CN1247531A - 芳基磺酰基异羟肟酸衍生物 - Google Patents
芳基磺酰基异羟肟酸衍生物 Download PDFInfo
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- CN1247531A CN1247531A CN98802460A CN98802460A CN1247531A CN 1247531 A CN1247531 A CN 1247531A CN 98802460 A CN98802460 A CN 98802460A CN 98802460 A CN98802460 A CN 98802460A CN 1247531 A CN1247531 A CN 1247531A
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- alkyl
- aryl
- compound
- heteroaryl
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- -1 Arylsulfonyl hydroxamic Chemical compound 0.000 title claims abstract description 84
- 239000002253 acid Substances 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
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- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims abstract description 9
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 8
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- 230000000694 effects Effects 0.000 claims abstract description 7
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- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 102
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 66
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- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
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- 125000006720 (C1-C6) alkyl (C6-C10) aryl group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 2
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- 150000001413 amino acids Chemical class 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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- 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
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Classifications
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- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
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- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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Abstract
本发明公开了式(Ⅰ)化合物,其中R1、R2、R3、R4、R5、R6、R7、R8、R9和Q如文中所定义,该化合物可用于治疗关节炎、癌症、组织溃疡、黄斑变性、再狭窄、牙周疾病、大疱性表皮松解、巩膜炎以及特征在于基质金属蛋白酶活性的其它疾病、AIDS、脓毒症、脓毒性休克和涉及TNF产生的其它疾病。此外,本发明的化合物还可用于和常规非甾体抗炎药(NSAID)和镇痛剂的联合治疗,以及和细胞毒性药物如阿霉素、柔红霉素、顺铂、依托泊甙、紫杉酚、taxotere和其它生物碱如长春新碱联合用于治疗癌症。
Description
本发明涉及芳基磺酰基异羟肟酸衍生物,该化合物是基质金属蛋白酶或肿瘤坏死因子(TNF)产生的抑制剂,因此可用于治疗关节炎、癌症、组织溃疡、黄斑变性、再狭窄、牙周疾病、大疱性表皮松解、巩膜炎以及特征在于基质金属蛋白酶活性的其它疾病、AIDS、脓毒症、脓毒性休克和涉及TNF产生的其它疾病。此外,本发明的化合物还可用于和常规的非甾体抗炎药(以下称为NSAID)和镇痛剂联合治疗来治疗关节炎,以及和细胞毒性药物如阿霉素、柔红霉素、顺铂、依托泊甙、紫杉酚、taxotere和其它生物碱如长春新碱联合来治疗癌症。
本发明还涉及使用所述化合物在哺乳动物、特别是人中治疗上述疾病的方法以及所用的药物组合物。
有许多种酶可以影响结构蛋白的破坏,这些酶是结构相关性金属蛋白酶。基质降解金属蛋白酶如明胶酶、溶基质素和胶原酶参与组织基质的降解(例如胶原的裂解)并与多种涉及异常***和基膜基质代谢的病理学情况如关节炎(例如骨关节炎和类风湿性关节炎)、组织溃疡(例如角膜溃疡、表皮溃疡和胃溃疡)、异常的伤口愈合、牙周疾病、骨疾病(例如佩吉特氏病和骨质疏松)、肿瘤转移或侵袭以及HIV感染(J.Leuk.Biol.,52(2):244-248,1992)有关。
肿瘤坏死因子被认为与许多传染病和自身免疫病有关(W.Fiers,FEBS Letters,1991,285,199)。此外,还证实了TNF是脓毒症和脓毒性休克中所出现的炎症反应的主要介质(C.E.Spooner等,临床免疫学和免疫病理学(Clinical Immunology andImmunopathology,1992,62 S11)。
表示单键或双键;
X是碳、氧或硫;
Y是碳、氧、硫、SO、SO2或氮;
R1、R2、R3、R4、R5、R6、R7、R8和R9选自氢;被一个或两个基团选择性取代的(C1-C6)烷基,所述基团选自(C1-C6)烷硫基、(C1-C6)烷氧基、三氟甲基、卤素、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳氨基、(C6-C10)芳硫基、(C6-C10)芳氧基、(C5-C9)杂芳氨基、(C5-C9)杂芳硫基、(C5-C9)杂芳氧基、(C6-C10)芳基(C6-C10)芳基、(C3-C6)环烷基、羟基、哌嗪基、(C6-C10)芳基(C1-C6)烷氧基、(C5-C9)杂芳基(C1-C6)烷氧基、(C1-C6)酰氨基、(C1-C6)酰硫基、(C1-C6)酰氧基、(C1-C6)烷基亚磺酰基、(C6-C10)芳基亚磺酰基、(C1-C6)烷基磺酰基、(C6-C10)芳基磺酰基、氨基、(C1-C6)烷基氨基或((C1-C6)烷基氨基)2;(C2-C6)链烯基、(C6-C10)芳基(C2-C6)链烯基、(C5-C9)杂芳基(C2-C6)链烯基、(C2-C6)链炔基、(C6-C10)芳基(C2-C6)链炔基、(C5-C9)杂芳基(C2-C6)链炔基、(C1-C6)烷基氨基、(C1-C6)烷硫基、(C1-C6)烷氧基、全氟(C1-C6)烷基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳氨基、(C6-C10)芳硫基、(C6-C10)芳氧基、(C5-C9)杂芳基氨基、(C5-C9)杂芳硫基、(C5-C9)杂芳氧基、(C3-C6)环烷基、(C1-C6)烷基(羟基亚甲基)、哌啶基、(C1-C6)烷基哌啶基、(C1-C6)酰氨基、(C1-C6)酰硫基、(C1-C6)酰氧基、R10(C1-C6)烷基,其中R10是(C1-C6)酰基哌嗪子基、(C6-C10)芳基哌嗪子基、(C5-C9)杂芳基哌嗪子基、(C1-C6)烷基哌嗪子基、(C6-C10)芳基(C1-C6)烷基哌嗪子基、(C5-C9)杂芳基(C1-C6)烷基哌嗪子基、吗啉代基、硫代吗啉代基、吡咯烷子基、哌啶基、(C1-C6)烷基哌啶基、(C6-C10)芳基哌啶基、(C5-C9)杂芳基哌啶基、(C1-C6)烷基哌啶基(C1-C6)烷基、(C6-C10)芳基哌啶基(C1-C6)烷基、(C5-C9)杂芳基哌啶基(C1-C6)烷基或(C1-C6)酰基哌啶基;
y是0或1;
W是氧或NR24,其中R24是氢或(C1-C6)烷基;
Z是-OR11或-NR24R11,其中R24如上所定义,R11如下所定义;氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氢吲哚基、异二氢吲哚基、四氢喹啉基、四氢异喹啉基或桥接的二氮杂二环烷基,所述桥接的二氮杂二环烷基选自:
其中r是1、2或3;
m是1或2;
p是0或1;
其中,各杂环基团可以选择性地被一个或两个取代基选择性地取代,所述取代基选自羟基、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C10)酰基、(C1-C10)酰氧基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C5-C9)杂芳基(C1-C6)烷基、羟基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)酰氧基(C1-C6)烷基、(C1-C6)烷硫基、(C1-C6)烷硫基(C1-C6)烷基、(C6-C10)芳硫基、(C6-C10)芳硫基(C1-C6)烷基、R12R13N-、R12R13NSO2-、R12R13NC=O-、R12R13NCO(C1-C6)烷基,其中R12和R13彼此独立地是氢、(C1-C6)烷基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基或(C5-C9)杂芳基(C1-C6)烷基,或者R12和R13可以同它们所连接的氮合在一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基或硫代吗啉基环;R14SO2-、R14SO2NH,其中R14是三氟甲基、(C1-C6)烷基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基或(C5-C9)杂芳基(C1-C6)烷基;R15CONR12,其中R12如上所定义并且R15是氢、(C1-C6)烷基、(C1-C6)烷氧基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基或(C5-C9)杂芳基(C1-C6)烷基;R16OOC、R16OOC(C1-C6)烷基,其中R16是(C1-C6)烷基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、5-二氢化茚基、CHR17OCOR18,其中R17是氢或(C1-C6)烷基并且R18是(C1-C6)烷基、(C1-C6)烷氧基或(C6-C10)芳基;CH2CONR19R20,其中R19和R20彼此独立地是氢或(C1-C6)烷基,或者可以同它们所连接的氮合在一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基或硫代吗啉基环;或R21O(C1-C6)烷基,其中R21是H2N(CHR22)CO并且其中的R22是天然D-或L-氨基酸的侧链;
