CN106916100A - A kind of E benzamide compound and its pharmaceutical formulation - Google Patents
A kind of E benzamide compound and its pharmaceutical formulation Download PDFInfo
- Publication number
- CN106916100A CN106916100A CN201710244253.7A CN201710244253A CN106916100A CN 106916100 A CN106916100 A CN 106916100A CN 201710244253 A CN201710244253 A CN 201710244253A CN 106916100 A CN106916100 A CN 106916100A
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- formula
- compound
- pyridines
- aminomethyl
- acryloyl group
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- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title claims abstract description 62
- -1 benzamide compound Chemical class 0.000 title claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims abstract description 42
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims abstract description 31
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims abstract description 25
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- QQEXMHVHLWKOQT-UHFFFAOYSA-N benzene;formamide Chemical compound NC=O.C1=CC=CC=C1 QQEXMHVHLWKOQT-UHFFFAOYSA-N 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
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- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical class N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
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- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
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- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003968 dna methyltransferase inhibitor Substances 0.000 description 1
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- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
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- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
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- 102000020233 phosphotransferase Human genes 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000009124 positive feedback regulation Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
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Classifications
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- 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
- C07D213/24—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 with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of E benzamide compound and its pharmaceutical formulation and application; the E benzamide compound has structure shown in formula (I); its chemical name is N (fluorophenyl of 2 amino 4) 4 [N [(E) 3 (3 pyridine) acryloyl group] aminomethyl] benzamide; in its structural formula, 3 pyridine acryloyl groups are configured as E types.E benzamide compound shown in the formula (I) has subtype-selective histon deacetylase (HDAC) inhibitory activity, the HDAC10 in main HDAC1, HDAC2, HDAC3 and ii b classes HDAC suppressed in I classes HDAC.E benzamide compound E benzamide compound shown in the formula (I) can be used for the treatment disease extremely related to histone deacetylase activity, such as cancer, including lymthoma, entity tumor and hematological system tumor etc..
Description
It is on April 4th, 2014 applying date that the application is, Application No. 201410136761.X, invention and created name is " one
The divisional application of kind of E benzamide compound and pharmaceutical formulation and application ".
Technical field
The invention belongs to chemical pharmacy field, and in particular to a kind of E benzamide compound and pharmaceutical formulation with
Using.
Background technology
Histon deacetylase (HDAC) (HDAC) is the enzyme that acetyl group on the lysine of histone is sloughed in class catalysis, in dyeing
Key effect is played on matter pyknosis and chromatin remodeling and the gene regulation for being determined, is the important composition portion of epigenetic regulation
Point.HDAC includes different hypotype (I class of four major class 18：HDAC1、2、3、8；II classes：HDAC4、5、6、7、9、10；Group III：
Sirt1-7；IV classes：HDAC11).HDAC adjusts the acetylation modification of histone with histone acetyltransferases (HAT) jointly,
HAT carries out acetylation to specific lysine (Lys) residue on histone, and HDAC is responsible for removing residue modification.Histone
Acetylation causes that chromatin Structure becomes lax, so as to be conducive to the combination of other DBPs (such as transcription factor), because
The acetylation of this histone can activate the transcription (chromatinic to reinvent) of specific gene.Meanwhile, HDAC also adjusts part
The acetylation modification of nonhistones proteinoid substrate, such as transcription regulatory factor (P53, NF- κ B), stress response protein
(Hsp70/90 etc.) and eucaryotic cell structure molecule (Tubulin etc.) etc., further influence the growth of cell propagation and other biological
Process (Haberland M, Montgomery RL, Olson EN.The many roles of histone
deacetylases in development and physiology:implications for disease and
therapy.Nat Rev Genet 2009；10(1):32-42；Khan O,La Thangue NB.HDAC inhibitors
in cancer biology:emerging mechanisms and clinical applications.Immunol Cell
Biol 2012；90(1):85-94).
Histon deacetylase (HDAC) inhibitor is one of focus in recent years in antineoplastic research field.Research table
Bright, it is swollen that histon deacetylase (HDAC) inhibitor can effectively suppress the propagation of tumour cell, induced tumor cell differentiation, induction
Apoptosis of tumor and Antineoplastic angiogenesis, migration to tumour cell, attack and shift inhibited (Kim HJ, Bae
SC.Histone deacetylase inhibitors:Molecular mechanisms of action and clinical
trials as anti-cancer drugs.Am J Transl Res 2011；3(20:166-179；John
RW.Histone-deacetylase inhibitors:Novel drugs for the treatment of cancer.Nat
Rev Drug Discov 2002；1(4):287-299；Tan J,Zhuang L.Apoptosis signal regulating
kinase 1is a direct target of E2F1and contributes to histone deacetylase
inhibitor induced apoptosis through positive feedback regulation of E2F1
apoptotic activity.J Biol Chem 2006；281(15):10508-10515；Park KC,Kim
SW.Potential anti-cancer activity of N-hydroxy-7-(2-naphthylthio)heptanomide
(HNHA),a Histone deacetylase inhibitor,against breast cancer both in vitro
and in vivo.Cancer Sci 2011；102(2):343-350).
Histon deacetylase (HDAC) inhibitor can be divided into four major classes, i.e. hydroximic acid, cyclic tetrapeptide class, short by chemical constitution
Chain fatty acid and benzamides.Preceding three major types compound suppresses I classes and all HDAC hypotypes of II classes, belongs to HDAC non-selective
Inhibitor, it is known that benzamide compound then show the selectivity of target effect, it is main suppress I classes HDAC (including
HDAC hypotypes 1,2,3, but do not suppress HDAC8).
The Vorinostat (SAHA) developed by Merck ＆ Co., Inc. is hydroximic acid histon deacetylase (HDAC) inhibitor, complete
Into after II clinical trial phases, be approved by the FDA in the United States in the end of the year 2006 with T-cell lymphoma,cutaneous (CTCL) as indication on
Apply in city；The Romidepsin (FK228) developed by Celgene companies of the U.S. is that cyclic tetrapeptide histone deacetylases suppress
Agent, listing was approved by the FDA in the United States in 2009 for the treatment of CTCL, and listing was approved by the FDA in the United States in 2011 for recurring
The treatment of property/intractable PTCL.But because SAHA and FK228 belong to HDAC non-selective inhibitors, while suppressing too many
Cell signal is preached path, therefore, its toxic and side effect is stronger, for example, SAHA can cause thrombosis and neurotoxicity (Duvic
M and Vu J.Vorinostat in cutaneous T-cell lymphoma.Drugs Today(Barc)2007,43,
585-599), the incidence of more than 3 grades FK228 relevant with medication adverse reactions is up to 66%, and has cardiac toxic
(http://www.istodax.com/pdfs/ISTODAX_PackageInsert.pdf).Meanwhile, Vorinostat and
The absorption Cmax (Cmax) of the two medicines of Romidepsin and Clinical efficacy direct correlation is apparently higher than its external suppression
Concentration needed for normal or growth of tumour cell, so as to normal cell there may be direct CDCC, rather than it should
The epigenetic regulation effect to tumour cell of the performance, further increases the toxic and side effect that medicine is used, serious limitation
They combine application (Azad N, et that other different mechanism of action medicines carry out combined therapy of tumour in oncotherapy
al.The future of epigenetic therapy in solid tumors---lessons from the
past.Nat Rev Clinic Oncology 2013；10(5):256-266；GI50Data of SAHA and FK-
228cited from reference dataset:http://dtp.nci.nih.gov/index.html；Cmax Cited
from prescribing information of(FK-228)and(SAHA))。
The Entinostat (MS-275) developed by German Bayer and U.S. Syndax is benzamide compound, is faced
Animal experiment shows before bed, and the compound has obvious active anticancer (Saito A.A to leukemia, lung cancer, carcinoma of the rectum etc.
synthetic inhibitor of histone deacetylase,MS-275,with marked in vivo
antitumor activity against human tumors.PNAS 1999,96(8):4592-4597).Although MS-275
It is HDAC selective depressants, but (half-life period close to 100 hours, medicine is removed because its Pharmacokinetics characteristic is poor
Thing exposed amount individual difference is big), the tolerance of extreme difference is shown in Phase I clinical trial, it is impossible to improve dosage, thus nothing
Method ensures the validity of its single medicine clinical test.
