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WO2019019130A1 - 含恩替诺特的化合物，其化合物晶型及其制备方法和药物组合物 - Google Patents

含恩替诺特的化合物，其化合物晶型及其制备方法和药物组合物 Download PDF

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WO2019019130A1
WO2019019130A1 PCT/CN2017/094851 CN2017094851W WO2019019130A1 WO 2019019130 A1 WO2019019130 A1 WO 2019019130A1 CN 2017094851 W CN2017094851 W CN 2017094851W WO 2019019130 A1 WO2019019130 A1 WO 2019019130A1
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Prior art keywords
compound
solvent
entinostat
acid
crystalline
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French (fr)
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盛晓红
盛晓霞
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Solipharma LLC
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Solipharma LLC
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Priority to PCT/CN2017/094851 priority Critical patent/WO2019019130A1/zh
Priority to CN201780092661.3A priority patent/CN110944978A/zh
Priority to US16/634,797 priority patent/US11208382B2/en
Publication of WO2019019130A1 publication Critical patent/WO2019019130A1/zh
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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
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present application relates to compounds formed by entenote and acid, and to crystalline forms of the compounds, processes for their preparation, pharmaceutical compositions and uses thereof.
  • Entinot also known as MS-275, chemical name N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide, English name Entinostat is a histone deacetylase inhibitor whose chemical structural formula is represented by the following formula (I).
  • the compound is a stable crystalline solid and should have one or more improved properties, particularly in terms of crystallinity, solubility, hygroscopicity, morphology, formulation processability, crystal form stability, chemical stability, and the like.
  • one of the contents of the present invention is to provide a compound formed by entenote and fumaric acid (abbreviated as "Compound A”) and a crystal form thereof (abbreviated as “crystal form of Compound A”) and a process for producing the same.
  • Compound A a compound formed by entenote and fumaric acid
  • crystal form of Compound A a crystal form thereof
  • the compound A is a compound of the formula (II) represented by the following formula (II), which is formed by entenote and fumaric acid, and the molar ratio of entenote and fumaric acid is 1:0.5.
  • the compound A is a eutectic or salt formed by entenet and fumaric acid, preferably a eutectic.
  • the compound A is in a crystalline form, preferably an unsolvate, a hydrate and an anhydrate, more preferably an anhydrate. In a more preferred embodiment, it uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern of the crystalline Compound A has a 2 ⁇ value of 3.9° ⁇ 0.2°, 13.4° ⁇ 0.2°, 16.4° ⁇ 0.2°.
  • characteristic peaks at 18.8 ° ⁇ 0.2 ° also characteristic peaks at 2 ⁇ values of 11.5 ° ⁇ 0.2 °, 15.3 ° ⁇ 0.2 °, 18.3 ° ⁇ 0.2 ° and 19.7 ° ⁇ 0.2 °; Characteristic peaks at ° ⁇ 0.2°, 10.9° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 26.2° ⁇ 0.2°; non-limiting, one specific example of the crystal form of the compound A has the structure shown in FIG. XRPD map.
  • Compound A of the present invention has a number of advantageous properties compared to prior art Entinol.
  • the prior art has a low solubility of Entinol, and the compound A of the present invention has high solubility in water, and has higher dissolution and bioavailability.
  • Compound A has good crystal form stability, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation dosage form containing entenote in the process of manufacture and storage, for example, avoiding uneven content of active ingredients, Problems such as increased impurities. Avoid special and expensive packaging.
  • the present invention provides a process for the preparation of Compound A, which comprises a method of directly reacting entenotenic acid with a half equivalent to one equivalent of a fumaric acid base, preferably in an organic solvent or solvent combination.
  • the organic solvent is a solvent which can dissolve entino or fumaric acid.
  • the present invention provides a process for the preparation of the crystalline form of Compound A, comprising any of the following methods:
  • the entinostat and fumaric acid are selected from the same solvent to form a solution;
  • the solvent is an alcohol or a ketone, more preferably ethanol;
  • the mass ratio of the entinostat to the solvent forming solution is from 10 mg/mL to 100 mg/mL, more preferably from 10 mg/mL to 30 mg/mL;
  • the molar ratio of entenote and fumaric acid is 1:0.5 to 1:1.0, more preferably 1:0.6 to 1:0.7;
  • the stirring time is from 1 day to 3 days;
  • the operation is carried out at 10 ° C to 40 ° C, more preferably at room temperature;
  • the solvent is an alcohol or a ketone, more preferably ethanol;
  • the mass ratio of the entinostat to the solvent is from 5 mg/mL to 50 mg/mL, more preferably from 5 mg/mL to 20 mg/mL;
  • the molar ratio of entenote and fumaric acid is 1:0.5 to 1:1.0, more preferably 1:0.6 to 1:0.7;
  • the volatilization process is carried out at 10 ° C to 40 ° C, more preferably at room temperature.
  • a second aspect of the present invention provides a compound formed by entenote and maleic acid (abbreviated as "Compound B”) and a crystal form thereof (abbreviated as "crystal form of Compound B”) and a process for producing the same.
  • Compound B a compound formed by entenote and maleic acid
  • crystal form of Compound B a crystal form thereof
  • the compound B has a structural formula represented by the following formula (III), a compound formed of entenote and maleic acid, and a molar ratio of entinostat to maleic acid of 1:1.
  • the compound B is a eutectic or salt formed by entenote and maleic acid, preferably a eutectic.
  • the compound B is in a crystalline form, preferably an unsolvate, a hydrate and an anhydrate, more preferably an anhydrate. In a more preferred embodiment, it uses Cu-K ⁇ radiation, and the crystalline compound B has an X-ray powder diffraction pattern at a 2 ⁇ value.
  • the compound B is a FTIR 3298cm -1 ⁇ 2cm -1, 1718cm -1 ⁇ 2cm -1 in wave number, 1545cm -1 ⁇ 2cm -1, 1499cm -1 ⁇ 2cm -1 , 1363cm -1 ⁇ 2cm -1 , 1313cm -1 ⁇ 2cm -1 , 1248cm -1 ⁇ 2cm -1 , 1147cm -1 ⁇ 2cm -1 , 1044cm -1 ⁇ 2cm -1 , 992cm -1 ⁇ 2cm -1, 860cm -1 ⁇ 2cm -1, 750cm -1 ⁇ 2cm -1, at 703cm -1 ⁇ 2cm -1, and 645cm -1 ⁇ 2cm -1 with characteristic peaks.
  • the compound B of the present invention has the following beneficial properties:
  • Compound B of the present invention has a number of advantageous properties compared to prior art Entinot.
  • the prior art entenote has a low solubility, while the compound B of the present invention has high solubility in water, and has higher dissolution and bioavailability.
  • Compound B has good crystal form stability, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation dosage form containing entinostat during manufacture and storage.
  • the compound B of the present invention is easier to be purified, and the process production cost is lower.
  • the present invention provides a process for the preparation of compound B, which comprises a method of directly reacting entenotenic acid with one equivalent of 1.5 equivalents of maleic acid base, preferably in an organic solvent or solvent combination;
  • the organic solvent is a solvent which can dissolve entino or maleic acid.
