CA2135921A1 - Nitic 1,2-benzo-isothiazolyl-3(2h)one-1, 1-dioxide esters, preparation method therefor and drugs containing same - Google Patents
Nitic 1,2-benzo-isothiazolyl-3(2h)one-1, 1-dioxide esters, preparation method therefor and drugs containing sameInfo
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- CA2135921A1 CA2135921A1 CA002135921A CA2135921A CA2135921A1 CA 2135921 A1 CA2135921 A1 CA 2135921A1 CA 002135921 A CA002135921 A CA 002135921A CA 2135921 A CA2135921 A CA 2135921A CA 2135921 A1 CA2135921 A1 CA 2135921A1
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- benzo
- dioxide
- isothiazolyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- A61P9/08—Vasodilators for multiple indications
-
- 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
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Abstract
Nitric esters of general formula (I), wherein Y is a substituted cycloalkyl group or a group (a) wherein 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 from 0 to 5, and n is an integer from 0 to 1, and a method for preparing same, are disclosed. Drugs containing such compounds and particularly having vasodilatory activity for use in treating or preventing cardio-vascular diseases, are also disclosed.
Description
,--` 2135921 NITRIC 1,2-BENZO-ISOTHIAZOLYL-3(2H)ONE-1,1-DIOXIDE ESTERS
PREPARATION METHODE THEREFOR AND
DRUGS CONTAINING SAME
The present invention is concerned with new nitric 1,2-benzo-iso-thiazolyl-3(2H)one~ dioxide esters substituted in position 2, a pre-paration method therefor and drugs contail~ing these esters.
These compounds have a vasodilatory activity which is highl~r speci-fically directed at vessels and which are hence ef~ective in the treat-- ment and the prevention of cardiovascular disorders, tissular ischemia, angina and hypertension.
- Nitric esters, such as trinitroglycerol or isosorbide dinitrate have long been used for the treatment of a~gina and other cardiovascu-Iar disorders, because they possess a vasodilatory activity which de-creases in particular the cardiac preload, which results in a decreased oxygen requirement for this organ. However, these compoumds suffer the -- çlinical drawback of developing a tolerance when admLnistered repea-; ~ tedly.
:- Accordingly, other nitric esters have been developed. For example, - the European Patent Applications EP-0473027, EP-04901~3, EP-0171977 and EP-0210581 describe nitrates derived from pyridinocarboxyamides, ben-zoxazinones, phthalimides and 1,4-benzodioxanes, respectively. However, there is still no pharmaceutical product available which would be sa-tisfactory and effectiYe against cardiovascular diseases; it is hence necessary to develop new compounds which would be more selective, which would possess a higher pharmacological activity and exhibit to a lesser extent the above-mentioned undesirable effect of tolerance.
The present i~vention encompasses a series of new nitric esters 2t,,,~", wherein the nitrate group is linked via a substituted or non substitu-ted alkyl chain to the nitrogen atom of a 1,2-benzo-isothiazo-Iy1-3(2H)one-1,1-dioxide moiety. These compounds possess a high vasodi-latory activity, a lesser level of tolerance and they can be prepared industrially; hence, they are satisfactory for use in actual practice.
} The compounds object of the present invention are nitric 2-al-~` 2l3~92l kyl-1,2-benzo-isothiszolyl-3(2H)one~ dioxide esters of the general formula (I) ~-Y - ( I) O O N~
o in which Y is a substituted cycloalkyl group or a group . R' ~C~).~-CI-(C~-- R
wherein R is a h~rdrogen atom, a meth~rl or a 2,4-dichlorophényl radical or a ni-trate residue, R' is a hydrogen atom or a methyl radical, m is an integer from O to 5, n is an ~teger from O to 1.
Some preferred examples of the compounds of the present in:vention ihclude: .
2-(2-nitratopropyl)-1,2-benzo-isothiazolyl-3(2H)one-1,14ioxide;
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-l~l-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-dichlorophényl)-2-nitratoéthyl)-1,2-benzo-isothiazolyl-3( 2H )one-1 ,1-dioxide;
2-nitratométhyl-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)one-1,1-dioxide.
The compounds of general formula (I) can be prepared by treating an alcohol o~ the general formula (II) or a halogenated compound of formu-la (III) ~\N-Y-OH (ll) ~N-Y-Cl t ~\
O O O . O
<
in which Y has the same definition as previous4~ a~d X LS a halogen atom, with nitric acid or another appropriate reagent.
They can thus be obtained in a similar manner with the reagents in-dicated in the following publications:
- P. Stoss, G. Schluter, R. Axmann; Arzeim.-Forch./Drug Res., (40) (I), N 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 products of general formula (II) are known and they can be prepared by conventional methods from commercially sold rea-gents. Thus, the 2-hydroxymethyl-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide was prepared according to the method of Choi, ~ee and Yoon, described in J. Heter. Chem., 26 (1989), 1073. The other 2-hydroxyal-kyl-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxides can also be obtained by known con~rentional processes, such as for e~cample through the reac-tion between the sodium salt of 1,2-benzo-isothiazoly1-3(2H)one-1,1-dioxide and the corresponding halogenated derivative of the general formula (IV):
.
