JPH07506844A - Nitric acid 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide esters, their production methods and drugs containing them - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Nitric acid 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide Stelles, their production and medicines containing them Field of invention The present invention provides a novel 1,2-benzo-isothiazolyl-3 nitric acid substituted at the 2-position. (2H)-one-1,1-dioxide esters, their production methods and their esters Concerning drugs containing sterol.

These compounds have vasodilatory effects that act on blood vessels in a highly specific manner and therefore , cardiovascular disorder, group Treatment of tissue ischemia, angina and hypertension It is effective for treatment and prevention.

Technology background Nitrate esters such as trinitroglycerol or isosorbide dinitrate are , which has a vasodilatory effect that particularly reduces cardiac preload, thereby stimulating this organ. It reduces the oxygen requirements of the body, making it a long-lasting treatment for angina and other cardiovascular disorders. It has been used for a while. However, these compounds, when given repeatedly, The clinical drawback is that resistance develops.

Therefore, other nitrate esters have been developed. For example, European Patent Application No. 04 No. 73027, No. 0490183, No. 0171977 and No. 0210581 The numbers are pyridinocarboxamide, benzoxazinone, phthalimide and 1. Discloses nitrates derived from each of 4-benzodioxane. death Satisfactory, effective and available pharmaceutical products against cardiovascular diseases does not yet exist.

Therefore, it is more selective, has a higher pharmacological effect, and is more Developing novel compounds that exhibit resistance to a lesser extent to the undesirable outcomes described above It is necessary to.

The present invention provides that the nitrate group is mediated by a substituted or unsubstituted alkyl chain. and 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide Includes a series of novel nitrate esters that are bonded to the nitrogen atom of the component. these The compounds have a high vasodilatory effect, cause lower levels of tolerance, and are not suitable for industrial use. Therefore, they are suitable for use in actual clinical practice. is satisfactory.

The object compound of the present invention is 2-alkyl-1,2-benzo-nitrate of the general formula (+). Isothiazolyl-3(2)1)one-1,1-dioxide ester.

In the formula, Y is a substituted cycloalkyl group or the group below.

(In the formula, R is a hydrogen atom, methyl, 2,4-dichlorophenyl group, or nitrate It is a residue, Ro is a hydrogen atom or a methyl group, m is an integer from 0 to 5, n is an integer of 0 or l. ) Some preferred examples of the compounds of the present invention include: 2-(2-nidradopropylene) )-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide , 2-(2,2-dimethyl-3-nidoradopropyl)-1,2-benzo-isothia Zolyl-3-(211)one-1,1-dioxide, 2-(3-nidradopropyl) )-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide , 2-(6-nitratohexyl)-1,2-benzo-isothiazolyl-3(2)1 )one-1,1-dioxide, 2-(2,3-dinitratoprovir)-1,2-benzo-inthiazolyl-3( 2H)one-1,l-dioxide, 2-(2-methyl-2-nidoradopropyl)-1,2-benzo-isothiazolyl -3(2H)-one-1,1-dioxide, 2-[2-(2,4-dichlorophenyl)-2-nidoradoethyl]-1,2-ben -isothiazolyl-3(2H)one-1,1-dioxide, 2-nidradome Chil-1,2-benzo-inthiazolyl-3(2)1)one-1,1-dioxy Do, 2-(2-nidoradocyclohexyl)-1,2-benzo-isothiazolyl-3( 2H)one-1,1-dioxide, 2-(2-nidoradoethyl)-1,2-benzo-isothiazolyl-3(2H) -1,l-The compound of general formula (+) is an alcohol of general formula (II) or a compound of general formula (+) The halogenated compound of formula (II+) is treated with nitric acid or other suitable reagent. It can be manufactured by

In the formula, Y is the same as defined above and X is a halogen atom. )like this and refer to them in the following literature: P, 5toss, G, 5chluter , R, Axmann; Arzeil L-Forch, /Drug Res, , (4O) (1), N'1 (1990).