  • the present invention provides a process for the preparation of the crystalline form of Compound B, comprising any of the following methods:
  • the entinostat and the maleic acid are selected from the same solvent to form a solution;
  • the solvent is an alcohol or a ketone, more preferably ethanol;
  • the mass ratio of the entinostat to the solvent forming solution is from 10 mg/mL to 100 mg/mL, more preferably from 10 mg/mL to 30 mg/mL;
  • the molar ratio of entenote and maleic acid is from 1:1.0 to 1:1.5, more preferably from 1:1.0 to 1:1.2;
  • the stirring time is from 1 day to 3 days;
  • the operation is carried out at room temperature
  • the solvent is an alcohol or a ketone, more preferably ethanol;
  • the mass ratio of the entinostat to the solvent is 5 to 50 mg/mL, more preferably 5 mg/mL to 20 mg/mL;
  • the molar ratio of entenote and maleic acid is from 1:1.0 to 1:1.5, more preferably 1:1.0 to 1:1.2;
  • the volatilization process is carried out at room temperature.
  • a third aspect of the present invention provides a compound formed by entenote and succinic acid (abbreviated as "Compound C”) and a crystal form thereof (abbreviated as "crystal form of Compound C”) and a process for producing the same.
  • Compound C a compound formed by entenote and succinic acid
  • crystal form of Compound C a crystal form thereof
  • the compound C is a compound formed by entenote and succinic acid, and the molar ratio of entenote and succinic acid is 1:0.5, and the structural formula is represented by the following formula (IV).
  • the compound C is a eutectic or salt formed by entenote and succinic acid, preferably a eutectic.
  • the crystalline form of the compound C is Cu-K ⁇ radiation
  • the X-ray powder diffraction pattern has a 2 ⁇ value of 3.7° ⁇ 0.2°, 7.3° ⁇ 0.2°, 9.2° ⁇ 0.2. °, 9.5 ° ⁇ 0.2 °, 16.6 ° ⁇ 0.2 °, 17.2 ° ⁇ 0.2 °, 17.8 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, 19.0 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 ° and There is a characteristic peak at 24.6 ° ⁇ 0.2 °; a non-limiting example, a specific example of the crystal form of the compound C has an XRPD pattern as shown in FIG.
  • the method for preparing the crystalline form of the compound C provided by the present invention comprises the steps of forming a solution of a mixture of entenote and succinic acid in a solvent and volatilizing to a solvent to obtain a crystalline form of the compound C.
  • the mass ratio of the entinostat to the solvent is 8 to 25 mg/mL;
  • the solvent is tetrahydrofuran
  • the molar ratio of entenote and succinic acid is 1:0.5;
  • the volatilization process is carried out at room temperature.
  • a fourth aspect of the present invention provides a compound formed by entenote and adipic acid (abbreviated as "Compound D”) and a crystal form thereof (abbreviated as “crystal form of Compound D”) and a process for producing the same.
  • Compound D a compound formed by entenote and adipic acid
  • crystal form of Compound D a crystal form of Compound D
  • the compound D is a compound formed by entenote and adipic acid, and the molar ratio of entenote and adipic acid is 1:1, and the structural formula is represented by the following formula (V).
  • the compound D is a eutectic or salt formed by entenote and adipic acid, preferably a eutectic.
  • the crystalline form of the compound D is Cu-K ⁇ radiation
  • the X-ray powder diffraction pattern has a 2 ⁇ value of 4.0° ⁇ 0.2°, 7.8° ⁇ 0.2°, and 11.7° ⁇ 0.2. °, 16.1 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °, 19.5 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, 23.7 ° ⁇ 0.2 °, 24.5 ° ⁇ 0.2 °, 25.9 ° ⁇ 0.2 ° and There is a characteristic peak at 27.5 ° ⁇ 0.2 °.
  • one specific example of the crystalline form of Compound D has an XRPD pattern as shown in FIG.
  • the method for preparing the crystalline form of the compound D provided by the present invention comprises the steps of separately forming a solution of entenote and adipic acid in a solvent, mixing and crystallization, and then separating the crystals and drying to obtain the above-mentioned Crystal form of Compound D.
  • the entinostat and adipic acid are selected from the same solvent to form a solution;
  • the solvent is acetone
  • the mass ratio of the entinostat to the solvent forming solution is from 16 mg/mL to 50 mg/mL;
  • the molar ratio of entinostat to adipic acid is 1:1.25;
  • the stirring time is from 1 day to 2 days;
  • the operation is carried out at room temperature.
  • the raw material "Entinol” may be a disclosed entinostat compound, a crystalline form thereof or an amorphous form thereof, for example including but not It is limited to the entinox obtained by the preparation method of the patent document US Pat. No. 6,174,905 B1. These patent documents are incorporated herein by reference in their entirety.
  • the "room temperature” means 10 to 30 °C.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation" can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the filtration under reduced pressure is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the "drying" can be accomplished using conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying.
  • the drying apparatus and method are not limited and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; the pressure may be reduced or normal pressure, preferably the pressure is less than 0.09 MPa.
  • the drying temperature is 10 to 40 ° C, and the drying time is 10 to 72 hours, preferably 2 to 24 hours, more preferably 2 to 8 hours.
  • crystalline means that the compound is characterized by the X-ray powder diffraction pattern indicated, having a unique ordered molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity.
  • the 2 ⁇ angle of the peaks in the XRPD pattern will typically vary slightly from instrument to sample. The difference in peak angle may vary by 1°, 0.8°, 0.5°, 0.3°, 0.1°, etc. depending on the instrument, and the sample may be ⁇ 0.2°.
  • the relative intensity of the peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • Single crystal form means a single crystal form as detected by X-ray powder diffraction.
  • the crystalline form of the entenet-containing compound of the present invention is pure, unitary, and substantially free of any other crystalline or amorphous form.
  • substantially free in the context of the invention, when used to refer to a new crystalline form, means that the new crystalline form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% by weight. ), especially at least 99% by weight.
  • a fifth aspect of the present invention provides a pharmaceutical composition for use in the preparation of a disease for treating or preventing differentiation or proliferation in a mammal; said differentiation with a mammal
  • diseases associated with proliferation include tumors (especially malignant tumors), autoimmune diseases, skin diseases, atherosclerosis, and parasitic diseases.
  • prevention refers to the prevention of a disease or condition in an individual who may be predisposed to having a disease or condition but has not yet suffered or manifested a disease or condition of the disease.
  • treating refers to one or more of the following: (1) inhibiting the disease; for example, inhibiting the disease or symptom in an individual who is suffering or showing the disease or condition; Improving the disease; for example, ameliorating, reversing, or delaying the disease and/or condition in an individual who suffers or exhibits the disease or condition.
  • the pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the crystalline forms of the entenet-containing compounds of the invention, and at least one pharmaceutically acceptable carrier or adjuvant, wherein said
  • the crystalline form of the entinostat-containing compound of the present invention comprises at least a crystalline form of a compound formed by entenote and fumaric acid or a crystalline form of a compound formed by entenote and maleic acid.
  • the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients, such as other anti-proliferative or anti-tumor drugs.
  • a method of treating a human patient comprises administering Compound A, Compound B, Compound C, or Compound D.
  • the above compounds are prepared in a form which can be administered by nasal, sublingual, rectal, oral, intravenous, intramuscular or subcutaneous administration, including tablets, capsules, film-coated tablets, films, suppositories, implants, Injectable sterile aqueous or oily solutions, suspensions, emulsions, ointments, creams, gels, patches, and nasal sprays.
  • Compound A, Compound B, Compound C, or Compound D can be administered orally in a single dose or in divided doses at a dose of 0.001 to 100 mg/kg of mammalian body weight per day.
  • a preferred dosage range is from 0.005 to 1 mg/kg body weight per day, administered orally or in divided doses.
