公开(公告)号：US4935491A

公开(公告)日：1990-06-19

申请号：US88431

申请日：1987-08-24

申请人： Karl Folkers ,  Anders Ljungqvist ,  Dong-Mei Feng ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

发明人： Karl Folkers ,  Anders Ljungqvist ,  Dong-Mei Feng ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

IPC分类号： A61K38/04 ,  A61K38/00 ,  A61P15/00 ,  C07K7/06 ,  C07K7/23

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

摘要： The objective of the research was the achievement of antagonists of the luteinizing hormone releasing hormone (LHRH) which would have adequate antagonistic activity to prevent ovulation, and yet would not have a pronounced structural feature to release a histamine, in vivo. Some existing antagonists of LHRH produced edema of the face and extremities in rats. This recent recognition of the edematogenic and anaphylactoid activities of an antagonist of LHRH necessitated new structural changes if such antagonists were to be considered for potential use as contraceptive agents in the human. Consequently, 57 peptides have been designed, synthesized and bioassayed toward achieving a potent antagonist which releases negligible histamine. Since there was no predictable structural sequence which offered assurance of such achievement, it was necessary to design, synthesize and bioassay a very large number of peptides having diverse structural changes toward ultimately discovering an antagonist with the necessary potency of antiovulatory activity and the necessary negligible release of histamine. Ultimately, this objective was achieved, and this application describes the diverse and unpredictable many positive steps which finally led to the objectives.

摘要翻译： 研究的目标是实现促黄体激素释放激素（LHRH）的拮抗剂，其具有足够的拮抗活性以防止排卵，并且在体内不具有释放组胺的显着结构特征。 一些现有的LHRH拮抗剂在大鼠中产生了四肢的水肿。 最近对LHRH拮抗剂引起的血液发生和过敏性活性的认识需要新的结构改变，如果这样的拮抗剂被认为可能用作人类的避孕药。 因此，已经设计，合成和生物测定了57种肽，以实现释放可忽略的组胺的有效拮抗剂。 由于没有可预测的结构序列来提供这种成就的保证，所以有必要设计，合成和生物测定大量具有不同结构变化的肽，以最终发现拮抗剂具有必需的抗疟药活性和必需的可忽略的释放 的组胺。 最终，这个目标已经实现，这个应用程序描述了最终导致目标的多样化和不可预测的许多积极步骤。

公开(公告)号：US4721775A

公开(公告)日：1988-01-26

申请号：US771546

申请日：1985-08-26

申请人： Karl Folkers ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

发明人： Karl Folkers ,  Cyril Y. Bowers ,  Pui-Fun L. Tang ,  Minoru Kubota

IPC分类号： A61K38/00 ,  C07K7/23 ,  C07K7/20

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

摘要： The chemical structure of the luteinizing hormone releasing hormone (LHRH) was elucidatd in 1971. Since then, a very large number of international investigators synthesized more than 100 monosubstituted and about 14 disubstituted analogs of LHRH. All of these analogs were synthesized from natural amino acids having the L-configuration. Not one of these approximately 114 analogs showed agonist activity equivalent to that of LHRH. Two of the 114 were about 60% as active, and neither one has had any utility. We have investigated the six individual L-amino acids which occur in positions 5, 7, and 8 of the four naturally occurring LHRH's which exist in porcine/ovine, salmon, and chicken tissue. There are a total of 16 peptides with these structural features, and we have discovered that not only one but five of these peptides are not only equivalent in certain assays in activity to LHRH, but that two of the five are surprisingly superior to LHRH in activity, and that two of the five have a unique and unpredictable dissociation of activity for the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). These five peptides are:A. p-Glu His Trp Ser His Gly Leu Arg Pro Gly-NH.sub.2,B. p-Glu His Trp Ser His Gly Trp Arg Pro Gly-NH.sub.2,C. p-Glu His Trp Ser His Gly Trp Gln Pro Gly-NH.sub.2,D. p-Glu His Trp Ser His Gly Trp Leu Pro Gly-NH.sub.2,E. p-Glu His Trp Ser Tyr Gly Trp Arg Pro Gly-NH.sub.2,Peptide C might be the naturally occurring as FSHRH, because of its dissociated release of LH and FSH. The discovery for the first time of decapeptides with L-amino acids equal to or more potent than LHRH was based on about 14 years of background. Our new peptides are particularly useful in medical fields for pituitary stimulation and inhibition, for enhancement or inhibition of fertility in humans and animals, for the therapy of hormone-dependent tumors, for special effects on sexual behavior in humans and animals, and for design of new categories of superagonists and antagonists. Extrapituitary effects by these new peptides may be observed on the central nervous system or reproductive organs of humans and animals that are different from those of LHRH. The latter will be especially true if some of these new peptides are found to be native peptides such as FSH-RH or the LHRH-like peptides that have been detected in the gonads that are yet to be identified. The reason for believing this projection is possible is that some of these peptides have high or unique LH and FSH releasing activity in the LHRH radioreceptor assay, as exemplified by the biological activities of peptide C.

