EP4157284A1

EP4157284A1 - Use of nmn to reduce immunodepression and immunosenescence

Info

Publication number: EP4157284A1
Application number: EP21728902.4A
Authority: EP
Inventors: Guillaume BERMOND; Laurent GARCON
Original assignee: Nuvamid SA
Current assignee: Nuvamid SA
Priority date: 2020-05-29
Filing date: 2021-05-26
Publication date: 2023-04-05
Also published as: WO2021239850A1; CN115968294A; US20230136569A1; FR3110836A1; FR3110836B1

Abstract

The invention relates to nicotinamide mononucleotide, one of the pharmaceutically acceptable derivatives thereof, one of the pharmaceutically acceptable precursors thereof or one of the pharmaceutically acceptable salts thereof, for use in reducing immunosenescence and/or enhancing immune response to vaccination, and further relates to compositions containing same.

Description

USING NMN TO REDUCE IMMUNODEPRESSION AND IMMUNOSENESCENCE

FIELD OF THE INVENTION

The present invention relates to the use of NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, for the treatment and prevention of immunosuppression, and more particularly immunosenescence. The present invention also relates to compositions comprising NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, for the treatment and prevention of immunosuppression, and more particularly. immunosenescence.

TECHNICAL BACKGROUND

[0002] Immunosuppression is the phenomenon of reduction of the primary immune response of an individual. For example, an immunocompromised subject may not exhibit a satisfactory immune defense response to bacterial and viral infections. Immunosuppression can be either hereditary, or caused by immunosuppressive therapy, or caused by a disease such as cancer, HIV infection, or an individual's aging.

[0003] Immunosenescence is a form of immunodepression and is the phenomenon of marked loss of efficiency of the immune system, whether it is innate and / or adaptive immunity, induced by the aging of the individual. Immunosenescence helps to increase the sensitivity of the elderly to viral and bacterial infections in particular. There are many causes of immunosenescence. Immunosenescence can be caused by old age, disease such as cancer or osteoporosis, smoking, diet, pollution, and other environmental factors.

[0004] Immunosenescence affects various types of cells in the bone marrow and thymus, mature lymphocytes in peripheral blood and secondary lymphatic organs, as well as elements of the innate immune system. The immune system can be divided into an innate part, composed mainly of monocytes, natural killer cells (NK) and dendritic cells (DC), and an adaptive part, represented by B and T lymphocytes. Innate immunity is better preserved, while more serious, often harmful and age-dependent changes occur in the adaptive immune system. Other changes in immunosenescence include involution of the thymus, which is characterized by a reduction in the overall size of the organ and replacement of functional cortex and medullary tissue with fat, reduction of number of naive T and B cells emerging from the thymus and the variety of immune cells. Naive cells are T or B cells that have not yet encountered antigen. Immunosenescence results in less efficient lymphocyte production, activation and reactivity. This results in increased susceptibility to inflammatory reactions and autoimmunity and decreased reactions to infections, tumors and vaccinations.

[0005] In addition, the immunological modifications induced by aging result in the appearance of a chronic low-level inflammation referred to in English by the term “inflammaging”. This inflammation is associated with a release of large quantities of pro-inflammatory agents and proteases in the tissues and in particular in the mucous membranes, inducing low-level inflammation. Chronic low-level inflammation can be defined as inflammation showing no classic clinical signs of inflammation namely redness, swelling, warmth, pain. However, there is a gradual increase in markers of inflammation such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-a), the receptor antagonist to interleukin 1 (IL-IRa) , C-reactive protein (CRP). This chronic low-level inflammation is present in the elderly and mobilizes the immune system, which cannot then defend the body in an appropriate manner against the intrusion of bacteria, fungi or viruses. This poses obvious public health problems.

[0006] All of the immune and inflammatory alterations associated with immunosenescence therefore pose obvious public health problems. There is therefore a need to develop new compositions making it possible to reduce the immunosenescence.

SUMMARY OF THE INVENTION

[0007] These objectives are achieved by virtue of nicotinamide mononucleotide (NMN) and compositions comprising it for their use in the prevention and / or treatment of immunosuppression, preferably immunosenescence.

The present invention relates to nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, for in the prevention and / or treatment of immunosenescence .

In one embodiment, the NMN derivative can be chosen from alpha nicotinamide mononucleotide (a-NMN), dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I):

[Chem. 1] or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its pharmaceutically acceptable crystals thereof, in which:

X is selected from O, CH ₂ , S, Se, CHF, CF ₂ and C = CFl ₂ ;

R 1 is selected from H, azido, cyano, C 1 -C 6 alkyl, thio-C 1 -C 6 alkyl, C 1 -C 8 heteroalkyl and OR; wherein R is selected from F1 and C1-C8 alkyl;

R2, R3, R4 and R ₅ are selected independently of one another from Fl, halogen, azido, cyano, hydroxyl, C ₁ -C ₁₂ alkylthio-C ₁ -C ₁₂ heteroalkyl, C ₁ -C ₁₂ , C ₁ -C ₁₂ haloalkyl and OR; wherein R is selected from F1, C ₁ -C ₁₂ alkyl, C (0) (Ci-Ci ₂ ) alkyl, C (0) NFI (Ci-Ci ₂ ) alkyl, C (0) 0 (Ci-Ci ₂ ) alkyl, C (0) aryl, C (0) (Ci-Ci ₂ ) alkyl aryl, C (0) NFI (Ci-Ci ₂ ) alkyl aryl, C (0) 0 (Ci-Ci ₂ ) alkyl aryl and C (0) CFI RAANFI2; wherein RAA is a side chain selected from a proteinogenic amino acid;

R ₆ is selected from F1, azido, cyano, C1-Cg alkyl, C1-Cg thio-alkyl, C1-Cg heteroalkyl and OR; wherein R is selected from F1 and C1-Cgalkyl;

R ₇ is chosen from in which n is an integer equal to 1 or 3; in which

Rg and Rio are independently selected from each other from OFI, ORn, NFIR13, NR13R14, alkyl, Ci-Cg alkenyl, _C2-C₆, alkynyl a C _2-C₆, a cycloalkyl C ₃ -C ₁₀ , a C ₅ -C ₁₂ aryl, (Ci- Cg) alkyl aryl, (Ci-Cg) aryl alkyl, (Ci-Cg) heteroalkyl, (Ci-Cg) heterocycloalkyl, a heteroaryl and NHCHR _A R _{A '} C (0) RI ₂ ; in which :

Ru is chosen from a C1-Cioalkyl, C ₃ -Ciocycloalkyl, C ₅ -Cig aryl, C ₁ -C ₁₀ alkylaryl, C ₅ - C ₁₂ substituted aryl, C ₁ -C ₁₀ heteroalkyl, C ₃ -C ₁₀ heterocycloalkyl, C ₁ -C ₁₀ haloalkyl, a heteroaryl, - (CH ₂ ) nC (0) (Ci-Ci ₅ ) alkyl, - (CH ₂ ) nOC (0) (Ci-Ci ₅ ) alkyl, - (CH ₂ ) nOC (0) 0 (Ci-Ci ₅ ) alkyl, - (CH ₂ ) „SC (0) (Ci-Ci ₅ ) alkyl, - (CFl ₂ ) nC (0) 0 (Ci-Ci ₅ ) alkyl and - ( CFl ₂₎ nC (0) 0 (Ci-Ci ₅₎ aryl; wherein n is an integer selected from 1 to 8; and P (0) (0H) 0P (0) (0H) ₂ ; R ₁₂ is selected from H, C ₁ -C ₁₀ alkyl, C ₂ -Cg alkenyl, C ₂ -Cg alkynyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -Cioheterocycloalkyl, C ₅ -Cig aryl , C ₁ -C ₄ alkylaryl and C ₅ -C ₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and cyano; and

RA and RA- are independently selected from H, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₁₀ thio-alkyl, C ₁ -C ₁₀ hydroxylalkyl, C ₁ -C ₁₀ alkylaryl and C ₅ -C ₁₂ aryl, C ₃ -C ₁₀ heterocycloalkyl, a heteroaryl, - (CH ₂ ) ₃ NHC (= NH) NH ₂ , (lH-indol-3- yl) methyl, (1H-imidazol-4-yl) methyl and a side chain chosen from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₆ alkoxy, halogen, nitro and cyano; Where

Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R ₉ -R ₁₀ - represents

-CH ₂ -CH ₂ -CHR-; wherein R is selected from H, (Cs-Ce) aryl and (Cs-Ce) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and cyano; Where

Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -Rg-Rio- represents -O-CH ₂ -CH ₂ -CHR-O-; in which R is chosen from H, a (Cs-Ce) aryl and (C ₅ -Ce) heteroaryl group, in which said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (Ci-C ₆ ) alkyl, a (Ci-C ₆ ) alkoxy and cyano;

Rg is selected from H, OR, NHR ₁₃ , NR ₁₃ R ₁₄ , NH-NHR ₁₃ , SH, CN, N ₃ and halogen; wherein R ₁₃ and R ₁₄ are independently selected from H, (C1-Cg) alkyl and (C1-Cg) alkyl aryl;

Y is selected from CH, CH ₂ , C (CH ₃ and CCH ₃ ;

- represents a single or a double bond along Y; and

^{LLL /} · represents the alpha or beta anomer depending on the position of Ri or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals or the compound of formula (Ia):

[Chem. 2] or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals, in which

X'i and X'2 are independently selected from O, CH2, S, Se, CHF, CF2, and C = CFl2;

R'i and R'13 are independently selected from F1, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR, wherein R is selected from F1 and a C1-C8 alkyl,

R _'2, R' 3, R _'4, R' 5, R '9, R' _10, R _'11, R' ₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, a C ₁ -C ₁₂ thioalkyl a C ₁ -C ₁₂ alkyl, hetero-alkyl C -C _12, haloalkyl Cl-Cl ₂ and OR wherein R may be selected from H, alkyl C ₁ -C ₁₂ , a C (0) (C ₁ -C ₁₂ ) alkyl, a C (0) NFI (Ci-Ci ₂ ) alkyl, a C (0) 0 (Ci-Ci ₂ ) alkyl, a C ( O) aryl, a C (0) (C ₁ -C ₁₂ ) aryl, a C (0) NFI (Ci-Ci ₂ ) alkyl aryl, a C (0) 0 (Ci-Ci ₂ ) alkyl aryl or a group C (0) CFIR _AA NFI2 in which R _AA is a side chain selected from a proteinogenic amino acid;

R '6 and R'g are independently selected from H, azido, cyano, C1-C8 alkyl and OR, wherein R is selected from F1 and C1-C8 alkyl;

R '7 and R' 14 are independently selected from F1, OR, NFIR, NRR ', N FH-NFH R, SFH, CN, N3 and halogen, wherein R and R' are independently selected from F1 and (Ci -Cg) alkyl aryl;

Y'i and Y ' ₂ are independently selected from CFI, CFI ₂ , C (CFl ₃ ) ₂ or CCFI ³ ;

M 'is chosen from F1 or a suitable counterion; represents a single or double bond depending on Y'i and Y'2; and -vwv represents an alpha or beta anomer depending on the position of R'I and R'13; and their combinations. In a first preferred embodiment, the pharmaceutically acceptable derivative is the compound of formula (I).

In a variant of the first embodiment, X represents oxygen.

In a variant of the first embodiment, Ri and R ₆ each represent, independently of one another, a hydrogen.

In a variant of the first embodiment, R ₂ , R ₃ , R ₄ and R ₅ each represent, independently of one another, a hydrogen or an OH.

In a variant of the first embodiment, Y represents a CH.

In a variant of the first embodiment, Y represents a CH2.

In a variant of the first embodiment, R ₇ represents hydrogen.

In a variant of the first embodiment, R ₇ represents P (0) (OH) ₂ .

