DE2105580A1 - 3-aryl-benzisothiazole 1,1-dioxide derivs - which ar e non -hyperglycaemic hypotensives - Google Patents

Abstract

Title derivs. of formula (I): and their optically active isomers (where R1 is H, halogen, CF3, CN, lower alkyl or lower alkoxy in one or more posns. of the phenyl ring; and R2 is H or lower alkyl, and R3 is H or R2+R3 is a double bond, R1 and R3 each only being H when the other is H) which are also inters. for other pharmaceuticals, are prepd. by cyclising a cpd. of formula (II): or by reacting saccharin with an R1-phenl magnesium bromide, opt. subjecting the resulting (I; R2+R3 = double bond) to catalytic hydrogenation, and opt. alkylating the resulting (I; R2=R3=H) with R12-Y (where Y is halogen or some other readily eliminatable anionic gp. and R12 is lower alkyl).

Description

New substituted 3-isothiazole-l, l-dioxides and their 2,3-dihydro derivatives The invention relates to new benzisothiazole-l, l-dioxides and their 2,3-dihydro derivatives of the general formula I. in which R1 is halogen atoms, a trifluoromethyl group, a nitrile group or lower alkyl or alkoxy radicals in mono- or multiple substitution on the phenyl nucleus, R2 is hydrogen or a lower alkyl group and R3 is a hydrogen atom or together with R2 is a double bond, with the radicals R1 and R3 only can simultaneously mean hydrogen, and optionally their optically active isomers.

The compounds according to the invention are prepared in a manner known per se by adding a) compounds of the general formula II in which R1 has the meaning given above - preferably without prior isolation - ring bottom, or that b) a compound of the formula III with a Grignard reagent (made from an aryl bromide of the general formula IV in which R1 has the meaning given above and converts magnesium) and / or c) the compounds of the formula Ia which can be prepared by process a) or b) wherein R1 has the abovementioned meaning, catalytically hydrogenated and that, if desired, d) the compounds of the general formula Ib formed by process c) in which R1 has the meaning given above, alkylated in the customary manner with an alkylating agent of the general formula V R2 - V in which R2 is a lower alkyl group and Y is a halogen atom or another radical which can easily be removed anionically.

The compounds of the formula II can be represented by way of example from the ammonium salt of the correspondingly substituted benzophenone sulfonic acid (IIa) by treatment with water-releasing agents such as P2O5,? Cl5 etc. (preferably in the presence of an inert solvent) or by reacting a reactive one Derivative of benzophenonsulphonic acid IIa, for example of the acid chloride, with ammonia in an inert solvent. The resulting benzophenonsulfonic acid amides (II) oyolize very easily with elimination of water to give compounds of the formula Ia, so that the isolation of the compounds of formula II is not necessary.

The implementation according to procedure b takes place under the liblichen conditions a Grignard reaction. The Grignard reagent is prepared in the usual way an aryl bromide of the general formula IV and magnesium shavings in ether and leaves to Saocharin (formula III), dissolved in an inert solvent, for example Tetrahydrofuran, add dropwise. It is then worked up in the usual way.

The hydrogenation according to process c) took place in an inert solution medium, preferably dioxane, with the addition of a hydrogenation catalyst such as, for example Raney Niokel under a hydrogen atmosphere, preferably under normal conditions.

The alkylation according to process d) takes place in an inert solvent, such as water or alcohol, in the presence of alkali, preferably at Room temperature.

Some of the starting compounds of the general formula II are new and can, for example, from O-sulfobenzoic anhydride by reaction with a corresponding substituted aromatic compound in the presence of Friedel-Crafts catalysts can be produced in a known manner.

Compounds of the general formula I in which R1 and R2 are those listed above Have meaning and R3 denotes a hydrogen atom, have an asymmetric one C atom and are therefore present as a Raoemat. The optically active antipodes are obtained therefrom in a known way.

The compounds according to the invention are valuable medicaments with in particular antihypertensive effect without having a hyperglycemic effect demonstrate. However, they can also be used as intermediate products for the production of other drugs to serve.

Such compounds of the formula I in which R2 and R3 form a double bond mean, have antihypertensive effects. However, you will prefer to processed into other medicinal products. A particularly good antihypertensive effect show those compounds in which the radicals R2 and R3 denote hydrogen atoms, and R1 is a halogen atom, in particular a chlorine atom, preferably in the 4-position, means. For the dosage of the compounds of the formula I, 50-1000 mg are preferred 100-500 mg as a single dose is suggested.

