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EP-4736947-A2 - NICOTINAMIDE MONONUCLEOTIDE DERIVATIVES IN THE TREATMENT AND PREVENTION OF POLYCYTHEMIA VERA.

EP4736947A2EP 4736947 A2EP4736947 A2EP 4736947A2EP-4736947-A2

Abstract

The present invention relates to a compound of Formula (III): or of Formula (IV): or a pharmaceutically acceptable salt or solvate thereof; for use in treating a red blood cell disorder, said compound being administrated to the subject sequentially, simultaneously and/or separately with at least one other active ingredient selected from a natural extract; opioid or non-opioid analgesics; NSAIDS; antidepressants; anticonvulsants; antibiotics; antioxidant such as CoQ10 and PQQ (pyrroloquinoline quinone); hydroxyurea, L-glutamine, kynurenine, kynurenic acid, tryptophan, voxelotor and crizanlizumab, or with blood transfusion.

Inventors

  • BERMOND, Guillaume
  • GARÇON, Laurent
  • CANAULT, Matthias
  • Cros, Cécile

Assignees

  • Nuvamid SA

Dates

Publication Date
20260506
Application Date
20211217

Claims (15)

  1. A compound of Formula (III): or of Formula (IV): or a pharmaceutically acceptable salt or solvate thereof; wherein: X is selected from O, CH 2 , S, Se, CHF, CF 2 and C=CH 2 ; R 1 is selected from H, azido, cyano, (C 1 -C 8 )alkyl, (C 1 -C 8 )thio-alkyl, (C 1 -C 8 )heteroalkyl and OR; wherein R is selected from H and (C 1 -C 8 )alkyl; R 2 , R 3 , R 4 and R 5 are independently selected from H, halogen, azido, cyano, hydroxyl, (C 1 -C 12 )alkyl, (C 1 -C 12 )thio-alkyl, (C 1 -C 12 )heteroalkyl, (C 1 -C 12 )haloalkyl and OR; wherein R is selected from H, (C 1 -C 12 )alkyl, -C(O)(C 1 -C 12 )alkyl, -C(O)NH(C 1 -C 12 )alkyl, -C(O)O(C 1 -C 12 )alkyl, -C(O)aryl, -C(O)(C 1 -C 12 )alkyl-(C 5 -C 12 )aryl, -C(O)NH(C 1 -C 12 )alkyl-(C 5 -C 12 )aryl, -C(O)O(C 1 -C 12 )alkyl-(C 5 -C 12 )aryl and -C(O)CHR AA NH 2 ; wherein R AA is a side chain selected from a proteinogenic amino acid; R 6 is selected from H, azido, cyano, (C 1 -C 8 )alkyl, (C 1 -C 8 )thio-alkyl, (C 1 -C 8 )heteroalkyl and OR; wherein R is selected from H and (C 1 -C 8 )alkyl; X' is selected from O, CH 2 , S, Se, CHF, CF 2 and C=CH 2 ; R 1' is selected from H, azido, cyano, (C 1 -C 8 )alkyl, (C 1 -C 8 )thio-alkyl, (C 1 -C 8 )heteroalkyl and OR; wherein R is selected from H and (C 1 -C 8 )alkyl; R 2' , R 3' , R 4 , and R 5' are independently selected from H, halogen, azido, cyano, hydroxyl, (C 1 -C 12 )alkyl, (C 1 -C 12 )thio-alkyl, (C 1 -C 12 )heteroalkyl, (C 1 -C 12 )haloalkyl and OR; wherein R is selected from H, (C 1 -C 12 )alkyl, -C(O)(C 1 -C 12 )alkyl, -C(O)NH(C 1 -C 12 )alkyl, -C(O)O(C 1 -C 12 )alkyl, -C(O)aryl, -C(O)(C 1 -C 12 )alkyl-(C 5 -C 12 )aryl, -C(O)NH(C 1 -C 12 )alkyl-(C 5 -C 12 )aryl, -C(O)O(C 1 -C 12 )alkyl-C 5 -C 12 aryl and -C(O)CHR AA NH 2 ; wherein R AA is a side chain selected from a proteinogenic amino acid; R 6' is selected from H, azido, cyano, (C 1 -C 8 )alkyl, (C 1 -C 8 )thio-alkyl, (C 1 -C 8 )heteroalkyl and OR; wherein R is selected from H and (C 1 -C 8 )alkyl; R 8' is selected from H, NR 15' R 16' , NH-NHR 15' , SH, CN, N 3 and halogen; wherein and R 15' and R 16' are independently selected from H, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl-(C 5 -C 12 )aryl and -CHR AA' CO 2 H wherein R AA' is a side chain selected from a proteinogenic or non-proteinogenic amino acid; Y' is selected from CH, CH 2 , CHCH 3 , C(CH 3 ) 2 and CCH 3 ; n is an integer selected from 1 to 3; - - - represents the point of attachment; - - - represents a single or double bond according to Y'; and represents the alpha or beta anomer depending on the position of R 1 ; R 8 is selected from H, NR 15 R 16 , NH-NHR 15 , SH, CN, N 3 and halogen; wherein R 15 and R 16 are independently selected from H, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl-(C 5 -C 12 )aryl and -CHR AA CO 2 H wherein R AA is a side chain selected from a proteinogenic or non-proteinogenic amino acid; Y is selected from CH, CH 2 , CHCH 3 , C(CH 3 ) 2 and CCH 3 ; - - - represents a single or double bond according to Y; and represents the alpha or beta anomer depending on the position of R 1 , for use in treating a red blood cell disorder, said compound being administrated to the subject sequentially, simultaneously and/or separately with : - at least one other active ingredient selected from a natural extract; opioid or non-opioid analgesics; NSAIDS; antidepressants; anticonvulsants; antibiotics; antioxidant such as CoQ10 and PQQ (pyrroloquinoline quinone); hydroxyurea, L-glutamine, kynurenine, kynurenic acid, tryptophan, voxelotor and crizanlizumab, or - blood transfusion.
