WO2022057387A1 - 3-(3-芳基/杂芳基-4-噻唑啉酮基)-n-芳基/杂环苯甲酰胺类化合物及其应用 - Google Patents
3-(3-芳基/杂芳基-4-噻唑啉酮基)-n-芳基/杂环苯甲酰胺类化合物及其应用 Download PDFInfo
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- WO2022057387A1 WO2022057387A1 PCT/CN2021/104268 CN2021104268W WO2022057387A1 WO 2022057387 A1 WO2022057387 A1 WO 2022057387A1 CN 2021104268 W CN2021104268 W CN 2021104268W WO 2022057387 A1 WO2022057387 A1 WO 2022057387A1
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- WIPO (PCT)
- Prior art keywords
- benzamide
- thiazolinone
- phenylbutyl
- nmr
- aryl
- Prior art date
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
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- 239000003112 inhibitor Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
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- 239000011541 reaction mixture Substances 0.000 description 2
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- 239000000758 substrate Substances 0.000 description 2
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- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
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- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
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- VBMQEOCJVKACBL-UHFFFAOYSA-N n-ethynyl-4-trimethylsilylaniline Chemical compound C[Si](C)(C)C1=CC=C(NC#C)C=C1 VBMQEOCJVKACBL-UHFFFAOYSA-N 0.000 description 1
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
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- 239000002689 soil Substances 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Images
Classifications
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/38—Nitrogen atoms
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- 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
-
- 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
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention relates to the field of synthetic medicine and chemical industry, and mainly relates to a 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compound and a preparation method and application thereof .
- Osteosarcoma also known as osteosarcoma, is a malignant bone tumor that occurs more commonly in adolescents or children under the age of 20 (Link MP: Osteosarcoma in adolescents and young adults: new developments and controversies. Commentary on the use of presurgical chemotherapy .Cancer Treat Res 62:383-385, 1993.), according to the epidemiological study of osteosarcoma: it is the most common in pediatric bone malignancies, accounting for about 5% of pediatric tumors. Osteosarcoma is still the highest mortality rate of malignant tumors in children and adolescents, second only to lymphoma and brain cancer, but early detection and timely treatment have greatly improved the survival rate of this disease.
- the treatment methods for different types of osteosarcoma are usually combined after surgery. It is worth noting that the cancer metastasis rate of patients with osteosarcoma is as high as 80%, and 90% of the patients with metastases are lung metastasis. Among them, the recurrence rate is 20-30%, in situ or in situ tissue may recur, and the survival rate after recurrence, in the past few decades, despite the adjustment of increased doses, the number of changes and the combination of multiple chemotherapy drugs and other treatment methods , the survival rate did not improve.
- the research on the therapeutic targets of osteosarcoma mainly focuses on the family of cell surface receptor tyrosine kinases (PTKs) and intracellular signaling targets.
- the main therapeutic drugs are divided into three categories: 1) immunomodulators; 2) receptor tyrosine kinase inhibitors; 3) intracellular signaling pathway inhibitors.
- new targets and treatment options for osteosarcoma include NK-kB ligands, folic acid inhibitors, etc., but they are all in the experimental research stage.
- this backbone compound may generate a series of new compound molecules with meaningful structure and activity, which may provide a new source of compounds for biological activity screening.
- the present invention provides a 3-(3-aryl/heteroaryl-4-thiazolinonyl)-N-aryl/heterocyclic benzene represented by formulas (I), (II) and (III)
- a carboxamide compound or a pharmaceutically acceptable salt the compound is a new compound, and there is no relevant report:
- Ar is aryl, aromatic heterocycle, alkyl substituted aryl, halogen substituted aryl, alkyl substituted heteroaryl, halogen substituted heteroaryl, trifluoromethyl substituted aryl, nitro substituted Aryl, decalinyl, furanalkyl, alkenyl, alkynyl, diphenylalkyl, bis(4-bromophenyl)alkyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl ;
- the aromatic heterocycle and heteroaryl are respectively selected from indole, benzotriazole, thiophene, furan, pyrrole, bislactam, piperazine, imidazole, oxazole, pyrazine;
- R 1 is a mono- or poly-substituted group selected from the group consisting of halogen, alkoxy, alkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen, aryl, three-membered ring, acetylene base;
- R 2 is cycloalkyl, alkylene oxide, alkyl or hydrogen
- R 3 is halogen, alkoxy, alkyl, cycloalkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
- n 0;1;2;4;5;6.
