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WO2018192576A1 - Procédé de préparation d'un composé inhibiteur de parp, et intermédiaire, forme amorphe, solvate, composition pharmaceutique et application de celui-ci - Google Patents

Procédé de préparation d'un composé inhibiteur de parp, et intermédiaire, forme amorphe, solvate, composition pharmaceutique et application de celui-ci Download PDF

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Publication number
WO2018192576A1
WO2018192576A1 PCT/CN2018/083969 CN2018083969W WO2018192576A1 WO 2018192576 A1 WO2018192576 A1 WO 2018192576A1 CN 2018083969 W CN2018083969 W CN 2018083969W WO 2018192576 A1 WO2018192576 A1 WO 2018192576A1
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compound
formula
solvent
solvate crystal
reaction
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PCT/CN2018/083969
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English (en)
Chinese (zh)
Inventor
蔡鸿飞
焦育红
金远锋
翁玉芳
赵坤
祝盼虎
蔡群芳
李必文
钟万德
汪晶
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上海迪诺医药科技有限公司
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Priority claimed from CN201810354319.2A external-priority patent/CN108822115B/zh
Priority claimed from CN201810354222.1A external-priority patent/CN110386939B/zh
Application filed by 上海迪诺医药科技有限公司 filed Critical 上海迪诺医药科技有限公司
Publication of WO2018192576A1 publication Critical patent/WO2018192576A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a process for the preparation of a PARP inhibiting compound, an intermediate thereof, an amorphous form, a solvate, a pharmaceutical composition and use thereof.
  • PARP is an abbreviation for "poly(ADP-ribose) polymerase”. Tumor cells repair with PARP enzymes including DNA damage caused by chemotherapy. researchers are investigating whether drugs that inhibit PARP enzymes can also weaken this self-repair mechanism and make tumor cells more sensitive to treatment and accelerate tumor cell death.
  • PARP inhibitors are a family of pharmacological inhibitors of poly ADP ribose polymerase that are important for promoting DNA repair, controlling RNA transcription, regulating cell death, and immune response. Therefore, there are many indications for the development of PARP inhibitors, the most important indication being for the treatment of tumors. Several forms of BRCA-deficient tumor cells are more dependent on the repair function of PARP than normal cells, thus making PARP an attractive target for tumor therapy.
  • CN103237799A relates to a series of pyridazine-1(2H)-one derivatives which have an inhibitory effect on PARP enzymes, and its disclosure of paragraph [0105] of Reaction Scheme 3 mentions its disclosed pyridazine-1(2H)-one derivatives.
  • CN103237799A also discloses a compound of the formula A-5:
  • the preparation method of the compound is also provided, and the obtained compound is a viscous substance which is inferior in fluidity, is unfavorable for transportation and storage, or has poor stability, and its preparation method is not suitable for efficient separation of large production.
  • the present invention provides a process for the preparation of a PARP inhibiting compound, an intermediate thereof, an amorphous form, a solvate, a pharmaceutical composition and use thereof.
  • the preparation method of the PARP inhibitor compound of the invention has high purity and yield of the target compound, and is more suitable for industrial production.
  • the present invention has for the first time found an amorphous form of the compound of the formula A-5 which has good fluidity and is advantageous for transportation and storage. At the same time, the amorphous solubility, bioavailability and the like of the compound of the formula A-5 of the present invention are also good.
  • the present invention provides crystals of a solvate of a compound of formula A-5 which is fluid and stable and substantially non-wetting.
  • the present invention also provides a pharmaceutical composition comprising an amorphous or solvate crystal of a compound of the formula A-5, and the amorphous or solvate crystal and a pharmaceutical composition thereof for preparing a disease improved by inhibiting PARP activity The application of the drug.
  • the invention provides a preparation method of the pharmaceutical compound A for inhibiting PARP activity and improving disease, and the reaction process is as follows:
  • R 1 and R 2 are each independently hydrogen or halogen
  • R is methyl, trifluoromethyl, (tert-butyl), (cyclohexyl), (2-furyl) or (phenyl);
  • the R 1 is preferably fluorine or chlorine.
  • the R 2 is preferably hydrogen.
  • Said R 1 is preferably located in the para position of the methylene group of the benzyl group.
  • the preparation method of the compound A of the present invention comprises the following steps:
  • the compound of formula I is present in solid form in the reaction mixture and is readily separated by a porous medium;
  • the reaction produces Compound A; wherein M is hydrogen, potassium, lithium, sodium or ammonium, preferably sodium.
  • step (1) comprises the steps of reacting a compound of formula II with HCl in an organic solvent to produce a compound of formula I.
  • the compound of formula II is preferably mixed with an organic solvent and then mixed with HCl at 10-40 ° C (for example 10 ° C, 15 ° C or 25 ° C) to carry out the reaction to give a compound of formula I.
  • the amount of the substance to which HCl is added may be 5 to 20 times, preferably 8 to 15 times, more preferably 8 to 12 times the amount of the substance of the compound of the formula II.
  • the post-treatment operation may be further included.
  • the post-treatment operation can be a conventional post-treatment method for such reactions in the art.
  • the present invention preferably comprises the steps of: subjecting the reaction liquid after completion of the reaction to solid-liquid separation (the operation of the solid-liquid separation is preferably filtration), and drying the filter cake (preferably drying at a constant temperature of 50 ° C to constant weight) to obtain a compound of the formula I. .
  • the operation of the solid-liquid separation it is preferred to further include an operation of washing (the washing solvent, preferably a reaction solvent).
  • step (1) comprises the steps of: dissolving the compound of formula II in an organic solvent, and adding HCl in an amount of 5-20 times the amount of the compound of formula II at 10-40 ° C, stirring. The reaction was carried out for 2-24 hours, filtered and dried to give a solid.
  • the organic solvent in the step (1) may be a conventional organic solvent for such a reaction in the art, preferably a C 1-5 alcohol (for example, methanol, ethanol, n-propanol and isopropanol).
  • a C 1-5 alcohol for example, methanol, ethanol, n-propanol and isopropanol.
  • the amount of the organic solvent to be used may not be specifically limited as long as the compound of the formula II can be completely dissolved.
  • the amount of the substance to which HCl is added is 8 to 15 times the amount of the substance of the compound of the formula II; further preferably 8 to 12 times.
  • the HCl may be a hydrogen chloride gas or an aqueous hydrochloric acid solution.
  • the molar concentration of the aqueous hydrochloric acid solution may be a conventional molar concentration for such a reaction in the art, preferably 2 to 12 mol/L (2 to 12 N), and more preferably 6 to 12 mol/L (6 to 12 N).
  • the reaction temperature of the step (1) may be a conventional temperature for such a reaction in the art, preferably 10 to 40 ° C (for example, 20 ° C, 25 ° C, 40 ° C, etc.), more preferably 25 ° C to 40 ° C.
  • the progress of the reaction of the step (1) can be carried out by a conventional detection method in the art, and is generally used as a reaction end point when the compound of the formula II disappears.
  • the reaction time is preferably 2 to 24 hours, for example 2 hours, 10 hours or 20 hours.
  • step (2) comprises the steps of: reacting a compound of formula I with compound B under the action of a condensing agent in an organic solvent to produce compound A.
  • the organic solvent may be a conventional organic solvent of such a reaction in the art, preferably a halogenated alkane solvent such as dichloromethane.
  • the amount of the organic solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the amount of the compound of the formula I and the amount of the compound B may be a conventional amount for such a reaction in the art, and the ratio of the two substances is preferably 1:1 to 2:1.
  • the temperature of the reaction may be a conventional temperature for such a reaction in the art, preferably 10 to 30 ° C, more preferably 15 to 25 ° C.
  • the progress of the reaction can be monitored by conventional detection methods in the art, generally as the end of the reaction when the compound of formula I disappears.
  • the time of the reaction is preferably from 2 to 8 hours, for example 2, 4, 5 or 8 hours.
  • step (2) comprises the steps of: mixing a compound of formula I with an organic solvent, adding a condensing agent and compound B, and reacting to produce a compound of formula A.
  • the following operations may further be included: mixing the reaction liquid after the completion of the reaction with water, filtering, and post-treatment (for example, the filtrate is allowed to stand for stratification, the organic phase is washed and dried), and concentrated (preferably reduced). Concentration by pressure) gave Compound A.
  • the reaction step (2) comprises the steps of: adding the solid obtained in the step (1) (the compound of the formula I) to a reaction vessel containing a dichloromethane, adding a condensing agent and a compound B, and reacting 2-8 After a few hours, it was filtered, worked up, and concentrated to give Compound A.
