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 。

公开(公告)号：US5098995A

公开(公告)日：1992-03-24

申请号：US342751

申请日：1989-04-25

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier

IPC分类号： A61K38/04 ,  A61K38/00 ,  A61P5/00 ,  C07K14/575 ,  C07K14/60

CPC分类号： C07K14/60 ,  A61K38/00

摘要： The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals, including humans and also resist enzymatic degradation in the body. The peptides have the sequence: (B)R.sub.1 -R.sub.2 -R.sub.3 -Ala-(Q.sub.1)R.sub.5 -Phe-Thr-R.sub.8 -Ser(Q.sub.2)R.sub.10 -Arg-R.sub.12 -(Q.sub.3)R.sub.13 -Leu-R.sub.15 -Gln-(Q.sub.4)Leu-R.sub.18 -(Q.sub.5)Ala-Arg-R.sub.21 -(Q.sub.6)R.sub.22 -(Q.sub.7)Leu-R.sub.24 -R.sub.25 -(Q.sub.8)R.sub.26 -(Q.sub.9)R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-R.sub.34 -Asn-Gln-Glu-R.sub.38 -R.sub.39 -R.sub.40 -Arg-R.sub.42 -R.sub.43 -R.sub.44 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His; B is H, C.sup.a Me, N.sup.a Me, desamino, Ac or For; R.sub.2 is Ala, D-Ala, NMA or D-NMA; R.sub.3 is Asp or D-Asp; R.sub.5 is Ile or Leu; R.sub.8 is Ser, Asn, Lys, Arg, Asp or Glu; R.sub.10 is Tyr, D-Tyr or Phe; R.sub.12 is Arg or Lys; R.sub.13 is Ile, Val, Leu or Ala; R.sub.15 is Gly or Ala; R.sub.18 is Ser or Tyr; R.sub.21 is Lys, D-Lys, Arg or D-Arg; R.sub.22 is Leu, Ile, Ala or Val; R.sub.24 is Gln or His; R.sub.25 is Asp or Glu; R.sub.26 is Ile or Leu; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn or Ser; R.sub.34 is Ser or Arg; R.sub.38 is Arg or Gln; R.sub.39 is Gly or Arg; R.sub.40 is Ala or Ser; R.sub.42 is Phe, Ala or Val; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid; Q.sub.1 -Q.sub.9 are either H or C.sup.a Me, provided however that one of Q.sub.1 -Q.sub.9 is C.sup.a Me. These peptides may also be used diagnostically, and the C-terminus can be shortened to residue-29.

摘要翻译： 本发明提供了合成肽，其在刺激包括人在内的动物中垂体GH的释放方面非常有效，并且还抵抗体内的酶降解。 肽具有以下顺序：（B）R1-R2-R3-Ala-（Q1）R5-Phe-Thr-R8-Ser（Q2）R10-Arg-R12-（Q3）R13-Leu-R15-Gn- （Q4）Leu-R18-（Q5）Ala-Arg-R21-（Q6）R22-（Q7）Leu-R24-R25-（Q8）R26-（Q9）R27-R28-Arg-Gln-Gln-Gly- Glu-R34-Asn-Gln-Glu-R38-R39-R40-Arg-R42-R43-R44其中R1是Tyr，D-Tyr，Met，Phe，D-Phe，pCl-Phe，Leu，His或D- 他的 B是H，CaMe，NaMe，desamino，Ac或For; R2是Ala，D-Ala，NMA或D-NMA; R3是Asp或D-Asp; R5是Ile或Leu; R8是Ser，Asn，Lys，Arg，Asp或Glu; R10是Tyr，D-Tyr或Phe; R12是Arg或Lys; R13是Ile，Val，Leu或Ala; R15是Gly或Ala; R18为Ser或Tyr; R21为Lys，D-Lys，Arg或D-Arg; R22是Leu，Ile，Ala或Val; R24是Gln或His; R25为Asp或Glu; R26是Ile或Leu; R27是Met，D-Met，Ala，Nle，Ile，Leu，Nva或Val; R28为Asn或Ser; R34是Ser或Arg; R38是Arg或Gln; R39为Gly或Arg; R40是Ala或Ser; R42是Phe，Ala或Val; R43是Asn或Arg; R44是天然氨基酸; Q1-Q9是H或CaMe，但Q1-Q9中的一个是CaMe。 这些肽也可以在诊断上使用，并且C末端可以缩短为残基29。

