WO2017133687A1 - 一种tlr7激动剂的三氟乙酸盐、晶型b、制备方法和用途 - Google Patents

一种tlr7激动剂的三氟乙酸盐、晶型b、制备方法和用途 Download PDF

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WO2017133687A1
WO2017133687A1 PCT/CN2017/072894 CN2017072894W WO2017133687A1 WO 2017133687 A1 WO2017133687 A1 WO 2017133687A1 CN 2017072894 W CN2017072894 W CN 2017072894W WO 2017133687 A1 WO2017133687 A1 WO 2017133687A1
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compound
formula
trifluoroacetate salt
crystalline
crystalline form
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PCT/CN2017/072894
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English (en)
French (fr)
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丁照中
孙飞
胡迎虎
周义龙
王峥
赵锐
杨玲
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正大天晴药业集团股份有限公司
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Priority to EP17747007.7A priority Critical patent/EP3412674B1/en
Priority to CN201780009751.1A priority patent/CN108602833B/zh
Priority to SG11201806688QA priority patent/SG11201806688QA/en
Priority to AU2017214135A priority patent/AU2017214135B2/en
Priority to CA3013521A priority patent/CA3013521C/en
Priority to ES17747007T priority patent/ES2834304T3/es
Priority to MX2018009503A priority patent/MX2018009503A/es
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to US16/075,303 priority patent/US10683296B2/en
Priority to DK17747007.7T priority patent/DK3412674T3/da
Priority to EA201891772A priority patent/EA037048B1/ru
Priority to NZ745023A priority patent/NZ745023A/en
Priority to JP2018540797A priority patent/JP6877450B2/ja
Priority to KR1020187024629A priority patent/KR102393281B1/ko
Priority to UAA201809128A priority patent/UA121276C2/uk
Priority to BR112018015878-0A priority patent/BR112018015878A2/zh
Publication of WO2017133687A1 publication Critical patent/WO2017133687A1/zh
Priority to PH12018501641A priority patent/PH12018501641B1/en
Priority to IL260981A priority patent/IL260981B/en
Priority to HK19101232.5A priority patent/HK1259182A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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 invention belongs to the field of medicinal chemistry, and in particular, the present invention relates to a TLR7 agonist (2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[ Trifluoroacetate salt of 3,2-d]pyrimidin-4-amine), a process for the preparation thereof, a pharmaceutical composition comprising the salt, and the use of the salt.
  • the present invention also relates to a crystalline form B of the above salt, a process for producing the same, a crystalline composition comprising the crystalline form B, a pharmaceutical composition comprising the crystalline form B or a crystalline composition thereof, and uses thereof.
  • Toll-like receptors are expressed in a variety of immune cells. Toll-like receptors recognize highly conserved structural motifs: pathogen-associated microbial patterns (PAMP) expressed by microbial pathogens or damage-associated molecular patterns (DAMP) released by necrotic cells. Activation of the signal cascade by stimulation of Toll-like receptors by the corresponding PAMP or DAMP results in activation of transcription factors such as AP-1, NF- ⁇ B and interferon regulatory factors (impulse response functions). This results in a variety of cellular responses, including the production of interferons, pro-inflammatory cytokines, and effector cytokines to produce an immune response. To date, 13 Toll-like receptors have been found in mammals.
  • PAMP pathogen-associated microbial patterns
  • DAMP damage-associated molecular patterns
  • Toll-like receptors 1, 2, 4, 5, and 6 are predominantly expressed on the cell surface, while Toll-like receptors 3, 7, 8, and 9 are expressed in endosomes.
  • Different Toll-like receptors can recognize ligands derived from different pathogens.
  • Toll-like receptor 7 (TLR7) is mainly expressed by plasmacytoid dendritic cells (pDC) and induces secretion of interferon alpha (IFN- ⁇ ) by ligand recognition.
  • Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8) are highly homologous, and thus the TLR7 ligand is in many cases also a TLR8 ligand.
  • TLR8 stimulation primarily induces the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) and chemokines.
  • TNF-alpha tumor necrosis factor alpha
  • Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or hepatitis C
  • TNF- ⁇ is a pro-inflammatory cytokine whose excessive secretion may cause serious side effects.
  • TLR7 agonists have been reported to date, such as Imiquimod (British Journal of Dermatology 2003; 149 (Suppl.
  • the invention provides a trifluoroacetate salt of a compound of formula I:
  • XRPD X-ray powder diffraction
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a trifluoroacetate salt of a compound of formula I of the invention, a crystalline form B of the invention, or a crystalline composition thereof.
  • the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, excipient and/or vehicle.
  • the present invention provides a process for the preparation of Form B of a trifluoroacetate salt of a compound of Formula I, the process comprising the steps of:
  • the invention provides a method of treating or preventing a Toll-like receptor 7 (TLR7)-related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of formula I of the invention.
  • TLR7 Toll-like receptor 7
  • the disease is a viral infection.
  • the invention also provides a trifluoroacetate salt of a compound of formula I of the invention, a crystalline form B of the invention, or a crystalline composition or pharmaceutical composition thereof, for use in the manufacture or prevention of a Toll-like receptor Use of 7 (TLR7) drugs for related diseases.
  • TLR7 Toll-like receptor Use of 7
  • the disease is a viral infection.
  • the present invention provides a trifluoroacetate salt of the compound of the formula I of the present invention for use in the treatment or prevention of a Toll-like receptor 7 (TLR7)-related disease, a crystalline form B of the present invention or a crystal thereof A composition or pharmaceutical composition.
  • TLR7 Toll-like receptor 7
  • the disease is a viral infection.
  • the viral infection is a hepatitis virus infection, in particular a type B or a Hepatitis virus infection.
  • Figure 1 XRPD pattern of Form B of the trifluoroacetate salt of the compound of Formula I.
  • Figure 2 DSC spectrum of Form B of the trifluoroacetate salt of the compound of Formula I.
  • composition refers to an active ingredient, optionally in combination with one or more pharmaceutically acceptable chemical ingredients such as, but not limited to, carriers and/or excipients.
  • the active ingredient is, for example, a compound of the formula I or a salt thereof, a crystalline form of the invention or a crystalline composition of the invention.
  • pharmaceutically acceptable carrier refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, including, but not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like.
  • Other about the carrier For information, reference may be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.
  • the term "excipient” generally refers to the vehicle, diluent and/or medium, etc. required to formulate an effective pharmaceutical composition.
  • administering refers to a method by which a compound or composition can be delivered to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like.
  • the term "effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • the "effective amount" of an active substance in the composition can be the amount required to achieve the desired effect when used in combination with another active substance in the composition. 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.
