Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
  • C07C53/126—Acids containing more than four carbon atoms
  • C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • 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
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/001—Acyclic or carbocyclic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
  • C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• VPA Valproic acid
• HDAC histone deacetylases
• VPA has recently been investigated as a potential anticancer therapeutic. It is not clear, however, if the ability of VPA to act as an HDAC inhibitor is related to its ability to treat seizures, bipolar disorders and prevent migraines.
• administration of VPA may provide therapeutic benefits, there are significant toxicities that have been associated with VPA. Indeed, VPA administration can be associated with significant liver toxicity, including acute hepatic liver failure. In particular, there is mounting evidence that a common metabolite of VPA, 4-ene-VPA (depicted below) is at least partly responsible for the toxicity associated with VPA.
• any active pharmaceutical ingredient there may be that the risks associated with administering VPA can outweigh the benefits of administering this compound for any type of specific treatment.
• the problem plaguing the art therefore, is that VPA, while beneficial, can provide too great of a toxicity risk to patients to be useful for use in treating certain patients.
• VPA can provide too great of a toxicity risk to patients to be useful for use in treating certain patients.
• side effects such as liver toxicity.
• Summary of the Invention It is an object of the present disclosure to overcome or at least mitigate one or more of the aforementioned disadvantages. Further, it is an object of the present disclosure to provide advantages and aspects not provided by hitherto known techniques. [0006]
• the present invention of the present disclosure provides at least one compound of Formula I wherein R 1 is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof.
• FIGURE 1 depicts the effects of bleeding time in mice treated with the compounds of the present invention. Tail bleeding time was assessed in mice treated with saline or 100 mg/kg of VPA, Compound Ia, Compound Ib, Rettie, A., et al., J. Biol. Chem., 263(27):13733-13738 (1988)Reference 4, ‘507 publication “D10” compound, or ‘507 publication “D11” compound and control.
• FIGURE 2 depicts platelet accumulation in cremaster laser-induced thrombosis assay (30 mg/kg).
• FIGURE 3 depicts fibrin formation in cremaster laser-induced thrombosis assay (30 mg/kg).
• FIGURE 4 depicts platelet accumulation in cremaster laser-induced thrombosis assay (100 mg/kg).
• FIGURE 5 depicts formation of the 4-ene-VPA metabolite formation in VPA, Compound Ia (Cmpd Ia) and Compound Ib (Cmpd Ib). Values were normalized with the formation of the 4-ene-VPA metabolite in VPA set to 1.0.
• the invention of the present disclosure relates at least one compound of Formula I wherein R 1 is either H or D and wherein D is deuterium, or a pharmaceutically acceptable salt thereof.
• the phrase “compounds of the present invention” as used herein means any one or more of the specific compounds of Formula I.
• compounds of formula (I) where R 1 represents H there is provided compounds of formula (I) where R 1 represents H.
• compounds of formula (I) where R 1 represents D are provided.
• Specific compounds of the present invention include compounds Ia and/or Ib and pharmaceutically acceptable salts thereof:
• Compound Ia may be referred to herein as 2-(Propyl-2,2,3,3-d 4 )pentanoic-4,4,5,5-d 4 acid, 2- [(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoic acid or 4,4,5,5-Tetradeutero-2-(2,2,3,3- tetradeuteropropyl)valeric acid (compound 1a) and compound Ib may be referred to herein as 2- (Propyl-2,2,3,3-d 4 )pentanoic-2,4,4,5,5-d 5 acid or 2,4,4,5,5-Pentadeutero-2-(2,2,3,3- tetradeuteropropyl)valeric acid (compound 1b).
• the compounds of the present invention are novel derivatives of valproic acid (VPA), in which specific hydrogen atoms have been replaced with deuterium isotopes ( 2 H) (represented as “D” in Formula I, compound Ia and compound Ib).
• VPA valproic acid
• the inventors have unexpectedly found that valproic acid having the specific deuteration patterns of Formula I have a surprising metabolic profile that reduces levels of a known toxic metabolite of VPA as well as increased safety profile that both treats conditions associated with excess fibrin deposition and/or thrombus formation as well as reducing excessive blood loss often seen in drugs targeting these conditions.
