WO1996012496A1

WO1996012496A1 - Use of n-[(1s,trans)-2-hydroxycyclopentyl]-adenosine for reducing myocardial injury

Info

Publication number: WO1996012496A1
Application number: PCT/EP1995/004089
Authority: WO
Inventors: James Louttit; Mark Francis Gurden
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1994-10-20
Filing date: 1995-10-18
Publication date: 1996-05-02
Anticipated expiration: 1997-04-20
Also published as: GB9421133D0; AU3843495A

Abstract

Compound of formula (1a), or physiologically acceptable salts or solvates thereof, in the reduction of myocardial infarction arising from severe myocardial ischaemia.

Description


  
 



   USE OF   N-l(lS,lRANS)-2-HYDROXYCYCLOPENTYLl-ADENOSINE    FOR REDUCING   MYOCAR   
 DIAL INJURY
The present invention relates to a new medical use of certain compounds and pharmaceutical compositions containing the same and more particularly relates to a new use of compounds which act as agonists at adenosine-1 (A1) receptors, and pharmaceutical compositions containing such compounds.



  International patent application publication number WO 92/20346 discloses a method of reducing myocardial reperfusion injury which comprises administration of adenosine, an adenosine-1 receptor agonist or an adenosine-2 receptor agonist, together with the antiarrhythmic agent lidocaine.



  International patent application publication number WO 92105177 discloses compounds which have adenosine agonist activity and which are said to be useful as anti-hypertensive and anti-ischaemic agents.



  European patent application publication number 0322 242 generally discloses compounds of formula (I):
EMI1.1     

Where X represents a hydrogen or chlorine atom, or a methyl group; and R represents a cycloalkyl or cycloalkenyl ring containing 5 to 8 carbon atoms, which ring is substituted by a hydroxy group, and is optionally substituted by a   C19alkyl    group; and salts and solvates thereof.



  Furthermore, EP0322242 specifically discloses   N-[(1 S,trans)-2-    hydroxycyclopentyl]adenosine, which has the structure:  
EMI2.1     

EP0322242 describes the subject compounds as being useful as anti-lipolytic agents. Furthermore, it is stated that "the compounds of the invention may independently affect cardiac function by reducing heart rate and conduction. The compounds may thus be used in the therapy of a number of cardiovascular disorders, for example cardiac arrythmias, particularly following myocardial infarction, and angina." The teaching of EP0322242 therefore, is that the above compounds of formula (I) thus possess the potential to exert anti-anginal and antidysrhythmic activities, similar to those exerted by   ss-adrenoceptor    blocking agents and calcium channel blocking agents.



  The priority document for EP0322242, namely   G88729994,    also describes compounds of formula (I) as being useful in reducing heart rate and conduction, and furthermore, "that the compounds may thus be used in the therapy of a number of cardiovascular disorders, for example ischaemic heart disease."   Go8729994    is teaching that the compounds of formula (I) therefore have potential to exert antidysrhythmic activities as discussed above, which dysrhythmic activities may be associated with, or result from, ischaemic heart disease. The type of ischaemic heart disease which may, for example, represent one possible cause of cardiac dysrhythmia, is "mild" ischaemic heart disease. The term 'mild'  ischaemic heart disease as used herein denotes ischaemic heart disease not resulting in irreversible myocardial damage (i.e. infarction).



  We have now unexpectedly found that a compound of formula (la) as described above is useful in the reduction of deleterious effects to the myocardium, such as reduction of myocardial infarction, arising from severe myocardial ischaemia. The term "severe myocardial ischaemia" as used herein denotes an ischaemic condition arising from abrupt interruption of coronary artery blood flow followed by reperfusion on restoration of such coronary artery blood flow. Such severe myocardial ischaemia can accompany, for example, coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), acute myocardial infarction, unstable angina and cardiac surgery including, in particular, cardiac transplantation.



  In a first aspect, the invention provides the use of a compound of formula   (la),    or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the reduction of myocardial infarction arising from severe myocardial ischaemia as described above.



