CN1138581A - 取代的联苯磺酰胺类内皮素拮挤剂 - Google Patents
取代的联苯磺酰胺类内皮素拮挤剂 Download PDFInfo
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- CN1138581A CN1138581A CN96102541A CN96102541A CN1138581A CN 1138581 A CN1138581 A CN 1138581A CN 96102541 A CN96102541 A CN 96102541A CN 96102541 A CN96102541 A CN 96102541A CN 1138581 A CN1138581 A CN 1138581A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
下式化合物抑制内皮素的活性。式中各符号如说明书中所定义。
Description
本发明涉及用于尤其是治疗高血压的内皮素(endothelin)拮抗剂。
下式化合物、其对映体和非对映体以及其可药用的盐是用作尤其是抗高血压剂使用的内皮素受体拮抗剂,整个说明书中,上述各符号的定义如下:
X和Y之一是N,而另一个是O;
R1和R2各直接键连到环碳上,并且各自独立地是
(a)氢;
(b)烷基或烷氧基;
(c)羟基;
(d)卤素;或
(e)氨基;
R3和R4各直接键连到环碳上,并且各自独立地是:
(a)氢;
(b)烷基、链烯基、炔基、烷氧基、环烷基、环烷基烷基、环
烯基、环烯基烷基、芳基、芳氧基、芳烷基或芳烷氧基,
它们都可以被Z1、Z2和Z3取代;
(c)卤素;
(d)羟基;
(e)氰基;
(f)硝基;
(g)-C(O)H或-C(O)R5;
(h)-CO2H或-CO2R5;
(i)-Z4-NR6R7;或
(j)-Z4-N(R10)-Z5-NR8R9;或
(k)R3和R4也可以一起是亚烷基或亚烯基,它们都可以被Z1、
Z2和Z3取代,与它们所连的碳原子一起构成4~8员饱和
的、不饱和的或芳族的环;
R5是烷基、链烯基、炔基、环烷基、环烷基烷基、环烯基、环烯基烷基、芳基或芳烷基,它们都可以被Z1、Z2和Z3取代;
R6、R7、R8、R9和R10各自独立地是
(a)氢;或
(b)烷基、环烷基、环烷基烷基、环烯基烷基、芳基或芳烷基,
它们都可以被Z1、Z2和Z3取代;或
R6和R7可以一起是亚烷基或亚烯基,它们都可以被Z1、Z2和Z3取代,与它们所连的氮原子一起形成3~8员饱和或不饱和的环;或R8、R9和R10中的任何两个可以一起是亚烷基或亚烯基,它们都可以被Z1、Z2和Z3取代,与它们所连的原子一起形成3~8员饱和或不饱和的环;R11、R12、R13和R14各自独立地是
(a)氢;
(b)烷基、链烯基、炔基、烷氧基、环烷基、环烷基烷基、环
烯基、环烯基烷基、芳基、芳氧基、芳烷基或芳烷氧基,
它们都可以被Z1、Z2和Z3取代;
(c)杂环、取代的杂环或杂环氧基;
(d)卤素;
(e)羟基;
(f)氰基;
(g)硝基;
(h)-C(O)H或-C(O)R5;
(i)-CO2H或-CO2R5;
(j)-SH、-S(O)nR5、-S(O)m-OH、-S(O)m-OR5、-O-S(O)m-OR5、
-O-S(O)mOH或-O-S(O)m-OR5;
(k)-Z4-NR6R7;或
(l)-Z4-N(R10)-Z5-NR8R9;Z1、Z2和Z3各自独立地是
(a)氢;
(b)卤素;
(c)羟基;
(d)烷基;
(e)链烯基;
(f)芳基;
(g)芳烷基;
(h)烷氧基;
(i)芳氧基;
(j)芳烷氧基;
(k)杂环、取代的杂环或杂环氧基;
(l)-SH、-S(O)nZ6、-S(O)m-OH、-S(O)m-OZ6、-O-S(O)m-Z6、
-O-S(O)mOH或-O-S(O)m-OZ6;
(m)氧代;
(n)硝基;
(o)氰基;
(p)-C(O)H或-C(O)Z6;
(q)-CO2H或-CO2Z6;
(r)-Z4-NZ7Z8;
(s)-Z4-N(Z11)-Z5-H;
(t)-Z4-N(Z11)-Z5-Z6;或
(u)-Z4-N(Z11)-Z5-NZ7Z8;
Z4和Z5各自独立地是
(a)一个单键;
(b)-Z9-S(O)n-Z10-;
(c)-Z9-C(O)-Z10-;
(d)-Z9-C(S)-Z10-;
(e)-Z9-O-Z10-;
(f)-Z9-S-Z10-;
(g)-Z9-O-C(O)-Z10-;或
(h)-Z9-C(O)-O-Z10-;
Z6是烷基、被一、二或三个卤素取代的烷基、链烯基、炔基、环烷基、环烷基烷基、环烯基、环烯基烷基、芳基、被一、二或三个卤素取代的芳基、被三卤代烷基取代的芳基或芳烷基;
Z7和Z8各自独立地是氢、烷基、环烷基、环烷基烷基、环烯基烷基、芳基或芳烷基,或者Z7和Z8一起是亚烷基或亚烯基,它们与其所连的氮原子一起形成3~8员饱和或不饱和的环;
Z9和Z10各自独立地是一个单键、亚烷基、亚烯基或亚炔基;
Z11是
(a)氢;或
(b)烷基、被一、二或三个卤素取代的烷基、环烷基、环烷基
烷基、环烯基烷基、芳基或芳烷基;或者Z7、Z8和Z11中的任何两个一起是亚烷基或亚烯基,它们与其所连的原子一起形成3~8员饱和或不饱和的环;
J、K、L、T和U各自独立地是N或C,条件是至少一个是N,并且最多两个是N;以及当J、K、L、T和U中只有一个是N时,该N可以被-O取代以形成N-氧化物;
各m独立地是1或2;
各n独立地是0、1或2;以及
p为0或1~2的整数。
对于化合物I,优选的是:
R1和R2各自独立地是氢、烷基或烷氧基;
R3和R4各自独立地是烷基;
R11、R12、R13和R14各是氢或取代的烷基,尤其是R12、R13和R14各为氢,而R11为被杂环、取代的杂环或-Z4-N(Z11)-Z5-Z6取代的烷基;以及
p为0。
最优选的化合物是下述化合物,其中
R1和R2各自独立地是低级烷氧基或氢;以及
R3和R4各自独立地是低级烷基,尤其是甲基。
下面所列的是本说明书中所用的各术语的定义。除非在特殊的情况下另有限定,否则这些定义适用于在整个本说明书中所用的术语,无论它们是单独使用还是作为另一基团的部分而使用。
“烷基”或“烷-”一词是指具有1~10个、优选1~7个碳原子的直链或支链的烃基。“低级烷基”一词是指1~4个碳原子的烷基。
“烷氧基”一词是指烷基-O-。“低级烷氧基”一词是指低级烷基-O-。
“芳基”或“芳-”一词是指苯基、萘基或联苯基。
“链烯基”一词是指具有至少一个双键的2~10个碳原子的直链或支链的烃基。优选2~4碳原子的基团。
“炔基”一词是指具有至少一个叁键的2~10个碳原子的直链或支链基团。优选2~4个碳原子的基团。
“亚烷基”一词是指被单键连接的1~5个碳原子的直链桥(如-(CH2)x-,其中X为1~5),它可以被1~3个低级烷基取代。
“亚烯基”一词是指具有一个或两个双键的2~5个碳原子的直链桥,它被单键连接,可以被1~3个低级烷基取代。亚烯基的实例有-CH=CH-CH=CH-、-CH2-CH=CH-、-CH2-CH=CH-CH2-、-C(CH3)2-CH=CH-和-CH(C2H5)-CH=CH-。
“亚炔基”一词是指其中具有叁键的2~5个碳原子的直链桥,它被单键连接,可以被1~3个低级烷基取代。亚炔基的实例有-C≡C-、-CH2-C≡C-、-CH(CH3)-C≡C-和-C≡C-CH(C2H5)-CH2-。
“链烷酰基”一词是指式-C(O)烷基所示的基团。
“环烷基”和“环烯基”一词是指3~8个碳原子的环烃基。
“羟烷基”一词是指包含一个或多个羟基的烷基如-CH2CH2OH、-CH2CHOHCH2OH、-CH(CH2OH)2等。
“卤素”和“卤”一词是指氟、氯、溴和碘。
“杂环”、“杂环的”和“杂环-”一词是指任选地取代的、全饱和或不饱和的、芳族或非芳族的环状基团,例如,4~7员单环、7~11员双环或10~15员环环体系,它在含至少一个碳原子的环中具有至少一个杂原子。含有杂原子的杂环基团中的各环可以有1、2或3个选自氮原子、氧原子或硫原子的杂原子的杂环,其中的氮原子和硫原子可任选地被氧化,并且氮原子可任选地被季铵化。所述杂环可在任何杂原子或碳原子处连接。
