CN1429108A - 磷酸盐运输抑制剂 - Google Patents
磷酸盐运输抑制剂 Download PDFInfo
- Publication number
- CN1429108A CN1429108A CN01809376A CN01809376A CN1429108A CN 1429108 A CN1429108 A CN 1429108A CN 01809376 A CN01809376 A CN 01809376A CN 01809376 A CN01809376 A CN 01809376A CN 1429108 A CN1429108 A CN 1429108A
- Authority
- CN
- China
- Prior art keywords
- benzoylamide
- bromophenyl
- sulfonamido
- amino
- bromo
- 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.)
- Pending
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims description 24
- 229910019142 PO4 Inorganic materials 0.000 title claims description 21
- 239000010452 phosphate Substances 0.000 title claims description 21
- 239000003112 inhibitor Substances 0.000 title description 7
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 28
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims abstract description 24
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 34
- -1 phenylazo, amino Chemical group 0.000 claims description 24
- 210000003734 kidney Anatomy 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 16
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 208000037157 Azotemia Diseases 0.000 claims description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002521 alkyl halide group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
- 125000005605 benzo group Chemical group 0.000 claims description 8
- 229930192474 thiophene Natural products 0.000 claims description 8
- 208000009852 uremia Diseases 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 6
- NRKRPXPIMUPXSO-UHFFFAOYSA-N 5-bromo-n-(4-bromophenyl)-2-(3-chloropropylsulfonylamino)benzamide Chemical compound ClCCCS(=O)(=O)NC1=CC=C(Br)C=C1C(=O)NC1=CC=C(Br)C=C1 NRKRPXPIMUPXSO-UHFFFAOYSA-N 0.000 claims description 5
- HCAWIDZCTIWCMU-UHFFFAOYSA-N 5-bromo-n-(4-bromophenyl)-2-[(2-fluorophenyl)sulfonylamino]benzamide Chemical compound FC1=CC=CC=C1S(=O)(=O)NC1=CC=C(Br)C=C1C(=O)NC1=CC=C(Br)C=C1 HCAWIDZCTIWCMU-UHFFFAOYSA-N 0.000 claims description 5
- WSOZAXMUCIEOOV-UHFFFAOYSA-N 5-bromo-n-(4-bromophenyl)-2-[(5-chlorothiophen-2-yl)sulfonylamino]benzamide Chemical compound S1C(Cl)=CC=C1S(=O)(=O)NC1=CC=C(Br)C=C1C(=O)NC1=CC=C(Br)C=C1 WSOZAXMUCIEOOV-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 230000032258 transport Effects 0.000 claims description 5
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 4
- DCHWSWIUQLKUPM-UHFFFAOYSA-N 5-bromo-n-(4-bromophenyl)-2-[(3-chloro-2-fluorophenyl)sulfonylamino]benzamide Chemical compound FC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CC=C(Br)C=C1C(=O)NC1=CC=C(Br)C=C1 DCHWSWIUQLKUPM-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 4
