CN103608336A - 9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1,4-二氮杂-螺[5.5]十一烷-5-酮二马来酸盐、其作为药物的用途及其制备方法 - Google Patents
9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1,4-二氮杂-螺[5.5]十一烷-5-酮二马来酸盐、其作为药物的用途及其制备方法 Download PDFInfo
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Abstract
本发明涉及式(I)化合物,其具有有利的药理学性质,尤其对酪胺酸激酶所介导的信号转导具有抑制作用,立体选择性制备所述化合物的方法,尤其是适于吸入的药物制剂,其治疗疾病的用途,尤其是治疗肿瘤疾病、良性前列腺增生以及肺部及呼吸道疾病的用途。
Description
本发明涉及式(I)化合物,
其具有有利的药理学性质,尤其对酪胺酸激酶所介导的信号转导具有抑制作用,立体选择性制备所述化合物的方法,尤其是适于吸入的药物制剂,其治疗疾病(尤其是肿瘤疾病、良性前列腺增生以及肺部及气道的疾病)的用途。
发明背景
喹唑啉衍生物在现有技术中已知为(例如)治疗肿瘤疾病以及肺部和气道疾病的活性物质。制备喹唑啉衍生物的方法描述于WO03082290和WO07068552。WO2009098061公开了本发明的二马来酸盐(化合物(I))的碱(化合物(II))。
本发明的目的为提供9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1,4-二氮杂-螺[5.5]十一烷-5-酮的盐,其因作为酪胺酸激酶抑制剂的医药功效而适用于治疗领域,亦即,用于治疗由酪胺酸激酶机能亢进引起的病理生理过程。
本发明中所制备的化合物应当满足作为药物的活性成分应当具备的物理及化学稳定性及其它性质,如结晶稳定性、不存在多晶型现象以及吸湿性较低,尤其不存在多晶型现象。本发明的另一目的为提供一种立体选择性制备本发明的化合物的方法。
附图说明
表1:化合物(I)的至30°2θ(包括30°2θ)的X射线衍射强度(标准化)
图1:化合物(I)的X射线粉末图。
图2:化合物(I)的DSC/TG图。
图3:化合物(I)的吸附等温线:a)动力学图,b)等温图。
发明详述
本发明通过提供了下文所述的尤其适于口服给药的式(I)化合物,其是高度结晶的,其吸湿性低及多晶型现象少,其药物制剂和合成方法,从而解决了上述问题。在本发明范围内,结晶稳定性指的是式(I)化合物的X射线粉末图在到较高2θ范围(优选直至20°2θ至40°2θ)内具有高强度的尖锐衍射峰。在本发明范围内,吸湿性低指的是在式(I)化合物的吸附实验中,观测到在所研究的10%至90%的湿度范围中水分吸收小于1%。在本发明范围内,多晶型现象少指的是在式(I)化合物自不同溶剂重结晶之后获得最多5种其它结晶变型、优选最多3种其它结晶变型、尤其优选无其它结晶变型。
本发明涉及式(I)的化合物
任选呈其互变异构体、溶剂合物或水合物的形式。
本发明另外涉及上述化合物用作药物、优选用于治疗气道的炎性或过敏性疾病、尤其优选用于治疗慢性阻塞性支气管炎(COPD)和/或慢性支气管炎。
式(I)化合物尤其优选在选自下列疾病的情况下使用:急性支气管炎;因细菌或病毒感染或真菌或蠕虫所引起的支气管炎;过敏性支气管炎;毒性支气管炎(toxic bronchitis);哮喘(内因性或过敏性);儿科哮喘;支气管扩张;变应性肺泡炎;过敏性或非过敏性鼻炎;慢性鼻窦炎;囊性纤维化或粘液粘稠病(mucoviscidosis);α-1-抗胰蛋白酶缺乏;咳嗽;肺气肿;间质性肺病;肺泡炎;反应过度性气道(hyperreactive airways);鼻息肉;肺水肿;各种原因的肺炎,例如辐射所引起的或因呼吸造成的肺炎或传染性肺炎;胶原性疾病(collagenoses),如红斑狼疮、全身性硬皮病、结节病(sarcoidosis)和伯克病(Boeck's disease),以及用于治疗由病毒、细菌或其它原因引起的哮喘和COPD中的并发症,用于治疗气道或肺的病毒或细菌感染。
亦尤其优选在涉及自身免疫反应的炎性或过敏性疾病的情况下使用式(I)化合物。亦尤其优选在呈良性或恶性肿瘤形式的疾病的情况下使用式(I)化合物。
本发明还涉及一种立体选择性制备式(I)化合物(任选呈其互变异构体、溶剂合物或水合物形式)的方法:
所述方法包括反应步骤(A)至(M),其中:
(A)为1,4-环己二酮-单乙二醇缩酮(1,4-cyclohexanedione-mono-ethyleneketal)反应形成式(1)化合物
(B)为式(1)化合物反应形成式(2)化合物
(C)为式(2)化合物反应形成式(3)化合物
(D)为式(3)化合物与保护基试剂反应形成式(4)化合物
(E)为还原式(4)化合物形成式(5)化合物
(F)为式(5)化合物反应形成式(6)化合物
(G)为式(6)化合物与式(13)化合物反应形成式(7)化合物
(H)为式(7)化合物反应形成式(8a)化合物或其互变异构形式(8b)
(I)为氯化式(8a)或式(8b)化合物形成式(9)化合物
(J)+(K)为式(9)化合物与3-氯-2-氟苯胺反应及保护基裂解形成式(11)或式(11A)化合物
(L)为裂解另一保护基形成式(II)化合物
(M)为式(II)化合物与马来酸反应形成式(I)化合物,任选呈其互变异构体、溶剂合物或水合物的形式,
其中,方法步骤(A)至(M)以指定顺序依次发生。
本发明还涉及一种立体选择性制备式(I)化合物(任选呈其互变异构体、溶剂合物或水合物形式)的方法,
其包括方法步骤(A)至(M),
其中方法步骤(J+K)以步骤(N+O)替代,其中
(N+O)为裂解式(9)化合物的保护基形成式(12)化合物,且随后与3-氯-2-氟苯胺反应,形成式(11)或式(11A)化合物
在优选的立体选择性制备式(I)化合物的方法中,该方法由方法步骤(I)、(J)、(K)、(L)及(M)组成或由方法步骤(I)、(N)、(O)、(L)及(M)组成,同时方法步骤(I)至(M)在各种情况下以指定顺序依次发生。
另外优选的立体选择性制备式(II)化合物方法的特征在于该方法由方法步骤(I)、(J)、(K)及(L)组成或由方法步骤(I)、(N)、(O)及(L)组成,同时方法步骤(I)至(L)在各种情况下以指定顺序依次发生。
方法步骤(G)尤其优选。
方法步骤(I)亦尤其优选。
本发明还涉及式(6)中间体,任选呈其互变异构体、溶剂合物或水合物的形式。
本发明还涉及式(7)中间体,任选呈其互变异构体、溶剂合物或水合物的形式。
本发明还涉及式(8)中间体,任选呈其互变异构体、溶剂合物或水合物的形式。
本发明还涉及式(9)中间体,任选呈其互变异构体、溶剂合物或水合物的形式。
本发明还涉及式(11)或式(11A)中间体,任选呈其互变异构体、溶剂合物或水合物的形式。
本发明还涉及含有式(I)化合物的药物组合物。优选为含有式(I)化合物的口服药物组合物。
在另一方面,本发明涉及药物组合,其除了包含权利要求1的式(I)化合物之外,其还含有一种或多种选自以下类别的化合物作为其他活性物质:β模拟剂、抗胆碱能药、皮质类固醇、PDE4-抑制剂、LTD4-受体拮抗剂、LTB4-受体拮抗剂、MAP激酶抑制剂、缓激肽受体拮抗剂、内皮素受体拮抗剂、CXCR1和/或CXCR2受体拮抗剂及止咳剂,或其两重或三重的组合。
在方法步骤A、C至L和N中,可使用选自下列试剂的替代性试剂:
方法步骤
A:除乙二胺及氯仿以外:
优选为苄基三乙基氯化铵/NaOH、四丁基氯化铵/KOH、苄基三乙基氯化铵/KOH、四丁基氯化铵/NaOH,尤其优选为苄基三乙基氯化铵/NaOH;
C:优选醇盐碱,选自NaOtBu、KOtBu和NaOEt,碳酸盐碱,选自Cs2CO3、K2CO3、Li2CO3和Na2CO3,尤其优选为甲醇钠;
D:除焦碳酸二叔丁酯(di-tert-butyldicarbonate)和DMAP(4-(二甲基氨基)-吡啶)以外:
优选为K2CO3、Cs2CO3、Li2CO3和Na2CO3,尤其优选为K2CO3;
E:优选为NaBH4和LiBH4,尤其优选为NaBH4;
F:除三氟乙酸酐以外:
作为碱优选为三乙胺、Hünig碱、N-甲基吗啉和N,N-二乙基苯胺,尤其优选为三乙胺;
G:除3-苄基-6-羟基-7-甲氧基-3H-喹唑啉-4酮以外:
