EP4045058A1 - Use of nicotinamide mononucleotide (nmn) for the prevention and/or treatment of rheumatoid arthritis, and corresponding compositions - Google Patents

Use of nicotinamide mononucleotide (nmn) for the prevention and/or treatment of rheumatoid arthritis, and corresponding compositions

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Publication number
EP4045058A1
EP4045058A1 EP20789620.0A EP20789620A EP4045058A1 EP 4045058 A1 EP4045058 A1 EP 4045058A1 EP 20789620 A EP20789620 A EP 20789620A EP 4045058 A1 EP4045058 A1 EP 4045058A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
pharmaceutically acceptable
nmn
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP20789620.0A
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German (de)
French (fr)
Inventor
Guillaume BERMOND
Laurent GARCON
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Nuvamid SA
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Nuvamid SA
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Publication of EP4045058A1 publication Critical patent/EP4045058A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • NPN NICTOTINAMIDE MONONUCLEOTIDE
  • the present invention relates to the use of nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, as well as compositions comprising it, for the treatment and / or prevention of polyarthritis rheumatoid.
  • NNN nicotinamide mononucleotide
  • a joint brings together two bone ends covered with cartilage as well as a synovial membrane enveloping the whole.
  • the role of the synovial membrane is to facilitate joint movements, by secreting a lubricant: the synovial fluid.
  • Inflammatory rheumatism mainly consists of inflammation of the synovial membrane. Too much synovial fluid is then secreted and the synovial membrane thickens abnormally. The soft tissues and bony surfaces of the joint are damaged. The joint becomes abnormally swollen and painful, preventing movement.
  • Rheumatoid arthritis is a chronic inflammatory rheumatism that most commonly affects the hands, wrists and knees but can also spread to other joints. Polyarthritis is sometimes associated with the presence of rheumatoid factor in the patient's blood and can lead to irreversible damage to the joints.
  • the treatments for polyarthritis include, on the one hand, symptomatic treatment to relieve inflammatory flare-ups and on the other hand, maintenance therapy.
  • Symptomatic treatments mainly comprise the administration of analgesics to reduce pain, non-steroidal anti-inflammatory drugs (NSAIDs) as well as cortisone or its derivatives to reduce inflammation.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • cortisone or its derivatives to reduce inflammation.
  • chronic administration of these drugs damages the stomach, liver and kidneys, among other things.
  • their effectiveness decreases over time requiring increased doses or the use of more aggressive drugs and often causing more side effects.
  • cortisone derivatives induces in particular bone fragility, neuropsychiatric effects, muscle wasting and a reduction in immunity, leaving the patient vulnerable to infections.
  • DMARDs most often include the administration of methotrexate, an anticancer drug successfully used to prevent and reduce the number of inflammatory flares.
  • methotrexate an anticancer drug successfully used to prevent and reduce the number of inflammatory flares.
  • this drug includes many side effects such as fever, anemia, respiratory problems, teratogenic risks and bone marrow toxicity among other risks. Therefore, it is not well tolerated by all patients.
  • Other medicines, in place of or in conjunction with methotrexate are used such as certain antimalarials and inhibitors of TNF (for "Tumor Necrosis Factor”), a protein involved in inflammatory processes.
  • TNF for "Tumor Necrosis Factor”
  • none of these drugs are free from side effects. In particular, there is a risk of weakening the immune system, as well as high toxicity on the patient's vital organs such as the liver and kidney.
  • rheumatoid arthritis stiffens and deforms the joints.
  • the gestures of daily life are becoming more and more difficult for patients to perform. Patients therefore end up needing to change their daily lives, quit their work and depend on outside help, which among other things implies a considerable cost for the health systems.
  • 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 rheumatoid arthritis.
  • NNN nicotinamide mononucleotide
  • the pharmaceutically acceptable derivative of NMN can be dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I): 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:
  • R 1 is selected from H, azido, cyano, (C-i-Cs) alkyl, (C-i-Cs) thio-alkyl, (C-i-Cs) heteroalkyl and OR; wherein R is selected from H and (C1-C8) alkyl;
  • R 2 , R3, R 4 and R5 are chosen independently of one another from H, halogen, azido, cyano, hydroxyl, (C 1 -C 12 ) alkyl, thio-(C 1 -C 12) alkyl ) heteroalkyl, (C 1 -C 12) haloalkyl, (C 1 -C 12) and OR; wherein R is selected from H, (C 1 -C 12 ) alkyl, C (0) (Ci-Ci 2 ) alkyl, C (0) NH (Ci-Ci 2 ) alkyl, C (0) 0 (Ci -Ci 2 ) alkyl, C (0) aryl, C (0) (Ci-Ci 2 ) alkyl aryl, C (0) NH (Ci-Ci 2 ) alkyl aryl, C (0) 0 (Ci-Ci 2 ) alkyl aryl and C (0) CHRAANH 2 ; wherein RAA is
  • Re is selected from H, azido, cyano, (C-i-Cs) alkyl, (C-i-Cs) thio-alkyl, (C-i-Cs) heteroalkyl and OR; in which R is selected from H and (C-i-Cs) alkyl;
  • R7 is selected from P (0) R9RIO and P (S) R9RIO; in which
  • R9 and R 10 are independently selected from OH, ORn, NHR 13 , NR13R14, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl , a cycloalkyl (C3-C 10) aryl, (C5-C 12), (Ci-C8) alkyl, aryl, (Ci-C8) alkyl aryl, (Ci-Ce) heteroalkyl, (Ci-Cs) heterocycloalkyl, heteroaryl and NHCHRARA C (0) RI2; in which :
  • R 11 is chosen from a group (C 1 -C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C5-C 18 ) aryl, (C1-C10) alkylaryl, (C5-C12) substituted aryl, (C1- C10) heteroalkyl, (C3-C10) heterocycloalkyl, (C 1 -C 10 haloalkyl, a heteroaryl, - (CH 2 ) nC (0) (C1-C10) alkyl, - (CH 2 ) n0C (0) (Ci- Ci 5 ) alkyl, - (CH 2 ) n 0C (0) 0 (Ci-Ci 5 ) alkyl, - (CH 2 ) n SC (0) (Ci-Cis) alkyl, - (CH 2 ) n C (0 ) 0 (Ci-Ci 5 ) alkyl and - (CH 2 ) n C
  • R12 is selected from H, C1-C10 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C10 haloalkyl, C3-C 10 cycloalkyl, C3-C 10 heterocycloalkyl, C5-C 18 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 -C6 alkyl, C 1 -C6 alkoxy and cyano; and
  • R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-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, C1-C6 alkyl, (C1-C6) alkoxy and cyano; or
  • R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R 10 - represents -O-CH 2 -CH 2 -CHR-O-; in which R is selected from H, a (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl group, in which said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (C 1 -C6) ) alkyl, a (C 1 -C6) alkoxy and cyano;
  • R 8 is selected from H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N 3 and halogen; wherein R 13 and Ru are independently selected from one another from H, (C1-C8) alkyl, (C1-Cs) alkyl aryl, and -CRBRC-C (0) -ORD wherein RB and Rc are independently a hydrogen atom, an (Oi-Ob) alkyl, an (Oi-Ob) alkoxy, benzyl, indolyl or imidazolyl, where the (Oi-Ob) alkyl and the (Oi-Ob) alkoxy can be optionally and independently each other substituted with one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol or carboxyl groups, and the benzyl group is optionally substituted with one or more of halogen or hydroxyl, or RB and Reform together with the carbon atom to which they are
  • Y is selected from CH, CH 2 , C (CH3) 2 and CCH3; represents a single or a double bond along Y;
  • ' / 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, and combinations thereof.
  • the pharmaceutically acceptable derivative is the compound of formula (I).
  • X represents oxygen.
  • Ri and R 6 each represent, independently of one another, a hydrogen.
  • R 2 , R3, R 4 and R5 each represent, independently of one another, a hydrogen or an OH.
  • Y represents a CH.
  • Y represents a CH2.
  • R7 represents P (0) (OH) 2.
  • X represents oxygen
  • Ri and Re each independently represents hydrogen; and or
  • R 2 , R3, R 4 and R5 each independently represents hydrogen or R 2 , R3, R 4 and R5 independently represents OH; and or
  • Y represents CH or CH2;
  • R7 represents P (0) R9RIO, in which R9 and R 10 are independently selected from OH, ORn, NHR13, NR13R14, C1-Csalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3- C10 cycloalkyl, C5-C12 aryl, Ci-Cs aryl alkyl, Ci-Cs alkyl aryl, Ci-Cs heteroalkyl, Ci-Cs heterocycloalkyl, heteroaryl and NHCRARA C (0) RI2.
  • the compound of the invention is chosen from the compounds below:
  • the pharmaceutically acceptable derivative is NMN-H:
  • the NMN 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 1000 mg / kg / day, preferably between 1 mg / kg / day and 100 mg / kg / day, more preferably between 5 mg / kg / day and 50 mg / kg / day, even more preferably between 10 mg / kg / day and 20 mg / kg / day.
  • the NMN can be administered orally, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous, transcutaneous, vaginal , epidural, intravesical, rectal or inhalation.
  • the NMN in a preferred embodiment, can be administered orally or by injection.
  • the NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts can be administered orally, preferably in the form of a sublingual tablet or a gastro-capsule. resistant.
  • NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts can be administered by injection, preferably intra-articularly.
  • NMN one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts
  • NMN can be used in the treatment and / or prevention of rheumatoid arthritis in mammals, preferably humans.
  • NMN one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be used in combination with at least one other therapeutic agent.
  • the at least one therapeutic agent can be an analgesic, a nonsteroidal anti-inflammatory drug, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, a T lymphocyte inhibitor, a B lymphocyte inhibitor. , a synthetic antimalarial, an anti-TNF, an enzymatic inhibitor of Janus kinases, an anti-interleukin and their combinations.
  • the analgesic can be chosen from paracetamol, aspirin, codeine, dihydrocodeine, tramadol, morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine and their combinations.
  • the nonsteroidal anti-inflammatory drug can be chosen from ibuprofen, ketoprofen, naproxen, alminoprofen, aceclofenac, mefenamic acid, niflumic acid, tiaprofenic acid, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, tenoxicam and their combinations.
  • the cortisone derivative can be chosen from betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone, triamcinolone and their combinations.
  • the immunosuppressant can be chosen from azathioprine, cyclophosphamide, chlorambucil, ciclosporin, methotrexate and their combinations.
  • the immunosuppressant can be methotrexate or ciclosporin, more preferably methotrexate.
  • the immunomodulator can be chosen from leflunomide, sulfasalazine and their combinations.
  • the synthetic antimalarial can be chosen from chloroquine, hydroxychloroquine and their combinations.
  • the anti-TNF can be chosen from infliximab, etanercept, adalimumab, certolizumab, golimumab and their combinations.
  • the enzymatic inhibitor of Janus kinases can be tofacitinib.
  • the anti-interleukin can be chosen from an anti-interleukin 1, an anti-interleukin 6, an anti-interleukin 12, an anti-interleukin 17, an anti-interleukin 23 and their combinations.
  • the anti-interleukin 1 can be anakinra.
  • the anti-interleukin 6 can be tocilizumab or sarilumab
  • the B lymphocyte inhibitor can be rituximab.
  • the T cell inhibitor can be abatacept.
  • the interleukin-12 inhibitor can be ustekinumab.
  • the interleukin 17 inhibitor can be chosen from ixekizumab and secukinumab.
  • the interleukin 23 inhibitor can be chosen from ustekinumab and guselkumab.
  • NMN one of its pharmaceutically acceptable derivatives, one of its pharmaceutically acceptable salts, is not used in combination with at least one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
  • SAM S-adenosyl-Lmethionine
  • astaxanthin berberine
  • pterostilbene pterostilbene
  • resveratrol metformin
  • levofloxacin and their combinations.
  • the present invention also relates to a composition
  • a composition comprising nicotinamide mononucleotide (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 the treatment of rheumatoid arthritis.
  • NNN nicotinamide mononucleotide
  • the composition according to the invention can be in the form of a tablet, a capsule, a sachet, a granule, a soft capsule, a lozenge, a lyophilizate, a suspension, a gel, a syrup, a solution, a water / oil emulsion, an oil / water emulsion, an oil, a cream, 'milk, spray, ointment, ampoule, suppository, eye drops, vaginal ovum, vaginal capsule, liquid for inhalation, a dry powder inhaler, a metered-valve pressurized inhaler.
  • composition according to the invention can be a pharmaceutical composition.
  • composition according to the invention can be a food supplement.
  • composition according to the invention can be administered by can be administered orally, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation.
  • composition according to the invention can be provided in unit form at a fixed dose.
  • composition according to the invention can be administered orally or by injection.
  • the composition comprising the NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts can be administered orally, preferably in the form of a sublingual tablet or of a gastro-resistant capsule.
  • NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts can be administered by injection, preferably intra-articularly.
  • composition according to the invention may further comprise at least one additional therapeutic agent as defined above for its use in the prevention and / or treatment of rheumatoid arthritis such as discussed above.
  • the composition according to the invention does not comprise one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
  • SAM S-adenosyl-Lmethionine
  • astaxanthin berberine
  • pterostilbene pterostilbene
  • resveratrol metformin
  • metformin metformin
  • levofloxacin and their combinations.
  • 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.
  • 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.
  • 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 (e.g.
  • 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-dimethylhexyl, 2,5- dimethylhexyl, 2,2- dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyle, 3,3-dimethylhexyl, 4,4- dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhex
  • 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.
  • alkylene 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.
  • alkylene includes methylene, ethylene, methylmethylene, propylene, ethylethylene and 1,2-dimethylethylene.
  • alkenyl 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.
  • alkynyl denotes a class of monovalent unsaturated hydrocarbyl groups, in which the unsaturation results from the presence of one or more carbon-carbon triple bond (s).
  • 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.
  • Alkoxy denotes an alkyl group as defined above, which is attached to another part by an oxygen atom.
  • 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.
  • Aryl 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.
  • aryl examples 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.
  • heteroaryl 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 a group amino functional 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).
  • Alanine ALA
  • ARG Asparagine
  • ASN Asparagine
  • ASP Aspartate
  • Cysteine Cysteine
  • Glutamate Glutamic acid
  • Non-proteinogenic amino acid 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, g-aminobutyrate, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, a-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine or D-glutamate
  • cycloalkyl as used herein is a cyclic alkyl group, i.e. a monovalent, saturated or unsaturated hydrocarbyl group having 1 or 2 ring structures.
  • 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.
  • 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.
  • the preparations must meet standards of sterility, general safety and purity, as required by regulatory authorities, such as for example the FDA or I ⁇ MA.
  • pharmaceutically acceptable excipient includes all pharmaceutically acceptable excipients as well as all pharmaceutically acceptable carriers, diluents, and / or adjuvants.
  • Halogen or "halo" means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro and chloro.
  • 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.
  • 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.
  • heteroatoms are linked along the alkyl chain only to carbon atoms, i.e. each heteroatom is separated from any other heteroatom by at least one carbon atom.
  • the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms can optionally be quaternized.
  • a heteroalkyl is linked to another group or to another molecule only through a carbon atom, i.e. the linking atom is not selected from heteroatoms included in the heteroalkyl group.
  • heteroaryl 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; of which at least one 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 being oxidizable and the heteroatoms nitrogen which can optionally be quaternized.
  • These rings can be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • heteroaryls mention may be made of furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazinyl, pyridazinyl, oxatriazolyl, thiatriazinazinyl, oxatriazolyl, thiatriazinazolyl, oxatriazolyl, thiatriazinazolyl, oxatriazolyl, thiatriazinazinyl, dioxinyl, thiazinyl, triazinyl, imidazo [2, 1 -b] [1, 3] thiazolyl, thieno [3, 2-b] furanyl, thieno [3, 2-b]
  • heterocycloalkyl 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”.
  • heterocyclyl refers to 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
  • Each ring of the heterocyclic group containing a heteroatom can have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the heteroatoms nitrogen 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 the valence permits.
  • the rings of multi-ring heterocycles can be fused, bridged and / or linked by one or more spiro atoms.
  • heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-isothiazolidinyl, piperidinyl, homzolinopinipolinopinyl, 3H-iso-indolinopideraidinyl, inderazolinopinopipolinopolino-inderazolinyl, 2-pipolinopolinopinyl, inderazolinopinyl, 2-piperidinyl, 3H-iso-iso-indol-indol-isidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazo
  • precursor as used here also denotes the pharmacologically acceptable derivatives of the compounds of formula (I) such as the esters of which the in vivo biotransformation product 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.
  • “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 components of the composition in which it is contained.
  • a “pharmaceutically acceptable” salt or excipient denotes any salt or 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.
  • the therapeutic ingredient is a small molecule, natural or synthetic.
  • the ingredient therapeutic is a biological molecule such as, for example, an oligonucleotide, siRNA, miRNA, DNA fragment, aptamer, antibody, etc.
  • “Pharmaceutically acceptable salts” include acid and base addition salts of These salts.
  • Suitable acid addition salts are formed from acids which form non-toxic salts, for example acetate, adipate, aspartate, benzoate, besylate , bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate e, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, bromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyrogluta
  • 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: i. 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. by converting one salt of the compound to another by reaction with a suitable acid or by means of a suitable ion exchange column.
  • the salt can precipitate from solution and be collected by filtration or can be recovered by evaporation of the solvent.
  • the degree of ionization of the salt can vary from completely ionized to almost non-ionized.
  • solvent 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.
  • 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.
  • 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 (-0); haloalkyl (eg, trifluoromethyl); cycloalkyl, which may be condensed or non-condensed monocyclic or polycyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocycloalkyl,
  • substituents can optionally be further substituted by a substituent chosen from these groups.
  • substituted denotes a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, -C (0) NRnRi 2 , - NRI 3 C (0) RU, halo, -OR13, cyano, nitro, haloalkoxy, -C (0) R13, -NR11R12, - SR13 , -C (0) 0Ri3, -0C (0) Ri3, -NRi 3 C (0) NRiiRi2, -0C (0) NRHRI 2 , -
  • Ru and R12 for each occurrence, are, independently, Fl, 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 Ru for each occurrence are, independently, F1, optionally substituted alkyl, optionally
  • administration means to provide the active principle, alone or as part of a pharmaceutically acceptable composition, to the patient in whom / to whom the The condition, symptom or disease must be treated or prevented.
  • Treatment are intended to include the alleviation, alleviation or ablation of a condition or disease and / or its associated symptoms.
  • Prevent refers 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.
  • bonds of an asymmetric carbon can be represented here by using a solid triangle ( a dotted triangle () or a zigzag line
  • 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 rheumatoid arthritis, as well as compositions thereof. including.
  • NNN nicotinamide mononucleotide
  • Nicotinamide adenine dinucleotide 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 in post-translational protein modifications. 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:
  • NMN NMN
  • pharmaceutically acceptable salts and / or derivatives and of the composition according to the invention made it possible to obtain a comparable effect on the swelling of the joints caused by rheumatoid arthritis. drugs commonly used to treat this pathology, without presenting the same side effects.
  • NMN makes it possible to treat the inflammatory attacks characteristic of rheumatoid arthritis by reducing the swelling of the joint significantly and with an efficiency comparable to conventional treatments.
  • chronic administration of NMN helps prevent, or at least reduce, the onset of these relapses. Indeed, administered chronically between each outbreak, NMN and compositions comprising it reduce inflammation and therefore prevent, or at least space out, rheumatoid arthritis outbreaks.
  • NMN a molecule naturally present in the body
  • the NMN does not pose any problem tolerance in patients.
  • the use of NMN and of the composition according to the invention in fact does not induce any allergy.
  • the use of NMN and of the composition according to the invention does not cause the side effects frequently encountered with conventional treatments.
  • NMN does not induce any phenomenon of physical or psychological dependence, unlike analgesics comprising morphine or opium derivatives. Furthermore, NMN does not induce any bone fragility or vulnerability to infection as seen with chronic administration of cortisone or its derivatives.
  • the use of NMN and the composition according to the invention for preventing and / or treating rheumatoid arthritis is therefore safe for patients.
  • NMN and the composition according to the invention can also be used in children and adults.
  • NMN is indeed well tolerated by children.
  • a patient is considered to be a child when his age is less than 18 years and he is an adult from 18 years. Therefore, the invention is also of interest for treating rheumatoid arthritis in children.
  • the NMN is in the form of a zwitterion.
  • 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.
  • NMN of one of its pharmaceutically acceptable derivatives or of one of its pharmaceutically acceptable salts, as well as of compositions comprising it according to the invention firstly makes it possible to treat the inflammation during relapses of rheumatoid arthritis by reducing inflammation and especially swelling of the joints.
  • this makes it possible, in the long term, to prevent the joints from becoming deformed, or at the very least to reduce the deformation of the joints or to delay said deformation.
  • the patient's joints are preserved.
  • the present invention therefore makes it possible to avoid, or at the very least to reduce, the use of conventional treatments for rheumatoid arthritis and therefore of rheumatoid arthritis. avoid, or at least reduce, the appearance of side effects associated with these therapies.
  • the invention therefore makes it possible to maintain the quality of life of the patient by allowing him to perform everyday actions with greater ease, and possibly to avoid the patient having to stop all professional activity .
  • the invention therefore helps to maintain the patient's quality of life, or at the very least to prevent it from deteriorating too much.
  • NMN its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts, as well as the compositions comprising it are used for preventing and / or treating rheumatoid arthritis. More precisely, they can be used on an ad hoc basis to treat a flare-up of rheumatoid arthritis or chronically to reduce inflammation and space the onset of flare-ups.
  • NMN, one of its derivatives or one of its pharmaceutically acceptable salts, as well as compositions comprising them can be used as a preventive or curative measure, in order to reduce the inflammation, and in particular the swelling, of the muscles. joints.
  • NMN its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts
  • the compositions according to the invention can be administered in a therapeutically effective amount.
  • a therapeutically effective amount of a composition means that the composition is administered to a patient in an amount sufficient to achieve the desired therapeutic effect.
  • NMN one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, is used in an amount of between 0.01 mg / kg / day and 1000 mg / kg / day, preferably between mg / kg / day and 100 mg / kg / day, more preferably between 5 mg / kg / day and 50 mg / kg / day, even more preferably between 10 mg / kg / day and 20 mg / kg / day.
  • One skilled in the art can adjust the dose of NMN to be administered depending on the age and weight of the patient.
  • 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.
  • the compositions are preferably provided in the form of tablets containing from 1.0 to 1000 milligrams of NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, especially 1 , 0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.
  • 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 a day, preferably one, two or three times a day, preferably three times a day.
  • the duration of treatment depends on 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.
  • 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, mode and time of administration, rate of excretion, drug combination, and host being treated.
  • 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 minimum of 50 mg / day and a maximum of 1000 mg / day.
  • the NMN and the composition according to the invention can be administered once a day or several times a day.
  • the NMN and the composition according to the invention can be administered between 1 and 12 times per day, preferably between 2 and 10 times per day, more preferably between 3 and 5 times per day.
  • NMN one of its pharmaceutically acceptable salts, one of its pharmaceutically acceptable derivatives and the compositions comprising it can be administered by the oral, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous or transcutaneous routes. , vaginal, epidural, intravesical, rectal or inhalation.
  • the composition according to the invention may be in the form of a tablet, a capsule, a sachet, a granule, a soft capsule, or 'a lyophilisate, a pellet, a suspension, a gel, a syrup, a solution, a water / oil emulsion, an oil / water emulsion, an oil, cream, milk spray, ointment, ampoule, suppository, eye drops, vaginal ovum, vaginal capsule, liquid for inhalation, dry powder inhaler , a pressurized metered-valve inhaler.
  • the NMN and the composition according to the invention are administered by injection, and in particular by subcutaneous, intravenous or intra-articular, preferably intra-articular, route.
  • the NMN and the composition according to the invention are administered orally.
  • the oral form according to the invention can also be immediate release: such a galenic form allows rapid absorption of the NMN and thus a delay reduced action.
  • Immediate-release dosage forms are in particular dispersible, orodispersible, effervescent tablets and oral lyophilisates.
  • the dispersible tablets are uncoated or film-coated tablets which can be dispersed in a liquid before administration in order to have a homogeneous dispersion. Dispersible tablets usually break up within three minutes when placed in water or a small amount of breast milk.
  • An effervescent tablet is a tablet designed to fragment and dissolve rapidly in water or other liquid, releasing carbon dioxide (CO2). This release induces the effervescence and fragmentation of the tablet.
  • An orodispersible tablet is a dispersible tablet that is placed on the tongue. The active principle is then absorbed from the gastrointestinal mucosa.
  • sublingual tablet is understood to mean an oral lyophilizate which is 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 oral form according to the invention can also be delayed release.
  • the dissolution and absorption of NMN takes place in the intestine, which limits gastric irritation or the degradation of fragile active ingredients at acidic pH.
  • They are mainly gastro-resistant 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 intestinal lipases.
