Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-09-07
1996-03-26
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142252, 5142255, 5142262, A61K 3154
Patent
active
055020496
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR 43/00312 filed Mar. 29, 1993.
FIELD OF THE INVENTION
The present invention relates to a novel therapeutic application of the phenothiazine derivatives of general formula: ##STR2## in which: the symbol R is an alkyl radical containing 1 to 5 carbon atoms in a straight or branched chain, and the symbols R.sub.1 and R.sub.2, which may be identical or different, are alkyl radicals containing 1 or 2 carbon atoms, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl radical, as well as their salts.
BACKGROUND OF THE INVENTION
It is understood that the products of general formula (I) exist in stereoisomeric forms, and that these stereoisomeric forms as well as the mixtures thereof fall within the scope of the present invention.
The phenothiazine derivatives which form the subject of the present invention are known for their analgesic and diuretic activity, as well as for their activity with respect to the central nervous system: U.S. Pat. No. 5,049,669 and U.S. Pat. No. 3,112,310.
DESCRIPTION OF THE INVENTION
It has now been found that a subclass of previously known phenothiazine derivatives, as well as their salts, additionally possess activity in the treatment of hypoxia and/or ischaemia. This subclass is defined by the general formula (I).
It was possible to demonstrate the activity of the products of general formula (I) in the method of N-methyl-DL-aspartic acid(NMDLA)-induced fits.
There is, in effect, a large amount of experimental data indicating that the excitatory neuromediator glutamate is a neurotoxin, and that the N-methyl-D-aspartate (NMDA) glutamate receptor (one of the glutamatergic receptors) complex is involved in the pathology of cerebral ischaemia.
It has been clearly demonstrated that NMDA antagonists manifest protective activity with respect to the damage caused by cerebral ischaemia or hypoxia: U. Dirnagl, J. Tanabe and W. Pulsinelli, Brain Research, 527, 62 (1990).
The phenothiazine derivatives of general formula (I), as well as their salts, are entirely suitable for the preparation of a medicinal product intended for the preventive and/or curative treatment of ischaemia and/or hypoxia, and in the following indications in particular: endarterectomy or during surgery necessitating an extracorporeal circulation;
Experimental Study
The activity was demonstrated in the following test, adapted from Singh, L. et al., Brit. J. Pharmacol., 99, 285 (1990).
The salt of N-methyl-DL-aspartic acid (NMDLA) at a concentration of 42.5 mg/cm.sup.3 is injected intravenously (i.v.) (0.14 cm.sup.3 /min) into the tail vein of a mouse (CD1 male, Charles River) until a convulsion is produced.
This convulsion represents the end-point of the test, and the mouse is killed immediately after the onset of this convulsion. The time elapsing between the injection of NMDLA and the fit is measured, and the threshold dose of NMDLA required to produce this fit is calculated for each mouse.
For the antagonists, the products under study are administered subcutaneously, 30 minutes before the injection of NMDLA at the threshold dose needed to introduce a fit. The results are expressed as a percentage increase in the time of onset of the fit, by comparison with the control group (which received only NMDLA), according to the following formula.
The minimum active dose is the first dose significantly different from the control which corresponds to a value of the above ratio of greater than 20.
It was demonstrated that the active doses lie in a range between 1 and 3 mg/kg.
The results obtained appear in the table below.
__________________________________________________________________________ % increase in the
time of onset of
convulsions at a
Example dose of 3 mg/kg
No. Structure s.c..
__________________________________________________________________________
##STR3## 41
2
##STR4## 28.5
3
##STR5## 64
4
##STR6## 28
5
##STR7## 61
6
##STR8## 28
7
##STR9## 24
__________________________________________________________________________
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patent: 4833138 (1989-05-01), Olney
patent: 5049669 (1991-09-01), Garret et al.
Tribulova et al., "Effect of chlorpromazine on the extent of ischemic changes of the myocardium. A histochemical study", Histochem. J. 16 383-384 (1984).
"Effetto preventivo di composti fenotiazinici e tioxantenici sulla necrosi epatica sperimentale da ischemia", Ann. Ist. Super. Sanita 7, 601-604 (1971).
G. E. Thomas et al., "Chlorpromazine Inhibits Loss of Contractile Function, Compliance and ATP in Ischemic Rabbit Heart", J Mol Cell Cardiol 15, 621-628 (1983).
Garret Claude
Rataud Jean
Stutzmann Jean-Marie
Cintins Marianne M.
Rhone-Poulenc Rorer S.A.
Weddington Kevin E.
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