WO2022012058A1 - Composé à cycles fusionnés, et intermédiaire de celui-ci, procédé de préparation associé et application - Google Patents

Composé à cycles fusionnés, et intermédiaire de celui-ci, procédé de préparation associé et application Download PDF

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WO2022012058A1
WO2022012058A1 PCT/CN2021/079576 CN2021079576W WO2022012058A1 WO 2022012058 A1 WO2022012058 A1 WO 2022012058A1 CN 2021079576 W CN2021079576 W CN 2021079576W WO 2022012058 A1 WO2022012058 A1 WO 2022012058A1
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formula
membered heteroaryl
independently
substituted
group
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PCT/CN2021/079576
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Chinese (zh)
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朱健
蒋青
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江苏凯迪恩医药科技有限公司
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a condensed ring compound and its intermediate, preparation method and application.
  • Wnt signaling pathway is known to play a role in the inductive interactions regulating growth and differentiation, and also in the homeostatic maintenance of postembryonic tissue integrity. Wnt stabilizes cytoplasmic leukin, which stimulates the expression of genes including cmyc, c-jun, fra-1 and cyclin D1.
  • Wnt signaling can lead to developmental defects and is implicated in the development of a variety of human cancers.
  • the Wnt pathway has also been found to be involved in the maintenance of stem or progenitor cells in a growing list of adult tissues including skin, blood, gut, prostate, muscle and nervous system.
  • MSCs Mesenchymal stem cells present in the bone marrow and most adult tissues are capable of self-renewal and differentiation into a variety of cell lineages, including chondrocytes, osteoblasts, and adipocytes (Pittenger, MF et al., Science, 1999.284 (5411). ):p.143-7), among which mesenchymal stem cells include synovial mesenchymal stem cells, bone marrow mesenchymal stem cells, etc. The study found that adult articular cartilage contains MSCs capable of multi-lineage differentiation (about 3% of cells). In view of the above characteristics of mesenchymal stem cells, how to realize the osteogenic and chondrogenic directional differentiation of mesenchymal stem cells and provide basis and ideas for the treatment of related diseases has become the focus of everyone's attention.
  • Wnt inhibitors that can be used in stem cell research or treatment of any disease characterized by aberrant activation of Wnt, as well as to induce mesenchymal stem cells for the treatment and/or amelioration of related diseases and disorders.
  • the present invention provides a condensed ring compound and its intermediate, preparation method and application which are different from the prior art.
  • the compounds of the present invention are useful as Wnt inhibitors and mesenchymal stem cell inducers for the treatment and/or amelioration of related diseases and disorders.
  • the present invention provides a compound represented by formula Ia or Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its interconversion Isomers or their prodrugs:
  • R 1, R 2, R 3, R 1 ', R 2' and R 3 ' is independently H, C 6 ⁇ C 18 aryl group or substituted with one or more of R 1-1 is C 6 ⁇ Aryl of C 18 (when there are multiple R 1-1s , the R 1-1s are the same or different);
  • Each R 1-1 is independently halogen or C 1 -C 4 alkyl
  • R 4 , R 5 , R 4 ' and R 5 ' are independently H or C 1 -C 4 alkyl, but R 4 and R 5 are not H at the same time;
  • R 6 and R 6 ' are independently C 6 ⁇ C 18 aryl group, and one or more of R 6-1 is a substituted C 6 ⁇ C 18 aryl group (when R 6-1 is a plurality of said R 6-1 is the same or different), a 5- to 10-membered heteroaryl group, or a 5- to 10-membered heteroaryl group substituted by one or more R 6-2 (when there are more than one R 6-2, the R 6-2 6-2 same or different); the heteroatoms in the 5-10-membered heteroaryl group are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 ; heteroatom one or more of the R 6- 2-substituted 5 to 10-membered heteroaryl group in the 5 to 10-membered heteroaryl group is independently selected from N, O and S, one kind or Various, the number of heteroatoms is 1, 2, 3 or 4;
  • R 6-1 and R 6-2 are independently amino or and
  • R 6-1-1 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group.
