Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-06-11
2000-10-10
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544278, A61R 31519, C07D49504
Patent
active
061302236
DESCRIPTION:
BRIEF SUMMARY
The invention relates to compounds of the formula I ##STR2## wherein
R.sup.1, R.sup.2 in each case independently of one another are H, A, OA, alkenyl, alkynyl, CR.sub.3 or Hal, wherein one of the radicals R or R.sup.2 is always .noteq.H,
R.sup.1 and R.sup.2 together are also alkylene having 3-5 C atoms,
R.sup.3, R.sup.4 in each case independently of one another are H, A, OA, NO.sub.2, NH.sub.2 NHA, NAA' or Hal,
R.sup.3 and R.sup.4 together also are --O--CH.sub.2 --CH.sub.2 --, --O--CH.sub.2 --O-- or --O--CH.sub.2 --CH.sub.2 --O--,
X is a 5- to 7-membered saturated heterocyclic ring which is mono- or disubstituted by R.sup.5, or a 5- to 7-membered unsaturated or saturated isocyclic ring which is mono- or disubstituted by R.sup.5,
R.sup.5 is COOH, COOA, CONH.sub.2, CONAA', CONHA, CN, CH.sub.2 COOH or CH.sub.2 CH.sub.2 COOH,
A,A' in each case independently of one another are H or alkyl having 1 to 6 C atoms,
Hal is F, Cl, Br or I and
n is 0, 1, 2 or 3,
Pyrimidine derivatives are known, for example, from EP 201 188 or WO 93/06104.
The invention was based on the object of discovering new compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties, coupled with a good tolerability.
In particular, they exhibit specific inhibition of cGMP-phosphodiesterase (PDE V).
Quinazolines having an inhibitory activity with regard to cGMP-phosphodiesterase 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 such as are described, for example, in WO 93/06104. The affinity of the compounds according to the invention for cGMP- and cAMP-phosphodiesterase is ascertained by determining their IC.sub.50 values (concentration of the inhibitor required to achieve a 50% inhibition of the enzyme activity).
Enzymes isolated by known methods can be used for carrying out the determinations (for example W. J. Thompson et al., Biochem. 1971, 10, 311). A modified "batch" method of W. J. Thompson and M. M. Appleman (Biochem. 1979, 18, 5228) can be used for carrying out the experiments.
The compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular cardiac insufficiency, and for treatment and/or therapy of disturbances in potency (erectile dysfunction).
The use of substituted pyrazolopyrimidinones for treating impotence is described, for example, in WO 94/28902.
The compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations of hares.
This biological action can be detected, for example, by the method described by F Holmauist et al. in J.Urol., 150, 1310-1315 (1993).
The inhibition of the contraction demonstrates the activity of the compounds according to the invention for therapy and/or treatment of disturbances in potency.
The compounds of the formula I can be employed as medicament active compounds in human and veterinary medicine. They can furthermore be employed as intermediate products for the preparation of further medicament active compounds.
The invention accordingly relates to the compounds of the formula I and a process for the preparation
a) of compounds of the formula I according to claim 1, and salts thereof, wherein X is a saturated 5- to 7-membered heterocyclic ring which is mono- or disubstituted by R.sup.5 and is bonded via N, ##STR3## wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n have the meanings given mono- or disubstituted by R.sup.5,
b) of compounds of the formula I according to claim 1, and salts thereof, wherein X is an unsaturated or saturated 5- to 7-membered isocyclic ring which is mono- or disubstituted by R.sup.5 and is bonded via C, ##STR4## wherein
R.sup.1, R.sup.2 and X have the meanings given ##STR5## wherein
R.sup.3, R.sup.4 and n have the meanings given,
c) in a compound of the formula I a radical R.sup.3, R.sup.4 and/or X is c
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Christadler Maria
Jonas Rochus
Kluxen Franz-Werner
Schelling Pierre
Balasubramanian V
Merck Patent Gesellschaft mit beschrankter Haftung
Raymond Richard L.
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