Therefore, selective DNA methylase inhibitor of the exploitation with subtype-selective and good human pharmacokineticses characteristic
Enzyme inhibitor is just particularly important.
Applicant discloses a kind of new benzamides in United States Patent (USP) US7,244,751B2 embodiments 2
Histon deacetylase (HDAC) inhibitor CS02100055, its chemical name is N- (2- amino -4- fluorophenyls) -4- [N- (3- pyridines
Acryloyl group) aminomethyl] benzamide, the compound has inhibitory activity (IC to total histon deacetylase (HDAC)50：8.4 μM),
Growth to kinds of tumor cells is inhibited.
Contain in the structural formula of N- (2- amino -4- fluorophenyls) -4- [N- (3- pyridines acryloyl group) aminomethyl] benzamide
There is inferior ethylene group (- CH=CH-), according to US7, that 244, the 751B2 preparation methods for implementing 2 are obtained is E isomers and Z
The mixture of configurational isomer.US7,244,751B2 and other prior arts do not disclose the compound E isomers or
The preparation method and physical and chemical parameter of Z configurational isomers.
Application documents CN103432077A application protection N- (2- amino -4- fluorophenyls) -4- [N- (3- pyridines acryloyl group)
Aminomethyl] solid dispersions that are formed of benzamide and polyvinylpyrrolidone (i.e. PVP), but present invention applicant has found,
Application documents CN103432077A does not obtain this solid dispersions really.According to disclosed in application documents CN103432077A
Information, embodiment 1 is according to cited document (Chinese Journal of New Drugs, the 6th phase, the 536-538 pages in 2004) obtainedization
Compound is N- (2- amino-5-fluorines phenyl) -4- [N- (3- pyridines acryloyl group) aminomethyl] benzamide, does not obtain N- (2-
Amino -4- fluorophenyls) -4- [N- (3- pyridines acryloyl group) aminomethyl] benzamide, therefore, also cannot just obtain N- (2- ammonia
Base -4- fluorophenyls) solid of -4- [N- (3- pyridines acryloyl group) aminomethyl] benzamides and polyvinylpyrrolidone disperses
Body, meanwhile, application documents CN103432077A is also not disclosed N- (2- amino -4- fluorophenyls) -4- [N- (3- pyridines acryloyl group)
Aminomethyl] solid dispersions that are formed of benzamide and polyvinylpyrrolidone any physical and chemical parameter (such as solid dispersions
Dissolubility data, dissolution data or X-ray powder diffraction figure).
Application documents CN103432077A also applies protecting N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyrroles
Pyridine) acryloyl group] aminomethyl] solid dispersions that are formed of benzamide and polyvinylpyrrolidone, but the present patent application human hair
Existing, application documents CN103432077A does not obtain this solid dispersions really.It is public according to application documents CN103432077A
The information opened, embodiment 3 according to cited document (US7,244,751B2) it is obtained be N- (2- amino -4- fluorophenyls) -
4- [N- (3- pyridines acryloyl group) aminomethyl] benzamide, does not obtain N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3-
(3- pyridines) acryloyl group] aminomethyl] benzamide (i.e. E-isomer), therefore, also cannot just obtain N- (2- amino -4- fluorine
Phenyl) solid of -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamides and polyvinylpyrrolidone disperses
Body, meanwhile, application documents CN103432077A is also not disclosed N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines)
Acryloyl group] aminomethyl] solid dispersions that are formed of benzamide and polyvinylpyrrolidone any physical and chemical parameter (such as solid
The dissolubility data of dispersion, dissolution data or X-ray powder diffraction figure).
The content of the invention
One of the object of the invention is to disclose a kind of E of the histon deacetylase (HDAC) inhibitory activity with subtype-selective
Configuration benzamide compound.
The two of the object of the invention are the preparation method for disclosing the compound.
The two of the object of the invention are the pharmaceutical formulation for disclosing the compound.
The four of the object of the invention are the application for disclosing the compound in the medicine for preparing treating cancer.
Compound of the present invention has a structure shown in formula (I), its chemical name be N- (2- amino -4- fluorophenyls) -
4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide, in its structural formula, the structure of 3- pyridine acryloyl groups
Type is E types,
The preparation method of compound of the present invention is as follows：
A () is by trans -3- (3- pyridines) acrylic acid and N, N '-carbonyl dimidazoles (CDI) reaction obtains (E) -3- (3- pyrroles
Pyridine) acryloyl group imidazoles reactive intermediate, then obtain 4- [N- [(E) -3- (3- pyridines) with the reaction of Aminomethylbenzoic Acid sodium
Acryloyl group] aminomethyl] Sodium Benzoate, then obtain 4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] through hydrochloric acid acidifying
Benzoic acid；
B () is by 4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoic acid and N, N '-carbonyl dimidazoles (CDI)
Reaction obtains 4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoyl imidazoles reactive intermediate, then adjacent with 4- fluorine
Phenylenediamine reaction obtains N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoyl
Amine.
Compound of the present invention is a kind of subtype-selective histon deacetylase (HDAC) inhibitor, main to suppress I classes
The HDAC10 in HDAC1, HDAC2, HDAC3 and ii b classes HDAC in HDAC, HDAC6,7 and 9 is not suppressed, to HDAC8 and 11
Suppression it is weaker.
Compound of the present invention is than N- (2- amino -4- fluorophenyls) -4- [N- (3- pyridines acryloyl group) aminomethyl] benzene
Formamide (i.e. E types and Z-type mixture) has more preferable histon deacetylase (HDAC) inhibitory activity.The compounds of this invention pair
The half enzyme activity inhibition concentration (IC of HDAC1, HDAC2, HDAC3 and HDAC1050) 95nM, 160nM, 67nM and 78nM are respectively,
And E types and Z-type mixture are to the half enzyme activity inhibition concentration (IC of HDAC1, HDAC2, HDAC3 and HDAC1050) be respectively
172nM, 345nM, 129nM and 143nM.
Compound of the present invention can be used for the treatment disease extremely related to histone deacetylase activity, such as cancer
Disease, including lymthoma, entity tumor and hematological system tumor etc..
Compound of the present invention is processed to conventional pharmaceutical formulation, such as tablet, capsule, injection.Said preparation can be with 1
~50% formula (I) compound and 50~99% pharmaceutic adjuvant.The pharmaceutic adjuvant, including《Pharmaceutical excipient handbook》
What (American Pharmaceutical Association, in October, 1986) or Chemical Industry Press published《Pharmaceutic adjuvant handbook》(Handbook of
Pharmaceutical Excipients, original work fourth edition) listed by carrier auxiliary material, but be not limited to these pharmaceutic adjuvants.
Compound of the present invention can be clinically administered by oral or injection system, wherein especially with oral way most
It is good.Dosage is daily 0.01~200mg/kg body weight, and optimal dosage is daily 0.1~50mg/kg body weight.
After oral solid formulation enters in vivo, it is both needed to by process in leaching, could be absorbed by organisms through biomembrane.Indissoluble
Property medicine limited by solubility due to its dissolution rate, have impact on drug absorption, therefore effect is slow, bioavilability compared with
It is low.
Solubility of the compound of the present invention in water is minimum, does not almost dissolve, and bioavilability is relatively low, therefore, carry
Its dissolution rate high and bioavilability are significant.
