公开(公告)号：US06461593B1

公开(公告)日：2002-10-08

申请号：US07838604

申请日：1992-02-19

Applicant: Takashi Hanioka ,  Judson T. McRee ,  Karl Folkers

Inventor： Takashi Hanioka ,  Judson T. McRee ,  Karl Folkers

IPC: A61K716

CPC classification number: A61K31/122 ,  A61K8/355 ,  A61K9/0063 ,  A61Q11/00

Abstract: The presence of diverse microorganisms in the gingiva of patients having periodontal disease is very well known to be deleterious to gingival health, and particularly to facilitate the appearance and development of dental cavities. Such microorganisms are always associated with periodontal disease, and if such microorganisms remain unchecked or uncontrolled, extraction of teeth are likely to occur. In the past, the presence of microorganisms in the gingiva of patients with periodontal disease has been periodically and erratically treated with anti-microbial agents, including antibiotics. For anti-microbial agents and antibiotics to be effective in the gingiva, such agents and antibiotics must come into direct contact with microorganisms, and such contact is known to be incomplete, partly because there may be barriers of fluid and tissue which prevent direct contact between the agents and antibiotics with the microorganisms. Also, such agents can be inactive for certain microorganisms and even when there is activity, such microorganisms can become metabolically resistant to the agents and antibiotics. A more effective way to reduce and to control microorganisms in the gingiva of patients with periodontal disease is to increase the efficacy of the immune system of the host. Coenzyme Q10 (CoQ10) has been known to increase the immune system, but previously it was unknown that CoQ10 could be a very effective mechanism to reduce and to eliminate microorganisms in the gingiva of patients with periodontal disease.

Abstract translation: 具有牙周病的患者牙龈中多种微生物的存在是众所周知的，对牙龈健康有害，特别是促进牙腔的外观和发育。 这样的微生物总是与牙周病有关，如果这种微生物保持不受控制或不受控制，则可能会出现牙齿的提取。在过去，牙周病患者的牙龈中的微生物的存在已经定期地和不定期地用抗 - 微生物剂，包括抗生素。 为了使抗微生物剂和抗生素在牙龈中有效，这种药剂和抗生素必须与微生物直接接触，这种接触已知是不完全的，部分原因是可能存在妨碍液体和组织之间直接接触的障碍 代理商和抗生素与微生物。 此外，这些药剂对于某些微生物也是无活性的，甚至当有活性时，这样的微生物可以代谢对药物和抗生素的抗性。减少和控制牙周病患者牙龈中微生物的更有效的方法是增加 宿主免疫系统的功效。 已知辅酶Q10（CoQ10）可增加免疫系统，但以前不知道CoQ10可能是减少和消除牙周病患者牙龈中微生物的非常有效的机制。

公开(公告)号：US4935491A

公开(公告)日：1990-06-19

申请号：US88431

申请日：1987-08-24

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

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

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

CPC classification number: C07K7/23 ,  A61K38/00 ,  Y10S930/13

Abstract: 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.

Abstract translation: 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

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

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

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

CPC classification number: C07K7/23 ,  A61K38/00 ,  Y10S930/13

Abstract: 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：US4550109A

公开(公告)日：1985-10-29

申请号：US615812

申请日：1984-05-31

Applicant: Karl Folkers ,  Klaus P. Laesecke

Inventor： Karl Folkers ,  Klaus P. Laesecke

IPC: A61K31/505 ,  A61K31/519 ,  A61P25/00 ,  C07D475/04 ,  C07D241/00

CPC classification number: C07D475/04

Abstract: The present invention provides lipoidal biopterin and tetrahydrobiopterin compounds of the general structure: ##STR1## wherein --R is absent when ring B has two double bonds,--R is hydrogen when the two double bonds in ring B are absent, and--R' and R" are selected from saturated or unsaturated, cyclic or non-cyclic hydrocarbons of 1 to 31 carbon units.The compounds provided by this invention are oil soluble and can readily be formulated as an oil based pharmaceutical useful for the treatment of phenylketonuria, Parkinsonism, depression, senile dementia, Alzheimer's disease and related biopterin deficiency diseases.

Abstract translation: 本发明提供了一般结构的脂质生物蝶呤和四氢生物喋呤化合物：其中当环B具有两个双键时-R不存在，当环B中的两个双键不存在时，-R是氢; -R'和 R“选自1至31个碳单元的饱和​​或不饱和的环状或非环状烃。 本发明提供的化合物是油溶性的，并且可以容易地配制成可用于治疗苯丙酮尿症，帕金森综合征，抑郁症，老年性痴呆，阿尔茨海默氏病和相关生物蝶呤缺乏症的油基药物。

公开(公告)号：US4504414A

公开(公告)日：1985-03-12

申请号：US479645

申请日：1983-03-28

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

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

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

CPC classification number: C07K7/23 ,  A61K38/00 ,  Y10S930/13

Abstract: 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.