R11是氢、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C5-C9)杂芳基(C1-C6)烷基、(C1-C6)烷基(C6-C10)芳基(C1-C6)烷基、(C1-C6)烷基(C5-C9)杂芳基(C1-C6)烷基、5-二氢化茚基、CHR17OCOR18或CH2CONR19R20,其中R17、R18、R19和R20如上所定义;
或者,R1和R2、或R3和R4、或R5和R6可以合在一起形成羰基;
或者,R1和R2、或R3和R4、或R5和R6、或R7和R8可以合在一起形成(C3-C6)环烷基、氧杂环己基、硫杂环己基、二氢化茚基或四氢萘基环或下式的基团:
其中R23是氢、(C1-C6)酰基、(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷基、(C5-C9)杂芳基(C1-C6)烷基或(C1-C6)烷基磺酰基;
Q是被氟、氯、(C1-C6)烷基、(C1-C6)烷氧基或全氟(C1-C3)烷基选择性取代的(C1-C10)烷基、(C6-C10)芳基、(C6-C10)芳氧基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基、(C6-C10)芳氧基(C5-C9)杂芳基、(C5-C9)杂芳基、(C1-C6)烷基(C6-C10)芳基、(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基、(C5-C9)杂芳氧基(C6-C10)芳基、(C1-C6)烷基(C5-C9)杂芳基、(C1-C6)烷氧基(C5-C9)杂芳基、(C6-C10)芳基(C1-C6)烷氧基(C5-C9)杂芳基、(C5-C9)杂芳氧基(C5-C9)杂芳基、(C6-C10)芳氧基(C1-C6)烷基、(C5-C9)杂芳氧基(C1-C6)烷基、(C1-C6)烷基(C6-C10)芳氧基(C6-C10)芳基、(C1-C6)烷基(C5-C9)杂芳氧基(C6-C10)芳基,(C1-C6)烷基(C6-C10)芳氧基(C5-C9)杂芳基,(C1-C6)烷氧基(C6-C10)芳氧基(C6-C10)芳基、(C1-C6)烷氧基(C5-C9)杂芳氧基(C6-C10)芳基或(C1-C6)烷氧基(C6-C10)芳氧基(C5-C9)杂芳基;
条件是,当Z是所定义的氮杂环丁基、吡咯烷基、吗啉基、硫代吗啉基、二氢吲哚基、异二氢吲哚基、四氢喹啉基、四氢异喹啉基、哌嗪基、(C1-C10)酰基哌嗪基、(C1-C6)烷基哌嗪基、(C6-C10)芳基哌嗪基、(C5-C9)杂芳基哌嗪基或桥接的二氮杂二环烷基时,Z必需是取代的;
条件是,只有当R8不是氢时,R7才不是氢;
条件是,只有当R5不是氢时,R6才不是氢;
条件是,只有当R4不是氢时,R3才不是氢;
条件是,只有当R1不是氢时,R2才不是氢;
条件是,当R1、R2和R9是含有杂原子的取代基时,杂原子不能直接连接在环的2位或6位上;
条件是,当X是氮时,R4不存在;
条件是,当X是氧、硫、SO、SO2或氮并且当R1、R2、R5和R6中的一个或多个基团是含有杂原子的取代基时,杂原子不能直接连接在4位或6位上;
条件是,当Y是氧、硫、SO、SO2或氮并且当R3、R4、R7和R8中的一个或多个基团彼此独立地是含有杂原子的取代基时,杂原子不能直接连接在3位或5位上;
条件是,当X是氧、硫、SO或SO2时,R3和R4不存在;
条件是,当y是1并且W是NR24或氧时,Z不能是羟基;
条件是,当Y是氧、硫、SO或SO2时,R5和R6不存在;
条件是,当Y是氮时,R6不存在;
条件是,当虚线表示双键时,R4和R6不存在;
条件是,当R3和R5彼此独立地是含有杂原子的取代基并且当虚线表示双键时,杂原子不能直接连接在位置X和Y上;
条件是,当X或Y的位置上是氧、硫、SO、SO2或氮时,X或Y中的另一个是碳;
条件是,当X或Y是杂原子时,虚线不表示双键;
条件是R1、R2、R3、R4、R5、R6、R7、R8和R9中至少有一个必需是式II所定义的基团。
若无另外说明,本文所用的术语“烷基”包括含有直链、支链或环状部分或其组合形成的饱和一价烃基。
本文所用的术语“烷氧基”包括O-烷基,其中的烷基如上所定义。
若无另外说明,本文所用的术语“芳基”包括从芳烃上除去一个氢后所形成的有机基团,例如苯基或萘基,这些基团可以选择性地被1-3个彼此独立地选自氟、氯、氰基、硝基、三氟甲基、(C1-C6)烷氧基、(C6-C10)芳氧基、三氟甲氧基、二氟甲氧基和(C1-C6)烷基的取代基所取代。
若无另外说明,本文所用的术语“杂芳基”包括从芳香杂环化合物上除去一个氢后所形成的有机基团,例如吡啶基、呋喃基、吡咯基、噻吩基、异噻唑基、咪唑基、苯并咪唑基、四唑基、吡嗪基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吡唑基、吲哚基、异吲哚基、嘌呤基、咔唑基、异噁唑基、噻唑基、噁唑基、苯并噻唑基或苯并噁唑基,这些基团可以选择性地被1或2个彼此独立地选自氟、氯、三氟甲基、(C1-C6)烷氧基、(C6-C10)芳氧基、三氟甲氧基、二氟甲氧基和(C1-C6)烷基的取代基所取代。
若无另外说明,本文所用的术语“酰基”包括通式RCO的基团,其中R是烷基、烷氧基(例如甲氧羰基)、芳基、芳烷基或芳基烷氧基,术语“烷基”或“芳基”如上所定义。
本文所用术语“酰氧基”包括O-酰基,其中的酰基如上所定义。
若无另外说明,本文所用的术语“D-或L-氨基酸”包括甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、色氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、羟脯氨酸、半胱氨酸、胱氨酸、甲硫氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸或组氨酸。
优选的式I化合物的构象包括异羟肟酸轴向位于2-位上。
式I化合物可以含有手性中心,因此可以以不同的对映体形式存在。本发明涉及式I化合物的所有光学异构体和立体异构体及其混合物。
优选的式I化合物包括其中Y是碳的化合物。
其它优选的式I化合物包括其中Q是(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基或(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基的化合物,其中的各末端芳基可选择性地被氟取代。
其它优选的式I化合物包括其中R2、R3、R6、R7和R9是氢的化合物。
更优选的式I化合物包括其中Y是碳;Q是(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基或(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基的化合物。
特别优选的式I化合物包括:
(2R,4R)-1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸;
(2R,4R)-1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸甲酯;
(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸;
(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸甲酯;
(2R,3S)-{1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-3-基}-氨基甲酸异丙酯;
3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基硫代吗啉-3-甲酸羟基酰胺;
3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基硫代吗啉-3-甲酸羟基酰胺;
(2R,4S)-1-[4-(4-氟苄氧基)-苯磺酰基]-4-羟基-哌啶-2-甲酸羟基酰胺;和
(2R,4R)-1-(4-甲氧基苯磺酰基)-4-(哌嗪-1-羰基)-哌啶-2-甲酸羟基酰胺盐酸盐。
其它本发明的化合物包括:
(3S)-4-[4-(2-氯-噻唑-5-基甲氧基)苯磺酰基]-2,2-二甲基硫代吗啉-3-甲酸羟基酰胺;
(3S)-2,2-二甲基-4-[4-(噻唑-5-基甲氧基)苯磺酰基]-硫代吗啉-3-甲酸羟基酰胺;
(3S)-2,2-二甲基-4-[4-(吡啶-4-基甲氧基)苯磺酰基]-硫代吗啉-3-甲酸羟基酰胺;
(3S)-4-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-2,2-二甲基硫代吗啉-3-甲酸羟基酰胺;
(3S)-2,2-二甲基-4-[4-(2-吡啶-4-基-乙氧基)苯磺酰基]-硫代吗啉-3-甲酸羟基酰胺;
(3S)-4-[4-(苯并噻唑-2-基甲氧基)苯磺酰基]-2,2-二甲基硫代吗啉-3-甲酸羟基酰胺;
(3S)-2,2-二甲基-4-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)苯磺酰基]-硫代吗啉-3-甲酸羟基酰胺;
(3S)-2,2-二甲基-4-[4-(1H-四唑-5-基甲氧基)苯磺酰基]-硫代吗啉-3-甲酸羟基酰胺;
(2R,3S)-{1-[4-(2-氯-噻唑-5-基甲氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-{2-羟基氨基甲酰基-1-[4-(噻唑-5-基甲氧基)-苯磺酰基]-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-{2-羟基氨基甲酰基-1-[4-(吡啶-4-基甲氧基)-苯磺酰基]-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-{1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-(1-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-2-羟基氨基甲酰基-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-{2-羟基氨基甲酰基-1-[4-(2-吡啶-4-基乙氧基)-苯磺酰基]-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-{1-[4-(苯并噻唑-2-基甲氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-{2-羟基氨基甲酰基-1-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)-苯磺酰基]-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-{2-羟基氨基甲酰基-1-[4-(1H-四唑-5-基甲氧基)-苯磺酰基]-哌啶-3-基}-氨基甲酸甲酯;
