WO2019019851A1 - 钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用 - Google Patents

钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用 Download PDF

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WO2019019851A1
WO2019019851A1 PCT/CN2018/092895 CN2018092895W WO2019019851A1 WO 2019019851 A1 WO2019019851 A1 WO 2019019851A1 CN 2018092895 W CN2018092895 W CN 2018092895W WO 2019019851 A1 WO2019019851 A1 WO 2019019851A1
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compound
formula
ray powder
diffraction pattern
powder diffraction
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French (fr)
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王峥
江涛涛
王吉标
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN201880010536.8A priority Critical patent/CN110300745B/zh
Publication of WO2019019851A1 publication Critical patent/WO2019019851A1/zh
Priority to US16/596,324 priority patent/US10947202B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon 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 invention belongs to the technical field of medicinal chemistry.
  • the present invention relates to 5-chloro-4-((4-(4-chloro-3-methylphenyl)piperazin-1-yl)methyl)-N-(cyclopropylsulfonyl)-2 a polymorph of a fluorobenzamide compound, a process for the preparation thereof, and a pharmaceutical composition prepared therefrom.
  • Nav1.7 plays an important role in a variety of pain states, including acute, chronic, inflammatory, and/or neuropathic pain.
  • Nav1.7 protein accumulates in neuromas, Especially the neuroma that causes pain.
  • Mutations in Nav1.7 function have been implicated in primary erythematous limb pain (a disease characterized by burning and inflammation of the extremities), and sudden extreme pain.
  • Reports on the use of non-selective sodium channel blockers lidocaine and mexiletine to alleviate the symptoms of hereditary erythematous limb pain, and the extent and severity of carbamazepine that effectively reduce the invasion of PEPD are consistent with the above observations. .
  • Nav1.7 is specifically expressed in DRG sensory neurons and not in other tissues such as cardiomyocytes and central nervous system, the development of its specific blockers for the treatment of chronic pain may not only improve the efficacy, but also greatly reduce the side effects. And selective inhibitors of the Nav1.7 ion channel are used in almost all types of pain treatment.
  • Nav1.7 ion channel inhibitors Although many patented Nav1.7 ion channel inhibitors have been reported in the patent literature, some in-depth studies have shown that some existing Nav1.7 ion channel inhibitors have selectivity for other ion channels, such as potassium channel and There are deficiencies in the stability of human liver microsomes, etc. Because of the cardiotoxicity associated with HERG potassium channels and the impact of predicting the stability of human liver microsomes in liver tissue clearance on drug development, there is an urgent need. Develop safer and more effective analgesics with higher efficacy and fewer side effects. Based on the foregoing work, the present invention has developed a variety of salt types and crystal forms of highly metabolic and highly selective Nav1.7 ion channel inhibitors, which contribute to further drug development.
  • the pharmaceutically acceptable salt is an acid salt or a basic salt
  • the acid salt is selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, L-milk Acid salt, maleate, fumarate, succinate, L-malate, adipate, L-tartrate, hippurate, citrate, mucate, glycolate, D-glucuronate, benzoate, gentisate, nicotinate, ethanedisulfonate, oxalate, methanesulfonate, besylate, 2-hydroxyethanesulfonate, hydrogen The bromate; the basic salt is selected from the group consisting of triethanolamine, sodium or potassium.
  • the pharmaceutically acceptable acid salt is selected from the group consisting of hydrochloride, sulfate, hydrobromide, phosphate, methanesulfonate, maleate, L-tartaric acid Salt, citrate, fumarate, in another preferred embodiment, the pharmaceutically acceptable base salt is selected from the group consisting of sodium or potassium salts.
  • the pharmaceutically acceptable acid salt is selected from the group consisting of hydrochloride, hydrobromide, methanesulfonate, and maleate.
  • the sodium or potassium salt is formed with a base selected from the group consisting of sodium hydroxide or potassium hydroxide.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, and potassium.
  • the compound of the formula X or a pharmaceutically acceptable salt thereof, or a polymorph thereof is in the form of an anhydrous form, a hydrate form or a solvate.
  • the polymorph is a polymorph of a compound of formula X.
  • the polymorph is a polymorph of a pharmaceutically acceptable salt of a compound of formula X, and the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, sulfate, hydrobromine An acid salt, a phosphate salt, a methanesulfonate salt, a maleate salt, an L-tartrate salt, a citrate salt, a fumarate salt, a sodium salt or a potassium salt.
  • the polymorph is a polymorph of a pharmaceutically acceptable salt of a compound of formula X, and the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, Methanesulfonate, maleate, sodium or potassium salt.
  • the polymorph is a polymorph of a pharmaceutically acceptable salt of a compound of formula X, and the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, maleate or Potassium salt.
  • the pharmaceutically acceptable salt of the compound of formula X is in anhydrous form.
  • the polymorph is in anhydrous form.
  • the pharmaceutically acceptable salt is a hydrochloride salt, wherein the molar ratio of hydrochloric acid to the compound of the formula X is (0.5-2):1, preferably (0.5-1.5):1.
  • the pharmaceutically acceptable salt is a hydrobromide salt wherein the molar ratio of hydrobromic acid to the compound of formula X is from 0.8 to 3.5:1, preferably from 1.0 to 3.0:1.
  • the pharmaceutically acceptable salt is a methanesulfonate wherein the molar ratio of methanesulfonic acid to the compound of formula X is from 0.5 to 3.5:1, preferably from 0.6 to 3.0:1.
  • the pharmaceutically acceptable salt is a maleate salt, wherein the molar ratio of maleic acid to the compound of formula X is (0.6-2):1, preferably (0.7-1.9) :1.
  • the pharmaceutically acceptable salt is a sodium hydroxide salt, wherein the molar ratio of sodium hydroxide to the compound of formula X is (0.3-3):1, preferably (0.4-2.8) :1.
  • the pharmaceutically acceptable salt is a potassium hydroxide salt, wherein the molar ratio of potassium hydroxide to the compound of the formula X is (0.5-3.5):1, preferably (0.6-3.3) :1.
  • the polymorph is a Form A crystal of the hydrochloride salt of the compound of Formula X, that is, Form A, and its X-ray powder diffraction pattern has a peak at a diffraction angle 2 ⁇ (°) of the lower group A1. : 12.19 ⁇ 0.20, 16.30 ⁇ 0.20, 17.76 ⁇ 0.20, 18.61 ⁇ 0.20, 23.23 ⁇ 0.20, 25.17 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form A further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group A2: 13.52 ⁇ 0.20, 14.39 ⁇ 0.20, 19.65 ⁇ 0.20, 20.26 ⁇ 0.20, 27.23 ⁇ 0.20, 29.48 ⁇ 0.20, 32.10 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form A is at 6 or more or all selected from A1 and A2 (eg 6, 7, 8, 9, 10, 11, 12, 13, etc.) has a peak at a diffraction angle 2 ⁇ (°) value.
  • the X-ray powder diffraction pattern of the Form A has peaks at 2 ⁇ (°) values shown in Table 1 below, and the relative intensities of the respective peaks are shown in Table 1.
  • the X-ray powder diffraction pattern of Form A is substantially as characterized by Figure 1-1.
  • the molar ratio of hydrochloric acid to the compound of formula X in Form A is (0.5-2)..1, preferably (0.5-1.5)..1.
  • the Form A also has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figures 1-3;
  • the crystalline form A has a melting point of 240 to 255 ° C, preferably 243 to 252 ° C.
  • the crystalline form A is in anhydrous form.
  • the polymorph is a hydrobromide B-type crystal of the compound of formula X, ie, Form B, the X-ray powder diffraction pattern of which has a diffraction angle 2 ⁇ (°) of the lower group B1. Peak: 12.40 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form B further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group B2: 8.27 ⁇ 0.20, 13.28 ⁇ 0.20, 16.53 ⁇ 0.20, 18.36 ⁇ 0.20, 18.68 ⁇ 0.20, 19.68 ⁇ 0.20, 20.07 ⁇ 0.20, 20.73 ⁇ 0.20, 22.60 ⁇ 0.20, 24.92 ⁇ 0.20, 25.35 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form B further comprises a peak at 2 or more values selected from the diffraction angle 2 ⁇ (°) of the lower group B3: 17.43 ⁇ 0.20.
  • the X powder diffraction pattern of Form B is selected from 6 or more or all of Groups B1, B2, and B3 (eg, 6, 7, 8, 9, 10, 11, 12, 13, etc.) has a diffraction angle 2 ⁇ (°) with a peak:
  • the X-ray powder diffraction pattern of Form B has peaks at 2 ⁇ (°) values shown in Table 2 below, and the relative intensities of the respective peaks are shown in Table 2.
  • the X-ray powder diffraction pattern of Form B is substantially characterized as in Figure 2-1.
  • the molar ratio of hydrobromic acid to the compound of formula X in the crystalline form B is from 0.8 to 3.5:1, preferably from 1.0 to 3.0:1.
  • the differential scanning calorimetry analysis pattern of Form B is substantially as characterized by Figure 2-2.
  • the polymorph is a mesylate C-type crystal of the compound of formula X, ie, Form C, the X-ray powder diffraction pattern of which has a diffraction angle 2 ⁇ (°) of the lower group C1. Peaks: 8.93 ⁇ 0.20, 15.32 ⁇ 0.20, 21.86 ⁇ 0.20, 22.56 ⁇ 0.20, 23.75 ⁇ 0.20, 25.69 ⁇ 0.20, 27.37 ⁇ 0.20.
  • the X-ray diffraction pattern of the Form C further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group C2: 14.36 ⁇ 0.20, 16.36 ⁇ 0.20 , 17.88 ⁇ 0.20, 18.68 ⁇ 0.20, 21.15 ⁇ 0.20, 21.35 ⁇ 0.20, 28.02 ⁇ 0.20.
  • the X-ray diffraction pattern of the Form C further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group C3: 12.95 ⁇ 0.20, 13.80 ⁇ 0.20 , 15.78 ⁇ 0.20, 17.24 ⁇ 0.20, 19.19 ⁇ 0.20.
  • the X-ray diffraction pattern of Form C is selected from 6 or more or all of Groups C1, C2, and C3 (eg, 6, 7, 8, 9, 10, 11,
  • the diffraction angle 2 ⁇ (°) of 12, 13, 14, 15, 16, 17, 18, 19, etc. has a peak at a value of 2 ⁇ (°).
  • the X-ray diffraction pattern of the Form C has peaks at 2 ⁇ (°) values shown in Table 3 below, and the relative intensities of the respective peaks are shown in Table 3.
  • the X-ray diffraction pattern of Form C is substantially characterized as in Figure 3-1.
  • the molar ratio of methanesulfonic acid to the compound of formula X in the crystalline form C is from 0.5 to 3.5:1, preferably from 0.6 to 3.0:1.
  • the differential scanning calorimetry analysis pattern of Form C is substantially as characterized by Figure 3-2.
  • the polymorph is a maleate D-type crystal of the compound of formula X, ie, Form D, the X-ray powder diffraction pattern of which has a diffraction angle 2 ⁇ (°) of the lower group D1. Peaks: 5.06 ⁇ 0.20, 8.24 ⁇ 0.20, 10.08 ⁇ 0.20, 15.14 ⁇ 0.20, 16.18 ⁇ 0.20, 18.95 ⁇ 0.20, 19.83 ⁇ 0.20, 20.40 ⁇ 0.20, 21.38 ⁇ 0.20, 22.14 ⁇ 0.20, 26.51 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form D further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group D2: 12.03 ⁇ 0.20, 16.77 ⁇ 0.20, 21.05 ⁇ 0.20, 23.94 ⁇ 0.20, 24.27 ⁇ 0.20, 24.70 ⁇ 0.20, 30.70 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form D further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group D3: 14.24 ⁇ 0.20, 19.33 ⁇ 0.20, 23.46 ⁇ 0.20, 25.10 ⁇ 0.20, 25.53 ⁇ 0.20, 28.09 ⁇ 0.20, 28.40 ⁇ 0.20, 28.85 ⁇ 0.20, 30.23 ⁇ 0.20, 31.15 ⁇ 0.20, 31.48 ⁇ 0.20, 33.57 ⁇ 0.20, 33.86 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form D is selected from 6 or more or all of Groups D1, D2, and D3 (eg, 6, 7, 8, 9, 10, 11) , 12, 13, 14, 15, etc.) have a peak at a diffraction angle 2 ⁇ (°). (See Table 4 for relative intensity of each peak):
  • the X-ray powder diffraction pattern of Form D is substantially characterized as in Figure 4-1.
  • the molar ratio of the maleate salt to the compound of the formula X in the crystal form D is (0.6-2):1, preferably (0.7-1.9):1.
  • the crystalline form D has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figure 4-3;
  • the crystalline form D has a melting point of from 200 to 210 ° C, preferably from 202 to 208 ° C.
  • the crystalline form D is in the anhydrous form.
  • the polymorph is a sodium salt E-1 type crystal of the compound of the formula X, that is, the crystal form E-1, and the X-ray powder diffraction pattern thereof has a diffraction angle 2 ⁇ of the lower group E-1-1.
  • the (°) value has a peak: 4.53 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-1 further comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group E-1-2: 6.52 ⁇ 0.20, 9.18 ⁇ 0.20, 16.80 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-1 comprises a peak at 2 or more diffraction angles 2 ⁇ (°) selected from the group E-1-3: 8.33 ⁇ 0.20, 10.32 ⁇ 0.20, 18.50 ⁇ 0.20, 19.42 ⁇ 0.20, 23.86 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-1 is selected from 6 or more selected from the group consisting of E-1-1, E-1-2, and E-1-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of the Form E-1 has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 5 below, and the relative intensities of the respective peaks are shown in Table 5.
  • the X-ray powder diffraction pattern of Form E-1 is substantially characterized as in Figure 5-1.
  • the molar ratio of the sodium salt to the compound of the formula X in the crystalline form E-1 is (0.3-3):1, preferably (0.4-2.8):1.
  • the differential scanning calorimetry analysis pattern of Form E-1 is substantially characterized as in Figure 5-2.
  • the polymorph is a sodium salt E-2 type crystal of the compound of the formula X, that is, the crystal form E-2, and the X-ray powder diffraction pattern thereof has a diffraction angle 2 ⁇ of the lower group E-2-1.
  • the (°) value has peaks: 6.90 ⁇ 0.20, 14.44 ⁇ 0.20, 16.96 ⁇ 0.20, 17.77 ⁇ 0.20, 18.42 ⁇ 0.20, 19.72 ⁇ 0.20, 22.22 ⁇ 0.20, 22.67 ⁇ 0.20, 27.94 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-2 further comprises peaks at two or more values selected from the diffraction angle 2 ⁇ (°) of the lower group E-2-2: 11.07 ⁇ 0.20, 19.15 ⁇ 0.20, 23.62 ⁇ 0.20, 24.47 ⁇ 0.20, 29.76 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-2 is selected from 6 or more or all of Group E-2-1 and E-2-2 (eg, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of the Form E-2 has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 6 below, and the relative intensities of the respective peaks are shown in Table 6.
  • the X-ray powder diffraction pattern of Form E-2 is substantially characterized as in Figure 6-1.
  • the molar ratio of the sodium salt to the compound of the formula X in the crystalline form E-2 is (0.3-3):1, preferably (0.4-2.8):1.
  • the differential scanning calorimetry analysis pattern of Form E-2 is substantially characterized as in Figure 6-2.
  • the polymorph is a sodium salt E-3 type crystal of the compound of the formula X, that is, the crystal form E-3, and the X-ray powder diffraction pattern thereof has a diffraction angle 2 ⁇ of the lower group E-3-1.
  • the (°) value has peaks: 7.12 ⁇ 0.20, 7.57 ⁇ 0.20, 9.94 ⁇ 0.20, 10.71 ⁇ 0.20, 17.68 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-3 further comprises peaks at 2 or more values selected from the diffraction angle 2 ⁇ (°) of the lower group E-3-2: 6.75 ⁇ 0.20, 14.37 ⁇ 0.20, 17.90 ⁇ 0.20, 18.81 ⁇ 0.20, 19.56 ⁇ 0.20, 20.63 ⁇ 0.20, 21.61 ⁇ 0.20, 22.47 ⁇ 0.20, 23.13 ⁇ 0.20, 23.66 ⁇ 0.20, 24.95 ⁇ 0.20, 25.17 ⁇ 0.20, 25.39 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-3 comprises a peak at 2 or more diffraction angles 2 ⁇ (°) selected from the group E-3-3: 12.73 ⁇ 0.20, 13.76 ⁇ 0.20, 19.92 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form E-3 is selected from 6 or more selected from the group consisting of E-3-1, E-3-2, and E-3-3 or All (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) have peaks at diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of the Form E-3 has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 7 below, and the relative intensities of the respective peaks are shown in Table 7.
  • the X-ray powder diffraction pattern of Form E-3 is substantially characterized as in Figures 7-1.
  • the molar ratio of sodium hydroxide to the compound of formula X in the crystalline form E-3 is (0.3-3):1, preferably (0.4-2.8):1.
  • the crystalline form E-3 has one or more characteristics selected from the group consisting of:
  • the differential scanning calorimetry analysis pattern is basically characterized by Figure 7-2;
  • thermogravimetric analysis map is basically characterized as shown in Figure 7-3.
  • the crystalline form E-3 is in the form of a solvate.
  • the crystal is a potassium salt F-type crystal of the compound of formula X, ie, Form F, and its X-ray powder diffraction pattern has a peak at a diffraction angle 2 ⁇ (°) selected from the group F-1. : 7.83 ⁇ 0.20, 17.68 ⁇ 0.20, 18.74 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the Form F comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group F-2: 6.95 ⁇ 0.20, 9.91 ⁇ 0.20, 12.62 ⁇ 0.20, 14.40 ⁇ 0.20, 16.47 ⁇ 0.20, 20.80 ⁇ 0.20, 21.16 ⁇ 0.20, 22.03 ⁇ 0.20, 23.12 ⁇ 0.20, 23.45 ⁇ 0.20, 24.42 ⁇ 0.20, 25.15 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the Form F comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group F-3: 10.73 ⁇ 0.20, 11.65 ⁇ 0.20, 13.61 ⁇ 0.20, 18.21 ⁇ 0.20, 19.97 ⁇ 0.20, 20.47 ⁇ 0.20, 21.51 ⁇ 0.20, 23.99 ⁇ 0.20, 26.69 ⁇ 0.20, 27.38 ⁇ 0.20, 28.27 ⁇ 0.20, 28.83 ⁇ 0.20, 29.67 ⁇ 0.20, 39.61 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the Form F is 6 or more or all selected from the group consisting of F-1, F-2, and F-3 (eg, 6, 7, 8, 9) , 10, 11, 12, 13, 14, 15, etc.) have a peak at a diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of the Form F has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 8 below, and the relative intensities of the respective peaks are shown in Table 8.
