CN1361687A - 磷酸盐转移抑制剂 - Google Patents
磷酸盐转移抑制剂 Download PDFInfo
- Publication number
- CN1361687A CN1361687A CN00810644A CN00810644A CN1361687A CN 1361687 A CN1361687 A CN 1361687A CN 00810644 A CN00810644 A CN 00810644A CN 00810644 A CN00810644 A CN 00810644A CN 1361687 A CN1361687 A CN 1361687A
- Authority
- CN
- China
- Prior art keywords
- benzoylamide
- sulfoamido
- bromophenyl
- bromo
- alkyl
- 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
Links
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims description 22
- 229910019142 PO4 Inorganic materials 0.000 title claims description 20
- 239000010452 phosphate Substances 0.000 title claims description 20
- 239000003112 inhibitor Substances 0.000 title description 7
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 30
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims abstract description 26
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 79
- 150000001875 compounds Chemical class 0.000 claims description 36
- -1 phenylazo, amino Chemical group 0.000 claims description 27
- 210000003734 kidney Anatomy 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 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 group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 208000037157 Azotemia Diseases 0.000 claims description 9
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- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 8
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- 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
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- 239000011734 sodium Substances 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
- 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
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
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- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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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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- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
本发明公开了N-芳基-2-磺酰胺基苯甲酰胺,用以治疗慢性肾衰竭和尿毒症骨疾病。
Description
发明领域
本发明涉及通过用某种N-芳基-2-磺酰胺基苯甲酰胺抑制磷酸盐滞留来治疗慢性肾衰竭、尿毒症骨疾病及相关疾病。
