CN1304930A - 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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- CN1304930A CN1304930A CN00104599A CN00104599A CN1304930A CN 1304930 A CN1304930 A CN 1304930A CN 00104599 A CN00104599 A CN 00104599A CN 00104599 A CN00104599 A CN 00104599A CN 1304930 A CN1304930 A CN 1304930A
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- alkyl
- aryl
- heteroaryl
- hydrogen
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/60—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 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
下式化合物,其中R1、R2、R3、R4、R5、R6、R7、R8、R9或Ar如上定义,用于治疗选自下述疾病,关节炎、癌症、组织溃疡、再狭窄、牙周疾病、表皮松解bullosa(大泡)、巩膜炎和其它以基质金属蛋白酶活性为特征的疾病,以及艾滋病、脓毒病、败血症休克以及其它涉及TNF产生的疾病。
Description
本申请是1996年4月18日提交的专利申请96104999.5“芳基磺酰基异羟肟酸衍生物”的分案申请。
本发明涉及芳基磺酰基异羟肟酸衍生物,它们是基质金属蛋白酰抑制剂或肿瘤坏死因子(以下称为TNF)产生抑制剂,而且它们可用于治疗下述疾病:关节炎,癌症,组织溃疡,再狭窄,牙周疾病,表皮松解bullosa(大泡),巩膜炎和以基质金属蛋白酶活性为特征的其它疾病,以及艾滋病,脓毒病,败血症休克和其它涉及TNF产生的疾病。
本发明还涉及用这些化合物治疗哺乳动物特别是人的上述疾病的方法和为此使用的药物组合物。
有一些酶能影响蛋白质结构的分解,而且它们在结构上与金属蛋白酶有关。基质降解金属蛋白酶,如明胶酶,基质溶素和胶原酶参与组织基质降解(例如胶原萎陷(Collapse))而且与许多病理学疾病有关,这些病理学疾病包括异常连接组织和基膜基质代谢,如关节炎(例如骨关节炎和风湿性关节炎),组织溃疡(例如角膜、表皮和胃溃疡),异常创伤愈合,牙周疾病,骨病(例如佩吉特疾病和骨质疏松),肿瘤转移或发作,以及HIV感染(J.Leuk.Biol.,52(2):244-248,1992)。
肿瘤坏死因子被认为与许多感染和自身免疫疾病有关(W.Fri-ers,FEBS Letters,1991,285,199)。此外,已经表明TNF是脓毒病和败血症休克中炎症反应的主要中介物(mediator)(C.E.Spoo-ner等人,CliniCal Immunology and Immunopathology,1992,62S11)。
本发明涉及下式化合物:或其药用可接受的盐,其中不连续链代表任意的双键;
X为碳、氧或硫;
Y为碳、氧、硫、亚砜、砜或氮;
R1、R2、R3、R4、R5、R6、R7、R8和R9选自氢,(C1-C6)烷基,该(C1-C6)烷基可任意被(C1-C6)烷氨基,(C1-C6)烷硫基、(C1-C6)烷氧基,三氟甲基,(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(C1-C6)烷基,(C1-C6)烷基(羟基亚甲基),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)烷氨基或((C1-C6)烷氨基)2取代;(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)炔基,(C6-C10)芳基(C2-C6)炔基,(C5-C9)杂芳基(C2-C6)炔基,(C1-C6)烷氨基,(C1-C6)烷硫基、(C1-C6)烷氧基,三氟甲基,(C1-C6)烷基(二氟亚甲基),(C1-C3)烷基(二氟亚甲基)(C1-C3)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,R13(C1-C6)烷基,其中R13为(C1-C6)酰基哌嗪基,(C6-C10)芳基哌嗪基,(C5-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,(C5-C9)杂芳基(C1-C6)烷基哌嗪基,吗啉代,硫代码啉代,哌啶子基,吡咯烷子基(pyrro-lidiono),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;
Z为羟基,(C1-C6)烷氧基或NR14R15,其中R14和R15分别独立地选自氢,(C1-C6)烷基,该(C1-C6)烷基可任意被(C1-C6)烷基哌啶基、(C6-C10)芳基哌啶基、(C5-C9)杂芳基哌啶基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C6-C10)芳基或(C3-C6)环烷基取代;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)酰基哌啶基,(C6-C10)芳基,(C5-C9)杂芳基,(C6-C10)芳基(C6-C10)芳基,(C3-C6)环烷基,R16(C2-C6)烷基,(C1-C5)烷基(CHR16)(C1-C6)烷基,其中R16为羟基,(C1-C6)酰氧基,(C1-C6)烷氧基,哌嗪基,(C1-C6)酰氨基,(C1-C6)烷硫基,(C6-C10)芳硫基,(C1-C6)烷基亚磺酰基,(C6-C10)芳基亚磺酰基,(C1-C6)烷基次硫酰基(sulfoxyl),(C6-C10)芳基次硫酰基,氨基,(C1-C6)烷氨基,((C1-C6)烷基)2氨基,(C1-C6)酰基哌嗪基,(C1-C6)烷基哌嗪基,(C6-C10)芳基(C1-C6)烷基哌嗪基,(C5-C9)杂芳基(C1-C6)烷基哌嗪基,吗啉代,硫代码啉代,哌啶子基或吡咯烷子基;R17(C1-C6)烷基,(C1-C5)烷基(CHR17)(C1-C6)烷基,其中R17为哌啶基或(C1-C6)烷基哌啶基;及CH(R18)COR19,其中R18为氢,(C1-C6)烷基,(C6-C10)芳基(C1-C6)烷基,(C5-C9)杂芳基(C1-C6)烷基,(C1-C6)烷硫基(C1-C6)烷基,(C6-C10)芳硫基(C1-C6)烷基,(C1-C6)烷基亚磺酰基(C1-C6)烷基,(C6-C10)芳基亚磺酰基(C1-C6)烷基,(C1-C6)烷基磺酰基(C1-C6)烷基,(C6-C10)芳基磺酰基(C1-C6)烷基,羟基(C1-C6)烷基,氨基(C1-C6)烷基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基氨基)2(C1-C6)烷基,R20R21NCO(C1-C6)烷基或R20OCO(C1-C6)烷基,其中R20和R21分别独立地选自氢,(C1-C6)烷基,(C6-C10)芳基(C1-C6)烷基及(C5-C9)杂芳基(C1-C6)烷基;和R19为R22O或R22R23N,其中R22和R23分别独立地选自氢,(C1-C6)烷基,(C6-C10)芳基(C1-C6)烷基和(C5-C9)杂芳基(C1-C6)烷基;
