WO2019114541A1 - 磷酸二酯酶-5抑制剂的晶型 - Google Patents

磷酸二酯酶-5抑制剂的晶型 Download PDF

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WO2019114541A1
WO2019114541A1 PCT/CN2018/117788 CN2018117788W WO2019114541A1 WO 2019114541 A1 WO2019114541 A1 WO 2019114541A1 CN 2018117788 W CN2018117788 W CN 2018117788W WO 2019114541 A1 WO2019114541 A1 WO 2019114541A1
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solvent
compound
formula
group
ketone
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PCT/CN2018/117788
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French (fr)
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王金远
王振华
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海南轩竹医药科技有限公司
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Priority to CN202310152883.7A priority Critical patent/CN116410183A/zh
Priority to CN201880076486.3A priority patent/CN111406053B/zh
Publication of WO2019114541A1 publication Critical patent/WO2019114541A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • 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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07B2200/07—Optical isomers
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure relates to a plurality of crystal forms of a compound having phosphodiesterase-5 (PDE-5) inhibitory activity, a process for preparing the same, a pharmaceutical composition containing the same, and a preparation thereof for enhancing cGMP signaling
  • PDE-5 phosphodiesterase-5
  • the use of the medicament in particular, relates to the use of these compounds in the manufacture of a medicament for the treatment and/or prevention of sexual dysfunction, benign prostatic hyperplasia, lower urinary tract symptoms (LUTS) and the like.
  • cGMP guanosine-3', 5'-cyclic phosphate, cyclic guanosine monophosphate
  • PDE-5 phosphodiesterase-5
  • PDE-5 inhibitors can be used in the treatment of a variety of diseases, including hypertension, heart failure, pulmonary hypertension, erectile dysfunction, benign prostatic hyperplasia, and female sexual dysfunction.
  • Erectile dysfunction is the most common sexual dysfunction in adult men, a disease in which the penis continues to fail to reach or maintain an erection to satisfy sexual life. ED is divided into organic ED, psychological ED and mixed ED. Although ED is not fatal, it will seriously affect the quality of life between husband and wife and affect the marital relationship.
  • ED has the same pathogenesis as LUTS, and is associated with contraction of smooth muscle or proliferation of smooth muscle cells. Therefore, by using PDE-5 inhibitors, it is entirely possible to treat LUTS with the same pathogenesis.
  • BPH benign prostatic hyperplasia
  • OAB overactive bladder
  • LUTS lower urinary tract symptoms
  • the compound 2-(3-azabicyclo[3.1.0]hexane-3-yl)-4-(3-chloro-4-methoxybenzylamino)-N-(trans) is disclosed in the patent application WO2014026467A1.
  • 4-Hydroxycyclohexylpyrimidine-5-carboxamide (hereinafter referred to as a compound of formula (I)) is a phosphodiesterase-5 (PDE-5) inhibitor, which has good enzymatic activity and pharmacokinetics.
  • PDE-5 phosphodiesterase-5
  • Nature and / or low toxicity make up for the shortcomings of existing clinical drugs, can be effectively used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), lower urinary tract symptoms (LUTS), etc. Or a variety of diseases.
  • the structure of the compound of the formula (I) is as follows.
  • crystal form plays an important role in the drug development process. Different crystal forms of the same drug have significant differences in solubility, stability and bioavailability. In order to better control the quality of the drug, the formulation is satisfied. For the requirements of production, transportation, storage, etc., we have studied the crystal form of the compound of formula (I) in order to find crystal forms with good properties.
  • the present disclosure provides a crystalline form A of a compound of formula (I), wherein the crystal form A is at 7.31 ⁇ 0.2°, 10.95 ⁇ in an X-ray powder diffraction pattern expressed in 2 ⁇ angles using Cu-K ⁇ radiation. There are characteristic peaks at 0.2°, 13.08 ⁇ 0.2°, 15.87 ⁇ 0.2°, 17.40 ⁇ 0.2°, and 20.56 ⁇ 0.2°.
  • the crystal form A is still at 10.04 ⁇ 0.2°, 11.86 ⁇ 0.2 on the basis of the above characteristic peaks. Characteristic peaks at °, 14.64 ⁇ 0.2 °, 18.98 ⁇ 0.2 °, 19.70 ⁇ 0.2 °, 22.28 ⁇ 0.2 °, 23.64 ⁇ 0.2 °, 24.05 ⁇ 0.2 °, 24.70 ⁇ 0.2 °, 25.75 ⁇ 0.2 °.
  • the crystal form A in the X-ray powder diffraction pattern expressed by the 2 ⁇ angle using Cu-Ka radiation, the crystal form A is still at 18.27 ⁇ 0.2°, 20.13 ⁇ 0.2 on the basis of the above characteristic peaks. Characteristic peaks at °, 21.66 ⁇ 0.2 °, 22.68 ⁇ 0.2 °, and 26.76 ⁇ 0.2 °.
  • the Form A has substantially the same X-ray powder diffraction pattern as Figure 18.
  • a DSC thermogram shows that Form A has an endothermic transition peak at about 160 °C - 185 °C. In some embodiments, a DSC thermogram shows that Form A has an endothermic transition peak at 165 °C to 170 °C. In some embodiments, the DSC thermogram shows that the maximum endothermic transition temperature (phase transition temperature) of the Form A, i.e., the temperature at the endothermic peak, is 166.5 ⁇ 3 °C. In some embodiments, the DSC analysis of Form A is shown in FIG.
  • the TGA pattern shows that Form A has no significant weight loss at 0 °C to 250 °C. In some embodiments, the TGA pattern of Form A is as shown in FIG.
  • the present disclosure provides a crystalline form B of a compound of formula (I) in an X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle using Cu-Ka radiation at 3.53 ⁇ 0.2°, 7.07 ⁇ There are characteristic peaks at 0.2°, 8.76 ⁇ 0.2°, 11.80 ⁇ 0.2°, 14.21 ⁇ 0.2°, 15.07 ⁇ 0.2°, and 18.47 ⁇ 0.2°.
  • the crystal form B is still at 10.32 ⁇ 0.2°, 10.60 ⁇ 0.2 on the basis of the above characteristic peaks. Characteristic peaks at °, 12.53 ⁇ 0.2 °, 13.02 ⁇ 0.2 °, 16.86 ⁇ 0.2 °, and 17.78 ⁇ 0.2 °.
  • the crystal form B in the X-ray powder diffraction pattern expressed by 2 ⁇ angle using Cu-Ka radiation, the crystal form B is still at 19.26 ⁇ 0.2°, 19.77 ⁇ 0.2 on the basis of the above characteristic peaks. Characteristic peaks at °, 20.18 ⁇ 0.2°, 20.54 ⁇ 0.2°, and 23.32 ⁇ 0.2°.
  • the crystal form B in the X-ray powder diffraction pattern expressed by the 2 ⁇ angle using Cu-Ka radiation, the crystal form B is still at 22.04 ⁇ 0.2°, 22.47 ⁇ 0.2 on the basis of the above characteristic peaks. Characteristic peaks at °, 23.64 ⁇ 0.2 °, 24.68 ⁇ 0.2 °, and 25.46 ⁇ 0.2 °.
  • the Form B has substantially the same X-ray powder diffraction pattern as in FIG.
  • the DSC thermogram shows that Form B has an endothermic transition peak at about 139 °C to 150 °C. In some embodiments, the DSC thermogram shows that the crystalline form B produces a maximum endothermic transition temperature (phase transition temperature), i.e., the temperature at the endothermic peak, at 144 ⁇ 3 °C. In some embodiments, the DSC analysis of Form B is shown in FIG.
  • the TGA pattern shows that Form B has no significant weight loss at 0 °C to 300 °C. In some embodiments, the TGA pattern of Form B is as shown in FIG.
  • the present disclosure provides a crystalline form C of a hydrate of a compound of formula (I), which is a compound per molecule of 2-(3-azabicyclo[3.1.0]hexane-3-yl)- Hydrate of 4-(3-chloro-4-methoxybenzylamino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide with 1 to 3 water molecules, preferably per molecule
  • the compound contains 1 to 2 water molecules, more preferably 1 molecule of water per molecule of the compound, and in the X-ray powder diffraction pattern expressed by 2 ⁇ angles using Cu-K ⁇ radiation, the crystal form C is 7.34 ⁇ 0.2°, 9.06 ⁇ 0.2°, 10.87 ⁇ 0.2°, 12.44 ⁇ 0.2°, 13.32 ⁇ 0.2°, 14.72 ⁇ 0.2°, 15.23 ⁇ 0.2°, 16.20 ⁇ 0.2°, 18.01 ⁇ 0.2°, 18.37 ⁇ 0.2°, 18.67 ⁇ 0.2°, Characteristic peaks at 19.10 ⁇ 0.2°, 20.58 ⁇ 0.2°, 20.99
  • the Form C has substantially the same X-ray diffraction pattern as shown in FIG.
  • a DSC thermogram shows that Form C has an endothermic transition peak at 100 °C to 120 °C. In some embodiments, the DSC thermogram shows that the transition temperature at which the Form C produces a maximum endotherm is 110 ⁇ 3 °C. In some embodiments, the Form C has a differential scanning calorimetry map that is substantially identical to that shown in FIG.
  • the TGA spectrum shows that the crystal form C is from 60 ° C to 110 ° C, preferably from 90 ° C to 110 ° C, preferably from 100 ° C to 110 ° C, and the weight loss is from about 3% to 4%. 3.5% to 3.7%. The weight loss is mainly the weight of the crystal water.
  • the TGA profile of Form C is as shown in FIG.
  • the present disclosure provides a crystalline form D of a compound of formula (I) which is a compound per molecule of 2-(3-azabicyclo[3.1.0]hexane-3-yl)-4-( a hydrate of 3-chloro-4-methoxybenzylamino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide with 1 to 3 water molecules, preferably 1 per molecule of the compound ⁇ 2 water molecules, more preferably 1 molecule of water per molecule of compound, in the X-ray powder diffraction pattern expressed by 2 ⁇ angle using Cu-K ⁇ radiation, the crystal form D is 3.42 ⁇ 0.2°, 6.89 ⁇ 0.2 °, 9.11 ⁇ 0.2°, 10.36 ⁇ 0.2°, 12.47 ⁇ 0.2°, 13.82 ⁇ 0.2°, 15.06 ⁇ 0.2°, 17.30 ⁇ 0.2°, 17.97 ⁇ 0.2°, 18.37 ⁇ 0.2°, 19.33 ⁇ 0.2°, 20.80 ⁇ 0.2 Characteristic peaks at °, 21.07 ⁇ 0.2 °, 22
  • the Form D has substantially the same X-ray diffraction pattern as shown in FIG.
  • the DSC thermogram shows that Form D has an endothermic transition peak at 100 °C to 120 °C. In some embodiments, the DSC thermogram shows that the transition temperature at which the Form D produces the maximum endotherm is 113 ⁇ 3 °C. In some embodiments, the Form D has a differential scanning calorimetry map that is substantially identical to that shown in FIG.
  • the TGA pattern shows that the Form D is between 90 ° C and 110 ° C, preferably between 100 ° C and 110 ° C, with a weight loss of between about 3% and 4%, preferably between 3.5% and 3.7%.
  • the weight loss is mainly the weight of the crystal water.
  • the TGA profile of Form D is as shown in FIG.
  • the present disclosure provides a crystalline form E of a hydrate of a compound of formula (I), which is a compound per molecule of 2-(3-azabicyclo[3.1.0]hexane-3-yl)- a water solvate of 4-(3-chloro-4-methoxybenzylamino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide and 1 to 3 water molecules, preferably Each molecule of the compound contains 1 to 2 water molecules, more preferably 1 molecule of water per molecule of the compound, and in the X-ray powder diffraction pattern expressed by 2 ⁇ angles using Cu-K ⁇ radiation, the crystal form E is 3.53 ⁇ 0.2 °, 7.01 ⁇ 0.2°, 9.38 ⁇ 0.2°, 10.18 ⁇ 0.2°, 10.52 ⁇ 0.2°, 10.80 ⁇ 0.2°, 12.18 ⁇ 0.2°, 14.03 ⁇ 0.2°, 14.76 ⁇ 0.2°, 15.75 ⁇ 0.2°, 17.54 ⁇ 0.2 Characteristic peaks at °, 18.74 ⁇ 0.2 °
  • the Form E has substantially the same X-ray diffraction pattern as shown in FIG.
  • the DSC thermogram shows that Form E has an endothermic transition peak at 100 °C to 120 °C. In some embodiments, the DSC thermogram shows that the transition temperature at which the Form E produces a maximum endotherm is 111 ⁇ 3 °C. In some embodiments, the Form D has a differential scanning calorimetry map that is substantially identical to that shown in FIG.
  • the TGA pattern shows that the Form E loses about 4% to 4.5% at 20 ° C to 90 ° C. The weight lost is impurities in the crystal form, organic solvent, and adsorbed water. In some embodiments, the TGA pattern shows that the Form E is between 90 ° C and 110 ° C, preferably between 100 ° C and 110 ° C, with a weight loss of between about 3% and 4%, preferably between 3% and 3.7%. The weight lost is mainly the weight of the crystal water. In some embodiments, the TGA profile of Form E is as shown in FIG.
  • the present disclosure also provides solvates of a plurality of compounds of formula (I) which are composed of one or more molecules of formula (I), preferably from 1 to 8 molecules of formula (I), preferably from 2 to 7 (I) a compound, preferably 3 to 6 compounds of the formula (I), preferably 4 to 5 of the compound of the formula (I), preferably 5 to 6 of the compound of the formula (I), preferably 2 to 3 of the compound of the formula (I), preferably 1 to 2 (I) a compound, a complex formed; wherein the organic solvent is selected from the group consisting of:
  • a halogenated hydrocarbon solvent preferably, the halogenated hydrocarbon solvent includes a saturated and unsaturated halogenated hydrocarbon solvent; preferably, the saturated halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane and trichloro Methane, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1 1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane and hexachloroethane; preferably, the unsaturated halogenated hydrocarbon solvent is selected from 1,1 - dichloroethylene, 1,2-dichloroethylene, trichloroethylene and tetrachloroethylene;
  • it is a saturated halogenated hydrocarbon solvent, more preferably dichloromethane or chloroform; more preferably dichloromethane; further preferably, the ratio of the number of molecules of the solvate in the solvate to the compound of the formula (I) Is 1: (2 ⁇ 3);
  • the nitrile solvent includes acetonitrile and propionitrile
  • it is acetonitrile; further preferably, the ratio of the number of molecules of acetonitrile to the compound of formula (I) in the solvate is 1: (5-6);
  • the alcohol solvent includes a fatty alcohol, an alicyclic alcohol, and an aromatic alcohol solvent; preferably, the fatty alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, and isopropanol.
