WO2007013842A1

WO2007013842A1 - Use of 4-((tert-butylimino)methyl) benzene-1,3-disulfonate n-oxide against maemorrhagic changes in the brain

Info

Publication number: WO2007013842A1
Application number: PCT/SE2006/000897
Authority: WO
Inventors: Hans-Göran HÅRDEMARK; Larry Rodichok; Sunita Sheth; Warren Wasiewski
Original assignee: Astrazeneca Ab
Priority date: 2005-07-26
Filing date: 2006-07-20
Publication date: 2007-02-01

Abstract

The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment or prophylaxis of haemorrhagic changes in the brain is disclosed.

Description

USE OF 4-((TERT-BUTYLIMINO) METHYL)

BENZENE-1,3-DISULFONATE N-OXIDE AGAINST

HAEMORRHAGIC CHANGES IN THE BRAIN

Field of the Invention

The present invention relates to a novel method for the treatment or prophylaxis of haemorrhagic changes in the brain. 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)-7V- tert-butylnitrone disodium salt] for the treatment or prophylaxis of haemorrhagic changes in the brain.

Background of the Invention

U.S. patent 5,488,145 discloses the compound α-(2,4-disulfophenyl)-iV-ter/-butylnitrone 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.

Lapchak et al, Stroke (2002) 33, 1665-1670 describe the effects of disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide on intracerebral haemorrhage in a large clot embolic stroke model in the rabbit. Administration of disodium A-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide caused an increase in the haemorrhage rate of 52% compared to control.

We have now surprisingly discovered that in humans, 4-[(tert-butylimino)methyl]benzene- 1,3-disulfonic acid N-oxide and pharmaceutically acceptable salts thereof are useful as a novel method for the treatment or prophylaxis of haemorrhagic changes in the brain. Brief Description of the Drawing

The Figure shows the occurrence of haemorrhagic transformation after treatment with disodium 4-[(ter?-butylimino)methyl]benzene-l,3-disulfonate acid N-oxide in combination with rt-PA.

Disclosure of the Invention

In accordance with the present invention, there is provided a method of treating or preventing haemorrhagic changes in the brain 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).

Thus, in one aspect of the present invention, there is provided a method of treating or preventing haemorrhagic changes in the brain 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 haemorrhagic changes in the brain.

In another aspect, the invention provides a compound of formula (II) for use in the treatment or prophylaxis of haemorrhagic changes in the brain.

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 haemorrhagic changes in the brain.

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 haemorrhagic changes in the brain.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with stroke which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.

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 haemorrhagic changes in the brain associated with stroke.

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 haemorrhagic changes in the brain associated with stroke.

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.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with ischaemic stroke which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with hemorrhagic stroke which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with ischaemic stroke 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 method of treating or preventing haemorrhagic changes in the brain associated with hemorrhagic stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.

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 haemorrhagic changes in the brain associated with ischaemic stroke.

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 haemorrhagic changes in the brain associated with haemorrhagic stroke.

The only currently approved pharmacological therapy for acute stroke is intravenous recombinant tissue plasminogen activator, rt-PA (Alteplase^®, Activase^®, Actilyse^®), which is believed to act by dissolving the blood clot obstructing an artery to an area of the brain. Other thrombolytic agents, for example, tenecteplase and desmoteplase, anti-platelet agents, for example, ReoPro^®, and anti-coagulants such as heparin and warfarin are in use or in development for the acute or preventive management of ischaemic stroke. Haemostatics, for example, NovoSeven^®, or other coagulation factor replacements are currently in use or in development for the treatment of haemorrhage in the brain. AU such thrombolytic and other agents with the potential to confer risks for haemorrhagic changes within the brain are included within the scope of the present application. The most significant complication of therapy with rt-PA is the occurrence of haemorrhage in the brain. When this haemorrhaging causes a worsening of the patient's stroke symptoms, it is called a symptomatic haemorrhage (SICH - symptomatic intracerebral haemorrhage). Symptomatic haemorrhage occurred in about 6% of patients in the pivotal trial of rt-PA in acute stroke conducted by the National Institutes of Health in the US.

As can be clearly seen from the data presented in the Figure and the Table, administration of disodium 4-[(fer^butylimino)methyl]benzene-l,3-disulfonate acidN-oxide (II) in conjunction with rt-PA produces a highly significant reduction in the rates of occurrence of both symptomatic intracerebral haemorrhage (SICH) and asymptomatic intracerebral haemorrhage (AICH) compared to the corresponding rates seen with the administration of rt-PA alone. Thus, the rate of occurrence of SICH is reduced from 6.4% to 2.5%. And the rate of occurrence of AICH is reduced from 20.9% to 12.9%.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with thrombolytic therapy which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with thrombolytic therapy 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 method of treating or preventing haemorrhagic changes in the brain associated with rt-PA therapy which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect, the invention provides a method of treating or preventing haemorrhagic changes in the brain associated with rt-PA therapy which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.

The data in the Table also clearly show that surprisingly the beneficial effects of administering disodium 4-[(ter?-butylimino)methyl]benzene-l,3-disulfonate acidN-oxide (II) in conjunction with rt-PA are equally apparent even when the administration of compound (II) is not started until after the administartion of rt-PA is complete. Thus, the compound of the present invention may be administered before, during or after the thrombolytic agent.