• the compounds of the invention and “a compound as described herein” are used interchangeably and can be used to indicate: the compound of Formula I, compound Ia, compound Ib.
• Pharmacologically active compounds where hydrogen has been substituted with deuterium generally display the same pharmacodynamic effects as their non-deuterated counterparts. Deuteration, however, may alter metabolism of the parent compound in unpredictable ways. For example, Rettie, A., et al., J. Biol. Chem., 263(27):13733-13738 (1988) (“Rettie”) reported that deuteration of VPA in specific locations of VPA both reduces and increases the formation of the 4-ene- VPA metabolite.
• Rettie notes that deuteration in the 4 and 4’-positions of VPA (4,4,4 ⁇ ,4 ⁇ - D 4 VPA), lead to considerably less formation of the 4-ene metabolite compared to VPA.
• deuteration in the 5 and 5’-positions of VPA would increase production of the 4-ene-VPA metabolite and thus increase toxicity associated with VPA administration.
• Rettie therefore, would suggest that deuteration of the 5 and/or 5’ positions of VPA should be avoided.
• the general concept of deuterated VPA is not new.
• Rettie generated deuterated VPA compounds.
• Rettie generated four deuterated compounds: (4,4,-D 2 VPA), (4,4,4 ⁇ ,4 ⁇ -D 4 VPA), (5,5,5-D 3 VPA) (5,5,5,5 ⁇ ,5 ⁇ ,5 ⁇ D 6 VPA).
• the ‘507 publication does not provide any guidance or suggestions on which specific compounds produce less 4- ene-VPA when metabolized or which specific compounds may provide any therapeutic benefit. Indeed, the ‘507 publication does not contain any activity or metabolism data of any kind. And of the few specific molecules that the ‘507 publication discloses, the 5 and 5’ positions are either fully deuterated, i.e., the compounds have six (6) 2 H isotopes at these two positions, or fully hydrogenated, i.e., the compounds have zero (0) 2 H isotopes at these two positions. [0021] United States Pre-Grant Publication No.2012/0071554 (PCT Publication No.
• WO 2010/062656 which was abandoned with no continuing applications filed thereon, also discloses deuterated VPA compounds.
• the ‘554 publication does not disclose or suggest any specific deuterated molecules having the specific pattern of deuteration of the compounds of the present invention.
• the ‘554 publication does not provide any guidance or suggestions on which specific compounds produce less 4-ene-VPA when metabolized or which specific compounds may provide any therapeutic benefit.
• the ‘554 publication does not contain any activity, stability or metabolism data of any kind.
• the 5 and 5’ positions are either fully hydrogenated, i.e., the compounds have zero (0) 2 H isotopes at these two positions, deuterated at only one of these positions, i.e., the compounds have three (3) 2 H isotopes at only one of these two positions, or are deuterated only once at each of these positions, i.e., the compounds have one (1) 2 H isotope at each of these two positions.
• the general concept of deuterated VPA may not be new, there is no guidance in the art that would suggest deuterating two hydrogens at each of the 5 and 5’ positions of VPA.
• the present invention provides novel, safer compounds for treating conditions for which deuterated VPA is or could be used as a monotherapy or part of a combination therapy.
• the compounds of the present invention also have unexpectedly superior therapeutic advantages over VPA.
• the compounds described herein, which are novel derivatives of VPA with specific deuteration patterns not only reduces formation of the toxic 4-ene-VPA metabolite, but may also provide an unexpectedly superior performance in reducing excess bleeding when administered compared to VPA.
• the invention also provides methods of using the compounds of the present invention for treating abnormal conditions associated with thrombus formation, excess fibrin deposition, and/or fibrosis.
• the present invention provides methods of treating abnormal conditions associated with thrombus formation, excess fibrin deposition and/or fibrosis in subjects in need of treatment thereof.
• the methods of treatment of abnormal conditions associated with thrombus formation, excess fibrin deposition and/or fibrosis comprise administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment thereof.
• a compound as described herein i.e., a compound of the invention, or a pharmaceutical composition as described herein, for use in the treatment and/or prevention of an abnormal condition associated with thrombus formation, excess fibrin deposition and/or fibrosis.
