EP4065129A1 - Utilisation de composés pour la prévention et/ou le traitement de la spondylarthrite ankylosante et compositions correspondantes - Google Patents

Utilisation de composés pour la prévention et/ou le traitement de la spondylarthrite ankylosante et compositions correspondantes

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Publication number
EP4065129A1
EP4065129A1 EP20811425.6A EP20811425A EP4065129A1 EP 4065129 A1 EP4065129 A1 EP 4065129A1 EP 20811425 A EP20811425 A EP 20811425A EP 4065129 A1 EP4065129 A1 EP 4065129A1
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EP
European Patent Office
Prior art keywords
alkyl
compound
aryl
formula
chosen
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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EP20811425.6A
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German (de)
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 EP4065129A1 publication Critical patent/EP4065129A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0368—Animal model for inflammation

Definitions

  • the present invention relates to the use of compounds of formula (I) or (Ia), as well as compositions comprising them, for the treatment and / or prevention of ankylosing spondylitis.
  • a joint brings together in particular 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.
  • Ankylosing spondylitis is an inflammatory rheumatism that most often affects the spine, pelvis and sacrum, characterizing a form of the so-called “axial" disease.
  • the so-called “peripheral” form affects joints other than the spine.
  • Ankylosing spondylitis can also affect the places where tendons and muscles are inserted in the bones, including the Achilles tendon, but also other organs such as the eye, heart and intestines.
  • Ankylosing spondylitis is strongly associated with the presence of the HLA B27 marker.
  • Ankylosing spondylitis is not rheumatoid arthritis: ankylosing spondylitis mainly occurs in young patients while rheumatoid arthritis and chronic rheumatism mainly affects older patients, the treatments are also different.
  • ankylosing spondylitis stiffens and deforms the joints, especially the spine. The patient feels a stiffening of the spine and the joints, and a more or less long period of "derusting" of the body is necessary for the patient in the morning in order to be able to move again. Inflammation of the spine can, as in the case of the sacroiliac joint, progress to ankylosis.
  • Ankylosis is an ossification of the articular involvement which welds the different bony parts forming the joint. This ankylosis causes a loss of mobility and a significant functional impairment.
  • One of the risks for the patient is that ankylosis resulting from bone formation develops in an abnormal posture of the spine. At present, there is no curative treatment and the pathophysiological mechanisms remain unknown.
  • SUBSTITUTE SHEET (RULE 26) Ankylosing spondylitis is a disease progressing by inflammatory flares during which the inflammation is particularly strong spaced by so-called periods of remission during which the patient can lead a normal life.
  • Symptomatic treatments for spondyloarthritis primarily include the administration of analgesics to reduce pain, nonsteroidal anti-inflammatory drugs (NSAIDs) as well as cortisone or its derivatives to reduce inflammation.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • cortisone or its derivatives to reduce inflammation.
  • chronic administration of these drugs damages the stomach, liver and kidneys, among other things.
  • cortisone derivatives induces in particular bone fragility, neuropsychiatric effects, muscle wasting and a reduction in immunity, leaving the patient vulnerable to infections.
  • their effectiveness is reduced over time, requiring increased doses or the use of more aggressive drugs and often causing more side effects such as anti-TNF, methotrexate or sulfasalazine for example.
  • Methotrexate is a cancer medicine used to prevent and reduce the number of flare-ups.
  • 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 drugs, replacing or in conjunction with methotrexate, are used such as inhibitors of TNF (for “Tumor Necrosis Factor”), a protein involved in inflammatory processes.
  • TNF for “Tumor Necrosis Factor”
  • Sulfasalazine an anti-inflammatory drug, is also used to treat some forms of ankylosing spondylitis when taking NSAIDs is not enough.
  • side effects are common and include an upset stomach, rash and mouth sores.
  • methotrexate and sulfasalazine are not effective for the axial forms of ankylosing spondylitis and their effectiveness is limited to the peripheral form.
  • surgery can correct the deformities of the skeleton and the disabling forms of the disease.
  • the present invention relates to a compound of formula (I):
  • R 1 is chosen from F1, azido, cyano, C 1 -C 8 alkyl, C 1 -C 8 thioalkyl, C 1 -C 8 heteroalkyl and OR; wherein R is selected from F1 and C1-C6 alkyl;
  • R Î , RA and Rs are chosen independently of one another from H, halogen, azido, cyano, hydroxyl, C 1 -C 12 alkyl, C 1 -C 12 thioalkyl, heteroalkyl in C 1 -C 1 2 haloalkyie C 1 -C 1 2 and OR; wherein R is selected from H, C1-CM alkyl, C (0) (C Cu) alkyl, C (0) NH (C1-C1 2 ) alkyl, C (0) 0 (C1-Ci 2 ) alkyl, C (0) aryl, C (0) ⁇ Ci-C 12 ) alkyl aryl, C (0) NH (Ci-Ci 2 ) alkyl aryl, C (0) 0 (Ci-Ci 2 ) alkyl aryl and C (0) ) CFIRAANFI 2 ; wherein RAA is a side chain selected from a proteinogenic amino acid;
  • Rg is chosen from F1, azido, cyano, Ci-Cgalkyle, Ci-Cgthio-alkyl, Ci-Cg heteroalkyl and OR; in which R is selected from Fi and C1-Cg alkyl;
  • R 7 is chosen from F1, P (0) RgRio and P (S) RgRio; in which
