(−)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate (YM758 monophosphate,

N-[2-[(3R)-3-[(3,4-Dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)carbonyl]-1-piperidinyl]ethyl]-4-fluorobenzamide Phosphate; (R)-(-)-N-[2-[3-[(6,7-Dimethoxy-1,2,3,4 -tetrahydroisoquinolin-2-yl)carbonyl]piperidino]ethyl]-4-fluorobenzamide monophosphate; YM 758;

CAS Number:   312752-86-6

312752-85-5 (free base)

YM 758, YM 758 Phosphate, (R)-(-)-N-[2-[3-[(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]piperidino]ethyl]-4-fluorobenzamide monophosphate, 312752-86-6, N-[2-[(3R)-3-[(3,4-Dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)carbonyl]-1-piperidinyl]ethyl]-4-fluorobenzamide Phosphate

567.543565 [g/mol]

C₂₆H₃₅FN₃O₈P

YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. A novel cardiovascular agent.

YM758 monophosphate (R)-1·H₃PO₄ has an inhibitory action for I_f current and shows a strong and specific activity selectively lowering a heart beat and decreasing oxygen consumption of heart muscle in a selective manner, whereby it is useful as a preventive and/or treating agent for diseases of circulatory system such as ischemic heart diseases (e.g., angina pectoris and myocardial infarction), congestive heart failure, arrhythmia, etc.

U.S. Patent No. 6,573,279, incorporated herein by reference, describes isoquinoline compounds with 1 channel blocker activity and their use in treating a variety of cardiovascular diseases. U.S. Patent Application Publication Nos. 20060084807 and

20070129357, each of which is incorporated herein by reference, describe methods for making those isoquinoline compounds as well as crystals of certain fluorobenzamide derivatives of them. U.S. Patent Publication No. 20090247572, incorporated herein by reference, relates to the use of one of these isoquinoline fluorobenzamide derivatives, (-)-N- {2-[(i?)-3-(6,7-dimethoxy-l ,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4- fluorobenzamide monophosphate (referred to in that patent publication as “compound A” and “chemical formulation I” and referred to herein as “YM758”), for treating atrial fibrillation.

To date, however, these isoquinoline compounds in general and YM758 in particular have not been developed as cardiovascular drugs. Thus, there remains a need for methods of using these compounds, alone and in combination with other cardiovascular drugs, to treat cardiovascular disease, as well as a need for pharmaceutical formulations and unit dose forms useful in such methods. This invention meets those needs.

Provided herein are fast-acting (immediate release) and modified (sustained) release oral formulations as well as intravenous formulations of YM758. The present invention also provides unit dose forms of these formulations. The present invention also provides methods for using these formulations and unit dose forms alone and in combination with other drugs for the treatment of cardiovascular disease, including but not limited to stable angina, atrial fibrillation, and heart failure. In these methods, the pharmaceutical formulations and unit dose forms of the invention may be dosed alone or in combination with other drugs, including but not limited to drugs such as beta-blockers, anti-arrhythmia drugs, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis. The invention also provides formulations and unit dose forms of YM758 and another drug selected from the group of drugs including beta-blockers, anti-arrhythmia drugs, calcium channel blockers, sodium channel blockers, potassium channel blockers, adenosine, and digitalis. The single agent and combination pharmaceutical formulations and unit dose forms of the invention include capsule, tablet, and solution formulations and unit dose forms that provide either immediate or sustained release. The pharmaceutical formulations in solution forms are, in various embodiments, suitable for intravenous, subcutaneous, intraperitoneal, and intramuscular administration.

Thus, in one aspect, the present invention provides an oral formulation comprising or consisting essentially of YM758 and optionally an excipient. As used herein, the excipient is suitable for administration to human patients with various cardiovascular diseases and includes, without limitation, one or more of the following: an additive, an anti- foaming agent, a binder, a chemical stabilizer, a coloring agent, a diluent, a disintegrating agent, an emulsifying agent, a filler, a flavoring agent, a glidant, a lubricant, a pH modifier, a plasticizer, a solubilizer, a swelling enhancer, a spheronization aid, a solubility enhancer, and a suspending agent. In some embodiments, the formulation is provided in a unit dose form, which may be, for example, a tablet or capsule. In various embodiments, the unit dose forms contain from about 5 mg to about 80 mg of YM758. In some embodiments, the unit dose forms contain from about 5 mg to about 50 mg of YM758. In other embodiments, the unit dose form contains from about 10 mg to about 40 mg of YM758. In one embodiment, the unit dose form contains about 25 mg of YM758.

