Nicotinamide mononucleotide derivatives and their use in treatment and prevention of erythrocyte disorders

Abstract

The present invention relates to nicotinamide mononucleotide derivatives of formula (I) for use in the treatment and / or prevention of blood disorders, in particular sickle cell disease. The invention also relates to a pharmaceutical composition comprising the compound of formula (I) for use in the treatment and / or prevention of erythrocyte disorders, in particular sickle cell disease.

Description

Technical Field

[0001] The present invention relates to nicotinamide mononucleotide derivative compounds for use in treating and / or preventing red blood cell disorders. Background of the Invention

[0002] A blood disorder is a condition that affects blood cells (such as red blood cells, white blood cells, or smaller circulating cells called platelets), which are crucial for clot formation. All three cell types are formed in the bone marrow, which is the soft tissue inside the skeleton. Red blood cells carry oxygen to the body's organs and tissues. White blood cells help the body fight infection. Platelets help the blood clot. A blood cell disorder can impair the formation and function of one or more of these types of blood cells.

[0003] Among blood disorders, sickle cell disease (SCD) or drepanocytosis is a group of inherited red blood cell disorders defined by missense point mutations in the beta globin sequence that result in a valine substitution for the glutamic acid residue at position 6. This mutated globin, termed sickle hemoglobin or hemoglobin S (HbS), aggregates and forms fibrillar deposits in the presence of low oxygen levels, leading to polymerized hemoglobin and promoting red blood cell (RBC) sickling.

[0004] The clinical manifestations of SCD result from at least three distinct pathophysiological mechanisms: loss of RBC variability leading to vasoocclusion and ischemia; shortened RBC lifespan leading to intravascular and extravascular hemolysis; and the sticky RBC surface increasing adhesion to the vascular endothelium, leading to vasoocclusion and vasculoproliferative lesions.

[0005] Recurrent acute painful crises or vaso-occlusive crises (VOCs) are considered the most common manifestation of SCD. VOCs are thought to occur when blood flow is obstructed, usually at the level of small blood vessels, leading to ischemic damage and pain.

[0006] Over time, patients will also experience serious acute and chronic complications. Acute complications include severe infections (such as meningitis, osteomyelitis, sepsis, etc.), as well as non-infectious complications (such as stroke, renal necrosis, priapism, etc.). Acute chest syndrome is a potentially life-threatening complication that may include symptoms such as chest pain and shortness of breath; some episodes of acute chest syndrome are triggered by infection. Chronic complications can occur in multiple organs and include neurocognitive impairment, chronic kidney damage, delayed puberty, avascular necrosis, retinopathy, pulmonary hypertension, skin ulcers, and chronic pain. Individuals with SCD face lifelong difficulties caused by persistent and progressive diseases.

[0007] SCD affects over 5 million individuals worldwide and is the most common genetic disease in France. Despite recent advances in the field, treatment for SCD patients is limited to symptomatic pain management, oxygen supplementation, antibiotics, red blood cell transfusions, and hydroxyurea. However, blood transfusions remain the most commonly used therapy for SCD patients.

[0008] Alternative approaches, such as bone marrow transplantation and gene therapy, have been developed, but they are still associated with toxicity and are considered only in the context of cerebrovascular disease. Furthermore, these approaches are not yet feasible in most countries where the disease prevalence is high.

[0009] Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous redox cofactor in red blood cells. NAD+ and its reduced form, NADH, play important roles in maintaining redox homeostasis. The redox ratio ([NADH]:[NAD++NADH]) of sickle cell erythrocytes is lower than that of normal erythrocytes.

[0010] The amino acid L-glutamine (USAN, glutamine) is required for the synthesis of NAD. Sickle-derived red blood cells uptake L-glutamine several times higher than normal red blood cells, primarily to increase total intracellular NAD levels. Oral administration of pharmaceutical-grade L-glutamine increases the NAD+ redox ratio in sickle-derived cells and is associated with patient-reported clinical improvements.

[0011] A phase 3 trial of L-glutamine in sickle cell disease (SCD) showed that the median number of painful crises over 48 weeks was lower in patients who received L-glutamine. Based on the results of this phase 3 trial, the FDA approved pharmaceutical-grade L-glutamine (Endari, Emmaus Medical) as a prescription drug to reduce the incidence of acute complications of sickle cell disease in adults and children 5 years of age and older.

[0012] The FDA recently approved several other options to treat SCD or reduce complications associated with SCD: Oxbryta TM ), which inhibits HbS polymerization by promoting the binding of oxygen to hemoglobin, has been approved for the treatment of SCD in adults and children aged 12 years and above; Clizumab (Adakveo TM ), a therapeutic monoclonal antibody that reduces cell aggregation during VOCs by inhibiting the cell adhesion molecule P-selectin, is approved for use in adults and children 16 years and older.

[0013] However, while current treatments have significantly extended the life expectancy of affected patients, they remain limited because the effectiveness of these drugs varies among patients and the clinical manifestations observed. Furthermore, further studies are needed to assess whether the beneficial effects on SCD complications observed over the years are maintained.

[0014] Therefore, it is of great significance to investigate new therapeutic targets for the treatment of SCD and its associated complications.

[0015] Therefore, an object of the present invention is to provide a safe preventive and / or therapeutic treatment for red blood cell disorders, in particular sickle cell disease, by providing nicotinamide mononucleotide or a derivative thereof for treating and / or preventing sickle cell disease.

[0016] Applicants have unexpectedly discovered that the nicotinamide mononucleotide derivatives according to the present invention are effective and well-tolerated agents for treating and / or preventing red blood cell disorders, in particular sickle cell disease, and / or complications associated with said red blood cell disorders, in particular sickle cell disease. Summary of the Invention

[0017] Therefore, the present invention relates to compounds of formula (I),

[0018]

[0019] or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0020] X is selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0021] R1 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;

[0022] R2, R3, R4 and R5 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; where R AA is a side chain selected from proteinogenic amino acids;

[0023] R6 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;

[0024] R7 is selected from P(O)R9R 10 、P(S)R9R 10 and in

[0025] R9 and R 10 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 NHCHR α R α’ C(O)R 12 ;in:

[0026] -R 11 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 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 )alkyl-(C5-C 12 )aryl; wherein m is an integer selected from 1 to 8; and -P(O)(OH)OP(O)(OH)2; and an internal or external counterion;

[0027] -R 12 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 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;

[0028] -R 13 and R 14 independently selected from H, (C1-C8)alkyl and (C1-C8)alkyl-(C5-C 12 ) aryl; and

[0029] -R α and R α’ 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 )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 protein amino acids or non-protein amino acids; wherein the aryl group is optionally selected from hydroxyl, (C1-C10 )alkyl, (C1-C6)alkoxy, halogen, nitro and cyano; or

[0030] R9 and R 10 Together with the phosphorus atom to which they are attached, they form a 6-membered ring, wherein -R9-R 10 - represents -O-CH2-CH2-CHR-O-; wherein R is selected from H, (C5-C6)aryl and (C5-C6)heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or two groups selected from halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano;

[0031] X' is selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0032] R1' 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;

[0033] 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-(C1-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; where R AA is a side chain selected from proteinogenic amino acids;

[0034] 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;

[0035] R 8' Selected from H, OR, NR 15' R 16' NH-NHR 15' , SH, CN, N3 and halogen; wherein R is selected from H and (C1-C8) alkyl, and R 15' and R 16' independently selected from H, (C1-C8) alkyl, (C1-C8) alkyl (C5-C 12 )aryl and -CHR AA’ CO2H, where R AA’ is a side chain selected from proteinogenic or non-proteinogenic amino acids;

[0036] Y' is selected from CH, CH2, CHCH3, C(CH3)2 and CCH3;

[0037] n is an integer selected from 1 to 3;

[0038] ---Indicates the connection point;

[0039] represents a single bond or a double bond according to Y'; and

[0040] Depends on R 1’ α or β anomer at the position of

[0041] R8 is selected from H, OR, NR 15 R 16 NH-NHR 15 , SH, CN, N3 and halogen; wherein R is selected from H and (C1-C8) alkyl, and R 15 and R 16 independently selected from H, (C1-C8) alkyl, (C1-C8) alkyl (C5-C 12 )aryl and -CHR AA CO2H, where R AA is a side chain selected from proteinogenic or non-proteinogenic amino acids;

[0042] Y is selected from CH, CH2, CHCH3, C(CH3)2 and CCH3;

[0043] represents a single bond or a double bond according to Y; and

[0044] represents the α or β anomer depending on the position of R1,

[0045] It is used to treat sickle cell disease.

[0046] According to one embodiment, X represents oxygen.

[0047] According to one embodiment, R1 and R6 are identical and represent hydrogen.

[0048] According to one embodiment, R3 and R4 are identical and represent hydrogen.

[0049] According to one embodiment, R2 and R5 are identical and represent OH.

[0050] According to one embodiment, Y is selected from CH and CH2.

[0051] According to one embodiment, wherein R7 is selected from P(O)R9R 10 or Among them R9 and R 10 As above, and wherein:

[0052] X' is oxygen;

[0053] R 1' and R 6' Each represents hydrogen;

[0054] R 2' 、R 3' 、R 4' and R 5' are independently selected from hydrogen and OH;

[0055] R 8’ It is NH2;

[0056] Y' is selected from CH and CH2;

[0057] n is equal to 2;

[0058] ---Indicates the connection point;

[0059] represents a single bond or a double bond, depending on Y'; and

[0060] Depends on R 1’ The α or β anomer isomer of the position.

[0061] According to one embodiment, R8 is NH2.

[0062] According to one embodiment, the compounds according to the invention are chosen from:

[0063]

[0064]

[0065] and pharmaceutically acceptable salts and solvates thereof.

[0066] According to one embodiment, the compound according to the invention is chosen from compounds 001, 002, 009, 010 and 011.

[0067] The present invention further relates to a pharmaceutical composition for treating sickle cell disease, comprising at least one compound of formula (I) as defined above and at least one pharmaceutically acceptable carrier.

[0068] According to one embodiment, the pharmaceutical composition for use according to the present invention, in addition to at least one compound of formula (I) as defined above, further comprises at least one other active ingredient selected from, but not limited to, natural extracts; opioid or non-opioid analgesics; NSAIDS; antidepressants; anticonvulsants; antibiotics; antioxidants, such as CoQ10 and PQQ (pyrroloquinoline quinone); hydroxyurea, L-glutamine, kynurenine, kynurenic acid, tryptophan, voxelator and crizumab.

[0069] definition

[0070] The following definitions and explanations apply to terms used throughout this application, including the specification and claims.

[0071] When describing the compounds of the present invention, unless otherwise indicated, the terms used are to be interpreted in accordance with the following definitions.

[0072] Unless otherwise indicated, substituents not specifically defined herein are named by naming the adjacent functionality toward the point of attachment followed by the terminal portion of the functionality. For example, the substituent "arylalkyl" refers to the group -(aryl)-(alkyl).

