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公开(公告)号：US4415558A
公开(公告)日：1983-11-15
申请号：US378999
申请日：1982-05-17
IPC分类号： A61K38/00 , C07K14/575 , A61K37/00 , C07C103/52
CPC分类号： C07K14/57509 , A61K38/00 , Y10S514/805
摘要： CRF (Corticotropin Releasing Factor) has the formula:H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH.sub.2.Analogs have been synthesized that are at least as potent as CRF, and CRF or these analogs or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin and corticosterone levels and/or a lowering of blood pressure over an extended period of time. In the analogs, one or more of the first three N-terminal residues may be deleted or may be substituted by a peptide up to 10 amino acids long and/or by an acylating agent containing up to 7 carbon atoms. Ala in the 41-position may also be substituted or deleted so long as the remaining C-terminus is amidated. Several other substitutions may also be made throughout the chain.
摘要翻译： CRF（促皮质素释放因子）具有下式：H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu- Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Ar g-Lys-Leu-Leu-Asp-Ile-Ala-NH 2。 已经合成至少与CRF一样有效的类似物，并且分散在药学上可接受的液体或固体载体中的CRF或这些类似物或其药学上可接受的盐可以施用于哺乳动物以实现ACTH，β-内啡肽的显着升高 ，β-促凝血酶和皮质酮水平和/或在长时间内降低血压。 在类似物中，前三个N末端残基中的一个或多个可以被缺失或可被长达10个氨基酸的肽和/或被含有至多7个碳原子的酰化剂所取代。 41位的Ala也可以被取代或缺失，只要其余的C末端被酰胺化即可。 还可以在整个链中进行几个其它取代。
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公开(公告)号：US4661472A
公开(公告)日：1987-04-28
申请号：US732531
申请日：1985-05-09
申请人： Jean E. F. Rivier , Janos I. Varga , Arnold T. Hagler , R. Scott Struthers , Marilyn H. Perrin , Catherine L. Rivier , Wylie W. Vale, Jr.
发明人： Jean E. F. Rivier , Janos I. Varga , Arnold T. Hagler , R. Scott Struthers , Marilyn H. Perrin , Catherine L. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/04 , A61K38/00 , A61K38/22 , A61K38/27 , A61P5/00 , C07K7/06 , C07K7/23 , C07K14/00 , C07K14/575 , A61K37/43
CPC分类号： C07K7/23 , A61K38/00 , Y10S930/13
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 are cyclic analogs of the decapeptide GnRH wherein there is a covalent bond between the residue in the 4-position and the residue in the 10-position. Examples of such bonds include the disulfide linkage between Cys residues, an amide linkage between a side chain amino group and a side chain carboxyl 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。 肽是十肽GnRH的环状类似物，其中在4-位的残基与10位的残基之间存在共价键。 这些键的实例包括Cys残基之间的二硫键，侧链氨基和侧链羧基之间的酰胺键，侧链烷基之间的二链键和侧链烷基与侧链烷基之间的碳键 侧链巯基。
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公开(公告)号：US4307083A
公开(公告)日：1981-12-22
申请号：US147555
申请日：1980-05-08
IPC分类号： A61K38/00 , C07K7/16 , C07K7/23 , A61K37/00 , C07C103/52
CPC分类号： C07K7/23 , C07K7/16 , A61K38/00 , Y10S514/80 , Y10S930/13
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 prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads. The peptides have the structure:R.sub.1 -R.sub.2 -R.sub.3 -Ser-Tyr-R.sub.4 -R.sub.5 -Arg-R.sub.6wherein R.sub.1 is selected from the group consisting of dehydro Pro, dehydro D-Pro, Acetyl dehydro Pro and acetyl dehydro D-Pro; R.sub.2 is selected from the group consisting of D-Phe, Phe, N.alpha.Me-Phe, His, D-His, D-Trp, Trp and N.alpha.Me-Leu; R.sub.3 is selected from the group consisting of D-Trp, Trp D-Phe, Phe, Pro and D-His; R.sub.4 is selected from the group consisting of Gly, D-Trp, D-Phe, imBzl-D-His and D-Tyr; R.sub.5 is selected from the group consisting of Leu and N.alpha.Me-Leu; and R.sub.6 is selected from the group consisting of Pro-Gly-NH.sub.2 and Pro-NH-CH.sub.2 -CH.sub.3.