+3-18, -R, Boschan, R, T, Merrow, R, W, Dolah ;Chew Rev, 55. (1955), 48T, -○, H, 1(ak ime iah i, H, Shargh i, H, 7, arr　iamayeh,　/L　Kha　af　1|Nezhad　： He lv, Ch ia Ac [,.

67, (1984), 906, -A, Mv K11lop, M, E, Ford; Tekeahedron, 30 ．． (1974), 2467, -G, 5natzke, H, Lauren t, R, Wierchert; Tetrahedron, 25. (1 969), V61, It can be obtained in an analogous manner using the reagents shown in .

The starting compounds of general formula (11) are known and can be prepared commercially by conventional methods. It can be manufactured from commercially available reagents. In this way, 2-hydro roxymethyl-1,2-penzolisothiazinyl-3(2B)one-1,1-di Oxide, J. Letterer, Chern, 26 (1989), Produced according to the method of Choi, Lee and Yoon, described in 1073. . Also, other 2-hydroxyalkyl-1,2-benzo-isothiazolyl-3- (2H) Oni/-1,1-dioxide, for example, J, Amer, Chem, H, L, Rice and G in Sac, 76, (1974), 302 , 1,2-benzo- Sodium salt of isothiazolyl-3(2H)one-1,1-dioxide and general Formula (IV) (wherein R, R', m and n are as defined above, and X is halo Represents a gen atom. ) obtained by known conventional methods by reaction with the corresponding halogenated derivative of be able to.

A further object of the invention is that at least one of the compounds of general formula (1) according to claim 1 This drug contains one type of

This drug has a vasodilatory effect and for the prevention or treatment of cardiovascular diseases can be used for.

This drug is used to treat cardiac or tissue ischemia, congestive heart failure, and congestive heart failure. It is particularly suitable for the treatment of iveheart failure) and hypertension.

Although the compounds (1) of the present invention can be administered alone, they may be and in a mixture with pharmaceutical excipients selected according to the means of useful pharmaceutical practice. Generally administered.

For example, they can be added to tablets containing excipients such as starch or lactose, alone or mixed with excipients, or additionally colorants or flavorings. It can be administered orally as a syrup or suspension. Also, it They can be injected parenterally, such as intramuscularly, intravenously, and subcutaneously. can.

If parenteral means are chosen, they are preferably in the form of a sterile aqueous solution. and the solution is made isotonic, for example by salt or glucose. It may also contain other solutes that are intended to be regulated.

The above drug was administered at a dose level of 0.001 N10mg/kg. can contain any one of the compounds of general formula (1). any one The amount of active ingredient contained in the dosage form is in the range of approximately 0.05 mg = 1 g. .

Intramuscular administration can be administered in a single dose or divided into up to three doses. However, intravenous administration includes a drip method for continuous administration.

necessarily the weight and conditions of the experimental material administered and the hand chosen for administration. There are stage-dependent changes.

Preparation of compounds of the invention by way of the following examples, which are not intended to be limiting. Explain.

Example 1 2-(2-nidoradopropyl)-1,2-benzo-isothiazolyl-3C2H) one-1,1-dioxide 1 pre-cooled in a container consisting of a mixture of water and ice at a temperature of 0 to 5°C. To a mixture of 0 ml of fuming gas and 30 ml of acetaldehyde, lOg (0,0 4 mol) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-diox Cid-2-(2-propatool) was added dropwise under stirring. The mixture, After stirring for 3 hours at the same temperature as above, it was mixed with 200ml of ice and water. and extracted with ethyl acetate (2×50+nl). Separate the organic phase and charcoal After washing with a solution saturated with potassium acid, washing with water and finally anhydrous Dry with sodium sulfide. Evaporate the solvent under reduced pressure and then add to ethanol. A solid with a melting point of 118-120°C was obtained after recrystallization at . recrystallization The yield of the subsequent reaction was 87%.

