WO2015149435A1 - Composé de benzamide en configuration e et formulation pharmaceutique et application correspondantes - Google Patents

Composé de benzamide en configuration e et formulation pharmaceutique et application correspondantes Download PDF

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WO2015149435A1
WO2015149435A1 PCT/CN2014/080585 CN2014080585W WO2015149435A1 WO 2015149435 A1 WO2015149435 A1 WO 2015149435A1 CN 2014080585 W CN2014080585 W CN 2014080585W WO 2015149435 A1 WO2015149435 A1 WO 2015149435A1
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compound
formula
solid dispersion
water
preparation
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PCT/CN2014/080585
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Chinese (zh)
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鲁先平
李志斌
徐学奎
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深圳微芯生物科技有限责任公司
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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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention belongs to the field of chemical pharmacy, and particularly relates to an E-configuration benzamide compound, a medicinal preparation and application.
  • Histone deacetylase is a class of enzymes that catalyze the acetylation of lysine from histones. It plays a key role in staining shield pyknosis and staining shield remodeling and the regulation of the genes involved. An important component of epigenetic regulation. HDAC consists of four different subtypes of 18 classes (Class I: HDAC1, 2, 3, 8; Class II: HDAC4, 5, 6, 7, 9, 10; Class III: Sirtl-7; Class IV: HDAC11) .
  • HDAC and histone acetyltransferase together regulate the acetylation of histones, HAT acetylates specific lysine (Lys) residues on histones, and HDAC is responsible for removing this residue modification.
  • the acetylation of histones makes the stained shield structure loose, which facilitates the binding of other DNA-binding proteins (such as transcription factors), so the acetylation of histones can activate the transcription process of specific genes (remodeling of staining shields).
  • HDAC also regulates the acetylation of some non-histone proteins, such as transcriptional regulators (P53, F-KB, etc.), stress response proteins (Hsp70/90, etc.), and cellular structural molecules (Tubulin et al). Etc., further affecting cell proliferation and other biological processes (Haberland M, Montgomery RL, Olson EN. The many roles of hi stone 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).
  • Histone deacetylase inhibitors are one of the hotspots in the field of antitumor drug research in recent years. Studies have shown that histone deacetylase inhibitors can effectively inhibit tumor cell proliferation, induce tumor cell differentiation, induce tumor cell apoptosis and anti-tumor angiogenesis, and inhibit tumor cell migration, invasion and metastasis ( Kim HJ, Bae SC. Hi stone 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 Nat Rev Drug Discov 2002; 1(4): 287-299; Tan J, Zhuang L.
  • Apoptosis signal regulating kinase 1 is a direct target of E2F1 and contributes to hi stone deacetylase inhibitor induced apoptosis through positive feedback regulation of E2F 1 Apoptotic activity.
  • Histone deacetylase inhibitors can be classified into four major classes according to their chemical structures, namely, hydroxamic acids, cyclic tetrapeptides, short-chain fatty acids, and benzamides.
  • the first three major classes of compounds inhibit all HDAC subtypes of class I and class II, and are HDAC non-selective inhibitors.
  • Known benzamides show selectivity for target action, mainly inhibiting class I HDACs (including HDAC). Subtypes 1, 2, 3, but do not inhibit HDAC8).
  • Vorinostat is a hydroxamic acid histone deacetylase inhibitor. After completing Phase II clinical trials, it was approved by the US FDA at the end of 2006 for cutaneous T lymphoma (CTCL). Developed for indications; Romidepsin (FK228), developed by Celgene, USA, is a cyclotetrapeptide histone deacetylase inhibitor, approved by the US FDA for marketing for CTCL in 2009, and was approved by the US FDA in 2011. Approved for treatment for relapsed/refractory PTCL. However, since both SAHA and FK228 are HDAC non-selective inhibitors and inhibit too many cellular signaling pathways, their toxic side effects are strong.
  • Entinostat developed by Bayer of Germany and Syndax of the United States, is a benzamide compound. , pre-clinical animal tests show that the compound has significant anti-cancer activity against blood cancer, lung cancer, rectal cancer, etc. (Saito A. A synthetic inhibitor of hi stone deacetylase, MS-275, with marked in vivo antitumor activity against human tumors. PNAS 1999, 96(8): 4592-4597). Although MS-275 is a selective inhibitor of HD AC, it is extremely poor in phase I clinical trials due to its poor pharmacokinetic properties in humans (clear half-life is close to 100 hours and individual differences in drug exposure). Tolerance, the dose cannot be increased, and thus the effectiveness of the single-agent clinical trial cannot be guaranteed.
