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Title:  Use of moxonidine for postmyocardial infarction treatment
United States Patent:  7,041,303
Issued: 
May 9, 2006

Inventors:
 Schoemaker; Regina Geertruida (Rotterdam, NL)
Assignee:
 Solvay Pharmaceuticals GmbH (Hannover, DE)
Appl. No.:
 917858
Filed:
 July 31, 2001


 

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Abstract

A method of treating myocardial damage secondary to myocardial infarction using moxonidine or a physiologically compatible salt thereof. Pharmaceutical preparations containing moxonidine and its physiologically compatible acid addition salts are suitable for use in acute myocardial infarction and/or postmyocardial infarction management. In addition to a beneficial influence, promoting recovery and/or rehabilitation, on the myocardial status following myocardial infarction, moxonidine and its physiologically compatible acid addition salts, especially when used in the management of postmyocardial infarction patients in the chronic stage, also show a preventive effect against the progression of heart failure after myocardial infarction.

SUMMARY OF THE INVENTION

The object of the invention is to provide new pharmaceutical preparations that exert a beneficial influence, promoting recovery and/or rehabilitation, on the myocardial status of myocardial infarction patients and which are therefore suitable for the treatment of myocardial damage secondary to myocardial infarction within the context of myocardial infarction and/or postmyocardial infarction management.

According to the invention, 4-chloro-5-[(4,5-dihydro-1H-imidazol-2-yl)-amino]-6-methoxy-2-methylpyrimidine and its physiologically compatible acid addition salts are used for the manufacture of pharmaceutical preparations for the treatment of myocardial damage secondary to myocardial infarction.

Suitable physiologically compatible acid addition salts of moxonidine include salts with inorganic acids, for example hydrohalic acid, or with organic acids, for example low molecular weight aliphatic mono- or dicarboxylic acids such as acetic acid, fumaric acid or tartaric acid or aromatic carboxylic acids such as e.g. salicylic acid.

The compounds used according to the invention fall within the scope of the 5-[(2-imidazolin-2-yl)-amino]-pyrimidine derivatives with blood pressure lowering properties described in German Patent Application No. 28 49 537, and are known from this patent application. Pharmaceutical preparations containing moxonidine are commercially available as antihypertensive medications under the trade name Physiotens® and are used medically as antihypertensive agents. The compounds can be manufactured in a manner known in the art according to the process described in the aforementioned patent application or in a manner analogous to these processes.

It has now surprisingly been found that moxonidine and its physiologically compatible acid addition salts exert a beneficial effect, promoting recovery and/or rehabilitation, on the myocardial status following myocardial infarction and are therefore suitable for the treatment of myocardial damage secondary to myocardial infarction in man and larger mammals.

A myocardial infarction is generally understood to mean necrosis of a circumscribed area of heart muscle due to persisting complete interruption or critical reduction of blood supply to this area. In addition to general therapeutic measures (analgesia and sedation, oxygen administration, bed rest and diet) the management of acute myocardial infarction comprises especially thrombolytic or fibrinolytic therapy with the aim of preserving as much (primary) ischemic myocardium as possible from final cell death (e.g. definitive necrosis) by reperfusing the ischemic area and thereby restricting the infarct size to the smallest possible area. Further (supportive) measures can contribute to improving myocardial status, especially in the region of the infarct area, both in the acute phase of myocardial infarction and in the postmyocardial infarction phase.

The compounds used according to the invention for the treatment of myocardial damage secondary to myocardial infarction are suitable for general use in the management of myocardial infarction. They can therefore already be used for the treatment of acute myocardial infarction and especially for postmyocardial infarction management both in patients who have already received fibrinolytic treatment and in patients without such lysis. In postinfarction patients with lysis, treatment with the compounds used according to the invention in particular also has the effect of preventing the development of cardiac insufficiency of myocardial origin (myocardial heart failure). This also applies to such patients who have already been treated with b-adrenoceptor blocking drugs.