发明背景
当肾受伤时,恢复内环境平衡的适应机制可以导致额外的伤害并无情地发展到肾疾病的末期(ESRD)(Hostetter et al,Am.J.Physiol.241:F85-F93(1981))。在美国,ESRD侵袭270000多病人。尽管利用透析和肾移植已显著地提高ESRD病人的生存率,但是在这些病人中仍存在大量的问题,这使得对他们的长期管理变得复杂了。影响ESRD病人发病率的早期和主要因素是由肾的排泄功能逐步丧失而引起的矿物质异常和骨代谢异常。在其它因素中,已确认磷酸盐(Pi)的滞留在肾衰竭的发展以及继发的甲状旁腺功能亢进(HPTH)和尿毒症骨疾病的产生中起主要作用。
关于Pi滞留在慢性肾衰竭(CRF)发展中作用的证据主要来自对实验动物的研究。Ibels et al,N.Engl.J.Med.298:122-126(1978)第一次在CFR大鼠模型中证实,限制饮食的Pi可防止肾功能恶化,其通过血清中肌酐水平的稳定性和增长来评价,降低蛋白尿,改善组织结构并降低死亡率。在肾中毒的血清肾炎的大鼠模型中获得了类似的发现(Karlinsky et al,Kidney Int.17:293-302(1980))。但是,这些研究受到了批评,因为低Pi饮食与降低食物摄取有关,从而通过本身降低的食物摄取而导致蛋白质摄取可以减轻CRF的发展。因此,Lumlertgul et al,Kidney Int.29:658-666(1986)给予5/6肾切除的大鼠以正常的Pi食物而给予一组以Pi胶合物。所有的大鼠均成对地喂食,并且具有相同的热量、蛋白质、碳水化合物、维生素和矿物质摄取量。在6周和12周时,摄取Pi胶合物的大鼠较未摄取Pi胶合物的大鼠表现出较低的蛋白质排泄、较低的肌酐水平、较低的肾钙含量和较少的组织瘢疤形成。该研究明确地证实,饮食Pi限制独立于实验动物的热量和蛋白质摄取量之外,对CRF的发展具有有益的作用。
除了上述的饮食Pi限制对CRF发展的有益作用之外,还发现饮食Pi过量可以加速CRF发展的证据。大量有关CRF大鼠模型的研究(Kleinknechtet al,Kidney Int.5:534-541(1979);Haut et al,Kidney Int.17:722-731(1980);Gimenez et al,Kidney Int.22:36-41(1982))表明,高Pi的饮食导致肾功能更迅速地恶化,通过血清肌酐的水平和组织损害的严重程度来评价。
一些证据还提出,饮食Pi限制可能会减缓患者的CRF发展。Maschio etal,Kidney Int.22:371-376(1982)和Maschio et al,Kidney Int.24:S273-S377(1983)使轻度或中度肾功能不全的病人食用蛋白质和Pi受到限制的食物76个月。他们发现,限定饮食组的肾功能下降速度低于对照组,特别是在轻度CRF患者中。Barsotti et al.,Kidney Int.24:S278-S284(1983)和Barsottiet al.,Clin.Nephrol 21:54-59(1984)使CRF患者食用低蛋白质饮食或低蛋白质-低Pi饮食并且发现,两组的肾功能下降速度在建立饮食限制制度之后降低了。重要的是,他们还观察到低蛋白质-低Pi饮食的患者中的下降速度比单独的低蛋白质饮食患者中的下降速度低。在4名低Pi饮食儿童的研究中,血清肌酐的水平在6个月的限制饮食期间较同样期间正常饮食的水平减半(McCrory et al,J.Pediatr.111:410-412(1987))。而且与对照期的儿童相比,这些低Pi饮食儿童的生长速度显著地增加了。其它人类研究(Barrientos et al,Electrolyte Metab.7:127-133(1982);Ciadrella er al,Nephron 42:196-199(1986);Gin et al,Metabolism 36:1080-1085(1987)),主要是短期研究,没有观察到Pi限制对CRF病程的作用。不过,通过上述的大量动物研究与不是很好控制的人类研究共同认为,饮食的Pi限制有助于延缓CRF,特别是轻度至中度的肾功能不全的发展。
Pi过量导致肾衰竭速度增加的机理还不清楚。但是,很多证据支持Pi与细胞Ca2+积聚之间的相互作用。在衰竭的肾中,于甲状旁腺激素(PTH)水平升高之后继发的Pi过滤载荷增加和Pi再吸收减少导致小管液Pi浓度增加。这导致透过上皮的Ca2+流量增加和细胞的Ca2+水平升高,产生Ca2+诱导的细胞伤害(Borle et al.,Endocrinology 102:1725-1732(1978))。此外,可能会发生钙-磷酸盐沉淀,导致肾钙化和肾钙质沉积(Lau,K.,Kidney Int.36:918-937(1989))。
最后,Shapiro et al.,Am.J.Physiol.258:F183-F188(1990)提出,通常与5/6肾切除的大鼠CRT模型有关的肾代谢亢进可能有助于该模型中CRF的发展。因而,限制饮食的Pi降低50%的肾氧消耗,并降低细胞内的Pi浓度,又不改变ATP浓度的稳定状态,这可通过该模型中的31P-NMR来评价。
