WO1997005128A1 - Cardioactive aspirinates - Google Patents

Cardioactive aspirinates Download PDF

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Publication number
WO1997005128A1
WO1997005128A1 PCT/IE1996/000046 IE9600046W WO9705128A1 WO 1997005128 A1 WO1997005128 A1 WO 1997005128A1 IE 9600046 W IE9600046 W IE 9600046W WO 9705128 A1 WO9705128 A1 WO 9705128A1
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Prior art keywords
aspirinate
cardioactive
compound
benzodioxanone
dichloromethane
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PCT/IE1996/000046
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French (fr)
Inventor
William Byrne
John Francis Gilmer
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Cal International Limited
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Priority to AU67088/96A priority Critical patent/AU6708896A/en
Publication of WO1997005128A1 publication Critical patent/WO1997005128A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the invention relates to derivatives of cardioactive aspirinates, processes for their production, compositions containing them and their use, particularly related to antiplatelet, antianginal, ⁇ -blocker and ACE inhibitor activity as appropriate.
  • EP-A-0,094,738 describes pharmaceutial benzodioxanone compounds and processes for their manufacture.
  • the cardioactive aspirinate is an aspirinate of an organic nitrate.
  • the aspirinate may be an aspirinate of isosorbide-5-mononitrate or isosorbide-2-mononitrate.
  • the invention provides the compounds:-
  • the cardioactive aspirinate is an aspirinate of a ⁇ -blocker.
  • the aspirinate may be an aspirinate of metoprolol or atenolol.
  • the invention provides the compounds:- 2-methyl,2-(metoprololoxy-)1,3-benzodioxanone
  • the cardioactive aspirinate is an aspirinate of an ACE inhibitor.
  • the cardioactive aspirinate is an aspirinate of captopril.
  • the invention provides the compound:-
  • the invention also provides pharmaceutical compositions of these compounds, processes for preparing them and their use as cardioactive agents.
  • the compounds described as 2-methylbenzodioxanones are structural isomers of cardioactive aspirinates. Included are the diastereomeric forms, enantiomeric forms and pharmaceutically acceptable salts of these compounds.
  • a feature of the invention is the nonacidic or "pro- aspirin” or “pro-salicylate” nature of the compounds involved.
  • the further significance of this property lies in the ability of the 2-methyl benzodioxanones to undergo hydrolysis to aspirin and or salicylic acid and an antianginal organic nitrate, a ⁇ -blocker or an ACE inhibitor as appropriate. All of the latter hydrolysis products are known compounds with well established clinical properties.
  • TXA 2 which promotes aggregation and prostacyclin (PGI 2 ) which inhibits it.
  • Aspirin inactivates cyclo-oxygenase (COX-1), acting mainly by irreversibly acetylating the active site on the enzyme, COX-1. This reduces both TXA 2 synthesis in platelets and prostacyclin synthesis in endothelium. Vascular endothelial cells can synthesise new enzyme whereas platelets cannot. After administration of aspirin, TXA 2 synthesis does not recover until the affected cohort of platelets is replaced. This process typically takes 7-10 days.
  • the compounds involved are suitable for administration through all normal routes of administration but the nonpolar nature of the materials may make them particularly suitable for topical administration.
  • the ⁇ -blockers or ⁇ -adrenoreceptor antagonists are mainly used as antidysrhythmic drugs in patients recovering from myocardial infarction or as prophylaxis in the prevention of that condition. They reduce mortality in the first year after a heart attack partly at least because of their ability to prevent ventricular dysrhythmias. They are also effective for atrial dysrhythmias which may arise from increased sympathetic activity. Atenolol, metoprolol, sotalol and pindalol are the most important examples. The combination of aspirin and a ⁇ -blocker has accepted clinical advantage. The specific examples cited below are for atenolol-2-methylbenzodioxanone and metoprolol-2-methylbenzodioxanone.
  • Metoprolol (40.11 g, 0.15 mol) was dissolved in a mixture (10:1) of t-butanol and distilled water (200 ml), and a solution of di-t-butyldicarbonate (32.74 g, 0.15 mol) in the same solvent (200 ml) was added dropwise at room temperature.
  • the reaction mixture was stirred for 20 hours at room temperature, and was then poured into distilled water.
  • the product was extracted several times with petroleum ether (40-60°C) . The organic fractions were combined, dried over sodium sulphate, and concentrated. The high purity level of the product rendered flash column chromatography unnecessary.
  • the title compound was obtained as an almost colourless oil (51.94 g, 95%).
