Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1996-03-29
1999-03-16
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514562, A61K 31225, A61K 31195
Patent
active
058831266
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/SE96/00320 filed Mar. 12, 1996.
FIELD OF THE INVENTION
The present invention relates to a new medical use of a certain cystine derivatives.
In particular the invention relates to the use of such cystine derivatives for the preparation of medicaments with effect against restenosis.
BACKGROUND OF THE INVENTION
Such cystine derivatives as to which the present invention has found a new pharmacological use are known from WO 91/185 94 and EP 463 514 to have immunomodulating activity. Nothing is reported or generally known concerning the pharmacological and/or therapeutic properties of these compounds with respect to effects or restenosis.
In connection with the present invention compounds of the general formula I are employed: ##STR1## wherein R is hydrogen, methyl, ethyl, n-propyl or a moiety -COR.sup.1, wherein R.sup.1 is a straight or branched akyl group having 1-12 carbon atoms, R.sup.2 is a straight or branched alkyl group having 1-12 carbon atoms and R.sup.3 is a moiety which provides an ester hydrolysable in body fluids to release the active compound in free acid form, or a physiologically acceptable salt and/or a stereochemical isomer thereof.
In particular compounds of the formula I wherein R is hydrogen or a moiety -CO-R.sup.1 wherein R.sup.1 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, isopropyl, 1-methylpropyl, 2-methylpropyl, tert. butyl, 3-methylbutyl or 2-metylbutyl, R.sup.2 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, isopropyl, 1-methylpropyl, 2-methylpropyl, tert. butyl, 3-methylbutyl or 2-methylbutyl and R.sup.3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or a physiologically acceptable salt and/or a stereochemical isomer thereof, are preferred.
The compounds of formula I are used in racemic form as well as stereoisomers (enantiomers, diastereomers). Of particular interest are the compounds having the L configuration, particularly interesting is N,N'-diacetyl-L-cystine.
The invention also involves the compound of formula I in the form of its physiologically acceptable salts, such as the salts of sodium, potassium, ammonium, calcium or magnesium. Also included are salts of the unesterified compounds with pharmaceutically acceptable organic bases, such as lysine, ethylenediamine, N,N'-dibenzylethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine and piperazine.
Lysine and arginine can be used in its D- or L- forms. Most preferred is the L-form.
The most preferred compound is di-L-lysinium-N,N'-diacetyl-L-cystinate (compound A).
The compounds of the general formula I may be prepared by any of the processes disclosed in EP 463 514. Salts of such compounds with organic bases are prepared according to any conventional method or any method disclosed in WO 93/11104.
PRIOR ART
Rapid development of the tunica intima occurs following mechanical injury to arteries. The most common such complication is the so called restenosis that occurs after percutaneous transluminal coronary angioplasty (PTCA), i.e. the removal of arteriosclerotic lesions causing stenosis in coronary vessels wih a balloon catheter, but similar complications can occur also as a result of other procedures and interventions.
After PTCA, restenosis develops in all patients. In approximately 1/3 of the patients, this consequence is so severe that within 3 to 6 months the developed restenosis requires renewed PTCA or coronary by-pass surgery. The need for chemotherapy that can substantially reduce the incidence of severe restenosis is thus obvious.
Acute thrombosis is a distinct risk during angioplastic manoeuvres, and heparin is therefore given during the surgical treatment. For the same reason aspirin is usually given for a period of time after the treatment. However,this medication does not reduce the development of restenosis in the months following the PTCA. Thus, there is today no generally accepted treatment available which reduces sufficiently the incidence of
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Bergstrand H.ang.kan
Pettersson Knut
Westerlund Christer
Astra Aktiebolag
Henley III Raymond
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