WO2016095650A1 - 盐酸优克那非的多晶型物及其制备方法、组合物和用途 - Google Patents

盐酸优克那非的多晶型物及其制备方法、组合物和用途 Download PDF

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WO2016095650A1
WO2016095650A1 PCT/CN2015/095059 CN2015095059W WO2016095650A1 WO 2016095650 A1 WO2016095650 A1 WO 2016095650A1 CN 2015095059 W CN2015095059 W CN 2015095059W WO 2016095650 A1 WO2016095650 A1 WO 2016095650A1
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polymorph
hydrochloride
eugenafil
preparation
organic solvent
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PCT/CN2015/095059
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English (en)
French (fr)
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张海波
陈令武
路显锋
梁慧兴
王永峰
施连勇
骆宏鹏
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扬子江药业集团有限公司
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Priority to KR1020177015107A priority Critical patent/KR102003847B1/ko
Priority to ES15869159T priority patent/ES2918948T3/es
Priority to RU2017120508A priority patent/RU2672249C9/ru
Priority to PL15869159.2T priority patent/PL3216791T3/pl
Priority to JP2017531776A priority patent/JP6473820B2/ja
Priority to US15/535,502 priority patent/US9884870B2/en
Priority to CA2971484A priority patent/CA2971484C/en
Priority to EP15869159.2A priority patent/EP3216791B1/en
Priority to DK15869159.2T priority patent/DK3216791T3/da
Publication of WO2016095650A1 publication Critical patent/WO2016095650A1/zh

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Definitions

  • the present application relates to, but is not limited to, the field of medical technology, and in particular, but not limited to polymorphic forms of the phosphodiesterase 5 inhibitor Eucerin hydrochloride, and methods for preparing the same, compositions and uses thereof.
  • Erectile dysfunction refers to the inability to reach and/or maintain a full erection to achieve a satisfactory sexual life.
  • ED can be divided into three categories according to different causes: psychogenicity, organic matter and mixedness. It is closely related to age but is not an inevitable disease in the process of aging.
  • Primary risk factors for ED include: hypertension, hyperlipidemia, diabetes, coronary and peripheral vascular disease, pelvic organ or spinal cord injury, or surgery. According to statistics, about 150 million men worldwide have different degrees of ED, and the number of patients will double by 2025.
  • PDE5 oral drug phosphodiesterase 5
  • dopaminergic activator a receptor blocker
  • intracavernosal injection therapy vacuum negative pressure device treatment
  • penile prosthesis treatment penile prosthesis treatment.
  • PDE5 inhibitor selective phosphodiesterase 5 (PDE5) inhibitor is the most mature ED treatment, and it is also the first-line drug for clinical treatment of ED.
  • Five of the drugs approved for marketing today are Sildenafil, Tadalafil, Vardenafil, Udenafil and Mironafil. Mirodenafil).
  • the Chinese patent application with the application number CN03142399.X published in 2004 discloses a series of compounds having a pyrrolopyrimidinone structure and their use for treating sexual dysfunction of animals including humans, especially male penile erectile dysfunction and PDE5 function.
  • the pharmaceutical use of the related disease; wherein, compound 1-HCl, ie 2-[2-ethoxy-5-(4-ethylpiperazine-1-sulfonyl)phenyl]-5-methyl-7-positive Propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one monohydrochloride has been publicly named as a characteristic compound of Example 1 of Chinese Patent Application CN03142399.X. .
  • This patent application only describes the preparation method of the compound in detail, but the study of the crystal form of its compound is not involved.
  • the morphology of the medicinal compound is important, and it involves the study of the appropriate dosage form, because if the morphology of the compound cannot be kept constant during clinical and stability studies, then the exact dose of the applied and determined doses will be inconsistent with the other batch. Comparison.
  • the pharmaceutical compound is applied as a product, it is important to understand the crystalline form of the compound employed in each dosage form in order to ensure that the same form of the drug is applied during the manufacturing process, as well as the same dosage of the drug in each dosage form.
  • the solid matter in nature can be in three states: stable state, metastable state, and unstable state, as well as crystalline materials.
  • the different crystal form of the compound will change with environmental conditions (such as temperature, humidity, light, pressure, etc.).
  • Stable or metastable (conditionally stable) crystalline material has drug-forming properties, and unstable crystalline material does not have drug-forming properties. Therefore, a stable and superior drug crystalline form state is used as a drug raw material and a crystal form thereof to ensure a drug. Clinical effectiveness, safety and quality control are necessary.
  • Embodiments of the present invention provide a stable polymorph of Eugenafil Form A hydrochloride.