2l3592l R~
X-(CH2)~-C-(CH2)1,-OH (IV) q R
wherein R, R', m and n were defined preYious4~ and X represents an oxygen atom, in a manner similar to that described by H. L. Rice and G.
R. Pettit ~n J. Amer. Chem. Soc., 76, (î974), 302.
A further object of the invention is a medicament includillg at - least one compound of the general formula (I), according to cla~
This medicament has a vasodilatory effect and can be used ~or the preventive or curative treatment of cardiovascular diseases.
- This medicament is particularly well suited for the treatment of cardiac or tissular ischemias, angina, congestive heart failure or : hypertension.
The compounds (I) of the present invention can be administered alone, but they are generally administered in mixture with a pharmaceu-tical vehicle selected according to the route of administration and -; . usual pharmaceu~ical practices.
;~- For example~ they can be administered orally either as tablets containing excipients such as starch or lactose, or in capstlles either alone or mixed with excipients, or f`urther as syrups or suspensions containing colouring or flavouring agents. They can also be in~ ected parenterally, such as for example intramuscularly, intravenously or subcutaneously .
When the parenteral route LS selected, they will be used preferably in the form of a sterile aqueous solution which can contain other solu-tes, such as for example a salt or glucose, designed for rendering the solution isotonic.
The medicaments will be capable of containing an amount of any one of the compounds of formula (I), in such a manner that the level of the dose administered be comprised between 0.001 and 10 mg/kg. The amount of active principle which will be contained in each one of the dosage forms will range from approximatel~r 0.05 mg to 1 g.
While the intrarnuscular administration can be made in a single dose or be devided into up to three doses, the intravenous administration can include a drip for a continuous administration. There will necessa-rily be variations which will depend upon the weigh and the condition of the subject- treated, as well as the route selected for the administration .
The following examples, which are not intended to be limiting, il-lustrate the preparation of the compounds of the present invention.
Example 1 2~2-NrrRAT( )PROPYL~1,2-BENZO~ISOTHIAZOLYL-3(2H)ONE-1,1-DIOXIDE
To a mixture of 10 ml of fuming nitric acid and 30 ml of aLcetic an-hydride cooled pre~ iously in a bath consisting of a mixture of water and ice, the temperature of whish is in the range 0-5 C, 10 g (0.04 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-propanol) are added dropwise and under stirring. After having stirred 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 extracted with ethyl acetate (2 x 50 ml). After having separated the organic phase, a washing is carried out by means of a solution saturated with potassium carbonate, ~ollowed by washing with water and finally drying over anhydrous sodium sulfate.
After evaporation of the solvent under reduced pressure, a solid is ob-tained which after recrystallization in ethanol has a melting point of 118-120-C. The yield of the reaction after recrystallization is o~ 87%.
ExamPle 2 2-(2,2-DIMl~THYL-3-NITRATOPROPYL)-1,2-BENZO-ISOTHLAZOLYL-3(2H)ONE-1 ,1-DIOXIDE
, On a mixture of 5 ml of fuming nitric acid and 15 ml of acetic an-hydride pre~riously cooled by means of a mixture of water and ice at the temperature of 0-5 C, 5.8 g (0.02 moles) of 1,2-benzo isothiazo-lyl-3(2H)one-1,1-dio~ide-2-(~,2-diméthy1-3-propanol) are added dropwise a~d under stirring. Aftes having stirred the mixture during three hours at this same temperature, it is poured into 70 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 30 ml). After having se-parated the organîc phase snd washed the same with a solution saturatedwith potassium carbonate, 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 in ethanol, has a melting point of 105-107-C. The yield of the reaction, after recrystallization, is of 77%.
Example 3 2-(3-NITRATOPROPYL)-1,2-BE~IZO-ISOTHIAZOLYL-3~2H)ONE~ DIOXIDE
On a mixture of 27 ml of fuming nitric acid and 95 ml of acetic ah-hydride, previously cooled in a bath comprised of a mixture of water and of ice, of which the temperature is in the range 0-5 C, 30 g (0.13 moles) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(3-propanol) are added by small amounts and under stirring. After having stirred the mixture for three hours at the same temperature, it is poured on 500 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 150 ml). After having separated the organic phase and washed the same with a solution saturated with potassium carbonate, it is washed with water and finally dried over anhydrous sodium sulfate.
After evaporation of the solvent under reduced pressure, a solid is ob-tained which, after recrystallization in ethanol, has a melting point of 71-72-C, The yield of the reaction, after recrystallization is of 92%.