公开(公告)号：US4605642A

公开(公告)日：1986-08-12

申请号：US583092

申请日：1984-02-23

申请人： Catherine L. Rivier ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Marvin R. Brown

发明人： Catherine L. Rivier ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Marvin R. Brown

IPC分类号： C07K1/06 ,  A61K38/00 ,  A61K38/04 ,  A61K38/22 ,  A61P5/00 ,  C07K1/02 ,  C07K1/04 ,  C07K14/00 ,  C07K14/575 ,  C07K7/10 ,  A61K37/24

CPC分类号： C07K14/57509 ,  A61K38/00

摘要： Several polypeptide analogs of the known members of the corticotropin releasing factor (CRF) family have been synthesized and tested including human and rat CRF which have the formula: H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH.sub.2. Peptides are herein disclosed that are potent competitive antagonists of CRF in mammals. One which has been found to be particularly potent is: H-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln-Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH.sub.2. These antagonists or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammals, including humans, to achieve a prevent elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels and/or a lowering of brain-mediated responses to stress over an extended period of time. They may also be used to affect mood, memory and learning, as well as diagnostically.

摘要翻译： 已经合成并测试了促肾上腺皮质激素释放因子（CRF）家族的已知成员的几种多肽类似物，包括人和大鼠CRF，其具有下式：H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp -Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn -Ar g-Lys-Leu-Met-Glu-Ile-Ile-NH 2。 本文公开了肽，其是哺乳动物中CRF的有竞争力的拮抗剂。 已发现特别有效的是：H-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Met-Leu-Glu-Met-Ala-Lys-Ala-Glu-Gln -Glu-Ala-Glu-Gln-Ala-Ala-Leu-Asn-Arg-Leu-Leu-Leu-Glu-Glu-Ala-NH 2.这些拮抗剂或其药学或兽医学上可接受的盐， 可以将可接受的液体或固体载体施用于包括人在内的哺乳动物，以达到防止ACTH，β-内啡肽，β-促性腺激素，其他产物的前乳糖皮质激素基因和皮质酮水平的提高和/或降低脑 - 在长时间内介导对压力的反应。 它们也可能用于影响情绪，记忆和学习以及诊断。

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。

公开(公告)号：US5109111A

公开(公告)日：1992-04-28

申请号：US498814

申请日：1990-03-23

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier ,  Jean-Francois Hernandez

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier ,  Jean-Francois Hernandez

IPC分类号： A61K38/00 ,  C07K14/575

CPC分类号： C07K14/57509 ,  A61K38/00 ,  Y10S514/805 ,  Y10S530/857

摘要： Several known members of the corticotropin releasing factor (CRF) family have been synthesized and tested, including human and rat CRF which have the formula: H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His- Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln- Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu- Ile-Ile-NH.sub.2. Peptides are herein disclosed that are potent competitive antagonists of CRF in mammals. One which has been found to be particularly potent is: H-D-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala- Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn- Arg-Lys-Leu-Nle-Glu-Ile-Ile-NH.sub.2. One that has shown particularly prolonged duration of potency is: H-D-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala- Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn- Arg-Lys-CML-Nle-Glu-Ile-Ile-NH.sub.2. These antagonists or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammals, including humans, to achieve a prevent elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels and/or a lowering of brain mediated responses to stress over an extended period of time. They may also be used to affect mood, memory and learning, as well as diagnostically.

摘要翻译： 已经合成并测试了促肾上腺皮质激素释放因子（CRF）家族的几个已知成员，包括人和大鼠CRF，其具有下式：H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu- Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg- Lys-Leu-Met-Glu-Ile-Ile-NH2。 本文公开了肽，其是哺乳动物中CRF的有竞争力的拮抗剂。 已经发现特别有效的是：HD-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln -Ala-His-Ser-Asn-Arg-Lys-Leu-Nle-Glu-Ile-Ile-NH2。 显示出特别延长的效力持续时间是：HD-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Nle-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln -Ala-His-Ser-Asn-Arg-Lys-CML-Nle-Glu-Ile-Ile-NH2。 分散在药学或兽医学上可接受的液体或固体载体中的这些拮抗剂或其药学或兽医学上可接受的盐可以施用于包括人在内的哺乳动物，以达到预防ACTH，β-内啡肽，β-促渗素，其他产物 pro-opiomelanocortin基因和皮质酮水平和/或在长时间内脑介导的应激反应的降低。 它们也可能用于影响情绪，记忆和学习以及诊断。

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.

