CN112351986A - 苯并噁唑衍生物的晶体 - Google Patents
苯并噁唑衍生物的晶体 Download PDFInfo
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- CN112351986A CN112351986A CN201980042488.5A CN201980042488A CN112351986A CN 112351986 A CN112351986 A CN 112351986A CN 201980042488 A CN201980042488 A CN 201980042488A CN 112351986 A CN112351986 A CN 112351986A
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Description
技术领域
本发明涉及一种具有磷酸二酯酶(PDE)4抑制作用的1-((2-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-(噻唑-2-基)苯并[d]噁唑-4-基)氧基)-1,1-二氟-2-甲基丙烷-2-醇的晶体。
背景技术
对于医药品而言,除了对疾病的有效性和安全性以外,还要求其具有相同的品质和保存稳定性。因此,要求医药品的原料药对于温度、湿度、及光的稳定性优异。
迄今为止,尚未报告提供一种具有优异的PDE4抑制活性且对温度、湿度、及光的稳定性也优异的化合物。
发明内容
[发明要解决的问题]
本发明的目的在于针对具有优异的PDE4抑制活性的化合物,提供一种适合作为医药品的原料药。
[解决问题的技术手段]
本发明人等为了解决所述课题而进行了锐意研究,结果成功地使具有化学稳定性的式(1)所示的化合物结晶化,发现了2种不同的晶型(I型晶体和II型晶体)。
式(1)所示的化合物的I型晶体和II型晶体在热稳定性试验、光稳定性试验、及加速稳定性试验中具有足够的化学稳定性。
也就是说,本发明是
<1>一种晶体,其是式(1)所示的1-((2-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-(噻唑-2-基)苯并[d]噁唑-4-基)氧基)-1,1-二氟-2-甲基丙烷-2-醇(式(1)所示的化合物)的晶体,
[化1]
[发明的效果]
本发明的晶体能够提供适合作为医药品的原料药。
本发明的式(1)所示的化合物的晶体具有优异的PDE4抑制活性,因此可用于治疗及/或预防由于PDE4所导致的疾病或者涉及PDE4的各种疾病。作为由于PDE4所导致的疾病或者涉及PDE4的疾病,例如可列举:哮喘、COPD(Chronic obstructive pulmoriarydisease,慢性阻塞性肺疾病)、间质性肺炎、特发性肺纤维化症、全身性硬化症、非酒精性脂肪性肝炎等各种纤维化疾病,克罗恩病或溃疡性结肠炎等炎症性肠病,多发性硬化症、风湿、强直性脊柱炎、痤疮、异位性皮炎、斑秃、过敏性结膜炎、干眼症、鼻炎、银屑病性关节炎、寻常性银屑病、结节病、贝赫切特综合征、系统性红斑狼疮、抑郁症、认知功能障碍、帕金森病、阿尔茨海默病、亨丁顿舞蹈症、精神分裂症、肌肉萎缩症、白斑病、化脓性汗腺炎、扁平苔藓、各种癌(大肠癌、肺癌、血癌、脑瘤等)、代谢性疾病(糖尿病、肥胖症等)。另外,式(1)所示的化合物的这些晶体在溶解性、吸湿性、溶液稳定性等方面也具有适合作为医药品的性质。
附图说明
图1是式(1)所示的化合物的I型晶体的X射线粉末衍射图谱。
图2是式(1)所示的化合物的II型晶体的X射线粉末衍射图谱。
图3是式(1)所示的化合物的I型晶体的差示扫描量热测定(DSC,Differentialscanning calorimetry)的热分析数据。
具体实施方式
所谓多晶型,是指某化合物形成2种以上的晶体。通常情况下,关于多晶型的各个晶型,已知其稳定性或物理性质会有所不同。另外,通常情况下,在存在多晶型的情况下,可能会发生晶体转变。晶体转变是一种在化学工业的干燥、粉碎、保存等中频繁地出现的现象。不会晶体转变为其他晶型的晶体适合作为医药品的原料药。因此,当获得多种晶型时,重要的是确认每种晶体的稳定性。