  • the X-ray powder diffraction pattern of Form F is substantially as characterized by Figure 8-1.
  • Form F further has one or more selected from the following features:
  • the differential scanning calorimetry map is basically characterized by Figure 8-2;
  • thermogravimetric analysis map is basically characterized as shown in Figure 8-3.
  • the Form F is in the form of a solvate.
  • the polymorph is a Form I crystal of the free base of the compound of Formula X, i.e., Form I, and its X-ray powder diffraction pattern is at a diffraction angle 2 ⁇ (°) of Group I-1. With peaks: 7.26 ⁇ 0.20, 18.38 ⁇ 0.20, 23.15 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form I comprises peaks at 2 or more diffraction angles 2 ⁇ (°) selected from Group I-2: 9.60 ⁇ 0.20, 14.39 ⁇ 0.20, 15.47 ⁇ 0.20, 22.67 ⁇ 0.20, 25.10 ⁇ 0.20, 29.45 ⁇ 0.20, 30.32 ⁇ 0.20, 36.79 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form I comprises peaks at 2 or more diffraction angles 2 ⁇ (°) selected from Group I-3: 11.10 ⁇ 0.20, 12.81 ⁇ 0.20, 16.03 ⁇ 0.20, 17.43 ⁇ 0.20, 19.06 ⁇ 0.20, 19.44 ⁇ 0.20, 19.99 ⁇ 0.20, 21.37 ⁇ 0.20, 23.68 ⁇ 0.20, 25.65 ⁇ 0.20, 28.30 ⁇ 0.20, 31.02 ⁇ 0.20, 31.69 ⁇ 0.20, 37.57 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form I is selected from 6 or more or all of Groups I-1, I-2, and I-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have a peak at a diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of Form I has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 9 below, and the relative intensities of the respective peaks are shown in Table 9.
  • the X-ray powder diffraction pattern of Form I is substantially as shown in Figure 9-1.
  • Form I has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figure 9-3;
  • the crystalline form I has a melting point of from 175 ° C to 185 ° C, preferably from 178 ° C to 185 ° C; or
  • the Form I is in anhydrous form.
  • the polymorph is a Form II crystal of the free base of the compound of Formula X, ie, Form II, and its X-ray powder diffraction pattern is at a diffraction angle 2 ⁇ (°) of Group II-1. With peaks: 6.84 ⁇ 0.20, 7.74 ⁇ 0.20, 9.94 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form II comprises peaks at 2 or more diffraction angles 2 ⁇ (°) selected from Group II-2: 7.11 ⁇ 0.20, 17.75 ⁇ 0.20, 18.86 ⁇ 0.20, 19.92 ⁇ 0.20, 23.38 ⁇ 0.20, 28.63 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form II comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group II-3: 10.72 ⁇ 0.20, 13.75 ⁇ 0.20, 15.37 ⁇ 0.20, 15.85 ⁇ 0.20, 18.13 ⁇ 0.20, 21.56 ⁇ 0.20, 24.43 ⁇ 0.20, 27.97 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form II is in 6 or more or all selected from Groups II-1, II-2, and II-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have a peak at a diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of Form II has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 10 below, and the relative intensities of the respective peaks are shown in Table 10.
  • the X-ray powder diffraction pattern of Form II is substantially as shown in Figure 10-1.
  • the Form II has one or more characteristics selected from the group consisting of:
  • the DVS curve is basically characterized as shown in Figure 10-3.
  • the polymorph is a type III crystal of the free base of the compound of formula X, ie, Form III, and its X-ray powder diffraction pattern is at a diffraction angle 2 ⁇ (°) of Group III-1. Has a peak: 4.09 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form III comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group III-2: 12.22 ⁇ 0.20, 16.34 ⁇ 0.20, 17.83 ⁇ 0.20, 18.63 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form III comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group III-3: 13.55 ⁇ 0.20, 14.46 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form III is at a diffraction angle 2 ⁇ (°) of 6 or more or all selected from Groups III-1, III-2, and III-3. There is a peak at the value.
  • the X-ray powder diffraction pattern of Form III has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 11 below, and the relative intensities of the respective peaks are shown in Table 11.
  • the X-ray powder diffraction pattern of Form III is substantially as shown in Figure 11-1.
  • the Form III has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figure 11-3; or
  • the crystalline form III is in the anhydrous form.
  • the polymorph is a type IV crystal of the free base of the compound of formula X, ie, Form IV, and its X-ray powder diffraction pattern is at a diffraction angle 2 ⁇ (°) of Group IV-1. Has a peak: 4.66 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form IV comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group IV-2: 5.28 ⁇ 0.20, 9.29 ⁇ 0.20, 16.49 ⁇ 0.20, 16.87 ⁇ 0.20, 17.56 ⁇ 0.20, 19.19 ⁇ 0.20, 23.89 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form IV comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group IV-3: 6.62 ⁇ 0.20, 8.46 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form IV comprises 6 or more or all of Groups IV-1, IV-2, and IV-3 (eg, 6, 7, 8 9,10, 11, 12, 13, 14, 15 and the like have a peak at a diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of Form IV has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 12 below, and the relative intensities of the respective peaks are shown in Table 12.
  • the X-ray powder diffraction pattern of Form IV is substantially as shown in Figure 12-1.
  • the Form IV has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figure 12-3; or
  • the Form IV is in the form of a solvate.
  • the polymorph is a V-form of the free base of the compound of Formula X, ie, Form V, and its X-ray powder diffraction pattern is at a diffraction angle 2 ⁇ (°) of Group V-1.
  • peaks 6.79 ⁇ 0.20, 14.31 ⁇ 0.20, 16.90 ⁇ 0.20, 17.58 ⁇ 0.20, 20.58 ⁇ 0.20, 21.90 ⁇ 0.20, 23.45 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the Form V comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from the group V-2: 13.67 ⁇ 0.20, 15.15 ⁇ 0.20, 16.35 ⁇ 0.20, 18.45 ⁇ 0.20, 20.96 ⁇ 0.20, 25.15 ⁇ 0.20, 28.19 ⁇ 0.20, 29.19 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form V is selected from 6 or more or all of Groups V-1 and V-2 (eg, 6, 7, 8, 9, 10) , 11, 12, 13, 14, 15, etc.) have a peak at a diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of the form V has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 13 below, and the relative intensities of the respective peaks are shown in Table 13.
  • the X-ray powder diffraction pattern of Form V is substantially as shown in Figure 13-1.
  • the crystalline form V has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figure 13-3; or
  • the Form V is in the form of a solvate.
  • the polymorph is a Form VI crystal of the free base of the compound of Formula X, ie Form VI, having an X-ray powder diffraction pattern at a diffraction angle 2 ⁇ (°) of Group VI-1. With peaks: 6.90 ⁇ 0.20, 7.14 ⁇ 0.20, 16.40 ⁇ 0.20, 16.92 ⁇ 0.20, 20.62 ⁇ 0.20, 23.52 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form VI comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group VI-2: 13.76 ⁇ 0.20, 14.26 ⁇ 0.20, 18.21 ⁇ 0.20, 18.46 ⁇ 0.20, 21.92 ⁇ 0.20, 25.13 ⁇ 0.20, 29.19 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form VI comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group VI-3: 17.65 ⁇ 0.20, 21.01 ⁇ 0.20, 22.55 ⁇ 0.20, 23.03 ⁇ 0.20, 26.31 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form VI is selected from 6 or more or all of Group VI-1, VI-2, and VI-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have a peak at a diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of the Form VI has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 14 below, and the relative intensities of the respective peaks are shown in Table 14.
  • the X-ray powder diffraction pattern of Form VI is substantially as shown in Figure 14-1.
  • the Form VI has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figure 14-3; or
  • the Form VI is in the anhydrous form.
  • the polymorph is a Form VII crystal of the free base of the compound of Formula X, that is, Form VII, and its X-ray powder diffraction pattern is at a diffraction angle 2 ⁇ (°) of Group VII-1. Has a peak: 7.11 ⁇ 0.20, 14.22 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form VII comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group VII-2: 18.16 ⁇ 0.20, 21.29 ⁇ 0.20, 29.25 ⁇ 0.20, 31.53 ⁇ 0.20, 36.50 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form VII comprises peaks at two or more diffraction angles 2 ⁇ (°) selected from Group VII-3: 23.02 ⁇ 0.20, 30.09 ⁇ 0.20, 37.46 ⁇ 0.20.
  • the X-ray powder diffraction pattern of Form VI is at 6 or more or all selected from Groups VII-1, VII-2, and VII-3 (eg, 6, 7, 8) , 9, 10, 11, 12, 13, 14, 15, etc.) have a peak at a diffraction angle 2 ⁇ (°).
  • the X-ray powder diffraction pattern of Form VII has peaks at diffraction angle 2 ⁇ (°) values as shown in Table 15 below, and the relative intensities of the respective peaks are shown in Table 15.
  • the X-ray powder diffraction pattern of Form VII is substantially as shown in Figure 15-1.
  • the Form VII has one or more characteristics selected from the group consisting of:
  • thermogravimetric analysis map is basically characterized as shown in Figure 15-3; or
  • the Form VII is in anhydrous form.
  • the compound of the formula X formed by the step (1) or (2) or a pharmaceutically acceptable salt thereof is subjected to crystallization treatment to obtain a crystal.
  • the method comprises any one of the following sub-methods (A)-(E) and (I), (II).
  • the crystal is a type A crystal of the hydrochloride salt of the compound of the formula X, that is, the crystal form A, and the step (3) comprises: crystallization treatment of the compound of the formula X in the presence of hydrochloric acid in an organic solvent, Thereby forming a crystal form A;
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is methanol.
  • the molar ratio of hydrochloric acid to the compound of the formula X is (0.5-2):1, preferably (0.5-1.5):1.
  • the crystallization treatment is a slow cooling.
  • the crystallization treatment temperature is 0 to 60 ° C, preferably 40 to 60 ° C.
  • the crystallization treatment time is 1-48 hours, preferably 2-40 hours.
  • the crystal is a Form B crystal of the hydrobromide salt of the compound of the formula X, ie, Form B, and in the step (3) comprises: a compound of the formula X in the presence of hydrobromic acid in an organic solvent Crystallizing treatment to form crystal form B;
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is ethyl acetate.
  • the molar ratio of hydrobromic acid to the compound of the formula X is from 0.8 to 3.5:1, preferably from 1.0 to 3.0:1.
  • the crystallization treatment is a slow cooling.
  • the crystallization treatment temperature is 0 to 60 ° C, preferably 40 to 60 ° C.
  • the crystallization treatment time is 1-48 hours, preferably 2-40 hours.
  • the crystal is a C-type crystal of the methanesulfonate of the compound of the formula X, ie, Form C, and in the step (3) comprises: a compound of the formula X in the presence of methanesulfonic acid in an organic solvent A crystallization treatment is performed to form a crystal form C.
  • the organic solvent is methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is ethyl acetate.
  • the molar ratio of methanesulfonic acid to the compound of the formula X is from 0.5 to 3.5:1, preferably from 0.6 to 3.0:1.
  • the crystallization treatment is slow cooling, anti-solvent addition or a combination thereof.
  • the crystallization treatment temperature is from 0 to 60 ° C, preferably from 40 to 60 ° C.
  • the crystallization treatment time is 1-48 hours, preferably 2-40 hours.
  • the crystal is a D-type crystal of the compound maleate of the formula X, ie, Form D, and in the step (3) comprises: a compound of the formula X in the presence of maleic acid in an organic solvent A crystallization treatment is performed to form a crystal form D.
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is acetone.
  • the molar ratio of maleic acid to the compound of the formula X is (0.6-2):1, preferably (0.7-1.9):1.
  • the crystallization treatment is slow cooling, anti-solvent addition or a combination thereof.
  • the crystallization treatment temperature is 0 to 60 ° C, preferably 40 to 60 ° C.
  • the crystallization treatment time is 1-48 hours, preferably 2-40 hours.
  • the crystal is an E-1 type crystal of the sodium hydroxide salt of the compound of the formula X, that is, the crystal form E-1, and includes in the step (3): in an organic solvent, in the presence of sodium hydroxide,
  • the compound of the formula X is subjected to a crystallization treatment to form a crystal form E-1.
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is acetonitrile.
  • the molar ratio of sodium hydroxide to the compound of the formula X is (0.3-3):1, preferably (0.4-2.8):1.
  • the crystallization treatment is slow cooling, anti-solvent addition, slow evaporation or a combination thereof.
  • the crystallization treatment temperature is 0 to 60 ° C, preferably 40 to 60 ° C.
  • the crystallization treatment time is 1-48 hours, preferably 2-40 hours.
  • the crystal is an E-2 type crystal of the sodium hydroxide salt of the compound of the formula X, that is, the crystal form E-2, and includes in the step (3): in an organic solvent, in the presence of sodium hydroxide,
  • the compound of the formula X is subjected to a crystallization treatment to form a crystal form E-2.
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is ethyl acetate.
  • the molar ratio of sodium hydroxide to the compound of the formula X is (0.3-3):1, preferably (0.4-2.8):1.
  • the crystallization treatment is slow cooling, anti-solvent addition or a combination thereof.
  • the crystallization treatment temperature is 0 to 60 ° C, preferably 40 to 60 ° C.
  • the crystallization treatment time is 1-48 hours, preferably 2-40 hours.
  • the crystal is an E-3 type crystal of the sodium hydroxide salt of the compound of the formula X, that is, the crystal form E-3, and includes in the step (3): in an organic solvent, in the presence of sodium hydroxide,
  • the compound of the formula X is subjected to a crystallization treatment to form a crystal form E-3.
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is acetonitrile.
  • the molar ratio of sodium hydroxide to the compound of the formula X is (0.3-3):1, preferably (0.4-2.8):1.
  • the crystallization treatment is slow cooling, anti-solvent addition, slow evaporation, or a combination thereof.
  • the crystallization treatment temperature is 0 to 60 ° C, preferably 40 to 60 ° C.
  • the crystallization treatment time is from 1 to 48 hours, preferably from 2 to 40 hours.
  • the crystal is a Form F crystal of the potassium salt of the compound of the formula X, ie, Form F, and in the step (3) comprises: crystallization of the compound of the formula X in the presence of potassium hydroxide in an organic solvent Processing to form Form F.
  • the organic solvent is selected from the group consisting of methanol, ethyl acetate, acetone, acetonitrile or a mixture thereof.
  • the organic solvent is methanol.
  • the molar ratio of potassium hydroxide to the compound of the formula X is (0.5 - 3.5): 1, preferably (0.6 - 3.3): 1.
  • the crystallization treatment is slow cooling, anti-solvent addition or a combination thereof.
  • the crystallization treatment temperature is 0 to 60 ° C, preferably 40 to 60 ° C.
  • the crystallization treatment time is 1-48 hours, preferably 2-40 hours.
  • the crystal is a Form I crystal of the free base of the compound of Formula X, that is, Form I, and in Step (3) includes: crystallizing the compound of Formula X in an organic solvent to form Form I.
  • the crystallization treatment is slow evaporation, slow cooling, anti-solvent addition, suspension stirring or a combination thereof, preferably slow evaporation and slow cooling.
  • the crystallization treatment is slow volatilization
  • the organic solvent is selected from the group consisting of acetone, acetonitrile, ethyl acetate or a mixture thereof.
  • the crystallization treatment is a slow cooling
  • the organic solvent is selected from the group consisting of methanol, ethanol, acetone, acetonitrile, ethyl acetate or a mixture thereof.
  • the crystallization treatment is an anti-solvent addition
  • the organic solvent is selected from the group consisting of dimethylacetamide and water, ethyl acetate and n-heptane.
  • the crystallization treatment is suspension stirring
  • the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, water, and A. Tert-butyl ether or a mixture thereof.
  • the crystal is a V-form crystal of the free base of the compound of the formula X, that is, the crystal form V, and in the step (3), the compound of the formula X is subjected to a crystallization treatment in an organic solvent to form a crystal form V.
  • the crystallization treatment is slow volatilization
  • the organic solvent is selected from tetrahydrofuran.
  • the crystal is a Form VI crystal of the free base of the compound of Formula X, that is, Form VI, and in Step (3) includes: crystallizing the compound of Formula X in an organic solvent to form Form VI.
  • the crystallization treatment is an anti-solvent addition
  • the organic solvent is selected from acetone and water.
  • the crystal is a VII type crystal of the free base of the compound of the formula X, that is, the form VII, and in the step (3), the compound of the formula X is subjected to a crystallization treatment in an organic solvent to form a form VII.
  • the crystallization treatment is an anti-solvent addition
  • the organic solvent is selected from the group consisting of methanol and water.
  • a pharmaceutical composition comprising: (a) a compound of formula X according to any one of the first aspects of the invention, or a pharmaceutically acceptable salt thereof, or a polymorph; and (b) a pharmaceutically acceptable carrier.
  • a fourth aspect of the invention provides the use of a compound of formula X according to any one of the first aspects of the invention, or a pharmaceutically acceptable salt thereof, or a polymorph thereof, or a pharmaceutical composition according to the third aspect, for use For the preparation of drugs for the treatment of pain, depression, cardiovascular disease, respiratory disease or mental illness.
  • compound of the invention includes a compound of formula X of the invention, a pharmaceutically acceptable salt of a compound of formula X of the invention, and a polymorph of the invention.
  • the compound of the formula X or the compound of the formula X may be used interchangeably, and unless otherwise specified, it generally means a free base form.
  • the compound of the formula X is 5-chloro-4-((4-(4-chloro-3-methylphenyl)piperazin-1-yl)methyl)-N-(cyclopropylsulfonyl) 2-fluorobenzamide.
  • free base sample or “free base” means the free base of the compound of formula X prepared in Example 1.
  • the pharmaceutically acceptable salt is preferably selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, L-lactate, maleate, fumarate, succinic acid.
  • Salt L-malate, adipate, L-tartrate, hippurate, citrate, mucate, glycolate, D-glucuronate, benzoate, gentisic acid Salt, nicotinate, ethanedisulfonate, oxalate, methanesulfonate, besylate, 2-hydroxyethanesulfonate and hydrobromide.
  • the solid does not exist in an amorphous form or in a crystalline form.
  • the molecules are positioned within the three-dimensional lattice lattice.
