CN1090614C - N-(芳酰基)甘氨酸异羟肟酸衍生物及相关化合物 - Google Patents

N-(芳酰基)甘氨酸异羟肟酸衍生物及相关化合物 Download PDF

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CN1090614C
CN1090614C CN96195846A CN96195846A CN1090614C CN 1090614 C CN1090614 C CN 1090614C CN 96195846 A CN96195846 A CN 96195846A CN 96195846 A CN96195846 A CN 96195846A CN 1090614 C CN1090614 C CN 1090614C
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E·F·克莱恩曼
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Abstract

式(I)化合物及其药用盐,其中R1,R2,AA和Y如说明书中定义,可抑制IV型磷酸二酯酶或抑制肿瘤坏死因子的产生,因而可用于治疗包括哮喘,关节炎和支气管炎的症状和疾病。

Description

N-(芳酰基)甘氨酸异羟肟酸衍生物及相关化合物
本发明涉及N-(芳酰基)甘氨酸异羟肟酸衍生物及有关化合物,这些化合物可以选择性地抑制IV型磷酸二酯酶(PDE)或抑制肿瘤坏死因子(TNF)的生成,因此可以用于治疗哮喘,关节炎,支气管炎,慢性阻塞性呼吸道疾病,牛皮癣,过敏性鼻炎,皮炎以及其它炎症性疾病,AIDS,脓毒症,腐败性休克,恶病质以及其它与TNF生成有关的疾病。本发明化合物具有合并的IV型PDE和TNF抑制活性。本发明还涉及这类化合物治疗哺乳动物,尤其是人类体内上述疾病的用途,此外还涉及用于此用途的药物组合物。
自从人们认识到环AMP是一个细胞内第二信使后(E.W.Sutherland,和T.W.Rall,pharmacol.Ref.,1960,12,265)抑制磷酸二酯酶就作为一个目标以用来调节和干预一系列疾病过程。新近,又有人对PDE进行了清楚的分类(J.A.Beavo及D.H.Reifsnyder,TIPS,1990,11,150),对其选择性的抑制导致了药物治疗的进展(C.D.Nicholson,R.A.Challiss及M.Shahid,TIPS,1991,12,19)。更具体讲,人们发现对IV型PDE的抑制可以导致对炎症介质释放的抑制(M.W.Verghese等人,J.Mol.Cell.Cardiol.,1989,12,(Suppl.II),S61)以及呼吸道平滑肌的松驰(T.J.Torphy等人在新的抗哮喘药方向edsS.R.O’Donnell及C.G.A.Persson,1988,37,Birkhauser-Verlag中的描述)。因此可以抑制IV型PDE但对其它类型PDE活性很低的化合物可以抑制炎症介质的释放、松驰呼吸道平滑肌而不引起心血管作用或抗血小板作用。
TNF被认为与许多感染和自身免疫疾病,如恶病质(W.Friers,FEBS Letters,1991,285,199)有关。进一步而言,TNF在脓毒症和腐败性休克中显示出其是炎症反应的初级介质(C.E.Spooner等人,临床免疫和免疫病理,1992,62,S11)。
本发明涉及式I化合物或其制药学上可接受的盐类,
其中R’选自甲基,乙基,二氟甲基及三氟甲基;
R2为(C1-C6)烷基,(C3-C7)烷氧基(C2-C4)烷基,苯氧基(C2-C6)烷基,(C3-C7)环烷基,(C6-C9)聚环烷基,苯基(C1-C8)烷基或2,3一二氢化茚基,其中所述R2基团的烷基部分可以任意地被一或多个氟原子取代,所述R2基团的芳基部分可任意地被一或多个选自(C1-C4)烷基,(C1-C4)烷氧基及卤素的基团所取代;