  • 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-resistant character of a capsule is measured in 0.1 M hydrochloric acid at 37 ° C as a disintegrating medium in a measuring device. disaggregation. 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 oral form according to the invention can also be prolonged and sequential release.
  • the sequential release (release at specific time interval) and sustained release (continuous release of the active ingredient until exhaustion) forms promote the spreading of the release of the active ingredient over time in order to maintain an effective plasma concentration for longer in the fluid. organism of the patient.
  • Such dosage forms make it possible to obtain relief for the patient for a longer period of time, and to space out the doses of the drug.
  • the NMN and the composition according to the invention are administered orally, in the form of an enteric capsule or a sublingual tablet.
  • NMN one of its pharmaceutically acceptable derivatives, one of its pharmaceutically acceptable salts and the compositions comprising them can also be used in combination with at least one other therapeutic agent, in particular the therapeutic agents used either occasionally to treat relapses.
  • rheumatoid arthritis that is to say symptomatic therapies, or as a basic treatment of rheumatoid arthritis.
  • a basic treatment is treatment taken daily, chronically, in order to prevent or space out attacks.
  • an analgesic a non-steroidal anti-inflammatory drug, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, a T cell inhibitor, a B cell inhibitor, a synthetic antimalarial, an anti-TNF, an enzyme inhibitor of Janus kinases, an anti-interleukin and their combinations .
  • analgesics can be used to treat and relieve flare-ups of inflammatory rheumatism, as a symptomatic treatment of the flare-up.
  • the analgesic can be chosen from paracetamol, aspirin, codeine, dihydrocodeine, tramadol, morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine and theirs. combinations.
  • the nonsteroidal anti-inflammatory drug can be chosen from ibuprofen, ketoprofen, naproxen, alminoprofen, aceclofenac, mefenamic acid, niflumic acid, tiaprofenic acid, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, tenoxicam and their combinations.
  • NSAID nonsteroidal anti-inflammatory drug
  • the cortisone derivative can be chosen from betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone and their combinations.
  • NMN, its derivatives or its pharmaceutically acceptable salts as well as the compositions comprising them can also be administered in combination with a basic treatment of rheumatoid arthritis such as an immunosuppressant, an immunomodulator, a T lymphocyte inhibitor, a B-cell inhibitor, a synthetic antimalarial, an anti-TNF, an enzyme inhibitor of Janus kinases, an anti-interleukin or combinations thereof.
  • a disease-modifying treatment in combination with NMN, one of its derivatives or one of its salts as well as compositions comprising them is also compatible with the administration of analgesics, NSAIDs, cortisone and / or cortisone derivatives to treat relapses.
  • the immunosuppressant can be chosen from azathioprine, cyclophosphamide, chlorambucil, ciclosporin, methotrexate and their combinations.
  • the immunosuppressant can be methotrexate or ciclosporin, more preferably methotrexate.
  • the immunomodulator can be selected from leflunomide, sulfasalazine and their combinations.
  • the B lymphocyte inhibitor can be rituximab.
  • Rituximab is particularly linked to CD20 B lymphocytes.
  • the T cell inhibitor can be abatacept.
  • Abatacept binds in particular to T cells expressing CD80 and CD86.
  • the synthetic antimalarial can be chosen from chloroquine, hydroxychloroquine and their combinations.
  • the anti-TNF can be selected from infliximab, etanercept, adalimumab, certolizumab, golimumab and their combinations.
  • the enzyme inhibitor of Janus kinases may be tofacitinib.
  • the anti-interleukin can be selected from an anti-interleukin-1, an anti-interleukin-6, an interleukin-12 inhibitor, an interleukin-17 inhibitor, an interleukin-23 inhibitor, and combinations thereof.
  • the anti interleukin 1 can be anakinra.
  • the anti-interleukin 6 may be tocilizumab.
  • the interleukin-12 inhibitor may be ustekinumab.
  • the interleukin-17 inhibitor can be selected from ixekizumab and secukinumab.
  • the interleukin 23 inhibitor can be selected from ustekinumab and guselkumab.
  • NMN one of its pharmaceutically acceptable derivatives, one of its pharmaceutically acceptable salts, is not used in combination with at least one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM ), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
  • SAM S-adenosyl-Lmethionine
  • astaxanthin berberine
  • pterostilbene pterostilbene
  • resveratrol metformin
  • levofloxacin and their combinations.
  • compositions according to the invention can comprise the nicotinamide mononucleotide, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient for the prevention and / or treatment of rheumatoid arthritis.
  • an "excipient” means any substance other than NMN in the composition and not having a therapeutic effect.
  • the excipient does not chemically interact with NMN or any additional therapeutic agent.
  • 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.
  • compositions according to the invention can be formulated with carriers, excipients and diluents which are suitable per se for these formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, water (sterile), methylcellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, edible oils, vegetable and mineral oils or suitable mixtures thereof.
  • carriers, excipients and diluents which are suitable per se for these formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrroli
  • the formulations may optionally contain other substances which are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preservatives, sweeteners, flavorings, flow regulators, mold release agents, etc.
  • the compositions can also be formulated so as to allow rapid, sustained or delayed release of the active compound (s) which they contain. Those skilled in the art know which excipient to choose depending on the dosage form they have chosen.
  • compositions according to the invention are preferably in the form of unit doses and can be packaged in an appropriate manner, for example in a box, a blister, a vial, a bottle, a sachet, an ampoule or in any other support. or an appropriate single-dose or multiple-dose container (which can be correctly labeled); optionally with one or more leaflet (s) containing product information and / or instructions for use.
  • composition according to the invention can be a pharmaceutical composition.
  • the excipient is a pharmaceutically acceptable excipient as defined above.
  • composition according to the invention can also be a food supplement.
  • composition according to the invention may further comprise at least one additional therapeutic agent as defined above for its use in the prevention and / or treatment of rheumatoid arthritis such as discussed above.
  • the composition according to the invention comprises at least one additional therapeutic agent
  • the composition may be in unit form at a fixed dose.
  • unit form at a fixed dose is understood to mean a composition comprising at least two active principles formulated in a single dosage form.
  • the composition according to the invention does not comprise one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
  • SAM S-adenosyl-Lmethionine
  • astaxanthin berberine
  • pterostilbene pterostilbene
  • resveratrol metformin
  • metformin metformin
  • levofloxacin and their combinations.
  • R 1 is selected from H, azido, cyano, C-i-Cs alkyl, thio-C-i-Cs alkyl, C-i-Cs heteroalkyl and OR; wherein R is selected from F1 and C1-C8 alkyl;
  • R 2 , R3, R 4 and R5 are chosen independently of one another from F1, halogen, azido, cyano, hydroxyl, C 1 -C 12 alkyl, C 1 -C 12 thio-alkyl, C 1 -C 12 heteroalkyl.
  • R is selected from F1, C 1 -C 12 alkyl, C (0) (Ci-Ci 2 ) alkyl, C (0) NH (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) CFIR AA NFI 2 ; wherein R AA is a side chain selected from a proteinogenic amino acid;
  • Re is selected from F1, azido, cyano, C-i-Cs alkyl, C-i-Cs thio-alkyl, C-i-Cs heteroalkyl and OR; in which R is selected from F1 and C-i-Cs alkyl;
  • R7 is selected from P (0) R9RIO and P (S) R9RIO; in which
  • R 9 and R 10 are selected independently of one another from OH, ORn, NHR 13, NR 13 R 14, alkyl Ci-Cs alkenyl, C 2 -C 8, a C 2 -C 8 alkynyl, a C3-C 10 cycloalkyl, a C5-C 12 aryl, (Ci-C8) alkyl aryl, (Ci-Cs) aryl alkyl, (Ci-Cs) heteroalkyl, (Ci-Cs) heterocycloalkyl, a heteroaryl and NHCHR A R A C (0) R I2 ; in which :
  • R 11 is selected from a group C 1 -C 10 alkyl, C3-C 10 cycloalkyl, C5-C 18 aryl, C 1 -C 10 alkylaryl, C5-C 12 substituted aryl, C 1 -C 10 heteroalkyl, C3-C 10 heterocycloalkyl, C 1 -C 10 haloalkyl, a heteroaryl, - (CH 2 ) n C (0) (C1-C15) alkyl, - (CH 2 ) n 0C (0) (Ci- Cis) alkyl, - (CH 2 ) n0C (0) 0 (Ci-Ci 5 ) alkyl, - (CH 2 ) nSC (0) (Ci-Ci 5 ) alkyl, (CH 2 ) nC (0) 0 (Ci-Ci 5 ) alkyl and - (CH 2 ) nC (0) 0 (Ci-Ci 5 ) alky
  • R9 and R10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R10- represents -CH 2 -CH 2 -CHR-; wherein R is selected from H, (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C 1 -C6 alkyl , a C 1 -C6 alkoxy and cyano; or
  • R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R 10 - represents -O-CH 2 -CH 2 -CHR-O-; in which R is selected from H, a (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl group, in which said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (C 1 -C6) ) alkyl, a (C 1 -C6) alkoxy and cyano;
  • R 8 is selected from H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N 3 and halogen; wherein R13 and Ru are independently selected from one another from H, (C1-C8) alkyl and (C1-Cs) alkyl aryl, and -CRBRC-C (0) -ORD wherein RB and Rc are independently a hydrogen atom, an (Oi-Ob) alkyl, an (Oi-Ob) alkoxy, benzyl, indolyl or imidazolyl, where the (Oi-Ob) alkyl and the (Oi-Ob)) alkoxy can be optionally and independently each other substituted with one or more of the halogen, amino, amido, guanidyl, hydroxyl, thiol or carboxyl groups, and the benzyl group is optionally substituted by one or more of the halogen or hydroxyl groups, or RB and together with the carbon atom to
  • Y is selected from CH, CH 2 , C (CH3) 2 and CCH3; - r - z represents a single or a double bond along Y; and 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 and their combinations.
  • the pharmaceutically acceptable derivative is the compound of formula (I).
  • X represents an oxygen
  • R 1 and R 6 each represent, independently of one another, a hydrogen.
  • R 2 , R3, R 4 and R5 each represent, independently of one another, a hydrogen or an OH.
  • Y represents a CH.
  • Y represents a CH 2.
  • R 7 represents P (0) (OH) 2.
  • the compound of the invention is chosen from the compounds below
  • the derivative of NMN can be dihydronicotinamide mononucleotide (denoted NMN-H).
  • the derivatives of formula (I) can be prepared according to the process described in international application WO 2017 / 024255A1 or US 10,611, 790 B2.
  • derivatives of formula (I) can be prepared according to the method described below.
  • 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), in which X, Ri, R2, R3, R4, Rs, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
  • the phosphorodichloridate of formula (B) is hydrolyzed to yield the phosphate of formula (C), in which X, Ri, R2, R3, R4, Rs, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
  • the compound of formula (A) is synthesized using various methods known to those skilled in the art.
  • 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, R 2 , R3, R 4 , Rs , R6, R7, Y are as described above for the compounds of formula I, leading to the compound of formula (A-1) which is then selectively deprotected to give the compound of formula (A), in which X, Ri, R2, R3, R4, Rs, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
  • R is an appropriate protective group known to those skilled in the art.
  • the protecting group is chosen from triarylmethyls and / or silyls.
  • triarylmethyl include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl and 4,4 ', 4 "-trimethoxytrityl.
  • silyl groups include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-. butyldiphenylsilyl, tri-iso-propylsilyloxymethyl and [2-
  • any hydroxyl group attached to the pentose is protected by an appropriate protective group known to those skilled in the art.
  • protecting groups are 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.
  • 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 (A-1).
  • Lewis acids include TMSOTf, BF3.0Et 2 , TiCL and FeC.
  • 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, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
  • 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:
  • a step of reducing the compound of formula lA is carried out, resulting in the compound of formula lE of formula below:
  • 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.
  • the compounds of formula (I) are selected from the compounds of the table below:
  • the compounds of the invention are the compounds of the table above or a pharmaceutically acceptable salt and / or solvate thereof.
  • FIG. 1 is a graph showing the change in the average weight of the mice as a function of the treatments.
  • FIG. 2 is a graph showing the evolution of the mean clinical score according to the treatments.
  • FIG. 3 is a graph showing the change in the average paw thickness of mice as a function of treatments.
  • FIG. 4 shows photographs of the paws of treated mice from each treatment group.
  • mice were divided into four groups each comprising ten mice: (i) a control group in which the mice are treated with the vehicle, that is to say a 0.9% NaCl solution (10 mL / kg) noted " Vehicle ”; (ii) a group of mice treated with K / BxN serum (10 mL / kg) denoted “KBxN”; (iii) a group of mice treated with serum K / BxN + dexamethasone (1 mg / kg) denoted “KBxN + dexamethasone”; and (iv) a group of mice treated with K / BxN + NMN serum (185 mg / kg) denoted “KBxN + NMN”.
  • the K / BxN serum is a serum obtained from genetically modified mice used as a model of rheumatoid arthritis. Administration of this serum induces chronic inflammation of the joints in mice to mimic rheumatoid arthritis.
  • Dexamethasone is a derivative of cortisone, a treatment traditionally used to fight against flare-ups of rheumatoid arthritis.
  • NMN is used here in the form of a zwitterion.
  • KBxN serum and NMN are administered to mice intraperitoneally.
  • Dexamethasone is administered subcutaneously.
  • mice are treated for 9 days according to the conditions mentioned above.
  • Mice paws Photos are taken on the 6th day of treatment.
  • the blood of the mice is taken on the 6 th and 10 th days of treatment.
  • Tissues were collected at I0 th day of treatment for histological analysis, the day after stopping treatment.
  • the clinical score and the weight of the mice are measured daily. The clinical score is established by measuring the thickness of each of the animal's front and hind legs, and by adding the associated score according to Table 1 below:
  • mice in the control group did not lose weight during the duration of the experiment.
  • administration of K / BxN serum induced significant weight loss in the three treated groups, indicating treatment-related distress in the animal.
  • the administration of dexamethasone induces an additional and significant weight loss compared to the group treated with KBxN alone as well as to the "KBxN + NMN" group.
  • NMN did not induce significant weight loss compared to the "KBxN" treated group. Therefore, NMN is well tolerated and more specifically, NMN is better tolerated than dexamethasone.
  • FIG. 2 shows the evolution of the clinical score among the different groups of mice.
  • the mean clinical score of the mice in the control group is zero: the vehicle therefore does not induce any inflammation of the joint.
  • Treatment of the mice with dexamethasone brings the clinical score back to values close to those of the control group.
  • the clinical score of mice treated with KBxN increases until the 6 th day after which it reaches a plateau, which indicates distress and severe inflammation in mice.
  • Treatment with NMN makes it possible to reduce the clinical score significantly from the 5 th day. The reduction in the clinical score is increasing from 8 th day of treatment. Therefore, the administration of NMN significantly reduces the inflammation of the joints in this model of rheumatoid arthritis.
  • the paw of the mouse treated with NMN has a volume similar to that of the mouse treated with the vehicle: the NMN is therefore effective in treating the inflammation induced by the injection of K / BxN serum and much better tolerated by mice than conventional dexamethasone treatment.
  • NMN NMN
  • NMN its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts, as well as the compositions comprising them can therefore be used successfully and safely to treat and prevent rheumatoid arthritis.
  • the present invention therefore makes it possible to find a therapeutic alternative to conventional treatments for rheumatoid arthritis, or at the very least to provide a therapeutic complement to conventional treatments in order to reduce their frequency of use and their dosage. Because of the harmlessness of NMN, of its pharmaceutically acceptable derivatives or of its pharmaceutically acceptable salts, as well as of the compositions comprising it, the present invention makes it possible to treat and / or prevent rheumatoid arthritis without inducing the side effects caused by the treatments. conventional.

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Abstract

The invention relates to nicotinamide mononucleotide, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, for use in the prevention and/or treatment of rheumatoid arthritis, as well as to compositions comprising same.

Description

Description Description
Titre de l'invention : Title of the invention:
UTILISATION DE NICTOTINAMIDE MONONUCLÉOTIDE (NMN)USE OF NICTOTINAMIDE MONONUCLEOTIDE (NMN)
POUR LA PREVENTION ET/OU LE TRAITEMENT DE LA POLYARTHRITE RHUMATOÏDE ET COMPOSITIONS CORRESPONDANTESFOR THE PREVENTION AND / OR TREATMENT OF RHEUMATOID ARTHRITIS AND CORRESPONDING COMPOSITIONS
DOMAINE DE L’INVENTION FIELD OF THE INVENTION
[0001] La présente invention porte sur l’utilisation de nicotinamide mononucléotide (NMN), un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, ainsi que de compositions le comprenant, pour le traitement et/ou la prévention de la polyarthrite rhumatoïde. The present invention relates to the use of nicotinamide mononucleotide (NMN), one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, as well as compositions comprising it, for the treatment and / or prevention of polyarthritis rheumatoid.
ARRIERE-PLAN TECHNIQUE TECHNICAL BACKGROUND
[0002] Une articulation rassemble notamment deux extrémités osseuses recouvertes de cartilage ainsi qu’une membrane synoviale enveloppant l’ensemble. Le rôle de la membrane synoviale est de faciliter les mouvements articulaires, en sécrétant un lubrifiant : le liquide synovial. Un rhumatisme inflammatoire consiste notamment en l'inflammation de la membrane synoviale. Le liquide synovial est alors secrété en trop grande quantité et la membrane synoviale s'épaissit anormalement. Les tissus mous et les surfaces osseuses de l'articulation sont alors endommagés. L’articulation devient anormalement gonflée et douloureuse, empêchant les mouvements. [0002] In particular, a joint brings together two bone ends covered with cartilage as well as a synovial membrane enveloping the whole. The role of the synovial membrane is to facilitate joint movements, by secreting a lubricant: the synovial fluid. Inflammatory rheumatism mainly consists of inflammation of the synovial membrane. Too much synovial fluid is then secreted and the synovial membrane thickens abnormally. The soft tissues and bony surfaces of the joint are damaged. The joint becomes abnormally swollen and painful, preventing movement.
[0003] La polyarthrite rhumatoïde est un rhumatisme inflammatoire chronique qui touche le plus souvent les mains, les poignets et les genoux mais peut également s'étendre à d’autres articulations. Les polyarthrites sont parfois associées à la présence du facteur rhumatoïde dans le sang du patient et peuvent entraîner des dommages irréversibles aux articulations. [0003] Rheumatoid arthritis is a chronic inflammatory rheumatism that most commonly affects the hands, wrists and knees but can also spread to other joints. Polyarthritis is sometimes associated with the presence of rheumatoid factor in the patient's blood and can lead to irreversible damage to the joints.
[0004] Les traitements de la polyarthrite comprennent d’une part un traitement symptomatique pour soulager les poussées inflammatoires et d’autre part un traitement de fond. [0004] The treatments for polyarthritis include, on the one hand, symptomatic treatment to relieve inflammatory flare-ups and on the other hand, maintenance therapy.
[0005] Les traitements symptomatiques comprennent principalement l’administration d’antalgiques pour réduire la douleur, d’anti-inflammatoires non stéroïdiens (AINS) ainsi que de cortisone ou de ses dérivés pour réduire l’inflammation. Cependant, l’administration chronique de ces médicaments endommagent, entre autres, l’estomac, le foie et les reins. De plus, leur efficacité se réduit avec le temps nécessitant l’augmentation des doses ou le recours à des médicaments plus agressifs et souvent, causant davantage d’effets secondaires. Par ailleurs, l’utilisation chronique de dérivés de la cortisone induit notamment une fragilité osseuse, des effets neuropsychiatriques, une fonte musculaire et une réduction de l’immunité, laissant le patient vulnérable aux infections. Symptomatic treatments mainly comprise the administration of analgesics to reduce pain, non-steroidal anti-inflammatory drugs (NSAIDs) as well as cortisone or its derivatives to reduce inflammation. However, chronic administration of these drugs damages the stomach, liver and kidneys, among other things. In addition, their effectiveness decreases over time requiring increased doses or the use of more aggressive drugs and often causing more side effects. Furthermore, the chronic use of cortisone derivatives induces in particular bone fragility, neuropsychiatric effects, muscle wasting and a reduction in immunity, leaving the patient vulnerable to infections.
[0006] Les traitements de fond comprennent le plus souvent l’administration de méthotrexate, un anticancéreux utilisé avec succès pour prévenir et réduire le nombre de poussées inflammatoires. Cependant, ce médicament comprend de nombreux effets secondaires tels que fièvre, anémie, troubles respiratoires, risques tératogènes et toxicité médullaire entre autres risques. De ce fait, il n’est pas correctement toléré par tous les patients. D’autres médicaments, en remplacement ou en conjonction avec le méthotrexate, sont utilisés tels que certains antipaludiques et des inhibiteurs du TNF (pour « Tumor Necrosis Factor » en anglais), protéine impliquée dans les processus inflammatoires. Cependant, aucun de ces médicaments n’est exempt d’effets secondaires. Il existe notamment un risque d’affaiblissement du système immunitaire, ainsi qu’une forte toxicité sur les organes vitaux du patient tels que le foie et le rein. [0006] DMARDs most often include the administration of methotrexate, an anticancer drug successfully used to prevent and reduce the number of inflammatory flares. However, this drug includes many side effects such as fever, anemia, respiratory problems, teratogenic risks and bone marrow toxicity among other risks. Therefore, it is not well tolerated by all patients. Other medicines, in place of or in conjunction with methotrexate, are used such as certain antimalarials and inhibitors of TNF (for "Tumor Necrosis Factor"), a protein involved in inflammatory processes. However, none of these drugs are free from side effects. In particular, there is a risk of weakening the immune system, as well as high toxicity on the patient's vital organs such as the liver and kidney.
[0007] De plus, la polyarthrite rhumatoïde raidit et déforme les articulations. Outre l’aspect esthétique difficile à supporter, les gestes de la vie quotidienne deviennent de plus en plus difficiles à exécuter pour les patients. Les patients finissent donc par avoir besoin de modifier leur quotidien, quitter leur travail et dépendre d’aide extérieure, ce qui implique entre autres un coût considérable pour les systèmes de santé. [0007] In addition, rheumatoid arthritis stiffens and deforms the joints. In addition to the aesthetic aspect that is difficult to bear, the gestures of daily life are becoming more and more difficult for patients to perform. Patients therefore end up needing to change their daily lives, quit their work and depend on outside help, which among other things implies a considerable cost for the health systems.
[0008] Il existe donc un besoin de développer de nouvelles compositions pour le traitement et/ou la prévention de la polyarthrite rhumatoïde qui réduisent les inconvénients de l’art antérieur. [0008] There is therefore a need to develop new compositions for the treatment and / or prevention of rheumatoid arthritis which reduce the drawbacks of the prior art.
RESUME DE L’INVENTION SUMMARY OF THE INVENTION
[0009] Ces objectifs sont atteints grâce à l’invention tel que décrite ci-dessous. [0010] La présente invention a pour objet le nicotinamide mononucléotide (NMN), un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, pour son utilisation dans la prévention et/ou le traitement de la polyarthrite rhumatoïde. These objectives are achieved thanks to the invention as described below. 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 rheumatoid arthritis.
