ANGINA AND CARDIOVASCULAR CONDITIONS

PRIORITY

[0001 J The present application claims the benefit of Indian Provi sional Patent Application No. 3365/CHE 2012 filed on 1 -August-20T2, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION

1 002] This disclosure generally relates to compounds and compositions for the treatment of angina and cardiovascular conditions. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, solvates, enantiomer, stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION

1 003) Stable angina is the most prevalent manifestation of coronary artery disease. Coronary artery disease (CAD) remains the most common cause of heart disease in the elderly, in whom it exhibits some unique features. It is more likely to be diffuse and severe and left main coronary artery stenosis and triplevessei disease are more prevalent. Diagnosis is less dependent on the presence of chest pain since other symptoms may present as an anginal equivalent in such patients. The ECG of elderly patients often shows abnormalities that are not specific for myocardial ischaemia. In such patients, and in those who are unable to perform sufficient exercise to increase the heart, rate to > 85% of predicted maximal heart rate for age and sex, radionuclide or pharmacological stress testing may be used.

(0004] CAD remains questionable, coronary arteriography should be considered. Physical examination and basic laboratory screening should be used to identify conditions which exacerbate myocardial ischaemia and will, therefore, affect treatment. The initial approach to treatment should include risk factor modification and initiation of an anti-ischaemic pharmacological regimen. The usual anti -anginal medications are as efficacious in the elderly as in the young; however, attention must be paid to altered pharmacodynamics and pharmacokinetics. When symptoms are poorly controlled by medical therapy or when multivessel or left main coronary artery stenosis is identified, myocardial revascularization should be considered.

[0005] The factors that may increase the difficulty of eliciting angina pectoris in the elderly, certain non-CAD cardiac disorders often seen in older patients may produce angina. The most common of these conditions is valvular aortic stenosis, usually secondary to degenerative calcification of the aortic valve in subjects older than 65 years. Similarly, angina is often seen in aortic regurgitation, even in the absence of significant valvular stenosis. Retrosternal chest pain is also a prominent feature in hypertrophic cardiomyopathy, particularly in the elderly. Furthermore, in the management of chronic ischaemic heart disease in the elderly, factors that can be modified, such as anaemia, hyperthyroidism, hypertension, congestive heart failure and supraventricular arrhythmia, should be identified and treated angina symptoms, uncontrolled by medical therapy, percutaneous transluminal coronary angiography may be a reasonable alternative to surgical revascul arization.

[0006] Although the ability to document angina pectoris in the elderly patient may be compromised, angina symptoms convey a similarly adverse prognosis, regardless of age. The therapeutic approach to the older angina patients should be dictated more by achievement of symptomatic relief than by considerations of long-term survival.

[0007] Free radicals are highly reactive moieties playing an important role in health and disease. The cardiovascular (CV) system is especially vulnerable to free radical damage because of myocardium and vascular tissue high oxygen consumption and relative paucity of antioxidant enzymes compared with other tissues. Oxidative stress mediated cell damage in the pathophysiology of several CV disorders has also been suggested, in view of the above, the present study was designed to investigate the effect of stress on cardiovasuc!ar changes and the possible involvement of free radicals. Restraint stres fRS) was used as an experimental stressor and elevated pins maze was used as a test for anxiety.

[0008 J Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment or delay of the onset of angina and cardiovascular conditions and its associated com plicati ons progression.

SUMMARY OF THE INVENTION

[0009] The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as angina and cardiovascular conditions.

[0010] The invention herein provides compositions comprising of formula 1 or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of angina and cardiovascul ar conditions and its associated complications.