The compounds according to the invention can be used alone or in combination with other pharmaceuticals, such as saluretics or other hypotenioa for use reach. Suitable application forms are, for example, tablets, capsules, suppositories, Juices, emulsions or dispersible powders. Corresponding tablets can, for example wisely by mixing the active ingredient (s) with bakanatic auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, Disintegrants, such as corn starch or alginic acid, such as starch or gelatin, soothing agents, such as magnesium stearate or talc, and / q the means to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained.

The tablets can also consist of several layers.

Correspondingly, coated tablets can be coated by coating them in the same way as the tablets cores produced with agents commonly used in dragee coatings, such as for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar, To achieve a depot effect or to avoid incompatibilities the core can also consist of several layers. The dragé casing can do the same consist of several layers to achieve a lepot effect, the above in the case of the tablets mentioned auxiliary substances can be used.

Juices of the active ingredients or combinations of active ingredients according to the invention can also use a sweetener such as saccharin, cyclamate, glycerin or Sugar, as well as a taste-improving agent, e.g. flavorings such as vanillin or orange extract.

You can also use suspending aids or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products of fatty alcohols with ethyleneoside, or contain protective substances such as p-hydroxybenzoates.

The one or more active ingredients or combinations of active ingredients Capsules can be produced, for example, by combining the active ingredients with inert Carriers, such as lactose or sorbitol, mixed and encapsulated in gelatin capsules.

Suitable suppositories can be made, for example, by mixing them with Carriers provided for this, such as neutral fats or polyethylene glycol or its derivatives.

The following examples serve to illustrate the invention, without them Limit scope: Pharmaceutical application examples a) Dragees 1 tablet core contains: 3- (4-chlorophenyl) -2, 3-dihydro-benzisothiazole 1, l-dioxide 100 mg milk sugar 185 mg corn starch 150 mg gelatine 10 mg magnesium stearate 5 mg 450 mg production: The mixture of the active substance with milk sugar and corn starch is made with a 10% aqueous gelatin solution through a sieve with 1 mm mesh size granulated, dried at 40 ° C and rubbed through a sieve again. The thus obtained Granules are mixed with magnesium stearate and compressed. The cores thus obtained are coated in the usual way with a shell, which with the help of an aqueous Suspension of sugar, titanium dioxide, talc and gum arabic is applied. The finished coated tablets are polished with beeswax. Dragee final weight: 600 mg b) Tablets 3- (4-chlorophenyl) -2,3-dihydro-benzisothiazole- 120 mg l, l-dioxide lactose 240 mg corn starch 220 mg soluble starch 14 mg magnesium stearate 6 mg 600 mg Manufacture: The active ingredient and magnesium stearate are mixed with an aqueous solution of the soluble starch granulated, the granules dried and mixed intimately with lactose and corn starch.

The mixture is then compressed into tablets weighing 600 mg.

o) Suppositories 1 suppository contains: 3- (4-chlorophenyl) -2,3-dihydro-benzisothiazole, l-dioxide 200 mg lactose 500 mg suppository mass 1300 mg 2000 mg Preparation: The finely powdered misohung of active ingredient and lactose is made with the help of an immersion -Homcgenizer stirred into the molten and 400C cooled suppository mass. The mass is poured into slightly pre-cooled molds at 35 ° C. Preparation Examples Example 1 3- (4-Chlorophenyl) -benzisothiazole-1,1-dioxide A solution of 146.4 g of saccharin in 800 ml of absolute ether is added to the Grignard reagent prepared from 195.2 g of 4-bromochlorobenzene and 24.8 g of magnesium shavings in 400 ml of absolute ether at OOC within approx. 2-3 hours Tetrahydrofuran was added dropwise. After standing overnight at room temperature, dilute hydrochloric acid is added and the organic phase is separated off. It is concentrated to dryness in vacuo and the residue that remains is treated with dilute sodium hydroxide solution to separate off the saccharin.

The 3- (4-chlorophenyl) -benzisothiazole-1, l-diozid is then suctioned off, washed several times with water and dried in a vacuum drying tank.

