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WO2015073967A1 - Nouveaux métabolites de composés de vanoxérine pour le traitement de maladies dopaminergiques - Google Patents

Nouveaux métabolites de composés de vanoxérine pour le traitement de maladies dopaminergiques Download PDF

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Publication number
WO2015073967A1
WO2015073967A1 PCT/US2014/065943 US2014065943W WO2015073967A1 WO 2015073967 A1 WO2015073967 A1 WO 2015073967A1 US 2014065943 W US2014065943 W US 2014065943W WO 2015073967 A1 WO2015073967 A1 WO 2015073967A1
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Prior art keywords
vanoxerine
treatment
hydroxide
piperazine compound
compound
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Arthur M. Brown
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • Presently disclosed embodiments are related to novel piperazine compounds, pharmaceutical compositions comprising the same and methods for treating dopaminergic diseases in mammals.
  • Vanoxerine (l-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperazine), its manufacture and/or certain pharmaceutical uses thereof are described in U.S. Patent No. 4,202,896, U.S. Patent No. 4,476,129, U.S. Patent No. 4,874,765, U.S. Patent No. 6,743,797 and U.S. Patent No. 7,700,600, as well as European Patent EP
  • Piperazine compounds and derivatives have been studied for their useful pharmacological properties. Many compounds have shown a strong specific dopaminergic activity and low toxicity. Dopaminergic activity has been assessed in both animal tests and in in vitro studies. These tests have identified certain piperazine compounds, including vanoxerine, to be useful in the treatment of Parkinson's disease and of pathological disorders caused by increased prolactin production, including galactorrhea, excessive puerperal lactation,
  • hypogonadism infertility, and with excessive excretion of growth hormone.
  • Vanoxerine in particular, its manufacture and/or certain pharmaceutical uses thereof are described in U.S. Pat. Nos. 4,202,896, 4,476,120, and 4,874,765, as well as European Patent EP 243,908 and PCT international Application WO 91/01732.
  • Vanoxerine has been used for treating cocaine addiction, acute effects of cocaine, and cocaine cravings in mammals, as well as dopamine agonists for the treatment of Parkinsonism, acromegaly, hyperprolactinemia and diseases arising from a hypofunction of the dopaminergic system. (See U.S. Patent No. 4,202,896 and WO 91/01732.)
  • Vanoxerine has also been used for treating and preventing cardiac arrhythmia in mammals.
  • U.S. Patent No. 4,202,896 described other piperazine compounds and looked at dosing various compounds for Parkinsonism, acromegaly, and prolactin induced disorders.
  • Parkinsonism 20-40 mg for acromegaly, and 5-25 mg for prolactin-induced disorders.
  • vanoxerine studies have looked at the safety profile of vanoxerine and stated that no side-effects should be expected with a daily repetitive dose of 50 mg of vanoxerine.
  • U. Sogaard, et al. International Clinical Psychopharmacology, "A Tolerance Study of Single and Multiple Dosing of the Selective Dopamine Uptake Inhibitor GBR 12909 in Healthy Subjects," 5:237-251 (1990).
  • Sogaard, et al. also found that upon administration of higher doses, some effects were seen with regard to concentration difficulties, increase systolic blood pressure, asthenia, and a feeling of drug influence, among other effects. Sogaard, et al.
  • a first embodiment of the disclosure comprises a piperazine compound having the following structure:
  • Rl, R2, R3, R4/R4', R5/R5', R6/R6', R7/R7', or R8, are either a hydrogen atom or a hydroxide and further provided that not all of Rl, R2, R3, R4/R4', R5/R5', R6/R6', R7/R7', or R8 are a hydrogen atom, and that only one of Rl, R2, R3, R4/R4', R5/R5', R6/R6', R7/R7', or R8 is a hydroxide.
  • An additional embodiment of the present invention comprises pharmaceutical compositions containing one or more of the novel piperazine compounds shown above in admixture with a pharmaceutically acceptable carrier.
  • compositions comprising the piperazine compound described herein in admixture with pharmaceutically acceptable excipients whereby the pharmaceutical composition is suitable for administration to mammals for treatment of dopaminergic diseases.
  • Further embodiments of the present disclosure comprise methods for treatment of certain diseases having abnormal dopaminergic activity, comprising administering an effective amount of a pharmaceutical piperazine compounds described herein.
