CN1147481C - 作为基质金属蛋白酶抑制剂的嘧啶-2,4,6-三酮 - Google Patents
作为基质金属蛋白酶抑制剂的嘧啶-2,4,6-三酮Info
- Publication number
- CN1147481C CN1147481C CNB008035261A CN00803526A CN1147481C CN 1147481 C CN1147481 C CN 1147481C CN B008035261 A CNB008035261 A CN B008035261A CN 00803526 A CN00803526 A CN 00803526A CN 1147481 C CN1147481 C CN 1147481C
- Authority
- CN
- China
- Prior art keywords
- cancer
- compound
- formula
- phenoxyphenyl
- pyrimidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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- 230000004962 physiological condition Effects 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
新的式I化合物,其中R1为氢,烷基,取代烷基,烯基,取代烯基,炔基,取代炔基,烷氧基,取代烷氧基,芳氧基,或烷基烷氧基,和R2为芳氧基;式I的酸化合物的药物可接受的盐及其前体药物,可以用于治疗和控制与白明胶酶-A和/或白明胶酶-B过度表达有关的癌症,特别是皮肤癌、乳腺癌、***癌、结肠癌、肺癌和胃癌,并还用于其它与细胞外基质未调控的降解有关的其它疾病,包括风湿性关节炎、骨关节炎、多发性硬化、角膜溃疡、牙周疾病等。
Description
技术领域
本发明涉及药物化学领域,具体地涉及用于治疗和控制与白明胶酶-A和/或白明胶酶-B过度表达有关的癌症以及与细胞外基质未调控的降解有关的其它疾病的新的式I化合物,及其药物可接受的盐和前体药物,和含有它们的药物组合物。
发明内容
本发明涉及式I化合物:
其中
R1为氢,烷基,取代烷基,烯基,取代烯基,炔基,取代炔基,烷氧基,取代烷氧基,芳氧基,或烷基烷氧基,和
R2为芳氧基;
式I的酸化合物的药物可接受的盐,及其前体药物。
本发明的化合物为基质金属蛋白酶抑制剂,用于治疗或控制与白明胶酶-A和/或白明胶酶-B过度表达有关的癌症,特别是皮肤癌、乳腺癌、***癌、结肠癌、肺癌和胃癌。本发明的化合物还用于其它与细胞外基质未调控的降解有关的其它疾病,包括风湿性关节炎、骨关节炎、多发性硬化、角膜溃疡、牙周疾病等。
前体药物是指一种化合物,其在生理条件下可以转化成式I化合物或其药物可接受的盐。前体药物优选为式I化合物或其药物可接受盐的酰基或烷基甲基醚衍生物。
在本文中使用的术语“烷基”是指含有最多13个、优选最多7个碳原子的直链或支链烷基基团,如甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、己基等。
术语“取代烷基”是指被一个或多个取代基取代的烷基,取代剂的例子是羟基、卤素和芳基。
术语“烯基”是指含有最多13个碳原子、优选最多7个碳原子、至少2个碳原子并含有至少一个双键的的直链或支链烃基,如乙烯基、丙烯基、丁烯基、戊烯基、己烯基等。
术语“取代烯基”是指被一个或多个取代基取代的烯基,取代剂的例子是羟基、卤素和芳基。
术语“炔基”是指含有最多13个碳原子、优选最多7个碳原子、至少2个碳原子并含有至少一个三键的的直链或支链烃基。
术语“取代炔基”是指被一个或多个取代基取代的炔基,取代剂的例子是羟基、卤素和芳基。
术语“烷氧基”是指含有最多11个碳原子、优选最多5个碳原子的直链或支链烷氧基,如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基等。
术语“取代烷氧基”是指被一个或多个取代基取代的烷氧基,取代剂的例子是羟基、卤素和芳基。
术语烷基烷氧基是指烷基或取代烷基基团与烷氧基或取代烷氧基基团的组合。