  • N-BOC compound (0.4 g, 0.8 mmol) is dissolved in dry dichloromethane (5 cm 3 ) and the solution cooled to ice bath temperature. Trifluoroacetic acid is added dropwise and the resulting solution allowed to stir for 2 hours. The mixture is diluted with dichloromethane (20 cm 3 ) and poured into saturated aqueous sodium bicarbonate (30 cm 3 ). The organic layer is collected and dried (Na 2 S0 4 ). The volatiles are removed on a rotary evaporator and the resulting pale yellow residue subjected to flash chromatography, eluting with petroleum ether- dichloromethane 1:1, to give the title compound as a colourless oil (0.15 g, 47%).
  • Atenolol 7 (26.63 g, 0.1 mol) was dissolved in a mixture (10:1) of t-butanol and distilled water (150 ml), and a solution of di-t-butyldicarbonate (21.83 g, 0.1 mol) in the same solvent (150 ml) was added dropwise at room temperature.
  • the reaction mixture was stirred for 20 hours at room temperature, and was then poured into distilled water.
  • the product was extracted several times with ether. The organic fractions were combined, dried over sodium sulphate, and concentrated.
  • the title compound 8 was obtained as an almost colourless oil (34.25 g, 94%).
  • N-BOC compound (0.65 g, 1.25 mmol) is dissolved in dry dichloromethane (5 cm 3 ) and the solution cooled to ice bath temperature. Trifluoroacetic acid is added dropwise and the resulting solution allowed to stir for 2 hours. The mixture is diluted with dichloromethane (20 cm 3 ) and poured into saturated aqueous sodium bicarbonate (30 cm 3 ). The organic layer is collected and dried (Na 2 S0 4 ) . The volatiles are removed on a rotary evaporator and the resulting pale yellow residue subjected to flash chromatography eluting with ethyl acetate-dichloromethane 1:1 to give the title compound as a colourless oil (0.31 g, 59%).
  • ACE angiotension-converting enzyme
  • the ACE inhibitors involved include captopril, lisinopril, and ramanipril.
  • the acid (2.4 g, 11 mmol) in methanol (25 cm 3 ) is treated dropwise with acetyl chloride (2.5 cm 3 ) and the solution stirred overnight.
  • the volatiles are removed on a rotary evaporator at 30°C and the residue partitioned between water (25 cm 3 ) and ethyl acetate (30 cm 3 ).
  • the ethyl acetate layer is collected and washed with saturated aqueous sodium bicarbonate (2 x 20 cm 3 ), dried (Na 2 S0 4 ) and the solvents removed in vacuo .
  • the residue is purified by flash chromatography eluting with ethyl acetate:petroleum ether (1:4) to give the methyl ester (1.6 g, 62%) as a clear colourless oil.
  • the pentafluorophenyl ester (0.77 g, 1.4 mmol) is dissolved in acetonitrile:water (30 cm 3 , 2:1) and K 2 C0 3 (2 g) is added. The mixture is stirred for 4 hours, acidified, and the volatiles removed in vacuo at 40°C. The residue is extracted with ethyl acetate (2 x 50 cm 3 ) which is then washed with water (2 x 20 cm 3 ). The ethyl acetate layer is collected, dried (Na 2 S0 * ) and the volatiles removed in vacuo to give the captopril dioxanone as an oil (0.35 g, 65%) .
  • Organic nitrates are widely used in the treatment of angina pectoris and also possess value as vasodilators in the treatment of cardiac insuf f iciency and an ability to reduce the infarcted area in acute myocardial infarction .
  • Unstable angina is caused by platelet-f ibrin thrombus as coronary artery atheroma .
  • Aspirin is an important drug in this regard because it reduces the incidence of myocardial infarction .
  • Concomitant administration of aspirin and an organic nitrate has accepted a clinical advantage to the patient .
  • nitrates involved principally include isosorbide-5-mononitrate, isosorbide-2-mononitrate and other esterif iable organic nitrates .
  • Acetyl salicoyl chloride (1.06 g, 5.3 mmol) and isosorbide-5-nitrate (1 g, 5.2 mmol) are dissolved in chloroform (10 cm 3 ).
  • the reaction mixture is stirred at room temperature for 1 hour and brought to reflux for 20 minutes.
  • the mixture is then diluted with diethyl ether (50 cm 3 ) and washed successively with saturated aqueous sodium bicarbonate (2 x 20 cm 3 ) and water (2 x 20 cm 3 ), dried over sodium sulfate and filtered.
  • the volatiles are removed in vacuo giving a pale yellow oil which is dissolved in dichloromethane (5 cm 3 ) and diethyl ether (20 cm 3 ) is added.
  • the dioxanone 5 (50 mg) in methanol:THF:water (10 cm 3 ) was treated with 2M. NaOH (0.3 cm 3 ) and the mixture stirred at room temperature for 2 hours.
