WO2020142865A1 - Benzamide compound, intermediates, preparation method, and application - Google Patents

Benzamide compound, intermediates, preparation method, and application 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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PCT/CN2019/070573
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French (fr)
Chinese (zh)
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蒋青
乐小勇
陈新
胡代强
朱健
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江苏凯迪恩医药科技有限公司
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Priority to CN201980019552.8A priority Critical patent/CN112004798A/en
Priority to PCT/CN2019/070573 priority patent/WO2020142865A1/en
Publication of WO2020142865A1 publication Critical patent/WO2020142865A1/en

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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

Disclosed in the present invention are a Benzamide compound, intermediates, a preparation method, and an application. The present invention provides a Benzamide compound as represented by formula I, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, metabolites, stereoisomers, tautomers, or prodrugs thereof.The Benzamide compound has an application of inducing and stimulating mesenchymal stem cells (MSCs) to differentiate into chondrocytes to repair the cartilage. Also provided are a composition and method for treating, preventing or ameliorating arthritis or joint injury by applying the compound or composition of the present invention to a joint, cartilage tissue, or proximal cartilage tissue or the whole body. The present invention also provides a composition and method for inducing MSCs to differentiate into chondrocytes.

Description

一种苯甲酰胺类化合物、中间体、制备方法及应用Benzamide compound, intermediate, preparation method and application 技术领域Technical field
本发明涉及一种苯甲酰胺类化合物、中间体、制备方法及应用。The invention relates to a benzamide compound, intermediate, preparation method and application.
背景技术Background technique
近年来，随着全球入口老龄化加重，越来越多的人为软骨损失困扰，其中尤其以骨性关节炎(Osteoarthritis,OA)患者为重，骨关节炎(OA)是一种多因素引起的退行性病变，最常见的肌骨病症。通常以关节软骨退化、关节边缘和软骨下骨反应性增生为特征，临床表现为缓慢发展为关节疼痛、压痛、关节肿胀、活动受限和关节畸形等症状。目前全世界约有2.37亿人患有症状和活动限制性OA，这是全球范围内与残疾有关的第三大疾病。预计到2030年，OA将成为导致残疾的第一大疾病。在疾病的最后阶段，通常需要进行全膝置换。In recent years, with the aging of global entrances increasing, more and more people are suffering from cartilage loss, especially in patients with osteoarthritis (Osteoarthritis, OA), which is caused by multiple factors. 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. Currently, about 237 million people worldwide suffer from symptoms and activity-restricted OA, which is the third largest disability-related disease worldwide. It is expected that by 2030, OA will become the first major illness leading to disability. In the final stage of the disease, a total knee replacement is usually required.
骨关节炎(OA)特征在于关节软骨的进行性分解，并最终导致滑膜关节的功能性障碍(Reginster,J.Y.和N.G..Khaltaev,2002,Supp1:p.1-2)，OA由数种发病机理介导，包括胞外基质的酶降解、缺陷的新基质的形成、细胞死亡以及软骨的异常活化和肥大性分化[Goldring,M.B.和S.R.Goldring Sci,2010.1192(1):p.230-7]，目前对于OA基本上以疼痛干预和手术处置进行治疗。Osteoarthritis (OA) 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.
存在于骨髓和大多数成体组织中的间充质干细胞(MSC)能够自我更新并分化成为多种细胞谱系，包括软骨细胞、成骨细胞和脂肪细胞(Pittenger,M.F.等人，Science,1999.284(5411):p.143-7)，其中间充质干细胞包括滑膜间充质干细胞、骨髓间充质干细胞等，研究发现，成体关节软骨含有能够多谱系分化的MSC(细胞的大约3％)。在OA软骨中，这些细胞成倍数增加。这些存在的间充质干细胞(MSC)具备分化软骨细胞的能力，因此保留了修复受损的软骨的能力(Grogan,S.P.等人，Arthritis Res Ther,2009.11(3):p.R85；Koelling,S.等人，Cell Stem Cell,2009.4(4):p.324-35)。Mesenchymal stem cells (MSCs) 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. These existing mesenchymal stem cells (MSC) have the ability to differentiate chondrocytes, so they retain the ability to repair damaged cartilage (Grogan, SP et al., Arthritis Res Ther, 2009.11(3): p.R85; Koelling, S . Et al. Cell Stem Cell, 2009.4(4): p.324-35).
但是，目前仍缺乏通过诱导间充质干细胞用于治疗和/或改善相关的疾病和病症的化合物。However, there is still a lack of compounds for the treatment and/or amelioration of related diseases and disorders by inducing mesenchymal stem cells.
发明内容Summary of the invention
本发明所要解决的问题是现有的间充质干细胞诱导类化合物不足的缺陷，而提供了一种苯甲酰胺类化合物、中间体、制备方法及应用。该苯甲酰胺类化合物具有诱导刺激 间充质干细胞(MSC)分化成软骨细胞，修复软骨的应用；还提供了治疗、预防或改善关节炎或关节损伤的组合物和方法，通过本发明的化合物或组合物施用于关节、软骨组织或软骨近端组织或全身来进行；本发明还提供用于诱导间充质干细胞(MSC)分化成软骨细胞的组合物和方法。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.
本发明是通过下述技术方案来解决上述技术问题的。The present invention solves the above technical problems through the following technical solutions.
本发明提供了一种如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药：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:
Figure PCTCN2019070573-appb-000001
Figure PCTCN2019070573-appb-000001
其中，X为O或S；Among them, X is O or S;
R为-OH、
Figure PCTCN2019070573-appb-000002
或、未取代或被一个或多个R a取代的C 3～C 5杂环烷基；所述的C 3～C 5杂环烷基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～3个，其中至少含有一个N原子，且其通过N原子与所述的
Figure PCTCN2019070573-appb-000003
相连；当取代基R a为多个时，所述的取代基相同或不同； R is -OH,
Figure PCTCN2019070573-appb-000002
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
Figure PCTCN2019070573-appb-000003
Connected; when a plurality of substituent groups R a, the same or different substituents;
R a独立地为卤素、-OH、-CN、-NH 2、-COOH或＝O(即，碳原子上的两个偕氢被基团O取代)； R a is independently halogen, -OH, -CN, -NH 2 , -COOH, or =O (ie, two geminal hydrogens on a carbon atom are replaced by the group O);
Figure PCTCN2019070573-appb-000004
为未取代或被一个或多个R 1取代的C 6～C 10芳基、或、未取代或被一个或多个R 2取代的5～6元的杂芳基；所述的5～6元的杂芳基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～2个；当取代基R 1或R 2为多个时，所述的取代基相同或不同；
Figure PCTCN2019070573-appb-000004
It is an unsubstituted or substituted C 6 -C 10 aryl group by one or more R 1 , or, an unsubstituted or substituted 5- or 6-membered heteroaryl group substituted by one or more R 2 ; said 5 to 6 In the heteroaryl group of the element, 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和R 2独立地为卤素、-OH、-CN、-NH 2、-COOH、
Figure PCTCN2019070573-appb-000005
未取代或被一个或多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-8取代的C 3～C 6环烷基、未取代或被一个或多个R 1-9取代的C 6～C 10芳基、未取代或被一个或多个R 1-10取代的5～6元的杂芳基、未取代或被一个或多个R 1-11取代的C 1～C 6烷基-O-、未取代或被一个或多个R 1-12 取代的C 1～C 6烷基-C(＝O)-、未取代或被一个或多个R 1-13取代的C 1～C 6烷基-C(＝O)O-、未取代或被一个或多个R 1-14取代的C 1～C 6烷基-O-C(＝O)-、或、未取代或被一个或多个R 1-15取代的C 1～C 6烷基-C(＝O)NH-；所述的5～6元的杂芳基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～3个；当取代基R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为多个时，所述的取代基相同或不同； R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH,
Figure PCTCN2019070573-appb-000005
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-, 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-; in the 5-6 membered heteroaryl group, the hetero atom One or more selected from N, O and S, the number of heteroatoms is 1 to 3; when the substituents R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1- 11. When there are a plurality of R 1-12 , R 1-13 , R 1-14 or R 1-15 , the substituents are the same or different;
或者，当取代基R 1或R 2为多个时，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-5取代的C 4～C 6环烷基、或、未取代或被一个或多个R 1-6取代的C 3～C 5杂环烷基；(即，与所述的C 6～C 10芳基或5～6元的杂芳基形成并环)；所述的C 3～C 5杂环烷基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～3个；当取代基R 1-5或R 1-6为多个时，所述的取代基相同或不同； Alternatively, when there are a plurality of substituents R 1 or R 2 , 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和R 1-4独立地为H或C 1～C 6烷基； R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently H or C 1 -C 6 alkyl;
R 1-5、R 1-6、R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为卤素、-OH、-CN、-NH 2、-COOH、-CONH 2、C 1～C 6烷基、C 1～C 6烷基-O-、C 1～C 6烷基-C(＝O)-、C 1～C 6烷基-C(＝O)O-、或C 1～C 6烷基-O-C(＝O)-； R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently halogen, -OH, -CN, -NH 2 , -COOH, -CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl -O-, C 1 -C 6 Alkyl-C(=O)-, C 1 -C 6 alkyl-C(=O)O-, or C 1 -C 6 alkyl-OC(=O)-;
且，当X为-O-时，R为未取代或被一个或多个R a取代的C 3～C 6杂环烷基。 And, when X is -O-, R is unsubstituted or substituted with one or more of R a C 3 ~ C 6 heterocycloalkyl.
本发明中，所述的如式I所示的苯甲酰胺类化合物中某些取代基的定义可如下所述，未提及的取代基的定义均如上任一方案所述。In the present invention, the definitions of certain substituents in the benzamide compounds represented by Formula I may be as follows, and the definitions of unmentioned substituents are as described in any of the above schemes.
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000006
位于所述的
Figure PCTCN2019070573-appb-000007
的邻位、间位或对位；例如邻位。 In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000006
Located at
Figure PCTCN2019070573-appb-000007
Adjacent, meta or para; for example, adjacent.
在本发明一优选实施方案中，R为未取代或被一个或多个R a取代的5元杂环烷基，所述的5元杂环烷基中，杂原子选自N、O和S中的一种或多种，杂原子数为2个，所述的5元杂环烷基优选噻唑烷基(例如
Figure PCTCN2019070573-appb-000008
)。 In a preferred embodiment of the present invention, 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
Figure PCTCN2019070573-appb-000008
).
在本发明一优选实施方案中，所述的R a的个数为1或2。 In a preferred embodiment of the present invention, the number of Ra is 1 or 2.
在本发明一优选实施方案中，所述的R a位于
Figure PCTCN2019070573-appb-000009
的邻位、间位或对位，较佳地为邻位。 In a preferred embodiment of the present invention, the Ra is located
Figure PCTCN2019070573-appb-000009
Adjacent position, meta position or para position, preferably adjacent position.
在本发明一优选实施方案中，所述的R a为氟、氯、溴或碘。 In a preferred embodiment of the present invention, said Ra is fluorine, chlorine, bromine or iodine.
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000010
中，所述的5～6元的杂芳基通过碳原子与所述的
Figure PCTCN2019070573-appb-000011
相连接。 In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000010
In the above, the 5- to 6-membered heteroaryl group is linked to the
Figure PCTCN2019070573-appb-000011
Connected.
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000012
为未取代或被一个或多个R 1取代的苯基。 In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000012
Is a phenyl group that is unsubstituted or substituted with one or more R 1 .
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000013
为未取代或被一个或多个R 2取代的6元杂芳基，所述的6元杂芳基中，杂原子选自N，杂原子数为1～2个，所述的6元杂芳基优选吡啶基(例如
Figure PCTCN2019070573-appb-000014
)。 In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000013
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.
Figure PCTCN2019070573-appb-000014
).
在本发明一优选实施方案中，所述的R 1和R 2的个数独立地为1、2、3或4。 In a preferred embodiment of the present invention, the number of R 1 and R 2 is independently 1 , 2 , 3 or 4.
在本发明一优选实施方案中，所述R 1或R 2独立地位于
Figure PCTCN2019070573-appb-000015
的邻位、间位或对位，较佳地为间位或对位。 In a preferred embodiment of the present invention, the R 1 or R 2 is independently located
Figure PCTCN2019070573-appb-000015
Adjacent position, meta position or para position, preferably meta position or para position.
在本发明一优选实施方案中，所述的R 1或R 2为氟、氯、溴或碘，又例如氟或氯。 In a preferred embodiment of the present invention, R 1 or R 2 is fluorine, chlorine, bromine or iodine, and for example, fluorine or chlorine.
在本发明一优选实施方案中，所述的R 1或R 2为未取代或被一个或多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-11取代的C 1～C 6烷基-O-、未取代或被一个或多个R 1-12取代的C 1～C 6烷基-C(＝O)-、未取代或被一个或多个R 1-13取代的C 1～C 6烷基-C(＝O)O-、未取代或被一个或多个R 1-14取代的C 1～C 6烷基-O-C(＝O)-、或、未取代或被一个或多个R 1-15取代的C 1～C 6烷基-C(＝O)NH-，其中，所述的C 1～C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1-C 4的烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，再例如甲基。 In a preferred embodiment of the present invention, 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 hexyl) independently C 1 -C 4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Radicals, sec-butyl or tert-butyl, again methyl.
在本发明一优选实施方案中，所述的R 1或R 2为未取代或被一个或多个R 1-9取代的苯基。 In a preferred embodiment of the present invention, said R 1 or R 2 is unsubstituted or substituted by one or more R 1-9 phenyl.
在本发明一优选实施方案中，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-6取代的1,3-二氧戊环(例如
Figure PCTCN2019070573-appb-000016
其中
Figure PCTCN2019070573-appb-000017
的碳碳键与所述的C 6～C 10芳基或5～6元 的杂芳基共用形成并环)。 In a preferred embodiment of the present invention, 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
Figure PCTCN2019070573-appb-000016
among them
Figure PCTCN2019070573-appb-000017
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).
在本发明一优选实施方案中，所述的R 1-1、R 1-2、R 1-3或R 1-4中，所述的C 1-C 6的烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1-C 4的烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，再例如异丁基。 In a preferred embodiment of the present invention, in said R 1-1 , R 1-2 , R 1-3 or R 1-4 , the C 1 -C 6 alkyl group (eg methyl, ethyl (Propyl, propyl, butyl, pentyl or hexyl) are independently C 1 -C 4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl, for example isobutyl.
在本发明一优选实施方案中，所述的R 1-5、R 1-6、R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为氟、氯、溴或碘，又例如氟。 In a preferred embodiment of the present invention, the R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1- 12. R 1-13 , R 1-14 or R 1-15 are fluorine, chlorine, bromine or iodine, and for example, fluorine.
在本发明一优选实施方案中，所述的R 1-5、R 1-6、R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为C 1～C 6烷基、C 1～C 6烷基-O-、C 1～C 6烷基-C(＝O)-、C 1～C 6烷基-C(＝O)O-、或C 1～C 6烷基-O-C(＝O)-，其中，所述的C 1～C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1-C 4的烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a preferred embodiment of the present invention, the R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1- 12 , R 1-13 , R 1-14 or R 1-15 are C 1 ～C 6 alkyl, C 1 ～C 6 alkyl-O-, C 1 ～C 6 alkyl-C(＝O)- , C 1 -C 6 alkyl-C(=O)O-, or C 1 -C 6 alkyl-OC(=O)-, wherein the C 1 -C 6 alkyl (eg methyl, Ethyl, propyl, butyl, pentyl, or hexyl) independently C 1 -C 4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl.
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000018
为
Figure PCTCN2019070573-appb-000019
In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000018
for
Figure PCTCN2019070573-appb-000019
在本发明一优选实施方案中，所述的R为
Figure PCTCN2019070573-appb-000020
In a preferred embodiment of the present invention, the R is
Figure PCTCN2019070573-appb-000020
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000021
为-CONH 2。 In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000021
-CONH 2 .
在本发明一优选实施方案中，所述的R 1或R 2为三氟甲基。 In a preferred embodiment of the present invention, said R 1 or R 2 is trifluoromethyl.