在本说明书中,将2种不同的晶型分别称为I型晶体及II型晶体。
本发明涉及1-((2-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-(噻唑-2-基)苯并[d]噁唑-4-基)氧基)-1,1-二氟-2-甲基丙烷-2-醇(式(1)所示的化合物)的晶体、及包含该晶体的医药组合物。再者,式(1)所示的化合物可利用国际公开第2018/124060(国际申请PCT/JP2017/046610)中所记载的方法进行制造,但并不限定于该制造方法。
在本发明中,所谓I型晶体是指在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.7°、14.5°、17.0°、18.9°、19.4°、23.3°、25.7°处具有特征峰,且基于差示扫描量热测定(DSC)所得的吸热峰温度显示为205±3℃。优选在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.7°、9.4°、13.2°、13.7°、14.5°、15.7°、17.0°、18.9°、19.4°、22.9°、23.3°、25.7°、28.7°、35.7°处具有特征峰,且基于差示扫描量热测定(DSC)所得的吸热峰温度显示为205±3℃。
在本发明中,所谓II型晶体是指在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.8°、14.7°、15.7°、19.3°、25.0°处具有特征峰。优选在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.4°、7.8°、8.2°、12.7°、13.6°、14.3°、14.7°、15.7°、16.5°、19.3°、22.1°、25.0°、25.6°处具有特征峰。
再者,各晶体能够通过X射线粉末衍射等进行区分。基于X射线粉末衍射所得的衍射角的值会由于设备或数据分析方法等的差异而产生±0.2°范围内的误差。另外,X射线粉末衍射的每个峰的相对强度会根据晶体习性或取样条件等差异而有所变化。在X射线粉末衍射中确认晶体同一性时,重要的是衍射角或整体图谱,可能会由于测定条件而略有变动。而且,差示扫描量热测定(DSC)的吸热峰温度的值会由于设备或样品量等的差异而产生±3℃范围内的误差。在差示扫描量热测定(DSC)中确认晶体同一性时,重要的仍是整体图谱,可能会由于测定条件而略有变动。所谓差示扫描量热测定(DSC)的吸热峰温度是指吸热峰的峰顶温度。
I型晶体可利用各种方法进行制造,其中可利用以下方法进行制造。
利用选自醇溶剂、酯溶剂、卤素溶剂或水的1种溶剂或2种以上的混合溶剂等,使利用国际公开第2018/124060(国际申请PCT/JP2017/046610)中所记载的方法而获得的式(1)所示的化合物结晶化,从而能够获得I型晶体。溶剂量并无特别限定,例如优选相对于式(1)所示的化合物的重量而言为1~200倍量(v/w)。温度并无特别限定,例如优选为10℃~所使用溶剂的回流温度。当进行晶析时,对式(1)所示的化合物的所述溶剂的溶液,实施选自冷却、浓缩、添加醇溶剂、添加酯溶剂、添加混合溶剂、添加脂肪族烃溶剂或添加水的1种以上的操作。冷却温度并无特别限定,例如优选为-10℃~10℃。浓缩并无特别限定,例如优选相对于式(1)所示的化合物的重量而言为1~10倍量(v/w)。醇溶剂、酯溶剂、混合溶剂、脂肪族烃溶剂及水的量并无特别限定,例如优选相对于式(1)所示的化合物的重量而言为0.01~100倍量(v/w)。接下来,还可以将所获得的晶体加入到醇溶剂、酯溶剂或它们的混合溶剂中,进行加热后放置冷却。
II型晶体可利用各种方法进行制造,其中可利用以下方法进行制造。
