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    Peptides intermediates for making GnRH antagonists
    2.
    发明授权
    Peptides intermediates for making GnRH antagonists 失效
    用于制备GnRH拮抗剂的肽中间体

    公开(公告)号：US06747125B1

    公开(公告)日：2004-06-08

    申请号：US08727798

    申请日：1996-10-07

    申请人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula Guess Theobald ,  John S. Porter

    发明人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula Guess Theobald ,  John S. Porter

    IPC分类号： C07K1600

    CPC分类号： C07D249/14 ,  A61K38/00 ,  C07C277/08 ,  C07C279/28 ,  C07K1/006 ,  C07K7/23 ,  Y10S514/80 ,  Y10S930/11 ,  Y10S930/13

    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:

    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一组合成肽中：

    GnRH analogs
    3.
    发明授权
    GnRH analogs 失效
    GnRH类似物

    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 。

    GNRH antagonists XIII
    4.
    发明授权
    GNRH antagonists XIII 失效
    GNRH拮抗剂十三

    公开(公告)号：US5506207A

    公开(公告)日：1996-04-09

    申请号：US210627

    申请日：1994-03-18

    申请人： Jean E. F. Rivier ,  John S. Porter ,  Carl A. Hoeger ,  Guangcheng Jiang ,  Catherine L. Rivier

    发明人： Jean E. F. Rivier ,  John S. Porter ,  Carl A. Hoeger ,  Guangcheng Jiang ,  Catherine L. Rivier

    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

    CPC分类号： C07K7/23 ,  A61K38/00

    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。

    GnRH analogs
    5.
    发明授权
    GnRH analogs 失效
    GNRH模拟

    公开(公告)号：US5169932A

    公开(公告)日：1992-12-08

    申请号：US545239

    申请日：1990-06-27

    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： A61K38/22 ,  A61K38/00 ,  A61K38/04 ,  C07C279/24 ,  C07C279/28 ,  C07C313/30 ,  C07D249/14 ,  C07K7/02 ,  C07K7/23 ,  C07K14/575

    CPC分类号： C07K7/23 ,  C07C279/24 ,  C07C279/28 ,  C07C313/30 ,  C07D249/14 ,  C07K7/02 ,  A61K38/00 ,  C07C2101/14 ,  Y10S514/80 ,  Y10S930/11

    摘要： Peptides which include unnatural amino acides 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-position, the 5-position, the 6-position and/or the 8-position. Such unnatural amino acids are useful in the synthesis of peptides and have the formula U*: ##STR1## where n is an integer from 1 to 6; Y is N--CN, N--CONHR.sub.9, S, O or CH--NO.sub.2 ; R.sub.9 is H, Ac, lower alkyl, aromatic or heterocyclic; X is NH, O, S, M.sub.1 (CH.sub.q).sub.p M.sub.2 or M.sub.1 --(CH.sub.2).sub.p' --M.sub.2 (CH.sub.2).sub.p" --M.sub.3, where M.sub.1 is NR.sub.10, O, S or CHR.sub.3 wherein R.sub.3 is methyl, ethyl, propyl, phenyl, pyridinyl, pyrimidinyl or purinyl, q is 1 or 2; p, p' and p" are integers between O and 6; R.sub.10 is H, lower alkyl or the like, and M.sub.2 and M.sub.3 are M.sub.1, COOH, CONH.sub.2, COOR.sub.3 or CN; R.sub.1 is H, alkyl, modified alkyl, alkenyl, alkynyl, aryl or a direct bond to X; R.sub.2 is R.sub.1, OH, NH.sub.2, NHR.sub.1, or heterocycle.

    摘要翻译： 包括非天然氨基酸的肽，其抑制或促进垂体分泌促性腺激素并抑制性腺释放类固醇。 施用有效量的这种肽作为GnRH拮抗剂可防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 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-位，5-位，6-位和/或8-位存在至少一个非天然氨基酸残基。 这种非天然氨基酸可用于肽的合成并具有式U *：其中n是1至6的整数; Y是N-CN，N-CONHR9，S，O或CH-NO2; R9是H，Ac，低级烷基，芳族或杂环基; X是NH，O，S，M1（CHq）pM2或M1-（CH2）p'-M2（CH2）p'-M3，其中M1是NR10，O，S或CHR3，其中R3是甲基，乙基，丙基 ，苯基，吡啶基，嘧啶基或嘌呤基，q为1或2; p，p'和p“是O和6之间的整数; R10为H，低级烷基等，M2和M3为M1，COOH，CONH2，COOR3或CN; R 1是H，烷基，改性烷基，链烯基，炔基，芳基或与X的直接键; R2是R1，OH，NH2，NHR1或杂环。

    Method of making peptides
    6.
    发明授权
    Method of making peptides 失效
    制作肽的方法

    公开(公告)号：US5169935A

    公开(公告)日：1992-12-08

    申请号：US541810

    申请日：1990-06-20

    申请人： Carl A. Hoeger ,  Paula G. Theobald ,  John S. Porter ,  Jean E. F. Rivier

    发明人： Carl A. Hoeger ,  Paula G. Theobald ,  John S. Porter ,  Jean E. F. Rivier

    IPC分类号： C07K1/06 ,  C07K7/23

    CPC分类号： C07K1/064 ,  C07K7/23 ,  Y02P20/55

    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。

    Amino acids useful in making GnRH analogs
    7.
    发明授权
    Amino acids useful in making GnRH analogs 失效
    用于制备GnRH类似物的氨基酸

    公开(公告)号：US5352796A

    公开(公告)日：1994-10-04

    申请号：US78965

    申请日：1993-06-17

    申请人： Carl A. Hoeger ,  Jean E. F. Rivier ,  John S. Porter

    发明人： Carl A. Hoeger ,  Jean E. F. Rivier ,  John S. Porter

    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

    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： Unnatural amino acids are provided which 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).sub.n 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; or the formula (b): ##STR3## where R.sub.11 is H or acyl and W is as defined in (a), and preferably R.sub.11 is H and W is ##STR4## 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： 可以提供非天然氨基酸，其可以并入肽中，其抑制或促进垂体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为（CH 2）n或 n为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; 或式（b）：其中R11为H或酰基，W为如（a）中所定义的式（b）：其中R 11为H且W为本文所公开的肽，其为存在十肽GnRH的类似物 在3-，5-，6-和/或8-位的至少一个非天然氨基酸残基。

    GnRH analogs
    10.
    发明授权
    GnRH analogs 失效
    GnRH类似物

    公开(公告)号：US5580957A

    公开(公告)日：1996-12-03

    申请号：US210619

    申请日：1994-03-18

    申请人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula G. Theobald ,  John S. Porter

    发明人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula G. Theobald ,  John S. Porter

    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。