公开(公告)号：US4642332A

公开(公告)日：1987-02-10

申请号：US727711

申请日：1985-04-26

申请人： Karl Folkers ,  Xu Jie-Cheng ,  Cyril Y. Bowers

发明人： Karl Folkers ,  Xu Jie-Cheng ,  Cyril Y. Bowers

IPC分类号： A61K38/00 ,  C07K7/23 ,  C07K7/20

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

摘要： Two sets of hormonal peptides are synthesized which are super agonists of the luteinizing hormone releasing hormone (LHRH). Chronic administration results in the inhibition of LHRH which is responsible for stimulating cell growth in the testes. One peptide has the D(dextro)-form of a monoheterocyclic amino acid in position six (D-3-pyridyl-alanine) while the other peptide has a bi-heterocyclic amino acid in that same position (.beta.-(3-quinolyl)-D-.alpha.-alanine. Both peptides are less metabolically reactive than those in the prior art and yet both peptides are significantly more potent than LHRH itself.

摘要翻译： 合成两组激素肽，它们是促黄体激素释放激素（LHRH）的超激动剂。 慢性给药导致LHRH的抑制，其负责刺激睾丸中的细胞生长。 一个肽具有位置6（D-3-吡啶基 - 丙氨酸）的单杂环氨基酸的D（右旋）形式，而另一个肽在同一位置具有双杂环氨基酸（β-（3-喹啉基） -D-α-丙氨酸。两种肽的代谢反应性都低于现有技术，但两种肽都比LHRH本身显着更强。

公开(公告)号：US4504414A

公开(公告)日：1985-03-12

申请号：US479645

申请日：1983-03-28

申请人： Karl Folkers ,  Cyril Y. Bowers ,  Teresa M. Kubiak ,  Janusz Stepinski

发明人： Karl Folkers ,  Cyril Y. Bowers ,  Teresa M. Kubiak ,  Janusz Stepinski

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

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

摘要： Pyridyl-alanyl decapeptides have been effectively synthesized and found to have antiovulatory activity. The exemplary [N-Ac-D-2-Nal.sup.1,pCl-D-Phe.sup.2, D-3-Pal.sup.3,D-Arg.sup.6,D-Ala.sup.10 ]-LHRH has very high potency to inhibit ovulation, both parenterally and orally. Also, this exemplary pyridyl-alanyl-decapeptide showed an unexpected prolonged duration of antiovulatory activity. Such pyridyl-alanyl-decapeptides are useful to control reproduction.

摘要翻译： 已经有效地合成了吡啶基丙氨酸十肽，发现具有抗疟药活性。 示例性的[N-Ac-D-2-Nal1，pCl-D-Phe2，D-3-Pal3，D-Arg6，D-Ala10] -LHRH具有非常高的效力以抑制排卵，肠胃外和口服。 此外，该示例性吡啶基 - 丙氨酰 - 十肽显示出预期的持久的抗疟药活性。 这种吡啶基 - 丙氨酰 - 十肽可用于控制繁殖。

公开(公告)号：US4656247A

公开(公告)日：1987-04-07

申请号：US727710

申请日：1985-04-26

申请人： Karl Folkers ,  Xu Jie-Cheng ,  Cyril Y. Bowers

发明人： Karl Folkers ,  Xu Jie-Cheng ,  Cyril Y. Bowers

IPC分类号： A61K38/00 ,  C07K7/23 ,  C07K7/20

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

摘要： Two sets of hormonal peptides are synthesized which are super agonists of the lutenizing hormone releasing hormone (LHRH). Chronic administration results in the inhibition of LHRH which is responsible for stimulating cell growth in the testes. One peptide has the D(dextro)-form of a mono-heterocyclic amino acid in position six (D-3-pyridyl-alanine) while the other peptide has a bi-heterocyclic amino acid in that same position (.beta.-(3-quinolyl)-D-.alpha.-alanine. Both peptides are less metabolically reactive than those in the prior art and yet both peptides are significantly more potent than LHRH itself.

