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    • 4. 发明授权
    • Synthesis of N-substituted oligomers
    • N-取代的低聚物的合成
    • US5831005A
    • 1998-11-03
    • US441826
    • 1995-05-16
    • Ronald N. ZuckermanJanice M. KerrStephen B. H. KentWalter H. MoosReyna J. SimonDane A. Goff
    • Ronald N. ZuckermanJanice M. KerrStephen B. H. KentWalter H. MoosReyna J. SimonDane A. Goff
    • A61K38/00C07B61/00C07K1/04C07K7/06C07K7/08C07K14/00C08G69/10
    • C40B50/14C07K1/04C07K1/047C07K14/001C07K7/06C07K7/08C08G69/10A61K38/00B01J2219/00497B01J2219/00596B01J2219/0072C07B2200/11C40B40/10
    • A solid-phase method for the synthesis of N-substituted oligomers, such as poly (N-substituted glycines) (referred to herein as poly NSGs) is used to obtain oligomers, such as poly NSGs of potential therapeutic interest which poly NSGs can have a wide variety of side-chain substituents. Each N-substituted glycine monomer is assembled from two "sub-monomers" directly on the solid support. Each cycle of monomer addition consists of two steps: (1) acylation of a secondary amine bound to the support with an acylating agent comprising a leaving group capable of nucleophilic is displacement by --NH.sub.2, such as a haloacetic acid, and (2) introduction of the side-chain by nucleophilic displacement of the leaving group, such as halogen (as a resin-bound .alpha.-haloacetamide) with a sufficient amount of a second sub-monomer comprising an --NH.sub.2 group, such as a primary amine, alkoxyamine, semicarbazide, acyl hydrazide, carbazate or the like. Repetition of the two step cycle of acylation and displacement gives the desired oligomers. The efficient synthesis of a wide variety of oligomeric NSGs using automated synthesis technology of the present method makes these oligomers attractive candidates for the generation and rapid screening of diverse peptidomimetic libraries. The oligomers of the invention, such as N-substituted glycines (i.e. poly NSGs) disclosed here provide a new class of peptide-like compounds not found in nature, but which are synthetically accessible and have been shown to possess significant biological activity and proteolytic stability.
    • 用于合成N-取代的低聚物(例如聚(N-取代的甘氨酸)(本文称为多聚NSG))的固相方法用于获得低聚物,例如聚NSG可具有的潜在治疗兴趣的聚NSG 各种各样的侧链取代基。 每个N-取代的甘氨酸单体直接在固体支持物上由两个“亚单体”组装。 单体添加的每个循环由两个步骤组成:(1)用包含能够亲核的离去基团的酰化剂与载体结合的仲胺的酰化被-NH 2取代,例如卤代乙酸,和(2)引入 的侧链通过亲核取代离去基团,例如卤素(作为树脂结合的α-卤代乙酰胺)与足够量的包含-NH 2基团的第二亚单体如伯胺,烷氧基胺, 氨基脲,酰肼,卡巴肼等。 重复酰化和置换的两个步骤循环,得到所需的低聚物。 使用本发明方法的自动化合成技术有效合成各种各样的低聚NSG使得这些寡聚物成为用于不同肽模拟文库的产生和快速筛选的有吸引力的候选者。 本文公开的本发明的低聚物,例如N-取代的甘氨酸(即多聚NSG)提供了一类新型的肽样化合物,它们在自然界中没有发现,但是它们是合成可及的,并且已被证明具有显着的生物活性和蛋白水解稳定性 。
    • 7. 发明授权
    • Synthesis of N-substituted oligomers
    • N-取代的低聚物的合成
    • US5977301A
    • 1999-11-02
    • US485106
    • 1995-06-07
    • Ronald N. ZuckermanJanice M. KerrStephen B. H. KentWalter H. MoosReyna J. SimonDane A. Goff
    • Ronald N. ZuckermanJanice M. KerrStephen B. H. KentWalter H. MoosReyna J. SimonDane A. Goff
    • A61K38/00C07B61/00C07K1/04C07K7/06C07K7/08C07K14/00C08G69/10
    • C40B50/14C07K1/04C07K1/047C07K14/001C07K7/06C07K7/08C08G69/10A61K38/00B01J2219/00497B01J2219/00596B01J2219/0072C07B2200/11C40B40/10
    • A solid-phase method for the synthesis of N-substituted oligomers, such as poly (N-substituted glycines) (referred to herein as poly NSGs) is used to obtain oligomers, such as poly NSGs of potential therapeutic interest which poly NSGs can have a wide variety of side-chain substituents. Each N-substituted glycine monomer is assembled from two "sub-monomers" directly on the solid support. Each cycle of monomer addition consists of two steps: (1) acylation of a secondary amine bound to the support with an acylating agent comprising a leaving group capable of nucleophilic displacement by --NH.sub.2, such as a haloacetic acid, and (2) introduction of the side-chain by nucleophilic displacement of the leaving group, such as halogen (as a resin-bound .alpha.-haloacetamide) with a sufficient amount of a second sub-monomer comprising an --NH.sub.2 group, such as a primary amine, alkoxyamine, semicarbazide, acyl hydrazide, carbazate or the like. Repetition of the two step cycle of acylation and displacement gives the desired oligomers. The efficient synthesis of a wide variety of oligomeric NSGs using automated synthesis technology of the present method makes these oligomers attractive candidates for the generation and rapid screening of diverse peptidomimetic libraries. The oligomers of the invention, such as N-substituted glycines (i.e. poly NSGs) disclosed here provide a new class of peptide-like compounds not found in nature, but which are synthetically accessible and have been shown to possess significant biological activity and proteolytic stability.
