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US 12,378,278 B2Granted
Mimetics of heparin oligosaccharides
AssigneeBoard of Trustees of Michigan State University
InventorsXuefei Huang, Jicheng Zhang
Life of this patent
Estimating the term…
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.
Claims16
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, SO3H, or SO3−;
- R1 is SO3H, SO3−, or —C(O)CH3;
- R2 is C1-6 alkyl, H, or is a negative charge;
- X is NH, S, or O;
- PG1 is H, Fmoc, —C(O)CH3, —C(O)CF3, and Boc;
- and
- PG is H, C1-6 alkyl, allyl or benzyl.
6 more elements
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 23rd product mixture;
- (b3) treating the 23rd product mixture with sodium hydride and BnBr in DMF, to afford a 24th product mixture;
- (c3) treating the 24th product mixture with sodium cyanoborohydride and trifluoroacetic acid in DMF, to afford a 25th product mixture comprising a compound of formula 30
- (d3) treating the 25th product mixture with allyl bromide and sodium hydride, to afford a 26th product mixture;
- (e3) treating the 26th product mixture with 9-BBN, sodium hydroxide, and hydrogen peroxide, to afford a 27th product mixture;
- (f3) treating the 27th product mixture with TEMPO and BAIB in dichloromethane and water, to afford a 28th product mixture;
- (g3) treating the 28th product mixture with BnBr in DME, to afford a 29th product mixture;
- (h3) treating the 29th product mixture with DDQ in dichloromethane and water to afford a 30th product mixture;
- and
- (13) treating the 30th product mixture with FmocCl and pyridine in dichloromethane to afford a 31st product mixture comprising the compound of formula 31.
27 more elements
A method of making a compound of formula (Ia)
- wherein, independently at each occurrence:
- R is H, SO3H, or SO3;
- R1 is SO3H, SO3−, or C(O) CH3;
- R2a is C1-6 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, SO3H, or SO3;
- R′ is H, SO3H, or SO3;
- R1 is SO3H, SO3, or C(O) CH3;
- R3 is SO3H, SO3−, or C(O) CH3;
- R2a is C1-6 alkyl;
- R2a′ is C1-6 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, SO3H, or SO3;
- R′ is H, SO3H, or SO3;
- R1 is SO3H, SO3, or C(O) CH3;
- R3 is SO3H, SO3, or C(O) CH3;
- the method comprising:
- (a3) reacting a compound of formula (Id′)
- under deprotection conditions, to afford a sixteenth product mixture comprising a compound of formula (Ie)
- and
- (b3) reacting the sixteenth product mixture with a compound of formula (Ic)
- wherein R2a is Me,
- under coupling conditions, to afford a seventeenth product mixture comprising the compound of formula (If).
35 more elements
Dependencies are inferred from the claim text.