CN101663034B - 用于排尿障碍的治疗剂 - Google Patents
用于排尿障碍的治疗剂 Download PDFInfo
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- CN101663034B CN101663034B CN200880012411.5A CN200880012411A CN101663034B CN 101663034 B CN101663034 B CN 101663034B CN 200880012411 A CN200880012411 A CN 200880012411A CN 101663034 B CN101663034 B CN 101663034B
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- Prior art keywords
- methyl
- amino
- sulfonyl
- phenyl
- isobutyl group
- Prior art date
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Classifications
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
- C07D277/36—Sulfur atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Public Health (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
本发明公开了EP1拮抗剂,尤其是通式(I)表示的化合物,其盐、其溶剂合物或其前药。该化合物、其盐、其溶剂合物或其前药有效用于预防或治疗排尿障碍和/或改善与排尿障碍相关的状况(如,尿势弱、尿线分叉、尿线间断、排尿延迟、腹压排尿、尿末滴沥)。(I)中所有符号如说明书中所定义。
Description
发明领域
本发明涉及通过使用EP1拮抗剂用于预防或治疗排尿障碍(尿排出障害)和/或改善排尿障碍症状。
发明背景
在解剖学中,“下尿路”,是指膀胱和尿道外口之间的途径,且其具有收集尿的尿液储存功能和排出尿的排尿功能。
根据国际禁制协会(International Continence Society)的标准委员会(Standardisation Sub-committee)的报告,下尿路症状大致分为3类:蓄尿障碍(urinary storage disorder)的症状,排尿障碍的症状和排尿后症状。蓄尿障碍的症状为在蓄尿阶段发生的症状,包括例如,白天尿频、夜间尿频、尿急、尿失禁、遗尿等。另一方面,排尿障碍的症状为在排尿阶段发生的症状,包括例如,尿势弱(尿勢低下)、尿线分叉(尿線分割)、尿线间断(尿線途絶)、排尿延迟(排尿遅延)、腹压排尿(腹压排尿)、尿末滴沥(終末滴下)等。排尿后症状为在排尿后即刻发生的症状,包括例如,残尿的感觉、排尿后尿滴下等。
膀胱逼尿肌收缩性和膀胱出口尿道闭合压力之间的不平衡导致蓄尿障碍和排尿障碍。即,蓄尿障碍是由于活动过度的膀胱(逼尿肌不随意收缩)、膀胱出口抵抗低下、膀胱容量减少或它们的组合。另一方面,排尿障碍是由于膀胱逼尿肌收缩性降低、膀胱出口抵抗增大或它们的组合。因此,它们的致病机理和症状彼此不同。
虽然,目前抗胆碱能药物用作蓄尿障碍(即,活动过度的膀胱)的治疗药物,但是其产生由于逼尿肌收缩性降低导致的残尿增加或尿潴留(尿閉)、口干(唾液分泌降低)、便秘和认知障碍的恶化。
另一方面,作为排尿障碍的治疗药物,使用增加膀胱逼尿肌收缩力的药物(例如,胆碱能药物如氨甲酰甲胆碱(bethanechol),乙酰胆碱酯酶抑剂如地斯的明(distigmine)等),或用于产生尿道平滑肌松弛和减弱尿道抵抗的药物(例如,α1受体拮抗剂如坦洛新,哌唑嗪,阿夫唑嗪,萘哌地尔,乌拉地尔等)。胆碱能药物导致膀胱肌肉在尿液储存期也收缩,且损伤膀胱的尿液储存功能。而且,其对于孕妇,消化性溃疡,器质性肠梗阻(organic ileus),哮喘和甲状腺功能亢进是禁忌的,因为它具有下述副作用,如流泪、出汗、胃肠道障碍、腹痛等。由于这些,还没有发现令人满意的药物。乙酰胆碱酯酶抑制剂导致膀胱逼尿肌收缩,但是由于其强力的烟碱作用,其导致尿道括约肌收缩,且增加尿道抵抗。因此,排尿效率恶化,且临床作用不足。而且,指出了高压排尿的风险。而且,一些乙酰胆碱酯酶抑制剂不能用于治疗,因为其作用时间短(非专利文件1)。另一方面,据报导α1受体拮抗剂具有改善自觉症状的作用,所述症状如残尿感、夜间尿频等。然而,α1受体拮抗剂具有起立性低血压等降压作用的副作用,因此使用其治疗时必须注意。
此时,本发明中涉及的EP1是前列腺素E2(下文缩写为PGE2)受体亚型EP1、EP2、EP3和EP4(非专利文件2)中的一种,且已知EP1涉及利尿(非专利文件3)。而且,已知促进排尿的PGE2的膀胱注射治疗对于尿潴留患者是有效的(非专利文件4)。因此,拮抗EP1的化合物(即EP1拮抗剂)被认为可用作尿频的治疗药物。
虽然EP1拮抗剂和下尿路疾病之间的关系基于这些发现公开于日本专利号3741120、WO2002/15902、WO2003/43655、WO2005/00534、WO2005/10534和WO2006/121097,但是这些专利文件仅仅公开了EP1拮抗剂有效用于预防和治疗″蓄尿障碍″如尿频和尿失禁。这些专利文件既没有证明也没有实质上启示EP1拮抗剂能够有效用于″排尿障碍″,其作用机理和症状是完全不同的
而且,其它公开了本发明中涉及的EP1拮抗剂的专利文件(例如,EP878465、WO98/27053、WO92/19617、WO96/06822、WO97/00863、WO99/47497、WO2000/20371、WO2001/19814和WO2001/19819)完全没有公开EP1拮抗剂有效用于排尿障碍。
[非专利文件1]Takamichi Hattori,Kosaku Yasuda.″Shinkeiseiboukou noShindan to Chiryo″第2版,第105-106页,Igakushoin.
[非专利文件2]J.Lipid Mediat.Cell Signal.,1995;12:379-391.
[非专利文件3]General Pharmacology,1992;23(5):805-809.
[非专利文件4]European of Urology,1978;4(5):366.