或R14和R15,或R20和R21,或R22和R23一起形成氮杂环丁基、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(quinolinyl)、四氢异喹啉基、(C1-C6)酰基哌嗪基、(C1-C6)烷基哌嗪基、(C6-C10)芳基哌嗪基、(C5-C9)杂芳基哌嗪基或选自以下基团的桥合二氮杂双环烷基环。ab
cde其中r为1,2或3;
m为1或2;
P为0或1;及
Q为氢、(C1-C3)烷基、(C1-C6)酰基或(C1-C6)烷氧基氨基甲酰基;
或R1和R2,或R3和R4,或R5和R6一起形成羰基;
或R1和R2,或R3和R4,或R5和R6,或R7和R8可以一起形成一(C3-C6)环烷基、氧杂环己基、硫代环己基、2,3-二氢化茚基或1,2,3,4-四氢化萘基环或一下式基团其中R24为氢、(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;和
Ar为(C6-C10)芳基或(C5-C9)杂芳基,其中每个可任意被(C1-C6)烷基,一个或两个(C1-C6)烷氧基、(C6-C10)芳氧基或(C5-C9)杂芳氧基取代;
条件是当R8不是氢时,R7不是氢;
条件是当R5不是氢时,R6不是氢;
条件是当R4不是氢时,R3不是氢;
条件是当R1不是氢时,R2不是氢;
条件是当R1、R2和R9是含有杂原子的取代基时,杂原子不能直接连结在2-或6-位;
条件是当X是氮时,R4不存在;
条件是当X是氧、硫、亚砜、砜或氮而且R1、R2、R5和R6中的一个或多个基团为含有杂原子的取代基时,杂原子不能直接连结在4-或6-位;
条件是当Y为氧、硫、亚砜、砜或氮而且R3、R4、R7和R8中的一个或多个基团各自为含有杂原子的取代基时,杂原子不能直接连结在3-或5-位;
条件是当X为氧、硫、亚砜或砜时,R3和R4不存在;
条件是当Y为氮时,R4不存在;
条件是当Y为氧、硫、亚砜或砜时,R5和R6不存在;
条件是当Y为氮时,R6不存在;
条件是当不连续链代表双键时,R4和R6不存在;
条件是当不连续链代表双键时R3和R5各自为含杂原子取代基,杂原子不能直接连结在位置X和Y上;
条件是当X或Y位任一个为氧、硫、亚砜、砜或氮时,另一个X或Y为碳;
条件是当X或Y定义为杂原子时,不连续链不代表双键;
条件是当R1、R2、R3、R4、R5、R6、R7、R8和R9均定义为氢或(C1-C6)烷基,X或Y任一个为氧、硫、亚砜、砜或氮,或不连续链代表双键。
这里所用术语“烷基”(除非另有说明)包括饱和的单价含有直链、支链或环部分或其结合的烃基。
这里所用术语“烷氧基”包括O-烷基,其中烷基如上定义。
这里所用术语“芳基”(除非另有说明)包括从芳香烃除去一个氢原子衍生的有机基团,如苯基或萘基,其任意被1-3个分别选自下列基团所取代: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。
这里所用术语“杂芳基”(除非另有说明)包括从芳香杂环化合物除去一个氢原子衍生的有机基团,如吡啶基、呋喃基、Pyroyl、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,并且任意被1-2个独立选自下列基团所取代: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)芳基。
这里所用术语“酰基”(除非另有说明)包括通式RCO基团,其中R为烷基、烷氧基、芳基、芳基烷基或芳基烷氧基和术语“烷基”或“芳基”如上定义。
这里所用“酰氧基”包括O-酰基基团,其“酰基”如上定义。
式Ⅰ化合物的优选构象包括2-位上异羟肟酸的轴向排列(axiallydisposed)。
式Ⅰ化合物可以有手性中心,因此其中存在不同的对映体形式。本发明包括式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为氧、氮或硫的那些化合物。
其它优选的式Ⅰ化合物包括其中Ar为4-甲氧基苯基或4-苯氧基苯基的那些化合物。
其它优选的式Ⅰ化合物包括其中R8为(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、羧酸或羧酸(C1-C6)烷基的那些化合物。
其它优选的式Ⅰ化合物包括其中R2、R3、R6、R7和R9均为氢的那些化合物。
更优选的式Ⅰ化合物包括其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R8为(C6-C18)芳基炔基或(C5-C9)杂芳基炔基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为氧,Ar为4-甲氧基苯基或4-苯氧基苯基及R8为(C6-C10)芳基炔基或(C5-C9)杂芳基炔基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R8为羧酸或羧酸(C1-C6)烷基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为氧,Ar为4-甲氧基苯基或4-苯氧基苯基及R8为羧酸或羧酸(C1-C6)烷基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R5为(C6-C10)芳基炔基或(C5-C9)杂芳基炔基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为氧,Ar为4-甲氧基苯基或4-苯氧基苯基及R5为(C6-C10)芳基炔基或(C5-C9)杂芳基炔基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R5为羧酸或羧酸(C1-C6)烷基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为氧,Ar为4-甲氧基苯基或4-苯氧基苯基及R5为羧酸或羧酸(C1-C6)烷基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R5为(C1-C6)烷基氨基的那些化合物。
更优选的式Ⅰ化合物包括其中Y为氧,Ar为4-甲氧基苯基或4-苯氧基苯基及R8为(C1-C6)烷基氨基的那些化合物。
特别优选的化合物如下:
(2R,3S)-N-羟基-3-乙炔基-1-(4-甲氧基苯磺酰基)-哌啶-2-甲酰胺;
(2R,3S)-N-羟基-1-(4-甲氧基苯磺酰基)-3-(5-甲氧基噻吩-2-基-乙炔基)-哌啶-2-甲酰胺;
(2R,3R)-N-羟基-1-(4-甲氧基苯磺酰基)-3-(3-哌啶-3-基-丙-2-炔)-哌啶-2-甲酰胺;
(2S,3R)-N-羟基-4-(4-甲氧基苯磺酰基)-2-吡啶-3-基-吗啉-3-甲酰胺;
(2S,3R)-N-羟基-2-羟基氨基甲酰基-4-(4-甲氧基苯磺酰基)-吗啉-3-甲酰胺;
(2R,3R)-N-羟基-2-羟基氨基甲酰基-4-(4-甲氧基苯磺酰基)-哌啶-2-甲酰胺;
(2R,3S)-N-羟基-1-(4-甲氧基苯磺酰基)-3-(4-苯基吡啶-2-基)-哌啶-2-甲酰胺;
(2S,3R)-N-羟基-1-(4-甲氧基苯磺酰基)-2-(4-苯基吡啶-2-基)-吗啉-2-甲酰胺;
(2R,3S)-N-羟基-3-(2-氯-4-氟苯基)-1-(4-甲氧基苯磺酰基)-哌啶-2-甲酰胺;和
