Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-05-01
2001-07-31
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S564000, C514S567000, C514S645000
Reexamination Certificate
active
06268397
ABSTRACT:
The present invention relates to the use in therapy of some (&agr;-aminomethyl-3,4-dichlorobenzyl)thioacetamide derivatives.
The present invention relates more specifically to the use of these compounds for inhibiting dopamine reuptake.
In EP-0,158,545, a description has already been given of a class of compounds of formula
in which X is S or So,
Z is a C
1
-C
4
alkoxy group or an NH
2
or NHOH group,
Z is a C
1
-C
4
alkyl group,
R is H or CH
3
, and
R
1
and R
2
represent H, F, Cl or Br.
These compounds have been described as anti-depressants.
In EP-0,406,088, a description has, in addition, been given of [&agr;-(tert-butylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its addition salts with pharmaceutically acceptable acids. This compound has also been described as an antidepressant and for promoting food intake.
The present invention is based on the discovery that:
[&agr;-(tert-butylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its laevorotatory isomer,
[&agr;-(tert-amylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its isomers,
[&agr;-(1-adamantylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its isomers, as well as the addition salts of these compounds with pharmaceutically acceptable acids, are potent inhibitors of dopamine reuptake, and may accordingly be used in therapy.
Consequently, the present invention relates to the use of a compound selected from:
[&agr;-(tert-butylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its laevorotatory isomer,
[&agr;-(tert-amylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its isomers,
[&agr;-(1-adamantylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its isomers, as well as the addition salts of these compounds with pharmaceutically acceptable acids, for the manufacture of a medicinal product which inhibits dopamine reuptake.
The outcome of inhibiting dopamine reuptake is an increase in the concentration of dopamine and of 3-methoxytyramine (3MT) in the synaptic space without modifying the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and of homovanillic acid (HVA). This property manifests itself in an increase in the functioning of the central dopaminergic pathways, which is appraised objectively by behavioural modifications such as the appearance of stereotyped movements, an increase in locomotor activity and a reductions in the period of immobility in animals subjected to the test of “behavioural despair”.
As a result of their properties of inhibition of dopamine reuptake, the compounds may be used in the following indications:
anhedonia, that is to say loss of interest and a withdrawal from all the usual pleasurable activities,
stimulation of cognition,
catatonic-type schizophrenia (according to DSM IV Classification)
Parkinson's disease,
pharmacological dependence on drugs such as cocaine.
For the first four indications, there exists a deficiency of functioning of the central dopaminergic systems, which may be corrected by inhibiting dopamine reuptake, the outcome of which is an improvement in dopaminergic transmissions resulting from the economical use of the dopamine synthesized and released.
For the last indication, pharmacological dependence on drugs such as cocaine, substances which inhibit dopamine reuptake bind to the site of transport of dopamine and hence compete for this site with drugs such as cocaine, thereby preventing these drugs from acting.
In these indications, the compounds may be administered orally at daily doses of 0.01 to 10 mg/kg, and preferably 0.1 to 5 mg/kg.
More generally, the compounds may be administered to man or animals orally or parenterally.
The compounds are generally administered in the form of solid, semi-solid or liquid compositions.
As examples of compositions, tablets, hard gelatin capsules, suppositories, solutions or suspensions for injection may be mentioned, as well as retard forms and slow-release implanted forms. In these compositions, the active principle is generally mixed with one or more customary pharmaceutically acceptable excipients well known to a person skilled in the art.
Among the compounds defined above, preference is given to [&agr;-(tert-butylaminomethyl)-3,4-dichlorobenzyl]-thioacetamide and most especially the laevorotatory isomer, that is to say (−)-[&agr;-(tert-butylaminomethyl)-3,4-dichlorobenzyl]thioacetamide and its addition salts with pharmaceutically acceptable acids.
The present invention relates, in addition, to
[&agr;-(tert-amylaminomethyl)-3,4-dichlorobenzyl]thioacetamide, and its isomers and the addition salts of these compounds with pharmaceutically acceptable acids,
[&agr;-(1-adamantylaminomethyl)-3,4-dichlorobenzyl]thioacetamide, its isomers and the addition salts of these compounds with pharmaceutically acceptable acids.
The isomers of [&agr;-(tert-butylaminomethyl)-3,4-dichlorobenzyl]thioacetamide may be obtained by separating the diastereoisomeric salts formed, respectively, with 1(−)-malic acid and d(+)-malic acid and racemic methyl [&agr;-(tert-butylaminomethyl)-3,4-dichlorobenzyl]-thioacetate, and ammonolysis of each of the isomers separated.
The compounds containing of a tert-amyl or 1-adamantyl group may be obtained according to processes similar to those described in EP-A-0,158,545 and EP-A-0,406,088.
The examples which follow illustrate the preparation of the new compounds.
REFERENCES:
patent: 5621011 (1997-04-01), Lafon
patent: 0 158 545 (1985-10-01), None
patent: 0 406 088 (1991-01-01), None
Chemical Abstracts AN 1990:491276, Allan et al. Jan. 1990.*
Chemical Abstracts AN 1995:802729, Smolders et al., Jan. 1995.*
Kemp and Vellaccio: Organic Chemistry, Chapter 5: Stereochemistry I: An Introduction, pp. 166, 168 and 172, 1980.
Celsa Bennett
Hsu Grace
Jacobson & Holman PLLC
Laboratoire. L. Lafon
LandOfFree
Use of (&agr;-aminomethyl-3,4-dichlorobenzyl) thioacetamide... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of (&agr;-aminomethyl-3,4-dichlorobenzyl) thioacetamide..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of (&agr;-aminomethyl-3,4-dichlorobenzyl) thioacetamide... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2559503