[0011] Avantageusement, le dérivé pharmaceutiquement acceptable du NMN peut être le dihydronicotinamide mononucléotide (noté NMN-H), le composé de formule (I) : ou un de ses stéréoisomères, un de ses sels, un de ses hydrates, un de ses solvatés ou un de ses cristaux pharmaceutiquement acceptable de celui-ci, dans lequel : Advantageously, the pharmaceutically acceptable derivative of NMN can be dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I): 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 est choisi parmi O, Chh, S, Se, CHF, CF2 et C=CH2; X is selected from O, Chh, S, Se, CHF, CF 2 and C = CH 2 ;
Ri est choisi parmi H, azido, cyano, alkyle en (C-i-Cs), thio-alkyle en (C-i-Cs), hétéroalkyle en (C-i-Cs) et OR ; dans lequel R est choisi parmi H et alkyle en (C-i-Cs) ; R 1 is selected from H, azido, cyano, (C-i-Cs) alkyl, (C-i-Cs) thio-alkyl, (C-i-Cs) heteroalkyl and OR; wherein R is selected from H and (C1-C8) alkyl;
R2, R3, R4 et R5 sont choisis indépendamment l’un de l’autre parmi H, halogène, azido, cyano, hydroxyle, alkyle en (C1-C12), thio-alkyle en (C1-C12), hétéroalkyle en (C1-C12), haloalkyle en (C1-C12) et OR ; dans lequel R est choisi parmi H, alkyle en (C1-C12), C(0)(Ci-Ci2)alkyle, C(0)NH(Ci-Ci2)alkyle, C(0)0(Ci-Ci2)alkyle, C(0)aryle, C(0)(Ci-Ci2)alkyle aryle, C(0)NH(Ci-Ci2)alkyle aryle, C(0)0(Ci-Ci2)alkyle aryle et C(0)CHRAANH2 ; dans lequel RAA est une chaîne latérale choisie parmi un acide aminé protéinogène ; R 2 , R3, R 4 and R5 are chosen independently of one another from H, halogen, azido, cyano, hydroxyl, (C 1 -C 12 ) alkyl, thio-(C 1 -C 12) alkyl ) heteroalkyl, (C 1 -C 12) haloalkyl, (C 1 -C 12) and OR; wherein R is selected from H, (C 1 -C 12 ) alkyl, C (0) (Ci-Ci 2 ) alkyl, C (0) NH (Ci-Ci 2 ) alkyl, C (0) 0 (Ci -Ci 2 ) alkyl, C (0) aryl, C (0) (Ci-Ci 2 ) alkyl aryl, C (0) NH (Ci-Ci 2 ) alkyl aryl, C (0) 0 (Ci-Ci 2 ) alkyl aryl and C (0) CHRAANH 2 ; wherein RAA is a side chain selected from a proteinogenic amino acid;
Re est choisi parmi H, azido, cyano, (C-i-Cs) alkyle, (C-i-Cs) thio-alkyle, (C-i-Cs) hétéroalkyle et OR ; dans lequel R est choisi parmi H et (C-i-Cs) alkyle; Re is selected from H, azido, cyano, (C-i-Cs) alkyl, (C-i-Cs) thio-alkyl, (C-i-Cs) heteroalkyl and OR; in which R is selected from H and (C-i-Cs) alkyl;
R7 est choisi parmi P(0)R9RIO et P(S)R9RIO ; dans lequel R7 is selected from P (0) R9RIO and P (S) R9RIO; in which
R9 et R10 sont choisis indépendamment l’un de l’autre parmi OH, ORn, NHR13, NR13R14, un alkyle en (C-i-Cs), un alcényle en (C2-C8), un alcynyl en (C2-C8), un cycloalkyl en (C3-C10), un aryle en (C5-C12), (Ci-C8)alkyle aryle, (Ci-C8)aryle alkyle, (Ci-Ce) heteroalkyle, (Ci-Cs) heterocycloalkyle, un heteroaryle et NHCHRARA C(0)RI2 ; dans lequel : R9 and R 10 are independently selected from OH, ORn, NHR 13 , NR13R14, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl , a cycloalkyl (C3-C 10) aryl, (C5-C 12), (Ci-C8) alkyl, aryl, (Ci-C8) alkyl aryl, (Ci-Ce) heteroalkyl, (Ci-Cs) heterocycloalkyl, heteroaryl and NHCHRARA C (0) RI2; in which :
R11 est choisi parmi un groupe (C1-C10) alkyle, (C3-C10) cycloalkyle, (C5-C18) aryle, (C1-C10) alkylaryle, (C5-C12) aryle substitué, (C1-C10) heteroalkyle, (C3-C10) heterocycloalkyle, (C1-C10 haloalkyle, un heteroaryle, -(CH2)nC(0)(Ci-Ci5)alkyle, - (CH2)n0C(0)(Ci-Ci5)alkyle, -(CH2)n0C(0)0(Ci-Ci5)alkyle, -(CH2)nSC(0)(Ci- Cis)alkyle, -(CH2)nC(0)0(Ci-Ci5)alkyle and -(CH2)nC(0)0(Ci-Ci5)alkyle aryle; dans lesquels n est un entier choisi de 1 à 8; P(0)(0H)0P(0)(0H)2; halogène, nitro, cyano, C-i-Ce alkoxy, C-i-Ce haloalkoxy, -N(Rna)2, C-i-Ce acylamino, -CORnb, -O CORnb ; NHS02(CI-C6 alkyl), - S02N(Rna)2 SO2 dans lequel chacun de Rna est indépendamment choisi parmi H et un (C-i-Ce) alkyle et Rub est indépendamment choisi parmi OH, C1-C6 alkoxy, NH2, NH(CI-C6 alkyle) ou N(Ci-C6alkyle)2 ; R 11 is chosen from a group (C 1 -C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C5-C 18 ) aryl, (C1-C10) alkylaryl, (C5-C12) substituted aryl, (C1- C10) heteroalkyl, (C3-C10) heterocycloalkyl, (C 1 -C 10 haloalkyl, a heteroaryl, - (CH 2 ) nC (0) (C1-C10) alkyl, - (CH 2 ) n0C (0) (Ci- Ci 5 ) alkyl, - (CH 2 ) n 0C (0) 0 (Ci-Ci 5 ) alkyl, - (CH 2 ) n SC (0) (Ci-Cis) alkyl, - (CH 2 ) n C (0 ) 0 (Ci-Ci 5 ) alkyl and - (CH 2 ) n C (0) 0 (Ci-Ci 5 ) alkyl aryl; where n is an integer selected from 1 to 8; P (0) (0H) 0P (0) (0H) 2 ; halogen, nitro, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, -N (Rn a ) 2, C1-Ce acylamino, -CORnb, -O CORnb; NHS02 (CI-C6 alkyl ), - SO2N (Rn a ) 2 SO2 in which each of Rn a is independently selected from H and a ( C1-C6) alkyl and Ru b is independently selected from OH, C1-C6 alkoxy, NH2, NH (CI-C6 alkyl) or N (C1-C6alkyl) 2;
R12 est choisi parmi H, C1-C10 alkyle, C2-C8 alcényle, C2-C8 alcynyle, C1-C10 haloalkyle, C3-C10 cycloalkyle, C3-C10 heterocycloalkyle, C5-C18 aryle, C1-C4 alkylaryle and C5-C12 heteroaryle; dans lesquels lesdits groupes aryle ou heteroaryle sont optionnellement substitué parmi un ou deux groupes choisi parmi un halogène, trifluoromethyl, C1-C6 alkyle, C1-C6 alkoxy et cyano; et R12 is selected from H, C1-C10 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C10 haloalkyl, C3-C 10 cycloalkyl, C3-C 10 heterocycloalkyl, C5-C 18 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 -C6 alkyl, C 1 -C6 alkoxy and cyano; and
RA et RA’ sont indépendamment choisi parmi H, un (C1-C10) alkyle, (C2-C10) alcényle, (C2-C10) alcynyle, (C3-C10) cycloalkyle, (C1-C10) thio-alkyle, (C1-C10) hydroxylalkyle, (C1-C10) alkylaryle and (C5-C12) aryle, (C3-C10) heterocycloalkyle, un heteroaryle, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1 H-imidazol-4-yl)methyl et une chaîne latérale choisie parmi un acide aminé protéinogène ou un acide aminé non protéinogène; dans lesquels lesdits groupes aryle sont optionnellement substitué avec un groupe choisi parmi un hydroxyle, (C1-C10) alkyl, (C-i-Ce) alkoxy, un halogène, un nitro et un cyano; ou R A and R A ' are independently selected from H, a (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, (C1-C10) thio-alkyl, (C1-C10) hydroxylalkyl, (C1-C10) alkylaryl and (C5-C12) aryl, (C3-C10) heterocycloalkyl, a heteroaryl, - (CH 2 ) 3NHC (= NH) NH 2 , (1H -indol-3-yl) methyl, (1 H-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; or
R9 et R10 forment ensemble avec les atomes de phosphore auxquels ils sont attaché un cycle à 6 membres dans lequel -R9-R10- représente -CH2-CH2-CHR-; dans lequel R est choisi parmi H, un groupe (Cs-Ce) aryle et (Cs-Ce) heteroaryle, dans lequel lesdits groupes aryle ou heteroaryle sont optionnellement substitués par un halogène, trifluoromethyl, un C1-C6 alkyle, un (C1-C6) alkoxy et cyano; ou R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-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, C1-C6 alkyl, (C1-C6) alkoxy and cyano; or
R9 et R10 forment ensemble avec les atomes de phosphore auxquels ils sont attaché un cycle à 6 membres dans lequel -R9-R10- représente -O-CH2-CH2-CHR-O-; dans lequel R est choisi parmi H, un groupe (C5-C6) aryle et (C5-C6) heteroaryle, dans lequel lesdits groupes aryle ou heteroaryle sont optionnellement substitués par un halogène, trifluoromethyl, un (C1-C6) alkyle, un (C1-C6) alkoxy et cyano; R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R 10 - represents -O-CH 2 -CH 2 -CHR-O-; in which R is selected from H, a (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl group, in which said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (C 1 -C6) ) alkyl, a (C 1 -C6) alkoxy and cyano;
R8 est choisi parmi H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N3 et halogène ; dans lequel R13 et Ru sont choisis indépendamment l’un de l’autre parmi H, (C1-C8) alkyle, (C-i-Cs) alkyle aryle, et -CRBRC-C(0)-ORD dans lequel RB et Rc sont indépendamment un atome d'hydrogène, un (Oi-Ob) alkyle, un (Oi-Ob) alkoxy, benzyle, indolyle ou imidazolyle, où le (Oi-Ob) alkyle et le (Oi-Ob) alkoxy peuvent être éventuellement et indépendamment l’un de l’autre substitué par un ou plusieurs des groupes halogène, amino, amido, guanidyle, hydroxyle, thiol ou carboxyle, et le groupe benzyle est éventuellement substitué par un ou plusieurs des groupes halogène ou hydroxyle, ou RB et Reforment ensemble avec l'atome de carbone auquel ils sont attachés un groupe cycloalkyle en C3-C6 éventuellement substitué par un ou plusieurs halogènes, amino, amido, guanidyle, hydroxyle, thiol et carboxyle et RD est un hydrogène, un (C1-C6) alkyle, un (C2-C6) alcényle, un (C2-C6) alcynyle ou un (C3- Ce) cycloalkyle ; R 8 is selected from H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N 3 and halogen; wherein R 13 and Ru are independently selected from one another from H, (C1-C8) alkyl, (C1-Cs) alkyl aryl, and -CRBRC-C (0) -ORD wherein RB and Rc are independently a hydrogen atom, an (Oi-Ob) alkyl, an (Oi-Ob) alkoxy, benzyl, indolyl or imidazolyl, where the (Oi-Ob) alkyl and the (Oi-Ob) alkoxy can be optionally and independently each other substituted with one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol or carboxyl groups, and the benzyl group is optionally substituted with one or more of halogen or hydroxyl, or RB and Reform together with the carbon atom to which they are attached a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogens, amino, amido, guanidyl, hydroxyl, thiol and carboxyl and RD is a hydrogen, a (C 1 -C6 ) alkyl, a (C 2 -C6) alkenyl, a (C 2 -C6) alkynyl or a (C3-Ce) cycloalkyl;
Y est choisi parmi CH, CH2, C(CH3)2 et CCH3 ; représente une simple ou une double liaison selon Y ; et Y is selected from CH, CH 2 , C (CH3) 2 and CCH3; represents a single or a double bond along Y; and
'/vw- représente l'anomère alpha ou bêta selon la position de Ri ou un de ses stéréoisomères, un de ses sels, un de ses hydrates, un de ses solvatés ou un de ses cristaux, et leurs combinaisons. ' / 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, and combinations thereof.
[0012] Dans un premier mode de réalisation préféré, le dérivé pharmaceutiquement acceptable est le composé de formule (I). In a first preferred embodiment, the pharmaceutically acceptable derivative is the compound of formula (I).
[0013] Dans une variante du premier mode de réalisation, X représente un oxygène. [0014] Dans une variante du premier mode de réalisation, Ri et R6 représentent chacun indépendamment l’un de l’autre un hydrogène. 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.
[0015] Dans une variante du premier mode de réalisation, R2, R3, R4 et R5 représentent chacun indépendamment l’un de l’autre un hydrogène ou un OH. In a variant of the first embodiment, R 2 , R3, R 4 and R5 each represent, independently of one another, a hydrogen or an OH.
[0016] Dans une variante du premier mode de réalisation, Y représente un CH. In a variant of the first embodiment, Y represents a CH.
[0017] Dans une variante du premier mode de réalisation, Y représente un CH2. In a variant of the first embodiment, Y represents a CH2.
[0018] Dans une variante du premier mode de réalisation, R7 représente P(0)(OH)2. In a variant of the first embodiment, R7 represents P (0) (OH) 2.
[0019] Dans une variante du premier mode de réalisation, In a variant of the first embodiment,
X représente un oxygène ; et/ou X represents oxygen; and or
Ri et Re représente chacun indépendamment un hydrogène ; et/ou Ri and Re each independently represents hydrogen; and or
R2, R3, R4 et R5 représente chacun indépendamment un hydrogène ou R2, R3, R4 et R5 représente indépendamment OH ; et/ou R 2 , R3, R 4 and R5 each independently represents hydrogen or R 2 , R3, R 4 and R5 independently represents OH; and or
Y représente un CH ou un CH2 ; et/ou Y represents CH or CH2; and or
R7 représente P(0)R9RIO, dans lequel R9 et R10 sont indépendamment choisis parmi OH, ORn, NHR13, NR13R14, C-i-Csalkyle, C2-C8 alcényle, C2-C8 alcynyle, C3- C10 cycloalkyle, C5-C12 aryle, Ci-Cs aryle alkyle, C-i-Cs alkyle aryle, Ci-Cs heteroalkyle, Ci-Cs heterocycloalkyle, heteroaryle et NHCRARA C(0)RI2. R7 represents P (0) R9RIO, in which R9 and R 10 are independently selected from OH, ORn, NHR13, NR13R14, C1-Csalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3- C10 cycloalkyl, C5-C12 aryl, Ci-Cs aryl alkyl, Ci-Cs alkyl aryl, Ci-Cs heteroalkyl, Ci-Cs heterocycloalkyl, heteroaryl and NHCRARA C (0) RI2.
[0020] Dans une variante particulièrement préférée du premier mode de réalisation, le composé de l’invention est choisi parmi les composés ci-dessous : In a particularly preferred variant of the first embodiment, the compound of the invention is chosen from the compounds below:
[0021] [Tableau 1] [0021] [Table 1]
[0022] Dans un mode de réalisation préféré, le dérivé pharmaceutiquement acceptable est le NMN-H : In a preferred embodiment, the pharmaceutically acceptable derivative is NMN-H:
[0023] Avantageusement, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être utilisé dans une quantité comprise entre 0,01 mg/kg/jour et 1000 mg/kg/jour, de préférence entre 1 mg/kg/jour et 100 mg/kg/jour, de manière davantage préférée entre 5 mg/kg/jour et 50 mg/kg/jour, de manière encore plus préférée entre 10 mg/kg/jour et 20 mg/kg/jour. Advantageously, the NMN, 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 1000 mg / kg / day, preferably between 1 mg / kg / day and 100 mg / kg / day, more preferably between 5 mg / kg / day and 50 mg / kg / day, even more preferably between 10 mg / kg / day and 20 mg / kg / day.
[0024] Avantageusement, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être administré par voie orale, oculaire, sublinguale, intraveineuse, intraartérielle, intramusculaire, intra-articulaire, sous-cutanée, transcutanée, vaginale, péridurale, intravésicale, rectale ou inhalation. Advantageously, the NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered orally, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous, transcutaneous, vaginal , epidural, intravesical, rectal or inhalation.
[0025] Dans un mode de réalisation préféré, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être administré par voie orale ou injectable. In a preferred embodiment, the NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered orally or by injection.
[0026] Dans un mode de réalisation préféré, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être administré par voie orale, de préférence sous forme d’un comprimé sublingual ou d’une gélule gastro-résistante. [0027] Dans un mode de réalisation alternatif préféré, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être administré par voie injectable, de préférence intra-articulaire. In a preferred embodiment, the NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered orally, preferably in the form of a sublingual tablet or a gastro-capsule. resistant. In a preferred alternative embodiment, NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered by injection, preferably intra-articularly.
[0028] Avantageusement, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être utilisé dans le traitement et/ou la prévention de la polyarthrite rhumatoïde chez des mammifères, de préférence des humains. Advantageously, NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be used in the treatment and / or prevention of rheumatoid arthritis in mammals, preferably humans.
[0029] Avantageusement, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être utilisé en combinaison avec au moins un autre agent thérapeutique. Advantageously, NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be used in combination with at least one other therapeutic agent.
[0030] Avantageusement, l’au moins un agent thérapeutique peut être un antalgique, un anti-inflammatoire non stéroïdien, la cortisone, un dérivé de la cortisone, un immunosuppresseur, un immunomodulateur, un inhibiteur de lymphocytes T, un inhibiteur de lymphocytes B, un antipaludique de synthèse, un anti-TNF, un inhibiteur enzymatique des Janus kinases, un anti-interleukine et leurs combinaisons. Advantageously, the at least one therapeutic agent can be an analgesic, a nonsteroidal anti-inflammatory drug, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, a T lymphocyte inhibitor, a B lymphocyte inhibitor. , a synthetic antimalarial, an anti-TNF, an enzymatic inhibitor of Janus kinases, an anti-interleukin and their combinations.
[0031 ] Avantageusement, l’antalgique peut être choisi parmi le paracétamol, l’aspirine, la codéine, la dihydrocodéine, le tramadol, la morphine, la buprénorphine, le fentanyl, l’hydromorphone, la nalbuphine, l’oxycodone, la péthidine et leurs combinaisons. Advantageously, the analgesic can be chosen from paracetamol, aspirin, codeine, dihydrocodeine, tramadol, morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine and their combinations.
[0032] Avantageusement, l’anti-inflammatoire non stéroïdien peut être choisi parmi l’ibuprofène, le kétoprofène, le naproxène, l’alminoprofène, l’acéclofénac, l’acide méfénamique, l’acide niflumique, l’acide tiaprofénique, le célécoxib, le dexkétoprofène, le diclofénac, l’étodolac, l’étoricoxib, le fénoprofène, le flurbiprofène, l’indométacine, le méloxicam, le nabumétone, le piroxicam, le sulindac, le ténoxicam et leurs combinaisons. Advantageously, the nonsteroidal anti-inflammatory drug can be chosen from ibuprofen, ketoprofen, naproxen, alminoprofen, aceclofenac, mefenamic acid, niflumic acid, tiaprofenic acid, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, tenoxicam and their combinations.
[0033] Avantageusement, le dérivé de la cortisone peut être choisi parmi la bétaméthasone, la ciprofloxacine, le cortivazol, la dexaméthasone, la fludrocortisone, le méthylprednisolone, le prednisolone, la triamcinolone et leurs combinaisons. [0034] Avantageusement, l’immunosuppresseur peut être choisi parmi l'azathioprine, le cyclophosphamide, le chlorambucil, la ciclosporine, le méthotrexate et leurs combinaisons. Advantageously, the cortisone derivative can be chosen from betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone, triamcinolone and their combinations. Advantageously, the immunosuppressant can be chosen from azathioprine, cyclophosphamide, chlorambucil, ciclosporin, methotrexate and their combinations.
[0035] Dans un mode de réalisation préféré, l’immunosuppresseur peut être le méthotrexate ou la ciclosporine, de manière davantage préférée le methotrexate. [0035] In a preferred embodiment, the immunosuppressant can be methotrexate or ciclosporin, more preferably methotrexate.
[0036] Avantageusement, l’immunomodulateur peut être choisi parmi le léflunomide, la sulfasalazine et leurs combinaisons. Advantageously, the immunomodulator can be chosen from leflunomide, sulfasalazine and their combinations.
[0037] Avantageusement, l’antipaludique de synthèse peut être choisi parmi la chloroquine, l’hydroxychloroquine et leurs combinaisons. Advantageously, the synthetic antimalarial can be chosen from chloroquine, hydroxychloroquine and their combinations.
[0038] Avantageusement, l’anti-TNF peut être choisi parmi l'infliximab, l'etanercept, l'adalimumab, le certolizumab, le golimumab et leurs combinaisons. Advantageously, the anti-TNF can be chosen from infliximab, etanercept, adalimumab, certolizumab, golimumab and their combinations.
[0039] Avantageusement, l’inhibiteur enzymatique de Janus kinases peut être le tofacitinib. Advantageously, the enzymatic inhibitor of Janus kinases can be tofacitinib.
[0040] Avantageusement, l’anti-interleukine peut être choisi parmi un anti-interleukine 1, un anti-interleukine 6, un anti-interleukine 12, un anti-interleukine 17, un anti interleukine 23 et leurs combinaisons. Advantageously, the anti-interleukin can be chosen from an anti-interleukin 1, an anti-interleukin 6, an anti-interleukin 12, an anti-interleukin 17, an anti-interleukin 23 and their combinations.
[0041] Avantageusement, l’anti-interleukine 1 peut être l’anakinra. Advantageously, the anti-interleukin 1 can be anakinra.
[0042] Avantageusement, l’anti-interleukine 6 peut être le tocilizumab ou le sarilumabAdvantageously, the anti-interleukin 6 can be tocilizumab or sarilumab
[0043] Avantageusement, l’inhibiteur de lymphocytes B peut être le rituximab. Advantageously, the B lymphocyte inhibitor can be rituximab.
[0044] Avantageusement, l’inhibiteur de lymphocytes T peut être l’abatacept. Advantageously, the T cell inhibitor can be abatacept.
[0045] Avantageusement, l’inhibiteur de l’interleukine 12 peut être l’ustekinumab. Advantageously, the interleukin-12 inhibitor can be ustekinumab.
[0046] Avantageusement, l’inhibiteur de l’interleukine 17 peut être choisi parmi l’ixékizumab et le sécukinumab. Advantageously, the interleukin 17 inhibitor can be chosen from ixekizumab and secukinumab.
[0047] Avantageusement, l’inhibiteur de l’interleukine 23 peut être choisi parmi l’ustekinumab et le guselkumab. Advantageously, the interleukin 23 inhibitor can be chosen from ustekinumab and guselkumab.
[0048] De préférence, le NMN, un de ses dérivés pharmaceutiquement acceptables, un de ses sels pharmaceutiquement acceptables, n’est pas utilisé en combinaison avec au moins l’un des composés choisis parmi le folate, S-adenosyl-Lmethionine (SAM), l’astaxanthine, la berberine, le pterostilbène, le resveratrol, la metformine, levofloxacine, et leurs combinaisons. Preferably, NMN, one of its pharmaceutically acceptable derivatives, one of its pharmaceutically acceptable salts, is not used in combination with at least one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
[0049] La présente invention porte également sur une composition comprenant du nicotinamide mononucléotide (NMN), un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, et au moins un excipient pharmaceutiquement acceptable pour son utilisation dans la prévention et/ou le traitement de la polyarthrite rhumatoïde. The present invention also relates to a composition comprising nicotinamide mononucleotide (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 the treatment of rheumatoid arthritis.
[0050] Avantageusement, la composition selon l’invention peut se présenter sous la forme d’un comprimé, d’une gélule, d’un sachet, d’un granulé, d’une capsule molle, d’une pastille, d’un lyophilisât, d’une suspension, d’un gel, d’un sirop, d’une solution, d’une émulsion eau/huile, d’une émulsion huile/eau, d’une huile, d’une crème, d’un lait, d’une pulvérisation, d’une pommade, d’une ampoule, d’un suppositoire, d’un collyre, d’une ovule vaginale, d’une capsule vaginale, d’un liquide pour inhalation, d’un inhalateur à poudre sèche, d’un inhalateur pressurisé à valve doseuse. Advantageously, the composition according to the invention can be in the form of a tablet, a capsule, a sachet, a granule, a soft capsule, a lozenge, a lyophilizate, a suspension, a gel, a syrup, a solution, a water / oil emulsion, an oil / water emulsion, an oil, a cream, 'milk, spray, ointment, ampoule, suppository, eye drops, vaginal ovum, vaginal capsule, liquid for inhalation, a dry powder inhaler, a metered-valve pressurized inhaler.
[0051] Avantageusement, la composition selon l’invention peut être une composition pharmaceutique. Advantageously, the composition according to the invention can be a pharmaceutical composition.
[0052] Avantageusement, la composition selon l’invention peut être un complément alimentaire. Advantageously, the composition according to the invention can be a food supplement.
[0053] Avantageusement, la composition selon l’invention peut être administrée par peut être administré par voie orale, oculaire, sublinguale, intraveineuse, intraartérielle, intramusculaire, intra-articulaire, sous-cutanée, transcutanée, vaginale, péridurale, intravésicale, rectale ou inhalation. Advantageously, the composition according to the invention can be administered by can be administered orally, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation.
[0054] Avantageusement, la composition selon l’invention peut se présenter sous une forme unitaire à dose fixe. Advantageously, the composition according to the invention can be provided in unit form at a fixed dose.
[0055] Avantageusement, la composition selon l’invention peut être administrée par voie orale ou injectable. Advantageously, the composition according to the invention can be administered orally or by injection.
[0056] Dans un mode de réalisation préféré, la composition comprenant le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être administré par voie orale, de préférence sous forme d’un comprimé sublingual ou d’une gélule gastrorésistante. [0057] Dans un autre mode de réalisation préféré, le NMN, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être administré par voie injectable, de préférence intra-articulaire. In a preferred embodiment, the composition comprising the NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered orally, preferably in the form of a sublingual tablet or of a gastro-resistant capsule. In another preferred embodiment, NMN, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, can be administered by injection, preferably intra-articularly.
