WO2020124500A1 - Composé hétérocyclique contenant de l'azote, procédé de préparation correspondant et utilisation associée - Google Patents

Composé hétérocyclique contenant de l'azote, procédé de préparation correspondant et utilisation associée Download PDF

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Publication number
WO2020124500A1
WO2020124500A1 PCT/CN2018/122419 CN2018122419W WO2020124500A1 WO 2020124500 A1 WO2020124500 A1 WO 2020124500A1 CN 2018122419 W CN2018122419 W CN 2018122419W WO 2020124500 A1 WO2020124500 A1 WO 2020124500A1
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Prior art keywords
alkyl
substituted
unsubstituted
formula
nitrogen
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PCT/CN2018/122419
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English (en)
Chinese (zh)
Inventor
乐小勇
蒋青
朱健
陈新
胡代强
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江苏凯迪恩医药科技有限公司
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Priority to CN201880067236.3A priority Critical patent/CN111601789A/zh
Priority to PCT/CN2018/122419 priority patent/WO2020124500A1/fr
Publication of WO2020124500A1 publication Critical patent/WO2020124500A1/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1

Definitions

  • the invention relates to a nitrogen-containing heterocyclic compound, its preparation method and application.
  • osteoarthritis the most common musculoskeletal disorder. It is usually characterized by degeneration of articular cartilage, reactive hyperplasia of the joint margin and subchondral bone, and the clinical manifestation is the slow development of symptoms such as joint pain, tenderness, joint swelling, restricted mobility, and joint deformity.
  • OA osteoarthritis
  • Osteoarthritis is characterized by the progressive breakdown of articular cartilage and ultimately leads to functional disorders of synovial joints (Reginster, JY and NG. Khaltaev, 2002, Supp1: p.1-2), OA is caused by several types Mechanism-mediated, including enzymatic degradation of extracellular matrix, formation of defective new matrix, cell death and abnormal activation of cartilage and hypertrophic differentiation [Goldring, MB and SRGoldring Sci, 2010.1192(1): p.230-7] At present, OA is basically treated with pain intervention and surgical treatment.
  • MSCs Mesenchymal stem cells present in the bone marrow and most adult tissues can self-renew and differentiate into a variety of cell lineages, including chondrocytes, osteoblasts, and adipocytes (Pittenger, MF et al., Science, 1999.284 (5411 ):p.143-7), where mesenchymal stem cells include synovial mesenchymal stem cells, bone marrow mesenchymal stem cells, etc., studies have found that adult articular cartilage contains MSCs (about 3% of cells) capable of multi-lineage differentiation. In OA cartilage, these cells increase exponentially.
  • MSC mesenchymal stem cells
  • the problem to be solved by the present invention is the deficiency of the existing mesenchymal stem cell-induced compound deficiency, and provides a nitrogen-containing heterocyclic compound, intermediate, preparation method and application.
  • the nitrogen-containing heterocyclic compound has the application of inducing the differentiation of mesenchymal stem cells (MSC) into chondrocytes and repairing cartilage.
  • MSC mesenchymal stem cells
  • compositions and methods for treating, preventing, or ameliorating arthritis or joint damage by applying the compounds or compositions of the present invention to joints, cartilage tissue, or proximal cartilage tissue, or the entire body.
  • the invention also provides compositions and methods for inducing mesenchymal stem cells (MSC) to differentiate into chondrocytes.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a nitrogen-containing heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salts, its hydrates, its solvates, its polymorphs, its metabolites, its stereoisomers, its Tautomer or its prodrug:
  • X is O or S
  • Y is methylene
  • Z is a single bond or C 1 ⁇ C 4 alkylene
  • R a is C 6 ⁇ C 10 aryl group
  • R B is 5 to 6-membered heteroaryl, unsubstituted or substituted with one or more R c- substituted C 4 -C 8 cycloalkenyl, or, unsubstituted or substituted with one or more Rd , C 4 -C 8 heterocycloalkenyl
  • the hetero atom One or more selected from N, O, and S, and the number of hetero atoms is 1 to 2
  • the hetero atom is selected from one of N, O, and S
  • the number of heteroatoms is 1 to 2
  • the number of heteroatoms is 1 to 2
  • the substituents are the same or different;
  • the hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1 to 2; when there are multiple substituents R 1 or R 2 , the substituents are the same Or different
  • R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH, Unsubstituted or substituted with one or more of R 1-7 is C 1 ⁇ C 6 alkyl, unsubstituted or substituted with one or more of R 1-8 is C 3 ⁇ C 6 cycloalkyl, unsubstituted or substituted by a R 1-9 is substituted with one or more C 6 ⁇ C 10 aryl group, unsubstituted or substituted with one or more R 1-10 substituted 5- to 6-membered heteroaryl, unsubstituted or substituted with one or plural R 1 s -11 substituted C 1 ⁇ C 6 alkyl-O-, unsubstituted or substituted by one or more R 1-12 C 1 ⁇ C 6 alkyl-C( ⁇ O)-, unsubstituted or substituted by one or Multiple R 1-13 substituted C 1 ⁇ C 6 alkyl-C( ⁇ O)O-, un
  • R 1-1 and R 1-2 , R 1-3 and R 1-4 are independently H or C 1 -C 6 alkyl
  • the definitions of certain substituents in the nitrogen-containing heterocyclic compound as shown in Formula I may be as follows, and the definitions of unmentioned substituents are as described in any of the above schemes.