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。 施用有效量防止雌性哺乳动物卵的排卵和/或性腺释放类固醇。 肽具有以下结构：R1-R2-R3-Ser-Tyr-R4-R5-Arg-R6，其中R1选自脱氢Pro，脱氢D-Pro，乙酰脱氢Pro和乙酰基脱氢D-Pro; R2选自D-Phe，Phe，NαMe-Phe，His，D-His，D-Trp，Trp和NαMe-Leu; R3选自D-Trp，Trp D-Phe，Phe，Pro和D-His; R4选自Gly，D-Trp，D-Phe，imBzl-D-His和D-Tyr; R5选自Leu和NαMe-Leu; 并且R 6选自Pro-Gly-NH 2和Pro-NH-CH 2 -CH 3。
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公开(公告)号：US5493006A
公开(公告)日：1996-02-20
申请号：US078558
申请日：1993-06-16
IPC分类号： A61K38/00 , C07K14/575 , C07K14/695
CPC分类号： C07K14/57509 , A61K38/00
摘要： Improved CRF peptide antagonists have the formula: ##STR1## wherein R.sub.20 is Cys or Glu; R.sub.23 is Cys, Lys or Orn; provided that when R.sub.20 is Cys, R.sub.23 is Cys and when R.sub.20 is Glu, R.sub.23 is Lys or Orn; or a nontoxic addition salt thereof. Specific CRF antagonists disclosed include (cyclo 20-23) [D-Phe.sup.12, Lys.sup.23, Nle.sup.21,38, ]rCRF(12-41); (cyclo 20-23) [D-Phe.sup.12, Orn.sup.23, Nle.sup.21,38 ]rCRF(12-41) and (cyclo 20-23) [D-Phe.sup.12, Cys.sup.20, Cys.sup.23, Nle.sup.21,38 ]rCRF(12-41).
摘要翻译： 改进的CRF肽拮抗剂具有下式：其中R 20是Cys或Glu; R23是Cys，Lys或Orn; 条件是当R 20为Cys时，R 23为Cys，当R 20为Glu时，R 23为Lys或Orn; 或其无毒的加成盐。 公开的具体CRF拮抗剂包括（环20-23）[D-Phe12，Lys23，Nle21,38] rCRF（12-41）; （环20-23）[D-Phe12，Orn23，Nle21,38] rCRF（12-41）和（环20-23）[D-Phe12，Cys20，Cys23，Nle21,38] rCRF（12-41）。
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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：US5245009A
公开(公告)日：1993-09-14
申请号：US715752
申请日：1991-06-14
申请人： Wayne D. Kornreich , Jean-Francois Hernandez , Jean E. F. Rivier , Catherine L. Rivier , Wylie W. Vale, Jr.
