WO2019057142A1 - 一种内磺酰胺化合物结晶 - Google Patents

一种内磺酰胺化合物结晶 Download PDF

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WO2019057142A1
WO2019057142A1 PCT/CN2018/106889 CN2018106889W WO2019057142A1 WO 2019057142 A1 WO2019057142 A1 WO 2019057142A1 CN 2018106889 W CN2018106889 W CN 2018106889W WO 2019057142 A1 WO2019057142 A1 WO 2019057142A1
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Prior art keywords
formula
compound
crystal
ray powder
crystallization
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PCT/CN2018/106889
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English (en)
French (fr)
Inventor
张喜全
徐文卫
李明明
孔敏敏
吴叔峰
张爱明
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Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Original Assignee
Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Application filed by Centaurus Biopharma Co Ltd, Chia Tai Tianqing Pharmaceutical Group Co Ltd, Lianyungang Runzhong Pharmaceutical Co Ltd filed Critical Centaurus Biopharma Co Ltd
Priority to JP2020516394A priority Critical patent/JP6951562B2/ja
Priority to FIEP18859556.5T priority patent/FI3686191T3/fi
Priority to KR1020207011426A priority patent/KR102707847B1/ko
Priority to EP18859556.5A priority patent/EP3686191B1/en
Priority to PL18859556.5T priority patent/PL3686191T3/pl
Priority to CA3076405A priority patent/CA3076405A1/en
Priority to AU2018337153A priority patent/AU2018337153B2/en
Priority to US16/649,120 priority patent/US11254665B2/en
Priority to CN201880059881.0A priority patent/CN111065630B/zh
Publication of WO2019057142A1 publication Critical patent/WO2019057142A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 belongs to the technical field of medicine and relates to a crystal of an internal sulfonamide compound, and more particularly to (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3- Difluorocyclobutyl)amino)-2-oxoethyl)-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-isothiazolidine-3-carboxamide 1 , 1-dioxide crystals, a process for the preparation thereof, a crystal composition, a pharmaceutical composition and use thereof.
  • IDH isocitrate dehydrogenase
  • NAD(+) as an electron acceptor
  • NADP(+) as an electron acceptor
  • IDHs There are five IDHs reported, three of which are NAD(+)-dependent isocitrate dehydrogenases, which are located in the mitochondrial matrix; and two are NADP(+)-dependent isocitrate dehydrogenases, one Located in the mitochondria and the other in the cytoplasm.
  • IDH mutations there are IDH mutations in various tumors (such as glioma, sarcoma, acute myeloid leukemia, etc.), and the mutation site is the arginine residue located in the catalytic center (IDH1/R132H, IDH2/R140Q, IDH2/R172K).
  • Bleeker et al. performed IDH1 mutations on 672 tumors from different sources and 84 different tumor cell lines, and found that this mutation was specifically concentrated in glioma [Bleeker et al., 2009. IDH1 Mutations at residue p.R132(IDH1(R132))occur frequently in high-grade gliomas but not in other solid tumors.Hum Mutat.30:7-11.].
  • An internal sulfonamide compound of the formula I having the chemical name: (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluoro) Cyclobutyl)amino)-2-oxoethyl)-2-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-isothiazolidine-3-carboxamide 1,1 - dioxide,
  • One aspect of the present application is to provide a compound of formula I, characterized in that the compound of formula I is in crystalline form.
  • the crystal may be a crystal of an unsolvate or a crystal of a solvate such as a hydrate crystal.
  • the crystal of the compound of the formula I has a good IDH1 inhibitory activity, and the crystal exhibits high stability, has advantages in physical properties, safety and metabolic stability, and has high pharmaceutical value.
  • Another aspect of the present application is to provide a hydrate crystal of a compound of formula I, said hydrate crystal comprising from 0.5 to 3 water molecules per molecule.
  • Another aspect of the present application is to provide a monohydrate of Formula II,
  • the monohydrate of Formula II is in crystalline form.
  • the monohydrate crystal of Formula II is characterized in that the X-ray powder diffraction spectrum has diffraction peaks at about 14.40°, 20.28°, 20.94°, 22.02°, and 24.46° as indicated by 2 ⁇ values. .
  • the monohydrate crystal of Formula II is characterized in that the X-ray powder diffraction spectrum is represented by 2 ⁇ values at about 9.12°, 13.32°, 14.40°, 15.64°, 16.46°, 20.28°, There are diffraction peaks at 20.94°, 22.02°, 22.98°, 24.46°, and 29.34°.
  • the monohydrate crystal of Formula II is characterized in that the X-ray powder diffraction spectrum is expressed by 2 ⁇ values at about 5.52°, 9.12°, 13.32°, 14.40°, 15.64°, 16.46°, There are diffraction peaks at 19.14, 19.32, 20.28, 20.94, 21.20, 22.02, 22.98, 23.52, 24.46, 26.06, 29.34 and 31.74.
  • the monohydrate crystal of Formula II is characterized in that the X-ray powder diffraction spectrum is expressed by 2 ⁇ values at about 5.52°, 9.12°, 13.32°, 14.40°, 14.90°, 15.64°, 16.46, 19.14, 19.32, 20.28, 20.94, 21.20, 22.02, 22.98, 23.52, 24.46, 25.74, 26.06, 27.32, 27.98, 28.90, 29.34, 31.00 There are diffraction peaks at 31.74°, 32.22° and 33.32°.
  • the monohydrate crystal of Formula II is characterized in that the X-ray powder diffraction spectrum is expressed by 2 ⁇ values at about 5.52°, 9.12°, 10.30°, 10.48°, 11.96°, 13.32°, 14.40, 14.90, 15.64, 16.46, 17.28, 17.58, 18.60, 19.14, 19.32, 20.28, 20.94, 21.20, 22.02, 22.98, 23.52, 24.46, 25.74 There are diffraction peaks at 26.06°, 26.74°, 27.32°, 27.98°, 28.40°, 28.90°, 29.34°, 30.36°, 31.00°, 31.74°, 32.22°, 32.82°, 33.32° and 37.84°.
  • the monohydrate crystal of Formula II has peak characteristics and intensity of X-ray powder diffraction spectrum characteristic peaks as shown in Table 1:
  • the monohydrate crystal of Formula II has an X-ray powder diffraction spectrum as shown in FIG.
  • the monohydrate crystal of Formula II has a differential scanning calorimetry (DSC) measurement map having a starting point at about 186 ° C and an absorption peak at about 193 ° C.
  • DSC differential scanning calorimetry
  • the monohydrate crystal of Formula II has a differential scanning calorimetry (DSC) measurement chart as shown in FIG.
  • the monohydrate crystal of Formula II has a thermogravimetric analysis (TGA) pattern as shown in FIG.
  • Another aspect of the present application is to provide a crystalline composition wherein the monohydrate crystal of the above formula II accounts for 50% or more, preferably 70% or more, more preferably 75% or more, based on the weight of the crystalline composition. More preferably, it is 80% or more, more preferably 90% or more, more preferably 95% or more, and most preferably 98% or more.
  • the crystalline composition may also contain minor amounts of other crystalline or amorphous forms of the compound of formula I.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of a monohydrate crystal of the above formula II, or a crystalline composition of the monohydrate crystal of the above formula II.
  • the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier or other excipient.
  • the present application provides a monohydrate crystal of the above formula II, a crystalline composition of the monohydrate crystal of the above formula II, or a pharmaceutical composition as described above for use in the preparation of a medicament for treating cancer induced by an IDH1 mutation. use.
  • the monohydrate crystal of the above formula II of the present application, the crystalline composition of the monohydrate crystal of the above formula II, or the above pharmaceutical composition may be used alone or in combination with other drugs for the preparation of a cancer induced by the IDH1 mutation. medicine.
  • the application provides a method of treating cancer induced by an IDH1 mutation comprising administering to a mammal in need thereof a therapeutically effective amount of a monohydrate crystal of the above formula II, crystal of the monohydrate crystal of the above formula II A composition, or a pharmaceutical composition as described above.
  • the mammal is preferably a human.
  • the present application provides a monohydrate crystal of the above formula II for treating cancer caused by an IDH1 mutation, a crystalline composition of the monohydrate crystal of the above formula II, or the above pharmaceutical composition.
  • Another aspect of the present application is to provide a non-solvent crystalline form of the compound of Formula I.
  • the crystallization of the compound of formula I is characterized in that the X-ray powder diffraction spectrum has a diffraction peak at about 8.64, 9.34, 20.72, 21.30 or 24.02 with a 2 theta value.
  • the crystallization of the compound of formula I characterized in that the X-ray powder diffraction spectrum is represented by 2 ⁇ values at about 8.64°, 9.34°, 14.62°, 19.66°, 20.04°, 20.46°, 20.72°. There are diffraction peaks at 21.30°, 22.46°, 24.02° or 27.42°.
  • the crystallization of the compound of Formula I is characterized by an X-ray powder diffraction spectrum expressed by 2 ⁇ values at about 8.64°, 9.34°, 14.62°, 15.18°, 16.36°, 17.04°, 17.60°. There are diffraction peaks at 18.40, 19.66, 20.04, 20.46, 20.72, 21.30, 22.16, 22.46, 24.02, 27.42, 28.46 or 30.16.
  • the crystallization of the compound of Formula I is characterized by an X-ray powder diffraction spectrum expressed by 2 ⁇ values at about 8.64°, 9.34°, 14.62°, 15.18°, 16.36°, 17.04°, 17.60°. , 18.14°, 18.40°, 18.88°, 19.66°, 20.04°, 20.46°, 20.72°, 21.30°, 22.16°, 22.46°, 22.92°, 23.16°, 24.02°, 25.14°, 25.48°, 25.92°, 27.42 There are diffraction peaks at °, 28.46° or 30.16°.
  • the crystallization of the compound of Formula I is characterized by an X-ray powder diffraction spectrum expressed as a value of 2 ⁇ at about 8.64°, 9.34°, 11.18°, 12.80°, 13.68°, 14.62°, 15.18°.
  • the crystallization of the compound of Formula I, the peak position and intensity of the characteristic peak of the X-ray powder diffraction spectrum have the characteristics shown in Table 2:
  • the X-ray powder diffraction spectrum of the crystal of the compound of Formula I is shown in FIG.