Formula I

[0011] In certain embodiments, the present invention relates to the compounds and compositions of formula 1, or pharmaceutically acceptable salts thereof,

Formula 1 2| Wherein,

R' independently represents H, D, null,







n is ndependently 1 , 2, 3, 4 or 5;

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently R D, -Of 1, -OD, C _r C ₆ -aikyi, ~NH ₂ or -COCM ₃ ; R' independently represents H, D, null,

11

10 13 16

O 



it is independently L 2, 3, 4 or 5;

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently H, D, -OH, -OD, Cj-Ce-alkyi, -N¾ or -COC¾.

|0 J3j in the illustrative embodinients, examples of compounds of formula 1 are forth below;

(1-2)

(1 -3)

[0014] Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of angina and cardiovascular conditions or its rel ated complications.

[0015] The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptabie carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal admi istration, or transdermal, administration.

[0016] Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein The kits may further comprise instructions for use in the treatment of angina and cardiovascular conditions or its related complications.

[0017] The compositions described herein have several uses. The present application provides, for example, methods of treating patient suffering from angina and cardiovascular conditions or its related complications manifested from metabolic or genetic conditions or disorders, angina, and cardiovascular conditions, chronic diseases or disorders; neurodegenerative disorder ^' s. Hepatol ogy, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications. DE AILED ^' DESCRIPTION OF THE INVENTION

Definitions

[0018] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0019] The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula 1 to be used as prodrugs). The compounds of the present inventi oo can also be sotvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula 1 (hydration).

(0020] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characierized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingo!d and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or !evorotatory (i .e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". [0021] As used herein, the term "metabolic condition" refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders thai result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent.

[0022] The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0023] The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, tntrapericardial, intraarterial, intrathecal, intracapsular., intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and imrastemal injection and infusion.

[0024] A "patient ^" ' "subject," or "host" to be treated by the subject method may mean either a. human o non-human animal, such as primates, mammals, and vertebrates.

[0025] The phrase "pharmaceutically acceptable" is art-recognized. in certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

10 26] The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carrier include: (! ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium car oxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (1 1) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; ( 15) algitiie acid; (16) pyrogen -free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations. j ^' 0027] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal,

1 028) The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g. , disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

|0029| The term "predicting" as used herein refers to assessing the probability related diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the centra! nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention.

[00301 The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it, inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as Angina and cardiovascul r conditions related disorders includes such as chronic Aneurysm, Angina, Atherosclerosis, Cerebrovascular Accident (Stroke), Cerebrovascular disease, Congestive Heart Failure, Coronary Artery Disease, Myocardial infarction (Heart Attack), Peripheral vascular disease. Aortic Dissection, Aortic Stenosis, Arrhythmia (Irregular Heartbeat), Atrial Fibrillation. Cardiomyopathy, Chest Pain, Claudication, Congenital Heart Disease, Congestive Heart Failure, Deep Vein Thrombosis, Edema, Endocarditis, Fainting, Fitness. Exercise for a Healthy Heart, Heart Attack, Heart Attack and Atherosclerosis Prevention, Heart Valve Disease, Vascular Disease, Ventricular Septal Defect and other related diseases or any other medical condition of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.

[0031 1 The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at. a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of particular composition without necessitating undue experimentation.

[0032] In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inaciivation, and excretion rates of the drug as well as the deliver)' rate of the salts and compositions from the subject compositions, it is to be noted that dosage values may also vary with the severity of the condition to be alleviated, it is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing wtii be determined using techniques known to one skilled in the art.

[0033] Additionally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nam re of the disease or condition.

[0034] In certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used. [0035] When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.

|0036] The phrases "systemic administration," "administered systemically," "peripheral administration ^' ' and "administered peripherally" are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemicaiiy, may be termed 'local" or "topical" or "regional" administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other li ke processes.

10037] The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a sait or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to el iminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation. [0038] The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.

