WO2020001460A1 - 氮杂双环基取代的三唑类衍生物的可药用盐、晶型及制备方法 - Google Patents

氮杂双环基取代的三唑类衍生物的可药用盐、晶型及制备方法 Download PDF

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WO2020001460A1
WO2020001460A1 PCT/CN2019/092940 CN2019092940W WO2020001460A1 WO 2020001460 A1 WO2020001460 A1 WO 2020001460A1 CN 2019092940 W CN2019092940 W CN 2019092940W WO 2020001460 A1 WO2020001460 A1 WO 2020001460A1
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formula
compound
represented
phosphate
crystal form
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PCT/CN2019/092940
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English (en)
French (fr)
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王林
邵启云
冯君
贺峰
曹笑立
杜振兴
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980021641.6A priority Critical patent/CN111902406B/zh
Publication of WO2020001460A1 publication Critical patent/WO2020001460A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • PCT / CN2017 / 118784 (application date December 27, 2017) describes a compound 1- (2-chloro-4-fluorophenyl) -3- (5- (methoxymethyl) -4- ( 6-methoxypyridin-3-yl) -4H-1,2,4-triazol-3-yl) -3-azabicyclo [3.1.0] hexane, showing a highly selective OTR as a free base Inhibition can effectively block the downstream function of oxytocin receptor mediated by oxytocin.
  • Polymorphism is of great significance for the development of drugs that are suitable for industrial production and have good biological activity.
  • the pharmaceutically acceptable salt of the compound represented by the formula A is selected from the group consisting of hydrochloride, sulfate, hydrobromide, mesylate, phosphate, citrate, acetate, maleate, and tartaric acid. Salts, succinates, benzoates or fumarate, preferably hydrochloride, phosphate, hydrobromide.
  • the chemical formula of the compound represented by Formula A with the acid molecule is 1: 2 to 2: 1, and may be 1: 2, 1: 1, 2: 1.
  • the chemical ratio of the compound represented by Formula A to hydrogen chloride is 1: 1.
  • the chemical formula of the compound represented by Formula A and sulfuric acid is 1: 1 or 2: 1.
  • the chemical ratio of the compound represented by Formula A to phosphoric acid is 1: 1, 2: 1.
  • the chemical ratio of the compound represented by Formula A to methanesulfonic acid is 1: 1.
  • the present disclosure also provides a method for preparing the aforementioned pharmaceutically acceptable salt, including: a step of forming a salt of the compound represented by Formula A with an acid selected from the group consisting of hydrochloric acid (or hydrogen chloride solution), sulfuric acid, hydrobromic acid, and methanesulfonic acid. , Phosphoric acid, citric acid, acetic acid, maleic acid, tartaric acid, succinic acid, benzoic acid or fumaric acid, preferably hydrochloric acid (or hydrogen chloride solution), phosphoric acid, and hydrobromic acid.
  • an acid selected from the group consisting of hydrochloric acid (or hydrogen chloride solution), sulfuric acid, hydrobromic acid, and methanesulfonic acid.
  • Phosphoric acid citric acid, acetic acid, maleic acid, tartaric acid, succinic acid, benzoic acid or fumaric acid
  • hydrochloric acid or hydrogen chloride solution
  • phosphoric acid and hydrobromic acid.
  • the solvent used for salt formation in this disclosure is selected from the group consisting of isopropanol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tert-butyl ether, acetonitrile, ethanol, 1,4-dioxane, and ethyl acetate. At least one.
  • the method for preparing the aforementioned pharmaceutically acceptable salt further includes the steps of volatile solvent or stirring crystallization, filtration, drying and the like.
  • composition comprising a pharmaceutically acceptable salt of the aforementioned compound and a pharmaceutically acceptable excipient, optionally from at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
  • the present disclosure also provides the use of the aforementioned pharmaceutically acceptable salts in the manufacture of a medicament for the treatment or prevention of a disease or condition known or shown to inhibit the effects of oxytocin, said disease or condition being selected from sexual dysfunction, Impaired libido, sexual arousal disorder, orgasmic disorder, painful sexual intercourse, premature ejaculation, prenatal delivery, labor complications, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension, liver Sclerosis, renal hypertension, high intraocular pressure, obsessions and behavioral disorders, and neuropsychiatric diseases are preferably selected from sexual dysfunction, sexual arousal disorder, orgasmic disorder, pain during intercourse, and premature ejaculation.
  • the present disclosure also provides the use of the aforementioned pharmaceutically acceptable salts in the manufacture of a medicament for antagonizing oxytocin.
  • the present disclosure provides the X-ray powder diffraction pattern of the crystalline form I of the hydrochloride salt of the compound represented by Formula A as a diffraction angle of 2 ⁇ , with characteristic peaks at 7.98, 17.16, 21.74, 23.00, 25.00, 27.04, 32.54 .
  • the crystalline form I of the hydrochloride salt of the compound represented by Formula A is an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 7.98, 8.44, 13.38, 17.16, 18.10, 19.02, 21.74 There are characteristic peaks at 23.00, 25.00, 27.04, 32.54.
  • the crystal form I of the hydrochloride salt of the compound represented by Formula A is 7.98, 8.44, 12.62, 13.38, 15.22, 17.16, 18.10, 19.02, 19.80 There are characteristic peaks at 21.36, 21.74, 23.00, 25.00, 27.04, 32.54.
  • the X-ray powder diffraction pattern of the crystalline form I of the hydrochloride of the compound represented by Formula A as represented by a diffraction angle of 2 ⁇ is shown in FIG. 1.
  • the present disclosure also provides a method for preparing Form I of the hydrochloride salt of the compound represented by Formula A, including:
  • a solvent (I) which is dissolved by stirring or heating, and the solvent (I) is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tertiary At least one of butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and;
  • the volume (ml) used for the solvent (I) is 1 to 50 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (I) is preferably isopropyl alcohol / isopropyl ether.
  • the volume ratio of isopropyl alcohol / isopropyl ether is 1: 1 to 1: 2.
  • the hydrogen chloride solution described in this disclosure is selected from, but not limited to, a hydrogen chloride isopropanol solution or a hydrogen chloride tetrahydrofuran solution.
  • the present disclosure provides the X-ray powder diffraction pattern of the crystal form II of the hydrochloride salt of the compound represented by Formula A as a diffraction angle of 2 ⁇ , with characteristic peaks at 7.98, 13.80, 17.10, 18.10, 18.92, 21.44, 26.50 .
  • the crystal form II of the hydrochloride salt of the compound represented by Formula A is an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 7.98, 8.34, 12.56, 13.80, 17.10, 18.10, 18.92 There are characteristic peaks at 21.44, 22.92, and 26.50.
  • the X-ray powder diffraction pattern of the crystal form II of the hydrochloride salt of the compound represented by Formula A as represented by the diffraction angle 2 ⁇ is shown in FIG. 4.
  • the present disclosure also provides a method for preparing Form II of the hydrochloride salt of the compound represented by Formula A, including:
  • a solvent (II) which is dissolved by stirring or heating, and the solvent (II) is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tertiary At least one of butyl ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and;
  • the volume (ml) used for the solvent (II) is 1 to 50 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (I) is preferably isopropyl alcohol / isopropyl ether.
  • the volume ratio of isopropyl alcohol / isopropyl ether is 1: 2 to 1: 4, and may be 1: 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4.
  • the present disclosure also provides the crystal form III of the hydrochloride salt of the compound represented by Formula A.
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle has characteristics at 7.40, 14.02, 18.66, 22.14, 23.76, 27.06, 30.58 peak.
  • the crystal form III of the hydrochloride salt of the compound represented by Formula A is an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 7.40, 14.02, 15.16, 18.66, 19.60, 21.12, 22.14 There are characteristic peaks at 23.76, 27.06, and 30.58.
  • the crystal form III of the hydrochloride salt of the compound represented by Formula A is an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 7.40, 13.16, 14.02, 14.80, 15.16, 16.88, 17.40 There are characteristic peaks at 18.66, 19.60, 21.12, 22.14, 23.76, 27.06, and 30.58.
  • the present disclosure also provides a method for preparing Form III of the hydrochloride salt of the compound represented by Formula A, including:
  • the compound of formula A is added to a solvent (III) and dissolved by stirring or heating.
  • the solvent (III) is selected from isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, and methyl tert-butyl. At least one of an ether, acetonitrile, ethanol, 1,4-dioxane, ethyl acetate, and;
  • the volume (ml) of the solvent (III) is 1 to 50 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (III) is preferably isopropanol / tetrahydrofuran.
  • the volume ratio of the isopropanol / tetrahydrofuran is 1: 1 to 1: 4, and may be 1: 1, 2: 3, 1: 2, 1: 3, 1: 4.
  • the present disclosure also provides the crystal form IV of the hydrochloride salt of the compound represented by Formula A.
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is characterized at 12.26, 18.73, 20.34, 21.41, 23.72, 24.82, 32.58. peak.
  • the crystalline form IV of the hydrochloride salt of the compound represented by Formula A is an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 9.59, 10.02, 12.26, 17.26, 18.73, 20.34, 21.41 There are characteristic peaks at 23.72, 24.82, 32.58.
  • the crystalline form IV of the hydrochloride salt of the compound represented by Formula A is an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 9.59, 10.02, 12.26, 17.26, 18.73, 20.34, 21.41 There are characteristic peaks at 22.93, 23.72, 24.82, 27.02, 32.58.
  • the present disclosure also provides an X-ray powder diffraction pattern of the salt hydrobromide salt of the compound of formula A in the form of a diffraction angle 2 ⁇ at 6.12, 7.91, 8.18, 17.12, 18.00, 18.86, 25.14. There are characteristic peaks.
  • the crystal form A of the salt hydrobromide of the compound represented by the formula A is an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ angle at 6.12, 7.91, 8.18, 17.12, 18.00, 18.86 There are characteristic peaks at 25.14, 12.44, 15.98, and 17.12.
  • the crystalline form A of the salt hydrobromide of the compound represented by formula A is an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ at 6.12, 7.91, 8.18, 12.44, 13.57, 15.98 There are characteristic peaks at 17.12, 17.12, 18.00, 18.86, 21.28, 25.14, 26.04, 28.57.
  • This disclosure also provides a method for preparing Form A of a hydrobromide salt of a compound of Formula A, including:
  • the solvent (IV) is selected from At least one of isopropyl alcohol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tert-butyl ether, acetonitrile, ethanol, 1,4-dioxane, and ethyl acetate, preferably isopropyl alcohol / Isopropyl ether, isopropyl alcohol / isopropyl acetate, and;
  • the volume (ml) used for the solvent (IV) is 1 to 40 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times;
  • the solvent (IV) is preferably isopropyl alcohol / isopropyl ether, isopropyl alcohol / isopropyl acetate ester.
  • the volume ratio of isopropyl alcohol / isopropyl ether is 1: 1 to 1: 3, and may be 1: 1, 1: 2, 1: 3.
  • the volume ratio of isopropyl alcohol / isopropyl acetate is 1: 1 to 1: 3, and may be 1: 1, 1: 2, 1: 3.
  • the present disclosure also provides an X-ray powder diffraction pattern of the crystal form A of the compound phosphate represented by Formula A in a diffraction angle of 2 ⁇ , with characteristic peaks at 5.09, 10.29, 12.89, 16.26, 20.86, 22.67.