(2R,3S)-1-[4-(2-氯-噻唑-5-基甲氧基)-苯磺酰基]-3-羟基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-1-[4-(噻唑-5-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-1-[4-(吡啶-4-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-[4-(4-氟苄氧基)-苯磺酰基]-3-羟基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-3-羟基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-1-[4-(2-吡啶-4-基-乙氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-[4-(苯并噻唑-2-基甲氧基)-苯磺酰基]-3-羟基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-1-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-1-[4-(1H-四唑-5-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-[4-(2-氯-噻唑-5-基甲氧基)-苯磺酰基]-3-羟基-3-甲基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-3-甲基-1-[4-(噻唑-5-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-3-甲基-1-[4-(吡啶-4-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-[4-(4-氟苄氧基)-苯磺酰基]-3-羟基-3-甲基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-3-羟基-3-甲基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-3-甲基-1-[4-(2-吡啶-4-基乙氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-[4-(苯并噻唑-2-基甲氧基)-苯磺酰基]-3-羟基-3-甲基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-3-甲基-1-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,3S)-3-羟基-3-甲基-1-[4-(1H-四唑-5-基甲氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(3R)-4-[4-(2-氯-噻唑-5-基甲氧基)苯磺酰基]-2,2-二甲基吗啉-3-甲酸羟基酰胺;
(3R)-2,2-二甲基-4-[4-(噻唑-5-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-2,2-二甲基-4-[4-(吡啶-4-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-4-[4-(4-氟苄氧基)-苯磺酰基]-2,2-二甲基吗啉-3-甲酸羟基酰胺;
(3R)-4-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-2,2-二甲基吗啉-3-甲酸羟基酰胺;
(3R)-2,2-二甲基-4-[4-(2-吡啶-4-基-乙氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-4-[4-(苯并噻唑-2-基甲氧基)苯磺酰基]-2,2-二甲基吗啉-3-甲酸羟基酰胺;
(3R)-2,2-二甲基-4-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-2,2-二甲基-4-[4-(1H-四唑-5-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(2R,4R)-1-[4-(2-氯-噻唑-5-基甲氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸;
(2R,4R)-2-羟基氨基甲酰基-1-[4-(噻唑-5-基甲氧基)-苯磺酰基]-哌啶-4-甲酸;
(2R,4R)-2-羟基氨基甲酰基-1-[4-(吡啶-4-基甲氧基)-苯磺酰基]-哌啶-4-甲酸;
(2R,4R)-1-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-2-羟基氨基甲酰基-哌啶-4-甲酸;
(2R,4R)-2-羟基氨基甲酰基-1-[4-(2-吡啶-4-基-乙氧基)-苯磺酰基]-哌啶-4-甲酸;
(2R,4R)-1-[4-(苯并噻唑-2-基甲氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸;
(2R,4R)-2-羟基氨基甲酰基-1-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)-苯磺酰基]-哌啶-4-甲酸;
(2R,4R)-2-羟基氨基甲酰基-1-[4-(1H-四唑-5-基甲氧基)-苯磺酰基]-哌啶-4-甲酸;
(3R)-4-[4-(2-氯-噻唑-5-基甲氧基)苯磺酰基]-3-甲基-吗啉-3-甲酸羟基酰胺;
(3R)-3-甲基-4-[4-(噻唑-5-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-3-甲基-4-[4-(吡啶-4-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-4-[4-(4-氟苄氧基)-苯磺酰基]-3-甲基-吗啉-3-甲酸羟基酰胺;
(3R)-4-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-3-甲基-吗啉-3-甲酸羟基酰胺;
(3R)-3-甲基-4-[4-(2-吡啶-4-基-乙氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-4-[4-(苯并噻唑-2-基甲氧基)苯磺酰基]-3-甲基-吗啉-3-甲酸羟基酰胺;
(3R)-3-甲基-4-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(3R)-3-甲基-4-[4-(1H-四唑-5-基甲氧基)苯磺酰基]-吗啉-3-甲酸羟基酰胺;
(2R)-1-[4-(2-氯-噻唑-5-基甲氧基)苯磺酰基]-2-甲基-3-氧代-哌啶-2-甲酸羟基酰胺;
(2R)-2-甲基-3-氧代-1-[4-(噻唑-5-基甲氧基)苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R)-2-甲基-3-氧代-1-[4-(吡啶-4-基甲氧基)苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R)-1-[4-(4-氟苄氧基)-苯磺酰基]-2-甲基-3-氧代-哌啶-2-甲酸羟基酰胺;
(2R)-1-{4-[2-(4-氟苯基)-乙氧基]苯磺酰基}-2-甲基-3-氧代-哌啶-2-甲酸羟基酰胺;
(2R)-2-甲基-3-氧代-1-[4-(2-吡啶-4-基-乙氧基)苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R)-1-[4-(苯并噻唑-2-基甲氧基)苯磺酰基]-2-甲基-3-氧代-哌啶-2-甲酸羟基酰胺;
(2R)-2-甲基-3-氧代-1-[4-(5-三氟甲基-苯并噻唑-2-基甲氧基)苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R)-2-甲基-3-氧代-1-[4-(1H-四唑-5-基甲氧基)苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R,4S)-1-(4-苄氧基-苯磺酰基)-4-丁氨基甲基-4-羟基-哌啶-2-甲酸羟基酰胺;
(2R,4S)-4-丁氨基甲基-1-[4-(4-氟苄氧基)-苯磺酰基]-4-羟基-哌啶-2-甲酸羟基酰胺;
(2R,4S)-4-苄氨基-1-(4-苄氧基-苯磺酰基)-哌啶-2-甲酸羟基酰胺;
(2R,4S)-4-苄氨基-1-[4-(4-氟苄氧基)-苯磺酰基]-哌啶-2-甲酸羟基酰胺;
(2R)-1-[4-(4-氟苄氧基)-苯磺酰基]-4-氧代-哌啶-2-甲酸羟基酰胺;
(2R,4R)-1-(4-苄氧基-苯磺酰基)-4-羟基-哌啶-2-甲酸羟基酰胺;
(2R,4R)-1-[4-(4-氟苄氧基)-苯磺酰基]-4-羟基-哌啶-2-甲酸羟基酰胺;
(2R)-1-[4-(4-氟苄氧基)-苯磺酰基]-4-甲基-哌啶-2-甲酸羟基酰胺;
(2R,5S)-1-[4-(4-氟苄氧基)-苯磺酰基]-5-羟基-哌啶-2-甲酸羟基酰胺;
(2R,5S)-1-(4-苄氧基-苯磺酰基)-5-羟基-哌啶-2-甲酸羟基酰胺;
(2R,5R)-1-(4-苄氧基-苯磺酰基)-5-羟基-哌啶-2-甲酸羟基酰胺;
(2R,5R)-1-[4-(4-氟苄氧基)-苯磺酰基]-5-羟基-哌啶-2-甲酸羟基酰胺;
(2R,3S)-1-(4-苄氧基-苯磺酰基)-3-羟基-哌啶-2-甲酸羟基酰胺;
(2R,4S)-1-(4-苄氧基-苯磺酰基)-4-羟基-哌啶-2-甲酸羟基酰胺;
(2R,4S)-1-[4-(4-氟苄氧基)-苯磺酰基]-4-羟基-哌啶-2-甲酸羟基酰胺;
1-(4-丁氧基-苯磺酰基)-3-(吗啉-4-羰基)-哌啶-2-甲酸羟基酰胺;
1-[4-(4-氟苄氧基)-苯磺酰基]-3-(吗啉-4-羰基)-哌啶-2-甲酸羟基酰胺;
1-[3-(4-氟-苄氧基)-丙烷-1-磺酰基]-3-(吗啉-4-羰基)-哌啶-2-甲酸羟基酰胺;
1-(4-丁氧基-苯磺酰基)-3-(吡咯烷-1-羰基)-哌啶-2-甲酸羟基酰胺;
1-[4-(4-氟苄氧基)-苯磺酰基]-3-(吡咯烷-1-羰基)-哌啶-2-甲酸羟基酰胺;
1-[3-(4-氟-苄氧基)-丙烷-1-磺酰基]-3-(吡咯烷-1-羰基)-哌啶-2-甲酸羟基酰胺;和
1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸。
本发明还涉及药物组合物,该药物组合物用于在哺乳动物、包括人中(a)治疗关节炎、和细胞毒性抗癌剂协同来治疗癌症、和常规的NSAID和镇痛剂联合来治疗组织溃疡、黄斑变性、再狭窄、牙周疾病、大疱性表皮松解、巩膜炎,以及治疗特征在于基质金属蛋白酶活性的其它疾病、AIDS、脓毒症、脓毒性休克和涉及肿瘤坏死因子(TNF)产生的其它疾病或(b)抑制基质金属蛋白酶或肿瘤坏死因子(TNF)的产生,所述药物组合物含有治疗有效量的式I化合物或其可药用盐以及可药用载体。
本发明还涉及在哺乳动物、包括人中抑制(a)基质金属蛋白酶或(b)肿瘤坏死因子(TNF)产生的方法,该方法包括向所述哺乳动物施用有效量的式I化合物或其可药用盐。
本发明还涉及在哺乳动物、包括人中治疗选自关节炎、癌症、组织溃疡、黄斑变性、再狭窄、牙周疾病、大疱性表皮松解、巩膜炎的一组疾病的方法,治疗上述疾病时可将式I化合物和常规的NSAID和镇痛剂联合以及和细胞毒性抗癌剂联合,以及治疗特征在于基质金属蛋白酶活性的其它疾病、AIDS、脓毒症、脓毒性休克和涉及肿瘤坏死因子(TNF)产生的其它疾病的方法,该方法包括向所述哺乳动物施用治疗所述疾病有效量的式I化合物或其可药用盐。
反应方案3
反应方案4
制备例1描述了式VI中间体的制备。按照反应方案1的方法将式VI化合物转变成式I化合物。式XVI的原料可以按照本领域普通技术人员熟知的方法制备。
在制备例1的反应1中,将式XVI化合物通过如下步骤转变成相应的式VI的羟基酯化合物:将XVI首先与芳基磺酰基卤化物在三乙胺和非质子溶剂如二氯甲烷、四氢呋喃或二氧六环的存在下,在约20℃至约30℃、优选室温下反应。将形成的化合物进一步与下式的化合物反应:其中R25是苄氧羰基、(C1-C6)烷基、苄基、烯丙基或叔丁基,反应在六甲基二硅氮烷钠和四氢呋喃-二甲基甲酰胺溶剂混合物的存在下在约-20℃至约20℃、优选约0℃的温度下进行,生成式VI的羟基酯化合物。
