MXPA00012880A - Agents with an antidepressive effect - Google Patents

Abstract

The invention relates to the use of 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothizole (pramipexol), its (+) or (-) enantiomers or one of its pharmacologically compatible salts, combined with sertralin, for treating depression and depressive conditions more effectively.

Description

AGENT WITH ANTIDEPRESSIVE EFFECT CONTAINING PRAMIPEXOL AND AN ADDITIONAL ANTIDEPRESSANT F RMACO Field of the Invention The present invention concerns an agent with antidepressant effect that contains 2-amino-, 5, 6, 7-tetrahydro-6-propylamino-benzothiazole, its (+) or (-) enantiomer, its salts by addition of pharmacologically compatible acids and a usual antidepressant agent. The combination of pramipexole with sertraline is of special interest.

Background of the Invention Pramipexole - that is, dihydrochloride 2 - . 2 - . 2-amino-6-n-propylamino-, 5, 6, 7-tetrahydrobenzo-thiazole - is a dopamine D3 / D2 agonist, the synthesis of which has been described in European Patent 186,087 and in the patent of E.U.A. 4,886,812. Pramipexole is known in the first place for the treatment of schizophrenia and especially for the treatment of Parkinson's disease. From the German Patent Application DE 38 43 227 it is disclosed that pramipexole decreases the level of prolactin in serum, and it is further known from German Patent Application DE 39 33 REF .: 126010 738 to use pramipexole to lower high n? vele.5 of TSH. Transdermal application is disclosed in U.S. Pat. No. 5,112,842, and Patent Application WO PCT / EP93 / 03389 discloses the use of pramipexole as an antidepressant agent. Details about the preparation of the title compound can be taken from European Patent Document EP-A-85,116,016, and hereby e. expressly refers to the bibliography quoted therein.

Description of the Invention Surprisingly, it was finally found that pramipexole in combination with another antidepressant agent develops an antidepressant effect clearly more altered than that which can be produced by the two individual components themselves. The immediate initiation of the effect of the combination of active substances must be particularly emphasized. The improved effect of pramipexole by simultaneous administration of another antidepressant agent was discovered in investigations carried out with rats according to the so-called "forced swimming test = forcee 's wimmi ng t es t". Details about this research method can be found, for example, in the quotes from Wi l lor, Psych opharma col ogy 83, 1 - 1 6 (1 984) or from Borsi ni ,. _... J_J ^, m »a» É? - ^. ^ Js »J_, ^ ¡¡¡ita iMim and Mel i, Psych oph a rma col ogy 94_, 1 4 7 - 1 60 (1 988) . The assay was carried out using the preferred combination of pramipexole and setralin (1S-cis) -4- (3,4-dichlorophenyl) -l, 2, 3, 4-tetrahydro-N-methyl-1-naphthalenamine or its salts of addition. The animals were subdivided into different groups and in each case one of the groups received either a sodium chloride solution, a therapeutically effective amount of pramipexole, a therapeutic amount of a second antidepressant agent, which was not pramipexole, or a combined administration of pramipexole and the other antidepressant agent, in each case in the same therapeutic amount, as the animals that received exclusively one of the two active substances. The combination of 2-amino-, 5, 6, 7-tetrahydro-6-propyl-amino-benzothiazole, its (+) or (-) enantiomer, or its salts by the addition of compatible acids, and of (lS-cis) - 4 - (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (sertraline) as well as its salts by the addition of acids - especially preferred in the combination of pramipexole and sertraline in each case in the form of its hydrochlorides. The antidepressant agent, which was not pramipexole, was selected from the following known compounds: The concept of combination is understood according to the invention as a combination of active substances, with both active substances in a formulation, and also as a combination in the sense of individual formulations of the active substances, which are applied by a time-dependent therapeutic measure. Orally applicable pharmaceutical formulations for pramipexole are known from the state of the art and can be purchased under the trade name Sifrol. The individual active substances can be packaged as a kit, in the sense of a combination of individual drug packages, as well as separately.

The combination of pramipexole and another antidepressant agent can be formulated analogously to the usual galenic preparations, as a rule in common with a pharmaceutical carrier. That is, an effective dose of the individual components is formulated and eventually a pharmaceutical carrier in the form of a tablet, dragee, capsule, wafer, powder, solution, suspension, emulsion, syrup, suppository, etc. For pramipexole, the pharmaceutically active dose per patient is between 0.01 and 10 mg, preferably between 0.08 and 5 mg. The therapeutically active doses of the second antidepressant in the combination are indicated in the following Table.

"Jj-.it" - "-" faith ", ..- £, nr In the combination according to the invention, the recommended dosage can also be found in individual cases below the single dosage recommended up to now of the monocomponent preparation e.