AA为(AA-1)或(AA-2),其中
(AA-1)为
Figure C9619584600052
其中R3和R4各自独立地选自氢,三氟甲基,(C1-C6)烷基,-(CH2)nCO2H,-(CH2)nCONH2、-(CH2)n苯基,-(CH2)XOH,及-(CH2)XNH2,其中X的范围为1-5,n的范围为0-5,R5为氢,OH或(C1-C6)烷基,m的范围为0-5;且
(AA-2)为
Figure C9619584600053
其中P的范围从1-4;且
Y为NHOH或OH。
这里所用的术语“烷基”除非另有说明,包括具有直链或支链基团的单价烃基。
所用的术语“烷氧基”包括O-烷基基团,其中“烷基”定义同上。
所用的术语“环烷基”包括饱和单价环烃基团,包括环丁基,环戊基及环庚基。
所用的术语“聚环烷基”包括饱和单价聚环基团,其包含稠合的环的集合,如二环或三环。这类的环集合包括双环庚基,双环丁基,三环辛基以及全氢化并环戊二烯基。
所用的术语“芳基”除非另有说明,包括衍生自去除一个氢原子的芳烃的有机基团,如被1-3个选自氟,氯,三氟甲基,(C1-C6)烷氧基,(C6-C10)芳氧基,三氟甲氧基,二氟甲氧基及(C1-C6)烷基取代基任意取代的苯基或萘基。
所用的“治疗”除非另有说明,是指(i)治疗,缓解或减轻对IV型PDE抑制或TNF生成抑制有响应的症状和疾病中不期望的效果或不期望的有关症状的方法,这些症状和疾病在哺乳动物(包括人类)中是时常发生的。(ii)预防哺乳动物发生这些症状和疾病的方法,且(iii)延缓这些症状和疾病在哺乳动物体内发作的方法。所用的术语“treat”(治疗)及“treating”(治疗)的定义与上述相同。
所用的术语“治疗有效剂量”,除非另有说明是指可有效抑制IV型PDE或抑制TNF生成的剂量,或是指在上述所定义的对IV型PDE抑制或TNF生成抑制有响应的症状和疾病进行治疗时达到有效的量。
式I化合物包括一些具有手性中心的化合物,因此存在不同的对映体。本发明涉及所有式I化合物的光学异构体和立体异构体以及它们的混合物。
优选的式I化合物包括那些R1为甲基的化合物。
其它优选的式I化合物包括那些R2为环戊基的化合物。
其它优选的式I化合物包括那些AA为基团(i)且R3为氢,甲基,三氟甲基或-CH2OH的化合物。
其它优选的式I化合物包括那些AA为基团(AA-1)且R4为氢的化合物。
其它优选的式I化合物包括那些AA为基团(AA-1)且R5为氢的化合物。
其它优选的式I化合物包括那些AA为基团(AA-1)且m为0的化合物。
其它优选的式I化合物包括那些Y为-NHOH的化合物。
特别优选的式I化合物有:
α-单氟甲基-α-N-[(3-环戊氧-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸;
α-二氟甲基-α-N-[(3-环戊氧-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸;
α-乙基-α-N-[(3-环戊氧-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸;
α-丙基-α-N-[(3-环戊氧-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸;
α-N-[(3-环戊氧基-4-甲氧基)苯甲酰基]-D-胱氨酸异羟肟酸;
α-三氟甲基-α-N-[(3-环戊氧基-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸;
α-N-[(3-环戊氧-4-甲氧基)苯甲酰基]-D-丝氨酸异羟肟酸;
α-N-[(3-环戊氧-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸;及
