tumour drug-induced toxicity, in a subject in need thereof.

[0366] Drug-induced toxicity

[0367] According to one embodiment, the toxicity is induced by at least one drug selected from the group consisting of anti-tumour drugs, anti-depressants, anti-retrovirals, anti-diabetics, anti-hypertensives, anti-arrhythmics, CNS stimulants, anti-malarials, immunosuppressants such as cyclosporin, anti-fungals such as ketoconazole, cytokines, interferons, anabolic androgens, adrenergic stimulants such as ephedrine, neuromodulators such as catecholamines, COX inhibitors such as NSAIDs, and mixtures thereof.

[0368] By "anti-tumour drug" or "anti-tumour agent" is meant a drug used in the treatment of cancer. It can also be referred to as a chemotherapeutic agent.

[0369] Non-limiting examples of anti-tumour drugs include:

[0370] anthracyclines such as doxorubicin, bleomycin, dactinomycin, epirubicin, idarubicin, mitomycin, mitoxantrone, porfiromycin and valrubicin;

[0371] alkylating agents such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine, streptozocin, temozolomide, thiotepa, trabectedin, platinum coordination complexes, carboplatin, cisplatin and oxaliplatin;

[0372] taxanes such as cabazitaxel, docetaxel and paclitaxel;

[0373] - topoisomerase inhibitors such as etoposide, irinotecan, teniposide, topotecan;

[0374] - antimetabolites such as antifolates: methotrexate, premetrexed, pralatrexate and trimetrexate; purine analogues: azathioprine, cladribine, fludarabine, mercaptopurine and thioguanine; and pyrimidine analogues: azacitidine, capecitabine, cytarabine, decitabine, floxuridine, 5-fluorouracil, gemcitabine and troxacitabine / tecogalan;

[0375] - protein kinase inhibitors such as abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, binimetinib, bortezomib, bosutinib, brigatinib, cabozantinib, capivasatinib, ceritinib, cobimetinib, crizotinib, dabrafenib, daroxabid, dasatinib, duvelitinib, encorafenib, erlotinib, gefitinib, gilteritinib, glesatinib, ibrutinib, idelalisib, imatinib, infigratinib, ixazomib, lapatinib, larotrectinib, lenvatinib, lorlatinib, midostaurin, neratinib, nilotinib, niraparib, olaparib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sonidegib, sorafenib, sunitinib, talazoparib, trametinib, vandetanib, vemurafenib and vismodegib;

[0376] - biological response modifiers such as interleukin (IL-2), denileukin diftitox and interferon gamma;

[0377] - histone deacetylase inhibitors such as belinostat, panobinostat, romidepsin and vorinostat;

[0378] - hormonal agents such as antiandrogens: abiraterone, apalutide, bicalutamide, cyproterone, enzalutamide, flutamide and nilutamide; antiestrogens (including aromatase inhibitors): anastrozole, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen and toremifene; gonadotropin-releasing hormone analogues: degarelix, goserelin, histrelin, leuprolide and triptorelin; and peptide hormones: lanreotide, octreotide and pasireotide;

[0379] - monoclonal antibodies such as alemtuzumab, atezolizumab, avutumab, bevacizumab, bintrafusp alfa, brentuximab vedotin, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, erlotinib, gemtuzumab, inotuzumab ozogamicin, ipilimumab, mogamulizumab, mosunetuzumab, nacolomab tafenatox, nivolumab, ofatumumab, olaratumab, panitumumab, pembrolizumab, polatuzumab vedotin-piiq, ramucirumab, rituximab, tositumomab, and trastuzumab;

[0380] - vinca alkaloids such as vinblastine, vincristine, and vinorelbine; and

[0381] - other anticancer drugs such as mitobronitol, bortezomib, estramustine, ixabepilone, asparaginase (pegaspargase), bexarotene, eribulin, everolimus, hydroxycarbamide, ixabepilone, lenalidomide, mitotane, omaraciclib, pomalidomide, tagraxofusp, talazoparib, temsirolimus, thalidomide, and venglustat.

[0382] Non-limiting examples of antidepressants include:

[0383] - tricyclic antidepressants such as amitriptyline, clomipramine, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine;

[0384] - tetracyclic antidepressants such as amoxapine, maprotiline, mianserin, mirtazapine, and seproxetine;

[0385] - selective serotonin reuptake inhibitors such as citalopram, escitalopram, fluvoxamine, fluoxetine, fluvoxamine, paroxetine, and sertraline;

[0386] - serotonin-norepinephrine reuptake inhibitors such as desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine;

[0387] - serotonin modulators and stimulators such as vilazodone and vortioxetine;

[0388] - serotonin antagonists and reuptake inhibitors such as nefazodone and trazodone;

[0389] - norepinephrine reuptake inhibitors such as atomoxetine, reboxetine, teniloxazine, and viloxazine;

[0390] - norepinephrine-dopamine reuptake inhibitors such as bupropion; and

[0391] - monoamine oxidase inhibitors such as isocarboxazid, phenoxazine, and tranylcypromine.

[0392] Non-limiting examples of antiretroviral drugs include nucleoside reverse transcriptase inhibitors such as zidovudine.

[0393] Non-limiting examples of antihypertensive drugs include:

[0394] - calcium channel blockers selected from dihydropyridines such as nifedipine, phenylalkylamines such as verapamil, and benzothiazepines such as diltiazem;

[0395] - beta adrenergic receptor antagonists such as isoprenaline;

[0396] Non-limiting examples of CNS stimulants include methylphenidate, amphetamine and methamphetamine.

[0397] According to a preferred embodiment, the drug-induced toxicity is an antineoplastic drug-induced toxicity.

[0398] The present application thus relates to nicotinamide mononucleotide derivatives as described above for use in the treatment of an antineoplastic drug-induced toxicity.

[0399] According to one embodiment, the toxicity is caused by at least one antineoplastic drug selected from the group consisting of anthracyclines, alkylating agents, taxanes, antimetabolites, monoclonal antibodies, tyrosine kinase inhibitors, and mixtures thereof. According to one embodiment, the antineoplastic drug-induced toxicity is caused by at least one drug selected from the group consisting of anthracyclines, alkylating agents, taxanes, antimetabolites, biological response modifiers, histone deacetylase inhibitors, hormonal drugs, vinca alkaloids, topoisomerase inhibitors, monoclonal antibodies, tyrosine kinase inhibitors, and mixtures thereof.

[0400] According to a preferred embodiment, the antineoplastic drug-induced toxicity is an anthracycline-induced toxicity caused by at least one drug selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone and valrubicin.

[0401] According to a more preferred embodiment, the antineoplastic drug-induced toxicity is an anthracycline-induced toxicity caused by doxorubicin.