仅在美国,慢性肾衰竭(CRF)就侵袭超过270000位病人,估计每年的医疗保健费开支达68亿美元。影响CRF病人发病率的早期和主要因素是由于肾排泄功能逐步丧失所导致的电解质和骨代谢异常。已经确认磷酸盐(Pi)滞留在CRF发展和尿毒症骨疾病发展中起主要作用。
文献研究表明,饮食的Pi限制减缓了动物模型和少量病人研究中的CRF发展;降低了CRF动物模型和病人中血浆PTH水平的升高;并增加了1,25(OH)2维生素D和肠的Ca2+吸收的循环水平。
这样,通过消化道和肾抑制Pi转移被认为是有助于减缓CRF和尿毒症骨疾病发展。所以,通过消化道和肾抑制Pi转移有助于减缓CRF和尿毒症骨疾病发展。
因此,除了磷酸盐的饮食限制之外,还需要寻求一种可供选择的降低哺乳动物内磷酸盐滞留的方法,以治疗肾疾病和尿毒症骨疾病。
发明概述
本发明涉及使用N-芳基-2-磺酰胺基苯甲酰胺作为磷酸盐转移抑制剂以选择性地抑制肾和/或肠内Pi转移的治疗慢性肾衰竭和尿毒症骨疾病的新方法。
发明详述
本发明涉及使用磷酸盐转移抑制剂来治疗慢性肾衰竭、尿毒症骨疾病及其它相关疾病,如磷酸盐滞留导致的高磷酸盐血症、维生素D新陈代谢和继发性甲状旁腺功能亢进。优选用于本发明的抑制剂是那些选择性地抑制很多物种包括人的组织、优选肾和肠组织中Na+依赖的Pi转移的抑制剂。
本发明涉及下面式(I)所代表的化合物作为钠依赖的磷酸盐转移抑制剂的用途:其中:R1和R2独立地选自氢,烷基,链烯基,芳烷基,酰基,芳酰基,卤代烷基,芳基,杂芳基,卤素,羧基,烷氧羰基,氨甲酰基,烷基氨甲酰基,芳基氨甲酰基,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,芳酰氨基,烷基硫基,芳烷基硫基,芳基硫基,烷基亚硫酰基,芳基亚硫酰基,芳烷基亚硫酰基,烷基硫酰基,芳基硫酰基,芳烷基硫酰基,氨磺酰,芳基磺酰胺基和烷基磺酰胺基;或者R1和/或R2部分代表与其取代的环形成苯并噻吩,萘,喹啉或异喹啉的稠合单元;或者(R1)n和/或(R2)m及其所取代的环代表选自噻吩,呋喃,吡啶,嘧啶和吡嗪,以及它们的苯并类似物中的杂环;及R3独立地选自烷基,卤代烷基,R1芳基与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,和噻唑,以及它们的苯并类似物。
本文所使用的“烷基”是指通过碳碳单键连接在一起的任选取代的烃基。优选的烷基取代基完全如所指出的那样。该烷基烃基可以是直链、支链或环状的,也可以是饱和或不饱和的。
本文所使用的“芳基”是指任选取代的芳香族基团,该芳香族基团至少具有一个具有共轭电子体系的环,同时包含多至2个的共轭或稠合环系。“芳基”包括碳环芳基、杂环芳基和二芳基基团,所有的芳基均可以任选地被取代。优选的芳基取代基完全如所指出的那样。
本发明的化合物可以包含一个或多个不对称碳原子,并且可以以外消旋体和旋光的形式存在。所有这些化合物和非对映异构体均预期包括在本
发明的范围之内。
优选的化合物包括但不限于:
N-苯基-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;
5-甲氧基-N-(3三氟甲基苯基)-2-(4-氯苯基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰胺基)苯甲酰胺
5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(4-甲氧基苯基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-氯苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-5-氯-2-(3-氯-2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氯苯基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(2-噻吩基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(2-甲氧基羰基-3-噻吩基磺酰胺基)苯甲酰胺;
N-(3,4-二氯苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;
5-溴-N-(4-氯苯基)-2-(3,4-二氯苯基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(苯基磺酰胺基)苯甲酰胺;和
5-甲氧基-N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺。
当存在碱性基团时,所使用的可药用的盐包括酸加成盐,如包括硫酸盐,盐酸盐,富马酸盐,马来酸盐,磷酸盐,氨基磺酸盐,乙酸盐,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。可药用的盐可以由酸得到,如盐酸,马来酸,硫酸,磷酸,氨基磺酸,乙酸,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。