• Administering a pharmaceutical composition as described herein may reduce excessive blood loss in the subject being treated.
• methods of treating or preventing conditions marked or associated with thrombus formation, excess fibrin deposition and/or fibrosis as described herein (and compounds for use in such methods) may also involve reducing excessive blood loss in the subject being treated.
• Examples of conditions marked or associated with thrombus formation and/or excess fibrin deposition for which one or more of the compounds of the present invention may be used to treat and/or prevent in a subject include but are not limited to atherosclerosis, myocardial infarction, ischemic stroke, deep vein thrombosis, superficial vein thrombosis, thrombophlebitis, pulmonary embolism, disseminated intravascular coagulation, renal vascular disease and intermittent claudication.
• the condition is selected from the group consisting of myocardial infarction, ischemic stroke, deep vein thrombosis and pulmonary embolism.
• Particular pathological conditions associated with fibrosis include but are not limited to cardiac fibrosis, such as myocardial fibrosis, atrial fibrosis, fibrosis associated with cardiac hypertrophy and remodelling, fibrosis associated with myocardial infarction, atrial fibrillation and heart failure, right and left heart failure with reduced as well as preserved ejection fraction, cardiac fibrosis associated with lung disease, fibrosis associated with pulmonary arterial hypertension, fibrosis associated with thromboembolic disease, fibrosis associated with NASH, liver cirrhosis and portal hypertension, kidney fibrosis with and without systemic hypertension, pulmonary fibrosis (e.g.
• idiopathic pulmonary fibrosis peritoneal fibrosis, i.e. progressive fibrous thickening of the peritoneal membrane, conjunctival fibrosis, i.e., overproduction of collagen type I in the membranes of the inner surfaces of the eyelids and the front of the eyeball, and/or renal fibrosis associated with chronic kidney disease.
• the methods of using the compounds of the present invention for treating abnormal conditions associated with thrombus formation, excess fibrin deposition, and/or fibrosis may reduce excessive blood loss in the subject.
• several conditions and risk factors are associated with increased susceptibility to thrombotic events (i.e. thrombus formation).
• the treatment or prevention is in a patient having one or more such condition/risk factor.
• the patient at increased risk of developing a pathological condition associated with excess fibrin deposition and/or thrombus formation is a patient who: [0032] (i) is suffering from one or more medical condition associated with increased risk of thrombus formation, such as metabolic syndrome (e.g.
• (ii) has previously experienced one or more incidence of a pathological condition associated with excess fibrin deposition and/or thrombus formation, such as one or more incidence of myocardial infarction, ischemic stroke and pulmonary embolism (e.g. one or more incidence of ischemic stroke, such as a major ischemic stroke, minor ischemic stroke or TIA); and/or [0034] (iii) has one or more lifestyle and/or environmental factors placing them at said increased risk, such the patient being a smoker, obese and/or having decreased mobility (e.g. the patient is bed- ridden, such as a patient in a medical unit or elderly care unit).
• a pathological condition associated with excess fibrin deposition and/or thrombus formation such as one or more incidence of myocardial infarction, ischemic stroke and pulmonary embolism (e.g. one or more incidence of ischemic stroke, such as a major ischemic stroke, minor ischemic stroke or TIA); and/or [0034]
• pathological conditions that may be treated or prevented in accordance with the invention are those that are caused wholly or at least in part by an increased fibrin deposition and/or reduced fibrinolytic capacity due to local or systemic inflammation.
• These include, but are not limited to, myocardial infarction, stable angina pectoris, unstable angina pectoris, intermittent claudication, ischemic stroke, transient ischemic attack, deep vein thrombosis and pulmonary embolism.
• Particular biomarkers that may identify local or systemic inflammation include high sensitive C- reactive protein (hs-CRP) (at or above 2.0 mg/l serum) and fibrinogen (at or above 3g/l serum) (Corrado E., et al.
• the treatment or prevention includes reversal and prevention of fibrosis.
• the treatment or prevention includes reversal and prevention of either primary or secondary fibrosis or both, remodelling and repair as well as effects on fibrosis associated with cardiovascular disease, inflammatory disease, fibrosis associated with activation of the Renin- Angiotensin-System, the mineral corticoid receptor and PAI-1 as well as other systemic diseases.