优选为三苯基膦/偶氮二甲酸二异丙酯、三苯基膦/偶氮二甲酸二乙酯、三丁基膦/1,1'-(偶氮二羰基)二哌啶,尤其优选为三苯基膦/偶氮二甲酸二异丙酯;
H:催化剂,优选选自Pd/C和Pd(OH)2,尤其优选为Pd/C;
I:优选为N-氯代丁二酰亚胺/三苯基膦(组合)、草酰氯、亚硫酰氯、磷酰氯、五氯化磷、四氯化碳/三苯基膦、二氯三苯基膦和P,P-二氯-苯基氧化膦,尤其优选为N-氯代丁二酰亚胺/三苯基膦(组合);
J+K:除3-氯-2-氟苯胺以外:
优选为HCl、甲磺酸、乙磺酸、对甲苯磺酸和HBr,尤其优选为HCl;
L:优选为乙醇胺、氨和Ba(OH)2,尤其优选为乙醇胺;
I+N:优选为N-氯代丁二酰亚胺/三苯基膦(组合)、HCl、草酰氯、亚硫酰氯、磷酰氯、五氯化磷、四氯化碳/三苯基膦、二氯三苯基膦和P,P-二氯-苯基氧化膦、甲磺酸、乙磺酸、对甲苯磺酸和HBr,尤其优选为N-氯代丁二酰亚胺/三苯基膦(组合)和HCl。
在上述方法步骤中优选使用选自按各种情况所列的以下溶剂:
方法步骤
C:ACN(CH3CN)、EtOH、MeOH、iPrOH、H2O、THF和NMP;
D:ACN、EtOH和NMP;
J:ACN、二烷、THF和EtOH;
M:EtOH、MeOH和H2O;
N:二烷/CAN和THF/二烷;
上述方法步骤优选在以下温度范围中进行:
方法步骤:
A:优选为-15℃至40℃,尤其优选为0℃至20℃;
B:优选为0℃至100℃,尤其优选为75℃至100℃;
C:优选为0℃至65℃,尤其优选为15℃至30℃;
D:优选为10℃至80℃,尤其优选为15℃至35℃;
E:优选为0℃至40℃,尤其优选为0℃至15℃;
F:优选为-10℃至60℃,尤其优选为0℃至35℃;
G:优选为10℃至65℃,尤其优选为45℃至60℃;
H:优选为20℃至85℃,尤其优选为70℃至85℃;
I:优选为20℃至100℃,尤其优选为70℃至95℃;
J:优选为20℃至100℃,尤其优选为50℃至85℃;
K:优选为20℃至100℃,尤其优选为50℃至85℃;
L:优选为50℃至80℃,尤其优选为70℃至80℃;
M:优选为0℃至75℃,尤其优选为0℃至70℃;
N:优选为20℃至100℃,尤其优选为50℃至85℃;
O:优选为50℃至100℃,尤其优选为70℃至80℃。
优选使用选自苄基、Cbz、三氟乙酰基和Boc的保护基,尤其为三氟乙酰基和Boc。
上式中所用缩写Boc代表叔丁氧基羰基且Cbz代表苄氧基羰基。
反应方程式1示例性说明了本发明的合成方法。所有化合物均以其碱的形式显示。
反应方程式1(1/2)合成化合物(I)
反应方程式1(2/2)
下面的实施例用于以实施例的方式示例性说明制备式(I)化合物的方法。这些应当理解为对于说明的示例性说明,而非对其主题进行限制。
实施例1
1,4-二氧杂-9,12-二氮杂-二螺[4.2.5.2]十五烷-13-酮
方法步骤A
在5℃,将15.1kg50%氢氧化钠溶液滴加至437g氯化苄基三乙基铵和2700ml乙二胺于19.2L二氯甲烷中的混合物中。随后,在5℃至15℃,在接下来4.5小时内下滴加6000g的1,4-环己二酮-单乙二醇缩酮和6100g氯仿于4.8L二氯甲烷中的溶液。用3L二氯甲烷冲洗滴液漏斗。15小时后,在15℃至25℃,添加18L水和39L二氯甲烷。分离各相,用20L二氯甲烷萃取水相。合并的有机相通过蒸馏进行浓缩。在已蒸馏出72L溶剂之后,向悬浮液中添加48L异丙醇,随后再蒸馏出30L溶剂。冷却至3℃之后,滤出沉淀物,用7.5L冷异丙醇洗涤两次。在50℃真空干燥后,获得6144g产物。
质谱(ESI+):m/z=227[M+H]+
实施例2
1,4-二氮杂-螺[5.5]十一烷-5,9-二酮
方法步骤B
在80℃至100℃,在15分钟内将14.5kg的4M HCl的二烷溶液滴加至含6085g的1,4-二氧杂-9,12-二氮杂-二螺[4.2.5.2]十五烷-13-酮的25kg乙酸中。用3kg乙酸冲洗滴液漏斗。140分钟后,将悬浮液冷却至20℃。2小时后,滤出沉淀物,用12L二烷洗涤两次。在60℃真空干燥后,获得5333g呈盐酸盐形式的产物。
质谱(ESI+):m/z=183[M+H]+
方法步骤C
在室温,在3小时内将含5200g的1,4-二氮杂-螺[5.5]十一烷-5,9-二酮盐酸盐的52L乙腈与4370ml的30%甲醇钠的甲醇溶液混合。用1L甲醇冲洗滴液漏斗。添加250g碳酸钠,将混合物搅拌16小时。蒸馏出30L溶剂,在添加20L乙腈之后过滤悬浮液。用10L乙腈洗涤滤饼。自滤液中蒸馏出22L溶剂,含有产物的残余物直接在下一步骤中进一步反应。
实施例3
5,9-二氧代-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤D
将6573g碳酸钾和145g的4-(二甲基氨基)-吡啶添加至前面的混合物(含有1,4-二氮杂-螺[5.5]十一烷-5,9-二酮)中。随后在30分钟内滴加含6487g焦碳酸二叔丁酯的8L乙腈。用2L乙腈冲洗滴液漏斗。在100分钟之后,在10℃将混合物添加至20L水中。其经2L水、5L乙腈和16L甲苯冲洗。在相分离之后,将有机相与10L甲苯合并。蒸馏出55L溶剂。添加30L甲基环己烷和10L甲苯之后,混合物以产物接种,在20℃至30℃将悬浮液搅拌14小时。添加20L甲基环己烷,将混合物冷却至-5℃。在2.5小时之后,滤出沉淀物,用10L甲基环己烷洗涤。在50℃真空干燥后,获得5160g产物。
质谱(ESI+):m/z=283[M+H]+
实施例4
(顺式)-9-羟基-5-氧代-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤E
在3℃,在17分钟内将含201g硼氢化钠的5L水滴加至5000g的5,9-二氧代-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯于35L水中的混合物中。用1.4L水冲洗滴液漏斗。在15分钟之后,添加30L甲基-四氢呋喃。在添加10L饱和碳酸钾溶液之后,分离各相,用20L甲基-四氢呋喃萃取水相。用1L饱和盐水溶液洗涤合并的有机相。分离出有机相,用27.5L甲基-四氢呋喃稀释。蒸馏出55L溶剂。随后添加15L甲基-四氢呋喃,蒸馏出15L溶剂。随后添加20L甲基-四氢呋喃,蒸馏出20L溶剂。随后添加20L甲基-四氢呋喃,蒸馏出20L溶剂。含有产物的残余物直接在下一步骤中进一步反应。
质谱(ESI+):m/z=285[M+H]+
实施例5
(顺式)-9-羟基-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤F
将11.1L三乙基氨基添加至来自先前混合物的有机相中。随后,在3℃至25℃,在30分钟内滴加5170ml三氟乙酸酐。在15分钟之后,添加12.4L甲醇。在1小时之后,真空蒸馏出30L溶剂。随后,添加15.3L甲醇,真空蒸馏出8L溶剂。添加12.4L甲醇,在1℃至10℃,在50分钟内滴加35L水。在2℃经1小时之后,离心出沉淀物,用水与甲醇2:1的10L混合物洗涤,随后用10L水再次洗涤。在循环空气干燥器中在55℃干燥后,获得5299g呈顺/反式混合物形式的产物。
将此粗产物悬浮于70L甲苯中。随后,蒸馏出500ml溶剂,随后添加10L甲苯。冷却溶液,在52℃将其以产物接种。在1℃经3小时之后,离心出沉淀物,用8L冷甲苯洗涤。在55℃真空干燥后,获得4398g产物,其仍含有约4%的反式产物。
质谱(ESI+):m/z=381[M+H]+
实施例6
(反式)-9-(3-苄基-7-甲氧基-4-氧代-3,4-二氢-喹唑啉-6-基氧基)-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤G
在50℃至55℃,在100分钟内将2471ml偶氮二甲酸二异丙酯滴加至3500g的(顺式)-9-羟基-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯、2362g的3-苄基-6-羟基-7-甲氧基-3H-喹唑啉-4-酮和3292g三苯基膦于45L四氢呋喃中的混合物中。用4L四氢呋喃冲洗滴液漏斗,真空蒸馏出30L溶剂。随后,在连续添加60L乙醇期间,在常压下蒸馏出另外30L溶剂。其以产物接种,缓慢冷却至室温。在19小时之后,过滤出沉淀物,用15L乙醇洗涤。在50℃真空干燥后,获得4710g产物。