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000022
为
Figure PCTCN2019070573-appb-000023
Figure PCTCN2019070573-appb-000024
In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000022
for
Figure PCTCN2019070573-appb-000023
Figure PCTCN2019070573-appb-000024
在本发明一优选实施方案中，所述的
Figure PCTCN2019070573-appb-000025
为
Figure PCTCN2019070573-appb-000026
Figure PCTCN2019070573-appb-000027
In a preferred embodiment of the present invention, the
Figure PCTCN2019070573-appb-000025
for
Figure PCTCN2019070573-appb-000026
Figure PCTCN2019070573-appb-000027
在本发明一优选实施方案中，X为S，R为-OH或
Figure PCTCN2019070573-appb-000028
In a preferred embodiment of the present invention, X is S and R is -OH or
Figure PCTCN2019070573-appb-000028
在本发明一优选实施方案中，X为-O-，R为未取代或被一个或多个R a取代的C 3～C 6杂环烷基。 In a preferred embodiment of the present invention, X is -O-, and R is unsubstituted or substituted with one or more R a C 3 -C 6 heterocycloalkyl.
在本发明一优选实施方案中，R 1和R 2独立地为卤素、-OH、-CN、-NH 2、-COOH、
Figure PCTCN2019070573-appb-000029
未取代或被一个或多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-9取代的C 6～C 10芳基；或者，当取代基R 1或R 2为多个时，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-5取代的C 4～C 6环烷基、或、未取代或被一个或多个R 1-6取代的C 3～C 5杂环烷基。 In a preferred embodiment of the present invention, R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH,
Figure PCTCN2019070573-appb-000029
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.
在本发明一优选实施方案中，X为S；R为-OH或
Figure PCTCN2019070573-appb-000030
较佳地，R为-OH，
Figure PCTCN2019070573-appb-000031
位于所述的
Figure PCTCN2019070573-appb-000032
的间位或对位； In a preferred embodiment of the present invention, X is S; R is -OH or
Figure PCTCN2019070573-appb-000030
Preferably, R is -OH,
Figure PCTCN2019070573-appb-000031
Located at
Figure PCTCN2019070573-appb-000032
Position or alignment of
Figure PCTCN2019070573-appb-000033
为未取代或被一个或多个R 1取代的C 6～C 10芳基、或、未取代或被一个或多个R 2取代的5～6元的杂芳基；较佳地，
Figure PCTCN2019070573-appb-000034
为未取代或被一个或多个R 2取代的5～6元的杂芳基；
Figure PCTCN2019070573-appb-000033
Is a C 6 to C 10 aryl group that is unsubstituted or substituted with one or more R 1 , or a 5- to 6-membered heteroaryl group that is unsubstituted or substituted with one or more R 2 ; preferably,
Figure PCTCN2019070573-appb-000034
Is a 5-6 membered heteroaryl group that is unsubstituted or substituted by one or more R 2 ;
R 1和R 2独立地为卤素、-OH、-CN、-NH 2、-COOH、
Figure PCTCN2019070573-appb-000035
未取代或被一个或 多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-9取代的C 6～C 10芳基；或者，当取代基R 1或R 2为多个时，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-5取代的C 4～C 6环烷基、或、未取代或被一个或多个R 1-6取代的C 3～C 5杂环烷基。 R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH,
Figure PCTCN2019070573-appb-000035
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.
在本发明一优选实施方案中，所述的如式I所示的苯甲酰胺类化合物中某些取代基的定义可如下所述，未提及的取代基的定义均如上任一方案所述：In a preferred embodiment of the present invention, the definitions of certain substituents in the benzamide compounds shown in formula I can be as follows, and the definitions of unmentioned substituents are as described in any of the above schemes :
X为O；R为未取代或被一个或多个R a取代的C 3～C 5杂环烷基；较佳地
Figure PCTCN2019070573-appb-000036
位于所述的
Figure PCTCN2019070573-appb-000037
的邻位； X is O; R is unsubstituted or substituted with one or more of R a C 3 ~ C 5 heterocycloalkyl; preferably
Figure PCTCN2019070573-appb-000036
Located at
Figure PCTCN2019070573-appb-000037
Adjacent to
Figure PCTCN2019070573-appb-000038
为未取代或被一个或多个R 1取代的C 6～C 10芳基、或、未取代或被一个或多个R 2取代的5～6元的杂芳基；较佳地，
Figure PCTCN2019070573-appb-000039
为未取代或被一个或多个R 2取代的5～6元的杂芳基；
Figure PCTCN2019070573-appb-000038
Is a C 6 to C 10 aryl group that is unsubstituted or substituted with one or more R 1 , or a 5- to 6-membered heteroaryl group that is unsubstituted or substituted with one or more R 2 ; preferably,
Figure PCTCN2019070573-appb-000039
Is a 5-6 membered heteroaryl group that is unsubstituted or substituted by one or more R 2 ;
R 1和R 2独立地为卤素、-CN、-COOH、未取代或被一个或多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-9取代的C 6～C 10芳基；或者，当取代基R 1或R 2为多个时，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-5取代的C 4～C 6环烷基、或、未取代或被一个或多个R 1-6取代的C 3～C 5杂环烷基；较佳地，R 1和R 2独立地为卤素、-CN、-COOH、未取代或被一个或多个R 1-7取代的C 1～C 6烷基。 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 substituted with R 1-7 .
在本发明一优选实施方案中，所述的如式I所示的苯甲酰胺类化合物优选下列任一化合物：In a preferred embodiment of the present invention, the benzamide compound represented by Formula I is preferably any of the following compounds:
Figure PCTCN2019070573-appb-000040
Figure PCTCN2019070573-appb-000040
Figure PCTCN2019070573-appb-000041
Figure PCTCN2019070573-appb-000041
Figure PCTCN2019070573-appb-000042
Figure PCTCN2019070573-appb-000042
由此，在本说明书通篇中，本领域技术人员可对所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药中所述基团及其取代基进行选择，以提供稳定的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐，包括但不限于本发明的实施例中所述的化合物。Thus, throughout the specification, those skilled in the art can refer to the 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.
本发明还包括同位素标记的本发明所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，其中一个或多个原子被一个或多个具有特定原子质量或质量数的原子取代。可以掺入本发明化合物中的同位素的实例包括但不限于氢，碳，氮，氧，氟，硫和氯的同位素(例如 2H， 3H， 13C， 14C， 15N， 18O， 17O， 18F， 35S和 36Cl)。同位素标记的本发明化合物可用于化合物及其前药和代谢物的组织分布的测定；用于此类测定的优选同位素包括 3H和 14C。此外，在某些情况下，用较重的同位素(例如氘(2H或D))取代可以提供增加的代谢稳定性，这提供了治疗优势，例如增加的体内半衰期或减少的剂量需求。 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. Examples of 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.
本发明的同位素标记的化合物通常可以根据本文所述的方法通过用同位素标记的试剂取代非同位素标记的试剂来制备。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.
本发明所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药可通过包括与化学领域公知方法相似的方法合成，其步骤和条件可参考本领域类似反应的步骤和条件，特别是根据本文说明进行合成。起始原料通常是来自商业来源，例如Aldrich或可使用本领域技术人员公知的方法(通过SciFinder、Reaxys联机数据库得到)容易地制备。The benzamide compounds represented by formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, their stereoisomers, their mutual The variant isomers or prodrugs thereof can be synthesized by methods similar to those well known in the chemical arts. For the steps and conditions, reference may be made to the steps and conditions of similar reactions in the art, especially in accordance with 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).
本发明中，所述的如式I所示的苯甲酰胺类化合物，也可以通过已制备得到的所述的如式I所示的苯甲酰胺类化合物，采用本领域常规方法，经外周修饰进而得到其他所述的如式I所示的苯甲酰胺类化合物。In the present invention, 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.
本发明提供了一种所述的如式I所示的苯甲酰胺类化合物的制备方法，其为方案一或方案二；其中，方案一包括如下步骤：在有机溶剂中，将如式II所示的化合物与如式 III所示的化合物进行如下所示的酰胺化反应，得到所述的如式I所示的苯甲酰胺类化合物即可；其中X为O；
Figure PCTCN2019070573-appb-000043
的定义如上所示； 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;
Figure PCTCN2019070573-appb-000043
Is defined as shown above;
Figure PCTCN2019070573-appb-000044
Figure PCTCN2019070573-appb-000044
方案二包括如下步骤，在水和有机溶剂中，在碱存在下，将如式I’所示的化合物进行如下所示的水解反应，得到所述的如式I所示的苯甲酰胺类化合物即可；其中X＝S；R’为C 1-C 4烷基-O-；R为-OH；
Figure PCTCN2019070573-appb-000045
的定义如上所示； Scheme 2 includes the following steps. In a water and an organic solvent, in the presence of a base, the compound shown in Formula I′ is subjected to the hydrolysis reaction shown below to obtain the benzamide compound shown in Formula I That is; where X = S; R'is C 1 -C 4 alkyl-O-; R is -OH;
Figure PCTCN2019070573-appb-000045
Is defined as shown above;
Figure PCTCN2019070573-appb-000046
Figure PCTCN2019070573-appb-000046
方案一中，所述的有机溶剂可为本领域该类反应中常规的有机溶剂，本发明中较佳地为环醚类溶剂(例如四氢呋喃)。In scheme one, 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.
方案一中，所述的有机溶剂的用量可不做具体限定，以不影响反应即可；本发明中，所述的式II所示的化合物与所述的有机溶剂的质量体积比较佳地为0.01g/mL～0.2g/mL(例如0.04g/mL～0.05g/mL)。In scheme one, 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).
方案一中，所述的如式II所示的化合物与所述的如式III所示的化合物的摩尔比可为本领域该类反应中常规的摩尔比，本发明中所述的如式II所示的化合物与所述的如式III所示的化合物的摩尔比较佳地为2:1～1:1。In Scheme 1, 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.
方案一中，所述的酰胺化反应的温度可为本领域该类反应中常规的温度，本发明中较佳地为室温(10℃～30℃)。In the first scheme, 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.
方案一中，所述酰胺化反应的进程可以采用本领域中的常规监测方法(例如TLC或NMR)进行监测，一般以所述的如式II所示的化合物消失或不再反应时为反应终点。In Scheme 1, the progress of the amidation reaction can be monitored by using conventional monitoring methods in the art (such as TLC or NMR). Generally, the end point of the reaction is when the compound of Formula II disappears or no longer reacts .
方案二中，R’中的C 1-C 4的烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基。 In scheme two, 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.
方案二中，所述的有机溶剂可为本领域该类反应中常规的有机溶剂，本发明中较佳地为环醚类溶剂(例如四氢呋喃)。In scheme two, 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.
方案二中，所述的碱可为本领域该类反应中常规的碱，本发明中较佳地为碱金属氢 氧化物(例如氢氧化锂)。In scheme two, 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.
方案二中，所述的有机溶剂的用量可不做具体限定，以不影响反应即可；本发明中，所述的式I’所示的化合物与所述的有机溶剂的质量体积比较佳地为0.01g/mL～0.2g/mL(例如0.1g/mL～0.2g/mL)。In scheme two, 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).
方案二中，所述的碱与所述的水的质量体积比较佳地为0.01g/mL～0.2g/mL(例如0.1g/mL～0.2g/mL)。In the second solution, 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).
方案二中，所述的碱与所述的如式I’所示的化合物的摩尔比可为本领域该类反应中常规的摩尔比，本发明中所述的碱与所述的如式I’所示的化合物的摩尔比较佳地为4:1～1:1。In scheme two, 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.
方案二中，所述的水解反应的温度可为本领域该类反应中常规的温度，本发明中较佳地为室温(10℃～30℃)。In the second scheme, 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.
方案二中，所述水解反应的进程可以采用本领域中的常规监测方法(例如TLC或NMR)进行监测，一般以所述的如式I’所示的化合物消失或不再反应时为反应终点。In scheme two, the progress of the hydrolysis reaction can be monitored by using conventional monitoring methods in the art (such as TLC or NMR). Generally, the end point of the reaction is when the compound represented by Formula I′ disappears or no longer reacts .
本发明还提供了如下所示的化合物：The present invention also provides the following compounds:
Figure PCTCN2019070573-appb-000047
Figure PCTCN2019070573-appb-000047
其中，X为S，R’和
Figure PCTCN2019070573-appb-000048
的定义如上所示。 Where X is S, R'and
Figure PCTCN2019070573-appb-000048
Is defined as shown above.
所述的如式I’所示的化合物可为如下任一结构：The compound represented by formula I'may have any of the following structures:
Figure PCTCN2019070573-appb-000049
Figure PCTCN2019070573-appb-000049
Figure PCTCN2019070573-appb-000050
Figure PCTCN2019070573-appb-000050
本发明提供了一种所述的如式I’所示的化合物的制备方法，其包括如下步骤：在有机溶剂中，将如式I”所示的化合物与硫化试剂进行如下所示的硫化反应，得到所述的如式I’所示的化合物即可；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';
Figure PCTCN2019070573-appb-000051
Figure PCTCN2019070573-appb-000051
其中，X’为O；X、R’和
Figure PCTCN2019070573-appb-000052
的定义如上所示。 Where X'is O; X, R'and
Figure PCTCN2019070573-appb-000052
Is defined as shown above.
所述的硫化反应中，所述的有机溶剂可为本领域该类反应中常规的有机溶剂，本发明中较佳地为芳烃类溶剂(例如甲苯)。In the vulcanization reaction, 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.
所述的硫化反应中，所述的硫化试剂可为本领域该类反应中常规的硫化试剂，本发明中较佳地为劳森试剂。In the vulcanization reaction, 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.
所述的硫化反应中，所述的有机溶剂的用量可不做具体限定，以不影响反应即可；本发明中，所述的如式I”所示的化合物与所述的有机溶剂的质量体积比较佳地为0.01g/mL～0.2g/mL(例如0.1g/mL)。In the vulcanization reaction, 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).
所述的硫化反应中，所述的如式I”所示的化合物与所述的硫化试剂的摩尔比可为本领域中常规的摩尔比，本发明中所述的如式I”所示的化合物与所述的硫化试剂的摩尔比较佳地为1:1～1:3(例如1:2)。In the vulcanization reaction, 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).
所述的硫化反应中，所述的硫化反应的温度可为本领域该类反应中常规的温度，本发明中较佳地为100℃～120℃。In the vulcanization reaction, 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.
所述的硫化反应中，所述硫化反应的进程可以采用本领域中的常规监测方法(例如TLC或NMR)进行监测，一般以所述的如式I”所示的化合物消失或不再反应时为反应终点。In the vulcanization reaction, 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.
本发明还提供了一种药物组合物，其包含所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，和至少一种药用辅料。所述药物组合物还可以包含一种或多种 另外的活性成分。举例来说，这种药物组合物可以包含一种或多种另外的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药。作为另外一种选择或除此之外，所述药物组合物还可以例如包含除如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药以外的一种或多种活性成分。The present invention also provides 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. For example, 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. Alternatively or in addition, 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.
在本发明一优选实施方案中，所述的药物组合物还包括胶原、壳聚糖及透明质酸中的一种或多种形成的复合支架；应用于诱导间充质干细胞分化软骨细胞。In a preferred embodiment of the present invention, 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.
在本发明一优选实施方案中，所述的药物组合物还可包括适于配制用于关节内递送的组分；所述的用于关节内递送的组分包括但不限于：血管生成素样3蛋白(ANGPTL3)或其软骨形成变体，口服鲑降钙素，SD-6010(iNOS抑制剂)，维生素D3(胆碱钙化醇)，胶原蛋白水解物，FGF18，BMP7，鳄梨大豆未皂化物(ASU)和透明质酸中的一种或多种。ANGPTL3在WO/2011/008773(以其整体并入本文)中更详细地描述。In a preferred embodiment of the present invention, 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).
在所述的药物组合物中，所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药的剂量，可为治疗有效量。In the pharmaceutical composition, the benzamide compound represented by 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.
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定，最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。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.
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。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.
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土 豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。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 and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed Acid; pyrogen-free water; isotonic salt; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coating materials, sweeteners, flavors and spices, preservatives and antioxidants.
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。The pharmaceutical 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.
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放***形式提供。例如，常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定，可能需要特殊装置来施用或给予药物，例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Specialflask)。药物剂型常常由药物、赋形剂和容器/密封***组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性，并且可提供获得所需药物释放曲线的方法。因此，添加到药物中的赋形剂类型可视各种因素而定，例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(European Pharmacopoeia,EP)和英国药典(British pharmacopoeia,BP)；美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物，例如《非活性组分指南》(Inactive Ingredient Guide,1996)；Ash和Ash编写的《药物添加剂手册》(Hand book of Pharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY；etc.)。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. For example, 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. Depending on the route of administration used, 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. One or more excipients (also called inactive ingredients) 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. (See US Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); US Food and Drug Administration (the US Food and Drug Administration) Administration, www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, such as "Inactive Components Guide" (Inactive, Guide, 1996); "Handbook of Drug Additives" by Ash and Ash "(Handbook of Pharmaceutical Additives, 2002, United Information Resources (Synapse Information, Inc., Endicott NY; etc.).
