CN1585636A - 内皮素受体拮抗剂用于治疗肿瘤性疾病的用途 - Google Patents
内皮素受体拮抗剂用于治疗肿瘤性疾病的用途 Download PDFInfo
- Publication number
- CN1585636A CN1585636A CNA028222520A CN02822252A CN1585636A CN 1585636 A CN1585636 A CN 1585636A CN A028222520 A CNA028222520 A CN A028222520A CN 02822252 A CN02822252 A CN 02822252A CN 1585636 A CN1585636 A CN 1585636A
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- China
- Prior art keywords
- diazosulfide
- benzyl
- methoxyphenyl
- ketone
- furan
- 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.)
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Classifications
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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Abstract
本发明涉及内皮素受体拮抗剂在制备用于治疗肿瘤性疾病的药物中的用途。
Description
本发明涉及内皮素受体拮抗剂在制备用于抑制肿瘤细胞生长的药物中的用途,所述内皮素受体拮抗剂选自:
(a)EP 0733626中所述的式I化合物及其盐,
其中:
-A=B-C=D-为-CH=CH-CH=CH-基团,其中1或2个CH已被N替代,
Ar为Ph或萘基,各自为未取代的,或被H、卤素、A、不超过6个碳原子的链烯基、Ph、OPh、NO2、NR4R5、NHCOR4、CF3、OCF3、CN、OR4、COOR4、(CH2)nCOOR4、(CH2)nNR4R5、-N=C=O或NHCONR4R5单取代、二取代或三取代,
R1、R2和R3彼此独立地为不存在、H、卤素、A、CF3、NO2、NR4R5、CN、COOR4或NHCOR4,
R4和R5彼此独立地为H或A,或者一起为-CH2-(CH2)n-CH2-,
A为具有1至6个碳原子的烷基,
Ph为苯基,
X为O或S,
卤素为F、Cl、Br或I,
n为1、2或3;
(b)EP 0758650中所述的式I化合物及其盐,
其中:
X为饱和、完全不饱和或部分不饱和的3-元至4-元亚烷基链,其中1至3个碳原子可被N替代,和/或1或2个碳原子可被1至2个O原子和/或1至2个S原子替代,但其中最多不超过3个碳原子被替代,此外,其中可以出现亚烷基链和/或位于其中的氮原子被A、R8和/或NR4R4’单取代、二取代或三取代,此外,其中亚烷基链中的一个CH2基团也可被C=O基团替代,
A为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子或被-CR4=CR4’-基团替代,此外,1至7个H原子可被F替代,
R1为H或A,
R2为COOR4、CN、1H-四唑-5-基或CONHSO2R8,
R3为Ar,
R4和R4’彼此独立地为H、具有1至6个碳原子的烷基或苄基,
Ar为苯基或萘基,各自为未取代的或被R5、R6或R7单取代、二取代或三取代,或
基团,
其为未取代的或在苯基部分被R5或R6单取代或二取代,R5、R6和R7彼此独立地为R4、OR4、卤素、CF3、OCF3、OCHF2、OCH2F、NO2、NR4R4’、NHCOR4、CN、NHSO2R4、COOR4、COR4、CONHSO2R8、O(CH2)nR2、OPh、O(CH2)nOR4或S(O)mR4,
R8为苯基或萘基,各自为未取代的或被A、OR1、NR4R4’或卤素单取代、二取代或三取代,
E为CH2或O,
D为羰基或[C(R4R4’)]n,
卤素为F、Cl、Br或I,
m为0、1或2,
n为1或2;
(c)EP 0755934中所述的式I化合物及其盐,
其中:
-Y-Z-为-NR7-CO-、-N=C(OR7)-或-N=CR8-,
R1为Ar,
R2为COOR6、CN、1H-四唑-5-基或CONHSO2Ar,
R3、R4和R5彼此独立地为R6、OR6、S(O)mR6、卤素、NO2、NR6R6’、NHCOR6、NHSO2R6、OCOR6、COOR6或CN,
R6和R6’彼此独立地为H、具有1至6个碳原子的烷基、苄基或苯基,
R7为(CH2)nAr,
R8为Ar或OAr,
Ar为未取代的或被R9、R10或R11单取代、二取代或三取代的苯基,或未取代的萘基,或
其为未取代的或在苯基部分被R9或R10单取代或二取代,或
基团,
其为未取代的或在环己二烯部分被R9或R10单取代或二取代,R9、R10和R11彼此独立地为R6、OR6、卤素、CF3、OCF3、OCHF2、OCH2F、NO2、NR6R6’、NHCOR6、CN、NHSO2R6、COOR6、COR6、CONHSO2Ar、O(CH2)nR2、O(CH2)nOR6或S(O)mR6,
E为CH2、S或O,
D为羰基或[C(R6R6’)]n,
卤素为F、Cl、Br或I,
X为O或S,
m为0、1或2,
n为1或2;
(d)EP 0757039中所述的式I化合物及其盐,
其中:
-Y-Z-为-NR7-CO-、-N=C(OR7)-或-N=CR8-,
R1为Ar,
R2为COOR6、(CH2)nCOOR6、CN、1H-四唑-5-基或CONHSO2Ar,
R3、R4和R5彼此独立地为R6、OR6、S(O)mR6、卤素、NO2、NR6R6’、NHCOR6、NHSO2R6、OCOR6、COR6、COOR6或CN,或者其中R3和R4可一起为O(CH2)nO基团,
R6和R6’彼此独立地为H、具有1至6个碳原子的烷基、苄基或苯基,
R7为(CH2)nAr,
R8为Ar或OAr,
Ar为未取代的或被R9、R10或R11单取代、二取代或三取代的苯基,或未取代的萘基,或
基团,
其为未取代的或在苯基部分被R9或R10单取代或二取代,或
其为未取代的或在环己二烯部分被R9或R10单取代或二取代,
R9、R10和R11彼此独立地为R6、OR6、卤素、CF3、OCF3、OCHF2、OCH2F、NO2、NR6R6’、NHCOR6、CN、NHSO2R6、COOR6、COR6、CONHSO2Ar、O(CH2)nR2、O(CH2)nOR6或S(O)mR6,
E为CH2、S或O,
D为羰基或[C(R6R6’)]n,
X为O或S,
卤素为F、Cl、Br或I,
m为0、1或2,
n为1、2或3;
(e)EP 0796250中所述的式I化合物及其盐,
其中:
Y为-C(R4R4’)-C(R4R4’)-、-CR4=CR4’-或-C(R4R4’)-S-,
R1为Het、Ar、R3或R4,
R2为Ar或基团,其为未取代的或在苯基部分被A、R3、OR4、NH2、NHA、NA2、NO2、CN、卤素、NHCOR4、NHSO2R4、COOR4、COR4、CONHSO2R6、O(CH2)nR3、OPh、O(CH2)nOR4或S(O)mR4单取代或二取代,或
其为未取代的或在环己二烯基部分被A、R3、OR4、NH2、NHA、NA2、NO2、CN、卤素、NHCOR4、NHSO2R4、COOR4、COR4、CONHSO2R6、O(CH2)nR3、OPh、O(CH2)nOR4或S(O)mR4单取代或二取代,
R3为CN、COOH、COOA、CONHSO2R5或1H-四唑-5-基,R4和R4’彼此独立地为H、A,或苯基或苄基,各自为未取代的或被烷氧基单取代,
R5为A或Ar,
R6为苯基或萘基,各自为未取代的或被A、OR5、NH2、NHA、NA2、NO2、CN或卤素单取代、二取代或三取代,
A为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR4=CR4’-基团替代,此外,1至7个H原子可被F替代,或苄基,
Ar为苯基或萘基,各自为未取代的或被A、OR4、NH2、NHA、NA2、NO2、CN、卤素、NHCOR4、NHSO2R4、COOR4、COR4、CONHSO2R6、O(CH2)nR3、OPh、O(CH2)nOR4或S(O)mR4单取代、二取代或三取代,
Het为单环或双环饱和、不饱和或芳香族杂环基团,其具有1至4个N、O和/或S原子,经由N或C键合,其可以是未取代的或被卤素、A、R3、NH2、NHA、NA2、CN、NO2和/或羰基氧单取代、二取代或三取代,
D为羰基或[C(R4R4’)]n,
E为CH2、S或O,
卤素为F、Cl、Br或I,
X为O或S,
m为0、1或2,
n为1或2;
(f)WO 9719077中所述的式I化合物及其盐,
其中:
R为
或
X为O或S,
R1为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO3-A、SO2NHA、CN或甲酰基,
R2为H或A,
R3、R5、R6、R7和R8彼此独立地为H、卤素、OH、OA、O-亚烷基-R4、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R4、NASO2A、NASO2-R4、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NH-苯基、NHCOOA、NA-酰基、NHR4、NHCOOR4、NHCOO-苄基、NHSO2-苄基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOR2、O(CH2)nOR2、CH2OH或CH2OA,
R3和R6或者一起为-O-CH2-O-、-O-CH2-CH2-O-、-O-CH2-CH2-、-O-CF2-O-或-O-CF2-CF2-O-,
R4为未取代的或被R3和/或R6单取代或多取代的苯基,
A为具有1至6个碳原子的烷基,
卤素为氟、氯、溴或碘,
n为1或2;
(g)WO 9730982中所述的式I化合物或互变异构成环形式,以及(E)-异构体和所有异构体的盐,
其中:
R为
X为O或S,
R1为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO3-A、SO2NHA、CN或甲酰基,
R2、R3和R4彼此独立地为未取代的或被以下基团单取代或多取代的苯基:卤素、OH、OA、O-亚烷基-R5、A、S-A、SOA、SO2A、SOR5、SO2R5、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R5、NASO2A、NASO2-R5、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NHR5、NHCOOA、NA-酰基、NHCOOCH2R5、NHSO2CH2R5、NHCOO-亚烷基-OA、NH(CO)NA2、1-哌啶基-CO-NH、1-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
基团,或
其中R2另外地为A或环烷基,
R5为未取代的或被以下基团单取代或多取代的苯基:卤素、OH、OA、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NASO2A、NH(CO)NH2、NH(CO)NHA、甲酰基、NHCOOA、NA-酰基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
A为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR6=CR6’-基团替代,和/或1至7个H原子可被F替代,
D为羰基或[C(R6R6’)]m,
E为CH2、S或O,
Y为O或S,
R6和R6’彼此独立地为H、F或A,
卤素为氟、氯、溴或碘,
n为1或2,且
m为1或2;
(h)WO 9730996中所述的式I化合物及其盐,
其中:
-A=B-C=D-为-CH=CH-CH=CH-基团,此外其中1或2个CH可被N替代,
Het为单环或双环饱和、不饱和或芳香族杂环基,具有1至4个N、O和/或S原子,其为未取代的或被-Z-R6取代,
R1、R2和R3彼此独立地为不存在、H、卤素、A、CF3、NO2、NR4R5、CN、COOR4或NHCOR4,
R4和R5彼此独立地为H或A,或者一起为-CH2-(CH2)n-CH2-,
R6为苯基、苯并噻二唑-5-基或苯并噁二唑-5-基,各自为未取代的或被R7、R8和/或R9单取代、二取代或三取代,
R7、R8和R9彼此独立地为A、O-A、CN、COOH、COOA、卤素、甲酰基或-CO-A,或者R7和R8一起为-O-(CH2)m-O-,
A为具有1至6个碳原子的烷基,
X为O或S,
Z为-CO-、-CONH-、-CO-(CH2)n-、-CH=CH-、-(CH2)n-、-CONHCO-、-NHCONH-、-NHCOO-、-O-CONH-、-CO-O-或-O-CO-,
卤素为F、Cl、Br或I,
m为1或2,且
n为1、2或3;
i)DE 19609597中所述的式I化合物及其生理学可接受的盐,
其中:
Ar为萘基,其被NH2、NHA或NA2单取代,且
A为具有1至6个碳原子的烷基;
j)DE 19612101中所述的式I化合物及其盐,
其中:
-Y-Z-为-NR4-CO或-N=CR5-,
R1为Ar,
R2为H、具有1至6个碳原子、未取代的或被OR3或卤素单取代、二取代或三取代的烷基,或(CH2)mPh或(CH2)m-环烷基,其各自为未取代的或被R3、OR3或卤素单取代、二取代或三取代,
R3和R3’彼此独立地为H、具有1至6个碳原子的烷基或苄基,
R4为CH2Ar,
R5为OCH2Ar,
Ar为未取代的或被R6、R7或R8单取代、二取代或三取代的苯基,
或
其为未取代的或在苯基部分被R6单取代,或
其为未取代的或在环己二烯部分被R6单取代,
E为CH2或O,
D为羰基或(CH2)n,
E和D 或者一起为CH=CR9,
R6和R6’彼此独立地为R3、OR3或卤素,
R7为R3、OR3、卤素、NO2、NH2、NHR3、NR3R3’、NHCOR3、COOR3、O(CH2)nR3或O(CH2)nOR3,
R8为Ph,其为未取代的或被R3、OR3、卤素、NO2、NH2、NHR6、NR6R6’、NHCOR3或COOR3单取代、二取代或三取代,
R9为H、OH、CH2OH或COOR3,
卤素为F、Cl、Br或I,
Ph为苯基,
m为0或1,
n为1或2;
k)WO 9827091中所述的式I化合物及其盐,
其中:
R为苯基,其为未取代的或被R3、R4或R5单取代、二取代或三取代,或为2,1,3-苯并噻二唑基,其为未取代的或被R2单取代,
R1为A,其中1至7个H原子可被F替代,或为-S-A或-O-A,或苯基或-亚烷基-苯基,其各自为未取代的或被R3单取代,或噻吩基,其为未取代的或被R3单取代,
R2为A、F、Cl、Br或-O-A,
R3、R4和R5彼此独立地为A、-O-A、-S-A、-O-亚烷基-COOH、-亚烷基-COOH或COOH,
R3和R4或者一起为-O-CH2-O-,且
A为具有1至7个碳原子的烷基;
l)WO 9827077中所述的式I化合物或互变异构成环形式,以及(E)-异构体和所有异构体的盐,
其中:
R为
或
X为O或S,
R1为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO3-A、SO2NHA、CN或甲酰基,
R2、R3和R4彼此独立地为苯基,其为未取代的或被R7单取代或多取代,其中R2另外地为A或环烷基,
条件是:基团R2、R3或R4中的至少一个为R8基团,其为未取代的或被R7单取代或多取代,
R5为苯基,其为未取代的或被以下基团单取代或多取代:卤素、OH、OA、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NASO2A、NH(CO)NH2、NH(CO)NHA、甲酰基、NHCOOA、NA-酰基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