  • the condensing agent may be a conventional condensing agent for such reactions in the art, preferably HOBT (1-hydroxybenzotriazole), EDCI (1-(3-dimethylaminopropyl)- 3-ethyl-carbodiimide hydrochloride), or a mixed system of HOBT and EDCI.
  • the amount of the condensing agent may be a conventional amount for such a reaction in the art, and it is preferably a ratio of the substance to the compound of the formula I in an amount of from 1:1 to 5:1.
  • the condensing agent is a mixed system of HOBT and EDCI, and the ratio of the amount of the HOBT to the EDCI is 1:0.8-1:1.5.
  • the compound A is preferably one of the following structures:
  • the invention also provides a compound of formula I (wherein the compound of formula I may be an intermediate for the manufacture of a medicament for the inhibition of PARP activity to improve disease):
  • R 1 , R 2 and heterocyclic group The definition is as described above.
  • the invention also provides a process for the preparation of a compound of formula I, which comprises the steps of:
  • the compound of formula I is present in solid form in the reaction mixture and is readily separated by a porous medium;
  • R 1 , R 2 and heterocyclic group The definition is as described above.
  • the compound of the formula II of the present invention can be prepared by the method described in the example of CN103237799A, using HATU/DIPEA/DMF, but this method produces a small amount of by-product tetramethylurea which is difficult to separate or remove.
  • the preparation of the compound of the formula II of the present invention preferably comprises the steps of: reacting a compound of the formula III and a compound C under the action of a condensing agent and an acid binding agent to obtain a compound of the formula II; wherein the condensing agent is HOBT (1-hydroxybenzotriazole), or a mixed system of HOBT and EDCI (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride);
  • the compound C is R 1 , R 2 and heterocyclic groups
  • the definition is as described above.
  • the preparation of the compound of the formula II is preferably carried out in the presence of a solvent.
  • the solvent may be a conventional solvent for such a reaction in the art, preferably a halogenated alkane solvent such as dichloromethane.
  • the amount of the solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the condensing agent may be used in an amount conventionally used in the field of such a reaction condensing agent, preferably in a ratio of 1.5 to 1-3:1 to the amount of the compound of the compound of the formula III.
  • the condensing agent is a mixed system of HOBT and EDCI
  • the ratio of the amounts of the substances of HOBT and EDCI is preferably 1:0.8-1:1.5, for example 1:1.
  • the acid scavenger can be a conventional acid scavenger for such reactions in the art, such as ethylenediamine and/or N,N-diisopropylethylamine.
  • the amount of the acid scavenger may be a conventional amount for such a reaction in the art, and the ratio of the amount of the acid to the amount of the condensing agent is preferably from 0.5:1 to 1.5:1.
  • the temperature of the reaction is preferably from 10 to 40 °C.
  • the progress of the reaction can be monitored by conventional detection methods in the art, for example, by TLC, when the compound of formula III disappears, the end point of the reaction.
  • the time of the reaction is preferably from 2 to 24 hours, for example 2 hours, 4 hours or 24 hours.
  • the compound of formula III, compound B and a condensing agent are mixed, and then an acid binding agent is added to carry out the reaction.
  • the post-treatment operation may be a conventional method and condition for such post-treatment in the art, and the present invention preferably includes the following steps: separating and concentrating the reaction liquid after completion of the reaction (for example, concentration under reduced pressure).
  • the reaction liquid after completion of the reaction is subjected to extraction (the organic solvent for extraction is preferably a halogenated alkane solvent, and after extraction, the organic phase may be dried, for example, dried over anhydrous magnesium sulfate or anhydrous sodium sulfate), and then the organic phase is subjected to an organic phase. concentrate.
  • the method for preparing the compound of formula II comprises the steps of: adding formula III, compound C to the reaction vessel in a certain ratio, adding 1-hydroxybenzotriazole, 1-(3-dimethylamino) Propyl)-3-ethylcarbodiimide hydrochloride, temperature control 10-40 ° C, dropwise addition of triethylamine or N, N-diisopropylethylamine, temperature control 10-40 ° C, stirring reaction, 2-24 hours, separated and concentrated to obtain a solid;
  • the compound C is R 1 , R 2 and heterocyclic groups
  • the definition is as described above.
  • reaction vessel Before adding the compound of the formula III and the compound C to the reaction vessel in a certain ratio, it is preferred to first add a reaction solvent to the reaction vessel.
  • HOBT and EDCI may be simultaneously added to the reaction system, or may be sequentially added to the reaction system.
  • the amount ratio of the compound of the formula III to the substance of the compound C is from 1:1 to 1:3.
  • the formula III may be 2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid.
  • the invention also provides a compound of Formula I-a, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 and a heterocyclic group The definition is as described above.
  • the pharmaceutically acceptable salt is hydrochloride, p-toluenesulfonate, tartrate, maleate, lactate, methanesulfonate, sulfate, phosphate, lemon
  • the acid salt or acetate is further preferably a tosylate salt, a hydrochloride salt or a tartrate salt; the pharmaceutically acceptable salt of the present invention can be synthesized by a conventional chemical method.
  • formula I-a is of the following formula I-a-1:
  • the pharmaceutically acceptable salt of the compound of formula I-a-1 is the hydrochloride salt.
  • the compound of formula Ia can be used not only for the preparation of a pharmaceutical compound A which inhibits PARP enzymatic activity, but the applicant demonstrates, by in vitro experiments, a compound of formula Ia (e.g., formula Ia-1) or a pharmaceutically acceptable salt thereof itself It also has good PARP enzyme inhibitory activity.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I-a, or a pharmaceutically acceptable salt thereof, of the invention, together with a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition of the present invention may be formulated into a pharmaceutical preparation together with some commonly used excipients in the pharmaceutical field, and the preparation may be a tablet, a capsule, an injection, an aerosol, a suppository, a film, a pill, or a topical preparation. Agent, ointment, etc.
  • the invention also provides the use of a compound of formula I-a (e.g., a compound of formula I-a-1), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease ameliorated by inhibition of PARP activity.
  • a compound of formula I-a e.g., a compound of formula I-a-1
  • a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease ameliorated by inhibition of PARP activity.
  • the invention also provides a method of inhibiting a disease that is ameliorated by PARP activity comprising administering to a mammal in need thereof an effective amount of a compound of formula Ia (e.g., a compound of formula Ia-1) of the invention or a pharmaceutically acceptable thereof Salt.
  • a compound of formula Ia e.g., a compound of formula Ia-1 of the invention or a pharmaceutically acceptable thereof Salt.
  • the present invention also provides an amorphous form of the compound of the formula A-5, which has no crystal diffraction peak in the XRPD pattern.
  • the content of the amorphous formula A-5 compound of the compound of the formula A-5 is preferably between 98.0% and 102.0%, further preferably between 99.0 and 100.0%;
  • the HPLC purity of the crystal form is not less than 99.5%, and the total amount is not more than 0.5%.
  • the present invention also provides a method for preparing an amorphous form of the PARP inhibitor compound of the formula A-5, which comprises the steps of: mixing a mixed solution of the compound of the formula A-5 and a benign solvent with a non-degradable solvent;
  • the volume-to-mass ratio of the benign solvent to the compound of the formula A-5 is from 1 mL/g to 10 mL/g, and the volume-to-mass ratio of the poor organic solvent to the compound of the formula A-5 is from 10 mL/g to 100 mL/g.
  • the benign solvent generally means that the compound of the formula A-5 has a good solubility in the benign solvent, that is, when the volume ratio of the benign solvent to the compound of the formula A-5 is 1 mL/g to 10 mL. At /g, the compound of formula A-5 is completely soluble in the benign solvent.
  • the poor solvent generally means a mixture of the compound of the formula A-5 and a benign solvent, and after mixing with the poor solvent, the compound of the formula A-5 can be precipitated as a solid, that is, when the defect When the volume-mass ratio of the solvent to the compound of the formula A-5 is more than 10 mL/g, the compound of the formula A-5 cannot be completely dissolved in the defective solvent.
  • the benign solvent is one of ethanol, methanol, acetone, methyl ethyl ketone, ethyl acetate, isobutyl acetate, isopropanol, n-propanol, tetrahydrofuran, toluene and dichloromethane or A variety.
  • the undesirable solvent is one of isopropyl ether, n-hexane, n-pentane, n-heptane, n-octane, methyl tert-butyl ether, petroleum ether and cyclohexane or A variety.
