WO2019007299A1 - 一种苯基嘧啶酮化合物的盐、多晶型物及其药物组合物和用途 - Google Patents

一种苯基嘧啶酮化合物的盐、多晶型物及其药物组合物和用途 Download PDF

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WO2019007299A1
WO2019007299A1 PCT/CN2018/093965 CN2018093965W WO2019007299A1 WO 2019007299 A1 WO2019007299 A1 WO 2019007299A1 CN 2018093965 W CN2018093965 W CN 2018093965W WO 2019007299 A1 WO2019007299 A1 WO 2019007299A1
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compound
solution
formula
solvent
ether
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PCT/CN2018/093965
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English (en)
French (fr)
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沈敬山
何洋
陈伟铭
李剑峰
田广辉
公绪栋
王震
张容霞
柳永建
蒋华良
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中国科学院上海药物研究所
苏州旺山旺水生物医药有限公司
上海特化医药科技有限公司
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Application filed by 中国科学院上海药物研究所, 苏州旺山旺水生物医药有限公司, 上海特化医药科技有限公司 filed Critical 中国科学院上海药物研究所
Priority to KR1020207003446A priority Critical patent/KR102323090B1/ko
Priority to AU2018298154A priority patent/AU2018298154B2/en
Priority to EP18827841.0A priority patent/EP3650444B8/en
Priority to JP2020500605A priority patent/JP7450842B2/ja
Priority to CN201880002904.4A priority patent/CN109476610B/zh
Priority to RU2020105706A priority patent/RU2761213C2/ru
Publication of WO2019007299A1 publication Critical patent/WO2019007299A1/zh
Priority to US16/736,300 priority patent/US11434226B2/en

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    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to 5,6-diethyl-2-[2-n-propoxy-5-(2-(4-methylpiperazin-1-yl)acetamido)phenyl]pyrimidin-4 (3H) Salts and polymorphs of ketones (Compound Z), and pharmaceutical compositions containing same, methods for preparing various salts and polymorphs, and their use in the preparation of pharmaceutical compositions.
  • the compound Z has a problem of less water solubility in a free state, is not easily dissolved, and has a certain influence on the preparation process in the application as a pharmaceutical preparation; on the other hand, the compound itself has a pungent odor, It also has an effect when applied as a pharmaceutical preparation for human use. It is therefore an object of the present invention to find a suitable form of the compound Z for the preparation of a drug which should have the advantages of good stability, high water solubility, low hygroscopicity, no bad odor and the like.
  • the inventors of the present invention synthesized and separated various salts and crystals of the compound Z, and conducted various physical and chemical properties. As a result, it was found that a salt of the compound Z having good physical properties and a crystallized or solvated form thereof can be used as a raw material.
  • the present invention has been accomplished by pharmaceutical use or as an intermediate for the manufacture of a drug substance.
  • the present invention relates to the compound 5,6-diethyl-2-[2-n-propoxy-5-(2-(4-methylpiperazin-1-yl)acetamido)phenyl]pyrimidin-4 ( Salts of 3H)-ketones (i.e., compound Z), and polymorphs, as well as pharmaceutical compositions and pharmaceutical unit dosage forms containing the same.
  • the invention further relates to co-crystals or complexes of compound Z, as well as pharmaceutical compositions comprising the same.
  • the invention also relates to a process for the preparation of the above substances.
  • One aspect of the invention provides a compound of formula (I), and pharmaceutically acceptable polymorphs, solvates, hydrates, cocrystals, anhydrates or amorphouss thereof:
  • X includes, but is not limited to, an organic acid or an inorganic acid.
  • the organic acid includes, but is not limited to, maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, formic acid, acetic acid, propionic acid, malonic acid, oxalic acid, benzoic acid, phthalic acid, methanesulfonic acid.
  • benzenesulfonic acid toluenesulfonic acid, naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, camphoric acid, camphorsulfonic acid, salicylic acid, acetylsalicylic acid, aspartic acid, glutamic acid, lactic acid, glucose Acid, vitamin C acid, gallic acid, mandelic acid, malic acid, sorbic acid, trifluoroacetic acid, taurine, high taurine, 2-hydroxyethanesulfonic acid, cinnamic acid, mucic acid; It is not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid; and other similar protic acids.
  • X is preferably maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, mucic acid, acetic acid, methanesulfonic acid, hydrochloric acid, nitric acid or sulfuric acid.
  • X is hydrochloric acid, that is, the compound of the formula (I) is preferably a compound of the following formula (I-A):
  • Form A and Form B of the hydrochloride salt of Compound Z which has a diffraction angle 2 ⁇ of 9.3 ° ⁇ 0.2 °, 12.2 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2.
  • the crystal form A has a diffraction angle 2 ⁇ of 6.1 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, 12.2 ° ⁇ 0.2 °, 15.3 ° ⁇
  • X-ray diffraction peaks at 0.2°, 16.7° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 22.9° ⁇ 0.2°
  • the crystal form A is a monohydrate having the following structure:
  • the crystal form B has a diffraction angle 2 ⁇ of 12.5° ⁇ 0.2°, 13.5° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.5° ⁇ 0.2°, 19.9° ⁇ 0.2°, 23.0° ⁇ 0.2°, 26.5° ⁇ 0.2.
  • the crystal form B at the diffraction angle 2 ⁇ is 12.5 ° ⁇ 0.2 °, 12.8 ° ⁇ 0.2 °, 13.5 ° ⁇ 0.2 °, 14.1 ° ⁇ X-ray diffraction peaks were present at 0.2°, 17.9° ⁇ 0.2°, 19.5° ⁇ 0.2°, 19.9° ⁇ 0.2°, 23.0° ⁇ 0.2°, 26.5° ⁇ 0.2°, and 26.8° ⁇ 0.2°.
  • Most preferred is Form A of the hydrochloride salt of Compound Z.
  • the single crystal structure was measured by an X-ray single crystal diffractometer, and the manufacturer was Japanese Rigaku (Japan rigaku); instrument model: SuperNova, Dual, Cu at zero, Atlas S2. Detection temperature: 100K.
  • Form A of the present invention contains water in an amount of 3.28 to 5.35 wt%, more specifically, water in an amount of 3.28 to 3.98 wt%, and the water content can be measured by Karl Fischer method.
  • salt includes pharmaceutically acceptable salts, as well as pharmaceutically unacceptable salts. It is not preferred to use a pharmaceutically unacceptable salt for the patient, but the salt can be used to provide pharmaceutical intermediates and bulk pharmaceutical forms.
  • salt or “pharmaceutically acceptable acid addition salt” refers to a salt prepared using a pharmaceutically acceptable acid to form a salt with compound Z, including but not limited to organic acid salts and inorganic acids.
  • the salt is preferably a salt of maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, mucic acid, acetic acid, methanesulfonic acid, hydrochloric acid, nitric acid or sulfuric acid, most preferably methanesulfonic acid, fumaric acid, a salt of hydrochloric acid.
  • Another embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of formula (I), or a polymorph, solvate, hydrate, cocrystal, anhydrate, or amorphous thereof, and Dosage form.
  • the salt of the compound of formula (I) of the present invention placed in air or by recrystallization, will absorb water to produce a hydrate in the form of adsorbed water, and acid addition salts containing such water are also included in the present invention.
  • solvate of the present invention is not particularly limited as long as it is a solvent used for the production of a salt or a crystal, and specifically, for example, a hydrate, an alcoholate, an acetonate or a toluene may be used. Preference is given to hydrates and alcoholates.
  • a further embodiment of the invention relates to a process for the preparation of a pharmaceutical composition and dosage form comprising a compound of formula (I), or a polymorph, solvate, hydrate, co-crystal, anhydrate, or amorphous form thereof.
  • the specific preparation method is as follows.
  • Compound Z can be prepared by reference to the examples of WO2010/066111. Compound Z can also be prepared by the following method:
  • the reaction temperature is usually from room temperature to 100 ° C
  • the solvent is preferably dichloromethane, toluene, chloroform or N, N-dimethylformamide
  • the base is preferably potassium carbonate or sodium carbonate
  • the reaction temperature is usually from 0 ° C to 50 ° C, and the solvent is preferably methanol, ethanol or N,N-dimethylformamide;
  • the reaction temperature is usually from 50 to 120 ° C
  • the solvent is preferably chloroform, methanol, ethanol, ethylene glycol monomethyl ether, N,N-dimethylformamide or 1,4-dioxane.
  • the base is preferably potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide.
