CN1732163B - 作为抗炎和免疫调节及抗增殖试剂的芳香化合物 - Google Patents
作为抗炎和免疫调节及抗增殖试剂的芳香化合物 Download PDFInfo
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- CN1732163B CN1732163B CN2003801073546A CN200380107354A CN1732163B CN 1732163 B CN1732163 B CN 1732163B CN 2003801073546 A CN2003801073546 A CN 2003801073546A CN 200380107354 A CN200380107354 A CN 200380107354A CN 1732163 B CN1732163 B CN 1732163B
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- aryl
- carboxylic acid
- cycloalkyl
- thiophene
- alkyl
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Classifications
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- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
本发明涉及用作药物的通式(II)化合物及其盐和生理功能性衍生物。
Description
本发明涉及可用作抗炎、免疫调节和抗增殖试剂的新化合物。具体地，本发明涉及抑制二氢乳清酸脱氢酶(DHODH)的新化合物，其制备方法，含有该成分的药物组合物及其治疗和预防疾病的用途，特别是其在可得益于对二氢乳清酸脱氢酶(DHODH)的抑制的疾病中的用途。
类风湿性关节炎(RA)是特别普遍的疾病，特别是在老年人中。用例如非甾族抗炎试剂的常规药物对其进行治疗不能得到满意效果。鉴于人口老龄化的问题，尤其是在发达的西方国家或在日本，迫切需要开发用于治疗RA的新型药物。
公开号为WO 99/38846的国际专利申请和欧洲专利EP 0,646,578号公开了据报道称可用于治疗RA的化合物。
近期，Aventis公司以ARAVA商标将一种通过新作用机理来对抗类风湿性关节炎的药物来氟米特(leflunomide)推上了市场[欧洲专利EP78018号，公开号为WO 97/34600的国际专利申请]。来氟米特具有免疫调节及抗炎性能[欧洲专利EP 217206号，德国专利DE 2524929号]。所述作用机理是基于对一种嘧啶生物合成酶——二氢乳清酸脱氢酶(DHODH)的抑制。
在体内，DHODH催化细胞生长所必需的嘧啶的合成。抑制DHODH能抑制(病理性)快速增殖的细胞的生长，而以正常速度生长的细胞可从正常的代谢循环中获得所需的嘧啶碱类。对免疫反应最重要的细胞类型——淋巴细胞只能利用合成的嘧啶来进行生长，对DHODH抑制的反应尤其敏感。抑制淋巴细胞生长的物质是治疗自身免疫性疾病的重要药物。
DHODH抑制剂来氟米特(ARAVA)是这类化合物(来氟米特类)中用于治疗类风湿性关节炎的第一种药物。公开号为WO 99/45926的国际申请是公开了作为DHODH抑制剂的化合物的另一参考文献。
在公开号为WO 98/57937的国际申请，欧洲专利第463444号和欧洲专利第150034号，Nucleosides & Nucleotides 1997，16(10 & 11)，2025-2033；Egyptian Journal of Pharmaceutical Sciences 1991，32(1-2)，331-339，Journal für Praktische Chemie 1991，333(4)，619-624，Archives ofPharmacal Research 1990，13(4)，338-341，Sulfur Letters 1988，7(4)，127-136，Synthesis 1988，6 449-452，Sulfur Letters 1987，7(19)，19-24，Archiv der Pharmazie 1987，320(12)，1281-1283，Natl.Def.Med.Cent.1983，35(1)，57-64和Sch.Pharm.Sci.1977，97(4)，410-415中描述了多种与取代的马来酰亚胺稠合的五元芳香环系。
本发明的目的是提供能用于治疗需要抑制DHODH的疾病的替代的有效试剂。
相应地，发现了对DHODH尤其是人DHODH具有抑制作用的新化合物类型。
本发明也涉及通式(II)化合物，
其中，
A为五元杂芳香环系，其含有一个或多个选自S、O、N、NR4、SO2和SO的X基团；
D为O、S、SO2、NR4或CH2；
Z1和Z2相互独立地为O、S或NR5；
R1独立地代表H、卤素、卤代烃基、卤代烃基氧基、-CO2R”、-SO3H、-OH、-CONR*R”、-CR”O、-SO2-NR*R”、-NO2、-SO2-R”、-SO-R*、-CN、烃基氧基、烃基硫基、芳基、-NR”-CO2-R’、-NR”-CO-R*、-NR”-SO2-R’、-O-CO-R*、-O-CO2-R*、-O-CO-NR*R”；环烃基、烃基氨基、羟基烃基氨基、-SH、杂芳基或烃基；
R*独立地代表H、烃基、环烃基、氨基烃基、烃基氧基、-OH、-SH、烃基硫基、羟基烃基、卤代烃基、卤代烃基氧基、芳基或杂芳基；
R’独立地代表H、-CO2R”、-CONHR”、-CR”O、-SO2NR”、-NR”-CO-卤代烃基、-NO2、-NR”-SO2-卤代烃基、-NR”-SO2-烃基、-SO2-烃基、-NR”-CO-烃基、-CN、烃基、环烃基、氨基烃基、烃基氨基、烃基氧基、-OH、-SH、烃基硫基、羟基烃基、羟基烃基氨基、卤素、卤代烃基、卤代烃基氧基、芳基、芳基烃基、或杂芳基；
R”独立地代表卤素、卤代烃基、羟基烃基、烃基、环烃基、芳基、杂芳基或氨基烃基；
R2为H或OR6、NHR7、NR7OR7，或者R2与和R8相连的氮原子形成五元或六元杂环，其条件是R2为-[CH2]s且R8不存在；
R3为H、烃基、环烃基、芳基、烃基氧基、O-芳基；O-环烃基、卤素、氨基烃基、烃基氨基、羟氨基、羟基烃基、卤代烃基氧基、杂芳基、烃基硫基、S-芳基；S-环烃基、芳基烃基或卤代烃基；
R4为H、烃基、环烃基、芳基或杂芳基；
R5为H、OH、烃基氧基、O-芳基、烃基或芳基；
R6为H、烃基、环烃基、芳基、芳基烃基、杂芳基、烃基芳基、烃基氧基烃基、酰基甲基、(酰氧基)烃基、不对称(酰氧基)烃基二酯或二烃基磷酸酯。
R7为H、OH、烃基、芳基、烃基氧基、O-芳基、环烃基或O-环烃基；
R8为氢或烃基；
E为烃基或环烃基，或者单环或多环的取代或未取代的环系，其可含有一个或多个X基团并且包含至少一个芳香环；
Y为氢、卤素、卤代烃基、卤代烃基氧基、烃基、环烃基、单环或多环的取代或未取代的环系，所述环系可含有一个或多个X基团并且包含至少一个芳香环，或
m为0或1；
n为0或1；
p为0或1；
q为0或1；
s为0-2；及
t为0-3；
其条件是不包括以下化合物：
环A含有五个原子，Z1＝Z2＝O，R2与和R8相连的氮原子形成五元杂环且R2为-[CH2]s、R8不存在及s为0的化合物；
环A含有三个碳原子和两个氮原子，Z1＝Z2＝O，R2与和R8相连的氮原子形成五元杂环且R2为-[CH2]s、R8不存在及s为0的化合物；
4-[4-(萘-2-基)噻唑-2-基氨基羰基]-呋喃-3-羧酸；及
5-[4-(萘-2-基)噻唑-2-基氨基羰基]-2H-[1，2，3]-三唑-4-羧酸。
除非另有说明，烃基指直链或支链的C1-C6烷基，优选直链或支链的1-5个碳原子的碳链，直链或支链的C1-C6链烯基，或者直链或支链的C1-C6炔基，其可任意地被一个或多个取代基R’取代，优选被卤素取代；
所述C1-C6烷基、C1-C6链烯基和C1-C6炔基残基可选自：-CH3、-C2H5、-CH＝CH2、-C≡CH、-C3H7、-CH(CH3)2、-CH2-CH＝CH2、-C(CH3)＝CH2、-CH＝CH-CH3、-C≡C-CH3、-CH2-C≡CH、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3、-C5H11、-C6H13、-C(R′)3、-C2(R′)5、-CH2-C(R′)3、-C3(R′)7、-C2H4-C(R′)3、-C2H4-CH＝CH2、-CH＝CH-C2H5、-CH＝C(CH3)2、-CH2-CH＝CH-CH3、-CH＝CH-CH＝CH2、-C2H4-C≡CH、-C≡C-C2H5、-CH2-C≡C-CH3、-C≡C-CH＝CH2、-CH＝CH-C≡CH、-C≡C-C≡CH、-C2H4-CH(CH3)2、-CH(CH3)-C3H7、-CH2-CH(CH3)-C2H5、-CH(CH3)-CH(CH3)2、-C(CH3)2-C2H5、-CH2-C(CH3)3、-C3H6-CH＝CH2、-CH＝CH-C3H7、-C2H4-CH＝CH-CH3、-CH2-CH＝CH-C2H5、-CH2-CH＝CH-CH＝CH2、-CH＝CH-CH＝CH-CH3、-CH＝CH-CH2-CH＝CH2、-C(CH3)＝CH-CH＝CH2、-CH＝C(CH3)-CH＝CH2、-CH＝CH-C(CH3)＝CH2、-CH2-CH＝C(CH3)2、-C(CH3)＝C(CH3)2、-C3H6-C≡CH、-C≡C-C3H7、-C2H4-C≡C-CH3、-CH2-C≡C-C2H5、-CH2-C≡C-CH＝CH2、-CH2-CH＝CH-C≡CH、-CH2-C≡C-C≡CH、-C≡C-CH＝CH-CH3、-CH＝CH-C≡C-CH3、-C≡C-C≡C-CH3、-C≡C-CH2-CH＝CH2、-CH＝CH-CH2-C≡CH、-C≡C-CH2-C≡CH、-C(CH3)＝CH-CH＝CH2、-CH＝C(CH3)-CH＝CH2、-CH＝CH-C(CH3)＝CH2、-C(CH3)＝CH-C≡CH、-CH＝C(CH3)-C≡CH、-C≡C-C(CH3)＝CH2、-C3H6-CH(CH3)2、-C2H4-CH(CH3)-C2H5、-CH(CH3)-C4H9、-CH2-CH(CH3)-C3H7、-CH(CH3)-CH2-CH(CH3)2、-CH(CH3)-CH(CH3)-C2H5、-CH2-CH(CH3)-CH(CH3)2、-CH2-C(CH3)2-C2H5、-C(CH3)2-C3H7、-C(CH3)2-CH(CH3)2、-C2H4-C(CH3)3、-CH(CH3)-C(CH3)3、-C4H8-CH＝CH2、-CH＝CH-C4H9、-C3H6-CH＝CH-CH3、-CH2-CH＝CH-C3H7、-C2H4-CH＝CH-C2H5、-CH2-C(CH3)＝C(CH3)2、-C2H4-CH＝C(CH3)2、-C4H8-C≡CH、-C≡C-C4H9、-C3H6-C≡C-CH3、-CH2-C≡C-C3H7、-C2H4-C≡C-C2H5；