  • Another preferred dosage range is 0.01 to 0.5 mg/kg body weight per day, administered orally or in divided doses.
  • the specific dosage and interval of administration need to be based on the individual condition of the subject, such as gender, age, weight, health status, and tolerance. Forced to adjust.
  • the compound may contain at least one compound as specified herein, admixed with a pharmaceutically acceptable carrier, excipient, adjuvant, or a resorbable carrier in the form of a capsule, sachet, sachet, paper or other outer shell or Disposable containers such as ampoules are enclosed or enclosed.
  • the carrier, excipient, adjuvant may be a solid, semi-solid or liquid material.
  • Carriers, excipients, and adjuvants which can be used in the pharmaceutical composition of the present invention are, for example, starch, sugar, syrup, sorbitol, mannitol, glycol, paraffin, kaolin, calcium silicate, silica, polyethylene. Pyrrolidone, calcium phosphate, cocoa butter, esters, oils, alginates, gums, methylcellulose, microcrystalline cellulose, lubricants, binders, disintegrants, and the like.
  • Preferred pharmaceutical forms of the invention are tablets, capsules, film-coated tablets, films, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions, emulsions, ointments, creams, gels, patches Agent and nasal spray.
  • Figure 1 is an XRPD pattern of entinostat Form A prepared in accordance with US Pat. No. 6,174,905 B1.
  • Figure 2 is an XRPD pattern of entinostat Form B prepared by reference to CN102137846B
  • Figure 3 is an XRPD pattern of entinostat Form C prepared by reference to CN102137846B
  • Figure 8 is a DSC pattern of the crystalline form of Compound A of the present invention
  • Figure 9 is a DSC pattern of the crystalline form of Compound B of the present invention
  • X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. Angle range: 3 ⁇ 40 ° 2 ⁇ , step size: 0.02 ° 2 ⁇ , speed: 0.2 seconds / step.
  • Thermogravimetric analysis data was taken from the TA Instruments Q500TGA. Using segmented high-resolution detection, 10 ° C / min heating rate, nitrogen protection.
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400 MHZ NMR spectrometer. The sample was dissolved with deuterated reagents.
  • IR Infrared spectroscopy
  • Entinol is prepared by the method of Example 48 of the patent document US Pat. No. 6,174,905 B1.
  • Form B and Form C were prepared by the method of Example 1 in Patent Document CN102137846B.
  • the TGA spectrum is shown in Fig. 10, and the weight loss is 0.3% before 100 ° C, which is an anhydride, and the decomposition temperature is 160 ° C.
  • Compound A was obtained by replacing the solvent in Example 4 with the following table.
  • Compound A was obtained by replacing the solvent in Example 9 with the following table.
  • the samples prepared in Examples 3 to 10 have the same or similar XRPD patterns (not shown), DSC patterns (not shown), TGA patterns (not shown), and Examples 3 to 10.
  • the sample was the same compound as the sample of Example 2.
  • the TGA spectrum is shown in Fig. 11, and the weight loss is 0.3% before 100 ° C, which is an anhydride, and the decomposition temperature is 125 ° C.
  • Compound B was obtained by replacing the solvent in Example 14 with the following table.
  • Compound B was obtained by replacing the solvent in Example 9 with the following table.
  • the samples prepared in Examples 13 to 20 had the same or similar XRPD patterns (not shown), DSC patterns (not shown), TGA patterns (not shown), and Examples 13 to 20.