  There is further provided use of a compound of formula   (lea),    or a physiologically acceptable salt or solvate thereof, in the manufacture of a medicament for the reduction of deleterious effects to the myocardium, particularly impairment of cardiac function, associated with any of coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), acute myocardial infarction, unstable angina and cardiac surgery. Furthermore, a compound of formula (la) may be beneficial as an adjunct to cardioplegic treatment administered during cardiac surgery.



  In a second or alternative aspect, the present invention provides a method of reducing myocardial infarction arising from severe myocardial ischaemia in a human or animal subject as described above, which method comprises administering to said subject an effective amount of a compound of formula   (la),    or a physiologically acceptable salt or solvate thereof.  



  There is further provided by the present invention, a method of reducing deleterious effects to the myocardium associated with any of coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), acute myocardial infarction, unstable angina and cardiac surgery, in a human or animal subject, which method comprises administering to said subject an effective amount of a compound of formula   (la),    or a physiologically acceptable salt or solvate thereof.



  Physiologically acceptable salts of a compound of formula (la) are disclosed in
EP0322242 and include acid addition salts derived from inorganic or organic acids, such as sulphates, phosphates, benzoates, camphor sulphonates, ptoluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, maleates,   sal icyl ates,    fumarates, succinates, lactates, glutarates, glutaconates, acetates and tricarballylates. Solvates include hydrates.



  A compound of formula (la) is effective in the reduction of myocardial infarction arising from severe myocardial ischaemia, if administered prior to the onset of abrupt interruption of coronary blood flow experienced during severe myocardial ischaemia. Furthermore, a particularly unexpected finding is that a compound of formula (la) is effective in the reduction of myocardial infarction arising from severe myocardial ischaemia, if administered after the onset of abrupt interruption in coronary blood flow but prior to the onset of reperfusion. A compound of formula (la) is therefore useful as an adjunct to   thrombolysis.   

 

  In a further or alternative aspect of the present invention there is provided a product containing a compound of formula   (la),    or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, as a combined preparation for simultaneous, separate or sequential use, during a thrombolytic procedure.



  Suitable thrombolytic agents include, for example, APSAC, aspirin, plasmin, prourokinase, streptokinase, tissue plasminogen activator and urokinase. Where a compound of formula (la) is administered simultaneously with a thrombolytic agent, the active agents may be combined in a single pharmaceutical composition.



  Such compositions are novel and form a further aspect of the present invention.  



  The invention thus provides a pharmaceutical composition comprising a compound of formula (la) or a physiologically acceptable salt or solvate thereof and a thrombolytic agent together with a pharmaceutically acceptable excipient.



  The present invention further provides use of a compound of formula   (lea),    or a physiologically acceptable salt or solvate thereof, in the manufacture of a medicament comprising a compound of formula   (lea)    or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, for use during a thrombolytic procedure.



  There is provided use of a thrombolytic agent substantially as described above, in the manufacture of medicament comprising a compound of formula (1a) or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, for use during a thrombolytic procedure.



  Furthermore, use of a compound of formula   (lea)    or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, in the manufacture of a medicament for use during a thrombolytic procedure.



  The invention provides a method of treatment of a human or animal subject which method comprises administering to said subject effective amounts of a compound of formula   (1 a),    or a physiologically acceptable salt or solvate thereof, and a thrombolytic agent, simultaneously, separately, or sequentially during a thrombolytic procedure.



  Compositions according to the invention are conveniently formulated for parenteral administration. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.



  Preferably the compositions will be presented as solutions for intravenous administration, such as injectable unit dosage forms or the like.



  There is further provided by the present invention a pharmaceutical composition comprising a compound of formula   (lea),    or a physiologically acceptable salt or solvate thereof adapted for injectable administration for the reduction of  myocardial infarction arising from severe myocardial ischaemia, together with one or more pharmaceutically acceptable carriers or excipients therefor. Furthermore a pharmaceutical composition comprising a compound of formula   (lea),    or a physiologically acceptable salt or solvate thereof as described above, for reducing deleterious effects to the myocardium associated with coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute myocardial infarction, unstable angina and cardiac surgery.