R’独立地代表H、-CO2R”、-CONHR”、-CR”O、-SO2NR”、-NR”-CO-卤代烃基、-NO2、-NR”-SO2-卤代烃基、-NR”-SO2-烃基、-SO2-烃基、-NR”-CO-烃基、-CN、烃基、环烃基、氨基烃基、烃基氨基、烃基氧基、-OH、-SH、烃基硫基、羟基烃基、羟基烃基氨基、卤素、卤代烃基、卤代烃基氧基、芳基、芳基烃基或杂芳基；
R”独立地代表卤素、卤代烃基、羟基烃基、烃基、环烃基、芳基、杂芳基或氨基烃基；
环烃基指含有3-8个碳原子的非芳香环系，优选4-8个碳原子，其中所述环上的一个或多个碳原子上可被X基团取代，X如上文所定义；所述C3-C8环烃基残基可选自-环C3H5、-环C4H7、-环C5H9、-环-C6H11、-环-C7H13、-环-C8H15；
烃基氧基指O-烃基基团，所述烃基如上文所定义；所述烃基氧基优选甲氧基、乙氧基、异丙氧基、叔丁氧基或戊氧基；
烃基硫基指S-烃基基团，所述烃基如上文所定义；
卤代烃基指被1-5个卤原子取代的烃基，所述烃基如上文所定义；所述卤代烃基优选-C(R10)3、-CR10(R10′)2、-CR10(R10′)R10″、-C2(R10)5、-CH2-C(R10)3、-CH2-CR10(R10′)2、-CH2-CR10(R10′)R10″、-C3(R10)7或-C2H4-C(R10)3，其中R10、R10′、R10″代表F、Cl、Br或I，优选为F；
羟基烃基指HO-烃基基团，所述烃基如上文所定义；
卤代烃基氧基指被1-5个卤原子取代的烃基氧基，所述烃基如上文所定义；所述卤代烃基氧基优选-OC(R10)3、-OCR10(R10)2、-OCR10(R10′)R10″、-OC2(R10)5、-OCH2-C(R10)3、-OCH2-CR10(R10′)2、-OCH2-CR10(R10′)R10″、-OC3(R10)7或-OC2H4-C(R10)3，其中R10、R10′、R10″代表F、Cl、Br或I，优选为F；
羟基烃基氨基指(HO-烃基)2-N-基团或HO-烃基-NH-基团，所述烃基如上文所定义；
烃基氨基指HN-烃基或N-二烃基基团，所述烃基如上文所定义；
卤素基团指氯、溴、氟或碘，优选为氟；
芳基优选指具有5-15个碳原子的芳基，其可任意地被一个或多个取代基R’取代，其中R’如上文所定义；所述芳基优选为苯基、-CH2Ph、-C2H4Ph、-CH＝CH-Ph、-C≡C-Ph、-o-C6H4-R′、-m-C6H4-R′、-p-C6H4-R′、-o-CH2-C6H4-R′、-m-CH2-C6H4-R′、-p-CH2-C6H4-R′；
杂芳基指含有至少一个诸如O、N、S的杂原子的五元或六元杂环基团。该杂环基团可与其它环稠合。例如，这类基团可选自噻唑-2-基、噻唑-4-基、噻唑-5-基、异噻唑-3-基、异噻唑-4-基、异噻唑-5-基、1，2，4-噁二唑-3-基、1，2，4-噁二唑-5-基、1，2，4-噻二唑-3-基、1，2，4-噻二唑-5-基、1，2，5-噁二唑-3-基、1，2，5-噁二唑-4-基、1，2，5-噻二唑-3-基、1-咪唑基、2-咪唑基、1，2，5-噻二唑-4-基、4-咪唑基、1-吡咯基、2-吡咯基、3-吡咯基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、3-哒嗪基、4-哒嗪基、2-吡嗪基、1-吡唑基、3-吡唑基、4-吡唑基、1H-四唑-2-基、1H-四唑-3-基、四唑基、吲哚基、二氢吲哚基、苯并-[b]-呋喃基、苯并[b]苯硫基、苯并咪唑基、苯并噻唑基、喹唑啉基、quinoxazolinyl(喹啉并噁唑啉基)、或优选为喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基。该杂环基团可任意地被一个或多个取代基R’取代，其中R’如上所定义。
E的含义包括可任意被一个或多个取代基R’取代的烃基，其中所述烃基如上所定义；或任意地被一个或多个取代基R’取代的环烃基，例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基；或碳环芳香基团，例如苯基、1-萘基、2-萘基、蒽基，特别是1-蒽基和2-蒽基；及杂环芳基，例如N-咪唑基、2-咪唑基、2-噻吩基、3-噻吩基、2-呋喃基、3-呋喃基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、2-吡喃基、3-吡喃基、4-吡喃基、3-吡唑基、4-吡唑基、5-吡唑基、2-吡嗪基、2-噻唑基、4-噻唑基、5-噻唑基、2-噁唑基、4-噁唑基和5-噁唑基。E也包括碳环芳香环或杂芳环与一个或多个其它杂芳环稠合的多环芳香环系，例如9H-噻吨-10，10-二氧化物。
本发明还提供包含通式(II)化合物以及药物可接受的稀释剂或载体的药物组合物，其中所述通式(II)化合物包括了所放弃的化合物，且可以是游离态或其药物可接受的盐和生理功能性衍生物。
本文所用的术语“生理功能性衍生物”指本身不具有药物活性，但可在体内，即在给药后的个体内，转化为其药物活性形式的化合物。生理功能性衍生物的例子是前药，例如本发明下文所述的前药。
另一方面，本发明还提供治疗或预防可得益于抑制二氢乳清酸脱氢酶(DHODH)的疾病状态的方法，包括将有效剂量的通式(II)化合物和其生理可接受的盐或生理功能性衍生物给药。
本发明还涉及通式(II)化合物及其药理学可耐受的盐或生理功能性衍生物在生产用于预防和治疗疾病的药物中的用途，所述预防和治疗可得益于对嘧啶生物合成酶的抑制。
此外，本发明提供制备诸如通式(II)化合物的本发明化合物的方法。
通式(II)化合物可通过多种方法得到。在本发明优选实施方案中，采用如下方法合成通式(II)的衍生物。
方法1：
二羧酸二甲酯的合成如公开号为WO 02/07655的国际申请中所述。
如T.Harrison et.al.，Tetrahedron Vol.45，No.16，1989，5247-5262中所述可在所述二羧酸二甲酯的环系上进行取代。然后将该二羧酸二甲酯转化为对应的酸酐。
然后将这些酸酐与对应的胺反应得到所需的通式(II)的酰胺。这一反应步骤类似于公开号为WO 02/07655的国际申请中所述的反应步骤。
每种情况下[r＝0]的通式(II)化合物均可通过与公开号为WO02/07655的国际申请中所述的四种方法类似的方法制备。
此外，本发明提供制备所需的通式(II)的异羟肟酸的方法。
合成通式(II)化合物的一种方法包括将酸转化为对应的酰基氯，并将该酰基氯与羟胺反应(Watanabe et al.，1989，J.Org.Chem.，54，17，4088-4097；Shishido et al.，1992，J.Org.Chem.，57，10，2876-2883)。
其它制备通式(II)的方法如Woo et al.，2002，J.Med.Chem.45，2877-2885；Knorr et al.，1989，Tetrahedron Lett.，30，1927-1930，Carpino，1993，J.Am.Chem.Soc.，115，4397-4398和Albericio et.al.，1998，J.Org.Chem.，63，9678-9683所述。
另一制备通式(II)化合物的方法是将对应的酯与羟胺反应，如Stowellet al.，1995，J.Med.Chem.，38，8，1411-1413所述。
通式(II)的酰胺的合成如J.Zabicky在″The Chemistry of Amides″，S.Patai(编辑)的系列，″The Chemistry of Functional Groups″，John Wiley&Sons，1975，p.74-131中所述。制备硫代酰胺的方法如Houben-Weyl，J.Falbe(编辑)，G.Thieme Verlag，vol.E5，p.1219-59中所述。制备硫酰胺的方法如Caldwell et al.，J.Am.Chem.Soc.1944，66，1479-82，或Flynn et al.，Med.Chem.Res.，1998，8，219-43和Dziadulewicz et al.，Bioorg.Med.Chem.Lett.2001，11，5，705-10中所述。