- 125000005239 aroylamino group Chemical group 0.000 claims description 4
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 4
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 4
- 125000001769 aryl amino group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 150000004867 thiadiazoles Chemical class 0.000 claims description 4
- IRADZDAOMPBHHH-UHFFFAOYSA-N 2-(benzenesulfonamido)-n-(4-bromophenyl)benzamide Chemical compound C1=CC(Br)=CC=C1NC(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CC=C1 IRADZDAOMPBHHH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- IEDKKYDVXYWGHP-UHFFFAOYSA-N n-(4-bromophenyl)-2-(thiophen-2-ylsulfonylamino)benzamide Chemical compound C1=CC(Br)=CC=C1NC(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=CS1 IEDKKYDVXYWGHP-UHFFFAOYSA-N 0.000 claims description 3
- XSTBCXIZGXSRFC-UHFFFAOYSA-N n-(4-bromophenyl)-5-chloro-2-[(3-chloro-2-fluorophenyl)sulfonylamino]benzamide Chemical compound FC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1C(=O)NC1=CC=C(Br)C=C1 XSTBCXIZGXSRFC-UHFFFAOYSA-N 0.000 claims description 3
- ASCOCYHAPWYEIP-UHFFFAOYSA-N n-(4-butoxyphenyl)-2-[(3,4-difluorophenyl)sulfonylamino]benzamide Chemical compound C1=CC(OCCCC)=CC=C1NC(=O)C1=CC=CC=C1NS(=O)(=O)C1=CC=C(F)C(F)=C1 ASCOCYHAPWYEIP-UHFFFAOYSA-N 0.000 claims description 3
- XLJBFJLPDVBNJY-UHFFFAOYSA-N n-(4-chlorophenyl)-2-[(2-fluorophenyl)sulfonylamino]benzamide Chemical compound FC1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NC1=CC=C(Cl)C=C1 XLJBFJLPDVBNJY-UHFFFAOYSA-N 0.000 claims description 3
- QWYVEPXXCBVMKY-UHFFFAOYSA-N n-(4-chlorophenyl)-2-[(3,4-difluorophenyl)sulfonylamino]benzamide Chemical compound C1=C(F)C(F)=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NC1=CC=C(Cl)C=C1 QWYVEPXXCBVMKY-UHFFFAOYSA-N 0.000 claims description 3
- GKBOHTHLKUBUOW-UHFFFAOYSA-N n-(4-chlorophenyl)-2-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonylamino]benzamide Chemical compound CC1=NOC(C)=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NC1=CC=C(Cl)C=C1 GKBOHTHLKUBUOW-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本发明公开了用于治疗慢性肾衰竭和尿毒症性骨疾病的N-芳基-2-磺酰氨基苯甲酰胺。
Description
发明领域
本发明涉及通过某些N-芳基-2-磺酰氨基苯甲酰胺抑制磷酸盐潴留来治疗慢性肾衰、尿毒症性骨疾病、以及相关疾病。
发明背景
当肾脏受到损害时,包括恢复体内平衡在内的适应机制可导致另外的损伤和无法遏制地不断发展成晚期肾病(ESRD)(Hostetter等,《美国生理学杂志》(Am.J.Physiol.)241:F85-F93(1981))。美国有270,000以上的患者患有ESRD。虽然使用透析和肾移植戏剧性地提高了ESRD患者的存活率,但在这些患者中出现了使其长期性治疗复杂化的许多问题。ESRD患者发病的早期和主要的原因是因肾的分泌功能的不断丧失而导致的无机物和骨代谢异常。在其它因素中,已明确磷酸盐(Pi)潴留在肾衰竭和继发性甲状旁腺机能亢进(HPTH)和尿毒症性骨疾病的发展中起主要作用。