(2S,3R)-N-羟基-2-(2-氯-4-氟苯基)-1-(4-甲氧基苯磺酰基)-哌啶-3-甲酰胺。
本发明还涉及哺乳动物包括人的(a)治疗下述疾病的药物组合物,关节炎、癌症、组织溃疡、再狭窄、牙周疾病、表皮松解bu-llosa(大泡)、巩膜炎和其它以基质金属蛋白酶活性为特征的疾病、艾滋病、脓毒病、败血症休克以及其它涉及肿瘤坯死因子(TNF)产生的疾病或(b)抑制基质金属蛋白酶或肿瘤坏死因子(TNF)产生的药物组合物,所述组合物包括治疗或抑制有效量的式(Ⅰ)的化合物或其药用可接受的盐和药用可接受的载体。
本发明还涉及抑制(a)哺乳动物包括人的基质金属蛋白酶或(b)肿瘤坏死因子(TNF)产生的方法,包括给药予所述哺乳动物有效量的式(Ⅰ)的化合物或其药用可接受的盐。
本发明还涉及治疗哺乳动物包括人的下述疾病的方法,所述疾病包括关节炎、癌症、组织溃疡、再狭窄、牙周疾病、表皮松解bullosa(大泡)、巩膜炎和其它以基质金属蛋白酶活性为特征的疾病、艾滋病、脓毒病、败血症休克以及其它涉及肿瘤坏死因子(TNF)产生的疾病,该方法包括给药予所述哺乳动物治疗这些疾病有效量的式(Ⅰ)的化合物或其药用可接受的盐。
下列反应流程说明了本发明化合物的制备,在反应流程中和以下讨论中R1、R2、R3、R4、R5、R6、R7、R8、R9、n和Ar如上定义,除非另有说明。
制备1
在制备1的反应1中,将式ⅩⅥ化合物转化为相应的式Ⅵ化合物的羟基酯,即首先将ⅩⅥ与芳基磺酰卤在三乙胺和质子惰性溶剂如二氯甲烷、四氢呋喃或二噁烷的存在下,在温度约为20℃至30℃,优选室温反应。然后将所形成的化合物与下式化合物,其中R25为苄氧羰基,(C1-C6)烷基、苄基、烯丙基或叔丁基,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存在下及温度约为-20℃至20℃,优选0℃下反应形成式Ⅵ化合物的羟基酯。
在制备2的反应1中,将式ⅩⅧ的胺化合物(其中R25如上定义)转化为相应的式ⅩⅦ化合物的芳基磺酰胺,即通过(1)ⅩⅧ与芳基磺酰卤在三乙胺和质子惰性溶剂,如二氯甲烷、四氢呋喃或二噁烷的存在下,在温度约为20℃至30℃,优选室温反应,(2)将所形成化合物与下式化合物,在六甲基二硅氮烷钠和四氢呋喃-二甲基甲酰胺混合溶剂存在下,及温度约为-20℃至20℃,优选0℃反应,(3)将所形成化合物与臭氧在二氯甲烷-甲醇溶液中及温度约为-90℃至-70℃,优选-78℃进一步反应。将所形成的不稳定臭氧化合物与三苯膦反应形成式ⅩⅦ的芳基磺酰胺化合物。在制备2的反应2中,将式ⅩⅦ的芳基磺酰胺化合物转化为相应的式Ⅵ化合物的羟基酯,即通过ⅩⅦ与下式化合物反应。其中W为锂、镁、铜或铬,
在流程1的反应1中,通过内酯化和接着进行克莱森重排将式Ⅵ化合物(其中R25保护基为苄氧羰基、(C1-C6)烷基、苄基、烯丙基或叔-丁基)转化为相应的式Ⅴ的吗啉酮化合物。从式Ⅵ化合物除去R25保护基的反应是在适于所用具体R25保护基的条件下进行的。这些条件包括:(a)用氢和氢化催化剂如10%钯-炭(其中R25为苄氧羰基)处理,(b)皂化(其中R25为低级烷基),(c)氢解(其中R25为苄基),(d)用强酸如三氟乙酸或盐酸处理,其中R25为叔丁基,(e)用三丁基氢化锡和乙酸在催化剂双(三苯膦)氯化钯(Ⅱ)处理,其中R25为烯丙基。
在流程1的反应2中,通过式Ⅴ与六甲基二硅氮烷锂在质子惰性溶剂如四氢呋喃中,在温度约为-90℃至-70℃,优选-78℃反应使式Ⅴ化合物的吗啉酮转化为式Ⅳ的羧酸化合物。然后将三甲基甲硅烷基氯加到反应混合物中,真空除去四氢呋喃溶剂并用甲苯代替。将所得反应混合物加至温度约为100℃至约120℃,优选110℃,并用盐酸处理形成式Ⅳ化合物的羧酸。
在流程1的反应3中,通过用1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺和1-羟基苯并三唑在极性溶剂中如二甲基甲酰胺中处理式Ⅳ化合物,接着经过约15分钟至1小时,优选30分钟后加入羟胺至反应混合物中使式Ⅳ化合物的羧酸转化为相应的式Ⅲ的异羟肟酸化合物。羟胺优选从盐形式如羟胺盐酸盐现场在碱如N-甲基吗啉的存在下产生。另外,羟胺被保护的衍生物或其盐形式(其中羟基是用叔-丁基、苄基或烯丙基醚保护的)可在(苯并三唑-1-基氧)三(二甲氨基)磷鎓六氟磷酸盐和碱如N-甲基吗啉的存在下被使用。除去羟胺保护基可通过氢解苄基保护基或用强酸如三氟乙酸处理叔丁基保护基。烯丙基保护基通过用三丁基氢化锡和乙酸在催化剂双(三苯膦)氯化钯(Ⅱ)的存在下处理除去。N,O-双(4-甲氧基苄基)羟胺也可被用作保护的羟胺衍生物,其中去保护用甲磺酸和三氟乙酸的混合物进行。
在流程1的反应4中,如果需要,通过用氢和氢催化剂如10%钯-炭处理Ⅲ使式Ⅲ的异羟肟酸化合物转化为相应的式Ⅱ的哌啶化合物。
在流程2的反应1中,通过Ⅸ与被保护的下式羟胺衍生物
R27ONH·HCl其中R27为叔丁基、苄基或烯丙基、在二环己基碳化二亚胺、二甲氨基吡啶和质子惰性溶剂如二氯甲烷的存在下反应使式Ⅸ的芳基磺酰基哌嗪化合物(其中R26为苄氧羰基、苄基或叔丁氧羰基)转化为式Ⅷ化合物。选择R26保护基以便可选择性地除去R26而不除去R27保护基,因此,R26不能与R27相同。从式Ⅸ化合物中除去R26保护基是在适于所用具体R26保护基的条件下进行。这些条件包括(a)用氢和氢化催化剂,如10%钯-炭处理,其中R26为苄氧羰基,(b)氢解(其中R26为苄基)或(c)用强酸如三氟乙酸或盐酸处理,其中R26为叔丁氧羰基。
在流程2的反应2中,如果需要,通过Ⅷ与烷基卤化物(其中R5为(C1-C6)烷基)反应使式Ⅷ化合物转化为式Ⅶ的异羟肟酸化合物。然后除去R27异羟肟酸保护基是用氢解苄基保护基或用强酸如三氟乙酸处理叔-丁基保护基。烯丙基保护基可用三丁基氢化锡和乙酸在催化剂双(三苯膦)氯化钯(Ⅱ)存在下处理除去。
在流程3的反应1中,通过Ⅻ与碳化二亚胺和碱如三乙胺反应使式Ⅻ的芳基磺酰胺化合物(其中R25如上定义)转化为相应的式Ⅺ的哌嗪化合物。根据在流程1的反应3中所述方法使式Ⅺ化合物进一步反应得到式Ⅹ的异羟肟酸化合物。
在流程4的反应1中,除去R28保护基及随后式ⅩⅫ化合物(其中Y为氧、硫或碳)的还原胺化得到相应的式ⅩⅪ的亚胺化合物的反应是在适于所用具体的R28保护基的条件下进行的。这些条件包括在流程2的反应1中用于除去R26保护基的那些反应条件。
在流程4的反应2中,通过ⅩⅪ与式R2M(其中M为锂、镁卤化合物或铯卤化物)的亲核试剂反应使式ⅩⅪ的亚胺化合物转化为相应的式ⅩⅩ的哌啶化合物。该反应在溶剂醚如乙醚或四氢呋喃中,在温度约为-78℃至0℃优选约-70℃下进行。
在流程4的反应3中,式ⅩⅩ的哌啶化合物的磺酰化得到相应的式ⅩⅨ的芳基磺酰基哌啶化合物是通过ⅩⅩ与芳基磺酰卤在三乙胺和质子惰性溶剂如二氯甲烷,四氢呋喃或二噁烷在温度约为20℃至30℃优选室温下反应实现的。
在流程4的反应4中,根据在流程1反应3中所述方法使式ⅩⅨ的芳基磺酰基哌啶化合物转化为式ⅩⅨ的异羟肟酸化合物。
在流程5的反应中1,通过除去R29保护基和随后式ⅩⅩⅥ化合物的还原胺化可使式ⅩⅩⅥ化合物,其中R29和R31保护基分别独立地选自苄氧羰基、苄基和叔丁氧羰基及R30为苄氧羰基、(C1-C6)烷基、苄基、烯丙基或叔丁基,转化为相应的式ⅩⅩⅤ的亚胺化合物。选择R29保护基以便选择性地除去R29而不除去R31保护基。从式ⅩⅩⅥ化合物除去R29保护基是在适于所用具体R29保护基而不影响R31保护基的条件下进行。这些条件包括(a)用氢和氢化催化剂如10%钯-炭处理,其中R29为苄氧羰基和R31为叔-丁基,(b)皂化(其中R29为(C1-C6)烷基和R31为叔丁基),(c)氢解(其中R29为苄基和R31为(C1-C6)烷基或叔丁基),(d)用强酸如三氟乙酸或盐酸处理,其中R29为叔丁基和R31为(C1-C6)烷基、苄基或烯丙基、或(e)用三丁基氢化锡和乙酸在催化剂双(三苯膦)氯化钯(Ⅱ)的存在下处理,其中R29为烯丙基和R31为烷基、苄基或叔丁基。可以选择R30保护基以便在相同反应步骤如R29保护基被除去。
