WO2007013843A1 - Use of 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate n-oxide against myocardial ischaemia - Google Patents
Use of 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate n-oxide against myocardial ischaemia Download PDFInfo
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- WO2007013843A1 WO2007013843A1 PCT/SE2006/000898 SE2006000898W WO2007013843A1 WO 2007013843 A1 WO2007013843 A1 WO 2007013843A1 SE 2006000898 W SE2006000898 W SE 2006000898W WO 2007013843 A1 WO2007013843 A1 WO 2007013843A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a novel method for the treatment or prophylaxis of myocardial ischaemia and/or myocardial infarction.
- the invention relates to the use of disodium 4-[(te ⁇ -butylimino)methyl]benzene-l,3-disulfonate acidN-oxide [ ⁇ - (2,4-disulfophenyl)-7V- tert-butylnitrone disodium salt] for the treatment or prophylaxis of myocardial ischaemia and/or myocardial infarction.
- U.S. patent 5,488,145 discloses the compound ⁇ -(2,4-disulfophenyl)-iV-tert-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.
- a method of treating or preventing myocardial ischaemia which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
- a method of treating or preventing myocardial infarction 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.
- 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.
- the compound of formula (I) is the disodium salt of formula (II).
- a method of treating or preventing myocardial ischaemia which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- a method of treating or preventing myocardial infarction which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- a method of treating or preventing myocardial ischaemia associated with stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- a method of treating or preventing myocardial infarction associated with stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of myocardial ischaemia.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of myocardial infarction.
- the invention provides a compound of formula (II) for use in the treatment or prophylaxis of myocardial ischaemia.
- the invention provides a compound of formula (II) for use in the treatment or prophylaxis of myocardial infarction.
- 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 myocardial ischaemia. 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 myocardial infarction.
- 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 myocardial ischaemia.
- 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 myocardial infarction.
- 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 myocardial ischaemia associated with stroke.
- 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 myocardial infarction associated with stroke.
- 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 the compound 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.
- 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.
- Acute stroke is associated with a concomitant increased risk of myocardial ischemia and there is evidence that certain types of stroke, especially hemorrhagic ones, may have a direct effect on cardiac physiology resulting in ECG changes typical of myocardial ischemia.
- the most common long-term cause of death after stroke is cardiac related.
- 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.
- 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.
- 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.
- 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.
- 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 myocardial ischaemia and/or myocardial infarction.
- Disodium 4-[(fert-butylimino)methyl]benzene-l,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:
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Abstract
The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment or prophylaxis of myocardial ischaemia and/or myocardial infarction is disclosed.
Description
Use of 4- [ (tert-butylimino)methyl] benzene-1, 3-disulfonate N- oxide against myocardial ischaemia
Field of the Invention
The present invention relates to a novel method for the treatment or prophylaxis of myocardial ischaemia and/or myocardial infarction. In particular, the invention relates to the use of disodium 4-[(te^-butylimino)methyl]benzene-l,3-disulfonate acidN-oxide [α- (2,4-disulfophenyl)-7V- tert-butylnitrone disodium salt] for the treatment or prophylaxis of myocardial ischaemia and/or myocardial infarction.
Background of the Invention
U.S. patent 5,488,145 discloses the compound α-(2,4-disulfophenyl)-iV-tert-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.
We have now surprisingly discovered that 4-[(tert-butylimino)methyl]benzene-l,3- disulfonic acid N-oxide and pharmaceutically acceptable salts thereof are useful as a novel method for the treatment or prophylaxis of myocardial ischaemia and/or myocardial infarction.
Disclosure of the Invention In one embodiment, there is provided a method of treating or preventing myocardial ischaemia 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 embodiment, there is provided a method of treating or preventing myocardial infarction 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 embodiment, there is provided a method of treating or preventing myocardial infarction which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
In one embodiment, there is provided a method of treating or preventing myocardial ischaemia associated with stroke which comprises administering an effective amount of a compound of formula (II) to a patient in need thereof.
