Nicotinamide Mononucleotide Derivatives and Their Use in the Treatment and Prevention of Red Blood Cell Disorders

Abstract

The present invention relates to a nicotinamide mononucleotide derivative of formula (I) which is used for treating and / or preventing blood disorders, especially sickle cell disease. The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) which is used for treating and / or preventing red blood cell disorders, especially sickle cell disease.

Description

Technical Field

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

[0002] Blood disorders are conditions that affect blood cells (such as red blood cells, white blood cells, or the smaller circulating cells known as platelets), which are crucial for clot formation. All three of these cell types are formed in the bone marrow, which is the soft tissue inside bones. Red blood cells carry oxygen to the body's organs and tissues. White blood cells help the body fight infections. Platelets help the blood clot. Blood cell disorders 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 a missense point mutation in the β-globin sequence, which results in the substitution of the glutamic acid residue at position 6 with valine. This mutant globin, called sickle hemoglobin or hemoglobin S (HbS), aggregates and forms fibrous precipitates under 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 different pathophysiological mechanisms: the loss of RBC deformability leads to vaso-occlusion and ischemia; the shortened RBC lifespan leads to intravascular and extravascular hemolysis; the sticky RBC surface increases adhesion to the vascular endothelium, thereby causing vaso-occlusion and resulting in proliferative vascular lesions.

[0005] Recurrent acute pain 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 injury and pain.

[0006] Over time, patients will also experience severe 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 infections. Chronic complications can occur in multiple organs, including neurocognitive impairment, chronic kidney injury, delayed puberty, avascular necrosis, retinopathy, pulmonary hypertension, skin ulcers, and chronic pain. Individuals with SCD face lifelong difficulties due to the persistent and progressive nature of the disease.

[0007] Sickle cell disease (SCD) affects more than 5 million individuals globally and is the most common genetic disease in France. Despite recent progress in the field, treatment of SCD patients is limited to symptomatic treatment of pain, oxygen supplementation, antibiotics, red blood cell transfusions, and hydroxyurea. However, transfusion remains the most commonly used therapy for treating SCD patients.

[0008] Alternative methods have been developed, such as bone marrow transplantation and gene therapy, but they are still associated with toxicity and are only considered in cases of cerebrovascular lesions. Additionally, these methods are not yet feasible in most countries with a high incidence of the disease.

[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 balance. The redox ratio ([NADH]:[NAD+ + NADH]) in sickle red blood cells is lower than that in normal red blood cells.

[0010] The synthesis of NAD requires the amino acid L-glutamine (USAN, glutamine). Sickle red blood cells take up L-glutamine several times more than normal red blood cells, mainly to increase the total intracellular NAD level. Oral administration of pharmaceutical-grade L-glutamine can increase the NAD+ redox ratio in sickle cells and is associated with clinically reported improvements in patients.

[0011] A phase 3 trial of L-glutamine in SCD showed a lower median number of pain crises within 48 weeks in patients receiving L-glutamine treatment. 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 in sickle cell disease in adults and children 5 years of age and older.

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

[0013] However, while current treatments have significantly extended the life expectancy of affected patients, they remain limited as the effectiveness of these drugs varies among patients and the observed clinical manifestations. Additionally, further research is needed to evaluate whether the beneficial effects on SCD complications observed over the years are retained.

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

[0015] Accordingly, an object of the present invention is to provide a safe prophylactic and / or therapeutic treatment for erythrocyte disorders (specifically, sickle cell disease) by providing nicotinamide mononucleotide or a derivative thereof for treating and / or preventing sickle cell disease.

[0016] The applicant unexpectedly found that the nicotinamide mononucleotide derivatives according to the present invention are effective agents for treating and / or preventing erythrocyte disorders (specifically, sickle cell disease) and / or complications associated with said erythrocyte disease (specifically, sickle cell disease) and are well tolerated. Summary of the Invention

[0017] Accordingly, the present invention relates to a compound 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, hydroxy, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl, and OR; wherein R is selected from H, (C1-C 12 )alkyl, -C(O)(C1-C 12 )alkyl, -C(O)NH(C1-C 12 )alkyl, -C(O)O(C1-C 12 )alkyl, -C(O)aryl, -C(O)(C1-C 12 )alkyl-(C5-C 12) aryl, -C(O)NH(C1-C 12 ) alkyl-(C5-C 12 ) aryl, -C(O)O(C1-C 12 ) alkyl-(C5-C 12 ) aryl and -C(O)CHR AA NH2; wherein R AA is a side chain selected from protein 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 wherein

[0025] R9 and R 10 are independently selected from OH, OR 11 、NR 13 R 14 、(C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C 10 ) cycloalkyl, (C5-C 12 ) aryl, (C5-C 12 ) aryl-(C1-C8)alkyl, (C1-C8)alkyl-(C5-C 12 ) aryl, (C1-C8)heteroalkyl, (C3-C8)heterocycloalkyl, (C5-C 12 ) heteroaryl and NHCHR α R α’ C(O)R 12 ; wherein:

[0026] -R 11 is selected from (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C5-C 12 ) aryl, (C1-C 10 ) alkyl-(C5-C 12 ) aryl, substituted (C5-C 12 ) aryl, (C1-C 10 ) heteroalkyl, (C1-C 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 with 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 side chains selected from protein amino acids or non-protein amino acids; wherein the aryl group is optionally substituted with a group selected from hydroxy, (C1-C10 ) substituted by groups of alkyl, (C1-C6) alkoxy, halogen, nitro and cyano; or

[0030] R9 and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, where -R9-R 10 - represents -O-CH2-CH2-CHR-O-; where R is selected from H, (C5-C6) aryl and (C5-C6) heteroaryl, and 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;

[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; where 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, hydroxy, (C1-C 12 ) alkyl, (C1-C 12 ) thioalkyl, (C1-C 12 ) heteroalkyl, (C1-C 12 ) haloalkyl, and OR; where 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 protein amino acids;

[0034] R 6’Selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; where 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; where R is selected from H and (C1-C8)alkyl, and R 15' and R 16' are 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 protein or non-protein 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] represents a point of attachment;

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

[0040] represents an α or β anomeric isomer depending on the position of R 1’ ;

[0041] R8 is selected from H, OR, NR 15 R 16 , NH-NHR 15 , SH, CN, N3 and halogen; where R is selected from H and (C1-C8)alkyl, and R 15 and R 16 are 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 protein or non-protein amino acids;

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

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

[0044] represents an α or β anomeric isomer depending on the position of R1,

[0045] It is used for treating sickle cell disease.

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

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

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

[0049] According to one embodiment, R2 and R5 are the same 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 wherein R9 and R 10 as described 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’ is NH2;

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

[0057] n is equal to 2;

[0058] represents a point of attachment;

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

[0060] represents an α or β anomeric isomer depending on the position of R 1’ .

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

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

[0063]

[0064]

[0065] and its pharmaceutically acceptable salts and solvates thereof.

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

[0067] The present invention further relates to a pharmaceutical composition for treating sickle cell disease, which comprises 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, kynuric acid, tryptophan, Voxelator and Crizanlizumab.

[0069] Definition

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

[0071] When describing the compounds of the present invention, unless otherwise specified, the terms used shall be interpreted according to the following definitions.

[0072] Unless otherwise specified, the naming of substituents not explicitly defined herein is to name the adjacent functional group towards the point of attachment followed by the terminal part of the functional group. For example, the substituent "arylalkyl" means 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 the formula C n H 2n+1a hydrocarbyl radical, where n is a number greater than or equal to 1. Generally, the alkyl groups of the present invention contain from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 2 carbon atoms. The alkyl group can be straight-chain or branched. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl), hexyl and its isomers (e.g., n-hexyl, isohexyl), heptyl and its isomers (e.g., n-heptyl, isoheptyl), octyl and its isomers (e.g., n-octyl, isooctyl), nonyl and its isomers (e.g., n-nonyl, isononyl), decyl and its isomers (e.g., n-decyl, isodecyl), undecyl and its isomers, dodecyl and its isomers. 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 groups include but are 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-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl.

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

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

[0077] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon radical group which may be straight-chain or branched and which contains one or more carbon-carbon double bonds. Suitable alkenyl groups contain from 2 to 12 carbon atoms, preferably from 2 to 8 carbon atoms, and still more preferably from 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 radical groups in which the unsaturation results from the presence of one or more carbon-carbon triple bonds. Alkynyl groups generally, 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 its isomers, 2-hexynyl and its isomers, etc.

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

[0080] The term "amino acid" as used herein refers to an α-amino carboxylic acid, i.e., a molecule containing a carboxylic acid functional group and an amine functional group at the α-position of the carboxylic acid group, such as protein amino acids or non-protein amino acids.