  • R 1 , R 2 , R 3 , R 1 ', R 2 ' and R 3 ' are independently C 6 -C 18 aryl or one or more R 1-1 substituted
  • the C 6 -C 18 aryl group is a C 6 -C 14 aryl group (such as phenyl, naphthyl, anthracenyl or phenanthrenyl), and further may be benzene base.
  • R 1 , R 2 , R 3 , R 1 ', R 2 ' and R 3 ' are independently one or more R 1-1 substituted C 6 -C 18 aryl groups , the number of the R 1-1 is one.
  • R 1-1 when R 1-1 is halogen, the halogen is F, Cl, Br or I, and it can also be F.
  • R 1 , R 2 , R 3 , R 1 ', R 2 ' and R 3 ' are independently one or more R 1-1 substituted C 6 -C 18 aryl groups
  • the one or more aryl groups of C 6 -C 18 substituted by R 1-1 are fluorophenyl groups, which may further be
  • R 4 , R 5 , R 4 ' and R 5 ' are independently C 1 -C 4 alkyl groups
  • the C 1 -C 4 alkyl groups are methyl, Ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl, which can be methyl or isopropyl.
  • R 6 and R 6 ' are independently 5-10-membered heteroaryl groups or 5-10-membered heteroaryl groups substituted by one or more R 6-2 , the 5- to 10-membered heteroaryl groups
  • the heteroatom in the 10-membered heteroaryl group may be N, and the number of heteroatoms may be one.
  • R 6 and R 6 ' are independently a 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted by one or more R 6-2, the 5- to 10-membered heteroaryl
  • the 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group.
  • R 6 and R 6 ' are independently 5-10-membered heteroaryl groups or 5-10-membered heteroaryl groups substituted by one or more R 6-2 , the 5- to 10-membered heteroaryl groups
  • the heteroatom in the 10-membered heteroaryl group may be N, and the number of heteroatoms may be 1; the 5-10-membered heteroaryl group may further be a pyridyl group, such as
  • R 6 and R 6 ' is independently substituted with one or more R 6-2 is 5 to 10-membered heteroaryl, said R 6-2 is a number .
  • R 6-2 when the R 6-1-1 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl , or tert-butyl, and can also be or tert-butyl.
  • R 6 and R 6 ' are independently one or more R 6-2 substituted 5-10-membered heteroaryl groups
  • the one or more R 6-2 substituted heteroaryl groups 5-10-membered heteroaryl group is
  • the compound represented by formula Ia or Ib its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer In its isomer, its tautomer or its prodrug:
  • R 1 and R 1 ' are independently C 6 ⁇ C 18 aryl group, or substituted with one or more of R 1-1 is C 6 ⁇ C 18 aryl group;
  • R 2 , R 3 , R 2 ′ and R 3 ′ are independently H;
  • R 1-1 is halogen
  • R 4 and R 5 is a C 1 -C 4 alkyl group, and the other is H;
  • R 4 ' and R 5 ' are H;
  • R 6 and R 6 ' are independently 5-10-membered heteroaryl or 5-10-membered heteroaryl substituted by one or more R 6-2;
  • Each R 6-2 is independently and
  • R 6-1-1 is a C 1 -C 4 alkyl group.
  • R 1 and R 1 ' are independently one or more C 6 -C 18 aryl groups substituted by R 1-1.
  • R 6 and R 6 ′ are independently one or more R 6-2 substituted 5-10-membered heteroaryl groups.
  • the compound represented by Formula Ia its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, Among its tautomers or prodrugs:
  • R 1 is a C 6 -C 18 aryl group or a C 6 -C 18 aryl group substituted by one or more R 1-1s;
  • R 2 and R 3 are H;
  • R 1-1 is halogen
  • R 4 is a C 1 -C 4 alkyl group
  • R 5 is H or C 1 -C 4 alkyl
  • R 6 is a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted by one or more R 6-2;
  • Each R 6-2 is independently and
  • R 6-1-1 is a C 1 -C 4 alkyl group.