  • the sample was the same compound as the sample of Example 12.
  • Compound A or Compound B, starch and magnesium stearate were mixed and passed through a 20 mesh sieve and filled into hard capsules in an amount of 414 mg.
  • the crystal form of the compound A and the crystal form of the compound B in the present invention were respectively subjected to a crystal form stability test under the following conditions: room temperature, high temperature (50 ° C), and the test results are shown in the following table:

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Abstract

涉及式（I）所示的恩替诺特与酸性对离子形成的化合物，与恩替诺特已知的固体形式相比，涉及的化合物在溶解度、稳定性等方面具有优势。还涉及所述化合物的晶型及其制备方法，其药物组合物及其在制备用于预防和/或治疗与分化或增殖相关的疾病中的用途。

Description

含恩替诺特的化合物，其化合物晶型及其制备方法和药物组合物 技术领域
本申请涉及恩替诺特与酸形成的化合物，还涉及所述化合物的晶型及其制备方法、其药物组合物和用途。
背景技术
恩替诺特，又名MS-275，化学名称为N-(2-氨基苯基)-4-[N-(吡啶-3-基)甲氧基羰基氨基甲基]苯甲酰胺，英文名为Entinostat，是一种组蛋白去乙酰化酶抑制剂，其化学结构式如下式(I)所示。
Figure PCTCN2017094851-appb-000001
专利文献US6174905B1报道了化合物恩替诺特的合成方法并提供了熔点和红外等数据；专利文献CN 102137846 B报道了恩替诺特的多晶型物A形式、多晶型物B形式、多晶型物C形式和非晶相形式，并提供了XRD、DSC、FT-Raman和FT-IR图谱。本发明人研究发现，参考US6174905B1实施例48和CN102137846B实施例1制备得到的多晶型物A、B、C形式具有水溶性低的缺点；参考JP4360660B2专利中比较例4中结果，恩替诺特有一个明显的化学杂质，且无法通过溶剂重结晶方法纯化。另外，据本领域人员所公知，非晶相形式多具有晶型不稳定、易吸湿、流动性差等缺点。
鉴于现有技术尚存不足，本领域仍需要开发具有更多改进性能的结晶态的恩替诺特，以满足药物制剂对于活性成分溶解度、稳定性、形貌等物化性质的严格要求。
发明内容
针对现有技术的不足，本发明的目的是提供恩替诺特与酸性对离子形成的化合物以及它们的晶型和制备方法、包含所述化合物的药物组合物和用途。所述化合物为稳定的结晶态固体，应具有一种或多种改进的特性，特别在结晶度、溶解度、吸湿性、形貌、制剂可加工性、晶型稳定性、化学稳定性等方面。
根据本发明目的，本发明的内容之一是提供恩替诺特与富马酸形成的化合物(简称“化合物A”)及其晶型(简称“化合物A的晶型”)及其制备方法。
所述的化合物A，结构式如下式(II)所示，由恩替诺特和富马酸形成的化合物，且恩替诺特和富马酸的摩尔比为1:0.5。
Figure PCTCN2017094851-appb-000002
所述化合物A为恩替诺特与富马酸形成的共晶或盐，优选为共晶。
在本发明的一个优选实施方案中，所述的化合物A为结晶态，优选为非溶剂化物、水合物和无水物，更优选为无水物。在一个更优选的实施方案中，其使用Cu-Kα辐射，所述结晶态化合物A的X-射线粉末衍射图在2θ值为3.9°±0.2°、13.4°±0.2°、16.4°±0.2°和18.8°±0.2°处具有特征峰；还在2θ值为11.5°±0.2°、15.3°±0.2°、18.3°±0.2°和19.7°±0.2°处具有特征峰；还在2θ值为7.7°±0.2°、10.9°±0.2°、22.8°±0.2°和26.2°±0.2°处具有特征峰；非限制性地，所述化合物A的晶型的一个具体实例具有如图4所示的XRPD图谱。
在本发明的一个优选实施方案中，所述化合物A的傅里叶红外光谱在波数为3369cm-1±2cm-1、1713cm-1±2cm-1、1664cm-1±2cm-1、1605cm-1±2cm-1、1556cm-1±2cm-1、1504cm-1±2cm-1、1282cm-1±2cm-1、1248cm-1±2cm-1、1220cm-1±2cm-1、1135cm-1±2cm-1、1044cm-1±2cm-1、759cm-1±2cm-1、712cm-1±2cm-1和640cm-1±2cm-1处具有特征峰。
与现有技术的恩替诺特相比，本发明的化合物A有以下有益性质：
(1)由对比例1可知，本发明的化合物A具有更好的水中溶解度。
(2)XRPD图谱可知，本发明的化合物A具有更高的结晶度。
(3)由对比例2可知，本发明的化合物A的晶型具有优良的晶型稳定性。
(4)由对比例3可知，本发明的化合物A具有更低的杂质(RRT＝1.403)含量，更少的杂质数目和更高的化学纯度，且在室温、高温、高湿和加速条件下具有优良的化学稳定性。
以上有益性质表明：与现有技术的恩替诺特的相比，本发明的化合物A具有多种优势性能。现有技术的恩替诺特溶解度低，本发明化合物A水中溶解度高，具有更高的溶出度和生物利用度。化合物A的晶型稳定性好，能更好地保证药物活性成分自身和含有恩替诺特的制剂剂型在制造和存储等过程中质量、安全性和稳定性，例如避免活性成分含量不均匀、杂质增加等问题。避免特殊和昂贵的包装。
本发明提供化合物A的制备方法，包括将恩替诺特酸与半个当量到一个当量的富马酸碱直接反应的方式，优选在有机溶剂或溶剂组合液中酸碱反应的方式。所述有机溶剂为可以溶解恩替诺特或富马酸的溶剂。
本发明提供化合物A的晶型的制备方法，包括下述方法中的任意一种：
(1)分别将恩替诺特和富马酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述的化合物A的晶型；
优选地，所述恩替诺特与富马酸选择同一种溶剂形成溶液；
优选地，所述溶剂为醇类或酮类，更优选为乙醇；
优选地，所述恩替诺特与溶剂形成溶液时的质量体积比为10mg/mL～100mg/mL，更优选为10mg/mL～30mg/mL；
优选地，所述恩替诺特与富马酸的摩尔比为1:0.5～1:1.0，更优选为1:0.6～1:0.7；
优选地，所述搅拌时间为1天～3天；
优选地，所述操作过程在10℃～40℃下进行，更优选在室温下进行；
(2)将恩替诺特与富马酸的混合物在溶剂中形成溶液，挥发至溶剂干，得到所述的化合物A的晶型；
优选地，所述溶剂为醇类或酮类，更优选为乙醇；
优选地，所述恩替诺特与溶剂的质量体积比为5mg/mL～50mg/mL，更优选为5mg/mL～20mg/mL；
优选地，所述恩替诺特与富马酸的摩尔比为1:0.5～1:1.0，更优选为1:0.6～1:0.7；
优选地，所述挥发过程在10℃～40℃下进行，更优选在室温下进行。
根据本发明目的，本发明的内容之二是提供恩替诺特与马来酸形成的化合物(简称“化合物B”)及其晶型(简称“化合物B的晶型”)及其制备方法。
所述的化合物B，其结构式如下式(III)所示，由恩替诺特和马来酸形成的化合物，且恩替诺特和马来酸的摩尔比为1:1。
Figure PCTCN2017094851-appb-000003
所述化合物B为恩替诺特与马来酸形成的共晶或盐，优选为共晶。
在本发明的一个优选的实施方案中，所述的化合物B为结晶态，优选为非溶剂化物、水合物和无水物，更优选为无水物。在一个更优选的实施方案中，其使用Cu-Kα辐射，所述结晶态化合物B的X-射线粉末衍射图在2θ值为 9.8°±0.2°、15.9°±0.2°、19.7°±0.2°和23.2°±0.2°处具有特征峰；还在2θ值为14.1°±0.2°、14.8°±0.2°、17.7°±0.2°和18.9°±0.2°处具有特征峰；还在2θ值为14.5°±0.2°、21.4°±0.2°、23.8°±0.2°和24.8°±0.2°处具有特征峰；非限制性地，所述结晶态化合物B的一个具体实例具有如图5所示的XRPD图谱。
