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WO1999034800A1 - Utilisation d'un derive de phenylthienylmethylene piperidine pour la fabrication d'un medicament destine au traitement de troubles de la mobilite - Google Patents

Utilisation d'un derive de phenylthienylmethylene piperidine pour la fabrication d'un medicament destine au traitement de troubles de la mobilite Download PDF

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Publication number
WO1999034800A1
WO1999034800A1 PCT/EP1999/000144 EP9900144W WO9934800A1 WO 1999034800 A1 WO1999034800 A1 WO 1999034800A1 EP 9900144 W EP9900144 W EP 9900144W WO 9934800 A1 WO9934800 A1 WO 9934800A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
treatment
movement disorder
movement disorders
manufacture
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1999/000144
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English (en)
Inventor
Duncan Robertson Rae
Jonathan Huw Connick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akzo Nobel NV
Original Assignee
Akzo Nobel NV
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 Akzo Nobel NV filed Critical Akzo Nobel NV
Priority to AU27165/99A priority Critical patent/AU2716599A/en
Publication of WO1999034800A1 publication Critical patent/WO1999034800A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen

Definitions

  • the present invention relates to a new medical use of a phenylthienylmethylene piperidine derivative and, in particular to a new method of treatment for movement disorders.
  • Movement disorders occur frequently and can have destructive effects on the lives of people. For example, it is established that the lifetime prevalence of Parkinson's disease is about 2 %. After head trauma about 12 % of afflicted persons will suffer from a persistent movement disorder. More than 40 % of patients in a mental hospital are additionally troubled by a movement disorder. In particular, patients treated with drugs to combat psychosis are suffering from, or are at risk of movement disorders. Drugs used in the treatment of psychosis or schizophrenia are known to induce movement disorders as side effects.
  • formula (I) which is 1-methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine; or its pharmaceutically acceptable acid addition salts or solvates thereof, for the manufacture of a medicament for the treatment or prophylaxis of movement disorders.
  • the compound as defined above and its pharmaceuticaly acceptable acid addition salts and solvates will be referred to collectively as compounds according to the present invention.
  • movement disorder refers to a syndrome or symptom, irrespective of their causation, such as akinesia, hypokinesia, (orofacial) hyperkinesia, an acute dystonic reaction, akathisia, athetosis, chorea, (hemi)ballismus, a drug induced extra-pyramidal side effect, myoclonus, muscle rigidity, a tic, tremor, (tardive) dystonia, cervical dystonia, spasmodic torticollis, tardive dyskinesia, and symptoms similar to a symptom exhibited by individuals suffering from Parkinson's disease.
  • akinesia hypokinesia, (orofacial) hyperkinesia
  • an acute dystonic reaction akathisia, athetosis, chorea, (hemi)ballismus
  • a drug induced extra-pyramidal side effect myoclonus, muscle rigidity, a tic, tremor, (tardive) dystonia
  • patients with, or at risk of, movement disorders induced as side effects of previous or ongoing use of other drugs, more specifically those used in the treatment of schizophrenia, can be treated with medicaments of this invention.
  • the present invention provides a method of treating movement disorders, preferably those with akinesia, hypokinesia or muscle rigidity, in particular when drug induced, in an animal or human, which comprises treating said animal or human with a therapeutical ly effective amount of 1 -methyl-4-[(4- chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine, or a pharmaceutically acceptable acid addition salt or solvate thereof.
  • the compounds according to the present invention have utility in treating any of the aforementioned types of movement disorders.
  • Suitable acid addition salts include hydrochloric, fumaric, maleic, methanesulfonic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation.
  • Preferred salts are those obtained with fumaric acid (in which case the compound is denoted Org 22709) and succinic acid (in which case the compound is denoted Org 23430).
  • the amount of a compound according to the present invention, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder being treated.
  • a suitable daily dose for any of the above mentioned disorders will be in the range of 0.01 - 30 mg, more usually 0.1 - 15 mg, per kg body weight of the treated person or animal.
  • treatments can be further optimised by increasing the dose up to 2-10 times in the course of a chronic treatment.
  • the desired dose may be presented as one, two, three, four or more sub-doses administered at appropriate intervals throughout the day.
  • the present invention further provides a pharmaceutical formulation for use in the treatment of movement disorders comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier thereof and optionally other therapeutic agents.
  • the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.
  • suitable carriers are various carbohydrates, gum acacia, calcium phosphate, gelatin, talc, magnesium stearate or mineral oil.
