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公开(公告)号：US20120283196A1
公开(公告)日：2012-11-08
申请号：US13513550
申请日：2009-12-04
申请人： Sophie Barthélémy , Christian Bisang , Frank Otto Gombert , Alexander Lederer , Daniel Obrecht , Barbara Romagnoli , Jürg Zumbrunn , Tobias Remus , Guillaume Lemercier
发明人： Sophie Barthélémy , Christian Bisang , Frank Otto Gombert , Alexander Lederer , Daniel Obrecht , Barbara Romagnoli , Jürg Zumbrunn , Tobias Remus , Guillaume Lemercier
摘要： β-Hairpin peptidomimetics of the general formula Cyclo(-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-), and pharmaceutically acceptable salts thereof, with Xaa 1-Xaa 16 being amino acid residues of certain types which are defined in the description and the claims, have CXCR4 antagonizing properties and prolonged half-lives in vivo and can be used for preventing HIV infections in healthy individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections eases of peripheral blood stem cells and/or as agents to induce mobilization of stem cells to regulate tissue repair. These peptidomimetics can be manufactured by a process which is based on a mixed solid-and solution phase synthetic strategy.
摘要翻译： （-Xaa1-Xaa2-Xaa3-Xaa4-Xaa8-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-）的通式肽模拟物及其药学上可接受的盐 其中Xaa 1-Xaa 16是在说明书和权利要求书中定义的某些类型的氨基酸残基，具有CXCR4拮抗特性和体内延长的半衰期，并且可用于预防健康个体的HIV感染或减缓 并阻止感染患者的病毒进展; 或由CXCR4受体活性介导或产生癌症; 或其中免疫性疾病介导或由CXCR4受体活性产生; 或用于治疗免疫抑制; 或在血浆分离术收集期间减少外周血干细胞和/或作为诱导干细胞调动以调节组织修复的试剂。 这些肽模拟物可以通过基于混合固相和溶液相合成策略的方法来制造。
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公开(公告)号：US20120202821A1
公开(公告)日：2012-08-09
申请号：US13388891
申请日：2009-08-05
申请人： Daniel Obrecht , Philipp Ermert , Said Oumouch , Franck Lach , Anatol Luther , Karsten Marx , Kerstin Möhle
发明人： Daniel Obrecht , Philipp Ermert , Said Oumouch , Franck Lach , Anatol Luther , Karsten Marx , Kerstin Möhle
IPC分类号： A61K31/407 , A61K31/4985 , A61K31/4745 , A61P1/00 , A61P15/06 , A61P25/06 , A61P25/18 , A61P25/24 , A61P27/02 , A61P27/06 , C07D498/04 , A61P25/00
CPC分类号： C07D498/04 , A61K31/407 , A61K31/437 , A61K31/4985 , C07D497/18 , C07D498/18
摘要： Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of type (I) are constituted by three distinct building blocks: an aromatic template a, a conformation modulator b and a spacer moiety c as detailed in the description and the claims. Macrocycles of type (I) are readily manufactured by parallel synthesis or combinatorial chemistry. They are designed to interact with specific biological targets. In particular, they show agonistic or antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT2B (5-HT2B receptor), and on the prostaglandin F2•receptor (FP receptor). They are thus potentially useful for the treatment of hypomotility disorders of the gastrointestinal tract such as diabetic gastroparesis and constipation type irritable bowl syndrome; of CNS related diseases like migraine, schizophrenia, psychosis or depression; of ocular hypertension such as associated with glaucoma and preterm labour.
摘要翻译： 构形限制的（I）型的空间定义的12-30元大环环体系由描述和权利要求书中详细描述的三个不同的构成单元构成：芳族模板a，构象调节剂b和间隔子部分c。 类型（I）的大环化合物容易通过平行合成或组合化学制备。 它们旨在与具体的生物目标相互作用。 特别地，它们表现出对胃动素受体（MR受体），5-HT2B（5-HT2B受体）5型血清素受体和前列腺素F2受体（FP受体）的激动作用或拮抗作用。 因此，它们可用于治疗胃肠道的运动障碍，如糖尿病性胃轻瘫和便秘型肠易激综合征; CNS相关疾病如偏头痛，精神分裂症，精神病或抑郁症; 的高眼压症如青光眼和早产。
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公开(公告)号：US20070060570A1
公开(公告)日：2007-03-15
申请号：US10557664
申请日：2004-05-24
申请人： Martin Eberle , Daniel Obrecht , Philipp Ermert , Franck Lach , Anatol Luther , Felix Bachmann , Alessandro Strebel
发明人： Martin Eberle , Daniel Obrecht , Philipp Ermert , Franck Lach , Anatol Luther , Felix Bachmann , Alessandro Strebel
IPC分类号： A61K31/55 , A61K31/454 , A61K31/4015 , A61K31/4025 , C07D403/02
CPC分类号： C07D401/04 , C07D207/48 , C07D401/14 , C07D403/12 , C07D405/04 , C07D405/14 , C07D409/04 , C07D409/14
摘要： The invention relates to compounds of formula (I) wherein R1 represents aryl, aralkyl or heteroaryl, R2 is aryl or heteroaryl and R3 is aryl, heteroaryl or optionally substituted aminomethyl, to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using compounds of formula (I) or of pharmaceutical compositions containing same.