  • the crystallization of the compound of Formula I, the differential scanning calorimetry (DSC) measurement chart has a starting point at about 103 ° C and an absorption peak at about 130 ° C.
  • the crystallization of the compound of Formula I, the thermogravimetric analysis (TGA) pattern is shown in FIG.
  • the crystallization of the compound of the above formula I may be converted to the monohydrate of the above formula II in the presence of water, wherein the source of water may be a small amount of water contained in the solvent during the preparation, or may be prepared.
  • the filtration and drying steps contact the water in the environment or contact the water in the environment during storage.
  • the crystal of the compound of the above formula I is isolated from the source of all water during the preparation and storage process, and the obtained crystal of the compound of the formula I can be substantially pure relative to the monohydrate crystal of the above formula II. form.
  • Another aspect of the present application provides a crystalline composition wherein the crystalline compound of the above formula I accounts for more than 50% by weight, preferably more than 70%, more preferably 75% or more, more preferably more than 75% by weight of the crystalline composition. 80% or more, more preferably 90% or more, more preferably 95% or more, and most preferably 98% or more.
  • the crystalline composition may also contain minor amounts of other crystalline or amorphous forms of the compound of formula I, such as the monohydrate crystal of formula II.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline composition of a compound of formula I above, or a crystalline composition of a compound of formula I above.
  • the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier or other excipient.
  • the application provides a crystalline composition of a compound of formula I above, a crystalline composition of a compound of formula I above, or a use of a pharmaceutical composition as described above for the manufacture of a medicament for the treatment of a cancer induced by an IDH1 mutation.
  • the crystalline compound of the above formula I of the present application is crystallized, the crystalline composition of the above compound of the formula I, or the above pharmaceutical composition can be used alone or in combination with other drugs for the preparation of a medicament for treating cancer induced by the IDH1 mutation.
  • the application provides a method of treating cancer induced by an IDH1 mutation comprising administering to a mammal in need thereof a therapeutically effective amount of a crystalline composition of a compound of formula I above, a crystalline composition of a compound of formula I above, or a medicament as described above combination.
  • the mammal is preferably a human.
  • the application provides a crystalline composition of the above compound of formula I, a crystalline composition of a compound of formula I above, or a pharmaceutical composition as described above, for use in the treatment of a cancer induced by an IDH1 mutation.
  • Another aspect of the present application is to provide an amorphous form of a compound of formula I.
  • the amorphous form of the compound of formula I has an X-ray powder diffraction spectrum as shown in FIG.
  • the amorphous form of the compound of Formula I has a differential scanning calorimetry (DSC) measurement map having a starting point at about 103 ° C and an absorption peak at about 121 ° C.
  • DSC differential scanning calorimetry
  • the amorphous form of the compound of Formula I is shown in FIG.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound amorphous form of formula I.
  • the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier or other excipient.
  • the application provides the use of a compound of formula I, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a cancer induced by an IDH1 mutation.
  • the pharmaceutically acceptable carrier can be either solid or liquid.
  • the solid carrier can include one or more of a flavoring agent, a lubricant, a solubilizing agent, a suspending agent, a filler, a binder, a tablet disintegrating agent, or an encapsulating material.
  • Suitable solid carriers include, for example, magnesium stearate, talc, sucrose, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone.
  • Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups and the like.
  • Suitable liquid carriers for oral and parenteral administration include water, alcohols, oils and the like.
  • the pharmaceutical composition can be formulated into a certain dosage form, and the administration route is preferably oral administration, parenteral administration (including subcutaneous, intramuscular, and intravenous), rectal administration, and the like.
  • parenteral administration including subcutaneous, intramuscular, and intravenous
  • rectal administration and the like.
  • dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, troches, syrups or suspensions
  • suitable forms for parenteral administration include aqueous or non-aqueous injections.
  • Solutions or emulsions; dosage forms suitable for rectal administration include suppositories using hydrophilic or hydrophobic carriers.
  • the above dosage forms may also be formulated into a dosage form suitable for rapid release, delayed release or modified release of the active ingredient, as desired.
  • the IDH1 mutation described herein has a R132X mutation; in some embodiments of the present application, the R132X mutation is selected from the group consisting of R132H, R132C, R132L, R132V, R132S, and R132G; in some preferred embodiments, the R132X mutation is selected from the group consisting of R132H and R132C .
  • the cancer induced by the IDH1 mutation is selected from the group consisting of glioblastoma (glioma), myelodysplastic syndrome (MDS), and myeloid proliferative neoplasm (MPN).
  • glioblastoma glioma
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML Acute myeloid leukemia
  • sarcoma preferably chondrosarcoma, fibrosarcoma
  • melanoma non-small cell lung cancer
  • the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN), acute myeloid leukemia (AML), cholangiocarcinoma, chondrosarcoma Or angioimmunoblastic non-Hodgkin's lymphoma (NHL) or the like, preferably including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), glioma, cholangiocarcinoma or chondrosarcoma.
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • cholangiocarcinoma chondrosarcoma
  • NDL angioimmunoblastic non-Hodgkin's lymphoma
  • AML acute myeloid leukemia
  • MDS myelodysplastic
  • Another aspect of the present application provides a process for the preparation of a monohydrate crystal of formula II, which comprises: (1) dissolving a compound of formula I in an organic solvent, stirring until the solution is clear; (2) adding water to step (1). In solution; (3) cooling and crystallization, filtration, and drying.
  • the organic solvent in the step (1) is selected from the group consisting of methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, acetone, tetrahydrofuran, and acetonitrile.
  • the molar volume ratio of the compound of the formula I to the organic solvent in the step (1) is 1 mmol: 2 to 20 mL; preferably 1 mmol: 2 to 15 mL. Further preferably 1 mmol: 2 to 10 mL.
  • the temperature of the compound of the formula I in the step (1) dissolved in the organic solvent is 20 to 100 ° C; preferably 20 to 80 ° C; further preferably 20 to 60 ° C.
  • the molar volume ratio of the compound of the formula I in the step (1) to the water in the step (2) is 1 mmol: 0.01 to 5 mL; preferably 1 mmol: 0.01 to 3 mL; further preferably 1 mmol: 0.05 to 2 mL.
  • the crystallization temperature in the step (3) is -10 ° C to 25 ° C; preferably 0 ° C to 10 ° C; further preferably 0 ° C - 5 ° C.
  • the drying conditions in the step (3) include drying at room temperature, drying under reduced pressure or blast drying, preferably under reduced pressure.
  • the drying equipment is a fume hood, a vacuum oven or a blast oven, preferably a vacuum oven.
  • the drying temperature is from 20 ° C to 60 ° C; preferably from 20 ° C to 40 ° C; more preferably from 30 ° C to 40 ° C.
  • the source of water in the method for preparing the monohydrate crystal of Formula II, may be water contained in the organic solvent in addition to the step (2), or the container may be in open contact during the preparation process. Moisture in the environment, or contact with the environment during crystallization, filtration, and drying.
  • the application provides a method for preparing the crystal of the compound of the above formula I, comprising: (1) dissolving the compound of the formula I in an anhydrous organic solvent, stirring until the solution is clarified, adding 4A molecular sieve for drying; (2) filtering with nitrogen, filtering the filtrate Cooling and crystallization; (3) Nitrogen protection filtration and drying.
  • the anhydrous organic solvent in the step (1) is selected from the group consisting of dichloromethane, isopropanol, n-hexane, ethyl acetate or methyl tert-butyl.
  • One or more mixed solvents in the ether preferably dichloromethane or isopropanol; further preferably dichloromethane.
  • the molar volume ratio of the compound of the formula I in the step (1) to the anhydrous organic solvent is 1 mmol: 2 to 10 mL; preferably 1 mmol: 2 to 8 mL. Further preferably 1 mmol: 3 to 5 mL.
  • the step of adding the 4A molecular sieve to the step (1) is dried for 1 to 4 hours; preferably 1 to 3 hours; further preferably 1 to 2 hours.
  • the mass to volume ratio of the 4A molecular sieve to the anhydrous organic solvent in the step (1) is 1 g: 2 to 10 mL; preferably 1 g: 2 to 6 mL; More preferably, it is 1 g: 4-6 mL.
  • the compound of the formula I in the step (1) is dissolved in an anhydrous organic solvent at a temperature of 20 to 100 ° C; preferably 20 to 80 ° C; further preferably 20 to 60 ° C.
  • the crystallization temperature in the step (2) is -20 ° C to 25 ° C; preferably -10 ° C to 10 ° C; further preferably - 10 ° C - 0 ° C.
  • the drying conditions in the step (3) include drying at room temperature, drying under reduced pressure or drying by air, preferably drying under reduced pressure.
  • the drying equipment is a fume hood, a vacuum oven or a blast oven, preferably a vacuum oven.
  • the drying temperature is from 20 ° C to 60 ° C; preferably from 20 ° C to 40 ° C; more preferably from 30 ° C to 40 ° C.
  • the present application provides a process for the preparation of an amorphous form of a compound of formula I, which comprises: (1) dissolving a compound of formula I in an anhydrous organic solvent, stirring until the solution is clear; (2) concentrating under reduced pressure to give a solid, dry.
  • the anhydrous organic solvent in the step (1) is selected from the group consisting of ethyl acetate, dichloromethane, methanol, ethanol, and acetone. Or a plurality of mixed solvents; preferably one or more mixed solvents of ethyl acetate, dichloromethane or methanol; further preferably a mixed solvent of dichloromethane, ethyl acetate and dichloromethane.
  • the molar volume ratio of the compound of the formula I and the anhydrous organic solvent in the step (1) is 1 mmol: 1 to 10 mL; preferably 1 mmol: 2 ⁇ 8 mL; further preferably 1 mmol: 3 to 6 mL.
  • the compound of the formula I in the step (1) is dissolved in an anhydrous organic solvent at a temperature of 20 to 60 ° C; preferably 20 to 40 ° C; More preferably, it is 20-30 degreeC.
  • the drying conditions described in the step (2) include drying at room temperature, drying under reduced pressure or blast drying, preferably under reduced pressure.
  • the drying equipment is a fume hood, a vacuum oven or a blast oven, preferably a vacuum oven.
  • the drying temperature is from 20 ° C to 60 ° C; preferably from 20 ° C to 40 ° C; more preferably from 30 ° C to 40 ° C.