[0039] This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula Ϊ may be formulated for systemic or topical or oral admini tration. The pharmaceutical composition may be also formulated for oral administration, oral solution, injection, subdevmai administration, or transdermal administration. The pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

[0040] In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula Ϊ) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formul I or composi tio as part of a prophylactic or therapeutic treatment The desired concentration of formula I or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated, it is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

[0041] Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula 1 may be adjusted to accommodate variations i the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adtdt or child, and the nature of the disease or condition. [0042] The concentration and/or amount of any compound of formula Ϊ may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentrati n and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the saits or compositions, and local blood flow before an after administration of therapeutic formulations disclosed herein. One such method is microdialysis, as reviewed by T. E. Robinson et al„ 1 91, microdialysis in the neurosciences, Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in test animal. Dialysis fluid is pumped through the loop. When compounds with formula 1 such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysaie in proportion to their local tissue concentrations. The progress of diffusion of the salts or compositions may be determined thereby with suitable calibration procedures using known concentrations of salts or compositions.

[0043] ^' i certain embodiments, the dosage of the subject compounds of formula Ϊ provided herein may be determined by reference to the plasma concentrations of the therapeutic, composition or other encapsulated materials. For example, the maximum plasma concentration (Cniax) and the area under the plasma concentration -time curve from time 0 to infinity may be used.

|0044] Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas Ϊ is in the range of about 0.0! mg/kg/day to about 100 mg/kg day in single or divided doses, for instance 0.01 mg kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas 1 may be administered at a dose of, for example, less than 0.2 mg/kg day, 0.5 mg/kg/day, 1 .0 mg kg/day, 5 mg/kg/day, 30 mg/kg/day, 20 mg kg day, 30 mg kg/day, or 40 mg kg/day. Compounds of Formula I may also be administered to a human patient at a. close of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50% _s 40%, 30%, 20%, or 1 0% of the compound of formula Ϊ required for the same therapeutic benefit.

[004S| An effecti ve amount of the compounds of formula 1 described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.

[0046] An effective amount may be sufficient to prohibit, treat alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve damage or demyelization and/or elevated reactive oxidative-nitrosative species and/or abnormalities in physiological homeostasis' , in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration, as appropriate. The amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to-patient variability, the dosages given above are a guideline and the physician may titrate doses of the dru to achieve the treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.

[0047] The compositions provided by this application may he administered to a subject in need of treatment by a variet of conventional routes of administration, including orally, topically, parenteral!y, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered iraranasally, as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. .Furthermore, the compositions may be administered to a subject in need of treatment, by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active passive) mediated drug delivery, by stereotactic injection, or in nanoparticle

[0048] The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceuttcai carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings., binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearaie, sodium !auryl sulfate and talc are often useful for fcabletting purposes. Solid compositions of a similar type may also be employed as fillers i soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof. The compounds of formula I may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.

[0049] For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media empioyed are all readily available by standard techniques known to those skilled in the art.

[0050] The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 1.0, 50, 1 0, 300, 500, 700, S00 mg of the compounds of formul 1 disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula 1

[0051] Generally, a composition as described herein may be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose is desired at the target tissue or organ. For buccal administration the active composition .may take the form of tablets or lozenges formul ated in a conventional manner.

[0052] The dosage administered will he dependent upon the identity of the metabolic disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment if any; the frequency of treatment and therapeutic ratio.

[0053] illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 nag/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host body weight.

[0054] Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasaUy, pharyngolaryngeally, bronchiaUy, intravaginally, rectaJly, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.

[0055] The compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non- parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient. For oral administration either solid or fluid unit dosage forms can be prepared.

[0056] As discussed above, the tablet core contains one or more hydropliilic polymers. Suitable hydropliilic polymers include, but are not limited to, water swellabie cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocoilokls, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof. Examples of suitable water swellabie cellulose derivatives include, but are not limited to, sodium carboxymethylceiluiose, cross-linked hydroxypfopylcellu!ose, hydroxy propyl cellulose (HPC), hydroxypropylinethylcelluiose (HPMC), hydroxyisopropy I cellulose, hy droxybuty lcel lulose, hydroxyphenyleellulose, hydroxyethy!cellul ose (HEC), hydroxypent l cellulose, hydroxypropylethylcellulose, hydroxypropylbutyicellulose. and hydroxypropylethylcellulose, and mixtures thereof. Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, polyethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crosslinked acrylic acid homopo!ymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL ^lM Examples of suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arable, tragaeanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, sclerogiucan, gum arabic, inulm, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and mixiures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium tri silicate; magnesium aluminum silicate; and mixtures thereof. Examples of suitabie gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof. Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylceliulose sodium, and mixtures thereof.

