WO2025011733A1

WO2025011733A1 - Nicotinamide mononucleotide and derivatives thereof and use thereof in the treatment and prevention of polycythemia

Info

Publication number: WO2025011733A1
Application number: PCT/EP2023/068863
Authority: WO
Inventors: Guillaume BERMOND; Laurent GARÇON; Matthias CANAULT; Cecile Cros
Original assignee: Nuvamid SA
Current assignee: Nuvamid SA
Priority date: 2023-07-07
Filing date: 2023-07-07
Publication date: 2025-01-16
Anticipated expiration: 2026-01-07

Abstract

The present invention relates to nicotinamide mononucleotide and derivatives thereof of Formula (Z) for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia. The present invention further relates to pharmaceutical compositions comprising compounds of Formula (Z) for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia.

Description

NICOTINAMIDE MONONUCLEOTIDE AND DERIVATIVES THEREOF AND

USE THEREOF IN THE TREATMENT AND PREVENTION OF

POLYCYTHEMIA

FIELD OF INVENTION

The present invention relates to a pharmaceutical composition comprising a compound of nicotinamide mononucleotide or derivatives thereof, for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia.

BACKGROUND OF INVENTION

A blood disorder is a condition affecting blood cells such as red blood cells, white blood cells, or the smaller circulating cells called platelets, which are critical for clot formation. All three cell types form in the bone marrow, which is the soft tissue inside the bones. Red blood cells transport oxygen to the body’s organs and tissues. White blood cells help the body fight infections. Platelets help the blood to clot. Blood cell disorders impair the formation and function of one or more of these types of blood cells. Blood cell disorders include, among others, polycythemia.

Polycythemia, also called polycythaemia, erythrocytosis or polyglobulia, refers to increased red blood cell mass. The clinical significance of polycythemia, due to any cause, is related to hyper- viscosity of blood. This viscosity can be defined by the amount of hemoglobin (HgB) or by hematocrit (Het). Nevertheless, the threshold of hemoglobin and hematocrit differ according to the age of the patient. Polycythemia can also be associated with increased level of platelet or white blood cells.

Polycythemia is a group of diseases which includes on the one hand, relative, also called transient polycythemia, and on the other hand, absolute polycythemia comprising primary and secondary polycythemia.

Relative polycythemia, also known as pseudopolycythemia, Gaisbock syndrome, spurious polycythemia or stress erythrocytosis, is characterised by a decrease in the volume of plasma, and not by a true increase of the number of red blood cells in blood. Thus, relative polycythemia is measured by a concentration increase of RBCs in blood due to decreased plasma volume. Causes of this disorder include, but are not limited to, loss of body fluids such as through burns, dehydration, stress, temporary hypoxia such as sleep apnea and high altitude, or in the case of Gaisbock syndrome, primarily occurring in obese men, a reduction of plasma volume due to hypertension. In case of chronic exposure to hypoxia, relative polycythemia can develop into secondary absolute polycythemia, described below.

In one embodiment, the clinical manifestations of relative polycythemia are, but not limited to, pruritus, gouty arthritis, peptic ulcer disease, redness and burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances, and combinations thereof, preferably fatigue, weakness, stomach pain , shortness of breath, dizziness, and combinations thereof.

In another embodiment, clinical manifestations of relative polycythemia are, but not limited to, itching, gouty arthritis, peptic ulcer disease, redness, weight loss, fatigue, sweating, headache, vertigo, tinnitus, visual disturbances, splenomegaly, clotting, cardiac shunting, chronic pulmonary disease and combinations thereof.

Absolute polycythemia comprises primary and secondary polycythemia.

Primary polycythemia is characterized by an excessive response of the erythroid progenitors to circulating cytokines, resulting in a primary process in the bone marrow, and causing increased proliferation and/or decreased apoptosis, resulting in a surproduction and thus accumulation of red blood cells in blood.

Polycythemia vera (PV), which is a primary polycythemia, is also known as Vaquez disease, Osler-Vaquez disease or acquired primary erythrocytosis. Polycythemia vera is a myeloproliferative disease defined by an anormal proliferation of red blood cells, leading to a high level of red blood cell and hemoglobin in blood. Most of patients with polycythemia vera have a mutation in the gene sequence of Janus kinase 2 (JAK2), namely JAK2 V617F, which results in a valine residue at position 617 being substituted by a phenylalanine. This mutation negatively regulates the JAK2 activity and confers hypersensitivity and independence of hematopoietic progenitors to cytokines. The identification of this mutation contributes to the diagnostic of myeloproliferative syndromes. Indeed, the mutation JAK2 V617F has a prevalence of 80% to 97% in polycythemia vera.

Primary familial polycythemia, which is a primary polycythemia, is also known as Familial erythrocytosis, is caused by a mutation in the erythropoietin receptor gene. Erythropoietin binds to its receptor to stimulate erythropoiesis, the process that leads to the production of red blood cells. In this condition, mutation of the erythropoietin receptor causes it to be hypersensitive to erythropoietin, leading to the excess of production of red blood cells.

In an embodiment, clinical manifestations of primary polycythemia are, but not limited to, pruritus, gouty arthritis, peptic ulcer disease, redness and burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances and combinations thereof, preferably fatigue, weakness, stomach pain , shortness of breath, dizziness and combinations thereof.

In another embodiment, clinical manifestations of primary polycythemia are, but not limited to, itching, gouty arthritis, peptic ulcer disease, redness, weight loss, fatigue, sweating, headache, vertigo, tinnitus, visual disturbances, splenomegaly, clotting, cardiac shunting, chronic pulmonary disease and combinations thereof.

Secondary polycythemia, also known as secondary erythrocytosis or secondary erythrocythemia, relates to an increase of erythropoietin production in response to chronically low oxygen levels, leading to a high viscosity of blood throughout a high level of red blood cells in blood. In opposition to the primary polycythemia, the secondary polycythemia does not process inside the bone marrow. In one embodiment, clinical manifestations of secondary polycythemia are, but not limited to, fatigue, headache, weight loss, weakness, chronic pulmonary disease, chronic hypoxemia, erythromyalgia, clubbing or cyanosis.

In another embodiment, the clinical manifestations of secondary polycythemia are, but not limited to, pruritus, gouty arthritis, peptic ulcer disease, redness and burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances and combinations thereof, preferably fatigue, weakness, stomach pain , shortness of breath, dizziness and combinations thereof

Therefore, the research for new therapeutic targets to treat polycythemia, especially polycythemia vera (PV) and relative polycythemia (RP) and complications associated with PV and RP are of great importance.

The purpose of the present invention is thus to provide a safe prophylactic and/or therapeutic treatment of polycythemia, especially polycythemia vera or relative polycythemia, by administering a pharmaceutical composition comprising nicotinamide mononucleotide or derivatives thereof for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia.

The Applicant surprisingly found that compounds comprising nicotinamide mononucleotide or derivatives thereof according to the invention are potent agents to treat and/or prevent polycythemia, especially polycythemia vera or relative polycythemia and/or complications associated with, and are well tolerated.

SUMMARY

This invention thus relates to a compound for use in the treatment and/or prevention of polycythemia, the compound being selected from a compound of Formula (I) or Formula (la), selected from compound I-A, compound I-B, compound I-C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-I, compound I- J, compound la-A, compound la-B, compound la-C, compound la-D, compound la-E, compound la-F, compound la-G, compound la-H, compound Ia-I, and combinations thereof, and pharmaceutically acceptable salts and solvates thereof, wherein [Table 1]

According to one embodiment, the compound according to the invention is selected from a compound of Formula (I), selected from compound I-A, compound I-B, compound I- C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-I, compound I- J, and combinations thereof, and pharmaceutically acceptable salts and solvates thereof, wherein [Table 2]

According to one embodiment, the compound according to the invention is selected from a compound of Formula (la), selected from compound la- A, compound la-B, compound la-C, compound la-D, compound la-E, compound la-F, compound la-G, compound la- H, compound Ia-I, and combinations thereof, and pharmaceutically acceptable salts and solvates thereof, wherein [Table 3]

According to one embodiment, the compound according to the invention is selected from compound I-A, compound I-B, compound la-A, compound la-B, and compound la-C.

