CN102858774B - 嘧啶衍生物及其在治疗呼吸系统疾病比如copd中的用途 - Google Patents
嘧啶衍生物及其在治疗呼吸系统疾病比如copd中的用途 Download PDFInfo
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Abstract
式(I)化合物是中性白细胞弹性酶的抑制剂，其中A是C-R1或N；-X1-X2-是CR15=N-或-NR19-CO-；而R1-R6，R15，R15和R19如权利要求中所定义。
Description
发明领域
本发明涉及杂环化合物，其是具有人类中性白细胞弹性酶抑制性特性的嘧啶衍生物，及其在治疗中的用途。
发明背景
人类中性白细胞弹性酶(HNE)是32kDa丝氨酸蛋白酶，其存在于中性白细胞的嗜苯胺蓝颗粒中。其在宽范围细胞外基质蛋白，包括纤维连接蛋白、层粘连蛋白、蛋白聚糖、类型III和类型IV胶原以及弹性蛋白的降解中发挥作用(Bieth,G.In Regulation of Matrix accumulation,Mecham,R.P.(Eds),Academic Press,NY,USA1986,217-306)。HNE长期以来被认为在经由组织结构蛋白的降解来修复和处理受损组织的体内平衡中发挥重要作用。其也涉及通过细菌体的降解防御细菌入侵。除了其对基质组织的效果之外，HNE还牵涉于IL-8基因表达的上调以及诱导IL-8自肺上皮细胞释放。在烟草烟雾暴露诱导的慢性梗阻性肺病动物模型中，HNE的小分子抑制剂和蛋白质抑制剂均抑制炎性反应和气肿的发展(Wright,J.L.et al.Am.J.Respir.Crit.Care Med.2002,166,954-960；Churg,A.et al.Am.J.Respir.Crit.Care Med.2003,168,199-207)。从而，在特征为中性白细胞内流的慢性呼吸系统疾病中，HNE在基质破坏和放大炎性反应中均可挥发作用。确实，HNE据信在数种肺病，包括慢性阻塞性肺疾病(COPD)，囊性纤维化(CF)，急性呼吸窘迫综合症(ARDS)，肺气肿，肺炎和肺纤维化中发挥作用。其是也牵涉于牵涉组织重塑的数种心血管疾病中，例如心力衰竭和急性心肌梗死后缺血性组织伤害的产生。
COPD是涵盖三种不同病理学病症的伞式术语(umbrella term)，其全都导致对气流的限制：慢性支气管炎，气肿和小气道疾病。一般地，三种全都不同程度地存在于患COPD的患者中，并且三种全都可以归因于中性白细胞介导的炎症，其得到COPD患者的支气管肺泡渗漏(BAL)流体中观察到的增加的中性白细胞数量的支持(Thompson,A.B.；Daughton,D.；et al.Am.Rev.Respir.Dis.1989,140,1527-1537)。COPD中的主要病原决定因素长期以来被认为是蛋白酶-抗蛋白酶平衡(也称为'弹性酶：抗弹性酶假设')，其中HNE和内源抗蛋白酶比如α1-抗胰蛋白酶(α1-AT)、分泌性白细胞蛋白酶抑制剂(SLPI)和前elafin的不平衡导致COPD的各种炎性病症。患蛋白酶抑制剂α1-抗胰蛋白酶的遗传缺失的个体发展出严重性随时间增加的气肿(Laurrell,C.B.；Erikkson,SScand.J.Clin.Invest.196315,132-140)。因此，过量的HNE是破坏性的，其导致肺形态分解、损失弹性和肺中导气管中肺泡附着点的破坏(气肿)，并且同时增加微脉管渗透性和粘液高分泌(慢性支气管炎)。
发明简述
本发明提供新化合物，其是HNE的抑制剂，并且用于治疗其中HNE活性发挥作用的疾病或病症。
发明详述
在一种实施方式中，本发明提供式(I)化合物：
其中
A是C-R1或N；
R1和R2选自氢，卤素，硝基，氰基，-S(O)nR7，氨基，一-或二-C1-C6-烷基氨基，-NHCOR8，-NH(C＝O)NHR9，-NHSO2R10，C1-C6-烷基，C2-C6-烯基，C2-C6-炔基，羟基，C1-C6-烷氧基或C2-C6-烯氧基，其中C1-C6-烷基和C1-C6-烷氧基能够用1至3个相同或不同的选自卤素、羟基和C1-C4-烷氧基的残基进一步取代；
n是0，1或2；
R4是氢；
R3和R5独立地选自氢，卤素和C1-C6-烷基，其能够用卤素进一步取代；
R7选自C1-C6-烷基，羟基-C1-C6-烷基，C1-C4-烷氧基，氨基，一-或二-C1-C4-烷基氨基，羟基羰基，氨基羰基，C3-C6-环烷基，苯基或C2-C6-烯基；其中C3-C6-环烷基能够用C1-C4-烷基、羟基和C1-C4-烷氧基中的一个或多个取代，而苯基能够用卤素、氰基、C1-C4-烷基、二氟甲基、三氟甲基、二氟甲氧基、三氟甲氧基和C1-C4-烷氧基中的一个或多个取代；
R8和R9独立地选自氢和C1-C6-烷基，而R10是C1-C6-烷基；
R6是-CO2R11，-CONR12R13或-COR14；
-X1-X2-是-CR15＝N-或-NR19-CO-；
R12是氢或C1-C6烷基；
R11，R13，R14各自独立地代表式-[Alk1]p-[Q]t-[Alk2]q-Z残基，其中p，q和t独立地是0或1，条件是p，q和t并不同时是0；
Alk1和Alk2各自独立地代表C1-C6亚烷基残基；
Q代表具有3-9个环成员的二价单环或双环碳环或杂环残基；
Z是
(i)5或6个环成员的单环杂环或7或8个环成员的桥连的杂环系统，其中环杂原子是氮，所述单环环或桥连的环系经由环碳连接至分子其余部分，并且其中环氮可以通过用C1-C3烷基或苄基取代季铵化，所述苄基是在其苯基环中任选经取代的；或者
(ii)-N(RA)(RB)，其中RA和RB独立地是氢，或C1-C6-烷基，C3-C6-环烷基，或在苯基环中任选经取代的苯基(C1-C6)烷基-；或者，与它们连接至的氮一起形成5至7个环原子的单环杂环，其可以含有选自N、O和S的其它杂原子；或者
(iii)-N+(RA)(RB)(RC)，其中
RA，RB和RC独立地是C1-C6-烷基，C3-C6-环烷基，或在苯基环中任选经取代的苯基(C1-C6)烷基-；或者
RA是C1-C6-烷基，C3-C6-环烷基，或在苯基环中任选经取代的苯基(C1-C6)烷基-，而RB和RC与它们连接至的氮一起形成5至7个环原子的单环杂环，其可以含有选自N、O和S的其它杂原子；或者
RA，RB和RC与它们连接至的氮一起形成7或8环成员的桥连的杂环系统；
(iv)-NRAC(＝NRB)NRCRD其中
RA，RB，RC和RD独立地是氢或C1-C6烷基；或RA，RB，RC和RD中的任意两个独立地是氢或C1-C6-烷基，而其余两个一起代表C1-C6亚烷基残基；或者
(v)-C(＝NRA)NRBRC，其中