The water solubility of formula (I) compound be can improve the invention provides one kind, its dissolution rate and bioavilability improved
Solid dispersions.The solid dispersions are made up of formula (I) compound and water soluble carrier material, formula (I) compound and water
The weight ratio of solubleness carrier material is 1:1~1:20.Applicant is by studying discovery, formula (I) compound and water-solubility carrier material
Material is by weight 1:1~1:20 are combined, and formula (I) compound can be highly dispersed at water with molecular forms or amorphous state
In solubleness carrier material, so as to substantially improve the water solubility of formula (I) compound, its dissolution rate and bioavilability are improved.
In some embodiments, formula (I) compound is 1 with the weight ratio of water soluble carrier material:1；In some embodiments, formula
(I) compound and the weight ratio of water soluble carrier material are 1:5；In other embodiments, formula (I) compound and water solubility
The weight ratio of carrier material is 1:20.
Preferably, the water soluble carrier material in formula (I) compound solid dispersion of the present invention is PVP, gathers
Ethylene glycol or poloxamer, more preferably PVP K30.
Present invention also offers the preparation method of the formula (I) compound solid dispersion.Methods described is：Weigh respectively
Formula (I) compound and water soluble carrier material, add organic solvent, be heated to formula (I) compound and water soluble carrier material is complete
CL, then boils off organic solvent, collects solid, dry, pulverize and obtains final product.Wherein, formula (I) compound is carried with water-soluble
The weight ratio preferably 1 of body material:1~1:20.It is husky that the water soluble carrier material is preferably PVP, polyethylene glycol or pool Lip river
Nurse, more preferably PVP K30.The organic solvent is preferably absolute ethyl alcohol, 95% ethanol, methyl alcohol, acetonitrile or acetone.It is described
The weight ratio preferably 1 of formula (I) compound and organic solvent:100~1:1000, more preferably 1:200~1:1000.At some
In embodiment, formula (I) compound is 1 with the weight ratio of organic solvent:200；In some embodiments, the formula
(I) compound and the weight ratio of organic solvent are 1:250；In other embodiments, formula (I) compound is molten with organic
The weight ratio of agent is 1:1000.The heating is preferably 60 DEG C~90 DEG C heating.The organic solvent that boils off is included but is not limited to
Depressurized with Rotary Evaporators and boil off organic solvent.The drying is preferably and dries 2h~8h in 60 DEG C~80 DEG C, in some implementations
For 60 DEG C dry 8h in scheme；In some embodiments for 80 DEG C dry 2h；It is in other embodiments 80 DEG C of dryings
4h.Described crushing preferably crushed 60~100 mesh sieves.
Solubility of the present invention to the formula (I) compound solid dispersion in water detected, as a result display type
(I) solubility of the compound in water is 4.64 μ g/mL；And be by weight 1 by formula (I) compound and PVP K30:5 systems
Into solubility [by formula (1) compound based on] of the solid dispersions in water be 66.7 μ g/mL, improve than formula (I) compound
14.4 times, show that formula of the present invention (I) compound solid dispersion physical efficiency increases the solubility of formula (I) compound, accelerate its molten
Go out speed.
The present invention also using dissolution in vitro experiment respectively determine formula (I) compound, embodiment 7 by formula (I) compound with
PVP K30 is 1 by weight:1 solid dispersions being made, embodiment 8 by formula (I) compound and PVP K30 by weight
Than being 1:5 solid dispersions being made, embodiment 9 are 1 by formula (I) compound and PVP K30 by weight:20 be made consolidate
The dissolution situation of body dispersion, the sampling amount of four kinds of samples is respectively 100mg, 200mg, 600mg and 2100mg.Assay method
For：According to dissolution method (two the second methods of annex X C of Chinese Pharmacopoeia version in 2010), with water 1000mL as dissolution medium, turn
Speed is 50rpm, is operated in accordance with the law, during through 45min, takes solution 10mL filtrations, takes subsequent filtrate dilute with water 20 molten as test sample again
Liquid；It is another to take formula (I) compound about 25mg, it is accurately weighed, in putting 100mL measuring bottles, plus after 95% appropriate amount of ethanol ultrasonic dissolution, dilution
To scale, precision pipettes 1mL to 50mL measuring bottles, the solution containing about 5 μ g is diluted with water in every 1mL, as reference substance solution；According to
UV-VIS spectrophotometry mensuration absorbance at the wavelength of 258nm, calculates dissolution rate.Measurement result shows that formula (I) is changed
The dissolution rate of compound is 4.71%, and solid dispersions, the solid dispersions of the preparation of embodiment 8 and implementation prepared by embodiment 7
The dissolution rate of solid dispersions prepared by example 9 is respectively 60.3%, 79.1% and 82.2%, has significantly compared with formula (I) compound
Improve.
The present invention also determines obtained containing formula (I) compound solid point by embodiment 11 respectively using dissolution in vitro experiment
The tablet and the identical prescription of use of a prose style free from parallelism press the dissolution situation of the obtained conventional tablet containing formula (I) compound of embodiment 4.Survey
The method of determining is：6, sample is taken, according to dissolution method (two the second methods of annex X C of Chinese Pharmacopoeia version in 2010), with water
1000mL is dissolution medium, and rotating speed is 50rpm, is operated in accordance with the law, during through 45min, takes solution 10mL filtrations, takes subsequent filtrate as confession
Test sample solution；It is another to take formula (I) compound about 25mg, it is accurately weighed, in putting 100mL measuring bottles, plus 95% appropriate amount of ethanol ultrasonic dissolution
Afterwards, scale is diluted to, precision pipettes 1mL to 50mL measuring bottles, the solution containing about 5 μ g is diluted with water in every 1mL, as reference substance
Solution；According to UV-VIS spectrophotometry at the wavelength of 258nm mensuration absorbance, calculate dissolution rate.Measurement result shows,
The dissolution rate of the obtained tablet containing formula (I) compound solid dispersion of embodiment 11 is 99.4%, and general obtained in embodiment 4
The dissolution rate of logical tablet is 57.8%, and the dissolution rate of the obtained tablet containing formula (I) compound solid dispersion of embodiment 11 shows
Write and improve, almost complete dissolution.
The present invention is also examined prepared formula (I) compound solid dispersion using x-ray powder diffraction
Examine.In the X-ray powder diffraction figure of formula (I) compound, there is strong diffraction maximum (Fig. 1) in 3~50 ° of regions；Made in embodiment 7
The X-ray powder of the solid dispersions of standby solid dispersions, solid dispersions prepared by embodiment 8 and the preparation of embodiment 9 spreads out
Penetrate in figure, in 3~50 ° of regions, the characteristic diffraction peak without formula (I) compound, present amorphous solid feature disperse peak (Fig. 2,
Fig. 3 and Fig. 4)；In the X-ray powder diffraction figure of PVP K30, in 3~50 ° of regions, the feature of amorphous solid is presented more
Dissipate peak (Fig. 5)；In formula (I) compound and mechanical impurity (the weight ratio respectively 1 of PVP K30:1、1:5 and 1:20) X-
In ray powder diffraction pattern, still it is observed that the characteristic diffraction peak (Fig. 6, Fig. 7 and Fig. 8) of formula (I) compound.Experiment table
Bright, in solid dispersions of the present invention, formula (I) compound is highly dispersed in carrier material, with molecular forms or without fixed
Shape state is dispersed therein.
Formula (I) compound solid dispersion of the present invention can be made with treatment cancer with conventional pharmaceutic adjuvant combination
The pharmaceutical preparation of disease function, including oral solid formulation, such as tablet, capsule or granule.Pharmaceutical preparation of the present invention
(I) the compound solid dispersion of 5wt%~50wt% and the pharmaceutic adjuvant of 50wt%~95wt% can be contained.It is wherein described
Pharmaceutic adjuvant, including glidant such as talcum powder, magnesium stearate, superfine silica gel powder, including disintegrant such as sodium carboxymethyl starch, crosslinking
PVP, low-substituted hydroxypropyl cellulose etc., including filler such as lactose, microcrystalline cellulose, starch.