• the fibrosis is selected from the group consisting of cardiac fibrosis, arterial fibrosis, pulmonary fibrosis, fibrosis associated with pulmonary arterial hypertension, fibrosis associated with thromboembolic disease, fibrosis associated with NASH, kidney fibrosis, eye fibrosis, skin fibrosis, liver fibrosis, pancreas fibrosis and other GI tract fibrosis.
• the one or more of the compounds of the present invention may be used to treat and/or prevent diseases associated with pulmonary or systemic increased blood pressure.
• the one or more of the compounds of the present invention may be used to treat and/or prevent pulmonary arterial hypertension (PAH) and/or chronic thromboembolic pulmonary hypertension (CTEPH).
• PAH pulmonary arterial hypertension
• CTEPH chronic thromboembolic pulmonary hypertension
• the one or more of the compounds of the present invention may be used to treat and/or prevent thrombus formation associated with increased pulmonary pressure, including but not limited to, pulmonary arterial hypertension (PAH) and/or chronic thromboembolic pulmonary hypertension (CTEPH).
• PAH pulmonary arterial hypertension
• CTEPH chronic thromboembolic pulmonary hypertension
• the invention also provides methods of using the compounds of the present invention to inhibit histone deacetylase. In other words, the present invention provides methods of inhibit histone deacetylase in subjects in need of inhibition thereof.
• the methods of inhibiting histone deacetylase comprise administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of inhibition of histone deacetylase thereof.
• a compound as described herein, or a pharmaceutical composition as described herein for the manufacture of a medicament for the inhibition of histone deacetylase.
• a compound as described herein, or a pharmaceutical composition as described herein for use in the inhibition of histone deacetylase.
• the invention also provides methods of using the compounds of the present invention to treat a subject diagnosed as having bipolar disorder.
• the present invention provides methods of treating bipolar disorder in a subject in need of treatment thereof.
• the methods of treatment of bipolar disorder comprise administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment thereof.
• a compound as described herein, or a pharmaceutical composition as described herein for use in the treatment and/or prevention of bipolar disorder are also provided.
• the invention also provides methods of using the compounds of the present invention to treat a subject diagnosed as having epilepsy.
• the present invention provides methods of treating epilepsy in a subject in need of treatment thereof.
• the methods of treatment of epilepsy comprise administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment thereof.
• a compound as described herein, or a pharmaceutical composition as described herein for use in the treatment and/or prevention of epilepsy.
• the methods of treatment of epilepsy comprise administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment thereof.
• the invention also provides methods of using the compounds of the present invention to prevent a migraine headache in a subject. In other words, the present invention provides methods of reducing the likelihood or reducing the frequency of migraine headaches in a subject in need of reduction thereof.
• the methods of treatment of a migraine headache comprise administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment thereof.
• a compound as described herein, or a pharmaceutical composition as described herein for use in the treatment and/or prevention of a migraine headache.
• the methods of treatment and methods using the compounds of the present invention comprise administering one of more the compounds of the present invention to a subject in need of treatment thereof.
• Suitable dosage ranges of the compounds of the invention are generally about 0.0001 milligrams/dose to 2000 milligrams/dose of a compound of the invention per kilogram body weight, per day.
• the dose is from about 0.001 milligram to about 4000 milligrams per kilogram body weight, or from about 0.01 milligram to about 3000 milligrams per kilogram body weight, or from about 0.1 milligram to about 2000 milligrams per kilogram body weight, or from about 0.1 milligram to about 1500 milligrams per kilogram body weight, or from about 0.1 milligram to about 1000 milligrams per kilogram body weight, or from about 1 milligram to about 500 milligrams per kilogram body weight, or from about 1 milligram to about 100 milligrams per kilogram body weight, or from about 1 milligram to about 90 milligrams per kilogram body weight, or from about 1 milligram to about 80milligrams per kilogram body weight, or from about 1 milligram to about 70 milligrams per kilogram body weight, or
• one of more of the compounds of the present invention are administered at a dose of about 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg, 7 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg or 100 mg/kg.