单独的或组合形式的术语“芳基”,是指芳香碳环或杂环,它是未取代的或被一个或多个,优选一个至三个取代基取代,取代基的例子是烷基、羟基、烷氧基和卤素。芳香碳环的例子是苯基和萘基。芳香杂环的例子是吡啶基、吡咯基、噻吩基、吡唑基、咪唑基、噻唑基、噁唑基、***基、四唑基、噁二唑基、硫二唑基、苯并呋喃基、苯并噻吩基、benzinidazalo、苯并***基、喹啉基、异喹啉基和吲哚基。最优选芳基为未取代的苯基或被一个或多个,优选一个至三个取代基取代的苯基,取代基的例子是卤素、烷基、羟基、烷氧基和卤素。
术语“卤素”是指氟、氯、溴或碘。
术语“酰基”是指从链烷酸衍生的基团,例如乙酰基、丙酰基或丁酰基,或从芳香羧酸衍生的基团,例如苯甲酰基。链烷酸上的取代基的例子包括下列中的一个或多个基团:羟基、烷氧基、氨基、卤素、硫烷基、羧基、羧酸衍生物或烷基亚磺酰基等。芳香羧酸上的取代基的例子包括下列中的一个或多个基团:卤素、烷基、羟基、苯甲氧基、烷氧基、卤代烷基、硝基、氨基、氰基等。
优选R1为氢,烷基,取代烷基,或取代烷氧基。更优选R1为氢,含有最多7个碳原子的烷基,含有最多7个碳原子的取代烷基(优选羟甲基),或含有最多5个碳原子的取代烷氧基(优选苯甲氧基)。
优选R2在对位。更优选R2为苯氧基。
最优选的是化合物5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮,5-己基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮,5-苯甲氧甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮,和5-(2-羟基乙基)-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮。
式I化合物可以通过下列反应路线I-II制备。
式I化合物可以通过下列反应路线I制备。
反应路线1
式III化合物是通过在非质子溶剂如四氢呋喃(THF)中应用强碱如氢化钠、二异丙基氨基化锂或二(三甲基甲硅烷基)氨基化锂处理式II化合物来制备的。然后将得到的阴离子与碳酸二甲酯或氯甲酸甲酯在从室温到回流温度下进行反应,得到式III化合物。
式IV化合物是通过式III化合物在碱性溶液如甲醇钠的甲醇溶液中、回流下与脲反应来制备的。
式I化合物的制备是通过式IV化合物在非质子溶剂如THF中与强碱如氢化钠、二异丙基氨基化锂或二(三甲基甲硅烷基)氨基化锂反应,形成阴离子。然后将该阴离子在从室温到回流温度下应用烷基卤化物如甲基碘、己基溴、烯丙基溴或苄基氯甲基醚进行处理。然后通过色谱除去N-取代的-2,4,6-三酮,以提供所需的式I化合物。
式II化合物是已知的,或可以通过已知方法制备。
式I化合物还可以按反应路线II的描述进行制备。
式V化合物的制备是通过式III化合物在非质子溶剂如THF中与强碱如氢化钠、二异丙基氨基化锂或二(三甲基甲硅烷基)氨基化锂反应。然后将得到的阴离子在从室温到回流温度下应用烷基卤化物如甲基碘、己基溴、烯丙基溴或苄基氯甲基醚进行处理。
在式V化合物中R1为羟甲基的情况下,式V化合物还可以通过式III化合物在非质子溶剂如THF中与强碱如氢化钠、二异丙基氨基化锂或二(三甲基甲硅烷基)氨基化锂反应进行制备。然后将得到的阴离子用环氧乙烷处理。或者,在式V化合物中R1为羟甲基的情况下,式V化合物的制备还可以通过式III化合物、2-(2-丙烯基)-2-(4-苯氧基-苯基)丙二酸二甲酯与臭氧进行氧化裂解,并应用膦或硫醇还原得到的臭氧化物,得到醛,然后应用还原剂如硼氢化钠将得到的醛还原成醇。
式I化合物是通过在膏状Mg(OCH3)2存在下、80-100℃、完成反应所需的时间内加热式I化合物与脲来制备的。
如果需要,式I的酸化合物可以按照已知方法与碱反应转化成药物可接受的盐。适合的盐不仅是从无机碱衍生的那些盐,例如钠、钾或钙盐,还有从有机碱,例如乙二胺、单乙醇胺或二乙醇胺衍生的那些盐。
前体药物的制备,例如通过活性酸与式I化合物按已知方法反应,或通过卤代甲基烷基醚与式I化合物按已知方法反应。
式I化合物及其药物可接受的盐和前体药物能抑制基质金属蛋白酶,因此可用于治疗或控制与白明胶酶-A和/或白明胶酶-B过度表达有关的癌症,特别是皮肤癌、乳腺癌、***癌、结肠癌、肺癌和胃癌。本发明的化合物还用于其它与细胞外基质未调控的降解有关的其它疾病,包括风湿性关节炎、骨关节炎、多发性硬化、角膜溃疡、牙周疾病等。