在流程5的反应2中,通过ⅩⅩⅤ与式R2M(其中M为锂,卤化镁或卤化钙)的亲核试剂反应使式ⅩⅩⅤ的亚胺化合物转化为相应的式ⅩⅩⅣ化合物。该反应在醚溶剂如乙醚或四氢呋喃,在温度约为-78℃至0℃,优选-70℃下进行。
在流程5的反应3中,皂化式ⅩⅩⅣ的哌嗪化合物得到相应的式Ⅲ芳基磺酰基哌嗪化合物是根据流程4中反应3中所述方法进行的。
在流程5的反应4中,通过(1)如果需要,从ⅩⅩⅢ除去R30和R31保护基,接着(2)根据流程1反应3中所述方法使ⅩⅩⅢ反应使式ⅩⅩⅢ芳基磺酰基哌嗪化合物转化为ⅩⅣ的异羟肟酸化合物。从式ⅩⅩⅢ化合物除去R30和R31保护基是在适于所用具体R30和R31保护基的条件下进行。这些条件包括在流程1的反应1中所述用于除去R25保护基的那些条件。
本发明酸性化合物的药用可接受的盐为用碱形成的盐,即阳离子盐如碱金属和碱土金属盐,如钠、锂、钾、钙、镁及铝盐如铝、三甲基铝、二乙基铝、和三(羟甲基)甲基铝盐。
类似酸加成盐,如无机酸、有机羧酸和有机磺酸例如盐酸、甲磺酸、马来酸的盐也可能被提供一个碱基,如吡啶基(该结构的组成部分)。
式(Ⅰ)化合物或其药用可接受的盐(以下称为本发明化合物)抑制基质金属蛋白酶或肿瘤坏死因子(TNF)的能力以及用它们治疗以基质金属蛋白酶或肿瘤坏死因子为特征的疾病的效果用以下体外鉴定试验来证明。
生物鉴定
抑制人胶原酶(MMP-1)
将人重组体胶原酶与胰蛋白酶用以下比例进行活化:每100μg胶原酶10μg胰蛋白酶。将胰蛋白酶和胶原酶在室温培养10分钟,然后加入5倍过量(50μg/10μg胰蛋白酶)大豆胰蛋白酶抑制剂。
于二甲亚砜中配制10mM抑制剂储液然后根据下列程序稀释:
10mM→120μM→12μM→1.2μM→0.12μM
将每种浓度25微升加到96孔微荧光盘的适当孔中,一式三份。加入酶和底物以后抑制剂的最终浓度为1∶4稀释度。在孔D1-D6中建立阳性对照(酶,无抑制剂),在孔D7-D12建立空白(无酶,无抑制剂)。
将胶原酶稀释至400ng/ml,然后将25μl加到微荧光盘的适当孔中。用于鉴定的胶原酶的最终浓度为100ng/ml。
底物(DNP-Pro-Cha-Gly-Cys(Me)-Ala-Lys(NMA)-NH2)被配成在二甲亚砜中5mM储液并用鉴定缓冲液稀释至20μM。加入50μl底物于微荧光盘中的每个孔中得到最终浓度为10μM,这时鉴定开始。
用荧光读数器(360nM激发,460nm发射)在0时间及间隔20分钟记数。该鉴定在室温进行典型鉴定所需的3小时。
对于空白和含有胶原酶的样品(取三份测定的平均值),作荧光-时间关系图。选择好信号(空白)的时间点和曲线上线性部分的时间点(通常约120分钟)来确定IC50值。每个化合物的每种浓度的零时刻作为空白,并从120分钟数据中减去这些值。用抑制剂浓度对%对照数据(抑制剂荧光值除以单独胶原酶荧光值×100)作图。从50%对照时得到的信号的抑制剂浓度来确定IC50值。
如果IC50值小于0.03μM,那么测定抑制剂的浓度为0.3μM、0.03μM、0.03μM和0.003μM。
对明胶酶(MMP-2)的抑制
抑制明胶酶活性用Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2底物(10μM)在抑制人胶原酶(MMP-1)相同的条件下进行鉴定。
将72KD明胶酶用1mM APMA(对氨基苯基乙酸汞)在4℃活化15小时,并稀释至鉴定用的最终浓度为100mg/ml。抑制剂象抑制人胶原酶(MMP-1)中一样进行稀释得到鉴定用的最终浓度为30μM、3μM、0.3μM和0.03μM。每种浓度一式三份。
用荧光读数器(360nm激发,460nm发射)在0时间及间隔20分钟记数,共进行4小时。
如同每个抑制人胶原酶(MMP-1)确定IC50值。如果IC50值小于0.03μM,那么被测定抑制剂的浓度为0.3μM、0.03μM、0.003μM和0.003μM。
抑制基质溶素活性(MMP-3)
抑制基质溶素活性是依据Weingarten和Feder所述改进的分光光度鉴定法(Weingarten,H,and Feder,J.,Spectrophotometr-ic Assay for Vertebrate Collagenase,Anal,Biochem,147,437-440)进行的。水解硫代类肽(thio peptolide)底物[Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]Co-Leu-Gly-OC2H5]产生硫醇片断,该片断在ELLman试剂存在下可被监测。
将人重组体原基质溶素与胰蛋白酶用1μl比例为10mg/ml胰蛋白酶储液每26μg基质溶素进行活化。将胰蛋白酶和基质溶素在37℃培养15分钟接着将10μl的10mg/ml大豆胰蛋白酶抑制剂在37℃培养10分钟以淬灭蛋白酶活性。
鉴定用总体积250μl分析缓冲液(200mM氯化钠,50mM MES,和10mM氯化钙,PH6.0)在96孔微升盘中进行。用分析缓冲液稀释活化的基质溶素至25μg/ml。把Ellman试剂(3-羧基-4-硝基苯基二硫化物)配成1M的二甲基甲酰胺储液并每孔用50μl分析缓冲液稀释至5mM,使最终浓度为1mM。
于二甲亚砜中配制10mM抑制剂储液并用分析缓冲液连续稀释以便加入50μl至适当孔中产生最终浓度为3μM、0.3μM、0.003μM和0.0003μM。所有情况均一式三份。
用分析缓冲液稀释300mM肽底物的二甲亚砜储液至15mM,并且每孔加入50μl得到底物最终浓度为3μM,这时开始鉴定。空白包括肽底物和Ellman试剂(无酶)在405nM用Molecular DevicesUvmax盘读数器监测产品的形成。
用对胶原酶鉴定相同的方法确定IC50值。
抑制MMP-13
将人重组体MMP-13用2mM APMA(对氨基苯基乙酸汞)在37℃活化1.5小时,并用分析缓冲液(50mM Tris,PH7.5,200mM氯化钠,5mM氯化钙,20μM氯化锌,0.02%brij)稀释至400mg/ml。将25微升稀释的酶加到96孔微荧光盘的每个孔中。然后用在鉴定中为1∶4的比例通过添加抑制剂和底物来稀释酶,得到鉴定用的最终浓度为100mg/ml。
于二甲亚砜中配制成10mM的抑制剂储液,然后用分析缓冲液按抑制人胶原酶(MMP-1)中每个抑制剂稀释程序进行稀释:将每种浓度的25微升加到微荧光盘中,一式三份。鉴定中最终浓度为30μM、3μM、0.3μM和0.03μM。
用为抑制人胶原酶(MMP-1)中的方法制备底物(Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)并将50μl加到每个孔中使鉴定最终浓度为10μM。用荧光读数器(360nM激发,450nm发射)在0时间及每隔5分钟记数,共进行1小时。
阳性对照组有酶和底物(无抑制剂),空白组仅含底物。
IC50值用每个抑制人胶原酶(MMP-1)中的方法确定。如果IC50值小于0.03μM,那么被测定的抑制剂的最终浓度为0.3μM、0.03μM、0.003μM和0.0003μM。
抑制TNF的产生
