Aminothiophene carboxylic acid amides and the use thereof as pho

Details Aminothiophene carboxylic acid amides and the use thereof as pho Aminothiophene carboxylic acid amides and the use thereof as pho

1999-04-14

2000-11-07

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

444443, 549 57, 549 60, 549 69, A61K 3138, C07D33356, C07D40700, C07D33336

Patent

active

061437778

DESCRIPTION:

BRIEF SUMMARY
The invention relates to compounds of the formula I ##STR2## where R.sup.1 and R.sup.2, independently of one another, are each H, A, OA, alkenyl, alkynyl, CF.sub.3 or Hal, one of the radicals R.sup.1 or R.sup.2 always being.noteq.H, NO.sub.2, NH.sub.2 or Hal, --O--CH.sub.2 --O-- or --O--CH.sub.2 --CH.sub.2 --O--, atoms, ring which is unsubstituted or monosubstituted or disubstituted by COCH, COOA, CONH.sub.2, CONAA', CONHA, CN, NHSO.sub.2 A, Nd(SO.sub.2 A).sub.2 or SO.sub.2 A,
It was the object of the invention to provide novel compounds having valuable properties, in particular those which can be used for the preparation of drugs.
It was found that the compounds of the formula I and their salts have very valuable pharmacological properties in combination with good tolerance.
In particular, they exhibit a specific inhibition of CGMP phosphodiesterase (PDE V).
Quinazolines having cGMP-phosphodiesterase-inhibiting activity are described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994). Pyrazolopyrimidones which are suitable for the treatment of disturbances of potency are described, for example, in WO 94/28902.
The biological activity of the compounds of the formula I can be determined by methods as described, for example, in WO 93/06104 or WO 94/28902. The affinity of the compounds according to the invention for cGMP- and cAMP-phosphodiesterase is determined by determining their IC.sub.50 values (inhibitor concentration which is required to achieve 50% inhibition of the enzyme activity). determinations (e.g. 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 tests.
The compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular of myocardial insufficiency, and for the therapy of disturbances of potency.
The compounds of the formula I can be used as drug active ingredients in human and veterinary medicine. Furthermore, they can be used as intermediates for the preparation of further drug active ingredients.
The invention accordingly relates to the compounds of the formula I and a process for the preparation of compounds of the formula I according to claim 1 and their salts, ##STR3## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n have the stated meanings, ##STR4## wherein R.sup.1, R.sup.2, R.sup.5 and A have the stated meanings ##STR5## wherein R.sup.3, R.sup.4 and n have the stated meanings, R.sup.5 is converted into another radical R.sup.3, R.sup.4 and/or R.sup.5 by hydrolysing an ester or reducing a nitro group, treatment with a base.
Above and below, the radicals R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, A, L and n have the meanings stated in the case of the formulae I, II, III, IV and V, unless expressly stated otherwise.
A and A' independently of one another are each preferably H or alkyl having 1-6 C atoms.
In the above formulae, alkyl is preferably straight-chain 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, also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl or isopentyl.
Alkylene is preferably straight-chain and is preferably propylene, butylene or pentylene.
Of the radicals R.sup.1 and R.sup.2, one is preferably H while the other is preferable propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R.sup.1 and R.sup.2 together are also preferably propylene, butylene or pentylene.
Hal is preferably F, Cl or Br, but also I.
Alkenyl is preferably vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl or sec-butenyl, 1-pentenyl, isopentenyl or 1-hexenyl also being preferred.
Alkynyl is preferably ethynyl, propyn-1-yl and furthermore butyn-1-yl, bityn-2-yl, pentyn-1-yl, pentyn-2-yl or pentyn-3-yl.
The radicals R.sup.3 and R.sup.4 may be identical or different and are preferably in the 3- or 4-position of the phenyl ring. They are, for example, independently of one another, each H, alkyl, a

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