CN100372831C - 磺酸,其衍生物及含有它们的药物组合物 - Google Patents
磺酸,其衍生物及含有它们的药物组合物 Download PDFInfo
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- CN100372831C CN100372831C CNB2004800068672A CN200480006867A CN100372831C CN 100372831 C CN100372831 C CN 100372831C CN B2004800068672 A CNB2004800068672 A CN B2004800068672A CN 200480006867 A CN200480006867 A CN 200480006867A CN 100372831 C CN100372831 C CN 100372831C
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- Prior art keywords
- phenyl
- sulphonamide
- ethene
- benzoyl
- ethane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及用选择的磺酸，其衍生物及含有这些化合物的药物组合物来抑制由白介素-8(IL-8)与CR1和CXCR2膜受体相互作用所诱导的嗜中性白细胞(PMN白细胞)趋化激活。这些化合物可用来预防和治疗所述激活引起的病理。尤其是，选择的磺酸及其衍生物不具有环加氧酶抑制活性，特别用于治疗嗜中性白细胞依赖性病理，例如牛皮癣、溃疡性结肠炎、黑素瘤、慢性阻塞性肺部疾病(COPD)、大疱性类天疱疮、类风湿性关节炎、特发性纤维化、肾小球性肾炎，以及用于预防和治疗由缺血和再灌注引起的损伤。
Description
技术领域
本发明涉及磺酸及其衍生物以及含有它们的药物组合物，所述化合物及组合物可用于预防和治疗多形核嗜中性白细胞(PMN白细胞)在炎症部位恶性聚集所致的组织损伤。
发明背景
特定的血细胞(巨噬细胞、粒细胞、中性粒细胞、多形核细胞)通过一种称之趋化的过程沿着化学刺激物的浓度梯度迁移而应答该刺激剂(当以称为趋化因子的物质刺激时)。主要的公知刺激剂或趋化因子的代表为补体C5a的分解产物、细菌表面溶解产生或来自合成肽的一些N-甲酰肽，例如甲酰基-甲硫氨酰基-亮氨酰基-苯丙氨酸(f-MLP)，主要是各种细胞因子，包括白介素-8(IL-8，也称CXCL8)。白介素-8是一种内源性趋化因子，由大部分有核细胞产生，例如成纤维细胞和巨噬细胞。
在一些以嗜中性白细胞恶性聚集为特征的病理状态中，部位上较严重的组织损伤与嗜中性白细胞的浸润有关。最近，已经普遍证实了嗜中性白细胞激活在确定缺血后再灌注和肺部高氧相关性损伤中的作用。
IL-8的生物活性受该白介素与CXCR1和CXCR2膜受体相互作用介导，所述膜受体属于在人嗜中性白细胞和某些类别T细胞表面上表达的七种跨膜受体家族(L Xu等人，J.Leukocyte Biol.，57，335，1995)。已经知道一些能够辨别CXCR1与CXCR2的选择性配体，其中GRO-α是CXCR2选择性趋化因子的一个例子。
虽然已知CXCR1激活在IL-8介导的趋化性中具有重要作用，但最近有人提出，CXCR2激活在牛皮癣等慢性炎性疾病中也可能发挥病理生理作用。事实上，IL-8对角化细胞功能产生作用也支持了牛皮癣中IL-8的病理生理作用。
实际上有证据显示，IL-8是上皮细胞增殖和血管生成的有效刺激物，而上皮细胞增殖和血管生成是牛皮癣发病机制的两个重要方面(A.Tuschil等人，J Invest Dermatol，99，294，1992；Koch AE等人，Science，258，1798，1992)。
此外，不断有证据显示，IL-8在黑素瘤进展和转移中的病理生理作用受CXCR2激活的介导(L.R.Bryan等人，Am J Surg，174，507，1997)。
IL-8通过CXCR2受体通道在肺部疾病(肺损伤、急性呼吸窘迫综合征、哮喘、慢性肺炎和囊性纤维化)，特别是在慢性阻塞性肺病发病机制中有潜在致病作用已有广泛描述(D.WP Hay和H.M.Sarau.，Current Opinion inPharmacology 2001，1：242-247)。
在研究酮洛芬(S)和(R)单对映体对于其外消旋物消炎活性的贡献以及它们在细胞因子调节中的作用时(P.Ghezzi et al.，J.Exp.Pharm.Ther.，287，969，1998)，已经证实，两种对映体及其与手性与非手性有机碱形成的盐以剂量依赖方式抑制IL-8在人PMN白细胞内诱导的Ca2+离子胞内浓度趋化性和升高(专利申请US6,069,172)。后来，又证明了(C.Bizzarri等人，Biochem.Pharmacol.61，1429，2001)，酮洛芬与属于非类固醇消炎药(NSAID)一类的其他分子，例如，氟比洛芬、布洛芬和吲哚美辛，具有相同的抑制IL-8生物活性的性质。NSAID的典型环加氧酶(COX)抑制活性限制了这些化合物在嗜中性白细胞依赖性病理和炎性疾病中的治疗应用，例如牛皮癣、特发性肺纤维化、急性呼吸衰竭、再灌注和肾小球性肾炎引起的损伤。抑制由对环加氧酶作用所产生的前列腺素合成涉及增加细胞因子的生成，这如同TNF-α一样，在扩大不希望有的嗜中性白细胞促炎作用中起作用。
已经发现了一些适合“体内”给予的几类新的有效和选择性IL-8生物活性抑制剂。R-2-芳基丙酸酰胺和N-酰基磺酰胺被形容为IL-8诱导的嗜中性白细胞趋化性和脱粒的有效抑制剂(WO01/58852；WO00/24710)。此外，新的R和S-2-苯基丙酸最近被认为是有效的IL-8抑制剂，完全没有不希望的COX抑制作用(PCT/EP02/12939)。
发明内容
我们已经发现一类磺酸及其衍生物具有有效地抑制IL-8诱导的嗜中性白细胞趋化性和脱粒的能力。
因此，本发明提供通式(I)所示的磺酸和衍生物：
及其药学上可接受的盐的用途，
式中，
Ar是由1至3个取代基取代的苯基，所述取代基独立地选自卤素、C1-C4-烷基、C1-C4-烷氧基、羥基、C1-C4-酰氧基、苯氧基、氰基、硝基、氨基、C1-C4-酰基氨基、卤代-C1-C3-烷基、卤代-C1-C3-烷氧基、苯甲酰基，或者Ar是取代或未取代的5-6元杂芳环；
X代表-CH2-或-CH(CH3)-基团，或者通式(II)所示的E构型烯基，其中R′是H或CH3；
Y选自O(氧)和NH；并且
-当Y是O(氧)，R是H(氢)；
-当Y是NH，R选自以下基团：
-H、C1-C5-烷基、C1-C5-环烷基、C1-C5-烯基、C1-C5-酰基；
-通式-CH2-CH2-Z-(CH2-CH2O)nR”所示的残基，其中R”是H或C1-C5-烷基，n是0至2的整数，Z是氧或硫；
-通式-(CH2)n-NRaRb所示的残基，其中n是0至5的整数，Ra和Rb可相同或不同，各自是C1-C6-烷基、C1-C6-烯基，或者，另一个选择，Ra和Rb与它们所连接的氮原子一起形成一个通式(III)所示的3-7元杂环，
其中W代表单键、CH2、O、S、N-Rc，Rc是H、C1-C6-烷基或C1-C6-烷基苯基，
在制备抑制IL-8诱导的人PMN趋化性的药物中的用途。
上述定义所用的术语“取代的”指用选自C1-C5-烷基、卤素、羟基、C1-C5-烷氧基、氨基、C1-C5-烷基氨基、硝基或氰基的基团取代。
Ar是取代的苯基，选自3’-苯甲酰基苯基、3’-(4-氯-苯甲酰基)-苯基、3’-(4-甲基-苯甲酰基)-苯基、3’-乙酰基-苯基、3’-丙酰基-苯基、3’-异丁酰基-苯基、4’-三氟甲磺酰氧基-苯基、4’-苯磺酰氧基-苯基、4’-三氟甲磺酰氨基-苯基、4’-苯磺酰氨基-苯基、4’-苯磺酰甲基-苯基、4’-乙酰氧基苯基、4’-丙酰氧基-苯基、4’-苯甲酰氧基-苯基、4’-乙酰基氨基-苯基、4’-丙酰基氨基-苯基、4’-苯甲酰基氨基-苯基，或者是选自吡啶、吡咯、噻吩、呋喃、吲哚的杂芳环。
当Y是NH，优选的R基团是
-H、C1-C5烷基、C1-C5酰基；
-通式-CH2-CH2-O-(CH2-CH2O)R”所示的残基，其中R”是H或C1-C5-烷基；
-通式-(CH2)n-NRaRb所示的残基，其中n是2至3的整数，优选为3，基团NRaRb是N，N-二甲胺、N，N-二乙胺、1-哌啶基，4-吗啉基、1-吡咯烷基、1-哌嗪基、1-(4-甲基)哌嗪基。
本发明还提供上述定义的通式(I)所示的新颖的磺酸及衍生化合物，其选自：
1-(4-异丁基苯基)乙磺酸
1-(4-异丁基苯基)乙磺酸
1-[4-(1-氧-2-异二氢吲哚基)苯基]乙磺酸
1-[4-(1-氧-2-异二氢吲哚基)苯基]乙磺酸
2-(4-苯基磺酰氧基)乙磺酸
2-(4-苯基磺酰氧基)乙磺酸
(1-甲基-5-乙酰基吡咯基)-1-甲磺酸
2-(3-苯甲酰基苯基)乙磺酸
2-(3-异丙基苯基)乙磺酸。
E-2-(4-异丁基苯基)乙烯磺酸
E-2-(3-苯甲酰基苯基)乙烯磺酸
E-2-(4-甲磺酰氨基苯基)乙烯磺酸
E-2-(4-三氟甲磺酰氧基苯基)乙烯磺酸
E-2-(4-异丁基苯基)乙烯磺酰胺
E-2-(3-苯甲酰基苯基)乙烯磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯磺酰胺