  • the temperature of the mixing is preferably -10 to 40 ° C (for example, 20 to 40 ° C, or 25 to 30 ° C).
  • the mixing operation may be further included at the same time or after the end of the mixing operation.
  • the temperature of the mixed liquid at the time of stirring is preferably -10 to 40 ° C, more preferably 20 to 40 ° C, for example, 25 to 35 ° C.
  • the time for continuing the stirring may not be specifically limited, so that no solid precipitation is allowed.
  • the post-treatment operation may be further included.
  • the post-treatment operation may be a conventional operation of such post-treatment in the art, and preferably includes the following steps: the mixture obtained after the stirring is continued, subjected to solid-liquid separation, and dried.
  • the operation of the solid-liquid separation is preferably filtration.
  • the filter cake obtained after the solid-liquid separation is preferably washed.
  • the washing solvent is preferably the above-mentioned poor solvent.
  • the drying is preferably dried under reduced pressure.
  • a mixed solution of the compound of the formula A-5 and a benign solvent is preferably added to the poor solvent.
  • the manner of addition is preferably added dropwise.
  • the speed of the dropwise addition may not be specifically limited as long as it does not affect the precipitation of the compound of the formula A-5.
  • the amorphous form of the compound of the formula A-5 comprises the steps of: dissolving the compound of the formula A-5 with a benign solvent, dropping into a poor solvent, stirring, precipitating the solid, and filtering.
  • the volume ratio of the benign solvent to the compound of the formula A-5 is from 1 mL/g to 10 mL/g, and the volume-to-mass ratio of the poor solvent to the compound of the formula A-5 is from 10 mL/g to 100 mL/g.
  • the temperature of the precipitated solid is from -10 to 40 ° C, preferably from 20 to 40 ° C, for example from 25 to 35 ° C.
  • the HPLC purity of the compound of the formula A-5 may be 70% or more, preferably 70% to 99%.
  • the HPLC purity of the compound of the formula A-5 is 100%, the specific amorphous form of the present invention can also be obtained by the production method of the present invention.
  • the invention also provides an amorphous pharmaceutical composition comprising the compound of formula A-5.
  • the pharmaceutical composition preferably comprises an amorphous and pharmaceutically acceptable adjuvant of the compound of formula A-5.
  • the present invention also provides the use of an amorphous form of the compound of the formula A-5 or a pharmaceutical composition thereof for the preparation of a medicament for amelioration of a disease by inhibiting PARP activity.
  • the invention also provides a method of inhibiting a disease that is ameliorated by PARP activity, the method comprising administering to a patient in need thereof a therapeutically effective amount of an amorphous or pharmaceutical composition of a compound of formula A-5.
  • the invention also provides a solvate crystal of a compound of formula A-5:
  • the solvate crystal is an ester solvate crystal of the compound of formula A-5; preferably an ethyl acetate solvate crystal of the compound of formula A-5, formic acid of a compound of formula A-5 Ethyl ester solvate crystals, methyl acetate solvate crystals of the compound of formula A-5 or n-propyl formate solvate crystals of the compound of formula A-5.
  • the infrared absorption spectrum of the solvate crystal has an absorption band, expressed as a reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2 cm -1 ), which has an absorption peak at 1668, 1636, 1496, 1449, and 804.
  • the solvate crystal is ethyl acetate solvate crystal A of the compound of formula A-5, in the X-ray powder diffraction pattern of crystal A, at a diffraction angle of 2 ⁇ ⁇ 0.2° of 8.193. , having characteristic peaks at 14.137, 17.799, 19.483, 20.062, 20.861, and 23.837; preferably at diffraction angles 2 ⁇ ⁇ 0.2° of 8.193, 9.507, 11.141, 13.547, 14.137, 15.935, 16.732, 17.799, 19.483, 20.062, 20.861, and 23.837 Has a characteristic peak.
  • the data of the X-ray diffraction powder diffraction pattern of the ethyl acetate solvate crystal A of the compound of the formula A-5 is shown in Table 1 below:
  • the ethyl acetate solvate crystal A of the compound of formula A-5 has an X-diffraction powder diffraction pattern as shown in FIG.
  • the infrared absorption spectrum of the ethyl acetate solvate crystal A of the compound of the formula A-5 has an absorption band expressed by the reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2 cm -1 ), It has absorption peaks at the following positions: 1166.67, 1635.93, 1 495.51, 1450.38, and 805.05, and further preferably has absorption peaks at the following positions: 3345.84, 3204.48, 1173.55, 1166.67, 1635.93, 1495.51, 1450.38, 800.55, and 682.88.
  • the ethyl acetate solvate crystal A of the compound of formula A-5 has an infrared spectrum as shown in FIG.
  • the ethyl acetate solvate crystal A of the compound of the formula A-5 is preferably subjected to a gas phase detection of ethyl acetate in an amount of from 12 to 20%.
  • the solvate crystal is ethyl formate solvate crystal B of the compound of formula A-5, in the X-ray powder diffraction pattern of crystal B, the diffraction angle is 2 ⁇ ⁇ 0.2° is 8.471.
  • the data of the X-ray diffraction powder diffraction pattern of the ethyl formate solvate crystal B of the compound of the formula A-5 is shown in Table 2 below:
  • the ethyl formate solvate crystal B of the compound of formula A-5 has an X-diffraction powder diffraction pattern as shown in FIG.
  • the infrared absorption spectrum of the ethyl formate solvate crystal B of the formula A-5 has an absorption band represented by a reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2 cm -1 ), which There are absorption peaks at the following positions: 1667.77, 1336.87, 1 946.32, 1448.70, and 804.45; and further preferably have absorption peaks at the following positions: 3447.16, 3190.04, 1723.60, 1667.77, 1336.87, 1946.32, 1448.70, 804.45, and 771.41.
  • the ethyl formate solvate crystal B of the compound of formula A-5 has an infrared spectrum as shown in FIG.
  • the ethyl formate solvate crystal B of the formula A-5 is preferably subjected to gas phase detection of ethyl formate in an amount of from 5 to 15%.
  • the solvate crystal is a methyl acetate solvate crystal C of the compound of formula A-5, in the X-ray powder diffraction pattern of the crystal C, at a diffraction angle of 2 ⁇ ⁇ 0.2° of 8.454.
  • the methyl acetate solvate crystal C of the compound of formula A-5 has an X-diffraction powder diffraction pattern as shown in FIG.
  • the infrared absorption spectrum of the methyl acetate solvate crystal C of the formula A-5 has an absorption band, expressed as a reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2 cm -1 ), which There are absorption peaks at the following positions: 1166.61, 16307.02, 1946.34, 1449.40, and 804.71; further preferably, there are absorption peaks at the following positions: 3447.25, 3189.85, 1744.78, 1668.61, 1670.02, 1492.34, 1449.40, 804.71, and 771.49.
  • the methyl acetate solvate crystal C of the compound of formula A-5 has an infrared spectrum as shown in FIG.
  • the methyl acetate solvate crystal C of the formula A-5 is preferably subjected to a gas phase detection of methyl acetate in an amount of from 5 to 15%.
  • the solvate crystal is a n-propyl formate solvate crystal D of the compound of formula A-5, in the X-ray powder diffraction pattern of the crystal D, at a diffraction angle of 2 ⁇ ⁇ 0.2° of 8.152.
  • the n-propyl formate solvate crystal D of the compound of formula A-5 has an X-diffraction powder diffraction pattern as shown in FIG.
  • the infrared absorption spectrum of the n-propyl formate solvate crystal D of the formula A-5 has an absorption band, expressed as a reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2 cm -1 ), It has absorption peaks at the following positions: 1166.42, 1163.53, 1496.39, 1449.31, and 804.41, and further preferably has absorption peaks at 344.7.01, 3203.32, 1726.16, 1668.42, 1163.53, 1946.39, 1449.31, 804.41, and 772.26.
  • the n-propyl formate solvate crystal D of the compound of formula A-5 has an infrared spectrum as shown in FIG.
  • the n-propyl formate solvate crystal D of the compound of the formula A-5 is preferably subjected to a gas phase detection of a content of n-propyl formate of from 12 to 20%.
  • the present invention also provides a process for the preparation of a solvate crystal of the PARP inhibitor of the formula A-5, which comprises the steps of: precipitating a compound of the formula A-5 from a solvent or a solvent-containing solution.
  • the compound of formula A-5 is amorphous (i.e., amorphous).
