Substituted 4-amino-2-aryl-tetrahydoquinazolines, their...

Details Substituted 4-amino-2-aryl-tetrahydoquinazolines, their... Substituted 4-amino-2-aryl-tetrahydoquinazolines, their...

2000-02-04

2003-12-09

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S258100, C514S266400, C544S283000, C544S242000, C544S293000

Reexamination Certificate

active

06660746

ABSTRACT:

The present invention relates to compounds of formula I
wherein R
1
, R
2
and R
3
have the meanings indicated below, which are valuable pharmaceutically 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 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 formula I, their use for therapy and prophylaxis of the designated disease states, and for the production of pharmaceuticals therefor, and pharmaceutical compositions which comprise a compound of formula I.
cGMP is an important intracellular messenger which triggers 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 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 unclear. The binding of NO to the heme with formation of a pentacoordinated heme-nitrosyl complex has been discussed as a 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 an &agr;- and a &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. Subtypes &agr;
1
and &bgr;
1
are mainly expressed in the brain and the lung, while &bgr;2 is especially found in liver and kidney. Subtype &agr;
2
was detected in human fetal brain. 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 region 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, for example, 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, to an increase in the blood pressure, to platelet activation, or to increased cell proliferation or adhesion, for example. As a result, the formation of endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina pectoris, thromboses, myocardial infarcts, 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 and prevention of such diseases.
For the pharmacological stimulation of sGC until now, almost exclusively compounds were 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 by Vesely in a series of publications. However, the compounds described, which are mostly hormones, plant hormones, vitamins, or natural substances such as lizard toxins, predominantly showed 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. (
Brt. 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 activity. An inhibitory action on platelet aggregation for various indazoles is described in EP-A-667 345. Heterocyclylmethyl-substituted and benzyl-substituted pyrazoles exhibiting sGC stimulating activity are furthermore described in WO-A-98/16 507 and WO-A-98/16 223. Certain tetrahydroquinazolines are already known. For example, in DE-A40 29 654, 2-phenyltetrahydroquinazolines having fungicidal activity are described which in the 4-position carry specific amino substituents containing alkynyl groups. In U.S. Pat. No. 3,346,452 and U.S. Pat. No. 3,322,759, tetrahydroquinazolines are described which carry an aminoalkylamino group in the 4-position and which have analgesic activity Specific bicyclic pyrimidines are described in WO-A-97/47 601 which act as dopamine receptor antagonists and can be employed for the treatment of schizophrenia, and which carry a heterocyclylalkylamino substituent in which the heterocycle is bonded via a ring nitrogen atom. 2-Phenyl-cycloalkanopyrimidines are described in JP-A-071228 573 which are serotonin receptor antagonists and are suitable as psychopharmaceuticals, and which carry a piperazino or homopiperazino substituent in the 4-position. 2-Phenylcycloalkanopyrimidines are described in EP-A-826 673 which act on benzodiazepine receptors and have, for example, an anxiolytic activity, and which carry specific amino substituents in the 4-position which contain aminocarbonyl groups.
Surprisingly, it has now been found that the fused pyrimidines of formula I according to the invention bring about strong guanylate cyclase activation, which makes them suitable for the therapy and prophylaxis of diseases which are associated with a low cGMP level.
The present invention thus relates to compounds of formula I
wherein
R
1
and R
2
, which are selected independently of one another and which can be identical or different, are hydrogen, or (C
1
-C
10
)-alkyl which can be substituted by one or more identical or different substituents selected from hydroxy, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkyl-S(O)
m
—, (C
3
-C
7
)-cycloalkyl, phenyl, naphthyl, and pyridyl, or are (C
3
-C
9
)-cycloalkyl which can be substituted by one or more identical or different substituents selected from (C
1
-C
4
)-alkyl, benzyl, hydroxy, amino, H—CO—O—, (C
1
-C
4
)-alkyl-CO—O—, (C
1
-C
4
) -alkyl-O—CO—O—, H—CO—NH—, (C
1
-C
4
)-alkyl-CO—NH—, (C
1
-C
4
)-alkyl-O—CO—NH—, phenyl-CO—NH—, (C
1
-C
4
)-alkyl-SO
2
—NH—, and phenyl-SO
2
—NH—, or are a residue of a 5-membered to 7-membered saturated heterocyclic ring which contains one or two identical or different heteroatom ring mem

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