- Het is a heterocycle selected from: pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen-substituted heteroaryl, nitro-substituted heteroaryl, decalinyl, furanalkyl, alkenyl, alkynyl, diphenylalkyl, di(4-bromophenyl)alkyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl;
- the heteroaryl group is selected from indole, benzotriazole, thiophene, pyrrole, bislactam, piperazine, imidazole, oxazole, and pyrazine.
- Ar is phenyl, aromatic heterocycle, C1-C6 alkyl substituted phenyl, halogen substituted phenyl, C1-C6 alkyl substituted heteroaryl, halogen substituted heteroaryl, trifluoromethyl substituted benzene phenyl, nitro-substituted phenyl, naphthylmethyl, furylmethyl, allyl, propargyl, benzhydryl, bis(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl , nitro-substituted heteroaryl; wherein, the aromatic heterocycle and heteroaryl are respectively selected from indole, benzotriazole, thiophene, furan, pyrrole, bislactam, piperazine, imidazole, oxazole, Pyrazine, etc.;
- R 1 is a mono- or poly-substituted group selected from the group consisting of halogen, C1-C10 alkoxy, methyl, ethyl, isopropyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
- R 2 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 epoxy alkyl, hydrogen, etc.;
- R 3 is halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
- Het is a heterocycle selected from the group consisting of: pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen substituted heteroaryl, trifluoromethyl substituted aryl , nitro-substituted aryl, naphthalene C1-C6 alkyl, furan C1-C6 alkyl, alkene C1-C6 alkyl, alkyne C1-C6 alkyl, diphenyl C1-C6 alkyl, bis(4-bromobenzene base) C1-C6 alkyl group, trifluoromethyl-substituted heteroaryl group, nitro-substituted heteroaryl group; wherein, the heteroaryl group is selected from indole, benzotriazole, thiophene, pyrrole, bis-indole Amide, piperazine, imidazole
- Ar is phenyl, aromatic heterocycle, methyl-substituted phenyl, halogen-substituted phenyl, methyl-substituted heteroaryl, halogen-substituted heteroaryl, trifluoromethyl-substituted phenyl, nitro-substituted Phenyl, naphthylmethyl, furylmethyl, allyl, propargyl, benzhydryl, bis(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl, nitro substituted heteroaryl
- R 1 is a mono- or poly-substituted group selected from the group consisting of halogen, C1-C10 alkoxy, methyl, ethyl, isopropyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
- R 2 is methyl, ethyl, isopropyl, cyclopropane, glycidyl, hydrogen, etc.;
- R 3 is F, methoxy, methyl, cyclopropanyl, nitro, cyano, trifluoromethyl, phenyl, hydrogen;
- Het is a heterocycle selected from the group consisting of: pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone, pyrimidine, halogen substituted heteroaryl, trifluoromethyl substituted aryl , nitro-substituted aryl, naphthylmethyl, furylmethyl, allyl, propargyl, benzhydryl, bis(4-bromophenyl)methyl, trifluoromethyl substituted heteroaryl, Nitro-substituted heteroaryl; wherein, the heteroaryl is selected from indole, benzotriazole, thiophene, pyrrole, bislactam, piperazine, imidazole, oxazole, and pyrazine.
- 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compounds or pharmaceutically acceptable salts of the present invention include but are not limited to the following:
- the present invention also provides the raw materials used in the compounds represented by formula (II) and (III)
- the synthetic method of the raw material used in the compound shown in the formula (III) specifically includes the following four methods:
- the crude product obtained in the previous step was placed in a three-necked flask, palladium carbon with a content of 10% was added, methanol was added after nitrogen protection, and the nitrogen was replaced with hydrogen. Soil suction filtration, the filtrate was collected, and the solvent was spin-dried, which was directly used in the next step.
