NOVEL METABOLITES OF VANOXERINE COMPOUNDS FOR

THE TREATMENT OF DOPAMINERGIC DISEASES

FIELD OF THE INVENTION

[0001] Presently disclosed embodiments are related to novel piperazine compounds, pharmaceutical compositions comprising the same and methods for treating dopaminergic diseases in mammals.

BACKGROUND

[0002] 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

243,903 and PCT International Application WO 91/01732, each of which is incorporated herein by reference in its entirety.

[0003] 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.

[0004] 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. (See U.S. Patent No. 6,743,797 and U.S. Patent No. 7,700,600.) [0005] Numerous studies of vanoxerine compounds have been undertaken in various models where they have proven to be among the most potent and selective DA reuptake inhibitors. Van der Zee, P. et al., Eur. J. Med. Chem. 1980 15:363-370; Anderson, P.H, J.

Neuro-chem 1987, 48: 1887-1896. For instance, the re-uptake process was studied because of the inactivation of neurotransmitters, like dopamine, which are released into the synaptic cleft by nervous impulses. These studies show that the inhibition of the dopamine uptake may lead to increased concentration of dopamine in the synaptic cleft and potentiation of the dopamine effect on the post-synaptic receptor. This inhibition was studied in in vitro models by incubation of synaptosomes of the corpus striatum of the rat as described by P. Van der Zee and W. Hespe, Neruopharmacol 17:483-490 (1978).

[0006] Similarly, affinity to dopamine receptors has been described in publications, including D.R. Burt et al. Mol. Pharmacol., 12, 800-812 (1976), describing the affinity of the piperazine compounds to the dopamine receptors in a membrane fraction of the corpus striatum of the rat. Stereotypy tests in the rat after administration of central active dopaminergic substances are regarded as a relevant test. Studies have shown that the dopaminergic D-2 receptors, the stimulation of which is the cause of stereotypy, are also the dopamine receptors showing insufficient activity in Parkinson's disease, for instance in M. Schachter c.s., Nature,

286, 158-159 (1980).

[0007] Furthermore, tests in rat studies have utilized the protective capability of these compounds against l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine (MPTP). In 1979 it was reported that MPTP causes degeneration of the dopaminergic system in man. Davis et al.

Psychiat. Res. 1, 249 (1979); Burns et al. Proc. Natl. Acad. Sci 80; 4546 (1983). The selective damaging effects of MPTP on the dopaminergic system is analogous to any number of damaging diseases on the human or animal dopaminergic system, and thus provides a suitable test vehicle for investigating compounds. Accordingly, in U.S. 4,874,765, numerous tests were performed on male CFY mice to test various piperazine derivatives. The data from U.S. 4,874,765 showed that piperazine compounds, administered orally and/or intraperitoneally to animals before treatment with MPTP significantly inhibited the neurotoxic dopamine depleting activity of the MPTP compound and that the piperazine compounds further possessed low toxicity. [0008] Additional studies, including those forming the basis of U.S. Patent No. 4,476,129 studied the stereotypy in rat. The tests were carried out with female Wistar rats under conditions with a low level of stimuli. U.S. 4,476,129 studied at least 19 compounds and recorded behaviors at 15, 30, 60, 120, 180, 240, and 300 minutes after administration of a piperazine substance. Furthermore, the study looked at the dopamine and haloperidol receptor binding. It was determined that piperazine compounds had strong affinity for binding to dopamine receptors.

[0009] U.S. Patent No. 4,202,896 described other piperazine compounds and looked at dosing various compounds for Parkinsonism, acromegaly, and prolactin induced disorders.

These different disorders received doses of 50-200 mg per day for human adults for

Parkinsonism, 20-40 mg for acromegaly, and 5-25 mg for prolactin-induced disorders.

[0010] Certain compounds known for impacting the dopaminergic system including most currently available Class III anti- arrhythmic agents is that their effect increases or becomes more manifest at or during bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia. On the other hand, during tachycardia or the conditions for which these agents or drugs are intended and most needed, they lose most of their effect. This loss or diminishment of effect at fast heart rates has been termed "reverse use-dependence" (Hondeghem and Snyders, "Class III antiarrhythmic agents have a lot of potential but a long way to go: Reduced

effectiveness and dangers of reverse use dependence," Circulation, 81:686-690 (1990); Sadanaga et ah, "Clinical evaluation of the use-dependent QRS prolongation and the reverse use-dependent QT prolongation of class III anti- arrhythmic agents and their value in predicting efficacy," Amer. Heart Journal 126: 114-121 (1993)), or "reverse rate-dependence" (Bretano, "Rate dependence of class III actions in the heart," Fundam. Clin. Pharmacol. 7:51-59 (1993); Jurkiewicz and Sanguinetti, "Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III anti-arrhythmic agent: Specific block of rapidly activating delayed rectifier K+current by dofetilide," Circ. Res. 72:75-83 (1993)). Thus, an agent that has a use-dependent or rate- dependent profile, opposite that possessed by most current class III anti- arrhythmic agents, should provide not only improved safety but also enhanced efficacy.