当存在酸性官能团如羧酸或酚时,可药用的盐还包括碱加成盐,如包括苄星,氯普鲁卡因,胆碱,二乙醇胺,乙二胺,葡甲胺,普鲁卡因,铝,钙,锂,镁,钾,钠,铵,烷胺和锌的碱加成盐。
本发明提供上述式(I)的化合物可以利用标准技术来制备。制备本文所描述的优选化合物的所有策略均按本部分所描述的那样来进行。使用本文所描述的方案作模型,本领域的普通技术人员可以很容易地制备本发明的其它化合物。
通过适当的处理和任意的化学官能团保护,用类似于上述的方法和实验部分所描述的方法合成余下的式(I)的化合物。
方案1
为了用式(I)的化合物或其可药用的盐来治疗人或其它动物,一般根据标准的药学配制方法将其配制成药物组合物。
本发明的化合物可以通过不同的途径给药,这些途径包括静脉内、腹膜内、皮下、肌肉内、口腔、局部(经皮)或经粘膜给药。对于全身给药,优选口腔给药。例如,对于经口腔给药,该化合物可以配制成常规的口服剂形式,如胶囊、药片,以及液体制剂的形式,如糖浆、酏剂和浓缩滴剂。
作为选择,可以使用注射剂(肠胃外给药),例如肌肉注射、静脉注射、腹膜内注射和皮下注射。对于注射剂,将本发明的化合物配制在液体溶液中,优选配制在生理上适宜的缓冲液或溶液中,例如盐水溶液、Hank溶液或Ringer溶液。另外,可以将本发明的化合物配制成固体形式,并在使用之前立即溶解或悬浮。也可以制成冻干的形式。
还可以通过经粘膜或经皮的方式全身给药。对于经粘膜或经皮给药,制剂中使用适于透过屏障的渗透剂。这种渗透剂在本领域中一般是已知的,并且包括例如用于经粘膜给药的胆汁盐和梭链孢酸衍生物。另外,可以使用清洁剂以促进渗透。经粘膜给药可以通过例如鼻腔喷剂、直肠栓剂或阴道栓剂来进行。
对于局部给药,可以将本发明的化合物配制成本领域公知的软膏、油膏剂、凝胶剂或霜剂。
欲给药的不同化合物的量可以通过标准方法来确定,同时考虑到诸如化合物的IC50、EC50、生物半衰期,病人的年龄、身高和体重,以及与病人有关的疾病和不适等因素。这些和其它要考虑的因素的重要性对于本领域的普通技术人员来说是已知的。
给药量还取决于给药途径和口腔的生物利用度。例如,对于低口腔生物利用度的化合物,需要给药较高的剂量。
优选所述的组合物为单位剂量的形式。例如,对于口腔给药,可以给药药片或胶囊;对于鼻腔给药,可以给药计量的气雾剂;对于经皮给药,可以给药局部制剂或膏药;而对于经粘膜给药,可以给药口腔药膜。每种情况下,配制的剂量均为病人可按单个剂量给药的剂量。
每一口腔给药的剂量单位适当地包含0.01~500mg/kg、优选0.1~50mg/kg的式(I)化合物或其可药用的盐,按游离碱计。对于肠胃外、鼻腔、口腔吸入、经粘膜或经皮给药途径,日剂量适当地包含0.01~100mg/kg的式(I)化合物。局部使用的制剂适当地包含0.01~5.0%的式(I)化合物。活性成分的给药可以每日1~6次,优选每日1次,以足以显示出所需的活性,这对本领域的技术人员来说是显而易见的。
本文所使用的疾病的“治疗”包括但不限于疾病的防止、阻滞和预防。
通过口腔给药的具有活性的式(I)化合物及其可药用盐的组合物可以配制成糖浆、药片、胶囊和锭剂。糖浆制剂一般是由化合物或其盐和调味剂或着色剂在液体载体如乙醇、花生油、橄榄油、甘油或水中的悬浮液或溶液组成的。如果该组合物是药片状的,可以使用制备固体制剂所常用的任何药物载体。这种载体的实例包括硬脂酸镁、石膏粉、滑石粉、明胶、阿拉伯胶、硬脂酸、淀粉、乳糖和蔗糖。如果该组合物是胶囊状的,任何常规微囊化包装都是适宜的,例如使用前述载体于硬的明胶胶囊壳中。如果该组合物为软明胶壳胶囊的形式,可以考虑使用制备分散液或悬浮液所常用的任何药物载体,例如含水树胶、纤维素、硅酸盐或油,并且加到软的明胶胶囊壳中。
典型的肠胃外的组合物是由化合物或其盐在无菌的含水或非水载体中的溶液或悬浮液组成的,所述的含水或非水载体任选包含非肠胃可接受的油,如聚乙二醇、聚乙烯吡咯烷酮、卵磷脂、花生油或芝麻油。
典型的用于吸入的组合物为溶液、悬浮液或乳液的形式,其可以作为干粉或以气雾剂的形式给药,使用常规的推进剂,如二氯二氟甲烷或三氯氟甲烷。
典型的栓剂制剂包括以这种方式给药时具有活性的式(I)化合物或其可药用的盐,同时具有粘合剂和/或润滑剂,如聚乙二醇、明胶、可可脂或其它低熔点的植物蜡或脂肪或者它们的合成类似物。
典型的皮或经皮制剂包括常规的含水或非水赋形剂,如乳膏、软膏、洗液或糊剂,或者为加有药品的硬膏、膏药或药膜。
优选该组合物为单位剂量的形式,例如药片、胶囊或计量的气雾剂剂型,以便病人以单个剂型给药。
当将本发明的化合物按照本发明给药时,没有发现不可接受有毒作用。
钠依赖的磷酸盐转移抑制是通过试验化合物抑制邻近的管状细胞吸收放射性标定的无机磷酸盐的能力来确定的。可以使用人、兔子或大鼠的适宜细胞。
细胞制备及磷酸盐吸收评价