将利用国际公开第2018/124060(国际申请PCT/JP2017/046610)中所记载的方法所获得的式(1)所示的化合物溶解于选自醇溶剂、酯溶剂、卤素溶剂或水的1种溶剂或2种以上的混合溶剂等中,然后进行冷却而使其结晶化,从而能够获得II型晶体。溶剂量并无特别限定,例如优选相对于式(1)所示的化合物的重量而言为1~200倍量(v/w)。使式(1)所示的化合物溶解的温度并无特别限定,例如优选为10℃~所使用溶剂的回流温度。用于晶析的冷却并无特别限定,优选为-30℃~10℃,且优选急速地进行冷却。接下来,还可以对通过所述冷却析出晶体的悬浮液实施选自浓缩、添加醇溶剂、添加酯溶剂、添加混合溶剂、添加脂肪族烃溶剂或添加水的1种以上的操作。浓缩并无特别限定,例如优选相对于式(1)所示的化合物的重量而言为1~10倍量(v/w)。醇溶剂、酯溶剂、混合溶剂、脂肪族烃溶剂及水的量并无特别限定,例如优选相对于式(1)所示的化合物的重量而言为0.01~100倍量(v/w)。
所谓醇溶剂,是指甲醇、乙醇、2-丙醇、正丁醇等,优选为甲醇、乙醇、或2-丙醇。它们可单独使用1种,也可以并用2种以上。
所谓酯溶剂,是指甲酸甲酯、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯等。它们可单独使用1种,也可以并用2种以上。
所谓卤素溶剂,是指二氯甲烷、氯仿、1,2-二氯乙烷等。它们可单独使用1种,也可以并用2种以上。
所谓脂肪族烃溶剂,是指戊烷、己烷、环己烷、庚烷等,优选己烷、或庚烷。它们可单独使用1种,也可以并用2种以上。
所谓混合溶剂,是指选自醇溶剂、酯溶剂、卤素溶剂、脂肪族烃溶剂或水的1种以上的混合溶剂等,优选甲醇与乙酸乙酯、乙醇与乙酸乙酯、2-丙醇与乙酸乙酯、己烷与乙酸乙酯。混合溶剂的比率范围为1/10~10/1(v/v),优选为1/2~2/1(v/v)。
实施例
以下,举出实施例,对本发明具体地加以说明,但本发明的范围并不限定于这些实施例。
X射线粉末衍射使用RIGAKU公司制造的SmartLab(放射源:CuKα、波长:扫描速度:1.0039°/分钟、步长:0.0100°、X射线输出:40kV30mA、测定温度:室温)。差示扫描量热测定(DSC)使用TA Instruments公司制造的Q200(升温速度:5℃/分钟、氮气流量:50mL/分钟、样品盘:简易密闭)。
式(1)所示的化合物可利用如下所示的国际公开第2018/124060(国际申请PCT/JP2017/046610)中所记载的方法获得。
参考合成例1
式(1)所示的化合物的合成
(步骤1)(((2-硝基-1,3-苯撑)双(氧基))双(甲撑))二苯
将2-硝基间苯二酚(5g)溶解于N,N-二甲基甲酰胺(88mL)中,加入苄基溴(8.4mL、2.2当量)及碳酸铯(25g、2.4当量),于室温下搅拌12小时。向反应液中加入乙酸乙酯,利用1%盐酸水溶液对有机层进行清洗后,利用蒸馏水再次对有机层进行清洗。利用无水硫酸镁使有机层干燥后,对其进行过滤并将滤液减压浓缩,将己烷加入到所获得的残渣中而析出固体,对所析出的固体进行过滤收集,获得标题化合物10g。
(步骤2)3-(苄氧基)-2-硝基苯酚
将步骤1中所获得的化合物(10g)溶解于二氯甲烷(270mL)中,于-78℃下加入三氯化硼的1.0M庚烷溶液(45mL、1.5当量),并于-78℃下搅拌1小时。以10分钟将甲醇加入到反应液中,升温至室温并加入蒸馏水。利用二氯甲烷对该混合物进行2次萃取,并利用无水硫酸镁使有机层干燥。对经过干燥的有机层进行过滤并对滤液进行减压浓缩,利用硅胶柱层析法(己烷:乙酸乙酯=9.5:0.5)对所得的残渣进行纯化,获得标题化合物4.7g。
(步骤3)3-(苄氧基)-6-溴-2-硝基苯酚
向步骤2中所获得的化合物(3.0g)中加入乙腈(41mL)、氯化三甲基硅烷(0.16mL、0.1当量)及N-溴代琥珀酰亚胺(2.2g、1.0当量),在室温下搅拌1小时。于0℃下向反应液中加入水,利用乙酸乙酯进行萃取后,利用无水硫酸镁使有机层干燥。于过滤后,对滤液进行减压浓缩,利用硅胶柱层析法(己烷:乙酸乙酯=7:3)对所得的残渣进行纯化,获得标题化合物3.1g。
(步骤4)2-氨基-3-(苄氧基)-6-溴苯酚
于0℃下向连二亚硫酸钠(3.1g、8当量)的水溶液(63mL)中滴加步骤3中所获得的化合物(3.1g)的乙醇溶液(37mL)。使其成为室温后,加入水(30mL)和乙醇(18mL),并搅拌1小时20分钟。对反应液进行过滤,用乙醇进行清洗。对滤液进行减压浓缩,于0℃下将水(67mL)加入到所得的残渣中并进行搅拌。过滤收集固体,用蒸馏水、乙酸乙酯进行清洗后,进行减压干燥而获得标题化合物3.3g。