  • the reaction was monitored by TLC (sigel 254, dichloromethane as mobile phase, UV or Iodine stain visualisation) using authentic samples of N- BOC metoprolol 7, aspirin 6, salicylic acid and N-BOC- metoprolol-acetate. After 2 hours hydrolysis was complete with N-BOC metoprolol 7, aspirin 6 and salicylic 2 acid formed.
  • 2-methybenzodioxanone derivatives described are nonacidic and are hydrolysed in vitro to aspirin and/or salicylic acid and an organic nitrate, a ⁇ -blocker or an ACE inhibitor, all of which have established clinical properties.
  • cardioactive aspirinates other than those specifically mentioned above are within the scope of the invention.
  • the products may be formulated in any suitable compositions using conventional excipients/vehicles.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

2-Methylbenzodioxanone isomers of cardioactive aspirinates are hydrolysed in vitro to aspirin and/or salicylic acid and an organic nitrate, a β-blocker or an Ace Inhibitor. The compound may be an isomer of an aspirinate of a nitrate such as isosorbide-5-mononitrate or isosorbide-2-mononitrate. The compound may also be an isomer of an aspirinate of a β-blocker such as atenolol or metoprolol. In addition, the compound may be an isomer of an aspirinate of an Ace Inhibitor such as captopril.

Description

CARDIOACTIVE ASPIRINATES
The invention relates to derivatives of cardioactive aspirinates, processes for their production, compositions containing them and their use, particularly related to antiplatelet, antianginal, β-blocker and ACE inhibitor activity as appropriate.
EP-A-0,094,738 describes pharmaceutial benzodioxanone compounds and processes for their manufacture.
According to the invention, there is provided 2- methylbenzodioxanone isomers of cardioactive aspirinates.
In one embodiment of the invention, the cardioactive aspirinate is an aspirinate of an organic nitrate.
In this case, the aspirinate may be an aspirinate of isosorbide-5-mononitrate or isosorbide-2-mononitrate.
In particular, the invention provides the compounds:-
2-methyl,2-(isosorbide-2-nitrate-5-oxy-)l,3- benzodioxanone
2-methyl ,2-(isosorbide-5-nitrate-2-oxy-)l,3- benzodioxanone
In another embodiment of the invention, the cardioactive aspirinate is an aspirinate of a β-blocker.
In this case, the aspirinate may be an aspirinate of metoprolol or atenolol.
In particular, the invention provides the compounds:- 2-methyl,2-(metoprololoxy-)1,3-benzodioxanone
2-methyl,2-(atenololoxy-)1,3-benzodioxanone. In a further embodiment of the invention, the cardioactive aspirinate is an aspirinate of an ACE inhibitor.
In this case, the cardioactive aspirinate is an aspirinate of captopril.
In particular, the invention provides the compound:-
2 -methyl , 2 - (methyloxy-captoprilthio- ) 1 , 3- benzodioxanone
The invention also provides pharmaceutical compositions of these compounds, processes for preparing them and their use as cardioactive agents.
The compounds described as 2-methylbenzodioxanones are structural isomers of cardioactive aspirinates. Included are the diastereomeric forms, enantiomeric forms and pharmaceutically acceptable salts of these compounds.
A feature of the invention is the nonacidic or "pro- aspirin" or "pro-salicylate" nature of the compounds involved. The further significance of this property lies in the ability of the 2-methyl benzodioxanones to undergo hydrolysis to aspirin and or salicylic acid and an antianginal organic nitrate, a β-blocker or an ACE inhibitor as appropriate. All of the latter hydrolysis products are known compounds with well established clinical properties.
Aspirin alters the balance between thromboxane A2 (
TXA2) which promotes aggregation and prostacyclin (PGI2) which inhibits it. Aspirin inactivates cyclo-oxygenase (COX-1), acting mainly by irreversibly acetylating the active site on the enzyme, COX-1. This reduces both TXA2 synthesis in platelets and prostacyclin synthesis in endothelium. Vascular endothelial cells can synthesise new enzyme whereas platelets cannot. After administration of aspirin, TXA2 synthesis does not recover until the affected cohort of platelets is replaced. This process typically takes 7-10 days. Also inhibition of the cyclo¬ oxygenase of the vascular endothelium requires higher concentrations of aspirin than does platelet cyclo¬ oxygenase. Therefore low doses of aspirin decrease the synthesis of thromboxane A2 without drastically reducing prostacyclin synthesis. Clinical trials have now demonstrated the efficacy of aspirin in treatment regimes for acute myocardial infarction, in reducing the incidence of reinfarction following recovery and in preventing occlusive vascular disease in individuals at particular risk.
The compounds involved are suitable for administration through all normal routes of administration but the nonpolar nature of the materials may make them particularly suitable for topical administration.
The invention will be more clearly understood from the following description thereof given by way of example only.
