WO1997040680A1

WO1997040680A1 - Antioxidant compound

Info

Publication number: WO1997040680A1
Application number: PCT/US1997/007037
Authority: WO
Inventors: Giora Z. Feuerstein; Paul G. Lysko
Original assignee: Smithkline Beecham Corporation
Priority date: 1996-04-29
Filing date: 1997-04-25
Publication date: 1997-11-06
Also published as: EP0907318A4; EP0907318A1; JP2000510110A

Abstract

A new antioxidant use of, and method of treatment using, a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Description

ANTIOXIDANT COMPOUND

Field of the Invention

The present invention relates to a new medical use of, and method of treatment using, the compound of Formula I, as an oxygen radical scavenger, or as an antioxidant, for the protection of vital organs, particularly the organs of the cardiovascular system e.g. the heart, the central nervous system, and the renal system, from oxidative tissue damage. In particular, the present invention provides a new use for the compound of this invention for making pharmaceutical compositions useful in the prevention of organ reperfusion injury, particularly cardioprotection, that is protection of the cardiovascular system from traumatic and post-traumatic injury associated with myocardial infarction, neuroprotection, that is protection of the central nervous system from traumatic and post-traumatic injury associated with stroke, and renal protection.

Background of the Invention

Morbidity and mortality associated with disease-induced ischemic trauma of the vital organs, for instance as seen in acute myocardial infarction, represent major health problems in the developed world.

Considerable biochemical, physiological and pharmacological evidence supports the occurrence and importance of oxygen free radical -induced lipid peroxidation (LPO) in cardiac ischemia/reperfusion injury (Meerson, F. Z. et al., Basic Res. Cardiol. (1982) 77, 465-485; Downey, J. M., Ann. Rev. Physiol. ( 1990) 52, 487-504). It has been proposed that reoxygenation of ischaemic myocardium leads to generation of 0₂ and H₂O₂ within the tissue which can, in the presence of transition metal ions, become converted into highly-reactive hydroxyl radicals (OH) which initiate LPO, a radical chain reaction, leading to changes in cell membrane integrity and tissue injury (McCord, J. M., N. Engl. J. Med. (1985), 312, 159-163; McCord, J. M., Fed. Proc, (1987) 46, 2402; Kagan, V. E., Lipid Peroxidation in Biomembranes, (1988) CRC Press, Boca Raton Florida). Marked activation of LPO in experimental myocardial infarction, as well as reoxygenation following transitory ischemia, have been demonstrated (Meerson et al., 1982; Rao et al., Adv. Exp. Med. Biol., (1983) 161, 347-363). Exposure of myocytes or whole heart to oxidant- generating systems produced severe injury, including inactivation of the ATP- dependent Ca"¹""¹" sequestering system of cardiac sarcoplasmic reticulum (Halliwell, B. and Gutteridge, J. M. C. Free Radicals in Biology and Medicine, 2d ed., ( 1989) Clarendon Press, Oxford, England, 442-444). A significant increase in plasma LPO levels has also been reported recently in patients with myocardial infarction, especially during the initial 48 hrs after an attack (Loeper et al., Clinica Chimica Acta, ( 1991 ) 196, 1 19-126). The importance of LPO and oxygen radicals in tissue damage associated with ischemia is further supported by the protective effect of natural and synthetic antioxidants such as vitamin E and the lazaroid U-74500A (Levitt, M.A., Clin. Res. (1991) 39, 265A) or antioxidant enzymes such as superoxide dismutase (SOD) and catalase in diverse ischemic models (for review see Halliwell and Gutteridge, 1989).

Given the high incidence of disease-induced ischemic trauma of the vital organs, in particular, of the cardiovascular system including the heart, of the central nervous system including the brain, and of the renal system, together with the high survival rate of patients suffering these traumas in the developed world, there is a great need for pharmaceutical agents which prevent the occurence of such traumas and which protect the vital organs of patients in post-traumatic recovery from organ ischemic reperfusion injury.

Summary of the Invention

In a first aspect, the present invention provides a new medical use for the compound of Formula I as an oxygen radical scavenger or as an antioxidant for the protection of vital organs from oxidative damage. In particular, the present invention provides a new use for the compound of this invention to make pharmaceutical compositions useful in the prevention of organ reperfusion injury, particularly useful in cardioprotection, neuroprotection and renal protection.