Example 4 2~6-NITRATOHEm~1,2-BENZO-ISOTHLAZOLYL-3(2H)ONE-l,l-DIOXiDE
On a mixture of 8 ml of fuming nitric acid and 25 ml of acetic an-hydride previously cooled in a bath consisting of a mixture of water and of ice having a temperature in the range 0-5 C1 10 g (0.04 moles) of 1,2-benzo-isothiazoly1-3-(2H)one~ dioxide-2-(6-hexanol) are added by small amounts and under stirring. After having stirred the mixture for three hours at this same temperature, it is poured on 150 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 50 ml).
After having separated the organic phase and washed the same with a so-lution saturated with potassium carbonate, it is washed with water and finally dried on anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, an oil is obtained which solidifies la-ter. After recrystallization of the solids in ether, a solid is obtai-ned, the melting point of which is of 28-30'C. The yield of the reac-tion after recrystallization is of 60%.
Example 5 2-(2,3-DINITRATOPROPYL)-1,2-BENZO-ISOTHlAZOLYL-3(2H)ONE-1,1-DIOXIDE
, , .
On a mixture of 10 ml of fuming nitric acid and 30 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water and ice, the temperature of which is in the range 0-5Cv 5 g (0.02 mo-les) of - 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2 j3-propanodiol) are added by small amounts and while stirring. After having stirred the mixture during three hours at this same temperature, it is poured on 125 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 50 ml). After having separated the organic phase and washed the same with a solution saturated with potassium carbonate, it is washed with water and fi~ally dried over anhydrous sodium sulfate. After eva-poration of the solvent under reduced pressure, a solid is obtained which, after recrystallization in ethanol, has a melting point of 103-105-C. The yield of the reaction, after recrystallization is of 50%.
, ExemPle 6 i2~2-METHYL-2-NITRATOPROPYL)-1,2-BENZO-ISOTHLAZOLYL-- 3(2H)ONE-1,1-DIOXIDE
,~
On a mixture o~ 12 ml of ruming nitric acid and of 42 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water and ice, the temperature of which is in the range 0-5 C, 14 g (0.06 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-méthy1-2-pro-pa~ol) are added by small amounts and under stirring. After having stirred the mixture during two hours and a half at this same tempera-. .
ture, it is poured on 200 ml of a mixture or water and ice and extrac-ted with ethyl acetate (2 x 75 ml). After ha~ting separated the organic phase and washed the sarne with a solution saturated with potassium car-bonate, it is washed with water and final4~ dried over anhydrous sodium sulfate. The evaporation under reduced pressure of the solvent produces a solid which, after recrystallization in ethyl acetate, has a melting point of 88-90-C. The yield of the reaction, after recrystallization, is of 85%.
.
ExamPle 7 ..2~2~2,4-DICHLOROPHENYL)-2-NITRATOETHYL]-1,2-BENZO--. . ISOTHIAZO.LYL-3(2H)ONE-1,1-DIOXIDE
On a mixture of 15 ml of fuming nitric acid and 55 ml of acetic an-: ~ hydride, previousb cooled in a bath consisting of a~mixture of water .
and ice, the temperature of which is in the range 0-5-C, 25 g (0.06 mo-les) Or: 1,2-benzo-isothiazo4r1-3(2Hjone-1,1-dioxide-2-12-(2,4-dichloro-phenyl-2-ethanoll are added by small amounts and under stirring. After having stirred the mixture during two hours and a half at this same temperature, it is poured on 250 ml of a mixture of ice and water and extr~lcted :with ethyl acetate (2 x 150 ml).. After having separated the organic~ phas~ and washed the same by means of a solution saturated with potassium:c~onllte, it is washed with~water and finally dried over an-hydrow sodium sulfate. The e~/sporation under reduced pressure of the solvent r~oduces a solid which, after lecrystallization in ethanol, has`
a melting point of I67-170-C. The yield of the reaction, after recrys-tallization, is of 85%.
ExemPle 8 2-NITRATOMETHYL-1,2-BENZO-ISOTHIAZOLYL-3(2H)ONE-1,1-DIOXIDE
On a mixture of 12 ml of fuming nitric acid and 41 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water and ice, the temperature of which is in the range Q-5-C, 13 g (0.06 mo-les) of 1,2-benzo-isothiazoly1-3(2H)one-1,1-dioxide-2-méthanol are ad-, ;, :, 2135921 .
: ~ -- 9 ded by small amounts and under stirring. After having stirred the mix-ture during three hours at this same temperature, it is poured on 200 ml of a mixture of ice and water and extracted with ethyl acetate (2x75 ml). After having separated the organic phase and washed the same with a solution saturated with potassium carbonate, it is then washed with water and finally dried over anhydrous sodium sulfate. The evaporation under reduced pressure of the solvent produces a solid which, after re-crystallization in methanol, has a melting point of 67-69-C. The yield of the reaction, after recrystallization, is o~ 667O.
. .
i Exemple 9 2-(2-NITRATOCYCLOHEXYL)-1,2-BENZO-~SOTHLAZOLYL-3(2H)ONE-1,1-DIOXIDE
; . ~ . .
