公开(公告)号：US20210023231A1

公开(公告)日：2021-01-28

申请号：US17042039

申请日：2019-03-29

Applicant: NOF CORPORATION ,  TOKYO INSTITUTE OF TECHNOLOGY

Inventor： Hiroki YOSHIOKA ,  Masaki KAMIYA ,  Yuji YAMAMOTO ,  Midori HIRAI ,  Akiko SASAKI ,  Nobuhiro NISHIYAMA ,  Makoto MATSUI ,  Hiroyasu TAKEMOTO ,  Kazuki MIYAUCHI ,  Takahiro NOMOTO ,  Keishiro TOMODA

IPC: A61K47/60 ,  C08G65/333 ,  C07K19/00 ,  C07K5/103 ,  C07K7/06 ,  A61K38/23 ,  A61K38/19 ,  A61K38/27

Abstract: The invention provides a bio-related substance bonded to a high-molecular-weight polyethylene glycol derivative that does not cause vacuolation of cells. The bio-related substance bonded to a degradable polyethylene glycol derivative is represented by the formula (A):
wherein m is 1-7, n1 and n2 are each independently 45-682, p is 1-4, R is an alkyl group having 1-4 carbon atoms, Z is an oligopeptide with 2-8 residues composed of neutral amino acids excluding cysteine, Q is a residue of a compound having 2-5 active hydrogens, D is the bio-related substance, L1, L2, L3, L4 and L5 are each independently a single bond or a divalent spacer, and y is 1-40.

公开(公告)号：US20210147624A1

公开(公告)日：2021-05-20

申请号：US17042711

申请日：2019-03-29

Applicant: NOF CORPORATION ,  TOKYO INSTITUTE OF TECHNOLOGY

Inventor： Hiroki YOSHIOKA ,  Masaki KAMIYA ,  Yuji YAMAMOTO ,  Midori HIRAI ,  Akiko SASAKI ,  Nobuhiro NISHIYAMA ,  Makoto MATSUI ,  Hiroyasu TAKEMOTO ,  Kazuki MIYAUCHI ,  Takahiro NOMOTO ,  Keishiro TOMODA

IPC: C08G65/333 ,  C08G65/325 ,  A61K47/65

Abstract: The invention provides a high-molecular-weight polyethylene glycol derivative that does not cause vacuolation of cells. The degradable polyethylene glycol derivative is represented by the following formula (1): wherein m is 1-7, n1 and n2 are each independently 45-682, p is 1-4, R is an alkyl group having 1-4 carbon atoms, Z is an oligopeptide with 2-8 residues composed of neutral amino acids excluding cysteine, Q is a residue of a compound having 2-5 active hydrogens, X is a functional group capable of reacting with a bio-related substance, and L1, L2, L3, L4 and L5 are each independently a single bond or a divalent spacer.

公开(公告)号：US20170107325A1

公开(公告)日：2017-04-20

申请号：US15300699

申请日：2015-03-30

Applicant: NOF CORPORATION

Inventor： Takuma TSUBUSAKI ,  Yuji YAMAMOTO

IPC: C08G65/333 ,  C07D317/24 ,  C07D405/06 ,  C07D317/20

CPC classification number: C08G65/33396 ,  C07D317/20 ,  C07D317/22 ,  C07D317/24 ,  C07D317/28 ,  C07D405/06 ,  C08G65/329 ,  C08G65/3317 ,  C08G65/333 ,  C08G65/33324 ,  C08G65/33337 ,  C08G65/33341 ,  C08G65/3346 ,  C08G65/337

Abstract: A hydrophilic polymer derivative having a cyclic benzylidene acetal linker represented by the following formula (1): wherein R1 and R6 are each independently a hydrogen atom or a hydrocarbon group; R2, R3, R4 and R5 are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom; X1 is a chemically reactive functional group; P is a hydrophilic polymer, s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; w is an integer of 1 to 8; and Z1 and Z2 are each independently a selected divalent spacer.