- the present invention also provides a 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/
- a method for synthesizing a heterocyclic benzamide compound or a pharmaceutically acceptable salt the specific steps are as follows, including the following (A), (B), (C), (D) as shown: (the compound designed in the present invention is
- the synthetic routes are all consistent with the following methods, the following methods only describe the synthetic methods of formula (I) and formula (III), and reaction formulas (A)-1, (A)-2 and (A)-3 are synthetic raw materials Step, the synthetic method of formula (II) see formula (I))
- the m-bromoaniline is coupled with cyclopropaneboronic acid under the catalysis of palladium acetate/cyclohexylphosphorus system to obtain m-cyclopropanylaniline.
- the ester compound (5mmol, 1.0eq) obtained in the first step was reacted with LiOH (5.25mmol, 1.05eq) in a solvent of methanol:water (4:1) at room temperature for 20 hours, and monitored by spot plate The substrate was completely consumed.
- the methanol in the solvent was removed by rotary evaporation, and the remaining reaction solution was poured into 50 mL of water, and 3N HCl was added dropwise to acidify, and a large amount of white solids were precipitated.
- Use pH test paper to monitor until pH 1 .
- the white solid was filtered off with a Buchner funnel, and the white solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and rotary-evaporated to obtain a carboxylic acid product.
- the carboxylic acid product (1.5 mmol, 1.0 eq) obtained in the second step and 1-hydroxybenzotriazole (ie, HOBt, 3.0 mmol, 2.0 eq) were dissolved in 20 mL of tetrahydrofuran, and under ice bath conditions, added N,N-diisopropylethylamine (DIPEA, 4.5 mmol, 3.0 eq), after stirring for 20 minutes, the compound long-chain amine was added, and stirring was continued for 10 minutes.
- DIPEA N,N-diisopropylethylamine
- the condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 3 mmol, 2.0 eq) was added in batches, and after the reaction for two hours, the spot plate was monitored, and the raw materials were completely consumed. .
- An appropriate amount of saturated sodium bicarbonate was sequentially added to the reaction solution, washed with saturated brine, and extracted three times with ethyl acetate.
- the present invention also provides the 3-(3-(heteroaryl)-4-thiazolinone)-N-arylbenzamide compound represented by the formula (III) or a pharmaceutically acceptable salt thereof.
- the synthetic method, the solvent used in the method of the present invention includes alkanes, halogenated alkanes, ethers, halogenated ethers, substituted benzenes, alcohols, esters, ketones, halogenated benzenes, heteroaromatic hydrocarbons, One or a combination of amides, sulfoxides and water.
- the basic synthesis steps of the method are as follows:
- compound 2 (1.5 mmol, 1.0 eq) and 1-hydroxybenzotriazole (ie, HOBt, 3.0 mmol, 2.0 eq) were dissolved in 20 mL of tetrahydrofuran.
- propylethylamine DIPEA, 4.5mmol, 3.0eq
- the compound alkylamine was added, and stirring was continued for 10 minutes.
- the condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 3 mmol, 2.0 eq) was added in batches, and after the reaction for two hours, the spot plate was monitored, and the raw materials were completely consumed.
- the present invention also proposes an acid addition salt formed by the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound and an acid; wherein, the acid is hydrochloric acid, sulfuric acid , phosphoric acid, hydrobromic acid, acetic acid, salicylic acid, tartaric acid, lactic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, pyruvic acid or succinic acid, etc.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt, and A pharmaceutically acceptable carrier.
- the pharmaceutical composition is formulated into pills, capsules, creams, gels, excipients, injectable fluids, aerosols, syrups or transdermal patches and the like.
- the present invention also provides the 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compounds or pharmaceutically acceptable salts, or pharmaceutical combinations
- the 3-(3-aryl/heteroaryl-4-thiazolinone)-N-aryl/heterocyclic benzamide compounds are used to inhibit the proliferation, growth, migration, infiltration, Metastasis and recurrence, or promote tumor cell apoptosis.
- the tumor cells are osteosarcoma cells, colorectal cancer cells, leukemia cells, lung cancer cells, pancreatic cancer cells and the like.
- the osteosarcoma cells include SJSA-1, U2OS, HOS, MNNG/HOS, MG63, 143b;
- the pancreatic cancer cells include PANC-1;
- the lung cancer cells include A549;
- the colorectal cancer cells include HCT116;
- the leukemia cells include Jurkat.