  Suitably, a compound of formula (la) is present in a composition according to the present invention at a concentration in the range of 1 to   500slg/ml,    particularly 10 to   300g/ml,    more particularly 50 to   1501lg/ml,    and preferably at about   100Crg/ml.   



  A particularly apt composition according to the present invention comprises, or consists essentially of: (a) 50 to   150zg/ml,    preferably about   1001lg/ml,    of a compound of formula   (la),   
 or a physiologically acceptable salt or solvate thereof; (b) 8.5 to   9.5mgiml,    preferably about   9.00mgiml,    of a sodium salt, preferably
 sodium chloride; (c) water being present as the balance of the composition, typically to
 formulate the composition in 1.0ml injectable form.



  Suitable doses of a compound of formula (la) or a physiologically acceptable salt or solvate thereof, for use in the methods of the invention will vary with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian. In general, however, a suitable dose will be in the range of from about 0.0002 to about 0.1 mg/kg body weight of the recipient, such as from about 0.0003 mg/kg to about 0.05 mg/kg, preferably from about 0.0004 mg/kg to about 0.01 mg/kg.



  Methods for the preparation of a compound of formula (la) are described in
EP0322242.  



  As hereinbefore described, it is a particularly unexpected aspect of the present invention that, not only does administration of a compound of formula (la) prior to abrupt interruption of coronary artery blood flow provide protection against myocardial infarction, but protection is also afforded if the compound of formula (la) is administered after interruption in coronary artery blood flow but before reperfusion. This means that the methods of the present invention are applicable not only where severe myocardial ischaemia is planned or expected, for example in cardiac surgery, but also in cases of unexpected severe myocardial ischaemia, for example in heart attack, unstable angina and during thrombolysis.



  The invention is further illustrated by the following non-limiting examples.



  ExamPle 1   Cardioorotective    Action of   N4( IS.      trans)-2-hvdroxvcvcloPentvlladenosine   
Surgical Preparation
Rabbits
New Zealand White rabbits (male, weight range 2.4-3.2kg, Charles River Ltd) were anaesthetised with Na pentobarbitone. The trachea was cannulated and the animal was respired with room air, the right jugular vein was cannulated to allow subsequent administration of anaesthetic and drug substances. The right femoral artery was cannulated for measurement of blood pressure, heart rate was electronically derived from the pressure signal. Subcutaneous needles were positioned on the limbs and lead   Il    of the electrocardiograph (ECG) was recorded.

 

  The heart was exposed by a left lateral thoracotomy in the 5th rib space, the pericardium was cut and a braided polyester suture was passed around a branch of the left coronary artery. A plastic sheath was passed over the suture and the artery was occluded by pulling the suture through the sheath and clamping it against the myocardial surface, subsequent release of the clamp allowed repeated occlusion and reperfusion of the vessel. As it was not always possible to visualise the coronary artery, successful occlusion was confirmed by an elevation in the ST segment of the ECG, an index of myocardial ischaemia. Data were recorded and analysed using a Modular Instruments Inc data acquisition system. Animals were  heparinised and allowed 15 minutes recovery after surgery was completed prior to the start of the experiment.



  Pigs
Large White pigs (either sex, weight range 25 - 35 kgs, Ashwell Farms Ltd) were sedated with azaperone and anaesthetised with Na pentobarbitone. The trachea was cannulated and the animal respired with room air. The left femoral vein was cannulated to allow constant infusion of anaesthetic. The right femoral vein was cannulated for drug administration, the right femoral artery was cannulated for measurement of blood pressure, heart rate was electronically derived from the pressure signal. The right carotid artery was cannulated and the cannula was advanced into the left ventricle to allow measurement of left ventricular pressure.