[0073] In the present invention, the following terms have the following meanings:

[0074] The term "alkyl" by itself or as part of another substituent refers to a group of the formula C n H 2n+1The alkyl radical of the present invention is alkyl free radical, wherein n is a number greater than or equal to 1. Usually, the alkyl group of the present invention comprises 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 2 carbon atoms. The alkyl group can be straight chain or branched. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and isomers thereof (for example, normal-pentyl, isopentyl), hexyl and isomers thereof (for example, normal-hexyl, isohexyl), heptyl and isomers thereof (for example, normal-heptyl, isoheptyl), octyl and isomers thereof (for example, normal-octyl, isooctyl), nonyl and isomers thereof (for example, normal-nonyl, different nonyl), decyl and isomers thereof (for example, normal-decyl, different decyl), undecyl and isomers thereof, dodecyl and isomers thereof. Preferably, the alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Saturated branched alkyl includes but is not limited to isopropyl, sec-butyl, isobutyl, tert-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-di ... ,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.

[0075] Cx-Cy alkyl refers to an alkyl group containing x to y carbon atoms.

[0076] When the suffix "ene" ("alkylene") is used in conjunction with an alkyl group, this means that the alkyl group, as defined herein, has two single bonds as points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene.

[0077] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon group, which may be linear 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, and more preferably 2 to 6 carbon atoms. Examples of alkenyl groups include vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and other similar groups.

[0078] As used herein, the term "alkynyl" refers to a class of monovalent unsaturated hydrocarbon groups in which the unsaturation is derived from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as the alkenyl groups described above. Non-limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and isomers thereof, 2-hexynyl and isomers thereof, and the like.

[0079] The term "alkoxy" as used herein refers to any group -O-alkyl, wherein alkyl is as defined above. Suitable alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy and n-pentoxy.

[0080] As used herein, the term "amino acid" refers to an α-aminated carboxylic acid, ie, a molecule comprising a carboxylic acid functional group and an amine functional group α to the carboxylic acid group, such as a proteinogenic amino acid or a non-proteinogenic amino acid.

[0081] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon radical having a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently linked, typically containing 5 to 12 atoms; preferably 6 to 10, at least one of which is aromatic. The aromatic ring may optionally contain one to two additional rings (cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems listed herein. Non-limiting examples of aryl groups include phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalene-1- or -2-yl, 4-, 5-, 6-, or 7-indenyl, 1-, 2-, 3-, 4-, or 5-acenaphthyl, 3-, 4-, or 5-acenaphthyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7-, or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.

[0082] As used herein, the term "cycloalkyl" is a cyclic alkyl, alkenyl, or alkynyl group, i.e., a monovalent saturated or unsaturated hydrocarbon group having one or two ring structures. Cycloalkyl groups include monocyclic or bicyclic hydrocarbon groups. Cycloalkyl groups may contain three or more carbon atoms in the ring, and typically, according to the present invention, may contain 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

[0083] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo. Preferred halogen groups are fluoro and chloro.

[0084] The term "haloalkyl," alone or as part of another group, refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. Cx-Cy haloalkyl refers to an alkyl group containing from x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

[0085] The term "heteroalkyl" refers to an alkyl group as defined above in which one or more carbon atoms are replaced by heteroatoms selected from oxygen, nitrogen and sulphur atoms. In a heteroalkyl group, heteroatoms are only bound to carbon atoms along the alkyl chain, i.e., each heteroatom is separated from any other heteroatoms by at least one carbon atom. However, nitrogen and sulphur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. A heteroalkyl group is bonded only to another group or molecule via carbon atoms, i.e., the bonding atom is not selected from the heteroatoms contained in the heteroalkyl group.

[0086] When at least one carbon atom in an aryl group is replaced with a heteroatom, the resulting ring is referred to herein as a heteroaryl ring.

[0087] As used herein, the term "heteroaryl", whether alone or as part of another group, refers to an aromatic ring of 5 to 12 carbon atoms or a ring system comprising one or two fused or covalently bonded rings, typically comprising 5 or 6 atoms; at least one of which is aromatic, wherein one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl groups include furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triaziny l), imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furyl, thieno[3,2-b]thienyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indole oxazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2- a] pyridyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

[0088] When at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resulting ring is referred to herein as a "heterocycloalkyl" or "heterocyclyl."

[0089] As used herein, the terms "heterocyclyl", "heterocycloalkyl" or "heterocycle", whether alone or as part of another group, refer to non-aromatic, fully saturated or partially unsaturated (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or containing 3 to 10 ring atoms in total) cyclic groups having at least one heteroatom in at least one ring containing carbon atoms. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Any carbon atom of the heterocyclic group may be substituted by oxo (e.g., piperidone, pyrrolidone). Where valence permits, the heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system. The rings of polycyclic heterocycles may be fused, bridged and / or connected by one or more spiro atoms. Non-limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxolanyl, 1-dihydrothiophene, N-formylpiperazinyl, and morpholin-4-yl.

[0090] The term "hydroxyalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by an -OH moiety.

[0091] The term "thioalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a -SH moiety.

[0092] 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 a living organism. Non-limiting examples of non-protein amino acids are ornithine, citrulline, argininosuccinic acid, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, δ-aminolevulinic acid, β-alanine, cystathionine, γ-aminobutyric acid, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, α-aminobutyric acid, 2-aminoisobutyric acid, D-leucine, D-valine, D-alanine, or D-glutamic acid.

[0093] As used herein, the term "proteinogenic amino acid" refers to an amino acid that is incorporated into proteins during the translation of messenger RNA by ribosomes in an organism, i.e., alanine (ALA), arginine (ARG), asparagine (ASN), aspartic acid (ASP), cysteine ​​(CYS), glutamic acid (glutamate) (GLU), glutamine (GLN), glycine (GLY), histidine (HIS), isoleucine (ILE), leucine (LEU), lysine (LYS), methionine (MET), phenylalanine (PHE), proline (PRO), pyrrolysine (PYL), selenocysteine ​​(SEL), serine (SER), threonine (THR), tryptophan (TRP), tyrosine (TYR) or valine (VAL).

[0094] As used herein, the term "prodrug" means a pharmacologically acceptable derivative of a compound of formula (I), for example, an ester of the active drug whose biotransformation product is in vivo. Prodrugs are characterized by increased bioavailability and are easily metabolized into active compounds in vivo. Suitable prodrugs for the purposes of the present invention include phosphoramidates, HepDirect, (S)-acyl-2-thioethyl (SATE), carboxylates, particularly alkyl esters, aryl esters, acyloxyalkyl esters, and dioxole carboxylates; ascorbic acid esters.

[0095] The term "substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced by any desired group that is substantially stable under the reaction conditions in its unprotected form or when protected by a protecting group. Examples of preferred substituents include, but are not limited to, halogen (chlorine, iodine, bromine or fluorine); alkyl; alkenyl; alkynyl, as described above; hydroxyl; alkoxy; nitro; thiol; thioether; imine; cyano; amine; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); monocyclic or fused or non-fused polycyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or monocyclic or fused or non-fused polycyclic heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), monocyclic or Fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl); amino (primary, secondary or tertiary); CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such moieties may also be optionally substituted with fused ring structures or bridges, such as -OCH2O-. These substituents may also be optionally further substituted with substituents selected from such groups. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, 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 、-SR 19 、-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)Rr20 、-OS(O)R r20 、S(O) r NR 17 R 18 , -O, -S, and -NR 19 , where r is 1 or 2; R 17 and R 18 , is independently at each occurrence 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 it is attached, is optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R 19 and R 20 , is independently, at each occurrence, 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.

[0096] Asymmetric carbon bonds are represented by solid triangles in this article. Point Triangle or jagged lines express.

[0097] The term "active ingredient" refers to a molecule or substance whose administration to a subject slows or halts the progression, worsening, or deterioration of one or more symptoms of a disease or condition; alleviates the symptoms of a disease or condition; or cures the disease or condition. According to one embodiment, the therapeutic ingredient is a small molecule, either natural or synthetic. According to another embodiment, the therapeutic ingredient is a biomolecule, such as an oligonucleotide, siRNA, miRNA, DNA fragment, aptamer, antibody, or the like.

[0098] The term "administering" or variations thereof (eg, "to administer") means providing an active agent or ingredient, alone or as part of a pharmaceutically acceptable composition, to a patient for the condition, symptom, or disease to be treated.

[0099] 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 invention, "drug" encompasses both medical drugs ("pharmaceutical drugs" or "active ingredients") and non-medical drugs, such as recreational drugs (e.g., psychoactive drugs).

[0100] "Pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition are compatible with each other and not deleterious to the patient.

[0101] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," or "pharmaceutical vehicle" refer to an inert medium or vehicle used as a solvent or diluent in which the active pharmaceutical ingredient is formulated and / or administered and which does not produce adverse, allergic, or other reactions in animals, preferably humans, when administered. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption blockers, and other similar ingredients. For human administration, the formulation must meet the sterility, general safety, and purity standards set by regulatory agencies such as the FDA or EMA. For the purposes of this invention, "pharmaceutically acceptable excipient" includes all pharmaceutically acceptable excipients, as well as all pharmaceutically acceptable carriers, diluents, and / or adjuvants.

[0102] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamates, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthoate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, sucrose salt, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts.

[0103] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lysine, magnesium, meglumine, morpholine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0104] Hemisalts of acids and bases can also be formed, such as hemisulphate and hemicalcium salts.

[0105] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods:

[0106] (i) by reacting a compound of formula (I) with a desired acid;

[0107] (ii) by reacting a compound of formula (I) with a desired base;

[0108] (iii) by removing acid- or base-labile protecting groups from suitable precursors of the compound of formula (I) or by ring-opening a suitable cyclic precursor (e.g. using the desired lactone or lactam); and / or

[0109] (iv) converting one salt of a compound of formula (I) into another salt by reaction with a suitable acid or passing through a suitable ion exchange column.

[0110] All of these reactions are typically performed in solution. The salt can precipitate from the solution and be collected by filtration, or it can be recovered by evaporating the solvent. The degree of ionization in the salt can vary from completely ionized to nearly non-ionized.

[0111] Although pharmaceutically acceptable salts are generally preferred with respect to the salts of the compounds of the present invention, it should be noted that the present invention in its broadest sense also includes non-pharmaceutically acceptable salts, which may be used, for example, for the isolation and / or purification of the compounds of the present invention. For example, salts formed with optically active acids or bases may be used to form diastereomeric salts that may facilitate the separation of optically active isomers of the compounds of formula (I).

[0112] The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and containing a stoichiometric or substoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" refers to a solvate.

[0113] The term "human" refers to subjects of both sexes and at any stage of development (ie, newborn, infant, juvenile, adolescent, adult).

[0114] The term "subject" refers to a mammal, preferably a human. According to the present invention, a subject is a mammal, preferably a human, suffering from a red blood cell disorder and / or one or more complications associated with a red blood cell disorder, particularly sickle cell disease and / or complications associated with sickle cell disease. In one embodiment, the subject is a "patient," i.e., a mammal, preferably a human, who is awaiting or currently receiving medical care, or who was / is currently the subject of / will be the subject of a medical procedure, or is being monitored for a red blood cell disorder and / or one or more complications associated with a red blood cell disorder, particularly sickle cell disease and / or one or more complications associated with sickle cell disease.