  • Rg and Rio are chosen independently of one another from OH, ORn, NHR13, NRURM, a C 1 -C 8 alkyl, a C 2 -C 8 alkenyl, a C 2 -C 8 alkynyl, a C cycloalkyl 3 -C1 0 , a Cs-Ci3 ⁇ 4 (Ci-Cg) alkyl aryl, (Ci-Ca) aryl alkyl, (Ci-Cg) heteroalkyl, (Ci-Cg) heterocycloaikyle, a heteroaryl and NHCHR A R A 'C (0) RI 2 ; in which :
  • - Ru is chosen from a C1-C1 0 alkyl group, C 3 -C1 0 cycloalkyl, Cs-Cig aryl, C 1 -C 10 alkylaryl, Cs-Ci 2 substituted aryl, C 1 -C 10 heteroalkyl, C 3 .C1 0 heterocycloaikyl, C 1 -C 10 haloalkyl, a heteroaryl, - ⁇ CH 2 ) C (0) (Ci-Cisjalkyl, - (CH 2 ) n OC (0) (C Ci 5 ) alkyl, - (CH 2 ) n 0C (0) 0 (Ci-Ci S ) alkyl, - ⁇ CH 2 ) n SC (0) (Ci-Ci 5 ) alkyl, (CH 2 ) n C (0) 0 (Ci-Ci5) alkyl and - (CH 2 ) n C (0) 0 (C1
  • SUBSTITUTE SHEET (RULE 26) - R 12 is chosen from H, Ci-Cioalkyl, C 2 -Cg alkenyl, C Î -CS alkynyl, Ci-Cio haloalkyl, C 3 -C 10 cycloalkyl, C 3 .C 10 heterocycloalkyl, C 5 -C 1B aryl, C 1 -C 4 alkylaryl and Cs-Cu heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C 1 -C 6 alkyl, CrC B alkoxy and cyano; and
  • R is selected from H, (C 5 -C 6 ) aryl and (Cs-Cg) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifiuoromethyl, C1-Cs alkyl, C1 -C B alkoxy and cyano; or
  • Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -Rg-Rio- represents “O-CH 2 -CH 2 -CHR-O-; in which R is chosen from H, a (C S -C B ) aryl and (Cs-Ce) heteroaryl group, in which said aryl or heteroaryl groups are optionally substituted by a halogen, trifiuoromethyl, a (Ci-Cs) alkyl, a (Ci-Ce) alkoxy and cyano;
  • Rg is chosen from H, OR, NHR 13 , NR 13 R 14 , NH — NHR 13 , SH, CN, N 3 and halogen; wherein R 13 and R u are independently selected from H, (C1-Cg) alkyl, (C1-Cg) alkyl aryl, and -CR B RC-C (0) -ORD in which R B and R c are independently a hydrogen atom, a (Ci-C 6 ) alkyl, a (Ci-C 6 ) alkoxy, benzyl, indolyl or imidazolyl, where the (CI- C6 ) alkyl and the (Ci- Ce)) alkoxy may be optionally and independently of each other substituted by 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 groups halogen or hydroxyl
  • - Y is chosen from CH, CH 2 , C (CH 3 ) 2 and CCH 3 ;
  • SUBSTITUTE SHEET (RULE 26) or a compound of formula (Ia): or one of its stereoisomers, one of its salts, one of its hydrates, one of its solvates or one of its crystals, in which
  • R'i and R'13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR, wherein R is selected from F1 and a C1-C8 alkyl,
  • R '2, R' i, R '4, R's, R's, R' 10, R 'n R'" are independently selected from Fl, halogen, azido, cyano, hydroxyl, an alkyl -C Ci 2, a thioalkyl C1-C12, a hetero-alkyl CJ-CJ, 2, haloalkyl Ci-Ci 2 and OR wherein R may be selected from H, alkyl Ci-Ci 2, C (0) (Ci-Ci 2 ) alkyl, a C (0) NH (Ci-Ci 2 ) alkyl, a C (0) 0 (Ci-Ci 2 ) alkyl, a C (O) aryl, a C (0 ) (C1-C12 ⁇ aryl, a C (0) NFi (Ci-Ci 2 ) alkyl aryl, a C (0) 0 (Ci-Ci 2 ) alkyl aryl or a group C
  • R'7 and R ' are independently selected from H, OR, NH R, NRR', NH-NHR, SH, CN, N3 and halogen, wherein R and R 'are independently selected from H and (Ci- Cs) alkyl aryl;
  • Y'i and Y '2 are independently selected from CH, CH 2 , C (CH 3 ) 2 or CCH 3 ; - M 'is chosen from H or a suitable counterion; represents a single or double bond depending on Y'i and Y ' 2 ; and ⁇ LLL * - * represents an alpha or beta anomer depending on the position of R'i and R'13; and their combinations.
  • the pharmaceutically acceptable derivative is the compound of formula (I).
  • X represents oxygen
  • Ri and RB each represent, independently of one another, a hydrogen.
  • R 2 , R 1 , R 4 and Rs each independently represent a hydrogen or an OH.
  • Y represents a CH.
  • Y represents a CH 2 .
  • R 7 represents hydrogen.
  • R 7 represents P (0) (0H) 2 - In a variant of the first embodiment,
  • X represents oxygen
  • Ri and R e each independently represents hydrogen; and / or R 2 , R 3 , R 4 and R 5 each independently represents hydrogen or R 2 , R 1 , R and R 5 independently represents OH; and or
  • Y represents CH or CH 2 ;
  • R 7 represents P (0) R s Rio, in which R 9 and Rio are independently selected from OH, ORn, NHR i3 , NR13R14, C1-C 8 alkyl, C 2 -C 3 alkenyl, C 2 -C 8 alkynyl, C 3 .Cio ycloalkySe, C 5 -Ci 2 aryl, Ci-C 8 aryl alkyl, Ci-C 3 alkyl aryl, Ci-Cs heteroalkyl, Ci-Ca heterocycloalkyl, heteroaryl and NHCRARA'C (0) RI 2 .
  • the compound of the invention is chosen from the compounds of formula i-A to l-J:
  • the pharmaceutically acceptable derivative is the compound of formula (Ia).
  • X'I and X'2 each independently represent oxygen.
  • R'7 and R'14 each independently represent an NH 2 .
  • R'I and / or R '13 each independently represent a hydrogen.
  • R'6 and / or R'8 each independently represent a hydrogen.
  • R'2, R'3, R'4, R'5, R'9, R'10, R'11 and R'12 each independently represent hydrogen.
  • R'2, R'3, R'4, R'5, R'9, R'10, R'11 and R'12 each independently represent an OH.
  • U ⁇ and Y '2 each independently represent a CH.
  • U ⁇ and Y'2 each independently represent a CH2.
  • the compound according to the invention is chosen from the compounds of formula la-A to la-l:
  • the compound of formula (I) is alpha-NMIM of formula IF: In a variant of the first preferred embodiment, the compound of formula (I) is IMMN-H of formula 1D or IC.
  • the compound of formula (I) is nicotinamide riboside (denoted NR) of formula lG or lH or dihydronicotinamide riboside (denoted -NR-H) of formula lJ or I-I.
  • the compound of formula (I) is chosen from compound lA, compound lB, compound lC,, compound lD, compound lE, compound lF, compound lG, compound lH, compound ll, compound lJ, preferably compound lC, compound lD or compound lF, and combinations thereof. More preferably, the compound of formula (I) is chosen from compound IB, compound IC, compound ID, compound IF and their combinations.