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造，例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。如上文所述，本发明的组合物可包括一种或一种以上生理学上可接受的非活性成分，这些非活性成分会促进活性分子被加工成用于医药用途的制剂。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. As described above, 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.
本发明所述的药物组合物可以任何形式给药，包括注射(关节腔)、粘膜、局部或胃肠外(输注、注射、植入、皮下、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏 剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于适于胃肠外给药的液体剂型。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). Examples of topical preparations include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of 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. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, liquid dosage forms suitable for parenteral administration.
液体形式制剂包括溶液，悬浮液和乳液，例如水或水/丙二醇溶液。对于注射，液体制剂可以在聚乙二醇水溶液中配制成溶液。Liquid form preparations include solutions, suspensions and emulsions, for example water or water/propylene glycol solutions. For injection, liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
适合使用的水溶液可以通过将活性组分溶解在水中并根据需要加入合适的着色剂，稳定剂和增稠剂来制备。适合使用的水性悬浮液可以通过将细碎的活性组分用粘性材料分散在水中来制备，所述粘性材料例如天然或合成树胶，树脂，甲基纤维素，羧甲基纤维素钠，羟丙基甲基纤维素，海藻酸钠，聚乙烯吡咯烷酮，黄蓍胶和***树胶，以及分散剂或润湿剂，例如天然存在的磷脂(例如，卵磷脂)，环氧烷与脂肪酸的缩合产物(例如，聚氧乙烯硬脂酸酯)，环氧乙烷与长链脂族醇的缩合产物(例如，十七烷基氧基乙醇)，环氧乙烷与衍生自脂肪酸和己糖醇的偏酯(例如聚氧乙烯山梨糖醇单油酸酯)的缩合产物，或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如，聚氧乙烯脱水山梨糖醇单油酸酯)。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 with partial esters derived from fatty acids and hexitol anhydrides (for example, polyoxyethylene sorbitan monooleate) .
含水悬浮液还可含有一种或多种防腐剂，例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯，一种或多种着色剂，一种或多种调味剂和一种或多种甜味剂，例如蔗糖，阿斯巴甜或糖精。可以调整制剂的渗透压。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. The osmotic pressure of the preparation can be adjusted.
本发明还提供了所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物在制备蛋白多糖(Aggrecan)、Ⅱ型胶原(Collagen II)和Sox9中的一种或多种诱导剂中的应用。所述的“蛋白多糖(Aggrecan)、Ⅱ型胶原(Collagen II)和Sox9中的一种或多种诱导剂”可通过蛋白多糖(Aggrecan)、Ⅱ型胶原(Collagen II)和Sox9中的一种或多种诱导间充干细胞向软骨细胞分化。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.
在本发明一优选实施方案中，所述的诱导剂为药物。In a preferred embodiment of the present invention, the inducer is a drug.
本发明还提供了所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物在制备药物中的应用。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.
在本发明一优选实施方案中，所述的药物是指可用于治疗或预防与诱导间充干细胞向软骨细胞分化作用有关的疾病的药物；所述的疾病优选：关节炎或关节损伤，例如类风湿性关节炎、牛皮癣性关节炎、强直性脊柱炎、多关节型幼年特发性关节炎、骨质疏 松症、或骨关节炎等；所述的诱导间充干细胞向软骨细胞分化是指通过蛋白多糖(Aggrecan)、Ⅱ型胶原(Collagen II)和Sox9中的一种或多种诱导间充干细胞向软骨细胞分化。In a preferred embodiment of the present invention, 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.
在本发明一优选实施方案中，所述的诱导剂用于在体外扩增培养物中的软骨细胞群；可以进行自体或同种异体软骨细胞移植。移植可任选地与治疗一起同时施用，所述治疗包括施用本发明所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物。在这些方法中，例如，软骨细胞可以从受损关节的未受损的小承重区域通过关节镜进行收获，并且可以在本发明所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物存在下培养，以在移植前增加细胞数量。然后将膨胀的培养物与本发明所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物混合，并置于关节空间中或直接放入缺损中。In a preferred embodiment of the present invention, 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. In these methods, for example, 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.
本发明还提供了一种改善哺乳动物的关节炎或关节损伤的方法，该方法包括向哺乳动物的关节施用有效剂量的所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药或如上所述的药物组合物。所述的疾病优选：关节炎或关节损伤，例如类风湿性关节炎、牛皮癣性关节炎、强直性脊柱炎、多关节型幼年特发性关节炎、骨质疏松症、或骨关节炎等。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.
本文提供了一种诱导间充质干细胞分化为软骨细胞的方法，该方法包括使间充质干细胞接触足够量的所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药或如上所述的药物组合物。Provided herein is a method for inducing mesenchymal stem cells to differentiate into chondrocytes, the method 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.
所述的软骨细胞产生并维持由胶原蛋白和蛋白多糖组成的软骨基质。软骨细胞来源于间充质干细胞(MSC)的分化。MSC是多能干细胞，其可以分化成几种不同类型的细胞，包括但不限于成骨细胞，软骨细胞和脂肪细胞。分化是由较不特化的细胞类型形成的特化细胞类型的过程，例如来自MSC的软骨细胞。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.
本发明所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上 所述的药物组合物可以通过直接注射到关节的滑液中，全身给药(口服或静脉内)或直接注射到软骨缺损中，单独使用或与合适的载体复合以延长蛋白质的释放。The benzamide compounds represented by formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, their stereoisomers, their mutual The variant isomer or its prodrug, or the pharmaceutical composition as described above 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.
本发明所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物可以与骨膜或软骨膜移植物组合使用，所述骨膜或软骨膜移植物含有可以形成软骨和/或有助于将移植的软骨细胞或其前体细胞保持在适当位置的细胞。本发明的所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物可用于与关节的灌洗，骨髓的刺激，磨损关节成形术，软骨下钻孔或软骨下骨的微骨折一起修复软骨损伤。另外，在由于施用本发明的所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如上所述的药物组合物而导致软骨生长之后，可能需要额外的手术治疗以使新形成的软骨表面适当地轮廓化。在一些实施方案中，药物组合物可以配制用于关节内递送。The benzamide compounds represented by formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, their stereoisomers, their mutual The variant isomer or its prodrug, or the pharmaceutical composition as described above 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 benzamide compounds of formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, their stereoisomers, their Tautomers or their prodrugs, or pharmaceutical compositions as described above, can be used to repair cartilage damage together with joint lavage, bone marrow stimulation, abraded arthroplasty, subchondral drilling or microfragmentation of subchondral bone . In addition, due to the administration of the benzamide compounds of formula I, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, their metabolites, and their stereotypes according to the invention After the isomer, its tautomer or its prodrug, or a pharmaceutical composition as described above causes cartilage growth, additional surgical treatment may be required to properly contour the newly formed cartilage surface. In some embodiments, the pharmaceutical composition may be formulated for intra-articular delivery.
定义和一般术语Definitions and general terms
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are consistent with the CAS version of the periodic table of elements, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , The entire contents of which are incorporated herein by reference.
术语“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, it includes the content specified by the present invention, but does not exclude other aspects.
一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的。除非其他方面表明，一个取代基团可以在被取代基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with specific substituents. Further, when the group is substituted with one or more 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. Unless otherwise indicated, 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.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该 基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and 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.
本发明中，“卤”、“卤素”或“卤代”各自独立地为氟、氯、溴或碘(例如氟或氯)。In the present invention, "halo", "halogen" or "halo" are each independently fluorine, chlorine, bromine or iodine (for example fluorine or chlorine).
术语“烷基”意指包括具有指定碳原子数目的支链和直链的饱和脂族烃基。例如，C 1-C 6，如在“C 1-C 6烷基”中定义为包括在直链或者支链结构中具有1、2、3、4、5、或者6个碳原子的基团。例如，“C 1-C 6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基、异丁基、戊基、和己基等等。 The term "alkyl" is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, 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 . For example, "C 1 -C 6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, pentyl, and hexyl, etc. .
在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“卤代-(C 1～C 6烷基)”中的C 1～C 6烷基应当理解为C 1～C 6亚烷基。 In some specific structures, 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.
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH 2-)，亚乙基(包括-CH 2CH 2-或-CH(CH 3)-)，亚异丙基(包括-CH(CH 3)CH 2-或-C(CH 3) 2-)等等。 The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Examples of 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.
术语“环烷基”是指饱和单环、多环或者桥接碳环取代基。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基，等等；其中，所述的C 3-C 6环烷基，具有3-6个碳原子的环，包括环丙基、环丁基、环戊基和环己基。 The term "cycloalkyl" refers to a saturated monocyclic, polycyclic, or bridged carbocyclic substituent. Examples of 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.
术语“杂环烷基”表示含有1-4个选自O、N和S的杂原子的3-10元饱和杂环***的基团。在包含一个或多个氮原子的杂环烷基基团中，连接点可以是碳或氮原子，只要化合价许可。杂环烷基基团或者可以是单环的(“单环的杂环烷基”)或者是融合的、桥联的或螺的环***(例如二环***(“二环的杂环烷基”))并且是饱和的。杂环烷基二环的环***可以在一个或两个环中包括一个或多个杂原子。环中-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化物。在此定义范围内的杂环烷基包括但不限于：氮杂环丁基、环氧丙烷基、硫杂环丁烷基、四氢呋喃基、吡咯烷基、二氧戊环基、哌啶基、四氢吡喃基、硫化环戊烷基、哌嗪基、吗啉基、氮杂环庚烷基、氧杂环庚烷基、以及硫杂环庚烷基。杂环基中-CH 2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基、2-哌啶酮基、3-吗啉酮基、3-硫代吗啉酮基和氧代四氢嘧啶基等。 The term "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 -CH 2 -group in the ring may optionally be replaced by -C(=O)-. 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.
术语“芳基”是指具有6-14个环原子以及提供在芳香族环***中的零个杂原子单环的或多环的(例如，二环的或三环的)4n+2芳香族环***(例如，在循环阵列中具有6，10，或14个共享的p电子)的基团(“C 6-C 14芳基”)。上述芳基单元的实例包括苯基、 萘基、菲基、或者蒽基。 The term "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.
术语“杂芳基”是指具有环碳原子以及提供在该芳香族环***中的1-4个环杂原子(其中每个杂原子独立地选自氮、氧以及硫)的5-10元单环的或二环的4n+2芳香族环***(例如，在循环阵列中具有6或10个共享的p电子)的基团(“5-10元杂芳基”)。在此定义范围内的杂芳基包括但不限于：吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并***基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。The term "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.
术语“卤代烷基”表示卤素任意位置取代的烷基。由此，“卤代烷基”包含以上卤素和烷基的定义。The term "haloalkyl" refers to an alkyl group substituted with halogen at any position. Thus, "haloalkyl" includes the above definitions of halogen and alkyl.
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2019070573-appb-000053
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。 Those skilled in the art can understand that, according to the conventions used in the art, this application describes the structural formula used in the group
Figure PCTCN2019070573-appb-000053
It means that the corresponding group is connected to other fragments and groups in the compound through this site.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地为”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地为”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless explicitly stated otherwise, 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. In more detail, 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.
在此描述的化合物可以包含一个或多个非对称中心，并且从而能以多种异构体形式存在，例如，对映体和/或非对映体。例如，在此描述的化合物可以处于单一的对映体、非对映体或几何异构体的形式，或可以处于立体异构体的混合物形式，包括外消旋混合物以及包含一种或多种立体异构体的混合物。异构体可以通过本领域的技术人员已知的方法从混合物中分离出来，包括手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或优选的异构体可以通过不对称合成来制备。参见，例如，Jacques等人，对映体、外消旋体和解决方案(Enantiomers,Racemates and Resolutions)(Wiley Interscience，纽约，1981)；Wilen等人，四面体(Tetrahedron)33：2725(1977)；Eliel，碳化合物的立体化学(Stereochemistry of Carbon Compounds)(McGraw-Hill，NY，1962)；以及Wilen，拆分剂和光学分辨率表(Tables of Resolving Agents and Optical Resolutions)p.268(E.L.Eliel编辑，巴黎圣母院大学出版社(Univ.of Notre Dame Press))，巴黎圣母院(Notre Dame)，在1972)。另外，本发明涵盖如在此描述的呈单一的异构体(基本上不含其他异构体)的化合物，并且可替代地，呈多种异构体的混合物。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. For example, 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. See, for example, Jacques et al., Enantiomers, Racemates and Solutions (Enantiomers, Racemates and Resolutions) (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33: 2725 (1977) ; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Resolving Agents and Optical Resolution Tables (Tables of Resolving Agents and Optical Resolutions) p.268 (ELEliel Editor, University of Notre Dame Press (Univ. of Notre Dame Press), Notre Dame (Notre Dame, in 1972). In addition, the present invention encompasses compounds that are single isomers (substantially free of other isomers) as described herein, and, alternatively, are mixtures of multiple isomers.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化 合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"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. .
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。"Enantiomer" refers to two isomers of a compound that cannot overlap but form a mirror image relationship with each other.
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"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.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereo chemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemicals (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereo chemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少0％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。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. In certain embodiments, 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.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。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.
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称为质子转移互变异构体(prototro pictautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valen cetautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "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. For example, proton tautomers (also called prototropictautomers) include interconversion through proton migration, such as ketone-enol isomerization and imine- Enamine isomerization. Valence tautomers (valencetautomer) include interconversion through the recombination of some bonding electrons. A specific example of 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.
在本发明中所使用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" used in the present invention 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.
术语“药学上可接受的盐”表示由适宜的非毒性有机酸、无机酸、有机碱或无机碱与化合物I形成的盐，其保留化合物I的生物活性。所述的有机酸可为本领域常规的能成盐的各种有机酸，优选甲磺酸、对甲苯磺酸、马来酸、富马酸、柠檬酸、酒石酸、苹果酸、乳酸、甲酸、乙酸、丙酸、三氟乙酸、草酸、丁二酸、苯甲酸、羟乙基磺酸、萘磺酸和水杨酸中的一种或多种。所述的无机酸可为本领域常规的能成盐的各种无机酸，优选盐酸、硫酸和磷酸中的一种或多种。所述的有机碱可为本领域常规的能成盐的各种有机碱，优选吡啶类、咪唑类、吡嗪类、吲哚类、嘌啉类、叔胺类和苯胺类中的一种或多种。所述的叔胺类有机碱优选三乙胺和/或N,N-二异丙基乙胺。所述的苯胺类有机碱优选N,N-二甲基苯胺。所述的吡啶类有机碱优选吡啶、甲基吡啶、4-二甲氨基吡啶和2-甲基-5-乙基吡啶中的一种或多种。所述的无机碱可为本领域常规的能成盐的各种无机碱，优选碱金属氢化物、碱金属的氢氧化物、碱金属的烷氧化物、碳酸钾、碳酸钠、碳酸锂、碳酸铯、碳酸氢钾和碳酸氢钠中的一种或多种。所述的碱金属氢化物优选氢化钠和/或氢化钾。所述的碱金属的氢氧化物优选氢氧化钠、氢氧化钾和氢氧化锂中的一种或多种。所述的碱金属的烷氧化物优选甲醇钠、乙醇钠、叔丁醇钾和叔丁醇钠中的一种或多种。The term "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.
本发明的“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。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.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式I所示苯甲酰胺类化合物)的任何化合物是在本发明的范围和主旨内的前药。例如，含有羧基的化合物可形成生理上可水解的酯，其通过在体内水解以得到式I所示化合物本身而充当前药。所述前药优选口服给药，这是因为水解在许多情况下主要在消化酶的影响下发生。当酯本身具有活性或水解发生在血液中时，可使用肠胃外给药。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, 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) is a prodrug within the scope and spirit of the present invention. For example, 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. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). The conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included in the scope of the present invention.
本发明所使用的术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所 得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。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. Accordingly, 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.
本发明的如式I所示的化合物和其盐意图包括所有固态形式的如式I化合物和其盐。如式I化合物和其盐还意图涵盖所有溶剂化(例如水合)和非溶剂化形式的式I化合物和其盐。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.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。The "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. The term "hydrate" refers to an association formed by the solvent molecule being water.
