Methods of Treating Multiple Sclerosis

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:
• R3 is C1-6 alkyl;
• R4 and R5 are each independently hydrogen, C1-6 alkyl, or substituted C1-6 alkyl;
• R6 and R7 are each independently hydrogen, C1-6 alkyl, substituted C1-6 alkyl, C1-6 heteroalkyl, substituted C1-6 heteroalkyl, C4-12 cycloalkylalkyl, substituted C4-12 cycloalkylalkyl, C7-12 arylalkyl, or substituted C7-12 arylalkyl;
• or R6 and R7 together with the nitrogen to which they are attached form a ring chosen from C5-10 heteroaryl, substituted C5-10 heteroaryl, C5-10 heterocycloalkyl, and substituted C5-10 heterocycloalkyl;
• and
• wherein each substituent is independently halogen, —OH, —CN, —CF3, ═O, —NO2, benzyl, —C(O)NR82, —R8, —OR8, —C(O)R8, —COOR8, or —NR82 wherein each R8 is independently hydrogen or C1-4 alkyl;
• or
• (ii) a compound represented by formula (XII):
• or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof, wherein:
• R46 is unsubstituted C1-6 alkyl;
• is
• X is N, O, S, or SO2;
• 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;
• R47, R48, R49, and R50 are each, independently, hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl or C(O)OR52;
• and
• R52 is hydrogen or substituted or unsubstituted C1-6 alkyl;
• and
• each R51 is, independently, hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-10 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 R51's attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl, substituted or unsubstituted C3-10 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 R51's attached to different atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C3-C10 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 0.5×109/L persisting for more than six months.

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 0.5×109/L persisting for more than six months.