The present invention is using by formula (I) compound and PVP K30 by weight 1:The tablet of 5 solid dispersions being made enters
Clinical efficacy investigation is gone.The key II clinical trial phases for the treatment of relapsed or stubborn lymphoma peripheral T cell (PTCL) show
Show, Overall response rate is 32.9%, more than the 3 grade incidences of adverse reaction relevant with medication are 39%, and toxic and side effect is far below
Romidepsin；The II clinical trial phases for the treatment of CTCL (CTCL) show that Overall response rate is 32.0%；Joint
The Ib clinical trial phases of taxol and Carboplatin in patients non-small cell lung cancer show that Overall response rate is 10%, and 5 have brain metastes focus
Patient through treatment after, the brain metastes stoves for having 2 patients all disappear.Clinical test shows, is disperseed by formula (I) compound solid
System into oral formulations, clinically have preferable curative effect to cancer patient.Wherein, the cancer be lymthoma, entity swell
Knurl or hematological system tumor, preferably lymphoma peripheral T cell (PTCL), CTCL (CTCL) and lung cancer.
The present invention is using by formula (I) compound and PVP K30 by weight 1:The tablet of 5 solid dispersions being made enters
The human body medicine of the oral above-mentioned Solide dispersion tablets of 30mg of 33 late period Lymphomas (21 PTCL, 12 CTCL) of having gone is for power
Research is learned, under the acceptable tolerance of patient, the dosage range has clear and definite clinical treatment efficacy as described above.Its patient
In vivo with the absorption Cmax of Clinical efficacy direct correlation, i.e., maximum plasma concentration (Cmax) suppresses just in vitro significantly lower than it
Concentration often or needed for growth of tumour cell, so as to not produce direct CDCC to normal cell, but with to swollen
The epigenetic regulation effect of oncocyte.Its human tolerance is improved obviously, and shows the piece of this oral administration solid dispersion
Advantage of the agent on drug safety is improved.
Brief description of the drawings
Fig. 1 shows the X-ray powder diffraction figure of formula (I) compound；
Fig. 2 show embodiment 7 prepare formula (I) compound-PVP K30 solid dispersions (weight ratio be 1:1) X- is penetrated
Line powder diagram；
Fig. 3 show embodiment 8 prepare formula (I) compound-PVP K30 solid dispersions (weight ratio be 1:5) X- is penetrated
Line powder diagram；
Fig. 4 show embodiment 9 prepare formula (I) compound-PVP K30 solid dispersions (weight ratio be 1:20) X- is penetrated
Line powder diagram；
Fig. 5 shows the X-ray powder diffraction figure of PVP K30；
Fig. 6 shows that (weight ratio is 1 to formula (I) compound-PVP K30 mechanical impurity:1) X-ray powder diffraction figure；
Fig. 7 shows that (weight ratio is 1 to formula (I) compound-PVP K30 mechanical impurity:5) X-ray powder diffraction figure；
Fig. 8 shows that (weight ratio is 1 to formula (I) compound-PVP K30 mechanical impurity:20) X-ray powder diffraction figure.
Specific embodiment
The embodiment of the invention discloses a kind of E of the histon deacetylase (HDAC) inhibitory activity with subtype-selective
Benzamide compound and its pharmaceutical formulation and application.Those skilled in the art can use for reference present disclosure, be suitably modified work
Skill parameter is realized.In particular, all similar replacements and change are for a person skilled in the art aobvious and easy
See, they are considered as being included in the present invention.Product of the invention and application are described by preferred embodiment,
Related personnel substantially can not depart from present invention, spirit and scope to product as herein described and application be modified or
Suitably change with combining to realize and apply the technology of the present invention.
For a further understanding of the present invention, with reference to embodiment, the present invention is described in detail.It is of the present invention
Percentage is weight percentage in addition to especially indicating.(I) compound of formula described in the embodiment of the present invention except especially indicate in addition to,
N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide is, the present invention is real
(I) the compound solid dispersion of formula described in example is applied in addition to especially indicating, N- (2- amino -4- fluorophenyls) -4- [N- are
[(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide solid dispersions.Number range described in this description, such as
Measurement unit or percentage, are for providing undoubted desk reference.This is special in practice for those skilled in the art
When sharp, using outside this scope or temperature, concentration, quantity of single number etc. is different from, expected knot still can be obtained
Really.Wherein, the X-ray powder diffraction and dissolution determination test method are as follows：
X-ray powder diffraction test condition：Instrument：D/MAX-1200 (Japanese Rigaku companies)；Radiation source：Cu-Kα
(40kV、40mA)。
Dissolution determination condition：Instrument：RC806 type drug dissolution analyzers；Dissolution medium：Water 1000mL；Rotating speed：
50rpm, temperature：37±0.5℃.
Embodiment 1：The preparation of 4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoic acid
298g (2.00mol) trans -3- is added in 5 liters of three mouthfuls of glass flasks equipped with mechanical agitation and reflux condensing tube
(3- pyridines) acrylic acid, 324g (2.00mol) N, N '-carbonyl dimidazoles and 3000mL tetrahydrofurans are small in about 45 DEG C of reactions about 3
When be obtained (E) -3- (3- pyridines) acryloyl group imidazoles reactive intermediate solution.
It is another equipped with churned mechanically 10 liters of three mouthfuls of glass flasks in add 302g (2.00mol) to aminomethyl phenyl first
Acid, 80g (2.00mol) NaOH and 2000mL water, are stirred at room temperature about 30 minutes, and above-mentioned (E) -3- (3- pyridines) is then added dropwise
Acryloyl group imidazoles reactive intermediate solution, room temperature reaction about 8 hours.By reactant mixture vacuum concentration removal tetrahydrofuran,
Add 2000mL saturated nacl aqueous solutions, pH value be neutralized to equal to 5 with concentrated hydrochloric acid, filtering, filter cake respectively with 400mL water and
400mL absolute ethyl alcohol drip washing, is vacuum dried to obtain crude product.Crude product is dissolved in 2000mL 1mol/L sodium hydroxide solutions, with dense
Hydrochloric acid is neutralized to pH value equal to 4, and filtering, filter cake uses 400mL water and 400mL absolute ethyl alcohol drip washing respectively, is vacuum dried to obtain 4- [N-
[(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoic acid, weight 298g, yield 52.8%, (the HPLC side of content 99.57%
Method is determined).IR(KBr)cm-1：3269,3059,1653,1624,1543,1275,1226,976.LC-MS(m/z)：281(M-
1).Elementary analysis (C16H14N2O3) calculated value：C 68.08, H 5.00, N 9.92；Measured value：C 67.85, H 5.08, N
9.86.Nuclear magnetic resonance (INOVA 500, DMSO-d6) hydrogen spectrum, carbon spectrum, DEPT spectrum, gCOSY spectrum, gHMQC spectrum, gHMBC spectrum survey
Fixed number evidence and analysis result are shown in Table 1.
The 4- of table 1 [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoic acid nuclear magnetic resonance datas and parsing
According to 7 hydrogen, the coupling constant (J of 8 hydrogen7-8=16), confirm " 3- (3- pyridines) acryloyl group " is configured as E
Type.
Embodiment 2：N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzene first
The preparation of acid amides
282g (1.00mol) 4- [N- are added in 5 liters of three mouthfuls of glass flasks equipped with mechanical agitation and reflux condensing tube
[(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoic acid, 162g (1.00mol) N, N '-carbonyl dimidazoles and 2820mL tetra-
Hydrogen furans, reacts about 3 hours in 45 DEG C, 4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] is obtained during benzoyl is active
Between liquid solution.
