# US 10,945,997 B2 · Polymer derivative of macrolide immunosuppressant > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,945,997 B2 - Document ID: US10945997B2 - Status: Granted - Kind: B2 - Application number: 16/066,692 - Filed: 2016-12-19 - Published: 2020-05-21 - Granted: 2021-03-16 - Earliest claimed: 2016-01-08 - Assignees: Nippon Kayaku Kabushiki Kaisha - Applicants: Nippon Kayaku Kabushiki Kaisha - Inventors: Nao Yoneki; Akihiro Sekiguchi; Kana Mizunuma; Yuki Kobayashi; Junpei Konno; Kan Saiga; Keiichirou Yamamoto - Web page: https://patentgrep.com/patent/US10945997B2 ## CPC - A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin - C08G 69/40: Polyamides containing oxygen in the form of ether groups (C08G69/12, C08G69/32 take precedence) - A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol - A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT} - C08G 69/10: Alpha-amino-carboxylic acids {(polysuccinimides C08G73/1092)} - C08G 69/48: Polymers modified by chemical after-treatment - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS ## Abstract An object of the invention is to obtain a preparation which shows enhanced effectiveness and safety compared to tacrolimus, has the concentration in blood maintained at a constant level without individual differences, whereby the control of the amount of administration depending on the blood kinetics (blood trough concentration) becomes unnecessary. The present invention relates to a polymeric derivative of tacrolimus, in which a polyethylene glycol segment and an alcoholic hydroxy group of tacrolimus are bonded to side-chain carboxy groups of a polyaspartic acid derivative. ## Claims ### Claim 1 A polymeric derivative of tacrolimus, comprising a polyaspartic acid derivative, a polyethylene glycol segment, and tacrolimus, wherein the polyethylene glycol segment and an alcoholic hydroxy group of tacrolimus are bonded to side-chain carboxy groups of the polyaspartic acid derivative. ### Claim 2 (depends on 1) The polymeric derivative of tacrolimus according to claim 1, wherein the polymeric derivative is represented by the following General Formula (1): wherein R1 represents a group selected from a group consisting of a hydrogen atom, a (C1-C8) alkyl group, and a polyethylene glycol segment; R2 represents a group selected from a group consisting of a hydrogen atom, a (C1-C8) acyl group, and a (C1-C8) alkoxycarbonyl group; R3 represents a residue of an alcoholic hydroxy group of tacrolimus; R4 represents a polyethylene glycol segment; R5 represents —N(R6)CONH(R7) (wherein R6 and R7, which may be identical or different, each represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amino group); X1 represents a bond or a linking group; a and b each represent an integer from 1 to 299; c, d, and e each represent zero or an integer of 298 or less; a+b+c+d+e represents an integer from 2 to 300; and the order of arrangement of the various repeating units of the polyaspartic acid derivative is arbitrary. ### Claim 3 (depends on 1) The polymeric derivative of tacrolimus according to claim 1, wherein the polymeric derivative is represented by the following General Formula (2): wherein R1 represents a group selected from a group consisting of a hydrogen atom, a (C1-C8) alkyl group, and a polyethylene glycol segment; R2 represents a group selected from a group consisting of a hydrogen atom, a (C1-C8) acyl group, and a (C1-C8) alkoxycarbonyl group; R3 represents a residue of an alcoholic hydroxy group of tacrolimus; R4 represents a polyethylene glycol segment; R5 represents —N(R6)CONH(R7) (wherein R6 and R7, which may be identical or different, each represent a (C3-C6) cyclic alkyl group or a (C1-C5) alkyl group which may be substituted with a tertiary amino group); X1 represents a bond or a linking group; f, g, h, and i each represent zero or an integer of 299 or less; f+g and h+i each represent an integer from 1 to 299 or less; j, k, l, m, and n each represent zero or an integer of 298 or less; f+g+h+i+j+k+l+m+n represents an integer from 2 to 300; and the order of arrangement of the various repeating units of the polyaspartic acid derivative is arbitrary. ### Claim 4 (depends on 2) The polymeric derivative of tacrolimus according to claim 2, wherein X1 represents a bond. ### Claim 5 (depends on 2) The polymeric derivative of tacrolimus according to claim 2, wherein X1 represents an aspartic acid derivative. ### Claim 6 (depends on 2) The polymeric derivative of tacrolimus according to claim 2, wherein X1 is represented by the following General Formula (3) or General Formula (4): wherein R8 and R9 each independently represent a hydrogen atom or a (C1-C8) alkyl group; R10 represents one or more groups selected from a group consisting of an amino group, a linear, branched or cyclic (C1-C20) alkylamino group which may have a substituent, a linear, branched or cyclic (C7-C20) aralkylamino group which may have a substituent, a (C5-C20) aromatic amino group which may have a substituent, and an amino acid residue having a protected carboxy group; and CY—CZ represents CH—CH or C═C (double bond). ### Claim 7 (depends on 6) The polymeric derivative of tacrolimus according to claim 6, wherein R8 and R9 both represent a hydrogen atom; and CY—CZ represents CH—CH. ### Claim 8 (depends on 2) The polymeric derivative of tacrolimus according to claim 2, wherein the