  • the X-ray powder diffraction spectrum of the sample was measured under the following conditions: Instrument: Minflex II; Sample pretreatment: Direct compression; Sample tray: Glass tank; DivSlit: 1.25°; SctSlit: 1.25°; RecSlit: 0.3 mm 2 ⁇ angle range: 3 ⁇ 60 °; scanning speed 10 ° / min; Cu target tube pressure and current: 30KV, 15mA.
  • the DSC spectrum was measured under the following conditions: instrument: METTLER TOLEDO DSC1; temperature range: 40-300 ° C; heating rate: 10 ° C/min.
  • thermogravimetric analysis was carried out under the following conditions: instrument: NETZSCH TG 209F3; temperature range: 30 to 300 ° C; heating rate: 10 ° C / min.
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the band (especially at a low angle) may be due to crystallization.
  • the dominant orientation effect due to the difference in conditions, particle size, and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of the XRD spectrum have similarities as a whole, and the relative intensity error may be large.
  • DSC measures the transition temperature when crystallization absorbs or releases heat due to changes in its crystal structure or crystal melting.
  • the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ⁇ 5 °C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range.
  • the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance.
  • “Mammal” includes humans and domestic animals such as laboratory mammals and domestic pets (e.g., cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domestic mammals, such as wild mammals.
  • pharmaceutical composition refers to a formulation of a compound of the present application and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes all pharmaceutically acceptable carriers for its use.
  • the pharmaceutical composition facilitates administration of the compound to the organism.
  • terapéuticaally effective amount refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • &quot pharmaceutically acceptable carrier" refers to those carriers which are administered with the active ingredient which are not irritating to the organism and which do not impair the biological activity and properties of the active compound.
  • pharmaceutically acceptable carrier&quot refers to those carriers which are administered with the active ingredient which are not irritating to the organism and which do not impair the biological activity and properties of the active compound.
  • room temperature means 20 to 25 °C.
  • the source of the anhydrous organic solvent may be commercially available or may be obtained by a laboratory anhydrous treatment of a commercially available organic solvent.
  • the laboratory treatment method of anhydrous dichloromethane is: adding calcium hydride to dichloromethane for reflux for 3-4 hours, distilling, and storing by 4A molecular sieve.
  • Figure 1 is an X-ray powder diffraction pattern (XRPD) of the monohydrate crystal of Formula II of Example 5.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) diagram of the monohydrate crystal of Formula II of Example 5.
  • XRPD X-ray powder diffraction pattern
  • Figure 5 is a differential scanning calorimetry (DSC) curve for the crystallization of the compound of Formula I of Example 7.
  • FIG. 6 is a thermogravimetric analysis (TGA) diagram of the crystallization of the compound of Formula I of Example 7.
  • Figure 7 is an X-ray powder diffraction pattern (XRPD) of the amorphous material of Example 9.
  • Figure 8 is a differential scanning calorimetry (DSC) curve for the amorphous material of Example 9.
  • Figure 9 is an X-ray powder diffraction pattern calculated for the single crystal of Example 4.
  • Step B (S)-2-Amino-4-chlorosulfonylbutanoic acid methyl ester hydrochloride
  • Step D (S)-2-(4-cyanopyridin-2-yl)isothiazolidine-3-carboxylic acid methyl ester 1,1-dioxide
  • Step E (S)-2-(4-cyanopyridin-2-yl)isothiazolidine-3-carboxylic acid 1,1-dioxide
  • Step F (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-2 -(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-isothiazolidine-3-carboxamide 1,1-dioxide
  • Example 1 1.0 g of the compound of the formula I prepared in Example 1 was added to 2.5 mL of anhydrous methanol, stirred until it was dissolved, and the membrane was filtered. 2 mL of the above filtrate was taken, 0.2 mL of water was added to the filtrate, and the mixture was allowed to stand at room temperature, and crystals were gradually precipitated, and the crystal was a single crystal of the formula II monohydrate crystal.
  • Example 3 Unit cell parameters of the crystal of formula II monohydrate
  • Example 4 Single crystal of formula II monohydrate crystallized X-ray powder diffraction data
  • Example 1 1.0 g of the compound of the formula I prepared in Example 1 was added to 5 mL of anhydrous dichloromethane, stirred at room temperature to dissolve, and 1 g of 4A molecular sieves were added, and the mixture was stirred and dried for 2 hours, and filtered under nitrogen. The filtrate was concentrated to a half volume of solvent under reduced pressure at room temperature, then transferred to -10 ° C and stirred under nitrogen. The filter cake was dried under reduced pressure at 40 ° C to give the compound of formula I crystal.
  • Test Example 1 Stability test of formula II monohydrate crystal
  • ND No Detection
  • Test Example 2 Stability test of the crystal of the compound of the formula I
  • Test Example 3 Stability test of the amorphous form of the compound of formula I
  • Resazurin is a traditional redox dye that can be reduced from a blue azurite without fluorescence to a pink fluorescent substance, resorufin.
  • the relative fluorescence unit (RFU) of -570 nm, Em 590-620 nm) was measured and quantified.
  • resazurin is widely used for the determination of the viability of bacteria, cells and the enzyme activity of oxidoreductase.
  • the lipoamide dehydrogenase terminates the IDH1m reaction by attenuating the available cofactor NADPH, which oxidizes NADPH to NADP and reduces resazurin to a highly fluorescent resorufin, quantified by readily detectable fluorophores.
  • the compound was pre-incubated with IDH-WT and NADP, and then the reaction was initiated by the addition of isocitrate, Diaphorase (lipoamide dehydrogenase) and the corresponding substrate Resazurin (Resazurin). After a certain period of time under linear conditions, The amount of fluorescent substance is detected.
  • NADP was reduced to NADPH, which reduced the resazurin to a highly fluorescent resorufin under the action of lipoamide dehydrogenase.
  • the detected fluorophore was used to quantify the cofactors generated after a specific reaction time. The amount of NADPH, thereby calculating the inhibitory effect of the compound on IDH-WT.
  • the specific mode of operation was as follows: 2.5 ⁇ L of 3 ⁇ gradient diluted compound was added to a 384-well plate, followed by the addition of 5 ⁇ L of reaction buffer containing 40 nM IDH1 (R132H/R132C) and 20 ⁇ M NADPH (20 mM Tris-HCl, pH 7.5; 150 mM). NaCl; 10 mM MgCl 2 ; 0.4 mg/mL BSA (bovine serum albumin) and 2 mM DTT (dithiothreitol). The test mixture was then incubated at 23 ° C for 16 hours, after which 2.5 ⁇ L of reaction buffer containing 4 mM ⁇ -KG was added to initiate the reaction.
  • the phosphoglycerate dehydrogenase PHGDH is capable of reducing NAD to NADPH in the presence of 2-HG, which can be quantitatively determined by lipoamide dehydrogenase and its substrate Resazurin (Resazurin).
  • HT-1080 cells are IDH1 (R132C) mutant human fibrosarcoma cell lines
  • U87 cells are IDH1 (R132H) mutant human glioblastoma line, supplemented with 10% fetal bovine serum, 100units/mL penicillin, 0.1mg /mL streptomycin in RPMI-1640 medium was cultured.
  • the cells were trypsinized and seeded in a 6-well plate at a density of 5 ⁇ 10 5 and cultured overnight in a 37 ° C incubator.
  • the test compound (0.1% final concentration of DMSO) was added the next day, and incubation was continued for 24 hours.
  • the culture solution of each sample was aspirated, and after centrifugation at 1000 rpm for 10 minutes, the supernatant was aspirated, and the content of 2-HG therein was examined. Further, after the cells were washed with PBS (phosphate buffered saline solution), the cells were collected by trypsinization, and the cells were washed once, and the intracellular 2-HG content was measured.
  • PBS phosphate buffered saline solution
  • the intracellular 2-HG assay was as follows: The cells were resuspended in 300 ⁇ L of reaction buffer (40 mM Tris-HCl, pH 8.5; 150 mM NaCl), and the cells were disrupted by sonication. Centrifuge at 12,000 rpm for 10 minutes at 4 ° C to remove insoluble materials. Aspirate 25 ⁇ L of the supernatant to determine the protein concentration by BCA kit, and transfer 200 ⁇ L of the supernatant to a new set of centrifuge tubes, add 4 ⁇ L of 3 M HCl to each tube, leave it at room temperature for 5 minutes, and centrifuge at room temperature for 1 minute at 12,000 rpm for 5 minutes.
  • reaction buffer 40 mM Tris-HCl, pH 8.5; 150 mM NaCl
  • the sample of the sample to be tested or the standard of the above sample was diluted 5 ⁇ , and then 5 ⁇ L was added to the 384-well plate, and 10 ⁇ L of the detection mixture (8 ⁇ M PHGDH (phosphoglycerate dehydrogenase); 0.5 mM NAD; 0.1 U was added to each well. /ml Diaphorase and 10 ⁇ M Resazurin), reacted at 23 ° C for 60 minutes, and the fluorescence value was measured by Flexstation 3 under Ex535/Em595.
  • the measured fluorescence values were calibrated with the protein concentration of the corresponding sample before comparison.
  • the extracellular 2-HG assay was as follows: 500 ⁇ L of the culture supernatant was taken, 10 ⁇ L of 3 M HCl was added to each tube, and left at room temperature for 5 minutes, after which 18 ⁇ L of 2 M Tris base was added to each well and left at room temperature for 5 minutes. Centrifuge at 12,000 rpm for 2 minutes. pH test paper detection pH is approximately equal to 8.0.
  • 2-HG standard curve preparation 2-HG stock solution was diluted to 500 ⁇ M with complete medium, and then 500 ⁇ L was subjected to double gradient dilution for a total of 10 points. The following operations are the same as above, including an acid treatment and a base neutralization step.
  • mice Male Sprague-Dawley rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into groups of 3, and the test sample suspension (5 mg/kg) was administered orally by a single oral administration. Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with a small animal anesthesia machine, 0.3 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube.
  • the sample was centrifuged at 4 ° C, 4000 rpm for 5 min, and the plasma was transferred to a centrifuge tube and placed in -80. °C is saved until analysis.