In another aspect, the present invention provides formulations comprising or consisting essentially of YM758 and optionally an excipient that are suitable for intravenous, subcutaneous, intraperitoneal, and intramuscular administration. As used herein, the excipient is suitable for administration to human cardiovascular disease patients and includes, without limitation, one or more of the following: an additive, an anti-foaming agent, a chemical stabilizer, a diluent, an emulsifying agent, a pH modifier, a buffering agent, an osmolality modifier, a salt, a solubilizer, a solubility enhancer, and a suspending agent. In some embodiments, the formulation is a solution formulation. In one embodiment, the solution formulation is provided in a unit dose form, which may be, for example, in a vial, an ampoule or an intravenous bag. In various embodiments, the unit dose forms contain from about 5 mg to about 80 mg of YM758. In some embodiments, the unit dose forms contain from about 5 mg to about 50 mg of YM758. In another embodiment, the unit dose form contains from about 10 mg to about 40 mg of YM758. In one embodiment, the unit dose form contains about 25 mg of YM758. [0008] In various embodiments, the oral formulation is an immediate release formulation, including, and unit dose forms of this formulation include, without limitation, a gelatin capsule comprising a YM758 formulation.

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SEE

WO 2013116738

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REFERENTIAL EXAMPLE 5A solution (5 ml) of 300 mg of 4-fluorobenzoyl chloride in acetonitrile was dropped into 10 ml of a solution of 650 mg of the compound of Referential Example 4 in acetonitrile under cooling with ice. The reaction mixture was warmed to room temperature and stirred for 4 hours. An aqueous solution of NaHCO₃ was added to the reaction mixture and, after stirring for 20 minutes, the solvent was evaporated in vacuo. To the resulting residue were added chloroform and an aqueous solution of NaHCO₃ followed by extracting with chloroform. The chloroform layer was dried over magnesium sulfate and filtered, then the solvent was evaporated in vacuo. The resulting residue was purified by a silica gel column chromatography (chloroform: MeOH=50:1 to 10:1) and purified by an active alumina column chromatography (hexane: EtOAc=1:1, then EtOAc and EtOAc: MeOH=50:1) to give 600 mg of a colorless oily substance. The oily substance was dissolved in 10 ml of EtOH and 180 mg of 85% phosphoric acid was added thereto. The reaction mixture was heated to completely dissolve and cooled to room temperature. The resulting crystals were filtered and recrystallized from 95% EtOH-water to give 632 mg of (−)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate as colorless crystals.

NMR: δ 1.25-1.50 (1H, m), 1.53-1.76 (3H, m), 2.15-2.80 (6H, m), 2.95-3.10 (3H m), 3.40-3.50 (2H, m), 3.60-3.75 (8H, m), 4.50 (1H, q), 4.63 (1H, q), 6.73 (1H, s), 6.78, 6.85 (1H, s in combination), 7.29 (2H, t), 7.91-7.95 (2H, m), 8.60 (1H, br).

FAB-MS m/z: 470 (M⁺+1).

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Synthesis

^aReagents and conditions:

(a) Boc₂O, NaHCO₃, EtOAc–water, 50%;

(b) aq. KOH, CHCl₃, then 3, K₂CO₃, CH₃CN, 84%;

(c) (1) 4 M HCl/EtOAc, EtOH, (2) aq. KOH, CHCl₃, quantitative yield;

(d) 7, THF, CHCl₃, SiO₂column chromatography, 57%;

(e) (1) aq. NaOH, EtOH, (2) aq. HCl;

(f) (1) 10·HCl, aq. KOH, CHCl₃, (2) EDC·HCl, HOBt, DMF;

(g) aq. H₃PO₄, EtOH, 93% in three steps;

(h) recrystallization with EtOH/water, 74%. Overall yield: 16%.

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