[0081] The term "aryl" as used herein refers to a polyunsaturated aromatic hydrocarbon radical having a single ring (i.e., phenyl), or multiple aromatic rings fused together (such as naphthyl), or covalently linked, usually containing 5 to 12 atoms; preferably 6 to 10, where at least one ring is aromatic. The aromatic rings may optionally contain one or two additional rings (cycloalkyl, heterocyclic or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic systems listed herein. Non-limiting examples of aryl 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, 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 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbon groups. The cycloalkyl group may contain 3 or more carbon atoms in the ring, and generally, according to the present invention, it may contain 3 to 10, more preferably 3 to 8, still more preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropyl is particularly preferred.

[0083] The term "halo" or "halogen" means fluoro, chloro, bromo or iodo. Preferred halogen groups are fluorine and chlorine.

[0084] The term "haloalkyl", alone or as part of another group, means an alkyl group having the meaning defined above, wherein 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, etc. Cx-Cy haloalkyl means an alkyl group containing x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

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

[0086] When at least one carbon atom in the aryl group is replaced by a heteroatom, the resulting ring is herein referred to 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 cyclic system containing 1 or 2 fused or covalently bonded rings, usually containing 5 or 6 atoms; at least one of which is aromatic, and one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quarternised. Such rings may be fused to aryl, cycloalkyl, heteroaryl, or heterocyclic rings. Non-limiting examples of such heteroaryls include: furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, 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, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indazolyl, 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, thienopyridyl, purinyl, imidazo[1,2-a]pyridyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxo-pyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxo-pyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

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

[0089] As used herein, the terms "heterocyclic group", "heterocycloalkyl" or "heterocycle", whether alone or as part of another group, refer to non-aromatic, fully saturated or partially unsaturated (e.g., monocyclic of 3 to 7 ring atoms, bicyclic of 7 to 11 ring atoms or a total of 3 to 10 ring atoms) 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 optionally be oxidized and the nitrogen heteroatoms may optionally be quaternised. Any carbon atom of the heterocyclic group may be substituted by oxo (e.g., piperidone, pyrrolidone). When valence allows, the heterocyclic group may be attached to any heteroatom or carbon atom of the ring or cyclic system. The rings of polycyclic heterocycles may be fused, bridged and / or linked by one or more spiro atoms. Non-limiting exemplary heterocyclic groups include oxetanyl, piperidyl, azetidinyl, 2-imidazolinyl, pyrazolidyl, imidazolidinyl, isoxazolinyl, oxazolidyl, isoxazolidyl, thiazolidyl, isothiazolidyl, piperidyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidyl, 2,5-oxopyrrolidinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-S-oxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothienyl, N-formylpiperazinyl and morpholin-4-yl.

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

[0091] The term "thioalkyl" refers to an alkyl group having the meaning as defined above, wherein one or more hydrogen atoms are replaced by -SH moieties.

[0092] As used herein, the term "non-protein amino acid" refers to an amino acid that is not naturally encoded or not 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 "protein amino acid" refers to an amino acid that is incorporated into a protein during the process of ribosomal translation of messenger RNA in an organism, namely alanine (ALA), arginine (ARG), asparagine (ASN), aspartic acid (ASP), cysteine (CYS), glutamic acid (GLU), glutamine (GLN), glycine (GLY), histidine (HIS), isoleucine (ILE), leucine (LEU), lysine (LYS), methionine (MET), phenylalanine (PHE), proline (PRO), pyrrolysine (PYL), selenocysteine (SEL), serine (SER), threonine (THR), tryptophan (TRP), tyrosine (TYR) or valine (VAL).

[0094] As used herein, the term "prodrug" means a pharmacologically acceptable derivative of a compound of formula (I), for example, a biotransformation product in vivo that is an ester of the active drug. Prodrugs are characterized by increased bioavailability and are readily metabolized in vivo to the active compound. Suitable prodrugs for the purposes of the present invention include aminophosphates, HepDirect, (S)-acyl-2-thioethyl (SATE), carboxylic acid esters, especially alkyl esters, aryl esters, acyloxyalkyl esters and dioxolane carboxylic acid esters; 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 which is substantially stable under the reaction conditions in unprotected form or under the protection of 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; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amino; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl which is monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocycloalkyl which is monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), aryl or heteroaryl which is monocyclic or fused or non-fused polycyclic (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuryl); amino (primary, secondary or tertiary); CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such moieties may also optionally be substituted by a fused ring structure or a bridge, such as -OCH2O-. These substituents may also optionally be further substituted by 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 -N-R 19 , where r is 1 or 2; R 17 and R 18 , each time it appears, is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl; or R 17 and R 18 , together with the nitrogen to which it is attached, is optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R 19 and R 20 , each time it appears, is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

[0096] The bond of an asymmetric carbon can be represented herein using a solid triangle dot triangle or a zigzag line to denote.

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

[0098] The term "administer" or variations thereof (e.g., "administering") refers to providing an active agent or active ingredient, either alone or as part of a pharmaceutically acceptable composition, to a patient having a disorder, symptom, or disease to be treated.

[0099] The term "drug" refers to any substance that causes a physiological or psychological change in a subject when administered to the subject. In the context of the present invention, "drug" encompasses medical drugs ("medicinal drugs" or "active ingredients") and non-medical drugs, such as recreational drugs (e.g., psychoactive drugs).

[0100] "Pharmaceutically acceptable" means that the components of a pharmaceutical composition are compatible with each other and harmless to the patient.

[0101] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" or "drug carrier" refer to an inert medium or carrier used as a solvent or diluent in which the pharmaceutically active ingredient is formulated and / or administered and which does not produce adverse, allergic or other reactions when administered to animals, preferably humans. It includes all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, absorption blockers and other similar components. For human administration, the preparation must comply with the sterility, general safety and purity standards established by regulatory agencies such as the FDA or EMA. For the purposes of the present 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 that form non-toxic salts. Examples include: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclohexanesulfamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethylsulfonate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salt.

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

[0104] Half salts of acids and bases can also be formed, such as half sulfate and half calcium salts.

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

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

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

[0108] (iii) By removing an acid- or base-labile protecting group from a suitable precursor 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) By reacting with a suitable acid or by passing through a suitable ion-exchange column, converting one salt of the compound of formula (I) into another salt.

[0110] All of these reactions are generally carried out in solution. The salt can be precipitated from the solution and collected by filtration, or can be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to almost non-ionized.

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

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

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

[0114] The term "subject" refers to a mammal, preferably a human. According to the present invention, the 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, especially 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 waiting to receive or is receiving medical care, or who has been / will be the subject of a medical procedure, or who is being monitored for a red blood cell disorder and / or one or more complications associated with a red blood cell disorder, especially 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 the amount of an active agent or ingredient that is intended to prevent, reduce, alleviate, or slow down (reduce) one or more symptoms of a red blood cell disorder and / or a complication associated with a red blood cell disorder, without causing significant negative or adverse side effects to a subject in need of treatment, particularly sickle cell disease and / or a complication associated with sickle cell disease.

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

[0117] The term "complications associated with sickle cell disease" includes, but is not limited to, acute chest syndrome, acute pain crisis, chronic pain, growth and puberty delay, avascular necrosis, eye problems such as retinopathy, gallstones, heart problems including coronary artery disease and pulmonary hypertension, meningitis, osteomyelitis, and infections such as sepsis; joint problems, kidney problems, leg ulcers, liver complications, pregnancy complications, priapism, severe anemia, stroke, renal necrosis, or asymptomatic brain injury. Complications associated with sickle cell disease generally include disease exacerbation or the appearance of new signs, symptoms, or pathological changes, which may spread throughout the body and affect other organs, and may lead to the development of new diseases from existing diseases. Complications may also occur due to various treatments. Detailed Description

[0118] Accordingly, the present invention relates to the use of nicotinamide mononucleotide derivatives in the treatment of red blood cell disorders. Specifically, the present invention relates to nicotinamide mononucleotide derivatives for the treatment of 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] Wherein:

[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; where R is selected from H and (C1-C8)alkyl;

[0126] R2, R3, R4 and R5 are independently selected from H, halogen, azido, cyano, hydroxy, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl, and OR; where 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 protein amino acids;

[0127] R6 is selected from H, azido, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; where R is selected from H and (C1-C8)alkyl;

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

[0129] R9 and R 10 are independently selected from OH, OR 11 、NR 13 R 14 、(C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C5-C 12aryl-(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 ; wherein:

[0130] -R 11 is selected from (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C5-C 12 ) aryl, (C1-C 10 ) alkyl-(C5-C 12 ) aryl, substituted (C5-C 12 ) aryl, (C1-C 10 ) heteroalkyl, (C1-C 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 internal or external counterions;