  • the compound represented by Formula Ia its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, Among its tautomers or prodrugs:
  • R 1 is a C 6 -C 18 aryl group or a C 6 -C 18 aryl group substituted by one or more R 1-1s;
  • R 2 and R 3 are H;
  • R 1-1 is halogen
  • R 4 is H or C 1 -C 4 alkyl
  • R 5 is a C 1 -C 4 alkyl group
  • R 6 is a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted by one or more R 6-2;
  • Each R 6-2 is independently and
  • R 6-1-1 is a C 1 -C 4 alkyl group.
  • the compound represented by Formula Ia its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, Among its tautomers or prodrugs:
  • R 1 is a C 6 -C 18 aryl group or a C 6 -C 18 aryl group substituted by one or more R 1-1s;
  • R 2 and R 3 are H;
  • R 1-1 is halogen
  • R 4 is H
  • R 5 is a C 1 -C 4 alkyl group
  • R 6 is a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted by one or more R 6-2;
  • Each R 6-2 is independently and
  • R 6-1-1 is a C 1 -C 4 alkyl group.
  • the compound shown in formula Ib its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, Among its tautomers or prodrugs:
  • R 1 ' is a C 6 -C 18 aryl group substituted by one or more R 1-1;
  • R 2 ' and R 3 ' are H;
  • R 1-1 is halogen
  • R 4 ' and R 5 ' are H;
  • R 6 ' is a 5-10-membered heteroaryl group or a 5-10-membered heteroaryl group substituted by one or more R 6-2;
  • Each R 6-2 is independently and
  • R 6-1-1 is a C 1 -C 4 alkyl group.
  • the compound represented by the formula Ia or Ib is any of the following compounds:
  • the present invention also provides a preparation method of the above-mentioned compound shown in formula Ia or Ib,
  • the described preparation method of the compound shown in formula Ia is method 1 or method 2:
  • the method 1 includes the following steps: in a solvent, in the presence of a deprotection reagent, the compound represented by the formula IIa is subjected to the deprotection reaction of the following formula to obtain the compound represented by the formula Ia,
  • Q is an amino protecting group
  • R 1 , R 2 , R 3 , R 4 and R 6 are as defined above;
  • Method 2 includes the following steps: in a solvent, in the presence of a cyclization reagent, the compound shown in formula IIIa and the compound shown in formula IVa are subjected to the following cyclization reaction to obtain the compound shown in formula Ia. That's it,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as above, and R 5 is not hydrogen;
  • Method 3 includes the following steps: in a solvent, in the presence of a deprotection reagent, the compound shown in formula IIb is subjected to the deprotection reaction of the following formula to obtain the compound shown in formula Ib,
  • Q' is an amino protecting group
  • R 1 ', R 2 ', R 3 ', R 4 ' and R 6 ' are defined as described above;
  • Method 4 includes the following steps: in a solvent, in the presence of a cyclization reagent, the compound shown in formula IIIb and the compound shown in formula IVb are subjected to the following cyclization reaction to obtain the compound shown in formula Ib. You can;
  • R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' and R 6 ' are defined as above, and R 5 ' is not hydrogen.
  • the conditions and operations of the deprotection reactions described in methods 1 and 3 can be conventional conditions and operations in the art, and the following conditions and operations are particularly preferred in the present invention.
  • the amino protecting group can be a conventional amino protecting group in the art, preferably tetrahydropyranyl (THP).
  • the solvent can be a conventional solvent in the art, or a chlorinated hydrocarbon solvent, and further can be dichloromethane.
  • the deprotection reagent may be a conventional deprotection reagent in the art, or may be an organic silane compound (eg, triethylsilane) and an organic acid (eg, trifluoroacetic acid).
  • organic silane compound eg, triethylsilane
  • organic acid eg, trifluoroacetic acid
  • the molar ratio of the organosilane compound to the organic acid may be 1:1 to 1:5, for example, 1:2.5.