(步骤5)4-(苄氧基)-7-溴苯并[d]噁唑-2-硫醇
将步骤4中所获得的化合物(3.3g)溶解于乙醇(15mL)中,加入0.5M氢氧化钾的乙醇溶液(35mL)和二硫化碳(2.9mL、5当量),于50℃下加热1小时20分钟。使其成为室温后,加入水(68mL)和5M盐酸(6mL)。过滤收集固体,获得标题化合物2.3g。
(步骤6)3-(4-(苄氧基)-7-溴苯并[d]噁唑-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯
向步骤5中所获得的化合物(2.3g)和3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.5g、1.1当量)中加入间二甲苯(17mL),于120℃下搅拌一晚。加入1N氢氧化钠水溶液(20mL),用乙酸乙酯进行萃取。利用无水硫酸镁使有机层干燥后,进行过滤并对滤液进行减压浓缩,利用硅胶柱层析法(己烷:乙酸乙酯=50:1~己烷:乙酸乙酯7:3)对所获得的残渣进行纯化,获得标题化合物2.9g。
(步骤7)3-(4-(苄氧基)-7-(噻唑-2-基)苯并[d]噁唑-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯
在步骤6中所获得的化合物(2.9g)中加入甲苯(19mL),并加入2-噻唑基溴化锌的0.5M四氢呋喃溶液(29mL、2.5当量)和1,1'-双(二苯基膦基)二茂铁二氯化钯(II)-二氯甲烷络合物(480mg、0.1当量),在氩气氛围下、90℃下搅拌6小时。向反应液中加入饱和碳酸氢钠水溶液并进行硅藻土过滤。用乙酸乙酯对滤液进行萃取后,利用无水硫酸镁使有机层干燥。于过滤后,对滤液进行减压浓缩,利用硅胶柱层析法(己烷:乙酸乙酯9:1~己烷:乙酸乙酯=1:1)对所得的残渣进行纯化,获得标题化合物2.5g。
(步骤8)3-(4-羟基-7-(噻唑-2-基)苯并[d]噁唑-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯
将步骤7中所获得的化合物(1.5g)溶解于四氢呋喃(60mL)中,在氩气氛围下加入20%氢氧化钯/碳(水分含量为50%)(2.5g),填充氢气并于50℃下搅拌4.5小时。对反应液进行硅藻土过滤并对滤液进行减压浓缩,利用硅胶柱层析法(氯仿~氯仿:甲醇=94:6)对所得的残渣进行纯化,获得标题化合物1.0g。
(步骤9)3-(4-(2-乙氧基-1,1-二氟-2-侧氧基乙氧基)-7-(噻唑-2-基)苯并[d]噁唑-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯
将步骤8中所获得的化合物(1.0g)溶解于乙腈(24mL)中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(3.6mL、10当量)和2-溴-2,2-二氟乙酸乙酯(3.1mL、10当量),并在室温下搅拌2小时。向反应液中加入饱和氯化铵水溶液,用乙酸乙酯进行3次萃取。利用无水硫酸镁使有机层干燥后,对其进行过滤并对滤液进行减压浓缩,利用硅胶柱层析法(己烷~己烷:乙酸乙酯=5:5)对所得的残渣进行纯化,获得标题化合物1.0g。
(步骤10)3-(4-(1,1-二氟-2-羟基-2-甲基丙氧基)-7-(噻唑-2-基)苯并[d]噁唑-2-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯
将步骤9中所获得的化合物(92mg)溶解于四氢呋喃(1.7mL)中,于0℃下加入溴化甲基镁的0.95M四氢呋喃溶液(0.85mL、5当量)。升温至室温后搅拌1小时,加入饱和氯化铵水溶液,用乙酸乙酯进行3次萃取。利用无水硫酸镁使有机层干燥后,对其进行过滤并对滤液进行减压浓缩,利用硅胶柱层析法(己烷~己烷:乙酸乙酯~乙酸乙酯)对所得的残渣进行纯化,获得标题化合物82mg。
(步骤11)1-((2-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-(噻唑-2-基)苯并[d]噁唑-4-基)氧基)-1,1-二氟-2-甲基丙烷-2-醇(式(1)所示的化合物)的合成
