WO1999034800A1

WO1999034800A1 - Use of phenylthienylmethylene piperidine derivative in the manufacture of a medicament for the treatment of movement disorders

Info

Publication number: WO1999034800A1
Application number: PCT/EP1999/000144
Authority: WO
Inventors: Duncan Robertson Rae; Jonathan Huw Connick
Original assignee: Akzo Nobel N.V.
Priority date: 1998-01-09
Filing date: 1999-01-05
Publication date: 1999-07-15
Also published as: AU2716599A

Abstract

This invention provides the use of the compound having 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 preparation of a medicament for the treatment or prophylaxis of movement disorders.

Description

USE OF PHENYLTHIENYLMETHYLENE PIPERIDINE DERIVATIVE IN THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF MOVEMENT DISORDERS

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.

In the International Application WO 98/21206 (Akzo Nobel N.V.) phenylmethylene piperidine derivatives are described for use in the treatment of psychotic disorders. Surprisingly, it has now been found that one of these compounds, namely 1 -methyl- 4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine, can also be used for the treatment of movement disorders.

Accordingly, the present invention provides the use of the compound having the formula (I)

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.

The term movement disorder as used here 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.

The terms symptom and syndrome are used here interchangeably since the skilled person understands the equivalence and the difference of these terms dependent on the context and knows that those differences in meaning are not relevant in the context of this specification.

The use for the treatment of akinesia, of hypokinesia and of muscle rigidity is the preferred use of the medicaments of this invention.

In particular, 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.

According to a further aspect, 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. In the case of tolerance development, 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.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. Accordingly, 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. Some examples of 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 Minipump™.

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. The reaction may be conveniently carried out using standard conditions for dehydration of an alcohol. For example, by use of 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)

Formula (III)

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.

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. For example, 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. For example, 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.

In an alternative method, 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.

Where necessary or desired, following one of the above processes, 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).

(iii) converting the compound of formula (I) into a pharmaceutically acceptable salt or solvate of the compound of formula (I)

The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.

Example 1 :

Preparation of 4-chloro-2-,4-fluorobenzovP-thiophene

Crushed aluminium chloride (24.3 g) was added to a stirred solution of 2-(4- fluorobenzoyl)-thiophene (15.0 g) in dry dichloromethane (150 ml) at ~5 °C and after 1 h a solution of chlorine [5.16 g in carbon tetrachloride (26.3 ml)] was added drop- wise, maintaining the temperature at ~5°C. When the addition was complete, the temperature was allowed to rise to -12 °C, over 1.5 h, and the reaction mixture was stirred at this temperature for 1 h. The solution was re-cooled to -5 °C, a further quantity of chlorine (1.3 g) in carbon tetrachloride (6.8 ml) was added and the solution was stirred at this temperature for a further 1 h then allowed to stand overnight at ~20°C. The solution was again re-cooled to 5 °C, a further amount of chlorine (2.6 g) in carbon tetrachloride (13 ml) was added, the temperature was raised to ~20 °C and the mixture was stirred for 2 h. The mixture was cooled in an ice-bath, water (200 ml) was added followed by ether (400 ml) and the layers were separated. The ether layer was washed neutral with water, dried over Na2SO4 and evaporated to give a brown gum (18.9 g) which was crystallised from ether/hexane to give 4-chloro-2-(4-fluorobenzoyl)-thiophene, (10.3 g), 77.6% (GLC).

Example 2

Preparation of 1 -methyl-4-.(4-chloro-2-thienyl)-(4-fluorophenv0methylenel- piperidine

a) (fumarate salt)

Step 1 : -(4-fluorophenyl)- -(4-chioro-2-thienyl)- 1 -methyl-4-pipehdinemethanol

4-Chloro-1-methylpiperidine.HCI (18.7 g) was basified with aq. ammonium hydroxide and the solution was extracted with ether and the extract was washed with brine, dried (Na2SO4) and evaporated to give 4-chloro-1-methylpiperidine (14.7 g) as an almost colourless oil.