  • the alicyclic alcohol solvent is selected from the group consisting of cyclopentanol, cyclopentanol, and a ring Hexanol, cyclohexanol and cyclohexanethanol;
  • the aromatic alcohol solvent is selected from the group consisting of benzyl alcohol, phenylethyl alcohol and phenylpropanol;
  • the alcohol solvent is a fatty alcohol solvent, preferably methanol, ethanol, isopropanol or tert-butanol; more preferably methanol; further preferably, the solvate is a molecule of methanol and a compound of the formula (I) The ratio of the number is 1: (1 ⁇ 2);
  • the ketone solvent includes a fatty ketone and a cyclic ketone solvent; preferably, the aliphatic ketone solvent is selected from the group consisting of methyl ethyl ketone, methyl isopropyl ketone, acetone, methyl butyl a ketone and methyl isobutyl ketone; preferably, the cyclic ketone solvent is selected from the group consisting of cyclopropanone, cyclohexanone, isophorone, and N-methylpyrrolidone;
  • the ketone solvent is an aliphatic ketone solvent, preferably acetone; further preferably, the ratio of the number of molecules of acetone to the compound of formula (I) in the solvate is 1: (5-6);
  • an ester solvent preferably, the ester solvent includes a fatty ester and an aromatic ester solvent; preferably, the fatty ester solvent is selected from the group consisting of methyl formate, ethyl formate, propyl formate, and acetic acid Ester, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, methyl propionate, ethyl propionate, propyl propionate and isopropyl propionate; preferably, said The aromatic ester solvent is dimethyl phthalate;
  • a fatty ester solvent is preferred, and methyl formate, ethyl formate, methyl acetate or ethyl acetate is more preferred.
  • the solvate of the compound of formula (I) is a crystalline form.
  • the present disclosure provides a crystalline form of a solvate of a compound of formula (I), which is derived from 2 to 3 molecules of 2-(3-azabicyclo[3.1.0]hexane-3-yl) 4-(3-Chloro-4-methoxybenzylamino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide formed with one molecule of dichloromethane, crystal of the solvent compound
  • the type uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern at 2 ⁇ angle is 9.69 ⁇ 0.2°, 10.48 ⁇ 0.2°, 11.87 ⁇ 0.2°, 13.18 ⁇ 0.2°, 14.17 ⁇ 0.2°, 15.78 ⁇ 0.2°.
  • the crystalline form of the solvent compound has substantially the same X-ray diffraction pattern as shown in FIG.
  • the DSC thermogram shows that the crystalline form of the solvate has an endothermic transition peak at 135 °C to 145 °C. In some preferred embodiments, the crystalline form of the solvate produces a maximum endotherm at a transition temperature of 142 ⁇ 3 °C. In some preferred embodiments, the crystalline form of the solvate has substantially the same differential scanning calorimetry profile as shown in FIG.
  • the TGA pattern shows that the crystalline form of the solvate has a weight loss at 130 ° C to 145 ° C and a weight loss of 5.5% to 6%.
  • the crystalline form of the solvent compound has substantially the same thermogravimetric profile as shown in FIG.
  • the present disclosure provides a crystalline form of a solvate of a compound of formula (I) consisting of from 5 to 6 molecules of 2-(3-azabicyclo[3.1.0]hexane-3- 4-(3-chloro-4-methoxybenzylamino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide formed with one molecule of acetonitrile, crystal of the solvate
  • the type uses Cu-K ⁇ radiation and represents the X-ray powder diffraction pattern at 2 ⁇ angles at 3.30 ⁇ 0.2°, 9.65 ⁇ 0.2°, 10.05 ⁇ 0.2°, 10.56 ⁇ 0.2°, 11.07 ⁇ 0.2°, 11.86 ⁇ 0.2°.
  • the crystalline form of the solvate has substantially the same X-ray diffraction pattern as shown in FIG.
  • the DSC thermogram shows that the crystalline form of the solvate has an endothermic transition peak at 135 °C to 145 °C. In some preferred embodiments, the crystalline form of the solvate produces a maximum endotherm at a transition temperature of 142 ⁇ 3 °C. In some preferred embodiments, the crystalline form of the solvate has substantially the same differential scanning calorimetry profile as shown in FIG.
  • the TGA pattern shows that the crystalline form of the solvate is weight loss at 130 ° C to 150 ° C and the weight loss is from 1% to 2%.
  • the crystalline form of the solvate has substantially the same thermogravimetric profile as shown in FIG.
  • the present disclosure provides a crystalline form of a solvate of a compound of formula (I) consisting of from 5 to 6 molecules of 2-(3-azabicyclo[3.1.0]hexane. 3-yl)-4-(3-chloro-4-methoxybenzylamino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide formed with one molecule of acetone, said solvate
  • the crystal form is expressed by Cu-K ⁇ radiation in an X-ray powder diffraction pattern at 2 ⁇ angle, at 3.34 ⁇ 0.2°, 8.71 ⁇ 0.2°, 9.63 ⁇ 0.2°, 11.07 ⁇ 0.2°, 11.80 ⁇ 0.2°, 13.16 ⁇ There are characteristic peaks at 0.2°, 14.17 ⁇ 0.2°, 16.87 ⁇ 0.2°, 17.62 ⁇ 0.2°, 19.35 ⁇ 0.2°, 19.77 ⁇ 0.2°, 20.19 ⁇ 0.2°, 22.81 ⁇ 0.2°, 23.32 ⁇ 0.2°.
  • the crystalline form of the solvate has substantially the same X-ray diffraction pattern as shown in FIG.
  • the DSC thermogram shows that the crystalline form of the solvate has an endothermic transition peak at 135 °C to 145 °C. In some preferred embodiments, the crystalline form of the solvate produces a maximum endotherm at a transition temperature of 141 ⁇ 3 °C. In some preferred embodiments, the crystalline form of the solvate has substantially the same differential scanning calorimetry profile as shown in FIG.
  • the TGA pattern shows that the crystalline form of the solvate has a weight loss at 110 ° C to 145 ° C and a weight loss of from 2% to 2.5%.
  • the crystalline form of the solvate has substantially the same thermogravimetric profile as shown in FIG.
  • the present disclosure provides a crystalline form of a solvate of a compound of formula (I) consisting of from 2 to 2 molecules of 2-(3-azabicyclo[3.1.0]hexane. 3-yl)-4-(3-chloro-4-methoxybenzylamino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide formed with one molecule of methanol, said solvate
  • the crystal form is represented by Cu-K ⁇ radiation, and the X-ray powder diffraction pattern at 2 ⁇ angle is 4.98 ⁇ 0.2°, 10.01 ⁇ 0.2°, 10.54 ⁇ 0.2°, 12.38 ⁇ 0.2°, 13.99 ⁇ 0.2°, 14.58 ⁇ There are characteristic peaks at 0.2°, 15.05 ⁇ 0.2°, 16.87 ⁇ 0.2°, 17.84 ⁇ 0.2°, 20.12 ⁇ 0.2°, 20.73 ⁇ 0.2°, 22.22 ⁇ 0.2°, and 23.97 ⁇ 0.2°.
  • the crystalline form of the solvate has substantially the same X-ray diffraction pattern as shown in FIG.
  • the DSC thermogram shows that the crystalline form of the solvate has an endothermic transition peak at 105 °C to 120 °C, and the transition temperature at which the maximum endotherm is generated is 113.5 ⁇ 3 °C. In some preferred embodiments, the DSC thermogram shows that the crystalline form of the solvate also has an endothermic transition peak at 160 °C - 170 °C, and the transition temperature at which the maximum endotherm is generated is 166 ⁇ 3 °C. In some preferred embodiments, the crystalline form of the solvate has substantially the same differential scanning calorimetry profile as shown in FIG.
  • the TGA pattern shows that the crystalline form of the solvate has a weight loss at 100 ° C to 120 ° C and a weight loss of 5.5% to 6%.
  • the crystalline form of the solvate has substantially the same thermogravimetric profile as shown in FIG.
  • the present disclosure provides a process for the preparation of Form A of a compound of formula (I), which comprises the step of adding a compound of formula (I) to a mixed solvent of an organic solvent and water, and heating to 30 ° C. After 100 ° C, then the temperature was lowered to 0 ° C to 55 ° C, a solid was precipitated, and the solid was collected by filtration, and the obtained solid was optionally dried to give crystal form A.
  • the compound of formula (I) (ie, 2-(3-azabicyclo[3.1.0]hexane-3-yl)-4-(3-chloro-4-methoxybenzylamino)-N- (trans-4-hydroxycyclohexyl)pyrimidine-5-carboxamide) can be prepared by the method disclosed in Example 11 of the patents WO2014026467A1 and Example 11-1, and the obtained product is expressed by Cu-K ⁇ radiation at a 2 ⁇ angle. No significant characteristic peak was observed in the X-ray powder diffraction pattern, which was amorphous.
  • the heating is from 1 h to 10 h, preferably from 1 h to 5 h, preferably from 1 h to 2 h. In some preferred embodiments, heating is continued until the compound is completely dissolved.
  • heating to 40 ° C to 90 ° C preferably 50 ° C to 80 ° C, preferably 60 ° C to 70 ° C, preferably 65 ° C to 75 ° C, preferably 70 ° C to 80 ° C, preferably 75 ° C to 85 ° C It is preferably 90 ° C to 100 ° C. In some preferred embodiments, heating is continued until the compound is completely dissolved.
  • the temperature is lowered to 10 ° C to 50 ° C, preferably to 20 ° C to 50 ° C; preferably to 25 ° C to 50 ° C; preferably to 30 ° C to 50 ° C; preferably to 35 ° C ⁇ 45 °C; preferably to 40 ° C to 50 ° C.
  • the temperature is lowered by means of, but not limited to, natural cooling and cooling, ice bath cooling, cooling using a refrigeration device, etc., and it is preferred in the present disclosure to perform cooling in a manner of natural cooling.
  • the step of adding seed crystals of Form A during the cooling process is also included to facilitate formation and precipitation of the crystalline form.
  • the seed crystal of Form A can be prepared by the preparation method of other crystal form A without seeding described in the present disclosure.
  • the organic solvent is selected from one or a combination of two or more solvents selected from the group consisting of fatty alcohols, alicyclic alcohols, and aromatic alcohol solvents; preferably
  • the fatty alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-hexanol, ethylene glycol, propylene glycol, and glycerol;
  • the alicyclic alcohol solvent is selected from the group consisting of cyclopentanol, cyclopentanol, cyclohexanol, cyclohexylethanol, and cyclohexanethanol; and the aromatic alcohol solvent is selected from the group consisting of benzyl alcohol, phenylethyl alcohol, and phenylpropanol.
  • the organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, n-hexanol, ethylene glycol, propylene glycol, Glycerol, cyclopentanol, cyclopentanol, cyclohexanol, cyclohexanol, cyclohexylethanol, benzyl alcohol, phenylethyl alcohol, and phenylpropanol, and any combination thereof.
  • the organic solvent is selected from the group consisting of methanol, ethanol, and isopropanol.
  • the alcohol solvent referred to above is not limited to the specific examples listed, and any solvent belonging to the above classification can fulfill the function of the present disclosure, that is, the crystal form A of the compound represented by the formula (I) can be obtained.
  • the "any combination between two or more solvents” means a solvent formed by mixing the above organic solvents in a certain ratio. Including but not limited to the following specific examples: methanol / ethanol, methanol / isopropanol, methanol / ethanol / isopropanol, methanol / tert-butanol, methanol / cyclopentanol, methanol / benzyl alcohol, ethanol / isopropanol, ethanol /tert-butanol and so on.
  • the organic solvent is an organic solvent that is at least slightly soluble in water, more preferably an organic solvent that is miscible with water.
  • the mixed solvent of the organic solvent and water is selected from a mixed solvent system consisting of a fatty alcohol and water in a specific ratio.
  • the fatty alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and t-butanol.
  • the mixed solvent system is selected from the group consisting of methanol and water, ethanol and water, isopropanol with water, and a mixed solvent system of t-butanol and water.
  • the specific ratio is from 60:1 to 1:1, preferably 59:1, preferably 58:1, preferably 57:1, preferably 56:1, preferably 55:1, of the organic solvent to water.
  • the drying method includes, but is not limited to, natural drying at room temperature, infrared lamp drying, oven drying, dryer drying, preferably drying under vacuum; a preferred drying temperature is 30 ° C. 60 ° C, preferably 30 ° C to 55 ° C, preferably 35 ° C to 45 ° C, preferably 40 ° C to 50 ° C.
  • the present disclosure also provides a process for the preparation of Form B of a compound of Formula (I) comprising dissolving a compound of formula (I) in an amorphous form in an organic solvent or a mixed solvent of an organic solvent and water, and heating to 40 After the temperature is dissolved from °C to 100 °C, the temperature is lowered to 0 ° C to 40 ° C to precipitate a solid, and then dried at 40 ° C to 110 ° C for 1 day to 10 days to obtain Form B.
  • the present disclosure also provides a process for the preparation of Form B of the compound of formula (I), which comprises dissolving a compound of formula (I) in an organic solvent or a mixed solvent of an organic solvent and water, and after the compound is substantially dissolved, a solvent is precipitated. The compound solid is then dried at 40 ° C to 110 ° C for 1 day to 10 days to obtain Form B.
  • the organic solvents are each independently selected from:
  • a halogenated hydrocarbon solvent preferably, the halogenated hydrocarbon solvent includes a saturated and unsaturated halogenated hydrocarbon solvent; preferably, the saturated halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane and trichloro Methane, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1 1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane and hexachloroethane; preferably, the unsaturated halogenated hydrocarbon solvent is selected from 1,1 - dichloroethylene, 1,2-dichloroethylene, trichloroethylene and tetrachloroethylene;
  • it is a saturated halogenated hydrocarbon solvent, more preferably dichloromethane or chloroform; (2) a nitrile solvent; preferably, the nitrile solvent includes acetonitrile and propionitrile; preferably acetonitrile;
  • the alcohol solvent includes a fatty alcohol, an alicyclic alcohol, and an aromatic alcohol solvent; preferably, the fatty alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, and isopropanol.