In a variant of the first embodiment,

X represents oxygen; and or

R 1 and R ₆ each independently represents hydrogen; and or

R ₂ , R ₃ , R ₄ and R ₅ each independently represents hydrogen or R ₂ , R ₃ , R ₄ and R ₅ independently represents OH; and or

Y represents CH or CH2; and or

R ₇ represents P (0) RgRio, in which Rg and Rio are independently selected from OH, ORn, NHR13, NR13R14, C1-Cgalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-Ciocycloalkyl, C5-C12 aryl, Ci -Cg aryl alkyl, Ci-Cg alkyl aryl, Ci-Cgheteroalkyle, Ci-Cgheterocycloalkyl, heteroaryl and NHCRARA C (0) RI2.

In a particularly preferred variant of the first embodiment, the compound of the invention is chosen from the compounds of formula I-A to I-J:

[0020] [Table 1]

In a second preferred embodiment, the pharmaceutically acceptable derivative is the compound of formula (Ia).

In a variant of the second embodiment, CΊ and X'2 each independently represent oxygen.

In a variant of the second embodiment, R'7 and R'14 each independently represent an NH2.

In a variant of the second embodiment, R'I and / or R'13 each independently represent hydrogen.

In a variant of the second embodiment, R'6 and / or R'8 each independently represent hydrogen.

In a variant of the second embodiment, R'2, R'3, R'4 _, R'5, R'9, R'10, R'11 and R'12 each independently represent hydrogen.

In a variant of the second embodiment, R'2, R'3, R'4 _, R'5, R'9, R'10, R'11 and R'12 each independently represent an OH.

In a variant of the second embodiment, Y'1 and Y'2 each independently represent a CH.

In a variant of the second embodiment, Y'1 and Y'2 each independently represent a CH2.

In a variant of the second embodiment, the compound according to the invention is chosen from the compounds of formula la-A to la-l:

[0031] [Table 2]

9

SUBSTITUTE SHEET (RULE 26) [0033] [Chem.3]

In a preferred embodiment, the pharmaceutically acceptable derivative is NMN-H:

[0035] [Chem 4]

Advantageously, the pharmaceutically acceptable precursor is nicotinamide riboside (denoted NR):

[0037] [Chem.5] or dihydronicotinamide riboside (noted -NR-H) of formula: [Chem.6]

Advantageously, the nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered orally, ocular, sublingual, parenteral, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation.

Preferably, the nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered orally or parenterally, preferably orally.

Preferably, the parenteral route can be chosen from among the intraarterial route, the intravenous route, the intramuscular route, the subcutaneous route, the intraperitoneal route, more preferably the intravenous route.

Advantageously, the nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be in the form of a tablet, a capsule, or '' a sachet, a granule, a soft capsule, a pellet, a lyophilisate, a suspension, a gel, a syrup, a solution, an emulsion water / oil, oil / water emulsion, oil, cream, milk, spray, ointment, ampoule, suppository, eye drops , vaginal egg, vaginal capsule, liquid for inhalation, dry powder inhaler, pressurized metered valve inhaler, powder.

Preferably, the nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, is in the form of a powder, a suspension, or a solution, a water / oil emulsion or an oil / water emulsion. Advantageously, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be used in an amount of between 0.01 mg / kg / day and 500 mg / kg / day, preferably between 0.1 mg / kg / day and 350 mg / kg / day, more preferably between 0.5 and 100 mg / kg / day, even more preferably 5 mg / kg / day at 50 mg / kg / day.

Advantageously, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered to a mammal, preferably a human.

In one embodiment, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered to a human aged at least 45 years, preferably of 'at least 50 years, preferably at least 55 years, preferably at least 60 years, preferably at least 65 years, more preferably at least 70 years, still more preferably d at least 75 years of age for the treatment of immunosenescence.

In one embodiment, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered to a human aged at least 15 years, preferably of at least 20 years, more preferably at least 25 years, more preferably at least 30 years, even more preferably at least 35 years for the prevention of immunosenescence.

Advantageously, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered in combination with at least one other therapeutic agent.

In at least one embodiment, the at least one other therapeutic agent is a vaccine which can be chosen from live attenuated vaccines, inactivated vaccines, multivalent vaccines or combination vaccines.

In at least one embodiment, said vaccine is chosen from a vaccine against a virus, a bacterium, a parasite or a yeast and / or a fungus, or their combinations.

Preferably, said vaccine is a vaccine against a virus selected from Influenzavirus, Coronavirus, Respirovirus, Pneumovirus, Metapneumovirus, Adenovirus, Enterovirus, Rhinovirus, Hepatovirus, Erbovirus, Aphtovirus, Norovirus, Alphavirus, Rubivirus, Flavivirus, Hepivirus, Pestivirus, Ebola, Morbillivirus, Rubulavirus, Henipavirus, Arenavirus, Orthobunyavirus, Phlebovirus, Rotavirus, Simplexvirus, Varicellovirus, Papillomavirus, Cytomegalovirus or their combinations.

More preferably, the vaccine against the virus is chosen from Influenza irus, Coronavirus, Rhinovirus, Respirovirus, Pneumovirus or Metapneumovirus, more preferably Influenzavirus.

In one embodiment, said vaccine is a vaccine against a bacterium selected from Pneumococcus, Streptococcus, Corynebacterium, Clostridium, Mycobacterium, Bordetella, Neisseiri and their combinations.

Preferably, the Mycobacterium is Mycobacterium tuberculosis. Preferably, said Nesseiria is Neisseria meningitis.

In one embodiment, said vaccine is a vaccine against a parasite selected from Schistosoma, Leishmania, Babesia and their combinations.

In one embodiment, said vaccine is a vaccine against a yeast and / or a fungus selected from Trichophyton, Toxoplasma, Eimeria, Candida and their combinations.

In one embodiment, the at least one therapeutic agent is radiotherapy, chemotherapy or combinations thereof.

Advantageously, the radiotherapy can be chosen from X or gamma irradiation.

Advantageously, the chemotherapy can be chosen from an antimetabolite, an alkylating agent, a topoisomerase inhibitor, an anthracycline, and their combinations.

Advantageously, the alkylating agent can be chosen from dacarbazine, temozolomide, streptozocin, cyclophosphamide, ifofosfamide, melphalan, procarbazine, busulfan, triphosphoramide, hexamethylmelamine, chlormethine, salts platinum such as cisplatin, carboplatin, oxaliplatin and combinations thereof.

Advantageously, the at least one therapeutic agent is an immunosuppressive treatment.

Advantageously, the immunosuppressive treatment can be chosen from an anti-metabolite, a TNF alpha inhibitor, an interleukin-1 (IL1) inhibitor, a cortisone derivative, a calcineurin inhibitor, rapamycin, a anti-CD25 antibodies, lymphoablative therapy and combinations thereof.

Advantageously, the antimetabolite can be chosen from azathioprine, methotrexate, mycophenolic acid, mycophenolate mofetil, fludarabine, and their combinations. Advantageously, the cortisone derivative is chosen from betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone, triamcinolone and their combinations.

Advantageously, the calcineurin inhibitor can be chosen from cyclosporine, tacrolimus and their combinations.

Advantageously, the lymphoablative treatment can be chosen from chemotherapy, radiotherapy, an alkylating agent, an intercalator, an anthracycline, anti-thymocyte globulins, a CD52 monoclonal antibody, an OKT3 monoclonal antibody and their combinations.

Advantageously, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered concomitantly with the administration of at least one additional therapeutic agent.

Advantageously, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered for a period of between 10 and 60 days, preferably between 14 and 42 days, more preferably for about 30 days prior to the administration of at least one additional therapeutic agent.

Advantageously, the immunosuppression can be a primary immunosuppression or a secondary immunosuppression.

Advantageously, the primary immunosuppression is of hereditary origin and can be chosen from a predominantly humoral primary immunosuppression, a predominantly cellular primary immunosuppression, a combined deficiency, a deficiency in complement proteins, or a deficiency of the. macrophage and polynucelar activity.

Advantageously, the predominantly humoral primary immunosuppression can be chosen from agammaglobulinemia linked to sex or Bruton's disease, common hypogammaglobulinemia of variable expression or a selective deficit in immunoglobulins such as a deficiency in IgA, IgD , IgG and / or IgM.

Advantageously, the predominantly cellular primary immunosuppression can be chosen from 22qll microdeletion or Di George's syndrome, Hong and Good's syndrome, Nezelof's syndrome, purine nucleoside phosphorylase deficiency, isolated T lymphocyte deficiency. . Advantageously, the combined deficit can be chosen from the severe combined immunodeficiency by adenosine deaminase deficiency. denuded lymphocyte syndrome, congenital amegakaryocytosis with developmental abnormality of T and B lines, Wiskott-Aldrich syndrome, ataxia Telangiectasia, chronic mucocutaneous candidiasis, acrodermatitis enteropathica, Hyper IgE syndrome.

Advantageously, the complement protein deficit is chosen from the complement component 1 (C1) inhibitor deficiency (hereditary angioedema), C3 deficiency, C4 deficiency, C5, C6 deficiency, C7, C8 and / or C9.

Advantageously, the deficit in the activity of the macrophage and of the polynuclear can be chosen from septic granulomatosis, myeloperoxidase deficiency, Chediak Higashi syndrome. actin dysfunction, Shwachman syndrome.

In one embodiment, the immunosuppression can be secondary.

Advantageously, the secondary immunosuppression can be due to an HIV infection, sarcoidosis, thymoma, thymic hypoplasia, acute leukemia, chronic lymphoid leukemia, malignant lymphoma, multiple myeloma, Waldenstrom's disease, cortisone derivative therapy, immunosuppressive therapy, thymus removal, chemotherapy, radiotherapy, viral infection, bacterial infection, infection caused by fungus and / or yeast, infection caused by a parasite , dietary deficiency, autoimmune disease, chronic renal failure, blood malignancy, toxic blood disease, asplenia, hyposplenia, metabolic disease, cancer affecting the immune system, drug therapy, splenectomy, drug addiction , alcoholism, immunosenescence and combinations thereof, preferably immunosenescence.

Advantageously, the metabolic disease can be chosen from type 2 diabetes, cirrhosis, non-alcoholic fatty liver disease, obesity, and combinations thereof.

In one embodiment, the treatment can be immunosuppressive therapy, corticosteroid, chemotherapy, radiotherapy, and combinations thereof.

Advantageously, the immunosuppression can be characterized by at least one of the markers chosen from neutropenia, lymphopenia, a CD4 / CD8 ratio of less than 1, and their combination.

Preferably, the invention is particularly useful for treating or preventing immunosenescence. Advantageously, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered to a human aged at least 40 years old, preferably at least 45 years old, preferably at least 50 years old, preferably at least 55 years old, preferably at least 60 years old, preferably at least 65 years old, more preferably at least 70 years old, still more more preferably at least 75 years old, even more preferably at least 80 years old to treat immunosenescence.

Advantageously, NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, as well as the compositions comprising it can be administered to a human aged at least 15 years, preferably at least 20 years, more preferably at least 25 years, more preferably at least 30 years, even more preferably at least 35 years for the prevention of immunosenescence

Advantageously, the reduction in immunosenescence can be measured by the reduction of a marker chosen from thymic involution, at least one cytokine chosen from IL1, IL2, IL6, IL12, IL15, IL18, IL22; TNF alpha, Interferon gamma, C reactive protein, amounts of senescent T cells resident in spleen, level of circulating IgG immunoglobulin produced by memory B cells, level of circulating IgA immunoglobulin produced by memory B cells, at and their combinations.

Advantageously, the reduction in immunosenescence can be measured by the increase of a marker chosen from the production of new naive T cells, the ability to respond to new antigens, the accumulation of memory T cells, the number of circulating B cells, levels of circulating immunoglobulin produced by naive cells (IgD and / or IgM), vaccine immunogenicity, increased CD4 / CD8 ratio, IL1-Ralpha level, level of IL4, IL10 level, TGFbeta 1 level, cell sedimentation rate, and combinations thereof.

A subject of the invention is also a composition comprising the nicotinamide mononucleotide, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives, one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient for prevention and / or the treatment of immunosuppression, preferably immunosenescence, as defined above.

