S1P LYASE INHIBITORS FOR THE TREATMENT OF CEREBRAL MALARIA

1 . A method of treating, managing or preventing cerebral malaria, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of an S1P lyase inhibitor.

2 . The method of claim 1 , wherein the S1P lyase inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen, alkyl or aryl;

R 3 is OR 3A , NHC(O)R 3A , NHSO 2 R 3A or hydrogen;

each R 3A is independently hydrogen or alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl optionally substituted with halo;

R 6 is OR 6A or OC(O)R 6A ;

R 7 is OR A or OC(O)R 7A ;

R 8 is OR 8A or OC(O)R 8A ;

R 9 is hydrogen, CH 2 OR 9A or CH 2 OC(O)R 9A ; and

each R 6A , R 5A , R 8A and R 9A is independently hydrogen or lower alkyl.

3 . The method of claim 2 , wherein the compound is of the formula:

wherein:

R 1 is lower alkyl;

R 3 is hydrogen, OR 3A , NHC(O)R 3A or NHSO 2 R 3A ;

R 9 is hydrogen or CH 2 OH; and

each R 3A is independently hydrogen or lower alkyl.

4 . The method of claim 3 , wherein the compound is (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)-ethanone oxime.

5 . The method of claim 1 , wherein the S1P lyase inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is an optionally substituted heterocycle;

R 5 is OR 5A or OC(O)R 5A ;

R 6 is OR 6A or OC(O)R 6A ;

R 7 is OR A or OC(O)R 7A ;

R 8 is hydrogen, CH 2 OR 8A or CH 2 OC(O)R 8A ; and

each of R 5A , R 6A , R 5A and R 8A is independently hydrogen or lower alkyl.

6 . The method of claim 5 , wherein the compound is of the formula:

wherein:

X is N or NR 9 ;

Y is CR 4 , N, NR 9 , O or S;

Z is CR 4 , CHR 4 , N, NR 9 , O or S;

R 1 is hydrogen or optionally substituted lower alkyl; and

R 3 is optionally substituted alkyl;

each R 4 is independently OR 4A , OC(O)R 4A , hydrogen, halogen, or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl;

each R 9 is independently hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; and

each R 4A is independently hydrogen or optionally substituted alkyl.

7 . The method of claim 5 , wherein the compound is of the formula:

wherein:

X is N or NR 9 ;

Y is CR 4 , N, NR 9 , O or S;

Z is CR 4 , CHR 4 , N, NR 9 , O or S;

R 1 is hydrogen or optionally substituted lower alkyl; and

R 3 is optionally substituted alkyl;

each R 4 is independently OR 4A , OC(O)R 4A , hydrogen, halogen, or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl;

each R 9 is independently hydrogen or optionally substituted alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heterocycle, alkylheterocycle, or heterocyclealkyl; and

each R 4A is independently hydrogen or optionally substituted alkyl.

8 . The method of claim 1 , which further comprises administering to the patient an additional active agent.

9 . The method of claim 8 , wherein the additional active agent is an anti-malarial drug.

10 . The method of claim 9 , wherein the anti-malaria drug is quinine, quinidine, artemether or artesunate.

11 . The method of claim 8 , wherein the additional active agent is an osmotic diuretic (e.g., mannitol, urea).

12 . The method of claim 8 , wherein the additional active agent is an anti-convulsant (e.g., diazepam, phenyloin, phenobarbital, phenobarbitone).

13 . The method of claim 8 , wherein the additional active agent is an anti-pyretic (e.g., paracetamol).

14 . The method of claim 8 , wherein the additional active agent is an anti-oxidant.

15 . The method of claim 8 , wherein the additional active agent is an anti-inflammatory drug.

16 . The method of claim 15 , wherein the anti-inflammatory drug is an NSAID, steroid, cyclosporin, thalidomide, revlimid, anti-TNF antibody (e.g., infliximab, etanercept), or pentoxifylline).

17 . The method of claim 8 , wherein the additional active agent is curdlan sulfate, curcumin, or LMP-420.

18 . A pharmaceutical formulation comprising an S1P lyase inhibitor and an additional active agent, wherein the additional active agent is an anti-malarial drug.

19 . The formulation of claim 18 , wherein the anti-malaria drug is quinine, quinidine, artemether or artesunate.

20 . A single unit pharmaceutical dosage form, which comprises an S1P lyase inhibitor and an anti-malarial drug.

21 . The dosage form of claim 20 , which is suitable for transdermal or topical delivery to a patient.

22 . The dosage form of claim 21 , which is a patch.