The present invention further relates to a pharmaceutical composition for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia, comprising the compound as defined herein above and at least one pharmaceutically acceptable carrier. According to one embodiment, the pharmaceutical composition for use according to the invention, comprises in addition to the pharmaceutical compound as defined herein above, at least one other active ingredient. This other active ingredient can be selected from, but not limited to, interferon alpha-2a, interferon alpha-2b, Janus kinase 2 inhibitor, hydroxyurea, busulfan, acetylsalicylic acid, allopurinol, Hl antagonist, phosphorus-32, uramustine, pipobroman, phospholipase A2 inhibitor, or nitrogen mustards such as melphalan, preferably Janus kinase 2 inhibitor or hydroxyurea. The combination can be sequential, simultaneous and/or separate.

According to one embodiment, the pharmaceutical composition is administered in combination with phlebotomy or oxygen therapy, wherein the combination is sequential, simultaneous and/or separate.

According to one embodiment, the pharmaceutical composition for use according to the invention allows to reduce hematocrit in patients with polycythemia, preferably polycythemia vera or relative polycythemia.

According to one embodiment, the treatment and/or prevention with the pharmaceutical composition according to the invention comprises the improvement/relief of pruritus, gouty arthritis, peptic ulcer disease, redness and burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances and combinations thereof, preferably fatigue, weakness, stomach pain , shortness of breath, dizziness and combinations thereof.

In another embodiment, clinical manifestations of relative polycythemia are, but not limited to, itching, gouty arthritis, peptic ulcer disease, redness, weight loss, fatigue, sweating, headache, vertigo, tinnitus, visual disturbances, splenomegaly, clotting, cardiac shunting, chronic pulmonary disease, and combinations thereof. According to one embodiment, the present invention further relates to a compound of formula (I) or (la) for use in the treatment and/or prevention of polycythemia vera or relative polycythemia.

DEFINITIONS

The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the adjacent functionality toward the point of attachment followed by the terminal portion of the functionality. For example, the substituent "arylalkyl" refers to the group -(aryl)-(alkyl).

In the present invention, the following terms have the following meanings:

The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula CnFbn+i wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise 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 1 to 2 carbon atoms. Alkyl groups may be linear or branched. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), hexyl and its isomers (e.g. n-hexyl, isohexyl), heptyl and its isomers (e.g. n-heptyl, iso-heptyl), octyl and its isomers (e.g. n-octyl, iso-octyl), nonyl and its isomers (e.g. n-nonyl, iso-nonyl), decyl and its isomers (e.g. n-decyl, iso-decyl), undecyl and its isomers, dodecyl and its isomers. Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Saturated branched alkyls include, without being limited to, i-propyl, s-butyl, i-butyl, t- butyl, i-pentyl, 2-methylbutyl, 3 -methylbutyl, 2-m ethylpentyl, 3 -methylpentyl, 4-methylpentyl, 2-m ethylhexyl, 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-m ethyl-3 -ethylpentyl, 2-methyl-4-ethylpentyl,

2-methyl-2-ethylhexyl, 2-methyl-3 -ethylhexyl, 2-methyl-4-ethylhexyl, 2, 2-di ethylpentyl,

3.3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl. Cx-Cy-alkyl refers to alkyl groups which comprise x to y carbon atoms.

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

The term "alkenyl" as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 12 carbon atoms, preferably between 2 and 8 carbon atoms, still more preferably between 2 and 6 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.

The term "alkynyl" as used herein refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Non limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2- hexynyl and its isomers-and the like.

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

The term "amino acid" as used herein refers to an alpha-aminated carboxylic acid, i.e. a molecule comprising a carboxylic acid functional group and an amine functional group in alpha position of the carboxylic acid group, for example a proteinogenic amino acid or a non-proteinogenic amino acid.

The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenyl, biphenylenyl, 5- or 6- tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6- or 7-indenyl, 1- 2-, 3-, 4-or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 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.

The term "cycloalkyl" as used herein is a cyclic alkyl, alkenyl or alkynyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.

The term "haloalkyl" alone or as part of another group, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogen atoms are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1 -trifluoroethyl and the like. C_x-C_y-haloalkyl are alkyl groups which comprise x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl. The term "heteroalkyl" means an alkyl group as defined above in which one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulfur atoms. In heteroalkyl groups, the heteroatoms are linked along the alkyl chain only to carbon atoms, i.e. each heteroatom is separated from any other heteroatom by at least one carbon atom. However, the nitrogen and sulphur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. A heteroalkyl is bonded to another group or molecule only through a carbon atom, i.e. the bonding atom is not selected from the heteroatoms included in the heteroalkyl group.

Where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

The term "heteroaryl" as used herein by itself or as part of another group refers to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is 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 quatemized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3] thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazoIofl, 5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl,

1.3 -benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl,

1.2.3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl,

2.1.3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl,

6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl. Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocycloalkyl" or "heterocyclyl".

The terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi- ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, 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-oxopiperidinyl, 2-oxopyrrolodinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin- 1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1,4-oxathianyl, IH-pyrrolizinyl, tetrahydro- 1,1 -di oxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

The term "hydroxy alkyl" refers to an alkyl radical having the meaning as defined above wherein one or more hydrogen atoms are replaced with -OH moieties.

The term "thio-alkyl" refers to an alkyl radical having the meaning as defined above wherein one or more hydrogen atoms are replaced with -SH moieties. The term “non-proteinogenic amino acid” as used herein refers to an amino acid not naturally encoded or found in the genetic code of living organism. Non limiting examples of non-proteinogenic amino acid are ornithine, citrulline, argininosuccinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, 5-aminolevulinic acid, P-alanine, cystathionine, y-aminobutyrate, DOPA, 5 -hydroxytryptophan, D-serine, ibotenic acid, a-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine or D-glutamate.

The term "proteinogenic amino acid" as used herein refers to an amino acid that is incorporated into proteins during translation of messenger RNA by ribosomes in living organisms, i.e. Alanine (ALA), Arginine (ARG), Asparagine (ASN), Aspartate (ASP), Cysteine (CYS), Glutamate (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).

The term "prodrug" as used herein means the pharmacologically acceptable derivatives of compounds of Formula (I) or compounds of Formula (la) as described herein, such as esters whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include phosphoramidates, HepDirect, (S)-acyl-2-thioethyl (SATE), carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters.

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 an unprotected form or when protected by a protecting group. Examples of preferred substituents include, without being limited to, halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl, as described above; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-0); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); CO₂CH₃; CONH₂; OCH₂CONH₂; NH₂; SO₂NH₂; OCHF₂; CF₃; OCF₃; and such moieties may also be optionally substituted by a fused-ring structure or bridge, for example -OCH2O-. These substituents may optionally be further substituted with a substituent selected from such groups. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a substituent selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroarylalkyl, a haloalkyl, - C(O)NR₁₇R₁₈, -NR₁₉C(O)R₂₀, a halo, -OR₁₉, cyano, nitro, a haloalkoxy, -C(O)R₁₉, - NR17R18, -SR19, -C(O)OR19, -OC(O)R19, -NR19C(O)NR17R18, -OC(O)NR17R18, - NR19C(O)OR20, -S(O)rR19, -NR19S(O)Rr20, -OS(O)Rr20, S(O)rNR17R18, -O, -S, and -N- R₁₉, wherein r is 1 or 2; R₁₇ and R₁₈, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl; or R17 and R18 taken together with the nitrogen to which they are attached is optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R₁₉ and R₂₀ for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group. The bonds of an asymmetric carbon can be represented here using a solid triangle ( ), a dashed triangle ( ) or a zigzag line ( ). The term “active ingredient”, or a variant thereof (e.g. “active agent” or “therapeutic ingredient”) refers to a molecule or a substance whose administration to a subject slows down or stops the progression, aggravation, or deterioration of one or more symptoms of a disease, or condition; alleviates the symptoms of a disease or condition; cures a disease or condition. According to one embodiment, the therapeutic ingredient is a small molecule, either natural or synthetic. According to another embodiment, the therapeutic ingredient is a biological molecule such as for example an oligonucleotide, a siRNA, a miRNA, a DNA fragment, an aptamer, an antibody and the like. The term "administration", or a variant thereof (e.g., “administering"), means providing the active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented. The term “drug” refers to any substance that causes a change in physiology or psychology of a subject when administrated to the subject. In the context of the invention, “drug” encompasses both drugs for medical use (“medicinal drug” or “active ingredient”) and drugs for non-medical use, e.g., recreational drugs (e.g., psychoactive drugs). By "pharmaceutically acceptable" it is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient. The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” or “pharmaceutical vehicle” 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 an adverse, allergic or other reaction when administered to an animal, preferably a human being. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption retardants and other similar ingredients. For human administration, preparations must meet standards of sterility, general safety and purity as required by regulatory agencies such as, but without being limited to, the FDA or EMA. For the purposes of the invention, "pharmaceutically acceptable excipient" includes all pharmaceutically acceptable excipients as well as all pharmaceutically acceptable carriers, diluents, and/or adjuvants.