  • the compound of the formula (I) can be produced by forming a salt of the corresponding acid with the compound Z, for example, by using one of the following methods:
  • the compound of the formula (I-A) can be prepared by forming a salt of hydrogen chloride with the compound Z, for example, by using one of the following methods:
  • the A and E solvents may be each independently selected from the group consisting of water, a nonaqueous solvent, and a mixed solvent thereof, and more specifically, selected from the group consisting of water, alcohols, ethers, esters, hydrocarbons, ketones, and the like. Mix solvents and the like. More specifically, the methyl solvent and the ethyl solvent are each independently selected from the group consisting of water; esters (eg, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, methyl formate, ethyl formate, propyl formate).
  • esters eg, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, methyl formate, ethyl formate, propyl formate.
  • ethers such as: ether, propyl ether, diisopropyl ether, petroleum ether, ethylene glycol Monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol dimethyl ether, tetrahydrofuran, dioxane , dimethoxyethane, diglyme); ketones (eg acetone, methyl ethyl ketone, N-methylpyrrolidone, diethyl ketone); hydrocarbons (eg n-pentane, n-hexane) , heptan
  • the reaction temperature varies depending on the reagent or solvent, etc., and is usually from -20 ° C to 200 ° C, preferably from 0 ° C to 100 ° C.
  • the reaction time is not limited and is usually from 10 minutes to 10 hours.
  • the hydrogen chloride may be present in the form of a gas or may be present in the form of an aqueous or non-aqueous solvent such as hydrochloric acid, a hydrogen chloride methanol solution, or a hydrogen chloride ethanol solution.
  • Another aspect of the invention also provides polymorphs of the salt of compound Z (i.e., a compound of formula I) and processes for their preparation. Seed crystals can be added as needed in the process.
  • the seed crystal here refers to a "seed" of a compound of the formula (I) or a self-made crystalline substance of the compound of the formula (I) for inducing crystallization.
  • the polymorph of the salt of compound Z (i.e., the compound of formula I) can be prepared by one of the following methods:
  • a pentane solvent may be added to the mixed solution E;
  • step 5 standing still to precipitate the target, or stirring to precipitate the target, or adding the corresponding seed crystal to the solution prepared in step 4) to precipitate;
  • a pentane solvent may be added to the solution F;
  • a compound Z salt ie, a compound of formula (I) is suspended in a propylene solvent to form a suspension G;
  • a pentane solvent may be added to the solution G;
  • step 3 heating, stirring, cooling to precipitate the target, or adding seed crystals to the solution prepared in step 2) to precipitate;
  • the polymorph of the compound of formula (I-A) can be prepared by one of the following methods:
  • a pentane solvent may be added to the mixed solution E;
  • step 5 standing still to precipitate the target, or stirring to precipitate the target, or adding the corresponding seed crystal to the solution prepared in step 4) to precipitate;
  • a pentane solvent may be added to the solution F;
  • a pentane solvent may be added to the solution G;
  • step 3 heating, stirring, cooling to precipitate the target, or adding seed crystals to the solution prepared in step 2) to precipitate;
  • the propylene solvent, the butane solvent and the pentane solvent may be the same or different, and the definitions of the solvents C, D and pent are the same as defined in the above-mentioned A and B solvents, and the temperature range is the salt of the preparation compound Z (ie, The temperature range of the compound I) is the same.
  • the compound Z hydrochloride is added to an alcohol, dissolved by heating, and the solid is precipitated by cooling, and the crystal form A of the compound Z hydrochloride is isolated.
  • the compound Z hydrochloride is added to the alcohol and ester mixed system, dissolved by heating, and the solid is precipitated by cooling, and the crystal form A of the compound Z hydrochloride is isolated.
  • the alcohol is preferably a C1-C4 linear or branched alkanol such as methanol, ethanol, isopropanol; the alcohol is more preferably ethanol.
  • the esters include, but are not limited to, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, methyl formate, ethyl formate, propyl formate, butyl formate; the ester is more preferably ethyl acetate.
  • the diffraction angle (2 ⁇ ) in powder X-ray diffraction may cause an error in the range of ⁇ 0.2°, and therefore the value of the following diffraction angle should be understood to also include a value in the range of about ⁇ 0.2°. Therefore, the present invention includes not only crystals which are completely coincident with peaks (diffraction angles) in the powder X-ray diffraction spectrum, but also crystals having an error of ⁇ 0.2° and a peak (diffraction angle).
  • the present invention provides Form A of Compound Z hydrochloride, which is a monohydrate.
  • the X-ray powder diffraction data of Form A of Compound Z hydrochloride is as follows: X-ray powder diffraction is expressed in terms of 2 ⁇ angle, wherein the crystal form is 6.1 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 ° There are diffraction peaks at 12.2 ° ⁇ 0.2 °, 15.3 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, and 22.9 ° ⁇ 0.2 °.
  • a single crystal of Form A was subjected to single crystal X-ray diffraction analysis, and the X single crystal diffraction pattern showed that Form A contained one molecule of bound water.
  • the crystal form A is at least about 3482.81 cm -1 , 3405.67 cm -1 , 3293.82 cm -1 , 3046.98 cm -1 , 2967.91 cm -1 , 2871.49 cm - in the infrared absorption spectrum measured by the potassium bromide tableting method .
  • the crystal form A in the Raman spectrum is at least about 3163.21 cm -1 , 2961.12 cm -1 , 2932.78 cm -1 , 1662.17 cm -1 , 1620.11 cm -1 , 1606.17 cm -1 , 1561.04 cm -1 , 1542.89 cm -1 , 1422.64cm -1 , 1292.54cm -1 , 1267.48cm -1 , 1244.31cm -1 , 1224.67cm -1 , 854.02cm -1 , 825.78cm -1 have characteristic peaks.
  • the invention also provides Form B of Compound Z hydrochloride.
  • the DSC of Form B of Compound Z hydrochloride showed an endothermic peak at 211.36 ° C.
  • the spectral data are as follows:
  • the DSC measurement conditions are as follows:
  • the X-ray powder diffraction data of Form B of Compound Z hydrochloride is as follows: X-ray powder diffraction is expressed in terms of 2 ⁇ angle, wherein the crystal form is at 12.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.5° ⁇ 0.2°. There are diffraction peaks at 14.1 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 19.5 ° ⁇ 0.2 °, 19.9 ° ⁇ 0.2 °, 23.0 ° ⁇ 0.2 °, 26.5 ° ⁇ 0.2 °, and 26.8 ° ⁇ 0.2 °.
  • the crystal form B in the Raman spectrum is at least about 3163.44 cm -1 , 2296.94 cm -1 , 2927.45 cm -1 , 2871.46 cm -1 , 1688.06 cm -1 , 1617.18 cm -1 , 1600.94 cm -1 , 1552.40 cm -1 , 1537.62 cm -1 , 1404.60 cm -1 , 1242.62 cm -1 , and 657.62 cm -1 have characteristic peaks.
  • the present invention also provides an amorphous form of the compound Z hydrochloride, the X-ray powder diffraction pattern of which is substantially as shown in Fig. 7.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable adjuvant, preferably a maleate salt selected from compound Z, a pharmaceutical composition of one or more of succinate, methanesulfonate, citrate, hydrochloride, tartrate, fumarate, mucate, acetate and sulfate, more preferably Is a pharmaceutical composition comprising Form A of Compound Z hydrochloride having the X-ray powder diffraction pattern listed in Table 1.
  • the excipients may be excipients, binders, lubricants, disintegrators, colorants, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents commonly used in the medical field.
  • the agent, the buffer, the preservative, the antioxidant, the stabilizer, the absorption enhancer, and the like may be appropriately used in combination with the above additives as needed.
  • the salt of the compound Z of the present invention is formulated in an oral pharmaceutical composition in admixture with at least one pharmaceutical excipient, each containing from 10 mg to 200 mg of the active ingredient.
  • the main active ingredient component is mixed with a pharmaceutical carrier such as starch, lactose, magnesium stearate or the like, and a sugar coating or other suitable substance may be administered, or It is treated such that the tablet has an effect of prolonging or slowing, and the tablet is released in a continuous manner by a predetermined amount of active ingredient.
  • a pharmaceutical carrier such as starch, lactose, magnesium stearate or the like
  • a sugar coating or other suitable substance may be administered, or It is treated such that the tablet has an effect of prolonging or slowing, and the tablet is released in a continuous manner by a predetermined amount of active ingredient.
  • the active ingredient is mixed with a diluent, and the resulting mixture is filled into a capsule to obtain a capsule.
  • the acid addition salt of the compound Z of the present invention when used as a therapeutic or prophylactic agent for the above diseases, may be used alone or with a suitable pharmacologically acceptable excipient or diluent.
  • the mixture may be administered orally or in a non-oral manner such as an injection, a powder, a spray or a suppository, such as a tablet, a capsule, a granule, a powder or a syrup.
  • the amount of the drug to be used varies depending on the symptoms and age, and in the case of an adult, it can be administered 1 to 7 times per symptom depending on the symptoms per day, and the administration amount is 0.01 mg to 1000 mg, and the administration method is not limited.
