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1.发明授权Bicyclic GnRH antagonists and a method for regulating the secretion of gonadotropins 失效双环GnRH拮抗剂和调节促性腺激素分泌的方法
公开(公告)号：US5371070A
公开(公告)日：1994-12-06
申请号：US973989
申请日：1992-11-09
摘要： Peptides which have substantial bioactivity to inhibit the secretion of gonadotropins by the pituitary gland and to inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation and/or the release of steroids by the gonads. They may also be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are bicyclic analogs of the decapeptide GnRH having two covalent bonds, between the residues in the 4- and 10-positions and the residues in the 5- and 8-positions. The latter linkage includes peptide bonds between a residue of an .alpha.-amino acid outside of the main chain and a side-chain carboxyl group of the 5-position residue and a side-chain amino group of the 8-position residue.
摘要翻译： 具有大量生物活性以抑制垂体分泌促性腺激素并抑制性腺释放类固醇的肽。 施用有效量的这种GnRH拮抗剂可防止性腺的排卵和/或释放类固醇。 它们也可用于治疗类固醇依赖性肿瘤，如前列腺和乳腺肿瘤。 肽是具有两个共价键的十肽GnRH的双环类似物，在4-和10-位之间的残基和5-和8-位的残基之间。 后一连接包括在主链外部的α-氨基酸的残基与5位残基的侧链羧基和8位残基的侧链氨基之间的肽键。
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公开(公告)号：US5064939A
公开(公告)日：1991-11-12
申请号：US475767
申请日：1990-02-06
申请人： Jean E. F. Rivier , Steven C. Koerber , Arnold T. Hagler , Catherine L. Rivier , Wylie W. Vale, Jr.
发明人： Jean E. F. Rivier , Steven C. Koerber , Arnold T. Hagler , Catherine L. Rivier , Wylie W. Vale, Jr.
摘要： Peptides which inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. These peptides may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides include cyclic, bicyclic and tricyclic analogs of the decapeptide GnRH, and preferably there are at least two covalent bonds between the residues in the 4- and 10-positions, the residues in the 5- and 8-positions and the residues in the 1- and 3-positions, respectively. Examples of such bonds include a disulfide linkage between Cys residues, an amide linkage between a side chain amino group and a side chain carboyxl group, a dicarba linkage between side-chain alkyl groups, and a carba linkage between a side-chain alkyl group and a side-chain sulfhydryl group.
摘要翻译： 抑制垂体分泌促性腺激素并抑制性腺释放类固醇的肽。 施用有效量的这种GnRH拮抗剂防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 这些肽可用于治疗类固醇依赖性肿瘤，例如前列腺和乳腺肿瘤。 肽包括十肽GnRH的环状，双环和三环类似物，并且优选在4-和10-位残基之间存在至少两个共价键，5-和8-位中的残基和 分别为1-和3-位。 这种键的实例包括Cys残基之间的二硫键，侧链氨基和侧链羰基之间的酰胺键，侧链烷基之间的二氨键，侧链烷基与侧链烷基之间的连接 侧链巯基。
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公开(公告)号：US5807986A
公开(公告)日：1998-09-15
申请号：US579216
申请日：1995-12-28
申请人： Jean E. F. Rivier , John S. Porter
发明人： Jean E. F. Rivier , John S. Porter
IPC分类号： G01N33/48 , A61K38/00 , C07C233/47 , C07C233/56 , C07C235/42 , C07C271/22 , C07C279/14 , C07K1/04 , C07K1/10 , C07K7/06 , C07K7/23 , C07K14/575 , C07K14/655 , G01N33/68 , C07K1/00
CPC分类号： C07C271/22 , C07C233/47 , C07C233/56 , C07C235/42 , C07C279/14 , C07K1/047 , C07K14/57509 , C07K14/655 , C07K7/23 , A61K38/00
摘要： Compounds termed "betides" mimic peptides and contain one or more residues of aminoglycine, C.sup..alpha. -aminoalanine, aminosarcosine or the like wherein the side chain amino group has been acylated and optionally also alkylated. Generally, betides have the formula: X.sub.N -X.sub.1 -X.sub.2 -X.sub.3 -X.sub.m -X.sub.4 -X.sub.5 -X.sub.6 -X.sub.C, where X.sub.N is an acyl or other N-terminal group or a peptide up to about 50 amino acids in length having such a group; X.sub.C is OH, NH.sub.2 or other C-terminal group or a peptide up to about 50 amino acids in length having such a group; and X.sub.1 -X.sub.6 are each independently a betidamino acid or .alpha.-amino acid or des-X; and X.sub.m is a peptide up to about 50 amino acids or des-X; provided however that at least one of X.sub.1 -X.sub.6 is a betidamino acid residue having the formula: ##STR1## wherein R.sub.0 is H or CH.sub.3, R and R.sub.2 are H or lower alkyl, and R.sub.3 is an acyl group, an isocyanate or isothiocyanate group, a sulfonyl group or the like. To make a betide, an aminoglycine residue is subjected to side chain acylation, and optionally also alkylation, after it is coupled into a peptide intermediate. By synthesizing betides with multiple substituents at one or more positions in an otherwise peptidic chain, efficient screening of betides which mimic peptides having a large number of different natural or unnatural amino acid substituents at a particular position, and optionally both D- and L-isomers thereof, is possible.