质谱(ESI+):m/z=645[M+H]+
实施例7
(反式)-9-(4-羟基-7-甲氧基-喹唑啉-6-基氧基)-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤H
将470g钯/炭(10%)添加至4700g的(反式)-9-(3-苄基-7-甲氧基-4-氧代-3,4-二氢-喹唑啉-6-基氧基)-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯于33L异丙醇和33L二烷中的混合物中。在80℃氢化4小时后,在60℃过滤混合物,用10L异丙醇与10L二烷的混合物洗涤。自滤液中真空蒸馏出58L溶剂,添加32L叔丁基甲基醚。在2小时之后,在0℃至5℃过滤出沉淀物,用15L叔丁基甲基醚洗涤。在50℃真空干燥后,获得4153g产物。
质谱(ESI+):m/z=555[M+H]+
实施例8
(反式)-9-(4-氯-7-甲氧基-喹唑啉-6-基氧基)-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
方法步骤I
在60℃,在1分钟内将含1590g的N-氯代丁二酰亚胺的20L乙腈添加至5500g的(反式)-9-(4-羟基-7-甲氧基-喹唑啉-6-基氧基)-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯和3122g三苯基膦于24L二烷中的混合物中。用4L乙腈冲洗滴液漏斗,将混合物加热至80℃至90℃持续30分钟。含有产物的混合物在下一步骤中直接使用。
实施例9
(反式)-9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯
(反式)-9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-5-酮盐酸盐
方法步骤J+K
在50℃至60℃,经20分钟将1733g的3-氯-2-氟苯胺添加至上述混合物中之后。用2L乙腈冲洗滴液漏斗。随后添加7.8kg的4M盐酸的二烷溶液,在55℃至80℃,将混合物搅拌45分钟。在冷却至1℃之后,过滤出沉淀物,用10L乙醇洗涤。将沉淀物悬浮于40L乙醇中,与290g的3-氯-2-氟苯胺合并。在70℃至80℃,将悬浮液搅拌45分钟,随后在室温搅拌13小时。过滤出沉淀物,用10L乙醇洗涤。在60℃真空干燥后,获得4853g呈盐酸盐形式的产物。
质谱(ESI+):m/z=582[M+H]+
或:
方法步骤O
将3.42g的(反式)-9-(4-氯-7-甲氧基-喹唑啉-6-基氧基)-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-5-酮和1.25g的3-氯-2-氟苯胺于40ml乙醇中的混合物加热至80℃,持续2小时。在悬浮液已冷却至20℃且搅拌16小时之后,过滤出沉淀物,用10mL乙醇及10mL叔丁基甲基醚洗涤。在100℃真空干燥后,获得3.28g产物。
质谱(ESI+):m/z=582[M+H]+
实施例10
(反式)-9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1,4-二氮杂-螺[5.5]十一烷-5-酮
方法步骤L
将4700g的(反式)-9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-5-酮和5150g乙醇胺于47L乙醇中的混合物加热至75℃至80℃,持续17小时。在悬浮液已冷却至20℃之后,过滤出沉淀物,用15L乙醇洗涤。在60℃真空干燥后,获得3776g呈单乙醇溶剂合物形式的产物。
质谱(ESI+):m/z=486[M+H]+
1H NMR(400MHz,DMSO):9,60(1H,s);8,37(1H,s);7,82(1H,s);7,44-7,55(2H,m),7,37(1H,s);7,28(1H,t);7,22(1H,s);4,63-4,69(1H,m);4.33(1H,t);3,96(3H,s);3,41-3,49(2H,m);3.11-3.16(2H,m);2,82-2,87(2H,m);2,30(1H,s);2,14-2,23(2H,m);1,84-1,97(4H,m);1,44-1,51(2H,m);1.06(3H,t)。
实施例11
(反式)-9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1,4-二氮杂-螺[5.5]十一烷-5-酮二马来酸盐化合物
方法步骤M
在77℃,将1680g马来酸于7L乙醇和7L水中的溶液添加至含3500g的(反式)-9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1,4-二氮杂-螺[5.5]十一烷-5-酮单乙醇溶剂合物的18L乙醇中。用3L乙醇冲洗滴液漏斗。在66℃以产物接种溶液,在5分钟之后将35L乙醇滴加至悬浮液中。将悬浮液冷却至20℃,在此温度搅拌1小时。随后将其冷却至1℃,在此温度搅拌16小时。过滤出沉淀物,用10L乙醇洗涤两次。在60℃真空干燥后,获得4362g产物。
质谱(ESI+):m/z=486[M+H]+
1H NMR(400MHz,DMSO):8.50(1H,s);8,24(1H,s);7,93(1H,s);7,50-7,57(2H,m),7,29-7.35(1H,m);7,27(1H,s);6.15(4H,s);4,65-4,71(1H,m);3,98(3H,s);3,45-3,51(2H,m);3.39-3.44(2H,m);2,38-2,48(2H,m);2,06-2,15(2H,m);1,83-2.02(4H,m)。
实施例12
(反式)-9-(4-氯-7-甲氧基-喹唑啉-6-基氧基)-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一5-酮
方法步骤I+N
在60℃,在2分钟内将含19.6g的N-氯代丁二酰亚胺的240mL乙腈添加至60g的(反式)-9-(4-羟基-7-甲氧基-喹唑啉-6-基氧基)-5-氧代-1-(2,2,2-三氟-乙酰基)-1,4-二氮杂-螺[5.5]十一烷-4-甲酸叔丁酯和37.5g三苯基膦于300mL二烷中的混合物中。加热混合物至80℃至90℃,持续100分钟。在50℃至60℃经20分钟后,将84mL的4M盐酸的二烷溶液添加至混合物中,在50℃至85℃将混合物搅拌3小时。在环境温度搅拌17小时后,将混合物冷却至5℃,过滤出沉淀物。用二烷/乙腈的1:1混合物和叔丁基甲基醚洗涤滤饼。在50℃干燥后,获得40g产物。
质谱(ESI+):m/z=473[M+H]+
数据收集
使用以下设备和测试条件来收集所附数据。
X射线粉末衍射仪
采用加装位置敏感检测器的STOE Stadi P X-衍射粉末衍射仪,以弯曲光锗(curved germanium)(111)为主线单色器波长的传送模式测定:CuKα1,X-射线管的功率:40kV,40mA;检测范围:3-40°2θ。
热分析设备
使用Mettler Toledo制造的DSC822。使用下列测量参数:加热速率:10K/分钟;坩埚类型:多孔铝坩埚;气氛:N2,80ml/分钟流速;典型重量:3-10mg。
使用Mettler Toledo制造的TGA/SDTA851联合Nicolet FT-IR4700光谱仪,用于分析分离的挥发性馏分。使用下列测量参数:加热速率:10K/分钟;坩埚类型:开口式氧化铝坩埚;气氛:N2,20ml/分钟流速;典型重量:15-25mg。
可根据附图2中的DSC/TG图确定化合物(I)的熔点。
用于水分吸收试的设备
使用Surface Measurement Systems(=SMS)制造的DVS-1来测试吸湿性能:利用湿度条件:10%至90%相对湿度,以10%递增,记录吸附和解吸概况,典型重量:10-20mg。
不同形式的相应图(动力学和等温图)示于图3a)和图3b)中。
生物学测试
化合物(I)的生物学性质研究如下,例如:
EGF-R介导的信号传输的抑制可(例如)使用表达人EGF-R且存活和增殖依赖于EGF或TGF-α刺激的细胞来显示。将鼠造血细胞系(murinehaematopoietic cell line)遗传修饰以表达功能性人EGF-R。因此该细胞系的增殖可通过EGF刺激。
测试如下进行:
将细胞于RPMI/1640培养基中培养。以20ng/ml人EGF(Promega)刺激增殖。为研究本发明的化合物的抑制活性,将这些化合物溶于100%二甲亚砜(DMSO)中,并以多种稀释浓度添加至培养物中,最大DMSO浓度为1%。将培养物在37℃下培养48小时。
为测定本发明的化合物的抑制活性,使用Cell Titer96TM AqueousNon-Radioactive Cell Proliferation Assay(Promega)以O.D.单位来测量相对细胞数。将相对细胞数计算为对照的百分比,且由此推导抑制细胞增殖50%的活性物质浓度(IC50)。
表2
适应症
如已发现,式(I)化合物的特征在于其在治疗领域中的通用性。应特别提及本发明式(I)化合物基于其作为酪氨酸抑制剂的医药功效而优选适用的可能应用。
如人EGF受体的实例所显示,本发明的通式(I)化合物因此抑制通过酪氨酸激酶的信号转导,且因此适用于治疗由酪氨酸激酶的机能亢进引起的病理生理学过程。这些过程为例如良性或恶性肿瘤(尤其上皮及神经上皮来源的肿瘤)、癌转移及血管内皮细胞的异常增殖(血管新生)。
本发明的化合物(I)亦适用于预防和治疗气道及肺的疾病,该疾病伴随有由酪氨酸激酶刺激引起的粘液产量增大或改变,例如在气道的炎性疾病中,如慢性支气管炎、慢性阻塞性支气管炎、哮喘、支气管扩张、过敏性或非过敏性鼻炎或窦炎、囊性纤维化、α1-抗胰蛋白酶缺乏或咳嗽、肺气肿、肺纤维化及反应过度性气道。
该化合物(I)亦适用于治疗与酪氨酸激酶活性破坏相关的胃肠道及胆管及胆囊的疾病,其如可见于(例如)慢性炎症变化(如胆囊炎、节段性回肠炎(Crohn's disease)、溃疡性结肠炎及胃肠道溃疡),或如可存在于与分泌增加相关的胃肠道疾病中(如梅内特里耶氏疾病(Ménétrier's disease)、分泌腺瘤及蛋白质损失综合征)。
另外,化合物(I)可用以治疗其它由酪氨酸激酶的异常功能引起的疾病,如表皮过度增殖(牛皮癣)、良性前列腺增生(BPH)、炎性过程、免疫系统疾病、造血细胞过度增殖、鼻息肉等。
组合
式(I)化合物可单独使用或与式(I)的其它活性物质组合使用。这些组合可同时或依次给药。任选地,式(I)化合物亦可与W组合使用,其中W表示药理学活性物质,且选自(例如):β模拟剂、抗胆碱能药、皮质类固醇、PDE4-抑制剂、LTD4-受体(cysLT1、cysLT2、cysLT3)拮抗剂、LTB4-受体(BLT1、BLT2)拮抗剂、MAP激酶(如p38、ERK1、ERK2、JNK1、JNK2、JNK3或SAP)的抑制剂、缓激肽(BK1、BK2)拮抗剂、内皮素受体拮抗剂、CXCR1和/或CXCR2受体拮抗剂,和止咳物质。
另外,可将W的双重或三重组合与式(I)化合物组合。W与式(I)化合物的组合的实例将可以为:
●W表示与抗胆碱能药、皮质类固醇、PDE4-抑制剂、EGFR-抑制剂或LTD4-受体拮抗剂组合的β模拟剂,
●W表示与β模拟剂、皮质类固醇、PDE4-抑制剂、EGFR-抑制剂或LTD4-受体拮抗剂组合的抗胆碱能药,
●W表示与PDE4-抑制剂、EGFR-抑制剂或LTD4-受体拮抗剂组合的皮质类固醇,
●W表示与EGFR-抑制剂或LTD4-受体拮抗剂组合的PDE4-抑制剂,
●W表示与抗胆碱能药组合的EGFR-抑制剂。
在本文中可使用的β模拟剂的实例优选包括选自下列的化合物:阿福特罗(arformoterol)、卡莫特罗(carmoterol)、福莫特罗(formoterol)、茚达特罗(indacaterol)、沙美特罗(salmeterol)、沙丁胺醇(albuterol)、班布特罗(bambuterol)、比托特罗(bitolterol)、溴沙特罗(broxaterol)、卡布特罗(carbuterol)、克仑特罗(clenbuterol)、非诺特罗(fenoterol)、海索那林(hexoprenalin)、异丁特罗(ibuterol)、α-乙基异丙肾上腺素(isoetharin)、异丙肾上腺素(isoprenalin)、左沙丁胺醇(levosalbutamol)、马布特罗(mabuterol)、美卢君(meluadrin)、间羟异丙肾上腺素(metaproterenol)、米维特罗(milveterol)、奥西那林(orciprenalin)、吡布特罗(pirbuterol)、丙卡特罗(procaterol)、瑞普特罗(reproterol)、利米特罗(rimiterol)、利托君(ritodrin)、沙甲胺醇(salmefamol)、索特瑞醇(soterenol)、沙芬特罗(sulphonterol)、特布他林(terbutalin)、噻拉米特(tiaramid)、托鲁布特罗(tolubuterol)、净特罗(zinterol)和6-羟基-8-{1-羟基-2-[2-(4-甲氧基-苯基)-1,1-二甲基-乙基氨基基]-乙基}-4H-苯并[1,4]嗪-3-酮、8-{2-[2-(2,4-二氟-苯基)-1,1-二甲基-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、8-{2-[2-(3,5-二氟-苯基)-1,1-二甲基-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、8-{2-[2-(4-乙氧基-苯基)-1,1-二甲基-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、8-{2-[2-(4-氟-苯基)-1,1-二甲基-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、N-(5-{2-[3-(4,4-二乙基-2-氧代-4H-苯并[d][1,3]嗪-1-基)-1,1-二甲基-丙基氨基]-1-羟基-乙基}-2-羟基-苯基)-甲磺酰胺、N-(5-{2-[3-(4,4-二乙基-6-氟-2-氧代-4H-苯并[d][1,3]嗪-1-基)-1,1-二甲基-丙基氨基]-1-羟基-乙基}-2-羟基-苯基)-甲磺酰胺、N-(5-{2-[3-(4,4-二乙基-6-甲氧基-2-氧代-4H-苯并[d][1,3]嗪-1-基)-1,1-二甲基-丙基氨基]-1-羟基-乙基}-2-羟基-苯基)-甲磺酰胺、N-(5-{2-[1,1-二甲基-3-(2-氧代-4,4-二丙基-4H-苯并[d][1,3]嗪-1-基)-丙基氨基]-1-羟基-乙基}-2-羟基-苯基)-甲磺酰胺、8-{2-[1,1-二甲基-3-(2-氧代-2,3-二氢-苯并咪唑-1-基)-丙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、8-{2-[1,1-二甲基-3-(6-甲基-2-氧代-2,3-二氢-苯并咪唑-1-基)-丙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、8-{2-[1,1-二甲基-3-(2-氧代-5-三氟甲基-2,3-二氢-苯并咪唑-1-基)-丙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、8-{2-[1,1-二甲基-3-(3-甲基-2-氧代-2,3-二氢-苯并咪唑-1-基)-丙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮、N-[2-羟基-5-((1R)-1-羟基-2-{2-[4-(2-羟基-2-苯基-乙基氨基)-苯基]-乙基氨基}-乙基)-苯基]-甲酰胺、8-羟基-5-((1R)-1-羟基-2-{2-[4-(6-甲氧基-联苯-3-基氨基)-苯基]-乙基氨基}-乙基)-1H-喹啉-2-酮、8-羟基-5-[(1R)-1-羟基-2-(6-苯乙基氨基-己基氨基)-乙基]-1H-喹啉-2-酮、5-[(1R)-2-(2-{4-[4-(2-氨基-2-甲基-丙氧基)-苯基氨基]-苯基}-乙基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮、[3-(4-{6-[(2R)-2-羟基-2-(4-羟基-3-羟甲基-苯基)-乙基氨基]-己基氧基}-丁基)-5-甲基-苯基]-脲、4-((1R)-2-{6-[2-(2,6-二氯-苯甲氧基)-乙氧基]-己基氨基}-1-羟基-乙基)-2-羟甲基-苯酚、3-(4-{6-[(2R)-2-羟基-2-(4-羟基-3-羟甲基-苯基)-乙基氨基基]-己基氧基}-丁基)-苯磺酰胺、3-(3-{7-[(2R)-2-羟基-2