  • active ingredient refers to a chemical entity that is effective to treat or prevent a target disorder, disease or condition.
  • therapeutic agent refers to a chemical entity that is effective to treat or prevent a target disorder, disease or condition.
  • the term may refer to, for example, a compound of formula I or a trifluoroacetate thereof, a crystalline form of the invention or a crystalline composition of the invention.
  • the diffraction pattern obtained from crystalline compounds is often characteristic for a particular crystal form, where the relative intensity of the band (especially at low angles) 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°, typically about ⁇ 0.1°. Therefore, this error should be taken into account when determining each crystal structure. If the crystalline form of the invention is described as being substantially as specified in the drawings, the term "substantially” is also intended to encompass such variability in the diffraction peak position.
  • d represents the crystal plane distance
  • ⁇ is Diffraction angle.
  • the peak positions of the XRPD spectrum have similarities as a whole, and the relative intensity error may be large.
  • some of the diffraction lines are missing due to factors such as a decrease in content. At this time, it is not necessary to rely on all the bands observed in the high-purity sample, and even one band may be given.
  • the crystals are characteristic.
  • the X-ray powder diffraction spectrum is determined by the following method: Instrument: Bruker D8 ADVANCE X-ray diffractometer; Method: Target: Cu: K-Alpha; Wavelength Tube pressure: 40 kV; tube flow Current: 40 mA; scanning range: 4 to 40 °; sample rotation speed: 15 rpm; scanning speed: 10 ° / minute.
  • DSC Differential Scanning Calorimetry
  • the thermal transition temperature and melting point error is typically within about 5 °C, typically within about 3 °C, in a continuous analysis.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology 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.
  • DSC differential scanning calorimetry
  • crystalline composition refers to a solid form comprising Form B of the present invention.
  • the amount of the crystalline form B contained in the crystalline composition may be 50% or more, 80% or more, 90% or more, or 95% or more.
  • the crystalline composition may optionally comprise other crystalline forms or other shaped forms of a compound of formula I or a salt thereof (e.g., trifluoroacetate) or impurities other than these.
  • a salt thereof e.g., trifluoroacetate
  • SEM-Cl for 2-(trimethylsilyl)ethoxymethyl chloride
  • SEM for 2-(trimethylsilyl)ethoxymethyl
  • DIPEA for diisopropylethylamine
  • TFA Represents trifluoroacetic acid
  • DMF stands for N,N-dimethylformamide
  • n-BuOH stands for n-butanol
  • NH 3 ⁇ H 2 O stands for ammonia water
  • Na stands for sodium metal
  • XRPD stands for X-ray powder diffraction
  • DSC stands for differential heat analysis.
  • the present invention provides a trifluoroacetate salt of a compound of formula I:
  • the molar ratio of the compound of formula I to trifluoroacetic acid in the trifluoroacetate salt of the compound of formula I is from 1:0.5 to 2, preferably 1:1.
  • the trifluoroacetate salt of the compound of formula I of the present invention can be prepared by a conventional trifluoroacetate preparation process, for example by mixing a compound of formula I with trifluoroacetic acid or by preparing a compound of formula I.
  • the trifluoroacetic acid salt was obtained directly without isolating the trifluoroacetic acid used in the process.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • the diffraction peak of Form B of the trifluoroacetate salt of the compound of Formula I has the following characteristics:
  • the X-ray powder diffraction pattern of Form B of the trifluoroacetate salt of the compound of Formula I The spectrum is basically as shown in Figure 1.
  • Form B of the trifluoroacetate salt of the compound of formula I of the present invention can also be characterized by DSC at an onset temperature of 171.4 ° C ⁇ 5 ° C and a peak temperature of 173.4 ° C ⁇ 5 ° C.
  • the DSC spectrum of Form B of the trifluoroacetate salt of the compound of Formula I is shown in FIG.
  • the molar ratio of the compound of formula I to trifluoroacetic acid in Form B of the trifluoroacetate salt of the compound of Formula I is from 1:0.5 to 2, preferably 1:1.
  • the present invention also provides a crystalline composition comprising a trifluoroacetate salt form B of a compound of formula I.
  • Form B comprises 50% by weight or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more by weight of the crystalline composition.
  • the crystalline composition may comprise, in addition to Form B, other crystalline or amorphous forms of the compound of Formula I or a salt thereof (e.g., trifluoroacetate) or impurities other than these.
  • the present invention also provides a process for the preparation of Form B of a trifluoroacetate salt of a compound of Formula I, which comprises precipitating a trifluoroacetate salt of a compound of Formula I from a solvent.
  • the method comprises the steps of:
  • the crystallization solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, ethyl acetate, water or a mixed solvent thereof; preferably ethanol .
  • the amount of the crystallization solvent added per gram of the trifluoroacetic acid salt of the compound of the formula I is from 1 to 5 mL, preferably from 2 to 3 mL.
  • step 1) the purpose of heat dissolution is to form a homogeneous system of the trifluoroacetate salt of the compound of formula I with the crystallization solvent.
  • the present invention provides a pharmaceutical composition comprising an effective amount of a trifluoroacetate salt of the compound of formula I, Form B or a crystalline composition comprising said Form B.
  • the pharmaceutical compositions may or may not contain pharmaceutically acceptable carriers, excipients and/or vehicles.
  • compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into a solid, Semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc. .
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • Typical routes of administration of a compound of the invention or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, Intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers, excipients and/or vehicles which are well known in the art. These carriers, excipients and vehicles enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients. Dosing.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, fillers such as sugars including lactose, sucrose, mannitol or sorbitol; cellulose formulations such as microcrystalline cellulose, corn starch, wheat starch, rice starch and potato starch; Other substances, such as silica gel, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; disintegrating agents such as sodium carboxymethyl starch, cross-linked carboxylate Sodium methylcellulose, crosslinked polyvinylpyrrolidone, agar or alginic acid may also be used, such as sodium alginate.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • the crystalline form B of the trifluoroacetate salt of the compound of the formula I of the present invention has the advantages of high purity, high crystallinity, and good stability.
  • the preparation method of the crystal form B of the invention is simple, the solvent is cheap and easy to obtain, the crystal form condition is mild, and it is suitable for industrial production.
  • a trifluoroacetate salt of a compound of the formula I as described in the paragraph [1], which is characterized by the formula I The molar ratio of the compound to trifluoroacetic acid is from 1:0.5 to 2, preferably 1:1.
  • a pharmaceutical composition comprising an effective amount of a trifluoroacetate salt of a compound of the formula I as described in the paragraph [1] or [2].
  • the disease is a viral infection, preferably the viral infection is a hepatitis virus infection, in particular a hepatitis B or hepatitis C virus infection.
