CH685700A5 - Nitric esters of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide, process for the preparation of these esters and medicaments containing these esters. - Google Patents

Description

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CH 685 700 A5

Description

The present invention relates to new nitric esters of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide substituted in position 2, a process for the preparation of these esters, and medicaments which contain these esters.

These compounds have a very specific vasodilatory activity on the vessels and are therefore effective in the therapy and prevention of cardiovascular disorders, in tissue ischemia, in angina pectoris and in hypertension.

Nitric esters, such as trinitroglycerin or isosorbide dinitrate, have been used for a long time for the treatment of angina pectoris and for other cardiovascular disorders because they have a vasodilator activity which notably decreases the preload of the heart where it results in a lesser need for oxygen for this organ. However, these compounds present the clinical problem of developing tolerance during chronic administration.

Other nitric esters have therefore been developed. For example, European patent applications EP 0 473 027, EP 0 490 183, EP 0 171 977 and EP 0 210 581 describe nitrates derived from pyridi-necarboxyamides, benzoxazinones, phthalimides and 1,4-benzodioxanes respectively. However, there is still no satisfactory and effective pharmaceutical product against cardiovascular diseases; it is therefore necessary to search for new compounds which are more selective, have greater pharmacological activity and develop to a lesser extent the undesirable and already mentioned effect of tolerance.

The present invention includes a series of new nitric esters in which the nitrate group is linked by an alkyl chain substituted or not for the nitrogen atom of a 1,2-benzo-isothiazolyl-3 (2H) one-1 group. , 1-dioxide. These compounds have a high vasodilating activity, have a lower degree of tolerance and can be prepared on an industrial scale; they are therefore satisfactory from the point of view of practical use.

The compounds which are the subject of the present invention are nitric esters of 2-alkyl-1,2-benzo-isothia-zolyl-3 (2H) one-1,1-dioxide of general formula (I)

O "

(I)

Nn li

0

in which y is a substituted cycloalkyl group, or a group

R '

I

- (CH2) m-C- (CH2) n-R

in which

R is a hydrogen atom, a methyl radical, a 2,4-dichlorophenyl radical or a nitrate residue,. R 'is a hydrogen atom or a methyl radical,

m is an integer between 0 and 5,

n is an integer between 0 and 1.

Some preferred examples of compounds of the present invention are: 2- (2-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (2,2-dimethyl-3-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (3-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (6-nitratohexy!) - 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (2,3-dinitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (2-methyl-2-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- [2- (2,4-dichlorophenyl) -2-nitratoethyl] -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide;

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CH 685 700 A5

2-nitratomethyl-1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide 2- (2-nitratocyclohexyl) -1,2-benzo-isothiazo-lyl-3 (2H) one-1,1 -dioxide;

2- (2-nitratoethyi) -1,2-benzo-isothiazolyi-3 (2H) one-1,1-dioxide.

The compounds of general formula (I) can be prepared by treatment of an alcohol of general formula (II) or of a halogenated compound of general formula (III)

OH

(II)

x (III)

in which Y has the same definition as above and X is a halogen atom, with nitric acid or another suitable reagent.

They can thus be obtained in an analogous manner with the reagents indicated in the following publications:

- P. Stoss, G. Schlüter, R. Axmann; Arzneim.-Forch./Drug Res., 40 (I), Nr. 1 (1990), 13-18

- R. Boschan, R. T. Merrow, R. W. Dolah; Chem. Rev., 55, (1955), 485.

- G. H. Hakimelahi, H. Sharghi, H. Zarrimmayeh, A. Khalafi-Nezhad; Helv. Chim. Act., 67, (1984), 906.

- A. Mv Killop, M. E. Ford; Tetrahedron, 30, (1974), 2467.

- G. Snatzke, H. Laurent, R. Wierchert; Tetrahedron, 25, (1969), 761.

The starting materials of general formula (II) are known and can be prepared by standard methods from commercial reagents. Thus, 2-hydroxymethyl-1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide was prepared according to the Choi, Lee and Yoon method described in J. Heter. Chem., 26, (1989), 1073. The other 2-hydroxyalkyl-1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxides can also be obtained by known standard methods, such as for example reaction between the sodium salt of 1,2-benzo-isothiazolyi-3 (2H) one-1,1-dioxide and the corresponding halogenated derivative of general formula (IV):

R '

X- (CH2) m-C- (CH: I

R

) n-OH

(IV)

where R, R ', m and n have been defined previously and where X represents an oxygen atom in a manner analogous to that described by H. L. Rice and G. R. Pettit in J. Amer. Chem. Soc., 76, (1974), 302.