α-N-[(3-环戊氧-4-甲氧基)苯甲酰基]-D-丙氨酸异羟肟酸。
本发明进一步涉及用于在哺乳动物体内(包括人类)抑制IV型PDE和抑制TNF生成的药物组合物,其包含有治疗有效剂量的式I化合物或其制药学上可接受的盐类,和制药学上可接受的载体。
本发明进一步涉及治疗下列症状和疾病的药物组合物,这些症状或疾病包括哮喘,关节炎,支气管炎,慢性阻塞性呼吸道疾病,牛皮癣,过敏性鼻炎,皮炎,AIDS,腐败性休克以及其它在哺乳动物体内(包括人类)对IV型PDE的抑制或TNF生成抑制有响应的症状和疾病,该组合物包含治疗有效剂量的式I化合物或其制药学上可接受的盐类,和制药学上可接受的载体。
本发明进一步涉及在哺乳动物体内抑制IV型PDE或抑制TNF生成的方法,其包括给予所需治疗的哺乳动物治疗有效剂量的式I化合物或其制药学上可接受的盐类。
本发明进一步涉及治疗下列症状或疾病的方法,如哮喘,关节炎,支气管炎,慢性阻塞性呼吸道疾病,牛皮癣,过敏性鼻炎,皮炎,AIDS,腐败性休克以及其它在哺乳动物体内对IV型PDE抑制或TNF生成抑制有响应的情况或疾病,其包括给予所需治疗的哺乳动物治疗有效剂量的式I化合物或其制药学上可接受的盐类。
下列反应路线1说明了本发明化合物的制备。除非另有说明,路线1中和以后讨论中所用的R1,R2,R3,R4,R5,AA,n,m,p和Y的定义同上。在路线1中以及随后的制备和实例中,除非另有说明,所有的合成反应以及其它操作步骤均在室温(20-25℃)下进行。
                       反应路线1
Figure C9619584600091
在路线1的反应1中,借助肽化学领域内熟知的偶联方法,使式V羧酸与O-苄羟胺进行偶联,可以获得式VI化合物。式V羧酸可从各种商业渠道获得,也可按本领域内熟知的合成方法获得。优选的偶联方法是:在0°-30℃(优选的是20-25℃)下,使式V化合物与O-苄基羟胺盐酸盐,1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐以及碱(如三乙胺)在惰性溶剂中(如CH2Cl2)进行结合,反应时间2-48小时(最好是16小时)。
路线1反应2中,用酸如盐酸或三氟乙酸对式VI化合物进行处理,以除去叔丁氧羰基基团,得到式VII盐,其中HX中的X为氯或三氟乙酸根,且m,R3,R4和R5的定义同上。
路线1反应3中,借助肽化学领域内熟知的偶联方法,使式VII盐与式VIII苯甲酸衍生物进行偶联,制备得到式IX化合物。式VIII苯甲酸衍生物可用本领域内熟知的合成方法来制备。例如,3-环戊氧基-4-甲氧苯甲酸可按M.N.Palfreyman等人在药物化学杂志,Vol.37,P.1696(1994)中所描述的方法进行制备,这里可将其作为参考。优选的偶联方法是在0-30℃(优选的是20-25℃)下,使式VIII化合物与式VII盐、1-(3-二甲基氨丙基)-3-乙基碳化二亚胺盐酸盐和碱(例如三乙胺)在惰性溶剂中(如CH2Cl2)进行结合,反应时间2-48小时(优选16小时)。
路线1反应4中,使式IX化合物在Pd(OH)2存在下,于一种溶剂(如甲醇或乙醇)中进行氢化反应,时间4-48小时(优选是16小时),得到式X化合物。
当路线1说明了式I化合物(其中AA为(AA-1))的制备方法的同时,也就决定了式I化合物(其中AA为(AA-2))必须按照相同的路线来制备,特殊的地方是在第一步反应中,用相同结构但AA部分为(AA-2)而不是(AA-1)的物质代替式V化合物。这类化合物可从商业渠道获得,也可用本领域内熟知的方法来制备。然后同前实施反应1-4。
为了制备式I化合物(其中Y为OH而不是NHOH),从路线1的第三个反应开始进行反应,其中式VII化合物被式XI化合物:HX·NHR5CR3R4(CH2)mCO2CH2ph所取代。式XI化合物有市售,或可用本领域内熟知的方法来制备。式XI化合物与式VIII化合物的偶联在路线1反应3中有所描述。然后按上述路线1反应4制备式I化合物(其中Y为OH)。