  Sub-cutaneous needles were positioned on the limbs and lead II of the ECG was recorded. The heart was exposed by a midline   stemotomy,    the pericardium was cut and the left anterior descending coronary artery was dissected free of connective tissue and underlying myocardium. A suture was placed around the artery and the vessels were occluded by tying the suture on to a plastic sheath, reperfusion was achieved by removal of the sheath restoring blood flow. Animals were heparinised (250   ulkg)    and allowed 15 minutes recovery after surgery was completed prior to the start of the experiment. Data were recorded and analysed using a Modular Instruments Inc data acquisition system.



  Induction of Infarction
Rabbits
Infarcts were induced by occluding the coronary artery for 30 minutes and allowing subsequent reperfusion for a period not less than 2 hours.   N-[(IS,    trans)-2   Hydroxycyclopentyl]adenosine    (compound of formula   (la))    was administered as a bolus over 1 minute either 10 or 60 minutes prior to the induction of severe myocardial ischaemia or 10 minutes prior to, or upon, reperfusion (the results are shown in Figures 1 and 2 respectively). Alternatively, N-[(i S,trans)-2hydroxycyclopentyl]adenosine was administered as a 30 minute infusion ending 10 minutes prior to the induction of severe myocardial ischaemia (the results are shown in Figure 3).  



  Pins
Infarcts were induced by occluding the coronary artery for 50 minutes and allowing subsequent reperfusion for a period not less than 3 hours.   N-[(1S,trans)-2-      hydroxycyclopentyl]adenosine    was administered as a bolus over 1 minute, 10 minutes prior to the induction of severe myocardial ischaemia (the results are shown in Figure 4).



  Measurement of Infarct Size
Infarct size was expressed as a percentage of the area that was at risk of infarction. Hearts were removed after the period of reperfusion and flushed with heparinised saline and area at risk was defined by occluding the coronary artery and injecting fluorescent microspheres. Hearts were then cut into slices and stained with triphenyltetrazolium chloride to disclose the area of necrosis; the viable tissue is stained red while necrotic tissue remain unstained. After staining, the slices are illuminated with UV light and the areas which were perfused with fluorescent microspheres glow, any dark areas are considered to have been at risk of infarction. The areas of necrosis and risk are then measured by computer planimetry and the results expressed as percentage of area at risk of infarction which has subsequently become necrotic.

 

  Example 2
A pharmaceutical formulation containing   N-[(1S,trans)-2-    hydroxycyclopentyl]adenosine was prepared as follows.



  Quantities per mL:
N-[(1 S,trans)-2-hydroxycyclopentyl]adenosine   1 00g   
Sodium Chloride 9.00mg
Water for injection to   1.0my      N-((1 S,trans)-2-hydroxycyclopentyl]adenosine    and sodium chloride were dissolved in turn in the major portion of water for injection and mixed thoroughly. The solution was filtered through a sterilised 0.2 micron filter then filled aseptically  under air into clean ampoules. The ampoules were then sealed and the sealed ampoules autoclaved at 1210C for 15 minutes.

Claims

r : w 1. A pharmaceutical composition comprising a compound of formula (it), or a physiologically acceptable salt or solvate thereof, EMI11.1 adapted for injectable administration for the reduction of myocardial infarction arising from severe myocardial ischaemia, together with one or more pharmaceutically acceptable carriers or excipients therefor.

2. A pharmaceutical composition comprising a compound of formula (lea), or a physiologically acceptable salt or solvate thereof, EMI11.2 for reducing deleterious effects to the myocardium associated with any of coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute myocardial infarction, unstable angina and cardiac surgery.

3. A composition according to claim 1 or 2, wherein said compound of formula (1 a), or a physiologically acceptable salt or solvate thereof, is present at a concentration in the range of 50 to 150rg/ml.

4. A composition according to Claim 3, wherein said compound of formula (la) is present at a concentration of about 100Crg/ml.

5. A pharmaceutical composition comprising: (a) 50 to 150 > g/mí of a compound of formula (la) or a physiologically acceptable salt or solvate thereof; EMI12.1 (b) 8.5 to 9.5 mgtml of sodium chloride; and (c) water being present as the balance of the composition.