  • the temperature of the deprotection reaction may be 10 ⁇ 40° C., for example, room temperature.
  • the progress of the deprotection reaction can be monitored by conventional methods in the art (eg TLC, HPLC, nuclear magnetic resonance), and usually the end point of the reaction is that the compound represented by formula IIa or IIb no longer reacts or disappears.
  • the time of the deprotection reaction can be 10-18 hours, such as overnight.
  • the reaction solution after the reaction is concentrated, and the solid is precipitated and column chromatography is performed.
  • the conditions and operations of the concentration can all adopt the conventional conditions and operations in the art.
  • the conditions and operations for the precipitation of solids can all be conventional conditions and operations in the art.
  • the reagent used for the described solid precipitation can be an inorganic base, more preferably ammonia water (for example, the concentration of ammonia water is 5 mol/L).
  • the conditions and operations of the column chromatography can all adopt the conditions and operations conventional in the art.
  • the eluents used in the column chromatography can be alcohol reagents and chlorinated hydrocarbon reagents, and further can be dichloromethane and methanol (for example, the volume ratio of dichloromethane and methanol is 20:1-10:1).
  • the conditions and operations of the cyclization reaction described in methods 2 and 4 can be conventional conditions and operations in the art, and the following conditions and operations are particularly preferred in the present invention.
  • the solvent can be a conventional solvent in the art, or an amide solvent, and further can be DMF.
  • the cyclization reagent may be a conventional reagent in the art, or may be an alkali metal metabisulfite (eg, sodium metabisulfite).
  • alkali metal metabisulfite eg, sodium metabisulfite
  • the molar ratio of the cyclization reagent to the compound represented by formula IIIa or IIIb may be 4:1 to 1:1, for example, 2:1.
  • the temperature of the cyclization reaction can be 100-140°C, for example, 120°C.
  • the progress of the cyclization reaction can be monitored by conventional methods in the art (eg, TLC, HPLC, NMR), and usually the end point of the reaction is that the compound represented by formula IIIa or IIIb no longer reacts or disappears.
  • the time of the deprotection reaction may be 3 to 9 hours, for example, 6 hours.
  • the reaction solution after the reaction is cooled to room temperature, and solid is precipitated.
  • the conditions and operations for the precipitation of solids can all be conventional conditions and operations in the art.
  • the reagent used for the described solid precipitation can be water.
  • the present invention also provides a compound of formula IIa, IIb or IIIb:
  • Q or Q ' is an amino protecting group
  • R 1, R 2, R 3, R 4, R 6, R 1', R 2 ', R 3', R 4 ', R 5' and R 6 ' is an amino protecting group
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula Ia or Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereo Isomers, tautomers or prodrugs thereof, and pharmaceutical excipients.
  • the present invention also provides a compound represented by formula Ia or Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its mutual Use of the variant or its prodrug, or the above-mentioned pharmaceutical composition in the preparation of an inducer.
  • the above-mentioned inducer can induce proteoglycan (Aggrecan), type II collagen (Collagen II), sox9, type I collagen (collagen I), type X collagen (collagen X), osteogenic transcription gene ( Elevated expression of one or more genes in RUNX2) or alkaline phosphatase (ALP).
  • Aggrecan proteoglycan
  • type II collagen Collagen II
  • sox9 type I collagen
  • type X collagen type X collagen
  • osteogenic transcription gene Elevated expression of one or more genes in RUNX2
  • ALP alkaline phosphatase
  • the inducer can induce synovial stem cells to differentiate into chondroblasts and/or osteoblasts.
  • the inducer can also be used as a bone building agent, or in the treatment or prevention of periodontal disease, arthritis (such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic joints). one or more of osteoarthritis, osteoarthritis), joint damage, cartilage repair, osteogenesis regeneration, osteoporosis, osteopenia, spinal fusion, periodontal disease, and bone tumors.
