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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：US5439885A
公开(公告)日：1995-08-08
申请号：US104862
申请日：1993-08-10
IPC分类号： A61K38/00 , C07K14/575 , C07K14/695 , A61K38/35
CPC分类号： C07K14/57509 , A61K38/00 , Y10S930/26
摘要： Analogs of CRF, which are based upon hCRF, oCRF and alpha-helical CRF, are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels. Analogs include those having the formula (see SEQ ID NO:9): Y-Ser-Xaa.sub.2 -Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Xaa.sub.12 -His-Leu-Leu-Arg-Glu-Val-Leu-Xaa.sub.20 -Xaa.sub.21 -Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Gln-Leu-Ala-Gln-Gln-Ala-Xaa.sub.32 -Ser-Asn-Arg-Xaa.sub.36 -Leu-Xaa.sub.38 -Xaa.sub.39 -Ile-Xaa.sub.41 -NH.sub.2, wherein Y is an acyl group having 7 or fewer carbon atoms or hydrogen; Xaa.sub.2 is Glu or Gln; Xaa.sub.12 is Phe or D-Phe; Xaa.sub.20 is Ala or Glu; Xaa.sub.21 is Met or Nle; Xaa.sub.22 is Ala or Thr; Xaa.sub.23 is Arg or Lys; Xaa.sub.24 is D-Ala or Ala; Xaa.sub.25 is Glu or Asp; Xaa.sub.32 is D-His or His; Xaa.sub.36 is Lys or Arg; Xaa.sub.38 is Met, Nle or Leu; Xaa.sub.39 is Ala, Glu or Asp; Xaa.sub.41 is Ile or Ala; provided however that at least one of Xaa.sub.20 and Xaa.sub.39 is Ala and that the N-terminus may be shortened by a sequence of up to about 5 residues. By shortening the N-terminus by 11 residues, particularly potent CRF antagonists are created. These analogs or their pharmaceutically acceptable salts, dispersed in an acceptable liquid or solid carrier, can be administered to humans.
摘要翻译： 公开了基于hCRF，oCRF和α螺旋CRF的CRF的类似物，其可以被施用以实现ACTH，β-内啡肽，β-促肌动蛋白，其前产妇的皮质酮皮质酮水平的其他产物和皮质酮水平的显着升高 。 类似物包括具有式（见SEQ ID NO：9）的那些：Y-Ser-Xaa2-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Xaa12-His-Leu-Leu-Arg-Glu -Val-Leu-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Gln-Leu-Ala-Gln-Gln-Ala-Xaa32-Ser-Asn-Arg-Xaa36-Leu-Xaa38-Xaa39-Ile-Xaa41-NH2 其中Y是具有7个或更少碳原子或氢的酰基; Xaa2是Glu或Gln; Xaa12是Phe或D-Phe; Xaa20是Ala或Glu; Xaa21是Met或Nle; Xaa22是Ala或Thr; Xaa23是Arg或Lys; Xaa24是D-Ala或Ala; Xaa25是Glu或Asp; Xaa32是D-His或他的; Xaa36是Lys或Arg; Xaa38是Met，Nle或Leu; Xaa39是Ala，Glu或Asp; Xaa41是Ile或Ala; 但是，Xaa20和Xaa39中的至少一个是Ala，并且N末端可以被至多约5个残基的序列缩短。 通过将N末端缩短11个残基，产生特别有效的CRF拮抗剂。 分散在可接受的液体或固体载体中的这些类似物或其药学上可接受的盐可以施用于人。
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公开(公告)号：US5235036A
公开(公告)日：1993-08-10
申请号：US709091
申请日：1991-05-31
IPC分类号： A61K38/00 , C07K14/575
CPC分类号： C07K14/57509 , A61K38/00 , Y10S930/26
摘要： Analogs of CRF, which are based upon hCRF, oCRF and alpha-helical CRF, are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels. Analogs include those having the formula: Y-R.sub.1 -R.sub.2 -R.sub.3 -R.sub.4 -R.sub.5 -Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-R.sub.20 -R.sub.21 -R.sub.22 -R.sub.23 -R.sub.24 -R.sub.25 -Gln-Leu-Ala-Gln-Gln-Ala-R.sub.32 -Ser-Asn-Arg-Lys-Leu-R.sub.38 -R.sub.39 -Ile-R.sub.41 -NH.sub.2, wherein Y is an acyl group having 7 or fewer carbon atoms or hydrogen; R.sub.1 is Ser or desR.sub.1 ; R.sub.2 is Glu, Gln or desR.sub.2 ; R.sub.3 is Glu or desR.sub.3 ; R.sub.4 is Pro or desR.sub.4 ; R.sub.5 is Pro or desR.sub.5 ; R.sub.20 is Ala or Glu; R.sub.21 is Met or Nle; R.sub.22 is Ala or Thr; R.sub.23 is Arg or Lys; R.sub.24 is D-Ala or Ala; R.sub.25 is Glu or Asp; R.sub.32 is D-His or His; R.sub.38 is Met, Nle or Leu; R.sub.39 is Ala, Glu or Asp; R.sub.41 is Ile or Ala; provided however that at least one of R.sub.20 and R.sub.39 is Ala. One example is [Ala.sup.20 ]-oCRF. These analogs or their pharmaceutically acceptable salts, dispersed in an acceptable liquid or solid carrier, can be administered to humans.