人72kDa白明胶酶按照已知方法从胎儿肺纤维原细胞的条件培养液纯化。该酶以原型在-80℃下储存,使用前通过在37℃下用1mM氨基苯基乙酸汞化物(APMA)处理1小时进行活化,然后在使用前用反应缓冲液进行渗析。人嗜中性粒细胞白明胶酶(95kDa白明胶酶)按照已知方法从NSO-细胞的条件培养液纯化。该酶同样以酶原型在-80℃下储存。在37℃下用胰岛素(5μg/mL)处理1小时进行活化,然后加入牛胰腺胰岛素抑制剂至50μg/mL。人matrilysin从作为泛素熔合构建体的细菌表达***获得,Welch,A.R.,Holman,C.M.,Browner,M.F.,Gehring,M.R.,Kan,C.-C.,& VanWart,H.E.(1995)Arch.Biochem.Biophys.324,59-64。应用1mM APMA(1小时,37℃)活化,然后纯化matrilysin的成熟型,并将活性酶在-80℃下储存。人胶原酶-3的催化域通过类似于matrilysin的方法获得。用于该研究的胶原酶-3的最终型由全长胶原酶序列的残基Tyr104-Asn274构成。人stromelysin-1的催化域通过E.大肠杆菌表达来制备,并按照已知方法纯化;该活化的催化域在-80℃下储存。
应用荧光团底物的检测方法:Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2,(Dnp=二硝基苯基;Cha=环己基丙氨酸;Cys(Me)=S-甲基半胱氨酸,Lys(NMA)=Nε-甲基邻氨基苯甲酰基-l-赖氨酸)。储备液在DMSO中制备。式I化合物(抑制剂)的储备溶液也在DMSO中制备。在指示的酶缓冲液中,所有反应具有的净最终DMSO水平在5%(v/v)。
对于白明胶酶-A和白明胶酶-B,该缓冲液为pH 7.5,50mM TrisHCl,200mM NaCl,5mM CaCl2,20μM ZnCl2,0.05%(wt/v)Brij-35。对于matrilysin和胶原酶-3的催化域,该缓冲液组成为pH 7.5,50mM Hepes,200mM NaCl,5mM CaCl2,20μM ZnCl2,0.05%(wt/v)Brij-35。在所有情况下最终底物浓度为10μM。酶的近似浓度为:白明胶酶-A,0.8nM;白明胶酶-B,0.5nM;胶原酶-3,0.4nM;matrilysin,10nM。对于进行肽裂解检测,含有缓冲液和式I化合物的容器在37℃下进行预平衡,然后通过连续加入酶和底材的浓缩储备液起始反应,在37℃下持续保温。在30-120分钟之间的连续时间点,取出50μL等分试样,通过在黑色、平底微量滴定板的孔上加入150μL 30mM EDTA(pH7.4)终止酶反应。通过终止反应的荧光读数(激发波长:355nm;发射波长:460nM)来确定底物的转化程度。阳性对照在没有抑制剂情况下进行,阴性对照没有酶,显示出可以忽略的自发裂解。
荧光对时间(30-120分)作图是线性的;与标准相比,在所有情况下下显示底物转化<20%。从适合荧光时程的线性最小二乘方获得每个抑制剂浓度的比率。在抑制剂浓度[I]下的抑制百分比计算如下:
%抑制[I]=100(1-比率[I]/比率PC)
其中
%抑制[I]=在抑制剂浓度[I]下的抑制百分比
比率[I]=在抑制剂浓度[I]下的比率
比率PC=阳性对照的比率
然后通过将%抑制[I]的浓度关系符合单一结合等温线,获得该抑制剂的IC50。
%抑制[I]=100(([I]/(IC50+[I]))
stromelysin-1的测定:应用相同的底物但用改进的方案来测定stromelysin-1的催化域。该检测缓冲液位为pH 6.5 50mM Mes,2.5mMEDTA,5mM CaCl2,和0.05%(wt/v)Brij-35。底物浓度为10μM,酶浓度为10nM。反应在室温下进行。在黑色、平底微量滴定板的孔上合并适当部分的缓冲液、底物和抑制剂。通过加入一部分酶储备液开始反应,60分钟后,直接读取产生的荧光数。阳性对照在没有抑制剂情况下进行,阴性对照没有酶,显示出在检测过程中增长有限;为了矫正酶反应,将该背景荧光值从阳性对照和抑制反应的值中减去。
该%抑制[I]计算如下:
%抑制[I]=100(1-荧光[I]/荧光PC)