RA，RB和RC独立地是氢或C1-C6-烷基；或RA，RB和RC中的任一个是氢或C1-C6-烷基，而其余两个一起代表C1-C6亚烷基残基；
(vi)-NRAC(＝NRC)RB，其中
RA，RB和RC独立地是氢或C1-C6烷基；或RA，RB和RC中的任一个是氢或C1-C6-烷基，而其余两个一起代表C1-C6亚烷基残基；
R19选自氢，(C1-C6)烷基，苯基，具有5或6个环原子的单环杂芳基，苯基(C1-C6)烷基，羟基(C1-C6)烷基，和三氟甲基；
R15选自苯基(C1-C6)烷基，氰基(-CN)，NH2-(C1-C6)烷基，NHRE-(C1-C6)烷基，NRERF-(C1-C6)烷基，-COOH，-CORE，-SO2RE，-CONH2，-CONHRE，-SO2NHRE，-CONRERF，和-SO2NRERF，其中RE和RF独立地是(C1-C6)烷基，苯基或具有5或6个环原子的单环杂芳基，或者RE和RF在连接至相同氮原子的情况下形成环状氨基环。
上述式(I)化合物可以以盐，特别是其药学上可接受的盐，N-氧化物，水合物和溶剂化物的形式制备。对本文化合物的任意权利要求，或者提及"本发明化合物"、"本发明涉及的化合物"、"式(I)化合物"等之处包括这样的化合物，其以或不以盐、N-氧化物、水合物或溶剂化物形式存在。
本发明的化合物可以用于治疗或预防其中牵涉HNE的疾病，例如慢性阻塞性肺疾病(COPD)，慢性支气管炎，肺纤维化，肺炎，急性呼吸窘迫综合症(ARDS)，肺气肿，吸烟-诱导的气肿和囊性纤维化。
因此，本发明的其它方面是(i)药物组合物，包含本发明化合物和药学上可接受的载体或赋形剂；和(ii)本发明化合物用于制备药物的用途，所述药物用于治疗或预防其中牵涉HNE的疾病或病症。
命名法
如本文所用，术语"Ca-Cb-烷基"，其中a和b是整数，是指具有a至b个碳原子的直链或支链的烷基残基。从而，例如在a是1而b是6的情况下，术语包括甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基和正己基。
如本文所用，术语"Ca-Cb-烯基"，其中a和b是整数，是指具有a至b个碳原子的直链或支链的烯基部分，其具有至少一个视情况为E或Z立体构型的双键。从而，例如在a是2和b是6的情况下，术语包括，例如，乙烯基，烯丙基，1-和2-丁烯基和2-甲基-2-丙烯基。
如本文所用，术语"Ca-Cb-炔基"，其中a和b是整数，是指具有a至b个碳原子且此外具有1个三键的直链或支链的烃基团。从而，例如在a是1而b是6的情况下，术语包括例如，乙炔基(-C≡CH)，1-丙炔基，1-和2-丁炔基，2-甲基-2-丙炔基，2-戊炔基，3-戊炔基，4-戊炔基，2-己炔基，3-己炔基，4-己炔基和5-己炔基。
如本文所用，术语"二价Ca-Cb-亚烷基残基"，其中a和b是整数，是指具有a至b个碳原子和两个未成键化合价的饱和烃链。
如本文所用，术语"二价Ca-Cb-亚烯基残基"，其中a和b是整数，是指具有a至b个碳原子和至少一个双键的二价烃链。
如本文所用，无限制的术语"碳环"是指一-、二-或三环残基或桥连的单环或双环残基，其具有多至16个全是碳的环原子，包括芳基和环烷基。桥连的碳环残基具有单环或双环环，其中两个环原子通过亚烷基桥联接，比如二环[2.2.2]辛烷，二环[3.1.1]庚烷和金刚烷残基。
如本文所用，无限制的术语"环烷基"是指单环饱和碳环残基，其具有3-8个碳原子，包括例如，环丙基，环丁基，环戊基，环己基，环庚基，环辛基，二环[2.2.2]辛烷基和金刚烷基。
如本文所用，无限制的术语"芳基"是指一-、二-或三-环状碳环芳族残基，并且包括具有通过共价键直接连接的两个单环碳环芳族环的残基。所述残基的示例是苯基、联苯基和萘基。
如本文所用，无限制的术语"杂芳基"是指一-、二-或三-环状芳族残基，其含有一个或多个选自S、N和O的杂原子，并且包括具有通过共价键直接连接的两个所述单环环或者一个所述单环环和一个单环芳基环的残基。所述残基的示例是噻吩基，苯并噻吩基，呋喃基，苯并呋喃基，吡咯基，咪唑基，苯并咪唑基，噻唑基，苯并噻唑基，异噻唑基，苯并异噻唑基，吡唑基，噁唑基，苯并噁唑基，异噁唑基，苯并异噁唑基，异噻唑基，三唑基，苯并三唑基，噻二唑基，噁二唑基，吡啶基，哒嗪基，嘧啶基，吡嗪基，三嗪基，吲哚基和吲唑基。在杂芳基环含有sp2氮的情况下，比如吡啶或咪唑的情况中，所述氮可以是季氮，比如吡啶鎓或咪唑鎓中的氮。
如本文所用，无限制的术语"杂环基"或"杂环"或"杂环烷基"包括如前文所定义的"杂芳基"，并且在其非芳族含义中涉及一-、二-或三-环状或桥连的单环或双环非芳族残基，其含有一个或多个选自S、N和O的杂原子，并且涉及含有一个或多个所述杂原子的单环非芳族残基，其共价连接至又一所述残基或至单环碳环残基。桥连的杂环残基具有含有至少一个S、N或O环原子的单环或双环环，其中两个环原子，比如两个环碳，或环氮和环碳，通过亚烷基桥联接，比如1-氮杂-二环[2.2.2]辛烷残基。在环氮以上述方式桥连的情况下，其可以被进一步取代为季氮中心。所述残基的示例是吡咯基，呋喃基，噻吩基，哌啶基，咪唑基，噁唑基，异噁唑基，噻唑基，噻二唑基，吡唑基，吡啶基，吡咯烷基，嘧啶基，吗啉基，哌嗪基，吲哚基，吗啉基，苯并呋喃基，吡喃基，异噁唑基，苯并咪唑基，亚甲基二氧基苯基，亚乙基二氧基苯基，马来酰亚胺基，琥珀酰亚氨基和1-氮杂-二环[2.2.2]辛烷基或1甲基-1-氮杂-二环[2.2.2]辛烷基。
除非上下文中另有指定，用于本文的任意部分的术语"取代"意指用多至四个相容的取代基取代，其各自独立地可以是，例如，C1-C6-烷基，环烷基，C1-C6-烷氧基，羟基，羟基-C1-C6-烷基，巯基，巯基-C1-C6-烷基，C1-C6-烷硫基，苯基，具有5或6个环原子的单环杂芳基，卤素(包括氟、溴和氯)，三氟甲基，三氟甲氧基，硝基，腈(-CN)，氧代，-COOH，-COORG，-CORG，-SO2RG，-CONH2，-SO2NH2，-CONHRG，-SO2NHRG，-CONRGRH，-SO2NRGRH，-NH2，-NHRG，-NRGRH，-OCONH2，-OCONHRG，-OCONRGRH，-NHCORG，-NHCOORG，-NRHCOORG，-NHSO2ORG，-NRHSO2OH，-NRHSO2ORG,-NHCONH2，-NRGCONH2，-NHCONHRH，-NRGCONHRH，-NHCONRGRH或-NRGCONRGRH，其中RG和RH独立地是C1-C6-烷基，C3-C6-环烷基，苯基或具有5或6个环原子的单环杂芳基，或RG和RH在连接至相同氮原子的情况下形成环状氨基环，比如哌啶基，吗啉基或哌嗪基。"可选取代基"可以是前述取代基之一。