  • the alicyclic alcohol solvent is selected from the group consisting of cyclopentanol, cyclopentanol, and a ring Hexanol, cyclohexanol and cyclohexanethanol;
  • the aromatic alcohol solvent is selected from the group consisting of benzyl alcohol, phenylethyl alcohol and phenylpropanol;
  • the alcohol solvent is a fatty alcohol solvent, preferably methanol, ethanol, isopropanol or tert-butanol; (4) a ketone solvent; preferably, the ketone solvent includes aliphatic ketones and cyclic ketones a solvent; preferably, the aliphatic ketone solvent is selected from the group consisting of methyl ethyl ketone, methyl isopropyl ketone, acetone, methyl methyl ketone, and methyl isobutyl ketone; preferably, the cyclic ketone solvent is selected from the group consisting of cyclopropanone and a ring. Hexanone, isophorone and N-methylpyrrolidone;
  • the ketone solvent is an aliphatic ketone solvent, preferably acetone;
  • an ester solvent preferably, the ester solvent includes a fatty ester and an aromatic ester solvent; preferably, the fatty ester solvent is selected from the group consisting of methyl formate, ethyl formate, propyl formate, and acetic acid Ester, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, methyl propionate, ethyl propionate, propyl propionate and isopropyl propionate; preferably, said The aromatic ester solvent is dimethyl phthalate;
  • a fatty ester solvent is preferred, and methyl formate, ethyl formate, methyl acetate or ethyl acetate is more preferred.
  • the preferred organic solvent is a water-miscible organic solvent, for example, selected from the group consisting of methanol, ethanol, acetonitrile and acetone; further preferably, the organic solvent and water
  • the mixing ratio is from 1:1 to 100:1, preferably 90:1, preferably 85:1, preferably 80:1, preferably 75:1, preferably 70:1, preferably 65:1, preferably 60:1, preferably 55: 1, preferably 50:1, preferably 45:1, preferably 40:1, preferably 35:1, preferably 30:1, preferably 25:1, preferably 20:1, preferably 15:1, preferably 10:1, preferably 5: 1, preferably 1:1.
  • heating is continued until the mixed solvent is refluxed.
  • the temperature is lowered to 10 ° C to 40 ° C, preferably 20 ° C to 35 ° C, preferably 25 ° C.
  • the way to cool down includes ice water bath cooling, self-heating cooling and cooling.
  • drying is carried out at 70 ° C to 100 ° C.
  • Preferred drying methods include vacuum drying, blast drying.
  • the drying process may optionally be carried out multiple times at different temperatures using different drying methods; preferably drying for 2 days to 8 days, preferably drying for 5 days to 6 days, preferably drying for 7 days. ⁇ 8 days.
  • the present disclosure also provides crystalline forms (e.g., Form A or B) of a compound of Formula (I) with a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition can be prepared in any pharmaceutically acceptable dosage form for administration to a patient in need thereof by oral, parenteral, rectal or pulmonary administration.
  • it can be prepared into a conventional oral solid preparation such as a tablet, a capsule, a pill, a granule, etc.; or an oral liquid preparation, such as an oral solution, an oral suspension, a syrup, etc.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • parenteral administration it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection.
  • injection When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
  • rectal administration it can be made into a suppository or the like.
  • pulmonary administration it can be prepared as an inhalant or a spray.
  • the present disclosure also provides a combination of a crystalline form of a compound of formula (I) (eg, Form A or B) with one or more second therapeutically active agents, which can be crystallized with a compound of Formula (I) Types (eg, Form A or B) are administered simultaneously or sequentially for the treatment of a patient in need thereof.
  • the second therapeutically active agent is selected from the group consisting of vasodilators, sex hormones, prostaglandin E1, prostacyclin, norepinephrine, hypoglycemic agents, alpha-adrenergic receptor blockers, mixed alpha, beta-resistance Broken agent, ⁇ -blocker, 5 ⁇ -reductase inhibitor, serotonin reuptake inhibitor, ⁇ 2-adrenergic receptor blocker, ACE inhibitor, NEP inhibitor, central dopamine, vasoactive intestinal peptide , calcium channel blockers, thiazide diuretics, or mixtures thereof.
  • the present application also provides a combination comprising a crystalline form of a compound of formula (I) (eg, Form A or B) or a pharmaceutical composition thereof, and one or more second therapeutically active agents, wherein said second The therapeutically active agent is selected from the group consisting of vasodilators, sex hormones, prostaglandin E1, prostacyclin, norepinephrine, hypoglycemic agents, alpha-adrenergic receptor blockers, mixed alpha, beta-blockers, alpha- Blockers, 5 ⁇ -reductase inhibitors, serotonin reuptake inhibitors, ⁇ 2-adrenergic receptor blockers, ACE inhibitors, NEP inhibitors, central dopamine agents, vasoactive intestinal peptides, calcium channel blockers Agent, thiazide diuretic and any combination thereof.
  • the second therapeutic agent can be administered simultaneously or sequentially with a crystalline form of the compound of formula (I), such as Form A or B.
  • the present disclosure also provides the use of a crystalline form of a compound of formula (I), such as Form A or B, for the manufacture of a medicament for the treatment and/or prevention of a disease mediated by a PDE-5 enzyme.
  • the disease is selected from the group consisting of: sexual dysfunction disease, benign prostatic hyperplasia, overactive bladder, disease of lower urinary tract symptoms, hypertension, heart failure, pulmonary hypertension, non-alcoholic fatty liver Kind or more.
  • the sexual dysfunction is selected from the group consisting of erectile dysfunction, premature ejaculation, and female sexual dysfunction.
  • the prostatic hyperplasia is benign prostatic hyperplasia.
  • the present disclosure also provides a method of treating and/or preventing a disease mediated by a PDE-5 enzyme, comprising administering to a subject in need thereof an effective amount of a crystalline form of the compound of Formula (I) (eg, Steps of Form A or B).
  • the disease is selected from the group consisting of sexual dysfunction disease, benign prostatic hyperplasia, overactive bladder, disease of lower urinary tract symptoms, hypertension, heart failure, pulmonary hypertension, nonalcoholic fatty liver disease.
  • the sexual dysfunction is selected from the group consisting of erectile dysfunction, premature ejaculation, and female sexual dysfunction.
  • the prostatic hyperplasia is benign prostatic hyperplasia.
  • the present disclosure also provides a crystalline form (eg, Form A or B) of the compound of Formula (I) described for use in the treatment and/or prevention of a disease mediated by a PDE-5 enzyme.
  • the disease is selected from the group consisting of sexual dysfunction disease, benign prostatic hyperplasia, overactive bladder, disease of lower urinary tract symptoms, hypertension, heart failure, pulmonary hypertension, nonalcoholic fatty liver disease.
  • the sexual dysfunction is selected from the group consisting of erectile dysfunction, premature ejaculation, and female sexual dysfunction.
  • the prostatic hyperplasia is benign prostatic hyperplasia.
  • the present disclosure also provides the use of a crystalline form (eg, Form A or B) of the compound of Formula (I) for the preparation of a reagent for inhibiting the level of a PDE-5 enzyme in a cell.
  • the agent is for use in an in vivo or in vitro method.
  • the present disclosure also provides a crystalline form (eg, Form A or B) of the compound of Formula (I) described for use in inhibiting the level of a PDE-5 enzyme in a cell.
  • a crystalline form eg, Form A or B
  • the crystalline form is for use in an in vivo or in vitro method.
  • the present disclosure also provides a method of inhibiting the level of PDE-5 in a cell comprising the step of administering to the cell an effective amount of a crystalline form (e.g., Form A or B) of a compound of Formula (I).
  • the method is performed in vivo or in vitro.
  • the present disclosure also provides the use of a crystalline form (eg, Form A or B) of the compound of Formula (I) for the preparation of a reagent for enhancing cGMP signaling in a cell.
  • the agent is for use in an in vivo or in vitro method.
  • the present disclosure also provides a crystalline form (eg, Form A or B) of the compound of Formula (I) described for use in enhancing cGMP signaling in a cell.
  • the crystalline form is for use in an in vivo or in vitro method.
  • the present disclosure also provides a method of enhancing cGMP signaling function in a cell comprising the step of administering to the cell an effective amount of a crystalline form (e.g., Form A or B) of a compound of Formula (I).
  • the method is performed in vivo or in vitro.
  • the compound may exist in two or more crystalline states, and the molecules of the same structure are crystallized into different solid forms, which are called “polymorphs", and are translated into polymorphs or polymorphs.
  • polymorphs When referring to a particular crystalline form, it is often referred to as “crystal form”, which is the term "crystalline form” as used herein.
  • the position of the absorption peak in each of the crystal form X-ray powder diffraction patterns may be within a range of ⁇ 0.2° of the above specific numerical value of the invention, for example, in the range of ⁇ 0.1°, by differential scanning calorimetry.
  • the thermal transition temperature may be in the range of the above specific numerical value ⁇ 3.0 ° C (for example, ⁇ 1.0 ° C or ⁇ 2.0 ° C).
  • the present disclosure also uses thermogravimetric analysis (TGA) to analyze the relationship between the degree of decomposition or sublimation of the crystal form, the degree of evaporation (loss of weight), and temperature.
  • TGA refers to a method of increasing the temperature of a test piece and measuring the change in weight of the test sample with temperature. It should be understood that the same crystal form is affected by sample purity, particle size, different types of equipment, different test methods, etc., and the obtained values have certain errors.
  • the temperature at which the crystal form is decomposed or sublimated and evaporated may be within the range of the above-mentioned specific numerical value of ⁇ 3.0 ° C, for example, ⁇ 2.0 ° C.
  • room temperature As used herein, the terms “room temperature”, “normal temperature” refer to the ambient temperature of the interior, and generally refers to 20-30 °C, such as 20-25 °C.
  • the raw materials used in the preparation of each crystal form are the compounds of the formula (I) (i.e., 2-(3-azabicyclo[3.1.0]hexane-3-yl)-4-, unless otherwise specified.
  • the method disclosed in -1 is prepared.
  • the term "subject" refers to an animal, particularly a mammal, preferably a human.
  • the term "effective amount” refers to an amount sufficient to achieve the desired therapeutic or prophylactic effect, for example, to achieve a reduction in the symptoms associated with the condition to be treated.
  • the term "treatment” is intended to alleviate or eliminate a disease state or disorder to which it is directed. If the subject receives a therapeutic amount of the crystalline form or a pharmaceutical composition thereof as described herein, one or more indications and symptoms of the subject exhibit observable and/or detectable Upon reduction or improvement, the subject was successfully "treated". It will also be appreciated that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment, but achieving some biological or medical related results.
  • the crystalline form of the compound of formula (1), in particular crystalline form A or B, of the present disclosure has at least one of the following
  • the preparation method is simple and suitable for industrial production
  • Figure 3 is a 1 H-NMR of Form B of the compound of formula (I).
  • Figure 5 is a TGA-DSC analysis chart of Form C of the compound of Formula (I), the left ordinate represents the weight (%), the right ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Figure 6 is an X-ray powder diffraction pattern of Form D of the compound of Formula (I), the ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle (2?).
  • Fig. 7 is a TGA-DSC analysis chart of the crystal form D of the compound of the formula (I), the left ordinate represents the weight (%), the right ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Figure 8 is an X-ray powder diffraction pattern of Form E of the compound of Formula (I), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2?).
  • Fig. 9 is a TGA-DSC analysis chart of the crystal form E of the compound (I), the right side ordinate represents the weight (%), the left ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Figure 10 is an X-ray powder diffraction pattern of a dichloromethane solvent compound of the compound of the formula (I), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • Figure 11 is a TGA-DSC analysis chart of a dichloromethane solvent compound of the compound of the formula (I), the left ordinate represents the weight (%), the right ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C). ).
  • Figure 12 is an X-ray powder diffraction pattern of an acetonitrile solvent compound of the compound of the formula (I), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • Figure 13 is a DSC analysis of an acetonitrile solvent compound of the compound of formula (I), the left ordinate represents heat flow (W/g), the right ordinate represents weight (%), and the abscissa represents temperature T (°C).
  • Figure 14 is an X-ray powder diffraction pattern of an acetone solvent compound of the compound of the formula (I), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • Figure 15 is a TGA-DSC analysis chart of the acetone solvent compound of the compound of the formula (I), the left ordinate represents the weight (%), the right ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Figure 16 is an X-ray powder diffraction pattern of a methanol solvent compound of the compound of the formula (I), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • Figure 17 is a TGA-DSC analysis chart of a methanol solvent compound of the compound of the formula (I), the right ordinate represents the weight (%), the left ordinate represents the heat flow (W/g), and the abscissa represents the temperature T (°C).
  • Figure 18 is an X-ray powder diffraction pattern of Form A of the compound of Formula (I), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • Figure 19 is a TGA-DSC analysis chart of Form A of the compound of Formula (I), the right ordinate represents the weight (%), the left ordinate represents heat flow (W/g), and the abscissa represents temperature T (°C).
  • Figure 20 is a 1 H-NMR of Form A of the compound of formula (I).
  • X-ray reflection parameters Cu, K ⁇ ; incident slit: 0.6 mm; divergence slit: 1 mm; scanning mode: continuous; scanning range: 3.0 to 45.0 degrees; sampling step size: 0.02 degrees; scanning time per step: 19.8 s; Detector angle: 2.0 degrees.
  • Form A in the X-ray powder diffraction diagram is shown in Figure 18, which has peaks at the following diffraction 2 ⁇ angles: 7.31 ⁇ 0.2 °, 10.04 ⁇ 0.2 °, 10.95 ⁇ 0.2 °, 11.86 ⁇ 0.2 °, 13.08 ⁇ 0.2°, 14.64 ⁇ 0.2°, 15.87 ⁇ 0.2°, 17.40 ⁇ 0.2°, 18.27 ⁇ 0.2°, 18.98 ⁇ 0.2°, 19.70 ⁇ 0.2°, 20.13 ⁇ 0.2°, 20.56 ⁇ 0.2°, 20.90 ⁇ 0.2°, 21.66 ⁇ 0.2°, 22.28 ⁇ 0.2°, 22.68 ⁇ 0.2°, 23.64 ⁇ 0.2°, 24.05 ⁇ 0.2°, 24.70 ⁇ 0.2°, 25.75 ⁇ 0.2°, 26.76 ⁇ 0.2°, 27.68 ⁇ 0.2°, 28.02 ⁇ 0.2°, 28.36 ⁇ 0.2°, 29.26 ⁇ 0.2°, 29.69 ⁇ 0.2°, 30.54 ⁇ 0.2°, 31.20 ⁇ 0.2°, 31.71 ⁇ 0.2°, 32.87 ⁇ 0.2
  • the solid state thermal properties of Form A of the compound of formula (I) were investigated by differential scanning calorimetry (DSC).