在慢性肾衰竭(CRF)的发展中关于Pi潴留作用的证据主要来自对实验动物的研究。Ibels等,《新英格兰医学杂志》(N.Engl.J.Med.)298:122-126,(1978),首先在CRF的大鼠模型中证实了:限制饮食Pi阻止了肾功能的衰退,这可通过血清肌酸酐水平的稳定和提高、蛋白尿减少、组织的改进和死亡率降低来进行评定。在肾中毒性血清肾炎的大鼠模型中出现类似情况(KaR1insky等,Kidney Int.17:293-302(1980))。然而,这些研究存在的问题在于:低Pi饮食与减少食物摄入相关,因而自身的蛋白质摄入可减缓CRF的发展。因此,Lumlertgul等,Kidney Int.29:658-666,(1986)对5/6肾切除大鼠给予正常Pi饮食而有一组给予Pi粘合剂。所有大鼠都是成对喂养、给予相似的热量、蛋白质、碳水化合物、维生素和矿物质。在第6和12周时,与不接受Pi粘合剂的大鼠相比,摄入Pi粘合剂的大鼠出现低蛋白质分泌、低血清肌酸水平、低肾钙含量和组织瘢痕形成较少。这一研究明确表明了:在实验动物中,限制饮食Pi可对依赖于热量和蛋白质摄入的CRF发展产生有益作用。
除了上述的限制饮食Pi可对CRF的发展产生有益作用外,还发现:饮食Pi过量可加速CRF的发展。对CRF大鼠模型的许多研究(K1einknecht等,Kidney Int.5:534-541,(1979);Haut等,Kidney Int.17:722-731,(1980);Gimenez等,Kidney Int.22:36-41,(1982))已表明,高Pi饮食可导致肾功能更快速衰退,这可通过血清肌酸酐水平和组织损伤的程度来进行评定。
一些证据还提示限制Pi饮食可减缓患者的CRF进展。Maschio et等,Kidney Int.,22:371-376,(1982)和Maschio等,Kidney Int.,24:S 273-S 277,(1983)对轻度或中度肾功能不全患者限制蛋白质和Pi的饮食达76个月。他们发现:饮食限制组的肾功能的下降速度比对照组慢,尤其是轻度CRF患者。Barsotti等,Kidney Int.24:S278-S284,(1983)和Barsotti等,Clin.Nephrol.21:54-59,(1984)对CRF患者给予低蛋白质饮食或低蛋白质-低Pi饮食,发现施行饮食限制后两组中的肾功能的下降速度减慢了。重要的是,他们还观察到:与仅仅接受低蛋白质饮食相比,给予低蛋白质-低Pi饮食的患者的下降速度较慢。在对给予低Pi饮食的4个孩子的一项研究中,与正常饮食的相似期间相比,给予限制饮食的6个月中血清肌酸酐水平降低了一半(McCrory等,J.Pediatr.111:410-412,(1987)。而且,与对照组相比,给予低Pi饮食的这些孩子的生长速度显著加快。其它有关人的研究(Barrientos等,《电解质代谢》(Electrolyte Metab.)7:127-133,(1982);Ciadrella等,Nephron 42:196-199,(1986);Gin等,《代谢》(Metabolism)36:1080-1085,(1987)),主要是短期的研究,没有发现Pi限制对CRF的过程有影响。然而,上述大量动物研究以及对适当防治的少数人的研究表明:Pi的饮食性限制在减缓CRF进程中是有益的,尤其在轻度或中度肾功能不全的患者中是如此。
关于Pi过量导致肾衰竭速度加快的机制,现在尚不清楚。但是,大多数证据支持Pi与细胞的Ca2+聚集之间的相互作用。在正在衰竭的肾脏中,继发于甲状旁腺激素(PTH)水平升高的过滤Pi负荷量增加和Pi再吸收降低将导致小管液体Pi浓度增加。这引起经上皮的Ca2+流量增加和Ca2+诱导细胞损伤的细胞Ca2+水平升高(BoR1e等,《内分泌学》(Endocrinology)102:1725-1732,(1978))。或者,磷酸钙沉淀可出现肾钙化和肾钙质沉着(Lau,K.,KidneyInt.36:918-937,(1989))。
最后,Shapiro等,《美国生理学杂志》258:F183-F188,(1990)提出:大鼠中通常与CRF的5/6肾切除模型相关的肾代谢亢进可引起这些模型中的CRF进一步发展。因此,限制饮食Pi减少了50%肾耗氧量并降低了细胞内的Pi浓度而不会改变ATP的稳态浓度,这可通过该模型中的31P-NMR来评定。
慢性肾衰竭(CRF)仅在美国就有270,000以上患者、每年的保健费用估计达$60.8亿。CRF患者发病的早期和主要的原因是肾的分泌功能的进行性减弱而导致的电解质和骨代谢异常。已证实磷酸盐(Pi)潴留在CRF的发展和尿毒症性骨疾病的发展中起主要作用。
文献研究已显示:在动物模型和少数患者研究中,限制饮食Pi可减缓CRF的发展;降低CRF动物模型和患者中的血浆高PTH水平;和提高1,25(OH)2维生素D的循环水平和肠Ca2+吸收。
因此,我们认为抑制肠和肾的Pi运输有益于减缓CRF和尿毒症性骨疾病的发展。
所以,为治疗哺乳动物的肾疾病和尿毒症性骨疾病,除限制磷酸盐饮食外,需要寻找另一种减少哺乳动物的磷酸盐潴留的方法。
发明概述
本发明涉及在治疗慢性肾衰和尿毒症性骨疾病中用N-芳基-2-磺酰氨基苯甲酰胺作为选择性抑制肾和/或肠中Pi运输的磷酸盐运输抑制剂的新方法。
发明的详细描述
本发明涉及磷酸盐运输抑制剂用于治疗慢性肾衰和尿毒症性骨疾病、以及其它相关疾病例如血磷酸盐过多、维生素D代谢、和由磷酸盐潴留引起的继发性甲状旁腺机能亢进的应用。优选,本文所用的抑制剂是选择性抑制那些来自包括人在内的许多种组织(尤其是肾和肠组织)中的Na+-依赖性Pi运输的抑制剂。
R1和R2各自选自:氢、烷基、链烯基、芳烷基、酰基、芳酰基、卤烷基、芳基、杂芳基、卤素、羧基、羧烷氧基、氨基甲酰基、烷基氨基甲酰基、芳基氨基甲酰基、氰基、烷氧基、羟基、苯偶氮基、氨基、硝基、烷基氨基、芳基氨基、芳烷基氨基、酰氨基、芳酰基氨基、烷硫基、芳烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、芳烷基亚磺酰基、烷基磺酰基、芳基磺酰基、芳烷基磺酰基、氨磺酰基、芳基磺酰氨基、和烷基磺酰氨基;
或R1和/或R2部分代表与其取代的环形成的苯并噻吩、萘、喹啉、或异喹啉的稠合单元;
或(R1)n和/或(R2)m和其取代的环代表选自以下的杂环:噻吩、呋喃、吡啶、嘧啶、和吡嗪、以及其苯并类似物;和
R3独自选自烷基、卤烷基、R1芳基和R1芳烷基、以及R1取代的杂环,该杂环选自噻吩、呋喃、吡啶、嘧啶、吡嗪、咪唑、异噁唑、噻二唑、噁二唑、和噻唑、以及其苯并类似物。
本文中,“烷基”是指通过C-C单键连接在一起的可被取代或不被取代的烃基。优选的烷基取代基如全文所述。烷烃可以是直链、支链或环状、饱和或不饱和的。
本文中,“芳基”是指其中至少一个环具有共轭的π电子体系的可被取代或不取代的芳族基团、包含两个共轭的或稠合的环体系。“芳基”包括碳环芳基、杂环芳基和联芳基,它们都可被取代或不被取代。优选的芳基取代基如全文所述。