分离兔子的邻近的管状细胞并根据Sakhrani,L.M.et al.,Am.J.Physiol.246:F757-F764(1984)的方法进行培养,该文献所公开的全部内容引入本文作为参考。自Clonetics(San Diego,CA)购得人的邻近的管状细胞并按供应商的说明书进行培养。在实验那天,用0.5mM EDTA的磷酸盐缓冲盐水采集培养板上的细胞。将该细胞在吸收缓冲剂(见下面)中洗涤2次,并在37℃的相同缓冲剂中平衡30分钟。将该细胞的等分试样(100μl,0.5~106个细胞)分配到玻璃试管中。加入50μl的药物溶液或缓冲液,然后加入50μl含100μM[32P]-K2HPO4(0.5~1μCi/试管)的吸收缓冲液。待在37℃下改变一段时间(通常4分钟)之后,用4ml冷的终止液(见下面)终止吸收,并通过离心作用在该溶液中洗涤细胞3次。将片状的细胞溶解于0.5ml 1N的NaOH,并在液体闪烁计数器中计数32P。磷酸盐的吸收以pmol磷酸盐/mg细胞蛋白质来表示。
终止液 吸收缓冲液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%
在上述对兔子和人的邻近管状细胞的整个细胞评价体系中,通过过滤采集细胞并测量32P吸收。也可以使用33P而非32P。使用人类邻近管状细胞时,5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰胺基)苯甲酰胺、5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺和5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰胺基)苯甲酰胺的IC50分别为12、15和14μM。
下面的实施例解释可用于本发明的化合物和药物组合物的制备。这些实施例不是用来限制如上定义的本发明和如下定义的权利要求的范围。
实施例1
N-(4-溴苯基)-2-氨基-5-溴苯甲酰胺
将一份11.6ml 2.0M的三甲基铝(23.2mmol)在0℃下加到4.0g(23.25mmol)的4-溴苯胺溶液中。将反应混合物在环境温度下保持45分钟,然后冷却至0℃。一小份一小份地加入2-氨基-5-溴苯甲酸甲酯(4.72g,23.25mmol),待激烈的气体逸出停止后,将反应混合物在环境温度下保持18小时。然后将反应混合物倒入250ml 10%的HCl(进一步发生气体逸出)中,并通过过滤收集所生成的固体。依次用水和甲苯洗涤该固体,然后在室温下干燥之。TCL二氧化硅,CHCl3∶MeOH 9∶1再加一滴甲酸,Rf0.80~0.90和NMR与真实样品相同。这是分析各种芳族和杂芳族邻氨基苯甲酸及苯胺类似物的一般方法。
将12.1g(50mmol)5-溴靛红酸酐,9.4g(55mmol)4-溴苯胺和0.2g(5mmol)NaOH于150ml二噁烷中的混合物回流18小时。过滤冷却后的反应混合物并在真空下浓缩。剩余物在加入95%EtOH下进行结晶。通过过滤收集固体并用乙醇洗涤。通过薄层色谱(二氧化硅,15%EtOAc的己烷溶液)纯化样品,给出所预期的NMR、MS和元素分析。
类似的方法从5-氯靛红酸酐和4-溴苯胺开始,得到N-(4-溴苯基)-2-氨基-5-氯苯甲酰胺,其给出所预期的NMR、MS和元素分析。
实施例2
5-溴-N-(4-溴苯基)-2-(4-氯苯基磺酰胺基)苯甲酰胺
将N-(4-溴苯基)-2-氨基-5-溴苯甲酰胺(8.64g,23.3mmol),4-氯苯磺酰氯(4.98g,23.6mmol)和7.37g(93.2mmol)于300ml CH2Cl2中的溶液在室温下静置2天。将反应混合物在真空下浓缩,并将剩余物溶解于EtOAc。将该溶液用10%HCl、水、5%NaHCO3、水洗涤2次,并用MgSO4干燥。浓缩并在10%EtOAc己烷溶液中重结晶,得到具有令人满意的NMR、MS和元素分析的产物。
实施例3
5-溴-N-(4-溴苯基)-2-(4-溴苯基磺酰胺基)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-溴苯磺酰氯和28μl(340μmol)吡啶于1ml CH2Cl2中的溶液搅拌18小时。然后加入84.5mg(382μmol)聚胺树脂HL(Nova Biochem,4.53mmol/g),将混合物搅拌18小时,并通过过滤除去固体。真空下浓缩并通过制备HPLC(C18,20-95%乙腈-0.1%含水TFA)纯化,得到具有令人满意的HPLC-MS分析的产物。
使用类似于实施例2和3的方法,由5-溴-N-(4-溴苯基)-2-(4-氯苯基磺酰胺基)苯甲酰胺与下列磺酰氯反应得到产物:3-氯苯基-,4-氯苯基-,3,4-二氯苯基-,3-氯-4-氟-,2-氟苯基-,2,5-二甲氧基苯基-,3,4-二甲氧基苯基-,4-正丁氧基苯基-,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-氰基苯基-,3,5-二氯苯基-,苯乙烯基-,2-甲氧基羰基-3-噻吩基-,4-碘苯基-,2,6-二氯苯基,4-叔丁基苯基-,以及2,2,2-三氟乙基-磺酰氯。这些产物给出令人满意的HPLC-MS分析。
本说明书中所引用的所有出版物,包括但不限于专利和专利申请,均引入本文作为参考,每一出版物均具体和单独地如全文公开那样引入本文作为参考。
上面的描述充分地公开了本发明,其包括优选实施方案。对本文所具体公开的实施方案的变更和改进均在下面的权利要求书的范围之内。无须更详尽的细节,确信本领域的技术人员通过前述的说明书可以最大程度地利用本发明。因此,本文的实施例仅能理解成是对本发明的解释,而无论如何不能当成是对本发明的限制。其中要求了排他性所有权或特权的本发明的实施方案限定于权利要求书中。