[0131] -R 12 is selected from hydrogen, (C1-C 10 ) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C1-C 10 ) haloalkyl, (C3-C 10 ) cycloalkyl, (C3-C 10 ) heterocycloalkyl, (C5-C 12 ) aryl, (C1-C4) alkyl-(C5-C 12 ) aryl and (C5-C 12)Heteroaryl; wherein said aryl or heteroaryl 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 are 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 the side chains of proteinogenic or non-proteinogenic amino acids; wherein said aryl group is optionally substituted by a group selected from hydroxy, (C 1- C 10 )alkyl, (C 1- C6)alkoxy, halogen, nitro, and cyano; or

[0134] R9 and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, wherein -R9-R 10 - represents -O-CH2-CH2-CHR-O-; wherein R is selected from H, (C5-C6)aryl, and (C5-C6)heteroaryl, wherein said aryl or heteroaryl group is optionally substituted by 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, azide, cyano, hydroxy, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl, and OR; where 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 protein amino acids;

[0138] R6 ’ is selected from H, azide, cyano, (C1-C8)alkyl, (C1-C8)thioalkyl, (C1-C8)heteroalkyl and OR; where R is selected from H and (C1-C8)alkyl;

[0139] R 8' is selected from H, OR, NR 15' R 16' , NH-NHR 15' , SH, CN, N3 and halogen; where R is selected from H and (C1-C8)alkyl, and R 15' and R 16' are 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 protein or non-protein 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] represents a point of attachment;

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

[0144] represents an α- or β-anomeric isomer depending on the position of R 1’ ;

[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 are independently selected from H, (C1-C8) alkyl, (C1-C8) alkyl(C5-C 12 ) aryl and -CHR AA CO2H, wherein R AA is a side chain selected from protein or non-protein amino acids;

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

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

[0148] represents an α- or β-anomeric isomer 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, hydroxy, (C1-C 12 ) alkyl, (C1-C 12 ) thioalkyl, (C1-C 12 ) heteroalkyl, (C1-C 12 ) haloalkyl, and OR; wherein R is selected from H, (C1-C 12 ) alkyl, -C(O)(C1-C 12 ) alkyl, -C(O)NH(C1-C 12 ) alkyl, -C(O)O(C1-C 12)alkyl, -C(O)aryl, -C(O)(C1-C 12 )alkylaryl, -C(O)NH(C1-C 12 )alkyl-(C5-C 12 )aryl, -C(O)O(C1-C 12 )alkyl-(C5-C 12 )aryl and -C(O)CHR AA NH2; wherein R AA is a side chain selected from protein 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 wherein:

[0155] R9 and R 10 are independently selected from OH, OR 11 , NHR 13 , NR 13 R 14 , (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C5-C 12 )aryl-(C1-C8)alkyl, (C1-C8)alkyl-(C5-C 12 )aryl, (C1-C8)heteroalkyl, (C3-C8)heterocycloalkyl, (C5-C 12 )heteroaryl and NHCHR α R α’ C(O)R 12 ; wherein:

[0156] -R 11 is selected from (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C5-C 12 )aryl, (C1-C 10 )alkyl-(C5-C 12 )aryl, substituted (C5-C 12 )aryl, (C1-C 10 )heteroalkyl, (C1-C 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; where m is an integer selected from 1 to 8; and -P(O)(OH)OP(O)(OH)2; and internal or external counterions;

[0157] -R 12 Selected from hydrogen, (C1-C 10 )Alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C1-C 10 )Halogenated alkyl, (C3-C 10 )Cycloalkyl, (C3-C 10 )Heterocycloalkyl, (C5-C 12 )Aryl, (C1-C4) alkyl-(C5-C 12 )Aryl and (C5-C 12 )Heteroaryl; where 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;

[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’ 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 side chains selected from protein amino acids or non-protein amino acids; wherein said aryl group is optionally substituted with a group selected from hydroxy, (C 1- C 10 )alkyl, (C 1- C6)alkoxy, halogen, nitro, and cyano; or

[0160] R9 and R 10 together with the phosphorus atom to which they are attached 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 said aryl or heteroaryl group is optionally substituted with 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, hydroxy, (C1-C 12 )alkyl, (C1-C 12 )thioalkyl, (C1-C 12 )heteroalkyl, (C1-C 12 )haloalkyl, and OR; wherein R is selected from H, (C1-C 12 )alkyl, -C(O)(C1-C 12 )alkyl, -C(O)NH(C1-C 12 )alkyl, -C(O)O(C1-C 12 )alkyl, -C(O)aryl, -C(O)(C1-C 12 )alkylaryl, -C(O)NH(C1-C 12 )alkyl-C5-C 12 aryl, -C(O)O(C1-C 12 )alkyl-C5-C 12 aryl, and -C(O)CHR AA NH2; wherein RAA is a side chain selected from protein amino acids;

[0164] R 6’ is selected from H, azide, cyano, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) heteroalkyl, and OR; where R is selected from H and (C1-C8) alkyl;

[0165] R 8' is selected from H, OR, NHR 15' 、NR 15' R 16' 、NH-NHR 15' 、SH, CN, N3, and halogen; where R 15' and R 16' are 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 double bond according to Y’; and

[0169] represents an α or β anomeric isomer depending on the position of R 1’ ;

[0170] R8 is selected from H, OR, NHR 15 、NR 15 R 16 、NH-NHR 15 、SH, CN, N3, and halogen; where R 15 and R 16 are 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 double bond according to Y; and

[0173] represents an α or β anomeric isomer depending on the position of R1.

[0174] The nicotinamide mononucleotide derivative 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. In addition, the nitrogen atom in the pyridine moiety of the nicotinamide group may carry a positive charge when quaternized. The presence of one or more charged atoms in the nicotinamide mononucleotide derivative of the present invention depends on conditions that those skilled in the art will recognize, specifically pH conditions.

[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, hydroxy, C1-C 12 alkyl, and OR; where R is as described above. In a preferred embodiment, R2, R3, R4, and R5 are independently selected from hydrogen, hydroxy, and OR; where 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 the same. In one embodiment, R2 and R3 are the same and represent OH. In one embodiment, R2 and R3 are the same and represent hydrogen.

[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 the same. In one embodiment, R4 and R5 are the same and represent OH. In one embodiment, R4 and R5 are the same 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 the same. In a preferred embodiment, R3 and R4 are the same and represent OH. In a more preferred embodiment, R3 and R4 are the same 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 the same. In a preferred embodiment, R2 and R5 are the same and represent hydrogen. In a more preferred embodiment, R2 and R5 are the same 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, both R1 and R6 are 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 ; wherein R9 and R 10 are as described above. In a preferred embodiment, R7 is P(O)(OH)2.

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

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

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

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

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

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

[0198] R 8' is selected from H, OR and NR 15' R 16' ; where R 15' and R 16' are as described above, preferably R 8' is NHR 15' ; where R 15' is as described above, more preferably R 8' is NH2;

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

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

[0201] represents a point of attachment;

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

[0203] represents an α or β endo-isomer depending on the position of R 1' .

[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 R1' is hydrogen;

[0208] R2, R3, R4, R5, R 2’ , R 3' , R 4' and R 5' are independently selected from hydrogen, halogen, hydroxy, (C1-C 12 )alkyl and OR; where R is as described above, preferably R2, R3, R4, R 5、 R 2’ , R 3' , R 4' and R 5' are independently selected from hydrogen, hydroxy and OR; where R is as described above, more preferably R2, R3, R4, R5, R 2’ , R 3' , R 4' and R 5' are independently selected from hydrogen and OH;

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

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

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

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

[0213] represents a point of attachment;

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

[0215] represents an α or β endo-isomer depending on the position of R1 and R 1’ end groups.

[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 15R 16 ; wherein R 15 and R 16 are as described above. In a preferred embodiment, R8 is NHR 15 ; wherein R 15 is as described above. In one embodiment, R8 is selected from NH2.

[0218] According to one embodiment, Y is CH or CH2. In one embodiment, Y is CH. In one embodiment, Y is CH2.

[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 are as described above for the compounds of formula (I).

[0222] According to some embodiments, the preferred compounds of 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 are as described above for the compounds of formula (I).

[0225] According to some embodiments, the preferred compounds of 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 are as described above for the compounds of formula (I).

[0228] According to some embodiments, the preferred compounds of 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 compounds 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 compounds 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 compounds of formula (I).

[0237] According to some embodiments, preferred compounds of general 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 compounds of formula (I).

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

[0241]

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

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

[0244]

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

[0246] According to a preferred embodiment, the nicotinamide mononucleotide derivatives used in the present invention have 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 are as described above for the compounds of formula (I).

[0249] According to one embodiment, the 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 are as described above for the compounds of formula (I).

[0252] According to one embodiment, the 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 are as described above for the compounds of formula (I).