如本文所用，术语"盐"包括本发明化合物的碱加成盐和酸加成盐，所述化合物是酸性的，能够与碱形成盐，包括药学上可接受的盐，所述碱是比如碱金属氢氧化物，例如氢氧化钠和氢氧化钾；碱土金属氢氧化物例如氢氧化钙、氢氧化钡和氢氧化镁；与有机碱例如N-甲基-D-葡萄糖胺，胆碱三(羟基甲基)氨基-甲烷，L-精氨酸，L-赖氨酸，N-乙基哌啶，二苄胺等。碱性的那些化合物(I)能够与无机酸和有机酸形成盐，包括药学上可接受的盐，所述无机酸是例如氢卤酸比如盐酸或氢溴酸，硫酸，硝酸或磷酸等，而所述有机酸是例如乙酸，酒石酸，琥珀酸，富马酸，马来酸，苹果酸，水杨酸，柠檬酸，甲磺酸，对甲苯磺酸，苯甲酸，苯磺酸，谷氨酸，乳酸，和扁桃酸等。具有季氮的那些化合物(I)还能够与药学上可接受的平衡离子形成季盐，上述平衡离子是比如氯阴离子，溴阴离子，乙酸阴离子，甲酸阴离子，对-甲苯磺酸阴离子，琥珀酸阴离子，半琥珀酸阴离子，萘二磺酸阴离子，甲磺酸阴离子，昔萘酸阴离子等。
含有一个或多个真实或潜在手性中心的本发明化合物，因为不对称碳原子的存在，能够作为各手性中心为R或S立体构型的许多非对映异构体存在。本发明包括全部所述非对映异构体及其混合物。
在式(I)的本发明化合物，以任意相容的组合：
含有A的环是苯基或3-吡啶基环。
R1和R2选自对于式(I)定义的取代基类型中的任意种，包括氢，卤素比如氟和氯，硝基，氰基，-S(O)2(C1-C3烷基)比如甲磺酰基，氨基，一-或二-C1-C6-烷基氨基比如甲基氨基和二甲基氨基，-NHCOCH3，-NH(C＝O)NHCH3，-NHSO2CH3，C1-C6-烷基比如甲基，乙基或正-或异丙基，C2-C6-烯基比如乙烯基或烯丙基，C2-C6-炔基比如CH≡C-，羟基，C1-C6-烷氧基比如甲氧基或乙氧基或C2-C6-烯氧基比如烯丙基氧基，其中C1-C6烷基和C1-C6-烷氧基能够用1至3个相同或不同的选自卤素比如氟、羟基和C1-C4-烷氧基残基进一步取代。
在本发明化合物的一种类型中，含有A的环是苯基，R1是氢，而R2是氢或2-甲磺酰基。在又一类型，含有A的环是3-吡啶基而R2是氢或2-甲磺酰基。
R3和R5也可以选自对于式(I)定义的取代基类型中的任意种，比如氢，氟，氯或溴，和C1-C6-烷基比如甲基，其能够用卤素进一步取代，比如三氟甲基。在本发明化合物的一种类型中，R5是氢而R3是3-三氟甲基，3-氯或3-溴。
R6是-CO2R11，-CONR12R13或-COR14，其中R11，R13，R14各自独立地代表式-[Alk1]p-[Q]t-[Alk2]q-Z残基，其中
p，q和t独立地是0或1，条件是p，q和t并非同时是0；
Alk1和Alk2各自独立地代表C1-C6亚烷基残基比如-CH2-，-CH2CH2-或-CH2CH2CH2-；
Q代表具有3-9个环成员的二价单环或双环碳环或杂环残基，比如1,3-环戊亚基，1,4-环己亚基，1,4-亚苯基，2,5-吡啶亚基，1,4-哌啶亚基，或1,4-哌嗪亚基残基；
Z是
(i)5或6个环成员的单环氮杂环比如吡啶基或咪唑基环或7或8个环成员的桥连的氮杂环系统比如1-氮杂-二环[2.2.2]辛烷环，所述单环环或桥连的环系经由环碳连接至分子其余部分，并且其中环氮可以通过用C1-C3烷基比如甲基、苯基或苄基取代季铵化，所述苄基是在其苯基环中任选经取代的；或者
(ii)-N(RA)(RB)，其中RA和RB独立地是氢，或C1-C6-烷基比如甲基，乙基或正-或异丙基，C3-C6-环烷基比如环丙基，环戊基或环己基，或在苯基环中任选经取代的苯基(C1-C6)烷基比如苄基；或者，与它们连接至的氮一起形成5至7个环原子的单环杂环，其可以含有选自N、O和S的其它杂原子，比如哌啶、哌嗪或吗啉环；或者
(iii)-N+(RA)(RB)(RC)，其中
RA，RB和RC独立地是C1-C6-烷基比如甲基，乙基或正-或异丙基，C3-C6-环烷基比如环丙基，环戊基或环己基，或在苯基环中任选经取代的苯基(C1-C6)烷基比如苄基；或者
RA是C1-C6-烷基比如甲基，乙基或正-或异丙基，C3-C6-环烷基比如环丙基，环戊基或环己基，或在苯基环中任选经取代的苯基(C1-C6)烷基比如苄基，而RB和RC与它们连接至的氮一起形成5至7个环原子的单环杂环，其可以含有选自N、O和S的其它杂原子，比如哌啶、哌嗪或吗啉环；或者
RA，RB和RC与它们连接至的氮一起形成7或8环成员的桥连的杂环系统；
(iv)-NRAC(＝NRB)NRCRD其中
RA，RB，RC和RD独立地是氢或C1-C6-烷基比如甲基；或RA，RB，RC和RD中任意两个独立地是氢或C1-C6-烷基，而其余两个一起代表C1-C6亚烷基残基比如-CH2-，-CH2CH2-或-CH2CH2CH2-；或
(v)-C(＝NRA)NRBRC，其中
RA，RB和RC独立地是氢或C1-C6-烷基比如甲基；或RA，RB和RC中的任一个是氢或C1-C6-烷基比如甲基，而其余两个一起代表C1-C6亚烷基残基比如-CH2-，-CH2CH2-或-CH2CH2CH2-；
(vi)-NRAC(＝NRC)RB，其中
RA，RB和RC独立地是氢或C1-C6-烷基比如甲基；或RA，RB和RC中的任一个是氢或C1-C6-烷基比如甲基，而其余两个一起代表C1-C6亚烷基残基比如-CH2-，-CH2CH2-或-CH2CH2CH2-。
更复杂的R6取代基包括-CO2R11，-CONR12R13或-COR14代表的那些，其中R11，R13和R14具有式-[Alk1]p-[Q]t-[Alk2]q-Z，其中-[Alk1]p-[Q]t-[Alk2]q-选自结构(IV)和(V)，其中V1和V2各自独立地是0、1、2、3或4，而X是具有3-9个环成员的二价单环或双环碳环或杂环残基比如1,4-环己亚基，1,3环戊亚基，1,4-亚苯基，或2,4-吡啶亚基，并且Z选自结构(VI)-(XVI)，其中RA，RB，RC，和RD如对于式(I)的定义，而V1，V2，和V3各自独立地是0、1、2、3或4。
胺和吡啶氮原子，在存在于基团(VI)-(XIV)中的情况下，可以用任选经取代的C1-C6-烷基或苄基季铵化。
在本发明化合物的一种类型中，R6具有式-CO2R11，其中R11代表式-Alk2-Z残基，其中Alk2和Z如上文所定义和讨论。例如，在该类型化合物中，Alk2可以是-CH2-，-CH2CH2-或-CH2CH2CH2-而Z可以是-N(RA)(RB)或-N+(RA)(RB)(RC)，其中RA，RB和RC独立地是C1-C6-烷基比如甲基、乙基或正丙基或异丙基，C3-C6-环烷基比如环丙基、环戊基或环己基，或者苯基(C1-C6)烷基-比如苄基，任选在其苯基环中是被取代的。从而，R6可以是-CO2CH2CH2N(CH3)2或-CO2CH2CH2N+(CH3)3