本发明的化合物可包含一个或多个不对称碳原子、并且可以外消旋形式或活性或非活性形式存在。预计所有这些化合物和非对映体都包含在本
发明的范围之内。
优选的化合物包括,但不限于:
N-苯基-2-(3-三氟甲基苯磺酰氨基)苯甲酰胺;
5-甲氧基-N-(3-三氟甲基苯基)-2-(4-氯苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(4-甲氧苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-5-氯-2-(3-氯-2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氯苯基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(2-噻吩基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(2-甲氧羰基-3-噻吩基磺酰氨基)苯甲酰胺;
N-(3,4-二氯苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-氯苯基)-2-(3,4-二氯苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氟苯基磺酰氨基)苯甲酰胺;
N-(4-丁氧基苯基)-2-(3,4-二氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,5-二甲基异噁唑-4-磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(2,1,3-苯并噻二唑-4-磺酰基氨基)-苯甲酰胺;
N-(3-三氟甲氧苯基)-2-(5-溴-噻吩-2-磺酰基氨基)-苯甲酰胺;
N-(4-溴苯基)-2-(苯基磺酰氨基)苯甲酰胺和
5-甲氧基-N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺。
当存在碱性基时、所用药学上可接受的盐包括酸加成盐,例如含硫酸盐、盐酸盐、富马酸盐、马来酸盐、磷酸盐、氨基磺酸盐、醋酸盐、柠檬酸盐、乳酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎尼酸盐的那些盐。药学上可接受的盐可从这些酸中得到,例如:盐酸、马来酸、硫酸、磷酸、氨基磺酸、醋酸、柠檬酸、乳酸、酒石酸、丙二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己基氨基磺酸、富马酸、和奎尼酸。
药学上可接受的盐也包括碱加成盐,例如当酸性功能基团如羧酸或石炭酸存在时包括苯乍生、氯普鲁卡因、胆碱、二乙醇胺、1,2-乙二胺、葡甲胺、普鲁卡因、铝、钙、锂、镁、钾、钠、铵、烷基胺、和锌的那些盐。
本发明提供上述式(I)化合物,它可采用标准的工艺进行制备。这里所述的优选化合物的所有制备方法均可以按本节所述的方案进行实施。用本文所述的方案作为一个模板,本领域任何一个普通技术人员可很容易制造本发明的其它化合物。
对任意化学官能度进行适当的处理和保护,采用与上述类似的方法和与实验部分所描述的类似方法来合成其它的式(I)化合物。
反应方案1
为了用式(I)化合物或其药学上可接受的盐治疗人和其它哺乳动物,通常是根据标准制药工艺配制成药物组合物。
本发明化合物可通过不同的途径给药,包括静脉内的、腹膜内的、皮下的、肌内的、口服的、局部的(经皮的)、或经粘膜的给药。对于系统给药,优选口服。对于口服给药,例如,将化合物配制成常规的口服剂型,如胶囊、片剂、和液体制剂如糖浆剂、酏剂、和浓缩液滴。
或者,可使用注射剂(非肠道给药),例如,肌内、静脉内、腹膜内、和皮下给药。为了注射,在液体溶液中配制本发明的化合物,优选在生理学上相容的缓冲液或溶液如盐水溶液、Hank’s溶液、或Ringer’s溶液中。另外,可将化合物配制成固体形式、使用前立即再溶解或悬浮。也可制备冻干形式。
系统给药也可通过经粘膜或经皮的方式进行。对于经粘膜或经皮给药,在制剂中使用适于渗透屏障的渗透剂。这类渗透剂通常是本领域已知的,包括,例如经粘膜给药的胆汁盐和羧链孢酸衍生物。另外,洗涤剂可用于促进渗透。经粘膜给药,例如可通过鼻喷雾、肛门栓或阴道栓。
对于局部给药,可将本发明化合物配制成软膏、油膏、凝胶、或乳膏,这些通常是本领域已知的。
各种化合物的服用量可根据标准程序来确定,考虑的因素例如有:化合物IC50、EC50、化合物的生物半衰期、患者的年龄、块头和体重、以及所患的相关疾病或失调。对于本领域普通技术人员来说,所考虑的这些和其它因素的重要性是公知的。
给药量也有赖于给药途径和口服生物可利用度。例如,对于口服生物可利用率低的化合物,必须给予相对较高的剂量。
优选该组合物为单位剂量形式。对于口服药,例如可服用片剂、或胶囊;对于鼻用药,可用计量式气雾剂剂型;对于经皮施用的药,可用局部制剂或贴剂;对于经粘膜传输的药,可用口腔贴剂。在每一情况中,给药剂量要使患者可单次使用的量。
用于口服给药的每剂量单位,适宜的是以游离碱计算含0.01-500mg/Kg式(I)化合物或其药学上可接受的盐,优选0.1-50mg/Kg。用于非肠道、鼻内、口吸入、经粘膜或经皮的途径给药的每日剂量以含0.01-100mg/Kg式(I)化合物为宜。局部制剂以含0.01-5.0%式(I)化合物为宜。每天服用活性成分1-6次,优选一次,足以产生所需的活性即可,这对于本领域技术人员来说显然是易于做到的。
本文中,对疾病的“治疗”包括,但不限于对疾病的抑制、减缓和预防。
当式(I)化合物及其药学上可接受的盐的活性组合物口服给药时、可将其配制成糖浆剂、片剂、胶囊剂和锭剂。糖浆制剂通常由液体载体如乙醇、花生油、橄榄油、甘油或水中的化合物或盐的悬浮液或溶液与调味剂或着色剂组成。若组合物为片剂形式,可以使用常规用于制备固体制剂的任何药学上的载体。这些载体的例子包括硬脂酸镁、白陶土、滑石、明胶、阿拉伯胶、硬脂酸、淀粉、乳糖和蔗糖。若组合物为胶囊形式,任何常规的包胶都适宜,例如,使用包在硬的明胶胶囊壳中的前述载体。若组合物是软明胶壳胶囊的形式,任何常规用于制备分散体或悬浮液的药学载体,例如,含水树胶、纤维素、硅酸盐、或油,都可考虑用于软明胶胶囊壳中。