[0255] According to one embodiment, the 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 are as described above for the compounds of formula (I).

[0258] According to one embodiment, the 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 are as described above for the compounds of formula (I).

[0261] According to one embodiment, the 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 are as described above for the compounds of formula (I).

[0264] According to one embodiment, the 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 are as described above for the compounds of formula (I).

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

[0268]

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

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

[0271]

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

[0273] According to another preferred embodiment, the nicotinamide mononucleotide derivatives used in the present invention have 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 compounds of formula (I).

[0276] According to one embodiment, the 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 compounds of formula (I).

[0279] According to one embodiment, the 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 compounds of formula (I).

[0282] According to one embodiment, the 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 compounds of formula (I).

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

[0286]

[0287] or a pharmaceutically acceptable salt or solvate thereof; wherein R6, R 6’ , R8, R 8’ , Y, Y’, and are as described above for the compounds of formula (I).

[0288] According to one embodiment, the 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 are as described above for the compounds of formula (I).

[0291] According to one embodiment, the 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 are as described above for the compounds of formula (I).

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

[0295]

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

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

[0298]

[0299] or a pharmaceutically acceptable salt or solvate thereof; wherein are as described above for the compounds of formula (I).

[0300] According to one embodiment, the nicotinamide mononucleotide derivatives used in the present invention are selected from Compounds 001 to 014 in Table 1 below or a pharmaceutically acceptable salt or solvate thereof:

[0301] [Table 1]

[0302]

[0303]

[0304]

[0305] According to one embodiment, preferred nicotinamide mononucleotide derivatives are compounds 001 to 014 or pharmaceutically acceptable salts or solvates thereof.

[0306] 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.

[0307] According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 001, 002, 009, 010, and 011 or pharmaceutically acceptable salts or solvates thereof.

[0308] According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 001 and 002 or pharmaceutically acceptable salts or solvates thereof.

[0309] According to another embodiment, more preferred nicotinamide mononucleotide derivatives are compounds 009, 010, and 011 or pharmaceutically acceptable salts or solvates thereof.

[0310] According to one embodiment, even more preferred nicotinamide mononucleotide derivatives are compounds 002, 010, and 011 or pharmaceutically acceptable salts or solvates thereof.

[0311] All references to the compounds of formula (I) and their sub-formulae include references to their salts, solvates, multicomponent complexes, and liquid crystals. All references to the compounds of formula (I) and their sub-formulae include references to their polymorphs and crystal habits.

[0312] All references to the compounds of formula (I) and their sub-formulae include references to their pharmaceutically acceptable prodrugs.

[0313] 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 a nicotinamide mononucleotide derivative as defined above herein and at least one pharmaceutically acceptable carrier.

[0314] According to one embodiment, the pharmaceutical composition, in addition to containing the nicotinamide mononucleotide derivative defined above herein, further contains at least one other active ingredient, and the active ingredient is selected from, for example, 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, kynuric acid, tryptophan, Voxelator, and Crizanlizumab.

[0315] Non-limiting examples of natural extracts are glycoprotein extracts; terpene extracts containing pentacyclic triterpenes (such as betulin), pentacyclic triterpene metabolites (such as betulinic acid), triterpenoids, roselle lactone, sesquiterpenes, ergoline; flavonoid extracts containing flavones, flavonols, flavanones, flavanols, bioflavones 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 frondosa, milk thistle, artichoke, turmeric, dandelion, Coptis chinensis, beet, and ginger.

[0316] Method

[0317] According to another aspect, the present invention relates to a method for preparing a compound of formula (I) as described above herein.

[0318] Specifically, the compound of formula (I) can be prepared from substrates A-E as described below. Those skilled in the art should understand that these reaction schemes are by no means restrictive and can be varied without departing from the spirit and scope of the present invention.

[0319] According to one embodiment, the method involves, in the first step, monophosphorylating the compound of formula (A) in the presence of phosphoryl chloride and trialkyl phosphate to produce a dichlorophosphate of formula (B):

[0320]

[0321] wherein X, R1, R2, R3, R4, R5, R6, R8, Y, and are as described above.

[0322] In the second step, the dichlorophosphate of formula (B) is hydrolyzed to produce a phosphate of formula (C),

[0323]

[0324] wherein X, R1, R2, R3, R4, R5, R6, R7, R8, Y, and as described above.

[0325] In an alternative embodiment, when R7 in formula (I) is , then 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:

[0326]

[0327] wherein R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 8' , X', Y', and as described above; to obtain the compound of formula (I) as described above.

[0328] Subsequently, hydrolysis gives the compound of formula (I).

[0329] According to one embodiment, the compound of formula (A) is synthesized using various methods known to those skilled in the art.

[0330] According to one embodiment, the compound of formula (A) wherein Y is CH, called the compound of formula (A-a), is synthesized by reacting a pentose of formula (D) with a nitrogen derivative of formula (E) to obtain a compound of formula (A-1), which is then selectively deprotected to obtain the compound of formula (A-a),

[0331]

[0332] wherein X, R1, R2, R3, R4, R5, R6, R7, R8, Y and as described above and R is a protecting group.

[0333] 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 include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl, and 4,4',4''-trimethoxytrityl. Non-limiting examples of silyl groups include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsilyloxymethyl, and [2-(trimethylsilyl)ethoxy]methyl.

[0334] According to one embodiment, any hydroxyl group attached to the pentose is protected by a suitable protecting group known to those skilled in the art.

[0335] The choice and exchange of protecting groups are within the responsibility of those skilled in the art. The protecting groups can also be removed by methods well-known to those skilled in the art, such as with an acid (e.g., an inorganic acid or an organic acid), a base, or a fluorine source.

[0336] According to a preferred embodiment, the nicotinamide of formula (E) is coupled with the pentose of formula (D) by reaction in the presence of a Lewis acid to produce the compound of formula (A-1). Non-limiting examples of the Lewis acid include TMSOTf, BF3.OEt2, TiCl4, and FeCl3.

[0337] According to one embodiment, the method of the present invention further includes reducing the compound of formula (A-a) by various methods well-known to those skilled in the art to produce the compound of formula (A-b), where Y is CH2, X, R1, R2, R3, R4, R5, R6, R8, and as defined above.

[0338] According to a specific embodiment, the present invention relates to a method for preparing compounds 001, 003, 005, 007, and 009.

[0339] In the first step, the nicotinamide of formula (E-i) is coupled with ribose tetraacetate of formula (D-i) by reaction in the presence of a Lewis acid to obtain the compound of formula (A-1-i):

[0340]

[0341] In the second step, ammonolysis of the compound of formula (A-1-i) is carried out to produce compound 005:

[0342]

[0343] In the third step, compound 005 is monophosphorylated in the presence of phosphoryl chloride and trialkyl phosphate to produce the dichlorophosphate of formula (B-i):

[0344]

[0345] In the fourth step, the dichlorophosphate of formula (B-i) is hydrolyzed to produce compound 001:

[0346]

[0347] Alternatively, in the fifth step, the phosphate compound 001 obtained in the fourth step is reacted with the dichlorophosphate compound of formula (B-i) obtained in the third step to obtain compound 009.

[0348] According to one embodiment, a step of reducing compound 005 is carried out to produce compound 007.

[0349] Then, as described in the fourth step, compound 007 is mono-phosphorylated and hydrolyzed to compound 003.

[0350] The above methods for preparing compounds 001, 003, 005 and 007 can be easily applied to the synthesis of compounds 002, 004, 006 and 008 by using a suitable starting ribose tetraacetic acid of formula (D-ii):

[0351]

[0352] The above method for preparing the dimer compound 009 can be easily applied to the synthesis of dimer compounds 010 - 014 by using the corresponding suitable dichlorophosphate and phosphate intermediates.

[0353] Treatment of erythrocyte disorders

[0354] As described above, the treatment needs of erythrocyte disorders, especially sickle cell disease, have not been met. Therefore, an object of the present invention is to provide a treatment for erythrocyte disorders, especially sickle cell disease, for subjects in need thereof. Specifically, the present invention relates to the nicotinamide mononucleotide derivatives defined above for treating erythrocyte disorders, especially sickle cell disease, in subjects in need thereof.

[0355] Erythrocyte disorders

[0356] Therefore, in one embodiment, the present invention relates to the treatment of erythrocyte disorders. Non-limiting examples of erythrocyte disorders include anemia, such as iron deficiency anemia, pernicious anemia, aplastic anemia, autoimmune hemolytic anemia; thalassemia; hemoglobin Sβ0 thalassemia; hemoglobin Sβ+ thalassemia; hemoglobin SC; hemoglobin standard deviation; hemoglobin SE; hemoglobin SS; polycythemia vera and sickle cell disease.

[0357] According to a preferred embodiment, the blood disorder is an erythrocyte disorder as described above.

