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1. 发明授权

US07847063B2 GLP-1 derivative 失效
标题翻译： GLP-1衍生物
公开(公告)号：US07847063B2
公开(公告)日：2010-12-07
申请号：US10550624
申请日：2004-03-26
申请人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Fumio Takaiwa , Takahito Jomori , Yuji Hayashi , Akira Tashita , Yukari Kobara
发明人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Fumio Takaiwa , Takahito Jomori , Yuji Hayashi , Akira Tashita , Yukari Kobara
IPC分类号： A61K38/00 , C07K14/00
CPC分类号： C12N15/8257 , C07K14/605 , C12N15/8216
摘要： The present invention provides a method for highly producing a recombinant protein in a plant storage organ and a GLP-1 derivative. The plant storage organ in which the recombinant protein is highly produced is obtained by transformation with the use of a vector which comprises a recombinant protein gene, a cytokinin-related gene, a drug-resistant gene and a removable DNA element, in which the cytokinin-related gene and the drug-resistant gene exist in the positions so that they can behave together with the DNA element, while the recombinant protein to be expressed in the plant storage organ exists in the position so that it would not behave together with the DNA element. The GLP-1 is produced by using the method, and a derivative having been stabilized against enzymatic digestion is further provided.
摘要翻译：本发明提供了在植物贮藏器官和GLP-1衍生物中高度产生重组蛋白的方法。通过使用包含重组蛋白基因，细胞分裂素相关基因，耐药性基因和可移除DNA元件的载体转化获得重组蛋白质高度产生的植物贮藏器官，其中细胞分裂素相关基因和耐药基因存在于可以与DNA元件一起表现的位置，而在植物储存器官中表达的重组蛋白存在于与DNA不一致的位置元件。通过使用该方法制备GLP-1，进一步提供了稳定的酶促消化的衍生物。

2. 发明申请

US20070033676A1 Process for producing plant storage organ with high production of recombinant protein and novel recombinant protein 失效
标题翻译：生产重组蛋白和新型重组蛋白的植物贮藏器具生产工艺
公开(公告)号：US20070033676A1
公开(公告)日：2007-02-08
申请号：US10550624
申请日：2004-03-26
申请人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Humio Takaiwa , Takahito Jomori , Yuji Hayashi , Akira Tashita , Yukari Kobara
发明人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Humio Takaiwa , Takahito Jomori , Yuji Hayashi , Akira Tashita , Yukari Kobara
IPC分类号： A01H5/00 , C12N15/82 , A01H1/00 , C07K14/605
CPC分类号： C12N15/8257 , C07K14/605 , C12N15/8216
摘要： The present invention provides a method for highly producing a recombinant protein in a plant storage organ and a GLP-1 derivative. The plant storage organ in which the recombinant protein is highly produced is obtained by transformation with the use of a vector which comprises a recombinant protein gene, a cytokinin-related gene, a drug-resistant gene and a removable DNA element, in which the cytokinin-related gene and the drug-resistant gene exist in the positions so that they can behave together with the DNA element, while the recombinant protein to be expressed in the plant storage organ exists in the position so that it would not behave together with the DNA element. The GLP-1 is produced by using the method, and a derivative having been stabilized against enzymatic digestion is further provided.
摘要翻译：本发明提供了在植物贮藏器官和GLP-1衍生物中高度产生重组蛋白的方法。通过使用包含重组蛋白基因，细胞分裂素相关基因，耐药性基因和可移除DNA元件的载体转化获得重组蛋白质高度产生的植物贮藏器官，其中细胞分裂素相关基因和耐药基因存在于与DNA元件一起表现的位置，而在植物储存器官中表达的重组蛋白存在于与DNA不一致的位置元件。通过使用该方法制备GLP-1，进一步提供了稳定的酶促消化的衍生物。