[0057] The carrier may contain one or more suitabie excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, dtsintegrants, lubricants, glidants, release-modifying excipients, superdisintegranis, antioxidants, and mixtures thereof

[0058] Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxy propylmetliylee!lulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylceliulose, tara, gum arabic, tragacanth, pectin, xanthan, geilan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, sclerogiucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, ce!lulosics, sucrose, and starches; and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross- linked carboxymethylceliulose, starches, macrocrystalline cellulose, and mixtures thereof

[0059 ^" ] Suitabie lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, giyeerides waxes, and mixtures thereof. Suitable glidants include, but are not limited to, colloidal silicon dioxide. Suitabie release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof. [0060] Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers t ereof, and mixtures thereof. Examples of suitable water-insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof. Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Exampies of suitable fats include, but are not limited to, hydrogen ated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, tree fatty acids and their salts, and mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palrnitostearate., glyceryl monostearate, glyceryl iristearate, glyceryl trilaur late. glyceryl myri state, GlycoWax- 32. lauroyl macrogol-32 glycerides, stearoyi macrogol-32 giycerides, and mixtures thereof. Examples of suitable phospholipids include phosphatidyl choline, phosphatidyl serene, phosphatidyl enosiiol, phosphotidic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candeliila wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross-linked povidone (crospovi one). In one embodiment the tablet core contains up to abou 5 percent by weight of such super dismtegrant.

[0061] Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, buiylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof. [0062] in one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns. In embodiment, the immediate release coating is typicall compressed at a density of more than about 0.9 g/cc. as measured by the weight and volume of that specific layer.

[0063] In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet, in one embodiment, the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent,

[0064] In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.

10065] in one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer coatins portion is included of a dried aranulation including the pharmaceutically active agent.

1 066] Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form. Typical, immediate release formulations i nclude compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are known in the art. [0067] The i mmediate rel ease dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantify of the active agent with conventional pharmaceutical excipienis. The immediate release dosage unit may or may not be coated, and may or may not be admixed with, the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads).

[0068] Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington— The Science and Practice of Pharmacy", 20th. Ed,, Lippincott Williams & Wilkins, Baltimore, Md, 2000), A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are weliknovvn and described in die art The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.

[0069] An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.

10070 j Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. [0071] A pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release.

[0072] Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. % to 70 wi. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt % to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration.

|0073] Another dosage form contains a compressed tablet or a capsule having a drug- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage unit contains a plurality of beads, granules particles thai release drug substantially immediately following oral administration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.

[0074] For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.

[0075] Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula I or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art, For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishin Company, Easton, Pa., 19th Edition (1 95).

[00761 In addition, in certain embodiments, subject compositions of the present application maybe lyophi!ized or subjected to another appropriate dryin technique such as spray crying. The subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.

[0077] Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmac . The amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.

[0078] Methods of preparing these formulations or compositions include the step of bringing i to association subject compositions with the carrier and, optionally, one or more accessory ingredients In general, the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers., or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0079] The compounds of formula I described herein may be admini stered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0,005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.01 - 1.0% w/w, of medicament relative to the total weight of the formulation. [0080] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymefhylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) huinectants, such as glycerol; (4) disintegrating agents, such as agar- agar, calcium carbonate, potato or tapioc starch, aiginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents, hi the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0081] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemu!sions, solutions, suspensions, syrups and elixirs. In addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emul sifters, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol., benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, ietrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0082] Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylaled isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystaJline cellulose, alumiiiu.m metahydroxide, bento te, agar-agar and tragacanth, and mixtures thereof,

|ΌΘ83] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compound(s) and composition^). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0084] Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject, composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives., buffers., or propel 1 ants that may be required. For transdermal administration, the complexes may include lipophiiic and hydrophilic groups to achieve the desired water solubility and transport properties.

