WO2015010217A1 - Dimiracetam in the treatment of depression - Google Patents

Abstract

Dimiracetam or a solvate thereof is a suitable effective substance for being used in the treatment and/or prevention of depression.

Description

Dimiracetam in the treatment of depression

Cross References to Related Applications

This application claims the priority of Swiss patent application 1306/13, filed July 24, 2013, the disclosure of which is incorporated herein by reference in its entirety.

Field of the Invention

This invention concerns an effective substance, namely dimiracetam, and compositions comprising such effective substance for the treatment of mental disorders, in particular depression.

Background of the Invention

Depression is a common mental disorder that occurs in persons of all genders, ages, and backgrounds, affecting about 121 million people worldwide. Symptoms of depression include, but are not limited to, depressed mood, loss of interest or pleasure, feelings of guilt or low self-esteem, disturbed sleep or appetite, low energy, and poor concentration, or any combination thereof. These problems can become chronic or recurrent and lead to substantial impairments in an individual's ability to take care of his or her everyday responsibilities.

The social importance of depression can be measured by the Fears Lived with a Disability (YLDs) and/or the Disability Adjusted Life Years ( DALYs ; i.e., the sum of years of potential life lost due to premature mortality and the years of productive life lost due to disability) . Depression is the leading cause of disability as measured by YLDs and the fourth leading contribu- tor to the global burden of disease as measured by DALYs in 2000. By the year 2020, depression is projected to reach second place in the ranking of DALYs calcuated for all ages, in both men and women. Today, depression is al- ready the second cause of DALYs in the age category 15-44 years for both sexes combined. Whereas there are clearly a number of currently available treatments for depression, a significant proportion of patients are either incompletely treated (many residual symptoms remain) or do not respond to treatment at all. Thus, novel treatments for depression are needed.

Nootropic agents are cognitive enhancers with very few side effects and extremely low toxicity. This makes them very desirable effective substances. The race- tarn family members share a pyrrolidone nucleus, i.e.

There is no generally accepted mechanism of action for racetams. One of the racetams, nefiracetam, i; reported as anti-depressant. This is also the only race- tarn known to show affinity for the muscarinic receptors in the nanomolar range. Other, although less effective, racetams are aniracetam and nebracetam (see

http: //en. wikipedia. org/wiki /Racetarn) .

Nefiracetam is the compound with the following formula:

In WO 2007/104035 nootropic agents are described as agents for the treatment of several diseases, one of them depression. Among other compounds, racetams are suggested as suitable agents but only piracetam is explicitly mentioned in connection with the treatment of depression although not the subject of any example.

Disclosure of the Invention

Hence, it is a general object of the invention to provide a potent effective substance for the treatment or prophylaxis of depression that has low side effects and low toxicity.

It is another object of the invention to provide a pharmaceutical composition comprising such effective substance for the treatment or prophylaxis of depression .

It is yet another object of the invention to provide a method for the treatment or prophylaxis of depression .

It is still another object of the invention to provide an article of manufacture for the treatment or prophylaxis of depression.

It has now been found that dimiracetam is a good antidepressant.

Dimiracetam is known to be a nootropic drug of the racetam family and has already been described for its effect in the treatment of neuropathic pain and of cognitive impairments. Dimiracetam is the compound with the following formula:

Dimiracetam differs from other members of the racetam family in that it is a bicycle and therefore ste- rically less flexible than other family members.

It has now been found that dimiracetam is a superior anti-depressant than other members of the racetam family.

Brief Description of the Drawings

The invention will be better understood and objects other than those set forth above will become ap- parent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed figures that illustrate the results of:

Figure 1: Rat Porsolt test, acute; mobility time measured 30 minutes after drug administration in groups of 8 rats (*: P<0.05; **: P<0.01) .

Figure 2: Rat Porsolt test, 10-day repeated b.i.d. administration; mobility time measured 60 minutes after drug administration administration in groups of 8 rats (* : P<0.05; **: P<0.01) . First chronic test.

Figure 3: Rat Porsolt test, 10-day repeated b.i.d. administration; mobility time measured 60 minutes after drug administration in groups of 12 rats (*:

P<0.05; ** : P<0.01) . Second chronic test.

