WO2014059346A1 - Procédés de traitement d'états impliquant la dopamine par l'administration de composés de pipérazine - Google Patents

Procédés de traitement d'états impliquant la dopamine par l'administration de composés de pipérazine Download PDF

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Publication number
WO2014059346A1
WO2014059346A1 PCT/US2013/064650 US2013064650W WO2014059346A1 WO 2014059346 A1 WO2014059346 A1 WO 2014059346A1 US 2013064650 W US2013064650 W US 2013064650W WO 2014059346 A1 WO2014059346 A1 WO 2014059346A1
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WO
WIPO (PCT)
Prior art keywords
treatment
pharmaceutically acceptable
compound
piperazine compound
mammal
Prior art date
Application number
PCT/US2013/064650
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English (en)
Inventor
Arthur M. Brown
Original Assignee
Brown Arthur M
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Brown Arthur M filed Critical Brown Arthur M
Publication of WO2014059346A1 publication Critical patent/WO2014059346A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • 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
    • C07D295/092—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 with aromatic radicals attached to the chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • 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.
  • 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.
  • 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.
  • a first embodiment of the present invention comprises a piperazine compound having the following structure:
  • 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, hypogonadism, and acromegaly by administering an effective amount of a pharmaceutical piperazine compound as identified in the paragraph above.
  • FIG. 1 is a drawing of the novel piperazine compound described herein.
  • 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.
  • 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.
  • 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 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.
  • 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 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.
  • 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.
  • 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 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.
  • 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.
  • 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, 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.

Abstract

Les modes de réalisation divulgués de l'invention se rapportent à des compositions pharmaceutiques et à des procédés de prévention ou de traitement d'états impliquant la dopamine, tels que la maladie de Parkinson, comprenant l'administration à un mammifère en ayant besoin, d'une quantité efficace d'un métabolite de vanoxérine.
PCT/US2013/064650 2012-10-11 2013-10-11 Procédés de traitement d'états impliquant la dopamine par l'administration de composés de pipérazine WO2014059346A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201261712620P 2012-10-11 2012-10-11
US61/712,620 2012-10-11
US201361794151P 2013-03-15 2013-03-15
US61/794,151 2013-03-15

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WO2014059346A1 true WO2014059346A1 (fr) 2014-04-17

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Cited By (1)

* 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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476129A (en) * 1982-06-29 1984-10-09 Gist-Brocades N.V. 4-[2-[Bis(halophenyl)methoxy]-ethyl]-α-(substituted phenyl)-1-piperazinealkanol derivatives, processes for their preparation and pharmaceutical preparations containing them
WO1991001732A1 (fr) * 1989-08-03 1991-02-21 The United States Of America, Represented By The Secretary, United States Department Of Commerce Inhibiteurs de reabsorption de dopamine, serotonine ou norepinephrine de dissociation lente (liaison etroite) pris comme antagonistes de la cocaine, l'amphetamine et la phenecyclidine
US6387389B1 (en) * 1996-10-31 2002-05-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines and their use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476129A (en) * 1982-06-29 1984-10-09 Gist-Brocades N.V. 4-[2-[Bis(halophenyl)methoxy]-ethyl]-α-(substituted phenyl)-1-piperazinealkanol derivatives, processes for their preparation and pharmaceutical preparations containing them
WO1991001732A1 (fr) * 1989-08-03 1991-02-21 The United States Of America, Represented By The Secretary, United States Department Of Commerce Inhibiteurs de reabsorption de dopamine, serotonine ou norepinephrine de dissociation lente (liaison etroite) pris comme antagonistes de la cocaine, l'amphetamine et la phenecyclidine
US6387389B1 (en) * 1996-10-31 2002-05-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines and their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MATTHEW J. HANSARD ET AL.: "Dopamine reuptake inhibition and failure to evoke dyskinesia in MPTP-treated primates", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 451, no. 2, 2002, pages 157 - 160 *

Cited By (1)

* 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

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