[0402] The present application thus relates to nicotinamide mononucleotide derivatives as described above for use in the treatment of an antineoplastic drug-induced toxicity.

[0403] According to one embodiment, the toxicity as described above is an acute toxicity. According to one embodiment, the toxicity as described above is a chronic toxicity.

[0404] According to one embodiment, the toxicity as described above is selected from the group consisting of cardiotoxicity, nephrotoxicity, neurotoxicity, hematotoxicity, hepatotoxicity, lymphotoxicity, gastrointestinal toxicity, dermal toxicity, metabolic toxicity, ototoxicity, reproductive toxicity, skeletal toxicity, genotoxicity, and urotoxicity. According to one embodiment, the toxicity as described above is selected from the group consisting of cardiotoxicity, nephrotoxicity, hematotoxicity, hepatotoxicity, lymphotoxicity, gastrointestinal toxicity, dermal toxicity, metabolic toxicity, reproductive toxicity, skeletal toxicity, genotoxicity, and urotoxicity.

[0405] In one embodiment, the toxicity is not neurotoxicity. In one embodiment, the toxicity is not ototoxicity.

[0406] According to a preferred embodiment, the toxicity is cardiotoxicity.

[0407] According to one embodiment, the cardiotoxicity is selected from the group consisting of heart failure, left ventricular failure, myocardial ischemia, myocardial infarction, hypokalemia, QT interval prolongation, torsades de pointes, arrhythmia, pericarditis, myocarditis, bradycardia, hypertension, and thromboembolic events.

[0408] According to one embodiment, the cardiotoxicity is not arrhythmia.

[0409] The present application also relates to a pharmaceutical composition comprising at least one compound of the present application for use as described above and at least one pharmaceutically acceptable carrier for the treatment of a toxicity as described above.

[0410] Subject in need of treatment

[0411] It is preferred that the subject in need of treatment and / or prevention is a warm-blooded animal, more preferably a human being. According to one embodiment, the subject is a male. According to one embodiment, the subject is a female.

[0412] According to one embodiment, the subject is an adult, i.e. above 18 years of age. According to one embodiment, the subject is a child, i.e. below 18 years of age. According to one embodiment, the subject is an infant, i.e. above one month and below two years of age. According to one embodiment, the subject is a neonate, i.e. from birth to less than one month of age.

[0413] According to a preferred embodiment, the subject is older than 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 years of age. In one embodiment, the subject is older than 65, 70, 75, 80, 85, 90 or 95 years of age.

[0414] According to another preferred embodiment, the subject is less than 20 years old, 15 years old, 10 years old or 5 years old. In one embodiment, the subject is less than 18 years old, 17 years old, 16 years old, 15 years old, 14 years old, 13 years old, 12 years old, 11 years old, 10 years old, 9 years old, 8 years old, 7 years old, 6 years old, 5 years old, 4 years old, 3 years old or 2 years old.

[0415] According to one embodiment, the subject is receiving or will receive a drug susceptible to induce the above toxicity as described above, for the treatment of a condition for which he is in need of treatment. In particular, the subject is receiving or will receive an antineoplastic drug as described above.

[0416] According to one embodiment, the subject is receiving or will receive a treatment with at least one drug susceptible to induce the above toxicity, for which the cumulative dose, preferably the yearly cumulative dose, is greater than 100 mg / m 2 , 200 mg / m 2 , 300 mg / m 2 , 400 mg / m 2 , 500 mg / m 2 , 600 mg / m 2 , 700 mg / m 2 , 800 mg / m 2 , 900 mg / m 2 or 1000 mg / m 2 . In one embodiment, the subject in need of treatment is receiving a treatment with at least one drug described above, for which the cumulative dose is greater than 400 mg / m 2 , 500 mg / m 2 , 600 mg / m 2 , 700 mg / m 2 , 800 mg / m 2 , 900 mg / m 2 or 1000 mg / m 2 .

[0417] According to one embodiment, the subject does not have any underlying pathology.

[0418] According to one embodiment, the subject is at risk of developing the above toxicity. According to one embodiment, the subject is at risk of developing a toxicity induced by at least one drug as described above. According to one embodiment, the subject is at risk of developing a toxicity induced by at least one antineoplastic drug. According to one embodiment, the subject is at risk of developing a toxicity induced by at least one anthracycline drug. According to one embodiment, the subject is at risk of developing a toxicity induced by doxorubicin.

[0419] According to one embodiment, the subject is at risk of developing cardiotoxicity. According to one embodiment, the subject is at risk of developing cardiotoxicity induced by at least one of the above-mentioned drugs. According to one embodiment, the subject is at risk of developing cardiotoxicity induced by at least one anti-tumor drug. According to one embodiment, the subject is at risk of developing cardiotoxicity induced by at least one anthracycline drug. According to one embodiment, the subject is at risk of developing cardiotoxicity induced by doxorubicin.

[0420] According to one embodiment, the subject has at least one risk factor, i.e. a pre-existing disease, condition, habit or behavior that can lead to an increased risk of developing toxicity, in particular drug-induced toxicity.

[0421] According to one embodiment, the subject presents at least one risk factor selected from the group consisting of active chemotherapy, concomitant radiotherapy or cardiac irradiation, concomitant treatment, previous surgery such as coronary artery bypass graft; angioplasty; vascular stent, previous left ventricular dysfunction, myocardial infarction, angina pectoris, congestive heart failure or cardiovascular comorbidities, genetic predisposition, autoimmune disease or condition, cardiovascular disease or condition, active smoking, long-term passive smoking (also known as environmental exposure smoking), alcoholism, drug abuse, obesity (BMI > 35), cystic fibrosis, diabetes, dyslipidemia, hypertension, renal insufficiency, immunodeficiency, immunosuppression, cancer immunotherapy or antibody therapy, active hepatitis B virus (HBV) infection, hepatitis C virus (HCV) or human immunodeficiency virus (HIV), pregnant women, in particular pregnant women with significant heart disease, whether congenital or acquired, pulmonary arterial hypertension, sedentary, patients under 4 years of age, patients over 65 years of age.

[0422] According to one embodiment, the subject has already developed a toxicity as described above. According to one embodiment, the subject has already developed a toxicity induced by at least one of the drugs as described above. According to one embodiment, the subject has already developed a toxicity induced by at least one anti-tumor drug. According to one embodiment, the subject has already developed a toxicity induced by at least one anthracycline drug. According to one embodiment, the subject has already developed a toxicity induced by doxorubicin.

[0423] According to one embodiment, the subject has at least one comorbidity, i.e. a disease or condition that coexists with the toxicity.

