Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2003-02-19
2004-09-21
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C546S146000, C546S226000, C514S255030, C514S307000, C514S330000
Reexamination Certificate
active
06794507
ABSTRACT:
The present invention relates to novel compounds having an anticoagulating action (so-called anticoagulants) and to their pharmacologically acceptable salts and solvates and hydrates, to pharmaceutical compositions comprising them as active ingredient, to processes for the preparation of such compounds, salts and compositions, and to the use thereof for the prevention and/or treatment of thromboembolic conditions. Those compounds, salts and compositions are very effective factor Xa inhibitors. The present invention relates also to pro-drugs, optically active forms, racemates and diastereoisomers of those compounds and salts.
Thromboembolic conditions are caused by an increased tendency to blood clotting in people with risk factors, such as, for example relatively major operations, prolonged immobilisation, fractures of the lower extremities, obesity, blood fat metabolism disorders, infections with gram-negative organisms, cancer and older age.
Venous thromboses may lead to the development of oedema or inflammation of the tissue drained by the affected vein. Thrombosis of a deeper vein (so-called deep vein thrombosis) may lead to serious complications, such as, for example, pulmonary embolism. Arterial thrombosis may lead to ischaemic necrosis of the tissue supplied by the affected artery, such as, for example, to myocardial infarct in the case of an affected coronary artery. Other thromboembolic conditions are, for example, arteriosclerosis, apoplexy (stroke), Angina pectoris, Claudicatio intermittens.
Under normal physiological conditions, natural blood clotting protects against greater blood loss from a damaged blood vessel. During blood clotting, liquid blood is converted into a blood clot, a gelatinous mass which seals injured blood vessels by forming a plug. In that process, soluble fibrinogen present in the plasma is converted into the fibrous-gelatinous clotting substance fibrin in a multi-stage process, the so-called coagulation cascade.
A distinction is made between two different processes for activating blood clotting. The intrinsic blood clotting process is initiated when blood comes into contact with non-physiological surfaces. The extrinsic blood clotting process is initiated by injury to blood vessels. Both blood clotting processes join in a common process in which the blood clotting factor X, a serine protease, is converted into its active form (factor Xa). Factor Xa, together with factor Va and Ca
2+
in the so-called prothrombinase complex, causes prothrombin to be converted into thrombin which in turn, by removal of peptides, releases fibrin monomers from fibrinogen which are capable of coagulating to form fibrin fibres. Finally, factor XIII brings about cross-linking and thus stabilisation of the fibrin fibres.
Anticoagulants are used both for the prevention and for the treatment of thromboembolic conditions. As far as anticoagulants in the narrower sense are concerned, heparin, which is immediately effective and which directly inhibits certain blood clotting factors, is distinguished from the vitamin K antagonists (for example coumarin derivatives). The latter inhibit the production in the liver of certain clotting factors which is dependent on the presence of vitamin K, and begin to take effect only slowly. Other anticoagulant agents are the fibrinolytics, which bring about direct or indirect activation of the fibrinolytic system, and thrombocyte aggregation inhibitors, such as, for example, acetylsalicylic acid. A more seldom used method is reduction of the fibrinogen level in the blood by the enzyme ancrod. The object of using anticoagulant agents is to prevent the development of a blood clot that could close a vessel or also to dissolve it again once it has formed.
The above-mentioned anticoagulants in the narrower sense, i.e. heparin and vitamin K antagonists, have disadvantages. In the case of heparin, a distinction is made between unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH). A disadvantage with UFH is the fact that it generally has to be administered intravenously, has a varying anticoagulant effect and therefore necessitates frequent monitoring of the patient and adaptation of the dosage. Although LMWH can be used subcutaneously in a constant, unmonitored dosage, because of its short chain length its effect is greatly reduced in comparison with UFH.
The vitamin K antagonists, such as, for example, warfarin, exhibit differing degrees of activity from patient to patient, presumably owing to genetic factors. In addition to the slow onset of action mentioned above, it involves the disadvantage that patients have to be monitored and individual adaptation of the dosage is required.
Other known anticoagulants belong to the group of the thrombin inhibitors. Current synopses of the relevant research activity in that field can be found, for example, in Jules. A. Shafer, Current Opinion in Chemical Biology, 1988, 2: 458-485, Joseph P. Vacca, Current Opinion in Chemical Biology, 2000, 4: 394-400 and in Fahad Al-Obeidi and James A. Ostrem, DDT, Vol. 3, No. 5, May 1998: 223-231.
A crucial disadvantage of thrombin inhibitors is that, in order to obtain the desired effect, it is necessary to suppress thrombin activity in vivo to such a great extent that the tendency to haemorrhage may increase, which makes dosage difficult.
In contrast, factor Xa inhibitors cause suppression of the new formation of thrombin from prothrombin, whereas they do not impair existing thrombin activity which is necessary for primary haemostasis.
In addition to the above-mentioned synoptic articles, the following may be mentioned here by way of example: DE 197 43 435, DE 197 55 268, DE 198 19 548, DE 198 39 499 and WO 0031068.
The range of action and the range of side-effects of those factor Xa inhibitors have not yet been fully investigated in some cases.
An object of the present invention was to provide novel compounds having useful properties, especially an anticoagulating action.
More precisely, the object was to provide novel factor Xa inhibitors having improved activity, reduced side-effects and/or increased selectivity. In addition, suitable pharmaceutical compositions were to be provided. Those compounds and compositions were to be administrable especially orally.
A further object of the present invention was to provide a process for the preparation of those novel compounds.
Those novel compounds were furthermore to be suitable for use in the prevention and/or treatment of thromboembolic conditions.
The present invention describes anticoagulant compounds, their pharmacologically acceptable salts and solvates and hydrates and formulations that are novel, have a high activity and selectivity and can be administered orally. The present invention further relates to pro-drugs, optically active forms, racemates and diastereoisomers of those compounds and salts. The said compounds and salts may also themselves be pro-drugs which are activated only by metabolism. Pharmaceutical compositions comprising the said compounds or salts etc. as active ingredient are also described. A number of direct and simple syntheses of the compounds, pro-drugs, salts and compositions of the invention and of intermediates that are useful in such systems is also described. The use of those active ingredients for the prevention and/or treatment of thromboembolic conditions is also described.
The present invention relates to a compound of the general formula (I):
wherein
X is Cl, Br or R
1
—N═CH(—NH
2
)— wherein
R
1
is H, —OH, —C(═O)OR
2
, alkyl, aralkyl, aralkyloxy or a heteroalkyl group, such as, for example, alkoxy, acyl or acyloxy, wherein R
2
is alkyl, such as methyl, ethyl or tert.-butyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl, such as benzyl;
Ar is arylene, heteroarylene, heteroarylalkylene or aralkylene, X being bonded directly to the aromatic ring system;
R
3
is H, alkyl, such as C
1
-C
4
-alkyl, heteroalkyl or aralkyl;
the groups R
4
independently of one another are alkyl groups that may be substituted
Cappi Michael W.
Eckl Robert
Fuchs Thilo
Schabbert Silke
Corless Peter F.
Edwards & Angell LLP
Hsi Jeffrey D.
Kumar Shailendra
Morphochem AG
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