[0115] As used herein, the term "therapeutically effective amount" (or more simply "effective amount") refers to an amount of an active agent or ingredient intended to prevent, reduce, alleviate, or slow down (decrease) one or more symptoms of red blood cell disorders and / or complications associated with red blood cell disorders, particularly sickle cell disease and / or complications associated with sickle cell disease, without causing significant negative or adverse side effects to the subject in need of treatment.

[0116] As used herein, the terms "treat," "treatment," or "therapy" refer to therapeutic therapy, prophylactic (or preventative) therapy, or both therapeutic therapy and prophylactic (or preventative) therapy, wherein the objective is to prevent, reduce, alleviate, and / or slow down (reduce) one or more symptoms of a red blood cell disorder and / or complications associated with a red blood cell disorder, particularly sickle cell disease and / or complications associated with sickle cell disease, in a subject in need thereof. In one embodiment, "treatment" or "therapy" refers to therapeutic therapy. In another embodiment, "treatment" or "therapy" refers to prophylactic or preventative therapy. In another embodiment, "treatment" or "therapy" refers to both prophylactic (or preventative) therapy and therapeutic therapy.

[0117] The term "complications associated with sickle cell disease" includes, but is not limited to, acute chest syndrome, acute pain crises, chronic pain, delayed growth and puberty, avascular necrosis, eye problems such as retinopathy, gallstones, heart problems including coronary artery disease and pulmonary hypertension, infections such as meningitis, osteomyelitis, and sepsis; joint problems, kidney problems, leg ulcers, liver complications, pregnancy complications, priapism, severe anemia, stroke, kidney necrosis, or asymptomatic brain damage. Complications associated with sickle cell disease typically include worsening of the disease or the development of new signs, symptoms, or pathological changes that may spread throughout the body and affect other organs and may result in the development of new conditions in addition to existing conditions. Complications may also occur as a result of various treatments. DETAILED DESCRIPTION

[0118] Therefore, the present invention relates to the use of nicotinamide mononucleotide derivatives in treating red blood cell disorders. In particular, the present invention relates to nicotinamide mononucleotide derivatives for treating sickle cell disease.

[0119] Nicotinamide mononucleotide derivatives

[0120] In one embodiment, the nicotinamide mononucleotide derivative used in the present invention is a compound of formula (I)

[0121]

[0122] or a pharmaceutically acceptable salt or solvate thereof;

[0123] in:

[0124] X is selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0125] R1 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;

[0126] R2, R3, R4 and R5 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; where R AA is a side chain selected from proteinogenic amino acids;

[0127] R6 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;

[0128] R7 is selected from H, P(O)R9R 10 、P(S)R9R 10 and in

[0129] R9 and R 10 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 NHCHR α R α’ C(O)R 12 ;in:

[0130] -R 11 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 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 )alkyl-(C5-C 12 )aryl; wherein m is an integer selected from 1 to 8; and -P(O)(OH)OP(O)(OH)2; and an internal or external counterion;

[0131] -R 12 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 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;

[0132] -R 13 and R 14 independently selected from H, (C1-C8)alkyl and (C1-C8)alkyl-(C5-C 12 ) aryl; and

[0133] -R α and R α’ are independently selected from hydrogen, (C 1- C 10 )alkyl, (C 2- C 10 )alkenyl, (C2-C 10 ) alkynyl, (C 3- 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 proteinogenic amino acids or non-proteinogenic amino acids; wherein the aryl group is optionally selected from hydroxyl, (C 1- C 10 )alkyl, (C 1- C6) substituted with alkoxy, halogen, nitro and cyano groups; or

[0134] R9 and R 10 Together with the phosphorus atom to which they are attached, they form a 6-membered ring, wherein -R9-R 10 - represents -O-CH2-CH2-CHR-O-; wherein R is selected from H, (C5-C6)aryl and (C5-C6)heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with one or two groups selected from halogen, trifluoromethyl, (C1-C6)alkyl, (C1-C6)alkoxy and cyano;

[0135] X' is selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0136] 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;

[0137] R2' 、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; where R AA is a side chain selected from proteinogenic amino acids;

[0138] R6′ 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;

[0139] R 8' Selected from H, OR, NR 15' R 16' NH-NHR 15' , SH, CN, N3 and halogen; wherein R is selected from H and (C1-C8) alkyl, and R 15' and R 16' independently selected from H, (C1-C8) alkyl, (C1-C8) alkyl (C5-C 12 )aryl and -CHR AA’ CO2H, where R AA’ is a side chain selected from proteinogenic or non-proteinogenic amino acids;

[0140] Y' is selected from CH, CH2, CHCH3, C(CH3)2 and CCH3;

[0141] n is an integer selected from 1 to 3;

[0142] ---Indicates the connection point;

[0143] represents a single bond or a double bond according to Y'; and

[0144] Depends on R 1’ α or β anomer at the position of

[0145] R8 is selected from H, OR, NR 15 R 16 NH-NHR 15 , SH, CN, N3 and halogen; wherein R is selected from H and (C1-C8) alkyl, and R 15 and R 16 independently selected from H, (C1-C8) alkyl, (C1-C8) alkyl (C5-C 12 )aryl and -CHR AA CO2H, where R AA is a side chain selected from proteinogenic or non-proteinogenic amino acids;

[0146] Y is selected from CH, CH2, CHCH3, C(CH3)2 and CCH3;

[0147] represents a single bond or a double bond according to Y; and

[0148] represents the α or β anomer depending on the position of R1.

[0149] In one embodiment, in formula (I):

[0150] X is selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0151] R1 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;

[0152] R2, R3, R4 and R5 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; where R AA is a side chain selected from proteinogenic amino acids;

[0153] R6 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;

[0154] R7 is selected from H, P(O)R9R 10 、P(S)R9R 10 and in:

[0155] R9 and R 10 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 NHCHR α R α’ C(O)R 12 ;in:

[0156] -R 11 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 10 )haloalkyl, -(CH2) m C(O)(C1-C 15 )alkyl, -(CH2) m OC(O)(C1-C15 )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 an internal or external counterion;

[0157] -R 12 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 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;

[0158] -R 13 and R 14 independently selected from H, (C1-C8)alkyl and (C1-C8)alkyl-(C5-C 12 ) aryl;

[0159] -R α and R α’ are independently selected from hydrogen, (C 1- C 10 )alkyl, (C 2- C 10 )alkenyl, (C2-C 10 ) alkynyl, (C 3- 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 proteinogenic amino acids or non-proteinogenic amino acids; wherein the aryl group is optionally selected from hydroxyl, (C 1- C 10 )alkyl, (C 1- C6) substituted with alkoxy, halogen, nitro and cyano groups; or

[0160] R9 and R 10 Together with the phosphorus atom to which they are attached, they form a 6-membered ring, wherein -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;

[0161] X' is selected from O, CH2, S, Se, CHF, CF2 and C=CH2;

[0162] 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;

[0163] 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; where RAA is a side chain selected from proteinogenic amino acids;

[0164] 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;

[0165] R 8' Selected from H, OR, NHR 15' NR 15' R 16' NH-NHR 15' , SH, CN, N3 and halogen; among which R 15' and R 16' independently selected from H, (C1-C8)alkyl and (C1-C8)alkylaryl;

[0166] Y' is selected from CH, CH2, C(CH3)2 and CCH3;

[0167] n is an integer selected from 1 to 3;

[0168] represents a single bond or a double bond according to Y'; and

[0169] Depends on R 1’ α or β anomer at the position of

[0170] R8 is selected from H, OR, NHR 15 NR 15 R 16 NH-NHR 15 , SH, CN, N3 and halogen; among which R 15 and R 16 independently selected from H, (C1-C8)alkyl and (C1-C8)alkylaryl;

[0171] Y is selected from CH, CH2, C(CH3)2 and CCH3;

[0172] represents a single bond or a double bond according to Y; and

[0173] represents the α or β anomer depending on the position of R1.

[0174] The nicotinamide mononucleotide derivatives of the present invention may contain one or more charged atoms. Specifically, when present, the phosphate group may carry one or more charges, preferably one or more negative charges. Additionally, the nitrogen atom of the pyridinium portion of the nicotinamide group may carry a positive charge upon quaternization. The presence of one or more charged atoms in the nicotinamide mononucleotide derivatives of the present invention depends on conditions, particularly pH, as will be appreciated by those skilled in the art.

[0175] According to one embodiment, X is selected from O, CH2 and S. In some embodiments, X is oxygen.

[0176] According to one embodiment, R1 is selected from hydrogen and OH. According to one embodiment, R1 is selected from hydrogen. In one embodiment, R1 is selected from OH.

[0177] According to one embodiment, R2, R3, R4 and R5 are independently selected from 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 hydrogen, hydroxyl and OR; wherein R is as described above. In a more preferred embodiment, R2, R3, R4 and R5 are independently selected from hydrogen and OH.

[0178] According to one embodiment, R2 and R3 are identical. In one embodiment, R2 and R3 are identical and represent OH. In one embodiment, R2 and R3 are identical and represent hydrogen.

[0179] According to one embodiment, R2 and R3 are different. In a preferred embodiment, R2 is hydrogen and R3 is OH. In a more preferred embodiment, R2 is OH and R3 is hydrogen.

[0180] According to one embodiment, R4 and R5 are identical. In one embodiment, R4 and R5 are identical and represent OH. In one embodiment, R4 and R5 are identical and represent hydrogen.

[0181] According to one embodiment, R4 and R5 are different. In a preferred embodiment, R4 is OH and R5 is hydrogen. In a more preferred embodiment, R4 is hydrogen and R5 is OH.

[0182] According to one embodiment, R3 and R4 are different. In one embodiment, R3 is OH and R4 is hydrogen. In one embodiment, R3 is hydrogen and R4 is OH.

[0183] According to one embodiment, R3 and R4 are identical. In a preferred embodiment, R3 and R4 are identical and represent OH. In a more preferred embodiment, R3 and R4 are identical and represent hydrogen.

[0184] According to one embodiment, R2 and R5 are different. In one embodiment, R2 is hydrogen and R5 is OH. In one embodiment, R2 is OH and R5 is hydrogen.

[0185] According to one embodiment, R2 and R5 are identical. In a preferred embodiment, R2 and R5 are identical and represent hydrogen. In a more preferred embodiment, R2 and R5 are identical and represent OH.

[0186] According to one embodiment, R6 is selected from hydrogen and OH. In one embodiment, R6 is selected from OH. In a preferred embodiment, R6 is hydrogen.

[0187] According to one embodiment, R1 and R6 are each independently selected from hydrogen and OH. According to one embodiment, R1 and R6 are both hydrogen atoms.

[0188] According to one embodiment, R7 is selected from hydrogen, P(O)R9R 10 and

[0189] According to one embodiment, R7 is selected from P(O)R9R 10 and

[0190] According to one embodiment, R7 is hydrogen. In another embodiment, R7 is not a hydrogen atom.