-(4-羟基-3-羟甲基-苯基)-乙基氨基]-庚氧基}-丙基)-苯磺酰胺、4-((1R)-2-{6-[4-(3-环戊烷磺酰基-苯基)-丁氧基]-己基氨基}-1-羟基-乙基)-2-羟甲基-苯酚、N-1-金刚烷基-2-{3-[(2R)-2-({(2R)-2-羟基-2-[4-羟基-3-(羟甲基)苯基]乙基}氨基)丙基]苯基}乙酰胺、(1R)-5-{2-[6-(2,2-二氟-2-苯基-乙氧基)-己基氨基]-1-羟基-乙基}-8-羟基-1H-喹啉-2-酮、(R,S)-4-(2-{[6-(2,2-二氟-4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟甲基)苯酚、(R,S)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基-乙基)-2-(羟甲基)苯酚、(R,S)-4-(2-{[4,4-二氟-6-(4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟甲基)苯酚、(R,S)-4-(2-{[6-(4,4-二氟-4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟甲基)苯酚、(R,S)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基-乙基)-8-羟基喹啉-2(1H)-酮、(R,S)-[2-({6-[2,2-二氟-2-(3-甲基苯基)乙氧基]己基}氨基)-1-羟乙基]-2-(羟甲基)苯酚、4-(1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟乙基)-2-(羟甲基)苯酚、(R,S)-2-(羟甲基)-4-(1-羟基-2-{[4,4,5,5-四氟-6-(3-苯基丙氧基)己基]氨基}乙基)苯酚、(R,S)-[5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基-乙基)-2-羟基苯基]甲酰胺、(R,S)-4-[2-({6-[2-(3-溴苯基)-2,2-二氟乙氧基]己基}氨基)-1-羟乙基]-2-(羟甲基)苯酚、(R,S)-N-[3-(1,1-二氟-2-{[6-({2-羟基-2-[4-羟基-3-(羟甲基)苯基]乙基}氨基)己基]氧基}乙基)苯基]-脲、3-[3-(1,1-二氟-2-{[6-({2-羟基-2-[4-羟基-3-(羟甲基)苯基]乙基}氨基)己基]氧基}乙基)苯基]咪唑啶-2,4-二酮、(R,S)-4-[2-({6-[2,2-二氟-2-(3-甲氧苯基)乙氧基]己基}氨基)-1-羟乙基]-2-(羟甲基)苯酚、5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟乙基)-8-羟基喹啉-2(1H)-酮、4-((1R)-2-{[4,4-二氟-6-(4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟甲基)苯酚、(R,S)-4-(2-{[6-(3,3-二氟-3-苯基丙氧基)己基]氨基}-1-羟基-乙基)-2-(羟甲基)苯酚、(R,S)-(2-{[6-(2,2-二氟-2-苯基乙氧基)-4,4-二氟己基]氨基}-1-羟乙基)-2-(羟甲基)苯酚、(R,S)-4-(2-{[6-(2,2-二氟-3-苯基丙氧基)己基]氨基}-1-羟乙基)-2-(羟甲基)苯酚、3-[2-(3-氯-苯基)-乙氧基]-N-(2-二乙基氨基-乙基)-N-{2-[2-(4-羟基-2-氧代-2,3-二氢-苯并噻唑-7-基)-乙基氨基]-乙基}-丙酰胺、N-(2-二乙基氨基-乙基)-N-{2-[2-(4-羟基-2-氧代-2,3-二氢-苯并噻唑-7-基)-乙基氨基]-乙基}-3-(2-萘-1-基-乙氧基)-丙酰胺、7-[2-(2-{3-[2-(2-氯-苯基)-乙基氨基]-丙基硫基}-乙基氨基)-1-羟基-乙基]-4-羟基-3H-苯并噻唑-2-酮,
任选呈外消旋体、对映异构体、非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、溶剂合物或水合物的形式。根据本发明,β模拟剂的酸加成盐优选选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐及对甲苯磺酸盐。
在本文中可使用的抗胆碱能药的实例优选包括选自下列的化合物:噻托铵(tiotropium)盐(优选溴化物盐)、氧托铵(oxitropium)盐(优选溴化物盐)、氟托铵(flutropium)盐(优选溴化物盐)、异丙托铵(ipratropium)盐(优选溴化物盐)、阿地铵(aclidinium)盐(优选溴化物盐)、格隆铵(glycopyrronium)盐(优选溴化物盐)、曲司铵(trospium)盐(优选氯化物盐)、托特罗定(tolterodine)、(3R)-1-苯乙基-3-(9H-呫吨-9-羰基氧基)-1-氮双环[2,2,2]辛烷盐。在上述盐中,阳离子为药理学活性组份。上述盐优选可含有氯离子、溴离子、碘离子、硫酸根、磷酸根、甲磺酸根、硝酸根、马来酸根、乙酸根、柠檬酸根、富马酸根、酒石酸根、草酸根、琥珀酸根、苯甲酸根或对甲苯磺酸根作为X-阴离子,而优选氯离子、溴离子、碘离子、硫酸根、甲磺酸根或对甲苯磺酸根作为抗衡离子。在所有盐中,尤其优选为氯化物、溴化物、碘化物及甲磺酸盐。
其它化合物为:托品醇(tropenol)2,2-二苯基丙酸酯甲溴化物、东茛菪醇(scopine)2,2-二苯基丙酸酯甲溴化物、东茛菪醇2-氟-2,2-二苯基乙酸酯甲溴化物、托品醇2-氟-2,2-二苯基乙酸酯甲溴化物、托品醇3,3',4,4'-四氟二苯羟乙酸酯甲溴化物、东茛菪醇3,3',4,4'-四氟二苯羟乙酸酯甲溴化物、托品醇4,4'-二氟二苯羟乙酸酯甲溴化物、东茛菪醇4,4'-二氟二苯羟乙酸酯甲溴化物、托品醇3,3'-二氟二苯羟乙酸酯甲溴化物、东茛菪醇3,3'-二氟二苯羟乙酸酯甲溴化物;托品醇9-羟基-芴-9-甲酸酯甲溴化物、托品醇9-氟-芴-9-甲酸酯甲溴化物、东茛菪醇9-羟基-芴-9-甲酸酯甲溴化物、东茛菪醇9-氟-芴-9-甲酸酯甲溴化物;托品醇9-甲基-芴-9-甲酸酯甲溴化物、东茛菪醇9-甲基-芴-9-甲酸酯甲溴化物、环丙基茛菪醇二苯羟乙酸酯甲溴化物、环丙基茛菪醇2,2-二苯基丙酸酯甲溴化物、环丙基茛菪醇9-羟基-呫吨-9-甲酸酯甲溴化物、环丙基茛菪醇9-甲基-芴-9-甲酸酯甲溴化物、环丙基茛菪醇9-甲基-呫吨-9-甲酸酯甲溴化物、环丙基茛菪醇9-羟基-芴-9-甲酸酯甲溴化物、环丙基茛菪醇4,4'-二氟二苯羟乙酸甲基酯甲溴化物、托品醇9-羟基-呫吨-9-甲酸酯甲溴化物、东茛菪醇9-羟基-呫吨-9-甲酸酯甲溴化物、托品醇9-甲基-呫吨-9-甲酸盐-甲溴化物、东茛菪醇9-甲基-呫吨-9-甲酸盐-甲溴化物、托品醇9-乙基-呫吨-9-甲酸酯甲溴化物、托品醇9-二氟甲基-呫吨-9-甲酸酯甲溴化物、东茛菪醇9-羟基甲基-呫吨-9-甲酸酯甲溴化物。在本发明的范围内,上述化合物亦可以盐形式使用,而可使用甲基-X盐来代替甲溴化物,其中X可具有上文中对X-给出的含义。
可用作皮质类固醇的化合物优选为选自下列的化合物:倍氯米松(beclomethasone)、倍他米松(betamethasone)、布地奈德(budesonide)、布替可特(butixocort)、环索奈德(ciclesonide)、地夫可特(deflazacort)、地塞米松(dexamethasone)、埃替泼诺(etiprednol)、氟尼缩松(flunisolide)、氟替卡松(fluticasone)、氯替泼诺(loteprednol)、莫美他松(mometasone)、泼尼松龙(prednisolone)、泼尼松(prednisone)、罗氟奈德(rofleponide)、曲安西龙(triamcinolone)、替泼尼旦(tipredane)及孕甾-1,4-二烯-3.20-二酮、6-氟-11-羟基-16,17-[(1-甲基亚乙基)双(氧基)]-21-[[4-[(硝基氧基)甲基]苯甲酰基]氧基]、-(9CI)(NCX-1024)、16,17-亚丁基二氧基-6,9-二氟-11-羟基-17-(甲硫基)雄甾-4-烯-3-酮(RPR-106541)、(S)-6,9-二氟-17-[(2-呋喃基羰基)氧基]-11-羟基-16-甲基-3-氧代-雄甾-1,4-二烯-17-硫代羰酸氟甲酯、(S)-6,9-二氟-11-羟基-16-甲基-3-氧代-17-丙酰氧基-雄甾-1,4-二烯-17-硫代羰酸(2-氧代-四氢-呋喃-3S-基)酯、6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-(2,2,3,3-四甲基环丙基羰基)氧基-雄甾-1,4-二烯-17β-甲酸氰基甲酯,任选呈其外消旋体、对映异构体或非对映异构体的形式且任选呈其盐及衍生物、其溶剂合物和/或水合物的形式。对类固醇的任何提及包括对其任何可存在的盐或衍生物、水合物或溶剂合物。类固醇的可能的盐及衍生物的实例可为:如钠盐或钾盐的碱金属盐、磺基苯甲酸盐、磷酸盐、异烟碱酸盐、乙酸盐、二氯乙酸盐、丙酸盐、磷酸二氢盐、棕榈酸盐、特戊酸盐或糠酸盐。