A. β-blocker ASPIRINATES
The β-blockers or β-adrenoreceptor antagonists are mainly used as antidysrhythmic drugs in patients recovering from myocardial infarction or as prophylaxis in the prevention of that condition. They reduce mortality in the first year after a heart attack partly at least because of their ability to prevent ventricular dysrhythmias. They are also effective for atrial dysrhythmias which may arise from increased sympathetic activity. Atenolol, metoprolol, sotalol and pindalol are the most important examples. The combination of aspirin and a β-blocker has accepted clinical advantage. The specific examples cited below are for atenolol-2-methylbenzodioxanone and metoprolol-2-methylbenzodioxanone.
EXAMPLE 1
N-BOC Metoprolol
Figure imgf000006_0001
Metoprolol (40.11 g, 0.15 mol) was dissolved in a mixture (10:1) of t-butanol and distilled water (200 ml), and a solution of di-t-butyldicarbonate (32.74 g, 0.15 mol) in the same solvent (200 ml) was added dropwise at room temperature. The reaction mixture was stirred for 20 hours at room temperature, and was then poured into distilled water. The product was extracted several times with petroleum ether (40-60°C) . The organic fractions were combined, dried over sodium sulphate, and concentrated. The high purity level of the product rendered flash column chromatography unnecessary. The title compound was obtained as an almost colourless oil (51.94 g, 95%).
H NMR'. δ(CDCl3; ppm): 1.14-1.24 (6H,m,CH(CH3)2) , 1.47
(9H, s, OC(CH3)3), 2.80 (2H, t, ArCH2) , 3.36-3.40
(5H, m, OCH and CHzN) , 3.54 (2H, t, MeOCHz) , 3.82-4.04 (4H, m, ArOCHj, CHOH and NCH), 4.91 (IH, br s, OH), 6.80-6.83 (2H, m, ArH), 7.09- 7.12 (2H, m, ArH) .
EXAMPLE 2
Preparation of 2-.metΛ i,2-(.V-BOC-.metoproioloxy-)1,3- benzodioxanone
Figure imgf000007_0001
A suspension of acetyl salicylic acid (1.0 g, 5.5 mmol) in dichloromethane (10 cm3) is treated with trifluoroacetic anhydride (1.15 g, 0.77 cm3, 5.5 mmol) at room temperature for 30 minutes. N-BOC-metoprolol (1.6 g, 4.36 mmol) in dichloromethane is added dropwise and the resulting solution allowed to stir for a further 15 minutes. The mixture is diluted with dichloromethane (100 cm3) and poured into saturated aqueous sodium bicarbonate (50 cm3). The organic layer is collected, dried (Na2S04) and the volatiles removed in vacuo to give the crude dioxanone as a clear colourless oil. Purification by flash chromatography on silica gel eluting with petroleum ether (40:60) :diethyl ether 2:1 gives the title compound as a mixture of diastereomers (1.8 g, 64%), δ(270 MHz., CDC13) 1.07-1.25 (6H, m, CH(CH3)2), 1.45 (9H, 2 x s, OC(CH3)3) , 1.9 (3H, 2 x s, CH3), 2.81 (2H, t, ArCH2), 3.35 (3H, s, OCH3), 3.38-3.60 (4H, m, MeOCH2 and CH2N) , 3.95-4.04 (3H, br m, ArOCH2 and NCH), 4.73 (IH, m, NCH2CH) , 6.8-7.4 (6H, m, ArH), 7.4-8.0 (4H, m, ArH).
EXAMPLE 3
Preparation of 2-methyl , 2- ( etoprololoxy- ) 1 , 3- benzodioxanone
Figure imgf000008_0001
The N-BOC compound (0.4 g, 0.8 mmol) is dissolved in dry dichloromethane (5 cm3) and the solution cooled to ice bath temperature. Trifluoroacetic acid is added dropwise and the resulting solution allowed to stir for 2 hours. The mixture is diluted with dichloromethane (20 cm3) and poured into saturated aqueous sodium bicarbonate (30 cm3). The organic layer is collected and dried (Na2S04). The volatiles are removed on a rotary evaporator and the resulting pale yellow residue subjected to flash chromatography, eluting with petroleum ether- dichloromethane 1:1, to give the title compound as a colourless oil (0.15 g, 47%). EXAMPLE 4
N-BOC Atenolol
Figure imgf000009_0001
8
Atenolol 7 (26.63 g, 0.1 mol) was dissolved in a mixture (10:1) of t-butanol and distilled water (150 ml), and a solution of di-t-butyldicarbonate (21.83 g, 0.1 mol) in the same solvent (150 ml) was added dropwise at room temperature. The reaction mixture was stirred for 20 hours at room temperature, and was then poured into distilled water. The product was extracted several times with ether. The organic fractions were combined, dried over sodium sulphate, and concentrated. The title compound 8 was obtained as an almost colourless oil (34.25 g, 94%).
