| 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 |
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.
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).
A novel, practical, and efficient synthesis of (−)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate (YM758 monophosphate, (R)-1·H3PO4 (Figure 1) is described. The target molecule (R)-1 has a potent If current channel inhibitor. Medicinal chemistry synthetic routes were very long and suffered from extensive use of chlorinated solvents and silica-gel column chromatography. A number of steps in the medicinal chemistry route were also unattractive for large-scale synthesis due to some reasons for example the use of unstable intermediates.
An important objective of a new synthetic route was avoidance of such a use of unstable intermediate, and it was achieved by the discovery of an important 4,5-dihydrooxazole intermediate 19 and ring-opening N-alkylation of chiral amine with 19 under acidic condition. The new procedure does not require any purification by column chromatography for all steps.
The overall yield was significantly improved from 14% or 34% to 49% compared to that of the medicinal synthetic routes. This highly efficient process was successfully demonstrated at a pilot-scale operation, yielding 36.5 kg of (R)-1·H3PO4.
(−)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide Monophosphate (YM758 Monophosphate, (R)-1·H3PO4)
Filed under: Uncategorized Tagged: cardiovascular diseases, YM758
