Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-26
2001-12-18
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06331546
ABSTRACT:
This application claims benefit under 35 U.S.C. § 119 of application no. 19951702.9, filed on Oct. 27, 1999 in Germany, which is incorporated in its entirety by reference herein.
The invention relates to the use of 2-amino-3,4-dihydroquinazolines of the formula I
and of their pharmaceutically tolerable salts for the production of a medicament for the therapy and prophylaxis of ischemic conditions. In formula I:
R1 and R2 are
hydrogen, F, Cl, Br, I, straight-chain or branched C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy,
R3is hydrogen, straight-chain or branched C
1
-C
4
-alkyl or phenyl, the phenyl nucleus being unsubstituted or carrying one to three substituents selected from the group consisting of F, Cl, CH
3
and CH
3
O.
The use of compounds of the formula I and of their salts is preferred, in which:
R1 and R2 are hydrogen, fluorine, chlorine, straight-chain or branched C
1
-C
4
-alkyl, C
1
C
4
-alkoxy;
R3 is hydrogen or methyl.
If one of the three substituents R1, R2 and R3 contains an asymmetric center, the invention includes compounds of S and R configuration. The compounds can be present as optical isomers, as diastereoisomers, as racemates or as mixtures thereof.
Compounds of the formula I are known from EP 530 994, where they are described as inhibitors of HIV reverse transcriptase in the indication AIDS;
U.S. Pat. No. 3,560,050, in which their analgesic, diuretic and anti-inflammatory action is described;
and from Kosasayama et al., Chem. Pharm. Bull. 27, 880 (1979) and Ishikawa et al. Ibid, 28, 1357 (1980), where it was possible to show an inhibition of platelet aggregation for 2-amino-4-phenyl-3,4-dihydroquinazoline.
Surprisingly, it has now been found that these known compounds are distinguished by inhibition of Na
+
/H
+
exchange. Thus, as a result of their pharmacological properties, they are outstandingly suitable for the production of antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and also for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I used according to the invention, as a result of inhibition of the cellular Na
+
/H
+
exchange mechanism, can serve as pharmaceuticals for the treatment of all acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby. This relates to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantation, where the compounds used according to the invention can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and during transfer to the recipient's body. The compounds used according to the invention are also valuable pharmaceuticals having a protective action when carrying out angioplastic surgical interventions, for example on the heart and on peripheral vessels. According to their protective action against ischemically induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and of bacterial shock.
Moreover, the compounds of the formula I used according to the invention are distinguished by strong inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of vascular smooth muscle cells. The compounds of the formula I used according to the invention are therefore suitable as valuable therapeutics for illnesses in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophy and hyperplasia, in particular in prostate hyperplasia and prostate hypertrophy.
The compounds used according to the invention are efficacious inhibitors of the cellular sodium/proton antiporter (Na
+
/H
+
exchanger), which is raised in numerous diseases (essential hypertension, atherosclerosis, diabetes etc.) even in those cells which are easily accessible to measurements, such as, for example, in erythrocytes, platelets or leukocytes. The compounds used according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostics for the determination and differentiation of certain forms of hypertension, but also of atherosclerosis, of diabetes, proliferative diseases etc. Moreover, the compounds of the formula I used according to the invention are suitable for preventive therapy for the prevention of the genesis of high blood pressure, for example of essential hypertension.
It has moreover been found that compounds of the formula I used according to the invention exhibit a favorable influence on serum lipoproteins. It is generally recognized that for the formation of arteriosclerotic vascular changes, in particular of coronary h eart disease, excessively high blood fat values, so-called hyperlipoproteinemias, are an essential risk factor. The lowering of raised serum lipoproteins therefore has exceptional importance for the p rophyl axis and the regression of atherosclerotic changes. In addition to the reduction of the total serum cholesterol, the lowering of the proportion of specific atherogenic lipid fractions of this total cholesterol, in particular of the low density lipoproteins (LDL) and of the very low density lipoproteins (VLDL) has particular importance, as these lipid fractions are an atherogenic risk factor. However, a protective function against coronary heart disease is ascribed to the high density lipoproteins. Accordingly, hypolipidemics should be able to lower not only the total cholesterol, but in particular the VLDL and LDL serum cholesterol fractions. It has now been found that the compounds of the formula I used according to the invention exhibit valuable therapeutically utilizable properties with respect to the influencing of the serum lipid levels. Thus they significantly reduce the raised serum concentration of LDL and VLDL, such as are to be observed, for example, due to increased dietetic intake of a cholesterol- and lipid-rich diet or in pathological metabolic changes, for example genetically related hyperlipidemias. They can therefore be used for the prophylaxis and for the regression of atherosclerotic changes, in that they exclude a causal risk factor. These include not only the primary hyperlipidemias, but also certain secondary hyperlipidemias, such as occur, for example, in diabetes. Moreover, the compounds of the formula I used according to the invention lead to a marked reduction in the infarcts induced by metabolic anomalies and in particular to a significant decrease in the induced infarct size and its degree of severity. Furthermore, the compounds of the formula I used according to the invention lead to an effective protection against endothelial damage induced by metabolic anomalies. With this protection of the vessels against the syndrome of endothelial dysfunction, compounds of the formula I are useful pharmaceuticals for the prevention and treatment of coronary vasospasms, of atherogenesis and of atherosclerosis, left-ventricular hypertrophy and dilated cardiomyopathy, and thrombotic diseases.
The compounds I used according to the invention are therefore advantageously used
for the production of a medicament for the treatment of
Albus Udo
Jansen Hans-Willi
Weichert Andreas
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner LLP
Henley III Raymond
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