  • the bone building agents can enhance fracture recovery and stimulate bone growth at the site of bone, joint or dental implants.
  • the present invention also provides a compound represented by formula Ia or Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its mutual Use of the variant or its prodrug, or the above-mentioned pharmaceutical composition, in the preparation of an inhibitor of one or more proteins in the Wnt pathway.
  • the present invention also provides a compound represented by formula Ia or Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its mutual Use of the variant or its prodrug, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating and/or preventing a disease associated with one or more proteins in the Wnt pathway.
  • the disease associated with one or more proteins in the Wnt pathway may be cancer, a disease associated with abnormal angiogenesis, a disease associated with cell proliferation and cell cycle, or a Wnt signaling component.
  • the cancer can be one or more of colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, bone cancer and leukemia.
  • the diseases related to abnormal angiogenesis can be hematopoietic system tumors of lymphoid lineage, hematopoietic system tumors of myeloid lineage, tumors of mesenchymal origin, tumors of central and peripheral nervous system and melanoma, seminoma, Kaposi's sarcoma, benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromas, atherosclerosis, arthritis, nephritis, restenosis after angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxin One or more of shock and fungal infection.
  • the disease caused by the variation or disorder of one or more of the Wnt signaling components can be colon polyposis, osteoporosis, pseudoglioma syndrome, familial exudative vitreous Retinopathy, retinal angiogenesis, early coronary heart disease, congenital limb amputation syndrome, paramesonephric reversion and virilization, SERKAL syndrome, type 2 diabetes, Fuhrman syndrome, AARRS short limb syndrome, dental nails Cutaneous dysplasia, obesity, split hand/foot deformity, caudal duplication syndrome, congenital missing teeth, Wilms tumor, skeletal dysplasia, focal skin hypoplasia, neural tube defect, alpha thalassemia syndrome, fragility One or more of Syndrome X, ICF Syndrome, Angelman Syndrome, Parr-Williams Syndrome, Belle-Williams Syndrome, Norrie Disease and Rett Syndrome.
  • the present invention also provides a compound represented by formula Ia or Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its mutual Use of the variant or its prodrug, or the above-mentioned pharmaceutical composition in the preparation of a medicine.
  • the drug can make synovial stem cells differentiate into chondroblasts and/or osteoblasts.
  • the medicament can also be used as a bone building agent, or for the treatment or prevention of periodontal disease, arthritis (such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis). , osteoarthritis), joint damage, cartilage repair, osteogenesis regeneration, osteoporosis, osteopenia, spinal fusion, periodontal disease and one or more of bone tumors.
  • arthritis such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis.
  • osteoarthritis joint damage, cartilage repair, osteogenesis regeneration, osteoporosis, osteopenia, spinal fusion, periodontal disease and one or more of bone tumors.
  • the bone building agents can enhance fracture recovery and stimulate bone growth at the site of bone, joint or dental implants.
  • the medicament can be used to treat and/or prevent diseases associated with one or more proteins in the Wnt pathway.
  • the medicines in the medicines, can be used to treat and/or prevent cancer, diseases related to abnormal angiogenesis, diseases related to cell proliferation and cell cycle, or one of Wnt signaling components. Disease caused by one or more variants or disorders.
  • cancer wherein the cancer, the disease associated with abnormal angiogenesis, the disease associated with cell proliferation and cell cycle, or the mutation or dysregulation of one or more of the Wnt signaling components
  • diseases caused are the same as before.
  • the present invention also provides a method for inducing synovial mesenchymal stem cells to differentiate into chondroblasts, inducing osteoblast differentiation or inhibiting osteoclast formation, comprising administering to a subject (preferably, a therapeutically effective amount to the subject)
  • a subject preferably, a therapeutically effective amount to the subject
  • the above-mentioned compound represented by formula Ia or Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomerism need to be treated Construct or its prodrug, or the above-mentioned pharmaceutical composition.
  • the subject can be a mammal, and further can be a human.
  • the chondroblasts and/or osteoblasts are derived from the differentiation of synovial mesenchymal stem cells.