  • the crystal form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , and has characteristic peaks at 5.09, 10.29, 12.89, 15.46, 16.26, 19.52, 20.86, 22.67, 25.46. .
  • the X-ray powder diffraction pattern of the crystal form A represented by a diffraction angle of 2 ⁇ is 5.09, 10.29, 12.89, 15.46, 16.26, 19.52, 20.86, 22.67, 23.68, 24.08, 25.46 There are characteristic peaks at 26.54 and 30.86.
  • the present disclosure also provides a method for preparing crystal form A of the phosphate of the compound represented by Formula A, including:
  • the solvent (V) used in this method has a volume (ml) of 1 to 50 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the present disclosure also provides an X-ray powder diffraction pattern of the crystal form B of the compound phosphate represented by Formula A in the diffraction angle 2 ⁇ angle, with characteristic peaks at 5.00, 14.24, 16.18, 20.51,21.54, 22.49, 30.54 .
  • the crystal form B of the phosphate of the compound represented by formula A, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 5.00, 14.24, 15.26, 16.18, 17.23, 20.51,21.54, There are characteristic peaks at 22.49,30.00,30.54.
  • the crystal form B of the phosphate of the compound represented by formula A, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 5.00, 14.24, 15.26, 16.18, 17.23, 20.51,21.54, There are characteristic peaks at 22.49,30.00,30.54,25.16,26.44.
  • the present disclosure also provides a method for preparing a crystalline Form B of a phosphate compound of Formula A, including:
  • the solvent (VI) used in this method has a volume (ml) of 1 to 50 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the present disclosure also provides an X-ray powder diffraction pattern of the crystal form C of the compound phosphate represented by Formula A in a diffraction angle of 2 ⁇ , with characteristic peaks at 4.92, 9.91, 11.08, 15.98, 20.18, 20.74, 22.44. .
  • the crystal form C of the phosphate of the compound represented by Formula A, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle, is 4.92, 9.91, 11.08, 15.98, 18.11, 20.18, 20.74, There are characteristic peaks at 22.44 and 23.25.
  • the crystal form C of the phosphate of the compound represented by Formula A is 4.92, 9.91, 11.08, 11.94, 14.83, 15.98, 18.11, There are characteristic peaks at 19.28, 20.18, 20.74, 22.44, 23.25.
  • the present disclosure also provides a method for preparing a crystal form C of a compound of formula A, including:
  • the volume (ml) used for the solvent (VII) is 1 to 50 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the present disclosure also provides the crystal form D of the compound phosphate represented by Formula A, and an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.14, 9.98, 10.31, 16.49, 19.49, 20.94, 22.75 .
  • the crystal form D of the phosphate of the compound represented by Formula A is 5.14, 9.98, 10.31, 12.67, 14.47, 15.66, 16.49, There are characteristic peaks at 19.49, 20.94, 22.75.
  • the crystal form D of the phosphate of the compound represented by Formula A is 5.14, 9.98, 10.31, 12.67, 14.00, 14.47, 15.66, There are characteristic peaks at 16.49, 19.49, 20.94, 21.64, 22.75.
  • the present disclosure also provides a method for preparing a crystal form D of a phosphate compound of formula A, including:
  • the volume (ml) used for the solvent (VIII) is 1 to 50 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the present disclosure also provides an X-ray powder diffraction pattern of the crystal form F of the compound phosphate represented by Formula A in a diffraction angle of 2 ⁇ , with characteristic peaks at 4.96, 5.35, 16.06, 20.39, 22.33, 25.19.
  • the crystal form F of the phosphate of the compound represented by Formula A is 4.96, 5.35, 10.27, 12.77, 16.06, 20.39, 22.33, There are characteristic peaks at 25.19.
  • the crystal form F of the phosphate of the compound represented by Formula A is 4.96, 5.35, 10.27, 12.77, 15.27, 16.06, 20.39, There are characteristic peaks at 22.33, 23.28, 25.19, 26.34.
  • the present disclosure also provides a method for preparing a crystal form F of a phosphate compound of Formula A, including:
  • the volume (ml) used for the solvent (IX) is 1 to 50 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the present disclosure also provides an X-ray powder diffraction pattern of the crystal form G of the compound phosphate represented by Formula A in a diffraction angle of 2 ⁇ , with characteristic peaks at 5.26, 16.08, 16.81, 19.60, 20.90, 23.01,23.96 .
  • the crystal form G of the phosphate of the compound represented by Formula A is 5.26, 10.33, 12.58, 16.08, 16.81, 19.60, 20.90, There are characteristic peaks at 23.01, 23.96, 25.47.
  • the crystal form G of the phosphate of the compound represented by Formula A is 5.26, 10.33, 12.58, 16.08, 16.81, 19.60, 20.90, There are characteristic peaks at 23.01, 23.96, 25.47, 26.58, 31.62.
  • the present disclosure also provides a method for preparing a crystalline form G of a phosphate compound of formula A, including:
  • the volume (ml) used for the solvent (X) is 1 to 50 times the weight (g) of the compound, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the present disclosure also provides an X-ray powder diffraction pattern of the crystal form H of the compound phosphate represented by Formula A in a diffraction angle of 2 ⁇ , with characteristic peaks at 5.32, 15.97, 16.16, 19.69, 20.10, 21.76.
  • the crystal form H of the phosphate of the compound represented by Formula A is 5.32, 10.31, 10.72, 12.56, 13.18, 15.97, 16.16, There are characteristic peaks at 19.69, 20.10, 21.76.
  • composition comprising a crystalline form of the aforementioned pharmaceutically acceptable salt and a pharmaceutical excipient, optionally from a pharmaceutically acceptable carrier, diluent, or excipient.
  • the method for preparing a crystalline form in the present disclosure further includes steps such as filtration, washing or drying.
  • compositions prepared from the aforementioned crystalline forms also provides pharmaceutical compositions prepared from the aforementioned crystalline forms.
  • the present disclosure also provides the use of a crystalline form of the aforementioned pharmaceutically acceptable salt for the manufacture of a medicament for the treatment or prevention of a disease or condition known or shown to inhibit the beneficial effects of oxytocin, said disease or condition being selected from the group consisting of Dysfunction, Loss of libido, Sexual arousal disorder, Orgasmic disorder, Painful intercourse, Premature ejaculation, Prenatal delivery, Complications of delivery, Appetite and eating disorders, Benign prostatic hyperplasia, Preterm delivery, Dysmenorrhea, Congestive heart failure, High arteries Blood pressure, cirrhosis, renal hypertension, high intraocular pressure, obsessions and behavioral disorders, and neuropsychiatric disorders are preferably selected from sexual dysfunction, sexual arousal disorder, orgasmic disorder, pain during intercourse, and premature ejaculation.
  • the present disclosure also provides the use of the aforementioned crystalline form of a pharmaceutically acceptable salt in the manufacture of a medicament for antagonizing oxytocin.
  • Deliquescence Absorb sufficient water to form a liquid
  • Hygroscopicity The moisture gain is less than 15% but not less than 2%;
  • the moisture gain is less than 2% but not less than 0.2%
  • the hygroscopic weight gain is less than 0.2%.
  • the "X-ray powder diffraction pattern" described in this disclosure is obtained using Cu-K ⁇ radiation measurement.
  • ⁇ is the wavelength of X-rays
  • the "2 ⁇ or 2 ⁇ angle" described in this disclosure refers to the diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.30, which can be -0.30, -0.29, -0.28 , -0.27, -0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.12,- 0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19,
  • crystal plane spacing or crystal plane spacing (d value) refers to the selection of three non-parallel unit vectors a, b, and c that connect two adjacent lattice points in space.
  • the lattice is divided into juxtaposed parallelepiped units, called the crystal plane spacing.
  • the space lattice is divided according to the determined parallelepiped unit connection to obtain a set of straight grids, which are called space lattices or lattices.
  • the lattice and the lattice reflect the periodicity of the crystal structure with geometric points and lines, respectively. Different crystal planes have different interplanar distances (that is, the distance between two adjacent parallel crystal planes); the unit is Or Egypt.
  • the “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference during the temperature rise or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical change to obtain phase change information of the sample.
  • the drying temperature described in the present disclosure is generally 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C, and can be dried under normal pressure or reduced pressure. Preferably, the drying is performed under reduced pressure.
  • the reagents used in this disclosure are commercially available.
  • Heating rate 10.0 °C / min
  • Heating rate 10.0 °C / min
  • DVS dynamic moisture adsorption
  • the test adopts SMS DVA Advantage, at 25 ° C, the humidity change is 50% -95% -0% -95% -50%, the step is 10% (the last step is 5%), the judgment standard is dm / dt is not greater than 0.02 %.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts ([delta]) at 10 - given in units of 6 (ppm) a.
  • the NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was four. Methylsilane (TMS).
  • MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • the HPLC was measured using an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 ⁇ 4.6 mm column).
  • the monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin layer chromatography developing system including: A: Dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.
  • TLC thin layer chromatography
  • A Dichloromethane / methanol system
  • B n-hexane / ethyl acetate system
  • C petroleum ether / ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust
  • Figure 1 XRPD pattern of Form I of the hydrochloride salt of the compound represented by Formula A.
  • FIG. 1 DSC spectrum of Form I of the hydrochloride salt of the compound represented by Formula A.
  • FIG. 3 TGA spectrum of Form I of the hydrochloride salt of the compound represented by Formula A.
  • Figure 4 XRPD pattern of Form II of the hydrochloride salt of the compound of Formula A.
  • Figure 5 DSC pattern of Form II of the hydrochloride salt of the compound of Formula A.
  • FIG. 6 TGA pattern of crystalline Form II of the hydrochloride salt of the compound represented by Formula A.
  • Figure 7 XRPD pattern of Form III of the hydrochloride salt of the compound of Formula A.
  • Figure 8 DSC pattern of Form III of the hydrochloride salt of the compound represented by Formula A.
  • Figure 9 TGA pattern of Form III of the hydrochloride salt of the compound represented by Formula A.
  • Figure 10 DVS pattern of Form I of the hydrochloride salt of the compound represented by Formula A.
  • FIG. 11 is a comparison chart of X-ray powder diffraction before and after DVS of Form I of a hydrochloride of a compound represented by Formula A.
  • FIG. 11 is a comparison chart of X-ray powder diffraction before and after DVS of Form I of a hydrochloride of a compound represented by Formula A.
  • Figure 12 DVS pattern of Form III of the hydrochloride salt of the compound represented by Formula A.
  • FIG. 13 is a comparison chart of X-ray powder diffraction before and after DVS of Form III of a hydrochloride of a compound represented by Formula A.
  • FIG. 13 is a comparison chart of X-ray powder diffraction before and after DVS of Form III of a hydrochloride of a compound represented by Formula A.
  • Figure 14 XRPD pattern of Form IV of the hydrochloride salt of the compound represented by Formula A.
  • Figure 15 XRPD pattern of Form A of the hydrobromide salt of the compound represented by Formula A.
  • FIG. 16 XRPD pattern of the crystal form A of the compound phosphate represented by Formula A.
  • Figure 17 DSC pattern of Form A of the compound phosphate represented by Formula A.
  • FIG. 18 XRPD pattern of the crystal form B of the compound phosphate represented by Formula A.
  • FIG. 19 DSC pattern of the crystal form B of the compound phosphate represented by Formula A.
  • Figure 20 XRPD pattern of Form C of the compound phosphate represented by Formula A.