  • the Z is methylene, ethylene (eg -CH 2 CH 2 -or -CH(CH 3 )-) or isopropylene (eg -CH(CH 3 ) CH 2 -or -C(CH 3 ) 2 -), preferably methylene.
  • the , Said C 6 ⁇ C 10 aryl group is unsubstituted or substituted with one or more R a substituted phenyl.
  • the Is a bridged heterobicycloalkenyl group which is unsubstituted or substituted with one or more Rd , and the bridged heterobicycloalkenyl group is preferably 7-oxabicyclo[2.2.1]heptenyl (e.g. ).
  • the numbers of Ra , Rb , Rc and Rd are independently 1 or 2.
  • the Ra , Rb , Rc and Rd are independently located Adjacent position, meta position or para position, preferably adjacent position.
  • the Ra , Rb , Rc or Rd are fluorine, chlorine, bromine or iodine.
  • the 5- to 6-membered heteroaryl group is linked to the Connected.
  • the I s a phenyl group that is unsubstituted or substituted with one or more R 1 .
  • the Is a 6-membered heteroaryl group that is unsubstituted or substituted by one or more R 2 , in the 6-membered heteroaryl group, the hetero atoms are selected from N, the number of hetero atoms is 1 to 2, and the 6-membered hetero group Aryl is preferably pyridyl (e.g. ).
  • the number of R 1 and R 2 is independently 1 , 2 , 3 or 4.
  • the R 1 or R 2 is independently located Adjacent position, meta position or para position, preferably meta position or para position.
  • R 1 or R 2 is fluorine, chlorine, bromine or iodine, and for example, fluorine or chlorine.
  • said R 1 or R 2 is unsubstituted or substituted with one or more R 1-7 C 1 -C 6 alkyl, unsubstituted or substituted with one or more R 1 -11 substituted C 1 ⁇ C 6 alkyl-O-, unsubstituted or substituted by one or more R 1-12 C 1 ⁇ C 6 alkyl-C( ⁇ O)-, unsubstituted or substituted by one or Multiple R 1-13 substituted C 1 ⁇ C 6 alkyl-C( ⁇ O)O-, unsubstituted or substituted by one or more R 1-14 C 1 ⁇ C 6 alkyl-OC( ⁇ O )-, or, unsubstituted or substituted by one or more R 1-15 C 1 ⁇ C 6 alkyl-C( ⁇ O)NH-, wherein the C 1 ⁇ C 6 alkyl (for example Group, ethyl, propyl, butyl, pentyl, or hexy
  • said R 1 or R 2 is phenyl which is unsubstituted or substituted by one or more R 1-9 .
  • two adjacent R 1 and C 6 to C 10 aryl groups are directly connected to two Cs, or two adjacent R 2 and 5 to 6 membered heteroaryl groups
  • Two Cs directly connected to each other together form 1,3-dioxolane unsubstituted or substituted by one or more R 1-6 (eg among them
  • the carbon-to-carbon bond is shared with the C 6 -C 10 aryl group or the 5-6 membered heteroaryl group to form a paracyclic ring).
  • the C 1 -C 6 alkyl group (for example, methyl, ethyl Group, propyl, butyl, pentyl or hexyl) independently C 1 -C 4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl, for example isobutyl.
  • R 1-13 , R 1-14 or R 1-15 are fluorine, chlorine, bromine or iodine, and for example, fluorine.
  • the C 1 -C 6 alkyl eg methyl,
  • the R 1 or R 2 is trifluoromethyl or hydroxymethyl (for example ).
  • the R 1 or R 2 is
  • Y is methylene and Z is a single bond.
  • Y is Z is a single bond or C 1 -C 4 alkylene group, preferably Z is a single bond.
  • It is a C 6 -C 10 aryl group which is unsubstituted or substituted with one or more Ra, preferably an unsubstituted C 6 -C 10 aryl group.
  • R a, R b, R c or R d is -COOH or It is preferably -COOH.
  • R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH,
  • R 1-7 is C 1 ⁇ C 6 unsubstituted alkyl, unsubstituted or substituted with one or more of R 1-9 is C 6 ⁇ C 10 aryl group, or unsubstituted or substituted C 1 -C 6 alkyl-O- substituted with one or more R 1-11 ; or, when there are multiple substituents R 1 or R 2 , two adjacent R 1 and C 6 -C 10 aromatic Two Cs directly connected to the base, or two adjacent R 2 and two Cs directly connected to the 5-6 membered heteroaryl, together formed: unsubstituted or substituted by one or more R 1-6 Substituted C 3 -C 5 heterocycloalkyl.
