Polyethylene glycol substituted acyl borates

Patent metadata

Field	Value
Publication number	US-9944750-B2
Application number	US-201515110910-A
Country	US
Kind code	B2
Filing date	Jan 9, 2015
Priority date	Jan 10, 2014
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

Polyethylene glycol substituted acyl borates, methods for their preparation, and the use of the polyethylene glycol substituted acyl borates for the preparation of polyethylene glycol substituted macromolecules. The polyethylene glycol substituted acyl borate has the general formula (I)

wherein PEG denotes a polyethylene glycol-based substituent; a is an integer from 1 to 12; X1, X2, and X3 are independently of one another selected from the group made of F, OR, N+R3, N+R2OR, N+R2SR, and N+R2NR2, and are optionally forming a cyclic or a bicyclic structure; and R is an organic substituent or H.

First claim

The invention claimed is:

1. A polyethylene glycol substituted acyl borate of the general formula (I)

wherein
PEG denotes a polyethylene glycol-based substituent;
a is an integer from 1 to 12;
X 1 , X 2 , and X 3 are independently of one another selected from the group consisting of F, OR, N + R 3 , N + R 2 OR, N + R 2 SR, and N + R 2 NR 2 , and are optionally forming a cyclic or a bicyclic structure;
R is an organic substituent or H;
the linker denotes an organic or heterorganic moiety;
the cyclic structure is a five- or six-membered heterocycle and the bicyclic structure comprises two five- or six-membered heterocycles; and
the organic substituent refers to a hydrocarbon-based moiety, which is covalently attached to a remainder of a compound and which may optionally also comprise one or more heteroatoms.

2. The polyethylene glycol substituted acyl borate according to claim 1 , wherein a is from 1 to 8.

3. The polyethylene glycol substituted acyl borate according to claim 1 , wherein X 1 , X 2 , and X 3 are F.

4. The polyethylene glycol substituted acyl borate according to claim 1 , wherein X 1 is F, and X 2 and X 3 are OR, and wherein X 2 and X 3 are forming a five- or six-membered heterocycle,
and wherein the polyethylene glycol substituted acyl borate is selected from the group consisting of (II) to (XI)

wherein R 1 and R 2 are independently of one another selected from the group consisting of hydrogen, C 1 -C 16 alkyl, C 1 -C 16 alkoxy, halogen, C 1 -C 16 alkenyl, C 1 -C 16 alkynyl, nitrile, nitro, C 1 -C 16 aliphatic ester, amide, and C 1 -C 16 thioalkyl; and
R 3 is a C 1 -C 16 alkyl.

5. The polyethylene glycol substituted acyl borate according to claim 1 , wherein X 1 is F, X 2 is selected from the group consisting of N + R 3 , N + R 2 OR, N + R 2 SR, and N + R 2 NR, and X 3 is OR, and wherein X 2 and X 3 are forming a five- or six-membered heterocycle,
and wherein the polyethylene glycol substituted acyl borate is selected from the group consisting of (XII) to (XV)

wherein R 1 and R 2 are independently of one another selected from the group consisting of hydrogen, C 1 -C 16 alkyl, C 1 -C 16 alkoxy, halogen, C 1 -C 16 alkenyl, C 1 -C 16 alkynyl, nitrile, nitro, C 1 -C 16 aliphatic ester, amide, and C 1 -C 16 thioalkyl.

6. The polyethylene glycol substituted acyl borate according to claim 1 , wherein X 1 and X 3 are OR, and X 2 is selected from the group consisting of N + R 3 , N + R 2 OR, N + R 2 SR, and N + R 2 NR 2 , and wherein X 1 , X 2 and X 3 are forming a bicyclic structure,
and wherein the polyethylene glycol substituted acyl borate is selected from the group consisting of (XVI) to (XXXI)

wherein
R 1 and R 2 are independently of one another selected from the group consisting of hydrogen, C 1 -C 16 alkyl, C 1 -C 16 alkoxy, halogen, C 1 -C 16 alkenyl, C 1 -C 16 alkynyl, nitrile, nitro, C 1 -C 16 aliphatic ester, amide, and C 1 -C 16 thioalkyl;
R 3 , R 4 , R 5 , and R 6 are independently of one another selected from the group consisting of hydrogen, methyl, phenyl, and two geminal substituents forming a carbonyl;
R 7 is selected from the group consisting of hydrogen, methyl, benzyl, phenyl, and substituted phenyl;
R 8 is selected from the group consisting of hydrogen, methyl, iso-propyl, benzyl, tert-butyl, sec-butyl, iso-butyl, and substituted phenyl;
Z is selected from the group consisting of O, S, NH and NCH 3 ; and
m and n are independently of one another selected from the group consisting of 0, 1, 2, and 3.