- On a mixture of 32 ml of fuming nitric acid and 110 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water r. and ice, the temperature of which is in the range 0-5 C, 40 g (0.14 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-cyclohexanol), are added by small amounts and under stirring. After having stirred the ,., i~, mixture during four hours at this same temperature, it is poured on 400 ml of a mixture of ice and of water and extracted with ethyl acetate (2 x 150 ml). After having separated the organic phase and wæhed the same with ~a solution saturated with potassium carbonate, it is washed with water and finally dried over anlurdrous sodium sulfate. The evaporation under reduced pressure of the solvent produces a solid which, after re-crystallization in ethanol, has a melting point of 136-13~ C. The ~ield of the reaction, after recrystallization, is of 50%.
.',, ;'- ExamPle 10 2~2-NITRATOETHYL)-1,2-BENZO-ISOTHIAZOLYL
3(2H)ONE-1,1-D~OXIDE
On a mixture of 30 ml of fuming nitric acid and of 100 ml of acetic an-hydride, previously cooled in a bath coQsisting of a mixture of water and ice, of which the temperature is in the range 0-5 C, 30 g (0.13 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-ethanol) are , .~ . ,~.
, added by small amounts and under stirring. After having stirred the mixture during two hours at this same temperature, it is poured on 450 ml Or a mixture of ice and water and extracted with ethyl acetate (2 x 200 ml). The organic phase is then separated and washed with a solu-tion saturated with potassium carbonate, then washed with water and fi-nally dried over anhydrous sodium sulfate. The evaporation under redu-ced pressure of the solvent produces a solid, which after recrystalli-zation in ethanol, has a melting point of 117-119-C. The yield of the reaction, after recrystallization, is of 967~.
Pharmacological tests have shown that the compounds of the general for-mula (I) of the present invention have a marked vasodilatory, hypoten-sive and blood flow enhancing action; they can be employed for the pre-ventive or curative treatment of disorders of the cardiovascular sys-tem. This designation encompasses, amongst others, disorders of the cerebral or peripheral circulation, tissular -ischemia and more particularly cardiac ischemia, congestive heart failure and hyperten-sion.
.... .
The relaxant potency of the compou~ds of the general formula (I) is determined by means of "in vitro" tests carried out on rings of rat aorta contracted by norepinephrine. The thoracic aorta is extracted and cut into rings 3 mm wide. These rings are suspended in a bath filled with a Krebs solution at a constant temperature of 37 C through which is flowed a mixture of 02/C02 (95/S). Once the equilibrium has been reached, the aorta is contracted under the action of norepinephrine.
Finally, the relaxation obtained by increasing concentrations of com-pounds (I) of the present invention is noted.
., The relaxant potency of the various compounds is expressed by IGo, which is the concentration at which a relaxation of 50% of the contrac-tion induced by norepinephrine is reached.
The results Or the tests are given in table 1, which includes the results obtained with dinitrate isosorbide used as reference.
21~5921 RESUETS-OF "IN VITRO" TESTS
_ _ _ Compound according to example N- NE spasm (aorta) ICs~ (M~
_ .
3 3.1xl0 6 5.0x10 7 1.6x10 8 3.6x10 9 7.8xl~
10 , l.SxlO~
Isosorbide dinitrate 7.6x105 ~.
PREPARATION METHODE THEREFOR AND
DRUGS CONTAINING SAME
The present invention is concerned with new nitric 1,2-benzo-iso-thiazolyl-3(2H)one~ dioxide esters substituted in position 2, a pre-paration method therefor and drugs contail~ing these esters.
These compounds have a vasodilatory activity which is highl~r speci-fically directed at vessels and which are hence ef~ective in the treat-- ment and the prevention of cardiovascular disorders, tissular ischemia, angina and hypertension.
- Nitric esters, such as trinitroglycerol or isosorbide dinitrate have long been used for the treatment of a~gina and other cardiovascu-Iar disorders, because they possess a vasodilatory activity which de-creases in particular the cardiac preload, which results in a decreased oxygen requirement for this organ. However, these compoumds suffer the -- çlinical drawback of developing a tolerance when admLnistered repea-; ~ tedly.
:- Accordingly, other nitric esters have been developed. For example, - the European Patent Applications EP-0473027, EP-04901~3, EP-0171977 and EP-0210581 describe nitrates derived from pyridinocarboxyamides, ben-zoxazinones, phthalimides and 1,4-benzodioxanes, respectively. However, there is still no pharmaceutical product available which would be sa-tisfactory and effectiYe against cardiovascular diseases; it is hence necessary to develop new compounds which would be more selective, which would possess a higher pharmacological activity and exhibit to a lesser extent the above-mentioned undesirable effect of tolerance.
The present i~vention encompasses a series of new nitric esters 2t,,,~", wherein the nitrate group is linked via a substituted or non substitu-ted alkyl chain to the nitrogen atom of a 1,2-benzo-isothiazo-Iy1-3(2H)one-1,1-dioxide moiety. These compounds possess a high vasodi-latory activity, a lesser level of tolerance and they can be prepared industrially; hence, they are satisfactory for use in actual practice.