[0424] According to one embodiment, the subject presents at least one comorbidity selected from the group consisting of hypertension, coronary artery disease, atrial fibrillation, diabetes, chronic renal failure, cerebrovascular disease, anemia and obesity.

[0425] According to one embodiment, the subject in need of treatment and / or prevention according to the application is diagnosed by a medical professional. For example, cardiotoxicity is diagnosed by any examination routinely performed in the medical environment, including echocardiography, and the aim is to identify a global or regional decrease in contractile function, i.e. a decrease in left ventricular ejection fraction >10% points to a value of less than <50%, usually used as a decision threshold to define cardiotoxicity.

[0426] In addition, the severity of cardiotoxicity can be assessed according to the measurement of the mean resting corrected QT interval obtained from three consecutive ECGs, as follows:

[0427] - QTc less than 330 ms = very short QT;

[0428] - QTc from 330 ms to 370 ms = short QT;

[0429] - QTc from 370 ms to 400 ms = normal QT;

[0430] - QTc from 400 ms to 460 ms = possible long QT;

[0431] - QTc from 460 ms to 470 ms = long QT; and

[0432] - QTc greater than 470 ms = very long QT.

[0433] According to one embodiment, the subject presents a QTc less than 330 ms. In one embodiment, the subject presents a QTc from 330 ms to 370 ms. In one embodiment, the subject presents a QTc from 400 ms to 460 ms. In one embodiment, the subject presents a QTc from 460 ms to 470 ms. In one embodiment, the subject presents a QTc greater than 470 ms.

[0434] According to its clinical presentation, a cardiotoxic event can be classified into three types:

[0435] (1) Acute cardiotoxicity, i.e. occurring during treatment or immediately after treatment, characterized by inhibition of myocardial contractility, which can return to normal within a week after stopping chemotherapy;

[0436] (2) Early-onset chronic progressive cardiotoxicity, i.e. characterized by the appearance of systolic or diastolic ventricular dysfunction within one year after the end of chemotherapy; and

[0437] (3) Late-onset chronic progressive cardiotoxicity, i.e. characterized by cardiac dysfunction after a latency of one year or more after the end of chemotherapy.

[0438] According to one embodiment, the subject suffers from acute cardiotoxicity. According to one embodiment, the subject suffers from early-onset chronic progressive cardiotoxicity. According to one embodiment, the subject suffers from late-onset chronic progressive cardiotoxicity.

[0439] Therapeutic effect

[0440] According to one embodiment, the use of a nicotinamide mononucleotide derivative as described above prevents, reduces, alleviates, and / or slows down (lessens) one or more symptoms of drug-induced toxicity, in particular of anti-neoplastic drug-induced toxicity, more particularly of anti-neoplastic drug-induced cardiotoxicity.

[0441] According to one embodiment, the use of a compound as described above reduces the risk of a subject experiencing at least one of the above drug-induced toxicities by at least 1% to 10%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 11% to 20%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 21% to 30%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 31% to 40%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 41% to 50%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 51% to 60%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 61% to 70%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 71% to 80%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 81% to 90%. In one embodiment, the use of a compound as described above can reduce the risk of toxicity by at least 91% to 100%.

[0442] Method of administration

[0443] The compounds of the application described above can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal, subcutaneous, or intradermal), inhalation spray, nasal, rectal, sublingual, or topical routes of administration and can be formulated, alone or together, in suitable dosing unit formulations comprising conventional non-toxic pharmaceutically-acceptable vehicles, adjuvants and vehicles as appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cows, sheep, dogs, cats, monkeys, etc., the compounds of the application are also effective for use in humans. The pharmaceutical compositions for use in administering the compounds of the application can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is present in the amount which is effective for the purpose intended, as described herein. The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0444] The pharmaceutical composition containing the active ingredient can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0445] Compositions intended for oral use can be prepared according to any method known in the art of pharmacy, such as in mixtures with one or more excipients. Such excipients can be sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Tablets of the application can be coated by known techniques including U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. Oral formulations can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

[0446] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Suitable excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally occurring phosphatide, such as lecithin, or an ester or partial ester of a hexitol such as inositol, with a fatty acid, such as stearic acid, or a condensation product of these with an ethylene oxide / propylene oxide block product, for example polyoxyethylene stearates or polyoxyethylene sorbitol esters, or a condensation product of an alkylol with an aldehyde or ketone such as acetone, butanone or pinacone. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oily suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0447] Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring and coloring agents.

[0448] The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the present application can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, ointments, creams, gels, solutions or suspensions, etc., containing compounds of the present application are employed. (In this application, topical application should include mouth washes and gargles.)

[0449] Dosing regimen

[0450] In the treatment of toxicity, preferably cardiotoxicity, a suitable dosage level of the nicotinamide mononucleotide derivative of the present application is generally about 0.01 mg to 500 mg per kg patient body weight per day, administered in single or multiple doses. Preferably, the dosage level will be about 0.1 mg / kg / day to about 350 mg / kg / day; more preferably about 0.5 mg / kg / day to about 100 mg / kg / day. Suitable dosage levels can be about 0.01 mg / kg / day to 250 mg / kg / day, about 0.05 mg / kg / day to 100 mg / kg / day, or about 0.1 mg / kg / day to 50 mg / kg / day. Within this range the dosage can be 0.05 mg / kg / day to 0.5 mg / kg / day, 0.5 mg / kg / day to 5 mg / kg / day, or 5 mg / kg / day to 50 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 milligram to 1000 milligrams of the active ingredient, particularly 1.0 milligram, 5.0 milligrams, 10.0 milligrams, 15.0 milligrams, 20.0 milligrams, 25.0 milligrams, 50.0 milligrams, 75.0 milligrams, 100.0 milligrams, 150.0 milligrams, 200.0 milligrams, 250.0 milligrams, 300.0 milligrams, 400.0 milligrams, 500.0 milligrams, 600.0 milligrams, 750.0 milligrams, 800.0 milligrams, 900.0 milligrams, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, 1 to 3 times per day, 1 to 2 times per day, or once.

[0451] According to one embodiment, the subject in need of treatment receives a treatment with at least one nicotinamide mononucleotide derivative as described above, with a cumulative dose, preferably annual cumulative dose, greater than 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, 1000 mg / kg, 2500 mg / kg or 5000 mg / kg. In one embodiment, the subject in need of treatment receives a treatment with at least one nicotinamide mononucleotide derivative as described above, with a cumulative dose, preferably annual cumulative dose, greater than 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, 1000 mg / kg, 2500 mg / kg or 5000 mg / kg.

[0452] The nicotinamide mononucleotide derivatives can be administered in a regimen of 1 to 4 times per day, preferably once daily, twice daily or three times daily. It will be appreciated, however, that specific dose levels and administration frequencies for any particular patient can vary and depend on a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disorder being treated, and the host being treated.