[0358] According to a more preferred embodiment, the erythrocyte disorder is sickle cell disease.

[0359] Therefore, according to one embodiment, the compounds of the present invention as described above are used for treating erythrocyte disorders as described above.

[0360] According to a preferred embodiment, the compounds of the invention as described above are used for the treatment of sickle cell disease.

[0361] "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 β-globin sequence, which results in the substitution of the glutamic acid residue at position 6 by valine. This mutant globin, called sickle hemoglobin or hemoglobin S (HbS), aggregates and forms fibrous precipitates under low oxygen levels, resulting in polymerized hemoglobin and promoting sickling of red blood cells (RBCs).

[0362] Over time, patients may experience various chronic complications associated with sickle cell disease. According to one embodiment, the complications associated with sickle cell disease generally include disease exacerbation or the appearance of new signs, symptoms, or pathological changes, which may spread throughout the body and affect other organs, and may lead to the development of new diseases caused by sickle cell disease.

[0363] Non-limiting examples of complications associated with sickle cell disease include acute chest syndrome, acute pain crisis, chronic pain, growth and puberty delay, 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, renal necrosis, or asymptomatic brain injury.

[0364] Therefore, according to one embodiment, the compounds of the invention as described above are used for the treatment of the complications associated with sickle cell disease as described above.

[0365] The invention also relates to a pharmaceutical composition comprising at least one compound as described above for use in the invention and at least one pharmaceutically acceptable carrier, for the treatment of red blood cell disorders, especially sickle cell disease.

[0366] Subjects in need of treatment

[0367] Preferably, the subjects in need of treatment and / or prophylactic treatment are warm-blooded animals, more preferably humans. According to one embodiment, the subject is male. According to one embodiment, the subject is female.

[0368] According to one embodiment, the subject is an adult, i.e., 18 years of age or older. 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., between one month and two years old. According to one embodiment, the subject is a neonate, i.e., having an age from birth to less than one month. According to another preferred embodiment, the subject is less than 20, 15, 10, 5 or 1 year old. In one embodiment, the age / month of 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.

[0369] According to one embodiment, the subject does not have any underlying pathologies.

[0370] According to one embodiment, the subject is at risk of developing an erythrocyte disorder as described above. According to one embodiment, the subject is at risk of developing sickle cell disease.

[0371] According to one embodiment, a subject at risk of developing sickle cell disease belongs to an ethnic group selected from African descendants, including African Americans; Hispanic Americans from Central and South America; people of Middle Eastern, Southern European, Asian, Indian, and Mediterranean descent.

[0372] 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 a medical setting, including neonatal or prenatal screening, aimed at determining whether the subject has an abnormal hemoglobin gene in their red blood cells.

[0373] Therapeutic effect

[0374] According to one embodiment, a nicotinamide mononucleotide derivative as described above is used to prevent, reduce, alleviate, and / or slow down (reduce) one or more symptoms of an erythrocyte disorder and / or its complications.

[0375] In a preferred embodiment, a nicotinamide mononucleotide derivative as described above is used to prevent, reduce, alleviate, and / or slow down (reduce) one or more symptoms of sickle cell disease (SCD) and / or complications associated with sickle cell in a subject in need thereof.

[0376] In one embodiment, the symptoms of SCD include, but are not limited to, recurrent acute pain crises, vaso-occlusive crises (VOC), vascular occlusion, ischemia, intravascular hemolysis, extravascular hemolysis, hemolytic anemia, vascular occlusion, and vasoproliferative lesions.

[0377] In one embodiment, a nicotinamide mononucleotide derivative as described above is used to prevent, reduce, alleviate, and / or slow down (reduce) sickling of red blood cells (RBC).

[0378] In one embodiment, the nicotinamide mononucleotide derivative as described above is used to prevent, reduce, alleviate, and / or slow down (decrease) the loss of RBC deformability that is typically observed in SCD.

[0379] In one embodiment, the nicotinamide mononucleotide derivative as described above is used to prevent, reduce, alleviate, and / or slow down (decrease) the shortening of the lifespan of RBCs that is typically observed in SCD.

[0380] In one embodiment, the nicotinamide mononucleotide derivative as described above is used to prevent, reduce, alleviate, and / or slow down (decrease) the adhesion on the surface of RBCs that is typically observed in SCD.

[0381] Over time, a patient may experience various chronic complications associated with sickle cell disease. According to one embodiment, the complications associated with sickle cell disease generally include disease exacerbation or the appearance 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.

[0382] In one embodiment, the complications associated with SCD include acute and chronic complications. Acute complications include severe infections (such as meningitis, osteomyelitis, sepsis, etc.), and 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 infections. Chronic complications can occur in multiple organs, including neurocognitive disorders, chronic kidney injury, delayed puberty, avascular necrosis, retinopathy, pulmonary hypertension, skin ulcers, and chronic pain. Individuals with SCD face continuous and evolving lifelong difficulties due to the disease.

[0383] In one embodiment, non-limiting examples of the complications associated with SCD include acute chest syndrome, acute pain crisis, chronic pain, growth and puberty delay, 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, renal necrosis, or asymptomatic brain injury.

[0384] Methods of administration

[0385] The compounds of the present invention as described above can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation spray, nasal, rectal, sublingual or topical routes, and can be formulated singly or together in suitable dosage unit formulations which contain conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients appropriate for each route of administration. 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 compositions for administering the compounds of the present invention can conveniently be in dosage unit form and can be prepared by any methods well-known in the pharmaceutical art. All methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. Generally, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical compositions, the content of the active target compound is sufficient to produce the desired effect on the course of the disease or the disorder. As used herein, the term "composition" is intended to include a product containing the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from the combination of the specified amounts of the specified ingredients.

[0386] The pharmaceutical compositions containing the active ingredient can 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.

[0387] Compositions for oral use can be prepared by any method known in the art of pharmaceutical compositions, which compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets contain a mixture of the active ingredient and pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, delayed release materials such as glyceryl monostearate or glyceryl distearate can be employed. They can also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. Preparations for oral use can also be made as hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is admixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil.

[0388] The aqueous suspension contains a mixture of an active substance and an excipient suitable for the manufacture of an aqueous suspension. This excipient is a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; the dispersing agent or wetting agent can be a naturally occurring phospholipid (such as lecithin), or a condensation product of an alkylene oxide and a fatty acid (such as polyethylene glycol stearate), or a condensation product of ethylene oxide and a long-chain fatty alcohol (such as heptadecaethyleneoxycetanol), or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol (such as polyoxyethylene sorbitan monooleate), or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol anhydride (such as polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more colorants, one or more flavoring agents, and one or more sweetening agents (such as sucrose or saccharin). The oily suspension can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (e.g., those mentioned above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant (such as ascorbic acid). The dispersible powders and granules suitable for the preparation of an aqueous suspension by adding water provide the active ingredient, which is mixed with a dispersing agent or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing agents or wetting agents and suspending agents are listed by those mentioned above. Other excipients may also be present, such as sweetening agents, flavoring agents and colorants.

[0389] Syrups and elixirs can be formulated with sweetening agents such as glycerin, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives, flavoring agents and colorants.

[0390] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension. Such suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension formulated in a non-toxic parenterally acceptable diluent or solvent, such as a solution formulated in 1,3-butanediol. Available acceptable carriers and solvents are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are often used as solvents or suspending media. For this purpose, various less irritating non-volatile oils can be employed, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid are also used in the preparation of injectables. The compounds of the present invention can also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with suitable non-irritating excipients which are solid at ordinary temperature but liquid at rectal temperature and thus melt in the rectum and release the drug. Such materials are cocoa butter and polyethylene glycol. For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the present invention are used. (For the purposes of this application, topical application shall include mouthwashes and gargles.)

[0391] Dosage regimen

[0392] In the treatment of sickle cell disease, a suitable dosage level of the nicotinamide mononucleotide derivative of the present invention is generally about 0.01 to 500 mg / kg patient body weight / day, which can be administered in a single dose 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 can 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 can 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 the active ingredient, especially tablets containing 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 the active ingredient for adjusting the dosage for the patient to be treated based on symptoms.

[0393] According to one embodiment, a subject in need thereof receives treatment with at least one of the nicotinamide mononucleotide derivatives described above, with a cumulative dose preferably 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 the nicotinamide mononucleotide derivative described above, with a cumulative dose preferably 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.

[0394] The nicotinamide mononucleotide derivative can be administered 1 to 4 times a day, preferably once, twice or three times a day. However, it should be understood that the specific dosage level and administration frequency 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 disorder, and the host being treated.

