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WO2023143321A1 - 他伐帕敦的晶型及其制备方法和用途 - Google Patents

他伐帕敦的晶型及其制备方法和用途 Download PDF

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Publication number
WO2023143321A1
WO2023143321A1 PCT/CN2023/072961 CN2023072961W WO2023143321A1 WO 2023143321 A1 WO2023143321 A1 WO 2023143321A1 CN 2023072961 W CN2023072961 W CN 2023072961W WO 2023143321 A1 WO2023143321 A1 WO 2023143321A1
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Prior art keywords
crystal form
csii
compound
csi
crystal
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PCT/CN2023/072961
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English (en)
French (fr)
Inventor
覃海燕
史佳明
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苏州科睿思制药有限公司
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Priority to CN202380015156.4A priority Critical patent/CN118401513A/zh
Publication of WO2023143321A1 publication Critical patent/WO2023143321A1/zh

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    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to a crystal form of tavapadun and a preparation method and use thereof.
  • Parkinson's disease is a chronic neurodegenerative disease characterized by progressive motor decline, including decreased body movement, slowness of movement, stiffness, tremors, and postural instability. Globally, disability and death attributable to Parkinson's disease are increasing faster than any other neurological disease. Humans still need to develop new and more effective drugs to treat Parkinson's disease.
  • Parkinson's is caused by the death of dopamine-producing neurons in the brain.
  • Dopamine is a neurotransmitter that drives motor function through complex interactions between the striatum, thalamus, and motor cortex.
  • the D1/D5 receptor subtype is expressed in a subset of neurons and functions to regulate signaling from the thalamus to the cortex, this pathway is known as the direct motor pathway and is responsible for the proper initiation of motor activity .
  • D2/D3 receptor subtypes expressed by distinct groups of neurons signal through the indirect motor pathway, indirectly modulating signaling from the thalamus to the cortex, which leads to inhibition of motor activity. A balance between these two sets of neurons allows for proper motor control.
  • Tavapadon (Tavapadon), developed by Cerevel Therapeutics, is used to treat early and late Parkinson's disease, and has achieved positive results in the clinical stage. It is the first drug that can improve patients' motor symptoms. Oral D1/D5 receptor agonists.
  • the chemical name of the drug is (-)-1,5-dimethyl-6-(2-methyl-4- ⁇ [3-(trifluoromethyl)pyridin-2-yl]oxy ⁇ phenyl)pyrimidine -2,4(1H,3H)-dione (hereinafter referred to as "compound I”), its structural formula is as follows:
  • a crystal is a solid in which compound molecules are arranged three-dimensionally in a microstructure to form a lattice.
  • Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms.
  • Compounds may exist in one or more crystalline forms, but their existence and properties cannot be specifically predicted.
  • APIs with different crystal forms have different physical and chemical properties, which may lead to different dissolution and absorption of drugs in the body, which in turn affects the clinical efficacy of drugs to a certain extent.
  • the crystal form is crucial to product performance.
  • the physical and chemical properties of the crystal form are crucial to the production process.
  • Example 7 of the prior art WO2014207601A1 only discloses the solid of Compound I.
  • the inventors of the present application repeated the preparation method, tested the obtained solid by XRPD, and found that it was different from the crystal form of Compound I provided by the present invention .
  • the solid has poor stability, is prone to crystal transformation, and cannot meet the requirements for medicinal use.
  • solvates of different solvents in research namely 1,4-dioxane solvate, toluene solvate, acetic acid solvate, hexafluoroisopropanol solvate, 2-Methyltetrahydrofuran solvate, tetrahydrofuran solvate, dimethyl carbonate solvate, diethyl carbonate solvate, chlorobenzene solvate, anisole solvate, benzyl alcohol solvate, above Solvates are not suitable for pharmaceutical use because they contain more organic solvents, so it is very difficult to obtain a new crystal form that meets pharmaceutical standards.
  • the present invention provides a crystal form of compound I, a preparation method thereof and a pharmaceutical composition comprising the new crystal form.
  • the present invention provides the crystal form CSI of Compound I (hereinafter referred to as "crystal form CSI").
  • the X-ray powder diffraction pattern of the crystal form CSI has a diffraction angle 2 ⁇ value of 15.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, 25.0° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSI has characteristic peaks at diffraction angles 2 ⁇ of 15.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 25.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSI has a diffraction angle 2 ⁇ value of 17.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, 24.0° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSI has characteristic peaks at diffraction angles 2 ⁇ of 17.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSI has a diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 16.4° ⁇ 0.2°, 24.5° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSI has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 16.4° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSI has diffraction angle 2 ⁇ values of 15.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, 25.0° ⁇ 0.2°, 17.9° ⁇ 0.2° , 24.0° ⁇ 0.2°, 21.2° ⁇ 0.2°, 8.4° ⁇ 0.2°, 16.4° ⁇ 0.2°, 24.5° ⁇ 0.2°, 9.3° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.9 1, or 2, or 3, or 4, or 5, or 6, or 7 of ° ⁇ 0.2°, 18.5° ⁇ 0.2°, 29.1° ⁇ 0.2°, 32.7° ⁇ 0.2° , or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 have characteristic peaks.
  • the X-ray powder diffraction pattern of crystalline form CSI is substantially as shown in FIG. 1 .
  • crystalline form CSI is the anhydrate.
  • the present invention also provides a preparation method of the crystalline form CSI, the preparation method comprising: stirring the compound I solid in an alcohol or ketone solvent, and separating to obtain the crystalline form CSI.