单环杂环基的实例包括吡咯烷基、吡咯基、吡唑基、氧杂环丁烷基、吡唑啉基、咪唑基、咪唑啉基、咪唑烷基、噁唑基、噁唑烷基、异噁唑啉基、异噁唑基、噻唑基、噻二唑基、噻唑烷基、异噻唑基、异噻唑烷基、呋喃基、四氢呋喃基、噻吩基、噁二唑基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、4-哌啶酮基、吡啶基、哌嗪基、嘧啶基、哒嗪基、四氢吡喃基、吗啉基、硫吗啉基、亚砜化的硫吗啉基、砜化的硫吗啉基、1,3-二氧杂环戊烷基和四氢-1,1-二氧代噻吩基等。
双环杂环基的实例包括吲哚基、苯并噻唑基、苯并噁唑基、苯并噻吩基、喹宁环基、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基(如呋喃并[2,3-c]吡啶基、呋喃并[3,2-b]吡啶基或呋喃并[2,3-b]吡啶基)、二氢异吲哚基、二氢喹唑啉基(如3,4-二氢-4-氧代喹唑啉基)等。
三环杂环基的实例包括咔唑基、苯并吲哚基、菲咯啉基、吖啶基、菲啶基、呫吨基等。
“取代的杂环”一词是指被下列基团中的1,2或3个基团取代的杂环:
(a)烷基,尤其是低级烷基;(b)羟基(或保护的羟基);(c)卤素;(d)氧代(即=O);(e)氨基、烷基氨基或二烷基氨基;(f)烷氧基;(g)碳环如环烷基;(h)羧基;(i)杂环氧基;(j)烷氧羰基如未取代的低级烷氧羰基;(k)氨甲酰基、烷基氨甲酰基或二烷基氨甲酰基;(l)巯基;(m)硝基;(n)氰基;(o)烷氧甲酰;(p)亚磺酰氨基、亚磺酰氨基烷基或亚磺酰氨基二烷基;(q)R5-CO-NR6-;(r)R5-SO2-NR6-;(s)芳基;(t)烷基羰氧基;(u)芳基羰氧基;(v)芳硫基;(w)芳氧基;(x)烷硫基;(y)甲酰基;(z)芳烷基;或(a’)被烷基、环烷基、烷氧基、羟基、氨基、烷氨基、二烷氨基、卤素或三卤代烷基取代的芳基。
“杂环氧基”一词是指通过氧桥键连的杂环基团。
整个说明书中,基团及其取代基被选择以提供稳定的部分及化合物。
式I化合物形成盐,这些盐也包括在本发明的范围内。虽然其它盐也可以用于例如分离或纯化本发明化合物,但优选可药用的(即无毒的、生理上可接受的)盐。
式I化合物可以与下列物质形成盐:碱金属如钠、钾和锂;碱土金属如钙和镁;有机碱如二环己基胺、叔丁胺、苯乍生、N-甲基-D-葡糖酰胺(glucamide)和hydrabamine;以及氨基酸如精氨酸、赖氨酸等。这些盐可以通过化合物I在一种所述盐发生沉淀的介质中与所希望的离子反应得到,也可以在含水介质中进行所述反应,接着冷冻干燥,由此得到所述盐。
当R1~R4或R11~R14取代基含有碱性部分如氨基或取代的氨基时,化合物I可以与各种有机和无盐酸形成盐。这样的盐包括与盐酸、氢溴酸、甲磺酸、硫酸、乙酸、马来酸、苯磺酸、甲苯磺酸形成的盐以及各种其他磺酸盐、硝酸盐、磷酸盐、硼酸盐、乙酸盐、酒石酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、水杨酸盐等。这样的盐可以通过化合物与相当量的酸在一种介质中反应制备,在所述介质中,所述盐发生沉淀。或者所述反应在含水介质中进行,接着冷冻干燥,由此得到所述盐。
此外,当R1~R4或R11~R14取代基含有碱性部分如氨基时,可以形成两性离子(“内盐”)。
化合物I的R1~R4或R11~R14中的一些可以含有不对称碳原子。因此,这些化合物I可以以对映异构或非对映异构的形式或以其外消旋混合物的形式存在。所有这些都包括在本发明范围内。此外,甚至在不存在不对称碳原子时化合物I也可以以对映体形式存在,所有这些对映体也都包括在本发明的范围内。
式I化合物是ET-1、ET-2和/或ET-3的拮抗剂,可用于治疗与ET水平升高有关的病症(如透析、外伤和手术)以及所有内皮素依赖性疾病。这样它们可用作抗高血压剂,通过服用具有本发明化合物中的一种(或其结合)的组合物,降低了高血压哺乳动物(如人)主体的血压。它们也可以用于妊娠诱导的高血压和昏迷(子痫前期和惊厥),急性门静脉高血压和用红细胞生成素治疗后继发的高血压。
本发明化合物也可用于治疗与肾、血管小球和肾小球膜细胞功能有关的疾病,包括急性和慢性肾衰竭、血管小球损伤、继发于年老的或与透析有关的肾损害、肾硬化(尤其是高血压性肾硬化)、肾中毒(包括与成像和造影剂有关的或与环孢菌素有关的肾中毒)、肾局部缺血、主膀胱输尿管回流、肾小球硬化症等。本发明化合物也可用于治疗与旁分泌(paracrine)和内分泌功能有关的疾病。
本发明化合物也可用于治疗内毒素血症或内毒素休克以及出血休克。
本发明化合物也可用于氧不足和局部缺血疾病以及作为抗局部缺血剂用于治疗例如心、肾和脑的局部缺血和再灌流(reperfusion)(例如心肺旁路手术后所发生的)、冠状和脑血管痉挛等。
此外,本发明化合物也可用作抗心律失常药;抗心绞痛药;抗纤维性颤动剂;止喘药;抗动脉粥样硬化剂和抗动脉硬化剂;用于心肺旁路的心麻痹溶液的添加剂;溶解血栓治疗的辅助剂;以及止泻剂。本发明化合物可用于治疗心肌梗塞;治疗外周血管疾病(如雷诺氏病和高安氏病);治疗心肥大(如肥大性心肌疾病);治疗成人和婴儿的主肺动脉高血压(如plexogenic,栓子的)以及继发于心力衰竭、辐射和化疗损伤或其他损伤的肺高血压;治疗中枢神经系统血管病症如中风、偏头痛和蛛网膜下出血;治疗中枢神经系统行为疾病;治疗胃肠疾病如溃疡性结肠炎、克罗恩氏病、胃粘膜损伤、溃疡性和缺血性肠病;治疗基于胆囊或胆小管的疾病如胆管炎;治疗胰腺炎;调节细胞生长;治疗良性前列腺肥大;血管成形术后或包括移植的任何步骤后的再狭窄(restenosis);治疗充血性心力衰竭,包括抑制纤维变性;抑制左心室扩张、变形和机能障碍;以及治疗肝细胞中毒和猝死。本发明化合物可以用于治疗镰刀细胞疾病,包括该疾病的疼痛危险期的开始和发展;治疗产生ET的肿瘤的有害结果如产生于血管外皮细胞瘤的高血压;治疗早期或已发展的肝病和损伤包括伴随的并发症(如肝中毒、纤维变性和肝硬变);治疗尿道和/或膀胱的痉挛疾病;治疗肝肾综合征;治疗免疫疾病包括结节性脉管炎如狼疮、全身硬化症、混合的冰沉球蛋白血症;以及治疗与肾机能障碍和肝中毒有关的纤维变性。本发明化合物可用于治疗代谢性和神经学上的疾病;癌症;胰岛素依赖型或非胰岛素依赖型糖尿病;神经病;视网膜病;母呼吸固苦综合征;痛经;癫痫;出血性和局部缺血性中风;骨变形;牛皮癣;以及慢性炎病如类风湿性关节炎、骨关节炎、类肉瘤病和湿疹性皮炎(各种类型的皮炎)。
本发明化合物也可以与下列药物结合配制:内皮素转化酶(ECE)抑制剂如phosphoramidon;凝血烷受体拮抗剂;钾通道开通剂;凝血酶抑制剂(如水蛭素等);生长因子抑制剂如PDGF活性的调节剂;血小板激活因子(PAF)拮抗剂;血管紧张素II(A II)受体拮抗剂;肾素抑制剂;血管紧张素转化酶(ACE)抑制剂如甲巯丙脯酸、zofenpril、fosinopril、ceranapril、alacepril、enalapril、delapril、pentopril、quinapril、ramipril、lisinopril以及这些化合物的盐;中性内肽酶(NEP)抑制剂;NEP-ACE双重抑制剂;HMG CoA还原酶抑制剂如pravastatin和mevacor;角鲨烯合成酶抑制剂;胆汁酸螯合物如消胆胺;钙通道阻断剂;钾通道激活剂;β-肾上腺素能药剂;抗心律失常药;利尿剂如氯噻嗪、双氢克尿噻、三氟甲噻、氢氟噻嗪、苄氟噻嗪、甲基氯噻嗪、三氯噻嗪、多噻嗪或benzotbiazide以及利尿酸、tricrynafen、氯噻酮、速尿、musolimine、布美他尼、三氨喋呤、阿米洛利和安体舒通以及这些化合物的盐类;以及溶解血栓剂如组织纤溶酶原激活剂(tPA)、重组tPA、链激酶、尿激酶、prourokinase和甲氧苯酰化的纤溶酶原链激酶激活剂复合体(APSAC)。如果配制成固定剂量,这样的结合产物在下述剂量范围内使用本发明化合物和在已批准剂量范围内使用其他活性药剂。本发明化合物也可以与抗真菌和免疫抑制剂如两性霉素B、环孢菌素等一起配制或与它们结合使用,以对抗血管小球收缩和继发于这些化合物的肾中毒。本发明化合物也可以与血液透析结合使用。
本发明化合物可以在大约0.1至大约100mg/kg的剂量范围内的有效量被口服或经胃肠外途径给予已知患有这样的疾病的各种哺乳动物如人,所述剂量范围优选是大约0.2至大约50mg/kg,更优选为大约0.5至大约25mg/kg(或大约1至大约2500mg,优选大约5至大约2000mg),通过单剂量或分成2-4个分日剂量给药。