本发明的“酯”是指含有羟基或羧基的化合物形成的体内可水解的酯。这样的酯是，例如在人或动物体内水解产生母体醇或酸的药学上可接受的酯。本发明式I化合物含有羧基，可以与适当的基团形成体内可水解的酯，这样的基团包括，但不限于，烷基、芳基烷基等。The "ester" in the present invention refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl group or a carboxyl group. Such 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.
如本文所用的，“哺乳动物”是指被分类为哺乳动物的任何哺乳动物，包括人，驯养动物和农畜，以及动物园、竞技或宠物动物，如牛(例如母牛)、马、狗、绵羊、猪、兔、山羊、猫等。As used herein, "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.
“治疗有效量或剂量”或“治疗上足够量或剂量”或“有效或足够量或剂量”是指产生治疗效果的剂量。确切的剂量将取决于治疗的目的，并且本领域技术人员可以使用已知技术确定(参见，例如，Lieberman，Pharmaceutical Dosage Forms(vols.1-3,1992)；Lloyd，The Pharmaceutical，Science and Technology of Pharmaceutical Compounding(1999)；Pickar，Dosage Calculations(1999)；和Remington：The Science and Practice of Pharmacy，20th Edition，2003，Gennaro，Ed.，Lippincott，Williams&Wilkins)。"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).
“治疗”，“治疗”加“改善”和“改善”是指在治疗或改善损伤，病理，病症或症状(例如疼痛)方面的任何成功标志，包括任何目标或主观参数，如缓解；减轻症状；减少症状或病症的频率或持续时间；或者，在某些情况下，预防症状或病症的发作。症状的治疗或改善可以基于任何客观或主观参数；包括例如身体检查的结果。"Treatment", "Treatment" plus "Improvement" and "Improvement" refer 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.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.
本发明的积极进步效果在于：该苯甲酰胺类化合物对于蛋白多糖(Aggrecan)、Ⅱ型胶原(Collagen II)和Sox9中的一种或多种具有较好的诱导表达活性；具有诱导刺激间充质干细胞(MSC)分化成软骨细胞，修复软骨的作用。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.
具体实施方式detailed description
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described by way of examples below, but it does not limit the present invention to the scope of the described examples. The experimental methods not specified in the following examples are selected according to conventional methods and conditions, or according to the product description.
下述实例中，室温是指10-30℃；过夜是指8-15小时，例如12小时；eq是指当量；溶剂比例如PE:EA是指体积比；Lawessons reagent是指劳森试剂。In the following examples, 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.
实施例1Example 1
2-(2-氧代噻唑烷-3-羰基)苯甲酸的合成：Synthesis of 2-(2-oxothiazolidine-3-carbonyl)benzoic acid:
Figure PCTCN2019070573-appb-000054
Figure PCTCN2019070573-appb-000054
取10.0g(60.0mmol)邻苯二甲酸于250ml单颈瓶中，加150ml二氯甲烷，搅拌使其溶解，加入二环己基碳二亚胺(13.6g,66.0mmol)，4-二甲氨基吡啶(8g,66.0mmol)，室温搅拌30min。加入1,3-四氢噻唑-2-酮(5.4g,54.0mmol)，室温搅拌24h。抽滤，弃去滤饼，减压浓缩除去滤液中的溶剂。得浅黄色固体，加入约80mL 5％NaOH水溶液使其溶解，将水相转移至分液漏斗中，加80ml二氯甲烷萃取，弃去有机相。重复六至七次，洗掉反应中的杂质和未反应的原料。水相用1N HCl调pH至2-3，析出白色固体，抽滤，干燥得白色固体4.5g，产率33.3％。Take 10.0g (60.0mmol) of phthalic acid in a 250ml single-necked bottle, add 150ml of dichloromethane, stir to dissolve, add dicyclohexylcarbodiimide (13.6g, 66.0mmol), 4-dimethylamino Pyridine (8g, 66.0mmol), stirred at room temperature for 30min. 1,3-Tetrahydrothiazol-2-one (5.4g, 54.0mmol) was added and stirred at room temperature for 24h. Filter with suction, discard the filter cake, and concentrate under reduced pressure to remove the solvent in the filtrate. A light yellow solid was obtained. About 80 mL of 5% NaOH aqueous solution was added to dissolve it. 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%.
MS-:250.03； 1H-NMR(300MHz,DMSO-d6),δ:13.23(s,1H,-COOH),7.91(dd,1H,Ar-H),7.63(td,1H,Ar-H),7.52(td,1H,Ar-H),7.35(dd,1H,Ar-H),4.23-4.06(m,2H,-SCH 2),3.47-3.43(m,2H,-NCH 2)ppm。 MS-: 250.03; 1 H-NMR (300 MHz, DMSO-d6), δ: 13.23 (s, 1H, -COOH), 7.91 (dd, 1H, Ar-H), 7.63 (td, 1H, Ar-H) , 7.52 (td, 1H, Ar-H), 7.35 (dd, 1H, Ar-H), 4.23-4.06 (m, 2H, -SCH 2 ), 3.47-3.43 (m, 2H, -NCH 2 ) ppm.
2-(2-氧代噻唑烷-3-羰基)苯甲酰氯的合成：Synthesis of 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride:
Figure PCTCN2019070573-appb-000055
Figure PCTCN2019070573-appb-000055
取4.5g(17.91mmol)上一步产物于250ml单口瓶，加100ml四氢呋喃(分子筛干燥)，缓慢滴加4.26g(35.82mmol)氯化亚砜，加两滴DMF催化反应。加热至回流，搅拌6h。减压浓缩除去溶剂和未反应完的氯化亚砜，得棕褐色油状物4.7g，产率97.9％。(反应中注意避免水分进入反应体系，反应完马上投下一步反应。)Take 4.5g (17.91mmol) of the product from the previous step in a 250ml single-necked bottle, add 100ml of tetrahydrofuran (molecular sieve dried), slowly add 4.26g (35.82mmol) of sulfoxide chloride, and add two drops of DMF to catalyze the reaction. Heat to reflux and stir for 6h. Concentrate under reduced pressure to remove the solvent and unreacted sulfoxide chloride to obtain 4.7 g of tan oil, yield 97.9%. (Pay attention to avoid moisture entering the reaction system during the reaction, and immediately throw it to the next reaction after the reaction.)
2-(2-氧代噻唑烷-3-羰基)-N-(3-(三氟甲基)苯基)苯甲酰胺的合成：Synthesis of 2-(2-oxothiazolidine-3-carbonyl)-N-(3-(trifluoromethyl)phenyl)benzamide:
Figure PCTCN2019070573-appb-000056
Figure PCTCN2019070573-appb-000056
将上一步产物(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入2.8g间三氟甲基苯胺，室温搅拌1h，抽滤，滤饼为未反应完的间三氟甲基苯胺，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.5g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得白色固体(0.21g,0.53mmol)，产率3.0％。Dissolve the product from the previous step (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add 2.8g of m-trifluoromethylaniline, stir at room temperature for 1h, filter with suction, the filter cake is unreacted m-trifluoromethylaniline, the filtrate is spinned Dry, DCM:MeOH=50:1 column chromatography to obtain yellow oil 0.5g, at this time the product contains more 1,3-tetrahydrothiazol-2-one, PE:EA=5:1 continue column chromatography White solid (0.21 g, 0.53 mmol), yield 3.0%.
MS(m/z):(M+H) +＝395.0666； 1H-NMR(300MHz,DMSO-d6)δ:13.18(s,1H,-NH-),7.78(d,J＝7.41Hz,1H,Ar-H),7.41(t,J＝7.05Hz,1H,Ar-H),7.33-7.25(dd,J1＝15.78Hz,J2＝7.05Hz,2H,Ar-H),7.11-7.18(dd,J1＝12.51Hz,J2＝7.50Hz 2H,Ar-H),6.86(d,J＝6.02Hz,2H,Ar-H),4.56-4.48(m,1H,-SCH 2),4.31-4.22(m,1H,-SCH 2),3.44-3.53(m,1H,-NCH 2)ppm。 MS (m/z): (M+H) + = 395.0666; 1 H-NMR (300 MHz, DMSO-d6) δ: 13.18 (s, 1H, -NH-), 7.78 (d, J = 7.41 Hz, 1H , Ar-H), 7.41 (t, J = 7.05 Hz, 1H, Ar-H), 7.33-7.25 (dd, J1 = 15.78 Hz, J2 = 7.05 Hz, 2H, Ar-H), 7.11-7.18 (dd , J1 = 12.51 Hz, J2 = 7.50 Hz 2H, Ar-H), 6.86 (d, J = 6.02 Hz, 2H, Ar-H), 4.56-4.48 (m, 1H, -SCH 2 ), 4.31-4.22 ( m, 1H, -SCH 2 ), 3.44-3.53 (m, 1H, -NCH 2 ) ppm.
实施例2Example 2
N-(4-氰基苯基)-2-(2-氧代噻唑烷-3-羰基)苯甲酰胺的合成：Synthesis of N-(4-cyanophenyl)-2-(2-oxothiazolidine-3-carbonyl)benzamide:
Figure PCTCN2019070573-appb-000057
Figure PCTCN2019070573-appb-000057
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(2.1g,17.54mmol)对氨基苯腈，室温搅拌1h，抽滤，滤饼为未反应完的间对氨基苯腈，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.2g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得黄色固体(0.078g,0.22mmol)，产率1.3％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (2.1g, 17.54mmol) of p-aminobenzonitrile, stir at room temperature for 1h, filter with suction The filter cake is unreacted meta-p-aminobenzonitrile, and the filtrate is spin-dried. DCM:MeOH=50:1 column chromatography to obtain a yellow oil 0.2g. At this time, the product contains more 1,3-tetrahydrothiazole- 2-ketone, PE:EA=5:1 continued column chromatography to obtain a yellow solid (0.078g, 0.22mmol) with a yield of 1.3%.
HRMS(m/z):(M+H) +＝352； 1H-NMR(300MHz,DMSO-d6),δ:7.81-6.78(M,8H,Ar-H),4.45(s,-SCH 2),4.26(s,1H,-SCH 2),3.45(s,2H,-NCH 2)ppm。 HRMS (m/z): (M+H) + = 352; 1 H-NMR (300 MHz, DMSO-d6), δ: 7.81-6.78 (M, 8H, Ar-H), 4.45 (s, -SCH 2 ), 4.26 (s, 1H, -SCH 2 ), 3.45 (s, 2H, -NCH 2 ) ppm.
实施例3Example 3
2-(2-氧噻唑烷-3-羰基)-N-(4-(三氟甲基)苯基)苯甲酰胺的合成：Synthesis of 2-(2-oxiazolidine-3-carbonyl)-N-(4-(trifluoromethyl)phenyl)benzamide:
Figure PCTCN2019070573-appb-000058
Figure PCTCN2019070573-appb-000058
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(2.8g,17.54mmol)对三氟甲基苯胺，室温搅拌1h，抽滤，滤饼为未反应完的对三氟甲基苯胺，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.23g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得黄色固体(0.052g,0.13mmol)，产率0.7％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (2.8g, 17.54mmol) of p-trifluoromethylaniline, and stir at room temperature for 1h, Suction filtration, the filter cake is unreacted p-trifluoromethylaniline, the filtrate is spin-dried, DCM: MeOH = 50: 1 column chromatography to obtain a yellow oil 0.23g, this time the product contains more 1,3-tetra Hydrothiazol-2-one, PE:EA=5:1 continued column chromatography to obtain a yellow solid (0.052g, 0.13mmol), yield 0.7%.
HRMS(m/z):(M+H) +＝395.0666； 1H-NMR(300MHz,DMSO-d6),δ:7.80(d,J＝7.62Hz,3H,Ar-H),7.41(t,J＝7.80Hz,3H,Ar-H),7.32(t,J＝7.47Hz,1H,Ar-H),7.17(d,J＝7.29Hz,1H,Ar-H),6.76(d,J＝7.98Hz,2H,Ar-H),4.51-4.49(m,1H,-SCH 2),4.27-4.25(m,1H,-SCH 2),3.48-3.46(m,2H,-NCH 2)ppm。 HRMS (m/z): (M+H) + = 395.0666; 1 H-NMR (300 MHz, DMSO-d6), δ: 7.80 (d, J = 7.62 Hz, 3H, Ar-H), 7.41 (t, J = 7.80 Hz, 3H, Ar-H), 7.32 (t, J = 7.47 Hz, 1H, Ar-H), 7.17 (d, J = 7.29 Hz, 1H, Ar-H), 6.76 (d, J = 7.98 Hz, 2H, Ar-H), 4.51-4.49 (m, 1H, -SCH 2 ), 4.27-4.25 (m, 1H, -SCH 2 ), 3.48-3.46 (m, 2H, -NCH 2 ) ppm.
实施例4Example 4
N-(4-氰基-3-(三氟甲基)苯基)-2-(2-氧代噻唑烷-3-羰基)苯甲酰胺的合成：Synthesis of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(2-oxothiazolidine-3-carbonyl)benzamide:
Figure PCTCN2019070573-appb-000059
Figure PCTCN2019070573-appb-000059
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(3.26g,17.54mmol)4-氨基-2-三氟甲基苯甲腈，室温搅拌1h，抽滤，滤饼为未反应完的 4-氨基-2-三氟甲基苯甲腈，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.30g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得白色固体(0.10g,0.24mmol)，产率1.4％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (3.26g, 17.54mmol) 4-amino-2-trifluoromethylbenzene Tolunitrile, stirred at room temperature for 1h, filtered with suction, the filter cake was unreacted 4-amino-2-trifluoromethyl benzonitrile, the filtrate was spin-dried, DCM: MeOH = 50: 1 column chromatography to give a yellow oil 0.30 g. At this time, the product contains more 1,3-tetrahydrothiazol-2-one. PE:EA=5:1 and continued column chromatography to obtain a white solid (0.10 g, 0.24 mmol) with a yield of 1.4%.
HRMS(m/z):(M+H) +＝420.0595； 1H-NMR(300MHz,DMSO-d6),δ:13.32(s,1H,-NH),7.86-7.79(dd,J 1＝10.50Hz,J 2＝8.43Hz 2H,Ar-H),7.45(t,J＝7.20Hz,1H,Ar-H),7.35(t,J＝7.20Hz,1H,Ar-H),7.24(d,J＝7.47Hz,1H,Ar-H),7.12(s,1H,Ar-H),7.02(d,J＝8.28Hz,1H,Ar-H),4.50(s,1H,-SCH 2),4.28(s,1H,-SCH 2),3.51-3.46(m,2H,-NCH 2)ppm。 HRMS (m/z): (M+H) + = 420.0595; 1 H-NMR (300 MHz, DMSO-d6), δ: 13.32 (s, 1H, -NH), 7.86-7.79 (dd, J 1 = 10.50 Hz, J 2 = 8.43 Hz 2H, Ar-H), 7.45 (t, J = 7.20 Hz, 1H, Ar-H), 7.35 (t, J = 7.20 Hz, 1H, Ar-H), 7.24 (d, J = 7.47 Hz, 1H, Ar-H), 7.12 (s, 1H, Ar-H), 7.02 (d, J = 8.28 Hz, 1H, Ar-H), 4.50 (s, 1H, -SCH 2 ), 4.28 (s, 1H, -SCH 2 ), 3.51-3.46 (m, 2H, -NCH 2 ) ppm.
实施例5Example 5
Figure PCTCN2019070573-appb-000060
Figure PCTCN2019070573-appb-000060
N-(3-氰基-4-氟苯基)-2-(2-氧代噻唑烷-3-羰基)苯甲酰胺的合成：Synthesis of N-(3-cyano-4-fluorophenyl)-2-(2-oxothiazolidine-3-carbonyl)benzamide:
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(2.39g,17.54mmol)5-氨基-2-氟苯腈，室温搅拌1h，抽滤，滤饼为未反应完的5-氨基-2-氟苯腈，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.1g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得黄色固体(0.02g,0.054mmol)，产率0.3％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (2.39g, 17.54mmol) 5-amino-2-fluorobenzonitrile, room temperature Stir for 1h, filter with suction, the filter cake is unreacted 5-amino-2-fluorobenzonitrile, the filtrate is spin-dried, DCM: MeOH = 50: 1 column chromatography to obtain a yellow oil 0.1g, this time the product contains relatively More 1,3-tetrahydrothiazol-2-one, PE:EA=5:1 continued column chromatography to obtain a yellow solid (0.02g, 0.054mmol), a yield of 0.3%.