在本发明的一个优选实施方案中，所述化合物B的傅里叶红外光谱在波数为3298cm-1±2cm-1、1718cm-1±2cm-1、1545cm-1±2cm-1、1499cm-1±2cm-1、1363cm-1±2cm-1、1313cm-1±2cm-1、1248cm-1±2cm-1、1147cm-1±2cm-1、1044cm-1±2cm-1、992cm-1±2cm-1、860cm-1±2cm-1、750cm-1±2cm-1、703cm-1±2cm-1和645cm-1±2cm-1处具有特征峰。
与现有技术的恩替诺特相比，本发明的化合物B有以下有益性质：
(1)由对比例1可知，本发明的化合物B具有更好的水中溶解度。
(2)由对比例2可知，本发明的化合物B的晶型具有优良的晶型稳定性。
(3)由对比例4可知，当使用溶剂重结晶时，本发明的化合物B更容易被纯化。
以上有益性质表明：与现有技术的恩替诺特相比，本发明的化合物B具有多种优势性能。现有技术的恩替诺特溶解度低，而本发明化合物B水中溶解度高，具有更高的溶出度和生物利用度。化合物B的晶型稳定性好，能更好地保证药物活性成分自身和含有恩替诺特的制剂剂型在制造和存储等过程中质量、安全性和稳定性。本发明的化合物B更容易被纯化，工艺生产成本更低。
本发明提供化合物B的制备方法，包括将恩替诺特酸与一个当量到1.5个当量的马来酸碱直接反应的方式，优选在有机溶剂或溶剂组合液中酸碱反应的方式；所述有机溶剂为可以溶解恩替诺特或马来酸的溶剂。
本发明提供化合物B的晶型的制备方法，包括下述方法中的任意一种：
(1)分别将恩替诺特和马来酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到化合物B的晶型；
优选地，所述恩替诺特与马来酸选择同一种溶剂形成溶液；
优选地，所述溶剂为醇类或酮类，更优选为乙醇；
优选地，所述恩替诺特与溶剂形成溶液时的质量体积比为10mg/mL～100mg/mL，更优选为10mg/mL～30mg/mL；
优选地，所述恩替诺特与马来酸的摩尔比为1:1.0～1:1.5，更优选为1:1.0～1:1.2；
优选地，所述搅拌时间为1天～3天；
优选地，所述操作过程在室温下进行；
(2)将恩替诺特与马来酸的混合物在溶剂中形成溶液，挥发至溶剂干，得到所述的化合物B的晶型；
优选地，所述溶剂为醇类或酮类，更优选为乙醇；
优选地，所述恩替诺特与溶剂的质量体积比为5～50mg/mL，更优选为5mg/mL～20mg/mL；
优选地，所述恩替诺特与马来酸的摩尔比为1:1.0～1:1.5，更优选为 1:1.0～1:1.2；
优选地，所述挥发过程在室温下进行。
根据本发明目的，本发明的内容之三是提供恩替诺特与琥珀酸形成的化合物(简称“化合物C”)及其晶型(简称“化合物C的晶型”)及其制备方法。
所述的化合物C，为恩替诺特和琥珀酸形成的化合物，且恩替诺特和琥珀酸的摩尔比为1:0.5，其结构式如下式(IV)所示。
Figure PCTCN2017094851-appb-000004
所述化合物C为恩替诺特与琥珀酸形成的共晶或盐，优选为共晶。
在本发明的一个优选实施方案中，所述化合物C的晶型使用Cu-Kα辐射，其X-射线粉末衍射图在2θ值为3.7°±0.2°、7.3°±0.2°、9.2°±0.2°、9.5°±0.2°、16.6°±0.2°、17.2°±0.2°、17.8°±0.2°、18.5°±0.2°、19.0°±0.2°、20.4°±0.2°、20.8°±0.2°和24.6°±0.2°处具有特征峰；非限制性地，所述化合物C的晶型的一个具体实例具有如图6所示的XRPD图谱。
本发明提供的所述化合物C的晶型的制备方法，包括以下步骤：将恩替诺特与琥珀酸的混合物在溶剂中形成溶液，挥发至溶剂干，得到所述的化合物C的晶型。
优选地，所述恩替诺特与溶剂的质量体积比为8～25mg/mL；
优选地，所述溶剂为四氢呋喃；
优选地，所述恩替诺特与琥珀酸的摩尔比为1:0.5；
优选地，所述挥发过程在室温下进行。
根据本发明目的，本发明的内容之四是提供恩替诺特与己二酸形成的化合物(简称“化合物D”)及其晶型(简称“化合物D的晶型”)及其制备方法。
所述的化合物D，为恩替诺特和己二酸形成的化合物，且恩替诺特和己二酸的摩尔比为1:1，其结构式如下式(V)所示。
Figure PCTCN2017094851-appb-000005
所述化合物D为恩替诺特与己二酸形成的共晶或盐，优选为共晶。
在本发明的一个优选实施方案中，所述化合物D的晶型使用Cu-Kα辐射，其X-射线粉末衍射图在2θ值为4.0°±0.2°、7.8°±0.2°、11.7°±0.2°、16.1°±0.2°、18.7°±0.2°、19.5°±0.2°、20.6°±0.2°、21.6°±0.2°、23.7°±0.2°、24.5°±0.2°、25.9°±0.2°和27.5°±0.2°处具有特征峰。
非限制性地，所述化合物D的晶型的一个具体实例具有如图7所示的XRPD图谱。
本发明提供的所述化合物D的晶型的制备方法，包括以下步骤：分别将恩替诺特和己二酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述的化合物D的晶型。
优选地，所述恩替诺特与己二酸选择同一种溶剂形成溶液；
优选地，所述溶剂为丙酮；
优选地，所述恩替诺特与溶剂形成溶液时的质量体积比为16mg/mL～50mg/mL；
优选地，所述恩替诺特与己二酸的摩尔比为1:1.25；
优选地，所述搅拌时间为1天～2天；
优选地，所述操作过程在室温下进行。
根据本发明目的，类似地，根据所述的化合物A、化合物B、化合物C和化合物D的合成方法，还可以合成恩替诺特与苯磺酸、柠檬酸、D-葡萄糖酸、乙醇酸、L-乳酸、L-苹果酸、丙二酸、磷酸、丙酸、硫酸、酒石酸、对甲基苯磺酸、戊酸、棕榈酸、帕莫酸、癸二酸、硬脂酸、月桂酸、乙酸、对氯苯磺酸、乙二磺酸、2-乙基-丁二酸、富马酸、粘酸、D-葡萄糖醛酸、α-酮戊二酸、马尿酸、盐酸、马来酸、1,5-萘二磺酸、乙磺酸、甲磺酸和草酸形成的盐或共晶等。
本发明的含恩替诺特的化合物的晶型的各制备方法中：原料“恩替诺特”可以为已公开的恩替诺特化合物、其晶型或其无定型物，例如包括但不限于参照专利文献US6174905B1中制备方法得到的恩替诺特。这些专利文献通过引用其全文的方式并入到本申请中。
本发明中使用的术语有：
所述“室温”，是指10～30℃。
所述“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分，优选300～900转/分。
所述“分离”可以采用本领域的常规方法，例如离心或过滤。优选减压过滤，一般是在室温下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以减压或常压，优选压力小于0.09MPa。干燥温度为10～40℃，干燥时间为10～72小时，优选为2～24小时，更优选为2～8小时。
本发明中所述的“晶型”是指化合物被所示X-射线粉末衍射图谱表征所证实的，在晶格内具有独特有序的分子排列或构型。本领域技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。XRPD图谱中的峰的2θ角度通常会随着仪器和样品不同而略有不同。峰角度的差值根据不同仪器，不同样品等可能相差1°，0.8°，0.5°，0.3°，0.1°等，通常允许误差±0.2°。峰的相对强度可能随样品、样品制备和其他实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素。样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
本发明所述含恩替诺特的化合物的晶型是纯的、单一的，基本没有混合任何其他晶型或非晶态。本发明中“基本没有”当用来指新晶型时，指这个新晶型占所存在的化合物的至少80％(重量)，更指至少90％(重量)，尤其指至少95％(重量)，特别是指至少99％(重量)。