所述活性成分也可以用于就每单位剂量而言含大约5至大约500mg的式I化合物或其混合物的组合物如片剂、胶囊、溶液或悬浮液中或用于供伤口愈合用的局部形式中(0.01-5%重量式I化合物,每天处理1~5次)。它们可以通过常规方式与生理上可接受的媒介物或载体、赋形剂、粘结剂、防腐剂、稳定剂、香料等结合,或与如被已接受的药物实践所提倡的局部用载体如Plastibase(用聚乙烯胶凝的矿物油)结合。
本发明化合物也可以被局部给药用来治疗外周血管疾病,这样,可以将它们制成乳油或软膏。
式I化合物也可以配制成组合物如用于非经胃肠道给药的无菌溶液或悬浮液。在被已接受的药物实践所要求的单位剂量形式中,大约0.1至500mg式I化合物与生理学上可接受的媒介物、载体、赋形剂、粘结剂、防腐剂、稳定剂等结合。活性物质在这些组合物或制剂中的量应使得可以获得适当的所指明范围内的剂量。
本发明化合物可以通过相似于Murugesan等人于1995年7月24日所提交的美国申请系列号08/493,331(Attomey Docket No.HA662c)中所述的方法的方法制备,所述文献在此作为参考引入。本发明化合物也可通过诸如下面所述的方法制备。在下述各方法中,R11、R12、R13和/或R14可以在任何适当时候转化成不同的R11、R12、R13和/或R14基团,如在上述U.S.申请系列号08/493,331中所述的。例如一个是烷基的R11基团可以通过技术上已知的方法转化成一个是被氨基或酰胺基团取代的烷基的R11基团。
反应式I
如上述反应式I所示,标题化合物4可以通过适当保护的苯基磺酰胺-2-硼酸中间体2与4-杂环芳基卤化物1的Pd(O)催化的偶联来制备。偶联在合适的碱如含水碳酸钾和溶剂如甲苯和乙醇的混合物存在下进行。通过除去保护基,将得到的化合物转化成标题化合物4。
如果中间体2的硼酸基团被三烷基锡基团代替,那么中间体2也可以偶联到其中-OSO2CF3代替了卤素基团的化合物1上。
反应式I中所示的硼酸中间体2可以如下述反应式II所示从2-溴苯基磺酰胺5(其制备描述在EP公开号0,569,193(1993)中)通过下述方法制备,即,用合适的烷基锂(如正丁基锂)锂化,随后用硼酸三烷基酯(如硼酸三异丙基酯)处理,最后加入含水酸如盐酸水溶液:
反应式II(在所示的各反应式中,“Port”是适当的、磺酰胺官能团的保护基。这也描述在EP公开号0,569,193(1993)中)
B.标题化合物也可以通过下述反应式III和IV所示的另一条路线制备:
反应式III
如上述反应式III所示,4’-杂环芳基卤化物1可以经由所示的程序转化成硼酸中间体6。该化合物6通过与化合物5进行Pd(O)催化偶联,提供了联芳基类似物3。脱保护后,联芳基类似物3变成了标题化合物4。如果化合物6中的硼酸基团被三烷基锡基团代替,那么化合物6也可以偶联到其中-OSO2CF3代替了卤素基团的化合物5上。
反应式IV 如反应式IV所示,标题化合物4可通过下述方法制备,即硼酸衍生物2与1,4-二溴苯7进行Pd(O)催化的偶联,提供了4’-溴-联苯衍生物8。然后化合物8与杂环硼酸或杂环锡衍生物(其中R15是低级烷基)的Pd(O)偶联,脱保护后,提供了标题化物4’。
(关于联芳基合成中的一般战略,参见例如Bringmann等人,Angew.Chem.Int,Ed.Engl.29(1990)977-991。关于杂环,参见例如V.N.Kalinin,Synth.413-432(1992)和T.R.Bailey,Tetrahedron Lett.27(1986)4407-4410)。
C.4’-杂环芳基卤化物1可以由本领域技术人员通过文献中所述的各种方法制备。几个代表性的实例如下所示:
i.) 反应式V
如在反应式V中所示,在碱和合适的溶剂存在下4-溴苯基硼酸10与杂环卤化物9的Pd(O)催化的交叉偶联提供了4’-杂环芳基卤化物1’。许多4’-杂环如吡啶类和嘧啶类可以用此方法制备。参见例如Mitchell和Wallbank,Tet.Lett.,32,2273(1991)。
如所示的,杂环硼酸或有关的锡化合物(9)可以在Pd(O)存在下与1,4-二溴苯7偶联,提供4’-杂环芳基卤化物1’(其中p=0)。
式9所示的化合物也可以从市场上买到,或可以通过技术上已知的方法制备。参见“The Chemistry of Heterocyclic Compounds”,JohnWiley & Sons.
在一些情况下,可用锡化合物代替硼酸化合物进行偶联反应。(再次,关于联芳基合成中的一般战略,参见Bringmann等人,Angew.Chem.Int.,Ed.Engl.29(1990)977-991)。
4’-杂环芳基卤化物1也可以从相应的、其中4’-位带有活性基团如氰基而不是杂环的化合物制备。通过用技术上已知的方法将所述活性基团转化成所希望的4’-杂环进行所述制备。例如,4’-氰基芳基卤化物可以转化成相应的4’-脒基芳基卤化物,
通过诸如Wagner等人,Chem.Ber.104,2975-2983(1971)中所述的方法将后一化合物转化成4’-嘧啶芳基卤化物1。上述Wagner等人的文献在此引入作为参考。
D.4’-烷基吡啶或嘧啶标题化合物也可以通过下述反应式VII所示的另一条路线制备。在这些化合物中,K、L和T是C,J和U中至少一个是N,p是1或2:
如所示的,用通过技术上已知的方法制备的维悌希叶立德12处理2-卤代吡啶或2-卤代嘧啶11,接着用碱水如碳酸钠水解中间体,提供相应的4-溴苯基烷基吡啶/嘧啶1”。1”与2的Pd(O)催化的交叉偶联,接着除去保护基,提供了标题化合物4”。(参见例如E.C.Tayor和S.F.Martin,J.Am.Chem.Soc.,94,(1972)2874)。
E.下述反应式VIII中给出了典型的形成N-氧化物的实例:
反应式VIII
所示的适当的吡啶类似物可以用各种已知的氧化剂如间氯过苯甲酸或过乙酸氧化成相应的N-氧化物衍生物。上述反应式也适用于其它异构的吡啶类似物。
现在本发明将进一步通过下述工作实施例来描述,这些实施例是本发明优选具体实施方案。这些实施例是说明性的而不是限制性的。
实施例1
A.2-(4-溴苯基)嘧啶
向在氩气保护下的0.8g(4.0mmol)对溴苯基硼酸和0.23g(0.2mmol)四(三苯膦)钯(O)在20ml甲苯中的溶液中加入10ml 2M碳酸钠水溶液,接着加入在10ml 95%乙醇中的1.0g(6.23mmol)2-溴嘧啶。将混合物回流1.5小时,用100ml水稀释,用3×50ml乙酸乙酯提取。将合并后的有机提取液用100ml盐水洗一次,干燥、蒸发。残留物在100g硅胶上用己烷/乙酸乙酯3∶1洗脱进行层析,得到0.82g白色固状的化合物A。
B.N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-4’-(2-嘧啶基)[1,1’-联苯]-2-磺酰胺
向在氩气保护下的0.35g(0.91mmol)2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺和0.052g(0.045mmol)四(三苯膦)钯(O)在20ml甲苯中的溶液中,加入10ml 2M碳酸钠水溶液,接着加入0.278g(1.18mmol)在10ml 95%乙醇中的化合物A。将混合物回流1.5小时,用100ml水稀释,用3×50ml乙酸乙酯提取。合并的有机提取液用100ml盐水洗一次,干燥,蒸发。残留物在75g硅胶上用己烷/乙酸乙酯2∶1洗脱进行层析,得到了0.14g(39%)无色胶状的化合物B。
C.N-(3,4-二甲基-5-异噁唑基)-4’-(2-嘧啶基)[1,1’-联苯]-2-磺酰胺
向0.13g(0.25mmol)化合物B在6ml 95%乙醇中的溶液中加入6ml6N盐酸水溶液,回流1.5小时。然后浓缩混合物,再用10ml水稀释,并用碳酸氢钠水溶液将该溶液中和至pH7。用冰乙酸将该溶液再酸化至pH4,用3×50ml乙酸乙酯提取,合并的有机提取液用水洗一次,干燥,蒸发(0.11g),在30×500mm ODS S10柱上用70%溶剂B(90%甲醇、10%水、0.1%三氟乙酸)和30%溶剂A(10%甲醇、90%水、0.1%三氟乙酸)进行反相制备性HPLC来纯化该物质。收集适当的流份,用碳酸氢钠水溶液中和至pH7,浓缩至10ml。然后用冰乙酸将该溶液酸化至pH4,滤出白色固体,干燥,得到0.09g(87%)标题化合物。M.p.>210℃。
1H NMR(CDCl3):δ1.70(s,3H),2.00(s,3H),6.49
(br s,1H),7.09-8.70(m,10H).