  • X is O; Y is methylene; Z is a single bond;
  • R a or R d is COOH or
  • R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH,
  • R substituents are not substituted with 1-7 C 1 ⁇ C 6 alkyl, unsubstituted or substituted with one or more R 1-9 is C 6 ⁇ C 10 aryl group, unsubstituted or substituted with one or C 1 -C 6 alkyl-O- substituted with multiple R 1-11 ; or, when there are multiple substituents R 1 or R 2 , adjacent two R 1 and C 6 -C 10 aryl Two directly connected Cs, or two adjacent R 2 and two C directly connected to a 5-6 membered heteroaryl, together form an unsubstituted or substituted by one or more R 1-6 C 3 ⁇ C 5 heterocycloalkyl;
  • R 1 and R 2 are independently -CN, -COOH, unsubstituted or substituted with one or more R 1-7 C 1 -C 6 alkyl, unsubstituted or substituted with one or more R 1 -9 substituted C 6 -C 10 aryl, unsubstituted or C 1 -C 6 alkyl-O- substituted with one or more R 1-11 or, when there are multiple substituents R 1 or R 2 , Two adjacent R 1 and two C directly connected to the C 6 -C 10 aryl group together form a C 3 -C 5 heterocycloalkyl group which is unsubstituted or substituted by one or more R 1-6 .
  • the definition of certain substituents in the nitrogen-containing heterocyclic compound as shown in Formula I can be as follows, and the definitions of unmentioned substituents are as described in any of the above schemes :
  • X is S, Y is Z is a single bond or C 1 ⁇ C 4 alkylene;
  • R a is C 6 ⁇ C 10 aryl group, preferably unsubstituted C 6 ⁇ C 10 aryl group;
  • R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH,
  • R substituents are not substituted with 1-7 C 1 ⁇ C 6 alkyl, unsubstituted or substituted with one or more R 1-9 is C 6 ⁇ C 10 aryl group, unsubstituted or substituted with one or C 1 -C 6 alkyl-O- substituted with multiple R 1-11 ; or, when there are multiple substituents R 1 or R 2 , adjacent two R 1 and C 6 -C 10 aryl Two Cs directly connected, or two adjacent R 2 and two Cs directly connected to the 5-6 membered heteroaryl, together formed: unsubstituted or substituted by one or more R 1-6 C 3 ⁇ C 5 heterocycloalkyl;
  • R 1 and R 2 are independently halogen, OH, CN, COOH, or, unsubstituted or substituted with one or more R 1-7 C 1 -C 6 alkyl.
  • the nitrogen-containing heterocyclic compound represented by Formula I is preferably selected from any of the following compounds:
  • those skilled in the art can refer to the nitrogen-containing heterocyclic compound represented by Formula I, its pharmaceutically acceptable salts, its hydrates, its solvates, and its polycrystals Groups, their metabolites, their stereoisomers, their tautomers or their prodrugs, and their substituents are selected to provide a stable nitrogen-containing heterocyclic compound as shown in Formula I, Its pharmaceutically acceptable salts, its hydrates, its solvates, its polymorphs, its metabolites, its stereoisomers, its tautomers or its prodrugs, including but not limited to the practice of the invention The compounds described in the examples.
  • the present invention also includes isotope-labeled nitrogen-containing heterocyclic compounds represented by Formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, and their A stereoisomer, its tautomer, or a prodrug thereof, in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number.
  • isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (eg, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl).
  • Isotope-labeled compounds of the invention can be used for the determination of the tissue distribution of compounds and their prodrugs and metabolites; preferred isotopes for such determinations include 3 H and 14 C.
  • substitution with heavier isotopes such as deuterium (2H or D) can provide increased metabolic stability, which provides therapeutic advantages such as increased half-life in vivo or reduced dosage requirements.
  • the isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents according to the methods described herein.
  • the nitrogen-containing heterocyclic compound represented by Formula I can be synthesized by methods similar to those well known in the chemical arts.
  • steps and conditions refer to the steps and conditions of similar reactions in the art, especially according to the instructions herein.
  • the starting materials are usually from commercial sources such as Aldrich or can be easily prepared using methods well known to those skilled in the art (available through SciFinder, Reaxys online database).
  • the nitrogen-containing heterocyclic compound as shown in Formula I can also be prepared through the preparation of the nitrogen-containing heterocyclic compound as shown in Formula I, using conventional methods in the art, and the peripheral modification Furthermore, the other nitrogen-containing heterocyclic compound represented by Formula I described above is obtained.