    • 用于合成N-取代的低聚物(例如聚(N-取代的甘氨酸)(本文称为多聚NSG))的固相方法用于获得低聚物,例如聚NSG可具有的潜在治疗兴趣的聚NSG 各种各样的侧链取代基。 每个N-取代的甘氨酸单体直接在固体支持物上由两个“亚单体”组装。 单体添加的每个循环由两个步骤组成:(1)用包含能通过-NH 2的亲核置换的离去基团(如卤代乙酸)的酰化剂酰化与载体结合的仲胺,和(2)引入 通过亲核取代离去基团的侧链,例如卤素(作为树脂结合的α-卤代乙酰胺)与足够量的包含-NH 2基团的第二亚单体如伯胺,烷氧基胺,氨基脲 酰基酰肼,肼基甲酸酯等。 重复酰化和置换的两个步骤循环,得到所需的低聚物。 使用本发明方法的自动化合成技术有效合成各种各样的低聚NSG使得这些寡聚物成为用于不同肽模拟文库的产生和快速筛选的有吸引力的候选者。 本文公开的本发明的低聚物,例如N-取代的甘氨酸(即多聚NSG)提供了一类新型的肽样化合物,它们在自然界中没有发现,但是它们是合成可及的,并且已被证明具有显着的生物活性和蛋白水解稳定性 。
    • 9. 发明授权
    • Hindered linking agents and methods
    • 受阻连接剂和方法
    • US5183904A
    • 1993-02-02
    • US796048
    • 1991-11-20
    • Stephen F. CarrollDane A. Goff
    • Stephen F. CarrollDane A. Goff
    • A61K47/48C07D333/36C07D333/50C07D333/66C07D409/04
    • C07D333/50A61K47/48715C07D333/36C07D333/66C07D409/04
    • Novel compounds and methods for the formation of disulfide linkages are presented. The novel compounds employed are substituted 2-iminothiolane hydrohalide linking agents of the following formula (I): ##STR1## wherein, X is halogen;R.sub.1 is COOR.sub.5 ; halogen; nitro; unsubstituted or halogenated C.sub.1-8 alkyl; unsubstituted or halogenated C.sub.1-8 alkoxy; unsubstituted or halogenated C.sub.2-8 alkenyl; unsubstituted or halogenated C.sub.2-8 alkynyl; unsubstituted C.sub.3-8 cycloalkyl; unsubstituted aryl; aryl substituted with 1 to 3 substituents selected from halogen, amino, unsubstituted or halogenated C.sub.1-8 alkyl, or unsubstituted or halogenated C.sub.1-8 alkoxy; unsubstituted heterocycle; or heterocycle substituted with 1 to 3 substituents selected from amino, halogen, unsubstituted or halogenated C.sub.1-8 alkyl, or unsubstituted or halogenated C.sub.1-8 alkoxy;each of R.sub.2, R.sub.3 and R.sub.4 is independently hydrogen or selected from the values of R.sub.1 ; orR.sub.1 and R.sub.2 together form a C.sub.2-5 alkylene bridge, unsubstituted or substituted with one to five C.sub.1-4 alkyl groups; orR.sub.1 or R.sub.2 together with R.sub.3 form a C.sub.1-5 alkylene bridge, unsubstituted or substituted with one to five C.sub.1-4 alkyl groups; andR.sub.5 is hydrogen or C.sub.1-8 alkyl.Also included in the invention are methods for covalently linking two species, which methods comprise reacting one or both of the two species with a crosslinking agent of the above formula (I) and mixing the two species together. The resulting conjugated species containing the linking group are also included in the invention.Further included in the invention is the use of a quenching agent which allows direct measurement of the reaction of 2-iminothiolanes with nucleophilic groups.
    • 提出了新的化合物和形成二硫键的方法。 所用的新化合物是下式(I)的取代的2-亚氨基硫烷氢卤化物连接剂:其中X是卤素; R1为COOR5; 卤素; 硝基 未取代或卤代C 1-8烷基; 未取代或卤代C 1-8烷氧基; 未取代或卤代C 2-8烯基; 未取代或卤代C 2-8炔基; 未取代的C 3-8环烷基; 未取代的芳基; 被1至3个选自卤素,氨基,未取代或卤代C 1-8烷基的取代基取代的芳基,或未取代或卤代C 1-8烷氧基; 未取代的杂环; 或被1至3个选自氨基,卤素,未取代或卤代C 1-8烷基,或未取代或卤代C 1-8烷氧基取代的杂环; R 2,R 3和R 4各自独立地为氢或选自R 1的值; 或R 1和R 2一起形成未被取代或被一至五个C 1-4烷基取代的C 2-5亚烷基桥; 或R 1或R 2与R 3一起形成未被取代或被一至五个C 1-4烷基取代的C 1-5亚烷基桥; 并且R 5是氢或C 1-8烷基。 本发明还包括共价连接两种物质的方法,该方法包括使两种物质中的一种或两种与上式(I)的交联剂反应并将两种物质混合在一起。 所得到的含有连接基团的共轭物质也包括在本发明中。 进一步包括在本发明中的是使用猝灭剂,其允许直接测量2-亚氨基硫醇与亲核基团的反应。