JPWO2020037004A5

JPWO2020037004A5 -

Info

Publication number: JPWO2020037004A5
Application number: JP2021507505A
Authority: JP
Publication date: 2022-08-23

Claims

Compounds according to Formula I below:

or a salt, hydrate, prodrug, or isomer thereof,
X is selected from CR ^3b and N, wherein N is optionally oxidized to the corresponding N-oxide;
Y is selected from CR ^3c and N, wherein N is optionally oxidized to the corresponding N-oxide;
Z is selected from CR ^3d and N, wherein N is optionally oxidized to the corresponding N-oxide;
provided that at least one of X, Y, and Z is N or the corresponding N-oxide;
A is

and
^RN is selected from the group consisting of heterocyclyl and heteroaryl;
Said heterocyclyl moiety is selected from monocyclic, fused bicyclic, and bridged heterocyclyl, said monocyclic heterocyclyl containing 4 to 7 ring members, said fused bicyclic heterocyclyl and said bridged bicyclic Cyclic heterocyclyls contain 7-10 ring members, each heterocyclyl moiety having 1-3 heteroatoms as ring members selected from nitrogen (N), oxygen (O), and sulfur (S). , each heterocyclyl moiety containing at least one nitrogen atom as a ring member, optionally substituted with 1 to 3 R ⁶ moieties,
said heteroaryl moiety comprises 5 to 10 ring members, at least one ring member being a nitrogen atom, optionally substituted with 1 to ³ R moieties;
R ² , R ^3b , R ^3c and R ^3d are each independently H, halogen, C _1-6 alkyl, C
1-6 _haloalkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkyl-OH, —O—C _1-6 alkyl-OH, C _3-6 cycloalkyl-
is selected from the group consisting of C _1-4 alkoxy and hydroxyl group (--OH);
each of R ⁶ is a hydroxyl group (--OH), C _1-3 alkyl, C _1-3 alkyl-OH,
A compound selected from the group consisting of —O—C _1-3 alkyl, C _3-4 heteroalkyl, C _1-3 haloalkyl, —O—C _1-3 haloalkyl, halogen, and oxo.

Formula Ia, Ib, Ic, or Id:

2. The compound of claim 1, having

2. The compound of claim 1, wherein ^R2 is selected from the group consisting of H, halogen, _C1-6alkyl , _{C1-6haloalkyl} , _C1-6alkoxy , and _{C1-6haloalkoxy} .

2. The compound of claim 1, wherein ^R2 is selected from the group consisting of halogen, _C1-6alkyl , _{C1-6haloalkyl} , and _C1-6alkoxy .

5. The compound of claim 4, wherein ^R2 is _C1-6 alkyl or _C1-6 haloalkyl.

6. The compound of claim 5, wherein ^R2 is _CH3 or _CF3 .

7. The compound of claim 6, wherein ^R2 is _CH3 .

7. The compound of claim 6, wherein ^R2 is _CF3 .

R ^3b , R ^3c and R ^3d each, if present, are independent from the group consisting of H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy 2. The compound of claim 1, which is selected as

10. The compound of claim 9, wherein ^R3b , ^R3c , and ^R3d , if present, are each independently selected from the group consisting of H, halogen, and _C1-6alkoxy .

11. The compound of Claim 10, wherein ^R3b , ^R3c , and ^R3d , if present, are each selected from the group consisting of H, F, and methoxy.

2. The compound of claim 1, wherein ^R3c , if present, is methoxy.

2. The compound of claim 1, wherein ^RN is heterocyclyl or heteroaryl.

14. The compound of claim 13, wherein ^RN is heterocyclyl.

15. The compound of claim 14, wherein ^RN is monocyclic heterocyclyl.

^RN is

14. The compound of claim 13, which is

R ² is selected from the group consisting of H, C _1-6 alkyl, and C _1-6 haloalkyl;
R ^3c , if present, is H or C _1-6 alkoxy;
2. The compound of claim 1, wherein ^R3b or ^R3d , if present, is H or halogen; and ^RN is heterocyclyl or heteroaryl.

R ² is H or C _1-6 haloalkyl;
R ^3c , if present, is C _1-6 alkoxy;
R ^3b or R ^3d , if present, is H or halogen, and ^RN is

18. The compound of claim 17, which is

R ² is C _1-6 alkyl or C _1-6 haloalkyl,
3. The compound of claim 2, wherein ^R3c is _C1-6alkoxy and ^RN is heterocyclyl or heteroaryl.