  • the compound of formula (la) is chosen from compounds of formula la-A to la-1, more preferably from compound of formula la-B, compound of formula la-C, compound of formula la-E, the compound of the formula la-F, the compound of the formula la-H, the compound of the formula la-i and the compound of the formula la-G as well as combinations thereof
  • the compound of formula (I) or the compound of formula (Ia) can be used to prevent or treat the peripheral form of ankylosing spondylitis.
  • the compound of formula (I) or the compound of formula (Ia) can be used to prevent or treat the axial form of ankylosing spondylitis.
  • the compound of formula (I) or the compound of formula (Ia) can be used in an amount 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 compound of formula (I) or the compound of formula (Ia) can be administered orally, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation.
  • the compound of formula (I) or the compound of formula (Ia) can be administered orally.
  • the compound of formula (I) or the compound of formula (Ia) can be administered in the form of a sublingual tablet or an enteric capsule.
  • the compound of formula (I) or the compound of formula (Ia) can be administered intra-articularly.
  • the compound of formula (I) or the compound of formula (Ia) can be used in the treatment and / or prevention of ankylosing spondylitis in mammals, preferably humans.
  • the compound of formula (I) or the compound of formula (Ia) can be used in combination with at least one additional therapeutic agent.
  • the at least one additional therapeutic agent can be an analgesic, a non-steroidal anti-inflammatory drug, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, an anti-TNF, 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, dex ketoprofen, 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 and triamcinolone and their combinations.
  • the immunosuppressant can be chosen from azathioprine, cyclophosphamide, chlorambucii, 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, preferably sulfasalazine.
  • the anti-TNF can be chosen from infliximab, etanercept, adalimumab, certolizumab, golimumab and their combinations.
  • the anti-interleukin can be an anti-interleukin 17.
  • the interleukin 17 inhibitor can be chosen from ixekizumab and secukinumab.
  • the anti-interleukin can be an anti-interleukin 12, preferably ustekinumab.
  • the present invention also relates to a composition
  • a composition comprising a compound of formula (I) as defined in the present application and / or a compound of formula (Ia) as defined in the present application and at least one pharmaceutically acceptable excipient for its use. in the prevention and / or treatment of ankylosing spondylitis.
  • the compound of formula (I) is chosen from compound lA, compound lB, compound lC,, compound lD, compound lE, compound lF, compound lG, compound lH, compound 1- 1, compound lJ, preferably compound lC, compound lD or compound lF, and combinations thereof. More preferably, the compound of formula (I) is chosen from compound IB, compound IC, compound ID, compound IF and their combinations.
  • the compound of formula (la) is chosen from compounds of formula la-A to la-1, more preferably from compound of formula la-B, compound of formula la-C, compound of formula la-E, the compound of the formula la-F, the compound of the formula la-H, the compound of the formula la-i and the compound of the formula la-G as well as combinations thereof.
  • composition according to the invention further comprises at least one additional therapeutic agent such as those defined above.
  • 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 lyophilisate, a suspension, a
  • SUBSTITUTE SHEET (RULE 26) gel, syrup, solution, water / oil emulsion, oil / water emulsion, oil, cream, milk, spray, ointment, ampoule, suppository, eye drops, vaginal egg, vaginal capsule, inhalation liquid, dry powder inhaler, pressurized inhaler with metering valve.
  • 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 oral, ocular, sublingual, intravenous, intraarterial, intramuscular, intraarticular, subcutaneous, transcutaneous, vaginal, epidural, intravesical, rectal or inhalation route.
  • composition according to the invention can be administered orally.
  • composition according to the invention can be administered in the form of a sublingual tablet or a gastro-resistant capsule.
  • composition according to the invention 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 ankylosing spondylitis as set out above- above.
  • Another subject of the invention is a preparation in juxtaposed form (or kit of parts) comprising a compound of formula (I) as defined above and / or a compound of formula (Ia) as defined above. above and / or a composition according to the invention as defined above and at least one additional therapeutic agent for its use in the prevention and / or treatment of ankylosing spondylitis as described above.
  • Alkyl by itself or as part of another substituent, means a hydrocarbyl radical of formula CnH2n + 1 in which is a number greater than or equal to 1.
  • the alkyl groups of this invention include 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.
  • Alkyl groups can be linear or branched and can be substituted as indicated in the present invention.
  • the alkyls suitable for the implementation of the invention can be chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers such as n-pentyl and iso-pentyl, and hexyl and its isomers such as n-hexyl and iso-hexyl, heptyl and its isomers (eg n-heptyl, iso-heptyl), octyl and its isomers (eg n-octyl, iso-octyl), nonyl and its isomers (eg n-nonyl, iso-nonyl), decyl and its isomers
  • 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-methyibutyle, 2-methylpentyl,
  • 3-methylpentyle 4-methylpentyle, 2-methylhexyle, 3-methylhexyle, 4-methylhexyle, 5-methylhexyle, 2,3-dimethylbutyle, 2,3-dimethylpentyle, 2,4-dimethylpentyle, 2,3-dimethylhexyie, 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-ethylhexyle, 4-ethylhexyle, 2-methyl-2- ethylpentyle, 2-methyl-3-ethylpentyle, 2-methyl-4-ethylpentyle, 2-methyl-2-e
  • 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-dimethylene.
  • 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,
  • alkynyl refers to a class of ungrouped hydrocarbyl unsatuated monovalent res, wherein 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.
  • alkenyl groups SUBSTITUTE SHEET (RULE 26) above for alkenyl groups.
  • alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, etc.
  • Alkoxy refers to an alkyl group as defined above, which is attached to another part through 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.
  • 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 (cycioalkyl, 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, biphenyienyl, 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 means an aryl group substituted with an alkyl group.
  • Amino acid denotes an alpha-amino carboxylic acid, i.e. a molecule comprising a carboxylic acid functional group and an amine functional group in the alpha position of the carboxylic acid group, for example a proteinogenic amino acid or an amino acid non-proteinogenic.
  • Proteinogenic amino acid means an amino acid which is incorporated into proteins during translation of messenger RNA by ribosomes in living organisms, i.e. Alanine (ALA), Arginine (ARG), Asparagine (ASN), Aspartate (ASP), Cysteine (CYS), Glutamate (glutamic acid) (GLU), Glutamine (GLN), Glycine (GLY), Histidine (HIS), Isoleucine (ILE), Leucine (LEU), Lysine ( LYS), Methionine (MET), Phenylalanine (PHE), Proline (PRO), Pyrrolysine (PYL), Selenocysteine (SEL), Serine (SER), Threonine (THR), Tryptophan (TRP), Tyrosine (TYR) or Valine ( VAL).
