Use of 4- [ (tert-butylimino) methyl] benzene-l,3-disulfonate N- oxide against stroke-in-evolution

Field of the Invention

The present invention relates to a novel method for the treatment or prophylaxis of stroke- in-evolution. In particular, the invention relates to the use of disodium 4-[(tert~ butylimino)methyl]benzene-l,3-disulfonate acid N-oxide [α-(2,4-disulfophenyl)-N- tert- butylnitrone disodium salt] for the treatment or prophylaxis of stroke-in-evolution.

Background of the Invention U.S. patent 5,488,145 discloses the compound α-(2,4-disulfoρhenyl)-iV-tert-butyhiitrone and pharmaceutically acceptable salts thereof. U.S. patent 5,475,032 discloses the use of such compounds in the treatment of stroke and of progressive central nervous system function loss conditions. U.S. patent 5,508,305 discloses the use of such compounds for ameliorating the side effects caused by oxidative damage resulting from antineoplastic disease treatment. Similar disclosures are also made in WO 95/17876. U.S. patent 5,780,510 discloses the use of these same compounds in the treatment of concussion.

We have now surprisingly discovered that 4-[(tert-butylimino)methyl]benzene-l,3- disulfonic acid ν-oxide and pharmaceutically acceptable salts thereof are useful as a novel method for the treatment or prophylaxis of the condition known as stroke-in-evolution.

Disclosure of the Invention

In accordance with the present invention, there is provided a method of treating stroke-in- evolution which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Salts of compounds of formula (I) may be formed by reacting the free acid or another salt thereof, with two or more equivalents of an appropriate base, using methods that are well known in the art.

The salts of compounds of formulae (I) will normally be those formed with pharmaceutically acceptable cations. The cation may be a monovalent material such as sodium, potassium, lithium, ammonium, alkylammonium or diethanolammonium. Alternatively, it may be a polyvalent cation such as calcium, magnesium, aluminium or zinc. It may also be a mixed salt formed with a polyvalent cation such as calcium or magnesium in combination with a pharmaceutically acceptable anion such as halide (for example chloride), phosphate, sulphate, acetate, citrate or tartrate.

In one embodiment, the compound of formula (I) is the disodium salt of formula (II).

In another aspect, the invention provides a method of treating stroke-in-evolution which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of stroke-in-evolution.

In another aspect, the invention provides a compound of formula (II) for use in the treatment or prophylaxis of stroke-in-evolution.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of stroke-in-evolution.

In another aspect, the invention provides the use of a compound of formula (II) in the manufacture of a medicament for use in the treatment or prophylaxis of stroke-in- evolution.

In the context of the present specification, the term therapy also includes prophylaxis unless there are specific indications to the contrary.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

Processes for the manufacture of compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed in WO 01/51460 and WO 01/51461.

Stroke is caused by an interruption of blood flow to a portion of the brain. This is most often due to a blockage within an artery causing an ischemic stroke. Such strokes account for about 88% of all strokes. The most common cause of an ischemic stroke is intrinsic narrowing of an artery to the brain due to a combination of atherosclerosis (accumulation of fatty materials plus secondary inflammation) culminating in the formation of a blood clot in the narrowed area. In about 30% of strokes the obstruction is due to a blood clot (embolus) originating elsewhere, especially the heart or a major blood vessel supplying the

brain, that dislodges and travels to the brain to block a smaller artery within the brain itself. About 12% of all strokes are caused by rupture of a blood vessel within the brain, called an intracerebral haemorrhage, or over the surface of the brain, called a subarachnoid haemorrhage.

Stroke is an acute event. The phrase "stroke-in-evolution" is used to describe a specific condition in which an initial stroke appears to progress steadily from onset. This progression may be related to progressive brain oedema. Patients who suffer stroke-in- evolution are likely to develop more serious disabilities. Death is also a more frequent consequence. There is currently no approved medication for stroke-in-evolution.

We have now surprisingly established that 4-[(tert-burylimino)methyl]benzene-l,3- disulfonic acid N-oxide (I) and pharmaceutically acceptable salts thereof, particularly the disodium salt (II) are useful as a novel method for the treatment or prophylaxis of stroke- in-evolution.

The compounds of formula (I) and pharmaceutically acceptable salts thereof will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound or salt thereof (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

Specific formulations of pharmaceutically acceptable salts of a compound of formula (I), particularly formulations of a compound of formula (II), suitable for parenteral administration are disclosed in WO 01/89507.

The pharmaceutical compositions of this invention may be admύiistered in standard manner for the disease or condition that it is desired to treat. Suitable methods will be readily apparent to the man skilled in the art.

Parenteral administration, particularly intravenous administration, is preferred. The administration may involve the use of a bolus dose or doses and /or infusion.

For the treatment of stroke-in-evolution, the dosage administered will, of course, vary with the mode of administration, the treatment desired and the severity of the condition or disorder to be treated. Such parameters will normally be decided by the attending physician.

In addition to the compound of the present invention, the pharmaceutical composition may also contain, or be co-administered (simultaneously or sequentially) with, one or more other pharmacological agents of value in conjunction with stroke-in-evolution.

Examples Patients treated within 6 h of suffering an acute ischaemic stroke were randomised to receive either an intravenous bolus dose of disodium 4-[(tert-butylimino)methyl]benzene- 1,3-disulfonate acid N-oxide over 1 h and then a continued infusion over the next 71 h, or matching placebo, in addition to standard care.

Disodium 4-[(fer^butylimino)methyl]benzene- 1 ,3-disulfonate acid N-oxide concentrate solution for infusion (400 mg/ml; 20 ml vial) (WO 01/89507) was diluted in 500 ml of physiologic (9 mg/ml) saline to a final concentration of approximately 15 mg/ml. A loading dose of 151 ml (2270 mg) of the diluted solution was administered over the first hour and was followed by a maintenance dose adjusted for the patient's creatinine clearance (Clcrea - a measure of kidney function). The maintenance infusion was continued for another 71 hours. The maintenance doses adjusted for creatinine clearance were as follows:

Patients were formally assessed at enrolment, at 24 and 72 hours after enrolment, and at 7, 30 and 90 days.

Stroke-in-evolution occurred in only 6.5% of the 858 patients who received disodium 4- [(ter/-butylimino)methyl]benzene-l,3-disulfonate acid N.-oxide. In comparison, stroke-in- evolution occurred in 8.1% of 847 patients who received placebo.

During the administration of disodium 4-[(ter?-butylimino)methyl]benzene-l ,3-disulfonate acidN-oxide, stroke-in-evolution occurred in only 6.2% of patients, whilst it occurred in 7.0% of patients during the infusion of placebo.

These data clearly demonstrate the efficacy of disodium 4-[(tert- butylimino)methyl]benzene- 1 ,3 -disulfonate acid N-oxide in significantly treating the condition known as stroke-in-evolution.