  • MSCs are pluripotent stem cells that can differentiate into several different types of cells, including but not limited to osteoblasts, chondrocytes and adipocytes. Differentiation is the process of forming specialized cell types from less specialized cell types, such as chondrocytes from MSCs.
  • Said chondrocytes are produced or maintained by the expression of one or more genes in proteoglycan (Aggrecan), type II collagen (Collagen II) and sox9.
  • the described promotion of osteogenic differentiation and inhibition of osteoclast formation are composed of one of type I collagen (collagen I), type X collagen (collagen X), osteogenic transcription gene (RUNX2) or alkaline phosphatase (ALP). Or the expression of multiple genes is generated or maintained.
  • the present invention also provides a method of treating or preventing a disease associated with one or more proteins in the Wnt pathway, comprising administering to a subject (preferably a therapeutically effective amount to the subject) the above-described formula Ia for a subject in need of treatment Or the compound shown in Ib, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomer or its prodrug, or The above-mentioned pharmaceutical composition.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use.
  • patient is preferably a mammal, more preferably a human.
  • salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • acids addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • the pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluc
  • crystal form means that the ions or molecules in it are arranged in a strictly periodic manner in three-dimensional space in a certain manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism.
  • stereoisomers may exist as single stereoisomers or as mixtures thereof (eg, racemates).
  • stereoisomer refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • compound and “pharmaceutically acceptable salt”, if tautomers exist, may exist as single tautomers or as mixtures thereof, preferably as more stable tautomers The main form exists.
  • Atoms in the terms “compound” and “pharmaceutically acceptable salt” may exist in their natural or unnatural abundance. Taking a hydrogen atom as an example, its natural abundance means that about 99.985% of it is protium and about 0.015% is deuterium; its unnatural abundance means that about 95% of it is deuterium. That is, one or more atoms in the terms “compound” and “pharmaceutically acceptable salt” may be atoms that exist in unnatural abundance.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It resembles an alkyl group.
  • alkoxy refers to the group -OR X , wherein R X is an alkyl group as defined above.
  • cycloalkyl refers to a monovalent saturated cyclic alkyl group, preferably a monovalent saturated cyclic alkyl group having 3-7 ring carbon atoms, more preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl cyclopentyl, cyclopentyl or cyclohexyl.
  • heterocycloalkyl refers to a saturated monocyclic group having a heteroatom, preferably a 3-7 membered saturated one containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. single ring.
  • heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and the like.
  • Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4
  • aryl refers to a group having a 4n+2 aromatic ring system (eg, with 6, 10, or 14 shared p electrons in a cyclic array). Examples of the above-mentioned aryl unit include phenyl, naphthyl, phenanthryl, or anthracenyl.
  • heteroaryl refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur , such as furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazole base, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinoline olinyl, isoquinolinyl, etc.
  • pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • terapéuticaally effective amount refers to a dose that produces a therapeutic effect.
  • the exact dosage will depend on the purpose of the treatment and can be determined by one of skill in the art using known techniques (see, eg, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Pharmaceutical, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that: as a Wnt inhibitor and a mesenchymal stem cell inducer, the compound of the present invention can inhibit one or more of sox9, type I collagen, type X collagen, osteogenic transcription gene and alkaline phosphatase. This species has better induction effect, and then can be used to treat and/or improve related diseases and disorders.
  • the first step 3-bromo-5-nitropyridin-4-amine
  • Intermediate 1-4a Intermediate 1-2 (2.18 g, 10 mmol), Intermediate 1-3 (1.68 g, 1.2 eq), Pd(PPh 3 ) 4 (0.57 g, 0.05 eq), sodium bicarbonate ( 2.12g, 2eq), toluene (15ml), water (6ml), and ethanol (3ml) were added to a 50ml single-neck flask, replaced with nitrogen 5 times, heated to reflux for 8h reaction. After the reaction is completed, suction filtration, spin dry, and directly purify by silica gel column chromatography to obtain intermediate 1-4a as a yellow solid, and the yield is greater than 90%.