} The compounds object of the present invention are nitric 2-al-~` 2l3~92l kyl-1,2-benzo-isothiszolyl-3(2H)one~ dioxide esters of the general formula (I) ~-Y - ( I) O O N~
o in which Y is a substituted cycloalkyl group or a group . R' ~C~).~-CI-(C~-- R
wherein R is a h~rdrogen atom, a meth~rl or a 2,4-dichlorophényl radical or a ni-trate residue, R' is a hydrogen atom or a methyl radical, m is an integer from O to 5, n is an ~teger from O to 1.
Some preferred examples of the compounds of the present in:vention ihclude: .
2-(2-nitratopropyl)-1,2-benzo-isothiazolyl-3(2H)one-1,14ioxide;
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-l~l-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-dichlorophényl)-2-nitratoéthyl)-1,2-benzo-isothiazolyl-3( 2H )one-1 ,1-dioxide;
2-nitratométhyl-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)one-1,1-dioxide.
The compounds of general formula (I) can be prepared by treating an alcohol o~ the general formula (II) or a halogenated compound of formu-la (III) ~\N-Y-OH (ll) ~N-Y-Cl t ~\
O O O . O
<
in which Y has the same definition as previous4~ a~d X LS a halogen atom, with nitric acid or another appropriate reagent.
They can thus be obtained in a similar manner with the reagents in-dicated in the following publications:
- P. Stoss, G. Schluter, R. Axmann; Arzeim.-Forch./Drug Res., (40) (I), N 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 products of general formula (II) are known and they can be prepared by conventional methods from commercially sold rea-gents. Thus, the 2-hydroxymethyl-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide was prepared according to the method of Choi, ~ee and Yoon, described in J. Heter. Chem., 26 (1989), 1073. The other 2-hydroxyal-kyl-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxides can also be obtained by known con~rentional processes, such as for e~cample through the reac-tion between the sodium salt of 1,2-benzo-isothiazoly1-3(2H)one-1,1-dioxide and the corresponding halogenated derivative of the general formula (IV):
.
2l3592l R~
X-(CH2)~-C-(CH2)1,-OH (IV) q R
wherein R, R', m and n were defined preYious4~ and X represents an oxygen atom, in a manner similar to that described by H. L. Rice and G.
R. Pettit ~n J. Amer. Chem. Soc., 76, (î974), 302.
A further object of the invention is a medicament includillg at - least one compound of the general formula (I), according to cla~
This medicament has a vasodilatory effect and can be used ~or the preventive or curative treatment of cardiovascular diseases.
- This medicament is particularly well suited for the treatment of cardiac or tissular ischemias, angina, congestive heart failure or : hypertension.
The compounds (I) of the present invention can be administered alone, but they are generally administered in mixture with a pharmaceu-tical vehicle selected according to the route of administration and -; . usual pharmaceu~ical practices.
;~- For example~ they can be administered orally either as tablets containing excipients such as starch or lactose, or in capstlles either alone or mixed with excipients, or f`urther as syrups or suspensions containing colouring or flavouring agents. They can also be in~ ected parenterally, such as for example intramuscularly, intravenously or subcutaneously .
When the parenteral route LS selected, they will be used preferably in the form of a sterile aqueous solution which can contain other solu-tes, such as for example a salt or glucose, designed for rendering the solution isotonic.
The medicaments will be capable of containing an amount of any one of the compounds of formula (I), in such a manner that the level of the dose administered be comprised between 0.001 and 10 mg/kg. The amount of active principle which will be contained in each one of the dosage forms will range from approximatel~r 0.05 mg to 1 g.
While the intrarnuscular administration can be made in a single dose or be devided into up to three doses, the intravenous administration can include a drip for a continuous administration. There will necessa-rily be variations which will depend upon the weigh and the condition of the subject- treated, as well as the route selected for the administration .
The following examples, which are not intended to be limiting, il-lustrate the preparation of the compounds of the present invention.
Example 1 2~2-NrrRAT( )PROPYL~1,2-BENZO~ISOTHIAZOLYL-3(2H)ONE-1,1-DIOXIDE
To a mixture of 10 ml of fuming nitric acid and 30 ml of aLcetic an-hydride cooled pre~ iously in a bath consisting of a mixture of water and ice, the temperature of whish is in the range 0-5 C, 10 g (0.04 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-propanol) are added dropwise and under stirring. After having stirred 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 extracted with ethyl acetate (2 x 50 ml). After having separated the organic phase, a washing is carried out by means of a solution saturated with potassium carbonate, ~ollowed by washing with water and finally drying over anhydrous sodium sulfate.
After evaporation of the solvent under reduced pressure, a solid is ob-tained which after recrystallization in ethanol has a melting point of 118-120-C. The yield of the reaction after recrystallization is o~ 87%.
