WO2020142865A1 - Composé benzamide, intermédiaires, procédé de préparation et utilisation - Google Patents

Composé benzamide, intermédiaires, procédé de préparation et utilisation Download PDF

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Publication number
WO2020142865A1
WO2020142865A1 PCT/CN2019/070573 CN2019070573W WO2020142865A1 WO 2020142865 A1 WO2020142865 A1 WO 2020142865A1 CN 2019070573 W CN2019070573 W CN 2019070573W WO 2020142865 A1 WO2020142865 A1 WO 2020142865A1
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substituted
alkyl
unsubstituted
formula
compound represented
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Chinese (zh)
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蒋青
乐小勇
陈新
胡代强
朱健
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Jiangsu Kdn Pharmaceutical Technology CoLtd
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Jiangsu Kdn Pharmaceutical Technology CoLtd
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Priority to CN201980019552.8A priority Critical patent/CN112004798A/zh
Priority to PCT/CN2019/070573 priority patent/WO2020142865A1/fr
Publication of WO2020142865A1 publication Critical patent/WO2020142865A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms

Definitions

  • the invention relates to a benzamide compound, intermediate, preparation method and application.
  • OA osteoarthritis
  • Degenerative disease 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. It was found that adult articular cartilage contains MSCs (approximately 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 defect that the existing mesenchymal stem cells induce insufficient compounds, and provides a benzamide compound, intermediate, preparation method and application.
  • the benzamide compounds have the application of inducing the differentiation of mesenchymal stem cells (MSC) into chondrocytes and repairing cartilage; they also provide compositions and methods for treating, preventing or ameliorating arthritis or joint damage through the compounds of the present invention Or the composition is applied to a joint, cartilage tissue or proximal cartilage tissue or whole body to perform; the present invention also provides a composition and method for inducing differentiation of mesenchymal stem cells (MSC) into chondrocytes.
  • MSC mesenchymal stem cells
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a benzamide compound represented by formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorphic form thereof, a metabolite thereof, a stereoisomer thereof, a Tautomer or its prodrug:
  • X is O or S
  • R is -OH, Or, unsubstituted or substituted with one or more of R a C 3 ⁇ C 5 heterocycloalkyl;
  • C 3 ⁇ C 5 heterocycloalkyl group in the heteroatom is selected from N, O and S in a One or more, the number of heteroatoms is 1 to 3, which contains at least one N atom, and its Connected; when a plurality of substituent groups R a, the same or different substituents;
  • the hetero atom is 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 substitution The basis is 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
  • two adjacent R 1 and two C directly connected to the C 6 to C 10 aryl group, or two adjacent R 2 and 5 to Two Cs directly connected to a 6-membered heteroaryl group together form an unsubstituted or substituted C 1-4 C 6 cycloalkyl group by one or more R 1-5 , or, unsubstituted or substituted by one or more R 1-6 substituted C 3 ⁇ C 5 heterocycloalkyl; (ie, forming a fused ring with the C 6 ⁇ C 10 aryl group or 5-6 membered heteroaryl group); the C 3 ⁇ C 5 In heterocycloalkyl, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 3; when there are multiple substituents R 1-5 or R 1-6 , The substituents are the same or different;
  • R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently H or C 1 -C 6 alkyl;
  • R is unsubstituted or substituted with one or more of R a C 3 ⁇ C 6 heterocycloalkyl.
  • R is a 5-membered heterocycloalkyl group which is unsubstituted or substituted with one or more Ra, and in the 5-membered heterocycloalkyl group, the hetero atom is selected from N, O and S One or more of them, the number of hetero atoms is 2, and the 5-membered heterocyclic alkyl group is preferably a thiazolyl group ).
  • the number of Ra is 1 or 2.
  • the Ra is located Adjacent position, meta position or para position, preferably adjacent position.
  • said Ra is 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.
  • the 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 unsubstituted or substituted by one or more R 1-9 phenyl.
  • 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 eg methyl, ethyl (Propyl, propyl, butyl, pentyl or hexyl
  • the C 1 -C 4 alkyl groups such as 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 is
  • the -CONH 2 In a preferred embodiment of the present invention, the -CONH 2 .
  • said R 1 or R 2 is trifluoromethyl.
  • X is S and R is -OH or
  • X is -O-, and R is unsubstituted or substituted with one or more R a C 3 -C 6 heterocycloalkyl.