典型的非肠道组合物包括无菌的含水或非水载体中的化合物或盐的溶液或悬浮液,其中的载体可含或不含非肠道给药可接受的油,例如聚乙二醇、聚乙烯吡咯烷酮、卵磷脂、花生油或芝麻油。
典型的吸入用的组合物为溶液、悬浮液或乳液形式,使用常规的推进剂例如二氯二氟甲烷或三氯氟甲烷,它们可以以干粉剂或以气雾剂形式给药。
典型的栓剂包括当这样给药时具有活性的式(I)化合物或其药学上可接受的盐、以及粘合剂和/或润滑剂,例如聚乙二醇、明胶、可可脂或其他的低熔化植物蜡或脂肪或它们的合成类似物。
典型的皮肤制剂和经皮制剂包括常规的含水的或非水赋形剂,例如乳膏、软膏、洗剂或糊剂是含药物的硬膏剂、贴剂或膜剂形式。
优选本组合物为单位剂量形式,例如片剂、胶囊或计量式气雾剂剂型,以便患者可使用单次剂量。
当根据本发明的方式服用本发明化合物时,不会出现无法接受的毒性作用。
根据所试验的化合物通过近侧小管细胞抑制放射性标记的无机磷酸盐的摄取能力来确定其对钠依赖性磷酸盐运输的抑制作用。可以使用合适的人、兔、或鼠的细胞。
细胞制备和磷酸盐摄取测定
根据在此引用的公开出版物,Sakhrani,L.M.等,《美国生理学杂志》(Am.J.Physiol.)246:F757-F764,(1984)的方法分离和培养兔的近侧小管细胞。从Clonetics(San Diego,CA)购得人的近侧小管细胞并根据供应商的说明进行生长。在实验的当天,用磷酸盐缓冲盐水中的0.5mM EDTA收集细胞。在吸收的缓冲液(见下文)中洗涤该细胞两次并在同样的缓冲液中于37℃平衡30分钟。将等份细胞(100μl,0.5-1百万细胞)分布在玻璃试验管中。加入50μl药物溶液或缓冲液、然后加入50μl含100μM[32P]-K2HPO4(0.5-1μCi/管)的摄取缓冲液。在37℃改变时间(通常为4分钟)后,用4ml冷的终止溶液(见下文)终止摄取,并在此溶液中离心洗涤该细胞3次。将丸状细胞溶解在0.5ml 1N NaOH中、并用液体闪烁计数器计数32P。将磷酸盐摄取表示为pmol磷酸盐/mg细胞蛋白质。
终止溶液 摄取缓冲液pH7.4
甘露糖醇100mM NaCl 143mM
NaCl 100mM Hepes 15mM
砷酸钠10mM KCl 5.4mM
Hepes 5mM MgCl2 0.8mM
CaCl2 1.8mM
葡萄糖0.1%
在上述全部用于兔和人的近侧小管细胞的细胞测定系统中,通过过滤收获细胞并测定32p摄取。也可以用33P而不用32P。使用人的近侧小管细胞,5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩磺酰氨基)苯甲酰胺、5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺、和5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰氨基)苯甲酰胺的IC50分别为12、15和14μM。
下列实施例可用于举例说明本发明的化合物和药物组合物的制备。这些实施例并不是为了要限定本申请所述的和所要求保护的本发明的范围。
实施例1
N-(4-溴苯基)-2-氨基-5-溴苯甲酰胺
将2.0M三甲基铝(23.2mmol)溶液的11.6ml部分在0℃下加入4.0g(23.25mmol)4-溴苯胺溶液中。将该反应混合物在室温下保持45分钟,然后冷却至0℃。加入少量2-氨基-5-溴苯甲酸甲酯(4.72g,23.25mmol),剧烈的气体释放停止后,将反应混合物在室温下保持18小时。然后将反应混合物倒入250ml 10%HCl中(还出现气体释放),通过过滤收集所形成的固体。依次用水和甲苯洗涤该固体、然后在室温下干燥。使用一滴甲酸的硅胶薄层色谱,CHCl3∶MeOH 9∶1,Rf 0.80-0.90,NMR与真实样品相同。这是一种通常方法,采用了很多芳族和杂芳族邻氨基苯甲酸以及苯胺类似物。
将12.1g(50mmol)5-溴靛红酸酐、9.4g(55mmol)4-溴苯胺、和0.2g(5mmol)NaOH的150ml二噁烷溶液回流18小时。过滤冷却的反应混合物并在真空下浓缩。加入95%EtOH使残余物结晶。通过过滤收集该固体并用乙醇洗涤。通过薄层色谱(硅胶,己烷中的15%EtOAc)纯化该样品得到预期的NMR、MS、和元素分析。
起始于5-氯靛红酸酐和4-b溴苯胺的类似方法生成N-(4-溴苯基)-2-氨基-5-氯苯甲酰胺,得到预期的NMR、MS、和元素分析。
实施例2
5-溴-N-(4-溴苯基)-2-(4-氯苯基磺酰基氨基)苯甲酰胺
将N-(4-溴苯基)-2-氨基-5-溴苯甲酰胺(8.64g,23.3mmol)、4-氯代苯磺酰氯(4.98g,23.6mmol)、和7.37g(93.2mmol)吡啶的300ml CH2C12溶液在室温下保持2天。在真空下浓缩该反应混合物并将残余物溶解在EtOAc中。用10%HCl、水、5%NaHCO3、水洗涤该溶液两次、再经MgSO4干燥。从己烷的10%EtOAc中浓缩并再结晶得到具有令人满意的NMR、MS、和元素分析的产品。
实施例3
5-溴-N-(4-溴苯基)-2-(4-溴苯基磺酰基氨基)苯甲酰胺
将31.5mg(85μmol)N-(4-溴苯基)-2-氨基-5-溴苯甲酰胺、32.5mg(127.5μmol)4-溴代苯磺酰氯、和28μl(340μmol)吡啶的1ml CH2C12溶液搅拌18小时。然后加入84.5mg(382μmol)聚胺树脂HL(Nova Biochem,4.53mmol/g),搅拌该混合物18小时,通过过滤除去固体。在真空下浓缩并通过制备型HPLC(C18,20-95%乙腈的0.1%TFA水溶液)得到具有满意的HPLC-MS的产品。
采用与实施例2和3类似的方法,由5-溴-N-(4-溴苯基)-2-(4-氯苯基磺酰基氨基)苯甲酰胺与下列磺酰氯反应得到产品:3-氯苯基-、4-氯苯基-、3,4-二氯苯基-、3-氯-4-氟-、2-氟苯基-、2,5-二甲氧苯基-、3,4-二甲氧苯基-、4-正丁氧苯基-、2-三氟甲基苯基-、4-苯基偶氮苯基-、4-三氟甲基苯基-、3,5-二-三-氟甲基苯基-、2-甲基苯基-、2,4,6-三甲基苯基-、2-萘基-、甲烷-、三氟甲烷-、2-噻吩基、5-氯-2-噻吩基-、4-联苯基-、3-氯丙基-、4-氰苯基-、3,5-二氯苯基-、苯乙烯基-、2-甲氧羰基-3-噻吩基-、4-碘苯基-、2,6-二氯苯基-、4-叔丁基苯基-、和2,2,2-三氟乙基。这些产品的HPLC-MS分析结果令人满意。