  • polymorphism When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattices (this property is called "polymorphism"), forming crystals with different crystalline forms, and these various crystalline forms are It is called "polymorph”.
  • Different polymorphs of a given substance may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, bulk mode, flowability, and/or solid state stability.
  • the solubility limit of the compound of interest can be exceeded by operating the solution to complete production-scale crystallization. This can be done in a number of ways, for example, by slow cooling, by dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods.
  • the solubility of the compound of interest can be lowered by adding an antisolvent or a solvent having a low solubility in the compound or a mixture of such a solvent. Another alternative is to adjust the pH to reduce solubility.
  • crystallization See Crystallization, Third Edition, J W Mull Fns, Butt Frworth-HFin Fman Ltd., 1993, ISBN 0750611294.
  • solution stirring means that a solution of the compound of the formula X and the corresponding acid or the corresponding acid is mixed in a suitable solvent to form a turbid liquid, or the compound of the formula X is mixed with a suitable solvent to form a turbid liquid, followed by stirring.
  • a suitable solvent can be water or an organic solvent.
  • slow volatilization refers to a method in which a solution of a compound of the formula X or a solution containing a compound of the formula X and a corresponding acid is slowly volatilized at a certain temperature to obtain a crystal.
  • the "anti-solvent addition” according to the present invention is a method of decomposing a crystal by adding another suitable solvent to a solution of the compound of the formula X.
  • salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Similarly, in the final desired form of the medium having less solubility than the reactants, the completion of the synthesis reaction allows the final product to crystallize directly.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • room temperature generally refers to 4-30 ° C, preferably 20 ⁇ 5 ° C.
  • crystal of the present invention In the present invention, “crystal of the present invention”, “crystal form of the present invention”, “polymorph of the present invention” and the like are used interchangeably.
  • polymorph of the compound of the formula X and “polymorph of the compound of the formula X” are used interchangeably.
  • polymorph of the invention includes a free base of a compound of formula X or a pharmaceutically acceptable salt of a compound of formula X (eg, hydrochloride, sulfate, hydrobromide, phosphate, methanesulfonic acid).
  • a polymorph of a salt, a maleate, an L-tartrate, a citrate, a fumarate, or a solvate of a compound of formula X which also includes the same salt (eg, hydrochloride, sulfate)
  • Different polymorphs of hydrobromide, phosphate, methanesulfonate, maleate, L-tartrate, citrate, fumarate or solvate are examples of hydrobromide, phosphate, methanesulfonate, maleate, L-tartrate, citrate, fumarate or solvate.
  • Preferred polymorphs of the invention include, but are not limited to: (i) Form A, Form B, Form C, Form D, Form E-1, Form E-2, Form E -3, Form F (crystal form of salt); and (ii) Forms I, II, III, IV, V, VI, VII (crystal form of the compound of formula X).
  • the polymorph of the compound of formula X or a pharmaceutically acceptable salt can be characterized by known methods or apparatus, for example, in a variety of ways and apparatus as follows.
  • Methods for determining X-ray powder diffraction of crystalline forms are known in the art.
  • an X-ray powder diffractometer is used to acquire a spectrum using a copper radiation target at a scanning speed of 2° per minute.
  • the polymorph of the compound of the formula X of the present invention or a pharmaceutically acceptable salt thereof has a specific crystal form and has a specific characteristic peak in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • DSC differential calorimetric scanning analysis
  • a compound of formula X of the present invention can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers.
  • compositions of the present invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • the "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • terapéuticaally effective amount refers to an amount that is functional or active to a human and/or animal and that is acceptable to humans and/or animals.
  • the therapeutically effective amount of the compound of the present invention contained in the pharmaceutical composition of the present invention or the pharmaceutical composition is preferably from 0.1 mg to 5 g/kg (body weight).
  • the compounds of the invention or the pharmaceutical compositions of the invention are useful in the treatment of pain, depression, cardiovascular disease, respiratory disease or mental illness.
  • the disease or condition is selected from the group consisting of HIV-related pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, intestinal tract Jain syndrome, Crohn's disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, bone and joint Inflammation, atherosclerosis, sudden dystonia, myasthenia gravis syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudohyperaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety , schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, local and generalized tonic seizures, restless legs syndrome, Arrhythmia
  • the compounds of the invention or the pharmaceutical compositions of the invention may be used in combination with other drugs in certain diseases to achieve the desired therapeutic effect.
  • the main advantages of the present invention include: the compound of the present invention is highly selective to the Nav1.7 sodium ion channel and has stable stability of liver microsome metabolism relative to Nav1.5, Nav1.8, Cav3.2 and hERG potassium ion channels. Sex.
  • LC-MS liquid chromatography-mass spectrometry
  • 1 H NMR Bruk Fr A VAN CF-400 nuclear magnetic instrument, internal standard is tetramethylsilane (TMS).
  • LC-MS AgilFnt 1200 HPLC SystFm / 6140 MS LC/MS (purchased from Agilent), column WatFrsX-BridgF, 150 x 4.6 mm, 3.5 ⁇ m.
  • Preparative High Performance Liquid Chromatography prF-HPLC: WatFrs PHW007, column X Bridg F C18, 4.6*150 mm, 3.5 um.
  • ISCO Combiflash-Rf75 or Rf200 automatic column analyzer AgFla 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • Known starting materials can be synthesized by or according to methods known in the art, or can be used by companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich ChFmical Company, AccFla ChFm Bio Inc and Dari Chemicals. buy.
  • the reactions were all carried out under a nitrogen or argon atmosphere.
  • the solution means an aqueous solution.
  • DMF means dimethylformamide
  • DMSO means dimethyl sulfoxide
  • THF means tetrahydrofuran
  • DIFA means N,N-diisopropylethylamine
  • EA or EtOAc means ethyl acetate
  • PF means petroleum ether
  • DCDMH stands for 1,3-dichloro-5,5-dimethylhydantoin
  • EDC.HCl stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • ACN is acetonitrile.
  • MeOH is methanol
  • EtOH is ethanol
  • IPA is isopropanol
  • Actone is acetone
  • MTBE is methyl tert-butyl ether
  • THF is tetrahydrofuran.
  • the powder X-ray diffraction pattern was acquired by a method known in the art, and the XRPD pattern was collected on a D8 ADVANCE X-ray powder diffraction analyzer.
  • the XRPD test parameters are shown in Table 16 below.
  • each peak in the figure is determined by 2 ⁇ (°). It will be appreciated that different instruments and/or conditions may result in slightly different data being produced, with varying positions and relative intensities of the peaks.
  • the intensity division of the peaks only reflects the approximate size of the peaks at each location.
  • Each crystal form of the present invention has a diffraction peak having the highest peak height as a base peak, and its relative intensity is defined as 100%.
  • I 0 the ratio of the peak height to the peak height of the other peaks is taken as the relative intensity I/.
  • I0 the division of the relative intensity of each peak is defined as shown in Table 17 below:
  • Relative intensity I/I0 (%) definition 50 ⁇ 100 VS (very strong) 20 ⁇ 50 S (strong) 10-20 M (medium) 0 to 10 W (weak)
  • the salt of the present invention or its crystal form determines the acid-base molar ratio by HPLC/IC or 1 H NMR.
  • TGA and DSC spectra were collected on a TGA Q500 V20.10 Build 36 thermogravimetric analyzer and a DSC Q2000 V24.4 Build 116 differential scanning calorimeter.
  • the test parameters are shown in Table 19 below.
  • the dynamic moisture adsorption (DVS) curve was acquired on a DVS Intrinsic of SMS (Surface Measurement Systems).
  • the DVS test parameters are listed in Table 20 below.
  • Step 1 Compound Xa-1 (90 g, 0.438 mol), N-Boc-piperazine (114 g, 0.613 mol), pd 2 (dba) 3 (4.0 g, 0.004 mol), BINAP (5.1 g, 0.008 mol), A solution of potassium tert-butoxide (98 g, 0.876 mol) in 1,4-dioxane (1 L) was stirred at 100 ° C for 3 h. The filtrate was extracted with ethyl acetate (1 mL). ESI-MS [M+H] + : 311.2.
  • Step 2 A solution of compound Xa-2 (82 g, 0.264 mol) in MeOH (EtOAc) (EtOAc) The mixture was allowed to warm to room temperature overnight, and the reaction mixture was filtered and evaporated, mjjjjj ESI-MS [M+H] + : 211.1.
  • Step 1 Compound X-1 (100.1 g, 0.65 mol) was added to concentrated sulfuric acid (300 ml) and DCDMH (64.03 g, 0.325 mol) was added portionwise over 30 min. The mixture was slowly warmed to 40 ° C over 2 hours and the reaction was clarified. The mixture was slowly cooled to room temperature, a solid precipitated and stirred at room temperature for 16 h. The mixture was poured into ice water, filtered, and the filtered cake was washed with water and evaporated ESI-MS [M+H] + : 189.
  • Step 2 Compound X-2 (128 g, 0.677 mol), cyclopropylsulfonamide (164 g, 1.354 mol), EDC.HCl (260 g, 1.354 mol), DMAP (83 g, 0.677 mol), DIPEA (262 g, 2.031 mol) The mixed solution of dichloromethane (1200 mL) was stirred at room temperature for 3 days.
  • Step 3 Compound 3 (100 g, 0.342 mol), NBS (91.4 g, 0.514 mol) and azobisisobutyronitrile (2.8 g, 0.017 mol) in acetonitrile (1 L) was heated to 80 ° C and stirred for 3 hours. The filtrate was spun dry using a rotary evaporator.
  • Step 4 A mixed solution of compound X-4 (88 g, 0.237 mol), Compound Xa (58.7 g, 0.237 mol), potassium carbonate (65.4 g, 0.474 mol) in DMF (900 mL) was stirred at 80 ° C for 3 h. The reaction mixture was poured into water (1.5 L), EtOAc (EtOAc (EtOAc) Concentrate to dryness. The residue was purified by EtOAc EtOAcjjjjj MS m/z (ESI): 500.2 [M+H] + .
  • free base sample About 20 mg of the compound of the formula X prepared in Example 1 (hereinafter referred to as "free base sample”) was weighed into a glass vial, and an appropriate amount of the following solvent (Table 21) was added thereto to obtain a near-saturated solution, which was sufficiently dissolved by ultrasonication, and then filtered. Then, 20-200 uL of the corresponding solvent was added to the clarified solvent, and the mixture was slowly volatilized at room temperature. After the solvent was completely evaporated, the resulting solid was collected and subjected to XRPD test. The X-ray powder diffraction pattern is shown in Figure 9-1. The DSC/TGA/DVS diagrams are shown in Figures 9-2, 9-3, and 9-4.
  • the reaction liquid in the step 4 of Example 1 was poured into water, extracted with ethyl acetate, dried and concentrated. Add ethanol to suspension and stir for 2h, filter, and recrystallize the filter cake by methanol to obtain the free base crystal form II.
  • the powder X-ray diffraction pattern is shown in Figure 10-1 (the 2 ⁇ angle has been marked), and the DSC/DVS pattern is 10 -2 and 10-3 are shown.
  • the sample has a melting absorption peak at 130.44 ° C (starting temperature) and 167.49 ° C; the DVS curve indicates that the sample is hygroscopic.
  • the reaction liquid in the step 4 of Example 1 was poured into water, extracted with ethyl acetate, dried and concentrated. Add ethanol to dissolve, spin dry, add 1N hydrochloric acid and ethyl acetate, stir for 1-2h, filter to obtain the solid product is free base crystal form III, the powder X-ray diffraction pattern is shown in Figure 11-1 (2 ⁇ angle has been marked).
  • the DSC/TGA/DVS spectra are characterized as shown in Figures 11-2, 11-3 and 11-4. It can be seen from the DSC chart that there is an inflection point at about 100 ° C, a melting absorption peak at 181.9 ° C (starting temperature), and a weight loss of 0.714% when heated to 100 ° C.
  • the DVS curve indicates that the sample is slightly hygroscopic.
  • the sample was shaken in ACE and MeOH solvent at 50 ° C for 1 day, and the crystal form was unchanged.
  • the sample was mixed with Form IV and shaken in ACE and MeOH solvent at 50 ° C for 1 day, all converted to crystal.
  • Type I speculated that the sample is metastable crystalline, and Form I is more stable.
  • the reaction liquid in the step 4 of Example 1 was poured into water, extracted with ethyl acetate, dried, concentrated to a small amount of ethyl acetate, 1N hydrochloric acid was added and stirred for 1 hour, filtered, and the filter cake was washed with ethanol and filtered to obtain a solid product. That is, the free base crystal form IV, the powder X-ray diffraction pattern is shown in Figure 12-1 (the 2 ⁇ angle has been marked), and the DSC/TGA/DVS spectrum is characterized as shown in Figures 12-2, 12-3 and 12-4.
  • the free base sample only formed salt with hydrochloric acid, hydrobromic acid, methanesulfonic acid, maleic acid, and the free base sample was not salted with methanesulfonic acid in methanol, acetonitrile and acetone, and maleic acid in methanol, acetic acid. There is no salt in the ethyl ester and acetonitrile, and no salt with NaOH in methanol and acetone.
  • Forms A, D, E-3 and F were weighed separately at 60 ° C and 70 ° C at 70 ° RH, while another set of samples was sealed and stored at 5 ° C as a control, at 7 and 21 days. The crystal form and purity change were separately examined. Results As shown in Table 27 below, the four crystal forms showed good stability at 60 degrees and the crystal form did not change.
  • Forms A, D, E-3, and F are shown in Figures 1-5, 4-6, 7-5, and 8-5, respectively.
  • Form A absorbs 0.4% under the condition of RH of 95%, slightly hygroscopicity
  • Form D absorbs 0.07% under the condition of RH of 95%, and has almost no hygroscopicity
  • Form F absorbs moisture when RH is 85%. 4%, with hygroscopicity
  • Form E-3 absorbs 2% when RH is 85%, and has hygroscopicity.
  • the solubility of the five crystal forms in pH 4.5, pH 6.8, 0.1 M HCL was not significantly different from that of the free base samples, and the solubility of crystal forms E-1, E-3 and Form F in water was significantly improved. It reaches 2.7mg/ml or more.
  • hydrobromide salt of the compound of the formula X and the starch are mixed and sieved in a usual manner, and then uniformly mixed with the other components described above, and directly compressed.
  • the crystal form A and the starch are mixed and sieved, and then uniformly mixed with the other components described above, and directly compressed.
  • Capsules of Form I were prepared from the components shown in Table 31 below:
  • the crystalline form I and the starch are mixed and sieved, and then uniformly mixed with the other components described above, and filled into ordinary gelatin capsules.
  • Test Example 1 Manual patch clamp experiment of hNav1.7 and hNav1.5 channels
  • Diaphragm voltage clamp electrophysiology can directly measure and quantify current blockade of voltage-gated sodium channels (various Nav) and can determine the time and voltage dependence of blockade, which has been interpreted as resting, open and sodium channels The difference in binding in the inactive state reflects the inhibitory or activating effect of the compound (Hille, B., Journal of General Physiology (1977), 69: 497-515).
  • Representative compounds of the invention were tested using a manual patch clamp experiment.
  • the purpose of this study was to test the effect of compounds on the ion channel current on a stable cell line transfected with a particular ion channel using a manual patch clamp method.
  • the stable cell lines CHO-hNav1.7 and HEK-hNav1.5 used were from Genionics and WuXi Apptec (Shanghai), respectively.
  • the manual patch clamp experimental protocol is as follows:
  • the positive control drug and the test compound were first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and stored in a certain concentration (100 nM, 1000 nM) stock solution.
  • DMSO Sigma-Aldrich, D2650
  • the above stock solution was serially diluted with DMSO before the experiment, and then used outside the cell.
  • the solution is further diluted to give the test solution at the desired concentration.
  • the final concentration of DMSO in the extracellular fluid does not exceed 0.30%.
  • This stimulation procedure can also be referred to as a channel state dependent voltage stimulation procedure.
  • the other is a non-inactivation stimulation program that maintains the clamp potential at -120 mV, gives a voltage stimulus to -10 mV, continues for 20 ms to draw sodium current, and finally returns to the clamp potential. That is to say, under the conditions of the stimulation program, all the channels have not experienced the inactivation state, but are directly activated from the resting state.
  • the time interval of the above two voltage stimulation programs is 10s.
  • the inhibitory effect of the compound was calculated by the change in current before and after dosing, and the IC 50 value was fitted by the Hill equation.
  • a compound is state dependent on the channel if it exhibits a multiple of the channel effect under the two different voltage stimuli described above. The results are shown in Table 33 and Table 34, respectively.
  • the free base of the compound of the formula X of the present invention has a high inhibitory activity against Nav1.7, and further studies have found that a nitrogen atom and a benzene ring or a pyridine on a nitrogen-containing heterocyclic ring on a six-membered (piperazine ring) Whether the carbon atoms on the ring are directly connected or not has a significant effect on the inhibitory activity of Nav1.7. Studies have shown that when the nitrogen atom is not directly connected to the benzene ring or the pyridine ring, the benzene ring or the pyridine ring passes through a group such as a methylene group or a carbonyl group.
  • the inhibitory activity is significantly reduced. Further, when a benzene ring or a pyridine ring is bonded to a nitrogen atom through a group such as a methylene group or a carbonyl group, and R 6 is a methyl group, the inhibitory activity is remarkably lowered.
  • Test Example 2 Effect on hERG potassium channel
  • the cells used in this assay were CHO cell lines transfected with hERG cDNA and stably expressing the hERG channel (supplied by Sophion Bioscience, Denmark) with a cell number of P15.
  • the cells were cultured in medium containing the following components (all from Invitrogen): Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 ⁇ l/ml hygromycin B, 100 ⁇ l/ml Geneticin.
  • CHO hERG cells were grown in culture dishes containing the above culture medium and cultured in an incubator containing 5% CO 2 at 37 °C. CHO hERG cells were transferred to circular glass slides in petri dishes 24 to 48 hours prior to electrophysiological experiments and grown under the same culture and culture conditions as above. The density of CHO hERG cells on each round glass piece needs to be achieved by the vast majority of cells being independent, individual requirements.
  • Reagent External fluid mM
  • Internal fluid mM
  • CaCl 2 2 5.37 MgCl 2 1 1.75
  • KCl 4 120 NaCl 145 - Glucose 10 - HEPES 10 10 EGTA - 5 Na-ATP - 4 PH 7.4 (adjusted with NaOH) 7.25 (adjusted with KOH)
  • Osmotic pressure Osmotic pressure ⁇ 305mOsm
  • Osmotic pressure ⁇ 295mOsm
  • This experiment used a manual patch clamp system (HEKA EPC-10 signal amplification and digital conversion system, purchased from HEKA Electronic, Germany) for the recording of whole cell currents.