制备例2描述的是另一种制备式VI化合物的方法。式XVIII的原料可以按照本领域普通技术人员熟知的方法制备。在制备例2的反应1中,将式XVIII的胺化合物(其中的R25如上所定义)通过如下步骤转变成相应的式XVII的芳基磺酰基胺化合物:(1)将XVIII与芳基磺酰基卤化物在三乙胺和非质子溶剂如二氯甲烷、四氢呋喃或二氧六环的存在下,在约20℃至约30℃、优选室温下反应,(2)将形成的化合物与下式的化合物反应:反应在六甲基硅氮烷钠和四氢呋喃-二甲基甲酰胺溶剂混合物的存在下在约-20℃至约20℃、优选约0℃的温度下进行,然后(3)将形成的化合物与臭氧在二氯甲烷-甲醇溶液中于约-90℃至约-70℃、优选约-78℃的温度下反应。然后将形成的不稳定的臭氧化物与三苯膦反应生成式XVII的芳基磺酰基胺化合物。在制备例2的反应2中,通过将式XVII的芳基磺酰基胺化合物与下式化合物反应:其中W是锂、镁、铜或铬,将XVII转变成相应的式VI的羟基酯化合物。
反应方案1描述的是式II化合物的制备,该化合物是其中X和Y是碳;R4、R6和R7是氢并且X和Y之间的虚线不存在的式I化合物。在反应方案1的反应1中,将其中的R25保护基是苄氧羰基、(C1-C6)烷基、苄基、烯丙基或叔丁基的式VI化合物通过内酯化作用并随后进行Claisen重排将其转变成相应的式V的吗啉酮化合物。通过从式VI化合物中除去R25保护基促进反应,该反应在适于所用的具体R25保护基的条件下进行。所述条件包括:(a)如果R25是苄氧羰基,用氢和氢化催化剂如10%钯炭处理,(b)如果R25是低级烷基,进行皂化,(c)如果R25是苄基,氢解,(d)如果R25是叔丁基,用强酸如三氟乙酸或盐酸处理,或者(e)如果R25是烯丙基,用氢化三丁基锡和乙酸在催化剂二(三苯膦)氯化钯(II)的存在下处理。
在反应方案1的反应2中,将式V的吗啉酮化合物通过如下反应转变成式IV的羧酸化合物:将V与六甲基硅氮烷锂在非质子溶剂如四氢呋喃中,在约-90℃至约-70℃、优选-78℃的温度下反应。然后向反应混合物中加入三甲基硅烷氯,真空蒸除溶剂四氢呋喃并用甲苯代替。将得到的反应混合物加热至约100℃至约120℃、优选约110℃,然后用盐酸处理形成式IV的羧酸。
在反应方案1的反应3中,将式IV的羧酸化合物通过如下反应转变成相应的式III的异羟肟酸化合物:将IV用1-(3-二甲氨基丙基)-3-乙基碳二亚胺和1-羟基苯并***在极性溶剂如二甲基甲酰胺中处理,约15分钟至约1小时、优选约30分钟后,向反应混合物中加入羟胺。优选在碱如N-甲基吗啉的存在下从盐的形式如盐酸羟胺就地形成羟胺。或者,可在(苯并***-1-基氧)三(二甲氨基)鏻六氟磷酸盐和碱如N-甲基吗啉的存在下使用保护了的羟胺衍生物或其盐形式,其中的羟基以叔丁基、苄基或烯丙基醚的形式被保护。羟胺保护基的脱除可以通过如下方法来完成:对于苄基保护基,通过氢解;对于叔丁基保护基,用强酸如三氟乙酸处理。烯丙基保护基可以通过用氢化三丁基锡和乙酸在催化剂二(三苯膦)氯化钯(II)的存在下处理来除去。还可使用N,O-二(4-甲氧基苄基)羟胺作为保护的羟胺衍生物,其中,用甲磺酸和三氟乙酸的混合物完成脱保护。
在反应方案1的反应4中,如需要,将式III的异羟肟酸化合物通过如下反应转变成相应的式II的哌啶化合物:将III用氢和氢化催化剂如10%钯炭处理。
反应方案2描述的是式VII化合物的制备,该化合物是其中Y是氮;X是碳;R1、R2、R3、R4、R7和R8是氢;R6不存在的式I化合物。式IX的原料可以按照本领域普通技术人员熟知的方法制备。在反应方案2的反应1中,将其中R26是苄氧羰基、苄基或叔丁氧羰基的式IX的芳基磺酰基哌嗪化合物通过如下反应转变成式VIII的化合物:将IX与下式保护了的羟胺衍生物反应
R27ONH2·HCl其中R27是叔丁基、苄基或烯丙基,该反应在二环己基碳二亚胺、二甲氨基吡啶和非质子溶剂如二氯甲烷的存在下进行。对R26保护基的选择是可以在R27保护基的存在下被选择性地除去而不会影响R27保护基,因此,R26不能与R27相同。从式IX化合物除去R26保护基的反应在适于所用的具体R26保护基的条件下进行。所述条件包括:(a)如果R26是苄氧羰基,用氢和氢化催化剂如10%钯炭处理,(b)如果R26是苄基,氢解,或者(c)如果R26是叔丁氧羰基,用强酸如三氟乙酸或盐酸处理。
在反应方案2的反应2中,将式VIII化合物转变成相应的式VII的异羟肟酸化合物,其中R5是氢或(C1-C6)烷基,当R5是(C1-C6)烷基时,可将VIII与烷基卤化物反应。随后可以通过如下方法来脱除R27羟胺保护基:对于苄基保护基,通过氢解;对于叔丁基保护基,用强酸如三氟乙酸处理。烯丙基保护基可以通过用氢化三丁基锡和乙酸在催化剂二(三苯膦)氯化钯(II)的存在下处理来除去。
反应方案3描述的是式X化合物的制备,该化合物是其中Y是氮;X是碳;R2、R7、R8和R9是氢;R3和R4合在一起是羰基;R5是氢;R6不存在的式I化合物。在反应方案3的反应1中,将其中R25如上所定义的式XII的芳基磺酰基胺化合物通过与碳二亚胺和碱如三乙胺反应转变成相应的式XI的哌嗪化合物。将式XI化合物按照以上反应方案1反应3中描述的方法进一步反应生成式X的异羟肟酸化合物。
反应方案4描述的是式XIII化合物的制备。式XVIII的原料可以根据本领域普通技术人员熟知的方法制备。式XIII化合物是其中X是碳并且X和Y之间的虚线不存在的式I化合物。在反应方案4的反应1中,脱除R28保护基并随后还原胺化式XXII的化合物(其中Y是氧、硫或碳)生成相应的式XXI的亚胺化合物,该反应在适于所用的具体R28保护基的条件下进行。所述条件包括以上反应方案2的反应1中脱除R26保护基所用的条件。
在反应方案4的反应2中,将式XXI的亚胺化合物通过与式R2M(其中M是锂、卤化镁或卤化铈)的亲核试剂反应将其转变成相应的式XX的哌啶化合物。该反应在醚溶剂、例如***或四氢呋喃中于约-78℃至约0℃、优选约-70℃下进行。
在反应方案4的反应3中,将式XX的哌啶化合物磺酰化得到相应的式XIX的芳基磺酰基哌啶化合物,该反应通过将XX与芳基磺酰基卤化物在三乙胺和非质子溶剂如二氯甲烷、四氢呋喃或二氧六环的存在下,在约20℃至约30℃、优选室温下反应来完成。
在反应方案4的反应4中,将式XIX的芳基磺酰基哌啶化合物按照以上反应方案1的反应3中描述的方法转变成式XIII的异羟肟酸化合物。
反应方案5描述的是式XIV化合物的制备,该化合物是其中Y是氮;X是碳;X和Y之间的虚线不存在;R5是氢;R6不存在的式I化合物。在反应方案5的反应1中,将式XXVI化合物(其中R29和R31保护基彼此独立地选自苄氧羰基、苄基和叔丁氧羰基,R30是苄氧羰基、(C1-C6)烷基、苄基、烯丙基或叔丁基)通过脱除R29保护基并随后还原胺化式XXVI化合物将XXVI转变成相应的式XXV的的亚胺化合物。对R29保护基的选择是可以在R31保护基的存在下被选择性地除去而不会影响R31保护基。从式XXVI化合物中除去R29保护基在适于所用的具体R29保护基而不会影响R31保护基的条件下进行。所述条件包括:(a)如果R29是苄氧羰基而R31是叔丁基,用氢和氢化催化剂如10%钯炭处理,(b)如果R29是(C1-C6)烷基而R31是叔丁基,进行皂化,(c)如果R29是苄基而R31是(C1-C6)烷基或叔丁基,氢解,(d)如果R29是叔丁基而R31是(C1-C6)烷基、苄基或烯丙基,用强酸如三氟乙酸或盐酸处理,或者(e)如果R29是烯丙基而R31是(C1-C6)烷基、苄基或叔丁基,用氢化三丁基锡和乙酸在催化剂二(三苯膦)氯化钯(II)的存在下处理。对R30保护基的选择是,该保护基可以与R29保护基在同一反应步骤中被除去。
在反应方案5的反应2中,将式XXV的亚胺化合物通过与式R2M(其中M是锂、卤化镁或卤化钙)的亲核试剂反应将其转变成相应的式XXIV的化合物。该反应在醚溶剂、例如***或四氢呋喃中于约-78℃至约0℃、优选约-70℃下进行。
在反应方案5的反应3中,将式XXIV的哌啶化合物磺酰化得到相应的式XXIII的芳基磺酰基哌啶化合物,该反应按照以上反应方案4的反应3中的描述进行。
在反应方案5的反应4中,将式XXIII的芳基磺酰基哌啶化合物通过如下反应转变成式XIV的异羟肟酸化合物:(1)如需要,从XXIII上脱除R30和R31保护基,然后(2)将XXIII按照以上反应方案1的反应3中描述的方法进行反应。从式XXIII化合物上脱除R30和R31保护基在适于所用的具体R30和R31保护基的条件下进行。所述条件包括以上在反应方案1的反应1中脱除R25保护基所用的条件。
本发明酸性化合物的可药用盐是与碱形成的盐,即阳离子盐如碱金属和碱土金属盐如钠盐、锂盐、钾盐、钙盐、镁盐,以及铵盐,例如铵盐、三甲铵盐、二乙铵盐和三(羟甲基)甲铵盐。
同样,如果在结构中存在碱性基团如吡啶基,则还可以形成酸加成盐,例如无机酸、有机羧酸和有机磺酸盐,例如盐酸盐、甲磺酸盐、马来酸盐。
通过如下体外分析试验证实式I化合物或其可药用盐(本发明的化合物)抑制基质金属蛋白酶或肿瘤坏死因子(TNF)产生的能力及其在治疗特征在于基质金属蛋白酶或肿瘤坏死因产生的疾病中的有效性。生物学分析 人胶原酶(MMP-1)的抑制作用
将人重组胶原酶用胰蛋白酶以如下比例激活:10μg胰蛋白酶/100μg胶原酶。将胰蛋白酶和胶原酶室温保温10分钟,然后加入5倍过量(50μg/10μg)的大豆胰蛋白酶抑制剂。
在二甲亚砜中制备10mM抑制剂的储备液,然后用以下方案进行稀释:10mM→120μM→12μM→1.2μM→0.12.0μM
然后将25μl各浓度的稀释液一式三份加入到96孔微滴定板的适宜的孔中。加入酶和底物后,抑制剂的最终浓度将会稀释4倍。在D1-D6孔设置阳性对照(酶,无抑制剂),在D7-D12孔设置空白(无酶,无抑制剂)。
将胶原酶稀释至400ng/ml,然后取25μl加入到微滴定板的适宜的孔中。分析中胶原酶的最终浓度为100ng/ml。
在二甲亚砜中制备底物(DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)的5mM储备液,然后在分析缓冲液中稀释至20μM。通过向微滴定板的各孔中加入50μl底物开始分析,底物的最终浓度为10μM。
在时间0点读取荧光读数(360nm激发光,460nm发射光),然后以20分钟的间隔读取。试验在室温下进行,一般的分析时间为3小时。
然后对空白和含胶原酶的样品(将三次平行测定的数据平均)绘制荧光-时间曲线。选择可以产生良好信号(空白)的时间点和位于曲线的线性部分上的时间点(通常在120分钟左右)来测定IC50值。用时间零点作为各化合物各浓度下的空白并从120分钟的数据中减去这些值。将数据以抑制剂浓度-%对照(抑制剂荧光除以仅含胶原酶的荧光×100)绘制曲线。从所产生的信号为对照的50%的抑制剂浓度确定出IC50值。
如果报道的IC50值<0.03μM,则以0.3μM、0.03μM、0.03μM和0.003μM的浓度对抑制剂进行分析。明胶酶(MMP-2)的抑制作用
用DnP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2底物(10μM)在与抑制人胶原酶(MMP-1)相同的条件下分析对明胶酶活性的抑制作用。
将72kD的明胶酶用lmM APMA(对氨基苯基乙酸汞)在4℃活化15小时,然后稀释以便在分析中得到100mg/ml的最终浓度。按照与抑制人胶原酶(MMP-1)类似的方法稀释抑制剂以便在分析中得到30μM、3μM、0.3μM和0.03μM的最终浓度。每种浓度均一式三份地进行。
在时间0点读取荧光读数(360nm激发光,460nm发射光),然后以20分钟的间隔读取4小时。
按照与抑制人胶原酶(MMP-1)类似的方法测定IC50值。如果报道的IC50值<0.03μM,则以0.3μM、0.03μM、0.003μM和0.003μM的最终浓度对抑制剂进行分析。溶基质素(MMP-3)的抑制作用
对溶基质素活性的抑制作用是基于Weingarten和Feder所描述的改进的分光光度分析(Weingarten,H.和Feder,J.,脊椎动物胶原酶的分光光度分析,分析生物化学(Anal.Biochem.)147,437-440(1985))。硫代类胨底物[Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5]的水解产生硫醇片段,在Ellman’s试剂的存在下可对该片段进行监测。