It is another equipped with churned mechanically 5 liters of three mouthfuls of glass flasks in add 168g (1.33mol) 4- fluorine o-phenylenediamine and
800mL tetrahydrofurans, lead to nitrogen protection, are stirred at room temperature about 10 minutes, and above-mentioned 4- [N- [(E) -3- (3- pyridines) acryloyls are added dropwise
Base] aminomethyl] benzoyl reactive intermediate solution, room temperature reaction about 24 hours.Filtering, filter cake 400mL tetrahydrofuran drip washing,
It is vacuum dried to obtain crude product.Crude product is dissolved in 1200mL 2mol/L hydrochloric acid, 960mL 1mol/L NaOH solutions, stirring is added dropwise
About 10 minutes, filtering, filter cake 400mL water wash was transferred in 10 liters of reaction bulbs, added 6000mL water and 1200mL 1mol/L
NaOH solution, stir about 30 minutes, filtering, filter cake uses 1200mL water and 1200mL ethanol rinses respectively, is vacuum dried to obtain pure N-
(2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide, weight 206g, yield
52.7%, content 99.18% (HPLC methods measure).IR(KBr)cm-1：3412~3197,3042,2911,1653,1617,
1569,1516,1441,1417,973,838,796.FAB-MS(m/z)：391 (M+1), 390 (M).Elementary analysis
(C22H19FN4O2) calculated value：C 67.68, H 4.91, N 14.35；Measured value：C 67.68, H 4.88, N 14.25.Nuclear-magnetism is total to
Shake (INOVA 500, DMSO-d6) hydrogen is composed, carbon spectrum, DEPT spectrums, gCOSY spectrums, gHMQC spectrums, gHMBC are composed,19The determination data of F spectrums
And analysis result is shown in Table 2.
Table 2N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide core
MR data and parsing
According to 7 hydrogen, the coupling constant (J of 8 hydrogen7-8=16), confirm being configured as " 3- (3- pyridines) acryloyl group "
E types；According to the HMBC relevant peaks between 25 C, 19 H, confirm that 25 C are in 20 ortho positions of C；According to 25 between C and F
Coupling constant (JCF=9.8Hz), confirm that F is in 25 metas of C.
Embodiment 3：Measure of the test compound to the inhibitory activity of HDAC different subtypes
1st, experimental program
Using I, II, IV class HDAC totally 11 hypotypes (HDAC1~11) of purifying, using BSP Bioscoence companies
The deacetylation enzyme detection kit of production determines inhibitory activity of the test compound to HDAC different subtypes, and calculates its half
Enzyme activity inhibition concentration (IC50)。
2nd, experiment material and reagent
(1) N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide,
Prepared by the embodiment of the present invention 2, be dissolved in DMSO (100mM).
(2) N- (2- amino -4- fluorophenyls) -4- [N- (3- pyridines acryloyl group) aminomethyl] benzamide, by US7,
Prepared by 244,751B2 embodiments 2, be dissolved in DMSO (100mM).
(3) bovine serum albumin(BSA) (1mg/mL)
(4) the HDAC1-11 subtype proteins (0.4ng/ μ L, N-GST marks, BSP Biosciences) of purifying
(5) fluorogenic substrate (5mM) of acetylation modification
(6) 2x chromogenic reactions liquid (50 μM)
(7) acetylation detection buffer solution
(8) 96 hole detection plates
(9) 96 orifice plate fluorescence detectors (BioTek Synergy)
3rd, experimental procedure
(1) test compound is diluted to 300 respectively with acetylation detection buffer solution, 100,30,10,3,1,0.3,0.1,
0.03rd, 0.01 μM of concentration gradient；Acetylation substrate is diluted to 200 μM of working solution；The HDAC fusion proteins that will be purified are dilute
It is interpreted as the working solution of 0.4ng/ μ L；
(2) following composition is separately added into 96 orifice plates：5 μ L bovine serum albumin solutions (1mg/mL), 5 μ L purifying
HDAC fusion proteins (0.4ng/ μ L), 5 μ L acetylations substrate (200 μM), and 30 μ L acetylations detection buffer solution, mix.
(3) in addition to control reaction hole, the test compound for being separately added into 5 μ L various concentrations gradients to each reacting hole is molten
Liquid；Negative control hole is not added with HDAC fusion proteins, adds 10 μ L detection buffer solutions；Positive control wells are not added with test compound, plus
Enter 5 μ L detection buffer solutions.Each detection sets three repeating holes.
(4) after mixing reaction system, it is incubated 17 hours at normal temperatures.
(5) 50 μ L 2x chromogenic reaction liquid are added per hole, is incubated at room temperature 20 minutes.
(6) excitation wavelength (360nm) and launch wavelength are measured respectively using fluorescence detector (BioTek Synergy)
Fluorescence intensity when (460nm).
(7) the HDAC the enzyme activities after test compound are added to be calculated according to following formula：Active %=(F-Fb)/
(Ft-Fb).Wherein Ft is the fluorescence intensity of Positive control wells, and Fb is the signal intensity of negative control hole.To various concentrations gradient
The enzyme activity after test compound treatment carries out being calculated dose-dependent the enzyme activity curve, is obtained using statistical computation
Test compound suppresses the 503nhibiting concentration (IC of different HDAC hypotypes50)。
4th, experimental result
Experimental result is shown in Table 3.
Measurement result of the test compound of table 3 to the inhibitory activity of HDAC different subtypes
* formula (I) compound:N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl]
Benzamide
**CS02100055：N- (2- amino -4- fluorophenyls) -4- [N- (3- pyridines acryloyl group) aminomethyl] benzamide
The measurement result of table 3 shows：Formula (I) compound of the present invention is a kind of subtype-selective histon deacetylase (HDAC)
Inhibitor, the HDAC10 in main HDAC1, HDAC2, HDAC3 and ii b classes HDAC suppressed in I classes HDAC, does not suppress
HDAC6,7 and 9, the suppression to HDAC8 and 11 are weaker.Additionally, formula (I) compound of the present invention is than N- (2- amino -4- fluorobenzene
Base) -4- [N- (3- pyridines acryloyl group) aminomethyl] benzamide (i.e. E types and Z-type mixture) has to HDAC1,2,3 and 10
More preferable inhibitory activity.
Embodiment 4：The preparation of the conventional tablet containing formula (I) compound
Prescription (1000)：
Preparation technology：Formula (I) compound is crossed into 100 mesh sieves, formula (I) compound, PVP K30, the breast of recipe quantity is weighed
Sugar, microcrystalline cellulose and sodium carboxymethyl starch, are well mixed, and are wetting agent softwood with suitable quantity of water, with 20 mesh sieve series wet granulars,
4% is less than in 60 DEG C of dryings to pellet moisture, with 18 mesh sieve whole grains, the talcum powder and magnesium stearate of recipe quantity is added, mixing is equal
Even, compressing tablet is obtained final product.
Embodiment 5：The preparation of the conventional capsule agent containing formula (I) compound
Prescription (1000)：
Preparation technology：Formula (I) compound is crossed into 100 mesh sieves, formula (I) compound of recipe quantity, PVP K30, micro- is weighed
Crystalline cellulose, lactose and sodium carboxymethyl starch, are well mixed, and are wetting agent softwood with suitable quantity of water, with 20 mesh sieve series wet granulars,
4% is less than in 60 DEG C of dryings to pellet moisture, with 18 mesh sieve whole grains, recipe quantity magnesium stearate is added, is well mixed, filling capsule
Obtain final product.
Embodiment 6：The preparation of the plain particles agent containing formula (I) compound
Prescription (1000 bag)：
Preparation technology：Formula (I) compound is crossed into 100 mesh sieves, formula (I) compound, PVP K30, the breast of recipe quantity is weighed
Sugar, soluble starch, microcrystalline cellulose and sodium carboxymethyl starch, are well mixed, and are wetting agent softwood with suitable quantity of water, use 20 mesh
Sieve series wet granular, 4% is less than in 60 DEG C of dryings to pellet moisture, and with 18 mesh sieve whole grains, packing is obtained final product.
