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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present disclosure relates to novel compounds and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes.
• the disclosure also relates to methods for their preparation, and to pharmaceutical
• the present disclosure provides novel compounds that function as late sodium channel blockers.
• the disclosure provides compounds of A compound Formula I:
• R 2 is hydrogen, C S alkyl, Ci_ 8 alkoxy, -C(0)-0-R 26 , -C(0)-N(R 26 )(R 28 ),
• R is selected from the group consisting of hydrogen, hydroxyl, halo, Ci_ 4 alkyl,
• Ci_ 4 alkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo;
• R 4 is selected from the group consisting of hydrogen, optionally substituted Ci_ 4
• R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, amino, optionally substituted alkoxy, -CF 3 , -0-CF 3 , -CN, and
• R 20 and R 2"2 are in each instance independently selected from the group consisting of hydrogen, acyl, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and
• heterocyclyl, aryl or heteroaryl are optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, Ci_4 alkyl, mono- or dialkylamino, aminocarbonyl, -N0 2 , -S0 2 R 26 , -CN, Ci_ 3 alkoxy, -CF 3 , -OCF 3 , aryl, cycloalkyl, and heteroaryl; or;
• R 20 and R 22 when R 20 and R 22 are attached to a common nitrogen atom R 20 and R 22 may join to form a heterocyclic ring which is then optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, mono- or dialkylamino, aminocarbonyl, -N0 2 , -S0 2 R 26 , -CN, Ci_ 3 alkoxy, -CF 3 , -OCF 3 , and cycloalkyl;
• R is in each instance independently a bond or selected from Ci_ 6 alkylene
• R 24 , R 26 o , and R 28 o are in each instance independently selected from hydrogen, alkyl, aryl, or cycloalkyl, wherein the alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from hydroxyl, halo, Ci_ 4 alkoxy, -CF 3 , and -OCF 3 ;
• aryl or heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of hydroxyl, halo, -N0 2 , CN, -SF 5 , -Si(CH 3 ) 3 -0-CF 3 , -O-R 20 , -S-R 20 , -C(0)-R 20 , C(0)OH, -N(R 20 )(R 22 ), -C(O)-N(R 20 )(R 22 ), -N(R 20 )-C(O)-R 22 , -N(R 20 )- S(0) 2 -R 26 , -S(0) 2 - R 20 , -S(O) 2 -N(R 20 )(R 22 ), C 1-3 alkoxy, C 1-4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, cycloalkyl, heteroaryl, and heterocyclyl; wherein
• alkyl are optionally substituted with one, two, or three
• R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, amino, optionally substituted alkoxy, -CF 3 , -O-CF3, -CN, and
• Some embodiments of this disclosure provide a method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in need thereof a therapeutically effective dose of the compound of Formula I or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, solvate, or hydrate thereof.
• substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(0) n R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
• substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (-CH(NH 2 )CH 2 -), methylaminoethylene (-CH(NHMe)CH 2 -), 2-carboxypropylene isomers(-CH 2 CH(C0 2 H)CH 2 -), ethoxyethyl (-CH 2 CH 2 0-CH 2 CH 2 -),
• alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert- butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1 ,2-dimethylbutoxy, and the like.
• alkoxycarbonylamino refers to a group -N(R d )C(0)OR in which R is optionally substituted alkyl and R d is hydrogen or optionally substituted alkyl.
• alkylthio refers to the group -S-alkyl.
• aminosulfonyl refers to the group -S(0) 2 NRR, wherein each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl.
• partially saturated heteroaryls examples include dihydropyrrole, dihydropyridine, chroman, and the like.
• heteroaryloxy refers to the group heteroaryl-O-.
• heterocyclyl refers to a monoradical saturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
• substituted alkylthio refers to the group -S-substituted alkyl.
• the individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound by conventional means.
• the individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present disclosure, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
• Stepoisomers are isomers that differ only in the way the atoms are arranged in space.
• Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
• a 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture.
• the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
• Tautomeric isomers are in equilibrium with one another.
• amide containing compounds may exist in equilibrium with imidic acid tautomers.
• the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers.
• the triazolone containing compounds when R is H are understood to include their triazolol tautomers.
• the triazolol containing compounds are understood to include their triazolone tautomers.
• Non-limiting examples of these tautomers are shown below:
• R , R , and R are selected from a variety of substituents such as hydrogen, optionally substituted alkyl, aryl, heteroayl, cycloalkyl, cycloalkenyl, heterocyclyl, and the like.
• the above-mentioned amines refer to the compounds wherein either one, two, or three substituents on the nitrogen are as listed in the name.
• cycloalkenyl amine refers to cycloalkenyl-NH 2 , wherein "cycloalkenyl” is as defined herein.
• diheteroarylamine refers to NH(heteroaryl) 2 , wherein “heteroaryl” is as defined herein, and so on.
• suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,
• R 2 is hydrogen, C S alkyl, Ci_ 4 alkoxy, -C(0)-0-R 26 , -C(0)-N(R 26 )(R 28 ),
• cycloalkyl, aryl, heteroaryl, heterocyclyl wherein said alkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, alkoxy, halo, -N0 2 , -O-CF 3 , -0-CF 2 , aryl, heterocyclyl, heteroaryl, cycloalkyl, -N(R 20 )(R 22 ), -C(0)-R 20 , -C(0)-0-R 20 , -C(O)-N(R 20 )(R 22 ), -CN, and -O-R 20 , and wherein said alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl are optionally further substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N0 2 , -O-CF 3 , Ci_ 6
• R 1 is aryl
• C1 5 alkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, Ci_ 8 alkoxy, halo, -NO 2 , O-CF 3 , -0-CHF 2 , C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, -N(R 20 )(R 22 ), -C(0)-R 20 ,
• Ci_ 8 alkoxy, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, heterocyclyl, heteroaryl, or cycloalkyl are optionally further substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N0 2 , -O-CF 3 , Ci_ 6 alkyl, Ci_ 4 alkoxy, aralkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl,
• heteroaryl, cycloalkyl, or heterocyclyl are optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N0 2 , -0-CF , -0-CHF 2 , aryl, heterocyclyl, heteroaryl, cycloalkyl, -N(R 20 )(R 22 ), -C(0)-R 20 , -C(0)-0-R 20 , -C(O)-N(R 20 )(R 22 ), -CN, and -O-R 20 ;
• alkoxy, C 2-4 alkenyl, C 2 _ 4 alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl are optionally further substituted with one, two, or three substituents independently selected from deuterium, hydroxyl, halo, -N0 2 , -0-CF 3 , Ci_ 6 alkyl, Ci_ 4 alkoxy, aralkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, -N(R 20 )(R 22 ), -C(0)-R 20 , -C(0)-0-R 20 ,
• heterocyclyl, heteroaryl, cycloalkyl are optionally further substituted with one, two, or three
• R 4 is selected from the group consisting of hydrogen, optionally substituted alkyl,
• aryl is optionally further substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N0 2 ,
• R and R" are in each instance independently selected from the group consisting of hydrogen, acyl, C 1-15 alkyl, C 2 _i 5 alkenyl, C 2 _i 5 alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and wherein the C 1-15 alkyl, C 2 _i 5 alkenyl, C 2 _i 5 alkynyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, Ci_ 4 alkyl, mono- or dialkylamino, aminocarbonyl, -N0 2) -S0 2 R 26 , -CN, Ci_ 3 alkoxy, -CF 3 , -OCF 3 , aryl, cycloalkyl, and heteroaryl; or; when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic ring which is then optional
• R is in each instance independently a bond or selected from Ci_ 6 alkylene
• X is Ci_ 3 alkoxy or Ci_ 4 alkyl
• Ci_ 4 alkoxy, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, aryl, heterocyclyl, heteroaryl, or cycloalkyl are optionally further substituted with one, two, or three substituents
• L is straight or branched Ci_ 6 alkylene
• Ci_6 alkyl Ci_ 4 alkoxy, aralkyl, aryl,
• R is hydrogen or Ci_ 3 alkoxy. In another embodiment, R is hydrogen. In some embodiments, R 4 is hydrogen or phenyl substituted with OCF 3 . In some embodiments, wherein R 5 is hydrogen or alkyl. In some embodiments, each of R' and R' ' is hydrogen. [0114] In another embodiment, this disclosure relates to a compound of Formula IV:
• substituents independently selected from hydroxyl, halo, -NO 2 , -O-CF3, -CF 3 , -0-CHF 2 , -N(R 20 )(R 22 ), -C(0)-R 20 , -C(0)-0-R 20 , -C(O)-N(R 20 )(R 22 ), -CN, and -O-R 20 ;
• heterocyclyl, heteroaryl, or cycloalkyl are optionally further substituted with one, two, or three
• X is OCF 3 . In other embodiments, X is CF 3 .
• Q is aryl or heteroaryl
• R 1 aryl and heteroaryl substituents are mono or bicyclic rings having 1 to 3 heteroatoms selected from O, N, and S.
• exemplary R 1 moieties include, but are not limited to, the following:
• R 1 moiety is further substituted with 1 to 3 substituents as defined above.
• substituents on the R 1 ring structures include, but are not limited to hydrogen; methyl, ethyl, propyl, isopropyl, tert-butyl, halo; amino, alkylamino, such as methylamino, dialkylamino such as dimethylamino, aminoalkyl, alkaminoalkyl, dialkylaminoalkyl, aryloxy, such as phenoxy, substituted phenoxy with 1, 2, or 3 substituents selected from alkyl, halo, nitro, and the like; halo substituted alkyl such as CF 3 and CHF 2 ; methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, methythio, ethylthio, propylthio, halo substituted alkyoxy, such as trifluoromethoxy and dif
• R 4 moieties include, but are not limited to hydrogen, methoxy, and methyl.
