CN1204320A - 作为TNF-α和基质金属蛋白酶抑制剂的α-取代的芳基磺酰氨基异羟肟酸 - Google Patents
作为TNF-α和基质金属蛋白酶抑制剂的α-取代的芳基磺酰氨基异羟肟酸 Download PDFInfo
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- CN1204320A CN1204320A CN96199017A CN96199017A CN1204320A CN 1204320 A CN1204320 A CN 1204320A CN 96199017 A CN96199017 A CN 96199017A CN 96199017 A CN96199017 A CN 96199017A CN 1204320 A CN1204320 A CN 1204320A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/40—Acylated substituent nitrogen atom
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Abstract
式Ⅰ的化合物及其药用前药衍生物和药用盐,其中Ar,n,R1,R2,R3和R4如说明书中定义,显示有价值的药学性质,尤其是作为TNF-α活性和基质-降解金属蛋白酶抑制剂。因此,它们可以用于治疗广泛的疾病,例如作为治疗例如骨关节炎,风湿性关节炎的消炎药,或作为例如用于治疗和预防肿瘤生长,肿瘤转移,肿瘤发作或发展的抗肿瘤剂。它们以本身已知的方法制备。
Description
根据取代基的性质,本发明的化合物具有一个或多个不对称碳原子。而且环己烷取代基相互之间既可以是顺式也可以是反式。产生的非对映异构体,对映体和几何异构体包括在本发明中。
优选的是这样的本发明化合物,其中连接环己烷环的α-氨基异羟肟酸部分的不对称碳原子构型相当于D-氨基酸前体的构型被指定为(R)-构型。
药用前药衍生物是可以通过溶剂解或在生理条件下转化为本发明的游离的异羟肟酸的那些化合物,并且表示这样的异羟肟酸,其中CONHOH基团以O-酰基或非强制性取代的O-苄基衍生物的形式衍生的。优选的是O-苄基衍生物。
前药酰基衍生物优选地是从有机碳酸、有机羧酸或氨基甲酸衍生的。
从有机羧酸衍生的酰基衍生物是,例如,低级烷酰基,苯基-低级烷酰基或未取代或取代的芳酰基,如苯甲酰基。
从有机碳酸衍生的酰基衍生物是,例如,烷氧羰基,尤其是低级烷氧羰基,它是未取代的或被碳环或杂环芳基取代,或者是环烷氧羰基,尤其是C3-C7-环烷氧羰基,它是未取代的或被低级烷基取代。
从氨基甲酸衍生的酰基衍生物是,例如,氨基-羰基,该基团被低级烷基,碳环或杂环芳基-低级烷基,碳环或杂环芳基,低级亚烷基或被O或S间断的低级亚烷基取代。
前药非强制性取代的O-苄基衍生物优选地是苄基或被例如低级烷基,低级烷氧基,氨基,硝基,卤素和/或三氟甲基一-,二-,或三-取代的苄基。
本发明酸性化合物的药用盐是与碱形成的盐,即阳离子盐如碱金属或碱土金属盐,如钠,锂,钾,钙,镁,以及铵盐,如铵,三甲基铵,二乙基铵,和三-(羟甲基)-甲基铵盐。类似地,酸加成盐,如矿物酸,有机羧酸和有机磺酸,例如氢氯酸,甲磺酸,马来酸,也可以提供碱性基团,如吡啶基,构成结构的部分。
本文所用的一般定义具有本发明范围内的如下意义,除非另外说明。
术语“低级”在上下文中分别与有机基团或化合物相关,定义为如支链或非支链,最高并包括7个,优选地最高并包括4个,有利地是一个或两个碳原子的。
低级烷基是支链或非支链的并含有1至7个碳原子,优选地1-4个碳原子,并表示例如甲基,乙基,丙基,丁基,异丙基或异丁基。
低级烷氧基(或烷基氧基)优选地含有1-4个碳原子,并表示例如甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基或异丁氧基。
卤素优选地表示氯或氟但也可以是溴或碘。
芳基表示碳环或杂环芳基。
碳环芳基表示单环或双环芳基,例如苯基或被一个,两个或三个选自低级烷基,低级烷氧基,羟基,卤素,氰基,三氟甲基,低级亚烷二氧基和氧-C2-C3-亚烷基的基团一-,二-或三-取代的苯基;或1-或2-萘基。低级亚烷二氧基是连接在苯基的两个相邻碳原子上的二价取代基,例如亚甲二氧基或亚乙二氧基。氧-C2-C3-亚烷基也是连接在苯基的两个相邻碳原子上的二价取代基,例如氧基亚乙基或氧基亚丙基。氧-C2-C3-亚烷基-苯基的例子是2,3-二氢苯并呋喃-5-基。
优选的碳环芳基是苯基或被低级烷氧基,卤素,低级烷基或三氟甲基一取代的苯基,特别是苯基或被低级烷氧基,卤素或三氟甲基一取代的苯基,尤其是苯基。
杂环芳基表示单环或双环杂芳基,例如吡啶基,喹啉基,异喹啉基,苯并噻吩基,苯并呋喃基,苯并吡喃基,苯并硫代吡喃基,呋喃基,吡咯基,噻唑基,噁唑基,异噁唑基,三唑基,四唑基,吡唑基,咪唑基,噻吩基,或任何所说的基团被取代,尤其是被例如低级烷基或卤素一-或二-取代。吡啶基表示2-,3-或4-吡啶基,有利地是3-或4-吡啶基。噻吩基表示2-或3-噻吩基,有利地是2-噻吩基。喹啉基表示2-,3-或4-喹啉基,有利地是2-喹啉基。异喹啉基优选地表示1-,3-或4-异喹啉基。苯并吡喃基,苯并硫代吡喃基优选地分别表示3-苯并吡喃基或3-苯并硫代吡喃基。噻唑基优选地表示2-或4-噻唑基,有利地为4-噻唑基。三唑基优选地是1-,2-或5-(1,2,4-三唑基)。四唑基优选地是5-四唑基。咪唑基优选地是4-咪唑基。
优选地,杂环芳基是吡啶基,喹啉基,吡咯基,噻唑基,异噁唑基,三唑基,四唑基,吡唑基,咪唑基,噻吩基,或任何所说的基团被取代,尤其是被低级烷基或卤素一-或二-取代;特别是吡啶基。
联芳基优选地是碳环联芳基,例如联苯基,即2-,3-或4-联苯基,最好是4-联苯基,各自非强制性地被例如低级烷基,低级烷氧基,卤素,三氟甲基或氰基取代。
环烷基表示被低级烷基非强制性取代的饱和环状烃,含有3至10个环原子,并且最好是被低级烷基非强制性取代的环戊基,环己基,环庚基或环辛基。
碳环芳基-低级烷基优选地表示直链或支链芳基-C1-C4烷基,其中碳环芳基具有与上面定义相同的意义,例如苄基或苯基-(乙基,丙基或丁基),各自未取代或在苯环上如上面的碳环芳基一样被取代,最好是非强制性取代的苄基。
杂环芳基-低级烷基表示直链或支链杂环芳基-C1-C4烷基,其中杂环芳基具有与上面定义相同的意义,例如2-,3-或4-吡啶基甲基或(2-,3-或4-吡啶基)-(乙基,丙基或丁基);或2-或3-噻吩基甲基或(2-或3-噻吩基)-(乙基,丙基或丁基);2-,3-或4-喹啉基甲基或(2-,3-或4-喹啉基)-(乙基,丙基或丁基);或2-或4-噻唑基甲基或(2-或4-噻唑基)-(乙基,丙基或丁基)。