[0395] Monotherapy / Combination therapy

[0396] The nicotinamide mononucleotide derivative of the present invention can be used for monotherapy or combination therapy of a subject in need of treatment and / or prophylactic treatment. Thus, according to a first embodiment, the compound of the present invention is administered to a subject without any other active ingredient. According to a second embodiment, the compound of the present invention is administered to a subject in combination with at least one other active ingredient, such as the active ingredients described above.

[0397] In one embodiment, the compound and other active ingredients are administered to the subject sequentially, simultaneously and / or separately.

[0398] In one embodiment, the other active ingredients are selected from: natural extracts; opioid or non-opioid analgesics; NSAIDs; antidepressants; anticonvulsants; antibiotics; antioxidants such as CoQ10 and PQQ; hydroxyurea, L-glutamine, kynurenine, kynuric acid, tryptophan, voxelotor and clezutril.

[0399] 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 for use in the present invention, in addition to comprising at least one compound for use in the present invention, further comprises at least one other active ingredient, such as an active ingredient selected from the following: natural extracts; opioid or non-opioid analgesics; NSAIDs; antidepressants; anticonvulsants; antibiotics; antioxidants such as CoQ10 and PQQ; hydroxyurea, L-glutamine, kynurenine, kynuric acid, tryptophan, voxelotor and clezutrilumab.

[0400] According to one embodiment, the compound of the present invention is used in combination with blood transfusion, especially red blood cell transfusion. In one embodiment, the compound of the present invention is administered to a subject in a transfusion sequence, simultaneously and / or separately.

[0401] Multi-part kit

[0402] Another object of the present invention is a multi-part kit comprising a first part and a second part, the first part comprising the compound of the present invention as described above, and the second part comprising another active ingredient, such as an active ingredient selected from but not limited to the following: natural extracts; opioid or non-opioid analgesics; NSAIDs; antidepressants; anticonvulsants; antibiotics; antioxidants such as CoQ10 and PQQ; hydroxyurea, L-glutamine, kynurenine, kynuric acid, tryptophan, voxelotor and clezutrilumab.

[0403] In one embodiment, the component kit 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, such as the active ingredient as described above.

[0404] Treatment method

[0405] 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.

[0406] 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 the treatment of red blood cell disorders as described above.

[0407] The present invention also relates to a method for treating red blood cell disorders in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition as described herein. Description of the drawings

[0408] Figure 1 Is a histogram showing the percentage of F cells over time in the presence of compound 001 using an antibody against fetal hemoglobin by flow cytometry (FACS).

[0409] Figure 2 It is a histogram showing the reticulocyte count over time using Reticount by FACS in the presence of compound 001.

[0410] Figure 3 It is a histogram showing the ability of compound 001 to prevent sickling of SS RBCs over time under 1% O2 conditions. Kruskal-Wallis test was performed after non-parametric one-way ANOVA: *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

[0411] Figure 4 It is a histogram showing the ability of compound 010 to prevent sickling of SS RBCs over time under 1% O2 conditions. Kruskal-Wallis test was performed after non-parametric one-way ANOVA: *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

[0412] Figure 5 It is a histogram showing the ability of compound 011 to prevent sickling of SS RBCs over time under 1% O2 conditions. Kruskal-Wallis test was performed after non-parametric one-way ANOVA: *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

[0413] Figure 6 It 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 + L-glutamine under normoxic or hypoxic conditions.

[0414] Figure 7 It 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 + L-glutamine under normoxic or hypoxic conditions.

[0415] Figure 8 It 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. 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 MethodsAll materials were obtained from commercial suppliers and used without further purification. Thin-layer chromatography was carried out on TLC plastic sheets of silica gel 60F254 (layer thickness 0.2 mm) from Merck. Column chromatography purification was carried out on silica gel 60 (70 - 230 mesh ASTM, from Merck). Melting points were determined on a digital melting point apparatus (electric heating type IA8103), uncorrected, or on a Kofler bench WME (Wagner & Munz). IR, 1 H, 19 F, and 13 13C NMR spectra confirmed the structures of all compounds. Infrared spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer, and nuclear magnetic resonance spectra were recorded on Bruker AC 300, Advance DRX 400, and Advance DRX 500 spectrometers, using CDCl3, CD3CN, D2O, or DMSO-d6 as solvents, for 1 1H, 75 or 100 MHz for 13 13C, and 282 or 377 MHz for 19 19F spectra. Chemical shifts (δ) are expressed in parts per million relative to the signal, (i) for 1 1H indirectly as CHCl3 (δ 7.27), (ii) for 13 13C indirectly as CDCl3 (δ 77.2), (iii) for 19 19F directly as CFCl3 (internal reference) (δ 0). Chemical shifts are in ppm, and peak multiplicities are specified as follows: s, singlet; br s, broad singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; quint, quintet; m, multiplet.

[0419] High-resolution mass spectrometry (HRMS) was obtained from "Service central d’Analyse de Solaize" (Centre national de la recherche scientifique) and recorded on a Waters spectrometer using electrospray-TOF ionization (ESI-TOF).

[0420] General Experimental Procedures

[0421] Step 1: Synthesis of Compound of Formula A-1The compound of formula D (1.0 equivalent) was dissolved in dichloromethane. Nicotinamide of formula E (1.50 equivalents) and TMSOTf (1.55 equivalents) were added at room temperature. The reaction mixture was heated under reflux and stirred until the reaction was complete. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness to obtain tetraacetate A-1.

[0422] Step 2: Synthesis of Compound A-2 Dissolve tetraacetate A-1 in methanol and cool to -10 °C. Add 4,6 M ammonia in methanol (3.0 equivalents) at -10 °C and stir the mixture at this temperature until the reaction is complete. Add Dowex HCR (H+) resin to pH 6 - 7. Heat the reaction mixture to 0 °C and filter. Wash the resin with a mixture of methanol and acetonitrile. Concentrate the filtrate to dryness. Dissolve the residue in acetonitrile and concentrate to dryness. Dissolve the residue in acetonitrile to obtain a solution of Compound A-2.

[0423] Step 3: Synthesis of Compound A-3 Dilute the solution of the crude Compound A-2 in acetonitrile with trimethyl phosphate (10.0 equivalents). Distill acetonitrile under vacuum and cool the mixture to -10 °C. Add phosphorus oxychloride (4.0 equivalents) at 10 °C and stir the mixture at 10 °C until the reaction is complete.

[0424] Steps 4 and 5: Synthesis of Compound 001 Hydrolyze the mixture obtained in Step 3 above by adding a 50 / 50 mixture of acetonitrile and water, followed by addition of methyl tert-butyl ether. Filter the mixture and dissolve the solid in water. Neutralize the aqueous solution by adding sodium bicarbonate and extract with dichloromethane. Concentrate the aqueous layer to dryness to obtain the crude Compound 001, which is purified on a DOWEX 50wx8 chromatographic column, eluted with water, and then treated with a silica gel chromatographic column.

[0425] Steps 4 and 5: Synthesis of Compound 009 Hydrolyze the mixture by adding a 50 / 50 mixture of acetonitrile and water, followed by addition of tert-butyl methyl ether. Filter the mixture and dissolve the solid in water. Neutralize the aqueous solution by adding sodium bicarbonate and extract with dichloromethane. Concentrate the aqueous layer to dryness to obtain a crude mixture of di-NMN and NMN of Compound 009.

[0426] Separation of dinitromethane of Compound 009.

[0427] Purify by eluting with water on Dowex 50wx8 to separate NMN and di-NMN of Compound 009. The fraction containing di-NMN is concentrated to dryness. The residue is purified by column chromatography on silica gel (gradient isopropyl alcohol / water).

[0428] The pure fractions are combined and concentrated. The residue is lyophilized to obtain di-NMN as a beige solid.

[0429] 31 1H NMR: δ (ppm, referenced to 85% H3PO4: 0 ppm in D2O) = -11.72; 11H NMR: δ (ppm, referenced to TMS: 0 ppm in D2O) = 4.20 (ddd, J H-H = 11.9, 3.5, 2.4 Hz, 2H), 4.35 (ddd, J H-H = 11.9, 3.9, 2.2 Hz, 2H), 4.43 (dd, J H-H = 5.0, 2.6 Hz, 2H), 4.53 (t, J H-H = 5.0 Hz, 2H), 4.59 (m, 2H), 6.16 (d, J H-H = 5.4 Hz, 2H), 8.26 (d, J H-H = 8.1, 6.3 Hz, 2H), 8.93 (d, J H-H = 8.1 Hz, 2H), 9.25 (d, J H-H = 6.2 Hz, 2H), 9.41 (s, 2H); 13 13C NMR: 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]+.