  • An embodiment of the present invention also provides a method for preparing a stable polymorph of Eugenafil Form A according to any one of the embodiments of the present invention.
  • An embodiment of the present invention further provides a polymorph of Eugenafil A form produced by the method for preparing a stable polymorph of the Eugenafil form A according to any one of the embodiments of the present invention.
  • An embodiment of the present invention also provides a pharmaceutical composition comprising the stabilized polymorph of Eucerin hydrochloride Form A according to any of the embodiments of the present invention.
  • Embodiments of the present invention also provide the use of the stabilized polymorph of Eugenafil Form A according to any of the embodiments of the present invention.
  • the present invention provides a polymorph of Eucerin hydrochloride Form A, the X-ray powder diffraction pattern of the polymorph comprising at a 2 ⁇ value selected from three or more of the following Diffraction peaks: 8.4 ° ⁇ 0.2 °, 11.3 ° ⁇ 0.2 °, 13.9 ° ⁇ 0.2 °, 14.2 ° ⁇ 0.2 °, 14.7 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 19.7 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 °, 21.7 ° ⁇ 0.2 °, 22.4 ° ⁇ 0.2 °, 23.3 ° ⁇ 0.2 °, 23.8 ° ⁇ 0.2 °, 26.8 ° ⁇ 0.2 °, 27.5 ° ⁇ 0.2 °, 28.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the polymorph of the Eugenafil form A can comprise 8.4 ° ⁇ 0.2 °, 11.3 ° ⁇ 0.2 °, 13.9 ° ⁇ 0.2 °, 14.2 ° ⁇ 0.2°, 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.1° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.7° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.3° ⁇ 0.2 °, 23.8 ° ⁇ 0.2 °, 26.8 ° ⁇ 0.2 °, 27.5 ° ⁇ 0.2 °, 28.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the polymorph of the Eugenafil form A hydrochloride can be substantially identical to that shown in FIG.
  • the differential scanning calorimetry analysis of the polymorph of the Eugenafil form A hydrochloride may have an endothermic peak at 34-133 ° C and 231-250 ° C, respectively.
  • the differential scanning calorimetry analysis of the polymorph of the Eugenafil form A hydrochloride may have an endothermic peak at 86.4 ° C and 237.9 ° C, respectively.
  • the differential scanning calorimetry analysis of the polymorph of the Eugenafil form A hydrochloride can be substantially identical to that shown in FIG.
  • the polymorph of the Eugenapore hydrochloride type A provided by the embodiment of the present invention may have substantially the unit cell parameters as follows:
  • Unit cell size a Equal to 19.1 ⁇ 0.1
  • the density (calculated value) (g/cm 3 ) was 1.31 ⁇ 0.01.
  • a method for preparing a polymorph of Eugenafil hydrochloride type A comprises: suspending ikonafil hydrochloride in an aqueous solution or an organic solvent/water solution, and heating Dissolving, slowly cooling and crystallization, collecting solids by filtration, and drying to obtain polymorphs of Eugenapore hydrochloride type A;
  • the eugenafil hydrochloride is equilibrated in an aqueous solution or an organic solvent/water solution, and dried by filtration to obtain a polymorph of Eucerin hydrochloride Form A;
  • organic solvent is capable of dissolving eugenin hydrochloride and being capable of reacting with water under heating conditions Soluble solvent.
  • the kukonafil hydrochloride suspended in an organic solvent/water solution can be prepared by using Chinese Patent No. CN03142399.X.
  • the organic solvent may be selected from one or more selected from the group consisting of ethanol, methanol, n-propanol, acetonitrile, isopropanol, acetone, dimethyl sulfoxide, N-methylpyrrolidone, or tetrahydrofuran.
  • the volume ratio of organic solvent to water may range from 99/1 to 1/100.
  • the volume of organic solvent and water may range from 98/2 to 40/60.
  • the heating temperature may be in the range of 40 °C to 100 °C.
  • the heating temperature may be in the range of 60 °C to 90 °C.
  • the rate of slow cooling may range from 0.1 °C/min to 2.0 °C/min.
  • the rate of slow cooling may range from 0.1 °C/min to 0.8 °C/min.
  • the uknerabine hydrochloride refers to the monohydrochloride salt of ukenerafil.
  • an embodiment of the present invention provides a polymorph of Eugenafil A form produced by the method for preparing a polymorph of Eugenafil type A according to any one of the embodiments of the present invention.
  • the present invention provides a pharmaceutical composition comprising the polymorph of Eugenop A hydrochloride according to any one of the embodiments of the present invention.
  • the pharmaceutical composition may be formulated into solid oral preparations such as tablets, pills, capsules and powders; and liquid oral preparations such as suspending agents, solubilizing agents, emulsions and syrups.