[0453] Monotherapy / combination therapy

[0454] The nicotinamide mononucleotide derivatives of the application can be used in monotherapy or in combination therapy in a subject in need of treatment and / or prevention. Thus, according to a first embodiment, the nicotinamide mononucleotide derivatives for use according to the application are administered to a subject without any other active ingredient. According to a second embodiment, the nicotinamide mononucleotide derivatives for use according to the application are administered to a subject in combination with at least one other active ingredient.

[0455] In one embodiment, the compound and the other active ingredient(s) are administered sequentially, simultaneously and / or separately to the subject.

[0456] In one embodiment, the other active ingredient is selected from natural extracts, antineoplastic agents, antidepressants, antiretrovirals, beta blockers, antidiabetics, diuretics, antihypertensives, antiarrhythmics, CNS stimulants, antimalarials, immunosuppressants, antifungals, cytokines, interferons, anabolic androgens, adrenergic stimulants, neuromodulators, COX inhibitors, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ranolazine, metformin, mineralocorticoid receptor antagonists, hydroxymethylglutaryl coenzyme A reductase inhibitors, antioxidants such as self-nanoemulsifying formulations of quercetin, coenzyme Q10, vitamin E, L-carnitine, steroids, cyclosporine, mycophenolate, anti-TNF such as infliximab or etanercept, anti-Il 1 such as Sraninka, anti-PGF such as gleevec, anti-CD20 such as rituximab, maltol, PTEN modulators, chalcomorin, pyrroloquinoline quinone, urolithin.

[0457] In one embodiment, the other active ingredient is selected from antineoplastic agents, antidepressants, antiretrovirals, beta blockers, antidiabetics, diuretics, antihypertensives, antiarrhythmics, CNS stimulants, antimalarials, immunosuppressants, antifungals, cytokines, interferons, anabolic androgens, adrenergic stimulants, neuromodulators, COX inhibitors, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ranolazine, metformin, mineralocorticoid receptor antagonists, hydroxymethylglutaryl coenzyme A reductase inhibitors, antioxidants such as self-nanoemulsifying formulations of quercetin, coenzyme Q10, vitamin E, L-carnitine, steroids, cyclosporine, mycophenolate, anti-TNF such as infliximab or etanercept, anti-Il 1 such as Sraninka, anti-PGF such as gleevec, anti-CD20 such as rituximab, maltol, PTEN modulators, chalcomorin, pyrroloquinoline quinone, urolithin.

[0458] In one embodiment, the other active ingredient is a natural extract, such as a glycoprotein extract; a terpenoid extract containing pentacyclic triterpenes such as betulin, pentacyclic triterpene metabolites such as betulinic acid, transpiroins, rosolins, sesquiterpenes, hericenols; a flavonoid extract containing flavones, flavonols, flavanones, flavans, bioflavonoids or isoflavones; a polysaccharide extract containing PSP, PSK, CVG, HPB-3, H6PC20; or a polyaromatic molecule such as hericerins and hericenones; an extract from species such as Trametes versicolor, Hericium erinaceus, Grifola frondasa, milk thistle, Korean ginseng, turmeric, dandelion, Coptis, sugar beet and ginger.

[0459] According to one embodiment, the pharmaceutical composition of the application further comprises at least another active ingredient. According to one embodiment, the pharmaceutical composition for use of the application comprises, in addition to at least one compound for use of the application, at least one additional active ingredient, for example selected from natural extracts, antineoplastic agents, antidepressants, antiretroviral agents, beta blockers, antidiabetic agents, diuretics, antihypertensive agents, antiarrhythmic agents, CNS stimulants, antimalarial agents, immunosuppressants, antifungal agents, cytokines, interferons, androgens, adrenergic stimulants, neuromodulators, COX inhibitors, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ranolazine, metformin, mineralocorticoid receptor antagonists, hydroxymethylglutaryl coenzyme A reductase inhibitors, self-nanoemulsifying formulations of antioxidants such as quercetin, coenzyme Q10, vitamin E, L-carnitine, steroids, cyclosporine, mycophenolate mofetil, anti-TNF such as infliximab or etanercept, anti-Il 1 such as Sraninka, anti-PGF such as gleevec, anti-CD20 such as rituximab, maltol, PTEN modulators, narceine, pyrroloquinoline quinone, urolithin active ingredients.

[0460] According to one embodiment, the pharmaceutical composition further comprises at least another active ingredient selected from natural extracts. Non-limiting examples of natural extracts are glycoprotein extracts; terpenoid extracts containing pentacyclic triterpenes such as betulin, containing pentacyclic triterpene metabolites such as betulinic acid, transpiroins, rosaminols, sesquiterpenes, hericenones; flavonoid extracts containing flavones, flavonols, flavanones, flavans, bioflavonoids or isoflavones; polysaccharide extracts containing PSP, PSK, CVG, HPB-3, H6PC20; or polyaromatic molecules such as hericenals and heriktones; extracts from species such as Coriolus versicolor, Hericium erinaceus, Grifola frondosa, Cynara scolymus, Cynara cardunculus, Curcuma longa, Taraxacum officinale, Coptis chinensis, Beta vulgaris and Zingiber officinale.

[0461] Kit of parts

[0462] Another object of the application is a kit comprising a first part comprising a nicotinamide mononucleotide derivative of the application as described above and a second part comprising another active ingredient, for example an active ingredient selected from the group consisting of natural extracts, antitumor agents, antidepressants, antiretrovirals, beta blockers, antidiabetics, diuretics, antihypertensives, antiarrhythmics, CNS stimulants, antimalarials, immunosuppressants, antifungals, cytokines, interferons, androgens, adrenergic stimulants, neuromodulators, COX inhibitors, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ranolazine, metformin, mineralocorticoid receptor antagonists, hydroxymethylglutaryl coenzyme A reductase inhibitors, self-nanoemulsifying formulations of antioxidants such as quercetin, coenzyme Q10, vitamin E, L-carnitine, steroids, cyclosporine, mycophenolate, anti-TNF such as infliximab or etanercept, anti-Il 1 such as Sraninka, anti-PGF such as gleevec, anti-CD20 such as rituximab, myricetin, PTEN modulators, narigenin, pyrroloquinoline quinone, urolithin.

[0463] In one embodiment, the kit of the application comprises a first part comprising Compound 001, or a pharmaceutically acceptable salt or solvate thereof, and a second part comprising another active ingredient, for example an active ingredient as described above.

[0464] Method of treatment

[0465] The application also relates to the use of a nicotinamide mononucleotide derivative as described above, or a pharmaceutical composition thereof, for the treatment of toxicity induced by an antitumor agent as described above.