[0430] The synthesis of the compound of formula 010: Phosphorus oxychloride (3.0 equivalents) was added to trimethyl phosphate (20.0 equivalents) at -5 °C. β-NR chloride (1.0 equivalent) was added portionwise at -5 °C, and the reaction mixture was stirred overnight at -5 °C. Morpholine (3.0 equivalents) was added dropwise at -10 / 0 °C, and the mixture was stirred for 2 - 3 hours. Then α-NMN (1.0 equivalent) was added portionwise at -5 °C, and the reaction mixture was stirred overnight at -5 °C. Hydrolysis was carried out by dropwise addition of water (5 volumes) at -10 / 0 °C, and the mixture was stirred at 10 - 15 °C until complete homogenization. Then the reaction mixture was extracted with dichloromethane (6 * 10 volumes), and the aqueous phase was eluted and neutralized through a formate resin Purolite A600E (to neutralize the theoretical amount of HCl from POCl3). Then the eluate was concentrated under vacuum at 45 / 50 °C to obtain the crude product of α,β-di-NMN of formula 010. Through Dowex 50wx8 100 - 200 mesh H +The type of resin can remove some impurities by water elution. The fractions containing Compound 010 were combined and concentrated under vacuum at 45 - 50 °C. Then the crude product was purified by preparative chromatography on a Luna Polar RP 10μm stationary phase and eluted with an aqueous solution of 10 mM NaH2PO4. The pure fractions were combined and eluted with water on a Purolite C100EH H + resin (using H + fully exchanged with Na + in the required amount), and then eluted on a Purolite A600E acetate resin (fully exchanged with acetate for H2PO4 - in the required amount). The eluate was concentrated in vacuo and the residue was lyophilized to obtain Compound 010 as a white solid.

[0431] 31 1P RMN: δ (ppm, referenced to 85% H3PO4: 0 ppm in D2O) = -11.87, -11.69, -11.46, -11.29; 1 1H RMN: δ (ppm, referenced to TMS: 0 ppm in D2O) = 4.10 (ddd, J = 11.1, 6.1, 3.1 Hz, 1H), 4.15 - 4.25 (m, 2H), 4.36 (ddd, J = 12.2, 4.4, 2.4 Hz, 1H), 4.40 (dd, J = 4.9, 2.4 Hz, 1H), 4.44 (dd, J = 5.0, 2.7 Hz, 1H), 4.53 (t, J = 5.0 Hz, 1H), 4.5 (m, 1H), 4.85 (m, 1H), 4.92 (t, J = 5.3 Hz, 1H), 6.15 (d, J = 5.5 Hz, 1H), 6.51 (d, J = 5.7 Hz, 1H), 8.14 (dd, J = 8.0, 6.3 Hz, 1H), 8.26 (dd, J = 8.1, 6.3 Hz, 1H), 8.88 (d, J = 8.1 Hz, 1H), 8.92 (d, J = 8.1 Hz, 1H), 9.02 (d, J = 6.3 Hz, 1H), 9.24 (s, 1H), 9.26 (d, J = 6.4 Hz, 1H), 9.40 (s, 1H); 1313C NMR: δ (ppm, referenced to TMS: 0 ppm in D2O) = 64.83, 64.87 (CH2), 65.30, 65.35 (CH2), 70.65 (CH), 70.74 (CH), 71.92 (CH), 77.51 (CH), 87.03, 87.10 (CH), 87.19, 87.26 (CH), 96.57 (CH), 99.83 (CH), 126.89 (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]+.

[0432] The synthesis of the compound of formula 011: Phosphorus oxychloride (3.0 equivalents) was added to trimethyl phosphate (20.0 equivalents) at -5 °C. α-NR chloride (1.0 equivalent) was added portionwise at -5 °C, and the reaction mixture was stirred overnight at -5 °C. Morpholine (3.0 equivalents) was added dropwise at -10 / 0 °C, and the mixture was stirred for 2 - 3 hours. Then α-NMN (1.0 equivalent) was added portionwise at -5 °C, and the reaction mixture was stirred overnight at -5 °C. Hydrolysis was carried out by dropwise addition of water (5 volumes) at -10 / 0 °C, and the mixture was stirred at 10 - 15 °C until complete homogenization. Then the reaction mixture was extracted with dichloromethane (6*10 volumes), and the aqueous phase was eluted and neutralized through formate resin Purolite A600E (to neutralize the theoretical amount of HCl from POCl3). Then the eluate was concentrated in vacuo at 45 / 50 °C to obtain the crude product containing α,α-di-NMN of formula 011. Some impurities could be removed by eluting with water through Dowex 50wx8 100 - 200 mesh H + type resin. The fractions containing compound 011 were combined and concentrated in vacuo at 45 - 50 °C. Then the crude product was purified by preparative chromatography on a Luna Polar RP 10 μm stationary phase and eluted with an aqueous solution of 10 mM NaH2PO4. The pure fractions were combined and eluted with water on Purolite C100EH H + resin (exchanging Na + completely with H + in the required amount), and then eluted on Purolite A600E acetate type resin (exchanging H2PO4 - completely with acetate in the required amount). The eluate was concentrated in vacuo, and the residue was lyophilized to obtain compound 011 as a white solid.

[0433] 31 1H NMR: δ (ppm, referenced to 85% H3PO4: 0 ppm in D2O) = -11.40; 1 1H NMR: δ (ppm, referenced to TMS: 0 ppm in D2O) = 4.14 (ddd, J = 11.4, 3.4, 2.8 Hz, 2H), 4.23 (ddd, J = 11.6, 3.3, 2.8 Hz, 2H), 4.44 (dd, J = 4.8, 2.3 Hz, 2H), 4.88 (m, 2H), 4.96 (t, J = 5.3 Hz, 2H), 6.54 (d, J = 5.7 Hz, 2H), 8.15 (dd, J = 8.1, 6.2 Hz, 2H), 8.89 (d, J = 8.1 Hz, 2H), 9.05 (d, J = 6.3 Hz, 2H), 9.26 (s, 2H); 13 13C NMR: 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]+.

[0434] Example 2: Evaluation of the Compounds of the Invention in a Sickle Red Blood Cell Experimental Model

[0435] The aim of this study was to evaluate the effects of daily intraperitoneal injection of 185 mg / kg of Compounds 001, 010, and 011 as modulators of red blood cell sickling and fetal hemoglobin expression in red blood cells, and their potential role in the treatment of sickle cell disease in a murine model of SCD.

[0436] I. Materials and Methods

[0437] Materials

[0438] Animals:

[0439] Townes S / S mice on a 129 / B6 mixed genetic background.

[0440] Methods

[0441] 1. Preparation of the preparation

[0442] The powders of compounds 001, 010, and 011 (185 mg / kg) were dissolved in a vehicle (the solution was used within 1 day at room temperature). Fresh samples were prepared daily for each administration, except on weekends (the solution was prepared on Saturday and used on Saturday and Sunday).

[0443] 2. Sickle red blood cells

[0444] In Townes S / S mice, the murine α- and β-globin gene loci were deleted and replaced with the human α- and β-globin genes. When carrying two copies of the βS allele, the mice developed the human sickle disease phenotype, with sickle-shaped red blood cells appearing in blood smears.

[0445] 3. Experimental group

[0446] Group description:

[0447] Group 1: Vehicle (intraperitoneal)

[0448] Group 2: Compound 001 (185 mg / kg)

[0449] Group 3: Compound 010 (185 mg / kg)

[0450] Group 4: Compound 011 (185 mg / kg)

[0451] 4. Treatment

[0452] Mice were treated intraperitoneally once daily with compounds 001, 010, and 011 during all experimental periods (D0 to D15). The last injection occurred 24 hours before sacrifice.

[0453] 5. Blood collection

[0454] Retro-orbital blood collection was performed by facial vein bleeding at D0 (inclusive) and D5, D10, and D15.

[0455] 6. In vitro:

[0456] The percentage of F cells in vitro blood collection was evaluated by FACS using an antibody against fetal hemoglobin, and the reticulocyte count was evaluated by FACS using reticount. Erythrocyte sickling was evaluated under hypoxic conditions.

[0457] II. Results and Discussion

[0458] 1. Percentage of F cells

[0459] Figure 1Shows the percentage of F cells using an antibody against fetal hemoglobin by FACS.

[0460] The results showed that with the following treatments:

[0461] - Compound 001 (185 mg / kg / d, intraperitoneal) caused a significant increase in the mean F cells of mice from less than 5% to 8% during 15 days of treatment ( Figure 1 ).

[0462] 2. Reticulocyte count using reticount

[0463] Figure 2 Shows the reticulocyte count using Reticount by FACS.

[0464] The results showed that with the following treatments:

[0465] - Compound 001 (185 mg / kg / d, intraperitoneal) caused a significant decrease in the percentage of reticulocytes in mice from 70% to 30% during 15 days of treatment ( Figure 2 );

[0466] 3. RBC sickling under in vitro hypoxia

[0467] Figure 3 and 4 5 show the ability of Compound 001 ( Figure 3 ), 010 ( Figure 4 ) and 011 ( Figure 5 ) to prevent sickling of SSRBC under 1% O2 condition.