13C NMR(CDCl3):δ6.6,10.8,108.5,119.4,127.3,
127.8,128.0,129.0,130.3,132.5,133.1,137.4,
138.0,140.7,141.0,154.1,157.3,161.8,164.1.
实施例2
N-(3,4-二甲基-5-异噁唑基)-4’-(2-吡啶基)[1,1’-联苯]-2-磺酰胺
A.2-(4-溴苯基)吡啶
向在氩气保护下的2.0g(9.96mmol)对溴苯基硼酸和0.57g(0.5mmol)四(三苯膦)钯(O)在20ml甲苯中的溶液中加入15ml 2M碳酸钠水溶液,接着加入在15ml 95%乙醇中的3.16g(20mmol)2-溴吡啶。将混合物回流2小时,用100ml水稀释,用3×50ml乙酸乙酯提取。将合并后的有机提取液用100ml盐水洗一次,干燥、蒸发。残留物在100g硅胶上用己烷/乙酸乙酯4∶1洗脱进行层析,得到2.3g化合物A,放置后固化为浅黄色固体。
B.N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-4’-(2-吡啶基)[1,1’-联苯]-2-磺酰胺
向在氩气保护下的1.47g(3.84mmol)2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺和0.173g(0.15mmol)四(三苯膦)钯(O)在40ml甲苯中的溶液中,加入20ml 2M碳酸钠水溶液,接着加入1.0g(4.27mmol)在20ml 95%乙醇中的化合物A,将混合物回流2小时,用100ml水稀释,用3×50ml乙酸乙酯提取。合并的有机提取液用100ml盐水洗一次,干燥,蒸发,残留物在50g硅胶上用己烷/乙酸乙酯2∶1洗脱进行层析,得到了0.91g(47%)无色胶状的化合物B。
C.N-(3,4-二甲基-5-异噁唑基)-4’-(2-吡啶基)[1,1’-联苯]-2-磺酰胺
向0.9g(1.78mmol)化合物B在12ml 95%乙醇中的溶液中加入12ml 6N盐酸水溶液,回流2小时。然后浓缩混合物,再用25ml水稀释,并用碳酸氢钠水溶液将该溶液中和至pH7。用冰乙酸将该溶液酸化至pH4,用3×50ml乙酸乙酯提取,合并的有机提取液用水洗一次,干燥,蒸发(0.75g),将残留物在25g硅胶上用己烷/乙酸乙酯3∶2洗脱进行层析,得到0.53g(73%)标题化合物。M.p.85-90℃。
C22H19N3O3S·1.17H2O分析计算结果:
计算值:C,61.94;H,5.04;N,9.85;S,7.52。
测定值:C,62.10;H,4.66;N,9.69;S,7.81。
实施例3
A.3-(4-溴苯基)吡啶
向在氩气保护下的4-溴苯基硼酸(1.41g,7mmol)、3-溴吡啶(6.64g,42mmol)在50ml甲苯和40ml 95%乙醇中的溶液中加入四(三苯膦)(O)(809mg,0.7mmol),接着加入30ml 2M碳酸钠水溶液。将反应混合物在85℃加热1.5小时,冷却,用150ml乙酸乙酯稀释。分出有机液,用20ml水和20ml盐水洗涤,干燥,浓缩。残留物在硅胶上用4∶1己烷/乙酸乙酯洗脱进行层析,得到了无色油状的化合物A(1.5g,92%)。
B.N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-4’-(3-吡啶基)[1,1’-联苯]-2-磺酰胺
向在氩气保护下的2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺(384mg,1.0mmol)、化合物A(351mg,1.5mmol)在9ml甲苯和7.2ml 95%乙醇中的溶液中加入四(三苯膦)钯(O)(116mg,0.1mmol),接着加入5.4ml 2M碳酸钠水溶液。将反应混合物在75℃加热3小时,冷却,用50ml乙酸乙酯稀释。分出有机液,用10ml水和10ml盐水洗涤,干燥,浓缩。残留物在硅胶上用1∶2己烷/乙酸乙酯洗脱进行层析,得到无色胶状的化合物B(346mg,70%)。
C.N-(3,4-二甲基-5-异噁唑基)-4’-(3-吡啶基)[1,1’-联苯]-2-磺酰胺
向346g(0.70mmol)化合物B在10ml 95%乙醇中的溶液中加入10ml 6N盐酸水溶液,回流1小时。然后浓缩混合物,用碳酸氢钠水溶液将该溶液中和至pH8。然后将该溶液用冰乙酸再酸化至pH5。混合物用3×40ml乙酸乙酯提取。有机液用10ml水和10ml盐水洗涤,干燥,浓缩。残留物在硅胶上用100∶2.5二氯甲烷/甲醇洗脱层析,得到了标题化合物(199mg,70%),白色固体。M.p.96-106℃(无定形)。
C22H19N3O3S·0.44H2O的分析计算结果:
计算值:C,63.92;H,4.83;N,10.17;S,7.76。
测定值:C,63.95;H,4.64;N,10.14;S,7.55。
实施例4
A.2-氯-4,6-二甲氧基嘧啶
用30分钟时间将亚硝酸钠(11.04g,160mmol)在22ml水中的溶液加到在-8~-12℃的2-氨基-4,6-二甲氧基嘧啶(12.41g,80mmol)在66ml浓盐酸中的溶液中。将混合物在室温下搅拌过夜。过滤分出沉淀物,用少量水洗涤。将固体物溶于200ml二氯甲烷中,干燥(硫酸镁),过滤,浓缩滤液,得到白色固状的化合物A(3.74g,27%)。
B.2-(4-溴苯基)-4,6-二甲氧基嘧啶
向在氩气保护下的4-溴苯基硼酸(602mg,3mmol)、化合物A(524mg,3mmol)在22.5ml甲苯和18ml 95%乙醇中的溶液中加入四(三苯膦)钯(O)(208mg,0.18mmol),接着加入13.5ml 2M碳酸钠水溶液。将反应混合物在80℃加热1.25小时,冷却,用60ml乙酸乙酯稀释。分出有机液,用15ml水和15ml盐水洗涤,干燥,浓缩。残留物在硅胶上用4∶1己烷/二氯甲烷洗脱进行层析,得到了化合物B(170mg,19%),白色固体。
C.4’-(4,6-二甲氧基-2-嘧啶基)-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基][1,1’-联苯]-2-磺酰胺
向在氩气保护下的2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺(384mg,1.0mmol)、化合物B(339mg,1.15mmol)在9ml甲苯和7.2ml 95%乙醇中的溶液中加入四(三苯膦)钯(O)(116mg,0.1mmol),接着加入5.4ml 2M碳酸钠水溶液。将反应混合物在75℃加热3小时,冷却,用50ml乙酸乙酯稀释。分出有机液,用10ml水和10ml盐水洗涤,干燥,浓缩。残留物在硅胶上用3∶1己烷/乙酸乙酯洗脱进行层析,得到无色胶状的化合物B(370mg,67%)。
D.4’-(4,6-二甲氧基-2-嘧啶基)-N-(3,4-二甲基-5-异噁唑基)[1,1’-联苯]-2-磺酰胺
向化合物C(370mg,0.67mmol)在15ml 95%乙醇中的溶液中加入15ml 6N盐酸水溶液,回流45分钟,浓缩反应混合物,用碳酸氢钠溶液将溶液的pH调至8。然后用冰乙酸酸化至pH5。用3×50ml乙酸乙酯提取混合物。有机相用15ml水和15ml盐水洗涤,干燥,浓缩。残留物在硅胶上用10∶1然后5∶1二氯甲烷/乙酸乙酯洗脱进行层析,得到白色固状的标题化合物(185mg,60%)。M.p.83-93℃(无定形)。
C23H22N4O5S分析计算结果:
计算值:C,59.22;H,4.75;N,12.01;S,6.87。
测定值:C,59.15;H,4.76;N,11.73;S,6.56。
实施例5
A.4-(4-溴苯基)嘧啶
用8分钟时间将正丁基锂(1.6M在己烷中,8.0ml,13mmol)滴加到在于烘箱中干燥过的烧瓶中的、氩气保护下的、0℃的1,4-二溴苯(3.6g,15mmol)在乙醚(22ml)中的搅拌溶液中。在0℃搅拌30分钟后,将反应液冷却至-35℃,用10分钟加入嘧啶(1.2g,1.2ml,15mmol)在乙醚(15ml)中的溶液。在-35℃搅拌20分钟后,用水(4.5ml)骤冷反应后,转移到分液漏斗中。用乙醚(2×30ml)和二氯甲烷(30ml)提取,用硫酸镁干燥合并的有机层,蒸发溶剂后,得到4.2g物质。
将残留物溶于丙酮中,加入高锰酸钾的饱和丙酮溶液(~30ml)直到保持紫色不变。将该溶液回流10分钟。通过硅藻土(Celite)过滤反应物,用丙酮和乙醇冲洗,蒸发滤液,得到2.3g粗产物。用庚烷重结晶后,得到0.78g(24%)化合物A。M.p.81.0~83.5℃。
B.N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-4’-(4-嘧啶基)[1,1’-联苯]-2-磺酰胺
将2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺(1.0g,1.6mmol)在乙醇中的溶液(用氩气吹洗了20分钟,7.2ml)加到化合物A(0.50g,2.0mmol)在甲苯中的溶液(用氩气吹洗了20分钟,14ml)中。向该溶液中先后加入碳酸钠(0.45g)在水中的溶液(用氩气吹洗了20分钟,7.2ml)和四(三苯膦)钯(O)(0.13g,0.11mmol)。在氩气下回流4.5小时后,冷却该溶液,倒入盐水(20ml)中。用乙酸乙酯(2×70ml)提取,用硫酸镁干燥合并后的有机层,蒸发溶剂后,得到1.6g粗产物。快速层析(硅胶,50mm直径,50%乙酸乙酯/二氯甲烷),得到0.20g(25%)化合物B。
C.N’-(3,4-二甲基-5-异噁唑基)-4’-(4-嘧啶基)[1,1’-联苯]-2-磺酰胺