  • the HPLC purity of the compound of the formula A-5 may be 70% or more, preferably 99% or more.
  • the compound of formula A-5 when the compound of formula A-5 is amorphous (i.e., amorphous), it is preferably prepared by the amorphous preparation of the compound of formula A-5 above.
  • the solute in the solvent-containing solution, is a solvent in the solvate, preferably an ester solvent, and the solvent is an organic solvent other than the solvent in the solvate.
  • the organic solvent is preferably an alcohol solvent (for example, methanol), a nitrile solvent (for example, acetonitrile), an ether solvent (for example, tetrahydrofuran and/or 1,4-dioxane), and a halogenated alkane solvent (for example, dichloromethane).
  • an alcohol solvent for example, methanol
  • a nitrile solvent for example, acetonitrile
  • an ether solvent for example, tetrahydrofuran and/or 1,4-dioxane
  • a halogenated alkane solvent for example, dichloromethane
  • the solvent in the solvent-containing solution i.e., the solvent in the solvate
  • a process for the preparation of an ester solvate crystal of the compound of the formula A-5 which comprises the steps of: precipitating a compound of the formula A-5 from an ester solvent or a solution containing an ester solvent .
  • a process for the preparation of an ester solvate crystal of a compound of formula A-5 which comprises the steps of: mixing a compound of formula A-5 with an ester solvent or a solution containing an ester solvent, at 0 The crystal was stirred and stirred at ⁇ 40 ° C to obtain an ester solvate crystal of the compound of the formula A-5; and the volume ratio of the ester solvent to the compound of the formula A-5 was from 4 mL/g to 30 mL/g.
  • the ester solvent may be a conventional ester solvent in the art, preferably ethyl formate, methyl acetate, n-propyl formate, methyl propionate, ethyl acetate, n-propyl acetate. , ethyl propionate, n-butyl formate, methyl butyrate, n-butyl acetate, ethyl butyrate, n-butyl propionate or propyl butyrate; more preferably ethyl acetate, ethyl formate, methyl acetate Or n-propyl formate.
  • a conventional ester solvent in the art preferably ethyl formate, methyl acetate, n-propyl formate, methyl propionate, ethyl acetate, n-propyl acetate.
  • the ester solvent in the solution containing the ester solvent, is the same as described above; the solvent in the solution is preferably an organic solvent, further preferably an alcohol solvent (for example, methanol), a nitrile One or more of a solvent such as acetonitrile, an ether solvent such as tetrahydrofuran and/or 1,4-dioxane, and a halogenated alkane solvent such as dichloromethane.
  • an organic solvent for example, methanol
  • a nitrile One or more of a solvent such as acetonitrile, an ether solvent such as tetrahydrofuran and/or 1,4-dioxane, and a halogenated alkane solvent such as dichloromethane.
  • the ester solvent-containing solution has a mass fraction of the ester solvent of not less than 50%; further preferably not less than 85%; still more preferably not less than 95%.
  • the ester solvent-containing solution is preferably 195% (w/w) ethyl acetate and 5% (w/w) tetrahydrofuran; 290% (w/w) ethyl acetate and 10% (w/w) acetonitrile; %(w/w) ethyl acetate and 15% (w/w) tetrahydrofuran; 450% (w/w) ethyl acetate and 50% (w/w) acetonitrile; 590% w/w methyl acetate and 10% w/w acetonitrile or 650% (w/w) n-propyl formate and 50% (w/w) acetonitrile.
  • the volume ratio of the ester solvent or the ester solvent-containing solution to the compound of the formula A-5 is from 4 mL/g to 30 mL/g, more preferably from 6 mL/g to 10 mL/g.
  • the crystallization is carried out at a temperature of from 15 to 25 °C.
  • the filtration, washing and drying operations may be further included.
  • the organic solvent for washing is preferably an ester solvent in the ester solvent of the compound of the formula A-5.
  • the drying is usually carried out at 30-70 ° C, further preferably 30-60 ° C.
  • the drying time can be a dry time for the products of the art, generally until the weight of the product is substantially constant.
  • the drying operation may be blast dry or dried under reduced pressure as needed.
  • the method for preparing an ester solvate crystal of the compound of the formula A-5 comprising the steps of: dissolving the compound of the formula A-5 in an ester solvent or a solution containing an ester solvent, The mixture is stirred and crystallized at 0 to 40 ° C, filtered, and dried to obtain an ester solvate crystal of the formula A-5; the volume ratio of the ester solvent to the compound of the formula A-5 is 4 mL/g to 30 mL/ g.
  • the invention also provides a pharmaceutical composition comprising a solvate crystal of the compound of formula A-5.
  • the pharmaceutical composition preferably comprises a solvate crystal of the compound of formula A-5 and a pharmaceutically acceptable adjuvant.
  • the invention also provides a method of inhibiting a disease that is ameliorated by PARP activity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a solvate crystal of the compound of Formula A-5 or the pharmaceutical composition.
  • the present invention also provides the use of the solvate crystal of the formula A-5 or a pharmaceutical composition thereof for the preparation of a medicament for amelioration of a disease by inhibiting PARP activity.
  • the disease which is improved by inhibiting PARP activity is selected from the group consisting of cancer, vascular disease, inflammatory disease, rejection reaction, diabetes, Parkinson's disease, septic shock, ischemic injury, neurotoxicity, hemorrhagic disease. Shock and viral infections.
  • the cancer is defective in a homologous recombination-dependent DNA double-strand break repair pathway, or the cancer cell is defective in BRCA1 or BRCA2.
  • the compound Ia of the present invention or a pharmaceutically acceptable salt thereof, the compound Ia-1 or a pharmaceutically acceptable salt thereof, the amorphous form of the formula A-5 or the solvent of the above formula A-5 The crystal of the compound can be prepared for preventing the formation of poly(ADP-ribose) chains by inhibiting the activity of the cellular PARP enzyme.
  • Diseases treated include: vascular disease, septic shock, ischemic injury, brain and cardiovascular reperfusion injury, neurotoxicity (eg treatment of acute and/or chronic stroke and Parkinson's disease), hemorrhagic shock Eye-related oxidative damage; transplant rejection; inflammatory diseases such as arthritis, inflammatory bowel disease, ulcerative colitis or Crohn's disease; multiple sclerosis; secondary effects of diabetes; and cells after cardiovascular surgery
  • Acute treatment of toxicity, pancreatitis; atherosclerosis or inhibition of PARP activity improves disease;
  • the compound of the formula I is reacted with the compound B in a condensing agent, such as in a HOBT/EDCI mixed condensation system, and the by-products produced are relatively easy to separate and remove, and are simply extracted, washed, and separated by liquid separation during the post-treatment. It can be removed so that the resulting compound A is very high in purity and yield.
  • a condensing agent such as in a HOBT/EDCI mixed condensation system
  • HOBT/EDCI/TEA is used, and the by-products produced are easily separated and removed, and can be removed by simple extraction, washing and liquid separation in the post-treatment process, so that the purity of the formula II is obtained. And the yield is higher.
  • the present invention provides a compound of the formula I, which is a high-purity inhibitor of PARP activity and improves the disease.
  • the compound of the formula I is a novel compound which is used in the preparation of a high-purity drug compound A for inhibiting PARP activity and improving disease. Aspects have positive social significance.
  • the method for preparing compound A provided by the invention is simple in operation and is advantageous for industrial production.
  • the purity and the yield are high, the molar conversion rate per step is above 90%, and the process economy is high.
  • the compound I-a of the present invention or a pharmaceutically acceptable salt thereof can be used for the preparation of the pharmaceutical compound A which inhibits the activity of PARP enzyme, and in vitro experiments have confirmed that I-a or a pharmaceutically acceptable salt thereof also has good PARP inhibitory activity.
  • the compound of the formula A-5 of the present invention has good amorphous solubility, and a high dissolution rate can lead to supersaturation, thereby making the bioavailability high, which is beneficial to the absorption and utilization of the drug.
  • the amorphous form of the compound of the formula A-5 of the present invention has high stability and is advantageous for the preparation and use of the pharmaceutical composition.
  • the method for preparing the amorphous form of the compound of the formula A-5 of the present invention is simple, rapid, and easy to industrialize.
  • the amorphous form of the compound of the formula A-5 of the invention has good fluidity, good uniformity and easy preparation of the preparation.
  • the solvate of the compound of the formula A-5 of the present invention is a crystalline solid, and the XRPD characteristic peak is sharp, indicating that the crystal has good crystallinity, high purity and is not easy to coalesce.