  • the present invention provides a method for preparing the nitrogen-containing heterocyclic compound as shown in Formula I, which is Scheme I, Scheme II and Scheme III; wherein Scheme I includes the following steps: In an organic solvent, The compound represented by Formula II and the compound represented by Formula III are subjected to the cyclization reaction shown below to obtain the nitrogen-containing heterocyclic compound represented by Formula I;
  • Scheme two includes the following steps: In the phosphoric acid solution, the for The nitrogen-containing heterocyclic compound shown in Formula I undergoes an aromatization reaction to obtain for The nitrogen-containing heterocyclic compound shown in Formula I is sufficient; wherein, X is O; Y is methylene; Z and Is defined as shown above;
  • Scheme three includes the following steps: in an organic solvent, the compound represented by Formula I'and the sulfurization reagent are subjected to a sulfurization reaction as shown below to obtain the nitrogen-containing heterocyclic compound represented by Formula I;
  • the organic solvent may be a conventional organic solvent in this type of reaction in the art, and preferably an aromatic hydrocarbon solvent (such as toluene) in the present invention.
  • an aromatic hydrocarbon solvent such as toluene
  • the amount of the organic solvent may not be specifically limited so as not to affect the reaction; in the present invention, the mass volume of the compound represented by Formula II and the organic solvent is preferably 0.01 g/mL to 0.2g/mL (for example, 0.02g/mL to 0.03g/mL).
  • the molar ratio of the compound represented by Formula II to the compound represented by Formula III may be a conventional molar ratio in this type of reaction in the art, and the formula II described in the present invention
  • the molar ratio of the compound shown to the compound shown by Formula III is preferably 1.2:1 to 1:1.2.
  • the temperature of the cyclization reaction may be a conventional temperature in this type of reaction in the art, preferably 90°C to 120°C in the present invention.
  • the progress of the cyclization reaction can be monitored by conventional monitoring methods in the art (eg TLC or NMR), generally the end point of the reaction is when the compound of formula II disappears or no longer reacts .
  • the phosphoric acid solution may be a conventional phosphoric acid solution in this type of reaction in the art, and preferably 85% phosphoric acid aqueous solution in the present invention.
  • the molar volume ratio of the nitrogen-containing heterocyclic compound shown in Formula I to the phosphoric acid solution may be a conventional molar volume ratio in this type of reaction in the art, preferably 0.05 mol/L in the present invention ⁇ 0.2mol/L (0.1mol/L).
  • the temperature of the aromatization reaction may be a conventional temperature in this type of reaction in the art, preferably 90°C to 120°C in the present invention.
  • the progress of the aromatization reaction can be monitored by using conventional monitoring methods in the art (such as TLC or NMR), and the reaction is generally performed when the compound shown in Formula II disappears or no longer reacts end.
  • the organic solvent may be a conventional organic solvent in this type of reaction in the art, preferably an aromatic hydrocarbon solvent (such as toluene) in the present invention.
  • an aromatic hydrocarbon solvent such as toluene
  • the sulfidation reagent may be a conventional sulfidation reagent in this type of reaction in the art, and it is preferably Lawson's reagent in the present invention.
  • the amount of the organic solvent may not be specifically limited so as not to affect the reaction; in the present invention, the mass of the compound represented by formula I'and the organic solvent are relatively good It is 0.01 g/mL to 0.2 g/mL (for example, 0.02 g/mL).
  • the molar ratio of the compound represented by formula I′ to the sulfurization reagent may be a conventional molar ratio in the art, and the compound represented by formula I” described in the present invention is
  • the molar ratio of the vulcanizing agent is preferably 1:1 to 1:3 (for example, 1:2).
  • the temperature of the vulcanization reaction may be a conventional temperature in this type of reaction in the art, preferably 100°C to 120°C in the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the nitrogen-containing heterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorphic form thereof, Metabolites, their stereoisomers, their tautomers or their prodrugs, and at least one pharmaceutical excipient.
  • the pharmaceutical composition may also contain one or more additional active ingredients.
  • such a pharmaceutical composition may comprise one or more additional nitrogen-containing heterocycles represented by Formula I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, Its metabolites, its stereoisomers, its tautomers or its prodrugs.
  • the pharmaceutical composition may, for example, include, in addition to the nitrogen-containing heterocycle shown in Formula I, its pharmaceutically acceptable salts, its hydrates, its solvates, and many others One or more active ingredients other than the crystalline form, its metabolite, its stereoisomer, its tautomer or its prodrug.
  • the pharmaceutical composition further comprises a composite scaffold formed by one or more of collagen, chitosan and hyaluronic acid; it is used to induce mesenchymal stem cells to differentiate into chondrocytes.
  • the pharmaceutical composition may further include components suitable for formulation for intra-articular delivery; the components for intra-articular delivery include but are not limited to: angiogenin-like 3 protein (ANGPTL3) or its cartilage-forming variant, oral salmon calcitonin, SD-6010 (iNOS inhibitor), vitamin D3 (choline calciferol), collagen hydrolysate, FGF18, BMP7, avocado soybean unsaponified One or more of ASU and hyaluronic acid.
  • ANGPTL3 is described in more detail in WO/2011/008773 (incorporated in its entirety).
  • the nitrogen-containing heterocyclic compound as shown in Formula I its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its
  • the dosage of the stereoisomer, its tautomer or its prodrug may be a therapeutically effective amount.