HRMS(m/z):(M+H) +＝370.0665； 1H-NMR(300MHz,DMSO-d6)δ:7.81(d,J＝7.35Hz1H,Ar-H),7.42-7.30(m,2H,Ar-H),7.24-7.04(m,3H,Ar-H),6.96(s,1H,Ar-H),4.50-4.43(m,1H,-SCH 2),4.30-4.21(m,1H,-SCH 2),3.50-3.44(m,2H,-NCH 2)ppm。 HRMS (m/z): (M+H) + = 370.0665; 1 H-NMR (300 MHz, DMSO-d6) δ: 7.81 (d, J = 7.35 Hz 1H, Ar-H), 7.42-7.30 (m, 2H , Ar-H), 7.24-7.04 (m, 3H, Ar-H), 6.96 (s, 1H, Ar-H), 4.50-4.43 (m, 1H, -SCH 2 ), 4.30-4.21 (m, 1H , -SCH 2 ), 3.50-3.44 (m, 2H, -NCH 2 ) ppm.
实施例6Example 6
4-(2-(2-氧噻唑烷-3-羰基)苯甲酰胺基)苯甲酸的合成:Synthesis of 4-(2-(2-oxiazolidin-3-carbonyl)benzamide)benzoic acid:
Figure PCTCN2019070573-appb-000061
Figure PCTCN2019070573-appb-000061
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(2.4g,17.54mmol)对氨基苯甲酸，室温搅拌1h，抽滤，滤饼为未反应完的间对氨基苯甲酸，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.2g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得黄色固体(0.065g,0.17mmol)，产率0.9％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (2.4g, 17.54mmol) of p-aminobenzoic acid, stir at room temperature for 1h, filter with suction The filter cake is unreacted meta-p-aminobenzoic acid, the filtrate is spin-dried, DCM:MeOH=50:1 column chromatography to obtain a yellow oil 0.2g, at this time the product contains more 1,3-tetrahydrothiazole- 2-ketone, PE:EA=5:1 continued column chromatography to obtain a yellow solid (0.065g, 0.17mmol) with a yield of 0.9%.
HRMS(m/z):(M+H) +＝371.0678； 1H-NMR(300MHz,DMSO-d6),δ:7.78(d,J＝7.05Hz1H,Ar-H),7.62(d,J＝8.43Hz,2H,Ar-H),7.40(t,J＝7.44Hz,1H,Ar-H),7.30(t,J＝7.47Hz,1H,Ar-H),7.15(d,J＝7.44Hz,1H,Ar-H),6.65(d,J＝8.37Hz,2H,Ar-H),4.54-4.46(m,1H,-SCH 2),4.28-4.19(m,1H,-SCH 2),3.52-3.43(m,2H,-NCH 2)ppm。 HRMS (m/z): (M+H) + = 371.0678; 1 H-NMR (300 MHz, DMSO-d6), δ: 7.78 (d, J = 7.05 Hz 1H, Ar-H), 7.62 (d, J = 8.43Hz, 2H, Ar-H), 7.40 (t, J = 7.44Hz, 1H, Ar-H), 7.30 (t, J = 7.47Hz, 1H, Ar-H), 7.15 (d, J = 7.44Hz , 1H, Ar-H), 6.65 (d, J = 8.37Hz, 2H, Ar-H), 4.54-4.46 (m, 1H, -SCH 2 ), 4.28-4.19 (m, 1H, -SCH 2 ), 3.52-3.43 (m, 2H, -NCH 2 ) ppm.
实施例7Example 7
N-(3-氰基苯基)-2-(2-氧代噻唑烷-3-羰基)苯甲酰胺的合成:Synthesis of N-(3-cyanophenyl)-2-(2-oxothiazolidine-3-carbonyl)benzamide:
Figure PCTCN2019070573-appb-000062
Figure PCTCN2019070573-appb-000062
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(2.1g,17.54mmol)3-氨基苯甲腈，室温搅拌1h，抽滤，滤饼为未反应完的3-氨基苯甲腈，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.2g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得白色固体(0.047g,0.13mmol)，产率0.7％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (2.1g, 17.54mmol) 3-aminobenzonitrile, stir at room temperature for 1h, Suction filtration, the filter cake is unreacted 3-aminobenzonitrile, the filtrate is spin-dried, DCM:MeOH=50:1 column chromatography to obtain a yellow oil 0.2g, at this time the product contains more 1,3-tetra Hydrothiazol-2-one, PE:EA=5:1 continued column chromatography to obtain a white solid (0.047g, 0.13mmol), yield 0.7%.
HRMS(m/z):(M+H) +＝352.0731； 1H-NMR(300MHz,(DMSO-d6),δ:13.21(s,1H,Ar-H),7.80(d,J＝7.47Hz 1H,Ar-H),7.43(t,J＝7.20Hz,1H,Ar-H),7.33(t,J＝7.59Hz,1H,Ar-H),7.25-7.18(m,3H,Ar-H),6.96(s,1H,Ar-H),6.87(s,1H,Ar-H),4.49-4.47(m,1H, -SCH 2),4.26-4.24(m,1H,-SCH 2),3.52-3.44(m,2H,-NCH 2)ppm。 HRMS (m/z): (M+H) + = 352.0731; 1 H-NMR (300 MHz, (DMSO-d6), δ: 13.21 (s, 1H, Ar-H), 7.80 (d, J = 7.47 Hz 1H, Ar-H), 7.43 (t, J = 7.20 Hz, 1H, Ar-H), 7.33 (t, J = 7.59 Hz, 1H, Ar-H), 7.25-7.18 (m, 3H, Ar-H ), 6.96 (s, 1H, Ar-H), 6.87 (s, 1H, Ar-H), 4.49-4.47 (m, 1H, -SCH 2 ), 4.26-4.24 (m, 1H, -SCH 2 ), 3.52-3.44 (m, 2H, -NCH 2 ) ppm.
实施例8Example 8
N-(5-氰基吡啶-2-基)-2-(2-氧代噻唑烷-3-羰基)苯甲酰胺:N-(5-cyanopyridin-2-yl)-2-(2-oxothiazolidine-3-carbonyl) benzamide:
Figure PCTCN2019070573-appb-000063
Figure PCTCN2019070573-appb-000063
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(2.1g,17.54mmol)2-氨基-5-腈基吡啶，室温搅拌1h，抽滤，滤饼为未反应完的间2-氨基-5-腈基吡啶，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.1g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得白色固体(0.02g,0.05mmol)，产率0.3％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (2.1g, 17.54mmol) 2-amino-5-cyanopyridine, room temperature Stir for 1h, filter with suction, the filter cake is unreacted m- 2-amino-5-cyanopyridine, the filtrate is spin-dried, DCM:MeOH = 50:1 column chromatography to obtain a yellow oil 0.1g, this time the product contains More 1,3-tetrahydrothiazol-2-one, PE:EA=5:1 continued column chromatography to obtain a white solid (0.02g, 0.05mmol), yield 0.3%.
HRMS(m/z):(M+H) +＝353.0710； 1H-NMR(300MHz,DMSO-d6),δ:8.56(s,1H,Ar-H),7.93(d,J＝8.43Hz,2H,Ar-H),7.79(d,J＝7.35Hz,1H,Ar-H),7.43-7.31(m,2H,Ar-H),7.11(d,J＝7.26Hz,1H,Ar-H),6.68(d,J＝8.43Hz,1H,Ar-H),4.48(s,1H,-SCH 2),4.26(s,1H,-SCH 2),3.50(s,2H,-NCH 2)ppm。 HRMS (m/z): (M+H) + = 353.0710; 1 H-NMR (300 MHz, DMSO-d6), δ: 8.56 (s, 1H, Ar-H), 7.93 (d, J = 8.43 Hz, 2H, Ar-H), 7.79 (d, J = 7.35 Hz, 1H, Ar-H), 7.43-7.31 (m, 2H, Ar-H), 7.11 (d, J = 7.26 Hz, 1H, Ar-H ), 6.68 (d, J = 8.43 Hz, 1H, Ar-H), 4.48 (s, 1H, -SCH 2 ), 4.26 (s, 1H, -SCH 2 ), 3.50 (s, 2H, -NCH 2 ) ppm.
实施例9Example 9
N-(6-氰基-5-(三氟甲基)吡啶-3-基)-2-(2-氧代噻唑烷-3-羰基)苯甲酰胺的合成:Synthesis of N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(2-oxothiazolidine-3-carbonyl)benzamide:
Figure PCTCN2019070573-appb-000064
Figure PCTCN2019070573-appb-000064
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(3.28g,17.54)2-腈基-3-三氟甲基-5-氨基吡啶，室温搅拌1h，抽滤，滤饼为未反应完的 2-腈基-3-三氟甲基-5-氨基吡啶，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物1.0g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得白色固体0.49g(1.16mmol)，产率6.6％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (3.28g, 17.54) 2-cyano-3-trifluoromethyl- 5-Aminopyridine, stirred at room temperature for 1h, filtered with suction, the filter cake was unreacted 2-cyano-3-trifluoromethyl-5-aminopyridine, the filtrate was spin-dried, DCM:MeOH=50:1 column chromatography 1.0 g of yellow oil was obtained. At this time, the product contained more 1,3-tetrahydrothiazol-2-one. PE:EA=5:1 continued column chromatography to obtain 0.49 g (1.16 mmol) of white solid with a yield of 6.6 %.
HRMS(m/z):420.0504,(M+H) +＝421.0538； 1H-NMR(300MHz,DMSO-d6),δ:13.51(s,1H,-NH),8.23(s,1H,Ar-H),7.82(d,J＝7.62Hz,1H,Ar-H),7.50(d,J＝8.94Hz,2H,Ar-H),7.42-7.32(m,2H,Ar-H),4.51(s,1H,-SCH 2),4.29(s,1H,-SCH 2),3.50(m,2H,-NCH 2)ppm。 HRMS (m/z): 420.0504, (M+H) + = 421.0538; 1 H-NMR (300 MHz, DMSO-d6), δ: 13.51 (s, 1H, -NH), 8.23 (s, 1H, Ar- H), 7.82 (d, J = 7.62 Hz, 1H, Ar-H), 7.50 (d, J = 8.94 Hz, 2H, Ar-H), 7.42-7.32 (m, 2H, Ar-H), 4.51 ( s, 1H, -SCH 2 ), 4.29 (s, 1H, -SCH 2 ), 3.50 (m, 2H, -NCH 2 ) ppm.
实施例10Example 10
N-(5-甲基吡啶-3-基)-2-(2-氧代噻唑烷-3-羰基)苯甲酰胺的合成:Synthesis of N-(5-methylpyridin-3-yl)-2-(2-oxothiazolidine-3-carbonyl)benzamide:
Figure PCTCN2019070573-appb-000065
Figure PCTCN2019070573-appb-000065
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(1.89g,17.54mmol)3-氨基-5-甲基吡啶，室温搅拌1h，抽滤，滤饼为未反应完的3-氨基-5-甲基吡啶，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.19g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得白色固体(0.053g,0.15mmol)，产率0.9％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (1.89g, 17.54mmol) 3-amino-5-methylpyridine, room temperature Stir for 1h, filter with suction. The filter cake is unreacted 3-amino-5-methylpyridine. The filtrate is spin-dried. DCM:MeOH=50:1 column chromatography to obtain a yellow oil 0.19g. More 1,3-tetrahydrothiazol-2-one, PE:EA=5:1 continued column chromatography to obtain a white solid (0.053g, 0.15mmol), yield 0.9%.
HRMS(m/z):341.0834,(M+H) +＝342.0913； 1H-NMR(300MHz,DMSO-d6),δ:10.50(s,1H,-NH),8.33(s,1H,Ar-H),8.08(s,1H,Ar-H),7.82(m,4H,Ar-H),7.58(s,1H,Ar-H),3.87(t,J＝6.15Hz,2H,-SCH 2),3.50(m,J＝6.21Hz,2H,-NCH 2)ppm。 HRMS (m/z): 341.0834, (M+H) + = 342.0913; 1 H-NMR (300 MHz, DMSO-d6), δ: 10.50 (s, 1H, -NH), 8.33 (s, 1H, Ar- H), 8.08 (s, 1H, Ar-H), 7.82 (m, 4H, Ar-H), 7.58 (s, 1H, Ar-H), 3.87 (t, J = 6.15Hz, 2H, -SCH 2 ), 3.50 (m, J = 6.21 Hz, 2H, -NCH 2 ) ppm.
实施例11Example 11
2-氯-4-(2-(2-氧代噻唑烷-3-羰基)苯甲酰胺基)苯甲酸的合成:Synthesis of 2-chloro-4-(2-(2-oxothiazolidine-3-carbonyl)benzamide)benzoic acid:
Figure PCTCN2019070573-appb-000066
Figure PCTCN2019070573-appb-000066
将2-(2-氧代噻唑烷-3-羰基)苯甲酰氯(4.7g,17.54mmol)溶于100ml四氢呋喃中，加入(2.9g,17.54mmol)2-氯-4-氨基-苯甲酸，室温搅拌1h，抽滤，滤饼为未反应完的2-氯-4-氨基-苯甲酸，滤液旋干，DCM:MeOH＝50:1柱层析得黄色油状物0.19g，此时产物中含有较多1,3-四氢噻唑-2-酮，PE:EA＝5:1继续柱层析得白色固体(0.11g,0.27mmol)，产率1.5％。Dissolve 2-(2-oxothiazolidine-3-carbonyl)benzoyl chloride (4.7g, 17.54mmol) in 100ml of tetrahydrofuran, add (2.9g, 17.54mmol) 2-chloro-4-amino-benzoic acid, Stir at room temperature for 1 h, filter with suction, the filter cake is unreacted 2-chloro-4-amino-benzoic acid, the filtrate is spin-dried, DCM:MeOH = 50:1 column chromatography to obtain a yellow oil 0.19g Containing more 1,3-tetrahydrothiazol-2-one, PE:EA=5:1 continued column chromatography to obtain a white solid (0.11g, 0.27mmol) with a yield of 1.5%.
HRMS(m/z):404.0234,(M+H) +＝405.0309； 1H-NMR(300MHz,DMSO-d6),δ:13.17(s,2H,-NH,-COOH),7.80(d,J＝7.53Hz,1H,Ar-H),7.55(d,J＝8.22Hz 1H,Ar-H),7.46(t,J＝8.22Hz,1H,Ar-H),7.35(t,J＝7.47Hz,1H,Ar-H),7.21(d,J＝7.35Hz,1H,Ar-H),6.70(s,1H,Ar-H),6.60(d,J＝8.43Hz,1H,Ar-H),4.53-4.44(m,1H,-SCH 2),4.27-4.18(m,1H,-SCH 2),3.52-3.43(m,2H,-NCH 2)ppm。 HRMS (m/z): 404.0234, (M+H) + = 405.0309; 1 H-NMR (300 MHz, DMSO-d6), δ: 13.17 (s, 2H, -NH, -COOH), 7.80 (d, J = 7.53 Hz, 1H, Ar-H), 7.55 (d, J = 8.22 Hz 1H, Ar-H), 7.46 (t, J = 8.22 Hz, 1H, Ar-H), 7.35 (t, J = 7.47 Hz , 1H, Ar-H), 7.21 (d, J = 7.35Hz, 1H, Ar-H), 6.70 (s, 1H, Ar-H), 6.60 (d, J = 8.43Hz, 1H, Ar-H) , 4.53-4.44 (m, 1H, -SCH 2 ), 4.27-4.18 (m, 1H, -SCH 2 ), 3.52-3.43 (m, 2H, -NCH 2 ) ppm.
实施例12Example 12
Figure PCTCN2019070573-appb-000067
Figure PCTCN2019070573-appb-000067
将1克2-甲氧基苯甲酸(5.6mmol,1当量)加入50毫升单口瓶，依次加入10毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol)搅拌十分钟，加入4-胺基联苯(1.05g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.9g。Add 1 gram of 2-methoxybenzoic acid (5.6 mmol, 1 equiv) to a 50 ml single-necked bottle, add 10 ml of DMF, DIPEA (2.86 g, 23 mmol, 4 equiv) in turn, stir at room temperature for 5 minutes; add HATU (4.26 g , 11.2mmol) was stirred for ten minutes, 4-aminobiphenyl (1.05g, 6.2mmol) was added, and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.9 g of off-white compound.