  • the ester solvate of the compound of the formula A-5 of the present invention has good crystal stability, and the experimental results show that the solvate crystal of the compound of the formula A-5 provided by the present invention is under the condition of 75% high humidity bare discharge for 10 days.
  • the wettability is less than 1%, and it is considered that there is substantially no wettability, and the wettability is much smaller than that of the amorphous (ie, amorphous), so that the ester solvate crystal of the compound of the formula A-5 of the present invention is easy to store, thereby packaging Low requirements.
  • the ester solvate of the compound of the formula A-5 has a good fluidity and is easy to industrially produce.
  • the method for preparing a solvate crystal of the formula A-5 of the present invention is very suitable for large-scale production.
  • Solvate means a complex formed by combining a compound of formula A-5 with a solvent.
  • administering refers to the introduction of a medicament into a patient.
  • the therapeutic amount can be administered, which can be determined by a treating physician or the like.
  • an oral route of administration is preferred.
  • administering or administration of when used in connection with a compound or pharmaceutical composition (and grammatical equivalents), refers to direct administration and/or indirect administration, said direct Administration can be administered to the patient by the medical professional or by the patient himself, which can be the act of prescribing the drug.
  • the physician instructs the patient to administer the drug himself and/or to provide the patient with a prescription for administering the drug to the patient. In any event, administration requires delivery of the drug to the patient.
  • Excipient refers to an inert or inactive material used in the manufacture of pharmaceuticals, including, without limitation, any use as a binder, disintegrant, coating, compression/encapsulation aid, emulsion or lotion. , a lubricant, a parenteral injection, a sweetener or flavoring agent, a suspending/gelling agent or a moist granulating agent.
  • “Therapeutically effective amount” or “therapeutic amount” refers to the amount of a drug or agent that, when administered to a patient having a condition, will have an expected therapeutic effect, such as reducing, ameliorating, alleviating or eliminating the condition of the patient. One or more clinical manifestations.
  • the therapeutically effective amount will vary depending on the individual or condition being treated, the weight and age of the individual, the severity of the condition, the particular composition or excipient selected, the dosage regimen to be followed, All of these factors can be readily determined by those skilled in the art, such as time of administration, mode of administration, and the like.
  • the overall therapeutic effect does not have to be produced by administering one dose, but may only be produced after a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • a therapeutically effective amount in the context of treating anemia refers to an amount of a medicament that reduces, ameliorates, alleviates or eliminates one or more anemia symptoms of the patient.
  • Treatment are defined as acting on a disease, disorder, or condition with an agent to reduce or ameliorate the disease, disorder, or condition and/or its symptoms. Harmful or any other undesirable effect.
  • the treatments used herein include treatment of a human patient and include: (a) reducing the risk of a patient developing a condition that is determined to be predisposed to a disease but not yet diagnosed as having a condition, and (b) preventing the progression of the condition, And/or (c) alleviating the condition, ie causing regression of the condition and/or alleviating one or more symptoms of the condition.
  • An "XRPD pattern” is an x-y pattern having a diffraction angle (i.e., ° 2 ⁇ ) on the x-axis and intensity on the y-axis.
  • the peaks in this pattern can be used to characterize the solid state of the crystal.
  • variability in the XRPD data is often uniquely represented by the diffraction angle of the peak, and does not include the intensity of the peak, as the intensity of the peak may be particularly sensitive to the preparation of the sample (eg, particle size, moisture content, solvent content, and preferred orientation effects affect sensitivity)
  • samples of the same material prepared under different conditions may produce slightly different patterns; this variability is typically greater than the variability of the diffraction angle.
  • the variability in diffraction angle can also be sensitive to the preparation of the sample.
  • Other sources of variability come from instrument parameters and processing of raw X-ray data: different X-ray instrument operations use different parameters and these may result in XRPD patterns that are slightly different from the same solid morphology, and similarly, different software The packet processes the X-ray data in different ways and this also leads to variability.
  • These and other sources of variability are known to those skilled in the pharmaceutical arts. Due to the source of the variability, the diffraction angle in the XRPD pattern is assigned a variability of ⁇ 0.2° 2 ⁇ , that is, the invention includes not only crystals having exactly the same diffraction angle in X-ray powder diffraction, but also an error range of ⁇ 0.2°. Crystals with uniform internal diffraction angles.
  • Figure 1 is an XRPD pattern of the ethyl acetate solvate crystal A of the compound of the formula A-5 in a preferred embodiment of the present invention.
  • Figure 2 is an infrared spectrum of the ethyl acetate solvate crystal A of the compound of formula A-5 in a preferred embodiment of the invention.
  • Figure 3 is an amorphous XRPD pattern of a compound of formula A-5 in a preferred embodiment of the invention.
  • Figure 4 is an XRPD pattern of the ethyl formate solvate crystal B of the compound of formula A-5 in a preferred embodiment of the invention.
  • Figure 5 is an infrared absorption spectrum of ethyl formate solvate crystal B of the compound of formula A-5 in a preferred embodiment of the invention.
  • Figure 6 is an XRPD pattern of the methyl acetate solvate crystal C of the compound of formula A-5 in a preferred embodiment of the invention.
  • Figure 7 is an infrared absorption spectrum of a methyl acetate solvate crystal C of the compound of the formula A-5 in a preferred embodiment of the present invention.
  • Figure 8 is an XRPD pattern of crystalline D of n-propyl formate solvate of a compound of formula A-5 in a preferred embodiment of the invention.
  • Figure 9 is an infrared absorption spectrum of crystal D of n-propyl formate solvate of a compound of formula A-5 in a preferred embodiment of the invention.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • the 1 H NMR chemical shift ( ⁇ ) was recorded in PPM (10 -6 ).
  • NMR was performed on a Bruker AVANCE-400 spectrometer.
  • a suitable solvent is deuterated chloroform (CDCl 3 ) tetramethylsilane as an internal standard (TMS).
  • MS mass spectra
  • X-ray powder diffraction patterns were acquired on a Bruker D8 diffractometer using Cu-K ⁇ radiation (40 kV, 40 mA), ⁇ -2 ⁇ goniometer and Lynxeye detector. Check the performance of the instrument using the certified Corundum standard (NIST 1976). The software used for data collection is Diffrac Plus XRD Commander V6, and data is analyzed and presented using DIFFRAC.EVA V4.2.
  • the sample was run as a flat specimen under ambient conditions.
  • the sample was lightly packaged in a cavity that was cut into polished, zero background wafers. The details of the data collection are:
  • N,N-diisopropylethylamine (70.0 g, 0.54 mol) was added dropwise, and the mixture was stirred at room temperature for 2 hr. After adding 700 ml of water, stirring, liquid separation, organic phase washing, dried over anhydrous sodium sulfate, filtered,
  • the temperature was controlled at 10 ° C, and N,N-diisopropylethylamine (37.6 g, 0.29 mol) was added dropwise. After the completion of the dropwise addition, the reaction was stirred at a temperature of 40 ° C for about 24 hours, and the reaction of the starting material was completely monitored by TLC. After adding 500 ml of water, stirring, liquid separation, washing with an organic phase, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure at 40 ° C to give a white solid.
  • Example I-1 The oil obtained in Example I-1 (theoretical 112.3 g, 0.24 mol) was dissolved in 1.7 L of ethyl acetate. The temperature was adjusted to 15 ° C, concentrated hydrochloric acid (160 ml, 1.92 mol) was added dropwise, and the temperature was controlled at 20 ° C for 2 h. The TLC monitors the reaction of the starting material completely, and a large amount of solid precipitates; it is filtered, washed with a small amount of ethyl acetate, and the filter cake is dried at 50 ° C to a constant weight to obtain a solid of 82.8 g, a purity of 99.90%, a two-step yield of 85.0%;
  • Example I-2 The solid obtained in Example I-2 (theoretical 112.3 g, 0.24 mol) was completely dissolved in 1.2 L of methyl ethyl ketone, the temperature was controlled at 10 ° C, concentrated hydrochloric acid (300 ml, 3.6 mol) was added dropwise, and the temperature was controlled at 40 ° C for 10 h. The raw material reaction is complete, a large amount of solids are precipitated; filtered, rinsed with a small amount of methyl ethyl ketone, and the filter cake is dried to constant weight at 50 ° C to obtain a solid 81.0 g, purity 100.0%, two-step yield 83.1%, and nuclear magnetic and mass spectrometry data are implemented simultaneously.
