CN100368394C - N-(2-芳基-丙酰基)-磺胺类化合物及其药物组合物 - Google Patents
N-(2-芳基-丙酰基)-磺胺类化合物及其药物组合物 Download PDFInfo
- Publication number
- CN100368394C CN100368394C CNB998124516A CN99812451A CN100368394C CN 100368394 C CN100368394 C CN 100368394C CN B998124516 A CNB998124516 A CN B998124516A CN 99812451 A CN99812451 A CN 99812451A CN 100368394 C CN100368394 C CN 100368394C
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- Prior art keywords
- propionyl
- phenyl
- group
- benzoyl
- isobutyl
- 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.)
- Expired - Lifetime
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Abstract
通式(1)所示的化合物可用于预防和治疗因多形核嗜中性白细胞(PMN白细胞)在炎症部位恶性聚集造成的组织损伤，化合物中的R和R2由说明书定义。
Description
本发明涉及N-(2-芳基-丙酰基)-磺胺类化合物及其药物组合物，该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。
趋化性是一种细胞反应，它引起特定血细胞(巨噬细胞、粒细胞、多形核嗜中性白细胞)随着化学刺激(趋化因子)顺刺激剂的浓度梯度方向迁移。最具有代表性的趋化因子是补体剪切产物C5a，细菌表面裂解产生或合成的N-甲酰肽，例如甲酰基-甲硫氨酰-亮氨酰-苯丙氨酸(f-MLP)，最重要的是称为白介素IL-8的一类细胞因子。白介素IL-8是大多数有核细胞(成纤维细胞、巨噬细胞、内皮细胞和上皮细胞)接触TNF-α(肿瘤坏死因子)、白介素IL-1α和IL-1β和细菌细胞壁的脂多糖(LPS)时产生，或嗜中性白细胞本身在LPS和细菌N-甲酰肽(fMPL样肽)作用下产生的一种内源性趋化因子。这一趋化因子[又称嗜中性白细胞活化因子(NAF)、T细胞趋化因子、单核细胞源嗜中性白细胞趋化因子(MDNCF)]控制着一系列与IL-8受体结合的IL-8样趋化因子[GROα、β、γ和NAP-2](Chang等，免疫学杂志148：451，1992)。
在趋化因子的作用下，嗜中性白细胞发生形态改变，使它们倾向于迁移和活化，最后发生脱粒、耗氧，并产生氧自由基。
所有这些作用在嗜中性白细胞接触趋化因子后的数秒内发生，其生物化学特征在于胞内Ca2+离子、Na+离子和c-AMP水平瞬间升高，细胞膜电势因而改变。趋化因子诱导[Ca2+]i升高后，G蛋白、磷脂酶C、A2和花生四烯酸级联被活化，并形成环加氧酶和脂氧合酶产物(L.Harvath的“嗜中性白细胞趋化性调节”，医学化学报道年报，ps.233-235，Vol.24，1992和该论文所引用的文献)。嗜中性白细胞是抵挡细菌感染的第一道防线，因为它们会从外周血流通过内皮细胞界和组织基质向感染部位迅速迁移，在此发挥其特殊的作用，例如破坏微生物、清除被损伤细胞和促进组织修复(M.A.Goucerot-Podicalo等，病理学和生物学(巴黎)44，36，1996)。
在以嗜中性白细胞恶性聚集为特征的特定病理情况下，以上有益的聚集作用被组织损伤的进一步恶化所抵消，这种恶化延缓愈创过程，最严重时，可能导致患者死亡。
最近，有重要而可信的证据支持以下假设：局部缺血和重充血损伤，以及氧过多性肺损伤与存在活化嗜中性白细胞有关，而细胞损害则是这一作用的直接后果。实验模型[N.Sekido等，自然365，654，1993和T.Matsumoto等，实验室研究77，119，1997]和人临床病理学报道[A.Mazzone等，最新医学发展85，397，1994；T.C.Fisher和H.J.Meiselmann，凝血研究74(增刊1)，S21-S34，1994；G.Ricevuti等，动脉硬化91，1，1991]证实了这一点，其中，细胞损伤与PMN白细胞浸润的程度和范围直接、严格相关，IL-8细胞因子则越来越被认为是这种浸润的最具特异性和最强的活化剂。在这些情况的致病过程中，在诸如C5a、PAF、LTB4等激活嗜中性白细胞的各种趋化因子(它们参与嗜中性白细胞的直接迁移)之外，IL-8也具有重要作用：它由单核巨噬细胞产生，而这种产生能通过产生前新IL-8和附近非免疫细胞对其产生的诱导而介导其他炎性细胞迁移[A.P.Metiko等，临床研究杂志90，791，1992]。
在急性呼吸机能不全(ARDS)患者中，空间和肺液内嗜中性白细胞的恶性存在(疾病的特征之一)与细胞因子的高浓度显著相关。另一方面，患者肺水肿液内NAP-1/IL-8的浓度与诱导嗜中性白细胞趋化性所需的最佳浓度相符(E.J.Miller等，呼吸疾病评论146，437，1992)；最后，死亡率与肺泡液内的高浓度IL-8之间存在着密切的关联(A.Kurdowska等，免疫学杂志157，2699，1996)。
在这场争论中，特别重要的是用抗IL-8抗体所得的结果，该抗体能够在急性呼吸机能不全和管内滴注热灭活酿脓链球菌(OK-432)引起内毒素血症肺损伤的模型中中和细胞因子的作用(K.Yokoi等，实验室研究76，376，1997)。
急性心肌梗塞患者在发作后24小时内表现出血清IL-8显著升高(13-1100ng/L)。这一升高将在心肌细胞损伤的发展中起极其重要的作用，因为该细胞因子对嗜中性白细胞及其在组织损伤中的作用具有很强的刺激力(Y.Abe等，心脏病杂志70，132，1993)，在临床局部缺血情况发展中，这种作用更多地取决于重充血过程而不是缺血持续时间。
最近在一个重充血模型中证明，在兔脑内点局部缺血后，用抗IL-8抗体治疗能减轻脑水肿和缩小损伤面积(T.Matsumoto等，实验室研究，77，119，1997)。该模型中观察到的脑组织内IL-8显著升高证明：灌注组织内IL-8的局部产生及其在血管壁内活化嗜中性白细胞内的存在共同决定组织损伤的程度。
嗜中性白细胞与趋化剂之间的受体相互作用对于趋化性来说是决定性的；IL-8通过两种人嗜中性白细胞上和部分T细胞上的不同受体(CXCR1和CXCR2)参与这一作用(L.Xu等，白细胞生物学杂志57，335，1995)。N-(2-羟基-4-硝基苯基)-N′-(2-溴-苯基)脲选择性地抑制IL-8与嗜中性白细胞表面受体CXCR2结合，IC50为22nM，可证明这一点(J.R.White等，生物化学杂志273，10095，1998)。结果，IL-8(1nM)和GROα(10nM)激发的人嗜中性白细胞趋化性受到IC50相似(20-60nM)地抑制[补体C5a激发的趋化性的IC50则为50-330nM]，但并不抑制相同人嗜中性白细胞内IL-8或最佳浓度LTB4诱导的Ca2+ i动员。
最近(1998年2月28日)的WO98/07418提出了将苯基脲用于治疗白介素8(IL-8)介导的病理的专利。