  • R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH, Unsubstituted or substituted with one or more substituents R 1-7 is C 1 ⁇ C 6 alkyl, unsubstituted or substituted with one or more of R 1-9 is C 6 ⁇ C 10 aryl group; alternatively, when substituents R When 1 or R 2 are plural, two adjacent R 1 and two C directly connected to the C 6 to C 10 aryl group, or two adjacent R 2 and 5 to 6 membered heteroaryl group Two Cs directly connected to each other together form a C 4 ⁇ C 6 cycloalkyl group which is unsubstituted or substituted with one or more R 1-5 , or, C which is unsubstituted or substituted with one or more R 1-6 3 to C 5 heterocycloalkyl.
  • X is S; R is -OH or Preferably, R is -OH, Located at Position or alignment of
  • R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH, Unsubstituted or substituted with one or more substituents R 1-7 is C 1 ⁇ C 6 alkyl, unsubstituted or substituted with one or more of R 1-9 is C 6 ⁇ C 10 aryl group; alternatively, when substituents R When 1 or R 2 are plural, two adjacent R 1 and two C directly connected to the C 6 to C 10 aryl group, or two adjacent R 2 and 5 to 6 membered heteroaryl group Two Cs directly connected to each other together form a C 4 ⁇ C 6 cycloalkyl group which is unsubstituted or substituted with one or more R 1-5 , or, C which is unsubstituted or substituted with one or more R 1-6 3 to C 5 heterocycloalkyl.
  • X is O; R is unsubstituted or substituted with one or more of R a C 3 ⁇ C 5 heterocycloalkyl; preferably Located at Adjacent to
  • R 1 and R 2 are independently halogen, -CN, -COOH, unsubstituted or substituted C 1 -C 6 alkyl group by one or more R 1-7 , unsubstituted or substituted by one or more R 1-9 Substituted C 6 -C 10 aryl; 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, or, Two adjacent R 2 and two C directly connected to the 5-6 membered heteroaryl group together form a C 4 ⁇ C 6 cycloalkyl group which is unsubstituted or substituted by one or more R 1-5 , or , Unsubstituted or C 3 ⁇ C 5 heterocycloalkyl substituted by one or more R 1-6 ; preferably, R 1 and R 2 are independently halogen, -CN, -COOH, unsubstituted or substituted by one Or more C 1 -C 6 alkyl substitute
  • the benzamide compound represented by Formula I is preferably any of the following compounds:
  • benzamide compounds represented by Formula I their pharmaceutically acceptable salts, their hydrates, their solvates, and their polycrystals Groups, their metabolites, their stereoisomers, their tautomers or their prodrugs, and their substituents are selected to provide stable benzamide compounds of formula I
  • the pharmaceutically acceptable salts thereof include but are not limited to the compounds described in the examples of the present invention.
  • the present invention also includes isotopically labeled benzamide compounds of the present invention, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, and their A stereoisomer, its tautomer or its prodrug, 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. Furthermore, in some cases, 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.
  • isotopes such as deuterium (2H or D)
  • 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 benzamide compounds represented by formula I can be synthesized by methods similar to those well known in the chemical arts.
  • 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 benzamide compounds represented by formula I can also be prepared by using the benzamide compounds represented by formula I prepared by using conventional methods in the art and modified by the periphery Furthermore, the other benzamide compounds represented by Formula I can be obtained.
  • the present invention provides a method for preparing the benzamide compounds as shown in Formula I, which is Scheme I or Scheme II; wherein Scheme I includes the following steps: in an organic solvent, it will be as shown in Formula II
  • the compound shown and the compound shown in formula III are subjected to the amidation reaction shown below to obtain the benzamide compound shown in formula I; wherein X is O; Is defined as shown above;
  • the organic solvent may be a conventional organic solvent in this type of reaction in the art, preferably a cyclic ether solvent (such as tetrahydrofuran) in the present invention.
  • a cyclic ether solvent such as tetrahydrofuran
  • 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, 0.04g/mL to 0.05g/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 reactions of this type 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 2:1 to 1:1.
  • the temperature of the amidation reaction may be a conventional temperature in this type of reaction in the art, and it is preferably room temperature (10°C to 30°C) in the present invention.
  • the C 1 -C 4 alkyl group in R′ may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and for example methyl.