  • Figure 21 DSC pattern of Form C of the compound phosphate represented by Formula A.
  • FIG. 22 XRPD pattern of the crystal form D of the phosphate of the compound represented by Formula A.
  • FIG. 23 DSC pattern of the crystal form D of the compound phosphate represented by Formula A.
  • FIG. 24 XRPD pattern of the crystal form F of the compound phosphate represented by Formula A.
  • Figure 25 DSC pattern of the crystalline form F of the compound phosphate represented by formula A.
  • Fig. 26 XRPD pattern of the crystalline form G of the compound phosphate represented by formula A.
  • Figure 27 XRPD pattern of the crystalline form H of the compound phosphate represented by formula A.
  • Example 1 Compound A (1S, 5R) -1- (2-chloro-4-fluorophenyl) -3- (5- (methoxymethyl) -4- (6-methoxypyridine-3 -Yl) -4H-1,2,4-triazol-3-yl) -3-azabicyclo [3.1.0] hexane
  • the crude product 1d (1.35 g, 5.9 mmol) and sulfoxide (1.05 g, 8.85 mmol) were added to 10 mL of dichloromethane. After the addition was complete, the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 1e (1.3 g). The product was directly subjected to the next reaction without purification.
  • Step 5 (1S, 5R, E) -1- (2-chloro-4-fluorophenyl) -N- (6-methoxypyridin-3-yl) -3-azabicyclo [3.1.0 ] Hexane-3-thioimidate methyl ester 1h
  • Test Example 1 Determination of human OTR inhibitory activity
  • Oxytocin (synthesized by Jill Biochemical Co., Ltd.)
  • pcDNA3.1-hOTR (NM-000916) (synthesized and constructed into pcDNA3.1 plasmid by Jin Weizhi Biotechnology Co., Ltd.)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • HEK293 / human OTR stable transfected cells were seeded in a 96-well plate at a density of 25,000 cells / well.
  • the next day first use the reagents in the Fluo-4NW calcium analysis kit to prepare a loading buffer containing Fluo-4 dye, then remove the culture medium, add 100 ⁇ l of loading buffer containing Fluo-4 dye to each well, 37 ° Incubate for 30 minutes. When the time is up, move the board to room temperature and equilibrate for 10 minutes.
  • Compounds were prepared as 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , and 10 1 nM, 1 ⁇ l was added to each well, and the cells were incubated at room temperature for 10 minutes.
  • the test was performed with a flexstation 3 microplate reader. 50 ⁇ l of 3 nM oxytocin peptide was automatically added by the machine, and the value was immediately read at 494/516 nM.
  • Test Example 2 Determination of human V1aR inhibitory activity
  • pcDNA3.1-V1aR (NM-000706) (Synthesized and constructed into pcDNA3.1 plasmid by Jin Weizhi Biotechnology Co., Ltd.)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • HEK293 / human-derived V1aR stable transfected cells were seeded in a 96-well plate at a density of 25,000 cells / well.
  • the next day first use the reagents in the Fluo-4NW calcium analysis kit to prepare a loading buffer containing Fluo-4 dye, then remove the culture medium, add 100 ⁇ l of loading buffer containing Fluo-4 dye to each well, 37 ° Incubate for 30 minutes. When the time is up, move the board to room temperature for 10 minutes.
  • Compounds were prepared as 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , and 10 1 nM, 1 ⁇ l was added to each well, and the cells were incubated at room temperature for 10 minutes.
  • Detection was performed with a flexstation 3 microplate reader, and 50 ⁇ l of 3 nM vasopressin peptide was automatically added by the machine, and the value was immediately read at 494/516 nM.
  • Test Example 3 Determination of human V1bR inhibitory activity
  • pcDNA3.1-V1bR (NM-000706) (Synthesized and constructed into pcDNA3.1 plasmid by Jin Weizhi Biotechnology Co., Ltd.)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • HEK293 / human V1bR pool cells were seeded in 96-well plates at a density of 25,000 cells / well.
  • the next day first use the reagents in the Fluo-4NW calcium analysis kit to prepare a loading buffer containing Fluo-4 dye, and then remove the culture medium. Add 100 ⁇ l of loading buffer containing Fluo-4 dye to each well, 37 ° C. Incubate for 30 minutes. When the time is up, move the board to room temperature and equilibrate for 10 minutes. Compounds were prepared as 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , and 10 1 nM, 1 ⁇ l was added to each well, and the cells were incubated at room temperature for 10 minutes.
  • Detection was performed with a flexstation 3 microplate reader, and 50 ⁇ l of 3 nM vasopressin peptide was automatically added by the machine, and the value was immediately read at 494/516 nM.
  • Test Example 4 Determination of human-derived V2R inhibitory activity
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • HEK293 / human-derived V2R pool cells were dissociated from the cell culture dish using a cell dissociation solution without enzyme digestion. The cells were dissociated into individual cells. After termination, the cells were homogenized by centrifugation, and the supernatant was removed with experimental buffer 1 (1x HBSS + 20 mM HEPES + 0.1% BSA), resuspend the cells and count, adjust the cell density to 1250 cells / 5 ⁇ l, that is 2.5 * 10 5 / ml.
  • Agonist 460 ⁇ M vasopressin mother solution, first made up to 2 ⁇ M with DMSO, and then diluted to 0.5 nM concentration with experimental buffer 2.
  • the first spot is 20 ⁇ l of stock stock solution (2848nM). Dilute with the experimental buffer 1 4 times from the second spot to a total of 11 concentrations.
  • Standard curve wells need to add 5 ⁇ l / well of experimental buffer 2.
  • PheraStar multi-functional microplate reader reads HTRF signals.
  • LC / MS / MS method was used to determine the drug concentration in plasma of rats at different times after intragastric administration of compounds.
  • the pharmacokinetic behavior of the compounds in the present disclosure in rats was studied and their pharmacokinetic characteristics were evaluated.
  • SD rats were fasted orally after fasting overnight.
  • the doses were all 2.0 mg / kg, and the volume was 10.0 mL / kg.
  • Rats were administered by gavage. 0.2 mL of blood was collected from the orbit before and after 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, and placed in a heparinized test tube at 4 ° C, 3500 rpm / The plasma was separated by centrifugation for 10 minutes, and stored at -20 ° C, and the food was taken 2 hours after administration.
  • CONCLUSION The compounds have good pharmacokinetic absorption and have pharmacokinetic advantages.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.52%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • the XRPD spectrum of this crystalline sample is shown in Figure 1
  • the DSC spectrum is shown in Figure 2
  • the TGA spectrum is shown in Figure 3
  • the melting peak point is around 198.54 ° C.
  • the characteristic peak positions are shown in Table 1 below:
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.54%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • the XRPD spectrum of this crystal sample is shown in Figure 4, the DSC spectrum is shown in Figure 5, the TGA spectrum is shown in Figure 6, and the melting peak point is around 187.58 ° C.
  • the characteristic peak positions are shown in Table 2 below:
  • the aforementioned sample was heated to 65 ° C or 110 ° C and then taken out, and was detected as Form II by X-powder diffraction, and the form did not change.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.61%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.46%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • Form X was detected by X-powder diffraction.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.54%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • Form X was detected by X-powder diffraction.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.55%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • Form X was detected by X-powder diffraction.
  • the sample was placed under the conditions of 25 ° C, 10.0% RH-80.0% RH, and the water absorption increased with the increase of humidity.
  • the weight change was 0.7188%, less than 2% but not less than 0.2%.
  • the sample was slightly Hygroscopicity; during a humidity change of 0% -95%, the desorption process of the sample and the adsorption process basically coincide.
  • the DVS spectrum is shown in Figure 10, and the comparison of X-ray powder diffraction before and after DVS is shown in Figure 11.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.50%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • Form X was detected by X-powder diffraction.
  • the sample was placed under the conditions of 25 ° C, 10.0% RH-80.0% RH, and the water absorption increased with the increase of humidity.
  • the weight change was 1.9898%, less than 2% but not less than 0.2%.
  • the sample was slightly Hygroscopicity; the sample is slightly hygroscopic; during the humidity change from 0% to 95%, the desorption process of the sample and the adsorption process basically coincide; the DVS spectrum is shown in Figure 12, and the X-ray powder diffraction comparison before and after DVS is shown in Figure 13.
  • Example 21 Experiments of influencing factors of crystalline forms I and III of compound A hydrochloride
  • Forms I and III of Compound A hydrochloride crystals were placed flat and open, and the stability of the samples under the conditions of heating (40 ° C, 60 ° C), light (4500 Lux), and high humidity (RH75%, RH90%) were investigated.
  • the sampling inspection period is 24 days.
  • the ion chromatography (HPIC) test result of the obtained product showed that the content of phosphate acid was 22.92%, indicating that the molar ratio of the compound to phosphate in the salt was about 1: 1.
  • the XRPD spectrum of this crystalline sample is shown in Figure 16.
  • the DSC spectrum is shown in Figure 17.
  • the melting peak is around 165.33 ° C.
  • the characteristic peak positions are shown in Table 8 below:
  • the XRPD spectrum of this crystalline sample is 20, the DSC spectrum is shown in FIG. 21, and the melting peak point is near 162.26 ° C.
  • the characteristic peak position is shown in Table 10 below:
  • the XRPD pattern of this crystalline sample is shown in Figure 24.
  • the DSC pattern is shown in Figure 25.
  • the melting peak point is around 160.16 ° C.
  • the characteristic peak positions are shown in Table 12 below:
  • the XRPD pattern of the crystalline sample is shown in Figure 26.
  • the characteristic peak positions are shown in Table 13 below:
  • the crystal form A of the compound A phosphate was left at 40 ° C and RH 75% for 7 days.