3. 发明申请

US20080292732A1 Plant and Plant Storage Organ Having Glp-1 Derivative Accumulated Therein and Method of Producing the Same 失效
标题翻译：含有Glp-1衍生物的植物和植物储存器官及其生产方法
公开(公告)号：US20080292732A1
公开(公告)日：2008-11-27
申请号：US11662650
申请日：2004-09-14
申请人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Fumio Takaiwa , Hiroshi Yasuda , Takahito Jomori , Yuji Hayashi , Akira Tashita
发明人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Fumio Takaiwa , Hiroshi Yasuda , Takahito Jomori , Yuji Hayashi , Akira Tashita
IPC分类号： A61K36/00 , C12N15/82 , A01H5/00 , A61P31/10
CPC分类号： A61K38/26 , A23L33/105 , C12N15/8257
摘要： The present invention is to provide a plant and a plant storage organ thereof in which GLP-1 derivatives are accumulated, and a method of producing them in order to develop a method for ingesting orally GLP-1 derivatives at a low cost and to make use of it in diabetic treatment. A transgenic plant or a plant storage organ thereof in which GLP-1 derivatives are accumulated cleavable with a digestive enzyme is produced by a method comprising: integrating into a vector a linked GLP-1s-DNA which comprises tandem repeated “n” DNAs (“n” being an integer of 3 or more) encoding a GLP-1 derivative consisting of GLP-1 (7-36) or of an amino acid sequence of GLP-1 (7-36) in which one or a few amino acids are deleted, substituted and/or added, and C-terminal consists of Arg or Lys, and having GLP-1 activity; introducing the vector into a plant cell; and redifferentiating the obtained transformant. The transgenic plant and the plant storage organ are useful as a pharmaceutical composition or a food or drink for treating or preventing diabetes.
摘要翻译：本发明提供一种其中积聚有GLP-1衍生物的植物和植物贮藏器官及其生产方法，以便开发低成本摄取口服GLP-1衍生物的方法并使用的糖尿病治疗。 GLP-1衍生物可以用消化酶积聚可切割的转基因植物或植物贮藏器官是通过以下方法产生的：将连接的GLP-1s-DNA整合到载体中，所述连接的GLP-1s-DNA包含串联重复的“n”DNA（“ 编号由GLP-1（7-36）或GLP-1（7-36）的氨基酸序列组成的GLP-1衍生物的n“为3以上的整数，其中一个或几个氨基酸为缺失，取代和/或添加，C-末端由Arg或Lys组成，具有GLP-1活性; 将载体导入植物细胞; 并对所得转化体进行重新分化。转基因植物和植物贮藏器官可用作药物组合物或用于治疗或预防糖尿病的食物或饮料。

4. 发明授权

US07947876B2 Plant and plant storage organ having GLP-1 derivative accumulated therein and method of producing the same 失效
标题翻译：蓄积有GLP-1衍生物的植物贮藏器具及其制造方法
公开(公告)号：US07947876B2
公开(公告)日：2011-05-24
申请号：US11662650
申请日：2004-09-14
申请人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Humio Takaiwa , Hiroshi Yasuda , Takahito Jomori , Yuji Hayashi , Akira Tashita
发明人： Koichi Sugita , Saori Kasahara , Hiroyasu Ebinuma , Humio Takaiwa , Hiroshi Yasuda , Takahito Jomori , Yuji Hayashi , Akira Tashita
IPC分类号： A01H5/00 , C12N15/82
CPC分类号： A61K38/26 , A23L33/105 , C12N15/8257
摘要： The present invention is regarding plants and plant storage organs thereof in which GLP-1 derivatives are accumulated, and methods of producing them. The transgenic plants and plant storage organs thereof accumulate tandem repeated GLP-1 derivatives cleavable with intestinal digestive enzyme to monomeric molecules and are produced by methods comprising: integrating into vectors linked DNAs which comprise tandem repeated DNAs encoding the GLP-1 derivative with trypsin resistance in which the amino acid in the 26th position is Gln, the amino acid in the 34th position is Asn or Asp, and C-terminal consists of Arg or Lys to produce monomeric molecules; introducing the vectors into plant cells; and redifferentiating the obtained transformants. The edible transgenic plants and plant storage organs are useful for treating diabetes and can be ingested by diabetic patients.
摘要翻译：本发明涉及其中积累GLP-1衍生物的植物和植物贮藏器官及其生产方法。其转基因植物和植物储存器官将可与肠消化酶切割的串联重复的GLP-1衍生物积聚到单体分子中，并通过以下方法产生：包括：将包含编码GLP-1衍生物的串联重复DNA与胰蛋白酶抗性的连锁DNA连接其中第26位的氨基酸是Gln，第34位的氨基酸是Asn或Asp，C末端由Arg或Lys组成以产生单体分子; 将载体导入植物细胞; 并重新分化获得的转化体。可食用的转基因植物和植物贮藏器官可用于治疗糖尿病并可被糖尿病患者摄入。