Embodiment 7：(weight ratio is 1 to formula (I) compound-PVP K30 solid dispersions:1) preparation
4g formulas (I) compound and 4g PVP K30s are taken, 800g absolute ethyl alcohols are added, in 60 DEG C of heating water baths, makes formula (I)
Compound and PVP K30 are completely dissolved, and are depressurized with Rotary Evaporators and boil off absolute ethyl alcohol, collect solid, put hot air circulation baking
8h is dried in 60 DEG C in case, is crushed, cross 60 mesh sieves, obtain final product formula (I) compound solid dispersion.The 45min of the solid dispersions
Dissolution rate be 60.3%, its X-ray powder diffraction figure is shown in Fig. 2.
Embodiment 8：(weight ratio is 1 to formula (I) compound-PVP K30 solid dispersions:5) preparation
4g formulas (I) compound and 20g PVP K30s are taken, 1000g absolute ethyl alcohols are added, in 90 DEG C of heating water baths, makes formula
(I) compound and PVP K30 are completely dissolved, and are depressurized with Rotary Evaporators and boil off absolute ethyl alcohol, collect solid, put hot air circulation
2h is dried in 80 DEG C in baking oven, is crushed, cross 100 mesh sieves, obtain final product formula (I) compound solid dispersion.The solid dispersions
The dissolution rate of 45min is 79.1%, and its X-ray powder diffraction figure is shown in Fig. 3.
Embodiment 9：(weight ratio is 1 to formula (I) compound-PVP K30 solid dispersions:20) preparation
4g formulas (I) compound and 80g PVP K30s are taken, 4000g absolute ethyl alcohols are added, in 90 DEG C of heating water baths, makes formula
(I) compound and PVP K30 are completely dissolved, and are depressurized with Rotary Evaporators and boil off absolute ethyl alcohol, collect solid, put hot air circulation
4h is dried in 80 DEG C in baking oven, is crushed, cross 100 mesh sieves, obtain final product formula (I) compound solid dispersion.The solid dispersions
The dissolution rate of 45min is 82.2%, and its X-ray powder diffraction figure is shown in Fig. 4.
Embodiment 10：The preparation of the tablet containing formula (I) compound solid dispersion
Prescription (1000)：
Preparation technology：Solid dispersions, lactose, microcrystalline cellulose and the sodium carboxymethyl starch of recipe quantity are weighed, mixing is equal
It is even, it is wetting agent softwood with suitable quantity of water, with 20 mesh sieve series wet granulars, 4% is less than in 60 DEG C of dryings to pellet moisture, use 18 mesh
Sieve whole grain, adds the talcum powder of recipe quantity, is well mixed, and compressing tablet is obtained final product.
Embodiment 11：The preparation of the tablet containing formula (I) compound solid dispersion
Prescription (1000)：
Preparation technology：Solid dispersions, lactose, microcrystalline cellulose and the sodium carboxymethyl starch of recipe quantity are weighed, mixing is equal
It is even, it is wetting agent softwood with suitable quantity of water, with 20 mesh sieve series wet granulars, 4% is less than in 60 DEG C of dryings to pellet moisture, use 18 mesh
Sieve whole grain, adds the talcum powder and magnesium stearate of recipe quantity, is well mixed, and compressing tablet is obtained final product.
Embodiment 12：The preparation of the capsule containing formula (I) compound solid dispersion
Prescription (1000)：
Preparation technology：Solid dispersions, microcrystalline cellulose, lactose and the sodium carboxymethyl starch of recipe quantity are weighed, mixing is equal
It is even, it is wetting agent softwood with suitable quantity of water, with 20 mesh sieve series wet granulars, 4% is less than in 60 DEG C of dryings to pellet moisture, use 18 mesh
Sieve whole grain, adds recipe quantity magnesium stearate, is well mixed, and filling capsule is obtained final product.
Embodiment 13：The preparation of the granule containing formula (I) compound solid dispersion
Prescription (1000 bag)：
Preparation technology：Solid dispersions, lactose, soluble starch, microcrystalline cellulose and the carboxymethyl for weighing recipe quantity form sediment
Powder sodium, is well mixed, and is wetting agent softwood with suitable quantity of water, low to pellet moisture in 60 DEG C of dryings with 20 mesh sieve series wet granulars
In 4%, with 18 mesh sieve whole grains, packing is obtained final product.
Embodiment 14：Formula (I) compound solid dispersion tablet in treatment relapsed or stubborn periphery T cell of the present invention
The key II clinical trial phases of lymthoma
1st, the preparation of test medicine
20081020 batches of formula (I) compound solid dispersion tablets of the present invention：Take 180g formulas (I) compound and 900g
PVP K30, adds 36000g absolute ethyl alcohols, in 90 DEG C of heating water baths, is completely dissolved solid, is depressurized with Rotary Evaporators and steamed
Remove absolute ethyl alcohol, collect solid, to put and dry 2h in 80 DEG C in heated-air circulation oven, crush, cross 100 mesh sieves, obtain final product solid dispersion
Body；By gained solid dispersions and 1080g microcrystalline celluloses, 1800g lactose and 360g sodium carboxymethyl starches, it is well mixed, with
Suitable quantity of water is wetting agent softwood, whole with 18 mesh sieves in 60 DEG C of dryings to pellet moisture less than 4% with 20 mesh sieve series wet granulars
Grain, adds 180g talcum powder, mixes, and by 5mg specification compressing tablets, obtains final product.
20100322 batches of formula (I) compound solid dispersion tablets of the present invention：Take 160g formulas (I) compound and 800g
PVP K30, adds 32000g absolute ethyl alcohols, in 90 DEG C of heating water baths, is completely dissolved solid, is depressurized with Rotary Evaporators and steamed
Remove absolute ethyl alcohol, collect solid, to put and dry 2h in 80 DEG C in heated-air circulation oven, crush, cross 100 mesh sieves, obtain final product solid dispersion
Body；By gained solid dispersions and 960g microcrystalline celluloses, 1600g lactose and 320g sodium carboxymethyl starches, it is well mixed, with suitable
Amount water is wetting agent softwood, with 20 mesh sieve series wet granulars, in 60 DEG C of dryings to pellet moisture less than 4%, and with 18 mesh sieve whole grains,
160g talcum powder is added, is mixed, by 5mg specification compressing tablets, obtained final product.
20120509 batches of formula (I) compound solid dispersion tablets of the present invention：Take 158g formulas (I) compound and 790g
PVP K30, adds 31200g absolute ethyl alcohols, in 90 DEG C of heating water baths, is completely dissolved solid, is depressurized with Rotary Evaporators and steamed
Remove absolute ethyl alcohol, collect solid, to put and dry 2h in 80 DEG C in heated-air circulation oven, crush, cross 100 mesh sieves, obtain final product solid dispersion
Body；By gained solid dispersions and 948g microcrystalline celluloses, 1580g lactose and 316g sodium carboxymethyl starches, it is well mixed, with suitable
Amount water is wetting agent softwood, with 20 mesh sieve series wet granulars, in 60 DEG C of dryings to pellet moisture less than 4%, and with 18 mesh sieve whole grains,
158g talcum powder is added, is mixed, by 5mg specification compressing tablets, obtained final product.
2nd, testing program
This experiment is formula of the present invention (I) compound solid dispersion tablet in treatment relapsed or stubborn periphery T cell
The II clinical trial phases of lymthoma.Designed using single armed, nonrandom, open, polycentric II clinical trial phases.Observation PTCL suffers from
Efficacy and saferry of the person under fixed administering mode and dosage.Treatment is untill progression of disease or safety reasons are exited.