将人重组溶基质素原(prostromelysin)用胰蛋白酶以1μl10mg/ml胰蛋白酶储备液/26μg溶基质素的比例激活。将胰蛋白酶和溶基质素于37℃保温15分钟,然后与10μl 10mg/ml的大豆胰蛋白酶抑制剂一起于37℃保温10分钟以淬灭胰蛋白酶活性。
分析在总体积为250μl的分析缓冲液(200mM氯化钠、50mM MES和10mM氯化钙,pH6.0)中于96孔微滴定板上进行。将激活的溶基质素在分析缓冲液中稀释至25μg/ml。在二甲基甲酰胺中制备Ellman’s试剂(3-羧基-4-硝基苯基二硫化物)的1M储备液并用分析缓冲液稀释至5mM,每孔加50μl得到1mM的最终浓度。
在二甲亚砜中制备10mM抑制剂的储备液并在分析缓冲液中进行系列稀释,从而在向适宜的孔中加入50μl后可以产生3μM、0.3μM、0.003μM和0.0003μM的最终浓度。所有条件均一式三份地进行。
将300mM肽底物的二甲亚砜储备液在分析缓冲液中稀释至15mM,然后向各孔中加入50μl开始分析,底物的最终浓度为3mM。空白由肽底物和Ellman’s试剂组成,不含酶。用Molecular DevicesUVmax平板读数器于405nm监测产物的形成。
按照与胶原酶相同的方式测定IC50值。MMP-13的抑制作用
将人重组MMP-13用2mM APMA(对氨基苯基乙酸汞)在37℃活化1.5小时,然后在分析缓冲液(50mM Tris,pH 7.5,200mM氯化钠、5mM氯化钙、20μM氯化锌、0.02%Brij)中稀释至400mg/ml。将25μl稀释的酶加入到96孔微滴定板的各孔中。然后通过加入抑制剂和底物使酶稀释4倍,达到100mg/ml的最终浓度。
在二甲亚砜中制备10mM抑制剂的储备液,然后按照抑制人胶原酶(MMP-1)的抑制剂稀释方案在分析缓冲液中进行稀释。将25μl各浓度的稀释液一式三份加入微滴定板中。在分析中的最终浓度为30μM、3μM、0.3μM和0.003μM。
按照抑制人胶原酶(MMP-1)中的描述制备底物(DnP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)并向各孔中加入50μl达到10μM的最终分析浓度。在时间0点读取荧光读数(360nm激发光,450nm发射光),然后以5分钟的间隔读取1小时。
阳性对照由酶和底物组成并且不含抑制剂,空白仅由底物组成。
按照抑制人胶原酶(MMP-1)中的描述测定IC50值。如果报道的IC50值<0.03μM,则以0.3μM、0.03μM、0.003μM和0.0003μM的最终浓度对抑制剂进行分析。TNF产生的抑制作用
通过如下体外分析证实化合物或其可药用盐抑制TNF产生的能力及其在治疗涉及TNF产生的疾病中的有效性:
用一步Ficoll-泛影钠分离技术从抗凝人血中分离人单核细胞。(2)将单核细胞在含有二价阳离子的Hanks平衡盐溶液(HBSS)中洗涤三次,然后以2×106/ml的密度重新悬浮在含1%BSA的HBSS中。用Abbott Cell Dyn 3500分析仪测得的差示计数表明在这些制剂中单核细胞占总细胞的17-24%。
将180μl细胞悬浮液加入到平底96孔板(Costar)中。加入化合物和LPS(100ng/ml最终浓度)使终体积达到200μl。所有条件均一式三份地进行。在增湿的CO2保温箱中于37℃保温4小时后,取出平板并离心(约250×g 10分钟),取出上清液用R&D ELISA试剂盒分析TNFα。
为了向哺乳动物、包括人给药来抑制基质金属蛋白酶或抑制肿瘤坏死因子(TNF)的产生,可以采用各种常规的给药途径,包括口服、胃肠外和局部给药。通常,可将本发明的化合物以约0.1-25mg/kg治疗对象的体重/天的剂量口服或胃肠外给药,优选约0.3-5mg/kg。但是,根据治疗对象的情况可能需要对剂量进行改变。无论如何,应由负责给药的人确定具体患者的适宜剂量。
本发明的化合物可以通过各种不同的剂量形式给药。通常,所述剂型中治疗活性的本发明化合物的浓度为约5.0%至约70%wt。
口服给药可以采用片剂,所述片剂含有各种赋形剂如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸;各种崩解剂如淀粉(优选玉米淀粉、土豆淀粉或木薯淀粉)、藻酸和某些复合硅酸盐以及颗粒粘合剂如聚乙烯吡咯烷酮、蔗糖、明胶和***胶。此外,润滑剂如硬脂酸镁、十二烷基硫酸钠和滑石对于片剂的制备也是非常有用的。同样类型的固体成分还可在明胶胶囊中用作填料;在这一点上,优选的材料还包括乳糖或奶糖以及高分子量聚乙二醇。当需要用含水混悬液和/或酏剂进行口服给药时,可将活性成分与以下成分混合:各种甜味剂或矫味剂、着色剂或染料、乳化剂和/或助悬剂(如果需要的话)以及稀释剂如水、乙醇、丙二醇、甘油及其组合形式。对于动物而言,优选将活性成分包含在动物饲料或饮用水中,浓度为5-5000ppm,优选25-500ppm。
为了进行胃肠外给药(肌肉内、腹膜内、皮下和静脉内给药),通常制备活性成分的无菌可注射溶液。可以采用本发明的治疗化合物在芝麻油或花生油或含水丙二醇中的溶液。如需要,可将含水溶液适当地进行调节和缓冲,优选pH大于8,液体稀释剂首先应是等渗的。这些含水溶液适于静脉内注射。油溶液适于关节内、肌肉内和皮下注射。很容易通过本领域技术人员熟知的常规制药技术在无菌条件下完成所有这些溶液的制备。对于动物而言,可将化合物以约0.1-50mg/kg/天、优选0.2-10mg/kg/天的剂量肌肉内或皮下给药,所述剂量可单次给药或分成最多三次给药。
通过以下实施例对本发明进行描述,但本发明并不仅限于此。实施例1 (2R,4R)-1-(4-甲氧基-苯磺酰基)-4-(哌嗪-1-羰基)-哌啶-2-甲酸 羟基酰胺盐酸盐
(a)向搅拌中的、冷的(-78℃)(2R)-2-苄氧羰基氨基戊二酸1-叔丁酯5-甲酯(5,6g,15.9mmol)(按照有机化学杂志(J.Org.Chem.),55,1711-1721(1990)和药物化学杂志(J.Med.Chem.),39,73-85(1996)中的描述制备)的30ml四氢呋喃溶液中加入二(三甲基硅烷基)氨基锂(40ml,1M的四氢呋喃溶液,39.8mmol)。将得到的混合物于-45℃搅拌1小时然后冷却至-78℃。然后加入烯丙基溴(5.2ml,63.7mmol)。2小时后,于-78℃下加入1M盐酸终止反应。将混合物用***萃取。将合并的***萃取液用盐水洗涤,然后将该混合物用硫酸钠干燥。过滤并浓缩滤液后,将粗产物通过硅胶色谱纯化(用1∶5乙酸乙酯/己烷洗脱)得到(2R,4R)-4-烯丙基-2-苄氧羰基氨基-戊二酸-1-叔丁酯5-甲酯。
(b)将臭氧通入到搅拌中的、冷的(-78℃)(2R,4R)-4-烯丙基-2-苄氧羰基氨基-戊二酸-1-叔丁酯5-甲酯(5.0g,12.8mmol)在100ml10∶1甲醇/二氯甲烷和0.73ml乙酸中的溶液中直至蓝色不再消失。然后向溶液中通入氮气直至蓝色消失。将该混合物升温至室温并加入二甲硫醚化合物(2.8ml,3.83mmol)。将混合物搅拌48小时,用二氯甲烷稀释,用10%碳酸钠水溶液和盐水洗涤,然后将混合物用硫酸钠干燥。过滤并浓缩滤液得到透明油状的(2R,4S)-6-甲氧基-哌啶-1,2,4-三甲酸1-苄酯2-叔丁酯4-甲酯,该产物不经纯化直接用于下一步骤。
(c)将(2R,4S)-6-甲氧基-哌啶-1,2,4-三甲酸1-苄酯2-叔丁酯4-甲酯(4.85g,11.9mmol)和10%钯炭(500mg)的混合物在100ml乙醇中于45Psi氢气氛下振荡1.5小时。将混合物用尼龙过滤并浓缩滤液得到淡黄色油状的(2R,4R)-哌啶-2,4-二甲酸2-叔丁酯4-甲酯,该产物不经纯化直接用于下一步骤。
(d)向搅拌中的、冷的(0℃)(2R,4R)-哌啶-2,4-二甲酸2-叔丁酯4-甲酯(2.7g,11.1mmol)和三乙胺(4.6ml,33.3mmol)的30ml二氯甲烷溶液中加入4-甲氧基-苯磺酰氯(2.3g,11.1mmol)。将混合物升温至室温并搅拌4小时。加入氯化铵水溶液终止反应并将混合物用乙酸乙酯萃取。将合并的萃取液用盐水洗涤,将有机混合物用硫酸钠干燥。过滤并浓缩滤液后,将得到的粗产物通过硅胶色谱纯化(用3∶8乙酸乙酯/己烷洗脱)得到(2R,4R)-1-(4-甲氧基苯磺酰基)-哌啶-2,4-二甲酸2-叔丁酯4-甲酯。
(e)向搅拌中的、冷的(0℃)(2R,4R)-1-(4-甲氧基苯磺酰基)-哌啶-2,4-二甲酸2-叔丁酯4-甲酯(4.4g,10.6mmol)的30ml二氯甲烷溶液中滴加10ml三氟乙酸。将混合物于0℃搅拌1小时,然后室温搅拌8小时。浓缩得到(2R,4R)-1-(4-甲氧基苯磺酰基)-哌啶-2,4-二甲酸4-甲酯,该产物不经纯化直接用于下一步骤。
(f)室温下,向搅拌中的(2R,4R)-1-(4-甲氧基苯磺酰基)-哌啶-2,4-二甲酸4-甲酯(4.4g,12.3mmol)、O-苄基羟胺盐酸盐(2.15g,13.5mmol)和三乙胺(5.15ml,36.9mmol)的溶液中加入苯并***-1-基氧-三(二甲氨基)鏻六氟磷酸盐(6.0g,12.3mmol)。将得到的混合物搅拌24小时。将混合物用乙酸乙酯稀释并用1M盐酸、碳酸氢钠水溶液和盐水洗涤。将有机混合物用硫酸镁干燥,过滤并将滤液浓缩。将粗产物通过硅胶色谱纯化(用5%甲醇的二氯甲烷溶液洗脱)得到无色固体状(2R,4R)-2-苄氧基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-甲酸甲酯。
(g)向搅拌中的冷的(0℃)(2R,4R)-2-苄氧基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-甲酸甲酯(4.0g,8.6mmol)的10ml 9∶1甲醇/水的溶液中加入氢氧化锂一水合物(1.8g,43mmol)。将混合物搅拌2小时,然后加入Amberlite IR-120树脂(96g)。15分钟后,将混合物过滤并浓缩滤液得到(2R,4R)-2-苄氧基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-甲酸,该产物不经纯化直接用于下一步骤。
(h)室温下,向搅拌中的(2R,4R)-2-苄氧基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-甲酸(500mg,1.11mmol)、叔丁氧羰基哌嗪(226mg,1.21mmol)和三乙胺(0.47ml,3.33mmol)的溶液中加入苯并***-1-基氧-三(二甲氨基)鏻六氟磷酸盐(535mg,1.21mmol)。将得到的混合物搅拌24小时。将混合物用乙酸乙酯稀释并用1M盐酸、碳酸氢钠水溶液和盐水洗涤。将有机混合物用硫酸镁干燥,过滤并将滤液浓缩。将粗产物通过硅胶色谱纯化(用2%甲醇的二氯甲烷溶液洗脱)得到无色固体状(2R,4R)-4-[2-苄氧基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-羰基]-哌嗪-1-甲酸叔丁酯。
(i)将(2R,4R)-4-[2-苄氧基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-羰基]-哌嗪-1-甲酸叔丁酯(500mg,0.81mmol)和5%吸附于硫酸钡上的钯(250mg)的混合物在10ml甲醇中于40Psi氢气氛下振荡1.5小时。用尼龙过滤并浓缩滤液得到无色固体状的(2R,4R)-4-[2-羟基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-羰基]-哌嗪-1-甲酸叔丁酯,该产物不经纯化直接用于下一步骤。
(j)向冷的(0℃)(2R,4R)-4-[2-羟基氨基甲酰基-1-(4-甲氧基苯磺酰基)-哌啶-4-羰基]-哌嗪-1-甲酸叔丁酯(420mg,0.8mmol)的溶液中通入氯化氢气体10分钟。20分钟后,将混合物浓缩得到无色固体状的(2R,4R)-1-(4-甲氧基-苯磺酰基)-4-(哌嗪-1-羰基)-哌啶-2-甲酸羟基酰胺盐酸盐。质谱(常压化学离子化;碱性模式)m/z(M+H)427,366;1H NMR(二甲亚砜-d6,400MHz,ppm)δ10.70(bd,1H,