  • the XRPD pattern of the crystal sample is shown in Fig. 27, and the characteristic peak positions are as follows:

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Abstract

本披露中提供了氮杂双环基取代的三唑类衍生物的可药用盐、晶型及制备方法。具体而言，本披露中提供了式A所示化合物1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷的可药用盐、晶型及制备方法。相对于自由碱而言，该化合物可药用盐具有更高的纯度，更为优异的化学稳定性，对开发适合工业生产且生物活性良好的药物具有重要意义。(A)

Description

氮杂双环基取代的三唑类衍生物的可药用盐、晶型及制备方法
本申请要求申请日为2018/6/27的中国专利申请201810676344.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本披露中提供了化合物1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷的可药用盐及其制备方法。
背景技术
PCT/CN2017/118784(申请日2017年12月27日)描述了一种化合物1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷，作为游离碱显示了高选择性OTR抑制作用，可有效阻断催产素所介导的催产素受体的下游功能。
近一半药物分子都是以盐的形式存在，同时，成盐可改善药物某一些不理想的物理化学或生物学性质。开发出相对于1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷，在理化性质或药学性质方面具有更优异的性质的盐是具有重要意义的。
同时，鉴于固体药物晶型及其稳定性对其在临床治疗中的重要性，深入研究化合物1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷的可药用盐的多晶型，对开发适合工业生产且生物活性良好的药物是具有重要意义。
发明内容
本披露中提供了式A所示化合物(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷的可药用盐，
Figure PCTCN2019092940-appb-000001
其中，所述式A所示化合物的可药用盐选自盐酸盐，硫酸盐、氢溴酸盐、甲磺酸盐、磷酸盐、柠檬酸盐、乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐或富马酸盐，优选盐酸盐、磷酸盐、氢溴酸盐。
优选地，所述式A所示化合物的与酸分子的化学配比为1:2～2:1，可以为1:2、1:1、2:1。
在可选实施方案中，所述式A所示化合物与氯化氢的化学配比为1:1。
在可选实施方案中，所述式A所示化合物与硫酸的化学配比为1:1或2:1。
在可选实施方案中，所述式A所示化合物与磷酸的化学配比为1:1、2:1。
在可选实施方案中，所述式A所示化合物与甲磺酸的化学配比为1:1。
本披露中还提供了制备前述可药用盐的方法，包括：式A所示化合物与酸成盐的步骤，所述酸选自盐酸(或氯化氢溶液)，硫酸、氢溴酸、甲磺酸、磷酸、柠檬酸、乙酸、马来酸、酒石酸、琥珀酸、苯甲酸或富马酸，优选盐酸(或氯化氢溶液)、磷酸、氢溴酸。
本披露中成盐所用溶剂选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种。
进一步地，在可选实施方案中，制备前述可药用盐的方法还包括挥发溶剂或搅拌析晶，过滤、干燥等步骤。
本披露中还提供了一种药物组合物，其含有前述化合物的可药用盐和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料。
本披露中还提供了前述可药用盐在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物的用途，所述疾病或病症选自性功能障碍、性欲减退障碍、性唤起障碍、性高潮障碍、性交疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性前列腺增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病，优选地选自性功能障碍、性唤起障碍、性高潮障碍、性交疼痛障碍和早泄。
本披露中还提供了前述可药用盐在制备用于拮抗催产素的药物中的用途。
本披露中提供了式A所示化合物盐酸盐的晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,17.16,21.74,23.00,25.00,27.04,32.54处有特征峰。
在可选实施方案中，所述式A所示化合物盐酸盐的晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,8.44,13.38,17.16,18.10,19.02,21.74,23.00,25.00,27.04,32.54处有特征峰。
进一步地，所述式A所示化合物盐酸盐的晶型I，以衍射角2θ角度表示的X-射线粉 末衍射图谱，在7.98,8.44,12.62,13.38,15.22,17.16,18.10,19.02,19.80,21.36,21.74,23.00,25.00,27.04,32.54处有特征峰。
优选地，所述式A所示化合物盐酸盐的晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
本披露中还提供了式A所示化合物盐酸盐的的晶型I的制备方法，包括：
(a)将式A所示化合物加入溶剂(I)中，搅拌溶解或加热溶解，所述溶剂(I)选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种，和；
(b)滴加氯化氢溶液，搅拌析晶。
其中，所述溶剂(I)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍；所述溶剂(I)优选异丙醇/异丙醚。
在可选实施方案中，所述异丙醇/异丙醚的体积比为1:1～1:2。
本披露中所述氯化氢溶液选自但不限于氯化氢异丙醇溶液或氯化氢四氢呋喃溶液。
本披露中提供了式A所示化合物盐酸盐的晶型II，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,13.80,17.10,18.10,18.92,21.44,26.50处有特征峰。
在可选实施方案中，所述式A所示化合物盐酸盐的晶型II，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,8.34,12.56,13.80,17.10,18.10,18.92,21.44,22.92,26.50处有特征峰。
优选地，所述式A所示化合物盐酸盐的晶型II，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本披露中还提供了式A所示化合物盐酸盐的晶型II的制备方法，包括：
(a)将式A所示化合物加入溶剂(II)中，搅拌溶解或加热溶解，所述溶剂(II)选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种，和；
(b)滴加氯化氢溶液，搅拌析晶。
其中，所述溶剂(II)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍；所述溶剂(I)优选异丙醇/异丙醚。
在可选实施方案中，所述异丙醇/异丙醚的体积比为1:2～1:4，可以为1:2、1:2.5、1:3、1:3.5、1:4。
本披露中还提供了式A所示化合物盐酸盐的晶型III，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.40,14.02,18.66,22.14,23.76,27.06,30.58处有特征峰。
在可选实施方案中，所述式A所示化合物盐酸盐的晶型III，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.40,14.02,15.16,18.66,19.60,21.12,22.14,23.76,27.06,30.58处有特征峰。
在可选实施方案中，所述式A所示化合物盐酸盐的晶型III，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.40,13.16,14.02,14.80,15.16,16.88,17.40,18.66,19.60,21.12,22.14,23.76,27.06,30.58处有特征峰。
进一步地，所述式A所示化合物盐酸盐的晶型III，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本披露中还提供了式A所示化合物盐酸盐的晶型III的制备方法，包括：
(a)式A所示化合物加入溶剂(III)中，搅拌溶解或加热溶解，所述溶剂(III)选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种，和；
(b)滴加氯化氢溶液，搅拌析晶。
其中，所述溶剂(III)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍；所述溶剂(III)优选异丙醇/四氢呋喃。
在可选实施方案中，所述异丙醇/四氢呋喃的体积比为1:1～1:4，可以为1:1、2:3、1:2、1:3、1:4。
本披露中还提供了式A所示化合物盐酸盐的晶型IV，以衍射角2θ角度表示的X-射线粉末衍射图谱，在12.26,18.73,20.34,21.41,23.72,24.82,32.58处有特征峰。
在可选实施方案中，所述式A所示化合物盐酸盐的晶型IV，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.59,10.02,12.26,17.26,18.73,20.34,21.41,23.72,24.82,32.58处有特征峰。
在可选实施方案中，所述式A所示化合物盐酸盐的晶型IV，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.59,10.02,12.26,17.26,18.73,20.34,21.41,22.93,23.72,24.82,27.02,32.58处有特征峰。
进一步地，所述式A所示化合物盐酸盐的晶型IV，以衍射角2θ角度表示的X-射线粉末衍射图谱如图14所示。
本披露中还提供了式A所示化合物盐氢溴酸盐的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.12,7.91,8.18,17.12,18.00,18.86,25.14处有特征峰。
在可选实施方案中，所述式A所示化合物盐氢溴酸盐的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.12,7.91,8.18,17.12,18.00,18.86,25.14,12.44,15.98,17.12处有特征峰。
在可选实施方案中，所述式A所示化合物盐氢溴酸盐的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.12,7.91,8.18,12.44,13.57,15.98,17.12,17.12,18.00,18.86,21.28,25.14,26.04,28.57处有特征峰。
进一步地，所述式A所示化合物盐氢溴酸盐的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
本披露中还提供了式A所示化合物氢溴酸盐的晶型A的制备方法，包括：
(a)(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷加入溶剂(IV)中，搅拌溶解或加热溶解，所述溶剂(IV)选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种，优选异丙醇/异丙醚、异丙醇/乙酸异丙酯，和；
(b)滴加氢溴酸，搅拌析晶。
其中，所述溶剂(IV)所用体积(ml)为化合物重量(g)的1～40倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍；所述溶剂(IV)优选异丙醇/异丙醚、异丙醇/乙酸异丙酯。
在可选实施方案中，所述异丙醇/异丙醚的体积比为1:1～1:3，可以为1:1、1:2、1:3。
在可选实施方案中，所述异丙醇/乙酸异丙酯的体积比为1:1～1:3，可以为1:1、1:2、1:3。
本披露中还提供了式A所示化合物磷酸盐的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.09,10.29,12.89,16.26,20.86,22.67处有特征峰。
在可选实施方案中，所述的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.09,10.29,12.89,15.46,16.26,19.52,20.86,22.67,25.46处有特征峰。
在可选实施方案中，所述的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱， 在5.09,10.29,12.89,15.46,16.26,19.52,20.86,22.67,23.68,24.08,25.46,26.54,30.86处有特征峰。
进一步地，所述晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
本披露中还提供了式A所示化合物磷酸盐的晶型A的制备方法，包括：
(a)将式A所示化合物加入溶剂(V)中，搅拌溶解或加热溶解，所述溶剂(V)选自丙酮、乙酸乙酯、异丙醇中的至少一种，和；
(b)滴加磷酸或磷酸溶液，搅拌析晶。
本法所述溶剂(V)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍。
本披露中还提供了式A所示化合物磷酸盐的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.00,14.24,16.18,20.51,21.54,22.49,30.54处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.00,14.24,15.26,16.18,17.23,20.51,21.54,22.49,30.00,30.54处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.00,14.24,15.26,16.18,17.23,20.51,21.54,22.49,30.00,30.54,25.16,26.44处有特征峰。
进一步地，所述式A所示化合物磷酸盐的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
本披露中还提供了式A所示化合物磷酸盐的晶型B的制备方法，包括：
(a)将式A所示化合物加入溶剂(VI)中，搅拌溶解或加热溶解，所述溶剂(VI)选自1,4-二氧六环、异丙醇中的至少一种，和；
(b)滴加磷酸或磷酸溶液，搅拌析晶。
本法所述溶剂(VI)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍。