[0058] Dans un mode de réalisation préféré, la composition selon l’invention peut en outre comprendre au moins un agent thérapeutique supplémentaire tel que défini ci-dessus pour son utilisation dans la prévention et/ou le traitement de la polyarthrite rhumatoïde tel qu’exposé ci-dessus. In a preferred embodiment, the composition according to the invention may further comprise at least one additional therapeutic agent as defined above for its use in the prevention and / or treatment of rheumatoid arthritis such as discussed above.
[0059] De préférence, la composition selon l’invention ne comprend pas l’un des composés choisis parmi le folate, S-adenosyl-Lmethionine (SAM), l’astaxanthine, la berberine, le pterostilbène, le resveratrol, la metformine, levofloxacine, et leurs combinaisons. Preferably, the composition according to the invention does not comprise one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
DÉFINITIONS DEFINITIONS
[0060] Dans la présente invention, les termes suivants ont la signification suivante. In the present invention, the following terms have the following meaning.
[0061] Sauf indication contraire, la nomenclature des substituants qui ne sont pas explicitement définis dans la présente invention est obtenue en nommant la partie terminale de la fonctionnalité suivie de la fonctionnalité adjacente vers le point d'attache. 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.
[0062] « Alkyle » par lui-même ou en tant que partie d'un autre substituant, désigne un radical hydrocarbyle de formule CnH2n+1 dans laquelle n’est un nombre supérieur ou égal à 1. En général, les groupes alkyles de cette invention comprennent de 1 à 12 atomes de carbone, de préférence de 1 à 8 atomes de carbone, plus préférablement de 1 à 6 atomes de carbone, encore plus préférablement de 1 à 2 atomes de carbone. Les groupes alkyles peuvent être linéaires ou ramifiés et peuvent être substitués comme indiqué dans la présente invention. Les alkyles convenant à la mise en oeuvre de l’invention peuvent être choisis parmi methyle, ethyle, n-propyle, i-propyle, n- butyle, i-butyle, s-butyle and t-butyle, pentyle et ses isomères tels que n-pentyle et iso-pentyle, et hexyl eet ses isomères tels que n-hexyle et iso-hexyle, heptyle et ses isomères (par exemple n- heptyle, iso-heptyle), octyle et ses isomères (par exemple n-octyle, iso-octyle), nonyle et ses isomères (par exemple n-nonyle, iso-nonyle), décyle et ses isomères il (par exemple n-décyle, iso-décyle), undécyle et ses isomères, dodécyle et ses isomères. De préférence, les groupes alkyles peuvent être choisis parmi methyle, ethyle, n-propyle, i-propyle, n-butyle, i-butyle, s-butyle, t-butyle, n-pentyle, n-hexyle, n-heptyle, n-octyle, n-nonyle et n-decyle. Les groupes alkyles saturés et ramifiés peuvent être choisis, de manière non limitative, parmi isopropyle, sec-butyle, isobutyle, tert-butyle, isopentyle, 2-methylbutyle, 3-methylbutyle, 2-methylpentyle, 3-methylpentyle, 4-methylpentyle, 2-methylhexyle, 3-methylhexyle, 4- methylhexyle, 5-methylhexyle, 2,3-dimethylbutyle, 2,3-dimethylpentyle, 2,4- dimethylpentyle, 2,3-dimethylhexyle, 2,4-dimethylhexyle, 2,5-dimethylhexyle, 2,2- dimethylpentyle, 2,2-dimethylhexyle, 3,3-dimtheylpentyle, 3,3-dimethylhexyle, 4,4- dimethylhexyle, 2-ethylpentyle, 3-ethylpentyle, 2-ethylhexyle, 3-ethylhexyle, 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-diethylpentyle, 3,3-diethylhexyle, 2,2-diethylhexyle, et 3,3- diethylhexyle. Les groupes alkyle préférés sont les suivants : méthyle, éthyle, n- propyle, i-propyle, n-butyle, i-butyle, s-butyle et t-butyle. Les Cx-Cy-alkyles désignent les groupes alkyles qui comprennent de x à y atomes de carbone. "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 (e.g. n-nonyl, iso-nonyl), decyl and its isomers it (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-dimethylhexyl, 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- ethylhexyl, 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.
[0063] Lorsque le suffixe "ene" ("alkylène") est utilisé en conjonction avec un groupe alkyle, cela signifie que le groupe alkyle tel que défini ici a deux liaisons simples comme points d'attache à d'autres groupes. Le terme "alkylène" comprend le méthylène, l'éthylène, le méthylméthylène, le propylène, l'éthyléthylène et le 1 ,2- diméthyléthylène. 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-dimethylethylene.
[0064] Le terme "alcényle" tel qu'il est utilisé ici se réfère à un groupe hydrocarbyle insaturé, qui peut être linéaire ou ramifié, comprenant une ou plusieurs doubles liaisons carbone-carbone. Les groupes alcényles appropriés comprennent entre 2 et 12 atomes de carbone, de préférence entre 2 et 8 atomes de carbone, et encore plus préférablement entre 2 et 6 atomes de carbone. Des exemples de groupes alcényles sont l'éthényle, le 2-propényle, le 2-butényle, le 3-butényle, le 2- pentényle et ses isomères, le 2-hexényle et ses isomères, le 2,4-pentadiényle et les groupes similaires. 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.
[0065] 0067] Le terme "alcynyle", tel qu'il est utilisé ici, désigne une classe de groupes hydrocarbyle insaturés monovalents, dans lesquels l'insaturation résulte de la présence d'une ou plusieurs triple(s) liaison(s) carbone-carbone. Les groupes alcynyle ont généralement, et de préférence, le même nombre d'atomes de carbone que celui décrit ci-dessus pour les groupes alcényle. Des exemples non limitatifs de groupes alcynyle sont l'éthynyle, le 2-propynyle, le 2-butynyle, le 3- butynyle, le 2-pentynyle et ses isomères, le 2-hexynyle et ses isomères, etc. 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 carbon-carbon triple bond (s). 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.
[0066] « Alcoxy » désigne un groupe alkyle tel que défini ci-dessus, qui est attaché à une autre partie par un atome d'oxygène. Les exemples de groupes alcoxy comprennent les groupes méthoxy, isopropoxy, éthoxy, tert-butoxy, et autres. Les groupes alcoxy peuvent être éventuellement substitués par un ou plusieurs substituants. Les groupes alcoxy inclus dans les composés de cette invention peuvent être éventuellement substitués par un groupe solubilisant. [0066] "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.
[0067] « Aryle », tel qu'il est utilisé ici, désigne un groupe hydrocarbyle aromatique polyinsaturé ayant un seul cycle (par exemple phényle) ou plusieurs cycles aromatiques fusionnés ensemble (par exemple naphtyle) ou liés par covalence, contenant généralement 5 à 18 atomes, de préférence 5 à 12, de manière davantage préférée de 6 à 10, dont au moins un cycle est aromatique. Le cycle aromatique peut éventuellement comprendre un ou deux cycles supplémentaires (cycloalkyle, hétérocyclyle ou hétéroaryle) qui y sont fusionnés. L'aryle est également destiné à inclure les dérivés partiellement hydrogénés des systèmes carbocycliques énumérés ici. Les exemples d'aryle comprennent le phényle, le biphénylyle, le biphénylényle, le 5- ou 6-tétralinyle, le naphtalène-1- ou -2-yle, le 4-, 5-, 6 ou 7-indényle, le 1- 2-, 3-, 4- ou 5-acénaphtylényle, le 3-, 4- ou 5- acénaphtényle, 1- ou 2-pentalényle, 4- ou 5-indanyle, 5-, 6-, 7- ou 8- tétrahydronaphtyle, 1 ,2,3,4-tétrahydronaphtyle, 1 ,4-dihydronaphtyle, 1-, 2-, 3-, 4- ou 5-pyrényle. "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.
[0068] Lorsqu'au moins un atome de carbone dans un groupe aryle est remplacé par un hétéroatome, le cycle résultant est appelé ici cycle « hétéroaryle ». 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.
[0069] « Alkylaryle » désigne un groupe aryle substitué par un groupe alkyle. [0069] "Alkylaryl" denotes an aryl group substituted by an alkyl group.
[0070] « Acide aminé » désigne un acide carboxylique alpha-aminé, c'est-à-dire une molécule comprenant un groupe fonctionnel acide carboxylique et un groupe fonctionnel amine en position alpha du groupe acide carboxylique, par exemple un acide aminé protéinogène ou un acide aminé non protéinogène. "Amino acid" denotes an alpha-amino carboxylic acid, that is to say a molecule comprising a carboxylic acid functional group and a group amino functional in the alpha position of the carboxylic acid group, for example a proteinogenic amino acid or a non-proteinogenic amino acid.
[0071] « Acide aminé protéinogène » désigne un acide aminé qui est incorporé dans les protéines lors de la traduction de l'ARN messager par les ribosomes dans les organismes vivants, c'est-à-dire Alanine (ALA), Arginine (ARG), Asparagine (ASN), Aspartate (ASP), Cystéine (CYS), Glutamate (acide glutamique) (GLU), Glutamine (GLN), Glycine (GLY), Histidine (HIS), Isoleucine (ILE), Leucine (LEU), Lysine (LYS), Méthionine (MET), Phénylalanine (PHE), Proline (PRO), Pyrrolysine (PYL), Sélénocystéine (SEL), Sérine (SER), Thréonine (THR), Tryptophane (TRP), Tyrosine (TYR) ou Valine (VAL). "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).
[0072] « Acide aminé non protéinogène » tel qu'il est utilisé ici fait référence à un acide aminé qui n'est pas naturellement codé ou trouvé dans le code génétique d'un organisme vivant. Des exemples non limitatifs d'acide aminé non protéinogène sont l'ornithine, la citrulline, l'argininosuccinate, l'homosérine, l'homocystéine, l'acide cystéine-sulfinique, l'acide 2-aminomuconique, d-aminolevulinic acid, b- alanine, cystathionine, g-aminobutyrate, DOPA, 5-hydroxytryptophane, D-sérine, acide iboténique, a-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D- alanine ou D-glutamate "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, g-aminobutyrate, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, a-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine or D-glutamate
[0073] Le terme "cycloalkyle" tel qu'il est utilisé ici est un groupe alkyle cyclique, c'est- à-dire un groupe hydrocarbyle monovalent, saturé ou insaturé, ayant 1 ou 2 structures cycliques. Le terme "cycloalkyle" inclut les groupes hydrocarbyle monocycliques ou bicycliques. Les groupes cycloalkyle peuvent comprendre 3 atomes de carbone ou plus dans le cycle et généralement, selon la présente invention, comprendre de 3 à 10, plus préférablement de 3 à 8 atomes de carbone et encore plus préférablement de 3 à 6 atomes de carbone. Les exemples de groupes cycloalkyle comprennent, sans s'y limiter, le cyclopropyle, le cyclobutyle, le cyclopentyle, le cyclohexyle, le cyclopropyle étant particulièrement préféré. 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.
[0074] Par « excipient pharmaceutiquement acceptable », il est fait référence à un véhicule ou un support inerte utilisé en tant que solvant ou diluant dans lequel le principe actif est formulé et/ou administré, et qui ne produit pas une réaction indésirable, allergique ou autre lorsqu'il est administré à un animal, de préférence un être humain. Cela comprend tous les solvants, milieux de dispersion, revêtements, agents antibactériens et antifongiques, agents isotoniques, retardants d'absorption et autres ingrédients similaires. Pour l'administration humaine, les préparations doivent répondre à des normes de stérilité, de sécurité générale et de pureté, telles que requises par les offices de régulation, tels que par exemple la FDA ou IΈMA. Au sens de l’invention, « excipient pharmaceutiquement acceptable » inclut tous les excipients pharmaceutiquement acceptables ainsi que tous les supports, diluants, et/ou adjuvants pharmaceutiquement acceptables. 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, dispersion 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, as required by regulatory authorities, such as for example the FDA or IΈMA. 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.
[0075] « Halogène » ou « halo » signifie fluoro, chloro, bromo ou iodo. Les groupes halo préférés sont le fluoro et le chloro. "Halogen" or "halo" means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro and chloro.
[0076] « Haloalkyle » seul ou en combinaison, désigne un radical alkyle ayant la signification telle que définie ci-dessus, dans lequel un ou plusieurs atomes d'hydrogène sont remplacés par un halogène tel que défini ci-dessus. Parmi les exemples de tels radicaux halogénoalkyle, on peut citer le chlorométhyle, le 1- bromoéthyle, le fluorométhyle, le difluorométhyle, le trifluorométhyle, le 1 ,1 ,1- trifluoroéthyle et les radicaux similaires. Cx-Cy-haloalkyle et Cx-Cy-alkyle désignent des groupes alkyles qui comprennent de x à y atomes de carbone. Les groupes halogénoalkyle préférés sont le difluorométhyle et le trifluorométhyle. "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.
[0077] « Hétéroalkyle » désigne un groupe alkyle tel que défini ci-dessus, dans lequel un ou plusieurs atomes de carbone sont remplacés par un hétéroatome choisi parmi les atomes d'oxygène, d'azote et de soufre. Dans les groupes hétéroalkyle, les hétéroatomes sont liés le long de la chaîne alkyle uniquement à des atomes de carbone, c'est-à-dire que chaque hétéroatome est séparé de tout autre hétéroatome par au moins un atome de carbone. Toutefois, les hétéroatomes d'azote et de soufre peuvent éventuellement être oxydés et les hétéroatomes d'azote peuvent éventuellement être quaternisés. Un hétéroalkyle est lié à un autre groupe ou à une autre molécule uniquement par un atome de carbone, c'est-à-dire que l'atome de liaison n'est pas choisi parmi les hétéroatomes inclus dans le groupe hétéroalkyle. "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 any 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 linked to another group or to another molecule only through a carbon atom, i.e. the linking atom is not selected from heteroatoms included in the heteroalkyl group.
[0078] Le terme "hétéroaryle" tel qu'il est utilisé ici, seul ou en tant que partie d'un autre groupe, désigne, sans s'y limiter, des cycles aromatiques de 5 à 12 atomes de carbone ou des systèmes cycliques contenant 1 ou 2 cycles qui sont fusionnés ou liés par covalence, contenant généralement 5 ou 6 atomes ; dont au moins un est aromatique, dans lequel un ou plusieurs atomes de carbone dans un ou plusieurs de ces cycles sont remplacés par des atomes d'oxygène, d'azote et/ou de soufre, les hétéroatomes d'azote et de soufre pouvant éventuellement être oxydés et les hétéroatomes d'azote pouvant éventuellement être quaternisés. Ces cycles peuvent être fusionnés à un cycle aryle, cycloalkyle, hétéroaryle ou hétérocyclyle. Parmi les exemples non limitatifs de tels hétéroaryles, on peut citer furanyle, thiophényle, pyrazolyle, imidazolyle, oxazolyle, isoxazolyle, thiazolyle, isothiazolyle, triazolyle, oxadiazolyle, thiadiazolyle, tétrazolyle, oxatriazolyle, thiatriazolyle, pyridinyle, pyrimidyle, pyrazinyle, pyridazinyle, oxazinyle, dioxinyle, thiazinyle, triazinyle, imidazo [2, 1 -b] [1 ,3] thiazolyle, thiéno [3 ,2-b] furanyle, thiéno [3 ,2-b] thiophényle, thiéno [2,3-d] [l,3] thiazolyle, thiéno [2,3-d] imidazolyle, tétrazolo [l,5-a] pyridinyle, indolyle, indolizinyle, isoindolyle, benzofuranyle, isobenzofuranyle, benzothiophényle, isobenzothiophényle, indazolyle, benzimidazolyle, 1 ,3-benzoxazolyle, 1 ,2- benzisoxazolyle, 2,1-benzisoxazolyle,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; of which at least one 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 being oxidizable and the heteroatoms nitrogen which can optionally be quaternized. These rings can be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Among the nonlimiting examples of such heteroaryls, mention may be made of furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazinyl, pyridazinyl, oxatriazolyl, thiatriazinazinyl, oxatriazolyl, thiatriazinazolyl, oxatriazolyl, thiatriazinazinyl, dioxinyl, thiazinyl, 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, 1 benzimidazol, 3-benzazolyl, 1 benzimidazol 1, 2-benzisoxazolyl, 2,1-benzisoxazolyl,
1 ,3-benzothiazolyle, 1 ,2-benzoisothiazolyle, 2, 1 -benzoisothiazolyle, benzotriazolyle, 1 ,2,3-benzoxadiazolyle, 2,1 ,3- benzoxadiazolyle, 1 ,2,3- benzothiadiazolyle, 2,1 ,3-benzothiadiazolyle, thiénopyridinyle, purinyle, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2- oxopyridin-l(2H)-yl, 6-oxo- pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1 ,3- benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl. 1, 3-benzothiazolyl, 1, 2-benzoisothiazolyl, 2, 1 -benzoisothiazolyl, benzotriazolyl, 1, 2,3-benzoxadiazolyl, 2,1, 3-benzoxadiazolyl, 1, 2,3-benzothiadiazolyl, 2,1, 3- benzothiadiazolyl, thienopyridinyl, purinyl, imidazo [1,2-a] pyridinyl, 6-oxo-pyridazin-l (6H) -yl, 2-oxopyridin-l (2H) -yl, 6-oxo-pyridazin-l (6H) -yl, 2-oxopyridin-1 (2H) -yl, 1, 3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.
[0079] Lorsqu'au moins un atome de carbone dans un groupe cycloalkyle est remplacé par un hétéroatome, le cycle résultant est appelé ici "hétérocycloalkyle" ou "hétérocyclyle". 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".
[0080] Les termes "hétérocyclyle", "hétérocycloalkyle" ou "hétérocyclo", tels qu'ils sont utilisés ici par eux-mêmes ou en tant que partie d'un autre groupe, désignent des groupes cycliques non aromatiques, totalement saturés ou partiellement insaturés (par exemple, monocyclique de 3 à 7 chaînons, bicyclique de 7 à 11 chaînons ou contenant un total de 3 à 10 atomes de cycle) qui ont au moins un hétéroatome dans au moins un cycle contenant un atome de carbone. Chaque cycle du groupe hétérocyclique contenant un hétéroatome peut avoir 1 , 2, 3 ou 4 hétéroatomes choisis parmi les atomes d'azote, d'oxygène et/ou de soufre, où les hétéroatomes d'azote et de soufre peuvent éventuellement être oxydés et les hétéroatomes d'azote peuvent éventuellement être quaternisés. N'importe lequel des atomes de carbone du groupe hétérocyclique peut être substitué par un oxo (par exemple pipéridone, pyrrolidinone). Le groupe hétérocyclique peut être attaché à n'importe quel hétéroatome ou atome de carbone du cycle ou du système cyclique, lorsque la valence le permet. Les cycles des hétérocycles à plusieurs cycles peuvent être fusionnés, pontés et/ou reliés par un ou plusieurs atomes spiro. Les groupes hétérocycliques exemplaires non limitatifs comprennent les groupes oxétanyle, pipéridinyle, azétidinyle, 2-imidazolinyle, pyrazolidinyle, imidazolidinyle, isoxazolinyle, oxazolidinyle, isoxazolidinyle, thiazolidinyle, isothiazolidinyle, pipéridinyle, 3H- indolyle, indolinyle, isoindolinyle, 2-oxopipérazinyle, pipérazinyle, homopipérazinyle, 2-pyrazolinyle, 3-pyrazolinyle, tétrahydro-2H-pyranyle, 2H- pyranyle, 4H-pyranyle, 3,4-dihydro-2H-pyranyle, 3-dioxolanyle, 1 ,4-dioxanyle, 2, 5- dioximidazolidinyle, 2-oxopipéridinyle, 2-oxopyrrolodinyle, indolinyle, tétrahydropyranyle, tétrahydrofuranyle, tétrahydroquinolinyle, tétrahydroisoquinolin-1 -yle, tétrahydroisoquinolin-2-yle, tétrahydroisoquinolin-3- yle, tétrahydroisoquinoléine-4-yl, thiomorpholine-4-yl, oxyde de thiomorpholine-4- ylsulf, thiomorpholine-4-ylsulfone, 1,3- dioxolanyl, 1 ,4-oxathianyl, 1 H-pyrrolizinyl, tétrahydro-l,l-dioxothiophényl, N- formylpipérazinyl et morpholine-4-yl. 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 can have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the heteroatoms nitrogen 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 the 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, homzolinopinipolinopinyl, 3H-iso-indolinopideraidinyl, inderazolinopinopipolinopolino-inderazolinyl, 2-pipolinopolinopinyl, inderazolinopinyl, 2-piperidinyl, 3H-iso-iso-indol-indol-isidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, inderazolinopinyl, 3H-iso-iso-indol-indoleidinyl, , 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-3-yl tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-3-yl-tetrahydroisorphiolin-4-thymorphiolin-4-oxomolin-4-thymorphiolin-4-thetrahydroquinolin-1-tetrahydroisoquinolin-1-yl - ylsulf, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1, 4-oxathianyl, 1 H-pyrrolizinyl, tetrahydro-1, 1-dioxothiophenyl, N-formylpiperazinyl and morpholin-4-yl.
[0081] Le terme "précurseur" tel qu'il est utilisé ici désigne également les dérivés pharmacologiquement acceptables des composés de formule (I) tels que les esters dont le produit de biotransformation in vivo est le médicament actif. Les précurseurs sont caractérisés par une biodisponibilité accrue et sont facilement métabolisés en composés actifs in vivo. Les précurseurs appropriés aux fins de l'invention comprennent notamment les esters carboxyliques, en particulier les esters alkyliques, les esters aryliques, les esters acyloxyalkyliques et les esters carboxyliques de dioxolène ; les esters d'acide ascorbique. The term "precursor" as used here also denotes the pharmacologically acceptable derivatives of the compounds of formula (I) such as the esters of which the in vivo biotransformation product 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.
[0082] « Pharmaceutiquement acceptable » signifie approuvé ou susceptible d'être approuvé par un organisme de réglementation ou inscrit dans une pharmacopée reconnue pour l'utilisation chez les animaux, et plus préférablement chez l'homme. Il peut s'agir d'une substance qui n'est pas indésirable sur le plan biologique ou autre, c'est-à-dire que la substance peut être administrée à un individu sans provoquer d'effets biologiques indésirables ou d'interactions délétères avec l'un des composants de la composition dans laquelle elle est contenue. De préférence, un sel ou un excipient « pharmaceutiquement acceptable » désigne tout sel ou tout excipient autorisé par la Pharmacopée européenne (notée « Ph. Eur. ») et la pharmacopée américaine (désignée par « United States Pharmacopeia (USP) » en anglais). "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 components of the composition in which it is contained. Preferably, a “pharmaceutically acceptable” salt or excipient denotes any salt or excipient authorized by the European Pharmacopoeia (denoted “Ph. Eur.”) And the American Pharmacopoeia (denoted by “United States Pharmacopeia (USP)” in English) .
[0083] Le terme "principe actif désigne une molécule ou une substance dont l'administration à un sujet ralentit ou arrête la progression, l'aggravation ou la détérioration d'un ou de plusieurs symptômes d'une maladie ou d'un état ; soulage les symptômes d'une maladie ou d'un état ; guérit une maladie ou un état. Selon l'un de ces modes de réalisation, l'ingrédient thérapeutique est une petite molécule, naturelle ou synthétique. Selon une autre, l'ingrédient thérapeutique est une molécule biologique comme par exemple un oligonucléotide, un siRNA, un miRNA, un fragment d'ADN, un aptamère, un anticorps et autres. Les « sels pharmaceutiquement acceptables » comprennent les sels d'addition d'acides et de bases de ces sels. Les sels d'addition d'acide appropriés sont formés à partir d'acides qui forment des sels non toxiques. Il s'agit par exemple de l'acétate, l'adipate, l'aspartate, le benzoate, le bésylate, le bicarbonate/carbonate, le bisulfate/sulfate, le borate, le camsylate, le citrate, le cyclamate, l'édisylate, l'esylate, le formiate, le fumarate, le gluceptate, le gluconate, le glucuronate, l'hexafluorophosphate, l'hibenzate, le chlorhydrate/chlorure, le brom hydrate/bromure, l'hydroiodure/iodure, iséthionate, lactate, malate, maléate, malonate, mésylate, méthylsulfate, naphtylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogénophosphate/dihydrogénophosphate, pyroglutamate, saccharate, stéarate, succinate, tannate, tartrate, tosylate, trifluoroacétate et sels de xinofoate. Les sels basiques appropriés sont formés à partir de bases qui forment des sels non toxiques. On peut citer comme exemples les sels d'aluminium, d'arginine, de benzathine, de calcium, de choline, de diéthylamine, de diolamine, de glycine, de lysine, de magnésium, de méglumine, d'olamine, de potassium, de sodium, de trométhamine, de 2-(diéthylamino)éthanol, d'éthanolamine, de morpholine, de 4-(2-hydroxyéthyl)morpholine et de zinc. Des hémisels d'acides et de bases peuvent également être formés, par exemple, des hémisulfates et des sels de calcium chimique. Les sels pharmaceutiquement acceptables préférés sont le chlorhydrate/chlorure, le bromure/hydrobromure, le bisulfate/sulfate, le nitrate, le citrate et l'acétate. 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 ingredient therapeutic is a biological molecule such as, for example, an oligonucleotide, siRNA, miRNA, DNA fragment, aptamer, antibody, etc. "Pharmaceutically acceptable salts" include acid and base addition salts of These salts. Suitable acid addition salts are formed from acids which form non-toxic salts, for example acetate, adipate, aspartate, benzoate, besylate , bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate e, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, bromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, taccharannate / saccharate , tartrate, tosylate, trifluoroacetate and xinofoate salts. 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.