A为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR6=CR6’-替代,和/或1至7个H原子可被F替代,
D为羰基或[C(R6R6’)]m,
E为CH2、S或O,
Y为O或S,
R6和R6’彼此独立地为H、F或A,
R7为卤素、OH、OA、O-亚烷基-R5、A、S-A、S-OA、SO2A、S-OR5、SO2R5、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R5、NASO2A、NASO2R5、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NHR5、NHCOOA、NA-酰基、NHCOOCH2R5、NHSO2CH2R5、NHCOO-亚烷基-OA、NH(CO)NA2、1-哌啶基-CO-NH、1-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
R8为5至7元杂环基,具有1至4个N、O和/或S原子,或
基团,
G和Z彼此独立地为-CH=、N、O或S,
L为-CH=、-CH=CH-或-CH2-CH2-CH2-,
卤素为氟、氯、溴或碘,
n为0、1或2,且
m为1或2;
m)WO 9841515中所述的式I化合物及其盐,
其中:
X为O或S,
R1为H、卤素、OH、OA、A、NO2、NH2、NHA、NAA’、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、S(O)mR6、SO3H、SO2NR4R4’或甲酰基,
R2和R2’彼此独立地为A、(CH2)nAr、(CH2)nHet、CH2COAr、CH2COHet或OAr,
R2’额外地也为H,
R3为COOR4、CN、1H-四唑-5-基或CONHSO2R5,
R4和R4’彼此独立地为H或A,
R5为A或Ar,
R6为苯基或萘基,各自为未取代的或被A、NH2、NHA、NAA’、NO2、CN或卤素单取代、二取代或三取代,
R7和R7’彼此独立地为H或具有1至6个碳原子的烷基,
A和A’彼此独立地为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR7=CR7’-基团替代,和/或1至7个H原子可被F替代,或苄基,
Ar为苯基或萘基,各自为未取代的或被以下基团单取代、二取代或三取代:A、OR4、NH2、NHA、NAA’、NO2、CN、卤素、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、COOR4、OPh、CONH2、CONHA、CONAA’、COR4、CONHSO2R4、CONHSO2R6、O(CH2)nCOOR4、O(CH2)nOR4、SO3H、SO2NR4R4’、S(O)mR6或S(O)mR4,
Het为单环或双环饱和、不饱和或芳香族杂环基,具有1至4个N、O和/或S原子,经由N或C键合,其可为未取代的或被卤素、A、R3、NH2、NHA、NAA’、NO2和/或=O单取代、二取代或三取代,
卤素为氟、氯、溴或碘,
m为0、1或2,且
n为1或2,
其中如果R2为CH2COAr且R2’为H,则R3不为COOA;
n)WO 9841521中所述的式I化合物和(Z)-和(E)-异构体以及所有异构体的盐,
其中:
Z为单键或双键,
R1为
其为未取代的或在苯基部分被R7单取代,或
其为未取代的或在环己二烯部分被R7单取代,
R2为A、Ar-(CH2)m、环烷基-(CH2)m、Het-(CH2)m或R1-(CH2)m,
R3和R3’彼此独立地为OR4、NHSO2R5、NH2、NHA或NAA’,
R3和R3’或者一起为-O-,形成环状酐,
R4和R4’彼此独立地为H或A,
R5为A或Ar,
R6为苯基或萘基,各自为未取代的或被A、NH2、NHA、NAA’、NO2、CN或卤素单取代、二取代或三取代,
R7为A、COOR4、CN、1H-四唑-5-基、CONHSO2R5、卤素、OR4、NO2、NH2、NHA、NAA’、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、S(O)kR4、S(O)kR6、SO2NR4R4’或甲酰基,
R8和R8’彼此独立地为H或具有1至6个碳原子的烷基,
E为CH2或O,
D为羰基或(CR4R4’)n,
E和D或者一起为CR4=R4’,
X为S或O,
A和A’彼此独立地为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR8=CR8’-基团替代,和/或1至7个H原子可被F替代,或苄基,
Ar为苯基或萘基,各自为未取代的或被以下基团单取代、二取代或三取代:A、OR4、NH2、NHA、NAA’、NO2、CN、卤素、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、COOR4、OPh、CONH2、CONHA、CONAA’、COR4、CONHSO2R4、CONHSO2R6、O(CH2)nCOOR4、O(CH2)nOR4、SO2NR4R4’、S(O)kR6或S(O)kR4,
Het为单环或双环饱和、不饱和或芳香族杂环基,其具有1至4个N、O和/或S原子,经由N或C键合,其可为未取代的或被卤素、A、COOR4、CN、1H-四唑-5-基、CONHSO2R5、NH2、NHA、NAA’、NO2和/或=O单取代、二取代或三取代,
卤素为氟、氯、溴或碘,
k为0、1或2,
m为0、1或2,且
n为1或2;
o)WO 9842702中所述的式I化合物及其盐,
其中:
R为
或
X和Y彼此独立地为O或S,
R1为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO2-A、SO2NHA、CN或甲酰基,
R2、R3和R4彼此独立地为苯基,其为未取代的或被以下基团单取代或多取代:卤素、OH、OA、O-亚烷基-R5、A、S-A、S-OA、SO2A、S-OR5、SO2R5、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R5、NASO2A、NASO2-R5、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NHR5、NHCOOA、NA-酰基、NHCOOCH2R5、NHSO2CH2R5、NHCOO-亚烷基-OA、NH(CO)NA2、1-哌啶基-CO-NH、1-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
基团,或
R2另外地为A或环烷基,
R5为苯基,其为未取代的或被以下基团单取代或多取代:卤素、OH、OA、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NASO2A、NH(CO)NH2、NH(CO)NHA、甲酰基、NHCOOA、NA-酰基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
A为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR6=CR6’-替代,和/或1至7个H原子可被F替代,
D为羰基或[C(R6R6’)]m,
E为CH2、S或O,
R6和R6’彼此独立地为H、F或A,
R7为-O-C(=Y)-NH-R8,
R8为具有1至10个碳原子的烷基,其为未取代的或被R9单取代或二取代,且其中1至2个碳原子可被O和/或S替代和/或可被=O取代,
或环烷基,其中1至2个碳原子可被N、O和/或S替代,
R9为苯基,其为未取代的或被卤素单取代或二取代,萘基、A-O-C(=O)-或卤素,
卤素为氟、氯、溴或碘,
n为0、1或2,且
m为1或2;
p)WO 9842709中所述的式I化合物及其盐,
其中:
X为N-R3、O或S,
R为2,1,3-苯并噻二唑-4-或5-基,或2,1-苯并异噻唑-5-或6-基,各自为未取代的或被R2和/或R2’单取代或二取代,或苯基,其为未取代的或被R2和/或R2’单取代、二取代或三取代,
R1为H或A,
R2和R2’彼此独立地为H、A、OH、OA、卤素、OCF3、OCHF2、-O-CO-A、-O-亚烷基-COOR1、-O-亚烷基-CH2-OR1,或OCH2-苯基或-O-CO-苯基,各自为未取代的或在苯基部分被R4和/或R4’单取代或二取代,
R2和R2’或者一起为-OCH2O-、-OCH2CH2O-或-OCH2CH2-,
R3为H、A、亚烷基-O-A、-CO-OA,或亚烷基-苯基,其为未取代的或在苯基部分被R4和/或R4’单取代或二取代,
R4和R4’彼此独立地为H、A、OH、OA、卤素、COOR1或CH2OR1,
A为具有1至6个碳原子的烷基,
卤素为氟、氯、溴或碘;
q)WO 9905132中所述的式I化合物或互变异构成环形式,以及(E)-异构体和所有异构体的盐,
其中:
R为
X为O或S,
R1为H、卤素、OA或A,
R2、R3、R5和R6彼此独立地为H、卤素、A、OA或R4,
R4为-O-(CH2)n-Cy,
Cy为具有3至8个碳原子的环烷基,
A为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR5=CR5’-基团替代,和/或1至7个H原子可被F替代,
R5和R5’彼此独立地为H、F或A,
卤素为氟、氯、溴或碘,
n为0、1或2。
其它内皮素受体拮抗剂用于治疗肿瘤的用途在例如WO 99/06397、WO 98/57933和WO 96/06095中述及。
本发明的目的是提供药物制剂形式的药物的新用途,所述药物的性质优于已知可用于同一目的的药物。
令人惊讶的是,已发现上述式I化合物适合于治疗癌症疾病。
上述式I化合物及它们的盐显示非常有价值的药理学特性并且耐受性良好。所述化合物尤其显示对内皮素受体亚型ETA和ETB的高度亲和性。这些作用可通过常规的体外或体内方法测定,如例如P.D.Stein等人,J.Med.Chem.37,1994,329-331和E.Ohlstein等人,Proc.Natl.Acad.Sci.USA 91,1994,8052-8056所述。
式I化合物可用作人和兽药中的药物活性成分。它们还可用作制备其它药物活性成分的中间体。
术语“肿瘤细胞”意指癌细胞。
内皮素在下列类型的癌症中发挥作用:
前列腺癌:
前列腺癌细胞分泌内皮素-1,遭受转移的前列腺癌患者具有较高的血浆ET-1水平,ET1可刺激各种前列腺癌细胞系的增殖,ET1可刺激成骨细胞(Nelson JB等人,Nature Medicine 1/9 944-949,1995)。
ET 1在成骨细胞肿瘤模型中刺激骨的形成,ET 1影响前列腺癌形成转移(Nelson JB等人,Urology 53/5,1064-1069,1999)。
Atrasentan(Abbott,内皮素A受体拮抗剂)抑制体外各种前列腺癌细胞系的生长(Nelson JB等人,Cancer Research 56,663-668,1996)。卵巢癌:
内皮素1和内皮素A受体(ETAR)在卵巢癌中的表达,ET-1刺激原发卵巢癌细胞的增殖,BQ123(选择性内皮素A受体拮抗剂)抑制肿瘤细胞的增殖(Bagnato等人,Cancer Res 59,720-727,1999)。
ET1和ETAR在卵巢癌中的表达(Salani D等人,American Journal ofPathology 157/5,1537-1547,2000)。
ET-1保护卵巢癌细胞使其免于凋亡。该作用可通过BQ123(选择性内皮素A受体拮抗剂)消除(Del Bufalo D等人,Molecular pharmacology61/3,524532,2002)。
肠癌:
ETAR在肠肿瘤中的过度表达(AliH等人,Journal of CardiovascularPharmacology 36 S1 S69-S71,2000)。
ET-1刺激肠癌细胞系的增殖。该作用可被BQ123和BQ610(选择性内皮素A受体拮抗剂)抑制(Ali H等人,Gut 47,685-688,2000)。
ET-1在肠癌患者的肿瘤中过度表达。BQ123(选择性内皮素A受体拮抗剂)抑制大鼠转移模型中转移灶的形成(Asham E等人,BritishJournal of Cancer 81/11,1759-1763,2001)。
宫颈癌:
HPV阳性宫颈癌表达ET-1并过度表达内皮素A受体。ET-1刺激肿瘤细胞的增殖。该作用可被BQ123抑制(Venuti A等人,FASEB 14/14,2279-2283,2000)。
黑色素瘤:
在黑色素瘤中,内皮素B受体更为重要:
黑色素瘤细胞过度表达内皮素B受体。
内皮素A和内皮素B受体拮抗剂Bosetan抑制体外黑色素瘤的增殖(AACR摘要No.358,2002)。
胰腺:
内皮素A和内皮素B受体拮抗剂Ro 61-612/001抑制体外胰腺肿瘤细胞(ASPC-1)的增殖(AACR摘要No.3365,2000,目前无文章发表)。
体内实验:
按照类似于AACR摘要No.2075,2000:[Rosanol L等人,内皮素受体A拮抗剂ABT 627在卵巢癌异种移植物中抑制肿瘤生长和血管生成]的方法在卵巢癌细胞系中对所述物质进行实验。
内皮素受体拮抗剂在治疗癌症中的作用也可通过Shichiri等人在J.Clin.Invest.87,1867(1991)中所述的方法确定。
本发明优选涉及选自以下的内皮素受体拮抗剂和其生理学可接受的盐和/或溶剂合物在制备用于抑制肿瘤细胞生长的药物中的用途,
i)EP 0733626中所述的化合物:
(a)5-溴-2-乙基-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
(b)2,5-二氯-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
(c)5-溴-2-丙基-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
(d)5-二甲基氨基-N-(2,1,3-苯并噻二唑-5-基)萘磺酰胺;
(e)5-二甲基氨基-N-[6-甲基-(2,1,3-苯并噻二唑-5-基)]萘磺酰胺;
(f)5-二甲基氨基-N-[4-溴-(2,1,3-苯并噻二唑-5-基)]萘磺酰胺;
(g)5-二甲基氨基-N-(2,1,3-苯并噻二唑-4-基)萘磺酰胺;
(h)5-二甲基氨基-N-([1,2,5]-噁二唑-[3,4-b]-吡啶-6-基)萘磺酰胺;
(i)5-二甲基氨基-N-(1,2,5-苯并噁二唑-5-基)-1-萘磺酰胺;
(j)5-二甲基氨基-N-(6-溴-7-甲基-1,2,5-苯并噁二唑-5-基)-1-萘磺酰胺;
(k)2-苯基-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
ii)EP 0758650中所述的化合物:
(a)2-(1,3-苯并二氧戊环-5-基(benzodioxol-5-yl))-2-(1,3-二氢-1,3-二氧代异氮杂茚-5-基氧基)乙酸;
(b)2-(1,3-苯并二氧戊环-5-基)-2-(1,3-二氢-1,3-二氧代异氮杂茚-5-基氧基)-N-(4-叔丁基苯基磺酰基)乙酰胺;
(c)2-(1,3-苯并二氧戊环-5-基)-2-(1,3-二氢-1,3-二氧代异氮杂茚-5-基氧基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(d)2-(1,3-苯并二氧戊环-5-基)-2-(7-丙基喹啉-8-基氧基)乙酸;
(e)2-(1,3-苯并二氧戊环-5-基)-2-(7-丙基喹啉-8-基氧基)-N-(4-叔丁基苯基磺酰基)乙酰胺;
(f)2-(1,3-苯并二氧戊环-5-基)-2-(6-丙基吲哚-7-基氧基)乙酸;
(g)2-(1,3-苯并二氧戊环-5-基)-2-(1-甲基-2-丙基苯并咪唑-4-基氧基)乙酸;
iii)EP 0755934中所述的化合物:
(a)1,2-二氢-1-(2-甲氧基苄基)-4-(4-甲氧基苯基)-2-氧代-苯并呋喃[3,2-b]吡啶-3-羧酸;
(b)2-(2-甲氧基苄基氧基)-4-(4-甲氧基苯基)苯并呋喃[3,2-b]-吡啶-3-羧酸;
(c)4-(1,4-苯并二氧六环-6-基(benzodioxan-6-yl))-1,2-二氢-1-(2-甲氧基苄基)-2-氧代苯并呋喃[3,2-b]吡啶-3-羧酸;
(d)2-(2-甲氧基苯氧基)-4-(4-甲氧基苯基)苯并呋喃[3,2-b]-吡啶-3-羧酸;
(e)4-(1,4-苯并二氧六环-6-基)-1,2-二氢-1-(2-甲氧基苄基)-2-氧代-3-(1H-四唑-5-基)苯并呋喃[3,2-b]吡啶;
(f)1,2-二氢-1-(2,3-亚甲二氧基苄基)-4-(4-甲氧基苯基)-2-氧代苯并呋喃[3,2-b]吡啶-3-羧酸;
(g)1,2-二氢-1-(2,3-亚甲二氧基苄基)-7-甲基-4-(4-三氟甲氧基苯基)-2-氧代苯并呋喃[3,2-b]吡啶-3-羧酸;
(h)1,2-二氢-1-(2,3-亚甲二氧基苄基)-7-甲基-4-(4-甲氧基苯基)-2-氧代苯并噻吩[3,2-b]吡啶-3-羧酸;
(i)1,2-二氢-1-(2,1,3-苯并噻二唑-5-甲基)-4-(4-甲氧基-苯基)-2-氧代苯并呋喃[3,2-b ]吡啶-3-羧酸;
iv)EP 0757039中所述的化合物:
(a)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(2-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(b)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(4-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(c)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(3,4-亚甲二氧基苄基)-2-氧代-喹啉-3-羧酸;
(d)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(2-甲氧基苄基)-2-氧代-喹啉-3-乙酸;
(e)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(3,4-亚甲二氧基苄基)-2-氧代-喹啉-3-乙酸;
(f)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(2-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(g)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(4-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(h)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(6-氯-3,4-亚甲二氧基苄基)-2-氧代喹啉-3-羧酸;
(i)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(3,4-亚甲二氧基苄基)-2-氧代喹啉-3-羧酸;
(j)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(3-甲氧基苄基)-2-氧代喹啉-3-羧酸;
v)EP 0796250中所述的化合物:
(a)2-(1,3-苯并二氧戊环-5-基)-2-(2,3-二氢-4,6-二甲基哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(b)2-(1,3-苯并二氧戊环-5-基)-2-(6-(4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(c)2-(1,3-苯并二氧戊环-5-基)-2-(6-(4-氯苯基)-2,3,4,5-四氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(d)2-(1,3-苯并二氧戊环-5-基)-2-(6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(e)2-(1,3-苯并二氧戊环-5-基)-2-(4-甲基-6-苯基-2,3-二氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(f)2-(1,3-苯并二氧戊环-5-基)-2-(5-(3,4-二甲氧基苯基)-6-乙基-2H-3,6-二氢-1,3,4-噻二嗪-2-酮-3-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
vi)WO 9719077中所述的化合物:
(a)3-(1,3-苯并二氧戊环-5-基)-1-(2,1,3-苯并噻二唑-5-基甲基)-5-丙氧基吲哚-2-羧酸;
(b)3-(4-甲氧基苯基)-1-(2,1,3-苯并噻二唑-5-基甲基)-5-乙氧基吲哚-2-羧酸;
(c)3-(4-甲氧基苯基)-1-(2,1,3-苯并噻二唑-5-基甲基)-5-丙氧基吲哚-2-羧酸;
(d)3-(2,1,3-苯并噻二唑-5-基)-1-(4-甲氧基苄基)-5-乙氧基吲哚-2-羧酸;
(e)3-(2,1,3-苯并噻二唑-5-基)-1-(4-甲氧基苄基)-5-丙氧基吲哚-2-羧酸;
(f)3-(2,1,3-苯并噻二唑-5-基)-1-(3,4-亚甲二氧基苄基)-5,6-二甲氧基吲哚-2-羧酸;
vii)WO 9730982中所述的化合物:
2-(2,1,3-苯并噻二唑-5-基)-3-苄基-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二异丙氧基-5-甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-苄基-4-(1,4-苯并二氧六环-6-基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(1,4-苯并二氧六环-6-基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二异丙氧基-5-甲氧基苄基)-4-(1,4-苯并二氧六环-6-基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(1,3-苯并二氧戊环-5-基)-4-氧代-2-丁烯酸;
3-(2,1,3-苯并噻二唑-5-基)-4-苄基-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
3-(2,1,3-苯并噻二唑-5-基)-4-[(7-甲氧基-1,3-苯并二氧戊环-5-基)甲基]-5-羟基-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-(3-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-甲硫基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-苄氧基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3-二氢苯并呋喃-5-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2-甲基丙基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-叔丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-三氟甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-戊氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-己氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苯氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4,5-二甲氧基-3-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氯-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-甲基-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,3-二氢苯并呋喃-5-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苄氧基-2-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3,4-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-二氟甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-羟基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-异丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-己氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-甲氧基-5-丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-氟-2-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-5-乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基羰基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-苄氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-4-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
4-(2,1,3-苯并噻二唑-5-基甲基)-3-(7-甲氧基-1,3-苯并二氧戊环-5-基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二异丙氧基-5-甲氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,5-二甲氧基-4-异丙氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二甲氧基-5-异丙氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,5-二甲氧基-4-异丙氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
viii)WO 9730996中所述的化合物:
(a)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-N-(6-甲基-1,3-苯并二氧戊环-5-基)噻吩-2-甲酰胺;
(b)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-N-(6-乙酰基-1,3-苯并二氧戊环-5-基)噻吩-2-甲酰胺;
(c)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-N-(6-氰基-1,3-苯并二氧戊环-5-基)噻吩-2-甲酰胺;
(d)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-2-(6-甲基-1,3-苯并二氧戊环-5-基甲基羰基)噻吩;
ix)DE 19609597中所述的化合物:
(a)N-(2,1,3-苯并噻二唑-5-基)-5-N’-异丙基氨基-1-萘磺酰胺;
(b)N-(2,1,3-苯并噻二唑-5-基)-5-N’-丙基氨基-1-萘磺酰胺;
(c)N-(2,1,3-苯并噻二唑-5-基)-5-N’-甲基氨基-1-萘磺酰胺;
(d)N-(2,1,3-苯并噻二唑-5-基)-5-N’-乙基氨基-1-萘磺酰胺;
(e)N-(2,1,3-苯并噻二唑-5-基)-5-N’-丁基氨基-1-萘磺酰胺;
x)DE 19612 101中所述的化合物:
(a)4-(4-甲氧基苯基)-1,6-二氢-1-(2-甲氧基苄基)-2-甲基-6-氧代嘧啶-5-羧酸;
(b)4-(3,4-亚甲二氧基苯基)-1,6-二氢-1-(2-甲氧基苄基)-2-环丙基-6-氧代嘧啶-5-羧酸;
(c)4-(2-羧基-4-甲氧基-7-苯并呋喃基)-1,6-二氢-1-(2-甲氧基苄基)-2-甲基-6-氧代嘧啶-5-羧酸;
(d)4-(2-苯基-4-甲氧基苯基)-1,6-二氢-1-(2-甲氧基苄基)-2-甲基-6-氧代嘧啶-5-羧酸;
(e)4-(2-羧基-4-甲氧基-7-苯并呋喃基)-1,6-二氢-1-(5-苯并噻二唑基)-2-甲基-6-氧代嘧啶-5-羧酸;
(f)4-(4-甲氧基苯基)-1,6-二氢-1-(5-苯并噻二唑基)-2-甲基-6-氧代嘧啶-5-羧酸;
xi)WO 9827091中所述的化合物:
(a)4-(2,1,3-苯并噻二唑-5-基甲基)-1-苄基-3-丁基-1H-吡唑-5-羧酸;
(b)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(c)4-(2,1,3-苯并噻二唑-6-氯-5-基甲基)-1-(3-甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(d)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(2-羧基甲氧基-4-甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(e)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(2,4-二甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(f)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-苯基-1H-吡唑-5-羧酸;
(g)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-(2-噻吩基)-1H-吡唑-5-羧酸;
(h)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-环己基-1H-吡唑-5-羧酸;
(i)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(2-羧基甲氧基-4-甲氧基苄基)-3-丙氧基-1H-吡唑-5-羧酸;
xii)WO 9827077中所述的化合物:
(a)2-(2,1,3-苯并噻二唑-5-基)-3-(噻吩-2-基甲基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(5-甲氧基噻吩-2-基甲基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(c)3-(2,1,3-苯并噻二唑-5-基)-4-(呋喃-2-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
(d)3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3,4-二氢-2H-1,5-苯并二氧杂环庚三烯-7-基)-5H-呋喃-3-酮;