  • the present applicant discloses a novel benzamide histone deacetylase inhibitor CS02100055, which has the chemical name N-(2-amino-4-fluorobenzene, in Example 2 of U.S. Patent No. 7,244,751 B2. -4-[N-(3-pyridineacryloyl)aminomethyl]benzamide, which inhibits total histone deacetylase
  • a solid dispersion with polyvinylpyrrolidone and the application document CM03432077A also does not disclose N-(2--4-fluorophenyl)-4-[N-(3-pyridineacryloyl)aminomethyl]benzamide and Any physicochemical parameter of the solid dispersion formed by polyvinylpyrrolidone (eg, solubility data for solid dispersion, dissolution data, or X-ray powder diffraction pattern).
  • a solid dispersion of acryloyl]aminomethyl]benzamide with polyvinylpyrrolidone and the application document CN103432077A also does not disclose ⁇ -(2-amino-4-fluorophenyl)-4-[ ⁇ -[(£) Any physicochemical parameters of a solid dispersion of -3-(3-pyridine)acryloyl]aminomethyl]benzamide with polyvinylpyrrolidone (eg solubility data, dissolution data or X-ray powder diffraction pattern of solid dispersion) ).
  • One of the objects of the present invention is to disclose a quinone-type benzamide compound having a subtype-selective histone deacetylase inhibitory activity.
  • the second object of the present invention is to disclose a process for the preparation of the compound.
  • a second object of the invention is to disclose a pharmaceutical formulation of the compound.
  • the fourth object of the present invention is to disclose the use of the compound in the preparation of a medicament for treating cancer.
  • the compound of the present invention has the structure represented by the formula (I), and its chemical name is ⁇ -(2-amino-4-fluorophenyl)-4-[ ⁇ -[(£)-3-(3-pyridine) Acrylo]aminomethyl]benzamide, in which the configuration of the 3-pyridine acryloyl group is a type,
  • the preparation method of the compound of the present invention is as follows:
  • the compound of the present invention is a subtype-selective histone deacetylase inhibitor, mainly inhibiting the first
  • HDAC1 in HDAC1, HDAC2, HDAC3, and HDAC10 in Class lib HDAC do not inhibit HDAC6, 7 and 9, and have weaker inhibition of HDAC8 and 11.
  • the compound of the present invention has more than N-(2-amino-4-fluorophenyl)-4-[N-(3-pyridineacryloyl)aminomethyl]benzamide (i.e., a mixture of E and Z). Good histone deacetylase inhibitory activity.
  • the half-enzyme inhibitory concentrations (IC 50 ) of the compounds of the invention for HDAC1, HDAC2, HDAC3, and HDAC10 were 95 nM, 160 nM, 67 nM, and 78 nM, respectively, whereas the half-enzyme activity of the E-type and Z-type mixtures for HDAC1, HDAC2, HDAC3, and HDAC10, respectively.
  • Inhibitory concentrations (IC 50 ) were 172 nM, 345 nM, 129 nM and 143 nM 0
  • the compounds of the invention may be used to treat diseases associated with abnormal histone deacetylase activity, such as cancer, including lymphomas, solid tumors, and hematological tumors.
  • the compounds of the present invention are processed into conventional pharmaceutical preparations such as tablets, capsules, injections and the like.
  • the preparation may be 1 to 50% of the compound of the formula (I) and 50 to 99% of a pharmaceutical excipient.
  • the pharmaceutical excipients include the Handbook of Pharmaceutical Excipients (The Fourth Edition of the Handbook of Pharmaceutical Excipients) published by the Handbook of Pharmaceutical Excipients (American Pharmaceutical Association, October 1986) or Chemical Industry Press.
  • the carrier adjuvants are listed, but are not limited to these pharmaceutical excipients.
  • the compounds of the present invention can be administered clinically by oral or injection, with oral administration being most preferred.
  • the dosage is 0.01 200 mg/kg body weight per day, and the optimal dosage is 0.1 ⁇ 50 mg/kg body weight per day.
  • the oral solid preparation After the oral solid preparation enters the body, it needs to undergo a dissolution process to be absorbed by the body through the biofilm.
  • the poorly soluble drug affects the absorption of the drug because its dissolution rate is limited by the solubility, so the effect is slow and the bioavailability is low.
  • the compound of the present invention has extremely low solubility in water, is almost insoluble, and has low bioavailability, so that it is important to increase its dissolution rate and bioavailability.
  • the present invention provides a solid dispersion which improves the water solubility of the compound of formula (I), increases its dissolution rate and bioavailability.