  • the pharmaceutical composition may contain various conventional excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., and may also contain conventional functional excipients, such as Fillers (starch, sugar), binders (carboxymethylcellulose, etc.), dispersants (sodium carbonate, calcium, etc.), diluents (glycerol), absorption enhancers (quaternary ammonium compounds), lubricants ( Stearate) and absorbent (kaolin); can also be made into a paste for external use; it is also suitable for intravenous injection.
  • conventional excipients such as wetting agents, sweeteners, fragrances, preservatives, etc.
  • conventional functional excipients such as Fillers (starch, sugar), binders (carboxymethylcellulose, etc.), dispersants (sodium carbonate, calcium, etc.), diluents (glycerol), absorption enhancers (quaternary ammonium compounds), lubricants ( Stearate) and
  • oral administration of a pharmaceutical composition of a polymorph of Eugenop A hydrochloride of an embodiment of the present invention is the preferred route because this route is most convenient and avoids administration in the corpus cavernosum. Inconvenience encountered.
  • parenteral administration can be employed, for example, sublingual, buccal, transdermal, and injection.
  • the embodiment of the present invention provides the polymorph of Eugenafil hydrochloride type A according to any one of the embodiments of the present invention, or the Eugenapore hydrochloride type A according to any one of the embodiments of the present invention.
  • a polymorphic form of Eucerin hydrochloride Form A prepared by the method for producing a polymorph or a pharmaceutical composition comprising a polymorph of Eugenafil A according to any one of the embodiments of the present invention.
  • the disease associated with phosphodiesterase 5 may be: male sexual function (erectile) disorder, female sexual dysfunction, premature birth, dysmenorrhea, benign prostatic hyperplasia, bladder obstruction, incontinence, regular or Irregular angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral circulatory system disease, decreased vascular openness, chronic asthma, allergic asthma, bronchitis, allergic rhinitis, glaucoma, gastrointestinal disorders , horror precursor, Kawasaki comprehensive, nitrate tolerance, multiple sclerosis, diabetic peripheral nerve syndrome, Alzheimer's disease, acute respiratory failure, psoriasis, skin gangrene, cancer metastasis, hair loss, nutcracker esophagus, anal Split and hypoxic vasoconstriction.
  • male sexual function erectile
  • female sexual dysfunction premature birth
  • dysmenorrhea benign prostatic hyperplasia
  • bladder obstruction incontinence
  • the polymorph of Eugenafil hydrochloride type A provided by the embodiment of the invention has good physical and chemical stability and is easy to be industrially produced, and is a pharmaceutically acceptable and stable neononafil hydrochloride new crystal. type.
  • Figure 1 is a X-RD diagram of Euphoria hydrochloride Form A polymorph
  • Figure 2 is a DSC chart of the Eugenafil A polymorph
  • Figure 3 is a X-RD pattern of the Eugenafil Form B polymorph.
  • the DSC spectra of embodiments of the invention were collected on a TA Q200/Q2000 differential scanning calorimeter.
  • the experimental parameters are as follows:
  • the room temperature is generally 25 ⁇ 3 ° C
  • the Ukrainian hydrochloride Form B polymorph (1.0 g, the preparation method is shown in the comparative example) and 95% by volume aqueous ethanol solution (6 mL) were added to the flask at room temperature, stirred for 2 h, and separated by filtration. Drying under reduced pressure gave a yucazone A polymorph (0.8 g).
  • the X-RD diffraction pattern is shown in Figure 1, and the DSC is shown in Figure 2.
  • the inventors of the present application have unexpectedly discovered that the Ukrainian hydrochloride Form B polymorph is placed at room temperature. After one week, it can be converted into a type A polymorph, indicating that the type A polymorph is more stable than the type B polymorph.
  • Embodiment 2-3 The slow cooling process mentioned in the above may be cooled at a rate ranging from 0.1 ° C / min to 2.0 ° C / min, optionally at a rate ranging from 0.1 ° C / min to 0.8 ° C / min.
  • the cooling rate it can be adjusted several times according to the needs of the reaction process to obtain the Eugenafil A polymorph.
  • the polymorph of the Eugenafil hydrochloride type A of the invention has good physical and chemical stability and is easy to be industrially produced, and is a pharmaceutically acceptable and stable new form of Eugenafil hydrochloride.