  • the organic solvent may be a conventional organic solvent in this type of reaction in the art, preferably a cyclic ether solvent (such as tetrahydrofuran) in the present invention.
  • a cyclic ether solvent such as tetrahydrofuran
  • the base may be a conventional base in this type of reaction in the art, and preferably an alkali metal hydroxide (e.g., lithium hydroxide) in the present invention.
  • an alkali metal hydroxide e.g., lithium hydroxide
  • 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 I'and the organic solvent is preferably 0.01 g/mL to 0.2 g/mL (for example, 0.1 g/mL to 0.2 g/mL).
  • the mass volume of the alkali and the water is preferably 0.01 g/mL to 0.2 g/mL (for example, 0.1 g/mL to 0.2 g/mL).
  • the molar ratio of the base to the compound represented by formula I′ may be a conventional molar ratio in this type of reaction in the art, and the base to the formula I described in the present invention
  • the molar ratio of the compound shown by ' is preferably 4:1 to 1:1.
  • the temperature of the hydrolysis reaction may be a conventional temperature in this type of reaction in the art, and preferably it is room temperature (10°C to 30°C) in the present invention.
  • the present invention also provides the following compounds:
  • the present invention provides a method for preparing the compound represented by Formula I′, which includes the following steps: in an organic solvent, the compound represented by Formula I” and a sulfurization reagent are subjected to a sulfurization reaction as shown below To obtain the 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.
  • the vulcanization reagent may be a conventional vulcanization 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 It is preferably 0.01 g/mL to 0.2 g/mL (for example, 0.1 g/mL).
  • the molar ratio of the compound represented by Formula I" to the sulfidation reagent may be a conventional molar ratio in the art, and the molar ratio of Formula I" described in the present invention
  • the molar ratio of the compound to 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 progress of the vulcanization reaction can be monitored by conventional monitoring methods in the art (such as TLC or NMR). Generally, when the compound shown by Formula I disappears or no longer reacts Is the end of the reaction.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the benzamide compound as shown in 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 benzamide compounds of formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs , Its metabolites, its stereoisomers, its tautomers or its prodrugs.
  • the pharmaceutical composition may further include, for example, a benzamide compound represented by Formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, One or more active ingredients other than polymorphs, their metabolites, their stereoisomers, their tautomers or their prodrugs.
  • 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 benzamide compound represented by formula I in the pharmaceutical composition, 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 for dissolving the active ingredient at a desired rate after the subject receives the administration, or promoting 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 butter
  • 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, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and lyophilized preparation.
  • special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • Pharmaceutical dosage forms often consist of drugs, excipients, and container/sealing systems.
  • excipients also called inactive ingredients
  • excipients can be added to the compounds of the present invention to improve or promote the manufacture, stability, administration, and safety of the drug, and can provide the desired drug release Curve method. Therefore, 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) 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 needed.
  • 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, gum tragacanth 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 with 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 benzamide compounds as shown in formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, and their stereoisomers , Its tautomer or its prodrug, or the pharmaceutical composition as described above in the preparation of proteoglycan (Aggrecan), type II collagen (Collagen II) and Sox9 one or more inducers.
  • the "one or more inducers in proteoglycan (Aggrecan), type II collagen (Collagen II) and Sox9” can be obtained 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 the benzamide compounds as shown in formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, and their stereoisomers , Its tautomer or its prodrug, or the use of the 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 be optionally administered simultaneously with the treatment, which includes administration of the benzamide compound of formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its Polymorphs, their metabolites, their stereoisomers, their tautomers or their prodrugs, or pharmaceutical compositions as described above.
  • chondrocytes can be harvested from an unimpaired small load-bearing area of the damaged joint by arthroscopy, and can be described in the present invention as shown in Formula I benzamide compound, its pharmaceutical 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 benzamide compounds of formula I, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, metabolites,
  • 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 comprising administering an effective dose of the benzamide compound represented by Formula I to the joints of mammals, 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 benzamide compound represented by 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 benzamide compound represented by 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 benzamide compounds represented by formula I can be injected directly into the synovial fluid of the joint, administered systemically (oral or intravenous) or directly into the cartilage defect, used alone or in combination with The carrier is compounded to prolong the release of protein.
  • the benzamide compounds 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.
  • benzamide compounds of 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 pharmaceutical composition may be formulated for intra-articular delivery.