可使用的PDE4-抑制剂优选为选自下列的化合物:恩若非林(enprofyllin)、茶碱(theophyllin)、罗氟司特(roflumilast)、阿里氟洛(ariflo)(西洛司特(cilomilast))、托非司特(tofimilast)、普马芬群(pumafentrin)、利瑞司特(lirimilast)、阿匹司特(apremilast)、阿罗非林(arofyllin)、阿替唑仑(atizoram)、奥格司特(oglemilastum)、替托司特(tetomilast)及5-[(N-(2,5-二氯-3-吡啶基)-甲酰胺]-8-甲氧基-喹啉(D-4418)、N-(3,5-二氯-1-氧离子基-4-吡啶基)-甲酰胺]-8-甲氧基-2-(三氟甲基)-喹啉(D-4396(Sch-351591))、N-(3,5-二氯吡啶-4-基)-[1-(4-氟苄基)-5-羟基-吲哚-3-基]乙醛酸酰胺(AWD-12-281(GW-842470))、9-[(2-氟苯基)甲基]-N-甲基-2-(三氟甲基)-9H-嘌呤-6-胺(NCS-613)、4-[(2R)-2-[3-(环戊基氧基)-4-甲氧基苯基]-2-苯基乙基]-吡啶(CDP-840)、N-[(3R)-3,4,6,7-四氢-9-甲基-4-氧代-1-苯基吡咯并[3.2.1-jk][1.4]苯并二氮杂-3-基]-4-吡啶甲酰胺(PD-168787)、4-[6,7-二乙氧基-2.3-双(羟基甲基)-1-萘基]-1-(2-甲氧基乙基)-2(1H)-吡啶酮(T-440)、2-[4-[6,7-二乙氧基-2,3-双(羟基甲基)-1-萘基]-2-吡啶基]-4-(3-吡啶基)-1(2H)-酞嗪酮(T-2585)、(3-(3-环戊基氧基-4-甲氧基苄基)-6-乙基氨基-8-异丙基-3H-嘌呤(V-11294A)、β-[3-(环戊基氧基)-4-甲氧基苯基]-1,3-二氢-1,3-二氧代-2H-异吲哚-2-丙酰胺(CDC-801)、咪唑并[1,5-a]吡啶并[3.2-e]吡嗪-6(5H)-酮、9-乙基-2-甲氧基-7-甲基-5-丙基-(D-22888)、5-[3-(环戊基氧基)-4-甲氧基苯基]-3-[(3-甲基苯基)甲基]、(3S,5S)-2-哌啶酮(HT-0712)、4-[1-[3,4-双(二氟甲氧基)苯基]-2-(3-甲基-1-氧化-4-吡啶基)乙基]-α,α-双(三氟甲基)-苯甲醇(L-826141)、N-(3,5-二氯-1-氧代-吡啶-4-基)-4-二氟甲氧基-3-环丙基甲氧基苯甲酰胺、(-)p-[(4aR*.10bS*)-9-乙氧基-1,2,3,4,4a,10b-六氢-8-甲氧基-2-甲基苯并[s][1.6]二氮杂萘-6-基]-N,N-二异丙基苯甲酰胺、(R)-(+)-1-(4-溴苄基)-4-[(3-环戊基氧基)-4-甲氧基苯基]-2-吡咯烷酮、3-(环戊基氧基-4-甲氧基苯基)-1-(4-N'-[N-2-氰基-S-甲基-异硫脲基]苄基)-2-吡咯烷酮及顺式[4-氰基-4-(3-环戊基氧基-4-甲氧基苯基)环己烷-1-甲酸]、2-甲氧羰基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己-1-酮、顺式[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己-1-醇]、(R)-(+)-[4-(3-环戊基氧基-4-甲氧基苯基)亚吡咯烷-2-基]乙酸乙酯、(S)-(-)-[4-(3-环戊基氧基-4-甲氧基苯基)亚吡咯烷-2-基]乙酸乙酯、9-环戊基-5.6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4.3-a]吡啶及9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4.3-a]吡啶,
任选呈其外消旋体、对映异构体、非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、溶剂合物或水合物的形式。根据本发明,优选酸加成盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐及对甲苯磺酸盐。
在本文中所用的LTB4-受体拮抗剂优选为选自(例如)阿姆伦特(amebulant)(=[[4-[[3-[[4-[1-(4-羟基苯基)-1-甲基乙基]苯氧基]甲基]苯基]甲氧基]苯基]亚氨基甲基]-氨基甲酸乙酯)的化合物,任选呈其外消旋体、对映异构体、非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、溶剂合物或水合物的形式。根据本发明,优选酸加成盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐及对甲苯磺酸盐。
在本文中所用的LTD4-受体拮抗剂优选为选自下列的化合物:孟鲁司特(montelukast)、普鲁司特(pranlukast)、扎鲁司特(zafirlukast)及(E)-8-[2-[4-[4-(4-氟苯基)丁氧基]苯基]乙烯基]-2-(1H-四唑-5-基)-4H-1-苯并吡喃-4-酮(MEN-91507)、4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯硫基)丙氧基]-2-丙基苯氧基]丁酸(MN-001)、1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫基)甲基环丙烷乙酸、1-(((1(R)-3(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫基)甲基)环丙烷乙酸、[2-[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃基]氧基甲基]苯基]酸,任选呈其外消旋体、对映异构体、非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、溶剂合物或水合物的形式。根据本发明,优选酸加成盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐及对甲苯磺酸盐。
LTD4-受体拮抗剂任选能够形成的盐或衍生物是指(例如):碱金属盐(如钠盐或钾盐)、碱土金属盐、磺基苯甲酸盐、磷酸盐、异烟碱酸盐、乙酸盐、丙酸盐、磷酸二氢盐、棕榈酸盐、特戊酸盐或糠酸盐。
所用的MAP激酶抑制剂优选为选自下列的化合物:本他莫德(bentamapimod)(AS-602801)、多拉莫德(doramapimod)(BIRB-796)、5-氨基甲酰基吲哚(SD-169)、6-[(氨基羰基)(2,6-二氟苯基)氨基]-2-(2,4-二氟苯基)-3-吡啶甲酰胺(VX-702)、α-[2-[[2-(3-吡啶基)乙基]氨基]-4-嘧啶基]-2-苯并噻唑乙腈(AS-601245)、9,12-环氧基-1H-二吲哚并[1,2,3-fg:3',2',1'-kl]吡咯并[3,4-i][1.6]苯并1,4-二氮杂萘-10-甲酸(CEP-1347)、4-[3-(4-氯苯基)-5-(1-甲基-4-哌啶基)-1H-吡唑-4-基]-嘧啶(SC-409),任选呈其外消旋体、对映异构体、非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、溶剂合物或水合物的形式。