Postinfarction patients who have not undergone lysis pass into the chronic phase of myocardial infarction. For postinfarction patients in the chronic stage, the important role played by the sympathetic nervous system (SNS) in cardiovascular regulation is of particular significance. For example, sympathetic stimulation is the primary mechanism for increasing cardiac output, since this stimulation causes both an increase in myocardial contractility and heart rate. Acute myocardial infarction results, among other things, in activation of the SNS to maintain perfusion pressure and tissue perfusion. This acute situation can develop into a more chronic phase in which the sympathetic activation contributes to hypertrophy and remodelling processes in the non-infarcted myocardium. This process, however, can progress beyond the desired degree and the continued SNS activation may become harmful for various reasons:

  • 1) Chronic activation of the central sympathetic nervous system is to be regarded as unfavorable as regards the progression of heart failure. Persisting adrenergic stimulation results in a compensatory reduction of adrenergic receptors in the heart. The consequence of this protective mechanism of the heart against persistently elevated catecholamine levels, however, is significant impairment of the regulation of heart rate and the force of myocardial contraction via the autonomic nervous system.
  • 2) The SNS stimulation increases vascular tone and consequently the after load of the heart.
  • 3) Increased circulating catecholamine levels induce focal necrosis in the heart and contribute to the development of cardiac hypertrophy.
  • 4) Elevated plasma catecholamine levels contribute to the unfavorable increase of the heart rate and to the development of sometimes life-threatening cardiac arrhythmias.

    The prevention and abolition of excessive sympathic activation can therefore represent a desirable strategy for the management of myocardial infarction patients, especially also with the aim of preventing the progression of heart failure after myocardial infarction.

    It has now surprisingly been found that moxonidine used according to the invention for myocardial infarction and/or postmyocardial infarction management is distinguished by a surprising beneficial influence, promoting recovery and/or rehabilitation, on the functional status of the myocardium of myocardial infarction patients, especially of postmyocardial infarction patients in the chronic stage. Administration of moxonidine after myocardial infarction causes a reduction of cardiac weight and a reduction of sympathetic activation, as demonstrated by measurement of plasma noradrenaline levels. Moxonidine is therefore suitable for the reduction of excessive cardiac hypertrophy, especially in later phases of postmyocardial infarction treatment. Furthermore, moxonidine decreases plasma noradrenaline levels, allowing sympathetic activation after myocardial infarction to be effectively normalized.

    For the treatment of myocardial damage secondary to myocardial infarction according to the invention, moxonidine and its physiologically compatible acid addition salts can be administered orally, intravenously or transdermally in conventional pharmaceutical preparations.

    Thus, moxonidine and its physiologically compatible acid addition salts may be included, in an amount effective in promoting recovery and/or rehabilitation of myocardial status, with conventional pharmaceutical excipients and/or vehicles in solid or liquid pharmaceutical preparations. Examples of solid formulations, which can be formulated for immediate or sustained release of the drug, are preparations suitable for oral administration such as tablets, coated tablets, capsules, powders or granules, but also suppositories. These solid preparations may contain conventional pharmaceutical inorganic and/or organic vehicles such as lactose, talc or starch as well as conventional pharmaceutical excipients such as lubricants or tablet disintegrants. In case of patches the drug is placed in a drug reservoir, in particular e.g. in a drug matrix (e.g. a polymeric matrix). Liquid preparations such as solutions, suspensions or emulsions of the active ingredients can contain the usual diluents such as water, oils and/or suspending agents such as polyethylene glycols and the like. Further excipients may also be added, such as preservatives, flavoring agents and the like.

    The active ingredients can be mixed and formulated with the pharmaceutical adjuvants and/or carriers in a manner known in the art. To manufacture solid dosage forms, the active ingredients may for example be mixed with the excipients and/or vehicles in the usual manner and wet or dry granulated. The granules or powder can be filled directly into capsules or compressed into tablet cores in the usual manner. If desired, these cores can be coated in the manner known to the art. Patches or transdermal therapeutic systems can be constructed in the conventional manner, e.g. of cover layer, drug reservoir (self-adhesive or with additional adhesive layer) and stripp-off layer, as matrix controlled systems as well as membrane controlled systems (e.g. equipped with additional control membrane).
     

  • Claim 1 of 5 Claims

    1. A method of treating myocardial damage secondary to myocardial infarction in a patient who has suffered a myocardial infarction, said method comprising administering to said patient who has suffered the myocardial infarction an amount of 4-chloro-5-[(4,5-dihydro-1H-imidazol-2-yl)-amino]-6-methoxy-2-methylpyrimidine corresponding to formula I: ##STR2##  (see Original Patent)

    or a physiologically compatible salt thereof effective to inhibit myocardial damage secondary to myocardial infarction.

    ____________________________________________
    If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

     

     

         
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