Synthetic heparin pentasaccharides

1. A pentasaccharide building block for the preparation of synthetic heparinoids, said building block being of General Formula I,

in which the configuration of the monosaccharidic units and the stereochemistry of the internal linkages is defined as D-gluco-alpha-1,4-D-glucurono-beta-1,4-D-Gluco-alpha-1,4-L-idurono-beta-1,4-D-gluco, and the substituents are defined as; is selected from the group consisting of hydroxy, C 2 to C 10 alkoxy, aryloxy, thioalkyl, thioaryl, imidoyl, tbutyldiphenylsilyloxy; and a lipoaminoacid wherein the stereochemistry is alpha or beta, and alpha methoxy;

R H is benzyl;

R H1 is benzyl;

R H2 is benzyl;

R A is an azido function;

R S1 is selected from the group consisting of alkylacyl and arylacyl, and substituted alkylacyl, and arylacyl protecting groups;

R S2 is selected from the group consisting of alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R S3 is selected from the group consisting of 4-methoxyphenyl, substituted benzyl groups, alkylacyl, and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R S4 is selected from the group consisting of 4-methoxyphenyl, substituted benzyl groups, alkylacyl, and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R S5 is selected from the group consisting of alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R E1 is methyl;

R E2 is methyl;

R B is an azido function;

R B1 is an azido function;

R P1 is benzyl;

R P2 is selected from the group consisting of alkylacyl, arylacyl and alkylarylacyl, or substituted alkylacyl, arylacyl and alkylarylacyl protecting groups; carbonate protecting groups, and C 3 -C 5 alkenyl.

2. The pentasaccharide building block of claim 1 , wherein:

X 1 is selected from the group consisting of C 2 to C 10 alkoxy and aryloxy; and the stereochemistry may be alpha or beta; and alpha methoxy;

R S1 , R S2 , R S3 , R S4 and R S5 are independently selected from the group consisting of: alkylacyl and arylacyl and substituted alkylacyl and benzoyl-protecting groups; or, R S3 and R S4 are, independently, 4-methoxy benzyl;

R P2 is independently selected from alkylacyl, and arylacyl and substituted alkylacyl and arylacyl protecting groups.

3. The pentasaccharide building block of claim 1 ,

wherein:

X 1 is selected from the group consisting of C 2 to C 10 alkoxy and aryloxy; and the stereochemistry may be alpha or beta; and alpha methoxy;

R S1 is selected from the group consisting of alkylacyl and benzoyl protecting groups;

R S2 is selected from the group consisting of alkylacyl and benzoyl protecting groups;

R S3 is selected from the group consisting of 4-methoxyphenyl, 4-methoxybenzyl, alkylacyl and benzoyl protecting groups;

R S4 is selected from the group consisting of 4-methoxyphenyl, 4-methoxybenzyl, alkylacyl, and benzoyl protecting groups;

R S5 is selected from the group consisting of alkylacyl and benzoyl protecting groups;

R P2 is selected from the group consisting of benzoyl, 4-chlorobenzoyl, chloroacetyl, acetyl, levulinoyl, pivaloyl, 4-methoxybenzoyl, 4-azidobenzoyl, allyloxycarbonyl, ethoxycarbonyl, and tertbutoxycarbonyl.

4. The pentasaccharide building block of claim 1 ,

wherein:

X 1 is selected from the group consisting of C 2 to C 10 alkoxy and aryloxy; and the stereochemistry may be alpha or beta; and alpha methoxy;

R S1 , R S2 , R S3 , R S4 and R S5 are benzoyl; and

R P2 is selected from the group consisting of levulinoyl and benzoyl.

5. The pentasaccharide building block of claim 1 , wherein R S1 , R S2 , R S3 , R S4 and R S5 are independently selected from the group consisting of benzoyl and 4-chlorobenzoyl.

6. The pentasaccharide building block of claim 1 , wherein R S1 and R S2 are benzoyl.

7. The pentasaccharide building block of claim 1 , wherein R P2 is selected from the group consisting of chloroacetyl, acetyl, benzoyl, substituted benzoyl, pivaloyl, levulinyl and allyloxycarbonyl.

8. The pentasaccharide building block of claim 1 , wherein, R S1 and R S2 are benzoyl, R S3 , R S4 and R S5 are independently selected from the group consisting of benzoyl and 4-chlorobenzoyl, and R P2 is selected from the group consisting of chloroacetyl, acetyl, benzoyl, substituted benzoyl, pivaloyl, levulinyl and allyloxycarbonyl.