本披露中还提供了式A所示化合物磷酸盐的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.92,9.91,11.08,15.98,20.18,20.74,22.44处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.92,9.91,11.08,15.98,18.11,20.18,20.74,22.44,23.25处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.92,9.91,11.08,11.94,14.83,15.98,18.11,19.28,20.18,20.74,22.44,23.25处有特征峰。
进一步地，所述式A所示化合物磷酸盐的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱如图20所示。
本披露中还提供了式A所示化合物磷酸盐的晶型C的制备方法，包括：
(a)将式A所示化合物加入溶剂(VII)中，搅拌溶解或加热溶解，所述溶剂(VII)选自叔丁基二甲醚，和；
(b)滴加磷酸或磷酸溶液，搅拌析晶。
其中，所述溶剂(VII)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍。
本披露中还提供了式A所示化合物磷酸盐的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.14,9.98,10.31,16.49,19.49,20.94,22.75处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.14,9.98,10.31,12.67,14.47,15.66,16.49,19.49,20.94,22.75处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.14,9.98,10.31,12.67,14.00,14.47,15.66,16.49,19.49,20.94,21.64,22.75处有特征峰。
进一步地，所述式A所示化合物磷酸盐的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱如图22所示。
本披露中还提供了式A所示化合物磷酸盐的晶型D的制备方法，包括：
(a)将化合物(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷加入溶剂(VIII)中，搅拌溶解或加热溶解，所述溶剂(VIII)选自二氯甲烷，和；
(b)滴加磷酸或磷酸溶液，搅拌析晶。
其中，所述溶剂(VIII)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍。
本披露中还提供了式A所示化合物磷酸盐的晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.96,5.35,16.06,20.39,22.33,25.19处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.96,5.35,10.27,12.77,16.06,20.39,22.33,25.19处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.96,5.35,10.27,12.77,15.27,16.06,20.39,22.33,23.28,25.19,26.34处有特征峰。
进一步地，所述式A所示化合物磷酸盐的晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱如图24所示。
本披露中还提供了式A所示化合物磷酸盐的晶型F的制备方法，包括：
(a)将式A所示化合物加入溶剂(IX)中，搅拌溶解或加热溶解，所述溶剂(IX)选自甲基异丁酮，和；
(b)滴加磷酸或磷酸溶液，搅拌析晶。
其中，所述溶剂(IX)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍。
本披露中还提供了式A所示化合物磷酸盐的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.26,16.08,16.81,19.60,20.90,23.01,23.96处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.26,10.33,12.58,16.08,16.81,19.60,20.90,23.01,23.96,25.47处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.26,10.33,12.58,16.08,16.81,19.60,20.90,23.01,23.96,25.47,26.58,31.62处有特征峰。
进一步地，所述式A所示化合物磷酸盐的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱如图26所示。
本披露中还提供了式A所示化合物磷酸盐的晶型G的制备方法，包括：
(a)将化合物(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷加入溶剂(X)中，搅拌溶解或加热溶解，所述溶剂(X)选自甲基异丁酮，和；
(b)滴加磷酸或磷酸溶液，搅拌析晶。
其中，所述溶剂(X)所用体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍。
本披露中还提供了式A所示化合物磷酸盐的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.32,15.97,16.16,19.69,20.10,21.76处有特征峰。
在可选实施方案中，所述式A所示化合物磷酸盐的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.32,10.31,10.72,12.56,13.18,15.97,16.16,19.69,20.10,21.76处有特征峰。
进一步地，所述式A所示化合物磷酸盐的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱如图27所示。
本披露中还提供了一种药物组合物，其含有前述可药用盐的晶型和任选自药学上可接受的载体、稀释剂或赋形剂中的药用辅料。
在一些实施方案中，本披露中晶型的制备方法中还包括过滤，洗涤或干燥等步骤。
本披露中还提供了由前述晶型制备而成的药物组合物。
本披露中还提供了前述可药用盐的晶型在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物的用途，所述疾病或病症选自性功能障碍、性欲减退障碍、性唤起障碍、性高潮障碍、性交疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性前列腺增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病，优选地选自性功能障碍、性唤起障碍、性高潮障碍、性交疼痛障碍和早泄。
本披露中还提供了前述可药用盐的晶型在制备用于拮抗催产素的药物中的用途。
依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的界定，
潮解：吸收足量水分形成液体；
极具引湿性：引湿增重不小于15％；
有引湿性：引湿增重小于15％但不小于2％；
略有引湿性：引湿增重小于2％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
本披露中所述(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷盐酸盐的晶型I在10.0％RH-80.0％RH条件下，引湿增重0.7188％，略有引湿性。
本披露中所述(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷盐酸盐的晶型III在10.0％RH-80.0％RH，引湿增重1.9898％，略有引湿性。
本披露中所述的“X-射线粉末衍射图谱”为使用Cu-Kα辐射测量得到。
本披露中所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d Sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2019092940-appb-000002
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本披露中所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.30，可以为-0.30、-0.29、-0.28、-0.27、-0.26、-0.25、-0.24、-0.23、-0.22、-0.21、-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.30，优选为±0.20。
本披露中所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2019092940-appb-000003
或埃。
本披露中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本披露中所述干燥温度一般为25℃～100℃，优选40℃～70℃，可以常压干燥，也可 以减压干燥。优选地，干燥在减压下干燥。
对于本领域技术人员而言，本披露中化合物与酸分子的化学配比测定存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。随其所用之处的上下文而有一定程度的误差变化，该误差变化不超过正负10％，优选正负5％。
本披露中所用试剂可通过商业途径获得。
本披露中实验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：TA Q2000
吹扫气：氮气
升温速率：10.0℃/min
温度范围：25-250℃
2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)
(1)仪器型号：Bruker D8Discover A25 X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：10-48°
电压：40KV，电流：40mA
3、热重分析仪(Thermogravimetric Analysis,TGA)
仪器型号：TAQ500
吹扫气：氮气
升温速率：10.0℃/min
温度范围：25-250℃
4、DVS为动态水分吸附
检测采用SMS DVA Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)，判断标准为dm/dt不大于0.02％。
5、离子色谱(HPIC)：仪器
美国DionexICS-5000离子色谱仪；分离柱:IonPac AS14A，检测方式：电导；淋洗液：NaHCO 3 0.0010M+Na 2CO 3 0.0035M；流速1.0mL/min
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 - 6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ  advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
手性HPLC分析测定使用LC-10A vp(Shimadzu)或者SFC-analytical(Berger Instruments Inc.)。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
附图说明
图1：式A所示化合物盐酸盐的晶型I的XRPD图谱。
图2：式A所示化合物盐酸盐的晶型I的DSC谱图。
图3：式A所示化合物盐酸盐的晶型I的TGA谱图。
图4：式A所示化合物盐酸盐的晶型II的XRPD图谱。
图5：式A所示化合物盐酸盐的晶型II的DSC图谱。
图6：式A所示化合物盐酸盐的晶型II的TGA图谱。
图7：式A所示化合物盐酸盐的晶型III的XRPD图谱。
图8：式A所示化合物盐酸盐的晶型III的DSC图谱。
图9：式A所示化合物盐酸盐的晶型III的TGA图谱。
图10：式A所示化合物盐酸盐的晶型I的DVS图谱。
图11：式A所示化合物盐酸盐的晶型I的DVS前后X-射线粉末衍射对比图。
图12：式A所示化合物盐酸盐的晶型III的DVS图谱。
图13：式A所示化合物盐酸盐的晶型III的DVS前后X-射线粉末衍射对比图。
图14：式A所示化合物盐酸盐的晶型IV的XRPD图谱。
图15：式A所示化合物氢溴酸盐的晶型A的XRPD图谱。
图16：式A所示化合物磷酸盐的晶型A的XRPD图谱。
图17：式A所示化合物磷酸盐的晶型A的DSC图谱。
图18：式A所示化合物磷酸盐的晶型B的XRPD图谱。
图19：式A所示化合物磷酸盐的晶型B的DSC图谱。
图20：式A所示化合物磷酸盐的晶型C的XRPD图谱。
图21：式A所示化合物磷酸盐的晶型C的DSC图谱。
图22：式A所示化合物磷酸盐的晶型D的XRPD图谱。
图23：式A所示化合物磷酸盐的晶型D的DSC图谱。
图24：式A所示化合物磷酸盐的晶型F的XRPD图谱。
图25：式A所示化合物磷酸盐的晶型F的DSC图谱。
图26：式A所示化合物磷酸盐的晶型G的XRPD图谱。
图27：式A所示化合物磷酸盐的晶型H的XRPD图谱。
具体实施方式
以下将结合实施例或实验例更详细地解释本披露中，本披露中的实施例或实验例仅用于说明本披露中的技术方案，并非限定本披露中的实质和范围。
实施例1：化合物A(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-三唑-3-基)-3-氮杂双环[3.1.0]己烷
Figure PCTCN2019092940-appb-000004
第一步：(1S)-1-(2-氯-4-氟苯基)-2-(羟甲基)环丙基腈1c
将2-氯-4-氟苯基乙腈1a(1g，5.9mmol)溶解于20mL四氢呋喃中，干冰-丙酮浴冷 却至-20℃，缓慢加入双(三甲基硅基)氨基钠(5.9mL，11.8mmol)，加毕，搅拌30分钟，再加入(R)-2-(氯甲基)环氧乙烷1b(600mg，6.49mmol)，加毕，撤去干冰-丙酮浴，反应液温度自然升至室温，搅拌反应2小时。用饱和氯化铵溶液(20mL)淬灭反应，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，减压浓缩得到粗品标题产物1c(1.35g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):226.4[M+1]。
第二步：((2S)-2-(氨基甲基)-2-(2-氯-4-氟苯基)环丙基)甲醇1d
将氢化锂铝(672mg，17.7mmol)加入到15mL四氢呋喃中，冰浴冷却，加入粗品1c(1.33g，5.9mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。向反应液中依次加入水(0.7mL)、氢氧化钠溶液(10％，0.7mL)和水(2.1mL)，加毕，搅拌30分钟。反应液经硅藻土过滤，滤液减压浓缩，得到粗品标题产物1d(1.4g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):230.3[M+1]。
第三步：(1S,5R)-1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷盐酸盐1e
将粗品1d(1.35g，5.9mmol)和氯化亚砜(1.05g，8.85mmol)加入到10mL二氯甲烷中，加毕，搅拌反应3小时。反应液减压浓缩，得到粗品标题产物1e(1.3g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):212.3[M+1]。