The term “pharmaceutically acceptable salts” includes the acid addition and base salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bi sulphate/ sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/ dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine,

4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts.

Elemisalts of acids and bases may also be formed, for example, from hemisulphate and hemicalcium salts.

Pharmaceutically acceptable salts of compounds of Formula (I) may be prepared by one or more of these methods:

(i) by reacting the compound of Formula (I) with the desired acid;

(ii) by reacting the compound of Formula (I) with the desired base;

(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., a lactone or lactam, using the desired acid; and/or

(iv) by converting one salt of the compound of Formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

Pharmaceutically acceptable salts of compounds of Formula (la) may be prepared by one or more of these methods: (i) by reacting the compound of Formula (la) with the desired acid;

(ii) by reacting the compound of Formula (la) with the desired base;

(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula (la) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or

(iv) by converting one salt of the compound of Formula (la) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

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

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

The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and containing stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule, such as ethanol. The term ’hydrate’ refers to a solvate when said solvent is water.

The term "human" refers to a subject of both genders and at any stage of development (z'.e., neonate, infantjuvenile, adolescent, adult).

The term "subject" refers to a mammal, preferably a human. According to the present invention, a subject is a mammal, preferably a human, suffering from polycythemia, especially polycythemia vera or relative polycythemia and/or complications associated with. In one embodiment, the subject is a “patient”, i.e., a mammal, preferably a human, who/which is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure or is monitored for the development of polycythemia, especially polycythemia vera or relative polycythemia and/or one or more complications associated with.

The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject in need of treatment, preventing, reducing, alleviating or slowing down (lessening) one or more of the symptoms of a polycythemia, especially polycythemia vera or relative polycythemia and/or complications associated with.

The terms “treat”, “treating” or “treatment”, as used herein, refer to a therapeutic treatment, to a prophylactic (or preventive) treatment, or to both a therapeutic treatment and a prophylactic (or preventive) treatment, wherein the object is to prevent, reduce, alleviate, and/or slow down (lessen) one or more of the symptoms of a polycythemia, especially polycythemia vera or relative polycythemia, and/or of the complications associated with polycythemia, especially polycythemia vera or relative polycythemia, in a subject in need thereof. In one embodiment, “treating” or “treatment” refers to a therapeutic treatment. In another embodiment, “treating” or “treatment” refers to a prophylactic (or preventive) treatment. In yet another embodiment, “treating” or “treatment” refers to both a prophylactic (or preventive) treatment and a therapeutic treatment. In one embodiment, the therapeutic treatment can be curative and/or palliative.

The term “complications associated with polycythemia” includes, but is not limited to, stroke, heart attack, thrombus, deep vein thrombosis, pulmonary embolism, enlarged spleen causing discomfort, abdominal pain, decreased appetite, peptic ulcers, gout or acute leukemia and other related blood diseases such as myelofibrosis, acute myeloid leukemia or myeloplastic syndrome. Individuals with polycythemia face ongoing and evolving lifelong difficulties as a result of their disease.

The term "complications associated with polycythemia vera" includes, but is not limited to, stroke, heart attack, deep vein thrombosis, pulmonary embolism, enlarged spleen causing abdominal pain and decreased appetite, peptic ulcers, gout or acute leukemia. Polycythemia vera may progress into other related blood diseases including myelofibrosis, acute myeloid leukemia and myelodysplastic syndrome. Non limiting examples of complications associated with secondary polycythemia include pulmonary embolism, chronic pulmonary disease such as emphysema, chronic hypoxemia and Pickwickian syndrome. Complications associated with polycythemia vera generally involve a worsening of the disease or the development of new signs, symptoms or pathological changes that can spread throughout the body and affect other organs and can lead to the development of new diseases resulting from an existing disease. Complications can also occur as a result of various treatments.

The term “complications associated with relative polycythemia” includes, but is not limited to, fatigue, general weakness, poor exercise tolerance, thromboembolic complications, pulmonary hypertension and increased blood viscosity.

DETAILED DESCRIPTION

The present invention thus relates to the use of a pharmaceutical composition comprising a compound of nicotinamide mononucleotide or derivatives thereof for the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia.

The compound(s) used in the invention is selected from nicotinamide mononucleotide or a derivative thereof. The compound(s) may also be in the form of a pharmaceutically acceptable salt or solvate.

Nicotinamide mononucleotide

In one embodiment, the compound nicotinamide mononucleotide used in the present invention is the compound I-A as follows:

or a pharmaceutically acceptable salt or solvate thereof.

Nicotinamide mononucleotide derivatives In one embodiment, the nicotinamide mononucleotide derivative used in the present invention is a compound of Formula (Z) as follows:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

X is selected from O;

Ri is selected from H;

R2, R3, R4 and R5 are independently selected from H and hydroxyl,;

Re is selected from H;

R7 is selected from H, P(0)R₉RIO,

wherein:

R9 and Rio are independently selected from OH and O, and an internal or external counterion;

X’ is selected from O;

Ri’ is selected from HR2’, Rr, Rr and Rg’ are independently selected from H and hydroxyl;

Re’ is selected from H;

Rs’ is selected from NH2;

Y’ is selected from CH and CH2,; n is an integer selected from 1 to 3;

- represents the point of attachment;

^=-ZT: represents a single or double bond according to ¥’; and

^JWV‘ represents the alpha or beta anomer depending on the position of Ri<

Rs is selected from NH2;

Y is selected from CH and CH2; - represents a single or double bond according to Y; and f^cAAA/' represents the alpha or beta anomer depending on the position of Ri.

In one embodiment, the compound(s) of the present invention are selected from a compound of Formula (I) or a compound of Formula (la), selected from compound I- A, compound I-B, compound I-C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-I, compound I- J, compound la- A, compound la-B, compound la-C, compound la-D, compound la-E, compound la-F, compound la-G, compound la-H, compound Ia-I, and combinations thereof, and pharmaceutically acceptable salts and solvates thereof, wherein

[Table 1]

In one embodiment, the compound used in the present invention is selected from a compound of Formula (I), selected from compound I- A, compound I-B, compound I-C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-H, compound I-I, compound I-J, and combinations thereof, and pharmaceutically acceptable salts and solvates thereof, wherein

[Table 2]

In one embodiment, the compound used in the present invention is selected from a compound of Formula (Ia), selected from a compound Ia-A, compound Ia-B, compound Ia-C, compound Ia-D, compound Ia-E, compound Ia-F, compound Ia-G, compound Ia- H, compound Ia-I, and combinations thereof, and pharmaceutically acceptable salts and solvates thereof, wherein [Table 3]

According to one embodiment, preferred nicotinamide mononucleotide derivatives are compounds I-A to I-J or a pharmaceutically acceptable salt or solvate thereof.

According to one embodiment, preferred nicotinamide mononucleotide derivatives are compounds I-A, I-B, I-C, I-F, la-A, la-B, la-C, la-D, la-E and la-F or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds I-A, I-B, la-A, la-B and la-C or a pharmaceutically acceptable salt or solvate thereof.

According to one embodiment, more preferred nicotinamide mononucleotide derivatives are compounds I-A and la-B or a pharmaceutically acceptable salt or solvate thereof.

According to another embodiment, more preferred nicotinamide mononucleotide derivatives are compounds la-A, la-B and la-C or a pharmaceutically acceptable salt or solvate thereof.