[0011] With particular regard to 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). However, 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. also recognized that there were unexpected fluctuations in serum concentrations with regard to these healthy patients. While they did not determine the reasoning, control of such fluctuations may be important to treatment of patients. Studies have also looked at the ability of food to lower the first-pass metabolism of lipophilic basic drugs, such as vanoxerine. S.H. Ingwersen, et al. "Food intake increases the relative oral bioavailability of vanoxerine" Br. J. Clin. Pharmac; 35:308-130 (1993).

[0012] There is a need for new piperazine compounds, pharmaceutical compositions comprising the same, and methods of using the piperazine compound and pharmaceutical compositions for treatment of dopaminergic diseases.

SUMMARY

[0013] In accordance with these and other objects, a first embodiment of the disclosure comprises a piperazine compound having the following structure:

[0014] Wherein 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.

[0015] 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.

[0016] Further embodiments of the disclosure comprise pharmaceutical 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.

[0017] 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.

[0018] 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,

hypogonadism, and acromegaly by administering an effective amount of a pharmaceutical piperazine compound as identified in the paragraph above.

[0019] Additional advantages, objects and feature of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objects and advantages of the invention may be realized and attained as particularly pointed out in the appended claims.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0020] All references cited herein are hereby incorporated by reference in their entirety. [0021] As used herein, the term "about" is intended to encompass a range of values

+10% of the specified value(s). For example, the phrase "about 20" is intended to encompass +10% of 20, i.e. from 18 to 22, inclusive.

[0022] As used herein, the terms "vanoxerine metabolite" or "novel piperazine compounds" refer to the vanoxerine metabolites as described herein and pharmaceutically acceptable salts thereof.

[0023] As used herein, the term "pharmaceutically acceptable" refers to those

compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of and/or for consumption by human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.

[0024] As used herein, 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.

[0025] As used herein, "therapeutically 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. The term "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.

[0026] As used herein, "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

pharmaceutically acceptable composition comprising a vanoxerine metabolite.

[0027] As used herein, "administering" or "administer" refers to the actions of a medical processional or caregiver, or alternatively self-administration by the patient. [0028] 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.

[0029] Some piperazine compounds, including vanoxerine, are susceptible to metabolism by numerous mechanisms, including P450 and hepatic metabolism. In addition to metabolic processes, 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.

Ingwersen, et al., "Food intake increases the relative oral bioavailability of vanoxerine," Br. J. Clin. Pharmac 35:308-310 (1993). Furthermore, patients not only have different profiles with regard to metabolic variability of vanoxerine and metabolites, but also with regard to Cmax and tmax- Accordingly, in view of the potential for variability within patients and within the patient population as a whole, it is necessary and advantageous to provide methods for administration of novel piperazine compounds to a mammal that may minimize the variability or downstream metabolism of certain compounds.

[0030] Accordingly, the following structure identifies novel compounds for

administration to a mammal for treatment of dopaminergic diseases:

[0031] Wherein 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. Because of the nature of the molecule, R4 and R4' for example, are chemically equivalent, only one of R4 and R4' is a hydroxyl and the other being a hydrogen. Similarly, 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.

[0032] In a particularly preferred embodiment, one of R4/R4', R5/R5', R6/R6', R7/R7', or R8 is a hydroxyl.

[0033] The compositions described herein may be suitable for administration to patients to treat dopaminergic disease. For example, when providing treatment for patients, in some embodiments, 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. However, in other

embodiments, it is important to maintain a plasma concentration of one of more of the novel piperazine compounds for a given time period. For example, it is advantageous to maintain a plasma level within the range of about 5 to 400 ng/ml of one or more of the piperazine compounds for a period of about 1 to about 24 hours. Maintenance of the increased plasma concentration may require the administration of multiple doses over 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.