  • Intermediate 1-5a Intermediate 1-4a was dissolved in methanol, a catalytic amount of palladium on carbon was added, the air was replaced with hydrogen, the reaction was carried out at room temperature for 6 hours, suction filtration, and spin-dried to obtain dark red oily substance 1-5a, yield 95% .
  • Intermediate 1-4b Intermediate 1-4a (0.47g, 2mmol) was added to a 50ml single-neck flask, DMF (18ml), NaH (0.12g, 1.5eq) were added, and iodomethane (0.57g, 2eq) was added under ice bath ), and reacted in an ice bath for 30 min. After the reaction was completed, water was added, extracted with ethyl acetate, and then subjected to silica gel column chromatography to obtain the monomethylated product Intermediate 1-4b as a yellow solid with a yield of 41%.
  • R 1a is i-Bu:
  • the raw material 2-1 (3.4 g, 20 mmol) was dissolved in dichloromethane, cooled to 0°C in an ice bath, isovaleric acid chloride (1.5 eq) was dissolved in dichloromethane
  • Triethylamine (2eq) was added after post-dropping. Stir under ice bath for 30 min. Spin dry, add ethyl acetate to dissolve, wash the organic layer with dilute hydrochloric acid and saturated sodium bicarbonate, spin dry, and beat with dichloromethane to obtain 3.8 g of a white solid with a yield of 74%.
  • Intermediate 3-3 R 2 is THP: Intermediate 3-2 (R 2 is THP) was added to a 250ml three-necked flask, tetrahydrofuran (180ml), p-toluenesulfonic acid (0.69g, 0.1eq) were added, room temperature 3,4-Dihydropyran (6.72 g, 2 eq) was added dropwise and reacted at 40° C. for 8 h. Then, the solvent was evaporated under reduced pressure, and the crude product of Intermediate 3-3 was obtained by silica gel column chromatography. After beating with PE, a white solid was obtained, and the yield was 32%.
  • Intermediate 3-4 (boronic esterification): Intermediate 3-3 (R 2a is THP, 3.1 g, 10 mmol) was added to a 100 ml single-neck flask, and pinacol biboronate (3.0 g, 1.2 eq) was added , potassium acetate (2.94g, 3eq), Pd ( dppf) Cl 2 (0.36 g, 0.05eq), dioxane (26ml). The temperature was raised to reflux for 6 h, and after cooling, the intermediate 3-4 was filtered with suction, spin-dried, and purified by silica gel column chromatography as a white solid with a yield of 90%.
  • Intermediate 4-1 intermediate 3-4 (R 2a is THP, 1.07 g, 3 mmol), intermediate 2-2 (isovaleric acid, 0.93 g, 1.2 eq), sodium carbonate (0.95 g, 3 eq), Pd(dppf)Cl 2 (0.1g, 0.05eq), dioxane (9ml) and water (1.5ml) were added to a 50ml single-neck flask, nitrogen was replaced with air, and the temperature was raised to reflux and reacted for 8h. After cooling, suction filtration, spin drying, and purification by silica gel column chromatography to obtain Intermediate 4-1 as a yellow oil with a yield of 69%.
  • R 2a is THP, 1.07 g, 3 mmol
  • intermediate 2-2 isovaleric acid, 0.93 g, 1.2 eq
  • sodium carbonate 0.95 g, 3 eq
  • Pd(dppf)Cl 2 0.1g, 0.05eq
  • SMSCs Human-derived synovial mesenchymal stem cells
  • cartilage-forming genes proteoglycan (Aggrecan), type II collagen (Collagen II) and sox9, and osteogenic genes type I collagen (collagen I), type X collagen (collagen X), osteogenic transcription gene (RUNX2), basic Relative expression levels of genes such as phosphatase (ALP) in cells. Relative expression levels were detected using the LightCycler 480 II system (Roche). Basal levels of chondrogenic osteoblast differentiation were determined using vehicle (DMSO) as a control.