此外，本发明提供制备A为杂环系的通式(II)化合物的方法。例如，类似德国专利DE 3933573和D.P.Arnold，Aust.J.Chem.44，1991，323-330中所述的方法，将噻吩、呋喃和吡咯的3，4-二羧酸转化为对应的酸酐并与胺反应。
根据德国专利DE 3933573，由3-羧酸或2-羧酸通过对酸基进行酰胺化，并随后分别在2-或3-位进行邻位金属化，其后加入二氧化碳作为亲电子试剂，来分别合成噻吩、呋喃和吡咯的3-甲酰胺-2-羧酸或2-甲酰胺-3-羧酸。
根据文献方法可制备不同的4，5-取代的2，3-吡咯二羧酸酯及酸：
a)1-羟基-4，5-二甲基：由乙炔二羧酸二烷基酯和2，3-丁二酮单肟，I.Yavari et al.，Synth.Commun.26，1996，4495-4499。
b)3-羟基-4-烷基或-芳基：由乙炔二羧酸二烷基酯和氨基酸酯，P.Kolar et al.，Synth.Commun.24，1994，1887-1893。
c)混合的4，5-烷基/芳基：由乙炔二羧酸二烷基酯和芳基-或苄基腙，J.Barluenga et al.，Synthesis，1975，642-643。
d)4-甲基：由N-丙酮基邻苯二甲酰亚胺和草乙酸二乙酯，R.E.Lancaster et al.，J.Org.Chem.23，1958，1208-1209。
可将吡咯二酯转化为对应的酸和酸酐，以进行进一步的酰胺化反应，或直接转变为对应的单肼基羰基类化合物(mono-hydrazinocarbonyl)(M.T.Garcia-Lopez et al.，J.Chem.Soc.Perkin Trans.，1978，483-487)。类似W.K.Anderson et al.，J.Med.Chem.27，1984，1559-1565；E.H.Huntress et al.，J.Am.Chem.Soc.65，1943，2167-2169；L.H.Conover et al.，J.Am.Chem.Soc.72，1950，5221-5225；M.Robba et al.，Bull.Soc.Chim.Fr.，1969，1762-1768中所述的方法，由α-卤代-β-氧琥珀酸二乙酯和各自对应的硫代酰胺或硫脲合成2-烷基、2-芳基-或2-氨基噻唑-4，5-羧酸二乙酯。
如上所述，将所有的二酯转化为单酰胺。必须分离由所述酰胺化反应产生的区域异构体(regioisomer)混合物。
在加或不加三氟硼酸酯醚合物的条件下，通过用间-氯苯甲酸氧化前述的杂环，可将芳香结构中含有硫原子的芳香体系转化为对应的S-单氧化物或-二氧化物(N.Furukawa et al.，Heterocycles 44，1997，61-66)。
本发明还提供其中R2和与R8相连的氮原子形成六元杂环的通式(II)化合物的制备方法。
例如根据Tetrahedron 26，1970，4353-4360，由乙酰化的硫鎓甲酰胺(sulphonium methylide)和乙炔二羧酸二乙酯制备3-乙酰基-2-甲基呋喃-4，5-二羧酸二乙酯。将所述二酯转化为对应的酸酐，然后如上所述，与胺反应得到单酰胺化产物的区域异构体混合物。与文献S.Laufer et al.，Arch.Pharm.330，1997，307-312；S.K.C.Devi et al.，Synth.Commun.32，2002，1523-1528中的方法类似，通过在二氯甲烷中用二环己基碳二亚胺、4-二甲基氨基吡啶和乙醇对所述羧酸进行酯化，可将所述两种区域异构体分离，并且在二氯甲烷中用溴或在乙酸乙酯中用溴化铜可得到乙酰官能团α-溴化的3-乙酰基-2-甲基-4-酰胺-呋喃-5-羧酸乙酯。
最后使用溶于四氢呋喃的氢化钠可实现闭环，且在中性条件下用溶于1-甲基-2-吡咯烷酮的苯基巯基氟化钾使所述酯皂化(M.K.Nayak et al.，Chem.Lett.，1998，297-298)。
在通式(II)化合物中，芳香环系A含有5个碳原子。在优选实施方案中，本发明化合物含有两个共轭的双键。环系A中一个或多个碳原子可被X基团替代，其中X选自S、O、N、NR4、SO、CO或SO2。
在优选的实施方案中，通式(II)化合物中的芳香环系A选自：
在通式(II)化合物中R1优选为H、OH、CO2H或SO3H或四唑。
在通式(II)化合物中R2优选为OH、NH2、NHOH、NHR7、NR7OR7或OR6。
在优选实施方案中，通式(II)化合物中的R6为苯甲酰氧基甲基、异丁酰氧基甲基、4-氨基-丁酰氧基甲基、丁酰氧基甲基、1-(丁酰氧基)乙基、1-(丁酰氧基)-2，2-二甲基丙基，1-二乙基膦酰氧基乙基、2-(2-甲氧基乙氧基)-乙酰氧基甲基、对-氨基苯甲酰基甲基、烟酰氧基甲基(nicotinyloxymethyl)、新戊酰氧基甲基、戊二酰氧基甲基、[2-(2-甲氧基乙氧基)乙氧基]-乙酰氧基甲基、2-(吗啉-4-基)-乙基、1-二乙基-膦酰氧基甲基。
在通式(II)化合物中，R3为H、烃基、环烃基、芳基、烃基氧基、O-芳基；O-环烃基、卤素、氨基烃基、烃基氨基、羟氨基、卤代烃基、羟基烃基、卤代烃基氧基、杂芳基、烃基硫基、S-芳基；S-环烃基、芳基烃基，优选为H。
在通式(II)化合物中，R4为H、烃基、环烃基、芳基或杂芳基，优选为H。
在通式(II)中，R8为氢或烃基，优选为H或甲基。
在通式(II)中，Z1和Z2相互独立地为O、S或NR5，均优选为O。
在通式(II)中，Y为氢、卤素、烃基、取代或未取代的环烃基、取代或未取代的E、取代或未取代的O-E、取代或未取代的O-烃基芳基、取代或未取代的O-芳基烃基；在所述取代的情况下，优选由卤素取代所述烃基-、环烃基-或芳基-上的一个或多个氢原子。Y也可以是，
其中A、X、R1、R2、R8、Z1、Z2和p如上述所定义。优选地，Y为E，更优选地，Y是任意取代的苯基。
在通式(II)中，E是可被一个或多个取代基R’任意取代的烃基或环烃基，或E是单环或多环的取代或未取代的环系，其包含至少一个芳香环，还可包含一个或多个选自S、O、N、NR4、SO或SO2的X基团。在优选实施方案中，E为单环芳香环或二环或三环芳香环系，或环烃基。在环系中的碳原子被替代的情况下，优选1、2或3个碳原子被上述X基团替代。
在通式(II)中，E优选为任意被一个或多个R’取代的苯基、1-萘基、2-萘基、1-蒽基和2-蒽基。
在本发明的优选实施方案中，通式(II)化合物中的E为任意被一个或多个取代基R’取代的苯基，或任意被一个或多个取代基R’取代的环烃基。
在通式(II)中，优选的取代基R’是硝基、卤素、烃基氧基、卤代烃基、卤代烃基氧基、杂芳基、烃基或芳基，更优选的R’为Br、F、Cl、CF3、OCF3、乙氧基或甲氧基。
在通式(II)中，优选的杂芳基是咪唑基、噻吩基、呋喃基、吡啶基、嘧啶基、吡喃基、吡唑基、吡嗪基、噻唑基、1H-四唑-2-基、1H-四唑-3-基或噁唑基。
在通式(II)中，t优选为0、1或2。
在通式(II)中，s优选为0或1。
在通式(II)化合物中，D为O、S、SO2、NR4或CH2。当m＝1时，D优选S或更优选O。
在其它优选实施方案中，在通式(II)化合物中，m和q为零，且Y为氢、卤素、卤代烃基、卤代烃基氧基、烃基、环烃基或E，优选为F、CF3、OCF3、任意被一个或多个取代基R’取代的苯基，或更优选地，任意被一个或多个F、Cl、甲氧基、CF3或OCF3取代的苯基。
在通式(II)中，q为0-10，优选q为0、1或2。如果q为1，且n为0或1，则D优选为O(此时m＝1)。
在本发明特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为噻吩-2，3-二羧酸单酰胺，Y为H或F，或E为未取代的苯基或Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基。
在本发明另一特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为噻吩-2，3-二羧酸单酰胺，且E和Y分别为取代或未取代的亚苯基和苯基。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，R3为H(此时n＝1)，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为噻吩-2，3-二羧酸单酰胺。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为噻吩-2，3-二羧酸单酰胺。
在进一步特别优选的实施方案中，通式(II)化合物中D＝S(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O(此时r＝1)，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为噻吩-2，3-二羧酸单酰胺。
在本发明特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为呋喃-3，4-二羧酸单酰胺，Y为H或F，或E为未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基。
在本发明另一特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为呋喃-3，4-二羧酸单酰胺，且E和Y分别为取代或未取代的亚苯基和苯基。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，R3为H(此时n＝1)，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为呋喃-3，4-二羧酸单酰胺。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为呋喃-3，4-二羧酸单酰胺。