在研究评价酮洛芬(S)和(R)对映体对于其外消旋体消炎活性的贡献，以及它们在细胞因子调节中的作用时(P.Ghezzi等，实验医学和治疗学杂志，1999，在印)，出人意料地发现，具有手性和非手性有机碱(organic bases)的单对映体的盐剂量依赖性性地抑制IL-8在PMN白细胞内诱导的Ca2+胞内浓度升高([Ca2+]i(本申请人在意大利的专利申请n°MI98A000146(28.01.1998)。用La(镧)离子进行的竞争研究证明：这些盐对于嗜中性白细胞IL-8应答的抑制作用既不是受体相互作用的结果也不是IL-8受体表达受阻的结果，而是选择性抑制Ca2+作用的结果，这种抑制的程度足以阻止细胞因子激活嗜中性白细胞特有的一系列反应：嗜中性白细胞趋化性和脱粒(同时释放出弹性酶、组织蛋白酶等酶)。而且，单对映体还抑制C5a和fMLP诱导的趋化性和[Ca2+]i升高，虽然效率略低。
这两种单对映体的主要区别在于(R)对映体作为CO酶抑制剂的效力较低(低约10-100倍)。
所以，与(S)对映体相比，(R)对映体的PG合成抑制活力较低，PG则具有抑制和控制放大(例如)嗜中性白细胞促炎作用的TNF-α等细胞因子释放的作用。因此，在嗜中性白细胞依赖性病理和炎症，例如牛皮癣、原发性肺纤维变性、急性呼吸机能不全、重充血损伤和血管球性肾炎等的治疗中，(S)对映体的治疗性作用较低。
现在发现，2-芳基-丙酸的N-酰基-磺胺类化合物是IL-8诱导的嗜中性白细胞趋化性和脱粒有效的抑制剂。如W.H.Pirke和J.Mc Cune(层析法469，67，1989)所述，R(2)-[(4-异丁基)苯基]丙酰胺也具有类似的特性。所以，本发明也涉及它在治疗嗜中性白细胞依赖性病理中的用途。
更具体地说，本发明涉及以下通式(1)所示的新N-(2-芳基-丙酰基)-磺胺类化合物：
其中，R2是芳基；
R是直链或分支C1-16烷基，三氟甲基，环己基，邻甲苯基，3-吡啶基，2-吡啶基乙基，对氰基苯基甲基，对氨基苯基甲基，3-氰基-1-丙基，4-氨基丁基，烷氧基亚乙基CH3-(CH2)ni-(OCH2CH2)mi-，其中ni是0或1，mi是整数1-3，或是P1P2N-CH2-CH2-，其中P1和P2各自是H、C1-3烷基，苄氧基羰基α-、β-或γ-吡啶基羰基，羧基羰基或烷酯基羰基，P1和P2或者与相连的N原子构成苯二甲酰亚氨基、哌啶子基、吗啉代基；
R′是H或直链或分支C1-3烷基，以H为佳。
“芳基”以可被1-3个相同或不同取代基取代的苯基为佳，这些取代基选自卤素，C1-4烷基，C1-4烷氧基，羟基，C1-7酸基，氰基，硝基，氨基，C1-3酰基氨基，卤代C1-3烷基，卤代C1-3烷氧基，苯甲酰基，或如布洛芬、酮洛芬、萘普生、舒洛芬、卡洛芬、吡洛芬、芬洛芬等已知消炎性2-芳基丙酸的芳基部分。
较好的2-芳基丙酸的芳基是：4-异丁基苯基，3-苯甲酰基苯基，5-苯甲酰基-2-乙酸基苯基，3-苯氧基苯基，5-苯甲酰基噻吩-2-基，4-噻吩甲酰基(thienoyl)苯基，1-氧-2-异二氢氮杂茚基苯基，3-氯-4-(2，5-二氢-1H-吡咯-1-基)苯基，6-甲氧基-β-萘基，5-苯甲酰基-2-苯硫基，1-羟基苯基，或以下通式所示的基团
其中，A是苄基、苯甲酰基或苯甲酰基-肟、1-羟基-1-苯基甲基，B是H、羟基、C1-3酸基或氨基。
R2以上述已知消炎性2-芳基丙酸的芳基为佳。
特别优选的R2是4-(2-甲基丙基)-苯基，3-苯氧基-苯基，2-[4-(1-氧-2-异二氢氮杂茚基)苯基]，5-苯甲酰基噻吩-2-基，4-噻吩甲酰基苯基。
优选的C1-3酸基是乙酰基；优选的直链或分支C1-16烷基是甲基、己基、十二烷基和十六烷基；优选的C1-3烷基是甲基。
本发明中最为优选的通式(1)所示化合物是甲基所在的碳原子为R构型的那些。
本发明化合物可用已知方法制得，例如等分子量的通式(2)酸
其中，R2′与R2相同，或是可通过去保护转化为R2的基团，与通式(3)磺酰胺
其中，R和R′与前文所述的相同，在惰性溶剂中，在等分子量和/或略过量的碳二亚胺(例如二环己基碳二亚胺)、可溶性碳二亚胺(例如盐酸N-(3-二甲基-氨基-丙基)-N′-乙基碳二亚胺)或1，1′-羰基二咪唑等缩合剂和选自三乙基胺、4-(N，N-二甲基氨基)-吡啶、1，8-二氮杂二环[5.4.0]十一-7-烯和1，5-二氮杂二环[4.3.0]壬-5-烯的抗衡碱存在下反应生成。
或者，同样有效的另一过程包括：通式(3)所示的磺胺阴离子
其中，R如前述，与通式(2)酸的适当反应性形式在惰性溶剂中反应；更具体地说，在制备本发明手性N-酰基磺胺类化合物的过程中，通式(2)酸的氯化物是最佳反应形式，不会发生在通式(4)磺酰氯与通式(5)酰胺阴离子反应中可能发生的部分外消旋作用：
当以上过程所得化合物中的R2′是苯甲酰基时，所述苯甲酰基可通过已知的肟化反应或在合适催化剂存在下吸收1到2当量氢而发生的羰基还原成醇成烷(苄基)的反应，形成另一种不同的通式(1)化合物。
通式(1)所示化合物的N-酰基磺氨基是一个酸性足以与L-赖氨酸、L-精氨酸、三羧甲基氨甲烷或手性胺(例如麻黄碱、弱金鸡纳碱、金鸡纳啶等)等强碱和中强碱形成加成盐的基团，因而能够将该磺胺化合物光学拆分成(R)和(S)对映体。可用任选手性载体进行的TLC或多种柱层析等各种层析技术(参见W.H.Pirkle和J.McCune的前述论文)纯化和分离单对映体和非对映体，并用R-(-)-2-[(4′-异丁基)苯基]丙酰胺作为标准参照物评定其光学纯度。
烷基磺酸、芳基磺酸和杂芳基磺酸的氯化物，以及它们的酰胺是已知化合物，可以购得或方便地制得。所以，例如在将通式为CH3-(CH2)ni-(OCH2CH2)mi-OH(其中ni和mi如前所述)的聚氧乙烯醇转化为相应的甲苯磺酸酯或卤化物(X＝Cl，Br或I)后，转化产物与过量硫脲反应，可生成相应的异硫脲盐：CH3-(CH2)ni-(OCH2CH2)mi-S-(C＝NH)-NH2·HX，该产物再通过室温下的氯化直接转化为相应的磺酰氯：CH3-(CH2)ni-(OCH2CH2)mi-SO2Cl，然后转化为相应的磺酰胺(J.M.Sprague和T.B.Johnson，美国化学协会杂志59，1837，1937)。
通式为P1P2-N-CH2-CH2-SO2NH2的2-烷基-氨基乙磺酰胺是已知的化合物，或者可用已知方法方便地制得，其中，P1和P2是C1-3烷基，或者如前所述，P1和P2与相连的N原子形成环。有关氨基乙磺酰胺的合成，参见例如Miller等在化学协会杂志75，1941中所述；A.Le Berre和C.Porte(Bull.Soc.Chim(法国)II-602，1978)揭示了一种在乙烯-磺酰胺[CH2＝CH-SO2NH2]中加入仲胺(二甲基胺、哌啶和吗啉)的方法，作为制备2-二烷基氨基乙磺酰胺的一般方法，乙烯-磺酰胺的合成可参见A.S.Matlack，有机化学杂志23，729，1958，以及该论文所引用的文献所述。
通式(3)磺酰胺和通式(4)磺酰氯是已知的化合物，或者可用熟知的方法制得。
通式(2)所示的2-芳基丙酸是熟知用作镇痛和消炎药的化合物。已知许多它(包括其单对映体和外消旋体)的制备方法。已知许多光学拆分外消旋体的有效方法。对映体选择性合成主要涉及芳基丙酸(S)对映体的合成，但通过适当选择反应试剂(手性助剂)，也可改用于获得(R)对映体：参见，例如，用烷基芳基酮作为基质合成α-芳基烷酸，参见B.M.Trost和J.H.Rigby，有机化学杂志14，2936，1978；有关Meldrum酸的α-芳基化，参见J.T.Piney和B.A.Rowe，Tetrah.lett.，21，965，1980；有关酒石酸作为手性助剂的用途，参见G.Castaldi等，有机化学杂志52，3018，1987；有关α-羟基酯作为手性助剂的用途，参见R.D.Larsen等，美国化学协会杂志111，7650，1989和美国专利4,940,813以及其中引用的文献。
更具体地说，其中R2为3-苯甲酰基-2-羟基-苯基或3-苯甲酰基-2-氨基苯基的通式(2)所示芳基酸是已知化合物；其制备方法可参见本申请人的意大利专利1,283,649(23.04.1998)。