将0.9克(分子量331.08,2.72mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,2eq)，回流2小时。冷却到室温，加入30毫升水，20毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.5克。0.9 g (molecular weight 331.08, 2.72 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 2 eq) was added, and refluxed for 2 hours. Cool to room temperature, add 30 ml of water, extract 3 times with 20 ml of ethyl acetate, combine organic phases, wash with 20 ml of water, and discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.5 g .
将上述0.5克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.16克，23.95,4当量)，室温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体90毫克。Dissolve the above 0.5 grams of compound in 4 milliliters of tetrahydrofuran and 1 milliliter of water, add lithium hydroxide (0.16 grams, 23.95, 4 equivalents), stir at room temperature for about 2 hours, until the raw materials are basically reacted, prepare the liquid phase separation and purification to obtain the target compound, Light yellow solid 90 mg.
1H-NMR(400MHz，DMSO-d6)δ8.04-7.03(8H)；MS ES +：334.0；ES -：332.1。 1 H-NMR (400MHz, DMSO -d6) δ8.04-7.03 (8H); MS ES +: 334.0; ES -: 332.1.
实施例13Example 13
Figure PCTCN2019070573-appb-000068
Figure PCTCN2019070573-appb-000068
将1克2-甲氧基苯甲酸(5.6mmol,1当量)加入50毫升单口瓶，依次加入10毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol)搅拌十分钟，加入4-胺基联苯(1.05g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.9g。Add 1 gram of 2-methoxybenzoic acid (5.6 mmol, 1 equiv) to a 50 ml single-necked bottle, add 10 ml of DMF, DIPEA (2.86 g, 23 mmol, 4 equiv) in turn, stir at room temperature for 5 minutes; add HATU (4.26 g , 11.2mmol) was stirred for ten minutes, 4-aminobiphenyl (1.05g, 6.2mmol) was added, and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.9 g of off-white compound.
将0.9克(分子量331.08,2.72mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,2eq)，回流2小时。冷却到室温，加入40毫升水，30毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.6克。0.9 g (molecular weight 331.08, 2.72 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 2 eq) was added, and refluxed for 2 hours. Cool to room temperature, add 40 ml of water, extract 3 times with 30 ml of ethyl acetate, combine the organic phases, wash with 20 ml of water, and discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.6 g .
将上述0.6克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.17克，23.95,4当量)，室温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体100毫克。Dissolve the above 0.6 g of the compound in 4 ml of tetrahydrofuran and 1 ml of water, add lithium hydroxide (0.17 g, 23.95, 4 equivalents), stir at room temperature for about 2 hours, until the raw materials are basically reacted, prepare the liquid phase separation and purification to obtain the target compound, Light yellow solid 100 mg.
1H-NMR(400MHz，DMSO-d6)δ8.04-7.03(8H)；MS ES +：334.0；ES -：332.1。 1 H-NMR (400MHz, DMSO -d6) δ8.04-7.03 (8H); MS ES +: 334.0; ES -: 332.1.
实施例14Example 14
Figure PCTCN2019070573-appb-000069
Figure PCTCN2019070573-appb-000069
将1克2-甲氧基苯甲酸(5.6mmol,1当量)加入50毫升单口瓶，依次加入10毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol)搅拌十分钟，加入4-胺基联苯(1.05g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.9g。Add 1 gram of 2-methoxybenzoic acid (5.6 mmol, 1 equiv) to a 50 ml single-necked bottle, add 10 ml of DMF, DIPEA (2.86 g, 23 mmol, 4 equiv) in turn, stir at room temperature for 5 minutes; add HATU (4.26 g , 11.2mmol) was stirred for ten minutes, 4-aminobiphenyl (1.05g, 6.2mmol) was added, and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.9 g of off-white compound.
将0.9克(分子量331.08,2.72mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,2eq)，回流2小时。冷却到室温，加入30毫升水，20毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.6克。0.9 g (molecular weight 331.08, 2.72 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 2 eq) was added, and refluxed for 2 hours. Cool to room temperature, add 30 ml of water, extract 3 times with 20 ml of ethyl acetate, combine organic phases, wash with 20 ml of water, discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.6 g .
将上述0.6克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.17克,23.95,4当量)，室温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体110毫克。Dissolve the above 0.6 g of the compound in 4 ml of tetrahydrofuran and 1 ml of water, add lithium hydroxide (0.17 g, 23.95, 4 equivalents), stir at room temperature for about 2 hours, until the raw materials are basically reacted, prepare the liquid phase separation and purification to obtain the target compound, Light yellow solid 110 mg.
1H-NMR(400MHz，DMSO-d6)δ8.04-7.03(8H)；MS ES +:334.0；ES -：332.1。 1 H-NMR (400MHz, DMSO -d6) δ8.04-7.03 (8H); MS ES +: 334.0; ES -: 332.1.
实施例15Example 15
Figure PCTCN2019070573-appb-000070
Figure PCTCN2019070573-appb-000070
1克2-甲氧基苯甲酸(分子量180.04,5.6mmol,1当量)加入50毫升单口瓶，依次加入10 毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol,2当量)搅拌十分钟，加入3-氰基苯胺(7.31g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.7g。1g of 2-methoxybenzoic acid (molecular weight 180.04, 5.6mmol, 1 equivalent) was added to a 50ml single-necked bottle, followed by 10ml of DMF, DIPEA (2.86g, 23mmol, 4 equivalent), stirred at room temperature for 5 minutes; add HATU ( 4.26g, 11.2mmol, 2eq) was stirred for ten minutes, 3-cyanoaniline (7.31g, 6.2mmol) was added and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.7 g of off-white compound.
将0.7克(分子量298.06,2.35mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,1.9当量)，回流2小时。冷却到室温，加入30毫升水，20毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.5克。0.7 g (molecular weight 298.06, 2.35 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 1.9 equiv) was added and refluxed for 2 hours. Cool to room temperature, add 30 ml of water, extract 3 times with 20 ml of ethyl acetate, combine organic phases, wash with 20 ml of water, and discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.5 g .
将上述0.5克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.16克,4当量)，室温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体70毫克。Dissolve the above 0.5 g of compound in 4 ml of tetrahydrofuran and 1 ml of water, add lithium hydroxide (0.16 g, 4 equiv), and stir at room temperature for about 2 hours, until the raw materials are basically reacted, prepare the liquid phase separation and purification to obtain the target compound, light yellow 70 mg solid.
1H-NMR(400MHz，DMSO-d6)δ8.04-7.03(8H)；MS ES +：301.1；ES -：299.2。 1 H-NMR (400MHz, DMSO -d6) δ8.04-7.03 (8H); MS ES +: 301.1; ES -: 299.2.
实施例16Example 16
Figure PCTCN2019070573-appb-000071
Figure PCTCN2019070573-appb-000071
1克2-甲氧基苯甲酸(分子量180.04,5.6mmol,1当量)加入50毫升单口瓶，依次加入10毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol,2当量)搅拌十分钟，加入4-三氟甲基苯胺(1.05g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.8g。1g of 2-methoxybenzoic acid (molecular weight 180.04, 5.6mmol, 1 equivalent) was added to a 50ml single-necked bottle, followed by 10ml of DMF, DIPEA (2.86g, 23mmol, 4 equivalent), stirred at room temperature for 5 minutes; add HATU ( 4.26g, 11.2mmol, 2eq) was stirred for ten minutes, 4-trifluoromethylaniline (1.05g, 6.2mmol) was added and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.8 g of off-white compound.
将0.8克(分子量323.08,2.47mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,2eq)，回流2小时。冷却到室温，加入30毫升水，20毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.5克。0.8 g (molecular weight 323.08, 2.47 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 2 eq) was added and refluxed for 2 hours. Cool to room temperature, add 30 ml of water, extract 3 times with 20 ml of ethyl acetate, combine organic phases, wash with 20 ml of water, and discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.5 g .
将上述0.5克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.16克,4当量)，室 温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体90毫克。Dissolve the above 0.5 g of compound in 4 ml of tetrahydrofuran and 1 ml of water, add lithium hydroxide (0.16 g, 4 equiv), and stir at room temperature for about 2 hours, until the raw material is basically reacted, prepare the liquid phase separation and purification to obtain the target compound, light yellow 90 mg solid.
1H-NMR(400MHz，DMSO-d6)δ8.04-7.03(8H)；MS ES +：326.0；ES -：324.1。 1 H-NMR (400MHz, DMSO -d6) δ8.04-7.03 (8H); MS ES +: 326.0; ES -: 324.1.
实施例17Example 17
Figure PCTCN2019070573-appb-000072
Figure PCTCN2019070573-appb-000072
1克2-甲氧基苯甲酸(分子量180.04,5.6mmol,1当量)加入50毫升单口瓶，依次加入10毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol,2当量)搅拌十分钟，加入3-三氟甲基苯胺(9.98g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.8g。1g of 2-methoxybenzoic acid (molecular weight 180.04, 5.6mmol, 1 equivalent) was added to a 50ml single-necked bottle, followed by 10ml of DMF, DIPEA (2.86g, 23mmol, 4 equivalent), stirred at room temperature for 5 minutes; add HATU ( 4.26g, 11.2mmol, 2eq) was stirred for ten minutes, 3-trifluoromethylaniline (9.98g, 6.2mmol) was added and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.8 g of off-white compound.
将0.8克(分子量323.04,2.47mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,2当量)，回流2小时。冷却到室温，加入30毫升水，20毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.5克。0.8 g (molecular weight 323.04, 2.47 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 2 equiv) was added and refluxed for 2 hours. Cool to room temperature, add 30 ml of water, extract 3 times with 20 ml of ethyl acetate, combine organic phases, wash with 20 ml of water, and discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.5 g .
将上述0.5克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.16克，4当量)，室温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体85毫克。Dissolve the above 0.5 g of compound in 4 ml of tetrahydrofuran and 1 ml of water, add lithium hydroxide (0.16 g, 4 equiv), and stir at room temperature for about 2 hours, until the raw materials are basically reacted, prepare the liquid phase separation and purification to obtain the target compound, light yellow 85 mg solid.
H-NMR(400MHz，DMSO-d6)δ8.04-7.03(8H)；MS ES +：326.0。 H-NMR (400 MHz, DMSO-d6) δ 8.04-7.03 (8H); MS ES + : 326.0.
实施例18Example 18
Figure PCTCN2019070573-appb-000073
Figure PCTCN2019070573-appb-000073
1克2-甲氧基苯甲酸(分子量180.04,5.6mmol,1当量)加入50毫升单口瓶，依次加入10毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol,2当量)搅拌十分钟，加入4-氰基苯胺(7.31g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.7g。1g of 2-methoxybenzoic acid (molecular weight 180.04, 5.6mmol, 1 equivalent) was added to a 50ml single-necked bottle, followed by 10ml of DMF, DIPEA (2.86g, 23mmol, 4 equivalent), stirred at room temperature for 5 minutes; add HATU ( 4.26g, 11.2mmol, 2eq) was stirred for ten minutes, 4-cyanoaniline (7.31g, 6.2mmol) was added, and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.7 g of off-white compound.
将0.7克(分子量298.06,2.35mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,1.9当量)，回流2小时。冷却到室温，加入30毫升水，20毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.5克。0.7 g (molecular weight 298.06, 2.35 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 1.9 equiv) was added and refluxed for 2 hours. Cool to room temperature, add 30 ml of water, extract 3 times with 20 ml of ethyl acetate, combine organic phases, wash with 20 ml of water, and discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.5 g .
将上述0.5克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.16克,4当量)，室温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体60毫克。Dissolve the above 0.5 g of compound in 4 ml of tetrahydrofuran and 1 ml of water, add lithium hydroxide (0.16 g, 4 equiv), and stir at room temperature for about 2 hours, until the raw material is basically reacted, prepare the liquid phase separation and purification to obtain the target compound, light yellow 60 mg solid.
H-NMR(400MHz，DMSO-d6)δ8.04-7.03(8H)；MS ES +：301.0；ES -：299.1。 H-NMR (400MHz, DMSO- d6) δ8.04-7.03 (8H); MS ES +: 301.0; ES -: 299.1.
实施例19Example 19
Figure PCTCN2019070573-appb-000074
Figure PCTCN2019070573-appb-000074
1克2-甲氧基苯甲酸(分子量180.04,5.6mmol,1当量)加入50毫升单口瓶，依次加入10毫升DMF，DIPEA(2.86g,23mmol,4当量)，室温搅拌5分钟；加入HATU(4.26g,11.2mmol, 2当量)搅拌十分钟，加入2-氰基-3-三氟甲基-5-氨基吡啶(1.16g,6.2mmol)，室温磁力搅拌过夜。次日，浓缩除去溶剂，加入10毫升1mol/L盐酸和20毫升乙酸乙酯萃取，浓缩有机相，柱色谱分离，得到类白色化合物约0.8g。1g of 2-methoxybenzoic acid (molecular weight 180.04, 5.6mmol, 1 equivalent) was added to a 50ml single-necked bottle, followed by 10ml of DMF, DIPEA (2.86g, 23mmol, 4 equivalent), stirred at room temperature for 5 minutes; add HATU ( 4.26g, 11.2mmol, 2eq) was stirred for ten minutes, 2-cyano-3-trifluoromethyl-5-aminopyridine (1.16g, 6.2mmol) was added, and magnetically stirred at room temperature overnight. The next day, the solvent was concentrated and removed, 10 ml of 1 mol/L hydrochloric acid and 20 ml of ethyl acetate were added for extraction, and the organic phase was concentrated and separated by column chromatography to obtain about 0.8 g of off-white compound.
将0.8克(分子量367.04,2.18mmol)上步产物溶解于9毫升甲苯，加入劳森试剂(2.2g,4.43mmol,2当量)，回流2小时。冷却到室温，加入30毫升水，20毫升乙酸乙酯萃取3次，合并有机相，20毫升水洗，弃去水相；加入无水硫酸钠干燥，过滤，浓缩乙酸乙酯相得到黄色固体0.4克。0.8 g (molecular weight 367.04, 2.18 mmol) of the previous product was dissolved in 9 ml of toluene, Lawson's reagent (2.2 g, 4.43 mmol, 2 equivalents) was added, and refluxed for 2 hours. Cool to room temperature, add 30 ml of water, extract 3 times with 20 ml of ethyl acetate, combine organic phases, wash with 20 ml of water, discard the aqueous phase; add anhydrous sodium sulfate to dry, filter, and concentrate the ethyl acetate phase to obtain a yellow solid 0.4 g .
将上述0.4克化合物溶于4毫升四氢呋喃和1毫升水，加入氢氧化锂(0.15克,4当量)，室温搅拌约2小时，至原料基本反应完全，制备液相分离纯化得到目标化合物，淡黄色固体50毫克。Dissolve the above 0.4 g of compound in 4 ml of tetrahydrofuran and 1 ml of water, add lithium hydroxide (0.15 g, 4 equiv), and stir at room temperature for about 2 hours, until the raw materials are basically reacted, prepare the liquid phase separation and purification to obtain the target compound, light yellow 50 mg solid.
1H-NMR(400MHz，DMSO-d6)δ8.04-7.03(6H)；MS ES +：370.0。 1 H-NMR (400 MHz, DMSO-d6) δ 8.04-7.03 (6H); MS ES + : 370.0.
生物实施例1：人源性滑膜干细胞体外软骨诱导分化实验Biological Example 1: In vitro cartilage induction and differentiation experiment of human-derived synovial stem cells
1、实验材料1. Experimental materials
1.1实验样本1.1 Experimental sample
人源性滑膜干细胞：实验样本由南京市鼓楼医院提供。Human-derived synovial stem cells: The experimental samples were provided by Nanjing Gulou Hospital.
1.2实验试剂1.2 Experimental reagents
DMEM/F-12培养基，gibco公司DMEM/F-12 medium, gibco company
FBS，Sciencell公司FBS, Sciencell
Penicillin-Streptomycin Liquid，gibco公司Penicillin-Streptomycin Liquid, gibco
Collagenase Type I，gibco公司Collagenase Type I, gibco
0.25％胰蛋白酶EDTA，gibco公司0.25% trypsin EDTA, gibco
逆转录试剂盒(RR047A)，Takara公司Reverse transcription kit (RR047A), Takara Corporation
QPCR试剂盒(Q411-02)，南京诺唯赞生物科技有限公司QPCR kit (Q411-02), Nanjing Nuoweizan Biological Technology Co., Ltd.