The invention also relates to a medicament comprising at least one compound of general formula (I) according to claim 1.

This drug has a vasodilating effect and can be used for the preventive or curative treatment of cardiovascular diseases.

This medication is particularly suitable for the treatment of cardiac or tissue ischemia, angina pectoris, heart failure and hypertension.

The compounds (I) of the present invention can be administered alone, but they will generally be administered in admixture with a pharmaceutical vehicle selected according to the route of administration and standard pharmaceutical practice.

For example, they can be administered orally either in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or mixed with excipients or in the form of syrups or suspensions containing coloring agents or flavorings. They can also be injected parenterally, such as, for example, intramuscularly, intravenously or subcutaneously.

When parenteral administration is involved, they will preferably be used in the form of a sterile aqueous solution which may contain other solutes, such as for example a salt or glucose, intended to make the solution isotonic.

The medicaments may contain an amount of any of the compounds of general formula (I), such that the level of the dose administered is between 0.001-10 mg / kg. The quantity of active principle which each of the dosage forms may contain may be approximately between 0.05 mg and 1 g.

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CH 685 700 A5

While intramuscular administration can be applied in a single dose or divided up to three doses, intravenous administration can include a drip for continuous dosing. There will necessarily be variations which will depend on the weight and conditions of the subject to be treated as well as the route chosen for administration.

The following examples, which are not limiting, illustrate the preparation of the compounds of the present invention.

Example 1

2- (2-NITRATOPROPYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

To a mixture of 10 ml of fuming nitric acid and 30 ml of acetic anhydride previously cooled in a bath composed of a mixture of water and ice whose temperature is between 0 and 5 ° C., 10 is added. g (0.04 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- (2-propanol) dropwise and with stirring. After stirring the mixture for three hours at this same temperature, it is poured into a volume of 200 ml of a mixture of ice and water and it is extracted with ethyl acetate (2 x 50 ml) . After having separated the organic phase, washing is carried out using a saturated potassium carbonate solution, followed by washing with water and finally drying over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, a solid is obtained which, after recrystallization from ethanol, has a melting point of 118-120 ° C. The reaction yield, after recrystallization, is 87%.

Example 2

2- (2,2-DIMETHYL-3-NITRATOPROPYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1 -DIOXYDE

On a mixture of 5 ml of fuming nitric acid and 15 ml of acetic anhydride cooled beforehand using a bath composed of a mixture of water and ice at a temperature of 0-5 ° C , 5.8 g (0.02 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- (2,2-dimethyl-3-propanol) are added dropwise and waving. After stirring the mixture for three hours at this same temperature, it is poured into 70 ml of a mixture of water and ice and it is extracted with ethyl acetate (2 x 30 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is then washed with water and finally dried over anhydrous sodium sulfate. After evaporation of the solvent under pressure, a solid is obtained which, after recrystallization from ethanol, has a melting point of 105-107-C. The reaction yield, after recrystallization, is 77%.

Example 3

2- (3-NITRATOPROPYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 27 ml of fuming nitric acid and 95 ml of acetic anhydride, previously cooled in a bath composed of a mixture of water and ice whose temperature is between 0-5 ° C, is added 30 g (0.13 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- (3-propanol) in small quantities and with stirring. After stirring the mixture for three hours at this same temperature, it is poured into 500 ml of a mixture of water and ice and it is extracted with ethyl acetate (2 x 150 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is washed with water and finally dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, a solid is obtained which, after recrystallization from ethanol, has a melting point of 71-72 ° C. The reaction yield, after recrystallization, is 92%.

Example 4

2- (6-NITRATOHEXYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 8 ml of fuming nitric acid and 25 ml of acetic anhydride, previously cooled in a bath made of a mixture of water and ice whose temperature is between 0-5 ° C, is added 10 g (0.04 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- (6-hexano!) In small quantities and with stirring. After stirring the mixture for three hours at this same temperature, it is poured onto 150 ml of a mixture of water and ice and it is extracted with ethyl acetate (2 x 50 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is washed with water and finally dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, an oil is obtained which subsequently solidifies. After recrystallization of the solid from ether, a solid is obtained whose melting point is 28-30 ° C. The reaction yield, after recrystallization, is 60%.