  • a further embodiment of the disclosure includes a method of administering the pharmaceutical compound described herein, and pharmaceutically acceptable salts thereof, to a mammal for the treatment of Parkinson's, galactorrhea, excessive puerperal lactation,
  • vanoxerine metabolite or “novel piperazine compounds” refer to the vanoxerine metabolites as described herein and pharmaceutically acceptable salts thereof.
  • the term "subject” refers to a warm blooded animal such as a mammal, preferably a human or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and conditions described herein.
  • terapéuticaally effective amount refers to an amount which is effective in reducing, eliminating, treating, preventing or controlling the symptoms of the herein- described diseases and conditions.
  • controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.
  • unit dose means a single dose which is capable of being administered to a subject, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising a vanoxerine metabolite or a
  • composition comprising a vanoxerine metabolite.
  • administering refers to the actions of a medical processional or caregiver, or alternatively self-administration by the patient.
  • Administration of drug compounds leads to the metabolism and degradation of these compounds, often into a number of different compounds within the body. It is widely known that while a primary drug product may be administered, it may be one or more of the metabolic products that provides the efficacious drug. Similarly, one or more of the metabolic products may provide deleterious effects to the patient. Accordingly, it is advantageous to identify and isolate individual metabolites of advantageous drug products for administration to patients.
  • piperazine compounds including vanoxerine
  • vanoxerine are susceptible to metabolism by numerous mechanisms, including P450 and hepatic metabolism.
  • studies with regard to vanoxerine have shown that certain foods, whether high in fat or low in fat diet also impact metabolism and bioavailability for some or all patients. S.H.
  • Rl, R2, R3, R4/R4', R5/R5', R6/R6', R7/R7', or R8, are either a hydrogen atom or a hydroxide and further provided that not all of Rl, R2, R3, R4/R4', R5/R5', R6/R6', R7/R7', or R8 are a hydrogen atom, and that only one of Rl, R2, R3, R4/R4', R5/R5', R6/R6', R7/R7', or R8 is a hydroxide.
  • R4 and R4' are chemically equivalent, only one of R4 and R4' is a hydroxyl and the other being a hydrogen.
  • R5 and R5', R6 and R6' and R7 and R7' are equivalents of one another and wherein one is a hydroxyl, the other equivalent is a hydroxyl. Accordingly, just a single hydroxyl group is matched with all remaining unknown positions as hydrogen atoms.
  • one of R4/R4', R5/R5', R6/R6', R7/R7', or R8 is a hydroxyl.
  • compositions described herein may be suitable for administration to patients to treat dopaminergic disease.
  • the goal Cma X plasma concentration may be 5 ng/ml to 400 ng/ml of one or more of the novel piperazine compounds at one hour post administration.
  • the goal Cma X plasma concentration may be 5 ng/ml to 400 ng/ml of one or more of the novel piperazine compounds at one hour post administration.
  • a plasma concentration of one of more of the novel piperazine compounds for a given time period.
  • Alternative embodiments utilize an elevated physiological level for more than a day. Indeed, it may be advantageous to provide for elevated physiological level for days, weeks, months, and/or years to maintain sinus rhythm and to prevent recurrence of cardiac arrhythmia. Accordingly a daily or multiple times a day dose may be appropriate in some circumstances for providing such elevated levels.
  • concentration of one of more of the novel piperazine compounds for a given time period as measured by the mean concentration AUC.
  • Alternative embodiments utilize an elevated physiological level for more than a day. Indeed, it may be advantageous to provide for elevated physiological level for days, weeks, months, and/or years to treat the dopaminergic disease. Accordingly a daily or multiple times a day dose may be appropriate in some circumstances for providing such elevated levels and to minimize fluctuation of levels due to pharmacokinetic metabolism.
  • 1000 mg per unit dose is appropriate.
  • Other embodiments may utilize a dosage of about 50 mg to 800 mg, or about 25 to 100 mg, or about 100 mg to about 600 mg, or about 200 to about 400 mg.
  • Plasma level concentrations (and other physiological concentrations) of the novel piperazine compositions identified herein are increased by the administration of said
  • compositions to a mammal Preferred plasma level concentrations of one or more novel piperazine compounds, taken at a time point of 1 hour post administration are about 5 to about 400 ng/ml. In alternative embodiments, plasma level concentrations at 1 hour post
  • administration are about 20 to about 200 ng/ml, or about 20 to 100 ng/ml, or about 25 to about 75 ng/ml or about 40 to 50 ng/ml.