  • a pharmaceutical composition comprising an effective amount of the crystalline form B as described in any of paragraphs [6] to [10] or the crystalline composition according to the paragraph [21].
  • the disease is a viral infection, preferably the viral infection is a hepatitis virus infection, in particular a hepatitis B or hepatitis C virus infection.
  • the reaction solution was diluted with 70 L of water and diluted with ethyl acetate (15 L ⁇ 3).
  • the combined organic phases were washed sequentially with 1M aqueous hydrochloric acid (5 L ⁇ 2) and saturated brine (7 L ⁇ 2). Pressure distillation to remove solvent
  • the compound of formula III (6.40 kg, 20.11 mol, yield 94.50%) was obtained.
  • the compound of the formula III (1.60 kg, 5.03 mol) was dissolved in isopropanol (1.60 L) in a 10 L autoclave, and aqueous ammonia (4 L) was added in one portion at room temperature (25 ° C). The reaction mixture was stirred at 95 ° C for 7 hours and the reaction was monitored by HPLC. The reaction was allowed to cool to rt. The solid was slurried sequentially with ethyl acetate / n-heptane (1/1, 5L x 2) and EtOAc (EtOAc) (EtOAc) %).
  • the compound of formula V (1.10 kg, 3.27 mol) was dissolved in TFA (5.50 L), and the mixture was stirred at 25 ° C for 16 hr.
  • the TFA was distilled off under reduced pressure, and the residue was dissolved in methanol (1. 2L) and iced water (1.2 L), and the mixture was adjusted to pH 12 with concentrated aqueous ammonia, and then stirred for 2 hours. The precipitate was gradually precipitated in the solution. After filtration, the cake was white solid, which was then beaten with 15% aqueous ammonia (1.2 L ⁇ 3) and ethyl acetate (4 L) to give the compound of formula VI as a white solid (550.00 g) , 2.67 mol, 81.7%).
  • the compound of the formula VII (450.0 g, 1.32 mol) and isopropanol (4.5 L) were placed in a 30 L reaction vessel, stirred for 5 min, then glacial acetic acid (119.0 g, 1.98 mol) was added and the mixture was cooled to 0-10 °C.
  • Pyrrolidine (112.4 g, 1.58 mol) was added dropwise, maintaining the system temperature below 10 °C during the dropwise addition.
  • sodium triacetoxyborohydride (420.0 g, 1.98 mol) was added in portions, and reacted at 10 to 20 ° C for 3 hr, and the liquid phase was monitored until the starting material completely disappeared.
  • the compound of the formula VIII (440.0 g, 1.11 mol) and dichloromethane (7.0 L) were placed in a 20 L reactor, stirred to cool the system to below -15 ° C, and triethylsilane (880 mL, 5.55 mol) was added dropwise, and then continued. Trifluoroacetic acid (880 mL) was added dropwise, maintaining the system temperature below -10 °C during the dropwise addition. After the completion of the dropwise addition, the reaction was carried out at 0 ° C for 2 hr, and the liquid phase was monitored until the starting point disappeared.
  • Form B was placed in an open clean container and placed at 60 ° C for sampling on days 10, 20 and 30, respectively. The test results were compared with the initial test results on day 0.
  • Form B was placed in a constant temperature and humidity container for accelerated testing under conditions of 40 ° C / 75% humidity (open) and samples were taken on days 30, 60 and 90. The test results were compared with the initial test results on day 0.
  • Form B was sampled on day 5, day 10, and day 30 under a light environment of 5000 Lx ⁇ 500 Lx. The test results were compared with the initial test results on day 0.
  • GS-9620 and R848 used are as follows, wherein GS-9620 can be prepared by the method disclosed in US20100143301; R848 is purchased from Baiqi Bio (Cat. No. IMG-2208, specification 0.5 mg).
  • the culture plate containing the cells and the compound was cultured in a CO 2 incubator for 24 hours under the conditions of 37 ° C, 5% CO 2 concentration.
  • the compound of the formula I of the present invention exhibits a higher in vitro receptor binding activity to the Toll-like receptor 7 than the control (Toll-like receptor 7 agonist GS-9620) and exhibits a better than the control (Toll-like The agonist GS-9620) has a lower in vitro receptor binding activity to Toll-like receptor 8.
  • the compounds of the invention have distinct options for different receptors sexual differences, and the effect is better than the prior art.
  • the purpose of this example was to detect the expression level of cytokines after stimulating human peripheral blood mononuclear cells (PBMC) for 24 hours using the compound of formula I.
  • the cell supernatant was not diluted at the time of detection, and the level of IFN- ⁇ was directly detected.
  • the compound of formula I was first formulated into a 20 mmol concentration DMSO stock solution, and a 10-fold serial dilution of the cell culture medium was used to dilute a total of 11 points.
  • the compound with 9 dilution points (the highest concentration of compound was 200 ⁇ mol/L) was added to a 96-well plate at 50 ⁇ L per well, and then fresh human peripheral blood mononuclear cells were seeded, and each well was inoculated with 150 ⁇ L of system containing 450,000 cells. .
  • the cell culture plates were incubated at 37 ° C in a 5% CO 2 incubator for 24 hours, and after the completion of the culture, the plates were centrifuged at 1200 rpm for 5 minutes, and then the supernatant was collected and stored at -20 ° C for detection. Cytokine detection was performed on a flow cytometer using BD's Flow Cyclic Multiple Protein Assay (CBA). Using the above assay, we will stimulate the lowest drug concentration that produces 30 pg/mL of IFN-[alpha], defined as the MEC value of the compound in this cytokine stimulation assay. The experimental results are shown in Table 2 below:
  • the compound of the formula I of the present invention exhibits better IFN- ⁇ -inducing activity of PBMC in vitro than the control (GS-9620) and TNF- ⁇ -inducing activity comparable to the control (GS-9620).