根据本发明目的，本发明的内容之五是提供一种药物组合物，所述药物组合物在制备用于治疗或预防与哺乳动物分化或增殖相关的疾病中的用途；所述与哺乳动物分化或增殖相关的疾病包括肿瘤(特别是恶性肿瘤)、自身免疫性疾病、皮肤病、动脉粥样硬化症和寄生病等。本发明中所使用的术语“预防”是指在可能倾向于罹患疾病或症状、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病或症状。本发明中所使用的术语“治疗”是指下列中的一种或多种：(1)抑制该疾病；例如在正遭受或显示该疾病或症状的个体中抑制该疾病或症状；以及(2)改善该疾病；例如，在遭受或显示该疾病或症状的个体中改善、逆转、延缓该疾病和/或症状。所述药物组合物含有治疗和/或预防有效量的药物活性成分选自本发明的含恩替诺特的化合物的晶型，以及至少一种药学上可接受的载体或助剂，其中所述本发明的含恩替诺特的化合物的晶型至少包括恩替诺特与富马酸形成的化合物的晶型或恩替诺特与马来酸形成的化合物的晶型。任选地，所述药物组合物还可以包含一种或多种其他的药物活性成分，例如其他抗增殖或抗肿瘤药物。
根据本发明，治疗人类患者的方法包括施用化合物A、化合物B、化合物C、或化合物D。将上述化合物制备成可通过鼻部、舌下、直肠、口服、静脉内、肌内或皮下给药的制剂形式，包括片剂、胶囊剂、薄膜包衣片、薄膜、栓剂、植入物、可注射无菌水性或油性溶液、混悬剂、乳剂、软膏、乳膏、凝胶、贴剂和鼻喷剂。化合物A、化合物B、化合物C、或化合物D可以以一天0.001到100mg/kg哺乳动物体重的剂量，单次或分次口服给予。一个优选的剂量范围是一天0.005到1mg/kg体重，单次或分次口服给予。另一个优选的剂量范围是一天0.01到0.5mg/kg体重，单次或分次口服给予。具体的给药剂量和给药时间间隔需要根据用药对象的个体状况如性别、年龄、体重、健康状况、耐 受力等做调整。
化合物可以含有本文指定的至少一种化合物，混合以可药用载体、赋形剂、佐剂制成药物组合物或用胶囊、小药袋、扁囊、纸或其他外壳形式的可吸收载体或一次性容器如安瓿包附或包封。载体、赋形剂、佐剂可以是固体、半固体或液体材料。本发明的药物组合物中可使用的载体、赋形剂、佐剂的例如有淀粉、糖、糖浆、山梨醇、甘露醇、二醇、石蜡、高岭土、硅酸钙、二氧化硅、聚乙烯吡咯烷酮、磷酸钙、可可脂、酯、油、藻酸盐、胶、甲基纤维素、微晶纤维素、润滑剂、粘合剂、崩解剂等。
本发明优选的药物形式为片剂、胶囊剂、薄膜包衣片、薄膜、栓剂、植入物、可注射无菌水性或油性溶液、混悬剂、乳剂、软膏、乳膏、凝胶、贴剂和鼻喷剂。
附图说明
图1参照US6174905B1制备的恩替诺特晶型A的XRPD图谱
图2参照CN102137846B制备的恩替诺特晶型B的XRPD图谱
图3参照CN102137846B制备的恩替诺特晶型C的XRPD图谱
图4本发明化合物A的晶型的XRPD图谱
图5本发明化合物B的晶型的XRPD图谱
图6本发明化合物C的晶型的XRPD图谱
图7本发明化合物D的晶型的XRPD图谱
图8本发明化合物A的晶型的DSC图谱
图9本发明化合物B的晶型的DSC图谱
图10本发明化合物A的晶型的TGA图谱
图11本发明化合物B的晶型的TGA图谱
图12本发明化合物A的晶型的IR图谱
图13本发明化合物B的晶型的IR图谱
具体实施方案
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8 Advance diffractometer。角度范围：3～40°2θ，步长：0.02°2θ，速度：0.2秒/步。
差热分析数据采自于TA Instruments Q200MDSC。10℃/min的升温速度，氮气保护。
热重分析数据采自于TA Instruments Q500TGA。采用分段高分辨检测的方式，10℃/min的升温速度，氮气保护。
核磁氢谱数据(1HNMR)采自于BrukerAvance II DMX 400MHZ核磁共振波谱仪。用氘代试剂溶解样品。
红外光谱分析(IR)数据采自于Bruker Tensor 27，使用漫反射(KBr)和ATR。
高效液相色谱(HPLC):仪器为Ultimate 3000，色谱柱YMC-Pack ODS-AQ (4.6*250mm*5μm)，柱温40℃，流速1.5mL/min，检测波长254nm，进样量3μL，运行时间40分钟，流动相乙腈：10mM磷酸二氢钾＝1:2的混合液。
实施例中所用的各种试剂如无特别说明均为市售购买。
实施例中如无特别说明均为室温操作。
制备例1
参考专利文献US6174905B1中实施例48的方法制备得到恩替诺特。
HPLC:在RRT＝1.403处，有1.42％的最大单质。
其XRPD图谱图1所示，与专利文献CN102137846B中所述晶型A衍射图谱一致。
制备例2
参考专利文献CN102137846B中实施例1的方法制备得到晶型B和晶型C。
晶型B的XRPD图谱如图2所示。
HPLC：在RRT＝1.403处，有1.43％的最大单质。
晶型C的XRPD图谱如图3所示。
在RRT＝1.403处，有1.42％的最大单质。
实施例1
取80mg恩替诺特，加入8mL乙醇形成溶液，缓慢滴加1mL含有富马酸(0.5倍摩尔量)的乙醇溶液，室温搅拌析晶，2天后，离心，室温真空干燥，得到78mg化合物A，产率为84％。
1H-NMR(500MHz,Methanol-d4)δppm：8.58(d,J＝2.3Hz,1H),8.50(dd,J＝4.9,1.7Hz,1H),7.94(d,J＝8.0Hz,2H),7.89(dt,J＝7.9,2.0Hz,1H),7.50–7.35(m,3H),7.22–7.16(m,1H),7.09(td,J＝7.7,1.5Hz,1H),6.92(dd,J＝8.0,1.5Hz,1H),6.79(td,J＝7.6,1.4Hz,1H),6.75(s,1H),5.18(s,2H),4.39(d,J＝5.4Hz,2H)，显示化合物A中恩替诺特与富马酸的摩尔比为1:0.5。
实施例2
取60mg恩替诺特，加入2mL乙醇，适度升温后形成溶液，缓慢滴加1mL含有富马酸(0.6倍摩尔量)的乙醇溶液，室温搅拌析晶，3天后，离心，室温真空干燥，得到60mg化合物A，产率为87％。
其XRPD图谱如图4所示，为结晶态化合物A。
其DSC图谱如图8所示，熔点为166℃。
其TGA图谱如图10所示，100℃之前失重0.3％，为无水物，分解温度为160℃。
实施例3
取45mg恩替诺特，加入3mL丙酮形成溶液，缓慢滴加1mL含有富马酸(0.8倍摩尔量)的丙酮溶液，10℃搅拌析晶，1天后，离心，室温真空干燥，得到39mg化合物A，产率为75％。
实施例4
取100mg恩替诺特，加入0.5mL甲醇和0.5mL丙酮，适度升温后形成溶液，缓慢滴加1mL含有富马酸(1倍摩尔量)的甲醇溶液，40℃搅拌析晶，3天后，离心，室温真空干燥，得到75mg化合物A，产率为65％。
实施例5
对实施例4中的溶剂按以下表格进行替换均可获得化合物A。
Figure PCTCN2017094851-appb-000006
实施例6
取25mg恩替诺特和3.9mg富马酸，加入5mL乙醇形成溶液，室温挥发至溶剂干，得到26mg化合物A，产率为90％。
实施例7
取200mg恩替诺特和37.0mg富马酸，加入10mL乙醇，适度升温后形成溶液，室温挥发至溶剂干，得到220mg化合物A，产率为95％。
实施例8
取50mg恩替诺特和15.4mg富马酸，加入1mL甲醇形成溶液，40℃挥发至溶剂干，得到48mg化合物A，产率为83％。
实施例9
取90mg恩替诺特和25.0mg富马酸，加入1.5mL甲醇和1.5mL丙酮形成溶液，10℃挥发至溶剂干，得到85mg化合物A，产率为82％。
实施例10
对实施例9中的溶剂按以下表格进行替换均可获得化合物A。
Figure PCTCN2017094851-appb-000007
实施例3～10制备得到的样品与实施例2的样品具有相同或相似的XRPD图谱(未示出)、DSC图谱(未示出)、TGA图谱(未示出)，说明实施例3～10样品与实施例2的样品是相同的化合物。
实施例11
取100mg恩替诺特，加入10mL乙醇形成溶液，缓慢滴加2mL含有马来酸(1倍摩尔量)的乙醇溶液，室温搅拌析晶，2天后，离心，室温真空干燥，得到108mg化合物B，产率为83％。
1H-NMR(500MHz,Methanol-d4)δppm：8.65(d,J＝2.1Hz,1H),8.56(dd, J＝5.2,1.6Hz,1H),8.03(dt,J＝7.9,1.9Hz,1H),7.98(d,J＝8.0Hz,2H),7.58(dd,J＝7.9,5.0Hz,1H),7.45(d,J＝8.0Hz,2H),7.32–7.24(m,1H),7.20(td,J＝7.7,1.5Hz,1H),7.07(dd,J＝8.0,1.4Hz,1H),6.99(td,J＝7.6,1.5Hz,1H),6.30(s,2H),5.23(s,2H),4.40(s,2H)，显示化合物B中恩替诺特与马来酸的摩尔比为1:1。