[0085] The ointments, pastes, creams and gels may contain, in addition to subject, compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. Sprays may additionaliy contain customary propellents, such as chlorofiuorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0086] Methods of delivering a composition or compositions via a transdermal patch are known in the art. Exemplary patches and methods of patch, delivery are described in US Patent Nos. 6,974,588, 6,564,093, 6,332.716, 6,440,454, 6,267,983., 6,239, 180, and 6,103,275.

1 0871 in another embodiment, a transdermal patch may comprise: a substrate sheet comprising a. composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-poly urethane composite and 2-10 parts by weight of a styrene-ethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkylene terephthalate film; and a second adhesive layer comprising a st rene-diene-styrerie block copolymer containing a pharmaceutical agent layered on the primer layer. A method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkylene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkylene terephthalate film.

[0088] Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.

10089] Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule daigs,

[0090] Iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an ionfophoreiic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a.) repelling a charged ion from an electrode of the same charge, (b) eleetroosmosis, the eonvective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current

[0091] in some cases, it may be desirable to administer in the form of a. kit. it may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0092] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms {tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic- material that may be transparent.

[0093] Methods and compositions for the treatment of angina and cardiovascular conditions. Among other things, herein is provided a method of treating angina and cardiovascular conditions, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula. 1:

Formula 1

(f)094| Wherein,

R' independently represents H, D, null, 40

41

43

n is ndependently 1 , 2, 3, 4 or 5;

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently R D, -Of 1, -OD, C _r C ₆ -aikyi, ~NH ₂ or -COCM ₃ ; R' independently represents H, D, null,



10 13 16

O 



it is independently L 2, 3, 4 or 5;

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently B, D, -OH, -OD, Cj-Ce-alkyi, -N¾ or -COC¾.

Methods ar using compounds of formula I:

[0095] The invention also includes methods for treating Angina and cardiovascular conditions related disorders includes such as chronic Aneurysm, Angina, Atherosclerosis, Cerebrovascular Accident (Stroke), Cerebrovascular disease. Congestive Heart Failure, Coronary Artery Disease, Myocardial infarction (Heart Attack), Peripheral vascular disease, Aortic Dissection, Aortic Stenosis, Arrhythmia (Irregular Heartbeat), Atrial Fibrillation, Cardiomyopathy, Chest Pain, Claudication, Congenital Heart Disease, Congestive Heart Failure, Deep Vein Thrombosis, Edema, Endocarditis, Fainting, Fitness: Exercise for a Healthy Heart, Heart Attack, Heart Attack and Atherosclerosis Prevention, Heart Valve Disease, Vascular Disease, Ventricular Septal Defect and other related diseases or any other medical condition

METHODS OF MAKING

[0096] Examples of synthetic pathways useful for making compounds of formula I are set forth in example below and generalized in scheme 1 : Scheme-!:

j0097) Step- 1 : Synthesis of compound 3 :

[0098 J 2,6-dimethylaniiine 1 (100 g) and dicliloromethane (500 mL) are charged into a round-bottom flask and stirred for 5-10 minutes, Sodium carbonate (43.8 g) was added and the mixture was cooled to 10-15° C. Chloroacetyl chloride 2 (79 mL.) was slowly added at 10-15° C. and the mixture was maintained at 10-15° C. for 60-90 minutes. The temperature was raised to 25-35° C, and water (1.000 ml,) was added. The organic solvent was evaporated completely at 40-45° C under reduced pressure. The residue was cooled to 25-35° C. and maintained for 45-60 minutes. The obtained solid was filtered and washed with water (200 mL), then the solid was dried at 70° C. _s to afford 150 g of the compound 3

100 -2 : Sy nthesi s of compound 5 :