制药学上可接受的本发明化合物的酸加成盐包括(但不限于)那些与乙酸,乳酸,琥珀酸,马来酸,酒石酸,柠檬酸,葡糖酸,抗坏血酸,苯甲酸,肉桂酸,富马酸,硫酸,磷酸,盐酸,氢溴酸,甲苯磺酸,扁桃酸,二-对-甲苯-L-酒石酸以及有关的酸所形成的盐。式I化合物的酸加成盐可用常规方法获得,-即用大约一个化学当量的制药学上可接受的酸对式I碱的溶液或悬浮液进行处理。在分离盐时可采用常规的浓缩或重结晶技术。制药学上可接受的式I化合物的阳离子盐(其中Y为羟基)包括(但不限于)那些与钠,钾,钙,镁,铵,N,N’-二苄-1,2-亚乙基二胺,N-甲基葡糖胺(甲基葡胺),乙醇胺及二乙醇胺所成的。
式I化合物及其制药学上可接受的盐类抑制IV型PDE或抑制TNF生成以及由此表明它们用于治疗那些对IV型PDE抑制及TNF生成抑制有响应的疾病的有效性等方面的能力将通过下列体外分析实验来显示。
                      生物学实验
                  人类嗜曙红细胞PDE
将收集到的人类外周血置于1,2-亚乙基二胺四乙酸中,用哌嗪-N,N’-双-2-乙磺酸(PIPES)缓冲液稀释至1∶2,然后将其涂层于珀可溶液上。4℃下用2000rpm的速度离心30分钟形成梯度。随后的分离步骤在4℃下,基于Kita等人在J.Immunol.,152,5457(1994)中所描述的方法进行。从珀可梯度上收集嗜中性细胞嗜曙红细胞层,溶解红细胞。剩余的细胞用PIPES(1%FCS)洗涤,用抗-CD16微珠(MACS)培养1小时。然后使之经过磁性柱以去除嗜中性细胞。将嗜曙红细胞收集在洗脱液中,用台盼兰分析其生存力,用分类-快速染色分析其纯度。用此方法得到的嗜曙红细胞的纯度一般大于99%。
将纯化的嗜曙红细胞再悬浮于750μl PDE溶解缓冲液(20mM三乙胺,1mM乙二胺四乙酸,100μg/ml杆菌肽,2mM苄脒,50μM亮肽霉素,50μM PMSF,100μg/ml大豆胰蛋白酶抑制剂)中,并于液氮中快速冷冻。将细胞解冻并超声,对膜进行涡旋处理(对碎片进行台盼兰染色可证实其已被破坏)。将破坏的细胞于4℃下在45krpm的速度下离心30分钟分离膜。倾出胞液,将膜再悬浮至200μg/ml,用作水解分析中PDE的来源,其产生了3000-5000的计数窗。
将化合物溶于二甲亚砜中,浓度为1×10-2M,用水按1∶25稀释25倍至4×10-4M。此悬浮液用4%二甲亚砜按1∶10进行系列稀释。分析中二甲亚砜的最终浓度为1%。
磷酸二酯酶抑制实验
向12×75mm的玻璃管中加入:
25μl PDE分析缓冲液(200mM Tris/40mM MgCl2)
24μl 4nM/ml cAMP贮备液
25μl受试化合物
25μl PDE来源(膜)
背景对照=煮沸10分钟的膜
阳性对照-25μl未煮沸的膜
37℃水浴上培养25分钟。
样品煮沸5分钟后终止反应,将样品置于Affigel柱上(1ml床体积),其事先已用0.25M乙酸及0.1mM N-[2-羟乙基]哌嗪-N’-2-乙磺酸(HEPES)/0.1mM Nacl洗涤缓冲液(pH=8.5)进行平衡。用HEPES/Nacl便cAMP从柱上洗脱,用0.25M乙酸使51-AMP洗脱,体积为4ml。在3ml的闪烁液体中对1ml洗脱液([3H])计算1分钟。
底物转化=(cpm阳性对照×4)/总活性,对于有效实验而言,转化率必须在3-15%之间。
%抑制-1-(洗脱cpm-背景cpm/对照cpm-背景cpm)×100
IC50值由抑制滴定曲线(线性部分)的线性回归产生;以μM表示。
                         TNF