  • crystal form CSII of compound I provided by the invention
  • the X-ray powder diffraction pattern of the crystal form CSII has a diffraction angle 2 ⁇ value of 7.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angles 2 ⁇ of 7.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, and 17.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has a diffraction angle 2 ⁇ value of 18.7° ⁇ 0.2°, 23.2° ⁇ 0.2°, 26.0° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angles 2 ⁇ of 18.7° ⁇ 0.2°, 23.2° ⁇ 0.2°, and 26.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at one or two of the diffraction angle 2 ⁇ values of 23.8° ⁇ 0.2° and 24.4° ⁇ 0.2°; preferably Specifically, the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angles 2 ⁇ of 23.8° ⁇ 0.2° and 24.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.7° ⁇ 0.2° , 23.2° ⁇ 0.2°, 26.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.4° ⁇ 0.2°, 9.3° ⁇ 0.2°, 13.8° ⁇ 0.2°, 21.4° ⁇ 0.2°, 31.8° ⁇ 0.2°, 32.8
  • the X-ray powder diffraction pattern of the crystal form CSII has diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.7° ⁇ 0.2° , 23.2° ⁇ 0.2°, 26.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.4° ⁇ 0.2°, 9.3° ⁇ 0.2°, 13.8° ⁇ 0.2°, 21.4° ⁇ 0.2°, 31.8° ⁇ 0.2°, 32.8
  • the X-ray powder diffraction pattern of the crystal form CSII has diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2°, 15.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 18.7° ⁇ 0.2° , 23.2° ⁇ 0.2°, 26.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.4° ⁇ 0.2°, 9.3° ⁇ 0.2°, 13.8° ⁇ 0.2°, 21.4° ⁇ 0.2°, 31.8° ⁇ 0.2°, 32.8
  • Form CSII is substantially as shown in FIG. 4 using Cu-K ⁇ radiation.
  • Form CSII is an anhydrate.
  • the present invention also provides a preparation method of the crystalline form CSII, the preparation method comprising: heating the solid of Compound I, and then cooling to room temperature to obtain the crystalline form CSII.
  • the heating temperature is preferably 233-238°C, more preferably 235°C.
  • the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline form CSI, crystalline form CSII or any mixture of the above two crystalline forms and pharmaceutically acceptable excipients.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the above two crystal forms in the preparation of dopamine D1/D5 receptor agonist drugs.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the above two crystal forms in the preparation of a drug for treating Parkinson's disease.
  • the crystalline CSI API provided by the present invention has better physical and chemical stability.
  • the crystal form changes and the stability is not good.
  • the crystalline form of the CSI API does not change after being placed at 40°C/75%RH for at least 6 months, and the crystalline form does not change for at least 6 months when placed under 60°C/75%RH, and The purity remains essentially unchanged during storage. It shows that the crystalline CSI API has better stability than the existing technology under accelerated conditions and harsher conditions.
  • Crystalline CSI APIs have better stability under harsh conditions, which is beneficial to avoid the impact on drug quality due to crystal transformation or decrease in purity during drug storage.
  • the crystal form CSI provided by the present invention has good humidity stability, and the crystal form of CSI does not change after one cycle of 0%RH-95%RH-0%RH.
  • Crystalline CSI has good physical stability under the action of mechanical force.
  • the crystalline form of the CSI API remains unchanged after grinding. It is often necessary to grind or pulverize the API during the processing of the preparation. Good physical stability can reduce the risk of crystallinity reduction and crystal transformation of the API during the processing of the preparation.
  • Crystalline CSI has better physical and chemical stability, which ensures consistent and controllable quality of raw materials and preparations, and reduces drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSI provided by the present invention has high purity and good purification effect. After the raw materials are prepared into the crystal form of the present invention, the purity is significantly improved. In a specific example, using raw materials with a purity of 97.78%, after preparing the crystal form CSI of the present invention, the purity increased to 99.85%, and the purity increased by more than 2%, and the number of impurities was reduced by 5, and the maximum single impurity was 1.84%. reduced to 0.06%.
  • the chemical purity of drugs is of great significance to ensure the efficacy and safety of drugs and prevent the occurrence of adverse drug reactions.
  • Drug regulations have strict requirements on the content of impurities.
  • the crystal form CSI provided by the invention has high purity, good purification effect and strong impurity removal ability. Through crystallization, high-purity raw materials can be obtained, which effectively overcomes the disadvantages of low drug stability, poor curative effect, and high toxicity caused by low drug purity.
  • the crystal form CSI provided by the present invention has no dissolved residue. Residual solvents will not only affect the safety of the drug, but also affect the quality and stability of the drug. Residual solvents may cause drug crystal transformation or impurity formation during production and storage, resulting in changes in drug bioavailability and toxic side effects.
  • the crystal form CSI provided by the present invention has no solvent residue, and effectively overcomes the disadvantages of low drug stability, poor curative effect, and high toxicity caused by low drug purity or high solvent residue.
  • the crystal form CSI provided by the present invention has almost no hygroscopicity.
  • the test results show that the hygroscopic weight gain of crystal form CSI is only 0.05% under the condition of 80% RH.
  • strong hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physical and chemical stability of the API.
  • strong hygroscopicity will reduce the fluidity of APIs, thereby affecting the processing technology of APIs.
  • highly hygroscopic drugs need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, strong hygroscopicity is likely to cause changes in the content of active ingredients in the drug and affect the quality of the drug.
  • the crystal form CSI provided by the invention has weak hygroscopicity, has no strict requirements on drug production and storage, reduces the cost of drug production, storage and quality control, and has strong economic value.
  • the bulk drug of crystal form CSII provided by the present invention has better physical and chemical stability.
