# US 2019/0167638 A1 · Use of prodrugs of fumarates in treating heart failure diseases > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0167638 A1 - Document ID: US20190167638A1 - Status: Published application - Kind: A1 - Application number: 16/266,548 - Filed: 2019-02-04 - Published: 2019-06-06 - Earliest claimed: 2015-08-27 - Inventors: Vijaykumar Rajasekhar - Web page: https://patentgrep.com/patent/US20190167638A1 ## CPC - A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract Methods and pharmaceutical compositions comprising one or more prodrugs (e.g., aminoalkyl prodrugs) of monomethyl fumarate (MMF) thereof are provided herein for the treatment of a heart failure disease, including heart failure with preserved ejection fraction. The compounds of the present disclosure are configured to be converted in vivo, upon oral administration, to monomethyl fumarate. Upon conversion, the active moiety (i.e., monomethyl fumarate) of various embodiments is effective in treating subjects suffering from a heart failure disease, including heart failure with preserved ejection fraction. ## Claims ### Claim at position 1 1-20. (canceled) ### Claim 21 A method of treating heart failure with preserved ejection fraction in a subject having heart failure with preserved ejection fraction, the method comprising administering to the subject a therapeutically effective amount of one or more prodrugs of monomethyl fumarate comprising a compound of Formula (I), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, 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; and R2 and R3 either: (a) are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, 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; or (b) together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S. ### Claim 22 (depends on 1) The method of claim 1, wherein a pharmaceutical composition is administered to the subject, wherein said pharmaceutical composition comprises a therapeutically effective amount of the one or more prodrug of monomethyl fumarate that is shown to provide MMF plasma exposure comparable to dimethyl fumarate 120 mg to 720 mg per day. ### Claim 23 (depends on 1) The method of claim 1, wherein said pharmaceutical composition comprises 210 mg to 1260 mg of the compound. ### Claim 24 (depends on 1) The method of claim 1, wherein the one or more prodrugs of monomethyl fumarate are administered in combination with one or more second agents useful for treating heart failure, ### Claim 25 (depends on 24) The method of claim 24, wherein the second agent is selected from the group consisting of: a diuretic, an ACE-inhibitor, a beta-blocker, an angiotensin receptor blocker, isosorbide dinitrate, hydralazine, an angiotensin receptor-neprilysin inhibitor, an aldosterone antagonist, a PDE5 inhibitor, a statin, a neprilysin inhibitor, an aldosterone inhibitor, and an antitumor necrosis factor-alpha therapy. ### Claim 26 (depends on 25) The method of claim 25, wherein the second agent is the statin. ### Claim 27 (depends on 21) The method of claim 21, wherein treating comprises reducing mortality or improving survival in the subject having heart failure with preserved ejection fraction. ### Claim 28 (depends on 21) The method of claim 21, wherein treating comprises increasing maximum myocardial oxygen consumption in the subject. ### Claim 29 (depends on 28) The method of claim 28, wherein the maximum myocardial oxygen consumption is increased to greater than 14 mL/g/min. ### Claim 30 (depends on 21) The method of claim 21, wherein treating comprises one or more of: reducing ventricular stiffness and improving ventricular relaxation in the subject. ### Claim 31 A method of treating heart failure with preserved ejection fraction in a subject having heart failure with preserved ejection fraction, the method comprising administering to the subject a therapeutically effective amount of one or more prodrugs of monomethyl fumarate comprising a compound of Formula (III), or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, or co-crystal thereof: wherein: R1 is unsubstituted C1-C6 alkyl; is selected from the group consisting of: X is N, O, S, or SO2; Z is C or N; m is 0, 1, 2, or 3; n is 1 or 2; w is 0, 1, 2, or 3; t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R6, R7, R8 and R9 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl or C(O)ORa; and Ra is H or substituted or unsubstituted C1-C6 alkyl; and either: (a) each R10 is, independently, H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 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; or (b) two R10 attached to the same carbon atom, together with the carbon atom to which they are attached, form a carbonyl, 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; or (c) two R10 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. ### Claim 32 A method of treating heart failure with preserved ejection fraction in a subject having heart failure with preserved ejection fraction, the method comprising administering to the subject a therapeutically effective amount of one or more prodrugs of monomethyl fumarate comprising a compound of Formula (Ib), or a pharmaceutically acceptable polymorph, hydrate, solvate, or co-crystal thereof: A− is a pharmaceutically acceptable anion; R1 is unsubstituted C1-C6 alkyl; La is substituted or unsubstituted C1-C6 alkyl linker, substituted or unsubstituted C3-C10 carbocycle, substituted or unsubstituted C6-C10 aryl, 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; R3′ is substituted or unsubstituted C1-C6 alkyl; and either: (a) R2 and R3 are each, independently, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, 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; or (b) R2 and R3, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, or a substituted or unsubstituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S. ### Claim 33 (depends on 32) The method of claim 32, wherein a pharmaceutical composition is administered to the subject, wherein said pharmaceutical composition comprises a therapeutically effective amount of the one or more prodrug of monomethyl fumarate that is shown to provide MMF plasma exposure comparable to dimethyl fumarate 120 mg to 720 mg per day. ### Claim 34 (depends on 32) The method of claim 32, wherein said pharmaceutical composition comprises 210 mg to 1260 mg of the compound. ### Claim 35 (depends on 32) The method of claim 32, wherein the one or more prodrugs of monomethyl fumarate are administered in combination with one or more second agents useful for treating heart failure. ### Claim 36 (depends on 35) The method of claim 35, wherein the second agent is selected from the group consisting of: a diuretic, an ACE-inhibitor, a beta-blocker, an angiotensin receptor blocker, isosorbide dinitrate, hydralazine, an angiotensin receptor-neprilysin inhibitor, an aldosterone antagonist, a PDE5 inhibitor, a statin, a neprilysin inhibitor, an aldosterone inhibitor, and an antitumor necrosis factor-alpha therapy. ### Claim 37 (depends on 32) The method of claim 32, wherein treating comprises reducing mortality or improving survival in the subject having heart failure with preserved ejection fraction. ### Claim 38 (depends on 32) The method of claim 32, wherein treating comprises increasing maximum myocardial oxygen consumption in the subject. ### Claim 39 (depends on 38) The method of claim 38, wherein the maximum myocardial oxygen consumption is increased to greater than 14 mL/g/min. ### Claim 40 (depends on 32) The method of claim 32, wherein treating comprises one or more of: reducing ventricular stiffness and improving ventricular relaxation in the subject.