本说明书中引用作为参考的所有公开文献(包括但不限于专利和专利申请在内),如同专门和单独指定每一篇全文引入本发明作为参考一样。
上面的说明完全公开了本发明,包括其优选的实施方式在内。对本申请中具体公开的实施方案的修饰和改进都落在权利要求书的范围内。虽然未做更详尽的阐述,但我们相信本领域技术人员利用前面的说明完全可实施本发明。因此,本发明的实施例仅仅是用于举例说明而不是在任何程度上限定本发明的范围。在权利要求书中限定了本申请要求独占权或特权的本发明具体实施方案。
Claims (9)
1.一种抑制钠依赖性磷酸盐运输的方法,包括给有此需要的受试者施用一种安全和有效量的式(I)化合物:其中:
R1和R2各自选自:氢、烷基、链烯基、芳烷基、酰基、芳酰基、卤烷基、卤素、羧基、羧烷氧基、氨基甲酰基、烷基氨基甲酰基、芳基氨基甲酰基、氰基、烷氧基、羟基、苯偶氮基、氨基、硝基、烷基氨基、芳基氨基、芳烷基氨基、酰基氨基、芳酰基氨基、烷硫基、芳烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、芳烷基亚磺酰基、烷基磺酰基、芳基磺酰基、芳烷基磺酰基、氨磺酰基、芳基磺酰氨基、和烷基磺酰氨基;
或R1部分代表与其取代的环形成的苯并噻吩、萘、喹啉、或异喹啉的稠环;
或(R1)n和其取代的环代表选自以下的杂环:噻吩、呋喃、吡啶、嘧啶、和吡嗪、以及其苯并类似物;和
R3独自选自烷基、卤烷基、R1芳基和R1芳烷基、R1苯并芳基和R1苯并芳烷基、以及R1取代的杂环,该杂环选自噻吩、呋喃、吡啶、嘧啶、吡嗪、咪唑、异噁唑、噻二唑、噁二唑、和噻唑、以及其苯并类似物。
2.根据权利要求1的方法,其中化合物选自:
N-苯基-2-(3-三氟甲基苯磺酰氨基)苯甲酰胺;
5-甲氧基-N-(3-三氟甲基苯基)-2-(4-氯苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(4-甲氧苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-5-氯-2-(3-氯-2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氯苯基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(2-噻吩基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(2-甲氧羰基-3-噻吩基磺酰氨基)苯甲酰胺;
N-(3,4-二氯苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-氯苯基)-2-(3,4-二氯苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氟苯基磺酰氨基)苯甲酰胺;
N-(4-丁氧基苯基)-2-(3,4-二氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,5-二甲基异噁唑-4-磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(2,1,3-苯并噻二唑-4-磺酰基氨基)-苯甲酰胺;
N-(3-三氟甲氧苯基)-2-(5-溴-噻吩-2-磺酰基氨基)-苯甲酰胺;
N-(4-溴苯基)-2-(苯基磺酰氨基)苯甲酰胺和
5-甲氧基-N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺。
3.一种引起磷酸盐分泌和/或抑制磷酸盐吸收的方法,包括给有此需要的受试者施用一种安全和有效量的式(I)化合物:其中:
R1和R2各自选自:氢、烷基、链烯基、芳烷基、酰基、芳酰基、卤烷基、卤素、羧基、羧烷氧基、氨基甲酰基、烷基氨基甲酰基、芳基氨基甲酰基、氰基、烷氧基、羟基、苯偶氮基、氨基、硝基、烷基氨基、芳基氨基、芳烷基氨基、酰基氨基、芳酰基氨基、烷硫基、芳烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、芳烷基亚磺酰基、烷基磺酰基、芳基磺酰基、芳烷基磺酰基、氨磺酰基、芳基磺酰氨基、和烷基磺酰氨基;
或R1部分代表与其取代的环形成的苯并噻吩、萘、喹啉、或异喹啉的稠环;
或(R1)n和其取代的环代表选自以下的杂环:噻吩、呋喃、吡啶、嘧啶、和吡嗪、以及其苯并类似物;和
R3独自选自烷基、卤烷基、R1芳基和R1芳烷基、以及R1取代的杂环,该杂环选自噻吩、呋喃、吡啶、嘧啶、吡嗪、咪唑、异噁唑、噻二唑、噁二唑、和噻唑、以及其苯并类似物。
4.一种药物组合物,包含权利要求1的化合物和药学上可接受的载体。
5.一种通过抑制有此需要的哺乳动物的磷酸盐运输系统而治疗慢性肾衰竭的方法,包括给需要治疗的患者施用一种安全和有效量的式(I)化合物:其中:
R1和R2各自选自:氢、烷基、链烯基、芳烷基、酰基、芳酰基、卤烷基、卤素、羧基、羧烷氧基、氨基甲酰基、烷基氨基甲酰基、芳基氨基甲酰基、氰基、烷氧基、羟基、苯偶氮基、氨基、硝基、烷基氨基、芳基氨基、芳烷基氨基、酰基氨基、芳酰基氨基、烷硫基、芳烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、芳烷基亚磺酰基、烷基磺酰基、芳基磺酰基、芳烷基磺酰基、氨磺酰基、芳基磺酰氨基、和烷基磺酰氨基;
或R1部分代表与其取代的环形成的苯并噻吩、萘、喹啉、或异喹啉的稠环;
或(R1)n和其取代的环代表选自以下的杂环:噻吩、呋喃、吡啶、嘧啶、和吡嗪、以及其苯并类似物;和
R3独自选自烷基、卤烷基、R1芳基和R1芳烷基、R1苯并芳基和R1苯并芳烷基、以及R1取代的杂环,该杂环选自噻吩、呋喃、吡啶、嘧啶、吡嗪、咪唑、异噁唑、噻二唑、噁二唑、和噻唑、以及其苯并类似物。
6.根据权利要求5的方法,其中治疗的是尿毒症性骨疾病。
7.根据权利要求5的方法,其中肾中的磷酸盐运输被抑制。
8.根据权利要求5的方法,其中肠中的磷酸盐运输被抑制。
9.一种药物组合物,包括选自以下的化合物:
5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-甲基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-噻吩基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-甲氧羰基-3-噻吩基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(4-氰基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(甲基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(4-甲氧基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(苯基磺酰氨基)苯甲酰胺和
5-溴-N-(4-溴苯基)-2-(4-溴苯基磺酰氨基)苯甲酰胺;
和药学上可接受的载体。
N-苯基-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺;
5-甲氧基-N-(3-三氟甲基苯基)-2-(4-氯苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(4-甲氧基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-5-氯-2-(3-氯-2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氯苯基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(2-噻吩基磺酰氨基)苯甲酰胺;
N-(4-溴苯基)-2-(2-甲氧羰基-3-噻吩基磺酰氨基)苯甲酰胺;
N-(3,4-二氯苯基)-2-(2-氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺;
5-溴-N-(4-氯苯基)-2-(3,4-二氯苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氟苯基磺酰氨基)苯甲酰胺;
N-(4-丁氧苯基)-2-(3,4-二氟苯基磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(3,5-二甲基异噁唑-4-磺酰氨基)苯甲酰胺;
N-(4-氯苯基)-2-(2,1,3-苯并噻二唑-4-磺酰基氨基)-苯甲酰胺;
N-(3-三氟甲氧基苯基)-2-(5-溴-噻吩-2-磺酰基氨基)-苯甲酰胺;
N-(4-溴苯基)-2-(苯基磺酰氨基)苯甲酰胺和
5-甲氧基-N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰氨基)苯甲酰胺。
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US60/203,995 | 2000-05-12 |
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CN (1) | CN1429108A (zh) |
AU (1) | AU2001261471A1 (zh) |
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CZ (1) | CZ20023701A3 (zh) |
HU (1) | HUP0302234A2 (zh) |
IL (1) | IL152587A0 (zh) |
MX (1) | MXPA02011160A (zh) |
NO (1) | NO20025399L (zh) |
PL (1) | PL359931A1 (zh) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103183623A (zh) * | 2013-03-12 | 2013-07-03 | 中国医学科学院医药生物技术研究所 | 一组苯磺酰胺基苯甲酰胺类衍生物及制备和应用 |
CN105392483A (zh) * | 2013-04-12 | 2016-03-09 | 阿德利克斯公司 | 用于抑制磷酸盐转运的nhe3结合化合物和方法 |
CN105395532A (zh) * | 2015-11-25 | 2016-03-16 | 中国医学科学院医药生物技术研究所 | 2-苯磺酰胺基苯甲酰胺类化合物在肝损伤保护和肝纤维化防治中的应用 |
Families Citing this family (11)
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GB2378179A (en) * | 2001-08-03 | 2003-02-05 | Pantherix Ltd | Aromatic sulfonamides and their use in treating bacterial diseases |
US7119120B2 (en) | 2001-12-26 | 2006-10-10 | Genzyme Corporation | Phosphate transport inhibitors |
WO2010078449A2 (en) | 2008-12-31 | 2010-07-08 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
WO2018129556A1 (en) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
CN104902930A (zh) | 2012-08-21 | 2015-09-09 | 阿德利克斯公司 | 在治疗与液体潴留或盐分过载相关的疾病和胃肠道疾病中用于抑制nhe-介导的反向转运的化合物和方法 |
US10376481B2 (en) | 2012-08-21 | 2019-08-13 | Ardelyx, Inc. | Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