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Abstract

本申请公开了一种盐酸优克那非A型的多晶型物其制备方法、组合物和用途。该酸优克那非A型的多晶型物的粉末衍射图谱包括在选自以下的3个或更多个的2θ值处的衍射峰：8.4±0.2°，11.3±0.2°，13.9±0.2°，14.2±0.2°，14.7±0.2°，16.8±0.2°，17.1±0.2°，19.7±0.2°，21.0±0.2°，21.7±0.2°，22.4±0.2°，23.3±0.2°，23.8±0.2°，26.8±0.2°，27.5±0.2°，28.0°±0.2°。

Description

盐酸优克那非的多晶型物及其制备方法、组合物和用途 技术领域
本申请涉及但不限于医药技术领域，具体地说，涉及但不限于磷酸二酯酶5抑制剂盐酸优克那非的多晶型物及其制备方法、组合物和用途。
背景
勃起功能障碍(Erectile dysfunction，ED)是指持续不能达到和(或)维持充分勃起以获得满意的性生活。ED根据病因不同可分为心因性、器质性和混合性三大类，其与年龄密切相关但并不是老龄化过程中不可避免的疾病。ED的原发危险因素包括：高血压、高血脂、糖尿病、冠脉和外周血管疾病、盆腔器官或脊髓损伤或手术。据统计目前全球范围内约1.5亿男性患有不同程度ED，到2025年该患病人数将会增加一倍。ED的治疗选择方案较多，如口服药物磷酸二酯酶5(PDE5)抑制剂、多巴胺能活化剂、a受体阻断剂、阴茎海绵体内注射疗法、真空负压装置治疗、阴茎假体治疗等。其中选择性磷酸二酯酶5(PDE5)抑制剂是研究最为成熟的ED治疗药物，也是临床治疗ED的一线药物。如今已批准上市的该类药物有五种分别为西地那非(Sildenafil)、他达拉非(Tadalafil)、伐地那非(Vardenafil)、乌地那非(Udenafil)和米罗那非(Mirodenafil)。
2004年公开的申请号为CN03142399.X的中国专利申请公开了一系列具有吡咯并嘧啶酮结构的化合物及其用于治疗包括人在内的动物性功能障碍、特别是雄性阴茎勃起障碍以及PDE5功能相关疾病的药物用途；其中，化合物1-HCl，即2-[2-乙氧基-5-(4-乙基哌嗪-1-磺酰)苯基]-5-甲基-7-正丙基-3,7-二氢吡咯并[2,3-d]嘧啶-4-酮单盐酸盐已作为中国专利申请CN03142399.X实施例1的特征化合物被公开命名为盐酸优克那非。该专利申请仅对该化合物制备方法进行了详细的描述，但是对其化合物晶型的研究没有涉及。
发明概述
药用化合物的形态是重要的，它涉及到合适剂量形式的研究，因为在进行临床和稳定性研究中如果化合物的形态不能保持恒定，那么应用和测定的准确剂量一批与另一批就无从比较。一旦药用化合物作为产品应用，那么了解在各个剂型中应用的化合物的晶型是重要的，以便保证生产过程应用相同形态的药物，以及在各个剂型中含有相同剂量的药物。自然界中的固体物质可处于稳定态、亚稳定态、不稳定态三种状态，晶型物质亦如此。化合物不同晶型状态会随着环境条件变化(如：温度、湿度、光照、压力等)会发生转变，由于药用晶型物质的稳定性会影响到药品的临床有效性与安全性，故需要对晶型物质状态的稳定性研究。稳定或亚稳定(有条件的稳定)的晶型物质具有成药性，不稳定晶型物质不具有成药性，因此使用稳定优势的药物晶型物质状态作为药物原料及其制剂晶型，以保证药品临床有效性、安全性与质量可控性是非常有必要的。
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
本发明实施方案提供了一种稳定的盐酸优克那非A型的多晶型物。
本发明实施方案还提供了本发明任一实施方案所述的稳定的盐酸优克那非A型的多晶型物的制备方法。
本发明实施方案还提供了由本发明任一实施方案所述的稳定的盐酸优克那非A型的多晶型物的制备方法制得的盐酸优克那非A型的多晶型物。
本发明实施方案还提供了包含本发明任一实施方案所述的稳定的盐酸优克那非A型的多晶型物的药物组合物。
本发明实施方案还提供了本发明任一实施方案所述的稳定的盐酸优克那非A型的多晶型物的用途。
具体地说，本发明提供了一种盐酸优克那非A型的多晶型物，该多晶型物的X-射线粉末衍射图包括在选自以下3个或更多个的2θ值处的衍射峰：8.4°±0.2°，11.3°±0.2°，13.9°±0.2°，14.2°±0.2°，14.7°±0.2°，16.8°±0.2°，17.1°±0.2°，19.7°±0.2°，21.0°±0.2°，21.7°±0.2°，22.4°±0.2°，23.3°±0.2°，23.8°±0.2°，26.8°±0.2°，27.5°±0.2°，28.0°±0.2°。
在本发明的实施方案中，该盐酸优克那非A型的多晶型物的X-射线粉末衍射图可包含8.4°±0.2°，11.3°±0.2°，13.9°±0.2°，14.2°±0.2°，14.7°±0.2°，16.8°±0.2°，17.1°±0.2°，19.7°±0.2°，21.0°±0.2°，21.7°±0.2°，22.4°±0.2°，23.3°±0.2°，23.8°±0.2°，26.8°±0.2°，27.5°±0.2°，28.0°±0.2°。