Whole experiment cut-off is treated and follow-up 1 month or stopped treatment or dead for any reason to all patient in group's completed 6 weeks.
3rd, the title of test medicine, specification, lot number, usage and dosage
Title：Formula (I) compound solid dispersion tablet of the present invention
Specification：5mg/ pieces
Lot number：20081020,20100322,20120509
Usage and dosage：Patient takes medicine in 30 minutes after meal in early with warm water 200mL.Take medicine weekly (Monday four twice
Administration or two or five administrations, the rest may be inferred), without the rest period of being discontinued, each medication dose is 30mg.
4th, result of the test
In the key II of formula of the present invention (I) compound solid dispersion tablet in treatment relapsed or refractory PTCL
In clinical trial phase, 83 patients of group are entered altogether, in complete analysis collection (FAS) patient, Overall response rate is 32.9% (26/79), its
In 8 patient's complete incidence graphs (10.1%), the uncertain complete incidence graphs (5.1%) of 4 patients, 14 patients parts are alleviated
(17.7%) more than 3 grades, relevant with the medication incidences of adverse reaction are 39%.
Embodiment 15：The II phases of formula (I) compound solid dispersion tablet in treatment CTCL of the present invention
Clinical test
1st, the preparation of test medicine
With embodiment 14.
2nd, testing program
This experiment is the II phases of formula of the present invention (I) compound solid dispersion tablet in treatment CTCL
Clinical test.Experiment is divided into two stages.First using multicenter, random, open design, two groups of patients of preliminary observation are in difference
Efficacy and saferry under doses at intervals mode (3 weeks treatment cycle groups and 6 weeks treatment cycle groups).Based on more than two groups be spaced to
The analysis of experiments result of medicine, sets successive administration group, observes efficacy and saferry.Every patient takes medicine to progression of disease or goes out
Now untill not tolerable toxic reaction.
3rd, the title of test medicine, specification, lot number, usage and dosage
Title：Formula (I) compound solid dispersion tablet of the present invention
Specification：5mg/ pieces
Lot number：20081020,20100322,20120509
Usage and dosage：Patient takes medicine in 30 minutes after meal in early with warm water 200mL.Take medicine weekly (Monday four twice
Administration or two or five administrations, the rest may be inferred), each medication dose is 30mg.After treatment cycle group patient continuously takes medicine 2 weeks within 3 weeks
It is discontinued and rests 1 week, rest 2 weeks of being discontinued after treatment cycle group patient continuously took medicine 4 weeks in 6 weeks, successive administration group patient stop without drug withdrawal
The breath phase.
4th, result of the test
In the clinical examination of the II phases of formula of the present invention (I) compound solid dispersion tablet in treatment CTCL
In testing, 52 patients of group are entered altogether, wherein 3 weeks treatment cycle groups 13,6 weeks treatment cycle groups 13, successive administration group 26.
In complete analysis collection (FAS) patient, Overall response rate is 32.0% (16/50), three groups of remission rate is respectively 33.3% (4/12),
23.1% (3/13), 36.0% (9/25), wherein 1 patient of successive administration group is complete incidence graph, and other obtain the patient alleviated
It is part alleviation.
Embodiment 16：Formula (I) compound solid dispersion tablet joint taxol of the present invention and Carboplatin in patients are non-small
The Ib clinical trial phases of cell lung cancer
1st, the preparation of test medicine
With embodiment 14.
2nd, testing program
This experiment is that formula of the present invention (I) compound solid dispersion tablet combines taxol and Carboplatin in patients is non-small thin
The Ib clinical trial phases of born of the same parents' lung cancer.Designed using opening, single centre, dosage escalation.Subject is Patients with Non-small-cell Lung, examination
Test middle taxol and carboplatin dose is fixed, only the dosage of incremental formula (I) compound.
For alleviation or the patient of stabilization, administering drug combinations are up to 4 cycles, for hereafter still in non-state of progress
Person, is changed to formula (I) compound single therapy, and dosage is constant, and all subjects treat to progression of disease or appearance and cannot tolerate
Toxicity untill.
3rd, the title of test medicine, specification, lot number, usage and dosage
(1) formula (I) compound solid dispersion tablet of the present invention
Specification：5mg/ pieces
Lot number：20100322,20120509
Usage and dosage：Patient takes medicine in 30 minutes after meal in early with warm water 200mL.Take medicine weekly (Monday four twice
Administration or two or five administrations, the rest may be inferred), had a rest the phase without drug withdrawal.According to a group order is entered, the dosage that patient per takes is respectively
20mg, 30mg and 25mg.
(2) paclitaxel injection, carboplatin injection
Paclitaxel injection (PTX) and carboplatin injection (Paraplatin) are obtained by commercially available approach.
Usage and dosage：Each treatment cycle is three weeks, and all patient's each cycles give drip-feed taxol on the 5th day
175mg/m2, carboplatin AUC=5mg/mLmin.
4th, result of the test
This experiment enters 10 patients of group, wherein 20mg groups 3,30mg groups 4,25mg groups 3 altogether.The dosage limit of this experiment
Property toxicity processed is reacted for haematics toxicity.There is 1 patient to obtain part in 20mg groups to alleviate；5 patients for having brain metastes focus
After through treatment, 2 brain metastes stoves of patient all disappear.
Embodiment 17：Formula (I) Compound ira vitro cell growth inhibition test
1st, test method
Growth inhibition ratio is determined with MTS methods.Be inoculated with 96 orifice plates cell per well to be measured 5000 (the different speeds of growth
Cell inoculum concentration is different), culture adds formula (I) compound of various concentrations after 24 hours, add per hole after continuing to cultivate 48 hours
Enter 20 μ lMTS detection substrates (Promega), 37 DEG C be incubated 2 hours after read result with 490nm wavelength on ELIASA.Relatively
Amount of viable cell is calculated with experimental group/control group × 100%, and formula (I) compound concentration that cell growth suppresses 50% is designated as
GI50.Formula (I) compound is dissolved in DMSO, and 1 is carried out in dosing:1000 dilution, makes final concentration≤0.1% of DMSO.
Each experiment is independent in triplicate.
2nd, result of the test
Result of the test is shown in Table 4.
Table 4 formula (I) Compound ira vitro CA result
The measurement result of table 17 shows：Growth of formula (I) compound to normal cell, solid tumor cell and blood tumor cell
The middle position GI of suppression50Value is respectively 60 μM, 6.65 μM and 1.21 μM, and formula (I) compound needs concentration higher could be to normal
Cell produces direct CDCC.
Embodiment 18：The human pharmacokineticses research of formula (I) compound solid dispersion tablet of the present invention
The present embodiment is formula of the present invention (I) compound solid dispersion tablet in 33 late period Lymphomas (21
Example PTCL, 12 CTCL) in carry out human pharmacokineticses research.
1st, the preparation of test medicine
With embodiment 14.
2nd, testing program
With embodiment 14-15.Patient first take medicine after blood sampling time point be administration before and be administered after 1,2,6,12,
24th, 48 and 72h (8 time points).
3rd, the title of test medicine, specification, lot number, usage and dosage
Title：Formula (I) compound solid dispersion tablet of the present invention
Specification：5mg/ pieces
Lot number：20081020,20100322,20120509
Usage and dosage：Patient takes medicine in 30 minutes after meal in early with warm water 200mL, and dosage is 30mg.
4th, experiment material and reagent
Chromatographic Pure Methanol is purchased from Fisher companies；ACS grades of formic acid is purchased from sigma companies；Self-control tri-distilled water；Argon gas (>=
And liquid nitrogen (>=99.999%) is really letter industrial gasses marketing center purchased from Beijing 99.999%)；Blank human normal plasma is by solving
The hospitals of Fang Jun 307 provide.