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Abstract

本发明涉及一种TLR7激动剂2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺(式I)的三氟乙酸盐、其晶型B、其制备方法和用途。

Description

一种TLR7激动剂的三氟乙酸盐、晶型B、制备方法和用途 技术领域
本发明属于药物化学领域，具体而言，本发明涉及一种TLR7激动剂(2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺)的三氟乙酸盐、其制备方法、包含该盐的药物组合物以及该盐的用途。本发明还涉及上述盐的晶型B、其制备方法、包含该晶型B的结晶组合物、包含该晶型B或其结晶组合物的药物组合物以及它们的用途。
背景技术
Toll样受体表达于多种免疫细胞。Toll样受体识别高度保守结构基序：由微生物病原体表达的病原体相关的微生物模式(PAMP)或由坏死细胞释放的损伤相关分子模式(DAMP)。通过相应的PAMP或DAMP刺激Toll样受体引发信号级联导致转录因子如AP-1、NF-κB和干扰素调节因子(脉冲响应函数)的激活。这导致多种细胞反应，包括产生干扰素、促炎性细胞因子和效应细胞因子，从而产生免疫应答。迄今为在止哺乳动物中已发现13种Toll样受体。Toll样受体1、2、4、5和6主要表达在细胞表面上，而Toll样受体3、7、8和9表达在内体中。不同的Toll样受体可以识别不同病原体衍生的配体。Toll样受体7(TLR7)主要由浆细胞样树突细胞(pDC)表达，并通过配体识别而诱导干扰素α(IFN-α)的分泌。Toll样受体7(TLR7)和Toll样受体8(TLR8)高度同源，因此TLR7配体在很多情况下也是TLR8配体。TLR8刺激主要诱导产生细胞因子，如肿瘤坏死因子α(TNF-α)和趋化因子。干扰素α是治疗慢性乙型肝炎或丙型肝炎的主要药物之一，而TNF-α则是一种促炎细胞因子，其过多的分泌可能导致严重的副作用。迄今为止已经报道了几种TLR7激动剂，如咪喹莫特(Imiquimod,British Journal of Dermatology 2003；149(Suppl.66):5–8)、瑞喹莫德(Resiquimod,Antiviral Research 64(2004)79–83)、GS-9620(Gastroenterology(2013),144(7),1508-1517)，但对于具备更好的选择性、活性和安全性的新的TLR7激动剂仍然有很大需求。
中国专利申请201410405136.0(其内容整体援引加入本文)公开了一种这样的小分子，即2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺，它具有以下结构：
Figure PCTCN2017072894-appb-000001
发明内容
在一方面，本发明提供式I所示化合物的三氟乙酸盐：
Figure PCTCN2017072894-appb-000002
在另一方面，本发明还提供式I所示化合物的三氟乙酸盐的晶型B，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、14.0°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、22.2°±0.2°、23.5°±0.2°的衍射峰。
在又一方面，本发明还提供一种药物组合物，其包含有效量的本发明的式I所示化合物的三氟乙酸盐、本发明的晶型B或其结晶组合物。所述药物组合物还可以任选地包含药学上可接受的载体、赋形剂和/或介质。
在又一方面，本发明提供一种制备式I所示化合物的三氟乙酸盐的晶型B的方法，所述方法包括以下步骤：
1)将式I所示化合物的三氟乙酸盐溶于结晶溶剂中，优选通过加热使其溶解；和
2)冷却析晶、洗涤并干燥以获得所述晶型B。
在进一步的方面，本发明还提供一种治疗或预防Toll样受体7(TLR7)相关疾病的方法，所述方法包括向有此需要的个体给予有效量的本发明的式I所示化合物的三氟乙酸盐、本发明的晶型B或其结晶组合物或者药物组合物。优选地，所述疾病为病毒感染。
在进一步的方面，本发明还提供本发明的式I所示化合物的三氟乙酸盐、本发明的晶型B或其结晶组合物或者药物组合物在制备用于治疗或预防Toll样受体7(TLR7)相关疾病的药物中的用途。优选地，所述疾病为病毒感染。
在更进一步的方面，本发明还提供用于治疗或预防Toll样受体7(TLR7)相关疾病的本发明的式I所示化合物的三氟乙酸盐、本发明的晶型B或其结晶组合物或者药物组合物。优选地，所述疾病为病毒感染。
在本发明的一个实施方案中，所述病毒感染是肝炎病毒感染，特别是乙型或丙 型肝炎病毒感染。
附图说明
图1：式I所示化合物的三氟乙酸盐的晶型B的XRPD谱图。
图2：式I所示化合物的三氟乙酸盐的晶型B的DSC谱图。
具体实施方式
一般定义和术语
除非另有说明，本文所用的术语和短语具有下文所列的含义。特定的术语或短语在没有特别定义的情况下不应该认为是不确定的或不清楚的，而应该按照本领域技术人员通常理解的含义进行解释。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
除非另外专门定义，本文中使用的比例(包括百分比)或份数均按重量计。
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
表述“包含”或与其同义的类似表述“包括”、“含有”和“具有”等是开放性的，不排除额外的未列举的元素、步骤或成分。表述“由…组成”排除未指明的任何元素、步骤或成分。表述“基本上由…组成”指范围限制在指定的元素、步骤或成分，加上任选存在的不会实质上影响所要求保护的主题的基本和新的特征的元素、步骤或成分。应当理解，表述“包含”涵盖表述“基本上由…组成”和“由…组成”。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“药物组合物”指活性成分，其任选地与一种或多种药学上可接受的化学成分(例如，但不限于载体和/或赋形剂)组合。所述活性成分例如式I所示化合物或其盐，本发明的晶型或者本发明的结晶组合物。
术语“药学上可接受的载体”是指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。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他 信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。术语“赋形剂”通常是指配制有效的药物组合物所需要的媒介物、稀释剂和/或介质等。
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服、肠胃外(包括静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。
针对药物或药理学活性剂而言，术语“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。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”可以是与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。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。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗或预防目标紊乱、疾病或病症。在本文中，该术语可以指例如式I所示化合物或其三氟乙酸盐，本发明的晶型或者本发明的结晶组合物。