摘要翻译： 本发明涉及其中R 1表示芳基，芳烷基或杂芳基，R 2是芳基或杂芳基和R 3'的式（I）化合物， 是将芳族，杂芳基或任选取代的氨基甲基与合成式（I）化合物的药物组合物的合成方法，涉及式（I）化合物用于制备用于治疗 肿瘤和自身免疫疾病，以及使用式（I）化合物或含有其的药物组合物治疗肿瘤和自身免疫性疾病的方法。
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公开(公告)号：US20050239693A1
公开(公告)日：2005-10-27
申请号：US11062021
申请日：2005-02-18
申请人： Jan Vrijbloed , Daniel Obrecht , John Robinson , Odile Sellier , Marc Kessler
发明人： Jan Vrijbloed , Daniel Obrecht , John Robinson , Odile Sellier , Marc Kessler
CPC分类号： C07K5/06165 , A61K38/00 , C07K1/047 , C07K7/64 , Y02A50/473
摘要： Template-fixed β-hairpin peptidomimetics of the general formula wherein Z is a template-fixed chain of 12 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa and Acinetobacter. They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials, or as medicaments to treat or prevent infections. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.
摘要翻译： 模板固定的β-发夹肽模拟物，其通式如下：其中Z是12个α-氨基酸残基的模板固定链，其取决于其在链中的位置（从N-末端氨基酸开始计数）为Gly，或 Pro或某些类型，其作为上述式中的其余符号在说明书和权利要求书及其盐中定义，具有选择性抑制绿脓假单胞菌和不动杆菌等微生物生长或杀死微生物的性质。 它们可以用作食品，化妆品，药物或其他含营养材料的消毒剂，或用作治疗或预防感染的药物。 这些β-发夹肽模拟物可以通过基于混合固相和溶液相合成策略的方法制备。
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公开(公告)号：US20050181454A1
公开(公告)日：2005-08-18
申请号：US11029331
申请日：2005-01-05
申请人： John Robinson , Daniel Obrecht
发明人： John Robinson , Daniel Obrecht
IPC分类号： C07K5/10 , C07H21/04 , C07K1/04 , C07K7/02 , C07K7/06 , C07K7/08 , C07K7/64 , C07K14/00 , G01N33/53
摘要： Template-fixed β-hairpin loop mimetics comprising a template corresponding to one of the structures (a), (b), (c), (d), (e), (f), (g), (h) and a template-fixed chain of 4 to 20 α-amino acid residues which, if their α-C atom is asymmetric, have L-configuration can be manufactured by a novel process which is based on a mixed solid- and solution phase synthetic strategy. If desired, this process can be modified to give the enantiomers of these template-fixed β-hairpin loop mimetics. These enantiomers are novel compounds, and many of said template-fixed β-hairpin loop mimetics themselves are also novel compounds. The template-fixed β-hairpin loop mimetics and their enantiomers can mimic flat surfaces of proteins and thus be used to probe large surface protein-protein interactions. Accordingly they can serve as lead finding tools for protein targets where it is difficult to find small-molecular-weight lead compounds.
摘要翻译： 模板固定的β-发夹环模拟物，其包含对应于结构（a），（b），（c），（d），（e），（f），（g），（h）和 4至20个α-氨基酸残基的模板固定链，如果它们的α-C原子是不对称的，则具有L-构型可以通过基于混合固相和溶液相合成策略的新方法制备。 如果需要，可以修饰该方法以得到这些模板固定的β-发夹环模拟物的对映异构体。 这些对映体是新化合物，许多所述模板固定的β-发夹环模拟物本身也是新的化合物。 模板固定的β-发夹环模拟物及其对映体可以模拟蛋白质的平坦表面，因此可用于探测大的表面蛋白质 - 蛋白质相互作用。 因此，它们可以作为难以发现小分子量铅化合物的蛋白质靶标的主要发现工具。
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公开(公告)号：US06878804B1
公开(公告)日：2005-04-12
申请号：US10070217
申请日：1999-08-30
申请人： John A. Robinson , Daniel Obrecht
发明人： John A. Robinson , Daniel Obrecht
IPC分类号： C07K5/10 , C07H21/04 , C07K1/04 , C07K7/02 , C07K7/06 , C07K7/08 , C07K7/64 , C07K14/00 , G01N33/53 , A61K38/04 , C07K5/00 , C07K7/00 , C07K16/00 , C07K17/00
摘要： Template-fixed β-hairpin loop mimetics comprising a template corresponding to one of the structures (a), (b), (c), (d), (e), (f), (g), (h) and a template-fixed chain of 4 to 20 α-amino acid residues which, if their α-C atom is asymmetric, have L-configuration can be manufactured by a novel process which is based on a mixed solid- and solution phase synthetic strategy. If desired, this process can be modified to give the enantiomers of these template-fixed β-hairpin loop mimetics. These enantiomers are novel compounds, and many of said template-fixed β-hairpin loop mimetics themselves are also novel compounds. The template-fixed β-hairpin loop mimetics and their enantiomers can mimick flat surfaces of proteins and thus be used to probe large surface protein-protein interactions. Accordingly they can serve as lead finding tools for protein targets where it is difficult to find small-molecular-weight lead compounds.