  • a further aspect of the invention provides the use of a compound of formula (I) above for the manufacture of a medicament for the prevention or treatment of a disease associated with a PDE5 enzyme.
  • the diseases associated with the PDE5 enzyme are erectile dysfunction, pulmonary hypertension, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant angina, hypertension, congestive heart Decay, renal failure, atherosclerosis, stroke, peripheral vascular disease, Raynaud's disease, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by intestinal peristalsis.
  • Figure 1 is an X-ray powder diffraction pattern of Form A of the compound of formula (I-A);
  • Figure 2 is a thermogravimetric analysis diagram of the crystalline form A of the compound of the formula (I-A);
  • Figure 3 is an infrared spectrum of crystal form A of the compound of formula (I-A);
  • Figure 4 is an X-ray powder diffraction pattern of the crystalline form B of the compound of the formula (I-A);
  • Figure 5 is a differential scanning calorimetry diagram of Form B of the compound of formula (I-A);
  • Figure 6 is an infrared spectrum of Form B of the compound of formula (I-A);
  • Figure 7 is an X-ray powder diffraction pattern of the amorphous form of the compound of formula (I-A);
  • Figure 8 is a graph showing the plasma concentration-time curve of Compound Z and its different salts after administration
  • Figure 9 is an X-ray single crystal diffraction structure of the crystal form A of the compound of the formula (I-A);
  • Figure 10 is a Raman spectrum of crystal form A of the compound of formula (I-A);
  • Figure 11 is a Raman spectrum of Form B of the compound of the formula (I-A).
  • the salt of the compound Z provided by the present invention has the advantages of high stability, improved water solubility, no bad odor, and the like.
  • the various crystal forms of the different salts of the compound Z provided by the invention have the advantages of small hygroscopicity, good chemical stability, high purity, constant composition, simple preparation method, easy repetition, and easy storage of samples.
  • elemental analysis was performed using an Elementar Vario EL instrument; mass spectrometry was measured using a MAT-95 mass spectrometer (Finnigan); and nuclear magnetic resonance spectra were measured on a Mercury-300 and Mercury-400 nuclear magnetic resonance apparatus (Varian); Infrared absorption spectroscopy test instrument: American Nicolet Magna FTIR 6700 Fourier transform infrared spectrometer. Raman spectroscopy test instrument: Thermo Scientific DXR Raman Microscope. The infrared and Raman spectral wave numbers (cm -1 ) may contain an error of -0.5 to +0.5%, but such levels of error are within acceptable ranges in the present invention.
  • the compound Z (5 g, 0.01 mol) was suspended in 30 ml of absolute ethanol, and the sample was dissolved by heating to 65 ° C. Succinic acid (1.18 g, 0.01 mol) was added, and the mixture was stirred at 65 ° C for 40 minutes, and deactivated by adding activated carbon. The activated carbon was filtered, and the filtrate was stirred at room temperature for 30 min to give crystals.
  • the compound Z (5 g, 0.01 mol) was suspended in 40 ml of absolute ethanol, and 1 ml of methanesulfonic acid was added in an ice bath. After the addition, the temperature was raised to 60-70 ° C, stirred for 30 minutes, the activated carbon was decolorized, the activated carbon was filtered off, and the filtrate was reduced. The mixture was concentrated to a small volume, and ethyl acetate (EtOAc) was evaporated.
  • EtOAc ethyl acetate
  • the compound Z (51 g, 0.11 mol) was suspended in a mixed solvent of 400 ml of absolute ethanol and 10 ml of water, and 11 ml of concentrated hydrochloric acid was added thereto under ice bath. After the completion of the dropwise addition, the mixture was heated at 60 ° C for 30 minutes, activated carbon was added, and the mixture was heated and stirred for 30 minutes. In addition to the activated carbon, a part of the solvent was concentrated under reduced pressure, and ethyl acetate (600 ml) was added, and the product was gradually separated, filtered, and filtered to give the title compound 35 g.
  • the compound Z (5g) was dissolved in 19 ml of absolute ethanol and 0.5 ml of water, and 0.7 ml of concentrated sulfuric acid was added thereto under ice-cooling, and the mixture was heated under reflux for 30 minutes, and then naturally cooled to room temperature, concentrated under reduced pressure to a small volume, and then 30 ml of ethyl acetate was added thereto. The product was precipitated, suction filtered, and the filtrate dried to give 3.5 g.
  • the TGA curve of this Form A was reduced by 3.92% at 60 ° C to 170 ° C, and the TG spectrum is shown in FIG. 2 .
  • the test conditions were as follows: TG analytical instrument: mettler toledo TGA2 thermogravimetric analyzer; test conditions: purge gas, nitrogen 50 ml/min; temperature increase rate: 20 K/min; temperature range: 40 ° C - 300 ° C.
  • Example 5 The title compound (1 g) of Example 5 or 6 was added to ethanol (8 ml), which was dissolved in vacuo, and then cooled to room temperature to gradually precipitate a white solid. Filtration and filtration of EtOAc EtOAc m.
  • Example 5 The title compound (1 g) of Example 5 or 6 was added to ethanol (15 ml), which was dissolved in vacuo, and then isopropyl alcohol (15 ml). Filtration and drying of the filtrate gave 0.7 g of the title compound as crystals.
  • the water solubility of the basic compound of Compound Z is significantly smaller than that of Compound Z, and the water solubility has a significant influence on the preparation of pharmaceutical preparations, oral bioavailability and the like. Therefore, the salt formation of the compound Z is more advantageous for the preparation of a pharmaceutical preparation for human pharmaceutical use.
  • the basic compound of Compound Z forms a salt and masks the original pungent odor, and is more suitable for oral administration.
  • the experimental results show that the pharmacokinetics of the compound Z after salt formation is better than that of the compound of the compound Z, especially the in vivo pharmacokinetics of the compound Z hydrochloride is superior to that of the compound Z.
  • the compound of the formula I obtained after the compound Z is salted improves the water solubility of the compound Z, masks the bad odor of the compound Z, and improves the stability.
  • the hydrochloride salt of compound Z has good physical and chemical properties (good solubility and high stability), high oral bioavailability, and the best comprehensive drug-forming properties, and is more suitable for pharmaceutical preparation applications, and is more suitable for preservation.
  • Example 11 or 12 The crystal form A prepared in Example 11 or 12, the crystal form B prepared in Example 14, and the amorphous form prepared in Example 15 were subjected to measurement of an X-ray powder diffraction pattern, and the data are shown in Tables 4 and 5 and Figs. And 7 are shown.
  • the X-ray powder diffraction pattern was determined as follows:
  • Instrument model Bruker D8 advance, target: Cu K ⁇ (40kV, 40mA), sample to detector distance: 30cm, scanning range: 3°-40° (2 ⁇ value), scanning step: 0.1s.
  • the crystal form A has stable properties and low hygroscopicity, and is a preferred crystal form.