  • DSC curve for Form A is shown in Figure 19.
  • DSC test conditions Purge with nitrogen at 50 mL/min, collect data at a heating rate of 10 ° C/min between 25 ° C and 250 ° C, and plot with the endothermic peak facing down.
  • TGA test conditions Purge with nitrogen at 60 mL/min and collect data at room temperature to 350 °C at a heating rate of 10 °C/min.
  • the TGA curve for Form A is shown in Figure 19.
  • Preparation Method 1 A compound of the formula (I) (8.0 g) was taken, placed in a flask, dichloromethane (160 mL) was added, and the mixture was warmed to reflux and completely dissolved after 1.5 h. The temperature was slowly lowered, and solid precipitation began at 37 ° C. The temperature was further lowered to room temperature, stirred for 16 h, and filtered to give a solid. The mixture was vacuum dried at 70 ° C for 5 days, and then vacuum dried at 100 ° C for 3 days. The product (5.26 g) was weighed and tested by XRPD to form Form B.
  • Preparation Method 2 A compound of the formula (I) (1.0 g) was placed in a flask, and acetonitrile (40 mL) and water (1.6 mL) were added, and the mixture was warmed to reflux. It was naturally cooled to room temperature, and after 5 h, suction filtered to give a solid. It was dried under vacuum at 40 ° C for 16 h, then placed in a 105 ° C blast oven, taken out after 7 days, and tested by XRPD as Form B.
  • Preparation Method 3 A compound of the formula (I) (500 mg) was placed in a flask, and acetone (3 mL) was added thereto, and after the compound was substantially dissolved, a solid was precipitated. After stirring at room temperature for 1.5 h, it was filtered to give a solid. The obtained solid was vacuum dried at 100 ° C, taken out after 1 day, and the obtained sample was subjected to XRPD test to form Form B.
  • X-ray reflection parameters Cu, K ⁇ ; incident slit: 0.6 mm; divergence slit: 1 mm; scanning mode: continuous; scanning range: 3.0 to 45.0 degrees; sampling step size: 0.02 degrees; scanning time per step: 19.8 s; Detector angle: 2.0 degrees.
  • the X-ray powder diffraction pattern of Form B is shown in Figure 1, which has peaks at the following diffraction 2 ⁇ angles: 3.53 ⁇ 0.2 °, 7.07 ⁇ 0.2 °, 8.76 ⁇ 0.2 °, 10.32 ⁇ 0.2 °, 10.60 ⁇ 0.2°, 11.80 ⁇ 0.2°, 12.53 ⁇ 0.2°, 13.02 ⁇ 0.2°, 14.21 ⁇ 0.2°, 15.07 ⁇ 0.2°, 16.86 ⁇ 0.2°, 17.78 ⁇ 0.2°, 18.47 ⁇ 0.2°, 19.26 ⁇ 0.2°, 19.77 ⁇ 0.2°, 20.18 ⁇ 0.2°, 20.54 ⁇ 0.2°, 21.19 ⁇ 0.2°, 21.74 ⁇ 0.2°, 22.04 ⁇ 0.2°, 22.47 ⁇ 0.2°, 23.32 ⁇ 0.2°, 23.64 ⁇ 0.2°, 24.68 ⁇ 0.2°, 25.46 ⁇ 0.2°, 26.62 ⁇ 0.2°, 27.11 ⁇ 0.2°, 28.16 ⁇ 0.2°, 28.74 ⁇ 0.2°, 29.37 ⁇ 0.2°.
  • the solid state thermal properties of Form B of the compound of formula (I) were investigated by differential scanning calorimetry (DSC).
  • DSC curve for Form B is shown in Figure 2.
  • DSC test conditions Purge with nitrogen at 50 mL/min, collect data at a heating rate of 10 ° C/min between 25 ° C and 250 ° C, and plot with the endothermic peak facing down.
  • TGA test conditions Purge with nitrogen at 60 mL/min and collect data at room temperature to 350 °C at a heating rate of 10 °C/min.
  • the TGA curve for Form B is shown in Figure 2.
  • the temperature in the kettle was controlled to fluctuate within 30 to 15 ° C, and the conversion time between 30 ° C and 15 ° C was 1 h, and each time after the temperature conversion was 0.5 h, repeated After a total of 6 cycles of temperature rise and fall, the kettle reached 15 ° C again, and the temperature was gradually lowered to 5 ° C for two hours to precipitate a large amount of solid. Filtered after two hours.
  • the obtained solid was subjected to XRPD test, and the result was shown to be Form E.
  • the X-ray powder diffraction pattern of Form E is shown in Figure 8.
  • the DSC curve and the TGA curve of Form E are shown in Figure 9.
  • Test sample Form A of the compound of formula (I).
  • test sample was placed in a clean surface dish, set at 70 ° C for 1 day and 3 days, set at 105 ° C for 1 day, set the light for 5 days and 10 days, set 40 ° CRH 75% condition 10 On days and 30 days, the related substances, traits, contents, moisture, and XRPD of the test articles were examined.
  • Moisture According to the Chinese Pharmacopoeia 2015 edition of the four general rules 0832 moisture determination method first method 2 coulometric titration method.
  • XRPD Refer to the Chinese Pharmacopoeia 2015 edition of the four general rules of 0451 X-ray diffraction method.
  • Test sample Compound of formula (I) (amorphous); Form A of the compound of formula (I).
  • Test sample Form B of the compound of formula (I).
  • test sample was placed in a clean surface dish, set at 70 ° C for 1 day and 3 days, set at 105 ° C for 1 day, set the light for 5 days and 10 days, set 40 ° CRH 75% condition 10 On days and 30 days, the related substances, traits, contents, moisture, and XRPD of the test articles were examined.
  • Moisture According to the Chinese Pharmacopoeia 2015 edition of the four general rules 0832 moisture determination method first method 2 coulometric titration method.
  • XRPD Refer to the Chinese Pharmacopoeia 2015 edition of the four general rules of 0451 X-ray diffraction method. Relevant substances and contents: Refer to the Chinese Pharmacopoeia 2015 edition of the four general rules of 0512 high performance liquid chromatography.
  • Crystal forms C and D were examined separately. As a result, it was found that Form C and Form D were mutually converted at 70 °C. Unstable at room temperature, often a mixture of two crystal forms is obtained.
  • the crystal form E and the obtained solvent compound of each crystal form were examined. As a result, it was found to be defective in hygroscopicity and stability.
  • the crystal form A and the crystal form B of the invention exhibit good stability and low hygroscopicity characteristics, are convenient for the production of medicines, preparation, transportation and storage of preparations, and are more favorable for ensuring stability and safety of drug use.
  • the crystal form A and the crystal form B are more amorphous than the amorphous form and the crystal forms C, D, E and other solvates, and have better drug-forming properties.
  • Karl coefficient is one of the indicators to measure the fluidity of powder. The smaller the value, the better the powder.
  • the experimental results in Table 5 show that the Karl coefficient of crystal form B is smaller than amorphous, indicating that the fluidity of crystal form B is better than none. Stereotype.
  • the crystal form B and the amorphous compound material were respectively tableted in an appropriate amount, the tablet weight was fixed, the tablet thickness (tableting force) was adjusted, and the tablet hardness was measured. The hardness was measured as a function of the thickness of the tablet, and the compressibility of the drug substance was compared.
  • Test sample crystal form B of the compound of formula (I).
  • Test animals SD rats, male, 6 rats, weighing 260-275 g / only.
  • PO oral administration: 0.5% MC (methylcellulose) + 0.1% SDS (sodium lauryl sulfate)
  • Preparation method of blank solvent Weigh 5g of methyl cellulose, slowly add 995g of purified purified water, stir evenly, add 1g of SDS, stir until clarified.