Example 5
Preparation of 2-methyl , 2- ( N- OC-atenololoxy- ) 1,3- benzodioxanone
Figure imgf000009_0002
A suspension of acetyl salicylic acid (1.0 g, 5.5 mmol) in dichloromethane (10 cm3) is treated with trifluoroacetic anhydride (1.15 g, 0.77 cm3, 5.5 mmol) at room temperature for 30 minutes. N-BOC-atenolol (1.46 g, 4.0 mmol) in dichloromethane is added dropwise and the resulting solution allowed to stir for a further 15 minutes. The mixture is diluted with dichloromethane (100 cm3) and poured into saturated aqueous sodium bicarbonate (50 cm3). The organic layer is collected, dried (Na2S04) and the volatiles removed in vacuo to give the crude dioxanone as a clear colourless oil. Purification by flash chromatography on silica gel eluting with petroleum ether (40:60) :diethyl ether 1:2 gives the title compound as a mixture of diastereomers (1.15 g, 56%); δ(270 MHz., CDC13) 1.0-1.15 (6H, m, CH(Cfi3)2), 1.45 (9H, 2 x s OC(CHj)3), 1.9 (3H, 2 x s, CH3), 3.5 (2H, s, PhC&CONHz) , 3.5-3.60 (2H, m, C&N), 3.95-4.1 (3H, br m, ArOCHj and NCH)/ 4.8 (IH, br m, NCH2Cfi) 5.3-5.5 (2H, br m, CONH2) , 6.8-8.0 (8H, m, ArH).
EXAMPLE 6
Preparationof 2-methyl , 2- ( atenololoxy- )1, 3-benzodioxanone
Figure imgf000010_0001
The N-BOC compound (0.65 g, 1.25 mmol) is dissolved in dry dichloromethane (5 cm3) and the solution cooled to ice bath temperature. Trifluoroacetic acid is added dropwise and the resulting solution allowed to stir for 2 hours. The mixture is diluted with dichloromethane (20 cm3) and poured into saturated aqueous sodium bicarbonate (30 cm3). The organic layer is collected and dried (Na2S04) . The volatiles are removed on a rotary evaporator and the resulting pale yellow residue subjected to flash chromatography eluting with ethyl acetate-dichloromethane 1:1 to give the title compound as a colourless oil (0.31 g, 59%).
Bi ACE INHIBITOR ASPIRINATES
The inhibition of angiotension-converting enzyme (ACE) is important clinically in the control of hypertension, the prevention of secondary myocardial infarction and the improvement of survival after cardiac failure. Aspirin can exert a complementary influence in association with the ACE agents by reducing platelet aggregation and thus assisting the survival process.
The ACE inhibitors involved include captopril, lisinopril, and ramanipril.
The specific example given below is for captopril-2- methylbenzodioxanone.
EXAMPLE 7
Preparation of methyloxy-captopril
A A.c-e_>t chloride M .eOH
Figure imgf000011_0002
yl chloride, MeOH
Figure imgf000011_0001
The acid (2.4 g, 11 mmol) in methanol (25 cm3) is treated dropwise with acetyl chloride (2.5 cm3) and the solution stirred overnight. The volatiles are removed on a rotary evaporator at 30°C and the residue partitioned between water (25 cm3) and ethyl acetate (30 cm3). The ethyl acetate layer is collected and washed with saturated aqueous sodium bicarbonate (2 x 20 cm3), dried (Na2S04) and the solvents removed in vacuo . The residue is purified by flash chromatography eluting with ethyl acetate:petroleum ether (1:4) to give the methyl ester (1.6 g, 62%) as a clear colourless oil.
EXAMPLE 8
Preparation of 2-methyl , 2- ( captopril thio- ) 1 , 3- benzodioxanone
Figure imgf000012_0001
The pentafluorophenyl ester (0.77 g, 1.4 mmol) is dissolved in acetonitrile:water (30 cm3, 2:1) and K2C03 (2 g) is added. The mixture is stirred for 4 hours, acidified, and the volatiles removed in vacuo at 40°C. The residue is extracted with ethyl acetate (2 x 50 cm3) which is then washed with water (2 x 20 cm3). The ethyl acetate layer is collected, dried (Na2S0*) and the volatiles removed in vacuo to give the captopril dioxanone as an oil (0.35 g, 65%) .