在X-射线粉末衍射(XRPD或XRD)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、粒径和其他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，这在晶体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°，典型地约为±0.1°。因此，在确定每种晶型结构时，应该将此误差考虑在内。如果本发明的晶型被描述为基本上如指定附图所示，则术语“基本上”也意图涵盖衍射峰位中的这样的差异性。
在XRPD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XRPD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晶体是特征性的。
在本文中，X-射线粉末衍射光谱采用下述方法测定：仪器：Bruker D8ADVANCE X-射线衍射仪；方法：靶:Cu:K-Alpha；波长
Figure PCTCN2017072894-appb-000003
管压Voltage:40kV；管流Current：40mA；扫描范围：4～40°；样品旋转速度：15rpm；扫描速度：10°/ 分钟。
差示扫描量热分析(DSC)测定当晶体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。当描述某个化合物具有某一给定的DSC峰或熔点时，指的是该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体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。
在本文中，差示扫描量热分析(DSC)采用下述方法测定：仪器：TA Q2000差示扫描量热仪；方法：取样品(～1mg)置于DSC铝锅内进行测试，方法为：25℃～300℃，升温速率10℃/min。
术语“结晶组合物”指的是一种固体形式，其包含本发明的晶型B。在结晶组合物中包含的晶型B的量可以为50％以上、80％以上、90％以上或95％以上。除了本发明的晶型以外，结晶组合物还可以任选地包含其他晶型或无其他定形形式的式I化合物或其盐(如三氟乙酸盐)或者除了这些物质以外的杂质。本领域技术人员应当理解，结晶组合物中各成分的含量之和应当为100％。
本文采用下述缩略词：SEM-Cl代表2-(三甲硅烷基)乙氧甲基氯；SEM代表2-(三甲硅烷基)乙氧甲基；DIPEA代表二异丙基乙基胺；TFA代表三氟乙酸；DMF代表N,N-二甲基甲酰胺；n-BuOH代表正丁醇；NH3·H2O代表氨水；Na代表金属钠；XRPD代表X射线粉末衍射；DSC代表差热分析。
式I所示化合物的三氟乙酸盐
本发明提供式I所示化合物的三氟乙酸盐：
Figure PCTCN2017072894-appb-000004
在一实施方案中，在式I所示化合物的三氟乙酸盐中，式I所示化合物与三氟乙酸的摩尔比为1:0.5-2，优选1:1。
本发明的式I所示化合物的三氟乙酸盐可以采用常规的三氟乙酸盐制备工艺来制备，例如通过使式I所示化合物与三氟乙酸混合或者在制备式I所示化合物的过程中不分离所用的三氟乙酸而直接获得该三氟乙酸盐。
晶型B
本发明还提供式I所示化合物的三氟乙酸盐的晶型B，其在X-射线粉末衍射(XRPD)图谱中具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、14.0°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、22.2°±0.2°、23.5°±0.2°的衍射峰。
在一具体的实施方案中，晶型B在X-射线粉末衍射(XRPD)图谱中具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、12.4°±0.2°、14.0°±0.2°、14.9°±0.2°、16.1°±0.2°、16.6°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、21.1°±0.2°、21.8°±0.2°、22.2°±0.2°、23.5°±0.2°的衍射峰。
在更具体的实施方案中，晶型B在X-射线粉末衍射(XRPD)图谱中具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、12.4°±0.2°、13.3°±0.2°、14.0°±0.2°、14.9°±0.2°、16.1°±0.2°、16.6°±0.2°、17.3°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、21.1°±0.2°、21.8°±0.2°、22.2°±0.2°、23.1°±0.2°、23.5°±0.2°、24.4°±0.2°、24.7°±0.2°、26.1°±0.2°、28.2°±0.2°的衍射峰。
在一特定实施方案中，式I所示化合物的三氟乙酸盐的晶型B的衍射峰具有如下特征：
序号 2θ±0.2(°) 相对强度(％) 序号 2θ±0.2(°) 相对强度(％)
1 7.0 100.0 15 19.6 6.8
2 10.2 42.4 16 20.2 39.4
3 11.7 32.0 17 21.1 16.6
4 12.4 21.3 18 21.8 23.9
5 13.3 7.1 19 22.2 31.0
6 14.0 40.1 20 23.1 9.6
7 14.9 16.2 21 23.5 37.6
8 16.1 18.1 22 24.4 13.0
9 16.6 19.9 23 24.7 11.5
10 16.9 8.3 24 26.1 9.5
11 17.3 10.2 25 26.4 5.8
12 17.6 6.2 26 28.2 7.3
13 18.6 34.4 27 32.3 4.1
14 19.1 41.7      
在一实施方案中，式I所示化合物的三氟乙酸盐的晶型B的X-射线粉末衍射图 谱基本上如图1所示。
本发明的式I所示化合物的三氟乙酸盐的晶型B也可以用DSC进行表征，起始温度为171.4℃±5℃，峰值温度为173.4℃±5℃。
在一实施方案中，所述式I所示化合物的三氟乙酸盐的晶型B的DSC谱图如图2所示。
在另一实施方案中，式I所示化合物的三氟乙酸盐晶型B中的式I所示化合物与三氟乙酸的摩尔比为1:0.5-2，优选1:1。
本发明还提供包含式I所示化合物的三氟乙酸盐晶型B的结晶组合物。在一实施方案中，晶型B占结晶组合物重量50％以上，优选80％以上，更优选90％以上，最优选95％以上。结晶组合物除了晶型B以外还可以包含其他晶型或无定形形式的式I化合物或其盐(如三氟乙酸盐)或者除了这些物质以外的杂质。
制备方法
本发明还提供一种制备式I所示化合物的三氟乙酸盐的晶型B的方法，所述方法包括使式I所示化合物的三氟乙酸盐从溶剂中析出。
在一实施方案中，所述方法包括以下步骤：
1)将式I所示化合物的三氟乙酸盐溶于结晶溶剂中，优选通过加热使其溶解；和
2)冷却析晶、洗涤并干燥以获得所述晶型B。
在步骤1)中，所述结晶溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、丙酮、乙酸乙酯、水或它们的混合溶剂；优选乙醇。
在步骤1)中，每1g式I所示化合物的三氟乙酸盐对应加入的结晶溶剂量为1～5mL，优选2～3mL。
在步骤1)中，加热溶解的目的是使式I所示化合物的三氟乙酸盐与结晶溶剂形成均相体系。
药物组合物和给药
