EP2847197A1 - Promédicaments d'agents antiplaquettaires - Google Patents

Promédicaments d'agents antiplaquettaires

Info

Publication number
EP2847197A1
EP2847197A1 EP13787471.5A EP13787471A EP2847197A1 EP 2847197 A1 EP2847197 A1 EP 2847197A1 EP 13787471 A EP13787471 A EP 13787471A EP 2847197 A1 EP2847197 A1 EP 2847197A1
Authority
EP
European Patent Office
Prior art keywords
independently
formula
administration
compound
compositions
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13787471.5A
Other languages
German (de)
English (en)
Other versions
EP2847197A4 (fr
Inventor
Mahesh Kandula
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cellix Bio Pvt Ltd
Original Assignee
Cellix Bio Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/IB2012/053673 external-priority patent/WO2013024376A1/fr
Application filed by Cellix Bio Pvt Ltd filed Critical Cellix Bio Pvt Ltd
Publication of EP2847197A1 publication Critical patent/EP2847197A1/fr
Publication of EP2847197A4 publication Critical patent/EP2847197A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This disclosure generally relates to compounds and compositions for the treatment of a ierothrambosis. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, stereoisomers, enantiomers, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof.
  • Atherothrombosis refers to the formation of thrombus superimposed on preexisting atherosclerosis. This common pathophysiologic process results in morbid or fatal clinical ischemic events affecting the cerebral, coronary, or peripheral arterial circulation Because the platelet is a pivotal mediator in the initiation and propagation of thrombus formation, antiplatelet drugs have emerged as key agents for prevention of recurrent ischemic events.
  • vascular diseases ie, ischemic stroke, coronary artery disease [CAD], and peripheral arterial disease [PAD]
  • 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 Atherothrombosis,
  • the invention herein provides compositions comprising of formula 1 or pharmaceutical acceptabie sahs thereof.
  • the invention aiso provides pharmaceutical compositions comprising one or more compounds of formula 1 or i termediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of Atherothrombosis and its associated complications.
  • the present invention relates to the compounds and compositions of formula I or pharmaceutically acceptable salts thereof,
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently 1 , 2 or 6;
  • compositions comprising of formula II or pharmaceutical acceptable salts thereof.
  • the invention also provides pharmaceutical compositions compri sing one or snore compounds of formula ⁇ or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of Atherothromhosis and its associated complications.
  • the present invention relates to the compounds and compositions of formula II or pharmaceutically acceptable saits thereof.
  • R indepenclently represents D, B, methyl
  • a is independently 2,3 or 7;
  • each b is i ndependently 3, 5 or 6;
  • e is independently L 2 or 6;
  • c and d are each independently H, D, -OH, -OD, C-rCValky!, -N3 ⁇ 4 or -COC3 ⁇ 4. 013J
  • examples of compounds of formula I are forth below:
  • R l independently represents D, H, methyl
  • a is independently 2,3 or 7;
  • eac b is independently 3 ; 5 or 6:
  • e is independently 1 , 2 or 6;
  • c and d are each independently H, D, -OH, -OD, Ci-Cc-alkyi, -N3 ⁇ 4 or -COC3 ⁇ 4.
  • the present invention relates to the compounds and compositions of formula H active metabolite, formula Ha or pharmaceutically acceptable salts thereof.
  • 1 independently represents D, H, methyl
  • a is independently 2,3 or 7;
  • e is independently 1, 2 or 6;
  • c and d are each independently H, D, -OH, ⁇ OD, Ct-Ce-aJkyl, ⁇ N3 ⁇ 4 or -COCH3.
  • kits comprising any of the pharmaceutical compositions disclosed herein.
  • the kit may comprise instructions for use in the treatment of Atherothrombosis or its related complications.
  • the application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein.
  • the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdemial administration, or transdermal administration.
  • kits comprising the pharmaceutical compositions described herein.
  • the kits may further comprise instructions for use in the treatment of Atherothrombosis or its related complications.