实施例12
取300mg恩替诺特，加入10mL乙醇，适度升温后形成溶液，缓慢滴加6mL含有马来酸(1.2倍摩尔量)的乙醇溶液，室温搅拌析晶，3天后，离心，室温真空干燥，得到349mg化合物B，产率为89％。
其XRPD图谱如图5所示，为结晶态化合物B。
其DSC图谱如图9所示，熔点为129℃。
其TGA图谱如图11所示，100℃之前失重0.3％，为无水物，分解温度为125℃。
实施例13
取15mg恩替诺特，加入1mL丁酮形成溶液，缓慢滴加0.5mL含有马来酸(1.3倍摩尔量)的丙酮溶液，10℃搅拌析晶，1天后，离心，室温真空干燥，得到15mg化合物B，产率为76％。
实施例14
取100mg恩替诺特，加入0.5mL乙醇和0.5mL丙酮，适度升温后形成溶液，缓慢滴加2mL含有马来酸(1.5倍摩尔量)的乙醇溶液，40℃搅拌析晶，3天后，离心，室温真空干燥，得到99mg化合物B，产率为76％。
实施例15
对实施例14中的溶剂按以下表格进行替换均可获得化合物B。
Figure PCTCN2017094851-appb-000008
实施例16
取200mg恩替诺特和61.7mg马来酸，加入40mL乙醇形成溶液，室温挥发至溶剂干，得到245mg化合物B，产率为94％。
实施例17
取200mg恩替诺特和74.0mg马来酸，加入10mL乙醇，适度升温后形成溶液，室温挥发至溶剂干，得到230mg化合物B，产率为88％。
实施例18
取100mg恩替诺特和46.3mg马来酸，加入2mL三氟乙醇，适度升温后形成溶液，10℃挥发至溶剂干，得到107mg化合物B，产率为82％。
实施例19
取120mg恩替诺特和55.5mg马来酸，加入1.5mL乙醇和1.5mL丙酮，适度升温后形成溶液，40℃挥发至溶剂干，得到125mg化合物B，产率为80％。
实施例20
对实施例9中的溶剂按以下表格进行替换均可获得化合物B。
Figure PCTCN2017094851-appb-000009
实施例13～20制备得到的样品与实施例12的样品具有相同或相似的XRPD图谱(未示出)、DSC图谱(未示出)、TGA图谱(未示出)，说明实施例13～20样品与实施例12的样品是相同的化合物。
实施例21
取100mg恩替诺特和15.7mg琥珀酸，加入4mL四氢呋喃形成溶液，室温挥发至溶剂干，得到90mg化合物C，产率为78％。
其XRPD图谱如图6所示，为结晶态化合物C。
实施例22
取80mg恩替诺特，加入5mL丙酮形成溶液，缓慢滴加1mL含有己二酸(1.25倍摩尔量)的丙酮溶液，室温搅拌析晶，1天后，离心，室温真空干燥，得到86mg化合物D，产率为77％。
其XRPD图谱如图7所示，为结晶态化合物D。
实施例23
Figure PCTCN2017094851-appb-000010
将化合物A或化合物B、淀粉和硬脂酸镁混合并通过20目筛，以414mg的量装填到硬胶囊中。
实施例24
Figure PCTCN2017094851-appb-000011
将上述组份混合并压制成片剂，每片重223mg。
对比例1
取恩替诺特、本发明中的化合物A和化合物B进行表观水中溶解度测试，具体操作如下：
取约3mg样品置于100mL锥形瓶中，水浴温度为25℃±2℃，通过倍增法添加水，搅拌(约200转/分钟)，目测是否溶清，每次加水间隔3分钟，最大加水量为60mL。
结果见下表，显示本发明的化合物A和化合物B的水溶性均优于现有技术的恩替诺特。
Figure PCTCN2017094851-appb-000012
对比例2
分别取适量本发明中的化合物A的晶型和化合物B的晶型进行晶型稳定性试验，试验条件为:室温、高温(50℃)，试验结果见下表：
Figure PCTCN2017094851-appb-000013
结果显示：本发明恩替诺特化合物A的晶型和化合物B的晶型在室温和高温条件下放置14天晶型均未改变，晶型稳定性好。
对比例3
1、分别取适量恩替诺特和本发明中化合物A进行HPLC检测，计算RRT＝1.403处最大单杂的情况和纯度。
2、对恩替诺特和本发明中化合物A进行化学稳定性试验，试验条件为:室温、高温(40℃)、高湿(75％RH)和加速(40℃-75％RH)，放置时间为14天，进行HPLC检测，计算RRT＝1.403处最大单杂的变化情况、主成分变化情况和总杂个数变化情况。试验结果见下表：
Figure PCTCN2017094851-appb-000014
Figure PCTCN2017094851-appb-000015
结果显示：
1、相对于恩替诺特，本发明的化合物A中RRT＝1.403处的最大单杂明显降低，杂质个数少，纯度高。
2、恩替诺特和本发明的化合物A在室温、高温、高湿和加速条件下放置14天后，RRT＝1.403处杂质、主成分和杂质个数基本没变化。
以上结果说明：本发明的化合物A相对于恩替诺特，具有更低的杂质(RRT＝1.403)含量，更少的杂质数目和更高的化学纯度，且在常温、高温、高湿和加速条件下具有优良的化学稳定性。
对比例4
分别将50毫克制备例1的恩替诺特和50毫克本发明中的化合物B在1.3毫升甲醇中搅拌，加热溶解，1小时后再降温到4℃重结晶，进行HPLC检测。实验结果：恩诺特替经过重结晶后RRT＝1.403的杂质没有改变，和未重结晶前一致，为1.42％，主成分纯度为98.4％；本发明中的化合物B RRT＝1.403的杂质由未重结晶前的1.53％降为重结晶后的1.27％，主成分纯度由未重结晶前的98.3％提高到重结晶后的98.5％。结果显示相比现有的恩替诺特，本发明中的化合物B更易通过有机溶剂重结晶提高纯度。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (19)

  1. 一种如式(II)的化合物A：
    Figure PCTCN2017094851-appb-100001
  2. 根据权利要求1所述的化合物A，其特征在于，所述化合物A为恩替诺特与富马酸形成的共晶或盐，优选为共晶。
  3. 根据权利要求1或2所述的化合物A，其特征在于，所述化合物A为结晶态，使用Cu-Kα辐射，其X-射线粉末衍射图在2θ值为3.9°±0.2°、13.4°±0.2°、16.4°±0.2°和18.8°±0.2°处具有特征峰。
  4. 根据权利要求3所述的化合物A，其特征在于，所述结晶态化合物A的X-射线粉末衍射图还在2θ值为11.5°±0.2°、15.3°±0.2°、18.3°±0.2°和19.7°±0.2°处具有特征峰。
  5. 根据权利要求4所述的化合物A，其特征在于，所述结晶态化合物A的X-射线粉末衍射图还在2θ值为7.7°±0.2°、10.9°±0.2°、22.8°±0.2°和26.2°±0.2°处具有特征峰。
  6. 根据权利要求3-5中任一项所述的化合物A，其特征在于，所述化合物A的傅里叶红外光谱在波数为3369cm-1±2cm-1、1713cm-1±2cm-1、1664cm-1±2cm-1、1605cm-1±2cm-1、1556cm-1±2cm-1、1504cm-1±2cm-1、1282cm-1±2cm-1、1248cm-1±2cm-1、1220cm-1±2cm-1、1135cm-1±2cm-1、1044cm-1±2cm-1、759cm-1±2cm-1、712cm-1±2cm-1和640cm-1±2cm-1处具有特征峰。
  7. 根据权利要求1-2中任一项所述的化合物A的制备方法，包括将恩替诺特与半个当量到一个当量的富马酸直接反应的方式，优选在有机溶剂或溶剂组合中酸碱反应的方式；所述有机溶剂为可以溶解恩替诺特或富马酸的溶剂。
  8. 权利要求3～6中任一项所述的化合物A的晶型的制备方法，所述制备方法包括下述方法中的任意一种：
    (1)分别将恩替诺特和富马酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述的化合物A的晶型；所述溶剂为醇类或酮类，更优选为乙醇；
    优选地，所述恩替诺特与富马酸选择同一种溶剂形成溶液；