环烷基-低级烷基表示例如(环戊基-或环己基)-(甲基或乙基)。
酰基是从有机羧酸,碳酸或氨基甲酸衍生的。
酰基表示例如低级烷酰基,碳环芳基-低级烷酰基,低级烷氧羰基,芳酰基,二-低级烷基氨基羰基或二-低级烷基氨基-低级烷酰基。优选地,酰基是低级烷酰基。
低级烷酰基表示例如C1-C7-烷酰基,包括甲酰基,优选地为C2-C4烷酰基如乙酰基或丙酰基。
芳酰基表示例如苯甲酰基或被一个或两个选自低级烷基,低级烷氧基,卤素,氰基和三氟甲基的基团一-或二-取代的苯甲酰基;或1-或2-萘甲酰基;也例如吡啶基羰基。
低级烷氧羰基优选地表示C1-C4烷氧羰基,例如乙氧羰基。
低级亚烷基表示1至7个碳原子的直链或支链亚烷基,并优选地表示1至4个碳原子的直链亚烷基,例如亚甲基,亚乙基,异丙基或亚丁基链,或所说的亚甲基,亚乙基,异丙基或亚丁基链被C1-C3-烷基(最好是甲基)一-取代,或在相同或不同的碳原子上被C1-C3-烷基(最好是甲基)二取代,碳原子的总数最高且包括7。
低级亚烷二氧基优选地是亚乙二氧基或亚甲二氧基。
酯化的羧基是例如低级烷氧羰基或苄氧羰基。
酰胺化的羧基是例如氨基羰基,一-或二-低级烷基氨基羰基。
另一方案表示相对于环己烷环上的1,4-取代基具有反式构型的化合物,特别是式Ⅲ化合物其中Ar表示碳环或杂环芳基;R1表示低级烷基,环烷基,(碳环或杂环芳基)-低级烷基或低级烷氧基-低级烷基;R2表示氢或低级烷基;R3是氢,低级烷氧基或卤素;R4是氢或低级烷氧基;或者R3和R4与相邻的碳原子一起表示亚甲二氧基;n是1-4;其药用前药衍生物;其药用盐。
也优选的是所说的式Ⅲ化合物其中Ar表示如上定义的杂环芳基;R1表示如上定义的低级烷基,环烷基,或低级烷氧基-低级烷基;R2表示氢或低级烷基;R3和R4是氢或低级烷氧基;n是1-4;其药用前药衍生物;和其药用盐。
优选的是其中R3在对位而R4在间位的所说的化合物。
进一步优选的是所说的式Ⅲ化合物其中Ar表示如上定义的杂环芳基;R1表示低级烷基;R2表示氢;R3是对位-低级烷氧基;R4是氢;而n是1或2;和其药用盐。
特别优选的是式Ⅲ化合物其中Ar是吡啶基,尤其是3-或4-吡啶基;R1是低级烷基,尤其是直链C2-C5-烷基;R2和R4是氢,R3是对位-低级烷氧基;而n是1;和其药用盐。
进一步优选的是所说的化合物其中Ar是吡啶基;R1是C2-C4-烷基;R2和R4是氢,R3是对位-乙氧基;而n是1;和其药用盐。
应该特别提到下列本发明的化合物的一个下级组:其中R1是C2-C7烷基的化合物(分别为式Ⅰ,Ⅱ或Ⅲ)。
本发明特别涉及在实施例中描述的具体化合物,其药用前药衍生物和其药用盐,特别涉及在实施例中描述的具体化合物和其药用盐。
本发明化合物对于哺乳动物包括人显示有价值的药理性质。
首先,它们是TNF-α转化酶的抑制剂因而抑制TNF-α活性,例如抑制TNF-α,一种炎症和组织生长的重要间介器的产生和/或释放。这种性质使得本发明化合物首先可用于治疗哺乳动物的肿瘤(噁性和非噁性肿瘤)以及炎症,例如关节炎(如风温性关节炎),脓毒性休克,肠炎病,Crohn病等等。
而且,本发明化合物也抑制基质降解金属蛋白酶如明胶酶,溶基质素,胶原蛋白酶,和巨噬细胞金属弹性蛋白酶。因此本发明化合物抑制基质降解并可用于治疗哺乳动物的基质降解金属蛋白酶如明胶酶-,溶基质素-,胶原蛋白酶-,和巨噬细胞金属弹性蛋白酶-相关的病症。这类病症包括肿瘤(通过抑制肿瘤生长,肿瘤转移,肿瘤前进或发病和/或肿瘤血管生成),这类肿瘤是例如乳腺癌,肺癌,膀胱癌,结肠癌,卵巢癌和皮肤癌。其它用本发明化合物治疗的病症包括骨关节炎,支气管病(如通过抑制弹性硬蛋白的气喘)动脉粥样硬化症(例如通过抑制粥样硬化斑的破裂),以及急性冠状综合征,心脏发作(心局部缺血),中风(脑局部缺血),和血管形成术之后的restenosis。
可以用本发明化合物治疗的其它病症是其中包括髓鞘质破坏或损失的神经系统炎性脱髓鞘疾病(如多发性硬化),视神经炎,视神经脊髓炎(Devic’s病),弥漫性和转变性硬化(Schilder’s病)和急性播散性脑脊髓炎,以及脱髓鞘末梢神经病如运动原缺损的Landry-Guillain-Barre-Strohl综合征;以及组织溃疡(例如表皮和胃溃疡),异常伤愈合,牙周病,骨病(例如Paget’s病和骨质疏松症)。
本发明化合物在眼中的应用包括治疗眼炎,角膜溃疡,翼状胬肉,角膜炎,圆锥型角膜,开角青光眼,视网膜病,并且它们用于曲光手术(激光或切口)使负作用最小。
本发明化合物特别可用于治疗炎症,如风湿性关节炎,和肿瘤。
其有利效果在本文所述的本专业公知的药理试验中评价。
上述性质有利地用哺乳动物,例如大鼠,豚鼠,狗,兔子,或分离的器官和组织,以及哺乳动物的酶制剂的体外和体内试验证明。所说的化合物可以以溶液形式,优选地是水溶液用于体外,和肠内或非肠胃,优选地口服用于体内,例如以悬浮液或水溶液应用。体外剂量可以在约10-5摩尔和10-10摩尔浓度的范围内。体内剂量根据给药途径可以在约0.1至100mg/kg的范围内。
TNF-α产生和分泌的抑制(通过TNF-α转化酶的抑制)可以例如如Nature 370,555,558(1994)所述的测定。
通过LPS-刺激THP-1细胞在可溶性TNF-α生产上的作用可以如下测定:
所用的组织培养基是含有10%胎牛血清,1%青霉素和链霉素的RPM1640(Gibco cat#11875-036)。THP-1细胞(ATCC#202-TIB)以1×10+5细胞/孔加入100μl培养基或试验化合物中。细胞在37℃加湿的有5%CO2的室内用化合物预温育30分钟,然后用100ng/ml LPS(Sigma cat#L-4391)刺激4小时。将板离心,将用于TNF分析的100μl改善的培养基收获。在对照和试验培养物中TNF-α的量通过用重组TNF-α标准曲线的ELISA,用用于TNF分析的TNF ELISA板(Genyme)测定。吸收读数和数据计算在Molecular Devices板读数计上进行。结果以试验化合物的IC50表示。
在静脉内注射后小鼠内TNF-α血浆浓度上的作用可以如下测定:
通过管饲法以0.1ml玉米淀粉载体/10克体重对雌性Balb-Cbyi小鼠剂量施用试验化合物。试验化合物给药1至4小时后,注射0.1mg/kg从E.coli0127:B8(Difco#3880-25-0)得到的脂多糖在食盐水中的溶液。注射LPS1小时后,收集血液,用小鼠TNF-αELISA kit(Genyme)测定血浆TNF-α。每个治疗组用8只小鼠。结果以对照小鼠平均TNF-α浓度的%抑制表示。
在发炎的大鼠膝中TNF-α的滑液浓度上的作用可以如下测定:
通过管饲法以0.1ml玉米淀粉载体对雌性Lewis大鼠剂量施用试验化合物。试验化合物给药1至4小时后,注射0.1mg/kg从E.coli0127:B8(Difco#3880-25-0)得到的脂多糖到两膝。关节内注射LPS2小时后,两膝用0.1ml食盐水灌洗,将从相同大鼠得到的灌洗液合并。用与大鼠TNF-α交叉反应的小鼠TNF-αELISA kit(Genyme)测量。结果以从食盐-注射的膝中得到的滑液中平均TNF-α浓度的%抑制表示。
抗炎活性可以在本专业公知的标准炎症和关节炎动物模型,例如大鼠的辅助性关节炎模型和小鼠的胶原蛋白Ⅱ诱导的关节炎模型[mediators ofInflam.1,273-279(1992)]测定。
一个测定溶基质素活性抑制的试验是以用改进的Harrison等人的方法(Harrison,R.A.,Teahan J.,和Stein R.,A semicontinuous,highperformance chromatography based assay for stromelysin,Anal.Biochem.180,110-113(1989))水解物质P为基础的。在此试验中,物质P通过重组人溶基质素水解产生碎片,物质P7-11,它可以通过HPLC定量。在典型的试验中,10mM被试验化合物的储备溶液在试验缓冲液中稀释为50μM,与8μg重组人溶基质素(mol.wt.45-47 kDa,2单位;其中1单位在30分钟内产生20mmol物质P7-11)1∶1混合,并以最终体积0.125ml与0.5mM物质P在37℃温育30分钟。通过加入10mM EDTA使反应停止,物质P7-11在RP-8 HPLC上定量。抑制溶基质素的IC50和Ki从没有抑制剂的对照反应计算。
溶基质素活性也可以用人aggrecan作为底物测定。此试验体外证实该化合物可以抑制溶基质素对其高负电荷天然底物,aggrecan(大聚集蛋白多糖)的作用。在软骨中,存在蛋白多糖用于与透明质酸酯聚集连接。与透明质酸酯聚集的人蛋白多糖被用作底物。将试验在96-孔微滴板中进行便于快速评价化合物。该试验有三个主要步骤:1)将板用透明质酸酯(人脐带,400μg/ml)涂抹,用BSA(5mg/ml)定型,然后将蛋白多糖(人关节软骨D1-软骨素酶ABC消化的,2mg/ml)与透明质酸酯结合。在每个步骤之间要洗涤该板。2)缓冲液+抑制剂(1至5000nM)+重组人溶基质素(1-3单位/孔)被加入孔中。将板用带密封并在37℃温育过夜。然后将板洗涤。3)第一(3B3)抗体(小鼠IgM,1∶10000)被用于检测保留的碎片。第二抗体,过氧化酶-连接的抗-IgM,被结合到第一抗体。然后将OPD作为过氧化酶的底物加入,用硫酸使反应停止。抑制溶基质素活性的IC50被图解衍生并计算Ki。
胶原蛋白酶活性如下测定:将96-孔,平底微滴板首先用牛的Ⅰ型胶原蛋白(35μg/孔)在30℃用温的然后干燥的气氛在两天的周期内涂抹;将板清洗,晾干3-4小时,用Saran包裹密封并在冰箱中储存。人重组纤维细胞胶原蛋白酶和试验化合物(或缓冲液)被加入孔中(总体积=0.1ml)并将板在加湿的条件下在35℃温育2小时;用于每孔的胶原蛋白酶的量是引起大约80%的胶原蛋白的最大消化。将温育培养基从孔中除去,然后用缓冲液清洗,接着用水清洗。将Coomasie蓝染剂加入孔中25分钟,除去,将孔再用水清洗。将十二烷基硫酸钠(在50%二甲基甲酰胺/水中20%的浓度)加入使染色的胶原蛋白溶解,测量在570波长的光学密度。归因于胶原蛋白酶的光学密度降低(与没有酶的胶原蛋白相比)与在试验化合物存在下归因于酶的光学密度降低进行比较,计算酶活性抑制的百分数。从抑制剂的浓度(4-5种浓度,各自重复3次试验)范围测定IC50,并计算Ki值。
本发明化合物的效果可以在兔子体内测定。典型地,四只兔子在用溶于pH7.5的20mM Tris,10mM CaCl2,和0.15M NaCl中的重组人溶基质素在两膝(N=8)关节内注射至多4小时之前,用化合物剂量口服。2小时后,将兔子处死,收集滑液,释放到关节的硫酸角质素(KS)和硫酸化的葡糖胺聚糖(S-GAG)碎片被定量。硫酸角质素通过用Thonar的方法(Thonar,E.J.-M.A.,Le.K.,Caterson,B.,Pachman,L.M.,Glickman,P.,Katz,R.,Huff,J.,Keuttner,K.E.Quantitation of keratan sulfate in blood as amarker of cartilage catabolism,Arthr.Rheum.28,1367-1376(1985))测量。硫酸化的葡糖胺聚糖通过首先用链霉菌属透明质酸酶消化,然后用Goldberg的方法(Goldberg,R.L.和Kolibas,L.An improved methodfor determining proteoglycan synthesized by chondrocytes inculture.Connect.Tiss.Res.24,265-275(1990))测量DMB染料结合而测量。对于i.v.研究,将化合物溶于1ml PEG-400,而对于p.o.研究,化合物以每千克体重5ml强化玉米淀粉给药。
在关节炎病中对于保护软骨退化的效果可以在Arthritis andRheumatism,Vol.26,875-886(1983)中所述的,例如在骨关节炎模型中测定。
对于溃疡,例如眼溃疡的效果,可以在兔子体内通过测量碱烧伤角膜的角膜溃疡的降低而测定。
巨噬细胞金属弹性蛋白酶(MME)抑制活性可以通过如下截断重组小鼠巨噬细胞金属弹性蛋白酶测量[3H]-弹性蛋白的退化抑制而测定:
约2ng通过Q-琼脂糖柱色谱纯化的重组截断小鼠巨噬细胞金属弹性蛋白酶(FASEB Journal Vol.8,A151,1994),在5nM CaCl2,和400nMNaCl,[3H]-弹性蛋白(60000cpm/管),和20mM Tris,pH8.0存在下,以所需的浓度与试验化合物在37℃温育过夜。样品在一微离心机上在12000rpm旋转15分钟。上层清液的等分试样在闪烁计数器上定量测定降解的[3H]-弹性蛋白。从所得的试验化合物浓度和酶活性的抑制百分数测定IC50。
本发明化合物治疗肺气肿的效果可以以American Review ofRespiratory Disease117,1109(1978)中所述的模型测定
化合物的抗肿瘤作用可以例如通过根据本专业公知的方法学测量在Balb/c裸处理的小鼠皮下移植人肿瘤的生长与无效剂处理的小鼠相比而测定。举例性的肿瘤有例如雌性激素依赖的人乳腺癌BT20和MCF7,人膀胱癌T24,人结肠癌Colo205,人肺腺癌A549和人卵巢癌NIH-OVCAR3。