  • plasma level concentrations may be taken at a time point of about 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours post administration, or taken a multiple time points to provide additional data for maximizing the modifications in the methods described herein.
  • Cmax taken at a time point of 1 hour post administration are about 10 to about 200 ng/ml.
  • plasma level concentrations at 1 hour post administration are about 10 to about 200 ng/ml, or about 20 to about 200 ng/ml, or about 20 to 100 ng/ml, or about 25 to about 75 ng/ml or about 40 to 50 ng/ml.
  • tmax is appropriately reached at about 1 hour post administration.
  • t ⁇ is appropriately reached at about 30 minutes, or about 90 minutes, or about 120 minutes, or about 240 minutes post administration.
  • pharmaceutically acceptable salts thereof can be synthesized by conventional chemical methods using starting materials and reagents known and available to those skilled in the art.
  • such salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • compositions of the novel piperazine compound may also be employed in the methods of the present invention.
  • pharmaceutically acceptable salts of the novel piperazine compound include, but are not limited to, salts of the novel piperazine compound formed from non-toxic inorganic or organic acids.
  • Such pharmaceutically acceptable salts include, but are not limited to, the following: salts derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; salts derived from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, benzoic, salicylic, sulfanilic, 2-acetoxy- benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like; and salts derived from amino acids, such as glutamic add or aspartic acid. See U.S. Patent 6,187,802 and WO 91/01732.
  • Suitable methods for treatment of conditions having dopaminergic relation activity include various dosing schedules. Dosing may include single daily doses, multiple daily doses, single bolus doses lasting more than one day, extended release doses, IV or continuous dosing through implants or controlled release mechanisms. These dosing regimens in
  • Such a pharmaceutical composition may be administered by any technique capable of introducing a pharmaceutically active agent to the desired site of action, including, but not limited to, buccal, sublingual, nasal, oral, topical, rectal and parenteral administration. Delivery of the compound may also be through the use of controlled release formulations in subcutaneous implants or transdermal patches.
  • a suitable composition containing the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof may be prepared in the form of tablets, dragees, capsules, syrups and aqueous or oil suspensions.
  • the inert ingredients used in the preparation of these compositions are known in the art.
  • tablets may be prepared by mixing the active compound with an inert diluent, such as lactose or calcium phosphate, in the presence of a disintegrating agent, such as potato starch or microcrystalline cellulose, and a lubricating agent, such as magnesium stearate or talc, and then tableting the mixture by known methods.
  • Tablets may also be formulated in a manner known in the art so as to give a sustained release of the novel piperazine compound of the present invention, or a
  • Such tablets may, if desired, be provided with enteric coatings by known method, for example by the use of cellulose acetate phthalate.
  • Suitable binding or granulating agents are e.g. gelatine, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or starch gum.
  • Talc, colloidal silicic acid, stearin as well as calcium and magnesium stearate or the like can be used as anti-adhesive and gliding agents.
  • Tablets may also be prepared by wet granulation and subsequent compression.
  • the pharmaceutically acceptable salt thereof, and at least one diluent, and optionally a part of the disintegrating agent is granulated together with an aqueous, ethanolic or aqueous-ethanolic solution of the binding agents in an appropriate equipment, then the granulate is dried.
  • preservative, surface acting, dispersing, disintegrating, gliding and anti- adhesive additives can be mixed to the dried granulate and the mixture can be compressed to tablets or capsules.
  • Tablets may also be prepared by the direct compression of the mixture containing the active ingredient together with the needed additives. If desired, the tablets may be transformed to dragees by using protective, flavoring and dyeing agents such as sugar, cellulose derivatives (methyl- or ethylcellulose or sodium carboxymethylcellulose), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, aromatizing agents, iron oxide pigments and the like which are commonly used in the pharmaceutical industry.
  • protective, flavoring and dyeing agents such as sugar, cellulose derivatives (methyl- or ethylcellulose or sodium carboxymethylcellulose), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, aromatizing agents, iron oxide pigments and the like which are commonly used in the pharmaceutical industry.
  • a mixture of the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, and the desired additives may be filled into a capsule, such as a hard or soft gelatin capsule.