在进一步特别优选的实施方案中，通式(II)化合物中D＝S(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O(此时r＝1)，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为呋喃-3，4-二羧酸单酰胺。
在本发明特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为五元芳香环系，其中一个碳原子被O替代，或Y为H或F，且E为未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基。
在本发明另一特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为五元芳香环系，其中一个碳原子被O替代，或E和Y分别为取代或未取代的亚苯基和苯基。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，R3为H(此时n＝1)，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为五元芳香环系，其中一个碳原子被O替代。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为五元芳香环系，其中一个碳原子被O替代。
在进一步特别优选的实施方案中，通式(II)化合物中D＝S(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为五元芳香环系，其中一个碳原子被O替代。
在本发明特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为五元芳香环系，其中一个碳原子被S替代，或Y为H或F，且E为未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基。
在本发明另一特别优选的实施方案中，通式(II)化合物中q＝0、t＝1、Z1＝O、Z2＝O，且A为五元芳香环系，其中一个碳原子被S替代，或E和Y分别为取代或未取代的亚苯基和苯基。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，R3为H(此时n＝1)，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为五元芳香环系，其中一个碳原子被S替代。
在进一步特别优选的实施方案中，通式(II)化合物中D＝O(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为五元芳香环系，其中一个碳原子被S替代。
在进一步特别优选的实施方案中，通式(II)化合物中D＝S(此时m＝1)，n＝0，q＝1、t＝1、Z1＝O、Z2＝O，E为未取代的亚苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3或OCF3取代的苯基，且A为五元芳香环系，其中一个碳原子被S替代。
在进一步特别优选的实施方案中，通式(II)化合物中Z1＝O(此时r＝1)，Z2＝O，q＝0，t＝1，R2＝OH，R8＝H，E为未取代的亚苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的苯基，且A为五元芳香环系，其中一个碳原子被S替代。
在进一步特别优选的实施方案中，通式(II)化合物中Z1＝O，Z2＝O，q＝0或1，t＝2，E为未取代的亚苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的亚苯基，Y是未取代的苯基或由Cl、F和/或CF3或OCF3取代的苯基，且R2和与R8相连的氮原子共同形成六元杂环，其条件是R2为-[CH2]s，R8不存在；且A为呋喃。
在进一步特别优选的实施方案中，通式(II)化合物中Z1＝O，Z2＝O，q＝0或1，t＝2，E为未取代的亚苯基或由Cl、F和/或CF3、OCH3、OCH2CH3或OCF3取代的亚苯基，Y为H或F，且R2和与R8相连的氮原子共同形成六元杂环，其条件是R2为-[CH2]s，R8不存在；且A为呋喃。
本发明的待使用的通式(II)化合物可与无机或有机酸或碱形成盐。这类盐的例子如碱金属盐，特别是钠盐和钾盐，或铵盐。
本发明化合物可用于多种能受益于嘧啶代谢抑制的人或动物疾病，优选为人类疾病。这类疾病是：
-纤维变性、眼色素层炎、鼻炎、哮喘或athropathy，特别是关节病
-各种形式的风湿病
-急性免疫学事件和病症，例如脓毒病、脓毒性休克、内毒素性休克、革兰氏阴性脓毒病、中毒性休克综合征、急性呼吸窘迫综合征、中风、再灌注损伤、CNS损伤、严重的过敏症形式、移植物对宿主的反应和宿主对移植物的反应、阿耳茨海默氏病或热病、再狭窄、慢性肺炎性疾病、矽肺、肺肉瘤病、骨再吸收疾病。这些免疫学事件也包括所需的对免疫系统的调节和抑制。
-各类自身免疫性疾病，特别是类风湿性关节炎、类风湿性脊椎炎、骨关节炎、痛风性关节炎、多发性硬化、胰岛素依赖性糖尿病和非胰岛素依赖性糖尿病、及红斑狼疮、溃疡性结膜炎、Morbus Crohn、炎性肠道疾病，以及其它慢性炎症、慢性腹泻；
-诸如牛皮癣的皮肤病
-进行性视网膜萎缩
-包括机会感染在内的各类感染。
本发明化合物及用其制备的药物通常用于治疗细胞增殖病症，治疗或预防免疫学疾病或疾病状态(例如炎性疾病、神经免疫学疾病、自身免疫性疾病或其它疾病)。
本发明化合物也可用于开发免疫调节和抗炎药物，或更广泛地用于治疗可受益于抑制嘧啶生物合成的疾病。
本发明化合物还可用于治疗由恶性细胞增殖引起的疾病，例如各类血液癌症和实体癌症(solid cancer)。因此，本发明化合物及用其制备的药物通常用于调节细胞活化、细胞增殖、细胞存活、细胞分化、细胞循环、细胞成熟和细胞死亡，或者诱导代谢的系统变化，例如糖、脂质或蛋白代谢的变化。其还可用于支持细胞的产生制造(generation poiesis)或者提供组织生成和降解的治疗性控制和细胞、组织养护和血细胞内环境稳定的治疗性调节，所述细胞的产生制造包括由例如毒性试剂、辐射、免疫治疗、成长缺陷、营养不良、吸收障碍、免疫失调、贫血等等引起的细胞缺失或破坏之后的血细胞生长和产生(促造血作用)。
这些疾病或疾病状态包括但不限于癌症，例如血液肿瘤(例如白血病、淋巴瘤、骨髓瘤)或实体肿瘤(例如乳房、前列腺、肝、膀胱、肺、食管、胃、结肠直肠、泌尿生殖、胃肠、皮肤、胰、脑、子宫、结肠、头和颈、以及卵巢、黑瘤、星型细胞瘤、小细胞肺癌、神经胶质瘤、基底细胞癌和鳞状细胞癌、诸如卡波西氏肉瘤和骨肉瘤的肉瘤)，治疗与T-细胞相关的病症，如再生障碍性贫血和迪乔治氏综合征、格雷夫斯病。
已发现来氟米特能抑制细胞培养物中的HCMV复制。眼疱疹是发达国家中最常见的传染性失明的原因。仅在美国，每年就有约50,000病例，其中90％是初始感染的复发。用抗病毒剂和皮质类固醇治疗复发病例。另一种疱疹病毒——巨细胞病毒是艾滋病患者中视网膜损伤和失明的常见原因。本发明化合物可单独使用或与诸如Ganciclovir和Foscarnet的其它抗病毒化合物结合使用来治疗这类疾病。
本发明化合物还可用于人和动物中由原生动物感染引起的疾病。这类牲畜或人致病性原生动物优选为顶复亚门或肉鞭虫门的细胞内活性寄生虫，特别是锥虫属、疟原虫(Plasmodia)、利什曼原虫属、巴贝虫(Babesia)和泰累尔梨浆虫(Theileria)、隐孢子虫属、Sacrocystida、变形虫(Amoebia)、球虫类和毛滴虫目。这些活性物质或对应的药物特别适合于治疗由镰状疟原虫引起的热带疟疾，由间日疟原虫或卵形疟原虫引起的间日疟，以及治疗由三日疟原虫引起的三日疟。其还适用于治疗由鼠弓形体引起的弓形体病，由例如贝氏等孢子球虫引起的球虫病，由猪-人肉孢子虫引起的肠肉孢子虫病，由痢疾变形虫引起的痢疾，由小型隐孢子虫引起的隐孢子虫病，由克氏锥虫引起的Chargas’病，由布氏罗德西亚锥虫或布氏冈比亚锥虫引起的昏睡病，皮肤和内脏及其它形式的利什曼病。其还适用于治疗感染牲畜致病性原生动物的动物，所述牲畜致病性原生动物如引起牛二梨浆贝虫病的病原体——小泰累尔氏梨浆虫，在非洲引起牛非洲锥虫病的病原体——刚果锥虫刚果亚种或活动锥虫vivax亚种、布氏锥虫布氏亚种，引起苏拉病的布氏伊氏锥虫，引起牛和水牛的牛梨浆虫病的病原体——二联梨浆虫，引起欧洲牛巴贝虫病(Babesiosis)及狗、猫和绵羊巴贝虫病的病原体——牛巴贝虫，引起绵羊、牛和猪的肉孢子虫病的病原体——ovicanis和ovifelis肉孢子虫，引起牛和鸟类的隐孢子虫病的病原体——隐孢子虫，引起兔、牛、绵羊、山羊、猪和鸟类，特别是鸡和火鸡的球虫病的病原体——艾美球虫属和等孢子球虫属的病原体。本发明化合物优选用于治疗球虫病或疟疾感染，或制备用于治疗这些疾病的药物或食物。
这种治疗可以是预防性的或治疗性的。在疟疾治疗中，本发明化合物可与其它抗疟疾试剂结合。
本发明化合物还可用于病毒感染或由例如卡氏肺囊虫引起的其它感染。
通式(II)化合物及其药理学可接受的盐本身、彼此结合的混合物形式或药物制剂形式可用作治疗剂对动物，优选为哺乳动物特别是人、狗和鸡进行给药，其可在肠道内或非肠道使用，并含有有效剂量的至少一种式(II)化合物或其盐作为活性成分，以及常规药用无害赋形剂和添加剂。通式(II)化合物也可以其盐形式给药，该盐形式是通过将对应化合物与生理学可接受的酸和碱反应得到。