J=2.7Hz),9.06(bs,2H),8.84(bs,1H),7.70(dd,2H,
J=8.9,2.9Hz),7.06(dd,2H,
J=8.9,2.9Hz),4.42(bs,1H),3.80(s,3H),3.80-3.20(m,6H),3.04(m,4H),2.76(m,1H),1.79(bd,1H,
J=13.5Hz),1.52(bd,1H,
J=12.6Hz),1.32(m,1H)1.14(m 1H).实施例2 (2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基- 哌啶-4-甲酸甲酯
(a)氮气氛下,向搅拌中的(2R,4R)-哌啶-2,4-二甲酸2-叔丁酯4-甲酯(920mg,3.78mmol)和三乙胺(1.58ml,11.3mmol)的10ml二氯甲烷溶液中加入3-(4-氟苯氧基)-丙烷-1-磺酰氯(1.05g,4.16mmol)的2ml二氯甲烷溶液。将混合物室温(22℃)搅拌16小时,然后用20ml1N盐酸和20ml二氯甲烷稀释。分出有机层,用盐水洗涤并用硫酸钠干燥。过滤并浓缩滤液得到2.8g黄色油,将其通过快速色谱纯化(用3∶2己烷/乙酸乙酯洗脱)得到1.15g黄色油状(2R,4R)-1-[3-(4-氟-苯氧基)-丙烷-1-磺酰基]-哌啶-2,4-二甲酸2-叔丁酯4-甲酯。
(b)向搅拌中的、冷的(0℃)(2R,4R)-1-[3-(4-氟-苯氧基)-丙烷-1-磺酰基]-哌啶-2,4-二甲酸2-叔丁酯4-甲酯(1.15g,2.5mmol)的10ml二氯甲烷溶液中加入10ml三氟乙酸。将混合物于16小时内升温至室温(22℃)。将混合物真空浓缩得到970mg橙色固体状的(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-哌啶-2,4-二甲酸4-甲酯粗品。
(c)室温(22℃)下,向搅拌中的(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-哌啶-2,4-二甲酸4-甲酯(970mg,2.4mmol)的5ml二氯甲烷溶液中加入三乙胺(1.0ml,7.2mmol)和O-苄基羟胺盐酸盐(410mg,2.64mmol)。向形成的溶液中加入苯并***-1-基氧-三(二甲氨基)鏻六氟磷酸盐(1.17g,2.64mmol)并将该混合物在氮气氛下搅拌16小时。将混合物用25ml 1N盐酸和25ml乙酸乙酯稀释。分出有机层并将水层用乙酸乙酯萃取(2次)。将合并的有机层用饱和碳酸钠水溶液(1次)和盐水洗涤(1次)。将有机层用硫酸钠干燥,过滤并将滤液真空浓缩。将粘稠的黄色残余物通过快速色谱纯化(用1∶1乙酸乙酯/己烷洗脱)得到810mg透明油状的(2R,4R)-2-苄氧基氨基甲酰基-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-哌啶-4-甲酸甲酯。
(d)将(2R,4R)-2-苄氧基氨基甲酰基-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-哌啶-4-甲酸甲酯(800mg,1.57mmol)和200mg 5%吸附于硫酸钡上的钯的混合物在15ml甲醇中于40Psi氢气氛下在Parr装置中振荡2小时。将混合物通过0.45μm的尼龙滤纸除去催化剂并将滤液浓缩得到650mg白色泡沫状的(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸甲酯。质谱(常压化学离子化;碱性模式),417(M-1);1H NMR(400MHz,CDCl3)δ6.94-6.97(m,2
H),6.80-6.83(m,2
H),4.56(s,1
H),4.03(t,2
H,
J=5.3Hz),3.83(d,1
H,
J=12.9Hz),3.68(s,3
H),3.15-3.28(m,3
H),2.76(t,1
H,
J=11.5Hz),2.54(d,1
H,
J=13.5Hz),2.26(d,2
H,
J=5.9Hz),2.02(m,1
H,
J=13.0Hz),1.73-1.78(m,1
H),1.56-1.62(m,1
H).实施例3 (2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基- 哌啶-4-甲酸
向搅拌中的、冷的(0℃)(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸甲酯(400mg,0.96mmol)在5ml甲醇/水混合物(10∶1)中的溶液中加入氢氧化锂一水合物(120mg,2.88mmol)。0℃下3小时后,加入预冲洗(甲醇)过的Amberlite树脂(4.1g)。将混合物过滤并将滤液浓缩得到370mg白色泡沫状的(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸:MS(常压化学离子化;碱性模式),403(M-1)。实施例4 (2R,4R)-1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶- 4-甲酸甲酯
4-(4-氟苄氧基)-苯磺酰氯。MS:465(M-1)。
实施例4的标题化合物用以上试剂通过与实施例2类似的方法制得。实施例5 (2R,4R)-1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶- 4-甲酸MS:451(M-1)。
实施例5的标题化合物用1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸甲酯按照与实施例3类似的方法制得。实施例6 2R,3S-{1-[4-(4-氟苄氢基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶- 3-基}-氨基甲酸异丙酯
(a)向搅拌中的、冷的(0℃)已知化合物(Agami,C.;Hamon,L;Kadouri-Puchot,C.;Le Guen,V,有机化学杂志,1996,61,5736-5742)[4S-4α,9α,9aα]-1-氧代-4-苯基-八氢-吡啶并[2,1-c][1,4]噁嗪-9-甲酸甲酯(8.28g,2.86mmol)的100ml四氢呋喃溶液中加入2.39ml浓盐酸。5ml后,将混合物浓缩至干。将得到的固体悬浮在乙酸乙酯中并将该混合物搅拌1小时。过滤收集固体,用乙酸乙酯冲洗,干燥得到9.04g白色固体。
将2g该固体溶于26ml 6N盐酸并加热回流6小时。将混合物冷却至0℃,然后用3N氢氧化钠中和并真空浓缩。将得到的固体悬浮在氯仿中并通过45μm尼龙滤纸。将滤液浓缩得到黄色的油,将其通过快速色谱纯化(用含1%乙酸的2∶1己烷/乙酸乙酯洗脱)得到802mg白色固体状[4S-4α,9α,9aα]-1-氧代-4-苯基-八氢-吡啶并[2,1-c][1,4]噁嗪-9-甲酸。
(b)22℃及氮气氛下,向搅拌中的[4S-4α,9α,9aα]-1-氧代-4-苯基-八氢-吡啶并[2,1-c][1,4]噁嗪-9-甲酸(568mg,2.06mmol)的15ml苯溶液中加入三乙胺(0.28ml,2.06mmol)和二苯基磷酰基叠氮化物(0.44ml,2.06mmol)。将混合物于22℃搅拌45分钟,回流50分钟,然后加入2-丙醇(3.2ml,41.2mmol)。继续回流20小时,将混合物冷却至22℃并真空浓缩。将残余物加入乙酸乙酯中并将形成的溶液用5%柠檬酸、水、饱和碳酸氢钠水溶液和盐水洗涤。将有机层干燥(硫酸钠),过滤并将滤液真空浓缩。将黄色残余物通过快速色谱纯化(用3∶1己烷/乙酸乙酯洗脱)得到402mg白色固体状[4S-4α,9α,9aα](1-氧代-4-苯基-八氢-吡啶并[2,1-c][1,4]噁嗪-9-基)-氨基甲酸异丙酯。
(c)将[4S-4α,9α,9aα](1-氧代-4-苯基-八氢-吡啶并[2,1-c][1,4]噁嗪-9-基)-氨基甲酸异丙酯(900mg,2.71mmol)和20%吸附在碳上的氢氧化钯(920mg)的混合物在77ml乙醇/水(10∶1)中于45Psi氢气氛下在Parr装置中振荡72小时。将混合物通过0.45μm的尼龙滤纸除去催化剂并将滤液浓缩得到610mg白色固体状2R,3S-3-异丙氧羰基氨基-哌啶-2-甲酸。MS:229(M-1)。
(d)向搅拌中的2R,3S-3-异丙氧羰基氨基-哌啶-2-甲酸(320mg,1.39mmol)的5ml二氯甲烷溶液中依次加入三乙胺(0.58ml,4.17mmol)和4-(4-氟苄氧基)-苯磺酰氯(460mg,1.53mmol)。22℃下16小时后,将混合物在1N盐酸和乙酸乙酯之间进行分配。分出有机层,用盐水洗涤并用硫酸钠干燥。过滤并将滤液浓缩得到480mg淡黄色固体状的2R,3S-1-[4-(4-氟苄氧基)-苯磺酰基]-3-异丙氧羰基氨基-哌啶-2-甲酸粗品。
(e)向搅拌中的、冷的(0℃)2R,3S-1-[4-(4-氟苄氧基)-苯磺酰基]-3-异丙氧羰基氨基-哌啶-2-甲酸粗品(380mg,0.77mmol)的5ml二氯甲烷溶液中依次加入三乙胺(0.32ml,2.31mmol)和苯并***-1-基氧-三(二甲氨基)鏻六氟磷酸盐(510mg,1.15mmol)。将形成的溶液于0℃及氮气氛下搅拌2分钟,然后加入O-(三甲基甲硅烷基乙基)羟胺盐酸盐(195mg,1.15mmol)。将混合物于14小时内缓慢升温至22℃。将混合物真空浓缩,将残余物用水稀释并用乙酸乙酯/***(1∶1;3次)萃取。将合并的有机萃取液用饱和碳酸钠水溶液(2次)、水(2次)和盐水(1次)洗涤。将有机层用硫酸镁干燥,过滤并将滤液真空浓缩。将黄色残余物通过快速色谱纯化(用65∶36己烷/乙酸乙酯洗脱)得到300mg白色泡沫状2R,3S-1-[4-(4-氟苄氧基)-苯磺酰基]-2-(2-三甲基硅烷基-乙氧基氨基甲酰基)-哌啶-3-基]-氨基甲酸异丙酯。MS:610(M+1)。
(f)向搅拌中的、冷的(0℃)2R,3S-1-[4-(4-氟苄氧基)-苯磺酰基]-2-(2-三甲基硅烷基-乙氧基氨基甲酰基)-哌啶-3-基]-氨基甲酸异丙酯(265mg,0.44mmol)的4ml二氯甲烷溶液中加入3ml三氟乙酸。将得到的无色溶液于2小时内升温至23℃,然后继续搅拌28小时。将混合物真空浓缩得到固体/泡沫,将其悬浮在乙酸乙酯∶己烷(1∶6)中并搅拌10小时。过滤收集白色固体,用己烷冲洗,进一步通过快速色谱纯化(用含1%乙酸的7∶3乙酸乙酯/己烷洗脱)得到130mg白色固体/泡沫状2R,3S-{1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-3-基}-氨基甲酸异丙酯。MS:510(M+1)。实施例7 3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基-硫代吗啉-3-甲酸 羟基酰胺
(a)向搅拌中的已知化合物(PCT公开号WO 97/20824)3-(S)-二甲基己基硅烷基-2,2-二甲基-四氢-2H-1,4-噻嗪-3-甲酸酯(1.17g,3.70mmol)的6ml二氯甲烷溶液中依次加入三乙胺(1.02ml,7.40mmol)和4’-氟联苯基磺酰氯(1.0g,3.70mmol)。将形成的溶液于23℃搅拌56小时。将反应混合物用二氯甲烷稀释并用水洗涤。将有机层真空浓缩;将残余物溶于甲醇,将混合物加热回流6小时。将混合物冷却至23℃并真空浓缩。将残余物通过快速色谱纯化(用含0.1%乙酸的3∶7乙酸乙酯/己烷洗脱)得到670mg白色泡沫/固体状的3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基-硫代吗啉-3-甲酸。MS:427(M+NH4)。