E-2-(4-异丁基苯基)乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-(3-苯甲酰基苯基)乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-(4-异丁基苯基)乙烯-N-甲基磺酰胺
E-2-(3-苯甲酰基苯基)乙烯-N-甲基磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-甲基磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-甲基磺酰胺
E-2-(4-异丁基苯基)乙烯-N-(2″-甲氧基乙基)磺酰胺
E-2-(3-苯甲酰基苯基)乙烯-N-(2″-甲氧基乙基)磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-(2″-甲氧基乙基)磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-(2″-甲氧基乙基)磺酰胺
(1-甲基-5-异丁酰基(isobutirryl)吡咯基)-1-甲磺酰胺
(1-甲基-5-乙酰基吡咯基)-1-甲磺酰胺
1-(4-异丁基苯基)乙磺酰胺
1-(4-异丁基苯基)乙磺酰胺
1-(3-异丙基苯基)乙磺酰胺
1-(4-异丁基苯基)乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-(3-苯甲酰基苯基)乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-[4-(甲磺酰氨基)苯基]乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-(4-异丁基苯基)乙烷-N-(2-甲氧基乙基)磺酰胺
1-(3-苯甲酰基苯基)乙烷-N-(2-甲氧基乙基)磺酰胺
1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-(2-甲氧基乙基)磺酰胺
1-[4-(甲磺酰氨基)苯基]乙烷-N-(2-甲氧基乙基)磺酰胺
1-(4-异丁基苯基)乙烷-N-甲基磺酰胺
1-(3-苯甲酰基苯基)乙烷-N-甲基磺酰胺
1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-甲基磺酰胺
1-[4-(甲磺酰氨基)苯基]乙烷-N-甲基磺酰胺
1-[4-异丁基苯基]乙烷-N-乙酰基磺酰胺
E-2-(3-苯甲酰基苯基)-2-甲基-乙烯磺酰胺
E-2-(3-异丙基苯基)-2-甲基-乙烯磺酰胺
E-2-(4-异丁基苯基)-2-甲基-乙烯磺酰胺
及其药学上可接受的盐。
较佳地，所述盐是钠盐。
上述的乙磺酰胺是手性化合物，本发明提供外消旋物和(+)和(-)单对映体。
当本发明的通式(I)化合物带有酸性或碱性基团时，它们一般是以其与药学上可接受的有机和无机酸或碱形成的加成盐形式分离出来。
这样的酸的例子选自盐酸、硫酸、磷酸、甲磺酸、反丁烯二酸、柠檬酸。
这样的碱的例子选自氢氧化钠、氢氧化钾、氢氧化钙、(D，L)-赖氨酸、L-赖氨酸、氨基丁三醇。
YR是OH的通式(I)化合物可通过将相应的通式(IV)所示的化合物(其中J是H或COCH3)与合适的氧化剂(例如H2O2、HClO和过氧酸，优选为间氯过苯甲酸)反应而制成。
通式(I)中Y是NH，X是-CH2-的化合物可通过将相应的磺酰卤化物(例如磺酰氯)与1或2当量的通式NH2R所示的胺，有需要的话，在合适的有机或无机碱存在下，反应而制成。
通式(I)中Y是NH，X是-CH(CH)3-的化合物可这样制成：将相应的通式(IV)所示的硫醇与合适的N-溴酰亚胺，例如如N-溴邻苯酰亚胺(bromoftalimmide)，反应，再氧化硫原子，然后使磺酰胺衍生物脱保护，具体方法见以下实施例。
通式(I)中Y是NH，X是通式(II)所示基团的化合物可通过将相应的磺酰卤化物(例如磺酰氯)与通式NH2R所示的胺反应而制成。
本发明的化合物特别用作IL-8诱导的人PMN趋化性的抑制剂。
本发明的另一个目的是提供上述的新颖的磺酸及衍生化合物，它们用作药物。
“体外”评估通式(I)化合物抑制由IL-8和GRO-α片段诱导的多形核白细胞(下文用PMN表示)和单核细胞趋化性的能力。为此，从身体健康的成人志愿者身上抽取肝素化人血液，从该血液分离出PMN，通过葡聚糖沉降去除单核细胞(按照W.J.Ming等人公开的方法，J.Immunol.，138，1469，1987)，通过低渗溶液处理去除红血细胞。以锥虫蓝排除法计算细胞活力，用DiffQuick染色后再估算细胞离心产物中的循环多形核百分比。
在趋化性试验中采用人重组IL-8(Pepro Tech)作为刺激剂，实际上获得相同的结果：将冻干蛋白溶解在一定体积含有0.2％牛血清蛋白(BSA)的HBSS中，配成10-5M的母液，用HBSS稀释至10-9M用于趋化性试验。
在趋化性试验过程中(按照W.Falket等人，J.Immunol.Methods，33，239，1980)，采用5微米孔径的PVP-free过滤器，并有适合进行相同试验的细微室。
本发明通式(I)的化合物的评估浓度范围是10-6至10-10M，因此，以相同浓度把它们加入细微室下部孔和上部孔中。按照上述方法(Van Damme J.等人，Eur.J.Immunol.，19，2367，1989)，评估本发明通式(I)的化合物抑制IL-8诱导的人单核细胞趋化性的能力。
表2列出一些代表性化合物在IL-8诱导的PMN趋化性试验中的生物结果(抑制数据，C＝10-8M)
特别优选使用这样的通式(I)化合物，其中Ar基团是3’-苯甲酰基苯基、3’-(4-氯-苯甲酰基)-苯基、3’-(4-甲基-苯甲酰基)-苯基、3’-乙酰基-苯基、3’-丙酰基-苯基、3’-异丁酰基-苯基、4’-三氟甲磺酰氧基-苯基、4’-苯磺酰氧基-苯基、4’-三氟甲磺酰氨基-苯基、4’-苯磺酰氨基-苯基、4’-苯磺酰甲基-苯基、4’-乙酰氧基苯基、4’-丙酰氧基-苯基、4’-苯甲酰氧基-苯基、4’-乙酰基氨基-苯基、4’-丙酰基氨基-苯基、4’-苯甲酰基氨基-苯基，这些化合物具有能有效地抑制GRO-α诱导的PMN趋化性的附加性质；这种性质可使这些化合物对CXCR2通道有特异性的参与或者与CXCR1信号传导联合的IL-18相关病理有治疗用途。
虽然考虑到感兴趣的治疗应用最好选用IL-8和GRO-α诱导的生物活性的的双重抑制剂，但是选择性作用于CXCR1 IL-8受体或者CXCR2GRO-/IL-8受体的上述化合物，可用于治疗下文所述的特定病理。
采用Patrignani等人所述的步骤(J.Pharmacol.Exper.Ther.，271，1705，1994)，完全在血液中体外评估通式(I)化合物，结果发现它们作为环加氧酶(COX)的抑制剂是完全无效的。
多数情况下，通式(I)化合物在10-5至10-7M浓度范围内不会干扰脂多糖(LPS，1微克/毫升)刺激小鼠巨噬细胞诱导产生PGE2。可记录的对PGE2产生的抑制通常低于统计学显著性的极限，一般不超过基数值的15-20％。抑制COX的效率降低是本发明化合物在治疗应用中的一个优点，其作用与抑制前列腺素合成是巨噬细胞刺激物增强TNF-α合成(LPS或过氧化氢诱导)一样大，TNF-α是中性粒细胞激活的重要介导剂，也是细胞因子IL-8产生的刺激物。
考虑到上述讨论的实验结果和白介素-8(IL-8)及其同源物在涉及嗜中性白细胞激活和浸润过程中的作用，本发明的化合物特别适用于治疗某些疾病，例如牛皮癣(R.J.Nicholoff等人，Am.J.Pathol.，138，129，1991)。可用本发明化合物治疗的的其他疾病是慢性肠炎症病理，例如溃疡性结肠炎(Y.R.Mahida等人，Clin.Sci.，82，273，1992)和黑素瘤、急性呼吸窘迫综合征、大疱性类疱疮、类风湿性关节炎(M.Selz等人，J.Clin.Invest.，87，463，1981)、特发性纤维化(前面引用的E.J.Miller和P.C.Carré等人，J.Clin.Invest.，88，1882，1991)、肾小球性肾炎(T.Wada等人，J.Exp.Med.，180，1135，1994)以及预防和治疗由局部缺血和再灌注引起的损伤。
CXCR1和CXCR2激活的抑制剂可用于上述的应用，特别是可用于治疗慢性炎症病理(例如牛皮癣)，其中两种IL-8受体的激活被认为对于该疾病的进展有重要的病理生理作用。
事实上已众所周知，激活CXCR1是IL-8介导的PMN趋化性所必需的(Hammond M等人，J Immunol，155，1428，1995)。另一方面，CXCR2的激活是牛皮癣患者IL-8介导的上皮细胞增殖和血管生成所必需的已为人所知(Kulke R等人，J Invest Dermatol，110，90，1998)。
此外，CXCR2选择性拮抗剂特别用于治疗重要肺部疾病，例如慢性阻塞性肺病(D.WP Hay and H.M.Sarau.，Current Opinion in Pharmacology 2001，1：242-247)。
所以，本发明的另一个目的在于提供通式(I)化合物在制备治疗牛皮癣、溃疡性结肠炎、黑素瘤、慢性阻塞性肺病(COPD)、大疱性类疱疮、类风湿性关节炎、特发性纤维化、肾小球性肾炎及预防和治疗由局部缺血和再灌注引起的损伤的药物中的用途，还有这些化合物的使用。含有本发明化合物及其合适载体的药物组合物也在本发明的范围之内。