[0466] The application also relates to the use of a nicotinamide mononucleotide derivative as described above for the manufacture of a medicament for the treatment of toxicity induced by an antitumor agent as described above.

[0467] The application also relates to a method for the treatment of toxicity induced by an antitumor agent as described above in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a nicotinamide mononucleotide derivative as described herein, or a pharmaceutical composition thereof. BRIEF DESCRIPTION OF DRAWINGS

[0468] Figure 1 is a histogram showing the survival rate of mice 5 days after treatment with DOX (20 mg / kg) or vehicle. ## p<0.01 : Fisher test Dox mice treated with vehicle versus control mice, £ p<0.05, ££ p<0.01 : Fisher test Dox mice treated with vehicle versus Dox mice treated with NMN analog.

[0469] Figure 2A shows the body weight change in mice treated with compounds 001, 010 and 011 (180 mg / kg) or vehicle, before (light grey symbols) and 5 days after (dark grey symbols) injection of saline or DOX (20 mg / kg). ***p<0.001 : two-way ANOVA followed by Bonferroni post-hoc Body weight before Dox injection versus body weight 5 days after Dox injection.

[0470] Figure 2B is a histogram showing the body weight (BW) gain calculated as follows: body weight at the day of sacrifice minus body weight before injection in mice treated with compounds 001, 010 and 011 (180 mg / kg) or vehicle, with and without injection of DOX (20 mg / kg). ***p<0.001 : Mann-Whitney test Dox mice treated with vehicle versus control mice, $$p<0.01, $$$p<0.001 : one-way ANOVA followed by post-hoc Dunnett test Dox mice treated with vehicle versus Dox mice treated with NMN analogs.

[0471] Figure 3 is a histogram showing the left ventricular (LV) end-diastolic volume (Figure 3A) and LV end-systolic volume (Figure 3B) and ejection fraction (Figure 3C) 5 days after injection of saline or DOX (20 mg / kg). **p<0.01, ***p<0.001 : Mann-Whitney test Dox mice treated with vehicle versus control mice, $p<0.05, $$$p<0.001 : Kruskal-Wallis test followed by post-hoc Dunn test Dox mice treated with vehicle versus Dox mice treated with NMN analogs.

[0472] Figure 4 is a histogram showing the LV end-diastolic diameter and LV end-systolic diameter (Figures 4A and 4B, respectively), fractional shortening (Figure 4C) and heart rate (Figure 4D) 5 days after injection of saline or DOX (20 mg / kg). **p<0.01, ***p<0.001 : t-test or Mann-Whitney test Dox mice treated with vehicle versus control mice, $$$p<0.001 : one-way ANOVA followed by post-hoc Dunnett test or Kruskal-Wallis test followed by post-hoc Dunn Dox mice treated with vehicle versus Dox mice treated with NMN analogs (180 mg / kg) or vehicle.

[0473] Figure 5 is a histogram showing the LV anterior wall thickness at systole and diastole (Figures 5A and 5B, respectively) and the posterior wall thickness at systole and diastole (Figures 5C and 5D, respectively) after injection of saline or DOX (20 mg / kg) for 5 days. *P < 0.05, **P < 0.01 : Mann- Whitney test Dox mice treated with vehicle vs control mice.

[0474] Figure 6 is a histogram showing the heart weight (Figure 6A) and the heart weight normalized to tibia length (Figure 6B) after injection of saline or DOX (20 mg / kg) for 5 days. ***p < 0.001 : t-test Dox mice treated with vehicle vs control mice.

[0475] Figure 7 is a histogram showing the LDH concentration in plasma of mice (U / L, Figure 7A) and LDH (fold change, Figure 7B) after injection of saline or DOX (20 mg / kg) for 5 days. |**p < 0.01 : Mann- Whitney test Dox mice treated with vehicle vs control mice; $p < 0.05: Kruskal-Wallis test Dox mice treated with vehicle vs Dox mice treated with NMN analog (180 mg / kg) or vehicle. Examples

[0476] The present application is further illustrated by the following examples.

[0477] Example 1 : Synthesis of compounds of the invention

[0478] Materials and methods

[0479] All materials were purchased from commercial suppliers and used without further purification. Thin layer chromatography was performed on Merck silica gel 60 F254 (0.2 mm thickness) TLC plastic sheets. 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 IA 8103), uncorrected, or on a Kofler hot stage WME (Wagner & Munz). IR, 1 H, 19 F and 13 C NMR spectra confirmed the structure of all compounds. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer, NMR spectra were recorded on Bruker AC 300, Advance DRX 400 and Advance DRX 500 spectrometers, using CDC13, CD3CN, D20 or DMSO-d6 as solvents, and are reported in ppm (δ) relative to the solvent peak, coupling constants in Hz. 1H, 75 MHz or 100 MHz 13 C and 282 MHz or 377 MHz 19 F spectra. Chemical shifts (d) are expressed in parts per million relative to internal (i) to CDCI3for 1 H, (ii) to CDCI3for 13 C, and directly (iii) to CFCl3(internal standard) for 19 F. Chemical shifts are in ppm, multiplicities of the peaks are designated 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 spectrometry (HRMS) was obtained from the "Service central d'analyse de Solaize" (Centre National de la Recherche Scientifique) using electrospray-TOF ionization (ESI-TOF) recorded on a Waters spectrometer.

[0480] General experimental procedure

[0481] Step 1 : synthesis of compound of formula (A-1 -i)

[0482] The compound of formula (D-i) (1.0 eq) was dissolved in dichloromethane. The nicotinamide of formula (E-i) (1.50 eq) and TMSOTf (1.55 eq) were added at room temperature. The reaction mixture was heated under reflux and stirred until the reaction was complete. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness to give the tetraacetate (A-1 -i).

[0483] Step 2: synthesis of compound 005

[0484] The tetraacetate (A-1 -i) was dissolved in methanol and cooled to -10 °C. A 4.6 M solution of ammonia in methanol (3.0 eq) was added at -10 °C and the mixture was stirred at this temperature until the reaction was complete. Dowex HCR (H+) resin was added to pH 6 to 7. The reaction mixture was heated to 0 °C and filtered. The resin was rinsed with a mixture of methanol and acetonitrile. The filtrate was concentrated to dryness. The residue was dissolved in acetonitrile and concentrated to dryness. The residue was dissolved in acetonitrile to give a solution of compound 005.

[0485] Step 3: synthesis of compound of formula (B-i)

[0486] The crude acetonitrile solution of compound 005 was diluted with trimethyl phosphate (10.0 eq). Acetonitrile was distilled under vacuum and the mixture was cooled to -10 °C. Phosphorous oxychloride (4.0 eq) was added at 10 °C and the mixture was stirred at 10 °C until the reaction was complete.

