CN100436438C - 2-苯基吡喃-4-酮衍生物作为环加氧酶-2的抑制剂 - Google Patents
2-苯基吡喃-4-酮衍生物作为环加氧酶-2的抑制剂 Download PDFInfo
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- CN100436438C CN100436438C CNB2004800087372A CN200480008737A CN100436438C CN 100436438 C CN100436438 C CN 100436438C CN B2004800087372 A CNB2004800087372 A CN B2004800087372A CN 200480008737 A CN200480008737 A CN 200480008737A CN 100436438 C CN100436438 C CN 100436438C
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- phenyl
- alkyl
- amino
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- -1 hydroxyl carbonyl Chemical group 0.000 claims description 53
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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Abstract
本发明涉及通式I的2-苯基吡喃-4-酮衍生物,其制备方法,含有它们的药物组合物及其医学应用。
Description
本发明涉及新的有治疗效用的2-苯基吡喃-4-酮衍生物,它们的制备方法,含有它们的药物组合物及其作为药物的应用。
已知环加氧酶(COX)的非选择性抑制阻止了由环加氧酶-2(COX-2)介导的与发炎有关的前列腺素的超量生产,但同时也使组织丧失了主要由环加氧酶(COX-1)介导的对于某些组织的健康所必需的前列腺素基础水平。非甾类消炎药物是COX的非选择性抑制剂,因此,具有减小肾血流量、降低血小板功能、消化不良和胃溃疡等副作用。
我们现已发现,某些2-苯基吡喃-4-酮衍生物选择性地优先抑制COX-2而非COX-1,可用于治疗COX-2介导的疾病及其症状,例如发炎、疼痛、发热和哮喘,而副作用很小。
根据本发明,提供了一种式(1)的2-苯基吡喃-4-酮或其可药用的盐:
其中:
R1代表烷基基团;
R2代表烷基,C3-C7环烷基,吡啶基,噻吩基,萘基,四氢化萘基或2,3-二氢化茚基,或是代表苯基,该苯基可以是未被取代的或者被一个或多个卤原子或烷基、三氟甲基、羟基、烷氧基、甲硫基、氨基、一或二烷基氨基、羟烷基或羟羰基取代;
R3和R4可以相同或不同,代表氢原子,或代表未被取代的或被一个或多个卤原子取代的烷基、链烯基或炔基;
X代表单键、氧原子或亚甲基,更优选代表氧原子。
式(1)化合物在亚磺酰基的硫原子处有一个手性中心,或中用星号*标出。因此,如果化合物中没有其它的手性中心,则该化合物以两种不同的对映体形式存在;如果化合物中有另外的手性中心,则存在各种非对映体形式。本发明包括了所有这些立体异构化合物及其混合物。本说明书中使用的化学式打算表示所有可能的立体异构形式或其任何混合物。
在一项优选的实施方案中,本发明提供了式(1)化合物,其中R1代表未被取代的烷基,更优选代表甲基。
在另一实施方案中,本发明提供一种式(1)化合物,其中X代表一个单键或氧原子,更优选代表氧原子。
在又一实施方案中,本发明提供一种式(1)化合物,其中R3代表示氢原子或未被取代的C1-3烷基,优选代表氢原子。
在另一实施方案中,本发明提供一种式(1)化合物,其中R2代表一个支链烷基、C3-C7环烷基、萘基、四氢化萘基或2,3-二氢化茚基,未被取代的苯基或者被一个或多个卤原子、烷基和/或烷氧基取代的苯基;优选代表未被取代的苯基或被独立选卤原子、甲氧基或甲基的1、2或3个取代基取代的苯基;更优选被独立选自卤原子和甲基的1或2个取代基取代的苯基。
最优选的是,R2代表下式的任选被取代的苯基:
其中Ra和Rb选自氢原子、卤原子、烷基和/或烷氧基,更优选代表卤原子,最好是R2为2,4-二氟苯基,4-氯-2-氟苯基或4-溴-2-氟苯基。
除非另外说明,本文所用的烷基一词包括任选被取代的,有1-20个碳原子,优选1-12个碳原子的直链或支链基团。更优选烷基基团是有1-8、优选1-6、更优选1-4个碳原子的“低级烷基”基团。
其实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基、正戊基、1-甲基丁基、2-甲基丁基、异戊基、1-乙基丙基、1,1-二甲基丙基、1,2-二甲基丙基、正己基或1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、2-甲基戊基、3-甲基戊基、异己基。