  • the plasma samples were extracted by protein precipitation, and the extract was analyzed by LC-MS/MS, HPLC conditions: flow rate: 0.4 mL/min; mobile phase A: water/formic acid (99.9/0.1, v/v); mobile phase B: acetonitrile / formic acid (99.9 / 0.1, v / v); injection amount: 5 ⁇ L; column temperature: room temperature; autosampler temperature: room temperature; running time: 2.5 minutes.

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Abstract

本申请涉及一种内磺酰胺化合物结晶，具体涉及(S)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-2-(4-氰基吡啶-2-基)-N-(3-氟苯基)-异噻唑烷-3-甲酰胺1,1-二氧化物结晶、其制备方法、其结晶组合物、药物组合物及其用途。本申请式Ⅱ的一水合物结晶的X-射线粉末衍射光谱用2θ值表示在约14.40°、20.28°、20.94°、22.02°和24.46°处有衍射峰。本申请式Ⅱ的一水合物结晶具有较好的IDH1抑制活性，且该结晶表现出较高的稳定性，在物理性质、安全性及代谢稳定性方面具备优势，有较高的成药价值。

Description

一种内磺酰胺化合物结晶
相关申请的交叉引用
本申请要求于2017年09月22日向中国国家知识产权局提交的申请号201710863924.8中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于医药技术领域，涉及一种内磺酰胺化合物结晶，更具体而言涉及(S)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-2-(4-氰基吡啶-2-基)-N-(3-氟苯基)-异噻唑烷-3-甲酰胺1,1-二氧化物结晶，其制备方法，其结晶组合物、药物组合物及其用途。
背景技术
IDH(isocitrate dehydrogenase)全称异柠檬酸脱氢酶，是细胞内三羧酸循环过程中最主要的关键酶，它们能够催化异柠檬酸氧化脱羧生成2-氧化戊二酸(即，α-酮戊二酸)。IDH有两个不同的亚型，其中一个亚型利用NAD(+)作为电子受体，另一个亚型利用NADP(+)作为电子受体。已经报道的IDH有五种，其中3种为NAD(+)依赖型异柠檬酸脱氢酶，它们位于线粒体基质；还有两种为NADP(+)依赖型异柠檬酸脱氢酶，一种位于线粒体，另一种位于胞质。
研究发现多种肿瘤(如神经胶质瘤、肉瘤、急性粒细胞白血病等)存在IDH突变，突变位点是位于催化中心的精氨酸残基(IDH1/R132H、IDH2/R140Q、IDH2/R172K)。2009年，Bleeker等对672例不同来源的肿瘤和84个不同的肿瘤细胞系进行了IDH1突变的检测，发现这种突变特异性集中发生在脑胶质瘤中[Bleeker et al.,2009.IDH1 mutations at residue p.R132(IDH1(R132))occur frequently in high-grade gliomas but not in other solid tumors.Hum Mutat.30:7-11.]。但后续的文献报道显示，急性髓细胞白血病、前列腺癌、副神经节瘤等也存在IDH1的突变[Green et al.,2010,Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms.N Engl J Med.362:369-370.]。Bleeker等发现在IDH1突变的病例中，R132H占了86.9％，其它类型如R132C、R132G、R132L、R132V、R132S所占比例较小[Bleeker et al.,2009]。
发明内容
一种结构如式Ⅰ所示的内磺酰胺化合物，其化学名称为：(S)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-2-(4-氰基吡啶-2-基)-N-(3-氟苯基)-异噻唑烷-3-甲酰胺1,1-二氧化物，
Figure PCTCN2018106889-appb-000001
本申请的一个方面在于提供式Ⅰ化合物，其特征在于：所述式Ⅰ化合物是结晶形式的。
所述结晶可以是非溶剂合物的结晶，也可以是溶剂合物的结晶，例如水合物结晶。
所述式Ⅰ化合物的结晶具有较好的IDH1抑制活性，且该结晶表现出较高的稳定性，在物理性质、安全性及代谢稳定性方面具备优势，有较高的成药价值。
本申请的另一个方面在于提供式Ⅰ化合物的水合物结晶，所述水合物结晶每分子含有0.5～3个水分子。
本申请的另一个方面在于提供了式Ⅱ所示的一水合物，
Figure PCTCN2018106889-appb-000002
本申请的一种实施方式中，式Ⅱ的一水合物是结晶形式的。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约14.40°、20.28°、20.94°、22.02°和24.46°处有衍射峰。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约9.12°、13.32°、14.40°、15.64°、16.46°、20.28°、20.94°、22.02°、22.98°、24.46°和29.34°处有衍射峰。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约5.52°、9.12°、13.32°、14.40°、15.64°、16.46°、19.14°、19.32°、20.28°、20.94°、21.20°、22.02°、22.98°、23.52°、24.46°、26.06°、29.34°和31.74°处有衍射峰。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约5.52°、9.12°、13.32°、14.40°、14.90°、15.64°、16.46°、19.14°、19.32°、20.28°、20.94°、21.20°、22.02°、22.98°、23.52°、24.46°、25.74°、26.06°、27.32°、27.98°、28.90°、29.34°、31.00°、31.74°、32.22°和33.32°处有衍射峰。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约5.52°、9.12°、10.30°、10.48°、11.96°、13.32°、14.40°、14.90°、15.64°、16.46°、17.28°、17.58°、18.60°、19.14°、19.32°、20.28°、20.94°、21.20°、22.02°、22.98°、23.52°、24.46°、25.74°、26.06°、26.74°、27.32°、27.98°、28.40°、28.90°、29.34°、30.36°、31.00°、31.74°、32.22°、32.82°、33.32°和37.84°处有衍射峰。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其X-射线粉末衍射光谱特征峰的峰位置及强度具有表1所表示的特征：
表1
编号 2θ(度) 相对强度(I/I 0)
1 5.52 7
2 9.12 25
3 10.30 11
4 10.48 12
5 11.96 8
6 13.32 40
7 14.40 97
8 14.90 15
9 15.64 26
10 16.46 26
11 17.28 10
12 17.58 13
13 18.60 13
14 19.14 28
15 19.32 25
16 20.28 55
17 20.94 100
18 21.20 34
19 22.02 91
20 22.98 35
21 23.52 23
22 24.46 57
23 25.74 17
24 26.06 24
25 26.74 10
26 27.32 19
27 27.98 17
28 28.40 10
29 28.90 15
30 29.34 24
31 30.36 14
32 31.00 20
33 31.74 27
34 32.22 18
35 32.82 12
36 33.32 15
37 37.84 13
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其X-射线粉末衍射光谱如图1所示。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其差示扫描量热(DSC)测量图在约186℃处有起始点，在约193℃处有吸收峰。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其差示扫描量热(DSC)测量图如图2所示。
本申请的一种实施方式中，式Ⅱ的一水合物结晶，其热重分析(TGA)图如图3所示。
本申请的另一个方面在于提供了一种结晶组合物，其中上述式Ⅱ的一水合物结晶占所述结晶组合物重量的50％以上，较好是70％以上，较好是75％以上，更好是80％以上，更好是90％以上，更好是95％以上，最好是98％以上。所述结晶组合物中，还可能含有少量的式Ⅰ化合物其它结晶或非结晶形式。
本申请提供一种药物组合物，其包含治疗有效量的上述式Ⅱ的一水合物结晶，或上述式Ⅱ的一水合物结晶的结晶组合物。所述药物组合物可以包含至少一种药学上可接受的载体或其他赋形剂。
另一方面，本申请提供了上述式Ⅱ的一水合物结晶，上述式Ⅱ的一水合物结晶的结晶组合物，或上述药物组合物在制备用于治疗由IDH1突变诱发的癌症的药物中的用途。本申请的上述式Ⅱ的一水合物结晶，上述式Ⅱ的一水合物结晶的结晶组合物，或上述药物组合物可单独地或与其他药物联用，用于制备治疗由IDH1突变诱发的癌症的药物。
另一方面，本申请提供了治疗由IDH1突变诱发的癌症的方法，其包括向有需要的哺乳动物给予治疗有效量的上述式Ⅱ的一水合物结晶，上述式Ⅱ的一水合物结晶的结晶组合物，或上述药物组合物。哺乳动物优选为人类。
另一方面，本申请提供了用于治疗由IDH1突变诱发的癌症的上述式Ⅱ的一水合物结晶，上述式Ⅱ的一水合物结晶的结晶组合物，或上述药物组合物。
本申请的另一个方面在于提供式Ⅰ化合物的非溶剂结晶形式。
本申请的一种实施方式中，式Ⅰ化合物的结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、20.72°、21.30°或24.02°处有衍射峰。