[0191] According to one embodiment, R7 is P(O)R9R 10 ; Among them R9 and R 10 As described above. In a preferred embodiment, R7 is P(O)(OH)2.

[0192] According to another embodiment, R7 is where R 1' 、R 2' 、R 3' 、R 4' 、R 5' 、R 6' 、R 8' 、R9、X'、Y'、n、---、 and As described above for the compound of formula (I).

[0193] According to a preferred embodiment, R7 is in:

[0194] X' is selected from O, CH2 and S, preferably X' is O;

[0195] R 1' Selected from hydrogen and OH, preferably R1' is hydrogen;

[0196] R 2’ 、R 3' 、R 4' and R 5' independently selected from hydrogen, halogen, hydroxyl, (C1-C 12 ) alkyl and OR; wherein R is as described above, preferably R 2’ 、R 3' 、R 4' and R 5' Independently selected from hydrogen, hydroxyl and OR; wherein R is as described above, more preferably R 2' 、R 3' 、R 4' and R 5' independently selected from hydrogen and OH;

[0197] R 6' Selected from hydrogen or OH, preferably R 6' is hydrogen;

[0198] R 8' Selected from H, OR and NR 15' R 16' ; where R 15' and R 16' As mentioned above, R 8' It is NHR 15' ; where R 15' As mentioned above, more preferably R 8' It is NH2;

[0199] Y' is selected from CH and CH2;

[0200] n is an integer selected from 1 to 3;

[0201] ---Indicates the connection point;

[0202] represents a single bond or a double bond, depending on Y'; and

[0203] Depends on R 1' The α or β anomer isomer of the position.

[0204] In one embodiment, in formula (I):

[0205] R7 is

[0206] X and X' are independently selected from O, CH2 and S, preferably X and X' are O;

[0207] R1 and R 1' are independently selected from hydrogen and OH, preferably R1 and R 1'is hydrogen;

[0208] R2, R3, R4, R5, R 2’ 、R 3' 、R 4' and R 5' independently selected from hydrogen, halogen, hydroxyl, (C1-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' 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' independently selected from hydrogen and OH;

[0209] R6 and R 6' are independently selected from hydrogen and OH, preferably R6 and R 6' is hydrogen;

[0210] R8 and R 8' independently selected from H, OR and NR 15' R 16' ; where R 15' and R 16' As mentioned above, R8 and R 8' It is NHR 15' ; where R 15' As mentioned above, more preferably R8 and R 8' It is NH2;

[0211] Y and Y' are independently selected from CH and CH2;

[0212] n is an integer selected from 1 to 3;

[0213] ---Indicates the connection point;

[0214] represents a single bond or a double bond depending on Y'; and

[0215] It depends on R1 and R 1’ The α or β anomer of the compound isomer isomer.

[0216] According to one embodiment, n is 1. According to one embodiment, n is 2. According to one embodiment, n is 3.

[0217] According to one embodiment, R8 is selected from H, OR and NR 15 R 16 ; where R 15and R 16 As described above. In a preferred embodiment, R8 is NHR 15 ; where R 15 As described above. In one embodiment, R8 is selected from NH2.

[0218] According to one embodiment, Y is CH or CH 2 . In one embodiment, Y is CH . In one embodiment, Y is CH 2 .

[0219] According to some embodiments, the nicotinamide mononucleotide derivative used in the present invention has the general formula (II):

[0220]

[0221] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, X, Y, and As described above for the compound of formula (I).

[0222] According to some embodiments, preferred compounds of general formula (II) are those of formula (II-1):

[0223]

[0224] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, Y, and As described above for the compound of formula (I).

[0225] According to some embodiments, preferred compounds of general formula (II) are those of formula (II-2):

[0226]

[0227] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R3, R4, R5, R6, R8, Y, and As described above for the compound of formula (I).

[0228] According to some embodiments, preferred compounds of general formula (II) are those of formula (II-3):

[0229]

[0230] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R5, R6, R8, Y, and As described above for the compound of formula (I).

[0231] According to some embodiments, preferred compounds of general formula (II) are those of formula (II-4):

[0232]

[0233] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R8, Y, and As described above for the compound of formula (I).

[0234] According to some embodiments, preferred compounds of general formula (II) are those of formula (II-5):

[0235]

[0236] or a pharmaceutically acceptable salt or solvate thereof; wherein R8, Y, and As described above for the compound of formula (I).

[0237] According to some embodiments, preferred compounds of formula (II) are those of formula (II-6):

[0238]

[0239] or a pharmaceutically acceptable salt or solvate thereof; wherein Y, and As described above for the compound of formula (I).

[0240] According to some embodiments, preferred compounds of formula (II) are those of formula (II-7):

[0241]

[0242] or a pharmaceutically acceptable salt or solvate thereof; wherein As described above for the compound of formula (I).

[0243] According to some embodiments, the present invention relates to compounds of formula (II-8):

[0244]

[0245] or a pharmaceutically acceptable salt or solvate thereof; wherein As described above for the compound of formula (I).

[0246] According to a preferred embodiment, the nicotinamide mononucleotide derivative used in the present invention has the general formula (III):

[0247]

[0248] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, X, Y, and As described above for the compound of formula (I).

[0249] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-1):

[0250]

[0251] or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R8, Y, and As described above for the compound of formula (I).

[0252] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-2):

[0253]

[0254] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R3, R4, R5, R6, R8, Y, and As described above for the compound of formula (I).

[0255] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-3):

[0256]

[0257] or a pharmaceutically acceptable salt or solvate thereof; wherein R2, R5, R6, R8, Y, and As described above for the compound of formula (I).

[0258] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-4):

[0259]

[0260] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R8, Y, and As described above for the compound of formula (I).

[0261] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-5):

[0262]

[0263] or a pharmaceutically acceptable salt or solvate thereof; wherein R8, Y, and As described above is the compound of formula (I).

[0264] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-6):

[0265]

[0266] or a pharmaceutically acceptable salt or solvate thereof; wherein Y, and As described above for the compound of formula (I).

[0267] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-7):

[0268]

[0269] or a pharmaceutically acceptable salt or solvate thereof; wherein As described above for the compound of formula (I).

[0270] According to one embodiment, preferred compounds of general formula (III) are those of formula (III-8):

[0271]

[0272] or a pharmaceutically acceptable salt or solvate thereof; wherein As described above for the compound of formula (I).

[0273] According to another preferred embodiment, the nicotinamide mononucleotide derivative used in the present invention has the general formula (IV):

[0274]

[0275] 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 compound of formula (I).

[0276] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-1):

[0277]

[0278] 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 compound of formula (I).

[0279] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-2):

[0280]

[0281] or a pharmaceutically acceptable salt or solvate thereof; wherein 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 compound of formula (I).

[0282] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-3):

[0283]

[0284] 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 compound of formula (I).

[0285] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-4):

[0286]

[0287] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R6’ , R8, R 8’ 、Y、Y'、 and As described above for the compound of formula (I).

[0288] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-5):

[0289]

[0290] or a pharmaceutically acceptable salt or solvate thereof; wherein R8, R 8' 、Y、Y'、 and As described above for the compound of formula (I).

[0291] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-6):

[0292]

[0293] or a pharmaceutically acceptable salt or solvate thereof; wherein Y, Y', and As described above for the compound of formula (I).

[0294] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-7):

[0295]

[0296] or a pharmaceutically acceptable salt or solvate thereof; wherein As described above for the compound of formula (I).

[0297] According to one embodiment, preferred compounds of general formula (IV) are those of formula (IV-8):

[0298]

[0299] or a pharmaceutically acceptable salt or solvate thereof; wherein As described above for the compound of formula (I), according to one embodiment, the nicotinamide mononucleotide derivative used in the present invention is selected from compounds 001 to 014 in Table 1 below, or pharmaceutically acceptable salts or solvates thereof:

[0300] [Table 1]

[0301]

[0302]

[0303]

[0304] According to one embodiment, the preferred nicotinamide mononucleotide derivative is Compounds 001 to 014 or a pharmaceutically acceptable salt or solvate thereof.

[0305] According to one embodiment, preferred nicotinamide mononucleotide derivatives are compounds 001, 002, 003, 004, 009, 010, 011, 012, 013 and 014 or pharmaceutically acceptable salts or solvates thereof.

[0306] According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 001, 002, 009, 010 and 011 or pharmaceutically acceptable salts or solvates thereof.

[0307] According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 001 and 002 or pharmaceutically acceptable salts or solvates thereof.

[0308] According to another embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 009, 010 and 011 or pharmaceutically acceptable salts or solvates thereof.

[0309] According to one embodiment, even more preferred nicotinamide mononucleotide derivatives are compounds 002, 010 and 011 or pharmaceutically acceptable salts or solvates thereof.

[0310] All references to compounds of formula (I) and subformulae thereof include references to their salts, solvates, multicomponent complexes and liquid crystals. All references to compounds of formula (I) and subformulae thereof include references to their polymorphs and crystal habits.

[0311] All references to compounds of formula (I) and subformulae thereof include reference to pharmaceutically acceptable prodrugs thereof.

[0312] The nicotinamide mononucleotide derivatives used in the present invention may be in the form of a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises the nicotinamide mononucleotide derivative as defined above and at least one pharmaceutically acceptable carrier.

[0313] According to one embodiment, the pharmaceutical composition comprises, in addition to the nicotinamide mononucleotide derivative defined above, at least one other active ingredient, selected from, but not limited to, natural extracts; opioid or non-opioid analgesics; NSAIDS; antidepressants; anticonvulsants; antibiotics; antioxidants, such as CoQ10 and PQQ (pyrroloquinoline quinone); hydroxyurea, L-glutamine, kynurenine, kynurenic acid, tryptophan, voxelator, and crizumab.

[0314] Non-limiting examples of natural extracts are glycoprotein extracts; terpenoid extracts containing pentacyclic triterpenes (e.g., betaine), pentacyclic triterpenoid metabolites (e.g., betainic acid), triterpenoids, roselle lactones, sesquiterpenes, ergotins; flavonoid extracts containing flavones, flavonols, flavanones, flavanol bioflavonoids, or isoflavones; polysaccharide extracts containing PSP, PSK, CVG, HPB-3, H6PC20; or polyaromatic molecules such as hericerins and hericenones; from species such as Trametes versicolor, Hericium erinaceus, Grifola frondasa, milk thistle, artichoke, turmeric, dandelion, Coptis chinensis, sugar beet, and ginger.

[0315] method

[0316] According to another aspect, the present invention relates to a process for the preparation of a compound of formula (I) as described herein above.

[0317] Specifically, compounds of formula (I) can be prepared from substrates AE as described below. It will be understood by those skilled in the art that these reaction schemes are by no means limiting and that variations may be made without departing from the spirit and scope of the present invention.

[0318] According to one embodiment, the process involves, in a first step, monophosphorylating a compound of formula (A) in the presence of phosphorus oxychloride and a trialkyl phosphate to produce a dichlorophosphate of formula (B):

[0319]

[0320] Among them, X, R1, R2, R3, R4, R5, R6, R8, Y, and As described above.