  • the invention further includes a pharmaceutical formulation as hereinbefore described, in combination with packaging material adapted for the pharmaceutical formulation, said packaging material including instructions for the use of the pharmaceutical formulation in the treatment of movement disorders.
  • Formulations include those adapted for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and epidural) administration.
  • the formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et a/., Remington's Pharmaceutical Sciences (18 th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical Preparations and their manufacture). Such methods include the process of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients, carrying out said process by exclusion of contamination with traces of pathogens and harmful chemicals.
  • Such accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents and wetting agents.
  • Formulations adapted for oral administration may be presented as discrete units such as tablets or capsules each containing a predetermined amount of active ingredient; as powder or granulates; as a solution or suspension.
  • the active ingredient may also be presented as a bolus or paste, or may be contained within liposomes or microparticles.
  • Formulations adapted for rectal administration may be presented as a suppository or enema.
  • Formulations adapted for parenteral administration include aqueous and non- aqueous sterile injection.
  • the formulations may be presented in unit-dose or multi- dose containers, for example sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
  • Formulation adapted for nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
  • Formulations may, for example, be presented in a suitable sustained release form, for example, in a device such as the MinipumpTM.
  • the compounds according to the invention may be presented for use in the form of a veterinary formulation, such formulations may be prepared by methods conventional in the art.
  • the compounds according to the present invention may be produced by various methods known in the art of organic chemistry in general. Starting materials are either known and readily available from chemical sources or may themselves be produced by conventional techniques. For example, the compounds may be synthesised using methods described in "The Chemistry of Heterocyclic Compounds” , vol 44, "Thiophene and its derivatives", parts 1-5, Ed. S. Gronowitz, J. Wiley and Sons, and in A.R. Katritsky and C.W. Rees, "Comprehensive Heterocyclic Chemistry", Part 4 Ed. C.W. Bird and G.H.Cheesman, Pergamon Press.
  • the compound of formula (I) may for instance be prepared by reacting a compound of formula (II)
  • Formula (II) with a suitable dehydrating agent for example, a mineral acid such as hydrochloric acid or by using phosphorus oxychloride.
  • a suitable dehydrating agent for example, a mineral acid such as hydrochloric acid or by using phosphorus oxychloride.
  • the reaction may be conveniently carried out using standard conditions for dehydration of an alcohol.
  • phosphorus oxychloride in the presence of a suitable solvent such as pyridine at a temperature in the range of 80 to 120 °C.
  • the compound of formula (II) may be prepared by addition of a suitable organometallic reagent, such as a Grignard reagent derived from 1 -methyl-4- chloropiperidine, to a compound of formula (III)
  • a suitable organometallic reagent such as a Grignard reagent derived from 1 -methyl-4- chloropiperidine
  • the reaction is typically carried out in the presence of an apolar aprotic solvent such as ether or tetrahydrofuran, at a temperature of -30 to 67 °C.
  • an apolar aprotic solvent such as ether or tetrahydrofuran
  • the compounds of formula (II) may also be prepared by treating the compound of formula (IV)
  • Formula (IV) with an appropriate organometallic reagent such as a Grignard, or a lithium reagent derived from a halogen-substituted benzene.
  • an appropriate organometallic reagent such as a Grignard, or a lithium reagent derived from a halogen-substituted benzene.
  • the compound of formula (II) may conveniently be prepared by treating the compound of formula (IV) with a 4- fluoro-phenyl magnesium halide using standard reaction conditions.
  • the compound of formula (III) may be prepared by methods known in the chemical literature.
  • the compound may be prepared as described in example 1 by chlorination of the 2-(4-fluorobenzoyl)thiophene.
  • the latter compound is prepared using methods known in the art, for example, by Friedel-Crafts benzoylation of the thiophene.
  • the compound of formula (III) and (IV) may be prepared by Friedel-Crafts acylation or benzoylation of 3-chloro-2-bromo-thiophene in the presence of a catalyst such as ferric chloride or aluminium chloride in an apolar solvent such as dichloromethane at a temperature in the range of 10-25 °C. Reductive de-bromination of the initially formed product gives the required compound.
  • Such reduction may be carried out by catalytic hydrogenation using a suitable catalyst such as palladium on charcoal in a suitable solvent such as ethanol or acetic acid at a temperature in the range of 15-25 °C and at a pressure of between 1 and 50 psi, or by use of activated zinc in the above mentioned solvents at a temperature in the range of 20-65 °C.
  • a suitable catalyst such as palladium on charcoal in a suitable solvent such as ethanol or acetic acid
  • any one or more of the following further steps in any order may be performed: (i) converting a salt or solvate of the compound of formula (I) into the compound of formula (I), (ii) converting a salt or solvate of the compound of formula (I) into another salt or solvate the compound of formula (I).