下列体外分析实验显示了式I化合物及其制药学上可接受的盐类抑制TNF生成、破坏其有效性从而用来治疗与TNF生成有关的疾病的能力:
将收集到的人类志愿者的外周血(100ml)置于乙二胺四乙酸(EDTA)中。借助Ficoll/Hypaque方法分离出单核细胞,用不完全Hank’s平衡盐溶液(HBSS)洗涤三次。将细胞再悬浮于预热的RPMI(含有5%FCS,谷氨酰胺,pen/step,及制霉菌素)中,终浓度为每ml含1×106个细胞。将上述每ml含1×106个细胞的溶液在24孔平皿中进行单细胞涂布。37℃下培养(5%CO2)2小时,使细胞附着于平皿。随后轻轻地洗去未附着的细胞。向其中加入受试化合物(10μl)、每个化合物选择3-4个浓度,再培养1小时。向合适的池中加入脂多(LPS)(10μl)。将其于37℃下培养过夜(18小时)。在培养期结束后,用夹层ELISA(R&D Quantikine kit)分析TNF。用线性回归分析求出每个化合物的IC50值。
在治疗和预防人类炎症疾病给药时,式I化合物及其制药学上可接受的盐类(下文中也称为本发明活性化合物)的口服剂量通常为0.1-400mg/每天/每个成年患者(平均体重70kg)。因此对于典型的成年患者来说,每个药片或胶囊含有0.1-500mg活性化合物,且其存在于合适的制药学上可接受的载体中。静脉给药的典型剂量为0.1-40mg/每单位剂量。对于鼻内或吸入给药而言,通常是配成0.1-1%(W/V)的溶液。在实际应用中,医生将根据患者的具体情况决定最适合的剂量,其将依照患者的年龄,体重及对药物的反应而变化。上述剂量只是说明一般情况,当然,在某些特定情况下,较高或较低的剂量范围更为合适,这些剂量范围也包括在本发明的范围之内。
对于人类给药而言,为了抑制TNF,可有各种常规途径,包括口服非肠道及局部给药途径。通常,活性化合物以口服或非肠道形式给药,剂量每天为0.1-25mg/待治疗患者kg体重,优选0.3-5mg/kg。式I化合物可以软膏剂或霜剂形式局部给药,浓度约为0.5%-1%,通常每天在受伤处使用2-3次。然而,根据待治患者的情况有时也需要进行剂量变化。在任何情况下,负责给药的人员都应根据不同的给药对象来决定合适的给药剂量。
对于人类使用而言,本发明活性化合物可以单独给药,但通常是以与制药学上的稀释剂或载体相混合的形式给药,这些稀释剂和载体需要根据给药途径及标准的制药惯例来选择。例如,它们可以口服给药,采用的是含有这类赋形剂(如淀粉或乳糖)的药片,或采用单独的或与赋形剂相混合的胶囊或ovales,也可以采用含有香味剂或增色剂的酏剂或悬浮液。它们可经非肠道注射给药,例如,静脉,肌肉或皮下注射给药。对于非肠道给药,最好采用无菌水溶液形式,其可以含有其它物质;例如,足够量的盐或葡糖以使溶液等渗。
下列制备和实例将说明本发明,但无意于限制本发明的详细内容。在下列制备和实例中,术语“t-BOC”代表叔丁氧羰基基团,符号“Bn”代表苄基基团。
制备1
O-苄基-α-N-t-BOC-甘氨酸异羟肟酸酯
向3.0g(0.017mol)α- N-(叔丁氧羰基)甘氨酸,2.7g(0.017mol)O-苄基羟胺盐酸盐及60ml CH2Cl2组成的混合物中加入3.6ml(2.6g,0.026mol)三乙胺,然后再加入5.0g(0.026mol)1-(3-二甲基氨丙基)-3-乙基碳化二亚胺。悬浮液于N2气并室温下搅拌16小时。蒸发澄清的混合物,将半固体物溶于300ml EtOAc中,依次用1NHCl溶液(2×200ml),饱和NaHCO3水溶液(2×200ml)洗涤,MgSO4干燥。滤除干燥剂,蒸发溶液,得4.3g(90%)标题化合物,其为澄清油状物。Rf0.2(2∶3EtOAc-己烷)。1H-NMR(CDCl3):δ1.37(9H,s),2.62(2H,br s),4.82(2H,s),5.10(1H,br s),7.23-7.35(5H,m),8.89(1H,br s).