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Abstract

一种苯基嘧啶酮化合物的盐、多晶型物及其药物组合物和用途，具体公开一种如下式(I-A)所示的苯基并嘧啶酮化合物的盐酸盐，及其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形形式，包含它们的药物组合物和药物单元剂型，制备上述物质的方法和它们的用途。

Description

一种苯基嘧啶酮化合物的盐、多晶型物及其药物组合物和用途 技术领域
本发明涉及5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮(化合物Z)的盐及多晶型物，以及含它们的药物组合物，用于制备各种盐及多晶型的方法及其在制备药物组合物中的用途。
发明背景
国际申请案WO2010/066111公开了一系列具有PDE5抑制活性的化合物，在体外酶抑制剂筛选试验中表现出对PDE5酶极高的活性和选择性。其中包括化合物5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮(化合物Z)，其结构式如下：
Figure PCTCN2018093965-appb-000001
发明内容：
本申请的发明人发现，化合物Z在游离态存在水溶性较小的问题，不易溶解，在作为药物制剂应用中对制剂工艺造成了一定的影响；另一方面，该化合物本身带有刺激性气味，在作为人用药物制剂应用时也有一定影响。因此本发明的一个目的是找到化合物Z的适于成药的化合物存在形式，该形式应当具有稳定性好、水溶性高、吸湿性低、无不良气味等优点。
作为药品应用的化合物及其盐、以及其结晶及无定形物的物性对药物的生物利用度、原料药的纯度、制剂的处方等会产生较大影响，因此，在药品开发中，必须研究该化合物的哪种盐、晶型、无定形物作为药品是最好的。即由于上述物性依赖于各种化合物的属性，所以通常情况下很难预测具有良好物性的原药用的盐、晶型、无定形物，因此需要对各化合物进行多种实验研究。
因此，本发明的另一目的在于提供化合物Z的各种盐及它们的结晶及其无定形物，其具有高稳定性、低吸湿性、高纯度、更易于药物加工和配制的优点。
本申请发明人对化合物Z的各种盐、结晶进行合成、分离，并进行各种物理化学性质研究，结果发现了具有良好物性的化合物Z的盐和其结晶、溶剂化物形式，可做为原料药应用或作为用于制造原料药的中间体，从而完成了本发明。
本发明涉及化合物5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮(即化合物Z)的盐，及多晶型物，以及包含它们的药物组合物和药物单元剂型。本发明另外涉及化合物Z的共结晶或复合物，以及包含它们的药物组合物。本发明还涉及制备上述物质的方法。
本发明的一个方面提供一种式(I)所示的化合物及其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物：
Figure PCTCN2018093965-appb-000002
其中，X包括但不限于有机酸或无机酸。例如，所述有机酸包括但不限于马来酸、琥珀酸、柠檬酸、酒石酸、富马酸、甲酸、乙酸、丙酸、丙二酸、草酸、苯甲酸、邻苯二甲酸、甲磺酸、苯磺酸、甲苯磺酸、萘磺酸、1,5-萘二磺酸、樟脑酸、樟脑磺酸、水杨酸、乙酰水杨酸、天门冬氨酸、谷氨酸、乳酸、葡萄糖酸、维C酸、没食子酸、杏仁酸、苹果酸、山梨酸、三氟乙酸、牛磺酸、高牛磺酸、2-羟基乙磺酸、肉桂酸、粘酸；所述无机酸包括但不限于盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、高氯酸；以及其他类似的质子酸。
其中，X优选为马来酸、琥珀酸、柠檬酸、酒石酸、富马酸、粘酸、乙酸、甲磺酸、盐酸、硝酸或硫酸。
X更加优选的是盐酸，即式(I)化合物优选为如下式(I-A)化合物：
Figure PCTCN2018093965-appb-000003
式(I)化合物更优选的是化合物Z的盐酸盐的晶型A和晶型B，所述晶型A在衍射角2θ为9.3°±0.2°、12.2°±0.2°、16.7°±0.2°处具有X-射线衍射峰，更具体地，所述晶型A在衍射角2θ为6.1°±0.2°、9.3°±0.2°、11.1°±0.2°、12.2°±0.2°、15.3°±0.2°、16.7°±0.2°、21.6°±0.2°、22.9°±0.2°处具有X-射线衍射峰，所述晶型A为一水合物，具有如下结构：
Figure PCTCN2018093965-appb-000004
所述晶型B在衍射角2θ为12.5°±0.2°、13.5°±0.2°、17.9°±0.2°、19.5°±0.2°、19.9°±0.2°、23.0°±0.2°、26.5°±0.2°、26.8°±0.2°处具有X-射线衍射峰，更具体地，所述晶型B在衍射角2θ为12.5°±0.2°、12.8°±0.2°、13.5°±0.2°、14.1°±0.2°、17.9°±0.2°、19.5°±0.2°、19.9°±0.2°、23.0°±0.2°、26.5°±0.2°、26.8°±0.2°处具有X-射线衍射峰。最优选所述化合物Z的盐酸盐的晶型A。
本发明还提供了化合物Z的盐酸盐的晶型A的单晶，将晶型A的单个晶体进行单晶X射线衍射分析，X单晶衍射图谱见附图9，其为单斜晶系，空间群Pc，轴长
Figure PCTCN2018093965-appb-000005
晶面夹角α＝90°，β＝106.47(5)°，γ＝90°，体积
Figure PCTCN2018093965-appb-000006
每晶胞的分子数Z＝2。
单晶结构由X射线单晶衍射仪测定，制造商日本理学(日本株式会社 理学(rigaku))；仪器型号：SuperNova,Dual,Cu at zero,AtlasS2。检测温度：100K。
本发明的晶型A包含3.28至5.35wt％的量的水，更具体地说为3.28至3.98wt％的量的水，含水量可以通过卡尔费休法(Karl Fischer method)测量。
本文中所述“盐”，包括药学上可接受的盐，以及药学不可接受的盐。不优选对患者使用药学不可接受的盐，但所述的盐可用于提供药物中间体和散装药物形式。
本文中所述“药学可接受的盐”或“药学可接受的酸加成盐”是指使用药学可接受的酸与化合物Z成盐而制备的盐，包括但不限于有机酸盐和无机酸盐，优选的是马来酸、琥珀酸、柠檬酸、酒石酸、富马酸、粘酸、乙酸、甲磺酸、盐酸、硝酸或硫酸的盐，最优选的是甲磺酸、富马酸、盐酸的盐。
本发明的另一个实施方案涉及包含治疗或预防有效量的式(I)化合物，或其多晶型物、溶剂化物、水合物、共结晶、无水物、或无定形物的药物组合物和剂型。
非必须的，本发明的式(I)化合物的盐放置在空气中或通过重结晶，将会吸收水分产生吸附水形式的水合物，含有这样水分的酸加成盐也包含在本发明中。
本发明所述“溶剂合物”，只要是制造盐以及结晶时使用的溶剂即可，无特殊限定，具体而言，例如可以是水合物、醇合物、丙酮合物、甲苯合物等，优选水合物、醇合物。
本发明的又一个实施方案涉及包含式(I)化合物，或其多晶型物、溶剂化物、水合物、共结晶、无水物、或无定形形式的药物组合物和剂型的制备方法。
具体制备方法如下。
1. 5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐(式I化合物)的制备方法
化合物Z可参照WO2010/066111的实施例制备。化合物Z也可采用如下方法制备：
1)化合物Z-3在碱存在下和硫酸二甲酯发生甲基化反应得到Z-4；
2)化合物Z-4和氨气反应得到Z-5；
3)化合物Z-5和2-乙基-3-氧代戊酸甲酯在碱存在下脱水环合得到化合物Z，
Figure PCTCN2018093965-appb-000007
其中，在上述步骤1)中，反应温度通常在室温～100℃，溶剂优选二氯甲烷、甲苯、氯仿或N,N-二甲基甲酰胺，碱优选碳酸钾或碳酸钠；
在上述步骤2)中，反应温度通常在0℃～50℃，溶剂优选甲醇、乙醇或N,N-二甲基甲酰胺；
在上述步骤3)中，反应温度通常在50～120℃，溶剂优选氯仿、甲醇、乙醇、乙二醇单甲醚、N,N-二甲基甲酰胺或1,4-二氧六环，碱优选碳酸钾、碳酸钠、甲醇钠或乙醇钠。
式(I)化合物可采用相应的酸与化合物Z形成盐而制备得到，例如，采用如下方法之一：
方法一：
1)化合物Z溶于甲溶剂，配成溶液a；
2)相应的酸X溶于乙溶剂，配成溶液b；
3)将溶液a加入溶液b，或将溶液b加入溶液a，制得混合溶液，从混合溶液中分离得到化合物Z的盐(即式I化合物)；
方法二：
1)化合物Z溶于甲溶剂，配成溶液a；
