(19) TZZ __T (11) EP 2 692 771 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: (51) Int Cl.: 05.02.2014 Bulletin 2014/06 C08G 65/329 (2006.01) (21) Application number: 12764912.7 (86) International application number: PCT/JP2012/058069 (22) Date of filing: 28.03.2012 (87) International publication number: WO 2012/133490 (04.10.2012 Gazette 2012/40) (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • YOSHIOKA, Hiroki GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Kanagawa 210-0865 (JP) PL PT RO RS SE SI SK SM TR • MATANI, Takashi Kanagawa 210-0865 (JP) (30) Priority: 30.03.2011 JP 2011076682 • YAMAMOTO, Yuji Kanagawa 210-0865 (JP) (71) Applicant: NOF Corporation 20-3 Ebisu 4-chome, Shibuya-ku (74) Representative: HOFFMANN EITLE Tokyo 150-6019 (JP) Patent- und Rechtsanwälte Arabellastrasse 4 81925 München (DE) (54) POLYOXYETHYLENE DERIVATIVE HAVING A PLURALITY OF HYDROXYL GROUPS AT END (57) The present invention provides a novel polyoxyethylene derivative having plural hydroxyl groups at a terminal end thereof, particularly a polyoxyethylene derivative having plural hydroxyl groups at a terminal end thereof, which can be effectively used in uses for modifying bio-related substances and can be industrially produced. A polyoxyethylene derivative represented by the formula (1) : wherein a whole molecular weight of the polyoxyethylene derivative is 500 to 160, 000; n is 5 to 3650; 1L, L2, and L3 each independently represent an alkylene group, a phenylene group, an ester bond, an amide bond, an ether bond, a urethane bond, a carbonate bond, a secondary amino group, or a combination thereof; X represents a functional group capable of reacting with a bio-related substance; Y represents a hydrophilic group having plural hydroxyl groups made from a residual group of xylitol or volemitol or a residual group of polyglycerin of trimer to 31- mer; Z represents a residual group of a compound having 2 to 5 active hydrogen atoms; b and c are as follows: 1 ≤b≤4, 1≤c≤4, and 2≤b+c≤5; and d and e each independently are 0 or 1. EP 2 692 771 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 692 771 A1 Description Technical Field 5 [0001] The present invention relates to a polyoxyethylene derivative having plural hydroxyl groups at a terminal end thereof, which is used in uses for modifying bio-related substances. Background Art 10 [0002] Recently, development on medicaments have been carried out, which use bio-related substances such as intercellular signaling substances such as hormones and cytokines, antibodies, and enzymes. When injected to a living body, these bio-related substances are usually cleared from the body because of the filtration through glomeruli in the kidney and the uptake by macrophages in the liver, spleen, and the like. Therefore, they have short half-lives in blood and hence it is difficult to obtain a sufficient pharmacological effect. For solving the problems, it is attempted to encapsula te 15 the bio-related substances in liposomes or polymer micelles and to chemically modify the bio-related substances with an amphiphatic polymer such as a sugar chain or polyethylene glycol or albumin. By these attempts, the behavior of the bio-related substances in a living body is improved through increase in their molecular weight or formation of a hydration layer. Moreover, it is also known that effects of decreasing toxicity and antigenicity and enhancing solubility of sparingly water-soluble pharmaceuticals are obtained by the modification with polyoxyethylene. 20 [0003] Non-Patent Documents 1 and 2 have report that there is a case of an ABC (accelerated blood clearance) phenomenon in which half-lives in blood decrease at the second or later administration as compared with the case at the first administration when liposomes or nano particles modified with polyoxyethylene are repeatedly administrated to the same individual. It is considered that this is because an antibody to the polyoxyethylene with which the liposomes or nano particles have been modified is expressed and it is said that the antibody recognizes various sites, such as a 25 terminal end of the polyoxyethylene chain and a repeating structure of the polyoxyethylene. On the other hand, there is a reported example that liposomes and nano particles modified with some hydrophilic polymers such as polyglycerin hardly induce the ABC phenomenon. However, with hydrophilic polymers other than the polyoxyethylene, a sufficient circulation in blood cannot be obtained and also the polymers are poor in examples in clinical use, so that they are not sufficient as alternatives of polyoxyethylene. 