- the present invention discloses a 3-(3-aryl-4-thiazolinone)-N-arylbenzamide compound or a pharmaceutically acceptable salt and a preparation method thereof,
- the compounds or compositions have inhibitory activity on tumor cells, can be used to treat osteosarcoma, colorectal cancer, pancreatic cancer, leukemia and other related diseases, and are of great significance in the study of tumor diseases.
- Fig. 1 is a schematic diagram of 1 H NMR and 13 C NMR of the product 1 obtained in Example 1 of the present invention.
- Fig. 2 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 2 obtained in Example 2 of the present invention.
- Fig. 3 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 3 obtained in Example 3 of the present invention.
- Figure 4 is a schematic diagram of 1 H NMR and 13 C NMR of the product 4 obtained in Example 4 of the present invention.
- Example 5 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 5 obtained in Example 5 of the present invention.
- FIG. 6 is a schematic diagram of 1 H NMR and 13 C NMR of the product 6 obtained in Example 6 of the present invention.
- FIG. 7 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 7 obtained in Example 7 of the present invention.
- FIG. 8 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 8 obtained in Example 8 of the present invention.
- FIG. 9 is a schematic diagram of 1 H NMR and 13 C NMR of the product 9 obtained in Example 9 of the present invention.
- Example 10 is a schematic diagram of 1 H NMR and 13 C NMR of the product 10 obtained in Example 10 of the present invention.
- FIG. 11 is a schematic diagram of 1 H NMR and 13 C NMR of the product 11 obtained in Example 11 of the present invention.
- Figure 12 is a schematic diagram of 1 H NMR and 13 C NMR of the product 12 obtained in Example 12 of the present invention.
- Figure 13 is a schematic diagram of 1 H NMR and 13 C NMR of the product 13 obtained in Example 13 of the present invention.
- Figure 14 is a schematic diagram of 1 H NMR and 13 C NMR of the product 14 obtained in Example 14 of the present invention.
- Example 15 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 15 obtained in Example 15 of the present invention.
- Example 16 is a schematic diagram of 1 H NMR and 13 C NMR of the product 16 obtained in Example 16 of the present invention.
- Example 17 is a schematic diagram of 1 H NMR and 13 C NMR of the product 17 obtained in Example 17 of the present invention.
- Example 18 is a schematic diagram of 1 H NMR, 13 C NMR and 19 F NMR of the product 18 obtained in Example 18 of the present invention.
- FIG. 19 is a schematic diagram of 1 H NMR ( FIG. 19A ) and 13 C NMR ( FIG. 19B ) of the product 19 obtained in Example 19.
- FIG. 19A 1 H NMR
- FIG. 19B 13 C NMR
- FIG. 20 is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
- FIG. 20A is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
- FIG. 20B is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
- FIG. 20 is a schematic diagram of 1 H NMR ( FIG. 20A ) and 13 C NMR ( FIG. 20B ) of the product 20 obtained in Example 20.
- FIG. 21 is a schematic diagram of 1 H NMR ( FIG. 21A ) and 13 C NMR ( FIG. 21B ) of the product 21 obtained in Example 21.
- FIG. 21A is a schematic diagram of 1 H NMR ( FIG. 21A ) and 13 C NMR ( FIG. 21B ) of the product 21 obtained in Example 21.
- FIG. 21B is a schematic diagram of 1 H NMR ( FIG. 21A ) and 13 C NMR ( FIG. 21B ) of the product 21 obtained in Example 21.
- FIG. 22 is a schematic diagram of 1 H NMR ( FIG. 22A ) and 13 C NMR ( FIG. 22B ) of the product 22 obtained in Example 22.
- FIG. 22A 1 H NMR
- FIG. 22B 13 C NMR
- FIG. 23 is a schematic diagram of 1 H NMR ( FIG. 23A ) and 13 C NMR ( FIG. 23B ) of the product 23 obtained in Example 23.
- FIG. 23A 1 H NMR
- FIG. 23B 13 C NMR
- Figure 24 is a schematic representation of1H NMR (Figure 24A) and13C NMR ( Figure 24B) of the product 24 obtained in Example 24.
- Figure 25 is a schematic diagram of1H NMR (Figure 25A) and13C NMR (Figure 25B) of the product 25 obtained in Example 25.
- Figure 26 is the 1 H NMR of the product 26 obtained in Example 26 ( Figure 26).