  • the solid dispersion is composed of a compound of the formula (I) and a water-soluble carrier material, and the weight ratio of the compound of the formula (I) to the water-soluble carrier material is from 1:1 to 1:20.
  • Applicants have found through research that the compound of formula (I) is combined with a water-soluble carrier material in a weight ratio of 1:1-1:20, and the compound of formula (I) can be highly dispersed in a water-soluble carrier material in a molecular form or in an amorphous state.
  • the weight ratio of the compound of formula (I) to the water-soluble carrier material is 1:1; in some embodiments, the weight ratio of the compound of formula (I) to the water-soluble carrier material is 1:5; In some embodiments, the weight ratio of the compound of formula (I) to the water soluble carrier material is 1:20.
  • the water-soluble carrier material in the solid dispersion of the compound of the formula (I) of the present invention is a poly
  • the ketene, polyethylene glycol or poloxamer is more preferably povidone K30.
  • the invention also provides a process for the preparation of the solid dispersion of the compound of formula (I).
  • the method comprises: weighing the compound of the formula (I) and the water-soluble carrier material separately, adding an organic solvent, heating to the compound of the formula (I) and the water-soluble carrier material, completely dissolving, then evaporating the organic solvent, collecting the solid, drying, Smash it.
  • the weight ratio of the compound of the formula (I) to the water-soluble carrier material is preferably from 1:1 to 1:20.
  • the water-soluble carrier material is preferably povidone, polyethylene glycol or poloxamer, more preferably povidone oxime 30.
  • the organic solvent is preferably anhydrous ethanol, 95% ethanol, methanol, acetonitrile or acetone.
  • the weight ratio of the compound of the formula (I) to the organic solvent is preferably 1:100 to 1:1000, more preferably 1:200 to 1:1000. In some embodiments, the weight ratio of the compound of formula (I) to the organic solvent is 1:200; in some embodiments, the weight ratio of the compound of formula (I) to the organic solvent is 1:250; In some embodiments, the weight ratio of the compound of formula (I) to the organic solvent is 1:1000.
  • the heating is preferably 60 ° C to 90 ° C heating.
  • the evaporation of the organic solvent includes, but is not limited to, evaporation of the organic solvent under reduced pressure using a rotary evaporator.
  • the drying is preferably from 60 ° C to 80 ° C for 2 h to 8 h, in some embodiments, 60 ° C for 8 h; in some embodiments, 80 ° C for 2 h; in other embodiments In the scheme, it is dried at 80 ° C for 4 h.
  • the comminution is preferably pulverized through a 60 100 mesh sieve.
  • the present invention detects the solubility of the solid dispersion of the compound of the formula (I) in water, and the result shows that the solubility of the compound of the formula (I) in water is 4.64 g/mL; and the compound of the formula (I) and povidone K30
  • the solubility of the solid dispersion prepared in a weight ratio of 1:5 in water [based on the compound of the formula (1)] was 66.7 g/mL, which was 14.4 times higher than that of the compound of the formula (I), indicating the formula of the present invention ( I)
  • the solid dispersion of the compound increases the solubility of the compound of formula (I) and accelerates its dissolution rate.
  • the present invention also employs an in vitro dissolution test to separately determine a compound of the formula (I), and a solid dispersion of the compound of the formula (I) and povidone K30 in a weight ratio of 1:1, and the embodiment 8 (I) a solid dispersion of the compound and povidone K30 in a weight ratio of 1:5, and a solid dispersion of the compound of formula (I) and povidone K30 in a weight ratio of 1:20
  • the sample sizes of the four samples were 100 mg, 200 mg, 600 mg, and 2100 mg, respectively.
  • the determination method is as follows: according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), using water 1000mL as the dissolution shield, the rotation speed is 50rpm, according to the law, after 45min, take the solution 10mL filtered, continue The filtrate was diluted 20 times with water as the test solution; another 25 mg of the compound of formula (I) was accurately weighed, placed in a lOOmL volumetric flask, and dissolved in an appropriate amount of 95% ethanol, diluted to the mark, and accurately transferred from 1 mL to 50 mL.
  • the present invention also provides an in vitro dissolution test for the determination of a tablet containing the solid dispersion of the compound of the formula (I) prepared in accordance with Example 11 and the use of the compound of the formula (I) prepared in accordance with Example 4 using the same formulation. Dissolution of the tablets.