摘要翻译： 称为“betide”的化合物模拟肽并含有一个或多个氨基糖基，Cα-氨基丙氨酸，氨基肌氨酸等残基，其中侧链氨基已被酰化并任选也被烷基化。 一般来说，肽具有下式：XN-X1-X2-X3-Xm-X4-X5-X6-XC，其中XN是酰基或其它N-末端基团或长达约50个氨基酸的肽，具有这样的 组; XC是OH，NH2或其它C末端基或长达约50个氨基酸的肽，具有这样的基团; 和X 1 -X 6各自独立地为二氨基酸或α-氨基酸或des-X; Xm是至多约50个氨基酸或des-X的肽; 但是X-X6中的至少一个是具有下式的下式氨基酸残基：其中R 0是H或CH 3，R 2和R 2是H或低级烷基，R 3是酰基，异氰酸酯或异硫氰酸酯基 ，磺酰基等。 为了使之发生反应，氨基糖残基在其被偶联到肽中间体后进行侧链酰化，并且任选地也进行烷基化。 通过在另一个肽链的一个或多个位置合成具有多个取代基的肽，有效筛选模拟在特定位置具有大量不同天然或非天然氨基酸取代基的肽，以及任选的D-和L-异构体 是可能的。
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公开(公告)号：US5296468A
公开(公告)日：1994-03-22
申请号：US6729
申请日：1993-01-21
申请人： Carl A. Hoeger , Jean E. F. Rivier , Paula G. Theobald , John S. Porter , Catherine L. Rivier , Wylie W. Vale, Jr.
发明人： Carl A. Hoeger , Jean E. F. Rivier , Paula G. Theobald , John S. Porter , Catherine L. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07C279/24 , C07C279/28 , C07C313/30 , C07D249/14 , C07K7/02 , C07K7/23 , A61K37/38 , C07K7/06 , C07K7/20
CPC分类号： C07K7/02 , C07C279/24 , C07C279/28 , C07C313/30 , C07D249/14 , C07K7/23 , A61K38/00 , C07C2101/14 , Y10S514/80 , Y10S930/11
摘要： Peptides which include unnatural amino acids and which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such peptides that are GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The antagonists may be used to treat steroid-dependent tumors, such as prostatic and mammary tumors. The peptides are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions. Such unnatural amino acids are useful in the synthesis of peptides and have the formula U.sup.* : ##STR1## where W is (CH.sub.2).sub.n or ##STR2## n is an integer from 1 to 6; and j=1, 2 or 3. Preferably, either Y is N--CN, X is NH and R.sub.2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pridyl or ##STR3## where R.sub.11 is H or acyl.