[0468] The treated mouse SS RBCs collected at D0, D5, D10 and D15 were hypoxically treated in a hypoxic chamber (1% O2) for 30 minutes. Then the percentage of sickled RBCs at each time point with Compound 001, 010 and 011 was evaluated.

[0469] The results showed that with the following treatments:

[0470] - Compound 001 (185 mg / kg / d, intraperitoneal) caused a significant (p<0.001) decrease in the percentage of sickle cells in mice from 40% at D0 to less than 10% after 15 days of treatment ( Figure 4 ).

[0471] - Compound 010 (185 mg / kg / d, intraperitoneal) caused a significant (p<0.0001) decrease in the percentage of sickle cells in mice from 32% at D0 to less than 15% after 15 days of treatment.

[0472] - Compound 011 (185 mg / kg / d, intraperitoneal) caused the percentage of sickle cells in mice to decrease significantly (p < 0.001) from 31% at D0 to 20% after 15 days of treatment.

[0473] III. Conclusions These results indicate that treatment with compounds 001, 010, and / or 011 can reduce red blood cell sickling under hypoxic conditions and increase the proportion of circulating red blood cells expressing fetal hemoglobin, suggesting their potential role in the treatment of sickle cell disease.

[0474] Example 3: Efficacy comparison of NMN (Compound 001) versus L-glutamine in an experimental model of sickle red blood cells The aim 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 has been approved by the FDA for the treatment of patients with sickle cell disease (SCD) because it has been shown that the administration of L-Gln can reduce the severity and frequency of VOC.

[0475] I. Materials and Methods

[0476] Animals

[0477] Townes S / S mice with a 129 / B6 mixed genetic background, 8 - 12 weeks old.

[0478] Methods

[0479] 1. Preparation of the preparation

[0480] Dissolve the powder of Compound 001 (185 mg / kg) in a carrier (the solution is used for up to 1 day at room temperature). Dissolve the powder of L-glutamine (180 mg / kg) in a carrier (the solution is used for up to 1 day at room temperature). Prepare fresh samples daily for each administration, except on weekends (the solution is prepared on Saturday and used on Saturday and Sunday).

[0481] 2. Sickle red blood cells

[0482] In Townes S / S mice, the α- and β-globin gene loci of the mice are deleted and replaced by human genes encoding α- and β-globin. When carrying two copies of the βS allele, the mice develop a human sickle disease phenotype with sickle-shaped red blood cells in blood smears.

[0483] 3. Experimental group

[0484] Group description:

[0485] Group 1: Carrier PBS (intraperitoneal)

[0486] Group 2: Compound 001 (185 mg / kg)

[0487] Group 3: L-Gln (185 mg / kg)

[0488] Group 4: Compound 001 (185 mg / kg) + L-Gln (185 mg / kg)

[0489] 4. Treatment

[0490] During all experimental periods (D0 to D15), mice received a single daily intraperitoneal treatment with Compound 001, L-Gln, or the Compound 001 + L-Gln combination. The last injection occurred 24 hours prior to sacrifice.

[0491] 5. Blood collection

[0492] Retro-orbital blood collection was performed at D0 and D15.

[0493] 6. In vitro:

[0494] Ex vivo blood parameters and RBC sickling were evaluated under normoxia (20% O2) and hypoxia (1% O2 for 0.5 h).

[0495] II. Results and Discussion

[0496] 1. Red blood cells

[0497] Figure 6 Shows the concentration of red blood cells in the blood of animals treated with Compound 001, L-Gln, or Compound 001 + L-Glutamine under normoxia or hypoxia.

[0498] The results showed that with the following treatments:

[0499] - L-Gln did not affect the concentration of red blood cells under normoxia or hypoxia.

[0500] - Compared to vehicle or L-Gln, Compound 001 (185 mg / kg / d, intraperitoneal) caused a significant increase in RBC concentration under normoxia and hypoxia. Hypoxia did not cause a decrease in RBCs in the blood of mice treated with Compound 001.

[0501] - The combination of Compound 001 and L-Gln did not improve the results obtained with Compound 001 alone.

[0502] 2. Hemoglobin concentration

[0503] Figure 7Shows the concentration of hemoglobin in the blood of animals treated with Compound 001, L-Gln, or Compound 001 + L-glutamine under normoxia or hypoxia.

[0504] The results showed that with the following treatments:

[0505] - L-Gln control vehicle did not affect hemoglobin concentration under normoxia or hypoxia.

[0506] - Compared with the vehicle or L-Gln, Compound 001 (185 mg / kg / d, intraperitoneal) caused a significant increase in hemoglobin concentration under normoxia and hypoxia. Hypoxia did not cause a decrease in hemoglobin in the blood of mice treated with Compound 001.

[0507] - The combination of Compound 001 and L-Gln did not improve the results obtained with Compound 001 alone.

[0508] 3. Hematocrit percentage

[0509] Figure 8 Shows the percentage of hematocrit in the blood of animals treated with Compound 001, L-Gln, or Compound 001 + L-glutamine under normoxia or hypoxia.

[0510] The results showed that with the following treatments:

[0511] - L-Gln control vehicle did not affect the percentage of hematocrit under normoxia or hypoxia.

[0512] - Compared with the vehicle or L-Gln, Compound 001 (185 mg / kg / d, intraperitoneal) caused a significant increase in the percentage of hematocrit under normoxia and hypoxia. Hypoxia did not cause a decrease in the percentage of hematocrit in the blood of mice treated with Compound 001.

[0513] - The combination of Compound 001 and L-Gln did not improve the results obtained with Compound 001 alone.

[0514] III. Conclusion Therefore, it was demonstrated that the compound of formula I according to the present invention can increase the amount of RBCs, hemoglobin concentration, and percentage of hematocrit in the blood of a subject, specifically a subject suffering from sickle cell disease, under normoxic and hypoxic conditions. Thus, the compounds of the present invention are at least as effective as the standard drug L-Gln for treating sickle cell disease in the United States.

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a product for the treatment of sickle cell disease, wherein the compound is selected from the group consisting of formula 001, 002, 003, 004, 009, 010, 011, 012, 013 and 014, and the product is for preventing, reducing, alleviating and / or slowing down red blood cell sickling 2. Use of the compound according to claim 1, wherein the product is further for preventing, reducing, alleviating and / or slowing down the loss of RBC deformability typically observed in sickle cell disease.

3. Use of the compound according to claim 1, wherein the product is further for preventing, reducing, alleviating and / or slowing down the shortening of the lifespan of red blood cells typically observed in sickle cell disease.

4. Use of the compound according to claim 1, wherein the product is further for preventing, reducing, alleviating and / or slowing down the adhesion on the surface of RBCs typically observed in sickle cell disease.

5. Use of the compound according to claim 1, wherein the product is for preventing, reducing, alleviating and / or slowing down one or more symptoms of sickle cell disease in a subject in need thereof, and the symptoms of sickle cell disease are selected from the group consisting of: acute pain crisis, vaso-occlusive crisis, vascular occlusion, ischemia, intravascular hemolysis, extravascular hemolysis, and angioproliferative lesions.

6. Use of a pharmaceutical composition in the preparation of a drug for the treatment of sickle cell disease, the drug for preventing, reducing, alleviating and / or slowing down red blood cell sickling, and the pharmaceutical composition comprises at least one compound as defined in any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier.

7. Use of the pharmaceutical composition according to claim 6, which, in addition to containing at least one compound as defined in any one of claims 1 to 5, further comprises at least one other active ingredient selected from but not limited to the following substances; natural extracts; opioid or non-opioid analgesics; NSAIDs; antidepressants; anticonvulsants; antibiotics; antioxidants; hydroxyurea, L-glutamine, kynurenine, kynuric acid, tryptophan, voxelotor and crizanlizumab; wherein the natural extracts are selected from glycoprotein extracts; terpene extracts containing betaine, betaine acid, triterpenoids, roselide, sesquiterpenes, ergot alkaloids; flavonoid extracts containing flavones, flavonols, flavanones, flavanols, bioflavones or isoflavones; polysaccharide extracts containing HPB-3, H6PC20; hericenone or hericenone ketone; from species selected from Trametes versicolor, Hericium erinaceus, Grifola frondosa, Silybum marianum, Cynara scolymus, Curcuma longa, Taraxacum officinale, Coptis chinensis, Beta vulgaris and Zingiber officinale.

8. Use of the pharmaceutical composition according to claim 7, wherein the antioxidant is selected from at least one other active ingredient, and the at least one other active ingredient is selected from CoQ10 and pyrroloquinoline quinone.

Images