    优选地，所述恩替诺特与溶剂形成溶液时的质量体积比为10mg/mL～100mg/mL，更优选为10mg/mL～30mg/mL；
    优选地，所述恩替诺特与富马酸的摩尔比为1:0.5～1:1.0，更优选为1:0.6～1:0.7；
    优选地，所述搅拌时间为1天～3天；
    优选地，所述操作过程在10℃～40℃下进行，更优选在室温下进行；
    (2)将恩替诺特与富马酸的混合物在溶剂中形成溶液，挥发至溶剂干，得到所述的化合物A的晶型；所述溶剂为醇类或酮类，更优选为乙醇；
    优选地，所述恩替诺特与溶剂的质量体积比为5mg/mL～50mg/mL，更优选为5mg/mL～20mg/mL；
    优选地，所述恩替诺特与富马酸的摩尔比为1:0.5～1:1.0，更优选为1:0.6～1:0.7；
    优选地，所述挥发过程在10℃～40℃下进行，更优选在室温下进行。
  9. 一种如式(III)的化合物B：
    Figure PCTCN2017094851-appb-100002
  10. 根据权利要求9所述的化合物B，其特征在于，所述化合物B为恩替诺特与马来酸形成的共晶或盐，优选为共晶。
  11. 根据权利要求9或10所述的化合物B，其特征在于，所述化合物B为结晶态，使用Cu-Kα辐射，其X-射线粉末衍射图在2θ值为9.8°±0.2°、15.9°±0.2°、19.7°±0.2°和23.2°±0.2°处具有特征峰。
  12. 根据权利要求11所述的化合物B，其特征在于，所述结晶态化合物B的X-射线粉末衍射图还在2θ值为14.1°±0.2°、14.8°±0.2°、17.7°±0.2°和18.9°±0.2°处具有特征峰。
  13. 根据权利要求12所述的化合物B，其特征在于，所述结晶态化合物B的X-射线粉末衍射图还在2θ值为14.5°±0.2°、21.4°±0.2°、23.8°±0.2°和24.8°±0.2°处具有特征峰。
  14. 根据权利要求10-13中任一项所述的化合物B，其特征在于，所述化合物B的傅里叶红外光谱在波数为3298cm-1±2cm-1、1718cm-1±2cm-1、1545cm-1±2cm-1、1499cm-1±2cm-1、1363cm-1±2cm-1、1313cm-1±2cm-1、1248cm-1±2cm-1、1147cm-1±2cm-1、1044cm-1±2cm-1、992cm-1±2cm-1、860cm-1±2cm-1、750cm-1±2cm-1、703cm-1±2cm-1和645cm-1±2cm-1处具有特征峰。
  15. 根据权利要求9-10中任一项所述的化合物B的制备方法，包括将恩替诺特酸与一个当量到1.5个当量的马来酸碱直接反应的方式，优选在有机溶剂或溶剂组合液中酸碱反应的方式；所述有机溶剂为可以溶解恩替诺特或马 来酸的溶剂。
  16. 权利要求11～14中任一项所述的化合物B的晶型的制备方法，所述制备方法包括下述方法中的任意一种：
    (1)分别将恩替诺特和马来酸在溶剂中形成溶液，混合后搅拌析晶，进而分离晶体，干燥，得到所述的化合物B的晶型；所述溶剂为醇类或酮类，更优选为乙醇；
    优选地，所述恩替诺特与马来酸选择同一种溶剂形成溶液；
    优选地，所述恩替诺特与溶剂形成溶液时的质量体积比为10mg/mL～100mg/mL，更优选为10mg/mL～30mg/mL；
    优选地，所述恩替诺特与马来酸的摩尔比为1:1.0～1:1.5，更优选为1:1.0～1:1.2；
    优选地，所述搅拌时间为1天～3天；
    优选地，所述操作过程在室温下进行；
    (2)将恩替诺特与马来酸的混合物在溶剂中形成溶液，挥发至溶剂干，得到所述的化合物B的晶型；所述溶剂为醇类或酮类，更优选为乙醇；
    优选地，所述恩替诺特与溶剂的质量体积比为5～50mg/mL，更优选为5mg/mL～20mg/mL；
    优选地，所述恩替诺特与马来酸的摩尔比为1:1.0～1:1.5，更优选为1:1.0～1:1.2；
    优选地，所述挥发过程在室温下进行。
  17. 一种药物组合物，其包含治疗有效量的权利要求1～6中任一项所述的化合物A，权利要求9～14中任一项所述的化合物B，以及至少一种药学上可接受的载体或助剂。
  18. 权利要求1～6中任一项所述的化合物A，权利要求9～14中任一项所述的化合物B在制备用于治疗或预防与哺乳动物分化或增殖相关的疾病中的用途增殖。
  19. 一种治疗和/或预防与哺乳动物分化或增殖相关的疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的一种或多种选自权利要求1～6中任一项所述的化合物A，权利要求9～14中任一项所述的化合物B或权利要求17所述的药物组合物。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11208382B2 (en) 2017-07-28 2021-12-28 Hangzhou Solipharma Co., Ltd. Entinostat-containing compound, crystal form of compound thereof, and preparation method therefor and pharmaceutical composition thereof

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174905B1 (en) * 1996-09-30 2001-01-16 Mitsui Chemicals, Inc. Cell differentiation inducer
JP4360660B2 (ja) * 1999-11-09 2009-11-11 三井化学株式会社 モノアシルフェニレンジアミン誘導体の精製法
CN102137846A (zh) * 2008-08-29 2011-07-27 拜耳先灵医药股份有限公司 N-(2-氨基苯基)-4-[n-(吡啶-3-基)甲氧基羰基氨基甲基]苯甲酰胺(ms-275)多晶型物b

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3354090B2 (ja) * 1996-09-30 2002-12-09 シエーリング アクチエンゲゼルシャフト 分化誘導剤
WO2004058234A2 (en) * 2002-12-27 2004-07-15 Schering Aktiengesellschaft Pharmaceutical combinations of phthalazine vegf inhibitors and benzamide hdac inhibitors
CN110944978A (zh) 2017-07-28 2020-03-31 杭州领业医药科技有限公司 含恩替诺特的化合物,其化合物晶型及其制备方法和药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174905B1 (en) * 1996-09-30 2001-01-16 Mitsui Chemicals, Inc. Cell differentiation inducer
JP4360660B2 (ja) * 1999-11-09 2009-11-11 三井化学株式会社 モノアシルフェニレンジアミン誘導体の精製法
CN102137846A (zh) * 2008-08-29 2011-07-27 拜耳先灵医药股份有限公司 N-(2-氨基苯基)-4-[n-(吡啶-3-基)甲氧基羰基氨基甲基]苯甲酰胺(ms-275)多晶型物b

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11208382B2 (en) 2017-07-28 2021-12-28 Hangzhou Solipharma Co., Ltd. Entinostat-containing compound, crystal form of compound thereof, and preparation method therefor and pharmaceutical composition thereof

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