所述治疗剂可以例如药丸、片剂、包被的片剂、糖衣片、硬和软明胶胶囊、溶液剂、糖浆剂、乳剂或悬浮液剂形式口服给药，或作为气雾剂混合物给药。然而，也可以例如栓剂形式进行直肠给药，以注射剂或输注剂形式进行非肠道给药，或以软膏、乳膏或酊剂的形式经皮给药。
除式(II)的活性化合物外，所述药物组合物还可包含常规的通常为惰性的载体材料或赋形剂。因此，所述药物制剂还可含有添加剂，例如填充剂、膨胀剂、崩解剂、结合剂、助流剂、润湿剂、稳定剂、乳化剂、防腐剂、甜味剂、着色剂、调味剂或香料、缓冲物质，此外还有用于获得贮存效果的溶剂或增溶剂或试剂，以及用于改变渗透压的盐，包被试剂或抗氧剂。其还可含有两种或更多种式(II)化合物，或其药理学可接受的盐以及其它治疗活性物质。
因此，本发明化合物可以单一物质的形式使用，或与其它活性化合物结合使用，例如与已知用于治疗前述疾病的药物结合，其中在后一情况下可观察到有利的附加增强效果。对人类的适合给药剂量是5-500mg。
可使用药用惰性无机或有机赋形剂制备所述药物制剂。例如，可使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等来制备药丸、片剂、包被的片剂和硬明胶胶囊。用于软明胶胶囊和栓剂的赋形剂为例如脂肪、蜡、半固体和液体多元醇、天然或硬化油等。适合用于生产溶液剂和糖浆剂的赋形剂是例如水、蔗糖、转化糖、葡萄糖、多元醇等。适合用于生产注射溶液剂的赋形剂是例如水、乙醇、甘油、多元醇或植物油。
所述剂量可在很宽范围内变化，并应适合每种情况下的个体的疾病状态。对上述用途，适合的剂量将根据给药方式、待治疗的具体疾病状态及所需效果而改变。然而，通常在约1-100mg/kg动物体重的剂量比率可得到满意的效果，优选为1-50mg/kg。适用于大型哺乳动物，如人的剂量比率约为从10mg/天到3g/天，通常每天给药一次，以分散剂量给药2-4次，或以缓释形式给药。
在根据本发明的优选给药方式，口服给药情况下，通常每天剂量约为每个人类个体10-5000mg，优选为50-500mg。在其它给药的方式的情况下，每天剂量为类似的范围。
还可使用式(II)化合物的能在体内释放所述活性化合物的前体(前药)或适当修饰的形式。这类前体，如R6或R1优选实施方案的前体，可通过例如用酯基屏蔽所述自由的酸基团来获得，其随后可在体内转化为所述自由的酸基团[F.W.Sum et.al.Bioorg.&Med.Chem.Lett.9(1999)，1921-1926；Ada Rephaeli et.al.Drug Development Research 50(2000)379-391；H.Ishikawa，Current Med.Chem.6(1999)，575-597]。R6或R1的优选实施方案的另一前体是四唑，如J.Herr，Bioorg.& Med.Chem.Lett.10(2002)，3379-3393所述，其为羧酸基团的另一种代谢耐受的等排(isosteric)替代物。其它R5优选实施方案的前体可通过例如用羟基屏蔽所述脒，其随后在体内转化为所述自由的脒[R.M.Scarborough，J.Med.Chem.43，19，(2000)，3454-3473]。
实施例
方法A：合成五元杂芳烃2，3-二羧酸单酰胺衍生物的通用方法
惰性气氛下，将所述联苯-衍生物溶解于干燥的二氯甲烷中，一次加入三乙胺(1.2equ)。向其中滴加入溶解于二氯甲烷的新制备的噻吩-3-碳酰氯(1.2equ)或呋喃-3-碳酰氯(1.2equ)或对应的杂芳烃-2’-碳酰氯。滴加完毕后将所得混合物加热至45℃维持4小时。真空下除去溶剂。将该酰胺溶于四氢呋喃并冷却至-78℃。将丁基锂(2equ)在15分钟内加入，并将所得混合物在-78℃搅拌30分钟。一次加入固体二氧化碳，并使所述混合物在4小时内升温至室温。用2n HCl猝灭该反应，并用乙酸乙酯萃取三次。合并的有机层用碳酸氢钠和盐水洗涤，用MgSO4干燥并过滤。真空下除去溶剂。用HPLC(使用水/乙腈梯度溶液)纯化上述物质得到纯产物。
方法C：用于所述五元杂芳烃3，4-羧酸单酰胺衍生物的通用方法
将噻吩-3，4-二羧酸或呋喃-3，4-二羧酸悬浮在醋酸酐中，并加热至100℃维持3小时。将反应溶液冷却至室温。真空下除去溶剂。干燥6小时后以定量收率得到所述酸酐。将所得酸酐溶于二氯甲烷(0.36mmol/ml)。向该溶液中加入联苯胺衍生物(1equ)，并将反应混合物加热至45℃维持12小时。真空下除去溶剂。所得产物用HPLC纯化。收率在30％-70％之间。
实施例1：
通过方法A合成的3-(联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.25(mc，9H，CH3)，3.17(mc，6H，CH2)，7.12-7.83(m，9H，CHAr)，7.26(mc，1H，CH)，7.62(mc，1H，CH)，14.88(s，1H，NH)。LC/(+)-ESI-MS：m/z＝324[M+H]+。
实施例2：
通过方法A合成的3-(2′-乙氧基-3，5-二氟-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.22(mc12H，CH3)3.12(mc，6H，CH2)，3.99(mc，2H，CH2)，6.87-7.30(m，6H，CHAr)，7.27(mc，1H，CH)，7.58(mc，1H，CH)，14.47(s，1H，NH)。LC/(+)-ESI-MS：m/z＝404[M+H]+。
实施例3：
通过方法A合成的3-(3′-乙氧基-3，5-二氟-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.21(mc，9H，CH3)1.27(mc，3H，CH3)3.11(mc，6H，CH2)，4.03(mc，2H，CH2)，6.81-7.25(m，6H，CHAr)，7.26(mc，1H，CH)，7.57(mc，1H，CH)，14.44(s，1H，NH)。LC/(+)-ESI-MS：m/z＝404[M+H]+。
实施例4：
通过方法A合成的3-(3，5-二氟-2′，4′-二甲氧基-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.21(mc，9H，CH3)，3.09(mc，6H，CH2)，3.73(s，3H，CH3)，3.74(s，3H，CH3)，6.48-7.24(m，5H，CHAr)，7.26(mc，1H，CH)，7.57(mc，1H，CH)，14.44(s，1H，NH)。LC/(+)-ESI-MS：m/z＝420[M+H]+。
实施例5：
通过方法A合成的3-(2，3，5，6-四氟-2′-甲氧基-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.23(mc，9H，CH3)，3.14(mc，6H，CH2)，3.72(s，3H，CH3)，6.94-7.42(m，H，CHAr)，7.31(mc，1H，CH)，7.59(mc，1H，CH)，14.67(s，1H，NH)。LC/(+)-ESI-MS：m/z＝426[M+H]+。
实施例6：
通过方法A合成的3-(2′-氯-3，5-二氟-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.21(mc，9H，CH3)，3.08(mc，6H，CH2)，6.99-7.54(m，6H，CHAr)，7.28(mc，1H，CH)，7.59(mc，1H，CH)，14.67(s，1H，NH)。LC/(+)-ESI-MS：m/z＝394[M+H]+。
实施例7：
通过方法A合成的3-(3，5，2′-三氟-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.22(mc，9H，CH3)，3.11(mc，6H，CH2)，7.01-7.54(m，6H，CHAr)，7.27(mc，1H，CH)，7.58(mc，1H，CH)，14.74(s，1H，NH)。LC/(+)-ESI-MS：m/z＝378[M+H]+。
实施例8：
通过方法A合成的3-(2-氯-2′-甲氧基-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.26(mc，9H，CH3)3.17(mc，6H，CH2)，6.82-8.01(m，7H，CHAr)，7.26(mc，1H，CH)，7.61(mc，1H，CH)，15.1(s，1H，NH)。LC/(+)-ESI-MS：m/z＝388[M+H]+。
实施例9：
通过方法A合成的3-(2，3，5，6-四氟-3′-三氟甲氧基-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，LC/(+)-ESI-MS：m/z＝480[M+H]+。
实施例10：
通过方法A合成的3-(3-氟-3′-甲氧基-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝3.75(s，3H，CH3)，6.79-7.47(m，6H，CHAr)，7.77(mc，2H，CH)，8.20(mc，1H，CHAr)，11.10(s，1H，NH)。LC/(+)-ESI-MS：m/z＝372[M+H]+。
实施例11：
通过方法A合成的3-(3，5-二氟-3′-三氟甲氧基-联苯-4-基氨基甲酰基)-噻吩-2-羧酸，1H-NMR：δ＝1.22(mc，9H，CH3)，3.13(mc，6H，CH2)，7.22-7.68(m，6H，CHAr)，7.27(mc，1H，CH)，7.57(mc，1H，CH)，14.67(s，1H，NH)。LC/(+)-ESI-MS：m/z＝444[M+H]+。
