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US-20260124188-A1 - mGluR receptor antagonists for use in prevention andor treatment of bone marrow lesions (BML) andor osteoporosis, cartilage loss, osteosclerosis and osteitis in a mammal

US20260124188A1US 20260124188 A1US20260124188 A1US 20260124188A1US-20260124188-A1

Abstract

The present invention relates to mGluR5 antagonists, or compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), or a pharmaceutically acceptable salt thereof, enantiomer, isotope, or mixture thereof, or a pharmaceutical composition comprising said TT00, for use in prevention and/or treatment of bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML related to osteoporosis, cartilage loss, osteosclerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis or combined with a) pain, b) GERD, c) anxiety and/or d) stress in mammals, such as humans, apes or dogs, cats, pigs, cows or horses.

Inventors

  • Claes Thulin

Assignees

  • ORPHELION AB

Dates

Publication Date
20260507
Application Date
20231004
Priority Date
20221028

Claims (20)

  1. 1 . A method of preventing and/or treating bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis in mammals, comprising: administering to a mammal in need thereof an effective amount of an agent selected from the group consisting of: mGluR5 antagonists, or compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5-[(1R)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, (TT001) and 4-[5-[(1S)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002), and combinations thereof, or a pharmaceutically acceptable salt thereof, enantiomer, isotope, or mixture thereof.
  2. 2 . The method according to claim 1 , wherein the bone marrow lesions (BML) are related to osteoporosis, cartilage loss, osteosclerosis and/or osteitis.
  3. 3 . The method according to claim 1 , wherein the bone marrow lesions (BML) are related to rheumatoid arthritis, osteosarcoma and/or osteoarthritis.
  4. 4 . The method according to claim 1 , wherein the bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML are related to osteophorosis, osteoporasis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis and a) pain.
  5. 5 . The method according to claim 1 , wherein both bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML are related to osteoporosis, osteo clerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis and b) gastroesophageal reflux disease (GERD).
  6. 6 . The method according to claim 1 , wherein both bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML are related to osteoporosis, osteosclerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis and c) anxiety.
  7. 7 . The method according to claim 1 , wherein both bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML are related to osteoporosis, osteo clerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis and d) stress.
  8. 8 . A pharmaceutical composition comprising mGluR5 antagonists, or compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5-[(1R)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, (TT001) and/or 4-[5-[(1S)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002), or a pharmaceutically acceptable salt thereof, enantiomer, isotope, or mixture thereof, in the association with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in prevention and/or treatment of bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML related to osteophorosis, osteosclerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis, in mammals.
  9. 9 . A pharmaceutical composition comprising (i) mGluR5 antagonists, or compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5-[(1R)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, CAS Number 934282-55-0 (TT001) and/or 4-[5-[(1S)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002), or a pharmaceutically acceptable salt thereof, enantiomer, isotope or mixture thereof, and a pharmaceutically acceptable excipient, carrier or diluent, and (ii) at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent, for use in prevention and/or treatment of bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML related to osteoporosis, osteosclerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis in mammals.
  10. 10 . A pharmaceutical composition comprising (i) mGluR5 antagonists, or compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5-[(1R)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, (TT001) and/or 4-[5-[(1S)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002), or a pharmaceutically acceptable salt thereof, enantiomer, isotope, or mixture thereof, (ii) at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in prevention and/or treatment of bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML related to osteoporosis, osteosclerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis in mammals.
  11. 11 . The pharmaceutical composition comprising (i) mGluR5 antagonists, or compounds TT00, TT001 and/or TT002 according to claim 8 , for use in prevention and/or treatment of both bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML related to osteophorosis, osteosclerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis, and a) pain, b) GERD, c) anxiety and/or d) stress in mammals, such as humans, apes, dogs, cats, pigs, cows or horses.