  • a capsule and/or caplet may also be formulated using known methods to give sustained release of the active compound.
  • Liquid oral dosage forms of the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof may be an elixir, suspension and/or syrup, where the compound is mixed with a non-toxic suspending agent.
  • Liquid oral dosage forms may also comprise one or more sweetening agent, flavoring agent, preservative and/or mixture thereof.
  • a suitable composition containing the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof may be prepared in the form of a suppository.
  • the suppository may contain a suppository mass commonly used in pharmaceutical practice, such as Theobroma oil, glycerinated gelatin or a high molecular weight polyethylene glycol.
  • a suitable composition of the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof may be prepared in the form of an injectable solution or suspension.
  • the active ingredient can be dissolved in aqueous or non-aqueous isotonic sterile injection solutions or suspensions, such as glycol ethers, or optionally in the presence of solubilizing agents such as polyoxyethylene sorbitan monolaurate, monooleate or monostearate.
  • sterile injection solutions or suspensions such as glycol ethers
  • solubilizing agents such as polyoxyethylene sorbitan monolaurate, monooleate or monostearate.
  • Parenteral administration may be through intravenous, intradermal, intramuscular or subcutaneous injections.
  • a composition containing the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof may also be administered nasally, for example by sprays, aerosols, nebulized solutions and/or powders. Metered dose systems known to those in the art may also be used.
  • compositions of the novel piperazine compound of the present invention may be administered to the buccal cavity (for example, sublingually) in known pharmaceutical forms for such administration, such as slow dissolving tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/or powders.
  • compositions containing the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, for topical administration may comprise a matrix in which the pharmacologically active compound is dispersed such that it is held in contact with the skin in order to administer the compound transdermally.
  • a suitable transdermal composition may be prepared by mixing the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, for example paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
  • novel piperazine compound of the present invention may be dispersed in a pharmaceutically acceptable cream or ointment base.
  • the amount of the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, contained in a topical formulation should be such that a therapeutically effective amount delivered during the period of time for which the topical formulation is intended to be on the skin.
  • novel piperazine compound of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the novel piperazine compounds of the present invention, or a pharmaceutically acceptable salt thereof, to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
  • the amount the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, present in an internal source should be such that a therapeutically effective amount is delivered over a long period of time.
  • an injectable solution of the novel piperazine compound of the present invention can contain various additives such as preservatives, such as benzyl alcohol, methyl or propyl 4-hydroxybenzoate,
  • benzalkonium chloride phenylmercury borate and the like; as well as antioxidants, such as ascorbic acid, tocopherol, sodium pyrosulfate and optionally complex forming agents, such as an ethylenediamine tetraacetate salt for binding the metal traces, as well as buffers for adjusting the pH value and optionally a local anaesthetizing agent, e.g. lidocaine.
  • the injectable solution containing the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof is filtered before filling into the ampule and sterilized after filling.
  • novel piperazine compounds and methods of using the same are carried out with one or more of the novel piperazene compounds and optionally with certain excipients.
  • the excipients are selected to ensure the delivery of a consistent amount of the said compound and to maintain plasma levels of the said compound in a convenient unit dosage form and to optimize the dosing for the particular cardiac arrhythmia occurrence. All excipients must be inert, organoleptically acceptable, and compatible with vanoxerine metabolites.
  • excipients used in a solid oral formulation commonly include fillers or diluents, binders, disintegrants, lubricants, antiadherents, glidants, wetting and surface active agents, colors and pigments, flavoring agents, sweeteners, adsorbents, and taste-maskers.
  • Diluents may advantageously be added to a small amount of the active drug to increase the size of the tablet.
  • a suitable diluent for use in the inventive compositions is lactose, which exists in two isomeric forms, alpha-lactose or beta-lactose, and can be either crystalline or amorphous.
  • lactose include spray dried lactose monohydrate (such as Super- TabTM), alpha-lactose monohydrate (such as Fast Flo®), anhydrous alpha-lactose, anhydrous beta-lactose, and agglomerated lactose.
  • diluents include sugars, such as compressible sugar NF, dextrose excipient NF, and dextrates NF.
  • a preferred diluent is lactose monohydrate (such as Fast Flo®).
  • Other preferred diluents include microcrystalline cellulose (such as Avicel® PH, and CeolusTM), and microfine cellulose (such as Elcema®).