US9765050B2 (en) | 2014-12-30 | 2017-09-19 | Novira Therapeutics, Inc. | Pyridyl reverse sulfonamides for HBV treatment |
JP6713051B2 (ja) * | 2016-08-30 | 2020-06-24 | 日本曹達株式会社 | スルホニルアミノベンズアミド化合物および有害生物防除剤 |
JP2020505333A (ja) | 2017-01-09 | 2020-02-20 | アルデリックス, インコーポレイテッド | Nhe媒介性アンチポートの阻害薬 |
CN110267944B (zh) | 2017-01-09 | 2024-03-08 | 阿德利克斯股份有限公司 | 可用于治疗胃肠道病症的化合物 |
WO2019232384A1 (en) | 2018-06-01 | 2019-12-05 | Promega Corporation | Inhibitors of oplophorus luciferase-derived bioluminescent complexes |
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KR20020022716A (ko) * | 1999-06-24 | 2002-03-27 | 스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스 | 마크로파지 스캐빈저 수용체 길항제 |
AR030911A1 (es) * | 1999-07-20 | 2003-09-03 | Smithkline Beecham Corp | Uso de n-aril-2-sulfonamidobenzamidas para la manufactura de un medicamento para el tratamiento de la insuficiencia renal cronica y composiciones farmaceuticas |
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2001
- 2001-05-11 MX MXPA02011160A patent/MXPA02011160A/es unknown
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- 2001-05-11 WO PCT/US2001/015324 patent/WO2001087294A1/en not_active Application Discontinuation
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- 2001-05-11 JP JP2001583762A patent/JP2003533477A/ja not_active Withdrawn
- 2001-05-11 CN CN01809376A patent/CN1429108A/zh active Pending
- 2001-05-11 AU AU2001261471A patent/AU2001261471A1/en not_active Abandoned
- 2001-05-11 KR KR1020027015094A patent/KR20020093983A/ko not_active Application Discontinuation
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- 2001-05-11 PL PL35993101A patent/PL359931A1/xx not_active Application Discontinuation
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103183623A (zh) * | 2013-03-12 | 2013-07-03 | 中国医学科学院医药生物技术研究所 | 一组苯磺酰胺基苯甲酰胺类衍生物及制备和应用 |
CN105392483A (zh) * | 2013-04-12 | 2016-03-09 | 阿德利克斯公司 | 用于抑制磷酸盐转运的nhe3结合化合物和方法 |
CN105392483B (zh) * | 2013-04-12 | 2019-03-15 | 阿德利克斯公司 | 用于抑制磷酸盐转运的nhe3结合化合物和方法 |
CN105395532A (zh) * | 2015-11-25 | 2016-03-16 | 中国医学科学院医药生物技术研究所 | 2-苯磺酰胺基苯甲酰胺类化合物在肝损伤保护和肝纤维化防治中的应用 |
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JP2003533477A (ja) | 2003-11-11 |
ZA200209106B (en) | 2003-10-23 |
IL152587A0 (en) | 2003-05-29 |
WO2001087294A1 (en) | 2001-11-22 |
MXPA02011160A (es) | 2003-03-10 |
AU2001261471A1 (en) | 2001-11-26 |
NO20025399D0 (no) | 2002-11-11 |
HUP0302234A2 (hu) | 2003-11-28 |
KR20020093983A (ko) | 2002-12-16 |
CZ20023701A3 (cs) | 2003-11-12 |
BR0110034A (pt) | 2003-05-27 |
CA2408667A1 (en) | 2001-11-22 |
PL359931A1 (en) | 2004-09-06 |
NO20025399L (no) | 2002-11-11 |
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