发明内容
本发明要解决的问题
需要安全和有效用于预防、治疗和/或症状改善排尿障碍的药物。
解决问题的方法
由于蓄尿障碍和排尿障碍的致病机理彼此不同,所以根据致病机理向各个病人给药。虽然据报导EP1拮抗剂有效用于治疗″蓄尿障碍″,但是从未知道EP1拮抗剂对表现出相反的症状的患有″排尿障碍″的患者有效。如果特征在于单一EP1拮抗活性的药物有效用于所有患有下尿路疾病的患者,那么该药物能够被经济地和迅速地开发。而且,对下尿道疾病的广泛治疗对于医生和患者是有用的。
本发明的发明人已经根据这些背景进行了深入的研究,并且发现本发明中涉及的EP1拮抗剂增加尿流速率(这是评估排尿的客观发现)和降低残尿比率。根据这些发现,本发明人已经发现EP1拮抗剂有效用于预防、治疗和/或症状改善排尿障碍,并由此完成本发明。
即,本发明涉及
(1)预防、治疗和/或症状改善排尿障碍的药物,其包含式(I)表示的化合物,其盐、其溶剂合物或其前药:
其中所有符号具有与下述相同的含义;
(2)根据上述(1)的药物,其中式(I)表示的化合物为3-甲基-4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸或4-[6-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸;
(3)根据上述(1)的药物,其中排尿障碍的症状为尿势弱、尿线分叉、尿线间断、排尿延迟、腹压排尿和/或尿末滴沥;
(4)根据上述(1)的药物,其对于膀胱逼尿肌(detrusor muscle)具有收缩作用,且对于膀胱出口抵抗(抵抗)具有减弱作用;
(5)根据上述(1)的药物,其增加尿流速率(尿流率)和/或降低残尿比率(残尿率);
(6)药物,其包含式(I)表示的化合物,其盐、其溶剂合物或其前药与α1受体拮抗剂和/或乙酰胆碱酯酶抑制剂的组合;
(7)预防、治疗和/或症状改善排尿障碍的方法,其包括向哺乳动物给药有效量的式(I)表示的化合物,其盐、其溶剂合物或其前药;和
(8)式(I)表示的化合物,其盐、其溶剂合物或其前药在制备用于预防、治疗和/或改善排尿障碍症状的药物中的用途。
发明效果
本发明中涉及的EP1拮抗剂有效用于预防、治疗和/或改善排尿障碍症状(如,尿势弱、尿线分叉、尿线间断、排尿延迟、腹压排尿、尿末滴沥等),因为其发挥对于膀胱逼尿肌的收缩作用和对于膀胱出口抵抗的减弱作用,而增加尿流速率和降低残尿比率。
实施本发明的最佳实施方案
在本发明的说明书中,EP1拮抗剂包括下述化合物,例如日本专利号3426252中公开的式(A)表示的化合物,其烷基酯、其盐、其溶剂合物及其前药:
其中基团
各自独立地表示C5-15碳环或含有1个或2个氧、硫或氮原子的5-7元杂环;
Z1A表示-COR1A、-C1-4亚烷基-COR1A、-CH=CH-COR1A、-C≡C-COR1A、-O-C1-3亚烷基-COR1A(其中R1A表示羟基、C1-6烷氧基或式-NR6AR7A表示的基团(其中R6A和R7A各自独立地表示氢原子或C1-4烷基))或-C1-5亚烷基-OH表示的基团;
Z2A表示氢原子、C1-4烷基、C1-4烷氧基、硝基、卤素、三氟甲基、三氟甲氧基、羟基或式-COR1A表示的基团(其中R1A具有与上述相同的含义);
Z3A表示单键或C1-4亚烷基;
Z4A表示SO2或CO;
Z5A表示
(1)C1-8烷基、C2-8烯基或C2-8炔基,
(2)苯基、C3-7环烷基、含1个或2个氧、硫或氮原子的5-7元杂环,或
(3)被苯基或C3-7环烷基取代的C1-4烷基、C2-4烯基或C2-4炔基,其中上述(2)和(3)中的苯基、C3-7环烷基和含1个或2个氧、硫或氮原子的5-7元杂环可以被1-5个R5A基团取代(多于1个R5A独立地表示氢原子、C1-6烷基、C1-6烷氧基、C1-6烷硫基、硝基、卤素、三氟甲基、三氟甲氧基或羟基);
R2A表示-CONR8A-、-NR8ACO-、-CONR8A-C1-4亚烷基-、-C1-4亚烷基-CONR8A-、-NR8ACO-C1-4亚烷基-、-C1-4亚烷基-NR8ACO-、-C1-3亚烷基-CONR8A-C1-3亚烷基-、-C1-3亚烷基-NR8ACO-C1-3亚烷基-(其中R8A表示氢原子或C1-4烷基)、O、S、-NZ6A-表示的基团(其中Z6A表示氢原子或C1-4烷基)、-Z7A-C1-4亚烷基-、-C1-4亚烷基-Z7A-、-C1-3亚烷基-Z7A-C1-3亚烷基-(其中Z7A表示O、S或NZ6A(其中Z6A具有与上述相同的含义))、-CO-、-CO-C1-4亚烷基-、-C1-4亚烷基-CO-、-C1-3亚烷基-CO-C1-3亚烷基-、-C2-4亚烷基、C2-4亚烯基或C2-4亚炔基;
R3A表示氢原子、C1-6烷基、C1-6烷氧基、C1-6烷硫基、硝基(ニトロ)、卤素、三氟甲基、三氟甲氧基、羟基或羟基甲基;
R4A表示(1)氢原子,(2)C1-8烷基、C2-8烯基或C2-8炔基,(3)被1个或2个选自下述的基团取代的C1-6烷基:COOZ8A、CONZ9AZ10A、OZ8A(其中,Z8A、Z9A和Z10A独立地表示氢原子或C1-4烷基)和C1-4烷氧基-C1-4烷氧基,(4)C3-7环烷基,或(5)被苯基或C3-7环烷基取代的C1-4烷基、C2-4烯基或C2-4炔基(上述(4)和(5)中的苯基或C3-7环烷基可以被1-5个R5A基团取代(R5A具有与上述相同的含义));
nA和tA各自独立地表示1-4的整数;
其中当
表示苯环,且(Z2A)tA不表示COR1A时,
R2A和Z3A各自独立地仅连接于
的1-或2-位,
且Z1A仅连接于苯环的3-或4-位,(通式的符号的详细定义相应于专利说明书中描述的那些);
EP878465中描述的式(B)表示的化合物,其盐、其溶剂合物及其前药:
其中
表示下式表示的基团
R1B表示羟基、C1-4烷氧基或式NR6BR7B表示的基团(其中R6B和R7B各自独立地表示氢原子或C1-4烷基);
R2B表示氢原子或C1-4烷基;
R3B和R4B各自独立地表示C1-4烷基、卤素原子或三氟甲基;
R5B表示氢原子、C1-4烷基、卤素原子或三氟甲基;
YB表示顺-亚乙烯基或反-亚乙烯基;
符号
表示单键或双键;
其中当
表示式
R1B表示羟基或C1-4烷氧基;R2B表示氢原子;YB表示顺-亚乙烯基;
且符号
表示单键时,
不表示
(通式的符号的详细定义相应于专利说明书中描述的那些);
WO2006/121097中描述的式(E)表示的化合物,其烷基酯、其盐、其溶剂合物及其前药:
其中
表示任选被取代的5-8元杂环;
表示环烷基、苯环或杂环;
R1E表示低级烷基或杂环,其每个任选被取代;
R2E表示C1-12烷基、环烷基、芳基、杂环、-低级亚烷基-环烷基、-低级亚烷基-芳基或-低级亚烷基-杂环,其中R2E中的C1-12烷基、环烷基、芳基和杂环可被取代;
R3E表示-OH、-C(O)-ROE、-C(O)-NR5ER5aE、1H-四唑-5-基或5-氧代-4,5-二氢-1,2,4-噁二唑-3-基;
ROE和ROOE相同或不同,且表示氢原子或低级烷基;
R5E和R5aE相同或不同,且表示-ROE、-低级亚烷基-N ROEROOE、-低级亚烷基-COROE、环烷基、芳基、杂环、-低级亚烷基-环烷基、-低级亚烷基-芳基、-低级亚烷基-杂环、-SO2-低级烷基、-SO2-低级亚烷基-OROE或-SO2-低级亚烷基-O-C(O)-低级烷基,其中R5E和R5aE中的环烷基、芳基和杂环可以被取代;
R4E表示卤素、低级烷基、卤代-低级烷基、氰基、硝基、-OROE、-O-卤代-低级烷基、-C(O)ROE或-NROEC(O)ROOE;
mE为0、1或2,其中当mE为2时,2个R4E可以相同或不同;
JE表示低级亚烷基、低级亚烯基、-O-低级亚烷基-、-低级亚烷基-O-、-O-低级亚烯基、-低级亚烯基-O-、-C(O)NROE或-NROEC(O)-;
XE表示单键、低级亚烷基、低级亚烯基、-O-低级亚烷基-、-O-低级亚烯基-、-NROE-低级亚烷基-、-S(O)nE-低级亚烷基-或-S(O)nE-低级亚烯基-;
nE为0、1或2;
LE表示单键、-C(O)-或-S(O)2-(通式的符号的详细定义相应于专利说明书中描述的那些);
WO 2007/072782中公开的式(G)表示的化合物,其烷基酯、其盐、其溶剂合物及其前药:
其中R1G和R2G相同或不同,且表示氢原子、卤素、低级烷基、卤代-低级烷基、-OH、-O-低级烷基或
R1G和R2G可与它们相连的碳一起形成5-8元环烯环或苯环;
R3G表示-OH、-O-低级烷基或-NH-SO2-(低级烷基,其可被选自-OH和-O-C(=O)-低级烷基的基团取代);
AG表示任选取代的杂环;
BG表示任选取代的苯基或任选取代的单环杂芳基;
CG表示任选取代的亚苯基或任选取代的单环亚杂芳基;
XG表示低级亚烷基、低级亚烯基、-O-低级亚烷基或-低级亚烷基-O-;
YG表示单键、低级亚烷基、低级亚烯基或-O-低级亚烷基;
ZG表示低级亚烷基(通式的符号的详细定义相应于专利说明书中描述的那些);和
日本专利号3741120中描述的式(I)表示的化合物,其盐、其溶剂合物及其前药:
其中R1表示-COOR1-1(其中R1-1表示氢原子或C1-6烷基)、5-四唑基、5-氧代-1,2,4-噁二唑基、-CH2OH或5-氧代-1,2,4-噻二唑基;
R2表示氢原子、甲基、甲氧基或氯;
R3和R4表示下述组合:(1)甲基和甲基,(2)甲基和氯,(3)氯和甲基,或(4)三氟甲基和氢原子,或
R3和R4与和它们相连的碳原子一起形成(5)环戊烯,(6)环己烯或(7)苯环;
R5表示异丙基、异丁基、2-甲基-2-丙烯基、环丙基甲基、甲基、乙基、丙基或2-羟基-2-甲基丙基;
Ar表示任选被甲基残基取代的噻唑基、吡啶基或5-甲基-2-呋喃基;
n为0或1;其中当R1为5-四唑基、5-氧代-1,2,4-噁二唑基或5-氧代-1,2,4-噻二唑基时,n为0。
在本发明中,式(I)中R1-1的C1-6烷基尤其包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
在本发明中,式(I)中的Ar优选为5-甲基-2-呋喃基、2-噻唑基、5-甲基-2-噻唑基、2-吡啶基或3-吡啶基,R1优选为-COOR1-1,且R1-1优选为氢原子。
在本发明中,优选的式(I)化合物为下述化合物:即,
(1)4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(2)4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(3)4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(4)4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(5)4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(6)4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸(下文中缩写为化合物D),
(7)3-甲基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(8)3-甲基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(9)3-氯-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(10)3-氯-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(11)3-甲氧基-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(12)3-甲基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸(下文中缩写为化合物C),