制备2
O-苄基-α-N[(3-环戊氧基-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸酯
室温下,将4.3g制备1化合物及20ml 4M HCl二噁烷溶液搅拌4小时,此过程用CaCl2管防止大气中的水份进入。用TLC检测直至全部起始原料消耗完毕,蒸发溶液,得3.2g O-苄基-甘氨酸异羟肟酸酯盐酸盐,其为粘性固体。
向上述1.35g(6.35mmol)固体,1.50g(6.35mmol)3-环戊氧基-4-甲氧苯甲酸及60ml CH2Cl2组成的混合物中加入1.33ml(966mg,9.53mmol)三乙胺,再加入1.83g(9.53mmol)1-(3-二甲基氨丙基)-3-乙基碳化二亚胺。室温搅拌16小时后,蒸发混合物,将残渣溶于150mlEtOAc中,依次用1N HCl溶液(2×75ml),饱和NaHCO3水溶液(2×75ml)洗涤,MgSO4干燥。滤除干燥剂,蒸发滤液,残渣用闪式柱层析纯化(75g硅胶),以4∶1EtOAc-己烷作洗脱液,得773mg(30%)标题化合物,其为泡沫状物。Rf0.35(EtOAc)1H-NMR(DMSO-d6):δ1.44-2.00(9H,m),3.75(5H,br s),4.70-4.82(1H,m),4.74(2H,s),6.95(1H,d,J=8),7.22-7.46 (7H,m),8.54(1H,m).
                         制备3-16
按照制备实例1所述方法,可以制得下列具式II的化合物,除了用a-N-t-BOC-AA-OH氨基酸(其中AA的定义见表1)代替a-N-t-BOC-甘氨酸作起始原料。
a-N-t-BOC-A A-NHOBn
                      表1
Figure C9619584600161
Figure C9619584600171
制备17
o-苄基-(3-环戊氧基-4-甲氧基)苯甲酰基异羟肟酸酯
按照制备1所述方法,用3-环戊氧-4-甲氧苯甲酸代替a-N-t-BOC-甘氨酸,可以制得标题化合物,经己烷/CH2Cl2重结晶后,其为飞扬性白色结晶,m.p.120.5-121℃。元素分析计算式为C20H23NO4:C,70.36;H,6.79;N,4.10,实测值:C,70.31;H,6.97;N,4.43。
制备18
叔-丁基-a-N-苄氧-α-N-[(3-环戊氧基-4-甲氧)苯甲酰基]甘氨酸
N2气下,向干燥的25ml三颈瓶中加入77.8mg(1.62mmol)50%NaH的矿物油溶液,随后用己烷洗涤。将裸露的氢化物悬浮于1mlTHF中,向其中滴加504mg(1.48mmol)制备17化合物的4ml THF溶液。停止生成H2气后,混合物变为澄清,向其中加入261μl(315mg,1.62mmol)乙酸叔丁酯。2小时后再加447μl乙酸叔丁酯。室温搅拌16小时后,用50ml乙醚稀释,水洗(1×30ml),1N NaOH溶液洗涤(3×30ml),MgSO4干燥,蒸发得846mg油状物。
用20%EtOAc-己烷作洗脱液对油状物进行闪式柱层析纯化,得476mg油状物,其可自动结晶,在己烷中进行研制,得392mg白色固体,m.p.87-89℃。该物再用己烷重结晶得302mg白色针状标题化合物,m.p.88-89℃。元素分析计算式C26H33NO6:C,68.55;H,7.30;N,3.07,实测值:C,68.84;H,7.57;N,3.02。
制备19
O-苄基-α-N-苄氧基-α-N-[(3-环戊氧基-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸酯
采用CaCl2干燥管,使1.64g(4.11mmol)制备18化合物和20ml三氟乙酸组成的混合物于室温下搅拌45分钟。蒸发混合物,残渣溶于100ml乙醚中,用H2O(3×75ml),盐水(1×75ml)洗涤,MgSO4干燥,蒸发得1.42gα-N-苄氧-α-N-[(3-环戊氧基-4-甲氧)苯甲酰基]甘氨酸。
按照与制备1相似的方法,用上述酸取代α-N-(叔-丁氧羰基)甘氨酸,可以制得标题化合物,其为泡沫状物。                                1H-NMR(CDCl3):δ1.48-1.95(8H,m),3.88(3H,s),4.38(2H,s),4.58-4.68(1H,m),4.69(2H,s),4.93(2H,s),6.83(1H,d,J=8),7.07-7.16(2H,m),7.23-7.42(10H,m),9.27(1H,s).