R ² is C _1-6 haloalkyl,
R ^3b , if present, is H or halogen;
R ^3c is C _1-6 alkoxy, and R ^N is

20. The compound of claim 19, which is

21. The compound of claim 20, wherein ^R2 is _CF3 and ^R3c is methoxy.

2. The compound of Claim 1, or a salt, hydrate, or prodrug thereof, selected from the group consisting of:

A formate salt of the compound of claim 1 .

A sulfate salt of the compound of claim 1 .

A citrate salt of the compound of claim 1 .

A hydrochloride salt of the compound of claim 1 .

A prodrug of the compound of claim 1.

A pharmaceutical composition comprising a compound according to any one of claims 1-27 and a pharmaceutically acceptable excipient.

A composition for promoting bone formation in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1-27 .

30. The composition of claim 29, wherein said bone formation is promoted at a surgical site of injury or local condition.

31. The composition of Claim 30, wherein said bone formation is promoted at a surgical site selected from the group consisting of fractures and weakened bones.

31. The composition of claim 30, wherein the subject is in need of spinal fusion, arthrodesis, or an orthopedic or periodontal synthetic bone graft or implant.

said bone formation is promoted at the surgical site; inflammation, celiac disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease, gastrectomy, amenorrhea, Cushing's disease, Cushing's syndrome, eating disorders, hyperparathyroidism, hyperthyroidism, hyperprolactinemia , Klinefelter's syndrome, thyroid disease, Turner's syndrome, steroid-induced osteoporosis, seizure- or depression-induced osteoporosis, immobility, arthritis, gonadotropin-releasing hormone agonist-induced low bone mass, thyroid drug-induced low bone mass, dilanthine (phenytoin) Depakote-induced low bone mass, chemotherapy-induced low bone mass, immunosuppressant-induced low bone mass, anticoagulant-induced low bone mass, Graves' disease, juvenile rheumatoid arthritis, malabsorption syndrome, anorexia nervosa, renal disease, anticonvulsant therapy, corticosteroid therapy, immunosuppressive therapy, inadequate nutrition, smoking, alcohol abuse, pregnancy-related osteoporosis, copper deficiency, type 2 aminoaciduria, Werner's syndrome , Heidu-Cheney syndrome, juvenile cortical hyperossification deformans, type 2 methylmalonic aciduria, cystathionine β-synthase deficiency, exemestane, hyper-IgE syndrome, hemochromatosis, singleton Merten syndrome, β-thalassemia, reflex sexual intercourse Neuropathic osteodystrophy, sarcoidosis, Winchester syndrome, Hallermann-Strife syndrome (HSS), cyproterone, glycerol kinase deficiency, Bonnet-Dechaume-Blanc syndrome, prednisolone use, heparin use, senile cutaneous atrophy osteodystrophy , Torg osteolytic syndrome, orchiectomy, Fabry disease, pseudoprogeria syndrome, Walcott-Larrison syndrome, ankylosing spondylitis, myeloma, systemic infantile hyalinosis, Albright's hereditary osteodystrophy, anorexia nervosa , autoimmune lymphoproliferative syndrome, Brown-Sequard syndrome, Diamond-Blackfan anemia, galactorrhea, hyperprolactinemia, ovarian hypoplasia, renal disease, Menkes disease, menopause, neuritis, ovarian function due to FSH resistance insufficiency, familial ovarian insufficiency, premature aging, primary biliary cirrhosis, prolactinoma, familial prolactinoma, renal osteodystrophy, underweight, Werner's syndrome, bone cancer, brittle bone disease, osteonecrosis, osteomalacia, dysplasia fibrosis, osteogenesis imperfecta, Paget's disease,
30. The composition of claim 29, having a secondary low bone mass disease selected from the group consisting of osteoarthritis, osteomyelitis, tardive osteogenesis imperfecta, and congenital osteogenesis imperfecta .

30. The composition of claim 29, wherein the subject has a low bone mass/density condition, fracture, or periodontal disease.