  • substituted means that one or more hydrogen atoms in a given structure are replaced with 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. When more than one position in the given structural formula can be substituted with one or more substituents selected from specific groups, then 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 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, t-butyl, sec-butyl, isobutyl, pentyl, and hexyl, etc. .
  • 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 “alkyl group” should be understood as a C 1 -C 6 alkylene group.
  • alkylene refers to 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.
  • 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, and the like; wherein, the C 3 -C 6 Cycloalkyl, a ring with 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • 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, oxetanyl, and thiepanyl.
  • Examples of the -CH 2 -group substituted by -C( ⁇ O)- in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, 2-piperidinone, 3-morpholinone, 3 -Thiomorpholinone and oxotetrahydropyrimidinyl etc.
  • 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 circular 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 refers to 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 the atoms or groups are arranged differently 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 form a mirror image relationship with 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 atom (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 exist.
  • each asymmetric atom has an enantiomeric excess of at least 0%, at least 60% enantiomeric excess, at least 70% enantiomeric excess, in (R)- or (S)-configuration, at least 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 called prototropictautomers
  • proton migration such as ketone-enol isomerization and imine- Enamine isomerization.
  • 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.
  • Another example of 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 with Compound I, which retains the biological activity of Compound I.
  • the organic acid may 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 various organic bases that can form salts in the art, 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. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of 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 benzamide 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 radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioisotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • 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, etc.
  • 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 their salts of the present invention are intended to include all solid-state compounds of formula I and their salts.
  • 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. Such groups include, but are not limited to, alkyl, arylalkyl 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; relief 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 can 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 benzamide compound has a good inducing expression 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
  • 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.
  • the aqueous phase was transferred to a separatory funnel, extracted with 80 ml of dichloromethane, and the organic phase was discarded. Repeat six to seven times to wash away impurities and unreacted raw materials in the reaction.
  • the aqueous phase was adjusted to pH 2-3 with 1N HCl, a white solid was precipitated, filtered with suction, and dried to obtain 4.5 g of white solid with a yield of 33.3%.
  • 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 800 ml, 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 into cDNA.
  • the relative expression levels of Aggrecan, Collagen II and Sox9 in cells were detected. The relative expression level was measured 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, and sox9, and the internal reference gene was GAPDH.
  • the three genes Aggrecan, Collagen II, and sox9 are cartilage 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
  • 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 C 1.0-5.0 5.0-20.0 10.0-100.0 D >5.0 >20.0 >100

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Abstract