-X1-X2-是-CR15＝N-或-NR19-CO-，其中R15和R19如前文对式(I)的所定义。从而
R19可以是，例如氢，甲基，乙基，正丙基或异丙基，2-,3-或4-吡啶基，2-或3-噻吩基，噁唑基，异噁唑基，噻唑基，异噻唑基，咪唑基，苄基，羟基甲基，2-羟基乙基，或三氟甲基；和
R15可以是，例如苄基；氰基(-CN)；氨基甲基；2-氨基乙基；NHRE-(C1-C6)烷基，其中RE是甲基或乙基而(C1-C6)烷基是-CH2-或-CH2CH2-；NRERF-(C1-C6)烷基，其中RE和RF独立地是甲基或乙基而(C1-C6)烷基是-CH2-或-CH2CH2-；-COOH；或-CORE，-SO2RE，-CONH2，-CONHRE，-SO2NHRE，-CONRERF，或-SO2NRERF，其中RE和RF独立地是甲基或乙基，或者RE和RF在连接至相同氮原子的情况下形成环状氨基环。
特定基团R1-R6的实例包括本文实施例化合物中存在的那些。
本发明化合物的治疗效用涉及已知至少部分由人类中性白细胞弹性酶的作用介导的任意疾病。例如，本发明化合物可以有益地治疗慢性阻塞性肺疾病(COPD)，囊性纤维化(CF)，急性呼吸窘迫综合症(ARDS)，肺气肿，肺炎和肺纤维化。
本发明也涉及药物配制剂，其包含作为活性成分的本发明化合物。其它化合物可以与本发明化合物相组合，用于预防和治疗肺的炎性疾病。从而，本发明也涉及用于预防和治疗肺的炎性疾病的药物组合物，其包含治疗有效量的本发明化合物和一种或多种其它治疗剂。
用于与本发明化合物组合治疗的适宜治疗剂包括：(1)皮质类固醇，例如氟替卡松或布地奈德；(2)β2-肾上腺素能受体激动剂，例如沙美特罗或福莫特罗；(3)白三烯调节剂，例如孟鲁司特或普仑司特；(4)抗胆碱能药，例如选择性的毒蕈碱-3(M3)受体拮抗剂比如噻托溴铵；(5)磷酸二酯酶-IV(PDE-IV)抑制剂，例如罗氟司特或西洛司特；(6)止咳药，比如可待因或右啡烷；和(7)非甾族抗炎剂(NSAID)，例如布洛芬或酮洛芬。
第一和第二活性成分的重量比可以变化并且取决于各成分的有效剂量。一般地，使用各自的有效剂量。
当然，本发明化合物的预防或治疗剂量的大小，随待治疗病症的严重性、特定化合物及其给药途径而变化，并且一般地通过药物领域所需的临床试验来确定。其还根据个体患者的年龄、体重和应答而变化。通常，在单一或分开的剂量中，日剂量范围的范围是约0.001mg至约100mg每kg哺乳动物体重，优选0.01mg至约50mg每kg，和最优选0.1至10mg每kg。另一方面，在某些情况下可以使用超出这些限制的剂量。
本发明的又一方面提供药物组合物，其包含本发明化合物和药学上可接受的载体。术语"组合物"，如药物组合物中，期望涵盖这样的产品，其包含活性成分，和构成载体的惰性成分(药学上可接受的赋形剂)，以及任意产品，其直接或间接得自各成分中任意两种或更多种的组合、复合或聚集，或者得自各成分中一种或多种的解离，或者得自各成分中一种或多种的其它类型的反应或相互作用。相应地，本发明的药物组合物涵盖通过混合本发明化合物、额外的活性成分和药学上可接受的赋形剂得到的任意组合物。
本发明的药物组合物包含作为活性成分的本发明化合物或其药学上可接受的盐，并且还可以含有药学上可接受的载体和任选地其它治疗成分。术语"药学上可接受的盐"是指盐，其制备自药学上可接受的非毒性碱或酸，所述碱或酸包括无机碱或酸和有机碱或酸。
可以将任意适宜的给药途径用于向提供哺乳动物，特别是人类，有效剂量的本发明化合物。在治疗用途中，活性化合物可以通过任意方便、适宜或有效的途径给予。适宜的给药途径是本领域技术人员已知的，并且包括口服、静脉内、直肠、肠胃外、局部、眼、鼻、颊和肺(通过吸入)。
适于通过吸入给药的组合物是已知的，并且可以包括已知用于所述组合物中的载体和/或稀释剂。组合物可以含有0.01-99％重量的活性化合物。优选，单元剂量包含1μg至10mg量的活性化合物。
最适宜的剂量水平可以通过本领域技术人员已知的任意适宜方法确定。然而，应理解用于任意特别患者的特定量将取决于各种因素，包括所用特定化合物的活性，患者的年龄、体重、膳食、一般健康和性别，给药时间，给药途径，排泄速率，任意其它药物的使用，和进行治疗的疾病的严重性。
对于通过吸入递送，活性化合物优选是微粒形式。它们可以通过各种技术，包括喷雾-干燥，冻干和微粒化来制备。
实例是，本发明组合物可以制备成用于自雾化器递送的悬浮液或制备成在液体推进剂中的气雾剂，例如用于加压式定量吸入器(PMDI)之中。适用于PMDI中的推进剂是技术人员已知的，包括CFC-12，HFA-134a，HFA-227，HCFC-22(CCl2F2)和HFA-152(CH4F2和异丁烷)。
在本发明的优选实施方式中，本发明组合物是无水粉末形式，用于用无水粉末吸入器(DPI)递送。DPI的许多类型是已知的。
用于通过给药递送的微粒可以用帮助递送和释放的赋形剂来配制。例如，在无水粉末配制剂中，微粒可以用帮助从DPI流入肺的大载体颗粒配制。适宜的载体颗粒是已知的，并且包括乳糖颗粒；它们可以具有大于90μm的质量中位数空气动力学直径。
在气雾剂类配制剂的情况中，优选的组合物是：
本发明化合物可以与用于治疗/预防/抑制或改善本发明化合物用以治疗的疾病或病症的其它药物组合使用。所述其它药物可以通过其一般使用的途径和用量与本发明化合物同时地或按顺序地给予。在本发明化合物与一种或多种其它药物同时使用的情况下，除了本发明化合物之外还含有所述其它药物的药物组合物是优选的。相应地，本发明药物组合物包括除了本发明化合物之外还含有一种或多种其它活性成分的那些。
本发明试剂可以以吸入形式给予。气雾剂产生能够这样进行：用例如压力-驱动式喷雾雾化器或超声雾化器，优选用推进剂-驱动式计量气雾剂或者自例如吸入式胶囊或其它"干燥粉末"递送系统不用推进剂地给药微粒化活性化合物。
取决于所用吸入器系统，活性化合物可以如描述的那样给药。除了活性化合物之外，给药形式还可以额外含有赋形剂，例如推进剂(例如在计量式气雾剂情况下的Frigen)，表面活性物质，乳化剂，稳定剂，防腐剂，矫味剂，填料(例如在粉末吸入剂情况下的乳糖)，或者，如果适当，其它活性化合物。
出于吸入目的，可以使用许多系统，其中用适于患者的吸入技术能够产生并给予最佳颗粒尺寸的气雾剂。除了使用转接器(间隔物、膨胀剂)和梨形容器(例如)之外，还可使用用于计量式气雾剂的发出喷烟(puffer)喷雾的自动装置尤其是在粉末吸入剂情况下，可以使用许多技术方案(例如 或例如EP-A-0505321中描述的吸入剂)。
合成方法