35. The low bone mass condition of claim 34, wherein the low bone mass condition is selected from osteoporosis, osteopenia, osteogenesis imperfecta (OI), osteoporosis-pseudoglioma syndrome (OPPG), and secondary low bone mass conditions. composition .

The low bone mass conditions include osteoporosis, osteopenia, and osteoporosis-pseudoglioma syndrome (OPPG).
36. The composition of claim 35, wherein the composition is selected from the group consisting of:

30. The composition of claim 29, further comprising administering an osteoconductive matrix to said subject.

38. The composition of claim 37, wherein the osteoconductive matrix comprises an osteoinductive agent selected from the group consisting of bone allograft, bone autograft, and periodontal ligament cells.

The osteoconductive matrix is calcium salt, calcium sulfate, calcium phosphate, calcium phosphate cement, hydroxyapatite, coral-derived hydroxyapatite (HA), dicalcium phosphate, tricalcium phosphate (TCP), calcium carbonate, collagen, plaster of paris, phosphophorins, borosilicates, biocompatible ceramics, calcium phosphate ceramics, demineralized bone matrix, biphasic calcium phosphate, biocomposites, tantalum, titanium, polytetrafluoroethylene, sulfates, hydrogels, bioglasses, or combinations thereof; 38. The composition of claim 37.

A medical device comprising a structural support, wherein an implantable portion of said structural support is adapted to be permanently implanted within a subject, said implantable portion being attached to bone. , the structural support carries at least a partial outer coating , a partial inner coating, or both, comprising the compound of claim 1, at least one of which is any of claims 1-27. 2. The medical device , comprising the compound of claim 1 .

41. The medical device of claim 40, wherein the structural support allows osteoblasts/bone cells to migrate to the structural support and deposit bone mineral.

41. The medical device of claim 40, wherein the structural support has at least a partial outer coating, at least a partial inner coating, or at least a partial outer and inner coating.

41. The medical device of Claim 40, wherein the structural support has an at least partial internal coating.

41. The medical device of Claim 40, wherein the structural support is a cage, pin, rod, screw, orthopedic implant, or dental implant.

41. The medical device of Claim 40, wherein the structural support comprises a material selected from metals, polymers, ceramics, or combinations thereof.

46. The medical device of claim 45, wherein the metal is stainless steel, cobalt, chromium, chrome, titanium alloys, titanium, tantalum, or Trabecular Metal(R).

41. The medical device of claim 40, wherein said structural support is a titanium cage.

41. The medical device of claim 40, wherein the structural support is used for hip, knee, ankle, shoulder, dental implants or spinal fixation.

46. The medical device of Claim 45, wherein the ceramic is calcium phosphate, aluminum oxide, zirconium oxide, silicon oxide or hydroxyapatite.

Scaffolds and matrices wherein the structural support comprises synthetic materials, biological materials, biocomposites, naturally occurring polymers, synthetic biodegradable polymers, synthetic non-biodegradable polymers, bioceramics, bioglasses, or combinations thereof 41. The medical device of claim 40, wherein

4. The structural support is a scaffold or matrix comprising silk, collagen, gelatin, fibrinogen, elastin, keratin, actin, myosin, cellulose, amylose, dextran, chitin, chitosan, glycosaminoglycans, DNA or RNA. 40. The medical device according to 40.

The structural support is a scaffold or matrix comprising PLA, PGA, PLLA, PLGA, PCL, PLDLA, PDS, PGCL, PEA, PCA, PDLLA, PEU, PBT, HAP, TCP, CP ceramic, BCP, or TCP 41. The medical device of claim 40.

41. The medical device of Claim 40, wherein the structural support is a matrix comprising particles of porous material.

54. The medical device of claim 53, wherein the matrix has a pore size of at least 5 [mu]m.

41. The medical device of Claim 40, further comprising an anabolic agent.

wherein said anabolic agent is selected from the group consisting of parathyroid hormone (PTH) or analogs thereof, sclerostin antibody inhibitors, sclerostin inhibitors, BMPs, BMP agonists, bone marrow stem cell populations, and mesenchymal stem cell populations; 56. The medical device of claim 55.

57. The medical device of Claim 56, wherein the anabolic agent is parathyroid hormone (PTH) or an analogue thereof.

57. The medical device of claim 56, wherein said anabolic agent is selected from the group consisting of BMP2, BMP7, and BMP4.