In a second aspect, the present invention also provides a method of treatment for prevention of oxidative tissue damage to organs afflicted with disease-induced ischemic trauma, particularly cardioprotection, neuroprotection and renal protection, in mammals comprising internally administering to a mammal, preferably a human, in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In particular, the preferred pharmaceutically acceptable salt of the Formula I compound is the hydrochloric acid salt. Detailed Description of the Invention

Bucindolol, which is 2-[2-hydroxy-3-[[2-(lH-indol-3-yl)-l,l- dimethylethyl]amino]propoxy]-benzonitrile, is the compound of Formula I and it has the following structure:

(i)

This compound is claimed in GB Patent No. 2001633 (the '633 patent). Reference should be made to said patent for its full disclosure, including the methods of preparing this compound. The entire disclosure of the '633 patent is incoφorated herein by reference.

In the present invention, Bucindolol may be used as its free base or as a pharmaceutically acceptable salt thereof. The preferred pharmaceutically acceptable salt is the hydrochloric acid salt.

During ischemic organ trauma, as in acute myocardial infarction or stroke, a high proportion of ischemic organ cells become irreversibly damaged and necrotic, the extent of injury being dependent upon the length of time that the trauma, e.g. the arterial occlusion, persists. The protection of myocardial cells from such damage and necrosis during occlusion occurring during myocardial infarction and post- infarction reperfusion is essential to achieving the therapeutic goal of restoration of cardiac function; here and throughout this application this property is referred to by the term "cardioprotection" and its synonyms. The protection of the central nervous system neurons from such damage and necrosis during occlusion occurring in stroke and post-traumatic reperfusion is essential to achieving the therapeutic goal of restoration of neurological function; here and throughout this application this property is referred to by the term "neuroprotection" and its synonyms.

While traditional β-adrenoceptor antagonists, for instance propranolol, have a significant cardioprotective effect, they also often have undesireable side effects such as bradycardia, elevated disatolic blood pressure and total peripheral resistance cardiodepression. However, Bucindolol is effective as a cardioprotective agent at antihypertensive doses which unexpectedly minimize these consequences. At antihypertensive doses the combination of β-adrenoceptor blocking and vasodilatory properties of Bucindolol provides cardioprotection during and after acute myocardial infarction. It is believed that the cardioprotective effects of β-adrenoceptor antagonists at such dosages result from an improvement in the balance between myocardial oxygen supply and demand by reducing myocardial work, which occurs secondary to reductions in both heart rate and contractility.

We have recently discovered, by use of electron paramagnetic resonance (EPR) studies, that Bucindolol is an oxygen radical scavenger. We have also discovered that, as an oxygen scavenger, the above-described compound acts to inhibit LPO, and further that this compound is a suφrisingly effective protective agent in generally preventing a wide variety of disease states associated with oxidative tissue damage to the organs due to LPO following ischemic traumas. In particular, the compound of the present invention is especially useful in cardioprotection, that is, prevention of acute myocardial infarction, and reduction of morbidity resulting from the sequelae of myocardial infarction and reperfusion. Also, in particular, the compound of the present invention is especially useful in neuroprotection, that is, prevention of stroke, and reduction of morbidity resulting from the sequelae of stroke.

Bucindolol exhibits cardioprotection, and is especially useful for providing a beneficial cardioprotective effect by prevention of oxidative tissue damage in ischemic human myocardium; thus this compound has utility as adjunctive therapy following myocardial infarction. Chronic administration of this compound can both reduce the risk of acute myocardial infarction in individuals at risk thereof as well as provide adjunctive therapy by reducing the magnitude of oxidative tissue damage following an ischemic cardiac event. Because hypertensive individuals are at increased risk of stroke, the cardioprotective use of the present compound at appropriate dosing regimens in combination with antihypertensive therapy significantly reduces the risk of acute myocardial infarction, reinfarction, the area of infarcted tissue should reinfarction occur, and sudden cardiac death in such patients.