[0487] Steps 4 and 5: Synthesis of compounds 0001 and 009

[0488] The mixture obtained in step 3 above was hydrolyzed by addition of a 50 / 50 mixture of acetonitrile and water, followed by the addition of methyl tert-butyl ether. The mixture was filtered and the solid was dissolved in water. Sodium bicarbonate was added to neutralize the aqueous solution, which was extracted with dichloromethane. The aqueous layer was concentrated to dryness to give a crude mixture of compound 001 and compound 009.

[0489] Compounds 001 and 009 were isolated after purification by elution with water on Dowex 50wx8. The fractions containing compound 001 were concentrated and further purified by silica gel chromatography. The fractions containing compound 009 were concentrated to dryness. The residue was purified by silica gel column chromatography (gradient elution, isopropanol / water). The pure fractions were combined and concentrated. The residue was freeze-dried to give compound 009 as a beige solid.

[0490] Characterization of compound 009: 31 P RMN: δ (ppm, reference 85% H3PO4: 0 ppm in D2O) = -11.72; 1 HRMN: δ (ppm, reference TMS: 0 ppm in D2O) = 4.20 (ddd, J H-H = 11.9, 3.5, 2.4 Hz, 2H), 4,35 (ddd, J H-H = 11.9, 3.9, 2.2 Hz, 2H), 4.43 (dd, J H-H = 5,0, 2.6 Hz, 2H), 4.53 (t, J H-H = 5.0 Hz, 2H), 4.59 (m, 2H), 6.16 (d, J H-H = 5.4 Hz, 2H), 8.26 (dd, J H-H = 8.1, 6.3 Hz, 2H), 8.93 (d, J H-H = 8.1 Hz, 2H), 9.25 (d, J H-H = 6.2 Hz, 2H), 9.41 (s, 2H); 13 C RMN: δ (ppm, reference TMS: 0 ppm in 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 [M nicotinamide + H]+, 650.8 [M + H]+.

[0491] Synthesis of compound 010

[0492] Phosphorous oxychloride (3.0 eq) was added to trimethyl phosphate (20.0 eq) at -5 °C. The 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 °C / 0 °C and the mixture was stirred for 2 h to 3 h. Then the a-NMN (compound 002) (1.0 eq) was added in portions at -5 °C and the reaction mixture was stirred overnight at -5 °C. The hydrolysis was performed by dropwise addition of water (5 volumes) at -10 °C / 0 °C and the mixture was stirred at 10 °C to 15 °C until complete homogenization. Then the reaction mixture was extracted with dichloromethane (6*10 volumes) and the aqueous phase was neutralized by elution through a resin of Purolite A600E formate form (theoretical amount of HCl from POCI3 neutralization). Then the eluate was concentrated under vacuum at 45 °C / 50 °C to obtain the crude containing a,β-diNMN (compound 010). The crude was eluted with water through a Dowex 50wx8 100 mesh to 200 mesh resin to remove some impurities. The fractions containing compound 010 were combined and concentrated under vacuum at 45 °C to 50 °C. Then the crude was purified by preparative chromatography on a Luna Polar RP 10 pm stationary phase eluted with 10 mM NaH2P04 aqueous solution. The pure fractions were combined and eluted with water through a resin of Purolite C100EH HCO3 form (H2P04 + + + + - The eluate was concentrated under vacuum and the residue was freeze-dried to obtain compound 010 as a white solid.

[0493] 31 PRMN: δ (ppm, reference 85% H3P04: 0 ppm in D20) = -11.87, -11.69, -11.46, -11.29; 1 ​​​​H RMN:δ (ppm, reference TMS: 0 ppm in D2O) = 4.10 (ddd, J = 11.1, 6.1, 3.1 Hz, 1H), 4.15-4.25 (m, 2H), 4.36 (ddd, J = 12.2, 4.4, 2.4 Hz, 1H), 4.40 (dd, J = 4.9, 2.4 Hz, 1H), 4.44 (dd, J = 5.0, 2.7 Hz, 1H), 4.53 (t, J = 5.0 Hz, 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, reference TMS: 0 ppm in 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(C H),128.54(CH),132.44(Cq),133.81(Cq),139.85(CH),140.92(CH),142.50(CH),143.49(CH),1 45.06 (CH), 145.97 (CH), 165.64 (Cq), 165.88 (Cq); MS (ES+): m / z=122.8[M nicotinamide+H]+, 650.9[M+H]+.

[0494] Synthesis of Compound 011

[0495] Phosphorus trichloride (3.0 equivalents) was added to trimethyl phosphate (20.0 equivalents) at -5°C. α-NR chloride (1.0 equivalent) was added in portions at -5°C, and the reaction mixture was stirred overnight at -5°C. Morpholine (3.0 equivalents) was added dropwise at -10°C / 0°C, and the mixture was stirred for 2 to 3 hours. Then, α-NMN (compound 002) (1.0 equivalent) was added in portions at -5°C, and the reaction mixture was stirred overnight at -5°C. Hydrolysis was carried out by adding water (5 volumes) dropwise at -10°C / 0°C, and the mixture was stirred until completely homogenized at 10 to 15°C. The reaction mixture was then extracted with dichloromethane (6 x 10 volumes), and the aqueous phase was eluted through a resin in the form of Purolite A600E formate (the theoretical amount of HCl neutralized from POCl3). The eluent was then concentrated under vacuum at 45°C / 50°C to obtain a crude product containing α,α-diNMN (compound 011). The crude product was then filtered through a Dowex 50wx8 filter (100-200 mesh). + Elution with a resin of type 100 can remove some impurities. The fractions containing compound 011 were combined and concentrated under vacuum at 45°C to 50°C. The crude product was then purified by preparative chromatography on a Luna Polar RP 10 μm stationary phase, eluting with a 10 mM NaH₂PO₄ aqueous solution. The purified fractions were combined and purified by Purolite C100EH₂H₂. + Elute the resin with water (using H) + Complete exchange of Na + (The required amount), and then eluted on a resin in the form of Acetate (completely exchanging H2PO4 with acetate). - (Required amount). The eluent was concentrated under vacuum, and the residue was freeze-dried to give compound 011 as a white solid.

[0496] 31 P RMN:δ(ppm, reference 85% H3PO4: 0ppm in D2O)=-11.40; 1 H RMN:δ(ppm, reference TMS: 0ppm in 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, reference TMS: 0ppm in 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[M nicotinamide + H]+,650.8[M + H]+.

[0497] Example 2: Evaluation of compounds of the invention in a doxorubicin-induced cardiotoxicity model

[0498] The aim of this study was to evaluate the effects of intraperitoneal (ip) administration of compounds 001, 010, and 011 at a dose of 180 mg / kg on the progression of doxorubicin-induced cardiotoxicity.

