Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-02-09
2000-08-29
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514267, 544278, 544250, A61K 31519, C07D49504
Patent
active
061109207
DESCRIPTION:
BRIEF SUMMARY
The invention relates to compounds of the formula I ##STR2## in which R.sup.1, R.sup.2 in each case independently of one another are H, A, OA, alkenyl, alkinyl, NO.sub.2, CF.sub.3 or Hal, where one of the radicals R.sup.1 or R .sup.2 is always .noteq.H, Hal, NO.sub.2, NH.sub.2, NHA or NAA', --O--CH.sub.2 --O or --O--CH.sub.2 --CH.sub.2 --O--, atoms, which is unsubstitued or mono-, di- or trisubstituted by A, Hal or CF.sub.3 and in which additionally further CH.sub.2 groups can be replaced by NH, NA, S or O bonded via N or C,
Pyrimidine derivatives are disclosed, for example, in EP 201 188 or in WO 93/06104.
The invention was based on the object of finding novel compounds which have valuable properties, in particular those which can be used for the preparation of pharmaceuticals.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties combined with good tolerance.
In particular, they show specific inhibition of cGMP phosphodiesterase (PDE V).
Quinazolines which have cGMP phosphodiesterase-inhibitory activity are described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994).
The biological activity of the compounds of the formula I can be determined by methods as they are described, for example, in Wo 93/06104. The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by determining their IC.sub.50 values (concentration of inhibitor required for achieving a 50% inhibition of enzyme activity). To carry out the determinations, enzymes which have been isolated by customary methods may be used (for example W. J. Thompson et al., Biochem. 1971, 10, 311). To carry out the experiments, a modified batch method of W. J. Thompson and M. M. Appleman (Biochem. 1979, 18, 5228) may be used.
Thus, the compounds are suitable for treating diseases of the cardiovascular system, in particular cardiac insufficiency, and for the therapy of impaired potency.
The compounds of the formula I can be employed as pharmaceutically active ingredients in human and veterinary medicine. Furthermore, they can be employed as intermediates for the preparation of other pharmaceutically active ingredients.
Accordingly, the invention relates to the compounds of the formula I and to a process for the preparation which X is bonded via N, characterized in that a compound of the formula II ##STR3## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n have the abovementioned meanings and L is Cl, Br, OH, SCH.sub.3 or a reactive esterified OH group one NH group and which is unsubstituted or mono-, di- or trisubstituted by A, Hal or CF.sub.3 and in which additionally further CH.sub.2 groups can be replaced by NH, NA, S or O, or which X is bonded via C, characterized in that a compound of the formula III ##STR4## in which R.sup.1, R.sup.2 and X have the abovementioned meanings, ##STR5## in which R.sup.3, R.sup.4 and n have the abovementioned meanings, or R.sup.3 and/or R.sup.4 is converted into a different radical R.sup.1, R.sup.2, R.sup.3 and/or R.sup.4 by reducing a nitro group, by converting a primary or a secondary amino group into an alkylated amine by reductive amination or by acylating such an amino group, and/or in that a basic compound of the formula I is converted into a salt thereof by treatment with an acid.
The radicals R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, L and n hereinabove and hereinbelow have the meanings given in formulae I, II, III, IV and V unless other details are given expressly.
A and A' are by preference in each case independently of one another alkyl having 1-6 C atoms.
In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 C atoms, preferably 1, 2, 3, 4 or 5 C atoms, and is preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl or isopentyl.
Alkylene is by preference unbranched and is preferably propylene, butylene or pentylene.
Amongst the radicals R.sup.1 and R.sup.2, one is by preference H
REFERENCES:
patent: 4146716 (1979-03-01), Cox et al.
patent: 4196207 (1980-04-01), Webber
Christadler Maria
Kluxen Franz-Werner
Rochus Jonas
Schelling Pierre
Merck Patent Gesellschaft mit beschrankter Haftung
Patel Sudhaker B.
Raymond Richard L.
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