Agents with an antidepressive effect

The invention relates to the use of 2-amino-4,5,6,7tetrahydro-6-propylamino-benzothiazole (pramipexole), its (+) - or (-) - enantiomers, or some of its pharmacologically tolerable salts, in combination with sertraline , for improved treatment of depression and depressive disorders.

49795 Β

The present invention relates to antidepressant agents comprising 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole, its (+) or (-) enantiomer, its pharmacologically tolerable acid addition salts and customary antidepressant. Of particular importance is the combination of pramipexole with sertraline.

State of the art

Pramipexole, which is (-) - 2-amino-6-n-propylainine (> 4,5,6,7-t-trahydrobenzo-thiazole, is dopamine-D₃/ D₂ agonist, the synthesis of which is described in European patent 186 087 and in U.S. patent 4,886,812. Pramipexole is primarily known for the treatment of schizophrenia, and especially for the treatment of Parkinson's disease. In German patent application DE 38 43 227 it is disclosed that pramipexole lowers serum prolactin levels, furthermore, it is known from German patent application DE 39 33 738 that pramipexole is used to lower high TSH levels. U.S. Patent 5,112,842 discloses transdermal administration, and WO patent application PCT / EP93 / 03389 describes the use of pramipexole as an antidepressant.

Details on the preparation of the compound in question can be found in EP-A 85 ​​116 016, and reference will be made here exclusively to the literature cited therein.

Description of the invention

Unexpectedly, it has been found that pramipexole, its (+) N (-) enantiomer I of its pharmacologically tolerable acid addition salts, in combination with some other antidepressant, exhibits a markedly increased antidepressant effect than both individual components alone. Particular emphasis should be placed on the immediate onset of action of a combination of active substances.

49795 Β

Improved effect of pramipexole with concomitant administration of another antidepressant was found in experiments on rats given pramipexole and sertraline, in the so-called. forced swimming test ”. Details of this test procedure can be found, e.g. in articles, Willner, Psychopharmacology 83. 1 - 16 (1984) or, in Borsina and Meli, Psychopharmacology 94,147 -160 (1988).

For the particularly preferred combination, pramipexole and sertraline, (1S-cis) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro (> N-methyl-1-naphthalenans, or its addition salts with acids, the test was performed as follows. The animals were divided into different groups and one of the grapes received either saline solution, or a therapeutically effective amount of pramipexole, a therapeutic amount of sertraline, or a combination of both antidepressants, always in the same therapeutic amounts as animals receiving only one of the two active substances. .

A particularly preferred combination consists of 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole, its (+) - or (-) - enantiomers, their tolerable acid addition salts, and (1S -cis) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (sertraline), as well as its acid addition salts, with the combination of pramipexole and sertraline, always in the form of their hydrochlorides.

In addition to sertraline, another antidepressant may be used in combination with pramipexole. Of these other antidepressants, it is primarily one from the group:

alprazolam, chlordiazepoxide, clomipramine, quinpyrrole, dibenzepine, doxepin, mirtazapine, moclobemide, nefazodone, nortriptyline, opipramol, paroxetine, trimipramine, tryptophan, venlafaxime, or viloxazine with

49795 Β fluvoxamine, loferpramine, maprotiline, mianserin, sertraline, sulpiride, tranylcypromine, trazolone,

The term combination means, according to the invention, a combination of active substances, both active substances, in one preparation (formulation), and also a combination of individual preparations (formulations) of active substances, which are used in a time-dependent therapeutic procedure.

Pharmaceutical formulations of pramipexole, which can be administered orally, are known on the basis of the prior art, and can be e.g. gain on German ffi in US-US market.

The individual active substances can also be packaged as a kit that is a packaged combination of individual drugs, but they can also be packaged separately.

The combination of pramipexole and an expensive antidepressant can be formulated analogously to conventional galenic preparations, typically in conjunction with pharmaceutical carriers. That is, an effective dose of the individual components, and in the case of a pharmaceutical carrier, is prepared in the form of tablets, dragees, capsules, wafer preparations, powders, solutions, suspensions, emulsions, syrups, suppositories, etc .. For pramipexole, the pharmaceutically effective dose for a patient is between 0.01 and 10 mg, preferably between 0.08 and 5 mg.

Therapeutically effective doses of the second antidepressant, in combination, are given in the following table.

(25-100mg) (5mg) (10-25mg) (1-5 mg) (10-250mg) (5-50 mg) alprazolam, chlordiazepoxide, clomipramine, quinpyrole, dibenzepine doxepin, (20 mg) (50 mg) ( 50-200mg) (10mg) (25-100mg) (25-250mg) paroxetine, sertraline, sulpiride, trauilcipromin, trazodone, trimipramine,

49795 Β

<td>(50 -100 mg)</td><td>fluvoxamine,</td><td>(500mg-2.5g)</td><td>tryptophan,</td>

<td>(35-75mg)</td><td>lofepramine,</td><td>(30-75mg)</td><td>venlafaxim, ie,</td>

<td>(10-75mg)</td><td>maprotiline,</td><td>(100 mg)</td><td>viloxazine.</td>

<td>(10 - 30 mg)</td><td>mianserin,</td><td></td><td></td>

<td>(30 mg)</td><td>mirtazapine,</td><td></td><td></td>

<td>(150-300 mg)</td><td>moclobemide,</td><td></td><td></td>

<td>(100-300 mg)</td><td>nefazodone,</td><td></td><td></td>

<td>(10-25mg)</td><td>nortriptyline,</td><td></td><td></td>

<td>(50 mg)</td><td>opipramol,</td><td></td><td></td>

The recommended dosage, in individual cases, of the combination according to the invention, may be below the hitherto recommended single dosage of the monopreparation.