5. 发明授权

US5869460A Sulfated and phosphated saccharide derivatives, process for the preparation of the same and use thereof 失效
标题翻译：硫酸化和磷酸化的糖衍生物，其制备方法和用途
公开(公告)号：US5869460A
公开(公告)日：1999-02-09
申请号：US739423
申请日：1996-10-29
申请人： Toshinao Usui , Takao Igami , Takuji Kakigami , Hitoshi Hamashima , Takahito Jomori , Akira Tashita , Yoshiro Ishiwatari , Shoji Yokochi , Takahiko Mitani , Yasuo Suzuki , Akira Hasegawa
发明人： Toshinao Usui , Takao Igami , Takuji Kakigami , Hitoshi Hamashima , Takahito Jomori , Akira Tashita , Yoshiro Ishiwatari , Shoji Yokochi , Takahiko Mitani , Yasuo Suzuki , Akira Hasegawa
IPC分类号： C07H1/00 , A61K31/70 , A61K31/7028 , A61P29/00 , A61P43/00 , C07H1/02 , C07H3/06 , C07H5/08 , C07H11/04 , C07H15/04 , C07H15/00
CPC分类号： A61K31/7024 , C07H11/04 , C07H3/06 , C07H5/08 , Y02P20/55
摘要： There are described sulfated and phosphated saccharide erivatives of the Formula ##STR1## wherein R.sub.1 is hydrogen atom or a residue of sulfate, phosphate or L-fucose; R.sub.2, R.sub.3 and R.sub.4 are hydrogen atom or a residue of sulfate or phosphate, respectively; 1 is an integer of 0 or 1;m is an integer of 0-15; and n is an integer of 0-21, or pharmaceutically acceptable salts thereof, a process for the preparation of the derivatives and salts as well as use thereof, as an anti-inflammatory agent.
摘要翻译：其中R1表示氢原子或硫酸盐，磷酸盐或L-岩藻糖残基;硫酸盐，磷酸盐或L-岩藻糖残基; R2，R3和R4分别是氢原子或硫酸盐或磷酸盐的残基; 1是0或1的整数; m为0-15的整数; n为0-21的整数，或其药学上可接受的盐，作为抗炎剂的衍生物和盐的制备方法及其用途。

6. 发明申请

US20060194720A1 Glp-1 derivatives and transmicosal absorption preparations thereof 失效
标题翻译： Glp-1衍生物及其经半吸收制剂
公开(公告)号：US20060194720A1
公开(公告)日：2006-08-31
申请号：US10530125
申请日：2003-10-10
申请人： Yuji Hayashi , Mitsuhiro Makino , Toshiyuki Kouzaki , Motohiro Takeda , Takahito Jomori
发明人： Yuji Hayashi , Mitsuhiro Makino , Toshiyuki Kouzaki , Motohiro Takeda , Takahito Jomori
IPC分类号： C07K14/605 , A61K38/22
CPC分类号： C07K14/605 , A61K38/26 , Y10S514/866
摘要： The invention relates to a GLP-1 derivative including an amino acid sequence of GLP-1 (7-35) having deletion, substitution and/or addition of one or more amino acids and having Waa-(Xaa)n-Yaa (in which Waa is Arg or Lys, Xaa is Arg or Lys, n is an integer of 0 to 14, and Yaa is Arg, Arg-NH2, Lys, Lys-NH2 or Hse) added to the C-terminus of the peptide having a GLP-1 activity. These derivatives are derivatives highly absorbable via a mucous membrane. In the invention, the GLP-1 derivative can be conferred with resistance to dipeptidyl peptidase IV by substituting amino acid 8 in its GLP-1 amino acid sequence with Ser, or with resistance to trypsin by substituting amino acids 26 and 34 with Gln and Asn, respectively. The efficiency of absorption of the GLP-1 derivatives of the invention via mucous membranes can be further improved by preparing a composition using a charge-regulated fat emulsion regulated to be negatively charged thereon.
摘要翻译：本发明涉及包含具有缺失，取代和/或添加一个或多个氨基酸并具有Waa-（Xaa）n-Yaa）的GLP-1（7-35）氨基酸序列的GLP-1衍生物（其中 Waa为Arg或Lys，Xaa为Arg或Lys，n为0〜14的整数，Yaa为Arg，Arg-NH 2 Lys，Lys-NH 2 >或Hse）加入具有GLP-1活性的肽的C末端。这些衍生物是通过粘膜高度吸收的衍生物。在本发明中，通过用Ser取代其GLP-1氨基酸序列中的氨基酸8或通过用Gln和Asn取代氨基酸26和34对胰蛋白酶具有抗性，GLP-1衍生物可赋予对二肽基肽酶IV的抗性，分别。本发明的GLP-1衍生物通过粘膜吸收的效率可以通过使用调节为带负电荷的电荷调节脂肪乳剂制备组合物而进一步改善。

