Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids

Patent metadata

Field	Value
Publication number	US-2018251602-A1
Application number	US-201615760398-A
Country	US
Kind code	A1
Filing date	Sep 14, 2016
Priority date	Sep 16, 2015
Publication date	Sep 6, 2018
Grant date	—

Abstract

The invention relates to carbohydrate ligands and moieties, respectively, mimicking glycoepitopes comprised by glycosphingolipids of the nervous system, particularly glycoepitopes comprised by glycosphingolipids of the cerebroside, the globoside-, the ganglioside- and the sulfoglucuronyl paragloboside type, which are bound by anti-glycan antibodies associated with neurological diseases. The invention further relates to the use of these carbohydrate ligands/moieties, in diagnosis as well as for the treatment of neurological diseases associated with anti-glycan antibodies. In particular, the invention relates to compounds of formula (I) and (II) and to therapeutically acceptable polymers comprising a multitude of these compounds, including polymers with loading of one compound of formula (I) or (II) or combinations of several compounds of formula (I), and/or (II). The compounds of formula (I) are defined as:

wherein
R I1 is Z or

wherein
R I2 is H, SO 3 H, or

wherein
R I3 is H or

wherein
R I4 is H or

wherein
R I5 and R I6 are independently H or

wherein
R I7 is H or

and compounds of formula (II) are defined as:

wherein
R II1 is Z or

wherein
R II2 is Z or

wherein Z is —N(R a )—A—B—CH 2 —(CH 2 ) q —SH, wherein Ra is H, C 1 -C 4 -alky, C 1 -C 4 alkoxy, CH 2 C 6 H 5 , CH 2 CH 2 C 6 H 5 , OCH 2 C 6 H 5 , or OCH 2 CH 2 C 6 H 5 ;
A is C 1 -C 7 -alkylene, C 1 -C 7 -alkoxy, C 1 -C 4 -alkyl—(OCH 2 CH 2 ) p O—C 1 -C 4 -alkyl, or C 1 -C 7 -alkoxy-R b , wherein R b is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6, preferably p is 1, 2 or 3, and further preferably p is 1;
B is NHC(O), S or CH 2 ;
q is 0 to 6, preferably q is 1, 2, 3 or 4, and further preferably q is 1 or 2.

First claim

1 . A compound comprising a carbohydrate moiety and a linker Z, wherein said carbohydrate moiety mimics a glycoepitope comprised by a glycosphingolipid of the nervous system, wherein
said linker Z is —N(R a )—A—B—CH 2 (CH 2 ) q —SH, wherein
R a is H, C 1 -C 4 -alkyl, CH 2 C 6 H 5 , CH 2 CH 2 C 6 H 5 , OCH 2 C 6 H 5 , or OCH 2 CH 2 C 6 H 5 ;
A is C 1 -C 7 -alkylene, C 1 -C 7 -alkoxy, C 1 -C 4 -alkyl—(OCH 2 CH 2 ) p O—C 1 -C 4 -alkyl, or C 1 -C 7 -alkoxy-R b , wherein R b is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6, preferably p is 1, 2 or 3, and further preferably p is 1;
B is NHC(O), S or CH 2 ;
q is 0 to 6, preferably q is 1, 2, 3 or 4, and further preferably q is 1 or 2; and
wherein said linker Z is covalently bound via its —N(R a )-group to the reducing end of said carbohydrate moiety.

2 . The compound of claim 1 , wherein said compound is a compound of formula (I) or formula (II), wherein formula (I) is

wherein R I1 is Z or

wherein R I2 is H, SO 3 H, or

wherein R I3 is H or

wherein R I4 is H or

wherein R I5 and R I6 are independently H or

wherein RI 7 is H or

and wherein formula (II) is

wherein R II1 is Z or

wherein R II2 is Z or

wherein Z is —N(R a )—A—B—CH 2 —(CH 2 ) q —SH, wherein
R a is H, C 1 -C 4 -alkoxy, CH 2 C 6 H 5 , CH 2 CH 2 C 6 H 5 , OCH 2 C 6 H 5 , or OCH 2 CH 2 C 6 H 5 ;
A is C 1 -C 7 -alkylene, C 1 -C 7 -alkoxy, C 1 -C 4 -alkyl—(OCH 2 CH 2 ) p O—C 1 -C 4 -alkyl, or C 1 -C 7 -alkoxy-R b , wherein R b is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6, preferably p is 1, 2 or 3, and further preferably p is 1;
B is NHC(O), S or CH 2 ;
q is 0 to 6, preferably q is 1, 2, 3 or 4, and further preferably q is 1 or 2.