摘要翻译： 模板固定的β-发夹环模拟物，其包含对应于结构（a），（b），（c），（d），（e），（f），（g），（h）和 4至20个α-氨基酸残基的模板固定链，如果它们的α-C原子是不对称的，则具有L-构型可以通过基于混合固相和溶液相合成策略的新方法制备。 如果需要，可以修饰该方法以得到这些模板固定的β-发夹环模拟物的对映异构体。 这些对映体是新化合物，许多所述模板固定的β-发夹环模拟物本身也是新的化合物。 模板固定的β-发夹环模拟物及其对映异构体可以模拟蛋白质的平坦表面，因此可用于探测大表面蛋白质 - 蛋白质相互作用。 因此，它们可以作为难以发现小分子量铅化合物的蛋白质靶标的主要发现工具。
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公开(公告)号：US08629112B2
公开(公告)日：2014-01-14
申请号：US13577153
申请日：2010-02-05
申请人： Frank Otto Gombert , Alexander Lederer , Daniel Obrecht , Barbara Romagnoli , Christian Bisang , Christian Ludin
发明人： Frank Otto Gombert , Alexander Lederer , Daniel Obrecht , Barbara Romagnoli , Christian Bisang , Christian Ludin
IPC分类号： A61K31/00
摘要： Specific template-fixed β-hairpin peptidomimetics of the general formula (I) wherein the single elements T or P are α-amino acid residues connected from the carbonyl (C═O) point of attachment to the nitrogen (N) of the next element in clockwise direction and wherein said elements, depending on their positions in the chain, are defined in the description and the claims have the property to act on the receptor CXCR7. Thus, these β-hairpin peptidomimetics can be useful in the treatment or prevention of diseases or conditions in the area of dermatological disorders, metabolic diseases, inflammatory diseases, fibrotic diseases, infectious diseases, neurological diseases, cardiovascular diseases, respiratory diseases, gastro-intestinal tract disorders, urological diseases, ophthalmic diseases, stomatological diseases, haematological diseases and cancer; or the mobilization of stem cells.
摘要翻译： 通式（I）的具体的模板固定β-发夹肽模拟物，其中单个元件T或P是从连接的羰基（C = O）连接到下一个元素的氮（N）连接的α-氨基酸残基 顺时针方向，并且其中所述元件取决于它们在链中的位置在描述中定义，并且权利要求具有作用于受体CXCR7的性质。 因此，这些β-发夹肽模拟物可用于治疗或预防皮肤病，代谢疾病，炎性疾病，纤维化疾病，传染病，神经系统疾病，心血管疾病，呼吸系统疾病，胃肠道疾病或疾病 泌尿系疾病，眼科疾病，口腔病，血液病和癌症; 或干细胞的动员。
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公开(公告)号：US07091313B2
公开(公告)日：2006-08-15
申请号：US11029331
申请日：2005-01-05
申请人： John A. Robinson , Daniel Obrecht
发明人： John A. Robinson , Daniel Obrecht
IPC分类号： A61K38/00
摘要： Template-fixed β-hairpin loop mimetics comprising a template corresponding to one of the structures (a), (b), (c), (d), (e), (f), (g), (h) and a template-fixed chain of 4 to 20 α-amino acid residues which, if their α-C atom is asymmetric, have L-configuration can be manufactured by a novel process which is based on a mixed solid- and solution phase synthetic strategy. If desired, this process can be modified to give the enantiomers of these template-fixed β-hairpin loop mimetics. These enantiomers are novel compounds, and many of said template-fixed β-hairpin loop mimetics themselves are also novel compounds. The template-fixed β-hairpin loop mimetics and their enantiomers can mimic flat surfaces of proteins and thus be used to probe large surface protein-protein interactions. Accordingly they can serve as lead finding tools for protein targets where it is difficult to find small-molecular-weight lead compounds.