本发明提供一种药物组合物，其包含有效量的式I所示化合物的三氟乙酸盐、晶型B或包含所述晶型B的结晶组合物。此外，该药物组合物还可以含有或不含有药学上可接受的载体、赋形剂和/或介质。
以纯的形式或以适宜的药物组合物形式给药本发明化合物可通过提供类似用途的药剂的任何可接受给药模式来进行。本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的载剂、稀释剂或赋形剂组合而制备，且可配制成固态、 半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
给药本发明的化合物或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
在优选的实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药物可接受的载体、赋形剂和/或介质混合，来配制该药物组合物。这些载体、赋形剂和介质能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的赋形剂包括但不限于：填充剂，如糖，包括乳糖、蔗糖、甘露醇或山梨糖醇；纤维素制剂例如微晶纤维素、玉米淀粉、小麦淀粉、大米淀粉和马铃薯淀粉；以及其它物质，如硅胶、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羟甲基纤维素钠和/或聚乙烯吡咯烷酮；崩解剂，如羧甲淀粉钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、琼脂或藻酸，也可以使用盐，如藻酸钠。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
有益效果
本发明的式I所示化合物的三氟乙酸盐的晶型B具有纯度高、结晶度高、稳定性好等优点。同时，本发明的晶型B的制备方法简单，溶剂价廉易得，晶型条件温和，适合工业化生产。
可通过如下段落[1]至段落[20]中所述的内容对本发明的技术方案加以说明：
[1]一种式I所示化合物的三氟乙酸盐，
Figure PCTCN2017072894-appb-000005
[2]如段落[1]所述的式I所示化合物的三氟乙酸盐，其特征在于，式I所示化 合物与三氟乙酸的摩尔比为1:0.5～2，优选1:1。
[3]一种药物组合物，所述药物组合物包括有效量的如段落[1]或[2]所述的式I所示化合物的三氟乙酸盐。
[4]如段落[1]或[2]所述的式I所示化合物的三氟乙酸盐、或者段落[3]所述的药物组合物在制备治疗Toll样受体7相关疾病的药物中的用途。
[5]如段落[4]所述的用途，其特征在于，所述疾病为病毒感染，优选地所述病毒感染是肝炎病毒感染，特别是乙型或丙型肝炎病毒感染。
[6]一种式I所示化合物的三氟乙酸盐的晶型B，其特征在于，在X-射线粉末衍射图谱中，具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、14.0°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、22.2°±0.2°、23.5°±0.2°的衍射峰。
[7]如段落[6]所述的晶型B，其特征在于，在X-射线粉末衍射图谱中，具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、12.4°±0.2°、14.0°±0.2°、14.9°±0.2°、16.1°±0.2°、16.6°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、21.1°±0.2°、21.8°±0.2°、22.2°±0.2°、23.5°±0.2°的衍射峰。
[8]如段落[7]所述的晶型B，其特征在于，在X-射线粉末衍射图谱中，具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、12.4°±0.2°、13.3°±0.2°、14.0°±0.2°、14.9°±0.2°、16.1°±0.2°、16.6°±0.2°、17.3°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、21.1°±0.2°、21.8°±0.2°、22.2°±0.2°、23.1°±0.2°、23.5°±0.2°、24.4°±0.2°、24.7°±0.2°、26.1°±0.2°、28.2°±0.2°的衍射峰。
[9]如段落[6]-[8]中任一项所述的晶型B，其特征在于，所述晶型B具有基本上如图1所示的X-射线粉末衍射图。
[10]如段落[6]-[9]中任一项所述的晶型B，其特征在于，用DSC进行表征时，所述晶型B的起始温度为171.4℃±5℃，峰值温度为173.4℃±5℃。
[11]如段落[6]-[10]中任一段所述的晶型B的制备方法，所述方法包括以下步骤：
1)使式I所示化合物的三氟乙酸盐溶于结晶溶剂中，加热溶解；
2)冷却析晶、洗涤、干燥以获得所述晶型B。
[12]如段落[11]所述的制备方法，其特征在于，步骤1)中所述结晶溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、丙酮、乙酸乙酯或它们混合溶剂、或者水。
[13]如段落[12]所述的制备方法，其特征在于，所述结晶溶剂为乙醇。
[14]如段落[11]-[13]中任一项所述的制备方法，其特征在于，步骤1)中，每1g式I所示化合物的三氟乙酸盐对应加入的结晶溶剂量为1～5mL。
[15]如段落[14]所述的制备方法，其特征在于，每1g式I所示化合物的三氟乙酸盐对应加入的结晶溶剂量为2～3mL。
[16]如段落[11]-[16]中任一项所述的制备方法，其特征在于，步骤1)中，所述加热溶解是使式I所示化合物的三氟乙酸盐与结晶溶剂形成均相体系。
[17]一种结晶组合物，其特征在于，段落[6]-[10]中任一段所述的晶型B占结晶组合物重量的50％以上，优选80％以上，更优选90％以上，最优选95％以上。
[18]一种药物组合物，包含有效量的如段落[6]-[10]中任一段中所述晶型B或者如段落[21]所述的结晶组合物。
[19]如段落[6]-[10]中任一段所述的晶型B、如段落[17]所述的结晶组合物、或者如段落[18]所述的药物组合物在制备治疗Toll样受体7相关疾病的药物中的用途。
[20]如段落[19]所述的用途，其特征在于，所述疾病为病毒感染，优选地所述病毒感染是肝炎病毒感染，特别是乙型或丙型肝炎病毒感染。
实施例
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。制备例中的合成反应一般是在惰性氮气下、无水溶剂中进行的。
质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD：SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
制备例1：2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺三氟乙酸盐的制备
式III：2,4-二氯-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶
Figure PCTCN2017072894-appb-000006