本发明的实例，其中X1-X2是-CR15＝N-，能够根据方案1-4制备。化合物，其中X1-X2是-NR19-CO-，能够根据方案5-10制备。基团R11，基团R13和基团R14是式-[Y]m-[Alk1]p-[Q]t-[Alk2]q-Z基团或随后能够转化为其的基团。对于化合物，其中X1-X2是-CR15＝N-或-NR19-CO-，可以例如但不排它地根据方案11将所述基团引入。
在方案1中，可以将3-氨基-1,2,4-三唑、醛比如4-氰基苯甲醛和具有β吸电子基团E(例如酯、酰胺或酮)的酮反应，以形成中间体(1)，然后能够在铜催化下将其用适宜的芳基取代硼酸比如3-(三氟甲基)苯基取代硼酸芳基化，提供类型(2)的实例。所述反应可以在碱例如吡啶或三乙胺存在下，在存在或不存在溶剂比如二氯甲烷时进行。全部反应可以在必须与所用试剂相容的各种溶剂中进行，并且可以在取决于所用溶剂的各种适宜温度，一般0-80℃，进行。
方案1
外消旋混合物(1)或(2)的对映异构体能通过手性HPLC分离。另选地，其中能够在(1)或(2)的结构中例如但不排它地通过裂解相应酯产生羧酸，可以通过与手性碱结晶进行拆分(方案2和3)。
方案2
方案3
方案1中的三组分反应还可以以立体特异性方式进行：用手性路易斯酸(方案4)排它或相对其对映异构体过量地提供所需立体异构体(J.Am.Chem.Soc.，2005，127，16386-16387)。
方案4
本发明的其它实例(6)能够根据方案5制备。可以将O-甲基脲、醛和具有β吸电子基团E(例如酯、酰胺或酮)的酮在碱比如碳酸氢钠存在下反应，以形成中间体(3)。与活化的氯甲酸酯，比如4-硝基苯基氯甲酸酯或五氟苯基氯甲酸酯反应，产生(4)。然后用取代的肼实现闭环，提供(5)。(5)的芳基化能够用芳基取代硼酸，比如3-(三氟甲基)苯基取代硼酸，在铜催化下和在碱例如吡啶或三乙胺存在下，进行。该反应能够用或不用溶剂地进行。基团R'可以在适宜条件下除去，并且在R'＝H的情况下，氮原子可以用标准化学方法烷基化或酰化。全部反应可以在必须与所用试剂相容的各种溶剂中进行，并且可以在取决于所用溶剂的各种适宜温度，一般0-80℃，进行。
方案5
外消旋混合物(3)、(5)或(6)的对映异构体可以通过手性HPLC分离。方案6至9显示将羧酸基团引入手性中间体如何可以允许通过手性盐结晶而拆分。
方案6
方案7
方案8
方案9
方案5的三组分反应还可以以立体特异性方式进行，排它地或对映异构体过量地提供更具活性的对映异构体(J.Am.Chem.Soc,2005,127,16386-16387)。
方案10
在方案1、3、4、5、8、9和10中，基团E可以在各种阶段用标准化学方法进行修饰。方案11描述，在基团E是酯的情况下，该官能团如何可以用本领域技术人员已知的化学方法转化。
方案11
一般实验细节
反应并非在惰性气氛下进行，除非另有指定。在分离用柱进行的情况下，使用自动色谱系统其使用预先堆积的聚丙烯柱，含有平均颗粒尺寸35-70μm(230-400网眼)的二氧化硅。PE-AX柱'是指预先堆积的聚丙烯柱，其含有二氧化硅类具有化学键合的季铵官能团的吸着剂。全部溶剂和商业试剂原样使用。
制备型HPLC条件
HPLC系统1
C18-反相封端柱(250x21.2mm Gemini柱，颗粒尺寸5μm)，用梯度洗脱A：水；B：乙腈(含0.1％甲酸)，流速一般为18ml/min，梯度为1％/min的B增加。于254nm进行UV检测。
分析式LC-MS条件
LC-MS方法1
Waters Platform LC，配有C18-反相柱(30x4.6mm PhenomenexLuna，颗粒尺寸3μm)，洗脱A：水+0.1％甲酸；B：甲醇+0.1％甲酸。梯度：
检测-MS，ELS，UV
MS离子化方法-电喷雾(正和负离子)
LC-MS方法2
Waters Micromass ZQ2000，配有C18-反相柱(100x2.1mmAcquity BEH，颗粒尺寸1.7μm)，保持于40℃，洗脱A：水+0.1％甲酸；B：乙腈+0.1％甲酸。梯度：
检测-MS，UV PDA
MS离子化方法-电喷雾(正/负离子)
实验部分所用缩写：
DCM 二氯甲烷
DIPEA 二-异丙基乙胺
DMF N,N-二甲基甲酰胺
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐
HPLC 高效液相色谱
IPA 异丙醇
RT 室温
Rt 保留时间
中间体1
7-(4-氰基苯基)-5-甲基-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-羧酸烯丙基酯
在90℃，将3-氨基-1,2,4-三唑(1.28mg，15.24mmol)和三乙胺(2.2ml，15.25mmol)在IPA(30ml)中加热，直至绝大多数固体溶解。加入4-氰基苯甲醛(2.0g，15.27mmol)和乙酰乙酸烯丙酯(2.17g，15.28mmol)，在90℃加热反应过夜。蒸发挥发物，残余物在乙酸乙酯和水间分配。滤除一些固体物质，分离乙酸乙酯层，用盐水洗涤，干燥(Na2SO4)，减少体积。过滤沉淀的固体，用乙酸乙酯洗涤，与先前获得的固体合并。淡黄色产品在40℃真空干燥。
收率：1.42g(29％)
LC-MS(方法1)：Rt＝2.88分钟，m/z＝322[M+H]+
中间体2
7-(4-氰基苯基)-5-甲基-4-(3-三氟甲基苯基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-羧酸烯丙基酯
将中间体1(1.42g，4.42mmol)，3-(三氟甲基)苯基取代硼酸(1.68g，8.85mmol)，乙酸铜(II)(1.08g，8.85mmol)和三乙胺(1.23ml，8.85mmol)溶于DCM(15ml)，将反应通大气搅拌7天。加入额外量的取代硼酸，三乙胺和乙酸铜(II)，再过7天之后，将混合物用DCM和1M HCl(aq)稀释，通过C盐过滤。分离有机层，用盐水洗涤，干燥(Na2SO4)，蒸发。将粗制褐色油溶于甲醇，经过已用甲醇处理的柱洗脱。蒸发溶剂，粗制产品在柱(120g)上进行色谱法，用5-100％乙酸乙酯/戊烷洗脱。获得的产品是黄色沫状物。
收率：276mg(13％)
LC-MS(方法1)：Rt＝3.90分钟，m/z＝466[M+H]+
中间体3
7-(4-氰基苯基)-5-甲基-4-(3-三氟甲基苯基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-羧酸
将中间体2(276mg，0.594mmol)，吗啉(206mg，2.37mmol)和四(三苯基膦)钯(0)(68mg，0.059mmol)溶于DCM(5ml)，让溶液在RT静置1小时。将反应混合物用DCM稀释，加水。滤除固体物质。