(13)3-甲氧基-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(14)3-甲氧基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(15)3-甲氧基-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(16)3-氯-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(17)3-氯-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(18)3-甲基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]肉桂酸,
(19)4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(20)4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(21)4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(22)3-甲基-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(23)3-甲基-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(24)3-甲基-4-[2-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(25)3-甲基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(26)4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(27)N-[4-氯-5-甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(28)3-甲氧基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(29)N-[4,5-二甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(30)N-[4,5-二甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(5-甲基-2-呋喃基)磺酰胺,
(31)N-[4-氯-5-甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(32)N-[4-氯-5-甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-(5-甲基-2-呋喃基)磺酰胺,
(33)N-[4-氯-5-甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(34)4-[6-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(35)4-[6-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(36)4-[7-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-1,2,3,4-四氢萘(テトラヒドロナフタレン)-6-基氧基甲基]苯甲酸,
(37)4-[7-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]-1,2,3,4-四氢萘-6-基氧基甲基]苯甲酸,
(38)N-[4,5-二甲基-2-[2-甲基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-(5-甲基-2-呋喃基)磺酰胺,
(39)N-[4,5-二甲基-2-[2-甲基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(40)N-[4,5-二甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(5-甲基-2-呋喃基)磺酰胺,
(41)N-[4,5-二甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(42)N-[4,5-二甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(43)3-甲基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(44)N-[4,5-二甲基-2-[2-甲氧基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(5-甲基-2-呋喃基)磺酰胺,
(45)N-[4,5-二甲基-2-[2-甲氧基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-(5-甲基-2-呋喃基)磺酰胺,
(46)4-[6-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸(下文中缩写为化合物E),
(47)3-甲基-4-[6-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸(下文中缩写为化合物F),
(48)3-甲基-4-[6-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(49)4-[2-[N-(2-甲基-2-丙烯基)-N-(5-甲基-2-呋喃基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(50)3-甲基-4-[6-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(51)3-甲基-4-[6-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(52)4-[6-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(53)4-[3-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-2-萘基氧基甲基]苯甲酸,
(54)3,5-二甲基-4-[2-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(55)3-甲基-4-[6-[N-(2-甲基-2-丙烯基)-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(56)4-[6-[N-环丙基甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]-3-甲基苯甲酸,
(57)4-[6-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]-3-甲基苄醇,
(58)3-甲基-4-[6-[N-甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(59)4-[6-[N-乙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]-3-甲基苯甲酸,
(60)4-[6-[N-甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(61)4-[6-[N-乙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(62)4-[6-[N-丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(63)4-[4,5-二甲基-2-[N-(2-甲基-2-丙烯基)-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(64)4-[6-[N-(2-甲基-2-丙烯基)-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(65)4-[6-[N-环丙基甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(66)4-[6-[N-(2-丙烯基)-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(67)3-甲基-4-[6-[N-丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(68)3-甲基-4-[6-[N-(2-丙烯基)-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(69)4-[4,5-二甲基-2-[N-甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]苯甲酸,
(70)4-[4,5-二甲基-2-[N-乙基-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]苯甲酸,
(71)4-[4,5-二甲基-2-[N-(5-甲基-2-呋喃基磺酰基)-N-丙基氨基]苯氧基甲基]苯甲酸,
(72)4-[3-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]萘(ナフタレン)-2-基氧基甲基]-3-甲基苯甲酸,
(73)4-[3-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]萘-2-基氧基甲基]-3-甲基苯甲酸,
(74)4-[3-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]萘-2-基氧基甲基]肉桂酸,
(75)4-[3-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]萘-2-基氧基甲基]肉桂酸,
(76)3-甲基-4-[3-[N-异丙基-N-(5-甲基-2-呋喃基磺酰基)氨基]萘-2-基氧基甲基]肉桂酸,
(77)3-甲基-4-[3-[N-异丁基-N-(5-甲基-2-呋喃基磺酰基)氨基]萘-2-基氧基甲基]肉桂酸,
(78)4-[4,5-二甲基-2-[N-[(5-甲基-2-呋喃基)磺酰基]-N-2-丙烯基氨基]苯氧基甲基]苯甲酸,
(79)4-[4,5-二甲基-2-[N-甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(80)4-[4,5-二甲基-2-[N-乙基-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(81)4-[4,5-二甲基-2-[N-(5-甲基-2-呋喃基磺酰基)-N-丙基氨基]苯氧基甲基]-3-甲基苯甲酸,