  • Suitable diluents also include starch and starch derivatives.
  • Starches include native starches obtained from wheat, corn, rice and potatoes. Other starches include
  • pregelatinized starch NF and sodium starch glycolate NF.
  • Starches and starch derivatives can also function as disintegrants.
  • Other diluents include inorganic salts, including, but not limited to, dibasic calcium phosphate USP (such as Di-Tab® and Emcompress®), tribasic calcium phosphate NF (such as Tri-Tab® and Tri-Cafos®), and calcium sulfate NF (such as
  • Polyols such as mannitol, sorbitol, and xylitol may also serve as diluents. Many diluents can also function both as disintegrants and as binders, and these additional properties should be taken into account when developing particular formulations.
  • Disintegrants may be included to break larger particles, such as tablets, granules, beads, nonpareils and/or dragees, into smaller particles comprising the active pharmaceutical ingredient and, optionally, other excipients which may facilitate dissolution of the active ingredient and/or enhance bioavailability of the active ingredient.
  • Starch and starch derivatives including cross-linked sodium salt of a carboxymethyl ether of starch (such as sodium starch glycolate NF, Explotab®, and Primogel®) are useful disintegrants.
  • a preferred disintegrant is cross-linked sodium carboxymethyl cellulose (such as Croscarmellose Sodium NF, Ac-Di- Sol®).
  • Other suitable disintegrants include, but are not limited to, cross-linked
  • polyvinylpyrrolidone such as Crospovidone NF
  • microcrystalline cellulose such as Avicel® PH
  • Binders may also be used as an excipient, particularly during wet granulation processes, to agglomerate the active pharmaceutical ingredient and the other excipients.
  • a particular binder is generally selected to improve powder flow and/or to improve compactibility.
  • Suitable binders include, but are not limited to, cellulose derivatives, such as microcrystalline cellulose NF, methylcellulose USP, carboxymethycellulose sodium USP, hydroxypropyl methylcellulose USP, hydroxyethyl cellulose NF, and hydroxypropyl cellulose NF.
  • binders include polyvidone, polyvinyl pyrrolidone, gelatin NF, natural gums (such as acacia, tragacanth, guar, and pectin), starch paste, pregelatinized starch NF, sucrose NF, corn syrup, polyethylene glycols, sodium alginate, ammonium calcium alginate, magnesium aluminum silicate and polyethylene glycols.
  • Lubricants may be used, particularly in tablet formulations, to prevent sticking of the ingredients and/or dosage form to the punch faces and to reduce friction during the compression stages.
  • Suitable lubricants include, but are not limited to, vegetable oils (such as corn oil), mineral oils, polyethylene glycols (such as PEG-4000 and PEG-6000), salts of stearic acid (such as calcium stearate and sodium stearyl fumarate), mineral salts (such as talc), inorganic salts (such as sodium chloride), organic salts (such as sodium benzoate, sodium acetate, and sodium oleate) and polyvinyl alcohols.
  • a preferred lubricant is magnesium stearate.
  • a novel piperazine compound generally comprises from about 20-50% by weight of the pharmaceutical composition, more preferably from about 25-40% and most preferably from about 30-35%.
  • suitable amounts of each excipient may be determined by one skilled in the art considering such factors as the particular mode of administration (e.g. oral, sublingual, buccal, etc.), amount of active ingredient (e.g. 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200mg, 400mg, etc.), particular patient (e.g. adult human, human child, etc.) and dosing regimen (e.g. once a day, twice a day, etc.).
  • Solid dosage forms of a novel piperazine compound can be prepared using any of the methods and techniques known and available to those skilled in the art.
  • Example 1 28 patients participated in a study of vanoxerine. 25 patients took a
  • a total of 270 human plasma samples were received (in duplicate). The samples were shipped frozen over dry ice. The samples were stored at -70°C (nominal) until analysis.
  • vanoxerine and 17-hydroxyl vanoxerine concentrations in human plasma samples were performed against their respective calibration curve within concentration range of 1 to 250 ng/mL.
  • the content determination of 16-hydroxyl vanoxerine and all other hydroxyl metabolites in human plasma samples was performed against 17-hydroxyl vanoxerine calibration curve within concentration range of 1 to 250 ng/mL.
