Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-15
2001-02-20
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06191153
ABSTRACT:
The present invention relates to antidepressant agents. More particularly, it relates to the use of 2-amino-6-n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, particularly the (−)-enantiomer thereof, and the pharmacologically acceptable acid addition salts thereof as pharmaceutical compositions having an antidepressant activity.
The compounds referred to above are known in pharmaceutical compositions primarily for treating schizophrenia and Parkinson's disease. Details of the preparation of these compounds, the (−)-enantiomers of which are also referred to in the literature as SND 919 or pramipexol, can be found in European Patent Application EP-A 85 116 016.
Surprisingly, it has now been found that pramipexol and related compounds have antidepressant properties. Particularly significant in this context is that pramipexol has an unexpectedly low &agr;-receptor affinity and thus has a highly selective activity whilst being extremely well tolerated. The previously unknown long duration of activity of pramipexol (half life 12.5 hours) and its unexpectedly high bioavailability of more than 80% have proved particularly advantageous in the use of this substance as an antidepressant.
According to one aspect of the invention, therefore, we provide the use of 2-amino-6-n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole and the pharmacologically acceptable acid addition salts thereof for treating depression.
We further provide a method of treating depression in a human or animal subject which comprises administering to said subject an effective amount of a compound as defined above.
The antidepressant activity of pramipexol was demonstrated in preclinical trials in the “forced swimming test” . Details of this behavioural test are described for example by Willner, Psychopharmacology 83, 1-16 (1984) and by Borsini and Meli, Psychopharmacology 94, 147-160 (1988).
Pramipexol (SND 919) was investigated on eight rats, by comparison with amineptine, a known antidepressant. Both substances were dissolved in physiological saline solution and administered by parenteral route. The results are shown in Table 1.
TABLE 1
Investigation of SND 919 and amineptine in the
“forced swimming test”
Dose
Immobility time
Compound
mg/kg
(sec.)
Saline solution
—
208 ± 10
SND 919
0.03
210 ± 14
SND 919
0.10
165 ± 6
SND 919
0.30
102 ± 17
Amineptine
20.00
134 ± 19
The results obtained demonstrate that SND 919 is clearly superior to amineptine.
2-amino-6-n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, particularly the (−)-enantiomer thereof, and the pharmacologically acceptable acid addition salts thereof can be given for the treatment of depression, in the form of conventional galenic preparations consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, e.g. plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, etc. A therapeutically active single dose for the indication discovered according to the invention is within the range from 0.1 to 30 mg, preferably from 1 to 5 mg. In addition to being administered by oral or intravenous route pramipexol may also be taken transdermally. Suitable release systems for this purpose are known from the prior art, e.g. European Patent Application 428 038.
REFERENCES:
patent: 38 43 227 (1990-07-01), None
patent: 0 186 087 (1986-07-01), None
patent: 0 417 637 (1991-03-01), None
Benkert, et al; “Dopamine Autoreceptor Agonists in the Treatment of Schizophrenia and Major Depression”; Pharmacopsychiatry; 1992; 25/6; pp. 254-260.
Brooks, et al; “The Pharmacology of Pramipexole in the Spontaneously Hypertensive Rat”; European J. Pharmacology, 200; 1991; pp. 339-341.
Borsini, et al; “Is the Forced Swimming Test a Suitable Model for Revealing Antidepressant Activity?”; Psychopharmacology 94; 1988; pp. 147-160.
Carter, et al; “Pramipexole, A Dopamine D2 Autoreceptor Agonist, Decreases, the Extracellular Concentration of Dopamine In Vivo”; Eur. J. Pharmacol. Bd. 200, Nr. 1; 1991; pp. 65-72.
deGruyter, et al; “Praemenstruelles Syndrom”; W. Pschyrembel 'Klinisches Woerterbuch; 1981; p. 958.
Borsini Franco
Hammer Rudolf
Lehr Erich
Mierau Joachim
Boehringer Ingelheim KG
Raymond Robert P.
Reamer James H.
Stempel Alan R.
Witkowski Timothy X.
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