其中荧光[I]=在60分钟时观察到的抑制剂浓度[I]的矫正荧光
荧光PC=在60分钟时观察到的阳性对照的矫正荧光
然后通过将%抑制[I]符合如上所示的单一位点结合等温线,获得该抑制剂的IC50。
在下表中提供了式I化合物的IC50。
化合物 | Strom-1 | Matr | Coll-3 | GelA | GelB |
A | 2μM | >50μM | 65nM | 80nM | 52nM |
B | 2μM | >50μM | 78nM | 67nM | 50nM |
C | 930nM | >50μM | 47nM | 26nM | 23nM |
D | ------ | ------ | ------ | 59nM | 118nM |
A=5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮
B=5-己基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮
C=5-苯甲氧甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮
D=5-(2-羟基乙基)-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮。
式I化合物及其盐和前体药物可以用作医药,例如以药物制剂的形式,其可以口服给药,例如以片剂、包衣片、糖衣丸、硬或软明胶胶囊、溶液、乳剂、混悬液的的形式。它们还可以直肠给药,例如以栓剂的形式,或非胃肠给药,例如以注射液的形式。
为了生产药物制剂,这些化合物可以与治疗惰性、无机或有机载体复配。乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐可以用作如片剂、包衣片、糖衣丸和硬明胶胶囊的载体。软明胶胶囊适合的载体为植物油、蜡、脂肪、半固体或液体多元醇。然而根据活性成分的性质,在软明胶胶囊的情况下通常不需要载体。制备溶液剂和糖浆剂适合的载体为水、多元醇、蔗糖、转化糖和葡萄糖。注射剂适合的载体为水、醇、多元醇、甘油和植物油。栓剂适合的载体为天然或硬化油、蜡、脂肪和半液体多元醇。
该药物制剂还可以含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、用于改变渗透压的盐、缓冲液、包衣剂或抗氧剂。它们还可以含有其它有治疗价值的物质。
式I化合物及其上述盐和前体药物可以用于治疗或控制与白明胶酶-A和/或白明胶酶-B过度表达有关的癌症,特别是皮肤癌、乳腺癌、***癌、结肠癌、肺癌和胃癌。本发明的化合物还用于其它与细胞外基质未调控的降解有关的其它疾病,包括风湿性关节炎、骨关节炎、多发性硬化、角膜溃疡、牙周疾病等。该剂量可以在很宽的范围内变化,并会根据每个具体病例的个体需要而调整。通常,在成年人口服或非胃肠给药时,每日剂量大约为10mg-1000mg,优选100mg-500mg应该是合适的,尽管当发现有利时可以超过该上限。每日剂量可以单剂量或多剂量给药,或者对于非胃肠给药,可以持续输注给药。
下列实施例是为了说明而不是为了限制本发明。在本文中,THF表示四氢呋喃,EtOAc表示乙酸乙酯。
具体实施方式
实施例1
向干燥THF(30mL)中的NaH悬浮液(1.02g 60%的在用己烷洗涤的矿物油中的NaH,0.61g,23.6mmol)中,加入在干燥THF(10mL)中的(4-苯氧苯基)乙酸甲酯(2.7g,11.1mmol)。将得到的混合物在室温下搅拌30分钟,然后加入碳酸二甲酯(4.0g,3.75mL,44.4mmol)。将加热得到的反应混合物回流过夜,然后冷却至室温,用1 N HCl(60mL)猝灭反应,用***(2×100mL)提取。合并有机体提取物,用水洗涤,然后用盐水洗涤,干燥(Na2SO4),浓缩,应用HPLC(多孔微球硅胶,应用15%EtOAc/己烷洗脱)纯化,得到2.56g 2-(4-苯氧基苯基)丙二酸二甲酯白色固体:1H NMR(200mHz,CDCl3,)δ7.39-6.92(9H,m),4.65(1H,s),3.75(6H,s)。
实施例2