本发明化合物或其药用可接受的盐抑制TNF产生的能力及因此用它们治疗涉及TNF产生的疾病的效果通过下列体外鉴定来证明。
用一步Ficoll-hypague分离技术从抗凝聚人血浆分离人单核细胞。(2)用含二价阳离子的Hanks平衡盐溶液(HBSS)洗涤单核细胞三次,并再悬浮至于含1%BSA的密度为2×106/ml的HBSS中。用Abbott Cell Dyn 3500分析仪测定差值计数,该测定显示在这些制备中单核细胞范围占总细胞的17-24%。
将180μl细胞悬浮液等分在平底96孔盘(Costar)中。加入化合物和LPS(最终浓度100ng/ml)得到最终体积200μl。所有情况均为一式三份。在湿CO2培养箱中培养4小时后,除去盘子并离心(10分钟约250×g),除去上清液并用R & D ELISA Kit鉴定TNFα。
为抑制基质金属蛋白酶或肿瘤坏死因子的产生而对人给药,可以使用各种常规途径包括口服,非肠道和表面给药。一般地,对于口服或非肠道给药,对于要治疗的患者每天需活性化合物剂量范围约为0.1和25mg/kg(体重),优选约为0.3至5mg/kg。然而,根据要治疗患者的疾病情况,剂量的某些变化将是需要的。无论如何,负责给药的人将确定个体患者的适当剂量。
本发明化合物可在很宽范围内以不同剂量形式进行给药,一般地,本发明化合物的治疗有效量为以剂量形式浓度范围约5.0%至70%(重量)。
对于口服给药,含有各种赋形剂如微晶纤维素,柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸的片剂可与各种崩解剂如淀粉(优选玉米、马铃薯或木薯淀粉),藻酸和某些复合硅酸盐及粒化粘结剂如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶一起使用。另外,根据成片需要,经常使用润滑剂如硬脂酸镁,月桂硫酸钠和滑石。相似类型的固体组合物也可以使用如在明胶胶囊中的填充剂;在这种结合中优选物质还包括乳糖或奶糖以及高分子量的聚乙二醇。当口服需要液体悬浮剂和/或酏剂时,活性成分可与各种甜味剂或校味剂,着色物质或染色剂结合使用,如果需要,乳化剂和/或悬浮剂以及稀释剂如水、乙醇、丙二醇、甘油和各种类结合剂均可使用。
对于非肠道给药(肌内、腹膜内、表皮下和静脉内使用),通常制备活性成分的灭菌注射溶液。本发明治疗化合物的芝麻油或花生油溶液或乙二醇水溶液均可以被使用。水溶液应为适当调节和缓冲的,优选PH大于8,如果必要,首先使液体稀释剂等渗。这些液体溶液适于静脉注射需要。油性溶液适于关节内、肌内和表皮下注射需要。所有这些在灭菌条件下的溶液制剂均可根据本领域技术人员已知的标准药物学技术容易地制备。
另外,将本发明化合物表面给药是可能的,例如,要治疗皮肤炎症时,根据标准药物学方法,将本发明化合物制成乳剂、凝胶、冻胶、糊剂和软膏。
用下列实施例说明本发明,但它并不限定本发明的范围。
实施例1
(+)-(2R*,3R*)-(N-羟基)-1-(4-甲氧基-苯磺酰基)-3-甲基-1,2,3,6-四氢吡啶-2-甲酰胺
(a)向(E)-1-氨基-3-戊-2-醇(2.0g,10.0mmol)的二氯甲烷(50ml)溶液中加入三乙胺(160μl,11.0mmol),接着加入4-甲氧基苯磺酰氯(2.07g,10,0mmol)。将混合物在室温搅拌12小时并用乙酸乙酯稀释。将混合物用水,10%柠檬酸洗涤,干燥(硫酸镁),过滤并浓缩。用硅胶色谱(用2∶1乙酸乙酯-己烷洗脱)纯化粗产物得到(N-(2-羟基-戊-3-烯基)-4-甲氧基苯磺酰胺。
(b)在0℃向(±)-(E)-N-(2-羟基-戊-3-烯基)-4-甲氧基苯磺酰胺(1.2g,4.42mmol)的四氢呋喃-二甲基甲酰胺(10ml,约3∶1)溶液中加入双(三甲基甲硅烷基)氨化钠(4.9ml,1.0M的四氢呋喃溶液)。10分钟后,加入溴乙酸叔丁酯(786ml,4.83mmol)。将混合物温热至室温,搅拌1小时并用饱和氯化铵溶液骤冷。用乙酸乙酯萃取混合物并将合并的萃取液干燥(硫酸钠),过滤并浓缩。用硅胶色谱(用1∶1乙酸乙酯-己烷洗脱)纯化粗产物得到[(2-羟基-戊-3-烯基)-(4-甲氧基苯磺酰基)-氨基)乙酸叔丁酯。
(c)向(±)-(E)-N-(2-羟基-戊-3-烯基)-(4-甲氧基苯磺酰基)-氨基]-乙酰叔丁酯(900mg,2.43mmol)的苯(10ml)溶液中加入三氟乙酸(56μl,0.73mol)。将溶液80℃加热3小时,冷却至室温并浓缩得到(±)-(E)-4-(4-甲氧基苯磺酰基)-6-丙烯基吗啉-2-酮,该产物不需进一步纯化。
(d)在-78℃向双(三甲基甲硅烷基)氨化钠(2.67mmol,1.0M于四氢呋喃)的四氢呋喃(5.0ml)溶液中加入从上步得到的粗(±)-(E)-4-(4-甲氧基苯磺酰基)-6-丙烯基吗啉-2-酮。15分钟后,加入三甲基甲硅烷基氯(1.53ml,12.15mmol)并将混合物温热至室温。除去溶剂(真空)并用甲苯(10ml)代替。将所得混合物在110℃加热3小时,冷却至室温并用1N盐酸处理。搅拌10分钟后,用乙酸乙酯萃取混合物并干燥(硫酸钠)合并的萃取液,过滤并浓缩。用硅胶色谱(用2∶1乙酸乙酯-己烷与1%乙酸洗脱)纯化粗产物得到(±)-(2R*,3R*)-1-(4-甲氧基-苯磺酰基)-3-甲基-1,2,3,6-四氢吡啶-2-羧酸。
(e)向(±)-(2R*,3R*)-1-(4-甲氧基-苯磺酰基)-3-甲基-1,2,3,6-四氢吡啶-2-羧酸(100mg,0.36mmol)的二甲基甲酰胺(5ml)溶液中加入羟基苯并三唑(53mg,0.39mmol)和1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(75mg,0.39mmol)。1小时后,加入盐酸羟胺(75mg,1.08mmol),接着加入三乙胺(150μl,1.08mmol)。搅拌过夜后,用水稀释混合物并用乙酸乙酯萃取。干燥合并的萃取液,过滤并浓缩。用硅胶色谱(用2∶1乙酸乙酯-己烷与1%乙酸洗脱)纯化粗产物得到(±)-(2R*,3R*)-(N-羟基)-1-(4-甲氧基苯磺酰基)-3-甲基-1,2,3,6-四氢吡啶-2-甲酰胺为白色固体。熔点173℃(分解)。质谱(热喷):m/Z 326(m-C(O)N(H)OH,100%,m,7%),(m+H,30%),(m+NH4,10%),1NMR(CDCl3,250MHz,ppm):δ7.72(d,J=8.9Hz,2H),7.03(d,J=8.9Hz,2H),5.66(dq,J=13.0,2.7Hz,1H),5.45(dd,13.0,1.9Hz),4.37(d,7.0Hz,1H)4.06-3.82(m,2H),3.82(s,3H),3.43-3.30(m,1H),2.62-2.31(m,1H),0.97(d,7.5Hz,3H)。
实施例2
N-羟基-1-(4-甲氧基笨磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-甲酰胺。
(a)向甘氨酸叔丁酯(5.0g,29.82mmol)的二氯甲烷(50ml)溶液中加入三乙胺(6.65ml,62.63mmol),接着加入4-甲氧基苯磺酰氯(29.82mmol,6.2g)。将溶液搅拌24小时,用水洗涤并用乙酸乙酯萃取。干燥(硫酸钠)合并的萃取液,过滤并浓缩。用硅胶色谱(用6∶1已烷-乙酸乙酯洗脱)纯化粗产物得到(4-甲氧基苯磺酰氨基)乙酸叔丁酯。