2)直接在溶液a中加入相应的酸X，再从溶液中分离得到化合物Z的盐(即式I化合物)；
方法三：
1)将相应的酸X溶于乙溶剂，配成溶液b；
2)将化合物Z直接加入到溶液b中，再从溶液中分离得到化合物Z的盐(即式I化合物)；
优选的，式(I-A)化合物可采用氯化氢与化合物Z形成盐而制备得到，例如，采用如下方法之一：
方法一：
1)化合物Z溶于甲溶剂，配成溶液a；
2)氯化氢溶于乙溶剂，配成溶液b；
3)将溶液a加入溶液b，或将溶液b加入溶液a，制得混合溶液，从混合溶液中分离得到化合物Z的盐酸盐(即式(I-A)化合物)；
方法二：
1)化合物Z溶于甲溶剂，配成溶液a；
2)直接在溶液a中加入相应的氯化氢，再从溶液中分离得到化合物Z的盐酸盐(即式(I-A)化合物)；
方法三：
1)将氯化氢溶于乙溶剂，配成溶液b；
2)将化合物Z直接加入到溶液b中，再从溶液中分离得到化合物Z的盐酸盐(即式(I-A)化合物)。
上述方法中，所述甲、乙溶剂可以各自独立地选自水、非水溶剂及其混合溶剂，更具体地，选自水、醇类、醚类、酯类、烃类、酮类及其混合溶剂等。更特别地，所述甲溶剂、乙溶剂各自独立地为选自水；酯类(例如乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯；醇类(例如甲醇、乙醇、丙醇、异丙醇、丁醇、乙二醇、丙二醇)；醚类(例如：乙醚、丙醚、异丙醚、石油醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇单丙醚、乙二醇二甲醚、乙二醇二乙醚、丙二醇单甲醚、丙二醇单乙醚、丙二醇二甲醚、四氢呋喃、二氧六环、二甲氧基乙烷、二甘醇二甲醚)；酮类(例如：丙酮、丁酮、N-甲基吡咯烷酮、二乙基甲酮)；烃类(例如：正戊烷、正己烷、庚烷、)，芳烃类(例如：甲苯、苯、二甲苯、氯苯、二氯苯)；卤代烷类(例如：二氯甲烷、氯仿或1,2－二氯乙烷、四氯化碳)；酸类(乙酸、丙酸)；腈类(例如：乙腈、丙腈)中的一种或多种；
所述相应的酸的定义与式(I)中X的定义相同。
反应温度随试剂或溶剂等的变化而变化，通常在-20℃到200℃，优选0℃到100℃。
反应时间不限，通常是10分钟～10小时。
所述氯化氢可以以气体形式存在，也可以以含水或非水溶剂形式存在，如盐酸、氯化氢甲醇溶液、氯化氢乙醇溶液。
2.化合物Z盐(式I化合物)的多种晶型的制备方法
本发明另一方面还提供了化合物Z的盐(即式I化合物)的多晶型物以及它们的制备方法。在所述方法中可以根据需要添加晶种。此处晶种指 式(I)化合物或自制的式(I)化合物晶体物质的“种子”，用来诱导结晶。
化合物Z的盐(即式I化合物)的多晶型物可以采用如下方法之一制备：
方法一：
1)将碱式的化合物Z溶于丙溶剂，配成溶液C；
2)相应的酸X溶于丁溶剂，配成溶液D；
3)将溶液C加入溶液D，或将溶液D加入溶液C，或者直接在溶液C中加入相应的酸X，制得混合溶液E；
4)非必需地，在混合溶液E中可加入戊溶剂；
5)静置使目标物析出，或搅拌使目标物析出，或向步骤4)制备的溶液中加入相应的晶种使其析出；
方法二：
1)化合物Z盐(即式(I)化合物)溶于丙溶剂，配成溶液F；
2)非必需地，在溶液F中可加入戊溶剂；
3)静置使目标物缓慢析出，或搅拌使目标物析出，或向步骤2)制备的溶液中加入相应的晶种使其析出；
方法三：
1)化合物Z盐(即式(I)化合物)悬浮于丙溶剂，配成混悬液G；
2)非必需地，在溶液G中可加入戊溶剂；
3)加热、搅拌，放冷使目标物析出，或向步骤2)制备的溶液中加入晶种使其析出；
优选的，式(I-A)所示的化合物的多晶型物可以采用如下方法之一制备：
方法一：
1)将碱式的化合物Z溶于丙溶剂，配成溶液C；
2)氯化氢溶于丁溶剂，配成溶液D；
3)将溶液C加入溶液D，或将溶液D加入溶液C，或者直接在溶液C中加入氯化氢，制得混合溶液E；
4)非必需地，在混合溶液E中可加入戊溶剂；
5)静置使目标物析出，或搅拌使目标物析出，或向步骤4)制备的溶液中加入相应的晶种使其析出；
方法二：
1)式(I-A)所示的化合物溶于丙溶剂，配成溶液F；
2)非必需地，在溶液F中可加入戊溶剂；
3)静置使目标物缓慢析出，或搅拌使目标物析出，或向步骤2)制备的溶液中加入相应的晶种使其析出；
方法三：
1)式(I-A)所示的化合物悬浮于丙溶剂，配成混悬液G；
2)非必需地，在溶液G中可加入戊溶剂；
3)加热、搅拌，放冷使目标物析出，或向步骤2)制备的溶液中加入晶种使其析出；
其中，所述丙溶剂、丁溶剂、戊溶剂可相同也可不同，且溶剂丙、丁和戊的定义与上述甲、乙溶剂的定义相同，所述温度范围与制备化合物Z的盐(即式I化合物)的温度范围相同。
特别的，所述的化合物Z的盐酸盐的晶型A的优选制备方法如下：
将化合物Z加入醇中，加入盐酸，加热，非必需地加入活性碳脱色，将得到的滤液加入酯，静置或搅拌，即有固体析出，再分离，得到式(I-A)化合物的晶型A。
特别的，所述的化合物Z的盐酸盐的晶型A的优选制备方法如下：
将化合物Z盐酸盐加入醇中，加热溶解，冷却析出固体，分离即得化合物Z盐酸盐的晶型A。
特别的，所述的化合物Z的盐酸盐的晶型A的优选制备方法如下：
将化合物Z盐酸盐加入醇和酯混合体系中，加热溶解，冷却析出固体，分离即得化合物Z盐酸盐的晶型A。
所述醇优选为C1-C4直链或支链烷醇，例如甲醇、乙醇、异丙醇；所述醇更优选为乙醇。
所述酯包括但不限于乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯；所述酯更优选为乙酸乙酯。
3.化合物Z盐(式I化合物)的表征
一般情况下，粉末X射线衍射中的衍射角度(2θ)可以在±0.2°的范围内产生误差，因此下述衍射角度的值应当理解为也包含±0.2°左右的范围内的数值。所以，本发明不仅包括与粉末X射线衍射谱图中的峰(衍射角度)完全一致的结晶，还包括以±0.2°左右的误差与峰(衍射角度)一致的结晶。
(1)化合物Z盐酸盐的晶型A的表征
本发明提供了化合物Z盐酸盐的晶型A，其为一水合物。
化合物Z盐酸盐的晶型A的X-射线粉末衍射数据如下：以2θ角度表示X-射线粉末衍射，其中该晶型在6.1°±0.2°、9.3°±0.2°、11.1°±0.2°、12.2°±0.2°、15.3°±0.2°、16.7°±0.2°、21.6°±0.2°、22.9°±0.2°处有衍射峰。
将晶型A的单个晶体进行单晶X射线衍射分析，X单晶衍射图谱显示晶型A含有一分子结合水。该晶型A在通过溴化钾压片法测量的红外吸收光谱中，至少约在3482.81cm -1、3405.67cm -1、3293.82cm -1、3046.98cm -1、2967.91cm -1、2871.49cm -1、1656.55cm -1、1604.48cm -1、1579.41cm -1、1494.56cm -1、1226.50cm -1、973.88cm -1、813.81cm -1处具有特征峰。
该晶型A在拉曼光谱中，至少约在3163.21cm -1、2961.12cm -1、2932.78cm -1、1662.17cm -1、1620.11cm -1、1606.17cm -1、1561.04cm -1、1542.89cm -1、1422.64cm -1、1292.54cm -1、1267.48cm -1、1244.31cm -1、1224.67cm -1、854.02cm -1、825.78cm -1处具有特征峰。
(2)化合物Z盐酸盐的晶型B的表征
本发明还提供了化合物Z盐酸盐的晶型B。
化合物Z盐酸盐的晶型B的DSC测得其在211.36℃处有吸热峰，谱图数据如下：
初始值(Onset)＝211.36±3℃，峰值(Peak)＝214.03±3℃
DSC测定条件如下：
仪器型号：Perkin Elmer DSC 8500，温度范围：50-280℃，扫描速率：10℃/min，氮气流速：50ml/min。
化合物Z盐酸盐的晶型B的X-射线粉末衍射数据如下：以2θ角度表示X-射线粉末衍射，其中该晶型在12.5°±0.2°、12.8°±0.2°、13.5°±0.2°、14.1°±0.2°、17.9°±0.2°、19.5°±0.2°、19.9°±0.2°、23.0°±0.2°、26.5°±0.2°、26.8°±0.2°处有衍射峰。
该晶型B在拉曼光谱中，至少约在3163.44cm -1、2965.94cm -1、2927.45cm -1、2877.46cm -1、1689.06cm -1、1617.18cm -1、1600.94cm -1、1552.40cm -1、1537.62cm -1、1404.60cm -1、1242.62cm -1、657.62cm -1处具有特征峰。
(3)化合物Z盐酸盐的无定形形式的表征