Figure 4: Mouse Porsolt test, acute; dimiracetam was tested either ip ( intraperitoreally) or po (per os, by mouth) in groups of 19-27 mice each and mo- bility time was assessed 30 minutes after drug administration (*: P<0.05; **: P<0.01).

Modes for Carrying Out the Invention

The effect of dimiracetam in the treatment of depression has been studied in animal models, in parti- clar the so called Porsolt Test (Porsolt RD, Bertin A, Jalfre M. (1977). "Behavioral despair in mice: a primary screening test for antidepressants". Archives Internationales de Pharmacodynamie et de Therapie 229 (2) : 327- 336) . This test is also called behavioural despair test or forced swimming test. The Porsolt Test is a test used to measure the effect of antidepressant drugs on the behaviour of laboratory animals (typically rats or mice) .

Beside amitriptyline, a well known antidepressant used as a reference compound in the experiments shown in this application, only dimiracetam, of all the tested racetam derivatives, showed antidepressant activity by significantly increasing the mobility time of the rats in both the acute and chronic experiments.

Wherever the term dimiracetam is used in this document it covers any combination of the R- and S- enantiomers, in particular the racemate, and the pure isolated enantiomers, each as such or as pharmaceutically acceptable solvate.

The present invention also provides a method of treating depression in a human which comprises admin- istering to a person in need thereof a therapeutically effective amount of dimiracetam.

The term "therapeutically effective amount" refers to that amount of a compound sufficient to modulate one or more of the symptoms of the condition or dis- ease being treated.

The present invention provides a pharmaceutical composition comprising dimiracetam or a pharmaceuti- cally acceptable solvate thereof and a pharmaceutically acceptable vehicle, adjuvant, carrier, or diluent.

The compounds according to the present invention may be administered by any route, including, but not limited to, orally, intramuscularly, subcutaneously, in- tranasally, intravenously, sublingually or intrarectally . In one embodiment of the invention, the route of administration may be oral, intravenous or intramuscular.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable vehicles or carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid vehicle or carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers , lubricants, suspending agents, binders, or tablet disintegrating agents. In powders, the vehicle or carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the dimiracetam is mixed with the vehicle or carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

In the scope of this specification, solid carriers are intended to include encapsulating materials suitable for e.g. providing capsules in which the active component (with or without other carriers) is surrounded by encapsulating material which is thus in association with it. Similarly, cachets are included in the possible carriers.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycer- ides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into conveniently sized moulds and allowed to cool and solidify. Suitable vehicles or carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa but- ter, and the like.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water- propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in aqueous polyethylene glycol solu- tion. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided ac- tive component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Dimiracetam may also be used for prophylaxis, e.g. in the treatment of persons who previously had suffered a depression or persons that have a genetic predis^¬ position .

The pharmaceutical composition may be in unit dosage form. In such form, the composition is divided in- to unit doses containing appropriate quantities of the active component. Examples for unit dosage forms are capsules, cachets, or tablets.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual reg- imen and dosage level at the most appropriate for a particular patient.

In the scope of the invention, i.e. in the treatment addressed, the effect of dimiracetam usually is exerted if administered via any route provided that suitable haematic levels are achieved. Suitable haematic levels are assumed to be in a range of about 50 to about 750 micromolar .

Suitable daily doses for dimiracetam as such or as solvate range for

oral administration from about 1 to about 100 mg/kg, preferably about 8 to about 70 mg/kg, in particular about 15 to about 65 mg/kg or for

intramuscular administration from about 5 to about 25 mg/kg, in particular from about 8 to about 20 mg/kg or for

intravenous administration from about 2 to about 20 mg/kg, in particular 5 to 20 mg/kg or for

rectal administration from about 8 to about 70 mg/kg, preferably 10 to 65 mg/kg, in particular 15 to 35 mg/kg.

In this document, term "about" means ± 10% of the value it modifies. For example, "about 100" means 90 to 110.

If desired, part of the dosage may be administered by one route and another part by another route, e.g. a fixed part intravenously and a variable part orally if need be.

Unit doses may be administered conventionally once or more than once a day.