在肿瘤血管生成方面的效果可以例如如Galardy et al,CancerRes.54,471591994)中所述的以小丸用Walker256癌移植以刺激淋巴血管的血管生成的大鼠体内测定。
本发明化合物在动脉粥样硬化症方面的效果可以如Sukhova etal,Circulation 90,I 404(1994)所述的,用由胆固醇-喂养的兔子得到的含有活化的基质金属蛋白酶的动脉粥样硬化斑评价。在兔子动脉粥样硬化斑中对基质金属蛋白酶的活性方面的抑制作用可以通过如Galis etal,J.Clin.Invest.94,2493(1994)中所述的,就地酶图法测定,并且是斑稳定化的指示。
在血管再狭窄和血管再成型方面的效果可以在大鼠气胀术颈动脉模型中评价。
在神经系统脱髓鞘疾病,如多发性硬化方面的效果可以通过如Gijbelset al,J.Clin.Invest.94,2177(1994)所述的通过测量小鼠的实验性抗免疫脑脊髓炎的逆转而评价。
作为TNF-α转化酶和基质金属蛋白酶抑制剂,本发明化合物特别可以用于哺乳动物用作治疗例如骨关节炎,风湿性关节炎的抗炎剂,和治疗和预防肿瘤生长,肿瘤转移,肿瘤发作或progession的抗肿瘤剂。
式Ⅰ化合物可以例如通过式Ⅳ的羧酸或其反应活性功能衍生物,其中Ar,n和R1-R4具有与上面相同的定义,与式Ⅴ的羟胺,NH2-OH (Ⅴ)非强制性地以保护的形式,或其盐缩合而制备;而且,如果需要,临时保护任何干扰的反应活性基团,然后释放生产的本发明化合物;并且,如果需要,将生产的本发明化合物转化为其它本发明化合物,和/或,如果需要,将产生的游离化合物转化为盐或将产生的盐转化为游离化合物或转化为其它盐;和/或将所得的异构体或外消旋体分离为单个异构体或外消旋体;和/或,如果需要,将外消旋体拆分为对映体。
在本文所述的方法中转化为本发明化合物的起始化合物和中间体中,存在的官能团,如氨基,羧基和羟基,通过在制备有机化学中常见的普通保护基非强制性保护。保护的氨基,羧基和羟基是在温和的条件下转化为游离氨基和羟基而不毁坏分子骨架或没有其它不良的副反应发生的基团。
引入保护基的目的是要在用于进行需要的化学转化的条件下保护官能团不与反应组分发生不需要的反应。对于具体反应保护基的需要和选择是本专业熟练的技术人员已知的,并且取决于被保护官能团(羟基,氨基等等)的性质,取代基作为其一部分的分子的结构和稳定性和反应条件。
满足这些条件和其引入和除去的公知保护基在,例如,J.F.W.McOmie,“Protective Groups in Organic Chemistry”,PlenumPress,London,New York,1973,T.W.Greene,“Protective Groups inOrganic Synthesis”,Wiley,New York,1991中叙述。
在上面所述的方法中,羧酸的反应化学官能团衍生物表示,例如,酐尤其是混合酐,酰卤,酰基叠氮化物,低级烷基酯和其活化的酯。混合酐优选地是从新戊酸产生的,或碳酸的低级烷基(乙基,异丁基)半酯产生的;酰卤是例如氯化物或溴化物;活化的酯例如丁二酰亚胺基,邻苯二甲酰亚胺基或4-硝基苯基酯;低级烷基酯是例如甲基或乙基酯。
在本文所述的任何反应中醇的反应活性酯化的衍生物表示所说的醇通过强酸,尤其是强无机酸,如氢卤酸。尤其是氢氯酸,氢溴酸或氢碘酸,或硫酸,或强有机酸,尤其是强有机磺酸,如脂族或芳香族磺酸,例如甲磺酸,4-甲基苯磺酸或4-溴苯磺酸酯化。所说的反应活性酯化的衍生物特别是卤素,例如氯,溴或碘,或脂族或芳香族取代的磺酰氧基,例如甲磺酰氧基,4-甲基苯磺酰氧基(甲苯磺酰氧基)或三氟甲磺酰氧基。
上述合成本发明化合物的方法可以根据本专业公知用于制备异羟肟酸和其衍生物的方法进行。
根据上述方法的合成,包括式Ⅳ的游离羧酸与式Ⅴ的非强制性羟基保护的羟胺衍生物的缩合可以在缩合剂,例如1,1’-羰基二咪唑,或N-(二甲基氨基丙基)-N’-乙基碳环二亚胺或二环己基碳二亚胺存在下进行,有或没有1-羟基苯并三唑,在惰性极性溶剂,如二甲基甲酰胺或二氯甲烷中,优选在室温下进行。
包括如前定义的式Ⅳ酸的反应活性功能衍生物的缩合的合成,例如酰氯或混合酐与非强制性保护的羟胺,或其盐,在碱如三乙胺存在下的反应可以在优选地约-78℃至+75℃的温度范围,在惰性有机溶剂如二氯甲烷或甲苯中进行。
在上述方法中(式Ⅴ的)羟胺的保护形式是其中羟基例如作为叔丁基醚,苄基醚,三苯甲基醚,四氢吡喃基醚,或作为三甲基甲硅烷基衍生物的基团。所说的保护基的脱去根据本专业公知的方法,例如氢解或酸水解进行。羟胺优选地从羟胺盐,如盐酸羟胺就地产生。
式Ⅳ的起始羧酸可以如下制备:
式Ⅵ的氨基酸:其中R2是氢或低级烷基,它非强制性地用低级烷醇(如甲醇)或用苄基醇酯化,用式Ⅶ的合适的磺酸的反应活性功能衍生物其中R3和R4具有如前定义的意义,例如用相应的磺酰氯,在合适的碱,如三乙胺或二环己基胺存在下,用极性溶剂如四氢呋喃,二噁烷或乙腈,处理得到式Ⅷ化合物其中R2-R4具有如前定义的意义,而R5是氢或羧基保护基,例如低级烷基或苄基。
式Ⅵ,Ⅶ和Ⅻ的原料要么是本专业已知的,要么可以通过本专业公知的或本文所述的方法制备。
式Ⅵ的光学活性D-氨基酸(R-对映体)可以根据本专业已知的方法,例如根据Coll.Czech.Comm.49,712-742(1984)和Angew.Chem.Int.Ed.(Engl.)27,1194(1988)中所述的方法制备。
式Ⅷ的中间体可以通过用下式醇的反应活性酯化的衍生物
R1-OH (Ⅹ)其中R1定义同式Ⅰ,在本专业公知的用于醚形成的条件下处理转化为式Ⅸ的中间体其中R1-R5具有如前定义的意义。
另外,式Ⅸ的中间体可以通过在式Ⅹ的醇(R1-OH)存在下还原式Ⅺ的酮而制备其中R2-R5具有如式Ⅷ中定义的意义。还原性O-烷基化可以基本上如J.Am.Chem.Soc.94,3659(1972)所述的,用一-,二-或三烷基甲硅烷或一-,二-或三芳基甲硅烷在酸性介质中,例如在三氟乙酸存在下进行。产生的顺式和反式异构体可以通过已知的方法,如硅胶色谱分开。
另外,其中R2是氢的式Ⅺ酮中间体可以根据常规的方法转化为其中R2是低级烷基(且R2和OR1在相同的碳原子上)的式Ⅷ叔醇中间体,随后用R1-OH的反应活性酯化的衍生物,如三氟甲磺酰基衍生物醚化。
式Ⅺ的酮可以依次通过在自由基,例如TEMPO(2,2,6,6-四甲基-1-哌啶氧基自由基)存在下用例如次氯酸钠处理氧化式Ⅷ的醇而制备。
用式Ⅻ的醇
Ar-(CH2)nOH (Ⅻ)其中Ar和n具有如本文定义的意义,的反应活性酯化的衍生物(如卤化物,例如氯,溴或碘衍生物)在适当的碱,如碳酸钾或二环己基胺存在下,在极性溶剂,如二甲基甲酰胺中处理式Ⅸ的中间体产生式Ⅳ化合物的酯。该酯然后要么用氢解法要么用标准的酯水解的温和方法,优选地在酸性条件下,转化为式Ⅳ的酸,该方法取决于酯化基团的性质。