7. 发明授权

US07291594B2 GLP-1 derivative and preparation thereof absorbable via mucous membrane 失效
标题翻译： GLP-1衍生物及其可通过粘膜吸收的制剂
公开(公告)号：US07291594B2
公开(公告)日：2007-11-06
申请号：US10530125
申请日：2003-10-10
申请人： Yuji Hayashi , Mitsuhiro Makino , Toshiyuki Kouzaki , Motohiro Takeda , Takahito Jomori
发明人： Yuji Hayashi , Mitsuhiro Makino , Toshiyuki Kouzaki , Motohiro Takeda , Takahito Jomori
IPC分类号： A61K38/26 , C07K14/605
CPC分类号： C07K14/605 , A61K38/26 , Y10S514/866
摘要： A GLP-1 derivative is provided including an amino acid sequence of GLP-1 (7-35) having deletion, substitution and/or addition of one or more amino acids and having Waa-(Xaa)n-Yaa (in which Waa is Arg or Lys, Xaa is Arg or Lys, n is an integer of 0 to 14, and Yaa is Arg, Arg-NH2, Lys, Lys-NH2 or Hse) added to the C-terminus of the peptide having a GLP-1 activity. These derivatives are highly absorbable via a mucous membrane. The GLP-1 derivative can be conferred with resistance to dipeptidyl peptidase IV by substituting amino acid 8 in its GLP-1 amino acid sequence with Ser, or with resistance to trypsin by substituting amino acids 26 and 34 with Gln and Asn, respectively.The absorption efficiency of the GLP-1 derivatives via mucous membranes can be further improved by preparing a composition using a charge-regulated fat emulsion regulated to be negatively charged thereon.
摘要翻译：提供GLP-1衍生物，其包含具有缺失，取代和/或添加一个或多个氨基酸并具有Waa-（Xaa）n-Yaa的GLP-1（7-35）的氨基酸序列（其中Waa为 Arg或Lys，Xaa是Arg或Lys，n是0-14的整数，Yaa是Arg，Arg-NH 2，Lys，Lys-NH 2或 Hse）加入具有GLP-1活性的肽的C末端。这些衍生物通过粘膜是高度可吸收的。通过用Ser取代其GLP-1氨基酸序列中的氨基酸8，或分别用Gln和Asn取代氨基酸26和34，对胰蛋白酶具有抗性，GLP-1衍生物可赋予对二肽基肽酶IV的抗性。通过使用调节为带负电荷的电荷调节脂肪乳液制备组合物，可以进一步提高通过粘膜的GLP-1衍生物的吸收效率。

8. 发明授权

US06809113B2 Antagonists of MCP-1 function and methods of use thereof 失效
标题翻译： MCP-1功能的拮抗剂及其使用方法
公开(公告)号：US06809113B2
公开(公告)日：2004-10-26
申请号：US10087208
申请日：2002-02-27
申请人： Edgardo Laborde , Louise Robinson , Fanying Meng , Brian T. Peterson , Hugo O. Villar , Steven E. Anuskiewicz , Yoshiro Ishiwata , Shoji Yokochi , Yukiharu Matsumoto , Takuji Kakigami , Hideaki Inagaki , Takahito Jomori , Kouji Matsushima
发明人： Edgardo Laborde , Louise Robinson , Fanying Meng , Brian T. Peterson , Hugo O. Villar , Steven E. Anuskiewicz , Yoshiro Ishiwata , Shoji Yokochi , Yukiharu Matsumoto , Takuji Kakigami , Hideaki Inagaki , Takahito Jomori , Kouji Matsushima
IPC分类号： A61K3135
CPC分类号： C07D401/12 , C07D215/48 , C07D241/42 , C07D265/36 , C07D319/18 , C07D405/12 , C07D407/12 , C07D409/12 , C07D417/12
摘要： Compounds which are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection; pharmaceutical compositions comprising these compounds; and the use of these compounds and compositions in the prevention or treatment of such diseases.
摘要翻译：作为MCP-1拮抗剂的化合物起作用，可用于预防或治疗慢性或急性炎性或自身免疫性疾病，特别是与异常淋巴细胞或单核细胞积累相关的疾病如关节炎，哮喘，动脉粥样硬化，糖尿病性肾病，炎性肠病，克罗恩病，多发性硬化，肾炎，胰腺炎，肺纤维化，牛皮癣，再狭窄和移植排斥反应; 包含这些化合物的药物组合物; 以及这些化合物和组合物在预防或治疗这些疾病中的用途。