实施例12：
通过方法A合成的3-(联苯-4-基氨基甲酰基)-呋喃-2-羧酸，LC/(+)-ESI-MS：m/z＝308[M+H]+。
实施例13：
通过方法C合成的4-(联苯-4-基氨基甲酰基)-噻吩-3-羧酸，1H-NMR：δ＝7.24-8.0(m，9H，CHAr)，8.47(mc，2H，CH)。LC/(+)-ESI-MS：m/z＝324[M+H]+。
实施例14：
通过方法C合成的4-(2-氯-2′-甲氧基-联苯-4-基氨基甲酰基)-噻吩-3-羧酸，1H-NMR：δ＝3.76(s，3H，CH3)，6.97-8.14(m，7H，CHAr)，8.40-8.55(m，2H，CH)，11.92(s，1H，NH)。LC/(+)-ESI-MS：m/z＝388[M+H]+。
实施例15：
通过方法C合成的4-(3，5，2′-三氟-联苯-4-基氨基甲酰基)-噻吩-3-羧酸，1H-NMR：δ＝7.23-7.69(m，6H，CHAr)，8.56(mc，2H，CH)，11.54(s，1H，1NH)。LC/(+)-ESI-MS：m/z＝378[M+H]+。
实施例16：
通过方法C合成的4-(3′-乙氧基-3，5-二氟-联苯-4-基氨基甲酰基)-噻吩-3-羧酸，1H-NMR：δ＝1.40(mc，3H，CH3)，4.17(mc，2H，CH2)，6.94-7.50(m，6H，CHAr)，8.58(mc，2H，CH)。LC/(+)-ESI-MS：m/z＝404[M+H]+。
实施例17：
通过方法C合成的4-(2′-乙氧基-3，5-二氟-联苯-4-基氨基甲酰基)-噻吩-3-羧酸，1H-NMR：δ＝1.37(mc，3H，CH3)，4.14(mc，2H，CH2)，7.01-7.47(m，6H，CHAr)，8.58(mc，2H，CH)。LC/(+)-ESI-MS：m/z＝404[M+H]+。
实施例18：
通过方法C合成的4-(3，5-二氟-3′-三氟甲氧基-联苯-4-基氨基甲酰基)-噻吩-3-羧酸，1H-NMR：δ＝7.37-8.4(m，6H，CHAr)，8.58(mc，2H，CH)。LC/(+)-ESI-MS：m/z＝444[M+H]+。
实施例19：
通过方法C合成的4-(3-氟-3′-甲氧基-联苯-4-基氨基甲酰基)-噻吩-3-羧酸，LC/(+)-ESI-MS：m/z＝372[M+H]+。
实施例20：
通过方法C合成的4-(联苯-4-基氨基甲酰基)-呋喃-3-羧酸，LC/(+)-ESI-MS：m/z＝308[M+H]+。
实施例21：
通过方法A合成的2-(联苯-4-基氨基甲酰基)-噻吩-3-羧酸，LC/(+)-ESI-MS：m/z＝324[M+H]+。
实施例22：
通过方法A合成的2-(联苯-4-基氨基甲酰基)-呋喃-3-羧酸，LC/(+)-ESI-MS：m/z＝308[M+H]+。
3.DHODH活性的抑制分析
标准的分析混合物含有50μM decyclo ubichinone、100μM二氢乳清酸，60μM 2，6-二氯靛酚，以及20mU DHODH。所用重组酶的单位体积活性为30U/ml。在50mM TrisHCl(150mM KCl，0.1％Triton X-100，pH8.0)、30℃、最终体积1ml的条件下进行检测。将各组分混合，通过加入二氢乳清酸引发反应。通过分光光度法检测600nm处光吸收的降低对所述反应过程跟踪2分钟。
在标准分析中再用借助抑制剂的数量变化进行抑制研究。为确定IC50值(50％抑制所需的抑制剂浓度)至少需应用五种不同的抑制剂浓度。
用Prof.M.Lffler，Marburg，Germany[M.L
ffler，Chem.Biol.Interact.124，(2000)，61-76]提供的重组人以及重组小鼠DHODH进行这些研究。
使用来氟米特A77-1726的活性代谢产物作为参考[J.J
ckel et.al.Biochemical Pharmacology 56(1998)，1053-1060]。
实施例1、2、3、4、5、6、7、8、10、11、14、15、16、17、18、19、21、13、12、22、20显示了对小于1μl的人DHODH的抑制作用。
实施例9、21显示了对1-5μl的人DHODH的抑制作用。
Claims (5)
1.通式(II)化合物及其盐，
其中，
A 为五元杂芳香环系，其含有一个选自S或O的X基团；
D 为CH2；
Z1和Z2相互独立地为O或S；
R1 独立地代表H；
R2 为OR6或NHR7；
R3 为H；
R6 为H或烃基；
R7 为H、OH或烃基；
R8 为氢或烃基；
E 为被一个或多个取代基R’任选取代的苯基；
Y 为被一个或多个取代基R’任选取代的苯基；
R’独立地代表硝基、卤素、烃氧基、卤代烃基或卤代烃氧基，
m 为0；
n 为0；
q 为0；及
t 为0-3；
且其中所述烃基指直链或支链的C1-C6烷基、直链或支链的C1-C6烯 基或者直链或支链的C1-C6炔基；
其条件是不包括以下化合物：
3-(甲基-苯基-氨基甲酰基)-噻吩-2-羧酸甲酯；
3-(甲基-苯基-氨基甲酰基)-噻吩-2-羧酸；
2-苯基氨基甲酰基-呋喃-3-羧酸；
2-(甲基-苯基-氨基甲酰基)-噻吩-3-羧酸甲酯；
2-(甲基-苯基-氨基甲酰基)-噻吩-3-羧酸；
3-(3-三氟甲基苯基氨基甲酰基)-噻吩-2-羧酸；
3-苯基氨基甲酰基-噻吩-2-羧酸；
2-(3-三氟甲基苯基氨基甲酰基)-噻吩-3-羧酸；
2-(4-氯-苯基氨基甲酰基)-噻吩-3-羧酸；
2-苯基氨基甲酰基-噻吩-3-羧酸；
2-(4-氯-2-氟-5-丙-2-炔基氧-苄基氨基甲酰基)-噻吩-3-羧酸；
2-(4-氯-2-氟-5-甲氧基羰基甲氧基-苄基氨基甲酰基)-噻吩-3-羧酸；
2-(3-三氟甲基-苯基氨基甲酰基)-呋喃-3-羧酸。
2.药物组合物，含有游离态的权利要求1所述的化合物，或其药物可接受的盐，以及药物可接受的稀释剂或载体。
3.权利要求1所述的化合物或其药理学可耐受的盐在制备药物中的用途，所述药物用于治疗疾病或治疗适应症，其中在所述治疗中抑制二氢乳清酸脱氢酶是有利的。
4.如权利要求3所述的用途，其中所述疾病或适应症选自风湿病、急性免疫紊乱、自身免疫性疾病、由恶性细胞增殖引起的疾病、炎性疾病、在人和动物中由原生动物感染引起的疾病及由病毒感染和卡氏肺囊虫引起的疾病。
5.制备通式(II)化合物及其盐的方法，
其中，
A 为五元杂芳香环系，其含有一个选自S或O的X基团；
D 为O、S、SO2、NR4或CH2；
Z1和Z2相互独立地为O、S或NR5；
R1 独立地代表H、卤素、卤代烃基、卤代烃基氧基、-CO2R”、-SO3H、-OH、-CONR*R”、-CR”O、-SO2-NR*R”、-NO2、-SO2-R”、-SO-R*、-CN、烃基氧基、烃基硫基、芳基、-NR”-CO2-R’、-NR”-CO-R*、-NR”-SO2-R’、-O-CO-R*、-O-CO2-R*、-O-CO-NR*R”；环烃基、烃基氨基、羟基烃基氨基、-SH、杂芳基或烃基；
R* 独立地代表H、烃基、环烃基、氨基烃基、烃基氧基、-OH、-SH、烃基硫基、羟基烃基、卤代烃基、卤代烃基氧基、芳基或杂芳基；
R’独立地代表H、-CO2R”、-CONHR”、-CR”O、-SO2NR”、-NR”-CO-卤代烃基、-NO2、-NR”-SO2-卤代烃基、-NR”-SO2-烃基、-SO2-烃基、-NR”-CO-烃基、-CN、烃基、环烃基、氨基烃基、烃基氨基、烃基氧基、-OH、-SH、烃基硫基、羟基烃基、羟基烃基氨基、卤素、卤代烃基、卤代烃基氧基、芳基、芳基烃基、或杂芳基；
R” 独立地代表卤素、卤代烃基、羟基烃基、烃基、环烃基、芳基、杂芳基或氨基烃基；
R2 为H或OR6、NHR7、NR7OR7，或者R2与和R8相连的氮原子形成五元或六元杂环，其条件是R2为-[CH2]s且R8不存在；
R3 为H、烃基、环烃基、芳基、烃基氧基、O-芳基；O-环烃基、卤素、氨基烃基、烃基氨基、羟氨基、羟基烃基、卤代烃基氧基、杂芳基、烃基硫基、S-芳基；S-环烃基、芳基烃基或卤代烃基；
R4 为H、烃基、环烃基、芳基或杂芳基；
R5 为H、OH、烃基氧基、O-芳基、烃基或芳基；
R6 为H、烃基、环烃基、芳基、芳基烃基、杂芳基、烃基芳基、烃基氧基烃基、酰基甲基、酰氧基烃基、不对称酰氧基烃基二酯或二烃基磷酸酯；
R7 为H、OH、烃基、芳基、烃基氧基、O-芳基、环烃基或O-环烃基；
R8 为氢或烃基；
E 为烃基或环烃基，或者单环或多环的取代或未取代的环系，其可含有一个或多个X基团并且包含至少一个芳香环；
Y 为氢、卤素、卤代烃基、卤代烃基氧基、烃基、环烃基、单环或多环的取代或未取代的环系，所述环系可含有一个或多个X基团并且包含至少一个芳香环，或
m 为0或1；
n 为0或1；
p 为0或1；
q 为0或1；
s 为0-2；及
t 为0-3，
所述方法包括：
使通式(III)的酸酐，
其中A、X、R1和t的定义如前所述，和通式(IV)的胺反应，
其中E、D、R3、R8、Y、m、n和q的定义如前所述；或使通式(V)的羧酸衍生物，
其中A、X、R1、R2和t的定义如前所述，R9为卤素或烃氧基，与通式(VI)的羟胺反应，
其中E、D、R3、R8、Y、m、n和q的定义如前所述。
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| CN2003801073546A Expired - Fee Related CN1732163B (zh) | 2002-12-23 | 2003-12-17 | 作为抗炎和免疫调节及抗增殖试剂的芳香化合物 |