  • the determination method is as follows: Take 6 samples, according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC second method), use water 1000mL as the dissolution shield, the rotation speed is 50rpm, operate according to law, after 45min, take the solution 10mL Filtration, take the filtrate as the test solution; another compound of formula (I) about 25mg, accurately weighed, placed in a lOOmL volumetric flask, add 95% ethanol to dissolve in the appropriate amount, dilute to the mark, accurately transfer lmL to A 50 mL volumetric flask was diluted with 7j to obtain a solution containing about 5 g per i m L as a reference solution; the absorbance was measured by ultraviolet-visible spectrophotometry at a wavelength of 258 nm, and the dissolution was calculated.
  • the present invention also investigates the prepared solid dispersion of the compound of the formula (I) by X-ray powder diffraction.
  • the X-ray powder diffraction pattern of the compound of formula (I) there is a strong diffraction peak in the region of 3 to 50° (Fig. 1); the solid dispersion prepared in Example 7, the solid dispersion prepared in Example 8, and the implementation
  • the characteristic diffraction peak of the compound of the formula (I) exhibits a characteristic dispersion peak of an amorphous solid (Fig. 2, Fig. 3 and Fig.
  • the solid dispersion of the compound of the formula (I) of the present invention can be combined with a conventional pharmaceutical excipient to prepare a pharmaceutical preparation having a cancer-treating function, including an oral solid preparation such as a tablet, a capsule or a granule.
  • the pharmaceutical preparation of the present invention may contain 5 wt% to 50 wt% of the (I) solid dispersion of the compound and 50 wt% to 95 wt% of the excipient.
  • the pharmaceutical excipients including glidants, such as talc, magnesium stearate, micronized silica gel, etc., include disintegrating agents such as sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, and the like. Fillers such as lactose, microcrystalline cellulose, starch, and the like are included.
  • the present invention utilizes a solid dispersion made from a compound of formula (I) and povidone K30 in a weight ratio of 1:5.
  • the tablet was examined for clinical efficacy.
  • a phase II clinical trial of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) showed a total response rate of 32.9%, a drug-related grade 3 or higher adverse event rate of 39%, and low toxic side effects.
  • PTCL peripheral T-cell lymphoma
  • the overall response rate was 32.0%
  • the lb phase clinical trial of paclitaxel and carboplatin in the treatment of non-small cell lung cancer showed a total response rate of 10%.
  • cancer is a lymphoma, a solid tumor or a hematological tumor, preferably peripheral T cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL) and lung cancer.
  • PTCL peripheral T cell lymphoma
  • CTCL cutaneous T-cell lymphoma
  • the present invention utilizes a tablet of a solid dispersion prepared from a compound of formula (I) and povidone K30 in a weight ratio of 1:5. 33 patients with advanced lymphoma (21 PTCL, 12 CTCL) orally administered 30 mg of the above solid.
  • Human pharmacokinetic studies of dispersible tablets have a defined clinical therapeutic efficacy as described above, with acceptable tolerance to the patient.
  • the concentration of the absorption peak directly associated with clinical effectiveness in the patient, ie, the maximum plasma concentration (Cmax) is significantly lower than the concentration required to inhibit normal or tumor cell growth in vitro, thereby not directly cytotoxic to normal cells. Rather, it has epigenetic regulation of tumor cells. Its human tolerance is significantly improved, indicating that the tablet of this oral solid dispersion has the advantage of improving the safety of the drug.
  • Figure 1 shows an X-ray powder diffraction pattern of the compound of formula (I);
  • Figure 2 shows an X-ray powder diffraction pattern of the compound of formula (I) - Povidone K30 solid dispersion (weight ratio of 1:1) prepared in Example 7;
  • Figure 3 shows an X-ray powder diffraction pattern of the compound of formula (I) - Povidone K30 solid dispersion (weight ratio of 1:5) prepared in Example 8;
  • Figure 4 shows the compound of formula (I) - Povidone K30 solid dispersion prepared in Example 9 (weight ratio is
  • Figure 5 shows an X-ray powder diffraction pattern of povidone K30
  • Figure 6 shows an X-ray powder diffraction pattern of the compound (I) compound-povidone K30 mechanical mixture (weight ratio of 1:1);
  • Figure 7 shows an X-ray powder diffraction pattern of the compound (I)-Povidone K30 mechanical mixture (weight ratio of 1:5);
  • Figure 8 shows an X-ray powder diffraction pattern of the compound of formula (I) - Povidone K30 mechanical mixture (weight ratio of 1:20).
  • the present invention discloses a subtype-selective histone deacetylase inhibitory activity.
  • Dissolution measurement conditions Instrument: RC806 drug dissolution tester; dissolution medium shield: water lOOOOmL; rotation speed: 50 rpm, temperature: 37 ⁇ 0.5 °C.
  • the filter cake was rinsed with 400 mL of water and 400 mL of anhydrous ethanol, respectively, and vacuumed to obtain a crude product.