[0499] I. Materials and Methods

[0500] Material

[0501] Animals: 76 male mice, 8 weeks old at arrival, from Janvier Labs, Le Genest St Isle, 53941 St Berthevin, France. Each animal was identified using an electronic chip. Each cage was numbered. Based on the animal number / cage and cage number, each animal was assigned a unique number with a group name and mouse number. Matching cards used to identify the cages housing the laboratory animals contained the following information: experiment name, experiment number, and cage number.

[0502] Compounds: Compounds 001, 010, and 011, prepared according to Example 1 or commercially available, were stored at +4°C before use. The carrier was physiological buffer solution.

[0503] method

[0504] 1. Preparation of formulations

[0505] Dissolve the powders (180 mg / kg) of compounds 001, 010, and 011 in the carrier (this solution can be used for a maximum of 1 day at room temperature). Prepare fresh samples daily for each application, except weekends (the solution is prepared on Saturday and used on Saturday and Sunday).

[0506] 2. Doxorubicin-induced cardiotoxicity

[0507] Cardiotoxicity was induced by a single intraperitoneal injection of 20 mg / kg doxorubicin (DOX). Doxorubicin was prepared at a concentration of 2 mg / ml and administered at a volume of 10 mL / kg.

[0508] The mortality rate was tracked throughout the experimental phase.

[0509] 3. Experimental groups

[0510] Group description:

[0511] Group 1: Carrier (intraperitoneal injection)

[0512] Group 2: Doxorubicin (20 mg / kg)

[0513] Group 3: Doxorubicin (20 mg / kg) + Compound 001 180 mg / kg

[0514] Group 4: Doxorubicin (20 mg / kg) + Compound 010 180 mg / kg

[0515] Group 5: Doxorubicin (20 mg / kg) + Compound 011 180 mg / kg

[0516] Group assignment:

[0517] Each group involved 14 to 24 mice.

[0518] In accordance with the guidelines for non-clinical laboratory studies, the experimental and control groups of animals were housed under identical conditions. The planned study duration was 11 days.

[0519] 4. Doxorubicin induction

[0520] At D0, mice were administered DOX (20 mg / kg) via intraperitoneal injection.

[0521] 5. Treatment

[0522] Treatment with compounds 001, 010, and 011 began 5 days before DOX injection and continued daily from D5 to D0.

[0523] Mice were treated with intraperitoneal injections of compounds 001, 010, and 011 30 minutes before DOX injection.

[0524] During the experiment (D0 to D5), mice were given intraperitoneal injections of compounds 001, 010, and 011 once daily. The last injection occurred 24 hours before sacrifice.

[0525] 6. Body weight, survival and clinical examination

[0526] Assess weight at the time of admission and on day 5.

[0527] Survival rates were recorded daily until the end of the experiment (D5).

[0528] 7. Blood and urine collection

[0529] Retroocular blood samples were collected at the time of induction and on days 1 and 5 after DOX induction to assess biomarkers (especially LDH).

[0530] 8. Organ harvesting

[0531] On D5, the heart and tibia were harvested.

[0532] 9. Cardiac function assessment by echocardiography

[0533] Five days after doxorubicin injection, noninvasive two-dimensional echocardiography (ECG) was performed on anesthetized animals (1.5% to 2% isoflurane) using a VF16-5 probe (Siemens, Acuson NX3 Elite). Digital images of the heart were obtained in parasternal long-axis and short-axis views after removing hair from the chest.

[0534] Assess the following cardiac functions on ECG:

[0535] - Left ventricular (LV) end-systolic diameter and LV end-diastolic diameter;

[0536] -End-systolic volume of the lower ventricle (LV) and end-diastolic volume of the lower ventricle (LV);

[0537] -Shortening rate;

[0538] - Ejection fraction;

[0539] - Heart rate; and

[0540] -Anterior and posterior wall thickness during diastole and systole.

[0541] II. Results and Discussion

[0542] 1. Survival

[0543] Figure 1 The survival rates of mice induced or uninduced with DOX (20 mg / kg) were shown 5 days after doxorubicin injection.

[0544] DOX mice were treated with compounds 001, 010, and 011 (180 mg / kg) or with a carrier.

[0545] As shown in the figure, almost 50% of the doxorubicin mice treated with the carrier died before the end of the experimental procedure.

[0546] Treatment with compound 001 often improved survival rates (78% survival rate), but this was not statistically significant, possibly due to crossover of the survival curves. However, treatment with compounds 010 or 011 significantly improved survival rates (98% and 100%, respectively) compared to the untreated group (50% survival rate).

[0547] 2. Body weight

[0548] Figure 2A shows the changes in body weight of mice treated with compounds 001, 010, and 011 (180 mg / kg) or their carriers before injection of saline or DOX (20 mg / kg) (light gray symbols) and 5 days after injection (dark gray symbols).

[0549] Figure 2B shows the weight gain, calculated as follows: subtract the weight before injection from the weight on the day of execution.

[0550] Surviving mice treated with the loading agent exhibited major signs of distress associated with severe weight loss (-4.2 g ± 0.5 g). The weight loss observed after doxorubicin administration was significantly reduced by compounds 001, 010, and 011 (p < 0.01, p < 0.001, and p < 0.001, respectively).

[0551] 3. Cardiac function

[0552] 3.1. Left ventricular end diastolic / systolic volume and ejection fraction

[0553] Figure 3 shows the left ventricular (LV) end-diastolic volume (Figure 3A), LV end-systolic volume (Figure 3B), and ejection fraction (Figure 3C) 5 days after injection of saline solution or DOX (20 mg / kg), with or without treatment with compounds 001, 010, and 011.

[0554] As shown in Figure 3, compared with the control group, the end-systolic volume of the left ventricle (LV) under doxorubicin induction (Figure 3B) was significantly increased, while the end-diastolic volume (Figure 3A) was not significantly different, resulting in a significant decrease in ejection fraction (38.9% ± 1.3% in the doxorubicin group and 64.8% ± 0.6% in the control group) (Figure 3c).

[0555] Compared with DOX-induced animals receiving the doxorubicin load, compounds 001, 010, and 011 reduced end-systolic left ventricular volume compared with the doxorubicin load group (Figure 3B), with compound 010 showing statistical significance (P<0.05).

[0556] Compared with untreated DOX animals, treatment with compounds 001, 010 and 011 significantly increased the ejection fraction (56.9% ± 0.6% in doxorubicin mice treated with NMN (P < 0.05), 58.2% ± 0.5% in doxorubicin mice treated with compound 011 (p < 0.001), and 60.0% ± 0.6% in doxorubicin mice treated with compound 010 (p < 0.001)) (Figure 3C).