在本发明的一种实施方案中，该盐酸优克那非A型的多晶型物的X-射线粉末衍射图可以基本上与图1中所示的一致。
在本发明的实施方案中，该盐酸优克那非A型的多晶型物的差示扫描量热法分析图分别在34-133℃和231-250℃可有吸热峰。
在本发明的一种实施方案中，该盐酸优克那非A型的多晶型物的差示扫描量热法分析图分别在86.4℃和237.9℃可有吸热峰。
在本发明的一种实施方案中，该盐酸优克那非A型的多晶型物的差示扫描量热法分析图可以基本上与图2中所示的一致。
在本发明的实施方案中，本发明实施方案提供的盐酸优克那非A型的多晶型物，其晶胞参数可基本如下：
晶胞大小：a
Figure PCTCN2015095059-appb-000001
等于19.1±0.1
b
Figure PCTCN2015095059-appb-000002
等于12.7±0.1
c
Figure PCTCN2015095059-appb-000003
等于11.3±0.1
体积等于
Figure PCTCN2015095059-appb-000004
空间群P21/c
密度(计算值)(g/cm3)为1.31±0.01。
另一方面，本发明实施方案提供的一种盐酸优克那非A型的多晶型物的制备方法，包括：将盐酸优克那非混悬于水溶液或有机溶剂/水溶液中，加热使其溶解，缓慢降温析晶，过滤收集固体，并干燥即得到盐酸优克那非A型的多晶型物；
或者，将盐酸优克那非在水溶液或有机溶剂/水溶液中平衡，过滤干燥得到盐酸优克那非A型的多晶型物；
其中，所述有机溶剂为在加热条件下能够使盐酸优克那非溶解并能与水 互溶的溶剂。
在本发明的实施方案中，混悬于有机溶剂/水溶液中的所述盐酸优克那非可以采用中国专利CN03142399.X制备得到。
在本发明的实施方案中，所述有机溶剂可以选自乙醇、甲醇、正丙醇、乙腈、异丙醇、丙酮、二甲亚砜、N-甲基吡咯烷酮、或四氢呋喃中的一种或多种。
在本发明的实施方案中，有机溶剂与水的体积比可以为99/1-0/100。
在本发明的实施方案中，有机溶剂与水的体积可以为98/2-40/60。
在本发明的实施方案中，所述加热的温度可以在40℃～100℃的范围内。
在本发明的实施方案中，所述加加热的温度可以在60℃～90℃的范围内。
在本发明的实施方案中，所述缓慢降温的速度可以在0.1℃/min～2.0℃/min的范围内。
在本发明的实施方案中，所述缓慢降温的速度可以在0.1℃/min～0.8℃/min的范围内。
在本发明的实施方案中，所述盐酸优克那非是指优克那非的单盐酸盐。
第三方面，本发明实施方案提供了由本发明任一实施方案所述的盐酸优克那非A型的多晶型物的制备方法制得的盐酸优克那非A型的多晶型物。
第四方面，本发明提供了一种药物组合物，其包含本发明任一实施方案所述的盐酸优克那非A型的多晶型物。
在本发明的实施方案中，该药物组合物可以制成固体口服制剂，如片剂，丸剂，胶囊和粉末剂；也可以制成液体口服制剂，如悬浮剂、溶解剂、乳剂和糖浆剂。
在本发明的实施方案中，该药物组合物可以含有常规的各种赋型剂，如润湿剂、增甜剂、芳香剂和防腐剂等，也可以含有常规的功能性赋型剂，如填充剂(淀粉、糖类)、粘合剂(羧甲基纤维素等)、分散剂(碳酸钠、钙等)、稀释剂(甘油)、吸收促进剂(季铵类化合物)、润滑剂(硬酯酸盐)和吸收剂(高岭土)；也可以制成膏剂外用；同样适合于制成静脉注射剂。
一般来说，对于人类，口服给药本发明实施方案的盐酸优克那非A型的多晶型物的药物组合物是优选的途径，因为这个途径最为方便，避免了在阴茎海绵体内用药时遇到的不便。当患者有吞咽障碍或口服后有药物吸收损伤时，可以采用非肠道用药，例如经舌下、颊、透皮和注射给药。
第五方面，本发明实施方案提供了本发明任一实施方案所述的盐酸优克那非A型的多晶型物、或由本发明任一实施方案所述的盐酸优克那非A型的多晶型物的制备方法制备的盐酸优克那非A型的多晶型物、或本发明任一实施方案所述的包含盐酸优克那非A型的多晶型物的药物组合物用于制备治疗或预防包括人在内的雄性动物勃起机能障碍以及与磷酸二酯酶5有关疾病的药物的用途。
在本发明的实施方案中，所述与磷酸二酯酶5有关的疾病可以为：男性性功能(勃起)障碍、女性性功能障碍，早产，痛经，良性前列腺增生，膀胱阻塞，失禁，规则或不规则心绞痛，高血压，肺高压，充血性心衰，动脉硬化，中风，外周循环系统疾病，血管开放性降低，慢性哮喘，过敏性哮喘，支气管炎，过敏性鼻炎，青光眼，胃肠运动紊乱，惊厥前兆，川崎综合性，硝酸酯耐受，多发性硬化，糖尿病外周神经综合症，阿尔茨海默症，急性呼吸系统衰竭，牛皮癣，皮肤坏疽，癌细胞转移，脱发，胡桃夹食管，肛裂和缺氧性血管收缩。
本发明实施方案提供的盐酸优克那非A型的多晶型物，有良好的物理和化学稳定性，易于工业化生产，为一种药学上可接受的、稳定的盐酸优克那非新晶型。