  • a round glass slide with CHO hERG cells grown on it was placed in an electrophysiological recording cell under an inverted microscope.
  • the extracellular fluid was continuously perfused in the recording tank (about 1 ml per minute).
  • the experimental procedure uses conventional whole-cell patch clamp current recording techniques. Unless otherwise stated, the experiments were carried out at regular room temperature ( ⁇ 25 ° C). The cells were clamped at a voltage of -80 mV.
  • the cell clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and after 5 seconds it was clamped to -50 mV to eliminate inactivation and generate tail current.
  • the tail current peak is used as the value of the hERG current magnitude.
  • Cisapride ( ⁇ , purchased from Sigma) was used in the experiment as a positive control to ensure that the cells used were of normal quality.
  • test data was analyzed by HEKA Patchmaster (V2x73.2), Microsoft Excel and data analysis software provided by Graphpad Prism 5.0.
  • the free base of the compound of the formula X has little inhibitory activity on the potassium ion channel of hERG, and thus has selective inhibition of the potassium ion channel.
  • Buffer A 1 L of a 1 mM EDTA (Sigma, V900157-100G), 100 mM potassium dihydrogen phosphate solution was prepared.
  • Buffer B 1 L of a solution of 1 mM EDTA, 100 mM dipotassium hydrogen phosphate was prepared.
  • Buffer C Take 700 mL of Buffer B, titrate with Buffer A, and adjust to pH 7.4.
  • liver microsome solution 2.2 20 uL (20 mg/mL) human liver microsomes (Corning Lot. NO. 4133007) stock solution was added to 513.4 uL of buffer C and operated on wet ice. A 0.75 mg/mL liver microsome solution was prepared.
  • the mixture of the test compound and the ketochrome mixture were separately dispensed onto the reaction plate and operated on wet ice.
  • reaction plate was preheated in a 37-degree water bath incubator for 5 min.
  • 15 uL of reduced coenzyme II solution was added to each well to start the reaction and timed.
  • 135 uL of ice-acetonitrile containing an internal standard was added to each well to terminate the reaction.
  • reaction plate was sealed with an aluminum film and placed on a shaking mixer at 500 rpm for 5 min. The plate was then centrifuged in a centrifuge for 15 min at 3750 rpm.
  • the K value and the scale factor are calculated by those skilled in the art according to the methods described in the prior art and the liver microsome product specification.

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Abstract

一种钠离子通道抑制剂及其药学上可接受的盐和多晶型物，所述钠离子通道抑制剂是结构如式(X)所示的化合物。该钠离子通道抑制剂的制备方法，其多晶型物及制备方法，以及其药物组合物。所述化合物和药物组合物用于治疗疼痛、抑郁症、心血管疾病、呼吸系统疾病或精神疾病。

Description

钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用 技术领域
本发明属于药物化学技术领域。具体地，本发明涉及5-氯-4–((4-(4-氯-3-甲基苯基)哌嗪-1-基)甲基)-N-(环丙基磺酰基)-2-氟苯甲酰胺化合物的多晶型物、其制备方法和由其制备的药物组合物。
背景技术
最近，英国的Cox等在Nature上首次报道了编码电压门控Nav1.7通道的SCN9A基因突变导致遗传个体无痛症的出人意料研究结果。该遗传突变的个体先天失去痛觉，但机体的其它功能完全正常，此外最近的研究表明，表达在DRG神经元的电压门控Nav1.7通道参与痛信号的产生并发挥控制痛觉信号传入的闸门功能。该研究提示Nav1.7通道可能会成为选择性治疗疼痛并无副作用的药物靶点。
越来越多的身体证据表明Nav1.7在多种疼痛状态(包括急性、慢性、炎性和/或神经性疼痛)中扮演重要的角色，在人类中，Nav1.7蛋白质积累于神经瘤，特别是引起疼痛的神经瘤。Nav1.7功能增加的突变(不论是遗传性或偶发性)已被认为涉及原发性红斑性肢痛(一种特征为四肢的灼痛和发炎的疾病)，和突发性极度疼痛症。有关非选择性钠通道阻断剂利多卡因和美西律可缓和遗传性红斑性肢痛的症状，以及卡马西平可有效地减低PEPD的侵袭的次数和严重度的报道结果与上述观察相一致。Nav1.7在疼痛中扮演的角色的其他证据可见于SCN9A基因的功能丧失的突变的显型。后续的研究已显示会导致SCN9A基因的功能丧失与CIP显型的许多不同的突变。
由于Nav1.7特异地在DRG感觉神经元表达而不在心肌细胞和中枢神经系统等其它组织表达，因此研发其特异阻断剂用于治疗慢性痛，不仅可能提高疗效，且副作用也会大大减少，并且Nav1.7离子通道的选择性抑制剂几乎可用于各种疼痛的治疗。
目前虽已有专利文献报道了多类Nav1.7离子通道抑制剂，然而经过深入研究后发现，现有的一些Nav1.7离子通道抑制剂在对其他离子通道的选择性，如钾离子通道以及对人肝微粒体稳定性等方面存在不足，由于与HERG钾离子通道相关的心脏毒性以及预测化合物在肝组织清除率的人肝微粒体稳定性指标对药物开发的影响至关重要，因此迫切需要开发更加安全有效的镇痛药，使其具有较高功效和较少副作用。本发明正是在前述工作的基础上开发了代谢好且高选择性Nav1.7离子通道抑制剂的多种盐型和晶型，有助于进一步的药物开发。
发明内容
在本发明的第一方面，提供了一种结构如式(X)所示的化合物或其药学上可接受的盐或其多晶型物：
Figure PCTCN2018092895-appb-000001
在另一优选例中，所述药学上可接受的盐为酸式盐或碱式盐，其中酸式盐选自下组：盐酸盐、硫酸盐、磷酸盐、乙酸盐、L-乳酸盐、马来酸盐、富马酸盐、琥珀酸盐、L-苹果酸盐、己二酸盐、L-酒石酸盐、马尿酸盐、柠檬酸盐、粘酸盐、乙醇酸盐、D-葡萄糖醛酸盐、苯甲酸盐、龙胆酸盐、烟酸盐、乙二磺酸盐、草酸盐、甲磺酸盐、苯磺酸盐、2-羟基乙磺酸盐、氢溴酸盐；碱式盐选自下组：三乙醇胺盐、钠盐或钾盐。
在另一优选例中，所述药学上可接受的酸式盐选自下组：盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐、L-酒石酸盐、柠檬酸盐、富马酸盐、在另一优选例中，所述药学上可接受的碱式盐选自下组：钠盐或钾盐。
在另一优选例中，所述药学上可接受的酸式盐选自下组：盐酸盐、氢溴酸盐、甲磺酸盐、马来酸盐。
在另一优选例中，所述钠盐或钾盐为与选自下组的碱所形成的：氢氧化钠或氢氧化钾。
在另一优选例中，所述药学上可接受的盐选自下组：盐酸盐、马来酸盐、钾盐。
在另一优选例中，所述式X化合物或其药学上可接受的盐、或其多晶型物为无水形式、水合物形式或溶剂合物形式。
在另一优选例中，所述多晶型物为式X化合物的多晶型物。
在另一优选例中，所述多晶型物为式X化合物药学上可接受的盐的多晶型物，且所述药学上可接受的盐选自：盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐、L-酒石酸盐、柠檬酸盐、富马酸盐、钠盐或钾盐。
在另一优选例中，所述多晶型物为式X化合物药学上可接受的盐的多晶型物，且所述药学上可接受的盐选自：盐酸盐、氢溴酸盐、甲磺酸盐、马来酸盐、钠盐或钾盐。
在另一优选例中，所述多晶型物为式X化合物药学上可接受的盐的多晶型物，且所述药学上可接受的盐选自：盐酸盐、马来酸盐或钾盐。
在另一优选例中，所述式X化合物药学上可接受的盐为无水形式。
在另一优选例中，所述多晶型物为无水形式。
在另一优选例中，所述药学上可接受的盐为盐酸盐，其中，盐酸与式X化合物的摩尔比为(0.5-2):1，较佳的(0.5-1.5):1。
在另一优选例中，所述药学上可接受的盐为氢溴酸盐，其中氢溴酸与式X化合物的摩尔比为0.8-3.5:1，较佳的1.0-3.0:1。
在另一优选例中，所述药学上可接受的盐为甲磺酸盐，其中，甲磺酸与式X化合物的摩尔比为0.5-3.5:1，较佳的0.6-3.0:1。
在另一优选例中，所述药学上可接受的盐为马来酸盐，其中，马来酸与式X化合 物的摩尔比为(0.6-2):1，较佳的(0.7-1.9):1。
在另一优选例中，所述药学上可接受的盐为氢氧化钠盐，其中，氢氧化钠与式X化合物的摩尔比为(0.3-3):1，较佳的(0.4-2.8):1。
在另一优选例中，所述药学上可接受的盐为氢氧化钾盐，其中，氢氧化钾与式X化合物的摩尔比为(0.5-3.5):1，较佳的(0.6-3.3):1。
在另一优选例中，所述多晶型物为式X化合物盐酸盐的A型结晶，即晶型A，其X射线粉末衍射图在下组A1的衍射角2θ(°)值处具有峰：12.19±0.20、16.30±0.20、17.76±0.20、18.61±0.20、23.23±0.20、25.17±0.20。
在另一优选例中，所述晶型A的X射线粉末衍射图还包含在2个或2个以上选自下组A2的衍射角2θ(°)值处的峰：13.52±0.20、14.39±0.20、19.65±0.20、20.26±0.20、27.23±0.20、29.48±0.20、32.10±0.20。
在另一优选例中，所述晶型A的X射线粉末衍射图在选自A1和A2中的6个或更多个或全部(如6,7,8,9,10,11,12,13等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型A的X射线粉末衍射图在下表1所示的2θ(°)值处具有峰，各峰相对强度如表1所示。
表1
Figure PCTCN2018092895-appb-000002
在另一优选例中，所述的晶型A的X射线粉末衍射图谱基本如图1-1所表征。
在另一优选例中，所述晶型A中盐酸与式X化合物的摩尔比为(0.5-2)︰1，较佳的(0.5-1.5)︰1。
在另一优选例中，所述晶型A还具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图1-2所表征；
(2)热重分析图谱基本如图1-3所表征；
(3)所述晶型A的熔点为240-255℃，较佳的为243-252℃。
在另一优选例中，所述晶型A为无水形式。
在另一优选例中，所述多晶型物为式X化合物的氢溴酸盐B型结晶，即晶型B，其X射线粉末衍射图在下组B1的衍射角2θ(°)值处具有峰：12.40±0.20。
在另一优选例中，所述晶型B的X射线粉末衍射图还包含在2个或2个以上选自下组B2的衍射角2θ(°)值处的峰：8.27±0.20、13.28±0.20、16.53±0.20、18.36±0.20、18.68±0.20、19.68±0.20、20.07±0.20、20.73±0.20、22.60±0.20、24.92±0.20、25.35±0.20。
在另一优选例中，所述晶型B的X射线粉末衍射图还包含在2个或2个以上选自下组B3的衍射角2θ(°)值处的峰：17.43±0.20。
在另一优选例中，所述晶型B的X粉末衍射图在选自组B1、B2和B3中的6个或更多个或全部(如6,7,8,9,10,11,12,13等)的衍射角2θ(°)值处具有峰：
在另一优选例中，所述晶型B的X射线粉末衍射图在下表2所示的2θ(°)值处具有峰，各峰相对强度如表2所示。
表2
Figure PCTCN2018092895-appb-000003
在另一优选例中，所述晶型B的X射线粉末衍射图谱基本如图2-1所表征。
在另一优选例中，所述晶型B中，氢溴酸与式X化合物的摩尔比为0.8-3.5:1，较佳的1.0-3.0:1。
在另一优选例中，所述晶型B的差示扫描量热法分析图谱基本如图2-2所表征。
在另一优选例中，所述多晶型物为式X化合物的甲磺酸盐C型结晶，即晶型C，其X射线粉末衍射图在下组C1的衍射角2θ(°)值处具有峰：8.93±0.20、15.32±0.20、21.86±0.20、22.56±0.20、23.75±0.20、25.69±0.20、27.37±0.20。
在另一优选例中，所述晶型C的X射线衍射图还包含在2个或2个以上选自下组C2的衍射角2θ(°)值处的峰：14.36±0.20、16.36±0.20、17.88±0.20、18.68±0.20、21.15±0.20、21.35±0.20、28.02±0.20。
在另一优选例中，所述晶型C的X射线衍射图还包含在2个或2个以上选自下组C3的衍射角2θ(°)值处的峰：12.95±0.20、13.80±0.20、15.78±0.20、17.24±0.20、19.19±0.20。
在另一优选例中，所述晶型C的X射线衍射图在选自组C1、C2和C3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15,16,17,18,19等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型C的X射线衍射图在下表3所示的2θ(°)值处具有峰，各峰相对强度如表3所示。
表3
Figure PCTCN2018092895-appb-000004
在另一优选例中，所述晶型C的X射线衍射图谱基本如图3-1所表征。
在另一优选例中，所述晶型C中，甲磺酸与式X化合物的摩尔比为0.5-3.5:1，较佳的0.6-3.0:1。
在另一优选例中，所述晶型C的差示扫描量热法分析图谱基本如图3-2所表征。
在另一优选例中，所述多晶型物为式X化合物的马来酸盐D型结晶，即晶型D，其X射线粉末衍射图在下组D1的衍射角2θ(°)值处具有峰：5.06±0.20、8.24±0.20、10.08±0.20、15.14±0.20、16.18±0.20、18.95±0.20、19.83±0.20、20.40±0.20、21.38±0.20、22.14±0.20、26.51±0.20。
在另一优选例中，所述晶型D的X射线粉末衍射图还包含在2个或2个以上选自下组D2的衍射角2θ(°)值处的峰：12.03±0.20、16.77±0.20、21.05±0.20、23.94±0.20、24.27±0.20、24.70±0.20、30.70±0.20。
在另一优选例中，所述晶型D的X射线粉末衍射图还包含在2个或2个以上选自下组D3的衍射角2θ(°)值处的峰：14.24±0.20、19.33±0.20、23.46±0.20、25.10±0.20、25.53±0.20、28.09±0.20、28.40±0.20、28.85±0.20、30.23±0.20、31.15±0.20、31.48±0.20、33.57±0.20、33.86±0.20。
在另一优选例中，所述晶型D的X射线粉末衍射图在选自组D1、D2和D3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。(各峰相对强度见表4)：
表4
Figure PCTCN2018092895-appb-000005
在另一优选例中，所述晶型D的X射线粉末衍射图谱基本如图4-1所表征。
在另一优选例中，所述晶型D中，马来酸盐与式X化合物的摩尔比为(0.6-2):1，较佳的(0.7-1.9):1。
在另一优选例中，所述晶型D具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图4-2所表征；
(2)热重分析图谱基本如图4-3所表征；
(3)所述晶型D的熔点为200-210℃，较佳的为202-208℃。
在另一优选例中，所述晶型D为无水形式。
在另一优选例中，所述多晶型物为式X化合物的钠盐E-1型结晶，即晶型E-1，其X射线粉末衍射图在下组E-1-1的衍射角2θ(°)值处具有峰：4.53±0.20。
在另一优选例中，所述晶型E-1的X射线粉末衍射图还包含在2个或2个以上选自下组E-1-2的衍射角2θ(°)值处的峰：6.52±0.20、9.18±0.20、16.80±0.20。
在另一优选例中，所述晶型E-1的X射线粉末衍射图包含在2个或2个以上选自下组E-1-3的衍射角2θ(°)值处的峰：8.33±0.20、10.32±0.20、18.50±0.20、19.42±0.20、23.86±0.20。
在另一优选例中，所述晶型E-1的X射线粉末衍射图在选自组E-1-1、E-1-2和E-1-3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型E-1的X射线粉末衍射图在如下表5所示的衍射角2θ(°)值处具有峰，各峰相对强度如表5所示。
表5
Figure PCTCN2018092895-appb-000006
在另一优选例中，所述晶型E-1的X射线粉末衍射图谱基本如图5-1所表征。