在80℃搅拌化合物B(0.20g,0.40mmol)在乙醇(6.0ml)和6N盐酸(6.0ml)中的溶液。7小时后,真空蒸发乙醇,残留物转移到装有二氯甲烷/水的分液漏斗中。用饱和碳酸氢钠溶液将水层调至pH1.5。用二氯甲烷(4×20ml)提取,用硫酸镁干燥,并蒸发溶剂后,得到0.24g粗产物。快速层析(硅胶,15mm直径,8%甲醇/二氯甲烷),接着用热乙醇重结晶后,得到42mg(26%)标题化合物。M.p.211.0~214.0℃。
C21H18N4O3S·0.16H2O的分析计算结果:
计算值:C,61.61;H,4.51;N,13.68;S,7.83。
测定值:C,61.66;H,4.42;N,13.63;S,7.60。
实施例6
N’-(3,4-二甲基-5-异噁唑基)-4’-(4-吡嗪基)[1,1’-联苯]-2-磺酰胺
A.4-(4-溴苯基)吡嗪
用8分钟时间将正丁基锂(1.6M在己烷中,8.0ml,13mmol)滴加到在于烘箱中干燥过的烧瓶中的、氩气保护下的、0℃的1,4-二溴苯(3.6g,15mmol)在乙醚(22ml)中的搅拌溶液中。在0℃搅拌30分钟后,将反应液用13分钟加入到于-78℃下搅拌着的吡嗪(0.86g,11ml,0.86mmol)在四氢呋喃(34ml)中的溶液中。一旦加完,就让干燥空气(通过硫酸钙床)鼓泡通过该溶液。30分钟后撤去冷浴,然后再30分钟后,用水(4.5ml)骤冷反应,将反应物转移到分液漏斗中。用二氯甲烷(2×50ml)提取,用硫酸镁干燥合并的有机层,蒸发溶剂后,得到3.9g物质。快速层析(硅胶,75mm直径,5%乙酸乙酯/二氯甲烷),得到0.93g(36%)化合物A。M.p.105.0-107.5℃。
B.N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-4’-(4-吡嗪基)[1,1’-联苯]-2-磺酰胺
将2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺(1.0g,1.6mmol)在乙醇中的溶液(用氩气吹洗了20分钟,7.2ml)加到化合物A(0.50g,2.0mmol)在甲苯中的溶液(用氩气吹洗了20分钟,14ml)中。向该溶液中先后加入碳酸钠(0.45g)在水中的溶液(用氩气吹洗了20分钟,7.2ml)和四(三苯膦)钯(O)(0.13g,0.11mmol)。在氩气下回流4小时后,冷却该溶液,倒入盐水(20ml)中。用乙酸乙酯(2×70ml)提取,用硫酸镁干燥合并后的有机层,蒸发溶剂后,得到1.6g粗产物。快速层析(硅胶,50mm直径,50%乙酸乙酯/二氯甲烷),得到0.15g(19%)化合物B。
C.N’-(3,4-二甲基-5-异噁唑基)-4’-(4-吡嗪基)[1,1’-联苯]-2-磺酰胺
在90℃搅拌化合物B(0.15g,0.30mmol)在乙醇(4.6ml)和6N盐酸(4.6ml)中的溶液。3小时后,真空蒸发乙醇,残留物转移到装有二氯甲烷/水的分液漏斗中。用饱和碳酸氢钠溶液将水层调至pH1.5。用二氯甲烷(4×20ml)提取,用硫酸镁干燥,并蒸发溶剂后,得到0.18g粗产物。快速层析(硅胶,15mm直径,7%甲醇/二氯甲烷),得到94mg几乎纯的产物。经制备性HPLC(YMC S10,30×500mm,含1%三氟乙酸的68.4%甲醇水溶液,25ml/分钟,17-19.5分钟各流份),得到标题化合物(64mg,52%)。M.p.131.0~134.0℃。
C21H18N4O3S·0.50H2O的分析计算结果:
计算值:C,60.71;H,4.61;N,13.49;S,7.72。
测定值:C,60.49;H,4.37;N,13.17;S,7.09。
实施例7
将4-溴苯基硼酸(2.0g,10mmol)在乙醇(用氩气吹洗了30分钟,44ml)中的溶液加到5-溴嘧啶(1.9g,12mmol)在甲苯中的溶液(用氩气吹洗了30分钟,87ml)中。向该溶液中加入碳酸氢钠(2.7g)水溶液(用氩气吹洗了30分钟,44ml),接着加入四(三苯膦)钯(O)(0.76g,0.66mmol)。在氩气下于75℃搅拌1小时后,冷却该溶液,然后倒入盐水(50ml)中。用乙酸乙酯(2×250ml)提取,用硫酸镁干燥合并后的有机层,蒸发溶剂后,得到3.4g粗产物。快速层析(硅胶,50mm直径,5-10%乙酸乙酯/二氯甲烷),接着用热乙醇重结晶,得到1.0g(42%)化合物A。M.p.144.0-146.5℃。
B.N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-4’-(5-嘧啶基)[1,1’-联苯]-2-磺酰胺
将2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺(1.0g,1.6mmol)在乙醇中的溶液(用氩气吹洗了20分钟,7.2ml)加到化合物A(0.50g,2.0mmol)在甲苯中的溶液(用氩气吹洗了20分钟,14ml)中。向该溶液中先后加入碳酸钠(0.45g)在水中的溶液(用氩气吹洗了20分钟,7.2ml)和四(三苯膦)钯(O)(0.13g,0.11mmol)。在氩气于75℃搅拌4小时后,冷却该溶液,倒入盐水(20ml)中。用乙酸乙酯(2×70ml)提取,用硫酸镁干燥合并后的有机层,蒸发溶剂后,得到1.8g粗产物。快速层析(硅胶,50mm直径,50%乙酸乙酯/己烷,接着10%甲醇/乙酸乙酯),得到0.15g(19%)化合物B。
C.N-(3,4-二甲基-5-异噁唑基)-4’-(5-嘧啶基)[1,1’-联苯]-2-磺酰胺
在90℃搅拌化合物B(0.15g,0.30mmol)在乙醇(4.6ml)和6N盐酸(4.6ml)中的溶液。2小时后,真空蒸发乙醇,残留物转移到装有二氯甲烷/水的分液漏斗中。用饱和碳酸氢钠溶液将水层调至pH2.0。用二氯甲烷(4×20ml)提取,用硫酸镁干燥,并蒸发溶剂后,得到0.13g粗产物。快速层析(硅胶,15mm直径,7%甲醇/二氯甲烷),得到了54mg几乎纯的产物。经制备性HPLC(YMC S-10,30×500mm,含1%三氟乙酸的66.8%甲醇水溶液,25ml/分钟,16-18.7分钟的各流份),得到25mg(20%)标题化合物。M.p.105.0~109.0℃。
C21H18N4O3S·0.40C2HF3O2·0.90H2O的分析计算结果:
计算值:C,55.91;H,4.35;N,11.96;S,6.85。
测定值:C,55.92;H,3.97;N,11.61;S,7.29。
实施例8
N-(3,4-二甲基-5-异噁唑基)-4’-(2-吡啶基)[1,1’-联苯]-2-磺酰胺,N4’-氧化物
A.N-(3,4-二甲基-5-异噁唑基)-4’-(2-吡啶基)[1,1’-联苯]-2-磺酰胺,N4’-氧化物
向0.15g(0.37mmol)上述实施例2的标题化合物在5ml二氯甲烷中的溶液中加入0.088g间氯过苯甲酸,并将混合物在室温下搅拌3小时。然后蒸发反应混合物,残留物通过反相制备性HPLC(在30×500mm ODS S10柱上,用58%溶剂B(90%甲醇、10%水和0.1%三氟乙酸)和42%溶剂A(10%甲醇、90%水、0.1%三氟乙酸)为流动相纯化。收集适当的流份,用碳酸氢钠水溶液中和至pH7,浓缩至10ml。然后用冰乙酸将该溶液酸化至pH4。滤出白色固体,干燥,得到0.088g(56%)标题化合物。M.p.110-117℃。
C22H19N3O4S·1.70H2O的分析计算结果:
计算值:C,58.44;H,4.99;N,9.29;S,7.09。
测定值:C,58.82;H,4.36;N,8.91;S,6.75。
实施例9
A.2-溴-6-甲氧基吡啶
将5.0g(21.24mmol)2,6-二溴吡啶和8.2ml(35.875mmol)25%甲醇钠/甲醇在15ml甲醇中的溶液回流下搅拌大约26小时,此时,TLC(1∶1乙酸乙酯/己烷)表明无2,6-二溴吡啶存在了。将反应混合物冷却至室温,倒入冷的5%碳酸氢钠水溶液中,用乙醚提取。蒸发后,将残留物溶于乙醚中,用盐水洗涤,干燥(硫酸镁),蒸发至干,得到3.6g 90%无色油状物。
B.2-(4-溴苯基)-6-甲氧基吡啶
向1.88g(10mmol)化合物A和0.5g(2.5mmol)4-溴苯基硼酸在20ml脱气甲苯和16ml脱气乙醇的混合物中的溶液中加入0.175g(0.15mmol)四(三苯膦)钯(O)和12ml脱气2N碳酸钠水溶液。将混合物在75℃搅拌3小时。将反应混合物冷至室温,用200ml乙酸乙酯稀释,用水洗后,用甲苯洗,干燥(硫酸镁),蒸发。快速层析(50mm×6”;25%-50%乙酸乙酯/己烷),得到1.86g起始原料和产物的混合物,再层析两次(50mm×6”;1%乙酸乙酯/己烷,然后50mm×7”;0.75%乙酸乙酯/己烷)后,得到230mg(35%)无色油状物及混合流份。
C.N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]-4’-(6-甲氧基-2-吡啶基)[1,1’-联基]-2-磺酰胺
向在5.5ml脱气甲苯和3.7ml脱气乙醇的混合物中的230mg(0.87mmol)化合物B和280mg(0.73mmol)2-二羟硼基-N-(3,4-二甲基-5-异噁唑基)-N-[(2-甲氧基乙氧基)甲基]苯磺酰胺中加入84mg(0.072mmol)四(三苯膦)钯(O)和3.2ml脱气2N碳酸钠水溶液。将混合物在85℃搅拌3小时,冷却至室温,用乙酸乙酯稀释,用水洗后,再用盐水洗,干燥(硫酸镁),蒸发。快速层析(50mm×6”;30%-40%-50%乙酸乙酯/己烷),得到172mg油-固状残留物(45%)。
D.N-(3,4-二甲基-5-异噁唑基)-4’-(6-甲氧基-2-吡啶基)[1,1’-联苯]-2-磺酰胺