本发明的化合物与常规使用的佐剂、运载体、稀释剂或赋形剂实际上可放在一起制成药物组合物及其单位剂量形式，其形式可为固体，如片剂或填充胶囊，或液体，如溶液、悬浮液、乳液、酏剂或它们的填充胶囊，所有形式均可口服，或以灭菌注射液的形式供肠道外(包括皮下)用药。这些药物组合物及其单位剂量形式可包括按传统比例配制的成分，可另外加入或不加入活性化合物或活性成分，而单位剂量形式也可含有任何适当有效量的活性成分，与每天服用的剂量相称。
当本发明的酸用作药物时，一般以药物组合物的形式给药。这些组合物可采用药学领域已知的方式来制备，它们包括至少一活性化合物。通常，本发明化合物的给予量是药物有效量。但化合物的实际给予量一般由医生根据有关情况来决定，包括治疗情况、所选择的给药途径、实际给予的化合物、各个患者的年龄、体重和反应、患者症状的严重性等等。
本发明的药物组合物的给药途径有多种，包括口服、直肠、透皮、皮下、静脉内、肌内及鼻内给药。根据所选的输送路径，化合物最好配成注射液或口服组合物。口服组合物可制成本体溶液或悬浮液或本体粉末。然而，最常见的是把组合物制成单位剂量形式以方便准确计算剂量。术语“单位剂量形式”是指适合人体和其它哺乳动物的单位剂量的物质单个单位，每个单位含有经过预先计算的预定量活性物质，与一合适的药学赋形剂一起产生所希望的治疗效果。典型的单位剂量形式包括预填充和预测量的液体组合物的安瓿或注射器或者丸剂、片剂、胶囊等固体组合物。在这些组合物中，酸化合物往往是微量组分(占重量约0.1％至约50％，优选占重量约1％到约40％)，其余为各种赋形剂或者载体和处理助剂，有助形成所需的剂量形式。
适合口服的液体形式可包括一合适的水性或非水性赋形剂和缓冲剂、悬浮剂和分散剂、着色剂、调味剂等。液体形式，包括下面提到的注射组合物，通常要储存于黑暗环境中，以避免遇光产生任何催化作用，如生成过氧化氢或过氧化物。固体形式可包括例如下列任何一种成分或有类似性质的化合物：粘合剂，如微细晶体纤维素、黄茋胶或明胶；赋形剂，如淀粉或乳糖；崩解剂，如藻胶酸、原胶或玉米淀粉；润滑剂，如硬脂酸镁；助流剂，如胶体二氧化硅；甜味剂，如蔗糖或糖精；或香味剂，如薄荷、水杨酸盐或甜橙味剂。
注射组合物一般是基于注射灭菌盐水或磷酸盐缓冲盐水或其它本领域已知的注射载体。如上所述，这些组合物中以通式(I)表示的酸衍生物一般是微量组分，其重量往往在0.05至10％之间，其余为注射载体等。每天平均剂量取决于许多因素，如疾病的严重性和患者的情况(年龄、性别、体重)。通式(I)化合物的每日剂量通常不是固定的，由1毫克或几毫克直至高达1500毫克，可选择分成多次给药。由于长时间服食本发明化合物毒性低，所以可以给予较高剂量。
上述口服或注射组合物的成份仅仅是作代表性说明。其它一些物质或加工技术等可参考本文的引用文献(宾夕法尼亚洲的Mack出版社，Remingto’sPharmaceutical Seiences Handbook第八部分，第18版，1990)。
给予本发明的化合物可以缓释形式或经由缓释药物输送系统。代表性缓释物质的描述也可参考上述引用文献Remingto’s Pharmaceutical SeiencesHandbook。
结合下列实施例对本发明加以详细说明，但这并不构成对本发明的范围的限制。
具体实施方式
實施例1
通式R-Ar-C(CH
3
)H-SO
3
H所示的芳基甲磺酸、1-芳基乙磺酸及其相关对映体
的通用合成方法
在强烈搅拌条件下，向取代苯(17mmol)和乙酰氯(18mmol)在干二氯甲烷(25mL)中的冷却(T＝0-4℃)溶液分批加入AlCl3(18mmol)。移去冰浴，溶液回流至起始材料明显地完全消失(2-3小时)。室温冷却后，将混合物倒入冷却的2N盐酸溶液中，搅拌30分钟。再把酸溶液转移到另一个漏斗，用二氯甲烷(3×20mL)萃取。收集有机萃取液，用氯化钠饱和溶液(2×25mL)洗涤，硫酸钠干燥，真空蒸发，得到纯的芳基苯乙酮(14.45-16.15mmol)，得率很高(85-95％)。
边搅拌边向芳基苯乙酮(11.5mmol)在甲醇(40mL)中的溶液分批加入硼氢化钠(17.2mmol)。使混合物回流直至起始材料完全消失(3小时)。室温冷却后，在混合物中加入1M HCl，蒸馏去掉甲醇。水相用乙酸乙酯(3×15mL)萃取，收集有机萃取液，用氯化钠饱和溶液(2×25mL)洗涤，硫酸钠干燥，真空蒸发，得到纯的1-芳基乙醇(得率约75％)。
边搅拌边向1-芳基乙醇(4.5mmol)在干三氯甲烷(10mL)中的溶液中加入硫代乙酸(5.39mmol)和碘化锌(2.24mmol)。反应混合物回流3小时；室温冷却后，混合物用水(15mL)稀释，再转移到另一个漏斗。摇动分离两相。有机相先用碳酸氢钠饱和溶液(3×20mL)再用氯化钠饱和溶液洗涤，硫酸钠干燥，真空蒸发，得到纯的1-芳基乙基硫代乙酸酯(得率约80％)。
在60℃搅拌1-芳基乙基硫代乙酸酯(0.91mmol)在冰醋酸(2mL)中的溶液，并滴入30％H2O2(4.56mmol)处理；所得到的溶液在60℃搅拌24小时，再与甲苯共沸蒸馏除去乙酸。残留物用水(5mL)稀释，1N NaOH中和，二乙醚(2×15mL)洗涤，并经冻干处理后，得到1-芳基乙磺酸钠盐的外消旋物混合物，为白色固体(得率约90％)。
光学拆分
外消旋的1-芳基乙磺酸钠盐用装有Amberlite IR-120树脂(H+型)的柱过滤，洗脱液为水，得到产物，为粘稠油。按照Akguen等人公开的芳基丙酸光学拆分方法(Arzneim.-Forsch./Drug Res.，46(II)，Nr.9，891-894(1996))，使相应的(+)或(-)α-苯基乙基铵盐在乙醇溶液中重结晶，可分离两种异构体。分离出来的纯对映体为钠盐。
按照上述方法，制成以下化合物：
(-)-1-(4-异丁基苯基)乙磺酸钠盐(1)
以市售异丁基苯为起始材料，合成了该化合物。
[α]D＝-35(c＝1；H2O)
1H-NMR(DMSO-d6)：δ7.25(d，2H，J＝7Hz)；7.05(d，2H，J＝7Hz)；3.62(m，1H)；2.37(d，2H，J＝7Hz)；1.86(m，1H)；1.40(d，3H，J＝7Hz)；0.91(d，6H，J＝7Hz)。
(+)-1-(4-异丁基苯基)乙磺酸钠盐(2)
以市售异丁基苯为起始材料，合成了该化合物。
[α]D＝+34.5(c＝1；H2O)
1H-NMR(DMSO-d6)：δ7.25(d，2H，J＝7Hz)；7.08(d，2H，J＝7Hz)；3.62(m，1H)；2.37(d，2H，J＝7Hz)；1.86(m，1H)；1.42(d，3H，J＝7Hz)；0.90(d，6H，J＝7Hz)。
(-)-1-[4-(1-氧-2-异二氢吲哚基)苯基]乙磺酸钠盐(3)
按照上述方法，以中间体4-(1-氧-2-异二氢吲哚基)苯乙酮为起始材料，合成了该化合物。所用的中间体参照Ichiro，T.等人的方法(Heterocycles43：11，2343-2346(1996))由市售试剂苯二醛和4-氨基苯乙酮制成。
[α]D＝-52.4(c＝1；H2O)
1H-NMR(DMSO-d6)：δ7.68(m，3H)；7.35(m，3H)；7.15(d，2H，J＝7Hz)；4.68(s，2H)；3.65(q，1H，J1＝7Hz，J2＝3Hz)；1.28(d，3H，J＝7Hz)。
(+)-1-[4-(1-氧-2-异二氢吲哚基)苯基]乙磺酸钠盐(4)
按照上述方法，以中间体4-(1-氧-2-异二氢吲哚基)苯乙酮为起始材料，合成了该化合物。所用的中间体参照Ichiro，T.等人的方法(Heterocycles 43：11，2343-2346(1996))由市售试剂苯二醛和4-氨基苯乙酮制成。
[α]D＝+50(c＝1；H2O)
1H-NMR(DMSO-d6)：δ7.708(m，3H)；7.35(m，3H)；7.18(d，2H，J＝7Hz)；4.68(s，2H)；3.65(q，1H，J1＝7Hz，J2＝3Hz)；1.30(d，3H，J＝7Hz)。
(-)-2-(4-苯基磺酰氧基)乙磺酸钠盐(5)
按照上述方法，以中间体4-苯磺酰氧基苯乙酮为起始材料，合成了该化合物。所用的中间体按照已知的实验方法由市售试剂4-羟基苯乙酮制成。
[α]D＝-47.5(c＝1；H2O)
1H-NMR(D2O)：δ7.90(d，2H，J＝7Hz)；7.70(t，1H，J＝7Hz)；7.55(t，2H，J＝7Hz)；7.32(d，2H，J＝7Hz)；6.95(d，2H，J＝7Hz)；3.64(m，1H)；1.41(d，3H，J＝7Hz)。
(+)-2-(4-苯基磺酰氧基)乙磺酸钠盐(6)
按照上述方法，以中间体4-苯磺酰氧基苯乙酮为起始材料，合成了该化合物。所用的中间体按照已知的实验方法由市售试剂4-羟基苯乙酮制成。
[α]D＝+49(c＝1；H2O)
1H-NMR(D2O)：δ7.93(d，2H，J＝7Hz)；7.70(t，1H，J＝7Hz)；7.55(t，2H，J＝7Hz)；7.32(d，2H，J＝7Hz)；6.91(d，2H，J＝7Hz)；3.67(m，1H)；1.41(d，3H，J＝7Hz)。
(1-甲基-5-乙酰基吡咯基)-1-甲磺酸钠盐(7)