向NaOCH3溶液(通过将0.23g的金属Na与7.2mL干燥CH3OH反应制备)中,加入2-(4-苯氧基苯基)丙二酸二甲酯(1.0g,3.33mmol),然后加入脲(0.4g,6.66mmol)。将得到的白色反应混合物回流24小时,然后冷却至0℃,用3N盐酸酸化。过滤白色固体,用水洗涤,干燥得到900mg粗产品。用EtOAc/己烷(1∶1)研磨进一步纯化,得到5-(4-苯氧基苯基)嘧啶-2,4,6-三酮白色粉末(830mg):1H NMR(400mHz,CDCl3)3∶2酮/烯醇型δ11.38(2xNH酮型,s),10.58(2xNH烯醇型,s),7.46-6.91(9H,m),4.85(H-5,s);C16H12N2O4的HRMS计算值为296.0796;测定值为296.0806。
实施例3
在惰性气氛下进行:
向干燥THF中的NaH悬浮液(16.21g 60%的在矿物油中的NaH,9.72mg,0.405mmol)中,加入5-(4-苯氧苯基)嘧啶-2,4,6-三酮(100mg,0.34mmol)。将混合物在室温下搅拌30分钟后,加入甲基碘(48.2mg,0.34mmol)。在室温下搅拌反应物3小时,然后加入另外的NaH(24mg 60%的在矿物油中的NaH,14mg,0.60mmol),然后加入甲基碘(96.4mg,0.86mmol)。在室温下搅拌反应混合物2小时,然后回流过夜。反应溶液用EtOAc稀释,然后用1 N HCl猝灭反应。分离有机层,用水、盐水洗涤,干燥(Na2SO4),浓缩,然后通过应用硅胶板(1000微米)的Chromatotron上的色谱进行纯化,先用30%EtOAc/己烷洗脱,然后用50%EtOAc/己烷洗脱,最后用EtOAc洗脱,以洗脱顺序先后得到1,3-二-N-甲基-5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮(7.3mg),和1-N-甲基-5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮(10.0mg),和5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮(27mg)。
5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮的光谱数据:1H NMR(200mHz,CD3OD)δ 7.37-6.95(9H,m),1.77(3H,s);C17H14N2O4的HRMS计算值为310.0954;测定值为310.0963。
1-N-甲基-5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮的光谱数据:1HNMR(200mHz,CDCl3)δ 8.38(1NH,s),7.39-6.92(9H,m),3.31(3H,s),1.86(3H,s);C18H16N2O4的HRMS计算值为324.1110;测定值为324.1116。
1,3-二-N-甲基-5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮的光谱数据:1H NMR(200mHz,CDCl3)δ7.38-6.91(9H,m),3.34(6H,s),1.85(3H,s);C19H18N2O4的HRMS计算值为338.1267;测定值为338.1267。
实施例4
步骤1:
在惰性气氛下进行:
向干燥THF(20mL)中的NaH悬浮液(144mg 60%的在用己烷洗涤的矿物油中的NaH,86.4mg,3.6mmol)中,小心加入2-(4-苯氧基苯基)丙二酸二甲酯(900mg,3.0mmol)。将得到的混合物在室温下搅拌1小时,然后加入1-碘代己烷(1.27g,0.89mL,6.0mmol)。在室温下搅拌反应混合物1小时,然后回流过夜。将反应物冷却至室温,用1 N HCl(20mL)猝灭反应,用***(2×40mL)提取。合并后的有机提取物用饱和Na2S2O3、水洗涤,然后用盐水洗涤,干燥(Na2SO4),浓缩,通过使用具有硅胶板(4000微米)的Chromatotron进行色谱纯化,用13%EtOAc/己烷洗脱,得到950mg的2-(4-苯氧基苯基)-2-正己基丙二酸二甲酯粘稠油状物:1H NMR(200mHz,CDCl3,)δ7.39-6.92(9H,m),3.75(6H,s),2.10(2H,t),1.29(8H,m),0.87(3H,t)。
