Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-05-04
1997-01-07
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 19, 514 43, 536 2411, 548200, C07D27706, A01K 31425
Patent
active
055917585
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new organic nitrates, to processes for their preparation and to their use in the treatment of vascular diseases and in particular in the treatment of angina.
An angina pectoris attack results from a sudden and reversible myocardial ischaemia and occurs when the oxygen demands of the myocardium are greater than the supplies from the coronary circulation.
Organic nitrates, which have been used for many years in the treatment of an anginal attack, induce a relaxation of the vascular smooth muscle fibre by raising the level of soluble cyclase guanylate, via nitric oxide formed during the conversion of the nitrates in the presence of cysteine.
In general, their haemodynamic effects are as follows: ventricular filling pressures and the volume of the left ventricle (LV), and therefore reduction in the ventricular parietal tension; ejection time from the left ventricle; and al., Rev. Med. Brux., 1989, 10, 82-88).
The leader amongst these products is trinitrin, which has a very rapid action; other derivatives have been developed and have a less rapid and more prolonged action than the latter.
In addition to trinitrin (nitroglycerine), the following may be mentioned as examples of organic nitrates: tetranitroerythritol, hexanitroinositol, tetranitropentaerythritol, propatyl nitrate, isosorbide 5-mononitrate (IS-5-MN), isosorbide dinitrate, isosorbide 2-mononitrate (IS-2-MN), isomannide 2-nitrate and trinitrotriethanolamine, and their substituted derivatives, in particular the aminopropanol derivatives of 1,4:3,6-dianhydrohexitol nitrates.
After penetration into the smooth muscle fibre, the organic nitrates would act by activating cyclase guanylate, in accordance with the following scheme: ##STR1## which shows that it is the S-nitrosothiol (R"-SNO), which would activate the cyclase guanylate.
The intracellular depletion of thiol groups would be responsible for the phenomenon of tachyphylaxis to organic nitrates, defined as the loss in activity of a substance during its repeated administration, with the need to increase the dose in order to obtain the same effect.
The prevention of this tachyphylaxis may take several forms: short-acting formulations) (U. ELKAYAM, Ann. Inter. Med., 1991, 114, 8, 667-677) avoided; European Patent Application EP 362 575 describes, for example, fatty acid nitrates bonded to sulphur-containing amino acids, which prevent or attenuate the tachyphylaxis. However, with regard to the compounds described in said application, the recession available is not sufficient either in respect of pharmacology or in respect of toxicology.
The Applicant consequently aimed to provide novel organic nitrates which have a distinctly improved activity (in particular at the level of transport and crossing of cell barriers) and do not give rise to any tachyphylaxis and for which the toxicology and pharmacology of the starting materials is well known.
The present invention relates to organic nitrates, characterised in that they correspond to the following formula I: ##STR2## in which radical C: R.sub.1 represents a hydrogen atom, a (straight-chain, branched or cyclic) C.sub.1 to C.sub.6 alkyl group, an optionally substituted phenyl or an optionally substituted benzyl; C.sub.1 to C.sub.6 alkyl group, an optionally substituted phenyl, an optionally substituted benzyl, a C.sub.1 -C.sub.6 acyl group, an optionally substituted benzoyl, an alkoxycarbonyl or a CO--X group in which X represents a radical C or a radical D, E, F or G as defined below, and m represents 1 (5-centred ring) or 2 (5-centred ring); ##STR3## in which radical D: R.sub.1 and R.sub.2 have the same meaning as above; C.sub.1 to C.sub.6 O-alkyl group, an optionally substituted O-phenyl group, an optionally substituted O-benzyl group, a radical E as defined above, a radical of the type Y--B-- or an NH--CH(COOR.sub.3)CH.sub.2 --S--R.sub.4 group, in which R.sub.4 represents a hydrogen atom, a (straight-chain, branched or cyclic) C.sub.1 to C.sub.6 alkyl group, an optionally substituted phenyl, an optionally substituted S-phe
REFERENCES:
patent: 5385922 (1995-01-01), Bron
Berdeaux Alain
Bohn Helmut
Dreux Jacques
Martorana Piero
Nallet Jean-Pierre
Gerstl Robert
Laboratoires Hoechst, SA
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