30 [0004] On the other hand, in Patent Document 1, there is a description relating to a bio-related substance modified with a polyoxyethylene derivative having one hydroxyl group at a terminal end thereof. When a polyoxyethylene derivative having a hydroxyl group at a terminal end thereof is used, data showing decreased antigenicity are obtained as compared with the case of a polyoxyethylene derivative having a alkoxy group at a terminal end thereof. Such placement of the hydroxyl group at the terminal end of the polyoxyethylene derivative is considered to be one remedial measure for 35 contributing a decrease in antigenicity of polyoxyethylene. However, since the polyoxyethylene derivative described in the document is purified using a reverse-phase chromatography, the yield decreases to a large extent and hence the derivative is not suitable for industrial production. Moreover, in recent years, development of pharmaceutical agents showing more improved circulation in blood has been in progress and there is a need for further decreasing antigenicity. [0005] Since the placement of plural hydroxyl groups at a terminal end of polyoxyethylene leads to formation of a 40 stronger and larger hydrated layer around a carrier, it is considered that the interaction with an opsonin is lowered and, as a result, the antigenicity can be further decreased. There are the following documents on polyoxyethylene having plural hydroxyl groups. [0006] In many documents including Patent Documents 2 and 3, there are descriptions relating to targeting-type preparations wherein a monosaccharide or polysaccharide having plural hydroxyl groups is introduced into a terminal 45 end of a hydrophilic polymer and a drug is bonded thereto. However, the saccharides are used for getting a targeting property through a carbohydrate recognition mechanism present in a living body and it is not intended to improve antigenicity. [0007] Patent Documents 4 and 5 describes hydrophobic polyoxyalkylene having a polyglycerin derivative with a large number of hydroxyl groups. Such hydrophobic polyoxyalkylene is a surfactant which utilizes the hydrophilicity of polyg- 50 lycerin. In these documents, only examples of hydrophobic polyoxyalkylene are shown and it is difficult to obtain a highly pure polyoxyethylene derivative suitable for modifying bio-related substances by the production methods described therein. [0008] Patent Document 6 describes a copolymer of polyoxyethylene and polyglycidol. In the method of manufacturing a random or block polymer described in the document, the polyglycidol is converted into branched polymers having 55 plural branches and into a mixture of polymers having various structures. As a raw material for medicaments, a highly pure compound having a single structure is required and a mixture is not preferred. Furthermore, it is necessary for a mixture to define a compositional ratio and the like of components contained therein at application for registration of pharmaceutical raw materials and thus much difficulty exists. Moreover, it is difficult to control the number of hydroxyl 2 EP 2 692 771 A1 groups in the polymer at the polymerization of glycidol and hence there is a problem that viscosity of a polymer solution increases when the number of hydroxyl groups increases. [0009] As above, it is a current situation that a polyoxyethylene derivative suitable for modification of relatedbio- substances, having plural hydroxyl groups that can improve half-lives in blood and antigenicity at one terminal end, and 5 capable of industrial production has not been obtained. Prior Art Documents Patent Documents 10 [0010] Patent Document 1: JP-T-2006-510601 Patent Document 2: WO2006/028129 15 Patent Document 3: WO2008/096904 Patent Document 4: JP-A-2007-31554 Patent Document 5: JP-A-2008-188557 Patent Document 6: WO2005/037911 20 Non-Patent Documents [0011] Non-Patent Document 1: T. Ishida, H. Kiwada, et al., J. control. Release. 122, 349-355 (2007) 25 Non-Patent Document 2: W. Jiskoot, R. M. F. van Schie, et al. , Pharmaceutical Research, 26, 6, 1303-1314 (2009) Summary of the Invention Problems to be Solved by the Invention 30 [0012] An object of the invention is to provide a novel polyoxyethylene derivative having plural hydroxyl groups at a terminal end thereof. More specifically, it is to provide a polyoxyethylene derivative having plural hydroxyl groups at a terminal end thereof, which can be effectively used in uses for modifying bio- related substances and can be industrially produced. 35 Means for Solving the Problems [0013] As a result of the extensive studies for solving the above problems, the present inventors have accomplished a polyoxyethylene derivative having plural hydroxyl groups at a terminal end thereof, the derivative comprising the 40 following constitution. [0014] Namely, the invention is as follows.