DEFINITIONS

In the present invention, the following terms have the following meaning. Unless otherwise indicated, the nomenclature of substituents which are not explicitly defined in the present invention is obtained by naming the terminal part of the functionality followed by the functionality adjacent to the point of attachment.

"Alkyl" by itself or as part of another substituent, denotes a hydrocarbyl radical of formula CnH2n + 1 in which is a number greater than or equal to 1. In general, the alkyl groups of This invention comprises from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 2 carbon atoms. The alkyl groups can be linear or branched and can be substituted as indicated in the present invention. The alkyls suitable for the implementation of the invention can be chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers such as n-pentyl and iso-pentyl, and hexyl and its isomers such as n-hexyl and iso-hexyl, heptyl and its isomers (eg n-heptyl, iso-heptyl), octyl and its isomers (eg n-octyl, iso-octyl), nonyl and its isomers (eg n-nonyl, iso-nonyl), decyl and its isomers (eg n-decyl, iso-decyl), undecyl and its isomers, dodecyl and its isomers. Preferably, the alkyl groups can be chosen from 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. The saturated and branched alkyl groups can be chosen, without limitation, from isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyle, 2-methylpentyle, 3-methylpentyle, 4-methylpentyle, 2-methylhexyl, 3-methylhexyle, 4-methylhexyle, 5- methylhexyle, 2,3-dimethylbutyle, 2,3-dimethylpentyle, 2,4-dimethylpentyle, 2,3-dimethylhexyle, 2,4-dimethylhexyle, 2,5- dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3- dimtheylpentyle, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4- ethylhexyle, 2-methyl-2-ethylpentyle, 2-methyl-3-ethylpentyle, 2- methyl-4-ethylpentyle, 2-methyl-2-ethylhexyle, 2-methyl-3-ethylhexyle, 2-methyl-4-ethylhexyle, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. Preferred alkyl groups are: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. Cx-Cy-alkyls refer to alkyl groups which include from x to y carbon atoms.

When the suffix "ene"("alkylene") is used in conjunction with an alkyl group, it means that the alkyl group as defined herein has two single bonds as points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylene. 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 have between 2 and 12 carbon atoms, preferably between 2 and 8 carbon atoms, and even 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 groups similar.

The term "alkynyl", as used herein, denotes a class of monovalent unsaturated hydrocarbyl groups, in which the unsaturation results from the presence of one or more triple bond (s) carbon-carbon. Alkynyl groups generally and preferably have the same number of carbon atoms as described above for 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, etc.

[0092] "Alkoxy" denotes an alkyl group as defined above, which is attached to another part by an oxygen atom. Examples of alkoxy groups include methoxy, isopropoxy, ethoxy, tert-butoxy, and the like. The alkoxy groups can be optionally substituted with one or more substituents. The alkoxy groups included in the compounds of this invention may be optionally substituted with a solubilizing group.

[0093] "Aryl" as used herein refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (eg phenyl) or more aromatic rings fused together (eg naphthyl) or covalently linked, generally containing 5 to 18 atoms, preferably 5 to 12, more preferably 6 to 10, of which at least one ring is aromatic. The aromatic ring can optionally comprise one or two additional rings (cycloalkyl, heterocyclyl or heteroaryl) which are fused therein. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic systems listed herein. Examples of aryl include phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalene-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5- 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.

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

"Alkylaryl" denotes an aryl group substituted by an alkyl group. "Amino acid" denotes an alpha-amino carboxylic acid, that is to say a molecule comprising a carboxylic acid functional group and an amine functional group in the alpha position of the carboxylic acid group, for example a proteinogenic amino acid or a non-proteinogenic amino acid.

"Proteinogenic amino acid" denotes an amino acid which is incorporated into proteins during the translation of messenger RNA by ribosomes in living organisms, that is to say 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).

"Non-proteinogenic amino acid" as used herein refers to an amino acid which is not naturally encoded or found in the genetic code of a living organism. Non-limiting examples of non-proteinogenic amino acids are ornithine, citrulline, argininosuccinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, d-aminolevulinic acid, b -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 "cycloalkyl" as used herein is a cyclic alkyl group, i.e. a monovalent, saturated or unsaturated hydrocarbyl group having 1 or 2 ring structures. The term "cycloalkyl" includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups can have 3 or more carbon atoms in the ring and generally, according to the present invention, have 3 to 10, more preferably 3 to 8 carbon atoms and even more preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

By "pharmaceutically acceptable excipient", it is meant to a vehicle or an inert support used as solvent or diluent in which the active principle is formulated and / or administered, and which does not produce an undesirable reaction, allergic or the like when administered to an animal, preferably a human. This includes all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents, absorption retardants and other similar ingredients. For human administration, the preparations must meet standards of sterility, general safety and purity, such as as required by regulatory offices, such as for example the FDA or GEMA. 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 “white blood cells” or “leukocytes” is understood to mean the cells of the immune system. This generic term encompasses neutrophils, eosinophils, basophils, T and B lymphocytes as well as monocytes.

[0102] "Halogen" or "halo" means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro and chloro.

[0103] "Haloalkyl", alone or in combination, denotes an alkyl radical having the meaning as defined above, in which one or more hydrogen atoms are replaced by a halogen as defined above. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. Cx-Cy-haloalkyl and Cx-Cy-alkyl denote alkyl groups which have from x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

"Heteroalkyl" denotes an alkyl group as defined above, in which one or more carbon atoms are replaced by a heteroatom chosen from oxygen, nitrogen and sulfur atoms. In heteroalkyl groups, heteroatoms are linked along the alkyl chain only to carbon atoms, i.e. each heteroatom is separated from all other heteroatom by at least one carbon atom. However, the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms can optionally be quaternized. A heteroalkyl is bonded to another group or molecule only through a carbon atom, i.e. the linking atom is not selected from heteroatoms included in the heteroalkyl group.

[0105] The term "heteroaryl" as used herein, alone or as part of another group, denotes, without limitation, aromatic rings of 5 to 12 carbon atoms or ring systems containing 1 or 2 rings which are fused or covalently linked, generally containing 5 or 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, the nitrogen and sulfur heteroatoms possibly possibly be oxidized and the nitrogen heteroatoms possibly being quaternized. These rings can be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Among the examples no limitative of such heteroaryls, mention may be made of furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, pyridiazinyl, oxatriazinyl, thiatriazolyl, pyridiazinyl, thiatriazolyl, pyridiazinyl, thiatriazolyl, pyridiazine triazinyl, imidazo [2, 1 -b] [1, 3] thiazolyl, thieno [3, 2-b] furanyl, thieno [3, 2-b] thiophenyl, thieno [2,3-d] [1,3] thiazolyl, thieno [2,3-d] imidazolyl, tetrazolo [1,5-a] pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazol benzisoxazolyl, 2,1- benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyle, 1,2,3-benzoxadiazolyle, 2,1,3- benzoxadiazolyl, 1,2,3- benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo [1,2-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.

[0106] When at least one carbon atom in a cycloalkyl group is replaced by a heteroatom, the resulting ring is referred to herein as "heterocycloalkyl" or "heterocyclyl".

The terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo", as used herein by themselves or as part of another group, denote non-aromatic, fully saturated or partially cyclic groups. unsaturated (eg, 3- to 7-membered monocyclic, 7 to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) that have at least one heteroatom in at least one ring containing one carbon atom. 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 can optionally be quaternized. Any of the carbon atoms of the heterocyclic group can be substituted with an oxo (eg piperidone, pyrrolidinone). The heterocyclic group can be attached to any heteroatom or carbon atom of the ring or ring system, when valence permits. The rings of multi-ring heterocycles can be fused, bridged and / or linked by one or more spiro atoms. Exemplary non-limiting heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-isothiazolidinyl, piperidinyl, 3H-isothiazolidinyl, piperidinyl, homzolinopinipolinopinipolinopipolinopipolinopinyl, 2-pipolinopinipolinopipolinopinyl, 2-pipolinopinipolinopinyl, inderazolinopinyl, 3H-iso-iso-indolinopidazolidinyl, oxazolidine , 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, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2- yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulf oxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl and morpholin-4-yl.

The term "leukopenia" designates a blood disorder characterized by a number of white blood cells less than 4000 those / µl of blood.

The term "lymphopenia" denotes a blood disorder characterized by a lower than normal number of lymphocytes during a blood count, ie less than 1500 per mm ³ .

The term "neutropenia" is a hematological disorder characterized by a low level of granulocytes, or polymorphonuclear, neutrophils in the blood. Normal neutropenia is set at less than 2000 neutrophils / mi of blood. Mild neutropenia corresponds to a level of 1000 to 1500 neutrophils / ml of blood. Moderate neutropenia corresponds to a level of 500 to 1000 neutrophils / ml of blood. Severe neutropenia corresponds to a level of less than 500 neutrophils / ml of blood. Agranulocytosis corresponds to a neutrophil count of less than 100 / mm3 of blood.

The expression “elderly person” designates a human chosen from a human aged at least 60 years, a human at least 65 years old, a human at least 70 years old, a human at least 75 years old. years old, a human of at least 80 years old, a human of at least 85 years old, a human at least 90 years old, a human at least 95 years old.

The term "precursor" as used here also denotes the pharmacologically acceptable derivatives of the compounds of formula (I) or (Ia) such as esters of which the product of in vivo biotransformation is the active drug. The precursors are characterized by increased bioavailability and are readily metabolized to active compounds in vivo. The precursors suitable for the purposes of the invention include in particular the carboxylic esters, in particular the alkyl esters, the aryl esters, the acyloxyalkyl esters and the carboxylic esters of dioxolene; ascorbic acid esters.

[0113] "Pharmaceutically acceptable" means approved or likely to be approved by a regulatory body or listed in a pharmacopoeia recognized for use in animals, and more preferably in humans. It may be a substance which is not biologically or otherwise undesirable, i.e. the substance can be administered to an individual without causing adverse biological effects or harmful interactions with one of the components of the composition in which it is contained. Preferably, a “pharmaceutically acceptable” salt or excipient denotes any salt or any excipient authorized by the European Pharmacopoeia (denoted “Ph. Eur.”) And the American Pharmacopoeia (denoted by “United States Pharmacopeia (USP)” in English).

The term "active principle" denotes a molecule or a substance whose administration to a subject slows down or stops the progression, worsening or deterioration of one or more symptoms of a disease or a condition. ; relieves symptoms of a disease or condition; cures a disease or condition. According to one of these embodiments, the therapeutic ingredient is a small molecule, natural or synthetic. According to another, the therapeutic ingredient is a biological molecule such as, for example, an oligonucleotide, an siRNA, a miRNA, a DNA fragment, an aptamer, an antibody and the like. "Pharmaceutically acceptable salts" include the acid and base addition salts of such salts. Suitable acid addition salts are formed from acids which form non-toxic salts. These are for example acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate , esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate and trifluoroacetate, tannoroactrate, salts xinofoate. Suitable basic salts are formed from bases which form non-toxic salts. Mention may be made, as examples, of the salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2- (diethylamino) ethanol, ethanolamine, morpholine, 4- (2-hydroxyethyl) morpholine and zinc. Acid and base hemi-salts can also be formed, for example, hemi-sulphates and chemical calcium salts. Preferred pharmaceutically acceptable salts are hydrochloride / chloride, bromide / hydrobromide, bisulfate / sulfate, nitrate, citrate and acetate.

Pharmaceutically acceptable salts can be prepared by one or more of these methods: by reacting the compound with the desired acid; ii. reacting the compound with the desired base; iii. by removing a protective group labile in acid or basic medium from a suitable precursor of the compound or by opening the ring of a suitable cyclic precursor, for example a lactone or a lactam, using the desired acid; or iv. converting one salt of the compound into another by reaction with a suitable acid or by means of a suitable ion exchange column.