  • Alanine ALA
  • ARG Asparagine
  • ASN Asparagine
  • ASP Aspartate
  • Cysteine Cysteine
  • Glutamate Glutamic acid
  • GLU
  • 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,
  • SUBSTITUTE SHEET (RULE 26) homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, d-aminolevulinic acid, b-alanine, cystathionine, y-aminobutyrate, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, a-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine or D-glutamate
  • cycioalkyl as used herein is a cyclic alkyl group, i.e., a monovalent, saturated or unsaturated hydrocarbyl group having 1 or 2 ring structures.
  • cycioalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycioalkyl 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 cycioalkyl groups include, but are not limited to, cyclopropyl, cyclobutyie, cyclopentyl, cydohexyl, 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 other when it is 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 the EMA.
  • 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
  • SUBSTITUTE SHEET (RULE 26) or to another molecule only by a carbon atom, that is to say the linking atom is not chosen from the heteroatoms included in the heteroalkyl group.
  • heteroaryl refers to, without limitation, aromatic rings of 5 to 12 carbon atoms or ring systems containing 1 or 2 rings which are fused or covalently linked, usually containing 5 or 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, the nitrogen and sulfur heteroatoms possibly possibly be oxidized and the nitrogen heteroatoms possibly being quaternized.
  • These rings can be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • heteroaryls mention may be made of furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isoth iazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, pyridrazinazolyl, pyridrazinazolyl, pyridrazinazolyl, oxatriaznyl, pyridrazinazolyl, oxatriazolyl, pyridazinazolyl, pyridazinazolyl, triazolyl , dioxinyl, thiazinyl, triazinyl, imidazo [2, 1 -b] [1, 3] thiazolyl, thieno [3, 2-b] furanyl, thieno [3, 2-b] thiopheny
  • 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 denote non-aromatic, fully saturated or partially unsaturated cyclic groups (eg. example, 3- to 7-membered monocyclic, 7 to 11-membered bicyclic or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one ring containing a 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 Nitrogen heteroatoms can optionally be quaternized. Any of the carbon atoms of the heterocyclic group can be substituted with an oxo (eg piperidone, pyrrolidinone).
  • the heterocyclic group can be attached to any heteroatom or carbon atom of the ring or ring system, when 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
  • SUBSTITUTE SHEET (RULE 26) oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H- indolyl, indolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H- indolyl, indolinyl, isoindopoliniprazinyl, 2-pyzoliniprazinyl, 2-pyzoliniprazinazinyl, 2-pyzoliniprazinazinyl, 2-pyzolini
  • precursors as used herein also denotes pharmacologically acceptable derivatives of compounds of formula (I) or (Ia) such as esters whose 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 acyloxyaikyl 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 recognized pharmacopoeia for use in animals, and more preferably in humans. It may be a substance which is not biologically or otherwise undesirable, i.e. the substance can be administered to an individual without causing adverse biological effects or harmful interactions with one of the components of the composition in which it is contained.
  • 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) .
  • active ingredient or "therapeutic agent” denotes a molecule or substance the administration of which to a subject slows down or stops the progression, worsening or deterioration of one or more symptoms of a disease or disease. a state ; relieves symptoms of a disease or condition; cures a disease or condition.
  • the therapeutic ingredient is a small molecule, natural or synthetic.
  • the therapeutic ingredient is a biological molecule such as for example an oligonucleotide, siRNA, miRNA, DNA fragment, aptamer, antibody and the like.
  • “Pharmaceutically acceptable salts” include the acid and base addition salts of such salts. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • SUBSTITUTE SHEET (RULE 26) hibenzate, hydrochloride / chloride, bromhydrate / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate , pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, 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, Hemisulphates 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. converting one salt of the compound into another by reaction with a suitable acid or by means of a suitable ion exchange column.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization of the salt can vary from fully 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 group is replaced by any desired group which is substantially stable under the reaction conditions in an unprotected form or when protected by a. protecting group.
  • substituents include, but are not limited to, halogen (choro, 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; oxygen (-O); haloalkyl (eg, trifluoromethyl);
  • cycloalkyl which may be condensed or non-condensed monocyclic or polycyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocycloalkyl, which may be condensed or non-condensed monocyclic or polycyclic (eg, pyrrolidinyl, piperidinyl, piperazinyl, piperazinyl, piperazinyl, piperidinyl, piperazinyl morpholinyl or thiazinyl), monocyclic or polycyclic fused or unfused, aryl or heteroaryl (e.g.
  • 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) Ri 4 , halo, - OR 13 , cyano, nitro, haloalkoxy, -C (0) Ri 3 , -NR 11 R 12 , -SR 13 , -C (0) ORT 3 , -OC (0) Ri 3 , -NRi 3 C (0) RuRi 2 , - OC (0) NRnRi 2 , - R 13 C (0) 0Ri
  • administering means providing the active ingredient, alone or in the context of a pharmaceutically acceptable composition, to the patient in whom / to whom the condition, the symptom or disease must be treated or prevented.
  • SUBSTITUTE SHEET (RULE 26) "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.
  • Prevent refers to a method of delaying or preventing the onset of a condition or disease and / or of its related symptoms, to prevent a patient from acquiring a condition or disease, or to reduce the risk of a patient contracting a condition or disease.
  • bonds of an asymmetric carbon can be represented here using a solid triangle (“), a dotted triangle ⁇ ) or a zigzag line (' LL ⁇ ⁇ '),
  • a subject of the present invention is the compound of formula (I) and / or the compound of formula (Ia) for its use in the prevention and / or treatment of ankylosing spondylitis, as well as compositions comprising it.
  • Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. NAD exists in the cell either in its oxidized form NAD + or in its reduced form NADH. The role of NAD is that of an electron transporter involved in the redox reactions of the metabolism. NAD is also involved in many cellular processes such as ADP ribosylation as part of post-translational modifications of proteins.
  • 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 synthesis of NAD is the rescue route by which the cell, and mainly the cell nucleus, recycles compounds to reform NAD from precursors. 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 I-E:
  • the inventors have in fact demonstrated that the compound of formula (I) or of formula (Ia) as well as the composition according to the invention made it possible to obtain an effect on the swelling of the joints caused by ankylosing spondylitis, without however exhibiting any adverse effects. 'side effects. More precisely, the inventors have observed that the compounds of formula (I) or of formula (Ia) as well as the compositions comprising them made it possible to treat the inflammatory outbreaks characteristic of ankylosing spondylitis by reducing the swelling of the joints, the inflammation in the of the spine and ankylosis of the pelvis significantly. Moreover, the chronic administration of NMN makes it possible to prevent, or at the very least to space out, the occurrence of these outbreaks.