  • the effective amount of the compound, pharmaceutical composition or drug of the present invention can be easily determined through routine experimentation, and the most effective and convenient route of administration and the most appropriate formulation can also be determined through routine experimentation.
  • the pharmaceutical excipients can be those widely used in the field of pharmaceutical production.
  • the excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or to promote the activity of the subject after the administration of the composition
  • the ingredients are effectively absorbed.
  • the pharmaceutical adjuvant may be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipients may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
  • excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; auxiliary materials such as cocoa
  • composition of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding, or lyophilizing processes.
  • the pharmaceutical dosage form of the compound of the present invention can be provided in the form of immediate release, controlled release, sustained release or target drug release system.
  • commonly used dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and lyophilized preparation.
  • special devices may be needed to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • compositions often consist of drugs, excipients, and container/sealing systems.
  • excipients also called inactive ingredients
  • the type of excipients added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps.
  • Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias.
  • the pharmaceutical dosage form of the compound of the present invention can be manufactured by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, manufacturing sugar-coated pills, tableting, suspending, squeezing, spray drying, Grinding, emulsification, (nano/micron level) encapsulation, wrapping or freeze-drying process.
  • the composition of the present invention may include one or more physiologically acceptable inactive ingredients that will facilitate the processing of the active molecule into a formulation for medical use.
  • the pharmaceutical composition of the present invention can be administered in any form, including injection (joint cavity), mucosa, topical or parenteral (infusion, injection, implantation, subcutaneous, intramuscular) administration.
  • the pharmaceutical composition of the present invention may also be a controlled-release or delayed-release dosage form (for example, liposomes or microspheres).
  • topical preparations include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations.
  • preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • suitable formulations of the pharmaceutical composition include, but are not limited to, liquid dosage forms suitable for parenteral administration.
  • Liquid form preparations include solutions, suspensions and emulsions, for example water or water/propylene glycol solutions.
  • liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • Suitable aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, stabilizers and thickeners as required.
  • Suitable aqueous suspensions can be prepared by dispersing finely divided active components in water with viscous materials such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl Methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic, and dispersants or wetting agents, such as naturally occurring phospholipids (eg, lecithin), condensation products of alkylene oxides and fatty acids (eg , Polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (for example, heptadecyloxyethanol), ethylene oxide and partial esters derived from fatty acids and hexitol ( For example, condensation products of polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide
  • the aqueous suspension may also contain one or more preservatives, such as ethyl paraben or n-propyl paraben, one or more colorants, one or more flavoring agents and one or more Sweeteners such as sucrose, aspartame or saccharin.
  • preservatives such as ethyl paraben or n-propyl paraben
  • colorants such as ethyl paraben or n-propyl paraben
  • flavoring agents such as sucrose, aspartame or saccharin.
  • Sweeteners such as sucrose, aspartame or saccharin.
  • the present invention also provides the nitrogen-containing heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salts, its hydrates, its solvates, its polymorphs, its metabolites, and its stereoisomers ,
  • the "one or more inducers in proteoglycan (Aggrecan), type II collagen (Collagen II) and Sox9” can be passed through one of proteoglycan (Aggrecan), type II collagen (Collagen II) and Sox9 Or a variety of induced mesenchymal stem cells differentiate into chondrocytes.
  • the inducer is a drug.
  • the present invention also provides a nitrogen-containing heterocyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorphic form thereof, a metabolite thereof, and a stereoisotope thereof Use of a conformer, its tautomer or its prodrug, or a pharmaceutical composition as described above in the preparation of a medicament.
  • the drug refers to a drug that can be used to treat or prevent diseases related to the induction of differentiation of mesenchymal stem cells into chondrocytes;
  • the diseases are preferably: arthritis or joint damage, such as Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, osteoporosis, or osteoarthritis;
  • the induction of differentiation of mesenchymal stem cells into chondrocytes means One or more of proteoglycan (Aggrecan), type II collagen (Collagen II) and Sox9 induce mesenchymal stem cells to differentiate into chondrocytes.
  • the inducer is used to expand the chondrocyte population in culture in vitro; autologous or allogenic chondrocyte transplantation can be performed.
  • the transplant can optionally be administered simultaneously with the treatment, which includes administration of the nitrogen-containing heterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, of the invention
  • the nitrogen-containing heterocyclic compound represented by Formula I a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, of the invention
  • chondrocytes can be harvested from an unimpaired small weight-bearing area of the damaged joint by arthroscopy, and can be described in the nitrogen-containing heterocyclic compound represented by Formula I of the present invention, its pharmacy In the presence of an acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomer or its prodrug, or a pharmaceutical composition as described above Culture to increase the number of cells before transplantation.
  • the swollen culture is then combined with the nitrogen-containing heterocyclic compound of formula I, its pharmaceutically acceptable salts, its hydrates, its solvates, its polymorphs, its metabolites, its The stereoisomers, their tautomers or their prodrugs, or the pharmaceutical composition as described above are mixed and placed in the joint space or directly into the defect.