  • the crude product was dissolved in 2000 mL of 1 mol/L sodium hydroxide solution, neutralized with concentrated hydrochloric acid until the pH was equal to 4, filtered, and the filter cake was rinsed with 400 mL of water and 400 mL of anhydrous ethanol respectively, and the vacuum was dried to obtain 4-[N -[(£)-3-(3-Pyridinyl)acryloyl]aminomethyl]benzoic acid, weight 298 g, yield 52.8%, content 99.57% (determined by HPLC method).
  • the crude product was dissolved in 1200 mL of 2 mol/L hydrochloric acid, 960 mL of 1 mol/L NaOH solution was added dropwise, stirred for about 10 minutes, filtered, and the filter cake was rinsed with 400 mL of water, transferred to a 10 liter reaction bottle, and added with 6000 mL of water and 1200 mL.
  • Example 3 Determination of inhibitory activity of test compounds on different subtypes of HDAC
  • HDAC1 11 the inhibitory activity of the test compounds on different subtypes of HDAC was determined using a deacetylase assay kit manufactured by BSP Bioscoence, and calculated. Half of its enzyme inhibition concentration (IC 50 ).
  • the enzymatic activity of the test compound treated with different concentration gradients was calculated to obtain a dose-dependent enzymatic activity curve, and the semi-inhibitory concentration (IC 50 ) of the test compound to inhibit different HDAC subtypes was obtained by statistical calculation.
  • the compound of the formula (I) of the present invention is more specific than N-(2-amino-4-fluorophenyl)-4-[N-(3-pyridineacryloyl)aminomethyl]benzamide (ie, type E and Z-type mixture) has better inhibitory activity against HDAC 1, 2, 3 and 10.
  • Example 5 Preparation of a general capsule containing a compound of formula (I)
  • Preparation process Compound of formula (I) After 100 mesh sieve, weigh the prescribed amount of the compound of formula (I), povidone K30, microcrystalline cellulose, lactose and sodium carboxymethyl starch, mix well, use appropriate amount of water as a wetting agent to make soft materials, use 20 Mesh the wet granules, dry at 60 °C until the granules moisture is less than 4%, sift the granules with a 18 mesh sieve, add the prescribed amount of magnesium stearate, mix well, and fill the capsules.
  • Example 6 Preparation of ordinary granules containing a compound of formula (I)
  • Example 7 Preparation of Compound of Formula (I) - Povidone K30 Solid Dispersion (1:1 by Weight) 4 g of the compound of formula (I) and 4 g of povidone K30 were added, and 800 g of absolute ethanol was added at 60 °. C water bath plus Heat, completely dissolve the compound of formula (I) and povidone K30, distill off anhydrous ethanol under reduced pressure on a rotary evaporator, collect the solid, and dry it in a hot air circulating oven at 60 ° C for 8 h, crush, pass 60 mesh sieve That is, a solid dispersion of the compound of the formula (I) is obtained.
  • the solid dispersion had a dissolution rate of 60.3% at 45 minutes, and its X-ray powder diffraction pattern is shown in Fig. 2.
  • Example 8 Preparation of compound of formula (I) - Povidone K30 solid dispersion (weight ratio 1:5) 4 g of compound of formula (I) and 20 g of povidone K30 were added, and 1000 g of absolute ethanol was added at 90°. C 7j bath heating, the compound of formula (I) and povidone K30 were completely dissolved, anhydrous ethanol was evaporated under reduced pressure on a rotary evaporator, and the solid was collected, and placed in a hot air circulating oven at 80 ° C for 2 h, pulverized, passed A 100 mesh sieve gives a solid dispersion of the compound of formula (I). The solid dispersion had a dissolution rate of 79.1% at 45 min, and its X-ray powder diffraction pattern is shown in Fig. 3.
  • Example 9 Preparation of Compound of Formula (I) - Povidone K30 Solid Dispersion (weight ratio 1:20) 4 g of the compound of formula (I) and 80 g of povidone K30 were added, and 4000 g of absolute ethanol was added at 90 °. C water bath heating, the compound of formula (I) and povidone K30 were completely dissolved, and anhydrous ethanol was evaporated under reduced pressure on a rotary evaporator, and the solid was collected, placed in a hot air circulating oven at 80 ° C for 4 h, pulverized, passed through 100 Mesh screening, that is, a solid dispersion of the compound of formula (I). The solid dispersion had a dissolution rate of 82.2% at 45 min, and its X-ray powder diffraction pattern is shown in Fig. 4.