Abstract translation: 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：US3974187A

公开(公告)日：1976-08-10

申请号：US553927

申请日：1975-02-28

Applicant: Yieh-Ping Wan ,  Karl Folkers

Inventor： Yieh-Ping Wan ,  Karl Folkers

IPC: A61K31/12 ,  A61P1/02 ,  A61P7/06 ,  C07C45/00 ,  C07C46/00 ,  C07C50/28 ,  C07C67/00 ,  C07C49/73

CPC classification number: C07C50/28 ,  C07C46/00

Abstract: Synthetic 2,3-dimethoxy-5-methyl-1,4-benzoquinone is converted into a series of new 6-alkyl derivatives. These 6-alkyl derivatives have straight carbon chains which are both saturated and unsaturated. The unsaturated derivatives contain one, two, three and four double bonds. These new synthetic quinones are analogs of the naturally occurring forms of coenzyme Q and have the same fundamental electron-transfer capacity of the natural forms of coenzyme Q. Although the degree of the activity of these new synthetic analogs differ, some of these new synthetic analogs are effective substitutes for the natural forms of coenzyme Q.

Abstract translation: 合成的2,3-二甲氧基-5-甲基-1,4-苯醌转化为一系列新的6-烷基衍生物。 这些6-烷基衍生物具有饱和和不饱和的直链碳链。 不饱和衍生物含有一个，两个，三个和四个双键。 这些新的合成醌是天然存在形式的辅酶Q的类似物，并且具有与天然形式的辅酶Q相同的基本电子传递能力。虽然这些新的合成类似物的活性程度不同，但是这些新的合成类似物 是辅酶Q的天然形式的有效替代品。

公开(公告)号：US3974135A

公开(公告)日：1976-08-10

申请号：US261007

申请日：1972-06-08

Applicant: Karl Folkers ,  Hans Sievertsson

Inventor： Karl Folkers ,  Hans Sievertsson

IPC: A61K38/00 ,  C07K7/23 ,  C07C103/52 ,  C07G7/00

CPC classification number: C07K7/23 ,  A61K38/00 ,  Y10S514/80 ,  Y10S930/13

Abstract: A synthetic decapeptide, L-pglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-L-arginyl-L-prolyl-glycinamide having the hormonal activity of the luteinizing hormone releasing hormone (LRH) of the hypothalamus gland of mammals is provided by utilizing, as key starting materials, the amino acids, pyroglutamic acid, histidine, tryptophan, serine, tyrosine, glycine, leucine, arginine, proline. Synthesis of the decapeptide is accomplished by coupling, in appropriate protected forms, all of the remaining amino acids, individually or in combination, to the starting amino acid, or amino acid group or to the terminal amino acid resulting from combinations with one or more other amino acids, bound to a resin or carrier followed by release of the decapeptide from the carrier as the amide or other form which is converted to the amide, L-pglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-L-arginyl-L-prolyl-glycinamide.

Abstract translation: 具有促黄体生成激素释放激素（LRH）的激素活性的合成十肽L- L-谷氨酰-L-组氨酰基-L-色氨酰-L-丝氨酰-L-酪氨酰 - 甘氨酰-L-赖氨酸-L-精氨酰-L-脯氨酰基 - 甘氨酰胺 ）作为关键原料，通过利用氨基酸，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，脯氨酸来提供哺乳动物的下丘脑腺体。 十肽的合成通过以适当的保护形式将所有残留的氨基酸单独或组合连接到起始氨基酸或氨基酸基团或与由一种或多种其它的组合产生的末端氨基酸 氨基酸，结合到树脂或载体上，随后将十肽从载体中释放为酰胺或转化为酰胺的其它形式，L-谷氨酰-L-组氨酰-L-色氨酰-L-丝氨酰-L-酪氨酰基 甘氨酰-L-赖氨酸-L-精氨酰-L-脯氨酰基 - 甘氨酰胺。

公开(公告)号：US4642332A

公开(公告)日：1987-02-10

申请号：US727711

申请日：1985-04-26

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

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

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

CPC classification number: C07K7/23 ,  A61K38/00 ,  Y10S930/13

Abstract: 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.

Abstract translation: 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：US4885167A

公开(公告)日：1989-12-05

申请号：US155891

申请日：1988-02-16

Applicant: Karl Folkers ,  Janusz Wolaniuk

Inventor： Karl Folkers ,  Janusz Wolaniuk

IPC: A61K38/43

CPC classification number: A61K31/122 ,  Y10S514/907

Abstract: 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.

Abstract translation: 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：US4656247A

公开(公告)日：1987-04-07

申请号：US727710

申请日：1985-04-26

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

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

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

CPC classification number: C07K7/23 ,  A61K38/00 ,  Y10S930/13

Abstract: 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.

Abstract translation: 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。