Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-01
2004-03-02
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06699857
ABSTRACT:
The present invention relates to the field of erythropoiesis. In particular, the present invention relates to the use of tetrahydroquinolinyl-6-methyldihydrothiadiazinones for the prophylaxis and/or treatment of anaemias. Novel tetrahydroquinolinyl-6-methyldihydrothiadiazinone derivatives, and their preparation, are also described.
Anemias are characterized by the erythrocyte count, hemoglobin concentration and/or hematocrit decreasing below the age-related and sex-specific reference values. However, a decrease in one of these parameters is only a sign of an anemia when the blood volume is normal but not when the decrease is associated with acute, relatively marked blood losses, exsiccosis (pseudopolyglobulism) or hydremia (pseudoanemia). (Pschyrembel, Klinisches Wörterbuch [Clinical Dictionary], 257th edition, 1994, Walter de Gruyter Verlag, page 59 ff., entry “Anemia”; Römpp Lexikon Chemie [Römpp Chemistry Encyclopedia], version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry “Anemia”).
As a consequence of the decreased capacity of the blood to transport oxygen, anemia is characterized clinically by, inter alia, disturbances in oxygen-dependent metabolism and organ functions; when the anemia develops acutely, for example as a consequence of the loss of blood, shock symptoms can appear, and, when it develops chronically, there is frequently a slowly progressing course associated with decline in performance, tiredness, dyspnea and tachycardia.
The different forms of anemia can be subdivided or classified either in accordance with the morphology and hemoglobin content of the erythrocytes or in accordance with etiology (for example into posthemorrhagic anemia, pregnancy anemia, tumor anemia, infection anemia and deficiency anemias). It is furthermore possible to subdivide the different forms of anemia in accordance with their pathogenesis while taking into consideration the causes which are in principle possible, for example into anemias caused by excessive loss of blood (for example acute or chronic hemorrhagic anemia), anemias resulting from reduced or ineffective erythropoiesis (for example iron deficiency anemias, nephrogenic anemias or myelopathic anemias) and anemias resulting from excessive erythrocyte breakdown (what are termed hemolytic anemias) (Pschyrembel, Klinisches Wörterbuch, 257th edition, 1994, Walter de Gruyter Verlag, page 59 ff., entry “anemia”; Roche-Lexikon Medizin [Roche Medical Encyclopedia], 4th edition, 1999, Urban & Schwarzenberg, entry “anemia”).
In practice, the methods for treating anemias which are disclosed in the prior art prove to be very difficult and not particularly efficient. Large numbers of side-effects, which are frequently serious to the patient, usually occur.
Thus, in the therapy of iron deficiency anemias, use is generally made of iron preparations which are administered either orally or parenterally. When they are administered orally, it is, in particular, gastrointestinal disturbances which are observed as side-effects. The simultaneous administration of antacids, for the purpose of treating the gastrointestinal disturbances, impairs absorption of the iron. Furthermore, the absorption of iron from the intestinal tract is in any case only very limited because of the ability of the mucosa to impede the passage of iron. On the other hand, a dose which is administered orally should not be too high because, if it is, symptoms of poisoning can then occur, in the worst case even a hemorrhagic gastroenteritis which is associated with shock symptoms and leads to death. Administration of the iron therapy parenterally, which likewise proves to be difficult because of the plasma only having a low ability to bind iron, can lead, particularly when an overdose is given, to nausea, vomiting, cardialgias and headaches, heat sensations and a severe fall in blood pressure associated with collapse, and, furthermore, to the deposition of iron in the reticuloendothelium (hemosiderosis); the blood vessel walls are damaged by the intravenous injection and thrombophlebitis and clot formation must be expected. Dosing proves to be extremely difficult since all the iron which cannot be bound physiologically when it is administered parenterally then has a toxic effect (Gustav Kuschinsky, Heinz Lüllmann and Thies Peters, Kurzes Lehrbuch der Pharmakologie und Toxikologie [Short Textbook of Pharmacology and Toxicology], 9th edition, 1981, Georg Thieme Verlag Stuttgart, pages 139 ff.; Ernst Mutschler, Arzneimittelwirkungen, 30 Lehrbuch der Pharmakologie und Toxikologie [Effects of Medicaments, Textbook of Pharmacology and Toxicology], Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1986, pages 383 ff.).
For somewhat more than 10 years now, recombinant erythropoietin (rhEPO), 35 which is prepared by genetic manipulation, has been available for therapeutic employment for treating severe anemias. This is because, it is known that recombinant human (rh) EPO stimulates erythropoiesis humorally, as a result of which it has come to be used as an antianemic agent in the therapy of severe anemias, particularly in renal and nephrogenic anemias. In addition, rh EPO is used for increasing the number of endogenous blood cells in order to decrease the requirement for transfusions of foreign blood.
Erythropoietin (EPO) is a glycoprotein which has a molecular weight of about 34 000 Da. More than 90% of the EPO is synthesized in the kidney, and the EPO which is produced in this organ is secreted into the blood. The primary physiological function of EPO is that of regulating erythropoiesis in the bone marrow. In this location, EPO stimulates the proliferation and maturation of the erythrocytic precursor cells.
However, powerful side-effects occur when rh EPO is administered. These side effects include the development and amplification of high blood pressure and the causation of an encephalopathy-like symptomatology, leading all the way to tonic/clonic convulsions and cerebral or myocardial infarction due to thromboses. Furthermore, rh EPO is not available orally and has therefore to be administered intraperitoneally (i.p.), intravenously (i.v.) or subcutaneously (s.c.), thereby restricting its use to the therapy of severe anemias (Kai-Uwe Eckardt, “Erythropoietin: Karriere eines Hormons” [Career of a Hormone], Deutsches [Career of a Hormone], Deutsches Ärzteblatt 95, issue 6 dated Feb. 6, 1998 (41), pages A-285 to A-290; Rote Liste [Red List] 1998, Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH, see “Epoetin alpha” and “Epoetin beta”).
The publications EP 721 950, DE 42 30 755 and DE 43 38 948 disclose various quinolylthiadiazin-2-one-3-carboxylates which have a cardiovascular effect.
In addition the publication J. Prakt. Chem. Chem.-Ztg. (1997), 339 (4), 315-321 has described the enantiomeric resolution to give the (+)-3,6-dihydro-6-methyl-5-(1,2,3,4-tetrahydro-6-quinolinyl)-2H-1,3,4-thiadiazin-2-one.
An object of the present invention is now to find substances which are particularly suitable for treating anemias more efficiently and which, at the same time, avoid the disadvantages of the methods for treating anemias which are known from the prior art.
Another object of the present invention is that of providing novel compounds for the abovementioned purpose and also a process for preparing them.
It has now been found, surprisingly, that the compounds of the general formula (I)
in which
A, D and E are identical or different and represent hydrogen, halogen, trifluoromethyl or hydroxyl or represent (C
1
-C
6
)-alkyl or represent (C
1
-C
6
)-alkoxy,
R
1
and R
2
are identical or different and represent hydrogen or represent (C
1
-C
6
)-alkyl, in particular represent (C
1
-C
4
)-alkyl,
R
3
represents a radical of the formula —(X)
a
—R
4
,
in which
X represents CO or SO
2
,
a denotes a number 0 or 1,
and
R
4
denotes (C
3
-C
8
)-cycloalkyl or (C
6
-C
10
)-aryl or a 5- to 6-membered aromatic heterocycle having up to 3 ring heteroatoms from the series S, N and/or O, it being
Bechem Martin
Bräunlich Gabriele
Gerdes Christoph
Lögers Michael
Lustig Klemens
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