摘要翻译： 合成了两组激素释放激素（LHRH）的超激动剂。 慢性给药导致LHRH的抑制，其负责刺激睾丸中的细胞生长。 一个肽具有位置6上的单杂环氨基酸（D-3-吡啶基 - 丙氨酸）的D（右旋）形式，而另一个肽在相同位置具有双杂环氨基酸（β-（3- 喹啉基）-D-α-丙氨酸。两种肽的代谢反应性都低于现有技术，但两种肽比LHRH本身显着更有效。

公开(公告)号：US4824669A

公开(公告)日：1989-04-25

申请号：US31487

申请日：1987-03-27

申请人： Karl Folkers ,  Kazumasa Muratsu

发明人： Karl Folkers ,  Kazumasa Muratsu

IPC分类号： A61K9/00 ,  A61K31/12 ,  A61K47/44

CPC分类号： A61K9/0019 ,  A61K31/12 ,  A61K47/44

摘要： The present invention comprises a stable and non-toxic coenzyme Q.sub.10 formulation suitable for intravenous administration to an animal to produce clinically effective blood levels of coenzyme Q.sub.10. Clinically effective blood levels of coenzyme Q.sub.10 are generally agreed to be between about 2 ug/ml and about 4 ug/ml. The formulation consists essentially of a clinically accepted fatty emulsion having an oil phase and coenzyme Q.sub.10 dissolved in the oil phase. The formulation preferably contains coenzyme Q.sub.10 at a level between about 7.5 ug/ml and about 30 ug/ml. The clinically accepted fatty emulsion comprises at least one vegetable oil, preferably corn oil, peanut oil, safflower oil, olive oil or soybean oil.

摘要翻译： 本发明包括稳定且无毒的辅酶Q10制剂，其适于静脉内施用于动物以产生临床有效的辅酶Q10血液水平。 辅酶Q10的临床有效血液水平通常约为约2μg/ ml至约4μg/ ml。 该制剂基本上由具有溶于油相中的油相和辅酶Q10的临床可接受的脂肪乳剂组成。 制剂优选含有约7.5μg/ ml至约30μg/ ml水平的辅酶Q10。 临床上接受的脂肪乳剂包含至少一种植物油，优选玉米油，花生油，红花油，橄榄油或大豆油。

公开(公告)号：US3953416A

公开(公告)日：1976-04-27

申请号：US432903

申请日：1974-01-14

申请人： Karl Folkers ,  Bruce L. Currie ,  Jaw-Kang Chang ,  Hans Sievertsson ,  Conny Bogentoft

发明人： Karl Folkers ,  Bruce L. Currie ,  Jaw-Kang Chang ,  Hans Sievertsson ,  Conny Bogentoft

IPC分类号： A61K38/00 ,  C07K5/103 ,  C07K7/23 ,  C07C103/52 ,  C07G7/00

CPC分类号： C07K5/1005 ,  C07K7/23 ,  A61K38/00 ,  Y10S514/80 ,  Y10S930/13

摘要： A synthetic decapeptide, L-pglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-L-arginyl-L-prolyl-glycinamide which has the hormonal activities of the luteinizing hormone releasing hormone (LRH) of the hypothalamus gland of mammals is produced by utilizing as the key starting materials, the amino acids, glutamic acid or pyroglutamic acid, histidine, tryptophan, serine, tyrosine, glycine, leucine, arginine, and proline. Synthesis of the decapeptide is accomplished by coupling, in appropriate combinations of appropriate protected forms of the amino acids, and finally deprotecting to yield the amide, L-pglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-L-arginyl-L-prolyl-glycinamide.

摘要翻译： 具有黄体生成激素释放激素的激素活性的合成十肽L- L-谷氨酰-L-组氨酰-LL-色氨酰-L-丝氨酰-L-酪氨酰 - 甘氨酰-L-赖氨酸-L-精氨酰-L-脯氨酰甘氨酰胺 通过利用氨基酸，谷氨酸或焦谷氨酸，组氨酸，色氨酸，丝氨酸，酪氨酸，甘氨酸，亮氨酸，精氨酸和脯氨酸的关键起始物质产生哺乳动物下丘脑的LRH）。 十肽的合成通过以合适的保护形式的氨基酸的适当组合偶联，最后脱保护得到酰胺，L-谷氨酰基-L-组氨酰基-L-色氨酸-L-丝氨酰-L-酪氨酰 - 甘氨酰基 -L-赖氨酸-L-精氨酰-L-脯氨酰基 - 甘氨酰胺。

公开(公告)号：US3944659A

公开(公告)日：1976-03-16

申请号：US314750

申请日：1972-12-13

申请人： Karl Folkers ,  Karl Nils Gunnar Johansson ,  Bruce L. Currie

发明人： Karl Folkers ,  Karl Nils Gunnar Johansson ,  Bruce L. Currie

IPC分类号： A61K38/00 ,  C07K14/575 ,  A61K27/04 ,  A61K17/08

CPC分类号： C07K14/575 ,  A61K38/00 ,  Y10S436/804 ,  Y10S436/814 ,  Y10S436/817

摘要： A method for producing the Folliculotropin Releasing Hormone (FRH) biosynthetically is provided by utilizing, as key starting materials, fresh hypothalamic tissue, a buffered incubation medium, an ATP synthesizing system, radioactively labeled amino acids and a mixture of 21 naturally occuring amino acids. Biosynthesis of the FRH is accomplished by incubation of the hypothalamic tissue for a short period of time in the presence of all the reagents necessary to promote the biosynthetic system to produce the Folliculotropin Releasing Hormone (FRH) of the hypothalamus gland of mammals. Examples of methods to isolate the FRH free of the luteotropin releasing hormone (LRH) are provided.