• daily doses are in the range of about 1 to 4000 mg per patient (e.g.1 to 3000 mg or 1 to 2000 mg per patient), administered in single or multiple doses.
• one of more of the compounds of the present invention are administered at a daily dose of about about 10 mg to about 2000 mg, from about 50 mg to about 1300 mg, e.g., about 100 mg to about 1200 mg, or from about 50 mg to about 1000 mg, e.g., about 100 mg to about 800 mg, about 100 mg to about 600 mg, or about 200 mg to about 600 mg, e.g., about 100 mg to about 800 mg, or about 200 mg to about 600 mg.
• the daily doses may be administered as a single bolus dose or the total dose may be divided over multiple doses, e.g., 2, 3, 4, 5, 6, 7 or 8 doses, per day.
• the compounds of the present invention include pharmaceutically acceptable salts of the compounds of Formula I.
• pharmaceutically acceptable salt(s), includes but is not limited to salts of acidic or basic groups that may be present in compounds used in the present compositions.
• Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions including, but not limited to, sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-tolue ⁇ ; ⁇ -methylene-bis
• compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
• the compounds described herein are acidic in nature and are capable of forming salts with e.g. various pharmacologically acceptable cations.
• examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
• Particular examples of pharmaceutically acceptable addition salts include those derived from metals such as calcium, magnesium, potassium or, preferably sodium.
• such salts may be present as a “hemi-salt” (i.e. in a 2:1 ratio of compound to counterion).
• the compounds described herein may also for complexes with various amines.
• amines include, alkylamines, aminoalcohols (e.g.2-(dimethylamino)ethanol), basic amino acids (e.g. lysine), quartenary amines (e.g. choline).
• therapeutically effective amount of a composition of the invention is measured by the therapeutic effectiveness of a compound of the invention, wherein at least one adverse effect of a disorder is ameliorated or alleviated.
• the terms “preventing” or “prevention” is intended to include reducing the frequency or likelihood of (e.g.
• treatment refers to reducing or amelioration of a disease, disorder, abnormal condition or at least one discernible symptom thereof. In another embodiment, “treatment” or “treating” refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient.
• treatment refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
• treatment or “treating” refers to delaying the onset of a disease, disorder or abnormal condition.
• compositions of the invention are administered to a patient, for example a human.
• a patient for example a human.
• the terms subject and patient are used interchangeably herein.
• the subject can be a non-human mammal as well, e.g., for veterinary use for companion pets or for farming or livestock animals. Examples of non-human subject include but are not limited to non-human primates, dogs, cats, cows, pigs, oxen, horses, etc.
• the compounds of the invention may be administered by any convenient or conventional route, for example, oral, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings, e.g., oral mucosa, rectal and intestinal mucosa, etc., and may be administered together with another biologically active agent. Administration can be systemic or local.
• Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer a compound or composition of the invention.
• Methods of administration include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally or topically, for example to the ears, nose, eyes, or skin.
• the compounds of the invention are administered orally.
• the compounds of the invention can be delivered in a vesicle, for example a liposome.
• the compounds of the invention can be delivered in a controlled release system.
• a pump may be used. See Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N. Engl. J. Med.321:574.
• polymeric materials can be used.
• compositions known in the art and described for valproic acid, and pharmaceutically acceptable salts thereof may be used when administering the compounds of the present invention.
• the compositions and methods of the present invention contemplate substituting VPA in these known formulations with one or more of the compounds of the present invention.
• the present compositions will contain a therapeutically effective amount of a compound of the invention, together with a suitable amount of a pharmaceutically acceptable vehicle so as to provide the form for proper administration to the patient.
• the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
• vehicle refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.
• Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
• auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
• Water can be a vehicle when the compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
• Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
• excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
• suitable pharmaceutical vehicles are described in “Remington’s Pharmaceutical Sciences” by A. R. Gennaro.
• the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
• the compounds of the invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to humans.
• compounds of the invention for intravenous administration are solutions in sterile isotonic aqueous buffer.
• the compositions may also include a solubilizing agent.
• compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection.
• a local anesthetic such as lignocaine to ease pain at the site of the injection.