6. Use of a compound of formula (1 a), or a physiologically acceptable salt or solvate thereof, EMI13.1 in the manufacture of medicament for the reduction of myocardial infarction arising from severe myocardial ischaemia.

7. Use of a compound of formula (lea), or a physiologically acceptable salt or solvate thereof, EMI13.2 in the manufacture of a medicament for reducing deleterious effects to the myocardium associated with any of coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute myocardial infarction, unstable angina and cardiac surgery.

8. Use according to claim 6 or 7, wherein said compound of formula (1 a), or a physiologically acceptable salt or solvate thereof, is included in said medicament at a concentration in the range of 50 to 1 50giml.

9. A method of reducing myocardial infarction arising from severe myocardial ischaemia in a human or animal subject, which method comprises administering an effective amount of a compound of formula (lea), or a physiologically acceptable salt or solvate thereof, EMI14.1 to a said human or animal subject.

10. A method of reducing deleterious effects to the myocardium associated with any of coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute myocardial infarction, unstable angina and cardiac surgery, in a human or animal subject, which method comprises administering an effective amount of a compound of formula (lea), or a physiologically acceptable salt or solvate thereof, EMI15.1 to a said human or animal patient.

11. A method according to of claim 9 or 10, wherein an effective amount of said compound of formula (lea), or a physiologically acceptable salt or solvate thereof, is in the range of 0.0004 to 0.Olmglkg body weight of said subject.

12. A method according to any of claims 9 to 11, wherein said compound of formula (lea), or physiologically acceptable salt or solvate thereof, is administered prior to the onset of abrupt interruption of coronary artery blood flow experienced during severe myocardial ischaemia.

13. A method according to any of claims 9 to 11, wherein said compound of formula (1 a), or physiologically acceptable salt or solvate thereof, is administered after the onset of abrupt interruption of coronary artery blood flow but prior to the onset of reperfusion.

14. A product containing a compound of formula (lea), or a physiologically acceptable salt or solvate thereof EMI16.1 and a thrombolytic agent, as a combined preparation for simultaneous, separate or sequential use, during a thrombolytic procedure.

15. A pharmaceutical composition comprising a compound of formula (lea), or a physiologically acceptable salt or solvate thereof, EMI16.2 and a thrombolytic agent, together with a pharmaceutically acceptable excipient.

16. Use of a compound of formula (lea), or a physiologically acceptable salt thereof, EMI17.1 in the manufacture of a medicament comprising a compound of formula (1 a), and a thrombolytic agent, for use during a thrombolytic procedure.

17. Use of a thrombolytic agent in the manufacture of medicament comprising: (a) a compound of formula (1 a), and EMI17.2 (b) a thrombolytic agent, for use during a thrombolytic procedure.

18. Use of a compound of formula (lea), EMI18.1 and a thrombolytic agent, in the manufacture of a medicament for use during a thrombolytic procedure.

19. A method of treatment of a human or animal subject which method comprises administering effective amounts of a compound of formula (1a), EMI18.2 and a thrombolytic agent, simultaneously, separately, or sequentially during a thrombolytic procedure.

20. A product as defined in claim 14, wherein said thrombolytic agent is selected from the group consisting of APSAC, aspirin, plasmin, prourokinase, streptokinase, tissue plasminogen activator and urokinase.

21. A composition according to claim 15, wherein said thrombolytic agent is selected from the group consisting of APSAC, aspirin, plasmin, prourokinase, streptokinase, tissue plasminogen activator and urokinase.

22. Use according to any of claims 16 to 18, wherein said thrombolytic agent is selected from the group consisting of APSAC, aspirin, plasm in, prourokinase, streptokinase, tissue plasminogen activator and urokinase.

23. A method according to claim 19, wherein said thrombolytic agent is selected from the group consisting of APSAC, aspirin, plasmin, prourokinase, streptokinase, tissue plasminogen activator and urokinase.

24. A pharmaceutical composition substantially as herein before described.

25. Use in the manufacture of a medicament substantially as herein before described.

26. A method of treatment of a human or animal subject substantially as herein before described.