在另一优选例中，所述晶型E-1中，钠盐与式X化合物的摩尔比为(0.3-3):1，较佳的(0.4-2.8):1。
在另一优选例中，所述晶型E-1的差示扫描量热法分析图谱基本如图5-2所表征。
在另一优选例中，所述多晶型物为式X化合物的钠盐E-2型结晶，即晶型E-2，其X射线粉末衍射图在下组E-2-1的衍射角2θ(°)值处具有峰：6.90±0.20、14.44±0.20、16.96±0.20、17.77±0.20、18.42±0.20、19.72±0.20、22.22±0.20、22.67±0.20、27.94±0.20。
在另一优选例中，所述晶型E-2的X射线粉末衍射图还包含在2个或2个以上选自下组E-2-2的衍射角2θ(°)值处的峰：11.07±0.20、19.15±0.20、23.62±0.20、24.47±0.20、29.76±0.20。
在另一优选例中，所述晶型E-2的X射线粉末衍射图在选自组E-2-1和E-2-2中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型E-2的X射线粉末衍射图在如下表6所示的衍射角2θ(°)值处具有峰，各峰相对强度如表6所示。
表6
Figure PCTCN2018092895-appb-000007
在另一优选例中，所述晶型E-2的X射线粉末衍射图谱基本如图6-1所表征。
在另一优选例中，所述晶型E-2中，钠盐与式X化合物的摩尔比为(0.3-3):1，较佳的(0.4-2.8):1。
在另一优选例中，所述晶型E-2的差示扫描量热法分析图谱基本如图6-2所表征。
在另一优选例中，所述多晶型物为式X化合物的钠盐E-3型结晶，即晶型E-3，其X射线粉末衍射图在下组E-3-1的衍射角2θ(°)值处具有峰：7.12±0.20、7.57±0.20、9.94±0.20、10.71±0.20、17.68±0.20。
在另一优选例中，所述晶型E-3的X射线粉末衍射图还包含在2个或2个以上选自下组E-3-2的衍射角2θ(°)值处的峰：6.75±0.20、14.37±0.20、17.90±0.20、18.81±0.20、19.56±0.20、20.63±0.20、21.61±0.20、22.47±0.20、23.13±0.20、23.66±0.20、24.95±0.20、25.17±0.20、25.39±0.20。
在另一优选例中，所述晶型E-3的X射线粉末衍射图包含在2个或2个以上选自下组E-3-3的衍射角2θ(°)值处的峰：12.73±0.20、13.76±0.20、19.92±0.20。
在另一优选例中，所述晶型E-3的X射线粉末衍射图在选自组E-3-1、E-3-2和E-3-3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型E-3的X射线粉末衍射图在如下表7所示的衍射角2θ(°)值处具有峰，各峰相对强度如表7所示。
表7
Figure PCTCN2018092895-appb-000008
Figure PCTCN2018092895-appb-000009
在另一优选例中，所述晶型E-3的X射线粉末衍射图谱基本如图7-1所表征。
在另一优选例中，所述晶型E-3中，氢氧化钠与式X化合物的摩尔比为(0.3-3):1，较佳的(0.4-2.8):1。
在另一优选例中，所述晶型E-3具有选自下组中的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图7-2所表征；
(2)热重分析图谱基本如图7-3所表征。
在另一优选例中，所述晶型E-3为溶剂合物形式。
在另一优选例中，所述晶体为式X化合物的钾盐F型结晶，即晶型F，其X射线粉末衍射图在选自组F-1的衍射角2θ(°)值处具有峰：7.83±0.20、17.68±0.20、18.74±0.20。
在另一优选例中，所述晶型F的X射线粉末衍射图包含在2个或2个以上选自组F-2的衍射角2θ(°)值处的峰：6.95±0.20、9.91±0.20、12.62±0.20、14.40±0.20、16.47±0.20、20.80±0.20、21.16±0.20、22.03±0.20、23.12±0.20、23.45±0.20、24.42±0.20、25.15±0.20。
在另一优选例中，所述晶型F的X射线粉末衍射图包含在2个或2个以上选自组F-3的衍射角2θ(°)值处的峰：10.73±0.20、11.65±0.20、13.61±0.20、18.21±0.20、19.97±0.20、20.47±0.20、21.51±0.20、23.99±0.20、26.69±0.20、27.38±0.20、28.27±0.20、28.83±0.20、29.67±0.20、39.61±0.20。
在另一优选例中，所述晶型F的X射线粉末衍射图在选自F-1、F-2、F-3中的6个或更多或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型F的X射线粉末衍射图在如下表8所示的衍射角2θ(°)值处具有峰，各峰相对强度如表8所示。
表8
Figure PCTCN2018092895-appb-000010
在另一优选例中，所述晶型F的X射线粉末衍射图谱基本如图8-1所表征。
在另一优选例中，所述晶型F还具有选自以下特征中的一个或多个：
(1)差示扫描量热分析图谱基本如图8-2所表征；
(2)热重分析图谱基本如图8-3所表征。
在另一优选例中，所述晶型F为溶剂合物形式。
另一优选例中，所述多晶型物为式X所示化合物游离碱的I型结晶，即晶型I，其X射线粉末衍射图在组I-1的衍射角2θ(°)值处具有峰：7.26±0.20、18.38±0.20、23.15±0.20。
在另一优选例中，所述晶型I的X射线粉末衍射图包含在2个或2个以上选自组I-2的衍射角2θ(°)值处的峰：9.60±0.20、14.39±0.20、15.47±0.20、22.67±0.20、25.10±0.20、29.45±0.20、30.32±0.20、36.79±0.20。
在另一优选例中，所述晶型I的X射线粉末衍射图包含在2个或2个以上选自组I-3的衍射角2θ(°)值处的峰：11.10±0.20、12.81±0.20、16.03±0.20、17.43±0.20、19.06±0.20、19.44±0.20、19.99±0.20、21.37±0.20、23.68±0.20、25.65±0.20、28.30±0.20、31.02±0.20、31.69±0.20、37.57±0.20。
在另一优选例中，所述晶型I的X射线粉末衍射图在选自组I-1、I-2和I-3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型I的X射线粉末衍射图在如下表9所示的衍射角2θ(°)值处具有峰，各峰相对强度如表9所示。
表9
Figure PCTCN2018092895-appb-000011
在另一优选例中，所述晶型I的X射线粉末衍射图谱基本如下图9-1所示。
在另一优选例中，所述晶型I具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图9-2所表征；
(2)热重分析图谱基本如图9-3所表征；
(3)所述晶型I熔点为175℃-185℃，较佳的为178℃-185℃；或
(4)DVS曲线图如图9-4所表征。
在另一优选例中，所述晶型I为无水形式。
另一优选例中，所述多晶型物为式X所示化合物游离碱的II型结晶，即晶型II，其X射线粉末衍射图在组II-1的衍射角2θ(°)值处具有峰：6.84±0.20、7.74±0.20、9.94±0.20。
在另一优选例中，所述晶型II的X射线粉末衍射图包含在2个或2个以上选自组II-2的衍射角2θ(°)值处的峰：7.11±0.20、17.75±0.20、18.86±0.20、19.92±0.20、23.38±0.20、28.63±0.20。
在另一优选例中，所述晶型II的X射线粉末衍射图包含在2个或2个以上选自组II-3的衍射角2θ(°)值处的峰：10.72±0.20、13.75±0.20、15.37±0.20、15.85±0.20、18.13±0.20、21.56±0.20、24.43±0.20、27.97±0.20。
在另一优选例中，所述晶型II的X射线粉末衍射图在选自组II-1、II-2和II-3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型II的X射线粉末衍射图在如下表10所示的衍射角2θ(°)值处具有峰，各峰相对强度如表10所示。
表10
Figure PCTCN2018092895-appb-000012
在另一优选例中，所述晶型II的X射线粉末衍射图谱基本如图10-1所示。
在另一优选例中，所述晶型II具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图10-2所表征；或
(2)DVS曲线图基本如图10-3所表征。
另一优选例中，所述多晶型物为式X所示化合物游离碱的III型结晶，即晶型III，其X射线粉末衍射图在组III-1的衍射角2θ(°)值处具有峰：4.09±0.20。
在另一优选例中，所述晶型III的X射线粉末衍射图包含在2个或2个以上选自组III-2的衍射角2θ(°)值处的峰：12.22±0.20、16.34±0.20、17.83±0.20、18.63±0.20。
在另一优选例中，所述晶型III的X射线粉末衍射图包含在2个或2个以上选自组III-3的衍射角2θ(°)值处的峰：13.55±0.20、14.46±0.20。
在另一优选例中，所述晶型III的X射线粉末衍射图在选自组III-1、III-2和III-3中的6个或更多个或全部的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型III的X射线粉末衍射图在如下表11所示的衍射角2θ(°)值处具有峰，各峰相对强度如表11所示。
表11
Figure PCTCN2018092895-appb-000013
Figure PCTCN2018092895-appb-000014
在另一优选例中，所述晶型III的X射线粉末衍射图谱基本如图11-1所示。
在另一优选例中，所述晶型III具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图11-2所表征；
(2)热重分析图谱基本如图11-3所表征；或
(3)DVS图如图11-4所表征。
在另一优选例中，所述晶型III为无水形式。
另一优选例中，所述多晶型物为式X所示化合物游离碱的IV型结晶，即晶型IV，其X射线粉末衍射图在组IV-1的衍射角2θ(°)值处具有峰：4.66±0.20。
在另一优选例中，所述晶型IV的X射线粉末衍射图包含在2个或2个以上选自组IV-2的衍射角2θ(°)值处的峰：5.28±0.20、9.29±0.20、16.49±0.20、16.87±0.20、17.56±0.20、19.19±0.20、23.89±0.20。
在另一优选例中，所述晶型IV的X射线粉末衍射图包含在2个或2个以上选自组IV-3的衍射角2θ(°)值处的峰：6.62±0.20、8.46±0.20。
在另一优选例中，所述晶型IV的X射线粉末衍射图包含在组IV-1、IV-2和IV-3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型IV的X射线粉末衍射图在如下表12所示的衍射角2θ(°)值处具有峰，各峰相对强度如表12所示。
表12
Figure PCTCN2018092895-appb-000015
在另一优选例中，所述晶型IV的X射线粉末衍射图谱基本如图12-1所示。
在另一优选例中，所述晶型IV具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图12-2所表征；
(2)热重分析图谱基本如图12-3所表征；或
(3)DVS图如图12-4所表征。
在另一优选例中，所述晶型IV为溶剂合物形式。
另一优选例中，所述多晶型物为式X所示化合物游离碱的V型结晶，即晶型V，其X射线粉末衍射图在组V-1的衍射角2θ(°)值处具有峰：6.79±0.20、14.31±0.20、16.90±0.20、17.58±0.20、20.58±0.20、21.90±0.20、23.45±0.20。
在另一优选例中，所述晶型V的X射线粉末衍射图包含在2个或2个以上选自组V-2的衍射角2θ(°)值处的峰：13.67±0.20、15.15±0.20、16.35±0.20、18.45±0.20、20.96±0.20、25.15±0.20、28.19±0.20、29.19±0.20。
在另一优选例中，所述晶型V的X射线粉末衍射图在选自组V-1和V-2中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型V的X射线粉末衍射图在如下表13所示的衍射角2θ(°)值处具有峰，各峰相对强度如表13所示。
表13
Figure PCTCN2018092895-appb-000016
在另一优选例中，所述晶型V的X射线粉末衍射图谱基本如图13-1所示。
在另一优选例中，所述晶型V具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图13-2所表征；
(2)热重分析图谱基本如图13-3所表征；或
(3)DVS图如图13-4所表征。
在另一优选例中，所述晶型V为溶剂合物形式。
另一优选例中，所述多晶型物为式X所示化合物游离碱的VI型结晶，即晶型VI，其X射线粉末衍射图在组VI-1的衍射角2θ(°)值处具有峰：6.90±0.20、7.14±0.20、16.40±0.20、16.92±0.20、20.62±0.20、23.52±0.20。
在另一优选例中，所述晶型VI的X射线粉末衍射图包含在2个或2个以上选自组VI-2的衍射角2θ(°)值处的峰：13.76±0.20、14.26±0.20、18.21±0.20、18.46±0.20、21.92±0.20、25.13±0.20、29.19±0.20。
在另一优选例中，所述晶型VI的X射线粉末衍射图包含在2个或2个以上选自组VI-3的衍射角2θ(°)值处的峰：17.65±0.20、21.01±0.20、22.55±0.20、23.03±0.20、26.31±0.20。
在另一优选例中，所述晶型VI的X射线粉末衍射图在选自组VI-1、VI-2和VI-3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型VI的X射线粉末衍射图在如下表14所示的衍射角2θ(°)值处具有峰，各峰相对强度如表14所示。
表14
Figure PCTCN2018092895-appb-000017
Figure PCTCN2018092895-appb-000018
在另一优选例中，所述晶型VI的X射线粉末衍射图谱基本如图14-1所示。
在另一优选例中，所述晶型VI具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图14-2所表征；
(2)热重分析图谱基本如图14-3所表征；或
(3)DVS图如图14-4所表征。
在另一优选例中，所述晶型VI为无水形式。
另一优选例中，所述多晶型物为式X所示化合物游离碱的VII型结晶，即晶型VII，其X射线粉末衍射图在组VII-1的衍射角2θ(°)值处具有峰：7.11±0.20、14.22±0.20。
在另一优选例中，所述晶型VII的X射线粉末衍射图包含在2个或2个以上选自组VII-2的衍射角2θ(°)值处的峰：18.16±0.20、21.29±0.20、29.25±0.20、31.53±0.20、36.50±0.20。
在另一优选例中，所述晶型VII的X射线粉末衍射图包含在2个或2个以上选自组VII-3的衍射角2θ(°)值处的峰：23.02±0.20、30.09±0.20、37.46±0.20。
在另一优选例中，所述晶型VI的X射线粉末衍射图在选自组VII-1、VII-2和VII-3中的6个或更多个或全部(如6,7,8,9,10,11,12,13,14,15等)的衍射角2θ(°)值处具有峰。
在另一优选例中，所述晶型VII的X射线粉末衍射图在如下表15所示的衍射角2θ(°)值处具有峰，各峰相对强度如表15所示。
表15
Figure PCTCN2018092895-appb-000019
在另一优选例中，所述晶型VII的X射线粉末衍射图谱基本如图15-1所示。
在另一优选例中，所述晶型VII具有选自下组的一个或多个特征：
(1)差示扫描量热法分析图谱基本如图15-2所表征；
(2)热重分析图谱基本如图15-3所表征；或
(3)DVS图如图15-4所表征。
在另一优选例中，所述晶型VII为无水形式。
本发明的第二方面，提供了一种制备本发明第一方面所述的式X所示化合物或其药学上可接受盐的制备方法，包括步骤：
(1)在碱性条件下，将式X-4与X-a进行反应，从而成式X化合物；
Figure PCTCN2018092895-appb-000020
(2)任选的将式X化合物与酸或碱进行成盐反应，从而形成药学上可接受的盐；
(3)任选的将步骤(1)或(2)所形成的式X化合物或其药学上可接受的盐进行结晶处理，从而得到晶体。
在另一优选例中，所述方法包括以下子方法(A)-(E)和(I)、(II)中的任一子方法。
(A)所述晶体为式X化合物盐酸盐的A型结晶，即晶型A，并且在步骤(3)中包括：在有机溶剂中，在盐酸存在下，对式X化合物进行结晶处理，从而形成晶型A；
在另一优选例中，子方法(A)中，所述有机溶剂选自下组：甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为甲醇。
在另一优选例中，在子方法(A)中，盐酸与式X化合物的摩尔比为(0.5-2):1，较佳的(0.5-1.5):1。
在另一优选例中，在子方法(A)中，结晶处理方式为缓慢降温。
在另一优选例中，在子方法(A)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(A)中，结晶处理时间1-48小时，较佳的为2-40小时。
(B)所述晶体为式X化合物氢溴酸盐的B型结晶，即晶型B，并且在步骤(3)中包括：在有机溶剂中，在氢溴酸的存在下，对式X化合物进行结晶处理，从而形成晶型B；
在另一优选例中，在子方法(B)中，所述有机溶剂选自下组：甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为乙酸乙酯。
在另一优选例中，在子方法(B)中，氢溴酸与式X化合物的摩尔比为0.8-3.5:1，较佳地为1.0-3.0:1。
在另一优选例中，在子方法(B)中，结晶处理方式为缓慢降温。
在另一优选例中，在子方法(B)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(B)中，结晶处理时间1-48小时，较佳的为2-40小时。
(C)所述晶体为式X化合物甲磺酸盐的C型结晶，即晶型C，并且在步骤(3)中包括：在有机溶剂中，在甲磺酸的存在下，对式X化合物进行结晶处理，从而形成晶型C。
在另一优选例中，在子方法(C)中，所述有机溶剂为甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为乙酸乙酯。
在另一优选例中，在子方法(C)中，甲磺酸与式X化合物的摩尔比为0.5-3.5:1，较佳的0.6-3.0:1。
在另一优选例中，在子方法(C)中，结晶处理方式为缓慢降温、反溶剂添加或其组合。
在另一优选例中，在子方法(C)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(C)中，结晶处理时间1-48小时，较佳的为2-40小时。