R(-)-N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺及其L(+)-赖氨酸盐；
R(-)-N-2-[(3-苯甲酰基苯基)-丙酰基]-甲磺酰胺；
R(-)-N-(2-[3-(1ξ-羟基-1ξ-苯基)甲基]-丙酰基)-甲磺酰胺；
R(-)-N-甲基，N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺；
R(-)-N-[2-(3-苄基苯基)丙酰基]-甲磺酰胺；
(±)N-[2-(5′-苯甲酰基-2′-乙酸基苯基)-丙酰基]-甲磺酰胺；
盐酸R(-)-N-2-[(4-异丁基苯基)-丙酰基]-2-氨基乙基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-2-苯二甲酰亚氨基乙磺酰胺；
R(-)-N-[2-(3-苯甲酰基苯基)-丙酰基]，N′-苄酯基氨基乙磺酰胺；
R(-)-N-[2-(3-苯氧基苯基)-丙酰基]，N′-苄酯基氨基乙磺酰胺；
R(-)-N-[2-[4-(1-氧-2-异二氢氮杂茚基)苯基]丙酰基]，N′-苄酯基氨基乙磺酰胺；
N-[2-(5-苯甲酰基-噻吩-2-基)-丙酰基]-(2-苄酯基氨基)-乙磺酰胺；
N-[2-(4-噻吩甲酰基-苯基)丙酰基]-(2-苄酯基氨基)-乙磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-(2-苄酯基氨基)-乙磺酰胺；
R(-)-N-[2-(3-苯甲酰基苯基)-丙酰基]-(2-氨基)-乙磺酰胺；
R(-)-N-[2-(3-苯氧基苯基)-丙酰基]-(2-氨基)-乙磺酰胺；
N-[2-(5-苯甲酰基-噻吩-2-基)-丙酰基]-(2-氨基)-乙磺酰胺；
N-[2-(4-噻吩甲酰基-苯基)丙酰基]-(2-氨基)-乙磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-环己基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-十二烷基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-对氰基苯基甲磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-3-氰基-1-丙磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-2-甲氧基乙磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-3，6-二-庚基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-3，6-二-辛基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-3，6，9-三-癸基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-3，6，9-三-十一烷基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-2-二甲基氨基乙基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-2-(哌啶-1-基)-乙基磺酰胺；
R(-)-N-[2-(4-异丁基苯基)-丙酰基]-2-(吗啉-4-基)-乙基磺酰胺。
用葡聚糖进行肝素化健康供血者血液沉降，用如此制得的PMN细胞研究本发明的化合物；用Ficoll/Hypaque去除单核细胞，通过低渗溶液处理去除红细胞。用Turk和台盼蓝排除法计算PMN白细胞的细胞活力，在用Diff Quinck染色后计算细胞离心产物中的PM细胞核百分比(W.J.Ming等，免疫学杂志138，1469，1987)。
在后文所述的各“体外”试验中，PMN与本发明化合物都在37℃一起培养10分钟。
在趋化性试验以及评价Ca2+离子胞质溶胶水平的试验中，用人重组IL-8(Pepro Tech.)作为刺激剂：将冻干蛋白质溶解在HBSS(Hank′s平衡盐溶液)中达100ng/ml浓度，以HBSS稀释至10ng/ml用于趋化性试验，稀释至25-50ng/ml用于评价[Ca2+]i细胞修饰的试验。
在趋化性试验(按照W.Falket等，免疫学方法杂志33，239，1980)中采用5mm孔径的PVP滤膜和适合进行48份相同试验的树脂玻璃显微照相机。显微照相机有一片48孔的树脂玻璃片，各孔容量为25μl，配有一块48孔的盖玻片，这样，盖上盖玻片并旋紧后即在显微照相机内形成50μl的上部空间。
在含有PMN悬浮液的上部和下部的孔内加入相同浓度的被测化合物，上部孔内含有PMN悬浮液，下部孔内含有载体，其中加有或没有IL-8(或其他刺激剂)。
例如，10-6-10-11M浓度的R(-)-N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺(DF1681)，剂量依赖性地抑制IL-8(10ng/ml)诱导的趋化性。结果表示为迁移PMN的数量，是3次独立实验的平均值±S.D.，参见图1中的柱状图。
(S)(+)-N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺和R(-)-N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺的IC50为10-7-10-8M。
图2中的结果证实：本发明化合物选择性地抑制IL-8诱导的趋化性，而不抑制C5a(10-9)或f-MLP(10-8)诱导的趋化性，至少10-6-10-7M浓度的DF1681是如此[结果表示为迁移PMN的数量，是3次独立实验的平均值±S.D.]。
按照C.Bizzarri等(血液86，2388，1995)所述的实验模型测定胞质溶胶[Ca2+]i变化：用贴附有PMN的玻片，加入1μMfura-2AM来实时测定[Ca2+]i的变化。将PNM细胞离心产物重悬在含5％FCS(胎牛血清)的RPMI1640培养液中达3×106个细胞/ml，然后(平板)接种到25mm直径的圆形玻片上，将其在37℃培养箱内放置30分钟。用BBS(平衡盐溶液)洗涤3次去除非贴附细胞后，所有贴附细胞继续培养至多4小时，然后加入Fura-2AM。
例如，后文表格中记录了用3名不同供血者的人PMN白细胞，用R(-)-N-2-[3-(苯甲酰基苯基)-丙酰基]-甲磺酰胺(DF1661)和R(-)-N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺(DF1681)所得的结果。据信，当刺激物导致[Ca2+]i高出基线值34％时，这些白细胞被对IL-8是有反应。
表
IL-8(50ng/ml) 254±23(n＝20)
DF1661(10-6M)+IL-8(50ng/ml) 184±16(n＝10)
DF1681(10-6M)+IL-8(50ng/ml) 159±16(n＝10)
以应答细胞平均值和标准差(SEM)为反应数据，表示为与[Ca2+]i基线值相比的百分比；其中n是试验重复次数。在这些试验中，不同组中无应答细胞百分比互不相同：只用IL-8处理的组为30％，DF1661预处理组为40％，DF1681预处理组则为70％。