La présente invention concerne un composé benzamide, des intermédiaires, un procédé de préparation et une utilisation. La présente invention concerne un composé benzamide représenté par la formule I, et leurs sels, hydrates, solvates, polymorphes, métabolites, stéréoisomères, tautomères, ou promédicaments pharmaceutiquement acceptables. Le composé benzamide a une utilisation dans l'induction et la stimulation de cellules souches mésenchymateuses (MSC) pour se différencier en chondrocytes afin de réparer le cartilage. L'invention concerne également une composition et une méthode de traitement, de prévention ou de soulagement de l'arthrite ou d'une lésion articulaire par application du composé ou de la composition selon la présente invention à une articulation, un tissu cartilagineux ou un tissu cartilagineux proximal 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/CN2019/070573 2019-01-07 2019-01-07 Composé benzamide, intermédiaires, procédé de préparation et utilisation Ceased WO2020142865A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4910211A (en) * 1987-08-07 1990-03-20 Kanebo Ltd. Novel benzothiazole and antirheumatic agent comprising it as an active ingredient
JPH02207078A (ja) * 1989-02-06 1990-08-16 Kanebo Ltd ベンゾチアゾール誘導体
CN1144217A (zh) * 1995-06-05 1997-03-05 布里斯托尔-迈尔斯斯奎布公司 具有类视色素样活性的化合物
US20030055287A1 (en) * 1997-11-25 2003-03-20 Masanori Tohnishi Phthalic acid diamide derivatives, fluorine-containing aniline compounds as starting material, agricultural and horticultural insecticides, and a method for application of the insecticides
US20030055263A1 (en) * 2001-07-11 2003-03-20 Boehringer Ingelheim Pharma Kg Carboxylic acid derivatives, medicaments comprising these compounds, their use and processes for their production
CN1826339A (zh) * 2003-04-25 2006-08-30 赛诺菲安万特 2－酰氨基－4－苯基噻唑衍生物,其制备方法及其在治疗学上的应用
US20100305124A1 (en) * 2009-04-03 2010-12-02 Bayer Cropscience Ag Acylated Aminopyridine and Aminopyridazine Insecticides
CN102477001A (zh) * 2010-11-29 2012-05-30 江苏先声药物研究有限公司 一种苯甲酰胺类组蛋白去乙酰化酶抑制剂
CN105228626A (zh) * 2013-03-15 2016-01-06 加州生物医学研究所 用于诱导软骨形成的化合物和方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4910211A (en) * 1987-08-07 1990-03-20 Kanebo Ltd. Novel benzothiazole and antirheumatic agent comprising it as an active ingredient
JPH02207078A (ja) * 1989-02-06 1990-08-16 Kanebo Ltd ベンゾチアゾール誘導体
CN1144217A (zh) * 1995-06-05 1997-03-05 布里斯托尔-迈尔斯斯奎布公司 具有类视色素样活性的化合物
US20030055287A1 (en) * 1997-11-25 2003-03-20 Masanori Tohnishi Phthalic acid diamide derivatives, fluorine-containing aniline compounds as starting material, agricultural and horticultural insecticides, and a method for application of the insecticides
US20030055263A1 (en) * 2001-07-11 2003-03-20 Boehringer Ingelheim Pharma Kg Carboxylic acid derivatives, medicaments comprising these compounds, their use and processes for their production
CN1826339A (zh) * 2003-04-25 2006-08-30 赛诺菲安万特 2－酰氨基－4－苯基噻唑衍生物,其制备方法及其在治疗学上的应用
US20100305124A1 (en) * 2009-04-03 2010-12-02 Bayer Cropscience Ag Acylated Aminopyridine and Aminopyridazine Insecticides
CN102477001A (zh) * 2010-11-29 2012-05-30 江苏先声药物研究有限公司 一种苯甲酰胺类组蛋白去乙酰化酶抑制剂
CN105228626A (zh) * 2013-03-15 2016-01-06 加州生物医学研究所 用于诱导软骨形成的化合物和方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
KAZUHIRO KOBAYASHI, YUUHO SHIGEMURA, DAIKI FUJIWARA: "Synthesis of 3-iminobenzo[c]thiophen-1(3H)-one Derivatives Based on the Reaction of 2-lithio-N, N-dimethylbenzamides with Isothiocyanates", HETEROCYCLES, vol. 94, no. 6, 18 April 2017 (2017-04-18), pages 1152 - 1158, XP009521965, ISSN: 1881-0942, DOI: 10.3987/COM-17-13698 *
PAN WANG, SHAN TANG , AIWEN LEI: "Electrochemical Intramolecular Dehydrogenative C-S Bond Formation for the Synthesis of Benzothiazoles", GREEN CHEMISTRY, vol. 19, no. 9, 21 March 2017 (2017-03-21), pages 2092 - 2095, XP055718620, ISSN: 1463-9262, DOI: 10.1039/c7gc00468k *
QIANG ZHANG, YOUYI PENG, WILLIAM J. WELSH: "Efficient New Approach for the Synthesis of N, N-dialkylamino-1, 2, 4-triazoles", HETEROCYCLES, vol. 68, no. 12, 2 November 2006 (2006-11-02), pages 2635 - 2645, XP009521964, ISSN: 1881-0942, DOI: 10.3987/COM-06-10886 *
ROBERT J PERRY , SCOTT E TUNNEY , DAVID B WILSON: "Polyimide Formation through the Palladium-Mediated Carbonylation and Coupling of Bis(o-iodo amides) and Diamines", MACROMOLECULES, vol. 29, no. 3, 29 January 1996 (1996-01-29), pages 1014 - 1020, XP000548550, ISSN: 0024-9297, DOI: 10.1021/ma950890g *
W.Q ZHOU , R.D LU , X WANG: "Theoretical Studies on Nonlinear Polarizability of Substitution Thiourea", JOURNAL OF MOLECULAR STRUCTURE THEOCHEM, vol. 624, no. 1-3, 25 April 2003 (2003-04-25), pages 123 - 127, XP027123715, ISSN: 0166-1280, DOI: 10.1016/S0166-1280(02)00753-4 *

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