在阅读并理解了附图和详细描述后，可以明白其他方面。
附图简述
附图是用来提供对本发明实施例的进一步理解，并且构成说明书的一部分，与下面的具体实施方式一起用于解释本发明实施例，但并不构成对本发明实施例的限制。在附图中：
图1为盐酸优克那非A型多晶型物X-RD图；
图2为盐酸优克那非A型多晶型物DSC图；
图3为盐酸优克那非B型多晶型物X-RD图。
本发明的具体实施方式
下面结合实施例对本发明作进一步详细的说明，应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限定本发明。
本发明实施方案的XRPD图在PANalytical(帕纳科)Empyrean X射线粉末衍射分析仪上采集，XRPD参数如下：
Figure PCTCN2015095059-appb-000005
本发明实施方案的DSC图谱在TA Q200/Q2000差示扫描量热仪上采集。实验参数如下：
Figure PCTCN2015095059-appb-000006
*:室温一般为25±3℃
实施例1：
室温条件下，将盐酸优克那非B型多晶型物(1.0g，其制备方法见对比例)和95体积％乙醇水溶液(6mL)加入烧瓶中，搅拌2h，经过滤分离，所得的固体减压干燥，得盐酸优克那非A型多晶型物(0.8g)。其X-RD衍射图如图1所示，DSC如图2所示。
实施例2：
室温条件下，将盐酸优克那非B型多晶型物(1.0g)和50体积％甲醇水溶液(3mL)加入烧瓶中，加热至70℃使其溶解，缓慢降温至-10℃，过滤，所得的固体减压干燥，得盐酸优克那非A型多晶型物(0.8g)。其X-RD衍射图如图1所示，DSC如图2所示。
实施例3：
室温条件下，将盐酸优克那非A型多晶型物(0.5g)、B型多晶型物(0.5g)和水(2mL)加入烧瓶中，加热至90℃使其溶解，缓慢降温至-5℃，过滤，所得的固体减压干燥，得盐酸优克那非A型多晶型物(0.7g)。其X-RD衍射图如图1所示，DSC如图2所示。
对比例：
盐酸优克那非B型多晶型物的制备
将游离碱(优克那非，参照中国专利申请CN03142399.X制备，1.0g)溶于乙醚(10ml)和二氯甲烷(10ml)中，搅拌下向其中滴加用乙醚(10ml)稀释的4M盐酸-二氧六环(0.51ml)溶液。滴完后室温下继续搅拌20分钟，过滤，所得的固体减压干燥，得盐酸优克那非B型多晶型物(1.0g)。熔点：147-150℃，其X-RD衍射图如图3所示。
本申请的发明人意外地发现，盐酸优克那非B型多晶型物在室温条件放 置一周后可转变为A型多晶型物，表明A型多晶型物比B型多晶型物稳定。
虽然本发明所揭露的实施方式如上，但所述的内容只是为了便于理解本发明而采用的实施方式，并非用以限定本发明。任何本发明所属技术领域内的技术人员，在不脱离本发明所揭露的精神和范围的前提下，可以在实施的形式上及细节上作任何的修改与变化，例如，在实施例2-3中所提及的缓慢降温过程，可以以0.1℃/min～2.0℃/min范围的速度降温，可选地以0.1℃/min～0.8℃/min范围的速度降温。对于降温速度的掌控，可以根据反应进程的需要进行多次调节，以获得盐酸优克那非A型多晶型物。
但本发明的专利保护范围，仍须以所附的权利要求书所界定的范围为准。
工业实用性
本发明的盐酸优克那非A型的多晶型物，有良好的物理和化学稳定性，易于工业化生产，为一种药学上可接受的、稳定的盐酸优克那非新晶型。

Claims (16)

  1. 盐酸优克那非A型的多晶型物，所述多晶型物的X-射线粉末衍射图包括在选自以下的3个或更多个2θ值处的衍射峰：8.4°±0.2°，11.3°±0.2°，13.9°±0.2°，14.2°±0.2°，14.7°±0.2°，16.8°±0.2°，17.1°±0.2°，19.7°±0.2°，21.0°±0.2°，21.7°±0.2°，22.4°±0.2°，23.3°±0.2°，23.8°±0.2°，26.8°±0.2°，27.5°±0.2°，28.0°±0.2°。
  2. 如权利要求1所述的多晶型物，其中，所述多晶型物的晶胞参数基本如下：
    晶胞大小：a
    Figure PCTCN2015095059-appb-100001
    等于19.1±0.1
    b
    Figure PCTCN2015095059-appb-100002
    等于12.7±0.1
    c等于11.3±0.1
    体积等于
    Figure PCTCN2015095059-appb-100004
    空间群P21/c
    密度为1.31±0.01g/cm3。
  3. 如权利要求1所述的多晶型物，其中，所述多晶型物的X-射线粉末衍射图包括在以下的2θ值处的衍射峰：8.4°±0.2°，11.3°±0.2°，13.9°±0.2°，14.2°±0.2°，14.7°±0.2°，16.8°±0.2°，17.1°±0.2°，19.7°±0.2°，21.0°±0.2°，21.7°±0.2°，22.4°±0.2°，23.3°±0.2°，23.8°±0.2°，26.8°±0.2°，27.5°±0.2°，和28.0°±0.2°。