(D)所述晶体为式X化合物马来酸盐的D型结晶，即晶型D，并且在步骤(3)中包括：在有机溶剂中，在马来酸的存在下，对式X化合物进行结晶处理，从而形成晶型D。
在另一优选例中，在子方法(D)中，所述有机溶剂选自下组：甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为丙酮。
在另一优选例中，在子方法(D)中，马来酸与式X化合物的摩尔比为(0.6-2):1，较佳的(0.7-1.9):1。
在另一优选例中，在子方法(D)中，结晶处理方式为缓慢降温、反溶剂添加或其组合。
在另一优选例中，在子方法(D)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(D)中，结晶处理时间1-48小时，较佳的为2-40小时。
(E)所述晶体为式X化合物氢氧化钠盐的E-1型结晶，即晶型E-1，并且在步骤(3)中包括：在有机溶剂中，在氢氧化钠的存在下，对式X化合物进行结晶处理，从而形成晶型E-1。
在另一优选例中，在子方法(E)中，所述有机溶剂选自下组：甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为乙腈。
在另一优选例中，在子方法(E)中，氢氧化钠与式X化合物的摩尔比为(0.3-3):1，较佳的(0.4-2.8):1。
在另一优选例中，在子方法(E)中，结晶处理方式为缓慢降温、反溶剂添加、缓慢挥发或其组合。
在另一优选例中，在子方法(E)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(E)中，结晶处理时间1-48小时，较佳的为2-40小时。
(F)所述晶体为式X化合物氢氧化钠盐的E-2型结晶，即晶型E-2，并且在步骤(3)中包括：在有机溶剂中，在氢氧化钠的存在下，对式X化合物进行结晶处理，从而形成晶型E-2。
在另一优选例中，在子方法(F)中，所述有机溶剂选自下组：甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为乙酸乙酯。
在另一优选例中，在子方法(F)中，氢氧化钠与式X化合物的摩尔比为(0.3-3):1，较佳的(0.4-2.8):1。
在另一优选例中，在子方法(F)中，结晶处理方式为缓慢降温、反溶剂添加或其组合。
在另一优选例中，在子方法(F)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(F)中，结晶处理时间1-48小时，较佳的为2-40小时。
(G)所述晶体为式X化合物氢氧化钠盐的E-3型结晶，即晶型E-3，并且在步骤(3)中包括：在有机溶剂中，在氢氧化钠的存在下，对式X化合物进行结晶处理，从而形成晶型E-3。
在另一优选例中，在子方法(G)中，所述有机溶剂选自下组：甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为乙腈。
在另一优选例中，在子方法(G)中，氢氧化钠与式X化合物的摩尔比为(0.3-3):1，较佳的(0.4-2.8):1。
在另一优选例中，在子方法(G)中，结晶处理方式为缓慢降温、反溶剂添加、缓慢挥发或其组合。
在另一优选例中，在子方法(G)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(G)中，结晶处理时间1-48小时，较佳的为2-40小时。
(H)所述晶体为式X化合物钾盐的F型结晶，即晶型F，并且在步骤(3)中包括：在有机溶剂中，在氢氧化钾的存在下，对式X化合物进行结晶处理，从而形成晶型F。
在另一优选例中，在子方法(H)中，所述有机溶剂选自下组：甲醇、乙酸乙酯、丙酮、乙腈或其混合物，较佳地，所述有机溶剂为甲醇。
在另一优选例中，在子方法(H)中，氢氧化钾与式X化合物的摩尔比为(0.5-3.5):1，较佳的(0.6-3.3):1。
在另一优选例中，在子方法(H)中，结晶处理方式为缓慢降温、反溶剂添加或其组合。
在另一优选例中，在子方法(H)中，结晶处理温度为0-60℃，较佳的为40-60℃。
在另一优选例中，在子方法(H)中，结晶处理时间1-48小时，较佳的为2-40小时。
(I)所述晶体为式X化合物游离碱的I型结晶，即晶型I，并且在步骤(3)中包括：在有机溶剂中，对式X化合物进行结晶处理，从而形成晶型I。
在另一优选例中，子方法(I)中，所述结晶处理为缓慢挥发、缓慢降温、反溶剂添加、悬浮搅拌或其组合，优选缓慢挥发和缓慢降温。
在另一优选例中，子方法(I)中，所述结晶处理为缓慢挥发，所述有机溶剂选自下组：丙酮、乙腈、乙酸乙酯或其混合物。
在另一优选例中，子方法(I)中，所述结晶处理为缓慢降温，所述有机溶剂选自下组：甲醇、乙醇、丙酮、乙腈、乙酸乙酯或其混合物。
在另一优选例中，子方法(I)中，所述结晶处理为反溶剂添加，所述有机溶剂选自以下组合：二甲基乙酰胺和水，乙酸乙酯和正庚烷。
在另一优选例中，子方法(I)中，所述结晶处理为悬浮搅拌，所述有机溶剂选自下组：甲醇、乙醇、异丙醇、丙酮、乙腈、乙酸乙酯、水、甲基叔丁基醚或其混合物。
(M)所述晶体为式X化合物游离碱的V型结晶，即晶型V，并且在步骤(3)中包括：在有机溶剂中，对式X化合物进行结晶处理，从而形成晶型V。
在另一优选例中，子方法(M)中，所述结晶处理为缓慢挥发，所述有机溶剂选自四氢呋喃。
(N)所述晶体为式X化合物游离碱的VI型结晶，即晶型VI，并且在步骤(3)中包括：在有机溶剂中，对式X化合物进行结晶处理，从而形成晶型VI。
在另一优选例中，子方法(N)中，所述结晶处理为反溶剂添加，所述有机溶剂选 自丙酮和水。
(O)所述晶体为式X化合物游离碱的VII型结晶，即晶型VII，并且在步骤(3)中包括：在有机溶剂中，对式X化合物进行结晶处理，从而形成晶型VII。
在另一优选例中，子方法(O)中，所述结晶处理为反溶剂添加，所述有机溶剂选自甲醇和水。
在本发明的第三方面，提供了一种药物组合物，所述药物组合物包括：(a)本发明第一方面中任一所述的式X化合物或其药学上可接受盐、或其多晶型物；以及(b)药学可接受的载体。
本发明的第四方面提供了本发明第一方面中任一所述的式X化合物或其药学上可接受盐、或其多晶型物，或第三方面所述药物组合物的用途，用于制备治疗疼痛、抑郁症、心血管疾病、呼吸系统疾病或精神疾病的药物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1-1.晶型A的X射线粉末衍射图谱
图1-2.晶型A的差示扫描量热法分析图谱
图1-3.晶型A的热重分析图谱
图1-4.晶型A的HPLC图谱
图1-5.晶型A的DVS曲线图
图2-1.晶型B的X射线粉末衍射图谱
图2-2.晶型B的差示扫描量热法分析图谱
图3-1.晶型C的X射线粉末衍射图谱
图3-2.晶型C的差示扫描量热法分析图谱
图3-3.晶型C的 1H NMR谱
图4-1.晶型D的X射线粉末衍射图谱
图4-2.晶型D的差示扫描量热法分析图谱
图4-3.晶型D的热重分析图谱
图4-4.晶型D的HPLC图谱
图4-5.晶型D的 1H NMR谱
图4-6.晶型D的DVS曲线图
图5-1.晶型E-1的X射线粉末衍射图谱
图5-2.晶型E-1的差示扫描量热法分析图谱
图6-1.晶型E-2的X射线粉末衍射图谱
[根据细则91更正 26.07.2018]　
图6-2.晶型E-2的差示扫描量热法分析图谱
图7-1.晶型E-3的X射线粉末衍射图谱
图7-2.晶型E-3的差示扫描量热法分析图谱
图7-3.晶型E-3的热重分析图谱
图7-4.晶型E-3的HPLC图谱
图7-5.晶型E-3的DVS曲线图
图8-1.晶型F的X射线粉末衍射图谱
图8-2.晶型F的差示扫描量热分析图谱
图8-3.晶型F的热重分析图谱
图8-4.晶型F的HPLC图谱
图8-5.晶型F的DVS曲线图
图9-1.晶型I的X射线粉末衍射图谱
图9-2.晶型I的差示扫描量热法分析图谱
图9-3.晶型I的热重分析图谱
图9-4.晶型I的DVS曲线图
图10-1.晶型II的X射线粉末衍射图谱
图10-2.晶型II的差示扫描量热法分析图谱
图10-3.晶型II的DVS曲线图
图11-1.晶型III的X射线粉末衍射图谱
图11-2.晶型III的差示扫描量热法分析图谱
图11-3.晶型III的热重分析图谱
图11-4.晶型III的DVS曲线图
图12-1.晶型IV的X射线粉末衍射图谱
图12-2.晶型IV的差示扫描量热法分析图谱
图12-3.晶型IV的热重分析图谱
图12-4.晶型IV的DVS曲线图
图13-1.晶型V的X射线粉末衍射图谱
图13-2.晶型V的差示扫描量热法分析图谱
图13-3.晶型V的热重分析图谱
图13-4.晶型V的DVS曲线图
图14-1.晶型VI的X射线粉末衍射图谱
图14-2.晶型VI的差示扫描量热法分析图谱
图14-3.晶型VI的热重分析图谱
图14-4.晶型VI的DVS曲线图
图15-1.晶型VII的X射线粉末衍射图谱
图15-2.晶型VII的差示扫描量热法分析图谱
图15-3.晶型VII的热重分析图谱
图15-4.晶型VII的DVS曲线图
具体实施方式
如本文所用，术语“本发明化合物”包括本发明的式X化合物，本发明的式X化合物药学上可接受的盐以及本发明的多晶型物。
式X化合物
本发明中，式X化合物”或“式X所示的化合物”可以互换使用，除非特别说明，一般都是指游离碱形式。
本发明中，式X化合物为5-氯-4–((4-(4-氯-3-甲基苯基)哌嗪-1-基)甲基)-N-(环丙基磺酰基)-2-氟苯甲酰胺。
本发明中，“游离碱样品”或“游离碱”是指实施例1制备的式X化合物游离碱。
式X化合物药学上可接受的盐
本发明中，所述的药学上可接受的盐优选自下组：盐酸盐、硫酸盐、磷酸盐、乙酸盐、L-乳酸盐、马来酸盐、富马酸盐、琥珀酸盐、L-苹果酸盐、己二酸盐、L-酒石酸盐、马尿酸盐、柠檬酸盐、粘酸盐、乙醇酸盐、D-葡萄糖醛酸盐、苯甲酸盐、龙胆酸盐、烟酸盐、乙二磺酸盐、草酸盐、甲磺酸盐、苯磺酸盐、2-羟基乙磺酸盐和氢溴酸盐。
多晶型物
固体不是以无定形的形式就是以结晶的形式存在。在结晶形式的情况下，分子定位于三维晶格格位内。当化合物从溶液或浆液中结晶出来时，它可以不同的空间点阵排列结晶(这种性质被称作“多晶型现象”)，形成具有不同的结晶形式的晶体，这各种结晶形式被称作“多晶型物”。给定物质的不同多晶型物可在一个或多个物理属性方面(如溶解度和溶解速率、真比重、晶形、堆积方式、流动性和/或固态稳定性)彼此不同。
结晶
可以通过操作溶液，使得感兴趣化合物的溶解度极限被超过，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，缓慢降温，通过在相对高的温度下溶解化合物，然后冷却溶液至饱和极限以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。可通过加入抗溶剂或化合物在其中具有低的溶解度的溶剂或这样的溶剂的混合物，来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请参见Crystallization,第三版,J W MullFns,ButtFrworth-HFinFman Ltd.，1993,ISBN0750611294。
本发明所述的“悬浮搅拌”是指将式X化合物和相应的酸或相应酸的溶液在合适的溶剂中混合形成浑浊液，或者将式X化合物与合适的溶剂混合形成浑浊液后搅拌得到晶体的一种方法。合适的溶剂可以为水或有机溶剂。
本发明所述的“缓慢挥发”是指将式X化合物的溶液或含式X化合物和相应酸的溶液置于一定温度下缓慢挥发掉溶剂，得到晶体的一种方法。
本发明所述的“反溶剂添加”是指向式X化合物的一种溶液中加入另一种合适溶剂后析出得到晶体的一种方法。
假如期望盐的形成与结晶同时发生，如果盐在反应介质中比原料溶解度小，那么加入适当的酸或碱可导致所需盐的直接结晶。同样，在最终想要的形式比反应物溶解度小的介质中，合成反应的完成可使最终产物直接结晶。
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。一个实施例是在高温下将感兴趣的化合物溶解在溶剂中，随后通过受控方式加入适当体积的抗溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。
如本文所用，术语“室温”一般指4-30℃，较佳地指20±5℃。
本发明的多晶型物
本发明中，“本发明的晶体”、“本发明的晶型”、“本发明的多晶型物”等可互换使用。
本发明中，“式X化合物的多晶型物”和“式X化合物游离碱的多晶型物”等可互换使用。
如本文所用，术语“本发明的多晶型物”包括式X化合物游离碱或式X化合物药学上可接受的盐(如盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐、L-酒石酸盐、柠檬酸盐、富马酸盐)，或式X化合物各种溶剂合物的多晶型物，还包括相同的盐(如盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐、L-酒石酸盐、柠檬酸盐、富马酸盐)或溶剂合物的不同多晶型物。
优选的本发明多晶型物包括(但并不限于)：(i)晶型A、晶型B、晶型C、晶型D、晶型E-1、晶型E-2、晶型E-3、晶型F(盐的晶型)；和(ii)晶型I、II、III、IV、V、VI、VII(式X化合物的晶型)。
多晶型物的鉴定和性质
可采用已知的方法或仪器对式X化合物或药学上可接受盐的多晶型物进行表征，例如采用如下多种方式和仪器。
X射线粉末衍射
测定晶型的X射线粉末衍射的方法在本领域中是已知的。例如使X射线粉末衍射仪，以2°每分钟的扫描速度，采用铜辐射靶获取图谱。
本发明的式X化合物或其药学上可接受的盐的多晶型物，具有特定的晶型形态，在X-射线粉末衍射(XRPD)图中具有特定的特征峰。
示差扫描量热分析
又称“差示量热扫描分析”(DSC)，是在加热过程中，测量被测物质与参比物之间的能量差与温度之间关系的一种技术。DSC图谱上的峰位置、形状和峰数目与物质的性质有关，故可以定性地用来鉴定物质。本领域常用该方法来检测物质的相变温度、玻璃化转变温度、反应热等多种参数。
式X化合物的药物组合物及其应用
通常，本发明式X化合物或其药学可接受的盐可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非 胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
如本文所用，“治疗有效量”是指可对人和/或动物产生功能或活性的且可被人和/或动物所接受的量。
本发明的药物组合物或所述药用组合物中含有的本发明化合物的治疗有效量优选为0.1mg-5g/kg(体重)。
本发明化合物或本发明的药用组合物可用于治疗疼痛、抑郁症、心血管疾病、呼吸系统疾病或精神疾病。
在另一优选例中，所述疾病或病症选自与HIV相关的疼痛、HIV治疗诱导的神经病变、三叉神经痛、带状疱疹后神经痛、急性疼痛、热敏感、结节病、肠易激综合征、克罗恩病、与多发性硬化(MS)有关的疼痛、肌萎缩性侧索硬化(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿性关节炎、骨关节炎、动脉粥样硬化、突发性张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退、双相抑郁症、焦虑症、精神分裂症、钠通道毒素相关病症、家族性红斑性肢痛症、原发性红斑性肢痛症，家族性直肠疼痛、癌症、癫痫、局部和全身强直性发作、不宁腿综合征、心律失常、纤维肌痛、在由中风或神经损伤导致的缺血性疾病状态下的神经保护、快速性心律失常、心房颤动和心室颤动、神经性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、手术后疼痛、生产疼痛、分娩疼痛、牙痛、慢性疼痛、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、周围神经损伤、三叉神经痛、带状疱疹后神经痛、急性疼痛、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛或纤维肌痛。
本发明的化合物或本发明的药用组合物在某些疾病中可以与其它药物联合应用，以达到预期的治疗效果。
本发明的主要优点包括：相对于Nav1.5、Nav1.8、Cav3.2和hERG钾离子通道，本发明化合物对Nav1.7钠离子通道具有高度选择性，并具有稳定的肝微粒体代谢稳定性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
试剂与仪器
化合物的结构和纯度通过核磁共振(1HNMR)和/或液质联用质谱(LC-MS)来确定。 1HNMR：BrukFrAVANCF-400核磁仪，内标为四甲基硅烷(TMS)。LC-MS：AgilFnt 1200 HPLCSystFm/6140MS液质联用质谱仪(购自安捷伦)，柱子WatFrsX-BridgF,150×4.6mm,3.5μm。制备高效液相色谱(prF-HPLC)：用WatFrs PHW007，柱子XBridgF C18,4.6*150mm,3.5um。
采用ISCO Combiflash-Rf75或Rf200型自动过柱仪，AgFla 4g、12g、20g、40g、80g、120g一次性硅胶柱。
已知的起始原料可以采用或按照本领域已知的方法来合成，或可以于ABCR GmbH&Co.KG，Acros Organics，Aldrich ChFmical Company，韶远化学科技(AccFla ChFmBioInc)和达瑞化学品等公司处购买。
实施例中无特殊说明，反应均在氮气或氩气氛下进行。实施例中无特殊说明，溶液是指水溶液。
如本文所用，DMF表示二甲基甲酰胺，DMSO表示二甲基亚砜，THF表示四氢呋喃，DIFA表示N,N-二异丙基乙胺，EA或EtOAc表示乙酸乙酯，PF表示石油醚，DCDMH表示1,3-二氯-5,5-二甲基海因，EDC.HCl表示1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，ACN为乙腈，MeOH为甲醇，EtOH为乙醇，IPA为异丙醇，Actone为丙酮，MTBE为甲基叔丁基醚，THF表示四氢呋喃。
通用方法
粉末X衍射图谱是通过本领域的已知方法，XRPD图谱在D8ADVANCE X射线粉末衍射分析仪上采集，XRPD测试参数如下表16所示。
表16
参数 XRPD
X射线源 Cu K(λ＝1.54056Angstrom)
光管设定 40千伏，40毫安
检测器 PSD
扫描范围(2θ(°)) 4°～40°
扫描步长(2θ(°)) 0.05
扫描速率 1秒/步
图中各峰的位置由2θ(°)确定。可以理解，不同的仪器和/或条件可导致产生的数据会略有不同，各峰的位置和相对强度会有变化。峰的强度划分仅仅反映了各位置上峰的近似大小。本发明各晶型均以其峰高最高的衍射峰作为基峰，定义其相对强度为 100％，作为I 0，其它各峰以其峰高与基峰峰高的比值作为其相对强度I/I0，各峰相对强度的划分定义如下表17所示：
表17
相对强度I/I0(％) 定义
50～100 VS(很强)
20～50 S(强)
10～20 M(中等)
0～10 W(弱)
本发明的盐或其晶型通过HPLC/IC或 1H NMR确定酸碱摩尔比。
液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d6作为溶剂。
高效液相色谱在Agilent1260 HPLC上采集，具体仪器和测试参数见下表18。
表18
Figure PCTCN2018092895-appb-000021