本发明的通式(1)所示的N-2-芳基丙酰基磺酰胺具有能够“体外”抑制白介素-8激发的PMN人白细胞趋化性的特征。本发明的酰基磺酰胺剂量依赖性地抑制PMN人白细胞趋化性，IC50(具有50％作用的剂量)为10-7-10-9M，并对IL-8诱导的趋化性具有显著的选择性和特异性。要“体外”抑制其他趋化因子(5Ca，细菌来源或合成的甲酰肽(f-LMP))诱导的趋化性，则浓度需提高1至2个数量级。本发明化合物能够抑制受IL-8刺激的人PNM内的胞内[Ca2+]i升高，这一升高与人PMNL的活化有关(J.H.Liu等，传染病杂志166，1089(1992))，这证明了本发明化合物的特异性。
与甲基的绝对构象无关，本发明化合物对CO和PG的产生没有显著作用。实际上，在LPS刺激的鼠巨噬细胞内(1mg/ml)，本发明化合物(评价浓度为10-5-10-7M)对PGE2产生的抑制通常低于统计学显著性，而且从未超过基线值的10-15％。
(LPS刺激的)鼠巨噬细胞并非增强促进嗜中性白细胞活化和趋化性以及IL-8合成的TNFα合成的适宜刺激物，此时，这一非相关性PGE2合成抑制是本发明相比部分2-芳基-丙酸的优点。在由过氧化氢刺激的TNF-α合成中也存在这种作用(TNF-α合成的非增强作用)。
根据以上实验证据，以及，已知白介素-8(IL-8)及其同类物参与牛皮癣(B.J.Nickoloff等，美国病理学杂志138，129，1991)、类风湿性关节炎(M.Selz等，临床研究杂志87，463，1991)，溃疡性结肠炎(Y.R.Mahkla等，临床科学82，273，1992)，急性呼吸机能不全(ARDS)和原发性纤维变性(P.C.Carre等，临床研究杂志88，1802，1991和E.J.Miller等，美国呼吸疾病论述，同上)，血管球性肾炎(T.Wada等，实验医学杂志180，1135，1994)，本发明化合物可用于以上疾病的治疗。
为了以上治疗目的，可用常规技术和赋型剂，例如“Remington药学手册”，Mack出版社，第18版，1990所述，将本发明化合物配制成药物组合物。
本发明的组合物的给予形式可以是肌内或静脉推注，皮肤病制剂(霜剂、液剂、喷雾剂和药膏)，以及以胶囊、片剂、糖浆、控释剂等形式口服。
平均日用量取决于多种因素，例如疾病的严重程度和患者情况(年龄、性别和体重)。该剂量一般为每日1或数毫克(mg)至1500mg本发明化合物，可以分多次给予。因为本发明化合物的毒性很低，所以，可以给予更高的剂量，甚至可以用于长期治疗。
以下实施例进一步说明了本发明。
制备
按照J.M.Sprague和T.B.Jonson在J.A.C.S.59，1837，1937和E.Miller等在ibidem62，2099(1940)中所述的方法制备烷基-、芳基烷基-、杂芳基烷基-磺酰胺和通式为CH3-(CH2)ni-(OCH2-CH2)mi-SO2NH2的烷氧基-聚氧乙烯磺酰胺，其中，ni是0或1，mi是整数1-3。
因此，例如，2-乙氧基乙基氯与略微过量的硫脲在醇中回流反应，可得到2-盐酸2-乙氧基乙基硫脲。在该盐的溶液中在25℃冷却并通入Cl2，于是分离出黄色油状物，将该物质溶于***，以硫酸钠干燥。挥发去除溶剂，得到2-乙氧基乙基磺酰氯，将其缓慢加入氢氧化铵溶液，得到2-乙氧基乙磺酰胺，根据需要，可对其进行稀释醇重结晶或柱层析纯化。采用以上过程制备了以下化合物：
2-甲氧基-乙磺酰胺，
2-(2-甲氧基-乙氧基)-乙磺酰胺或3，6-二-庚基磺酰胺；
2-(2-甲氧基-乙氧基)-乙磺酰胺或3，6-二-庚基磺酰胺；
2-(2-乙氧基-乙氧基)-乙磺酰胺或3，6-二-辛基磺酰胺；
3，6，9-三-癸基磺酰胺；
3，6，9-三-十一烷基磺酰胺。
实施例1
制备N-酰基磺酰胺的一般方法
A)通式(2)酸的氯化物与通式(3)磺酰胺阴离子反应：
R(-)-N-[2-(4-异丁基苯基)丙酰基]-甲磺酰胺
a)制备通式(2)酸的氯化物：
R(-)-2-(4-异丁基苯基)丙酸(R-布洛芬，4g，0.019mol)的亚硫酰氯(7.4ml)悬浮液回流4小时；然后室温下自然冷却。真空蒸发过量的亚硫酰氯。用数滴无水二烷洗涤残留物数次并真空蒸发溶剂，以去除最后的微量亚硫酰氯。得到4.66g(0.019mol)R(-)-2-(4-异丁基苯基)丙酰氯黄色油状物，将其溶于数ml无水四氢呋喃(THF)中。
b)制备磺酰胺阴离子：
将甲磺酰胺(2.3g，0.0243mol)加入叔丁氧钾(2.73g，0.0244mol)的THF(28ml)悬浮液中，混合物室温下搅拌30分钟。然后，搅拌加入R(-)-2-(4-异丁基)丙酰氯(4.66g，0.019mol)溶液，反应混合物室温下搅拌过夜。
过滤出分层的无机盐，真空蒸发去除溶剂，将油状残留物分配在CH2Cl2(30ml)和磷酸二氢钠饱和溶液之间。用水洗涤(2×10ml)有机相，用CH2Cl2萃取(2×10ml)水相。合并有机萃得液，以硫酸钠干燥，并真空蒸发溶剂，然后，在油状残留物的无水MeOH(10ml)溶液中加2微滴浓硫酸，将微量未转化的R(-)-2-(4-异丁基苯基)丙酸都酯化成甲酯。混合物在室温下放置过夜，小心地真空蒸发溶剂，将残留物分配在水(10ml)和二氯甲烷(25ml)之间。弃水相，用NaHCO3饱和溶液萃取(2×20ml)有机相。合并碱相，用浓盐酸酸化，并用CH2Cl2萃取(3×15ml)。常规洗涤至中性后，以Na2SO4干燥合并的有机萃得液，真空蒸发溶剂后得1.86g(0.0066mol)R(-)-N-[2-(4-异丁基苯基)丙酰基]-甲磺酰胺：m.p.：103-105℃(dec.)；[α]D＝-68°(c＝1；CH3OH)；1H-NMR(DMSO-d6)δ7.3(d，2H J＝8Hz)；7.09(d，2H J＝7Hz)；3.42(q，1H，J＝8Hz)；2.8(s，3H)；2.45(d，2H，J＝7Hz)；1.55(m，1H)；1.3(d，3H，J＝Hz)；0.95(d，6H，J＝7Hz)。
B)在缩合剂存在下，通式(2)酸与通式(3)磺酰胺直接缩合：
将N，N-二甲基氨基吡啶(2.363g，0.0194mol)，盐酸N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺(3.721g，0.0194mol)和甲磺酰胺(1.845g，0.0194mol)依次加入R-(-)-布洛芬(4g，0.0194mol)的无水CH2Cl2溶液(30ml)；混合物搅拌过夜。蒸发溶剂，残留物用乙酸乙酯(40ml)皂化，合并的有机相用水(15ml)和20％柠檬酸水溶液(2×10ml)洗涤，并用硫酸钠干燥，然后蒸发溶剂，得到2.2g(0.0076mol)R(-)-N-[2-(4-异丁基苯基)丙酰基]-甲磺酰胺：m.p.：103-105℃(dec.)；[α]D＝-68°(c＝1；CH3OH)。
实施例2
按照实施例1的方法，制备以下化合物：
S(+)-N-[2-(4-异丁基苯基)丙酰基]甲磺酰胺：m.p.：109-111℃(dec.)；[α]D＝+73°(c＝1；CH3OH)；1H-NMR(CDCl3)δ7.65(bs，1H，NH)；7.2-7.0(m，4H)；3.65(q，1H，J＝8Hz)；3.25(s，3H)；2.5(d，2H，J＝7Hz)；1.85(m，1H)；1.5(d，3H，J＝8Hz)；0.95(d，6H，J＝7Hz)。
R(-)-N-[2-(3-苯甲酰基苯基)-丙酰基]-甲磺酰胺：浅黄色油状物；[α]D＝-73°(c＝1；CH3OH)；1H-NMR(CDCl3)δ8.25(bs，1H，NH)；7.80-7.35(m，9H)；3.80(q，J＝7Hz，1H)；3.21(s，3H)；1.55(d，J＝7Hz，3H)。
S(+)-N-[2-(3-苯甲酰基苯基)-丙酰基]-甲磺酰胺：浅黄色油状物；[α]D＝+67°(c＝1；CH3OH)；1H-NMR(CDCl3)δ8.5(bs，1H，NH)；7.9-7.45(m，9H)；3.75(q，J＝7Hz，1H)；3.21(s，3H)；1.55(d，J＝7Hz，3H)。