• the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
• the compound of the invention is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
• Formulations for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
• Orally administered compositions may contain one or more optionally agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
• the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
• Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds of the invention.
• fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
• delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
• a time delay material such as glycerol monostearate or glycerol stearate may also be used.
• Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
• a process for the preparation of a compound of formula (III) comprising the step of hydrogenation of a compound of formula (IV), under conditions known to those skilled in the art (such as in the presence of a suitable catalyst, e.g. a rhodium catalyst) and the presence of a suitable source of deuterium (e.g. deuterium gas).
• a suitable catalyst e.g. a rhodium catalyst
• a suitable source of deuterium e.g. deuterium gas
• a suitable base metal e.g. a metal hydride, such a sodium hydride
• a suitable alkylating agent e.g. a suitable alkyl halide, such as propargyl bromide
• a compound of formula (Ia) or Ib)) comprising: a process for preparing a compound for formula (IV) as described herein; followed by a process for preparing a compound for formula (III) as described herein; followed by a process for preparing a compound for formula (II) as described herein; followed by a process for preparing a compound for formula (I) as described herein.
• Compounds of formula (V) may be commercially available and/or may be synthesized using techniques known to those skilled in the art. [0081] Such compounds may be isolated from their reaction mixtures and, if necessary, purified using conventional techniques as known to those skilled in the art. Thus, processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention (e.g. isolation and optionally purification of the compound of formula I). [0082] Examples [0083] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.
• reaction flask was evacuated and flushed with nitrogen repeatedly.
• the reaction flask was connected to the hydrogenation manifold and the reaction flask evacuated and flushed with deuterium.
• the mixture was stirred under deuterium.
• the reaction mixture was filtered through celite and washed with water and brine.
• the organic phase was dried over MgSO 4 , filtered and concentrated.
• the residue was purified by kugelrohr distillation (10 mbar@ 130 °C).
• Dimethyl 2,2-bis(2,2,3,3-tetradeuteriopropyl)propanedioate Dimethyl 2-prop-2-ynyl-2-(2,2,3,3-tetradeuteriopropyl)propanedioate (18 g, 83 mmol) and tris(triphenylphosphine)rhodium(I) chloride (1.54 g, 1.66 mmol, 2%) were mixed in 300 ml of toluene.
• the reaction flask was evacuated and flushed with nitrogen repeatedly.
• the reaction flask was connected to the hydrogenation manifold and the reaction flask evacuated and flushed with deuterium. The mixture was stirred under deuterium.
• 2,2-Bis(2,2,3,3-tetradeuteriopropyl)propanedioic acid Sodium hydroxide (13.9 g, 348 mmol) was dissolved in 100 ml of water. Dimethyl 2,2-bis(2,2,3,3- tetradeuteriopropyl)propanedioate (13 g, 58 mmol) in 50 ml of methanol was added. The reaction mixture was stirred at reflux for 5 hours and at room temperature overnight. The reaction mixture was washed with 2*50 ml of DCM. The aqueous phase was concentrated under vacuum to remove traces of DCM. The solution was cooled on ice and 80 ml of 5 M HCl was added. A white precipitate formed.
• Compound Ia sodium hemi salt”, 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoic acid and sodium 2- [(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoate
• Compound Ia (8.00 g, 52.5 mmol) and finely ground sodium hydroxide (1.05 g, 26.3 mmol) were mixed in 20 ml of MTBE. The mixture was stirred at 50 °C for 30 minutes. A Clear, light brown solution was obtained. After cooling on ice, 80 ml of acetonitrile was added. A massive precipitate formed.
• mice were administered Compound Ia (Formula Ia), Compound Ib (Formula Ib), “ 2 H 4 -VPA” from Rettie, A., et al., J. Biol.
• mice were sedated with 250 ⁇ L of ketamine solution (Ketamine (100 ⁇ L)/xylazine (50 ⁇ L) in 850 ⁇ L Saline solution). The mice were then placed face down on a heat pad on top of the bead bath to enable the tail to be pulled into a saline-filled tube. 5mm of the tail as cut with a scalpel and the tail was placed in a saline-filled tube and a timer started. The timer was stopped when the bleeding stopped, but the possibility of re-bleeds was observed from 10 minutes after initial bleeding stopped. If the mouse bleeds continuously for 10 minutes, the experiment was halted and the mouse was euthanized.