  4. 如权利要求3所述的多晶型物，所述多晶型物的X-射线粉末衍射图基本上与图1中所示的一致。
  5. 如权利要求1所述的多晶型物，其中，所述多晶型物的差示扫描量热法分析图分别在34-133℃和231-250℃有吸热峰，优选地，分别在86.4℃和237.9℃有吸热峰。
  6. 如权利要求5所述的多晶型物，其中，所述多晶型物的差示扫描量热法分析图基本上与图2中所示的一致。
  7. 一种盐酸优克那非A型的多晶型物的制备方法，包括：
    将盐酸优克那非混悬于水溶液或有机溶剂/水溶液中，加热使所述盐酸优克那非溶解，缓慢降温析晶，过滤收集固体，并干燥，即得到盐酸优克那非A型的多晶型物；或者，
    将盐酸优克那非在水溶液或有机溶剂/水溶液中达到溶解平衡，过滤干燥得到盐酸优克那非A型的多晶型物；
    其中，所述有机溶剂为在加热条件下能够使盐酸优克那非溶解并能与水互溶的溶剂。
  8. 如权利要求7所述的制备方法，其中，所述有机溶剂选自乙醇、甲醇、正丙醇、乙腈、异丙醇、丙酮、二甲亚砜、N-甲基吡咯烷酮、或四氢呋喃中的一种或多种。
  9. 如权利要求7所述的制备方法，其中，所述有机溶剂与水的体积比为99:1-0:100，优选地，为98:2-40:60。
  10. 如权利要求7所述的制备方法，其中，所述加热的温度在40℃～100℃的范围内，优选地，在60℃～90℃的范围内。
  11. 如权利要求7所述的制备方法，其中，所述缓慢降温的速度在0.1℃/min～2.0℃/min的范围内，优选地，在0.1℃/min～0.8℃/min的范围内。
  12. 由如权利要求7至11中任一权利要求所述的制备方法制得的盐酸优克那非A型的多晶型物。
  13. 一种药物组合物，包含如权利要求1～6中任一权利要求所述的、或如权利要求12所述的盐酸优克那非A型的多晶型物。
  14. 如权利要求13所述的药物组合物，其中，所述药物组合物制成固体口服制剂，如片剂，丸剂，胶囊和粉末剂，或制成液体口服制剂，如悬浮剂、溶解剂、乳剂和糖浆剂。
  15. 如权利要求13或14所述的药物组合物，还包括赋型剂，优选地，功能性赋型剂。
  16. 如权利要求1～6中任一权利要求所述的盐酸优克那非A型的多晶型物、或由如权利要求7～11中任一权利要求所述的制备方法制得的盐酸优克那非A型的多晶型物、或如权利要求13-15任一权利要求所述的药物组合物在制备用于治疗或预防雄性动物勃起机能障碍以及与磷酸二酯酶5有关疾病的药物中的用途，其中所述雄性动物包括人。
PCT/CN2015/095059 2014-12-19 2015-11-19 盐酸优克那非的多晶型物及其制备方法、组合物和用途 WO2016095650A1 (zh)

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KR1020177015107A KR102003847B1 (ko) 2014-12-19 2015-11-19 염산 욘커나필(yonkenafil)의 결정다형 및 그 제조 방법, 조성물과 용도
ES15869159T ES2918948T3 (es) 2014-12-19 2015-11-19 Sustancia polimórfica de hidrocloruro de yonkenafil, método de preparación de la misma y composición y uso de la misma
RU2017120508A RU2672249C9 (ru) 2014-12-19 2015-11-19 Полиморф гидрохлорида йонкенафила, способ его получения, и композиция на его основе, и его применение
PL15869159.2T PL3216791T3 (pl) 2014-12-19 2015-11-19 Substancja polimorficzna chlorowodorku jonkenafilu, sposób jej wytwarzania oraz jej kompozycja i zastosowanie
JP2017531776A JP6473820B2 (ja) 2014-12-19 2015-11-19 塩酸ヨンケナフィルの多形体及びその調製方法、組成物並びに用途
US15/535,502 US9884870B2 (en) 2014-12-19 2015-11-19 Polymorphic substance of yonkenafil hydrochloride, preparation method therefor, and composition and use thereof