[0034] However, in other embodiments, it is important to maintain a plasma

concentration of one of more of the novel piperazine compounds for a given time period, as measured by the mean concentration AUC. For example, it is advantageous to maintain a plasma level within the range of about 5 to about 400 ng/ml of one or more of the piperazine compounds for a period of about 1 to about 24 hours. Doing so may require the administration of multiple doses over 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 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.

[0035] In some embodiments, e.g. for the treatment of adult humans, a dosage of 1 mg to

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.

[0036] 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. Alternatively, 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.

[0037] Additionally, modification of Cmax and tmax is appropriate to maintain consistent plasma level concentrations of one or more novel piperazine compounds. Cmax taken at a time point of 1 hour post administration are about 10 to about 200 ng/ml. In alternative embodiments, 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. Conversely tmax is appropriately reached at about 1 hour post administration. In other embodiments, t^ is appropriately reached at about 30 minutes, or about 90 minutes, or about 120 minutes, or about 240 minutes post administration. [0038] The novel piperazine compounds of the present invention and the

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. For example, with respect to pharmaceutically acceptable slats, generally, 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.

[0039] Pharmaceutically acceptable salts of the novel piperazine compound may also be employed in the methods of the present invention. These 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.

[0040] 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

accordance with the method allow for the administration of the novel piperazine compound in an appropriate amount to provide an efficacious level of the compound in the blood stream or in other target tissues.

[0041] 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.

[0042] For oral administration, 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. For example, 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.

[0043] 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

pharmaceutically acceptable salt thereof. 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.

[0044] Tablets may also be prepared by wet granulation and subsequent compression. A mixture containing the novel piperazine compound of the present invention, or a

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.

Thereafter, other 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.

[0045] 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.

[0046] For the preparation of capsules or caplets, 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. The contents of a capsule and/or caplet may also be formulated using known methods to give sustained release of the active compound.

[0047] 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.

[0048] For rectal administration, 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. In addition to the active ingredient, 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.

[0049] For parenteral administration, 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. For the preparation of injectable solutions or suspensions, 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. These solutions or suspension may be prepared from sterile powders or granules having one or more carriers or diluents mentioned for use in the formulations for oral administration. Parenteral administration may be through intravenous, intradermal, intramuscular or subcutaneous injections. [0050] 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.

[0051] Pharmaceutical compositions of the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, 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.

[0052] 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.

[0053] Alternatively, the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, 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.

[0054] The novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, 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.

[0055] In addition, an injectable solution of the novel piperazine compound of the present invention, or a pharmaceutically acceptable salt thereof, 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.

[0056] The 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. The 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.

[0057] 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. Various types of lactose include spray dried lactose monohydrate (such as Super- Tab™), alpha-lactose monohydrate (such as Fast Flo®), anhydrous alpha-lactose, anhydrous beta-lactose, and agglomerated lactose. Other 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 Ceolus™), and microfine cellulose (such as Elcema®).

[0058] 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

Compactrol®). 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.

[0059] 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) and microcrystalline cellulose (such as Avicel® PH).

[0060] Binders may also be used as an excipient, particularly during wet granulation processes, to agglomerate the active pharmaceutical ingredient and the other excipients. In all formulation, whether prepared by wet or dry granulation, 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. Other suitable 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.

[0061] 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.

[0062] In preferred embodiments, 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%. Furthermore, 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.).

[0063] 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.

[0064] All patents and publications cited herein are hereby fully incorporated by reference in their entirety. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that such publication is prior art or that the present invention is not entitled to antedate such publication by virtue of prior invention. Examples

[0065] The materials, methods, and examples presented herein are intended to be illustrative, and not to be construed as limiting the scope or content of the invention. Unless otherwise defined, all technical and scientific terms are intended to have their art-recognized meanings.

[0066] Example 1: 28 patients participated in a study of vanoxerine. 25 patients took a

300 mg dose of vanoxerine and 3 patients took a placebo. Each patient gave samples before administration of their dose, and then again at nine further time points, 30 minutes after admiration, 1, 2, 3, 4, 6, 8, 12, and 24 hours post administration.

[0067] The study attempted to identify new metabolites of vanoxerine, as described herein, their concentrations in the body and to determine whether some of these novel metabolites may be suitably used in new compositions for treatment of dopaminergic disease. In particular, in view of the possibility for widespread variance of certain metabolites, the ability to target particular compounds and to administer these compounds may lead to more efficacious treatments and reduce side effects from administration of broader compounds that have additional metabolic breakdown in the body.

[0068] Samples:

[0069] 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.