[0321] In the second step, the dichlorophosphate of formula (B) is hydrolyzed to produce the phosphate of formula (C),

[0322]

[0323] Among them, X, R1, R2, R3, R4, R5, R6, R7, R8, Y, and As described above.

[0324] In an alternative embodiment, when in formula (I) R7 is When the phosphate compound of formula (C) obtained in the second step is reacted with the dichlorophosphate compound of formula (B') obtained as described in the first step:

[0325]

[0326] where R 1' 、R 2' 、R 3' 、R 4' 、R 5' 、R 6' 、R 8' , X', Y', and As described above; a compound of formula (I) as described above is obtained.

[0327] Subsequent hydrolysis affords the compound of formula (I).

[0328] According to one embodiment, the compound of formula (A) is synthesized using various methods known to those skilled in the art.

[0329] According to one embodiment, the compound of formula (A) wherein Y is CH, referred to as the compound of formula (Aa), is synthesized by reacting a pentose of formula (D) with a nitrogen derivative of formula (E) to obtain a compound of formula (A-1), which is then selectively deprotected to obtain a compound of formula (Aa).

[0330]

[0331] Among them, X, R1, R2, R3, R4, R5, R6, R7, R8, Y and As described above and R is a protecting group.

[0332] 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. 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, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl, and [2-(trimethylsilyl)ethoxy]methyl.

[0333] According to one embodiment, any hydroxyl groups attached to the pentose are protected by suitable protecting groups known to those skilled in the art.

[0334] The selection and exchange of protecting groups is within the purview of those skilled in the art. Protecting groups can also be removed by methods well known to those skilled in the art, such as with an acid (eg, an inorganic or organic acid), a base, or a fluorine source.

[0335] According to a preferred embodiment, the nitrogen nicotinamide of formula (E) is coupled with the pentose of formula (D) by reaction in the presence of a Lewis acid to produce a compound of formula (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF3.OEt2, TiCl4 and FeCl3.

[0336] According to one embodiment, the method of the present invention further comprises reducing the compound of formula (Aa) by various methods well known to those skilled in the art to produce a compound of formula (Ab), wherein Y is CH2, X, R1, R2, R3, R4, R5, R6, R8, and As defined above.

[0337] According to a specific embodiment, the present invention relates to a method for preparing compounds 001, 003, 005, 007 and 009.

[0338] In the first step, nicotinamide of formula (Ei) is coupled with ribose tetraacetic acid of formula (Di) by reaction in the presence of a Lewis acid to give a compound of formula (A-1-i)):

[0339]

[0340] In the second step, ammonia treatment of the compound of formula (A-1-i) is performed to produce compound 005:

[0341]

[0342] In the third step, compound 005 is monophosphorylated in the presence of phosphorus oxychloride and a trialkyl phosphate to produce a dichlorophosphate of formula (Bi):

[0343]

[0344] In the fourth step, the dichlorophosphate of formula (Bi) is hydrolyzed to produce compound 001:

[0345]

[0346] Alternatively, in the fifth step, the phosphate compound 001 obtained in the fourth step is reacted with the dichlorophosphate compound of formula (Bi) obtained in the third step to obtain compound 009.

[0347] According to one embodiment, a step of reducing compound 005 is performed to produce compound 007.

[0348] Then, as described in the fourth step, the compound of formula 007 is monophosphorylated and hydrolyzed to compound 003.

[0349] The above-described method for preparing 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 ribose tetraacetic acid of formula (D-ii):

[0350]

[0351] The above method for preparing dimer compound 009 can be easily applied to the synthesis of dimer compounds 010-014 by using the corresponding appropriate dichlorophosphate and phosphate intermediates.

[0352] Treatment of red blood cell disorders

[0353] As noted above, there is an unmet need for treatment of erythrocyte disorders, particularly sickle cell disease. Therefore, it is an object of the present invention to provide treatments for erythrocyte disorders, particularly sickle cell disease, in subjects in need thereof. Specifically, the present invention relates to nicotinamide mononucleotide derivatives as defined above for use in treating erythrocyte disorders, particularly sickle cell disease, in subjects in need thereof.

[0354] Red blood cell disorders

[0355] Thus, in one embodiment, the present invention relates to the treatment of red blood cell disorders. Non-limiting examples of red blood cell disorders include anemias, such as iron deficiency anemia, pernicious anemia, aplastic anemia, autoimmune hemolytic anemia; thalassemia; hemoglobin Sβ0 thalassemia; hemoglobin Sβ+ thalassemia; hemoglobin SC; hemoglobin SD; hemoglobin SE; hemoglobin SS; polycythemia vera and sickle cell disease.

[0356] According to a preferred embodiment, the blood disorder is a red blood cell disorder as described above.

[0357] According to a more preferred embodiment, the red blood cell disorder is sickle cell disease.

[0358] Thus, according to one embodiment, the compounds of the invention as described above are used for the treatment of red blood cell disorders as described above.

[0359] According to a preferred embodiment, the compounds of the present invention as described above are used for the treatment of sickle cell disease.

[0360] "Sickle cell disease" (SCD) or "sickle cell anemia" refers to a group of inherited red blood cell disorders defined by a missense point mutation in the beta globin sequence that results in a valine substitution for the glutamic acid residue at position 6. This mutated globin, termed sickle hemoglobin or hemoglobin S (HbS), aggregates and forms fibrillar deposits in the presence of low oxygen levels, resulting in polymerized hemoglobin and promoting red blood cell (RBC) sickling.

[0361] Over time, patients may experience various chronic complications associated with sickle cell disease. According to one embodiment, complications associated with sickle cell disease typically include worsening of the disease or the development of new signs, symptoms, or pathological changes that may spread throughout the body and affect other organs and may lead to the development of new diseases caused by sickle cell disease.

[0362] Non-limiting examples of complications associated with sickle cell disease include acute chest syndrome, acute pain crises, chronic pain, delayed growth and puberty, avascular necrosis, eye problems such as retinopathy, gallstones, heart problems including coronary artery disease and pulmonary hypertension, infections such as meningitis, osteomyelitis, and sepsis; joint problems, kidney problems, leg ulcers, liver complications, pregnancy complications, priapism, severe anemia, stroke, kidney necrosis, or silent brain damage.

[0363] Thus, according to one embodiment, the compounds of the invention as described above are used to treat complications associated with sickle cell disease as described above.

[0364] The present invention also relates to pharmaceutical compositions comprising at least one compound as described above for use in the present invention and at least one pharmaceutically acceptable carrier for use in the treatment of red blood cell disorders, in particular sickle cell disease.

[0365] Those who need treatment

[0366] Preferably, the subject in need of therapeutic and / or prophylactic treatment is a warm-blooded animal, more preferably a human. According to one embodiment, the subject is a male. According to one embodiment, the subject is a female.

[0367] According to one embodiment, the subject is an adult, i.e., over 18 years of age. According to one embodiment, the subject is a child, i.e., under 18 years of age. According to one embodiment, the subject is an infant, i.e., one who is one month old but under two years of age. According to one embodiment, the subject is a newborn, i.e., one who is from birth to less than one month old. According to another preferred embodiment, the subject is less than 20, 15, 10, 5, or 1 year old. In one embodiment, the subject is less than 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 year old or less than 5 months old.

[0368] According to one embodiment, the subject does not suffer from any underlying pathology.

[0369] According to one embodiment, the subject is at risk of developing a red blood cell disorder as described above.According to one embodiment, the subject is at risk of developing sickle cell disease.

[0370] According to one embodiment, the subject at risk for developing sickle cell disease is from an ethnic group selected from the group consisting of: people of African descent, including African Americans; Hispanics from Central and South America; and people of Middle Eastern, Southern European, Asian, Indian, and Mediterranean ancestry.

[0371] According to one embodiment, a subject in need of therapeutic and / or prophylactic treatment is diagnosed by a health professional. For example, sickle cell disease can be diagnosed by various screening tests routinely performed in medical settings, including newborn or prenatal screening to determine whether a subject has an abnormal hemoglobin gene in their red blood cells.

[0372] Treatment effect

[0373] According to one embodiment, the nicotinamide mononucleotide derivatives as described above are used to prevent, reduce, alleviate and / or slow down (reduce) one or more symptoms of a red blood cell disorder and / or its complications.

[0374] In a preferred embodiment, the nicotinamide mononucleotide derivatives as described above are used to prevent, reduce, alleviate and / or slow down (reduce) one or more symptoms of sickle cell disease (SCD) and / or sickle cell associated complications in a subject in need thereof.

[0375] In one embodiment, symptoms of SCD include, but are not limited to, recurrent acute painful crises, vaso-occlusive crises (VOCs), vascular occlusion, ischemia, intravascular hemolysis, extravascular hemolysis, hemolytic anemia, vascular occlusion, and vascular proliferative changes.

[0376] In one embodiment, the nicotinamide mononucleotide derivatives as described above are used to prevent, reduce, alleviate and / or slow (reduce) sickling of red blood cells (RBCs).

[0377] In one embodiment, the use of a nicotinamide mononucleotide derivative as described above prevents, reduces, alleviates, and / or slows (reduces) the loss of RBC deformability typically observed in SCD.

[0378] In one embodiment, the use of a nicotinamide mononucleotide derivative as described above prevents, reduces, alleviates, and / or slows (reduces) the shortening of RBC lifespan typically observed in SCD.

[0379] In one embodiment, the nicotinamide mononucleotide derivatives as described above are used to prevent, reduce, alleviate and / or slow down (reduce) the adhesion to RBC surfaces typically observed in SCD.

[0380] Over time, patients may experience various chronic complications associated with sickle cell disease. According to one embodiment, complications associated with sickle cell disease typically include worsening of the disease or the development of new signs, symptoms, or pathological changes that may spread throughout the body and affect other organs and may lead to the development of new diseases caused by sickle cell disease.

[0381] In one embodiment, complications associated with SCD include acute and chronic complications. Acute complications include severe infections (such as meningitis, osteomyelitis, sepsis, etc.), as well as non-infectious complications (such as stroke, renal necrosis, priapism, etc.). Acute chest syndrome is a potentially life-threatening complication that may include symptoms such as chest pain and shortness of breath; some episodes of acute chest syndrome are triggered by infection. Chronic complications can occur in multiple organs and include neurocognitive disorders, chronic kidney damage, delayed puberty, ischemic necrosis, retinopathy, pulmonary hypertension, skin ulcers, and chronic pain. Individuals with SCD face persistent and evolving lifelong difficulties due to the disease.

[0382] In one embodiment, non-limiting examples of complications associated with SCD include acute chest syndrome, acute pain crisis, chronic pain, delayed growth and puberty, avascular necrosis, eye problems such as retinopathy, gallstones, heart problems including coronary heart disease and pulmonary hypertension, infections such as meningitis, osteomyelitis, and sepsis; joint problems, kidney problems, leg ulcers, liver complications, pregnancy complications, priapism, severe anemia, stroke, kidney necrosis, or silent brain damage.