分离DCM，干燥(Na2SO4)，蒸发。将残余物与乙腈研磨，提供更多的固体。用HPLC系统1，从母液中获得额外量的产品。
收率：183mg(72％)
LC-MS(方法2)：Rt＝4.26分钟，m/z＝426[M+H]+
中间体4
4-(4-氰基苯基)-2-甲氧基-6-甲基-1,4-二氢-嘧啶-5-羧酸烯丙基酯
将4-氰基苯甲醛(13.1g，100mmol)溶于DMF(200ml)，加入碳酸氢钠(33.4g，400mmol)，随后是O-甲基异脲半硫酸盐(14.8g，120mmol)和乙酰乙酸烯丙酯(15.06g，110mmol)。在氮下于70℃加入混合物过夜。在让其冷却至RT之后，过滤混合物，蒸发滤液。将获得的橙色油在乙酸乙酯和水之间分配。分离有机层，用盐水洗涤，干燥(Na2SO4)，蒸发。将粗制产品通过快速二氧化硅色谱纯化，用0-30％乙酸乙酯/DCM洗脱，提供纯中间体4，是黄色沫状物。
收率：16.8g(53％)
LC-MS(方法1)：Rt＝2.18分钟，m/z＝312[M+H]+
中间体5
5-(4-氰基苯基)-2,7-二甲基-3-氧代-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-6-羧酸烯丙基酯
将中间体4(2.15g，6.91mmol)和吡啶(4.5ml)溶于DCM(20ml)，将溶液在冰浴中冷却。加入4-硝基苯基氯甲酸酯(1.38g，6.91mmol)，搅拌反应，同时保持冷却。
在2小时之后，加入甲基肼(550μl，10.4mmol)，在10分钟之后，将反应用DCM稀释，用水洗涤，干燥(Na2SO4)，蒸发。与甲苯共沸除去痕量吡啶。产品在柱(120g)上纯化，用40-80％乙酸乙酯/环己烷洗脱。获得中间体5，是淡黄色固体。
收率：1.22g(50％)
LC-MS(方法1)：Rt＝2.79分钟，m/z＝352[M+H]+
中间体6
5-(4-氰基苯基)-2,7-二甲基-3-氧代-8-(3-三氟甲基苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-6-羧酸烯丙基酯
在RT在空气中，将中间体5(1.01g，2.88mmol)，3-(三氟甲基)苯基取代硼酸(1.09g，5.74mmol)，乙酸铜(II)(525mg，4.27mmol)和吡啶(455mg，5.76mmol)在DCM(15ml)中搅拌。在16小时之后，加入三乙胺(1.16g，11.5mmol)，将反应再搅拌3天。然后加入吡啶(10ml)，在50℃在空气中加热反应7天。在冷却之后，蒸发吡啶，将残余物在DCM和1M HCl(aq)间分配。两相混合物通过C盐过滤，分离有机层，干燥(Na2SO4)，蒸发。残余物用乙酸乙酯和戊烷1:1混合物处理，滤除固体。蒸发滤液，粗制产品在柱(80g)上纯化，用20-100％乙酸乙酯/戊烷洗脱。获得中间体6，是橙色胶状物。
收率：277mg(19％)
LC-MS(方法1)：Rt＝3.81分钟，m/z＝496[M+H]+
中间体7
5-(4-氰基苯基)-2,7-二甲基-3-氧代-8-(3-三氟甲基苯基)-2,3,5,8-四氢[1,2,4]三唑并[4,3-a]嘧啶-6-羧酸
用类似于中间体3的描述的方法，中间体7制备自中间体6。
LC-MS(方法1)：Rt＝3.20分钟，m/z＝456[M+H]+
实施例1
7-(4-氰基苯基)-5-甲基-4-(3-三氟甲基苯基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-羧酸2-二甲基氨基乙基酯
将中间体3(50mg，0.118mmol)，N,N-二甲基乙醇胺(209mg，2.35mmol)和HATU(53mg，0.141mmol)溶于DMF(1ml)，让溶液在RT静置过夜。蒸发溶剂，产品用HPLC系统1纯化。
收率：10mg(17％)
LC-MS(方法2)：Rt＝3.41分钟，m/z＝497.18[M+H]+
实施例2
5-(4-氰基苯基)-2,7-二甲基-3-氧代-8-(3-三氟甲基苯基)-2,3,5,8-四氢[1,2,4]三唑并[4,3-a]嘧啶-6-羧酸2-二甲基氨基乙基酯
用类似于合成实施例1所用的方法，实施例2制备自中间体7。
LC-MS(方法2)：Rt＝3.46分钟，m/z＝527.31[M+H]+
实施例3
{2-[5-(4-氰基苯基)-2,7-二甲基-3-氧代-8-(3-三氟甲基苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-6-羰基氧基]乙基}三甲基铵溴化物
将实施例2(26mg，0.05mmol)溶于30％的溴甲烷/乙腈溶液(4ml)。让反应在RT静置过夜。蒸发挥发物。将残余物溶于水，冻干，提供实施例3，是白色固体。
收率：31mg(100％)
LC-MS(方法2)：Rt＝3.45分钟，m/z＝541.31[M+H]+
生物学测试
测试实施例化合物的HNE抑制活性。
荧光肽底物
测试在96-孔板中进行，总测试体积为100μl。酶(人类白细胞弹性酶，Sigma E8140)的最终浓度是0.00036单元/孔。使用肽底物(MeO-Suc-Ala-Ala-Pro-ValAMC，Calbiochem#324745)，其最终浓度为100μΜ。DMSO在测试缓冲剂中的最终浓度是1％(0.05M Tris.HCl，pH7.5，0.1M NaCl；0.1M CaCl2；0.0005％brij-35)。加入酶开始酶促反应。酶促反应在RT进行，在30分钟之后通过加入最终浓度50μg/孔的50μl大豆胰蛋白酶抑制剂(Sigma T-9003)停止。
在FLEXstation(Molecular Devices)上用380nm激发和460nm发射滤光器读取荧光。从1000nM至0.051nM的10种浓度的浓度系列测定各化合物效能。结果是两次实验的平均值，所述实验各自重复地进行。
各化合物在范围1-200nM内具有活性。
Claims (10)
1.式(I)化合物：
其中
A是C-R1；
R1和R2是氢；
R4是氢；
R3是三氟甲基，氯或溴；
R5是氢；
R6是-CO2R11；
-X1-X2-是-NR19-CO-；
R11代表式-[Alk1]p-[Q]t-[Alk2]q-Z残基，其中
p，q独立地是0或1，t是0，条件是p，q和t并不同时是0；
Alk1和Alk2各自独立地代表C1-C6亚烷基残基；
Z是
(ii)-N(RA)(RB)，其中RA和RB独立地是氢或C1-C6-烷基；或者
(iii)-N+(RA)(RB)(RC)，其中