(82)4-[4,5-二甲基-2-[N-(5-甲基-2-呋喃基磺酰基)-N-(2-丙烯基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(83)4-[4,5-二甲基-2-[N-(2-羟基-2-甲基丙基)-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(84)4-[6-[N-(2-羟基-2-甲基丙基)-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]-3-甲基苯甲酸,
(85)4-[4,5-二甲基-2-[N-环丙基甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]苯甲酸,
(86)4-[4,5-二甲基-2-[N-(2-羟基-2-甲基丙基)-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]苯甲酸,
(87)4-[6-[N-(2-羟基-2-甲基丙基)-N-(5-甲基-2-呋喃基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(88)4-[4,5-二甲基-2-[N-环丙基甲基-N-(5-甲基-2-呋喃基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(89)4-[2-[N-异丙基-N-(2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(90)4-[2-[N-异丁基-N-(2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(91)4-[2-[N-异丙基-N-(2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(92)4-[2-[N-异丁基-N-(2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(93)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(94)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸(下文中缩写为化合物G),
(95)4-[2-[N-异丙基-N-(2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(96)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-2-噻唑基磺酰胺,
(97)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-2-噻唑基磺酰胺,
(98)N-[4-三氟甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-2-噻唑基磺酰胺,
(99)N-[4-三氟甲基-2-[4-(5-氧代-1,2,4-噻二唑-3-基-1,2,4-噻二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-2-噻唑基磺酰胺,
(100)4-[2-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(101)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(102)3-氯-4-[2-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(103)3-甲基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(104)3-甲基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(105)3-甲氧基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(106)3-甲氧基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(107)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(108)N-[4-三氟甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(109)N-[4-三氟甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(110)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(111)3-氯-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(112)3-甲氧基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(113)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(114)3-甲基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(115)3-甲基-4-[2-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(116)3-甲氧基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(117)3-氯-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(118)3-氯-4-[2-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(119)4-[2-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(120)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(121)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]肉桂酸,
(122)3-甲基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(123)3-氯-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(124)3-甲基-4-[2-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(125)3-甲基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(126)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(127)3-甲基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(128)3-甲基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]肉桂酸,
(129)N-[4-氯-5-甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(130)N-[4-氯-5-甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺(下文中缩写为化合物J),
(131)4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(132)N-[4-三氟甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(133)N-[4-三氟甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(134)3-氯-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(135)N-[4,5-二甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(136)N-[4,5-二甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(137)N-[4,5-二甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(138)N-[4,5-二甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(139)N-[4-氯-5-甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(140)N-[4-氯-5-甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(141)N-[4-氯-5-甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(142)N-[4-氯-5-甲基-2-[2-甲基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(143)3-甲氧基-4-[2-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(144)N-[4,5-二甲基-2-[2-甲基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(145)N-[4,5-二甲基-2-[2-甲基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(146)N-[4,5-二甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺(下文中缩写为化合物L),
(147)N-[4,5-二甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-(4-甲基-2-噻唑基)磺酰胺,
(148)N-[4,5-二甲基-2-[2-甲氧基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(149)N-[4,5-二甲基-2-[2-甲氧基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-(4-甲基-2-噻唑基)磺酰胺,