  • compositions described herein have several uses.
  • the present application provides, for example, methods of treating a patient suffering from Atherothrombosis or its related complications manifested from metabolic conditions, chronic diseases or disorders; Hepatol ogy. Cancer. Neurological, Hematological, Orthopedic, Cardiovascular, Renal, Skin. Vascular or Ocular complications. DETAILED DESCRI TION OF THE INVENTION
  • the compounds of the present invention can be present in the form of pharmaceuticaiiy 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, formula H, formula la or formula Ha to be used as prodrugs).
  • the compounds of the present invention can also be solvated, i.e. liydrated. 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, formula II, formul la or formula Ila (hydration).
  • isomers 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 chirai centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers tha are non- supeiiroposable mirror images of each other are termed "ena tiomers.” 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 characterized by the absolute configuration of its asvmmetric center or centers and is described by the - and S-sequencing rules of Calm, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chirai compound can exist as either individual en ntionier or as a mixture thereof.
  • the term “metabolic condition” refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that 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,
  • polymorph as used herein is art-recognized and refers to one crystal structure of a. given compound.
  • parenteral administration and “administered parenteraliy” as used herein refer t modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, hitraperi cardial, intraarterial, intrathecal intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and mtrastemal injection and infusion.
  • a "patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.
  • 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.
  • pharmaceutically acceptable carrier- 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.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacantk (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 ⁇ ) 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)
  • 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 hydroiyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • the terra "prophylactic or therapeutic" treatment is art-recognized and includes administration t 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).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • predicting 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 central 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.
  • treating 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.. oausma 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 treating the epilepsy, migraine, neuropathic pain, post herpetic neuralgia, pain, Creutzfeld- Jakob disease, Alzheimer's disease, multiple sclerosis, Batten disease, multiple sclerosis Parkinson's disease (FD) , restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, sexual dysfunction, amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, convulsions, partial seizures, or as an adjunctive therapy for partial, myoclonic, tonsc-clonic seizures, mood-stabilizin agent.
  • ALS amyotrophic lateral sclerosis
  • bipolar disorder Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder, schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder 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.
  • the phrase "therapeutically effective amount" is an art-recognized term.
  • 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.
  • 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 conditio 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.
  • 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, 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 he alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over lime 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,
  • the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters.
  • 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 nature of the disease or condition.
  • 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 piasma concentration (Cmax) and the area under the piasma concentration-time curve from time 0 to infinity may be used.
  • sustained release When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized.
  • 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.
  • 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.
  • systemic administration “administered systemieally,” “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.
  • the phrase "therapeutically effective amount" is an art-recognized term.
  • 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.
  • 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 admini stered, 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.
  • the present disclosure also contemplates prodrugs of the compositions disclosed herei n, as well as pharmaceutically acceptable salts of said prodrugs.
  • This application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I, formula ⁇ , formula la o formula Ha may be formulated for systemic or topical or oral administration.
  • the pharmaceutical composition may be also formulated for oral administration, oral solution, injection, snbdermal administration, or transdermal administration.
  • the phamiaceutical composiiioo may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.
  • the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula I, formula ⁇ , formula la or tormuia lla) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I, formula 11, formula la or formula Ha or composition as part of a prophylactic or therapeutic treatment.
  • formula ! The desired concentration of formula !, formula ii, formula la or formula Ha or its pharmaceutical acceptable salts will depend on absorption, inacfivation, 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.
  • the optimal concentration and/or quantities or amounts of any particular compound of formula 1, formula If formula ia or formula lia may be adjusted to accommodate variations in the treatment: parameters.
  • 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, adu!t or child, and the nature of the disease or condition.
  • concentration and/or amount of any compound of formula I, formula ⁇ , formula la or formula Ha may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration 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 salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein.
  • One such method is niicrodial sis, as reviewed by T. E. Robinson et a.l , 1991 , 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 a test animal . Dialysis fluid is pumped through the loop. When compounds with formula I, formula 0, formiila la or formula Ila such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysate 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.