RA，RB和RC独立地是C1-C6-烷基；或者
R19选自氢和C1-C6烷基。
2.权利要求1要求保护的化合物，其中R11具有式-[Alk1]p-[Q]t-[Alk2]q-Z，其中-[Alk1]p-[Q]t-[Alk2]q-是结构(IV)，其中V1是0、1、2、3或4，并且Z是结构(VI)，其中RA如权利要求1所定义
并且其中胺氮原子，可以是季铵化的。
3.权利要求1或2要求保护的化合物，其中-X1-X2-是-NR19-CO-而R19是甲基。
4.权利要求1或2要求保护的化合物，其是药学上可接受的盐形式。
5.化合物，其选自
7-(4-氰基苯基)-5-甲基-4-(3-三氟甲基苯基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-羧酸2-二甲基氨基乙基酯；
5-(4-氰基苯基)-2,7-二甲基-3-氧代-8-(3-三氟甲基苯基)-2,3,5,8-四氢[1,2,4]三唑并[4,3-a]嘧啶-6-羧酸2-二甲基氨基乙基酯；和
{2-[5-(4-氰基苯基)-2,7-二甲基-3-氧代-8-(3-三氟甲基苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-6-羰基氧基]乙基}三甲基铵溴化物。
6.药物组合物，包含权利要求1至5中任一项要求保护的化合物和药学上可接受的载体或赋形剂。
7.权利要求6要求保护的药物组合物，其经调整用于口服给药或通过肺途径给药。
8.权利要求1至5中任一项要求保护的化合物用于制备药物的用途，所述药物用于治疗其中牵涉HNE的疾病或病症。
9.根据权利要求8的用途，其中所述疾病或病症是慢性阻塞性肺疾病，慢性支气管炎，肺纤维化，肺炎，急性呼吸窘迫综合症，肺气肿，吸烟-诱导的气肿或囊性纤维化。
10.根据权利要求8的用途，其中所述疾病或病症是哮喘，鼻炎，牛皮癣，特应性皮炎，非特应性皮炎，克罗恩病，溃疡性结肠炎，或肠易激疾病。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB1004178.8A GB201004178D0 (en) | 2010-03-12 | 2010-03-12 | Enzyme inhibitors |
| GB1004178.8 | 2010-03-12 | ||
| PCT/GB2011/050477 WO2011110858A1 (en) | 2010-03-12 | 2011-03-10 | Pyrimidine derivatives and their use in the treatment of respiratory diseases such as copd |
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| CN102858774A CN102858774A (zh) | 2013-01-02 |
| CN102858774B true CN102858774B (zh) | 2015-05-06 |
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| EP (1) | EP2545056B1 (zh) |
| JP (1) | JP6065180B2 (zh) |
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| CN (1) | CN102858774B (zh) |
| AU (1) | AU2011225902B2 (zh) |
| BR (1) | BR112012022879A2 (zh) |
| CA (1) | CA2792725C (zh) |
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| SG (1) | SG184012A1 (zh) |
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| KR20140060513A (ko) * | 2011-09-14 | 2014-05-20 | 키에시 파르마슈티시 엣스. 피. 에이. | 인체 호중구 엘라스타제 억제제인 테트라히드로트리아졸로피리미딘 유도체 |
| RS58129B1 (sr) * | 2012-12-18 | 2019-02-28 | Chiesi Farm Spa | Derivati 3-okso-2,3,5,8-tetrahidro-[1,2,4]triazolo[4,3-a]pirimidina za tretman respiratornih bolesti |
| US20140221335A1 (en) | 2013-02-06 | 2014-08-07 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| US9115093B2 (en) | 2013-03-04 | 2015-08-25 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| EP3083626B1 (en) | 2013-12-16 | 2017-10-25 | CHIESI FARMACEUTICI S.p.A. | Tetrahydrotriazolopyrimidine derivatives as human neutrophil elastase inhibitors |
| USRE47493E1 (en) | 2014-02-20 | 2019-07-09 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| US9487528B2 (en) | 2014-06-09 | 2016-11-08 | Chiesi Farmaceutici S.P.A. | Compounds |
| CA2951734A1 (en) | 2014-06-12 | 2015-12-17 | Chiesi Farmaceutici S.P.A. | Novel compounds |