[0084] Les sels pharmaceutiquement acceptables peuvent être préparés par une ou plusieurs de ces méthodes : i. en faisant réagir le composé avec l'acide souhaité ; ii. en faisant réagir le composé avec la base souhaitée ; iii. en éliminant un groupe protecteur labile en milieu acide ou basique d'un précurseur approprié du composé ou en ouvrant le cycle d'un précurseur cyclique approprié, par exemple une lactone ou un lactame, en utilisant l'acide désiré ; ou iv. en transformant un sel du composé en un autre par réaction avec un acide approprié ou au moyen d'une colonne d'échange d'ions appropriée. Pharmaceutically acceptable salts can be prepared by one or more of these methods: i. 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. by converting one salt of the compound to another by reaction with a suitable acid or by means of a suitable ion exchange column.
[0085] Toutes ces réactions sont généralement effectuées en solution. Le sel peut précipiter de la solution et être recueilli par filtration ou peut être récupéré par évaporation du solvant. Le degré d'ionisation du sel peut varier de complètement ionisé à presque non ionisé. 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 evaporation of the solvent. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.
[0086] « Solvaté » est utilisé ici pour décrire un complexe moléculaire comprenant le composé de l'invention et une ou plusieurs molécules de solvant pharmaceutiquement acceptables, par exemple, l'éthanol. "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.
[0087] Le terme "substituant" ou "substitué" signifie qu'un radical hydrogène sur un composé ou un groupe est remplacé par tout groupe souhaité qui est substantiellement stable dans les conditions de la réaction sous une forme non protégée ou lorsqu'il est protégé par un groupe protecteur. Les exemples de substituants préférés comprennent, sans s'y limiter, un halogène (chloro, iodo, bromo ou fluoro) ; un alkyle ; un alcényle ; un alcynyle, tel que décrit ci-dessus ; un hydroxy ; un alcoxy ; un nitro ; un thiol ; un thioéther ; une imine ; un cyano ; un amido ; un phosphonato ; une phosphine ; un carboxyle ; un thiocarbonyle ; un sulfonyle ; un sulfonamide ; une cétone ; un aldéhyde ; un ester ; un oxygène (-0) ; un haloalkyle (par ex, trifluorométhyle) ; un cycloalkyle, qui peut être monocyclique ou polycyclique condensé ou non condensé (par exemple, cyclopropyle, cyclobutyle, cyclopentyle ou cyclohexyle), ou un hétérocycloalkyle, qui peut être monocyclique ou polycyclique condensé ou non condensé (par exemple, pyrrolidinyle, pipéridinyle, pipérazinyle, morpholinyle ou thiazinyle), monocyclique ou polycyclique fusionné ou non fusionné, aryle ou hétéroaryle (par exemple, aryle, hétéroaryle, pyrrolidinyle, pipéridinyle, pipérazinyle, morpholinyle ou thiazinyle), monocyclique ou polycyclique fusionné ou non fusionné (par exemple, aryle, hétéroaryle, pyrrolidinyle, pipéridinyle, pipérazinyle, morpholinyle ou thiazinyle), phényle, naphtyle, pyrrolyle, indolyle, furanyle, thiophényle, imidazolyle, oxazolyle, isoxazolyle, thiazolyle, triazolyle, tétrazolyle, pyrazolyle, pyridyle, quinolinyle, isoquinolinyle, acridinyle, pyrazinyle, pyridazinyle, pyrimidinyle, benzimidazolyle, benzothiophényle ou benzofuranyle) ; amino (primaire, secondaire ou tertiaire) ; CO2CH3 ; CONH2 ; OCH2CONH2 ; NH2 ; SO2NH2 ; OCHF2 ; CF3 ; OCF3 ; et ces groupements peuvent également être éventuellement substitués par une structure ou un pont annulaire fusionné, par exemple -OCFI2O-. Ces substituants peuvent éventuellement être encore substitués par un substituant choisi parmi ces groupes. Dans certaines représentations, le terme "substituant" ou l'adjectif "substitué" désigne un substituant choisi dans le groupe constitué par un alkyle, un alcényle, un alcynyle, un cycloalkyle, un cycloalcényle, un hétérocycloalkyle, un aryle, un hétéroaryle, un arylalkyle, un hétéroarylalkyle, un haloalkyle, -C(0)NRnRi2, - NRI3C(0)RU, un halo, -OR13, cyano, nitro, un haloalcoxy, -C(0)Ri3, -NR11R12, - SR13, -C(0)0Ri3, -0C(0)Ri3, -NRi3C(0)NRiiRi2, -0C(0)NRHRI2, -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 (-0); 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, morpholinyl or thiazinyl), monocyclic or polycyclic fused or unfused, aryl or heteroaryl (eg, aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), non-fused or fused polycyclic or polycyclic or polycyclic by fused or thiazinyl (example, aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyrazolinyl, isoolinyl, isoxazolyl, pyrazolinyl, pyrrazinyl, isizolinyl, pyrrazinyl, isonolinyl, pyrolyl, isizolinyl, pyrolyl , pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl or benzofuranyl); amino (primary, secondary or tertiary); CO2CH3; CONH2; OCH2CONH2; NH 2 ; SO2NH2; OCHF 2 ; CF 3 ; OCF 3 ; and these groups can also be optionally substituted by a structure or a fused annular bridge, for example -OCFI2O-. These substituents can optionally be further substituted by a substituent chosen from these groups. In some 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, heteroarylalkyl, haloalkyl, -C (0) NRnRi 2 , - NRI 3 C (0) RU, halo, -OR13, cyano, nitro, haloalkoxy, -C (0) R13, -NR11R12, - SR13 , -C (0) 0Ri3, -0C (0) Ri3, -NRi 3 C (0) NRiiRi2, -0C (0) NRHRI 2 , -
NRI3C(0)0RU, -S(0)rR13, -NRi3S(0)rRu, -0S(0)rRu, S(0)rNRnRi2, -O, -S, et - N-R13, où r est 1 ou 2 ; Ru et R12, pour chaque occurrence, sont, indépendamment, Fl, un alkyle éventuellement substitué, un alcényle éventuellement substitué, un alcynyle éventuellement substitué, un cycloalkyle éventuellement substitué, un cycloalcényle éventuellement substitué, un hétérocycloalkyle éventuellement substitué, un aryle éventuellement substitué, un hétéroaryle éventuellement substitué, un arylalkyle éventuellement substitué, ou un hétéroarylalkyle éventuellement substitué ; ou Ru et R12 pris ensemble avec l'azote auquel ils sont attachés sont un hétérocycloalkyle éventuellement substitué ou un hétéroaryle éventuellement substitué ; et R13 et Ru pour chaque occurrence sont, indépendamment, Fl, un alkyle éventuellement substitué, un alcényle éventuellement substitué, un alcynyle éventuellement substitué, un cycloalkyle éventuellement substitué, un cycloalcényle éventuellement substitué, un hétérocycloalkyle éventuellement substitué, un aryle éventuellement substitué, un hétéroaryle éventuellement substitué, un arylalkyle éventuellement substitué, ou un hétéroarylalkyle éventuellement substitué. Dans certaines variantes, le terme "substituant" ou l'adjectif "substitué" désigne un groupe solubilisant. NRI 3 C (0) 0RU, -S (0) rR13, -NRi 3 S (0) rRu, -0S (0) rRu, S (0) rNRnRi 2 , -O, -S, and - N-R13, where r is 1 or 2; Ru and R12, for each occurrence, are, independently, Fl, 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 Ru for each occurrence are, independently, F1, 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 variations, the term "substituent" or the adjective "substituted" denotes a solubilizing group.
[0088] Le terme « administration », ou une variante de ce terme (par exemple, « administrer »), signifie fournir le principe actif, seul ou dans le cadre d'une composition pharmaceutiquement acceptable, au patient chez qui/à qui l'état, le symptôme ou la maladie doit être traité ou prévenu. The term "administration", or a variant of this term (for example, "to administer"), means to provide the active principle, alone or as part of a pharmaceutically acceptable composition, to the patient in whom / to whom the The condition, symptom or disease must be treated or prevented.
[0089] « Traiter », « soigner » et « traitement », tels qu'ils sont utilisés dans la présente invention, sont censés inclure le soulagement, l'atténuation ou l'ablation d'un état ou d'une maladie et/ou de ses symptômes associés. "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.
[0090] « Prévenir », « empêcher » et « prévention », tels qu'ils sont utilisés dans la présente invention, font référence à une méthode permettant de retarder ou d'empêcher l'apparition d'un état ou d'une maladie et/ou de ses symptômes connexes, d'empêcher un patient de contracter un état ou une maladie, ou de réduire le risque qu'un patient contracte un état ou une maladie. "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.
[0091] Les liaisons d'un carbone asymétrique peuvent être représentées ici en utilisant un triangle plein ( un triangle pointillé ( ) ou une ligne en zigzag The bonds of an asymmetric carbon can be represented here by using a solid triangle ( a dotted triangle () or a zigzag line
DESCRIPTION DETAILLEE DE L’INVENTION DETAILED DESCRIPTION OF THE INVENTION
[0092] La présente invention a pour objet le nicotinamide mononucléotide (NMN), un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, pour son utilisation dans la prévention et/ou le traitement de la polyarthrite rhumatoïde ainsi que des compositions le comprenant. 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 rheumatoid arthritis, as well as compositions thereof. including.
[0093] Le nicotinamide adénine dinucléotide (NAD) est une coenzyme présente dans toutes les cellules vivantes. Le NAD existe dans la cellule soit sous sa forme oxydée NAD+, soit sous sa forme réduite NADH. Le rôle de NAD est celui d’un transporteur d’électrons intervenant dans les réactions d’oxydoréduction du métabolisme. Le NAD intervient en outre dans de nombreux processus cellulaires tels que la ribosylation de l’ADP dans le cadre de modifications post- traductionnelles des protéines. [0094] Le NAD peut être synthétisé de novo par la cellule à partir d’acides aminés comme le tryptophane ou l’aspartate. Cependant, cette synthèse est marginale car la principale voie de synthèse de NAD est la voie de sauvetage par laquelle la cellule, et principalement le noyau cellulaire, recycle des composés pour reformer le NAD à partir de précurseurs. Les précurseurs du NAD comprennent la niacine, le nicotinamide riboside, le nicotinamide mononucléotide et le nicotinamide. 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 in post-translational protein modifications. 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.
[0095] Le NMN est un des composés permettant la synthèse de NAD par la voie de sauvetage et a pour formule : NMN is one of the compounds allowing the synthesis of NAD by the rescue route and has the formula:
[0096] Les inventeurs ont en effet démontré que l’utilisation du NMN, de ses sels et/ou dérivés pharmaceutiquement acceptables et de la composition selon l’invention permettait d’obtenir un effet sur le gonflement des articulations provoqué par la polyarthrite rhumatoïde comparable aux médicaments couramment utilisés pour traiter cette pathologie, sans pour autant présenter les mêmes effets secondaires. Plus exactement, les inventeurs ont constaté que le NMN permettait de traiter les poussées inflammatoires caractéristiques de la polyarthrite rhumatoïde en réduisant le gonflement de l’articulation de manière significative et avec une efficacité comparable aux traitements conventionnels. Par ailleurs, l’administration chronique de NMN permet de prévenir, ou à tout le moins d’espacer, la survenue de ces poussées. En effet, administré de manière chronique entre chaque poussée, le NMN et les compositions le comprenant permettent de réduire l’inflammation et par conséquent d’éviter, ou à tout le moins d’espacer, les poussées de polyarthrite rhumatoïde. The inventors have in fact demonstrated that the use of NMN, of its pharmaceutically acceptable salts and / or derivatives and of the composition according to the invention made it possible to obtain a comparable effect on the swelling of the joints caused by rheumatoid arthritis. drugs commonly used to treat this pathology, without presenting the same side effects. More precisely, the inventors have found that NMN makes it possible to treat the inflammatory attacks characteristic of rheumatoid arthritis by reducing the swelling of the joint significantly and with an efficiency comparable to conventional treatments. In addition, chronic administration of NMN helps prevent, or at least reduce, the onset of these relapses. Indeed, administered chronically between each outbreak, NMN and compositions comprising it reduce inflammation and therefore prevent, or at least space out, rheumatoid arthritis outbreaks.
[0097] De plus, l’utilisation de NMN, molécule naturellement présente dans le corps, présente de nombreux avantages. Notamment, le NMN ne pose aucun problème de tolérance chez les patients. L’utilisation de NMN et de la composition selon l’invention n’induit en effet aucune allergie. De plus, l’utilisation de NMN et de la composition selon l’invention ne provoque pas les effets secondaires fréquemment rencontrés avec les traitements conventionnels. In addition, the use of NMN, a molecule naturally present in the body, has many advantages. In particular, the NMN does not pose any problem tolerance in patients. The use of NMN and of the composition according to the invention in fact does not induce any allergy. In addition, the use of NMN and of the composition according to the invention does not cause the side effects frequently encountered with conventional treatments.
[0098] Le NMN n’induit notamment aucun phénomène de dépendance physique ou psychologique, contrairement aux antalgiques comprenant de la morphine ou les dérivés de l’opium. Le NMN n’induit en outre aucune fragilité osseuse ou vulnérabilité aux infections comme cela est observé avec l’administration chronique de cortisone ou de ses dérivés. L’utilisation de NMN et de la composition selon l’invention pour prévenir et/ou traiter la polyarthrite rhumatoïde est donc sûre pour les patients. In particular, NMN does not induce any phenomenon of physical or psychological dependence, unlike analgesics comprising morphine or opium derivatives. Furthermore, NMN does not induce any bone fragility or vulnerability to infection as seen with chronic administration of cortisone or its derivatives. The use of NMN and the composition according to the invention for preventing and / or treating rheumatoid arthritis is therefore safe for patients.
[0099] Le NMN et la composition selon l’invention peuvent également être utilisés chez l’enfant et l’adulte. Le NMN est en effet bien toléré par les enfants. Dans le contexte de l’invention, on considère qu’un patient est un enfant lorsque son âge est inférieur à 18 ans et qu’il est un adulte à partir de 18 ans. Par conséquent, l’invention trouve également son intérêt pour traiter la polyarthrite rhumatoïde chez les enfants. [0099] The NMN and the composition according to the invention can also be used in children and adults. NMN is indeed well tolerated by children. In the context of the invention, a patient is considered to be a child when his age is less than 18 years and he is an adult from 18 years. Therefore, the invention is also of interest for treating rheumatoid arthritis in children.
[0100] Dans un mode de réalisation particulièrement préféré, le NMN se trouve sous la forme d’un zwitterion. On entend par « zwitterion » une espèce chimique moléculaire possédant des charges électriques de signe opposé et situées, en général, sur des atomes non adjacents de la molécule. [0100] In a particularly 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.
[0101] L’utilisation de NMN, d’un de ses dérivés pharmaceutiquement acceptables ou d’un de ses sels pharmaceutiquement acceptables, ainsi que de compositions le comprenant selon l’invention permet premièrement de traiter l’inflammation lors de poussées de polyarthrite rhumatoïde en réduisant l’inflammation et notamment le gonflement des articulations. Ainsi, cela permet d’éviter, à long terme, que les articulations ne se déforment, ou à tout le moins de réduire la déformation des articulations ou de retarder ladite déformation. Ainsi, les articulations du patient sont préservées. [0101] The use of NMN, of one of its pharmaceutically acceptable derivatives or of one of its pharmaceutically acceptable salts, as well as of compositions comprising it according to the invention firstly makes it possible to treat the inflammation during relapses of rheumatoid arthritis by reducing inflammation and especially swelling of the joints. Thus, this makes it possible, in the long term, to prevent the joints from becoming deformed, or at the very least to reduce the deformation of the joints or to delay said deformation. Thus, the patient's joints are preserved.
[0102] La réduction de l’inflammation, et notamment du gonflement, des articulations ainsi que la prévention des poussées inflammatoires permettent également de réduire la douleur liée à l’inflammation et de réduire le raidissement des articulations. Cela permet donc d’éviter l’administration, ou à tout le moins de réduire la fréquence d’administration et la dose, de médicaments utilisés pour lutter contre les symptômes de l’inflammation à savoir les antalgiques, les anti inflammatoires non stéroïdiens, la cortisone et/ou la cortisone et ses dérivés. Cela permet en outre d’éviter d’administrer des traitements de fond utilisés de manière conventionnelle pour traiter les rhumatismes inflammatoires chroniques tel que le méthotrexate, ou à tout le moins de réduire leur dose d’administration. [0102] The reduction of inflammation, and in particular of swelling, of the joints as well as the prevention of inflammatory outbreaks also make it possible to reduce pain associated with inflammation and reduce stiffening of the joints. This therefore makes it possible to avoid the administration, or at the very least to reduce the frequency of administration and the dose, of drugs used to combat the symptoms of inflammation, namely analgesics, non-steroidal anti-inflammatory drugs, cortisone and / or cortisone and its derivatives. This also makes it possible to avoid administering the DMARDs conventionally used to treat chronic inflammatory rheumatism such as methotrexate, or at the very least to reduce their dose of administration.
[0103] En réduisant le recours aux thérapies utilisées de manière conventionnelles, voire en les remplaçant, la présente invention permet donc d’éviter, ou à tout le moins de réduire, l’utilisation des traitements conventionnels de la polyarthrite rhumatoïde et donc d’éviter, ou à tout le moins de réduire, l’apparition d’effets secondaires liés à ces thérapies. By reducing the use of therapies used in a conventional manner, or even replacing them, the present invention therefore makes it possible to avoid, or at the very least to reduce, the use of conventional treatments for rheumatoid arthritis and therefore of rheumatoid arthritis. avoid, or at least reduce, the appearance of side effects associated with these therapies.
[0104] Outre l’aspect thérapeutique, l’invention permet donc de maintenir la qualité de vie du patient en lui permettant d’accomplir les gestes du quotidien avec davantage de facilité, et éventuellement d’éviter au patient de devoir arrêter toute activité professionnelle. L’invention participe donc à maintenir la qualité de vie du patient, ou à tout le moins éviter qu’elle ne se dégrade trop. [0104] In addition to the therapeutic aspect, the invention therefore makes it possible to maintain the quality of life of the patient by allowing him to perform everyday actions with greater ease, and possibly to avoid the patient having to stop all professional activity . The invention therefore helps to maintain the patient's quality of life, or at the very least to prevent it from deteriorating too much.
[01051 Utilisation [01051 Use
[0106] Selon la présente invention, le NMN, ses dérivés pharmaceutiquement acceptables ou ses sels pharmaceutiquement acceptables, ainsi que les compositions le comprenant sont utilisés pour prévenir et/ou traiter la polyarthrite rhumatoïde. Plus exactement, ils peuvent être utilisés de manière ponctuelle pour traiter une poussée de polyarthrite rhumatoïde ou de manière chronique pour réduire l’inflammation et espacer l’apparition de poussées. En d’autres termes, le NMN, un de ses dérivés ou un de ses sels pharmaceutiquement acceptables, ainsi que des compositions les comprenant peuvent être utilisés à titre préventif ou curatif, afin de réduire l’inflammation, et en particulier le gonflement, des articulations. According to the present invention, NMN, its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts, as well as the compositions comprising it are used for preventing and / or treating rheumatoid arthritis. More precisely, they can be used on an ad hoc basis to treat a flare-up of rheumatoid arthritis or chronically to reduce inflammation and space the onset of flare-ups. In other words, NMN, one of its derivatives or one of its pharmaceutically acceptable salts, as well as compositions comprising them can be used as a preventive or curative measure, in order to reduce the inflammation, and in particular the swelling, of the muscles. joints.
[0107] Le NMN, ses dérivés pharmaceutiquement acceptables ou ses sels pharmaceutiquement acceptables, et les compositions selon l’invention peuvent être administrés à une quantité thérapeutiquement efficace. Dans le contexte de l’invention, une quantité thérapeutiquement efficace d’une composition signifie que la composition est administrée à un patient en quantité suffisante pour obtenir l’effet thérapeutique désiré. [0107] NMN, its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts, and the compositions according to the invention can be administered in a therapeutically effective amount. In the context of the invention, a therapeutically effective amount of a composition means that the composition is administered to a patient in an amount sufficient to achieve the desired therapeutic effect.
[0108] Le NMN, un de ses précurseurs pharmaceutiquement acceptables, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, est utilisé dans une quantité comprise entre 0,01 mg/kg/jour et 1000 mg/kg/jour, de préférence entrel mg/kg/jour et 100 mg/kg/jour, de manière davantage préférée entre 5 mg/kg/jour et 50 mg/kg/jour, de manière encore plus préférée entre 10 mg/kg/jour et 20 mg/kg/jour. L’homme du métier peut adapter la dose de NMN à administrer en fonction de l’âge et du poids du patient. [0108] NMN, one of its pharmaceutically acceptable precursors, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, is used in an amount of between 0.01 mg / kg / day and 1000 mg / kg / day, preferably between mg / kg / day and 100 mg / kg / day, more preferably between 5 mg / kg / day and 50 mg / kg / day, even more preferably between 10 mg / kg / day and 20 mg / kg / day. One skilled in the art can adjust the dose of NMN to be administered depending on the age and weight of the patient.
[0109] Un niveau de dosage approprié peut être d'environ 0,01 à 250 mg/kg par jour, d'environ 0,05 à 100 mg/kg par jour, ou d'environ 0,1 à 50 mg/kg par jour. Dans cette fourchette, la dose peut être de 0,05 à 0,5, 0,5 à 5 ou 5 à 50 mg/kg par jour. Pour l'administration orale, les compositions sont de préférence fournies sous forme de comprimés contenant de 1,0 à 1000 milligrammes du NMN, un de ses précurseurs pharmaceutiquement acceptables, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, notamment 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 et 1000.0 milligrammes de l'ingrédient actif pour l'ajustement symptomatique de la dose au patient à traiter. Par exemple, la posologie peut être comprise entre 100mg/jour et 5000mg/jour, de préférence entre 500mg/jour et 1000mg/jour. Les composés peuvent être administrés selon un schéma de 1 à 4 fois par jour, de préférence une, deux ou trois fois par jour, de préférence trois fois par jour. La durée du traitement dépend et est déterminée par le médecin. Elle peut aller d'un jour à un an ou même plus, de préférence d'une semaine à trois mois, plus préférablement de deux semaines à six semaines. Il sera toutefois entendu que le niveau de dose spécifique et la fréquence de dosage ainsi que la durée pour un patient donné peuvent varier et dépendront de divers facteurs, notamment l'activité du composé spécifique employé, la stabilité métabolique et la durée d'action de ce composé, l'âge, le poids corporel, l'état de santé général, le sexe, le régime alimentaire, le mode et le moment d'administration, le taux d'excrétion, la combinaison de médicaments, et l'hôte soumis au traitement. [0109] 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 the form of tablets containing from 1.0 to 1000 milligrams of NMN, a pharmaceutically acceptable precursor thereof, a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof, 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 adjustment of the dose to the patient to be treated. 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 a day, preferably one, two or three times a day, preferably three times a day. The duration of treatment depends on 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, mode and time of administration, rate of excretion, drug combination, and host being treated.
[0110] Le NMN, un de ses précurseurs pharmaceutiquement acceptables, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, peut être administré à une dose quotidienne de 10 mg/kg, avec un minimum de 50 mg/jour et un maximum de 1000 mg/jour. [0110] 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 minimum of 50 mg / day and a maximum of 1000 mg / day.
[0111] Le NMN et la composition selon l’invention peuvent être administrés une fois par jour ou plusieurs fois par jour. Notamment, le NMN et la composition selon l’invention peuvent être administrés entre 1 et 12 fois par jour, de préférence entre 2 et 10 fois par jour, de manière davantage préférée entre 3 et 5 fois par jour. [0111] The NMN and the composition according to the invention can be administered once a day or several times a day. In particular, the NMN and the composition according to the invention can be administered between 1 and 12 times per day, preferably between 2 and 10 times per day, more preferably between 3 and 5 times per day.
[0112] Mode d’administration et forme galénique [0112] Method of administration and dosage form
[0113] Le NMN, un de ses sels pharmaceutiquement acceptables, un de ses dérivés pharmaceutiquement acceptables et les compositions le comprenant peuvent être administrés par voie orale, oculaire, sublinguale, intraveineuse, intraartérielle, intramusculaire, intra-articulaire, sous-cutanée, transcutanée, vaginale, péridurale, intravésicale, rectale ou inhalation. [0113] NMN, one of its pharmaceutically acceptable salts, one of its pharmaceutically acceptable derivatives and the compositions comprising it can be administered by the oral, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous or transcutaneous routes. , vaginal, epidural, intravesical, rectal or inhalation.