  • test solution is administered according to the following method:
  • AUC inf represents the area under the curve of medicine 0 ⁇ ⁇
  • T max represents the peak plasma concentration
  • T 1/2 represents elimination half-life
  • Form B of a single oral compound in rats has obvious absorption and elimination processes after administration, indicating that the crystal form can exert good pharmacological effects in vivo and is suitable for preparation of pharmaceutical products.

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Abstract

本发明属于医药领域，具体涉及式(I)化合物的多种晶型及其制备方法，以及含有所述晶型的药物制剂及药物组合物，以及其在制备增强cGMP信号传导功能的药物中的应用，特别是涉及这些化合物在制备治疗和/或预防性功能障碍、前列腺增生、下尿路症状等疾病的药物中的应用。

Description

磷酸二酯酶-5抑制剂的晶型 技术领域
本公开涉及一种具有磷酸二酯酶-5(PDE-5)抑制活性的化合物的多种晶型及其制备方法，含有所述晶型的药物组合物，及其在制备增强cGMP信号传导功能的药物中的应用，特别是涉及这些化合物在制备治疗和/或预防性功能障碍、前列腺增生、下尿路症状(LUTS)等疾病的药物中的应用。
背景技术
cGMP(鸟苷-3’,5’-环磷酸，环磷酸鸟苷)是一种环状核苷酸，存在于动植物细胞中，是一种细胞内的第二信使，参与广泛的细胞反应，它能够被PDE-5(磷酸二酯酶-5)水解，当PDE-5被抑制以后，cGMP的水平就会升高，从而产生多种生理效应，比如血管平滑肌舒张等。因此，PDE-5抑制剂可以用于多种疾病的治疗，包括高血压、心力衰竭、肺动脉高压、勃起功能障碍、前列腺增生以及女性性功能障碍等多种疾病。
勃起功能障碍(Erectile dysfunction，ED)是成年男子最常见的性功能障碍，指阴茎持续不能达到或者维持勃起以满足性生活的一种疾病。ED分为器质性ED、心理性ED和混合性ED。ED虽不致命，但会严重影响夫妻之间的生活质量，影响夫妻感情。
从流行病学角度出发，很多老年男性患者在患有ED的同时，还有可能伴随其它的泌尿生殖系统疾病，比如良性前列腺增生症(BPH)、膀胱过度活化(OAB)等下尿路症状(LUTS)，这些疾病给老年患者带来了巨大的痛苦，严重的影响着他们的生活。通过病理学分析，ED与LUTS具有相同的发病机制，都与平滑肌的收缩或者平滑肌细胞增殖有关，因此，通过使用PDE-5抑制剂，完全有可能治疗具有相同发病机制的LUTS。
专利申请WO2014026467A1中公开了化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺(以下简称式(I)化合物)为磷酸二酯酶-5(PDE-5)抑制剂，其具有较好的酶学活性、药代动力学性质和/或较低的毒性，弥补了现有临床药物的不足之处，可有效用于治疗勃起功能障碍(ED)、良性前列腺增生症(BPH)、下尿路症状(LUTS)等一种或多种疾病。式(I)化合物的结构如下。
Figure PCTCN2018117788-appb-000001
晶型的研究在药物研发过程中发挥着重要的作用，同一药物的不同晶型在溶解度、稳定性、生物利用度等方面存在着显著的差异，为了更好地控制药物的质量，满足制剂、生产、运输、存储等情况的要求，我们对式(I)化合物的晶型进行了研究，以期发现具有良好性质的晶型。
发明内容
化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺的无定型状态，在稳定性、溶解性、纯度等理化性质方面存在不足，不能满足制剂、生产、运输、存储等情况的要求。因此，本公开提供了多种式(I)化合物及其溶剂化物(例如水合物)的晶型，包括晶型A、B、C、D、E。具体地，
本公开提供了一种式(I)化合物的晶型A，在使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图谱中，所述的晶型A在7.31±0.2°、10.95±0.2°、13.08±0.2°、15.87±0.2°、17.40±0.2°、20.56±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射图谱中，所述晶型A在包含上述特征峰的基础上，还在10.04±0.2°、11.86±0.2°、14.64±0.2°、18.98±0.2°、19.70±0.2°、22.28±0.2°、23.64±0.2°、24.05±0.2°、24.70±0.2°、25.75±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射图谱中，所述晶型A在包含上述特征峰的基础上，还在18.27±0.2°、20.13±0.2°、21.66±0.2°、22.68±0.2°、26.76±0.2°处有特征峰。
在一些实施方案中，所述晶型A具有与图18实质相同的X-射线粉末衍射图。
在一些实施方案中，DSC热图谱显示，所述晶型A在约160℃-185℃处存在一个吸热转变峰。在一些实施方案中，DSC热图谱显示，所述晶型A在165℃～170℃处存在吸热转变峰。在一些实施方案中，DSC热图谱显示，所述晶型A的最大吸热时转变 温度(相变温度)，即吸热峰峰值处的温度，为166.5±3℃。在一些实施方案中，所述晶型A的DSC分析图如图19所示。
在一些实施方案中，TGA图谱显示，所述晶型A在0℃～250℃处无明显失重现象。在一些实施方案中，所述晶型A的TGA图如图19所示。
在另一个方面，本公开提供了一种式(I)化合物的晶型B，在使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射图谱中，其在3.53±0.2°、7.07±0.2°、8.76±0.2°、11.80±0.2°、14.21±0.2°、15.07±0.2°、18.47±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射图谱中，所述晶型B在包含上述特征峰的基础上，还在10.32±0.2°、10.60±0.2°、12.53±0.2°、13.02±0.2°、16.86±0.2°、17.78±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射图谱中，所述晶型B在包含上述特征峰的基础上，还在19.26±0.2°、19.77±0.2°、20.18±0.2°、20.54±0.2°、23.32±0.2°处有特征峰。
在一些实施方案中，在使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射图谱中，所述晶型B在包含上述特征峰的基础上，还在22.04±0.2°、22.47±0.2°、23.64±0.2°、24.68±0.2°、25.46±0.2°处有特征峰。
在一些实施方案中，所述晶型B具有与图1实质相同的X-射线粉末衍射图。
在一些实施方案中，DSC热图谱显示，所述晶型B在约139℃～150℃处存在一个吸热转变峰。在一些实施方案中，DSC热图谱显示，所述晶型B产生最大吸热量时的转变温度(相变温度)，即吸热峰峰值处的温度，为144±3℃。在一些实施方案中，所述晶型B的DSC分析图如图2所示。
在一些实施方案中，TGA图谱显示，所述晶型B在0℃～300℃处无明显失重现象。在一些实施方案中，所述晶型B的TGA图如图2所示。
在另一个方面，本公开提供一种式(I)化合物的水合物的晶型C，其是由每分子化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与1～3个水分子形成的水合物，优选每分子化合物含1～2个水分子，更优选每分子化合物含1个水分子，在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，所述晶型C在7.34±0.2°、9.06±0.2°、10.87±0.2°、12.44±0.2°、13.32±0.2°、14.72±0.2°、15.23±0.2°、16.20±0.2°、18.01±0.2°、18.37±0.2°、18.67±0.2°、19.10±0.2°、20.58±0.2°、20.99±0.2°、21.68±0.2°、22.22±0.2°、22.75±0.2°、23.30±0.2°处有特征峰；
在一些实施方案中，所述晶型C有与如图4所示实质相同的X-射线衍射图谱。
在一些实施方案中，DSC热图谱显示，所述晶型C在100℃～120℃处存在一个吸热转变峰。在一些实施方案中，DSC热图谱显示，所述晶型C产生最大吸热量时的转变温度为110±3℃。在一些实施方案中，所述晶型C具有与如图5所示实质相同的差示扫描量热分析图谱。
在一些实施方案中，TGA图谱显示，所述晶型C在60℃～110℃时，优选温度在90℃～110℃，优选温度在100℃～110℃，失重约3％～4％，优选3.5％～3.7％。所失重量主要为结晶水的重量。在一些实施方案中，所述晶型C的TGA图谱如图5所示。
在另一个方面，本公开提供一种式(I)化合物的晶型D，其是由每分子化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与1～3个水分子形成的水合物，优选每分子化合物含1～2个水分子，更优选每分子化合物含1个水分子，在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，所述晶型D在3.42±0.2°、6.89±0.2°、9.11±0.2°、10.36±0.2°、12.47±0.2°、13.82±0.2°、15.06±0.2°、17.30±0.2°、17.97±0.2°、18.37±0.2°、19.33±0.2°、20.80±0.2°、21.07±0.2°、22.75±0.2°、23.34±0.2°、24.33±0.2°处有特征峰。
在一些实施方案中，所述晶型D具有与如图6所示实质相同的X-射线衍射图谱。
在一些实施方案中，DSC热图谱显示，所述晶型D在100℃～120℃处存在一个吸热转变峰。在一些实施方案中，DSC热图谱显示，所述晶型D产生最大吸热量时的转变温度为113±3℃。在一些实施方案中，所述晶型D具有与如图7所示实质相同的差示扫描量热分析图谱。
在一些实施方案中，TGA图谱显示，所述晶型D在90℃～110℃时，优选100℃～110℃，失重约3％～4％，优选3.5％～3.7％。所失重量主要为结晶水的重量。在一些实施方案中，所述晶型D的TGA图谱如图7所示。
在另一个方面，本公开提供一种式(I)化合物的水合物的晶型E，其是由每分子化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与1～3个水分子形成的水溶剂合物，优选每分子化合物含1～2个水分子，更优选每分子化合物含1个水分子，在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，所述晶型E在3.53±0.2°、7.01±0.2°、9.38±0.2°、10.18±0.2°、10.52±0.2°、10.80±0.2°、12.18±0.2°、14.03±0.2°、14.76±0.2°、15.75±0.2°、17.54±0.2°、18.74±0.2°、19.06±0.2°、21.07±0.2°、21.66±0.2°、22.79±0.2°、24.05±0.2°处有特征峰。
在一些实施方案中，所述晶型E有与如图8所示实质相同的X-射线衍射图谱。
在一些实施方案中，DSC热图谱显示，所述晶型E在100℃～120℃处存在一个吸热转变峰。在一些实施方案中，DSC热图谱显示，所述晶型E产生最大吸热量时的转变温度为111±3℃。在一些实施方案中，所述晶型D具有与如图9所示实质相同的差示扫描量热分析图谱。
在一些实施方案中，TGA图谱显示，所述晶型E在20℃～90℃时，失重约4％～4.5％。所失的重量为晶型中的杂质、有机溶剂、吸附水。在一些实施方案中，TGA图谱显示，所述晶型E在90℃～110℃时，优选100℃～110℃，失重约3％～4％，优选3％～3.7％。所失的重量主要为结晶水的重量。在一些实施方案中，所述晶型E的TGA图谱如图9所示。
本公开还提供了多种式(I)化合物的溶剂化物，其是由每分子有机溶剂与一或多分子式(I)化合物，优选1～8分子式(I)化合物，优选2～7分子式(I)化合物，优选3～6分子式(I)化合物，优选4～5分子式(I)化合物，优选5～6分子式(I)化合物，优选2～3分子式(I)化合物，优选1～2分子式(I)化合物，形成的复合物；其中，所述的有机溶剂选自：
(1)卤代烃类溶剂；优选地，所述卤代烃类溶剂包括饱和和不饱和的卤代烃类溶剂；优选地，所述饱和卤代烃类溶剂选自二氯甲烷、三氯甲烷、四氯化碳、1,1-二氯乙烷、1,2-二氯乙烷、1,1,1-三氯乙烷、1,1,2-三氯乙烷、1,1,1,2-四氯乙烷、1,1,2,2-四氯乙烷、五氯乙烷和六氯乙烷；优选地，所述不饱和卤代烃类溶剂选自1,1-二氯乙烯、1,2-二氯乙烯、三氯乙烯和四氯乙烯；
优选为饱和卤代烃类溶剂，更优选为二氯甲烷或三氯甲烷；更优选为二氯甲烷；进一步优选地，所述溶剂化物中二氯甲烷与式(I)化合物的分子个数比例为1:(2～3)；
(2)腈类溶剂；优选地，所述腈类溶剂包括乙腈和丙腈；
优选为乙腈；进一步优选地，所述溶剂化物中乙腈与式(I)化合物的分子个数比例为1:(5～6)；
(3)醇类溶剂；优选地，所述醇类溶剂包括脂肪醇、脂环醇及芳香醇类溶剂；优选地，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正己醇、乙二醇、丙二醇和丙三醇；优选地，所述脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇和环己乙醇；优选地，所述芳香醇类溶剂选自苯甲醇、苯乙醇和苯丙醇；
优选地，所述醇类溶剂为脂肪醇溶剂，优选为甲醇、乙醇、异丙醇或叔丁醇；更优选为甲醇；进一步优选地，所述溶剂化物中甲醇与式(I)化合物的分子个数比例为1:(1～2)；
(4)酮类溶剂；优选地，所述酮类溶剂包括脂肪酮类及环酮类溶剂；优选地，所述脂肪酮类溶剂选自甲乙酮、甲基异丙基酮、丙酮、甲基丁酮和甲基异丁酮；优选地，所述环酮类溶剂选自环丙酮、环己酮、异佛尔酮和N-甲基吡咯烷酮；
优选地，所述酮类溶剂为脂肪酮类溶剂，优选为丙酮；进一步优选地，所述溶剂化物中丙酮与式(I)化合物的分子个数比例为1:(5～6)；
(5)酯类溶剂；优选地，所述酯类溶剂包括脂肪酯类及芳香酯类溶剂；优选地，所述脂肪酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯、丙酸甲酯、丙酸乙酯、丙酸丙酯和丙酸异丙酯；优选地，所述芳香酯类溶剂为邻苯二甲酸二甲酯；
优选为脂肪酯类溶剂，更优选为甲酸甲酯、甲酸乙酯、乙酸甲酯或乙酸乙酯。
在一些实施方案中，所述式(I)化合物的溶剂化物是晶型。
在一些实施方案中，本公开提供了一种式(I)化合物溶剂化物的晶型，其由每2～3分子2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与一分子二氯甲烷形成，所述溶剂化合物的晶型在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，在9.69±0.2°、10.48±0.2°、11.87±0.2°、13.18±0.2°、14.17±0.2°、15.78±0.2°、17.03±0.2°、17.54±0.2°、18.23±0.2°、19.18±0.2°、19.52±0.2°、19.93±0.2°、20.78±0.2°、21.63±0.2°、22.85±0.2°、23.48±0.2°处有特征峰。
在一些优选实施方案中，所述溶剂化合物的晶型具有与图10所示实质相同的X-射线衍射图谱。
在一些优选实施方案中，DSC热图谱显示，所述溶剂化物的晶型在135℃～145℃处存在一个吸热转变峰。在一些优选的实施方案中，所述溶剂化物的晶型产生最大吸热量时的转变温度为142±3℃。在一些优选的实施方案中，所述溶剂化物的晶型具有与图11所示实质相同的差示扫描量热分析图谱。