(b)氮气氛下,向搅拌中的、冷的(0℃)3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基-硫代吗啉-3-甲酸(605mg,1.48mmol)的5ml二氯甲烷溶液中加入三乙胺(0.62ml,4.43mmol)。加入苯并***-1-基氧-三(二甲氨基)鏻六氟磷酸盐(980mg,2.22mmol)并将形成的溶液搅拌5分钟,然后加入O-(三甲基硅烷基乙基)羟胺盐酸盐(376mg,2.22mmol)。移走冰浴,将混合物于23℃搅拌20小时。将混合物用氯化铵水溶液稀释并用1∶1乙酸乙酯/***萃取(3次)。将合并的有机萃取液用饱和碳酸钠水溶液(2次)、水(1次)和盐水(1次)洗涤。将有机层用硫酸镁干燥,过滤并将滤液真空浓缩。将残余的黄色油通过快速色谱纯化(用3∶7乙酸乙酯/己烷洗脱)得到650mg白色泡沫状3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基-硫代吗啉-3-甲酸(2-三甲基硅烷基-乙氧基)-酰胺。MS:523(M-1)。
(c)将3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基-硫代吗啉-3-甲酸(2-三甲基硅烷基-乙氧基)-酰胺(650mg,1.24mmol)的8ml三氟乙酸溶液于22℃搅拌16小时。将混合物真空浓缩并将残余物用二氯甲烷和***研制。蒸除溶剂得到550mg褐色固体。将固体悬浮在1∶1***/己烷中并温和地搅拌20小时。过滤收集固体(用1∶1***/己烷冲洗)并干燥得到470mg白色固体状3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基-硫代吗啉-3-甲酸羟基酰胺。MS:423(M-1)。实施例8 3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基-硫代吗啉-3-甲 酸羟基酰胺
(a)向搅拌中的、冷的(0℃)已知化合物(比利时专利公开号BE893025)2,2-二甲基-硫代吗啉-3-甲酸(600mg,3.42mmol)的10ml 1∶1水/二氧六环的溶液中加入6N氢氧化钠(1.2ml,7.1mmol)。向得到的溶液中加入4-(4-氟苄氧基)苯磺酰氯(1.08g,3.77mmol)。30分钟和60分钟后,再次加入1g 4-(4-氟苄氧基)苯磺酰氯和1.2ml 6N氢氧化钠。将混合物(约pH 12)用水稀释并用***萃取(1次)。将***层用1N氢氧化钠洗涤;将合并的碱性含水层用浓盐酸酸化至pH3,然后将酸性混合物用乙酸乙酯萃取(3次)。将合并的有机萃取液干燥(硫酸钠),过滤并将滤液真空浓缩得到820mg白色固体状的3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基-硫代吗啉-3-甲酸。MS:438(M-1)。
(b)氮气氛下,向搅拌中的、冷的(0℃)3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基-硫代吗啉-3-甲酸(820mg,1.87mmol)的5ml二氯甲烷溶液中加入三乙胺(0.52ml,3.74mmol)。加入苯并***-1-基氧-三(二甲氨基)鏻六氟磷酸盐(1.24g,2.81mmol)并将形成的溶液搅拌5分钟,然后加入O-(叔丁基二甲基硅烷基)羟胺盐酸盐(550mg,3.74mmol)。移走冰浴,将混合物于23℃搅拌16小时。将混合物用氯化铵水溶液稀释并用乙酸乙酯萃取(3次)。将合并的有机萃取液用水和盐水洗涤,然后用硫酸钠干燥。过滤并将滤液浓缩得到粘稠的黄色油,将其通过快速色谱纯化(用1∶3乙酸乙酯/己烷洗脱)得到270mg白色泡沫状的3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基-硫代吗啉-3-甲酸(叔丁基二甲基硅烷氧基)-酰胺。MS:569(M+1)。
(c) 向搅拌中的、冷的(0℃)3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基-硫代吗啉-3-甲酸(叔丁基二甲基硅烷氧基)-酰胺(270mg,0.47mmol)的10ml四氢呋喃溶液中加入两滴浓盐酸。30分钟后,将混合物用15ml四氢呋喃稀释并将混合物真空浓缩至体积为约5ml。用四氢呋喃将体积调至约25ml并将混合物再次浓缩至约5ml。将该过程重复两次,然后将混合物浓缩至干。将得到的固体悬浮在己烷和***的混合物中并将混合物搅拌16小时。过滤收集固体,***冲洗,干燥得到180mg白色固体状3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基-硫代吗啉-3-甲酸羟基酰胺。MS:453(M-1)。1H NMR(400MHz,
dmso-d 6)δ10.63(s,1
H),8.80(bs,1
H)7.59-7.61(m,2
H),7.46-7.50(m,2
H),7.17-7.21(m,2
H),7.09-7.12(m,2
H),5.12(s,2
H),3.99(s,1
H),3.87-3.93(m,1
H),3.69(d,1
H,J=12.7Hz),2.78-2.86(m,1
H),2.44-2.50(m,1
H),1.35(s,3
H),1.12(s,3
H).制备例1 4-(4-氟苄氧基)苯磺酰氯
向搅拌中的4-羟基苯磺酸钠二水合物(5.13g,22.1mmol)的23ml 1N氢氧化钠溶液中加入4-氟苄基溴(3.3ml,26.5mmol)的20ml乙醇溶液。将该混合物加热回流2天,然后冷却至室温(22℃),此刻开始形成白色沉淀。过滤收集片状白色固体,用乙酸乙酯和***冲洗,干燥得到4.95g 4-(4-氟-苄氧基)-苯磺酸钠盐。向搅拌中的4-(4-氟-苄氧基)-苯磺酸钠盐(13.0g,42.7mmol)的50ml亚硫酰氯溶液中加入2滴二甲基甲酰胺,然后将该溶液在温和的回流下加热8小时。将混合物浓缩得到黄色固体,将该固体悬浮在乙酸乙酯中并过滤。将滤液浓缩得到11.2g淡黄色固体状4-(4-氟苄氧基)苯磺酰氯:1H NMR(400MHz,CDCl3)δ7.95-7.98(m,2H),7.38-7.41(m,2H),7.08-7.12(m,4H),5.12(s,2H)。制备例2 3-(4-氟苯氧基)-丙烷-1-磺酰氯
室温(22℃)下,向搅拌中的4-氟苯酚(5.0g,44.6mmol)的50ml甲苯溶液中加入氢化钠(60%的矿物油分散液,1.78g,44.6mmol)。20分钟后,缓慢加入1,3-丙磺酸内酯(3.9ml,44.6mmol)的甲苯溶液并将该混合物搅拌16小时。加入甲醇终止反应并将混合物真空浓缩得到米色固体。将该固体悬浮在乙酸乙酯中,过滤,收集固体并干燥得到10.9g米色的3-(4-氟苯氧基)-丙烷-1-磺酸钠盐。向搅拌中的3-(4-氟苯氧基)-丙烷-1-磺酸钠盐(2.0g,7.8mmol)的10ml亚硫酰氯溶液中加入1滴二甲基甲酰胺,然后将该溶液加热回流16小时。将混合物冷却至0℃,用25ml***稀释缓慢加入水终止反应。分出有机层,将水层用25ml***萃取。将合并的有机层用盐水洗涤并用硫酸钠干燥。过滤并浓缩得到1.75g黄色油状的3-(4-氟苯氧基)-丙烷-1-磺酰氯:1H NMR(400MHz,CDCl3)δ6.96-7.00(m,2H),6.80-6.84(m,2H),4.10(t,2H,J=5.5Hz),3.91(t,2H,J=7.5Hz),2.47-2.54(m,2H)。制备例3 4’-氟联苯磺酰氯
将氯磺酸(8.7ml,0.13mol)滴加到搅拌中的、冷的(0℃)4-氟联苯(10.2g,59mmol)中。0℃下30分钟后,将反应混合物倒在冰上。过滤收集形成的白色沉淀并溶于氯仿。将氯仿溶液用水和盐水洗涤,用硫酸镁干燥,浓缩得到白色固体。将4’-氟联苯磺酸用乙酸乙酯结晶并将剩余的物质用己烷结晶,由此分离得到所需的4’-氟联苯磺酰氯(4.3g)。
Claims (35)
1.下式化合物或其可药用盐:
X是碳、氧或硫;
Y是碳、氧、硫、SO、SO2或氮;
R1、R2、R3、R4、R5、R6、R7、R8和R9选自氢;被一个或两个基团选择性取代的(C1-C6)烷基,所述基团选自(C1-C6)烷硫基、(C1-C6)烷氧基、三氟甲基、卤素、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳氨基、(C6-C10)芳硫基、(C6-C10)芳氧基、(C2-C9)杂芳氨基、(C2-C9)杂芳硫基、(C2-C9)杂芳氧基、(C6-C10)芳基(C6-C10)芳基、(C3-C6)环烷基、羟基、哌嗪基、(C6-C10)芳基(C1-C6)烷氧基、(C2-C9)杂芳基(C1-C6)烷氧基、(C1-C6)酰氨基、(C1-C6)酰硫基、(C1-C6)酰氧基、(C1-C6)烷基亚磺酰基、(C6-C10)芳基亚磺酰基、(C1-C6)烷基磺酰基、(C6-C10)芳基磺酰基、氨基、(C1-C6)烷基氨基或((C1-C6)烷基)2氨基;(C2-C6)链烯基、(C6-C10)芳基(C2-C6)链烯基、(C2-C9)杂芳基(C2-C6)链烯基、(C2-C6)链炔基、(C6-C10)芳基(C2-C6)链炔基、(C2-C9)杂芳基(C2-C6)链炔基、(C1-C6)烷基氨基、(C1-C6)烷硫基、(C1-C6)烷氧基、全氟(C1-C6)烷基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳氨基、(C6-C10)芳硫基、(C6-C10)芳氧基、(C2-C9)杂芳基氨基、(C2-C9)杂芳硫基、(C2-C9)杂芳氧基、(C3-C6)环烷基、(C1-C6)烷基(羟基亚甲基)、哌啶基、(C1-C6)烷基哌啶基、(C1-C6)酰氨基、(C1-C6)酰硫基、(C1-C6)酰氧基、R10(C1-C6)烷基或下式的基团:其中n是0-6;
y是0或1;
W是氧或>NR24;
Z是-OR11、-NR24R11、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氢吲哚基、异二氢吲哚基、四氢喹啉基、四氢异喹啉基或桥接的二氮杂二环烷基,所述桥接的二氮杂二环烷基选自:
其中r是1、2或3;
m是1或2;
p是0或1;
V是氢、(C1-C3)烷基、(C1-C6)烷基(C=O)-、(C1-C6)烷氧基(C=O)-、(C6-C10)芳基(C=O)-、(C6-C10)芳氧基(C=O)-、(C6-C10)芳基(C1-C6)烷基(C=O)-、(C6-C10)芳基(C1-C6)烷氧基(C=O)-或(C1-C6)烷氧基(C=O)-O-;
其中,各杂环基团(即含有一个或多个杂原子的Z环基团)可以选择性地被一个或两个取代基彼此独立地取代,所述取代基选自羟基、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C10)酰基、(C1-C10)酰氧基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷基、羟基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)酰氧基(C1-C6)烷基、(C1-C6)烷硫基、(C1-C6)烷硫基(C1-C6)烷基、(C6-C10)芳硫基、(C6-C10)芳硫基(C1-C6)烷基、R12R13N-、R12R13NSO2-、R12R13N(C=O)-、R12R13N(C=O)-(C1-C6)烷基、R14SO2-、R14SO2NH-、R15(C=O)-[N(R12)]-、R16O(C=O)-或R16O(C=O)-(C1-C6)烷基;
其中R10是(C1-C6)酰基哌嗪基、(C6-C10)芳基哌嗪基、(C2-C9)杂芳基哌嗪基、(C1-C6)烷基哌嗪基、(C6-C10)芳基(C1-C6)烷基哌嗪基、(C2-C9)杂芳基(C1-C6)烷基哌嗪基、吗啉基、硫代吗啉基、吡咯烷基、哌啶基、(C1-C6)烷基哌啶基、(C6-C10)芳基哌啶基、(C2-C9)杂芳基哌啶基、(C1-C6)烷基哌啶基(C1-C6)烷基、(C6-C10)芳基哌啶基(C1-C6)烷基、(C2-C9)杂芳基哌啶基(C1-C6)烷基或(C1-C6)酰基哌啶基;