步骤2:
如下制备Mg(OCH3)2:在氩气氛下向25mL圆底烧瓶中加入Mg tunings(90mg,3.70mmol)、干燥CH3OH(2 mL)、2滴CCl4和催化量的镁粉。发生放热反应,观察到有氢气生成。最初的放热反应基本结束后,将反应混合物加热回流1小时,然后冷却至室温。将2-(4-苯氧基苯基)-2-正己基丙二酸二甲酯(500mg,1.30mmol)和脲(162mg,2.70mmol)加入到Mg(OCH3)2中。在85-90℃下加热反应混合物1小时,然后蒸馏掉过量的CH3OH,直到获得流体糊状物,然后将该糊状物在85-90℃下加热过夜。将反应物冷却至室温,用EtOAc稀释,1N HCl洗涤。将酸性水层用EtOAc再提取。合并后的EtOAc提取物用水、盐水洗涤,干燥(MgSO4),浓缩。得到的油状物用HPLC(多孔微球硅胶,应用30%EtOAc/己烷作为洗脱剂)纯化,得到330mg 5-正己基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮白色泡沫状物:1H NMR(400mHz DMSO-d6)δ11.71(2NH,s),7.42-6.99(9H,m),2.22(2H,t),1.24(8H,m),0.85(3H,t);C22H24N2O4的HRMS计算值为380.1736;实测值为380.1740。
实施例5
步骤1:
在惰性气氛下进行:
向干燥THF(30mL)中的NaH悬浮液(0.37g 60%的在用己烷洗涤的矿物油中的NaH,0.22g,9.2mmol)中,小心加入2-(4-苯氧基苯基)丙二酸二甲酯(2.5g,8.33mmol)。将得到的混合物在室温下搅拌30分钟,然后加入苄基氯甲基醚(1.43g,1.27mL,9.16mmol)。反应混合物在室温下搅拌过夜,用饱和NH4Cl猝灭反应,然后用***(100mL)提取。将该醚提取物干燥(MgSO4),浓缩得到4.0g粘稠油状物。将其用HPLC(多孔微球硅胶,应用15%EtOAc/己烷洗脱)纯化,得到2.1g 2-苄氧基甲基-2-(4-苯氧基苯基)丙二酸二甲酯粘稠油状物:1H NMR(200mHz,CDCl3,)δ7.48-6.95(14H,m),4.55(2H,s),4.20(2H,s),3.75(6H,s)。
步骤2:
如实施例4步骤2所描述从Mg(116mg,4.76mmol)、干燥CH3OH(3.0mL)、1滴CCl4和催化量的镁粉制备Mg(OCH3)2。向其中加入2-苄氧基甲基-2-(4-苯氧基苯基)丙二酸二甲酯(700.0mg,1.67mmol),和脲(208.0mg,3.47mmol),反应混合物加热回流,然后蒸馏掉过量的CH3OH,直到获得糊状物。将得到的糊状物在85-90℃下加热过夜。如实施例4所述进行处理,浓缩后得到粘稠油状物(0.75g),其通过使用具有硅胶板(4000微米)的Chromatotron进行色谱纯化,用40%EtOAc/己烷洗脱得到180mg 5-苄氧基甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮白色固体:1H NMR(400mHzDMSO-d6)δ8.01(2NH,s),7.38-6.94(15H,m),4.58(2H,s),4.27(2H,s);C24H20N2O5的HRMS计算值为416.1372;实测值为416.1383。
实施例6
步骤1:
将2-(4-苯氧基苯基)丙二酸二甲酯(2.56g,8.54mmol)的干燥THF(50mL)溶液冷却至-78℃,然后加入二异丙基氨基化锂(4.7mL 2M THF溶液,9.8mmol)。将反应物在-78℃下搅拌1小时,然后加入烯丙基溴(11.4mg,9.4mmol)。将反应物在-78℃下搅拌3小时,然后升温至室温,在75℃油浴中加热,直至TLC显示反应已完成。将该反应冷却至室温,并用1 N HCl猝灭反应。用***提取,干燥***提取物(MgSO4),得到粗产物。通过硅胶60(70-230目)用EtOAc过滤进行纯化,随后将其用HPLC(多孔微球硅胶,应用11%EtOAc/己烷洗脱)纯化,得到1.8g 2-(2-丙烯基)-2-(4-苯氧基苯基)丙二酸二甲酯粘稠油状物:1H NMR(200mHz,CDCl3,)δ 7.4-6.85(9H,m),5.75(1H,m),5.05(2H,m),3.75(6H,s),3.1(2H,d)。