  • the compound of formula (I) or of formula (Ia) and the compositions comprising them make it possible to reduce inflammation and therefore to avoid, or at the very least to space. , flare-ups of ankylosing spondylitis.
  • the compounds and compositions according to the invention are particularly effective for treating the axial form as well as the peripheral form of ankylosing spondylitis.
  • NMN a molecule naturally present in the body, has many advantages. In particular, NMN does not pose any tolerance problem in patients. The use of NMN and of the composition according to the invention in fact induces no 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.
  • the compounds of formula (I) or (Ia) structurally close to NMN exhibit the same advantages.
  • the compounds of formula (I) or (Ia) and the compositions according to the invention in particular do not induce any phenomenon of physical or psychological dependence, unlike analgesics comprising morphine or opium derivatives.
  • the compounds of formula (I) or (Ia) and the compositions according to the invention also do not induce any bone fragility or vulnerability to infections as is observed with the chronic administration of cortisone or its derivatives.
  • the use of the compounds of formula (I) or (Ia) and the compositions according to the invention for preventing and / or treating ankylosing spondylitis is therefore safe for patients.
  • SUBSTITUTE SHEET (RULE 26)
  • the compounds of formula (I) or (Ia) and the compositions according to the invention can also be used in children and adults. They are 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 also finds its interest in treating ankylosing spondylitis in children.
  • the compounds of formula (I) or (Ia) 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.
  • Reducing inflammation, including swelling, in the joints and preventing flare-ups also help reduce pain associated with inflammation and reduce stiffness in 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 ankylosing spondylitis, namely analgesics, non-steroidal anti-inflammatory drugs, cortisone and / or cortisone and its derivatives.
  • drugs used to combat the symptoms of ankylosing spondylitis namely analgesics, non-steroidal anti-inflammatory drugs, cortisone and / or cortisone and its derivatives.
  • This also makes it possible to avoid administering the treatments conventionally used to treat ankylosing spondylitis such as methotrexate, or at the very least to reduce their frequency of administration or their dose.
  • the present invention therefore makes it possible to avoid, or at the very least to reduce, the use of conventional treatments for ankylosing spondylitis and therefore to avoid, or at the very least to reduce the appearance of side effects linked to 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 quality of life of the patient, or at the very least to prevent it from deteriorating too much.
  • the compounds of formula (!) Or (la) and the compositions according to the invention are used for preventing and / or treating ankylosing spondylitis. More precisely, they can be used on an ad hoc basis to treat a flare-up of ankylosing spondylitis or chronically to reduce inflammation and space out the onset of flare-ups.
  • the compounds of formula (!) Or (la) and the compositions according to the invention are used for preventing and / or treating ankylosing spondylitis. More precisely, they can be used on an ad hoc basis to treat a flare-up of ankylosing spondylitis or chronically to reduce inflammation and space out the onset of flare-ups.
  • the compounds of formula (!) Or (la) and the compositions according to the invention are used for preventing and / or treating ankylosing spondylitis. More precisely, they can be used on an ad hoc basis to treat a flare-up of ankylosing spondylitis or chronically to
  • SUBSTITUTE SHEET (RULE 26) formula (I) or (Ia) and the compositions according to the invention can be used as a preventive or curative measure, in order to reduce the inflammation, and in particular the swelling of the joints, of the spine and ankylosis of the pelvis. peripheral and axial forms of ankylosing spondylitis.
  • compositions according to the invention can be administered in a therapeutically effective amount.
  • a therapeutically effective amount means that the composition is administered to a patient in an amount sufficient to achieve the desired therapeutic effect.
  • the compounds of formula (I) or (la) is used in an amount 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.
  • Those skilled in the art can adapt the dose of NMN to be administered as a function of the age and weight of the patient, and of the intensity of the pain to be treated.
  • 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 the active ingredient, in particular 1.05.0, 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.
  • 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 a day to a year or even longer, preferably from a 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 timing of administration, rate of excretion, combination of drugs, and submitted host to treatment.
  • the compounds of formula (I) or (Ia) and the compositions according to the invention can be administered once a day or several times a day.
  • the compounds of formula (I) or (Ia) and the compositions 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.
  • SUBSTITUTE SHEET (RULE 26)
  • the dose administered and the frequency of administration depend in particular on the level of development of the inflammation. They can also depend on various factors such as the weight, age and sex of the patient.
  • the present invention relates in particular to 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 chosen from H, azido, cyano, C 1 -C 8 alkyl, thio-C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl;
  • R 2 , 3 , 4 and s are chosen independently of one another from H, halogen, azido, cyano, hydroxyl, C 1 -C 12 alkyl, C 1 -C 12 thioalkyl, heteroalkyl in C 1 -C 12 haloalkyl, C 1 -C 12 and OR; wherein R is selected from H, C1-Cn 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-Cn) 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;
  • - e is chosen from H, azido, cyano, Ci-Csalkyl, Ci-Cgthio-alkyl, Ci-Cg heteroalkyl and OR; wherein R is selected from H and C1-CB alkyl;
  • - R7 is chosen from H, PfOJRgRia and PtSJReRio; in which
  • - Rg and Rio are chosen independently of one another from OH, ORu, NHR 13 , NR 13 R 14 , a C 1 -C 8 alkyl, a C 2 -C 8 alkenyl, a C 2 -Ca alkynyl, a C 3 -C 10 cycloalkyl, a C 5 -C 12 aryl, (Ci-Cs) alkyl aryte, (Ci- Cg) aryl alkyl, (Ci-Cs) heteroalkyl, (Ci-Cg) heterocycloalkyl, a heteroaryl and NHCHRARA'C (0) RI 2 ; in which :
