Substituted amidoalkyl-uracils and their use

Details Substituted amidoalkyl-uracils and their use Substituted amidoalkyl-uracils and their use

2001-07-16

2003-11-18

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S253000, C544S278000, C514S260100

Reexamination Certificate

active

06649618

ABSTRACT:

The present invention relates to novel chemical compounds, to a process for their preparation and to their use as medicaments, in particular for the prevention and/or therapy of ischaemia and reperfusion damage.
The elucidation of the molecular mechanism of cell death is the subject of intense biomedical research efforts. The aim is to find specifically active compounds which have modulating action in this process. When the individual biochemical steps resulting in cell death were examined, attention was drawn to poly(ADP-ribose)-synthetase (PARS), a protein which is expressed strongly in the cell nucleus and which is involved in deoxyribonucleic acid (DNA) damage repair [Szabo and Dawson, Trends in Pharmacological Sciences, 19, 287-298 (1998)].
Activation of PARS plays an important role in N-methyl-D-aspartate (NMDA)- and NO-induced neurotoxicity [Zhang et al., Science, 263, 687-689 (1994); Wallis et al., NeuroReport, 5, 245-248 (1993)], cerebral ischaemia [Endres et al., J. Cereb. Blood Flow Metabol., 17, 1143-1151 (1997)], traumatic brain injuries [Wallis et al., Brain Res., 710, 169-177 (1996)] and ischaemia/reperfusion damage to heart and skeletal muscle [Thiemermann et al., Proc. Nat. Acad. Sci., 94, 679-683 (1997)]. In addition, inhibition of PARS appears to have a positive effect on the therapy of arthritis [Szaboet al., Japanese J. Pharm., 75, Supp. I:102 (1997)], diabetes [Shimabukuro et al., J. Clin. Invest., 100, 290-295 (1997)] and endotoxic or septic shock [Zingarelli et al., Shock, 5, 258-264 (1996)], radiosensitization of hypoxic tumour cells [Weltin et al., Oncol. Res., 6, 399-403 (1994)], chronic colitis [Jijon et al., Am. J. Physiol. Gastrointest. Liver Physiol., 279, G641-51 (2000)], sudden deafness [Tabuchi et al., Ann. Otol. Rhinol. Laryngol., 110(2), 118-21 (2001)], inflammatory pulmonary disorders, such as, for example, asthma and chronic bronchitis [Cuzzocrea et al., Eur. J. Pharm., 342, 67-76 (1998)] and cancer.
PARS, an enzyme which constructs polymeric ADP-ribose units from nicotinamide adenosine dinucleotide (NAD
+
) as substrate, is activated when the DNA is damaged by single- or double-strand breaks. The polymeric ADP-ribose units formed are attached both to PARS itself and to other proteins, for example histones, topoisomerases and polymerases.
Increased activation of PARS results in a massive NAD
+
consumption. The marked decrease of the NAD
+
concentration and the resulting impediment of ATP synthesis (decrease of the ATP concentration) causes deterioration of the energetic state of the cell, which may lead to premature cell death (necrosis).
In the heart, reperfusion of ischaemic myocardium results in the generation of radicals, neutrophil infiltration, destruction of the myocardial tissue structure, contraction dysfunctions and necrosis. The H
2
O
2
generated during the reperfusion phase reacts rapidly with NO, forming peroxynitrite. NO, peroxynitrite and H
2
O
2
cause DNA strand breaks, thus resulting in overstimulation of PARS.
A further important point in the case of reperfusion damage is the accumulation of neutrophils in the reperfused myocardium. Activation of PARS increases the infiltration of neutrophils by stimulating the expression of P-selectin and ICAM-1.
Healthy PARS knock-out mice capable of reproduction are substantially protected against reperfusion damage. Infiltration of neutrophils is reduced by 50% and the structure of the myocardial tissue remains intact during the reperfusion phase.
In cases of ischaemia and reperfusion damage to heart and brain, low-molecular-weight PARS inhibitors, such as, for example, 3-aminobenzamide and 1,5-dihydroxyisoquinoline, protect the tissue against necrotic cell death (reduction of the infarct size by 30 to 48%) and delay myocardial and neuronal dysfunction.