公开(公告)号：US20180298143A1

公开(公告)日：2018-10-18

申请号：US16010972

申请日：2018-06-18

Applicant: NOF CORPORATION

Inventor： Takuma TSUBUSAKI ,  Yuji YAMAMOTO

IPC: C08G65/48 ,  C08G65/334 ,  C08G65/333 ,  C08G65/332 ,  C08G65/331 ,  C08G65/26

Abstract: A hydrophilic polymer derivative having a benzylidene acetal linker whose hydrolysis rate at the pH of a weakly acidic environment in the living body can be accurately controlled. A hydrophilic polymer derivative having a benzylidene acetal linker, which is represented by the following formula (1): wherein R1 is a hydrogen atom or a hydrocarbon group; R2, R3, R4, R5, and R6 are each independently a hydrogen atom or a substituent and at least one of R3, R4, and R5 is an electron-withdrawing substituent or at least one of R2 and R6 represents a substituent; X1 is a chemically reactive functional group; P is a hydrophilic polymer; w is an integer of 1 to 8; and Z1 and Z2 are an independently selected divalent spacer.

公开(公告)号：US20180078651A1

公开(公告)日：2018-03-22

申请号：US15563346

申请日：2016-03-30

Applicant: NOF CORPORATION

Inventor： Takuma TSUBUSAKI ,  Yuji YAMAMOTO

IPC: A61K47/60 ,  C08G65/333

Abstract: A biodegradable polyethylene glycol derivative in which a polyethylene glycol chain is linked by an acetal linker capable of accurately controlling the hydrolysis rate under different pH environments in the living body, and whose division rate into a polyethylene glycol chain of low molecular weight in the living body can be accurately controlled. The biodegradable polyethylene glycol derivative is represented by formula (1) or formula (2) as described.

公开(公告)号：US20190309102A1

公开(公告)日：2019-10-10

申请号：US16451448

申请日：2019-06-25

Applicant: NOF CORPORATION

Inventor： Takuma TSUBUSAKI ,  Yuji YAMAMOTO

IPC: C08F8/12 ,  A61K39/395 ,  A61K45/00 ,  A61K47/22 ,  C07C45/36 ,  A61K47/50 ,  C07K16/00 ,  C07K19/00 ,  C07K16/18

Abstract: An antibody-drug conjugate having a cyclic benzylidene acetal linker represented by formula (1) or formula (2), wherein Y is an antibody; D is a drug; R1 and R6 are each independently a hydrogen atom or a hydrocarbon group; R2, R3, R4 and R5 are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom; s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; w is an integer of 1 to 20; and Z1 and Z2 are each independently a selected divalent spacer:

公开(公告)号：US20180312466A1

公开(公告)日：2018-11-01

申请号：US16023167

申请日：2018-06-29

Applicant: NOF CORPORATION

Inventor： Yuji YAMAMOTO ,  Hiroki YOSHIOKA ,  Fumiaki MANABE

IPC: C07D207/452 ,  G01N33/543 ,  C08G65/334 ,  C08G65/331 ,  C08G65/333 ,  C08G65/26 ,  C07D209/48

CPC classification number: C07D207/452 ,  C07D209/48 ,  C08G65/2612 ,  C08G65/3312 ,  C08G65/33337 ,  C08G65/33396 ,  C08G65/3344 ,  C08L2203/02 ,  G01N33/54353

Abstract: A branched hetero polyethylene glycol according to the present invention is represented by the formula [1]: wherein X and Y represent each an atomic group containing at least a functional group which reacts with a functional group present in a bio-functional molecule to form a covalent bond and the functional group contained in the atomic group X and the functional group contained in the atomic group Y are different from each other; s is an integer of 2 to 8, which represents the number of polyethylene glycol chains; n is the number of average added moles for the polyethylene glycol chain and 20≤n≤2000; and E is a branching linker moiety having s-valent bonding valency for the polyethylene glycol chains and having monovalent bonding valency for the functional group Y.

公开(公告)号：US20160326317A1

公开(公告)日：2016-11-10

申请号：US15216573

申请日：2016-07-21

Applicant: NOF CORPORATION

Inventor： Hiroki YOSHIOKA ,  Midori HIRAI ,  Hitoshi NAKATSUHARA ,  Yuji YAMAMOTO

IPC: C08G65/26

CPC classification number: C08G65/2609 ,  C08G65/2696 ,  C08G65/329 ,  C08G65/3322 ,  C08G65/33306 ,  C08G65/33337 ,  C08G65/33368 ,  C08G65/33389 ,  C08G2650/30

Abstract: A multi-arm polyethylene glycol derivative having a narrow molecular weight distribution represented by the formula (1): wherein, L represents a group selected from a linear or branched alkylene, arylene, or cycloalkylene group having two or more carbon atoms and combinations thereof, which may have an ether bond in a chain; X represents a dehydroxylation residue of a linear sugar alcohol having 5 or 7 carbon atoms; m is the number of polyethylene glycol chains bonded to X and represents 4 or 6; n is the average addition molar number of oxyethylene groups and represents an integer of 3 to 600; Y represents a single bond or an alkylene group as further defined herein; and Z represents a chemically reactive functional group.

