WO1999034801A1

WO1999034801A1 - Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of depression

Info

Publication number: WO1999034801A1
Application number: PCT/EP1999/000145
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: 1999-01-05
Publication date: 1999-07-15
Anticipated expiration: 2000-07-09
Also published as: AU2279099A

Abstract

This invention provides the use of a diphenylmethylene piperidine derivative having formula (A) wherein n is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment or prophylaxis of depression.

Description

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

The present invention relates to a new medical use of diphenylmethylene piperidine derivatives 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 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 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 ^vneed for new drugs, with other mechanisms of action than existing anti-depressants, for the treatment of depression.

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.

In WO 97/03065 (Akzo Nobel N.V.), the contents of which is incorporated herein by reference, certain diphenylmethylene piperidine derivatives are described for use in the treatment of psychotic disorders.

Surprisingly, it has now been found that these diphenylmethylene piperidine derivatives can also be used for the treatment of depression.

Accordingly, the present invention provides the use of a diphenylmethylene piperidine derivative having the formula A,

formula A wherein n is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prophylaxis of depression.

The preferred position of the fluoro atoms at the phenyl rings is at the para-position.

Preferred compounds are 1-[4-[4-[bis-(4-fluorophenyl)methylene]-1-piperidinyl-1- oxobutylj-pyrrolidine and 1 -[4-[4-[bis-(4-fluorophenyl)methylene]-1 -piperidinyl-1 - oxobutylj-piperidine, or a pharmaceutically acceptable salt or a solvate thereof.

The compounds as defined above and its pharmaceuticaly 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 therapeutically effective amount of an above defined diphenylmethylene piperidine derivative, 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 the hydrochloride, the methane- sulfonate salt, and the (E) but-2-ene 1 ,4-dioate (fumarate) salt.

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 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 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 of the invention may be prepared by any method known in the art for the preparation of a compound of similar structure. Typically the compounds are prepared by the methods described in WO 97/03065. The preferred compounds of the present invention are specifically disclosed therein.

The following example is for illustration and should not be considered to be limiting in anyway:

Example: 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 desipramineHCI

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 in a dose-related manner and significantly increases the number of food pellets obtained and overall efficiency per session. This reflects the antidepressant effect of desipramine.

Experiment 2

Effect of 1 -[4-[4-[bis-(4-fluorophenyl)methylene]-1 -piperidinyl-1 -oxobutylj-pyrrolidine hydrochloride (1 :1 )salt (Org 22110)

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 12 2.4 174.1 3.8

1 12 3.4 161.2 5.7

3 12 5.2 138.1 * 6.8*

10 12 24.3** 72.5** 15.6**

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

Conclusion

ORG 22110 suppresses lever pressing in a dose-related manner and significantly increased the number of pellets obtained and overall efficiency per session. This reflects the antidepressant effect of Org 22110.

Claims

Claims:

1. Use of a diphenylmethylene piperidine derivative having the formula A

formula A wherein n is 1 or 2; or a pharmaceutically acceptable acid addition salt or solvate thereof, for the manufacture of a medicament in the treatment or prophylaxis of depression.

2. Use of a diphenylmethylene piperidine derivative according to claim 1 , wherein the fluoro substituents are in the para-position of the phenyl groups.

3. Use of a diphenylmethylene piperidine derivative according to claim 1 or 2 wherein n is 1.

4. A pharmaceutical composition adapted for the treatment or prophylaxis of depression comprising a diphenylmethylene piperidine derivative having the formula A as defined in claim 1 together with suitable carrier material.

5. A method of treating a person for depression which comprises treating said person with a therapeutically effective amount of a diphenylmethylene piperidine derivative having the formula A as defined in claim 1.

6. 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.