According to one embodiment, even more preferred nicotinamide mononucleotide derivatives are compounds I-B, la-Band la-C or a pharmaceutically acceptable salt or solvate thereof.

All references to compounds of Formula (I) or compounds of Formula (la) and subformulae thereof include references to salts, solvates, multi-component complexes and liquid crystals thereof All references to compounds of Formula (I) or compounds of Formula (la) and subformulae thereof include references to polymorphs and crystal habits thereof

All references to compounds of Formula (I) or compounds of Formula (la) and subformulae thereof include references to pharmaceutically acceptable prodrugs thereof

The nicotinamide mononucleotide derivatives used in the present invention can be under the form of a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a compound according to the present invention selected from nicotinamide mononucleotide or derivative thereof as defined hereinabove, and at least one pharmaceutically acceptable carrier.

According to one embodiment, the pharmaceutical composition comprises, in addition to a compound according to the present invention selected from nicotinamide mononucleotide and derivatives thereof as defined hereinabove, at least one additional active ingredient, e.g., an active ingredient selected from, but not limited to, interferon alpha-2a, interferon alpha-2b, Janus kinase 2 inhibitor; hydroxyurea, busulfan, acetylsalicylic acid, allopurinol, Hl antagonist, phosphorus-32, uramustine, pipobroman, phospholipase A2 inhibitor, or nitrogen mustards such as melphalan, preferably Janus kinase 2 inhibitor or hydroxyurea. The combination can be sequential, simultaneous and/or separate.

According to one embodiment, the pharmaceutical composition comprises, in addition to a nicotinamide mononucleotide derivative as defined hereinabove, at least one additional treatment, e.g., phlebotomy or oxygen therapy, wherein the combination is sequential, simultaneous and/or separate.

Process

According to another aspect, the invention relates to a method for the preparation of a compound of Formula (I) or a compound of Formula (la) as described hereinabove.

In particular, the compounds of Formula (I) or compound of Formula (la) may be prepared as described below from substrates A-E. It shall be understood by a person skilled in the art that these schemes are in no way limiting and that variations may be made without departing from the spirit and scope of this invention.

According to one embodiment, the method involves in a first step the mono-phosphorylation of a compound of Formula (A), in the presence of phosphoryl chloride and a trialkyl phosphate, to yield the phosphorodichloridate of Formula (B):

wherein X, Ri, R2, R3, R4, Rs, Re, Rs, Y, - and are as described herein above.

In a second step, the phosphorodichloridate of Formula (B) is hydrolyzed to yield the phosphate of Formula (C):

wherein X, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, Y, and are as described herein above. In an alternative embodiment, when in Formula (Z) R₇ is

the second step is then reacted, with a phosphorodichloridate compound of Formula (B’) obtained as described in the first step:

wherein R_1’, R_2’, R_3’, R_4’, R_5’, R_6’, R_8’, X’, Y’, and are as described herein above; to give the compound of Formula (Z) as described herein above; followed by hydrolysis to yield the compound of Formula (Z). According to one embodiment, the compound of Formula (A) is synthesized using various methods known to the person skilled in the art. According to one embodiment, the compound of Formula (A) wherein Y is CH, referred to as compound of Formula (A-a), is synthesized by reacting the pentose of Formula (D) with a nitrogen derivative of Formula (E) leading to the compound of Formula (A-1), which is then selectively deprotected to give the compound of Formula (A-a),

wherein X, R₁, R₂, R₃, R₄, R₅, R₆, R₈, Y and are as described herein above and R is a protective group. According to one embodiment, R is an appropriate protective group known to the skilled person in the art. In one embodiment, the protecting group is selected from triarylmethyls and silyls. 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, tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. According to one embodiment, any hydroxyl group attached to the pentose is protected by an appropriate protective group known to the person skilled in the art. The choice and exchange of protective groups is the responsibility of the person skilled in the art. Protective groups can also be removed by methods well known to the skilled person, for example, with an acid (e.g. mineral or organic acid), base or fluoride source. According to a preferred embodiment, the nitrogen nicotinamide of Formula (E) is coupled to the pentose of Formula (D) by a reaction in the presence of a Lewis acid leading to the compound of Formula (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF₃.OEt₂, TiCl₄ and FeCl₃. According to one embodiment, the method of the present invention further comprises a step of reducing the compound of Formula (A-a) by various methods well known to the skilled person in the art, leading to the compound of Formula (A-b) wherein Y is CH₂ and X, R₁, R₂, R3, R₄, R₅, R₆, R₈, and are as defined above. According to a specific embodiment, the present invention relates to a method for the preparation of the compounds I-A, I-C, I-G, I-I and Ia-A. In a first step, the nicotinamide of Formula (E-i) is coupled to the ribose tetraacetate of Formula (D-i) by a coupling reaction in the presence of a Lewis acid, resulting in the compound of Formula (A-1-i):

In a second step, an ammoniacal treatment of the compound of Formula (A-l-i) is carried out, leading to the compound I-G:

In a third step, the mono-phosphorylation of compound I-G, in the presence of phosphoryl chloride and a trialkyl phosphate, leads to the phosphorodichloridate of Formula (B-i):

In a fourth step, the phosphorodichloridate of Formula (B-i) is hydrolyzed to yield the compound I- A:

Alternatively, in a fifth step, the phosphate compound I- A obtained in the fourth step is then reacted, with the phosphorodichloridate compound of Formula (B-i) obtained as described in the third step, to give compound la-A.

According to one embodiment, a step of reducing compound I-G is carried out, leading to compound I-I.

The compound of formula I-I is then monophosphorylated as described in the fourth step and hydrolyzed to the compound I-C.

The above method for the preparation of the compounds I-A, I-C, I-G and I-I can be easily adapted to the synthesis of compounds I-B, I-F, I-H and I-J by using the suitable starting ribose tetraacetate of Formula (D-ii):

The above method for the preparation of the dimer compound la-A can be easily adapted to the synthesis of dimer compounds la-B, la-C, la-D, la-E, la-F by using corresponding suitable phosphorodichloridate and phosphate intermediates.

Treatment and prophylaxis of polycythemia

As mentioned above, there is an unmet need for the treatment of polycythemia, especially polycythemia vera or relative polycythemia.

This is thus an object of the present invention to provide a treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia, for subjects in need thereof.

Especially, the present invention relates to a pharmaceutical composition comprising a compound of nicotinamide mononucleotide or derivatives thereof as defined hereinabove for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia, in a subject in need thereof. Polycythemia

In one embodiment, the present invention is thus directed to the treatment and/or prevention of polycythemia. Non limiting examples of polycythemia include relative and absolute polycythemia.

According to a more preferred embodiment, the polycythemia is absolute polycythemia.

According to a more preferred embodiment, the polycythemia is primary absolute polycythemia.

According to a more preferred embodiment, the polycythemia is polycythemia vera.

According to a more preferred embodiment, the polycythemia is relative polycythemia.

Thus, according to one embodiment, the pharmaceutical compound of the invention as described herein above is for use in the treatment and/or prophylaxis of polycythemia as described herein above.

According to a preferred embodiment, the compound of the invention as described herein above is for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia.

By “myeloproliferative neoplasms”, it is referred to a group of different blood cancers, including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis.

By “polycythemia”, “polycythaemia”, “polyglobulia” or “erythrocytosis”, it is referred to an abnormality in the production of blood cells, particularly the red blood cells.

By “polycythemia vera”, “polycythaemia vera”, “PV”, “Vaquez disease” or “Osler- Vaquez disease”, it is referred to a rare form of blood cancer, characterized by an overproduction of blood cells, particularly the red blood cells. Most of patients with Polycythemia vera have a mutation in the gene sequence of Janus kinase 2 (JAK2), namely JAK2 V617F, which results in a valine residue at position 617 being substituted by a phenylalanine. By “relative polycythemia”, it is referred to a group of pathologies characterized by elevated hematocrit marked with a normal to high red cell mass and a smaller than normal or decreased blood volume, due to decreased plasma volume.

Over time, patients may experience various chronic complications associated with polycythemia. According to one embodiment, complications associated with polycythemia generally involve a worsening of the disease or the development of new signs, symptoms or pathological changes that can spread throughout the body and affect other organs and can lead to the development of new diseases resulting from polycythemia.