[0557] 3.2. Left ventricular end diastolic / systolic diameter, fractional shortening and heart rate

[0558] Figure 4 shows the end-diastolic diameter and end-systolic diameter of the left ventricular tract (LV) (Figures 4A and 4B, respectively), shortening rate (Figure 4C), and heart rate (Figure 4D) 5 days after injection of saline solution or DOX (20 mg / kg).

[0559] As shown in Figure 4, mice treated with doxorubicin showed a significant increase in left ventricular diameter during systole (Figure 4B), while there was no significant difference in diastolic diameter (Figure 4A), resulting in a decrease in shortening rate (33.5% ± 0.4% vs. 43.2% ± 0.5% in the control group) (Figure 4C). Treatment with compounds 001, 010, and 011 significantly increased the shortening rate to approximately 38% (P < 0.001 for all three groups).

[0560] Furthermore, compared with the control group, doxorubicin significantly reduced heart rate (365.1 bpm ± 23.9 bpm in the doxorubicin group versus 525.6 bpm ± 19.8 bpm in the control group). Treatment with compounds 001, 010, and 011 resulted in an increase in heart rate, with compound 010 significantly increasing this parameter (470.1 bpm ± 18.8 bpm (P < 0.001)).

[0561] 3.3. Left ventricular anterior and posterior wall thickness in systole and diastole

[0562] Figure 5 shows the anterior wall thickness of the left ventricular tract (LV) during systole and diastole (Figures 5A and 5B, respectively) and the posterior wall thickness during systole and diastole (Figures 5C and 5D, respectively) 5 days after injection of saline solution or DOX (20 mg / kg).

[0563] Doxorubicin significantly reduces the thickness of the anterior and posterior walls during systole, but not during diastole, and any treatment has a significant effect.

[0564] Treatment of DOX mice with compounds 001, 010, and 011 (180 mg / kg) did not significantly increase the thickness of the anterior and posterior walls during contraction.

[0565] 4. Heart weight

[0566] Figure 6 shows the heart weight (Figure 6A) and heart weight normalized to tibial length (Figure 6B) 5 days after injection of saline solution or DOX (20 mg / kg).

[0567] DOX mice were treated with compounds 001, 010, and 011 (180 mg / kg) or with a carrier.

[0568] As shown in Figures 6A and 6B, doxorubicin significantly reduced heart weight compared to the control group (102.3 mg ± 4.6 mg in the doxorubicin group and 128.9 mg ± 3.3 mg in the control group). Treatment with compounds 010 and 011 tended to increase heart weight, but this was not statistically significant compared to DOX-loaded mice. Similar results were obtained when heart weight was normalized to tibia length.

[0569] 5. Biomarker assessment

[0570] Figure 7 shows the concentration (U / L, Figure 7A) and fold difference (Figure 7B) of LDH in mouse plasma 5 days after injection of saline or DOX (20 mg / kg).

[0571] DOX mice were treated with compounds 001, 010, and 011 (180 mg / kg) or with a carrier.

[0572] Plasma LDH (lactate dehydrogenase) was measured 5 days after doxorubicin injection. As shown in Figures 7A and 7B, compared with the control group, doxorubicin induced cell damage, manifested as a more than 3-fold increase in LDH release. Treatment with NMN reduced LDH release by more than 35%, but this was not statistically significant. However, treatment with compounds 010 and 011 resulted in a 50% to 55% decrease in LDH levels, with significant effects (P<0.05).

[0573] III. Conclusion

[0574] In summary, the results showed that doxorubicin induced cardiac dysfunction characterized by impaired cardiac contractility and filling, as well as cellular cardiac damage. Doxorubicin also led to high mortality and severe weight loss.

[0575] Treatment with compounds 001, 010, and 011 significantly improved survival, weight loss, and prevented cardiac function degeneration, as evidenced by their effects on ejection fraction, shortening rate, and heart rate.

Claims

1. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of doxorubicin-induced cardiotoxicity; (I) wherein: X is O; R1 is H; R2, R3, R4 and R5 are independently selected from H and hydroxyl; R6 is H; X' is O; R7is P(O)R9R 10 or ; wherein: R9and R 10 are OH; Y' is CH; R 1’ is H; R 2’ , R 3’ , R 4’ and R 5’ are independently selected from H and hydroxyl; R 6’ is H; R 8’ is NH2; n is equal to 2; R8 is NH2; represents a connection point; represents a single or double bond depending on Y'; and R depends on the position, representing an alpha or beta anomer; and 1’ R depends on the position, representing an alpha or beta anomer; and Y is CH; 2. Use according to claim 1, wherein the compound of formula (I) is selected from: represents a single or double bond depending on Y; and denotes the alpha or beta anomer, depending on the position of R1. and pharmaceutically acceptable salts thereof.

3. Use according to claim 1 or claim 2, wherein the cardiotoxicity is selected from the group consisting of heart failure, left ventricular failure, myocardial ischemia, myocardial infarction, QT interval prolongation, torsades de pointes, arrhythmia, pericarditis, myocarditis, bradycardia, hypertension and thromboembolic events.

4. Use according to claim 1 or claim 2, wherein the compound of formula (I) is comprised in a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

5. Use according to claim 4, wherein the pharmaceutical composition further comprises at least one active ingredient selected from the group consisting of antineoplastic agents, antidepressants, antiretrovirals, beta blockers, antidiabetic agents, diuretics, antihypertensive agents, antiarrhythmic agents, antimalarial agents, immunosuppressants, antifungal agents, cytokines, adrenergic stimulants, neuromodulators, COX inhibitors, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ranolazine, mineralocorticoid receptor antagonists, hydroxymethylglutaryl coenzyme A reductase inhibitors, antioxidants, L-carnitine, steroids, cyclosporine, mycophenolate, anti-TNF, anti-Il 1, anti-PGF, anti-CD20 antibodies, maltol, PTEN modulators, nobiletin, pyrroloquinoline quinone, urolithin.

6. Use according to claim 5, wherein the antioxidant is a self-nanoemulsifying formulation of quercetin; the anti-TNF is infliximab or etanercept; the anti-Il 1 is Sraninka; the anti-PGF is gleevec; the anti-CD20 antibody is rituximab.

7. Use according to claim 5, wherein the neuromodulator is a CNS stimulant.

8. Use according to claim 5, wherein the antioxidant is vitamin E or Q10 coenzyme.

9. Use according to claim 5, wherein the steroid is an anabolic androgenic steroid.

10. Use according to claim 5, wherein the antidiabetic agent is metformin.

11. Use according to claim 5, wherein the cytokine is an interferon. ​

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