  • Crystal form CSII raw materials have better stability under harsh conditions, which is beneficial to avoid the impact on drug quality due to crystal transformation or purity decline during drug storage
  • the crystal form CSII has good humidity stability. After the crystalline form CSII of the present invention is cycled once at 0%RH-95%RH-0%RH, the crystalline form remains unchanged.
  • the crystal form CSII has good physical stability under the action of mechanical force.
  • the crystalline form of the crystalline form CSII API remains unchanged after grinding. It is often necessary to grind or pulverize the API during the processing of the preparation. Good physical stability can reduce the risk of crystallinity reduction and crystal transformation of the API during the processing of the preparation.
  • the good physical and chemical stability of the crystal form of the API can ensure that the drug will not undergo crystal transformation and basically no impurities will occur during the production and storage process.
  • the crystal form CSII has good physical and chemical stability, which ensures consistent and controllable quality of raw materials and preparations, and reduces drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSII provided by the present invention has no dissolved residue. Residual solvents will not only affect the safety of the drug, but also affect the quality and stability of the drug. Residual solvents may cause drug crystal transformation or impurity formation during production and storage, resulting in changes in drug bioavailability and toxic side effects.
  • the crystal form CSII provided by the present invention has no solvent residue, and effectively overcomes the shortcomings of low drug purity or high solvent residue, such as low drug stability, poor curative effect, and high toxicity.
  • the crystal form CSII provided by the present invention has almost no hygroscopicity.
  • the test results show that the hygroscopic weight gain of crystal form CSII is only 0.19% under the condition of 80% RH.
  • strong hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physical and chemical stability of the API.
  • strong hygroscopicity will reduce the fluidity of APIs, thereby affecting the processing technology of APIs.
  • highly hygroscopic drugs need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, strong hygroscopicity is likely to cause changes in the content of active ingredients in the drug and affect the quality of the drug.
  • the crystal form CSII provided by the invention has weak hygroscopicity, has no strict requirements on drug production and storage, reduces the cost of drug production, storage and quality control, and has strong economic value.
  • Figure 1 is the XRPD pattern of crystal form CSI
  • Figure 2 is the TGA diagram of crystal form CSI
  • Figure 3 is the DSC diagram of crystal form CSI
  • Figure 4 is the XRPD pattern of crystal form CSII
  • Figure 5 is the TGA diagram of crystal form CSII
  • Figure 6 is the DSC diagram of crystal form CSII
  • Figure 7 XRPD overlay of crystalline form CSI and prior art solid (upper: crystalline form CSI, lower: prior art solid)
  • Figure 8 XRPD overlay of crystal form CSII and prior art solid (upper: crystal form CSII, lower: prior art solid)
  • Figure 9 is the XRPD overlay of the prior art solid at 40°C/75%RH sealed (with desiccant) for 10 days (top: after placement, bottom: before placement)
  • Figure 10 is the XRPD comparison chart of crystalline form CSI before and after storage under different conditions (from top to bottom: before storage, after 6 months of exposure at 25°C/60%RH, sealed at 25°C/60%RH (with desiccant) after 6 months, at 40°C/75%RH open for 6 months, at 40°C/75%RH sealed (with desiccant) for 6 months, at 60°C/75 %RH sealed (after 6 months with desiccant)
  • Figure 11 is the DVS adsorption curve of crystalline CSI
  • Figure 12 is the XRPD overlay of crystal form CSI before and after DVS test (top: before test, bottom: after test)
  • Figure 13 is the XRPD overlay of crystal form CSI before and after grinding (upper: before grinding, lower: after grinding)
  • Figure 14 is the DVS adsorption curve of crystal form CSII
  • Figure 15 is the XRPD overlay of crystal form CSII before and after DVS testing (upper: before testing, lower: testing back)
  • Figure 16 is the XRPD overlay of crystal form CSII before and after grinding (upper: before grinding, lower: after grinding)
  • the X-ray powder diffraction pattern of the present invention is collected on Bruker X-ray powder diffractometer.
  • the method parameter of X-ray powder diffraction of the present invention is as follows:
  • thermogravimetric analysis (TGA) figure of the present invention is collected on TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • Differential scanning calorimetry (DSC) figure of the present invention is collected on TA Q2000.
  • the method parameter of differential scanning calorimetry (DSC) of the present invention is as follows:
  • the Dynamic Moisture Sorption (DVS) figure of the present invention is collected on the Intrinsic Dynamic Moisture Sorption Instrument produced by SMS Company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameter of described dynamic water adsorption instrument is as follows:
  • Relative humidity range 0%RH-95%RH
  • Proton nuclear magnetic resonance data ( 1 H NMR) were collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5mg sample, dissolve it with 0.5mL deuterated chloroform, and make a 2-10mg/mL solution.
  • test methods of the related substances of the present invention are shown in Table 1.
  • the "stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and mechanical stirring Preferably 100-300 rpm.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is: put the sample to be separated in a centrifuge tube, and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural drying.
  • the drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying is carried out in a fume hood, forced air oven or vacuum oven.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • anhydrous substance refers to a solid substance that does not contain crystal water or crystal solvent.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • the XRPD diffraction data of the crystal has fingerprints.
  • the field identifies different crystal forms based on the XRPD diffraction data.
  • characteristic peaks Those skilled in the art will select several representative peaks in the XRPD spectrum as characteristic peaks to characterize the crystal. When selecting characteristic peaks, the peak position, peak intensity and peak shape should be considered comprehensively.
  • the X-ray powder diffraction pattern will vary depending on the condition of the instrument, the preparation of the sample and the purity of the sample.