M.p. 212-214 °; Yield 14.8 g Analogously to Example 1, the following substances were synthesized: 3- (4-fluorophenyl) -benziso thiazole-1,1-dioxide from 4-fluorophenylmagnesium bromide and saccharin, melting point 192-194 ° 3- (4-methylphenyl ) -benzisothiazole-1,1-dioxide from 4-methyl-phenylmagnesium bromide and saccharin, melting point 178-180 ° C. 3- (4-methoxyphenyl) -benzisothiazole-1,1-dioxide from 4-methoxyphenylmagnesium bromide and saccharin, melting point 201-204 ° C 3- (3-chlorophenyl) -benzisothiazole-1,1-dioxide from 3-chloro-phenylmagnesium bromide and saccharin, melting point 1500 ° C .; Yield: 11.8%. Example 2 2- (4-Chlorophenyl) -2,3-dihydro-benzisothiazole-1-dioxide 2l, 7 g of 3- (4-chlorophenyl) -benzisothiazole-1,1-dioxide are mixed in approx.

300 ml 1) 1 oxane dissolved and over Kaney nickel under normal conditions hydrogenated After taking up the theoretical amount of hydrogen (2.48 liters at 25 ° C and 756 Torr within 2.5 hours) is sucked off by the catalyst and that Filtrate treated with activated charcoal.

The solution is concentrated to about 1/3 of its volume in vacuo and mixed with approximately 100 ccm of water. The 3- (4-chlorophenyl) -2,3-dihydro-benzisothiazole-1,1-dioxide separates here the end.

It is filtered off, washed with a little methanol and ether and dried.

Yield: 17.5 g corresponding to 62.7% of theory, melting point 178-180 ° C.

The following substances were prepared analogously to Example 2: 3- (3-chlorophenyl) -2,3-dihydro-benzisothiazole-1,1-dioxide from 3- (3-chlorophenyl) -benzisothiazole-1,1-dioxide mp: 137- 139 ° C; 3- (4-methylphenyl) -2,3-dihydro-benzisothiazole-1,1-dioxide from 3- (4-methylphenyl) -benzisothiazole-1,1-dioxide; mp: 166-167 ° C; Example 3 3- (4-Chlorophenyl) -2-methyl-3H-benzisothiazole-l .l-dioxide 2.0 g of D- (4-chlorophenyl) -2,3-dihydrobenzizothiazole-1,1-dioside are dissolved in a mixture of 10 ml of 2N sodium hydroxide solution and 20 ml of water and add 1- + 2 to this solution within 5 minutes oom dimethyl sulfate was added dropwise at 25 ° C. (ice cooling). The mixture is stirred for a further 2 hours at room temperature and the precipitate which has separated out is filtered off with suction. After washing with water and drying in a vacuum drying cabinet, 1.5 g of 3- (chlorophenyl) -2-methyl-3H-benzisothiazole-1,1-dioxide with a melting point of 129 ° -131 ° are obtained.

Yield: 71.4 ffi of theory

Claims (5)

patent claims 1.) Compounds of the general formula I where R1 is hydrogen, halogen atoms, a trifluoromethyl group, a nitrile group or lower alkyl or alkoxy radicals in mono- or multiple substitution on the phenyl nucleus, R2 is a hydrogen atom or a lower alkyl group, and R3 is a hydrogen atom or together with R2 is a double bond, although the radicals R1 and R3 can only be hydrogen at the same time, and optionally their optically active isomers. 2.) Compounds according to claim 1, characterized in that R2 and R3 together denote a double bond and R1 has the stated meaning except hydrogen Has. 3.) Compounds according to claim 1, characterized in that R2 is a Hydrogen atom or a lower alkyl group and R3 denotes a hydrogen atom, while R1 has the meaning given, as well as their optically active isomers. 4.) Process for the preparation of compounds of the general formula I. in which R1, R2 and R3 have the meaning given above, characterized in that a) compounds of the general formula II where R1 has the meaning given above - preferably without prior isolation - pouring a ring or b) a compound of the formula III with a Grignard reagent (made from an aryl bromide of the general formula IV in which R1 has the meaning given above and converts magnesium) and / or c) the compounds of the formula Ia which can be prepared by process a) or b) in which R1 has the abovementioned meaning, catalytically hydrogenated and that, if desired, d) the compounds of the general formula Ib formed by process c) in which R1 has the meaning given above with an alkylating agent of the general formula V R2Y V in which R2 is a lower alkyl group and Y is a halogen atom or another radical which can easily be split off anionically, alkylated in the customary manner. 5.) Pharmaceutical preparations containing one or more compounds according to claim 1. -6.) Process for the production of pharmaceutical preparations according to claim 5, characterized in that the active ingredient or ingredients from claim 1 are mixed in a known manner with customary pharmaceutical auxiliaries and / or excipients and - converted into commercially available formulations. 3- (4-Chlorophenyl) -2,3-dihydroben2iBothiazole-1 dioxide. 3- (4-chlorophenyl) -benzisothiazole-1,1-dioocide.