以市售试剂1-甲基-2-吡咯乙酸甲酯为起始材料，它与乙酰氯进行FriedelCrafts酰基化反应，得到(1-甲基-5-乙酰基吡咯基)-1-甲乙酸酯，由此合成了该化合物。再将酯基团水解。按照WO02/0704095记载的实验步骤，得到相关的(1-甲基-5-乙酰基吡咯基)-1-甲磺酸钠盐。
1H-NMR(DMSO-d6)：δ7.5(s，1H)；6.18(s，1H)；3.60(s，3H)；3.51(s，2H)；2.10(s，3H)。
(±)-2-(3-苯甲酰基苯基)乙磺酸钠盐(8)
以市售试剂3-(1-氰基乙基)苯甲酸为起始材料，它与苯进行Friedel Crafts酰基化反应，得到2-(3′-苯甲酰基苯基)丙腈，由此合成了该化合物。再将酯基团水解。按照WO02/0704095记载的实验步骤，得到相关的2-(3′-苯甲酰基苯基)乙磺酸钠盐。
1H-NMR(D2O)：δ7.80(d，2H，J＝7Hz)；7.70(s，1H)；7.62(d，1H，J＝7Hz)；7.51(m，2H)；7.30(m，3H)；3.62(m，1H)；1.40(d，3H，J＝7Hz)。
(±)-2-(3-异丙基苯基)乙磺酸钠盐(9)
以市售试剂3-(1-氰基乙基)苯乙酮为起始材料，它经过Wittig反应及利用公知方法还原亚甲基后，得到2-(3-异丙基苯基)丙腈，由此合成了该化合物。按照WO02/0704095记载的实验步骤，得到相关的2-(3-异丙基苯基)乙磺酸钠盐。
1H-NMR(D2O)：δ7.30(m，2H)；7.10(m，2H)；3.92(m，1H)；3.63(m，1H)；1.42(d，3H，J＝7Hz)；1.25(d，6H，J＝8Hz)。
實施例2
E-芳基乙烯磺酸(鈉鹽)的制备
将芳基乙磺酸溶解在亚硫酰氯(5mL)中，制成的溶液回流过夜。室温冷却后，真空蒸发亚硫酰氯，粗芳基乙磺酰氯用干THF(5mL)稀释，在0℃的冰水浴中冷却；于4℃加入1N NaOH水溶液(0.64mmol)；移去冰水浴，反应混合物静止放置约1小时，温度升至室温，产生白色固体沉淀。真空过滤有机钠盐，用THF洗涤，放在40℃的真空烘箱内干燥，得到纯的E-芳基乙烯磺酸钠盐(0.32-0.51mmol)，为白色粉末(得率为50-80％)。
按照上述方法，制成以下化合物：
E-2-(4-异丁基苯基)乙烯磺酸钠盐(10)
1H-NMR(D2O)：δ7.60(d，1H，J＝8Hz)；7.55-7.32(m，4H)；7.05(d，1H，J＝14Hz)；2.62(m，2H)；1.90(m，1H)；0.97(d，6H，J＝7Hz)。
E-2-(3-苯甲酰基苯基)乙烯磺酸钠盐(11)
1H-NMR(D2O)：δ7.80(d，2H，J＝7Hz)；7.70(s，1H)；7.65(d，1H，J＝8Hz)；7.62(d，1H，J＝7Hz)；7.51(m，2H)；7.30(m，3H)；7.00(d，1H，J＝14Hz)。
E-2-(4-甲磺酰氨基苯基)乙烯磺酸钠盐(12)
1H-NMR(DMSO-d6)：δ7.60(d，1H，J＝8Hz)；7.35(d，2H，J＝8Hz)；7.20(d，2H，J＝8Hz)；7.07(d，1H，J＝14Hz)；6.51(bs，1H，SO2NH)；3.00(s，3H)。
E-2-(4-三氟甲磺酰氧基苯基)乙烯磺酸钠盐(13)
1H-NMR(CDCl3)：δ7.62(d，1H，J＝8Hz)；7.50(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；7.05(d，1H，J＝14Hz)。
实施例3
E-芳基乙烯磺酰胺的通用合成方法
将芳基乙磺酸(0.64mmol)溶解在亚硫酰氯(5mL)中，制成的溶液回流过夜。室温冷却后，真空蒸发亚硫酰氯，粗芳基乙磺酰氯用干THF(5mL)稀释，在0℃的冰水浴中冷却；滴入选定的胺(1.28mmol)。移去冰水浴，反应混合物静止放置至温度升至室温。待起始试剂完全消失之后，真空蒸发溶剂，在残留物中加入三氯甲烷(10mL)和水(10mL)；摇动分离两相，有机相用水(3×15mL)洗涤，硫酸钠干燥，真空蒸发，得到粗产物，其经过快速色谱法纯化，分离得到纯的E/Z-芳基乙烯磺酰胺(0.32-0.51mmol)，为无色油(得率为50-80％)。
按照上述方法，使用的胺为氨水(0.5M，溶剂为1，4-二恶烷)，制成以下化合物：
E-2-(4-异丁基苯基)乙烯磺酰胺(14)
1H-NMR(CDCl3)：δ7.55(d，1H，J＝14Hz)；7.38(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；6.88(d，1H，J＝14Hz)；4.75(bs，2H，SO2NH2)；2.55(d，2H，J＝7Hz)；1.94(m，1H)；1.02(d，6H，J＝7Hz)。
E-2-(3-苯甲酰基苯基)乙烯磺酰胺(15)
1H-NMR(CDCl3)：δ7.80(d，2H，J＝7Hz)；7.72(s，1H)；7.62(d，1H，J＝8Hz)；7.52(d，1H，J＝14Hz)；7.50(m，2H)；7.30(m，3H)；6.88(d，1H，J＝14Hz)；4.75(bs，2H，SO2NH2)。
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯磺酰胺(16)
1H-NMR(CDCl3)：δ7.60(d，1H，J＝8Hz)；7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；7.10(d，1H，J＝14Hz)；4.85(bs，2H，SO2NH2)。
E-2-[4-(甲磺酰氨基)苯基]乙烯磺酰胺(17)
1H-NMR(CDCl3)：δ7.55(d，1H，J＝14Hz)；7.37(d，2H，J＝8Hz)；7.22(d，2H，J＝8Hz)；6.90(d，1H，J＝14Hz)；6.45(bs，1H，SO2NH)；4.80(bs，2H，SO2NH2)；2.98(s，3H)。
按照上述方法，使用的胺为3-(二甲基氨基)丙胺，制成以下化合物：
E-2-(4-异丁基苯基)乙烯-(N，N-二甲基氨基丙基)磺酰胺(18)
1H-NMR(CDCl3)：δ7.45(m，3H)；7.20(d，2H，J＝7Hz)；6.70(d，1H，J＝14Hz)；6.40(bs，1H，SO2NH)；3.18(m，2H)；2.55(m，4H)；2.30(s，6H)；1.92(m，1H)；1.75(m，2H)；0.97(d，6H，J＝7Hz)。
E-2-(3-苯甲酰基苯基)乙烯-N-(N，N-二甲基氨基丙基)磺酰胺(19)
1H-NMR(CDCl3)：δ7.82(d，2H，J＝7Hz)；7.74(s，1H)；7.60(d，1H，J＝8Hz)；7.50(d，1H，J＝14Hz)；7.45(m，2H)；7.26(m，3H)；6.70(d，1H，J＝14Hz)；6.45(bs，1H，SO2NH)；3.15(m.，2H)；2.50(m，4H)；2.35(s，6H)。
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-(N，N-二甲基氨基丙基)磺酰胺(20)
1H-NMR(CDCl3)：δ7.62(d，1H，J＝14Hz)；7.48(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；7.00(d，1H，J＝14Hz)；6.50(bs，1H，SO2NH)；3.17(m.，2H)；2.48(m，4H)；2.35(s，6H)。
E-2-[4-(甲磺酰氨基)苯基]乙烯-(N，N-二甲基氨基丙基)磺酰胺(21)
1H-NMR(CDCl3)：δ7.57(d，1H，J＝14Hz)；7.37(d，2H，J＝8Hz)；7.22(d，2H，J＝8Hz)；6.75(d，1H，J＝14Hz)；6.50(bs，2H，SO2NH)；3.15(m，2H)；2.98(s，3H)；2.50(m，4H)；2.40(s，6H)。
按照上述方法，使用的胺为甲胺(2M，溶剂为THF)，制成以下化合物：
E-2-(4-异丁基苯基)乙烯-N-甲基磺酰胺(22)
1H-NMR(CDCl3)：δ7.55(d，1H，J＝14Hz)；7.38(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；6.88(d，1H，J＝14Hz)；4.80(bs，1H，SO2NH)；2.75(d，3H，J＝4Hz)；2.55(d，2H，J＝7Hz)；1.95(m，1H)；1.04(d，6H，J＝7Hz)。
E-2-(3-苯甲酰基苯基)乙烯-N-甲基磺酰胺(23)
1H-NMR(CDCl3)：δ7.81(d，2H，J＝7Hz)；7.70(s，1H)；7.62(d，1H，J＝8Hz)；7.55(d，1H，J＝14Hz)；7.45(m，2H)；7.30(m，3H)；6.90(d，1H，J＝14Hz)；4.60(bs，1H，SO2NH)；2.70(d，3H，J＝4Hz)。
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-甲基磺酰胺(24)
1H-NMR(CDCl3)：δ7.60(d，1H，J＝8Hz)；7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；7.10(d，1H，J＝14Hz)；4.85(bs，1H，SO2NH)；2.70(d，3H，J＝4Hz)。