将式II化合物(2,4-二氯-5H-吡咯并[3,2-d]嘧啶)(4.00kg，21.28mol)溶解于DMF(20.00L)中；在室温(25℃)下分批加入DIPEA(2.58kg，20.00mol)，随后搅拌30min。将反应液用冰浴降温至0℃，然后在5小时内，以1～2滴/秒的滴速，缓慢滴加SEM-Cl(4.00kg，24.00mol)。滴加完成后，将反应液在0℃下搅拌反应4小时，HPLC监测反应完全。将反应液用70L水淬灭稀释后，用乙酸乙酯(15L×3)萃取，将合并的有机相依次用1M的盐酸水溶液(5L×2)和饱和食盐水(7L×2)洗涤，减压蒸馏除去溶剂 后得式III化合物(6.40kg，20.11mol，产率94.50％)。
1H NMR(400MHz,DMSO-d6)δ8.24-8.35(m,1H)，6.70-6.85(m,1H)，5.77(s,2H)，3.45-3.57(m,2H)，0.74-0.86(m,2H)，0.00(s,9H)。
式IV：2-氯-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2017072894-appb-000007
在10L高压釜中，将式III化合物(1.60kg,5.03mol)溶于异丙醇(1.60L)，在室温(25℃)下一次性加入氨水(4L)。将反应混合物在95℃下搅拌7小时，HPLC监测反应完毕。使反应液自然冷却到室温，经布氏漏斗过滤后得到黑褐色固体。将该固体依次用乙酸乙酯/正庚烷(1/1，5L×2)打浆，用乙酸乙酯(4L)打浆，得到棕色固体形式的式IV化合物(1.25kg,4.18mol，产率83.1％)。
1H NMR(400MHz,DMSO-d6)δ7.61-7.77(m,1H)，6.97-7.19(m,2H)，6.28-6.38(m,1H)，5.54-5.67(m,2H)，3.43-3.53(m,2H)，0.76-0.91(m,2H)，0.07(s,9H)。
式V：2-丁氧基-5-((2-(三甲基硅基)乙氧基)甲基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2017072894-appb-000008
在氮气保护下，将金属钠(525.05g，22.84mol)缓慢分批加入到n-BuOH(17.0L)中；加入完毕后，使体系升温至60℃，并在该温度下持续搅拌，直至金属钠全部溶解。随后，将体系冷却至25℃，将式IV化合物(1.95kg，6.53mol)分批加入，搅拌混合均匀后，将反应物在90℃下持续搅拌8小时，HPLC监测反应完全。使反应混合物自然降温至25℃后，缓慢倒入30L饱和氯化铵水溶液中，随后用乙酸乙酯(15L×3)萃取。将合并的有机相用饱和食盐水(20L×2)洗涤，经无水Na2SO4干燥、过滤后，减压蒸馏除去溶剂后，将残余物在正庚烷(4L)中打浆，过滤分离得到固体。将该固体再在乙酸乙酯(5L)中打浆，得到黄白色固体形式的式V化合物(1.53kg，4.55mol，69.7％)。
1H NMR(400MHz,DMSO-d6)δ7.49-7.54(m,1H)，6.54-6.62(m,2H)，6.15-6.20(m,1H)，5.54(s,2H)，4.10-4.22(m,2H)，3.42-3.55(m,2H)，1.58-1.73(m, 2H)，1.35-1.47(m,2H)，0.90-0.96(m,3H)，0.83-0.89(m,2H)，0.05(s,9H)。
式VI：2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2017072894-appb-000009
将式V化合物(1.10kg,3.27mol)溶于TFA(5.50L)，将反应液在25℃下持续搅拌16小时，HPLC监测反应完全。减压蒸馏除去TFA，将剩余物溶解在甲醇(1.2L)和冰水(1.2L)中，均匀搅拌下，用浓氨水调节体系pH至12，然后搅拌2小时。溶液中不断有沉淀析出，过滤后，滤饼为白色固体，将其依次用15％的氨水(1.2L×3)和乙酸乙酯(4L)打浆，得到白色固体形式的式VI化合物(550.00g，2.67mol，81.7％)。
1H NMR(400MHz,甲醇-d4)δ7.37(d,J＝2.89Hz,1H)，6.29(d,J＝3.01Hz,1H)，4.27(t,J＝6.53Hz,2H)，1.75(d,J＝7.91Hz,2H)，1.44-1.61(m,2H)，1.00(t,J＝7.40Hz,3H)。
式VII：4-((4-氨基-2-丁氧基-5H-吡咯并[3,2-d]嘧啶-7-基)-羟基甲基)苯甲醛
Figure PCTCN2017072894-appb-000010
将对苯二甲醛(790.64mg，5.82mmol)和异丙醇(10mL)投入至三口瓶中，搅拌下加入2-丁氧基-5H-吡咯并[3,2-d]嘧啶-4-胺(1.00g，4.85mmol)，将体系降温至0℃，之后继续搅拌10min。加入纯化水(10mL)和碳酸钾(804.17mg，5.82mmol)，在25℃反应16hr，LCMS监控至原料反应完全。反应完全后，有固体析出。过滤，将所得固体用20mL纯化水打浆，用30mL(乙酸乙酯/正庚烷＝1/20)打浆，过滤，干燥，得到黄色固体形式的式VII化合物(1.50g，4.41mmol，收率：90.9％)。
1H NMR(400MHz,甲醇-d4)δ9.94(s,1H),7.86(d,J＝8.16Hz,2H),7.72(d,J＝8.16Hz,2H),7.12-7.17(m,1H),6.19(s,1H),4.28(t,J＝6.53Hz,2H),1.68-1.77(m,2H),1.44-1.54(m,2H),0.97(t,J＝7.34Hz,3H)。
式VIII：(4-氨基-2-丁氧基-5H–吡咯并[3,2-d]嘧啶-7-基)(4-(吡咯烷-1-基甲基)苯基)甲醇
Figure PCTCN2017072894-appb-000011
将式VII化合物(450.0g，1.32mol)和异丙醇(4.5L)投入30L反应釜中，搅拌5min，之后加入冰醋酸(119.0g，1.98mol)，搅拌使体系降温至0-10℃。滴加吡咯烷(112.4g，1.58mol)，在滴加中保持体系温度低于10℃。滴加完成后，分批次加入三乙酰氧基硼氢化钠(420.0g，1.98mol)，在10-20℃下反应3hr，液相监控至原料完全消失。反应完全后，加入纯化水5L，使溶液温度降至-10℃左右，加入15％氨水12L，加入过程中保持溶液温度低于0℃。搅拌有固体析出，过滤，将所得滤饼用2L水打浆，用2L×2乙酸乙酯打浆，过滤，在40℃下减压烘干12hr，得到黄色固体形式的式VIII化合物(465.0g，1.18mol，收率89.4％，水分0.9％)。
1H NMR(400MHz,甲醇-d4)δ7.46(d,J＝7.91Hz,1H),7.29(d,J＝8.03Hz,1H),7.09(s,1H),6.12(s,1H),4.29(t,J＝6.53Hz,2H),3.60(s,2H),2.52(br.s.,4H),1.66-1.83(m,6H),1.49(d,J＝7.53Hz,2H),0.98(t,J＝7.40Hz,3H)。
式I：2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺
Figure PCTCN2017072894-appb-000012
将式VIII化合物(440.0g，1.11mol)和二氯甲烷(7.0L)投入20L反应釜中，搅拌使体系降温至-15℃以下，滴加三乙基硅烷(880mL，5.55mol)后，继续滴加三氟乙酸(880mL)，在滴加中保持体系温度低于-10℃。滴加完毕后，在0℃下反应2hr，液相监控至原料点消失。反应完全后，将反应液浓缩至干，加入乙酸乙酯2.2L，搅拌使体系降温至0℃以下，之后加入饱和碳酸钠溶液调节溶液pH＝9-10，此过程中保持温度低于10℃。过滤，将所得滤饼用2.2L水打浆后过滤，减压烘干，得到白色固体形式的式I的三氟乙酸盐550g，其中式I所示化合物与三氟乙酸的摩尔比为1:1。