| US9475779B2 (en) | 2014-07-31 | 2016-10-25 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| US9440930B2 (en) | 2014-07-31 | 2016-09-13 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| US9458113B2 (en) | 2014-07-31 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| US9290457B2 (en) | 2014-07-31 | 2016-03-22 | Boehringer Ingelheim International Gmbh | Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| US9657015B2 (en) | 2014-07-31 | 2017-05-23 | Boehringer Ingelheim International Gmbh | Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity |
| US9890169B2 (en) | 2015-12-14 | 2018-02-13 | Chiesi Farmaceutici S.P.A. | Triazolinone compounds as HNE inhibitors |
| UA123109C2 (uk) | 2016-05-31 | 2021-02-17 | К'Єзі Фармачеутічі С.П.А. | Сполуки імідазолону як інгібітори нейтрофіл-еластази людини |
| EP3464268B1 (en) | 2016-05-31 | 2020-03-11 | Chiesi Farmaceutici S.p.A. | Novel compounds |
| EP3464269B1 (en) | 2016-05-31 | 2020-04-01 | Chiesi Farmaceutici S.p.A. | Heterocyclic compounds for use in the treatment of a hne related disease |
| KR20220079527A (ko) | 2019-09-17 | 2022-06-13 | 메레오 바이오파마 4 리미티드 | 이식편 거부반응, 폐쇄성 세기관지염 증후군 및 이식편 대 숙주병의 치료에 사용하기 위한 알베레스타트 |
| IL297211A (en) | 2020-04-16 | 2022-12-01 | Mereo Biopharma 4 Ltd | Methods involving the neutrophil elastase inhibitor albalstat for the treatment of respiratory disease mediated by alpha-1 antitrypsin deficiency |
| AU2022373971A1 (en) | 2021-10-20 | 2024-04-04 | Mereo Biopharma 4 Limited | Neutrophil elastase inhibitors for use in the treatment of fibrosis |
| TW202340195A (zh) | 2021-12-22 | 2023-10-16 | 義大利商吉斯藥品公司 | 作為嗜中性白血球彈性蛋白酶抑制劑之三唑酮衍生物鹽 |
| WO2023118258A1 (en) | 2021-12-22 | 2023-06-29 | Chiesi Farmaceutici S.P.A. | Triazolone derivative salt as neutrophil elastase inhibitor |
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- 2011-03-10 EP EP11709794.9A patent/EP2545056B1/en active Active
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- 2011-03-10 KR KR1020127022792A patent/KR20130018671A/ko active IP Right Grant
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- 2011-03-10 CN CN201180011540.4A patent/CN102858774B/zh not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2792725C (en) | 2018-01-02 |
| BR112012022879A2 (pt) | 2016-06-14 |
| EP2545056B1 (en) | 2017-09-06 |
| SG184012A1 (en) | 2012-10-30 |
| RU2012138579A (ru) | 2014-04-20 |
| KR20130018671A (ko) | 2013-02-25 |
| EP2545056A1 (en) | 2013-01-16 |
| US20130150380A1 (en) | 2013-06-13 |
| CA2792725A1 (en) | 2011-09-15 |
| US9156844B2 (en) | 2015-10-13 |
| JP6065180B2 (ja) | 2017-01-25 |
| AU2011225902B2 (en) | 2015-11-05 |
| JP2013522182A (ja) | 2013-06-13 |
| GB201004178D0 (en) | 2010-04-28 |
| RU2581839C2 (ru) | 2016-04-20 |
| WO2011110858A1 (en) | 2011-09-15 |
| CN102858774A (zh) | 2013-01-02 |
| HK1180322A1 (zh) | 2013-10-18 |
| MX2012010004A (es) | 2012-10-05 |
| AU2011225902A1 (en) | 2012-10-04 |
| IL221873A (en) | 2016-05-31 |
| UA109000C2 (uk) | 2015-07-10 |
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