3 . The compound of claim 1 or claim 2 , wherein said compound is a compound of formula (I).

4 . The compound of claim 1 or claim 2 , wherein said compound is a compound of formula (II).

5 . The compound of any one of claims 1 to 4 , wherein said compound is a compound of formula 4*, 9*, 13*, 17*, 21*, 25*, 29*, 33*, or any one 46*-60*.

wherein Z is —N(R a )—A—B—CH 2 —(CH 2 ) q —SH, wherein
R a is H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, CH 2 C 6 H 5 , CH 2 CH 2 C 6 H 5 , OCH 2 C 6 H 5 , or OCH 2 CH 2 C 6 H 5 ;
A is C 1 -C 7 -alkylene, C 1 -C 7 -alkoxy, C 1 -C 4 -alkyl—(OCH 2 CH 2 ) p O—C 1 -C 4 -alkyl, or C 1 -C 7 -alkoxy-R b , wherein R b is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6, preferably p is 1, 2 or 3, and further preferably p is 1;
B is NHC(O), S or CH 2 ;
q is 0 to 6, preferably q is 1, 2, 3 or 4, and further preferably q is 1 or 2.

6 . The compound of any one of claims 1 to 5 , wherein
R a is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , CH 2 C 6 H 5 , OCH 2 C 6 H 5 ;
A is O(CH 2 ) p CH 2 , (CH 2 ) p CH 2 , CH 2 (OCH 2 CH 2 ) p OCH 2 , (OCH 2 CH 2 ) p OCH 2 CH 2 or O(CH 2 ) p C 6 H 5 ;
B is NHC(O), S or CH 2 .

7 . The compound of any one of claims 1 to 6 , wherein said linker Z is of a formula selected from any one of the formula (a) to (g):

wherein p is between 0 and 6, preferably 1 to 3, in particular 1, and q is between 0 and 6, preferably between 1, 2 and 4, in particular 1 or 2.

8 . The compound of any one of claims 1 to 7 , wherein said compound is a compound of formula 4, 9, 13, 17, 21, 25, 29, 33, 37, 41, 44, 56, 58 or 77.

9 . A polymer comprising a multitude of compounds of any one of the claims 1 to 8 wherein said compounds are connected to the polymer backbone by way of said linker Z, and wherein said connection is effected via the SHgroup of said linker Z, and wherein preferably said multitude of compounds is (i) a multitude of compounds of formula (I), (ii) a multitude of compounds of formula (II) or (iii) a multitude of compounds of formula (I) and of formula (II), wherein said compounds (I) and (II) are defined as in any one of the claims 2 to 8 .

10 . The polymer according to claim 9 , wherein the polymer backbone is an α-amino acid polymer, an acrylic acid or methacrylic acid polymer or copolymer, a N-vinyl-2-pyrrolidone-vinyl alcohol copolymer, a chitosan polymer, or a polyphosphazene polymer, and wherein preferably the polymer backbone is an α-amino acid polymer, wherein further preferably the polymer backbone is an α-amino acid polymer and said α-amino acid of said α-amino acid polymer is lysine, ornithine, glutamic acid or aspartic acid.

11 . The polymer according to claim 9 or 10 , wherein the polymer backbone is poly-lysine, and wherein preferably the molecular weight of the polymer backbone is 1′000 Da to 300′000 Da.

12 . The polymer according to any one of claims 9 to 11 , wherein the percentage of loading of the carbohydrate moiety of said compound onto the polymer backbone is between 10 and 90%, preferably between 20 and 70%, and in particular between 30 and 60%.

13 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 , preferably a compound of formula (I) or formula (II) according to any one of claims 2 to 8 , or a polymer according to any one of claims 9 to 12

14 . A compound according to any one of claims 1 to 8 , preferably a compound of formula (I) or formula (II) according to any one of claims 2 to 8 , or a polymer according to any one of claims 9 to 12 , or a pharmaceutical composition of claim 13 for use in a method of treating a neurological disease, wherein preferably said neurological disease is selected from multiple sclerosis, Parkinson's disease, Alzheimer's disease, dementia, and an immune-mediated neuropathy, wherein preferably said immune-mediated neuropathy is sel

Assignees

• Univ Basel
• Univ Basel

Inventors

• Herrendorff Ruben
• Ernst Beat
• Steck Andreas
• Pfister Hélène
• Navarra Giulio

Classifications

• C07H15/12 Primary

  attached to a nitrogen atom of the saccharide radical · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C08G69/48 Primary

  Polymers modified by chemical after-treatment · CPC title