本申请的一种实施方式中，式Ⅰ化合物的结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、14.62°、19.66°、20.04°、20.46°、20.72°、21.30°、22.46°、24.02°或27.42°处有衍射峰。
本申请的一种实施方式中，式Ⅰ化合物的结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、14.62°、15.18°、16.36°、17.04°、17.60°、18.40°、19.66°、20.04°、20.46°、20.72°、21.30°、22.16°、22.46°、24.02°、27.42°、28.46°或30.16°处有衍射峰。
本申请的一种实施方式中，式Ⅰ化合物的结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、14.62°、15.18°、16.36°、17.04°、17.60°、18.14°、18.40°、18.88°、19.66°、20.04°、20.46°、20.72°、21.30°、22.16°、22.46°、22.92°、23.16°、24.02°、25.14°、25.48°、25.92°、27.42°、28.46°或30.16°处有衍射峰。
本申请的一种实施方式中，式Ⅰ化合物的结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、11.18°、12.80°、13.68°、14.62°、15.18°、15.58°、16.36°、17.04°、17.60°、18.14°、18.40°、18.88°、19.66°、20.04°、20.46°、20.72°、21.30°、22.16°、22.46°、22.92°、23.16°、24.02°、24.32°、24.92°、25.14°、25.48°、25.92°、26.30°、27.42°、27.84°、28.46°、30.16°、30.98°或33.18°处有衍射峰。
本申请的一种实施方式中，式Ⅰ化合物的结晶，其X-射线粉末衍射光谱特征峰的峰位置及强度具有表2所表示的特征：
表2
编号 2θ(度) 相对强度(I/I 0)
1 8.64 25
2 9.34 28
3 11.18 14
4 12.80 14
5 13.68 17
6 14.62 30
7 15.18 23
8 15.58 18
9 16.36 27
10 17.04 25
11 17.60 25
12 18.14 23
13 18.40 28
14 18.88 24
15 19.66 38
16 20.04 33
17 20.46 34
18 20.72 51
19 21.30 100
20 22.16 31
21 22.46 41
22 22.92 23
23 23.16 21
24 24.02 55
25 24.32 19
26 24.92 19
27 25.14 20
28 25.48 24
29 25.92 24
30 26.30 18
31 27.42 30
32 27.84 19
33 28.46 21
34 30.16 24
35 30.98 18
36 33.18 18
在本申请的一种实施方式中，式Ⅰ化合物的结晶，其X-射线粉末衍射光谱如图4所示。
在本申请的一种实施方式中，式Ⅰ化合物的结晶，其差示扫描量热(DSC)测量图在约103℃处有起始点，在约130℃处有吸收峰。
在本申请的一种实施方式中，式Ⅰ化合物的结晶，其差示扫描量热(DSC)测量图如图5所示。
在本申请的一种实施方式中，式Ⅰ化合物的结晶，其热重分析(TGA)图如图6所示。
在本申请的一种实施方式中，上述式Ⅰ化合物结晶可以在水的存在下向上述式Ⅱ的一水合物结晶转化，其中水的来源可以是制备过程中溶剂中含有的少量水，或制备过程中过滤、干燥步骤接触环境中的水，或储存过程中接触环境中的水。
在本申请的一种实施方式中，上述式Ⅰ化合物结晶在制备及存储过程中隔绝一切水的来源，所得到的上述式Ⅰ化合物结晶相对于上述式Ⅱ的一水合物结晶可以基本为纯的形式。
本申请的另一个方面在于提供了一种结晶组合物，其中上述式Ⅰ化合物结晶占所述结晶组合物重量的50％以上，较好是70％以上，较好是75％以上，更好是80％以上，更好是90％以上，更好是95％以上，最好是98％以上。所述结晶组合物中，还可能含有少量的式Ⅰ化合物其它结晶或非结晶形式，例如式Ⅱ的一水合物结晶。
本申请提供一种药物组合物，其包含治疗有效量的上述式Ⅰ化合物结晶，或上述式Ⅰ化合物结晶的结晶组合物。所述药物组合物可以包含至少一种药学上可接受的载体或其他赋形剂。
另一方面，本申请提供了上述式Ⅰ化合物结晶，上述式Ⅰ化合物结晶的结晶组合物，或上述药物组合物在制备用于治疗由IDH1突变诱发的癌症的药物中的用途。本申请的上述式Ⅰ化合物结晶，上述式Ⅰ化合物结晶的结晶组合物，或上述药物组合物可单独地或与其他药物联用，用于制备治疗由IDH1突变诱发的癌症的药物。
另一方面，本申请提供了治疗由IDH1突变诱发的癌症的方法，其包括向有需要的哺乳动物给予治疗有效量的上述式Ⅰ化合物结晶，上述式Ⅰ化合物结晶的结晶组合物，或上述药物组合物。哺乳动物优选为人类。
另一方面，本申请提供了用于治疗由IDH1突变诱发的癌症的上述式Ⅰ化合物结晶，上述式Ⅰ化合物结晶的结晶组合物，或上述药物组合物。
本申请的另一个方面在于提供式Ⅰ化合物的无定型物。
在本申请的一种实施方式中，式Ⅰ化合物的无定型物，其X-射线粉末衍射光谱如图7所示。
在本申请的一种实施方式中，式Ⅰ化合物的无定型物，其差示扫描量热(DSC)测量图在约103℃处有起始点，在约121℃处有吸收峰。
在本申请的一种实施方式中，式Ⅰ化合物的无定型物，其差示扫描量热(DSC)测量图如图8所示。
另一方面，本申请提供一种药物组合物，其包含治疗有效量的式Ⅰ化合物无定型物。所述药物组合物可以包含至少一种药学上可接受的载体或其他赋形剂。
另一方面，本申请提供了式Ⅰ化合物无定型物或其药物组合物在制备用于治疗由IDH1突变诱发的癌症的药物中的用途。
本申请中，药学上可接受的载体可以是固体或液体。固体载体可包括调味剂、润滑剂、增溶剂、悬浮剂、填充剂、粘合剂、片剂崩解剂或胶囊化材料中的一种或多种物质。合适的固体载体例如包括：硬脂酸镁、滑石、蔗糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮。液体载体用于制备溶液、悬浮液、乳液、糖浆等组合物。对于口服和非肠道给药的合适的液体载体包括水、醇类、油等。
本申请中，药物组合物可制成一定的剂型，给药途径优选经口服给药、肠胃外给药(包括皮下、肌肉内和静脉内)、直肠给药等。例如，适合经口给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、糖浆剂或混悬剂；适合肠胃外给药的剂型包括水性或非水性的注射用溶液或乳液；适合直肠给药的剂型包括使用亲水性或疏水性载体的栓剂。根据需要，上述剂型还可制成适于活性成分的快速释放、延迟释放或调节释放的剂型。
本申请所述IDH1突变具有R132X突变；在本申请的一些实施方式中，R132X突变选自R132H、R132C、R132L、R132V、R132S和R132G；在一些优选的实施方式中，R132X突变选自R132H和R132C。
本申请的一些实施方式中，所述的由IDH1突变诱发的癌症选自：成胶质细胞瘤(神经胶质瘤)、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、肉瘤(优选软骨肉瘤、纤维肉瘤)、黑色素瘤、非小细胞肺癌、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)。在更具体的实施方案中，待治疗的癌症是神经胶质瘤、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、胆管癌、软骨肉瘤、或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)等，优选地包括急性骨髓性白血病(AML)、骨髓增生异常综合征(MDS)、神经胶质瘤、胆管癌或软骨肉瘤。
本申请的另一个方面在于提供式Ⅱ的一水合物结晶的制备方法，包括：(1)将式Ⅰ化合物溶于有机溶剂中，搅拌至溶液澄清；(2)加水至步骤(1)得到的溶液中；(3)降温析晶，过滤，干燥。
在本申请的一些实施方式中，式Ⅱ的一水合物结晶的制备方法中，步骤(1)所述有机溶剂选自甲醇、乙醇、异丙醇、乙二醇、丙二醇、丙酮、四氢呋喃、乙腈、二氯甲烷或乙酸乙酯中的一种或多种混合溶剂；优选甲醇、乙醇或丙酮；进一步优选甲醇或乙醇。
在本申请的一些实施方式中，式Ⅱ的一水合物结晶的制备方法中，步骤(1)所述式Ⅰ化合物与有机溶剂的摩尔体积比为1mmol：2～20mL；优选1mmol：2～15mL；进一步优选1mmol：2～10mL。
在本申请的一些实施方式中，式Ⅱ的一水合物结晶的制备方法中，步骤(1)所述式Ⅰ化合物溶解于有机溶剂的温度为20～100℃；优选20～80℃；进一步优选20～60℃。
在本申请的一些实施方式中，式Ⅱ的一水合物结晶的制备方法中，步骤(1)所述式Ⅰ化合物与步骤(2)所述水的摩尔体积比为1mmol：0.01～5mL；优选1mmol：0.01～3mL；进一步优选1mmol：0.05～2mL。
在本申请的一些实施方式中，式Ⅱ的一水合物结晶的制备方法中，步骤(3)所述析晶温度为-10℃～25℃；优选0℃～10℃；进一步优选0℃～5℃。
在本申请的一些实施方式中，式Ⅱ的一水合物结晶的制备方法中，步骤(3)所述干燥条件包括常温干燥、减压干燥或鼓风干燥，优选减压干燥。干燥设备为通风橱、真空烘箱或鼓风烘箱，优选真空烘箱。干燥温度为20℃～60℃；优选20℃～40℃；进一步优选30℃～40℃。
在本申请的一些实施方式中，式Ⅱ的一水合物结晶的制备方法中，水的来源除了步骤(2)中加水，还可以是有机溶剂中含有的水分，或制备过程中容器敞口接触环境中的水分，或析晶、过滤、干燥过程中接触环境中的水分。
另一方面，本申请提供上述式Ⅰ化合物结晶的制备方法，包括：(1)将式Ⅰ化合物溶于无水有机溶剂中搅拌至溶液澄清，加入4A分子筛干燥；(2)氮气保护过滤，滤液降温析晶；(3)氮气保护过滤、干燥。
在本申请的一些实施方式中，上述式Ⅰ化合物结晶的制备方法中，步骤(1)所述无水有机溶剂选自二氯甲烷、异丙醇、正己烷、乙酸乙酯或甲基叔丁基醚中的一种或多种混合溶剂；优选二氯甲烷或异丙醇；进一步优选二氯甲烷。
在本申请的一些实施方式中，上述式Ⅰ化合物结晶的制备方法中，步骤(1)所述式Ⅰ化合物与无水有机溶剂的摩尔体积比为1mmol：2～10mL；优选1mmol：2～8mL；进一步优选1mmol：3～5mL。
在本申请的一些实施方式中，上述式Ⅰ化合物结晶的制备方法中，步骤(1)所述加入4A分子筛干燥的时间为1～4小时；优选1～3小时；进一步优选1～2小时。
在本申请的一些实施方式中，上述式Ⅰ化合物结晶的制备方法中，步骤(1)所述4A分子筛与无水有机溶剂的质量体积比为1g：2～10mL；优选1g：2～6mL；进一步优选1g：4～6mL。