1.3实验仪器1.3 Experimental instruments
PCR扩增仪，Biometra公司PCR Amplifier, Biometra
实时荧光定量PCR仪(LC480II)，ROCHE公司Real-time fluorescence quantitative PCR instrument (LC480II), ROCHE company
1.4主要工作液配制1.4 Preparation of main working fluid
1.4.1PBS溶液(1L)的配制1.4.1 Preparation of PBS solution (1L)
天平称取NaCl 8g，KCl 0.2g，Na 2HPO 4·12H 2O 3.58g，KH 2PO 4 0.24g，ddH 2O定容至800ml，加入适量NaOH调pH至7.2后ddH 2O定容至1L，高压消毒后使用。 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.
1.4.2 0.4％I型胶原降解酶的配制1.4.2 Preparation of 0.4% type I collagen degrading enzyme
称取0.08g I型胶原降解酶，加入20ml DMEM/F-12培养基，混匀，0.22μm滤器过滤灭菌，现配现用。Weigh 0.08g of type I collagen degrading enzyme, add 20ml of DMEM/F-12 medium, mix well, filter sterilize with 0.22μm filter, it is now used.
1.4.3药物的配制1.4.3 Preparation of drugs
n(mmol)＝(Wt(mg)/Mol·Wt)×HPLC(％)，药物加入DMSO溶解。n(mmol)=(Wt(mg)/Mol·Wt)×HPLC(%), the drug is dissolved in DMSO.
2.实验方法2. Experimental method
2.1人滑膜间充干细胞分离培养2.1 Isolation and culture of human synovial mesenchymal stem cells
第一天：提取样本。在超净工作台将滑膜组织取出，PBS冲洗，并且去除脂肪部分。将滑膜组织剪碎，吸去PBS，加入含Ⅰ型胶原降解酶的DMEM/F-12培养基，加入1％双抗，37℃、5％CO 2细胞培养箱消化过夜。 Day 1: Take samples. Remove the synovial tissue on the ultra-clean workbench, rinse with PBS, and remove the fat part. The synovial tissue was shredded, PBS was sucked off, DMEM/F-12 medium containing type I collagen degrading enzyme was added, 1% double antibody was added, and digested overnight at 37°C and 5% CO 2 cell incubator.
第二天：滤器过滤后液体1500rpm，5min，20℃离心。离心后吸去上清，加入2ml含10％FBS DMEM/F-12培养基将细胞吹打均匀。10cm培养皿中加入8ml含10％FBS的DMEM/F-12培养基，再加入2ml细胞悬液，轻轻晃匀，加入1％青霉素链霉素(双抗)，37℃、5％CO 2细胞培养箱中培养。 The next day: After filtering the filter, the liquid was centrifuged at 1500 rpm, 5 min, and 20°C. After centrifugation, the supernatant was aspirated, and 2 ml of 10% FBS DMEM/F-12 medium was added to pipette the cells evenly. Add 8ml of DMEM/F-12 medium containing 10% FBS to a 10cm Petri dish, add 2ml of cell suspension, shake gently, add 1% penicillin streptomycin (double antibody), 37°C, 5% CO 2 Culture in a cell incubator.
待细胞贴壁后，每2-3天换一次液，细胞融合度约90％时胰蛋白酶EDTA消化离心传代种板。After the cells adhere to the wall, change the fluid every 2-3 days. When the cell fusion degree is about 90%, trypsin EDTA digestion and centrifugation and subculture seed plate.
2.2QPCR检测及结果分析2.2QPCR detection and result analysis
将人源性滑膜间充质干细胞(SMSC)接种到六孔板的每个孔，5％CO 2，37℃培养至每孔细胞密度达到95％。以10μM的终浓度像细胞中加入化合物(在DMSO溶液中)，并在5％CO 2，37℃下培养细胞21天。Trizol法提取RNA，逆转录成cDNA。检测蛋白多糖(Aggrecan)、Ⅱ型胶原(Collagen II)，Sox9在细胞内的相对表达量。相对表达量使用LightCycler 480II***检测(Roche)。使用载体(DMSO)作为对照来确定软骨细胞分化的基础水平。本实验中待测的目的基因为Aggrecan,Collagen II,sox9，内参基因为GAPDH。其中Aggrecan,Collagen II,sox9三个基因为成软骨基因。QPCR结果分析，若Aggrecan,Collagen II,sox9基因的表达量升高，则证明在药物的诱导下滑膜间充干细胞有向软骨细胞分化的趋势。选择蛋白多糖(Aggrecan)、Ⅱ型胶原(Collagen II)，Sox9表达量较载体对照高的化合物进行下一步诱导实验。 Human-derived synovial mesenchymal stem cells (SMSCs) were seeded into each well of a six-well plate, 5% CO 2 , and cultured at 37°C until the cell density per well reached 95%. Compounds (in DMSO solution) were added to the cells at a final concentration of 10 μM, and the cells were cultured for 21 days at 37° C. in 5% CO 2 . 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. Among them, 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), Sox9 expression higher than the vehicle control compound for the next induction experiment.
EXCEL统计结果。计算△Ct＝Ct(目的基因)-Ct(内参基因)，得出每组每一个目的基因的△Ct。再计算△△Ct＝△Ct(给药组)-△Ct(对照组)，对所得结果取相反数，得到-△△Ct。最后，对-△△Ct进行2的幂运算，即2 -△△Ct，得出目的基因表达的相对变化。具体结果如表： EXCEL statistical results. Calculate △Ct=Ct (target gene)-Ct (internal reference gene) to get ΔCt for each target gene in each group. Calculate △△Ct=△Ct (administration group)-△Ct (control group), and take the opposite number to get -△△Ct. Finally, perform a power of 2 on -△△Ct , that is, 2 -△△Ct , to get the relative change of target gene expression. The specific results are shown in the table:
表：不同化合物在体外对人源性滑膜干细胞体外软骨诱导分化Table: Different compounds induce human-derived synovial stem cells to differentiate into cartilage in vitro
Figure PCTCN2019070573-appb-000075
Figure PCTCN2019070573-appb-000075
备注：A～D分别代表不同活性级别，具体见下表：Remarks: A～D represent different activity levels, see the table below for details:
活性级别Activity level mAGGRECANmAGGRECAN mCOL2A1mCOL2A1 SOX9SOX9
AA 0-0.50-0.5 0-1.00-1.0 0-1.00-1.0
BB 0.5-1.00.5-1.0 1.0-5.01.0-5.0 1.0-10.01.0-10.0
CC 1.0-5.01.0-5.0 5.0-20.05.0-20.0 10.0-100.010.0-100.0
DD >5.0>5.0 >20.0>20.0 >100>100
Kartogenin具体结构为：
Figure PCTCN2019070573-appb-000076
The specific structure of Kartogenin is:
Figure PCTCN2019070573-appb-000076
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely examples, and various changes or changes can be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (20)

  1. 一种如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药：A benzamide compound of formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomerism Body or its prodrug:
    Figure PCTCN2019070573-appb-100001
    Figure PCTCN2019070573-appb-100001
    其中，X为O或S；Among them, X is O or S;
    R为-OH、
    Figure PCTCN2019070573-appb-100002
    或、未取代或被一个或多个R a取代的C 3～C 5杂环烷基；所述的C 3～C 5杂环烷基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～3个，其中至少含有一个N原子，且其通过N原子与所述的
    Figure PCTCN2019070573-appb-100003
    相连；当取代基R a为多个时，所述的取代基相同或不同；     R is -OH,
    Figure PCTCN2019070573-appb-100002
    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
    Figure PCTCN2019070573-appb-100003
    Connected; when a plurality of substituent groups R a, the same or different substituents;
    R a独立地为卤素、-OH、-CN、-NH 2、-COOH或＝O； R a is independently halogen, -OH, -CN, -NH 2 , -COOH, or =O;
    Figure PCTCN2019070573-appb-100004
    为未取代或被一个或多个R 1取代的C 6～C 10芳基、或、未取代或被一个或多个R 2取代的5～6元的杂芳基；所述的5～6元的杂芳基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～2个；当取代基R 1或R 2为多个时，所述的取代基相同或不同；
    Figure PCTCN2019070573-appb-100004
    It is an unsubstituted or substituted C 6 -C 10 aryl group by one or more R 1 , or, an unsubstituted or substituted 5- or 6-membered heteroaryl group substituted by one or more R 2 ; said 5 to 6 In the heteroaryl group of the element, 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和R 2独立地为卤素、-OH、-CN、-NH 2、-COOH、
    Figure PCTCN2019070573-appb-100005
    未取代或被一个或多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-8取代的C 3～C 6环烷基、未取代或被一个或多个R 1-9取代的C 6～C 10芳基、未取代或被一个或多个R 1-10取代的5～6元的杂芳基、未取代或被一个或多个R 1-11取代的C 1～C 6烷基-O-、未取代或被一个或多个R 1-12取代的C 1～C 6烷基-C(＝O)-、未取代或被一个或多个R 1-13取代的C 1～C 6烷基-C(＝O)O-、未取代或被一个或多个R 1-14取代的C 1～C 6烷基-O-C(＝O)-、或、未取代或被一个或多个R 1-15取代的C 1～C 6烷基-C(＝O)NH-；所述的5～6元的杂芳基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～3个；当取代基R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14 或R 1-15为多个时，所述的取代基相同或不同；     R 1 and R 2 are independently halogen, -OH, -CN, -NH 2 , -COOH,
    Figure PCTCN2019070573-appb-100005
    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-, 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-; in the 5-6 membered heteroaryl group, the hetero atom One or more selected from N, O and S, the number of heteroatoms is 1 to 3; when the substituents R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1- 11. When there are a plurality of R 1-12 , R 1-13 , R 1-14 or R 1-15 , the substituents are the same or different;
    或者，当取代基R 1或R 2为多个时，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-5取代的C 4～C 6环烷基、或、未取代或被一个或多个R 1-6取代的C 3～C 5杂环烷基；所述的C 3～C 5杂环烷基中，杂原子选自N、O和S中的一种或多种，杂原子数为1～3个；当取代基R 1-5或R 1-6为多个时，所述的取代基相同或不同； Alternatively, when there are a plurality of substituents R 1 or R 2 , 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; in the C 3 -C 5 heterocycloalkyl, the hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms 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和R 1-4独立地为H或C 1～C 6烷基； R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently H or C 1 -C 6 alkyl;
    R 1-5、R 1-6、R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为卤素、-OH、-CN、-NH 2、-COOH、-CONH 2、C 1～C 6烷基、C 1～C 6烷基-O-、C 1～C 6烷基-C(＝O)-、C 1～C 6烷基-C(＝O)O-、或C 1～C 6烷基-O-C(＝O)-； R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently halogen, -OH, -CN, -NH 2 , -COOH, -CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl -O-, C 1 -C 6 Alkyl-C(=O)-, C 1 -C 6 alkyl-C(=O)O-, or C 1 -C 6 alkyl-OC(=O)-;
    且，当X为-O-时，R为未取代或被一个或多个R a取代的C 3～C 6杂环烷基。 And, when X is -O-, R is unsubstituted or substituted with one or more of R a C 3 ~ C 6 heterocycloalkyl.
  2. 如权利要求1所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，其特征在于，所述的
    Figure PCTCN2019070573-appb-100006
    位于所述的
    Figure PCTCN2019070573-appb-100007
    的邻位、间位或对位；     The benzamide compound of formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, Its tautomer or its prodrug is characterized by the
    Figure PCTCN2019070573-appb-100006
    Located at
    Figure PCTCN2019070573-appb-100007
    Adjacent, interposition or counterposition;
    和/或，R为-OH、
    Figure PCTCN2019070573-appb-100008
    或、未取代或被一个或多个R a取代的5元杂环烷基，所述的5元杂环烷基中，杂原子选自N、O和S中的一种或多种，杂原子数为2个；所述的5元杂环烷基优选噻唑烷基；     And/or, R is -OH,
    Figure PCTCN2019070573-appb-100008
    Or, unsubstituted or substituted with one or more R a 5-membered heterocycloalkyl, a 5-membered heterocycloalkyl, a heteroatom selected from N, O and S, one or more of, heteroaryl The number of atoms is 2; the 5-membered heterocyclic alkyl group is preferably a thiazolyl group;
    和/或，所述的R 1-1或R 1-2为H或C 1-C 4的烷基； And/or, said R 1-1 or R 1-2 is H or C 1 -C 4 alkyl;
    和/或，所述的R a为氟、氯、溴、碘、或＝O； And/or, said Ra is fluorine, chlorine, bromine, iodine, or =O;
    和/或，所述的
    Figure PCTCN2019070573-appb-100009
    中，所述的5～6元的杂芳基通过碳原子与所述的
    Figure PCTCN2019070573-appb-100010
    相连接；     And/or
    Figure PCTCN2019070573-appb-100009
    In the above, the 5- to 6-membered heteroaryl group is linked to the
    Figure PCTCN2019070573-appb-100010
    Connected
    和/或，所述的
    Figure PCTCN2019070573-appb-100011
    为未取代或被一个或多个R 1取代的苯基、或、未取代或被一个或多个R 2取代的6元杂芳基，所述的6元杂芳基中，杂原子选自N，杂原子数为1～2个；所述的6元杂芳基较佳地为吡啶基；     And/or
    Figure PCTCN2019070573-appb-100011
    Is unsubstituted or substituted with one or more R 1 phenyl, or, unsubstituted or substituted with one or more R 2 6-membered heteroaryl, in the 6-membered heteroaryl, the heteroatom is selected from N, the number of heteroatoms is 1 to 2; the 6-membered heteroaryl group is preferably pyridyl;
    和/或，所述的R 1或R 2为氟、氯、溴、碘、-OH、-CN、-NH 2、-COOH、
    Figure PCTCN2019070573-appb-100012
    未取代或被一个或多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-8取代的C 3～C 6环烷基、未取代或被一个或多个R 1-9取代的苯基、未取代或被一个或多个R 1-10取代的5～6元的杂芳基、未取代或被一个或多个R 1-11取代的C 1～C 6烷基-O-、未取代或被一个或多个R 1-12取代的C 1～C 6烷基-C(＝O)-、未取代或被一个或多个R 1-13取代的C 1～C 6烷基-C(＝O)O-、未取代或被一个或多个R 1-14取代的C 1～C 6烷基-O-C(＝O)-、或、未取代或被一个或多个R 1-15取代的C 1～C 6烷基-C(＝O)NH-，其中，所述的C 1～C 6烷基独立地为C 1～C 4烷基，较佳地独立地甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；     And/or R 1 or R 2 is fluorine, chlorine, bromine, iodine, -OH, -CN, -NH 2 , -COOH,
    Figure PCTCN2019070573-appb-100012
    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 Or more than one R 1-9 substituted phenyl, unsubstituted or substituted with one or more R 1-10 5-6 membered heteroaryl, unsubstituted or substituted with one or more R 1-11 C 1 to C 6 alkyl-O-, unsubstituted or substituted by one or more R 1-12 C 1 to C 6 alkyl-C(=O)-, unsubstituted or substituted by one or more R 1- 13- substituted C 1 -C 6 alkyl-C(=O)O-, unsubstituted or substituted with one or more R 1-14 C 1 -C 6 alkyl-OC(=O)-, or, C 1 -C 6 alkyl-C(=O)NH- which is unsubstituted or substituted by one or more R 1-15 , wherein the C 1 -C 6 alkyl is independently C 1 -C 4 Alkyl, preferably independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    或者，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-6取代的1,3-二氧戊环； Alternatively, two adjacent R 1 and two C directly connected to the C 6 -C 10 aryl group, or two adjacent two R 2 and two C directly connected to the 5-6 membered heteroaryl group , Together forming 1,3-dioxolane that is unsubstituted or substituted by one or more R 1-6 ;
    和/或，所述的R 1-3或R 1-4为H或C 1～C 4烷基； And/or, said R 1-3 or R 1-4 is H or C 1 ˜C 4 alkyl;
    和/或，所述的R 1-5、R 1-6、R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为氟、氯、溴、碘、-OH、-CN、-NH 2、-COOH、-CONH 2、C 1～C 6烷基、C 1～C 6烷基-O-、C 1～C 6烷基-C(＝O)-、C 1～C 6烷基-C(＝O)O-、或C 1～C 6烷基-O-C(＝O)-；其中，所述的C 1～C 6烷基独立地为C 1～C 4烷基。 And/or, said R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1- 13 , R 1-14 or R 1-15 are fluorine, chlorine, bromine, iodine, -OH, -CN, -NH 2 , -COOH, -CONH 2 , C 1 ～C 6 alkyl, C 1 ～C 6 Alkyl-O-, C 1 -C 6 alkyl-C(=O)-, C 1 -C 6 alkyl-C(=O)O-, or C 1 -C 6 alkyl-OC(=O )-; wherein, the C 1 -C 6 alkyl group is independently a C 1 -C 4 alkyl group.