Non limiting examples of complications associated with polycythemia vera include stroke, heart attack, deep vein thrombosis, pulmonary embolism, enlarged spleen causing abdominal pain and decreased appetite, peptic ulcers, gout or acute leukemia. Polycythemia vera may progress into other related blood diseases including myelofibrosis, acute myeloid leukemia and myelodysplastic syndrome.

Non limiting examples of complications associated with secondary polycythemia include pulmonary embolism, chronic pulmonary disease such as emphysema, chronic hypoxemia and Pickwickian syndrome.

Non limiting examples of complications associated with relative polycythemia include fatigue, general weakness, poor exercise tolerance, thromboembolic complications, pulmonary hypertension and increased blood viscosity.

Thus, according to one embodiment, the compound of the invention as described herein above is for use in the treatment and/or prevention of a complication associated with polycythemia, especially polycythemia vera or relative polycythemia as described herein above.

The present invention also concerns a pharmaceutical composition comprising at least one compound for use of the invention as described hereinabove, and at least one pharmaceutically acceptable carrier for use in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia. Subjects in need of treatment

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

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

According to one embodiment, the subject does not suffer from any other underlying pathology.

According to one embodiment, the subject is at risk of developing a polycythemia as described above. According to one embodiment, the subject is at risk of developing polycythemia vera or relative polycythemia.

According to one embodiment, the subject in need of therapeutic and/or preventive treatment is diagnosed by a health professional. For example, polycythemia may be diagnosed by various screening test routinely carried out in the medical setting, including newborn or prenatal screening, and aim to identify if the subject has a mutation in Janus kinase 2 gene.

Therapeutic effect

According to one embodiment, the use of a nicotinamide mononucleotide as described above prevents, reduces, alleviates, and/or slows down (lessens) one or more of the symptoms of polycythemia, especially polycythemia vera or relative polycythemia, and/or complications thereof, in a subject in need thereof. In a preferred embodiment, the use of a nicotinamide mononucleotide derivative as described hereinabove prevents, reduces, alleviates, and/or slows down (lessens) one or more of the symptoms of polycythemia and/or complications thereof, in a subject in need thereof

In a preferred embodiment, the use of a nicotinamide mononucleotide derivative as described hereinabove prevents, reduces, alleviates, and/or slows down (lessens) one or more of the symptoms of polycythemia vera or relative polycythemia and/or complications thereof, in a subject in need thereof

In one embodiment, the symptoms of polycythemia include, without being limited to, pruritus, gouty arthritis, peptic ulcer disease, redness and/or burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances and combinations thereof

In another embodiment, the symptoms of polycythemia include, without being limited to, pruritus, gouty arthritis, peptic ulcer disease, redness and burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances and combinations thereof, preferably fatigue, weakness, stomach pain, shortness of breath, dizziness and combinations thereof

According to one embodiment, the present invention allows to reduce hematocrit in patients with polycythemia, preferably polycythemia vera or relative polycythemia.In one embodiment, the use of a pharmaceutical composition comprising a compound of nicotinamide mononucleotide or derivatives thereof as described above prevents, reduces, alleviates, and/or slows down (lessens) the abnormally high hematocrit usually observed in polycythemia. In one embodiment, the use of a nicotinamide mononucleotide or derivatives thereof as described above prevents, reduces, alleviates, and/or slows down (lessens) the thickness of blood usually observed in polycythemia.

Over time, patients may experience various chronic complications associated with polycythemia, especially polycythemia vera or relative polycythemia. According to one embodiment, complications associated with polycythemia, especially polycythemia vera or relative polycythemia generally involve a worsening of the disease or the development of new signs, symptoms or pathological changes that can spread throughout the body and affect other organs and can lead to the development of new diseases resulting from polycythemia, especially polycythemia vera or relative polycythemia.

In one embodiment, the complications associated with polycythemia include stroke, heart attack, thrombus, deep vein thrombosis, pulmonary embolism, enlarged spleen causing discomfort, abdominal pain, decreased appetite, peptic ulcers, gout or acute leukemia and other related blood diseases such as myelofibrosis, acute myeloid leukemia or myeloplastic syndrome. Individuals with polycythemia face ongoing and evolving lifelong difficulties as a result of their disease.

Methods of administration

The compounds of the invention as describes hereinabove, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations comprising conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical compositions comprising the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may comprise one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets comprise the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be 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, a time delay material, such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol , such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant, such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.

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

Dosing regimen

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for the compound of nicotinamide mononucleotide or derivatives thereof of the invention will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 350 mg/kg per day, more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient as described hereinabove, particularly 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 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.

According to one embodiment, the subject in need thereof receives a treatment of at least one compound of nicotinamide mononucleotide or derivatives thereof as described above at a cumulative dose, preferably an annual at a cumulative dose, of 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. In one embodiment, the subject in need receives a treatment of nicotinamide mononucleotide derivative as described above as described above at a cumulative dose, preferably an annual at a cumulative dose, of greater than 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg or 1000 mg/kg.

The compound of nicotinamide mononucleotide or derivatives thereof may be administered on a regimen of 1 to 4 times per day, preferably once, twice or three times per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Monotherapy/Combination therapy

The compound(s) of Formula (I) and/or Formula (la) of the invention may be used in monotherapy or in combination therapy in a subject in need of therapeutic and/or preventive treatment. Thus, according to a first embodiment, the compound for use of the invention is administered to the subject without any other active ingredient. According to a second embodiment, the compound for use of the invention is administered to the subject in combination with at least one additional active ingredient, e.g., an active ingredient as described hereinabove. In one embodiment, the compound is administrated to the subject sequentially, simultaneously and/or separately with the other active ingredient.

In one embodiment, the other active ingredient is selected from interferon alpha-2a, interferon alpha-2b, Janus kinase 2 inhibitor, hydroxyurea, busulfan, acetylsalicylic acid, allopurinol, Hl antagonist, phosphorus-32, uramustine, pipobroman, phospholipase A2 inhibitor, or nitrogen mustards such as melphalan, preferably Janus kinase 2 inhibitor or hydroxyurea.

According to one embodiment, the pharmaceutical composition of the invention further comprises at least another active ingredient. According to one embodiment, the pharmaceutical composition for use of the invention as described hereinabove comprises, in addition to the at least one compound for use of the invention, at least one additional active ingredient, e.g., an active ingredient selected from interferon alpha-2a, interferon alpha-2b, Janus kinase 2 inhibitor, hydroxyurea, busulfan, acetylsalicylic acid, allopurinol, Hl antagonist, phosphorus-32, uramustine, pipobroman, phospholipase A2 inhibitor, or nitrogen mustards such as melphalan preferably Janus kinase 2 inhibitor or hydroxyurea. The combination can be sequential, simultaneous and/or separate.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for interferon alpha-2a or alpha-2b will be generally about 45 pg to 450pg per weekly or bi-weekly. Preferably, the dosage will be about 45 pg, 90pg, 180pg, 270pg, 360pg or 450pg per week or bi-weekly.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for Janus kinase 2 inhibitor will be generally about 5mg once a day to 15mg twice a day. Preferably, the dosage will be about 5mg once a day, 5mg twice a day, 20mg once a day, lOmg twice a day, or 15mg twice a day.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for hydroxyurea will be generally about 500mg to 3000mg per day. Preferably, the dosage will be about 500mg, lOOOmg per day, 1500mg per day, or 3000mg per day. In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for busulfan will be generally about 2mg per day to 14mg per day. Preferably, the dosage will be about 2mg per day, or 4mg per day.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for acetylsalicylic acid will be generally about 40mg per day to 900mg per day. Preferably, the dosage will be about 40mg per day, 75mg per day, 81 mg per day, lOOmg per day, 300mg per day, or 900mg per day.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for allopurinol will be generally about lOOmg per day to 900mg per day. Preferably, the dosage will be about lOOmg per day, 200mg per day, 300mg per day. 400mg per day, 500mg per day, 600mg per day, 700mg per day, 800mg per day, or 900mg per day.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for Hl antagonist will be generally about 4mg per day to 240mg per day. Preferably, the dosage will be about 4mg per day, lOmg per day, 30mg per day, 120mg per day, 180mg per day or 240 mg per day.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for anagrelide will be generally about 0.5mg per day to lOmg per day. Preferably, the dosage will be about 0.5mg per day, Img per day, 2mg per day, 2.5mg per day, 5mg per day, lOmg per day.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for phosphorus-32 will be generally about 50 MBq to 300 MBq. Preferably, the dosage will be about 100 MBq to 200 MBq, more preferably about 50 MBq, 100 MBq, 150MBq, 200 MBq or 300 MBq.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for pipobroman will be generally about 2mg per day to lOOmg per day. Preferably, the dosage will be about 2mg per day, 4mg per day, 25mg per day, 50mg per day, 70mg per day, or lOOmg per day. In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for nitrogen mustards, such as melphalan, will be generally about 2mg per day to lOmg per day. Preferably, the dosage will be about 2mg per day, 4mg per day, 6mg per day, or lOmg per day.