(b)在0℃向(4-甲氧基苯磺酰胺基)乙酸叔丁酯(3.0g,10mmol)的四氢呋喃-二甲基甲酰胺(ml,约3∶1)溶液中加入双(三甲基甲硅烷基)氨化钠(10.0ml,1.0M的四氢呋喃溶液)。10分钟后,加入4-溴-2-甲基-2-丁烯(1.27μl,11.0mmol)。将混合物温热至室温,搅拌1小时并用饱和氯化铵溶液骤冷。用乙酸乙酯萃取混合物并干燥(硫酸钠)合并的萃取液,过滤并浓缩。用硅胶色谱(用1∶1乙酸乙酯-己烷洗脱)纯化粗产物得到[(4-甲氧基苯磺酰基)-(3-甲基-丁-2-烯基)-氨基)乙酸丁酯。
(c)在-78℃将臭氧通入[(4-甲氧基苯磺酰基)-(3-甲基-丁-2-烯基)氨基]乙酸叔丁酯(2.0g,5.4mmol)的二氯甲烷-甲醇(50ml,约1∶1)溶液中至到蓝色不变。加入三苯膦(4.24g,16.2mmol)并将所得溶液在室温搅拌3小时。浓缩得到粗产物,将其用硅胶色谱(用1∶1乙酸乙酯-己烷洗脱)纯化得到[(4-甲氧基苯磺酰基)-(2-氧-乙基)-氨基]-乙酸叔丁酯。
(d)向氯化铬(Ⅱ)(1.3g,10.49mmol)的二甲基甲酰胺(20ml)浆液中加入氯化镍(Ⅱ)(0.026mmol,1mg)的二甲基甲酰胺(1ml)悬浮液,接着加入(反)-β-碘笨乙烯(1.20g,5.24mmol)和[(4-甲氧基苯磺酰基)-2-氧-乙基)氨基]乙酸叔丁酯(900mg,2.62mmol)的二甲基甲酰胺(5ml)混合物。将所得溶液搅拌三小时,用水稀释并用乙酸乙酯萃取。将合并的萃取液用盐水洗涤,干燥(硫酸钠),过滤并浓缩。用硅胶色谱(用3∶2己烷-乙酸乙酯洗脱)纯化粗产物得到(±)-(E)-(2-羟基-4-苯基-丁-3-烯基)-(4-甲氧基苯磺酰基)-氨基]乙酸叔丁酯。
(e)将(±)-(E)-[(2-羟基-4-苯基-丁-3-烯基)-(4-甲氧基苯磺酰基)-氨基]乙酸叔丁酯经过实施例1c所述条件。将粗产物从氯仿中重结晶得到(±)-(E)-4-(4-甲氧基苯磺酰基)-6-苯乙烯基-吗啉-2-酮。
(f)将(±)-(E)-(4-甲氧基苯磺酰基)-6-苯乙烯基-吗啉-2-酮经过实施例1d所述条件。用硅胶色谱(用2∶1己烷-乙酸乙酸与1%乙酸洗脱)纯化粗产物得到(±)-(2R*-3R*)-1-(4-甲氧基苯磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-羧酸。
(g)将(±)-(2R*-3R*)-1-(4-甲氧基苯磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-羧酸经过实施例1e所述条件。用硅胶色谱(用1∶1己烷-乙酸乙酯与1%乙酸洗脱)纯化粗产物得到N-羟基-1-(4-甲氧基苯磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-甲酰胺为白色固体。熔点151-154℃(分解)。质谱[PBMC w/C.I(NH3)]: m/Z 388(m+NH4,100%), 1H NMR(CD3OD)δ7.75(d,J=8.5Hz,2H),7.38-7.12(m,5H),7.04(d,J=8.5Hz,2H),5.91(d,J=8.9Hz,1H),5.28(d,J=9.9Hz,1H),4.89(s,H2O),4.57(d,6.8Hz,1H),4.07(ABq,JAB=18.0Hz,ΔvAB=39.1Hz,2H),3.85(0,3H),3.39(bs,CD3OD) 。
实施例3
(+)-(2R*-3R*)-N-羟基-1-(4-甲氧基笨磺酰基)-3-苯基-哌啶-2-甲酰胺
(a)向(±)-(2R*-3R*)-1-(4-甲氧基苯磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-羧酸(65mg,0.17mmol)(得自实施例2)的溶液中加入苄基盐酸羟胺(32mg,0.20mmol),二环己基碳化二亚胺(41mg,0.20mol)和二甲氨基吡啶(27mg,0.22mmol)。将所得混合物搅拌过夜,用乙酸乙酯稀释,用CeliteTM过滤并蒸发。用硅胶色谱纯化粗产物(用1∶1己烷-乙酸乙酯洗脱)得到(±)-(2R*-3R*)-N-苄氧基-1-(4-甲氧基苯磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-甲酰胺。
(b)向(±)-(2R*-3R*)-N-苄氧基-1-(4-甲氧基苯磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-甲酰胺(35mg,0.073mmol)的乙醇(5ml)溶液中加入10%钯-炭(10mg,5mol)。抽空烧瓶并回注氢气(重复两次)。将反应混合物搅拌1小时,然后用CeliteTM过滤并浓缩。收集白色固体产物(±)-(2R*-3R*)-N-羟基-1-(4-甲氧基苯磺酰基)-3-苯基哌啶-2-甲酰胺。熔点163℃(分解)。质谱[PBMS w/C.I.(NH3)]:m/Z 390(m+H2),(m+NH4),1H NMR(CD3OD)δ7.73(d,J=8.9Hz,2H),7.31-737(m,5H),7.04(d,8.9Hz,2HO,4.89(s,H2O),4.34(d,J=5.4Hz,1H),3.86(s,3H),3.74-3.63(m,2H),3.31(bs,CD3OD),2.99-2.90(m,1H),2.58-2.52(m,1H),1.94-1.88(m,1H),1.67-160(m,2H)。
实施例4
(+)-N-羟基-1-(4-甲氧基苯磺酰基)-2-哌嗪甲酰胺盐酸盐
(a)向(±)-4-苄氧羰基-2-哌嗪羧酸(1.90g,7.2mmol)的二烷-水(10ml,约1∶1)溶液中加入1N氢氧化钠溶液(15ml,15mmol),接着加入4-甲氧基苯磺酰氯。将溶液搅拌1小时,用盐酸酸化并用乙酸乙酯萃取。将合并的萃取液干燥(硫酸钠),过滤并浓缩。用硅胶色谱(用2∶1乙酸乙酯-己烷与1%乙酸洗脱)纯化粗产物得到(±)-1-(4-甲氧基苯磺酰胺)-4-苄氧羰基-2-哌嗪羧酸。
(b)向(±)-1-(4-甲氧基苯磺酰基)-4-苄氧羰基-2-哌嗪羧酸(100mg,0.23mmol)的二氯甲烷(5ml)溶液中加入O-叔丁基盐酸羟胺(35mg,0.28mmol),二甲氨基吡啶(37mg,0.30mmol)和二环己基碳化二亚胺(57mg,0.28mmol)。搅拌过夜后,用己烷稀释反应物并滤出固体沉淀。浓缩溶液并用硅胶色谱(用2∶1乙酸乙酯-己烷与1%乙酸洗脱)纯化粗产物得到(±)-N-(叔丁氧基)-1-(4-甲氧基苯磺酰基)-4-苄氧羰基-2-哌嗪甲酰胺。
(c)向(±)-N-(叔丁氧基)-1-(4-甲氧基苯磺酰基)-4-苄氧羰基-2-哌嗪甲酰胺(68mg,0.134mmol)的甲醇(6ml)溶液中加入10%钯-碳(7mg)。将烧瓶抽空并用氢气再充气(重复二次)。将反应混合物搅拌1小时,同时用CelieTM过滤并浓缩。产物(±)-N-(叔丁氧基)-1-(4-甲氧基苯磺酰基)-2-哌嗪甲酰胺用于下步而不需进一步纯化。
(d)向(±)-N-(叔丁氧基)-1-(4-甲氧基苯磺酰基)-2-哌嗪甲酰胺(30mg)的二氯甲烷溶液中加入1滴乙醇。将溶液冷却至-10℃并鼓泡氯化氢气体5分钟。然后密封反应器并搅拌24小时,同时蒸发使体积减至1/3,过滤沉淀并干燥(真空)得到(±)-N-羟基-1-(4-甲氧基苯磺酰基)-2-哌嗪甲酰胺盐酸盐为白色固体。熔点167℃(分解)。质谱(热喷):m/Z 343(m+1 100%).1H NMR(CD3OD,250 MHz,ppm):δ7.76(d,J=8.9Hz,2H),7.07(d,J=8.9Hz,2H),3.87(bs,H2O),4.19(d,J=3.3Hz,1H),3.87(s,3H),3.58(bd,J=6.2Hz,1H),3.42(bd,J=6.1Hz,1H),3.30(bs,CD3OD),3.16(d,J=13.5Hz,1H),2.87(bd,J=13.3Hz,1H),2.69(dd,J=13.3,3.0 Hz 1H),2.51(dt,J=12.5,3.8Hz,1H)。