  • - Ru is chosen from a group C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, Cs-Cis aryl, C 1 -C 10 alkylaryl, Cs-Ci 2 substituted aryl, C 1 -C 10 heteroalkyl, C 3 - C 10 heterocycloalkyl, C 1 -C 10 haloalkyl, a heteroaryl, - (CH 2 ) nC (0) ⁇ Ci-CisJalkyl, - (CH 2 ) n0C (0) (Ci-Ci 5 ) alkyl, - (CH 2 ) n 0C (0) 0 (Ci-Cis) alkyl, - (CH 2 ) n SC (0) (Ci-Cis) alkyl, (CH 2 ) n C (0) 0 (Ci-Cis) alkyl and - (CH 2 ) nC (0) 0 (C1-Cis) alkyl
  • R 12 is chosen from H, Ci-Cio alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, Ci, Ci 0 haloalkyl, C 3 .C 10 cycloalkyl, C 3 .C 10 heterocycloalkyl, C 5 -C 18 aryl, C 1 -C 4 alkylaryl and Cs-Ci 2 heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted from one or two groups selected from halogen, trifluoromethyl, C1- C6 alkyl, C1-C 6 alkoxy and cyano; and
  • R is selected from H, a (Cg-Cg) aryl and (C 5 -C 6) heteroaryl, wherein said aryl or heteroaryl groups are optionnelîement substituted by halogen, trifluoromethyl, a C -C 6 alkyl, Ci-C 6 alkoxy and cyano; or
  • Rg and Rio together with the phosphorus atoms to which they are attached form a 6-membered ring in which -Rg-Rio- represents -0-CH 2 -CH 2 -CHR-0-; wherein R is selected from H, (C £ -Cs) aryl and (C 5 -Ce) heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, (C1-C 6 ) alkyl , a (Ci-C B ) alkoxy and cyano;
  • R 8 is chosen from H, OR, NHR 13 , NR 13 R 14 , NH-NHR 13 , SH, CN, N 3 and halogen; wherein R 13 and R M are independently selected from one another from H, (C1-Cg) alkyl and (C1-Cg) alkyl aryl, and -CRBRC-C (0) -ORD in which RB and R c are independently hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, benzyl, indolyl or imidazolyl, where (C1-Cg) alkyl and Se (C1-Cg)) alkoxy may be optionally and independently of each other substituted by one or more of the halogen, amino, amido, guanidyl, hydroxyl, thol or carboxyl group, and the benzyl group is optionally substituted by one or more of the halogen or hydroxyl groups, or R B and together with the carbon atom to which
  • SUBSTITUTE SHEET (RULE 26) - Y is chosen from CFI, CH 2 , C (CH 3 ) 2 and CCFI 3 ;
  • R'2, R ' 3 ,' 4 , R's, R ' 9 , R' 10, R'n, R'12 are independently selected from H, halogen, azido, cyano, hydroxyl, C1 alkyl C12, a thioalkyl C1-C12, a hetero-alkyl Ci-Cn haloalkyl Ci-Ci 2 and OR wherein R may be selected from H, C1-C12, C (0) (Cj-C ⁇ ) alkyl, a C (0) NH (Ci-C 12 ) alkyl, a C (0) 0 (Ci-Ci 2 ) aikyle, a C (O) aryie, a C (0) (C1 -C12) aryl, a
  • R'e and R'B are independently selected from F1, azido, cyano, C1-C8 alkyl and OR, wherein R is selected from F1 and C1-C8 alkyl; - R'7 and R'w are independently chosen from H, OR, NHR, NRR ', NFI-NFIR, SH, CN, N3 and a halogen, in which R and R' are independently chosen from Fl and a (Ci- Cg) aikyl aryl;
  • Y'I and Y '2 are independently selected from CFI, CFI 2 , C (CFh) 2 OR CCFI 3 ;
  • M ' is chosen from H or a suitable counterion
  • SUBSTITUTE SHEET (RULE 26) ⁇ uvw represents an alpha or beta anomer depending on the position of R'i and R '13 ; and combinations thereof for use in the prevention and / or treatment of ankylosing spondylitis.
  • the pharmaceutically acceptable derivative is the compound of formula (!),
  • X represents oxygen
  • i and R & each independently represent a hydrogen.
  • R 2 , R 3 , R 4 and Rs each independently represent a hydrogen or an OH.
  • Y represents a CH.
  • Y represents a CH 2 .
  • R? represents hydrogen
  • 7 represents P (0) (0H) 2 .
  • the compound of the invention is chosen from the compounds of formula lA to lJ:
  • the compound of formula (I) is chosen from compound lA, compound lB, compound lC,, compound lD, compound lE, compound lF, compound lG, compound lH, compound 1- 1, compound lJ, preferably compound lC, compound iD or compound lF, and combinations thereof. So
  • the compound of formula (I) is selected from compound IB, compound IC, compound ID, compound IF and combinations thereof.
  • the pharmaceutically acceptable derivative is the compound of formula (Ia).
  • X'I and X'2 each independently represent oxygen.
  • R'7 and Ft'14 each independently represent a
  • R'I and / or R'13 each independently represent a hydrogen.
  • R'6 and / or R'8 each independently represent a hydrogen.
  • R'2, R'3, R'4, R'5, R'9, R'10, R'11 and R'12 each independently represent hydrogen.
  • R'2, R'3, R'4 , R'5, R'9, R'10, R'11 and R'12 each independently represent an OH.
  • U ⁇ and Y'2 each independently represent a CH.
  • Y'1 and Y'2 each independently represent a CH2.
  • the compound according to the invention is chosen from the compounds of formula la-A to lad:
  • the compound of formula (I) is chosen from compound lA, compound lB, compound lC,, compound lD, compound lE, compound lF, compound lG, compound lH, compound ll, compound lJ, preferably compound lC, compound lD or compound lF, and combinations thereof. More preferably, the compound of formula (I) is chosen from compound IB, compound IC, compound ID, compound IF and their combinations.
  • the compound of formula (la) is chosen from compounds of formula la-A to la-1, more preferably from compound of formula la-B, compound of formula la-C, compound of formula la-E, the compound of the formula la-F, the compound of the formula la-H, the compound of the formula la-1 and the compound of the formula la-G as well as combinations thereof.
  • compositions according to the invention can be administered orally, ocular, sublingual, intravenous, intraarterial, intramuscular, intra-articular, subcutaneous, transcutaneous, vaginal, epidural, intervesical, rectal or inhalation.
  • the compounds or 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 compounds of formula (I) or (Ia) as well as the compositions according to the invention are administered by injection, and in particular by the subcutaneous, intravenous or intra-articular route, preferably intra-articularly. .
  • the compounds of formula (I) or (Ia) as well as the compositions 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 precursor of NAD and thus a reduced time of action.
  • Immediate-release dosage forms are in particular dispersible, effervescent, orodispersible and sublingual tablets.
  • 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 other liquid.
  • An effervescent tablet is a tablet designed to break up and dissolve rapidly in water or other liquid, releasing carbon dioxide (CO2). This release induces 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 lyophilisate 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 a delayed release.