R11是氢、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷基、(C1-C6)烷基(C6-C10)芳基(C1-C6)烷基、(C1-C6)烷基(C2-C9)杂芳基(C1-C6)烷基、5-二氢化茚基、-CHR17O-(C=O)-R18或-CH2(C=O)-NR19R20;
R12和R13彼此独立地是氢、(C1-C6)烷基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基或(C2-C9)杂芳基(C1-C6)烷基,或者R12和R13可以同它们所连接的氮合在一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基或硫代吗啉基环;
R14是三氟甲基、(C1-C6)烷基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基或(C2-C9)杂芳基(C1-C6)烷基;
R15是氢、(C1-C6)烷基、(C1-C6)烷氧基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基或(C2-C9)杂芳基(C1-C6)烷基;
R16是(C1-C6)烷基、(C6-C10)芳基、(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷基、5-二氢化茚基、-[CH(R17)]O-(C=O)-R18、-CH2(C=O)-NR19R20或R21O(C1-C6)烷基;
R17是氢或(C1-C6)烷基;
R18是(C1-C6)烷基、(C1-C6)烷氧基或(C6-C10)芳基;
R19和R20彼此独立地是氢或(C1-C6)烷基,或者可以同它们所连接的氮合在一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基或硫代吗啉基环;
R21是H2N(CHR22)(C=O)-;
R22是天然D-或L-氨基酸的侧链;
R23是氢、(C1-C6)酰基、(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷基、(C2-C9)杂芳基(C1-C6)烷基或(C1-C6)烷基磺酰基;
R24是氢或(C1-C6)烷基;
或者,R1和R2或R3和R4或R5和R6可以合在一起形成羰基;
或者,R1和R2或R3和R4或R5和R6可以合在一起形成(C3-C6)环烷基、氧杂环己基、硫杂环己基、二氢化茚基或四氢萘基环或下式的基团:
Q是被氟、氯、(C1-C6)烷基、(C1-C6)烷氧基或全氟(C1-C3)烷基选择性取代的(C1-C10)烷基、(C6-C10)芳基、(C6-C10)芳氧基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基、(C6-C10)芳氧基(C2-C9)杂芳基、(C2-C9)杂芳基、(C1-C6)烷基(C6-C10)芳基、(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基、(C2-C9)杂芳氧基(C6-C10)芳基、(C1-C6)烷基(C2-C9)杂芳基、(C1-C6)烷氧基(C2-C9)杂芳基、(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基、(C2-C9)杂芳氧基(C2-C9)杂芳基、(C6-C10)芳氧基(C1-C6)烷基、(C2-C9)杂芳氧基(C1-C6)烷基、(C1-C6)烷基(C6-C10)芳氧基(C2-C9)杂芳基、(C1-C6)烷基(C2-C9)杂芳氧基(C6-C10)芳基,(C1-C6)烷基(C6-C10)芳氧基(C2-C9)杂芳基,(C1-C6)烷氧基(C6-C10)芳氧基(C6-C10)芳基、(C1-C6)烷氧基(C2-C9)杂芳氧基(C6-C10)芳基或(C1-C6)烷氧基(C6-C10)芳氧基(C2-C9)杂芳基;
条件是,当y是0,Q不是(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基或(C6-C10)芳基(C1-C6)烷氧基(C1-C9)杂芳基,并且R1-R9中有任何一个是式II的基团时,则当Z是所定义的氮杂环丁基、吡咯烷基、吗啉基、硫代吗啉基、二氢吲哚基、异二氢吲哚基、四氢喹啉基、四氢异喹啉基、哌嗪基、(C1-C10)酰基哌嗪基、(C1-C6)烷基哌嗪基、(C6-C10)芳基哌嗪基、(C2-C9)杂芳基哌嗪基或桥接的二氮杂二环烷基时,Z必需是取代的;
条件是,当y是0,Q不是(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基或(C6-C10)芳基(C1-C6)烷氧基(C1-C9)杂芳基时,则R1、R2、R3、R4、R5、R6、R7、R8和R9中至少有一个必需是式II所定义的基团;
条件是,当Q是(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基或(C6-C10)芳基(C1-C6)烷氧基(C1-C9)杂芳基时,则R1-R9可以不是式II的基团,但当R1、R2、R3、R4、R5、R6、R7、R8和R9均是氢或(C1-C6)烷基时,则或者X或Y是氧、硫、SO、-SO2-或氮,或者虚线是代表双键;
条件是,只有当R8不是氢时,R7才不是氢;
条件是,只有当R5不是氢时,R6才不是氢;
条件是,只有当R4不是氢时,R3才不是氢;
条件是,只有当R1不是氢时,R2才不是氢;
条件是,当R1、R2和R9是含有杂原子的取代基时,杂原子不能直接连接在环的2位或6位上;
条件是,当X是氮时,R4不存在;
条件是,当X是氧、硫、SO、SO2或氮并且当R1、R2、R5和R6中的一个或多个基团是含有杂原子的取代基时,杂原子不能直接连接在4位或6位上;
条件是,当Y是氧、硫、SO、SO2或氮并且当R3、R4、R7和R8中的一个或多个基团彼此独立地是含有杂原子的取代基时,杂原子不能直接连接在3位或5位上;
条件是,当X是氧、硫、SO或SO2时,R3和R4不存在;
条件是,当y是1并且W是NR24或氧时,Z不能是羟基;
条件是,当Y是氧、硫、SO或SO2时,R5和R6不存在;
条件是,当Y是氮时,R6不存在;
条件是,当虚线表示双键时,R4和R6不存在;
条件是,当R3和R5彼此独立地是含有杂原子的取代基时,当虚线表示双键时,杂原子不能直接连接在位置X和Y上;
条件是,当X或Y的位置上是氧、硫、SO、SO2或氮时,X或Y中的另一个是碳;
条件是,当X或Y是杂原子时,虚线不表示双键。
2.权利要求1的化合物,其中Y是碳、SO、SO2或氧。
3.权利要求1的化合物,其中Q是(C6-C10)芳基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基或(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基,其中的各末端芳基选择性地被氟取代。
4.权利要求1的化合物,其中R2、R3、R6、R7和R9是氢。
5.权利要求1的化合物,其中Y是碳;Q是(C1-C6)烷氧基(C6-C10)芳基、(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基或(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基。
6.权利要求1的化合物,其中Y是氧、硫、SO、或SO2。
7.权利要求3的化合物,其中Y是氧、硫、SO、或SO2。
8.权利要求1的化合物,其中R7-R9中至少有一个不是氢。
9.权利要求3的化合物,其中R7-R9中至少有一个不是氢。
10.权利要求6的化合物,其中R7-R9中至少有一个不是氢。
11.权利要求7的化合物,其中R7-R9中至少有一个不是氢。
12.权利要求1的化合物,其中R7-R9中至少有一个是(C1-C6)烷基。
13.权利要求3的化合物,其中R7-R9中至少有一个是(C1-C6)烷基。
14.权利要求6的化合物,其中R7-R9中至少有一个是(C1-C6)烷基。
15.权利要求7的化合物,其中R7-R9中至少有一个是(C1-C6)烷基。
16.权利要求1的化合物,其中R7-R9中至少有一个是甲基。
17.权利要求3的化合物,其中R7-R9中至少有一个是甲基。
18.权利要求6的化合物,其中R7-R9中至少有一个是甲基。
19.权利要求7的化合物,其中R7-R9中至少有一个是甲基。
20.权利要求1的化合物,其中R7和R8合在一起形成羰基,R9是(C1-C6)烷基。
21.权利要求3的化合物,其中R7和R8合在一起形成羰基,R9是(C1-C6)烷基。
22.权利要求6的化合物,其中R7和R8合在一起形成羰基,R9是(C1-C6)烷基。
23.权利要求7的化合物,其中R7和R8合在一起形成羰基,R9是(C1-C6)烷基。
24.权利要求1的化合物,其中R7和R8均是甲基。
25.权利要求3的化合物,其中R7和R8均是甲基。
26.权利要求6的化合物,其中R7和R8均是甲基。
27.权利要求7的化合物,其中R7和R8均是甲基。
28.权利要求1的化合物,其中R7和R8合在一起形成(C3-C6)环烷基。
29.权利要求3的化合物,其中R7和R8合在一起形成(C3-C6)环烷基。
30.权利要求6的化合物,其中R7和R8合在一起形成(C3-C6)环烷基。
31.权利要求7的化合物,其中R7和R8合在一起形成(C3-C6)环烷基。
32.权利要求1的化合物,其中所述化合物选自:
(2R,4R)-1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸;
(2R,4R)-1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸甲酯;
(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸;
(2R,4R)-1-[3-(4-氟苯氧基)-丙烷-1-磺酰基]-2-羟基氨基甲酰基-哌啶-4-甲酸甲酯;
(2R,3S)-{1-[4-(4-氟苄氧基)-苯磺酰基]-2-羟基氨基甲酰基-哌啶-3-基}-氨基甲酸异丙酯;
3-(S)-4-(4’-氟联苯基-4-磺酰基)-2,2-二甲基硫代吗啉-3-甲酸羟基酰胺;
3-(S)-4-[4-(4-氟苄氧基)苯磺酰基]-2,2-二甲基硫代吗啉-3-甲酸羟基酰胺;
(2R,4S)-1-[4-(4-氟苄氧基)-苯磺酰基]-4-羟基-哌啶-2-甲酸羟基酰胺;和
(2R,4R)-1-(4-甲氧基苯磺酰基)-4-(哌嗪-1-羰基)-哌啶-2-甲酸羟基酰胺盐酸盐。
33.药物组合物,该药物组合物用于在哺乳动物、包括人中(a)和常规的NSAID和镇痛剂联合以及和细胞毒性抗癌剂联合治疗选自关节炎、癌症、组织溃疡、黄斑变性、再狭窄、牙周疾病、大疱性表皮松解、巩膜炎的一组疾病,以及治疗特征在于基质金属蛋白酶活性的其它疾病、AIDS、脓毒症、脓毒性休克和涉及肿瘤坏死因子(TNF)产生的其它疾病或(b)抑制基质金属蛋白酶或肿瘤坏死因子(TNF)的生产,所述药物组合物含有治疗有效量的权利要求1的化合物和可药用载体。
34.在哺乳动物、包括人中抑制(a)基质金属蛋白酶或(b)肿瘤坏死因子(TNF)产生的方法,该方法包括向所述哺乳动物施用有效量的权利要求1的化合物。
35.在哺乳动物、包括人中治疗选自关节炎、癌症、组织溃疡、黄斑变性、再狭窄、牙周疾病、大疱性表皮松解、巩膜炎的一组疾病的方法,治疗上述疾病时可将式I化合物和常规的NSAID和镇痛剂联合以及和细胞毒性抗癌剂联合,以及治疗特征在于基质金属蛋白酶活性的其它疾病、AIDS、脓毒症、脓毒性休克和涉及肿瘤坏死因子(TNF)产生的其它疾病的方法,该方法包括向所述哺乳动物施用治疗所述疾病有效量的权利要求1的化合物。
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CN103998435A (zh) * | 2011-10-04 | 2014-08-20 | 法国国家健康医疗研究院 | 新型细胞凋亡诱导化合物 |
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