将170mg(0.325mmol)化合物C和7.5ml 6N盐酸在7.5ml乙醇中的混合物在75℃搅拌30分钟,加入另外的水。用饱和碳酸氢钠溶液将pH调至大约8,然后用乙酸调回至大约4.5。用3×50ml乙酸乙酯提取混合物,用水和盐水各25ml洗涤有机提取物,干燥(硫酸镁),蒸发。快速层析(25mm×6”;40%到50%乙酸乙酯/己烷),得到50mg半固状产物,用己烷研制以部分纯化,得到15mg白色固状的标题化合物。也分离到120mg回收的化合物C,再置于上述反应条件(6N盐酸和乙醇各4ml)下。如上后处理后,将粗产物与来自上述研制过程的母液合并,通过快速层析(2×25mm×8”;40%到50%乙酸乙酯/己烷)纯化,得到另外50mg白色固状的标题化合物(共65mg,46%收率)。M.p.132-134℃。
C23H21N3O4S·0.39H2O分析计算结果:
计算值:C,62.42;H,4.96;N,9.49;S,7.24。
测定值:C,62.70;H,4.87;N,9.21;S,6.93。
实施例10
下述化合物(1)-(5)也是通过这里所述的方法例如从上文所述的4’-脒芳基卤化物制备的:
(2)N-[[2’-[[(3,4-二甲基-5-异噁唑基)氨基]磺酰基]-4-(2-嘧啶基)[1,1’-联苯]-2-基]甲基]-N-甲基环己烷乙酰胺,具有下式结构:
(3)N-[[2’-[[(3,4-二甲基-5-异噁唑基)氨基]磺酰基]-4-(2-嘧啶基)[1,1’-联苯]-2-基]甲基]-N-甲基苯丙酰胺,具有下式结构:
(4)N-(3,4-二甲基-5-异噁唑基)-2’-[(3,3-二甲基-2-氧代-1-吡咯烷基)甲基]-4’-(2-嘧啶基)[1,1’-联苯]-2-磺酰胺,具有下式结构;
Claims (32)
X和Y之一是N,而另一个是O;
R1和R2各直接键连到环碳上,并且各自独立地是
(a)氢;
(b)烷基或烷氧基;
(c)羟基;
(d)卤素;或
(e)氨基;R3和R4各直接键连到环碳上,并且各自独立地是:
(a)氢;
(b)烷基、链烯基、炔基、烷氧基、环烷基、环烷基烷基、环
烯基、环烯基烷基、芳基、芳氧基、芳烷基或芳烷氧基,
它们都可以被Z1、Z2和Z3取代;
(c)卤素;
(d)羟基;
(e)氰基;
(f)硝基;
(g)-C(O)H或-C(O)R5;
(h)-CO2H或-CO2R5;
(i)-Z4-NR6R7;或
(j)-Z4-N(R10)-Z5-NR8R9;或
(k)R3和R4也可以一起是亚烷基或亚烯基,它们都可以被Z1、
Z2和Z3取代,与它们所连的碳原子一起构成4~8员饱和
的、不饱和的或芳族的环;
R5是烷基、链烯基、炔基、环烷基、环烷基烷基、环烯基、环烯基烷基、芳基或芳烷基,它们都可以被Z1、Z2和Z3取代;
R6、R7、R8、R9和R10各自独立地是
(a)氢;或
(b)烷基、环烷基、环烷基烷基、环烯基烷基、芳基或芳烷基,
它们都可以被Z1、Z2和Z3取代;或
R6和R7可以一起是亚烷基或亚烯基,它们都可以被Z1、Z2和Z3取代,与它们所连的氮原子一起形成3~8员饱和或不饱和的环;或R8、R9和R10中的任何两个可以一起是亚烷基或亚烯基,它们都可以被Z1、Z2和Z3取代,与它们所连的原子一起形成3~8员饱和或不饱和的环;
R11、R12、R13和R14各自独立地是
(a)氢;
(b)烷基、链烯基、炔基、烷氧基、环烷基、环烷基烷基、环
烯基、环烯基烷基、芳基、芳氧基、芳烷基或芳烷氧基,
它们都可以被Z1、Z2和Z3取代;
(c)杂环、取代的杂环或杂环氧基;
(d)卤素;
(e)羟基;
(f)氰基;
(g)硝基;
(h)-C(O)H或-C(O)R5;
(i)-CO2H或-CO2R5;
(j)-SH、-S(O)nR5、-S(O)m-OH、-S(O)m-OR5、-O-S(O)m-OR5、
-O-S(O)mOH或-O-S(O)m-OR5;
(k)-Z4-NR6R7;或
(l)-Z4-N(R10)-Z5-NR8R9;Z1、Z2和Z3各自独立地是
(a)氢;
(b)卤素;
(c)羟基;
(d)烷基;
(e)链烯基;
(f)芳基;
(g)芳烷基;
(h)烷氧基;
(i)芳氧基;
(j)芳烷氧基;
(k)杂环、取代的杂环或杂环氧基;
(l)-SH、-S(O)nZ6、-S(O)m-OH、-S(O)m-OZ6、-O-S(O)m-Z6、
-O-S(O)mOH或-O-S(O)m-OZ6;
(m)氧代;
(n)硝基;
(o)氰基;
(p)-C(O)H或-C(O)Z6;
(q)-CO2H或-CO2Z6;
(r)-Z4-NZ7Z8;
(s)-Z4-N(Z11)-Z5-H;
(t)-Z4-N(Z11)-Z5-Z6;或
(u)-Z4-N(Z11)-Z5-NZ7Z8;
Z4和Z5各自独立地是
(a)一个单键;
(b)-Z9-S(O)n-Z10-;
(c)-Z9-C(O)-Z10-;
(d)-Z9-C(S)-Z10-;
(e)-Z9-O-Z10-;
(f)-Z9-S-Z10-;
(g)-Z9-O-C(O)-Z10-;或
(h)-Z9-C(O)-O-Z10-;
Z6是烷基、被一、二或三个卤素取代的烷基、链烯基、炔基、环烷基、环烷基烷基、环烯基、环烯基烷基、芳基、被一、二或三个卤素取代的芳基、被三卤代烷基取代的芳基或芳烷基;
Z7和Z8各自独立地是氢、烷基、环烷基、环烷基烷基、环烯基烷基、芳基或芳烷基,或者Z7和Z8一起是亚烷基或亚烯基,它们与其所连的氮原子一起形成3~8员饱和或不饱和的环;
Z9和Z10各自独立地是一个单键、亚烷基、亚烯基或亚炔基;
Z11是
(a)氢;或
(b)烷基、被一、二或三个卤素取代的烷基、环烷基、环烷基
烷基、环烯基烷基、芳基或芳烷基;或者Z7、Z8和Z11中的任何两个一起是亚烷基或亚烯基,它们与其所连的原子一起形成3~8员饱和或不饱和的环;
J、K、L、T和U各自独立地是N或C,条件是至少一个是N,并且最多两个是N;以及当J、K、L、T和U中只有一个是N时,该N可以被-O取代以形成N-氧化物;
各m独立地是1或2;
各n独立地是0、1或2;以及
p为0或1~2的整数。
2.权利要求1的化合物,其中R1和R2各独立地为氢、烷基或烷氧基。
3.权利要求1的化合物,其中R3和R4各独立地为烷基。
4.权利要求1的化合物,其中R1和R2各独立地为氢或烷氧基;而R3和R4各独立地为烷基。
5.权利要求1的化合物,其中R1和R2各独立地为氢或低级烷氧基。
6.权利要求1的化合物,其中R3和R4各独立地为1~4个碳原子的烷基。
7.权利要求1的化合物,其中R3和R4各为甲基。
8.权利要求1的化合物,其中R1和R2各独立地为氢或低级烷氧基;而R3和R4各独立地为1~4个碳原子的烷基。
9.权利要求1的化合物,其中R1和R2各独立地为氢或低级烷氧基;而R3和R4各为甲基。
10.权利要求1的化合物,其中p为0。
11.权利要求1的化合物,其中p为0;R1和R2各独立地为氢或低级烷氧基;而R3和R4各为甲基。
12.权利要求1的化合物,其中R1和R2各独立地为氢或低级烷氧基;R3和R4各为甲基;R11、R12、R13和R14各为氢或取代的烷基;p为0。
13.权利要求12的化合物,其中R11、R12、R13和R14各为氢。
14.权利要求12的化合物,其中R12、R13和R14各为氢而R11为取代的烷基。
15.权利要求14的化合物,其中R11为被杂环、取代的杂环或-Z4-N(Z11)-Z5-Z6取代的烷基。
16.权利要求1的化合物,选自:
N-(3,4-二甲基-5-异噁唑基)-4’-(2-嘧啶基)[1,1’-联苯]-2-磺酰胺,
N-(3,4-二甲基-5-异噁唑基)-4’-(2-吡啶基)[1,1’-联苯]-2-磺酰胺,
N-(3,4-二甲基-5-异噁唑基)-4’-(3-吡啶基)[1,1’-联苯]-2-磺酰胺,
4’-(4,6-二甲氧基-2-嘧啶基)-N-(3,4-二甲基-5-异噁唑基)[1,1’-联苯]-2-磺酰胺,
N’(3,4-二甲基-5-异噁唑基)-4’-(4-嘧啶基)[1,1’-联苯]-2-磺酰胺,
N-(3,4-二甲基-5-异噁唑基)-4’-(4-吡嗪基)[1,1’-联苯]-2-磺酰胺,
N-(3,4-二甲基-5-异噁唑基)-4’-(5-嘧啶基)[1,1’-联苯]-2-磺酰胺,
N-(3,4-二甲基-5-异噁唑基)-4’-(2-吡啶基)[1,1’-联苯]-2-磺酰胺,N4’-氧化物,
N-(3,4-二甲基-5-异噁唑基)-4’-(6-甲氧基-2-吡啶基)[1,1’-联苯]-2-磺酰胺,
N-[[2’-[[(3,4-二甲基-5-异噁唑基)氨基]磺酰基]-4-(2-嘧啶基)[1,1’-联苯]-2-基]甲基]-N-甲基环己烷丙酰胺,
N-[[2’-[[(3,4-二甲基-5-异噁唑基)氨基]磺酰基]-4-(2-嘧啶基)[1,1’-联苯]-2-基]甲基]-N-甲基环己烷乙酰胺,
N-[[2’-[[(3,4-二甲基-5-异噁唑基)氨基]磺酰基]-4-(2-嘧啶基)[1,1’-联苯]-2-基]甲基]-N-甲基苯丙酰胺,
N-(3,4-二甲基-5-异噁唑基)-2’-[(3,3-二甲基-2-氧代-1-吡咯烷基)甲基]-4’-(2-嘧啶基)[1,1’-联苯]-2-磺酰胺,以及
N-(3,4-二甲基-5-异噁唑基)-2’-[[甲基(2,2,2-三氟乙基)氨基]甲基]-4’-(2-嘧啶基)[1,1’-联苯]-2-磺酰胺。
17.治疗与内皮素有关的哺乳动物疾病的方法,其中包括给予所述哺乳动物治疗与内皮素有关的疾病有效量的权利要求1的化合物。
18.治疗高血压的方法,其中包括给予治疗高血压有效量的权利要求1的化合物。
19.治疗肺高血压的方法,其中包括给予治疗肺高血压有效量的权利要求1的化合物。
20.治疗肾的、血管小球的或肾小球膜细胞疾病的方法,其中包括给予治疗肾的、血管小球的或肾小球膜细胞的疾病有效量的权利要求1的化合物。
21.治疗内毒素血症的方法,其中包括给予治疗内毒素血症有效量的权利要求1的化合物。
22.治疗局部缺血的方法,其中包括给予治疗局部缺血有效量的权利要求1的化合物。
23.抑制细胞生长的方法,其中包括给予抑制细胞生长有效量的权利要求1的化合物。