在一些优选的实施方案中，TGA图谱显示，所述溶剂化物的晶型在130℃～145℃处存在失重，所失重量为5.5％～6％。在一些优选的实施方案中，所述溶剂化合物的晶型具有与图11所示实质相同的热重曲线图谱。
在一些优选的实施方案中，本公开提供了一种式(I)化合物溶剂化物的晶型，其 由每5～6分子2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与一分子乙腈形成，所述溶剂化物的晶型在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，在3.30±0.2°、9.65±0.2°、10.05±0.2°、10.56±0.2°、11.07±0.2°、11.86±0.2°、13.20±0.2°、14.21±0.2°、15.81±0.2°、16.99±0.2°、17.66±0.2°、18.17±0.2°、18.73±0.2°、19.46±0.2°、19.89±0.2°、20.82±0.2°、21.88±0.2°、22.83±0.2°、23.28±0.2°、23.64±0.2°、25.00±0.2°处有特征峰。
在一些优选的实施方案中，所述溶剂化物的晶型具有与图12所示实质相同的X-射线衍射图谱。
在一些优选的实施方案中，DSC热图谱显示，所述溶剂化物的晶型在135℃～145℃处存在一个吸热转变峰。在一些优选的实施方案中，所述溶剂化物的晶型产生最大吸热量时的转变温度为142±3℃。在一些优选的实施方案中，所述溶剂化物的晶型具有与图13所示实质相同的差示扫描量热分析图谱。
在一些优选的实施方案中，TGA图谱显示，所述溶剂化物的晶型在130℃～150℃处存在失重，所失重量为1％～2％。在一些优选的实施方案中，所述溶剂化物的晶型具有与图13所示实质相同的热重曲线图谱。
在一些优选的实施方案中，本公开提供了一种式(I)化合物的溶剂化物的晶型，其由每5～6分子的2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与一分子丙酮形成，所述溶剂化物的晶型在用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，在3.34±0.2°、8.71±0.2°、9.63±0.2°、11.07±0.2°、11.80±0.2°、13.16±0.2°、14.17±0.2°、16.87±0.2°、17.62±0.2°、19.35±0.2°、19.77±0.2°、20.19±0.2°、22.81±0.2°、23.32±0.2°处有特征峰。
在一些优选的实施方案中，所述溶剂化物的晶型具有与图14所示实质相同的X-射线衍射图谱。
在一些优选的实施方案中，DSC热图谱显示，所述溶剂化物的晶型在135℃～145℃处存在一个吸热转变峰。在一些优选的实施方案中，所述溶剂化物的晶型产生最大吸热量时的转变温度为141±3℃。在一些优选的实施方案中，所述溶剂化物的晶型具有与图15所示实质相同的差示扫描量热分析图谱。
在一些优选的实施方案中，TGA图谱显示，所述溶剂化物的晶型在110℃～145℃处存在失重，所失重量为2％～2.5％。在一些优选的实施方案中，所述溶剂化物的晶型具有与图15所示实质相同的热重曲线图谱。
在一些优选的实施方案中，本公开提供了一种式(I)化合物的溶剂化物的晶型，其由每1～2分子的2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与一分子甲醇形成，所述溶剂化物的晶型在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，在4.98±0.2°、10.01±0.2°、10.54±0.2°、12.38±0.2°、13.99±0.2°、14.58±0.2°、15.05±0.2°、16.87±0.2°、17.84±0.2°、20.12±0.2°、20.73±0.2°、22.22±0.2°、23.97±0.2°处有特征峰。
在一些优选的实施方案中，所述溶剂化物的晶型具有与如图16所示实质相同的X-射线衍射图谱。
在一些优选的实施方案中，DSC热图谱显示，所述溶剂化物的晶型在105℃～120℃处存在一个吸热转变峰，产生最大吸热量时的转变温度为113.5±3℃。在一些优选的实施方案中，DSC热图谱显示所述溶剂化物的晶型在160℃-170℃处还存在一个吸热转变峰，产生最大吸热量时的转变温度为166±3℃。在一些优选的实施方案中，所述溶剂化物的晶型具有与图17所示实质相同的差示扫描量热分析图谱。
在一些优选的实施方案中，TGA图谱显示，所述溶剂化物的晶型在100℃～120℃处存在失重，所失重量为5.5％～6％。在一些优选的实施方案中，所述溶剂化物的晶型具有与图17所示实质相同的热重曲线图谱。
在另一个方面，本公开还提供了一种式(I)化合物的晶型A的制备方法，其步骤包括将式(I)化合物加至有机溶剂和水的混合溶剂中，加热至30℃～100℃，然后降温至0℃～55℃，析出固体，过滤收集所述固体，任选地对所得固体进行干燥，得晶型A。所述式(I)化合物(即，2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺)可以通过专利WO2014026467A1实施例11和实施例11-1中公开的方法制备得到，所得产品在用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图谱中未观察到明显特征峰，其为无定型。
在一些优选的实施方案中，加热1h～10h，优选1h～5h，优选1h～2h。在一些优选的实施方案中，加热至所述化合物完全溶解。
在一些优选的实施方案中，加热至40℃～90℃，优选50℃～80℃，优选60℃～70℃，优选65℃～75℃，优选70℃～80℃，优选75℃～85℃，优选90℃～100℃。在一些优选的实施方案中，加热至所述化合物完全溶解。
在一些优选的实施方案中，降温至10℃～50℃，优选降温至20℃～50℃；优选降温至25℃～50℃；优选降温至30℃～50℃；优选降温至35℃～45℃；优选降温至40℃ ～50℃。
在一些优选的实施方案中，以包括但不限于自然冷却降温、冰浴降温、使用制冷设备降温等方式进行降温，本公开中优选自然冷却的方式进行降温。
在一些优选的实施方案中，还包括在降温过程中加入晶型A的晶种的步骤，以利于晶型的形成和析出。所述的晶型A的晶种可由本公开所述的不加晶种的其他晶型A的制备方法制备得到。
在一些优选的实施方案中，所述有机溶剂选自下列溶剂中的一种或者两种或两种以上溶剂之间的任意组合：选自脂肪醇、脂环醇及芳香醇类溶剂；优选地，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正己醇、乙二醇、丙二醇和丙三醇；优选地，所述脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇和环己乙醇；所述芳香醇类溶剂选自苯甲醇、苯乙醇和苯丙醇。在一些优选的实施方案中，所述有机溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正己醇、乙二醇、丙二醇、丙三醇、环戊醇、环戊甲醇、环己醇、环己甲醇、环己乙醇、苯甲醇、苯乙醇和苯丙醇及其任意组合。在一些优选的实施方案中，所述有机溶剂选自甲醇、乙醇和异丙醇。
以上所指的醇类溶剂并不局限于所列出的具体实例，凡是属于上述分类中的溶剂都可以实现本公开的功能，即制备得到式(I)所示的化合物的晶型A。
所述“两种或两种以上溶剂之间的任意组合”是指上述有机溶剂按照一定比例混合形成的溶剂。包括但不限于以下具体实例：甲醇/乙醇、甲醇/异丙醇、甲醇/乙醇/异丙醇、甲醇/叔丁醇、甲醇/环戊醇、甲醇/苯甲醇、乙醇/异丙醇、乙醇/叔丁醇等。
在一些优选的实施方案中，所述有机溶剂为至少与水微溶的有机溶剂，更优选为与水互溶的有机溶剂。
在一些优选的实施方案中，所述有机溶剂和水的混合溶剂选自由脂肪醇和水以特定比例组成的混合溶剂体系。在一些优选地实施方案中，所述的脂肪醇选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇和叔丁醇。在一些优选的实施方案中，所述混合溶剂体系选自甲醇与水、乙醇与水、异丙醇与水和叔丁醇与水组成的混合溶剂体系。
在一些优选的实施方案中，所述特定比例为有机溶剂比水为60:1～1:1，优选59:1，优选58:1，优选57:1，优选56:1，优选55:1，优选54:1，优选53:1，优选52:1，优选51:1，优选50:1，优选49:1，优选48:1，优选47:1，优选46:1，优选45:1，优选44:1，优选43:1，优选42:1，优选41:1，优选40:1，优选39:1，优选38:1，优选37:1， 优选36:1，优选35:1，优选34:1，优选33:1，优选32:1，优选31:1，优选30:1，优选29:1，优选28:1，优选27:1，优选26:1，优选25:1，优选24:1，优选23:1，优选22:1，优选21:1，优选20:1，优选19:1，优选18:1，优选17:1，优选16:1，优选15:1，优选14:1，优选13:1，优选12:1，优选11:1，优选10:1，优选9:1，优选8:1，优选7:1，优选6:1，优选5:1，优选4:1，优选3:1，优选2:1，优选1:1。
在一些优选的实施方案中，所述的干燥方式包括但不限于室温下自然晾干、红外灯干燥、烘箱烘干、干燥器干燥，优选在真空条件下干燥；优选的干燥温度为30℃～60℃，优选30℃～55℃，优选35℃～45℃，优选40℃～50℃。
在另一个方面，本公开还提供了制备式(I)化合物晶型B的方法，包括将无定型形式的式(I)化合物溶于有机溶剂或有机溶剂与水的混合溶剂中，加热至40℃～100℃至化合物溶解后，降温至0℃～40℃，析出固体，然后在40℃～110℃下干燥1天～10天，得晶型B。
在另一个方面，本公开还提供了制备式(I)化合物晶型B的方法，包括将式(I)化合物溶于有机溶剂或有机溶剂与水的混合溶剂中，化合物基本溶解后，析出溶剂化合物固体，然后在40℃～110℃下干燥1天～10天，得晶型B。
在一些优选的实施方案中，在前述晶型B的两种制备方法中，所述有机溶剂各自独立地选自：
(1)卤代烃类溶剂；优选地，所述卤代烃类溶剂包括饱和和不饱和的卤代烃类溶剂；优选地，所述饱和卤代烃类溶剂选自二氯甲烷、三氯甲烷、四氯化碳、1,1-二氯乙烷、1,2-二氯乙烷、1,1,1-三氯乙烷、1,1,2-三氯乙烷、1,1,1,2-四氯乙烷、1,1,2,2-四氯乙烷、五氯乙烷和六氯乙烷；优选地，所述不饱和卤代烃类溶剂选自1,1-二氯乙烯、1,2-二氯乙烯、三氯乙烯和四氯乙烯；
优选为饱和卤代烃类溶剂，更优选为二氯甲烷或三氯甲烷；(2)腈类溶剂；优选地，所述腈类溶剂包括乙腈和丙腈；优选为乙腈；
(3)醇类溶剂；优选地，所述醇类溶剂包括脂肪醇、脂环醇及芳香醇类溶剂；优选地，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正己醇、乙二醇、丙二醇和丙三醇；优选地，所述脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇和环己乙醇；优选地，所述芳香醇类溶剂选自苯甲醇、苯乙醇和苯丙醇；
优选地，所述醇类溶剂为脂肪醇溶剂，优选为甲醇、乙醇、异丙醇或叔丁醇；(4) 酮类溶剂；优选地，所述酮类溶剂包括脂肪酮类及环酮类溶剂；优选地，所述脂肪酮类溶剂选自甲乙酮、甲基异丙基酮、丙酮、甲基丁酮和甲基异丁酮；优选地，所述环酮类溶剂选自环丙酮、环己酮、异佛尔酮和N-甲基吡咯烷酮；
优选地，所述酮类溶剂为脂肪酮类溶剂，优选为丙酮；
(5)酯类溶剂；优选地，所述酯类溶剂包括脂肪酯类及芳香酯类溶剂；优选地，所述脂肪酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯、丙酸甲酯、丙酸乙酯、丙酸丙酯和丙酸异丙酯；优选地，所述芳香酯类溶剂为邻苯二甲酸二甲酯；
优选为脂肪酯类溶剂，更优选为甲酸甲酯、甲酸乙酯、乙酸甲酯或乙酸乙酯。
当式(I)化合物溶于有机溶剂与水的混合溶剂中时，优选的有机溶剂为能与水互溶的有机溶剂，例如选自甲醇、乙醇、乙腈和丙酮；进一步优选地，有机溶剂与水的混合比例为1:1-100:1，优选90:1，优选85:1，优选80:1，优选75:1，优选70:1，优选65:1，优选60:1，优选55:1，优选50:1，优选45:1，优选40:1，优选35:1，优选30:1，优选25:1，优选20:1，优选15:1，优选10:1，优选5:1，优选1:1。
在一些优选的实施方案中，加热至混合溶剂回流。在一些优选的实施方案中，降温至10℃～40℃，优选20℃～35℃，优选25℃。降温的方式包括冰水浴降温、自热冷却降温。在一些优选的实施方案中，在70℃～100℃下干燥，优选的干燥方式包括真空干燥、鼓风干燥。在一些优选的实施方案中，干燥过程中可以任选的在不同温度下采用不同的干燥方式进行多次干燥；优选的干燥2天～8天，优选干燥5天～6天，优选干燥7天～8天。
本公开还提供了式(I)化合物的晶型(例如晶型A或B)与含有一种或多种药用载体和/或稀释剂的药物组合物。所述的药物组合物可制备成药学上可接受的任一剂型，以口服、肠胃外、直肠或经肺给药等方式施用于有需要的患者。用于口服给药时，可制成常规的口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
本公开还提供式(I)化合物的晶型(例如晶型A或B)与一种或多种第二治疗 活性剂的组合物，可将这些第二治疗剂与式(I)化合物的晶型(例如晶型A或B)同时或相继给药，用于治疗有需要的患者。所述的第二治疗活性剂选自血管扩张剂，性激素，前列腺素E1，前列环素，去甲肾上腺素，降血糖药，α-肾上腺素受体阻滞剂，混合的α,β-阻断剂，α-阻断剂，5α-还原酶抑制剂，5-羟色胺再摄取抑制剂，α2-肾上腺素受体阻滞剂，ACE抑制剂，NEP抑制剂，中枢多巴胺剂，血管活性肠肽，钙通道阻滞剂，噻嗪类利尿剂，或它们的混合物。
本申请还提供一种联合用药，其包括式(I)化合物的晶型(例如晶型A或B)或其药物组合物，以及一种或多种第二治疗活性剂，其中所述第二治疗活性剂选自血管扩张剂，性激素，前列腺素E1，前列环素，去甲肾上腺素，降血糖药，α-肾上腺素受体阻滞剂，混合的α,β-阻断剂，α-阻断剂，5α-还原酶抑制剂，5-羟色胺再摄取抑制剂，α2-肾上腺素受体阻滞剂，ACE抑制剂，NEP抑制剂，中枢多巴胺剂，血管活性肠肽，钙通道阻滞剂，噻嗪类利尿剂及其任意组合。所述第二治疗剂与式(I)化合物的晶型(例如晶型A或B)可同时或相继给药。
本公开还提供式(I)化合物的晶型(例如晶型A或B)在制备治疗和/或预防由PDE-5酶所介导的疾病的药物中的用途。在一些优选的实施方案中，所述疾病选自：性功能障碍疾病、前列腺增生、膀胱过度活化、下尿路症状的疾病、高血压、心力衰竭、肺动脉高压、非酒精性脂肪肝中的一种或多种。在一些优选的实施方案中，所述性功能障碍选自勃起功能障碍、早泄、女性性功能障碍。在一些优选的实施方案中，所述前列腺增生为良性前列腺增生。
本公开还提供一种治疗和/或预防由PDE-5酶所介导的疾病的方法，其包括向有此需要的受试者施用有效量的所述式(I)化合物的晶型(例如晶型A或B)的步骤。在一些优选的实施方案中，所述疾病选自性功能障碍疾病、前列腺增生、膀胱过度活化、下尿路症状的疾病、高血压、心力衰竭、肺动脉高压、非酒精性脂肪肝。在一些优选的实施方案中，所述性功能障碍选自勃起功能障碍、早泄、女性性功能障碍。在一些优选的实施方案中，所述前列腺增生为良性前列腺增生。
本公开还提供所述的式(I)化合物的晶型(例如晶型A或B)，其用于治疗和/或预防由PDE-5酶所介导的疾病。在一些优选的实施方案中，所述疾病选自性功能障碍疾病、前列腺增生、膀胱过度活化、下尿路症状的疾病、高血压、心力衰竭、肺动脉高压、非酒精性脂肪肝。在一些优选的实施方案中，所述性功能障碍选自勃起功能障碍、早泄、女性性功能障碍。在一些优选的实施方案中，所述前列腺增生为良性前列腺增生。
本公开还提供所述的式(I)化合物的晶型(例如晶型A或B)在制备试剂中的用途，所述试剂用于抑制细胞中PDE-5酶的水平。在一些优选的实施方案中，所述试剂用于体内或体外方法中。
本公开还提供所述的式(I)化合物的晶型(例如晶型A或B)，其用于抑制细胞中PDE-5酶的水平。在一些优选的实施方案中，所述晶型用于体内或体外方法中。
本公开还提供一种抑制细胞中PDE-5水平的方法，其包括向细胞施用有效量的式(I)化合物的晶型(例如晶型A或B)地步骤。在一些优选的实施方案中，所述方法在体内或体外进行。
本公开还提供所述的式(I)化合物的晶型(例如晶型A或B)在制备试剂中的用途，所述试剂用于增强细胞中cGMP信号传导功能。在一些优选的实施方案中，所述试剂用于体内或体外方法中。
本公开还提供所述的式(I)化合物的晶型(例如晶型A或B)，其用于增强细胞中cGMP信号传导功能。在一些优选的实施方案中，所述晶型用于体内或体外方法中。