3 4 5

[00100] 2-chloro-N-(2 _> 6-dimethylpheny]) acetamide 3 { i 00 g), piperazine 4 ( 182 g) and methanol (300 mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture was heated to reflux temperature and maintained for 2-3 hours. The mixture was cooled to 25-35° C. and water (800 mL) was added. The mixture was stirred for 1 5-30 minutes, then filtered to remove unwanted solid, and the filter was washed with water (200 mL). Dichloromeihane (400 fflL) was added to the filtrate and the mixture was stirred for 15-30 minutes. The layers are separated and the aqueous layer was extracted with dichioromethane (400 nil.). The combined organic layer was washed with a solution of sodium hydroxide (20 g) in water (350 mL) and the solvent was evaporated at 40-45° C. 500 nil, of n-hexane was added to Ihe residue at 25-35° C. and the mixture was maintained for 30-45 minutes. The solid was filtered under reduced pressure, washed with n-hexane (1.00 mL), and dried at 40° C, to afford 8S.5 of the intermediate compound 5,

[00.10.1 J Step-3: Synthesis of compound 8:

[00102] Stirring a mixture of a solution of compound 7 ( 18.0 mmol; 1.0 eq) and acid 6 (18.0 mmol; 1 .0 eq) in Dichioromethane (DCM) (200 mL; LR grade); l-etliyl-3-(3'- dimethylaminopropyl)carbodfinifde.HCl (EDCI.HC1) (527.0 mmol; 1.5 eq) and 4- D!methylammopyri<fineCDMAP) (18.0 mmol; 1.0 eq) at room temperature (RT) for 24 hours. Reaction was monitored by LLC, On completion of the reaction, the reaction mixture was diluted with DC (200 m ^' L), washed with water (2x300 mL) followed by brine solution (300 mL) and dried over anhydrous I aaSCL and evaporated under reduced pressure. The crude was purifi d by colitmo chromatography over 100-200 mesh silica gel by using ethyl acetate-pet ether to yield the intermediate 8.

[00103} Step-4: Synthesis of compound 10:

[001041 Compound 8 (100 mmol) arid water (400 mL) are charged into round-bottom flask and stirred for 5-1.0 minutes. A solution of sodium hydroxide (200 mmol) in water (1000 mL) was added at 25-35° C. and stirred for 45-60 minutes. EpicMorohydrin 9(100 mmol) was added at 25-35° C. and the mixture was maintained for 10-12 hours. Layers are separated. Water (400 mL) and a solution of sodium hydroxide (32.2 g) in water (100 mL) are added to the organic layer containing the product. The mixture was maintained at 25-35° C. for 5-6 hours. The layers are separated and 0% sodium hydroxide solution (300 mL) was added to the organic layer containing the product at 25-35° C. The mass was stirred for 20-30 minutes and layers are separated. The organic layer containing the product was distilled at 85-89° C. under reduced pressure, to yield intermediate 10. -5. Synthesis of compound 1 1 :

[00106 Compound 5, N-(2,6-d!methyipheny!)- 1 -pi perazine acetaniide (20 mmo!), compound 10 (20 mniol), and acetone (50mL) are charged into a round-bottom flask and stirred for 5-10 minutes. The mixture was heated to reflux temperature and maintained for 15-16 hours. The mixture was cooled to 25-30* C, further cooled to 20±2° C, maintained at 20±2° C. for 1 hour, and the formed solid was filtered and washed with acetone (2*20 m ^' L). The solid was dried at 60-65° C to yield the final compound 11. Chemical Formula; C29H35N504; Molecular Weight: 517.62; Elemental Analysis: C, 67.29; H, 6.82; N, 13.53; O, 12.36.

[00107] The term "sample" refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum..

EQUIVALENTS

[OOIOSf The present disclosure provides among other things compositions and methods for treating angina and cardiovascular conditions and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

INCORPORATION B Y REFERENCE

[00109) All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and iiidividuaiiv indicated to be incorporated by reference. In ease of conflict, the present application, including any definitions herein, will control.