在本申请的一些实施方式中，上述式Ⅰ化合物结晶的制备方法中，步骤(1)所述式Ⅰ化合物溶于无水有机溶剂的温度为20～100℃；优选20～80℃；进一步优选20～60℃。
在本申请的一些实施方式中，上述式Ⅰ化合物结晶的制备方法中，步骤(2)所述析晶温度为-20℃～25℃；优选-10℃～10℃；进一步优选-10℃～0℃。
在本申请的一些实施方式中，上述式Ⅰ化合物结晶的制备方法中，步骤(3)所述干燥条件包括常温干燥、减压干燥或鼓风干燥，优选减压干燥。干燥设备为通风橱、真空烘箱或鼓风烘箱，优选真空烘箱。干燥温度为20℃～60℃；优选20℃～40℃；进一步优选30℃～40℃。
另一方面，本申请提供了式Ⅰ化合物无定型物的制备方法，包括：(1)将式Ⅰ化合物溶于无水有机溶剂中，搅拌至溶液澄清；(2)减压浓缩，得到固体，干燥。
在本申请的一些实施方式中，上述式Ⅰ化合物无定型物的制备方法中，步骤(1)所述无水有机溶剂选自乙酸乙酯、二氯甲烷、甲醇、乙醇、丙酮中的一种或多种混合溶剂；优选乙酸乙酯、二氯甲烷或甲醇中的一种或多种混合溶剂；进一步优选二氯甲烷、乙酸乙酯和二氯甲烷的混合溶剂。
在本申请的一些实施方式中，上述式Ⅰ化合物无定型物的制备方法中，步骤(1)所述式Ⅰ化合物与无水有机溶剂的摩尔体积比为1mmol：1～10mL；优选1mmol：2～8mL；进一步优选1mmol：3～6mL。
在本申请的一些实施方式中，上述式Ⅰ化合物无定型物的制备方法中，步骤(1)所述式Ⅰ化合物溶于无水有机溶剂的温度为20～60℃；优选20～40℃；进一步优选20～30℃。
在本申请的一些实施方式中，上述式Ⅰ化合物无定型物的制备方法中，步骤(2)所述的干燥条件包括常温干燥、减压干燥或鼓风干燥，优选减压干燥。干燥设备为通风橱、真空烘箱或鼓风烘箱，优选真空烘箱。干燥温度为20℃～60℃；优选20℃～40℃；进一步优选30℃～40℃。
本申请中，样品的X-射线粉末衍射光谱在下述条件下测定：仪器：MinflexⅡ；样品前处理：直接压片；样品盘：玻璃槽；DivSlit：1.25°；SctSlit：1.25°；RecSlit：0.3mm；2θ角范围：3～60°；扫描速度10°/min；Cu靶管压及电流：30KV，15mA。
本申请中，DSC光谱在下述条件下测定：仪器：METTLER TOLEDO DSC1；温度范围：40～300℃；升温速率：10℃/min。
本申请中，TGA热重分析在下述条件下测定：仪器：NETZSCH TG 209F3；温度范围：30～300℃；升温速率：10℃/min。
需要说明的是，在X-射线粉末衍射光谱中，由结晶化合物得到的衍射谱图对于特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶型并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动、或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种结晶结构时，应该将此误差考虑在内。在XRD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。对于同种化合物的同种晶型，其XRD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的结晶是特征性的。
DSC测定当结晶由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，通常在约3℃之内，当我们说一个化合物具有一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的结晶形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言， 其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
定义
当用于本申请的说明书与所附的权利要求中时，除非有相反的指定，否则下列术语具有所指示的意义：
“哺乳动物”包括人和家畜如实验室哺乳动物与家庭宠物(例如猫、狗、猪、羊、牛、绵羊、山羊、马、家兔)，及非驯养哺乳动物，如野生哺乳动物等。
术语“药物组合物”是指本申请化合物与本领域中通常接受的用于传递生物活性化合物至哺乳动物例如人的介质的制剂。所述介质包括所有供其使用的药物可接受的载体。药物组合物有利于化合物向生物体的给药。
术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本申请中，“药学上可接受的载体”是指与活性成份一同给药的、对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。关于载体的其他信息，可以参考Remington:The Science and Practice ofPharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
本申请中，“摩尔比”与“物质的量比”相互等同。
本申请中，“室温”是指20～25℃。
本申请中，所述无水有机溶剂的来源可以是市售得到，也可以是市售有机溶剂经实验室无水处理得到。例如无水二氯甲烷的实验室处理方法为：二氯甲烷中加入氢化钙回流3-4小时，蒸馏，4A分子筛保存。
附图说明
图1为实施例5式Ⅱ的一水合物结晶的X-射线粉末衍射图(XRPD)。
图2为实施例5式Ⅱ的一水合物结晶的差示扫描量热(DSC)曲线。
图3为实施例5式Ⅱ的一水合物结晶的热重分析(TGA)图。
图4为实施例7式Ⅰ化合物结晶的X-射线粉末衍射图(XRPD)。
图5为实施例7式Ⅰ化合物结晶的差示扫描量热(DSC)曲线。
图6为实施例7式Ⅰ化合物结晶的热重分析(TGA)图。
图7为实施例9无定型物的X-射线粉末衍射图(XRPD)。
图8为实施例9无定型物的差示扫描量热(DSC)曲线。
图9为实施例4单晶计算得到的X-射线粉末衍射图。
具体实施方式
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。本领域技术人员应该理解：还有形成本申请化合物的其它合成途径，下面提供的是非限制性的实施例。
实施例1：式Ⅰ化合物的制备
步骤A：L-高胱氨酸二甲酯二盐酸盐
Figure PCTCN2018106889-appb-000003
冰浴搅拌下，向L-高胱氨酸(8.0g，29.8mmol)的甲醇悬浊液中滴加二氯亚砜(10.64g，89.4mmol)，溶液逐渐澄清，加毕，搅拌10min撤去冰浴，室温搅拌过夜，除去溶剂，得L-高胱氨酸二甲酯二盐酸盐(10.6g)。
1H-NMR(400MHz,DMSO-d 6):δ＝8.79(s,6H),3.75(s,6H),2.95-2.80(m,4H),2.52-2.47(m,2H),2.20-2.10(m,4H)。
步骤B：(S)-2-氨基-4-氯磺酰基丁酸甲酯盐酸盐
Figure PCTCN2018106889-appb-000004
冰浴搅拌下，向L-高胱氨酸二甲酯二盐酸盐(10.6g，28.8mmol)的乙醇(40mL)和氯仿(80mL)混合溶液中通氯气20分钟，有白色固体生成，过滤，氯仿洗涤，得到(S)-2-氨基-4-氯磺酰基丁酸甲酯盐酸盐(7.5g)。
1H-NMR(400MHz,DMSO-d 6):δ＝13.46(s,1H),8.57(s,2H),3.66(s,3H),3.18-2.95(m,2H),2.52-2.45(m,1H),2.22-1.97(m,2H)。
步骤C：(S)-异噻唑烷-3-甲酸甲酯1,1-二氧化物
Figure PCTCN2018106889-appb-000005
冰盐浴搅拌下，向(S)-2-氨基-4-氯磺酰基丁酸甲酯盐酸盐(4.5g，17.85mmol)的氯仿悬浊液中，滴加三乙胺的氯仿溶液，加完撤去冰盐浴，室温搅拌过夜，除去溶剂，硅藻土过滤，乙酸乙酯洗涤，除去溶剂得浅黄色油状物，即(S)-异噻唑烷-3-甲酸甲酯1,1-二氧化物(3.2g)。
1H-NMR(400MHz,CDCl 3):δ＝4.98(s,1H),4.21(dd,J＝8.3,4.6Hz,1H),3.84(s,3H),3.30–3.11(m,1H),3.09–2.90(m,1H),2.90–2.73(m,1H),2.60(ddd,J＝18.4,8.9,4.7Hz,1H)。
步骤D：(S)-2-(4-氰基吡啶-2-基)异噻唑烷-3-甲酸甲酯1,1-二氧化物
Figure PCTCN2018106889-appb-000006
向封管反应器中加入(S)-异噻唑烷-3-甲酸甲酯1,1-二氧化物(200mg，1.11mmol)、2-溴-4-氰基吡啶(204mg，1.11mmol)、碘化亚铜(105mg，0.55mmol)、N,N’-二甲基乙二胺(98mg，1.11mmol)和碳酸铯(723mg，2.22mmol)，加入二氧六环(8mL)，通入氮气5分钟，封管，80℃反应过夜，原料反应完，除去溶剂后进行柱层析(石油醚：乙酸乙酯＝1：1)分离，得到标题化合物(S)-2-(4-氰基吡啶-2-基)异噻唑烷-3-甲酸甲酯1,1-二氧化物(230mg)。
1H-NMR(400MHz,CDCl 3):δ＝8.40(dd,J＝5.2,0.8Hz,1H),7.69(t,J＝1.0Hz,1H),7.19(dd,J＝5.2,1.0Hz,1H),5.01(dd,J＝8.0,3.6Hz,1H),3.78(s,3H),3.64-3.55(m,1H),3.48-3.42(m，1H),2.95-2.84(m,1H),2.65-2.52(m,1H)。
步骤E:(S)-2-(4-氰基吡啶-2-基)异噻唑烷-3-甲酸1,1-二氧化物
Figure PCTCN2018106889-appb-000007
冰浴搅拌下，向(S)-2-(4-氰基吡啶-2-基)异噻唑烷-3-甲酸甲酯1,1-二氧化物(116mg，0.41mmol)的甲醇四氢呋喃溶液中滴加氢氧化锂的悬浊液，反应过夜，反应结束后，加10mL水稀释，乙酸乙酯萃取除杂，水相滴加1N盐酸使pH小于5，乙酸乙酯萃取，除去溶剂得(S)-2-(4-氰基吡啶-2-基)异噻唑烷-3-甲酸1,1-二氧化物(103mg)。
1H-NMR(400MHz,DMSO-d 6):δ＝13.5(s,1H),8.54(d,J＝5.0,1H),7.51(dd,J＝3.74,4.76Hz,1H),7.45(s,1H),4.95-4.90(m,1H),3.75-3.60(m,2H),2.85-2.72(m,1H),2.46-2.38(m,1H)。
步骤F：(S)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-2-(4-氰基吡啶-2-基)-N-(3-氟苯基)-异噻唑烷-3-甲酰胺1,1-二氧化物
Figure PCTCN2018106889-appb-000008