In the treatment of polycythemia, especially polycythemia vera or relative polycythemia, an appropriate dosage level for phospholipase A2 inhibitor will be generally about 5mg twice a day to 25mg twice a day. Preferably, the dosage will be about 5mg twice a day, lOmg twice a day, 15mg twice a day, 20mg twice a day, or 25mg twice a day.

According to one embodiment, the compound of the invention is used in combination with non-chemical therapies, such as phlebotomy or oxygen therapy. In one embodiment, the compound of the invention is administrated to the subject sequentially, simultaneously and/or separately with non-chemical therapies, such as phlebotomy or oxygen therapy. Oxygen therapy may be used to treat sleep apnea or obesity.

Kit of parts

Another object of the invention is a kit-of-parts comprising a first part comprising a compound of Formula (I) and/or Formula (la) of the invention, and a second part comprising another active ingredient, e.g., an active ingredient selected from, but not limited to, interferon alpha-2a, interferon alpha-2b, Janus kinase 2 inhibitor, hydroxyurea, busulfan or acetylsalicylic acid, allopurinol, Hl antagonist, phosphorus-32, uramustine, pipobroman, phospholipase A2 inhibitor, or nitrogen mustards such as melphalan preferably Janus kinase 2 inhibitor or hydroxyurea. The combination can be sequential, simultaneous and/or separate.

In one embodiment, the kit-of-parts of the invention comprises a first part comprising compounds I-A, I-B, la-A, la-B, la-C, or pharmaceutically acceptable salts or solvates thereof, and a second part comprising another active ingredient, e.g., an active ingredient as described hereinabove. In one embodiment, the kit of parts of the invention comprises a first part comprising a compound of Formula (I) and/or Formula (la) of the invention, and a second part comprising phlebotomy or oxygen therapy. The combination can be sequential, simultaneous and/or separate.

In one embodiment, the kit of parts as described hereinabove is used in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia.

In one embodiment, the kit of parts as described hereinabove is used in the treatment and/or prevention as described hereinabove, e.g., for an improvement/relief of polycythemia symptoms, such as, but not limited to, itching, gouty arthritis, peptic ulcer disease, redness, weight loss, fatigue, sweating, headache, vertigo, tinnitus, visual disturbances, splenomegaly, clotting, cardiac shunting, chronic pulmonary disease and combinations thereof.

In another embodiment, the kit of parts as described hereinabove is used in the treatment and/or prevention as described hereinabove, e.g., for an improvement/relief of polycythemia symptoms, such as, but not limited to, pruritus, gouty arthritis, peptic ulcer disease, redness and burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances and combinations thereof, preferably fatigue, weakness, stomach pain, shortness of breath, dizziness and combinations thereof.

According to one embodiment, the kit-of-parts for use according to the invention allows to reduce hematocrit in patients with polycythemia, preferably polycythemia vera or relative polycythemia.

Method of treatment This invention also relates to the use of a pharmaceutical composition as described hereinabove in the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia as described hereinabove.

This invention also relates to the use of a pharmaceutical composition as described hereinabove in the manufacture of a medication for the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia, as described hereinabove.

This invention also relates to a method for the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia, as described hereinabove in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition as described hereinabove.

This invention also relates to a method for the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia, as described hereinabove in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound of the invention and another active ingredient, e.g., an active ingredient as described hereinabove. In particular, the invention also relates to a method for the treatment and/or prevention of polycythemia, especially polycythemia vera or relative polycythemia, wherein the kit of parts as described above is administered.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a line chart showing the proliferation level of HEL 92.1.7 cells in presence of compound I-A at 0.01 pM, 0.06pM, 0.32pM, 1.6pM, 8pM and 40pM, and in absence of compound I-A, from Oh to 72h, using image analysis by Incucyte software.

Figure 2 is a histogram showing the proliferation of HEL 92.1.7 cells in presence of compound I-A at 0.01 pM, 0.06pM, 0.32pM, 1.6pM, 8pM and 40pM, and in absence of compound I-A, from Oh to 72h, using image analysis by Incucyte software. Figure 3 is a histogram showing the cytotoxicity of HEL 92.1.7. cells in presence of compound I-A at 0.32pM, 8pM and 40pM, and in absence of compound I-A, over 72h, using image analysis by Incucyte software.

Figure 4 is a line chart showing the percentage hematocrit in presence of compound I-A at 500 mg per day. The line chart comprises the administration of phlebotomy before the administration of compound I-A. The line chart comprises the administration of interferon alpha-2a in combination with compound I-A. The line chart comprises the administration of Janus kinase 2 inhibitor in combination with compound I-A.

Figure 5 is a line chart showing the hematocrit percentage in presence of compound I-A at 500 mg per day, over 14 months. The line chart comprises the administration of interferon alpha-2a in combination with compound I-A. The line chart comprises the administration of Janus kinase 2 inhibitor in combination with compound I-A.

Figure 6 is a line chart showing the hematocrit percentage in presence of compound I-A at 700 mg per day, over 5 years. The line chart comprises a phlebotomy before the administration of compound I-A.

EXAMPLES

The present invention is further illustrated by the following examples.

Example 1: Synthesis of compounds of the invention

Materials and Methods

All materials were obtained from commercial suppliers and used without further purification. Thin-layer chromatography was performed 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, Merck). Melting points were determined either on a digital melting point apparatus (Electrothermal IA 8103) and are uncorrected or on a Kotler bench type WME (Wagner & Munz). IR, ¹H, ¹⁹F and ¹³C NMR spectra confirmed the structures of all compounds. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer and NMR spectra were recorded, using CDCh, CD3CN, D2O or DMSO-de as solvent, on a Bruker AC 300, Advance DRX 400 and Advance DRX 500 spectrometers, for ¹H, 75 or 100 MHz for ¹³C and 282 or 377 MHz for ¹⁹F spectra. Chemical shifts (5) were expressed in parts per million relative to the signal indirectly (i) to CHCh (5 7.27) for ^XH and (ii) to CDCh (5 77.2) for ¹³C and directly (iii) to CFCh (internal standard) (5 0) for ¹⁹F. Chemical shifts are given in ppm and peak multiplicities are designated as follows: s, singlet; br s, broad singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quadruplet; quint, quintuplet; m, multiplet. The high-resolution mass spectra (HRMS) were obtained from the "Service central d'analyse de Solaize" (Centre national de la recherche scientifique) and were recorded on a Waters spectrometer using electrospray-TOF ionization (ESI-TOF).

General experimental procedures

Step 1: Synthesis of the compound of formula A- 1

The compound of formula D (1.0 equiv.) is dissolved in dichloromethane. Nicotinamide of formula E (1.50 equiv.) and TMSOTf (1.55 equiv.) are added at room temperature. The reaction mixture is heated under reflux and stirred until the reaction is complete. The mixture is cooled to room temperature and filtered. The filtrate is concentrated to dryness to give tetraacetate A-l.

Step 2: Synthesis of the compound of formula A-2

Tetraacetate A-l is dissolved in methanol and cooled to -10 °C. Ammonia 4,6 M in methanol (3,0 equivalents) at -10 °C is added and the mixture is stirred at this temperature until the reaction is complete. Dowex HCR (H+) resin is added up to pH 6-7. The reaction mixture is heated to 0 °C and filtered. The resin is washed with a mixture of methanol and acetonitrile. The filtrate is concentrated to dryness. The residue is dissolved in the acetonitrile and concentrated to dryness. The residue is dissolved in the acetonitrile to give a solution of the compound of formula A-2.