Thus, in another aspect, the invention provides a method of treating or preventing symptomatic haemorrhage in the brain associated with rt-PA therapy which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect, the invention provides a method of treating or preventing symptomatic haemorrhage in the brain associated with rt-PA therapy which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.

Symptomatic haemorrhage is defined as any neurological deterioration within 36 h of the initiation of rt-PA treatment of at least 4 points on the NIHSS, in combination with any blood on imaging.

In another aspect, the invention provides a method of treating or preventing asymptomatic haemorrhage in the brain associated with rt-PA therapy which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. In another aspect, the invention provides a method of treating or preventing asymptomatic haemorrhage in the brain associated with rt-PA therapy which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.

In one embodiment, administration of the compound of formula (II) is started before administration of the rt-PA.

In another embodiment, administration of the compound of formula (II) is started during administration of the rt-PA.

In one embodiment, administration of the compound of formula (II) is started after administration of the rt-PA has ceased.

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.

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 administered 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 or prevention of haemorrhagic changes in the brain, 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 thrombolytic therapy.

Example 1 A total of 1705 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-l,3-disulfonate acidN-oxide over 1 h and then a continued infusion over the next 71 h, or matching placebo, in addition to standard care. Concomitant treatment with an approved thrombolytic agent, specifically rt-PA, was allowed, but was not required. Disodium 4-[(tert-butylimino)methyl]benzene-l,3-disulfonate acidN-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:

In order to assess the effects of disodium 4-[(tert-butylimino)methyl]benzene-l,3- disulfonate acid N-oxide on haemorrhagic changes in the brain, patients were assessed using brain imaging (CT scans) at appropriate time points. For patients also receiving rt-PA, an initial CT/MR scan and a follow-up CT/MR scan at 72 hours were mandatory.

In the 240 patients who received disodium 4-[(tert-butylimino)methyl]benzene-l,3- disulfonate acid N-oxide as well as rt-PA, haemorrhagic changes in the brain (haemorrhagic transformation) were observed in 37 patients (15.4%). Of these 37 patients, only 6 patients exhibited symptomatic haemorrhagic changes (Figure).

In the 249 patients who received rt-PA but not disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acidN-oxide, haemorrhagic changes in the brain (haemorrhagic transformation) were observed in 68 patients (27.3%). Of these 68 patients, 16 patients exhibited symptomatic haemorrhagic changes (Figure).

These effects were seen whether the administration of disodium A-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide was commenced before, during or after administration of rt-PA (Table).

Table

As can be clearly seen from the data in the Table, intracerebral haemorrhages occurred in almost twice as many patients in the placebo group as in the group treated with compound (II), irrespective of the timing of the infusions in relation to one another. Thus, when given in combination with rt-PA, disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide reduced the risk of any haemorrhagic transformation (p<0.005 post hoc) and of symptomatic intracranial haemorrhage (p<0.05 post hoc).

Example 2

Patients treated within 6 h of suffering an acute intracerebral haemorrhage were randomised to receive either an intravenous bolus dose of disodium 4-[{tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide (II) over 1 h and then a continued infusion over the next 71 h, or matching placebo, in addition to standard care. The protocol for the administration of compound (II) was essentially as described in Example 1. The diagnosis of intracerebral haemorrhage was established by an initial neuroimaging scan (CT or MRI) and a follow-up scan was performed at 72 hours. Haematoma and oedema volumes were derived from the scans using standard procedures and the volume changes between baseline and 72 hours were monitored. Typically, haematoma volume and the volume of the oedema surrounding the primary intracerebral haemorrhage increase during this time period.

For those patients who received disodium 4-[(tert-butylimino)methyl]benzene-l,3- disulfonate acid N-oxide (II) (n = 287), the mean increase in haematoma volume during the first 72 hours was 4.5 mL, whereas for those patients who received placebo (n = 288), the mean increase in oedema volume was 6.7 mL. This effect was seen whether or not the patients were also being treated with anticoagulants such as warfarin or with anti-platelet agents such as aspirin.

These data demonstrate the efficacy of disodium 4-[(fert-butylimino)metliyl]benzene-l,3- disulfonate acid N-oxide (II) in reducing the growth of haematoma following an intracerebral haemorrhage.

Claims

C L A I M S

1. A method of treating or preventing haemorrhagic changes in the brain which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

2. A method according to Claim 1 wherein the compound is disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide.

3. A method according to either Claim 1 or Claim 2 wherein the haemorrhagic changes are associated with stroke.

4. A method according to Claim 3 wherein the stroke is ischaemic stroke.

5. A method according to Claim 3 wherein the stroke is haemorrhagic stroke.

6. A method according to any one of Claims 1 to 5 wherein the patient also receives thrombolytic therapy.

7. A method according to Claim 6 wherein the thrombolytic therapy comprises rt-PA.

8. A method according to Claim 7 wherein administration of the compound of Claim 2 is commenced prior to administration of rt-PA.

9. A method according to Claim 7 wherein administration of the compound of Claim 2 is commenced during administration of rt-PA.

10. A method according to Claim 7 wherein administration of the compound of Claim 2 is commenced after administration of rt-PA is complete.

11. A method according to any one of Claims 6 to 10 wherein the haemorrhagic change is symptomatic intracerebral haemorrhage.

12. A method according to any one of Claims 6 to 10 wherein the haemorrhagic change is asymptomatic intracerebral haemorrhage.

13. 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 haemorrhagic changes in the brain.