制备20-33
按照与制备2相同的方法,可以制得下列具式III的化合物,除了用指定制备中的化合物代替制备1中的化合物作起始原料。
                         表2
Figure C9619584600192
Figure C9619584600201
制备34
N-[(3-环戊基-4-甲氧基)苯甲酰基]甘氨酸苄酯
向0.500g(2.12mmol)3-环戊基-4-甲氧苯甲酸及0.470g(2.33mmol)甘氨酸苄酯盐酸盐的20ml CH2Cl2溶液混合物中加入0.410g(2.12mmol)1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐,然后再加0.236g(2.33mmol)三乙胺。混合物于室温下搅拌16小时。
蒸除溶剂,残渣用水稀释(150ml),乙醚提取(2×150ml)。合并的提取液依次用1N HCl(1×150ml),饱和NaHCO3洗涤,MgSO4干燥,蒸发得940mg白色固体。闪式柱层纯化(55g硅胶),以3∶7EtOAc∶己烷作洗脱液得518mg标题化合物,mp=108-109℃。1H NMR(CDCl3):δ1.40-1.95(8H,m),3.85(3H,s),4.24(2H,d,J=5),4.70-4.80(1H,m),5.20(2H,s),6.50(1H,br s),6.83(1H,d,J=8),7.10-7.40(7H,m).
实例1
α-N-[(3-环戊氧基-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸
将770mg制备2化合物,70mg Pd(OH)2及50ml甲醇的混合物置于Parr Shaker仪器中氢化16小时。滤除催化剂,蒸发滤液得一白色固体,其在乙醚中研制后得510mg标题化合物,m.p.160-161℃。元素分析计算式C15H20N2O5:C,57.54;H,6.55;N,8.95.实测值:C,57.48;H,6.51;N,8.74。
实例2-16
按照实例1所述方法,可以制备具有式IV的实例2-16中的化合物,除了用制备19-33中的化合物代替制备2中的化合物作起始原料。
Figure C9619584600241
                         表3
Figure C9619584600242
Figure C9619584600251
Figure C9619584600261
实例17
N[(3-环戊基-4-甲氧基)苯甲酰基]甘氨酸
按照实例1所述方法,用制备34中化合物代替制备2中化合物作起始物,可以制备实例17化合物,m.p.156-158℃。元素分析计算式C15H19NO5·1/4H2O:C,60.04;H,6.55;N,4.70。实测值:C,60.07;H,6.59;N,4.56。

Claims (8)

1.式I化合物或其制药学上可接受的盐类,
其中R1选自甲基,乙基,二氟甲基及三氟甲基;
R2为(C1-C6)烷基,(C3-C7)烷氧基(C2-C4)烷基,苯氧基(C2-C6)烷基,(C3-C7)环烷基,(C6-C9)多环烷基,苯基(C1-C8)烷基或2,3-二氢化茚基,其中所述R2基团的烷基部分可以任意地被一或多个氟原子取代,所述R2烷基部分可任意地被一或多个氟原子取代,其中R2基团的芳基部分可任意地被选自(C1-C4)烷基,(C1-C4)烷氧基及卤素进行一或多取代;
AA为
Figure C9619584600022
其中P的范围从1-4;且
Y为NHOH或OH,条件是当R1为甲基或乙基及R2为(C1-C6)烷基或(C3-C7)环烷基时,Y为NHOH。
2.权利要求1的化合物,其中R1为甲基。
3.权利要求1的化合物,其中R2为环戊基。
4.权利要求1的化合物,其中P为3。
5.权利要求1的化合物,其中Y为NHOH。
6.权利要求1的化合物选自下列化合物:
α-三氟甲基-α-N-[(3-环戊氧基-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸;
α-N-[(3-环戊氧基-4-甲氧基)苯甲酰基]-D-丝氨酸异羟肟酸;
α-N-[(3-环戊氧基-4-甲氧基)苯甲酰基]甘氨酸异羟肟酸。
7.用于哺乳动物体内抑制IV型磷酸二酯酶或肿瘤坏死因子生成的药物组合物,其包含治疗有效剂量的权利要求1要求的式I化合物以及制药学上可接受的载体。
8.治疗下列情况和疾病的药物组合物,这些疾病包括哮喘,关节炎,支气管炎,慢性阻塞性呼吸道疾病,牛皮癣,过敏性鼻炎,皮炎,AIDS,腐败性休克以及哺乳动物体内其它对IV型PDE抑制或TNF生成抑制有响应的情况和疾病,其包括治疗有效剂量的权利要求1化合物以及制药学上可接受的载体。
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