在步骤10中所获得的化合物(307mg)中加入氯仿(5.9mL),于0℃下加入三氟乙酸(1.4mL),并于0℃下搅拌3.5小时。向反应液中加入饱和碳酸氢钠水溶液,用氯仿进行萃取。利用无水硫酸镁使有机层干燥后,进行过滤并对滤液进行减压浓缩,利用氨基硅胶柱层析法(氯仿~氯仿:甲醇=9:1)对所得的残渣进行纯化,获得白色固体的式(1)所示的化合物223mg。
ESI-MS(m/z)423(M+H)+
1H-NMR(氯仿-d、TMS)δ(ppm):1.53(s,6H),1.65(d,J=9.3Hz,1H),2.82-2.87(m,1H),3.90-4.01(m,7H),7.23-7.25(m,1H),7.44(d,J=3.3Hz,1H),7.84(d,J=8.8Hz,1H),7.94(d,J=3.3Hz,1H).
实施例1
在参考合成例1中所获得的式(1)所示的化合物的固体(219mg)中加入乙酸乙酯与2-丙醇的混合溶剂(1:1、v/v)21.9mL,加热至60℃而使其溶解。对该溶液进行浓缩干燥,向所得的残渣中加入乙酸乙酯与2-丙醇的混合溶剂(1:1、v/v)4.38mL,于45℃下搅拌1小时。使其成为室温后,加入己烷21.9mL并搅拌1小时。进行过滤后,用己烷进行清洗并使其干燥,从而获得I型晶体194mg。所获得的I型晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.7°、9.4°、13.2°、13.7°、14.5°、15.7°、17.0°、18.9°、19.4°、22.9°、23.3°、25.7°、28.7°、35.7°处显示特征峰。将I型晶体的X射线粉末衍射图谱示于图1。对所获得的晶体进行差示扫描量热测定(DSC)分析,结果在205℃处确认到吸热峰。将I型晶体的差示扫描量热测定(DSC)的热分析数据示于图3。
实施例2
在实施例1中所获得的I型晶体584mg中加入甲醇50mL而使其溶解。进行减压浓缩而使重量变为约1/6,将所得的均匀溶液冷却至0℃,并搅拌10分钟,由此使固体析出。进行浓缩干燥后,向残渣中加入己烷与乙酸乙酯的混合溶剂(2:1、v/v)35mL,在室温下搅拌30分钟。进行过滤后,用己烷与乙酸乙酯的混合溶剂(2:1、v/v)进行清洗并使其干燥,由此获得II型晶体566mg。所获得的II型晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.4°、7.8°、8.2°、12.7°、13.6°、14.3°、14.7°、15.7°、16.5°、19.3°、22.1°、25.0°、25.6°处显示特征峰。将II型晶体的X射线粉末衍射图谱示于图2。
试验例1PDE4抑制评价
PDE4抑制活性是使用邻近闪烁分析(Scintillation Proximity Assay(SPA)),如下所示地进行测定。用含有50mM Tris-HCl(TRIS hydrochloride,三羟甲基氨基甲烷盐酸盐)pH值7.4、8.3mM MgCl2、1.7mM EGTA(Ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid,乙二醇双(2-氨基乙基醚)-N,N,N',N'-四乙酸)、及3mg/mL牛血清白蛋白(BSA)的反应用缓冲溶液,对溶解于二甲基亚砜中的检体化合物进行10倍稀释,将稀释后的溶液10mL加入到96孔分析盘中。另外,加入用反应用缓冲溶液进行了375倍稀释的PDE4 50mL后,加入用反应用缓冲溶液进行了1000倍稀释的[2,8-3H]-腺苷-3',5'-环磷酸三乙铵盐([2,8-3H]-Adenosine-3',5'-cyclic phosphate triethylammonium salt)40μL,于室温下静置120分钟。其后,加入含有200mM ZnSO4的RNA结合YSi-SPA磁珠(RNAbinding YSi-SPA Beads)悬浮液50mL,于室温下静置15分钟,使酶反应产物吸附在磁珠上。其后,利用96孔板用液体闪烁计数器测量放射活性。将未加入酶样品而仅加入反应用缓冲溶液的情况作为空白组,将虽加入酶样品但仅加入二甲基亚砜代替检体溶液的情况作为对照组,通过以下的计算式计算式(1)所示的化合物相对于对照组的抑制率。