However, the PARS inhibitors hitherto tested in animal experiments have various disadvantages. Thus, for example, 3-aminobenzamide is an unspecific PARS inhibitor which also inhibits cytochrome P
450
(Eriksson et al., Toxicology and applied Pharmacology, 136, 324-331 (1996)); in contrast, 5-iodo-6-amino-1,2-benzopyrone has serious side-effects (Szabo and Dawson, Trends in Pharmacol. Sciences, 19, 287-298 (1998)). Moreover, most inhibitors are not very potent and are therefore only efficacious in animals at a relatively high dosage (Thiemermann et al., Proc. Natl. Acad. Sci., 94, 679-683 (1997)).
JP-A-032645679 and Chem. Pharm. Bull. 38 (10), 2726-2732 (1990) disclose bicyclic 2,4-(1H,3H)-pyrimidinediones as 5-HT
2
antagonists for the treatment of cardiovascular diseases, depression and other mental disorders. U.S. Pat. No. 5,859,014 discloses tetrahydroquinazolinedione derivatives as &agr;
1
adrenergic receptor antagonists for the treatment of prostate hypertrophy. WO-A-00/42025 describes dihydropyrimidinones as PARS inhibitors. DE-A-1959705 and DE-A-2126148 list uracil derivatives for preparing crop protection agents. DE-A-2142317 mentions uracil derivatives having hypnotic properties. Furthermore, various bridged uracils are described in the literature as nucleoside analogues with potential antiviral action (for example Nucleosides Nucleotides 13 (1-3), 177-196; 13 (4), 891-902 (1994) and J. Med. Chem. 39 (3), 789-795 (1996)).
Accordingly, it is an object of the present invention to provide novel substances for the prevention and/or therapy of disorders, in particular of ischaemia and reperfusion damage.
Here, the compounds according to the invention presumably act as inhibitors of poly(ADP-ribose)-synthetase (PARS).
The present invention relates to compounds of the formula (I)
in which
A represents a ring member selected from the group consisting of:
—D—,
—CH
2
—D—,
—D—CH
2
—,
—CH═CH—CH
2
—,
—CH
2
—CH═CH—,
—CH
2
—CH
2
—D—,
—D—CH
2
—CH
2
and
—CH
2
—D—CH
2
—, in which
D represents —CH
2
—, —O— or —S—,
X represents (C
2
-C
10
)-alkylene or (C
3
-C
8
)-cycloalkylene which are optionally mono- or polysubstituted, independently of one another, by substituents selected from the group consisting of (C
1
-C
6
)-alkoxy, hydroxyl, amino, mono- and di-(C
1
-C
6
)-alkylamino and oxo,
R
1
represents hydrogen, (C
1
-C
6
)-alkyl which is optionally mono- or polysubstituted by halogen, or represents (C
3
-C
8
)-cycloalkyl,
R
2
represents a group of the formula —SO
2
—R
4
, —SO
2
—NR
5
R
6
, —CO—R
7
, —CO—NR
8
R
9
or —CO—OR
10
, in which
R
4
represents (C
1
-C
6
)-alkyl or (C
3
-C
8
)-cycloalkyl which are optionally substituted by (C
1
-C
4
)-alkoxy, (C
6
-C
10
)-aryl, 5- to 10-membered heteroaryl having up to 4 heteroatoms from the group consisting of N, O and/or S, or up to trisubstituted by halogen, where the aryl or heteroaryl radicals for their part are optionally substituted by hydroxyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkyl, halogen, cyano or nitro, or represents a group of the formula
—G—E
 in which
E represents (C
6
-C
10
)-aryl or a 5- to 13-membered saturated, partially unsaturated or aromatic heterocycle having up to four heteroatoms from the group consisting of N, O and S, where the ring systems are in each case optionally substituted up to five times by identical or different substituents selected from the group consisting of nitro, cyano, halogen, optionally benzamido-substituted (C
1
-C
6
)-alkyl, trifluoromethyl, (C
3
-C
6
)-cycloalkyl, hydroxyl, oxo, (C
1
-C
6
)-alkoxy, carboxyl, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
6
)-alkanoyl, amino, aminocarbonyl, mono- and di-(C
1
-C
6
)-alkylaminocarbonyl, (C
1
-C
6
)-alkanoylamido, (C
1
-C
6
)-alkylsulphonyl, (C
1
-C
6
)-alkylthio, optionally (C
1
-C
4
)-alkyl-, halogen- or nitro-substituted phenylsulphonyl,
 and
G is absent or represents (C
6
-C
10
)-arylene or 5- to 10-membered heteroarylene having up to 4 heteroatoms from the group consisting of N, O and S, which are in each case optionally substituted up to three times by identical or different substituents selected from the group consisting of nitro, cyano, halogen, (C
1

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