  3. 如权利要求2所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，其特征在于：所述的
    Figure PCTCN2019070573-appb-100013
    位于所述的
    Figure PCTCN2019070573-appb-100014
    的邻位；     The benzamide compound represented by formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorphic form, its metabolite, its stereoisomer according to claim 2 Its tautomer or its prodrug is characterized by:
    Figure PCTCN2019070573-appb-100013
    Located at
    Figure PCTCN2019070573-appb-100014
    Adjacent to
    和/或，所述的R 1-1或R 1-2为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, said R 1-1 or R 1-2 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，所述的R a的个数为1或2； And/or, the number of Ra is 1 or 2;
    和/或，所述的R a位于
    Figure PCTCN2019070573-appb-100015
    的邻位、间位或对位；     And/or, said Ra is located at
    Figure PCTCN2019070573-appb-100015
    Adjacent, interposition or counterposition;
    和/或，所述的R a为＝O； And/or, the Ra is =0;
    和/或，所述的R 1和R 2的个数独立地为1、2、3或4； And/or, the number of R 1 and R 2 is independently 1 , 2 , 3 or 4;
    和/或，所述R 1或R 2独立地位于
    Figure PCTCN2019070573-appb-100016
    的邻位、间位或对位；     And/or R 1 or R 2 are independently located
    Figure PCTCN2019070573-appb-100016
    Adjacent, interposition or counterposition;
    和/或，所述的R 1-3或R 1-4为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, said R 1-3 or R 1-4 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，所述的R 1-5、R 1-6、R 1-7、R 1-8、R 1-9、R 1-10、R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为氟、氯、溴、碘、-OH、-CN、-NH 2、-COOH、-CONH 2、C 1～C 6烷基、C 1～C 6烷基-O-、C 1～C 6烷基-C(＝O)-、C 1～C 6烷基-C(＝O)O-、或C 1～C 6烷基-O-C(＝O)-；其中，所述的C 1～C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 And/or, said R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 , R 1- 13 , R 1-14 or R 1-15 are fluorine, chlorine, bromine, iodine, -OH, -CN, -NH 2 , -COOH, -CONH 2 , C 1 ～C 6 alkyl, C 1 ～C 6 Alkyl-O-, C 1 ～C 6 alkyl-C(═O)-, C 1 ～C 6 alkyl-C(═O)O-, or C 1 ～C 6 alkyl-OC(═O ) -; wherein said C 1 ~ C 6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  4. 如权利要求3所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，其特征在于：所述的R为-OH、
    Figure PCTCN2019070573-appb-100017
    The benzamide compound represented by formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorphic form, its metabolite, its stereoisomer according to claim 3, The tautomer or its prodrug is characterized in that the R is -OH,
    Figure PCTCN2019070573-appb-100017
    和/或，所述的R 1或R 2为氟、氯、-OH、-CN、-COOH、三氟甲基、苯基或-CONH 2，或者，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成
    Figure PCTCN2019070573-appb-100018
    And/or, the R 1 or R 2 is fluorine, chlorine, -OH, -CN, -COOH, trifluoromethyl, phenyl or -CONH 2 , or two adjacent R 1 and C 6 ～C 10 two Cs directly connected to an aryl group, or two adjacent R 2 and two Cs directly connected to a 5-6 membered heteroaryl group, together forming
    Figure PCTCN2019070573-appb-100018
  5. 如权利要求4所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，其特征在于：所述的
    Figure PCTCN2019070573-appb-100019
    为
    Figure PCTCN2019070573-appb-100020
    Figure PCTCN2019070573-appb-100021
    The benzamide compound of formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, Its tautomer or its prodrug is characterized by:
    Figure PCTCN2019070573-appb-100019
    for
    Figure PCTCN2019070573-appb-100020
    Figure PCTCN2019070573-appb-100021
    和/或，所述的
    Figure PCTCN2019070573-appb-100022
    为
    Figure PCTCN2019070573-appb-100023
    Figure PCTCN2019070573-appb-100024
    Figure PCTCN2019070573-appb-100025
    And/or
    Figure PCTCN2019070573-appb-100022
    for
    Figure PCTCN2019070573-appb-100023
    Figure PCTCN2019070573-appb-100024
    Figure PCTCN2019070573-appb-100025
  6. 如权利要求1所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，其特征在于：所述的X为S，R为OH或
    Figure PCTCN2019070573-appb-100026
    或者，X为-O-，R为未取代或被一个或多个R a取代的C 3～C 6杂环烷基；     The benzamide compound of formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, Its tautomer or its prodrug is characterized in that X is S, R is OH or
    Figure PCTCN2019070573-appb-100026
    Alternatively, X is -O-, R is unsubstituted or substituted with one or more R a C 3 -C 6 heterocycloalkyl;
    和/或，R 1和R 2独立地为卤素、OH、CN、NH 2、COOH、
    Figure PCTCN2019070573-appb-100027
    未取代或被一个或多个R 1-7取代的C 1～C 6烷基、未取代或被一个或多个R 1-9取代的C 6～C 10芳基；或者，当取代基R 1或R 2为多个时，相邻的两个R 1与C 6～C 10芳基上直接连接的两个C、或、相邻的两个R 2与5～6元的杂芳基上直接连接的两个C，一起形成未取代或被一个或多个R 1-5取代的C 4～C 6环烷基、或、未取代或被一个或多个R 1-6取代的C 3～C 5杂环烷基。     And/or R 1 and R 2 are independently halogen, OH, CN, NH 2 , COOH,
    Figure PCTCN2019070573-appb-100027
    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.
  7. 如权利要求1所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，其特征在于：所述的如式I所示的苯甲酰胺类化合物为下列任一化合物：The benzamide compound of formula I, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, The tautomer or its prodrug is characterized in that the benzamide compound represented by Formula I is any of the following compounds:
    Figure PCTCN2019070573-appb-100028
    Figure PCTCN2019070573-appb-100028
    Figure PCTCN2019070573-appb-100029
    Figure PCTCN2019070573-appb-100029
  8. 一种如权利要求1～7任一项所述的如式I所示的苯甲酰胺类化合物的制备方法，其特征在于，其为方案一或方案二；其中，方案一包括如下步骤：在有机溶剂中，将如式II所示的化合物与如式III所示的化合物进行如下所示的酰胺化反应，得到所述的如式I所示的苯甲酰胺类化合物即可；其中X为O；A method for preparing a benzamide compound represented by Formula I according to any one of claims 1 to 7, characterized in that it is Scheme I or Scheme II; 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 amidation reaction shown below to obtain the benzamide compound represented by Formula I; wherein X is O;
    Figure PCTCN2019070573-appb-100030
    Figure PCTCN2019070573-appb-100030
    方案二包括如下步骤，在水和有机溶剂中，在碱存在下，将如式I’所示的化合物进行如下所示的水解反应，得到所述的如式I所示的苯甲酰胺类化合物即可；其中X为S；R’为C 1-C 4烷基-O-；R为-OH； Scheme 2 includes the following steps. In a water and an organic solvent, in the presence of a base, the compound shown in Formula I′ is subjected to the hydrolysis reaction shown below to obtain the benzamide compound shown in Formula I That is; where X is S; R'is C 1 -C 4 alkyl-O-; R is -OH;
    Figure PCTCN2019070573-appb-100031
    Figure PCTCN2019070573-appb-100031
  9. 如权利要求8所述的制备方法，其特征在于，方案一中，所述的有机溶剂为环醚类溶剂；The preparation method according to claim 8, wherein in the first solution, the organic solvent is a cyclic ether solvent;
    和/或，方案一中，所述的式II所示的化合物与所述的有机溶剂的质量体积比为0.01g/mL～0.2g/mL；And/or, in scheme 1, the mass volume ratio of the compound represented by formula II to the organic solvent is 0.01 g/mL to 0.2 g/mL;
    和/或，方案一中，所述的如式II所示的化合物与所述的如式III所示的化合物的摩尔比为2:1～1:1；And/or, in Scheme 1, the molar ratio of the compound represented by Formula II to the compound represented by Formula III is 2:1 to 1:1;
    和/或，方案一中，所述的酰胺化反应的温度为10℃～30℃；And/or, in the first scheme, the temperature of the amidation reaction is 10°C to 30°C;
    和/或，方案二中，R’中的C 1-C 4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, in the second scheme, the C 1 -C 4 alkyl group in R′ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl ;
    和/或，方案二中，所述的有机溶剂为环醚类溶剂；And/or, in the second scheme, the organic solvent is a cyclic ether solvent;
    和/或，方案二中，所述的碱为碱金属氢氧化物；And/or, in the second solution, the base is an alkali metal hydroxide;
    和/或，方案二中，所述的式I’所示的化合物与所述的有机溶剂的质量体积比为0.01g/mL～0.2g/mL；And/or, in the second scheme, the mass volume ratio of the compound represented by Formula I'to the organic solvent is 0.01 g/mL to 0.2 g/mL;
    和/或，方案二中，所述的碱与所述的水的质量体积比为0.01g/mL～0.2g/mL；And/or, in the second solution, the mass volume ratio of the alkali to the water is 0.01 g/mL to 0.2 g/mL;
    和/或，方案二中，所述的碱与所述的如式I’所示的化合物的摩尔比为4:1～1:1；And/or, in the second scheme, the molar ratio of the base to the compound represented by formula I'is 4:1 to 1:1;
    和/或，方案二中，所述的水解反应的温度为10℃～30℃。And/or, in the second scheme, the temperature of the hydrolysis reaction is 10°C to 30°C.
  10. 如下所示的化合物：The compounds shown below:
    Figure PCTCN2019070573-appb-100032
    Figure PCTCN2019070573-appb-100032
    式I’所示的化合物中，X为S，R’的定义如权利要求8或9所述，
    Figure PCTCN2019070573-appb-100033
    的定义如权利要求1～7任一项所述。     In the compound represented by formula I', X is S, and R'is as defined in claim 8 or 9,
    Figure PCTCN2019070573-appb-100033
    Is defined in any one of claims 1-7.
  11. 如权利要求10所示的化合物，其特征在于，如式I’所示的化合物为如下任一结构：The compound of claim 10, wherein the compound of formula I'has any of the following structures:
    Figure PCTCN2019070573-appb-100034
    Figure PCTCN2019070573-appb-100034
  12. 一种如权利要求10或11所述的式I’所示的化合物的制备方法，其特征在于，其包括如下步骤：在有机溶剂中，将如式I”所示的化合物与硫化试剂进行如下所示的硫化反应，得到所述的如式I’所示的化合物即可；A method for preparing a compound represented by formula I'according to claim 10 or 11, characterized in that it comprises the following steps: in an organic solvent, the compound represented by formula I" and a sulfurizing agent are carried out as follows In the vulcanization reaction shown, it is sufficient to obtain the compound represented by formula I′;
    Figure PCTCN2019070573-appb-100035
    Figure PCTCN2019070573-appb-100035
    其中，X’为O；X、R’和
    Figure PCTCN2019070573-appb-100036
    的定义如权利要求10或11所述。     Where X'is O; X, R'and
    Figure PCTCN2019070573-appb-100036
    Is defined as claimed in claim 10 or 11.
  13. 如权利要求12所述的制备方法，其特征在于，所述的有机溶剂为芳烃类溶剂；The preparation method according to claim 12, wherein the organic solvent is an aromatic hydrocarbon solvent;
    和/或，所述的硫化试剂为劳森试剂；And/or, the sulfurization reagent is Lawson's reagent;
    和/或，所述的如式I”所示的化合物与所述的有机溶剂的质量体积比为0.01g/mL～0.2g/mL；And/or, the mass-to-volume ratio of the compound represented by Formula I" to the organic solvent is 0.01 g/mL to 0.2 g/mL;
    和/或，所述的如式I”所示的化合物与所述的硫化试剂的摩尔比为1:1～1:3；And/or, the molar ratio of the compound represented by Formula I" to the sulfurization reagent is 1:1 to 1:3;
    和/或，所述的硫化反应的温度为100℃～120℃。And/or, the temperature of the vulcanization reaction is 100°C to 120°C.
  14. 一种药物组合物，其包含如权利要求1～7任一项所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药，和至少一种药用辅料。A pharmaceutical composition comprising the benzamide compound represented by formula I according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and more The crystal form, its metabolite, its stereoisomer, its tautomer or its prodrug, and at least one pharmaceutical excipient.
  15. 如权利要求14所述的药物组合物，还包括胶原、壳聚糖及透明质酸中的一种或多种形成的复合支架；The pharmaceutical composition according to claim 14, further comprising a composite scaffold formed by one or more of collagen, chitosan, and hyaluronic acid;
    和/或，还包括用于关节内递送的组分；所述的用于关节内递送的组分较佳地包括：血管生成素样3蛋白或其软骨形成变体，口服鲑降钙素，SD-6010，维生素D3，胶原蛋白水解物，FGF18，BMP7，鳄梨大豆未皂化物和透明质酸中的一种或多种。And/or, further includes components for intra-articular delivery; the components for intra-articular delivery preferably include: angiopoietin-like 3 protein or a cartilage-forming variant thereof, oral salmon calcitonin, One or more of SD-6010, vitamin D3, collagen hydrolysate, FGF18, BMP7, avocado soybean unsaponifiable and hyaluronic acid.
  16. 一种如权利要求1～7任一项所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如权利要求14或15所述的药物组合物在制备蛋白多糖、Ⅱ型胶原和Sox9中的一种或多种诱导剂中的应用。A benzamide compound represented by formula I according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, and a metabolite thereof , Its stereoisomer, its tautomer or its prodrug, or one or more inducers in the preparation of proteoglycan, type II collagen and Sox9 by the pharmaceutical composition according to claim 14 or 15 Application.
  17. 如权利要求16所述的应用，所述的诱导剂为药物；The use according to claim 16, wherein the inducer is a drug;
    或者，所述的诱导剂用于在体外扩增培养物中的软骨细胞群。Alternatively, the inducer is used to expand the chondrocyte population in culture in vitro.
  18. 如权利要求17所述的应用，所述的药物是指用于治疗或预防与诱导间充干细胞向软骨细胞分化作用有关的疾病的药物；所述的与诱导间充干细胞向软骨细胞分化作用有关的疾病较佳地包括：关节炎或关节损伤，例如类风湿性关节炎、牛皮癣性关节炎、强直性脊柱炎、多关节型幼年特发性关节炎、骨质疏松症、或骨关节炎。The use according to claim 17, wherein the medicament refers to a medicament for treating or preventing diseases related to the induction of differentiation of mesenchymal stem cells into chondrocytes; The diseases preferably include: arthritis or joint damage, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, osteoporosis, or osteoarthritis.
  19. 一种改善哺乳动物的关节炎或关节损伤的方法，该方法包括向哺乳动物的关节施用有效剂量的如权利要求1～7任一项所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如权利要求14或15所述的药物组合物。A method for improving arthritis or joint damage in a mammal, the method comprising administering an effective dose of a benzamide compound represented by formula I according to any one of claims 1 to 7 to a joint of a mammal, Its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomer or its prodrug, or as claimed in claim 14 or 15 The pharmaceutical composition described.
  20. 一种诱导间充质干细胞分化为软骨细胞的方法，该方法包括使间充质干细胞接 触足够量的如权利要求1～7任一项所述的如式I所示的苯甲酰胺类化合物、其药学上可接受的盐、其水合物、其溶剂化物、其多晶型、其代谢产物、其立体异构体、其互变异构体或其前药、或如权利要求14或15所述的药物组合物。A method for inducing mesenchymal stem cells to differentiate into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of the benzamide compound represented by formula I according to any one of claims 1 to 7, Its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its metabolite, its stereoisomer, its tautomer or its prodrug, or as claimed in claim 14 or 15 The pharmaceutical composition described.
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