本公开还提供一种增强细胞中cGMP信号传导功能的方法，其包括向细胞施用有效量的式(I)化合物的晶型(例如晶型A或B)地步骤。在一些优选的实施方案中，所述方法在体内或体外进行。
在本公开中除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。同时，为了更好地理解本发明，下面提供部分术语的定义和解释。
化合物可以两种或多种结晶状态存在，结构相同的分子，结晶成不同的固体形式，称为“polymorph”，译为多晶型物或多晶形等。当涉及具体结晶形式时，常称“crystal form”，即为本文中使用的术语“晶型”。
在本公开中，各晶型X射线粉末衍射图谱中吸收峰的位置可以在上述发明的具体数值±0.2°的范围内，例如在±0.1°的范围内，差示扫描量热法测定的吸热转变温度可以在上述具体数值±3.0℃(例如±1.0℃或±2.0℃)的范围内。
应当理解用不同类型设备或用不同的测试条件可能给出稍微不同的XRPD的图谱和峰值。不同晶型的图谱、峰值和各衍射峰的相对强度将受化合物纯度、样品的前处理、扫描速度、粒径和测试设备的校验和维修的影响。所提供的数值不能作为绝对值。
应当理解用不同类型设备或用不同的测试条件可能给出稍微不同的吸热转变温度读数。该数值将受化合物纯度、样品重量、加热速度、粒径和测试设备的校验和维修的影响。 所提供的数值不能作为绝对值。
本公开还采用热失重分析(TGA)对晶型发生分解或升华、蒸发的程度(失去重量)与温度的关系进行了分析。TGA是指以一定速度升温，测定供试品重量随温度变化的方法。应当理解同种晶型受样品纯度、粒径、不同类型设备、不同的测试方法等的影响，所得到的数值存在一定误差。晶型发生分解或升华、蒸发时的温度可以在上述公开的具体数值±3.0℃的范围内，例如±2.0℃的范围内。
如本文中所使用的，术语“室温”、“常温”是指室内环境温度，通常指20-30℃，例如20-25℃。
在本文中，如无特别说明，制备各晶型中所用原料为所述式(I)化合物(即，2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺)的无定型，其可以通过专利WO2014026467A1实施例11和实施例11-1中公开的方法制备得到。
如本文中所使用的，术语“受试者”是指动物，特别是哺乳动物，优选人。
如本文中所使用的，术语“有效量”是指足以实现所需治疗或预防效果的量，例如，实现减轻与待治疗疾病相关的症状的量。
如本文中所使用的，术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的所述晶型或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
本公开所述式(1)化合物的晶型，尤其是晶型A或B具有如下所述的至少一种
有益效果：
(1)制备方法简便，适合工业化生产；
(2)具有良好的性状，便于生产、检测、制剂制备、运输和储藏；
(3)纯度高、残留溶剂少，溶解度较高，稳定性好，质量易控；
(4)对PDE-5酶具有良好的抑制活性，在体内具有良好暴露量和/或生物利用度；
(5)具有良好的体内外药效，可用于治疗和/或预防勃起功能障碍、前列腺增生、下尿路症状、高血压等疾病。
附图说明
此处所述附图用于进一步说明本发明，构成本公开的一部分，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1是式(I)化合物的晶型B的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图2是式(I)化合物的晶型B的TGA-DSC分析图，右侧纵坐标表示重量(％)，左侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图3是式(I)化合物的晶型B的 1H-NMR。
图4是式(I)化合物的晶型C的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图5是式(I)化合物的晶型C的TGA-DSC分析图，左侧纵坐标表示重量(％)，右侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图6是式(I)化合物的晶型D的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图7是式(I)化合物的晶型D的TGA-DSC分析图，左侧纵坐标表示重量(％)，右侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图8是式(I)化合物的晶型E的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图9是(I)化合物的晶型E的TGA-DSC分析图，右侧侧纵坐标表示重量(％)，左侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图10是式(I)化合物的二氯甲烷溶剂化合物的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图11是式(I)化合物的二氯甲烷溶剂化合物的TGA-DSC分析图，左侧纵坐标表示重量(％)，右侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图12是式(I)化合物的乙腈溶剂化合物的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图13是式(I)化合物的乙腈溶剂化合物的DSC分析图，左侧纵坐标表示热流(W/g)，右侧纵坐标表示重量(％)，横坐标表示温度T(℃)。
图14是式(I)化合物的丙酮溶剂化合物的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图15是式(I)化合物的丙酮溶剂化合物的TGA-DSC分析图，左侧纵坐标表示重量(％)，右侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图16是式(I)化合物的甲醇溶剂化合物的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图17是式(I)化合物的甲醇溶剂化合物的TGA-DSC分析图，右侧纵坐标表示重量(％)，左侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图18是式(I)化合物的晶型A的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图19是式(I)化合物的晶型A的TGA-DSC分析图，右侧纵坐标表示重量(％)，左侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图20是式(I)化合物的晶型A的 1H-NMR。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。以下对至少一个示例性实施例的描述实际上仅仅是说明性的，决不作为对本发明及其应用或使用的任何限制。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1 晶型A的制备
制备方法一：取式(I)化合物(15g)置于容器中，然后加入乙醇和水的混合溶剂(100mL，乙醇:水＝40:1)，升温至溶剂回流，1h后降温，降至30℃时有固体析出。降至常温后16h过滤，得到白色固体，40℃真空干燥，得产物(12.02g，收率80.1％)，经XRPD测试，为晶型A。
制备方法二：取式(I)化合物(500mg)置于容器中，然后加入甲醇和水的混合溶剂(7mL，甲醇:水＝50:1)，缓慢升温至样品溶清，停止加热。1h后降至常温，常温搅拌4h后开始析出固体，过滤，得到白色固体，经XRPD测试，为晶型A。
制备方法三：取式(I)化合物(3.0g)置于容器中，然后加入异丙醇和水的混合溶剂(40mL，异丙醇:水＝40:1)，同时升温至80℃，样品完全溶解，降温至50℃，此时加入少量晶种，将温度降至40℃并维持16h后，析出大量白色固体，过滤，50℃真空干燥1.5h，得到固体(2.38g，收率79.3％)，经XRPD测试，为晶型A。
XRPD测试
X射线反射参数：Cu，Kα；入射狭缝：0.6mm；发散狭缝：1mm；扫描模式：连续；扫描范围：3.0～45.0度；取样步长：0.02度；每步扫描时间：19.8s；探测器角度：2.0度。晶型A在X-射线粉末衍射图示于图18中，该晶型在以下衍射2θ角度处有峰：7.31±0.2°、10.04±0.2°、10.95±0.2°、11.86±0.2°、13.08±0.2°、14.64±0.2°、15.87±0.2°、17.40±0.2°、18.27±0.2°、18.98±0.2°、19.70±0.2°、20.13±0.2°、20.56±0.2°、20.90±0.2°、21.66±0.2°、22.28±0.2°、22.68±0.2°、23.64±0.2°、24.05±0.2°、24.70±0.2°、25.75±0.2°、26.76±0.2°、27.68±0.2°、28.02±0.2°、28.36±0.2°、29.26±0.2°、29.69±0.2°、30.54±0.2°、31.20±0.2°、31.71±0.2°、32.87±0.2°、33.54±0.2°、33.96±0.2°。
差示扫描量热测试
通过差示扫描量热法(DSC)研究式(I)化合物的晶型A的固态热性能。晶型A的DSC曲线显示于图19中。DSC测试条件：用氮气以50mL/min吹扫，在25℃至250℃之间以10℃/min加热速率收集数据，在吸热峰朝下的情况下绘图。
热重分析
TGA测试条件：用氮气以60mL/min吹扫，在室温至350℃之间以10℃/min加热速率收集数据。晶型A的TGA曲线显于图19中。
核磁分析测试条件( 1H-NMR)
仪器：Bruker Advance III 400；溶剂：氘代DMSO。式(1)化合物的核磁氢谱显示于图20中。
实施例2 晶型B的制备
制备方法一：取式(I)化合物(8.0g)，置于烧瓶中，加入二氯甲烷(160mL)，升温至回流，1.5h后完全溶解。缓慢降温，至37℃时开始析出固体，继续降温至室温，搅拌16h，过滤，得到固体。置于70℃真空干燥5天，后置于100℃真空干燥3天，称量得产物(5.26g)，经XRPD测试，为晶型B。
制备方法二：取式(I)化合物(1.0g)，置于烧瓶中，加入乙腈(40mL)与水(1.6mL)，升温至溶液回流，回流1h后溶解。自然降温至室温，5h后抽滤，得到固体。40℃真空干燥16h，后置于105℃鼓风干燥箱中，7天后取出，经XRPD测试，为晶型B。
制备方法三：取式(I)化合物(500mg)，置于烧瓶中，加入丙酮3mL，化合物基本溶解后，析出固体。室温搅拌1.5h后过滤，得到固体。将所得到的固体置于100℃下真空干燥，1天后取出，得到的样品经XRPD测试为晶型B。
XRPD测试
X射线反射参数：Cu，Kα；入射狭缝：0.6mm；发散狭缝：1mm；扫描模式：连续；扫描范围：3.0～45.0度；取样步长：0.02度；每步扫描时间：19.8s；探测器角度：2.0度。晶型B的X-射线粉末衍射图示于图1中，该晶型在以下衍射2θ角度处有峰：3.53±0.2°、7.07±0.2°、8.76±0.2°、10.32±0.2°、10.60±0.2°、11.80±0.2°、12.53±0.2°、13.02±0.2°、14.21±0.2°、15.07±0.2°、16.86±0.2°、17.78±0.2°、18.47±0.2°、19.26±0.2°、19.77±0.2°、20.18±0.2°、20.54±0.2°、21.19±0.2°、21.74±0.2°、22.04±0.2°、22.47±0.2°、23.32±0.2°、23.64±0.2°、24.68±0.2°、25.46±0.2°、26.62±0.2°、27.11±0.2°、28.16±0.2°、28.74±0.2°、29.37±0.2°。
差示扫描量热测试
通过差示扫描量热法(DSC)研究式(I)化合物的晶型B的固态热性能。晶型B的DSC曲线显示于图2中。DSC测试条件：用氮气以50mL/min吹扫，在25℃至250℃之间以10℃/min加热速率收集数据，在吸热峰朝下的情况下绘图。
热重分析
TGA测试条件：用氮气以60mL/min吹扫，在室温至350℃之间以10℃/min加热速率收集数据。晶型B的TGA曲线显于图2中。
核磁分析测试条件( 1H-NMR)
仪器：Bruker Advance III 400；溶剂：氘代DMSO。式(1)化合物的核磁氢谱显示于图3中。
实施例3 晶型C的制备
取式(I)化合物5.0g，置于100mL圆底烧瓶中，加入50mL丙酮与5mL水，升温至溶液回流，迅速溶清，后自然降温至室温，搅拌16h，过滤得到白色固体。将该白色固体进行XRPD测试，结果显示为晶型C。晶型C的X-射线粉末衍射图示于图4中。晶型C的DSC曲线和TGA曲线显示于图5中。
实施例4 晶型D的制备
取式(I)化合物3.5g，置于100mL圆底烧瓶中，后加入35mL丙酮与3.5mL水，升温至溶液回流，溶清，维持此温度1h，后自然降温，8小时后过滤，得到固体。将得到的部分产品置于常温中敞口放置，16h后对所得产品进行XRPD测试，结果显示为晶型D。晶型D的X-射线粉末衍射图示于图6中。晶型D的DSC曲线和TGA曲线显示于图7中。
实施例5 晶型E的制备
取式(I)化合物20g，置于500mL反应釜中，加入300mL异丙醇与30mL水，升温至73℃，反应液澄清。在随后的24h内，降温至0℃，析出大量固体，重新升温至45℃，釜内反应液回归到澄清。再次将釜内温度降至15℃，有少量固体析出，此时将釜内温度控制在30～15℃内波动，30℃与15℃互相转换时间为1h，温度转换后各自停留0.5h，反复升降温共6个循环后，釜内再次到达15℃，两小时平缓降温至5℃，析出大量固体。两小时后过滤。对得到的固体进行XRPD测试，结果显示为晶型E。晶型E的X-射线粉末衍射图示于图8中。晶型E的DSC曲线和TGA曲线显示于图9中。
性质测试试验例：
实验例1 晶型A的性质考察
1)光、热稳定性试验
供试品：式(I)化合物的晶型A。
实验方法：将供试品铺于洁净表面皿中，置70℃条件下1天和3天，置105℃条件下1天，置光照条件下5天和10天，置40℃RH75％条件10天和30天，对供试品的有关物质、性状、含量、水分、XRPD进行考察。
水分：依据中国药典2015年版四部通则0832水分测定法第一法2库仑滴定法测定。
XRPD：参照中国药典2015年版四部通则0451X射线衍射法测定。
有关物质、含量：参照中国药典2015年版四部通则0512高效液相色谱法测定。
实验结果：
表1 晶型A的稳定性结果
Figure PCTCN2018117788-appb-000002
“/”表示未检测。
2)晶型A的引湿性试验
供试品：式(I)化合物(无定型)；式(I)化合物的晶型A。
实验方法：将供试品在25℃，RH80％条件下放置1天(样品瓶预先在该条件下放置1天)，结果如表2所示：
表2 引湿性考察结果
Figure PCTCN2018117788-appb-000003
实验例2 晶型B的性质考察
供试品：式(I)化合物的晶型B。
实验方法：将供试品铺于洁净表面皿中，置70℃条件下1天和3天，置105℃条件下1天，置光照条件下5天和10天，置40℃RH75％条件10天和30天，对供试品的有关物质、性状、含量、水分、XRPD进行考察。
水分：依据中国药典2015年版四部通则0832水分测定法第一法2库仑滴定法测定。
XRPD：参照中国药典2015年版四部通则0451X射线衍射法测定。有关物质、含量：参照中国药典2015年版四部通则0512高效液相色谱法测定。
实验结果：
表3 晶型B的稳定性结果
Figure PCTCN2018117788-appb-000004
实验例3 其它晶型的性质考察
Figure PCTCN2018117788-appb-000005
对晶型C、D的性质分别进行了考察。结果发现：晶型C和晶型D在70℃条件下可相互转化。常温下不稳定，往往得到的是两种晶型的混合物。
对晶型E以及得到的各晶体形式的溶剂化合物进行考察。结果发现，其吸湿性、稳定性存在缺陷。
实验例4 化合物无定型的性质考察
表4 无定型的稳定性结果
Figure PCTCN2018117788-appb-000006
实验结论：
在70℃条件下放置1至3天，晶型A、晶型B的性状、有关物质、含量、XRPD等性质均无明显变化；而无定型在该条件下，其性状发生变化，有关物质的含量有所增加。在光照、105℃条件下放置同等时间，晶型A、晶型B的性状、有关物质、含量、水分、XRPD无明显变化；而无定型在该条件下，其各性质发生了明显的变化，如性状由白色粉末变为黄色粉末，有关物质高达35.05％，含量下降至57％。