[0114] Selon le mode d’administration envisagé, la composition selon l’invention peut se présenter sous la forme d’un comprimé, d’une gélule, d’un sachet, d’un granulé, d’une capsule molle, d’un lyophilisât, d’une pastille, d’une suspension, d’un gel, d’un sirop, d’une solution, d’une émulsion eau/huile, d’une émulsion huile/eau, d’une huile, d’une crème, d’un lait d’une pulvérisation, d’une pommade, une ampoule, un suppositoire, un collyre, une ovule vaginale, d’une capsule vaginale, un liquide pour inhalation, d’un inhalateur à poudre sèche, d’un inhalateur pressurisé à valve doseuse. According to the mode of administration envisaged, the composition according to the invention may be in the form of a tablet, a capsule, a sachet, a granule, a soft capsule, or 'a lyophilisate, a pellet, a suspension, a gel, a syrup, a solution, a water / oil emulsion, an oil / water emulsion, an oil, cream, milk spray, ointment, ampoule, suppository, eye drops, vaginal ovum, vaginal capsule, liquid for inhalation, dry powder inhaler , a pressurized metered-valve inhaler.
[0115] Dans un mode de réalisation préféré, le NMN et la composition selon l’invention sont administrés par voie injectable, et notamment par voie sous-cutanée, intraveineuse ou intra-articulaire, de préférence intra-articulaire. [0115] In a preferred embodiment, the NMN and the composition according to the invention are administered by injection, and in particular by subcutaneous, intravenous or intra-articular, preferably intra-articular, route.
[0116] Dans un autre mode de réalisation également préféré, le NMN et la composition selon l’invention sont administrés par voie orale. [0116] In another also preferred embodiment, the NMN and the composition according to the invention are administered orally.
[0117] La forme orale selon l’invention peut également être à libération immédiate : une telle forme galénique permet une absorption rapide du NMN et ainsi un délai d’action réduit. Les formes galéniques à libération immédiate sont notamment les comprimés dispersibles, orodispersibles, effervescents et les lyophilisats oraux. The oral form according to the invention can also be immediate release: such a galenic form allows rapid absorption of the NMN and thus a delay reduced action. Immediate-release dosage forms are in particular dispersible, orodispersible, effervescent tablets and oral lyophilisates.
[0118] Les comprimés dispersibles sont des comprimés non enrobés ou pelliculés qui peuvent être dispersés dans un liquide avant administration afin d'avoir une dispersion homogène. Les comprimés dispersibles se désagrègent habituellement en trois minutes une fois mis dans de l'eau ou dans une petite quantité de lait maternel. [0118] The dispersible tablets are uncoated or film-coated tablets which can be dispersed in a liquid before administration in order to have a homogeneous dispersion. Dispersible tablets usually break up within three minutes when placed in water or a small amount of breast milk.
[0119] Un comprimé effervescent est un comprimé conçu pour se fragmenter et se dissoudre rapidement dans l’eau ou dans un autre liquide et ceci en libérant du dioxyde de carbone (C02). Cette libération induit l'effervescence et la fragmentation du comprimé. [0119] An effervescent tablet is a tablet designed to fragment and dissolve rapidly in water or other liquid, releasing carbon dioxide (CO2). This release induces the effervescence and fragmentation of the tablet.
[0120] Un comprimé orodispersible est un comprimé dispersible qu’on place sur la langue. Le principe actif est alors absorbé au niveau de la muqueuse gastro intestinale. [0120] An orodispersible tablet is a dispersible tablet that is placed on the tongue. The active principle is then absorbed from the gastrointestinal mucosa.
[0121] On entend par « comprimé sublingual » un lyophilisât oral se plaçant sous la langue afin que le principe actif soit absorbé par la muqueuse sublinguale, et notamment par les veine et artère ranines. The term “sublingual tablet” is understood to mean an oral lyophilizate which is placed under the tongue so that the active principle is absorbed by the sublingual mucosa, and in particular by the vein and artery ranins.
[0122] La forme orale selon l’invention peut également être à libération retardée. La dissolution et l’absorption du NMN s’effectuent au niveau intestinal, ce qui limite l’irritation gastrique ou la dégradation des principes actifs fragiles à pH acide. Il s’agit majoritairement de formes gastro-résistantes, c’est-à-dire que les comprimés ou granulés sont recouverts d’un film polymérique, insoluble en milieu acide mais perméable à l’eau en milieu alcalin ou de type lipidique dégradé par les lipases intestinales. [0122] The oral form according to the invention can also be delayed release. The dissolution and absorption of NMN takes place in the intestine, which limits gastric irritation or the degradation of fragile active ingredients at acidic pH. They are mainly gastro-resistant 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 intestinal lipases.
[0123] On entend par « gastro-résistante » une forme galénique qui ne se dissout pas dans l’estomac. De telles formes galéniques sont à libération différée c’est-à-dire qu’elles présentent un enrobage ou une composition d’enrobage résistant au pH acide de l’estomac (pH<2) pour se dissoudre dans l’intestin. Le caractère gastro résistant est déterminé en suivant le test établi par la Pharmacopée européenne. Brièvement, le caractère gastro-résistant d’une gélule est mesuré dans de l’acide chlorhydrique 0,1 M à 37°C comme milieu de désagrégation dans un appareil à désagrégation. Ce milieu mime les conditions physicochimiques de l’estomac. Les gélules sont incubées dans ce milieu pendant 1 h. La gélule ne doit présenter ni signe de désagrégation, ni fissure pouvant entraîner une perte de contenu. La gélule est ensuite incubée pendant 1h dans une solution de tampon phosphate de pH 6,8 à 37°C, cette solution mimant les conditions du milieu intestinal conformément aux recommandations de la pharmacopée européenne. La gélule doit être totalement désagrégée en moins d’une heure. 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-resistant character of a capsule is measured in 0.1 M hydrochloric acid at 37 ° C as a disintegrating medium in a measuring device. disaggregation. 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.
[0124] La forme orale selon l’invention peut également être à libération prolongée et séquentielle. Les formes à libération séquentielle (libération à intervalle de temps précis) et prolongée (libération continue du principe actif jusqu’à épuisement) favorisent l’étalement de la libération du principe actif dans le temps afin de maintenir une concentration plasmatique efficace plus longtemps dans l’organisme du patient. De telles formes galéniques permettent d’obtenir un soulagement du patient pendant un laps de temps plus long, et d’espacer les prises de médicament. [0124] The oral form according to the invention can also be prolonged and sequential release. The sequential release (release at specific time interval) and sustained release (continuous release of the active ingredient until exhaustion) forms promote the spreading of the release of the active ingredient over time in order to maintain an effective plasma concentration for longer in the fluid. organism of the patient. Such dosage forms make it possible to obtain relief for the patient for a longer period of time, and to space out the doses of the drug.
[0125] Dans un mode de réalisation davantage préféré, le NMN et la composition selon l’invention sont administrés par voie orale, sous forme d’une gélule gastrorésistante ou d’un comprimé sublingual. [0125] In a more preferred embodiment, the NMN and the composition according to the invention are administered orally, in the form of an enteric capsule or a sublingual tablet.
[0126] Le mode d’administration et la forme galénique sont déterminés par l’homme du métier en fonction de la localisation anatomique à traiter et du patient. Il est fait référence à la dernière édition de Remington's Pharmaceutical Sciences. [0126] The mode of administration and the dosage form are determined by a person skilled in the art depending on the anatomical location to be treated and the patient. Reference is made to the latest edition of Remington's Pharmaceutical Sciences.
[0127] Combinaisons thérapeutiques [0127] Therapeutic combinations
[0128] Le NMN, un de ses dérivés pharmaceutiquement acceptables, un de ses sels pharmaceutiquement acceptables et les compositions les comprenant peuvent également être utilisés en combinaison avec au moins un autre agent thérapeutique, en particulier les agents thérapeutiques utilisés soit ponctuellement pour traiter les poussées de polyarthrite rhumatoïde c’est-à-dire des thérapies symptomatiques, soit en traitement de fond de la polyarthrite rhumatoïde. [0128] NMN, one of its pharmaceutically acceptable derivatives, one of its pharmaceutically acceptable salts and the compositions comprising them can also be used in combination with at least one other therapeutic agent, in particular the therapeutic agents used either occasionally to treat relapses. rheumatoid arthritis, that is to say symptomatic therapies, or as a basic treatment of rheumatoid arthritis.
[0129] Un traitement de fond est un traitement pris au quotidien, de manière chronique, afin de prévenir ou espacer les crises. [0129] A basic treatment is treatment taken daily, chronically, in order to prevent or space out attacks.
[0130] Parmi les agents thérapeutiques pouvant être combinés conformément à l’invention, on peut citer un antalgique, un anti-inflammatoire non stéroïdien, la cortisone, un dérivé de la cortisone, un immunosuppresseur, un immunomodulateur, un inhibiteur de lymphocytes T, un inhibiteur de lymphocytes B, un antipaludique de synthèse, un anti-TNF, un inhibiteur enzymatique des Janus kinases, un anti-interleukine et leurs combinaisons. [0130] Among the therapeutic agents which can be combined in accordance with the invention, there may be mentioned an analgesic, a non-steroidal anti-inflammatory drug, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, a T cell inhibitor, a B cell inhibitor, a synthetic antimalarial, an anti-TNF, an enzyme inhibitor of Janus kinases, an anti-interleukin and their combinations .
[0131] Plus précisément, les antalgiques, les anti-inflammatoires non stéroïdiens, la cortisone et ses dérivés peuvent être utilisés pour traiter et soulager les poussées de rhumatismes inflammatoires, en tant que traitement symptomatique de la poussée inflammatoire. [0131] More specifically, analgesics, non-steroidal anti-inflammatory drugs, cortisone and its derivatives can be used to treat and relieve flare-ups of inflammatory rheumatism, as a symptomatic treatment of the flare-up.
[0132] L’antalgique peut être choisi parmi le paracétamol, l’aspirine, la codéine, la dihydrocodéine, le tramadol, la morphine, la buprénorphine, le fentanyl, l’hydromorphone, la nalbuphine, l’oxycodone, la péthidine et leurs combinaisons. The analgesic can be chosen from paracetamol, aspirin, codeine, dihydrocodeine, tramadol, morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine and theirs. combinations.
[0133] L’anti-inflammatoire non stéroïdien (AINS) peut être choisi parmi l’ibuprofène, le kétoprofène, le naproxène, l’alminoprofène l’acéclofénac, l’acide méfénamique, l’acide niflumique, l’acide tiaprofénique, le célécoxib, le dexkétoprofène, le diclofénac, l’étodolac, l’étoricoxib, le fénoprofène, le flurbiprofène, l’indométacine, le méloxicam, le nabumétone, le piroxicam, le sulindac, le ténoxicam et leurs combinaisons. The nonsteroidal anti-inflammatory drug (NSAID) can be chosen from ibuprofen, ketoprofen, naproxen, alminoprofen, aceclofenac, mefenamic acid, niflumic acid, tiaprofenic acid, celecoxib, dexketoprofen, diclofenac, etodolac, etoricoxib, fenoprofen, flurbiprofen, indomethacin, meloxicam, nabumetone, piroxicam, sulindac, tenoxicam and their combinations.
[0134] Le dérivé de la cortisone peut être choisi parmi la bétaméthasone, la ciprofloxacine, le cortivazol, la dexaméthasone, la fludrocortisone, le méthylprednisolone, le prednisolone et la triamcinolone et leurs combinaisons. The cortisone derivative can be chosen from betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone and their combinations.
[0135] Le NMN, ses dérivés ou ses sels pharmaceutiquement acceptables ainsi que les compositions les comprenant peuvent également être administrés en combinaison avec un traitement de fond de la polyarthrite rhumatoïde tels qu’un immunosuppresseur, un immunomodulateur, un inhibiteur de lymphocytes T, un inhibiteur de lymphocytes B, un antipaludique de synthèse, un anti-TNF, un inhibiteur enzymatique des Janus kinases, un anti-interleukine ou leurs combinaisons. L’utilisation d’un traitement de fond en combinaison avec le NMN, un de ses dérivés ou un de ses sels ainsi que de compositions les comprenant est également compatible avec l’administration d’antalgiques, d’AINS, de cortisone et/ou de dérivés de la cortisone pour traiter les poussées. [0136] L’immunosuppresseur peut être choisi parmi l'azathioprine, le cyclophosphamide, le chlorambucil, la ciclosporine, le méthotrexate et leurs combinaisons. De préférence, l’immunosuppresseur peut être le méthotrexate ou la ciclosporine, de manière davantage préférée le methotrexate. [0135] NMN, its derivatives or its pharmaceutically acceptable salts as well as the compositions comprising them can also be administered in combination with a basic treatment of rheumatoid arthritis such as an immunosuppressant, an immunomodulator, a T lymphocyte inhibitor, a B-cell inhibitor, a synthetic antimalarial, an anti-TNF, an enzyme inhibitor of Janus kinases, an anti-interleukin or combinations thereof. The use of a disease-modifying treatment in combination with NMN, one of its derivatives or one of its salts as well as compositions comprising them is also compatible with the administration of analgesics, NSAIDs, cortisone and / or cortisone derivatives to treat relapses. The immunosuppressant can be chosen from azathioprine, cyclophosphamide, chlorambucil, ciclosporin, methotrexate and their combinations. Preferably, the immunosuppressant can be methotrexate or ciclosporin, more preferably methotrexate.
[0137] L’immunomodulateur peut être choisi parmi le léflunomide, la sulfasalazine et leurs combinaisons. [0137] The immunomodulator can be selected from leflunomide, sulfasalazine and their combinations.
[0138] Avantageusement, l’inhibiteur de lymphocytes B peut être le rituximab. Le rituximab se lien en particulier aux lymphocytes B CD20. [0138] Advantageously, the B lymphocyte inhibitor can be rituximab. Rituximab is particularly linked to CD20 B lymphocytes.
[0139] Avantageusement, l’inhibiteur de lymphocytes T peut être l’abatacept. L’abatacept se lie en particulier aux lymphocytes T exprimant les CD80 et CD86. [0139] Advantageously, the T cell inhibitor can be abatacept. Abatacept binds in particular to T cells expressing CD80 and CD86.
[0140] L’antipaludique de synthèse peut être choisi parmi la chloroquine, l’hydroxychloroquine et leurs combinaisons. [0140] The synthetic antimalarial can be chosen from chloroquine, hydroxychloroquine and their combinations.
[0141] L’anti-TNF peut être choisi parmi l'infliximab, l'etanercept, l'adalimumab, le certolizumab, le golimumab et leurs combinaisons. [0141] The anti-TNF can be selected from infliximab, etanercept, adalimumab, certolizumab, golimumab and their combinations.
[0142] L’inhibiteur enzymatique de Janus kinases peut être le tofacitinib. [0142] The enzyme inhibitor of Janus kinases may be tofacitinib.
[0143] L’anti-interleukine peut être choisi parmi un anti-interleukine 1, un anti interleukine 6, un inhibiteur de l’interleukine 12, un inhibiteur de l’interleukine 17, un inhibiteur de l’interleukine 23 et leurs combinaisons. Notamment, l’anti interleukine 1 peut être l’anakinra. L’anti-interleukine 6 peut être le tocilizumab. [0143] The anti-interleukin can be selected from an anti-interleukin-1, an anti-interleukin-6, an interleukin-12 inhibitor, an interleukin-17 inhibitor, an interleukin-23 inhibitor, and combinations thereof. In particular, the anti interleukin 1 can be anakinra. The anti-interleukin 6 may be tocilizumab.
[0144] L’inhibiteur de l’interleukine 12 peut être l’ustekinumab. L’inhibiteur de l’interleukine 17 peut être choisir parmi l’ixékizumab et le sécukinumab. L’inhibiteur de l’interleukine 23 peut être choisi parmi l’ustekinumab et le guselkumab. [0144] The interleukin-12 inhibitor may be ustekinumab. The interleukin-17 inhibitor can be selected from ixekizumab and secukinumab. The interleukin 23 inhibitor can be selected from ustekinumab and guselkumab.
[0145] De préférence, le NMN, un de ses dérivés pharmaceutiquement acceptables, un de ses sels pharmaceutiquement acceptables, n’est pas utilisé en combinaison avec au moins l’un des composés choisis parmi le folate, S-adenosyl-Lmethionine (SAM), l’astaxanthine, la berberine, le pterostilbène, le resveratrol, la metformine, levofloxacine, et leurs combinaisons. Preferably, NMN, one of its pharmaceutically acceptable derivatives, one of its pharmaceutically acceptable salts, is not used in combination with at least one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM ), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
[0146] Compositions [0146] Compositions
[0147] Les compositions selon l’invention peuvent comprendre le nicotinamide mononucléotide, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, et au moins un excipient pharmaceutiquement acceptable pour la prévention et/ou le traitement de la polyarthrite rhumatoïde. The compositions according to the invention can comprise the nicotinamide mononucleotide, one of its pharmaceutically acceptable derivatives or one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient for the prevention and / or treatment of rheumatoid arthritis.
[0148] Dans le contexte de la présente invention, un « excipient » désigne toute substance autre que le NMN dans la composition et n’ayant pas d’effet thérapeutique. L’excipient n’interagit pas sur le plan chimique avec le NMN ou tout autre agent thérapeutique supplémentaire. [0148] In the context of the present invention, an "excipient" means any substance other than NMN in the composition and not having a therapeutic effect. The excipient does not chemically interact with NMN or any additional therapeutic agent.
[0149] L’excipient peut être choisi parmi un agent de charge, un lubrifiant, un arôme, un colorant, un émulsifiant, un agent de compression, un diluant, un conservateur, un gélifiant, un plastifiant, un tensioactif ou leurs combinaisons. [0149] 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.
[0150] Les compositions selon l’invention peuvent être formulées avec des supports, des excipients et des diluants qui conviennent en soi pour ces formulations, tels que le lactose, le dextrose, le saccharose, le sorbitol, le mannitol, les amidons, la gomme d'acacia, le phosphate de calcium, les alginates, la gomme adragante, la gélatine, le silicate de calcium, la cellulose microcristalline, polyvinylpyrrolidone, polyéthylène glycol, cellulose, eau (stérile), méthylcellulose, hydroxybenzoates de méthyle et de propyle, talc, stéarate de magnésium, huiles alimentaires, huiles végétales et minérales ou mélanges appropriés de celles-ci. Les formulations peuvent éventuellement contenir d'autres substances qui sont couramment utilisées dans les formulations pharmaceutiques, telles que des agents lubrifiants, des agents mouillants, des agents émulsifiants et de suspension, des agents dispersants, des désintégrants, des agents de charge, des charges, des agents de conservation, des édulcorants, des aromatisants, des régulateurs de débit, des agents de démoulage, etc. Les compositions peuvent également être formulées de manière à permettre une libération rapide, prolongée ou retardée du ou des composés actifs qu'elles contiennent. L’homme de l’art sait quel excipient choisir en fonction de la forme galénique qu’il aura choisie. [0150] The compositions according to the invention can be formulated with carriers, excipients and diluents which are suitable per se for these formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, water (sterile), methylcellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, edible oils, vegetable and mineral oils or suitable mixtures thereof. The formulations may optionally contain other substances which are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preservatives, sweeteners, flavorings, flow regulators, mold release agents, etc. The compositions can also be formulated so as to allow rapid, sustained or delayed release of the active compound (s) which they contain. Those skilled in the art know which excipient to choose depending on the dosage form they have chosen.
[0151] Les compositions selon l'invention sont de préférence sous forme de doses unitaires et peuvent être conditionnées de manière appropriée, par exemple dans une boîte, un blister, un flacon, une bouteille, un sachet, une ampoule ou dans tout autre support ou récipient approprié à dose unique ou à doses multiples (qui peut être correctement étiqueté) ; optionnellement avec une ou plusieurs notice(s) contenant des informations sur le produit et/ou des instructions d'utilisation. The compositions according to the invention are preferably in the form of unit doses and can be packaged in an appropriate manner, for example in a box, a blister, a vial, a bottle, a sachet, an ampoule or in any other support. or an appropriate single-dose or multiple-dose container (which can be correctly labeled); optionally with one or more leaflet (s) containing product information and / or instructions for use.
[0152] La composition selon l’invention peut être une composition pharmaceutique. En ce cas, l’excipient est un excipient pharmaceutiquement acceptable tel que défini ci-dessus. [0152] The composition according to the invention can be a pharmaceutical composition. In this case, the excipient is a pharmaceutically acceptable excipient as defined above.
[0153] La composition selon l’invention peut également être un complément alimentaire. [0153] The composition according to the invention can also be a food supplement.
[0154] Dans un mode de réalisation préféré, la composition selon l’invention peut en outre comprendre au moins un agent thérapeutique supplémentaire tel que défini ci-dessus pour son utilisation dans la prévention et/ou le traitement de la polyarthrite rhumatoïde tel qu’exposé ci-dessus. [0154] In a preferred embodiment, the composition according to the invention may further comprise at least one additional therapeutic agent as defined above for its use in the prevention and / or treatment of rheumatoid arthritis such as discussed above.
[0155] Lorsque la composition selon l’invention comprend au moins un agent thérapeutique supplémentaire, la composition peut se présenter sous une forme unitaire à dose fixe. On entend par « forme unitaire à dose fixe » une composition comprenant au moins deux principes actifs formulés dans une unique forme de dosage. [0155] When the composition according to the invention comprises at least one additional therapeutic agent, the composition may be in unit form at a fixed dose. The term “unit form at a fixed dose” is understood to mean a composition comprising at least two active principles formulated in a single dosage form.
[0156] De préférence, la composition selon l’invention ne comprend pas l’un des composés choisis parmi le folate, S-adenosyl-Lmethionine (SAM), l’astaxanthine, la berberine, le pterostilbène, le resveratrol, la metformine, levofloxacine, et leurs combinaisons. Preferably, the composition according to the invention does not comprise one of the compounds chosen from folate, S-adenosyl-Lmethionine (SAM), astaxanthin, berberine, pterostilbene, resveratrol, metformin, levofloxacin, and their combinations.