A medicament is suitably confectioned for daily administration of

50 to 4000 mg, preferably 250 to 3200 mg, more preferred 400 to 2500 mg in case of oral administra- tion;

200 to 1200 mg , preferably from 400 to 1000 mg in case of intramuscular administration; 50 to 1000 mg, preferably from 200 to 800 mg in case of intravenous administration; or

400 to 3500 mg, preferably at most 3200 mg and much preferred from 800 to 1600 mg for rectal admin- istration (in form of suppositories) .

The daily dosage in mg is referred to a mean patient body weight of 50 kg.

The preferred ranges are summarized in the Table 1 below:

Table 1 :

The pharmaceutical composition comprising dimiracetam may conveniently be formulated as tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parental or subcutaneous solutions, suspensions for parental administration; or suppositories for rectal administration; all of which are well known in the art.

For clinical use, dimiracetam is formulated into pharmaceutical formulations for oral, rectal, parenteral or any other mode of administration. The pharmaceu- tical formulation contains dimiracetam in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical prepa- rations are a further object of the invention. Depending on the mode of administration, the pharmaceutical composition can comprise from about 0.05 %w to about 99 %w (per cent by weight), or from about 0.05 %w to about 80 %w, or from about 0.10 %w to about 70 %w, or from about 0.10 %w to about 50 %w, of active ingredient, all percentages by weight being based on total composition. The active ingredient may be dimiracetam alone or dimiracetam and one or more other pharmaceutically effective compound (s) .

In the preparation of pharmaceutical formulations containing dimiracetam in the form of dosage units for oral administration dimiracetam may be mixed with solid, powdered ingredients, or another suitable ingredient, as well as with disintegrating agents and lubricat- ing agents. The mixture is then processed into granules or pressed into tablets.

Dimiracetam may be formulated as soft gelatin capsules or as hard gelatin capsules containing dimiracetam as such, e.g. as granules or they may contain dimi- racetam in combination with solid powdered ingredients. Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain dimiracetam mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains dimiracetam in a mixture with suitable vehicles for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration .

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g., solutions or suspensions containing dimiracetam. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution of dimiracetam in a pharmaceutically acceptable solvent. These solutions may also con- tain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use.

Since depression may be accompanied by other diseases in older people in particular by cognitive decline and slowing of both mentation and movements, and/or since depression may coexist with stroke, cardiovascular diseases, Parkinson's disease and pulmonary diseases, on- ly to mention some examples, dimiracetam may be administered in a combination therapy with other antidepressant or drug improving mental and/or physical efficiency. Com^¬ binations wherein dimiracetam or a pharmaceutically acceptable solvate thereof, or a pharmaceutical composition or formulation comprising dimiracetam or a solvate thereof may be administered concurrently, simultaneously, sequentially or separately. Other compounds that can be used in combination with dimiracetam may be selected from the following:

(i) antidepressants such as agomelatine, ami- triptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, elzasonan, es- citalopram, fluvoxamine, fluoxetine, gepirone, imipra- mine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxe- tine, robalzotan, sertraline, sibutramine, thionisoxe- tine, tranylcypromaine, trazodone, trimipramine , ven- lafaxine ;

(ii) atypical antipsychotics including for example quetiapine and lithium;

(iii) antipsychotics including for example amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, eszopiclone, haloperidol, ilop- eridone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone , perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suri- clone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasi- done;

(iv) anxiolytics including for example al- nespirone, azapirones, benzodiazepines , barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, brom- azepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazo- late, trepipam, temazepam, triazolam, uldazepam, zo- lazepam;

(v) anticonvulsants including for example carbamazepine, valproate, lamotrogine, gabapentin, pregabalin, topiramate, lacosamide, vigabatrin, tiaga- bine;

(vi) drugs for Alzheimer's therapies including for example donepezil, memantine, tacrine, rivastig- mine, galantamine;

(vii) drugs for Parkinson's therapies includ^¬ ing for example L-dopa, ropinirole, pramipexol, MAOB in- hibitors such as safinamide, selegine and rasagiline,

COMT inhibitors such as entacapone or tolcapone, A-2 inhibitors such as istradefylline, dopamine reuptake inhib- itors, N DA antagonists such as amantidine, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase;

(viii) drugs for migraine therapies including for example almotriptan, butalbital, dichloralphenazone, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan .

Such combination products employ the compounds of this invention within the dosage range de- scribed herein and the other pharmaceutically active compound or compounds within approved dosage ranges.