S(+)-N-[2-(2-氟-4-联苯基)丙酰基]-甲磺酰胺：m.p.：130-132℃(dec.)；[α]D＝+44°(c＝1；CH3OH)；1H-NMR(CDCl3)δ7.8(bs，1H，NH)；7.50-7.30(m，5H)；7.05-6.90(m，3H)；3.65(q，1H，J＝7Hz)；3.20(s，1H)；1.50(d，3H，J＝7Hz)。
R(-)-N-[2-(2-氟-4-联苯基)丙酰基]-甲磺酰胺：m.p.：106-108℃；[α]D＝-42°(c＝1；CH3OH)；1H-NMR(CDCl3)δ7.9(bs，1H，NH)；7.50-7.30(m，5H)；7.10-6.95(m，3H)；3.65(q，1H，J＝7Hz)；3.20(s，1H)；1.50(d，3H，J＝7Hz)。
实施例3
R(-)-N-甲基，N-[2-(4-异丁基苯基)丙酰基]-甲磺酰胺
N-酰基磺酰胺的酸性足以按以下过程与重氮烷反应生成N-酰基-N-烷基磺酰胺。
将冰浴冷却(4℃)的R(-)-N-[2-(4-异丁基苯基)丙酰基]-甲磺酰胺(0.3g，0.001mol)的无水***溶液滴加到0.67N的重氮甲烷的***溶液中，直至得到稳定的黄色。向以上冷却溶液中加入数滴冰醋酸以破坏过量的重氮甲烷。溶液在室温下静置，蒸发去除溶剂。将残留物重溶于甲苯，真空蒸发去除微量乙酸。柱层析(正己烷/CH2Cl2 7∶3)纯化油状残留物，得到R(-)-N-甲基-N-[2-(4-异丁基苯基)丙酰基]-甲磺酰胺(0.24g，0.00076mol)，无色油状物。[α]D＝-60°(c＝1；CH3OH)；1H-NMR(CDCl3)δ7.2-7.09(m，4)；4.15(q，1H，J＝8Hz)；3.2(s，3H)；2.9(s，3H)；2.45(d，2H，J＝7Hz)；1.75(m，1H)；1.35(d，3H，J＝8Hz)；0.95(d，6H，J＝7Hz)。
按照实施例1的方法，用等摩尔量的N-甲基-甲磺酰胺代替甲磺酰胺，可制得相同的化合物。
实施例4
R(-)-N-(2-[3-(1ξ-羟基-1ξ-苯基)甲基]-苯基)丙酰基]-甲磺酰胺
在0.5g N-(R(-)-2-[3-(苯甲酰基苯基)-丙酰基]-甲磺酰胺的乙醇溶液中加入0.05ml三乙基胺和催化量的5％Pd/C，将此溶液保持在H2气氛下，直至吸收掉1nol当量气体。用celite滤掉催化剂，将洗脱液蒸干。将残留物分配在***和5％NaH2PO4水溶液之间，从有机相可制得0.4g R(-)-N-(2-[3-(1ξ-羟基-1ξ-苯基)甲基]-苯基)丙酰基]-甲磺酰胺。
实施例5
R(-)-N-2[3-(苄基苯基)丙酰基]-甲磺酰胺；
在0.5g N-(R(-)-2-[3-(苯甲酰基苯基)-丙酰基]-甲磺酰胺的乙醇溶液中加入0.05ml三乙基胺和催化量的5％Pd/C，将此溶液保持在H2气氛下，直至吸收掉至少2mol当量气体。用celite滤掉催化剂，将洗处液蒸干。将残留物分配在***和5％NaH2PO4水溶液之间，从有机相可制得0.4g R(-)-N-2[3-(苄基苯基)丙酰基]-甲磺酰胺。
实施例6
(±)N-2-[(5′-苯甲酰基-2′-乙酸基苯基)-丙酰基]-甲磺酰胺
6g(±)4-乙酸基-3-(1′-甲基-2′-丙烯-1-基)-二苯甲酮的CH2Cl2(125ml)溶液中加入等体积的水，在此溶液中边剧烈搅拌边依次加入：冰醋酸(12ml)，Aliquat336(0.37g)，和分成小份的高锰酸钾(总量9.5g，0.060mol)。混合物室温下搅拌20小时，直至起始物完全消失。加入偏亚硫酸氢钠水溶液(7.2g溶于水，15ml)使反应混合物褪色，再加入CH2Cl2(10ml)，于是分层。有机相用盐水(2×25ml)洗涤，并用硫酸钠干燥，真空蒸发溶剂后得到高纯度的6.2g(±)N-2-[(5′-苯甲酰基-2′-乙酸基苯基)-丙酰基]-甲磺酰胺油状物。HPLC(H2O/CH3CN t＝06040，t＝120100，t＝150100。Bondapak C18 20cm，l＝254nm，室温，5.5分钟)。TLC(CH2Cl2/CH3OH/9∶1)Rf＝0.2；1H-NMR(CDCl3)δ7.95(s，1H)；7.85(dd，2H，J′＝7Hz)；7.75(dd，1H，J′＝7Hz)；7.6(m，1H)；7.45(7，2H，7Hz)；7.25(s，1H)；3.9(q，1H，8Hz)；2.35(s，3H)；1.5(d，3H，J＝8Hz)。
将该化合物用在实施例1的方法中，可制得(+)N-2-[(5′-苯甲酰基-2′-乙酸基苯基)-丙酰基]-甲磺酰胺。
实施例7
L(±)赖氨酸R(-)-N-[2-(4-异丁基苯基)丙酰基]甲磺酰胺盐
将L(+)赖氨酸(129mg，0.88mmol)的水溶液(1.3ml)加入R(-)-N-[2-(4-异丁基苯基)丙酰基]甲磺酰胺(250mg，0.88mmol)的1ml甲醇溶液。蒸发去除溶剂，残留物溶于***(5ml)，室温下搅拌过夜。氮气氛下迅速滤出分离产生的强吸湿性晶体，用无水***洗涤滤得物，50℃真空干燥2小时，得到360mg R(-)-N-[2-(4-异丁基苯基)丙酰基]甲磺酰胺的L(±)赖氨酸盐，呈浅黄色粉末状。[α]D＝-17.3°(c＝1.15；CH3OH)；1H-NMR(D2O)δ7.30(dd，4H，J＝8Hz)；3.77(t，1H，J＝7Hz)；3.65(q，1H，J＝7Hz)；(m，4)；4.15(q，1H，J＝8Hz)；3.2(s，3H)；2.9(s，3H)；2.45(d，2H，J＝7Hz)；3.05(m，5H)；2.52(d，2H，J＝7Hz)；1.92(m，2H)；1.75(m，2H)；1.50(m，3H)；1.40(d，3H，J＝7Hz)；0.90(6H，d，J＝7Hz)。
实施例8
R(-)-2-[(4′-异丁基)苯基]丙酰胺
用28％NH4OH水溶液代替实施例1中的磺酰氨基阴离子，按以下方法制备通式(2)酸的酰胺。将1g R(-)-2-[4-异丁基-苯基]丙酰氯溶于无水乙腈(1.5ml)的溶液滴加到28％NH4OH水溶液(3ml)中，冷却至0-5℃，滴加速度保持反应混合物温度不超过5℃。化合物室温搅拌1小时，减压蒸发溶剂，将所得残留物溶于乙酸乙酯(5ml)。将该溶液冷却至0-4℃，析出白色晶体沉淀，过滤并真空干燥后得到(1.218g；5.93mmol)R(-)-2-[(4′-异丁基)苯基]丙酰胺：m.p.：125-127℃；[α]D＝-28°(c＝1；CH3OH)；1H-NMR(CDCl3)δ7.20-7.05(m，4H)；5.25(bs，2H，NH2)；3.6(q，J＝8Hz，1H)；2.5(m，2H)；1.9(m，1H)；1.55(d，J＝8Hz，3H)；0.93(d，J＝7Hz，6H)。
实施例9
盐酸R(-)N-[2-(4-异丁基苯基)丙酰基]-(2-氨基)乙基磺酰胺
按照Winterbottom等(美国化学协会杂志69，1393-1401(1947))所述的方法，将21.4g邻苯二甲酸酐(0.145mol)加入氨基乙磺酸(17g，0.137mol)和乙酸钾(14.2g，0.145mol)在冰醋酸(48ml)中所成的悬浮液中，回流加热。加热持续至反应物完全消失(2.5小时)；冷却至0-5℃后产生沉淀，过滤分离，用冰醋酸和无水乙醇洗涤，真空下空气干燥(50℃)，得到31.2g 2-邻苯二甲酰亚氨基乙磺酸钾(m.p.＞300℃；1H-NMR(D2O)d 7.85(m，4H)，4.05(t，3H，J＝8Hz)，5.25(t，2H，J＝8Hz)。5g该盐在苯(50ml)中的悬浮液通过共沸蒸馏干燥，在其中加入2.56g五氯化磷(0.015mol)，回流1小时。然后加入第二份五氯化磷(2.56g，0.015mol)。混合物再回流90分钟，然后真空和减压蒸发溶剂和反应物。混合物再回流1.3小时，冷却至室温，减压蒸发溶剂。用30g精细研磨的冰吸收残留物，生成细小固体(过滤，水洗，干燥)状的2-邻苯二甲酰亚氨基乙磺酰氯(3.71g，m.p.＝158-159℃)。