  • Example 10 Preparation of tablets containing solid dispersion of the compound of the formula (I) (1000 tablets): Compound of the formula (I) - Povidone K30 solid dispersion (weight ratio 1:5) 30 g Lactose 50 g Micro Crystalline cellulose 30 g sodium carboxymethyl starch 10 g talc powder 5 g Preparation process: Weigh the prescribed amount of solid dispersion, lactose, microcrystalline cellulose and sodium carboxymethyl starch, mix well, and moisten with appropriate amount of water The soft material is made into a soft material, and the wet granules are sieved with a 20 mesh sieve, and dried at 60 ° C until the granule moisture is less than 4%.
  • Example 11 Preparation of tablets containing solid dispersion of the compound of formula (I) (1000 tablets): Compound (I) - Povidone K30 solid dispersion (weight ratio 1:5) 30 g Lactose 50 g Microcrystalline cellulose 30 g Sodium carboxymethyl starch 10 g Talc powder 5 g Magnesium stearate 0.2 g Preparation Process: Weigh the prescribed amount of solid dispersion, lactose, microcrystalline cellulose and sodium carboxymethyl starch, mix evenly, make soft material with proper amount of water as wetting agent, wet the particles with 20 mesh sieve, at 60 °C After drying to a particle size of less than 4%, use a 18 mesh sieve to granulate, add a prescribed amount of talc and magnesium stearate, mix well, and obtain the tablets.
  • Example 12 Preparation of a capsule containing a solid dispersion of the compound of the formula (I) (1000 capsules): Compound of the formula (I) - Povidone K30 solid dispersion (weight ratio 1:5) 30 g of microcrystalline fiber 55 g Lactose 35 g Sodium carboxymethyl starch 5 g Magnesium stearate 0.5 g Preparation process: Weigh the prescribed amount of solid dispersion, microcrystalline cellulose, lactose and sodium carboxymethyl starch, mix well, with appropriate amount of water For the soft material made of wetting agent, use 20 mesh sieve to make wet granules, dry at 60 °C until the granule moisture is less than 4%, sift the granules with 18 mesh, add the prescribed amount of magnesium stearate, mix well, fill The capsule is available.
  • Example 13 Preparation of granules containing solid dispersion of the compound of formula (I) (1000 packs): Compound of formula (I) - Povidone K30 solid dispersion (weight ratio 1:5) 30 g Soluble starch 500 g Microcrystalline cellulose 175 g sodium carboxymethyl starch 100 g Preparation process: Weigh the prescribed amount of solid dispersion, lactose, soluble starch, 4 crystal cellulose and sodium carboxymethyl starch, mix well, and moisten with appropriate amount of water.
  • the soft material is made into a soft material, and the wet granules are sieved with a 20 mesh sieve, and dried at 60 ° C until the granule moisture is less than 4%, and the granules are sieved with a 18 mesh sieve, and the mixture is obtained by dispensing.
  • Example 14 The key phase II clinical trial of the solid dispersion tablet of the compound of the formula (I) for treating relapsed or refractory peripheral T cell lymphoma
  • 20081020 batch of the solid dispersion tablet of the compound of the formula (I) of the present invention 180 g of the compound of the formula (I) and 900 g of povidone K30 are added, 36,000 g of absolute ethanol is added, and the mixture is heated in a water bath at 90 ° C to completely dissolve the solid.
  • the anhydrous ethanol was evaporated under reduced pressure on a rotary evaporator, and the solid was collected, dried in a hot air circulating oven at 80 ° C for 2 h, pulverized, and passed through a 100 mesh sieve to obtain a solid dispersion; the obtained solid dispersion and 1080 g of microcrystalline fiber were obtained.
  • Test plan This test is a phase II clinical trial of a solid dispersion tablet of a compound of formula (I) according to the invention for the treatment of relapsed or refractory peripheral T-cell lymphoma.
  • Treatment until withdrawal from disease progression or safety reasons.
  • the entire trial ended until all enrolled patients completed 6 weeks of treatment and were followed for 1 month or discontinued treatment or died for any reason.
  • Dosage The patient takes the medicine with warm water of 200mL 30 minutes after breakfast. Take the medicine twice a week
  • Test Results In a key phase II clinical trial of a solid dispersion tablet of the compound of formula (I) for the treatment of refractory or recurrent PTCL, a total of 83 patients were enrolled in the full analysis set (FAS). Among patients, the overall response rate was 32.9% (26/79), of which 8 patients had complete remission (10.1%), 4 patients were not sure of complete remission (5.1%), 14 patients had partial remission (17.7%), and medication The incidence of adverse reactions of grade 3 or higher was 39%.