Step 3: Synthesis of the compound of formula A-3 The solution of the crude compound of formula A-2 in acetonitrile is diluted with trimethyl phosphate (10.0 equivalents). The acetonitrile is distilled under vacuum and the mixture is cooled to -10 °C. Phosphorus oxychloride (4,0 equivalents) is added at 10 °C and the mixture is stirred at 10 °C until the reaction is complete. Steps 4 and 5: Synthesis of the compound of formula I-A The mixture obtained in step 3 above is hydrolyzed by the addition of a 50/50 mixture of acetonitrile and water, followed by the addition of methyl tert-butyl ether. The mixture is filtered and the solid is dissolved in water. The aqueous solution is neutralized by the addition of sodium bicarbonate and extracted with dichloromethane. The aqueous layer is concentrated to dryness to yield the crude formula I-A compound, which is purified on a DOWEX 50wx8 column with elution in water followed by a silica gel chromatographic column. Step 4 and step 5: Synthesis of compound of formula Ia-A The mixture is hydrolyzed by addition of a 50/50 mixture of acetonitrile and water, followed by addition of tert-butyl methyl ether. The mixture is filtered and the solid is dissolved in water. The aqueous solution is neutralized by addition of sodium bicarbonate and extracted with dichloromethane. The aqueous layer is concentrated to dryness to give a crude mixture of NMN and di-NMN of formula Ia-A. Isolation of di-NMN of formula Ia-A: NMN and di-NMN of formula Ia-A are separated by purification on Dowex 50wx8 with water elution. The fractions containing di-NMN are concentrated to dryness. The residue is purified by column chromatography on silica gel (gradient isopropanol/water). Pure fractions are combined and concentrated. The residue is freeze-dried to afford di-NMN as a beige solid. ³¹P RMN : į (ppm, reference 85% H3PO4 : 0 ppm dans D2O) = -11.72 ; ¹H RMN : į (ppm, reference TMS: 0 ppm dans D2O) = 4.20 (ddd, JH-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, JH-H = 5.0 Hz, 2H), 4.59 (m, 2H), 6.16 (d, JH-H = 5.4 Hz, 2H), 8.26 (dd, JH-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) ; ¹³C RMN : į (ppm, reference TMS: 0 ppm dans D2O) = 64.84 (CH2), 70.73 (CH), 77.52 (CH), 87.11 (CH), 99.88 (CH), 128.65 (CH), 133.89 (Cq), 139.84 (CH), 142.54 (CH), 146.04 (CH), 165.64 (Cq); MS (ES+) : m/z = 122.8 [Mnicotinamide + H]+, 650.8 [M + H]+. Synthesis of compound of formula Ia-B Phosphorus oxychloride (3.0 eq.) is added to trimethylphosphate (20.0 eq.) at -5°C. ȕ-NR chloride (1.0 eq.) is added by portions at -5°C and the reaction mixture stirred overnight at -5°C. Morpholine (3.0 eq.) is added dropwise at -10/0°C and the mixture stirred for 2-3 h. a-NMN (1.0 eq.) is then added by portions at -5°C and the reaction mixture stirred at -5°C overnight. Hydrolysis is performed by dropwise addition of water (5 vol.) at -10/0°C and the mixture is stirred until complete homogenization at 10-15°C. The reaction mixture is then extracted with dichloromethane (6*10 vol.) and the aqueous phase neutralized by eluting through Purolite A600E formate form resin (theoretical amount to neutralize HCl coming from POCl3). The eluate is then concentrated on vacuum at 45/50°C to give the crude containing the Į,ȕ-diNMN of formula 010. Elution with water through Dowex 50wx8100-200 mesh H⁺ form resin allows removing of some impurities. Fractions containing compound 010 are combined and concentrated on vacuum at 45-50°C. The crude is then purified by preparative chromatography on Luna Polar RP 10μm stationary phase with elution with a 10mM NaH₂PO₄ aqueous solution. Pure fractions are combined and eluted with water on Purolite C100EH H⁺ form resin (needed quantity to fully exchange Na⁺ by H⁺), then eluted on Purolite A600E acetate form resin (needed quantity to fully exchange H₂PO₄- by acetate). The eluate is concentrated on vacuum and the residue freeze-dried to afford compound Ia-B as a white solid. ³¹P RMN : į (ppm, reference 85% H3PO4 : 0 ppm dans D2O) = -11.87, -11.69, -11.46, -11.29; RMN : į (ppm, reference TMS: 0 ppm dans 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); ¹³C RMN : į (ppm, reference TMS: 0 ppm dans D2O) = 64.83, 64.87 (CH2), 65.30, 65.35 (CH2), 70.65 (CH), 70.74 (CH), 71.92 (CH), 77.51 (CH), 87.03, 87.10 (CH), 87.19, 87.26 (CH), 96.57 (CH), 99.83 (CH), 126.89 (CH), 128.54 (CH), 132.44 (Cq), 133.81 (Cq), 139.85 (CH), 140.92 (CH), 142.50 (CH), 143.49 (CH), 145.06 (CH), 145.97 (CH), 165.64 (Cq), 165.88 (Cq); MS (ES+) : m/z = 122.8 [Mnicotinamide + H]+, 650.9 [M + H]+. Synthesis of compound of formula Ia-C Phosphorus oxychloride (3.0 eq.) is added to trimethylphosphate (20.0 eq.) at -5°C. Į-NR chloride (1.0 eq.) is added by portions at -5°C and the reaction mixture stirred overnight at -5°C. Morpholine (3.0 eq.) is added dropwise at -10/0°C and the mixture stirred for 2-3 h. Į-NMN (1.0 eq.) is then added by portions at -5°C and the reaction mixture stirred at -5°C overnight. Hydrolysis is performed by dropwise addition of water (5 vol.) at -10/0°C and the mixture is stirred until complete homogenization at 10-15°C. The reaction mixture is then extracted with dichloromethane (6*10 vol.) and the aqueous phase neutralized by eluting through Purolite A600E formate form resin (theoretical amount to neutralize HCl coming from POCl₃). The eluate is then concentrated on vacuum at 45/50°C to give the crude containing the Į,Į-diNMN of formula Ia-C. Elution with water through Dowex 50wx8100-200 mesh H⁺ form resin allows removing of some impurities. Fractions containing the compound Ia-C are combined and concentrated on vacuum at 45-50°C. The crude is then purified by preparative chromatography on Luna Polar RP 10μm stationary phase with elution with a 10mM NaH₂PO₄ aqueous solution. Pure fractions are combined and eluted with water on Purolite C100EH H⁺ form resin (needed quantity to fully exchange Na⁺ by H⁺), then eluted on Purolite A600E acetate form resin (needed quantity to fully exchange H₂PO₄- by acetate). The eluate is concentrated on vacuum and the residue freeze-dried to afford compound Ia-C as a white solid. ³¹P RMN : į (ppm, reference 85% H3PO4 : 0 ppm dans D2O) = -11.40; ¹H RMN : į (ppm, reference TMS: 0 ppm dans 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); ¹³C RMN : į (ppm, reference TMS: 0 ppm dans D₂O) = 65.37 (CH2), 70.70 (CH), 71.95 (CH), 87.30 (CH), 96.62 (CH), 126.91 (CH), 132.45 (Cq), 140.94 (CH), 143.52 (CH), 145.07 (CH),165.90 (Cq); MS (ES+) : m/z = 122.7[Mnicotinamide + H]+, 650.8 [M + H]+. Example 2: Evaluation of compounds of the invention on a patient with polycythemia vera (figures 1, 2 and 3) The aim of the present study was to evaluate, the effects of administration of compound I-A at 0.01μM, 0.06 μM, 0.32 μM, 1.6 μM, 8 μM, and 40 μM, as modulator of polycythemia vera in erythroblast cell line. I. Materials and Methods 1. Cell culture HEL 92.1.7 is an erythroblast cell line isolated from the bone marrow of a 30-year-old, Caucasian, male patient with erythroleukemia. HEL 92.1.7 cells were cultured in RPMI 1640 media supplemented with 10% FBS at 37 °C in 5% CO2. The mechanism of proliferation of the HEL 92.1.7 cell line was driven by constitutive activation of JAK2 tyrosine kinase secondary to V617F gain-if-function mutation. 2. Proliferation evaluation Proliferation of cells were evaluated by live cell nuclear labeling using Incucyte Nuclight Rapid Red Dye for live cell nuclear labeling. 3. Image analysis Two view fields per well were quantified. Images were analyzed using an Incucyte software. Number of cells was quantified by phase contrast. 4. Protocol Cells seeded had a density of 10,000 cells per well. Were added to the cells compound I-A at 0.01μM, 0.06 μM, 0.32 μM, 1.6 μM, 8 μM, 40 μM and no compound I-A (control condition). 5. Experimental conditions Condition description: Condition 1: no compound I-A (control condition) Condition 2: compound I-A at 0.01μM, Condition 3: compound I-A at 0.06 μM, Condition 4: compound I-A at 0.32 μM, Condition 5: compound I-A at 1.6 μM, Condition 6: compound I-A at 8 μM, Condition 7: compound I-A at 40 μM. II. Results and discussion 1. Cell proliferation Figures 1, 2 and 3 show the cell proliferation of the HEL 92.1.7. The results demonstrate that treatments with compound I-A (0.01 μM, 0.06 μM, 0.32 μM, 1.6 μM, 8 μM, 40 μM, 200 μM) led to a significant decrease of the cell proliferation compared to the condition control without compound I-A, over 72 hours (figures 1, 2 and 3). Figure 2 shows a saturation effect of the treatment from 1000 μM of compound I-A. III. Conclusion These results indicate that treatments with compound I-A reduce the proliferation of red blood cells, illustrating their potential role in therapy for polycythemia, especially polycythemia vera. Example 3: Evaluation of compounds of the invention on a patient with polycythemia vera (figures 4 and 5)