1H NMR(400MHz,甲醇-d4)δ7.27(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.04(s,1H),4.32(t,J＝6.6Hz,2H),3.99(s,2H),3.60(s,2H),2.55-2.52(m,4H),1.85-1.71(m,6H),1.55-1.48(m,2H),1.00(t,J＝7.4Hz,3H)。
实施例1：2-丁氧基-7-(4-(吡咯烷-1-基甲基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-胺三氟乙 酸盐晶型B的制备。
将制备例1获得的白色固体(550g)和1.4L乙醇搅拌加热至回流，搅拌至全部溶解。过滤，将滤液在室温下搅拌析晶，得到白色固体。之后重复上述操作，重结晶一次，得到类白色固体210.0g，即为式I所示化合物三氟乙酸盐的晶型B，其中式I所示化合物与三氟乙酸的摩尔比为1:1。
结果显示，所获得的晶体具有基本上如图1所示的衍射峰。
实施例2：高温稳定性试验
依据《原料药与药物制剂稳定性试验指导原则》(中国药典2010版附录XIXC)，考察实施例1中制备的晶型B在加速试验高温条件下的稳定性。
将晶型B置于开口洁净容器中，于60℃下放置，分别于第10、20和30天取样检测。将检测结果与第0天的初始检测结果进行比较。
实施例3：高湿稳定性试验
依据《原料药与药物制剂稳定性试验指导原则》(中国药典2010版附录XIXC)，考察实施例1中制备的晶型B在加速试验高湿条件下的稳定性。
将晶型B置于恒温恒湿容器中进行加速试验，条件为40℃/75％湿度(敞口)，于第30、60和90天取样检测。将检测结果与第0天的初始检测结果进行比较。
实施例4：光照稳定性
依据《原料药与药物制剂稳定性试验指导原则》(中国药典2010版附录XIXC)，考察实施例1中制备的晶型B在光照条件下的稳定性。
将晶型B置于5000Lx±500Lx的光照环境下，于第5天、第10天和第30天取样。将检测结果与第0天的初始检测结果进行比较。
药物活性效果实施例
效果实施例1：Toll样受体7和Toll样受体8体外受体结合活性筛选方案
试剂：
HEK-blue hTLR7细胞和HEK-blue hTLR8细胞(来源于InvivoGen公司)
DMEM培养基
热灭活胎牛血清
抗支原体试剂NormocinTM
博来霉素
杀稻瘟菌素
所用的GS-9620和R848的结构如下，其中GS-9620可以参考US20100143301中公开的方法制备；R848购自百奇生物(货号IMG-2208，规格0.5mg)。
Figure PCTCN2017072894-appb-000013
方案：
(1)96孔化合物板的准备：利用液体工作站POD将化合物从10mmol/L浓度起始，用DMSO做3倍梯度稀释，共稀释10个点(从第2列到第11列，每个点2个重复)。在第12列加入1μL 5mg/mL的阳性化合物R848作为阳性对照，在第1列加入1μL DMSO作为阴性对照。每孔中含有的DMSO体积均为1μL。
(2)收集细胞培养瓶中的细胞，将细胞密度稀释成250,000个细胞/mL。
(3)加入200μL(50,000个细胞/孔)细胞悬液至准备好的化合物板中。每孔中DMSO终浓度为0.5％。
(4)将含有细胞和化合物的培养板放入CO2培养箱中培养24小时，培养条件为37℃，5％CO2浓度。
(5)培养24小时后，从细胞培养板中每孔取出20μL上清液转移到一块96孔透明检测板中。然后往检测板中每孔加入180μL Quanti-Blue试剂，并置于37℃，5％CO2培养箱孵育1小时。
(6)1小时后，用酶标仪OD650读板检测20μL上清液中碱性磷酸酶的含量。
(7)利用Prism软件分析数据，得出各化合物的EC50。
实验结果如表1所示：
表1
化合物名称 TLR7EC50(nM) TLR8EC50(nM)
GS-9620 517 7867
式I化合物 160 11632
本发明的式I所示化合物表现出比对照品(Toll样受体7激动剂GS-9620)更高的与Toll样受体7体外受体结合活性，并且表现出比对照品(Toll样受体7激动剂GS-9620)更低的与Toll样受体8体外受体结合活性。本发明的化合物对不同受体具有明显的选择 性差异，且效果优于现有技术。
效果实施例2：外周血单个核细胞试验方案
本实施例的目的在于检测利用式I所示化合物刺激人外周血单核细胞(PBMC)24h后细胞因子的表达水平。
检测时细胞上清液不稀释，直接检测IFN-α的水平。首先将式I的化合物配制成20mmol浓度的DMSO储存液，用细胞培养基做10倍梯度稀释，总共稀释11个点。取其中9个稀释点的化合物(化合物的最高浓度为200μmol/L)加入96孔板中，每孔50μL，然后接种新鲜的人外周血单核细胞，每孔接种150μL体系，其中含有450,000个细胞。将细胞培养板置于37℃和5％CO2培养箱中培养24小时，培养结束后将培养板以1200rpm的速度离心5分钟，随后收集上清并将其储存于-20℃以待检测。细胞因子的检测利用BD公司的流式液相多重蛋白定量技术(CBA)，在流式细胞仪上完成检测。利用上述检测方法，我们将刺激产生30pg/mL的IFN-α的最低药物浓度，定义为该化合物在该细胞因子刺激实验上的MEC值。实验结果如下表2所示：
表2
化合物名称 IFN-αMEC(nM) TNF-αMEC(nM)
GS-9620 50 500
式I的化合物 5 500
本发明的式I化合物表现出比对照品(GS-9620)更好的体外PBMC的IFN-α诱导活性、以及与对照品(GS-9620)相当的TNF-α的诱导活性。

Claims (9)

  1. 式I所示化合物的三氟乙酸盐
    Figure PCTCN2017072894-appb-100001
  2. 权利要求1的式I所示化合物的三氟乙酸盐，其特征在于，式I所示化合物与三氟乙酸的摩尔比为1:0.5～2，优选1:1。
  3. 式I所示化合物的三氟乙酸盐的晶型B，其特征在于，在X-射线粉末衍射图谱中，所述晶型B具有2θ＝7.0°±0.2°、10.2°±0.2°、11.7°±0.2°、14.0°±0.2°、18.6°±0.2°、19.1°±0.2°、20.2°±0.2°、22.2°±0.2°、23.5°±0.2°的衍射峰，
    Figure PCTCN2017072894-appb-100002
  4. 权利要求3的晶型B，其特征在于，用DSC进行表征时，所述晶型B的起始温度为171.4℃±5℃，峰值温度为173.4℃±5℃。
  5. 一种结晶组合物，其包含权利要求3或4的晶型B，其特征在于，所述晶型B占所述结晶组合物重量的50％以上，优选80％以上，更优选90％以上，最优选95％以上。
  6. 一种药物组合物，其包含有效量的权利要求1或2的式I所示化合物的三氟乙酸盐、权利要求3或4的晶型B、权利要求5的结晶组合物或者它们的组合。
  7. 权利要求1或2的式I所示化合物的三氟乙酸盐、权利要求3或4的晶型B、权利要求5的结晶组合物或者权利要求6的药物组合物在制备治疗Toll样受体7相关疾病的药物中的用途，优选地，所述疾病为病毒感染。
  8. 一种制备权利要求3或4的晶型B的方法，所述方法包括以下步骤：
    1)将式I所示化合物的三氟乙酸盐溶于结晶溶剂中；和
    2)冷却析晶、洗涤并干燥以获得所述晶型B。
  9. 权利要求8的方法，其特征在于，所述结晶溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、丙酮、乙酸乙酯、水及它们的混合溶剂；优选乙醇。
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