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Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120028985A1 (en) * | 2008-11-07 | 2012-02-02 | 4Sc Ag | Combinational therapy for treating autoimmune disease |
| TWI530286B (zh) * | 2009-05-04 | 2016-04-21 | 帕納特斯製藥格斯有限公司 | 作為抑制病毒化合物之抗發炎劑 |
| US8686048B2 (en) | 2010-05-06 | 2014-04-01 | Rhizen Pharmaceuticals Sa | Immunomodulator and anti-inflammatory compounds |
| EP2672963A4 (en) | 2011-02-08 | 2015-06-24 | Childrens Medical Center | METHOD FOR THE TREATMENT OF MELANOMA |
| RU2485112C1 (ru) * | 2012-04-26 | 2013-06-20 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Пермский государственный национальный исследовательский университет" | 4-(4-бромфенил)-4-оксо-2-{[3-(этоксикарбонил)-4,5-диметилтиен-2-ил]амино}-2-бутеновая кислота, обладающая противовоспалительной и анальгетической активностью |
| WO2015154820A1 (en) | 2014-04-11 | 2015-10-15 | Panoptes Pharma Gmbh | Anti-inflammatory agents as virostatic compounds |
| MX2016014634A (es) * | 2014-05-08 | 2017-04-10 | Panoptes Pharma Ges M B H | Compuestos para el tratamiento de enfermedades y trastornos oftalmicos. |
| CA3043938A1 (en) | 2016-12-21 | 2018-06-28 | Biotheryx, Inc. | Thienopyrrole derivatives for use in targeting proteins, compositions, methods, and uses thereof |
| RS65563B1 (sr) | 2018-03-16 | 2024-06-28 | Immunic Ag | Novi polimorfi kalcijumove soli kao anti-inflamatorni, imunomodulatorni i anti-proliferativni agensi |
| WO2022167402A1 (en) | 2021-02-02 | 2022-08-11 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of therapy comprising administering a therapeutically effective combination comprising a dhodh inhibitor and an idh inhibitor |
| AU2022253683A1 (en) | 2021-04-09 | 2023-10-26 | Immunic Ag | Deuterated dhodh inhibitors |
| IL313501A (en) | 2021-12-23 | 2024-08-01 | Immunic Ag | DHODH INHIBITORS CONTAINING CARBOXYLIC ACID BIOISOSTERE |
| WO2024200872A1 (en) | 2023-03-29 | 2024-10-03 | Immunic Ag | Vidofludimus and related structures acting as nurr1 agonists |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5386036A (en) * | 1990-07-20 | 1995-01-31 | Basf Aktiengesellschaft | Dicarboximides, their preparation and their use as herbicides |
Family Cites Families (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL186239B (nl) | 1975-06-05 | Hoechst Ag | Werkwijze voor de bereiding van een geneesmiddel met antiflogistische en/of analgetische werking, alsmede werkwijze voor de bereiding van een 2-hydroxyethylideencyaanazijnzuuranilide geschikt voor toepassing bij deze werkwijze. | |
| AU1526483A (en) * | 1982-06-14 | 1983-12-22 | Nippon Kayaku Kabushiki Kaisha | N-substituted-3,4,5,6-tetrahydrophthalamic acids |
| ZA839187B (en) * | 1982-12-10 | 1984-07-25 | Ciba Geigy Ag | Amide compounds |
| GB8311519D0 (en) * | 1983-04-27 | 1983-06-02 | Fisons Plc | Nitrogen heterocycles |
| GB8323293D0 (en) * | 1983-08-31 | 1983-10-05 | Zyma Sa | Substituted flavene and thioflavene derivatives |
| DE3402026A1 (de) | 1984-01-21 | 1985-07-25 | Basf Ag, 6700 Ludwigshafen | Neue 2-aminothiophenderivate |
| DE3534440A1 (de) | 1985-09-27 | 1987-04-02 | Hoechst Ag | Arzneimittel gegen chronische graft-versus-host-krankheiten sowie gegen autoimmunerkrankungen, insbesondere systemischen lupus erythematodes |
| DE3812225A1 (de) * | 1988-04-13 | 1989-10-26 | Basf Ag | Isoxazol(isothiazol)-5-carbonsaeureamide |
| DE59009528D1 (de) * | 1989-09-22 | 1995-09-21 | Basf Ag | Carbonsäureamide. |
| DE3932052A1 (de) * | 1989-09-26 | 1991-04-04 | Basf Ag | Oxazol- bzw. thiazolcarbonsaeureamide |
| DE3933573A1 (de) * | 1989-10-07 | 1991-04-18 | Basf Ag | Carbonsaeureamide, verfahren zu ihrer herstellung und ihre verwendung als herbizide |
| EP0463444B1 (de) * | 1990-06-23 | 1995-08-30 | BASF Aktiengesellschaft | Dicarbonsäureimide als Herbizide |
| DE4108181A1 (de) * | 1991-03-14 | 1992-09-17 | Basf Ag | Isoxazol- und isothiazol-5-carbonsaeureamide |
| JP3199380B2 (ja) * | 1992-04-02 | 2001-08-20 | スミスクライン・ビーチャム・コーポレイション | 化合物 |
| JP3055365B2 (ja) * | 1993-06-30 | 2000-06-26 | 東洋インキ製造株式会社 | ２，５−ジ（アリールアミノ）−３，６−ジヒドロテレフタル酸ジアルキルエステル類の製造法およびこれを中間体とするキナクリドン類の製造法 |