[0070] Method of analysis outlines:

[0071] Determination of vanoxerine and 17-hydroxyl vanoxerine concentrations in human plasma samples was 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.

[0072] 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 μΐ _^ aliquots of each sample, calibrator, and QC sample are added 20 μΐ _^ 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 μΐ _^ of diluent was added instead). To each sample, 200 μL· 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 μΐ _^ reconstitution solution (80:20:0.1 water: acetonitrile: formic acid). Samples were mixed, allow to stand for about 3 minutes and mixed again. 900 μΐ _^ 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 μΐ _^ 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.

[0073] Chromatographic conditions were as follows:

[0074] HPLC instrument: Waters Alliance e2795 HT with temperature controlled autosampler

[0075] Column: Waters XBridge C18 3.5μ 100 x 2.1 mm P.N. 186003022,

Lot No. 0143302711 with an appropriate guard column

[0076] Column temperature: 45°C

[0077] Autosampler temp: 5°C

[0078] Flow: 0.3 mL/min

[0079] Mobile phase A: 10 mM ammonium formate buffer: MeOH: ACN

80: 10: 10

[0080] Mobile phase B: 10 mM ammonium formate buffer: MeOH: ACN 5:50:45

[0081] Purge solvent: Water: ACN: formic acid 50:50:0.1 [0082] Wash solvent: Water: ACN: formic acid 50:50:0.1

[0083] Injection volume: 20 μΐ.

[0084] Run Time: 15 minutes

[0085] Gradient table:

[0086] Detection was based on electro-spray interface in positive mode (ESI+) LC-

MS/MS technique, using Micromass Quattro Premier XE MS/MS detector with MassLynx and QuanLynx software version 4.1. 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.

[0087] 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).

[0088] 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.

[0089] Results:

[0090] The identification of the metabolites was as follows:

[0091] Table 1: Concentrations ng/ml

[0092] Table 2: Standard Deviations

[0093] 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.

3 80.40 5.40 49.04 13.63 0.07 2.31 64.45

4 55.01 5.32 39.75 11.31 0.04 1.16 52.50

6 35.74 5.10 31.30 7.90 0.00 0.87 41.84

8 30.37 4.05 25.29 6.74 0.00 0.94 33.41

12 24.03 3.15 17.62 4.70 0.00 0.27 23.17

24 10.34 2.11 8.91 2.76 0.00 0.03 12.31

[0094] Tables 1 and 2, above, 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.

[0095] The 25 patients fall into two categories: 15 fell into a category of having the majority of time point levels that were below the average mean (as identified in Table 1) "low group average," and the remaining 10 patients had the majority of time points above the average mean "high group average."

[0096] Table 3: Low group average:

-15 1.00 1.00 1.00 1.00 1.00 1.00 1.00

.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00

1 24.47 0.00 17.68 1.67 0.00 0.98 20.45

2 27.50 3.10 59.32 7.56 0.13 1.05 71.04

3 28.16 4.18 44.96 9.05 0.00 0.58 57.77

4 22.66 3.28 34.95 7.06 0.00 0.46 45.53

6 16.11 3.72 30.77 7.28 0.00 0.16 42.04

8 14.20 3.51 21.42 3.71 0.00 0.00 28.30

12 11.19 2.27 15.60 2.86 0.00 0.00 20.34

24 3.07 1.69 10.44 1.72 0.00 0.00 13.40

[0098] Table 5: High group average:

[0099] Table 6: High group standard deviation:

[00100] As can be seen, in Table 3 and 5, the low group barely has plasma levels rise above 40 ng/ml at any time point in reference to vanoxerine. Whereas, the high group has levels that rise to nearly 200 ng/ml at a time of two (2) hours after administration. Furthermore, 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.

[00101] 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.

[00102] 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.

[00103] 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.

[00104] Certainly, in view of the relatively low bioavailability of vanoxerine, and the fact that there are significant accumulation of metabolites in the body, it is advantageous to directly administer certain metabolites so as to increase their concentration in a patient, as opposed to indirectly administering them through administering vanoxerine and allowing the body' s metabolism to generate the metabolites through the various metabolic pathways in the body. [00105] Indeed, in preferred embodiments, 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. In particularly preferred embodiments, 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.

[00106] Although the present invention has been described in considerable detail, those skilled in the art will appreciate that numerous changes and modifications may be made to the embodiments and preferred embodiments of the invention and that such changes and

modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all equivalent variations as fall within the scope of the invention.