(150)4-[6-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(151)4-[6-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(152)3-甲基-4-[6-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(153)3-甲基-4-[6-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(154)3-甲基-4-[2-[N-(2-甲基-2-丙烯基)-N-(4-甲基-2-噻唑基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(155)4-[2-[N-(2-甲基-2-丙烯基)-N-(4-甲基-2-噻唑基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(156)3-甲基-4-[2-[N-(2-甲基-2-丙烯基)-N-(4-甲基-2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(157)3-甲基-4-[6-[N-异丙基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(158)3-甲基-4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(159)3-甲基-4-[6-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(160)4-[6-[N-异丙基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(161)4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(162)4-[6-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(163)4-[6-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(164)3-甲基-4-[6-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(165)4-[2-[N-异丙基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(166)4-[2-[N-异丁基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(167)4-[2-[N-异丙基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(168)4-[2-[N-异丁基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(169)4-[6-[N-异丙基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(170)4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(171)3-甲基-4-[2-[N-异丙基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(172)3-甲基-4-[2-[N-异丁基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(173)3-甲基-4-[2-[N-异丙基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(174)3-甲基-4-[2-[N-异丁基-N-(2-噻唑基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(175)3-甲基-4-[6-[N-异丙基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(176)3-甲基-4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(177)4-[3-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]萘-2-基氧基甲基]苯甲酸,
(178)4-[3-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]萘-2-基氧基甲基]苯甲酸,
(179)4-[3-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]萘-2-基氧基甲基]-3-甲基苯甲酸,
(180)4-[3-[N-异丙基-N-[2-(4-甲基噻唑基)磺酰基]氨基]萘-2-基氧基甲基]-3-甲基苯甲酸,
(181)4-[3-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]萘-2-基氧基甲基]肉桂酸,
(182)4-[3-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]萘-2-基氧基甲基]肉桂酸,
(183)4-[4,5-二甲基-2-[N-甲基-N-(4-甲基-2-噻唑基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(184)4-[4,5-二甲基-2-[N-乙基-N-(4-甲基-2-噻唑基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(185)4-[4,5-二甲基-2-[N-丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(186)4-[4,5-二甲基-2-[N-(2-丙烯基)-N-(4-甲基-2-噻唑基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(187)4-[4,5-二甲基-2-[N-环丙基甲基-N-(4-甲基-2-噻唑基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(188)4-[4,5-二甲基-2-[N-(2-羟基-2-甲基丙基)-N-(4-甲基-2-噻唑基磺酰基)氨基]苯氧基甲基]-3-甲基苯甲酸,
(189)4-[6-[N-(2-甲基-2-丙烯基)-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(190)4-[6-[N-(4-甲基-2-噻唑基磺酰基)-N-(2-丙烯基)氨基]茚满-5-基氧基甲基]苯甲酸,
(191)4-[6-[N-环丙基甲基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(192)4-[3-[N-异丁基-N-[2-(4-甲基噻唑基)磺酰基]氨基]萘-2-基氧基甲基]苯甲酸,
(193)4-[3-[N-异丙基-N-(4-甲基-2-噻唑基磺酰基)氨基]萘-2-基氧基甲基]-3-甲基苯甲酸,
(194)4-[6-[N-乙基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(195)4-[6-[N-(4-甲基-2-噻唑基磺酰基)-N-丙基氨基]茚满-5-基氧基甲基]苯甲酸,
(196)4-[6-[N-甲基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(197)3-甲基-4-[6-[N-甲基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(198)4-[6-[N-乙基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]-3-甲基肉桂酸,
(199)3-甲基-4-[6-[N-(2-甲基-2-丙烯基)-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]肉桂酸,
(200)4-[6-[N-环丙基甲基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]-3-甲基肉桂酸,
(201)3-甲基-4-[6-[N-(4-甲基-2-噻唑基磺酰基)-N-(2-丙烯基)氨基]茚满-5-基氧基甲基]肉桂酸,
(202)4-[6-[N-(2-羟基-2-甲基丙基)-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]-3-甲基肉桂酸,
(203)3-甲基-4-[6-[N-(4-甲基-2-噻唑基磺酰基)-N-丙基氨基]茚满-5-基氧基甲基]肉桂酸,
(204)4-[6-[N-(2-羟基-2-甲基丙基)-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸,
(205)4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(206)4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-5-三氟甲基苯氧基甲基]苯甲酸,
(207)3-氯-4-[2-[N-异丙基-N-(2-吡啶基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(208)3-甲基-4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(209)3-甲基-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]苯甲酸,
(210)3-甲基-4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(211)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-3-吡啶基磺酰胺,
(212)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-3-吡啶基磺酰胺,
(213)4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(214)3-氯-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(215)3-甲基-4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(216)3-甲氧基-4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(217)3-甲氧基-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(218)3-甲基-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(219)3-甲基-4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸(下文中缩写为化合物H),
(220)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-2-吡啶基磺酰胺,
(221)N-[4-三氟甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(222)3-甲基-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]苯甲酸,
(223)4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]苯甲酸,
