Substituted isoindolones and their use as cyclic GMP...

Details Substituted isoindolones and their use as cyclic GMP... Substituted isoindolones and their use as cyclic GMP...

2000-10-06

2002-02-05

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S414000, C514S416000, C546S277100, C548S466000, C548S472000

Reexamination Certificate

active

06344468

ABSTRACT:

The present invention relates to substituted isoindolone derivatives of the formula I,
in which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined below, which are useful pharmaceutically active compounds for the therapy and prophylaxis of illnesses, for example cardiovascular diseases such as hypertension, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I are capable of modulating the body's production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of illnesses which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of the formula I, to their use for the therapy and prophylaxis of the abovementioned illnesses and for preparing pharmaceuticals for these, and also pharmaceutical preparations which comprise compounds of the formula I.
cGMP is an important intracellular messenger which triggers a number of pharmacological effects via the modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels. Examples are the relaxation of smooth muscles, the inhibition of thrombocyte activation and the inhibition of the proliferation of smooth-muscle cells and leukocyte adhesion. cGMP is produced by particulate and soluble guanylate cyclases (GC) as a response to a number of extra- and intracellular stimuli. In the case of the particulate guanylate cyclases, stimulation is essentially effected by peptidic messengers, such as the atrial natriuretic peptide or the cerebral natriuretic peptide. The soluble guanylate cyclases (sGC), which are cytosolic heterodimeric hem proteins, in contrast, are essentially regulated by a family of low-molecular-weight factors which are formed enzymatically. The most important stimulant is nitrogen monoxide (NO) or a closely related species. The function of other factors such as carbon monoxide or the hydroxyl radical is still largely unclear. Binding of NO to the hem with formation of a penta-coordinate hem-nitrosyl complex is being discussed as activation mechanism of the activation by NO. The associated release of the histidine which is bound in the basal state to the iron converts the enzyme into the active conformation.
Active soluble guanylate cyclases are in each case composed of an &agr; and a &bgr; subunit. Several subunit subtypes have been described which differ from one another with respect to sequence, tissue-specific distribution and expression in different development stages. The subtypes &agr;
1
and &bgr;
1
are mainly expressed in brain and lung, while &bgr;
2
is found in particular in liver and kidney. The subtype &agr;
2
was demonstrated in human fetal brain. The subunits referred to as &agr;
3
and &bgr;
3
were isolated from human brain and are homologous to &agr;
1
and &bgr;
1
. More recent works indicate an &agr;
2i
subunit which contains an insert in the catalytic domain. All subunits show great homologies in the region of the catalytic domain. The enzymes presumably contain one hem per heterodimer, which is bound via &bgr;
1
-Cys-78 and/or &bgr;
1
-His-105 and is part of the regulatory center.
Under pathologic conditions, the formation of guanylate-cyclase-activating factors can be reduced, or their degradation may be promoted owing to the increased occurrence of free radicals. The resulting reduced activation of the sGC leads, via a weakening of the respective cGMP-mediated cellular response, for example to an increase in the blood pressure, to platelet activation or to increased cell proliferation and cell adhesion. As a consequence, formation of endothelial dysfunction, atherosclerosis, hypertension, stable and unstable angina pectoris, thromboses, myocardial infarction, strokes or erectile dysfunction results. Pharmacological stimulation of sGC offers a possibility to normalize cGMP production and therefore makes possible the treatment and prevention of such disorders.