上述反应根据标准方法,在稀释剂存在或不存在下,优选地如对试剂惰性并且是溶剂,在催化剂存在下进行,缩合或所说的试剂分别和/或惰性气氛中,在低温,室温或升高的温度(优选地在或接近所用溶剂的沸点),在大气压或超-大气压进行。优选的溶剂,催化剂和反应条件在后面的实施例中给出。
本发明进一步包括本方法的任何变体,其中可以在其任何阶段得到的中间体产物被用作原料,进行剩余的步骤,或该方法在其任何阶段不连续,或其中原料在反应条件下就地形成,或其中反应成分以其盐或光学纯对映体形式被使用。
本发明化合物和中间体也可以根据本身公知的方法互相转化。
本发明也涉及任何新原料和其生产方法。
根据所选择的原料和方法,新化合物可以是一种可能的异构体或其混合物,例如,基本上纯的几何异构体(顺式或反式),光学异构体(对映体),外消旋体,或其混合物。前述可能的异构体或其混合物在本发明的范围内。
任何产生的异构体混合物都可以在成分的物理-化学差别的基础上,例如通过色谱和/或分级结晶,分离为纯的几何或光学异构体,非对映异构体,外消旋体。
任何产生的最终产物或中间体的外消旋体都可以通过已知的方法,例如通过分开用光学活性的酸或碱得到的其非对映异构体盐被拆分为光学对映体,并释放光学活性的酸性或碱性化合物。异羟肟酸或羧酸中间体可以例如通过d-或l-(α-甲基苄基胺,辛可尼定,辛可宁,奎宁,奎尼定,麻黄碱,脱氢枞胺,番木鳖碱或马钱子碱)-盐分级结晶拆分为其光学对映体。
最后,本发明的酸化合物既可以以游离形式,也可以以其盐得到。
本发明的酸化合物可以最好在醚或醇溶剂如低级烷醇存在下,用药用碱,例如碱金属氢氧化物转化为成盐。从后者的溶液,可以用醚,例如乙醚沉淀盐。产生的盐可以通过用酸处理转化为游离化合物。这些或其它盐也可以被用于纯化所得的化合物。
具有碱基团的本发明化合物能够转化为酸加成盐,尤其是药用盐。这些是,例如,与无机酸,如矿物酸,例如硫酸,磷酸或氢卤酸,或与有机羧酸,如(C1-C4)-烷羧酸形成的,这些酸是未取代或被卤素取代的,例如乙酸,如饱和或不饱和的二羧酸,例如草酸,丁二酸,马来酸或富马酸,如羟基羧酸,例如乙醇酸,乳酸,苹果酸,酒石酸或柠檬酸,如氨基酸,例如天冬氨酸或谷氨酸,或与有机磺酸,如(C1-C4)-烷-或芳基磺酸,它是未取代或取代的,例如被卤素取代,例如甲磺酸的盐。优选的是与盐酸,甲磺酸和马来酸形成的盐。
从游离化合物与其盐形式的化合物之间密切的关系来看,当在本文中涉及到化合物时,相应地也提到其盐,只要在该情形下是可能的或合适的。
该化合物,包括其盐,也可以以其水合物,或包括用于其结晶的其它溶剂的形式得到。
本发明的药物组合物是适合对哺乳动物,包括人,肠道,如口服或直肠,经皮和非肠道给药,用于抑制TNF-α转化酶和基质-降解金属蛋白酶,用于治疗与其对应的疾病的组合物,包括有效量的本发明药理活性化合物,单独或与一种或多种药用载体混合。
本发明的药理活性化合物可用于生产包括有效量的该化合物与适合肠道或非肠道应用的赋形剂或载体协力或混合的药物组合物。优选的是片剂和胶囊,包含活性成分以及a)稀释剂,例如乳糖,葡萄糖,蔗糖,甘露糖醇,山梨醇,纤维素和/或甘油;b)润滑剂,例如硅胶,滑石,硬脂酸,其镁或钙盐和/或聚乙二醇;对于片剂也包含c)粘合剂例如硅酸铝镁,淀粉糊,明胶,黄蓍胶,甲基纤维素,羧甲基纤维素钠和或聚乙烯基吡咯烷酮;如果需要d)崩解剂,例如淀粉,琼脂,藻酸或其钠盐,或泡腾混合物;和/或e)吸收剂,着色剂,香味剂和甜味剂。可注射组合物优选地是含水等渗溶液或悬浮液,而栓剂最后从脂肪乳化液或悬浮液制备。所说的组合物可以是无菌的和/或含有佐剂,如防腐剂,稳定剂,湿润剂或乳化剂,溶液促进剂,用于调节渗透压的盐和/或缓冲液。另外,它们还含有其它有治疗价值的物质。所说的组合物分别根据常规的混合,成粒或包衣方法制备,并含有约0.1至75%,优选地约1至50%的活性成分。
用于经皮施用的合适的制剂包括有效量的本发明化合物与载体。有利的载体包括帮助通过主体的皮肤的可吸收的药用溶剂。其特征在于,经皮器械是包含衬垫的绷带形式,含有非强制性带有载体的化合物的储液器,非强制性在延长的时间周期以控制的和预定的速度输送化合物到主体皮肤的速度控制阀,和保证器械与皮肤的手段。
合适的局部应用,例如往皮肤和眼睛施用的制剂优选地是本专业公知的水溶液,软膏,乳剂或凝胶。
药物制剂含有有效的TNF-α转化酶抑制量和/或和基质-降解金属蛋白酶抑制量的如前定义的本发明化合物,单独或与其它治疗剂结合,例如有环氧酶抑制活性的抗炎剂,或其它抗风湿剂如氨甲喋呤,各自为本专业报道的有效治疗剂量。
有环氧酶抑制活性的抗炎剂的例子有二氯苯胺苯乙酸,甲氧萘丙酸,布洛芬等等。
与其它活性成分协力,本发明化合物既可以与其它活性成分同时,也可以在其之前或之后给药,既可以通过相同或不同的给药途径分开或在相同的药物制剂中一起。
给药的活性化合物的剂量取决于温血动物(哺乳动物)的种类,体重,年龄和各自病情,也取决于给药的形式。对于约50至70kg的哺乳动物口服给药的单位剂量可含有约10至1000mg,最好约25至250mg的活性成分。
本发明也涉及应用本发明化合物和其药用盐,或其药物组合物的方法,在哺乳动物体内用于抑制TNF-α活性和抑制基质-降解金属蛋白酶,例如溶基质素,明胶酶,胶原蛋白酶,和巨噬细胞金属弹性蛋白酶,用于抑制组织基质退化,和用于治疗如本文所述的TNF-α和基质-降解金属蛋白酶相关的病症,例如炎症,风湿性关节炎,骨关节炎,以及肿瘤(肿瘤生长,转移,发展或发作),肺病,和本文所述的其它病症。肿瘤(癌)包括哺乳动物乳腺癌,肺癌,膀胱癌,结肠癌,前列腺癌和卵巢癌,和皮肤癌,包括黑瘤和Kaposi’s肉瘤。
下列实施例用于举例说明本发明而不构成限制。温度以摄氏度给出。如果不另外指出,则所有的蒸发都在减压下,优选地在约15至100mmHg(=20-133mbar)之间进行。最终产物,中间体和原料的结构通过标准的分析方法,例如微量分析和光谱表征(例如MS,IR,NMR)证实。所用的缩写是本专业常见的。用于[α]D测定的浓度以mg/ml表示。实施例1:N-(叔丁氧基)-2(R)-[(4-甲氧基苯磺酰基)(4-甲基吡啶基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺(0.84g,1.5mmol)在圆底烧瓶中溶于含有乙醇(0.1mL,1.5mmol)的二氯甲烷(50ml)中,将反应冷却至-10℃。通入卤化氢气体(从演示瓶)10分钟。将反应密封,使其缓慢温热至室温并搅拌4天。通过蒸发将溶剂减至1/3体积并用乙醚研制。将混合物过滤,除去滤饼,真空干燥给出下式的N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-甲基吡啶基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺盐酸盐白色固体,m.p.135-140℃原料如下制备:
将D-4-羟基苯基甘氨酸(10g)溶于3N氢氧化钠(20ml)。加入水(180ml)然后加入阮内镍(27g)。将反应混合物在约3个大气压和50-80℃氢化过夜。将反应混合物滤过Celite,并将体积减至约85ml,加入二噁烷(85ml)。将4-羟基环己基甘氨酸(见Coll.Czech.Chem.Comm.49,712-742(1984))溶液冷却至0℃,并用三乙胺(11.37ml)和4-甲氧基苯磺酰氯(10.95g)处理。将反应混合物温热至室温并搅拌一周。真空除去二噁烷,剩下的水溶液用1N盐酸稀释。收集产生的沉淀,用水和乙醚洗涤给出(R)-N-(4-甲氧基苯磺酰基)-4-羟基环己基甘氨酸。
将粗(R)-N-(4-甲氧基苯磺酰基)-4-羟基环己基甘氨酸(7.0g,20.4mmol)在含有N,N-二环己基胺(3.7g,20.4mmol)和苄基溴(3.5g,20.4mmol)的二甲基甲酰胺(100ml)中的混合物在室温下搅拌24小时。混合物用水稀释并用乙酸乙酯萃取。合并的有机萃取液用盐水洗涤,干燥(硫酸钠),过滤,真空浓缩给出(R)-N-(4-甲氧基苯磺酰基)-4-羟基环己基甘氨酸苄基酯非对映异构体混合物。
在0℃,往粗的(R)-N-(4-甲氧基苯磺酰基)-4-羟基环己基甘氨酸苄基酯(8.67g,20mmol)的二氯甲烷(66mL)溶液中滴加溴化钠(2.06g,20mmol)的水(10ml)溶液,接着加入2,2,6,6-四甲基-1-哌啶氧基自由基(TEMPO,27mg)。往此混合物中滴加5%次氯酸钠(34.2mL,34.3mmol,Clorox牌)和水(34.2mL)的水溶液,其中在加入之前用碳酸氢钠将pH调节至8.6。产生的pH调节的次氯酸钠水溶液的加入时间是30分钟,并保持反应温度为0℃继续搅拌20分钟。将二氯甲烷层分开,依次用10%硫酸氢钾水溶液(40mL),少量10%碘化钾水溶液(3×30mL),10%硫代硫酸钠水溶液(60mL),和盐水(40ml)洗涤。将有机层干燥(硫酸镁),过滤,真空浓缩给出固体,将其通过从乙酸乙酯结晶进一步纯化给出(R)-N-(4-甲氧基苯磺酰基)-4-氧代环己基甘氨酸苄基酯。
往(R)-N-(4-甲氧基苯磺酰基)-4-氧代环己基甘氨酸苄基酯(15g,34.6mmol)在含有苯基甲硅烷(5.2mL,43.3mmol)的正丙醇(7mL,93.2mmol)中的混合物中滴加三氟乙酸,混合物在室温下搅拌过夜。将混合物用乙酸乙酯稀释并用饱和碳酸氢钠水溶液洗涤。将有机层干燥(硫酸镁),过滤,真空浓缩。粗产物通过硅胶色谱(1%至5%乙酸乙酯/二氯甲烷)纯化给出(R)-N-(4-甲氧基苯磺酰基)-顺式-4-丙氧基环己基甘氨酸苄基酯和(R)-N-(4-甲氧基苯磺酰基)-反式-4-丙氧基环己基甘氨酸苄基酯。
往(R)-N-(4-甲氧基苯磺酰基)-反式-4-丙氧基环己基甘氨酸苄基酯(4.0g,8.42mmol)的二甲基甲酰胺(55mL)溶液中加入4-氯甲基吡啶盐酸盐(1.5g,8.95mmol),接着加入碳酸钾(11.6g,84.2mmol)。将反应混合物在室温下搅拌过夜。然后将混合物用水稀释并用乙酸乙酯萃取。合并的有机萃取液用盐水洗涤,干燥(硫酸钠)并蒸除溶剂,给出2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酸苄基酯粗产物。
将2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酸苄基酯(3.0g,5mmol)在含有3N盐酸(5mL,15mmol)的乙醇中的溶液在50psi在5%Pd/C(200mg)存在下在室温氢化4小时。将反应混合物滤过硅藻土,用乙醇洗涤,真空浓缩给出2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酸盐酸盐粗产物。
将2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酸盐酸盐(2.65g,4.82mmol),1-羟基苯并三唑(0.65g,4.81mmol),4-甲基吗啉(2.93mL,26.5mmol),和盐酸O-叔丁基羟胺(1.81g,14.4mmol)溶于二氯甲烷(100mL)。加入N-[二甲基氨基丙基]-N’-乙基碳二亚胺盐酸盐(1.1g,5.8mmol),将反应搅拌过夜。然后将反应用水稀释并用二氯甲烷萃取。合并的有机萃取液用盐水洗涤,干燥(硫酸钠),蒸除溶剂。粗产物通过硅胶色谱(5%甲醇/二氯甲烷)纯化给出N-(叔丁氧基)-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺。实施例2:类似于实施例1制备下列化合物:(a)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-甲氧基环己基)乙酰胺盐酸盐,m.p.145-155℃。(b)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-乙氧基环己基)乙酰胺盐酸盐,m.p.128-135℃。(c)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丁氧基环己基)乙酰胺盐酸盐,m.p.132-137℃。(d)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-戊氧基环己基)乙酰胺盐酸盐,m.p.135-145℃。(e)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-[反式-4-(2-苯乙氧基)环己基)乙酰胺盐酸盐,m.p.120-130℃。(f)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-[反式-4-(2-(1-萘基)乙氧基)环己基]乙酰胺盐酸盐,m.p.125-140℃。(g)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-异丙氧基环己基)乙酰胺盐酸盐,m.p.140-145℃。(h)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-异丁氧基环己基)乙酰胺盐酸盐,m.p.126-134℃。(i)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-环己氧基环己基)乙酰胺盐酸盐,m.p.135-144℃。