5th, laboratory apparatus and method
Instrument：Surveyor plus efficient liquid phase systems, equipped with automatic sampler, column oven and MS pumps, TSQ
Quantumultra mass spectrographs, the softwares of XcalIIur 2.0, purchased from Thermo Electron companies.
Chromatographic condition：Hypersil GOLD chromatographic columns, 100mm × 2.1mm, 5 μm；Water (containing 0.1% formic acid) ,-methyl alcohol (contained
0.1% formic acid) it is mobile phase, the methyl alcohol of 0-2min 5%, 2-2.5min 5%-95% methyl alcohol, the methyl alcohol of 2.5-5min 95%, 5-
5.5min95%-5% methyl alcohol, the methyl alcohol of 5.5-7min 5%；Flow velocity：0.2mL·min-1；Sample size：5μL.
Mass Spectrometry Conditions：Ionization mode+ESI；Spray voltage 4500V；Sheath gas 30psi；Auxiliary gas velocity 2psi；Capillary
300 DEG C of heating-up temperature；Source inducement voltage -10V；Collision atmospheric pressure 1.5psi；Scan pattern Selective reaction monitoring (SRM), monitoring
Ionic reaction is m/z 391.1 → 265.1 (formula (I) compound), m/z 377.1 → 359.2 (MS275)；Run time 7min.
The preparation of stock standard solutions：A certain amount of formula (I) compound and MS275 are weighed, is dissolved in methyl alcohol, be made
The storing solution of 1mg/mL, 4 DEG C of preservations of refrigerator.
The preparation of calibration standard curve sample and quality-control sample：Formula (I) compound stock solution is diluted to the work of series concentration
Make solution, 10 μ l working solutions are added in 90 μ l blood plasma formula (I) the compound standard plasma solutions for being made 1-1000ng/mL.
The preparation method of Quality control samples is identical with calibration standard curve sample, and the concentration of quality-control sample is 2,5,10,1000ng/
mL。
Sample treatment：100 μ L plasma samples (standard curve, Quality Control or clinical sample) are taken, 150 μ L acetonitriles are added
(MS275 containing 100ng/mL) protein precipitation, vortex mixed 1min, 17,000 × g centrifugation 20min, draws supernatant, 5 μ L sample introductions.
6th, plasma sample collection and preservation
Patient is centrifuged 10 points in 1,2,6,12,24,48 and 72h gathers whole blood 3-4mL before administration and after administration after mixing
Clock, takes supernatant blood plasma, is frozen in -20 DEG C of refrigerators.
7th, result of the test：
33 late period Lymphomas (21 PTCL, 12 CTCL) single oral 30mg formulas of the present invention (I) after the meal
After compound solid dispersion tablet, medicine is presented obvious absorption and elimination process in vivo, and body absorption exists certain
Individual difference, but blood medicine peak time (Tmax) and maximum plasma concentration (Cmax) of Most patients be closer to, and it is put down
Equal blood medicine peak time (Tmax) is 3.9 ± 3.5h, and maximum plasma concentration (Cmax) is 59.6 ± 47.0ng/mL
(152.66nM)。
Obviously, late in Lymphoma, formula of the present invention (I) compound solid dispersion of 30mg dosage is taken
Tablet, maximum plasma concentration (Cmax) is 0.153 μM in its patient's body, and the concentration is well below in vitro for normal cell, reality
The growth inhibiting middle position GI of body oncocyte and blood tumor cell50Value (respectively 60 μM, 6.65 μM and 1.21 μM), shows this
Preparation is less likely to produce direct cellulotoxic effect.
The explanation of above example is only intended to help and understands the present invention and its core concept.It should be pointed out that for this skill
For the those of ordinary skill in art field, under the premise without departing from the principles of the invention, some changing can also be carried out to the present invention
Enter and modify, these are improved and modification is also fallen into the protection domain of the claims in the present invention.
Claims (8)
1. a kind of E benzamide compound shown in formula (I), its chemical name is N- (2- amino -4- fluorophenyls) -4-
[N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide, in its structural formula, the configuration of 3- pyridine acryloyl groups
It is E types,
2. the preparation method of E benzamide compound shown in formula (I) described in a kind of claim 1：
A () is by trans -3- (3- pyridines) acrylic acid and N, N '-carbonyl dimidazoles (CDI) reaction obtains (E) -3- (3- pyridines) third
Enoyl- imidazoles reactive intermediate, then obtains 4- [N- [(E) -3- (3- pyridines) acryloyls with the reaction of Aminomethylbenzoic Acid sodium
Base] aminomethyl] Sodium Benzoate, then obtain 4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzene first through hydrochloric acid acidifying
Acid；
B () is by 4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoic acid and N, N '-carbonyl dimidazoles (CDI) reaction
4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzoyl imidazoles reactive intermediate is obtained, then with 4- fluorine neighbour's benzene two
Amine reaction obtains N- (2- amino -4- fluorophenyls) -4- [N- [(E) -3- (3- pyridines) acryloyl group] aminomethyl] benzamide.
3. a kind of pharmaceutical formulation, it is characterised in that comprising formula (I) compound and pharmaceutic adjuvant described in claim 1.
4. a kind of solid dispersions, it is characterised in that by formula (I) compound
With water soluble carrier material composition, formula (I) compound is 1 with the weight ratio of water soluble carrier material:1~1:20.
5. solid dispersions as claimed in claim 4, it is characterised in that the water soluble carrier material is PVP, poly- second
Glycol or poloxamer.
6. solid dispersions as claimed in claim 4, it is characterised in that the water soluble carrier material is PVP K30.
7. the preparation method of the solid dispersions described in claim 4, it is characterised in that weigh formula (I) compound and water respectively
Solubleness carrier material, adds organic solvent, is heated to formula (I) compound and water soluble carrier material is completely dissolved, and then boils off
Organic solvent, collects solid, dry, pulverize and obtains final product.
8. a kind of pharmaceutical formulation, it is characterised in that comprising solid dispersions and pharmaceutic adjuvant described in claim 4.
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| TWI808055B (en) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Combination therapies of hdac inhibitors and pd-1 inhibitors |
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| CN106242992A (en) * | 2016-07-25 | 2016-12-21 | 北京化工大学 | A kind of benzamide compound and the application in the medicine preparing anticancer propagation and/or treatment cancer thereof |
| CN106496053B (en) * | 2016-09-22 | 2018-01-05 | 潍坊医学院 | A kind of inhibitors of histone deacetylase N (2 ' aminocarbonyl phenyl) 4 (double (2 chloroethyl) amidos) benzamide and its preparation method and application |
| CN107865826B (en) * | 2016-09-27 | 2020-06-30 | 深圳微芯生物科技股份有限公司 | Solid dispersion of E-configuration benzamide compound |
| US20190046513A1 (en) * | 2017-08-10 | 2019-02-14 | Huya Bioscience International, Llc | Combination therapies of hdac inhibitors and tubulin inhibitors |
| CN112438978B (en) * | 2019-08-28 | 2024-03-01 | 深圳微芯生物科技股份有限公司 | Sidamide pharmaceutical composition and preparation method and application thereof |
| CN117597124A (en) * | 2021-07-08 | 2024-02-23 | 深圳微芯生物科技股份有限公司 | Siro-lonib and application of Siro-lonib in combined drug treatment of breast cancer |
| CN115703736B (en) * | 2021-08-04 | 2025-05-16 | 中国海洋大学 | Multi-target inhibitors targeting HDAC and NAD synthesis and uses thereof |
| CN115322171B (en) * | 2022-08-30 | 2023-03-17 | 深圳微芯生物科技股份有限公司 | TRKA (G667C) and FLT3 target inhibitor and composition of TRKA and FLT3 target inhibitor and cydapamide |
| CN120282948A (en) * | 2022-12-07 | 2025-07-08 | 微境生物医药科技(上海)有限公司 | HDAC inhibitor and application thereof |
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