  2. The compound of Formula (III) or of Formula (IV)for use according to claim 1, wherein X and, when present, X' represents an oxygen.
  3. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 1 or 2, selected from: Compounds (anomers) Structure 001 (beta) 002 (alpha) 003 (beta) 004 (alpha) 009 (beta, beta) 010 (beta, alpha) 011 (alpha, alpha) 012 (beta, beta) 013 (beta, alpha) 014 (alpha, alpha) and pharmaceutically acceptable salts and solvates thereof, preferably selected from compounds 001, 002, 009, 010 and 011.
  4. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 1 to 3, wherein the compound of formula (III) or of formula (IV) is compound 001.
  5. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 1 to 4, wherein the at least one other active ingredient is hydroxyurea.
  6. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 1 to 5, wherein the at least one other active ingredient is L-glutamine.
  7. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 1 to 6, wherein compound of Formula (III) or of Formula (IV) part is in a form suitable for oral administration.
  8. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 1 to 7, wherein red blood cell disorder is anemia, such as iron deficiency anemia, pernicious anemia, aplastic anemia, autoimmune hemolytic anemia; thalassemia; hemoglobin Sβ0 thalassemia; hemoglobin Sβ+ thalassemia; hemoglobin SC; hemoglobin SD; hemoglobin SE; hemoglobin SS; polycythemia vera and sickle cell disease.
  9. The compound of Formula (III) or of Formula (IV) for use according to claim 8 wherein red blood cell disorder is sickle cell disease.
  10. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 1 to 9, for use in treating, preventing, reducing, alleviating or slowing down at least one acute or chronic complication and/or at least one symptom of sickle cell disease.
  11. The compound of Formula (III) or of Formula (IV) for use according to claim 10, wherein the at least one acute or chronic complication and/or at least one symptom of sickle cell disease, is selected from recurrent acute pain crises, vaso-occlusive crises (VOCs), vascular obstruction, ischemia, intravascular hemolysis, extravascular hemolysis, hemolytic anemia, vascular obstruction, and vascular proliferative lesions, acute chest syndrome, chronic pain, delayed growth and puberty, avascular necrosis, eye problems such as retinopathy, gallstones, heart problems including coronary heart disease and pulmonary hypertension, infections such as meningitis, osteomyelitis, and sepsis; joint problems, kidney problems, chronic kidney injury, skin ulcers, leg ulcers, liver problems, pregnancy problems, priapism, severe anemia, stroke, renal necrosis, neurocognitive impairment and/or silent brain injury, preferably selected from recurrent acute pain crises, vaso-occlusive crises (VOCs), acute chest syndrome, chronic pain, intravascular hemolysis, extravascular hemolysis, hemolytic anemia and severe anemia.
  12. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 10 or 11, wherein the at least one acute or chronic complication and/or at least one symptom of sickle cell disease, is selected from recurrent acute pain crises, vaso-occlusive crises (VOCs), acute chest syndrome and/or chronic pain.
  13. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 10 or 11, wherein the at least one acute or chronic complication and/or at least one symptom of sickle cell disease, is selected from intravascular hemolysis, extravascular hemolysis, hemolytic anemia, severe anemia.
  14. The compound of Formula (III) or of Formula (IV) for use according to any one of claims 9 to 13, wherein the compound of Formula (III) or of Formula (IV) is administered at a dosage about 0.01 to 500 mg per kg patient body weight per day, in single or multiple doses.
  15. The compound of Formula (III) or of Formula (IV) for use according to anyone of claims 9 to 14, wherein the compound of Formula (III) or of Formula (IV) part is provided orally between 1.0 to 1000 milligrams.