发明人： Wayne D. Kornreich , Jean-Francois Hernandez , Jean E. F. Rivier , Catherine L. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/575
CPC分类号： C07K14/57509 , A61K38/00 , Y10S930/26
摘要： Disclosed are improved CRF peptide antagonists such as those having the formula: Y-D-Phe-R.sub.13 -Leu-Leu-Arg-R.sub.17 -R.sub.18 -Leu-R.sub.20 -Nle-R.sub.22 -R.sub.23 -R.sub.24 -R.sub.25 -R.sub.26 -Leu-R.sub.28 -R.sub.29 -Gln-R.sub.31 -R.sub.32 -R.sub.33 -R.sub.34 -Arg-R.sub.36 -R.sub.37 -Nle-R.sub.39 -R.sub.40 -R.sub.41 -NH.sub.2 wherein Y is Ac or hydrogen; R.sub.13 is His, Tyr or Glu; R.sub.17 is Cys, Glu, Asn or Lys; R.sub.18 is Val, Nle or Met; R.sub.20 is D-Cys, Glu, D-Glu, Aib or D-Ala; R.sub.22 is Ala, Aib, Thr, Asp or Glu; R.sub.23 is Arg, Orn, Har or Lys; R.sub.24 is Ala or Aib; R.sub.25 is Asp or Glu; R.sub.26 is Gln, Asn or Lys; R.sub.28 is Ala or Aib; R.sub.29 is Gln, Aib or Glu, R.sub.31 is Ala or Aib; R.sub.32 is His, Aib, Gly, Tyr or Ala; R.sub.33 is Ser, Aib, Asn, Leu, Thr or Ala; R.sub.34 is Asn or Aib; R.sub.36 is Lys, Orn, Arg, Har or Leu; R.sub.37 is Leu or Try; R.sub.39 is Glu, Aib or Asp; R.sub.40 is Ile, Aib, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln; and R.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Nva or Gln. Specific CRF antagonists disclosed include [D-Phe.sup.12, D-Ala.sup.20, Nle.sup.21,38,]-rCRF(12-41), [D-Phe.sup.12, Nle.sup.21,38, Aib.sup.33 ]-rCRF(12-41) and (c 17-20) [D-Phe.sup.12, Cys.sup.17, D-Cys.sup.20, Nle.sup.21,38 ]-rCRF(12-41).
摘要翻译： 公开了改进的CRF肽拮抗剂，例如具有下式的那些：肽，如YD-Phe-R13-Leu-Leu-Arg-R17-R18-Leu-R20-Nle-R22-R23-R24-R25-R26-Leu-R2 8- R29-Gln-R31-R32-R33-R34-Arg-R36-R37-Nle-R39-R40-R41-NH2，其中Y是Ac或氢; R13是His，Tyr或Glu; R17是Cys，Glu，Asn或Lys; R18为Val，Nle或Met; R20是D-Cys，Glu，D-Glu，Aib或D-Ala; R22是Ala，Aib，Thr，Asp或Glu; R23是Arg，Orn，Har或Lys; R24是Ala或Aib; R25为Asp或Glu; R26是Gln，Asn或Lys; R28是Ala或Aib; R29是Gln，Aib或Glu，R31是Ala或Aib; R32是His，Aib，Gly，Tyr或Ala; R33是Ser，Aib，Asn，Leu，Thr或Ala; R34是Asn或Aib; R36是Lys，Orn，Arg，Har或Leu; R37是Leu或Try; R39是Glu，Aib或Asp; R40是Ile，Aib，Thr，Glu，Ala，Val，Leu，Nle，Phe，Nva，Gly或Gln; R41是Ala，Ile，Gly，Val，Leu，Nle，Phe，Nva或Gln。 公开的具体的CRF拮抗剂包括[D-Phe12，D-Ala20，Nle21,38] -rCRF（12-41），[D-Phe12，Nle21,38，Aib33] -rCRF（12-41）和（c17- 20）[D-Phe12，Cys17，D-Cys20，Nle21,38] -rCRF（12-41）。
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公开(公告)号：US5098995A
公开(公告)日：1992-03-24
申请号：US342751
申请日：1989-04-25
IPC分类号： A61K38/04 , A61K38/00 , A61P5/00 , C07K14/575 , C07K14/60
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。
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公开(公告)号：US4605642A
公开(公告)日：1986-08-12
申请号：US583092
申请日：1984-02-23
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。
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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。
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公开(公告)号：US5109111A
公开(公告)日：1992-04-28
申请号：US498814
申请日：1990-03-23
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。
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