  12. 12 . The pharmaceutical composition comprising (i) mGluR5 antagonists, or compounds TT00, TT001 and/or TT002, for use according to claim 9 , wherein the at least one additional therapeutic agent is selected from the group comprising NSAIDs, anesthetics, corticosteroids, bisphosphonates, osteosarcoma drugs, anti-platelet drugs, anti-coagulant drugs, anti-thrombotic agent such as prostacyclin, and opiates.
  13. 13 . The pharmaceutical composition comprising (i) mGluR5 antagonists, or compounds TT00, TT001 and/or TT002 according to claim 9 , wherein the at least one additional therapeutic agent is selected from the group comprising NSAIDs selected from the group comprising butyl pyrazolidines, oxicams, propionic acid derivative, fenamic acid and coxibs; wherein the NSAIDs may be selected from the group comprising or consisting of oxicams, propionic acid derivatives and coxibs, any other non-steroidal anti-inflammatory or antirheumatic agents, opiates selected from the group comprising tramadol and tapentadol, corticosteroids selected from the group comprising cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone and hydrocortisone, bisphosphonates such as zoledronic acid, anti-thrombotic agent selected from the group comprising anticoagulant agents, such as Dabigatran, Desirudin, Apixaban, Betrixaban, Edoxaban, Fondaparinux, Rivaroxaban, Heparins, Heparin, Dalteparin, Enoxaparin, Tinzaparin, Warfarin, and antiplatelet drugs, such as Aspirin, Cangrelor, Clopidogrel, Dipyridamole, Prasugrel, Ticagrelor, Ticlopidine, Vorapaxar, and prostacyclin, defibrotide and anagrelide, and osteosarcoma drugs selected from the group comprising cisplatin, doxorubicin, ifosfamide, and high-dose methotrexate with leucovorin rescue.
  14. 14 . mGluR5 antagonists, or compounds TT00, TT001 and/or TT002 for use according to claim 1 , wherein the mGluR5 antagonists is selected from the group comprising 2-Methyl-6-(phenylethynyl)pyridine (MPEP), 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP), Acamprosate, Memantine, Fenobam, Basimglurant (R04917523), (4-fluorophenyl)-[(3S)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone (ADX63365), 3-Fluoro-5-{5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2-pyridinyl}benzonitrile (STX107), AZD2516, Mavoglurant, (αS)-α-Amino-α-[(1R,2R)-2-carboxycyclopropyl]-9H-xanthene-9-propanoic acid (LY344545), Dipraglurant (ADX48621), N-tricyclo[3.3.1.13,7]dec-1-yl-2-quinoxalinecarboxamide (NPS 2390), (S)-α-Methyl-4-carboxyphenylglycine ((S)-MCPG), 2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine (CTEP), DL-2-Amino-3-phosphonopropionic acid (DL-AP3), 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495) and [(3-fluorophenyl)methylene]hydrazone-3-fluorobenzaldehyde (DFB), N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), (S)-(4-fluoro-phenyl)-(3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]piperidin-1-yl)methanone (ASX47273), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU29).
  15. 15 . mGluR5 antagonists, or compounds TT00, TT001 and/or TT002 for use according to claim 1 , wherein the compound is TT001, or a hydrochloride or sulphate salt thereof.
  16. 16 . mGluR5 antagonists, or compounds TT00, TT001 and/or TT002 for use according to claim 1 , wherein the mammal is a human.
  17. 17 . mGluR5 antagonists, or compounds TT00, TT001 and/or TT002 for use according to claim 1 , or the pharmaceutical composition according to any one of claims 8 to 15 , wherein the mammal is a dog.
  18. 18 . The pharmaceutical composition according to claim 8 , wherein the mGluR5 antagonists is selected from the group comprising 2-Methyl-6-(phenylethynyl)pyridine (MPEP), 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP), Acamprosate, Memantine, Fenobam, Basimglurant (R04917523), (4-fluorophenyl)-[(3S)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone (ADX63365), 3-Fluoro-5-{5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2-pyridinyl}benzonitrile (STX107), AZD2516, Mavoglurant, (αS)-α-Amino-α-[(1R,2R)-2-carboxycyclopropyl]-9H-xanthene-9-propanoic acid (LY344545), Dipraglurant (ADX48621), N-tricyclo[3.3.1.13,7]dec-1-yl-2-quinoxalinecarboxamide (NPS 2390), (S)-α-Methyl-4-carboxyphenylglycine ((S)-MCPG), 2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine (CTEP), DL-2-Amino-3-phosphonopropionic acid (DL-AP3), 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495) and [(3-fluorophenyl)methylene]hydrazone-3-fluorobenzaldehyde (DFB), N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), (S)-(4-fluoro-phenyl)-(3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]piperidin-1-yl)methanone (ASX47273), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU29).
  19. 19 . The pharmaceutical composition according to claim 8 , wherein the compound is TT001, or a hydrochloride or sulphate salt thereof.
  20. 20 . The pharmaceutical composition according to claim 8 , wherein the mammal is a human.