EXAMPLE 9
Preparation of 2-methyl , 2- (methyloxy-captoprilthio- ) 1 , 3- benzodioxanone
Figure imgf000013_0001
Aspirin (0.5 g, 2.8 mmol) in dichloromethane is treated at room temperature with trifluoroacetic anhydride (0.55 g, 0.4 cm3) and the solution allowed to stir for 0.5 hours when the captopril ester (0.62 g, 2.8 mmol), in dichloromethane (10 cm3), is added dropwise via syringe. After 14 hours the reaction mixture is poured into saturated aqueous sodium bicarbonate (25 cm3), the organic phase is collected, dried (Na2S04) and the solvent removed in vacuo . Flash chromatography of the residue eluting with ethyl acetate:petroleum ether 1:1 affords the dioxanone as a mixture of diastereomers (0.79 g, 72%); Sl (300 MHz., CDC13) 1.15-1.25 (3H, m, CH3) , 1.8-2.1 (4H, m) , 2.12, 2.13 (3H, 2 x s, 2 x CH3) , 2.5-2.6 (IH, m) , 2.95-3.05 (2H, m), 3.5-3.6 (2H, m) , 3.66, 3.68 (3H, 2 x s, 2 x CH3), 4.3-4.5 (IH, m), 7.0 (ArH, m) , 7.8 (ArH, m), 7.57 (ArH, m) , 7.95 (ArH, m) .
EXAMPLE 10 - ALTERNATIVE SYNTHESIS
Preparation of 2-methyl ,2-(pentaf luorophenyloxy- captoprilthio-) 1, 3-benzodioxanone
Figure imgf000014_0001
Aspirin (0.94 g, 5.2 mmol) in dichloromethane (10 cm3) is treated with trifluoroacetic anhydride (1.09 g, 0.73 cm3, 5.2 mmol) and the solution allowed to stir at room temperature for 0.5 hours. The captopril ester (1.6 g, 0.4 mmol), in dichloromethane (5 cm3), is introduced dropwise via syringe. The mixture is allowed to stir for 1 hour, diluted with dichloromethane (50 cm3) and poured into saturated aqueous sodium bicarbonate (20 cm3). The organic layer is collected, dried (Na2S0A) and the volatiles removed in vacuo to afford the crude dioxanone as a pale yellow oil. Flash chromatography of this mixture eluting with ethyl acetate:petroleum ether (1:1) gives the dioxanone as an oil (1.0 g, 46%). £*_ ORGANIC NITRATE ASPIRINATES
Organic nitrates are widely used in the treatment of angina pectoris and also possess value as vasodilators in the treatment of cardiac insuf f iciency and an ability to reduce the infarcted area in acute myocardial infarction .
Unstable angina is caused by platelet-f ibrin thrombus as coronary artery atheroma . Aspirin is an important drug in this regard because it reduces the incidence of myocardial infarction . Concomitant administration of aspirin and an organic nitrate has accepted a clinical advantage to the patient .
The appropriate nitrates involved principally include isosorbide-5-mononitrate, isosorbide-2-mononitrate and other esterif iable organic nitrates .
EXAjffLE 11
Preparation of 2-methyl , 2- ( iεosorbide-2-nitrate-5-oxy- ) 1 , 3-benzodioxanone
Figure imgf000015_0001
A suspension of acetyl salicylic acid (1.0 g, 5.5 mmol) in dichloromethane (10 cm3) is treated with trifluoroacetic anhydride (1.15 g, 0.77 cm3, 5.5 mmol) at room temperature for 30 minutes. Isosorbide-2-nitrate (1.0 g, 5.2 mmol) in dichloromethane is added dropwise and the resulting solution allowed to stir for a further 15 minutes. The mixture is diluted with dichloromethane (100 cm3) and poured into saturated aqueous sodium bicarbonate (50 cm3). The organic layer is collected, dried (Na2S04) and the volatiles removed in vacuo to give the crude dioxanone as a clear colourless oil. Purification by flash chromatography on silica gel eluting with petroleum ether (40:60) :diethyl ether 1:2 gives the title compound as a mixture of diastereomers (1.5 g, 82%); δ (300 MHz, CDC13) 1.81 (3H, s, CH3), 1.82 (3H, s, CH3) , 3.49-3.63 (IH, m) , 3.75-4.04 (4H, m) , 4.47-4.69 (IH, m) , 7.0 (IH, m, ArH), 7.12 (IH, m, ArH), 7.55 (IH, m, ArH), 7.9 (IH, m, ArH).