  • the dosage of the subject compounds of formula I, formula II, formula la or formula lia provided herein may be determined by reference t the plasma concentrations of the therapeutic composition or other encapsulated materials.
  • the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • Cmax maximum plasma concentration
  • an effective dosage for the compounds of Formulas I is in the range of about 0.01 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 i 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, 10 mg/kg/day, 20 mg/kg/day, 30 mg kg day, or 40 mg/kg/day.
  • Compounds of Formula I, formula 11, formula la or formula Il may also be administered to a human patient at a dose of, for example, between 0. 1 mg and 1000 mg, between 5 nig 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.
  • compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula.
  • An effective amount of the compounds of formula I, formula 11, formula la or formula Oa described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.
  • 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 demyeiization and/or elevated reactive oxidative- nitrosative species and/or abnormalities in physiological homeostasis' s, in patients who are at risk for such complications.
  • these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriat
  • 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 admini tration and on the judgment of the prescribing physician.
  • the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.
  • 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.
  • compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, snclifding orally, topically, parenteraity, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasally, 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 nanoparticles
  • compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either si.ng.le or multiple doses.
  • Suitable pharmaceutical 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.
  • 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.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium iauryl sulfate and talc are often useful for ta.Met.ting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • 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.
  • diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • the compounds of formula I, formula I I, formula la or formula Ha may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.
  • 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.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the formulations may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I, formula 11, formula la or formula Ha discl sed herein, for instance, compounds of formula 1, formula 11, formula la or formula lia or pharmaceutical acceptable salts of a compounds of Formula I, formula 11, formula la or formula Ha.
  • a composition as described herein may be administered orally, or parenieral!y (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 orai 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.
  • the active composition may take the form, of tablets or lozenaes formulated in a conventional manner.
  • the dosage administered will be 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.
  • dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg kg; intramuscular, 1 to about 500 mg 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 wei ht.
  • an active ingredient can be present in the compositions of the present invention for localized use about the cutis, mtranasaHy, pharyngolaryngeally, bronchially, mtravaginally, rectally, or ocularly in a concentration of from about 0.0.1 to about 50% w w of the composition; preferafaiy about I 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.
  • 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-parenterai solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenterai solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenterai solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • solid or fluid unit dosage forms ca be prepared.
  • the tablet core contains one or more hydrophilic polymers.
  • Suitable hydrophilic polymers include, but are not limited to, water sweliable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.
  • suitable water sweliable cellulose derivatives include, but are not limited to, sodium carboxymethylcelluiose, cross-linked hydroxypropylcellulose, hydroxy propyl cellulose (UPC), hydroxypropylmethylcellulose (HPMC), hydroxyisoprapyiceil ulose, hydroxybutylcellulose, hydroxypheny lcell u ose, hydroxyefhylcellulose (HEC), hydroxy pentylcellulose, hydroxypropyleihylceilulose, hydroxypropyibutylcellulose, and hydroxypropylethylcelkilose, and mixtures thereof.
  • suitable polyalkylene glycols include, but axe not limited to, polyethylene glycol .
  • thermoplastic polyalkylene oxides include, but are not limited to, polyethylene oxide).
  • suitable acrylic polymers include, but are not limited to, potassium methacrylatedivisiySbenzene copolymer. polymemyhnethacrylaie, high-molecular weight cross! inked acrylic acid homopolymers and copolymers such as those commercial ly available from Noveon Chemicals under the tradename CARBOPOL fM .
  • suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arable, tragacanth, pectin, xanthan gum, gel!
  • Suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and Iaponite; magnesium tnsilicate; magnesium aluminum silicate; and mixtures thereof.
  • suitable gellin starches include, but are not.
  • suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-! inked agar, and cross-linked cai oxy m e th yl eel I ui ose sodium, and mixtures thereof.
  • the carrier may contain one or more suitable excipients for the formulation of tablets.