(e)3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(3,4-二氢-2H-1,5-苯并二氧杂环庚三烯-7-基)-5H-呋喃-2-酮;
(f)3-(2,1,3-苯并噻二唑-5-基)-4-(噻吩-3-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
xiii)WO 9841515中所述的化合物:
(a)2-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(2,1,3-苯并噻二唑-5-基甲基)乙酸;
(c)2-(2,1,3-苯并噻二唑-5-基)-2-(4-甲氧基羰基苄基)乙酸;
(d)2-(2,1,3-苯并噻二唑-5-基)-2-(4-甲氧基羰基苯基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(e)2-(2,1,3-苯并噻二唑-5-基)-2-(4-羧基苄基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(f)2-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基苄基)乙酸;
(g)2-(2,1,3-苯并噻二唑-5-基)-2-(4-甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
xiv)WO 9841521中所述的化合物:
(a)2-(1,3-苯并二氧戊环-5-基)-3-(2,1,3-苯并噻二唑-5-基)丁二酸;
(b)2,3-双(1,3-苯并二氧戊环-5-基)顺丁烯二酸;
(c)N,N-二丁基-2,3-双(1,3-苯并二氧戊环-5-基)顺丁烯二酰胺;
(d)2,3-双(1,3-苯并二氧戊环-5-基)顺丁烯二酸酐;
(e)2-(1,3-苯并二氧戊环-5-基)-3-苯基顺丁烯二酸酐;
xv)WO 9842702中所述的化合物及开链互变异构体:
[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(4-甲氧基苯基)-5H-呋喃-2-酮-5-基氧基羰基氨基]乙酸乙酯;
[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮-5-基氧基羰基氨基]乙酸乙酯;
N-1-萘基乙基-[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮-5-基]氨基甲酸酯;
2-[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮-5-基氧基羰基氨基]-3-甲基丁酸乙酯;
2-(2,1,3-苯并噻二唑-5-基)-3-(3-氟-4-甲氧基苯甲酰基)-4-(3,4,5-三甲氧基苯基)丁-2-烯酸;
3-(2,1,3-苯并噻二唑-5-基)-4-苄基-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-[(7-甲氧基-1,3-苯并二氧戊环-5-基)甲基]-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(甲硫基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-苄氧基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3-二氢苯并呋喃-5-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2-甲基丙基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-叔丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-三氟甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-戊基氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-己基氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苯氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4,5-二甲氧基-3-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氯-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-甲基-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,3-二氢苯并呋喃-5-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苄氧基-2-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3,4-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-二氟甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-羟基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-异丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-己基氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-甲氧基-5-丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-氟-2-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-5-乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基羰基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-苄氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-4-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
4-(2,1,3-苯并噻二唑-5-基)-3-(7-甲氧基-1,3-苯并二氧戊环-5-基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
xvi)WO 9842709中所述的化合物:
(a)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(b)3-(2-甲氧基苄基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(c)3-(2,5-二甲氧基苄基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(d)3-(1,3-苯并二氧戊环-5-基甲基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(e)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(4-甲氧基苯基)-8-氧杂-3-氮杂环戊二烯并[a]茚-2-羧酸;
(f)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(4-甲氧基苯基)-8-硫杂-3-氮杂环戊二烯并[a]茚-2-羧酸;
(g)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-羧基甲氧基-4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(h)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-羧基甲氧基-4-甲氧基苯基)-8-氧杂-3-氮杂环戊二烯并[a]茚-2-羧酸;
(i)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-羧基甲氧基-4-甲氧基苯基)-8-硫杂-3-氮杂环戊二烯并[a ]茚-2-羧酸;
xvii)WO 9905132中所述的化合物:
(a)2-(2,1,3-苯并噻二唑-5-基)-3-(4-环戊基氧基-3,5-二甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(4-环戊基氧基-3,5-二甲氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
(c)3-(2,1,3-苯并噻二唑-5-基)-4-(4-环戊基氧基-3,5-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
(d)3-(2,1,3-苯并噻二唑-5-基)-4-(4-环戊基氧基-3,5-二甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
(e)3-(2,1,3-苯并噻二唑-5-基)-4-(3-环戊基氧基-4,5-二甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
(f)3-(7-甲基-2,1,3-苯并噻二唑-5-基)-4-(4-环戊基氧基-3,5-二甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮。
本发明特别涉及选自以下的内皮素受体拮抗剂和其生理学可接受的盐和/或溶剂合物在制备用于抑制肿瘤细胞生长的药物中的用途:
(a)5-二甲基氨基-N-(2,1,3-苯并噻二唑-5-基)萘磺酰胺;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(3-氟-4-甲氧基苯甲酰基)-4-(3,4,5-三甲氧基苯基)丁-2-烯酸。
对于抑制肿瘤细胞的生长和治疗肿瘤疾病而言,特别优选使用对ETA受体具有高亲和性的内皮素受体拮抗剂。
此外,本发明还涉及上述式I化合物和优选化合物及其生理学可接受的盐和/或溶剂合物在制备用于治疗和/或预防癌症疾病的用途。
此外,本发明涉及所述化合物的用途,其中的癌症疾病选自前列腺癌、卵巢癌、肠癌、宫颈癌、黑色素瘤和胰癌。
本发明还涉及上述式I化合物和优选化合物及其生理学可接受的盐和/或溶剂合物在制备用于治疗肿瘤损伤的药物中的用途。
本发明还涉及上述式I化合物和优选化合物及其生理学可接受的盐和/或溶剂合物在制备用于治疗致前期癌(precancerogenic)损伤的药物中的用途。
术语“致前期癌损伤”指的是例如可导致肠癌的肠部良性肿瘤。
术语“致前期癌损伤”特别指的是US 5948911的第4栏,49-60行中提及的损害。
细胞凋亡(细胞死亡)的不规律性在致前期癌损伤的形成中扮演一定的角色。
同样已知的是细胞凋亡的调节在与细胞生长异常关联的疾病中扮演重要的角色,如例如良性前列腺增生、神经变性疾病,如例如帕金森氏病、自身免疫疾病,包括多发性硬化和类风湿性关节炎,或感染性疾病如AIDS。
式I化合物可调制细胞凋亡并用于治疗或预防癌症疾病。
本发明因此涉及所述式I化合物和上述优选化合物及其生理学可接受的盐和/或溶剂合物在制备用于调节人细胞凋亡的药物中的用途。
本发明还涉及上述式I化合物和优选化合物和/或其生理学可接受的盐在尤其是通过非化学方法制备药物制剂中的用途。可将这些化合物与至少一种固体、液体和/或半液体赋形剂或助剂以及任选与一种或多种其它活性成分相组合转化为适宜的剂型。
这些制剂可用作人和兽药中的药物。适宜的赋形剂是适合于经肠(例如口服)、胃肠外或局部施用且不与所述新化合物反应的有机或无机物质,例如水、植物油、苄醇、烷撑二醇、聚乙二醇、甘油三醋酸酯、明胶、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石或凡士林。适合于口服施用的特别地为片剂、丸剂、包衣片剂、胶囊剂、粉剂、颗粒剂、糖浆剂、汁液剂(iuice)或滴剂;适合于直肠施用的有栓剂;适合于胃肠外施用的有溶液剂、优选油基或水溶液剂,此外还有混悬剂、乳剂或植入剂;适合于局部施用的有软膏剂、霜剂或粉剂。也可将所述新化合物冻干,得到的冻干物用于例如制备注射制剂。适用的制剂可以是无菌的和/或包含助剂,如润滑剂、防腐剂、稳定剂和/或润湿剂、乳化剂用于调节渗透压的盐、缓冲物质、着色剂和矫味剂和/或多种其它活性成分,例如一种或多种维生素。它们还可作为鼻喷剂施用。
所述物质一般优选以每剂量单位约1至500mg、特别是5至100mg的剂量施用。日剂量优选为约0.02至10mg/kg体重。但是每位患者的具体剂量取决于多种因素,例如所使用的具体化合物的功效、年龄、体重、综合健康状况、性别、饮食、施用时间和方法、排泄率、药物组合和治疗所应用的具体疾病的严重性。优选口服施用。
Claims (7)
1.选自以下各组的内皮素受体拮抗剂在制备用于抑制肿瘤细胞生长的药物中的用途,
(a)EP 0733626中所述的式I化合物及其盐,
其中:
-A=B-C=D-为-CH=CH-CH=CH-基团,其中1或2个CH已被N替代,
Ar 为Ph或萘基,各自为未取代的或被H、卤素、A、不超过6个碳原子的链烯基、Ph、OPh、NO2、NR4R5、NHCOR4、CF3、OCF3、CN、OR4、COOR4、(CH2)nCOOR4、(CH2)nNR4R5、-N=C=O或NHCONR4R5单取代、二取代或三取代,
R1、R2和R3彼此独立地为不存在、H、卤素、A、CF3、NO2、NR4R5、CN、COOR4或NHCOR4,
R4和R5彼此独立地为H或A,或者一起为-CH2-(CH2)n-CH2-,
A 为具有1至6个碳原子的烷基,
Ph 为苯基,
X 为O或S,
卤素 为F、Cl、Br或I,
n 为1、2或3;
(b)EP 0758650中所述的式I化合物及其盐,
其中:
X 为饱和、完全不饱和或部分不饱和的3-元至4-元亚烷基链,其中1至3个碳原子可被N替代,和/或1或2个碳原子可被1至2个O原子和/或1至2个S原子替代,但其中最多不超过3个碳原子被替代,此外,其中可以出现亚烷基链和/或位于其中的氮原子被A、R8和/或NR4R4’单取代、二取代或三取代,此外,其中亚烷基链中的一个CH2基团也可被C=O基团替代,
A 为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子或被-CR4=CR4’-基团替代,此外,1至7个H原子可被F替代,
R1 为H或A,
R2 为COOR4、CN、1H-四唑-5-基或CONHSO2R8,
R3 为Ar,
R4和R4’彼此独立地为H、具有1至6个碳原子的烷基或苄基,
Ar 为苯基或萘基,各自为未取代的或被R5、R6或R7单取代、二取代或三取代,或
基团,
其为未取代的或在苯基部分被R5或R6单取代或二取代,
R5、R6和R7彼此独立地为R4、OR4、卤素、CF3、OCF3、OCHF2、OCH2F、NO2、NR4R4’、NHCOR4、CN、NHSO2R4、COOR4、COR4、CONHSO2R8、O(CH2)nR2、OPh、O(CH2)nOR4或S(O)mR4,
R8 为苯基或萘基,各自为未取代的或被A、OR1、NR4R4’或卤素单取代、二取代或三取代,
E 为CH2或O,
D 为羰基或[C(R4R4’)]n,
卤素 为F、Cl、Br或I,
m 为0、1或2,
n 为1或2;
(c)EP 0755934中所述的式I化合物及其盐,
其中:
-Y-Z- 为-NR7-CO-、-N=C(OR7)-或-N=CR8-,
R1 为Ar,