抑制率(%)={1-(添加样本时的数值-空白组值)/(对照组值-空白组值)}×100
另外,被试验化合物的PDE4抑制活性(抑制率为50%时的浓度)是根据抑制曲线而算出,所述抑制曲线是基于各浓度下的抑制率的曲线。
根据所述方法,式(1)所示的化合物的PDE4抑制活性(抑制率为50%时的浓度)小于100nM。
试验例2稳定性试验
将式(1)所示的化合物的I型晶体及II型晶体(分别约300mg)放入到玻璃瓶中,于各条件下进行保存。保存期过后,用HPLC(High performance liquid chromatography,高效液相层析法)对所取出的试样测定化学纯度。各试验的条件如下所示。
热稳定性试验:60℃、气密、持续时间3周
光稳定性试验:25℃、120万勒克斯小时(2000勒克斯、25天)
加速稳定性试验(气密):40℃、75%RH*、持续时间1个月
加速稳定性试验(开放):40℃、75%RH*、持续时间1个月
*RH:相对湿度
各稳定性的评价结果如表1所示,以残存率(HPLC的面积百分率相对于初始值的比(百分比表示))的形式示出晶体中所含的式(1)所示的化合物的量。
[表1]
各晶型的式(1)所示的化合物的残存率高,显示出较高的稳定性。
试验例3吸湿性试验
针对式(1)所示的化合物的I型晶体及II型晶体,使用水蒸气吸附测定装置(Surface Measurement Systems公司制造的DVS Advantage 1)进行等温吸附测定(试样约10mg、25℃、0~95%RH)。
吸湿性的评价结果如表2所示,以在95%RH下的重量增加率(较初始值增加的重量/初始值×100、※初始值:在0%RH下的重量平衡值)的形式示出。
[表2]
重量增加率(%) | |
I型晶体 | 0.6 |
II型晶体 | 10.7 |
本发明的形态例如可列举以下形态等。
<1>一种晶体,其是式(1)所示的1-((2-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-(噻唑-2-基)苯并[d]噁唑-4-基)氧基)-1,1-二氟-2-甲基丙烷-2-醇(式(1)所示的化合物)的晶体,
[化1]
<2>如所述<1>中所记载的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.7°、14.5°、17.0°、18.9°、19.4°、23.3°、25.7°处具有特征峰。
<3>如所述<1>中所记载的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.7°、9.4°、13.2°、13.7°、14.5°、15.7°、17.0°、18.9°、19.4°、22.9°、23.3°、25.7°、28.7°、35.7°处具有特征峰。
<4>如所述<2>或<3>中所记载的晶体,其特征在于,基于差示扫描量热测定(DSC)所得的吸热峰温度为205±3℃。
<5>如所述<1>中所记载的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.8°、14.7°、15.7°、19.3°、25.0°处具有特征峰。
<6>如所述<1>中所记载的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.4°、7.8°、8.2°、12.7°、13.6°、14.3°、14.7°、15.7°、16.5°、19.3°、22.1°、25.0°、25.6°处具有特征峰。
<7>一种医药组合物,其包含如所述<1>至<6>中任一项所记载的晶体。
[产业上的可利用性]
本发明所获得的1-((2-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-(噻唑-2-基)苯并[d]噁唑-4-基)氧基)-1,1-二氟-2-甲基丙烷-2-醇的晶体具有较高的稳定性,因此可用作医药品。
Claims (7)