  • Frozen samples were thawed at room temperature.
  • Samples, calibrators, QC samples, sample blanks (blank plasma) and reagent blanks (water) were processed at room temperature.
  • To 200 ⁇ ⁇ aliquots of each sample, calibrator, and QC sample are added 20 ⁇ ⁇ of 500 ng/mL of internal standard solution.
  • a sample blank (blank plasma) and reagent blank (water) were also prepared, but without addition of internal standard solution (20 ⁇ ⁇ of diluent was added instead).
  • 200 ⁇ L ⁇ of 1% ammonium hydroxide solution were added and vortex mixed. 3.0 mL of methyl tert-butyl ether were added and then vortex mix for 30 seconds.
  • the sample is then centrifuged for 5 minutes at 4000 rpm and then transferred for about 30 minutes at -70°C (nominal).
  • the upper (organic) layer was transferred into an evaporation tubes and then evaporated under N 2 stream at ⁇ 50°C for about 20 min.
  • Samples were then reconstituted in 1000 ⁇ ⁇ reconstitution solution (80:20:0.1 water: acetonitrile: formic acid). Samples were mixed, allow to stand for about 3 minutes and mixed again.
  • 900 ⁇ ⁇ of the sample solution was transferred to a 1.5 mL microcentrifuge tube and centrifuged for 5 minutes at 14000 rpm at room temperature.
  • 800 ⁇ ⁇ of the sample solution was transferred to a glass autosampler vial, and then transferred to the autosampler for analysis. Samples were separated using reversed-phase liquid chromatography with a C18 column.
  • Chromatographic conditions were as follows:
  • HPLC instrument Waters Alliance e2795 HT with temperature controlled autosampler
  • Mobile phase B 10 mM ammonium formate buffer: MeOH: ACN 5:50:45
  • Purge solvent Water: ACN: formic acid 50:50:0.1
  • Wash solvent Water: ACN: formic acid 50:50:0.1
  • Injection volume 20 ⁇ .
  • Detection was based on electro-spray interface in positive mode (ESI+) LC-
  • MRM transitions for vanoxerine, 17-hydroxyl vanoxerine (M01) and for internal standard were m/z 451 ⁇ 203, 467 ⁇ 203 and 433 ⁇ 185 respectively.
  • the MRM transition for all hydroxyl metabolites was m/z 467— > 203.
  • Calibration curve standards and QC samples were prepared by spiking vanoxerine, 17-hydroxyl vanoxerine and 16-hydroxyl vanoxerine into blank human plasma (with K 2 EDTA as anticoagulant).
  • Calibration standards nominal concentrations of 1, 2, 10, 50, 100, 200 and 250 ng/mL and QC samples nominal concentrations of 3, 20, 125 and 187.5 were prepared for each analyte.
  • Table 2 shows the standard deviations from the above 25 patients receiving vanoxerine. The three patients receiving a placebo are not included in the data and all data points indicated levels of vanoxerine below the lower limit of quantitation.
  • Tables 1 and 2 show tests of 25 patients with a 300 mg dose of vanoxerine. Blood was drawn from each of the test patients before the administration of the vanoxerine, and then at 9 additional time points, one half hour after administration, then 1, 2, 3, 4, 6, 8, 12, and 24 hours subsequent to administration. A quantity of (1) represents an amount that was below the lower limit of quantitation, which is ⁇ 1.139 ng/ml vanoxerine, and ⁇ 1.1141 ng/ml 17-hydroxyl vanoxerine.
  • the low group barely has plasma levels rise above 40 ng/ml at any time point in reference to vanoxerine.
  • the high group has levels that rise to nearly 200 ng/ml at a time of two (2) hours after administration.
  • the variability with regard to each of the groups is also wider in the high group average.
  • the standard deviations in Table 4 are lower than those in Table 6, (no T-test or 95% confidence was run), that the variability was greater in the high group than the low group.
  • Modulation of a dose provides for greater accuracy with regard to target plasma concentrations for the treatment of dopaminergic diseases. Utilization of certain methods allows for appropriate modulation of Cma X and tmax such that variability is minimized with patients. Furthermore, certain additional inhibitors may be advantageously utilized to improve first pass metabolism or bioavailability, such as P450 inhibitors. Furthermore, use of food modification, may, in certain instances provide additional consistency with regard to administration of piperazine compounds. Therefore, the methods provided for herein, provide for greater accuracy with regard to target physiological levels, thus increasing the safety profile, improving efficacy of treatment, and minimizing side effects that may be associated with treatment.