Bucindolol exhibits neuroprotection, and is especially useful for protecting cerebral tissue from stroke and neurotrauma and for preventing oxidative tissue damage of ischemic human cerebral tissue following occurrence of an ischemic event such as stroke or cerebral trauma. Thus, chronic administration of this compound can both reduce the risk of cerebral ischemia or stroke in individuals at risk thereof as well as provide adjunctive therapy by reducing the magnitude of oxidative tissue damage following an ischemic cerebral event. Because hypertensive individuals are at increased risk of stroke, the neuroprotective use of the present compound at appropriate dosing regimens in combination with antihypertensive therapy significantly reduces the risk of stroke, and the sequelae of stroke in such patients.

Bucindolol is useful for cardioprotection, neuroprotection and renal protection in humans according to the present invention at dosages ranging from about 25-400 mg/day p.o.

The present invention also provides a method of treatment for prevention of oxidative tissue damage to organs afflicted with disease-induced ischemic trauma in mammals comprising internally administering to a mammal, preferably a human, in need thereof an effective amount of Bucindolol, or a pharmaceutically acceptable salt thereof. The preferred pharmaceutically acceptable salt is the hydrochloric acid salt.

Bucindolol may be conveniently prepared as described in GB Patent No. 2001633.

Pharmaceutical compositions of Bucindolol for cardioprotective, neuroprotective and renal protective uses according to the present invention may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as ethanol, polyvinyl-pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternatively, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

The following examples are purely illustrative and are provided to teach how to use the compound of the present invention, but they are not intended to limit the scope of the present invention in any manner.

Biological Experimentals

The antioxidant activity of Bucindolol can be determined using a standard lipid peroxidase assay. The details of this in vitro assay are found in Feuerstein, et al., J. Hypertension. 11 (Supp. 4): S41-48 (1993).

The antioxidant protective effect of Bucindolol on cultured neurons is determined using the methods described in Stroke. 23: 1630-1636 (1992).

The figure represents a dose-response relationship of the neuroprotective effect of Carvedilol and Bucindolol in vitro. In this system, Bucindolol dose- dependently blocks oxygen radicals induced neruonal death at an IC50 = 1 lμM.

The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims.

Claims

What is claimed is:

1. A method of treatment for prevention of oxidative tissue damage to organs afflicted with disease-induced ischemic trauma in mammals comprising internally administering to a mammal in need thereof an effective amount of Bucindolol, which is a compound of Formula I:

(i) or a pharmaceutically acceptable salt thereof.

2. A method of treatment for cardioprotection in mammals comprising internally administering to a mammal in need thereof an effective amount of Bucindolol, which is a compound of Formula I:

(i) or a pharmaceutically acceptable salt thereof.

3. A method of treatment for cardioprotection of human patients surviving an acute myocardial infarction, comprising internally administering to a patient in need thereof an effective dose of a pharmaceutical composition comprising Bucindolol or a pharmaceutically acceptable salt thereof, said treatment reducing the risk of oxidative damage to myocardial tissue.

4. A method of treatment for the cardioprotection of hypertensive patients at risk for myocardial infarction, comprising internally administering to a human patient in need thereof an effective dose of a pharmaceutical composition comprising Bucindolol or a pharmaceutically acceptable salt thereof.

5. A method of treatment for renal protection in mammals comprising internally administering to a mammal in need thereof an effective amount of Bucindolol, which is a compound of Formula I:

(i) or a pharmaceutically acceptable salt thereof.

6. A method of treatment for renal protection of human patients surviving renal failure, comprising internally administering to a patient in need thereof an effective dose of a pharmaceutical composition comprising Bucindolol or a pharmaceutically acceptable salt thereof, said treatment reducing the risk of oxidative damage to renal tissue.

7. A method of treatment for neuroprotection in mammals comprising internally administering to a mammal in need thereof an effective amount of Bucindolol, which is a compound of Formula I:

(i) or a pharmaceutically acceptable salt thereof.

8. A method of treatment for neuroprotection of human patients surviving a stroke, comprising internally administering to a patient in need thereof an effective dose of a pharmaceutical composition comprising Bucindolol or a pharmaceutically acceptable salt thereof, said treatment reducing the risk of oxidative damage to cerebral tissue.