第四步：(1S,5R)-1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代酰胺1g
将5-异硫氰基-2-甲氧基吡啶1f(1.25g，7.5mmol，采用公知的方法“BiooRganic and Medicinal Chemistry Letters,2010,20(2),516-520”制备而得)和粗品1e(1.06g，5.0mmol)加入到20mL四氢呋喃中，加毕，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物1g(1.9g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):378.2[M+1]。
第五步：(1S,5R,E)-1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代亚氨酸甲酯1h
将粗品1g(1.86g，5.0mmol)加入到30mL四氢呋喃中，冰浴冷却，加入叔丁醇钾(2.2g，20mmol)，加毕，搅拌反应2小时。再加入对甲苯磺酸甲酯(1.86g，10.0mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。向反应液中加入冰水(90mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相减压浓缩，用硅胶柱色谱法以洗 脱剂体系B纯化所得残余物，得到标题产物1h(700mg)，产率：32.2％。
MS m/z(ESI):392.2[M+1]。
第六步：
将1h(180mg，0.46mmol)、甲氧基乙酰肼1i(239mg，2.3mmol)和三氟乙酸(52mg，0.46mmol)加入到8mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，反应液减压浓缩，用高效液相色谱法纯化所得残余物，得到化合物A(50mg)，产率：24.21％。
MS m/z(ESI):430.2[M+1]。
1H NMR(400MHz,CDCl3):δ8.22(s,1H),7.66(d,1H),7.27(t,1H),7.10(d,1H),6.91-6.89(m,2H),4.24(s,2H),4.01(s,3H),3.78(d,1H),3.57-3.55(m,2H),3.53(d,1H),3.25(s,3H),1.81-1.79(m,1H),1.10(t,1H),0.95(t,1H)。
测试例1：对人源OTR抑制活性的测定
一、实验材料及仪器
1.Fluo-4NW钙分析试剂盒(F36206，invitrogen)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO,10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.Flexstation 3多功能酶标仪(Molecular Devices)
8.多聚-D-赖氨酸96孔板，黑色/干净(356692，BD)
9.催产素(吉尔生化有限公司合成)
10.pcDNA3.1(invitrogen，V79020)
11.pcDNA3.1-hOTR(NM-000916)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
12.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-hOTR质粒，用
Figure PCTCN2019092940-appb-000005
3000转染试剂转入HEK293细胞；隔天开始加G418筛选，挑选单克隆细胞系。
提前一天将HEK293/人源OTR稳转株细胞以25000个/孔的密度种于96孔板中。第二天，先使用Fluo-4NW钙分析试剂盒中的试剂配制含Fluo-4染料的上样缓冲液，再去除培养基，每孔加入100μl含Fluo-4染料的上样缓冲液，37℃，孵育30分钟。到时间 后，把板子移至室温环境平衡10分钟。将化合物配成10 6、10 5、10 4、10 3、10 2、10 1nM，每孔加入1μl，室温孵育10分钟。用flexstation 3酶标仪进行检测，由机器自动加入3nM的催产素多肽50μl，立刻在494/516nM处读值。化合物的IC 50值可采用不同浓度对应的荧光值，经Graphpad Prism计算得到，IC 50＝28nM，表明化合物对人源OTR活性具有明显的抑制效果。
测试例2：对人源V1aR抑制活性的测定
一、实验材料及仪器
1.Fluo-4NW钙分析试剂盒(F36206，invitrogen)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO,10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.Flexstation 3多功能酶标仪(Molecular Devices)
8.多聚-D-赖氨酸96孔板，黑色/干净(356692，BD)
9.加压素(Tocris,2935)
10.pcDNA3.1(invitrogen，V79020)
11.pcDNA3.1-V1aR(NM-000706)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
12.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-V1aR质粒，用
Figure PCTCN2019092940-appb-000006
3000转染试剂转入HEK293细胞；隔天开始加G418筛选，挑选单克隆细胞系。
提前一天将HEK293/人源V1aR稳转株细胞以25000个/孔的密度种于96孔板中。第二天，先使用Fluo-4NW钙分析试剂盒中的试剂配制含Fluo-4染料的上样缓冲液，再去除培养基，每孔加入100μl含Fluo-4染料的上样缓冲液，37℃，孵育30分钟。到时间后，把板子移至室温环境平衡10分钟。将化合物配成10 6、10 5、10 4、10 3、10 2、10 1nM，每孔加入1μl，室温孵育10分钟。用flexstation 3酶标仪进行检测，由机器自动加入3nM的加压素多肽50μl，立刻在494/516nM处读值。化合物的IC 50值可采用不同浓度对应的荧光值，经Graphpad Prism计算得到，IC 50＝2885nM，表明化合物对人源V1aR活性没有抑制效果，说明对OTR活性具有选择性抑制作用。
测试例3：对人源V1bR抑制活性的测定
一、实验材料及仪器
1.Fluo-4NW钙分析试剂盒(F36206,invitrogen)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO,10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.Flexstation 3多功能酶标仪(Molecular Devices)
8.Poly-D-Lysine 96-well Microplates,black/clear(356692，BD)
9.加压素(Tocris,2935)
10.pcDNA3.1(invitrogen，V79020)
11.pcDNA3.1-V1bR(NM-000706)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
12.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-V1bR质粒，用
Figure PCTCN2019092940-appb-000007
3000转染试剂转入HEK293细胞；隔天开始加G418，得到HEK293/人源V1bR pool细胞系。
提前一天将HEK293/人源V1bR pool细胞以25000个/孔的密度种于96孔板中。第二天，先使用Fluo-4NW钙分析试剂盒中的试剂配制含Fluo-4染料的上样缓冲液，再去除培养基，每孔加入100μl含Fluo-4染料的上样缓冲液，37℃，孵育30分钟。到时间后，把板子移至室温环境平衡10分钟。将化合物配成10 6、10 5、10 4、10 3、10 2、10 1nM，每孔加入1μl，室温孵育10分钟。用flexstation 3酶标仪进行检测，由机器自动加入3nM的加压素多肽50μl，立刻在494/516nM处读值。化合物的IC 50值可采用不同浓度对应的荧光值，经Graphpad Prism软件计算得到，IC 50＝37568μM，表明化合物对人源V1bR活性没有明显抑制效果，说明对OTR活性具有选择性抑制作用。
测试例4：化合物对人源V2R抑制活性的测定
一、实验材料及仪器
1.cAMP动态2试剂盒-1,000次实验(62AM4PEB,Cisbio)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO，10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.PheraStar多功能酶标仪(BMG)
8.Corning/Costar 384孔无吸附微孔板-黑色NBS板(4514，Corning)
9.细胞解离液，不含酶，PBS(13151014-100ml，Thermo Fisher Scientific)
10.HBSS,钙,镁,不含酚红(14025-092，Invitrogen)
11.HEPES,1M缓冲液(15630-080，GIBCO)
12.BSA(0219989725，MP Biomedicals)
13.IBMX(I7018-250MG，sigma)
14.加压素(Tocris,2935)
15.pcDNA3.1(invitrogen，V79020)
16.pcDNA3.1-V2R(NM-000054)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
17.16.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-V2R质粒，用
Figure PCTCN2019092940-appb-000008
3000转染试剂转入HEK293细胞；隔天开始加G418，得到HEK293/人源V2R pool细胞系
1)消化细胞：
使用细胞解离液不含酶消化HEK293/人源V2R pool细胞从细胞培养皿中解离，将细胞解离成单个，终止后吹打均匀，离心，去除上清用实验缓冲液1(1x HBSS+20mM HEPES+0.1％BSA)重悬细胞并计数，将细胞密度调整为1250个细胞/5μl，即2.5*10 5/ml。
2)配药
化合物用纯DMSO配制化合物成20mM、6.67mM、2.22mM、0.74mM、0.25mM、0.0 8mM、27.4μM、9.14μM、3.05μM、1.02μM、0.34μM和0μM(DMSO)一系列的浓度。然后使用实验缓冲液2(实验缓冲液1+1mM IBMX)将化合物配成4倍使用浓度。
激动剂：以460μM的加压素母液，先用DMSO配成2μM，再用实验缓冲液2稀释成0.5nM浓度。
标准品：第一个点为20μl的储备原液(2848nM)，从第二个点开始按4倍依 次用实验缓冲液1进行稀释，共11个浓度。
3)加药孵育：
1.将混匀的细胞加入到384孔板中，5μl/孔，不用更换枪头。
2.加入配好的待测化合物和阳性化合物2.5μl/孔，需要更换枪头。
3. 1000rpm离心1min，震荡30sec混匀，室温静置孵育30min。
4.标准曲线孔需要加5μl/孔的实验缓冲液2。
5.加入配好的激动剂每孔2.5μl，需要更换枪头，1000rpm离心1min，震荡30sec混匀，室温静置孵育30min。
6.避光配制cAMP-d2(cAMP动态2试剂盒中的组份)和Anti-cAMP-Eu-Cryptate(cAMP动态2试剂盒中的组份)，按照1：4的比例与cAMP裂解液(cAMP动态2试剂盒中的组份)混匀。每孔加入配好的cAMP-d2液体5μl/孔，再加Anti-cAMP-Eu-Cryptate 5μl/孔，震荡30sec混匀，室温避光孵育1h。
4)读板：PheraStar多功能酶标仪进行HTRF的信号读取。
5)数据处理
本实验的数据使用数据处理软件Graphpad Prism处理，得到IC 50＝32604μM，表明化合物对人源V2R活性没有明显的抑制效果，说明对OTR活性具有选择性抑制作用。
测试例5：化合物的药代动力学测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予化合物后不同时刻血浆中的药物浓度。研究本披露中化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验动物
健康成年SD大鼠12只，雌雄各半，平均分成3组，每组4只，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.2药物配制
称取一定量药物，加2.5％体积的DMSO和97.5％体积的10％solutol HS-15配制成0.2mg/mL的无色澄清透明液体。
2.3给药
SD大鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为10.0mL/kg。
3.操作
大鼠灌胃给药，于给药前及给药后0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时由眼眶采血0.2mL，置于肝素化试管中，4℃、3500转/分钟离心10分钟分离血浆，于-20℃保存，给药后2小时进食。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆25μL，加入内标溶液喜树碱50μL(100ng/mL)，乙腈200μL，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液1.0μL进行LC/MS/MS分析。
4、药代动力学参数结果
化合物的药代动力学参数如下：
Figure PCTCN2019092940-appb-000009
结论：化合物的药代吸收较好，具有药代动力学优势。
实施例2：化合物A盐酸盐晶型I
将化合物A(100mg，0.233mmol)溶于0.8mL异丙醇和1.6mL异丙醚的混合溶剂中，滴加4M氯化氢的异丙醇溶液(0.064mL，0.256mmol)，加热搅拌，冷却至室温搅拌析晶，过滤，真空干燥，得到产物(60mg，产率：55.3％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.52％，表明该盐中化合物与盐酸的摩尔比约为1:1。
该结晶样品的XRPD图谱见图1，其DSC图谱见图2，TGA图谱见图3，融化峰值点在198.54℃附近，其特征峰位置如下表1所示：
表1
Figure PCTCN2019092940-appb-000010
Figure PCTCN2019092940-appb-000011
Figure PCTCN2019092940-appb-000012
实施例3：化合物A盐酸盐的晶型I
将化合物A(40mg，0.093mmol)溶于0.33mL异丙醇，加入4M氯化氢的异丙醇溶液(0.05mL，0.2mmol)，升温搅拌，加入0.66mL异丙醚，溶液稍有浑浊，自然冷却至室温搅拌16小时，析晶，过滤，干燥得到产物(30mg，产率：69.14％)，经X-粉末衍射检测为晶型I。
实施例4：化合物A盐酸盐的晶型II
将化合物A(75g，174.47mmol)溶于150mL异丙醇和450mL异丙醚的混合溶剂中，加热至45℃，滴加4M氯化氢的异丙醇溶液(92mL，366.39mmol)，45℃搅拌约5分钟，由清液变稍混，自然冷却至室温搅拌3小时，析晶，过滤，真空干燥，得到产物(74g，产率：90.95％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.54％，表明该盐中化合物与盐酸的摩尔比约为1:1。