[0383] Method of administration

[0384] The compounds of the present invention as described above can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), by inhalation spray, nasally, rectally, sublingually or topically, and can be formulated individually or together in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients suitable for each administration route. In addition to treating warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the present invention are also effective for human use. The pharmaceutical composition for administering the compounds of the present invention can be conveniently present in dosage unit form and can be prepared by any method known in the pharmaceutical field. All methods include the step of combining the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, the active ingredient is uniformly and tightly combined with a liquid carrier or a subdivided solid carrier or both, and then the product is shaped into the desired formulation to prepare the pharmaceutical composition if necessary. In the pharmaceutical composition, the content of the active target compound is sufficient to produce the desired effect on the course of the disease or the condition. As used herein, the term "composition" 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.

[0385] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use such as tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

[0386] Compositions for oral use can be prepared according to any method known in the art of pharmaceutical composition manufacture and may include one or more agents selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide a pharmaceutically elegant and palatable formulation. Tablets contain a mixture of the active ingredient and pharmaceutically acceptable, non-toxic excipients suitable for tablet preparation. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrant agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption from the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. They can also be coated by the techniques described in U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. Oral preparations can also be prepared as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium (such as peanut oil, liquid paraffin or olive oil).

[0387] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersants or wetting agents may be naturally occurring phospholipids (such as lecithin), or condensation products of alkylene oxides with fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain fatty alcohols (such as heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (such as polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweeteners (such as sucrose or saccharin). Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil, or coconut oil) or, for example, a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those described above) and flavoring agents may be added to provide a palatable oral formulation. These compositions may be preserved by adding an antioxidant (such as ascorbic acid). Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient, which is mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersants, wetting agents, and suspending agents are listed by those mentioned above. Other excipients may also be present, such as sweeteners, flavoring agents, and coloring agents.

[0388] Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, flavoring and coloring agents.

[0389] Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. Such suspensions can be formulated according to known techniques using suitable dispersants, wetting agents, and suspending agents, such as those mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Sterile, fixed oils are often used as solvents or suspending media. For this purpose, various low-irritation fixed oils, including synthetic mono- or diglycerides, can be used. Fatty acids, such as oleic acid, are also used in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are used. (For the purposes of this application, topical application shall include mouthwashes and gargles.)

[0390] Dosage regimen

[0391] In the treatment of sickle cell disease, suitable dosage levels of the nicotinamide mononucleotide derivatives of the invention are generally about 0.01 to 500 mg / kg of patient body weight per day, which can be administered in a single or multiple doses. Preferably, the dosage level is about 0.1 to about 350 mg / kg / day; more preferably, about 0.5 to about 100 mg / kg / day. Suitable dosage levels may be about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. For oral administration, the composition is preferably provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, in particular 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 mg of active ingredient, for adjusting the dosage of the patient to be treated based on the symptoms.

[0392] According to one embodiment, a subject in need thereof receives treatment with at least one nicotinamide mononucleotide derivative as described above, preferably at a 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, or 1000 mg / kg per year. In one embodiment, a subject in need thereof receives treatment with at least one nicotinamide mononucleotide derivative as described above, preferably at a cumulative dose greater than 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, or 1000 mg / kg per year.

[0393] Nicotinamide mononucleotide derivatives can be administered 1 to 4 times per day, preferably once, twice or three times per day. However, it should be understood that the specific dosage level and frequency of administration for any particular patient can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the specific condition, and the host being treated.

[0394] Monotherapy / combination therapy

[0395] The nicotinamide mononucleotide derivatives of the present invention can be used as monotherapy or in combination therapy for subjects in need of therapeutic and / or prophylactic treatment. Thus, according to a first embodiment, the compounds used in the present invention are administered to a subject without any other active ingredient. According to a second embodiment, the compounds used in the present invention are administered to a subject in combination with at least one other active ingredient, such as those described above.

[0396] In one embodiment, the compound and other active ingredients are administered to a subject sequentially, simultaneously, and / or separately.

[0397] In one embodiment, the other active ingredients are selected from the group consisting of: natural extracts; opioid or non-opioid analgesics; NSAIDS; antidepressants; anticonvulsants; antibiotics; antioxidants such as CoQ10 and PQQ; hydroxyurea, L-glutamine, kynurenine, kynurenic acid, tryptophan, vorseloto, and clizumab.

[0398] According to one embodiment, the pharmaceutical composition of the present invention further comprises at least one other active ingredient. According to one embodiment, the pharmaceutical composition used in the present invention, in addition to comprising at least one compound used in the present invention, further comprises at least one other active ingredient, for example, an active ingredient selected from the following substances: natural extracts; opioid or non-opioid analgesics; NSAIDs; antidepressants; anticonvulsants; antibiotics; antioxidants, such as CoQ10 and PQQ; hydroxyurea, L-glutamine, kynurenine, kynurenic acid, tryptophan, vorseloto, and clizumab.

[0399] According to one embodiment, the compounds of the present invention are used in combination with blood transfusion, in particular red blood cell transfusion. In one embodiment, the compounds of the present invention are administered to a subject sequentially, simultaneously and / or separately using a blood transfusion.

[0400] Multi-part kit

[0401] Another object of the present invention is a kit of parts comprising a first part and a second part, the first part comprising a compound of the invention as described above, and the second part comprising another active ingredient, for example an active ingredient selected from, but not limited to, the following substances: natural extracts; opioid or non-opioid analgesics; NSAIDS; antidepressants; anticonvulsants; antibiotics; antioxidants, such as CoQ10 and PQQ; hydroxyurea, L-glutamine, kynurenine, kynurenic acid, tryptophan, vorseloto and clizumab.

[0402] In one embodiment, the kit of parts of the present invention comprises a first part comprising Compound 001-014 or a pharmaceutically acceptable salt or solvate thereof, and a second part comprising another active ingredient, eg, an active ingredient as described above.

[0403] Treatment

[0404] The present invention also relates to the use of the compound or pharmaceutical composition of the present invention as described above in the treatment of red blood cell disorders as described above.

[0405] The present invention also relates to the use of the compound or pharmaceutical composition of the present invention as described above in the preparation of a medicament for treating the red blood cell disorders as described above.

[0406] The present invention also relates to a method of treating a red blood cell disorder as described above in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0407] Figure 1 is a histogram showing the percentage of F cells over time in the presence of Compound 001 by flow cytometry (FACS) using an antibody against fetal hemoglobin.

[0408] Figure 2 is a histogram showing reticulocyte counts over time in the presence of Compound 001 by FACS using Reticount.

[0409] Figure 3 is a histogram showing the ability of Compound 001 to prevent SS RBC sickling over time under 1% O2 conditions. Nonparametric one-way ANOVA followed by Kruskal-Wallis test: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0410] Figure 4 is a histogram showing the ability of Compound 010 to prevent SS RBC sickling over time under 1% O2 conditions. Nonparametric one-way ANOVA followed by Kruskal-Wallis test: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0411] Figure 5 is a histogram showing the ability of Compound 011 to prevent SS RBC sickling over time under 1% O 2 conditions. Nonparametric one-way ANOVA followed by Kruskal-Wallis test: *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0412] Figure 6 is a histogram showing the red blood cell concentration in the blood of SCD model mice treated with Compound 001, L-glutamine (L-Gln), or a combination of Compound 001 and L-glutamine under normoxic or hypoxic conditions.

[0413] Figure 7 is a histogram showing the hemoglobin concentration in the blood of SCD model mice treated with Compound 001, L-glutamine (L-Gln), or a combination of Compound 001 and L-glutamine under normoxic or hypoxic conditions.

[0414] Figure 8 is a histogram showing the hematocrit percentage in the blood of SCD model mice treated with Compound 001, L-glutamine (L-Gln), or a combination of Compound 001 + L-glutamine under normoxic or hypoxic conditions.

[0415] Example

[0416] The present invention is further illustrated in the following examples.

[0417] Example 1: Synthesis of the compounds of the present invention

[0418] Materials and methods

[0419] All materials were obtained from commercial suppliers and used without further purification. Thin layer chromatography was performed on TLC plastic sheets of Merck Silica Gel 60 F254 (layer thickness 0.2 mm). Column chromatography purification was performed on Silica Gel 60 (70-230 mesh ASTM, Merck). Melting points were determined on a digital melting point apparatus (Electrothermal IA 8103) and were uncorrected, or on a Kofler benchtop WME (Wagner & Munz). IR, 1 H. 19 F and 13 The structures of all compounds were confirmed by C NMR spectroscopy. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer, and NMR spectra were recorded on Bruker AC 300, Advance DRX 400, and Advance DRX 500 spectrometers using CDCl3, CD3CN, D2O, or DMSO-d6 as solvents. 1 H, 75 or 100MHz 13 C and 282 or 377MHz 19 F spectra. Chemical shifts (δ) are expressed in parts per million relative to the signal, (i) for 1 H is indirectly CHCl3 (δ7.27), (ii) for 13 C is indirectly CDCl3 (δ77.2), (iii) for 19 F is directly CFCl3 (internal reference) (δ0). Chemical shifts are in ppm and peak multiplicities are assigned as follows: s, singlet; br s, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; quint, quintet; m, multiplet.

[0420] High-resolution mass spectra (HRMS) were obtained from the "Service central d'analysis de Solaize" (National Center for Scientific Research) and recorded on a Waters spectrometer using electrospray-TOF ionization (ESI-TOF).

[0421] General experimental procedures

[0422] Step 1: Synthesis of compound of formula A-1

[0423] The compound of Formula D (1.0 equivalent) is dissolved in dichloromethane. Nicotinamide of Formula E (1.50 equivalents) and TMSOTf (1.55 equivalents) are added at room temperature. The reaction mixture is heated under reflux and stirred until the reaction is complete. The mixture is cooled to room temperature and filtered. The filtrate is concentrated to dryness to obtain tetraacetate A-1.

[0424] Step 2: Synthesis of compound of formula A-2

[0425] The tetraacetate A-1 is dissolved in methanol and cooled to -10°C. 4.6 M aqueous ammonia (3.0 equivalents) in methanol is added at -10°C and the mixture is stirred at this temperature until the reaction is complete. Dowex HCR (H+) resin is added to a pH of 6-7. The reaction mixture is heated to 0°C and filtered. The resin is washed with a mixture of methanol and acetonitrile. The filtrate is concentrated to dryness. The residue is dissolved in acetonitrile and concentrated to dryness. The residue is dissolved in acetonitrile to obtain a solution of the compound of formula A-2.

[0426] Step 3: Synthesis of compound of formula A-3

[0427] A solution of the crude compound of formula A-2 in acetonitrile was diluted with trimethyl phosphate (10.0 equivalents). Acetonitrile was distilled under vacuum and the mixture was cooled to -10°C. Phosphorus oxychloride (4.0 equivalents) was added at 10°C and the mixture was stirred at 10°C until the reaction was complete.

