Synthetic glycolipids and glycoliposome compositions : suitable for cargo delivery to the central nervous system

1 . A synthetic glycolipid having the formula (I)

wherein

A represents (CH 2 ) n with n being an integer from 2 to 10 or CH 2 —CH 2 —[O—CH 2 —CH 2 ] m with m being 2 or 3;

B represents NR 3 , with R 3 representing H, Me, Et or n-Pr;

represents

where R 1 represents OH and R 2 represents H, or where R 1 represents H and R 2 represents OH;

Y represents H when X and Z which are identical represent O—(CH 2 ) p —CH 3 , or X represents H when Y and Z which are identical represent O—(CH 2 ) p —CH 3 , with p being an integer from 5 to 18;

with the proviso that the synthetic glycolipid of formula (I) is different than the compound of formula (II) or (III)

where A=(CH 2 ) n′ with n′=2, 6, 10;

with the proviso that the synthetic glycolipid of formula (I) is different than the following compound

and with the proviso that the synthetic glycolipid of formula (I) is different than the compound of formula (IV)

where A represents CH 2 —CH 2 ;

and

B represents NH, R 5 is H and R 4 are identical OC x H y groups with x is 12, 14, 16, or 18 and y is 2x+1; or

B represents NMe, R 4 is OC 18 H 37 and R 5 is H;

or

where A represents —(CH 2 ) 6 —, B represents NH, R 5 is H and R 4 are both O(CH 2 ) 12 H.

2 . The synthetic glycolipid of claim 1 , wherein A represents (CH 2 ) n with n being an integer from 2 to 10.

3 . The synthetic glycolipid of claim 1 , wherein A represents (CH 2 ) n with n being 2 or 6.

4 . The synthetic glycolipid of claim 1 , wherein A represents CH 2 —CH 2 —[O—CH 2 —CH 2 ] m with m being 2 or 3.

5 . The synthetic glycolipid of claim 1 , wherein B represents NR 3 where R 3 is H or Me.

6 . The synthetic glycolipid of claim 1 , wherein X represents H, and Y and Z represent a group O—(CH 2 ) p —CH 3 , with p being an integer from 5 to 18.

7 . The synthetic glycolipid of claim 1 , wherein Y represents H, and X and Z represent a group O—(CH 2 ) p —CH 3 , with p being an integer from 5 to 18.

8 . The synthetic glycolipid of claim 1 , wherein

represents

where R 1 represents OH and R 2 represents H, or where R 1 represents H and R 2 represents OH.

9 . The synthetic glycolipid of claim 1 , wherein

represents

where R 1 represents OH and R 2 represents H, or where R 1 represents H and R 2 represents OH.

10 . The synthetic glycolipid of claim 1 , having the formula (Ia)

wherein

A represents (CH 2 ) n with n=6;

B represents NH;

R 1 represents OH and R 2 represents H;

Y represents H, and X and Z which are identical represent O—(CH 2 ) p —CH 3 , with p=13.

11 . A method for delivering a therapeutic or diagnostic agent to the central nervous system of a patient in need of the therapeutic or diagnostic agent, the method comprising:

entrapping the therapeutic or diagnostic agent into a glycoliposome comprising a plurality of synthetic glycolipids; and

administering the glycoliposome with the entrapped therapeutic or diagnostic agent to the patient;

wherein each synthetic glycolipid has the following formula (I)

wherein

A represents (CH 2 ) n with n being an integer from 2 to 10 or CH 2 —CH 2 —[O—CH 2 —CH 2 ] m with m being an integer from 1 to 5;

B represents NR 3 , with R 3 representing H, Me, Et or n-Pr;

represents

where R 1 represents OH and R 2 represents H, or where R 1 represents H and R 2 represents OH;

Y represents H when X and Z which are identical represent O—(CH 2 ) p —CH 3 , or X represents H when Y and Z which are identical represent O—(CH 2 ) p —CH 3 , with p being an integer from 5 to 18.

12 . The method of claim 11 , wherein each synthetic glycolipid has the formula (Ia)

wherein

A represents (CH 2 ) n with n=6;

B represents NH;

R 1 represents OH and R 2 represents H;

Y represents H, and X and Z which are identical represent O—(CH 2 ) p —CH 3 , with p=13.

13 . The method of claim 11 , wherein the therapeutic or diagnostic agent comprises:

(i) a peptide, peptide analog, peptidomimetic (peptide mimetic), or small molecule;

(ii) a neurotransmitter receptor ligand;

(iii) an opioid receptor ligand;

(iv) a k-opioid receptor antagonist; or

(v) Dynantin, JVA-901, Arodyn, Cyclodyn, Zyklophin, [Pro3]- and [Pro3, Arg8]-Dyn A-(1-11)NH 2 , Norbinaltorphimine (norBIN), 5′-Guanidinonaltrindole (GNTI), JDTic, ML140, ML140-11, Fedotozine, Asimadoline, ADL 10-1010, Salvinorin A, E-2078, SK-9709, JVA-901, or fragments or analogs thereof.

14 . The method of claim 11 , wherein the glycoliposome is administered intravenously, intranasally, sublingually, orally, by inhalation, topically, intrathecally, or via transdermal administration.

15 . The method of claim 11 , wherein the method is for the treatment of a CNS-related disease or disorder.

16 . The method of claim 11 , wherein the method is for the treatment of a neurodegenerative disease or disorder, depression, post-traumatic stress disorder, stress, anxiety, addiction, drug abuse or addiction, pain, eating disorder, psychiatric or mood disorders, psychosis, or schizophrenia.

17 . A process for preparing a synthetic glycolipid having the following formula (I)

wherein

A represents (CH 2 ) n with n being an integer from 2 to 10 or CH 2 —CH 2 —[O—CH 2 —CH 2 ] m with m being an integer from 1 to 5;

B represents NH;

represents

where R 1 represents OH and R 2 represents H, or where R 1 represents H and R 2 represents OH;

Y represents H when X and Z which are identical represent O—(CH 2 ) p —CH 3 , or X represents H when Y and Z which are identical represent O—(CH 2 ) p-CH 3 , with p being an integer from 5 to 18;

the process comprising:

reducing a compound of formula (V)

where represents

R′ 1 represents OAc and R′ 2 represents H, or where R′ 1 represents H and R′ 2 represents OAc;

into the corresponding amine; and

coupling the amine with a compound of formula (VI)

thereby forming the compound of formula (I Ac )

and

converting the compound of formula (I Ac ) into the synthetic glycolipid of formula (I).

18 . The process of claim 17 , wherein the step of reducing and coupling are performed as a one-pot synthesis.

19 . The process of claim 17 , wherein the reducing is performed by reacting a solution of the compound of formula (V) with a phosphine to form a first mixture comprising the amine, then the compound of formula (VI) is added to the first mixture and reacted with the amine in the presence of a coupling agent, to form a second mixture comprising the compound of formula (I Ac ).

20 . The process of claim 17 , wherein the reducing is performed by reacting a solution comprising the compound of formula (V) and formula (VI) with a phosphine to form a first mixture comprising the amine and the compound of formula (VI), and the coupling is performed by adding a coupling agent to then obtain a second mixture comprising the compound of formula (I Ac ).