  • suitable excipients include, but are not limited to, fillers, adsorbents, binders, di integrants, lubricants, g!idanis, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof.
  • Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydrox propylmethylcellulose; wet hinders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, earboxyraethyicelluiose, tara, gum arable, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstuian, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyciodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof.
  • dry binders such as polyvinyl pyrroli
  • Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked poly viny ! yrrol idone, cross-l inked carboxyniethy icel lulose, starches, niicroerystalline cellulose, and mixtures thereof.
  • Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-meitmg hydrophobic materials, copolymers thereof, and mixtures thereof.
  • 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.
  • suitable fats include, but are not limited to, hydrogenated 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.
  • suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di ⁇ , and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl moriosiearate, glyceryl tri siearate, glyceryl trilaur late, glyceryl myristate, GlycoWax- 932, lauroyl macrogol-32 glycerides, stearoyl macrogoi-32 glycerides, and mixtures thereof.
  • Suitable phospholipids include phosphatidyl choline, hosphati l serene, phosphotidyl enositol, phosphot dic acid, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, ieroerystaliine wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof.
  • super dissntegrants include, but are not limited to, eroscarraeiiose sodium, sodium starch gl col ate and cross- linked povidone (crospovidone).
  • the tablet core contains up to about 5 percent by weight of such super disintegrant.
  • antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxya isole, edetic acid, and edetate salts, and mixtures thereof.
  • 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.
  • 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.
  • the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer.
  • 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
  • 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. 100681 In one embodiment, the oiiier coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core, in another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.
  • Formulations with different drug release mechanisms described above could be combined i a final dosage form containing single or multiple units.
  • multiple units include multilayer tablets, capsules contai ing tablets, beads, or granules in a solid or liquid form.
  • Typical, immediate release formulations include 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.
  • the immediate release 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 quantity of the active agent, with conventional pharmaceuiicai excipients.
  • the immediate release dosage unit may or may not be coated, and may or may no 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).
  • 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 wellknown and described in die art.
  • the matrix devices are generally prepared b compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • 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,
  • 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 exampie, by coating a drug or a drug-containing composition with a selected coating material.
  • the drug-containing composition may be a tablet tor incorporation into a capsule, 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,
  • a pulsed release dosage form is one that mimics a multiple dosing profile without repeated closing 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.
  • Each dosage form contains a therapeutically effective amount of acti ve agent, in one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt % to 70 wt. %, 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.
  • 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.
  • 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.
  • the immediate release dosage unit contains a plurality of beads, granules particles that 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.
  • 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.
  • compositions of the present application maybe lyophilized or subjected to another appropriate drying technique such as spray diving.
  • 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.
  • 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 pharmacy.
  • 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.
  • Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients.
  • 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.
  • the compounds of formula I formula H, formula la or formula Ha described herein may be administered 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 formul tion 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.
  • the subject composition is mixed with one or more pharmaceutical iy acceptable earners 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, carhoxymethylce!u!ose, alginates, gelatin, polyvinyl pyrroHdone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca 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
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as tillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubtlizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, l ,3 ⁇ butylene glycol, oils (in particular, cottonseed, com, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubtlizing
  • Suspensions in addition to the subject compositions, may contain suspending agents such as, for example, ethoxyiated isostearyl alcohols, polyoxyethviene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxyiated isostearyl alcohols, polyoxyethviene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • 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 corapositiori(s).
  • 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 corapositiori(s).
  • 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
  • Dosage tonus for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • a subject composition may he mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellents that may be required.
  • the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties
  • 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, tragaeanth, 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 po!yatnide powder, or mixtures of such substances.
  • Spray may additionally contain customary propel! ants, such a chi orotl uoroh drocatbon s and volatile unsubstituted hydrocarbons, such as butane and propane.
  • 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 chl oride-polyurethane composite and 2-10 parts by weight of a slyrene-eihylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyaikyiene terephthaiate 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 polyaikyiene terephthaiate film, and a second adhesive layer comprising a styrene-diene-styrene 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 polyaikyiene terephthaiate 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 polyaikyiene terephthaiate film.