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-甲基磺酰胺(25)
1H-NMR(CDCl3)：δ7.56(d，1H，J＝14Hz)；7.35(d，2H，J＝8Hz)；7.20(d，2H，J＝8Hz)；6.92(d，1H，J＝14Hz)；6.50(bs，1H，SO2NH)；4.70(bs，1H，SO2NH)；3.00(s，3H)，2.75(d，3H，J＝4Hz)。
按照上述方法，使用的胺为2-甲氧基乙胺，制成以下化合物：
E-2-(4-异丁基苯基)乙烯-N-(2-甲氧基乙基)磺酰胺(26)
1H-NMR(CDCl3)：δ7.57(d，1H，J＝14Hz)；7.38(d，2H，J＝7Hz)；7.20(d，2H，J＝7Hz)；6.90(d，1H，J＝14Hz)；4.80(bs，1H，SO2NH)；3.74(m，2H)；3.55(m，2H)；3.45(s，3H)；2.52(d，2H，J＝7Hz)；1.95(m，1H)；1.05(d，6H，J＝7Hz)。
E-2-(3-苯甲酰基苯基)乙烯-N-(2-甲氧基乙基)磺酰胺(27)
1H-NMR(CDCl3)：δ7.80(d，2H，J＝7Hz)；7.72(s，1H)；7.62(d，1H，J＝8Hz)；7.55(d，1H，J＝14Hz)；7.40(m，2H)；7.30(m，3H)；6.95(d，1H，J＝14Hz)；4.62(bs，1H，SO2NH)；3.75(m，2H)；3.50(m，2H)；3.40(s，3H)。
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-(2-甲氧基乙基)磺酰胺(28)
1H-NMR(CDCl3)：δ7.62(d，1H，J＝8Hz)；7.50(d，2H，J＝7Hz)；7.30(d，2H，J＝7Hz)；7.15(d，1H，J＝14Hz)；4.80(bs，1H，SO2NH)；3.77(m，2H)；3.52(m，2H)；3.40(s，3H)。
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-(2-甲氧基乙基)磺酰胺(29)
1H-NMR(CDCl3)：δ7.58(d，1H，J＝14Hz)；7.35(d，2H，J＝8Hz)；7.25(d，2H，J＝8Hz)；6.90(d，1H，J＝14Hz)；6.52(bs，1H，SO2NH)；4.75(bs，1H，SO2NH)；3.70(m，2H)；3.50(m，2H)；3.40(s，3H)；3.05(s，3H)。
实施例4
芳基甲磺酰胺的通用合成方法
(1-甲基-5-异丁酰基吡咯基)-1-甲磺酰胺(30)
以市售试剂1-甲基-2-吡咯乙酸甲酯为起始材料，它与异丁酰氯进行Friedel Crafts酰基化反应，得到(1-甲基-5-异丁酰基吡咯基)-1-甲乙酸酯，由此合成了该化合物。再将酯基团水解。按照WO02/0704095记载的实验步骤，得到相关的(1-甲基-5-异丁酰基吡咯基)-1-甲磺酸钠盐。
将(1-甲基-5-异丁酰基吡咯基)-1-甲磺酸钠盐(0.64mmol)溶解在亚硫酰氯(5mL)中，制成的溶液回流过夜。待室温冷却之后，真空蒸发亚硫酰氯，粗(1-甲基-5-异丁酰基吡咯基)-1-甲磺酰氯用干THF(5mL)稀释，在0℃冰水浴中冷却；滴入氨水溶液(1.28mmol)。移去冰水浴，反应混合物静止放置直到温度升至室温。待起始试剂完全消失之后，真空蒸发溶剂，在残留物中加入三氯甲烷(10mL)和水(10mL)；摇动分离两相，有机相用水(3×15mL)洗涤，硫酸钠干燥，真空蒸发，得到粗产物，其经过快速色谱法纯化，分离得到纯的(1-甲基-5-异丁酰基吡咯基)-1-甲磺酰胺(0.60mmol)，为黄色油(得率为93％)。
1H-NMR(DMSO-d6)：δ7.5(s，1H)；6.18(s，1H)；4.65(bs，2H，SO2NH2)；3.60(s，3H)；3.51(s，2H)；3.38(m，1H)；1.25(d，6H，J＝8Hz)。
按照上述方法，采用(1-甲基-5-乙酰基吡咯基)-1-甲磺酸钠盐(7)(按照上述芳基甲磺酸的通用合成方法制备)，制成以下化合物：
(1-甲基-5-乙酰基吡咯基)-1-甲磺酰胺(31)
1H-NMR(DMSO-d6)：δ7.5(s，1H)；6.18(s，1H)；4.40(bs，2H，SO2NH2)；3.60(s，3H)；3.51(s，2H)；2.10(s，3H)。
对映选择性合成化合物32和33的(+)和(-)对映体
按照Davis F.A.等人的方法(J.Org.Chem.，58，4890-4896，(1993))对映选择性合成1-(4-异丁基苯基)乙磺酰胺的(+)和(-)对映体。该方法包括使由4-异丁基苄基磺酰胺(27)和N，N-二异丙基-(1S)-(+)-10-樟脑磺酰胺或者N，N-二异丙基-(1R)-(-)-10-樟脑磺酰胺制成的N-磺酰基樟脑亚胺进行非对映选择性C-甲基化反应。使非对映异构体酸水解可以得到所希望的化合物，二者均为透明油。
(-)-1-(4-异丁基苯基)乙磺酰胺(32)
[α]D＝-8.5(c＝1.2；CHCl3)
1H-NMR(CDCl3)：δ7.30(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.25(m，1H+bs SONH2)；2.45(d，2H，J＝7Hz)；1.87(m，4H)；0.97(d，6H，J＝7Hz)。
(+)-1-(4-异丁基苯基)乙磺酰胺(33)
[α]D＝+15(c＝1；CHCl3)
1H-NMR(CDCl3)：δ7.30(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.25(m，1H+bs SONH2)；2.45(d，2H，J＝7Hz)；1.87(m，4H)；0.97(d，6H，J＝7Hz)。
实施例5
芳基乙磺酰胺的替换合成
(+)-1-(3-异丙基苯基)乙磺酰胺(34)的合成
以市售试剂3-(1-氰基乙基)苯甲酸为起始材料，它按照Kindler K.等人(Chem.Ber.，99，226(1966))和Kindler K.等人(Liebigs Ann.Chem.，26，707(1967))描述的方法，得到中间体3-异丙基苯甲酸，由此合成了标题化合物。用LiAlH4还原苄基醇衍生物，再以硫代乙酸处理醇，得到中间体硫代乙酸乙酯。然后，按照Corey E.J.等人(Tet.Lett.，33，4099(1992))描述的方法，使硫醇衍生物进行水解反应。
向3-异丙基苄基硫醇(3.85g；23.2mmol)和叔丁醇钾(2.6g；23.2mmol)与二氯甲烷(15mL)的悬浮液加入18-冠-6(0.6g；2.3mmol)。在0°-4℃的温度范围内搅拌15分钟，加入N-溴-邻苯二甲酰亚胺(5.24g；23.2mmol)。加完后，移去冰水浴，溶液室温搅拌1小时；有机相用水(3×15mL)洗涤，硫酸钠干燥，真空蒸发，得到油状残留物，其经过快速色谱法纯化，得到3-异丙基苄基硫代邻苯二甲酰亚胺(6.05g；18.56mmol)，为浅黄色油(得率为80％)。然后，按照Davis F.A.等人(J.Org.Chem.，58，4890-4896，(1993))描述的方法进行甲基化反应，得到外消旋1-(3-异丙基苯基)乙基硫代邻苯二甲酰亚胺。用3-氯过苯甲酸(2当量)氧化，并以本领域公知的方法加入肼处理以切割苯二甲酰亚氨基，得到终产物1-(3-异丙基苯基)乙磺酰胺(31)。
1H-NMR(CDCl3)：δ7.28(m，2H)；7.05(m，2H)；4.40(bs，2H，SO2NH2)；3.90(m，1H)；3.65(m，1H)；1.35(d，3H，J＝7Hz)；1.20(d，6H，J＝8Hz)。
按照Gajda T.等人(Synthesis，1005(1981))与Burke P.O.等人(Synthesis，935(1985))描述的方法，以3-二甲基氨基丙基氯为烷基化试剂，使相应的1-芳基乙磺酰胺(按照上述方法制备)在相转移条件下进行烷基化反应。制成以下化合物：
(±)-1-(4-异丁基苯基)乙烷-N-(N，N-二甲基氨基丙基)磺酰胺(35)
1H-NMR(CDCl3)：δ7.32(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.26(m，1H)；4.10(bs，1H，SONH)；3.18(m，2H)；2.55(m，4H)；2.45(d，2H，J＝7Hz)；2.40(s，6H)；1.85(m，4H)；1.00(d，6H，J＝7Hz)。
(±)-1-(3-苯甲酰基苯基)乙烷-N-(N，N-二甲基氨基丙基)磺酰胺(36)
1H-NMR(CDCl3)：δ7.80(d，2H，J＝7Hz)；7.70(s，1H)；7.62(d，1H，J＝7Hz)；7.51(m，2H)；7.30(m，3H)；4.35(bs，1H，SO2NH)；3.62(m，1H)；3.18(m，2H)；2.55(m，4H)；2.40(s，6H)；1.30(d，3H，J＝7Hz)。
(±)-1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-(N，N-二甲基氨基丙基)磺酰胺(37)