9. 发明申请

US20100305177A1 PROPHYLACTIC OR THERAPEUTIC AGENT FOR DIABETIC MACULOPATHY 失效
标题翻译：用于糖尿病的预防或治疗药物
公开(公告)号：US20100305177A1
公开(公告)日：2010-12-02
申请号：US12842391
申请日：2010-07-23
申请人： Noriaki KATO , Hiroshi Nagano , Kaori Taniko , Takahito Jomori
发明人： Noriaki KATO , Hiroshi Nagano , Kaori Taniko , Takahito Jomori
IPC分类号： A61K31/4188 , A61P27/02
CPC分类号： A61K31/4166 , A01K2227/106 , A01K2267/0362 , A01K2267/0375 , C07D491/10 , G01N33/5088 , G01N2800/042
摘要： A prophylactic or therapeutic agent for diabeticmaculopathy, which can be administered for a long time and exhibits efficacy in a mechanism different from that of existing medicines. The invention relates to a prophylactic or therapeutic agent for diabetic maculopathy, comprising, as an active ingredient, a compound represented by the general formula: wherein X represents a halogen or a hydrogen atom, R1 and R2 concurrently or differently represent a hydrogen atom or an optionally substituted C1 to C6 alkyl group, or R1 and R2, together with a nitrogen atom bound thereto and optionally another nitrogen atom or an oxygen atom, are combined to form a 5- to 6-membered heterocycle. Preferably, the compound is (2S,4S)-6-fluoro-2′,5′-dioxospiro chroman-4,4′-imidazolidine]-2-carboxamide. The invention also provides a model animal with diabetic maculopathy produced by subjecting a diabetic animal to intraocular ischemia/reperfusion to express edema in a retinal visual cell layer or in a macula lutea.
摘要翻译：用于糖尿病性脑病的预防或治疗剂，其可以长时间施用并且以与现有药物不同的机制显示功效。本发明涉及一种糖尿病性黄斑病变的预防或治疗剂，其特征在于，作为活性成分，含有下列通式表示的化合物：其中，X表示卤素或氢原子，R 1和R 2可以同时或不同地表示氢原子或任选取代的C 1至C 6烷基，或R 1和R 2与连接的氮原子和任选另外的氮原子或氧原子一起形成5-至6-元杂环。优选地，该化合物是（2S，4S）-6-氟-2'，5'-二氧杂环苯并二氢吡喃-4,4'-咪唑烷] -2-甲酰胺。本发明还提供了一种通过使糖尿病动物进行眼内缺血/再灌注以在视网膜视细胞层或黄斑黄斑中表达水肿而产生的糖尿病性黄斑变性的模型动物。

10. 发明授权

US06998407B2 Antagonists of MCP-1 function and methods of use thereof 失效
标题翻译： MCP-1功能的拮抗剂及其使用方法
公开(公告)号：US06998407B2
公开(公告)日：2006-02-14
申请号：US10716652
申请日：2003-11-18
申请人： Edgardo Laborde , Louise Robinson , Fanying Meng , Brian T. Peterson , Hugo O. Villar , Steven E. Anuskiewicz , Yoshiro Ishiwata , Shoji Yokochi , Yukiharu Matsumoto , Takuji Kakigami , Hideaki Inagaki , Takahito Jomori , Kouji Matsushima
发明人： Edgardo Laborde , Louise Robinson , Fanying Meng , Brian T. Peterson , Hugo O. Villar , Steven E. Anuskiewicz , Yoshiro Ishiwata , Shoji Yokochi , Yukiharu Matsumoto , Takuji Kakigami , Hideaki Inagaki , Takahito Jomori , Kouji Matsushima
IPC分类号： A61K31/36 , A61K31/343 , C07D307/79 , C07D317/60
CPC分类号： C07D235/06 , C07D209/08 , C07D249/18 , C07D263/56 , C07D307/79 , C07D317/68 , C07D405/12 , C07D407/12 , C07D409/12 , C07D417/12
摘要： Chemical compounds which are antagonists of Monocyte Chemoattractant Protein-1 (MCP-1) function, pharmaceutical compositions comprising these compounds, methods of treatment employing these compounds and compositions, and processes for preparing these compounds. The compounds are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection.
摘要翻译：作为单核细胞趋化蛋白-1（MCP-1）功能拮抗剂的化合物，包含这些化合物的药物组合物，使用这些化合物和组合物的治疗方法，以及制备这些化合物的方法。该化合物可用于预防或治疗慢性或急性炎性或自身免疫疾病，特别是与异常淋巴细胞或单核细胞积累相关的疾病，如关节炎，哮喘，动脉粥样硬化，糖尿病性肾病，炎性肠病，克罗恩病，多发性硬化，肾炎，胰腺炎，肺纤维化，牛皮癣，再狭窄和移植排斥。

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