  • the dissolution and absorption of the precursor of NAD takes place in the intestine, which limits gastric irritation or the degradation of fragile active ingredients at acid pH, these are mainly gastroresistant forms, that is to say 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 disintegrating apparatus. This medium mimics the physicochemical conditions of the stomach. The capsules are incubated in this medium for 1 hour. The capsule must not show any signs of disintegration or cracks which could lead to loss of content.
  • the capsule is then incubated for 1 hour in a phosphate buffer solution of pH 6.8 at 37 ° C, this solution mimicking the conditions of the intestinal environment in accordance with the recommendations of the European Pharmacopoeia.
  • the capsule must be completely disintegrated in less than one hour.
  • the oral form according to the invention can also be prolonged and sequential release.
  • SUBSTITUTE SHEET active until exhaustion
  • Such dosage forms make it possible to obtain relief from the pain of the patient for a longer period of time, and to space out the drug intakes.
  • the compounds of formula (I) or (Ia) as well as the compositions according to the invention are administered orally, in the form of a gastro-resistant capsule or of a sublingual tablet. These dosage forms allow better absorption and better distribution to all organs.
  • the mode of administration and the galenic form are determined by those skilled in the art according to the anatomical location of the pain to be treated and of the patient.
  • compositions according to the invention can also be used in combination with at least one additional therapeutic agent, in particular the therapeutic agents used in the usual way to treat the attacks of ankylosing spondylitis.
  • analgesics can be used to treat and relieve flare-ups of ankylosing spondylitis.
  • the analgesic can be chosen from paracetamol, aspirin, codeine, dihydrocodeine, tramadol, morphine, buprenorphine, fentanyl, hydromorphone, nalbuphine, oxycodone, pethidine and their combinations.
  • the analgesic is a nonsteroidal anti-inflammatory drug (NSAID).
  • the nonsteroidal anti-inflammatory 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.
  • NMN nonsteroidal anti-inflammatory drug
  • NMN NMN in combination with NSAIDs makes it possible, on the one hand, to reduce the frequency of administration of NSAIDs as well as the dose of NSAIDs administered. Thus, this helps to reduce the side effects of NSAIDs for the patient. It also helps to prolong the effectiveness of NSAIDs in patients before changing the patient's treatment.
  • the cortisone derivative can be selected from betamethasone, ciprofloxacin, cortivazol, dexamethasone, fludrocortisone, methylprednisolone, prednisolone and triamcinolone and their combinations.
  • SUBSTITUTE SHEET (RULE 26)
  • the compounds of formula (I) or (Ia) as well as the compositions according to the invention can also be administered in combination with a treatment for ankylosing spondylitis such as an immunosuppressant, an immunomodulator, an anti-TNF, an anti-interleukin. or their combinations.
  • a treatment for ankylosing spondylitis such as an immunosuppressant, an immunomodulator, an anti-TNF, an anti-interleukin. or their combinations.
  • 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.
  • anti-TNF is understood to mean molecules making it possible to inhibit the action of TNF, such as antibodies directed against TNF, antibodies directed against the TNF receptor, competitive or non-competitive inhibitors of the binding of TNF to its sound. receiver.
  • anti-interleukin is understood to mean molecules making it possible to inhibit the action of a specific interleukin, such as antibodies directed against said interleukin, antibodies directed against the receptor for said interleukin, competitive or non-competitive inhibitors. binding of said interleukin to its receptor.
  • the immunosuppressant can be selected 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, preferably sulfasalazine.
  • the anti-TNF can be chosen from infliximab, etanercept, adalimumab, certolizumab, golimumab and their combinations.
  • the joint use of anti-TNF and NMN in the treatment of ankylosing spondylitis can be of particular interest, whether it is the axial or peripheral form of the disease.
  • the anti-interleukin can be an interleukin-17 inhibitor, selected from ixekizumab and secukinumab.
  • the anti-interleukin can also be an anti-interleukin-12, preferably ustekinumab.
  • Ustekinumab is an antibody that targets interleukin 12 and interleukin 23.
  • the administration of the compounds of formula (I) or of formula (Ia) according to the invention in combination with one of the abovementioned treatments for ankylosing spondylitis makes it possible in particular to reduce the frequency of administration of these treatments and / or the dose administered. , and therefore the occurrence and importance of side effects associated with these treatments.
  • the combined administration of the compounds according to the invention with the conventional treatments for ankylosing spondylitis also makes it possible to delay the moment when these treatments lose their effectiveness on the disease.
  • the combined administration of the compounds according to the invention with these treatments therefore makes it possible to prolong their effectiveness and therefore makes it possible to offer more therapeutic alternatives to patients.
  • composition according to the invention comprises a compound of formula (I) and / or a compound of formula (Ia) and at least one pharmaceutically acceptable excipient.
  • the composition according to the invention may further comprise at least one additional therapeutic agent such as those mentioned above for its use in the prevention and / or treatment of ankylosing spondylitis as described above.
  • an “excipient” denotes any substance other than the compounds according to the invention or a therapeutic agent in the composition and having no therapeutic effect.
  • the excipient does not chemically interact with NMN or any additional therapeutic agent.
  • the excipient can be selected from a bulking agent, a lubricant, a flavoring, a colorant, an emulsifier, a compressing agent, a diluent, a preservative, a gelling agent, a plasticizer, a surfactant or their combinations. Those skilled in the art know which excipient to choose depending on the dosage form that they have chosen.
  • 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.
  • Another subject of the invention is a preparation in juxtaposed form (or kit of parts) comprising a compound of formula (I) as defined above and / or a compound of formula (Ia) as defined above. above and / or a composition according to the invention as defined above and at least one additional therapeutic agent for its use in the prevention and / or treatment of ankylosing spondylitis as described above.
  • the compounds of formula (I) or of formula (Ia) can be prepared according to any method well known to those skilled in the art.
  • the compounds of formula (I) can be prepared according to the method described in international application WO 2017 / 024255A1 as well as according to the method described below.
  • the invention relates to a method for preparing the compounds of formula (I) as described above.
  • SUBSTITUTE SHEET (RULE 26) 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, 2 , R 3 , R 4 , Rs, Rs, 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, R 2 , R 3 , R 4 , Rs, Rs, Re, Y, and are as defined above for the compounds of formula (!).
  • 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 reacting the pentose of formula (D) with a nitrogen derivative of formula (E), in which R, R 2 , R 3 , R 4 , R s , R 6 , R7, Y are as described above for the compounds of formula I, leading to the compound of formula (Al) which is then selectively deprotected to give the compound of formula (A), in which X, Ri, R 2 , R3, R 4 , Rs, Rs, Ra, 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, triisopropylsyl, tert-. butyldiphenylsilyl, tri-isopropylsilyloxymethyl and [2- (trimethylsilyl) ethoxy] methyl.