7. The polyethylene glycol substituted acyl borate according to claim 1 , wherein X 1 , X 2 and X 3 are OR, and wherein X 1 , X 2 and X 3 are forming a bicyclic structure,
and wherein the polyethylene glycol substituted acyl borate is selected from the group consisting of (XXXII) to (XXXIV)

wherein
R 1 and R 2 are independently of one another selected from the group consisting of hydrogen, C 1 -C 16 alkyl, C 1 -C 16 alkoxy, halogen, C 1 -C 16 alkenyl, C 1 -C 16 alkynyl, nitrile, nitro, C 1 -C 16 aliphatic ester, amide, and C 1 -C 16 thioalkyl.

8. The polyethylene glycol substituted acyl borate according to claim 1 , being selected from the group consisting of (XXXV) to (LV)

wherein
Y is selected from the group consisting of CH, CR 1 , O, and NR 9 ;
Y 1 is selected from the group consisting of O, S, NH, alkylamino, and cyclo-alkylamino;
Z 1 and Z 2 are independently of one another selected from the group consisting of C 1 -C 8 alkyl, aryl, substituted aryl, C 1 -C 8 alkoxy, C 1 -C 8 thioalkyl, C 1 -C 8 alkyl amide, and aromatic amide;
R 1 is selected from the group consisting of hydrogen, C 1 -C 16 alkyl, C 1 -C 16 alkoxy, halogen, C 1 -C 16 alkenyl, C 1 -C 16 alkynyl, nitrile, nitro, C 1 -C 16 aliphatic ester, amide, and C 1 -C 16 thioalkyl; and
R 9 is selected from the group consisting of C 1 -C 16 alkyl, acyl, formyl, carbamoyl, aliphatic sulfonyl, and aromatic sulfonyl.

9. The polyethylene glycol substituted acyl borate according to claim 1 , wherein the polyethylene glycol substituent is a linear or branched polyethylene glycol substituent of up to 200 kDa, which is optionally substituted with one or more functional groups selected from the group consisting of hydroxyl, carboxylic acid, carboxylic acid ester, amine, thiol, carbonate, carbamate, azide, alkyne, hydroxylamine, hydrazine, aldehyde, ketone, maleimide, and halogen.

10. A method for the preparation of a polyethylene glycol substituted acyl borate according to claim 1 , wherein the formation of the linker involves a nucleophilic aromatic substitution reaction, a metal catalyzed cross-coupling reaction, a cycloaddition reaction, an olefin metathesis reaction, a thio-maleimide addition reaction, an oxime or hydrazine coupling reaction, or a nucleophilic addition reaction.

11. The method according to claim 10 , wherein
a polyethylene glycol substituted acyl borate of formula (XXXV), (XXXVI) or (XXXVII) is prepared by nucleophilic aromatic substitution; or
a polyethylene glycol substituted acyl borate of formula (XXXVIII), (XXXIX) or (XL) is prepared by a metal catalyzed cross-coupling reaction; or
a polyethylene glycol substituted acyl borate of one of formulas (XLI) to (XLVI) is prepared by a [4+2] or a [3+2] cycloaddition reaction; or
a polyethylene glycol substituted acyl borate of formula (XLVII) or (XLVIII) is prepared by an olefin metathesis reaction; or

Assignees

• Eth Zuerich

Inventors

• Bode Jeffrey
• Noda Hidetoshi
• Eros Gabor
• Mazunin Dmitry

Classifications

• C08G2650/04

  End-capping · CPC title

• A61K38/26

  Glucagons · CPC title

• C08G65/337 Primary

  containing other elements (organic compounds containing halogens only as halides of a carboxyl group C08G65/332) · CPC title

• C08L2203/02

  for biomedical use · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title