该结晶样品的XRPD谱图见图4，DSC谱图见图5，TGA谱图见图6，融化峰值点在187.58℃附近，其特征峰位置如下表2所示：
表2
Figure PCTCN2019092940-appb-000013
Figure PCTCN2019092940-appb-000014
测试：
在DSC检测过程中，将前述样品升温至65℃或110℃后取出，经X-粉末衍射检测为晶型II，晶型未发生变化。
实施例5：化合物A盐酸盐的晶型III
将化合物A(40mg，0.093mmol)溶于0.5mL异丙醇和0.5mL四氢呋喃的混合溶剂(V:V＝1:1)中，滴加4M氯化氢的异丙醇溶液(0.05mL，0.2mmol)，加热搅拌，冷却至室温搅拌析晶，过滤，真空干燥，得到产物(20mg，产率：46.09％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.61％，表明该盐中化合物与盐酸的摩尔比约为1:1。
该结晶样品的XRPD谱图见图7，DSC图见图8，TGA图见图9，融化峰值点在197.29℃附近，其特征峰位置如下表3所示：
表3
Figure PCTCN2019092940-appb-000015
Figure PCTCN2019092940-appb-000016
实施例6：化合物A盐酸盐晶型III
将化合物A(200mg，0.465mmol)溶于4mL异丙醇和四氢呋喃的混合溶剂(V:V＝2:3)中，升温至30℃，滴加4M氯化氢的异丙醇溶液(0.14mL，0.56mmol)，加热搅拌，冷却至室温搅拌析晶，过滤，真空干燥，得到产物(68mg，产率：31.3％)。经X-粉末衍射检测为晶型III。
实施例7：化合物A盐酸盐的晶型I
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.5mL异丙醇中，室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.46％，表明该盐中化合物与盐酸的摩尔比约为1:1。
经X-粉末衍射检测为晶型I。
实施例8：化合物A盐酸盐晶型I
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.5mL乙酸异丙酯中，室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.54％，表明该盐中化合物与盐酸的摩尔比约为1:1。经X-粉末衍射检测为晶型I。
实施例9：化合物A盐酸盐的晶型I
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.3mL乙醇和0.3mL异丙醚中，室温搅拌16小时。室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.44％，表明该盐中化合物与盐酸的摩尔比约为1:1。经X-粉末衍射检测为晶型I。
实施例10：化合物A盐酸盐的晶型I
将化合物A盐酸盐晶型II(1g，2.14mmol)溶于10mL异丙醇和乙酸异丙酯(V:V＝1:2)的混合溶剂中，室温搅拌，过滤，真空干燥，得到产物(600mg，产率：60％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.55％，表明该盐中化合物与盐酸的摩尔比约为1:1。经X-粉末衍射检测为晶型I。
测试1：
在DSC检测过程中，将前述样品升温至65℃或110℃后取出，经X-粉末衍射检测仍为晶型II，晶型未发生变化。
测试2：
将该样品放置于25℃、10.0％RH-80.0％RH之间条件下，随着湿度的增加吸水量也在增加，重量变化为0.7188％，小于2％但不小于0.2％，该样品略有引湿性；0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合。DVS谱图见图10，DVS前后X-射线粉末衍射对比见图11。
实施例11：化合物A盐酸盐的晶型I
将化合物A盐酸盐晶型I(30mg，0.064mmoL)、化合物A盐酸盐晶型II(30mg，0.064mmoL)、化合物A盐酸盐晶型III(30mg，0.064mmoL)溶于1mL异丙醇和乙酸异丙酯(V:V＝1:2)的混合溶剂中，避光，室温搅拌，过滤，真空干燥，得到产物(60mg，产率：66.6％)。
所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.50％，表明该盐中化合物与盐酸的摩尔比约为1:1。经X-粉末衍射检测为晶型I。
实施例12：化合物A盐酸盐的晶型III
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.5mL丙酮中，室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.59％。经X-粉末衍射检测为晶型III。
实施例13：化合物A盐酸盐的晶型III
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.5mL四氢呋喃中，室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。经X-粉末衍射检测为晶型III。
实施例14：化合物A盐酸盐的晶型III
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.3mL1,4-二氧六环和0.3mL四氢呋喃中，室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。经X-粉末衍射检测为晶型III。
实施例15：化合物A盐酸盐的晶型III
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.3mL四氢呋喃和0.3mL异丙醇中，室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。经X-粉末衍射检测为晶型III。
实施例16：化合物A盐酸盐的晶型III
将化合物A盐酸盐晶型II(37.1mg，0.07956mmol)溶于0.5mL1,4-二氧六环中，室温搅拌，过滤，真空干燥，得到产物(30mg，产率：80.86％)。经X-粉末衍射检测为晶型III。
实施例17：化合物A盐酸盐的晶型III
将化合物A盐酸盐晶型II(1g，2.14mmol)溶于10mL1,4-二氧六环中，室温搅拌，过滤，真空干燥，得到产物(600mg，产率：60％)。经X-粉末衍射检测为晶型III。所得产物的离子色谱(HPIC)检测结果：氯离子含量为7.41％。
测试1：
在DSC检测过程中，将前述样品升温至65℃或110℃后取出，经X-粉末衍射检测为晶型III，晶型未发生变化。
测试2：
将该样品放置于25℃、10.0％RH-80.0％RH之间条件下，随着湿度的增加吸水量也在增加，重量变化为1.9898％，小于2％但不小于0.2％，该样品略有引湿性；该样品略有引湿性；0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合；DVS谱图见图12，DVS前后X-射线粉末衍射对比见图13。
实施例18：盐酸盐的晶型IV
将化合物A盐酸盐的晶型III置于RH90％条件下24天后，该结晶样品的XRPD图谱见图14，其特征峰位置如下表4所示：
表4
Figure PCTCN2019092940-appb-000017
Figure PCTCN2019092940-appb-000018
实施例19：化合物A氢溴酸盐的晶型A
将化合物A(84mg，0.195mmol)溶于1mL异丙醇中，缓慢滴加47％氢溴酸(0.027mL，0.234mmol)，室温搅拌4小时，减压浓缩得粗品(100mg)，将粗品溶于0.4mL异丙醇，滴加1.2mL异丙醚，60℃搅拌1小时，缓慢降温至室温，搅拌，析晶，过滤，真空干燥，得到产物(90mg，产率：90％)。
所得产物的离子色谱(HPIC)检测结果：溴离子含量为15.77％，表明该盐中化合物与盐酸的摩尔比约为1:1。
该结晶样品的XRPD图谱图15，其特征峰位置如下表5所示：
表5
Figure PCTCN2019092940-appb-000019
实施例20：化合物A氢溴酸盐的晶型A
将化合物A(84mg，0.195mmol)溶于1mL异丙醇中，缓慢滴加47％氢溴酸(0.027 mL，0.234mmol)，室温搅拌4小时，反应液减压浓缩的粗品(100mg)，将粗品溶于0.4mL异丙醇，缓慢滴加1.2mL乙酸异丙酯，60℃搅拌1小时，缓慢降温至室温，搅拌，析晶，过滤，真空干燥，得到产物(90mg，产率：90％)。经X-粉末衍射检测为氢溴酸盐的晶型A。
实施例21：化合物A盐酸盐的晶型I、III影响因素实验
将化合物A盐酸盐晶的型I、III分别敞口平摊放置，考察在加热(40℃、60℃)、光照(4500Lux)、高湿(RH75％、RH90％)条件下样品的稳定性，取样考察期为24天。
表6
Figure PCTCN2019092940-appb-000020
结论：
表6的影响因素实验结果表明，化合物A盐酸盐的晶型I和III分别置于在40℃、60℃、光照(4500Lux)、RH75％条件下24天，化合物晶体结构未发生变化，未发生晶型 转变，具有好的稳定性。
实施例22：长期加速稳定性实验
将化合物A盐酸盐的晶型I和III分别置于25℃，60％RH和40℃，75％RH条件下，进行1个月、3个月和6个月稳定性考察，数据如下：
表7
Figure PCTCN2019092940-appb-000021
实验结论：
表7的实验结果表明，在25℃，60％RH条件下，盐酸盐的晶型I和III都具有较好的稳定性，但在40℃，75％RH条件下，盐酸盐的晶型I相对于晶型III具有更好的稳定性。
实施例23：化合物A磷酸盐的晶型A
将化合物A(20mg，0.047mmol)加入0.2mL丙酮中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。
所得产物的离子色谱(HPIC)检测结果：磷酸酸根含量为22.92％，表明该盐中化合物与磷酸根的摩尔比约为1:1。
该结晶样品的XRPD图谱图16，其DSC图谱见图17，融化峰值点在165.33℃附近，其特征峰位置如下表8所示：
表8
Figure PCTCN2019092940-appb-000022
Figure PCTCN2019092940-appb-000023
实施例24：化合物A磷酸盐的晶型A
将化合物A(20mg，0.047mmol)加入0.2mL乙酸乙酯中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型A。
实施例25：化合物A磷酸盐的晶型A
将化合物A(20mg，0.047mmol)加入0.2mL异丙醇中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型A。
实施例26：化合物A磷酸盐的晶型A
将化合物A(20mg，0.047mmol)加入0.2mL丙酮中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0987mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型A。
实施例27：化合物A磷酸盐的晶型A
将化合物A(20mg，0.047mmol)加入0.2mL乙酸乙酯中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0987mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型A。
实施例28：化合物A磷酸盐的晶型B
将化合物A(20mg，0.047mmol)加入0.2mL1,4-二氧六环中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。所得产物的离子色谱(HPIC)检测结果：磷酸酸根含量为21.94％，表明该盐中化合物与磷酸根的摩尔比约为1:1。
该结晶样品的XRPD图谱图18，其DSC图谱见图19，融化峰值点在162.50℃附近，其特征峰位置如下表9所示：
表9
Figure PCTCN2019092940-appb-000024
Figure PCTCN2019092940-appb-000025
实施例29：化合物A磷酸盐的晶型B
将化合物A(20mg，0.047mmol)加入0.2mL1,4-二氧六环中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0987mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型B。
实施例30：化合物A磷酸盐的晶型B
将化合物A(20mg，0.047mmol)加入0.2mL异丙醇中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0987mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型B。
实施例31：化合物A磷酸盐的晶型C
将化合物A(20mg，0.047mmol)加入0.2mL叔丁基二甲醚中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。所得产物的离子色谱(HPIC)检测结果：磷酸酸根含量为21.54％，表明该盐中化合物与磷酸根的摩尔比约为1:1。
该结晶样品的XRPD图谱图20，DSC图谱见图21，融化峰值点在162.26℃附近，其特征峰位置如下表10所示：
表10
Figure PCTCN2019092940-appb-000026
Figure PCTCN2019092940-appb-000027
Figure PCTCN2019092940-appb-000028
实施例32：化合物A磷酸盐的晶型C
将化合物A(20mg，0.047mmol)加入0.2mL叔丁基二甲醚中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0987mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型C。
实施例33：化合物A磷酸盐的晶型D
将化合物A(20mg，0.047mmol)加入0.2mL二氯甲烷中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。所得产物的离子色谱(HPIC)检测结果：磷酸酸根含量为18.18％，表明该盐中化合物与磷酸根的摩尔比约为1:1。
该结晶样品的XRPD图谱见图22，DSC图谱见图23，融化峰值点在159.44℃附近，其特征峰位置如下表11所示：
表11
Figure PCTCN2019092940-appb-000029
Figure PCTCN2019092940-appb-000030
实施例34：化合物A磷酸盐的晶型F
将化合物A(20mg，0.047mmol)加入0.2mL甲基异丁酮中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。所得产物的离子色谱(HPIC)检测结果：磷酸酸根含量为21.98％，表明该盐中化合物与磷酸根的摩尔比约为1:1。
该结晶样品的XRPD图谱图24，其DSC图谱见图25，融化峰值点在160.16℃附近，其特征峰位置如下表12所示：
表12
Figure PCTCN2019092940-appb-000031
实施例35：化合物A磷酸盐的晶型F
将化合物A(20mg，0.047mmol)加入0.2mL甲基异丁酮中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0987mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸盐的晶型F。