  • the target genes to be tested in this experiment are Aggrecan, Collagen II, sox9, Collagen I, Collagen X, RUNX2, and ALP, and the internal reference gene is GAPDH.
  • cartilage genes three genes, Aggrecan, Collagen II, and sox9, are cartilage genes, and collagen type I (collagen I), collagen X (collagen X), osteogenic transcription gene (RUNX2), and alkaline phosphatase (ALP) are osteogenic genes.
  • the gene, sox2 is a transcription factor that is a hallmark of induced stem cells. The specific results are shown in Table 1:
  • Table 2 refers to the relative expression levels of genes induced by the compounds of the present application compared to the control group (DMSO).

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Abstract

L'invention concerne un composé représenté par la formule Ia ou Ib, ainsi qu'un sel pharmaceutiquement acceptable, un hydrate, un solvate, un polymorphe, un métabolite, un stéréoisomère, un tautomère ou un promédicament de celui-ci. Le composé est utilisé en tant qu'inhibiteur de Wnt et inducteur de cellule souche mésenchymateuse. Il présente un effet d'induction satisfaisant sur un ou plusieurs éléments parmi le sox9, le collagène de type I, le collagène de type II, un gène de transcription ostéogénique et la phosphatase alcaline et peut ainsi être utilisé pour préparer un médicament afin de traiter et de soulager des maladies et des troubles pertinents.
PCT/CN2021/079576 2020-07-16 2021-03-08 Composé à cycles fusionnés, et intermédiaire de celui-ci, procédé de préparation associé et application WO2022012058A1 (fr)

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CN102595900A (zh) * 2009-08-10 2012-07-18 埃皮瑟瑞克斯有限公司 Wnt信号传导途径的吲唑抑制剂及其治疗用途
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CN104202984A (zh) * 2012-04-04 2014-12-10 萨穆梅德有限公司 Wnt信号通路的吲唑抑制剂及其治疗应用
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WO2016040182A1 (fr) * 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine et ses utilisations thérapeutiques
CN108472290A (zh) * 2015-11-06 2018-08-31 萨穆梅德有限公司 治疗骨关节炎
CN109476660A (zh) * 2016-06-01 2019-03-15 萨穆梅德有限公司 N-(5-(3-(7-(3-氟苯基)-3h-咪唑并[4,5-c]吡啶-2-基)-1h-吲唑-5-基)吡啶-3-基)-3-甲基丁酰胺的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102595899A (zh) * 2009-08-10 2012-07-18 埃皮瑟瑞克斯有限公司 作为wnt/b-联蛋白信号传导途径抑制剂的吲唑及其治疗用途
CN102595900A (zh) * 2009-08-10 2012-07-18 埃皮瑟瑞克斯有限公司 Wnt信号传导途径的吲唑抑制剂及其治疗用途
CN102821607A (zh) * 2009-12-21 2012-12-12 萨穆梅德有限公司 1H-吡唑并[3,4-b]吡啶及其治疗应用
CN104202984A (zh) * 2012-04-04 2014-12-10 萨穆梅德有限公司 Wnt信号通路的吲唑抑制剂及其治疗应用
CN105120862A (zh) * 2013-01-08 2015-12-02 萨穆梅德有限公司 Wnt信号途径的3-(苯并咪唑-2-基)-吲唑抑制剂及其治疗应用
WO2016040182A1 (fr) * 2014-09-08 2016-03-17 Samumed, Llc 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine et ses utilisations thérapeutiques
CN108472290A (zh) * 2015-11-06 2018-08-31 萨穆梅德有限公司 治疗骨关节炎
CN109476660A (zh) * 2016-06-01 2019-03-15 萨穆梅德有限公司 N-(5-(3-(7-(3-氟苯基)-3h-咪唑并[4,5-c]吡啶-2-基)-1h-吲唑-5-基)吡啶-3-基)-3-甲基丁酰胺的制备方法

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