Claims (8)
1.一种抑制钠依赖的磷酸盐转移的方法,该方法包括将安全有效量的式(I)的化合物给药于需要这种化合物的患者:其中:R1和R2独立地选自氢,烷基,链烯基,芳烷基,酰基,芳酰基,卤代烷基,卤素,羧基,烷氧羰基,氨甲酰基,烷基氨甲酰基,芳基氨甲酰基,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,芳酰氨基,烷基硫基,芳烷基硫基,芳基硫基,烷基亚硫酰基,芳基亚硫酰基,芳烷基亚硫酰基,烷基硫酰基,芳基硫酰基,芳烷基硫酰基,氨磺酰,芳基磺酰胺基和烷基磺酰胺基;或者R1部分代表稠环,该稠环与其所取代的环形成苯并噻吩,萘,喹啉或异喹啉;或者(R1)n及其所取代的环代表选自噻吩,呋喃,吡啶,嘧啶和吡嗪,以及它们的苯并类似物中的杂环;及R3独立地选自烷基,卤代烷基,R1芳基与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,和噻唑,以及它们的苯并类似物。
2.权利要求1的方法,其中该化合物选自:
N-苯基-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;
5-甲氧基-N-(3三氟甲基苯基)-2-(4-氯苯基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰胺基)苯甲酰胺
5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(4-甲氧基苯基磺酰胺基)苯甲酰胺;
5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-氯苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-5-氯-2-(3-氯-2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-氯苯基)-2-(3,4-二氯苯基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(2-噻吩基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(2-甲氧基羰基-3-噻吩基磺酰胺基)苯甲酰胺;
N-(3,4-二氯苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;
N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;
5-溴-N-(4-氯苯基)-2-(3,4-二氯苯基磺酰胺基)苯甲酰胺;
N-(4-溴苯基)-2-(苯基磺酰胺基)苯甲酰胺;和
5-甲氧基-N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺。
3.一种致使磷酸盐排泄和/或抑制磷酸盐吸收的方法,该方法包括将安全有效量的式(I)的化合物给药于需要这种化合物的患者:其中:R1和R2独立地选自氢,烷基,链烯基,芳烷基,酰基,芳酰基,卤代烷基,卤素,羧基,烷氧羰基,氨甲酰基,烷基氨甲酰基,芳基氨甲酰基,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,芳酰氨基,烷基硫基,芳烷基硫基,芳基硫基,烷基亚硫酰基,芳基亚硫酰基,烷基硫酰基,芳基硫酰基,芳烷基硫酰基,氨磺酰,芳基磺酰胺基和烷基磺酰胺基;或者R1部分代表稠环,该稠环与其所取代的环形成苯并噻吩,萘,喹啉或异喹啉;或者(R1)n及其所取代的环代表选自噻吩,呋喃,吡啶,嘧啶和吡嗪,以及它们的苯并类似物中的杂环;及R3独立地选自烷基,卤代烷基,R1芳基与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,和噻唑,以及它们的苯并类似物。
4.一种通过抑制需要治疗的哺乳动物中的磷酸盐转移系统来治疗慢性肾衰竭的方法,该方法包括将安全有效量的式(I)的化合物给药于需要这种化合物的患者:其中:R1和R2独立地选自氢,烷基,链烯基,芳烷基,酰基,芳酰基,卤代烷基,卤素,羧基,烷氧羰基,氨甲酰基,烷基氨甲酰基,芳基氨甲酰基,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,芳酰氨基,烷基硫基,芳烷基硫基,芳基硫基,烷基亚硫酰基,芳基亚硫酰基,烷基硫酰基,芳基硫酰基,芳烷基硫酰基,氨磺酰,芳基磺酰胺基和烷基磺酰胺基;或者R1部分代表稠环,该稠环与其所取代的环形成苯并噻吩,萘,喹啉或异喹啉;或者(R1)n及其所取代的环代表选自噻吩,呋喃,吡啶,嘧啶和吡嗪,以及它们的苯并类似物中的杂环;及
R3独立地选自烷基,卤代烷基,R1芳基与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,和噻唑,以及它们的苯并类似物。
