WO2014059346A1

WO2014059346A1 - Methods for the treatment of conditions involving dopamine through administration of piperazine compounds

Info

Publication number: WO2014059346A1
Application number: PCT/US2013/064650
Authority: WO
Inventors: Arthur M. Brown
Original assignee: Brown Arthur M
Priority date: 2012-10-11
Filing date: 2013-10-11
Publication date: 2014-04-17

Abstract

Disclosed embodiments are related to pharmaceutical compositions and methods for preventing or treating conditions involving dopamine, such as Parkinson's disease, comprising administering to a mammal in need thereof, an effective amount of a vanoxerine metabolite.

Description

METHODS FOR THE TREATMENT OF CONDITIONS INVOLVING DOPAMINE THROUGH ADMINISTRATION OF PIPERAZINE COMPOUNDS

FIELD OF INVENTION

[0001] The present application is generally related to pharmaceutical compositions and methods for preventing or treating conditions involving dopamine, such as Parkinson's disease, comprising administering to a mammal in need thereof, an effective amount of a vanoxerine metabolite.

BACKGROUND OF THE INVENTION

[0002] 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.

[0003] 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.

[0004] 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).

[0005] 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).

[0006] 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.

[0007] 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.

[0008] 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.

[0009] 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 OF THE INVENTION

[0010] In accordance with these and other objects, a first embodiment of the present invention comprises a piperazine compound having the following structure:

which is suitable for administration to mammals for treatment of certain dopaminergic diseases.

[0011] 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.

[0012] 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. [0013] 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.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 is a drawing of the novel piperazine compound described herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The embodiments of the invention and the various features and advantages thereto are more fully explained with references to the non-limiting embodiments and examples that are described and set forth in the following descriptions of those examples. Descriptions of well- known components and techniques may be omitted to avoid obscuring the invention. The examples used herein are intended merely to facilitate an understanding of ways in which the invention may be practiced and to further enable those skilled in the art to practice the invention. Accordingly, the examples and embodiments set forth herein should not be construed as limiting the scope of the invention, which is defined by the appended claims.

[0016] As used herein, terms such as "a," "an," and "the" include singular and plural referents unless the context clearly demands otherwise. [0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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, nebulised solutions and/or powders. Metered dose systems known to those in the art may also be used.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] Having now fully described this invention, it will be understood to those of ordinary skill in the art that the methods of the present invention can be carried out with a wide and equivalent range of conditions, formulations, and other parameters without departing from the scope of the invention or any embodiments thereof.

[0036] 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.

Claims

What is claimed is:

1. A piperazine compound having the following structure:

which is suitable for administration to a mammal for treatment of dopaminergic diseases.

2. The piperazine compound of claim 1 in further comprising an admixture with one or more pharmaceutically acceptable excipients.

3. The piperazine compound of claim 2 further wherein the pharmaceutically acceptable excipients include a diluent, a disintegrating agent, and a lubricating agent.

4. The piperazine compound of claim 3 further comprising an enteric coating.

5. A method for treatment of certain diseases having abnormal dopaminergic activity, comprising administering an effective amount of a pharmaceutical piperazine compound having the structure:

to a mammal.

6. The method of claim 5 further comprising administering the pharmaceutical piperazine compound in admixture with a pharmaceutically acceptable carrier.

7. The method according to claim 5, wherein said mammal is a human.

8. The method of claim 5 wherein the treatment of certain diseases having dopaminergic activity consists of the treatment of Parkinson's, galactorrhea, excessive puerperal lactation, hypogonadism, and acromegaly.

9. A method for preventing recurrence of an episode of certain diseases having dopaminergic activity in a mammal by administering an effective amount of the following compound:

to that mammal.

10. The method according to claim 9 further comprising administering the compound in admixture with a pharmaceutically acceptable carrier.

11. The method according to claim 9, wherein said mammal is a human.

12. The method of claim 9 wherein the treatment of certain diseases having dopaminergic activity consists of the treatment of Parkinson's, galactorrhea, excessive puerperal lactation, hypogonadism, and acromegaly.