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

[0117] "Solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

The term "substituent" or "substituted" means that a hydrogen radical on a compound or a group is replaced by any desired group which is substantially stable under the conditions of the reaction in an unprotected form or when it is. protected by a protective group. Examples of preferred substituents include, but are not limited to, halogen (chloro, iodo, bromo or fluoro); an alkyl; alkenyl; alkynyl, as described above; a hydroxy; an alkoxy; a nitro; a thiol; a thioether; an imine; a cyano; an amido; a phosphonato; a phosphine; a carboxyl; a thiocarbonyl; a sulfonyl; a sulfonamide; a ketone; an aldehyde; an ester; an oxygen (-O); haloalkyl (eg, trifluoromethyl); cycloalkyl, which may be condensed or non-condensed monocyclic or polycyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocycloalkyl, which may be condensed or non-condensed monocyclic or polycyclic (eg, pyrrolidinyl, piperidinyl, piperazinyl, piperazinyl, piperazinyl, piperidinyl, piperazinyl morpholinyl or thiazinyl), monocyclic or polycyclic fused or unfused, aryl or heteroaryl (e.g. aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), monocyclic or polycyclic fused or unfused (e.g. aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), monocyclic or polycyclic fused or unfused (e.g. pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrazinyl, isonazolinyl, pyrazolyl, pyrrazinyl, quinazolinyl, pyrazolyl, pyridyl, isonazolinyl, pyrazolyl, pyrrazinyl, quinazolinyl, pyrazolyl, pyrazinyl, isonazolinyl, pyrazolyl, pyrrazinyl, quinazolinyl, pyrazolyl, pyrrazinyl, quinazolinyl, pyrazolyl, pyrrazinyl, quinazolinyl, pyrazolyl, pyrazinyl, isonazolyl, pyrazolyl, pyrrazinyl, quinazolinyl, pyrazolyl, pyrrazinyl, quinazolinyl , benzimidazolyl, benzothiophenyl or benzofuranyl); amino (primary, secondary or tertiary); CO ₂ CH ₃ ; CONH2; OCH ₂ CONH ₂ ; NH ₂ ; S0 ₂ NH ₂ ; OCHF ₂ ; CF ₃ ; OCF ₃ ; and these groups can also be optionally substituted by a structure or a fused ring bridge, for example -OCH ₂ O- These substituents can optionally be further substituted by a substituent selected from these groups. In certain Representations, the term "substituent" or the adjective "substituted" denotes a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, a heteroarylalkyl, a haloalkyl, - C (0) NRnRi2, -NR _I3 C (0) R _I4 , a halo, -OR13, cyano, nitro, a haloalkoxy, -C (0) R13, -NR11R12, -SR13, - C (0) 0Ri3, -0C (0) Ri3, -NRi ₃ C (0) NRnRi ₂ , -0C (0) NRUR _I2 , -NR _I3 C (0) 0R _I4 , -S (0) rR13, -NRi ₃ S (0) rRi ₄ , - 0S (0) rRi ₄ , S (0) rNRnRi ₂ , -O, -S, and -N-R13, where r is 1 or 2; Ru and R12, for each occurrence, are, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or Ru and R12 taken together with the nitrogen to which they are attached are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R13 and R _I4 for each occurrence are, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In some embodiments, the term "substituent" or the adjective "substituted" denotes a solubilizing group.

The term "administration", or a variant of this term (for example, "to administer"), means to provide the active principle, alone or in the framework of a pharmaceutically acceptable composition, to the patient in whom / to whom the The condition, symptom or disease must be treated or prevented.

[0120] "Treat", "cure" and "treatment" as used in the present invention are intended to include the alleviation, alleviation or ablation of a condition or disease and / or its associated symptoms.

[0121] "Prevent", "prevent" and "prevention" as used in the present invention refer to a method of delaying or preventing the onset of a condition or disease. and / or its related symptoms, to prevent a patient from acquiring a condition or disease, or to reduce the risk of a patient for contracting a condition or disease.

[0122] The bonds of an asymmetric carbon can be represented here using a solid triangle ( ^"" " ^* ), a dotted triangle ( ^""") or a zigzag line (' ^wv ').

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts for its use in the prevention and / or treatment of immunosuppression, preferably immunosenescence .

[0124] A subject of the present invention is also a composition comprising NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient for its use in the prevention and / or treatment of immunosuppression, preferably immunosenescence.

Nicotinamide adenine dinucleotide (NAD) is a coenzyme present in all living cells. NAD exists in the cell either in its oxidized form NAD + or in its reduced form NADH. The role of NAD is that of an electron transporter involved in the redox reactions of the metabolism. NAD is also involved in many cellular processes such as ADP ribosylation as part of post-translational protein modifications.

[0126] NAD can be synthesized de novo by the cell from amino acids such as tryptophan or aspartate. However, this synthesis is marginal because the main route of NAD synthesis is the rescue route by which the cell, and mainly the cell nucleus, recycles compounds to reform NAD from precursors. The precursors of NAD include niacin, nicotinamide riboside, nicotinamide mononucleotide, and nicotinamide.

NMN is one of the compounds allowing the synthesis of NAD by the rescue route and has the formula:

[0128] [Chem. 7] [0129] The inventors have in fact discovered that the use of NMN makes it possible to reduce immunosuppression, and more particularly immunosenescence, or at the very least to reduce the signs thereof.

[0130] In a preferred embodiment, the NMN is in the form of a zwitterion. The term “zwitterion” is understood to mean a molecular chemical species possessing electric charges of the opposite sign and located, in general, on non-adjacent atoms of the molecule.

Use

[0131] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, as well as the compositions comprising them can be used to treat or prevent immunosuppression, preferably immunosenescence.

[0132] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered to a mammal, preferably a human.

[0134] The primary immunosuppression is of hereditary origin and can be chosen from humoral predominance, cellular predominance, a combined deficiency, a deficiency in complement proteins, or a deficiency in the activity of the macrophage and the polynucelar.

[0135] The predominantly humoral primary immunosuppression can be chosen from agammaglobulinemia linked to sex or Bruton's disease, common hypogammaglobulinemia of variable expression or a selective deficit in immunoglobulins such as a deficiency in IgA, IgD, IgG and / or IgM.

The predominantly cellular primary immunosuppression can be chosen from 22qll microdeletion or Di George's syndrome, Hong and Good's syndrome, Nezelof's syndrome, purine nucleoside phosphorylase deficiency, isolated T lymphocyte deficiency.

The combined deficit can be chosen from the severe combined immunodeficiency by adenosine deaminase deficiency. denuded lymphocyte syndrome, congenital amegakaryocytosis with developmental abnormality of T and B lines, Wiskott-Aldrich syndrome, ataxia Telangiectasia, chronic mucocutaneous candidiasis, acrodermatitis enteropathica, Hyper IgE syndrome. The deficit of macrophage and polynuclear activity can be chosen among septic granulomatosis, myeloperoxidase deficiency, Chediak Higashi syndrome. actin dysfunction, Shwachman syndrome.

[0138] The complement protein deficiency can be chosen from the complement component 1 (C1) inhibitor deficiency (hereditary angioedema), C3 deficiency, C4 deficiency, C5, C6, C7 deficiency. , C8 and / or C9.

[0139] The immunosuppression can be secondary or acquired. In particular, secondary immunosuppression may be due to HIV infection, sarcoidosis, thymoma, thymic hypoplasia, acute leukemia, chronic lymphoid leukemia, malignant lymphoma, multiple myeloma, Waldenstrom's disease, treatment by a cortisone derivative, immunosuppressive therapy, thymus removal, chemotherapy, radiotherapy, viral infection, bacterial infection, infection caused by fungus and / or yeast, infection caused by a parasite, nutritional deficiency, autoimmune disease, chronic renal failure, hematologic malignancy, toxic hematologic disease, asplenia, hyposplenia, metabolic disease, cancer affecting the immune system, drug therapy, splenectomy, drug addiction, alcoholism, immunosenescence and combinations thereof, preferably immunosenescence.

[0140] The metabolic disease can be selected from type 2 diabetes, cirrhosis, non-alcoholic fatty liver disease, obesity, and combinations thereof.

[0141] The treatment can be immunosuppressive treatment, a corticosteroid, chemotherapy, radiotherapy and their combinations.

Advantageously, the radiotherapy can be chosen from X-ray or gamma irradiation.

[0143] The chemotherapy can be chosen from an antimetabolite, an alkylating agent, a topoisomerase inhibitor, an anthracycline, and combinations thereof.

The alkylating agent can be chosen from dacarbazine, temozolomide, streptozocin, cyclophosphamide, ifofosfamide, melphalan, procarbazine, busulfan, triphosphoramide, rhexamethylmelamine, chlormethine, platinum salts such as cisplatin, carboplatin, oxaliplatin and their combinations. The antimetabolite can be selected from azathioprine, methotrexate, mycophenolic acid, mycophenolate mofetil, fludarabine, and combinations thereof. Anthracycline can be selected from doxorubicin, pegylated doxorubicin, daunorubicin, epirubucin, mitoxantrone, pirarubicin, idarubicin, acinomycin D, amsacrine, and combinations thereof. The topoisomerase inhibitor can be chosen from topoisomerase 1 inhibitors and topoisomerase 2 inhibitors and their combination. We can by way of example of topoisomerase 1 inhibitors, mention irinotecan and topotecan. As examples of topoisomerase 2 inhibitors, mention may be made of anthracyclines and etoposide.

[0145] In at least one embodiment, the at least one therapeutic agent is an immunosuppressive treatment.

Advantageously, the antimetabolite can be chosen from azathioprine, methotrexate, mycophenolic acid, mycophenolate mofetil, fludarabine, and their combinations.

Advantageously, the cortisone derivative is chosen from betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone, triamcinolone and their combinations.

Advantageously, the immunosuppression can be characterized by at least one of the markers chosen from neutropenia, lymphopenia, a CD4 / CD8 ratio of less than 1, and their combination. The CD4 + / CD8 + ratio is the ratio of helper T cells (with the CD4 surface marker) and cytotoxic T cells (with the CD8 surface marker). The CD4 + / CD8 + ratio in the peripheral blood of healthy adults and mice is approximately 2: 1, and an altered ratio may indicate diseases related to immunodeficiency or autoimmunity. An inverted CD4 + / CD8 + ratio (i.e. less than 1/1) indicates an impaired immune system.

[0152] Preferably, the invention is particularly useful for treating or preventing immunosenescence.

The reduction in immunosenescence can be measured by the reduction of a marker chosen from thymic involution, at least one cytokine chosen from IL1, IL2, IL6, IL12, IL15, IL18, IL22; TNF alpha, Interferon gamma, the increase of at least one cytokine selected from IL1-Ralpha, IL4, IL10, TGFbeta 1.1a C reactive protein, the amounts of senescent T cells resident in the spleen, the level of immunoglobulin IgG circulating produced by memory cells B, the level of circulating immunoglobulin IgA produced by memory cells B, to and their combinations. Thymic involution corresponds to a reduction in the volume of the thymus. The reduction in immunosenescence can be observed as the size of the thymus increases.

[0154] The reduction in immunosenescence can also be measured by the increase of a marker chosen from the production of new naive T cells, the capacity to respond to new antigens, the accumulation of memory T cells, the number circulating B cells, the level of circulating immunoglobulin IgD produced by naive cells, the level of circulating immunoglobulin IgM produced by naive cells, vaccine immunogenicity, CD4 / CD8 ratio, ILIRa level, blood level IL4 level, IL10 level, TGFbeta-1 level, sedimentation rate, and combinations thereof.

In particular, the inventors have demonstrated that the use of the compounds according to the invention, preferably the compounds 1A and 1B, make it possible in particular to increase the size of the thymus, to increase the number of CD8 + thymocytes, of increase the number of B lymphocytes in the bone marrow, increase the number of CD38 + B lymphocytes in the bone marrow, increase the number of CD45 + B lymphocytes in the bone marrow, increase the number of B lymphocyte precursors in bone marrow, increase the number of CD45 + T cells in the spleen, increase the number of activated B cells in the spleen, increase the number of memory B cells in the spleen, increase the number of cells Germline B cells in the spleen, increase the number of CD4 + T cells in the spleen, increase the number of memory CD4 + T cells in the spleen, increase the number of CD4 + effector T cells, increase the number of CD4 + T cells in the spleen, to increase the number memory CD8 + T cells in the spleen, increase the number of CD8 + effector T cells, increase the number of CD8 + memory effector T cells, increase the number of CD4 + and CD8 + cells after activation and reduce expression of ILlO.