Description

FIELD OF THE INVENTION The present invention relates to mGluR5 antagonists, or compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), or a pharmaceutically acceptable salt thereof, enantiomer, isotope, or mixture thereof, or a pharmaceutical composition comprising said TT00, for use in prevention and/or treatment of bone marrow lesions (BML) and/or osteoporosis, cartilage loss, osteosclerosis, osteitis, or BML related to osteoporosis, cartilage loss, osteosclerosis, osteitis, rheumatoid arthritis, osteosarcoma and/or osteoarthritis or said disorders combined with a) pain, b) GERD, c) anxiety and/or d) stress in mammals, such as humans, apes or dogs, cats, pigs, cows or horses. BACKGROUND Bone marrow lesions (BMLs), distinct from but originally known as ‘bone marrow edema’, can is be described as common and non-specific magnetic resonance imaging (MRI) findings associated with various pathologies. They have been most studied in knees or hips but are well-described in joints, especially joints from mammals suffering from Osteoarthritis (OA). BML also represents microscopic collapse within the necrotic subchondral bone and indicates an unfavourable prognosis. BMLs are characterized on MRI by ill-defined hypo intensity on T1-weighted non-fat-suppressed images, and hyperintensity on fluid-sensitive, T2-, proton density-, and intermediate-weighted fat-suppressed and short tau inversion recovery (STIR) images. Furthermore, they enhance after intravenous administration of contrast agents. BMLs have an array of different causes including, but not limited to, Trauma: Fracture, local transient osteoporosis, altered stress/biomechanics (plantar fasciitis, tendinitis/enthesitis), bone bruise, and osteochondral injuries (osteochondritis dissecans)Degenerative lesions: Osteoarthritis (hip, knee, other) and MODIC lesions (spine)Inflammatory lesions: Inflammatory arthropathies and enthesitis (rheumatoid arthritis (RA), Ankylosing spondylitis, psoriasis) and systemic chronic inflammation with fibrosis.Ischaemic lesions: Avascular necrosis (AVN), Complex regional pain syndrome (Sudeks atrophy of bone), Sickle cell anaemia (SCA),Infectious lesions: Osteomyelitis, diabetic foot, Charcot foot, sepsis (bone infarcts),Metabolic/endocrine lesions: Hydroxyapatite deposition disease (HADD), GoutLatrogenic lesions: Surgery, Radiotherapy, immunosuppressants (glucocorticoids, cyclosporin, cytostatics) BMLs are associated with a multitude of clinical features, such as pain, progression of a disease, such as those mentioned above, transient regional osteoporosis, bone bruises or contusions, osteochondritis dissecans, increased subchondral stress, seropositive inflammatory arthropathy, osteonecrosis of the bone, complex regional pain syndrome, tissue deposition of uric acid or hydroxyapatite crystals and osteomyelitis. There exist only a handful of treatment options for BML. Since the topic of BML is a complicated one, there is no medical consensus on the best treatment options. One treatment option is surgery, namely, core decompression, which is a surgical procedure that involves drilling tiny holes in the damaged bone surrounding the joint. The goal is to relieve pressure and improve blood flow in the area to promote healing. As with most surgical procedures, core decompression is associated with complications, such as fractures along the core track, perforations in the femoral head, and deep vein thrombosis. Pharmacological intervention strategies involve two types of medications that may help relieve pain in patients with BMLs. Prostacyclin is a vasodilator that promotes bone regeneration. Bisphosphonates are used to treat multiple bone diseases because they help prevent the breakdown of bone. Existing studies show that both medications can reduce pain, improve functionality, and reduce the appearance of lesions. The possible downside is that medications only reduce or mask symptoms, but don't treat bone and joint damage. The administration of bisphosphonates is often combined with administration of (nonsteroidal anti-inflammatory drugs) NSAIDs or corticosteroids. Both NSAIDs and corticosteroids are known to have serious side effects when used over longer periods. Glutamate is defined as an excitatory amino acid (EAA) neurotransmitter contained by the mammalian central nervous system (CNS). Evidence in literature is increasing with regard to the concept that glutamatergic signaling is also functional in non-neuronal tissues outside the CNS such as the pancreas, skin, and bone. Glutamate could have an important role in intercellular communications within bone-related cells. The involvement of EAA in peripheral nociceptive transduction has been reported in animal models suffering from acute arthritis. Certainly, glutamate may act as a more widespread “cytokine” rather than as a “neurotransmitter” and influence a variety of cellular activities in different tissues. The actions of