  • the present invention also provides a method for improving arthritis or joint damage in mammals.
  • the method comprises administering to the joints of mammals an effective dose of the nitrogen-containing heterocyclic compound represented by Formula I, which is pharmaceutically acceptable Accepted salts, their hydrates, their solvates, their polymorphs, their metabolites, their stereoisomers, their tautomers or their prodrugs or pharmaceutical compositions as described above.
  • the disease is preferably arthritis or joint damage, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, osteoporosis, or osteoarthritis.
  • a method for inducing mesenchymal stem cells to differentiate into chondrocytes comprising contacting the mesenchymal stem cells with a sufficient amount of the nitrogen-containing heterocyclic compound shown in Formula I, which is pharmaceutically acceptable Salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomer or its prodrug or pharmaceutical composition as described above.
  • the nitrogen-containing heterocyclic compound shown in Formula I which is pharmaceutically acceptable Salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomer or its prodrug or pharmaceutical composition as described above.
  • the chondrocytes produce and maintain a cartilage matrix composed of collagen and proteoglycan.
  • Chondrocytes are derived from the differentiation of mesenchymal stem cells (MSC). MSCs are pluripotent stem cells, which can differentiate into several different types of cells, including but not limited to osteoblasts, chondrocytes, and adipocytes. Differentiation is a process of specialized cell types formed by less specialized cell types, such as chondrocytes from MSC.
  • the nitrogen-containing heterocyclic compound represented by Formula I can be directly injected into the synovial fluid of the joint, administered systemically (oral or intravenous) or directly into the cartilage defect, used alone or with appropriate
  • the carrier is compounded to prolong the release of protein.
  • the nitrogen-containing heterocyclic compound represented by Formula I can be used in combination with a periosteum or periosteum graft containing cartilage that can form cartilage and/or contribute to transplantation Cells or their precursor cells are kept in place.
  • the nitrogen-containing heterocyclic compound represented by Formula I can be used to repair cartilage damage together with joint lavage, bone marrow stimulation, abraded arthroplasty, subchondral drilling or microfragmentation of subchondral bone .
  • the nitrogen-containing heterocyclic compound represented by Formula I due to the administration of the nitrogen-containing heterocyclic compound represented by Formula I, its pharmaceutically acceptable salts, its hydrates, its solvates, its polymorphs, its metabolites, and its stereotypes according to the present invention
  • additional surgical treatment may be required to properly contour the newly formed cartilage surface.
  • the pharmaceutical composition may be formulated for intra-articular delivery.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by specific substituents.
  • the substituents are mutually independent, that is, the one or more substituents may be different from each other, or may be the same of.
  • a substituent group may be substituted at each substitutable position of the substituted group.
  • the substituents may be substituted at the same positions or differently.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition for the variable lists “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” represents the linked group, respectively An alkylene group or an arylene group.
  • halo or halogen are each independently fluorine, chlorine, bromine, or iodine (for example, fluorine or chlorine).
  • alkyl is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 as defined in “C 1 -C 6 alkyl”, includes groups with 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched structure .
  • C 1 -C 6 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, pentyl, and hexyl, etc. .
  • the alkyl group when the alkyl group is clearly represented as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halo-(C 1 ⁇ C 6
  • the C 1 -C 6 alkyl group in the “alkyl group” should be understood as a C 1 -C 6 alkylene group.
  • alkylene means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group.
  • alkylene groups include methylene (-CH 2 -), ethylene (including -CH 2 CH 2 -or -CH(CH 3 )-), isopropylene (including -CH(CH 3 ) CH 2 -or -C(CH 3 ) 2 -) and so on.
  • the alkylene group may be optionally substituted with one or more substituents described in the present invention.
  • cycloalkyl refers to a saturated monocyclic, polycyclic, or bridged carbocyclic substituent.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.; wherein, C 3 ⁇ C 6 cycloalkyl Rings having 3 to 6 carbon atoms include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkenyl refers to a cyclic non-aromatic hydrocarbon group containing the specified number of carbon atoms and at least one carbon-carbon double bond. There is preferably one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present.
  • heterocycloalkyl refers to a group of 3-10 membered saturated heterocyclic systems containing 1-4 heteroatoms selected from O, N and S. In a heterocycloalkyl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as long as valency permits. Heterocycloalkyl groups may be either monocyclic (“monocyclic heterocycloalkyl") or fused, bridged or spiro ring systems (eg bicyclic systems ("bicyclic heterocycloalkyl ”)) and is saturated. Heterocycloalkyl bicyclic ring systems can include one or more heteroatoms in one or two rings.
  • the sulfur atom of the ring can optionally be oxidized to an S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxide.
  • Heterocycloalkyl within the scope of this definition includes, but is not limited to: azetidinyl, glycidyl, thietyl, tetrahydrofuranyl, pyrrolidinyl, dioxolyl, piperidinyl, Tetrahydropyranyl, sulfided cyclopentyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, and thiepanyl.