In another embodiment, there is provided a method of treating or preventing myocardial infarction 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of myocardial ischaemia.
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 myocardial infarction.
In another aspect, the invention provides a compound of formula (II) for use in the treatment or prophylaxis of myocardial ischaemia.
In another aspect, the invention provides a compound of formula (II) for use in the treatment or prophylaxis of myocardial infarction.
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 myocardial ischaemia.
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 myocardial infarction.
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 myocardial ischaemia.
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 myocardial infarction.
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 myocardial ischaemia 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 myocardial infarction associated with stroke.
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 the compound 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.
Patients who have suffered a stroke, or even a transient ischemic attack, have an increased risk of coronary artery disease. Acute stroke is associated with a concomitant increased risk of myocardial ischemia and there is evidence that certain types of stroke, especially hemorrhagic ones, may have a direct effect on cardiac physiology resulting in ECG changes typical of myocardial ischemia. The most common long-term cause of death after stroke is cardiac related.
We have now surprisingly established that 4-[(fer?-butylimino)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 myocardial ischaemia.
We have also now surprisingly established that 4-[(te^-butylimino)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 myocardial infarction.
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 of myocardial ischaemia and/or myocardial infarction 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 myocardial ischaemia and/or myocardial infarction.
Examples 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.
Disodium 4-[(fert-butylimino)methyl]benzene-l,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.
Myocardial infarction occurred during the infusion of the disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acidN-oxide in only 0.2% of 858 patients. In contrast, myocardial infarction occurred in 0.6% of the 847 patients who received placebo.
Overall reports of adverse events related to ischemic heart disease were only 1.4% in those patients treated with disodium 4-[(tert-butylimino)methyl]benzene-l,3-disulfonate acidN- oxide, compared to 2.2% in those treated with placebo.
The event of myocardial infarction occurred in 1.3% of those patients treated with disodium 4-[(fer^butylimino)methyl]benzene-l,3-disulfonate acidN-oxide and in 1.9% of those treated with placebo.
These data clearly demonstrate the efficacy of disodium 4-[(tert- butylimino)methyl]benzene-l,3-disulfonate acid N-oxide in significantly reducing myocardial ischaemia and/or myocardial infarction associated with acute ischemic stroke.
Claims
1. A method of treating myocardial ischaemia 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 of treating myocardial infarction which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
3. A method according to Claim 1 or Claim 2 wherein the compound is disodium 4- [(tert-butylimino)methyl]benzene-l,3-disulfonate acid N-oxide (II).
4. A method according to Claim 1 wherein the myocardial ischaemia is associated with stroke.
5. A method according to Claim 2 wherein the myocardial infarction is associated with stroke.
6. 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 myocardial ischaemia.
7. 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 myocardial infarction.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70266805P | 2005-07-26 | 2005-07-26 | |
| US60/702,668 | 2005-07-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007013843A1 true WO2007013843A1 (en) | 2007-02-01 |
Family
ID=37683650
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE2006/000898 Ceased WO2007013843A1 (en) | 2005-07-26 | 2006-07-20 | Use of 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate n-oxide against myocardial ischaemia |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2007013843A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5780510A (en) * | 1993-12-23 | 1998-07-14 | Oklahoma Medical Research Foundation | 2,4-disulfo phenyl butyl nitrone, its salts and their use as pharmaceuticals |
-
2006
- 2006-07-20 WO PCT/SE2006/000898 patent/WO2007013843A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5780510A (en) * | 1993-12-23 | 1998-07-14 | Oklahoma Medical Research Foundation | 2,4-disulfo phenyl butyl nitrone, its salts and their use as pharmaceuticals |
Non-Patent Citations (1)
| Title |
|---|
| JACKSON D.M. ET AL.: "Oxygen free radical traps for the treatment of ischemia-associated organ injury", CURRENT OPINION IN INVESTIGATIONAL DRUGS (THOMSON SCIENTIFIC), vol. 5, no. 1, 2004, pages 50 - 54, XP003004215 * |
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