  • the peak intensity of the diffraction peak in the X-ray powder diffraction figure may also vary with the variation of the experimental conditions. In fact, the peak intensity of the diffraction peak in the X-ray powder diffraction figure is related to the preferred orientation of the crystal.
  • the diffraction peak shown in the present invention Intensities are illustrative and not for absolute comparison. Therefore, when identifying whether the crystal forms are the same, the matching of peak positions is the first priority.
  • the X-ray powder diffraction pattern of the protected crystal form of the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the examples referred to here, and any characteristic peaks in these patterns are the same or Crystal forms with similar X-ray powder diffraction patterns all fall within the scope of the present invention.
  • Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of figures reflect the same or different crystal forms.
  • the crystalline forms CSI and crystalline forms CSII of the present invention are pure and substantially free of any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that this crystal form contains less than 20% (weight) of other crystal forms, especially refers to less than 10% (weight) of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.
  • said compound I as starting material includes but not limited to solid form (crystalline or amorphous), oily form, liquid form and solution.
  • compound I as starting material is in solid form.
  • Compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2014207601A1.
  • Sample 1 was vacuum-dried at 50°C for about 2 hours to obtain a dry solid, which was detected as crystalline form CSI by XRPD.
  • the XRPD pattern is shown in Figure 1, the XRPD data is shown in Table 3, and the TGA pattern is shown in Figure 2.
  • Its DSC diagram is shown in Figure 3, It has a first endothermic peak around 232°C, an exothermic peak around 234°C, and a second endothermic peak around 238°C.
  • Embodiment 2 the preparation method of crystal form CSII
  • Embodiment 4 repeats the preparation method of Compound I disclosed in the prior art
  • the crystal form CSI has diffraction peaks at 16.4°, 17.9°, 21.2°, and 24.0°, and the prior art solid has no diffraction peaks at these four places; the crystal form CSII has diffraction peaks at 15.1°, 18.7°, and 26.0°. The technical solid has no diffraction peaks at these 3 places.
  • the prior art solids are distinct from Form CSI and Form CSII.
  • Example 4 Take an appropriate amount of the prior art solid obtained in Example 4, seal it (with desiccant added) and package it, place it under the condition of 40° C./75% RH, and use XRPD to determine the crystal form before and after placing it.
  • the XRPD comparison chart is shown in Figure 9. The results show that after 10 days under the condition of 40°C/75%RH, crystal transformation will occur.
  • Crystalline CSI under the conditions of 25°C/60%RH open and sealed (with desiccant), 40°C/75%RH open and sealed (with desiccant) and 60°C/75%RH sealed (with desiccant) Stable for at least 6 months. The results show that the crystal form CSI has good stability, and has better stability than the prior art solid.
  • the chemical purity of the starting material and the crystal form CSI of the present invention was determined by HPLC, and the test results are shown in Table 6. The results show that the crystalline form of CSI has a significant purification effect.
  • Embodiment 9 The physical stability of crystal form CSI under the action of mechanical force
  • the crystalline form CSI was ground by a ball mill at a vibration speed of 500 rpm for 5 minutes, and XRPD tests were carried out before and after grinding. The results are shown in FIG. 13 . The results show that the crystalline form of CSI does not change after grinding, and the crystalline form of CSI has good physical stability under the action of mechanical force.
  • the crystal form CSII prepared by the present invention Take an appropriate amount of the crystal form CSII prepared by the present invention, pack it in a sealed (with desiccant) package and place it under the conditions of 25°C/60%RH and 40°C/75%RH, and use XRPD to determine the crystal form.
  • the results are shown in Table 7.
  • the crystalline form CSII can maintain the crystal form for at least one month under the conditions of 25°C/60%RH sealing (with desiccant) and 40°C/75%RH (with desiccant). The results show that the crystal form CSII has good stability, and has better stability than the prior art solid.
  • the XRPD patterns of crystal form CSII before and after DVS testing are shown in FIG. 15 .
  • the results showed that the crystalline form of CSII was the same before and after the DVS test, indicating that the crystalline form of CSII had good humidity stability.
  • Embodiment 12 The physical stability of crystal form CSII under the action of mechanical force
  • the crystalline form CSII was ground by a ball mill at a vibration speed of 500 rpm for 5 minutes, and XRPD tests were performed before and after grinding. The results are shown in FIG. 16 . The results show that the crystalline form of CSII does not change after grinding, and the crystalline form CSII has good physical stability under the action of mechanical force.