[0428] Steps 4 and 5: Synthesis of Compound 001

[0429] The mixture obtained in the above steps 3 is hydrolyzed by adding a 50 / 50 mixture of acetonitrile and water, and then methyl tert-butyl ether is added. The mixture is filtered and the solid is soluble in water. The aqueous solution is neutralized by adding sodium bicarbonate and extracted with dichloromethane. The water layer is concentrated into dryness to obtain a rough formula 001 compound, which is purified on a DOWEX 50wx8 chromatographic column, eluted with water, and then processed with a silica gel chromatography column.

[0430] Step 4 and Step 5: Synthesis of Compound 009

[0431] The mixture was hydrolyzed by adding a 50 / 50 mixture of acetonitrile and water, followed by tert-butyl methyl ether. The mixture was filtered and the solid dissolved in water. The aqueous solution was neutralized by adding sodium bicarbonate and extracted with dichloromethane. The aqueous layer was concentrated to dryness to yield a crude mixture of di-NMN and NMN of Formula 009.

[0432] Separation of dinitromethane of formula 009.

[0433] Purification was performed on Dowex 50wx8 using water as the eluent to separate NMN of Formula 009 and di-NMN. The fractions containing di-NMN were concentrated to dryness. The residue was purified by column chromatography on silica gel (gradient isopropanol / water).

[0434] The pure fractions were combined and concentrated. The residue was freeze-dried to give di-NMN as a beige solid.

[0435] 31 P RMN: δ (ppm, ref. 85% H3PO4: 0 ppm dans D2O) = -11.72; 1 H RMN: δ (ppm, ref. TMS: 0 ppm dans D2O) = 4.20 (ddd, J H-H =11.9, 3.5, 2.4Hz, 2H), 4.35(ddd, J H-H =11.9, 3.9, 2.2Hz, 2H), 4.43(dd, J H-H =5.0, 2.6Hz, 2H), 4.53(t, J H-H =5.0Hz, 2H), 4.59 (m, 2H), 6.16 (d, J H-H =5.4 Hz, 2H), 8.26 (d, J H-H =8.1, 6.3Hz, 2H), 8.93(d, J H-H =8.1 Hz, 2H), 9.25 (d, J H-H =6.2Hz, 2H), 9.41 (s, 2H); 13 C RMN: δ (ppm, referenced to 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]+.

[0436] Synthesis of compounds of formula 010

[0437] Phosphorus oxychloride (3.0 equiv) was added to trimethyl phosphate (20.0 equiv) at -5°C. β-NR chloride (1.0 equiv) was added portionwise at -5°C, and the reaction mixture was stirred at -5°C overnight. Morpholine (3.0 equiv) was added dropwise at -10 / 0°C, and the mixture was stirred for 2-3 hours. α-NMN (1.0 equiv) was then added portionwise at -5°C, and the reaction mixture was stirred at -5°C overnight. Water (5 vol) was added dropwise at -10 / 0°C for hydrolysis, and the mixture was stirred at 10-15°C until completely homogenized. The reaction mixture was then extracted with dichloromethane (6*10 vol), and the aqueous phase was neutralized by elution through formate resin Purolite A600E (with the theoretical amount of HCl to neutralize the POCl3). The eluate was then concentrated under vacuum at 45 / 50°C to yield crude α,β-di-NMN containing Formula 010. Through Dowex 50wx8 100-200 mesh H + The resin was eluted with water to remove some impurities. The fractions containing compound 010 were combined and concentrated under vacuum at 45-50°C. The crude product was then purified by preparative chromatography on a Luna Polar RP 10 μm stationary phase and eluted with 10 mM aqueous NaH2PO4. The pure fractions were combined and concentrated on a Purolite C100EH H + The resin was eluted with water (H + Complete exchange of Na + The required amount) was then eluted on Purolite A600E acetate resin (complete exchange of H2PO4 with acetate) - The eluate was concentrated in vacuo and the residue was lyophilized to give compound 010 as a white solid.

[0438] 31 P RMN:δ(ppm, ref. 85% H3PO4:0ppm dans D2O)=-11.87,-11.69,-11.46,-11.29; 1H RMN: δ (ppm, refer to TMS: 0ppm dans D2O)=4.10(ddd,J=11.1,6.1,3.1Hz,1H),4.15-4.25(m,2H),4.36(ddd,J=12.2,4.4,2.4Hz,1H),4.40(dd,J=4. 9,2.4Hz,1H),4.44(dd,J=5.0,2.7Hz,1H),4.53(t,J=5.0Hz,1H),4.5(m,1H),4.85(m,1H),4.92(t,J=5.3Hz,1H ),6.15(d,J=5.5Hz,1H),6.51(d,J=5.7Hz,1H),8.14(dd,J=8.0,6.3Hz,1H),8.26(dd,J=8.1,6.3Hz,1H),8.88( d,J=8.1Hz,1H),8.92(d,J=8.1Hz,1H),9.02(d,J=6.3Hz,1H),9.24(s,1H),9.26(d,J=6.4Hz,1H),9.40(s,1H); 13 C RMN: δ (ppm, refer to TMS: 0ppmdans D2O)=64.83,64.87(CH2),65.30,65.35(CH2),70.65(CH),70.74(CH),71.92(CH),77.51( CH),87.03,87.10(CH),87.19,87.26(CH),96.57(CH),99.83(CH),126.89(CH),128.54(CH ),132.44(Cq),133.81(Cq),139.85(CH),140.92(CH),142.50(CH),143.49(CH),145.06( CH), 145.97 (CH), 165.64 (Cq), 165.88 (Cq); MS (ES+): m / z=122.8[M nicotinamide+H]+, 650.9[M+H]+.

[0439] Synthesis of compounds of formula 011

[0440] Phosphorus oxychloride (3.0 equiv) was added to trimethyl phosphate (20.0 equiv) at -5°C. α-NR chloride (1.0 equiv) was added portionwise at -5°C, and the reaction mixture was stirred at -5°C overnight. Morpholine (3.0 equiv) was added dropwise at -10 / 0°C, and the mixture was stirred for 2-3 hours. α-NMN (1.0 equiv) was then added portionwise at -5°C, and the reaction mixture was stirred at -5°C overnight. Water (5 vol) was added dropwise at -10 / 0°C for hydrolysis, and the mixture was stirred at 10-15°C until completely homogenized. The reaction mixture was then extracted with dichloromethane (6*10 vol), and the aqueous phase was neutralized by elution with formate resin Purolite A600E (using the theoretical amount of HCl to neutralize the POCl3). The eluate was then concentrated in vacuo at 45 / 50°C to yield crude α,α-di-NMN containing Formula 011. Through Dowex 50wx8 100-200 mesh H + The resin was eluted with water to remove some impurities. The fractions containing compound 011 were combined and concentrated under vacuum at 45-50°C. The crude product was then purified by preparative chromatography on a Luna Polar RP 10 μm stationary phase and eluted with 10 mM aqueous NaH2PO4. The pure fractions were combined and concentrated on a Purolite C100EH H + The resin was eluted with water (H + Complete exchange of Na + The required amount) was then eluted on Purolite A600E acetate resin (complete exchange of H2PO4 with acetate) - The eluate was concentrated in vacuo and the residue was lyophilized to give compound 011 as a white solid.

[0441] 31 P RMN: δ (ppm, ref. 85% H3PO4: 0 ppm dans D2O) = -11.40; 1 H RMN: δ (ppm, reference TMS: 0ppm dans D2O) = 4.14 (ddd, J = 11.4, 3.4, 2.8Hz, 2H), 4.23 (ddd, J = 11.6, 3.3, 2.8Hz, 2H), 4.44 (dd, J = 4.8, 2.3Hz, 2H), 4.88 (m, 2H), 4.96 ( t, J=5.3Hz, 2H), 6.54 (d, J=5.7Hz, 2H), 8.15 (dd, J=8.1, 6.2Hz, 2H), 8.89 (d, J=8.1Hz, 2H), 9.05 (d, J=6.3Hz, 2H), 9.26 (s, 2H); 13C RMN: δ (ppm, referenced to TMS: 0 ppm 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), 0.165 (Cq); MS (ES+): m / z = 122.7 [M nicotinamide + H]+, 650.8 [M + H]+.

[0442] Example 2: Evaluation of the compounds of the present invention in sickle cell experimental model

[0443] The aim of this study was to evaluate the effects of compounds 001, 010, and 011 administered intraperitoneally at 185 mg / kg daily as modulators of erythrocyte sickling and fetal hemoglobin expression in erythrocytes and their potential role in treating sickle cell disease in a mouse model of SCD.

[0444] I. Materials and methods

[0445] Material

[0446] animal:

[0447] Townes S / S mice on a 129 / B6 mixed genetic background.

[0448] method

[0449] 1. Preparation of formulations

[0450] Compounds 001, 010, and 011 (185 mg / kg) powders were dissolved in vehicle (solutions were used at room temperature for up to 1 day). Fresh samples were prepared daily for each dosing, except on weekends (solutions were prepared on Saturday and used on Saturday and Sunday).

[0451] 2. sickle cell

[0452] In Townes S / S mice, the mouse α- and β-globin gene loci are deleted and replaced with human α- and β-globin genes. When carrying two copies of the βS allele, the mice develop the human sickle disease phenotype, with sickle-shaped red blood cells appearing in blood smears.

[0453] 3. Experimental group

[0454] Group Description:

[0455] Group 1: Vehicle (intraperitoneal)

[0456] Group 2: Compound 001 (185 mg / kg)

[0457] Group 3: Compound 010 (185 mg / kg)

[0458] Group 4: Compound 011 (185 mg / kg)

[0459] 4. deal with

[0460] Mice were treated intraperitoneally once daily during all experimental periods (D0 to D15) with compounds 001, 010 and 011. The last injection occurred 24 hours before sacrifice.

[0461] 5. Blood collection

[0462] Blood was collected via retro-orbital bleeding from the facial vein on D0 (when included) and D5, D10, and D15.

[0463] 6. In vitro:

[0464] Blood samples collected ex vivo were assessed for the percentage of F cells by FACS using an antibody against fetal hemoglobin, and reticulocyte counts were assessed by FACS using a reticounter. Red blood cell sickling was assessed under hypoxic conditions.

[0465] II. Results and Discussion

[0466] 1. The percentage of F cells

[0467] Figure 1 Shown are the percentages of F cells by FACS using an antibody against fetal hemoglobin.

[0468] The results showed that the following treatments were used:

[0469] -Compound 001 (185 mg / kg / d, intraperitoneally) caused a significant increase in the mean F cell count in mice from less than 5% to 8% within 15 days of treatment ( Figure 1 ).

[0470] 2. Reticulocyte count using reticount

[0471] Figure 2 Reticulocyte counts by FACS using a Reticount are shown.

[0472] The results showed that the following treatments were used:

[0473] -Compound 001 (185 mg / kg / d, intraperitoneal) caused a significant decrease in the percentage of reticulocytes from 70% to 30% in mice within 15 days of treatment ( Figure 2 );

[0474] 3. RBC sickling under hypoxia in vitro

[0475] Figure 3 、 4 and 5 show compound 001 ( Figure 3 )、010( Figure 4 ) and 011( Figure 5 ) Ability to prevent SSRBC sickling under 1% O2 conditions.