(224)N-[4-三氟甲基-2-[4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(225)4-[2-[N-异丙基-N-(2-吡啶基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(226)3-甲基-4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-4-甲基-5-氯苯氧基甲基]肉桂酸,
(227)3-甲基-4-[2-[N-异丁基-N-(2-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(228)4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(229)3-甲基-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸(下文中缩写为化合物I),
(230)N-[4-三氟甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-2-吡啶基磺酰胺,
(231)3-氯-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4,5-二甲基苯氧基甲基]肉桂酸,
(232)N-[4,5-二甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(233)N-[4,5-二甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-3-吡啶基磺酰胺,
(234)N-[4-氯-5-甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-3-吡啶基磺酰胺,
(235)N-[4,5-二甲基-2-[2-氯-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(236)N-[4,5-二甲基-2-[2-氯-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-3-吡啶基磺酰胺(下文中缩写为化合物K),
(237)N-[4,5-二甲基-2-[2-氯-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-3-吡啶基磺酰胺,
(238)3-甲基-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-4-氯-5-甲基苯氧基甲基]肉桂酸,
(239)N-[4,5-二甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-2-吡啶基磺酰胺,
(240)N-[4,5-二甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(241)N-[4,5-二甲基-2-[4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-3-吡啶基磺酰胺,
(242)3-氯-4-[2-[N-异丁基-N-(3-吡啶基磺酰基)氨基]-5-三氟甲基苯氧基甲基]肉桂酸,
(243)N-[4-氯-5-甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-2-吡啶基磺酰胺,
(244)N-[4-氯-5-甲基-2-[2-甲基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(245)N-[4,5-二甲基-2-[2-甲基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-2-吡啶基磺酰胺,
(246)N-[4,5-甲基-2-[2-甲基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-3-吡啶基磺酰胺,
(247)N-[4,5-二甲基-2-[2-甲氧基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(248)N-[4,5-二甲基-2-[2-甲氧基-4-(5-四唑基)苯基甲基氧基]苯基]-N-异丙基-2-吡啶基磺酰胺,
(249)N-[4,5-二甲基-2-[2-甲氧基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丁基-2-吡啶基磺酰胺,
(250)N-[4,5-二甲基-2-[2-甲氧基-4-(5-氧代-1,2,4-噁二唑-3-基)苯基甲基氧基]苯基]-N-异丙基-2-吡啶基磺酰胺,
它们的烷基酯、它们的盐、它们的溶剂合物及它们的前药。
更优选的化合物为3-甲基-4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸(下文中缩写为化合物A)和4-[6-[N-异丁基-N-(4-甲基-2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸(下文中缩写为化合物B),它们的烷基酯、它们的盐、它们的溶剂合物及它们的前药。
优选的式(E)化合物为下述化合物:即,
(E-1)4-{[(5-{异丁基[(5-甲基-2-呋喃基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-6-基)氧基]甲基}苯甲酸,
(E-2)4-{[(5-{异丁基[(4-甲基-1,3-噻唑-2-基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-6-基)氧基]甲基}苯甲酸,
(E-3)4-{[(5-{[(2S)-3-羟基-2-甲基丙基][(5-甲基-2-呋喃基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-6-基)氧基]甲基}苯甲酸,
(E-4)4-{[(6-{[(2R)-3-羟基-2-甲基丙基][(5-甲基-2-呋喃基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-5-基)氧基]甲基}苯甲酸,
(E-5)4-{[(5-{(2-氟丙基)[(5-甲基-2-呋喃基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-6-基)氧基]甲基}苯甲酸,
(E-6)4-[({6-[[(3-氟苯基)磺酰基](吡啶-2-基甲基)氨基]-2,3-二氢-1-苯并呋喃-5-基}氧基)甲基]苯甲酸,
(E-7)4-[({6-[[(3,5-二氟苯基)磺酰基](吡啶-2-基甲基)氨基]-2,3-二氢-1-苯并呋喃-5-基}氧基)甲基]苯甲酸,
(E-8)N-异丁基-5-甲基-N-(6-{[4-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)苄基]氧基}-2,3-二氢-1-苯并呋喃-5-基)呋喃-2-磺酰胺,
(E-9)4-{[(6-{异丁基[(4-甲基-1,3-噻唑-2-基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-5-基)氧基]甲基}苯甲酸,
(E-10)4-[({6-[[(4-甲基-1,3-噻唑-2-基)磺酰基](吡啶-2-基甲基)氨基]-2,3-二氢-1-苯并呋喃-5-基}氧基)甲基]苯甲酸,
(E-11)5-{[(5-{异丁基[(5-甲基-2-呋喃基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-6-基)氧基]甲基}噻吩-2-羧酸,
(E-12)3-氯-4-{[(5-{异丁基[(4-甲基-1,3-噻唑-2-基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-6-基)氧基]甲基}苯甲酸,
(E-13)4-{[(5-{异丁基[(5-甲基-2-呋喃基)磺酰基]氨基}-2,3-二氢-1-苯并噻吩-6-基)氧基]甲基}苯甲酸,
(E-14)5-{[(5-{异丁基[(4-甲基-1,3-噻唑-2-基)磺酰基]氨基}-2,3-二氢-1-苯并呋喃-6-基)氧基]甲基}噻吩-2-羧酸,
(E-15)4-[({5-[[(5-甲基-2-呋喃基)磺酰基](吡啶-2-基甲基)氨基]-2,3-二氢-1-苯并噻吩-6-基}氧基)甲基]苯甲酸,
(E-16)4-{[(5-{异丁基[(5-甲基-2-呋喃基)磺酰基]氨基}-1,1-二氧化-2,3-二氢-1-苯并噻吩-6-基)氧基]甲基}苯甲酸,
WO2006/121097的表19-82中公开的实施例1-516的化合物(由表中″Ex ″栏的编号表示),
该表83中公开的化合物,
它们的烷基酯、它们的盐、它们的溶剂合物及它们的前药。
优选的式(G)化合物为下述化合物:即,
(G-1)4-[({6-[[(4-甲基-1,3-噻唑-2-基)磺酰基](氧杂环丁烷-2-基甲基)氨基]-2,3-二氢-1H-茚满-5-基}氧基)甲基]苯甲酸,
(G-2)4-{[(6-{[(3-甲基氧杂环丁烷-3-基)甲基][(4-甲基-1,3-噻唑-2-基)磺酰基]氨基}-2,3-二氢-1H-茚满-5-基)氧基]甲基}苯甲酸,
(G-3)4-[({6-[[(3,5-二氟苯基)磺酰基](氧杂环丁烷-2-基甲基)氨基]-2,3-二氢-1H-茚满-5-基}氧基)甲基]苯甲酸,
(G-4)4-[({6-[[(4-甲基-1,3-噻唑-2-基)磺酰基](吡啶-2-基甲基)氨基]-2,3-二氢-1H-茚满-5-基}氧基)甲基]苯甲酸,
(G-5)4-[({6-[[(4-甲基-1,3-噻唑-2-基)磺酰基](四氢呋喃-3-基甲基)氨基]-2,3-二氢-1H-茚满-5-基}氧基)甲基]苯甲酸,
(G-6)4-[({6-[[(5-甲基-2-呋喃基)磺酰基](四氢呋喃-3-基甲基)氨基]-2,3-二氢-1H-茚满-5-基}氧基)甲基]苯甲酸,
(G-7)4-[({6-[(吡啶-2-基甲基)(吡啶-3-基磺酰基)氨基]-2,3-二氢-1H-茚满-5-基}氧基)甲基]苯甲酸,
(G-8)4-({4,5-二甲基-2-[[(4-甲基-1,3-噻唑-2-基)磺酰基](吡啶-2-基甲基)氨基]苯氧基}甲基)苯甲酸,
(G-9)4-({4-氯-5-甲基-2-[[(4-甲基-1,3-噻唑-2-基)磺酰基](吡啶-2-基甲基)氨基]苯氧基}甲基)苯甲酸,
(G-10)4-{[2-[[(4-甲基-1,3-噻唑-2-基)磺酰基](吡啶-2-基甲基)氨基]-5-(三氟甲基)苯氧基]甲基}苯甲酸,
(G-11)4-({4,5-二甲基-2-[(吡啶-2-基甲基)(吡啶-3-基磺酰基)氨基]苯氧基}甲基)苯甲酸,
(G-12)4-{[(6-{[(1-甲基-1H-吡唑-4-基)甲基][(4-甲基-1,3-噻唑-2-基)磺酰基]氨基}-2,3-二氢-1H-茚满-5-基)氧基]甲基}苯甲酸,
(G-13)4-({5-甲氧基-4-甲基-2-[[(4-甲基-1,3-噻唑-2-基)磺酰基](吡啶-2-基甲基)氨基]苯氧基}甲基)苯甲酸,
(G-14)4-({4,5-二甲基-2-[(吡啶-2-基甲基)(吡啶-2-基磺酰基)氨基]苯氧基}甲基)苯甲酸,
4-[({6-[[(2-氟苯基)磺酰基](吡啶-2-基甲基)氨基]-2,3-二氢-1H-茚满-5-基}氧基)甲基]苯甲酸,
(G-15)4-{[(6-{[(1-甲基-1H-咪唑-2-基)甲基][(4-甲基-1,3-噻唑-2-基)磺酰基]氨基}-2,3-二氢-1H-茚满-5-基)氧基]甲基}苯甲酸,