5.权利要求5的方法,其中治疗尿毒症骨疾病。
6.权利要求5的方法,其中肾脏中的磷酸盐转移受到抑制。
7.权利要求5的方法,其中肠中的磷酸盐转移受到抑制。
8.一种药物组合物,该组合物包括选自下列的化合物:5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(3-氯丙基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(2-甲基苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(2-噻吩基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(2-甲氧基羰基-3-噻吩基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(4-氰基苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(甲基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(4-甲氧基苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(4-溴苯基磺酰胺基)苯甲酰胺;N-苯基-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;5-甲氧基-N-(3-三氟甲基苯基)-2-(4-氯苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(5-氯-2-噻吩基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(3-氯-2-氟苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(3氟丙基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(4-甲氧基苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-溴苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;N-(4-氯苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;N-(4-溴苯基)-2-(3,3,3-三氟乙基磺酰胺基)苯甲酰胺;N-(4-溴苯基)-5-氯-2-(3-氯-2-氟苯基磺酰胺基)苯甲酰胺;N-(4-氯苯基)-2-(3,4-二氯苯基磺酰胺基)苯甲酰胺;N-(4-溴苯基)-2-(2-噻吩基磺酰胺基)苯甲酰胺;N-(4-溴苯基)-2-(2-甲氧基羰基-3-噻吩基磺酰胺基)苯甲酰胺;N-(3,4-二氯苯基)-2-(2-氟苯基磺酰胺基)苯甲酰胺;N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;5-溴-N-(4-氯苯基)-2-(3,4-二氯苯基磺酰胺基)苯甲酰胺;N-(4-溴苯基)-2-(苯基磺酰胺基)苯甲酰胺;和5-甲氧基-N-(4-氯苯基)-2-(3-三氟甲基苯基磺酰胺基)苯甲酰胺;及药学上可接受的载体。
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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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US7119120B2 (en) * | 2001-12-26 | 2006-10-10 | Genzyme Corporation | Phosphate transport inhibitors |
AU2005299771A1 (en) | 2004-10-21 | 2006-05-04 | High Point Pharmaceuticals, Llc | Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use |
JPWO2006077901A1 (ja) * | 2005-01-20 | 2008-06-19 | 塩野義製薬株式会社 | Ctgf発現阻害剤 |
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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 |
EP2384318B1 (en) | 2008-12-31 | 2017-11-15 | 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 |
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WO2012006477A1 (en) | 2010-07-07 | 2012-01-12 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