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Abstract

一种他伐帕敦（以下称为"化合物I"）的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备多巴胺D1/D5受体激动剂药物和治疗帕金森病药物中的用途。化合物I的晶型比现有技术具有一种或多种改进的性质，解决了现有技术存在的问题，对未来该药物的优化和开发具有重要价值。

Description

他伐帕敦的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及他伐帕敦的晶型及其制备方法和用途。
背景技术
帕金森氏症是一种慢性神经退行性疾病，主要症状为进行性运动功能衰退，包括身体运动减少，运动缓慢，僵硬，震颤和姿势不稳定。在全球范围，归因于帕金森病的残疾和死亡增长速度快于任何其他神经系统疾病。人类仍需要开发新的且更有效地治疗帕金森氏症的药物。
从病理上看，帕金森氏症是由大脑中产生多巴胺的神经元死亡引起的。多巴胺是一种神经递质，通过纹状体、丘脑和运动皮层之间的复杂相互作用来驱动运动功能。在多巴胺受体亚型中，D1/D5受体亚型在神经元的子集中表达，其功能是调节从丘脑到皮层的信号传导，该通路被称为直接运动通路，负责运动活动的适当启动。由不同神经元组表达的D2/D3受体亚型通过间接运动通路发出信号，间接调节从丘脑到皮层的信号传导，该途径导致运动活动的抑制。这两组神经元之间的平衡允许适当的运动控制。
令人惊喜的是，由Cerevel Therapeutics开发的小分子药物他伐帕敦(Tavapadon)，用于治疗早期和晚期帕金森病，在临床阶段取得了积极效果，是第一个可以改善患者运动症状的口服D1/D5受体激动剂。该药物化学名称为(-)-1,5-二甲基-6-(2-甲基-4-{[3-(三氟甲基)吡啶-2-基]氧基}苯基)嘧啶-2,4(1H,3H)-二酮(以下称为“化合物I”)，其结构式如下：
在开发小分子药物中，药物多晶型是药物研发中的常见现象，是影响药物质量的重要因素。晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。除此之外，晶型的理化性质对生产过程至关重要。
因此，为了得到有效的利于生产或利于化合物I制剂的晶型，需要对其结晶行为进行全面的考察，以得到能够满足化合物I药用需求的晶型。
经过发明人全面检索和研究发现，与化合物I相关的现有技术仅有一项，即WO2014207601A1，但是该现有技术仅申请保护化合物I的化合物结构，说明书中也仅公开其结构，制备方法和用途，并未进行晶型研究。更重要的是，现有技术WO2014207601A1的实施例7仅公开得到了化合物I的固体，本申请发明人重复其制备方法，利用XRPD测试所得固体，发现其与本发明提供的化合物I的晶型不同。并且，经本申请发明人对现有技术固体进行仔细研究后发现该固体稳定性差，容易发生转晶，无法满足药用要求。
为克服现有技术的缺点，仍然需要一种符合药用标准的新固体形态，特别是新晶型，以用于含化合物I药物的开发。本申请发明人研究发现化合物I极易成溶剂合物。本申请发明人在研究中共得到11种不同溶剂的溶剂合物，分别为1,4-二氧六环溶剂合物，甲苯溶剂合物，乙酸溶剂合物，六氟异丙醇溶剂合物，2-甲基四氢呋喃溶剂合物，四氢呋喃溶剂合物，碳酸二甲酯溶剂合物，碳酸二乙酯溶剂合物，氯苯溶剂合物，苯甲醚溶剂合物，苯甲醇溶剂合物，以上溶剂合物由于含有较多有机溶剂均不适合药用，因此想要获得一种符合药用标准的新晶型非常困难。在付出大量的创造性劳动后，意外的发现了本发明所述的化合物I的晶型，其在溶解度、引湿性、提纯效果、稳定性、黏附性、可压性、流动性、体内外溶出、生物有效性等方面中的至少一方面存在优势，特别是稳定性好、引湿增重小、无溶剂残留、纯度高，提纯效果好，解决了现有技术存在的问题，对含化合物I的药物开发具有非常重要的意义。
发明内容
本发明提供化合物I的晶型及其制备方法以及包含该新晶型的药物组合物。
根据本发明的目的，本发明提供化合物I的晶型CSI(以下称作“晶型CSI”)。
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为15.7°±0.2°、20.0°±0.2°、25.0°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为15.7°±0.2°、20.0°±0.2°、25.0°±0.2°有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为17.9°±0.2°、21.2°±0.2°、24.0°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为17.9°±0.2°、21.2°±0.2°、24.0°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为8.4°±0.2°、16.4°±0.2°、24.5°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为8.4°±0.2°、16.4°±0.2°、24.5°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为15.7°±0.2°、20.0°±0.2°、25.0°±0.2°、17.9°±0.2°、24.0°±0.2°、21.2°±0.2°、8.4°±0.2°、16.4°±0.2°、24.5°±0.2°、9.3°±0.2°、11.7°±0.2°、13.8°±0.2°、14.9°±0.2°、18.5°±0.2°、29.1°±0.2°、32.7°±0.2°中的1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处、或13处、或14处、或15处、或16处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSI的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSI为无水物。
根据本发明的目的，本发明还提供所述晶型CSI的制备方法，所述制备方法包括：将化合物I固体置于醇类或酮类溶剂中搅拌，分离得到晶型CSI。
根据本发明的目的，本发明提供的化合物I的晶型CSII(以下称作“晶型CSII”)
一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.8°±0.2°、15.1°±0.2°、17.0°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ为7.8°±0.2°、15.1°±0.2°、17.0°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为18.7°±0.2°、23.2°±0.2°、26.0°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ为18.7°±0.2°、23.2°±0.2°、26.0°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为23.8°±0.2°、24.4°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ为23.8°±0.2°、24.4°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