摘要翻译： 模板固定的β-发夹环模拟物，其包含对应于结构（a），（b），（c），（d），（e），（f），（g），（h）和 4至20个α-氨基酸残基的模板固定链，如果它们的α-C原子是不对称的，则具有L-构型可以通过基于混合固相和溶液相合成策略的新方法制备。 如果需要，可以修饰该方法以得到这些模板固定的β-发夹环模拟物的对映异构体。 这些对映体是新化合物，许多所述模板固定的β-发夹环模拟物本身也是新的化合物。 模板固定的β-发夹环模拟物及其对映体可以模拟蛋白质的平坦表面，因此可用于探测大的表面蛋白质 - 蛋白质相互作用。 因此，它们可以作为难以发现小分子量铅化合物的蛋白质靶标的主要发现工具。
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公开(公告)号：US5837807A
公开(公告)日：1998-11-17
申请号：US607734
申请日：1996-02-27
CPC分类号： C07K7/08
摘要： This invention is directed to tetrahydronaphthalene compounds of the formula ##STR1## wherein R.sup.1 is hydrogen, bromine, cyano, formyl, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, aryloxy, lower aralkoxy or aryl; R.sup.2 is an amino acid residue or a chain of 2 to 20 amino acid residues wherein reactive moieties in the side chains of the amino acid residue(s) is/are protected or unprotected, and wherein the amino group of the N-terminal amino acid is a free or protected amino group; A.sup.1, A.sup.2, A.sup.3 and A.sup.4 each are .alpha.-amino acid residues wherein A.sup.1 and A.sup.2 are in the L configuration and A.sup.3 and A.sup.4 are in the D configuration when the .alpha.-C atom of said .alpha.-amino acid residue is asymmetric; X is oxygen or sulphur; Y is a residue of the formula ##STR2## n is 0 or 1; R.sup.3 is hydrogen or lower alkyl; R.sup.4 is hydrogen or lower alkyl; and Z and the two C atoms together are an aromatic ring selected from the group of benzene, furan, thiophene, pyridine or pyrimidine, wherein said aromatic ring is substituted or unsubstituted; and salts thereof and their intermediates. The compounds are useful as mimetics of exposed helical domains of proteins in order to clarify their role with respect to interactions with other proteins or with DNA or RNA through .alpha.-helical conformation. They are therefore valuable aids in the determination of biologically active peptide sequences and are accordingly so-called "research tools". They are also potentially useful as medicaments.
摘要翻译： 本发明涉及下式的四氢化萘化合物，其中R 1是氢，溴，氰基，甲酰基，羟基，低级烷基，低级烯基，低级炔基，低级烷氧基，芳氧基，低级芳烷氧基或芳基。 R2是氨基酸残基或2至20个氨基酸残基的链，其中氨基酸残基的侧链中的活性部分被保护或未被保护，并且其中N-末端氨基酸的氨基 是一个游离或保护的氨基; A1，A2，A3和A4各自为α-氨基酸残基，其中A1和A2为L构型，当所述α-氨基酸残基的α-C原子不对称时，A3和A4为D构型; X是氧或硫; （a）下式的残基：（a）
（b）n为0或1; R3是氢或低级烷基; R4是氢或低级烷基; Z和两个C原子一起是选自苯，呋喃，噻吩，吡啶或嘧啶的芳环，其中所述芳环是取代或未取代的; 及其盐及其中间体。 这些化合物可用作蛋白质暴露的螺旋结构域的模拟物，以便澄清其在与其他蛋白质的相互作用或通过α-螺旋构象与DNA或RNA的作用。 因此，它们是测定生物活性肽序列的有价值的辅助因素，因此是所谓的“研究工具”。 它们也可能用作药物。 -
公开(公告)号：US5644024A
公开(公告)日：1997-07-01
申请号：US292128
申请日：1994-08-17
摘要： The present invention is concerned with tetrahydronaphthalene derivatives which are mimics of domains of peptides or proteins which can interact with other proteins or with DNA or RNA through .alpha.-helical conformation, said tetrahydronaphthalene derivatives having the formulae: ##STR1## are valuable aids in the determination of biologically active peptide sequences and are accordingly so-called "research tools". They are, however, also potentially suitable as medicaments.
摘要翻译： 本发明涉及四氢萘衍生物，其是模拟可通过α-螺旋构象与其他蛋白质或与其它蛋白质或DNA或RNA相互作用的肽或蛋白质的结构域，所述四氢萘衍生物具有下列结构式： 有用的帮助确定生物活性肽序列，因此是所谓的“研究工具”。 然而，它们也可能适合作为药物。
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