JP5827327B2 (ja) * | 2010-07-07 | 2015-12-02 | アーデリクス,インコーポレーテッド | リン酸輸送を阻害する化合物及び方法 |
JP5823514B2 (ja) | 2010-07-07 | 2015-11-25 | アーデリクス,インコーポレーテッド | リン酸輸送を阻害する化合物及び方法 |
JP5827326B2 (ja) * | 2010-07-07 | 2015-12-02 | アーデリクス,インコーポレーテッド | リン酸輸送を阻害する化合物及び方法 |
AU2012340200B2 (en) | 2011-11-17 | 2017-10-12 | Dana-Farber Cancer Institute, Inc. | Inhibitors of c-Jun-N-Terminal Kinase (JNK) |
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 |
US20150336892A1 (en) | 2012-08-21 | 2015-11-26 | 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 |
KR102287207B1 (ko) | 2013-04-12 | 2021-08-09 | 알데릭스, 인코포레이티드 | Nhe3-결합 화합물 및 포스페이트 수송을 저해하는 방법 |
WO2018043400A1 (ja) * | 2016-08-30 | 2018-03-08 | 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 |
EA201991676A1 (ru) | 2017-01-09 | 2020-01-30 | Арделикс, Инк. | Ингибиторы nhe-опосредованного антипорта |
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IL86462A (en) * | 1987-05-29 | 1992-12-01 | Fujisawa Pharmaceutical Co | Alkanesulfonanilide derivatives, processes for preparation thereof and pharmaceutical compositions comprising the same |
US5210079A (en) * | 1988-01-07 | 1993-05-11 | E. I. Du Pont De Nemours And Company | Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists |
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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 |
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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PL353741A1 (en) | 2003-12-01 |
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AR030911A1 (es) | 2003-09-03 |
CO5190714A1 (es) | 2002-08-29 |
JP2003504403A (ja) | 2003-02-04 |
IL147697A0 (en) | 2002-08-14 |
NZ516619A (en) | 2004-02-27 |
HUP0202938A3 (en) | 2006-07-28 |
KR20020015382A (ko) | 2002-02-27 |
NO20020278D0 (no) | 2002-01-18 |
CA2379657A1 (en) | 2001-01-25 |
EP1202729A1 (en) | 2002-05-08 |
CZ2002204A3 (cs) | 2002-11-13 |
MXPA02000753A (es) | 2002-07-22 |
TR200200112T2 (tr) | 2002-05-21 |
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WO2001005398A1 (en) | 2001-01-25 |
NO20020278L (no) | 2002-01-18 |
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