| GB9320299D0 (en) | 1993-10-01 | 1993-11-17 | Roussel Lab Ltd | Isoxazole derivatives |
| DE19547648A1 (de) | 1995-12-20 | 1997-06-26 | Hoechst Ag | Zubereitung, enthaltend High Density Lipoproteine und Crotonsäureamidderivate |
| DE19610955A1 (de) | 1996-03-20 | 1997-09-25 | Hoechst Ag | Kombinationspräparat, enthaltend 5-Methylisoxazol-4-carbonsäure-(4-trifluormethyl)- anilid und N-(4-Trifluormethylphenyl)-2-cyan-3- hydroxycrotonsäureamid |
| JP3076066B2 (ja) * | 1996-08-27 | 2000-08-14 | 塩野義製薬株式会社 | クロメン−３−カルボン酸誘導体 |
| JP2001506271A (ja) * | 1996-12-23 | 2001-05-15 | デュポン ファーマシューティカルズ カンパニー | Ｘａ因子阻害剤としての酸素またはイオウを含む複素環式芳香族化合物 |
| US6187797B1 (en) * | 1996-12-23 | 2001-02-13 | Dupont Pharmaceuticals Company | Phenyl-isoxazoles as factor XA Inhibitors |
| EP0946508B1 (en) * | 1996-12-23 | 2009-09-23 | Bristol-Myers Squibb Pharma Company | NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS |
| US6020357A (en) * | 1996-12-23 | 2000-02-01 | Dupont Pharmaceuticals Company | Nitrogen containing heteroaromatics as factor Xa inhibitors |
| BR9810151A (pt) * | 1997-06-19 | 2000-08-08 | Du Pont Pharm Co | Composto, composição farmacêutica e método para tratamento ou prevenção de uma desordem tromoboembólica |
| US6339099B1 (en) * | 1997-06-20 | 2002-01-15 | Dupont Pharmaceuticals Company | Guanidine mimics as factor Xa inhibitors |
| AU2108099A (en) | 1998-01-30 | 1999-08-16 | Procept, Inc. | Immunosuppressive agents |
| GB9804343D0 (en) | 1998-02-27 | 1998-04-22 | Univ Cardiff | Chemical compounds |
| WO2000026197A1 (en) * | 1998-10-29 | 2000-05-11 | Bristol-Myers Squibb Company | Novel inhibitors of impdh enzyme |
| PL352197A1 (en) * | 1999-06-24 | 2003-08-11 | Nihon Nohyaku Co Ltd | Diamide derivatives of heterocyclic dicarboxylic acid, insecticides for agriculture and horticulture and the method of making same |
| JP4706810B2 (ja) * | 1999-06-24 | 2011-06-22 | 日本農薬株式会社 | ピリジン環ジカルボン酸ジアミド誘導体及び農園芸用殺虫剤並びにその使用方法 |
| WO2001021160A2 (en) * | 1999-09-23 | 2001-03-29 | Axxima Pharmaceuticals Aktiengesellschaft | Carboxymide and aniline derivatives as selective inhibitors of pathogens |
| WO2001024785A2 (en) | 1999-10-01 | 2001-04-12 | Institute Of Molecular And Cell Biology | Dihydroorotate dehydrogenase inhibitors for the treatment of viral-mediated diseases |
| EP1652839A3 (en) * | 1999-10-28 | 2006-07-05 | Daiichi Pharmaceutical Co., Ltd. | Drug efflux pump inhibitor |
| EP1226123A1 (en) * | 1999-11-03 | 2002-07-31 | Du Pont Pharmaceuticals Company | Cyano compounds as factor xa inhibitors |
| JP2004501913A (ja) * | 2000-06-23 | 2004-01-22 | ブリストル−マイヤーズ スクイブ ファーマ カンパニー | ヘテロアリール−フェニル置換Ｘａ因子阻害剤 |
| RU2181270C1 (ru) | 2000-07-21 | 2002-04-20 | Общество с ограниченной ответственностью "Медицинское предприятие "ХИТ плюс" | Способ повреждения термонетолерантных патологических биоструктур организма теплокровных |
| JP2002128768A (ja) * | 2000-10-26 | 2002-05-09 | Dai Ichi Seiyaku Co Ltd | 薬剤排出ポンプ阻害作用を有する化合物 |
| JP2002322054A (ja) * | 2001-04-26 | 2002-11-08 | Dai Ichi Seiyaku Co Ltd | 薬剤排出ポンプ阻害薬 |
| JP4544857B2 (ja) * | 2001-06-11 | 2010-09-15 | ヴァイロケム ファーマ インコーポレイテッド | Ｆｌａｖｉｖｉｒｕｓ感染の治療または予防のための化合物および方法 |
| WO2003006424A1 (en) * | 2001-07-10 | 2003-01-23 | 4Sc Ag | Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
| DE10133665A1 (de) * | 2001-07-11 | 2003-01-30 | Boehringer Ingelheim Pharma | Carbonsäurederivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Herstellung |
| GB0219896D0 (en) * | 2002-08-27 | 2002-10-02 | Bayer Ag | Dihydropyridine derivatives |
| JP4093023B2 (ja) * | 2002-11-15 | 2008-05-28 | コニカミノルタビジネステクノロジーズ株式会社 | 非磁性一成分現像用トナーおよび画像形成方法 |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5386036A (en) * | 1990-07-20 | 1995-01-31 | Basf Aktiengesellschaft | Dicarboximides, their preparation and their use as herbicides |
Non-Patent Citations (2)
| Title |
|---|
| An EPR study of the radicals from5-nitrothiophenecarboxamides: a novel group of direct actingmutagens.Tetrahedron49 33.1993,49(33),7317-24. |
| An EPR study of the radicals from5-nitrothiophenecarboxamides: a novel group of direct actingmutagens.Tetrahedron49 33.1993,49(33),7317-24. * |
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