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WO1999034802A1 - Utilisation de derives de phenylthienylmethylene piperidine dans la fabrication d'un medicament pour le traitement de la depression - Google Patents

Utilisation de derives de phenylthienylmethylene piperidine dans la fabrication d'un medicament pour le traitement de la depression Download PDF

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Publication number
WO1999034802A1
WO1999034802A1 PCT/EP1999/000146 EP9900146W WO9934802A1 WO 1999034802 A1 WO1999034802 A1 WO 1999034802A1 EP 9900146 W EP9900146 W EP 9900146W WO 9934802 A1 WO9934802 A1 WO 9934802A1
Authority
WO
WIPO (PCT)
Prior art keywords
depression
chloro
treatment
methyl
fluorophenyl
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/EP1999/000146
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English (en)
Inventor
Duncan Robertson Rae
John Stuart Andrews
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 AU26168/99A priority Critical patent/AU2616899A/en
Publication of WO1999034802A1 publication Critical patent/WO1999034802A1/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 depression.
  • Depression is a major health problem in our society and also poses a tremendous financial burden on society due to lost self-support of persons suffering from depression. Life time prevalence for major depression is estimated to be between 5 to 10 %. Various forms of depression are distinguished which are separately diagnosed according to criteria given in handbooks for psychiatry, for example in
  • Treatment with existing antidepressant drugs remains without improvement in at least 30 % of patients elected for drug therapy. There is a strong need for new drugs, with other mechanisms of action than existing anti-depressants, for the treatment of depression.
  • Anti-depressants are distinguished from other classes, such as anxiolytics and antipsychotics. Drugs in one category may have side-effects aggravating other psychiatric diseases not belonging to the category for which the drug treatment is given.
  • formula (I) which is 1-methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-pipehdine; or its pharmaceutically acceptable acid addition salts or solvates thereof, for the manufacture of a medicament for the treatment or prophylaxis of depression.
  • depression is used here for the psychiatric disorder or the symptom characterised by chronic low mood and loss of capacity to experience pleasure.
  • This disease or symptom is well-recognised by a physician and can also be quantified, for example with the Hamilton Rating Scale for depression or the Montgomery and Asberg Depression Rating Scale.
  • the present invention provides a method of treating depression, 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.
  • 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 include fumaric acid (in which case the compound is denoted Org 22709) and succinic acid (in which case the compound is denoted Org 23430).
  • a suitable daily dose for the treatment of depression 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.
  • 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 depression 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 herein described, in combination with packaging material adapted for the pharmaceutical formulation, said packaging material including facilities for the use of the pharmaceutical formulation in the treatment of depression. In particular, such facilities can include precautions limiting the total dose contained in the package handed over to the person for treatment in order to reduce the risk of overdosing due the misuse of the available supply.
  • Formulations include those adapted for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) 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 al., 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, flavoring 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 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 Minipump TM
  • the compound 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 A.R. Katritsky and C.W. Rees, "Comprehensive Heterocyclic Chemistry", Part 4 Ed C.W. Bird and G.H.Cheesman, Pergamon Press.
  • the present invention further includes the following processes for the preparation of compounds according to the present invention.
  • the compound of formula (I) may be prepared by reacting a compound of formula
  • 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)
  • 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 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 a-(4-fluorophenyl)-a-(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol
  • Zinc dust (1.56 g) was added to a suspension of the crude product -(4- fluorophenyl)- ⁇ -(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol (0.78 g) 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]-piperidine (fumarate salt)
  • step 2 The crude material obtained 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.
  • mice Male rats of the Long Evans strain, weighing between 300-425g, are used in these experiments. The experiments are run in standard Skinner boxes. All rats have previous training in the DRL-72 procedure. Rats are divided into separate groups and the experiment undertaken using an independent groups design. The number of lever presses and pellets obtained in each 1 hour session are recorded and an efficiency score (pellets earned/responses) is calculated. Statistical analysis is by one factor independent groups ANOVA, followed by post hoc Tukey HSD tests where overall significance is obtained.
  • Desipramine suppresses lever pressing and increased both the number of pellets obtained and overall efficiency per session. This reflects the antidepressant effect of desipramine.
  • Org 23430 suppresses lever pressing increased both the number of pellets obtained and overall efficiency per session. This reflects the antidepressant effect of Org 23430.

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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

La présente invention concerne un nouvel usage médical de 1-méthyl-4-[(4-chloro-2-thiényl)-(4-fluorophényl)méthylène]-pipéridine, ou bien d'un sel d'addition d'acide ou d'un solvate de celui-ci pharmaceutiquement acceptables, et une nouvelle méthode de traitement de la dépression.
PCT/EP1999/000146 1998-01-09 1999-01-08 Utilisation de derives de phenylthienylmethylene piperidine dans la fabrication d'un medicament pour le traitement de la depression Ceased WO1999034802A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26168/99A AU2616899A (en) 1998-01-09 1999-01-08 Use of phenylthienylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of depression

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98200036 1998-01-09
EP98200036.6 1998-01-09

Publications (1)

Publication Number Publication Date
WO1999034802A1 true WO1999034802A1 (fr) 1999-07-15

Family

ID=8233284

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/000146 Ceased WO1999034802A1 (fr) 1998-01-09 1999-01-08 Utilisation de derives de phenylthienylmethylene piperidine dans la fabrication d'un medicament pour le traitement de la depression

Country Status (2)

Country Link
AU (1) AU2616899A (fr)
WO (1) WO1999034802A1 (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

Also Published As

Publication number Publication date
AU2616899A (en) 1999-07-26

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