Example 2 2-(2,2-dimethyl-3-nidoradopropyl)-1,2-benzo-isothia Zolyl-3(2H)-one-1,1-dioxide 5 ml of fuming nitric acid, pre-cooled with a mixture of water and ice, at a temperature of 0-5°C and 15 ml of acetaldehyde, 5.8 g (0.02 mol) of 1 ．． 2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-( 2,2-dimethyl-3-propanol) was added dropwise under stirring. said mixture After stirring the material for 3 hours at the same temperature as above, it was added to a mixture of 70 ml of water and ice. The mixture was poured and extracted with ethyl acetate (2×30+nl).

The organic phase is separated and washed with a solution saturated with potassium carbonate and then with water. and finally dried with anhydrous sodium sulfide. Evaporate the solvent under reduced pressure After recrystallization in ethanol, a solid with a melting point of 105-107°C is obtained. Obtained. The yield of the reaction after recrystallization was 77%.

Example 3 2-(3-nidoradopropyl)-1,2-benzo-isothiazolyl-3(2H) one-1,l-dioxide 27 pre-cooled in a bath containing a mixture of water and ice at a temperature of 0-5°C. To a mixture of ml of fuming nitric acid and 95 ml of acetaldehyde was added mol) of 1,2-benzo-isothiazolyl-3(2)1)one-1,1-diox Cid-2-(3-propatool) was added in portions under stirring. The mixture, After stirring for 3 hours at the same temperature as above, it was added to a mixture of 500 ml of water and ice. and extracted with ethyl acetate (2X150ml). Separate the organic phase and carbonate Wash with a solution saturated with potassium, then with water and finally with anhydrous sulfur. dried over sodium chloride. After evaporating the solvent under reduced pressure, it was added to ethanol. A solid with a melting point of 71-72° C. was obtained after recrystallization. Reaction after recrystallization The yield was 92%.

Example 4 2-(6-nitratohexyl)-1,2-benzo-isothiazolyl-3(2H) one-1,1-dioxide 8, pre-cooled in a bath consisting of a mixture of water and ice at a temperature of 0-5°C. To a mixture of ml of fuming nitric acid and 25 ml of acetaldehyde, lOg mol) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxy Do-2-(6-hexanol) was added portionwise with stirring. The mixture before After stirring for 3 hours at the same temperature as above, it was added to a mixture of 150 ml of water and ice. The mixture was poured and extracted with ethyl acetate (□×50+nl). Separate the organic phase and add potassium carbonate After washing with a solution saturated with sodium chloride, washing with water and finally washing with anhydrous sodium sulfide. Dry with thorium. Oil that later solidifies after evaporating the solvent under reduced pressure was gotten. having a melting point of 28-30°C after recrystallization of the solid in ether. A solid was obtained. The yield of the reaction after recrystallization was 60%.

Example 5 2-(2,3-dinitratopropyl)-1,2-benzo-isothiazolyl-3( 2H)one-1,1-dioxide 1 pre-cooled in a container consisting of a mixture of water and ice at a temperature of 0 to 5°C. 5 g (0,0 2 mol) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-diox Sid-2-(2,3-propanediol) was added portionwise with stirring. Before After stirring the mixture for 3 hours at the same temperature as above, it was mixed with 125 ml of water. Poured into mixture with ice and extracted with ethyl acetate (2x50ml). Separate the organic phase Remove and wash with a solution saturated with potassium carbonate, then with water, It was then dried over anhydrous sodium sulfide. After evaporating the solvent under reduced pressure, evaporate A solid with a melting point of 103-105°C was obtained after recrystallization in Nord.

The yield of the reaction after recrystallization was 50%.

Example 6 2-(2-methyl-2-nidoradopropyl)-1,2-benzo-isothiazolyl -3(2H)-one-1,1-dioxide 1, pre-cooled in a bath consisting of a mixture of water and ice at a temperature of 0-5°C. 14 g (0,0 6 mol) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-diox Sid-2-(2-methyl-2-propatol) was added in portions under stirring. Before After stirring the mixture for 2 and a half hours at the same temperature as above, it was poured into 200 ml of water. and ice and extracted with ethyl acetate (2X75ml). organic phase Separate and wash with a solution saturated with potassium carbonate, then with water and finally Finally, it was dried with anhydrous sodium sulfide. After evaporating the solvent under reduced pressure, A solid with a melting point of 88-90°C was obtained after recrystallization in ethanol. Re The yield of the reaction after crystallization was 85%.