ExamPle 2 2-(2,2-DIMl~THYL-3-NITRATOPROPYL)-1,2-BENZO-ISOTHLAZOLYL-3(2H)ONE-1 ,1-DIOXIDE
, On a mixture of 5 ml of fuming nitric acid and 15 ml of acetic an-hydride pre~riously cooled by means of a mixture of water and ice at the temperature of 0-5 C, 5.8 g (0.02 moles) of 1,2-benzo isothiazo-lyl-3(2H)one-1,1-dio~ide-2-(~,2-diméthy1-3-propanol) are added dropwise a~d under stirring. Aftes having stirred the mixture during three hours at this same temperature, it is poured into 70 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 30 ml). After having se-parated the organîc phase snd washed the same with a solution saturatedwith potassium carbonate, 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 in ethanol, has a melting point of 105-107-C. The yield of the reaction, after recrystallization, is of 77%.
Example 3 2-(3-NITRATOPROPYL)-1,2-BE~IZO-ISOTHIAZOLYL-3~2H)ONE~ DIOXIDE
On a mixture of 27 ml of fuming nitric acid and 95 ml of acetic ah-hydride, previously cooled in a bath comprised of a mixture of water and of ice, of which the temperature is in the range 0-5 C, 30 g (0.13 moles) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(3-propanol) are added by small amounts and under stirring. After having stirred the mixture for three hours at the same temperature, it is poured on 500 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 150 ml). After having separated the organic phase and washed the same with a solution saturated with potassium carbonate, it is washed with water and finally dried over anhydrous sodium sulfate.
After evaporation of the solvent under reduced pressure, a solid is ob-tained which, after recrystallization in ethanol, has a melting point of 71-72-C, The yield of the reaction, after recrystallization is of 92%.
Example 4 2~6-NITRATOHEm~1,2-BENZO-ISOTHLAZOLYL-3(2H)ONE-l,l-DIOXiDE
On a mixture of 8 ml of fuming nitric acid and 25 ml of acetic an-hydride previously cooled in a bath consisting of a mixture of water and of ice having a temperature in the range 0-5 C1 10 g (0.04 moles) of 1,2-benzo-isothiazoly1-3-(2H)one~ dioxide-2-(6-hexanol) are added by small amounts and under stirring. After having stirred the mixture for three hours at this same temperature, it is poured on 150 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 50 ml).
After having separated the organic phase and washed the same with a so-lution saturated with potassium carbonate, it is washed with water and finally dried on anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, an oil is obtained which solidifies la-ter. After recrystallization of the solids in ether, a solid is obtai-ned, the melting point of which is of 28-30'C. The yield of the reac-tion after recrystallization is of 60%.
Example 5 2-(2,3-DINITRATOPROPYL)-1,2-BENZO-ISOTHlAZOLYL-3(2H)ONE-1,1-DIOXIDE
, , .
On a mixture of 10 ml of fuming nitric acid and 30 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water and ice, the temperature of which is in the range 0-5Cv 5 g (0.02 mo-les) of - 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2 j3-propanodiol) are added by small amounts and while stirring. After having stirred the mixture during three hours at this same temperature, it is poured on 125 ml of a mixture of water and ice and extracted with ethyl acetate (2 x 50 ml). After having separated the organic phase and washed the same with a solution saturated with potassium carbonate, it is washed with water and fi~ally dried over anhydrous sodium sulfate. After eva-poration of the solvent under reduced pressure, a solid is obtained which, after recrystallization in ethanol, has a melting point of 103-105-C. The yield of the reaction, after recrystallization is of 50%.
, ExemPle 6 i2~2-METHYL-2-NITRATOPROPYL)-1,2-BENZO-ISOTHLAZOLYL-- 3(2H)ONE-1,1-DIOXIDE
,~
On a mixture o~ 12 ml of ruming nitric acid and of 42 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water and ice, the temperature of which is in the range 0-5 C, 14 g (0.06 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-méthy1-2-pro-pa~ol) are added by small amounts and under stirring. After having stirred the mixture during two hours and a half at this same tempera-. .
ture, it is poured on 200 ml of a mixture or water and ice and extrac-ted with ethyl acetate (2 x 75 ml). After ha~ting separated the organic phase and washed the sarne with a solution saturated with potassium car-bonate, it is washed with water and final4~ dried over anhydrous sodium sulfate. The evaporation under reduced pressure of the solvent produces a solid which, after recrystallization in ethyl acetate, has a melting point of 88-90-C. The yield of the reaction, after recrystallization, is of 85%.
.
