Methods of Treating Multiple Sclerosis

1 - 313 . (canceled)

314 . A method of treating a patient with multiple sclerosis, comprising the steps of:

(a) administering a pharmaceutical composition comprising a fumarate to the patient; wherein the fumarate is dimethyl fumarate, monomethyl fumarate, a combination of dimethyl fumarate and monomethyl fumarate, a prodrug of monoalkyl fumarate, a deuterated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of the foregoing, or a combination of any of the foregoing; with the proviso that ethyl hydrogen fumarate calcium salt, ethyl hydrogen fumarate magnesium salt, ethyl hydrogen fumarate zinc salt, and ethyl hydrogen fumarate copper salt are not present in the pharmaceutical composition;

wherein the prodrug of monoalkyl fumarate is:

(i) a compound represented by formula (III):

or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof, wherein:

R 3 is C 1-6 alkyl;

R 4 and R 5 are each independently hydrogen, C 1-6 alkyl, or substituted C 1-6 alkyl;

R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 4-12 cycloalkylalkyl, substituted C 4-12 cycloalkylalkyl, C 7-12 arylalkyl, or substituted C 7-12 arylalkyl; or R 6 and R 7 together with the nitrogen to which they are attached form a ring chosen from C 5-10 heteroaryl, substituted C 5-10 heteroaryl, C 5-10 heterocycloalkyl, and substituted C 5-10 heterocycloalkyl; and

wherein each substituent is independently halogen, —OH, —CN, —CF 3 , ═O, —NO 2 , benzyl, —C(O)NR 8 2 , —R 8 , —OR 8 , —C(O)R 8 , —COOR 8 , or —NR 8 2 wherein each R 8 is independently hydrogen or C 1-4 alkyl;

or

(ii) a compound represented by formula (XII):

or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof, wherein:

R 46 is unsubstituted C 1-6 alkyl;

is

X is N, O, S, or SO 2 ;

Z is C or N;

t is 0, 1, 2, or 3;

y is 1 or 2;

w is 0, 1, 2, or 3;

v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R 47 , R 48 , R 49 , and R 50 are each, independently, hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or C(O)OR 52 ; and

R 52 is hydrogen or substituted or unsubstituted C 1-6 alkyl; and

each R 51 is, independently, hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;

or, alternatively, two R 51 's attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl, substituted or unsubstituted C 3-10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;

or, alternatively, two R 51 's attached to different atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C 3 -C 10 carbocycle, substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;

(b) obtaining a complete blood count including lymphocyte count after 6 months of repeated administering of said pharmaceutical composition to said patient, and every 6 to 12 months thereafter; and

(c) interrupting administering of said pharmaceutical composition to said patient when the patient has a lymphocyte count less than 0.5×10 9 /L persisting for more than six months.

315 . The method of claim 314 , wherein the fumarate is dimethyl fumarate, monomethyl fumarate or a combination of dimethyl fumarate and monomethyl fumarate.

316 . The method of claim 314 , wherein the fumarate is dimethyl fumarate.

317 . The method of claim 314 , wherein the fumarate is the prodrug of monoalkyl fumarate.

318 . The method of claim 317 , wherein the prodrug is a compound represented by Formula (III) or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof.

319 . The method of claim 318 , wherein the prodrug is the following compound represented by Formula (III)

or a pharmaceutically acceptable clathrate or solvate thereof.

320 . The method of claim 317 , wherein the prodrug is a compound represented by Formula (XII) or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof.

321 . The method of claim 320 , wherein the prodrug is the following compound represented by Formula (XII)

or a pharmaceutically acceptable clathrate or solvate thereof.

322 . The method of claim 314 , wherein the administering is done orally.

323 . The method of claim 316 , wherein the administering is of 240 mg dimethyl fumarate twice daily orally.

324 . The method of claim 316 , wherein the administering is of 120 mg dimethyl fumarate twice daily orally for 7 days, followed by 240 mg dimethyl fumarate twice daily orally as a maintenance dose.

325 . The method of claim 322 , wherein the administering is of not greater than 720 mg daily total fumarates.

326 . The method of claim 322 , wherein the administering is of not greater than 480 mg daily total fumarates.

327 . A method of treating a patient with multiple sclerosis, comprising the steps of:

(a) administering a pharmaceutical composition consisting essentially of dimethyl fumarate and/or monomethyl fumarate to the patient;

(b) obtaining a complete blood count including lymphocyte count after 6 months of repeated administering of said pharmaceutical composition to said patient, and every 6 to 12 months thereafter; and

(c) interrupting administering of said pharmaceutical composition to said patient when the patient has a lymphocyte count less than 0.5×10 9 /L persisting for more than six months.

328 . The method of claim 327 , wherein the pharmaceutical composition consists essentially of dimethyl fumarate.

329 . The method of claim 327 , wherein the administering is done orally.

330 . The method of claim 328 , wherein the administering is of 240 mg dimethyl fumarate twice daily orally.

331 . The method of claim 328 , wherein the administering is of 120 mg dimethyl fumarate twice daily orally for 7 days, followed by 240 mg dimethyl fumarate twice daily orally as a maintenance dose.

332 . The method of claim 329 , wherein the administering is of not greater than 720 mg daily total fumarates.

333 . The method of claim 329 , wherein the administering is of not greater than 480 mg daily total fumarates.