WO2007/072782中公开的实施例1-4、153和165的化合物,
该表8-24中公开的化合物,
它们的烷基酯、它们的盐、它们的溶剂合物及它们的前药。
在本发明中,SC-51322(Hallinan等人,Bioorg.Med.Chem.Lett.,1994;4:509-514),SC-19220(Hallinan等人,J.Med.Chem.,1993;36:3293-3299),SC-51089(Hallinan等人,J.Med.Chem.,1996;39:609-613),ZD-4953(Ruel等人,Bioorg.Med.Chem.Lett.,9:2699-2704)和US4132847,US4775680,US5281590,US530464,US5324722,US5354746,US5354747,US5420270,US5441950,US5504077,EP752421,EP160408,EP193822,EP218077,EP300676,EP480641,EP512399,EP512400,EP534667,EP539977,EP694546,WO92/19617,WO93/07132,WO93/13082,WO96/03380,WO96/06822,WO96/11902,WO97/00863,WO97/00864,WO99/47497,WO2000/20371,WO2000/69465,WO2001/19814,WO2001/19819,WO2002/72098,WO2002/72145,WO2003/84917,WO2003/101959,WO2006/114272和WO2007/113289中公开的化合物可以引入作为其它EP1拮抗剂。
在本发明中,除非另有说明或对于本领域技术人员是明显的外,符号
表示在纸面的对侧(即α-构型)连接;符号
表示在纸面的前侧(即β-构型)连接;且符号
表示其为α-构型、β-构型或其任意混合物。
除非另有说明,所有异构体都包括在式(A),(B),(E),(G)和(I)表示的化合物中。例如,烷基、烯基、炔基、烷氧基、烷硫基、亚烷基、亚烯基和亚炔基指直链或支链的。而且,双键、环、稠环上的异构体(E-,Z-,顺-,反-异构体),不对称碳原子产生的异构体(R-,S-异构体,α-,β-构型,对映异构体,非对映异构体),旋光异构体(D-,L-,d-,l-异构体),色谱分离产生的极性化合物(较高极性的化合物、较低极性的化合物),平衡化合物,旋转异构体,其任意比例的混合物和外消旋混合物也包括在式(A),(B),(E),(G)和(I)表示的化合物中。
当式(A),(B),(E),(G)和(I)表示的化合物具有羧基时,这些化合物可以通过本身已知的方法转化为相应的酯。转化为酯是有用的,因为其增加了化合物的稳定性和吸收性。在本说明书中,优选的烷基酯是C1-6烷基酯(如,甲基酯、乙基酯、正丙基酯、异丙基酯、正丁基酯、异丁基酯、仲丁基酯、叔丁基酯、正戊基酯、正己基酯等),且最优选的烷基酯为C1-4烷基酯(如,甲基酯、乙基酯、正丙基酯、异丙基酯、正丁基酯、异丁基酯等)。
式(A),(E)和(G)表示的化合物的盐、这些化合物的烷基酯的盐、和式(B)和(I)表示的化合物的盐全是优选的。且更优选的盐是水溶性盐。适合的盐包括,例如,碱金属(如,钾、钠等)的盐、碱土金属(如,钙、镁等)的盐、铵盐、药学可接受的有机胺(如,四甲基铵、三乙基胺、甲基胺、二甲基胺、环戊基胺、苄基胺、苯乙基胺、哌啶、单乙醇胺、二乙醇胺、三(羟基甲基)氨基甲烷、赖氨酸、精氨酸、N-甲基-D-葡萄糖胺等)的盐。适合的酸加成盐包括,例如,无机酸盐,如,盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、硝酸盐等或有机酸盐,如,乙酸盐、乳酸盐、酒石酸盐、苯甲酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、羟乙基磺酸盐、葡萄糖醛酸盐、葡糖酸盐等。酸加成盐优选为水溶性盐。
式(A),(E)和(G)表示的化合物,其烷基酯或其盐,和式(B)和(I)表示的化合物或其盐可转化为相应的溶剂合物。优选无毒和水溶性的溶剂合物。适合的溶剂合物包括,例如,水或醇溶剂(如,乙醇等)的溶剂合物。
式(A),(E)和(G)表示的化合物,其烷基酯或其盐,和式(B)和(I)表示的化合物,其盐或其溶剂合物可以通过JP50003362B,JP52031404B或JP61052146B中描述的方法使用α-,β-或γ-环糊精或其混合物转化为相应的环糊精包合物。通过转化为相应的环糊精包合物,化合物的稳定性和在水中的溶解性增加,且因此在用于药物中是有用的。
式(A),(E)和(G)表示的化合物、其烷基酯或其盐,和式(B)和(I)表示的化合物、其盐或其溶剂合物的前药是指通过体内与酶、胃酸等的反应转化为式(A),(E)和(G)表示的化合物、其烷基酯、其盐,式(B)和(I)表示的化合物、其盐或其溶剂合物的化合物。当式(A),(B),(E),(G)和(I)表示的化合物具有氨基时,前药包括以下化合物,其中化合物的氨基被酰化、烷基化或磷酸化的化合物(如,其中式(A),(B),(E),(G)和(I)表示的化合物的氨基被二十烷酰化、丙氨酰化、戊基氨基羰基化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲氧基羰基化、四氢呋喃基化、吡咯烷基甲基化、新戊酰基氧基甲基化、乙酰氧基甲基化、叔丁基化等);当式(A),(B),(E),(G)和(I)表示的化合物具有羟基时,前药包括以下化合物,其中化合物的羟基被酰化、烷基化、磷酸化或硼酸化的化合物(如,其中式(A),(B),(E),(G)和(I)表示的化合物的羟基被乙酰化、棕榈酰化、丙酰化、新戊酰化、琥珀酰化、富马酰化、丙氨酰化、二甲基氨基甲基羰基化,等);当式(A),(B),(E),(G)和(I)表示的化合物具有羧基时,前药包括以下化合物,其中化合物的羧基被酯化或酰胺化的化合物(如,其中式(A),(B),(E),(G)和(I)表示的化合物的羧基转化为酯,如乙基酯、苯基酯、羧基甲基酯、二甲基氨基甲基酯、新戊酰基氧基甲基酯、乙氧基羰基氧基乙基酯、酞基酯、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯、环己基氧基羰基乙基酯,或其中羧基被甲基酰胺化的化合物)等。这些化合物可以通过本身已知的方法制备,且可以为水合物和非水合物中的任一种。且这些前药可以在生理条件下转化为式(A),(E)和(G)表示的化合物、其烷基酯或其盐,和式(B)和(I)表示的化合物、其盐或其溶剂合物,如″Iyakuhin no Kaihatsu″,Vol.7,″Bunshi Sekkei″,pp.163-198(Hirokawa Shoten,1990)所述。
而且,式(A),(E)和(G)表示的化合物、其烷基酯或其盐,和式(B)和(I)表示的化合物、其盐或其溶剂合物可以用同位素(如,3H、14C、35S、125I等)标记等。
制备本发明涉及的化合物的方法
式(A),(E)和(G)表示的化合物、其烷基酯或其盐,和式(B)和(I)表示的化合物、其盐或其溶剂合物可以通过描述于日本专利号3426252,EP878465,日本专利号3741120,WO2006/121097和WO2007/113289的方法,描述于JP52027753,JP55100360,WO2003/074483,Synlett 2002,No.1,239-242或Comprehensive Organic Transformations:A Guide to Functional GroupPreparations,2nd Edition(Richard C.Larock,John Wiley & Sons Inc,1999)中的已知方法,适当改善的方法或其组合方法制备。其它EP1拮抗剂可以通过描述于相应文件或专利文件中的制备方法而制备。
毒性
已经证实本发明中涉及的EP1拮抗剂具有低毒性且对于用作药物制剂足够安全。
药物应用
本发明中涉及的EP1拮抗剂有效用于预防、治疗和/或症状改善排尿障碍(如,尿势弱、尿线分叉、尿线间断、排尿延迟、腹压排尿、尿末滴沥等)。
本发明中涉及的EP1拮抗剂可以与其它药物组合给药以用于下述目的:
(1)补充和/或提高预防、治疗和/或症状改善的效果,
(2)改善动力学和吸收,降低剂量,和/或
(3)减轻副作用。
本发明中涉及的EP1拮抗剂与其它药物的组合可以作为药品(包含这些成分)中的组合物给药,或可以分别给药。当分别给药时,它们可以同时或有时间间隔地给药。有时间间隔的给药包括首先给药本发明的药物,然后给药其它药物的方法,和首先给药其它药物,然后给药本发明的药物的方法,且它们可以以相同的途径或不同的途径给药。
补充和/或提高使用本发明中涉及的EP1拮抗剂的预防、治疗和/或症状改善排尿障碍的效果的其它药物包括,例如,乙酰胆碱酯酶抑制剂(如,地斯的明、新斯的明等)或α1受体拮抗剂(如,坦洛新、哌唑嗪、阿夫唑嗪、萘哌地尔、乌拉地尔等)。
本发明中涉及的EP1拮抗剂和其它药物的重量比没有特别限制。任意2种或更多种其它药物可以组合给药。
基于上述机理,补充和/或提高使用本发明的EP1拮抗剂的预防、治疗和/或症状改善排尿障碍的效果的其它药物不仅包括目前已经发现的药物,而且包括将根据上述机理发现的药物。
对于使用本发明中涉及的EP1拮抗剂和用于上述目的的其它药物的组合,它们通常以口服或胃肠外给药的形式全身或局部给药。
本发明中涉及的EP1拮抗剂的剂量根据年龄、体重、症状、治疗效果、给药途径和治疗时间(随着化合物本身改变)而改变。通常,对于成人每人每次给药的剂量为1ng至100mg,每天口服给药1次至多次。或者,它们为0.1ng至10mg,最多每天几次通过胃肠外给药,或它们可以连续给药到静脉中每天1-24小时。
如上所述,剂量依赖于许多条件,且因此有时可能剂量低于上述具体范围,或可能需要高于上述具体范围的剂量。
本发明中涉及的EP1拮抗剂或本发明中涉及的EP1拮抗剂与其它药物的组合可以以下述形式给药,例如,口服的固体制剂或液体制剂,或注射剂、外用制剂、栓剂、滴眼剂或吸入剂,各自用于胃肠外给药。
口服给药的固体组合物包括片剂、丸剂、胶囊、可分散粉末和颗粒等。胶囊包括硬胶囊和软胶囊。
在这些口服使用的固体制剂中,一种或多种活性化合物单独混合或与下述物质混合:赋形剂(如,乳糖、甘露醇、葡萄糖、微晶纤维素、淀粉等),粘合剂(如,羟基丙基纤维素、聚乙烯吡咯烷酮、硅酸铝酸镁(magnesiummetasilicate aluminate)等),崩解剂(如纤维素乙醇酸钙等),润滑剂(如,硬脂酸镁等),稳定剂和溶出助剂(如,谷氨酸、天门冬氨酸等),然后用常规方式配制成制剂。如果需要,这些制剂可以用包衣试剂(如,蔗糖、明胶、羟基丙基纤维素、羟基丙基甲基纤维素酞酸酯等)包衣,或它们可以用2个或更多个包衣层包衣。而且,口服使用的固体组合物包括可吸收材料(如明胶)的胶囊。
口服给药的液体组合物包括药剂学可接受的溶液、混悬液、乳液、糖浆剂和酏剂等。在这些液体制剂中,可以将一种或多种活性化合物溶解、混悬或乳化到本领域中通常使用的稀释剂中(如,纯化水、乙醇或其混合物等)。除这些稀释剂外,所述组合物也可以含有一些添加剂,如润湿剂、助悬剂、乳化剂、甜味剂、香味剂、芳香剂、防腐剂或缓冲剂。
胃肠外给药的外用制剂包括,例如,软膏、凝胶、乳膏、泥敷剂(poultices)、贴片(patch)、搽剂、雾化剂、吸入剂和喷雾剂等。它们包括一种或多种活性化合物,且通过本身已知的方法或常规方法制备。