实施例5
N-羟基-1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-甲酰胺
(a)在0℃向(±)-苄氧羰基氨基-2-叔丁氧羰基氨基丙酸酯(2.8g,7.9mmol)的二氯甲烷(25ml)溶液中加入溶解在二噁烷(25ml)中的盐酸(g)溶液。将溶液在0℃搅拌4小时然后浓缩。将粗产物3-苄氧羰基氨基-2-氨基丙酸甲酯盐酸盐用于下步而无需进一步纯化。
(b)将3-苄氧羰基氨基-2-氨基丙酸甲酯盐酸盐经过实施例1a所述条件。用硅胶色谱(用1∶1己烷-乙酸乙酯洗脱)纯化粗产物得到(±)-3-苄氧羰基氨基-2-(4-甲氧基苯磺酰氨基)-丙酸甲酯。
(c)将(±)-3-苄氧羰基氨基-2-(4-甲氧基苯磺酰氨基)丙酸甲酯经过实施例1所述条件。用硅胶色谱(用3∶2乙酸乙酯-己烷洗脱)纯化粗产物得到(±)-3-苄氧羰基氨基-2-[叔丁氧羰基甲基-(4-甲氧基苯磺酰基)-氨基]丙酸甲酯。
(d)将(±)-3-苄氨羰基氨基-2-[叔丁氧羰基甲基-(4-甲氧基苯磺酰基)-氨基]丙酸甲酯经过实施例4C所述条件。将产物3-氨基-2-[叔丁氧羰基甲基-(4-甲氧基苯磺酰基)-氨基]丙酸甲酯用于下步而无需进一步纯化。
(e)在0℃向3-氨基-2-[叔丁氧羰基甲基-(4-甲氧基苯磺酰基)-氨基]丙酸甲酯(2.46g,6.1mmol)的二氯甲烷(20ml)溶液中加入三氟乙酸(5ml)。将上述溶液在0℃搅拌12小时然后浓缩。将粗产物3-氨基-2-[羧甲基-(4-甲氧基苯磺酰基)-氨基]丙酸甲酯三氟乙酸盐用于下步而无需进-步纯化。
(f)向3-氨基-2-[羧甲基-(4-甲氧基苯磺酰基)-氨基]丙酸甲酯三氟乙酸盐(2.11g,6.1mmol)的二氯甲烷(5ml)溶液中加入1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(1.76g,9.2mmol)和三乙胺(3.4ml,24.4mmol)。将所得混合物搅拌过液,用乙酸乙酯稀释并用1N盐酸洗涤。干燥(硫酸钠)有机相,过滤并浓缩。用硅胶色谱(用乙酸乙酯洗脱)纯化粗产物得到1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-羧酸甲酯。
(g)在0℃向1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-羧酸甲酯(200mg,0.61mmol)的甲醇-四氢呋喃-水(5ml,约6∶2∶1)溶液中加入氢氧化锂(64mg,1.53mmol)。将所得混合物搅拌30分钟,用1N盐酸酸化并用乙酸乙酯萃取。干燥(硫酸钠)合并的萃取液,过滤并浓缩。将粗产物1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-羧酸用于下步而无需进一步纯化。
(h)向1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-羧酸(166mg,0.53mmol)的二氯甲烷(5ml)溶液中加入邻-苄基盐酸羟胺(255mg,1.6mmol),1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(153mg,0.8mmol)和三乙胺(370μl,2.65mmol)。将所得混合物搅拌过夜,用乙酸乙酯稀释并用1N盐酸洗涤。干燥(硫酸钠)有机相,过滤并浓缩。用硅胶色谱(用5%甲醇的二氯甲烷洗脱)纯化粗产物得到N-(苄氧基)-1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-甲酰胺。
(ⅰ)将N-(苄氧基)-1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-甲酰胺经过实施例4c所述条件得到N-羟基-1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-甲酰胺的白色固体。质谱(热喷):m/Z 343(m+H,60%),(m+NH4,17%).1H NMR(CD3OD),250 MHz,ppmδ7.79(d,J=8.9Hz,2H),4.90(s,H2),4.47(dd,J=5.0,3.2Hz,1H),(4.03,s,2H),3.88(s,3H),3.47(dd,J=13.4,3.2Hz,1H),3.35-3.30(m,1H),3.30(s,CD3OD)。
实施例6
N-羟基-1-(4-甲氧基苯磺酰基)-吗啉-2-甲酰胺
(a)将吗啉-2-羧酸经过实施例4a所述条件得到1-(4-甲氧基苯磺酰基)-吗啉-2-羧酸。
(b)将1-(4-甲氧基苯磺酰基)-吗啉-2-羧酸经过实施例5h所述条件得到N-苄氧基-1-(4-甲氧基苯磺酰基)-吗啉-2-甲酰胺。
(c)将N-苄氧基-1-(4-甲氧基苯磺酰基)-吗啉-2-甲酰胺经过实施例4c所述条件得到N-羟基-1-(4-甲氧基苯磺酰基)-吗啉-2-甲酰胺为白色泡沫。质谱(热喷):m/Z 343(m+H,100%),[a]D:+57°(C=0.60,CHCl3,1H NMR(CDCL3,250 MHz,ppm)δ7.78(bd,J=8.0Hz,2H),7.38(bs,1H),7.01(bd,J=8.0Hz,2H),(4.34(bs,J=2H),3.87(s,3H),3.85-3.30(m,3H),3.30-3.15(m,2H)。
Claims (11)
1、下式化合物:或其药用可接受的盐,其中不连续链代表任意的双键;
X为碳、氧或硫;
Y为碳、亚砜、或砜;
R1、R2、R3、R4、R5、R6、R7、R8和R9选自氢,(C1-C6)烷基,该(C1-C6)烷基可任意被(C1-C6)烷氨基,(C1-C6)烷硫基、(C1-C6)烷氧基,三氟甲基,(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(C1-C6)烷基,(C1-C6)烷基(羟基亚甲基),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)烷氨基或((C1-C6)烷氨基)2取代;(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)炔基,(C6-C10)芳基(C2-C6)炔基,(C5-C9)杂芳基(C2-C6)炔基,(C1-C6)烷氨基,(C1-C6)烷硫基、(C1-C6)烷氧基,三氟甲基,(C1-C6)烷基(二氟亚甲基),(C1-C3)烷基(二氟亚甲基)(C1-C3)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,R13(C1-C6)烷基,其中R13为(C1-C6)酰基哌嗪基,(C6-C10)芳基哌嗪基,(C5-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,(C5-C9)杂芳基(C1-C6)烷基哌嗪基,吗啉代,硫代码啉代,哌啶子基,吡咯烷子基(pyrrolidino),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;
或下式基团其中n为0-6;