可使用的缓激肽拮抗剂优选为选自下列的化合物:艾替班特(icatibant)及1-哌嗪五铵、δ-氨基-4-[[4-[[[2,4-二氯-3-[[(2,4-二甲基-8-喹啉基)氧基]甲基]苯基]磺酰基]氨基]四氢-2H-吡喃-4-基]羰基]-N,N,N-三甲基-ε-氧代氯化物盐酸盐(1:1:1)(δS)-(MEN-16132),任选呈其外消旋体、对映异构体及非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、前药、溶剂合物或水合物的形式。
可使用的内皮素拮抗剂优选为选自下列的化合物:爱泰隆-1(actelion-1)、安博森坦(ambrisentan)、司他森坦(sitaxsentan)、N-(2-乙酰基-4,6-二甲基苯基)-3-[[(4-氯-3-甲基-5-异唑基)氨基]磺酰基]-2-噻吩甲酰胺(TBC-3214)及波生坦(bosentan),任选呈其外消旋体、对映异构体及非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、前药、溶剂合物或水合物的形式。
可使用的止咳物质优选为选自下列的化合物:氢可酮(hydrocodone)、卡拉美芬(caramiphen)、喷托维林(carbetapentane)及右甲吗喃(dextramethorphan),任选呈其外消旋体、对映异构体及非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、前药、溶剂合物或水合物的形式。
可使用的优选CXCR1或CXCR2拮抗剂优选为如3-[[3-[(二甲基氨基)羰基]-2-羟基苯基]氨基]-4-[[(R)-1-(5-甲基呋喃-2-基)丙基]氨基]环丁-3-烯-1,2-二酮(SCH-527123)的化合物,任选呈其外消旋体、对映异构体及非对映异构体的形式且任选呈其药理学上可接受的酸加成盐、前药、溶剂合物或水合物的形式。
根据本发明,优选物质为上述β模拟剂、抗胆碱能药、皮质类固醇、PDE4-抑制剂、LTB4(BLT1、BLT2)受体拮抗剂、LTD4(CysLT1、CysLT2、CysLT3)受体拮抗剂、MAP激酶(如p38、ERK1、ERK2、JNK1、JNK2、JNK3或SAP)的抑制剂、缓激肽受体拮抗剂、内皮素受体拮抗剂、止咳物质、CXCR1和/或CXCR2受体拮抗剂的酸加成盐,所述物质亦选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐、草酸盐、琥珀酸盐、苯甲酸盐和对甲苯磺酸盐。
药物组合物
本发明的化合物可通过口服、透皮、吸入、肠胃外或舌下途径来给药。本发明的化合物以活性成份形式存在于已知制剂中,例如于基本上由惰性药物载体及有效量的活性物质组成的组合物中,如片剂、包衣片剂、胶囊、口含剂、粉剂、溶液、悬浮液、乳液、糖浆、栓剂、透皮体系等。对于口服给药,本发明的化合物的有效剂量介于0.1毫克/剂与5000毫克/剂之间,优选介于1毫克/剂与500毫克/剂之间,更优选介于5-300毫克/剂之间,且对于静脉内、皮下或肌内给药,有效剂量介于0.001毫克/剂与50毫克/剂之间,优选介于0.1毫克/剂与10毫克/剂之间。对于吸入而言,根据本发明,含有0.01%至1.0%、优选0.1%至0.5%活性物质的溶液为合适的。对于通过吸入给药而言,使用粉剂、乙醇溶液或水溶液为优选。亦可能将本发明的化合物以溶液形式使用以供输注(优选于生理盐水或营养素盐水溶液中)。
本发明的化合物可独立使用或与本发明的其它活性物质结合使用,任选亦与其它药理学活性物质结合使用。合适制剂包括(例如)片剂、胶囊、栓剂、溶液、糖浆、乳液或可分散粉剂。相应片剂可(例如)通过混合活性物质与已知赋形剂来获得,已知赋形剂为例如惰性稀释剂,如碳酸钙、磷酸钙或乳糖;崩解剂,如玉米淀粉或海藻酸;粘合剂,如淀粉或明胶;润滑剂,如硬脂酸镁或滑石;和/或用于延迟释放的试剂,如羧甲基纤维素、酞酸乙酸纤维素或聚乙酸乙烯酯。片剂亦可包含若干层。
包衣片剂因此可通过以通常用于片剂包衣的物质(例如,可力酮(collidone)或虫胶、阿拉伯胶、滑石、二氧化钛或糖)涂覆与片剂类似制得的片芯来制备。为达成延迟释放或预防不兼容性,该芯亦可由许多层组成。类似地,片剂涂层可由许多层组成以达成延迟释放,其中可能将上述赋形剂用于片剂。
含有本发明的活性物质或其组合的糖浆可另外含有甜味剂,如糖精、赛克拉美(cyclamate)、甘油或糖;和风味增强剂(flavour enhancer),例如调味剂,如香兰素或香橙萃取物。其亦可含有悬浮助剂或稠化剂,如羧甲基纤维素钠;湿润剂,如脂肪醇与氧化乙烯的缩合产物;或防腐剂,如对羟基苯甲酸酯。
注射用溶液以常规方式(例如其中添加如对羟基苯甲酸酯的防腐剂,或如乙二胺四乙酸的碱金属盐的稳定剂),且转移至注射小瓶或安瓿中制备。
含有一种或多种活性物质或活性物质的组合的胶囊可例如通过混合活性物质与如乳糖或山梨醇的惰性载体且将其装填至明胶胶囊中来制备。
合适的栓剂可通过与为此目的而提供的载体(如中性脂肪或聚乙二醇或其衍生物)混合来制造。
对于医药用途而言,一般将本发明的化合物以0.01-100毫克/千克体重、优选0.1-15毫克/千克的剂量用于温血脊椎动物、尤其人类。对于给药而言,将其与一种或多种已知的惰性载体和/或稀释剂一起配制,例如与玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、聚乙烯吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨醇、水/聚乙二醇、丙二醇、十八烷醇、羧甲基纤维素或脂肪物质(如硬脂)或其合适混合物一起配制,以制造已知的盖伦制剂,如普通或包衣片剂、胶囊、粉剂、悬浮液、溶液、喷雾或栓剂。
以下实施例说明本发明而不限制其范围:
药物制剂的实施例
A)含有75mg活性物质的包衣片剂
组成:
1个片芯含有:
制备:
将活性物质与磷酸钙、玉米淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素及规定量一半的硬脂酸镁混合。在压片机中制得直径为13mm的素片,且接着使用合适机器将这些素片摩擦穿过筛孔尺寸为1.5mm的筛网,并与其余硬脂酸镁混合。在压片机中将此颗粒压制以形成所需形状的片剂。
片芯重量: 230mg
模: 9mm,凸面
在由此制得的片芯使用基本上由羟丙基甲基纤维素组成的膜包衣。以蜂蜡将最终的膜包衣片剂抛光。
包衣片剂的重量:245mg。
B)含有100mg活性物质的片剂
组成:
1个片剂含有:
制备方法:
将活性物质、乳糖和淀粉混合在一起,并用聚乙烯吡咯烷酮的水溶液均匀润湿。在将湿组合物过筛(2.0mm筛孔尺寸),并在架型干燥器中在50℃下干燥后,将其再次过筛(1.5mm筛孔尺寸),并添加润滑剂。将最终混合物压制成片剂。
片剂的重量: 220mg
直径: 10mm,双平面,在两侧均削切且在一侧刻凹痕
C)含有150mg活性物质的片剂
组成:
1个片剂含有:
制备:
将活性物质与乳糖、玉米淀粉和二氧化硅混合,并用20%聚乙烯吡咯烷酮水溶液润湿,将穿过筛孔尺寸为1.5mm的筛网。在45℃下干燥的颗粒剂再次穿过相同筛网,并与规定量的硬脂酸镁混合。由混合物压制片剂。
片剂的重量: 300mg
模: 10mm,平面
D)含有150mg活性物质的硬明胶胶囊
组成:
1个胶囊含有:
制备:
将活性物质与赋形剂混合,穿过筛孔尺寸为0.75mm的筛网,并使用合适的装置均匀混合。将最终的混合物装填至1号尺寸的硬明胶胶囊中。
胶囊填充: 约320mg
胶囊壳: 1号硬明胶胶囊。
E)含有150mg活性物质的栓剂
组成:
1个栓剂含有:
制备:
在栓剂物质熔融后,将活性物质均匀分布于其中,并将熔融物倒入冷却的模具中。
F)含有50mg活性物质的悬浮液
组成:
100mL悬浮液含有:
制备:
将蒸馏水加热至70℃。在搅拌下将对羟基苯甲酸甲酯及对羟基苯甲酸丙酯连同甘油及羧甲基纤维素钠盐一起溶解于其中。将溶液冷却至环境温度,并添加活性物质,在搅拌下使其均匀分散于其中。在糖、山梨醇溶液及调味剂已添加且溶解之后,在搅拌下抽空悬浮液以除去空气。
含有50mg活性物质的5ml悬浮液。
G)含有10mg活性物质的安瓿
组成:
活性物质 10.0mg
0.01N盐酸 适量
双蒸水 补足至2.0ml
制备:
将活性物质溶解于必要量的0.01N HCl中,以食盐使其等渗,无菌过滤,并转移至2ml安瓿中。
H)含有50mg活性物质的安瓿
组成:
活性物质 50.0mg
0.01N盐酸 适量
双蒸水 补足至10.0ml
制备:
将活性物质溶解于必要量的0.01N HCl中,以食盐使其等渗,无菌过滤,并转移至10ml安瓿中。
Claims (17)
3.权利要求1或2的化合物,其用作药物。
4.权利要求1或2的化合物,其用于治疗气道的炎性或过敏性疾病。
5.一种立体选择性制备权利要求1的式(I)化合物的方法,该式(I)化合物任选呈其互变异构体的形式:
其特征在于该方法包括反应步骤(A)至(M),其中:
(A)为1,4-环己二酮-单乙二醇缩酮反应形成式(1)化合物
(B)为式(1)化合物反应形成式(2)化合物
(C)为式(2)化合物反应形成式(3)化合物
(D)为式(3)化合物与保护基试剂反应形成式(4)化合物
(E)为还原式(4)化合物形成式(5)化合物
(F)为式(5)化合物反应形成式(6)化合物
(G)为式(6)化合物与式(13)化合物反应形成式(7)化合物
(H)为式(7)化合物反应形成式(8a)化合物或其互变异构形式(8b)
(I)为氯化式(8a)或式(8b)化合物形成式(9)化合物
(J)+(k)为式(9)化合物与3-氯-2-氟苯胺反应并裂解保护基,形成式(11)或式(11A)化合物
(L)为裂解另一保护基,形成式(II)化合物
(M)为式(II)化合物与马来酸反应形成式(I)化合物,该式(I)化合物任选呈其互变异构体的形式
其中,所述方法步骤(A)至(M)以指定顺序依次进行。
6.权利要求5的方法,其中该所述方法步骤(J+K)由步骤(N+O)替代,其中
(N+O)为裂解该式(9)化合物的保护基,形成式(12)化合物,且随后与3-氯-2-氟苯胺反应形成权利要求6中的式(11)或式(11A)化合物
7.权利要求5或6的方法,其用于立体选择性制备式(I)化合物,其中该方法由方法步骤(I)、(J)、(K)、(L)和(M)组成或由方法步骤(I)、(N)、(O)、(L)和(M)组成,其中所述方法步骤(I)至(M)在各种情况下以指定顺序依次发生。
8.权利要求6或7的方法,其用于立体选择性制备式(II)化合物,其中该方法由方法步骤(I)、(J)、(K)和(L)组成或由方法步骤(I)、(N)、(O)和(L)组成,其中所述方法步骤(I)至(L)在各种情况下以指定顺序依次发生。
9.权利要求5的方法步骤(G)。
10.权利要求5的方法步骤(I)。
11.权利要求5的式(6)中间体,任选呈其互变异构体的形式。
12.权利要求5的式(7)中间体,任选呈其互变异构体的形式。
13.权利要求65的式(8)中间体,任选呈其互变异构体的形式。
14.权利要求5的式(9)中间体,其任选呈其互变异构体的形式。
15.权利要求5的式(11)或式(11A)中间体,任选呈其互变异构体的形式。
16.药物组合物,其含有权利要求1的式(I)化合物。
17.药物组合,其除了包含一种或多种权利要求1的式(I)化合物以外,还包含一种或多种选自下列种类的化合物作为其他活性物质:β模拟剂、抗胆碱能药、皮质类固醇、PDE4-抑制剂、LTD4-受体拮抗剂、LTB4-受体拮抗剂、MAP激酶抑制剂、缓激肽受体拮抗剂、内皮素受体拮抗剂、CXCR1和/或CXCR2受体拮抗剂和止咳剂,或其两重或三重的组合。
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CN105017164A (zh) * | 2015-08-25 | 2015-11-04 | 佛山市赛维斯医药科技有限公司 | 含新型苯并喹唑啉和邻位氯结构的酪氨酸激酶抑制剂及用途 |
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CN109608470A (zh) * | 2018-12-17 | 2019-04-12 | 上海药明康德新药开发有限公司 | 叔丁基-9-氧亚基-2,5,8-三氮杂螺[3.5]壬烷-2-甲酸基酯的合成方法 |
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EP2289881A1 (de) | 2009-08-06 | 2011-03-02 | Boehringer Ingelheim International GmbH | Verfahren zur stereoselektiven Synthese bicyclischer Heterocyclen |
US8853225B2 (en) | 2011-02-01 | 2014-10-07 | Boehringer Ingelheim International Gmbh | 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazoline-6-yloxy]-1,4-diaza-spiro[5.5] undecane-5-one dimaleate, use thereof as a medicament and method for the production thereof |
EP2812317B1 (de) | 2012-02-09 | 2016-02-03 | Boehringer Ingelheim International GmbH | Verfahren zur stereoselektiven synthese von 1,4-geschützten 9-hydroxy-5-oxo-1,4-diaza-spiro [5.5]undecane |
WO2014012859A1 (en) * | 2012-07-19 | 2014-01-23 | Boehringer Ingelheim International Gmbh | Fumaric acid salt of 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy- chinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one, its use as medicament and the preparation thereof |
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AU2012213556A1 (en) | 2013-08-22 |
AP2013006989A0 (en) | 2013-07-31 |
EA023573B1 (ru) | 2016-06-30 |
TN2013000323A1 (en) | 2015-01-20 |
GEP20156423B (en) | 2016-01-11 |
WO2012104206A1 (de) | 2012-08-09 |
EA201300872A1 (ru) | 2014-01-30 |
JP2014504619A (ja) | 2014-02-24 |
US8906931B1 (en) | 2014-12-09 |
CO6781555A2 (es) | 2013-10-31 |
PE20141012A1 (es) | 2014-09-10 |
US20140371226A1 (en) | 2014-12-18 |
MX2013008870A (es) | 2013-08-14 |
KR20140011330A (ko) | 2014-01-28 |
EP2670736A1 (de) | 2013-12-11 |
IL227534A0 (en) | 2013-09-30 |
UY33889A (es) | 2012-08-31 |
CL2013002031A1 (es) | 2013-12-27 |
US20130030003A1 (en) | 2013-01-31 |
SG192216A1 (en) | 2013-09-30 |
ECSP13012847A (es) | 2014-09-30 |
US8853225B2 (en) | 2014-10-07 |
AP3531A (en) | 2016-01-13 |
BR112013019416A2 (pt) | 2019-09-24 |
MA34845B1 (fr) | 2014-01-02 |
AR085056A1 (es) | 2013-08-07 |
WO2012104206A9 (de) | 2013-11-21 |
CA2826193A1 (en) | 2012-08-09 |
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