摘要翻译： 通过利用新鲜的下丘脑组织，缓冲培养基，ATP合成系统，放射性标记的氨基酸和21种天然存在的氨基酸的混合物作为关键起始材料，提供了通过生物合成生产毛囊激素释放激素（FRH）的方法。 FRH的生物合成是通过在存在促进生物合成系统以产生哺乳动物下丘脑的Folliculotropin释放激素（FRH））所必需的所有试剂存在的情况下，短时间内孵育下丘脑组织而实现的。 提供了分离不含促黄体激素释放激素（LRH）的FRH的方法的实例。

公开(公告)号：US4885167A

公开(公告)日：1989-12-05

申请号：US155891

申请日：1988-02-16

申请人： Karl Folkers ,  Janusz Wolaniuk

发明人： Karl Folkers ,  Janusz Wolaniuk

IPC分类号： A61K38/43

CPC分类号： A61K31/122 ,  Y10S514/907

摘要： The present invention relates to the use of Coenzyme Q in the treatment of slow muscle degeneration, commonly known to those of skill in the art so a dystrophy or atrophy, and the accompanying cardiac complications typically identified in such patients. Administration of Coenzyme Q, and particularly the analog Coenzyme Q.sub.10 (CoQ.sub.10) to humans increases the pumping of blood by the heart, and thereby increases tissue oxygeneration throughout the body. The net physiological effect halts the progression of muscle deterioration and improves cardiac function. An overall improvement in the quality of life for these human subjects is also observed, said patients reportedly experiencing less fatigue.A method for treating human patients with progressive muscular dystrophies or the neurogenic atrophies with Coenzyme Q.sub.10 (CoQ.sub.10) specifically disclosed. The method is similarly effective for the treatment of any form of muscle degeneration or cardiac muscular dysfunction independently.

摘要翻译： 本发明涉及辅酶Q用于治疗慢性肌肉变性的用途，本领域技术人员通常已知营养不良或萎缩，以及通常在这些患者中鉴定的伴随的心脏并发症。 辅酶Q，特别是对人类的辅酶Q10（CoQ10）的施用增加了心脏对血液的泵吸，从而增加整个身体的组织氧合。 净生理效应阻止肌肉退化进展，改善心脏功能。 还观察到这些人类受试者的生活质量的总体改善，据说患者身体疲劳较少。 专门公开了用辅酶Q10（CoQ10）治疗进行性肌营养不良或神经源性萎缩的人类患者的方法。 该方法类似地有效地用于独立地治疗任何形式的肌肉变性或心脏肌肉功能障碍。

公开(公告)号：US4481139A

公开(公告)日：1984-11-06

申请号：US484646

申请日：1983-04-13

申请人： Karl Folkers ,  Xu Jie-cheng

发明人： Karl Folkers ,  Xu Jie-cheng

IPC分类号： A61K38/00 ,  C07K7/22 ,  C07C103/52

CPC分类号： C07K7/22 ,  A61K38/00 ,  Y10S930/13

摘要： Undecapeptides retaining the amino acids in positions 2, 3, 4, 5, 6, 8 and 10 of substance P (Arg.sup.1 -Pro.sup.2 -Lys.sup.3 -Pro.sup.4 -Gln.sup.5 -Gln.sup.6 -Phe.sup.7 -Phe.sup.8 -Gly.sup.9 -Leu.sup.10 -Met.sup.11 -NH.sub.2), but having substitutions in positions 1, 7, 9 and 11 of substance P have been discovered to have high antagonistic activity to block substance P in biological systems. Exemplifying these potent antagonists is D-Arg.sup.1,D-Trp.sup.7,D-Trp.sup.9 -Leu.sup.11 -Substance P, which is an effective inhibitor and has high potency. These antagonists of substance P are useful to elucidate some biological mechanisms of substance P, and to treat inflammatory responses in the eye for medical practice in ophthalmology, and to be novel analgesic agents for medical applications.

摘要翻译： 保留物质P（Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH2）的2,3,4,5,6,8和10位的氨基酸的十一肽，但是 已经发现在物质P的位置1,7,9和11中具有取代在生物系统中具有高的阻断物质P的拮抗活性。 这些有效的拮抗剂的例子是D-Arg1，D-Trp7，D-Trp9-Leu11-物质P，其是有效的抑制剂并且具有高效力。 物质P的这些拮抗剂可用于阐明物质P的一些生物学机制，并且用于治疗眼睛中用于眼科医学实践的炎症反应，并且是用于医学应用的新型止痛剂。