ESAMPLE 12
Preparation of 2-methyl , 2- ( isosorbide-5-ni trate-2-oxy- ) 1, 3-benzodioxanone
Method 1
Figure imgf000016_0001
A suspension of acetyl salicylic acid (1.0 g, 5.5 mmol) in dichloromethane (10 cm3) is treated with trifluoroacetic anhydride (1.15 g, 0.77 cm3, 5.5 mmol) at room temperature for 30 minutes. Isosorbide-5-nitrate (1.0 g, 5.2 mmol) in dichloromethane is added dropwise and the resulting solution allowed to stir for a further 15 minutes. The mixture is diluted with dichloromethane (100 cm3) and poured into saturated aqueous sodium bicarbonate (50 cm3). The organic layer is collected, dried (Na2S04) and the volatiles removed in vacuo to give the crude dioxanone as a clear colourless oil. Purification by flash chromatography on silica gel eluting with petroleum ether (40:60) :diethyl ether 1:2 gives the title compound as a white solid (1.6 g, 88%);
M.p. 125°C
δ^H (300 MHz., CDC13) 1.80 (3H, s, Me), 3.81 (IH, dd, J11 .2 , 6.6, 6"α-H), 3.93 (IH, dd, J10.3, 3.3, l"β-H), 3.94 (IH, dd, J11.5, 2.9, 6"β-H), 4.02 (IH, dt, J10.2, 1.1, l"α-H), 4.38 (IH, d, J4.8, 3"-H), 4.72 (IH, d, J4.3, 2"- H) 4.87 (IH, t, J5.2, 4"-H), 5.28 (IH, dt, J5.5, 2.3, 5"- H), 7.02 (IH, dd, Jl.0, 0.5, Ar3-H) , 7.17 (IH, dt, J7.0, 1.0, Ar5-H), 7.59 (IH, ddd, J8.3, 7.5, 2.0, Ar4-H) , 7.94 (IH, dd, J7.8, 1, Ar6-H).
δ13C (75.5 MHz., CDC13) 23.32, 68.94 (C6"), 74.10 (Cl"), 77.60 (C2"), 81.19 (C4"), 81.26 (C5M), 112.67, 116.93 (ArC3), 117.37 (ArCl), 123.46 (ArC5), 129.59 (ArC4), 136.78 (ArC6), 154.67 (ArC2), 160.06
IR (KBr. 3014, 2987, 2944, 2886, 2911 (aromatic and aliphatic C-H stretching) 1736 (C=0 stretching) 1645, 1630 (ON02 stretching) 1287 1245 1238 1097 (asymmetrical C-O-C stretching) 966 852 885 852 cm"1 Elemental analvsis C50.45;H4.22;N3.68, C15H1509N requires C50.49;H4.48;N3.95
Mass spectrum 354 (MH+) , 353 (M+) , 163 (M+-isosorbide-5- nitrate)
Thin layer chromatogram: siαel GF 254/dichloromethane rf=0.85
Density 1.523 g/cm3
Single crystal X ray appears opposite.
Wavelength 0.71069A Crystal system monoclinic
Index ranges 0<h<6, 0<k<8, -19<1<19 reflections collected 1585
Refinement method full matrix least-squares on
F2 R indices (all data) Rl - 0.0422, WR2 = 0.0707
EXAMPLE 13 - ALTERNATIVE SYNTHESIS
Method 2
Figure imgf000019_0001
Acetyl salicoyl chloride (1.06 g, 5.3 mmol) and isosorbide-5-nitrate (1 g, 5.2 mmol) are dissolved in chloroform (10 cm3). The reaction mixture is stirred at room temperature for 1 hour and brought to reflux for 20 minutes. The mixture is then diluted with diethyl ether (50 cm3) and washed successively with saturated aqueous sodium bicarbonate (2 x 20 cm3) and water (2 x 20 cm3), dried over sodium sulfate and filtered. The volatiles are removed in vacuo giving a pale yellow oil which is dissolved in dichloromethane (5 cm3) and diethyl ether (20 cm3) is added. The product crystallizes as a white solid after 8 hours. Recrystallisation from dichloromethane- ether-petroleum ether gives the dioxanone as colourless cubes, identical with the production of method 1 (1.07 g, 58%) . Qualitative thin layer studies on the breakdown of ISMN- benzodioxanone .1)
Figure imgf000020_0001
Conditions
The benzodioxanone 1 (50 mg, 0.014 mmol) was dissolved in acetonitrile:THF:pH 2.5 buffer (phosphate), (1:1:1, 10 cm3), giving a 1.4 mmol solution of the compound. The procedure was repeated using a 7.4 buffer, 1 M HCl (pH-1) and at pH=6.9. All solutions were maintained at 37°C while being monitored by TLC (sigel 254, dichloromethane as mobile phase, UV or Iodine stain visualisation) . The breakdown products were referenced using authentic samples of ISMN-2-acetate, salicylic acid and aspirin.
Conclusions
The dioxanone 1 undergoes rapid hydrolysis at pH=l to salicylic acid 2 and ISMN-2-acetate 3, followed by further hydrolysis of the acetate to ISMN 4. This process, which is essentially complete after 6 hours occurs more slowly at pH=3. At 6.8 and 7.0 hydrolysis is also observed, but only as far as the acetate 3. The reaction at pH=7 is rapid (complete after 3 hours) but again only the acetate 3 and salicylic acid 2 are observed.
Hydrolysis of 2-methγl .2- 1.V-BOC -metoprololoxγ- .1.3- benzodioxanone 16.