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公开(公告)号：US5510458A
公开(公告)日：1996-04-23
申请号：US162178
申请日：1993-12-14
申请人： Wayne D. Kornreich , Jean F. Hernandez , Jean E. Rivier , Catherine L. Rivier , Wylie W. Vale, Jr.
发明人： Wayne D. Kornreich , Jean F. Hernandez , Jean E. Rivier , Catherine L. Rivier , Wylie W. Vale, Jr.
IPC分类号： A61K38/00 , C07K14/575 , C07K14/695
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-Xaa.sub.13 -Leu-Leu-Arg-Xaa.sub.17 -Xaa.sub.18 -Leu-Xaa.sub.20 -Nle-Xaa.sub.22 -Xaa.sub.23 -Xaa.sub.24 -Xaa.sub.25 -Xaa.sub.26 -Leu-Xaa.sub.28 -Xaa.sub.29 -Gln-Xaa.sub.31 -Xaa.sub.32 -Xaa.sub.33 -Xaa.sub.34 -Arg-Xaa.sub.36 -Xaa.sub.37 -Nle-Xaa.sub.39 -Xaa.sub.40 -Xaa.sub.41 -NH.sub.2 wherein Y is Ac or hydrogen; Xaa.sub.13 is His, Tyr or Glu; Xaa.sub.17 is CML, Glu, Asn or Lys; Xaa.sub.18 is Val, Nle or Met; Xaa.sub.20 is Glu, D-Glu, Aib or D-Ala; Xaa.sub.22 is Ala, Aib, Thr, Asp or Glu; Xaa.sub.23 is Arg, Orn, Har or Lys; Xaa.sub.24 is Ala or Aib; Xaa.sub.25 is Asp or Glu; Xaa.sub.26 is Gln, Asn or Lys; Xaa.sub.28 is Ala or Aib; Xaa.sub.29 is Gln, Aib or Glu, Xaa.sub.31 is Ala or Aib; Xaa.sub.32 is His, Aib, Gly, Tyr or Ala; Xaa.sub.33 is Ser, Aib, Asn, Leu, Thr or Ala; Xaa.sub.34 is Asn or Aib; Xaa.sub.36 is Lys, Orn, Arg, Har or Leu; Xaa.sub.37 is Leu or Tyr; Xaa.sub.39 is Glu, Aib or Asp; Xaa.sub.40 is Ile, Aib, Thr, Glu, Ala, Val, Leu, Nle, Phe, Nva, Gly or Gln; and Xaa.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Nva or Gln, wherein CML may be substituted for Leu. 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.34 !-rCRF (12-41) , D-Phe.sup.12, CML.sup.17, Nle.sup.21,38 !-rCRF(12-41) , D-Phe.sup.12, Aib.sup.20, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, Aib.sup.29, Nle.sup.21,38 !-rCRF(12-41), D-Phe.sup.12, CML.sup.14, Nle.sup.21,38, Aib.sup.24,28,31 !-rCRF(12-41) and D-Phe.sup.12, CML.sup.15, Aib.sup.24,28,31 !-rCRF(12-41).
摘要翻译： PCT No.PCT / US92 / 05101 Sec。 371日期：1993年12月14日 102（e）日期1993年12月14日PCT提交1992年6月12日PCT公布。 出版物WO92 / 22576 日期为1992年12月23日。公开的是改进的CRF肽拮抗剂，例如具有下式的那些：YD-Phe-Xaa13-Leu-Leu-Arg-Xaa17-Xaa18-Leu-Xaa20-Nle-Xaa22-Xaa23-Xaa24-Xaa25- Xaa26-Leu-Xaa28-Xaa29-Gln-Xaa31-Xaa32-Xaa33-Xaa34-Arg-Xaa36-Xaa37-Nle-Xaa39-Xaa40-Xaa41-NH2，其中Y是Ac或氢; Xaa13是His，Tyr或Glu; Xaa17是CML，Glu，Asn或Lys; Xaa18是Val，Nle或Met; Xaa20是Glu，D-Glu，Aib或D-Ala; Xaa22是Ala，Aib，Thr，Asp或Glu; Xaa23是Arg，Orn，Har或Lys; Xaa24是Ala或Aib; Xaa25是Asp或Glu; Xaa26是Gln，Asn或Lys; Xaa28是Ala或Aib; Xaa29是Gln，Aib或Glu，Xaa31是Ala或Aib; Xaa32是His，Aib，Gly，Tyr或Ala; Xaa33是Ser，Aib，Asn，Leu，Thr或Ala; Xaa34是Asn或Aib; Xaa36是Lys，Orn，Arg，Har或Leu; Xaa37是Leu或Tyr; Xaa39是Glu，Aib或Asp; Xaa40是Ile，Aib，Thr，Glu，Ala，Val，Leu，Nle，Phe，Nva，Gly或Gln; Xaa41是Ala，Ile，Gly，Val，Leu，Nle，Phe，Nva或Gln，其中CML可以被Leu取代。 公开的具体CRF拮抗剂包括[D-Phe12，D-Ala20，Nle21,38] -rCRF（12-41），[D-Phe12，Nle21,38，Aib34] -rCRF（12-41），[D-Phe12， C-17，Nle 21,38] -rCRF（12-41），[D-Phe12，Aib20，Nle21,38] -rCRF（12-41），[D-Phe12，Aib29，Nle21,38] -rCRF（12-41 ），[D-Phe12，CML14，Nle21,38，Aib24,28,31] -rCRF（12-41）和[D-Phe12，CML15，Aib24,28,31] -rCRF（12-41）。
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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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