• R moieties include but are not limited to hydrogen, methyl, amino, dimethylamino, -CF 3 , -OCF 3 , -OCH 3 , - OCH 2 COOH , -NHCH 2 CH 3 , -CONHCH 3 , -CH 2 CONH 2 , -CH 2 CONHCH 3 , -CH 2 CON(CH 3 ) 2 , -CH 2 CONH(CH 2 ) 2 OH,
• R moieties include, but are not limited to the following:
• the compounds provided by the present disclosure are effective in the treatment of conditions known to respond to administration of late sodium channel blockers, including but not limited to cardiovascular diseases such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, and myocardial infarction.
• cardiovascular diseases such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain
• exercise induced angina pulmonary hypertension
• congestive heart disease including diastolic and systolic heart failure
• myocardial infarction including myocardial infarction.
• compounds provided by the present disclosure which function as late sodium channel blockers may be used in the treatment of diseases affecting the neuromuscular system resulting in pain, itching, seizures, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and disease states related to diabetes, such as diabetic peripheral neuropathy.
• Certain compounds of the disclosure may also possess a sufficient activity in modulating neuronal sodium channels, i.e., Na v 1.1., 1.2, 1.7, and/or 1.8, and may have appropriate pharmacokinetic properties such that they may active with regard to the central and/or peripheral nervous system. Consequently, some compounds of the disclosure may also be of use in the treatment of epilepsy or pain or itching of a neuropathic origin.
• the present disclosure is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, solvates, and prodrugs of such compounds.
• the present disclosure includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a hydrate of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g. a compound of Formula (I); such as a compound of Formula (I) named herein.
• this disclosure provides a method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I as described above.
• the disease state is a cardiovascular disease selected from one or more of atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, recurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension, and intermittent claudication.
• the disease state is diabetes or diabetic peripheral neuropathy.
• the disease state results in one or more of neuropathic pain, epilepsy, seizures, or paralysis.
• compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
• One mode for administration is parenteral, particularly by injection.
• the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the general methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
• compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
• excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
• the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
• the compositions are formulated in a unit dosage form.
• unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
• the compounds are generally administered in a pharmaceutically effective amount.
• each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, in some embodiments, from 0.1 to 700 mg of a compound a compound described herein.
• the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
• the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure.
• a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure.
• these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• the tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
• compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
• the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
• the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
• compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, in some embodiments, orally or nasally, from devices that deliver the formulation in an appropriate manner.
• Cardiovascular related diseases or conditions that can benefit from a combination treatment of the late sodium channel blockers of the disclosure with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastoalic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.
• angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastoalic heart failure and heart failure with preserved e
• antiarrhythmic agents antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.
• Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction.
• beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Badorece), and timolol (Blocadren).
• Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure.
• examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5 -mononitrate.
• Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart.
• Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.
• Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides.
• Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure.
• Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).
• Vasodilators reduce pressure on the blood vessels by making them relax and expand.
• vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa.
• ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.
• Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin. Antithrombotic Agents
• Antithrombotics inhibit the clotting ability of the blood.
• Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries.
• platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/llla inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin).
• Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.
• Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots.
• anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.
• Thrombolytic agents act to break down an existing blood clot.
• examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).
• Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clot formation.
• antihypertensive agents include alpha- 1 -adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); central alpha- adrenoceptor agonists, such as clonidine hydrochloride (Catapres), clonidine
• alpha/beta- adrenergic antagonists such as labetalol (Normodyne, Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, such as guanethidine (Ismelin), reserpine (Serpasil); central nervous system-acting antihypertensives, such as clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents; ACE inhibitors, such as perindopril
• Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood.
• lipid lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).
• statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).
• the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder.
• secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder.
• Such patients can benefit from treatment of a combination therapy comprising administering to the patient ranolazine in combination with at least one therapeutic agent.
• pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.
• COPD chronic obstructive pulmonary disease
• bronchitis bronchitis
• emphysema emphysema
• therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements.
• Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.
• metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose
• therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section
• Cardiovascular Agent Combination Therapy above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.
• Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.
• Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid);
• prostaglandins such as misoprostoL (Cytotec); sucralfate; and antacids.
• Patients presenting with an acute coronary disease event may exhibit conditions that benefit from administration of therapeutic agent or agents that are antibiotics, analgesics, antidepressant and anti-anxiety agents in combination with ranolazine.
• Antibiotics are therapeutic agents that kill, or stop the growth of,

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