1H-NMR(CDCl3)：δ7.50(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；4.30(bs，1H，SO2NH)；3.85(m，1H)；3.20(m，2H)；2.60(m，4H)；2.45(s，6H)；1.25(d，3H，J＝7Hz)。
(±)1-[4-(甲磺酰氨基)苯基]乙烷-N-(N，N-二甲基氨基丙基)磺酰胺(38)
1H-NMR(CDCl3)：δ7.37(d，2H，J＝8Hz)；7.22(d，2H，J＝8Hz)；6.45(bs，1H，SO2NH)；4.80(bs，1H，SO2NH)；3.82(m，1H)；3.25(m，2H)；2.98(s，3H)；2.65(m，4H)；2.45(s，6H)；1.05(d，3H，J＝7Hz)。
按照Gajda T.等人(Synthesis，1005(1981))和Burke PO.等人(Synthesis，935(1985))描述的方法，以2-溴乙基甲醚为烷基化试剂，使相应的1-芳基乙磺酰胺(按照上述方法制备)在相转移条件下进行烷基化反应。制成以下化合物：
(±)-1-(4-异丁基苯基)乙烷-N-(2-甲氧基乙基)磺酰胺(39)
1H-NMR(CDCl3)：δ7.30(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.25(m，1H)；4.80(bs，1H，SO2NH)；3.74(m，2H)；3.55(m，2H)；3.45(s，3H)；2.45(d，2H，J＝7Hz)；1.87(m，1H)；1.65(d，3H，J＝7Hz)；0.97(d，6H，J＝7Hz)。
(±)-1-(3-苯甲酰基苯基)乙烷-N-(2-甲氧基乙基)磺酰胺(40)
1H-NMR(CDCl3)：δ7.82(d，2H，J＝7Hz)；7.75(s，1H)；7.62(d，1H，J＝7Hz)；7.55(m，2H)；7.30(m，3H)；4.25(bs，1H，SO2NH)；3.75(m，2H)；3.60(m，1H)；3.55(m，2H)；3.48(s，3H)；1.55(d，3H，J＝7Hz)。
(±)-1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-(2-甲氧基乙基)磺酰胺(41)
1H-NMR(CDCl3)：δ7.50(d，2H，J＝7Hz)；7.25(d，2H，J＝7Hz)；4.30(bs，1H，SO2NH)；3.85(m，1H)；3.60(m，2H)；3.55(m，2H)；3.48(s，3H)；1.35(d，3H，J＝7Hz)。
(±)-1-[4-(甲磺酰氨基)苯基]乙烷-N-(2-甲氧基乙基)磺酰胺(42)
1H-NMR(CDCl3)：δ7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；6.45(bs，1H，SO2NH)；4.32(bs，1H，SO2NH)；3.85(m，1H)；3.62(m，2H)；3.55(m，2H)；3.48(s，3H)；3.00(s，3H)；1.35(d，3H，J＝7Hz)。
按照Muller E.等人(Liebigs Ann.Chem.，623，34(1959))和Saegusa T.等人(Lett.，6131(1966))描述的方法，以重氮甲烷为烷基化试剂，使相应的1-芳基乙磺酰胺(按照上述方法制备)进行单烷基化反应。制成以下化合物：
(±)-1-(4-异丁基苯基)乙烷-N-甲基磺酰胺(43)
1H-NMR(CDCl3)：δ7.25(d，2H，J＝7Hz)；7.18(d，2H，J＝7Hz)；4.80(bs，1H，SO2NH)；4.20(m，1H)；2.70(d，3H，J＝4Hz)；2.45(d，2H，J＝7Hz)；1.87(m，1H)；1.65(d，3H，J＝7Hz)；0.97(d，6H，J＝7Hz)。
(±)-1-(3-苯甲酰基苯基)乙烷-N-甲基磺酰胺(44)
1H-NMR(CDCl3)：δ7.82(d，2H，J＝7Hz)；7.75(s，1H)；7.62(d，1H，J＝7Hz)；7.55(m，2H)；7.30(m，3H)；4.25(bs，1H，SO2NH)；4.15(m，1H)；2.70(d，3H，J＝4Hz)；1.55(d，3H，J＝7Hz)。
(±)-1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-甲基磺酰胺(45)
1H-NMR(CDCl3)：δ7.52(d，2H，J＝7Hz)；7.28(d，2H，J＝7Hz)；4.10(bs，1H，SO2NH)；3.80(m，1H)；2.75(d，3H，J＝4Hz)；1.20(d，3H，J＝7Hz)。
(±)-1-[4-(甲磺酰氨基)苯基]乙烷-N-甲基磺酰胺(46)
1H-NMR(CDCl3)：δ7.50(d，2H，J＝7Hz)；7.27(d，2H，J＝7Hz)；6.50(bs，1H，SO2NH)；4.30(bs，1H，SO2NH)；3.90(m，1H)；3.05(s，3H)；2.70(d，3H，J＝4Hz)；1.32(d，3H，J＝7Hz)。
(±)-1-(4-异丁基苯基)乙烷-N-乙酰基磺酰胺(47)
如上所述，使相关的1-(4-异丁基苯基)乙磺酰胺与乙酰氯进行酰基化反应，合成了该化合物。
1H-NMR(CDCl3)：δ7.28(d，2H，J＝7Hz)；7.20(d，2H，J＝7Hz)；4.82(bs，1H，SO2NH)；4.30(m，1H)；2.45(d，2H，J＝7Hz)；1.85(m，1H)；1.80(s，3H)；1.65(d，3H，J＝7Hz)；0.97(d，6H，J＝7Hz)。
实施例6
E/Z2-芳基-2-甲基乙烯磺酰胺的通用合成方法
在20分钟内把适当的芳基苯乙酮(20mmol)(按照上述1-芳基乙烷磺酸的通用合成方法制成)在10mL叔丁基醇中的溶液滴入市售内鎓盐，碘亚甲基三苯基磷烷(25mmol)，保持反应温度在25℃以下，得到的混合物室温搅拌4小时。反应结束时，将混合物与50ml戊烷及50ml水摇匀，过滤，分离两层。水层用戊烷(3×50ml)萃取，硫酸钠干燥，经快速色谱法纯化后，得到纯的2-(芳基)碘化丙烯(E/Z异构体混合物)，(得率约70％)。按照Sotaro Miyano等人(Bull.Chem.Soc.J.，1197，52(1979))描述的方法，使羰基化合物进行上述Wittig烯化反应。
把2-(芳基)碘化丙烯(2mmol)溶解在乙腈(5mL)中，室温下加入到硫代乙酸钾(4mmol)在乙腈(2ml)中的溶液；反应混合物搅拌4小时。将该混合物用水淬灭，乙酸乙酯萃取；分离两相，有机相干燥，过滤，浓缩，得到2-芳基丙烯硫代乙酸酯(E/Z异构体混合物)(几乎为定量得率)。
在60℃搅拌2-芳基-2-甲基乙烯硫代乙酸酯(1.00mmol)在冰醋酸(2mL)中的溶液，滴入30％H2O2(4.56mmol)处理；得到的溶液在60℃搅拌24小时，然后，与甲苯共沸蒸馏除去乙酸。残留物用水(5mL)稀释，1N NaOH中和，二乙醚(2×15mL)洗涤，冻干，得到2-芳基-2-甲基乙烯磺酸钠盐(E/Z异构体混合物)，为白色固体(得率约90％)。
按照上述E-芳基乙烯磺酰胺的通用合成方法制备E/Z2-芳基-2-甲基乙烯磺酰胺，制成E/Z-2-芳基-2-甲基-乙烯磺酰胺(0.75-0.85mmol)(得率为85-95％)，为无色油。
按照上述方法，合成以下化合物：
E-2-(3-苯甲酰基苯基)-2-甲基乙烯磺酰胺(48)
1H-NMR(CDCl3)：δ7.75(m，3H)；7.62(m，2H)；7.53(m，4H)；6.15(d，1H，J＝1.4Hz)，5.96(d，1H，J＝1.3Hz)；4.38(bs，2H，SONH2)；2.10(d，3H，J＝1.4Hz)；2.0(d，3H，J＝1.3Hz)。
E-2-(3-异丙基苯基)-2-甲基乙烯磺酰胺(49)
1H-NMR(CDCl3)：δ7.28(m，1H)；7.15(m，1H)；7.05(m，2H)；6.15(d，1H，J＝1.4Hz)，5.96(d，1H，J＝1.3Hz)；4.38(bs，2H，SONH2)；3.15(m，1H)；2.10(d，3H，J＝1.4Hz)；2.0(d，3H，J＝1.3Hz)；1.25(d，6H，J＝7Hz)。
E-2-(4-异丁基苯基)-2-甲基乙烯磺酰胺(50)
1H-NMR(CDCl3)：δ7.32(d，2H，J＝7Hz)；7.23(d，2H，J＝7Hz)；6.15(q，1H，J＝1.4Hz)；5.96(q，1H，J＝1.3Hz)；4.35(bs，2H，SONH2)；2.45(d，2H，J＝7Hz)；2.10(d，3H，J＝1.4Hz)；2.0(d，3H，J＝1.3Hz)；1.88(m，1H)；0.97(d，6H，J＝7Hz)。
表1列出实施例1-6的一些化合物名称与结构。
表1
表2
IL-8(100ng/mL)诱导的人PMN趋化性的抑制(％)
*化合物的测试浓度为c＝10-7
Claims (16)
1.通式(I)所示的磺酸与衍生化合物，及其药学上可接受的盐，在制备抑制IL-8诱导的人多形核嗜中性白细胞趋化性的药物中的用途，
通式(I)中，Ar是非取代或由1至3个取代基取代的苯基，吡啶、吡咯或吲哚，所述取代基独立地选自C1-C4-烷基、C1-C4-烷氧基、C1-C4-酰氧基、苯氧基、氨基、C1-C4-酰基氨基、卤代-C1-C3-烷基、卤代-C1-C3-烷氧基、苯甲酰基；
X代表-CH2-或-CH(CH3)-基团，或者通式(II)所示的E构型烯基，其中R′是H或CH3；