TGA和DSC图谱分别在TGA Q500 V20.10 Build 36热重分析仪和DSC Q2000 V24.4 Build 116差示扫描量热仪上采集，测试参数如下表19所示。
表19
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铂金盘，敞开 铝盘，压盖
温度范围 25℃–设定温度 25℃–设定温度
扫描速率(℃/分钟) 10 10
保护气体 氮气 氮气
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。DVS测试参数列于下表20。
表20
参数 设定值
温度 25℃
样品量 10～20毫克
保护气体 氮气，0.1M Pa
dm/dt 0.01％/分钟
最小dm/dt平衡时间 5分钟
最大平衡时间 120分钟
RH范围 0％RH～95％RH
RH梯度 5％RH
可以理解的是，使用与上述仪器作用相同的其他类型的仪器或使用不同与本发明中使用的测试条件时，可能会得到另外的数值，因此，所引用的数值不应视为绝对的数值。
由于仪器的误差或操作人员的区别，本领域技术人员能理解，以上用于表征晶体的物理性质的参数可能有微小的差别，所以上述的参数仅用于辅助表征本发明提供的多晶型物，而不能视为是对本发明的多晶型物的限制。
化合物X-a的制备：
Figure PCTCN2018092895-appb-000022
步骤1：化合物X-a-1(90g,0.438mol),N-Boc-哌嗪(114g,0.613mol),pd 2(dba) 3(4.0g,0.004mol),BINAP(5.1g,0.008mol),叔丁醇钾(98g,0.876mol)的1,4-二氧六环(1L)溶液加热至100℃搅拌3h，混合物倒入水中，经硅藻土过滤，乙酸乙酯洗涤。滤液经乙酸乙酯萃取(1L*2)，合并有机层，饱和食盐水(500mL)洗涤，无水硫酸钠干燥后浓缩，残留物在乙醇中重结晶得44g固体化合物X-a-2。ESI-MS[M+H] +:311.2。
步骤2：化合物X-a-2(82g,0.264mol)的甲醇(800mL)溶液在冰浴下逐滴加入盐酸/1,4-二氧六环(4M，264mL)。混合物升至室温过夜，反应液过滤，甲醇洗涤后干燥得白色固体化合物X-a(72g,产率：100％)。ESI-MS[M+H] +:211.1。
实施例1 式X化合物的制备
Figure PCTCN2018092895-appb-000023
步骤1：将化合物X-1(100.1g,0.65mol)加入到浓硫酸(300ml)中，30分钟内分批加入DCDMH(64.03g,0.325mol)。混合物在2小时内缓慢升温至40℃，反应液澄清。混合物缓慢降至室温，有固体析出，并在室温下搅拌16h。混合物缓慢倒至冰水中，过滤，滤饼用水洗涤，干燥得白色固体化合物X-2(108g,产率：88.2％)。ESI-MS[M+H] +:189。
步骤2：化合物X-2(128g，0.677mol),环丙基磺酰胺(164g,1.354mol)，EDC.HCl(260g,1.354mol),DMAP(83g,0.677mol),DIPEA(262g,2.031mol)的二氯甲烷(1200mL)混合溶液室温搅拌3天。反应液悬干，固体加水(1L)溶解，浓盐酸调pH至3～4，乙酸乙酯萃取(800mL*3)，合并有机层，经饱和食盐水(800mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩去除大部分溶剂后过滤，滤饼经乙醇重结晶得白色固体化合物X-3(106g,产率：53.8％)。MS m/z(ESI):292[M+H] +。
步骤3：化合物3(100g,0.342mol),NBS(91.4g,0.514mol)和偶氮二异丁腈(2.8g,0.017mol)的乙腈(1L)溶液加热至80℃搅拌3小时。用旋转蒸发仪旋干滤液。残留物加乙酸乙酯(1L)溶解，经水(500mL)与饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩去除大部分溶剂后过滤，滤饼加入亚磷酸二乙酯(35.4g,0.257mol)和DIPEA(66g,0.513mol)，用盐酸(2N)调混合物的pH调至2～3，经饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩去除大部分溶剂后过滤，滤饼经石油醚洗涤，干燥得白色固体化合物X-4(88g,产率：65.4％)。MS m/z(ESI):370[M+H] +。
步骤4：化合物X-4(88g,0.237mol)、化合物X-a(58.7g,0.237mol)、碳酸钾(65.4g,0.474mol)的DMF(900mL)混合溶液80℃搅拌3h。反应液倒入水(1.5L)中，乙酸乙酯萃取(800mL*4)，合并有机层，经水(1000mL*2)与饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干。残留物经柱层析纯化得白色固体化合物X(87g,产率：73.7％)。MS m/z(ESI):500.2[M+H] +。
实施例2 式X化合物游离碱晶型Ⅰ的制备
方法一
称取约20mg的实施例1制备的式X化合物(以下称“游离碱样品”)至玻璃小瓶中，分别加入适量下列溶剂(表21)，得到近饱和溶液，超声使其充分溶解后，过滤后再向澄清溶剂中加入20-200uL相应溶剂，放置在室温下缓慢挥发。当溶剂完全挥干后，收集所得固体并进行XRPD测试。X射线粉末衍射图谱如图9-1所示。DSC/TGA/DVS图如9-2、9-3和9-4所示。由DSC图可知，在183.76℃(起始温度)有一个熔化吸收峰；加热至150℃几乎没有失重，加热至200℃时，失重1.159％；DVS曲线表示样品略有吸湿性。晶型I稳定性较好。
表21
溶剂 晶型
ACN 晶型I
Actone 晶型I
EtOAc 晶型I
方法二
分别称取约40-50mg的游离碱样品至玻璃小瓶中，在60℃水浴条件分别加入适量下列溶剂(表22)，搅拌使其溶解得到近饱和溶液，过滤后向澄清溶液中再加入20-200uL相应溶剂，关闭加热按钮，使其缓慢降温，待降至室温后，置于冰浴条件下继续降温至4℃左右，收集混悬液于12000r/min条件下离心15min，倾倒上清液，将固体置于室温条件下缓慢挥发过夜，收集所得固体并进行XRPD测试。
表22
溶剂 实验结果 晶型
ACN 于底部与杯壁有透明晶体颗粒析出 晶型I
MeOH 于底部有透明晶体颗粒析出 晶型I
EtOH 于底部有透明晶体颗粒析出 晶型I
IPA NA  
Actone 于底部有大量粉末状固体析出 晶型I
EtOAc 于底部有粉末状固体析出 晶型I
THF NA  
MTBE NA  
方法三
称取40mg左右的游离碱样品于玻璃小瓶中，分别加入适量的良溶剂，得到近饱和溶液，然后逐毫升加入反溶剂，观察是否有固体析出，继续加入反溶剂直至样品不在析出或者不可能析出为止。离心，倾倒上清液，挥干，收集所得到固体进行XRPD测试。具体溶剂见表23和表24。
表23室温条件下反溶剂添加法实验
Figure PCTCN2018092895-appb-000024
表24 60℃条件下反溶剂添加法实验
Figure PCTCN2018092895-appb-000025
方法四
分别称取约20mg的游离碱样品至玻璃小瓶中，加入1mL下列有机试剂，盖紧瓶 盖，用封口膜封口防止液体挥发，置于25℃，25r/min条件下震摇。后取出，于4℃，14000r/min条件下离心15min，倾倒上清液，将固体置于室温条件下缓慢挥发过夜，收集所得固体并进行XRPD测试。试验结果如下表25所示。
表25 25℃混合震摇实验小结
Figure PCTCN2018092895-appb-000026
实施例3式X化合物游离碱晶型II的制备
将实施例1步骤4中的反应液倒入水中，乙酸乙酯萃取，干燥、浓缩。加乙醇悬浮搅拌2h，过滤，滤饼经甲醇重结晶得固体产物即为游离碱晶型II，粉末X衍射图如图10-1所示(2θ角已标出)，DSC/DVS图如10-2和10-3所示。由DSC图可知，样品在130.44℃(起始温度)和167.49℃各有一个熔化吸收峰；DVS曲线表示样品有吸湿性。
实施例4 式X化合物游离碱晶型III的制备
将实施例1步骤4中的反应液倒入水中，乙酸乙酯萃取，干燥、浓缩。加乙醇溶解后旋干，再加入1N盐酸与乙酸乙酯，搅拌1-2h，过滤得固体产物即为游离碱晶型III,粉末X衍射图如图11-1所示(2θ角已标出)，DSC/TGA/DVS谱图如图11-2、11-3和11-4所表征。由DSC图可知，在100℃左右有拐点，181.9℃(起始温度)有一个熔化吸收峰；加热至100℃，失重0.714％；DVS曲线表示样品略有吸湿性。样品在ACE和MeOH溶剂中于50℃条件下震摇1天，晶型无改变；将样品与晶型Ⅳ混合，在ACE和MeOH溶剂中于50℃条件下震摇1天，均转变为晶型Ⅰ，推测样品位亚稳定晶型，晶型Ⅰ更为稳定。
实施例5 式X化合物游离碱晶型IV的制备
将实施例1步骤4中的反应液倒入水中，乙酸乙酯萃取，干燥，浓缩保留少量乙酸乙酯，加入1N盐酸并搅拌1h，过滤，滤饼经乙醇洗涤，再过滤，得到的固体产物即为游离碱晶型IV,粉末X衍射图如图12-1所示(2θ角已标出)，DSC/TGA/DVS谱图如图12-2、12-3和12-4所表征。由DSC图可知，在95.7℃、187.01℃和197.09℃各有一个熔化吸收峰；加热至100℃，失重2.269％，加热至200℃失踪1.344％；DVS曲线表示样品略有吸湿性。样品在ACE溶剂中于50℃条件下震摇1天，晶型无改变；将样品与晶型Ⅲ混合，在ACE和MeOH溶剂中于50℃条件下震摇1天，均转变为晶型Ⅰ，推测样 品位亚稳定晶型，晶型Ⅰ更为稳定。
实施例6 式X化合物游离碱晶型V的制备
称取约20mg的游离碱样品至玻璃小瓶中，加入适量THF，得到近饱和溶液，超声使其充分溶解后，过滤后再向澄清溶剂中加入20-200uL相应溶剂，放置在室温下缓慢挥发。当溶剂完全挥干后，收集所得固体并进行XRPD测试。得晶型V。X衍射图如图13-1所示(2θ角已标出)，DSC/TGA/DVS谱图如图13-2、13-3和13-4所表征。由DSC图可知，在178.91℃有一个熔化吸收峰，之前有放热峰；加热至120℃，失重6.189％，加热至250℃失重3.861％；DVS曲线表示样品略有吸湿性。样品加热至150℃后转变为晶型Ⅰ，推测样品为溶剂化物，晶型Ⅰ更为稳定。
实施例7 式X化合物游离碱晶型VI的制备
称取40mg的样品于玻璃小瓶中，加入丙酮得到近饱和溶液，然后逐毫升加入反溶剂水，观察是否有固体析出，继续加入反溶剂直至样品不再析出或者不可能析出为止。离心，倾倒上清液，挥干，收集所得到固体进行XRPD测试。得晶型VI。X衍射图如图14-1所示(2θ角已标出)，DSC/TGA/DVS谱图如图14-2、14-3和14-4所表征。由DSC图可知，在138.04℃有一个放热峰，在183.59℃有一个熔化吸收峰；由TGA图可知，加热至250℃，失重2.499％；DVS曲线表示样品略有吸湿性。样品加热至150℃后转变为晶型Ⅰ，推测样品为溶剂化物，晶型Ⅰ更为稳定。
实施例8 式X化合物游离碱晶型VII的制备
称取40mg的样品于玻璃小瓶中，加入甲醇得到近饱和溶液，然后逐毫升加入反溶剂水，观察是否有固体析出，继续加入反溶剂直至样品不在析出或者不可能析出为止。离心，倾倒上清液，挥干，收集所得到固体进行XRPD测试。得晶型VII。X衍射图如图15-1所示(2θ角已标出)，DSC/TGA/DVS谱图如图15-2、15-3和15-4所表征。由DSC图可知，在141.42℃有一个吸收峰，在148.02℃有一个放热峰，在184.06℃有一个熔化吸收峰；DVS曲线表示样品略有吸湿性。样品加热至150℃后转变为晶型Ⅰ，推测样品为溶剂化物，晶型Ⅰ更为稳定。
实施例9 式X化合物晶型A的制备
称取100mg游离碱样品加至20ml玻璃样品瓶中，50℃条件下，加入240μL 1M盐酸溶液，加入1mL甲醇保温反应4h，溶液为浑浊状态；4h后，缓慢降温至0℃，固体沉淀增多；离心分离得固体，挥干溶剂即得固体产物。所得结晶的粉末X衍射图如图1-1所示(2θ角已标出)，DSC/TGA谱图如图1-2和1-3所表征，样品在100℃前失重0.196％，样品的DSC图谱中有一个吸热峰，峰值温度为252.81℃。HPLC如图1-4所示；酸碱摩尔比为1:0.93，熔点为243℃-252℃，在本申请中定义该晶型为晶型A。
实施例10 式X化合物晶型B的制备
称取100mg游离碱样品加至20ml玻璃样品瓶中，50℃条件下，加入240μL 1M氢溴酸溶液，加入1mL乙酸乙酯保温反应4h，溶液为浑浊状态；4h后，缓慢降温至0℃，固体沉淀增多；离心分离得固体，挥干溶剂即得固体产物。所得结晶的粉末X衍射图如图2-1所示(2θ角已标出)，DSC谱图如图2-2所表征；熔点为253.89℃-258.89℃。在本申请中定义该晶型为晶型B。
实施例11 式X化合物晶型C的制备
称取100mg游离碱样品加至20ml玻璃样品瓶中，50℃条件下，加入240μL 1M甲磺酸溶液，加入1mL乙酸乙酯保温反应4h，溶液为浑浊状态；4h后，缓慢降温至0℃，固体沉淀增多；离心分离得固体，挥干溶剂即得固体产物。所得结晶的粉末X衍射图如图3-1所示(2θ角已标出)，DSC谱图如图3-2所表征； 1H NMR谱如图3-3所示，熔点为97.89℃-103.89℃。在本申请中定义该晶型为晶型C。
实施例12 式X化合物晶型D的制备
称取100mg游离碱样品加至20ml玻璃样品瓶中，加入1ml丙酮，50℃条件下，边搅拌边缓慢滴加240μL 1M马来酸溶液，数分钟后溶液变浑浊，保温反应4h。4h后，缓慢降温至0℃，固体沉淀增多；离心分离得固体，挥干溶剂即得固体产物。所得结晶的粉末X衍射图如图4-1所示(2θ角已标出)，DSC/TGA谱图如4-2和4-3所表征，样品在100℃前失重0.174％，样品的DSC图谱中有一个吸热峰，峰值温度为206.06℃。HPLC如图4-4所示；酸碱摩尔比为1:1， 1H NMR谱如图4-5所示，熔点为203.89℃-207.89℃。在本申请中定义该晶型为晶型D。
实施例13 式X化合物晶型E-3的制备
称取100mg游离碱样品加至20ml玻璃样品瓶中，加入1ml乙腈，50℃条件下，边搅拌边缓慢滴加240μL1M氢氧化钠溶液，溶液为澄清状态，保温反应4h。置于通风橱内挥干溶剂，溶剂较多时浓缩后再挥干溶剂。所得结晶的粉末X衍射图如图7-1所示(2θ角已标出)，DSC/TGA谱图如图7-2和7-3所表征，样品在100℃前失重0.856％，样品的DSC图谱中有两个吸热峰，峰值温度分别为134.50℃,198.38℃。HPLC如图7-4所示；成盐比1:0.78；在本申请中定义该晶型为晶型E-3。
实施例14 式X化合物晶型F的制备
称取100mg游离碱样品加至20ml玻璃样品瓶中，加入1ml甲醇，50℃条件下，边搅拌边缓慢滴加240μL 1M氢氧化钾溶液，数分钟后溶液变浑浊，保温反应4h。4h后缓慢降温至0℃，固体沉淀增多；离心分离得固体，挥干溶剂即得固体产物。所得结晶的粉末X衍射图如图8-1所示(2θ角已标出)，DSC/TGA谱图如图8-2和8-3所表征，样品在100℃前失重3.029％，样品的DSC图谱中有一个吸热峰，峰值温度为102.75℃。 HPLC如图8-4所示；成盐比为1：0.67，熔点为100.89℃-104.89℃。在本申请中定义该晶型为晶型F。
实施例15 式X化合物盐的各类晶型的制备方法
称取800mg游离碱样品，加入32ml四氢呋喃，超声使溶解，配制成25mg/ml的溶液，取0.8ml加入到1.5ml样品瓶中，用氮吹仪吹干溶剂，按照酸和游离碱摩尔比1.2:1的比例加入相应的酸或碱，后加入1ml相应溶剂，加热超声使澄清，50℃保温反应4h，后缓慢降温使析出固体，离心收集固体。澄清溶液尝试反溶剂添加的方法诱导析晶，所得固体挥干溶剂后用于XRPD测试。各类酸成盐结果如下表26所示：
表26
Figure PCTCN2018092895-appb-000027
结果表明，游离碱样品仅与盐酸、氢溴酸、甲磺酸、马来酸成盐，并且游离碱样品与甲磺酸在甲醇、乙腈和丙酮中不成盐，与马来酸在甲醇、乙酸乙酯和乙腈中不成盐，与NaOH在甲醇和丙酮中不成盐。
实施例16 稳定性实验
分别称取90mg晶型A、D、E-3和F在60℃条件下以及40℃70％RH放置，同时将另一组样品在5℃条件下密封保存作为对照，于7天和21天分别检测晶型和纯度变化。结果下表27所示，四种晶型在60度条件下稳定性良好，晶型未发生改变。
表27四种晶型的稳定性数据
Figure PCTCN2018092895-appb-000028
Figure PCTCN2018092895-appb-000029
-:低于检测限；NA:不检测
实施例17 引湿性实验
晶型A、D、E-3和F的DVS结果分别如图1-5、图4-6、图7-5和图8-5所示。晶型A在RH为95％的条件下吸湿0.4％，略有引湿性；晶型D在RH为95％的条件下吸湿0.07％，几乎没有引湿性；晶型F在RH为85％时吸湿4％，具有引湿性；晶型E-3在RH为85％时吸湿2％，具有引湿性。
实施例18 溶解度实验
室温下对晶型A、D、E-1、E-3和F及游离碱样品在0.1M HCL、pH4.5、pH6.8的缓冲液及水中的溶解度进行测试。试验中，分别绘制了游离碱样品与五种晶型的标曲。随后，分别称取6mg的API及五种晶型固体样品，分别加入2ml的溶媒，室温振摇4h，然后超声30min后离心，取上清液，0.45μm滤膜过滤进样，测定溶解度，结果如表28所示(浓度的单位为mg/ml)。
表28
Figure PCTCN2018092895-appb-000030
五种晶型在pH4.5，pH6.8,0.1M HCL中的溶解性与游离碱样品没有显著性差异，晶型E-1、E-3和晶型F在水中的溶解度显著提高，均达到2.7mg/ml以上。
实施例19 药物组合物
由以下表29所示的组分制备式X化合物氢溴酸盐的片剂：
表29
Figure PCTCN2018092895-appb-000031
按常规方法，将式X化合物氢溴酸盐、淀粉混合过筛，再与上述其它组分混合均匀，直接压片。
实施例20 药物组合物
由以下表30所示的组分制备晶型A的片剂：
表30
Figure PCTCN2018092895-appb-000032
按常规方法，将晶型A、淀粉混合过筛，再与上述其它组分混合均匀，直接压片。
实施例21 药物组合物
由以下表31所示的组分制备晶型I的胶囊：
表31
Figure PCTCN2018092895-appb-000033
Figure PCTCN2018092895-appb-000034
按常规方法，将晶型I、淀粉混合过筛，再与上述其它组分混合均匀，装入普通明胶胶囊。
对比例
下述对比例可参照式X化合物的类似方法制备，结构如下表32所示。
表32
Figure PCTCN2018092895-appb-000035
测试例1 hNav1.7和hNav1.5通道的手动膜片钳实验
膜片电压钳电生理学可以直接测量并定量电压门控钠通道(各种Nav)的电流阻断并可以测定阻断的时间和电压依赖，其已被解释为对钠通道的静息、开放和失活状态的结合差异来反映化合物的抑制或激活效应(Hille,B.,Journal of General Physiology(1977),69:497-515)。
本发明代表性的化合物采用手动膜片钳实验进行，本研究的目的是应用手动膜片钳的方法在转染特定离子通道的稳定细胞株上测试化合物对该离子通道电流的作用。其使用的稳定细胞株CHO-hNav1.7和HEK-hNav1.5分别来自Genionics公司和WuXi Apptec(上海)公司。
手动膜片钳实验方案如下：