将乙腈(15ml)中的28％氨溶液(15.5ml)滴加到2-邻苯二甲酰亚氨基乙磺酰氯的乙腈(30ml)溶液中，冷却至0-4℃，混合物在0-4℃搅拌30分钟，蒸发溶剂，将残留物加入热水，析出沉淀2-邻苯二甲酰亚氨基乙磺酰胺(0.8g)(m.p.＝206-209℃；1H-NMR(DMSO-d6)δ7.95(m，4H)，7.15(bs 2H，NH2)，4.05(t，3H，J＝8Hz)，3.35(t，2H，J＝8Hz))。
在惰性气氛下，将0.75g(0.00295mol)该化合物加入叔丁氧钾(0.331g，0.00295mol)的无水THF(7ml)悬浮液中；搅拌1小时，然后加入R(-)2-(4-异丁基-苯基)-丙酰氯(0.47g酸(0.00227mol)与亚硫酰氯反应新鲜制备的)的无水THF(2ml)溶液。混合物室温下搅拌24小时；滤出固体残留物，将溶剂蒸干，将残留物分配在水和乙酸乙酯之间。合并有机相，用水(2×25ml)和盐水(25ml)洗涤，用硫酸钠干燥，真空蒸发溶剂，得到油状残留物，快速层析(洗脱剂：CH2Cl2/CH3OH 98∶2)纯化，得到透明油状物，即0.6g N-[R(-)2-(4-异丁基-苯基)-丙酰基]-2-邻苯二甲酰亚氨基-乙磺酰胺。1H-NMR(CDCl3)δ8.05(m，4H)，7.15(m，4H)，7.05(bs，1H，NH)，4.05(t，3H，J＝8Hz)，3.35(m，3H)，2.50(d，2H，J＝7Hz)，1.92(m，1H)，1.20(d，3H，J＝8Hz)，0.95(d，6H，J＝7Hz)。
在该化合物(0.5g，1.12mmol)的乙醇(4ml)溶液中加入85％水合肼(0.4ml)，回流1小时。真空蒸发去除溶剂后，用水稀释，用2N盐酸酸化，过滤分离邻苯二甲酰肼。将滤液蒸干，得到0.332g盐酸R(-)-N-[2-(4-异丁基-苯基)-丙酰基]-(2-氨基)乙磺酰胺，又名盐酸R(-)-N-[2-(4-异丁基-苯基)-丙酰基]-牛磺酰胺。
实施例10
按实施例9的方法，用按照H.McIlwain(化学协会杂志75，1941)所述方法制备的N′-苄酯基氨基乙磺酰胺和选自以下所述的2-芳基丙酸氯化物：R(-)2-(3-苯甲酰基-苯基)丙酸，R(-)2-(3-苯氧基-苯基)-丙酸，R(-)2-[4-(1-氧-2-异二氢氮杂茚基)苯基]丙酸，2-(5-苯甲酰基噻吩-2-基)丙酸，2-(4-噻吩甲酰基-苯基)-丙酸和R(-)2-(4-异丁基-苯基)丙酸，分别获得以下化合物：
R(-)-N-[2-(3-苯甲酰基-苯基)-丙酰基]-(2-苄酯基氨基)-乙磺酰胺；
R(-)-N-[2-(3-苯氧基苯基)-丙酰基]-(2-苄酯基氨基)-乙磺酰胺；
R(-)-N-[2-[4-(1-氧-2-异二氢氮杂茚基)苯基]丙酰基]-(2-苄酯基氨基)-乙磺酰胺；
N-[2-(5-苯甲酰基-噻吩-2-基)-丙酰基]-(2-苄酯基氨基)-乙磺酰胺；
N-{2-[4-(2-噻吩甲酰基-苯基)]-丙酰基}-(2-苄酯基氨基)-乙磺酰胺；
R(-)-N-2-[4-(异丁基-苯基)-丙酰基]-(2-苄酯基氨基)-乙磺酰胺。
实施例11
2g R(-)-N-[2-[4-(异丁基-苯基)-丙酰基]-(2-苄酯基)-乙磺酰胺和0.1g钯黑在水(20ml)、甲醇(20ml)和乙酸(6ml)的混合物中形成悬浮液，氢气氛下搅拌；30分钟后，二氧化碳放气停止。过滤悬浮液，去除Pd，真空蒸发溶剂。NaOH存在下，将残留物保持在真空中。将此残留物溶于乙醇(5ml)，用HCl饱和的乙醇溶液处理，分离并过滤收集R(-)-N-[2-[4-(异丁基-苯基)-丙酰基]-(2-氨基)-乙磺酰胺。
按实施例10的方法，使用苄酯基氨基乙磺酰亚胺，得到以下以下化合物的盐酸盐：
R(-)-N-[2-(3-苯甲酰基-苯基)-丙酰基]-(2-氨基)-乙磺酰胺；
R(-)-N-[2-(3-苯氧基-苯基)-丙酰基]-(2-氨基)-乙磺酰胺；
R(-)-N-[2-[4-(1-氧-2-异二氢氮杂茚基)苯基]丙酰基]-(2-氨基)-乙磺酰胺；
N-[2-(5-苯甲酰基-噻吩-2-基)-丙酰基]-(2-氨基)-乙磺酰胺；
N-{2-[4-(2-噻吩甲酰基-苯基)]-丙酰基}-(2-氨基)-乙磺酰胺；
实施例12
在实施例1的方法中，使用选自以下所述的磺酰胺：环己基磺酰胺，己基磺酰胺，十二烷基磺酰胺或十六烷基磺酰胺，对氰基苯基甲磺酰胺，3-氰基-1-丙磺酰胺，2-甲氧基乙磺酰胺，3，6-二-庚基磺酰胺，3，6-二-辛基磺酰胺，3，6，9-三-癸基烷基磺酰胺，3，6，9-三-十一烷基磺酰胺，得到以下化合物：
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-环己基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-己基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-十二烷基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-十六烷基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-对氰基苯基甲磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-3-氰基-1-丙磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-2-甲氧基乙磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-3，6-二-庚基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-3，6-二-辛基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-3，6，9-三-癸基烷基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-3，6，9-三-十一烷基磺酰胺。
如有必要，当选自R(-)-N-[2-(4-异丁基-苯基)丙酰基]-对氰基苯基甲磺酰胺和R(-)-N-[2-(4-异丁基-苯基)丙酰基]-3-氰基-1-丙磺酰胺的氰基磺酰胺在含HCl汽体的乙醇中，在氧化铂存在下氢化时，可得到以下磺酰胺的盐酸化物：
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-对氨基-甲基苯基甲磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-4-氨基-1-丁磺酰胺。
实施例13
在实施例1方法中，用选自2-二甲基氨基-乙基磺酰胺、2-(哌啶-1-基)-乙基磺酰胺和2-(吗啉-4-基)-乙基磺酰胺的磺酰胺，得到：
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-2-二甲基氨基-乙基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-2-(哌啶-1-基)-乙基磺酰胺；
R(-)-N-[2-(4-异丁基-苯基)丙酰基]-2-(吗啉-4-基)-乙基磺酰胺。
实施例14
在实施例1的方法中，用R(-)-2-(3-苯甲酰基-苯基)丙酰氯和选自三氟甲基磺酰胺、邻甲苯基磺酰胺、3-吡啶基磺酰胺和4-吡啶基乙磺酰胺的磺酰胺得到以下化合物：