[0476] Treated mouse SS RBCs collected at D0, D5, D10, and D15 were subjected to hypoxia in a hypoxic chamber (1% O2) for 30 minutes. The percentage of sickled RBCs at each time point with Compounds 001, 010, and 011 was then assessed.

[0477] The results showed that the following treatments were used:

[0478] -Compound 001 (185 mg / kg / d, intraperitoneally) resulted in a significant (p<0.001) decrease in the percentage of sickle cells from 40% on D0 to less than 10% after 15 days of treatment ( Figure 4 ).

[0479] - Compound 010 (185 mg / kg / d, intraperitoneally) resulted in a significant (p<0.0001) decrease in the percentage of sickled cells from 32% on D0 to less than 15% after 15 days of treatment in mice.

[0480] - Compound 011 (185 mg / kg / d, intraperitoneally) resulted in a significant (p<0.001) decrease in the percentage of sickle cells from 31% on D0 to 20% after 15 days of treatment.

[0481] III. Conclusion

[0482] These results demonstrate that treatment with compounds 001, 010, and / or 011 reduces erythrocyte sickling in response to hypoxia and increases the proportion of circulating erythrocytes expressing fetal hemoglobin, suggesting their potential role in the treatment of sickle cell disease.

[0483] Example 3: Comparison of the efficacy of NMN (Compound 001) versus L-glutamine in the sickle cell model

[0484] The objective of this study was to evaluate the effects of daily administration of 185 mg / kg of Compound 001 and / or 180 mg / kg of L-glutamine (L-Gln) on hematological parameters and RBC sickling. In the United States, L-Gln is FDA-approved for the treatment of patients with sickle cell disease (SCD) as it has been shown to reduce the severity and frequency of VOCs.

[0485] I. Materials and Methods

[0486] animal

[0487] Townes S / S mice of 8-12 weeks old with a 129 / B6 mixed genetic background.

[0488] method

[0489] 1. Preparation of formulations

[0490] Compound 001 (185 mg / kg) powder was dissolved in vehicle (the solution was used at room temperature for up to 1 day). L-glutamine (180 mg / kg) powder was dissolved in vehicle (the solution was used at room temperature for up to 1 day). Fresh samples were prepared every day for each dosing, except on weekends (the solution was prepared on Saturday and used on Saturday and Sunday).

[0491] 2. sickle cell

[0492] In Townes S / S mice, the mouse α- and β-globin gene loci are deleted and replaced with human genes encoding α- and β-globin. When carrying two copies of the βS allele, the mice develop the human sickle disease phenotype, with sickle-shaped red blood cells appearing in blood smears.

[0493] 3. Experimental group

[0494] Group Description:

[0495] Group 1: Vehicle PBS (intraperitoneal)

[0496] Group 2: Compound 001 (185 mg / kg)

[0497] Group 3: L-Gln (185 mg / kg)

[0498] Group 4: Compound 001 (185 mg / kg) + L-Gln (185 mg / kg)

[0499] 4. deal with

[0500] During all experimental periods (D0 to D15), mice received intraperitoneal treatment with Compound 001, L-Gln, or a combination of Compound 001 + L-Gln once daily. The last injection occurred 24 hours before sacrifice.

[0501] 5. Blood collection

[0502] Retro-orbital blood sampling was performed at inclusion and D15.

[0503] 6. In vitro:

[0504] Ex vivo blood parameters and RBC sickling were assessed under normoxia (20% O2) and hypoxia (1% O2 for 0.5 h).

[0505] II. Results and Discussion

[0506] 1. Red blood cells

[0507] Figure 6 Shown are the concentrations of erythrocytes in the blood of animals treated with Compound 001, L-Gln, or Compound 001 + L-glutamine under normoxia or hypoxia.

[0508] The results showed that the following treatments were used:

[0509] -L-Gln did not affect the red blood cell concentration under normoxia or hypoxia.

[0510] -Compared to vehicle or L-Gln, Compound 001 (185 mg / kg / d, intraperitoneal) resulted in a significant increase in RBC concentrations under normoxia and hypoxia. Hypoxia did not result in a decrease in RBCs in the blood of mice treated with Compound 001.

[0511] - The combination of Compound 001 and L-Gln did not improve the results obtained with Compound 001 alone.

[0512] 2. Hemoglobin concentration

[0513] Figure 7 Shown are the hemoglobin concentrations in the blood of animals treated with Compound 001, L-Gln, or Compound 001 + L-glutamine under normoxia or hypoxia.

[0514] The results showed that the following treatments were used:

[0515] -L-Gln compared to vehicle did not affect hemoglobin concentrations under normoxia or hypoxia.

[0516] -Compared to vehicle or L-Gln, Compound 001 (185 mg / kg / d, intraperitoneal) resulted in a significant increase in hemoglobin concentration under normoxia and hypoxia. Hypoxia did not result in a decrease in hemoglobin in the blood of mice treated with Compound 001.

[0517] - The combination of Compound 001 and L-Gln did not improve the results obtained with Compound 001 alone.

[0518] 3. Hematocrit percentage

[0519] Figure 8 Shown are the percent hematocrit in the blood of animals treated with Compound 001, L-Gln, or Compound 001 + L-glutamine under normoxia or hypoxia.

[0520] The results showed that the following treatments were used:

[0521] -L-Gln did not affect the hematocrit percentage under normoxia or hypoxia compared to vehicle.

[0522] -Compared to vehicle or L-Gln, Compound 001 (185 mg / kg / d, intraperitoneal) resulted in a significant increase in hematocrit percentage under normoxia and hypoxia. Hypoxia did not result in a decrease in hematocrit percentage in the blood of mice treated with Compound 001.

[0523] - The combination of Compound 001 and L-Gln did not improve the results obtained with Compound 001 alone.

[0524] III. Conclusion

[0525] Thus, it was demonstrated that the compounds of Formula I according to the present invention can increase the number of RBCs, hemoglobin concentration, and hematocrit percentage in the blood of subjects, particularly those with sickle cell disease, under both normoxic and hypoxic conditions. Thus, the compounds of the present invention are at least as effective as L-Gln, the standard drug for treating sickle cell disease in the United States.

Claims

1. A formula (III) or a compound of formula (IV): or a pharmaceutically acceptable salt or solvate thereof for the preparation of a product for treating red blood cell disorders, the red blood cell disorders including anemias, such as iron deficiency anemia, pernicious anemia, aplastic anemia, autoimmune hemolytic anemia; thalassemia; hemoglobin Sβ0 thalassemia; hemoglobin Sβ+ thalassemia; hemoglobin SC; hemoglobin SD; hemoglobin SE; hemoglobin SS; polycythemia vera and sickle cell disease; in: X is selected from O, CH2, S, Se, CHF, CF2 and C=CH2; R1 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; R2, R3, R4 and R5 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; where R AA is a side chain selected from proteinogenic amino acids; R6 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; X' is selected from O, CH2, S, Se, CHF, CF2 and C=CH2; 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; 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; where R AA is a side chain selected from proteinogenic amino acids; 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; R 8’ Selected from H, NR 15’ R 16’ NH-NHR 15’ , SH, CN, N3 and halogen; among which R 15’ and R 16’ independently selected from H, (C1-C8) alkyl, (C1-C8) alkyl (C5-C 12 )aryl and -CHR AA’ CO2H, where R AA’ is a side chain selected from proteinogenic or non-proteinogenic amino acids; Y' is selected from CH, CH2, CHCH3, C(CH3)2 and CCH3; n is an integer selected from 1 to 3; ---Indicates the connection point; represents a single bond or a double bond according to Y'; and Depends on R 1’ α or β anomer at the position of R8 is selected from H, NR 15 R 16 NH-NHR 15 , SH, CN, N3 and halogen; and wherein R 15 and R 16 independently selected from H, (C1-C8) alkyl, (C1-C8) alkyl (C5-C 12 )aryl and -CHR AA CO2H, where R AA is a side chain selected from proteinogenic or non-proteinogenic amino acids; Y is selected from CH, CH2, CHCH3, C(CH3)2 and CCH3; represents a single bond or a double bond according to Y; and represents the α or β anomer depending on the position of R1.

2. Use of a compound of formula (III) or (IV) according to claim 1, wherein X and X', when present, represent oxygen.

3. The use of a compound according to claim 2, wherein R1 and R1', when present, represent hydrogen.

4. Use of a compound of formula (III) or (IV) according to claim 3, wherein R3 and R4 and R3' and R4', when present, are identical and represent hydrogen.

5. Use of a compound of formula (III) or (IV) according to claim 4, wherein R2 and R5 and R2' and R5', when present, are identical and represent OH.

6. Use of a compound of formula (III) or (IV) according to claim 5, wherein R6 and R6', when present, represent hydrogen.

7. Use of a compound of formula (III) or (IV) according to any one of claims 1 to 6, wherein the compound is selected from: and pharmaceutically acceptable salts and solvates thereof, Preferably it is selected from compounds 001, 002, 009, 010 and 011.

8. Use of a compound of formula (III) or (IV) according to any one of claims 1 to 7, wherein the compound is Compound 001.

9. Use of a compound of formula (III) or (IV) according to any one of claims 1 to 8, wherein the compound is in a form suitable for oral administration.

10. Use of a compound of formula (III) or (IV) according to any one of claims 1 to 9, wherein the product is for treating, preventing, reducing, alleviating or slowing down at least one acute or chronic complication and / or at least one symptom of sickle cell disease in a patient suffering from sickle cell disease.

11. The use of a compound of formula (III) or (IV) according to claim 10, wherein the at least one acute or chronic complication and / or at least one symptom of sickle cell disease is selected from recurrent acute painful crises, vaso-occlusive crises (VOCs), vascular occlusion, ischemia, intravascular hemolysis, extravascular hemolysis, hemolytic anemia, vascular occlusive and vascular proliferative disorders, acute chest syndrome, chronic pain, delayed growth and puberty, avascular necrosis, eye problems such as retinopathy, gallstones, heart problems including coronary heart disease and pulmonary hypertension, infections such as meningitis, osteomyelitis and sepsis; joint problems, kidney problems, chronic kidney damage, skin ulcers, leg ulcers, liver complications, pregnancy complications, priapism, severe anemia, stroke, kidney necrosis or asymptomatic brain damage.

12. The use of a compound according to claim 10, wherein the at least one acute or chronic complication and / or at least one symptom of sickle cell disease is selected from recurrent acute pain crises, vaso-occlusive crises, acute chest syndrome, chronic pain, preferably vaso-occlusive crises.

13. The use of the compound according to claim 10, wherein the at least one acute or chronic complication and / or at least one symptom of sickle cell disease is selected from intravascular hemolysis, extravascular hemolysis, hemolytic anemia and / or severe anemia.

14. Use of a compound of formula (III) or (IV) according to any one of claims 10 to 13, wherein the compound is administered at 0.01 to 500 mg / kg patient body weight / day in a single dose or multiple doses.

15. Use of a compound of formula (III) or (IV) according to any one of claims 10 to 14, wherein the compound of formula (III) or (IV) is provided orally at a dose of 1.0 to 1000 mg.

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