步骤2:
将2-(2-丙烯基)-2-(4-苯氧基苯基)丙二酸二甲酯(1.8g,5.3mmol)的CH2Cl2(200mL)溶液冷却至-70℃,然后向其中鼓入O3,直至持续出现蓝色。将该蓝色溶液用氩气脱气,并仍在-70℃下用Ph3P(4.0g,15.2mmol)处理,使其缓慢升温至室温。浓缩,然后用HPLC(多孔微球硅胶,应用20%EtOAc/己烷洗脱)纯化,得到1.66g油状物的醛。将其溶解到CH3OH(50mL)中,加入NaBH4(0.184g,4.85mmol),反应物在室温下搅拌30分钟。然后浓缩,将残渣溶解到EtOAc中,用水、盐水洗涤,然后干燥(MgSO4),浓缩得到1.55g 2-(2-羟乙基)-2-(4-苯氧基苯基)丙二酸二甲酯及其衍生的内酯的混合物。
步骤3:
如实施例4步骤2所描述从Mg(116mg,4.76mmol)、3mL CH3OH、1滴CCl4和催化量的镁粉制备Mg(OCH3)2。向其中加入上述2-(2-羟乙基)-2-(4-苯氧基苯基)丙二酸二甲酯及其衍生的内酯的混合物(521mg,1.67mmol)和脲(228mg,3.47mmol),反应混合物加热回流,然后蒸馏掉过量的CH3OH,直到获得糊状物。将得到的糊状物在85-90℃下加热8小时,然后冷却至室温。将反应物在EtOAc和10mL 1N HCl之间分配。分离EtOAc层,干燥(Na2SO4),浓缩得到600mg粗产物。通过使用具有硅胶板(2000微米)的Chromatotron的色谱进行纯化,用EtOAc洗脱得到120mg纯的5-(2-羟基乙基)-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮白色固体:IR(KBr)3214,3100,1765(sh),1705cm-1;1H NMR(400mHz,DMSO-d6)δ11.48(2H,br s,N-H),7.45-6.95(9H,m),4.85(1H,t,OH),3.50(2H,m),2.50(2H,m);C18H16N2O5的HRMS计算值为340.1059,实测值为340.1055。
实施例7
片剂配方
项目 | 成分 | mg/片 | |||||
5mg | 25mg | 100mg | 250mg | 500mg | 750mg | ||
内核 | |||||||
1 | 式I化合物 | 5.0 | 25.0 | 100.0 | 250.0 | 500.0 | 750.0 |
2 | 无水乳糖 | 104.4 | 84.4 | 36.8 | 23.5 | 47.0 | 70.5 |
3 | 交联羧甲基纤维素钠 | 6.0 | 6.0 | 7.5 | 15.0 | 30.0 | 45.0 |
4 | 聚烯吡酮K30 | 3.6 | 3.6 | 4.5 | 9.0 | 18.0 | 27.0 |
5 | 硬脂酸镁 | 1.0 | 1.0 | 1.2 | 2.5 | 5.0 | 7.5 |
核重 | 120 | 120 | 150 | 300 | 600 | 900 | |
薄膜包衣 | |||||||
6 | 羟丙基甲基纤维素6cps-2910 | 1.6 | 1.6 | 2.0 | 4.0 | 8.0 | 12.0 |
7 | 滑石粉 | 1.2 | 1.2 | 1.5 | 3.0 | 6.0 | 9.0 |
8 | 二氧化钛 | 1.2 | 1.2 | 1.5 | 3.0 | 6.0 | 9.0 |
片剂总重量 | 124 | 124 | 155 | 310 | 620 | 930 |
制备方法
1.将1、2和3项在合适的混合器中混合15分钟。
2.将步骤1的粉末混合物用15%聚烯吡酮K30溶液(第4项)制粒。
3.在50℃下干燥步骤2得到的颗粒。
4.将步骤3得到的颗粒通过合适的整粒装置。
5.将第5项加入到步骤4得到的整粒后的颗粒,混合5分钟。
6.将步骤5得到的颗粒在合适的压片机上压制。
7.应用适当的空气喷雾***,将步骤6得到的内核用含有羟丙基甲基纤
维素6cps-2910、滑石粉、和二氧化钛的薄膜包衣悬浮液包衣。
实施例8
胶囊配方
项目 | 成分 | mg/胶囊 | ||||
5mg | 25mg | 100mg | 250mg | 500mg | ||