(j)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-[反式-4-(2-甲氧基乙氧基)环己基]乙酰胺盐酸盐,m.p.108-117℃。(k)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-[反式-4-(2-氟乙氧基)环己基]乙酰胺盐酸盐,m.p.130-141℃。(l)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-新戊氧基环己基)乙酰胺盐酸盐,m.p.125-134℃。(m)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(顺式-4-甲氧基环己基)乙酰胺盐酸盐,m.p.142-149℃。(n)N-羟基-2(R)-[(4-甲氧基苯磺酰基)(3-吡啶甲基)氨基]-2-(反式-4-乙氧基环己基)乙酰胺盐酸盐。(o)N-羟基-2(R)-[(4-苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-甲氧基环己基)乙酰胺三氟乙酸盐,m.p.160-165℃。(p)N-羟基-2(R)-[(4-乙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-甲氧基环己基)乙酰胺盐酸盐,m.p.131℃。(q)N-羟基-2(R)-[(4-丙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺盐酸盐,m.p.163-165℃。(r)N-羟基-2(R)-[(4-丁氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺盐酸盐,m.p.163-165℃。(s)N-羟基-2(R)-[(3,4-二甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-甲氧基环己基)乙酰胺盐酸盐,m.p.164℃。(t)N-羟基-2(R)-{(4-甲氧基苯磺酰基)[2-(4-吡啶基)乙基]氨基}-2-(反式-4-乙氧基环己基)乙酰胺。(u)N-羟基-2(R)-[(4-乙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺盐酸盐,m.p.131℃。(v)N-羟基-2(R)-[(4-异丁氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-丙氧基环己基)乙酰胺盐酸盐,m.p.145-146℃。(w)N-羟基-2(R)-[(4-乙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-乙氧基环己基)乙酰胺盐酸盐,m.p.150-155℃。(x)N-羟基-2(R)-[(4-乙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-异丁氧基环己基)乙酰胺盐酸盐,m.p.168-169℃。(y)N-羟基-2(S)-[(4-丙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺盐酸盐,m.p.165-174℃。实施例3:(a)在0℃往N-(三苯基甲氧基)-2(R)-[(4-丙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-甲氧基-4-甲基环己基)乙酰胺(348mg,0.48mmol)在含有三乙基甲硅烷(260μl,1.63mmol)的二氯甲烷溶液中滴加三氟乙酸(260μl,3.4mmol)。20分钟后,将反应混合物直接真空浓缩并用二氯甲烷(4mL)稀释。产生的溶液冷却至0℃并用氯化氢气酸化。再次真空除去溶剂,残余物再次溶于二氯甲烷。将溶液研制,通过加入戊烷沉淀出产物。除去上层清液并重复该方法直至所有的三苯基甲烷被除去。保留的固体沉淀是N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-甲氧基-4-甲基环己基)乙酰胺盐酸盐,m.p.133℃。原料如下制备:
将在室温下的(R)-N-(4-甲氧基苯磺酰基)-4-氧代环己基甘氨酸苄基酯(见实施例1,5.0g,11.6mmol)的二氯甲烷(35mL)溶液加入四氯化钛溶液(1.0M二氯甲烷溶液)(21.2mL,21.2mmol)和二甲基锌溶液(1.0M戊烷溶液)(23.0mL,23.0mmol)在-78℃二氯甲烷(20mL)中的溶液。将反应混合物在-78℃搅拌30分钟,然后在2.5小时内慢慢温热至室温。将反应混合物倒入水(700mL)中并用氯仿萃取。将合并的有机萃取液用水洗涤,干燥(硫酸镁),过滤,并真空浓缩。粗产物通过硅胶色谱(40%,乙酸乙酯/己烷)纯化给出(R)-N-(4-甲氧基苯磺酰基)-反式-4-羟基-4-甲基环己基甘氨酸苄基酯和(R)-N-(4-甲氧基苯磺酰基)-顺式-4-甲基-4-羟基环己基甘氨酸苄基酯。
在室温下往(R)-N-(4-甲氧基苯磺酰基)-反式-4-羟基-4-甲基环己基甘氨酸苄基酯(600.0mg,1.34mmol)在含有2,6-二叔丁基吡啶(755μl,3.36mmol)的二氯甲烷(15mL)中的溶液中滴加三氟甲磺酸甲酯(305μl,2.68mmol)。将反应混合物在室温下搅拌过夜,然后用少量甲醇骤冷。将混合物用氯仿稀释,然后用饱和氯化铵水溶液和水洗涤。将有机层干燥(硫酸镁),过滤,并真空浓缩。粗产物通过硅胶色谱(35%乙酸乙酯/己烷)纯化给出(R)-N-(4-甲氧基苯磺酰基)-反式-4-甲氧基-4-甲基环己基甘氨酸苄基酯。
将苄基酯氢解为酸并如实施例1用O-三苯甲基羟胺(代替O-叔丁基羟胺)处理给出N-(三苯基甲氧基)-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-甲氧基-4-甲基环己基)乙酰胺。(b)类似地制备N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(顺式-4-甲氧基-4-甲基环己基)乙酰胺盐酸盐m.p.128℃。实施例4:制备每个含有25mg活性成分,例如N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺的3000个胶囊:
活性成分 75.00g
乳糖 750.00g
Avicel PH 102(微晶纤维素) 300.00gPolyplasdone XL(聚乙烯基吡咯烷酮) 30.00g
纯化水 q.s.