所述的任选被取代的烷基通常是未被取代的或者被1、2或3个相同或不同的取代基取代。取代基优选选自卤原子(最好是氟原子)、羟基和有1-4个碳原子的烷氧基。通常,烷基上的取代基本身是未被取代的。
当提到烷基基团可以任选地被取代时,这意味着包括如上定义的直链或支链的烷基基团,它们可以是未被取代的,或是在任何位置上被一个或多个取代基,例如被1、2或3个取代基取代。当存在两个或多个取代基时,该取代基可以相同或不同。
这里使用的链烯基一词包括有2-20个碳原子,或者优选有2-12个碳原子的单或多不饱和的直链或支链基团。更优选的是,链烯基是有2-8个、优选2-6个、更优选2-4个碳原子的“低级链烯基”。特别是,该链烯基优选是单或双不饱和基团。
实例包括乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基和4-戊烯基。
当提到链烯基可以任选地被取代时,它意味着包括如上定义的直链或支链链烯基基团,它们可以是未被取代的或者在任何位置上被一个或多个指定的取代基,例如被1、2或3个取代基取代。当存在两个或多个取代基时,该取代基可以相同或不同。
所述的任选被取代的链烯基通常是未被取代的或者被相同或不同的1、2或3个取代基取代。这些取代基选自卤原子,优选氟原子。
这里使用的炔基一词包括有2-20个碳原子,或者优选有2-12个碳原子的单或多不饱和的直链或支链基团。更优选的是,炔基是有2-8个、优选2-6个、更优选2-4个碳原子的“低级炔基”。特别是,该炔基基团优选是单或双不饱和基团。
实例包括1-丙炔基、2-丙炔基、1-丁炔基,2-丁炔基和3-丁炔基。
当提到炔基可以是任选地被取代时,意味着包括如上定义的直链或支链炔基,它们可以是未被取代的或者在任何位置上被一个或多个指定的取代基,例如1、2或3个取代基取代。当存在两个或多个取代基时,这些取代基可以相同或不同。
所述的任选被取代的炔基通常是未被取代的,或是被1、2或3个相同或不同的取代基取代。这些取代基选自卤原子,优选氟原子。
这里使用的烷氧基一词包括各有1-10个碳原子的烷基部分的,可任选被取代的直链或支链含氧基团。更优选的烷氧基团是有1-8个,优选1-6个,更优选1-4个碳原子的“低级烷氧基”。
烷氧基通常是未被取代的或者被1、2或3个相同或不同的取代基取代。这些取代基优选选自卤原子(优选氟原子)、羟基和有1-4个碳原子的烷氧基。
优选的烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、三氟甲氧基、二氟甲氧基、羟基甲氧基、2-羟基乙氧基或2-羟基丙氧基。
这里使用的一烷基氨基一词包括含有与二价-NH-基团连接的,有1-10个碳原子并可任选被取代的直链或支链烷基的基团。更优选的一烷基氨基基团是有1-8个,优选1-6个,更优选1-4个碳原子的“低级-烷基氨基”基团。
一烷基氨基基团通常含有一个烷基,该烷基是未被取代的或者被1、2或3个相同或不同的取代基取代。这些取代基优选选自卤原子(优选氟原子),羟基和有1-4个碳原子的烷氧基。
优选的可任选取代的一烷基氨基包括甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、仲丁氨基、叔丁氨基、三氟甲基氨基、二氟甲基氨基、羟甲基氨基、2-羟乙基氨基或2-羟丙基氨基。
这里使用的二烷基氨基一词包括含有一个三价的氮原子和与其连结的两个任选被取代的,有1-10个碳原子的直链或支链烷基的基团。更优选的二烷基氨基是在每个烷基基团中有1-8个,优选1-6个,更优选1-4个碳原子的“低级二烷基氨基”基团。
二烷基氨基基团一般含两个烷基,它们各是未被取代的或者被1、2或3个相同或不同的取代基取代。这些取代基优选选自卤原子(优选氟原子),羟基和有1-4个碳原子的烷氧基。
优选的可任选取代的二烷基氨基包括二甲基氨基,二乙基氨基,甲基(乙基)氨基,二(正丙基)氨基,正丙基(甲基)氨基,正丙基(乙基)氨基,二(异丙基)氨基,异丙基(甲基)氨基,异丙基(乙基)氨基,二(正丁基)氨基,正丁基(甲基)氨基,正丁基(乙基)氨基,正丁基(异丙基)氨基,二(仲丁基)氨基,仲丁基(甲基)氨基,仲丁基(乙基)氨基,仲丁基(正丙基)氨基,仲丁基(异丙基)氨基,二(叔丁基)氨在,叔丁基(甲基)氨基,叔丁基(乙基)氨基,叔丁基(正丙基)氨基,叔丁基(异丙基)氨基,三氟甲基(甲基)氨基,三氟甲基(乙基)氨基,三氟甲基(正丙基)氨基,三氟甲基(异丙基)氨基,三氟甲基(正丁基)氨基,三氟甲基(仲丁基)氨基,二氟甲基(甲基)氨基,二氟甲基(乙基)氨基,二氟甲基(正丙基)氨基,二氟甲基(异丙基)氨基,二氟甲基(正丁基)氨基,二氟甲基(仲丁基)氨基,二氟甲基(叔丁基)氨基,二氟甲基(三氟甲基)氨基,羟甲基(甲基)氨基,乙基(羟甲基)氨基,羟甲基(正丙基)氨基,羟甲基(异丙基)氨基,正丁基(羟甲基)氨基,仲丁基(羟甲基)氨基,叔丁基(羟甲基)氨基,二氟甲基(羟甲基)氨基,羟甲基(三氟甲基)氨基,羟乙基(甲基)氨基,乙基(羟乙基)氨基,羟乙基(正丙基)氨基,羟乙基(异丙基)氨基,正丁基(羟乙基)氨基,仲丁基(羟乙基)氨基,叔丁基(羟乙基)氨基,二氟甲基(羟乙基)氨基,羟乙基(三氟甲基)氨基,羟丙基(甲基)氨基,乙基(羟丙基)氨基,羟丙基(正丙基)氨基,羟丙基(异丙基)氨基,正丁基(羟丙基)氨基,仲丁基(羟丙基)氨基,叔丁基(羟丙基)氨基,二氟甲基(羟丙基)氨基,羟丙基(三氟甲基)氨基。