  • any hydroxyl group attached to the pentose is protected by an appropriate protective group known to 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.
  • an acid eg, an inorganic or organic acid
  • a base e.g., 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 (Al).
  • Lewis acids include TMSOTf, BF 3 .0EÎ 2 , TiCb 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 CH2 is and R 1, R 2, R 3, R 4, R 5 , R 6, R 5, Y, and are as defined above for the compounds of formula (I).
  • the present invention relates to a method of preparing compounds of formula! -A, 1-C, 1-E, 1-6.
  • 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, leading to the compound of formula Al:
  • a step of reducing the compound of formula I-A is carried out, resulting in the compound of formula I-E.
  • the compound of formula I-E is then mono-phosphorylated as described in the fourth step and hydrolyzed to yield the compound of formula I-G.
  • the compounds of formula (I) are selected from compounds 1-A to 1-J of the table below:
  • the compound of formula (I) is chosen from compound lA, compound lB, compound lC,, compound lD, compound lE, compound lF, compound lG, compound lH, compound ll, compound lJ, preferably compound lC, compound lD or compound lF, and combinations thereof. More preferably, the compound of formula (1) is chosen from compound IB, compound IC, compound ID, compound IF and their combinations.
  • the invention relates to a method for preparing the compound of formula I described above.
  • the phosphate compound of formula XII obtained in the second step is then reacted with a phophorodichloridate compound of formula XIII obtained as described in the first step, wherein X '2, R's, R's, R' 10, R 'n, R' 12, R '13, R'w, Y' 2, "and are as described herein for the formula to give the compound of formula la as described here.
  • the method further comprises a step of reducing the compound of formula la, using various methods known to those skilled in the art, to give the compound of formula la, where Y'i and Y '2 are identical and each represent CH 2 and where XT, X ' 2 , R'i, RT, R' 3 , R'4, R's, R's, R '?, R's, R's, R'10, R' 11, R '12, R' 13, R '14, Y'i, Y' 2 and ⁇ are as described here for formula la.
  • R is a suitable protecting group known to those skilled in the art.
  • Triarylmethyl and / or silyl groups are examples of suitable protecting groups.
  • Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl, and 4,4 ', 4 "-trimethoxytrityl.
  • Non-limiting examples of silyl groups include trimethyisilyl, letert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-iso-propylsilyloxymethyl and [2- (trimethylsilyi) ethoxy] methyl.
  • any hydroxy group attached to the pentose ring is protected by an appropriate protection group known to those skilled in this art.
  • the selection and exchange of protection groups is the responsibility of those who are competent in this area.
  • Any protecting group can also be removed by methods known in the art, for example, with an acid (eg, a mineral or an organic acid), a base or a source of fluoride.
  • the nitrogenous derivatives of formula XV are added to pentose XIV by a coupling reaction in the presence of a Lewis acid to give the compound of formula Xl.
  • suitable Lewis acids include TMSOTf, BF3.0Et2, TICl4 and FeCl3.
  • the invention relates to a method for preparing the compound of formula VIII, or their pharmaceutically acceptable salts and / or solvates.
  • the nicotinamide of formula XV is added to the ribose tetraacetate XIV, by a coupling reaction in the presence of a Lewis acid, to give the compound of formula Xl:
  • a fifth step the phosphate compound of formula XII obtained in the fourth step is then reacted with the phosphorodichloridate compound of formula X! obtained as described in the third step, to obtain the compound of formula VIII.
  • the invention relates to a method for preparing the compound of formula IX, or their pharmaceutically acceptable salts and / or solvates.
  • the compound of formula IX is obtained from the compound of formula VIII, previously synthesized as described above.
  • the compound of formula IX is obtained by reducing the compound of formula VIII, using a suitable reducing agent known to those skilled in the art, to give the compound of formula IX.
  • the preferred compounds of the invention are compounds la-A to la-i of Table 2:
  • the compound of formula (la) is chosen from the compound of formula ia-B, the compound of formula la-C, the compound of formula la-E, the compound of formula la-F, the compound of formula Ia -H, the compound of formula la-1 and the compound of formula la-G as well as combinations thereof.
  • FIGURES
  • 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 joint score as a function of the treatments.
  • FIG. 3 is a graph showing the evolution of the mean of the tail score as a function of the treatments.
  • TgA86 mice serving as a model of ankylosing spondylitis aged 3 weeks.
  • TgA86 mice develop peripheral and axial ankylosing spondylitis with an incidence of 100%.
  • the peripheral form is manifested by joint swelling and deformation of the legs while the axial form is clinically characterized by curved tails and pelvic ankylosis.
  • mice were divided into two groups each comprising ten mice: (i) a control group in which the mice are treated with the vehicle, i.e. a 0.9% NaCl solution (10 mL / kg) noted as “Vehicle”; (ii) a group of mice treated with NMIM (185 mg / kg) denoted “NMN”. The solutions are injected intraperitoneally.
  • SUBSTITUTE SHEET (RULE 26) The mice are treated for 10 weeks according to the conditions mentioned above. The joint score, tail score and weight of the mice are measured weekly. The joint score is established according to Table 3 below:
  • the tail score is an indicator to assess the axial form of anky osante spondylitis and ankylosis of the pelvis (see https://www.biomedcode.com/wp-content/uploads/2Q19/07/TgA86- white- paoer.pdf).
  • the tail score is established according to the following table 4:
  • FIG. 3 shows the evolution of the tail score making it possible to determine the improvement or the worsening of the axial form of ankylosing spondylitis in this mouse model.
  • the administration of NMN makes it possible to reduce the tail score in the treated mice compared to the control group, i.e. the spine of the mice is less deformed and the pelvis less stiff. The reduction is significant from the second week of treatment. Therefore, NMN is effective in treating the axial form of ankylosing spondylitis.
  • the compounds of formula (I) or (Ia) as well as the compositions comprising them can therefore be used successfully and safely to treat and prevent ankylosing spondylitis.
  • the present invention therefore makes it possible to provide a therapeutic alternative to conventional treatments for ankylosing spondylitis, 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 the compounds according to the invention as well as of the compositions comprising it, the present invention makes it possible to treat and / or prevent ankylosing spondylitis without inducing the side effects caused by conventional treatments.

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EP20811425.6A 2019-11-28 2020-11-27 Utilisation de composés pour la prévention et/ou le traitement de la spondylarthrite ankylosante et compositions correspondantes Withdrawn EP4065129A1 (fr)

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