- FIG. 27 is a schematic diagram of1H NMR (FIG. 27A) and13C NMR (FIG. 27B) of the product 27 obtained in Example 27.
- FIG. 27A is a schematic diagram of1H NMR (FIG. 27A) and13C NMR (FIG. 27B) of the product 27 obtained in Example 27.
- FIG. 27B is a schematic diagram of1H NMR (FIG. 27A) and13C NMR (FIG. 27B) of the product 27 obtained in Example 27.
- FIG. 28 is a schematic diagram of1H NMR (FIG. 28A) and13C NMR (FIG. 28B) of the product 28 obtained in Example 28.
- FIG. 28A is a schematic diagram of1H NMR (FIG. 28A) and13C NMR (FIG. 28B) of the product 28 obtained in Example 28.
- FIG. 28B is a schematic diagram of1H NMR (FIG. 28A) and13C NMR (FIG. 28B) of the product 28 obtained in Example 28.
- FIG. 28A 1H NMR
- FIG. 28B 13C NMR
- Figure 29 is a schematic diagram of1H NMR (Figure 29A) and13C NMR (Figure 29B) of the product 29 obtained in Example 29.
- FIG. 30 is a schematic diagram of 1 H NMR ( FIG. 30A ) and 13 C NMR ( FIG. 30B ) of the product 30 obtained in Example 30.
- FIG. 30A is a schematic diagram of 1 H NMR ( FIG. 30A ) and 13 C NMR ( FIG. 30B ) of the product 30 obtained in Example 30.
- FIG. 30B is a schematic diagram of 1 H NMR ( FIG. 30A ) and 13 C NMR ( FIG. 30B ) of the product 30 obtained in Example 30.
- Figure 31 is a schematic diagram of1H NMR (Figure 31A) and13C NMR ( Figure 31B) of the product 31 obtained in Example 31.
- Figure 32 is a schematic diagram of1H NMR (Figure 32A) and13C NMR ( Figure 32B) of the product 32 obtained in Example 32.
- FIG. 33 is a schematic diagram of1H NMR (FIG. 33A) and13C NMR (FIG. 33B) of the product 33 obtained in Example 33.
- FIG. 33A is a schematic diagram of1H NMR (FIG. 33A) and13C NMR (FIG. 33B) of the product 33 obtained in Example 33.
- FIG. 33B is a schematic diagram of1H NMR (FIG. 33A) and13C NMR (FIG. 33B) of the product 33 obtained in Example 33.
- FIG. 33A 1H NMR
- FIG. 33B 13C NMR
- Figure 34 is a schematic representation of1H NMR (Figure 34A) and13C NMR (Figure 34B) of the product 34 obtained in Example 34.
- Figure 35 is a schematic representation of1H NMR (Figure 35A) and13C NMR (Figure 35B) of the product 35 obtained in Example 35.
- FIG. 36 is a schematic diagram of1H NMR (FIG. 36A) and13C NMR (FIG. 36B) of the product 36 obtained in Example 36.
- FIG. 36A is a schematic diagram of1H NMR (FIG. 36A) and13C NMR (FIG. 36B) of the product 36 obtained in Example 36.
- FIG. 36B is a schematic diagram of1H NMR (FIG. 36A) and13C NMR (FIG. 36B) of the product 36 obtained in Example 36.
- FIG. 37 is a schematic diagram of1H NMR (FIG. 37A) and13C NMR (FIG. 37B) of the product 37 obtained in Example 37.
- FIG. 37A is a schematic diagram of1H NMR (FIG. 37A) and13C NMR (FIG. 37B) of the product 37 obtained in Example 37.
- FIG. 37B is a schematic diagram of1H NMR (FIG. 37A) and13C NMR (FIG. 37B) of the product 37 obtained in Example 37.
- Figure 38 is a schematic representation of1H NMR (Figure 38A) and13C NMR (Figure 38B) of the product 38 obtained in Example 38.
- Figure 39 is a schematic diagram of1H NMR (Figure 39A), 13C NMR ( Figure 39B) and19F NMR (Figure 39C) of the product 39 obtained in Example 39.
- FIG. 40 is a schematic diagram of 1 H NMR ( FIG. 40A ) and 13 C NMR ( FIG. 40B ) of the product 40 obtained in Example 2.