[0156] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered to a human aged at least 40 years old, preferably at least 45 years old, preferably at least 50 years old, preferably at least 55 years old, preferably at least 60 years old, preferably at least 65 years old, more preferably at least 70 years old, even more preferably at least 75 years old, even more preferably at least 80 years old to treat immunosenescence.

NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, as well as compositions comprising it can be administered to a human at least 15 years old, preferably at least 20 years old, more preferably at least 25 years old, more preferably at least 30 years old, of even more preferably at least 35 years for the prevention of immunosenescence.

These analyzes can be carried out according to any method well known to those skilled in the art, from serum or whole blood taken from the subject, preferably whole blood.

Method of administration and dosage form

Nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, as well as the compositions comprising them can be administered orally, ocular, sublingually, parenterally, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation.

Preferably, the parenteral route can be chosen from the intraarterial route, the intravenous route, the intramuscular route, the subcutaneous route, the intraperitoneal route, more preferably the intravenous route.

Preferably, the NMN and the composition according to the invention are administered orally.

The composition according to the invention can be in the form of a tablet, a capsule, a sachet, a granule, a soft capsule, a lyophilizate, a lozenge. , a suspension, a gel, a syrup, a solution, a water / oil emulsion, an oil / water emulsion, an oil, a cream, a milk from a spray, ointment, ampoule, suppository, eye drops, vaginal ovum, vaginal capsule, liquid for inhalation, dry powder inhaler, pressurized valve inhaler doser. Preferably, the composition according to the invention is in the form of a gastro-resistant capsule or of a sublingual tablet.

The term “gastro-resistant” is understood to mean a galenic form which does not dissolve in the stomach. Such dosage forms are delayed release, that is to say they have a coating or a coating composition resistant to the acidic pH of the stomach (pH <2) to dissolve in the intestine. The gastro-resistant character is determined by following the test established by the European Pharmacopoeia. Briefly, the gastro-resistance of a capsule is measured in acid 0.1 M hydrochloric acid at 37 ° C as a disintegrating medium in a disintegrating apparatus. This medium mimics the physicochemical conditions of the stomach. The capsules are incubated in this medium for 1 hour. The capsule must not show any signs of disintegration or cracks which could lead to loss of content. The capsule is then incubated for 1 hour in a phosphate buffer solution of pH 6.8 at 37 ° C., this solution mimicking the conditions of the intestinal environment in accordance with the recommendations of the European Pharmacopoeia. The capsule should be completely disintegrated within an hour.

The term “sublingual tablet” is understood to mean a galenic form placed under the tongue so that the active principle is absorbed by the sublingual mucosa, and in particular by the vein and artery ranins.

The galenic form of the composition according to the invention can also be immediate release: such a galenic form allows rapid absorption of the NAD precursor and thus a reduced time of action. Immediate-release dosage forms are in particular dispersible, orodispersible, effervescent tablets and oral lyophilisates.

The galenic form of the composition according to the invention can also be a delayed release. Dissolution and absorption of the NAD precursor take place in the intestine, which limits gastric irritation or the degradation of fragile active ingredients at acidic pH. They are mainly gastroresistant forms, that is to say that the tablets or granules are covered with a polymeric film, insoluble in acidic medium but permeable to water in alkaline medium or of the lipid type degraded by lipases. intestinal.

The galenic form of the composition according to the invention can also be sustained and sequential release. The forms with sequential release (release at specific time intervals) and prolonged (continuous release of the active principle until exhaustion) promote the spreading of the release of the active principle over time in order to maintain an effective plasma concentration for longer in the cell. organism of the patient.

[0169] 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 dose can 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 tablet form containing 1.0 to 1000 milligrams of the active ingredient, especially 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 symptomatic patient dose adjustment treat. For example, the dosage can be between 100mg / day and 5000mg / day, preferably between 500mg / day and 1000mg / day. The Compounds can be administered on a schedule of 1 to 4 times per day, preferably one, two or three times per day. Three times a day is fine. The duration of treatment depends on the patent and is determined by the doctor. It can range from one day to a year or even longer, preferably from one week to three months, more preferably from two weeks to six weeks. It will be understood, however, that the specific dose level and frequency of dosing as well as the duration for a given patient may vary and will depend on various factors, including the activity of the specific compound employed, the metabolic stability and the duration of action of. this compound, age, body weight, general health, sex, diet, method and time of administration, rate of excretion, combination of drugs, and the host subjected to treatment.

[0170] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered at a daily dose of 10 mg / kg, with a maximum of 1 g / day.

[0171] Preferably, the NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered at a daily dose of 10 mg / kg, with a maximum of 1 g /. day for a period of 10 to 60 days, preferably for a period of 14 to 42 days, more preferably for a period of about 30 days preceding the administration of at least one additional therapeutic agent, preferably a vaccine or a vaccine booster.

[0172] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered on day 1, on day 2, on day 3, on day 4, on day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, day 28, day 29, day 30, on day 31.

[0173] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be used in an amount of between 5 mg / day and 1000 mg / day.

Therapeutic combinations

Advantageously, the NMN and the composition according to the invention are used in combination with at least one additional therapeutic agent. In one embodiment, the composition according to the invention comprises NMN or a pharmaceutically acceptable salt, a pharmaceutically acceptable excipient and at least one additional therapeutic agent. In the context of the present invention, an "excipient" denotes any substance other than NMN in the composition and having no therapeutic effect. The excipient does not chemically interact with NMN or any additional therapeutic agent.

[0176] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, as well as the compositions comprising it can be administered in combination with at least one other therapeutic agent.

[0177] In at least one embodiment, the at least one other therapeutic agent is a vaccine which can be chosen from live attenuated vaccines and inactivated vaccines.

[0178] In one embodiment, said vaccine is chosen from a vaccine against a virus, a bacterium, a parasite or a yeast and / or a fungus, or their combinations.

[0179] Preferably, said vaccine is a vaccine against a virus chosen from Influenzavirus, Coronavirus, Respirovirus, Pneumovirus, Metapneumovirus, Adenovirus, Enterovirus, Rhinovirus, Hepatovirus, Erbovirus, Aphtovirus, Norovirus, Alphavirus, Rubivirus, Flavivirus, Hepacivirus, Ebola, Morbillivirus, Rubulavirus, Henipavirus, Arenavirus, Orthobunyavirus, Phlebovirus, Rotavirus, Simplexvirus, Varicellovirus, Papillomavirus, Cytomegalovirus or their combinations.

[0180] In one embodiment, said vaccine is a vaccine against a bacterium selected from Pneumococcus, Streptococcus, Corynebacterium, Clostridium, Mycobacterium, Bordetella, Neisseiri and their combinations.

[0181] In one embodiment, said vaccine is a vaccine against a parasite selected from Schistosoma, Leishmania, Babesia and their combinations.

[0182] In one embodiment, said vaccine is a vaccine against a yeast and / or a fungus selected from Trichophyton, Toxoplasma, Eimeria, Candida and their combinations.

[0183] In one embodiment, said vaccine is a vaccine against a bacterium selected from Pneumococcus, Streptococcus, Corynebacterium, Clostridium, Mycobacterium, Bordetella, Neisseiri and their combinations.

[0184] Preferably, the Mycobacterium is Mycobacterium tuberculosis. Preferably, said Nesseiria is Neisseria meningitis.

[0185] In one embodiment, said vaccine is a vaccine against a parasite selected from Schistosoma, Leishmania, Babesia and their combinations. [0186] In one embodiment, said vaccine is a vaccine against a yeast and / or a fungus selected from Trichophyton, Toxoplasma, Eimeria, Candida and their combinations.

[0187] In one embodiment, the at least one therapeutic agent is radiotherapy, chemotherapy or combinations thereof.

Advantageously, the radiotherapy can be chosen from X-ray or gamma irradiation.

Advantageously, the chemotherapy can be chosen from an antimetabolite, an alkylating agent, a topoisomerase inhibitor, an anthracycline, and their combinations as defined above.

The alkylating agent can be chosen from dacarbazine, temozolomide, streptozocin, cyclophosphamide, ifofosfamide, melphalan, procarbazine, busulfan, triphosphoramide, rhexamethylmelamine, chlormethine, platinum salts such as cisplatin, carboplatin, oxaliplatin and their combinations. The antimetabolite can be selected from azathioprine, methotrexate, mycophenolic acid, mycophenolate mofetil, fludarabine, and combinations thereof. Anthracycline can be selected from doxorubicin, pegylated doxorubicin, daunorubicin, epirubucin, mitoxantrone, pirarubicin, idarubicin, acinomycin D, amsacrine, and combinations thereof. The topoisomerase inhibitor can be chosen from topoisomerase 1 inhibitors and topoisomerase 2 inhibitors and their combination. By way of example of topoisomerase 1 inhibitors, mention may be made of irinotecan and topotecan. As examples of topoisomerase 2 inhibitors, mention may be made of anthracyclines and etoposide.

[0191] In at least one embodiment, the at least one therapeutic agent is an immunosuppressive treatment.

Advantageously, the calcineurin inhibitor can be chosen from cyclosporine, tacrolimus and their combinations. [0196] Advantageously, the lymphoablative treatment can be chosen from chemotherapy, radiotherapy, an alkylating agent, an intercalator, an anthracycline, anti-thymocyte globulins, a CD52 monoclonal antibody, an OKT3 monoclonal antibody and their combinations.

[0197] The excipient can be chosen from a bulking agent, a lubricant, a flavoring, a colorant, an emulsifier, a compressing agent, a diluent, a preservative, a gelling agent, a plasticizer, a surfactant or their combinations. Those skilled in the art know which excipient to choose depending on the dosage form that they have chosen.

The composition according to the invention can be a pharmaceutical composition. In this case, the excipient is a pharmaceutically acceptable excipient as defined above.

[0199] The composition according to the invention can also be a food supplement.