Example 7 2-[2-(2,4-dichlorophenyl)-2-nidoradoethyl]-1,2-ben -isothiazolyl-3(2H)one-1,1-dioxide with a temperature of 0 to 5℃ , 15 ml of fuming nitric acid, pre-cooled in a tank consisting of a mixture of water and ice. and 55 ml of acetaldehyde, 25 g (0.06 mol) of 1,2 -benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-[2- (2,4-dichlorophenyl)-2-ethanol] was added little by little while stirring. . After the mixture was stirred at the same temperature for 2 and a half hours, it was added to 250 ml of of water and ice and extracted with ethyl acetate (2X150ml). Yes Separate the organic phase and wash with a solution saturated with potassium carbonate, then with water. and finally dried with anhydrous sodium sulfide. The solvent was evaporated under reduced pressure Afterwards, a solid with a melting point of 167-170°C was obtained after recrystallization in ethanol. It was done. The yield of the reaction after recrystallization was 85% 2-nidoradomethyl-1,2-benzo -isothiazolyl-3(2H)one-1,1-dioxide water with a temperature of 0 to 5°C 12 ml of fuming nitric acid and 4 13 g (0.06 mol) of 1,2-benzene in a mixture with 1 ml of acetaldehyde -isothiazolyl-3(2H)one-1,1-dioxide-2-methanol was added little by little while stirring. The mixture was stirred for 3 hours at the same temperature as above. After that, it was poured into a mixture of 200 ml of water and ice and ethyl acetate (2x75 ml).

The organic phase is separated and washed with a solution saturated with potassium carbonate and then with water. and finally dried with anhydrous sodium sulfide. Evaporate the solvent under reduced pressure After recrystallization in methanol a solid was obtained with a melting point of 67-69°C. It was.

The yield of the reaction after recrystallization was 66%.

Example 9 2-(2-nitratonochlohexyl)-1,2-benzo-isothiazolyl-3( 2H)one-1,l-dioxide 3, pre-cooled in a bath consisting of a mixture of water and water at a temperature of 0 to 5 °C; To a mixture of 2 ml of fuming nitric acid and 110 ml of acetaldehyde, 40 g 14 mol) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dio Oxide-2-(2-cyclohexanol) was added portionwise with stirring. The mixture After stirring the mixture for 4 hours at the same temperature as above, it was mixed with 400 ml of ice and water. and extracted with ethyl acetate (2x150ml). Separate the organic phase and washed with a solution saturated with potassium carbonate, then with water, and the final and dried over anhydrous sodium sulfide. After evaporating the solvent under reduced pressure, the ethanol A solid with a melting point of 136-137 DEG C. was obtained after recrystallization in a mold. Re The yield of the reaction after crystallization was 50% for 2-(2-nidoradoethyl)-1,2-benzo -isothiazolyl-3(2H)one-1,1-dioxide 3, pre-cooled in a bath consisting of a mixture of water and ice at a temperature of 0 to 5 °C; To a mixture of 0 ml of fuming nitric acid and 100 ml of acetaldehyde, 30 g 13 mol) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dio Oxide-2-(2-ethanol) was added portionwise with stirring. The mixture, After stirring for 2 hours at the same temperature as above, it was added to a mixture of 450 ml of ice and water. and extracted with ethyl acetate (2x200ml). Then separate the organic phase , washed with a solution saturated with potassium carbonate, then washed with water, and finally Dry with anhydrous sodium sulfide. After evaporating the solvent under reduced pressure, ethanol A solid with a melting point of 117-119° C. was obtained after recrystallization in a molten glass. reunion The yield of the reaction after crystallization was 96%.

Pharmacological tests have shown that the compound of general formula (1) of the present invention causes significant vasodilation and It has been shown to have a lowering and blood flow enhancing effect, making them useful in preventing cardiovascular disorders. or can be used for treatment. This term refers to cerebral or peripheral Impairment of circulation, including tissue ischemia, more specifically cardiac ischemia, congestive heart Including insufficiency and hypertension.