1 | 式I化合物 | 5 | 25 | 100 | 250 | 500 |
2 | 含水乳糖 | 159 | 123 | 148 | 50 | 75 |
3 | 玉米淀粉 | 25 | 35 | 40 | 35 | 70 |
4 | 滑石粉 | 10 | 15 | 10 | 12 | 24 |
5 | 硬脂酸镁 | 1 | 2 | 2 | 3 | 6 |
填充物总重量 | 200 | 200 | 300 | 350 | 675 |
制备方法:
1.将第1、2和3项在合适的混合器内混合15分钟。
2.加入第4和5项,混合3分钟。
3.将步骤2的混合粉末填充到合适的胶囊中。
Claims (7)
2.按照权利要求1的化合物,其中R2在对位。
3.5-甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮。
4.5-己基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮。
5.5-苯甲氧基甲基-5-(4-苯氧基苯基)嘧啶-2,4,6-三酮。
6.一种用于治疗和控制皮肤癌、乳腺癌、***癌、结肠癌、肺癌、胃癌、类风湿性关节炎、骨关节炎、多发性硬化、角膜溃疡或牙周疾病的药物组合物,含有权利要求1的化合物和药物可接受的载体。
7.权利要求1的化合物在制备含有这些化合物的医药中的应用,所述医药用于治疗和控制皮肤癌、乳腺癌、***癌、结肠癌、肺癌、胃癌、类风湿性关节炎、骨关节炎、多发性硬化、角膜溃疡或牙周疾病。
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US6841671B2 (en) | 2000-10-26 | 2005-01-11 | Pfizer Inc. | Spiro-pyrimidine-2,4,6-trione metalloproteinase inhibitors |
KR20040004412A (ko) * | 2000-10-26 | 2004-01-13 | 화이자 프로덕츠 인크. | 스피로-피리미딘-2,4,6-트리온 메탈로프로테이나제 억제제 |
US6936620B2 (en) | 2001-12-20 | 2005-08-30 | Bristol Myers Squibb Company | Barbituric acid derivatives as inhibitors of TNF-α converting enzyme (TACE) and/or matrix metalloproteinases |
ATE304015T1 (de) | 2002-04-26 | 2005-09-15 | Pfizer Prod Inc | Triaryl-oxy-aryl-spiro-pyrimidin-2, 4, 6-trion metalloproteinase inhibitoren |
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MXPA04010550A (es) | 2002-04-26 | 2005-01-25 | Pfizer Prod Inc | Inhibidores de metaloproteinasa de pirimidina-2,4,6-triona. |
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EP1153015B1 (en) | 2004-09-29 |
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ATE277912T1 (de) | 2004-10-15 |
US6265578B1 (en) | 2001-07-24 |
ZA200106214B (en) | 2002-10-28 |
CA2361605C (en) | 2009-01-27 |
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AR035008A1 (es) | 2004-04-14 |
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