NMN derivatives and precursors

According to the invention, the NMN derivative can be chosen from alpha nicotinamide mononucleotide (α-NMN), dihydronicotinamide mononucleotide (denoted NMN-FI), the compound of formula (I):

[0201] [Chem. 1] or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its pharmaceutically acceptable crystals thereof, in which:

X is selected from O, CH2, S, Se, CHF, CF2 and C = CFl2;

R2, R3, R4 and R ₅ are independently selected from F1, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, thio-C1-C12 alkyl, C1-C12 heteroalkyl, haloalkyl in C1-C12 and OR; wherein R is selected from F1, C1-C12 alkyl, C (0) (Ci-Ci ₂ ) alkyl, C (0) NFI (Ci-Ci ₂ ) alkyl, C (0) 0 (Ci-Ci2) alkyl , C (0) aryl, C (0) (Ci-Ci ₂ ) alkyl aryl, C (0) NFI (Ci-Ci ₂ ) alkyl aryl, C (0) 0 (Ci-Ci ₂ ) alkyl aryl and C ( 0) CFIR _AA NFI ₂ ; wherein R _AA is a side chain selected from a proteinogenic amino acid; R ₆ is selected from H, azido, cyano, C1-Cg alkyl, C1-Cg thio-alkyl, C1-Cg heteroalkyl and OR; wherein R is selected from H and C1-Cgalkyl;

R ₇ is chosen from in which n is an integer equal to 1 or 3; in which

Rg and Rio are independently selected from OH, ORn, NHR ₁₃ , NR ₁₃ R ₁₄ _{, C 1} -C ₈ alkyl, C ₂ -C ₈ alkenyl, C 2 -C 8 alkynyl , a C ₃ -C ₁₀ cycloalkyl, a C ₅ -C ₁₂ aryl, (Ci-Cg) alkyl aryl, (Ci-Cg) aryl alkyl, (Ci-Cg) heteroalkyl, (Ci-Cg) heterocycloalkyl, a heteroaryl and NHCHR _A R _{A '} C (0) RI ₂ ; in which :

Ru is chosen from a Ci-Cioalkyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -Cig aryl, C ₁ -C ₁₀ alkylaryl, C ₅ - C ₁₂ substituted aryl, C ₁ -C ₁₀ heteroalkyl, C ₃ -C _{10 group} heterocycloalkyl, C ₁ -C ₁₀ haloalkyl, a heteroaryl, - (CH ₂ ) „C (0) (Ci-Ci ₅ ) alkyl, - (CH ₂ ) _n OC (0) (Ci-Ci ₅ ) alkyl, - ( CH ₂ ) _n OC (0) 0 (Ci-Ci ₅ ) alkyl, - (CH ₂ ) „SC (0) (C ₁ - Ci ₅ ) alkyl, - (CH ₂ ) _n C (0) 0 (Ci- Ci ₅ ) alkyl and - (CH ₂ ) _n C (0) 0 (Ci-Ci ₅ ) alkyl aryl; wherein n is an integer selected from 1 to 8; and P (0) (0H) 0P (0) (0H) ₂ ;

R ₁₂ is selected from H, C ₁ -C ₁₀ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, C ₅ -Cig aryl, C ₁ -C ₄ alkylaryl and C ₅ -C ₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and cyano; and

R _A and R _A - are independently selected from H, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₁₀ thio-alkyl, C ₁ -C ₁₀ hydroxylalkyl, C ₁ -C ₁₀ alkylaryl and C ₅ -C ₁₂ aryl, C ₃ -C ₁₀ heterocycloalkyl, a heteroaryl, - (CH ₂ ) ₃ NHC (= NH) NH ₂ , (lH-indol- 3-yl) methyl, (1H-imidazol-4-yl) methyl and a side chain chosen from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₆ alkoxy, halogen, nitro and cyano; Where

Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R _g -Rio- represents

-CH ₂ -CH ₂ -CHR-; wherein R is selected from H, (Cs-Ce) aryl and (Cs-Ce) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and cyano; Where Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R10- represents -O-CH2-CH2-CHR-O-; wherein R is selected from H, (Cs-Ce) aryl and (Cs-Ce) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, (Ci-Ce) alkyl, ( Ci-Ce) alkoxy and cyano;

Rg is selected from H, OR, NHR ₁₃ , NR ₁₃ R ₁₄ , NH-NHR ₁₃ , SH, CN, N ₃ and halogen; wherein R ₁₃ and R14 are independently selected from H, (C1-Cg) alkyl and (C1-Cg) alkyl aryl;

Y is selected from CH, CH ₂ , C (CH ₃ and CCH ₃ ;

- represents a single or a double bond along Y; and

^A ' ^w ' represents the alpha or beta anomer depending on the position of Ri or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals or the compound of formula (Ia):

X'i and X'2 are independently selected from O, CH2, S, Se, CHF, CF2, and C = CH2;

R'i and R '13 are independently selected from H, azido, cyano, C1-C8 alkyl, thio-C1-C8 alkyl, C1-C8 heteroalkyl, and OR, wherein R is selected from H and a C1-C8 alkyl,

R _'2, R' 3, R _'4, R' 5, R '9, R' _10, R _'11, R' ₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, a C ₁ -C ₁₂ thioalkyl a C ₁ -C ₁₂ alkyl, hetero-alkyl -C C12 haloalkyl -C Ci2et OR, wherein R may be selected from H, C1-C12, C (0) (C1-C12) alkyl, C (0) NH (Ci-Ci ₂₎ alkyl, a C (0) 0 (Ci-Ci ₂ ) alkyl, a C (O) aryl, a C (0) (C1-C12) aryl, a C (0) NH (Ci-Ci ₂ ) alkyl aryl, a C (0) 0 (Ci-Ci ₂ ) alkyl aryl or a group C (0) CHR _AA NH2 in which R _AA is a side chain chosen from a proteinogenic amino acid;

R ' ₆ and R'g are independently selected from H, azido, cyano, C1-C8 alkyl and OR, wherein R is selected from H and C1-C8 alkyl;

R ' ₇ and R' 14 are independently selected from H, OR, NHR, NRR ', NH-NHR, SH, CN, N3 and halogen, wherein R and R' are independently selected from H and (Ci-Cg ) alkyl aryl;

UΊ and Y'2 are independently selected from CH, CH2, C (CH _B ) 2 OR CCH ³ ;

M 'is chosen from H or a suitable counterion;

= - ^ _r p _re ESENTE a single or double bond depending on UΊ and Y'2; and -ww represents an alpha or beta anomer depending on the position of R'i and R '13; and their combinations.

In a first preferred embodiment, the pharmaceutically acceptable derivative is the compound of formula (I).

[0203] In a variant of the first embodiment, X represents an oxygen.

In a variant of the first embodiment, R 1 and R ₆ each represent, independently of one another, a hydrogen.

In a variant of the first embodiment, Y represents a CH.

[0207] In a variant of the first embodiment, Y represents a CH2.

In a variant of the first embodiment, R ₇ represents hydrogen.

In a variant of the first embodiment, R ₇ represents P (0) (OH) ₂ .

In a variant of the first embodiment, the compound of the invention is chosen from the compounds of formula I-A to I-J:

[0211] [Table 1]

In a preferred variant of the first preferred embodiment, the pharmaceutically acceptable derivative is alpha-NMN of formula:

[0213] [Chem.3]

[0214] In a second preferred embodiment, the pharmaceutically acceptable derivative is the compound of formula (Ia).

[0215] In a variant of the second embodiment, CΊ and X'2 each independently represent oxygen.

[0216] In a variant of the second embodiment, R'7 and R'14 each independently represent an NH2.

In a variant of the second embodiment, R'I and / or R'13 each independently represent a hydrogen.

[0218] In a variant of the second embodiment, R'6 and / or R'8 each independently represent a hydrogen.

[0219] In a variant of the second embodiment, R'2, R'3, R'4 _, R'5, R'9, R'10, R'11 and R'12 each independently represent hydrogen.

[0221] In a variant of the second embodiment, Y'1 and Y'2 each independently represent a CH. [0222] In a variant of the second embodiment, UΊ and Y'2 each independently represent a CH2.

[0224] [Table 2]

[0225] In a fourth preferred embodiment, the pharmaceutically acceptable derivative is NMN-H:

43

SUBSTITUTE SHEET (RULE 26) [0226] [Chem 4]

[0228] [Chem.5] or dihydronicotinamide riboside (noted -NR-H) of formula:

[Chem.6] or their combination. Preferably, the precursor is nicotinamide riboside (NR).

Preferably, the derivative of NMN is dihydronicotinamide mononucleotide (NMN-H) and / or alpha-NMN.

44 Process for the preparation of the compounds of formulas (I) and (la)

The derivatives of formula (I) or of formula (Ia) can be prepared according to any method well known to those skilled in the art.

[0231] Process for the preparation of the compounds of formula (I)

The derivatives of formula (I) can be prepared according to the process described in international application WO 2017 / 024255A1 and US patent 10,611,790 B2.

In particular, the derivatives of formula (I) as well as the alpha-NMN can be prepared according to the method described below.

[0234] In particular, the compounds of formula (I) disclosed here can be prepared as described below from substrates A-E. It will be understood by one skilled in the art that these reaction schemes are in no way limiting and that variations can be made without departing from the spirit and scope of the present invention.

[0235] According to one embodiment, the invention relates to a method for preparing the compounds of formula (I) as described above.

The method involves in a first step the mono-phosphorylation of a compound of formula (A), in the presence of phosphoryl chloride and of a trialkyl phosphate, to lead to the phosphorodichloridate of formula (B),

[0237] [Chem. 8] in which X, R1, R2, R3, R4, Rs, R ₆ , Rs, Y, "™ and -— are as defined above for the compounds of formula (I).

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

[0239] [Chem. 9]

45 in which X, R1, R2, R3, R4, Rs, R ₆ , Rs, Y, ™ and ——- are as defined above for the compounds of formula (I).

[0240] According to one embodiment, the compound of formula (A) is synthesized using various methods known to those skilled in the art.

[0241] According to one embodiment, the compound of formula (A) is synthesized by reaction of the pentose of formula (D) with a nitrogen derivative of formula (E), in which R, R2, R3, R4, Rs, R ₆ , R7, Y are as described above for the compounds of formula I, leading to the compound of formula (A1) which is then selectively deprotected to give the compound of formula (A),

[0242] [Chem.10] in which X, Ri, R2, R3, R4, Rs, R ₆ , Rs, Y, ™ and - ~ are as defined above for the compounds of formula (I).

[0243] According to one embodiment, R is an appropriate protective group known to those skilled in the art. In one embodiment, the protective group is chosen from triarylmethyls and / or 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.

[0244] According to one embodiment, any hydroxyl group attached to the pentose is protected by an appropriate protective group known to those skilled in the art.

[0245] The choice and the exchange of protecting groups fall within the competence of those skilled in the art. Protecting groups can also be removed by methods well known to those skilled in the art, for example, with an acid (eg, an inorganic or organic acid), a base or a source of fluoride.

46 In a preferred embodiment, the nitrogenous derivative of formula (E) is coupled to the pentose of formula (D) by a reaction in the presence of a Lewis acid resulting in the compound of formula (Al). Non-limiting examples of Lewis acids include TMSOTf, BF ₃ .0Et ₂ , T1Cl4 and

FeCI ₃ .

In one embodiment, the method of the present invention further comprises a step of reducing the compound of formula (A) by various methods well known to those skilled in the art leading to the compound of formula (A ') in which is CH2 and R1, R2, R3, R4, Rs, R ₆ , Rs, Y, * = and - - are as defined above for the compounds of formula (I).

[0248] In a particular embodiment, the present invention relates to a method for preparing compounds of formula I-A, I-C, I-E, I-G.

In a first step, the nicotinamide of formula E is coupled to the ribose tetraacetate of formula D by a coupling reaction in the presence of a Lewis acid, resulting in the compound of formula A-1:

[0250] [Chem.11]

In a second step, an ammoniacal treatment of the compound of formula A-l is carried out, resulting in the compound of formula l-A:

[0252] [Chem.12]

In a third step, the mono-phosphorylation of the compound of formula I-A, in the presence of phosphoryl chloride and of a trialkyl phosphate, results in the phophorodichloridate of formula I-A ′:

[0254] [Chem.13]

47

I-A Ï-A ’

In a fourth step, the phosphorodichloridate of formula B is hydrolyzed to yield the compound of formula I-C:

[0256] [Chem.14]

In one embodiment, a step of reducing the compound of formula I-A is carried out, resulting in the compound of formula I-E.

The compound of formula I-E is then mono-phosphorylated as described in the fourth step and hydrolyzed to yield the compound of formula I-G.

According to one embodiment, the compounds of formula (I) are selected from compounds 1-A to 1-J of the table below:

[0260] [Table 1]

48

[0261] In a preferred embodiment, the compounds of the invention are the compounds of formula I-A, I-C, I-E and I-G from the table above or a pharmaceutically acceptable salt and / or solvate thereof. In an even more preferred embodiment, the compound is the compound of formula 1-C or 1-D, a pharmaceutically acceptable salt and / or solvate thereof.