室温下，将3-氨基-5-氟吡啶(57mg，0.508mmol)和邻氯苯甲醛(72mg，0.512mmol)溶于甲醇中，搅拌30分钟，再向混合液中加入(S)-2-(4-氰基吡啶-2-基)异噻唑烷-3-甲酸1,1-二氧化物(136mg，0.508mmol)，搅拌10分钟，再加入1,1-二氟-3-异氰基环丁烷(参照专利CN103097340所述方法制备，60mg，0.508mmol)，搅拌过夜，除去溶剂，薄层层析分离，得到标题化合物(S)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-2-(4-氰基吡啶-2-基)-N-(3-氟苯基)-异噻唑烷-3-甲酰胺1,1-二氧化物(式Ⅰ化合物)。
1H-NMR(400MHz,CDCl 3):δ＝8.46(m,1H),7.67(d,J＝8.8Hz,1H),7.63(s,1H),7.22-6.84(m,8H),6.47(d,J＝3.6,1H),6.08(s,1H),4.82(d,J＝6.1Hz,1H),4.33(m,1H),3.68-3.60(m,1H),3.40-3.28(m,1H),3.10-2.98(m,2H),2.68-2.38(m,4H)。
m/z＝618[M+H] +。
实施例2：式Ⅱ一水合物结晶的单晶制备
将1.0g由实施例1制备得到的式Ⅰ化合物加入2.5mL无水甲醇中，搅匀至溶清，过滤膜。取上述滤液2mL，往滤液中加入0.2mL水，室温下静置放置，缓慢析出晶体，此结晶为式Ⅱ一水合物结晶的单晶。
实施例3：式Ⅱ一水合物结晶的晶胞参数
式Ⅱ一水合物结晶的晶体学数据和原子坐标等如表3、表4和表5所示：
表3.晶体学数据和结构精修
Figure PCTCN2018106889-appb-000009
Figure PCTCN2018106889-appb-000010
表4.原子坐标(×10 4)和等效各向同性位移参数
Figure PCTCN2018106889-appb-000011
Figure PCTCN2018106889-appb-000012
表5.氢原子坐标(×10 4)和各向同性位移参数
Figure PCTCN2018106889-appb-000013
Figure PCTCN2018106889-appb-000014
实施例4：式Ⅱ一水合物结晶的单晶计算X-射线粉末衍射数据
1.计算软件：Mercury 3.8(Build RC2)；波长：1.54056。
2.X-射线粉末衍射数据：
由式Ⅱ一水合物结晶的单晶计算得到的X-射线粉末衍射光谱特征峰的峰位置及强度如表6所示：
表6
编号 2θ(度) 相对强度(I/I 0)
1 5.48 16
2 9.14 62
3 10.30 9
4 12.00 6
5 13.34 26
6 14.44 100
7 14.94 10
8 15.70 24
9 16.52 34
10 17.70 9
11 18.70 7
12 19.20 21
13 19.38 15
14 20.42 42
15 21.00 61
16 21.30 31
17 21.90 23
18 22.08 52
19 22.26 22
20 23.08 31
21 23.60 6
22 24.56 35
23 24.74 23
24 25.88 8
25 26.22 19
26 27.46 10
27 27.68 7
28 28.14 8
29 29.08 12
30 29.50 21
31 30.56 12
32 31.26 9
33 31.86 10
34 32.36 8
35 32.96 5
36 33.58 7
37 36.40 7
38 38.02 12
实施例5：式Ⅱ一水合物结晶的制备
将1.0g由实施例1制备得到的式Ⅰ化合物加入15mL甲醇中，室温搅拌至溶液澄清，然后加入2mL水，降温至0～5℃搅拌析晶，过滤，40℃减压干燥，得0.5g式Ⅱ一水合物结晶。
实施例6：式Ⅱ一水合物结晶的制备
将17g由实施例1制备得到的式Ⅰ化合物加入75mL无水乙醇中，加热至60℃搅拌至溶液澄清，然后加入1.5mL水，降温至0～5℃搅拌析晶，过滤，40℃减压干燥，得15.8g式Ⅱ一水合物结晶。
实施例7：式Ⅰ化合物结晶的制备
将1.0g由实施例1制备得到的式Ⅰ化合物加入5mL无水二氯甲烷中，室温搅拌至溶清，加入1g 4A分子筛，搅拌干燥2小时，氮气保护过滤。滤液于室温减压浓缩出一半体积的溶剂，转移至-10℃于氮气保护下搅拌析晶，过滤。滤饼40℃减压干燥，得式Ⅰ化合物结晶。
实施例8：式Ⅰ化合物结晶的制备
将1.5g由实施例1制备得到的式Ⅰ化合物加入10mL无水异丙醇中，加热至60℃搅拌溶清，加入2g 4A分子筛，搅拌干燥2小时，氮气保护过滤。滤液密封，自然降温至室温于氮气保护下搅拌析晶，过滤。滤饼40℃减压干燥，得式Ⅰ化合物结晶。
实施例9：式Ⅰ化合物无定型物
将1.5g由实施例1制备得到的式Ⅰ化合物加入10mL无水二氯甲烷中，室温搅拌至溶清，减压浓缩，得到固体，40℃减压干燥，得式Ⅰ化合物无定型物。
实施例10：式Ⅰ化合物无定型物
将1g由实施例1制备得到的式Ⅰ化合物加入1mL无水乙酸乙酯和8mL无水二氯甲烷的混合溶剂中，室温搅拌至溶清，减压浓缩，得到固体，40℃减压干燥，得式Ⅰ化合物无定型物。
试验例1：式Ⅱ一水合物结晶的稳定性试验
按照ICH Q1A《新原料药及其制剂的稳定性试验》和中国药典2015年版四部9001《原料药物与制剂稳定性试验指导原则》对式Ⅱ一水合物结晶进行稳定性影响因素试验，包括高温、高湿及光照试验。结果如表7、表8和表9所示：
表7.高温试验稳定性结果
Figure PCTCN2018106889-appb-000015
Figure PCTCN2018106889-appb-000016
注：ND代表未检测到。
表8.高湿试验稳定性结果
Figure PCTCN2018106889-appb-000017
表9.光照试验稳定性结果
Figure PCTCN2018106889-appb-000018
试验例2：式Ⅰ化合物结晶的稳定性试验
按照ICH Q1A《新原料药及其制剂的稳定性试验》和中国药典2015年版四部9001《原料药物与制剂稳定性试验指导原则》对式Ⅰ化合物结晶进行稳定性影响因素试验，包括高温及高湿试验。结果如表10和表11所示：
表10高温试验稳定性结果
Figure PCTCN2018106889-appb-000019
表11高湿试验稳定性结果
Figure PCTCN2018106889-appb-000020
试验例3：式Ⅰ化合物无定型物的稳定性试验
按照ICH Q1A《新原料药及其制剂的稳定性试验》和中国药典2015年版四部9001《原料药物与制剂稳定性试验指导原则》对式Ⅰ化合物无定型物进行稳定性影响因素试验，包括高温及高湿试验。结果如表12和表13所示：
表12高温试验稳定性结果
Figure PCTCN2018106889-appb-000021
表13高湿试验稳定性结果
Figure PCTCN2018106889-appb-000022
试验例4：生物活性实验
酶测定：
刃天青是一种传统的氧化还原染料，经过氧化还原作用，能够从没有荧光的蓝色刃天青还原成粉红色的荧光物质试卤灵，试卤灵可以用荧光光度计(Ex＝530-570nm，Em＝590-620nm)的相对荧光单位(RFU)来测量并量化。目前刃天青被广泛用于细菌、细胞等的活力测定以及氧化还原酶的酶活检测。我们通过检测辅助因子NADPH的消减来测定化合物针对IDH1m的抑制活性，通过检测辅助因子NADPH的生成来测定化合物针对IDH WT的抑制活性。将化合物与IDH1m和NADPH进行预孵育，然后通过添加α-KG启动反应，线性条件下反应一定时间后，添加Diaphorase(硫辛酰胺脱氢酶)和相应的底物Resazurin(刃天青)进行检测。硫辛酰胺脱氢酶通过消减可供使用的辅助因子NADPH而终止IDH1m反应，它将NADPH氧化成NADP，并且将刃天青还原成高荧光的试卤灵，通过易于检测的荧光基团来量化在特定反应时间之后剩余的辅助因子NADPH的量。
将化合物与IDH-WT和NADP进行预孵育，然后通过添加异柠檬酸、Diaphorase(硫辛酰胺脱氢酶)和相应的底物Resazurin(刃天青)启动反应，线性条件下反应一定时间后，检测荧光物质的量。本实验将NADP还原成NADPH，后者在硫辛酰胺脱氢酶的作用下将刃天青还原成高荧光的试卤灵，通过检测的荧光基团来量化在特定反应时间之后生成的辅助因子NADPH的量，从而来计算化合物对IDH-WT的抑制作用。
具体操作方式为：将2.5μL 3×梯度稀释的化合物加到384孔板中，接着添加5μL含有40nM IDH1(R132H/R132C)和20μM NADPH的反应缓冲液(20mM Tris-HCl，pH7.5；150mM NaCl；10mM MgCl 2；0.4mg/mL BSA(牛血清白蛋白)和2mM DTT(二硫代苏糖醇))。然后将上述测试混合物在23℃孵育16小时，之后添加2.5μL含有4mMα-KG的反应缓冲液起始反应。室温孵育60分钟后，加入5μL反应缓冲液配制的终止混合物(0.4U/mL Diaphorase和20μM Resazurin)，使刃天青转化成试卤灵来测量剩余的NADPH。23℃孵育10分钟后，通过Flexstation 3在Ex535/Em595下进行荧光值测定。化合物分别在12个浓度下测定酶的活性，使用GraFit6.0软件(Erithacus Software)计算数据，得到该化合物的IC 50值。
2-HG测定：
磷酸甘油酸脱氢酶PHGDH在2-HG存在的情况下能够将NAD还原成NADPH，后者可以通过硫辛酰胺脱氢酶及其底物Resazurin(刃天青)进行定量测定。
HT-1080细胞是IDH1(R132C)突变的人纤维肉瘤细胞系，U87细胞是IDH1(R132H)突变的人胶质母细胞瘤系，用补加10％胎牛血清、100units/mL青霉素、0.1mg/mL链霉素的RPMI-1640培养基进行培养。
细胞通过胰酶消化并以5×10 5的密度接种于6孔板中，37℃培养箱中培养过夜。第二天加入待测化合物(DMSO终浓度为0.1％)，继续培养24小时。吸取各样品的培养液，1000rpm离心10分钟后，吸取上清，并检测其中2-HG的含量。另外，细胞经PBS(磷酸缓冲盐溶液)清洗后，通过胰酶消化并收集细胞，PBS清洗一次后进行细胞内2-HG含量测定。
细胞内2-HG测定方法如下：用300μL反应缓冲液(40mM Tris-HCl，pH8.5；150mM NaCl)重悬细胞，通过超声将细胞进行破碎处理。12,000rpm，4℃离心10分钟以去除不溶物质。吸取25μL上清通过BCA试剂盒进行蛋白浓度测定，另将200μL上清转移至一组新的离心管内，每管加入4μL的3M HCl，室温放置5分钟，12,000rpm室温离心5分钟。吸取100μL上清转移至96孔“V”底板中，每孔加入3.6μL的2M Tris base(氨基丁三醇)，室温放置5分钟。12,000rpm离心2分钟。pH试纸检测pH约等于8.0。
2-HG标准曲线制备：将2-HG储液用反应缓冲液稀释至500μM，之后取200μL进行两倍梯度稀释，共计10个点。以下操作同上，包括酸处理与碱中和步骤。