9. A method of synthesizing the pentasaccharide of claim 1 , comprising the steps of forming a trisaccharide EDC of formula II

wherein:

X 2 is selected from the group consisting of thioalkyl, thioaryl, and trichloroacetimidoyl, and the stereochemistry may be alpha or beta;

Rn is benzyl;

Rnz is benzyl;

R S3 is selected from the group consisting of 4-methoxyphenyl, substituted benzyl groups, alkylacyl, arylacyl, substituted alkylacyl and arylacyl protecting groups;

R S4 is selected from the group consisting of 4-methoxyphenyl, substituted benzyl groups, alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R S5 is selected from the group consisting of alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R E1 is methyl;

R B is an azido function;

R B1 is an azido function;

R P1 is benzyl;

R P2 is selected from the group consisting of alkylacyl, arylacyl and alkylarylacyl, and substituted alkylacyl, arylacyl and alkylarylacyl protecting groups; carbonate protecting groups, and C 3 -C 5 alkenyl;

and forming a disaccharide BA of formula III

wherein:

X 1 is selected from the group consisting of C 2 to C 10 o-alkoxy aryloxy, thioalkyl, thioaryl, a tbutyldiphenylsilyloxy, and a lipoaminoacid wherein the stereochemistry is alpha or beta, and alpha methoxy;

R H1 is benzyl;

R A is an azido function;

R S1 is selected from the group consisting of alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R S2 is selected from the group consisting of alkylacyl and, arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R Q is —(C═O)—OR E2 wherein R E2 is methyl;

R L is H;

and linking the trisaccharide to the disaccharide to form the pentasaccharide.

10. The method of claim 9 , wherein: X, is selected from the group consisting of alpha methoxy; R S1 , R S2 , R S3 , R S4 and R S5 are benzoyl, or, R S3 and R S4 are, independently, 4-methoxy benzyl; R P2 is levulinoyl; X 2 is selected from the group consisting of thiomethyl, thiocresyl, and trichloroacetimidoyl, and the stereochemistry may be alpha or beta.

11. A method of synthesizing the pentasaccharide of claim 1 , comprising the steps of forming a disaccharide ED of formula VIII,

wherein:

X 2 is selected from the group consisting of thioalkyl, thioaryl, and trichloroacetimidoyl, and the stereochemistry may be alpha or beta;

R S5 is selected from the group consisting of alkylacyl, benzoyl, and substituted alkylacyl and arylacyl protecting groups;

R H is benzyl;

R H2 is benzyl;

R B1 is an azido function;

R E1 is methyl;

R P1 is benzyl; and

R P2 is selected from the group consisting of alkylacyl, arylacyl and alkylarylacyl, and substituted alkylacyl, arylacyl and alkylarylacyl protecting groups, carbonate protecting groups, and C 3 -C 5 alkenyl;

and forming a trisaccharide CBA of formula IX

wherein

X 1 is alpha methoxy;

R B is an azido function;

R A is an azido function;

R S1 is selected from the group consisting of alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R S2 is selected from the group consisting of alkylacyl and arylacyl protecting groups;

R S3 is selected from the group consisting of 4-methoxyphenyl, substituted benzyl groups, alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R S4 is 4-methoxyphenyl substituted benzyl groups, alkylacyl and arylacyl, and substituted alkylacyl and arylacyl protecting groups;

R H is benzyl;

R H1 is benzyl;

R E2 is methyl;

and linking the disaccharide to the trisaccharide.

12. The method of claim 11 , wherein:

R S1 , R S2 , R S3 , R S4 - and R S5 are benzoyl;

R P2 is selected from the group consisting of benzoyl and levulinoyl; and

X 2 is selected from the group consisting of thiomethyl, thiocresyl, and trichloroacetimidoyl, and the stereochemistry may be alpha or beta.

13. The pentasaccharide of claim 1 ,

wherein:

X 1 is selected from the group consisting of alpha or beta thiomethyl, thiocresyl, trichloroacetimidoyl, t-butyldiphenylsilyloxy, and alpha methoxy; and

R S1 is selected from the group consisting of benzoyl and 4-chlorobenzoyl.

14. The pentasaccharide of claim 1 ,

wherein:

X 1 is selected from the group consisting of alpha or beta thiomethyl, thiocresyl, trichloroacetimidoyl, and t-butyldiphenylsilyloxy;

R S1 is selected from the group consisting of benzoyl and 4-chlorobenzoyl; and

R S2 is selected from the group consisting of benzoyl and substituted arylacyl protecting groups.

15. The pentasaccharide of claim 1 ,

wherein:

X 1 is alpha methoxy;

R S3 is selected from the group consisting of 4-methoxybenzyl, benzoyl, acetyl, and 4-chlorobenzoyl;

R S4 is selected from the group consisting of 4-methoxybenzyl, benzoyl, aceytyl, and 4-chlorobenzoyl.

16. The pentasaccharide of claim 1 ,

wherein:

X 1 is alpha methoxy.

17. The pentasaccharide of claim 1 , wherein:

X i is alpha methoxy;

R s5 is benzoyl.

18. The pentasaccharide building block of claim 1 ,

wherein:

X 1 is alpha methoxy;

R S1 , R S2 , R S3 , R S4 and R S5 are acetyl; and

R P2 is selected from the group consisting of levulinoyl and benzoyl.

19. The pentasaccharide building block of claim 1 ,

wherein:

X 1 is alpha methoxy; and

R P2 is levulinoyl.

20. The pentasaccharide building block of claim 1 ,

wherein:

X 1 is alpha methoxy;

R S1 , R S2 , and R S5 are acetyl;

R S3 , R S4 are 4-methoxybenzyl; and

R P2 is selected from the group consisting of levulinoyl and benzoyl.