49 [0262] Synthesis of the compounds of formula I in which R7 is n = 1:

In a first step, the synthesis can comprise the phosphorylation of alpha-nicotinamide riboside, in the presence of phosphorus chloride and of a trialkyl phosphate, to obtain a phosphorodichloridate:

[0264] The compound 1B (alpha NMN) is then added:

Alternatively, the compound according to the invention can be prepared by activating compound IB by the addition of carbonyldiimidazole (CDI):

[0266] To which alpha-nicotinamide riboside is added as follows:

50

[0267] Synthesis of the compounds of formula I in which R7 is n = 3:

A compound of formula I comprising three phosphate groups can be prepared as follows. Compound IB can be prepared by the addition of carbonyldiimidazole (CDI):

To which tertbutyleamine -phosphate is added:

51 [0268] Process for preparing the derivatives of formula (Ia)

[0269] In particular, the compounds of formula Ia presented here can be prepared as described below from substrates X-XIII. It will be understood by one of ordinary skill in the art that these diagrams are in no way limiting and that variations in detail can be made without departing from the spirit and scope of the present invention.

[0270] According to one embodiment, the invention relates to a method for preparing the compound of formula I described above.

The method firstly consists in mono-phosphorylating a compound of formula X, in the presence of phosphoryl chloride in a trialkyl phosphate, to obtain the phophorodichloridate compound XI,

[0272] [Chem.15] in which X'i, R'i, R '2, R'3, R'4, R's, R' ₆ , R'7, Y'i, - = and ^{, LLLL} are as defined above.

In a second step, the hydrolysis of the phosphorodichloridate XI obtained in the first step gives the phosphate compound of formula XII,

[0274] [Chem.16] wherein X'i, R'i, R '2, R'3, R'4, R's, R' ₆ , R'7, U'i, M ', and' ^{/ ww} are as defined above .

The phosphate compound of formula XII obtained in the second step is then reacted with a phophorodichloridate compound of formula XIII obtained as described in the first step,

52 [0276] [Chem.17] wherein X '2, R', R '9, R' _10, R _'11, R' _12, R _'13, R' _4, Y _'2, and ^{L * LL'} are as described herein for Formula la, to give the compound of formula la as described herein.

[0277] According to one embodiment, the process further comprises a step of reducing the compound of formula la, using various methods known to specialists, to give the compound of formula la, where Y'i and Y ' ₂ are identical. and each represent CH ₂ and where X'i, X ' ₂ , R'i, R' ₂ , R's, R ' ₄ , R'S, R' s, R'7, R 's, R' 9, R _'10 , R _'11, R' _12, R _'13, R' _14, Y ', Y' _2, and - are as described herein for formula Ia.

[0278] Alternatively, R is a suitable protecting group known to those skilled in the art. Examples of suitable protecting groups are triarylmethyl and / or silyl groups. 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.

[0279] According to one of the representations, any hydroxy group attached to the pentose ring is protected by an appropriate protection group known to specialists in this art.

[0280] The selection and exchange of protection groups fall within the competence of those who are competent in this field. Any protecting group can also be removed by methods known in the art, for example, with an acid (eg, a mineral or an organic acid), a base or a source of fluoride.

[0281] According to a preferred embodiment, the nitrogenous derivatives of formula XV are added to pentose XIV by a coupling reaction in the presence of a Lewis acid to give the compound of formula X-1. Non-limiting examples of suitable Lewis acids include TMSOTf, BF3.0Et2, TiCl4 and FeCl3.

[0282] According to a specific embodiment, the invention relates to a method for preparing the compound of formula VIII,

53 [0283] [Chem 18] or their pharmaceutically acceptable salts and / or solvates.

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

[0285] [Chem 19]

In a second step, an ammoniacal treatment of the compound of formula X-1 gives the compound of formula X:

[0287] [Chem.20]

In a third step, the mono-phosphorylation of a compound of formula X, in the presence of phosphoryl chloride in a trialkyl phosphate, gives the phophorodichloridate compound XI:

[0289] [Chem.21]

In a fourth step, the phophorodichloridate compound XI obtained in the third step is partially hydrolyzed to give the phosphate compound of formula XII:

54 [0291] [Chem.22]

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

[0293] According to another specific embodiment, the invention relates to a method for preparing the compound of formula IX,

[0294] [Chem.23] or their pharmaceutically acceptable salts and / or solvates.

According to one variant, the compound of formula IX is obtained from the compound of formula VIII, previously synthesized as described above.

[0296] In this embodiment, the compound of formula IX is obtained by reducing the compound of formula VIII, using a suitable reducing agent known to those skilled in the art, to give the compound of formula IX.

According to one embodiment, the preferred compounds of the invention are compounds la-A to la-1, listed in Table 2:

[0298] [Table 2]

55

56

SUBSTITUTE SHEET (RULE 26) [0299] Figure 1 is a graph showing the evolution of weight gain (Figure IA) and water consumption (Figure IB) among groups 1 to 4.

[0300] FIG. 2 is a graph showing the evolution of the weight and size of the thymus among groups 1 to 4.

[0301] Figure 3 is a graph showing the number of thymocytes among groups 1 to 4.

[0302] FIG. 4A is a graph showing the number of B cells in the bone marrow taken from mice, among groups 1 to 4.

[0303] FIG. 4B is a graph showing the number of CD38 + B cells in the bone marrow taken from mice, among groups 1 to 4.

[0304] FIG. 5A is a graph showing the number of CD45 + B cells in the bone marrow taken from mice, among groups 1 to 4.

[0305] FIG. 5B is a graph showing the number of pre-pro-B cells in the bone marrow taken from mice, among groups 1 to 4.

[0306] FIG. 5C is a graph showing the number of pro-B cells in the bone marrow taken from mice, among groups 1 to 4.

[0307] FIG. 5D is a graph showing the number of pre-B cells in the bone marrow taken from mice, among groups 1 to 4.

[0308] FIG. 5E is a graph showing the number of immature B cells in the bone marrow taken from mice, among groups 1 to 4.

[0309] FIG. 6A is a graph showing the number of CD45 + B cells in the spleen taken from mice, among groups 1 to 4.

[0310] FIG. 6B is a graph showing the number of activated B cells in the spleen taken from mice, among groups 1 to 4.

[0311] FIG. 6C is a graph showing the number of memory B cells in the spleen taken from mice, among groups 1 to 4.

[0312] Fig. 6D is a graph showing the number of germinal B cells in the spleen taken from mice, among groups 1 to 4.

[0313] FIG. 6E is a graph showing the number of plasma B cells in the spleen taken from mice, among groups 1 to 4.

57 [0314] FIG. 7A is a graph showing the number of CD4 + T cells in the spleen taken from mice, among groups 1 to 4.

[0315] Fig. 7B is a graph showing the number of CD4 + memory T cells in the spleen taken from mice, among groups 1 to 4.

[0316] FIG. 8A is a graph showing the number of naive CD8 + T cells in the spleen taken from mice, among groups 1 to 3.

[0317] Fig. 8B is a graph showing the number of effector CD8 + T cells in the spleen taken from mice, among groups 1 to 3.

[0318] FIG. 8C is a graph showing the number of CD8 + memory effector T cells in the spleen taken from mice, among groups 1 to 3.

[0319] Figure 8D is a graph showing the number of CD8 + memory T cells in the spleen taken from mice, among groups 1 to 3.

[0320] Fig. 9A is a graph showing the percentage of proliferation of CD4 + T cells, relative to unstimulated cells, among groups 1 to 4.

[0321] FIG. 9B is a graph showing the percentage of proliferation of CD8 + T cells, relative to unstimulated cells, among groups 1 to 4.

[0322] FIG. 10A is a graph showing the percentage of CD4 + T cells, stimulated and not stimulated by beads coated with anti-CD3 / CD28 antibodies, producing gamma interferon (IFNγ) among groups 1 to 4.

[0323] FIG. 10B is a graph showing the percentage of CD4 + T cells, stimulated and unstimulated by beads coated with anti-CD3 / CD28 antibodies, producing interleukin 10 (IL10) among groups 1 to 4.

EXAMPLE

In the remainder of the present description, the examples are provided by way of illustration of the present invention and are in no way intended to limit its scope.

[0325] Example 1 - Study of the Effects of Compounds I-A (b-NMN) and I-B (a-NMN) on Immunosenescence

[0326] The administration of b-NMN at 500 mg / kg, of α-NMN at 500 mg / kg and of the vehicle (water) is carried out by oral administration in drinking water (po) on young and old mice. . Solutions are prepared by dissolving b-NMN or α-NMN powder in vehicle (water).

58 The solution is used at room temperature for a maximum of 2 days and freshly prepared for each new administration. The mice are weighed weekly to adjust the dose of the compound to be administered. Throughout the phase, a standard diet and tap water will be provided ad libitum.

[0328] The study comprises 4 groups of 6 mice each:

Group 1: young mice (10 weeks old) + drinking water (vehicle)

Group 2: old mice (15 months old) + drinking water (vehicle)

Group 3: old mice (15 months old) + compound l-B (alpha-NMN) in drinking water

Group 4: old mice (15 months old) + compound l-A (beta-NMN) in drinking water

The water consumption of the mice is evaluated per cage, every two days. The mice are weighed weekly. Group 3 mice are sacrificed after 4 weeks for organ collection and characterization of T cell function. Group 4 mice are sacrificed after 6 weeks for organ collection and characterization of T cell function. On the day of sacrifice, the mice are anesthetized with Vetoflurane (isoflurane) and blood is drawn from the retorbital sinuses. The blood is incubated for 30 minutes at room temperature, then centrifuged at 1300 g for 10 minutes.

[0330] After sacrificing the mice, the spleen, thymus and bone marrow of each animal is removed. The thymus is weighed and measured to assess its involution. As an illustration, photos of the thymus are taken on 5 animals per group. The thymus is divided into two parts; a part is treated with formalin for a histological study. The second part is treated for the characterization of immune cells.

For the characterization of the cells, the thymus and the spleen are crushed on a sieve of 40 cells / μm on a 50 ml tube with a syringe plunger. The bone marrow is rinsed with RPMI culture medium using a needle and syringe. The cell suspension is then centrifuged at 400 g for 5 minutes at 4 ° C. Lysis of red blood cells is also performed before cell counting and use for cytometry.

[0332] The cells isolated from the spleen, thymus and bone marrow will be labeled with antibodies according to the following panels to identify the proportion of naive, effector and memory T and B cells.

The following spleen T cells are also sought for characterization according to the combination of proteins on their surface:

59 [0334] [Table 3]

[0335] The following spleen B cells are also sought for characterization according to the combination of proteins on their surface:

[0336] [Table 4]

The following thymocytes are also sought for characterization according to the combination of proteins on their surface:

[0338] [Table 5]

60 The following bone marrow cells are also sought for characterization according to the combination of proteins on their surface:

[0340] [Table 6]

[0341] Proliferation Assay: LAO + 5 weeks, splenocytes were labeled with 2.5 mM of CFSE and then cultured at a concentration of 0,25.10 ^e cells per well in a 96 well plate. The cells are stimulated with 2.5 μg of InfluvacTetra ^® and incubated at 37 ° C. for 96 hours. The cells are then labeled with anti-CD4 and CD8 antibodies and the proliferation of CD4 + and CD8 + T cells is analyzed by flow cytometry.

[0342] Parameters evaluated: The results of the flow cytometry are expressed in number or in proportion of cells per organ. The weight of the thymus is expressed in grams.

[0343] The consumption of compounds 1A and 1B do not significantly increase the weight of the treated mice compared to the untreated 15-month-old mice (FIG. 1A) and has no effect on the water consumption compared to the 11 week old mouse (Figure IB).

[0344] As shown in Figure 2, the size of the thymus is reduced considerably and significantly in old mice (group 2) compared to young mice (group 1), which reflects an involution of the thymus. Involution of the thymus with age is observed in humans and validates the model. The administration of alpha-NMN did not increase the volume or size of the thymus compared to elderly untreated mice. On the other hand, the administration of b-NMN makes it possible to increase the size of the thymus significantly compared to the mice of groups 2 and 3 to a level close to that of the young mice of group 1.

[0345] According to Figure 3, the total number of thymocytes is reduced in old mice (group 2). Only treatment with compound l-A (beta-NMN) makes it possible to increase the number of CD8 + thymocytes in aged mice.