R2 为COOR6、CN、1H-四唑-5-基或CONHSO2Ar,
R3、R4和R5彼此独立地为R6、OR6、S(O)mR6、卤素、NO2、NR6R6’、NHCOR6、NHSO2R6、OCOR6、COOR6或CN,
R6和R6’彼此独立地为H、具有1至6个碳原子的烷基、苄基或苯基,
R7 为(CH2)nAr,
R8 为Ar或OAr,
Ar 为未取代的或被R9、R10或R11单取代、二取代或三取代的苯基,或未取代的萘基,或
其为未取代的或在苯基部分被R9或R10单取代或二取代,或
基团,
其为未取代的或在环己二烯部分被R9或R10单取代或二取代,
R9、R10和R11彼此独立地为R6、OR6、卤素、CF3、OCF3、OCHF2、OCH2F、NO2、NR6R6’、NHCOR6、CN、NHSO2R6、COOR6、COR6、CONHSO2Ar、O(CH2)nR2、O(CH2)nOR6或S(O)mR6,
E 为CH2、S或O,
D 为羰基或[C(R6R6’)]n,
卤素 为F、Cl、Br或I,
X 为O或S,
m 为0、1或2,
n 为1或2;
(d)EP 0757039中所述的式I化合物及其盐,
其中:
-Y-Z- 为-NR7-CO-、-N=C(OR7)-或-N=CR8-,
R1 为Ar,
R2 为COOR6、(CH2)nCOOR6、CN、1H-四唑-5-基或CONHSO2Ar,
R3、R4和R5彼此独立地为R6、OR6、S(O)mR6、卤素、NO2、NR6R6’、NHCOR6、NHSO2R6、OCOR6、COR6、COOR6或CN,或者其中R3和R4可一起为O(CH2)n)基团,
R6和R6’彼此独立地为H、具有1至6个碳原子的烷基、苄基或苯基,
R7 为(CH2)nAr,
R8 为Ar或OAr,
Ar 为未取代的或被R9、R10或R11单取代、二取代或三取代的苯基,或未取代的萘基,或
基团,
其为未取代的或在苯基部分被R9或R10单取代或二取代,或
其为未取代的或在环己二烯部分被R9或R10单取代或二取代,
R9、R10和R11彼此独立地为R6、OR6、卤素、CF3、OCF3、OCHF2、OCH2F、NO2、NR6R6’、NHCOR6、CN、NHSO2R6、COOR6、COR6、CONHSO2Ar、O(CH2)nR2、O(CH2)nOR6或S(O)mR6,
E 为CH2、S或O,
D 为羰基或[C(R6R6’)]n,
X 为O或S,
卤素 为F、Cl、Br或I,
m 为0、1或2,
n 为1、2或3;
(e)EP 0796250中所述的式I化合物及其盐,
其中:
Y 为-C(R4R4’)-C(R4R4’)-、-CR4=CR4’-或-C(R4R4’)-S-,
R1 为Het、Ar、R3或R4,
R2 为Ar或
其为未取代的或在苯基部分被A、R3、OR4、NH2、NHA、NA2、NO2、CN、卤素、NHCOR4、NHSO2R4、COOR4、COR4、CONHSO2R6、O(CH2)nR3、OPh、O(CH2)nOR4或S(O)mR4单取代或二取代,或
基团,
其为未取代的或在环己二烯基部分被A、R3、OR4、NH2、NHA、NA2、NO2、CN、卤素、NHCOR4、NHSO2R4、COOR4、COR4、CONHSO2R6、O(CH2)nR3、OPh、O(CH2)nOR4或S(O)mR4单取代或二取代,
R3 为CN、COOH、COOA、CONHSO2R5或1H-四唑-5-基,
R4和R4’彼此独立地为H、A,或苯基或苄基,各自为未取代的或被烷氧基单取代,
R5 为A或Ar,
R6 为苯基或萘基,各自为未取代的或被A、OR5、NH2、NHA、NA2、NO2、CN或卤素单取代、二取代或三取代,
A 为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR4=CR4’-基团替代,此外,1至7个H原子可被F替代,
或苄基,
Ar 为苯基或萘基,各自为未取代的或被A、OR4、NH2、NHA、NA2、NO2、CN、卤素、NHCOR4、NHSO2R4、COOR4、COR4、CONHSO2R6、O(CH2)nR3、OPh、O(CH2)nOR4或S(O)mR4单取代、二取代或三取代,
Het 为单环或双环饱和、不饱和或芳香族杂环基团,其具有1至4个N、O和/或S原子,经由N或C键合,其可以是未取代的或被卤素、A、R3、NH2、NHA、NA2、CN、NO2和/或羰基氧单取代、二取代或三取代,
D 为羰基或[C(R4R4’)]n,
E 为CH2、S或O,
卤素 为F、Cl、Br或I,
X 为O或S,
m 为0、1或2,
n 为1或2;
(f)WO 9719077中所述的式I化合物及其盐,
其中:
R为
X 为O或S,
R1 为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO3-A、SO2NHA、CN或甲酰基,
R2 为H或A,
R3、R5、R6、R7和R8彼此独立地为H、卤素、OH、OA、O-亚烷基-R4、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R4、NASO2A、NASO2-R4、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NH-苯基、NHCOOA、NA-酰基、NHR4、NHCOOR4、NHCOO-苄基、NHSO2-苄基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOR2、O(CH2)nOR2、CH2OH或CH2OA,
R3和R6或者一起为-O-CH2-O-、-O-CH2-CH2-O-、-O-CH2-CH2-、-O-CF2-O-或-O-CF2-CF2-O-,
R4 为未取代的或被R3和/或R6单取代或多取代的苯基,
A 为具有1至6个碳原子的烷基,
卤素 为氟、氯、溴或碘,
n 为1或2;
(g)WO 9730982中所述的式I化合物或互变异构成环形式,以及(E)-异构体和所有异构体的盐,
其中:
R为
X 为O或S,
R1 为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO3-A、SO2NHA、CN或甲酰基,
R2、R3和R4彼此独立地为未取代的或被以下基团单取代或多取代的苯基:卤素、OH、OA、O-亚烷基-R5、A、S-A、SOA、SO2A、SOR5、SO2R5、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R5、NASO2A、NASO2-R5、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NHR5、NHCOOA、NA-酰基、NHCOOCH2R5、NHSO2CH2R5、NHCOO-亚烷基-OA、NH(CO)NA2、1-哌啶基-CO-NH、1-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
基团,或
基团,
其中R2另外地为A或环烷基,
R5 为未取代的或被以下基团单取代或多取代的苯基:卤素、OH、OA、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NASO2A、NH(CO)NH2、NH(CO)NHA、甲酰基、NHCOOA、NA-酰基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
A 为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR6=CR6’-基团替代,和/或1至7个H原子可被F替代,
D 为羰基或[C(R6R6’)]m,
E 为CH2、S或O,
Y 为O或S,
R6和R6’彼此独立地为H、F或A,
卤素 为氟、氯、溴或碘,
n 为1或2,且
m 为1或2;
(h)WO 9730996中所述的式I化合物及其盐,
其中:
-A=B-C=D-为-CH=CH-CH=CH-基团,此外其中1或2个CH可被N替代,
Het 为单环或双环饱和、不饱和或芳香族杂环基,具有1至4个N、O和/或S原子,其为未取代的或被-Z-R6取代,
R1、R2和R3彼此独立地为不存在、H、卤素、A、CF3、NO2、NR4R5、CN、COOR4或NHCOR4,
R4和R5 彼此独立地为H或A,或者一起为-CH2-(CH2)n-CH2-,
R6 为苯基、苯并噻二唑-5-基或苯并噁二唑-5-基,各自为未取代的或被R7、R8和/或R9单取代、二取代或三取代,
R7、R8和R9彼此独立地为A、O-A、CN、COOH、COOA、卤素、甲酰基或-CO-A,或者R7和R8一起为-O-(CH2)m-O-,
A 为具有1至6个碳原子的烷基,
X 为O或S,
Z 为-CO-、-CONH-、-CO-(CH2)n-、-CH=CH-、-(CH2)n-、-CONHCO-、-NHCONH-、-NHCOO-、-O-CONH-、-CO-O-或-O-CO-,
卤素 为F、Cl、Br或I,
m 为1或2,且
n 为1、2或3;
i)DE 19609597中所述的式I化合物及其生理学可接受的盐,
其中:
Ar 为萘基,其被NH2、NHA或NA2单取代,且
A 为具有1至6个碳原子的烷基;
j)DE 19612101中所述的式I化合物及其盐,
其中:
-Y-Z- 为-NR4-CO或-N=CR5-,
R1 为Ar,
R2 为H、具有1至6个碳原子、未取代的或被OR3或卤素单取代、二取代或三取代的烷基,或(CH2)mPh或(CH2)m-环烷基,其各自为未取代的或被R3、OR3或卤素单取代、二取代或三取代,
R3和R3’彼此独立地为H、具有1至6个碳原子的烷基或苄基,
R4 为CH2Ar,
R5 为OCH2Ar,
Ar 为未取代的或被R6、R7或R8单取代、二取代或三取代的苯基,或
其为未取代的或在苯基部分被R6单取代,或
其为未取代的或在环己二烯部分被R6单取代,
E 为CH2或O,
D 为羰基或(CH2)n,
E和D 或者一起为CH=CR9,
R6和R6’彼此独立地为R3、OR3或卤素,
R7 为R3、OR3、卤素、NO2、NH2、NHR3、NR3R3’、NHCOR3、COOR3、O(CH2)nR3或O(CH2)nOR3,
R8 为Ph,其为未取代的或被R3、OR3、卤素、NO2、NH2、NHR6、NR6R6’、NHCOR3或COOR3单取代、二取代或三取代,
R9 为H、OH、CH2OH或COOR3,
卤素 为F、Cl、Br或I,
Ph 为苯基,
m 为0或1,
n 为1或2;
k)WO 9827091中所述的式I化合物及其盐,
其中:
R 为苯基,其为未取代的或被R3、R4或R5单取代、二取代或三取代,或为2,1,3-苯并噻二唑基,其为未取代的或被R2单取代,
R1 为A,其中1至7个H原子可被F替代,或为-S-A或-O-A,或苯基或-亚烷基-苯基,其各自为未取代的或被R3单取代,或噻吩基,其为未取代的或被R3单取代,
R2 为A、F、Cl、Br或-O-A,
R3、R4和R5彼此独立地为A、-O-A、-S-A、-O-亚烷基-COOH、-亚烷基-COOH或COOH,
R3和R4或者一起为-O-CH2-O-,且
A 为具有1至7个碳原子的烷基;
l)WO 9827077中所述的式I化合物或互变异构成环形式,以及(E)-异构体和所有异构体的盐,
其中:
R为
X 为O或S,
R1 为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO3-A、SO2NHA、CN或甲酰基,
R2、R3和R4彼此独立地为苯基,其为未取代的或被R7单取代或多取代,其中R2另外地为A或环烷基,
基团,
条件是:基团R2、R3或R4中的至少一个为R8基团,其为未取代的或被R7单取代或多取代,
R5 为苯基,其为未取代的或被以下基团单取代或多取代:卤素、OH、OA、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NASO2A、NH(CO)NH2、NH(CO)NHA、甲酰基、NHCOOA、NA-酰基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
A 为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR6=CR6’-替代,和/或1至7个H原子可被F替代,
D 为羰基或[C(R6R6’)]m,
E 为CH2、S或O,
Y 为O或S,
R6和R6’彼此独立地为H、F或A,
R7 为卤素、OH、OA、O-亚烷基-R5、A、S-A、S-OA、SO2A、S-OR5、SO2R5、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R5、NASO2A、NASO2R5、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NHR5、NHCOOA、NA-酰基、NHCOOCH2R5、NHSO2CH2R5、NHCOO-亚烷基-OA、NH(CO)NA2、1-哌啶基-CO-NH、1-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
R8 为5至7元杂环基,具有1至4个N、O和/或S原子,或
G和Z 彼此独立地为-CH=、N、O或S,
L 为-CH=、-CH=CH-或-CH2-CH2-CH2-,
卤素 为氟、氯、溴或碘,
n 为0、1或2,且
m 为1或2;
m)WO 9841515中所述的式I化合物及其盐,
其中:
X 为O或S,
R1 为H、卤素、OH、OA、A、NO2、NH2、NHA、NAA’、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、S(O)mR6、SO3H、SO2NR4R4’或甲酰基,
R2和R2’彼此独立地为A、(CH2)nAr、(CH2)nHet、CH2COAr、CH2COHet或OAr,
R2’ 额外地也为H,
R3 为COOR4、CN、1H-四唑-5-基或CONHSO2R5,
R4和R4’彼此独立地为H或A,
R5 为A或Ar,
R6 为苯基或萘基,各自为未取代的或被A、NH2、NHA、NAA’、NO2、CN或卤素单取代、二取代或三取代,
R7和R7’彼此独立地为H或具有1至6个碳原子的烷基,
A和A’ 彼此独立地为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR7=CR7’-基团替代,和/或1至7个H原子可被F替代,
或苄基,
Ar 为苯基或萘基,各自为未取代的或被以下基团单取代、二取代或三取代:A、OR4、NH2、NHA、NAA’、NO2、CN、卤素、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、COOR4、OPh、CONH2、CONHA、CONAA’、COR4、CONHSO2R4、CONHSO2R6、O(CH2)nCOOR4、O(CH2)nOR4、SO3H、SO2NR4R4’、S(O)mR6或S(O)mR4,
Het 为单环或双环饱和、不饱和或芳香族杂环基,具有1至4个N、O和/或S原子,经由N或C键合,其可为未取代的或被卤素、A、R3、NH2、NHA、NAA’、NO2和/或=O单取代、二取代或三取代,
卤素 为氟、氯、溴或碘,
m 为0、1或2,且
n 为1或2,
其中如果R2为CH2COAr且R2’为H,则R3不为COOA;
n)WO 9841521中所述的式I化合物和(Z)-和(E)-异构体以及所有异构体的盐,
其中:
Z 为单键或双键,
R1 为
基团,
其为未取代的或在苯基部分被R7单取代,或
基团,
其为未取代的或在环己二烯部分被R7单取代,
R2 为A、Ar-(CH2)m、环烷基-(CH2)m、Het-(CH2)m或R1-(CH2)m,
R3和R3’彼此独立地为OR4、NHSO2R5、NH2、NHA或NAA’,
R3和R3’或者一起为-O-,形成环状酐,
R4和R4’彼此独立地为H或A,
R5 为A或Ar,
R6 为苯基或萘基,各自为未取代的或被A、NH2、NHA、NAA’、NO2、CN或卤素单取代、二取代或三取代,