硬脂酸镁 9.00g
将活性成分通过No.30手筛。
将活性成分,乳糖,Avicel PH 102和Polyplasdone XL在混合机内掺混15分钟。将掺合物用足量的水(约500mL)造粒,在烘箱中在35℃干燥过夜,并通过No.20筛。
将硬脂酸镁通过No.20筛,加入成粒的混合物中,该混合物在混合机内掺合5分钟。将掺合物装入No.0硬明胶胶囊内,各个胶囊含有相当于25mg活性成分的掺合物。
Claims (22)
1.式Ⅰ的化合物,其药用前药衍生物;或其药用盐;其中Ar表示碳环芳基,杂环芳基或联芳基;R1表示低级烷基,环烷基,(碳环或杂环芳基)-低级烷基,低级烷氧基-低级烷基,碳环芳基,杂环芳基,环烷基-低级烷基或卤素-低级烷基;R2表示氢或低级烷基;R3和R4独立地表示氢,低级烷基,低级烷氧基,卤素,羟基,酰氧基,低级烷氧基-低级烷氧基,三氟甲基或氰基;或者R3和R4与相邻的碳原子一起表示低级亚烷二氧基;n表示1至5的整数。
4.式Ⅲ的根据权利要求3的化合物,其药用前药衍生物,或其药用盐,其中Ar表示选自吡啶基,喹啉基,吡咯基,噻唑基,异噁唑基,三唑基,四唑基,吡唑基,咪唑基,噻吩基的杂环芳基,或任何所说的基团被低级烷基或卤素一-或二-取代;R1表示低级烷基;选自环戊基,环己基,环庚基,环辛基的环烷基,和任何所说的基团被低级烷基取代;或低级烷氧基-低级烷基;R2表示氢或低级烷基;R3和R4是氢或低级烷氧基;n是1-4。
5.式Ⅲ的根据权利要求3的化合物,其中R3在对位而R4在间位。
6.式Ⅲ的根据权利要求3的化合物或其药用盐,其中Ar是选自吡啶基,喹啉基,吡咯基,噻唑基,异噁唑基,三唑基,四唑基,吡唑基,咪唑基,噻吩基的杂环芳基,或任何所说的基团被低级烷基或卤素一-或二-取代;R1是低级烷基;R2是氢;R3是对位-低级烷氧基;R4是氢;n是1或2。
7.根据权利要求1至6任一项的化合物,其中Ar是吡啶基。
8.式Ⅲ的根据权利要求3的化合物或其药用盐,其中Ar是吡啶基,R1是低级烷基,R2和R4是氢;R3是对位-低级烷氧基;n是1。
9.根据权利要求8的化合物,其中Ar是3-或4-吡啶基。
10.式Ⅲ的根据权利要求3的化合物或其药用盐,其中Ar是3-或4-吡啶基,R1是直链C2-C5-烷基,R2和R4是氢;R3是对位-低级烷氧基;n是1。
11.式Ⅲ的根据权利要求3的化合物或其药用盐,其中Ar是4-吡啶基,R1是C2-C4-烷基,R2和R4是氢;R3是对位-乙氧基;n是1。
12.根据权利要求3的化合物,它是N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺,或其药用盐。
13.根据权利要求3的化合物,它是N-羟基-2(R)-[(4-乙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-丙氧基环己基)乙酰胺,或其药用盐。
14.根据权利要求3的化合物,它是N-羟基-2(R)-[(4-甲氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-乙氧基环己基)乙酰胺,或其药用盐。
15.根据权利要求3的化合物,它是N-羟基-2(R)-[(4-乙氧基苯磺酰基)(4-吡啶甲基)氨基]-2-(反式-4-异丁氧基环己基)乙酰胺,或其药用盐。
16.一种药物组合物,包含有效TNF-α转化酶抑制量的根据权利要求1-15任一项的化合物与一种或多种药用载体结合。
17.一种治疗哺乳动物TNF-α依赖病症的方法,该方法包括对需要治疗的哺乳动物施用有效TNF-α转化酶抑制量的根据权利要求1-15任一项的化合物。
18.一种治疗哺乳动物炎症,关节炎和肿瘤的方法,该方法包括对需要治疗的哺乳动物施用相应有效量的根据权利要求1-15任一项的化合物。
19.根据权利要求1-15任一项的化合物在治疗动物或人体的方法中的用途。
20.根据权利要求1-15任一项的化合物在治疗TNF-α依赖或基质-降解金属蛋白酶-依赖病症中的用途。
21.根据权利要求1-15任一项的化合物在生产用于治疗TNF-α依赖或基质-降解金属蛋白酶-依赖病症的药物组合物中的用途。
22.一种制备根据权利要求1的式Ⅰ化合物的方法,该方法包括式Ⅳ的羧酸或其反应活性功能衍生物,其中Ar,n和R1-R4具有与上面相同的定义,与式Ⅴ的羟胺,NH2-OH (Ⅴ)非强制性地以保护的形式,或其盐缩合而制备;而且,如果需要,临时保护任何干扰的反应活性基团,然后释放生产的本发明化合物;并且,如果需要,将生产的本发明化合物转化为其它本发明化合物,和/或,如果需要,将产生的游离化合物转化为盐或将产生的盐转化为游离化合物或转化为其它盐;和/或将所得的异构体或外消旋体分离为单个异构体或外消旋体;和/或,如果需要,将外消旋体拆分为光学对映体。
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CN108055865A (zh) * | 2015-06-18 | 2018-05-18 | Ucb生物制药私人有限公司 | 用于治疗的新的TNFα结构 |
US10705094B2 (en) | 2015-06-18 | 2020-07-07 | UCB Biopharma SRL | TNF receptor signaling modulator assay |
US10775385B2 (en) | 2015-06-18 | 2020-09-15 | UCB Biopharma SRL | Treatment of autoimmune and inflammatory disorders with asymmetric TNF alpha trimers |
US10969393B2 (en) | 2015-06-18 | 2021-04-06 | UCB Biopharma SRL | Complexes between anti-TNF antibodies, trimeric TNF proteins and organic molecules binding them |
US11022614B2 (en) | 2015-06-18 | 2021-06-01 | UCB Biopharma SRL | Antibodies binding to trimeric TNF alpha epitopes |
US11174311B2 (en) | 2016-12-21 | 2021-11-16 | UCB Biopharma SRL | Antibody against trimeric TNFα complex |
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