For the pharmacological stimulation of sGC, use has hitherto almost exclusively been made of compounds whose activity is based on an intermediate NO release, for example organic nitrates. The drawback of this treatment is the development of tolerance and a reduction of activity, and the higher dosage which is required because of this.
Various sGC stimulators which do not act via NO release were described by Vesely in a relatively large number of works. However, the compounds, most of which are hormones, plant hormones, vitamins or, for example, natural compounds such as lizard poisons, generally only have weak effects on the cGMP formation in cell lysates (D. L. Vesely, Eur. J. Clin. Invest. 15 (1985) 258; D. L. Vesely, Biochem. Biophys. Res. Comm. 88 (1979) 1244). A stimulation of hem-free guanylate cyclase by protoporphyrin IX was demonstrated by Ignarro et al. (Adv. Pharmacol. 26 (1994) 35). Pettibone et al. (Eur. J. Pharmacol. 116 (1985) 307) described an antihypertensive action of diphenyliodonium hexafluorophosphate and attributed this to a stimulation of sGC. According to Yu et al. (Brit. J. Pharmacol. 114 (1995) 1587), isoliquiritigenin, which has a relaxing action on isolated rat aortas, also activates sGC. Ko et al. (Blood 84 (1994) 4226), Yu et al. (Biochem. J. 306 (1995) 787) and Wu et al. (Brit. J. Pharmacol. 116 (1995) 1973) demonstrated an sGC-stimulating activity of 1-benzyl-3-(5-hydroxymethyl-2-furyl)-indazole and demonstrated an antiproliferative and thrombocyte-inhibiting action. EP-A-667 345 describes various indazoles as inhibitors of thrombocyte aggregation.
Various nitrogen-substituted 3-hydroxyisoindol-1-ones are known. In J. Org. Chem. 33 (1968) 3779, Winn and Zaugg describe the compounds of the formula I in which R
1
is unsubstituted phenyl, R
2
, R
3
, R
4
, R
5
and R
7
are hydrogen and R
6
is unsubstituted phenyl or 3,4-dimethoxyphenyl. However, they do not report on any pharmacological activity of the compounds. Surprisingly, it has now been found that the compounds of the formula I according to the invention effect a strong activation of guanylate cyclase, owing to which they are suitable for the therapy and prophylaxis of diseases associated with a low cGMP level.
Thus, the present invention relates to compounds of the formula I
in which
R
1
is (C
3
-C
7
)-cycloalkyl, phenyl or the radical of a 5-membered or 6-membered aromatic heterocycle which contains one or two identical or different heteroatoms selected from the group consisting of N, O and S, where the phenyl radical and the heterocyclic radical are unsubstituted or substituted by one or more identical or different radicals selected from the group consisting of (C
1
-C
4
)-alkyl, halogen, hydroxyl, (C
1
-C
4
)-alkoxy, benzyloxy, phenoxy, benzyl, phenyl, trifluoromethyl, cyano, hydroxycarbonyl, ((C
1
-C
4
)-alkoxy)carbonyl, aminocarbonyl, nitro, amino, (C
1
-C
4
)-alkylamino, di-((C
1
-C
4
)-alkyl)amino and ((C
1
-C
4
)-alkyl)-carbonylamino;
R
2
, R
3
, R
4
and R
5
independently of one another are hydrogen, halogen, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy;
R
6
is phenyl which is unsubstituted or substituted by one or more identical or different radicals selected from the group consisting of (C
1
-C
4
)-alkyl, halogen, hydroxyl, (C
1
-C
4
)-alkoxy, benzyloxy, phenoxy, benzyl, phenyl, trifluoromethyl, cyano, hydroxycarbonyl, ((C
1
-C
4
)-alkoxy)carbonyl, aminocarbonyl, nitro, amino, (C
1
-C
4
)-alkylamino, di-((C
1
-C
4
)-alkyl)amino and ((C
1
-C
4
)-alkyl)carbonylamino;
R
7
independently of R
6
has one of the meanings of R
6
or is hydrogen, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts;
where, if R
1
is unsubstituted phenyl and R
2
, R
3
, R
4
, R
5
and R
7
are hydrogen, R
6
may not simultaneously be unsubstituted phenyl or 3,4-dimethoxyphenyl.
Alkyl radicals may be straight-chain or branched. This also applies when they are part of other groups, for example of alkoxy groups. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The ter

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