A further object of the invention is an article of manufacture comprising a pharmaceutical composition of any one of claims 8 to 10, a container or package and a written description and administration instruction such as a package insert. In a preferred embodiment, the pharmaceutical composition is in the form of one or preferably several unit dosages such as several tablets, capsules, and powders in vials or ampoules, or solutions in vials or ampoules, or ready to use syringes to only mention some examples.

Experimental part:

The behavioural despair test (also called the

Porsolt test or forced swimming test) is a test used to measure the effect of antidepressant drugs on the behaviour of laboratory animals (typically mice or rats) .

All experiments were carried out in accord- ance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) for experimental animal care. All efforts were made to minimize the number of animals used and their suffering.

Ex . 1 : Evaluation of dimiracetam in mice

The test was performed according to Porsolt RD, Bertin A, Jalfre M. (1977). "Behavioral despair in mice: a primary screening test for antidepressants". Archives Internationales de Pharmacodynamie et de Therapie 229 (2) : 327-336) .

Male Swiss Webster mice (25 - 28 g) from Mo- rini breeding farm (San Polo d'Enza, RE, Italy) were used.

The results of this test are reported in Figure 4. Ex. 2: Evaluation of dimiracetam in rats , in comparison with other racetarn derivatives

Male Sprague Dowley rats (220-240 g) from breeding farm Harlan (Udine, Italy) were used. Four rats were housed per cage (26 x 41 cm) . The cages were placed in the experimental room 24 h before the test for acclimatization. The animals were fed a standard laboratory diet and tap water ad libitum and kept at 23 + 1 °C with a 12 h light/dark cycle, light on at 7 a.m.

The forced swimming test used was the same as described by Porsolt, modified for rat. Briefly, rats were dropped individually into glass cylinders (height: 45 cm, diameter: 20 cm) containing water maintained at 22-23°C and left there for 6 min. The water was deep enough to prevent the rats from touching the bottom of the aquarium. A rat was judged to be immobile when it floated in the water, in an upright position, and made only small movements to keep its head above water. The duration of mobility was recorded during the last 4 min of the 6-min test. An increase in the duration of mobili- ty time is indicative of an antidepressant-like effect.

The test performed in the scope of the present invention entailed a dose response assessment at 30 minutes after single administration (acute) and evaluation of the effect of one chronic dose (i.e. the dose that had the best effect after acute administration) given twice a day for 10 days. The endpoint measured was mobility time (i.e.

the time spent by rats in swimming) : the longer it is , the better the antidepressant effect.

The results of dimiracetam in the acute and chronic tests as well as of comparative compounds are

shown in Table 2 and in Figures 1 and 2 :

Table 2:

EFFECT OF SOME RACETAM COMPOUNDS (acute and repeated administration) IN THE RAT FORCED SWIMMING TEST

Each value in the Table is the mean ± sem of 8 rats. *P<0.05; **P< 0.01 vs. vehicle treated rats. All compounds were administered twice daily; test was performed on day 1, 30 min after administration and on day 11, 60 min after the last compound administration .

In this test, also illustrated by Figures 1 and 2, dimiracetam was the only racetam showing a statistically significant antidepressant activity, albeit not as potent as amitriptyline .

In a second chronic test , illustrated in Figure 3, only the vehicle and dimiracetam (100 mg/kg p.o.) were examined. The mean mobility time measured was 53 s for the vehicle and 102 s for the dimiracetam treated rats .

The suitability of different routes of administration is shown in Figure 4. While the ip. route is more efficient, also the p.o. route gave significant results .

Oxiracetam, levetiracetam and pramiracetam were chosen as reference compounds because they were mentioned in WO 2007/104035 and are known to be more potent nootropic agents than piracetam (oxiracetam is 2 to 4 times more potent and pramiracetam is 8 to 30 times more potent (see http://en.wikipedia.org/wiki/Racetam) and levetiracetam has been used since, besides of piracetam, it is the only racetam commercially available and extensive- ly used worldwide as an anticonvulsant.

While there are shown and described presently preferred embodiments of the invention, it is to be distinctly understood that the invention is not limited thereto but may be otherwise variously embodied and practiced within the scope of the following claims.

