Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-17
2003-09-30
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S234500, C514S258100, C544S061000, C544S116000, C544S253000
Reexamination Certificate
active
06627628
ABSTRACT:
This application is a nation stage filing of International Application No. PCT/EP99/08382, filed Nov. 3, 1999. This application also claims the benefit of priority under 35 U.S.C. §119(a) to German Patent Application No. 198 53 278.4, filed on Nov. 19, 1998.
The present invention relates to compounds of the formula I,
in which R
1
, 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 furthermore relates to processes for the preparation of compounds of the formula I, their use for the therapy and prophylaxis of the designated disease states and for the production of pharmaceuticals therefor, and pharmaceutical preparations which contain compounds of the formula I.
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 peptide signal 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 related 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 are 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 probably 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 were almost exclusively 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 weakening of action and the higher dose which therefore becomes necessary.
Various sGC stimulators which do not act via a release of NO were 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, consistently 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 hexafluorophoshate 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. For various indazoles an inhibitory action on platelet aggregation is described in EP-A-667 345; heterocyclylmethyl-substituted and benzyl-substituted pyrazoles are furthermore described in WO-A-98/16 507 and WO-A-98/16 223. In international patent application PCT/EP99/05636, pyrimidines are described which show an sGC-stimulating activity.
Certain cycloalkano[d]pyrimidines and cyclopenta[d]pyrimidines are already known. Thus, in DE-A-40 29 654 fungicidally active 2-phenylcyclo-alkanopyrimidines are described which in the 4-position carry specific amino substituents which contain alkynyl groups. In U.S. Pat. No. 3,346,452 and U.S. Pat. No. 3,322,759, cycloalkanopyrimidines are described which carry an aminoalkylamino group in the 4-position and which have analgesic actions. In WO-A-97/47 601 specific bicyclic pyrimidines are described which act as dopamine receptor antagonists and can be employed, for example, for the treatment of schizophrenia and which carry a heterocyclylalkylamino substituent in which the heterocycle is bonded via a ring nitrogen atom. In JP-A-07/228 573, 2-phenylcycloalkanopyrimidines are described which are serotonin receptor antagonists and are suitable as psychopharmaceuticals and which carry a piperazino substituent or homopiperazino substituent in the 4-position. In EP-A-826 673 2-phenylcycloalkanopyrimidines are described which act on benzodiazepine receptors and have, for example, an anxiolytic action and which in the 4-position carry specific amino substituents which contain aminocarbonyl groups.
Surprisingly, it has now been found that the pyrimidines of the formula I according to the invention 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 compounds of the formula I
in which
R
1
and R
2
, which are independent of one another and can be identical or different, are hydrogen, or (C
1
-C
8
)-alkyl which can be substituted by one or more identical or different substituents from the group consisting of hydroxyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkyl-S(O)
m
—, phenyl, naphthyl and pyridyl, or (C
3
-C
9
)-cycloalkyl which can be substituted by one or more identical or d
Schindler Ursula
Schoenafinger Karl
Strobel Hartmut
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
Rao Deepak
LandOfFree
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