EP4045058A1 - Verwendung von nikotinamid-mononukleotid (nmn) zur prävention und/oder behandlung von rheumatoider arthritis und entsprechende zusammensetzungen - Google Patents

Verwendung von nikotinamid-mononukleotid (nmn) zur prävention und/oder behandlung von rheumatoider arthritis und entsprechende zusammensetzungen

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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
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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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EP20789620.0A
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English (en)
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/de
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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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EP20789620.0A 2019-10-18 2020-10-15 Verwendung von nikotinamid-mononukleotid (nmn) zur prävention und/oder behandlung von rheumatoider arthritis und entsprechende zusammensetzungen Withdrawn EP4045058A1 (de)

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FR1911696A FR3102058A1 (fr) 2019-10-18 2019-10-18 Utilisation de NMN pour la prévention et/ou le traitement de la polyarthrite rhumatoïde et compositions correspondantes
PCT/EP2020/079014 WO2021074284A1 (fr) 2019-10-18 2020-10-15 Utilisation de nictotinamide mononucléotide (nmn) pour la prevention et/ou le traitement de la polyarthrite rhumatoïde et compositions correspondantes

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