The dioxanone 5 (50 mg) in methanol:THF:water (10 cm3) was treated with 2M. NaOH (0.3 cm3) and the mixture stirred at room temperature for 2 hours. The reaction was monitored by TLC (sigel 254, dichloromethane as mobile phase, UV or Iodine stain visualisation) using authentic samples of N- BOC metoprolol 7, aspirin 6, salicylic acid and N-BOC- metoprolol-acetate. After 2 hours hydrolysis was complete with N-BOC metoprolol 7, aspirin 6 and salicylic 2 acid formed.
It will be noted that the 2-methybenzodioxanone derivatives described are nonacidic and are hydrolysed in vitro to aspirin and/or salicylic acid and an organic nitrate, a β-blocker or an ACE inhibitor, all of which have established clinical properties.
It will be appreciated that various cardioactive aspirinates other than those specifically mentioned above are within the scope of the invention. The products may be formulated in any suitable compositions using conventional excipients/vehicles.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims

1. 2-methylbenzodioxanone isomers of cardioactive aspirinates.
2. A compound as claimed in claim 1 wherein the cardioactive aspirinate is an aspirinate of an organic nitrate.
3. A compound as claimed in claim 1 or 2 wherein the cardioactive aspirinate is an aspirinate of isosorbide-5-mononitrate.
4. A compound as claimed in claim 1 or 2 wherein the cardioactive aspirinate is an aspirinate of isosorbide-2-mononitrate.
5. 2-methyl , 2- ( isosorbide-2-nitrate-5-oxy-) 1,3- benzodioxanone.
6. 2-methyl , 2- ( isosorbide-5-nitrate-2-oxy-) 1, 3- benzodioxanone.
7. A compound as claimed in claim 1 wherein the cardioactive aspirinate is an aspirinate of a β- blocker.
8. A compound as claimed in claim 1 or 7 wherein the cardioactive aspirinate is an aspirinate of atenolol.
9. A compound as claimed in claim 1 or 7 wherein the cardioactive aspirinate is an aspirinate of metoprolol.
10. 2-methyl,2-(metoprololoxy-)1,3-benzodioxanone.
11. 2-methyl,2-(atenololoxy-)1,3-benzodioxanone.
12. A compound as claimed in claim 1 wherein the cardioactive aspirinate is an aspirinate of an ACE inhibitor.
13. A compound as claimed in claim 1 or 12 wherein the cardioactive aspirinate is an aspirinate of captopril.
14. 2-methyl,2-(methyloxy-captoprilthio-)l,3- benzodioxanone.
15. A compound substantially as hereinbefore described with reference to the examples.
16. A pharmaceutical composition including a compound as claimed in any preceding claim.
17. A process for preparing a compound as claimed in any of claims 1 to 15, the process being substantially as hereinbefore described with reference to the examples.
PCT/IE1996/000046 1995-07-27 1996-07-26 Cardioactive aspirinates WO1997005128A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061573A1 (en) * 1999-04-14 2000-10-19 Rhodia Chimie Novel benzodioxinones and method for obtaining same

Citations (4)

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Publication number Priority date Publication date Assignee Title
WO1983003411A1 (en) * 1982-03-24 1983-10-13 Bateman, Neil, E. Pharmaceutical compound and process for the manufacture thereof
WO1994003421A2 (en) * 1992-07-30 1994-02-17 Cal International Limited Esters and combinations of an organic nitrate and a salicylate
WO1995020571A1 (en) * 1994-01-28 1995-08-03 Cal International Limited A pharmaceutical product comprising a salicylate of an esterifiable ace-inhibitor
WO1995020568A1 (en) * 1994-01-28 1995-08-03 Cal International Limited Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO1983003411A1 (en) * 1982-03-24 1983-10-13 Bateman, Neil, E. Pharmaceutical compound and process for the manufacture thereof
EP0094738A1 (en) * 1982-03-24 1983-11-23 R.P. Scherer Corporation Pharmaceutical benzodioxane compounds and process for their manufacture
WO1994003421A2 (en) * 1992-07-30 1994-02-17 Cal International Limited Esters and combinations of an organic nitrate and a salicylate
WO1995020571A1 (en) * 1994-01-28 1995-08-03 Cal International Limited A pharmaceutical product comprising a salicylate of an esterifiable ace-inhibitor
WO1995020568A1 (en) * 1994-01-28 1995-08-03 Cal International Limited Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061573A1 (en) * 1999-04-14 2000-10-19 Rhodia Chimie Novel benzodioxinones and method for obtaining same
FR2792315A1 (en) * 1999-04-14 2000-10-20 Rhodia Chimie Sa NOVEL BENZODIOXINONES AND PROCESS FOR OBTAINING THEM

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