- FIG. 40A 1 H NMR
- FIG. 40B 13 C NMR
- Figure 41 is a schematic diagram of1H NMR (Figure 41A) and13C NMR ( Figure 41B) of the product 41 obtained in Example 41.
- Figure 42 is a schematic representation of1H NMR (Figure 42A) and13C NMR ( Figure 42B) of the product 42 obtained in Example 42.
- Figure 43 is a schematic diagram of1H NMR (Figure 43A), 13C NMR ( Figure 43B) and19F NMR (Figure 43C) of the product 43 obtained in Example 43.
- Figure 44 is a schematic representation of1H NMR (Figure 44A) and13C NMR (Figure 44B) of the product 44 obtained in Example 44.
- FIG. 45 is a schematic diagram of1H NMR (FIG. 45A) and13C NMR (FIG. 45B) of the product 45 obtained in Example 7.
- FIG. 45A is a schematic diagram of1H NMR (FIG. 45A) and13C NMR (FIG. 45B) of the product 45 obtained in Example 7.
- FIG. 45B is a schematic diagram of1H NMR (FIG. 45A) and13C NMR (FIG. 45B) of the product 45 obtained in Example 7.
- FIG. 45A 1H NMR
- FIG. 45B 13C NMR
- Figure 46 is a schematic representation of1H NMR (Figure 46A) and13C NMR (Figure 46B) of the product 46 obtained in Example 8.
- Figure 47 is a schematic representation of1H NMR (Figure 47A) and13C NMR (Figure 47B) of the product 47 obtained in Example 47.
- Figure 48 is a schematic representation of1H NMR (Figure 48A) and13C NMR (Figure 48B) of the product 48 obtained in Example 48.
- Figure 49 is a schematic representation of1H NMR (Figure 49A) and13C NMR (Figure 49B) of the product 49 obtained in Example 49.
- Figure 50 is a schematic diagram of1H NMR (Figure 50A) and13C NMR (Figure 50B) of the product 50 obtained in Example 50.
- FIG. 51 is the 1 H NMR of the product 51 obtained in Example 51.
- FIG. 51 is the 1 H NMR of the product 51 obtained in Example 51.
- Figure 52 is a schematic diagram of1H NMR (Figure 52A) and13C NMR ( Figure 52B) of the product 52 obtained in Example 52.
- Figure 53 is a schematic diagram of1H NMR (Figure 53A) and13C NMR ( Figure 53B) of the product 53 obtained in Example 53.
- Embodiment 5 is a diagrammatic representation of Embodiment 5:
- the present invention adopts the CCK-8 method to determine the effect of the 38 compounds 1 to 38 prepared by the present invention on 6 kinds of osteosarcoma cells (SJSA-1, U2OS, HOS, MNNG/HOS, MG63, 143b), 1 kind of pancreatic cancer cells ( The proliferation inhibitory effect of PANC-1), 1 type of lung cancer cell (A549), 1 type of colorectal cancer cell (HCT116) and 1 type of leukemia cell (Jurkat).
- a single cell suspension was prepared with DMEM medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 MNNG/HOS osteosarcoma cells per well were inoculated into a 96-well cell culture plate. Volume 100 ⁇ l.
- a single cell suspension was prepared with McCoy'5A medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 U-2-OS osteosarcoma cells per well were inoculated into 96-well cell culture plate, with a volume of 100 ⁇ l per well.
- a single cell suspension was prepared with 1640 medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and 2500 Jurkat leukemia cells per well were inoculated into a 96-well cell culture plate, with a volume of 100 ⁇ l per well.
- the 38 compounds (1 to 38) prepared by the present invention were dissolved in DMSO, respectively prepared into a drug solution with a final concentration of 1 ⁇ M with the corresponding cell culture medium, and added to ten different cells (100 ⁇ L/well) respectively.
- the control group was added with 1 ⁇ DMSO, and cultured in a CO 2 incubator for 72 hours;
- Cell proliferation activity (%) [A (dosing)-A (blank)]/[A (0 dosing)-A (blank)] ⁇ 100.
- ND stand for not detected.