ExamPle 7 ..2~2~2,4-DICHLOROPHENYL)-2-NITRATOETHYL]-1,2-BENZO--. . ISOTHIAZO.LYL-3(2H)ONE-1,1-DIOXIDE
On a mixture of 15 ml of fuming nitric acid and 55 ml of acetic an-: ~ hydride, previousb cooled in a bath consisting of a~mixture of water .
and ice, the temperature of which is in the range 0-5-C, 25 g (0.06 mo-les) Or: 1,2-benzo-isothiazo4r1-3(2Hjone-1,1-dioxide-2-12-(2,4-dichloro-phenyl-2-ethanoll are added by small amounts and under stirring. After having stirred the mixture during two hours and a half at this same temperature, it is poured on 250 ml of a mixture of ice and water and extr~lcted :with ethyl acetate (2 x 150 ml).. After having separated the organic~ phas~ and washed the same by means of a solution saturated with potassium:c~onllte, it is washed with~water and finally dried over an-hydrow sodium sulfate. The e~/sporation under reduced pressure of the solvent r~oduces a solid which, after lecrystallization in ethanol, has`
a melting point of I67-170-C. The yield of the reaction, after recrys-tallization, is of 85%.
ExemPle 8 2-NITRATOMETHYL-1,2-BENZO-ISOTHIAZOLYL-3(2H)ONE-1,1-DIOXIDE
On a mixture of 12 ml of fuming nitric acid and 41 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water and ice, the temperature of which is in the range Q-5-C, 13 g (0.06 mo-les) of 1,2-benzo-isothiazoly1-3(2H)one-1,1-dioxide-2-méthanol are ad-, ;, :, 2135921 .
: ~ -- 9 ded by small amounts and under stirring. After having stirred the mix-ture during three hours at this same temperature, it is poured on 200 ml of a mixture of ice and water and extracted with ethyl acetate (2x75 ml). After having separated the organic phase and washed the same with a solution saturated with potassium carbonate, it is then washed with water and finally dried over anhydrous sodium sulfate. The evaporation under reduced pressure of the solvent produces a solid which, after re-crystallization in methanol, has a melting point of 67-69-C. The yield of the reaction, after recrystallization, is o~ 667O.
. .
i Exemple 9 2-(2-NITRATOCYCLOHEXYL)-1,2-BENZO-~SOTHLAZOLYL-3(2H)ONE-1,1-DIOXIDE
; . ~ . .
- On a mixture of 32 ml of fuming nitric acid and 110 ml of acetic an-hydride, previously cooled in a bath consisting of a mixture of water r. and ice, the temperature of which is in the range 0-5 C, 40 g (0.14 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-cyclohexanol), are added by small amounts and under stirring. After having stirred the ,., i~, mixture during four hours at this same temperature, it is poured on 400 ml of a mixture of ice and of water and extracted with ethyl acetate (2 x 150 ml). After having separated the organic phase and wæhed the same with ~a solution saturated with potassium carbonate, it is washed with water and finally dried over anlurdrous sodium sulfate. The evaporation under reduced pressure of the solvent produces a solid which, after re-crystallization in ethanol, has a melting point of 136-13~ C. The ~ield of the reaction, after recrystallization, is of 50%.
.',, ;'- ExamPle 10 2~2-NITRATOETHYL)-1,2-BENZO-ISOTHIAZOLYL
3(2H)ONE-1,1-D~OXIDE
On a mixture of 30 ml of fuming nitric acid and of 100 ml of acetic an-hydride, previously cooled in a bath coQsisting of a mixture of water and ice, of which the temperature is in the range 0-5 C, 30 g (0.13 mo-les) of 1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide-2-(2-ethanol) are , .~ . ,~.
, added by small amounts and under stirring. After having stirred the mixture during two hours at this same temperature, it is poured on 450 ml Or a mixture of ice and water and extracted with ethyl acetate (2 x 200 ml). The organic phase is then separated and washed with a solu-tion saturated with potassium carbonate, then washed with water and fi-nally dried over anhydrous sodium sulfate. The evaporation under redu-ced pressure of the solvent produces a solid, which after recrystalli-zation in ethanol, has a melting point of 117-119-C. The yield of the reaction, after recrystallization, is of 967~.
Pharmacological tests have shown that the compounds of the general for-mula (I) of the present invention have a marked vasodilatory, hypoten-sive and blood flow enhancing action; they can be employed for the pre-ventive or curative treatment of disorders of the cardiovascular sys-tem. This designation encompasses, amongst others, disorders of the cerebral or peripheral circulation, tissular -ischemia and more particularly cardiac ischemia, congestive heart failure and hyperten-sion.
.... .
The relaxant potency of the compou~ds of the general formula (I) is determined by means of "in vitro" tests carried out on rings of rat aorta contracted by norepinephrine. The thoracic aorta is extracted and cut into rings 3 mm wide. These rings are suspended in a bath filled with a Krebs solution at a constant temperature of 37 C through which is flowed a mixture of 02/C02 (95/S). Once the equilibrium has been reached, the aorta is contracted under the action of norepinephrine.
Finally, the relaxation obtained by increasing concentrations of com-pounds (I) of the present invention is noted.
., The relaxant potency of the various compounds is expressed by IGo, which is the concentration at which a relaxation of 50% of the contrac-tion induced by norepinephrine is reached.
The results Or the tests are given in table 1, which includes the results obtained with dinitrate isosorbide used as reference.