R7 为A、COOR4、CN、1H-四唑-5-基、CONHSO2R5、卤素、OR4、NO2、NH2、NHA、NAA’、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、S(O)kR4、S(O)kR6、SO2NR4R4’或甲酰基,
R8和R8’彼此独立地为H或具有1至6个碳原子的烷基,
E 为CH2或O,
D 为羰基或(CR4R4’)n,
E和D 或者一起为CR4=R4’,
X 为S或O,
A和A’ 彼此独立地为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR8=CR8’-基团替代,和/或1至7个H原子可被F替代,
或苄基,
Ar 为苯基或萘基,各自为未取代的或被以下基团单取代、二取代或三取代:A、OR4、NH2、NHA、NAA’、NO2、CN、卤素、NHCOR4、NHCOR6、NHSO2R4、NHSO2R6、COOR4、OPh、CONH2、CONHA、CONAA’、COR4、CONHSO2R4、CONHSO2R6、O(CH2)nCOOR4、O(CH2)nOR4、SO2NR4R4’、S(O)kR6或S(O)kR4,
Het 为单环或双环饱和、不饱和或芳香族杂环基,其具有1至4个N、O和/或S原子,经由N或C键合,其可为未取代的或被卤素、A、COOR4、CN、1H-四唑-5-基、CONHSO2R5、NH2、NHA、NAA’、NO2和/或=O单取代、二取代或三取代,
卤素 为氟、氯、溴或碘,
k 为0、1或2,
m 为0、1或2,且
n 为1或2;
o)WO 9842702中所述的式I化合物及其盐,
其中:
R为
X和Y 彼此独立地为O或S,
R1 为H、卤素、OH、OA、A、亚烷基-O-A、NO2、NH2、NH-酰基、SO2NH2、SO2-A、SO2NHA、CN或甲酰基,
R2、R3和R4彼此独立地为苯基,其为未取代的或被以下基团单取代或多取代:卤素、OH、OA、O-亚烷基-R5、A、S-A、S-OA、SO2A、S-OR5、SO2R5、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NHSO2R5、NASO2A、NASO2-R5、NH(CO)NH2、NH(CO)NHA、甲酰基、NH(CO)NHR5、NHCOOA、NA-酰基、NHCOOCH2R5、NHSO2CH2R5、NHCOO-亚烷基-OA、NH(CO)NA2、1-哌啶基-CO-NH、1-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
基团,其中
R2另外地为A或环烷基,
R5 为苯基,其为未取代的或被以下基团单取代或多取代:卤素、OH、OA、A、S-A、NO2、NH2、NHA、NA2、NH-酰基、NHSO2A、NASO2A、NH(CO)NH2、NH(CO)NHA、甲酰基、NHCOOA、NA-酰基、NHCOO-亚烷基-OA、NH(CO)NA2、N-哌啶基-CO-NH、N-吡咯烷基-CONH、O(CH2)nCOOA、O(CH2)nCOOH、O(CH2)nOH、O(CH2)nOA、CH2OH、CH2OA、COOH、COOA、CH2COOH或CH2COOA,
A 为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR6=CR6’-替代,和/或1至7个H原子可被F替代,
D 为羰基或[C(R6R6’)]m,
E 为CH2、S或O,
R6和R6’彼此独立地为H、F或A,
R7 为-O-C(=Y)-NH-R8,
R8 为具有1至10个碳原子的烷基,其为未取代的或被R9单取代或二取代,且其中1至2个碳原子可被O和/或S替代和/或可被=O取代,
或环烷基,其中1至2个碳原子可被N、O和/或S替代,
R9 为苯基,其为未取代的或被卤素单取代或二取代,萘基、A-O-C(=O)-或卤素,
卤素 为氟、氯、溴或碘,
n 为0、1或2,且
m 为1或2;
p)WO 9842709中所述的式I化合物及其盐,
其中:
X 为N-R3、O或S,
R 为2,1,3-苯并噻二唑-4-或5-基,或2,1-苯并异噻唑-5-或6-基,各自为未取代的或被R2和/或R2’单取代或二取代,或苯基,其为未取代的或被R2和/或R2’单取代、二取代或三取代,
R1 为H或A,
R2和R2’彼此独立地为H、A、OH、OA、卤素、OCF3、OCHF2、-O-CO-A、-O-亚烷基-COOR1、-O-亚烷基-CH2-OR1,或
OCH2-苯基或-O-CO-苯基,各自为未取代的或在苯基部分被R4和/或R4’单取代或二取代,
R2和R2’或者一起为-OCH2O-、-OCH2CH2O-或-OCH2CH2-,
R3 为H、A、亚烷基-O-A、-CO-OA,或亚烷基-苯基,其为未取代的或在苯基部分被R4和/或R4’单取代或二取代,
R4和R4’彼此独立地为H、A、OH、OA、卤素、COOR1或CH2OR1,
A 为具有1至6个碳原子的烷基,
卤素 为氟、氯、溴或碘;
q)WO 9905132中所述的式I化合物或互变异构成环形式,以及(E)-异构体和所有异构体的盐,
其中:
R为
X 为O或S,
R1 为H、卤素、OA或A,
R2、R3、R5和R6彼此独立地为H、卤素、A、OA或R4,
R4 为-O-(CH2)n-Cy,
Cy 为具有3至8个碳原子的环烷基,
A 为具有1至6个碳原子的烷基,其中1或2个CH2基团可被O或S原子替代或被-CR5=CR5’-基团替代,和/或1至7个H原子可被F替代,
R5和R5’彼此独立地为H、F或A,
卤素 为氟、氯、溴或碘,
n为0、1或2。
2.选自以下各组的内皮素受体拮抗剂及其生理学可接受的盐和/或溶剂合物在制备用于抑制肿瘤细胞生长的药物中的用途,
i)EP 0733626中所述的化合物:
(a)5-溴-2-乙基-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
(b)2,5-二氯-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
(c)5-溴-2-丙基-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
(d)5-二甲基氨基-N-(2,1,3-苯并噻二唑-5-基)萘磺酰胺;
(e)5-二甲基氨基-N-[6-甲基-(2,1,3-苯并噻二唑-5-基)]萘磺酰胺;
(f)5-二甲基氨基-N-[4-溴-(2,1,3-苯并噻二唑-5-基)]萘磺酰胺;
(g)5-二甲基氨基-N-(2,1,3-苯并噻二唑-4-基)萘磺酰胺;
(h)5-二甲基氨基-N-([1,2,5]-噁二唑-[3,4-b]-吡啶-6-基)萘磺酰胺;
(i)5-二甲基氨基-N-(1,2,5-苯并噁二唑-5-基)-1-萘磺酰胺;
(j)5-二甲基氨基-N-(6-溴-7-甲基-1,2,5-苯并噁二唑-5-基)-1-萘磺酰胺;
(k)2-苯基-N-(2,1,3-苯并噻二唑-5-基)苯磺酰胺;
ii)EP 0758650中所述的化合物:
(a)2-(1,3-苯并二氧戊环-5-基)-2-(1,3-二氢-1,3-二氧代异氮杂茚-5-基氧基)乙酸;
(b)2-(1,3-苯并二氧戊环-5-基)-2-(1,3-二氢-1,3-二氧代异氮杂茚-5-基氧基)-N-(4-叔丁基苯基磺酰基)乙酰胺;
(c)2-(1,3-苯并二氧戊环-5-基)-2-(1,3-二氢-1,3-二氧代异氮杂茚-5-基氧基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(d)2-(1,3-苯并二氧戊环-5-基)-2-(7-丙基喹啉-8-基氧基)乙酸;
(e)2-(1,3-苯并二氧戊环-5-基)-2-(7-丙基喹啉-8-基氧基)-N-(4-叔丁基苯基磺酰基)乙酰胺;
(f)2-(1,3-苯并二氧戊环-5-基)-2-(6-丙基吲哚-7-基氧基)乙酸;
(g)2-(1,3-苯并二氧戊环-5-基)-2-(1-甲基-2-丙基苯并咪唑-4-基氧基)乙酸;
iii)EP 0755934中所述的化合物:
(a)1,2-二氢-1-(2-甲氧基苄基)-4-(4-甲氧基苯基)-2-氧代-苯并呋喃[3,2-b]吡啶-3-羧酸;
(b)2-(2-甲氧基苄基氧基)-4-(4-甲氧基苯基)苯并呋喃[3,2-b]-吡啶-3-羧酸;
(c)4-(1,4-苯并二氧六环-6-基)-1,2-二氢-1-(2-甲氧基苄基)-2-氧代苯并呋喃[3,2-b]吡啶-3-羧酸;
(d)2-(2-甲氧基苯氧基)-4-(4-甲氧基苯基)苯并呋喃[3,2-b]-吡啶-3-羧酸;
(e)4-(1,4-苯并二氧六环-6-基)-1,2-二氢-1-(2-甲氧基苄基)-2-氧代-3-(1H-四唑-5-基)苯并呋喃[3,2-b]吡啶;
(f)1,2-二氢-1-(2,3-亚甲二氧基苄基)-4-(4-甲氧基苯基)-2-氧代苯并呋喃[3,2-b]吡啶-3-羧酸;
(g)1,2-二氢-1-(2,3-亚甲二氧基苄基)-7-甲基-4-(4-三氟甲氧基苯基)-2-氧代苯并呋喃[3,2-b]吡啶-3-羧酸;
(h)1,2-二氢-1-(2,3-亚甲二氧基苄基)-7-甲基-4-(4-甲氧基苯基)-2-氧代苯并噻吩[3,2-b]吡啶-3-羧酸;
(i)1,2-二氢-1-(2,1,3-苯并噻二唑-5-甲基)-4-(4-甲氧基-苯基)-2-氧代苯并呋喃[3,2-b]吡啶-3-羧酸;
iv)EP 0757039中所述的化合物:
(a)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(2-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(b)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(4-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(c)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(3,4-亚甲二氧基苄基)-2-氧代-喹啉-3-羧酸;
(d)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(2-甲氧基苄基)-2-氧代-喹啉-3-乙酸;
(e)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-1-(3,4-亚甲二氧基苄基)-2-氧代-喹啉-3-乙酸;
(f)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(2-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(g)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(4-甲氧基苄基)-2-氧代喹啉-3-羧酸;
(h)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(6-氯-3,4-亚甲二氧基苄基)-2-氧代喹啉-3-羧酸;
(i)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(3,4-亚甲二氧基苄基)-2-氧代喹啉-3-羧酸;
(j)4-(1,3-苯并二氧戊环-5-基)-1,2-二氢-6-乙氧基-1-(3-甲氧基苄基)-2-氧代喹啉-3-羧酸;
v)EP 0796250中所述的化合物:
(a)2-(1,3-苯并二氧戊环-5-基)-2-(2,3-二氢-4,6-二甲基-哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(b)2-(1,3-苯并二氧戊环-5-基)-2-(6-(4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(c)2-(1,3-苯并二氧戊环-5-基)-2-(6-(4-氯苯基)-2,3,4,5-四氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(d)2-(1,3-苯并二氧戊环-5-基)-2-(6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(e)2-(1,3-苯并二氧戊环-5-基)-2-(4-甲基-6-苯基-2,3-二氢哒嗪-3-酮-2-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(f)2-(1,3-苯并二氧戊环-5-基)-2-(5-(3,4-二甲氧基苯基)-6-乙基-2H-3,6-二氢-1,3,4-噻二嗪-2-酮-3-基)-N-(4-异丙基苯基磺酰基)乙酰胺;
vi)WO 9719077中所述的化合物:
(a)3-(1,3-苯并二氧戊环-5-基)-1-(2,1,3-苯并噻二唑-5-基甲基)-5-丙氧基吲哚-2-羧酸;
(b)3-(4-甲氧基苯基)-1-(2,1,3-苯并噻二唑-5-基甲基)-5-乙氧基吲哚-2-羧酸;
(c)3-(4-甲氧基苯基)-1-(2,1,3-苯并噻二唑-5-基甲基)-5-丙氧基吲哚-2-羧酸;
(d)3-(2,1,3-苯并噻二唑-5-基)-1-(4-甲氧基苄基)-5-乙氧基吲哚-2-羧酸;
(e)3-(2,1,3-苯并噻二唑-5-基)-1-(4-甲氧基苄基)-5-丙氧基吲哚-2-羧酸;
(f)3-(2,1,3-苯并噻二唑-5-基)-1-(3,4-亚甲二氧基苄基)-5,6-二甲氧基吲哚-2-羧酸;
vii)WO 9730982中所述的化合物:
2-(2,1,3-苯并噻二唑-5-基)-3-苄基-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二异丙氧基-5-甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-苄基-4-(1,4-苯并二氧六环-6-基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(1,4-苯并二氧六环-6-基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二异丙氧基-5-甲氧基苄基)-4-(1,4-苯并二氧六环-6-基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(1,3-苯并二氧戊环-5-基)-4-氧代-2-丁烯酸;
3-(2,1,3-苯并噻二唑-5-基)-4-苄基-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