.8°±0.2°、15.1°±0.2°、17.0°±0.2°、18.7°±0.2°、23.2°±0.2°、26.0°±0.2°、23.8°±0.2°、24.4°±0.2°、9.3°±0.2°、13.8°±0.2°、21.4°±0.2°、31.8°±0.2°、32.8°±0.2°中的3处、或4处、或5处、或6处、或7处、或8处、或9处、或11处、或12处、或13处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.8°±0.2°、15.1°±0.2°、17.0°±0.2°、18.7°±0.2°、23.2°±0.2°、26.0°±0.2°、23.8°±0.2°、24.4°±0.2°、9.3°±0.2°、13.8°±0.2°、21.4°±0.2°、31.8°±0.2°、32.8°±0.2°中的3处、或4处、或5处、或6处、或7处、或8处、或9处、或11处、或12处、或13处有特征峰，且在19.2°-20.5°的范围内或24.8°-25.6°的范围内没有峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.8°±0.2°、15.1°±0.2°、17.0°±0.2°、18.7°±0.2°、23.2°±0.2°、26.0°±0.2°、23.8°±0.2°、24.4°±0.2°、9.3°±0.2°、13.8°±0.2°、21.4°±0.2°、31.8°±0.2°、32.8°±0.2°中的3处、或4处、或5处、或6处、或7处、或8处、或9处、或11处、或12处、或13处有特征峰，且在19.2°-20.5°的范围内和24.8°-25.6°的范围内没有峰。
非限制性地，使用Cu-Kα辐射，晶型CSII的X射线粉末衍射图基本如图4所示。
非限制性地，晶型CSII为无水物。
根据本发明的目的，本发明还提供所述晶型CSII的制备方法，所述制备方法包括：将化合物I的固体加热后，再冷却至室温，得到晶型CSII。
进一步地，所述加热的温度优选233-238℃，进一步优选235℃。
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSI、晶型CSII或以上两种晶型的任意混合及药学上可接受的辅料。
进一步地，本发明提供晶型CSI、晶型CSII或以上两种晶型的任意混合在制备多巴胺D1/D5受体激动剂药物中的用途。
更进一步地，本发明提供晶型CSI、晶型CSII或以上两种晶型的任意混合在制备治疗帕金森病药物中的用途。
有益效果
本发明提供的晶型CSI具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSI原料药具有更好的物理化学稳定性。
现有技术固体在40℃/75％RH条件下放置10天后，晶型发生转变，稳定性不佳。但是，晶型CSI原料药在40℃/75％RH条件下放置至少6个月晶型未发生变化，在60℃/75％RH条件下密封放置，至少6个月晶型未发生变化，并且储存过程中纯度基本保持不变。说明晶型CSI原料药在加速条件及更严苛的条件下，具有比现有技术更好的稳定性。
季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药和制剂的储存、运输、生产。因此，原料药在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSI原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
(2)本发明提供的晶型CSI具有良好的湿度稳定性，晶型CSI在0％RH-95％RH-0％RH循环一次后，晶型未发生变化。
(3)晶型CSI在机械力作用下具有良好的物理稳定性。晶型CSI原料药研磨后晶型保持不变。制剂加工过程中常需要将原料药研磨或粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSI具有更好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。
(4)本发明提供的晶型CSI具有较高的纯度和良好的提纯效果。将原料制备成本发明晶型后，纯度显著提高。在具体的实施例中，使用纯度为97.78％的原料，制备得到本发明晶型CSI后，纯度提升至99.85％，纯度提升超过2％，且杂质个数减少5个，最大单杂由1.84％降低至0.06％。
药物的化学纯度对于保证药物的疗效和安全性、防止药物不良反应的发生具有重要意义。药物法规对杂质含量都有严格的要求。本发明提供的晶型CSI纯度高，提纯作用好，有极强的杂质排除能力。通过结晶就能得到纯度较高的原料药，有效克服了药物纯度低带来的药物稳定性低、疗效差、毒性高等缺点。
(5)本发明提供的晶型CSI无溶残。残留溶剂不仅会影响药物的安全性，还会对药物质量和稳定性产生影响。残留溶剂可能会导致药物在生产和储存的过程中发生转晶或者杂质生成，从而引起药物生物利用度变化和毒副作用。本发明提供的晶型CSI无溶剂残留，有效地克服了药物纯度低或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
(6)本发明提供的晶型CSI几乎无引湿性。测试结果表明，晶型CSI在80％RH条件下引湿性增重仅0.05％。
一方面，强吸湿性易引起原料药发生化学降解和晶型转变，从而直接影响原料药的物理化学稳定性。此外，强吸湿性会降低原料药的流动性，从而影响原料药的加工工艺。另一方面，强吸湿性的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，强吸湿性容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSI引湿性弱，对药物生产和储存要求不苛刻，降低了药品生产、保存和质量控制成本，具有很强的经济价值。
本发明提供的晶型CSII具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSII原料药具有更好的物理化学稳定性。
现有技术固体在40℃/75％RH条件下放置10天后，晶型发生转变，稳定性不佳。但是，晶型CSII原料药在40℃/75％RH条件下密封放置，至少1个月晶型未发生变化，说明晶型CSII原料药在加速条件下，具有比现有技术更好的稳定性。
季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药和制剂的储存、运输、生产。因此，原料药在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSII原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响
(2)晶型CSII具有良好的湿度稳定性。本发明晶型CSII在0％RH-95％RH-0％RH循环一次后，晶型未发生变化。
(3)晶型CSII在机械力作用下具有良好的物理稳定性。晶型CSII原料药研磨后晶型保持不变。制剂加工过程中常需要将原料药研磨或粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSII具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。
(4)本发明提供的晶型CSII无溶残。残留溶剂不仅会影响药物的安全性，还会对药物质量和稳定性产生影响。残留溶剂可能会导致药物在生产和储存的过程中发生转晶或者杂质生成，从而引起药物生物利用度变化和毒副作用。本发明提供的晶型CSII无溶剂残留，有效地克服了药物纯度低或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
(5)本发明提供的晶型CSII几乎无引湿性。测试结果表明，晶型CSII在80％RH条件下引湿性增重仅0.19％。
一方面，强吸湿性易引起原料药发生化学降解和晶型转变，从而直接影响原料药的物理化学稳定性。此外，强吸湿性会降低原料药的流动性，从而影响原料药的加工工艺。另一方面，强吸湿性的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，强吸湿性容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSII引湿性弱，对药物生产和储存要求不苛刻，降低了药品生产、保存和质量控制成本，具有很强的经济价值。
附图说明
图1为晶型CSI的XRPD图
图2为晶型CSI的TGA图
图3为晶型CSI的DSC图
图4为晶型CSII的XRPD图
图5为晶型CSII的TGA图
图6为晶型CSII的DSC图
图7晶型CSI与现有技术固体的XRPD叠图(上：晶型CSI，下：现有技术固体)
图8晶型CSII与现有技术固体的XRPD叠图(上：晶型CSII，下：现有技术固体)
图9现有技术固体在40℃/75％RH密封(加干燥剂)放置10天后的XRPD叠图(上：放置后，下：放置前)
图10为晶型CSI在不同条件下放置前后的XRPD对比图(从上至下依次为：放置前，在25℃/60％RH敞口放置6个月后，在25℃/60％RH密封(加干燥剂)放置6个月后，在40℃/75％RH敞口放置6个月后，在40℃/75％RH密封(加干燥剂)放置6个月后，在60℃/75％RH密封(加干燥剂)放置6个月后)
图11为晶型CSI的DVS吸附曲线图
图12为晶型CSI在DVS测试前后的XRPD叠图(上：测试前，下：测试后)
图13为晶型CSI研磨前后的XRPD叠图(上：研磨前，下：研磨后)
图14为晶型CSII的DVS吸附曲线图
图15为晶型CSII在DVS测试前后的XRPD叠图(上：测试前，下：测试 后)
图16为晶型CSII研磨前后的XRPD叠图(上：研磨前，下：研磨后)
具体实施方式
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
TGA：热重分析
DSC：差示扫描量热分析
1H NMR：液态核磁氢谱
DVS：动态水分吸附
HPLC：高效液相色谱
RH：相对湿度
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Bruker X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα11.54060；Kα21.54439
Kα2/Kα1强度比例：0.50
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：N2
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：N2
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2，200毫升/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据(1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代氯仿溶解，配成2-10mg/mL的溶液。
本发明所述有关物质的测试方法如表1所示。
表1
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
所述“干燥”，采用本领域的常规方法完成，例如真空干燥，鼓风干燥或自然晾干。干燥温度可以是室温或更高，优选室温到约60℃，或者到50℃，或者到40℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
所述“室温”不是特定的温度值，是指10-30℃温度范围。
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。
所述“无水物”是指不含结晶水或结晶溶剂的固态物质。
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。晶体的XRPD衍射数据具有指纹性，本领域依据XRPD的衍射数据来鉴定不同的晶型，本领域技术人员会在XRPD图谱中选取若干具有代表性的峰作为特征峰来表征该晶体， 选择特征峰时综合考虑峰位置、峰强度以及峰形。但是，本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的峰强度也可能随着实验条件的变化而变化，事实上，X射线粉末衍射图中衍射峰的峰强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因此，在鉴定晶型是否相同时，峰位置的匹配是第一位。
本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSI和晶型CSII是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
除非特殊说明，以下实施例均在室温条件下操作。
根据本发明，作为原料的所述化合物I包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I为固体形式。
以下实施例中所使用的化合物I可根据现有技术制备得到，例如根据WO2014207601A1文献所记载的方法制备获得。
实施例1：晶型CSI的制备方法
如表2所示，称取相应质量的化合物I固体至玻璃小瓶中，向其中加入一定体积的溶剂形成悬浊液，然后在室温下搅拌2天，分离固体。表2中实施例所得固体分别标记为样品1及样品2。经XRPD检测，样品1及样品2均为本发明所述晶型CSI。
表2
将样品1在50℃真空干燥约2小时后得到干燥固体，经XRPD检测为晶型CSI，其XRPD图如图1所示，XRPD数据如表3所示，其TGA图如图2所示，加热至180℃时基本无质量损失，晶型CSI为无水物。其DSC图如图3所示， 其在232℃附近存在第一个吸热峰，在234℃附近存在一个放热峰，以及在238℃附近存在第二个吸热峰。
晶型CSI的核磁数据为：1H NMR(400MHz,Chloroform-d)δ8.36–8.31(m,1H),8.28(s,1H),8.04(dd,J＝7.8,1.9Hz,1H),7.21–7.11(m,4H),3.05(s,3H),2.20(s,3H),1.68(s,3H)，其中8.28ppm处为活泼氢。核磁数据显示晶型CSI中没有任何溶剂残留。
表3

实施例2：晶型CSII的制备方法
取5.98mg化合物I固体在氮气保护下以10℃/min加热至235℃，在235℃停留1分钟后再以10℃/min降温至室温，得到晶型CSII。其X射线粉末衍射图如图4所示，X射线粉末衍射数据如表4所示。
晶型CSII的核磁数据为：1H NMR(400MHz,Chloroform-d)δ8.76(s,1H),8.33(dd,J＝5.1,1.8Hz,1H),8.04(dd,J＝7.7,1.8Hz,1H),7.22–7.10(m,4H),3.05(s,3H),2.20(s,3H),1.68(s,3H)，其中8.76ppm处为活泼氢。核磁结果显示晶型CSII中没有任何溶剂残留。
表4

实施例3晶型CSII的TGA和DSC测试
取少量晶型CSII的固体，分别进行TGA和DSC测试。其TGA如图5所示，将其加热至200℃时基本无质量损失。其DSC如图6所示，其在240℃附近开始出现第一个吸热峰，对应晶型CSII的熔点。
实施例4重复现有技术公开的化合物I的制备方法
重复现有技术WO2014207601A1实施例7公开的化合物I的制备方法，得到现有技术固体。所得现有技术固体与晶型CSI的XRPD叠图如图7所示，所得现有技术固体与晶型CSII的XRPD叠图如图8所示。叠图表明，现有技术固体与晶型CSI和晶型CSII的XRPD图不同。进一步具体到，现有技术固体与晶型CSI和晶型CSII的XRPD图衍射峰的2θ值在15-25°的范围内有明显的区别。晶型CSI在16.4°、17.9°、21.2°、24.0°处有衍射峰，现有技术固体在此4处无衍射峰；晶型CSII在15.1°、18.7°、26.0°处有衍射峰，现有技术固体在此3处无衍射峰。因此，现有技术固体与晶型CSI和晶型CSII是不同的。
实施例5现有技术固体的稳定性
取适量实施例4所得现有技术固体，经密封(加干燥剂)包装后，放置在40℃/75％RH条件下，采用XRPD测定放置前后的晶型。XRPD对比图如图9所示。结果表明，在40℃/75％RH条件下放置10天后，会发生转晶。
实施例6晶型CSI的稳定性
取适量本发明制备得到的晶型CSI，采用对应包装条件包装后分别放置在25℃/60％RH、40℃/75％RH和60℃/75％RH条件下，采用HPLC和XRPD测定纯度与晶型。结果如表所示，XRPD对比图如图10所示。晶型CSI在25℃/60％RH敞口和密封(加干燥剂)、40℃/75％RH敞口和密封(加干燥剂)和60℃/75％RH密封(加干燥剂)条件下至少可稳定6个月。结果表明，晶型CSI有良好的稳定性，且比现有技术固体具有更好的稳定性。
表5
实施例7晶型CSI的提纯效果
采用HPLC测定起始物料、本发明晶型CSI的化学纯度，测试结果如表6所示。结果表明，晶型CSI具有显著的提纯效果。
表6
实施例8晶型CSI的引湿性
称取适量本发明晶型CSI，采用动态水分吸附(DVS)仪测试其引湿性。在25℃，0％RH-95％RH-0％RH相对湿度下循环一次，记录每个湿度下的质量变化，并且在DVS前后进行XRPD测试。晶型CSI的DVS吸附曲线如图11所示。实验结果表明，晶型CSI在80％RH条件下引湿性增重为0.05％，几乎无引湿性。
晶型CSI在DVS测试前后的XRPD图如图12所示。结果显示，晶型CSI在DVS测试前后晶型相同，表明晶型CSI有良好的湿度稳定性。
实施例9晶型CSI在机械力作用下的物理稳定性
将晶型CSI采用球磨机以500rpm的振动速度研磨5分钟，研磨前后进行XRPD测试，结果如图13所示。结果表明，晶型CSI在研磨后晶型没有发生变化，晶型CSI在机械力作用下有良好的物理稳定性。
实施例10晶型CSII的稳定性
取适量本发明制备得到的晶型CSII，采用密封(加干燥剂)包装条件包装后分别放置在25℃/60％RH和40℃/75％RH条件下，采用XRPD测定晶型。结果如表7所示。晶型CSII在25℃/60％RH密封(加干燥剂)、40℃/75％RH密封(加干燥剂)条件下至少可维持1个月晶型不变。结果表明，晶型CSII有良好的稳定性，且比现有技术固体具有更好的稳定性。
表7
实施例11晶型CSII的引湿性
称取适量本发明晶型CSII，采用动态水分吸附(DVS)仪测试其引湿性，在25℃，0％RH-95％RH-0％RH相对湿度下循环一次，记录每个湿度下的质量变化，并且在DVS前后进行XRPD测试。晶型CSII的DVS吸附曲线如图14所示，实验结果表明，晶型CSII在80％RH条件下引湿性增重为0.19％，几乎无引湿性。
晶型CSII进行DVS测试前后的XRPD图如图15所示。结果显示，晶型CSII在DVS测试前后晶型相同，表明晶型CSII有良好的湿度稳定性。
实施例12晶型CSII在机械力作用下的物理稳定性
将晶型CSII采用球磨机以500rpm的振动速度研磨5分钟，研磨前后进行XRPD测试，结果如图16所示。结果表明，晶型CSII在研磨后晶型没有发生变化，晶型CSII在机械力作用下有良好的物理稳定性。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (13)

  1. 化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为15.7°±0.2°、20.0°±0.2°、25.0°±0.2°处具有特征峰，
  2. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为17.9°±0.2°、21.2°±0.2°、24.0°±0.2°中的至少一处具有特征峰。
  3. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.4°±0.2°、16.4°±0.2°、24.5°±0.2°中的至少一处具有特征峰。
  4. 根据权利要求2所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.4°±0.2°、16.4°±0.2°、24.5°±0.2°中的至少一处具有特征峰。
  5. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图1所示。
  6. 化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.8°±0.2°、15.1°±0.2°、17.0°±0.2°处具有特征峰。
  7. 根据权利要求6所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为18.7°±0.2°、23.2°±0.2°、26.0°±0.2°中的至少一处具有特征峰。
  8. 根据权利要求6所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为23.8°±0.2°、24.4°±0.2°中的至少一处具有特征峰。
  9. 根据权利要求7所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为23.8°±0.2°、24.4°±0.2°中的至少一处具有特征峰。
  10. 根据权利要求6所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图4所示。
  11. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1或权利要求6所述的化合物I的晶型及药学上可接受的辅料。
  12. 权利要求1或权利要求6所述的化合物I的晶型在制备多巴胺D1/D5受体激动剂药物中的用途。
  13. 权利要求1或权利要求6所述的化合物I的晶型在制备治疗帕金森病药物中的用途。
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MARTINI, M. ET AL.: "Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity", ACS CHEMICAL NEUROSCIENCE, vol. 10, 6 August 2019 (2019-08-06), pages 4160 - 4182, XP055673903, DOI: 10.1021/acschemneuro.9b00410 *

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