这里使用的羟烷基一词包括有1-10个碳原子,优选1-6个碳原子的直链或支链烷基,其中任何烷基均可被一个或多个羟基取代。
这些基团的实例包括羟甲基,羟乙基,羟丙基,羟丁基和羟己基。
这里使用的环烷基一词包括饱和的碳环基团,而且除非另外指出,环烷基通常有3-7个碳原子。
环烷基一般是未被取代的或者被1、2或3个相同或不同的取代基取代。这些取代基优选选自卤原子(优选氟原子),羟基和有1-4个碳原子的烷氧基。当环烷基带有2个或更多的取代基时,这些取代基可以相同或不同。
实例包括环丙基、环丁基、环戊基、环己基和环庚基。优选环丙基、环戊基或环己基。当环烷基带有2个或更多的取代基时,这些取代基可以相同或不同。
这里使用的卤原子一词包括氯、氟、溴或碘原子,通常是氟、氯或溴原子,最优选的是氯或氟。卤一词在作为前缀使用时具有相同的含义。
这里使用的可药用的盐一词包括与可药用的酸或碱形成的盐。可药用的酸包括无机酸,例如盐酸,硫酸,磷酸,焦磷酸,氢溴酸,氢碘酸和硝酸,以及有机酸,例如柠檬酸,富马酸,马来酸,苹果酸,扁桃酸,抗坏血酸,草酸,琥珀酸,酒石酸,苯甲酸,乙酸,甲磺酸,乙磺酸,苯磺酸或对甲苯磺酸。可药用的碱包括碱金属(例如钠或钾)和碱土金属(例如钙或镁)氢氧化物及有机碱,例如烷基胺、芳烷基胺和杂环胺。
在被一个或多个卤原子或烷基、三氟烷基、羟基、烷氧基、甲硫基、氨基、一或二烷基氨基、羟烷基或羟羰基取代的苯基中,苯环可以被1、2、3、4或5个取代基,优选被1、2或3个取代基取代,各取代基独立地选自上述的可能的取代基。这就是说,苯基(通过其1-位与X或吡喃-4-环相连)可以在剩余的任何位置,即,第2、3、4、5或6-位被取代。有一个以上取代基的苯基可以在任何位置组合上被取代。例如有两个取代基的苯基可以在2和3,2和4,2和5,2和6,3和4,或3和5位处被取代。
本发明的2-苯基吡喃-4-酮衍生物的具体实例包括:
3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(4-氯-2-氟-苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(4-溴-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(2,4-二氟苯氧基)-6-乙基-5-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(4-氟-2-甲基苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(4-氯-2-甲基苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(2-氯-4-甲基苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(2-溴苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(3-溴苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(4-溴-2-氟苯氧在)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(4-溴-2-氯苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(2,4-二溴苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(2,4-二氟苯氧基)-6-甲基-2-[4-(乙基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(2-甲基苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(3-甲基苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
3-(2-氟-4-甲基氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮;
其所有可能的对映异构体形式及其混合物和可药用的盐。
特别有意义的是下式化合物的所有可能的对映异构体形式及其混合物和可药用的盐;
实施例 | R<sup>3</sup> | R<sup>a</sup> | R<sup>c</sup> | 构型 |
1 | Me | F | F | 外消旋 |
2 | Me | F | F | 对映体1a |
3 | Me | F | F | 对映体1b |
4 | Me | F | Cl | 外消旋 |
5 | Me | F | Cl | 对映体4a |
6 | Me | F | Cl | 对映体4b |
7 | Me | F | Br | 外消旋 |
8 | Me | F | Br | 对映体7a |
9 | Me | F | Br | 对映体7b |
本发明还提供了制备式(1)化合物方法
其中R1、R2、R3、R4和X的定义如上,该方法包括式(II)的巯基衍生物
其中R1、R2、R3、R4和X的定义如上,与氧化剂反应,若希望得到化合物的外消旋混合物时优选用偏过碘酸钠,若希望得到的式(1)化合物的混合物中富集着在亚磺酰手性中心处有特定构型的化合物,则使用四异丙醇钛、过氧化氢叔丁基和(R,R)或(S,S)形式酒石酸二乙酯的任一种的混合物。
式(II)的巯基衍生物和氧化剂之间的反应优选在有机溶剂中,最好是在氯化溶剂或氯化溶剂与C1-C4醇的混合物中,于-25℃至40℃的温度下进行。该氯化溶剂优选选自1,2-二氯乙烷、二氯甲烷、氯仿及其混合物。C1-C4醇优选选自甲醇和乙醇。优选的溶剂体系是1,2-二氯乙烷或二氯甲烷与甲醇或乙醇的混合物。
式(II)的巯基衍生物是已知的,可以按照WO 01/68633A1的说明制备。
其中存在碱性基团的式(1)的2-苯基吡喃-4-酮衍生物可以用本身已知的方法转化成可药用盐,优选通过用有机或无机酸例如富马酸、酒石酸、琥珀酸或盐酸处理,转化成酸加成盐。
以下的生物试验和数据进一步说明本发明。
COX-1和COX-2在人全血中的活性
将取自健康的献血者的新鲜血液收集在肝素化试管中(每ml 20单位肝素),这些献血者在抽血前至少7天内未服用任何非甾类消炎药物。对于COX-1活性测定,将每份500μl的血液与5μl载体(二甲基亚砜)或5μl试验化合物一起在37℃培养24小时。在停止培养前20分钟加入钙离子载体A23187(25μM)。离心(13000rpm下10分钟)分离血浆,在-30℃下保存,直至用酶免疫测定盒(EIA)测定TXB2含量。
每种化合物在5-6个不同浓度下培养,评价化合物的作用,重复测定三次。使用Inplot,Graphpad软件在一台IBM计算机上用非线性回归法得到IC50值。
对于COX-2活性测定,将500μl一份的血液在LPS(10μg/ml)存在下于37℃培养24小时,以诱发COX-2表达(Patriagnani等,J.Pharm.Exper.Ther.271;1705-1712(1994))。离心(13000rpm,10分钟)分离血浆,在-30℃下保存,直至用酶免疫测定盒(EIA)测定PEG2含量。将每种化合物(5μl一份)在5-6个不同的浓度以双份重复试样在LPS存在下培养24小时,研究抑制剂的效果。使用InplotGraphpad软件在一台IBM计算机上用非线性回归法得到IC50值。
由生物试验得到的结果列在表1中。
表1:COX-1和COX-2的抑制
实施例 | COX-1IC<sub>50</sub>(μM) | COX-2IC<sub>50</sub>(μM) | 比值COX-1/COX-2 |
1 | 100 | 0.96 | 104 |
2 | 100 | 2,1 | 48 |
3 | 86.6 | 0.27 | 321 |
4 | 81,1.3 | 0.37 | 219 |
5 | 72,9 | 2,47 | 30 |
6 | 100 | 0,25 | 400 |
7 | 77.0 | 0.57 | 135 |
8 | 32,1 | 1,58 | 20 |
9 | 73,1 | 0,17 | 430 |
如表1所示,式(1)的2-苯基吡喃-4-酮衍生物是有效的和选择性的COX-2抑制剂。因此,本发明化合物优选地是哺乳动物COX-2,例如人COX-2的选择性抑制剂。
本发明化合物还优选地对哺乳动物COX-1,例如人COX-1,具有低的抑制活性。抑制活性通常可以通过体外试验,例如上述试验测定。本发明的一些化合物还显示出意想不到的药物动力学型式。
优选的本发明化合物对于COX-2的IC50值小于50μM,优选小于10μM,更优选小于5μM,更加优选的是小于2.5μM。优选的本发明化合物对于COX-1的IC50值大于10μM,优选大于20μM。作为对抑制COX-2高于COX-1的选择性的标志,COX-1/COX-2IC50值之比优选大于10,更优选大于20,最优选大于50。
本发明还提供了式(1)化合物,用于治疗人体或动物体的方法,特别是用于治疗疼痛、发热或发炎,抑制前列腺素类激素诱发的平滑肌收缩或用于预防或治疗结肠直肠癌或神经变性疾病,例如阿尔茨海默氏病。
本发明还提供了式(1)化合物在制造用于治疼痛、发热或发炎,抑制前列腺素类激素诱发的平滑肌收缩,或用于预防或治疗结肠直肠癌的药物中的应用。
式(1)化合物可用于缓解许多种病症的疼痛、发热和炎症,包括风湿热,与流感或其它病毒感染有关的症状,普通感冒,腰疼和颈疼,痛经,头痛,牙痛,扭伤和拉伤,肌炎,神经痛,滑膜炎,粘液囊炎,腱炎,外科和牙科手术后损伤以及关节炎,包括类风湿性关节炎、骨关节炎、痛风性关节炎、脊椎关节病、全身性红斑狼疮和幼年型关节炎。它们也可以用于治疗皮肤炎性疾病,例如牛皮癣、湿诊、烧伤和皮炎。此外,这些化合物还可用来预防或治疗结肠直肠癌或神经变性疾病,例如,阿尔茨海默病。
式(1)化合物还会抑制前列腺素类激素诱发的平滑肌收缩,因此可用于治疗痛经、早产、哮喘和支气管炎。
式(1)化合物可以作为常规的非甾类消炎药物的替代品,特别是在这些非甾类消炎药可能被禁用的场合,例如治疗胃肠障碍的患者,包括消化性溃疡、胃炎、局限性肠炎、溃疡性结肠炎、憩室炎、节段性回肠炎、肠炎综合症和应激性肠综合症、胃肠出血和凝血障碍、肾病(例如肾功能损伤)、术前患者或服用抗凝血药的患者,以及对非甾类消炎药诱发的哮喘敏感的患者。
本发明化合物还可以用来治疗诸如下列疾病中的炎症:血管病,偏头痛,结节性多动脉炎,甲状腺炎,再生障碍性贫血,霍奇金病,硬皮病,I型糖尿病,重症肌无力,类肉瘤病,肾病综合症,贝切特综合症,多肌炎,超敏反应,结膜炎,齿龈炎和心肌缺血。
本发明化合物是环加氧酶-2的抑制剂,因此可用于治疗以上列举的环加氧酶-2介导的疾病。
因此,本发明化合物和其可药用盐,以及含有这些化合物和/或其盐的药物组合物,可用于治疗人体疾病的方法,该方法包括向需要这种治疗的患者施用有效数量的这样一种化合物或其可药用的盐。
本发明还提供了药物组合物,其中含有至少一种式(1)的2-苯基吡喃-4-酮衍生物或其可药用盐作为活性成分,和与其结合的一种可药用的赋形剂,例如载体或稀释剂。活性成分可以构成组合物重量的0.001-99%,优选0.01-90%,这取决于制剂的本质和施用前是否要进一步稀释。
本发明组合物优选制成的适合口服、局部、经鼻、吸入、直肠、透皮或注射给药的形式。
与活性化合物或其盐混合以形成本发明组合物的可药用的赋形剂是已知的,实际使用的赋形剂特别取决于所计划的施用该组合物的方法。
本发明组合物优选采用注射给药和口服给药。在这种情形,用于口服的组合物可采取片剂,缓释片剂,舌下片剂,胶囊或液体制剂,例如合剂、酏剂、糖浆或混悬剂等形式,它们均含有本发明的化合物;这些制剂可以用本领域熟知的方法制备。
可用于制备组合物的稀释剂包括与活性成分相容的液体和固体稀释剂,如果需要,加上着色剂或增味剂。片剂或胶囊剂可方便地含有2-500mg活性成分或相当数量的其盐。
适合口服使用的液体组合物可以是溶液或混悬液形式。溶液可以是活性化合物的水溶性盐或其它衍生物的水溶液与例如蔗糖结合形成糖浆。混悬剂可以含有本发明的不溶性活性化合物或其可药用盐,与水及混悬剂或增味剂结合。
用于非肠道注射的组合物可以由可溶性盐制备,它可以是或者不是冷冻干燥的,并可溶于无致热原的水介质或其它合适的非肠道注射液中。
有效剂量一般为每天10-600mg活性成分。日剂量可以每天一次或多次,优选1-4次给药。
本发明用以下制备例如实施例来说明,它们不以任何方式限制本发明的范围。
制备例1
3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲硫在)苯基]-4H-吡喃-4-酮
a)向2,4二氟苯酚(1.04g,8mmol)和2-溴-1-[4-(甲硫基)苯基]乙酮(1.96g,8mmol)在二氯甲烷(13ml)中的溶液加入碳酸钾(1.66g)和硫酸氢化四丁铵(0.14g)的水(5ml)溶液。将混合物在室温下搅拌16小时。加水(100ml),倒出有机相。碱性相用二氯甲烷(2×100ml)萃取。将有机溶液干燥(Na2SO4),减压除去溶剂。形成的固体用乙醚洗。得到2-(2,4-二氟苯氧基)-1-[4-(甲硫基)苯基]乙酮(1.69g,72%),为灰白色固体。
b)将以上化合物(1.68g,5.7mmol)加到预热至95-100℃的多磷酸(19g)在醋酸酐(8.5ml)中的溶液里。将混合物在同一温度加热5小时。冷却后,将反应混合物倒入冰水中,用乙酸乙酯(3×100ml)萃取,有机溶液用碳酸氢钠饱和溶液(2×100ml)、水和盐水洗,干燥(Na2SO4),减压除去溶剂。残留的油状物用硅胶柱色谱法纯化,乙酸乙酯/正己烷(1∶1)作为洗脱剂。得到3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲硫基)苯基]-4H-吡喃-4-酮(0.37g,17%),为灰白色固体。
δ(DMSO):2.41(s,3H),2.50(s,3H),6.40(s,1H),6.94(m,2H),7.39(m,3H),7.76(d,J=8.4Hz,2H).
制备例2
3-(4-氯-2-氟苯氧基)-6-甲基-2-[4-(甲硫基)苯基]-4H-吡喃-4-酮
按照制备例1所述步骤,由2-溴-1-[4-(甲硫基)苯基]乙酮和4-氯-2-氟苯酚得到,为灰白色固体(总产率16%)。
δ(DMSO):2.42(s,3H),2.50(s,3H),6.30(s,1H),6.73(dd,JHH=JHF=9.0Hz,1H),6.94(m,1H),7.14(dd,J=10.5,2.4Hz,1H),7.27(d,J=8.7Hz,2H),7.82(d,J=8.7Hz,2H).
制备例3
3-(4-溴-2-氟苯氧基)-6-甲基-2-[4-(甲硫基)苯基]-4H-吡喃-4-酮
按照制备例1所述步骤,由2-溴-1-[4-(甲硫基)苯基]乙酮和4-溴-2-氟苯酚得到,为灰白色固体(总产率17%)。
δ(DMSO):2.42(s,3H),2.50(s,3H),6.31(s,1H),6.68(dd,JHH=JHF=8.7Hz,1H),7.07(m,1H),7.26-7.30(m,3H),7.82(d,J=8.7Hz,2H).
实施例1
3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮
在0℃下向制备例1的标题化合物(1.36g,3.8mmol)在甲醇(17ml)中的溶液逐滴加入偏过碘酸钠(0.80g)的水(10ml)溶液,将混合物在该温度下搅拌2小时,室温下搅拌3天。然后将反应混合物倒入水中,用乙酸乙酯(3×100ml)萃取,将有机溶液干燥(Na2SO4),减压除去溶剂。残留物用硅胶柱色谱法纯化,二氯甲烷/乙酸乙酯/甲醇/乙酸(78∶17∶3∶2)作为洗脱剂。得到3-(2,4-二氟苯氧基)-6-甲基-2[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮(1.09g,77%),为灰白色固体。
m.p.:158-159℃
δ(DMSO):2.44(s,3H),2.76(s,3H),6.32(s,1H),6.67-6.92(m,3H),7.74(d,J=6.8Hz,2H),8.08(d,J=6.8Hz,2H).
实施例2
3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮-对映体1a
在搅拌下向四异丙醇钛(1.05ml,3.5mmol)和(R,R)-酒石酸二乙酯(2.45ml,14.2mmol)在无水1,2-二氯乙烷(25ml)中的冷却至-20℃的溶液中依次加入过氧化氢叔丁基的壬烷溶液(5.5M,1.29ml,7.1mmol)和制备例1的标题化合物(1.26g,3.5mmol)。将混合物在-20℃搅拌5小时,然后用5%的亚硫酸钠水溶液(50ml)和盐水洗。将有机层干燥(Na2SO4),减压除去溶剂。残留物用快速色谱法纯化,用乙酸乙酯/甲醇(95∶5)作为洗脱剂。得到3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮(0.18g,17%,100%ee),为灰白色固体,
[α]D 22=+82.3(c 0.25,MeOH)
m.p.:158-159℃
δ(DMSO):2.44(s,3H),2.76(s,3H),6.32(s,1H),6.67-6.92(m,3H),7.74(d,J=6.8Hz,2H),8.08(d,J=6.8Hz,2H)..
实施例3
3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮-对映体1b
按照实施例2中所述步骤,由制备例1的标题化合物和(S,S)-酒石酸二乙酯得到,为灰白色固体(57%,88.4%ee)。
[α]D 22=-71.5(c0.25,MeOH)
m.p.:158-159℃
δ(DMSO):2.44(s,3H),2.76(s,3H),6.32(s,1H),6.67-6.92(m,3H),7.74(d,J=6.8Hz,2H),8.08(d,J=6.8Hz,2H)..
实施例4
3-(4-氯-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮
按照实施例1中所述步骤,由制备例2的标题化合物和偏过碘酸钠得到,为灰白色固体(55%)。
m.p.:186-188℃
δ(DMSO):2.43(s,3H),2.78(s,3H),6.47(s,1H),7.03-7.15(m,2H),7.56(dd,J=10.8,2.4Hz,1H),7.84(d,J=8.6Hz,2H),7.99(d,J=8.6Hz,2H).
实施例5
3-(4-氯-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮-对映体4a
按照实施例2中所述步骤,由制备例2的标题化合物和(R,R)-酒石酸二乙酯得到,为灰白色固体(48%,100%ee)。
[α]D 22=+77.7(c 0.25,MeOH)
m.p.:186-188℃
δ(DMSO):2.43(s,3H),2.78(s,3H),6.47(s,1H),7.03-7.15(m,2H),7.56(dd,J=10.8,2.4Hz,1H),7.84(d,J=8.6Hz,2H),7.99(d,J=8.6Hz,2H).
实施例6
3-(4-氯-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮-对映体4b
按照实施例2中所述步骤,由制备例2的标题化合物和(S,S)-酒石酸二乙酯得到,为灰白色固体(49%,98.4%ee)。
[α]D 22=-77.0(c 0.25,MeOH)
m.p.:186-188℃
δ(DMSO):2.43(s,3H),2.78(s,3H),6.47(s,1H),7.03-7.15(m,2H),7.56(dd,J=10.8,2.4Hz,1H),7.84(d,J=8.6Hz,2H),7.99(d,J=8.6Hz,2H).
实施例7
3-(4-溴-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮
按照实施例1中所述步骤,由制备例3的标题化合物和偏过碘钠得到,为灰白色固体(43%)。
m.p.:201℃
δ(DMSO):2.43(s,3H),2.78(s,3H),6.47(s,1H),7.01(dd,JHH=JHF=9.0Hz,1H),7.24(m,1H),7.66(dd,J=10.8,2.1Hz,1H),7.84(d,J=8.7Hz,2H),7.98(d,J=8.7Hz,2H).
实施例8
3-(4-溴-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮-对映体7a
按照制备例2中所述步骤,由制备例3的标题化合物和(R,R)-酒石酸二乙酯得到,为灰白色固体(48%,98.8%ee)。
[α]D 22=+68.0(c0.5,MeOH)
m.p.:201℃
δ(DMSO):2.43(s,3H),2.78(s,3H),6.47(s,1H),7.01(dd,JHH=JHF=9.0Hz,1H),7.24(m,1H),7.66(dd,J=10.8,2.1Hz,1H),7.84(d,J=8.7Hz,2H),7.98(d,J=8.7Hz,2H).
实施例9
3-(4-溴-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮-对映体7b
按照实施例2中所述步骤,由制备例3的标题化合物和(S,S)-酒石酸二乙酯得到,为灰白色固体(53%,98.2%ee)。
[α]D 22=-71.3(c 0.5,MeOH)
m.p.:201℃
δ(DMSO):2.43(s,3H),2.78(s,3H),6.47(s,1H),7.01(dd,JHH=JHF=9.0Hz,1H),7.24(m,1H),7.66(dd,J=10.8,2.1Hz,1H),7.84(d,J=8.7Hz,2H),7.98(d,J=8.7Hz,2H).
实施例10
胶囊剂
按照以下配方制备25000只胶囊,每只含100mg 3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰基)苯基]-4H-吡喃-4-酮(活性成分):
活性成分 2.5kg
乳糖-水合物 5kg
胶体二氧化硅 0.05kg
玉米淀粉 0.5kg
硬脂酸镁 0.1kg
步骤
将以上成分经60目筛过筛,加到合适的混合器中,装25,000只明胶胶囊。
实施例11
片剂
按以下配方制备100000只药片,每片含50mg 3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮(活性成分):
活性成分 5kg
喷雾干燥的乳糖 19.9kg
微晶纤维素 3.9kg
硬脂酰富马酸钠 0.2kg
胶体二氧化硅 0.2kg
羧甲基淀粉 0.8kg
步骤
将全部粉末通过孔径为0.6mm的筛网,然后在合适的混合器中混合20分钟,使用9mm的圆面平板斜冲头压制成300mg的药片。该片剂的崩解时间为约3分钟。
Claims (21)
2.根据权利要求1的化合物,其中R1代表未被取代的C1-C20烷基。
3.根据权利要求2的化合物,其中R1是甲基。
4.根据权利要求1-3中任一项的化合物,其中X代表氧原子。
5.根据权利要求1至4中任一项的化合物,其中R3和R4代表氢原子或是未被取代的C1-3烷基。
6.根据权利要求5的一种化合物,其中R3和R4代表氢原子。
7.根据权利要求1至6中任一项的化合物,其中R2是支链C1-C20烷基,C3-C7环烷基,萘基,四氢化萘基或2,3-二氢化茚基,未被取代的苯基,或被一个或多个卤原子、C1-C20烷基和/或C1-C10烷氧基取代的苯基。
8.根据权利要求7的化合物,其中R2是未被取代的苯基或被1、2或3个独立选自卤原子、甲氧基或甲基的取代基取代的苯基。
9.根据权利要求8的化合物,其中R2代表被1或2个独立选自卤原子和甲基的取代基取代的苯基。
11.根据权利要求10的化合物,其中Ra和Rb选自卤原子。
12.根据权利要求11的化合物,其中R2是2,4-二氟苯基,4-氯-2-氟苯基或4-溴-2-氟苯基。
13.根据权利要求1-12中任一项的化合物,其中亚磺酰基的硫原子具有(S)构型。
14.根据权利要求1-12中任一项的化合物,其中亚磺酰基的硫原子具有(R)构型。
15.根据权利要求1、2和4至9中任一项的化合物,该化合物是:
3-(2,4-二氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮
3-(4-氯-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮
3-(4-溴-2-氟苯氧基)-6-甲基-2-[4-(甲基亚磺酰)苯基]-4H-吡喃-4-酮
其是(-)构型对映体形式,它们的混合物和其可药用的盐。
17.根据权利要求16的方法,其中的氧化剂:
(a)当要得到外消旋的亚磺酰基混合物时,用偏过碘酸钠;或者
(b)当要得到对映体富集的式(1)化合物时,用四异丙醇钛、过氧化氢叔丁基与(R,R)或(S,S)形式的酒石酸二乙酯的混合物。
18.根据权利要求17的方法,其中该反应在氯化溶剂或氯化溶剂与C1-C4醇的混合物中进行。
19.根据权利要求18的方法,其中的氯化溶剂是选自1,2-二氯乙烷、二氯甲烷、氯仿及其混合物。
20.一种药物组合物,其中含有根据权利要求1至15中任一项的化合物或其可药用盐与可药用的载体或稀释剂的混合物。
21.根据权利要求1至15中任一项的化合物或其可药用盐或根据权利要求20的组合物在制造药物方面的应用,该药物用于治疗疼痛、发热或炎症,抑制前列腺素类激素诱发的平滑肌收缩,或用于预防或治疗结肠直肠癌或神经变性疾病。
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ES2213485B1 (es) | 2003-02-13 | 2005-12-16 | Almirall Prodesfarma, S.A. | Derivados de la 2-fenilpiran-4-ona. |
ES2214130B1 (es) | 2003-02-13 | 2005-12-01 | Almirall Prodesfarma, S.A. | 2-3'-bipiridinas. |
-
2003
- 2003-02-13 ES ES200300355A patent/ES2213485B1/es not_active Expired - Fee Related
-
2004
- 2004-02-12 JP JP2006501815A patent/JP2006517560A/ja active Pending
- 2004-02-12 ES ES04710358T patent/ES2303938T4/es not_active Expired - Lifetime
- 2004-02-12 US US10/544,361 patent/US7582676B2/en not_active Expired - Fee Related
- 2004-02-12 EP EP04710358A patent/EP1592680B9/en not_active Expired - Lifetime
- 2004-02-12 WO PCT/EP2004/001295 patent/WO2004072058A1/en active IP Right Grant
- 2004-02-12 CN CNB2004800087372A patent/CN100436438C/zh not_active Expired - Fee Related
- 2004-02-12 DE DE602004013542T patent/DE602004013542D1/de not_active Expired - Fee Related
- 2004-02-12 AT AT04710358T patent/ATE394386T1/de not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000018753A1 (en) * | 1998-09-25 | 2000-04-06 | Almirall Prodesfarma, S.A. | 2-phenylpyran-4-one derivatives |
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WO2004072058A1 (en) | 2004-08-26 |
CN1768049A (zh) | 2006-05-03 |
ES2213485B1 (es) | 2005-12-16 |
ES2303938T3 (es) | 2008-09-01 |
ES2303938T4 (es) | 2009-06-05 |
EP1592680B1 (en) | 2008-05-07 |
US20060142380A1 (en) | 2006-06-29 |
US7582676B2 (en) | 2009-09-01 |
DE602004013542D1 (en) | 2008-06-19 |
JP2006517560A (ja) | 2006-07-27 |
ES2213485A1 (es) | 2004-08-16 |
EP1592680B9 (en) | 2009-03-25 |
ATE394386T1 (de) | 2008-05-15 |
EP1592680A1 (en) | 2005-11-09 |
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