3-(2,1,3-苯并噻二唑-5-基)-4-[(7-甲氧基-1,3-苯并二氧戊环-5-基)甲基]-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-(3-甲氧基苯基)-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-(2-甲氧基苯基)-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-甲硫基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-苄氧基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3-二氢苯并呋喃-5-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2-甲基丙基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-叔丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-三氟甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-戊氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-己氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苯氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4,5-二甲氧基-3-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氯-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-甲基-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,3-二氢苯并呋喃-5-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苄氧基-2-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3,4-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-二氟甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-羟基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-异丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-己氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-甲氧基-5-丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-甲氧基-5-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-氟-2-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-5-乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基羰基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-苄氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-4-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
4-(2,1,3-苯并噻二唑-5-基甲基)-3-(7-甲氧基-1,3-苯并二氧戊环-5-基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二异丙氧基-5-甲氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,5-二甲氧基-4-异丙氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4-二甲氧基-5-异丙氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,5-二甲氧基-4-异丙氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
2-(2,1,3-苯并噻二唑-5-基)-3-(3,4,5-三甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
viii)WO 9730996中所述的化合物:
(a)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-N-(6-甲基-1,3-苯并二氧戊环-5-基)噻吩-2-甲酰胺;
(b)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-N-(6-乙酰基-1,3-苯并二氧戊环-5-基)噻吩-2-甲酰胺;
(c)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-N-(6-氰基-1,3-苯并二氧戊环-5-基)噻吩-2-甲酰胺;
(d)3-(2,1,3-苯并噻二唑-5-氨基磺酰基)-2-(6-甲基-1,3-苯并二氧戊环-5-基甲基羰基)噻吩;
ix)DE 19609597中所述的化合物:
(a)N-(2,1,3-苯并噻二唑-5-基)-5-N’-异丙基氨基-1-萘磺酰胺;
(b)N-(2,1,3-苯并噻二唑-5-基)-5-N’-丙基氨基-1-萘磺酰胺;
(c)N-(2,1,3-苯并噻二唑-5-基)-5-N’-甲基氨基-1-萘磺酰胺;
(d)N-(2,1,3-苯并噻二唑-5-基)-5-N’-乙基氨基-1-萘磺酰胺;
(e)N-(2,1,3-苯并噻二唑-5-基)-5-N’-丁基氨基-1-萘磺酰胺;
x)DE 19612101中所述的化合物:
(a)4-(4-甲氧基苯基)-1,6-二氢-1-(2-甲氧基苄基)-2-甲基-6-氧代嘧啶-5-羧酸;
(b)4-(3,4-亚甲二氧基苯基)-1,6-二氢-1-(2-甲氧基苄基)-2-环丙基-6-氧代嘧啶-5-羧酸;
(c)4-(2-羧基-4-甲氧基-7-苯并呋喃基)-1,6-二氢-1-(2-甲氧基苄基)-2-甲基-6-氧代嘧啶-5-羧酸;
(d)4-(2-苯基-4-甲氧基苯基)-1,6-二氢-1-(2-甲氧基苄基)-2-甲基-6-氧代嘧啶-5-羧酸;
(e)4-(2-羧基-4-甲氧基-7-苯并呋喃基)-1,6-二氢-1-(5-苯并噻二唑基)-2-甲基-6-氧代嘧啶-5-羧酸;
(f)4-(4-甲氧基苯基)-1,6-二氢-1-(5-苯并噻二唑基)-2-甲基-6-氧代嘧啶-5-羧酸;
xi)WO 9827091中所述的化合物:
(a)4-(2,1,3-苯并噻二唑-5-基甲基)-1-苄基-3-丁基-1H-吡唑-5-羧酸;
(b)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(c)4-(2,1,3-苯并噻二唑-6-氯-5-基甲基)-1-(3-甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(d)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(2-羧基甲氧基-4-甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(e)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(2,4-二甲氧基苄基)-3-丁基-1H-吡唑-5-羧酸;
(f)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-苯基-1H-吡唑-5-羧酸;
(g)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-(2-噻吩基)-1H-吡唑-5-羧酸;
(h)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-甲氧基苄基)-3-环己基-1H-吡唑-5-羧酸;
(i)4-(2,1,3-苯并噻二唑-5-基甲基)-1-(2-羧基甲氧基-4-甲氧基苄基)-3-丙氧基-1H-吡唑-5-羧酸;
xii)WO 9827077中所述的化合物:
(a)2-(2,1,3-苯并噻二唑-5-基)-3-(噻吩-2-基甲基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(5-甲氧基噻吩-2-基甲基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(c)3-(2,1,3-苯并噻二唑-5-基)-4-(呋喃-2-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
(d)3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3,4-二氢-2H-1,5-苯并二氧杂环庚三烯-7-基)-5H-呋喃-3-酮;
(e)3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(3,4-二氢-2H-1,5-苯并二氧杂环庚三烯-7-基)-5H-呋喃-2-酮;
(f)3-(2,1,3-苯并噻二唑-5-基)-4-(噻吩-3-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
xiii)WO 9841515中所述的化合物:
(a)2-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(2,1,3-苯并噻二唑-5-基甲基)乙酸;
(c)2-(2,1,3-苯并噻二唑-5-基)-2-(4-甲氧基羰基苄基)乙酸;
(d)2-(2,1,3-苯并噻二唑-5-基)-2-(4-甲氧基羰基苯基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(e)2-(2,1,3-苯并噻二唑-5-基)-2-(4-羧基苄基)-N-(4-异丙基苯基磺酰基)乙酰胺;
(f)2-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基苄基)乙酸;
(g)2-(2,1,3-苯并噻二唑-5-基)-2-(4-甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
xiv)WO 9841521中所述的化合物:
(a)2-(1,3-苯并二氧戊环-5-基)-3-(2,1,3-苯并噻二唑-5-基)丁二酸;
(b)2,3-双(1,3-苯并二氧戊环-5-基)顺丁烯二酸;
(c)N,N-二丁基-2,3-双(1,3-苯并二氧戊环-5-基)顺丁烯二酰胺;
(d)2,3-双(1,3-苯并二氧戊环-5-基)顺丁烯二酸酐;
(e)2-(1,3-苯并二氧戊环-5-基)-3-苯基顺丁烯二酸酐;
xv)WO 9842702中所述的化合物及开链互变异构体:
[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(4-甲氧基苯基)-5H-呋喃-2-酮-5-基氧基羰基氨基]乙酸乙酯;
[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮-5-基氧基羰基氨基]乙酸乙酯;
N-1-萘基乙基-[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮-5-基]氨基甲酸酯;
2-[3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮-5-基氧基羰基氨基]-3-甲基丁酸乙酯;
2-(2,1,3-苯并噻二唑-5-基)-3-(3-氟-4-甲氧基苯甲酰基)-4-(3,4,5-三甲氧基苯基)丁-2-烯酸;
3-(2,1,3-苯并噻二唑-5-基)-4-苄基-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-[(7-甲氧基-1,3-苯并二氧戊环-5-基)甲基]-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(甲硫基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-苄氧基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3-二氢苯并呋喃-5-基甲基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2-甲基丙基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-叔丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-三氟甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-戊基氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-己基氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苯氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4,5-二甲氧基-3-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氯-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-甲基-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,5-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,3-二氢苯并呋喃-5-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基-5-甲氧基苄基)-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-苄氧基-2-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,3,4-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2,4-二甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-二氟甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-羟基-4-甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(2,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-异丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(3-氟-4-丙氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-羟基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-6-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-己基氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-4-异丙氧基苄基)-5-羟基-5-(1,4-苯并二氧六环-6-基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3-甲氧基-5-丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-异丙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(2-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二甲氧基-5-苄氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-氟-2-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基-5-乙氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(4-甲氧基羰基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4-二异丙氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-苄氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-4-甲基-5-基)-4-(3,4,5-三甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