实施例36：化合物A磷酸盐的晶型G
将化合物A(20mg，0.047mmol)加入0.2mL乙腈中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0517mmol)，搅拌反应，冷却，过滤，干燥得固体。所得产物的离子色谱(HPIC)检测结果：磷酸酸根含量为21.95％，表明该盐中化合物与磷酸根的摩尔比约为1:1。
该结晶样品的XRPD图谱图26，其特征峰位置如下表13所示：
表13
Figure PCTCN2019092940-appb-000032
实施例37：化合物A磷酸盐的晶型G
将化合物A(20mg，0.047mmol)加入0.2mL乙腈中，加热至45℃搅拌溶解，缓慢滴加磷酸(0.0987mmol)，搅拌反应，冷却，过滤，干燥得固体。经X-粉末衍射检测为磷酸 盐的晶型G。
实施例38：化合物A磷酸盐的晶型H
将化合物A磷酸盐的晶型A在40℃、RH75％条件下放置7天，该结晶样品的XRPD图谱见图27，其特征峰位置如下所示：
表14
Figure PCTCN2019092940-appb-000033

Claims (37)

  1. 式A所示化合物的可药用盐，所述可药用盐选自盐酸盐，硫酸盐、氢溴酸盐、甲磺酸盐、磷酸盐、柠檬酸盐、乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐或富马酸盐，优选盐酸盐、磷酸盐、氢溴酸盐
    Figure PCTCN2019092940-appb-100001
  2. 根据权利要求1所述的式A所示化合物的可药用盐，其特征在于，所述化合物与酸分子的化学配比为1:2～2:1，优选为1:2、1:1、2:1。
  3. 根据权利要求1或2所述的式A所示化合物的可药用盐的制备方法，包括：式A所示化合物与酸成盐的步骤。
  4. 根据权利要求3所述的制备方法，其特征在于，所述成盐反应所用溶剂选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种。
  5. 一种药物组合物，含有根据权利要求1所述的式A所示化合物的可药用盐和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料。
  6. 根据权利要求1所述的式A所示化合物的可药用盐在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物的用途，所述疾病或病症选自性功能障碍、性欲减退障碍、性唤起障碍、性高潮障碍、性交疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性前列腺增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病，优选性功能障碍、性唤起障碍、性高潮障碍、性交疼痛障碍和早泄。
  7. 根据权利要求1所述的式A所示化合物的可药用盐在制备用于拮抗催产素的药物中的用途。
  8. 式A所示化合物盐酸盐的晶型I，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,17.16,21.74,23.00,25.00,27.04,32.54处有特征峰
    Figure PCTCN2019092940-appb-100002
  9. 根据权利要求8所述的式A所示化合物盐酸盐的晶型I，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,8.44,13.38,17.16,18.10,19.02,21.74,23.00,25.00,27.04,32.54处有特征峰。
  10. 根据权利要求8或9所述的式A所示化合物盐酸盐的晶型I，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,8.44,12.62,13.38,15.22,17.16,18.10,19.02,19.80,21.36,21.74,23.00,25.00,27.04,32.54处有特征峰。
  11. 根据权利要求8-10任一项所述的式A所示化合物盐酸盐的晶型I，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
  12. 根据权利要求8所述的式A所示化合物盐酸盐的晶型I的制备方法，包括：
    (a)将式A所示化合物加入溶剂(I)中，搅拌溶解或加热溶解，所述溶剂(I)选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种，优选异丙醇/异丙醚，和；
    (b)滴加氯化氢溶液，搅拌析晶。
  13. 式A所示化合物盐酸盐的晶型II，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.98,13.80,17.10,18.10,18.92,21.44,26.50处有特征峰
    Figure PCTCN2019092940-appb-100003
  14. 根据权利要求13所述的式A所示化合物盐酸盐的晶型II的制备方法，包括：
    (a)将式A所示化合物加入溶剂(II)中，搅拌溶解或加热溶解，所述溶剂(II)优选异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种，和；
    (b)滴加氯化氢溶液，搅拌析晶。
  15. 式A所示化合物盐酸盐的晶型III，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.40,14.02,18.66,22.14,23.76,27.06,30.58处有特征峰
    Figure PCTCN2019092940-appb-100004
  16. 根据权利要求15所述的式A所示化合物盐酸盐的晶型III的制备方法，包括：
    (a)将式A所示化合物加入溶剂(III)中，搅拌溶解或加热溶解，所述溶剂(III)选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二氧六环、乙酸乙酯中的至少一种，优选异丙醇/四氢呋喃，和；
    (b)滴加氯化氢溶液，搅拌析晶。
  17. 式A所示化合物盐酸盐的晶型IV，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在12.26,18.73,20.34,21.41,23.72,24.82,32.58处有特征峰
    Figure PCTCN2019092940-appb-100005
  18. 式A所示化合物氢溴酸盐的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.12,7.91,8.18,17.12,18.00,18.86,25.14处有特征峰
    Figure PCTCN2019092940-appb-100006
  19. 根据权利要求18所述的式A所示化合物氢溴酸盐的晶型A的制备方法，包括：
    (a)式A所示化合物加入溶剂(IV)中，搅拌溶解或加热溶解，所述溶剂(IV)选自异丙醇、异丙醚、四氢呋喃、乙酸异丙酯、丙酮、甲基叔丁基醚、乙腈、乙醇、1,4-二 氧六环、乙酸乙酯中的至少一种，优选异丙醇/异丙醚、异丙醇/乙酸异丙酯，
    (b)滴加氢溴酸，搅拌析晶。
  20. 式A所示化合物磷酸盐的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.09,10.29,12.89,16.26,20.86,22.67处有特征峰
    Figure PCTCN2019092940-appb-100007
  21. 根据权利要求20所述的式A所示化合物磷酸盐的晶型A的制备方法，包括：
    (a)式A所示化合物加入溶剂(V)中，搅拌溶解或加热溶解，所述溶剂(V)选自丙酮、乙酸乙酯、异丙醇中的至少一种，
    (b)滴加磷酸或磷酸溶液，搅拌析晶。
  22. 式A所示化合物磷酸盐的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.00,14.24,16.18,20.51,21.54,22.49,30.54处有特征峰
    Figure PCTCN2019092940-appb-100008
  23. 制备权利要求22所述的式A所示化合物磷酸盐的晶型B的方法，包括：
    (a)式A所示化合物加入溶剂(VI)中，搅拌溶解或加热溶解，所述溶剂(VI)选自1,4-二氧六环、异丙醇中的至少一种，和；
    (b)滴加磷酸或磷酸溶液，搅拌析晶。
  24. 式A所示化合物磷酸盐的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.92,9.91,11.08,15.98,20.18,20.74,22.44处有特征峰
    Figure PCTCN2019092940-appb-100009
  25. 根据权利要求24所述的式A所示化合物磷酸盐的晶型C的制备方法，包括：
    (a)式A所示化合物加入溶剂(VII)中，搅拌溶解或加热溶解，所述溶剂(VII)选自叔丁基二甲醚，和；
    (b)滴加磷酸或磷酸溶液，搅拌析晶。
  26. 式A所示化合物磷酸盐的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.14、9.98、10.31、16.49、19.49、20.94、22.75处有特征峰
    Figure PCTCN2019092940-appb-100010
  27. 根据权利要求26所述的式A所示化合物磷酸盐的晶型D的制备方法，包括：
    (a)式A所示化合物加入溶剂(VIII)中，搅拌溶解或加热溶解，所述溶剂(IX)选自二氯甲烷，和；
    (b)滴加磷酸或磷酸溶液，搅拌析晶。
  28. 式A所示化合物磷酸盐的晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.96,5.35,16.06,20.39,22.33,25.19处有特征峰
    Figure PCTCN2019092940-appb-100011
  29. 根据权利要求28所述的式A所示化合物磷酸盐的晶型F的制备方法，包括：
    (a)式A所示化合物加入溶剂(IX)中，搅拌溶解或加热溶解，所述溶剂(IX)选自甲基异丁酮，和；
    (b)滴加磷酸或磷酸溶液，搅拌析晶。
  30. 式A所示化合物磷酸盐的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.26,16.08,16.81,19.60,20.90,23.01,23.96处有特征峰
    Figure PCTCN2019092940-appb-100012
  31. 根据权利要求30所述的式A所示化合物磷酸盐的晶型G的制备方法，包括：
    (a)式A所示化合物加入溶剂(IX)中，搅拌溶解或加热溶解，所述溶剂(IX)选自甲基异丁酮，和；
    (b)滴加磷酸或磷酸溶液，搅拌析晶。
  32. 式A所示化合物磷酸盐的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.32,15.97,16.16,19.69,20.10,21.76处有特征峰
    Figure PCTCN2019092940-appb-100013
  33. 根据权利要求8-11任一项所述的式A所示化合物盐酸盐的晶型I、权利要求13所述的式A所示化合物盐酸盐的晶型II、权利要求15所述的式A所示化合物盐酸盐的晶型III、权利要求17所述的式A所示化合物盐酸盐的晶型IV、权利要求18所述的式A所示化合物氢溴酸盐的晶型A、权利要求20所述的式A所示化合物磷酸盐的晶型A、权利要求22所述的式A所示化合物磷酸盐的晶型B、权利要求24所述的式A所示化合物磷酸盐的晶型C、权利要求26所述的式A所示化合物磷酸盐的晶型D、权利要求28所述的式A所示化合物磷酸盐的晶型F、权利要求30所述的式A所示化合物磷酸盐的晶型G或权利要求32所述的式A所示化合物磷酸盐的晶型H，其中，所述2θ角误差范围为±0.30，优选为±0.20。
  34. 一种药物组合物，含有根据权利要求8-11任一项所述的式A所示化合物盐酸盐 的晶型I、权利要求13所述的式A所示化合物盐酸盐的晶型II、权利要求15所述的式A所示化合物盐酸盐的晶型III、权利要求17所述的式A所示化合物盐酸盐的晶型IV、权利要求18所述的式A所示化合物氢溴酸盐的晶型A、权利要求20所述的式A所示化合物磷酸盐的晶型A、权利要求22所述的式A所示化合物磷酸盐的晶型B、权利要求24所述的式A所示化合物磷酸盐的晶型C、权利要求26所述的式A所示化合物磷酸盐的晶型D、权利要求28所述的式A所示化合物磷酸盐的晶型F、权利要求30所述的式A所示化合物磷酸盐的晶型G或权利要求32所述的式A所示化合物磷酸盐的晶型H和任选自药学上可接受的载体、稀释剂或赋形剂。
  35. 一种由根据权利要求8-11任一项所述的式A所示化合物盐酸盐的晶型I、权利要求13所述的式A所示化合物盐酸盐的晶型II、权利要求15所述的式A所示化合物盐酸盐的晶型III、权利要求17所述的式A所示化合物盐酸盐的晶型IV、权利要求18所述的式A所示化合物氢溴酸盐的晶型A、权利要求20所述的式A所示化合物磷酸盐的晶型A、权利要求22所述的式A所示化合物磷酸盐的晶型B、权利要求24所述的式A所示化合物磷酸盐的晶型C、权利要求26所述的式A所示化合物磷酸盐的晶型D、权利要求28所述的式A所示化合物磷酸盐的晶型F、权利要求30所述的式A所示化合物磷酸盐的晶型G或权利要求32所述的式A所示化合物磷酸盐的晶型H制备的药物组合物。
  36. 根据权利要求8-11任一项所述的式A所示化合物盐酸盐的晶型I、权利要求13所述的式A所示化合物盐酸盐的晶型II、权利要求15所述的式A所示化合物盐酸盐的晶型III、权利要求17所述的式A所示化合物盐酸盐的晶型IV、权利要求18所述的式A所示化合物氢溴酸盐的晶型A、权利要求20所述的式A所示化合物磷酸盐的晶型A、权利要求22所述的式A所示化合物磷酸盐的晶型B、权利要求24所述的式A所示化合物磷酸盐的晶型C、权利要求26所述的式A所示化合物磷酸盐的晶型D、权利要求28所述的式A所示化合物磷酸盐的晶型F、权利要求30所述的式A所示化合物磷酸盐的晶型G或权利要求32所述的式A所示化合物磷酸盐的晶型H在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物的用途，所述疾病或病症选自性功能障碍、性欲减退障碍、性唤起障碍、性高潮障碍、性交疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性前列腺增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病，优选性功能障碍、性唤起障碍、性高潮障碍、性交疼痛障碍和早泄。
  37. 根据权利要求8-11任一项所述的式A所示化合物盐酸盐的晶型I、权利要求13所述的式A所示化合物盐酸盐的晶型II、权利要求15所述的式A所示化合物盐酸盐的晶型III、权利要求17所述的式A所示化合物盐酸盐的晶型IV、权利要求18所述的式A所示化合物氢溴酸盐的晶型A、权利要求20所述的式A所示化合物磷酸盐的晶型A、权利要求22所述的式A所示化合物磷酸盐的晶型B、权利要求24所述的式A所示化合物磷酸盐的晶型C、权利要求26所述的式A所示化合物磷酸盐的晶型D、权利要求28所述的式A所示化合物磷酸盐的晶型F、权利要求30所述的式A所示化合物磷酸盐的晶型G或权利要求32所述的式A所示化合物磷酸盐的晶型H在制备用于拮抗催产素的药物中的用途。
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