  • Example I-4 The raw material reaction is complete, a large amount of solids are precipitated; filtered, rinsed with a small amount of methyl ethyl ketone, and the filter cake is dried to constant weight at 50 ° C to obtain a solid 81.0 g, purity
  • Example I-3 The solid obtained in Example I-3 (theoretical 112.3 g, 0.24 mol) was completely dissolved in 1.2 L of isopropanol, and the temperature was controlled at 25 ° C, 6 N concentrated hydrochloric acid (576 ml, 2.9 mol) was added dropwise, and the temperature was controlled at 25 ° C for 20 h. TLC monitored the reaction of the starting material completely, a large amount of solid precipitated; filtered, rinsed with a small amount of isopropanol, and the filter cake was dried to constant weight at 50 ° C to obtain a solid 90.6 g, purity 99.99%, two-step yield 93.0%, nuclear magnetic, Mass spectral data was identical to Example I-4.
  • the difference from the embodiment I-4 is that the dropwise addition of concentrated hydrochloric acid (160 mL, 1.92 mol) is replaced by 1.92 mol of hydrogen chloride gas to obtain a solid 90.1 g, a purity of 99.35%, a two-step yield of 92.5%, and a nuclear magnetic field.
  • the mass spectrometry data is the same as in Example I-4.
  • the difference from the embodiment I-5 is that the dropwise addition of concentrated hydrochloric acid (300 mL, 3.6 mol) is replaced by introducing 1.2 mol of hydrogen chloride gas to obtain a solid of 89.6 g, a purity of 99.15%, a two-step yield of 91.8%, and a nuclear magnetic field.
  • the mass spectrometry data is the same as in Example I-4.
  • Example I-6 Applicants replaced 6N concentrated hydrochloric acid (576 ml, 2.9 mol) in Example I-6 with 2N concentrated hydrochloric acid (1450 ml, 2.9 mol) to obtain a solid 90.1 g, purity 99.35%, two-step yield 92.5%, NMR, MS data. Same as Example I-4.
  • Example I-10 1-Cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl) Preparation of benzoyl)-2,5-diazabicyclo[2,2,1]heptan-2-yl)ethane-1,2-dione (Formula A-5)
  • Example I-4 The solid obtained in Example I-4 (80.0 g, 0.19 mol) was placed in a reaction vessel containing 800 ml of dichloromethane and stirred, and HOBT (39.2 g, 0.29 mol), EDCI (82.4 g, 0.43 mol) and 2-ring were added.
  • Example I-11 1-Cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl) Preparation of benzoyl)-2,5-diazabicyclo[2,2,1]heptan-2-yl)ethane-1,2-dione (Formula A-5)
  • Example I-5 The solid obtained in Example I-5 (80.0 g, 0.19 mol) was placed in a reaction vessel containing 800 ml of dichloromethane, stirred, and HOBT (31.1 g, 0.23 mol), EDCI (44.1 g, 0.23 mol) and 2-ring were added.
  • Example I-12 1-Cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl) Preparation of benzoyl)-2,5-diazabicyclo[2,2,1]heptan-2-yl)ethane-1,2-dione (Formula A-5)
  • Example I-6 The solid obtained in Example I-6 (80.0 g, 0.19 mol) was placed in a reaction vessel containing 800 ml of dichloromethane, stirred, and HOBT (31.1 g, 0.23 mol), EDCI (35.2 g, 0.18 mol) and 2-ring were added.
  • Example I-13 1-Cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl) Preparation of benzoyl)-2,5-diazabicyclo[2,2,1]heptan-2-yl)ethane-1,2-dione (Formula A-5)
  • Example I-8 The solid obtained in Example I-8 (80.0 g, 0.19 mol) was placed in a reaction vessel containing 800 ml of dichloromethane, stirred, and EDCI (44.1 g, 0.23 mol) and sodium 2-cyclopropyl-2-oxoacetate were added.
  • Example I-1 obtained an oily substance containing a small amount of by-product tetramethylurea
  • Examples I-2 and I-3 obtained a solid; but whether the formula II is present in the reaction mixture as an oil or a solid, as long as the formula I (for example, formula I-5) is formed in the subsequent step as a solid formed in the reaction mixture, and then simply filtered and dried.
  • a high purity compound of formula I e.g., formula I-5) is obtained.
  • a compound of the formula I (for example, formula I-5) of high purity is reacted with the compound B to produce a compound A of high purity with a purity of 99.9% or more and a yield of 90% or more.
  • the yield of the compound obtained in the process of the examples in CN103237799 is less than 60%, such as CN103237799A Example 2 and the process of the invention (for example: Examples 10 to 13), the same compound I-5, CN103237799A, Example 2, Formula I- The yield of 5 was 55%, which was much lower than the yield of the process of the invention.
  • Example I-14 PARP inhibition efficacy can be determined by the following experiment
  • test compound information is as follows:
  • Positive control AZD2281 chemical name: 1-(cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-pyridazine)methyl]-2-fluorobenzamide Acyl] piperazine.
  • the PARP enzyme reaction system was added to a 96-well plate pre-coated with a histone-labeled substrate, double-welld, and incubated for 1 hour at room temperature.
  • the reaction system consisted of: 50 ⁇ l of reaction buffer containing NAD + (Tris ⁇ HCl, pH 8.0), biotinylated NAD + (see 3), activated DNA (see 3), a PARP enzyme (see 3) and Test compound (see 2). After completion of the reaction when the enzyme incubation, each well was added 50 ⁇ l of a horseradish peroxidase-labeled streptavidin biotin room temperature for 30 minutes before addition of 100 ⁇ l developer using BioTek Synergy TM 2 plate reader reads the light emission value.
  • Enzyme activity % [(LL b ) / (L t - L b )] ⁇ 100.
  • L luminescence value of the test compound well added
  • L b luminescence value of no PARP or TNKS pore
  • L t luminescence value of the test compound not added
  • enzyme activity inhibition ratio % 100 - enzyme activity %.
  • the enzyme inhibitory activity of the compound is expressed as IC 50 and the inhibition curve is represented by a plot with standard deviation.
  • Example I-15 DNA binding activity test of recombinant human PARP1 enzyme
  • test compound information is as follows:
  • Positive control AZD2281 chemical name: 1-(cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-pyridazine)methyl]-2-fluorobenzamide Acyl] piperazine.
  • the enzymatic reaction was carried out in a 96-well plate with double replicate wells at room temperature. 45 ml of nick DNA containing 5 nM Alexa488 label, PARP1 buffer of PARP1 enzyme (see 3) and test compound (see 2) were incubated for 30 minutes at room temperature, then 5 ml of NAD was added to initiate PARP1 enzymatic reaction and incubated at room temperature 45 minute. Fluorescence intensities at 485 nM and 528 nM were read using a Tecan Infinite M1000 plate reader. Fluorescence intensity was converted to fluorescence polarization using Tecan Magellan 6 software and data processing was performed using Graphpad Prism software.
  • Fluorescence polarization (FP o ) without test compound in all data was defined as 0% activity
  • fluorescence polarization (FP t ) without NAD and test compound was defined as 100% activity
  • no PARP and fluorescence polarization (FP b) test the test compound was defined as background activity.
  • test compound of the present invention is calculated according to the following formula:
  • % activity [(FP-FP b )-(FP o -FP b )] / [(FP t -FP b )-(FP o -FP b )]*100.
  • Example II-1 50 g of the compound of the formula A-5 obtained in Example II-1 was dissolved in 100 ml of acetone to form an acetone solution of the compound of the formula A-5;
  • the XRPD pattern has no crystal diffraction peak, so the white powder is amorphous.
  • Example II-1 50 g of the compound of the formula A-5 obtained in Example II-1 was dissolved in 500 ml of ethanol to form an ethanol solution of the compound of the formula A-5;
  • Example II-1 50 g of the compound of the formula A-5 obtained in Example II-1 was dissolved in 250 ml of isobutyl acetate to form an isobutyl acetate solution of the compound of the formula A-5;
  • the mixture was stirred at 30 ° C; filtered, and the amount of n-pentane was rinsed; the filter cake was dried under reduced pressure to give 48 g of the compound of formula A-5 as a white powder.