  • heterocyclenyl refers to a 5-10 membered cyclic non-aromatic containing a specified number of carbon atoms and at least one carbon-carbon double bond, and containing 1-4 heteroatoms selected from O, N, and S Hydrocarbyl.
  • a carbon-carbon double bond is preferably present; and includes bicyclic groups.
  • aryl refers to a 4n+2 aromatic having 6-14 ring atoms and zero heteroatoms provided in the aromatic ring system, monocyclic or polycyclic (eg, bicyclic or tricyclic) Groups of ring systems (eg, having 6, 10, or 14 shared p-electrons in a cyclic array) ("C 6 -C 14 aryl").
  • Examples of the above aryl unit include phenyl, naphthyl, phenanthrenyl, or anthracenyl.
  • heteroaryl refers to a 5-10 member having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur) Groups of monocyclic or bicyclic 4n+2 aromatic ring systems (for example, having 6 or 10 shared p electrons in a cyclic array) ("5-10 membered heteroaryl").
  • Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnoline, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , Benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline.
  • haloalkyl means an alkyl group substituted with halogen at any position.
  • haloalkyl includes the above definitions of halogen and alkyl.
  • the description method "...independently” used in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can be independent Ground is the same or different specific group.
  • the description “...independently” may mean that in different groups, the specific options expressed between the same symbols do not affect each other; it may also mean that in the same group, the same symbol The specific options expressed between do not affect each other.
  • the compounds described herein may contain one or more asymmetric centers, and thus can exist in various isomer forms, for example, enantiomers and/or diastereomers.
  • the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and containing one or more A mixture of stereoisomers.
  • Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be asymmetric Prepared synthetically.
  • HPLC high pressure liquid chromatography
  • Stereoisomer refers to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Enantiomer refers to two isomers of a compound that cannot overlap but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Diastereomer mixtures can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • any asymmetric atoms (for example, carbon, etc.) of the compounds disclosed in the present invention can exist in racemic or enantiomerically enriched forms, such as (R)-, (S)-, or (R,S)-configuration forms exist.
  • each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least in (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography Method and/or step crystallization method.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be interconverted by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers also known as prototropictautomers
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use with humans and animals Used in contact with tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base and Compound I, which retains the biological activity of Compound I.
  • the organic acid can be various organic acids that can form salts in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid , Propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalene sulfonic acid and one or more of salicylic acid.
  • the inorganic acid may be various conventional inorganic acids capable of forming salts in the art, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic base may be a variety of conventional organic bases capable of forming salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines Species.
  • the tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine.
  • the aniline organic base is preferably N,N-dimethylaniline.
  • the pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine.
  • the inorganic base may be various inorganic bases conventionally capable of forming salts in the art, preferably alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate , One or more of potassium bicarbonate and sodium bicarbonate.
  • the alkali metal hydride is preferably sodium hydride and/or potassium hydride.
  • the alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • the alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium t-butoxide and sodium t-butoxide.
  • the "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing acid or base groups by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the compounds provided by the invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention.
  • Any compound that can be transformed in vivo to provide a biologically active substance ie, a nitrogen-containing heterocyclic compound represented by Formula I
  • a prodrug within the scope and spirit of the present invention.
  • a compound containing a carboxyl group can form a physiologically hydrolyzable ester, which is used as a medicine by hydrolyzing in vivo to obtain the compound represented by Formula I itself.
  • the prodrug is preferably administered orally, because hydrolysis occurs in many cases mainly under the influence of digestive enzymes. When the ester itself is active or hydrolysis occurs in the blood, parenteral administration can be used.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • the compounds of formula I and salts thereof of the present invention are intended to include all solid forms of compounds of formula I and salts thereof.
  • Compounds of formula I and their salts are also intended to cover all solvated (eg hydrated) and unsolvated forms of compounds of formula I and their salts.
  • the term "metabolite” used in the present invention refers to a product obtained by metabolizing a specific compound or its salt in the body.
  • the metabolite of a compound can be identified by techniques well known in the art, and its activity can be characterized by an experimental method as described in the present invention.
  • Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like.
  • the present invention includes metabolites of the compound, including metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • the compounds of formula I and salts thereof of the present invention are intended to include all solid forms of compounds of formula I and salts thereof.
  • Compounds of formula I and their salts are also intended to cover all solvated (eg hydrated) and unsolvated forms of compounds of formula I and their salts.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association formed by the solvent molecule being water.
  • esters in the present invention refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl group or a carboxyl group.
  • esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol or acid.
  • the compounds of formula I of the present invention contain carboxyl groups and can form in vivo hydrolyzable esters with appropriate groups.
  • groups include, but are not limited to, alkyl groups, arylalkyl groups, and the like.