(一)溶液及化合物的配制：采用全细胞膜片钳技术记录hNav1.7和hNav1.5电流。实验中，细胞外液的组成成分(mM)：HEPES：5,NaCl：40,KCl：3,CaCl 2：1,MgCl 2：1,CdCl 2：0.1,TEA-Cl：20。用NaOH调节pH值至7.3，同时用蔗糖调节渗透压至310-320mOsm，过滤后4℃保存。细胞内液的组成成分(mM)：HEPES：10,NaCl：10,CsOH：5,CsF：140,EGTA：1。用CsOH调节pH值至7.3，同时用蔗糖调节渗透压至280-290mOsm，过滤后-20℃保存。
阳性对照药和待测化合物先溶于100％DMSO(Sigma-Aldrich,D2650，配置成一 定浓度(100nM，1000nM)的储备溶液。实验前用DMSO将上述储备溶液进行系列稀释，然后再用细胞外液进一步稀释得到所需浓度的测试溶液。细胞外液中DMSO最终浓度不超过0.30％。
(二)手动膜片钳实验：取细胞悬液加于35mm的培养皿中，置于倒置显微镜载物台上。待细胞贴壁后，用细胞外液灌流，流速为1–2mL/min。玻璃微电极由微电极拉制仪两步拉制，其入水电阻值为2-5MΩ。通过Digidata 1440(Molecular Devices)和pCLAMP软件(10.2版，Molecular Devices)A/D–D/A数模转换，进行刺激发放及信号采集；膜片钳放大器(Multiclamp 700B，Molecular Devices)放大信号，滤波为4KHz。
在hNav1.7和hNav1.5手动膜片钳实验中运用两种不同的电压刺激程序。
一种是失活刺激程序，钳制电位设置在相对应通道的V 1/2，即大约50％的通道处于失活状态。接着给予电压至-120mV，持续50ms。然后去极化至-10mV，持续20ms引出钠电流，最后回到钳制电位。这种刺激程序也可以称之为通道状态依赖的电压刺激程序。
另一种是非失活刺激程序，保持钳制电位在-120mV,给予电压刺激至-10mV，持续20ms引出钠电流，最后回到钳制电位。也就是说在该种刺激程序条件下，所有的通道都没有经历过失活状态，而是直接从静息状态进行激活。
上述两种电压刺激程序的时间间隔均为10s。化合物的抑制效应通过加药前后的电流变化来进行计算，而IC 50数值由Hill方程进行拟合所得。如果化合物在上述两种不同的电压刺激下显示出对通道效应有一定倍数的差异，那么该化合物对该通道是具有状态依赖性的。结果分别见表33和表34。
表33本发明代表性化合物在两种浓度下对Nav1.7的抑制率
化合物 100nM(％) 1000nM(％)
式X化合物游离碱 86.90 97.68
C1 49.22 64.84
C2 52.03 64.05
C3 17.56 52.26
C4 18.58 58.91
C5 17.19 36.76
C6 11.15 67.25
C11 23.06 51.85
表34其他离子通道的选择性
Figure PCTCN2018092895-appb-000036
从表33可以看出，本发明式X化合物游离碱对Nav1.7具有较高的抑制活性，此外研究发现，对于六元(哌嗪环)上含氮杂环上氮原子和苯环或吡啶环上碳原子是否直接相连，对Nav1.7的抑制活性有明显的影响，研究表明当氮原子不与苯环或吡啶环直接相连时，即苯环或吡啶环通过亚甲基或羰基等基团与氮原子相连时，抑制活性有明 显的降低。此外若将苯环或吡啶环通过亚甲基或羰基等基团与氮原子相连，并且R 6为甲基时，抑制活性有明显的降低。
测试例2：对hERG钾离子通道的作用
2.1细胞培养
2.1.1本试验所用的细胞为转染有hERG cDNA与稳定表达hERG通道的CHO细胞系(由丹麦Sophion Bioscience公司提供)，细胞代数为P15。细胞培养在含有下列成分的培养基中(皆来源于Invitrogen)：Ham’s F12培养基，10％(v/v)灭活的胎牛血清，100μl/ml潮霉素B，100μl/ml Geneticin。
2.1.2 CHO hERG细胞生长于含上述培养液的培养皿中，并在37℃、含5％CO 2的培养箱中进行培养。电生理实验之前24到48小时，CHO hERG细胞被转移放置于培养皿中的圆形玻璃片上，并在以上相同的培养液及培养条件下生长。每个圆形玻璃片上CHO hERG细胞的密度需要达到绝大多数细胞是独立、单个的要求。
2.2实验溶液下列溶液(由Sophion推荐)用于电生理记录。本试验所用试剂由Sigma提供。
表35细胞內液与外液的组成成分
试剂 外液(mM) 內液(mM)
CaCl 2 2 5.37
MgCl 2 1 1.75
KCl 4 120
NaCl 145 -
Glucose 10 -
HEPES 10 10
EGTA - 5
Na-ATP - 4
PH 7.4(用NaOH调节) 7.25(用KOH调节)
渗透压 渗透压～305mOsm 渗透压～295mOsm
2.3电生理记录系统
本实验采用手动膜片钳系统(HEKA EPC-10信号放大及数字转换系统，购自德国HEKA Electronic)作全细胞电流的记录。表面生长有CHO hERG细胞的圆形玻璃片被放置于倒置显微镜下的电生理记录槽中。记录槽内以细胞外液作持续灌流(大约每分钟1毫升)。实验过程采用常规全细胞膜片钳电流记录技术。如无特殊说明，实验都是在常规室温下进行(～25℃)。细胞钳制在-80mV的电压下。细胞钳制电压去极化到+20mV以激活hERG钾通道，5秒后再钳制到-50mV以消除失活并产生尾电流。尾电流峰值用作hERG电流大小的数值。上述步骤记录的hERG钾电流在记录槽内持续的细胞外液灌流下达到稳定后则可以叠加灌流待测试药物，直到药物对hERG电流抑制作用达到稳定状态。一般以最近的连续3个电流记录线重合作为判断是否稳定状态的标准。达到稳定态势以后以细胞外液灌流冲洗直到hERG电流回复到加药物之前的大小。一个细胞上可以测试一个或多个药物，或者同一种药物的多个浓度，但是在不同药物之间需要以细胞外液冲洗。Cisapride(西沙比利，购自Sigma)被用于实验中作为阳性对照 以保证所使用的细胞质量正常。
2.4化合物处理和稀释
化合物先用DMSO溶解成10mM的浓度，然后再直接用细胞外液将化合物1000倍稀释成最终的10μM测试浓度。化合物测试液中DMSO的最终浓度为等于0.1％。阳性对照Cisapride(西沙比利)的测试浓度为0.1μM。所有贮备液和测试溶液都经过常规的5-10分钟的超声和振荡以保证化合物完全溶解。
2.5数据分析
试验数据由HEKA Patchmaster(V2x73.2)，Microsoft Excel以及Graphpad Prism 5.0提供的数据分析软件进行分析。
表36本发明代表性化合物对hERG钾离子通道的抑制
化合物 hERG抑制浓度IC50(μM)
式X化合物游离碱 >10μM
从表36可以看出，式X化合物游离碱对hERG钾离子通道的抑制活性很小，因此对钾离子通道具有选择性抑制。
测试例3：代谢稳定性测试
1.缓冲液的配制
缓冲液A：配制1L含有1mM EDTA(Sigma，V900157-100G)，100mM的磷酸二氢钾溶液。
缓冲液B：配制1L含有1mM EDTA，100mM的磷酸氢二钾溶液。
缓冲液C：取700mL缓冲液B，用缓冲液A滴定，调至PH为7.4即可。
2.待测化合物和阳性对照药(酮色林(Sigma S006-10MG))的配制
2.1取10mM待测化合物和10mM酮色林各10uL，再各加190uL的纯乙腈，分别配成500uM待测化合物和酮色林溶液。
2.2取20uL(20mg/mL)人肝微粒体(Corning Lot.NO.4133007)储存液加入到513.4uL的缓冲液C，在湿冰上操作。配制得到0.75mg/mL肝微粒体溶液。
2.3各取1.5uL上述待测化合物和酮色林溶液，分别加入到498.5uL(0.75mg/mL)的肝微粒体溶液中，在湿冰上操作。配制得到1.5uM待测化合物混合液和酮色林混合液。
2.4按照时间点0、5、15、30、45、60min，每孔30uL，分别将待测化合物混合液和酮色林混合液分装到反应板上，在湿冰上操作。
2.5称取5mg还原型辅酶Ⅱ(Roche，10621706001)，溶于1mL缓冲液C中。配制成6mM还原型辅酶Ⅱ溶液。将还原型辅酶Ⅱ溶液分装到反应板中。
2.6将丙米嗪溶成10mM的溶液，取100mL空白乙腈，加入10uL丙米嗪溶液。配成内标。
2.7在0min，每孔加入135uL含有内标的冰乙腈(Merck(Lot.1778229518))，再加入15uL缓冲液C。
2.8将反应板放入37度水浴恒温箱内预热5min。在反应板中，每孔加15uL还原 型辅酶Ⅱ溶液开始反应并计时。在5、15、30、45、60min时间点，每孔加入135uL含有内标的冰乙腈终止反应。
2.9将反应板用铝膜封好，放在震荡混合器上，500rpm，5min。再将反应板放在离心机中离心，15min，3750rpm。
2.10取样品和纯水按照1:1比例稀释，LC/MS检测。将得到的数值按照以下公式计算得到如表7所示的半衰期和清除率。
半衰期：0.693/K(孵化时间与浓度对数值作图出来的斜率)
清除率：(0.693/半衰期)*(1/蛋白质浓度(0.5mg\mL))*(比例因子)
其中K值和比例因子为本领域技术人员根据现有方法以及肝微粒体产品说明书记载的方法计算得到的。
表37人肝微粒体代谢稳定性实验结果
Figure PCTCN2018092895-appb-000037
从表37可以看出，式X化合物游离碱具有很好的代谢稳定性(T 1/2＞30min,T 1/2小于30min就表示不稳定)，研究发现取代基R 6的变化对代谢稳定性有明显的影响，当由环丙基变为甲基时，代谢稳定性明显降低。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种结构如式(X)所示的化合物的药学上可接受的盐、或其多晶型物。
    Figure PCTCN2018092895-appb-100001
  2. 如权利要求1所述的化合物的药学上可接受的盐、或其多晶型物，其特征在于，所述药学上可接受的盐为酸式盐或碱式盐，其中酸式盐选自下组：盐酸盐、硫酸盐、磷酸盐、乙酸盐、L-乳酸盐、马来酸盐、富马酸盐、琥珀酸盐、L-苹果酸盐、己二酸盐、L-酒石酸盐、马尿酸盐、柠檬酸盐、粘酸盐、乙醇酸盐、D-葡萄糖醛酸盐、苯甲酸盐、龙胆酸盐、烟酸盐、乙二磺酸盐、草酸盐、甲磺酸盐、苯磺酸盐、2-羟基乙磺酸盐、氢溴酸盐；碱式盐选自下组：三乙醇胺盐、钠盐、或钾盐。
  3. 如权利要求1所述的化合物的药学上可接受的盐、或其多晶型物，其特征在于，所述式X化合物的药学上可接受的盐、或其多晶型物为无水形式、水合物形式或溶剂合物形式。
  4. 如权利要求1所述的化合物的药学上可接受的盐、或其多晶型物，其特征在于所述多晶型物为式X化合物的多晶型物或式X化合物药学上可接受的盐的多晶型物，且所述药学上可接受的盐为酸式盐或碱式盐，其中酸式盐选自下组：盐酸盐、硫酸盐、氢溴酸盐、磷酸盐、甲磺酸盐、马来酸盐、L-酒石酸盐、柠檬酸盐、富马酸盐；碱式盐选自下组：钠盐、钾盐。
  5. 如权利要求1所述的化合物的药学上可接受的盐、或其多晶型物，其特征在于所述多晶型物选自下组：
    (1)式X化合物盐酸盐的A型结晶，即晶型A，其X射线粉末衍射图在下组A1的衍射角2θ(°)值处具有峰：12.19±0.20、16.30±0.20、17.76±0.20、18.61±0.20、23.23±0.20、25.17±0.20；
    (2)式X化合物氢溴酸盐的B型结晶，即晶型B，其X射线粉末衍射图在下组B1的衍射角2θ(°)值处具有峰：12.40±0.20；
    (3)式X化合物甲磺酸盐的C型结晶，即晶型C，其X射线粉末衍射图在下组C1的衍射角2θ(°)值处具有峰：8.93±0.20、15.32±0.20、21.86±0.20、22.56±0.20、23.75±0.20、25.69±0.20、27.37±0.20；
    (4)式X化合物马来酸盐的D型结晶，即晶型D，其X射线粉末衍射图在下组D1的衍射角2θ(°)值处具有峰：5.06±0.20、8.24±0.20、10.08±0.20、15.14±0.20、16.18±0.20、18.95±0.20、19.83±0.20、20.40±0.20、21.38±0.20、22.14±0.20、26.51±0.20；
    (5)式X化合物钠盐的E-1型结晶，即晶型E-1，其X射线粉末衍射图在下组E-1-1的衍射角2θ(°)值处具有峰：4.53±0.20；
    (6)式X化合物钠盐的E-2型结晶，即晶型E-2，其X射线粉末衍射图在下组E-2-1的衍 射角2θ(°)值处具有峰：6.90±0.20、14.44±0.20、16.96±0.20、17.77±0.20、18.42±0.20、19.72±0.20、22.22±0.20、22.67±0.20、27.94±0.20；
    (7)式X化合物钠盐的E-3型结晶，即晶型E-3，其X射线粉末衍射图在下组E-3-1的衍射角2θ(°)值处具有峰：7.12±0.20、7.57±0.20、9.94±0.20、10.71±0.20、17.68±0.20；
    (8)式X化合物钾盐的F型结晶，即晶型F，其X射线粉末衍射图在下组F-1的衍射角2θ(°)值处具有峰：7.83±0.20、17.68±0.20、18.74±0.20。
  6. 如权利要求1所述的化合物的药学上可接受的盐、或其多晶型物，其特征在于所述多晶型物选自下组：
    (9)式X化合物游离碱的I型结晶，即晶型I，其X射线粉末衍射图在组I-1的衍射角2θ(°)值处具有峰：7.26±0.20、18.38±0.20、23.15±0.20；
    (10)式X化合物游离碱的II型结晶，即晶型II，其X射线粉末衍射图在组II-1的衍射角2θ(°)值处具有峰：6.84±0.20、7.74±0.20、9.94±0.20；
    (11)式X化合物游离碱的III型结晶，即晶型III，其X射线粉末衍射图在组III-1的衍射角2θ(°)值处具有峰：4.09±0.20；
    (12)式X化合物游离碱的IV型结晶，即晶型IV，其X射线粉末衍射图在组IV-1的衍射角2θ(°)值处具有峰：4.66±0.20；
    (13)式X化合物游离碱的V型结晶，即晶型V，其X射线粉末衍射图在组V-1的衍射角2θ(°)值处具有峰：6.79±0.20、14.31±0.20、16.90±0.20、17.58±0.20、20.58±0.20、21.90±0.20、23.45±0.20；
    (14)式X化合物游离碱的VI型结晶，即晶型VI，其X射线粉末衍射图在组VI-1的衍射角2θ(°)值处具有峰：6.90±0.20、7.14±0.20、16.40±0.20、16.92±0.20、20.62±0.20、23.52±0.20；
    (15)式X化合物游离碱的VII型结晶，即晶型VII，其X射线粉末衍射图在组VII-1的衍射角2θ(°)值处具有峰：7.11±0.20、14.22±0.20。
  7. 如权利要求1所述的式X化合物的药学上可接受的盐、或其多晶型物，其特征在于：
    所述晶型A的X射线粉末衍射图谱基本如图1-1所表征；
    所述晶型B的X射线粉末衍射图谱基本如图2-1所表征；
    所述晶型C的X射线粉末衍射图谱基本如图3-1所表征；
    所述晶型D的X射线粉末衍射图谱基本如图4-1所表征；
    所述晶型E-1的X射线粉末衍射图谱基本如图5-1所表征；
    所述晶型E-2的X射线粉末衍射图谱基本如图6-1所表征；
    所述晶型E-3的X射线粉末衍射图谱基本如图7-1所表征；
    所述晶型F的X射线粉末衍射图谱基本如图8-1所表征；
    所述晶型I的X射线粉末衍射图谱基本如图9-1所表征；
    所述晶型II的X射线粉末衍射图谱基本如图10-1所表征；
    所述晶型III的X射线粉末衍射图谱基本如图11-1所表征；
    所述晶型IV的X射线粉末衍射图谱基本如图12-1所表征；
    所述晶型V的X射线粉末衍射图谱基本如图13-1所表征；
    所述晶型VI的X射线粉末衍射图谱基本如图14-1所表征；和
    所述晶型VII的X射线粉末衍射图谱基本如图15-1所表征。
  8. 一种制备式X化合物的药学上可接受的盐、或其多晶型物的方法，其特征在于包括步骤：
    (1)在碱性条件下，将式X-4与X-a进行反应，从而成式X化合物；
    Figure PCTCN2018092895-appb-100002
    (2)任选的将式X化合物与酸或碱进行成盐反应，从而形成式X化合物药学上可接受的盐；
    (3)任选的将步骤(1)所形成的式X化合物或步骤(2)所形成的式X化合物药学上可接受的盐进行结晶处理，从而获得式X化合物的多晶型物或式X化合物药学上可接受的盐的多晶型物。
  9. 一种药物组合物，其特征在于，所述药物组合物包括：(a)如权利要求1-7任一所述的式X化合物的药学上可接受的盐、或其多晶型物；以及(b)药学可接受的载体。
  10. 权利要求1-7任一所述的式X化合物的药学上可接受的盐、或其多晶型物，或权利要求9所述的药物组合物的用途，其特征在于用于治疗疼痛、抑郁症、心血管疾病、呼吸系统疾病或精神疾病。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020192553A1 (zh) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 磺酰基取代的苯并杂环甲酰胺衍生物、其制法与医药上的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015078374A1 (en) * 2013-11-27 2015-06-04 Genentech, Inc. Substituted benzamides and methods of use thereof
WO2016124139A1 (zh) * 2015-02-04 2016-08-11 上海海雁医药科技有限公司 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途
WO2017133591A1 (zh) * 2016-02-03 2017-08-10 上海海雁医药科技有限公司 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015078374A1 (en) * 2013-11-27 2015-06-04 Genentech, Inc. Substituted benzamides and methods of use thereof
WO2016124139A1 (zh) * 2015-02-04 2016-08-11 上海海雁医药科技有限公司 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途
WO2017133591A1 (zh) * 2016-02-03 2017-08-10 上海海雁医药科技有限公司 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020192553A1 (zh) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 磺酰基取代的苯并杂环甲酰胺衍生物、其制法与医药上的用途
WO2020192588A1 (zh) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 烷基氨磺酰基吲唑羧酰胺衍生物、其制法与医药上的用途

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