软膏通过本身已知的方法或常规方法制备。例如,它们通过将一种或多种活性化合物与基质(substrate)研磨或融合制备。用于软膏的基质选自已知的或常用的基质。其包括,例如,高级脂肪酸或高级脂肪酸酯(如,己二酸,肉豆蔻酸,棕榈酸,硬脂酸,油酸,己二酸酯,肉豆蔻酸酯,棕榈酸酯,硬脂酸酯,油酸酯等),蜡(如,黄蜂蜡,鲸蜡,地蜡等),表面活性剂(如,聚氧乙烯烷基醚磷酸酯等),高级醇(如,鲸蜡醇,硬脂醇,十六十八醇等),硅油(如,二甲基聚硅氧烷等),烃(如,亲水凡士林,白凡士林,纯化羊毛脂,液体石蜡等),二醇(如,乙二醇,二乙二醇,丙二醇,聚乙二醇,碳蜡(macrogol)等),植物油(如,蓖麻油,橄榄油,麻油,松节油等),动物油(如,貂油,卵黄油,角鲨烷,角鲨烯等),水,吸收促进剂和刺激抑制剂。这些基质独立使用或以2种或更多种的混合物使用。而且,可以含有润湿剂、防腐剂、稳定剂、抗氧化剂、芳香材料等。
凝胶通过本身已知的方法或常规方法制备。例如,它们通过将一种或多种活性化合物与基质融合而制备。用于凝胶的基质选自已知或常用的基质。其包括,例如,低级醇(如,乙醇,异丙醇等),胶凝剂(如,羧甲基纤维素,羟乙基纤维素,羟丙基纤维素,乙基纤维素等),中和剂(如,三乙醇胺,二异丙醇胺等),表面活性剂(如,聚乙二醇单硬脂酸酯等),胶质,水,吸收促进剂和刺激抑制剂。这些基质独立使用或以2种或更多种的混合物使用。而且,可以含有防腐剂、抗氧化剂、芳香材料等。
乳膏通过本身已知的方法或常规方法制备。例如,它们通过将一种或多种活性化合物和基质融合或乳化而制备。用于乳膏的基质选自已知或常用的基质。其包括,例如高级脂肪酸酯,低级醇,烃,多元醇(如,丙二醇,1,3-丁二醇等),高级醇(如,2-己基癸醇,鲸蜡醇等),乳化剂(如,聚氧乙烯烷基醚,脂肪酸酯等),水,吸收促进剂和刺激抑制剂。这些基质独立使用或以2种或更多种的混合物使用。而且,可以含有防腐剂、抗氧化剂、芳香材料等。
敷剂通过本身已知的方法或常规方法制备。例如,它们通过将一种或多种活性化合物和基质融合而制备,然后将其捏合放置到支持介质上。用于敷剂的基质选自已知或常用的基质。其包括,例如,增稠剂(如,聚丙烯酸,聚乙烯吡咯烷酮,阿拉伯胶,淀粉,明胶,甲基纤维素等),润湿剂(如,尿素,甘油,丙二醇等),填充剂(如,高岭土,氧化锌,滑石,钙,镁等),水,助溶剂,增稠剂和刺激抑制剂。这些基质独立使用或以2种或更多种的混合物使用。而且,可以含有防腐剂、抗氧化剂、芳香材料等。
贴片通过本身已知的方法或常规方法制备。例如,它们通过将一种或多种活性化合物和基质融合而制备,然后放置到支持介质上。用于贴片的基质选自已知或常用的基质。其包括,例如,聚合物基质,脂肪,高级脂肪酸,增稠剂和刺激抑制剂。这些基质独立使用或以2种或更多种的混合物使用。而且,可以含有防腐剂、抗氧化剂、芳香材料等。
搽剂通过本身已知的方法或常规方法制备。例如,它们通过将一种或多种活性化合物溶解、混悬或乳化到一种或多种选自下述的物质中制备:水,醇(如,乙醇,聚乙二醇等),高级脂肪酸,甘油,皂,乳化剂,助悬剂等。搽剂可以进一步含有防腐剂、抗氧化剂、芳香材料等。
雾化剂、吸入剂和喷雾剂可以包含(除常用稀释剂外)稳定剂,如亚硫酸氢钠和用于产生等渗的缓冲剂,例如,等渗剂,如氯化钠、柠檬酸钠或柠檬酸。
用于胃肠外给药的注射剂包括溶液,混悬剂,乳剂和使用前溶解或混悬到注射用溶剂中的固体形式。这些注射剂通过将一种或多种活性化合物溶解、混悬或乳化到溶剂中而制备。溶剂包括,例如,注射用蒸馏水,生理盐溶液,植物油,丙二醇,聚乙二醇,醇如乙醇,或其混合物。注射剂可进一步包含一些添加剂,如稳定剂,溶液佐剂(如,谷氨酸,天门冬氨酸,POLYSORBATE80(注册商标)等),助悬剂,乳化剂,安抚剂,缓冲剂,防腐剂等。这些注射剂可以通过在最后步骤灭菌而制备,或可以通过无菌操作而制备。或者,其可以以无菌固体形式制备,例如,冻干产品,其可以在使用前溶解在注射用的无菌水或一些其它无菌稀释剂中。
用于胃肠外给药的吸入剂包括气雾剂,吸入粉末或吸入液体。吸入液体可以在使用前溶解或混悬在水或其它适合的溶剂中。这些吸入剂通过本身已知的方法制备。例如,吸入液体通过视需要使用适合的添加剂,如抗菌剂(如,苯扎氯铵,对-羟基苯甲酸酯等),着色剂,缓冲剂(如,磷酸钠,乙酸钠等),等渗剂(如,氯化钠,浓甘油等),增稠剂(如,羧基乙烯基聚合物等),或吸收促进剂等而制备。
吸入粉末通过视需要使用适合的添加剂,如润滑剂(如,硬脂酸(stearinacid)及其盐等),粘合剂(如,淀粉,糊精等),稀释剂(如,乳糖,纤维素等),着色剂,抗菌剂(如苯扎氯铵,对-羟基苯甲酸酯等),吸收促进剂等而制备。
当给药用于吸入的液体时,通常使用喷雾器(如,雾化器,喷雾器),且当给药吸入粉末时,通常使用用于粉末药物的吸入给药设备。
用于胃肠外给药的其它组合物包括用于直肠内给药的栓剂和阴道给药的阴道栓剂,其各自包含一种或多种活性物质,且通过本身已知的方法制备
实施例
下文中,虽然本发明通过实施例和制剂例详细说明,但是本发明不限于此。在下述实施例中,可以在不偏离本发明的范围内改变多种条件。下述实施例的多种操作使用基于基础生物技术的常规方法。
实施例1:检测EP1拮抗剂活性
将表达小鼠EP1受体的细胞以104细胞/孔接种到96-孔板中,并用10%胎牛血清(FBS)/α改进的Eagle培养基(αMEM)在孵育箱中(37℃,5%CO2)培养2天。细胞用磷酸盐缓冲液洗涤,然后将负载缓冲液(load buffer)(含Fura2/AM(5μM)、吲哚美辛(20μM)和丙磺舒(2.5mM)的10%FBS/αMEM)加入到每孔中,并培养细胞1小时。弃去每孔的负载缓冲液,并将测定缓冲液(含吲哚美辛(2μM)、丙磺舒(2.5mM)、HEPES-NaOH(10mM)和1%牛血清白蛋白的Hank’s平衡盐溶液(HBSS))加入到每孔中,且将板在暗室中室温放置1小时。之后,将用测定缓冲液配制的本发明化合物(10μL)或PGE2(10μL)加入到每孔中,并使用药物荧光筛选系统(FDSS-4000,Hamamatsu Photonics K.K.)检测细胞内钙浓度。在暴露于交替的2个激发波长的细胞中监测在500nm处荧光强度比例的改变,作为细胞内钙浓度的变化。
根据PGE2(100nM)诱导的细胞内钙浓度上升的抑制率计算IC50值,并将其用作EP1拮抗活性的指标。结果示于下表1中。
表1
化合物 | IC50(μM) |
化合物A | 0.0069 |
化合物B | 0.0093 |
化合物C | 0.0078 |
化合物D | 0.0072 |
化合物E | 0.021 |
化合物F | 0.0041 |
化合物G | 0.025 |
化合物H | 0.0073 |
化合物I | 0.0092 |
化合物J | 0.0049 |
化合物K | 0.0037 |
化合物L | 0.0071 |
实施例2:在膀胱内输注三磷酸腺苷(下文缩写为ATP)导致的排尿障碍动物模型中评估
给药盐酸氯胺酮麻醉剂(15-20mg/kg)后,将雄性短尾猴(11岁,3只雄性(图1和图2中的符号″○″表示一个个体))固定到立体定位手术台上。膀胱导管的顶端通过三通旋塞(three-way stopcock)与压力传感器相连,且使用压力用放大器和记录仪记录膀胱内压力。三通旋塞的另一端与膀胱内输注用的注射器相连,该注射器与输注泵相连,一端与装满生理盐水的延长管相连,以从膀胱排出残尿。
将生理盐水以输注速率1.5至7.0mL/分钟输注到膀胱内,且排尿完成后立即终止膀胱内灌流,且去除残尿(下文中假定上述过程为单次膀胱测压(シングルシストメトリ一)),并重复该过程。通过生理盐水重复单次膀胱测压2次或更多次后,重复使用ATP溶液(0.01至1.0mmol/L)进行单次膀胱测压2次或更多次。且皮下给药化合物A(0.1mg/1mL/kg)后,使用ATP溶液进行单次膀胱测压。ATP灌流前、ATP灌流后和给药化合物A后进行的ATP灌流后,对于每个单次膀胱测压计算尿流速率(单位排尿时间的排尿量(mL/秒))和残尿比率(每排尿量的残尿量的比例(%))。结果示于图1和图2中。
化合物A恢复了由ATP灌流降低的尿流速率,并降低了残尿比率。
制剂例1:
使用常规方法混合3-甲基-4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸(5.0g),羧基甲基纤维素钙(20g),硬脂酸镁(10g)和微晶纤维素(920g),并打片得到10,000片,每片含0.5mg活性成分。
制剂例2:
使用常规方法混合3-甲基-4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸(2.0g),甘露醇(500g)和蒸馏水(10L),且溶液以常规方法灭菌,然后填充到小瓶中,每瓶含1ml,并以常规方法冻干得到10,000个小瓶,每瓶含0.2mg活性成分。
工业应用
本发明的EP1拮抗剂有效用于预防、治疗和/或症状改善排尿障碍(如,尿势弱,尿线分叉,尿线间断,排尿延迟,腹压排尿,尿末滴沥)。
附图简述
图1表示ATP灌流前(基线),ATP灌流后(ATP)和给药化合物A后进行的ATP灌流后(化合物A)的尿流速率(mL/秒)。
图2表示ATP灌流前(基线),ATP灌流后(ATP)和给药化合物A后进行的ATP灌流后(化合物A)的残尿比率(%)。
Claims (3)
1.3-甲基-4-[6-[N-异丁基-N-(2-噻唑基磺酰基)氨基]茚满-5-基氧基甲基]苯甲酸或其盐在制备用于预防、治疗排尿障碍和/或改善排尿障碍症状的药物中的用途。
2.根据权利要求1的用途,其中所述排尿障碍的症状为尿势弱、尿线分叉、尿线间断、排尿延迟、腹压排尿和/或尿末滴沥。
3.根据权利要求1的用途,其中所述药物增加尿流速率和/或降低残尿比率。
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PCT/JP2008/052486 WO2008099907A1 (ja) | 2007-02-16 | 2008-02-15 | 尿排出障害治療剤 |
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AU2008215431C1 (en) | 2013-10-17 |
KR101492552B1 (ko) | 2015-02-12 |
US9181187B2 (en) | 2015-11-10 |
IL200377A0 (en) | 2010-04-29 |
KR20090114433A (ko) | 2009-11-03 |
US20100076038A1 (en) | 2010-03-25 |
RU2452479C2 (ru) | 2012-06-10 |
JP5439817B2 (ja) | 2014-03-12 |
WO2008099907A1 (ja) | 2008-08-21 |
RU2009134485A (ru) | 2011-03-27 |
AU2008215431B2 (en) | 2012-09-06 |
IL200377A (en) | 2016-04-21 |
ZA200905681B (en) | 2010-04-28 |
AU2008215431A1 (en) | 2008-08-21 |
EP2123273A1 (en) | 2009-11-25 |
EP2123273A4 (en) | 2010-09-15 |
MX2009008606A (es) | 2009-09-16 |
JPWO2008099907A1 (ja) | 2010-05-27 |
ES2437323T3 (es) | 2014-01-10 |
CN101663034A (zh) | 2010-03-03 |
NZ578988A (en) | 2012-03-30 |
CA2677769A1 (en) | 2008-08-21 |
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