The purpose of this clinical study is to evaluate the effects of administration of compound I-A at 500 mg per day, as modulator of polycythemia vera.

1. Clinical profile

The test is carried out in a male patient bom on 19 December 1970.

The patient has the V617F mutation in the Janus kinase 2 gene.

2. Treatment

Before the treatment period with compound I-A, the patient was treated with phlebotomy and interferon alpha-2a.

During the treatment period with compound I-A, the patient was also treated with Janus kinase 2 inhibitor.

Firstly, the compound I-A is administered at 500 mg per day for two months.

Secondly, the compound I-A is not administered for 4 months.

Since then, the patient is being treated with compound I-A at 500 mg per day.

The combination of treatments is thus sequential.

The test is carried out with compound I-A in combination with interferon alpha-2a at 90 pg per week, and then in combination with Janus kinase 2 inhibitor at 20 mg per day, then 10 mg per day, then 5 mg per day.

3. Results and discussion

The figure 5 shows a decrease of Hematocrit (Ht) in correlation with the administration of the pharmaceutical composition according to the present invention.

The first day of administration of compound I-A, the percentage of Hematocrit was 43%. After two months of administration of compound I-A, the percentage of Hematocrit was 38%. Therefore, the results of figure 5 show a decrease of 5% in Hematocrit after two months of administration of the pharmaceutical composition according to the present invention.

4. Conclusion

Therefore, it was demonstrated that the compound I-A according to the present invention can decrease the Hematocrit level in the blood of a subject, especially a subject having polycythemia vera.

Example 4: Evaluation of compounds of the invention on a patient with relative polycythemia (figure 6)

The purpose of this clinical study is to evaluate the effects of administration of compound I-A at 700 mg per day, as modulator of secondary polycythemia.

1. Clinical profile

The test is carried out in a male patient born on 16 July 1943.

The patient is diagnosed with relative polycythemia.

2. Test

Firstly, the compound I-A is administered at 700 mg per day for 7 months.

Secondly, the compound I-A is not administered for 5 and a half months.

Thirdly, the compound I-A is administered at 700 mg per day for 3 years.

Before the administration of compound I-A, the patient was treated with phlebotomies for several years.

3. Results and discussion

The figure 6 shows a decrease of Hematocrit (Ht) and Platelet levels in correlation with the administration of the pharmaceutical composition according to the present invention.

Before the administration of compound I-A, Hematocrit was 47.3%, and the platelet count was 242 g/L. Thus, the administration of the pharmaceutical composition according to the present invention, from the first administration, led to a decrease of Hematocrit by 3.1, and a decrease of platelet count by 32 g/L.

Before the administration of compound I-A, Hematocrit was 53%, and the platelet count was 214 g/L. Thus, the administration of the pharmaceutical composition according to the present invention, from the second administration, led to a decrease of Hematocrit by 8.9%, and a decrease of platelet count by 4 g/L. 5 years after the administration of compound I-A, Hematocrit was 44.1%, and platelet count was 210

4. Conclusion

Therefore, it was demonstrated that the compound I-A according to the present invention can decrease the Hematocrit level and the platelet count in the blood of a subject, especially a subject having relative polycythemia.

Claims

1. A compound for use in the treatment and/or prevention of polycythemia, the compound being selected from compound I-A, compound I-B, compound I-C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-I, compound I- J, compound la-A, compound la-B, compound la-C, compound la-D, compound la-E, compound la-F, compound la-G, compound la- H, compound Ia-I, and combinations thereof, and pharmaceutically acceptable salts and solvates thereof, wherein

2. The compound for use according to claim 1, wherein the compound is selected from compound I- A, compound I-B, compound I-C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-I, compound I- J, and combinations thereof

3. The compound for use according to claim 1, wherein the compound is selected from compound la-A, compound la-B, compound la-C, compound la-D, compound la- E, compound la-F, compound la-G, compound la-H, compound Ia-I, and combinations thereof

4. The compound for use according to any one of claims 1 to 3, wherein the compound is selected from compound I-A, I-B, la-A, la-B, la-C, and combinations thereof

5. The compound for use according to claims 1 to 4, wherein polycythemia is polycythemia vera.

6. The compound for use according to claims 1 to 4, wherein polycythemia is relative polycythemia.

7. The compound for use according to claims 1 to 6, wherein the treatment and/or prevention comprise the improvement/relief of pruritus, gouty arthritis, peptic ulcer disease, redness and burning feeling on the skin, weight loss, fatigue, sweating, headaches, vertigo, dizziness, weakness, night sweats, insomnia, shortness of breath, angina, excessive bleeding or bruising, peripheral neuropathy, swelling and pain in the stomach, bone pain, tinnitus, visual disturbances, and combinations thereof, preferably fatigue, weakness, stomach pain, shortness of breath, dizziness, and combinations thereof

8. The compound for use according to claims 1 to 7, wherein the compound is administered in combination with non-chemical therapy such as phlebotomy or oxygen therapy, wherein the combination is sequential, simultaneous and/or separate.

9. The compound for use according to claims 1 to 8, wherein the administration of the compound allows to reduce hematocrit in patients with polycythemia.

10. A pharmaceutical composition for use in the treatment and/or prevention of polycythemia, the pharmaceutical composition comprising the compound as defined in any one of claims 1 to 9 and at least one pharmaceutically acceptable carrier.

11. The pharmaceutical composition for use according to claim 10, wherein the pharmaceutical composition further comprises at least one other active ingredient, preferably selected from interferon alpha-2a, interferon alpha-2b, Janus kinase 2 inhibitor, hydroxyurea, busulfan or acetylsalicylic acid, allopurinol, Hl antagonist, phosphorus-32, uramustine; pipobroman, phospholipase A2 inhibitor, or melphalan, preferably Janus kinase 2 inhibitor or hydroxyurea, wherein the administration is sequential, simultaneous and/or separate.

12. A kit of parts for use in the treatment and/or prevention of polycythemia, comprising a compound as defined in any one of claims 1 to 9 in one part and at least one other active ingredient in another part.

13. The kit of parts for use according to claim 12, wherein the other active ingredient is selected from interferon alpha-2a, interferon alpha-2b, Janus kinase 2 inhibitor, hydroxyurea, busulfan, acetylsalicylic acid, allopurinol, Hl antagonist, phosphorus-32, uramustine; pipobroman, phospholipase A2 inhibitor, or melphalan, preferably Janus kinase 2 inhibitor or hydroxyurea, wherein the administration is sequential, simultaneous and/or separate.