3-(2,1,3-苯并噻二唑-5-基)-4-(3,5-二甲氧基4-异丁氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
4-(2,1,3-苯并噻二唑-5-基)-3-(7-甲氧基-1,3-苯并二氧戊环-5-基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
xvi)WO 9842709中所述的化合物:
(a)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(b)3-(2-甲氧基苄基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(c)3-(2,5-二甲氧基苄基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(d)3-(1,3-苯并二氧戊环-5-基甲基)-1-(4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(e)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(4-甲氧基苯基)-8-氧杂-3-氮杂环戊二烯并[a]茚-2-羧酸;
(f)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(4-甲氧基苯基)-8-硫杂-3-氮杂环戊二烯并[a]茚-2-羧酸;
(g)3-(2,1,3-苯并噻二唑-5-基甲基-1-(3-羧基甲氧基-4-甲氧基苯基)-8-甲基-3,8-二氢-3,8-二氮杂环戊二烯并[a]茚-2-羧酸;
(h)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-羧基甲氧基-4-甲氧基苯基)-8-氧杂-3-氮杂环戊二烯并[a]茚-2-羧酸;
(i)3-(2,1,3-苯并噻二唑-5-基甲基)-1-(3-羧基甲氧基-4-甲氧基苯基)-8-硫杂-3-氮杂环戊二烯并[a]茚-2-羧酸;
xvii)WO 9905132中所述的化合物:
(a)2-(2,1,3-苯并噻二唑-5-基)-3-(4-环戊基氧基-3,5-二甲氧基苄基)-4-(4-甲氧基苯基)-4-氧代-2-丁烯酸;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(4-环戊基氧基-3,5-二甲氧基苄基)-4-(3-氟-4-甲氧基苯基)-4-氧代-2-丁烯酸;
(c)3-(2,1,3-苯并噻二唑-5-基)-4-(4-环戊基氧基-3,5-二甲氧基苄基)-5-羟基-5-(4-甲氧基苯基)-5H-呋喃-2-酮;
(d)3-(2,1,3-苯并噻二唑-5-基)-4-(4-环戊基氧基-3,5-二甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
(e)3-(2,1,3-苯并噻二唑-5-基)-4-(3-环戊基氧基-4,5-二甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮;
(f)3-(7-甲基-2,1,3-苯并噻二唑-5-基)-4-(4-环戊基氧基-3,5-二甲氧基苄基)-5-羟基-5-(3-氟-4-甲氧基苯基)-5H-呋喃-2-酮。
3.选自以下化合物及其生理学可接受的盐和/或溶剂合物的内皮素受体拮抗剂在制备用于抑制肿瘤细胞生长的药物中的用途,
(a)5-二甲基氨基-N-(2,1,3-苯并噻二唑-5-基)萘磺酰胺;
(b)2-(2,1,3-苯并噻二唑-5-基)-3-(3-氟-4-甲氧基苯甲酰基)-4-(3,4,5-三甲氧基苯基)丁-2-烯酸。
4.权利要求1、2或3所定义的内皮素受体拮抗剂在制备用于治疗和/或预防癌症疾病的药物中的用途。
5.权利要求1、2或3所定义的内皮素受体拮抗剂在制备用于治疗致前期癌损伤的药物中的用途。
6.权利要求1、2或3所定义的内皮素受体拮抗剂在制备用于调节人体细胞凋亡的药物中的用途。
7.权利要求4的用途,其中的癌症疾病选自前列腺癌、卵巢癌、肠癌、宫颈癌、黑色素瘤和胰癌。
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GB0219660D0 (en) * | 2002-08-23 | 2002-10-02 | Astrazeneca Ab | Therapeutic use |
GB0223367D0 (en) * | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Therapeutic treatment |
GB0223854D0 (en) * | 2002-10-12 | 2002-11-20 | Astrazeneca Ab | Therapeutic treatment |
GB0320806D0 (en) * | 2003-09-05 | 2003-10-08 | Astrazeneca Ab | Therapeutic treatment |
GB0403744D0 (en) | 2004-02-20 | 2004-03-24 | Astrazeneca Ab | Chemical process |
WO2005095972A2 (en) * | 2004-03-19 | 2005-10-13 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with g protein-coupled receptor etb (etb) |
ITMI20040874A1 (it) * | 2004-04-30 | 2004-07-30 | Ist Naz Stud Cura Dei Tumori | Derivati indolici ed azaindolici con azione antitumorale |
GB0425854D0 (en) * | 2004-11-25 | 2004-12-29 | Astrazeneca Ab | Therapeutic treatment |
GB0514743D0 (en) * | 2005-07-19 | 2005-08-24 | Astrazeneca Ab | Salt |
US7939545B2 (en) * | 2006-05-16 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
KR100989141B1 (ko) * | 2007-05-14 | 2010-10-20 | 경희대학교 산학협력단 | 시클로옥시게나제-2 저해제 |
WO2008140251A2 (en) * | 2007-05-14 | 2008-11-20 | University-Industry Cooperation Group Of Kyung Hee University | Cyclooxygenase-2 inhibitors |
CA2705318C (en) | 2007-11-15 | 2013-12-31 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
JP5285709B2 (ja) | 2007-11-16 | 2013-09-11 | ギリアード サイエンシス インコーポレーテッド | ヒト免疫不全ウイルスの複製阻害薬 |
MX2012015252A (es) | 2010-06-30 | 2013-05-30 | Ironwood Pharmaceuticals Inc | Estimuladores de sgc. |
CN107266433A (zh) | 2010-11-09 | 2017-10-20 | 铁木医药有限公司 | sGC刺激剂 |
CN104066731B (zh) | 2011-12-27 | 2016-06-15 | 铁木医药有限公司 | 可用作sgc刺激剂的2-苄基、3-(嘧啶-2-基)取代的吡唑类 |
US10183949B2 (en) | 2014-08-29 | 2019-01-22 | The University Of Tokyo | Pyrimidinone derivative having autotaxin-inhibitory activity |
Family Cites Families (20)
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US6063911A (en) * | 1993-12-01 | 2000-05-16 | Marine Polymer Technologies, Inc. | Methods and compositions for treatment of cell proliferative disorders |
DE19509950A1 (de) * | 1995-03-18 | 1996-09-19 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19527568A1 (de) * | 1995-07-28 | 1997-01-30 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
AU717172B2 (en) * | 1995-08-02 | 2000-03-16 | Smithkline Beecham Corporation | Endothelin receptor antagonists |
DE19528418A1 (de) * | 1995-08-02 | 1997-02-06 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19530032A1 (de) * | 1995-08-16 | 1997-02-20 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19537548A1 (de) * | 1995-10-09 | 1997-04-10 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
JPH09124620A (ja) * | 1995-10-11 | 1997-05-13 | Bristol Myers Squibb Co | 置換ビフェニルスルホンアミドエンドセリン拮抗剤 |
DE19543639A1 (de) * | 1995-11-23 | 1997-05-28 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19606980A1 (de) * | 1996-02-24 | 1997-08-28 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19607096A1 (de) * | 1996-02-24 | 1997-08-28 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19609597A1 (de) * | 1996-03-12 | 1997-09-18 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19612101A1 (de) * | 1996-03-27 | 1997-10-02 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19653037A1 (de) * | 1996-12-19 | 1998-06-25 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19653024A1 (de) * | 1996-12-19 | 1998-06-25 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19710831A1 (de) * | 1997-03-15 | 1998-09-17 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19711428A1 (de) * | 1997-03-19 | 1998-09-24 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19711785A1 (de) * | 1997-03-21 | 1998-09-24 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19712141A1 (de) * | 1997-03-22 | 1998-09-24 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE19731571A1 (de) * | 1997-07-23 | 1999-01-28 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
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2002
- 2002-10-10 JP JP2003541830A patent/JP2005510511A/ja active Pending
- 2002-10-10 KR KR1020047007032A patent/KR20050035181A/ko not_active Application Discontinuation
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- 2002-10-10 HU HU0402281A patent/HUP0402281A2/hu unknown
- 2002-10-10 EP EP02802624A patent/EP1441721A2/de not_active Withdrawn
- 2002-10-10 US US10/495,108 patent/US20050014769A1/en not_active Abandoned
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ZA200404544B (en) | 2005-02-08 |
US20050014769A1 (en) | 2005-01-20 |
JP2005510511A (ja) | 2005-04-21 |
HUP0402281A2 (hu) | 2005-02-28 |
WO2003039539A2 (de) | 2003-05-15 |
WO2003039539A3 (de) | 2003-11-06 |
BR0213684A (pt) | 2004-10-26 |
EP1441721A2 (de) | 2004-08-04 |
RU2004117596A (ru) | 2005-05-27 |
AR037343A1 (es) | 2004-11-03 |
KR20050035181A (ko) | 2005-04-15 |
PL369822A1 (en) | 2005-05-02 |
CA2465744A1 (en) | 2003-05-15 |
DE10155076A1 (de) | 2003-05-22 |
MXPA04004306A (es) | 2004-08-11 |
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