本发明还提供了化合物Z盐酸盐的无定形形式，其X-射线粉末衍射图 基本如附图7所示。
因此，另一方面，本发明提供包含一种或多种式(I)所示的化合物以及药学上可接受的辅料的药物组合物，优选地，是含有选自化合物Z的马来酸盐、琥珀酸盐、甲磺酸盐、柠檬酸盐、盐酸盐、酒石酸盐、富马酸盐、粘酸盐、乙酸盐和硫酸盐中的一种或多种的药物组合物，更优选地，是含有具有表1所列X-射线粉末衍射图谱的化合物Z盐酸盐的晶型A的药物组合物。
所述辅料可以为医药领域中通常使用的赋形剂、粘合剂、润滑剂、崩解剂、着色剂、矫味矫嗅剂、乳化剂、表面活性剂、助溶剂、悬浮剂、等渗剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、吸收促进剂等，也可根据需要适当组合上述添加剂进行使用。
优选的，本发明的化合物Z的盐在口服药物组合物中与至少一种药物赋形剂混合进行配制，每剂量含10mg～200mg活性成分。
当制备一种片剂型的固体组合物时，将主要活性成分组分与一种药物载体，例如淀粉、乳糖、硬脂酸镁等混合，可以给药片裹糖衣或其他适宜的物质，或者将其进行处理使得药片具有延长或减缓的作用，以及使得该药片以连续方式释放预定量的活性成分。
或者将活性成分与一种稀释剂混合，并将所得混合物装入胶囊中获得一种胶囊剂。
本发明的化合物Z的酸加成盐(即式I化合物)，在作为上述疾病的治疗药物或预防药物使用时，可以将其本身或与适宜的药理学上可接受的赋形剂、稀释剂等混合，以片剂、胶囊剂、颗粒剂、散剂或糖浆剂等经口给药或者以注射剂、粉针剂、喷剂或栓剂等非口服方式给药。
这些制剂可通过常规方法制备。
药物的使用量随症状、年龄等不同而不同，以成年人为例，可以每1～7日根据症状给药1～7次，给药量0.01mg～1000mg，给药方式不限。
本发明的又一方面提供上述式(I)所示的化合物在制备用于预防或治疗与PDE5酶相关的疾病的药物中的用途。所述与PDE5酶相关的疾病为勃起功能障碍、肺动脉高压、雌性的性功能障碍、早产、痛经、良性前列腺增生、膀胱出口梗阻、失禁、不稳定的和变异型心绞痛、高血压、充血性心衰、肾衰竭、动脉粥样硬化、中风、周围血管疾病、雷诺氏症、炎症性疾病、支气管炎、慢性哮喘、过敏性哮喘、过敏性鼻炎、青光眼或者特征为肠蠕动障碍的疾病等。
附图说明：
图1式(I-A)化合物晶型A的X-射线粉末衍射图；
图2式(I-A)化合物晶型A的热重分析图；
图3式(I-A)化合物晶型A的红外光谱图；
图4式(I-A)化合物晶型B的X-射线粉末衍射图；
图5式(I-A)化合物晶型B的差示扫描量热分析图；
图6式(I-A)化合物晶型B的红外光谱图；
图7式(I-A)化合物无定形态的X-射线粉末衍射图；
图8化合物Z及其不同盐给药后血药浓度-时间曲线图；
图9式(I-A)化合物晶型A的X-射线单晶衍射结构；
图10式(I-A)化合物晶型A的拉曼光谱图；
图11式(I-A)化合物晶型B的拉曼光谱图。
发明效果：
本发明提供的化合物Z的盐具有稳定性高、水溶性改善、无不良气味等优点。
本发明提供的化合物Z的不同盐的多种晶型具有吸湿性小、化学稳定性好、纯度高、组成恒定、制备方法简单且易重复、样品易贮存等优点。
具体实施方式
通过以下实施例进一步说明本发明，以下实施例仅用于更具体说明本发明的优选实施方式，不用于对本发明的技术方案进行限定。以下实施例所采用温度和试剂，均可用上文所述相应温度和试剂替代以实现本发明的目的。
下述实施例中，元素分析用Elementar Vario EL仪测定；质谱用MAT-95型质谱仪(Finnigan公司)测定；核磁共振谱在Mercury-300和Mercury-400核磁共振仪(Varian公司)上测定；红外吸收光谱测试仪器：美国Nicolet Magna FTIR 6700型付立叶变换红外光谱仪。拉曼光谱测试仪器：Thermo Scientific DXR Raman Microscope。所述红外和拉曼光谱波数(cm -1)可能含有-0.5至+0.5％的误差，但这种水平的误差在本发明中处于可接受的范围内。
实施例1：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮马来酸盐的制备
取化合物Z(5g,0.01mol)悬浮于50ml无水乙醇中，加热至65℃样品溶解，加入马来酸(1.16g,0.01mol)，65℃温度下加热40分钟，稍冷加入活性碳，维持该温度下30分钟，滤除活性炭，将得到的滤液于室温下搅拌30分钟，有固体析出，过滤，滤物干燥4小时，得白色固体的标题化合物(4g)，纯度99％(HPLC)。
实施例2：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮琥珀酸盐的制备
取化合物Z(5g,0.01mol)悬浮于30ml无水乙醇中，加热至65℃样品溶解，加入琥珀酸(1.18g,0.01mol),65℃温度下搅拌40分钟，稍冷加入活性碳脱色，滤除活性炭，将滤液于室温下搅拌30分钟，析出固体，过滤，滤物干燥，得白色固体的标题化合物(3g)，纯度>99％(HPLC)。
实施例3：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮富马酸盐的制备
取化合物Z(5g,0.01mol)悬浮于30ml无水乙醇中，加热至65℃样品溶解，加入富马酸(1.16g,0.01mol),65℃温度下搅拌40分钟，稍冷加入活性碳脱色，滤除活性炭，将滤液于室温下搅拌30分钟，析出固体，过滤，滤物干燥，得白色固体的标题化合物(3g)，纯度>99％(HPLC)。
实施例4：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮醋酸盐的制备
取化合物Z(5g,0.01mol)悬浮于30ml无水乙醇中，加热至65℃样品溶解，加入醋酸(0.6g,0.01mol),65℃温度下搅拌40分钟，稍冷加入活性碳脱色，滤除活性炭，将滤液于室温下搅拌30分钟，析出固体，过滤，滤物干燥，得白色固体的标题化合物(3g)，纯度>99％(HPLC)。
实施例5：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮甲磺酸盐的制备
取化合物Z(5g,0.01mol)悬浮于40ml无水乙醇中，冰浴下加入甲磺酸1ml，加毕，升温至60～70℃，搅拌30分钟，活性碳脱色，滤除活性炭，滤液减压浓缩至小体积，加入乙酸乙酯80ml，搅拌，逐渐析出产物，抽滤，滤物干燥，得标题化合物4.4g。
实施例6：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮酒石酸盐的制备
取化合物Z(5g,0.01mol)溶于25ml无水乙醇中，加入酒石酸1.5克，加热至60～70℃搅拌反应30分钟，放冷至室温，搅拌过夜，析出白色固 体，过滤，滤物干燥，得标题化合物4g。
实施例7：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮粘酸盐的制备
取化合物Z(5g,0.01mol)溶于25ml无水乙醇中，加入粘酸2.1克，加热至60～70℃搅拌反应30分钟，放冷至室温，搅拌过夜，析出白色固体，过滤，滤物干燥，得标题化合物4g。
实施例8：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐酸盐的制备
取化合物Z(51g,0.11mol)，加入乙腈(200ml)，冰浴下加入浓盐酸10.5ml，滴完后加热回流1小时，活性碳脱色，过滤，滤液冷至室温，浓缩至小体积，搅拌下逐渐析出产物。过滤，滤物干燥，得白色固体的标题化合物50克。高效液相检测，纯度>99％。ESI-MS:442(M+1)。 1H NMR(400MHz,DMSO-d 6)δ0.96(t,3H),1.03(t,3H),1.19(t,3H),1.72(m,2H),2.45(q,2H),2.56(q,2H),2.65-2.75(br,5H),2.90-3.03(br,2H),3.03-3.17(br,2H),3.25(s,2H),3.30-3.40(br,2H),4.01(t,2H),7.13(d,1H),7.79(dd,1H),8.00(d,1H),10.02(s,1H),10.86(br,1H),11.84(s,1H). 13C NMR(100MHz,DMSO-d 6)δ167.54,163.31,161.53,152.70,152.40,131.75,123.75,123.07,121.57,121.35,113.21,70.11,60.07,52.27,49.11,42.03,26.93,21.95,18.01,13.37,13.09,10.37.