24.治疗动脉粥样硬化的方法,其中包括给予治疗动脉粥样硬化有效量的权利要求1的化合物。
25.治疗再狭窄的方法,其中包括给予治疗再狭窄有效量的权利要求1的化合物。
26.治疗蛛网膜下出血的方法,其中包括给予治疗蛛网膜下出血有效量的权利要求1的化合物。
27.治疗良性前列腺肥大的方法,其中包括给予治疗良性前列腺肥大有效量的权利要求1的化合物。
28.治疗充血性心力衰竭的方法,其中包括给予治疗充血性心力衰竭有效量的权利要求1的化合物。
29.权利要求17的方法,其中所述的权利要求1的化合物与至少一种血管紧张素II(AII)受体拮抗剂、肾素抑制剂、血管紧张素转化酶(ACE)抑制剂或中性内肽酶(NEP)-ACE双重抑制剂结合使用。
30.用于治疗与内皮素有关的疾病的药物组合物,它包含治疗有效量的权利要求1的化合物和生理上可接受的媒介物或载体。
31.权利要求30的药物组合物,它进一步包含至少一种血管紧张素II(AII)受体拮抗剂、肾素抑制剂、血管紧张素转化酶(ACE)抑制剂或中性内肽酶(NEP)-ACE双重抑制剂。
32.下式的化合物或其对映体、非对映体或可药用的盐,其中
X和Y之一是N,而另一个是O;
R1和R2各直接键连到环碳上,并且各自独立地是
(a)氢;
(b)烷基或烷氧基;
(c)羟基;
(d)卤素;或
(e)氨基;
R3和R4各直接键连到环碳上,并且各自独立地是:
(a)氢;
(b)烷基、链烯基、炔基、烷氧基、环烷基、环烷基烷基、环
烯基、环烯基烷基、芳基、芳氧基、芳烷基或芳烷氧基,
它们都可以被Z1、Z2和Z3取代;
(c)卤素;
(d)羟基;
(e)氰基;
(f)硝基;
(g)-C(O)H或-C(O)R5;
(h)-CO2H或-CO2R5;
(i)-Z4-NR6R7;或
(j)-Z4-N(R10)-Z5-NR8R9;或
(k)R3和R4也可以一起是亚烷基或亚烯基,它们都可以被Z1、
Z2和Z3取代,与它们所连的碳原子一起构成4~8员饱和
的、不饱和的或芳族的环;
R5是烷基、链烯基、炔基、环烷基、环烷基烷基、环烯基、环烯基烷基、芳基或芳烷基,它们都可以被Z1、Z2和Z3取代;
R6、R7、R8、R9和R10各自独立地是
(a)氢;或
(b)烷基、环烷基、环烷基烷基、环烯基烷基、芳基或芳烷基,
它们都可以被Z1、Z2和Z3取代;或
R6和R7可以一起是亚烷基或亚烯基,它们都可以被Z1、Z2和Z3取代,与它们所连的氮原子一起形成3~8员饱和或不饱和的环;或R8、R9和R10中的任何两个可以一起是亚烷基或亚烯基,它们都可以被Z1、Z2和Z3取代,与它们所连的原子一起形成3~8员饱和或不饱和的环;
R11、R12、R13和R14各自独立地是
(a)氢;
(b)烷基、链烯基、炔基、烷氧基、环烷基、环烷基烷基、环
烯基、环烯基烷基、芳基、芳氧基、芳烷基或芳烷氧基,
它们都可以被Z1、Z2和Z3取代;
(c)卤素;
(d)羟基;
(e)氰基;
(f)硝基;
(g)-C(O)H或-C(O)R5;
(h)-CO2H或-CO2R5;
(i)-SH、-S(O)nR5、-S(O)m-OH、-S(O)m-OR5、-O-S(O)m-OR5、
-O-S(O)mOH或-O-S(O)m-OR5;
(j)-Z4-NR6R7;或
(k)-Z4-N(R10)-Z5-NR8R9;
Z1、Z2和Z3各自独立地是
(a)氢;
(b)卤素;
(c)羟基;
(d)烷基;
(e)链烯基;
(f)芳烷基;
(g)烷氧基;
(h)芳氧基;
(i)芳烷氧基;
(j)-SH、-S(O)nZ6、-S(O)m-OH、-S(O)m-OZ6、-O-S(O)m-Z6、
-O-S(O)mOH或-O-S(O)m-OZ6;
(k)氧代;
(l)硝基;
(m)氰基;
(n)-C(O)H或-C(O)Z6;
(o)-CO2H或-CO2Z6;
(p)-Z4-NZ7Z8;
(q)-Z4-N(Z11)-Z5-Z6;或
(r)-Z4-N(Z11)-Z5-NZ7Z8;Z4和Z5各自独立地是
(a)一个单键;
(b)-Z9-S(O)n-Z10-;
(c)-Z9-C(O)-Z10-;
(d)-Z9-C(S)-Z10-;
(e)-Z9-O-Z10-;
(f)-Z9-S-Z10-;
(g)-Z9-O-C(O)-Z10-;或
(h)-Z9-C(O)-O-Z10-;Z6是烷基、链烯基、炔基、环烷基、环烷基烷基、环烯基、环烯基烷基、芳基、或芳烷基;
Z7和Z8各自独立地是氢、烷基、环烷基、环烷基烷基、环烯基烷基、芳基或芳烷基,或者Z7和Z8一起是亚烷基或亚烯基,它们与其所连的氮原子一起形成3~8员饱和或不饱和的环;
Z9和Z10各自独立地是一个单键、亚烷基、亚烯基或亚炔基;
Z11是
(a)氢;或
(b)烷基、环烷基、环烷基烷基、环烯基烷基、芳基或芳烷基;或者Z7、Z8和Z11中的任何两个一起是亚烷基或亚烯基,它们与其所连的原子一起形成3~8员饱和或不饱和的环;
J、K、L、T和U各自独立地是N或C,条件是至少一个是N,并且最多两个是N;以及当J、K、L、T和U中只有一个是N时,该N可以被-O取代以形成N-氧化物;
各m独立地是1或2;
各n独立地是0、1或2;以及
p为0或1~2的整数。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/384,066 US5760038A (en) | 1995-02-06 | 1995-02-06 | Substituted biphenyl sulfonamide endothelin antagonists |
US384,066 | 1995-02-06 | ||
SG1996000999A SG46218A1 (en) | 1995-02-06 | 1996-02-06 | Substituted biphenyl sulfonamide endothelin antagonists |
Publications (2)
Publication Number | Publication Date |
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CN1138581A true CN1138581A (zh) | 1996-12-25 |
CN1060172C CN1060172C (zh) | 2001-01-03 |
Family
ID=26665074
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96102541A Expired - Fee Related CN1060172C (zh) | 1995-02-06 | 1996-02-06 | 取代的联苯磺酰胺类内皮素拮抗剂 |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP0725067A1 (zh) |
JP (1) | JPH08245600A (zh) |
CN (1) | CN1060172C (zh) |
CA (1) | CA2168154A1 (zh) |
CZ (1) | CZ29296A3 (zh) |
FI (1) | FI960516A (zh) |
HU (1) | HUP9600256A3 (zh) |
IL (1) | IL116916A (zh) |
NO (1) | NO305559B1 (zh) |
PL (1) | PL183283B1 (zh) |
SG (1) | SG46218A1 (zh) |
Families Citing this family (25)
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US5962490A (en) | 1987-09-25 | 1999-10-05 | Texas Biotechnology Corporation | Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
US6342610B2 (en) | 1993-05-20 | 2002-01-29 | Texas Biotechnology Corp. | N-aryl thienyl-, furyl-, and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
US6541498B2 (en) | 1993-05-20 | 2003-04-01 | Texas Biotechnology | Benzenesulfonamides and the use thereof to modulate the activity of endothelin |
US6376523B1 (en) | 1994-05-20 | 2002-04-23 | Texas Biotechnology Corporation | Benzenesulfonamides and the use thereof to modulate the activity of endothelin |
US6613804B2 (en) | 1993-05-20 | 2003-09-02 | Encysive Pharmaceuticals, Inc. | Biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin |
US6030991A (en) * | 1993-05-20 | 2000-02-29 | Texas Biotechnology Corp. | Benzenesulfonamides and the use thereof to modulate the activity of endothelin |