  • the metabolites M01, M02, M03, M04, and M05 represent compounds naturally broken down in the metabolism of vanoxerine. What is evident with regard to the tables, is the large standard deviations with regard to vanoxerine and certain of the metabolites. Accordingly, the ability to particularly tailor the administration of a specific metabolite that was not, heretofore identified in the literature, provides novel approaches to treatment of certain dopaminergic diseases.
  • the metabolites M01, M02, M03, M04, and M05 include the basic structure of the vanoxerine compound but for certain modifications.
  • the body breaks down the vanoxerine and processes it into a number of different metabolites, which vary in concentration based on the particular individual. Certain methods may therefore advantageously utilize one or more of the metabolites for treatment of dopaminergic diseases. Accordingly, methods of administration of the same are useful for such treatments.
  • concentrations in the plasma for one or more of the metabolites is between 1 and 1000 ng/ml at a time point of between 0 and 24 hours post administration of the piperazine compound.
  • the concentration is between 10 and 400 ng/ml, or 20 and 200 ng/ml, or 40 and 150 ng/ml, or 60 and 120 ng/ml at 0-24 hours post administration. Furthermore, it is suitable to maintain these concentrations over the course of a day, more than a day, a week, or longer, wherein the concentration is measured as the mean area under the curve, which changes over time due to pharmacokinetic metabolism, based on the intake and the elimination of the drug via bodily mechanisms. Accordingly, methods of administration of such metabolites to achieve and maintain such concentrations are necessary for the treatment of dopaminergic diseases as described herein.

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Abstract

Des modes de réalisation de la présente invention concernent des compositions comprenant de nouveaux composés de pipérazine appropriés pour être administrés à un mammifère pour le traitement de maladies dopaminergiques, et des méthodes d'administration de celles-ci.
PCT/US2014/065943 2013-11-15 2014-11-17 Nouveaux métabolites de composés de vanoxérine pour le traitement de maladies dopaminergiques Ceased WO2015073967A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022031407A1 (fr) * 2020-08-03 2022-02-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Ligands gpr101 pour le traitement de troubles liés à l'hormone de croissance
ES2920173A1 (es) * 2021-01-28 2022-08-01 Consejo Superior Investigacion Antimicrobianos frente a patogenos del genero streptococcus

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099148A1 (fr) * 1982-06-29 1984-01-25 Gist-Brocades N.V. Dérivés de pipérazine, leurs procédés de préparation en compositions pharmaceutiques les contenant
WO1998018769A1 (fr) * 1996-10-31 1998-05-07 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives a liberation prolongee d'analogues hydroxyles de 1-[2[bis(aryl)methoxy]ethyl]-piperazines et -homopiperazines substituees et leur utilisation comme antagonistes non competitifs du recaptage de la dopamine
US6835371B1 (en) * 1997-09-12 2004-12-28 David R. Elmaleh Diagnostic and therapeutic piperazine and piperidine compounds and process

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099148A1 (fr) * 1982-06-29 1984-01-25 Gist-Brocades N.V. Dérivés de pipérazine, leurs procédés de préparation en compositions pharmaceutiques les contenant
WO1998018769A1 (fr) * 1996-10-31 1998-05-07 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives a liberation prolongee d'analogues hydroxyles de 1-[2[bis(aryl)methoxy]ethyl]-piperazines et -homopiperazines substituees et leur utilisation comme antagonistes non competitifs du recaptage de la dopamine
US6835371B1 (en) * 1997-09-12 2004-12-28 David R. Elmaleh Diagnostic and therapeutic piperazine and piperidine compounds and process

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022031407A1 (fr) * 2020-08-03 2022-02-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Ligands gpr101 pour le traitement de troubles liés à l'hormone de croissance
ES2920173A1 (es) * 2021-01-28 2022-08-01 Consejo Superior Investigacion Antimicrobianos frente a patogenos del genero streptococcus
WO2022162265A1 (fr) * 2021-01-28 2022-08-04 Consejo Superior De Investigaciones Científicas (Csic) Antimicrobiens dirigés contre des pathogènes du genre streptocoque

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