Description of the experiments Pramipexole was used in dosages of 0.1 and 0.3 mg / kg. Additionally, investigations were carried out with 0.05 mg / kg of pramipexole. Sertraline was used, as stated in the Tables, in dosages of 5 and 10 mg / kg. The experiments were carried out in rats (male Wistar race, 250 -270 g) at RT (room temperature) respecting a natural rhythm of day and night. Pramipexole (HCl) was dissolved in a physiological solution of sodium chloride and sertraline (HCl) was dissolved in distilled water, both substances were injected in a volume of 2 ml / kg. Test for forced swimming in rats All immobility time was determined according to Pors ol and C olombrators (1 9 78) over the course of an observation period of five weeks. Pramipexole (0.05, 0.1 and 0.3 mg / kg) and sertraline (5 or 10 mg / kg) were added before the test at 24.5 and 1 hour intervals. ^ g ^^^^ | ^ te ^^ t ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ mentioned above together with sertraline (5 or 10 mg / kg) also three times, as described above. Each group consisted of 10 rats. Results Pramipexole - 0.1 mg / kg - does not modify the immobility time in the forced swimming test, while higher doses (0.3 mg) produce a significant decrease in the immobility time. A dosage of 5 mg / kg of sertraline alone does not reduce the immobility time either. However, the application in common of 5 mg / kg of sertraline and 0.1 mg / kg of pramipexole appreciably reduces the immobility time. In an essentially more pronounced degree this effect occurs in the case of higher dosages of sertraline. Sertraline alone at a dose of 10 mg / kg was inactive in the forced swimming trial, but was administered in combination with pramipexole (0.1, 0.3 mg / kg). This effect is reinforced in the case of higher dosages of pramipexole. Pramipexole in the dosage of 0.05 mg / kg does not show any influence on the immobility time, but in combination with sertraline there is a reduction in the immobility time.

These results demonstrate the unexpected smérgico effect of pramipexole in combination with sertraline as an antidepressant agent.

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

Pramipexole (0.1 or 0.3 mg / kg s.c.) and sertraline (5 mg / kg i.p.) are administered 3 times (24.5 and 1 hours) before the test. [ETM = typical error of the mean] Table 2. Effect of pramipexole (0.1 and 0.3 mg / kg) alone or in combination with sertraline (10 mg / kg) on the immobility time in the forced swimming test in rats.

Pramipexole (0.01 or 0.3 mg / kg s.c.) and sertraline (10 mg / kg i.p.) are administered 3 times (24.5 and 1 hours) before the test. [ETM = typical error of the mean] Table 3. Effect of pramipexole (0.1 and 0.3 mg / kg) alone or in combination with sertraline (5 and 10 mg / kg) on the immobility time in the forced swimming test in rats. ^ & ^ Pramipexole (0.05 mg / kg s.c.) and sertraline (5 lOmg / kg i.p.) are administered 3 times (24.5 and 1 hours) before the test. [ETM = typical error of the mean].

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (13)

1. CLAIMS 1. Agent for treating depressions containing 2-amino-4, 5, 6, 7-tetrahydro-6-propylamino-benzothiazole, one of its enantiomers or the acid addition salts in combination with Sentralin or one of its pharmacologically acceptable salts .
2. 2. Agent according to claim 1, characterized in that it contains the (+) - enantiomer of 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole or one of its acid addition salts.
3. 3. Agent according to claim 1, characterized in that it contains the (-) -enantiomer of 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole or one of its acid addition salts. Agent according to one of claims 1 to 3, characterized in that it contains 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole dichloride hydrochloride, in particular 2-amino-dihydrochloride monohydrate. 4, 5, 6, 7-tetrahydro-6-propylamino-benzothiazole. Agent according to claim 1, characterized in that the formulation contains 0.05-10 mg of 2-amino-4, 5, 6, 7-tetrahydro-6-propylamino-benzothiazole, one of its enantiomers or one of its acid addition salts, pramipexole or diclohirdrate monohydrate Pramipexole. Agent according to claim 1, characterized in that the formulation contains 0.088-1.5 mg of 2-amino-4, 5, 6, 7-tetrahydro-6-propylamino-benzothiazole, one of its enantiomers or one of its salts of acid addition, Pramipexole or dihydrochloride monohydrate Pramipexole. 7. Agent according to claim 6, characterized in that it contains between 0.088 and 1.1 mg of Pramipexole or between 0.125 and 1.5 mg of Pramipexole hydrochloride monohydrate monohydrate. Agent according to one of claims 1 to 7, characterized in that it contains between 25 and 200 ^ 9 of Sertraline. 9. Agent according to claim 8, characterized in that it contains 50 mg of Sertraline. 10. Use of an agent according to one of the preceding claims for the treatment of depressions or depressive states. 11. Use of an agent according to one of the preceding claims to produce a medicament for the treatment of depressions. 12. Procedure for the treatment of depressions in patients suffering from such a disease, characterized in that a combination of active substances is administered according to one of the preceding claims. 13. Process according to claim 12, characterized in that the active substances are taken sequentially in the form of individual compounds.