摘要翻译： 包括非天然氨基酸的肽，其通过垂体抑制或促进促性腺激素的分泌并抑制性腺释放类固醇。 施用有效量的这种肽作为GnRH拮抗剂可防止雌性哺乳动物卵的排卵和/或由性腺释放类固醇。 拮抗剂可用于治疗类固醇依赖性肿瘤，例如前列腺和乳腺肿瘤。 肽是十肽GnRH的类似物，其中在3-，5-，6-和/或8-位存在至少一个非天然氨基酸残基。 这样的非天然氨基酸可用于肽的合成，并具有其中W是（CH 2）n或（*化学结构*）n是1至6的整数的式U *：（*化学结构*）; 优选地，Y是N-CN，X是NH，R 2是烷基，改性烷基，链烯基，炔基，芳基或甲基酰基或（*化学结构*），其中R 11是H或酰基 。
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公开(公告)号：US5169935A
公开(公告)日：1992-12-08
申请号：US541810
申请日：1990-06-20
摘要： Methods for making peptides of a suitable length for solid phase synthesis, which peptides include in their sequence a pair of residues of a different character which have acylated side chains and a residue which has an N-alkylated side chain. A peptide intermediate is constructed on the resin using commercially available starting materials. The N-terminus can be acylated by removing the .alpha.-amino protecting group and acylating under standard conditions. First primary amino protecting groups included in those residues to be acylated are removed, and acylation is effected, preferably by using a carboxypyridine or a similar heterocyclic acylating agent. Following such side chain acylation, a second protecting group included in the residue to be N-alkylated is removed, and the N-alkylation reaction is carried out while the peptide remains on the resin using a borohydride and an appropriate aldehyde or ketone. Following cleavage from the resin and removal of any protecting groups still remaining, the peptide is appropriately purified, thus requiring only a single purification to be carried out while forming a synthetic peptide including residues for which the modified amino acids are not readily commercially available.
摘要翻译： 制备用于固相合成的合适长度的肽的方法，该肽在其序列中包括具有酰化侧链的不同特征的残基和具有N-烷基化侧链的残基。 使用市售原料在树脂上构建肽中间体。 可以通过除去α-氨基保护基并在标准条件下酰化来酰化N-末端。 除去要被酰化残留物中包括的第一个伯氨基保护基，优选通过使用羧基吡啶或类似的杂环酰化剂进行酰化。 在这样的侧链酰化之后，除去待N-烷基化的残基中的第二保护基，并且使用硼氢化钠和适当的醛或酮在肽保留在树脂上的同时进行N-烷基化反应。 在从树脂切割并除去仍然保留的任何保护基之后，肽被适当地纯化，因此仅需要进行单次纯化，同时形成包含修饰氨基酸不容易商业获得的残基的合成肽。
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公开(公告)号：US4701499A
公开(公告)日：1987-10-20
申请号：US799339
申请日：1986-02-03
IPC分类号： C07K1/04 , C07K5/097 , C08F8/18 , C08F12/08 , C08F112/08 , C08F212/08
CPC分类号： C07K5/0823 , C07K1/04 , Y10S930/28
摘要： Peptide N-alkylamides, and other C-terminal N-substituted amides, can be synthesized using solid-phase synthesis on a benzene-containing resin which is suitably methylated. Reactive amino groups are attached directly or indirectly to the methyl groups, for example, such as by reacting commercially available chloromethylated polystyrene resins with an alkylamine to create a resin-amine. The C-terminal amino acid of the desired peptide is linked to the resin-amine via an amide linkage, and the peptide is thereafter built in normal fashion. Treatment of the completed peptide intermediate with HF is effective to both effect deprotection and cleave the peptide from the resin in the form of the N-substituted amide. Examples include peptide N-ethylamides, N-fluoroethylamide, N-anilides and other substituted N-benzylamides.