Claims

Claims

1. Dimiracetam or a solvate thereof for the use in the treatment and/or prevention of depression.

2. Dimiracetam or a solvate thereof for the use of claim 1, wherein dimiracetam is in the form of a mixture of (S) and (R) enantiomer.

3. Dimiracetam or a solvate thereof for the use of claim 1, wherein dimiracetam is in the form of isolated (S) or (R) enantiomer.

4. Dimiracetam or a solvate thereof for the use of any one of the preceding claims, in a daily

oral dosage of about 1 to about 80 mg/kg, preferably about 5 to about 65 mg/kg, in particular about 8 to about 50 mg/kg, or a daily

intramuscular dosage from about 4 to about 25 mg/kg, in particular from about 8 to about 20 mg/kg or a daily

intravenous dosage from about 1 to about 20 mg/kg, in particular 4 to 15 mg/kg or a daily

rectal dosage from about 8 to about 70 mg/kg, preferably 10 to 65 mg/kg, in particular 15 to 35 mg/kg.

5. Dimiracetam or a solvate thereof for the use of any one of the preceding claims, in a daily dosage inducing haematic levels of 100 - 500 micromolar.

6. Dimiracetam or a solvate thereof for the use of any one of the preceding claims, in the form of a medicament suitable to administer a daily pro-Kg amount of dimiracetam of

- orally: about 1 to about 80 mg/kg, prefera^¬ bly about 5 to about 65 mg/kg, in particular about 8 to about 50 mg/kg, or

- intramuscularly: about 4 to about 25 mg/kg, in particular from about 8 to about 20 mg/kg, or

- intravenously: about 1 to about 20 mg/kg, in particular 4 to 15 mg/kg and/or a daily, or - rectally: about 8 to about 70 mg/kg, preferably 10 to 65 rag/kg, in particular 15 to 35 mg/kg.

7. Dimiracetam or a solvate thereof for the use of anyone of the preceding claims in combination with at least one further compound selected from the group consisting of

(i) antidepressants,

(ii) atypical antipsychotics,

(iii) antipsychotics,

(iv) anxiolytics,

(v) anticonvulsants,

(vi) drugs for Alzheimer's therapies,

(vii) drugs for Parkinson's therapies, and

(viii) drugs for migraine therapies

wherein the administration of dimiracetam and the at least one further compound may be concurrently, simultaneously, sequentially or separately.

8. A pharmaceutical composition comprising dimiracetam and at least one pharmaceutically acceptable. vehicle, adjuvant, carrier, or diluent.

9. The pharmaceutical composition of claim 8, wherein dimiracetam is present in an amount for daily administration of

50 to 4000 mg, preferably 250 to 3200 mg, more preferred 400 to 2500 mg in case of oral compositions;

200 to 1200 mg , preferably from 400 to 1000 mg in case of intramuscular compositions;

50 to 1000 mg, preferably from 200 to 800 mg in case of intravenous compositions; or

400 to 3500 mg, preferably at most 3200 mg and much preferred from 800 to 1600 mg for rectal compositions (suppositories) .

10. The pharmaceutical composition of claim 8, comprising at least one further compound selected from the group consisting of

(i) antidepressants, (ii) atypical antipsychotics,

(iii) antipsychotics,

(iv) anxiolytics,

(v) anticonvulsants,

(vi) drugs for Alzheimer's therapies,

(vii) drugs for Parkinson's therapies, and

(viii) drugs for migraine.

11. An article of manufacture comprising a pharmaceutical composition of any one of claims 8 to 10, a container or package and a written description and administration instruction such as a package insert.

12. A method of treating depression in a human which comprises administering to a person in need thereof a therapeutically effective amount of dimiracetam or a pharmaceutically acceptable solvate thereof.

13. The method of claim 12, wherein the effective daily amount is

- orally: about 1 to about 80 mg/kg, preferably about 5 to about 65 mg/kg, in particular about 8 to about 50 mg/kg;

- intramuscularly: about 4 to about 25 mg/kg, in particular from about 8 to about 20 mg/kg;

- intravenously: about 1 to about 20 mg/kg, in particular 4 to 15 mg/kg;

- rectally: about 8 to about 70 mg/kg, preferably 10 to 65 mg/kg, in particular 15 to 35 mg/kg, , and/or

a daily amount inducing haematic levels of 100 - 500 micromolar.