Z为羟基,(C1-C6)烷氧基或NR14R15,其中R14和R15分别独立地选自氢,(C1-C6)烷基,该(C1-C6)烷基可任意被(C1-C6)烷基哌啶基、(C6-C10)芳基哌啶基、(C5-C9)杂芳基哌啶基、(C6-C10)芳基、(C5-C9)杂芳基、(C6-C10)芳基(C6-C10)芳基或(C3-C6)环烷基取代;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)酰基哌啶基,(C6-C10)芳基,(C5-C9)杂芳基,(C6-C10)芳基(C6-C10)芳基,(C3-C6)环烷基,R16(C2-C6)烷基,(C1-C5)烷基(CHR16)(C1-C6)烷基,其中R16为羟基,(C1-C6)酰氧基,(C1-C6)烷氧基,哌嗪基,(C1-C6)酰氨基,(C1-C6)烷硫基,(C6-C10)芳硫基,(C1-C6)烷基亚磺酰基,(C6-C10)芳基亚磺酰基,(C1-C6)烷基次硫酰基(sulfoxyl),(C6-C10)芳基次硫酰基,氨基,(C1-C6)烷氨基,((C1-C6)烷基)2氨基,(C1-C6)酰基哌嗪基,(C1-C6)烷基哌嗪基,(C6-C10)芳基(C1-C6)烷基哌嗪基,(C5-C9)杂芳基(C1-C6)烷基哌嗪基,吗啉代,硫代码啉代,哌啶子基或吡咯烷子基;R17(C1-C6)烷基,(C1-C5)烷基(CHR17)(C1-C6)烷基,其中R17为哌啶基或(C1-C6)烷基哌啶基;及CH(R18)COR19,其中R18为氢,(C1-C6)烷基,(C6-C10)芳基(C1-C6)烷基,(C5-C9)杂芳基(C1-C6)烷基,(C1-C6)烷硫基(C1-C6)烷基,(C6-C10)芳硫基(C1-C6)烷基,(C1-C6)烷基亚磺酰基(C1-C6)烷基,(C6-C10)芳基亚磺酰基(C1-C6)烷基,(C1-C6)烷基磺酰基(C1-C6)烷基,(C6-C10)芳基磺酰基(C1-C6)烷基,羟基(C1-C6)烷基,氨基(C1-C6)烷基,(C1-C6)烷基氨基(C1-C6)烷基,((C1-C6)烷基氨基)2(C1-C6)烷基,R20R21NCO(C1-C6)烷基或R20OCO(C1-C6)烷基,其中R20和R21分别独立地选自氢,(C1-C6)烷基,(C6-C10)芳基(C1-C6)烷基及(C5-C9)杂芳基(C1-C6)烷基;和R19为R22O或R22R23N,其中R22和R23分别独立地选自氢,(C1-C6)烷基,(C6-C10)芳基(C1-C6)烷基和(C5-C9)杂芳基(C1-C6)烷基;
或R14和R15,或R20和R21,或R22和R23一起形成氮杂环丁基、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(quinolinyl)、四氢异喹啉基、(C1-C6)酰基哌嗪基、(C1-C6)烷基哌嗪基、(C6-C10)芳基哌嗪基、(C5-C9)杂芳基哌嗪基或选自以下基团的桥合二氮杂双环烷基环。abcde其中r为1,2或3;
m为1或2;
P为0或1;及
Q为氢、(C1-C3)烷基、(C1-C6)酰基或(C1-C6)烷氧基氨基甲酰基;
或R1和R2,或R3和R4,或R5和R6一起形成羰基;
或R1和R2,或R3和R4,或R5和R6,或R7和R8可以一起形成一(C3-C6)环烷基、氧杂环己基、硫代环己基、2,3-二氢化茚基或1,2,3,4-四氢化萘基环或一下式基团其中R24为氢、(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;和
Ar为(C6-C10)芳基或(C5-C9)杂芳基,其中每个可任意被(C1-C6)烷基,一个或两个(C1-C6)烷氧基、(C6-C10)芳氧基或(C5-C9)杂芳氧基取代;
条件是当R8不是氢时,R7不是氢;
条件是当R5不是氢时,R6不是氢;
条件是当R4不是氢时,R3不是氢;
条件是当R1不是氢时,R2不是氢;
条件是当R1、R2和R9是含有杂原子的取代基时,
杂原子不能直接连结在2-或6-位;
条件是当X是氮时,R4不存在;
条件是当X是氧、硫、亚砜、砜或氮而且R1、R2、R5和R6中的一个或多个基团为含有杂原子的取代基时,杂原子不能直接连结在4-或6-位;
条件是当Y为氧、硫、亚砜、砜或氮而且R3、R4、R7和R8中的一个或多个基团各自为含有杂原子的取代基时,杂原子不能直接连结在3-或5-位;
条件是当X为氧、硫、亚砜或砜时,R3和R4不存在;
条件是当Y为氮时,R4不存在;
条件是当Y为氧、硫、亚砜或砜时,R5和R6不存在;
条件是当Y为氮时,R6不存在;
条件是当不连续链代表双键时,R4和R6不存在;
条件是当不连续链代表双键时R3和R5各自为含杂原子取代基,杂原子不能直接连结在位置X和Y上;
条件是当X或Y位任一个为氧、硫、亚砜、砜或氮时,另一个X或Y为碳;
条件是当X或Y定义为杂原子时,不连续链不代表双键;
条件是当R1、R2、R3、R4、R5、R6、R7、R8和R9均定义为氢或(C1-C6)烷基,X或Y任一个为氧、硫、亚砜、砜或氮,或不连续链代表双键。
2、根据权利要求1的化合物,其中Ar为4-甲氧基苯基或苯氧基苯基。
3、根据权利要求1的化合物,其中R8为(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,羧酸或羧酸(C1-C6)烷基。
4、根据权利要求1的化合物,其中R2,R3、R6、R7和R9为氢。
5、根据权利要求1的化合物,其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R8为(C6-C10)芳基炔基或(C5-C9)杂芳基炔基。
6、根据权利要求1的化合物,其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R8为羧酸或羧酸(C1-C6)烷基。
7、根据权利要求1的化合物,其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R5为(C6-C10)芳基炔基或(C5-C9)杂芳基炔基。
8、根据权利要求1的化合物,其中Y为碳,Ar为4-甲氧基苯基或4-苯氧基苯基及R5为羧酸或羧酸(C1-C6)烷基。
9、根据权利要求1的化合物,其中Y为碳,Ar为4-甲氧基苯基或苯氧基苯基及R5为(C1-C6)烷基氨基。
10、根据权利要求1的化合物,其中所说化合物选自:
(+)-(2R*,3R*)-(N-羟基)-1-(4-甲氧基-苯磺酰基)-3-甲基-1,2,3,6-四氢吡啶-2-甲酰胺;
N-羟基-1-(4-甲氧基苯磺酰基)-3-苯基-1,2,3,6-四氢吡啶-2-甲酰胺;
(+)-(2R*-3R*)-N-羟基-1-(4-甲氧基苯磺酰基)-3-苯基-哌啶-2-甲酰胺;
(+)-N-羟基-1-(4-甲氧基苯磺酰基)-2-哌嗪-甲酰胺盐酸盐;
N-羟基-1-(4-甲氧基苯磺酰基)-5-氧代-哌嗪-2-甲酰胺;和
N-羟基-1-(4-甲氧基苯磺酰基)-吗啉-2-甲酰胺。
11、一种药物组合物,用于(a)治疗哺乳动物包括人的选自下述的疾病:关节炎、癌症、组织溃疡、再狭窄、牙周疾病、大疱性表皮松解、巩膜炎和其它以基质金属蛋白酶活性为特征的疾病,艾滋病、脓毒病、败血症休克以及其它涉及肿瘤坏死因子的产生的疾病或(b)抑制哺乳动物包括人的基质金属蛋白酶或肿瘤坏死因子的产生,包括治疗或抑制有效量的权利要求1的化合物或其药用可接受的盐和药用可接受的载体。
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