Description

FIELD OF INVENTION The present invention relates to nicotinamide mononucleotide derivatives compounds for use in the treatment and/or prevention of a red blood cell disorder. BACKGROUND OF INVENTION A blood disorder is a condition affecting blood cells such as red blood cells, white blood cells, or the smaller circulating cells called platelets, which are critical for clot formation. All three cell types form in the bone marrow, which is the soft tissue inside the bones. Red blood cells transport oxygen to the body's organs and tissues. White blood cells help the body fight infections. Platelets help the blood to clot. Blood cell disorders impair the formation and function of one or more of these types of blood cells. Among blood disorders, sickle cell disease (SCD) or drepanocytosis is a group of inherited red blood cell disorders defined by a missense point mutation in the sequence of beta globin, which results in a glutamic acid residue at position 6 being substituted by a valine. This mutated globin, called sickle hemoglobin or hemoglobin S (HbS), aggregates and forms fibrous precipitates upon low oxygen level, leading to polymerized hemoglobin and promoting red blood cell (RBC) sickling. Clinical manifestations of SCD derive from at least three different pathophysiologic mechanisms: the loss of deformability of the RBC leading to vascular obstruction and ischemia; a shortened lifespan of the RBC leading to both intravascular and extravascular hemolysis; a sticky RBC surface increasing adherence to the vascular endothelium which can result in vascular obstruction and can contribute to vascular proliferative lesions. Recurrent acute pain crises, or vaso-occlusive crises (VOCs) are considered among the most common manifestations of SCD. VOCs are believed to occur when blood flow is obstructed, usually at the level of the small blood vessels resulting in ischemic injury and pain. Over time patients will also experience significant acute and chronic complications. Acute complications include serious infections such as meningitis, osteomyelitis, and sepsis, and noninfectious complications such as stroke, renal necrosis, priapism. Acute chest syndrome is a potentially life-threatening complication that can involve chest pain and shortness of breath among other symptoms; some episodes of acute chest syndrome are triggered by infection. Chronic complications can emerge across multiple organs and include neurocognitive impairment, chronic kidney injury, delayed puberty, avascular necrosis, retinopathy, pulmonary hypertension, skin ulcers, and chronic pain. Individuals with SCD face ongoing and evolving lifelong difficulties as a result of their disease. SCD affects over 5 million subjects in the world, being the most common genetic disease in France. Despite the recent advances in the field, therapy for SCD patients is limited to symptomatic treatment of pain, oxygen supplementation, antibiotics, RBC transfusions and hydroxyurea. Nonetheless, blood transfusion remains the most applied therapy to treat patients suffering from SCD. Alternative approaches, such as bone marrow transplantation and gene therapy have been developed but are still associated with toxicity and are only considered in case of cerebral vasculopathy. Moreover, these approaches are not yet feasible in most countries where the incidence of the disease is elevated. Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous oxidation-reduction (redox) cofactor in red cells. NAD+ and its reduced form, NADH, play major roles in maintaining redox balance. Sickle red cells have a lower redox ratio ([NADH]:[NAD++NADH]) than normal red cells. The amino acid L-glutamine (USAN, glutamine) is required to synthesize NAD. Uptake of L-glutamine is several times greater in sickle red cells than in normal red cells, primarily to increase the total intracellular NAD level. Oral administration of pharmaceutical-grade L-glutamine was shown to raise the NAD redox ratio within sickle cells and was associated with patient-reported clinical improvement. A phase 3 trial of L-glutamine in SCD showed that the median number of pain crises over 48 weeks was lower among the patients who received L-glutamine. On the basis of the results of this phase 3 trial, the FDA granted approval of pharmaceutical grade L-glutamine (Endari, Emmaus Medical) as a prescription drug to reduce the rate of acute complications of sickle cell disease among adults and children 5 years of age and older. Some other protocols have recently been granted by the FDA to treat SCD or reduce complications associated with SCD: Voxelotor (Oxbryta™), which inhibits polymerization of HbS by promoting the binding of oxygen to hemoglobin, has been approved to treat SCD in adults and children 12 years of age and older; and Crizanlizumab (Adakveo™), a therapeutic monoclonal antibody that reduces the phenomenon of cell aggregation d