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CH 685 700 A5

Example 5

2- (2,3-DINITRATOPROPYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 10 ml of fuming nitric acid and 30 ml of acetic anhydride, previously cooled in a bath made of a mixture of water and ice whose temperature is between 0-5 ° C, is added 5 g (0.02 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- (2,3-propanodiol) in small quantities and with stirring. After stirring the mixture for three hours at this same temperature, it is poured onto 125 ml of a mixture of water and ice and it is extracted with ethyl acetate (2 x 50 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is washed with water and finally dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, a solid is obtained which, after recrystallization from ethanol, has a melting point of 103-105 ° C. The reaction yield, after recrystallization is 50%.

Example 6

2- (2-METHYL-2-NITRATOPROPYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 12 ml of fuming nitric acid and 42 ml of acetic anhydride, previously cooled in a bath made of a mixture of water and ice whose temperature is between 0-5 ° C, is added 14 g (0.06 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- (2-methyl-2-propanol) in small quantities and with stirring. After stirring the mixture for 2 h 30 min at this same temperature, it is poured into 200 ml of a mixture of water and ice and it is extracted using ethyl acetate (2 x 75 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is washed with water and finally dried over anhydrous sodium sulfate. Evaporation under reduced pressure of the solvent produces a solid which, after recrystallization from ethyl acetate, has a melting point of 8 ° -90 ° C. The reaction yield, after recrystallization, is 85%.

Example 7

2- [2- (2,4-DICHLOROPHENYL) -2-NITRATOETHYL] -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 15 ml of fuming nitric acid and 55 ml of acetic anhydride, previously cooled in a bath made of a mixture of water and ice whose temperature is between 0-5 ° C, is added 25 g (0.06 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- [2- (2,4-dichroIophenyl) -2-ethanol] in small quantities and shaking. After having stirred the mixture for 2 h 30 min at this same temperature, it is poured onto 250 ml of a mixture of ice and water and it is extracted with ethyl acetate (2 x 150 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is washed with water and finally dried over anhydrous sodium sulfate. Evaporation under reduced pressure of the solvent produces a solid which, after recrystallization from ethanol, has a melting point of 167-170 ° C. The reaction yield, after recrystallization is 85%.

Example 8

2-NITRATOMETHYL-1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 12 ml of fuming nitric acid and 41 ml of acetic anhydride, previously cooled in a bath made of a mixture of water and ice whose temperature is between 0-5 ° C, is added 13 g (0.06 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2-methanol in small quantities and with stirring. After stirring the mixture for three hours at this same temperature, it is poured onto 200 ml of a mixture of ice and water and it is extracted with ethyl acetate (2 x 75 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is then washed with water and finally dried over anhydrous sodium sulfate. Evaporation under reduced pressure of the solvent produces a solid which, after recrystallization from metha-nol, has a melting point of 67-69 ° C. The reaction yield, after recrystallization, is 66%.

Example 9

2- (2-NITRATOCYCLOHEXYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 32 ml of fuming nitric acid and 110 ml of acetic anhydride, previously cooled in a bath consisting of a mixture of water and ice whose temperature is between 0-5 ° C, is added 40 g (0.14 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2 (2-cyclohexanol) per

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CH 685 700 A5

small amounts and shaking. After stirring the mixture for four hours at this same temperature, it is poured onto 400 ml of a mixture of ice and water and it is extracted with ethyl acetate (2 x 150 ml). After separating the organic phase and washing it with a saturated potassium carbonate solution, it is then washed with water and finally dried over anhydrous sodium sulfate. Evaporation under reduced pressure of the solvent produces a solid which, after recrystallization from ethanol, has a melting point of 136-137 ° C. The reaction yield, after recrystallization, is 50%.

