WO2022105644A1 - 苯并噻唑类化合物的盐及其晶体形式和用途 - Google Patents

苯并噻唑类化合物的盐及其晶体形式和用途 Download PDF

Info

Publication number
WO2022105644A1
WO2022105644A1 PCT/CN2021/129537 CN2021129537W WO2022105644A1 WO 2022105644 A1 WO2022105644 A1 WO 2022105644A1 CN 2021129537 W CN2021129537 W CN 2021129537W WO 2022105644 A1 WO2022105644 A1 WO 2022105644A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pamoate
crystal
diffraction peaks
xrpd pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/129537
Other languages
English (en)
French (fr)
Inventor
李龙
易仕东
王天明
陈平运
杨成喜
王晶翼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Original Assignee
Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Kelun Pharmaceutical Research Co Ltd, Sichuan Kelun Pharmaceutical Research Institute Co Ltd filed Critical Sichuan Kelun Pharmaceutical Research Co Ltd
Priority to CN202510106569.4A priority Critical patent/CN119930541A/zh
Priority to JP2023518885A priority patent/JP2023550235A/ja
Priority to EP21893791.0A priority patent/EP4249476A4/en
Priority to CN202180064196.9A priority patent/CN116367833B/zh
Priority to US18/027,246 priority patent/US12583829B2/en
Priority to AU2021381638A priority patent/AU2021381638A1/en
Publication of WO2022105644A1 publication Critical patent/WO2022105644A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to salts of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole, crystalline forms and uses thereof.
  • Parkinson's disease is a motor system disorder of the nervous system. It is characterized by a progressive disease that affects movement and results in the loss of dopamine-producing brain cells, causing tremors in the hands, arms, legs, jaw and face and/or stiffness or stiffness of the extremities and trunk. The main symptoms include muscle stiffness, slow movement, resting tremor, and postural instability.
  • Compound I (S)-2-Amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (hereinafter referred to as "Compound I”) is a non-ergot dopamine receptor developed by Boehringer Ingelheim, Germany. body agonist. At present, the products on the market at home and abroad are mainly hydrochloride immediate-release tablets and hydrochloride sustained-release tablets, which are used for the treatment of Parkinson's disease and restless legs syndrome.
  • Parkinson's patients are mostly middle-aged and elderly, and the incidence of dysphagia in patients is as high as 70-90%, which increases the risk of aspiration pneumonia by 15-50%. Coughing increases the risk of aspiration pneumonia, which is one of the leading causes of death in Parkinson's patients.
  • the current clinical drugs are mainly oral, and they need to be administered multiple times a day. The single dose is large, and the compliance needs to be improved urgently.
  • the pulse-like stimulation secondary to the fluctuation of dopamine plasma concentration will further aggravate the level and function of dopaminergic receptors. Only continuous and stable dopamine stimulation can control or reduce the occurrence of adverse reactions of motor complications.
  • a long-term release regimen of more than 24 hours will also aid patient compliance, as patients with advanced PD are often non-compliant, making it difficult to assess whether the patient has received the appropriate dose of the drug.
  • long-acting sustained-release preparations such as oral sustained-release preparations, long-acting patches, and long-acting injections
  • long-acting sustained-release preparations salt form and its crystalline form.
  • a first aspect of the present invention provides a salt of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (whose structural formula is shown in formula I), wherein said salt selected from pamoate and palmitate,
  • the salt of the compound of formula I is palmitate.
  • a second aspect of the present invention provides crystals of Compound I salts, such as Compound I pamoate crystals A-S and palmitate crystals T-V.
  • a third aspect of the present invention provides a pharmaceutical composition comprising a salt of Compound I selected from the group consisting of pamoate and palmitate, in particular Compound I pamoate crystals or palmitate crystals, and one or more pharmaceutically acceptable carriers.
  • a fourth aspect of the present invention provides salts of Compound I or crystals thereof, particularly Compound I pamoate crystals A-S and palmitate crystals T-V or pharmaceutical compositions, in preparation for the treatment of Parkinson's disease and restless legs syndrome use in medicines for ailments.
  • the salt of compound I of the present invention or its crystals have low solubility, can achieve sustained release effect, and can prepare long-acting sustained-release preparations.
  • Fig. 1 is the X-ray powder diffraction (XRPD) pattern of compound I pamoate crystal A.
  • Figure 2 is the XRPD pattern of compound I pamoate crystal B.
  • Figure 3 is the XRPD pattern of compound I pamoate crystal C.
  • Figure 4 is the XRPD pattern of compound I pamoate crystal D.
  • Figure 5 is the XRPD pattern of compound I pamoate crystal E.
  • Figure 6 is the XRPD pattern of compound I pamoate crystal F.
  • Figure 7 is the XRPD pattern of compound I pamoate crystal G.
  • Figure 8 is the XRPD pattern of compound I pamoate crystal H.
  • Figure 9 is the XRPD pattern of compound I pamoate crystal I.
  • Figure 10 is the XRPD pattern of compound I pamoate crystal J.
  • Figure 11 is the XRPD pattern of compound I pamoate crystal K.
  • Figure 12 is the XRPD pattern of compound I pamoate crystal L.
  • Figure 13 is the XRPD pattern of Compound I pamoate crystal M.
  • Figure 14 is the XRPD pattern of compound I pamoate crystal N.
  • Figure 15 is the XRPD pattern of compound I pamoate crystal O.
  • Figure 16 is the XRPD pattern of compound I pamoate crystal P.
  • Figure 17 is the XRPD pattern of compound I pamoate crystal Q.
  • Figure 18 is the XRPD pattern of compound I pamoate crystal R.
  • Figure 19 is the XRPD pattern of compound I pamoate crystal S.
  • Figure 20 is the XRPD pattern of compound I palmitate crystal T.
  • Figure 21 is the XRPD pattern of compound I palmitate crystal U.
  • Figure 22 is the XRPD pattern of compound I palmitate crystal V.
  • composition refers to an active ingredient, which may optionally be combined with one or more pharmaceutically acceptable chemical ingredients such as, but not limited to, carriers and/or excipients.
  • the active ingredient is eg Compound I or its pamoate or palmitate, one or more of the crystalline forms of the present invention or one or more of the crystalline compositions of the present invention.
  • administration refers to methods by which a compound or composition can be delivered to the desired site of biological 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.
  • an "effective amount" of one active in a composition may be that amount required to achieve the desired effect when used in combination with another active in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition.
  • the term may refer to, for example, a compound of formula I or its pamoate or palmitate, one or more of the crystalline forms of the present invention, or one or more of the crystalline compositions of the present invention. variety.
  • amorphous refers to any solid substance that is not ordered in three dimensions.
  • amorphous solids can be characterized by known techniques including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques.
  • ssNMR solid state nuclear magnetic resonance
  • crystalline form or “crystal” as used herein refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or a parameter derived therefrom. XRPD patterns are typically characterized by peak position (abscissa) and/or peak intensity (ordinate).
  • the diffraction pattern obtained from a crystalline compound tends to be characteristic for a particular crystal form, where the relative intensities of the bands (especially at low angles) may vary due to crystalline Predominant orientation effects due to differences in conditions, particle size, and other measurement conditions vary. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form.
  • the relative positions of the peaks should be paid more attention to rather than their relative intensities.
  • there may be slight errors in the position of the peaks as is also well known in the crystallographic field.
  • the position of the peak may shift due to changes in temperature during sample analysis, sample movement, or instrument calibration, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining the structure of each crystal form.
  • the term "substantially” is also intended to encompass such differences in diffraction peak positions if a crystalline form of the present invention is described as substantially as shown in the designated figures.
  • d represents the crystal plane distance
  • ⁇ represents the wavelength of the incident X-ray
  • ⁇ is Diffraction angle.
  • the peak positions of its XRPD spectra are similar on the whole, and the relative intensity error may be larger. It should also be pointed out that in the identification of mixtures, due to factors such as content reduction, some diffraction lines will be missing. Certain crystals are characteristic.
  • 2 ⁇ refers to a peak position expressed in degrees based on an experimental setup of an X-ray diffraction experiment, and is usually the abscissa unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle theta with a lattice plane, the experimental setup requires recording the reflected beam at an angle of 2theta. It should be understood that references herein to particular 2[theta] values for particular crystal forms are intended to represent 2[theta] values (in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • thermogravimetric analysis (TGA) pattern refers to a curve recorded by a thermogravimetric analyzer.
  • DSC differential scanning calorimetry
  • nuclear magnetic resonance ( 1 H-NMR) spectrum refers to the signal peaks recorded by a nuclear magnetic resonance apparatus.
  • the term "substantially the same" for X-ray diffraction peak positions is meant to take into account representative peak positions and intensity variations.
  • the peak position (2 ⁇ ) will show some variation, typically as much as 0.1-0.2 degrees, and the instrument used to measure diffraction will also show some variation.
  • relative peak intensities can exhibit inter-instrument variation as well as variations due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be viewed as only is a qualitative measurement.
  • room temperature refers to 20°C ⁇ 5°C.
  • the present invention provides a salt of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (Compound I), wherein the salt is selected from pamoate and palmitate acid salt,
  • the salt of Formula I is a palmitate of Formula I.
  • the salt of Formula I is a pamoate salt of Formula I.
  • the stoichiometric ratio of Compound 1 to pamoic acid in Compound 1 pamoate is 1:1.
  • the present invention provides Compound I Pamoic Acid Crystalline A, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 4.76 ⁇ 0.2°, 7.07 ⁇ 0.2 °, 8.32 ⁇ 0.2°, 10.7 ⁇ 0.2°, 11.73 ⁇ 0.2°, 13.29 ⁇ 0.2°, 16.25 ⁇ 0.2°, 18.45 ⁇ 0.2°, 21.51 ⁇ 0.2°, 24.81 ⁇ 0.2° and 26.17 ⁇ 0.2° at 2 ⁇ Diffraction peaks.
  • the XRPD pattern of Compound I Pamoate Crystal A further includes diffraction peaks at 2 ⁇ at about 17.87 ⁇ 0.2°, 22.01 ⁇ 0.2°, 25.17 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal A comprises at about 4.76 ⁇ 0.2°, 7.07 ⁇ 0.2°, 8.32 ⁇ 0.2°, 10.7 ⁇ 0.2°, 11.73 ⁇ 0.2°, 13.29 ⁇ 0.2° , 16.25 ⁇ 0.2°, 17.87 ⁇ 0.2°, 18.45 ⁇ 0.2°, 21.51 ⁇ 0.2°, 22.01 ⁇ 0.2°, 24.81 ⁇ 0.2°, 25.17 ⁇ 0.2° and 26.17 ⁇ 0.2° at 2 ⁇ of diffraction peaks.
  • the XRPD pattern of Compound I Pamoate Crystal A includes the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal A is substantially as shown in FIG. 1 . In some preferred embodiments, the XRPD pattern of Compound I Pamoate Crystal A is shown in Figure 1 .
  • the present invention provides Compound I pamoic acid salt crystals B, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is included at about 5.79 ⁇ 0.2°, 6.38 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 10.95 ⁇ 0.2°, 14.72 ⁇ 0.2°, 17.61 ⁇ 0.2°, 18.40 ⁇ 0.2°, 19.81 ⁇ 0.2° and 22.18 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal B further includes diffraction peaks at 2 ⁇ at about 10.61 ⁇ 0.2°, 12.51 ⁇ 0.2°, 17.61 ⁇ 0.2° and 20.01 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I Pamoate Crystal B further includes diffraction peaks at 2 ⁇ at about 10.18 ⁇ 0.2°, 13.15 ⁇ 0.2° and 13.36 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal B comprises at about 5.79 ⁇ 0.2°, 6.38 ⁇ 0.2°, 10.61 ⁇ 0.2°, 10.95 ⁇ 0.2°, 12.51 ⁇ 0.2°, 14.72 ⁇ 0.2° , 17.61 ⁇ 0.2°, 18.40 ⁇ 0.2°, 19.81 ⁇ 0.2°, 20.01 ⁇ 0.2° and 22.18 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal B comprises at about 5.79 ⁇ 0.2°, 6.38 ⁇ 0.2°, 10.18 ⁇ 0.2°, 10.61 ⁇ 0.2°, 10.95 ⁇ 0.2°, 12.51 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 13.15 ⁇ 0.2°, 13.36 ⁇ 0.2°, 14.72 ⁇ 0.2°, 17.61 ⁇ 0.2°, 18.40 ⁇ 0.2°, 19.81 ⁇ 0.2°, 20.01 ⁇ 0.2° and 22.18 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal B includes the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal B is substantially as shown in FIG. 2 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal B is shown in FIG. 2 .
  • the present invention provides Compound I pamoate crystals C, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 7.43 ⁇ 0.2°, 11.18 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 11.98 ⁇ 0.2°, 14.78 ⁇ 0.2°, 20.20 ⁇ 0.2°, 20.97 ⁇ 0.2° and 23.30 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal C further includes diffraction peaks at 2 ⁇ at about 16.90 ⁇ 0.2°, 19.73 ⁇ 0.2°, 22.12 ⁇ 0.2° and 25.37 ⁇ 0.2°. More preferably, the XRPD pattern of compound I pamoate crystal C further includes diffraction peaks at 2 ⁇ at about 19.34 ⁇ 0.2° and 22.91 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal C comprises at about 7.43 ⁇ 0.2°, 11.18 ⁇ 0.2°, 11.98 ⁇ 0.2°, 14.78 ⁇ 0.2°, 16.90 ⁇ 0.2°, 19.73 ⁇ 0.2° , 20.20 ⁇ 0.2°, 20.97 ⁇ 0.2°, 22.12 ⁇ 0.2°, 23.31 ⁇ 0.2° and 25.37 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal C comprises at about 7.43 ⁇ 0.2°, 11.18 ⁇ 0.2°, 11.98 ⁇ 0.2°, 14.78 ⁇ 0.2°, 16.90 ⁇ 0.2°, 19.34 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 19.73 ⁇ 0.2°, 20.20 ⁇ 0.2°, 20.97 ⁇ 0.2°, 22.12 ⁇ 0.2°, 22.91 ⁇ 0.2°, 23.31 ⁇ 0.2° and 25.37 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal C comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal C is substantially as shown in FIG. 3 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal C is shown in FIG. 3 .
  • the present invention provides compound I pamoate crystals D, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 11.24 ⁇ 0.2°, 11.88 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 12.03 ⁇ 0.2°, 13.57 ⁇ 0.2°, 14.76 ⁇ 0.2°, 15.17 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.15 ⁇ 0.2° and 23.26 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal D further includes diffraction peaks at 2 ⁇ at about 15.17 ⁇ 0.2°, 16.92 ⁇ 0.2° and 24.24 ⁇ 0.2°. More preferably, the XRPD pattern of compound I pamoate crystal D further includes diffraction peaks at 2 ⁇ at about 19.3709 ⁇ 0.2° and 20.2490 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal D comprises at about 11.24 ⁇ 0.2°, 11.88 ⁇ 0.2°, 12.03 ⁇ 0.2°, 13.57 ⁇ 0.2°, 14.76 ⁇ 0.2°, 15.17 ⁇ 0.2° , 16.92 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.15 ⁇ 0.2°, 23.26 ⁇ 0.2° and 24.24 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal D comprises at about 11.24 ⁇ 0.2°, 11.88 ⁇ 0.2°, 12.03 ⁇ 0.2°, 13.57 ⁇ 0.2°, 14.76 ⁇ 0.2°, 15.17 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 16.92 ⁇ 0.2°, 19.37 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.15 ⁇ 0.2°, 23.26 ⁇ 0.2°, 24.24 ⁇ 0.2° and 20.25 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal D comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal D is substantially as shown in FIG. 4 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal D is shown in FIG. 4 .
  • the present invention provides Compound I pamoate crystals E, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 7.32 ⁇ 0.2°, 11.26 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 12.04 ⁇ 0.2°, 14.77 ⁇ 0.2°, 15.24 ⁇ 0.2°, 16.95 ⁇ 0.2°, 20.28 ⁇ 0.2°, 21.26 ⁇ 0.2°, and 23.27 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal E further includes diffraction peaks at 2 ⁇ at about 19.37 ⁇ 0.2° and 19.83 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal E comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystals E is substantially as shown in FIG. 5 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal E is shown in FIG. 5 .
  • the present invention provides compound I pamoate crystals F, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 11.19 ⁇ 0.2°, 12.10 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 14.67 ⁇ 0.2°, 15.48 ⁇ 0.2°, 18.11 ⁇ 0.2°, 20.25 ⁇ 0.2° and 23.33 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal F further includes diffraction peaks at 2 ⁇ at about 11.92 ⁇ 0.2°, 14.67 ⁇ 0.2°, 16.71 ⁇ 0.2° and 25.84 ⁇ 0.2°. More preferably, the XRPD pattern of compound I pamoate crystal F further includes diffraction peaks at 2 ⁇ at about 19.19 ⁇ 0.2° and 21.23 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal F comprises at about 11.19 ⁇ 0.2°, 11.92 ⁇ 0.2°, 12.10 ⁇ 0.2°, 14.67 ⁇ 0.2°, 15.48 ⁇ 0.2°, 16.71 ⁇ 0.2° , 18.11 ⁇ 0.2°, 20.25 ⁇ 0.2°, 23.33 ⁇ 0.2° and 25.84 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal F comprises at about 11.19 ⁇ 0.2°, 11.92 ⁇ 0.2°, 12.10 ⁇ 0.2°, 14.67 ⁇ 0.2°, 15.48 ⁇ 0.2°, 16.71 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 18.11 ⁇ 0.2°, 19.19 ⁇ 0.2°, 20.25 ⁇ 0.2°, 21.23 ⁇ 0.2°, 23.33 ⁇ 0.2° and 25.84 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal F comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal F is substantially as shown in FIG. 6 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal F is shown in FIG. 6 .
  • the present invention provides compound I pamoate crystals G, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 6.13 ⁇ 0.2°, 11.24 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 11.86 ⁇ 0.2°, 13.15 ⁇ 0.2°, 14.79 ⁇ 0.2°, 20.27 ⁇ 0.2° and 23.13 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal G further comprises at about 11.24 ⁇ 0.2°, 14.54 ⁇ 0.2°, 19.90 ⁇ 0.2°, 20.09 ⁇ 0.2°, 22.21 ⁇ 0.2°, 23.96 ⁇ 0.2° and 24.76° Diffraction peaks at 2 ⁇ of ⁇ 0.2°. More preferably, the XRPD pattern of compound I pamoate crystal G further includes diffraction peaks at 2 ⁇ at about 16.88 ⁇ 0.2°, 19.35 ⁇ 0.2° and 20.46 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal G comprises at about 6.13 ⁇ 0.2°, 11.24 ⁇ 0.2°, 11.86 ⁇ 0.2°, 13.15 ⁇ 0.2°, 14.54 ⁇ 0.2°, 14.79 ⁇ 0.2° , 19.90 ⁇ 0.2°, 20.09 ⁇ 0.2°, 20.27 ⁇ 0.2°, 22.21 ⁇ 0.2°, 23.13 ⁇ 0.2°, 23.96 ⁇ 0.2° and 24.76 ⁇ 0.2° at 2 ⁇ of diffraction peaks.
  • the XRPD pattern of Compound I Pamoate Crystal G comprises at about 6.13 ⁇ 0.2°, 11.24 ⁇ 0.2°, 11.86 ⁇ 0.2°, 13.15 ⁇ 0.2°, 14.54 ⁇ 0.2°, 14.79 ⁇ 0.2 degrees Diffraction peaks at 2 ⁇ of °.
  • the XRPD pattern of Compound I Pamoate Crystal G comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal G is substantially as shown in FIG. 7 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal G is shown in FIG. 7 .
  • the present invention provides compound I pamoate crystals H, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern is included at about 7.08 ⁇ 0.2°, 11.92 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 13.03 ⁇ 0.2°, 14.71 ⁇ 0.2°, 16.90 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.96 ⁇ 0.2°, 23.04 ⁇ 0.2° and 23.56 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal H further includes diffraction peaks at 2 ⁇ at about 11.76 ⁇ 0.2°, 13.03 ⁇ 0.2°, 20.27 ⁇ 0.2° and 26.66 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I Pamoate Crystal H further includes diffraction peaks at 2 ⁇ at about 11.30 ⁇ 0.2°, 14.71 ⁇ 0.2° and 19.97 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal H comprises at about 7.08 ⁇ 0.2°, 11.76 ⁇ 0.2°, 11.92 ⁇ 0.2°, 13.03 ⁇ 0.2°, 14.71 ⁇ 0.2°, 16.90 ⁇ 0.2° Diffraction peaks at 2 ⁇ at 20.27 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.96 ⁇ 0.2°, 23.04 ⁇ 0.2°, 23.56 ⁇ 0.2° and 26.66 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal H comprises at about 7.08 ⁇ 0.2°, 11.76 ⁇ 0.2°, 11.30 ⁇ 0.2°, 11.92 ⁇ 0.2°, 13.03 ⁇ 0.2°, 14.71 ⁇ 0.2° , 16.90 ⁇ 0.2°, 19.97 ⁇ 0.2°, 20.27 ⁇ 0.2°, 20.85 ⁇ 0.2°, 21.96 ⁇ 0.2°, 23.04 ⁇ 0.2°, 23.56 ⁇ 0.2° and 26.66 ⁇ 0.2° at 2 ⁇ of diffraction peaks.
  • the XRPD pattern of Compound I Pamoate Crystal H comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal H is substantially as shown in FIG. 8 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal H is shown in FIG. 8 .
  • the present invention provides Compound 1 pamoate crystals I, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 5.59 ⁇ 0.2°, 5.98 ⁇ 0.2 Diffraction peaks at 2 ⁇ of °, 9.39 ⁇ 0.2°, 20.39 ⁇ 0.2°, 25.27 ⁇ 0.2°, and 26.01 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal I further includes diffraction peaks at 2 ⁇ at about 7.62 ⁇ 0.2°, 8.22 ⁇ 0.2°, 11.59 ⁇ 0.2°, 18.09 ⁇ 0.2° and 22.59 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I Pamoate Crystal I further includes diffraction peaks at 2 ⁇ at about 7.80 ⁇ 0.2°, 9.88 ⁇ 0.2° and 23.40 ⁇ 0.2°.
  • the XRPD pattern of Compound 1 Pamoate Crystal I comprises at about 5.59 ⁇ 0.2°, 5.98 ⁇ 0.2°, 7.62 ⁇ 0.2°, 8.22 ⁇ 0.2°, 9.39 ⁇ 0.2°, 11.59 ⁇ 0.2° Diffraction peaks at 2 ⁇ at 18.09 ⁇ 0.2°, 20.39 ⁇ 0.2°, 22.59 ⁇ 0.2°, 25.27 ⁇ 0.2°, and 26.01 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal I comprises at about 5.59 ⁇ 0.2°, 5.98 ⁇ 0.2°, 7.62 ⁇ 0.2°, 7.80 ⁇ 0.2°, 8.22 ⁇ 0.2°, 9.39 ⁇ 0.2 Diffraction peaks at 2 ⁇ of °, 9.88 ⁇ 0.2°, 11.59 ⁇ 0.2°, 18.09 ⁇ 0.2°, 20.39 ⁇ 0.2°, 22.59 ⁇ 0.2°, 23.40 ⁇ 0.2°, 25.27 ⁇ 0.2°, and 26.01 ⁇ 0.2°.
  • the XRPD pattern of Compound 1 Pamoate Crystal I comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal I is substantially as shown in FIG. 9 .
  • the XRPD pattern of compound I pamoate crystal H is shown in FIG. 9 .
  • the present invention provides Compound I pamoate crystals J, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 5.33 ⁇ 0.2°, 7.13 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 10.90 ⁇ 0.2°, 14.57 ⁇ 0.2°, 16.62 ⁇ 0.2°, 19.80 ⁇ 0.2° and 25.29 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal J further includes diffraction peaks at 2 ⁇ at about 14.99 ⁇ 0.2°, 19.01 ⁇ 0.2° and 20.74 ⁇ 0.2°. More preferably, the XRPD pattern of compound I pamoate crystal J further includes diffraction peaks at 2 ⁇ at about 19.32 ⁇ 0.2° and 22.24 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal J comprises at about 5.33 ⁇ 0.2°, 7.13 ⁇ 0.2°, 10.90 ⁇ 0.2°, 14.57 ⁇ 0.2°, 14.99 ⁇ 0.2°, 16.62 ⁇ 0.2° , 19.01 ⁇ 0.2°, 19.80 ⁇ 0.2°, 20.74 ⁇ 0.2°, and 25.29 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal J comprises at about 5.33 ⁇ 0.2°, 7.13 ⁇ 0.2°, 10.90 ⁇ 0.2°, 14.57 ⁇ 0.2°, 14.99 ⁇ 0.2°, 16.62 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 19.01 ⁇ 0.2°, 19.32 ⁇ 0.2°, 19.80 ⁇ 0.2°, 20.74 ⁇ 0.2°, 22.24 ⁇ 0.2° and 25.29 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal J includes the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal J is substantially as shown in FIG. 10 . In some preferred embodiments, the XRPD pattern of Compound I Pamoate Crystal J is shown in Figure 10.
  • the present invention provides compound I pamoate crystals K, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 5.57 ⁇ 0.2°, 5.97 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 7.73 ⁇ 0.2°, 11.55 ⁇ 0.2°, 18.01 ⁇ 0.2° and 18.90 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal K further includes diffraction peaks at 2 ⁇ of about 9.34 ⁇ 0.2°, 19.79 ⁇ 0.2° and 25.84 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I pamoate crystal K further includes diffraction peaks at 2 ⁇ at about 23.25 ⁇ 0.2° and 25.10 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal K comprises at about 5.57 ⁇ 0.2°, 5.97 ⁇ 0.2°, 7.73 ⁇ 0.2°, 9.34 ⁇ 0.2°, 11.55 ⁇ 0.2°, 18.01 ⁇ 0.2° , 18.90 ⁇ 0.2°, 19.79 ⁇ 0.2° and 25.84 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal K comprises at about 5.57 ⁇ 0.2°, 5.97 ⁇ 0.2°, 7.73 ⁇ 0.2°, 9.34 ⁇ 0.2°, 11.55 ⁇ 0.2°, 18.01 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 18.90 ⁇ 0.2°, 19.79 ⁇ 0.2°, 23.25 ⁇ 0.2°, 25.10 ⁇ 0.2° and 25.84 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal K comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal K is substantially as shown in FIG. 11 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal K is shown in FIG. 11 .
  • the present invention provides Compound I pamoate crystals L, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 6.20 ⁇ 0.2°, 8.13 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 9.92 ⁇ 0.2°, 10.85 ⁇ 0.2°, 12.81 ⁇ 0.2° and 21.82 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal L further includes diffraction peaks at 2 ⁇ at about 15.29 ⁇ 0.2° and 25.86 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I pamoate crystal L further includes diffraction peaks at 2 ⁇ at about 19.29 ⁇ 0.2° and 25.63 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal L comprises at about 6.20 ⁇ 0.2°, 8.13 ⁇ 0.2°, 9.92 ⁇ 0.2°, 10.85 ⁇ 0.2°, 12.81 ⁇ 0.2°, 15.29 ⁇ 0.2° , diffraction peaks at 2 ⁇ at 21.82 ⁇ 0.2° and 25.86 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal L comprises at about 6.20 ⁇ 0.2°, 8.13 ⁇ 0.2°, 9.92 ⁇ 0.2°, 10.85 ⁇ 0.2°, 12.81 ⁇ 0.2°, 15.29 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 19.29 ⁇ 0.2°, 21.82 ⁇ 0.2°, 25.63 ⁇ 0.2° and 25.86 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal L comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I pamoate crystal L is substantially as shown in FIG. 12 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal L is shown in FIG. 12 .
  • the present invention provides Compound I pamoate crystals M, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern is comprised at about 6.31 ⁇ 0.2°, 11.55 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 14.49 ⁇ 0.2°, 15.94 ⁇ 0.2°, 19.58 ⁇ 0.2° and 23.50 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal M further includes diffraction peaks at 2 ⁇ at about 19.27 ⁇ 0.2°, 20.28 ⁇ 0.2° and 25.88 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I pamoate crystal M further includes diffraction peaks at 2 ⁇ at about 22.27 ⁇ 0.2° and 24.88 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal M comprises at about 6.31 ⁇ 0.2°, 11.55 ⁇ 0.2°, 14.49 ⁇ 0.2°, 15.94 ⁇ 0.2°, 19.58 ⁇ 0.2°, 19.27 ⁇ 0.2° , 20.28 ⁇ 0.2°, 23.50 ⁇ 0.2°, and 25.88 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal M comprises at about 6.31 ⁇ 0.2°, 11.55 ⁇ 0.2°, 14.49 ⁇ 0.2°, 15.94 ⁇ 0.2°, 19.58 ⁇ 0.2°, 19.27 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 20.28 ⁇ 0.2°, 22.27 ⁇ 0.2°, 23.50 ⁇ 0.2°, 24.88 ⁇ 0.2° and 25.88 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal M includes the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal M is substantially as shown in FIG. 13 . In some preferred embodiments, the XRPD pattern of Compound I Pamoate Crystal M is shown in FIG. 13 .
  • the stoichiometric ratio of Compound 1 to pamoic acid in Compound 1 pamoate is 2:1.
  • the present invention provides Compound I pamoate crystals N, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern is comprised at about 5.87 ⁇ 0.2°, 6.42 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 10.11 ⁇ 0.2°, 12.58 ⁇ 0.2°, 13.38 ⁇ 0.2°, 16.12 ⁇ 0.2° and 17.86 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal N further includes diffraction peaks at 2 ⁇ at about 10.55 ⁇ 0.2°, 14.74 ⁇ 0.2°, 24.90 ⁇ 0.2° and 26.45 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I pamoate crystal N further includes diffraction peaks at 2 ⁇ at about 10.87 ⁇ 0.2°, 23.55 ⁇ 0.2° and 24.29 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal N comprises at about 5.87 ⁇ 0.2°, 6.42 ⁇ 0.2°, 10.11 ⁇ 0.2°, 10.55 ⁇ 0.2°, 12.58 ⁇ 0.2°, 13.38 ⁇ 0.2° , 14.74 ⁇ 0.2°, 16.12 ⁇ 0.2°, 17.86 ⁇ 0.2°, 24.90 ⁇ 0.2° and 26.45 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal N comprises at about 5.87 ⁇ 0.2°, 6.42 ⁇ 0.2°, 10.11 ⁇ 0.2°, 10.55 ⁇ 0.2°, 10.87 ⁇ 0.2°, 12.58 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 13.38 ⁇ 0.2°, 14.74 ⁇ 0.2°, 16.12 ⁇ 0.2°, 17.86 ⁇ 0.2°, 23.55 ⁇ 0.2°, 24.29 ⁇ 0.2°, 24.90 ⁇ 0.2° and 26.45 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal N comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystals N is substantially as shown in FIG. 14 . In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal N is shown in FIG. 14 .
  • the present invention provides Compound I pamoate crystals O, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern is comprised at about 11.33 ⁇ 0.2°, 11.92 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 14.71 ⁇ 0.2°, 16.11 ⁇ 0.2°, 17.50 ⁇ 0.2° and 20.86 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal O further includes diffraction peaks at 2 ⁇ at about 20.27 ⁇ 0.2°, 23.04 ⁇ 0.2°, 23.57 ⁇ 0.2° and 27.70 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal O further includes diffraction peaks at 2 ⁇ at about 19.96 ⁇ 0.2°, 24.05 ⁇ 0.2°, 25.43 ⁇ 0.2° and 26.66 ⁇ 0.2°.
  • the XRPD pattern of Compound 1 Pamoate Crystal O comprises at about 11.33 ⁇ 0.2°, 11.92 ⁇ 0.2°, 14.71 ⁇ 0.2°, 16.11 ⁇ 0.2°, 17.50 ⁇ 0.2°, 20.27 ⁇ 0.2° , 20.86 ⁇ 0.2°, 23.04 ⁇ 0.2°, 23.57 ⁇ 0.2° and 27.70 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal O comprises at about 11.33 ⁇ 0.2°, 11.92 ⁇ 0.2°, 14.71 ⁇ 0.2°, 16.11 ⁇ 0.2°, 17.50 ⁇ 0.2°, 19.96 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 20.27 ⁇ 0.2°, 20.86 ⁇ 0.2°, 23.04 ⁇ 0.2°, 23.57 ⁇ 0.2°, 24.05 ⁇ 0.2°, 25.43 ⁇ 0.2°, 26.66 ⁇ 0.2° and 27.70 ⁇ 0.2°.
  • the XRPD pattern of Compound 1 Pamoate Crystal O comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal O is substantially as shown in FIG. 15 . In some preferred embodiments, the XRPD pattern of Compound I Pamoate Crystal O is shown in Figure 15.
  • the present invention provides Compound I pamoate crystals P, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern is comprised at about 5.79 ⁇ 0.2°, 6.36 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 10.58 ⁇ 0.2°, 10.90 ⁇ 0.2°, 13.32 ⁇ 0.2°, 14.69 ⁇ 0.2°, 17.61 ⁇ 0.2° and 25.26 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal P further includes diffraction peaks at 2 ⁇ at about 10.58 ⁇ 0.2°, 22.20 ⁇ 0.2°, 22.80 ⁇ 0.2° and 23.47 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I pamoate crystal P further includes diffraction peaks at 2 ⁇ at about 23.76 ⁇ 0.2° and 24.08 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystals P comprises at about 5.79 ⁇ 0.2°, 6.36 ⁇ 0.2°, 10.58 ⁇ 0.2°, 10.90 ⁇ 0.2°, 13.32 ⁇ 0.2°, 14.69 ⁇ 0.2° , 17.61 ⁇ 0.2°, 22.20 ⁇ 0.2°, 22.80 ⁇ 0.2°, 23.47 ⁇ 0.2°, and 25.26 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal P comprises at about 5.79 ⁇ 0.2°, 6.36 ⁇ 0.2°, 10.58 ⁇ 0.2°, 10.90 ⁇ 0.2°, 13.32 ⁇ 0.2°, 14.69 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 17.61 ⁇ 0.2°, 22.20 ⁇ 0.2°, 22.80 ⁇ 0.2°, 23.47 ⁇ 0.2°, 23.76 ⁇ 0.2°, 24.08 ⁇ 0.2° and 25.26 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal P comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystals P is substantially as shown in FIG. 16 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal P is shown in FIG. 16 .
  • the present invention provides Compound I pamoate crystals Q, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern is comprised at about 5.75 ⁇ 0.2°, 6.20 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 10.46 ⁇ 0.2°, 14.54 ⁇ 0.2°, 15.26 ⁇ 0.2° and 20.78 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal Q further includes diffraction peaks at 2 ⁇ at about 16.16 ⁇ 0.2°, 17.51 ⁇ 0.2° and 24.37 ⁇ 0.2°. More preferably, the XRPD pattern of compound I pamoate crystal Q further includes diffraction peaks at 2 ⁇ at about 17.98 ⁇ 0.2°, 21.74 ⁇ 0.2° and 23.58 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal Q comprises at about 5.75 ⁇ 0.2°, 6.20 ⁇ 0.2°, 10.46 ⁇ 0.2°, 14.54 ⁇ 0.2°, 15.26 ⁇ 0.2°, 16.16 ⁇ 0.2° , 17.51 ⁇ 0.2°, 20.78 ⁇ 0.2° and 24.37 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of compound I pamoate crystal Q comprises at about 5.75 ⁇ 0.2°, 6.20 ⁇ 0.2°, 10.46 ⁇ 0.2°, 14.54 ⁇ 0.2°, 15.26 ⁇ 0.2°, 16.16 Diffraction peaks at 2 ⁇ at ⁇ 0.2°, 17.51 ⁇ 0.2°, 17.98 ⁇ 0.2°, 20.78 ⁇ 0.2°, 21.74 ⁇ 0.2°, 23.58 ⁇ 0.2° and 24.37 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal Q comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I pamoate crystal Q is substantially as shown in FIG. 17 . In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal Q is shown in FIG. 17 .
  • the present invention provides Compound I pamoic acid salt crystals R, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern is comprised at about 5.97 ⁇ 0.2°, 11.45 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 12.06 ⁇ 0.2°, 13.41 ⁇ 0.2°, 17.75 ⁇ 0.2° and 18.77 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal R further includes diffraction peaks at 2 ⁇ at about 19.42 ⁇ 0.2°, 21.64 ⁇ 0.2°, 23.89 ⁇ 0.2°, 27.10 ⁇ 0.2° and 28.76 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I pamoate crystal R further includes diffraction peaks at 2 ⁇ at about 21.64 ⁇ 0.2°, 23.09 ⁇ 0.2° and 26.18 ⁇ 0.2°.
  • the XRPD pattern of Compound I Pamoate Crystal R comprises at about 5.97 ⁇ 0.2°, 11.45 ⁇ 0.2°, 12.06 ⁇ 0.2°, 13.41 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.77 ⁇ 0.2° , 19.42 ⁇ 0.2°, 21.64 ⁇ 0.2°, 23.89 ⁇ 0.2°, 27.10 ⁇ 0.2° and 28.76 ⁇ 0.2° diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I Pamoate Crystal R comprises at about 5.97 ⁇ 0.2°, 11.45 ⁇ 0.2°, 12.06 ⁇ 0.2°, 13.41 ⁇ 0.2°, 17.75 ⁇ 0.2°, 18.77 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 19.42 ⁇ 0.2°, 21.64 ⁇ 0.2°, 23.09 ⁇ 0.2°, 23.89 ⁇ 0.2°, 26.18 ⁇ 0.2°, 27.10 ⁇ 0.2° and 28.76 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal R comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I pamoate crystal R is substantially as shown in FIG. 18 . In some preferred embodiments, the XRPD pattern of compound I pamoate crystal R is shown in FIG. 18 .
  • the present invention provides Compound I pamoate crystals S, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern is comprised at about 5.84 ⁇ 0.2°, 6.34 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 10.06 ⁇ 0.2°, 11.14 ⁇ 0.2°, 13.25 ⁇ 0.2°, 14.65 ⁇ 0.2°, 18.26 ⁇ 0.2° and 25.25 ⁇ 0.2°.
  • the XRPD pattern of compound I pamoate crystal S further includes diffraction peaks at 2 ⁇ at about 19.33 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.68 ⁇ 0.2° and 24.06 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I pamoate crystal S further includes diffraction peaks at 2 ⁇ at about 20.20 ⁇ 0.2°, 22.09 ⁇ 0.2° and 24.06 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal S is included at about 5.84 ⁇ 0.2°, 6.34 ⁇ 0.2°, 10.06 ⁇ 0.2°, 11.14 ⁇ 0.2°, 13.25 ⁇ 0.2°, 14.65 ⁇ 0.2° , 18.26 ⁇ 0.2°, 19.33 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.68 ⁇ 0.2°, 24.06 ⁇ 0.2° and 25.25 ⁇ 0.2° at 2 ⁇ of diffraction peaks.
  • the XRPD pattern of Compound I Pamoate Crystal S is included at about 5.84 ⁇ 0.2°, 6.34 ⁇ 0.2°, 10.06 ⁇ 0.2°, 11.14 ⁇ 0.2°, 13.25 ⁇ 0.2°, 14.65 ⁇ 0.2 Diffraction peaks at 2 ⁇ at °, 18.26 ⁇ 0.2°, 19.33 ⁇ 0.2°, 20.20 ⁇ 0.2°, 21.53 ⁇ 0.2°, 22.09 ⁇ 0.2°, 22.68 ⁇ 0.2°, 24.06 ⁇ 0.2°, and 25.25 ⁇ 0.2°.
  • the XRPD pattern of Compound I pamoate crystal S includes the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I Pamoate Crystal S is substantially as shown in FIG. 19 . In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal S is shown in FIG. 19 .
  • the stoichiometric ratio of Compound 1 to palmitic acid in Compound 1 palmitate is 1:1.
  • the present invention provides Compound I palmitate crystals T, wherein the stoichiometric ratio of Compound I to palmitic acid is 1:1, and its XRPD pattern is included at about 6.17 ⁇ 0.2°, 9.73 ⁇ 0.2°, 10.20 ⁇ Diffraction peaks at 2 ⁇ at 0.2°, 11.52 ⁇ 0.2°, 12.44 ⁇ 0.2°, 15.16 ⁇ 0.2° and 21.40 ⁇ 0.2°.
  • the XRPD pattern of compound I palmitate crystal T further includes diffraction peaks at 2 ⁇ at about 13.82 ⁇ 0.2°, 16.36 ⁇ 0.2° and 16.65 ⁇ 0.2°. More preferably, the XRPD pattern of Compound I palmitate crystal T further includes diffraction peaks at 2 ⁇ at about 16.89 ⁇ 0.2°, 19.88 ⁇ 0.2° and 20.18 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystal T comprises at about 6.17 ⁇ 0.2°, 9.73 ⁇ 0.2°, 10.20 ⁇ 0.2°, 11.52 ⁇ 0.2°, 12.44 ⁇ 0.2°, 13.82 ⁇ 0.2°, 15.16 Diffraction peaks at 2 ⁇ at ⁇ 0.2°, 16.36 ⁇ 0.2°, 16.65 ⁇ 0.2° and 21.40 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystal T comprises at about 6.17 ⁇ 0.2°, 9.73 ⁇ 0.2°, 10.20 ⁇ 0.2°, 11.52 ⁇ 0.2°, 12.44 ⁇ 0.2°, 13.82 ⁇ 0.2°, Diffraction peaks at 2 ⁇ at 15.16 ⁇ 0.2°, 16.36 ⁇ 0.2°, 16.65 ⁇ 0.2°, 16.89 ⁇ 0.2°, 19.88 ⁇ 0.2°, 20.18 ⁇ 0.2° and 21.40 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystal T comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I palmitate crystal T is substantially as shown in FIG. 20 . In some preferred embodiments, the XRPD pattern of Compound I palmitate crystal T is shown in Figure 20.
  • the present invention provides Compound I palmitate crystals U, wherein the stoichiometric ratio of Compound I to palmitic acid is 1:1, and its XRPD pattern is included at about 5.95 ⁇ 0.2°, 15.15 ⁇ 0.2°, 17.90 ⁇ Diffraction peaks at 2 ⁇ at 0.2°, 20.57 ⁇ 0.2°, 21.44 ⁇ 0.2°, 21.83 ⁇ 0.2° and 25.82 ⁇ 0.2°.
  • the XRPD pattern of compound I palmitate crystal U further comprises diffraction peaks at 2 ⁇ at about 10.81 ⁇ 0.2°, 14.47 ⁇ 0.2°, 18.20 ⁇ 0.2°, 22.63 ⁇ 0.2° and 26.63 ⁇ 0.2°. More preferably, the XRPD pattern of compound I palmitate crystal U further includes diffraction peaks at 2 ⁇ at about 11.27 ⁇ 0.2° and 26.03 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystals U comprises at about 5.95 ⁇ 0.2°, 10.81 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.15 ⁇ 0.2°, 17.90 ⁇ 0.2°, 18.20 ⁇ 0.2°, 20.57 Diffraction peaks at 2 ⁇ of ⁇ 0.2°, 21.44 ⁇ 0.2°, 21.83 ⁇ 0.2°, 22.63 ⁇ 0.2°, 25.82 ⁇ 0.2° and 26.63 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystal U comprises at about 5.95 ⁇ 0.2°, 10.81 ⁇ 0.2°, 11.27 ⁇ 0.2°, 14.47 ⁇ 0.2°, 15.15 ⁇ 0.2°, 17.90 ⁇ 0.2°, Diffraction peaks at 2 ⁇ at 18.20 ⁇ 0.2°, 20.57 ⁇ 0.2°, 21.44 ⁇ 0.2°, 21.83 ⁇ 0.2°, 22.63 ⁇ 0.2°, 25.82 ⁇ 0.2°, 26.03 ⁇ 0.2° and 26.63 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystal U includes the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I palmitate crystal U is substantially as shown in FIG. 21 . In some preferred embodiments, the XRPD pattern of compound I palmitate crystal U is shown in FIG. 21 .
  • the present invention provides compound I palmitate crystals V, wherein the stoichiometric ratio of compound I to palmitic acid is 1:1, and its XRPD pattern is included at about 5.56 ⁇ 0.2°, 12.99 ⁇ 0.2°, 13.21 ⁇ Diffraction peaks at 2 ⁇ at 0.2°, 13.59 ⁇ 0.2°, 14.02 ⁇ 0.2°, 14.71 ⁇ 0.2° and 19.90 ⁇ 0.2°.
  • the XRPD pattern of compound I palmitate crystal V further comprises diffraction peaks at 2 ⁇ at about 11.19 ⁇ 0.2°, 19.66 ⁇ 0.2°, 22.61 ⁇ 0.2°, 22.80 ⁇ 0.2° and 23.43 ⁇ 0.2°. More preferably, the XRPD pattern of compound I palmitate crystal V further comprises diffraction peaks at 2 ⁇ at about 11.38 ⁇ 0.2°, 19.48 ⁇ 0.2°, 20.26 ⁇ 0.2° and 22.96 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystal V comprises at about 5.56 ⁇ 0.2°, 11.19 ⁇ 0.2°, 12.99 ⁇ 0.2°, 13.21 ⁇ 0.2°, 13.59 ⁇ 0.2°, 14.02 ⁇ 0.2°, 14.71 Diffraction peaks at 2 ⁇ of ⁇ 0.2°, 19.90 ⁇ 0.2°, 19.66 ⁇ 0.2°, 22.61 ⁇ 0.2°, 22.80 ⁇ 0.2° and 23.43 ⁇ 0.2°.
  • the XRPD pattern of Compound I palmitate crystal V comprises at about 5.56 ⁇ 0.2°, 11.19 ⁇ 0.2°, 11.38 ⁇ 0.2°, 12.99 ⁇ 0.2°, 13.21 ⁇ 0.2°, 13.59 ⁇ 0.2°, 14.02 ⁇ 0.2°, 14.71 ⁇ 0.2°, 19.48 ⁇ 0.2°, 19.90 ⁇ 0.2°, 19.66 ⁇ 0.2°, 20.26 ⁇ 0.2°, 22.61 ⁇ 0.2°, 22.80 ⁇ 0.2°, 22.96 ⁇ 0.2° and 23.43 ⁇ 0.2° Diffraction peaks at 2 ⁇ .
  • the XRPD pattern of Compound I palmitate crystal V comprises the following diffraction peaks at 2 ⁇ :
  • the XRPD pattern of Compound I palmitate crystal V is substantially as shown in FIG. 22 . In some preferred embodiments, the XRPD pattern of Compound I palmitate crystal V is shown in Figure 22.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a salt of compound I selected from pamoate and palmitate, especially compound I pamoate crystals or palmitic acid Salt crystals, and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide salts of compound I of the present invention (eg compound of formula I pamoate and compound of formula I palmitate, especially compound I pamoate crystals or palmitate crystals or its any combination) or a pharmaceutical composition, in the manufacture of a medicament for the treatment of Parkinson's disease and restless legs syndrome.
  • salts of compound I of the present invention eg compound of formula I pamoate and compound of formula I palmitate, especially compound I pamoate crystals or palmitate crystals or its any combination
  • a pharmaceutical composition in the manufacture of a medicament for the treatment of Parkinson's disease and restless legs syndrome.
  • Another object of the present invention is to provide salts of compound I of the present invention (eg compound of formula I pamoate and compound of formula I palmitate, especially compound I pamoate crystals or palmitate crystals or its any combination) or a pharmaceutical composition for the treatment of Parkinson's disease and restless legs syndrome.
  • salts of compound I of the present invention eg compound of formula I pamoate and compound of formula I palmitate, especially compound I pamoate crystals or palmitate crystals or its any combination
  • a pharmaceutical composition for the treatment of Parkinson's disease and restless legs syndrome.
  • Another object of the present invention is to provide a method for the treatment of Parkinson's disease and restless legs syndrome, which comprises administering to an individual in need thereof a therapeutically effective amount of a salt of Compound I of the present invention (eg, Compound of Formula I, bismuth) xynaphate and compound palmitate of formula I, especially compound I pamoate crystals or palmitate crystals or any combination thereof) or pharmaceutical composition.
  • a salt of Compound I of the present invention eg, Compound of Formula I, bismuth
  • compound palmitate of formula I especially compound I pamoate crystals or palmitate crystals or any combination thereof
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which is suitable for contact within the scope of sound medical judgment Human and/or other animal tissue without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • compositions of the present invention can be prepared by combining a compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable carrier.
  • compositions of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods and the like.
  • Typical routes of administration of the compounds of the present invention or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, Intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable carriers, excipients and/or vehicles well known in the art. These carriers, excipients and vehicles enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to patients Dosing.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable auxiliaries if desired, and processing the mixture into granules to obtain tablet or dragee core.
  • the pamoate and palmitate of compound I of the present invention have the advantages of high purity, good stability and the like. In addition, it has lower solubility and can be used in long-acting sustained-release formulations.
  • the pamoate and palmitate of Compound I of the present invention have prolonged T max and T 1/2 duration, and can maintain the effective blood drug concentration for a longer time, thereby confirming that they can achieve the effect of long-acting release.
  • the crystals of the present invention (such as crystal forms AS and TV) have the advantages of high purity and good stability. In addition, it has lower solubility and can be used in long-acting sustained-release formulations.
  • the crystal of the present invention has prolonged T max and T 1/2 duration, and can maintain the effective blood drug concentration for a longer time, thereby confirming that it can achieve the effect of long-term release.
  • the XRPD pattern of each crystal was collected using an X ⁇ Pert3 Powder diffractometer, which was irradiated with Cu palladium and continuously projected and scanned with Absolute scan at room temperature. The time is 50s, and the scan is performed once.
  • 40-10 °C cycle temperature rise and fall refers to the temperature at 40 °C for 1 h, then lowered to 10 °C for 1 h, and then heated to Incubate at 40°C for 1h, then cool down to 10°C for 1h, cycle (reciprocating), vibrate and suspend, and centrifuge after 24h to obtain compound I pamoate crystal A, which is detected by XRPD, and the obtained XRPD pattern is shown in Figure 1.
  • HPLC test conditions mobile phase: sodium octane sulfonate-potassium dihydrogen phosphate buffer (take 5.0 g of sodium octane sulfonate and 9.1 g of potassium dihydrogen phosphate, add 1000 ml of water to dissolve, and adjust the pH to 3.0 with phosphoric acid) - Acetonitrile (72:28); detection wavelength is 264nm; flow rate is 1.5ml per minute; column temperature is 40°C; injection volume: 10 ⁇ l; chromatographic column: octadecylsilane bonded silica gel as filler (CAPCELL PAK MG II C18, 4.6mm ⁇ 250mm, 5 ⁇ m).
  • crystals of the present invention have lower solubility relative to the free base of compound I, and can be used for long-acting sustained-release preparations.
  • the pamoate crystal D and crystal N were tested by the test method of 1-1, and the solubility test results are shown in the following table.
  • crystals of the present invention have lower solubility relative to the free base of compound I, and can be used for long-acting sustained-release preparations.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

本发明提供了如式I所示的苯并噻唑类化合物的盐及其晶体形式和用途，所述的盐选自双羟萘酸盐和棕榈酸盐，还提供了式I化合物的盐及其晶体形式在制备用于治疗帕金森病和不宁腿综合症的药物中的用途。

Description

苯并噻唑类化合物的盐及其晶体形式和用途
本申请要求2020年11月19日提交的题为“苯并噻唑类化合物的盐及其晶体形式和用途”的202011304450.1号中国申请的优先权，其内容整体援引加入本文。
技术领域
本发明涉及(S)-2-氨基-4,5,6,7-四氢-6-丙胺-苯并噻唑的盐及其晶体形式和用途。
背景技术
帕金森病(PD)是神经系统的运动系统障碍。其特征为进行性疾病，其影响运动并导致产生多巴胺的脑细胞的损失，引起手、臂、腿、颌和脸的震颤和/或四肢和躯干的强直或僵硬。主要症状包括肌肉僵硬、运动缓慢、静止震颤和姿势不稳定。
(S)-2-氨基-4,5,6,7-四氢-6-丙胺-苯并噻唑(在下文称作“化合物I”)，是德国勃林格殷格翰开发的非麦角类多巴胺受体激动剂。目前国内外上市产品主要为盐酸盐速释片和盐酸盐缓释片，用于治疗帕金森病和不宁腿综合症。
据调查发现帕金森患者多为中老年人，其中患者吞咽障碍发生率高达70-90％，使得吸入性肺炎危险性增加15-50％，吞咽障碍在疾病早期出现，伴随整个病程，极易引发呛咳，使吸入性肺炎危险性增加，而吸入性肺炎是帕金森患者死亡的主要原因之一。当前临床药物主要为口服，且1天需多次给药，单次用药量大，顺应性急需改善。此外，多巴胺血药浓度波动继发的脉冲样刺激，会进一步加剧多巴胺能受体水平和功能异常，只有持续平稳的多巴胺刺激才可控制或减少运动并发症不良反应的发生。另外，超过24小时的长期释放方案也将帮助患者依从，因为患有晚期PD的患者通常不顺从，使得难以评估患者是否已接受适当剂量的药物。
综上，临床提倡应用长效缓释制剂，如口服缓控释、长效贴剂、长效注射剂以保持稳定的血药浓度并提高患者顺应性；因而迫切需要寻求可用于长效缓释制剂的盐型及其晶体形式。
发明内容
本发明的第一方面提供(S)-2-氨基-4,5,6,7-四氢-6-丙胺-苯并噻唑(其结构式如式I所示)的盐，其中所述的盐选自双羟萘酸盐和棕榈酸盐，
Figure PCTCN2021129537-appb-000001
在一些实施方案中，式I所示化合物的盐为棕榈酸盐。
本发明的第二方面提供化合物I盐的晶体，例如化合物I双羟萘酸盐晶体A-S和棕榈酸盐晶体T-V。本发明的第三方面提供药物组合物，其包含化合物I的盐，所述的盐选自双羟萘酸盐和棕榈酸盐，特别是化合物I双羟萘酸盐晶体或棕榈酸盐晶体，以及一种或多种药学上可接受的载体。
本发明的第四方面提供化合物I的盐或其晶体，特别是化合物I双羟萘酸盐晶体A-S和棕榈酸盐晶体T-V或药物组合物，在制备用于治疗帕金森病和不宁腿综合症的药物中的用途。
本发明的化合物I的盐或其晶体具有较低的溶解度，可实现缓释效果，制备长效缓释制剂。
附图说明
图1为化合物I双羟萘酸盐晶体A的X射线粉末衍射(XRPD)图谱。
图2为化合物I双羟萘酸盐晶体B的XRPD图谱。
图3为化合物I双羟萘酸盐晶体C的XRPD图谱。
图4为化合物I双羟萘酸盐晶体D的XRPD图谱。
图5为化合物I双羟萘酸盐晶体E的XRPD图谱。
图6为化合物I双羟萘酸盐晶体F的XRPD图谱。
图7为化合物I双羟萘酸盐晶体G的XRPD图谱。
图8为化合物I双羟萘酸盐晶体H的XRPD图谱。
图9为化合物I双羟萘酸盐晶体I的XRPD图谱。
图10为化合物I双羟萘酸盐晶体J的XRPD图谱。
图11为化合物I双羟萘酸盐晶体K的XRPD图谱。
图12为化合物I双羟萘酸盐晶体L的XRPD图谱。
图13为化合物I双羟萘酸盐晶体M的XRPD图谱。
图14为化合物I双羟萘酸盐晶体N的XRPD图谱。
图15为化合物I双羟萘酸盐晶体O的XRPD图谱。
图16为化合物I双羟萘酸盐晶体P的XRPD图谱。
图17为化合物I双羟萘酸盐晶体Q的XRPD图谱。
图18为化合物I双羟萘酸盐晶体R的XRPD图谱。
图19为化合物I双羟萘酸盐晶体S的XRPD图谱。
图20为化合物I棕榈酸盐晶体T的XRPD图谱。
图21为化合物I棕榈酸盐晶体U的XRPD图谱。
图22为化合物I棕榈酸盐晶体V的XRPD图谱。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用的词语“约”是指本领域的普通技术人员认为在所述值的可接受的标准误差内，例如±0.05、±0.1、±0.2、±0.3、±1、±2或±3等。
在本文中，“化合物I”以及“式I所示的化合物”均是指结构式为如下式I的化合物，在本文中可以互换使用。
Figure PCTCN2021129537-appb-000002
术语“药物组合物”指活性成分，其可以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。所述活性成分例如化合物I或其双羟萘酸盐或棕榈酸盐，本发明的晶型中的一种或多种或者本发明的结晶组合物中的一种或多种。
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所示化合物或其双羟萘酸盐或棕榈酸盐，本发明的晶型中的一种或多种或者本发明的结晶组合物中的一种或多种。
如本文中所使用的术语“无定形”是指三维上无排序的任意固体物质。在一些情况中，无定形固体可通过已知技术表征，所述技术包括XRPD晶体学、固态核磁共振(ssNMR)波谱学、DSC或这些技术的一些组合。如以下所说明，无定形固体产生弥散的XRPD图谱，其通常包括一个或两个宽峰(即具有约5°2θ或更大的基宽的峰)。
如本文中所使用的术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。
如本文中所使用的术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。
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°。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。
如本文中所使用的术语“2θ”是指基于X射线衍射实验的实验设置的以度数表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果当入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶体形式的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。
如本文中所使用的术语“热重分析(TGA)图谱”是指由热重分析仪记录到的曲线。
如本文中所使用的术语“差示扫描量热(DSC)图谱”是指由差示扫描量热仪记录到的曲线。
如本文中所使用的术语“核磁共振( 1H-NMR)图谱”是指由核磁共振仪记录到的信号峰。
如本文中所使用的，对于X射线衍射峰位的术语“基本上相同”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1-0.2度，并且用于测量衍射的仪器也会显示一些变化。另外，本领域技术人员会理解相对峰强度会显示仪器间的变化以及由于结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素的变化，并应将其看作仅为定性测量。
如本文中所使用，术语“室温”是指20℃±5℃。
化合物I的盐及其晶体
本发明提供(S)-2-氨基-4,5,6,7-四氢-6-丙胺-苯并噻唑(化合物I)的盐，其中所述的盐选自双羟萘酸盐和棕榈酸盐，
Figure PCTCN2021129537-appb-000003
在另一些实施方案中，式化合物I的盐为式化合物I的棕榈酸盐。
在一些实施方案中，式化合物I的盐为式化合物I的双羟萘酸盐。
化合物I双羟萘酸盐及其晶体(1:1)
在一些实施方案中，化合物I双羟萘酸盐中化合物I与双羟萘酸的化学计量比为1:1。
晶体A
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体A，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约4.76±0.2°、7.07±0.2°、8.32±0.2°、10.7±0.2°、11.73±0.2°、13.29±0.2°、16.25±0.2°、18.45±0.2°、21.51±0.2°、24.81±0.2°和26.17±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体A的XRPD图谱还包括在约17.87±0.2°、22.01±0.2°、25.17±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体A的XRPD图谱包括在约4.76±0.2°、7.07±0.2°、8.32±0.2°、10.7±0.2°、11.73±0.2°、13.29±0.2°、16.25±0.2°、17.87±0.2°、18.45±0.2°、21.51±0.2°、22.01±0.2°、24.81±0.2°、25.17±0.2°和26.17±0.2°的2θ处的衍射峰。
在一些实施例方案中，化合物I双羟萘酸盐晶体A的XRPD图谱包括以下2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
4.76 100 14.25 15.85 21.17 12.59 28.65 13.31
7.07 36.26 14.95 7.49 21.51 41.57 29.22 2.76
8.32 19.16 15.48 12.07 22.01 35.79 29.62 8.06
8.99 22.47 16.25 21.60 23.45 8.29 29.81 12.33
9.17 18.79 16.41 12.08 24.56 24.26 31.03 2.93
9.39 13.46 16.74 10.79 24.81 84.08 32.41 2.05
9.96 16.5 17.32 11.47 25.17 43.31 33.95 5.98
10.7 28.43 17.87 25.74 25.61 18.72 34.89 2.63
11.05 5.50 18.45 33.05 25.81 11.58 35.57 3.76
11.73 42.62 18.69 17.24 26.17 25.73 36.11 2.85
12.17 11.42 19.13 17.14 26.46 6.62 36.80 3.25
12.68 15.05 19.64 12.37 26.88 17.87 38.31 2.08
12.91 17.42 20.23 25.98 27.37 5.07    
13.29 34.21 20.76 8.22 28.23 10.73    
在一些实施方案中，化合物I双羟萘酸盐晶体A的XRPD图谱基本上如图1所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体A的XRPD图谱如图1所示。
晶体B
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体B，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约5.79±0.2°、6.38±0.2°、10.95±0.2°、14.72±0.2°、17.61±0.2°、18.40±0.2°、19.81±0.2°和22.18±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体B的XRPD图谱还包括在约10.61±0.2°、12.51±0.2°、17.61±0.2°和20.01±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体B的XRPD图谱还包括在约10.18±0.2°、13.15±0.2°和13.36±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体B的XRPD图谱包括在约5.79±0.2°、6.38±0.2°、10.61±0.2°、10.95±0.2°、12.51±0.2°、14.72±0.2°、17.61±0.2°、18.40±0.2°、19.81±0.2°、20.01±0.2°和22.18±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体B的XRPD图谱包括在约5.79±0.2°、6.38±0.2°、10.18±0.2°、10.61±0.2°、10.95±0.2°、12.51±0.2°、13.15±0.2°、13.36±0.2°、14.72±0.2°、17.61±0.2°、18.40±0.2°、19.81±0.2°、20.01±0.2°和22.18±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体B的XRPD图谱包括如下2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.79 64.48 14.72 44.58 22.18 41.74 28.30 7.01
6.38 19.62 15.77 16.64 22.84 14.89 28.94 3.36
8.79 11.03 16.74 21.4 23.06 18.82 29.30 4.36
9.38 13.35 16.99 16.62 23.50 11.4 29.86 8.51
10.18 31.69 17.61 38.15 23.73 15.87 32.38 6.44
10.61 100 18.40 36.03 24.18 27.57 33.32 9.95
10.95 44.15 18.79 17.04 24.65 16.62 33.87 3.95
11.20 17.63 19.28 6.78 25.00 14.2 35.56 4.07
12.51 31.33 19.81 35.24 25.28 25.47 37.51 2.35
13.15 31.17 20.01 32.01 26.19 19.26    
13.36 76.04 20.46 6.51 26.46 20.68    
14.44 26.62 21.33 21.41 27.15 6.05    
在一些实施方案中，化合物I双羟萘酸盐晶体B的XRPD图谱基本上如图2所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体B的XRPD图谱如图2所示。
晶体C
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体C，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约7.43±0.2°、11.18±0.2°、11.98±0.2°、14.78±0.2°、20.20±0.2°、20.97±0.2°和23.30±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体C的XRPD图谱还包括在约16.90±0.2°、19.73±0.2°、22.12±0.2°和25.37±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体C的XRPD图谱还包括在约19.34±0.2°和22.91±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体C的XRPD图谱包括在约7.43±0.2°、11.18±0.2°、11.98±0.2°、14.78±0.2°、16.90±0.2°、19.73±0.2°、20.20±0.2°、20.97±0.2°、22.12±0.2°、23.31±0.2°和25.37±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体C的XRPD图谱包括在约7.43±0.2°、11.18±0.2°、11.98±0.2°、14.78±0.2°、16.90±0.2°、19.34±0.2°、19.73±0.2°、20.20±0.2°、20.97±0.2°、22.12±0.2°、22.91±0.2°、23.31±0.2°和25.37±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体C的XRPD图谱包括如下2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
6.14 10.41 16.13 6.61 22.12 22.49 29.85 17.75
7.43 17.62 16.61 24.64 22.91 40.27 30.52 13.05
10.11 2.94 16.90 34.42 23.31 54.64 31.56 12.89
10.54 4.96 17.14 15.7 23.52 18.37 32.16 8.14
11.18 53.18 17.56 3.03 24.19 11.85 33.11 4.14
11.45 15.47 17.83 21.03 24.46 9.23 34.26 7.77
11.67 22.17 18.41 13.59 24.94 18.48 34.73 11.38
11.98 74.3 18.72 21.32 25.37 27.48 35.59 10.85
13.37 11.72 19.34 51.54 26.29 10.45 36.79 8.54
13.68 27.29 19.73 39.88 26.67 9.81 38.04 5.01
14.78 100 20.20 76.83 27.46 9.36 39.28 2.41
15.09 26.67 20.68 13.81 28.24 12.56    
15.56 19.79 20.97 76.23 28.95 4.45    
在一些实施方案中，化合物I双羟萘酸盐晶体C的XRPD图谱基本上如图3所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体C的XRPD图谱如图3所示。
晶体D
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体D，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约11.24±0.2°、11.88±0.2°、12.03±0.2°、13.57±0.2°、14.76±0.2°、15.17±0.2°、20.85±0.2°、21.15±0.2°和23.26±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体D的XRPD图谱还包括在约15.17±0.2°、16.92±0.2°和24.24±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体D的XRPD图谱还包括在约19.3709±0.2°和20.2490±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体D的XRPD图谱包括在约11.24±0.2°、11.88±0.2°、12.03±0.2°、13.57±0.2°、14.76±0.2°、15.17±0.2°、16.92±0.2°、20.85±0.2°、21.15±0.2°、23.26±0.2°和24.24±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体D的XRPD图谱包括在约11.24±0.2°、11.88±0.2°、12.03±0.2°、13.57±0.2°、14.76±0.2°、15.17±0.2°、16.92±0.2°、19.37±0.2°、20.85±0.2°、21.15±0.2°、23.26±0.2°、24.24±0.2°和20.25±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体D的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
7.33 17.63 17.87 27.79 23.91 17.2 31.31 9.52
7.54 15.65 18.21 14.28 24.24 32.97 32.31 7.18
11.24 61.09 18.90 14.2 24.85 20.41 33.25 5.85
11.88 44.05 19.37 34.69 25.34 10.18 34.33 20.54
12.03 70.78 19.80 28.85 25.66 18.12 35.52 8.07
13.57 43.29 20.25 73.87 26.39 7.83 36.11 4.81
14.76 100 20.85 40.65 27.16 17.11 36.81 9.4
15.17 48.71 21.15 50.06 28.19 11.55 37.34 2.71
15.69 14.69 22.25 31.28 29.07 6.96 38.51 4.7
16.51 20 22.68 18.04 29.53 18.19    
16.92 38.43 22.91 24.52 29.93 7.52    
17.39 14.84 23.26 47.86 30.84 7.97    
在一些实施方案中，化合物I双羟萘酸盐晶体D的XRPD图谱基本上如图4所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体D的XRPD图谱如图4所示。
晶体E
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体E，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约7.32±0.2°、11.26±0.2°、12.04±0.2°、14.77±0.2°、15.24±0.2°、16.95±0.2°、20.28±0.2°、21.26±0.2°、和23.27±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体E的XRPD图谱还包括在约19.37±0.2°和19.83±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体E的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
7.32 11.94 17.49 11.08 23.27 55.73 29.95 7.55
7.58 11.53 17.93 18.75 23.95 22.75 31.26 7.97
11.26 87.17 18.19 11.48 24.27 28.78 31.65 4.64
12.04 84.85 19.36 29.35 24.85 13.82 32.34 9.85
13.60 25.62 19.83 32.4 25.38 10.39 33.21 7.11
14.77 80.63 20.28 100 25.85 8.62 34.33 15.66
15.24 31.61 20.87 23.47 27.19 14.51 35.50 8.11
15.72 15.9 21.26 31.12 28.22 12.01 36.79 10.12
16.55 16.49 22.26 33.82 29.07 7.97    
16.95 31.68 22.89 14.51 29.55 11.1    
在一些实施方案中，化合物I双羟萘酸盐晶体E的XRPD图谱基本上如图5所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体E的XRPD图谱如图5所示。
晶体F
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体F，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约11.19±0.2°、12.10±0.2°、14.67±0.2°、15.48±0.2°、18.11±0.2°、20.25±0.2°和23.33±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体F的XRPD图谱还包括在约11.92±0.2°、14.67±0.2°、16.71±0.2°和25.84±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体F的XRPD图谱还包括在约19.19±0.2°和21.23±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体F的XRPD图谱包括在约11.19±0.2°、11.92±0.2°、12.10±0.2°、14.67±0.2°、15.48±0.2°、16.71±0.2°、18.11±0.2°、20.25±0.2°、23.33±0.2°和25.84±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体F的XRPD图谱包括在约11.19±0.2°、11.92±0.2°、12.10±0.2°、14.67±0.2°、15.48±0.2°、16.71±0.2°、18.11±0.2°、19.19±0.2°、20.25±0.2°、21.23±0.2°、23.33±0.2°和25.84±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体F的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
6.17 30.22 17.44 26.4 23.33 69.75 31.07 30.5
7.35 23.57 18.11 64.47 24.02 32.91 31.58 9.24
11.19 72.48 18.75 6.32 24.35 23.03 32.44 4.34
11.92 85.65 19.19 57.73 24.67 10.23 33.04 8.18
12.10 79.72 19.78 42.76 25.24 21 34.24 12.08
13.78 46.64 20.25 69.24 25.84 33.43 35.29 7.02
14.67 80.22 21.23 61.03 26.95 25.88 35.67 5.37
14.84 46.68 21.39 46.85 28.29 8.74 36.59 10.53
15.48 100 22.28 18.46 29.57 8.79 38.20 5.21
16.71 79.17 22.91 24.46 29.81 16.98 38.98 2.98
在一些实施方案中，化合物I双羟萘酸盐晶体F的XRPD图谱基本上如图6所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体F的XRPD图谱如图6所示。
晶体G
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体G，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约6.13±0.2°、11.24±0.2°、11.86±0.2°、13.15±0.2°、14.79±0.2°、20.27±0.2°和23.13±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体G的XRPD图谱还包括在约11.24±0.2°、14.54±0.2°、19.90±0.2°、20.09±0.2°、22.21±0.2°、23.96±0.2°和24.76±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体G的XRPD图谱还包括在约16.88±0.2°、19.35±0.2°和20.46±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体G的XRPD图谱包括在约6.13±0.2°、11.24±0.2°、11.86±0.2°、13.15±0.2°、14.54±0.2°、14.79±0.2°、19.90±0.2°、20.09±0.2°、20.27±0.2°、22.21±0.2°、23.13±0.2°、23.96±0.2°和24.76±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体G的XRPD图谱包括在约6.13±0.2°、11.24±0.2°、11.86±0.2°、13.15±0.2°、14.54±0.2°、14.79±0.2°、16.88±0.2°、19.35±0.2°、19.90±0.2°、20.09±0.2°、20.27±0.2°、20.46±0.2°、22.21±0.2°、23.13±0.2°、23.96±0.2°和24.76±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体G的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
6.13 12.63 16.88 44.18 23.13 65.96 29.90 16.93
7.19 16.58 17.35 28.19 23.96 53.32 31.18 4.98
11.24 55.6 18.13 14.33 24.76 42.38 31.57 6.99
11.86 97.1 19.35 40.06 25.27 20.94 32.21 6.65
12.35 7.2 19.90 33.15 26.33 14.68 32.83 6.04
13.15 39.8 20.09 33.8 26.65 7.43 33.41 5.3
14.54 57.44 20.27 100 27.15 14.2 34.22 15.41
14.79 59.37 20.46 76.23 27.74 28.07 35.20 5.44
15.57 13.54 22.21 84.09 28.28 12.12 36.87 4.51
16.20 21.8 22.88 18.86 29.04 19.09 38.46 5.16
在一些实施方案中，化合物I双羟萘酸盐晶体G的XRPD图谱基本上如图7所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体G的XRPD图谱如图7所示。
晶体H
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体H，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约7.08±0.2°、11.92±0.2°、13.03±0.2°、14.71±0.2°、16.90±0.2°、20.85±0.2°、21.96±0.2°、23.04±0.2°和23.56±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体H的XRPD图谱还包括在约11.76±0.2°、13.03±0.2°、20.27±0.2°和26.66±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体H的XRPD图谱还包括在约11.30±0.2°、14.71±0.2°和19.97±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体H的XRPD图谱包括在约7.08±0.2°、11.76±0.2°、11.92±0.2°、13.03±0.2°、14.71±0.2°、16.90±0.2°、20.27±0.2°、20.85±0.2°、21.96±0.2°、23.04±0.2°、23.56±0.2°和26.66±0.2°的2θ处的衍射峰。在一些实施方案中，化合物I双羟萘酸盐晶体H的XRPD 图谱包括在约7.08±0.2°、11.76±0.2°、11.30±0.2°、11.92±0.2°、13.03±0.2°、14.71±0.2°、16.90±0.2°、19.97±0.2°、20.27±0.2°、20.85±0.2°、21.96±0.2°、23.04±0.2°、23.56±0.2°和26.66±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体H的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
6.26 8.71 17.14 17.24 22.30 22.48 28.03 6.75
7.08 25.59 17.46 15.68 23.04 40.88 28.53 28.75
7.34 2.15 17.87 10.99 23.56 41.52 28.85 6.51
11.30 28.73 18.56 9.59 23.79 20.91 29.29 8.73
11.76 24.55 19.03 11.32 24.06 30.13 29.91 9.57
11.92 78.74 19.39 16.92 24.68 11.47 30.42 5.51
12.62 8.51 19.97 30.49 25.43 39.08 30.79 13.77
13.03 33.14 20.27 60.84 25.82 15.27 31.44 7.51
14.29 16.25 20.85 66.48 26.16 5.19 32.01 3.9
14.71 100 21.27 8.57 26.66 32.98 32.26 5.09
16.11 30.48 21.96 54.69 27.25 13.71 33.50 15.44
16.90 47.33 22.17 28.39 27.69 24.91    
在一些实施方案中，化合物I双羟萘酸盐晶体H的XRPD图谱基本上如图8所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体H的XRPD图谱如图8所示。
晶体I
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体I，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约5.59±0.2°、5.98±0.2°、9.39±0.2°、20.39±0.2°、25.27±0.2°、和26.01±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体I的XRPD图谱还包括在约7.62±0.2°、8.22±0.2°、11.59±0.2°、18.09±0.2°和22.59±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体I的XRPD图谱还包括在约7.80±0.2°、9.88±0.2°和23.40±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体I的XRPD图谱包括在约5.59±0.2°、5.98±0.2°、7.62±0.2°、8.22±0.2°、9.39±0.2°、11.59±0.2°、18.09±0.2°、20.39±0.2°、22.59±0.2°、25.27±0.2°、和26.01±0.2°的2θ处的衍射峰。在另一个实施方案中，化合物I双羟萘酸盐晶体I的XRPD图谱包括在约5.59±0.2°、5.98±0.2°、7.62±0.2°、7.80±0.2°、8.22±0.2°、9.39±0.2°、9.88±0.2°、11.59±0.2°、18.09±0.2°、20.39±0.2°、22.59±0.2°、23.40±0.2°、25.27±0.2°、和26.01±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体I的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.59 59.67 12.52 17.9 19.91 21.88 26.01 49.2
5.98 39.04 12.84 10.94 20.39 33.49 26.46 17.61
7.62 28.24 13.32 7.36 20.95 3.15 26.67 11.1
7.80 31.25 14.44 12.69 22.02 13.49 29.56 8.3
8.22 34.39 15.67 16.3 22.59 25.91 31.16 7.15
9.39 72.02 16.06 13.57 22.88 18.16 32.57 2.63
9.88 32.2 16.67 23.35 23.40 37.95 34.32 2.95
11.13 18.93 17.48 23.57 24.06 7.39 36.36 2.55
11.59 30.15 18.09 42.54 24.73 12.19 38.68 2.28
12.10 12.8 19.01 17.3 25.27 100    
在一些实施方案中，化合物I双羟萘酸盐晶体I的XRPD图谱基本上如图9所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体H的XRPD图谱如图9所示。
晶体J
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体J，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约5.33±0.2°、7.13±0.2°、10.90±0.2°、14.57±0.2°、16.62±0.2°、19.80±0.2°和25.29±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体J的XRPD图谱还包括在约14.99±0.2°、19.01±0.2°和20.74±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体J的XRPD图谱还包括在约19.32±0.2°和22.24±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体J的XRPD图谱包括在约5.33±0.2°、7.13±0.2°、10.90±0.2°、14.57±0.2°、14.99±0.2°、16.62±0.2°、19.01±0.2°、19.80±0.2°、20.74±0.2°和25.29±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体J的XRPD图谱包括在约5.33±0.2°、7.13±0.2°、10.90±0.2°、14.57±0.2°、14.99±0.2°、16.62±0.2°、19.01±0.2°、19.32±0.2°、19.80±0.2°、20.74±0.2°、22.24±0.2°和25.29±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体J的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.33 79.42 17.24 18.39 22.24 33.93 29.39 5.67
7.13 14.19 18.20 7.4 22.99 22.42 30.81 6.71
8.18 5.21 18.62 14.39 23.15 22.54 31.59 2.04
10.90 81.48 19.01 46.44 23.69 14.78 32.05 7.35
12.90 6.35 19.32 84.3 25.29 25.25 33.31 6.64
14.57 73.96 19.80 100 26.17 4.77 33.94 4
14.99 50.46 20.22 53.7 26.65 7.43 34.66 7.94
16.07 11.52 20.74 73.06 27.50 7.93 36.61 1.99
16.62 42.67 21.65 15.04 28.99 5.49 38.98 3.87
在一些实施方案中，化合物I双羟萘酸盐晶体J的XRPD图谱基本上如图10所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体J的XRPD图谱如图10所示。
晶体K
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体K，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约5.57±0.2°、5.97±0.2°、7.73±0.2°、11.55±0.2°、18.01±0.2°和18.90±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体K的XRPD图谱还包括在约 9.34±0.2°、19.79±0.2°和25.84±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体K的XRPD图谱还包括在约23.25±0.2°和25.10±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体K的XRPD图谱包括在约5.57±0.2°、5.97±0.2°、7.73±0.2°、9.34±0.2°、11.55±0.2°、18.01±0.2°、18.90±0.2°、19.79±0.2°和25.84±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体K的XRPD图谱包括在约5.57±0.2°、5.97±0.2°、7.73±0.2°、9.34±0.2°、11.55±0.2°、18.01±0.2°、18.90±0.2°、19.79±0.2°、23.25±0.2°、25.10±0.2°和25.84±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体K的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.57 65.79 12.04 13.16 18.01 43.29 24.54 14.57
5.97 34.85 12.46 7.79 18.90 16.71 25.10 100
7.73 37.12 13.30 11.44 19.79 25.34 25.84 36.13
8.20 35.58 14.39 11.32 20.04 17.51 26.29 8.26
9.34 82.2 15.63 16.75 20.28 33.4 26.53 11.06
9.83 31.67 15.99 23.11 22.44 17.16 26.61 3.5
11.09 19.52 16.56 14.28 22.70 13.28 36.92 3.51
11.55 40.48 17.38 22.61 23.25 30.25    
在一些实施方案中，化合物I双羟萘酸盐晶体K的XRPD图谱基本上如图11所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体K的XRPD图谱如图11所示。
晶体L
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体L，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约6.20±0.2°、8.13±0.2°、9.92±0.2°、10.85±0.2°、12.81±0.2°和21.82±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体L的XRPD图谱还包括在约15.29±0.2°和25.86±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体L的XRPD图谱还包括在约19.29±0.2°和25.63±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体L的XRPD图谱包括在约6.20±0.2°、8.13±0.2°、9.92±0.2°、10.85±0.2°、12.81±0.2°、15.29±0.2°、21.82±0.2°和25.86±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体L的XRPD图谱包括在约6.20±0.2°、8.13±0.2°、9.92±0.2°、10.85±0.2°、12.81±0.2°、15.29±0.2°、19.29±0.2°、21.82±0.2°、25.63±0.2°和25.86±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体L的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
6.20 100 15.72 6.9 21.82 11.99 29.67 1.61
8.13 31.49 16.38 16.19 22.52 9.65 30.52 2.08
9.64 14.78 17.19 4.7 22.85 5.94 32.00 1.99
9.92 27.65 17.47 7.79 24.41 3.09 32.93 1.73
10.85 17.17 17.98 6.6 24.75 6.97 33.81 2.48
11.25 4.9 18.54 18.95 25.01 6.55 35.57 0.94
12.81 16.89 18.86 13.68 25.63 12.28 36.90 0.94
13.32 11.24 19.29 23.83 25.86 21.17 38.12 1.73
13.53 7.43 19.93 12.28 26.43 2.16 39.43 1.29
15.01 7.89 20.93 4.98 27.64 15.96    
15.29 14.61 21.28 21.64 28.45 2.95    
在一些实施方案中，化合物I双羟萘酸盐晶体L的XRPD图谱基本上如图12所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体L的XRPD图谱如图12所示。
晶体M
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体M，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约6.31±0.2°、11.55±0.2°、14.49±0.2°、15.94±0.2°、19.58±0.2°和23.50±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体M的XRPD图谱还包括在约19.27±0.2°、20.28±0.2°和25.88±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体M的XRPD图谱还包括在约22.27±0.2°和24.88±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体M的XRPD图谱包括在约6.31±0.2°、11.55±0.2°、14.49±0.2°、15.94±0.2°、19.58±0.2°、19.27±0.2°、20.28±0.2°、23.50±0.2°和25.88±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体M的XRPD图谱包括在约6.31±0.2°、11.55±0.2°、14.49±0.2°、15.94±0.2°、19.58±0.2°、19.27±0.2°、20.28±0.2°、22.27±0.2°、23.50±0.2°、24.88±0.2°和25.88±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体M的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
6.31 21.24 18.48 1.82 24.50 5.83 30.89 4.28
11.14 10.1 19.27 62.08 24.88 13.61 31.23 5.24
11.55 37.28 19.58 48.53 25.26 5.66 31.89 3.41
12.55 11.35 20.28 56.15 25.49 6.92 33.71 10.06
12.91 7.03 21.39 2.46 25.88 11.39 33.95 11.64
13.91 2.64 21.77 7.43 27.48 6.78 34.54 1.68
14.49 100 22.27 29.88 28.11 0.48 35.27 3.61
14.74 7.63 22.74 3.33 29.31 4.42 37.35 2.44
15.94 38.13 23.26 14.69 29.66 4.51 38.58 0.87
16.68 14.75 23.50 10.26 29.99 5.13 39.08 2.58
17.02 2.56 24.26 16.36 30.62 4.07 24.50 5.83
在一些实施方案中，化合物I双羟萘酸盐晶体M的XRPD图谱基本上如图13所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体M的XRPD图谱如图13所示。
化合物I双羟萘酸盐及其晶体(2:1)
在一些实施方案中，化合物I双羟萘酸盐中化合物I与双羟萘酸的化学计量比为2:1。
晶体N
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体N，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.87±0.2°、6.42±0.2°、10.11±0.2°、12.58±0.2°、13.38±0.2°、16.12±0.2°和17.86±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体N的XRPD图谱还包括在约10.55±0.2°、14.74±0.2°、24.90±0.2°和26.45±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体N的XRPD图谱还包括在约10.87±0.2°、23.55±0.2°和24.29±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体N的XRPD图谱包括在约5.87±0.2°、6.42±0.2°、10.11±0.2°、10.55±0.2°、12.58±0.2°、13.38±0.2°、14.74±0.2°、16.12±0.2°、17.86±0.2°、24.90±0.2°和26.45±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体N的XRPD图谱包括在约5.87±0.2°、6.42±0.2°、10.11±0.2°、10.55±0.2°、10.87±0.2°、12.58±0.2°、13.38±0.2°、14.74±0.2°、16.12±0.2°、17.86±0.2°、23.55±0.2°、24.29±0.2°、24.90±0.2°和26.45±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体N的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.87 50.69 14.74 75.86 21.47 16.32 26.11 7.31
6.42 20.09 15.62 18.67 22.22 37.25 26.45 12.56
9.01 8.73 16.12 37.95 22.62 24.95 26.94 6.63
10.11 29.52 16.89 14.69 22.84 20.56 27.35 10.52
10.55 60.03 17.16 19.02 23.01 17.03 28.04 3.34
10.87 46.88 17.86 33.61 23.55 15.02 28.80 11.74
11.23 15.05 18.43 52.59 24.00 6.47 29.54 2.18
11.84 11.28 19.04 10.16 24.29 20.66 30.01 5.7
12.58 32.03 19.59 19.52 24.90 20.21 30.50 4.29
13.00 7.95 19.87 16.22 25.13 18.31 31.68 5.48
13.38 100 20.31 19.93 25.40 15.34 32.17 2.79
14.27 11.17 20.97 8.99 25.56 11.56    
在一些实施方案中，化合物I双羟萘酸盐晶体N的XRPD图谱基本上如图14所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体N的XRPD图谱如图14所示。
晶体O
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体O，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约11.33±0.2°、11.92±0.2°、14.71±0.2°、16.11±0.2°、17.50±0.2°和20.86±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体O的XRPD图谱还包括在约20.27±0.2°、23.04±0.2°、23.57±0.2°和27.70±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体O的XRPD图谱还包括在约19.96±0.2°、24.05±0.2°、25.43±0.2°和26.66±0.2°的2θ处的衍射峰。在一些实施方案中，化合物I双羟萘酸盐晶体O的XRPD图谱包括在约11.33±0.2°、 11.92±0.2°、14.71±0.2°、16.11±0.2°、17.50±0.2°、20.27±0.2°、20.86±0.2°、23.04±0.2°、23.57±0.2°和27.70±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体O的XRPD图谱包括在约11.33±0.2°、11.92±0.2°、14.71±0.2°、16.11±0.2°、17.50±0.2°、19.96±0.2°、20.27±0.2°、20.86±0.2°、23.04±0.2°、23.57±0.2°、24.05±0.2°、25.43±0.2°、26.66±0.2°和27.70±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体O的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
11.33 29.18 17.50 21.39 23.57 31.96 31.15 3.9
11.92 100 19.96 36.09 24.05 26.35 35.14 11.82
13.06 18.27 20.27 77.96 25.43 35.48 37.09 6.37
14.71 88.59 20.86 90.51 26.66 25.49    
16.11 46.85 22.11 33.19 27.70 19.6    
16.89 18.47 23.04 44.04 30.27 2.71    
在一些实施方案中，化合物I双羟萘酸盐晶体O的XRPD图谱基本上如图15所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体O的XRPD图谱如图15所示。
晶体P
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体P，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.79±0.2°、6.36±0.2°、10.58±0.2°、10.90±0.2°、13.32±0.2°、14.69±0.2°、17.61±0.2°和25.26±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体P的XRPD图谱还包括在约10.58±0.2°、22.20±0.2°、22.80±0.2°和23.47±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体P的XRPD图谱还包括在约23.76±0.2°和24.08±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体P的XRPD图谱包括在约5.79±0.2°、6.36±0.2°、10.58±0.2°、10.90±0.2°、13.32±0.2°、14.69±0.2°、17.61±0.2°、22.20±0.2°、22.80±0.2°、23.47±0.2°和25.26±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体P的XRPD图谱包括在约5.79±0.2°、6.36±0.2°、10.58±0.2°、10.90±0.2°、13.32±0.2°、14.69±0.2°、17.61±0.2°、22.20±0.2°、22.80±0.2°、23.47±0.2°、23.76±0.2°、24.08±0.2°和25.26±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体P的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.79 57.05 16.72 29.29 22.20 67.88 29.35 3.9
6.36 19.21 16.97 21.7 22.80 22.45 29.99 5.89
8.81 9.5 17.38 5.71 22.99 22.64 30.27 3.94
10.15 33.3 17.61 47.83 23.47 18.42 30.98 3.82
10.58 100 18.33 56.34 23.76 21.59 31.67 4.42
10.90 41.33 18.71 20.03 24.08 32.62 32.36 8.72
11.17 19.56 18.93 16.22 24.51 9 33.35 12.85
11.70 5.26 19.50 19.06 24.70 12.85 33.89 2.14
12.50 35.98 19.77 28.99 24.94 13.61 35.31 5.04
13.19 40.76 19.89 42.23 25.26 32.75 35.62 3.72
13.32 89.16 20.03 42.73 26.37 24.71 36.03 4.64
14.44 29.3 20.34 15.28 27.13 9.44 36.47 3.34
14.69 55.55 20.48 11.04 27.60 3.09 37.50 3.5
15.61 15.55 21.28 37.18 28.31 15.42 39.37 1.45
15.90 18.97 21.94 17.28 28.79 6.66    
在一些实施方案中，化合物I双羟萘酸盐晶体P的XRPD图谱基本上如图16所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体P的XRPD图谱如图16所示。
晶体Q
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体Q，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.75±0.2°、6.20±0.2°、10.46±0.2°、14.54±0.2°、15.26±0.2°和20.78±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体Q的XRPD图谱还包括在约16.16±0.2°、17.51±0.2°和24.37±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体Q的XRPD图谱还包括在约17.98±0.2°、21.74±0.2°和23.58±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体Q的XRPD图谱包括在约5.75±0.2°、6.20±0.2°、10.46±0.2°、14.54±0.2°、15.26±0.2°、16.16±0.2°、17.51±0.2°、20.78±0.2°和24.37±0.2°的2θ处的衍射峰。在另一些优选的实施方案中，化合物I双羟萘酸盐晶体Q的XRPD图谱包括在约5.75±0.2°、6.20±0.2°、10.46±0.2°、14.54±0.2°、15.26±0.2°、16.16±0.2°、17.51±0.2°、17.98±0.2°、20.78±0.2°、21.74±0.2°、23.58±0.2°和24.37±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体Q的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.75 52.33 13.97 8.13 20.27 12.22 27.32 5.21
6.20 11.39 14.54 100 20.78 20.93 28.16 8.34
9.01 9.55 15.26 22.97 21.36 38.07 28.86 8.63
10.10 41.7 16.16 32.13 21.74 23.23 29.39 6.63
10.46 35.54 16.92 27.26 22.23 38.68 30.25 7.26
10.70 39.6 17.51 18.44 22.69 25.38 31.62 3.25
10.89 27.15 17.98 44.48 23.58 45.14 33.15 9.86
11.62 14.35 18.51 24.34 24.37 26.69 33.97 5.37
12.57 35.96 18.99 23.67 25.01 7.82 34.62 5.62
13.17 79.31 19.61 34.85 25.41 7.63 35.65 9.97
13.55 16.8 19.77 29.48 26.21 6.45 37.28 4.73
在一些实施方案中，化合物I双羟萘酸盐晶体Q的XRPD图谱基本上如图17所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体Q的XRPD图谱如图17所示。
晶体R
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体R，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.97±0.2°、11.45±0.2°、12.06±0.2°、13.41±0.2°、17.75±0.2°和18.77±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体R的XRPD图谱还包括在约19.42±0.2°、21.64±0.2°、23.89±0.2°、27.10±0.2°和28.76±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体R的XRPD图谱还包括在约21.64±0.2°、23.09±0.2°和26.18±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体R的XRPD图谱包括在约5.97±0.2°、11.45±0.2°、12.06±0.2°、13.41±0.2°、17.75±0.2°、18.77±0.2°、19.42±0.2°、21.64±0.2°、23.89±0.2°、27.10±0.2°和28.76±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体R的XRPD图谱包括在约5.97±0.2°、11.45±0.2°、12.06±0.2°、13.41±0.2°、17.75±0.2°、18.77±0.2°、19.42±0.2°、21.64±0.2°、23.09±0.2°、23.89±0.2°、26.18±0.2°、27.10±0.2°和28.76±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体R的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.97 53.51 19.11 16.93 26.18 10.23 32.16 7.67
10.90 39.56 19.42 20.99 26.66 6.3 32.74 2.1
11.45 44.85 20.36 16.55 27.10 15.42 33.12 2.07
12.06 10.04 21.19 41.66 27.67 8.06 34.30 10.26
12.31 22.51 21.64 48.3 28.39 1.7 35.41 4.58
13.41 39.96 21.98 8.55 28.76 10.66 35.79 5.09
14.72 34.38 22.32 33.93 29.33 6.53 36.69 4.75
16.18 14.59 23.09 73.04 29.87 4.11 36.87 3.48
17.05 2.88 23.49 21 30.51 10.55 37.97 7.65
17.75 100 23.89 55.03 30.85 2.08 39.63 1.37
18.77 55.22 24.80 15.13 31.28 11.28    
在一些实施方案中，化合物I双羟萘酸盐晶体R的XRPD图谱基本上如图18所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体R的XRPD图谱如图18所示。
晶体S
在一些实施方案中，本发明提供化合物I双羟萘酸盐晶体S，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.84±0.2°、6.34±0.2°、10.06±0.2°、11.14±0.2°、13.25±0.2°、14.65±0.2°、18.26±0.2°和25.25±0.2°的2θ处的衍射峰。优选地，化合物I双羟萘酸盐晶体S的XRPD图谱还包括在约19.33±0.2°、21.53±0.2°、22.68±0.2°和24.06±0.2°的2θ处的衍射峰。更优选地，化合物I双羟萘酸盐晶体S的XRPD图谱还包括在约20.20±0.2°、22.09±0.2°和24.06±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体S的XRPD图谱包括在约5.84±0.2°、6.34±0.2°、10.06±0.2°、11.14±0.2°、13.25±0.2°、14.65±0.2°、18.26±0.2°、19.33±0.2°、21.53±0.2°、22.68±0.2°、24.06±0.2°和25.25±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I双羟萘酸盐晶体S的XRPD图谱包括在约5.84±0.2°、6.34±0.2°、10.06±0.2°、11.14±0.2°、13.25±0.2°、14.65±0.2°、 18.26±0.2°、19.33±0.2°、20.20±0.2°、21.53±0.2°、22.09±0.2°、22.68±0.2°、24.06±0.2°和25.25±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I双羟萘酸盐晶体S的XRPD图谱包括如下的2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.84 40.37 14.65 100 21.11 21.74 27.80 7.58
6.34 13.66 15.47 24.51 21.53 33.74 28.60 12.51
10.06 38.13 16.14 34.05 22.09 45.98 30.16 6.99
10.44 56.63 17.06 18.77 22.68 46.47 31.76 3.59
10.73 42.12 17.84 24.89 23.48 17.16 33.28 5.8
11.14 31.27 18.26 63.88 24.06 24.52 34.03 5.91
11.79 11.98 18.85 11.15 24.60 22.74 34.87 6.41
12.55 34.85 19.33 20.1 25.25 21.3 35.60 4.62
13.25 93.16 19.66 31.74 26.24 16.84 37.34 3.84
13.57 16.21 20.20 40.65 26.78 13.11    
14.11 14.28 20.49 16.8 27.37 13.17    
在一些实施方案中，化合物I双羟萘酸盐晶体S的XRPD图谱基本上如图19所示。在一些优选的实施方案中，化合物I双羟萘酸盐晶体S的XRPD图谱如图19所示。
化合物I棕榈酸盐及其晶体(1:1)
在一些实施方案中，化合物I棕榈酸盐中化合物I与棕榈酸的化学计量比为1:1。
晶体T
在一些实施方案中，本发明提供化合物I棕榈酸盐晶体T，其中化合物I与棕榈酸的化学计量比为1:1，其XRPD图谱包括在约6.17±0.2°、9.73±0.2°、10.20±0.2°、11.52±0.2°、12.44±0.2°、15.16±0.2°和21.40±0.2°的2θ处的衍射峰。优选地，化合物I棕榈酸盐晶体T的XRPD图谱还包括在约13.82±0.2°、16.36±0.2°和16.65±0.2°的2θ处的衍射峰。更优选地，化合物I棕榈酸盐晶体T的XRPD图谱还包括在约16.89±0.2°、19.88±0.2°和20.18±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I棕榈酸盐晶体T的XRPD图谱包括在约6.17±0.2°、9.73±0.2°、10.20±0.2°、11.52±0.2°、12.44±0.2°、13.82±0.2°、15.16±0.2°、16.36±0.2°、16.65±0.2°和21.40±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I棕榈酸盐晶体T的XRPD图谱包括在约6.17±0.2°、9.73±0.2°、10.20±0.2°、11.52±0.2°、12.44±0.2°、13.82±0.2°、15.16±0.2°、16.36±0.2°、16.65±0.2°、16.89±0.2°、19.88±0.2°、20.18±0.2°和21.40±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I棕榈酸盐晶体T的XRPD图谱包括如下2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
6.17 100 16.65 12 22.88 7.68 28.37 1.3
7.49 0.69 16.89 11.65 23.25 3.61 28.72 4.32
9.73 7.35 17.91 1.69 23.67 0.7 29.71 1.11
10.20 9.57 18.74 5.62 24.09 2.75 30.21 0.42
11.52 5.48 19.29 4.53 24.30 2.13 30.64 1.48
12.44 11.53 19.59 5.81 24.79 2.39 31.25 1.81
13.15 2.62 19.88 57.7 25.34 2.78 31.64 2.25
13.82 12.67 20.18 36.92 25.83 4.84 32.01 1.19
14.19 6.2 20.57 6.92 26.29 4.1 32.34 1.61
14.54 1.46 21.40 98.19 26.64 3.26 33.11 0.84
15.16 24.44 21.85 2.31 27.11 1.67 33.53 0.96
16.36 10.22 22.29 1.25 28.01 0.87    
在一些实施方案中，化合物I棕榈酸盐晶体T的XRPD图谱基本上如图20所示。在一些优选的实施方案中，化合物I棕榈酸盐晶体T的XRPD图谱如图20所示。
晶体U
在一些实施方案中，本发明提供化合物I棕榈酸盐晶体U，其中化合物I与棕榈酸的化学计量比为1:1，其XRPD图谱包括在约5.95±0.2°、15.15±0.2°、17.90±0.2°、20.57±0.2°、21.44±0.2°、21.83±0.2°和25.82±0.2°的2θ处的衍射峰。优选地，化合物I棕榈酸盐晶体U的XRPD图谱还包括在约10.81±0.2°、14.47±0.2°、18.20±0.2°、22.63±0.2°和26.63±0.2°的2θ处的衍射峰。更优选地，化合物I棕榈酸盐晶体U的XRPD图谱还包括在约11.27±0.2°和26.03±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I棕榈酸盐晶体U的XRPD图谱包括在约5.95±0.2°、10.81±0.2°、14.47±0.2°、15.15±0.2°、17.90±0.2°、18.20±0.2°、20.57±0.2°、21.44±0.2°、21.83±0.2°、22.63±0.2°、25.82±0.2°和26.63±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I棕榈酸盐晶体U的XRPD图谱包括在约5.95±0.2°、10.81±0.2°、11.27±0.2°、14.47±0.2°、15.15±0.2°、17.90±0.2°、18.20±0.2°、20.57±0.2°、21.44±0.2°、21.83±0.2°、22.63±0.2°、25.82±0.2°、26.03±0.2°和26.63±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I棕榈酸盐晶体U的XRPD图谱包括如下2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
4.86 0.85 16.39 5.45 20.25 6.64 24.83 0.31
5.95 14.7 17.90 21.16 20.57 24.68 25.32 0.89
7.33 1.93 18.20 9.45 21.44 100 25.82 13.02
10.81 3.42 18.34 4.48 21.83 31.75 26.03 14.48
11.27 2.28 18.59 5.16 22.24 2.74 26.46 3.12
13.31 0.54 18.98 3.2 22.63 5.71 26.63 4.05
14.02 0.67 19.26 1.54 22.78 5.69 27.01 1.43
14.47 2.86 19.51 1.96 23.24 5.44 27.53 1.17
15.15 10.28 19.89 2.45 23.68 1.78 28.85 0.66
15.43 1.02 20.02 3.29 24.00 9.24 29.09 0.94
在一些实施方案中，化合物I棕榈酸盐晶体U的XRPD图谱基本上如图21所示。在一些优选的实施方案中，化合物I棕榈酸盐晶体U的XRPD图谱如图21所示。
晶体V
在一些实施方案中，本发明提供化合物I棕榈酸盐晶体V，其中化合物I与棕榈酸的化学计量比为1:1，其XRPD图谱包括在约5.56±0.2°、12.99±0.2°、13.21±0.2°、13.59±0.2°、14.02±0.2°、14.71±0.2°和19.90±0.2°的2θ处的衍射峰。优选地，化合物I棕榈酸盐晶体V的XRPD图谱还包括在约11.19±0.2°、19.66±0.2°、22.61±0.2°、22.80±0.2°和23.43±0.2°的2θ处的衍射峰。更优选地，化合物I棕榈酸盐晶体V的XRPD图谱还包括在约11.38±0.2°、19.48±0.2°、20.26±0.2°和22.96±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I棕榈酸盐晶体V的XRPD图谱包括在约5.56±0.2°、11.19±0.2°、12.99±0.2°、13.21±0.2°、13.59±0.2°、14.02±0.2°、14.71±0.2°、19.90±0.2°、19.66±0.2°、22.61±0.2°、22.80±0.2°和23.43±0.2°的2θ处的衍射峰。在另一些实施方案中，化合物I棕榈酸盐晶体V的XRPD图谱包括在约5.56±0.2°、11.19±0.2°、11.38±0.2°、12.99±0.2°、13.21±0.2°、13.59±0.2°、14.02±0.2°、14.71±0.2°、19.48±0.2°、19.90±0.2°、19.66±0.2°、20.26±0.2°、22.61±0.2°、22.80±0.2°、22.96±0.2°和23.43±0.2°的2θ处的衍射峰。
在一些实施方案中，化合物I棕榈酸盐晶体V的XRPD图谱包括如下2θ处的衍射峰：
2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％ 2θ(°)±0.2° 强度％
5.56 11.79 12.59 2.55 16.26 18.36 20.71 2.76
6.40 1.29 12.99 10.58 16.86 10.39 21.04 3.23
6.98 1.04 13.21 9.65 17.14 10.55 21.30 1.97
7.64 0.7 13.31 7.82 18.11 10.37 21.82 0.86
8.40 0.93 13.59 12.39 18.61 1.34 22.61 78.44
10.32 0.64 14.02 25.5 19.13 5.89 22.80 100
11.19 14.05 14.71 17.85 19.48 53.74 22.96 49.25
11.38 13.48 14.99 10.8 19.66 40.27 23.43 54.37
11.64 9.04 15.43 14.53 19.90 71.68 23.78 27.3
12.05 3.26 15.95 12 20.26 19.18 24.06 7.03
在一些实施方案中，化合物I棕榈酸盐晶体V的XRPD图谱基本上如图22所示。在一些优选的实施方案中，化合物I棕榈酸盐晶体V的XRPD图谱如图22所示。
药物组合物和用途
本发明的另一目的是提供一种药物组合物，其包含化合物I的盐，所述的盐选自双羟萘酸盐和棕榈酸盐，特别是化合物I双羟萘酸盐晶体或棕榈酸盐晶体，以及一种或多种药学上可接受的载体。
本发明的另一目的在于提供本发明的化合物I的盐(例如式I化合物双羟萘酸盐和式I化合物棕榈酸盐，特别是化合物I双羟萘酸盐晶体或棕榈酸盐晶体或其任意组合)或药物组合物，在制备用于治疗帕金森病和不宁腿综合症的药物中的用途。
本发明的另一目的在于提供本发明的化合物I的盐(例如式I化合物双羟萘酸盐和式I化合物棕榈酸盐，特别是化合物I双羟萘酸盐晶体或棕榈酸盐晶体或其任意组合)或药物组合物，用于治疗帕金森病和不宁腿综合症。
本发明的另一目的在于提供用于治疗帕金森病和不宁腿综合症的方法，其包括向有此需要的个体给药治疗有效量的本发明的化合物I的盐(例如式I化合物双羟萘酸盐和式I化合物棕榈酸盐，特别是化合物I双羟萘酸盐晶体或棕榈酸盐晶体或其任意组合)或药物组合物。
如本文中所使用的术语“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
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或其盐与适宜的药学上可接受的载体组合而制备。
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，如果需要则加入其他合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。
有益效果
本发明的化合物I的双羟萘酸盐以及棕榈酸盐具有纯度高、稳定性好等优点。另外，其具有更低的溶解度，可用于长效缓释制剂。本发明的化合物I的双羟萘酸盐以及棕榈酸盐具有延长的T max和T 1/2时长，能够维持更长时间的有效血药浓度，从而证实其能够实现长效释放的效果。
本发明的晶体(如晶型A-S和T-V)具有纯度高、稳定性好等优点。另外，其具有更低的溶解度，可用于长效缓释制剂。本发明的晶体具有延长的T max和T 1/2时长，能够维持更长时间的有效血药浓度，从而证实其能够实现长效释放的效果。
实施例
X射线粉末衍射(XRPD)：
采用X`Pert3 Powder粉末衍射仪采集各晶体的XRPD图谱，该仪器采用Cu钯照射，在室温下使用Absolute scan进行连续投射扫描，扫描2θ范围为3.5°至40°，步长为0.013°，停留时间为50s，扫描1次。
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。
实施例1：化合物I双羟萘酸盐晶体A的制备
50mg的化合物I与92mg双羟萘酸投入2mL甲醇中，置于40-10℃循环升降温(40-10℃循环升降温是指在40℃保温1h后降至10℃保温1h，再升温至40℃保温1h再降温至10℃保温1h，循环往复)下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体A，对其进行XRPD 检测，所得XRPD图谱如图1中所示。
实施例2：化合物I双羟萘酸盐晶体B的制备
50mg的化合物I与92mg双羟萘酸投入2mL乙腈中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体B，对其进行XRPD检测，所得XRPD图谱如图2中所示。
实施例3：化合物I双羟萘酸盐晶体C的制备
50mg的化合物I与92mg双羟萘酸投入2mL丙酮中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体C，对其进行XRPD检测，所得XRPD图谱如图3中所示。
实施例4：化合物I双羟萘酸盐晶体D的制备
50mg的化合物I与92mg双羟萘酸投入2mL甲醇中，置于40-10℃循环升降温下震荡悬浮，24h后离心，然后置于60℃干燥，得到化合物I双羟萘酸盐晶体D，对其进行XRPD检测，所得XRPD图谱如图4中所示。
实施例5：化合物I双羟萘酸盐晶体E的制备
50mg的化合物I与92mg双羟萘酸投入1mL乙腈和1mL水的混合溶剂中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体E，对其进行XRPD检测，所得XRPD图谱如图5中所示。
实施例6：化合物I双羟萘酸盐晶体F的制备
50mg的化合物I与92mg双羟萘酸投入3mL乙腈中，置于40-10℃循环升降温下震荡悬浮，24h后离心，然后置于60℃干燥，得到化合物I双羟萘酸盐晶体F，对其进行XRPD检测，所得XRPD图谱如图6中所示。
实施例7：化合物I双羟萘酸盐晶体G的制备
50mg的化合物I与92mg双羟萘酸投入4mL乙腈中，置于50℃震荡悬浮，4h后离心，得到化合物I双羟萘酸盐晶体G，对其进行XRPD检测，所得XRPD图谱如图7中所示。
实施例8：化合物I双羟萘酸盐晶体H的制备
50mg的化合物I与92mg双羟萘酸投入4mL甲醇中，置于50℃震荡悬浮，4h后离心，得到化合物I双羟萘酸盐晶体H，对其进行XRPD检测，所得XRPD图谱如图8中所示。
实施例9：化合物I双羟萘酸盐晶体I的制备
50mg的化合物I与92mg双羟萘酸投入1mL甲醇和1mL水的混合溶剂中，置于25℃震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体I，对其进行XRPD检测，所得XRPD图谱如图9中所示。
实施例10：化合物I双羟萘酸盐晶体J的制备
50mg的化合物I与92mg双羟萘酸投入2mLTHF中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体J，对其进行XRPD检测，所得XRPD图谱如图10中所示。
实施例11：化合物I双羟萘酸盐晶体K的制备
50mg的化合物I与92mg双羟萘酸投入1mL甲醇和3mL水的混合溶液中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体K，对其进行XRPD检测，所得XRPD图谱如图11中所示。
实施例12：化合物I双羟萘酸盐晶体L的制备
50mg的化合物I与92mg双羟萘酸投入0.4mL甲醇和1.6mL MTBE的混合溶液中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体L，对其进行XRPD检测，所得XRPD图谱如图12中所示。
实施例13：化合物I双羟萘酸盐晶体M的制备
50mg的化合物I与92mg双羟萘酸投入1mLTHF和1mL水的混合溶液中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体M，对其进行XRPD检测，所得XRPD图谱如图13中所示。
实施例14：化合物I双羟萘酸盐晶体N的制备
50mg的化合物I与46mg双羟萘酸投入2mL丙酮中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体N，对其进行XRPD检测，所得XRPD图谱如图14中所示。
实施例15：化合物I双羟萘酸盐晶体O的制备
50mg的化合物I与46mg双羟萘酸投入2mL甲醇中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体O，对其进行XRPD检测，所得XRPD图谱如图15中所示。
实施例16：化合物I双羟萘酸盐晶体P的制备
50mg的化合物I与46mg双羟萘酸投入2mL乙腈中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体P，对其进行XRPD检测，所得XRPD图谱如图16中所示。
实施例17：化合物I双羟萘酸盐晶体Q的制备
50mg的化合物I与46mg双羟萘酸投入2mL异丙醇中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体Q，对其进行XRPD检测，所得XRPD图谱 如图17中所示。
实施例18：化合物I双羟萘酸盐晶体R的制备
50mg的化合物I与46mg双羟萘酸投入2mLTHF中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体R，对其进行XRPD检测，所得XRPD图谱如图18中所示。
实施例19：化合物I双羟萘酸盐晶体S的制备
50mg的化合物I与46mg双羟萘酸投入0.4mL乙醇和1.6mL正庚烷的混合溶剂中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I双羟萘酸盐晶体S，对其进行XRPD检测，所得XRPD图谱如图19中所示。
实施例20：化合物I棕榈酸盐晶体T的制备
2.0g的化合物I与2.4g棕榈酸投入30mL乙酸乙酯中，置于25℃搅拌，2h后过滤，得到化合物I棕榈酸盐晶体T，对其进行XRPD检测，所得XRPD图谱如图20中所示。
实施例21：化合物I棕榈酸盐晶体U的制备
20mg化合物I棕榈酸盐晶体T(实施例20制备所得)投入1mL乙醇中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I棕榈酸盐晶体U，对其进行XRPD检测，所得XRPD图谱如图21中所示。
实施例22：化合物I棕榈酸盐晶体V的制备
20mg化合物I棕榈酸盐晶体T(实施例20制备所得)投入1mL丙酮中，置于40-10℃循环升降温下震荡悬浮，24h后离心，得到化合物I棕榈酸盐晶体V，对其进行XRPD检测，所得XRPD图谱如图22中所示。
试验例1：溶解度试验
1-1晶体T、晶体U、晶体V以及化合物I的溶解度
将样品投入纯水中，投入过量样品，室温震摇15h，过滤，HPLC检测。HPLC测试条件：流动相：辛烷磺酸钠-磷酸二氢钾缓冲液(取辛烷磺酸钠5.0g和磷酸二氢钾9.1g，加水1000ml使溶解，用磷酸调节pH值至3.0)-乙腈(72：28)；检测波长为264nm；流速为每分钟1.5ml；柱温为40℃；进样量：10μl；色谱柱：十八烷基硅烷键合硅胶为填充剂(CAPCELL PAK MG II C18，4.6mm×250mm，5μm)。
晶体 晶体T 晶体U 晶体V 化合物I
溶解度(mg/ml) 0.010 0.017 0.016 0.14
从上表数据可以看出，本发明的晶体相对于化合物I游离碱具有更低的溶解度，可用于长效缓释制剂。
1-2晶体D以及晶体N的溶解度
通过1-1的试验方法测试双羟萘酸盐晶体D以及晶体N，其溶解度测试结果如下表所示。
名称 溶解度(mg/ml)
晶体D 0.018
晶体N 0.046
化合物I 0.14
从上表数据可以看出，本发明的晶体相对于化合物I游离碱具有更低的溶解度，可用于长效缓释制剂。
试验例2 大鼠药代动力学试验
2-1双羟萘酸盐的大鼠药代动力学试验
取4只雌性大鼠，通过肌肉注射的方式向大鼠给药5mg/kg的化合物I的双羟萘酸盐晶体D，并且仅给药一次。在给药前以及给药后的5min、15min、30min、1h、2h、4h、8h、24h、48h、72h、96h、120h、144h、168h，分别采取静脉血液样品0.3ml(EDTA-K2抗凝)。随后测定给药后的血药浓度，并拟合药时曲线，以计算药代动力学参数。相关数据参见下表。
双羟萘酸盐晶体药代动力学数据
PK参数 数值
T 1/2(h) 4.88
T max(h) 0.625
C max(ng/ml) 389
AUC last(h*ng/ml) 1624
AUC INF(h*ng/ml) 1639
Vz_F(ml) 55549
Cl_F(ml/h) 7519
MRT last(h) 4.11
根据FDA资料(FDA.
Figure PCTCN2021129537-appb-000004
ER TM(pramipexole dihydrochloride),NDA 22-421,Serial 000 received 10/24/08)可知，对大鼠口服给药化合物I(普拉克索)，获得的T max为0.5h，T 1/2为3.18h。由此可见，相对于化合物I本身，本发明的化合物I的双羟萘酸盐晶体可以维持更长时间的有效血药浓度，具有更长的T max和T 1/2时长，实现了长效缓释的效果。
2-2棕榈酸盐的大鼠药代动力学试验
取4只雌性大鼠，通过肌肉注射的方式向大鼠给药5mg/kg的化合物I的棕榈酸盐晶体T，并且仅给药一次。在给药前以及给药后的5min、15min、30min、1h、2h、4h、8h、24h、48h、72h、96h、120h、144h、168h，分别采取静脉血液样品0.3ml(EDTA-K2抗凝)。随后测定给药后的血药浓度，并拟合药时曲线，以计算药代动力学参数。相关数据参见下表。
棕榈酸盐药代动力学数据
PK参数 数值
T 1/2(h) 21.0
T max(h) 1.33
C max(ng/ml) 949
AUC last(h*ng/ml) 10116
AUC INF(h*ng/ml) 10205
Vz_F(ml) 15091
Cl_F(ml/h) 521
MRT last(h) 22.3
根据FDA资料(FDA.
Figure PCTCN2021129537-appb-000005
ER TM(pramipexole dihydrochloride),NDA 22-421,Serial 000 received 10/24/08)可知，对大鼠口服给药化合物I(普拉克索)，获得的T max为0.5h，T 1/2为3.18h。由此可见，相对于化合物I本身，本发明的化合物I的棕榈酸盐晶体可以维持更长时间的有效血药浓度，具有更长的T max和T 1/2时长，实现了长效缓释的效果。
上述具体实施方式对本发明作进一步的详细描述。但不应将此理解为本发明上述主题的范围仅限于所列的实施例，凡基于本发明内容所实施的技术方案均落入于本发明的范围。

Claims (9)

  1. 式I化合物的盐，其中所述的盐选自棕榈酸盐和双羟萘酸盐，
    Figure PCTCN2021129537-appb-100001
  2. 如权利要求1中所示的式I化合物的盐，其中所述盐为式I化合物的棕榈酸盐。
  3. 如权利要求1或2中所示的式I化合物棕榈酸盐，其中式I化合物与棕榈酸的化学计量比为1:1。
  4. 如权利要求3中所示的式I化合物棕榈酸盐晶体T，其XRPD图谱包括在约6.17±0.2°、9.73±0.2°、10.20±0.2°、11.52±0.2°、12.44±0.2°、15.16±0.2°和21.40±0.2°的2θ处的衍射峰；优选地，还包括在约13.82±0.2°、16.36±0.2°和16.65±0.2°的2θ处的衍射峰；更优选地，还包括在约16.89±0.2°、19.88±0.2°和20.18±0.2°的2θ处的衍射峰；更优选地，化合物I棕榈酸盐晶体T的XRPD图谱基本上如图20所示，优选如图20所示。
  5. 如权利要求3中所示的式I化合物棕榈酸盐晶体U，其XRPD图谱包括在约5.95±0.2°、15.15±0.2°、17.90±0.2°、20.57±0.2°、21.44±0.2°、21.83±0.2°和25.82±0.2°的2θ处的衍射峰；优选地，还包括在约10.81±0.2°、14.47±0.2°、18.20±0.2°、22.63±0.2°和26.63±0.2°的2θ处的衍射峰；更优选地，还包括在约11.27±0.2°和26.03±0.2°的2θ处的衍射峰；更优选地，化合物I棕榈酸盐晶体U的XRPD图谱基本上如图21所示，优选如图21所示。
  6. 如权利要求3中所示的式I化合物棕榈酸盐晶体V，其XRPD图谱包括在约5.56±0.2°、12.99±0.2°、13.21±0.2°、13.59±0.2°、14.02±0.2°、14.71±0.2°和19.90±0.2°的2θ处的衍射峰；优选地，还包括在约11.19±0.2°、19.66±0.2°、22.61±0.2°、22.80±0.2°和23.43±0.2°的2θ处的衍射峰；更优选地，还包括在约11.38±0.2°、19.48±0.2°、20.26±0.2°和22.96±0.2°的2θ处的衍射峰；更优选地，化合物I棕榈酸盐晶体V的XRPD图谱基本上如图22所示，优选如图22所示。
  7. 如权利要求1中所示的式I化合物双羟萘酸盐，其中
    所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体D，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约11.24±0.2°、11.88±0.2°、12.03±0.2°、13.57±0.2°、14.76±0.2°、15.17±0.2°、20.85±0.2°、21.15±0.2°和23.26±0.2°的2θ处的衍射峰；优选地，还包括在约15.17±0.2°、16.92±0.2°和24.24±0.2°的2θ处的衍射峰；更优选地，还包括在约19.3709±0.2°和20.2490±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体D的XRPD图谱基本上如图4所示，优选如图4所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体A，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约4.76±0.2°、7.07±0.2°、8.32±0.2°、10.7±0.2°、11.73±0.2°、13.29±0.2°、16.25±0.2°、18.45±0.2°、21.51±0.2°、24.81±0.2°和26.17±0.2°的2θ处的衍射峰；优选地，还包括在约17.87±0.2°、22.01±0.2°、25.17±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体A的XRPD图谱基本上如图1所示，优选如图1所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体B，其中化合物I与双羟 萘酸的化学计量比为1:1，其XRPD图谱包括在约5.79±0.2°、6.38±0.2°、10.95±0.2°、14.72±0.2°、17.61±0.2°、18.40±0.2°、19.81±0.2°和22.18±0.2°的2θ处的衍射峰；优选地，还包括在约10.61±0.2°、12.51±0.2°、17.61±0.2°和20.01±0.2°的2θ处的衍射峰；更优选地，还包括在约10.18±0.2°、13.15±0.2°和13.36±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体B的XRPD图谱基本上如图2所示，优选如图2所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体C，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约7.43±0.2°、11.18±0.2°、11.98±0.2°、14.78±0.2°、20.20±0.2°、20.97±0.2°和23.30±0.2°的2θ处的衍射峰；优选地，还包括在约16.90±0.2°、19.73±0.2°、22.12±0.2°和25.37±0.2°的2θ处的衍射峰；更优选地，还包括在约19.34±0.2°和22.91±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体C的XRPD图谱基本上如图3所示，优选如图3所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体E，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约7.32±0.2°、11.26±0.2°、12.04±0.2°、14.77±0.2°、15.24±0.2°、16.95±0.2°、20.28±0.2°、21.26±0.2°和23.27±0.2°的2θ处的衍射峰；优选地，还包括在约19.37±0.2°和19.83±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体E的XRPD图谱基本上如图5所示，优选如图5所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体F，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约11.19±0.2°、12.10±0.2°、14.67±0.2°、15.48±0.2°、18.11±0.2°、20.25±0.2°和23.33±0.2°的2θ处的衍射峰；优选地，还包括在约11.92±0.2°、14.67±0.2°、16.71±0.2°和25.84±0.2°的2θ处的衍射峰；更优选地，还包括在约19.19±0.2°和21.23±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体F的XRPD图谱基本上如图6所示，优选如图6所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体G，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约6.13±0.2°、11.24±0.2°、11.86±0.2°、13.15±0.2°、14.79±0.2°、20.27±0.2°和23.13±0.2°的2θ处的衍射峰；优选地，还包括在约11.24±0.2°、14.54±0.2°、19.90±0.2°、20.09±0.2°、22.21±0.2°、23.96±0.2°和24.76±0.2°的2θ处的衍射峰；更优选地，还包括在约16.88±0.2°、19.35±0.2°和20.46±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体G的XRPD图谱基本上如图7所示，优选如图7所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体H，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约7.08±0.2°、11.92±0.2°、13.03±0.2°、14.71±0.2°、16.90±0.2°、20.85±0.2°、21.96±0.2°、23.04±0.2°和23.56±0.2°的2θ处的衍射峰；优选地，还包括在约11.76±0.2°、13.03±0.2°、20.27±0.2°和26.66±0.2°的2θ处的衍射峰；更优选地，还包括在约11.30±0.2°、14.71±0.2°和19.97±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体H的XRPD图谱基本上如图8所示，优选如图8所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体I，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约5.59±0.2°、5.98±0.2°、9.39±0.2°、20.39±0.2°、25.27±0.2°、和26.01±0.2°的2θ处的衍射峰；优选地，还包括在约7.62±0.2°、8.22±0.2°、11.59±0.2°、18.09±0.2°和22.59±0.2°的2θ处的衍射峰；更优选地，还包括在约7.80±0.2°、9.88±0.2°和23.40±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体I的XRPD图谱基本上如图9 所示，优选如图9所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体J，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约5.33±0.2°、7.13±0.2°、10.90±0.2°、14.57±0.2°、16.62±0.2°、19.80±0.2°和25.29±0.2°的2θ处的衍射峰；优选地，还包括在约14.99±0.2°、19.01±0.2°和20.74±0.2°的2θ处的衍射峰；更优选地，还包括在约19.32±0.2°和22.24±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体J的XRPD图谱基本上如图10所示，优选如图10所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体K，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约5.57±0.2°、5.97±0.2°、7.73±0.2°、11.55±0.2°、18.01±0.2°和18.90±0.2°的2θ处的衍射峰；优选地，还包括在约9.34±0.2°、19.79±0.2°和25.84±0.2°的2θ处的衍射峰；更优选地，还包括在约23.25±0.2°和25.10±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体K的XRPD图谱基本上如图11所示，优选如图11所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体L，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约6.20±0.2°、8.13±0.2°、9.92±0.2°、10.85±0.2°、12.81±0.2°和21.82±0.2°的2θ处的衍射峰；优选地，还包括在约15.29±0.2°和25.86±0.2°的2θ处的衍射峰；更优选地，还包括在约19.29±0.2°和25.63±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体L的XRPD图谱基本上如图12所示，优选如图12所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体M，其中化合物I与双羟萘酸的化学计量比为1:1，其XRPD图谱包括在约6.31±0.2°、11.55±0.2°、14.49±0.2°、15.94±0.2°、19.58±0.2°和23.50±0.2°的2θ处的衍射峰；优选地，还包括在约19.27±0.2°、20.28±0.2°和25.88±0.2°的2θ处的衍射峰；更优选地，还包括在约22.27±0.2°和24.88±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体M的XRPD图谱基本上如图13所示，优选如图13所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体N，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.87±0.2°、6.42±0.2°、10.11±0.2°、12.58±0.2°、13.38±0.2°、16.12±0.2°和17.86±0.2°的2θ处的衍射峰；优选地，还包括在约10.55±0.2°、14.74±0.2°、24.90±0.2°和26.45±0.2°的2θ处的衍射峰；更优选地，还包括在约10.87±0.2°、23.55±0.2°和24.29±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体N的XRPD图谱基本上如图14所示，优选如图14所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体O，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约11.33±0.2°、11.92±0.2°、14.71±0.2°、16.11±0.2°、17.50±0.2°和20.86±0.2°的2θ处的衍射峰；优选地，还包括在约20.27±0.2°、23.04±0.2°、23.57±0.2°和27.70±0.2°的2θ处的衍射峰；更优选地，还包括在约19.96±0.2°、24.05±0.2°、25.43±0.2°和26.66±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体O的XRPD图谱基本上如图15所示，优选如图15所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体P，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.79±0.2°、6.36±0.2°、10.58±0.2°、10.90±0.2°、13.32±0.2°、14.69±0.2°、17.61±0.2°和25.261±0.2°的2θ处的衍射峰；优选地，还包括在约10.58±0.2°、22.20±0.2°、22.80±0.2°和23.47±0.2°的2θ处的衍射峰；更优选地，还包括在约23.76±0.2°和24.08±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体P的XRPD图谱基本上如图16所示，优选如图16所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体Q，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.75±0.2°、6.20±0.2°、10.46±0.2°、14.54±0.2°、15.26±0.2°和20.78±0.2°的2θ处的衍射峰；优选地，还包括在约16.16±0.2°、17.51±0.2°和24.37±0.2°的2θ处的衍射峰；更优选地，还包括在约17.98±0.2°、21.74±0.2°和23.58±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体Q的XRPD图谱基本上如图17所示，优选如图17所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体R，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.97±0.2°、11.45±0.2°、12.06±0.2°、13.41±0.2°、17.75±0.2°和18.77±0.2°的2θ处的衍射峰；优选地，还包括在约19.42±0.2°、21.64±0.2°、23.89±0.2°、27.10±0.2°和28.76±0.2°的2θ处的衍射峰；更优选地，还包括在约21.64±0.2°、23.09±0.2°和26.18±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体R的XRPD图谱基本上如图18所示，优选如图18所示；
    或，所述式I化合物双羟萘酸盐为所示的式I化合物双羟萘酸盐晶体S，其中化合物I与双羟萘酸的化学计量比为2:1，其XRPD图谱包括在约5.84±0.2°、6.34±0.2°、10.06±0.2°、11.14±0.2°、13.25±0.2°、14.65±0.2°、18.26±0.2°和25.25±0.2°的2θ处的衍射峰；优选地，还包括在约19.33±0.2°、21.53±0.2°、22.68±0.2°和24.06±0.2°的2θ处的衍射峰；更优选地，还包括在约20.20±0.2°、22.09±0.2°和24.06±0.2°的2θ处的衍射峰；更优选地，化合物I双羟萘酸盐晶体S的XRPD图谱基本上如图19所示，优选如图19所示。
  8. 药物组合物，其包含：
    i)以下物质中的任意一种或多种：
    权利要求1或2的式I化合物的盐；
    权利要求3的式I化合物棕榈酸盐；
    权利要求4-6任一项所述的式I化合物棕榈酸盐晶体；
    权利要求7的式I化合物双羟萘酸盐；
    ii)一种或多种药学上可接受的载体。
  9. 任意一种或多种以下物质在制备用于治疗帕金森病和不宁腿综合症的药物中的用途：
    权利要求1或2的式I化合物的盐；
    权利要求3的式I化合物棕榈酸盐；
    权利要求4-6任一项所述的式I化合物棕榈酸盐晶体；
    权利要求7的式I化合物双羟萘酸盐；或者
    权利要求8的药物组合物。
PCT/CN2021/129537 2020-11-19 2021-11-09 苯并噻唑类化合物的盐及其晶体形式和用途 Ceased WO2022105644A1 (zh)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CN202510106569.4A CN119930541A (zh) 2020-11-19 2021-11-09 苯并噻唑类化合物的盐及其晶体形式和用途
JP2023518885A JP2023550235A (ja) 2020-11-19 2021-11-09 ベンゾチアゾール系化合物の塩、その結晶形及び使用
EP21893791.0A EP4249476A4 (en) 2020-11-19 2021-11-09 Salt of a benzothiazole compound, crystal form and use thereof
CN202180064196.9A CN116367833B (zh) 2020-11-19 2021-11-09 苯并噻唑类化合物的盐及其晶体形式和用途
US18/027,246 US12583829B2 (en) 2020-11-19 2021-11-09 Salt of benzothiazole compound, and crystal form and use thereof
AU2021381638A AU2021381638A1 (en) 2020-11-19 2021-11-09 Salt of benzothiazole compound, and crystal form and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011304450 2020-11-19
CN202011304450.1 2020-11-19

Publications (1)

Publication Number Publication Date
WO2022105644A1 true WO2022105644A1 (zh) 2022-05-27

Family

ID=81708355

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/129537 Ceased WO2022105644A1 (zh) 2020-11-19 2021-11-09 苯并噻唑类化合物的盐及其晶体形式和用途

Country Status (6)

Country Link
US (1) US12583829B2 (zh)
EP (1) EP4249476A4 (zh)
JP (1) JP2023550235A (zh)
CN (2) CN116367833B (zh)
AU (1) AU2021381638A1 (zh)
WO (1) WO2022105644A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115215818A (zh) * 2022-07-26 2022-10-21 山东京卫制药有限公司 一种普拉克索三苯乙酸盐及其药物缓释制剂
WO2025190207A1 (zh) * 2024-03-15 2025-09-18 四川科伦药物研究院有限公司 化合物的晶体及其制备方法和用途
EP4527377A4 (en) * 2022-05-16 2026-04-29 Sichuan Kelun Pharm Res Inst Co Ltd PREPARATION OF LONG-RELEASED PRAMIPEXOLE AND ITS PREPARATION PROCESS

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4731374A (en) * 1984-12-22 1988-03-15 Dr. Karl Thomae Gmbh Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
CN102784111A (zh) * 2011-05-17 2012-11-21 山东绿叶制药有限公司 一种多巴胺受体激动剂类药物的缓释制剂
US20140377365A1 (en) * 2013-06-19 2014-12-25 Map Pharmaceuticals, Inc. Sustained-release formulation of rotigotine
CN111212640A (zh) * 2017-08-17 2020-05-29 顾自强 单胺抗帕金森药物的双羟萘酸盐、其制备方法及其用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101484411A (zh) * 2006-06-27 2009-07-15 桑多斯股份公司 盐的新制备方法
CN113730349B (zh) 2020-05-28 2025-10-31 四川科伦药物研究院有限公司 一种药物组合物及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4731374A (en) * 1984-12-22 1988-03-15 Dr. Karl Thomae Gmbh Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
CN102784111A (zh) * 2011-05-17 2012-11-21 山东绿叶制药有限公司 一种多巴胺受体激动剂类药物的缓释制剂
US20140377365A1 (en) * 2013-06-19 2014-12-25 Map Pharmaceuticals, Inc. Sustained-release formulation of rotigotine
CN111212640A (zh) * 2017-08-17 2020-05-29 顾自强 单胺抗帕金森药物的双羟萘酸盐、其制备方法及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4249476A4

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4527377A4 (en) * 2022-05-16 2026-04-29 Sichuan Kelun Pharm Res Inst Co Ltd PREPARATION OF LONG-RELEASED PRAMIPEXOLE AND ITS PREPARATION PROCESS
CN115215818A (zh) * 2022-07-26 2022-10-21 山东京卫制药有限公司 一种普拉克索三苯乙酸盐及其药物缓释制剂
WO2025190207A1 (zh) * 2024-03-15 2025-09-18 四川科伦药物研究院有限公司 化合物的晶体及其制备方法和用途

Also Published As

Publication number Publication date
AU2021381638A9 (en) 2024-02-08
AU2021381638A1 (en) 2023-05-04
CN116367833B (zh) 2025-02-25
CN119930541A (zh) 2025-05-06
EP4249476A4 (en) 2025-04-16
JP2023550235A (ja) 2023-12-01
US20230365518A1 (en) 2023-11-16
EP4249476A1 (en) 2023-09-27
US12583829B2 (en) 2026-03-24
CN116367833A (zh) 2023-06-30

Similar Documents

Publication Publication Date Title
US8389512B2 (en) In vivo studies of crystalline forms of meloxicam
EP3438099B1 (en) Vortioxetine pamoic acid salt and crystal form thereof
WO2022105644A1 (zh) 苯并噻唑类化合物的盐及其晶体形式和用途
CN102351857B (zh) 盐酸托烷司琼化合物
WO2015176602A1 (zh) 替诺福韦艾拉酚胺复合物及其制备方法和用途
CN102367252A (zh) 一种盐酸托烷司琼化合物
WO2022199708A1 (zh) 卢美哌隆药用盐、制备方法、含其的药物组合物及应用
CN109996787B (zh) 难溶性复合物或其溶剂合物、药物组合物及其应用
US12371439B2 (en) Crystalline form B of tetrahydrothienopyridine compound, preparation method, composition and application thereof
MX2012006226A (es) Formulaciones, sales y polimorfos de transnorsertralina y usos de los mismos.
WO2019218883A1 (zh) 一种二氢嘧啶类化合物的固体形式及其制备方法和用途
CN104447682A (zh) 比拉斯汀化合物
HK40087445B (zh) 苯并噻唑类化合物的盐及其晶体形式和用途
HK40087445A (zh) 苯并噻唑类化合物的盐及其晶体形式和用途
WO2024007801A1 (zh) 受体酪氨酸激酶抑制剂与联苯环辛二稀木脂素的联合用药及其用途
JP7671362B2 (ja) 医薬組成物、その製造方法及び使用
US11292809B2 (en) Crystals of glycyrrhizic acid derivatives, crystalline compositions, pharmaceutical compositions and uses thereof
CN121930247A (zh) 苯并噁嗪噁唑烷酮类化合物otb-658的晶型ii及其制备方法和其组合物与用途
WO2025190207A1 (zh) 化合物的晶体及其制备方法和用途
CN120865120A (zh) 一种利鲁唑对甲苯磺酸盐及其制备方法
KR20250026776A (ko) 고요산혈증 또는 통풍 치료 또는 예방을 위한 화합물의 고체 결정형
CN117756723A (zh) 一种egfr抑制剂的衍生物及其应用
WO2025160513A1 (en) Crystalline forms of 5-(tetradecyloxy)furan-2-carboxylic acid and salts thereof
CN120230121A (zh) 苯并噁嗪噁唑烷酮类化合物otb-658的晶型i及其制备方法和其组合物与用途
WO2018162395A1 (en) Vinpocetine hydrochloride co-crystals

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21893791

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: AU2021381638

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2023518885

Country of ref document: JP

ENP Entry into the national phase

Ref document number: 2021381638

Country of ref document: AU

Date of ref document: 20211109

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021893791

Country of ref document: EP

Effective date: 20230619

WWG Wipo information: grant in national office

Ref document number: 202180064196.9

Country of ref document: CN

WWG Wipo information: grant in national office

Ref document number: 18027246

Country of ref document: US