21~5921 RESUETS-OF "IN VITRO" TESTS
_ _ _ Compound according to example N- NE spasm (aorta) ICs~ (M~
_ .
3 3.1xl0 6 5.0x10 7 1.6x10 8 3.6x10 9 7.8xl~
10 , l.SxlO~
Isosorbide dinitrate 7.6x105 ~.
Claims (10)
1. A compound of the general formula (I) (I) in which Y is a substituted cycloalkyl group or a group wherein R is a hydrogen atom, a methyl or a 2,4-dichlorophenyl radical or a ni-trate residue, R' is a hydrogen atom or a methyl radical, m is an integer from 0 to 5, n is an integer from 0 to 1.
2. Compounds according to claim 1, selected from:
2-(2-nitratopropyl)-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide;
2-(2,2-diméthyl-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-dichlorophényl)-2-nitratoéthyl]-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide;
2- nitratométhyl-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-nitratoéthyl)-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide.
2-(2-nitratopropyl)-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide;
2-(2,2-diméthyl-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-dichlorophényl)-2-nitratoéthyl]-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide;
2- nitratométhyl-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-nitratoéthyl)-1,2-benzo-isothiazolyl-3(2H)one-1,1-dioxide.
3. A method for the preparation of compounds of the general formula (I) according to claim 1, which consists in treating an alcohol of the general formula (II) (II) wherein Y has the same meaning as in claim 1, with nitric acid or ano-ther appropriate reactant.
4. A process for preparing compounds of the general formula (I) accor-ding to claim 1, which consists in treating a halogenated compound of the general formule (III) (III) wherein Y has the same meaning as in claim 1 and X is a halogen atom, with nitric acid or another appropriate reactant.
5. A medicament containing at least one compound of the general formu-la (I) according to one of claims 1 or 2.
6. A medicament according to claim 5, including at least one pharma-ceutically acceptable excipient.
7. A medicament according to one of claims 5 or 6 as vasodilator desi-gned for the preventive or curative treatment of cardiovascular disea-ses.
8. A medicament according to claim 7 for the treatment of cardiac or tissular ischemias.
9. A medicament according to one of claims 7 or 8 for the treatment of angina, congestive heart failure and hypertension.
10. A method for the preventive or the curative treatment of cardiovas-cular diseases, which consists in administering an effective dose of a medicament according to one of the claims 5 to 9, to a subject suffe-ring from a cardiovascular disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH782/93A CH685700A5 (en) | 1993-03-16 | 1993-03-16 | 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. |
| CH782/93-7 | 1993-03-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2135921A1 true CA2135921A1 (en) | 1994-09-29 |
Family
ID=4195059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002135921A Abandoned CA2135921A1 (en) | 1993-03-16 | 1994-03-15 | Nitic 1,2-benzo-isothiazolyl-3(2h)one-1, 1-dioxide esters, preparation method therefor and drugs containing same |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0640078A1 (en) |
| JP (1) | JPH07506844A (en) |
| AU (1) | AU6153694A (en) |
| CA (1) | CA2135921A1 (en) |
| CH (1) | CH685700A5 (en) |
| WO (1) | WO1994021618A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1288123B1 (en) * | 1996-09-04 | 1998-09-10 | Nicox Sa | USE OF NITRO-DERIVATIVES FOR URINARY INCONTINENCE |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4342761A (en) * | 1979-11-01 | 1982-08-03 | John Wyeth & Brother Limited | Piperidine derivatives |
| JPS6137766A (en) * | 1984-07-31 | 1986-02-22 | Sankyo Co Ltd | Phthalimide derivative and preparation thereof |
| DE3726425A1 (en) * | 1987-03-18 | 1988-09-29 | Bayer Ag | Basically substituted saccharins |
| DE4003541C1 (en) * | 1990-02-06 | 1991-08-08 | Alter S.A., Madrid, Es | |
| IT1244472B (en) * | 1990-12-14 | 1994-07-15 | Italfarmaco Spa | BENZOSSAZINONI AND BENZOTIAZINONI WITH CARDIOVASCULAR ACTIVITY |
-
1993
- 1993-03-16 CH CH782/93A patent/CH685700A5/en not_active IP Right Cessation
-
1994
- 1994-03-15 AU AU61536/94A patent/AU6153694A/en not_active Abandoned
- 1994-03-15 JP JP6520474A patent/JPH07506844A/en active Pending
- 1994-03-15 EP EP94908247A patent/EP0640078A1/en not_active Withdrawn
- 1994-03-15 WO PCT/CH1994/000057 patent/WO1994021618A1/en not_active Application Discontinuation
- 1994-03-15 CA CA002135921A patent/CA2135921A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994021618A1 (en) | 1994-09-29 |
| EP0640078A1 (en) | 1995-03-01 |
| JPH07506844A (en) | 1995-07-27 |
| CH685700A5 (en) | 1995-09-15 |
| AU6153694A (en) | 1994-10-11 |
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