WO1999034802A1

WO1999034802A1 - Use of phenylthienylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of depression

Info

Publication number: WO1999034802A1
Application number: PCT/EP1999/000146
Authority: WO
Inventors: Duncan Robertson Rae; John Stuart Andrews
Original assignee: Akzo Nobel NV
Current assignee: Akzo Nobel NV
Priority date: 1998-01-09
Filing date: 1999-01-08
Publication date: 1999-07-15
Anticipated expiration: 2000-07-09
Also published as: AU2616899A

Abstract

The present invention relates to a new medical use of 1-methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine, or a pharmaceutically acceptable acid addition salt or solvate thereof and to a new method of treatment for depression.

Description

USE OF PHENYLTHIENYLMETHYLENE PIPERIDINE DERIVATIVES IN THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF DEPRESSION

5

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.

10 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

15 the Diagnostic and Statistical Manual of Mental Disorders 4^th edition published by the American Psychiatric Association, Washington, D.C. (1994) and in the International Classification of Diseases (ICD-10) published by the World Health Organisation (Geneva). There is a continuous search for new methods of treatment of depression because existing methods still have disadvantages, such

20 as the side effects of drugs, the long duration of treatments, and more importantly the partial efficacy of treatments. 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.

25

Psychotropic drugs are divided in categories of therapeutic use. 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.

30

In the International Application WO 98/21206 (Akzo Nobel N.V.) phenylmethylene piperidine derivatives are described for use in the treatment of psychotic disorders.

35 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 depression. 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]-pipehdine; or its pharmaceutically acceptable acid addition salts or solvates thereof, for the manufacture of a medicament for the treatment or prophylaxis of depression.

The compound as defined above and its pharmaceutically acceptable acid addition salts will be referred to collectively as compounds according to the present invention.

The term 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.

According to a further aspect, 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).

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 and the age and condition of the recipient. 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.

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 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. 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 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

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 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-fluorobenzoyl)-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 dropwise, 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-f(4-chloro-2-thienyl)-(4-fluorophenyl)methylenel- piperidine

a) (fumarate salt)

Step 1 : a-(4-fluorophenyl)-a-(4-chloro-2-thienyl)-1-methyl-4-piperidinemethanol

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 -(4- fluorophenyl)-α-(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)

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.

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 0c

Example 3

Differential Reinforcement of Low Rates of Responding in rats.

In the procedure of Differential Reinforcement of Low Rates of Responding (DRL 72), rats encounter a situation where lever presses in an operant chamber are rewarded with food pellets only if a delay of 72 seconds occurs between each press. In the following the term reinforcement is used instead of reward, which terms have the same meaning in the context of this specification. A response with a delay of less than 72 seconds results in the resetting of the timer to zero and no reinforcement; again 72 seconds must elapse before a response will produce reinforcement. Antidepressant-like drugs show a similar profile of action in this test: there is a decrease in overall responding, an increase in the number of food pellets earned per session and in the overall efficiency of performance (O'Donnell and Seiden, J Pharmacol Exp Ther 224. 80-88. 1983).

Methods

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.

Results

Experiment 1

Effect of the well-known anti-depressant drug desipramine. HCI

Dose (mg/kg) Total Total

N Efficiency Response Reinforcement

0 12 2.2 171.6 3.5

1.25 12 6.1 128.1^** 7.4**

5 12 8.4 131.8* 9.6**

20 12 27.3** 67.2 ** 15.6**

The numbers in the table are means of 12 rats; * = p < 0.05; ** p < 0.01 ; Tukey test - dose vs placebo following a significant ANOVA.

Conclusion

Desipramine suppresses lever pressing and increased both the number of pellets obtained and overall efficiency per session. This reflects the antidepressant effect of desipramine. Experiment 2

Effect of 1 -methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine. succinate (1 :1 salt) (Org 23430).

Vehicle: Mulgofen (5% m/v) and NaCI (0.9% m/v) in water Route of administration: ip (30 mins prior to session)

Dose (mg/kg) Total Total

N Efficiency Response Reinforcement

0 10 10.4 120 10.1

1 10 14 97.5 11.9

3 10 12.7 99.3 12.1

10 10 30.9^* 67.3** 15.0*

Mean (SD); * = p < 0.05; p < 0.01 ; Tukey test - dose vs placebo following a significant ANOVA.

Conclusion

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.

Claims

1. Use of 1-methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]-piperidine, or a pharmaceutically acceptable acid addition salt or solvate thereof, for the manufacture of a medicament for the treatment or prophylaxis of depression.

2. Use according to claim 1 , wherein the medicament is in a unit dosage form.

3. A method of treating depression in a person which comprises treating said person with a therapeutically effective amount of 1 -methyl-4-[(4-chloro-2- thienyl)-(4-fluorophenyl)methylene]-piperidine.

4. A pharmaceutical formulation adapted for the treatment of depression comprising 1-methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)methylene]- piperidine, or a pharmaceutically acceptable acid addition salt or solvate thereof, in admixture with a pharmaceutically acceptable carrier.

5. A process for the manufacture of a pharmaceutical formulation according to claim 4 comprising bringing into association the active ingredient with a carrier and packaging the formulation by exclusion of harmful contaminants.