61 [0346] According to Figure 4, the number of B cells decreases significantly in old mice (group 2) compared to young mice (group 1) in the bone marrow. The administration of a-NMN (group 3) and b-NMN (group 4) significantly increases the number of B cells and restores a level identical or almost identical to that observed in young mice. (Figure 4A). As for CD38 + cells, the level of these cells is reduced in old mice (group 2) compared to young mice (group 1). The administration of a-NMN (group 3) and b-NMN (group 4) makes it possible to restore the quantity of CD38 + B cells to the level of that expressed by the young mice of group 1 (FIG. 4B).

[0347] As shown in Figures 5A to 5E, the level of B cells is significantly reduced in the old mice of group 2 compared to the young mice of group 1. The administration of a-NMN and b- NMN makes it possible to significantly increase the number of CD45 + B cells to levels even higher than that expressed in group 1 mice (see FIG. 5A). Administration of a-NMN and b-NMN also increases the number of pre-pro-B cells (Figure 5B) but has not shown any influence on the number of pro-B cells (Figure 5C). On the other hand, the administration of a-NMN (group 3) and of b-NMN (group 4) makes it possible to increase the number of pre-B cells (FIG. 5D) and of immature B cells (FIG. 5E).

[0348] The B cells present in the spleen of the mice of each of the groups were characterized. As shown in Figure 6A, the number of CD45 + T cells in the spleen was significantly increased by the administration of b-NMN (group 4) compared to other groups of mice. The administration of b-NMN also increases the number of activated B cells in the spleen significantly compared to other groups (Figure 6B), as well as memory B cells (Figure 6C) and germinal B cells ( figure 6D). The number of plasma cells is not changed among the 4 study groups (FIG. 6E).

[0349] The CD4 + T cells present in the spleen of the mice of each of the groups were characterized. As shown in Figure 7A, the total number of CD4 + T cells in the spleen is significantly increased by the administration of b-NMN (group 4) compared to other groups of mice. The administration of b-NMN also makes it possible to increase the memory T cells significantly compared to the other groups (FIG. 7B). Administration of a-NMN and b-NMN also increases the number of CD4 + effector T cells compared to group 3.

[0350] The CD8 + T cells present in the spleen of the mice of groups 1, 2 and 3 have been characterized. As shown in Figure 8A, the aged group 2 mice show less naive CD8 + T cells than the young group 1 mice. The administration of α-NMN (group 3) does not modify the

62 number of naive CD8 + T cells. The administration of α-NMN (group 3), on the other hand, makes it possible to restore the levels of effector CD8 + T cells (FIG. 8B), of memory CD8 + T cells (FIG. 8C) and of effector memory CD8 + T cells (FIG. 8D).

[0351] The total splenocytes were stained with Carboxyfluorescein succinimidyl ester (CFSE) and stimulated with beads coated with anti-CD3 / CD28 for 96 h. The mean fluorescence intensity of CFSE was analyzed and the ratio before and after stimulation was calculated. As shown by Figures 9A and 9B, the proliferation of CD4 and CD8 cells is not influenced by age. However, treatment with b-NMN significantly increased the proliferation of CD4 and CD8 cells compared to the other three groups of mice.

The total splenocytes were stimulated with beads coated with anti-CD3 / CD28 for 18 h. As shown in Figures 10A and 10B, aging reduced the proportion of IFNγ and IL10 producing cells upon stimulation with anti-CD3 / CD28 coated beads. For γ-IFN (Figure 10A), the response to stimulation was lower in elderly mice treated with vehicle or α-NMN and an absence of response in the b-NMN group was observed.

In conclusion, the administration of compounds I-A and I-B make it possible to significantly reduce the signs of immunosenescence.

63

Claims

Claims [Claim 1] Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof for its use in the prevention and / or treatment of immunosuppression, preferably of immunosenescence. [Claim 2] Nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts for its use according to claim 1 in which the NMN derivative can be chosen from alpha nicotinamide mononucleotide (a-NMN) , dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I):

X is selected from O, CH2, S, Se, CHF, CF2 and C = CFl2;

R2, R3, R4 and R ₅ are independently selected from F1, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, thio-C1-C12 alkyl, C1-C12 heteroalkyl, haloalkyl in C1-C12 and OR; wherein R is selected from F1, C1-C12 alkyl, C (0) (Ci-Ci ₂ ) alkyl, C (0) NFI (Ci-Ci ₂ ) alkyl, C (0) 0 (Ci-Ci2) alkyl , C (0) aryl, C (0) (Ci-Ci ₂ ) alkyl aryl, C (0) NFI (Ci-Ci ₂ ) alkyl aryl, C (0) 0 (Ci-Ci ₂ ) alkyl aryl and C ( 0) CFIR _AA NFI ₂ ; wherein R _AA is a side chain selected from a proteinogenic amino acid;

64 R ₇ is chosen from in which n is an integer equal to 1 or 3; in which

Rg and Rio are independently selected from OH, ORn, NHR ₁₃ , NR ₁₃ R ₁₄ _{, C 1} -C ₈ alkyl, C ₂ -C ₈ alkenyl, C 2 -C 8 alkynyl , a C ₃ -C ₁₀ cycloalkyl, a C ₅ -C ₁₂ aryl, (Ci-Cg) alkyl aryl, (Ci-Cg) aryl alkyl, (Ci-Cg) heteroalkyl, (Ci-Cg) heterocycloalkyl, a heteroaryl and NHCHR _A RA'C (0) RI ₂ ; in which :

Ru is selected from a Ci-Cioalkyl, C3-Ciocycloalkyl, C ₅ -Cig aryl, C1-C10 alkylaryl, C ₅ - C12 substituted aryl, C1-C10 heteroalkyl, C3-C10 heterocycloalkyl, C1-C10 haloalkyl, a heteroaryl, - (CH ₂ ) „C (0) (C ₁ -C ₁₅ ) alkyl, - (CH ₂ ) nOC (0) (Ci-Ci ₅ ) alkyl, - (CH ₂ ) nOC (0) 0 (Ci-Ci ₅ ) alkyl, - (CH ₂ ) „SC (0) (C ₁ - Ci ₅ ) alkyl, - (CH ₂ ) nC (0) 0 (Ci-Ci ₅ ) alkyl and - (CH ₂ ) nC (0) 0 (Ci-Ci ₅₎ aryl; wherein n is an integer selected from 1 to 8; and P (0) (0H) 0P (0) (0H) ₂ ;

R ₁₂ is selected from H, C ₁ -C ₁₀ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ heterocycloalkyl, C ₅ -Cig aryl , C ₁ -C ₄ alkylaryl and C ₅ -C ₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; and

R _A and R _A - are independently selected from H, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₁₀ thio-alkyl, C ₁ -C ₁₀ hydroxylalkyl, C ₁ -C ₁₀ alkylaryl and C ₅ -C ₁₂ aryl, C ₃ -C ₁₀ heterocycloalkyl, a heteroaryl, - (CH2) 3NHC (= NH) NH2, (lH-indol-3-yl ) methyl, (1H-imidazol-4-yl) methyl and a side chain chosen from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C ₁ -C ₁₀ alkyl, C1-C6 alkoxy, halogen, nitro and cyano; Where

Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -Rg-Rio- represents

-CH ₂ -CH ₂ -CHR-; wherein R is selected from H, (Cs-Ce) aryl and (Cs-Ce) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; Where

Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -Rg-Rio- represents -O-CH2-CH2-CHR-O-; wherein R is selected from H, (Cs-Ce) aryl and (C5-C6) heteroaryl, wherein said aryl or heteroaryl groups are

65 optionally substituted with a halogen, trifluoromethyl, a (Ci-Ce) alkyl, a (Ci-Ce) alkoxy and cyano;

Rg is selected from H, OR, NHR13, NR13R14, NH-NHR13, SH, CN, N3 and halogen; wherein R13 and R ₁₄ are independently selected from H, (C1-Cg) alkyl and (C1-Cg) alkyl aryl;

Y is selected from CH, CH2, C (CH3 and CCH3;

- represents a single or a double bond along Y; and v ^{/ vw '} represents the alpha or beta anomer depending on the position of Ri or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals or the compound of formula (Ia) :

X'i and X ' ₂ are independently selected from O, CH ₂ , S, Se, CHF, CF ₂ , and C = CH ₂ ;

R'i and R'13 are independently selected from H, azido, cyano, C1-C8 alkyl, thio-C1-C8 alkyl, C1-C8 heteroalkyl, and OR, wherein R is selected from H and a C1-C8 alkyl,

R _'2, R' 3, R _'4, R' 5, R '9, R' _10, R _'11, R' ₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, a C ₁ -C ₁₂ thioalkyl a C ₁ -C ₁₂ alkyl, hetero-alkyl C -C _12, haloalkyl Cl-Cl ₂ and OR wherein R may be selected from H, alkyl C ₁ -C ₁₂ , a C (0) (C ₁ -C ₁₂ ) alkyl, a C (0) NH (Ci-Ci ₂ ) alkyl, a C (0) 0 (Ci-Ci ₂ ) alkyl, a C ( O) aryl, a C (0) (C ₁ -C ₁₂ ) aryl, a C (0) NH (Ci-Ci ₂ ) alkyl aryl, a C (0) 0 (Ci-Ci ₂ ) alkyl aryl or a group

66 C (0) CHRAANH2 in which RAA is a side chain selected from a proteinogenic amino acid;

R ' ₇ and R' i ₄ are independently selected from H, OR, NHR, NRR ', NH-NHR, SH, CN, N ₃ and halogen, wherein R and R' are independently selected from H and (Ci -Cg) alkyl aryl;

Y'i and Y ' ₂ are independently selected from CH, CH ₂ , C (CH _B ) ₂ OR CCH ³ ;

M 'is chosen from H or a suitable counterion; represents a single or double bond depending on Y'i and Y '₂; and “w represents an alpha or beta anomer depending on the position of R'I and R'13; and their combinations.

[Claim 3] Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof for its use according to claim 1 or 2 in combination with at least one other therapeutic agent.

[Claim 4] Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof for its use according to claim 3 wherein the at least one other therapeutic agent is a vaccine which can be selected from live vaccines attenuated, inactivated vaccines, multivalent vaccines or combination vaccines.

[Claim 5] Nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts for its use according to claim 4 in which the vaccine is selected from a vaccine against a virus, a bacterium, a parasite, a yeast and / or a fungus, or combinations thereof.

[Claim 6] Nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts for its use according to Claim 5, in which said vaccine is chosen from a vaccine against the virus selected from Influenzavirus, Coronavirus, Respirovirus, Pneumovirus, Metapneumovirus, Adenovirus, Enterovirus, Rhinovirus, Hepatovirus, Erbovirus, Aphtovirus, Norovirus, Alphavirus, Rubivirus, Flavivirus, Hepacivirus, Pestivirus, Ebola, Morbillivirus, Rubulavirus, Henipavirus,

67 Arenavirus, Orthobunyavirus, Phlebovirus, Rotavirus, Simplexvirus, Varicellovirus, Papillomavirus, Cytomegalovirus or their combinations.

[Claim 7] Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof for its use according to one of the preceding claims wherein the reduction in immunosenescence can be determined by reduction of a marker chosen from thymic involution, levels of immunosenescence cytokines, amounts of senescent T cells resident in the spleen, level of circulating IgG immunoglobulin produced by memory B cells, level of circulating IgA immunoglobulin produced by memory cells B and their combinations.

[Claim 8] Nicotinamide mononucleotide (NMN), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof for its use according to one of the preceding claims wherein the reduction in immunosenescence can be determined by the increase in a marker chosen from the production of new naive T cells, the ability to respond to new antigens, the accumulation of memory T cells, number of circulating B cells, the level of circulating IgD immunoglobulin produced by naive cells, the level circulating IgM produced by naive cells, vaccine immunogenicity and combinations thereof.

[Claim 9] Nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts for its use according to one of the preceding claims in a form suitable for its administration by oral, ocular, sublingual or parenteral route, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation, preferably orally.

[Claim 10] A composition comprising nicotinamide mononucleotide, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient for its use according to one of claims 1 to 9.

68