  • Step 1 -(4-fluorophenyl)- -(4-chioro-2-thienyl)- 1 -methyl-4-pipehdinemethanol
  • Step 2 1 -Methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-pipehdine
  • Zinc dust (1.56 g) was added to a suspension of the crude product ⁇ -(4- fluorophenyl)- ⁇ -(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol (0.78g) in sodium hydroxide solution (4N; 7.8 ml) and the mixture boiled under reflux for 2.5 h. The mixture was cooled, water (15 ml) was added and the product was extracted into dichloromethane (30 ml). The extract was washed with water (3x 30 ml), dried (Na2SO4) and evaporated to give a brown gum (0.75 g).
  • Step 3 1-Methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-pipe ⁇ dine (fumarate salt)
  • the crude material from step 2 was dissolved in methanol, a solution of fumaric acid in methanol was added and the solution was evaporated to a low volume. Ether was added and the resultant crystals were collected to give the pure title compound as a pale solid (0.71 g); m.p. 209-210 °C.
  • akinesia or hypokinesia is a movement disorder characterised by a lack of initiative to move and a resulting minimal occurrance or absence of spontaneous voluntary movements. This movement disorder is also common in Parkinson's disease and occurs as a side effect of neuroleptic drugs.
  • Akinesia or hypokinesia can be measured in rats by measuring the time it takes for a rat to correct an unusual posture.
  • Such an akinetic or hypokinetic movement disorder in rats is more commonly known in animal behavioural pharmacology as catalepsy.
  • Catalepsy can be induced in rats by treating them with a high dose of an anti-psychotic compound.
  • Rats are pretreated with chlorpromazine and then placed in unusual positions. The time it takes to correct an unusual posture is measured.
  • Young male Wistar rats (100-125 g) are used. The experiment is performed with 6 groups of 5 animals, each of which receives different doses of Org 23430 [1-methyl- 4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine.succinate (1 ;1 salt)] or a control injection. Rats are randomly assigned to treatment groups. Ten minutes after the first injection 14 mg/kg chlorpromazine is given. Compounds are to be administered subcutaneously with an injection volume of 5 ml/kg. Rats are tested at 1 and 2 hours after administration of chlorpromazine for the presence or absence of catalepsy and are returned to their cages between tests.
  • the imposed postures are: vertical clinging to a grid, upright standing with a high support for the front paws, extension of hindlegs, placement on back, placement of spatula in the mouth and rotation in a wire mesh cylinder. Theoretically a maximum score of 6 can be reached.
  • the data are expressed as mean score ⁇ S.E.M.
  • the experimental design is a p x q factorial with repeated measurements on subjects over time.
  • the treatment factor consists of 4 levels and the time factor consists of 2 levels, 1 hour and 2 hours after chlorpromazine.
  • the statistical analysis of variance in the scores provides F-tests for group differences, time differences and group x time interactions. Significant group effects are further investigated using the Newman- Keuls multiple range test. Tests of significance are carried out at the 5% level unless otherwise stated.
  • the vehicle for drug administrations and control injection is 0.9% NaCI in water.
  • Org 23430 dose-dependently reverses or inhibits chlorpromazine-induced catalepsy.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation du composé de formule (I), lequel est 1-méthyl-4-[(4-chloro-2-thiényl)-(4-fluorophényl)méthylène]-pipéridine, ou bien de ses sels d'addition d'acide ou de ses solvates pharmaceutiquement acceptables, pour la préparation d'un médicament destiné au traitement ou à la prophylaxie des troubles de la mobilité.
PCT/EP1999/000144 1998-01-09 1999-01-05 Utilisation d'un derive de phenylthienylmethylene piperidine pour la fabrication d'un medicament destine au traitement de troubles de la mobilite Ceased WO1999034800A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27165/99A AU2716599A (en) 1998-01-09 1999-01-05 Use of phenylthienylmethylene piperidine derivative in the manufacture of a medicament for the treatment of movement disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98200038.2 1998-01-09
EP98200038 1998-01-09

Publications (1)

Publication Number Publication Date
WO1999034800A1 true WO1999034800A1 (fr) 1999-07-15

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Application Number Title Priority Date Filing Date
PCT/EP1999/000144 Ceased WO1999034800A1 (fr) 1998-01-09 1999-01-05 Utilisation d'un derive de phenylthienylmethylene piperidine pour la fabrication d'un medicament destine au traitement de troubles de la mobilite

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AU (1) AU2716599A (fr)
WO (1) WO1999034800A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2739968A (en) * 1950-12-05 1956-03-27 Schering Corp Substituted piperidines
WO1998021206A1 (fr) * 1996-11-14 1998-05-22 Akzo Nobel N.V. Derives de la piperidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2739968A (en) * 1950-12-05 1956-03-27 Schering Corp Substituted piperidines
WO1998021206A1 (fr) * 1996-11-14 1998-05-22 Akzo Nobel N.V. Derives de la piperidine

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Publication number Publication date
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