2.根据权利要求1所述的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.7°、14.5°、17.0°、18.9°、19.4°、23.3°、25.7°处具有特征峰。
3.根据权利要求1所述的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.7°、9.4°、13.2°、13.7°、14.5°、15.7°、17.0°、18.9°、19.4°、22.9°、23.3°、25.7°、28.7°、35.7°处具有特征峰。
4.根据权利要求2或3所述的晶体,其特征在于,基于差示扫描量热测定(DSC)所得的吸热峰温度为205±3℃。
5.根据权利要求1所述的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.8°、14.7°、15.7°、19.3°、25.0°处具有特征峰。
6.根据权利要求1所述的晶体,所述晶体在作为基于X射线粉末衍射所得的衍射角(2θ±0.2°),7.4°、7.8°、8.2°、12.7°、13.6°、14.3°、14.7°、15.7°、16.5°、19.3°、22.1°、25.0°、25.6°处具有特征峰。
7.一种医药组合物,其包含根据权利要求1至6中任一项所述的晶体。
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CN102317287A (zh) * | 2008-12-19 | 2012-01-11 | 利奥制药有限公司 | 作为磷酸二酯酶抑制剂、用于治疗皮肤病的三唑并吡啶化合物 |
CN105431427A (zh) * | 2013-07-10 | 2016-03-23 | 明治制果药业株式会社 | 新型pde4 抑制剂 |
WO2018124060A1 (ja) * | 2016-12-26 | 2018-07-05 | Meiji Seikaファルマ株式会社 | 新規化合物及びその薬理的に許容される塩 |
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CA3104829A1 (en) | 2020-01-02 |
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WO2020004517A1 (ja) | 2020-01-02 |
IL279763B1 (en) | 2023-10-01 |
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ZA202100484B (en) | 2022-08-31 |
US20210155630A1 (en) | 2021-05-27 |
CN112351986B (zh) | 2023-04-18 |
IL279763B2 (en) | 2024-02-01 |
IL279763A (en) | 2021-03-01 |
TWI788580B (zh) | 2023-01-01 |
KR20210024551A (ko) | 2021-03-05 |
AR114977A1 (es) | 2020-11-11 |
BR112020026202A2 (pt) | 2021-03-23 |
TW202000664A (zh) | 2020-01-01 |
AU2019293572A1 (en) | 2021-02-11 |
EP3816167A1 (en) | 2021-05-05 |
ES2926469T3 (es) | 2022-10-26 |
AU2019293572B2 (en) | 2024-01-04 |
EP3816167B1 (en) | 2022-08-03 |
JPWO2020004517A1 (ja) | 2021-02-25 |
NZ772151A (en) | 2024-03-22 |
JP6831496B2 (ja) | 2021-02-17 |
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