Dérivés du NMN NMN derivatives
[0157] Selon l’invention, le dérivé du NMN peut être choisi parmi le dihydronicotinamide mononucléotide (noté NMN-H), le composé de formule (I) : ou un de ses stéréoisomères, un de ses sels, un de ses hydrates, un de ses solvatés ou un de ses cristaux pharmaceutiquement acceptable de celui-ci, dans lequel : X est choisi parmi O, CH2, S, Se, CHF, CF2 et C=CFl2; According to the invention, the NMN derivative can be chosen from dihydronicotinamide mononucleotide (denoted NMN-H), the compound of formula (I): 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 ;
Ri est choisi parmi H, azido, cyano, alkyle en C-i-Cs, thio-alkyle en C-i-Cs, hétéroalkyle en C-i-Cs et OR ; dans lequel R est choisi parmi Fl et alkyle en C-i-Cs ; R 1 is selected from H, azido, cyano, C-i-Cs alkyl, thio-C-i-Cs alkyl, C-i-Cs heteroalkyl and OR; wherein R is selected from F1 and C1-C8 alkyl;
R2, R3, R4 et R5 sont choisis indépendamment l’un de l’autre parmi Fl, halogène, azido, cyano, hydroxyle, alkyle en C1-C12, thio-alkyle en C1-C12, hétéroalkyle en C1- C12, haloalkyle en C1-C12 et OR ; dans lequel R est choisi parmi Fl, alkyle en C1-C12, C(0)(Ci-Ci2)alkyle, C(0)NH(Ci-Ci2)alkyle, C(0)0(Ci-Ci2)alkyle, C(0)aryle, C(0)(Ci- Ci2)alkyle aryle, C(0)NFI(Ci-Ci2)alkyle aryle, C(0)0(Ci-Ci2)alkyle aryle et C(0)CFIRAANFI2 ; dans lequel RAA est une chaîne latérale choisie parmi un acide aminé protéinogène ; R 2 , R3, R 4 and R5 are chosen independently of one another from F1, halogen, azido, cyano, hydroxyl, C 1 -C 12 alkyl, C 1 -C 12 thio-alkyl, 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) NH (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) CFIR AA NFI 2 ; wherein R AA is a side chain selected from a proteinogenic amino acid;
Re est choisi parmi Fl, azido, cyano, C-i-Cs alkyle, C-i-Cs thio-alkyle, C-i-Cs hétéroalkyle et OR ; dans lequel R est choisi parmi Fl et C-i-Cs alkyle; Re is selected from F1, azido, cyano, C-i-Cs alkyl, C-i-Cs thio-alkyl, C-i-Cs heteroalkyl and OR; in which R is selected from F1 and C-i-Cs alkyl;
R7 est choisi parmi P(0)R9RIO et P(S)R9RIO ; dans lequel R7 is selected from P (0) R9RIO and P (S) R9RIO; in which
R9 et R10 sont choisis indépendamment l’un de l’autre parmi OH, ORn, NHR13, NR13R14, un alkyle en C-i-Cs, un alcényle en C2-C8, un alcynyl en C2-C8, un cycloalkyl en C3-C10, un aryle en C5-C12, (Ci-C8)alkyle aryle, (Ci-Cs)aryle alkyle, (Ci-Cs) heteroalkyle, (Ci-Cs) heterocycloalkyle, un heteroaryle et NHCHRARAC(0)RI2 ; dans lequel : R 9 and R 10 are selected independently of one another from OH, ORn, NHR 13, NR 13 R 14, alkyl Ci-Cs alkenyl, C 2 -C 8, a C 2 -C 8 alkynyl, a C3-C 10 cycloalkyl, a C5-C 12 aryl, (Ci-C8) alkyl aryl, (Ci-Cs) aryl alkyl, (Ci-Cs) heteroalkyl, (Ci-Cs) heterocycloalkyl, a heteroaryl and NHCHR A R A C (0) R I2 ; in which :
R11 est choisi parmi un groupe C1-C10 alkyle, C3-C10 cycloalkyle, C5-C18 aryle, C1-C10 alkylaryle, C5-C12 aryle substitué, C1-C10 heteroalkyle, C3-C10 heterocycloalkyle, C1-C10 haloalkyle, un heteroaryle, -(CH2)nC(0)(Ci-Ci5)alkyle, -(CH2)n0C(0)(Ci- Cis)alkyle, -(CH2)n0C(0)0(Ci-Ci5)alkyle, -(CH2)nSC(0)(Ci-Ci5)alkyle, (CH2)nC(0)0(Ci-Ci5)alkyle and -(CH2)nC(0)0(Ci-Ci5)alkyle aryle; dans lesquels n est un entier choisi de 1 à 8; P(0)(0H)0P(0)(0H)2, halogène, nitro, cyano, O-i-Ob alkoxy, C1-C6 haloalkoxy, -N(Rna)2, O-i-Ob acylamino, -CORnb, -O CORnb ; NHS02(CI-C6 alkyl), - S02N(Rna)2 SO2 dans lequel chacun de Rna est indépendamment choisi parmi H et un Ci-C6alkyle et Rub est indépendamment choisi parmi OH, O-i-Ob alkoxy, NH2, NH(CI-C6 alkyle) ou N(Ci-C6alkyle)2 ;; R12 est choisi parmi H, C1-C10 alkyle, C2-C8 alcényle, C2-C8 alcynyle, C1-C10 haloalkyle, C3-C10 cycloalkyle, C3-C10 heterocycloalkyle, C5-C18 aryle, C1-C4 alkylaryle and C5-C12 heteroaryle; dans lesquels lesdits groupes aryle ou heteroaryle sont optionnellement substitué parmi un ou deux groupes choisi parmi un halogène, trifluoromethyl, C1-C6 alkyle, C1-C6 alkoxy et cyano; et R 11 is selected from a group C 1 -C 10 alkyl, C3-C 10 cycloalkyl, C5-C 18 aryl, C 1 -C 10 alkylaryl, C5-C 12 substituted aryl, C 1 -C 10 heteroalkyl, C3-C 10 heterocycloalkyl, C 1 -C 10 haloalkyl, a heteroaryl, - (CH 2 ) n C (0) (C1-C15) alkyl, - (CH 2 ) n 0C (0) (Ci- Cis) alkyl, - (CH 2 ) n0C (0) 0 (Ci-Ci 5 ) alkyl, - (CH 2 ) nSC (0) (Ci-Ci 5 ) alkyl, (CH 2 ) nC (0) 0 (Ci-Ci 5 ) alkyl and - (CH 2 ) nC (0) 0 (Ci-Ci 5 ) alkyl aryl; wherein n is an integer selected from 1 to 8; P (0) (0H) 0P (0) (0H) 2, halogen, nitro, cyano, Oi-Ob alkoxy, C1-C6 haloalkoxy, -N (Rn a ) 2, Oi-Ob acylamino, -CORnb, -O CORnb; NHS02 (CI-C6 alkyl), - S0 2 N (Rn a ) 2 SO 2 wherein each of Rn a is independently selected from H and C1-C 6 alkyl and Ru b is independently selected from OH, Oi-Ob alkoxy , NH 2 , NH (CI-C 6 alkyl) or N (Ci-C 6 alkyl) 2 ;; R12 is selected from H, C1-C10 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C5-C18 aryl, C1-C4 alkylaryl and C5-C12 heteroaryl ; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C 1 -C6 alkyl, C 1 -C6 alkoxy and cyano; and
RA et RA’ sont indépendamment choisi parmi H, un C1-C10 alkyle, C2-C10 alcényle, C2-C10 alcynyle, C3-C10 cycloalkyle, C1-C10 thio-alkyle, C1-C10 hydroxylalkyle, C1-C10 alkylaryle and C5-C12 aryle, C3-C10 heterocycloalkyle, un heteroaryle, - (CH2)3NHC(=NH)NH2, (1 H-indol-3-yl)methyl, (1 H-imidazol-4-yl)methyl et une chaîne latérale choisie parmi un acide aminé protéinogène ou un acide aminé non protéinogène; dans lesquels lesdits groupes aryle sont optionnellement substitué avec un groupe choisi parmi un hydroxyle, C1-C10 alkyl, C1-C6 alkoxy, un halogène, un nitro et un cyano; ou RA and RA ' are independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 thio-alkyl, C1-C10 hydroxylalkyl, C1-C10 alkylaryl and C5- C12 aryl, C3-C10 heterocycloalkyl, a heteroaryl, - (CH2) 3NHC (= NH) NH2, (1 H-indol-3-yl) methyl, (1 H-imidazol-4-yl) methyl and a selected side chain from a proteinogenic amino acid or a non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C1-C10 alkyl, C1-C6 alkoxy, halogen, nitro and cyano; or
R9 et R10 forment ensemble avec les atomes de phosphore auxquels ils sont attaché un cycle à 6 membres dans lequel -R9-R10- représente -CH2-CH2-CHR-; dans lequel R est choisi parmi H, un groupe (C5-C6) aryle et (C5-C6) heteroaryle, dans lequel lesdits groupes aryle ou heteroaryle sont optionnellement substitués par un halogène, trifluoromethyl, un C1-C6 alkyle, un C1-C6 alkoxy et cyano; ou R9 and R10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R10- represents -CH 2 -CH 2 -CHR-; wherein R is selected from H, (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C 1 -C6 alkyl , a C 1 -C6 alkoxy and cyano; or
R9 et R10 forment ensemble avec les atomes de phosphore auxquels ils sont attaché un cycle à 6 membres dans lequel -R9-R10- représente -O-CH2-CH2-CHR-O-; dans lequel R est choisi parmi H, un groupe (C5-C6) aryle et (C5-C6) heteroaryle, dans lequel lesdits groupes aryle ou heteroaryle sont optionnellement substitués par un halogène, trifluoromethyl, un (C1-C6) alkyle, un (C1-C6) alkoxy et cyano; R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R 10 - represents -O-CH 2 -CH 2 -CHR-O-; in which R is selected from H, a (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl group, in which said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (C 1 -C6) ) alkyl, a (C 1 -C6) alkoxy and cyano;
R8 est choisi parmi H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N3 et halogène ; dans lequel R13 et Ru sont choisis indépendamment l’un de l’autre parmi H, (C1-C8) alkyle et (C-i-Cs) alkyle aryle, et -CRBRC-C(0)-ORD dans lequel RB et Rc sont indépendamment un atome d'hydrogène, un (O-i-Ob) alkyle, un (O-i-Ob) alkoxy, benzyle, indolyle ou imidazolyle, où le (O-i-Ob) alkyle et le (O-i-Ob)) alkoxy peuvent être éventuellement et indépendamment l’un de l’autre substitué par un ou plusieurs des groupes halogène, amino, amido, guanidyle, hydroxyle, thiol ou carboxyle, et le groupe benzyle est éventuellement substitué par un ou plusieurs des groupes halogène ou hydroxyle, ou RB et Reforment ensemble avec l'atome de carbone auquel ils sont attachés un groupe cycloalkyle en C3-C6 éventuellement substitué par un ou plusieurs halogènes, amino, amido, guanidyle, hydroxyle, thiol et carboxyle et RD est un hydrogène, un (C1-C6) alkyle, un (C2-C6) alcényle, un (C2-C6) alcynyle ou un (C3- Ce) cycloalkyle ; R 8 is selected from H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N 3 and halogen; wherein R13 and Ru are independently selected from one another from H, (C1-C8) alkyl and (C1-Cs) alkyl aryl, and -CRBRC-C (0) -ORD wherein RB and Rc are independently a hydrogen atom, an (Oi-Ob) alkyl, an (Oi-Ob) alkoxy, benzyl, indolyl or imidazolyl, where the (Oi-Ob) alkyl and the (Oi-Ob)) alkoxy can be optionally and independently each other substituted with one or more of the halogen, amino, amido, guanidyl, hydroxyl, thiol or carboxyl groups, and the benzyl group is optionally substituted by one or more of the halogen or hydroxyl groups, or RB and together with the carbon atom to which they are attached they form a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogens, amino, amido , guanidyl, hydroxyl, thiol and carboxyl and R D is hydrogen, (C 1 -C6) alkyl, (C 2 -C6) alkenyl, (C 2 -C6) alkynyl or (C3-Ce) cycloalkyl;
Y est choisi parmi CH, CH2, C(CH3)2 et CCH3 ; -r-z représente une simple ou une double liaison selon Y ; et représente l'anomère alpha ou bêta selon la position de Ri ou un de ses stéréoisomères, un de ses sels, un de ses hydrates, un de ses solvatés ou un de ses cristaux et leurs combinaisons. Y is selected from CH, CH 2 , C (CH3) 2 and CCH3; - r - z represents a single or a double bond along Y; and 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 and their combinations.
[0158] Dans un premier mode de réalisation préféré, le dérivé pharmaceutiquement acceptable est le composé de formule (I). In a first preferred embodiment, the pharmaceutically acceptable derivative is the compound of formula (I).
[0159] Dans une variante du premier mode de réalisation, X représente un oxygène. [0159] In a variant of the first embodiment, X represents an oxygen.
[0160] Dans une variante du premier mode de réalisation, Ri et R6 représentent chacun indépendamment l’un de l’autre un hydrogène. In a variant of the first embodiment, R 1 and R 6 each represent, independently of one another, a hydrogen.
[0161] Dans une variante du premier mode de réalisation, R2, R3, R4 et R5 représentent chacun indépendamment l’un de l’autre un hydrogène ou un OH. In a variant of the first embodiment, R 2 , R3, R 4 and R5 each represent, independently of one another, a hydrogen or an OH.
[0162] Dans une variante du premier mode de réalisation, Y représente un CH. In a variant of the first embodiment, Y represents a CH.
[0163] Dans une variante du premier mode de réalisation, Y représente un CH2. In a variant of the first embodiment, Y represents a CH 2.
[0164] Dans une variante du premier mode de réalisation, R7 représente P(0)(OH)2. In a variant of the first embodiment, R 7 represents P (0) (OH) 2.
[0165] Dans une variante du premier mode de réalisation, le composé de l’invention est choisi parmi les composés ci-dessous [0165] In a variant of the first embodiment, the compound of the invention is chosen from the compounds below
[0166] [Tableau 1] [0166] [Table 1]
0167] Le dérivé du NMN peut être le dihydronicotinamide mononucléotide (noté NMN- H). 0167] The derivative of NMN can be dihydronicotinamide mononucleotide (denoted NMN-H).
Procédé de préparation des composés de formule (I) Process for preparing the compounds of formula (I)
[0168] Les dérivés de formule (I) peuvent être préparés selon toute méthode bien connue de l’homme du métier. [0168] The derivatives of formula (I) can be prepared according to any method well known to those skilled in the art.
[0169] Les dérivés de formule (I) peuvent être préparés selon le procédé décrit dans la demande internationale WO 2017/024255A1 ou US 10,611 ,790 B2. The derivatives of formula (I) can be prepared according to the process described in international application WO 2017 / 024255A1 or US 10,611, 790 B2.
[0170] Notamment, les dérivés de formule (I) peuvent être préparés selon la méthode décrite ci-dessous. In particular, the derivatives of formula (I) can be prepared according to the method described below.
[0171] En particulier, les composés de formule (I) divulgués ici peuvent être préparés comme décrit ci-dessous à partir des substrats A-E. Il sera entendu par un homme du métier que ces schémas réactionnels ne sont en aucune façon limitatifs et que des variations peuvent être faites sans s'écarter de l'esprit et de la portée de la présente invention. 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.
[0172] Selon un mode de réalisation, l'invention concerne une méthode de préparation des composés de formule (I) tels que décrits ci-dessus. According to one embodiment, the invention relates to a method for preparing the compounds of formula (I) as described above.
[0173] La méthode implique dans une première étape la mono-phosphorylation d'un composé de formule (A), en présence de chlorure de phosphoryle et d’un phosphate de trialkyle, pour conduire au phosphorodichloridate de formule (B), dans lesquels X, Ri, R2, R3, R4, Rs, R6, Rs, Y, — et sont tels que définis ci- dessus pour les composés de formule (I). 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), in which X, Ri, R2, R3, R4, Rs, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
[0174] Dans une seconde étape, le phosphorodichloridate de formule (B) est hydrolysé pour conduire au phosphate de formule (C), dans lesquels X, R-i, R2, R3, R4, Rs, R6, Rs, Y, — et sont tels que définis ci- dessus pour les composés de formule (I). In a second step, the phosphorodichloridate of formula (B) is hydrolyzed to yield the phosphate of formula (C), in which X, Ri, R2, R3, R4, Rs, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
[0175] Selon un mode de réalisation, le composé de formule (A) est synthétisé à l'aide de diverses méthodes connues de l’homme du métier. [0175] According to one embodiment, the compound of formula (A) is synthesized using various methods known to those skilled in the art.
[0176] Selon un mode de réalisation, le composé de formule (A) est synthétisé par réaction du pentose de formule (D) avec un dérivé azoté de formule (E), dans lequel R, R2, R3, R4, Rs, R6, R7, Y sont tels que décrits ci-dessus pour les composés de formule I, conduisant au composé de formule (A-1 ) qui est ensuite déprotégé sélectivement pour donner le composé de formule (A), dans lesquels X, Ri, R2, R3, R4, Rs, R6, Rs, Y, — et sont tels que définis ci- dessus pour les composés de formule (I). [0176] 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, R 2 , R3, R 4 , Rs , R6, R7, Y are as described above for the compounds of formula I, leading to the compound of formula (A-1) which is then selectively deprotected to give the compound of formula (A), in which X, Ri, R2, R3, R4, Rs, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
[0177] Selon un mode de réalisation, R est un groupe protecteur approprié connu de l’homme du métier. Dans un mode de réalisation, le groupe protecteur est choisi parmi les triarylméthyles et/ou silyles. Des exemples non limitatifs de triarylméthyle comprennent les groupes trityle, monométhoxytrityle, 4,4'-diméthoxytrityle et 4,4',4"-triméthoxytrityle. Des exemples non limitatifs de groupes silyle comprennent les groupes triméthylsilyle, tert-butyldiméthylsilyle, triisopropylsilyle, tert-butyldiphénylsilyle, tri-iso-propylsilyloxyméthyle et [2-[0177] According to one embodiment, R is an appropriate protective group known to those skilled in the art. In one embodiment, the protecting 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-
(triméthylsilyl)éthoxy]méthyle. (trimethylsilyl) ethoxy] methyl.
[0178] Selon un mode de réalisation, tout groupe hydroxyle attaché au pentose est protégé par un groupe protecteur approprié connu de l’homme du métier. [0178] 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.
[0179] Le choix et l'échange des groupes protecteurs relèvent de la compétence de l’homme du métier. Les groupes protecteurs peuvent également être éliminés par des méthodes bien connues de l’homme du métier, par exemple, avec un acide (par exemple, un acide minéral ou organique), une base ou une source de fluorure. [0179] The choice and exchange of protecting groups are 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.
[0180] Dans un mode de réalisation préféré, le dérivé azoté de formule (E) est couplé au pentose de formule (D) par une réaction en présence d’un acide de Lewis conduisant au composé de formule (A-1). Des exemples non limitatifs d’acides de Lewis comprennent le TMSOTf, BF3.0Et2, TiCL et FeC . 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 (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF3.0Et 2 , TiCL and FeC.
[0181] Dans un mode de réalisation, la méthode de la présente invention comprend en outre une étape de réduction du composé de formule (A) par diverses méthodes bien connues de l’homme du métier conduisant au composé de formule (A’) dans lequel est CH2 et Ri, R2, R3, R4, Rs, R6, Rs, Y, — et sont tels que définis ci- dessus pour les composés de formule (I). 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, R6, Rs, Y, - and are as defined above for the compounds of formula (I).
[0182] Dans une première étape, le nicotinamide de formule E est couplé au ribose tétraacétate de formule D par une réaction de couplage en présence d’un acide de Lewis, conduisant au composé de formule A-1 : 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:
AeO OAc Actf ¾¾: AeO OAc Actf ¾¾:
D E A4 D E A4
[0183] Dans une seconde étape, un traitement ammoniacal du composé de formule A-1 est réalisé, conduisant au composé de formule l-A : In a second step, an ammoniacal treatment of the compound of formula A-1 is carried out, resulting in the compound of formula lA:
[0184] Dans une troisième étape, la mono-phosphorylation du composé de formule I- A, en présence de chlorure de phosphoryle et d’un phosphate de trialkyle, conduit au phosphorodichloridate de formule l-A’ : 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 phosphorodichloridate of formula I-A ′:
I-A I-A’ I-A I-A ’
[0185] Dans une quatrième étape, le phosphorodichloridate de formule B est hydrolysé pour conduire au composé de formule l-C : In a fourth step, the phosphorodichloridate of formula B is hydrolyzed to yield the compound of formula IC:
[0186] Dans un mode de réalisation, une étape de réduction du composé de formule l-A est réalisée, conduisant au composé de formule l-E de formule ci-dessous : In one embodiment, a step of reducing the compound of formula lA is carried out, resulting in the compound of formula lE of formula below:
[0187] Le composé de formule l-E est ensuite mono-phosphorylé comme décrit à la quatrième étape et hydrolysé pour conduire au composé de formule l-G. 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.
[0188] Selon un mode de réalisation, les composés de formule (I) sont sélectionnés parmi les composés du tableau ci-dessous : According to one embodiment, the compounds of formula (I) are selected from the compounds of the table below:
[0189] [Tableau 1] [0189] [Table 1]
[0190] Dans un mode de réalisation préféré, les composés de l’invention sont les composés du tableau ci-dessus ou un sel et/ou solvaté pharmaceutiquement acceptable de ceux-ci. [0190] In a preferred embodiment, the compounds of the invention are the compounds of the table above or a pharmaceutically acceptable salt and / or solvate thereof.
FIGURES FIGURES
[0191 ] [Fig. 1 ] est un graphique montrant l’évolution de la moyenne du poids des souris en fonction des traitements. [0191] [Fig. 1] is a graph showing the change in the average weight of the mice as a function of the treatments.
[0192] [Fig. 2] est un graphique montrant l’évolution de la moyenne du score clinique en fonction des traitements. [0192] [Fig. 2] is a graph showing the evolution of the mean clinical score according to the treatments.
[0193] [Fig. 3] est un graphique montrant l’évolution de la moyenne de l’épaisseur de la patte des souris en fonction des traitements. [0193] [Fig. 3] is a graph showing the change in the average paw thickness of mice as a function of treatments.
[0194] [Fig. 4] montre des photographies des pattes de souris traitées de chaque groupe de traitement. [0194] [Fig. 4] shows photographs of the paws of treated mice from each treatment group.
EXEMPLE EXAMPLE
[0195] Dans la suite de la présente description, les exemples sont fournis à titre illustratif de la présente invention et ne visent en aucun cas à en limiter la portée. 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.
[0196] L’efficacité de l’utilisation de NMN selon l’invention a été évaluée chez des souris dans un modèle de polyarthrite rhumatoïde. Brièvement, des souris femelles C57BL6/J âgées de huit semaines, pesant entre 18-20g au jour 0 des expériences, ont été réparties en quatre groupes comprenant chacun dix souris : (i) un groupe contrôle dans lequel les souris sont traitées avec le véhicule c’est-à-dire une solution de NaCI à 0,9% (10 mL/kg) noté « Véhicule » ; (ii) un groupe de souris traitées au sérum K/BxN (10 mL/kg) noté « KBxN » ; (iii) un groupe de souris traitées au sérum K/BxN + dexaméthasone (1 mg/kg) noté « KBxN + dexaméthasone » ; et (iv) un groupe de souris traitées au sérum K/BxN + NMN (185 mg/kg) noté « KBxN + NMN ». The effectiveness of the use of NMN according to the invention was evaluated in mice in a model of rheumatoid arthritis. Briefly, eight week old female C57BL6 / J mice weighing between 18-20g on day 0 of the experiments, were divided into four groups each comprising ten mice: (i) a control group in which the mice are treated with the vehicle, that is to say a 0.9% NaCl solution (10 mL / kg) noted " Vehicle ”; (ii) a group of mice treated with K / BxN serum (10 mL / kg) denoted “KBxN”; (iii) a group of mice treated with serum K / BxN + dexamethasone (1 mg / kg) denoted “KBxN + dexamethasone”; and (iv) a group of mice treated with K / BxN + NMN serum (185 mg / kg) denoted “KBxN + NMN”.
[0197] Le sérum K/BxN est un sérum obtenu à partir de souris génétiquement modifiées utilisées comme modèle de polyarthrite rhumatoïde. L’administration de ce sérum permet d’induire une inflammation chronique des articulations chez les souris afin de mimer une polyarthrite rhumatoïde. La dexaméthasone est un dérivé de la cortisone, un traitement classiquement utilisé pour lutter contre les poussées de polyarthrite rhumatoïde. Le NMN est utilisé ici sous forme de zwitterion. Le sérum KBxN et le NMN sont administrés aux souris par voie intrapéritonéale. La dexaméthasone est administrée par voie sous-cutanée. [0197] The K / BxN serum is a serum obtained from genetically modified mice used as a model of rheumatoid arthritis. Administration of this serum induces chronic inflammation of the joints in mice to mimic rheumatoid arthritis. Dexamethasone is a derivative of cortisone, a treatment traditionally used to fight against flare-ups of rheumatoid arthritis. NMN is used here in the form of a zwitterion. KBxN serum and NMN are administered to mice intraperitoneally. Dexamethasone is administered subcutaneously.
[0198] Les souris sont traitées pendant 9 jours selon les conditions mentionnées ci- dessus. Des photos des pattes des souris sont prises au 6ème jour de traitement. Le sang des souris est prélevé aux 6ème et I0ème jours de traitement. Les tissus sont prélevés au I0ème jour de traitement pour analyse histologique, soit le lendemain de l’arrêt des traitements. Le score clinique et le poids des souris sont mesurés quotidiennement. Le score clinique est établi en mesurant l’épaisseur de chacune des pattes avant et arrière de l’animal, et en additionnant le score associé selon le tableau 1 suivant : The mice are treated for 9 days according to the conditions mentioned above. Mice paws Photos are taken on the 6th day of treatment. The blood of the mice is taken on the 6 th and 10 th days of treatment. Tissues were collected at I0 th day of treatment for histological analysis, the day after stopping treatment. The clinical score and the weight of the mice are measured daily. The clinical score is established by measuring the thickness of each of the animal's front and hind legs, and by adding the associated score according to Table 1 below:
[0199] [Tableau 1] [0200] L’analyse statistique des résultats a été faite avec la méthode ANOVA à deux facteurs combinée au test de comparaisons multiples de Dunnett. La significativité des valeurs sont indiquées comme indiqué dans le tableau 2 : [0199] [Table 1] The statistical analysis of the results was carried out with the two-factor ANOVA method combined with Dunnett's multiple comparison test. The significance of the values are indicated as shown in Table 2:
[0201] [Tableau 2] [0201] [Table 2]
[0202] Comme on peut le voir sur la figure 1 , les souris du groupe contrôle n’ont pas perdu de poids lors de la durée de l’expérience. En revanche, l’administration du sérum K/BxN induit une perte de poids significative dans les trois groupes traités, indiquant une souffrance de l’animal liée au traitement. L’administration de dexaméthasone induit une perte de poids supplémentaire et significative par rapport au groupe traité par le KBxN seul ainsi qu’au groupe « KBxN + NMN ». Ces observations sont attendues et valident le modèle expérimental. En revanche, le NMN n’induit pas de perte de poids significative par rapport au groupe traité « KBxN ». Par conséquent, le NMN est bien toléré et plus précisément, le NMN est mieux toléré que la dexaméthasone. [0202] As can be seen in Figure 1, the mice in the control group did not lose weight during the duration of the experiment. In contrast, administration of K / BxN serum induced significant weight loss in the three treated groups, indicating treatment-related distress in the animal. The administration of dexamethasone induces an additional and significant weight loss compared to the group treated with KBxN alone as well as to the "KBxN + NMN" group. These observations are expected and validate the experimental model. In contrast, NMN did not induce significant weight loss compared to the "KBxN" treated group. Therefore, NMN is well tolerated and more specifically, NMN is better tolerated than dexamethasone.