A crystal of iodine was added to a stirred suspension of magnesium turnings (2.32 g) in redistilled tetrahydrofuran (THF) (10.0 g), followed by ethyl bromide (0.16 ml) and, after the iodine colour had disappeared (-5 min), a solution of the above 4-chloro-1- methylpiperidine (14.4 g) in THF (96 ml) was added dropwise over -30 min; a small amount of heating was applied so as to maintain a gentle reflux. After the addition was complete the mixture was boiled under reflux for a further 1.5 h then cooled to - 0 °C. A solution of 4-chloro-2-(4-fluorobenzoyl)thiophene (10.3 g; example 1 ) in THF (25 ml) was added dropwise over 40 min to the solution keeping the temperature below 10 °C and the mixture was boiled under reflux for 2.5 h. A saturated solution of ammonium chloride (100 ml) was added to the cooled mixture, followed by ether (500 ml), the insolubles were filtered off through dicalite and the layers were separated. The ether layer was washed with water, dried (Na2SO4) and evaporated, to yield a brown gum (18.2 g)

A mixture of hydrochloric acid (5 N; 60 ml) and hydrochloric acid (2N; 60 ml) was added to the above brown gum (10.8 g) and the stirred mixture was boiled under reflux for 0.75 h. When total solution occurred the reaction mixture was cooled to -5°

C and basified with aq. ammonium hydroxide. The product was extracted with dichloromethane, the extract was washed with water, dried (Na2SO4) and evaporated to give a brown gum (8.2 g) which was chromatographed on silica. Elution with dichloromethane/methanol (gradient elution 1-10% methanol gave a fraction which was evaporated to give α-(4-fluorophenyl)-α-(4-chloro-2-thienyl)-1- methyl-4-piperidinemethanol (1.07 g) containing some overchlorinated impurity.

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 α-(4- fluorophenyl)-α-(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]-pipeήdine (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.

b) (succinate salt)

64.6 g of 1-Methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine (see step 2 above) was dissolved in methanol (640 ml), succinic acid (24.88 g) was added, the solution was taken to dryness and the residual solid (89.4 g was dissolved in hot ethanol. (1.1 I). The solution was reduced in volume (200 ml), cooled in an ice/water bath and the resultant solid was filtered and washed with ethanol (200 ml). The solid was dried under vacuo at 50°C to give 1 -methyl-4-[(4- chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine.succinate (1 :1 salt) (78.2 g) as an off-white solid; m.p. 171 ^C

Example 3

The efficacy of medicaments of this invention is demonstrated in this example by their action on drug induced akinesia or hypokinesia in rats. 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. Six trials with different abnormal postures are run in each of which the animals are placed in an abnormal posture and scored positively with one point for maintaining the imposed posture for 10 seconds. 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. In particular, 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. Results

Experiment 1.

Experiment 2.

* p<0.05; N = 5 per dose.

Conclusion

Org 23430 dose-dependently reverses or inhibits chlorpromazine-induced catalepsy.

Claims

Claims:

1. Use of 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 movement disorders.

2. Use according to claim 1 characterised in that the movement disorder is akinesia, acute dystonic reactions, akathisia, athetosis, chorea, dystonia, hemiballismus, hypokinesia, hyperkinesia, muscle rigidity, myoclonus, spasmodic torticollis, tardive dyskinesia, tics or tremor.

3. Use according to claim 1 characterised in that the movement disorder is akinesia, hypokinesia, or muscle rigidity.

4. Use according to any one of the claims 1 to 3 characterised in that the movement disorder is a drug induced movement disorder.

5. A pharmaceutical composition adapted for the treatment or prophylaxis of movement disorders comprising a compound as defined in claim 1 together with suitable carrier material.

6. A method of treating a movement disorder in an animal or human which comprises treating said animal or human with a therapeutically effective amount of a compound as defined in claim 1.

7. A process for the manufacture of a pharmaceutical formulation according to claim 5 comprising bringing into association the active ingredient with a carrier and packaging the formulation by exclusion of harmful contaminants.