  • mammal refers to any mammal classified as a mammal, including humans, domesticated animals and farm animals, as well as zoo, competitive or pet animals such as cattle (eg cows), horses, dogs, Sheep, pigs, rabbits, goats, cats, etc.
  • “Therapeutically effective amount or dose” or “therapeutically sufficient amount or dose” or “effective or sufficient amount or dose” 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 those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Pharmaceutical, Science, and Technology) Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • Treatment refers to any sign of success in treating or ameliorating injury, pathology, condition or symptom (eg pain), including any goals or subjective parameters such as relief; alleviation of symptoms ; Reduce the frequency or duration of symptoms or conditions; or, in some cases, prevent the onset of symptoms or conditions.
  • the treatment or improvement of symptoms may be based on any objective or subjective parameters; including, for example, the results of physical examinations.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive progress effect of the present invention is that the nitrogen-containing heterocyclic compound has a good expression-inducing activity for one or more of proteoglycan (Aggrecan), type II collagen (Collagen II) and Sox9; Mesenchymal stem cells (MSCs) differentiate into chondrocytes and repair cartilage.
  • proteoglycan Aggrecan
  • type II collagen Collagen II
  • Sox9 Sox9
  • MSCs Mesenchymal stem cells differentiate into chondrocytes and repair cartilage.
  • room temperature means 10-30°C; overnight means 8-15 hours, such as 12 hours; eq means equivalent; solvent ratio such as PE:EA means volume ratio; Lawessons reagent means Lawson's reagent.
  • Human-derived synovial stem cells The experimental samples were provided by Nanjing Gulou Hospital.
  • the balance weighs NaCl 8g, KCl 0.2g, Na 2 HPO 4 ⁇ 12H 2 O 3.58g, KH 2 PO 4 0.24g, ddH 2 O to 800ml, add appropriate amount of NaOH to adjust the pH to 7.2 and then ddH 2 O to 1L, used after autoclaving.
  • n(mmol) (Wt(mg)/Mol ⁇ Wt) ⁇ HPLC(%), the drug is dissolved in DMSO.
  • SMSCs Human-derived synovial mesenchymal stem cells
  • Trizol method extracts RNA and reverse transcribes it into cDNA.
  • the relative expression levels of Aggrecan, Collagen II and Sox9 in cells were detected.
  • the relative expression level was detected using the LightCycler 480II system (Roche).
  • the carrier (DMSO) was used as a control to determine the basal level of chondrocyte differentiation.
  • the target genes to be tested in this experiment were Aggrecan, Collagen II, sox9, and the internal reference gene was GAPDH.
  • the three genes Aggrecan, Collagen II, and sox9 are chondrogenic genes.
  • QPCR analysis showed that if the expression levels of Aggrecan, Collagen II, and sox9 genes increased, it proved that the mesangial mesenchymal stem cells induced by drugs had a tendency to differentiate into chondrocytes.
  • Select proteoglycan Aggrecan
  • type II collagen Collagen II
  • Sox9 expression higher than the vehicle control compound for the next induction experiment was selected from the expression of the vehicle control compound for the next induction experiment.
  • a ⁇ D represent different activity levels, see the table below for details:
  • Activity level mAGGRECAN mCOL2A1 SOX9 A 0-0.5 0-1.0 0-1.0 B 0.5-1.0 1.0-5.0 1.0-10.0

Abstract

La présente invention concerne un composé hétérocyclique contenant de l'azote, un procédé de préparation correspondant et une utilisation associée. La présente invention concerne un composé hétérocyclique contenant de l'azote tel que représenté par la formule I, et un sel pharmaceutiquement acceptable, un hydrate, un solvate, un polymorphe, un métabolite, un stéréoisomère, un tautomère, ou un promédicament de celui-ci. Le composé hétérocyclique contenant de l'azote est utile dans l'induction et la stimulation de cellules souches mésenchymateuses (MSC) afin de se différencier en chondrocytes pour réparer le cartilage. L'invention concerne également une composition et une méthode de traitement, de prévention ou de soulagement de l'arthrite ou de dommages articulaires. Le composé ou la composition selon la présente invention peut être appliqué à une articulation, un tissu cartilagineux ou un tissu proximal cartilagineux, ou à tout le corps. La présente invention concerne en outre une composition et un procédé pour l'induction de cellules souches mésenchymateuses (MSC) afin de se différencier en chondrocytes.
PCT/CN2018/122419 2018-12-20 2018-12-20 Composé hétérocyclique contenant de l'azote, procédé de préparation correspondant et utilisation associée WO2020124500A1 (fr)

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Citations (2)

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CN1867331A (zh) * 2003-09-17 2006-11-22 美国政府健康及人类服务部 作为TNF－α调节剂的沙利度胺类似物
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CN1867331A (zh) * 2003-09-17 2006-11-22 美国政府健康及人类服务部 作为TNF－α调节剂的沙利度胺类似物
CN106459076A (zh) * 2014-05-13 2017-02-22 诺华股份有限公司 用于诱导软骨发生的化合物和组合物

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