将上述样品的待测细胞样品或标准品进行5×稀释，之后取5μL加到384孔板中，每孔加入10μL检测混合物(8μM PHGDH(磷酸甘油酸脱氢酶)；0.5mM NAD；0.1U/ml Diaphorase和10μM Resazurin)，23℃反应60分钟，通过Flexstation 3在Ex535/Em595下进行荧光值测定。
将所测荧光值用相应样品的蛋白质浓度进行校准后再行比较。
细胞外2-HG测定方法如下：各取500μL培养液上清，每管加入10μL的3M HCl，室温放置5分钟，之后每管孔加入18μL的2M Tris base，室温放置5分钟。12,000rpm离心2分钟。pH试纸检测pH约等于8.0。2-HG标准曲线制备：将2-HG储液用完全培养基稀释至500μM，之后取500μL进行两倍梯度稀释，共计10个点。以下操作同上，包括酸处理与碱中和步骤。将上述样品待测培养上清样品或标准品进行5×稀释，之后取5μL加到384孔板中，每孔加入10μL检测混合物(8μM PHGDH；0.5mM NAD；0.1U/mL Diaphorase和10μM Resazurin)，23℃反应60分钟，通过Flexstation 3在Ex535/Em595下进行荧光值测定。
根据本申请所述的生物学方法对式Ⅰ化合物进行分析，其结果如下：
式Ⅰ化合物对IDH1突变型(R132H和R132C)的抑制活性(IC 50)，如表14所示：
表14
化合物 IDH1(R132H)IC 50(nM) IDH1(R132C)IC 50(nM)
式Ⅰ化合物 <20 <20
试验例3：药代药动实验
雄性SD大鼠来源于北京维通利华实验动物技术有限公司，将大鼠分组，每组3只，分别口服单次灌胃给予待测样品混悬液(5mg/kg)。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。给药后第0.25、0.5、1、2、4、6、8和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC-MS/MS分析，其中HPLC条件为，流速：0.4mL/min；流动相A：水/甲酸(99.9/0.1,v/v)；流动相B：乙腈/甲酸(99.9/0.1,v/v)；进样量：5μL；柱温：室温；自动进样器温度：室温；运行时间：2.5分钟。
式Ⅰ化合物的药代动力学数据如表15所示：
表15
Figure PCTCN2018106889-appb-000023

Claims (25)

  1. 式Ⅱ所示的(S)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-2-(4-氰基吡啶-2-基)-N-(3-氟苯基)-异噻唑烷-3-甲酰胺1,1-二氧化物的一水合物的结晶，
    Figure PCTCN2018106889-appb-100001
    其特征是X-射线粉末衍射光谱用2θ值表示在约14.40°、20.28°、20.94°、22.02°和24.46°处有衍射峰。
  2. 权利要求1所述的式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约9.12°、13.32°、14.40°、15.64°、16.46°、20.28°、20.94°、22.02°、22.98°、24.46°和29.34°处有衍射峰。
  3. 权利要求2所述的式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约5.52°、9.12°、13.32°、14.40°、15.64°、16.46°、19.14°、19.32°、20.28°、20.94°、21.20°、22.02°、22.98°、23.52°、24.46°、26.06°、29.34°和31.74°处有衍射峰。
  4. 权利要求3所述的式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约5.52°、9.12°、13.32°、14.40°、14.90°、15.64°、16.46°、19.14°、19.32°、20.28°、20.94°、21.20°、22.02°、22.98°、23.52°、24.46°、25.74°、26.06°、27.32°、27.98°、28.90°、29.34°、31.00°、31.74°、32.22°和33.32°处有衍射峰。
  5. 权利要求4所述的式Ⅱ的一水合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约5.52°、9.12°、10.30°、10.48°、11.96°、13.32°、14.40°、14.90°、15.64°、16.46°、17.28°、17.58°、18.60°、19.14°、19.32°、20.28°、20.94°、21.20°、22.02°、22.98°、23.52°、24.46°、25.74°、26.06°、26.74°、27.32°、27.98°、28.40°、28.90°、29.34°、30.36°、31.00°、31.74°、32.22°、32.82°、33.32°和37.84°处有衍射峰。
  6. 权利要求1-5中任一项所述的式Ⅱ的一水合物结晶，其特征是，差示扫描量热(DSC)测量图在约186℃处有起始点。
  7. 结晶组合物，其中权利要求1-5中任一项所述的式Ⅱ的一水合物结晶占所述结晶组合物重量的50％以上，较好是70％以上，较好是75％以上，更好是80％以上，更好是90％以上，更好是95％以上，最好是98％以上。
  8. 药物组合物，其包含权利要求1-5中任一项所述的式Ⅱ的一水合物结晶或权利要求7所述的结晶组合物。
  9. 权利要求1-5中任一项所述的式Ⅱ的一水合物结晶、权利要求7所述的结晶组合物、或权利要求8所述的药物组合物在制备用于治疗由IDH1突变诱发的癌症的药物中的用途。
  10. 权利要求1-5中任一项所述的式Ⅱ的一水合物结晶的制备方法，包括：(1)将式Ⅰ所示的化合物溶于有机溶剂中，搅拌至溶液澄清；(2)加水至步骤(1)得到的溶液中；(3)降温析晶，过滤，干燥，
    Figure PCTCN2018106889-appb-100002
  11. 权利要求10所述的制备方法，其中步骤(1)所述有机溶剂选自甲醇、乙醇、异丙醇、乙二醇、丙二醇、丙酮、四氢呋喃、乙腈、二氯甲烷或乙酸乙酯中的一种或多种混合溶剂；优选甲醇、乙醇或丙酮；进一步优选甲醇或乙醇。
  12. 权利要求10所述的制备方法，其中步骤(1)所述式Ⅰ化合物与有机溶剂的摩尔体积比为1mmol：2～20mL；优选1mmol：2～15mL；进一步优选1mmol：2～10mL。
  13. 权利要求10所述的制备方法，其中步骤(1)所述式Ⅰ化合物溶解于有机溶剂的温度为20～100℃；优 选20～80℃；进一步优选20～60℃。
  14. 权利要求10所述的制备方法，其中步骤(1)所述式Ⅰ化合物与步骤(2)所述水的摩尔体积比为1mmol：0.01～5mL；优选1mmol：0.01～3mL；进一步优选1mmol：0.05～2mL。
  15. 权利要求10所述的制备方法，其中步骤(3)所述析晶温度为-10℃～25℃；优选0℃～10℃；进一步优选0℃～5℃。
  16. 式Ⅰ所示的(S)-N-((S)-1-(2-氯苯基)-2-((3,3-二氟环丁基)氨基)-2-氧代乙基)-2-(4-氰基吡啶-2-基)-N-(3-氟苯基)-异噻唑烷-3-甲酰胺1,1-二氧化物的结晶，
    Figure PCTCN2018106889-appb-100003
    其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、20.72°、21.30°或24.02°处有衍射峰。
  17. 权利要求16所述的式Ⅰ化合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、14.62°、19.66°、20.04°、20.46°、20.72°、21.30°、22.46°、24.02°或27.42°处有衍射峰。
  18. 权利要求17所述的式Ⅰ化合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、14.62°、15.18°、16.36°、17.04°、17.60°、18.40°、19.66°、20.04°、20.46°、20.72°、21.30°、22.16°、22.46°、24.02°、27.42°、28.46°或30.16°处有衍射峰。
  19. 权利要求18所述的式Ⅰ化合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、14.62°、15.18°、16.36°、17.04°、17.60°、18.14°、18.40°、18.88°、19.66°、20.04°、20.46°、20.72°、21.30°、22.16°、22.46°、22.92°、23.16°、24.02°、25.14°、25.48°、25.92°、27.42°、28.46°或30.16°处有衍射峰。
  20. 权利要求19所述的式Ⅰ化合物结晶，其特征是X-射线粉末衍射光谱用2θ值表示在约8.64°、9.34°、11.18°、12.80°、13.68°、14.62°、15.18°、15.58°、16.36°、17.04°、17.60°、18.14°、18.40°、18.88°、19.66°、20.04°、20.46°、20.72°、21.30°、22.16°、22.46°、22.92°、23.16°、24.02°、24.32°、24.92°、25.14°、25.48°、25.92°、26.30°、27.42°、27.84°、28.46°、30.16°、30.98°或33.18°处有衍射峰。
  21. 权利要求16-20中任一项所述的式Ⅰ化合物结晶，其特征是，差示扫描量热(DSC)测量图在约103℃处有起始点。
  22. 权利要求16-20中任一项所述的式Ⅰ化合物结晶的制备方法，包括：(1)将式Ⅰ化合物溶于无水有机溶剂中搅拌至溶液澄清，加入4A分子筛干燥；(2)氮气保护过滤，滤液降温析晶；(3)氮气保护过滤、干燥。
  23. 结晶组合物，其中权利要求16-20中任一项所述的式Ⅰ化合物结晶占所述结晶组合物重量的50％以上，较好是70％以上，较好是75％以上，更好是80％以上，更好是90％以上，更好是95％以上，最好是98％以上。
  24. 药物组合物，其包含权利要求16-20中任一项所述的式Ⅰ化合物结晶或权利要求23所述的结晶组合物。
  25. 权利要求16-20中任一项所述的式Ⅰ化合物结晶、权利要求23所述的结晶组合物、或权利要求24所述的药物组合物在制备用于治疗由IDH1突变诱发的癌症的药物中的用途。
PCT/CN2018/106889 2017-09-22 2018-09-21 一种内磺酰胺化合物结晶 Ceased WO2019057142A1 (zh)

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