元素分析：
  C(％) H(％) N(％) Cl(％)
实测值 58.36 7.68 14.19 7.63
理论值 58.11 7.72 14.12 7.15
实施例9：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐酸盐的制备
取化合物Z(51g,0.11mol)悬浮于400ml无水乙醇与10ml水的混合溶剂中，冰浴下加入浓盐酸11ml，滴完后60℃加热30分钟，加入活性碳，加热搅拌30分钟，滤除活性碳，减压浓缩部分溶剂，加入600ml乙酸乙酯，逐渐析出产物，抽滤，滤物干燥，得标题化合物35g。
实施例10：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮硫酸盐的制备
取化合物Z(5g)溶于19ml无水乙醇与0.5ml水中，冰浴下加入浓硫酸0.7ml，加热回流30分钟，自然降温至室温，减压浓缩至小体积，加入30ml 乙酸乙酯，逐渐析出产物，抽滤，滤物干燥，得产品3.5g。
实施例11：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐酸盐一水合物的制备(晶型A)
将化合物Z(51g,0.11mol)加入400ml无水乙醇中，加入浓盐酸11ml，滴完后60℃加热30分钟，加入活性炭，加热搅拌30分钟，滤除活性炭，滤液中加入600ml乙酸乙酯搅拌，逐渐析出产物，抽滤，滤物干燥，得标题化合物30g。
该晶型A的TGA曲线在60℃～170℃减重3.92％，TG谱见附图2。测试条件如下：TG分析仪器：mettler toledo TGA2热重分析仪；测试条件：吹扫气，氮气50ml/min；升温速度：20K/min；温度范围：40℃-300℃。
实施例12：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐酸盐一水合物的制备(晶型A)
将实施例5或6的标题化合物(1克)，加入乙醇(8ml)，加热溶解，自然冷至室温，逐渐析出白色固体。过滤，滤物干燥，得白色固体的标题化合物0.6克。
实施例13：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐酸盐一水合物的制备(晶型A)
将实施例5或6的标题化合物(1克)，加入乙醇(4ml)和乙酸乙酯(5ml)，加热溶解，自然冷至室温，逐渐析出白色固体。过滤，滤物干燥，得白色固体的标题化合物0.85克。
实施例14：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐酸盐的制备(晶型B)
将实施例5或6的标题化合物(1克)，加入乙醇(15ml)，加热溶解，再加入异丙醇(15ml)，自然冷至室温，逐渐析出白色固体。过滤，滤物干燥，得颗粒状晶体的标题化合物0.7克。
实施例15：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮盐酸盐的制备(无定形)
将实施例5或6的标题化合物(200mg)，加入氯仿(10ml)，室温搅拌，缓慢挥发，析出白色固体，过滤，滤物干燥，得片状固体的标题化合物0.15克。
实施例16：5,6-二乙基-2-[2-正丙氧基-5-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基]嘧啶-4(3H)-酮(化合物Z)的制备
Figure PCTCN2018093965-appb-000008
向100ml单颈瓶中加入甲醇(60ml)和化合物Z-1(10g)，氮气置换空气5次，加入活性镍0.3g，用氢气置换氮气5次，室温搅拌12小时，反应完全后过滤除去活性镍，减压浓缩滤液得到化合物Z-2(8g)，收率92％。
将化合物Z-2(1.94g，10mmol)加入至20ml二氯甲烷中，加入4-甲基-1-哌嗪乙酸(1.58g，10mmol)和N,N'-羰基二咪唑(1.94g，12mmol)，室温搅拌8小时，反应完毕，向反应体系中加入10ml水，搅拌，静置分层，有机相浓缩至干，得到化合物Z-3(2.34g)，收率70％。
将化合物Z-3(334g，1mol)加入至N,N-二甲基甲酰胺(1L)中，搅拌，加入碳酸钾(276g，2mol)和硫酸二甲酯(126g，1mol)，升温至40-50℃，搅拌12小时后，减压浓缩，得到残余物，加入1L水，室温搅拌，过滤得到260g化合物Z-4，类白色固体，收率75％。ESI-MS:349(M+1)。
将化合物Z-4(348g，1mol)溶于甲醇(1L)中，搅拌，升温至50℃，缓慢通入氨气，反应结束后，减压浓缩得到残余物，用甲基叔丁基醚结晶纯化得到198g化合物Z-5，收率59％。ESI-MS:334(M+1)。
将化合物Z-5(333g，1mol)溶于甲醇(2L)中，加入甲醇钠(54g，1mol)和2-乙基-3-氧代戊酸甲酯(158g，1mol)，加热至回流，保持回流12小时，冷却至室温，加入稀盐酸调节pH值至7，减压浓缩除去甲醇，加入乙酸乙酯萃取，静置分层，有机相浓缩至干得到410g化合物Z，收率93％。ESI-MS:442(M+1)。 1H NMR(400MHz,CDCl 3)δ1.12(t,6H),1.30(t,3H),1.96(m,2H),2.56(q,2H),2.67(q,2H),2.31(br,3H),2.45-2.55(br,4H),2.60-2.70(br,4H),3.14(s,2H),4.13(t,2H),6.99(d,1H),7.97(dd,1H),8.26 (d,1H),9.11(s,1H),11.14(br,1H). 13C NMR(100MHz,CDCl 3)δ167.99,163.87,161.74,153.41,150.78,131.23,124.33,123.93,121.31,119.23,113.06,70.95,61.37,54.76,53.05,45.57,27.17,21.97,18.24,12.93,12.65,10.16.
元素分析：
  C(％) H(％) N(％)
实测值 65.68 7.80 15.89
理论值 65.28 7.99 15.86
实验例
1.化合物Z的盐(即式I化合物)的优越性
(1)化合物溶解性的比较
选取实施例16制备的化合物Z与实施例1-7、9-10制备的化合物Z的不同盐，比较其溶解度。称取适量样品于玻璃样试管中，逐步递增加入选定的溶媒，观察澄清情况。测定了各种酸盐在pH为2、4.5、6.8和去离子水中的溶解度，结果如下：
表1不同pH值下的溶解度(mg/mL)
  水 pH＝2 pH＝4.5 pH＝6.8
化合物Z 1.5 5.3 38.1 1.7
化合物Z盐酸盐 >25.0 >22.8 >23.6 >26.6
化合物Z富马酸盐 >26.6 >24.2 >20.2 >27.0
化合物Z琥珀酸盐 >24.8 >20.8 >22.0 >20.8
化合物Z甲磺酸盐 >23.8 >22.4 >25.4 >23.2
化合物Z硫酸盐 >20.6 >20.2 >25.6 >24.4
化合物Z酒石酸盐 >153.2 >218.7 >155.4 >130.5
化合物Z粘酸盐 10.6 36.3 62.7 39.0
化合物Z醋酸盐 14.0 35.8 >101.8 22.6
化合物Z马来酸盐 5.8 6.1 21.4 46.4
由上表可见，化合物Z的碱式化合物的水溶性明显小于化合物Z的盐，而水溶性大小在制备药物制剂、口服生物利用度等方面具有举足轻重的影响。因此，将化合物Z成盐更有利于制成药物制剂用于人用药物用途。
(2)化合物外观、性状比较
选取实施例16制备的化合物Z的碱式化合物与实施例1-2，5-6，9制备的化合物Z的不同盐，比较了其外观性状，结果见下表：
表2化合物Z各种盐的外观、性状比较
  性状 气味
化合物Z 白色固体 有刺激性气味
化合物Z的马来酸盐 白色固体 无不良气味
化合物Z的盐酸盐 白色固体 无不良气味
化合物Z的琥珀酸盐 白色固体 无不良气味
化合物Z的甲磺酸盐 白色固体 无不良气味
化合物Z的酒石酸盐 白色固体 无不良气味
由上表可见，化合物Z的碱式化合物成盐后掩蔽了原有的刺激性气味，更适于口服给药。
(3)化合物稳定性的比较
选用实施例16制备的化合物Z的碱式化合物与实施例5、9和10制备的化合物Z的盐，采用影响因素试验，进行化学稳定性的比较，结果见下表:
表3化合物Z及其盐的稳定性试验结果：
Figure PCTCN2018093965-appb-000009
Figure PCTCN2018093965-appb-000010
由上表的影响因素比较试验结果可见，化合物Z的盐，尤其是盐酸盐在高温、光照、高湿条件下均很稳定，而化合物Z的稳定性相对较差，尤其是光照10天条件下，纯度明显下降。
(4)药代动力学性质的比较
将实施例16制备的化合物Z的碱式化合物、实施例9制备的化合物Z盐酸盐、实施例2制备的化合物Z琥珀酸盐、实施例3制备的化合物Z富马酸盐进行了大鼠体内药代动力学实验(灌胃给药，剂量3mg/kg)，结果示于说明书附图8。
实验结果表明，化合物Z成盐后的大鼠体内药代动力学性质与化合物Z的碱式化合物相比更优，尤其化合物Z盐酸盐的体内药代动力学性质明显优于化合物Z。
从上述实验结果可以看出，化合物Z成盐后得到的式I化合物，改善了化合物Z的水溶性，掩蔽了化合物Z的不良气味，提高了稳定性。尤其是化合物Z的盐酸盐，理化性质好(溶解性好、稳定性高)，口服生物利用度高，综合成药性最好，更适于制成药物制剂应用，也更适于保存。
2、化合物Z盐酸盐的晶型A和B的X-射线粉末衍射图谱