结果表明，本发明的晶型A、晶型B显示出良好的稳定性和低吸湿性特点，便于药品的生产、制剂的制备、运输和储藏，更有利于保证药物使用的稳定性和安全性。并且晶型A、晶型B相比无定型以及晶型C、D、E以及其他溶剂化物，综合考虑，具有更好的成药性。
实验例6 晶型B与无定型的流动性实验考察
1、原料处理
采用万能粉碎处理后测定以下各种性质。
2、实验仪器：百特粉体综合特征测试仪
3、实验结果及结论
表5.流动性实验结果
Figure PCTCN2018117788-appb-000007
卡尔系数是衡量粉体流动性的指标之一，其数值越小，表明粉体越好，表5实验结果表明，晶型B的卡尔系数小于无定型，表明晶型B的流动性优于无定型。
实验例7 晶型B与无定型的可压性实验考察
1、实验方法
分别取晶型B和无定型化合物原料适量压片，固定片重，调节压片厚度(压片力)，测定片剂硬度。考察硬度随压片厚度变化，对比原料药可压性。
2、实验结果及结论
表6.可压性实验结果
Figure PCTCN2018117788-appb-000008
注：压片厚度越小，压片力越大
表6的实验结果表明，相同压片厚度，晶型B压片硬度比无定型大，可压性更好，更利于制剂产品开发。
实验例8 晶型B在SD大鼠体内药代动力学实验
1、供试品：式(I)化合物的晶型B，。
受试动物：SD大鼠，雄性，6只，体重260-275克/只。
2、供试品给药药液的制备：
溶解方案：
PO(口服)给药：0.5％MC(甲基纤维素)+0.1％SDS(十二烷基硫酸钠)
空白溶媒的配制方法：称取5g甲基纤维素，缓慢加入995g搅拌着的纯化水中，搅拌均匀，再加入1g SDS，搅拌至澄清，即得。
具体配制方法：取晶型B 7.47mg置于组织研磨器中，加入24.6mL上述空白溶媒，以1000rpm的转速研磨均匀即得均匀混悬液。
3、实验方法
将供试品药液按照下表方法给药：
Figure PCTCN2018117788-appb-000009
采血时间点：
给药后0.167、0.5、1、2、4、6、8、24h
每个时间点通过尾静脉采集100μL左右的全血，放置到含有EDTA-K 2抗凝剂的抗凝管中，全血样品在4℃条件下8000转/分钟离心6分钟得到血浆样品，置于-80℃冰箱冻存。
4、血浆样品分析：
采用蛋白沉淀法：取血浆20μL，加入内标200μL，涡旋10分钟后，然后4000转/分钟离心20分钟，取上清液100μL，再加入100μL水，涡旋混匀3分钟后，LC-MS/MS分析。
5、实验结果：
表7 大鼠灌胃给予晶型B药代动力学参数(po:3mg/kg)
Figure PCTCN2018117788-appb-000010
AUC inf代表药时曲线下面积0→∞
T max代表血药浓度达峰时间
C max代表血药浓度达峰浓度
T 1/2代表消除半衰期
实验结论
大鼠单次口服化合物的晶型B，给药后有明显的吸收和消除过程，说明该晶型在生物体内能够发挥良好的药效，适合用于药品产品的制备。
最后应当说明的是：以上实施例仅用以说明本发明的技术方案而非对其限制；尽管 参照较佳实施例对本发明进行了详细的说明，所属领域的普通技术人员应当理解：依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换；而不脱离本发明技术方案的精神，其均应涵盖在本发明请求保护的技术方案范围当中。

Claims (14)

  1. 式(I)所示化合物晶型B，在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱中，在3.53±0.2°、7.07±0.2°、8.76±0.2°、11.80±0.2°、14.21±0.2°、15.07±0.2°、18.47±0.2°处有特征峰，
    Figure PCTCN2018117788-appb-100001
  2. 如权利要求1所述的晶型B，其X-射线粉末衍射图谱中，还在10.32±0.2°、10.60±0.2°、12.53±0.2°、13.02±0.2°、16.86±0.2°、17.78±0.2°处有特征峰；优选地，还在19.26±0.2°、19.77±0.2°、20.18±0.2°、20.54±0.2°、23.32±0.2°处有特征峰；优选地，还在22.04±0.2°、22.47±0.2°、23.64±0.2°、24.68±0.2°、25.46±0.2°处有特征峰；优选地，所述的晶型B的X-射线衍射图谱基本如图1所示。
  3. 如权利要求1或2所述的晶型B，DSC热图谱显示中，其在139℃～150℃处存在一个吸热转变峰；其产生最大吸热量时的转变温度即相变温度为144±3℃；优选地，所述的晶型B的差示扫描量热分析图基本如图2所示。
  4. 式(I)化合物的溶剂化合物，其特征在于，该溶剂化合物是由每分子有机溶剂与一或多分子式(I)化合物子,优选1～8分子式(I)化合物分子，优选2～7分子式(I)化合物，优选3～6分子式(I)化合物，优选4～5分子式(I)化合物，优选5～6分子式(I)化合物，优选2～3分子式(I)化合物，优选1～2分子式(I)化合物，形成的复合物，
    Figure PCTCN2018117788-appb-100002
    所述的有机溶剂选自：
    (1)卤代烃类溶剂；优选地，所述卤代烃类溶剂包括饱和和不饱和的卤代烃类溶剂，所述的饱和卤代烃类溶剂选自二氯甲烷、三氯甲烷、四氯化碳、1,1-二氯乙烷、1,2-二氯乙 烷、1,1,1-三氯乙烷、1,1,2-三氯乙烷、1,1,1,2-四氯乙烷、1,1,2,2-四氯乙烷、五氯乙烷和六氯乙烷，所述的不饱和卤代烃类溶剂选自1,1-二氯乙烯、1,2-二氯乙烯、三氯乙烯和四氯乙烯；
    优选为饱和卤代烃溶类剂，更优选为二氯甲烷或三氯甲烷；
    更优选为二氯甲烷；进一步优选地，所述溶剂化合物中二氯甲烷与式(I)化合物的分子个数比例为1:(2～3)；
    (2)腈类溶剂；优选地，所述腈类溶剂包括乙腈和丙腈；
    优选为乙腈；进一步优选地，所述溶剂化后中乙腈与式(I)化合物的分子个数比例为1:(5～6)；
    (3)醇类溶剂；优选地，所述醇类溶剂包括脂肪醇、脂环醇及芳香醇类溶剂；优选地，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正己醇、乙二醇、丙二醇和丙三醇；优选地，所述的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇和环己乙醇；优选地，所述芳香醇类溶剂选自苯甲醇、苯乙醇和苯丙醇；
    优选地，所述醇类溶剂为脂肪醇溶剂，优选为甲醇、乙醇、异丙醇或叔丁醇；
    更优选为甲醇；进一步优选地，所述溶剂化合物中甲醇与式(I)化合物的分子个数比例为1:(1～2)；
    (4)酮类溶剂；优选地，所述酮类溶剂括脂肪酮类及环酮类溶剂；优选地，所述的脂肪酮类溶剂选自甲乙酮、甲基异丙基酮、丙酮、甲基丁酮和甲基异丁酮；所述的环酮类溶剂选自环丙酮、环己酮、异佛尔酮和N-甲基吡咯烷酮；
    优选地，所述酮类溶剂为脂肪酮类溶剂，优选为丙酮；
    进一步优选地，所述溶剂化合物中丙酮与式(I)化合物的分子个数比例为1:(5～6)；
    (5)酯类溶剂；优选地，所述酯类溶剂包括脂肪酯类及芳香酯类溶剂；优选地，所述脂肪酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯、丙酸甲酯、丙酸乙酯、丙酸丙酯和丙酸异丙酯；优选地，所述芳香酯类溶剂为选自邻苯二甲酸二甲酯；
    优选为脂肪酯类溶剂，更优选为甲酸甲酯、甲酸乙酯、乙酸甲酯或乙酸乙酯。
  5. 制备权利要求1所述的式(I)化合物晶型B的方法，其特征在于将无定形式(I)化合物溶于有机溶剂或有机溶剂与水的混合液中，加热至40℃～100℃至化合物溶解后，降温至0℃～40℃，析出溶剂化合物固体，然后在40℃～110℃温度条件下干燥1天～10天，得晶型B。
  6. 如权利要求5所述的制备晶型B的方法，其特征在于，
    所述的有机溶剂选自：
    (1)卤代烃类溶剂；优选地，所述卤代烃类溶剂包括饱和或不饱和的卤代烃类溶剂；优选地，所述的饱和卤代烃类溶剂选自二氯甲烷、三氯甲烷、四氯化碳、1,1-二氯乙烷、1,2-二氯乙烷、1,1,1-三氯乙烷、1,1,2-三氯乙烷、1,1,1,2-四氯乙烷、1,1,2,2-四氯乙烷、五氯乙烷和六氯乙烷；优选地，所述的不饱和卤代烃类溶剂选自1,1-二氯乙烯、1,2-二氯乙烯、三氯乙烯和四氯乙烯；优选为饱和卤代烃类溶剂，更优选为二氯甲烷或三氯甲烷；
    (2)腈类溶剂；优选地，所述腈类溶剂包括乙腈或丙腈；优选为乙腈；
    (3)醇类溶剂；优选地，所述醇类溶剂包括脂肪醇、脂环醇及芳香醇类溶剂；优选地，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正己醇、乙二醇、丙二醇和丙三醇；优选地，所述的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇和环己乙醇；优选地，所述芳香醇类溶剂选自苯甲醇、苯乙醇和苯丙醇；优选地，所述醇类溶剂为脂肪醇溶剂，优选为甲醇、乙醇、异丙醇、叔丁醇；
    (4)酮类溶剂；优选地，所述酮类溶剂包括脂肪酮类及环酮类溶剂；优选地，所述的脂肪酮类溶剂选自甲乙酮、甲基异丙基酮、丙酮、甲基丁酮和甲基异丁酮；优选地，所述的环酮类溶剂选自环丙酮、环己酮、异佛尔酮和N-甲基吡咯烷酮；优选地，所述酮类溶剂为脂肪酮类溶剂，优选为丙酮；
    (5)酯类溶剂；优选地，所述酯类溶剂包括脂肪酯类及芳香酯类溶剂；优选地，所述脂肪酯类溶剂选自甲酸甲酯、甲酸乙酯、甲酸丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯、乙酸异丁酯、丙酸甲酯、丙酸乙酯、丙酸丙酯和丙酸异丙酯；优选地，所述芳香酯类溶剂为邻苯二甲酸二甲酯；优选为脂肪酯类溶剂，更优选为甲酸甲酯、甲酸乙酯、乙酸甲酯或乙酸乙酯；
    当式(I)化合物溶于有机溶剂与水的混合液中时，优选的有机溶剂为能与水互溶的有机溶剂，例如甲醇、乙醇、乙腈和丙酮；进一步优选地，有机溶剂与水的混合比例为1:1～100:1，优选1:1～90:1，优选1:1～80:1，优选1:1～70:1，优选1:1～60:1，优选1:1～50:1，优选1:1～40:1，优选1:1～35:1，优选1:1～30:1，优选1:1～25:1，优选1:1～20:1，优选1:1～10:1，优选1:1～5:1，优选1:1。
  7. 如权利要求5所述的制备晶型B的方法，其特征在于，
    加热过程中优选加热温度为加热至溶剂回流时的温度；
    降温过程中优选的降温温度为10℃～40℃，优选20℃～35℃，优选25℃；
    干燥过程中优选的干燥温度为70℃～100℃，优选的干燥方式包括真空干燥、鼓风干燥；优选的干燥时间为2天～8天，优选干燥时间为5天～6天，优选干燥时间为7天～8天。
  8. 如下所示式(I)化合物的水合物的晶型C，其是由每分子化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与1～3个水分子形成的水溶剂合物，优选每分子化合物含1～2个水分子，更优选每分子化合物含1个水分子，其特征在于使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射，所述晶型C在7.34±0.2°、9.06±0.2°、10.87±0.2°、12.44±0.2°、13.32±0.2°、14.72±0.2°、15.23±0.2°、16.20±0.2°、18.01±0.2°、18.37±0.2°、18.67±0.2°、19.10±0.2°、20.58±0.2°、20.99±0.2°、21.68±0.2°、22.22±0.2°、22.75±0.2°、23.30±0.2°处有特征峰；
    Figure PCTCN2018117788-appb-100003
    优选的所述晶型C有与如图4所示实质相同的X-射线衍射图谱；
    优选的，DSC热图谱中显示，温度在100℃～120℃处存在一个吸热转变峰，产生最大吸热量时的转变温度即相变温度为110±3℃；优选的所述的晶型C具有与如图5所示实质相同的差示扫描量热分析图谱；
    优选的，TGA图谱中显示，晶型C在温度60℃～110℃处存在失重，优选温度在90℃～110℃，所失重量为3％～4％，优选3.5％～3.7％；优选的所述晶型C具有与如图5所示实质相同的热重曲线图谱。
  9. 如下所示式(I)化合物的水合物的晶型D，其是由每分子化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与1～3个水分子形成的水溶剂合物，优选每分子化合物含1～2个水分子，更优选每分子化合物含1个水分子，其特征在于使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射，所述晶型D在3.42±0.2°、6.89±0.2°、9.11±0.2°、10.36±0.2°、12.47±0.2°、13.82±0.2°、15.06±0.2°、17.30±0.2°、17.97±0.2°、18.37±0.2°、19.33±0.2°、20.80±0.2°、21.07±0.2°、22.75±0.2°、23.34±0.2°、24.33±0.2°处有特征峰；
    Figure PCTCN2018117788-appb-100004
    优选的所述晶型D具有与如图6所示实质相同的X-射线衍射图谱；
    优选的，DSC热图谱中显示，温度在100℃～120℃处存在一个吸热转变峰，产生最大吸热量时的转变温度即相变温度为113±3℃；优选的所述的晶型D具有与如图7所示实质相同的差示扫描量热分析图谱；
    优选的，TGA图谱中显示，晶型D在温度90℃～110℃时，优选100℃～110℃，失重为3％～4％，优选3.5％～3.7％；优选的所述晶型D具有与如图7所示实质相同的热重曲线图谱。
  10. 如下所示式(I)化合物的水合物的晶型E，其是由每分子化合物2-(3-氮杂双环[3.1.0]己烷-3-基)-4-(3-氯-4-甲氧基苄胺基)-N-(反式-4-羟基环己基)嘧啶-5-甲酰胺与1～3个水分子形成的水溶剂合物，优选每分子化合物含1～2个水分子，更优选每分子化合物含1个水分子，其特征在于使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射，在3.53±0.2°、7.01±0.2°、9.38±0.2°、10.18±0.2°、10.52±0.2°、10.80±0.2°、12.18±0.2°、14.03±0.2°、14.76±0.2°、15.75±0.2°、17.54±0.2°、18.74±0.2°、19.06±0.2°、21.07±0.2°、21.66±0.2°、22.79±0.2°、24.05±0.2°；
    Figure PCTCN2018117788-appb-100005
    优选的所述晶型E有与如图8所示实质相同的X-射线衍射图谱；
    优选的，DSC热图谱显示，温度在100℃～120℃处存在一个吸热转变峰，产生最大吸热量时的转变温度即相变温度为111±3℃；优选的所述的晶型E具有与如图9所示实质相同的差示扫描量热分析图谱；
    优选的，在TGA图谱中，晶型E在温度100℃～110℃处存在失重，所失重量为3％～4％，优选3％～3.7％；优选的所述晶型E具有与如图9所示实质相同的热重曲线图谱。
  11. 含有权利要求1-3任一项所述的式(I)化合物的晶型B的药物组合物，其特征在于含有一种或多种药用载体和/或稀释剂，所述的药物组合物可制备成药学上可接受的任一剂型。
  12. 含有权利要求1-3任一项所述的式(I)化合物的晶型B的药物组合物，其特征在于，进一步包含一种或多种第二治疗活性剂，所述的第二治疗活性剂选自血管扩张剂，性激素，前列腺素E1，前列环素，去甲肾上腺素，降血糖药，α-肾上腺素受体阻滞剂，混合 的α,β-阻断剂，α-阻断剂，5α-还原酶抑制剂，5-羟色胺再摄取抑制剂，α2-肾上腺素受体阻滞剂，ACE抑制剂，NEP抑制剂，中枢多巴胺剂，血管活性肠肽，钙通道阻滞剂，噻嗪类利尿剂，或它们的混合物。
  13. 含有权利要求1-3任一项所述的式(I)化合物的晶型B在制备治疗和/或预防由PDE-5酶所介导的相关性疾病药物中的用途，所述的疾病选自：性功能障碍疾病、前列腺增生、膀胱过度活化、下尿路症状的疾病、高血压、心力衰竭、肺动脉高压、非酒精性脂肪肝。
  14. 如权利要求13所述的用途，所述的性功能障碍选自勃起功能障碍、早泄、女性性功能障碍；所述的前列腺增生为良性前列腺增生。
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