Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-01-24
2004-10-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S604000, C514S613000, C560S008000, C562S006000, C562S582000, C564S084000, C564S123000
Reexamination Certificate
active
06809089
ABSTRACT:
The present invention relates to compounds of the formula I
in which A
1
, A
2
, R
2
and R
3
have the meanings indicated below, which are valuable pharmaceutical active compounds for the therapy and prophylaxis of diseases, for example of cardiovascular disorders such as high blood pressure, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I have the ability to modulate the endogenous production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of disease states which are associated with a disturbed cGMP balance. The invention relates to the use of compounds of the formula I for the therapy and prophylaxis of the designated disease states and for the production of pharmaceuticals therefor, novel compounds of the formula I, pharmaceutical preparations comprising them and processes for their preparation.
cGMP is an important intracellular messenger, which elicits a number of pharmacological effects by means of the modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels. Examples are smooth muscle relaxation, the inhibition of platelet activation and the inhibition of smooth muscle cell proliferation and leukocyte adhesion. cGMP is produced by particulate and soluble guanylate cyclases as a response to a number of extracellular and intracellular stimuli. In the case of the particulate guanylate cyclases, the stimulation essentially takes place by means of peptidic messenger substances, such as the atrial natriuretic peptide or the cerebral natriuretic peptide. The soluble guanylate cyclases (sGC), which are cytosolic, heterodimeric heme proteins, however, are essentially regulated by a family of low molecular weight, enzymatically formed factors. The most important stimulant is nitrogen monoxide (NO) or a closely relates species. The importance of other factors such as carbon monoxide or the hydroxyl radical is still largely unclarified. The binding of NO to the heme with formation of a pentacoordinated heme-nitrosyl complex is discussed as an activation mechanism of activation by NO. The release associated therewith of the histidine which is bound to the iron in the basal state converts the enzyme into the activated conformation.
Active soluble guanylate cyclases are each composed of one &agr;- and one &bgr;-subunit. Several subtypes of the subunits have been described, which differ from one another with respect to sequence, tissue-specific distribution and expression in various stages of development. The subtypes &agr;
1
and &bgr;
1
are mainly expressed in the brain and lung, while &bgr;
2
is especially found in liver and kidney. The subtype &agr;
2
was detected in human fetal brain. The subunits designated as &agr;
3
and &bgr;
3
were isolated from human brain and are homologous to &agr;
1
and &bgr;
1
. More recent studies point to an &agr;
2i
subunit, which contains an insert in the catalytic domain. All subunits show great homology in the area of the catalytic domain. The enzymes presumably contain one heme per heterodimer, which is bonded via &bgr;
1
-Cys-78 and/or &bgr;
1
-His-105 and is part of the regulatory center.
The formation of guanylate cyclase-activating factors can be decreased under pathological conditions or increased degradation thereof can take place as a result of the increased occurrence of free radicals. The decreased activation of the sGC resulting therefrom leads, via the attenuation of the respective cGMP-mediated cell response, for example, to an increase in the blood pressure, to platelet activation or to increased cell proliferation and cell adhesion. As a result, the formation of endothelial dysfunction, atherosclerosis, high blood pressure, stable and unstable angina pectoris, thromboses, myocardial infarct, strokes or erectile dysfunction occurs. The pharmacological stimulation of the sGC offers a possibility for the normalization of cGMP production and thus allows the treatment or prevention of diseases of this type.
For the pharmacological stimulation of sGC, until now compounds have almost exclusively been used whose action is based on an intermediate release of NO, for example organic nitrates. The disadvantage of this method of treatment lies in the development of tolerance and reduction of activity and the higher dosage which therefore becomes necessary.
Various sGC stimulators which do not act via a release of NO have been described in a series of publications by Vesely. The compounds, which are mostly hormones, plant hormones, vitamins or, for example, natural substances such as lizard toxins, however, predominantly show only weak effects on 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). Stimulation of heme-free guanylate cyclase by protoporphyrin IX was detected by Ignarro et al. (Adv. Pharmacol. 26 (1994) 35). Pettibone et al. (Eur. J. Pharmacol. 116 (1985) 307) described a hypotensive action for diphenyliodonium hexafluorophosphate and attributed this to a stimulation of sGC. Isoliquiritiginin, which shows a relaxant action on isolated rat aortas, likewise activates sGC according to Yu et al. (Brit. J. Pharmacol. 114 (1995) 1587). 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) detected an sGC stimulating activity of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated an antiproliferative and platelet-inhibiting action.
A number of sulfonylaminocarboxylic acid N-arylamides of the formula I are already known. Compounds of this type are used, for example, in the production of photographic materials (see, for example, Chemical Abstracts 119, 105 755; 116, 245 151 and 104, 177 628) and, for this purpose, then in general contain in the N-aryl group as substituents easily oxidizable groups such as, for example, two hydroxyl groups in the para-position to one another. For various compounds of the formula I, a pharmacological action has also already been described. Thus, for example, in DE-A-35 23 705, an anthelmintic action is described for a series of 2-phenylsulfonylaminobenzamides. Antiparasitic, antimicrobial or fungicidal actions of 2-sulfonylaminobenzoic acid N-(hetero)arylamides are also mentioned, for example, in EP-A-420 805 and in Chemical Abstracts 122, 136 749; 120, 560; 119, 116 978; 116, 228 237; 116, 207 806; 115, 158 666 and 106, 152 850. According to EP-A-347 168, certain compounds of the formula I having a phenyl pivalate structure are elastase inhibitors and can be used in the treatment of atherosclerosis or arthritis. In Chemical Abstracts 104, 33 896, a psychotropic action is described for certain 2-sulfonylaminobenzoic acid N-phenoxyphenylamides. Various 2-trifluoromethylsulfonylamino- and 2-methylsulfonylamino-substituted benzamides are described as angiotensin II receptor antagonists having antihypertensive activity in Hypertension 15 (1998) 823, J. Med. Chem. 33 (1990) 1312, EP-A-253 310, EP-A-324 377, EP-A-449 699, EP-A-530 702 and U.S. Pat. No. 4,880,804.
Surprisingly, it has now been found that the compounds of the formula I bring about strong guanylate cyclase activation, on account of which they are suitable for the therapy and prophylaxis of diseases which are associated with a low cGMP level.
The present invention thus relates to the use of compounds of the formula I
in which
A
1
is a radical from the group consisting of phenyl, naphthyl and heteroaryl, which can all be substituted by one or more identical or different radicals R
1
;
the ring A
2
, which includes the carbon atoms which carry the groups CO—NH— and NH—SO
2
R
2
, is a benzene ring, a naphthalene ring, a saturated or partially unsaturated 3-membered to 7-membered carbocycle, a saturated, partially unsaturated or aromatic monocyclic 5-membered to 7-membered heterocycle which contains one or more ring heteroatoms from the group consisting of N, O and S, or a saturated, partially unsaturated or aromatic bicyclic 8-membered to 10-member
Schindler Ursula
Schoenafinger Karl
Strobel Hartmut
Aventis Pharma Deutschland GmbH
Fennigan, Henderson, Farabow, Garrett & Dunner, L.L.P.
Patel Sudhaker B.
Raymond Richard L.
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