[0203] La figure 2 montre l’évolution du score clinique parmi les différents groupes de souris. Comme on peut l’observer sur cette figure, la moyenne du score clinique des souris du groupe contrôle est à zéro : le véhicule n’induit donc aucune inflammation de l’articulation. Le traitement des souris à la dexaméthasone ramène le score clinique à des valeurs proches de celles du groupe contrôle. En revanche, le score clinique des souris traitées par le KBxN augmente jusqu’au 6ème jour à partir duquel il atteint un plateau, ce qui indique une souffrance et une forte inflammation chez la souris. Le traitement par le NMN permet de réduire le score clinique de manière significative dès le 5ème jour. La réduction du score clinique s’accentue à compter du 8ème jour de traitement. Par conséquent, l’administration de NMN permet de réduire de manière significative l’inflammation des articulations dans ce modèle de polyarthrite rhumatoïde. FIG. 2 shows the evolution of the clinical score among the different groups of mice. As can be seen in this figure, the mean clinical score of the mice in the control group is zero: the vehicle therefore does not induce any inflammation of the joint. Treatment of the mice with dexamethasone brings the clinical score back to values close to those of the control group. On the other hand, the clinical score of mice treated with KBxN increases until the 6 th day after which it reaches a plateau, which indicates distress and severe inflammation in mice. Treatment with NMN makes it possible to reduce the clinical score significantly from the 5 th day. The reduction in the clinical score is increasing from 8 th day of treatment. Therefore, the administration of NMN significantly reduces the inflammation of the joints in this model of rheumatoid arthritis.
[0204] Comme le montre la figure 3, l’administration de KBxN induit le gonflement des pattes des souris, conformément au modèle d’arthrite. Le traitement à la dexaméthasone permet de réduire significativement le gonflement de l’articulation de la cheville des souris. De même, le traitement au NMN permet de réduire le gonflement de la cheville de manière significative dès le 5ème jour, indiquant ainsi que le NMN permet de réduire l’inflammation de l’articulation induite par le sérum K/BxN. [0204] As shown in Figure 3, administration of KBxN induces swelling in the legs of mice, according to the arthritis model. Treatment with dexamethasone significantly reduces the swelling of the ankle joint in mice. Likewise, the NMN treatment makes it possible to reduce the swelling of the ankle significantly from the 5 th day, thus indicating that the NMN makes it possible to reduce the inflammation of the joint induced by the K / BxN serum.
[0205] Ces observations sont validées par les photographies des pattes des souris montrées à la figure 4 et prises à jour 6 sur lesquelles on peut voir que la patte de la souris traitée au K/BxN est très gonflée par rapport à la souris du groupe contrôle, signe d’une forte inflammation des articulations. En revanche, le traitement à la dexaméthasone et au NMN permet de réduire de manière importante le gonflement de la patte, et par conséquent l’inflammation de l’articulation. Plus précisément, comme le montre les photographies de la figure 4, la patte de la souris traitée par la dexaméthasone est beaucoup plus fine que celle de la souris traitée par le véhicule, ce qui est signe d’un amaigrissement important de la souris. Bien qu’efficace, la dexaméthasone induit une souffrance chez la souris par ses effets secondaires. A l’inverse, la patte de la souris traitée par le NMN a un volume similaire à celui de la souris traitée par le véhicule : le NMN est donc efficace pour traiter l’inflammation induite par l’injection de sérum K/BxN et beaucoup mieux toléré par les souris que le traitement conventionnel à la dexaméthasone. These observations are validated by the photographs of the paws of the mice shown in FIG. 4 and taken on day 6 on which we can see that the paw of the mouse treated with K / BxN is very swollen compared to the mouse in the group control, sign of strong inflammation of the joints. In contrast, treatment with dexamethasone and NMN significantly reduces the swelling of the paw, and consequently the inflammation of the joint. More specifically, as shown in the photographs in Figure 4, the paw of the mouse treated with dexamethasone is much thinner than that of the mouse treated with the vehicle, which is a sign of significant weight loss in the mouse. Although effective, dexamethasone causes suffering in mice through its side effects. Conversely, the paw of the mouse treated with NMN has a volume similar to that of the mouse treated with the vehicle: the NMN is therefore effective in treating the inflammation induced by the injection of K / BxN serum and much better tolerated by mice than conventional dexamethasone treatment.
[0206] L’administration de NMN permet donc de réduire l’inflammation observée dans un modèle de polyarthrite rhumatoïde de manière significative, sans pour autant induire les effets secondaires de la dexaméthasone, dérivé de la cortisone classiquement administré dans le cadre du traitement de la polyarthrite rhumatoïde. [0206] The administration of NMN therefore makes it possible to reduce the inflammation observed in a rheumatoid arthritis model significantly, without however inducing the side effects of dexamethasone, a cortisone derivative conventionally administered as part of the treatment of rheumatoid arthritis. rheumatoid arthritis.
[0207] Le NMN, ses dérivés pharmaceutiquement acceptables ou ses sels pharmaceutiquement acceptables, ainsi que les compositions les comprenant peuvent donc être utilisés avec succès et sécurité pour traiter et prévenir la polyarthrite rhumatoïde. La présente invention permet donc de trouver une alternative thérapeutique aux traitements conventionnels de la polyarthrite rhumatoïde, ou à tout le moins de proposer un complément thérapeutique aux traitements conventionnels afin de réduire leur fréquence d’utilisation et leur dosage. Du fait de l’innocuité du NMN, de ses dérivés pharmaceutiquement acceptable ou de ses sels pharmaceutiquement acceptables, ainsi que des compositions le comprenant, la présente invention permet de traiter et/ou prévenir la polyarhtrite rhumatoïde sans induire les effets secondaires provoqués par les traitements conventionnels. [0207] NMN, its pharmaceutically acceptable derivatives or its pharmaceutically acceptable salts, as well as the compositions comprising them can therefore be used successfully and safely to treat and prevent rheumatoid arthritis. The present invention therefore makes it possible to find a therapeutic alternative to conventional treatments for rheumatoid arthritis, or at the very least to provide a therapeutic complement to conventional treatments in order to reduce their frequency of use and their dosage. Because of the harmlessness of NMN, of its pharmaceutically acceptable derivatives or of its pharmaceutically acceptable salts, as well as of the compositions comprising it, the present invention makes it possible to treat and / or prevent rheumatoid arthritis without inducing the side effects caused by the treatments. conventional.

Claims

Revendications Claims
[Revendication 1] Nicotinamide mononucléotide (NMN), un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, pour son utilisation dans la prévention et/ou le traitement de la polyarthrite rhumatoïde. [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 rheumatoid arthritis.
[Revendication 2] Nicotinamide mononucléotide (NMN), un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, pour son utilisation selon la revendication 1 dans laquelle le dérivé pharmaceutiquement acceptable du NMN est le dihydronicotinamide mononucléotide (noté NMN-FI), le composé de formule (I) : ou un de ses stéréoisomères, un de ses sels, un de ses hydrates, un de ses solvatés ou un de ses cristaux pharmaceutiquement acceptable de celui-ci, dans lequel : [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 pharmaceutically acceptable derivative of NMN is dihydronicotinamide mononucleotide (noted NMN-FI), the compound of formula (I): 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 est choisi parmi O, CH2, S, Se, CHF, CF2 et C=CFl2; X is selected from O, CH 2 , S, Se, CHF, CF 2 and C = CFl 2 ;
Ri est choisi parmi H, azido, cyano, alkyle en (C-i-Cs), thio-alkyle en (C-i-Cs), hétéroalkyle en (C-i-Cs) et OR ; dans lequel R est choisi parmi Fl et alkyle en (C-i-Cs) ; R 1 is selected from H, azido, cyano, (C-i-Cs) alkyl, (C-i-Cs) thio-alkyl, (C-i-Cs) heteroalkyl and OR; wherein R is selected from F1 and (C1-C8) alkyl;
R2, R3, R4 et R5 sont choisis indépendamment l’un de l’autre parmi Fl, halogène, azido, cyano, hydroxyle, alkyle en (C1-C12), thio-alkyle en (C1-C12), hétéroalkyle en (C1-C12), haloalkyle en (C1-C12) et OR ; dans lequel R est choisi parmi Fl, alkyle en (C1-C12), C(0)(Ci-Ci2)alkyle, C(0)NH(Ci-Ci2)alkyle, C(0)0(Ci-Ci2)alkyle, C(0)aryle, C(0)(Ci-Ci2)alkyle aryle, C(0)NFI(Ci-Ci2)alkyle aryle, C(0)0(Ci-Ci2)alkyle aryle et C(0)CFIRAANFI2 ; dans lequel RAA est une chaîne latérale choisie parmi un acide aminé protéinogène ; R2, R3, R4 and R5 are independently selected from each other from Fl, halogen, azido, cyano, hydroxy, alkyl (C 1 -C 12) alkyl thio (C 1 -C 12), heteroalkyl, (C 1 -C 12) haloalkyl, (C 1 -C 12) and OR; wherein R is selected from F1, (C 1 -C 12 ) alkyl, C (0) (Ci-Ci 2 ) alkyl, C (0) NH (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) CFIRAANFI2; wherein RAA is a side chain selected from a proteinogenic amino acid;
Re est choisi parmi Fl, azido, cyano, (C-i-Cs) alkyle, (C-i-Cs) thio-alkyle, (C-i-Cs) hétéroalkyle et OR ; dans lequel R est choisi parmi Fl et (C-i-Cs) alkyle; R7 est choisi parmi P(0)R9RIO et P(S)R9RIO ; dans lequel Re is selected from F1, azido, cyano, (Ci-Cs) alkyl, (Ci-Cs) thio-alkyl, (Ci-Cs) heteroalkyl and OR; in which R is selected from F1 and (Ci-Cs) alkyl; R7 is selected from P (0) R9RIO and P (S) R9RIO; in which
R9 et R10 sont choisis indépendamment l’un de l’autre parmi OH, ORn , NHR13, NR13R14, un alkyle en (C-i-Cs), un alcényle en (C2-C8), un alcynyl en (C2-C8), un cycloalkyl en (C3-C10), un aryle en (C5-C12), (Ci-Cs)alkyle aryle, (Ci-Cs)aryle alkyle, (C-i-Cs) heteroalkyle, (Ci-Cs) heterocycloalkyle, un heteroaryle et N HCH RARA C(0)RI2 ; dans lequel : R9 and R 10 are independently selected from OH, ORn, NHR 13 , NR13R14, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl , cycloalkyl (C3-C 10) aryl, (C5-C 12), (Ci-Cs) alkyl, aryl, (Ci-Cs) alkyl aryl, (Ci-Cs) heteroalkyl, (Ci-Cs) heterocycloalkyl , a heteroaryl and N HCH RARA C (0) RI2; in which :
R11 est choisi parmi un groupe (C1-C10) alkyle, (C3-C10) cycloalkyle, (C5-C18) aryle, (C1-C10) alkylaryle, (C5-C12) aryle substitué, (C1-C10) heteroalkyle, (C3-C10) heterocycloalkyle, (C1-C10 haloalkyle, un heteroaryle, -(CH2)nC(0)(Ci-Ci5)alkyle, - (CH2)n0C(0)(Ci-Ci5)alkyle, -(CH2)n0C(0)0(Ci-Ci5)alkyle, -(CH2)nSC(0)(Ci- Ci5)alkyle, -(CH2)nC(0)0(Ci-Ci5)alkyle and -(CH2)nC(0)0(Ci-Ci5)alkyle aryle; dans lesquels n est un entier choisi de 1 à 8; P(0)(0H)0P(0)(0H)2; halogène, nitro, cyano, C-i-Ce alkoxy, C-i-Ce haloalkoxy, -N(Rna)2, C-i-Ce acylamino, -CORnb, -O CORnb ; NHS02(CI-C6 alkyl), - S02N(Rna)2 SO2 dans lequel chacun de Rna est indépendamment choisi parmi H et un (C-i-Ce) alkyle et Rub est indépendamment choisi parmi OH, O-i-Ob alkoxy, NH2, N H(CI -C6 alkyle) ou N(Ci-C6alkyle)2 ; R 11 is chosen from a group (C 1 -C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C5-C 18 ) aryl, (C1-C10) alkylaryl, (C5-C12) substituted aryl, (C1- C10) heteroalkyl, (C3-C10) heterocycloalkyl, (C 1 -C 10 haloalkyl, a heteroaryl, - (CH 2 ) nC (0) (C1-C10) alkyl, - (CH 2 ) n0C (0) (Ci- Ci 5 ) alkyl, - (CH 2 ) n 0C (0) 0 (Ci-Ci 5 ) alkyl, - (CH 2 ) n SC (0) (Ci-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; where n is an integer selected from 1 to 8; P (0) (0H) 0P (0) (0H) 2 ; halogen, nitro, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, -N (Rn a ) 2, C1-Ce acylamino, -CORnb, -O CORnb; NHS02 (CI-C6 alkyl), - SO2N (Rn a ) 2 SO2 in which each of Rn a is independently selected from H and a (C1-C6) alkyl and Rub is independently selected from OH, Oi-Ob alkoxy, NH2, NH (CI -C6 alkyl) or N (C1-C6alkyl) 2;
R12 est choisi parmi H, C1-C10 alkyle, C2-C8 alcényle, C2-C8 alcynyle, C1-C10 haloalkyle, C3-C10 cycloalkyle, C3-C10 heterocycloalkyle, C5-C18 aryle, C1-C4 alkylaryle and C5-C12 heteroaryle; dans lesquels lesdits groupes aryle ou heteroaryle sont optionnellement substitué parmi un ou deux groupes choisi parmi un halogène, trifluoromethyl, O-i-Ob alkyle, O-i-Ob alkoxy et cyano; et R12 is selected from H, C1-C10 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C5-C18 aryl, C1-C4 alkylaryl and C5-C12 heteroaryl ; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, O-i-Ob alkyl, O-i-Ob alkoxy and cyano; and
RA et RA’ sont indépendamment choisi parmi H, un (C1-C10) alkyle, (C2-C10) alcényle, (C2-C10) alcynyle, (C3-C10) cycloalkyle, (C1-C10) thio-alkyle, (C1-C10) hydroxylalkyle, (C1-C10) alkylaryle and (C5-C12) aryle, (C3-C10) heterocycloalkyle, un heteroaryle, -(CH2)3NHC(=NH)NH2, (1 H-indol-3-yl)methyl, (1 H-imidazol-4-yl)methyl et une chaîne latérale choisie parmi un acide aminé protéinogène ou un acide aminé non protéinogène; dans lesquels lesdits groupes aryle sont optionnellement substitué avec un groupe choisi parmi un hydroxyle, (C1-C10) alkyl, (C-i-Ce) alkoxy, un halogène, un nitro et un cyano; ou R9 et R10 forment ensemble avec les atomes de phosphore auxquels ils sont attaché un cycle à 6 membres dans lequel -R9-R10- représente -CH2-CH2-CHR-; dans lequel R est choisi parmi H, un groupe (C5-C6) aryle et (C5-C6) heteroaryle, dans lequel lesdits groupes aryle ou heteroaryle sont optionnellement substitués par un halogène, trifluoromethyl, un C1-C6 alkyle, un (C1-C6) alkoxy et cyano; ou RA and RA 'are independently selected from H, a (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, (C1-C10) thio-alkyl, (C1 -C10) hydroxylalkyl, (C1-C10) alkylaryl and (C5-C12) aryl, (C3-C10) heterocycloalkyl, a heteroaryl, - (CH2) 3NHC (= NH) NH2, (1 H-indol-3-yl) methyl, (1 H-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, (C1-C10) alkyl, (C1-C6) alkoxy, halogen, nitro and cyano; or R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R 10 - represents -CH 2 -CH 2 -CHR-; wherein R is selected from H, (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C 1 -C6 alkyl , a (C 1 -C6) alkoxy and cyano; or
R9 et R10 forment ensemble avec les atomes de phosphore auxquels ils sont attaché un cycle à 6 membres dans lequel -R9-R10- représente -O-CH2-CH2-CHR-O-; dans lequel R est choisi parmi H, un groupe (C5-C6) aryle et (C5-C6) heteroaryle, dans lequel lesdits groupes aryle ou heteroaryle sont optionnellement substitués par un halogène, trifluoromethyl, un (C1-C6) alkyle, un (C1-C6) alkoxy et cyano; R 9 and R 10 together with the phosphorus atoms to which they are attached form a 6-membered ring in which -R9-R 10 - represents -O-CH 2 -CH 2 -CHR-O-; in which R is selected from H, a (C 5 -C 6 ) aryl and (C 5 -C 6 ) heteroaryl group, in which said aryl or heteroaryl groups are optionally substituted by a halogen, trifluoromethyl, a (C 1 -C6) ) alkyl, a (C 1 -C6) alkoxy and cyano;
R8 est choisi parmi H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N3 et halogène ; dans lequel R13 et Ru sont choisis indépendamment l’un de l’autre parmi H, (C1-C8) alkyle, (C-i-Cs) alkyle aryle, et -CRBRC-C(0)-ORD dans lequel RB et Rc sont indépendamment un atome d'hydrogène, un (Oi-Ob) alkyle, un (Oi-Ob) alkoxy, benzyle, indolyle ou imidazolyle, où le (Oi-Ob) alkyle et le (Oi-Ob) alkoxy peuvent être éventuellement et indépendamment l’un de l’autre substitué par un ou plusieurs des groupes halogène, amino, amido, guanidyle, hydroxyle, thiol ou carboxyle, et le groupe benzyle est éventuellement substitué par un ou plusieurs des groupes halogène ou hydroxyle, ou RB et Reforment ensemble avec l'atome de carbone auquel ils sont attachés un groupe cycloalkyle en C3-C6 éventuellement substitué par un ou plusieurs halogènes, amino, amido, guanidyle, hydroxyle, thiol et carboxyle et RD est un hydrogène, un (C1-C6) alkyle, un (C2-C6) alcényle, un (C2-C6) alcynyle ou un (C3- Ce) cycloalkyle ; R 8 is selected from H, OR, NHR13, NRisRu, NH-NHR13, SH, CN, N 3 and halogen; wherein R 13 and Ru are independently selected from one another from H, (C1-C8) alkyl, (C1-Cs) alkyl aryl, and -CRBRC-C (0) -ORD wherein RB and Rc are independently a hydrogen atom, an (Oi-Ob) alkyl, an (Oi-Ob) alkoxy, benzyl, indolyl or imidazolyl, where the (Oi-Ob) alkyl and the (Oi-Ob) alkoxy can be optionally and independently each other substituted with one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol or carboxyl groups, and the benzyl group is optionally substituted with one or more of halogen or hydroxyl, or RB and Reform together with the carbon atom to which they are attached a C 3 -C 6 cycloalkyl group optionally substituted by one or more halogens, amino, amido, guanidyl, hydroxyl, thiol and carboxyl and RD is a hydrogen, a (C 1 -C6 ) alkyl, a (C 2 -C6) alkenyl, a (C 2 -C6) alkynyl or a (C3-Ce) cycloalkyl;
Y est choisi parmi CH, CH2, C(CH3)2 et CCH3 ; rrr représente une simple ou une double liaison selon Y ; et représente l'anomère alpha ou bêta selon la position de Ri ou un de ses stéréoisomères, un de ses sels, un de ses hydrates, un de ses solvatés ou un de ses cristaux, et leurs combinaisons. Y is selected from CH, CH 2 , C (CH3) 2 and CCH3; r rr represents a single or a double bond along Y; and 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, and combinations thereof.
[Revendication 3] Nicotinamide mononucléotide pour son utilisation selon la revendication 1 ou 2 dans une quantité comprise entre 0.01 mg/kg/jour et 1000 mg/kg/jour, de préférence 1 mg/kg/jour et 100 mg/kg/jour, de manière davantage préférée entre 5 mg/kg/jour et 50 mg/kg/jour, de manière encore plus préférée entre 10 mg/kg/jour et 20 mg/kg/jour. [Claim 3] Nicotinamide mononucleotide for its use according to claim 1 or 2 in an amount between 0.01 mg / kg / day and 1000 mg / kg / day, preferably 1 mg / kg / day and 100 mg / kg / day, more preferably between 5 mg / kg / day and 50 mg / kg / day, even more preferably between 10 mg / kg / day and 20 mg / kg / day.
[Revendication 4] Nicotinamide mononucléotide pour son utilisation selon l’une des revendications précédentes administré par voie orale, oculaire, sublinguale, intraveineuse, intraartérielle, intramusculaire, intra-articulaire, sous-cutanée, transcutanée, vaginale, péridurale, intravésicale, rectale ou inhalation. [Claim 4] Nicotinamide mononucleotide for its use according to one of the preceding claims administered orally, ocular, sublingually, intravenously, intraarterially, intramuscularly, intra-articular, subcutaneous, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation .
[Revendication 5] Nicotinamide mononucléotide pour son utilisation selon l’une des revendications précédentes en combinaison avec au moins un autre agent thérapeutique. [Claim 5] Nicotinamide mononucleotide for its use according to any of the preceding claims in combination with at least one other therapeutic agent.
[Revendication 6] Nicotinamide mononucléotide pour son utilisation selon la revendication 5 dans lequel l’au moins un agent thérapeutique est un antalgique, un anti-inflammatoire non stéroïdien, la cortisone, un dérivé de la cortisone, un immunosuppresseur, un immunomodulateur, un inhibiteur de lymphocytes T, un inhibiteur de lymphocytes B, un antipaludique de synthèse, un anti-TNF, un inhibiteur enzymatique des Janus kinases, un anti-interleukine et leurs combinaisons. [Claim 6] Nicotinamide mononucleotide for its use according to claim 5 wherein the at least one therapeutic agent is an analgesic, a nonsteroidal anti-inflammatory drug, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, an inhibitor lymphocytes, an inhibitor of B lymphocytes, a synthetic antimalarial, an anti-TNF, an enzymatic inhibitor of Janus kinases, an anti-interleukin and their combinations.
[Revendication 7] Nicotinamide mononucléotide pour son utilisation selon la revendication 6 dans lequel l’au moins un agent thérapeutique est un immunosuppresseur choisi parmi le methotrexate et la ciclosporine, de préférence le methotrexate. [Claim 7] Nicotinamide mononucleotide for its use according to claim 6 wherein the at least one therapeutic agent is an immunosuppressant selected from methotrexate and ciclosporin, preferably methotrexate.
[Revendication 8] Composition comprenant du nicotinamide mononucléotide, un de ses dérivés pharmaceutiquement acceptables ou un de ses sels pharmaceutiquement acceptables, et au moins un excipient pharmaceutiquement acceptable pour son utilisation selon l’une des revendications 1 à 7. [Claim 8] 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 7.
[Revendication 9] Composition pour son utilisation selon la revendication 8 comprenant en outre au moins un agent thérapeutique supplémentaire. [Claim 9] A composition for its use according to claim 8 further comprising at least one additional therapeutic agent.
[Revendication 10] Composition pour son utilisation selon la revendication 9 dans laquelle ledit au moins un agent thérapeutique supplémentaire est choisi parmi un antalgique, un anti-inflammatoire non stéroïdien, la cortisone, un dérivé de la cortisone, un immunosuppresseur, un immunomodulateur, un inhibiteur de lymphocytes T, un inhibiteur de lymphocytes B, un antipaludique de synthèse, un anti-TNF, un inhibiteur enzymatique des Janus kinases, un anti-interleukine et leurs combinaisons. [Claim 10] A composition for its use according to claim 9 wherein said at least one additional therapeutic agent is selected from an analgesic, a nonsteroidal anti-inflammatory drug, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, a inhibitor T lymphocytes, a B lymphocyte inhibitor, a synthetic antimalarial, an anti-TNF, an enzyme inhibitor of Janus kinases, an anti-interleukin and their combinations.
[Revendication 11] Composition pour son utilisation selon la revendication 10 se présentant sous une forme unitaire à dose fixe. [Claim 11] A composition for its use according to claim 10 in a unitary fixed dose form.
[Revendication 12] Composition pour son utilisation selon l’une des revendications 8 à 11 caractérisée en ce qu’elle est administrée sous forme orale ou injectable.[Claim 12] Composition for its use according to one of claims 8 to 11, characterized in that it is administered in oral or injectable form.
[Revendication 13] Composition pour son utilisation selon la revendication 12 caractérisée en ce qu’elle est administrée sous forme d’un comprimé sublingual ou d’une gélule gastrorésistante. [Claim 13] A composition for its use according to claim 12 characterized in that it is administered in the form of a sublingual tablet or an enteric capsule.
EP20789620.0A 2019-10-18 2020-10-15 Use of nicotinamide mononucleotide (nmn) for the prevention and/or treatment of rheumatoid arthritis, and corresponding compositions Withdrawn EP4045058A1 (en)

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