polyethylene glycol segment of R4 is represented by the following General Formula (5): R11—O—(CH2CH2O)o—R12—X2— (5) wherein R11 represents a hydrogen atom, or a linear, branched or cyclic (C1-C6) alkyl group which may have a substituent; R12 represents a (C2-C6) alkylene group; X2 represents a functional group bondable to a side-chain carboxy group of the polyaspartic acid derivative; and o represents an integer from 5 to 11,500. ### Claim 9 (depends on 2) The polymeric derivative of tacrolimus according to claim 2, wherein R1 represents a (C1-C6) alkyl group or a polyethylene glycol segment represented by the following General Formula (6): R13—O—(CH2CH2O)p—R14— (6) wherein R13 represents a hydrogen atom, or a linear, branched or cyclic (C1-C6) alkyl group which may have a substituent; R14 represents a (C2-C6) alkylene group; and p represents an integer from 5 to 11,500. ### Claim 10 (depends on 2) The polymeric derivative of tacrolimus according to claim 2, wherein R2 represents a (C1-C6) acyl group; o represents an integer from 10 to 3,000; and (a+b+c+d+e) or (f+g+h+i+j+k+l+m+n) represents an integer from 4 to 250. ### Claim 11 (depends on 10) The polymeric derivative of tacrolimus according to claim 10, wherein R2 represents a (C1-C3) acyl group; o represents an integer from 20 to 1,500; and (a+b+c+d+e) or (f+g+h+i+j+k+l+m+n) represents an integer from 8 to 200. ### Claim 12 (depends on 2) The polymeric derivative of tacrolimus according to claim 2, wherein R1 represents a methyl group, and R2 represents an acetyl group. ### Claim 13 (depends on 2) A method for producing the polymeric derivative of tacrolimus according to claim 2, wherein an alcoholic hydroxy group of tacrolimus and a polyethylene glycol segment are bonded to side-chain carboxy groups of a polyaspartic acid derivative via an ester bond, an amide bond, and/or a thioester bond using a dehydration condensing agent in an organic solvent. ### Claim 14 (depends on 2) A macrolide immunosuppressant comprising the polymeric derivative of tacrolimus according to claim 2 as an active ingredient. ### Claim 15 (depends on 3) The polymeric derivative of tacrolimus according to claim 3, wherein X1 represents a bond. ### Claim 16 (depends on 3) The polymeric derivative of tacrolimus according to claim 3, wherein X1 represents an aspartic acid derivative. ### Claim 17 (depends on 3) The polymeric derivative of tacrolimus according to claim 3, wherein X1 is represented by the following General Formula (3) or General Formula (4): wherein R8 and R9 each independently represent a hydrogen atom or a (C1-C8) alkyl group; R10 represents one or more groups selected from a group consisting of an amino group, a linear, branched or cyclic (C1-C20) alkylamino group which may have a substituent, a linear, branched or cyclic (C7-C20) aralkylamino group which may have a substituent, a (C5-C20) aromatic amino group which may have a substituent, and an amino acid residue having a protected carboxy group; and CY—CZ represents CH—CH or C═C (double bond). ### Claim 18 (depends on 17) The polymeric derivative of tacrolimus according to claim 17, wherein R8 and R9 both represent a hydrogen atom; and CY—CZ represents CH—CH. ### Claim 19 (depends on 3) The polymeric derivative of tacrolimus according to claim 3, wherein the polyethylene glycol segment of R4 is represented by the following General Formula (5): R11—O—(CH2CH2O)o—R12—X2— (5) wherein R11 represents a hydrogen atom, or a linear, branched or cyclic (C1-C6) alkyl group which may have a substituent; R12 represents a (C2-C6) alkylene group; X2 represents a functional group bondable to a side-chain carboxy group of the polyaspartic acid derivative; and o represents an integer from 5 to 11,500. ### Claim 20 (depends on 3) The polymeric derivative of tacrolimus according to claim 3, wherein R1 represents a (C1-C6) alkyl group or a polyethylene glycol segment represented by the following General Formula (6): R13—O—(CH2CH2O)p—R14— (6) wherein R13 represents a hydrogen atom, or a linear, branched or cyclic (C1-C6) alkyl group which may have a substituent; R14 represents a (C2-C6) alkylene group; and p represents an integer from 5 to 11,500. ### Claim 21 (depends on 3) The polymeric derivative of tacrolimus according to claim 3, wherein R2 represents a (C1-C6) acyl group; o represents an integer from 10 to 3,000; and (a+b+c+d+e) or (f+g+h+i+j+k+l+m+n) represents an integer from 4 to 250. ### Claim 22 (depends on 21) The polymeric derivative of tacrolimus according to claim 21, wherein R2 represents a (C1-C3) acyl group; o represents an integer from 20 to 1,500; and (a+b+c+d+e) or (f+g+h+i+j+k+l+m+n) represents an integer from 8 to 200. ### Claim 23 (depends on 3) The polymeric derivative of tacrolimus according to claim 3, wherein R1 represents a methyl group, and R2 represents an acetyl group. ### Claim 24 (depends on 3) A method for producing the polymeric derivative of tacrolimus according to claim 3, wherein an alcoholic hydroxy group of tacrolimus and a polyethylene glycol segment are bonded to side-chain carboxy groups of a polyaspartic acid derivative via an ester bond, an amide bond, and/or a thioester bond using a dehydration condensing agent in an organic solvent. ### Claim 25 (depends on 3) A macrolide immunosuppressant comprising the polymeric derivative of tacrolimus according to claim 3 as an active ingredient.