R(-)-N-[2-(3-苯甲酰基-苯基)丙酰基]-三氟甲基磺酰胺；
R(-)-N-[2-(3-苯甲酰基-苯基)丙酰基]-邻甲苯基磺酰胺；
R(-)-N-[2-(3-苯甲酰基-苯基)丙酰基]-(3-吡啶基)-磺酰胺；
R(-)-N-[2-(3-苯甲酰基-苯基)丙酰基]-2-(4-吡啶基)-乙磺酰胺。
实施例15
在0.35g R(-)-N-[2-(3-苯甲酰基-苯基)丙酰基]-三氟甲基磺酰胺在5ml吡啶中所成的溶液中加入0.11g盐酸羟基胺。混合物室温反应12小时，然后将该溶液滴加到40ml 2N H2SO4中。用乙酸乙酯萃取(3×8ml)生成的沉淀。合并有机相，用水洗至中性，以硫酸钠干燥并蒸干，得到0.36g R(-)-(Z，E)-N-[2-(3-苯甲酰基-苯基)丙酰基]三氟甲基磺酰胺肟。
用以上方法，用R(-)-N-[2-(3-苯甲酰基-苯基)丙酰基]-甲磺酰胺，可制得R(-)-(Z，E)-N-[2-(3-苯甲酰基-苯基)丙酰基]甲磺酰胺肟。
实施例16
R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-烟酰基-氨基)乙磺酰胺
烟酸(0.565g，4.6mmol)的亚硫酰氯(3.07ml，42.3mmol)溶液回流3小时，冷却至室温并真空干燥后，得到浅黄色固体状的烟酰氯(0.65g)。将该烟酰氯(0.64g，4.52mmol)在N，N-二甲基甲酰胺(DMF，1ml)中所成的混合物滴加到R(-)2-(4′-异丁基)苯基丙酰基-(2″-氨基)乙磺酰胺(0.6g，1.92mmol)和三乙基胺(1ml)在DMF(10ml)中所成的溶液中。所得混合物室温搅拌24小时。真空蒸发DMF，柱层析(洗脱液：CHCl3/CH3OH/环己烷/NH4OH 60∶14∶24∶2)纯化粗制残留物，得R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-烟酰基-氨基)乙磺酰胺：[α]D＝-10.7°(c＝0.15，EtOH)；呈无色油状(0.56g，1.34mmol)，MW＝417.53，MS＝m/z 418.5(ES)1；TLC(CHCl3/CH3OH/环己烷/NH4OH 60∶14∶24∶2)Rf＝0.4。1H-NMR(CD3OD)δppm 9.2-9.0(bs，1H，NH)；8.7-8.5(bs，1H，NH)；8.4(d，1H，J＝8Hz)；7.9(m，1H)；7.5-7.4(m，1H)；7.35(s，1H)；7.25(d，2H，J＝8Hz)；7.05(d，2H，J＝8Hz)；3.8-3.5(m，5H)；2.5(d，2H，J＝7Hz)；1.95-1.8(m，1H)；1.45(d，3H，J＝7Hz)；0.9(d，6H，J＝7Hz)。
在以上方法中，用异烟酸和甲基吡啶酸代替烟酸，得到以下化合物：
R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-异烟酰基-氨基)乙磺酰胺；
R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-甲基吡啶酰基-氨基)乙磺酰胺。
实施例17
R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-羧基羰基氨基)乙磺酰胺
将草酸乙酯酰氯(0.62g，4.52mmol)的DMF(1ml)溶液滴加到搅拌着的R(-)2-(4′-异丁基)苯基丙酰基-(2″-氨基)乙磺酰胺(0.6g，1.92mmol)和三乙基胺(1ml)在DMF(10ml)中所成的溶液中。所得化合物在室温下搅拌24小时。真空蒸发DMF，粗制残留物以水稀释，以***萃取(3×10ml)。收集有机萃得液，用水(2×15ml)、盐水(20ml)洗涤，硫酸钠干燥，真空蒸发后得无色油状R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-乙基草酰基氨基)乙磺酰胺(0.51g，1.25mmol)。
在以上R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-乙基草酰基氨基)乙磺酰胺(0.5g，1.22mmol)的二烷(1.55ml)溶液中加入1N NaOH(1.55ml)，室温下搅拌过夜。真空蒸发二烷，然后用水稀释水性残留物；加4N H2SO4，直至pH2；用二氯甲烷萃取(4×15ml)水相，收集有机相，用水(2×15ml)和盐水(15ml)洗涤，硫酸钠干燥，真空蒸发，得到R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-羧基羰基氨基)乙磺酰胺油状物(0.426g，1.1mmol)；TLC(CHCl3/CH3OH/H2O 65∶25∶4)Rf＝0.5；[α]D＝-60°(c＝1，CH3OH)；1H-NMR(CD3OD)δppm 10.55-10.0(bs，1H，COOH)；7.25(d，2H，J＝8Hz)；7.05(d，2H，J＝8Hz)；3.8-3.5(m，5H)；2.5(d，2H，J＝7Hz)；1.95-1.8(m，1H)；1.45(d，3H，J＝7Hz)；0.9(d，6H，J＝7Hz)。
实施例18
R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-苄氧基羰基氨基)乙磺酰胺
将氨基乙磺酸(1g，8mmol)溶于2N NaOH(4.3ml)，冰/水浴冷却后，同时滴加4N NaOH(2.14ml)和苄氧基羰基氯(3.27ml，8mmol)的甲苯(3ml)溶液。然后，混合物在0-5℃搅拌1小时。加入***终止反应。混合物于是分层。将水相冷却至0-5℃，加入37％HCl直至pH2。用乙酸乙酯萃取(3×10ml)酸性相，收集有机萃得液，用水(2×15ml)和盐水(15ml)洗涤，硫酸钠干燥并真空蒸发，得2-(N-苄氧基羰基氨基)乙磺酸粗产物，***研磨得白色固体纯产物(1.46g，5.64mmol，得率70.5％)。
将2-(N-苄氧基羰基氨基)乙磺酸(0.6g，2.31mmol)悬浮在无水甲苯(6ml)中，加入PCl5(0.65g，3.11mmol)。该混合物回流2小时，直至反应物完全溶解。室温冷却后，真空蒸发溶剂，得到粗制2-(N-苄氧基羰基氨基)乙磺酰氯，其程度足以进行下一步反应。
将粗制2-(N-苄氧基羰基氨基)乙磺酰氯溶于乙腈(10ml)。所得溶液在冰/水浴中冷却，滴加1∶1的28％NH4OH(5ml)和乙腈(5ml)。搅拌30分钟后，真空蒸发溶剂，粗制残留物在甲醇中重结晶，得到白色粉末状2-(N-苄氧基羰基氨基)乙磺酰胺(0.51g，1.96mmol)。
将R(-)布洛芬(0.32g，1.55mmol)溶于无水二氯甲烷(7.5ml)，在其中加入N，N-二甲基氨基吡啶(0.19g，1.55mmol)和二环己基碳二亚胺(0.32g，1.7mmol)，所得混合物搅拌30分钟。然后，加入2-(N-苄氧基羰基氨基)乙磺酰胺(0.4g，1.55mmol)，将该混合物搅拌过夜。滤出沉淀的N，N-二环己基脲，滤液经真空蒸发得粗制残留物，以乙腈稀释；滤出第二批N，N-二环己基脲，滤液经溶剂蒸发后用二氯甲烷稀释。有机相用2N HCl(2×10ml)、盐水(15ml)洗涤，硫酸钠干燥，真空蒸发，得白色粉末状R(-)2-(4′-异丁基)苯基丙酰基-(2″-N-苄氧基氨基甲酰基氨基)乙磺酰胺(0.44g，0.98mmol)；m.p.＝107-109℃；TLC(CH2Cl2/CH3OH 98∶2)Rf＝0.2；[α]D＝-47.4°(c＝1，EtOH)；1H-NMR(CD3OD)δppm 7.45-7.30(m，5H)；7.25-7.05(m，5H，NH)；5.4-5.3(bs，1H，NH)；5.1(s，2H)；3.75-3.5(m，5H)；2.45(d，3H，J＝7Hz)；1.95-1.8(m，1H)；1.5(d，3H，J＝7Hz)；0.9(d，6H，J＝7Hz)。