  • Example 15 Phase II clinical trial of a solid dispersion tablet of the compound of the formula (I) for treating skin T cell lymphoma of the present invention 1. Preparation of a test drug
  • Test-test protocol This test is a phase II clinical trial of a solid dispersion tablet of the compound of formula (I) for treating cutaneous T-cell lymphoma of the present invention.
  • the test is divided into two phases.
  • a multicenter, randomized, open-label design was used to initially evaluate the efficacy and safety of the two groups of patients at different intervals (three-week treatment cycle group and six-week treatment cycle group).
  • a continuous administration group was set to observe the efficacy and safety. Each patient takes the drug until the disease progresses or an intolerable toxicity occurs.
  • Solid dispersion tablet of the compound of the formula (I) of the present invention Specifications: 5mg / piece
  • Dosage The patient takes the medicine with warm water of 200mL 30 minutes after breakfast. Take the drug twice a week (four doses or two or five doses on Monday, and so on), each dose is 30mg.
  • the patients in the 3-week treatment cycle group were stopped taking the drug for 2 weeks, and the patients in the 6-week treatment cycle group were stopped after 2 weeks of continuous medication for 2 weeks.
  • the patients in the continuous administration group had no discontinuation period.
  • test results In the phase II clinical trial of the solid dispersion tablets of the compound of the formula (I) for treating cutaneous T-cell lymphoma, 52 patients were enrolled, including 13 patients in the 3-week treatment cycle group, 6 weeks. There were 13 patients in the treatment cycle group and 26 patients in the continuous drug administration group. In the total analysis set (FAS) patients, the overall response rate was 32.0% (16/50), and the response rates of the three groups were 33.3% (4/12), 23.1% (3/13), and 36.0% (9/). 25), 1 patient in the continuous administration group was complete remission, and other patients with remission were partial remission.
  • Example 16 The lb phase clinical trial of the solid dispersion tablet of the compound of the formula (I) combined with paclitaxel and carboplatin in the treatment of non-small cell lung cancer 1. Preparation of test drugs
  • Test-test protocol This test is a lb phase clinical trial of a solid dispersion tablet of the compound of formula (I) combined with paclitaxel and carboplatin for the treatment of non-small cell lung cancer. ⁇ Open, single center, dose escalation design. The subjects were patients with non-small cell lung cancer, and the doses of paclitaxel and carboplatin were fixed in the trial, only the dose of the compound of formula (I) was increased.
  • the combined dose is up to 4 cycles.
  • the compound of formula (I) is treated with monotherapy, the dose is unchanged, and all subjects are treated to disease progression or Until there is intolerable toxicity.
  • Paclitaxel injection taxol
  • carboplatin injection Bosding
  • Test results A total of 10 patients were enrolled in the trial, including 3 patients in the 20 mg group, 4 patients in the 30 mg group, and 3 patients in the 25 mg group. The dose limiting toxicity of this test is a hematologic toxicity. One patient in the 20 mg group received partial mitigation; in 5 patients with brain metastases, all of the brain metastases disappeared in 2 patients.
  • Example 17 In vitro cell growth inhibition test of the compound of the formula (I) 1. Test-method The growth inhibition rate was measured by the MTS method.
  • HuT-78 T fine-packed lymphoma 1.7 ⁇ 0.5 hematological tumor Jurkat T fine-packed lymphoma 6.3 ⁇ 0.9 1.21
  • MOLT-4 human acute lymphoblastic leukemia 1.21 ⁇ 0.5
  • THP-1 monocyte 1.86 ⁇ 0.6
  • the results of the assays in Table 17 indicate the median GI 5 of the growth inhibition of normal cells, solid tumor cells and hematological tumor cells by the compound of formula (I). The values are 60 ⁇ , 6.65 ⁇ and 1.21 ⁇ , respectively. Compounds of formula (I) require higher concentrations to produce direct cytotoxic effects on normal cells.
  • Example 18 Human pharmacokinetic study of the solid dispersion tablet of the compound of the formula (I) of the present invention. This example is a solid dispersion tablet of the compound of the formula (I) of the present invention in 33 patients with advanced lymphoma. Human pharmacokinetic studies in 21 patients with PTCL and 12 patients with CTCL.
  • Test-test plan Same as Example 14-15. The time point of blood stasis after the first dose of the patient is before and after administration.
  • Dosage The patient takes 200mL of warm boiled water 30 minutes after breakfast, and the dose is 30mg.