Abstract translation: 其中，L表示选自具有两个或更多个碳原子的直链或支链亚烷基，亚芳基或亚环烷基及其组合，其可以在链中具有醚键; X表示具有5或7个碳原子的直链糖醇的脱羟基残基; m是与X键合的聚乙二醇链的数目，代表4或6; n是氧乙烯基的平均加成摩尔数，为3〜600的整数。 Y代表本文进一步定义的单键或亚烷基; Z表示化学反应性官能团。

公开(公告)号：US20160264730A1

公开(公告)日：2016-09-15

申请号：US15033303

申请日：2014-10-24

Applicant: NOF CORPORATION

Inventor： Takuma TSUBUSAKI ,  Yuji YAMAMOTO

IPC: C08G65/08 ,  A61L27/18 ,  A61L31/06

CPC classification number: C08G65/08 ,  A61L27/18 ,  A61L31/06 ,  C08G65/26 ,  C08G65/2606 ,  C08G65/2618 ,  C08G65/2696 ,  C08G65/30 ,  C08G65/331 ,  C08G2650/58 ,  C08L2203/02

Abstract: A method of producing a medical polyoxypropylene polymer and a polyoxypropylene/polyoxyethylene block copolymer including (A) adding to a polyoxypropylene polymer which is obtained by ring-opening polymerization of propylene oxide to a starting substance having an active hydrogen reacting with the propylene oxide and contains allyl ether as an impurity, a tertiary alkoxide of alkali metal in an excess amount based on a molar number of the active hydrogen of the starting substance and heat treating at 115° C. or less to isomerize the allyl ether to propenyl ether; and (B) adding a mineral acid to the product obtained in step (A) to adjust pH to 4 or less and treating at 70° C. or less to hydrolyze the propenyl ether. Also disclosed is a method of producing a medical polyoxypropylene/polyoxyethylene block copolymer which includes performing ring-opening polymerization of ethylene oxide to the polyoxypropylene polymer obtained above.

Abstract translation: 一种生产医用聚氧丙烯聚合物和聚氧丙烯/聚氧乙烯嵌段共聚物的方法，包括（A）加入通过环氧丙烷开环聚合获得的具有活性氢与环氧丙烷反应的起始物质的聚氧丙烯聚合物，并含有 烯丙基醚作为杂质，基于起始物质的活性氢摩尔数过量的碱金属叔醇盐，在115℃或更低温度下进行热处理，将烯丙基醚异构化成丙烯基醚; 和（B）将无机酸添加到步骤（A）中获得的产物中以将pH调节至4以下，并在70℃以下处理以水解丙烯基醚。 还公开了制备医用聚氧丙烯/聚氧乙烯嵌段共聚物的方法，其包括对上述得到的聚氧丙烯聚合物进行环氧乙烷的开环聚合。

公开(公告)号：US20200291178A1

公开(公告)日：2020-09-17

申请号：US16887081

申请日：2020-05-29

Applicant: NOF CORPORATION

Inventor： Takuma TSUBUSAKI ,  Yuji YAMAMOTO

IPC: C08G65/333 ,  C07D405/06 ,  C08G65/329 ,  C07D317/22 ,  C07D317/28 ,  C08G65/331 ,  C08G65/337 ,  C08G65/334 ,  C07D317/20 ,  C07D317/24

Abstract: A hydrophilic polymer derivative having a cyclic benzylidene acetal linker represented by the following formula (1): wherein R1 and R6 are each independently a hydrogen atom or a hydrocarbon group; R2, R3, R4 and R5 are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom; X1 is a chemically reactive functional group; P is a hydrophilic polymer; s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; w is an integer of 1 to 8; and Z1 and Z2 are each independently a selected divalent spacer.