摘要翻译： 肽N-烷基酰胺和其它C-末端N-取代的酰胺可以使用合适甲基化的含苯树脂上的固相合成来合成。 反应性氨基直接或间接连接到甲基上，例如通过使市售氯甲基化聚苯乙烯树脂与烷基胺反应以产生树脂 - 胺。 所需肽的C-末端氨基酸通过酰胺键与树脂 - 胺连接，然后以正常方式构建肽。 用HF处理完成的肽中间体可有效地进行脱保护并以N-取代酰胺的形式从树脂切割肽。 实例包括肽N-乙酰胺，N-氟乙基酰胺，N-酰苯胺和其它取代的N-苄基酰胺。
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公开(公告)号：US4569967A
公开(公告)日：1986-02-11
申请号：US545077
申请日：1983-10-24
CPC分类号： C07K5/0823 , C07K1/04
摘要： Peptide N-alkylamides, and other C-terminal N-substituted amides, can be synthesized using solid-phase synthesis on a benzene-containing resin which is suitably methylated. Reactive amino groups are attached directly or indirectly to the methyl groups, for example, such as by reacting commercially available chloromethylated polystyrene resins with an alkylamine to create a resin-amine. The C-terminal amino acid of the desired peptide is linked to the resin-amine via an amide linkage, and the peptide is thereafter built in normal fashion. Treatment of the completed peptide intermediate with HF is effective to both effect deprotection and cleave the peptide from the resin in the form of the N-substituted amide. Examples include peptide N-ethylamides, N-fluoroethylamide, N-anilides and other substituted N-benzylamides.
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公开(公告)号：US5710249A
公开(公告)日：1998-01-20
申请号：US465854
申请日：1995-06-06
IPC分类号： A61K38/04 , A61K38/00 , C07C277/08 , C07C279/18 , C07C279/24 , C07C279/28 , C07C313/30 , C07D249/14 , C07K1/00 , C07K7/02 , C07K7/06 , C07K7/23 , C07K2/00
CPC分类号： C07C279/24 , C07C277/08 , C07C279/28 , C07C313/30 , C07D249/14 , C07K1/006 , C07K7/02 , C07K7/23 , A61K38/00 , C07C2101/14 , Y02P20/55
摘要： Methods of making unnatural amino acids are provided which unnatural amino acids can be incorporated into peptides which either inhibit or promote the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. These unnatural amino acids are useful in the synthesis of peptides and have the formula (a): ##STR1## where W is (CH.sub.2) or ##STR2## n is an integer from 1 to 6; j=1, 2 or 3, and preferably, Y is N--CN, X is NH and R.sub.2 is alkyl, modified alkyl, alkenyl, alkynyl, aryl or methyl pyridyl. Disclosed are peptides that are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions.
摘要翻译： 提供了制备非天然氨基酸的方法，其可将非天然氨基酸并入肽中，所述肽抑制或促进垂体腺分泌促性腺激素并抑制性腺释放类固醇。 这些非天然氨基酸可用于肽的合成并具有式（a）：其中W是（CH 2）或
n是1至6的整数; j = 1,2或3，优选Y为N-CN，X为NH，R 2为烷基，改性烷基，烯基，炔基，芳基或甲基吡啶基。 公开了作为十肽GnRH的类似物的肽，其中在3-，5-，6-和/或8-位存在至少一个非天然氨基酸的残基。 -
公开(公告)号：US5580957A
公开(公告)日：1996-12-03
申请号：US210619
申请日：1994-03-18
IPC分类号： A61K38/00 , C07C277/08 , C07C279/24 , C07C279/28 , C07C313/30 , C07D249/14 , C07K7/02 , C07K7/23 , C07K14/695
CPC分类号： C07C277/08 , C07C279/24 , C07C279/28 , C07C313/30 , C07D249/14 , C07K7/02 , C07K7/23 , A61K38/00 , C07C2101/14
摘要： Peptides which include unnatural amino acids and which either promote or inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such peptides that are GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads and may be used to treat steroid-dependent tumors. The agonists can be used for control of reproduction processes, to treat precocious puberty, endometriosis, and the like. The peptides are analogs of the decapeptide GnRH wherein there is at least one residue of an unnatural amino acid in the 3-, 5-, 6- and/or 8-positions. Unnatural amino acids having the following formula are incorporated in a preferred group of synthesized peptides: ##STR1## Methods for synthesizing such peptides having the triazole side chains are disclosed wherein one side chain modification (or two simultaneously) is carried out on an amino-substituted phenylalanine residue in a peptide chain which is a part of a peptidoresin.