Claims (12)
1.通式1所示的化合物，或其盐，
其中，R2是取代或非取代芳基，取代基选自卤素，C1-4烷基，C1-4烷氧基，羟基，C1-7酸基，氰基，硝基，氨基，C1-3酰基氨基，卤代C1-3烷基，卤代C1-3烷氧基，苯甲酰基，或者，R2选自4-噻吩-2-基羰基苯基、6-氯-9H-咔唑-2-基、3-氯-4-(2，5-二氢-1H-吡咯-1-基)苯基和3-苯氧基苯基；
R是直链或分支C1-16烷基，三氟甲基，环己基，邻甲苯基，3-吡啶基，2-吡啶基乙基，对氰基苯基甲基，对氨基苯基甲基，3-氰基-1-丙基，4-氨基丁基，烷氧基亚乙基CH3-(CH2)ni-(OCH2CH2)mi-，其中ni是0或1，mi是整数1-3，或是P1P2N-CH2-CH2-，其中P1和P2各自是H、C1-3烷基，苄氧基羰基，α-、β-或γ-吡啶基羰基，羧基羰基或烷酯基羰基，P1和P2或者与相连的N原子构成苯二甲酰亚氨基、哌啶子基、吗啉代基；
R′是H或直链或分支C1-3烷基。
2.根据权利要求1所述的化合物，其中的R′是H。
3.根据权利要求1或2所述的化合物，其中的R2选自4-异丁基苯基，5-苯甲酰基-噻吩-2-基，1-氧-2-异二氢氮杂茚基苯基甲氧基乙萘基，6-甲氧基-2-萘基，或以下通式所示的基团
其中，A是苄基、苯甲酰基或苯甲酰基-肟、1-羟基-1-苯基甲基，B是H、羟基、C1-3酸基或氨基。
4.根据权利要求1所示的化合物，其中式1所示甲基所在的不对称碳原子具有绝对R构型。
5.根据权利要求1所述的化合物，是R(-)-N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺或其L(+)-赖氨酸盐。
6.根据权利要求1所述的化合物，是R(-)-N-2-[(3-苯甲酰基苯基)-丙酰基]-甲磺酰胺。
7.权利要求1-6中任一项所述化合物用于制备抑制白介素8诱导的嗜中性白细胞趋化性和脱粒作用的药物的用途。
8.根据权利要求7所述的用途，所述药物是用于治疗牛皮癣，类风湿性关节炎，溃疡性结肠炎，急性呼吸机能不全，原发性纤维变性，血管球性肾炎的药物。
9.根据权利要求7或8所述的用途，所述化合物是R(-)-N-2-[(4-异丁基苯基)-丙酰基]-甲磺酰胺或其L(+)-赖氨酸盐。
10.一种药物组合物，含有权利要求1-6中任一项所述的化合物作为活性成分，并与合适的载体混合。
11.一种制备权利要求1-6中任一项所述化合物的方法，包括：在惰性溶剂中，在缩合剂存在下，等分子量的通式(2)酸
其中，R2′与权利要求1所定义的R2相同，或是可通过去保护转化为R2的基团，与通式(3)磺酰胺
其中，R和R′与权利要求1所定义的相同。
12.一种制备权利要求1-6中任一项所述化合物的方法，包括：通式(3′)所示的磺胺阴离子与通式(2)酸的氯化物在惰性溶剂中反应，
其中，R和R′与权利要求1所定义的相同，
R2′如权利要求11所定义。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1998MI002280A IT1303249B1 (it) | 1998-10-23 | 1998-10-23 | Alcune n-(2-aril-propionil)-solfonammidi e preparazionifarmaceutiche che le contengono. |
| ITMI98A002280 | 1998-10-23 |
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| CNA2004100856352A Division CN1615833A (zh) | 1998-10-23 | 1999-10-14 | N－(2－芳基－丙酰基)－磺胺类化合物及其药物组合物 |
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| CN100368394C true CN100368394C (zh) | 2008-02-13 |
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| CNB998124516A Expired - Lifetime CN100368394C (zh) | 1998-10-23 | 1999-10-14 | N-(2-芳基-丙酰基)-磺胺类化合物及其药物组合物 |
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| US (2) | US6887903B1 (zh) |
| EP (1) | EP1123276B1 (zh) |
| JP (1) | JP4194761B2 (zh) |
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| HK (1) | HK1041255B (zh) |
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| IT (1) | IT1303249B1 (zh) |
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| PL (1) | PL212210B1 (zh) |
| PT (1) | PT1123276E (zh) |
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| SK (1) | SK286372B6 (zh) |
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| CN103172548A (zh) * | 2011-12-20 | 2013-06-26 | 天津市国际生物医药联合研究院 | 甲磺酰胺类化合物的制备及其应用 |
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| ITMI20010206A1 (it) * | 2001-02-02 | 2002-08-02 | Dompe Spa | Uso della metansolfonammide di (r)-ibuprofene e dei suoi sali non tossici per la preparazione di medicamenti per il trattamento e la prevenz |
| ITMI20010395A1 (it) | 2001-02-27 | 2002-08-27 | Dompe Spa | Omega-amminoalchilammidi di acidi r-2-aril-propionici come inibitori della chemiotassi di cellule polimorfonucleate e mononucleate |
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| ITMI20012434A1 (it) | 2001-11-20 | 2003-05-20 | Dompe Spa | Acidi 2-aril-propionici e composizioni farmaceutiche che li contengono |
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