  • Example II-1 50 g of the compound of the formula A-5 obtained in Example II-1 was dissolved in 50 ml of methanol to form a methanol solution of the compound of the formula A-5; the reaction flask was charged with isopropyl ether (0.5 L), stirred, and slowly dropped into the system at 20 ° C. a methanol solution of the compound of the formula A-5, after completion, a large amount of white solid precipitated;
  • Example II-1 50 g of the compound of the formula A-5 obtained in Example II-1 was dissolved in 100 ml of ethyl acetate to form an ethyl acetate solution of the compound of the formula A-5;
  • Example II-1 50 g of the compound of the formula A-5 obtained in Example II-1 was dissolved in 200 ml of methyl ethyl ketone to form a methyl ethyl ketone solution of the compound of the formula A-5;
  • the XRPD patterns of the white powders obtained in Examples II-3 to II-7 were determined to be substantially the same as those in Example II-2.
  • sample The white powder (hereinafter referred to as: sample) obtained in Examples II-2 and II-5 was simulated in a commercial package (medicinal low-density polyethylene bag/medicinal composite film bag), and placed in a drug stability test chamber at a temperature of 40 At °C ⁇ 2°C, the relative humidity was 75% ⁇ 5% for 6 months, and samples were taken at 1, 2, 3, and 6 months. The following items were tested. The results are as follows:
  • the amorphous form of the compound of formula A-5 of the present invention has a temperature of 40 ° C ⁇ 2 ° C and a humidity of RH 75% ⁇ 5%. After being placed for 6 months, the results of various indexes have no significant change compared with the initial results of 0 days.
  • the amorphous form of the compound of the formula A-5 is preferred.
  • the applicant also tested the amorphous forms obtained in Examples II-3, II-4, II-6, and II-7, and the HPLC purity thereof was not less than 99.5%, and the total amount was not more than 0.5%.
  • the solubility test was carried out at 25 °C ⁇ 2 °C (according to the pre-test results, the appropriate amount of the test sample was weighed, the solvent was gradually added, shaken, observed to dissolve completely, and the solubility was judged according to the pharmacopoeia standard).
  • the test results of the amorphous sample of the compound 5 are shown in the following table.
  • each saturated solution is diluted with a 10% acetonitrile aqueous solution to a solution containing 0.05 mg of the main drug per 1 ml, that is, Each test solution is obtained; another appropriate amount of the reference substance is accurately weighed, dissolved in an appropriate amount of acetonitrile, and diluted with 10% acetonitrile aqueous solution to prepare a reference substance containing 0.05 mg of the main drug per 1 ml (sample obtained in Example II-1) ) solution.
  • the saturated solubility of the amorphous sample of the compound of the formula A-5 of the present invention in aqueous solutions of different pH values was examined by external standard method in terms of peak area. The results are shown in the following table.
  • solubility of the amorphous form of the compound of the formula A-5 of the present invention in an aqueous solution of pH 1.0 to 10 is about 1.0 mg/ml, indicating that the solubility of the compound is not pH-dependent.
  • III-1 to III-5 are preparations of ethyl acetate solvate crystal A of formula A-5
  • Example II-1 100 g of the target product obtained in Example II-1 was added to 600 ml of 100% (w/w) ethyl acetate to dissolve completely, and the mixture was stirred and crystallized at a controlled temperature of 10 °C. Filter and rinse with an appropriate amount of ethyl acetate. The filter cake was dried under reduced pressure to a constant weight at 55 ° C to give 92.0 g of ethyl acetate solvate crystals of formula A-5, yield 92.0%.
  • Example II-1 100 g of the target product obtained in Example II-1 was added to 2000 ml of an ethyl acetate solution (95% (w/w) ethyl acetate, 5% (w/w) tetrahydrofuran) to dissolve completely, and the mixture was stirred and crystallized at a controlled temperature of 20 °C. Filter and rinse with an appropriate amount of ethyl acetate. The filter cake was dried under reduced pressure at 40 ° C to a constant weight to obtain 91.5 g of ethyl acetate solvate crystals of formula A-5, yield 91.5%.
  • an ethyl acetate solution 95% (w/w) ethyl acetate, 5% (w/w) tetrahydrofuran
  • Example II-1 100 g of the target product obtained in Example II-1 was added to 1000 ml of an ethyl acetate solution (90% (w/w) ethyl acetate, 10% (w/w) acetonitrile) to dissolve completely, and the mixture was stirred and crystallized at a controlled temperature of 30 °C. Filter and rinse with an appropriate amount of ethyl acetate. The filter cake was dried under reduced pressure at 60 ° C to a constant weight to obtain 92.0 g of ethyl acetate solvate crystals of formula A-5, yield 92.0%.
  • an ethyl acetate solution 90% (w/w) ethyl acetate, 10% (w/w) acetonitrile
  • Example II-1 100 g of the target product obtained in Example II-1 was added to 400 ml of an ethyl acetate solution (85% (w/w) ethyl acetate, 15% (w/w) tetrahydrofuran) to dissolve completely, and the mixture was stirred and crystallized at a controlled temperature of 40 °C. Filter and rinse with an appropriate amount of ethyl acetate. The filter cake was air-dried to a constant weight at 30 ° C to obtain 90.4 g of ethyl acetate solvate crystal of formula A-5 in a yield of 90.4%.
  • an ethyl acetate solution 85% (w/w) ethyl acetate, 15% (w/w) tetrahydrofuran
  • Example II-1 100 g of the target product obtained in Example II-1 was added to 3000 ml of an ethyl acetate solution (50% (w/w) ethyl acetate, 50% (w/w) acetonitrile) to dissolve completely, and the mixture was stirred and crystallized at a controlled temperature of 0 °C. Filter and rinse with an appropriate amount of ethyl acetate. The filter cake was air-dried to constant weight at 70 ° C to obtain 90.9 g of ethyl acetate solvate crystal of formula A-5 in a yield of 90.9%.
  • an ethyl acetate solution 50% (w/w) ethyl acetate, 50% (w/w) acetonitrile
  • Fig. 1 The XRPD pattern of the ethyl acetate solvate crystal A of the compound of the formula A-5 is shown in Fig. 1.
  • the diffraction angle 2? and the relative intensity of each peak in Fig. 1 are shown in the following table.
  • the diffraction angles 2 ⁇ ⁇ 0.2° were 8.193, 14.137, 17.799, 19.483, 20.062, 20.861 and 23.837.
  • the infrared absorption spectrum of the ethyl acetate solvate crystal A of the compound of the formula A-5 is shown in Fig. 2 . Characterized by the following important bands, expressed as the reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2cm -1 ), which has absorption peaks at the following positions: 3345.84, 3204.48, 3077.83, 3009.85, 2984.15, 1173.55, 1693.68, 1166.67, 1653.93 1495.51, 145.38, 1405.77, 1372.64, 1331.30, 1241.81, 1109.35, 1155.83, 1106.21, 1081.60, 1042.61, 1000.42, 947.75, 929.26, 836.47, 805.05, 772.26, 750.17, 723.25, 682.88, 621.94, 577.80, 528.40, 486.00.
  • Example II-1 100 g of the target product obtained in Example II-1 was added to 2000 ml of ethyl formate solution (95% w/w ethyl formate, 5% w/w tetrahydrofuran) to dissolve completely, and the mixture was stirred and crystallized at a controlled temperature of 20 ° C. Filter and dilute the appropriate amount of ethyl formate. The filter cake was dried under reduced pressure at 40 ° C to a constant weight to obtain the ethyl formate solvate crystals of the compound of formula A-5 (92.4 g, yield 92.4%).
  • the XRPD pattern of the ethyl acrylate solvate crystal B of the compound of the formula A-5 is shown in Fig. 4, and the diffraction angles and relative intensities in the XRPD pattern are shown in the following table.
  • the X-ray powder diffraction pattern of the ethyl formate solvate crystal B of the compound of the formula A-5 has a characteristic peak at diffraction angles 2 ⁇ 0.2° of 8.471, 14.034, 16.131 and 19.679; It has characteristic peaks at diffraction angles 2 ⁇ 0.2° of 8.471, 9.776, 11.491, 14.034, 16.131, 19.679, 22.621, and 24.532; more preferably, the diffraction angles 2 ⁇ 0.2° are 8.471, 9.776, 11.151, 11.491, 14.034, 16.131, There are characteristic peaks at 16.790, 17.755, 18.626, 19.679, 22.621, 23.268, and 24.532.