Y选自O和NH；并且
-当Y是O，R是H；和
-当Y是NH，R选自以下基团：H、C1-C5-烷基、C1-C5-环烷基、C1-C5-酰基；通式-CH2-CH2-Z-(CH2-CH2O)nR”所示的残基，其中R”是H或C1-C5-烷基，n是0至2的整数，Z是氧；通式一(CH2)n-NRaRb所示的残基，其中n是0至5的整数，Ra和Rb可相同或不同，各自是C1-C6-烷基。
2.如权利要求1所述的用途，其特征在于：Ar是取代的苯基，选自3’-苯甲酰基苯基、3’-(4-氯-苯甲酰基)-苯基、3’-(4-甲基-苯甲酰基)-苯基、3’-乙酰基-苯基、3’-丙酰基-苯基、3’-异丁酰基-苯基、4’-三氟甲磺酰氧基-苯基、4’-苯磺酰氧基-苯基、4’-三氟甲磺酰氨基-苯基、4’-苯磺酰氨基-苯基、4’-苯磺酰甲基-苯基、4’-乙酰氧基苯基、4’-丙酰氧基-苯基、4’-苯甲酰氧基-苯基、4’-乙酰基氨基-苯基、4’-丙酰基氨基-苯基、4’-苯甲酰基氨基-苯基。
3.如权利要求1所述的用途，其特征在于：YR是OH。
4.如权利要求1所述的用途，其特征在于：Y是NH，R是：
H、C1-C5烷基、C1-C5酰基；
通式-CH2-CH2-O-(CH2-CH2O)R”所示的残基，其中R”是H或C1-C5-烷基；
通式-(CH2-)n-NRaRb所示的残基，其中n是2或3的整数，基团NRaRb是N，N-二甲胺、N，N-二乙胺。
5.如权利要求4所述的用途，其特征在于：n是3。
6.如权利要求1所述的通式(I)所示的磺酸和衍生化合物，选自以下化合物：
1-(4-异丁基苯基)乙磺酸
1-[4-(1-氧-2-异二氢吲哚基)苯基]乙磺酸
2-(4-苯基磺酰氧基)乙磺酸
(1-甲基-5-乙酰基吡咯基)-1-甲磺酸
2-(3-苯甲酰基苯基)乙磺酸
2-(3-异丙基苯基)乙磺酸
E-2-(4-异丁基苯基)乙烯磺酸
E-2-(3-苯甲酰基苯基)乙烯磺酸
E-2-(4-甲磺酰氨基苯基)乙烯磺酸
E-2-(4-三氟甲磺酰氧基苯基)乙烯磺酸
E-2-(4-异丁基苯基)乙烯磺酰胺
E-2-(3-苯甲酰基苯基)乙烯磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯磺酰胺
E-2-(4-异丁基苯基)乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-(3-苯甲酰基苯基)乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-(N，N-二甲基氨基丙基)磺酰胺
E-2-(4-异丁基苯基)乙烯-N-甲基磺酰胺
E-2-(3-苯甲酰基苯基)乙烯-N-甲基磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-甲基磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-甲基磺酰胺
E-2-(4-异丁基苯基)乙烯-N-(2″-甲氧基乙基)磺酰胺
E-2-(3-苯甲酰基苯基)乙烯-N-(2″-甲氧基乙基)磺酰胺
E-2-[4-(三氟甲磺酰氧基)苯基]乙烯-N-(2″-甲氧基乙基)磺酰胺
E-2-[4-(甲磺酰氨基)苯基]乙烯-N-(2″-甲氧基乙基)磺酰胺
(1-甲基-5-异丁酰基吡咯基)-1-甲磺酰胺
(1-甲基-5-乙酰基吡咯基)-1-甲磺酰胺
1-(4-异丁基苯基)乙磺酰胺
1-(3-异丙基苯基)乙磺酰胺
1-(4-异丁基苯基)乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-(3-苯甲酰基苯基)乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-[4-(甲磺酰氨基)苯基]乙烷-N-(N，N-二甲基氨基丙基)磺酰胺
1-(4-异丁基苯基)乙烷-N-(2-甲氧基乙基)磺酰胺
1-(3-苯甲酰基苯基)乙烷-N-(2-甲氧基乙基)磺酰胺
1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-(2-甲氧基乙基)磺酰胺
1-[4-(甲磺酰氨基)苯基]乙烷-N-(2-甲氧基乙基)磺酰胺
1-(4-异丁基苯基)乙烷-N-甲基磺酰胺
1-(3-苯甲酰基苯基)乙烷-N-甲基磺酰胺
1-[4-(三氟甲磺酰氧基)苯基]乙烷-N-甲基磺酰胺
1-[4-(甲磺酰氨基)苯基]乙烷-N-甲基磺酰胺
1-[4-异丁基苯基]乙烷-N-乙酰基磺酰胺
E-2-(3-苯甲酰基苯基)-2-甲基-乙烯磺酰胺
E-2-(3-异丙基苯基)-2-甲基-乙烯磺酰胺
E-2-(4-异丁基苯基)-2-甲基-乙烯磺酰胺
及其药学上可接受的盐。
7.如权利要求6所述的化合物，其特征在于：所述化合物是所述各乙磺酰胺化合物，且为各乙磺酰胺化合物的(-)或(+)单对映体。
8.如权利要求6或7所述的通式(I)中YR是OH的化合物的制备方法，其特征在于：所述方法包括使通式(IV)所示的中间体化合物，
其中J是H或COCH3，
与合适的氧化剂反应。
9.如权利要求8所述的方法，所述氧化剂为过氧酸。
10.如权利要求8所述的方法，所述氧化剂选自H2O2、HClO或间氯过苯甲酸。
11.如权利要求6或7所述的通式(I)中Y是NH，X是-CH2-或通式(II)所示的E构型乙烯基的化合物的制备方法，
其特征在于：所述方法包括使相应的磺酰卤化物与1或2当量的通式NH2R所示的胺反应。
12.如权利要求11所述的方法，所述磺酰卤化物是磺酰氯。
13.如权利要求6或7所述的通式(I)中Y是NH，X是-CH(CH)3-的化合物的制备方法，其特征在于：所述方法包括使通式(IV)所示的中间体化合物，
其中J是H或COCH3，
与合适的N-溴酰亚胺反应，再氧化硫原子，然后使磺酰胺衍生物脱保护。
14.如权利要求13所述的方法，所述N-溴酰亚胺是N-溴邻苯酰亚胺。
15.药物组合物，其特征在于：所述药物组合物含有如权利要求6或7所述的化合物及其合适的载体。
16.如权利要求1至4中任一项所述的用途，其特征在于：用来制备治疗牛皮癣、溃疡性结肠炎、黑素瘤、慢性阻塞性肺病、大疱性类天疱疮、类风湿关节炎、特发性纤维化、肾小球性肾炎以及预防和治疗由局部缺血和再灌注引起的损伤的药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03005783.0 | 2003-03-14 | ||
| EP03005783A EP1457485A1 (en) | 2003-03-14 | 2003-03-14 | Sulfonic acids, their derivatives and pharmaceutical compositions containing them |
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| CN1761645A CN1761645A (zh) | 2006-04-19 |
| CN100372831C true CN100372831C (zh) | 2008-03-05 |
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| Country | Link |
|---|---|
| US (1) | US7737139B2 (zh) |
| EP (2) | EP1457485A1 (zh) |
| JP (1) | JP4578466B2 (zh) |
| CN (1) | CN100372831C (zh) |
| AT (1) | ATE547397T1 (zh) |
| AU (1) | AU2004220360B2 (zh) |
| CA (1) | CA2514988C (zh) |
| DK (1) | DK1606248T3 (zh) |
| ES (1) | ES2386811T3 (zh) |
| HK (1) | HK1089431A1 (zh) |
| NO (1) | NO332782B1 (zh) |
| PT (1) | PT1606248E (zh) |
| RU (1) | RU2345063C2 (zh) |
| WO (1) | WO2004080951A2 (zh) |
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| US7504401B2 (en) | 2003-08-29 | 2009-03-17 | Locus Pharmaceuticals, Inc. | Anti-cancer agents and uses thereof |
| US20080125485A1 (en) | 2004-02-17 | 2008-05-29 | Action Medicines | Use of 2,5-Dihydroxybenzene Derivatives for Treating Actinic Keratosis |
| US20070149618A1 (en) | 2004-02-17 | 2007-06-28 | Action Medicines, S.L. | Methods of use for 2,5-dihydroxybenzene sulfonic acid compounds for the treatment of cancer, rosacea and psoriasis |