US5612359A (en) * | 1994-08-26 | 1997-03-18 | Bristol-Myers Squibb Company | Substituted biphenyl isoxazole sulfonamides |
ATE243203T1 (de) * | 1995-04-04 | 2003-07-15 | Texas Biotechnology Corp | Thienyl-, furyl-, pyrrolyl- und biphenylsulfonamide und derivate zur modulation der endothelin-aktivität |
US5846990A (en) * | 1995-07-24 | 1998-12-08 | Bristol-Myers Squibb Co. | Substituted biphenyl isoxazole sulfonamides |
JPH09124620A (ja) * | 1995-10-11 | 1997-05-13 | Bristol Myers Squibb Co | 置換ビフェニルスルホンアミドエンドセリン拮抗剤 |
US5856507A (en) * | 1997-01-21 | 1999-01-05 | Bristol-Myers Squibb Co. | Methods for the preparation of biphenyl isoxazole sulfonamides |
CN1211183A (zh) * | 1996-02-20 | 1999-03-17 | 布里斯托尔-迈尔斯斯奎布公司 | 联苯基异噁唑磺酰胺的制备方法 |
US5939446A (en) * | 1996-04-09 | 1999-08-17 | Bristol-Myers Squibb Co. | Heteroaryl substituted phenyl isoxazole sulfonamide endothelin antagonists |
US5804585A (en) * | 1996-04-15 | 1998-09-08 | Texas Biotechnology Corporation | Thieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin |
AU6187898A (en) * | 1997-01-30 | 1998-08-25 | Bristol-Myers Squibb Company | Method for preventing or treating low renin hypertension by administering an endothelin antagonist |
TW536540B (en) * | 1997-01-30 | 2003-06-11 | Bristol Myers Squibb Co | Endothelin antagonists: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphe |
US6030975A (en) * | 1997-03-14 | 2000-02-29 | Basf Aktiengesellschaft | Carboxylic acid derivatives, their preparation and use in treating cancer |
ES2241133T3 (es) | 1997-04-28 | 2005-10-16 | Encysive Pharmaceuticals Inc. | Sulfamidas para el tratamiento de los trastornos inducidos por la endotelina. |
US5783705A (en) | 1997-04-28 | 1998-07-21 | Texas Biotechnology Corporation | Process of preparing alkali metal salys of hydrophobic sulfonamides |
CA2326427A1 (en) * | 1998-03-31 | 1999-10-07 | Koichiro Yamada | Preventives/remedies for urinary disorder |
GEP20033114B (en) * | 1998-07-06 | 2003-11-25 | Bristol Myers Squibb Co | Biphenyl Sulfonamides as Dual Angiotensin Endothelin Receptor Antagonists, Method for Their Production and Pharmaceutical Compositions Containing the Same |
EP1165472A4 (en) | 1999-03-19 | 2002-11-20 | Bristol Myers Squibb Co | METHOD FOR PRODUCING BIPHENYL ISOXAZOLE |
US6455554B1 (en) | 1999-06-07 | 2002-09-24 | Targacept, Inc. | Oxopyridinyl pharmaceutical compositions and methods for use |
US6639082B2 (en) | 2000-10-17 | 2003-10-28 | Bristol-Myers Squibb Company | Methods for the preparation of biphenyl isoxazole sulfonamides |
JP6139272B2 (ja) * | 2012-06-01 | 2017-05-31 | 株式会社半導体エネルギー研究所 | 発光素子の作製方法 |
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NZ247440A (en) * | 1992-05-06 | 1995-04-27 | Squibb & Sons Inc | Phenyl sulphonamide derivatives, preparation and pharmaceutical compositions thereof |
-
1996
- 1996-01-26 CA CA002168154A patent/CA2168154A1/en not_active Abandoned
- 1996-01-26 IL IL11691696A patent/IL116916A/xx not_active IP Right Cessation
- 1996-01-31 CZ CZ96292A patent/CZ29296A3/cs unknown
- 1996-02-05 HU HU9600256A patent/HUP9600256A3/hu unknown
- 1996-02-05 FI FI960516A patent/FI960516A/fi unknown
- 1996-02-05 NO NO960473A patent/NO305559B1/no not_active IP Right Cessation
- 1996-02-06 PL PL96312650A patent/PL183283B1/pl unknown
- 1996-02-06 JP JP8019792A patent/JPH08245600A/ja active Pending
- 1996-02-06 EP EP96101685A patent/EP0725067A1/en not_active Withdrawn
- 1996-02-06 SG SG1996000999A patent/SG46218A1/en unknown
- 1996-02-06 CN CN96102541A patent/CN1060172C/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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PL183283B1 (pl) | 2002-06-28 |
CZ29296A3 (en) | 1996-09-11 |
IL116916A0 (en) | 1996-05-14 |
JPH08245600A (ja) | 1996-09-24 |
NO960473D0 (no) | 1996-02-05 |
IL116916A (en) | 2000-09-28 |
PL312650A1 (en) | 1996-08-19 |
SG46218A1 (en) | 1998-02-20 |
HUP9600256A3 (en) | 1998-08-28 |
EP0725067A1 (en) | 1996-08-07 |
NO305559B1 (no) | 1999-06-21 |
FI960516A0 (fi) | 1996-02-05 |
HUP9600256A2 (en) | 1997-10-28 |
HU9600256D0 (en) | 1996-03-28 |
CN1060172C (zh) | 2001-01-03 |
FI960516A (fi) | 1996-08-07 |
NO960473L (no) | 1996-08-07 |
CA2168154A1 (en) | 1996-08-07 |
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