- 25 compounds including compound 1 had a good inhibitory effect on MNNG/HOS cells; 24 compounds including compound 3 had a good inhibitory effect on MG63 cells; 15 compounds including compound 1 had a good inhibitory effect on 143b cells 25 compounds including compound 1 have good inhibitory effect on leukemia cell Jurkat; 17 compounds including compound 4 have good inhibitory effect on colorectal cancer cell HCT116; 19 compounds including compound 1 have good inhibitory effect on lung cancer cell A549 It has a good inhibitory effect; 17 compounds including compound 1 have a certain inhibitory effect on pancreatic cancer cell PANC-1. (Bold parts are data with inhibitory activity)
- the compound 44 of the present invention is effective for SJSA-1, U-2-OS, HOS , 143B, MNNG/HOS and MG63 osteosarcoma cells, A549 lung cancer cells, Jurkat leukemia cells all have a certain inhibitory effect, but the best inhibitory activity is MNNG/HOS and MG63 osteosarcoma cells, so the present invention is used in subsequent experiments.
- the compounds of the present invention were used to detect the cellular IC50 of two subtypes of osteosarcoma cells, MNNG/HOS and MG63 (Table 3).
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Abstract
Description
Claims (10)
- 一种3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐,其特征在于,其结构如式(I)、(II)、(III)所示:其中,Ar为芳基、芳杂环、烷基取代的芳基、卤素取代的芳基、烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘烷基、呋喃烷基、烯基、炔基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪;R 1为单取代基或多取代基,选自下列基团:氢、卤素、烷氧基、烷基、硝基、氰基、三氟甲基、苯基、氢、芳基、三元环、乙炔基;R 2为环烷基,环氧烷基、烷基或氢;R 3为卤素、烷氧基、烷基、环烷基、硝基、氰基、三氟甲基、苯基、氢;n=0;1;2;4;5;6。Het为杂环,选自:吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮、嘧啶、卤素取代的杂芳基、硝基取代的杂芳基、萘烷基、呋喃烷基、烯烷基、炔烷基、二苯烷基、二(4-溴苯基)烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述杂芳基选自吲哚、苯并三氮唑、噻吩、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪。
- 如权利1所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐,其特征在于,Ar为苯基、芳杂环、C1-C6烷基取代的苯基、卤素取代的苯基、C1-C6烷基取代的杂芳基、卤素取代的杂芳基、三氟甲基取代的苯基、硝基取代的苯基、萘甲基、呋喃甲基、烯丙基、炔丙基、二苯甲基、二(4-溴苯基)甲基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述芳杂环、杂芳基分别选自吲哚、苯并三氮唑、噻吩、呋喃、吡咯、双内酰胺、哌嗪、咪唑、恶唑、吡嗪;R 1为单取代基或多取代基,选自下列基团:卤素,C1-C10烷氧基,C1-C10烷基,硝基,氰基,三氟甲基,氢;R 2为C1-C6 烷基、C3-C6环烷基,C1-C6环氧烷基、氢;R 3为卤素、C1-C6烷氧基、C1-C6烷基、C3-C6环烷基、硝基、氰基、三氟甲基、苯基、氢;Het为杂环,选自:吡啶、喹啉、托烷、吩噻嗪、苯并二氮杂卓、呋喃、吡唑酮、嘧啶、卤素取代的杂芳基、三氟甲基取代的芳基、硝基取代的芳基、萘C1-C6烷基、呋喃C1-C6烷基、烯C1-C6烷基、炔C1-C6烷基、二苯C1-C6烷基、二(4-溴苯基)C1-C6烷基、三氟甲基取代的杂芳基、硝基取代的杂芳基;其中,所述杂芳基选自吲哚、苯并三氮唑、噻吩、吡咯、双内酰胺,哌嗪、咪唑、恶唑、吡嗪。
- 根据权利要求1或2所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐,其特征在于,选自于以下:3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)丁基)苯甲酰胺;3-(3-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;(Z)-3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-(噻吩-2-基)丁-3-烯-1-基)苯甲酰;3-(3-(2-甲氧基苯基)-5-甲基-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺3-(3-(2,4-二甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-甲基苯基)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;3-(3-(3-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(5-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(4-氟-2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-5-甲基-N-(4-苯基丁基)苯甲酰胺3-(3-(2-甲氧基苯基)-噻唑啉酮基)-N-(4-1N-吡唑丁基)苯甲酰胺;3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;3-(3-(2-甲氧基苯基)-4-噻唑啉酮基)-N-(4-Boc-哌嗪丁基)苯甲酰胺;3-(3-(2-氟-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(3-三氟甲基-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(3-三氟甲基-苯基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺。3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-(4-(4-氯)苯基丁基)苯甲酰胺;3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基乙基)苯甲酰胺;3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-(4-苯基丙基)苯甲酰胺;3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(4氯)苯基丁基)苯甲酰胺;3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(4氯)苯基丁基)苯甲酰胺;3-(3-(4-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-苯基丁基)苯甲酰胺;3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-苯基丁基)苯甲酰胺;3-(3-(3-环丙烷基苯)-4-噻唑啉酮基)-N-5-甲基-(4-(N-吡唑)苯基丁基)苯甲酰胺。3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-甲氧基-5-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;3-(3-(2-甲基-4-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺;3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-吡唑丁基)苯甲酰胺;3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-苯基丙基)苯甲酰胺;3-(3-(3-乙炔基苯)-4-噻唑啉酮基)-N-(4-N-苯基乙基)苯甲酰胺;3-(3-(2-甲基-5-乙炔基苯)-4(5-甲基)-噻唑啉酮基)-N-(4-N-吲哚丁基)苯甲酰胺;3-(3-(2-甲氧基苯)-4-噻唑啉酮基)-5-乙炔基-N-(4-苯基丁基)苯甲酰胺。3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺;3-(3-(2-(4-溴)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺;3-(3-(2-(4-氯)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺;3-(3-(2-(4-氟)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺;3-(3-(2-(4-甲基)吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺;N-(4-(1H-吡唑啉-1-基)丁基)-3-(3-(4-(3-乙基-2,6-二氧哌啶-3-基)苯基)-4-恶噻唑烷-2-基)苯甲酰胺;2-(2-(3-((4-(1H-吡唑啉-1-基)丁基)氨甲酰基)苯基)-4-恶噻唑烷-3-基)-4-甲基噻唑-5-羧酸乙酯;3-(3-(3-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺;3-(3-(4-吡啶基)-4-噻唑啉酮基)-N-(4-吡唑丁基)苯甲酰胺;3-氟-5-(4-氧代-3-(吡啶-2-基)噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-吡啶基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-吡嗪基)-4-噻唑啉酮基)-N-(4-苯基丁基)苯甲酰胺;3-(3-(2-吡啶基)-4-噻唑啉酮基)-5-氟-N-(4-苯基丁基)苯甲酰胺;3-(3-(4-(叔丁基)异恶唑-3-基)-4-恶噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺3-(3-([1,1'-联苯]-4-基)-4-恶噻唑烷-2-基)-N-(4-苯基丁基)苯甲酰胺。
- 根据权利要求1或2所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐,其特征在于,所述化合物与酸形成的酸加成盐;其中,所述酸是盐酸、硫酸、磷酸、氢溴酸、乙酸、水杨酸、酒石酸、乳酸、柠檬酸、甲磺酸、对甲苯磺酸、马来酸、丙酮酸、或琥珀酸。
- 一种药物组合物,其特征在于,其包含如权利要求1-3之任一项所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐,以及药学上可接受的载体。
- 根据权利要求5所述的药物组合物,其特征在于,所述药物组合物被配制成丸剂、胶囊剂、乳膏、凝胶剂、赋形剂、可注射流体、气雾剂、糖浆剂或透皮贴剂。
- 根据权利要求1-3之任一项所述的3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐在制备预防和/或治疗肿瘤的药物中的应用。
- 根据权利要求7所述的应用,其特征在于,所述3-(3-芳基/杂芳基-4-噻唑啉酮基)-N-芳基/杂环苯甲酰胺类化合物或药学上可接受的盐、或药物组合物用于抑制肿瘤细胞的增殖、生长、迁移、浸润、转移和复发,或促进肿瘤细胞凋亡。
- 根据权利要求7所述的应用,其特征在于,所述肿瘤包括骨肉瘤、白血病、胰腺癌、肺癌、结直肠癌。
- 根据权利要求9所述的应用,其特征在于,所述骨肉瘤细胞包括SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b;所述胰腺癌细胞包括PANC-1;所述肺癌细胞包括A549;所述结直肠癌细胞包括HCT116;所述白血病细胞包括Jurkat。
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