Description of the experiment

Pramipexole was administered in doses of 0.1 to 0.3 mg / kg. Additionally, experiments were performed with 0.05 mg / kg pramipexole. Sertalin, as indicated in the tables, was administered in doses of 5 to 10 mg / kg. The experiments were performed with rats (male Wistar, 250 270 g), at room temperature, while maintaining a natural rhythm day - night. Pramipexole (HCl) was dissolved in saline and sertraline (HCl) in distilled water, and both substances were injected in a volume of 2 ml / kg.

“Forced swimmmg test” with rats

The total immobilization time was determined according to Porsolt et al. (1978) by observation over a five-minute period. Pramipexole (0.05, 0.1 and 0.3 mg / kg) and sertraline (5 or 10 mg / kg) were administered three times at intervals of 24.5 and 1 hour before the test.

49795 Β

In the selected groups, pramipexole was also injected three times in the above-mentioned doses together with sertraline (5 or 10 mg / kg), as described above. Each group consisted of 10 rats.

Results

Pramipexole - 0.1 mg / kg - does not change the immobilization time in the forced swimming test, while higher doses (0.3 mg) cause a significant reduction in immobilization time.

A dose of 5 mg / kg of sertraline alone also does not reduce the time of immobilization. However, co-administration of 5 mg / kg sertraline and 0.1 mg / kg pramipexole markedly reduces immobilization time. In general, this effect occurs markedly with higher doses of sertraline.

Sertraline alone, given at a dose of 10 mg / kg, was inactive in the forced swimming test, but not in combination with pramipexole (0.1, 0.3 mg / kg). This effect is enhanced by higher doses of pramipexole. Pramipexole at a dose of 0.05 mg / kg does not show any effect on the time of immobilization, but in combination with sertraline there is a decrease in the time of immobilization.

These results show an unexpected synergistic effect of pramipexole in combination with sertraline, as an antidepressant.

49795 Β

Table 1. Effects of pramipexole (0.1 and 0.3 mg / kg), alone or in combination with sertraline (5 mg / kg), on the immobilization time of rats in the forced swimming test

<td rowspan="2">compounds (mg / kg)</td><td colspan="2">time of immobilization</td>

<td>mean ± SEM</td><td>P</td>

<td>1. carrier</td><td> 239,9 ±3,1</td><td> —</td>

<td>2 sertraline5</td><td> 257,0 ±7,0</td><td>ns vs 1</td>

<td>3. pramipexole 0.1</td><td> 223,4 ± 6,2</td><td>ns vs 1</td>

<td>4 pramipexole 0.3</td><td> 171,5 ±9,2</td><td>&lt;0.001 vs 1</td>

<td>5. sertraline 5 + pramipexole 0.1</td><td> 96,1 ± 10,3</td><td>&lt;0.001 vs 3</td>

<td>6. sertraline 5 + pramipexole 0.3</td><td> 18,1 ±3,5</td><td>&lt;0.001 vs 4</td>

Pramipexole (0.1 or 0.3 mg / kg sc) and sertraline (5 mg / kg ip) were given 3 times (24.5 and 1 hour) before the test.

Table2. Effect of pramipexole (0.1 and 0.3 mg / kg), alone or in combination with sertraline (10 mg / kg), on the immobilization time of rats in the forced swimming test

<td rowspan="2">compounds (mg / kg)</td><td colspan="2">time of immobilization</td>

<td>mean ± SEM</td><td>P</td>

<td>1. carrier</td><td> 237,9 ±2,7</td><td> _____</td>

<td>2 sertraline 10</td><td> 223,6 ±9,9</td><td>ns vs 1</td>

<td>3. pramipexole 0.1</td><td> 212,5 ± 6,9</td><td>ns vs 1</td>

<td>4 pramipexole 0.3</td><td> 142,9 ±7,9</td><td>&lt;0.001 vs 1</td>

<td>5. sertraline 10 + pramipexole 0.1</td><td> 133,3 ± 6,9</td><td>&lt;0.001 vs 3</td>

<td>6. sertraline 10 + pramipexole 0.3</td><td> 11,8 ±2,3</td><td>&lt;0.001 vs 4</td>

Pramipexole (0.1 or 0.3 mg / kg sc) and sertraline (10 mg / kg ip) were given 3 times (24.5 and 1 hour) before the test.

49795 Β

Table3. Effect of pramipexole (0.05 mg / kg), alone or in combination with sertraline (5 and 10 mg / kg), on the immobilization time of rats in the forced swimming test ”

<td rowspan="2">compounds (mg / kg)</td><td colspan="2">time of immobilization</td>

<td>mean ± SEM</td><td>P</td>

<td>1. carrier</td><td> 235,3 + 4,8</td><td> —</td>

<td>2 pramipexole 0.05</td><td> 245,5 ±7,8</td><td>ns vs 1</td>

<td>3. sertraline5</td><td> 247,5 ±3,0</td><td>ns vs 1</td>

<td>4 sertraline 10</td><td> 223,7 ±2,8</td><td>ns vs 1</td>

<td>5. sertraline 5 + pramipexole 0.05</td><td> 187,7 ±11,2</td><td>&lt;0.001 vs 2</td>

<td>6. sertraline 10 + pramipexole 0.05</td><td> 163,9 ±10,0</td><td>&lt;0.001 vs 2</td>

Pramipexole (0.05 mg / kg sc) and sertraline (5 and 10 mg / kg ip) were given 3 times (24.5 and 1 hour) before the test.