| ES2238924B1 (es) | 2004-02-17 | 2006-12-01 | Investread Europa, S.L. | Uso del acido 2,5-dihidroxibencenosulfonico, en la fabricacion de medicamentos de aplicacion en el tratamiento de enfermedades angiodependientes. |
| KR20070083484A (ko) | 2004-07-14 | 2007-08-24 | 피티씨 테라퓨틱스, 인크. | Ｃ형 간염 치료 방법 |
| US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7772271B2 (en) | 2004-07-14 | 2010-08-10 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| US7868037B2 (en) | 2004-07-14 | 2011-01-11 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| NZ553329A (en) | 2004-07-22 | 2010-09-30 | Ptc Therapeutics Inc | Thienopyridines for treating hepatitis C |
| TWI331523B (en) * | 2005-12-08 | 2010-10-11 | Nat Health Research Institutes | Vinylsulfonate compounds |
| DK2024329T3 (da) * | 2006-05-18 | 2013-11-04 | Dompe Spa | (2r)-2-[(4-sulfonyl)aminophenyl]propanamider og farmaceutiske sammensætninger indeholdende dem |
| WO2008020025A1 (en) | 2006-08-16 | 2008-02-21 | Action Medicines, S.L. | Use of 2,5-dihydroxybenzene derivatives for treating actinic keratosis |
| US20080113948A1 (en) | 2006-08-16 | 2008-05-15 | Action Medicines | Use of 2,5-Dihydroxybenzene Compounds and Derivatives for the Treatment of Psoriasis |
| CA2695864A1 (en) * | 2007-08-07 | 2009-02-12 | Schering Corporation | Gamma secretase modulators |
| CN103159674A (zh) * | 2013-04-03 | 2013-06-19 | 苏州安诺生物医药技术有限公司 | 2-苯烷酰胺类化合物及其制备方法、药物组合物和用途 |
| US9926327B2 (en) * | 2016-02-16 | 2018-03-27 | Zoetis Services Llc | Process for preparing 7H-pyrrolo[2,3-D]pyrimidine compounds |
| CN111747838B (zh) * | 2020-07-29 | 2023-04-07 | 深圳大学 | 一种电催化合成氘代布洛芬的方法 |
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| WO2000024710A1 (en) * | 1998-10-23 | 2000-05-04 | Dompe' S.P.A. | N-(2-aryl-propionyl)-sulfonamides and pharmaceutical preparations containing them |
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2003
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2004
- 2004-03-11 EP EP04719463A patent/EP1606248B1/en not_active Expired - Lifetime
- 2004-03-11 PT PT04719463T patent/PT1606248E/pt unknown
- 2004-03-11 ES ES04719463T patent/ES2386811T3/es not_active Expired - Lifetime
- 2004-03-11 US US10/544,396 patent/US7737139B2/en not_active Expired - Fee Related
- 2004-03-11 RU RU2005131846/04A patent/RU2345063C2/ru not_active IP Right Cessation
- 2004-03-11 CA CA2514988A patent/CA2514988C/en not_active Expired - Fee Related
- 2004-03-11 WO PCT/EP2004/050293 patent/WO2004080951A2/en active Application Filing
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- 2004-03-11 JP JP2006505463A patent/JP4578466B2/ja not_active Expired - Fee Related
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| CN1166834A (zh) * | 1994-10-13 | 1997-12-03 | 美国辉瑞有限公司 | 苯并吡喃和苯并稠合化合物，其制备方法和它们作为白三烯b4(ltb4)拮抗剂的用途 |
| WO2000024710A1 (en) * | 1998-10-23 | 2000-05-04 | Dompe' S.P.A. | N-(2-aryl-propionyl)-sulfonamides and pharmaceutical preparations containing them |
| CN1349521A (zh) * | 1999-03-26 | 2002-05-15 | Ucb公司 | 治疗哮喘、过敏和炎症的化合物和方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004220360A1 (en) | 2004-09-23 |
| US20060258730A1 (en) | 2006-11-16 |
| WO2004080951A3 (en) | 2004-11-04 |
| JP2006520367A (ja) | 2006-09-07 |
| CA2514988C (en) | 2013-07-16 |
| ES2386811T3 (es) | 2012-08-31 |
| NO20054672D0 (no) | 2005-10-11 |
| EP1606248A2 (en) | 2005-12-21 |
| WO2004080951A2 (en) | 2004-09-23 |
| US7737139B2 (en) | 2010-06-15 |
| NO20054672L (no) | 2005-12-13 |
| HK1089431A1 (en) | 2006-12-01 |
| AU2004220360B2 (en) | 2010-10-28 |
| ATE547397T1 (de) | 2012-03-15 |
| CN1761645A (zh) | 2006-04-19 |
| DK1606248T3 (da) | 2012-06-18 |
| PT1606248E (pt) | 2012-06-01 |
| NO332782B1 (no) | 2013-01-14 |
| CA2514988A1 (en) | 2004-09-23 |
| JP4578466B2 (ja) | 2010-11-10 |
| EP1606248B1 (en) | 2012-02-29 |
| RU2345063C2 (ru) | 2009-01-27 |
| EP1457485A1 (en) | 2004-09-15 |
| RU2005131846A (ru) | 2006-03-27 |
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