Mimetics of heparin oligosaccharides

Patent metadata

Field	Value
Publication number	US-12378278-B2
Application number	US-202017761857-A
Country	US
Kind code	B2
Filing date	Sep 21, 2020
Priority date	Sep 20, 2019
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

The present disclosure relates to disaccharides with defined sulfation patterns, and oligosaccharide mimetics comprising the disaccharides as repeating units linked in a head to tail fashion. The present disclosure further relates to methods of making the same, and to methods of using the same to mediate cell proliferation, cell differentiation, amyloid plaque formation, anti-coagulation, and neuronal growth.

First claim

The invention claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein, independently at each occurrence:
n is an integer from 1 to 40;
R is H, SO 3 H, or SO 3 − ;
R 1 is SO 3 H, SO 3 − , or —C(O)CH 3 ;
R 2 is C 1-6 alkyl, H, or is a negative charge;
X is NH, S, or O;
PG 1 is H, Fmoc, —C(O)CH 3 , —C(O)CF 3 , and Boc; and
PG is H, C 1-6 alkyl, allyl or benzyl.

2. The compound of claim 1 , wherein n is 1-20.

3. The compound of claim 2 , wherein n is 1, 2, 3, 10, or 20.

4. The compound of claim 3 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

6. A method of mediating cell proliferation, cell differentiation, amyloid plaque formation, anti-coagulation, or neuronal growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

7. A method of enhancing FGF-2 binding to FGF-R, the method comprising contacting a cell containing FGF-2 and FGF-R with a compound of claim 1 .

8. A method of stimulating cell proliferation, the method comprising contacting a cell with a compound of claim 1 .

9. A method of inhibiting blood coagulation, the method comprising the step of contacting a blood sample with a compound of claim 1 .

10. A heparin mimetic comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. A heparan mimetic comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. A method of synthesizing a compound of formula 34

the method comprising:
(a1) treating a compound of formula 32

with TEMPO and BAIB in a first solvent, to provide a first product mixture;
(b1) treating the first product mixture with potassium carbonate and methyl iodide in a second solvent, to provide a second product mixture comprising a compound of formula 33

(c1) treating the compound of formula 33 with silver triflate, p-toluenesulfonyl chloride, and

 at a temperature from −78° C. to 0° C., to provide a third product mixture;
(d1) treating the third product mixture with NaOMe in a third solvent to provide a fourth product mixture;
(e1) treating the fourth product mixture with FmocCl and pyridine in a fourth solvent, to provide a fifth product mixture; and
(f1) treating the fifth product mixture with DDQ in a fifth solvent to afford a sixth product mixture comprising the compound of formula 34;
or
a method of synthesizing a compound of formula 35

the method comprising:
(a2) treating a compound of formula 31

with a compound of formula 34

in the presence of silver triflate and p-toluenesulfonyl chloride, at a temperature from −78° C. to 0° C., to provide the compound of formula 35;
or
a method of synthesizing a compound of formula 31

the method comprising:
(a3) treating a compound of formula 29

with anisaldehyde dimethyl acetal and CSA in acetonitrile, to afford a 23 rd product mixture;
(b3) treating the 23 rd product mixture with sodium hydride and BnBr in DMF, to afford a 24 th product mixture;
(c3) treating the 24 th product mixture with sodium cyanoborohydride and trifluoroacetic acid in DMF, to afford a 25 th product mixture comprising a compound of formula 30

(d3) treating the 25 th product mixture with allyl bromide and sodium hydride, to afford a 26 th product mixture;
(e3) treating the 26 th product mixture with 9-BBN, sodium hydroxide, and hydrogen peroxide, to afford a 27 th product mixture;
(f3) treating the 27 th product mixture with TEMPO and BAIB in dichloromethane and water, to afford a 28 th product mixture;
(g3) treating the 28 th product mixture with BnBr in DME, to afford a 29 th product mixture;
(h3) treating the 29 th product mixture with DDQ in dichloromethane and water to afford a 30 th product mixture; and
(13) treating the 30 th product mixture with FmocCl and pyridine in dichloromethane to afford a 31 st product mixture comprising the compound of formula 31.

13. A method of making a compound of formula (Ia)

wherein, independently at each occurrence:
R is H, SO 3 H, or SO 3 ;
R 1 is SO 3 H, SO 3 − , or C(O) CH 3 ;
R 2a is C 1-6 alkyl;
the method comprising:
(a1) treating a compound of formula 36

under sulfation conditions, to provide a seventh product mixture; and
(b1) treating the seventh product mixture under deprotection conditions to afford an eighth product mixture comprising the compound of formula (Ia);
or
a method of synthesizing a compound of formula (Id)

wherein, independently at each occurrence:
R is H, SO 3 H, or SO 3 ;
R′ is H, SO 3 H, or SO 3 ;
R 1 is SO 3 H, SO 3 , or C(O) CH 3 ;
R 3 is SO 3 H, SO 3 − , or C(O) CH 3 ;
R 2a is C 1-6 alkyl;
R 2a ′ is C 1-6 alkyl;
the method comprising:
(a2) reacting a compound of formula (Ib)

under esterification conditions to afford a thirteenth product mixture;
(b2) reacting the thirteenth product mixture under deprotection conditions, to afford a fourteenth product mixture; and
(c2) reacting the fourteenth product mixture with the compound of formula (Ib) under coupling conditions, to provide a fifteenth product mixture comprising the compound of formula (Id);
or
a method of making a compound of formula (If)

wherein, independently at each occurrence:
R is H, SO 3 H, or SO 3 ;
R′ is H, SO 3 H, or SO 3 ;
R 1 i

Assignees

• Univ Michigan State

Inventors

• Huang Xuefei
• Zhang Jicheng

Classifications

• C07H15/203

  Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems · CPC title

• C08B37/0075

  Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C08B37/0006

  Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid · CPC title

• C08L5/00

  Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00 · CPC title