Use of low molecular weight thrombin inhibitor

Details Use of low molecular weight thrombin inhibitor Use of low molecular weight thrombin inhibitor

2000-11-06

2002-10-08

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S002600, C514S210030, C530S300000, C530S310000, C530S380000, C530S382000, C548S953000, C435S214000

Reexamination Certificate

active

06462021

ABSTRACT:

This invention relates to a new use of the low molecular weight thrombin inhibitor, melagatran and derivatives thereof.
Atrial fibrillation (AF) is characterised by grossly disorganised atrial electrical activity that is irregular in respect of both rate and rhythm. Patients with AF have no visually discernible timing pattern in atrial electrical activity when measured by surface ECG, or in electrogram sequences recorded by catheter electrodes.
During AF, the regular pumping action of the atria is replaced by irregular, disorganised and quivering spasms of atrial tissue. These spasms may be experienced as irregular heartbeat, palpitations, discomfort, dizziness and/or angina pectoris. Further, the inefficient pumping action of the heart tends to lead to significant morbidity related to reduced blood flow. More seriously, the reduced cardiac output can lead to blood pooling in the left atria and the formation of blood clots. Blood clots, mostly originating in the left atrium, can dislodge as an embolism and travel through the bloodstream to organs, e.g. the brain, spleen, kidneys etc. If the embolism travels to the brain, this may result in cerebral stroke and even death.
In the U.S. alone, AF affects an estimated two million people, with approximately 160,000 new cases being diagnosed each year. It has been estimated that AF is responsible for over 70,000 strokes each year in the U.S., and that the cost of treating these patients is more than U.S.$3.6 billion annually. The cost of drug treatment for AF alone has been estimated to be in excess of U.S.$400 million world-wide each year.
AF can be classified in two broadly defined groups: “valvular” AF and “non-valvular” AF (NVAF). In valvular AF, the arrhythmia is experienced due to a disorder of one or more of the heart valves (e.g. valvular disease), or the presence of mechanical (prosthetic) heart valves. Conversely, NVAF is AF experienced in the case where there is an absence of significant valvular disease or prosthesis.
Current drug therapies for AF include antiarryhthmic drugs, administered with a view to re-establishing a normal heartbeat, and anticoagulant and/or thrombolytic drugs, administered with a view to preventing thromboembolism and/or cerebral stroke.
However, it is estimated that only 40% of patients with AF who should benefit from anticoagulant therapy do so, owing to the risks associated with existing treatments. This also includes patients whose anticoagulant therapy is in combination with cardioversion (electrical or chemical). In particular, of the currently-available oral anticoagulants, warfarin (a vitamin K antagonist) carries the risk of bleeding, and the need for frequent laboratory control. Vitamin K antagonists also demonstrate a notable risk of interaction with other drugs and certain foods, e.g. those that are rich in Vitamin K, and their use requires monitoring of the patient's blood coagulation status. Medication containing acetylsalicylic acid (an antiplatelet agent) also carries the risk of bleeding.
Thus, there is a need for alternative and/or better anticoagulant treatments for use in patients with, or at risk of, AF, and especially NVAF.
International patent application WO 94/29336 discloses a group of compounds that are useful as inhibitors of serine proteases, such as thrombin and/or kininogenases. The thrombin-inhibiting compounds are thus indicated as anticoagulants, and the kininogenase-inhibiting compounds as antiinflammatory agents.
One of the thrombin-inhibiting compounds that is specifically disclosed in WO 94129336 is HOOC—CH
2
-(R)Cgl-Aze-Pab-H, which is also known as melagatran (see Example 1 of WO 94/29336, and the list of abbreviations in that document). International Patent Application WO 97/23499 discloses prodrugs of inter alia melagatran.
The use of melagatran and derivatives (including prodrugs) thereof in the treatment of thromboembolic events in patients with NVAF is not disclosed anywhere in the prior art.
We have now found that melagatran and derivatives thereof may be used in the treatment of thrombosis and/or thromboembolic events in patients with NVAF.
According to a first aspect of the invention there is provided the use of melagatran, or a pharmaceutically-acceptable derivative thereof, for the manufacture of a medicament for the treatment of an ischemic disorder, in a patient having, or at risk of, NVAF.
By patient “at risk of” NVAF, we include patients who are in danger of relapsing into NVAF.
For the avoidance of doubt, as used herein, the term “treatment” includes the therapeutic and/or prophylactic treatment of ischemic disorders.
“Pharmaceutically-acceptable derivatives” of melagatran include salts (e.g. pharmaceutically-acceptable non-toxic organic or inorganic acid addition salts) and solvates. It will be appreciated that the term further includes derivatives that have the same biological function and/or activity as melagatran. Moreover, for the purposes of this invention, the term also includes prodrugs of melagatran. The term “prodrug” includes any composition of matter that, following oral or parenteral administration, is metabolised in vivo to form melagatran in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term “parenteral” adminstration includes all forms of adminstration other than oral administration. Prodrugs of melagatran that may be mentioned include those disclosed generically and specifically in international patent application WO 97/23499. Preferred prodrugs are those of the formula R
1
O
2
C—CH
2
-(R)Cgl-Aze-Pab-OH (see the list of abbreviations in WO 97/23499), wherein R
1
represents C
1-10
alkyl or benzyl, such as linear or branched C
1-6
alkyl (e.g. C
1-4
alkyl, especially methyl, n-propyl, i-propyl, t-butyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab.
The term “ischemic disorders” will be understood by those skilled in the art to include any condition, the results of which include a restriction in blood flow in a part of the body. In this context, the term will also be understood to include thrombosis and hypercoagulability in blood and/or organs, tissues, etc.
The term “thrombosis” will be understood by those skilled in the art to include the formation, development or presence of a thrombus in animals including man, and which may result in embolism and/or ischemia. The term may thus include conditions such as atrophic thrombosis, arterial thrombosis, cardiac thrombosis, coronary thrombosis, creeping thrombosis, infective thrombosis, mesenteric thrombosis, placental thrombosis, propagating thrombosis. traumatic thrombosis and venous thrombosis.
The term “hypercoagulability” includes any state in which the blood is more readily coagulated than usual.
The term “NVAF” may be understood by those skilled in the art to mean grossly disorganised atrial electrical activity, which is irregular in respect of both rate and rhythm, leading to a hypercoagulable state and an increased risk of thrombosis originating from the left heart chambers, and particularly the left atrium. The term may thus also be understood to include AF (chronic, persistent, permanent and/or intermittent (paroxysmal)) in the absence of heart valvular disease (mostly rheumatic heart valvular disease e.g. mitral stenosis), or prosthesis, and to exclude patients with rheumatic mitral stenosis.
Particular disease states that may be mentioned include the prevention/treatment of ischemic heart disease, myocardial infarction, systemic embolic events in e.g. the kidneys, spleen etc, and, more particularly, of cerebral ischemia, including cerebral thrombosis, cerebral embolism and/or cerebral ischemia associated with non-cerebral thrombosis or embolism (in other words, the treatment/prophylaxis of thrombotic, or ischemic, stroke and of transient ischemic attack (TIA)) in patients with, or at risk of, NVAF. The skilled person will appreciate that patients with NVAF who are at risk of strok

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