用实施例11或12制备的晶型A、实施例14制备的晶型B和实施例15制备的无定形进行X-射线粉末衍射图谱的测定，数据如表4和5以及附图1、4和7所示。
X-射线粉末衍射图谱测定条件如下：
仪器型号：Bruker D8 advance，靶：Cu Kα(40kV，40mA)，样品到检测器距离：30cm，扫描范围：3°-40°(2θ值)，扫描步径：0.1s。
表4：化合物Z盐酸盐的晶型A的X-射线粉末衍射数据
衍射角度(2θ，°) 强度(I/I 0，％)
6.122 15.3
9.295 54.8
11.103 17.2
11.743 4.0
12.198 100.0
15.331 29.5
16.717 33.9
19.584 14.4
20.127 3.0
21.610 15.7
22.934 16.4
23.739 6.1
24.496 9.5
25.418 6.3
25.957 5.1
26.217 9.1
26.499 8.7
32.136 5.9
表5：化合物Z盐酸盐的晶型B的X-射线粉末衍射数据
衍射角度(2θ，°) 强度(I/I 0，％)
8.079 11.3
9.918 19.3
10.239 6.5
12.521 46.4
12.844 30.2
13.321 17.9
13.54 43.6
14.177 14.2
15.642 20.8
17.339 3.9
17.942 35.8
19.523 54.7
19.919 48.7
23.058 100
24.905 14.7
26.562 49
26.859 34.9
28.24 10.8
29.942 25.6
32.121 16
35.638 7.4
38.518 9.7
39.161 24.2
39.74 8.9
3.化合物Z盐酸盐的晶型A的优越性
用实施例11或12制备的晶型A、实施例14制备的晶型B和实施例15制备的无定形进行性能比较，结果见下表6。
表6化合物Z盐酸盐各种固体形态的性能比较
Figure PCTCN2018093965-appb-000011
由上表可见，晶型A性能稳定，吸湿性小，为优选晶型。

Claims (13)

  1. 一种如下式(I-A)所示的化合物或其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物：
    Figure PCTCN2018093965-appb-100001
  2. 根据权利要求1所述的式(I-A)所示的化合物或其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物，其为晶型A，所述晶型A在衍射角2θ为9.3°±0.2°、12.2°±0.2°、16.7°±0.2°处具有X-射线衍射峰；或者
    其为晶型B，所述晶型B在衍射角2θ为12.5°±0.2°、13.5°±0.2°、17.9°±0.2°、19.5°±0.2°、19.9°±0.2°、23.0°±0.2°、26.5°±0.2°、26.8°±0.2°处具有X-射线衍射峰；或者
    其为无定形物，所述无定形物表现出大致如图7所示的X-射线粉末衍射图谱。
  3. 根据权利要求2所述的式(I-A)所示的化合物或其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物，其特征在于，所述晶型A在衍射角2θ为6.1°±0.2°、9.3°±0.2°、11.1°±0.2°、12.2°±0.2°、15.3°±0.2°、16.7°±0.2°、21.6°±0.2°、22.9°±0.2°处具有X-射线衍射峰。
  4. 根据权利要求2所述的式(I-A)所示的化合物或其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物，其特征在于，所述晶型A在通过溴化钾压片法测量的红外吸收光谱中，至少在3482.81cm -1、3405.67cm -1、3293.82cm -1、3046.98cm -1、2967.91cm -1、2871.49cm -1、1656.55cm -1、1604.48cm -1、1579.41cm -1、1494.56cm -1、1226.50cm -1、973.88cm -1和813.81cm -1处有特征峰。
  5. 根据权利要求2所述的式(I-A)所示的化合物或其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物，其特征在于， 所述晶型A的单晶为单斜晶系，空间群Pc，轴长
    Figure PCTCN2018093965-appb-100002
    Figure PCTCN2018093965-appb-100003
    晶面夹角α＝90°，β＝106.47(5)°，γ＝90°。
  6. 一种权利要求1中所述的式(I-A)所示的化合物的制备方法，该方法包括：使化合物Z和氯化氢反应制备得到式(I-A)所示的化合物：
    Figure PCTCN2018093965-appb-100004
    优选地，按如下方法之一进行制备：
    方法一：
    1)将化合物Z溶于甲溶剂中，配成溶液a；
    2)将氯化氢溶于乙溶剂，配成溶液b；
    3)将溶液a加入溶液b，或将溶液b加入溶液a，制得混合溶液，从混合溶液中分离得到式(I-A)所示的化合物；
    方法二：
    1)将化合物Z溶于甲溶剂，配成溶液a；
    2)直接在溶液a中加入氯化氢，再从溶液中分离得到式(I-A)所示的化合物；
    方法三：
    1)将氯化氢溶于乙溶剂，配成溶液b；
    2)将化合物Z直接加入到溶液b中，再从溶液中分离得到式(I-A)所示的化合物；
    其中，所述甲、乙溶剂各自独立地为选自水和非水溶剂中的一种或多种。
  7. 根据权利要求6所述的制备方法，所述化合物Z采用如下方法制备：
    1)化合物Z-3在碱存在下和硫酸二甲酯发生甲基化反应得到Z-4；
    2)化合物Z-4和氨气反应得到Z-5；
    3)化合物Z-5和2-乙基-3-氧代戊酸甲酯在碱存在下脱水环合得到化合物Z
    Figure PCTCN2018093965-appb-100005
  8. 一种权利要求1中所述的式(I-A)所示的化合物的多晶型物的制备方法，其中按如下方法之一进行制备：
    方法一：
    1)将碱式的化合物Z溶于丙溶剂，配成溶液C；
    2)氯化氢溶于丁溶剂，配成溶液D；
    3)将溶液C加入溶液D，或将溶液D加入溶液C，或者直接在溶液C中加入氯化氢，制得混合溶液E；
    4)非必需地，在混合溶液E中可加入戊溶剂；
    5)静置使目标物析出，或搅拌使目标物析出，或向步骤4)制备的溶液中加入相应的晶种使其析出；
    方法二：
    1)将式(I-A)所示的化合物溶于丙溶剂，配成溶液F；
    2)非必需地，在溶液F中可加入戊溶剂；
    3)静置使目标物缓慢析出，或搅拌使目标物析出，或向步骤2)制备的溶液中加入相应的晶种使其析出；
    方法三：
    1)将式(I-A)所示的化合物悬浮于丙溶剂，配成混悬液G；2)非必需地，在溶液G中可加入戊溶剂；
    3)加热、搅拌，放冷使目标物析出，或向步骤2)制备的溶液中加入相应的晶种使其析出；
    所述丙、丁、戊溶剂各自独立地为选自水和非水溶剂中的一种或多种。
  9. 根据权利要求6或8所述的制备方法，所述非水溶剂为选自乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸丁酯、甲醇、乙醇、丙醇、异丙醇、丁醇、乙二醇、丙二醇、乙醚、丙醚、异丙醚、石油醚、乙二醇单甲醚、乙二醇单乙醚、乙二醇单丙醚、乙二醇二甲醚、乙二醇二乙醚、丙二醇单甲醚、丙二醇单乙醚、丙二醇二 甲醚、四氢呋喃、二氧六环、二甲氧基乙烷、二甘醇二甲醚、丙酮、丁酮、N-甲基吡咯烷酮、二乙基甲酮、正戊烷、正己烷、庚烷、甲苯、苯、二甲苯、氯苯、二氯苯、二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳、乙酸、丙酸、乙腈和丙腈中的一种或多种。
  10. 根据权利要求2中所述的晶型A的制备方法，其为如下方法之一：
    方法一，包括：将化合物Z加入醇中，加入盐酸，加热，非必需地加入活性炭脱色，将得到的滤液加入酯，静置或搅拌，即有固体析出，再分离，得到式(I-A)化合物的晶型A；
    方法二，包括：将化合物Z盐酸盐加入醇中，加热溶解，冷却析出固体，分离即得化合物Z盐酸盐的晶型A；
    方法三，包括：将化合物Z盐酸盐加入醇和酯混合体系中，加热溶解，冷却析出固体，分离即得化合物Z盐酸盐的晶型A。
  11. 一种药物组合物，其包含根据权利要求1或2所述的化合物或其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物，和药学上可接受的辅料。
  12. 根据权利要求1或2所述的化合物或其药学上可接受的多晶型物、溶剂化物、水合物、共结晶、无水物或无定形物在制备用于预防或治疗与PDE5酶相关的疾病的药物中的用途。
  13. 根据权利要求12所述的用途，所述与PDE5酶相关的疾病为勃起功能障碍、肺动脉高压、雌性的性功能障碍、早产、痛经、良性前列腺增生、膀胱出口梗阻、失禁、不稳定的和变异型心绞痛、高血压、充血性心衰、肾衰竭、动脉粥样硬化、中风、周围血管疾病、雷诺氏症、炎症性疾病、支气管炎、慢性哮喘、过敏性哮喘、过敏性鼻炎、青光眼或者特征为肠蠕动障碍的疾病。
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