IPC分类号： A61K38/24 ,  A61K38/00 ,  C07K1/04 ,  C07K1/113 ,  C07K7/23 ,  C07K14/575

CPC分类号： C07K7/23 ,  A61K38/00

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。

公开(公告)号：US5002931A

公开(公告)日：1991-03-26

申请号：US53235

申请日：1987-05-22

申请人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier

发明人： Jean E. F. Rivier ,  Wylie W. Vale, Jr. ,  Catherine L. Rivier

IPC分类号： A61K38/00 ,  A61K38/04 ,  A61K38/25 ,  A61P5/00 ,  A61P15/00 ,  A61P35/00 ,  A61P43/00 ,  C07K14/00 ,  C07K14/575 ,  C07K14/60 ,  C07K14/61

CPC分类号： C07K14/60 ,  A61K38/00

摘要： The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals, including humans, which have resistance to enzymatic degradation in the body, and which have the sequence: (B)R.sub.1 -R.sub.2 -R.sub.3 -Ala-Ile-Phe-Thr-R.sub.8 -Ser-(Q.sub.1)R.sub.10 - Arg-R.sub.12. (Q.sub.2)R.sub.13 -Leu-R.sub.15 -Gln-Leu-Ser-(Q.sub.3)Ala-Arg. R.sub.21 -(Q.sub.4)R.sub.22 -Leu-Gln-Asp-Ile-R.sub.27 -R.sub.28 -Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-R.sub.42 -R.sub.43 -R.sub.44 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His; B is H, C.sup.a Me, N.sup.a Me, desamino, Ac or For; R.sub.2 is Ala, D-Ala, NMA or D-NMA; R.sub.3 is Asp or D-Asp; R.sub.8 is Ser, Asn, Lys, Arg, Asp or Gln; R.sub.10 is Tyr, D-Tyr or Phe; R.sub.12 is Arg or Lys; R.sub.13 is Ile, Val, Leu or Ala; R.sub.15 is Gly or Ala; R.sub.21 is Lys, D-Lys or D-Arg; R.sub.22 is Leu, Ile, Ala or Val; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn or Ser; R.sub.42 is Phe, Ala or Val; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid; Q.sub.1 -Q.sub.4 are either H or C.sup.a Me, provided however that any or all of the residues between R.sub.30 and R.sub.44, inclusive, may be deleted.These peptides as well as their nontoxic salts may also be used diagnostically.

公开(公告)号：US4218439A

公开(公告)日：1980-08-19

申请号：US917781

申请日：1978-06-26

申请人： Catherine L. Rivier ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr.

发明人： Catherine L. Rivier ,  Jean E. F. Rivier ,  Wylie W. Vale, Jr.

IPC分类号： A61K38/00 ,  C07K7/23 ,  A61K37/00 ,  C07C103/52

CPC分类号： C07K7/23 ,  A61K38/00 ,  Y10S514/80 ,  Y10S930/13

摘要： A method for preventing reproduction by administering to male mammals a peptide which inhibits the secretion of gonadotropins by the pituitary gland and inhibits the release of steroids by the gonads. The peptide has the structure:p--Glu--His--Trp--Ser--Tyr--D--Trp--Leu--Arg--Pro--NH--CH.sub.2 --CH.sub.3.

摘要翻译： 一种通过向雄性哺乳动物施用抑制垂体分泌促性腺激素并抑制由性腺释放类固醇的肽来预防繁殖的方法。 肽具有以下结构：p-Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-NH-CH2-CH3。

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。

公开(公告)号：US5744450A

公开(公告)日：1998-04-28

申请号：US460246

申请日：1995-06-02

申请人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula Guess Theobald ,  John S. Porter ,  Catherine L. Rivier ,  Wylie Walker Vale, Jr.

发明人： Carl A. Hoeger ,  Jean E. F. Rivier ,  Paula Guess Theobald ,  John S. Porter ,  Catherine L. Rivier ,  Wylie Walker Vale, Jr.

IPC分类号： A61K38/00 ,  C07C277/08 ,  C07C279/28 ,  C07D249/14 ,  C07K1/00 ,  C07K7/23

CPC分类号： C07D249/14 ,  C07C277/08 ,  C07C279/28 ,  C07K1/006 ,  C07K7/23 ,  A61K38/00 ,  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: ##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.