摘要翻译： 包括非天然氨基酸并且促进或抑制垂体分泌促性腺激素并抑制性腺释放类固醇的肽。 施用有效量的这种肽作为GnRH拮抗剂可防止雌性哺乳动物卵的排卵和/或由性腺释放类固醇，并可用于治疗类固醇依赖性肿瘤。 激动剂可用于控制繁殖过程，治疗早熟青春期，子宫内膜异位症等。 肽是十肽GnRH的类似物，其中在3-，5-，6-和/或8-位有至少一个非天然氨基酸残基。 具有下列结构式的非天然氨基酸被掺入优选的合成肽组中：具有j = 1,2或3的合成肽。公开了合成具有三唑侧链的肽的方法，其中一个侧链修饰（或两个同时 ）在作为肽聚糖树脂的一部分的肽链中的氨基取代的苯丙氨酸残基上进行。
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公开(公告)号：US5506207A
公开(公告)日：1996-04-09
申请号：US210627
申请日：1994-03-18
IPC分类号： A61K38/00 , A61P13/02 , A61P15/00 , A61P29/00 , A61P31/12 , A61P35/00 , A61P37/04 , C07K7/06 , C07K7/23 , A61K38/04 , C07K7/00
摘要： Analogs of the decapeptide GnRH which include two significantly modified amino acids at positions 5 and 6 inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads and may be used to treat steroid-dependent tumors. Particularly effective peptides which are soluble in water at physiologic pH and which have a low tendency to gel when administered in vivo have the following formula:Ac-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Q.sub.1)(3-amino-1,2,4 triazole)-D-Aph(Q.sub.2)(3-amino 1,2,4-triazole)-Leu-Lys (isopropyl)-Pro-D-Ala-NH.sub.2,where Q.sub.1 and Q.sub.2 are amino acids, such as Gly, .beta.-Ala, Ala, D-Ala, Ser, Aib, Ahx and Gab. Examples of other GnRH antagonists includeAc-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Atz)-D-Aph(Ac)-Leu-Lys(isopropyl)-Pro-D-Ala-NH.sub.2,Ac-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(.beta.-Ala)(3-amino-1,2,4 triazole)-D-Aph(.beta.-Ala)(3-amino-1,2,4 triazole)-Leu-Lys(isopropyl)-Pro-D-Ala-NH.sub.2,Ac-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Ac-D-Ser)-D-Aph(Ac-D-Ser)-Leu-Lys(isopropyl)-Pro-D-Ala-NH.sub.2, andAc-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Ac)-D-Aph(Ac)-Leu-Lys(isopropyl)-Pro-D-Ala-NH.sub.2.
摘要翻译： 包括位置5和6在内的两个显着修饰的氨基酸的十肽GnRH的类似物抑制垂体腺分泌促性腺激素并抑制性腺释放类固醇。 施用有效量的这种GnRH拮抗剂防止雌性哺乳动物卵的排卵和/或由性腺释放类固醇，并可用于治疗类固醇依赖性肿瘤。 Ac-β-D-2NAL-（4Cl）D-Phe-D-3PAL-Ser-Aph在生理pH下可溶于水的并且在体内施用时具有低凝胶倾向的特别有效的肽具有下式： （Q1）（3-氨基-1,2,4-三唑）-D-Aph（Q2）（3-氨基-1,2,4-三唑）-Leu-Lys（异丙基）-Pro-D-Ala-NH 2， 其中Q1和Q2是氨基酸，例如Gly，β-Ala，Ala，D-Ala，Ser，Aib，Ahx和Gab。 其他GnRH拮抗剂的实例包括Ac-β-D-2NAL-（4Cl）D-Phe-D-3PAL-Ser-Aph（Atz）-D-Aph（Ac）-Leu-Lys（异丙基） Ala-NH2，Ac-β-D-2NAL-（4Cl）D-Phe-D-3PAL-Ser-Aph（β-Ala）（3-氨基-1,2,4-三唑）-D-Aph（β- Ala）（3-氨基-1,2,4-三唑）-Leu-Lys（异丙基）-Pro-D-Ala-NH 2，Ac-β-D-2NAL-（4Cl）D-Phe-D-3PAL-Ser （Ac-D-Ser）-D-Aph（Ac-D-Ser）-Leu-Lys（异丙基）-Pro-D-Ala-NH 2和Ac-β-D-2NAL-（4Cl） Phe-D-3PAL-Ser-Aph（Ac）-D-Aph（Ac）-Leu-Lys（异丙基）-Pro-D-Ala-NH 2。
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