Example 10

2- (2-NITRATOETHYL) -1,2-BENZO-ISOTHIAZOLYL-3 (2H) ONE-1,1-DIOXYDE

On a mixture of 30 ml of fuming nitric acid and 100 ml of acetic anhydride, previously cooled in a bath consisting of a mixture of water and ice whose temperature is between 0-5 ° C, is added 30 g (0.13 mole) of 1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide-2- (2-ethanol) in small quantities and with stirring. After stirring the mixture for two hours at this same temperature, it is poured onto 450 ml of a mixture of ice and water and it is extracted with ethyl acetate (2 x 200 ml). The organic phase is then separated, washed with a saturated potassium carbonate solution, then washed with water and finally dried over anhydrous sodium sulfate. Evaporation under reduced pressure of the solvent produces a solid which, after recrystallization from ethanol, has a melting point of 117-119 ° C. The reaction yield, after recrystallization is 96%.

Pharmacological tests have shown that the compounds of general formula (I) of the present invention have a marked vasodilating, hypotensive and increased blood flow action; they can be used in the therapy or prevention of diseases of the cardiovascular system. These diseases include, among others, disorders of the cerebral or peripheral circulation, tissue ischemia and more particularly cardiac ischemia, heart failure and hypertension.

The relaxing power of the compounds of general formula (I) is determined by means of “in vitro” tests carried out on rat aorta rings contracted by norepinephrine. The thoracic aorta is extracted and cut into 3 mm wide rings. These rings are suspended in an organ bath filled with Krebs liquid at a constant temperature of 37 ° crossed by a current of O2 / CO2 (95/5). Once balanced, the aorta contracts under the action of norepinephrine; finally, the relaxation obtained by increasing concentrations of the compounds (I) of the present invention is observed.

The relaxing power of the various compounds is expressed in IC50, that is to say, the concentration at which a relaxation of 50% of the contraction induced by norepinephrine is reached.

The results of the tests are given in Table 1, in which the results obtained with the isosorbide dinitrate used as a comparison standard have been included.

“IN VITRO” TEST RESULTS

Board

Composed according to Spasm NE (aorta)

Example No. IC50 (M)

3

3.1

x

10-6

6

have ö

X

10-6

7

1.6

X

IO ""

8

CD

co

X

10-4

9

7.8

X

10-4

10

1.5

X

10-5

isosorbide dinitrate

7.6

X

10-5

(comparison standard)

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Claims (9)

Claims 1. Compounds of general formula (I) 0 II 0 (I) 0 in which Y is a substituted cycloalkyl group, or a group R1! - (CH2) m-C- (CH2) „ i R in which R is a hydrogen atom, a methyl radical, a 2,4-dichlorophenyl radical or a nitrate residue, R 'is a hydrogen atom or a methyl radical, m is an integer between 0 and 5, n is an integer between 0 and 1. 2. Compounds according to claim 1, chosen from 2- (2-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (2,2-dimethyl-3-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (3-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (6-nitratohexyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (2,3-dinitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- (2-methyl-2-nitratopropyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2- [2- (2,4-dichlorophenyl) -2-nitratoethyl] -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 2-nitratomethyl-1,2-benzo-isothiazoly! -3 (2H) one-1,1-dioxide 2- (2-nitratocyclohexyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1- dioxide; 2- (2-nitratoethyl) -1,2-benzo-isothiazolyl-3 (2H) one-1,1-dioxide; 3. Method for preparing the compounds of general formula (I) according to claim 1, which consists in treating an alcohol of general formula (II) wherein Y has the same meaning as in claim 1, with nitric acid or another suitable reagent. O (II) 7 5 10 15 20 25 30 35 40 45 50 55 60 CH 685 700 A5 4. Process for the preparation of the compounds of general formula (I) according to claim 1, which consists in treating a halogenated compound of general formula (III) wherein Y has the same meaning as in claim 1 and X is a halogen atom, with nitric acid or another suitable reagent. 5. Medicament comprising at least one compound of general formula (I) according to one of claims 1 or 2. 6. Medicament according to claim 5, comprising at least one pharmaceutically acceptable excipient. 7. Medicament according to one of claims 5 or 6, as a vasodilator intended for the preventive or curative treatment of cardiovascular diseases. 8. A medicament according to claim 7 as an agent for the treatment of cardiac or tissue ischemia. 9. Medicament according to one of claims 7 or 8, as an agent for the treatment of angina pectoris, the treatment of heart failure and the treatment of hypertension. 0 N Y X (III) 8