CA2971484A CA2971484C (en) 2014-12-19 2015-11-19 Polymorphic substance of yonkenafil hydrochloride, preparation method therefor, and composition and use thereof
EP15869159.2A EP3216791B1 (en) 2014-12-19 2015-11-19 Polymorphic substance of yonkenafil hydrochloride, preparation method therefor, and composition and use thereof
DK15869159.2T DK3216791T3 (da) 2014-12-19 2015-11-19 Polymorft stof på basis af yonkenafil-hydrochlorid, fremgangsmåde til fremstilling heraf samt sammensætning og anvendelse heraf

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116478309A (zh) * 2023-05-19 2023-07-25 青海大学 锁阳精多糖、锁阳多糖化合物及制备方法和应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530054B (zh) * 2014-12-19 2018-01-19 扬子江药业集团有限公司 盐酸优克那非的多晶型物及其制备方法
CN106333953A (zh) * 2015-07-08 2017-01-18 珠海津之敦医药科技有限公司 尤克那非新用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1552714A (zh) * 2003-06-06 2004-12-08 ���ϸ����Ƽ���չ���޹�˾ 2-取代苯基-5，7-二烃基-3，7-二氢吡咯[2，3-d]嘧啶-4-酮衍生物，其制备方法及其药物用途
CN104530054A (zh) * 2014-12-19 2015-04-22 扬子江药业集团有限公司 盐酸优克那非的多晶型物及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2097384C1 (ru) * 1989-10-31 1997-11-27 Биокрист Фармасьютикалз Инк. Производные 2-амино-7-(chr2r3)-3н,5н-пирроло[3,2-d]-пиримидин-4-она, способы их получения и способ селективного ингибирования пролиферации т-лимфоцитов млекопитающего и не оказывающий воздействия на b-лимфоциты
WO2007067570A1 (en) * 2005-12-05 2007-06-14 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of disease
KR101377178B1 (ko) * 2010-04-05 2014-03-26 에스케이케미칼주식회사 Ｐｄｅ5 억제제를 함유하는 피부 주름 개선용 조성물

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1552714A (zh) * 2003-06-06 2004-12-08 ���ϸ����Ƽ���չ���޹�˾ 2-取代苯基-5，7-二烃基-3，7-二氢吡咯[2，3-d]嘧啶-4-酮衍生物，其制备方法及其药物用途
CN104530054A (zh) * 2014-12-19 2015-04-22 扬子江药业集团有限公司 盐酸优克那非的多晶型物及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3216791A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116478309A (zh) * 2023-05-19 2023-07-25 青海大学 锁阳精多糖、锁阳多糖化合物及制备方法和应用
CN116478309B (zh) * 2023-05-19 2024-05-17 青海大学 锁阳精多糖、锁阳多糖化合物及制备方法和应用

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