  • 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.
  • Transdermal patches may be passive or active. Passive transdermal drug deiivery systems currently available, such as the nicoiine, 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 drugs.
  • iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current.
  • An iontophoretic 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) eleeiroosmosis, the convective movement of solvent that occurs throug 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.
  • kits may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet.
  • 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 titratio of the individual components of the combination is desired by the prescribing physician.
  • 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 he transparent
  • 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, Ci-CValky!, ⁇ NH 2 . or ⁇ COC3 ⁇ 4.
  • a is independently 2,3 or 7;
  • each b is i ndependently 3, 5 or o;
  • e is independently L 2 or 6;
  • c and d are each independently H, D, -OH, -OD, Ct-Ce-alky!, -N3 ⁇ 4 or -COC3 ⁇ 4. 098J Methods and compositions tor the treatment of AiheiOthrombosis. Among other things, herein is provided a method of treating Atherothrombosis, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula la:
  • R. ! independently represents D, H, methyl
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently 1, 2 or 6,
  • e and d are each independently H, D, -Oil -OD, Ci-Cs-alkyi, - H2 or - €OC3 ⁇ 4.
  • Atherothrora osi s comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula Ha;
  • 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, C Qralkyi, - H? or -COC3 ⁇ 4.
  • M ihi is for using compounds of formula I:
  • the invention also includes methods for treating or management of atheroihrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascul r diseases and blood clots.
  • Step -7 Synthesis of Compound 10:
  • sample refers to a sample of a body fluid, to a sample of separated cel ls 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 scrum.
  • Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
  • Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as cetitrifugatton or cell sorting.
  • cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.
  • compositions and methods for treating AtherotJbrombosis and their complications are provided among other things compositions and methods for treating AtherotJbrombosis 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.

Abstract

La présente invention concerne des composés de formule I, de formule II, de formule Ia, de formule IIb ou bien ses sels pharmaceutiquement acceptables, ses formes polymorphes, ses solvates, ses énantiomères, ses stéréo-isomères et ses hydrates. Les compositions pharmaceutiques comprennent une quantité efficace de composés de formule I, de formule II, de formule Ia, de formule IIb et peuvent être utilisées pour le traitement ou la prise en charge de l'ischémie, de l'accident vasculaire cérébral, de la thrombose cérébrale, de la thrombose artérielle, des maladies cérébrovasculaires thrombotiques, cardiovasculaires et des caillots de sang.
EP13787471.5A 2012-05-07 2013-03-24 Promédicaments d'agents antiplaquettaires Withdrawn EP2847197A4 (fr)

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PCT/IB2012/053673 WO2013024376A1 (fr) 2011-08-16 2012-07-19 Compositions et procédés pour le traitement de l'athérotrombose
PCT/IB2013/052328 WO2013168024A1 (fr) 2012-05-07 2013-03-24 Promédicaments d'agents antiplaquettaires

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US6858734B2 (en) * 2003-04-23 2005-02-22 Rhodia Pharma Solutions Inc. Preparation of (S)-Clopidogrel and related compounds
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WO2006126676A1 (fr) * 2005-05-27 2006-11-30 Daiichi Sankyo Company, Limited Dérivé d'amine cyclique ayant un groupe alkyle substitué
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WO2013024376A1 (fr) * 2011-08-16 2013-02-21 Mahesh Kandula Compositions et procédés pour le traitement de l'athérotrombose
US9525998B2 (en) * 2012-01-06 2016-12-20 Qualcomm Incorporated Wireless display with multiscreen service
JP6097766B2 (ja) * 2012-01-27 2017-03-15 インターデイジタル パテント ホールディングス インコーポレイテッド マルチキャリアベースおよび／または疑似照合ネットワークにおいてｅｐｄｃｃｈを提供するためのシステムおよび／または方法
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ZA201408064B (en) 2016-04-28
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SG11201407307YA (en) 2014-12-30
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