  • Chromatographic pure methanol was purchased from Fisher Company; ACS grade formic acid was purchased from sigma company; self-made three distilled water; argon ( ⁇ ". 999 %) and liquid nitrogen ( ⁇ ". 999 %) purchased from Beijing Chengxin Industrial Gas Sales Center Blank healthy human plasma is provided by the People's Liberation Army 307 Hospital.
  • Shield spectrum conditions ionization mode + ESI; spray voltage 4500V; sheath gas flow rate 30 psi; auxiliary gas flow rate 2 psi; capillary heating temperature 300 ° C; source induced voltage -10 V; collision gas pressure 1.5 psi; scan mode selection It should be monitored (SRM) and the ion reaction monitored as m/z 391.1 ⁇ 265.1 (compound of formula (I)), m/z 377.1 ⁇ 359.2 (MS275); run time 7 min.
  • Preparation of the stock standard solution A certain amount of the compound of the formula (I) and MS275 were weighed and dissolved in methanol to prepare a stock solution of 1 mg/mL, and the water tank was stored at 4 ° C.
  • Preparation of calibration standard curve samples and shield control samples The compound stock solution of formula (I) is diluted into a series of working solutions, and 10 ⁇ working solution is added to 90 ⁇ l plasma to make 1-1000 ng/mL of the compound of formula (I). Plasma solution.
  • the preparation method of the shield control sample is the same as the calibration standard curve sample, and the concentration of the quality control sample is 2, 5, 10, 1000 ng/mL.
  • Sample processing method Take ⁇ plasma sample (standard curve, shield control or clinical sample), add 150 ⁇ acetonitrile (containing 100 ng/mL MS275) to precipitate protein, vortex for 1min, centrifuge at 17,000xg for 20min, aspirate supernatant, 5 ⁇ injection .
  • the maximum blood concentration (Cmax) in the patient is 0.153 ⁇ , which is much lower than that in vitro.
  • the median GI 5Q values for growth inhibition of normal cells, solid tumor cells, and hematological tumor cells (60 ⁇ , 6.65 ⁇ , and 1.21 ⁇ , respectively) indicate that the formulation is unlikely to produce a direct cytotoxic effect.

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Abstract

La présente invention se rapporte à un composé de benzamide en configuration E et à une formulation pharmaceutique et une application correspondantes. Le composé de benzamide en configuration E présente une structure représentée par la formule (I), présentant le nom chimique N-(2-amino-4-fluorophényl)-4-[N-[(E)-3-(3-pyridine)acryl]aminométhyl]benzamide et 3-pyridine-acryle dans la formule structurale présentant la configuration E. Le composé de benzamide en configuration E représenté par la formule (I) présente une activité inhibitrice sélective d'un sous-type d'une enzyme histone désacétylase et inhibe principalement HDAC1, HDAC2, HDAC3 dans des HADC de type I et HDAC10 dans des HDAC de type IIb. Le composé de benzamide en configuration E représenté par la formule (I) peut être utilisé pour traiter des maladies liées à une activité anormale de l'enzyme histone désacétylase, telles que le cancer, comprenant le lymphome, une tumeur solide et une tumeur du système sanguin et analogues.
PCT/CN2014/080585 2014-04-04 2014-06-24 Composé de benzamide en configuration e et formulation pharmaceutique et application correspondantes WO2015149435A1 (fr)

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CN106242992A (zh) * 2016-07-25 2016-12-21 北京化工大学 一种苯甲酰胺类化合物及其在制备抑制癌细胞增殖和/或治疗癌症的药物中的应用
CN106496053B (zh) * 2016-09-22 2018-01-05 潍坊医学院 一种组蛋白去乙酰酶抑制剂n‑(2’‑胺基苯基)‑4‑(双(2‑氯乙基)胺基)苯甲酰胺及其制备方法和应用
CN107865826B (zh) * 2016-09-27 2020-06-30 深圳微芯生物科技股份有限公司 一种e构型苯甲酰胺类化合物的固体分散体
JP2022545822A (ja) * 2019-08-28 2022-10-31 シェンチェン チップスクリーン バイオサイエンシズ カンパニー、リミテッド チダミド医薬組成物、その調製方法及びその適用
WO2023280244A1 (fr) * 2021-07-08 2023-01-12 深圳微芯生物科技股份有限公司 Utilisations du chiauranib et administration combinée de celui-ci pour le traitement du cancer du sein
CN115703736A (zh) * 2021-08-04 2023-02-17 中国海洋大学 靶向于hdac和nad合成的多靶点抑制剂及其用途
CN115322171B (zh) * 2022-08-30 2023-03-17 深圳微芯生物科技股份有限公司 一种trka(g667c)和flt3靶点抑制剂及其与西达本胺的组合物

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