• ketamine solution Keramine (100 ⁇ L)/xylazine (50 ⁇ L) in 850 ⁇ L Saline solution.
• Example 3 – Thrombosis Assessment of compounds of the invention The effects of the compounds of the invention and VPA on the ability and timing of clot formation were determined. Specifically, platelet accumulation and fibrin formation in the cremaster artery in forming a non-occlusive clot were measured following laser-induced insult to the vessel in 10- 12 week-old mice (C57BL/6 wild type mice purchased from Jackson Laboratories).
• Valproic acid (VPA) was purchased from Sigma-Aldrich as a powder and resuspended in 0.9% Sodium Chloride (saline) to prepare a final stock solution of each compound.
• the VPA and other compounds were administered via IP injection to the mice at a final concentration of 30 mg/kg and 100mg/kg.
• a Zeiss Axio Examiner Z1 fluorescent multichannel intravital microscope was used. The microscope was equipped with: (1) a solid laser launch system (LaserStack; Ablate! Photoablation system, Intelligent Imaging Innovations), (2) a high- speed sCMOS camera, and (3) a laser ablation system (Intelligent Imaging Innovations, Denver, CO, USA). SlideBook 6.0 digital microscopy software for image recording and analysis was also used. An anti-platelet antibody, and an anti-fibrin antibody, both commercially available, were used for imaging purposes.
• DyLight 488-conjugated rat anti-mouse platelet GP1b ⁇ antibody (0.1 ⁇ g/g; EMFRET Analytics) and Alexa Fluor 647-conjugated anti-fibrin (0.3 ⁇ g/g) were administered intravenously via a jugular vein cannula prior to vascular injury. Microcirculation was monitored and recorded under multichannel intravital microscopy. [00109] Multiple independent thrombi (6- 8 thrombi in each mouse) were induced in the arterioles (30- 50 ⁇ m diameter) in each mouse by a laser ablation system.
• compound Ia at a dose of 30 mg/kg provided a consistent decrease in both platelet accumulation and fibrin formation in this thrombosis assay over VPA, indicating that compound Ia is beneficial in treating or preventing conditions associated with excess fibrin deposition when compared with VPA and Compound Ib.
• compound Ia and compound Ib administered at a dose of 100 mg/kg provided consistent decrease in platelet accumulation over VPA in this thrombosis assay ( Figure 4).
• Example 4 Formation of 2-Propyl-4-pentenoic acid (4-ene metabolite) [00112] Formation of 2-Propyl-4-pentenoic acid (4-ene metabolite) in Cyp 2C9 in vitro experiments with VPA and compounds of the invention.
• VPA, compound Ia and compound Ib (all compounds at 1 mM) were incubated with Human CYP2C90.2 pmol/Pl bactosomes (Cypex, UK) in 100 mM potassium phosphate buffer pH 7.4 containing 5 mM magnesium chloride and 2mM NADPH.
• Samples were withdrawn before addition of NADPH (time 0) and at different time points (30, 60 and 180 minutes) after addition of NADPH. Samples were added to the same volume ice cold acetonitrile, vortexed, centrifuged at 10000 x g and stored at +4 o C until analysis. To increase the analytical sensitivity, the sample supernatants were derivatized with N-(3 Dimethylaminopropyl)-N ’ -ethylcarbodiimide) and 3- Nitrophenylhydrazibe hydrochloride. Resulting products were analysed using LC-MS/MS (UHPLC Agilent 6495, XSelect HSS T3 XP Column).
• the area under the curve calculations of formed 4-ene metabolite were based on the trapetzoidal rule, and the formation expressed as % 4-ene*min.
• the amounts of formed 4-ene metabolite for compounds Ia and Ib were compared with the formed amount 4-ene metabolite for VPA.
• the reduction of formed 4-ene metabolite was 96,7% when compared with VPA.
• the reduction of formed 4-ene metabolite was 88,8% when compared with VPA (see figure 5).

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