  • the infrared absorption spectrum pattern of the ethyl formate solvate crystal B of the formula A-5 is shown in Fig. 5. Characterized by the following important bands, expressed as the reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2cm -1 ), which has absorption peaks at the following positions: 3447.16, 3190.04, 3076.26, 3010.93, 2893.18, 1723.60, 1667.77, 1366.87, 1559.39 , 1476.32, 1448.70, 1406.16, 1137.35, 1329.87, 1258.92, 1239.50, 1180.47, 1155.24, 1107.13, 1081.35, 1042.77, 1027.06, 1001.43, 948.22, 927.67, 899.76, 836.95, 804.45, 771.41, 750.66, 723.72, 683.19, 655.68, 621.35 578.30, 540.65 and 486.11.
  • Example II-1 100 g of the target product obtained in Example II-1 was added to 1000 ml of methyl acetate solution (90% w/w methyl acetate, 10% w/w acetonitrile) to dissolve completely, and the mixture was stirred and crystallized at a controlled temperature of 30 °C. Filter and dilute the appropriate amount of methyl acetate. The filter cake was dried under reduced pressure at 60 ° C to a constant weight to obtain a crystals of methyl acetate solvate C 92.2 g of the compound of formula A-5, yield 92.2%.
  • methyl acetate solution 90% w/w methyl acetate, 10% w/w acetonitrile
  • the XRPD pattern of the methyl acetate solvate crystal C of the compound of the formula A-5 is shown in Fig. 6, and the diffraction angle 2? and its relative intensity in the XRPD pattern are shown in the following table.
  • the X-ray powder diffraction pattern of the methyl acetate solvate crystal C of the compound of the formula A-5 has a characteristic peak at a diffraction angle of 2 ⁇ ⁇ 0.2° of 8.454, 14.057, 16.11 and 19.681; Characteristic peaks at diffraction angles 2 ⁇ 0.2° of 8.454, 9.748, 11.548, 13.740, 14.057, 16.111, 19.681, and 22.619; more preferably, diffraction angles 2 ⁇ 0.2° are 8.454, 9.748, 11.144, 11.548, 13.740, 14.057, There are characteristic peaks at 16.111, 16.779, 17.778, 18.596, 19.681, 22.619 and 23.256.
  • the infrared absorption spectrum of the methyl acetate solvate crystal C of the compound of the formula A-5 is shown in Fig. 7, and is characterized by the following important bands, expressed by the reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2 cm -1 ), It has absorption peaks at the following positions: 3447.25, 319.985, 3090.97, 3010.12, 2896.69, 1744.78, 1668.61, 1617.02, 1549.53, 1946.34, 1449.40, 1406.28, 1370.92, 1333.37, 1240.52, 1213.97, 1191.31, 1155.98, 1106.65, 1081.38, 1042.71. 1001.04, 947.78, 928.16, 899.53, 836.47, 804.71, 771.49, 723.86, 683.14, 621.65, 578.05, 540.88 and 485.99.
  • Example II-1 100 g of the target product obtained in Example II-1 was added with 3000 ml of n-propyl formate solution (50% (w/w) n-propyl formate, 50% (w/w) acetonitrile) to dissolve completely, and controlled to stand at 0 ° C for stirring and crystallization. . Filter and dilute the proper amount of n-propyl formate. The filter cake was air-dried to constant weight at 70 ° C to obtain 107.8 g of n-propyl formate solvate crystal of the compound of formula A-5 in a yield of 91%.
  • n-propyl formate solution 50% (w/w) n-propyl formate, 50% (w/w) acetonitrile
  • the XRPD pattern of the compound A-5 compound n-propyl formate solvate crystal D is shown in Fig. 8, and the diffraction angles and relative intensities in the XRPD pattern are shown in the following table.
  • the X-ray powder diffraction pattern of the n-propyl formate solvate crystal D of the compound of the formula A-5 has characteristics at diffraction angles 2 ⁇ ⁇ 0.2° of 8.152, 13.989, 15.924, 19.459 and 22.237.
  • a peak preferably having a characteristic peak at a diffraction angle of 2 ⁇ ⁇ 0.2° of 8.152, 13.526, 13.989, 15.924, 16.720, 19.048, 19.459, 22.237, and 22.840; more preferably at a diffraction angle of 2 ⁇ ⁇ 0.2° of 8.152, 9.459, 11.647, 13.526 Characteristic peaks at 13.989, 15.407, 15.924, 16.720, 17.692, 18.423, 19.058, 19.459, 22.237, 22.840, 23.795 and 24.751.
  • the infrared absorption spectrum of the n-propyl formate solvate crystal of the compound of the formula A-5 is shown in Fig. 9, and is characterized by the following important bands, expressed by the reciprocal of the absorption wavelength (cm -1 ) ( ⁇ 2 cm -1 ) It has absorption peaks at the following positions: 34470.11, 3203.33, 3074.46, 3010.34, 2966.46, 2891.74, 1726.16, 1668.42, 1163.53, 1 496.39, 1449.31, 1406.54, 1372.26, 1330.16, 1258.84, 1239.49, 1168.01, 1154.17, 1106.97, 1081.28, 1044.04 1027.37, 1002.12, 948.21, 928.04, 899.53, 836.47, 804.41, 772.26, 724.08, 682.94, 655.68, 621.26, 577.89, 540.67 and 485.97.
  • Examples III-9 to III-13 are preparations of solvate crystals of the compound of formula A-5
  • Example III-1 The difference from Examples III-1, III-3, III-6, III-7, and III-8 was that the "target product obtained in Example II-1" was replaced with the "solid obtained in Example II-3 (The compound of the formula A-5 is amorphous (i.e., amorphous)), and the yield of the product is as follows:
  • the raw material is amorphous (i.e., amorphous) of the compound of the formula A-5 (Examples III-9 to III-13) It is easier to precipitate a solid from a solvent with respect to the compound of the formula A-5 (Examples III-1, III-3, III-6, III-7, III-8) of the target sample obtained in Example II-1, respectively. Moreover, the yield is significantly improved.
  • Samples (crystals obtained in Examples III-1 and III-9) were sampled, and commercial packages (medicinal low-density polyethylene bags/medicinal composite film bags) were simulated and placed in a drug stability test chamber at a temperature of 40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5% conditions for 3 months, sampling in the first, second, and third months, according to the following items to test, the results are shown in the table below.
  • Example III-1 Sample (ethyl acetate solvate crystal A of the compound of formula A-5) accelerated test results
  • Example III-9 Sample (ethyl acetate solvate crystal A of the compound of formula A-5) accelerated test results
  • the product has a temperature of 40 ° C ⁇ 2 ° C, humidity RH75% ⁇ 5%, after standing for 3 months, the results of the various indicators have no significant change compared with the initial results of 0 days, indicating the compound of formula A-5 of the present invention
  • the solvate crystals e.g., ethyl acetate solvate crystal A of the compound of formula A-5) are more stable.
  • the solvate crystal of the compound of the formula A-5 is substantially free of hygroscopicity, and the amorphous (i.e., amorphous) compound of the formula A-5 has a certain wettability, and the solvate crystal is relatively easy to store. Avoid packaging problems caused by moisture absorption of raw materials.

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Abstract

La présente invention concerne un procédé de préparation d'un composé inhibiteur de PARP, ainsi qu'un intermédiaire, une forme amorphe, un solvate, une composition pharmaceutique et une application de celui-ci. Le procédé de préparation d'un composé inhibiteur de PARP de la présente invention peut être utilisé pour préparer le composé cible avec une pureté élevée et un rendement élevé, et peut être appliqué à une production industrielle. De plus, la présente invention découvre, pour la première fois, une forme amorphe du composé tel que représenté par la formule A-5, et la forme amorphe présente une bonne fluidité et est pratique à transporter et à conserver. La présente invention concerne également un cristal d'un solvate du composé tel que représenté par la formule A-5, le cristal présentant une bonne fluidité et une bonne stabilité et ne présentant fondamentalement aucune hygroscopicité.
PCT/CN2018/083969 2017-04-21 2018-04-20 Procédé de préparation d'un composé inhibiteur de parp, et intermédiaire, forme amorphe, solvate, composition pharmaceutique et application de celui-ci WO2018192576A1 (fr)

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CN201810354222.1 2018-04-19
CN201810354319.2 2018-04-19
CN201810354319.2A CN108822115B (zh) 2017-04-21 2018-04-19 一种抑制parp活性的化合物的制备方法及其中间体
CN201810354222.1A CN110386939B (zh) 2018-04-19 2018-04-19 Parp抑制剂的溶剂合物晶体及其制备方法
CN201810354691.3A CN108727391A (zh) 2017-04-21 2018-04-19 Parp抑制剂化合物非晶形及其制备方法和应用
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WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras

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WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
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WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras

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