The relaxing efficacy of the compound of general formula (+) was demonstrated in rats contracted by norepinephrine. This was determined by "in vitro" tests carried out on aortic rings. the thoracic aorta , extracted and cut into rings 9 strokes wide. These rings are defined as 01/C0t(9515 ) mixture is flowed, kept at a temperature of 37 °C, filled with Krebs solution. floating in a bath.

After reaching equilibrium, the aorta was constricted under the action of norepinephrine. .

Finally, the relaxation obtained by increasing the concentration of the compound (+) of the present invention , recorded.

The relaxing potency of various compounds was measured by 50% relaxation of the contractions produced by norepinephrine. It is expressed by Ic, which is the concentration achieved.

The results of the above test were obtained using isosorbide dinitrate, which was used as a reference. The results are listed in Table 1.

Compound NE Spasticity (Aorta) IC, according to Example Number. (M)3 3.1X 10-' 6 5.0XIO-@ 7 1.6X10-' 8 3.6X10-' Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.

TD, TG), AT, AU, BB, BG, BR, BY.

CA, CH, CN, CZ, DE, DK, ES, FI, GB, HU, JP, KG, KP, KR, KZ, LK, LU, LV, MD, MG, MN, MW, NL, No, NZ.

PL, PT, RO, RU, SD, SE, SI, SK, TJ, TT, UA, US, UZ, VN (72) Inventor Statcola Vinyl Switzerland Zeher 1207 Genet ve rieux du rove elei 6 (72) Inventor Stromann Daniel Suisse Zeher 1920 Malte Innieryu Pre Volvai 6 (72) Inventor Schattelier Seeam Niss Federal Republic of Germany Day 75 00 Karlsruhe 1 Stettinerstrasse (72) Inventor Shi Schregelmilch Ronald Federal Republic of Germany Day 7500 Karlsruhe 41 Wilmer Schwebe Strasse 4 Firma Doctor Wilmer Schwepe Arzneimittel Abteilung Pharmaco oral

Claims (10)

[Claims] 1. A compound of general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼In the formula (I), Y is a substituted cycloalkyl or the following groups. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is a hydrogen atom, methyl, 2,4-dichlorophenyl group, or nitrate It is a residue, R' is a hydrogen atom or a methyl group, m is an integer of 0 to 5, n is an integer of 0 or 1. ) 2.2-(2-nitratopropyl)-1,2-benzo-isothiazolyl-3(2 H) one-1,1-dioxide, 2-(2,2-dimethyl-3-nitratopropyl)-1,2-benzoisothia zolyl-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-beta -isothiazolyl-3(2H)one-1,1-dioxide, 2-nitratome Chil-1,2-benzo-isothiazolyl-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) -1,1-dioxide, 2. A compound according to claim 1 selected from: 3. A method for producing a compound of general formula (I) according to claim 1, comprising: a compound of general formula (II) ) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, Y has the same meaning as in claim 1. It is one. ) with nitric acid or other suitable reagents. The method described above. 4. A method for producing a compound of general formula (I) according to claim 1, comprising: a compound of general formula (II) I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, Y is the meaning of claim 1. are the same, and X is a halogen atom. ) of halogenated compounds with nitric acid. or other suitable reagents. 5. The compound of general formula (I) according to any one of claims 1 or 2 at least A drug containing one type of 6. The drug according to claim 5, comprising at least one pharmaceutically acceptable excipient. 7. Claimed as a vasodilator used to prevent or treat cardiovascular disease. The drug according to any one of claim 5 or 6. 8. 8. Medication according to claim 7 for the treatment of cardiac or tissue ischemia. 9. Claim 7 or 8 for the treatment of angina, congestive heart failure and hypertension The drug described in any one of the following. 10. A method for preventing or treating cardiovascular diseases, comprising: a method according to claims 5 to 9; Administering an effective amount of the drug listed in any one of the preceding paragraphs to patients with cardiovascular disease. The method comprising: