US3297693A - Dihydro-benzothiadiazine-1, 1-dioxides - Google Patents

Description

United States Patent 3,297,693 DIHYDRO-BENZQTHHADEAZINE-LI-DIGXEDES George de Stevens and Lincoln Harvey Werner, Summit, NJ, assignors to Cilia Corporation, New York, N.Y.,

a corporation of Delaware No Drawing. Filed May 29, 1963, Ser. No. 284,007 The portion of the term of the patent subsequent to Dec. 29, 1981, has been disclaimer! 11 Claims. (Cl. 260--243) This application is a continuation-in-part application of our application Serial No. 791,045, filed February 4, 1959, now abandoned, which in turn is a continuation-in-part of our application Serial No. 764,482, filed September 29, 1958, now abandoned, which in turn is a continuation-inpart of our application Serial No. 751,620, filed July 29, 1958, now abandoned, which in turn is a continuation-inpart of our application Serial No. 740,582, filed June 9, 1958, now abandoned, which in turn is a continuation-inpart of our application Serial No. 727,242, filed April 9, 1958, now abandoned, which in turn is a continuation-inpart of our application Serial No. 718,452, filed March 3, 195 8, now abandoned.

The present invention concerns 3-0xy-lower alkyl-3,4- dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxides. More particularly, it relates to compounds of the formula:

in which R represents a hydroxy-lower alkyl, acyloxylower alkyl or etherified hydroxy-lower alkyl, each of the radicals R R and R stands for hydrogen or lower alkyl and R represents lower alkyl, halogeno-lower alkyl or halogen, or alkali metal salts thereof, as well as process for the preparation of such compounds.

The lower alkyl portion in the oxy-lower alkyl substituent is represented primarily by a lower alkylene radical having from one to seven carbon atoms; such radicals are 1,1-methylene, l,1-ethylene, 1,2-ethylene, 1,l-dimeth' yl-1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3-propylene, 2,2-propylene, 1,1-butylene, 1,2-butylene, 1,3-butylene, l,4butylene, 2,2-butylene, 2,3-butylene, 1,5-pentylene, 2,5-pentylene, etc.

The lower alkyl group may be substituted by free hydroxyl.

An acyloxy group represents primarily a hydroxyl group esterified by an organic carboxylic acid, for example, a substituted carbonic acid, e.g., methoXy-carbonic acid, ethoXy-carbonic acid or benzyloXy-carbonic acid, a lower aliphatic carboxylic acid, such as a lower alkanoic acid, e.g., acetic, propionic, or pivalic acid, lower alkenoic acids, e.g., acrylic or methylacrylic acid, lower aliphatic dicarboxylic acids, e.g., oxalic, malonic, succinic, glutaric, adipic, maleic or fumaric acid, or their halfesters with lower alkanols, e.g., methanol or ethanol. Carbocyclic aryl-carboxylic acids are primarily monocyclic carbocyclic aryl-carboxylic acids, e.g., benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids are primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g., phenylacetic or dihydrocinnamic acid, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryl-lower alkenyl carboxylic acids, e.g., cinnamic acid or substituted cinnamic acids. substituents of aromatic portions are particularly lower alkyl, e.g., methyl, hydroxyl, lower alkoxy, e.g., methoxy, or halogen, e.g., chlorine or bromine.

, mamas Patented Jan. 10, 1967 An etherified hydroxy-lower alkyl group is represented, for example, by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g., methoxy, ethoxy, n-propyloXy, isopropyloxy, n-butyloxy, isobutyloxy or similar alkoxy groups, lower alkenyloxy, e.g., vinyloxy, allyloxy or analogous alkenyloxy groups, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g., phenyloxy or substituted phenyloXy, or bicyclic carbocyclic aryloxy, e.g., l-naphthyloxy or Z-naphthyloxy or substituted naphthyloxy, or carbocyclic aryl-aliphatic hydrocarbonoxy, such as monocyclic carbocyclic aryl-loweralkoxy, e.g., benzyloxy or substituted benzyloxy. The aliphatic hydrocarbon, and particularly the carbocyclic aryl portions of the etherified hydroxyl groups may contain additional substituents; such substituents have been previously described as being present in the acyl portions of acyloxy groups.

The radicals R R and R represent primarily hydrogen; possible lower alkyl substituents are primarily methyl or ethyl.

The substituent R in the 6-position of the 3,4-dihydro- 2-H-[l,2,4]-benzothiadiazine-1,l-dioxides of this invention represents primarily halogen, such as fluorine, bro mine, or particularly chlorine. Furthermore, lower alkyl, e.g., methyl, or, more desirable, halogeno-lower alkyl, e.g., trifluoromethyl, may also be included as substituents of the 6-position.

An alkali metal salt is particularly a sodium or a potassium salt.

The 3-0xy-lower alkyl-3,4-dihydro-2-H-[1,2,4]-bouzothiadiazine-1,1-dioxides of this invention have diuretic and natriuretic properties and can be used as diuretic and natriuretic agents having improved properties to relieve excessive states of water and sodium retention, as connected, for example, with heart troubles. In addition, these compounds have antihypertensive properties, which can be utilized to counteract hypertensive conditions.

Particularly useful as diuretic and natriuretic agents are the 2-R -3-acyloXy-lower alkyl-4-R "-6-R -7-(N- R "-sulfamyl)-3,4-dihydro-2 H [1,2,4]-benzothiadiazine-1,1-dioxides, in which each of the radicals R R and R represents hydrogen or methyl, and R stands for methyl, trifluoromethyl, bromine or chlorine, and in which the acyl group is derived from a lower alkanoic acid, a monocyclic carbocyclic aryl-carboxylic acid or a monocyclic carbocyclic aryl-lower alkanoic acid. This group is represented by 2-R '-3lower alkanoyloxy-lower alkyl-6-R -7-sulfamyl-3,4-dihydr0-2-H-[1,2,4] benzothiadiazine-l,1-dioxides, in which R represents hydrogen or methyl, and R stands for chlorine or trifluoromethyl.

Another series of compounds of outstanding diuretic and natriuretic effects are the 2-R -3-etherified hydroxy lower alkyl-4-R -6-R -7-(N-R "-sulfamyl)-3,4-dihydro- 2-H-[1,2,4]-benzothiadiazine-1,1-dioxides, in which each of the radicals R R and R represents hydrogen or methyl, and R stands for methyl, trifiuoromethyl, bromine or chlorine, and in which the etherified hydroxyl group is represented by lower alkoxy, monocyclic carbocyclic aryloxy or monocyclic carbocyclic aryl-lower alkoxy. This group is represented by 2-R -3-l0wer alkoxylower alkyl-6-R -7-sulfamyl-3,4-dihydro-2-H-[1,2,4]-hen zothiadiazine-l,l-dioxides or 2-R 3-monocyclic carbocyclic aryloxy-lower alkyl-6 R 7-sulfamyl-3,4-dihydro-2- H-[1,2,4]-benzothiadiazine-1,l-dioxides, in which R represents hydrogen or methyl and R stands for chlorine or trifiuoromethyl.

The new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new 3,4-dihydro-2-H-[1,2,4]benzothiadiazine-1,1-dioxides or the salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, eg. oral, or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, ve etable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments. The pharmaceutical preparations may be in solid form, for example, as capsules, tablets or dragees, or in liquid form, for example, as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain, in combination, other therapeutically useful substances.

'The compounds of this invention are advantageously prepared by reacting an aniline compound of the formula:

in which R R R and R have the previously given meaning, with an aldehyde of the formula R CHO, in which R has the above-given meaning, or a derivative thereof, and, if desired, replacing in a resulting 3,4-dihydro-2-I-I-[1,2,4]-benzothiadiaziue-1,1-dioxide containing a sulfamyl-nitrogen with hydrogen, such hydrogen by lower alkyl, and/or, if desired, hydrolyzing in a resulting 3-acyloxy-lower alkyl-3,4-dihydro-2-H-[1,2,41-benzothiadiazine-1,l-dioxide the acyloxy group to a hydroxyl group, and/or, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting free compound into a salt thereof.

Although the aldehyde is preferably reacted with the aniline derivative in approximately stoichiometric amounts, it may also be given to the reaction mixture in excess amounts. The reaction may be performed in the absence of any condensing reagent, or in the presence of a base, such as an alkali metal hydroxide, e.g., lithium, sodium or potassium hydroxide, whereby the aldehyde is used in its reactive form. It may also be carried out in the presence of a small amount of an acid, for example, a mineral acid, such as hydrohalic acid, eg, hydrochloric or hydrobromic acid, or sulfuric acid, if desired, in anhydrous form. Furthermore, the aldehyde may be given into the reaction medium in a form which yields the desired reactant in situ. Thus, for example, an acetal of an aldehyde R -CHO with a lower alkanol, for example, methanol or ethanol, may be used, whereby the presence of an acid is necessary to convert the derivative, e.g., the acetal, into the reactive form. Such acetals are, for example, 1,1-dimethoxy-Z-methoxy-ethane, 1,1-diethoxy- 2-ethoxy-ethane, 1,l-diethoxy-2-phenoxy-ethane, etc.

The reaction may be carried out in the absence or preferably in the presence of a solvent, for example, an ether, e.g., p-dioxane or diethyleneglycol dimethylether, a lower alkanol, e.g., methanol or ethanol, or a formamide, e.g., dimethylformamide, or an aqueous mixture of such solvents or water. If desired, it may be completed at an elevated temperature, for example, on the steam bath or at the boiling temperature of the solvent. If necessary, the reaction may be performed under increased pressure or in the atmosphere of an inert gas, e.g., nitrogen.

The starting materials used in the above-described reactions are known, or, if new, may be prepared according to procedures used for the manufacture of known compounds. For example, by treatment of a 3-R -N-R aniline, in which R and R have the above-given meaning, with chlorosulfonic acid, two sulfonyl chloride groups are introduced to form 3-R -N-R -aniline-2,4-disulfonyl chlorides. These are subsequently reacted with ammonia, e.g., liquid or gaseous ammonia or a solution of ammonia in water or in a lower alkanol, methanol or ethanol, or with a lower alkylamine, e.g., methylamine or ethylamine,

to yield the desired starting materials of the above-mentioned type. The sulfamyl groups of the starting material may also be introduced in stages; for example, one of the sulfonyl chloride groups may be converted to a sulfamyl group with ammonia or a lower alkylamine by controlling the reaction as to amounts of the reactants and/or the reaction conditions, and the second sulfonyl chloride group may then be converted to the desired sulfamyl group.

A second procedure to prepare the compounds of this invention comprises reducing in compounds of the formulae:

in which R R R and R have the previously given meaning, the C=Ndouble bond of the 1,2,4-thiadiazine- 1,1-dioxide portion, and, if desired, replacing in any resulting 3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxide containing sulfamyl-nitrogens with hydrogen, such hydrogen by lower alkyl, and/or, hydrolyzing in a resulting 3-acyloxy-lower alkyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiaZine-1,l-dioxide the acyloxy group to a hydroxyl group, and/or, if desired, converting a resulting salt into a free compound, and/or, if desired, converting a free compound into a salt thereof.

The removal of the C=Ndouble bond may be achieved, for example, by treatment with a borohydride or an equivalent reducing agent capable of reducing such bond. The preferred reagents are alkali metal borohydrides, e.g., lithium borohydride, potassium borohydride or, particularly sodium borohydride. Other borohydrides are alkaline earth metal borohydrides such as calcium or strontium borohydride; aluminum borohydride may be used as well. Sodium dimethoxy borohydride is another possible reagent to be used in the reaction. If desired, these borohydrides may be used in the presence of an activating substance, such as, for example, aluminum chloride. The reaction may also be carried out in the presence of an alkaline reagent, such as an aqueous alkaline reagent, which may be diluted with other sol vents, such as those mentioned hereinbelow; such alkaline reagents are, for example, dilute aqueous solutions of alkali metal hydroxide, e.g., lithium, sodium or potassium hydroxide. If desired, organic solvents, such as ethers, e.g., 1,2-dimethoxy-ethane or diethyleneglycol dimethylether; lower alkanols, e.g., methanol, ethanol, propanol, or isopropanol; or liquid carboxylic acid amides, such as formamides, e.g., formamide or dimethylformamide, may be employed. The reduction is carried out at room temperature or at an elevated temperature, if necessary, in the atmosphere of an inert gas such as nitrogen.

The electrolytic reduction procedure provides for another possibility of removing the C=Ndouble bond; such procedure is carried out according to standard methods. Generally, it is performed on a cathode of high overpotential and at a current density greater than about 0.02 amp./cm. Cathodes with high overpotentials are, for example, those having an overpotential equal to or higher than cadmium, such as cadmium, zinc, mercury, lead amalgam or lead. Any appropriate anode, such as platinum, carbon, lead or stainless steel, and any appropriate anolyte, for example, dilute sulfuric acid or dilute hydrochloric acid, may be employed. A lead or platinum anode and a dilute sulfuric acid anolyte are preferred.

Any current density greater than about 0.02 amp./ cm. is sufficient to bring about the reduction of the G N-double bond; however, for practical reasons a current density higher than about 0.25 amp/cm. may diminish the efiiciency of the process due to increased hydrogen evolution.

The reduction is performed in an aqueous acidic medium, such as, for example, an aqueous solution of a strong inorganic acid, which ionizes readily and does not decompose at the current density employed, such as for example, sulfuric acid. In order to secure a complete solution of the starting material an additional solvent, such as, for example, a formamide, e.g., N,N-dimethylformamide, may be added. Lower alkanols, e.g., methanol or ethanol, may replace or may be added with a formamide to enhance the solubility of the starting material and the end product.

Diaphragms separating the .anlyte and the catholyte are more especially ion exchange membranes, such as ion exchange resins (Amberplex), Alundurn or parchment.

Any groups, which may be affected by the hydrogenation procedure, may be protected or simultaneously converted into hydrogenated groups.

The starting materials used in this reaction are known, or, if new, may be obtained according to procedures used for the preparation of the known compounds.

In resulting 3-oxy-lower alkyl-3,4-dihydro-2-H-[1,2,4]- benzothiadiazine-1, l-dioxides, containing sulfamyl-nitrogens with hydrogen, such hydrogen may be replaced by lower alkyl. Generally, an alkali metal salt of the starting material is formed and such salt is then reacted with the reactive ester of a lower alkanol. These esters are particularly those of lower alkanols, e.g., ethanol, or particularly methanol, with strong mineral acids, such as hydrohalic acids, e.g., hydrochloric, hydrobromic or bydriodic acid, or sulfuric acid. For example, treatment of the starting material with a di-lower .alkyl sulfate, such as, for example, dimethyl sulfate or diethyl sulfate, in the presence of an alkaline reagent, such as an alkali metal hydroxide, e.g., lithium, sodium or potassium hydroxide, is a preferred procedure. As solvents water or water miscible organic solvents, such as lower alkanols, e.g., methanol, ethanol, propanol, isopropanol or tertiary butanol; ethers, e.g., diethyleneglycol dimethylether, or formamides, e.g., dimethylformamide, may be used.

Generally, the alkylation reaction may be carried out under cooling, at room temperature, or at an elevated temperature, if necessary, in a closed vessel, e.g., sealed tube, under pressure and/or in the atmosphere of an inert gas, e.g., nitrogen.

An N-unsubstituted sulfamyl group in the carbocyclic portion of the molecule may simultaneously be alkylated; if necessary, this may be prevented to a large extent by varying the conditions and/or the molar ratios of the reactants. A resulting mixture of products may be separated into the single components, for example, by fractionated crystallization, utilizing the differing solubilities in different solvent systems.

The resulting product may be obtained in the form of the free compound or as a salt thereof. An alkali metal salt may be converted into the free compound by treatment with an aqueous acidic reagent, such as a mineral acid, for example, hydrohalic acid, e.g., hydrochloric acid, or sulfuric acid. A free compound may be converted into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g., sodium or potassium hydroxide, in a solvent, such as in a lower alkanol, e.g., methanol or ethanol, or in water and evaporating the solvent; or by reacting the free compound, for example, in an ether, e.g., p-dioxane or diethyleneglycol dimethylether, solution, with an alkali metal hydride or amide, e.g., sodium or potassium hydride or amide, and removing the solvent. Monoor polysalts may be obtained.

Any resulting racemate may be converted into the antipodes thereof according to methods used for resolving racernates.

The following examples illustrate the invention; they are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 To a solution of 5.8 g. of 5-chloro-2,4-disulfamylaniline in 30 ml. of diethyleneglycol dimethylether are added 1 ml. of a 2N solution of hydrogen chloride in anhydrous ethyl acetate and 4.2 g. of phenoxy-acetaldehyde diethylacetal, and the reaction mixture is heated to -90 for one hour. The solvents are removed under reduced pressure, the residue is triturated with hexane and on addi tion of-water a crystalline material is formed. The 6- chloro-3-phenoxymethyl-7-sulfamyl-3,4 dihydr-o 2 H- [l,2,4]- benzothiadiazine 1,1 dioxide is recrystallized from aqueous dimethyl-formamide, M.P 262264; yield: 6.5 g.

.Upon treatment of a solution of the 6-chloro-3-phenoxymethyl 7 sulfamyl-3,4-dihydro-2-H-[1,2,4] benzothiadiazine-1,1-dioxide in aqueous sodium hydroxide with dimethyl sulfate at 10 for one hour and a room temperature for an additional hour, the 6-chloro-2- methyl-3-phenoxymethyl 7 sulfamyl-3,4-dihydro-2-H- [1,2,4]-benzothiadiazine-1,l-dioxide can be prepared and may be separated from any simultaneously formed 6- chloro-2-methyl-3-phenoxymethyl 7 (N methyl sulfamyl)-3,4-dihydro-2-T-[1,2,4] benzothiadiazine 1,1- dioxide by fractionated crystallization.

A sodium salt may be prepared by evaporating a solution of the 6-chloro-3-phenoxymethyl-7-sulfa'myl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,1-dioxide in a stoichiometric amount of aqueous sodium hydroxide.

Instead of 5-chloro-2,4-disulfamyl-aniline, 2,4-disulfamyl-S-methyl aniline or 2,4 disulfamyl-S-trifiuoromethyl-aniline may be reacted with the diethylacetal of phenoxy-acetaldehyde to yield 6-methyl-3-phenoxymethyl- 7-sulfamyl-3,4-dihydro-2-H- [1,2,4] benzothiadiazine-l ,1- dioxide and 3 phenoxymethyl-7-sulfarnyl 6 trifluoromethyl-3,4-dihydro-2-H-[1,2,4] benzothiadiaz ine-Lbdioxide, respectively.

Example 2 To a solution of 1.2 g. of 3-acetoxymethyl-6-chloro-7- sulfamyl-[1,2,4]-benzothiadiazine-1,1-dioxide in 30 ml. of diethyleneglycol dimethylether is added 0.3 g. of sodium borohydride. The reaction mixture is allowed to stand at room temperature for 1 /2 hours and is then concentrated under reduced pressure. Water is added to the residue and the solution is neutralized with diluted aqueous hydrochloric acid. The solvent is removed under reduced pressure, water is added and the solid material is filtered off; the 3-acetoxymethyl-6-chlOro-7-sulfamyl-3,4-dihydro- 2-H-[1,2,4]-benzothiadiazine 1,1 dioxide is recrystallized twice from aqueous dimethylformamide, M.P. 264- 265; yield: 0.3 g.

The starting material is prepared by reacting 5-chloroaniline-2,4-disulfamyl chloride with acetoxy-glycolic acid chloride, followed by treatment with ammonia to yield the desired 3-acetoxymethyl-6-chloro-7-sulfamy1-[1,2,4]- benzothiadiazine-l,l-dioxide, M.P. 310-3 12.

Example 3 Toa solution of 5.9 g. of 5-chloro-2,4-disulfamyl-aniline in 30 ml. of diethyleneglycol dimethylether are added 1 ml. of a 2N solution of hydrogen chloride in ethyl acetate and 3.2 g. of ethoxy-acetaldehyde diethylacetal and the mixture is heated to 8090 for one hour and then cooled. Upon concentration under reduced pressure and addition of water an oily product is formed; the water is decanted and on addition of ether a crystalline material precipitates, which is filtered off. The 6-chloro-3-ethoxymethyl-7-sulfamyl-3,4-dihydro-2-H-[1,2,4] benzothiadiazine 1,1-dioxide is recrystallized three times from a 1:1- mixture of ethanol and water, M.P. 186'190; yield: 2.4 g.

By substituting in the above reaction methoxy-acetaldehyde diethylacetal or 3-ethoxy-propionaldehyde dimethylacetal for the ethox-y-acetaldehyde diethylacetal, the 6- chloro-3-methoxymethyl 7 sulfamyl-3,4 dihydro-2-H- [1,2,41-benzothiadiazine 1,1-dioxide and 6-chloro-3-(2- ethoxyethyl)-7-sulfamyl 3,4 dihydro-2-H-[l,2,4]-benzothiadiazine-l,l-dioxide, respectively, can be obtained.

Example 4 A mixture of -chloro-2,4-disulfamyl-aniline, benzylox-yacetaldehyde diethylacetal, a small amount of a sat-urated solution of hydrogen chloride in ethyl acetate and diethyleneglycol dimethylether, when treated as described in Example 3, yields the 3-benzyloxymethyl-6-chloro-7- sulfamyl 3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-l,1- dioxide, purified by recrystallization from aqueuos ethanol.

In place of benzyloxy-acetaldehyde diethyl-acetal substituted benzyloxy-acetaldehyde acetals, such as, for example, 4-methoxy-benzyloxy-acetaldehyde dimethylacetal, 4-chloro benzyloxy acetaldehyde diethylacetal or 3- methyl-benzyloxy-acetaldehyde diethylacetal, may be reacted with 5-ch1oro-2,4-disulfamyl-aniline to yield 6- chloro-3-(4-methoxy benzyloxymethyl)-7-sulfamyl-3,4- dihydro-2-H-[1,2,4]-benzothiadiazine 1,1 dioxide, 6- chloro-3-(4-chloro benzyloxymethyl)-7-sulfamyl 3,4- dihydro-2-H-[1,2,4]-benzothiadiazine 1,1 -dioxide and 6- chloro-3-(3-methyl benzyloxymethyl)-7-sulfamyl-3,4-dihydro-2-H-[1,2,4]-benz0thiadiazine 1,1 dioxide, respectively.

Example 5 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamide is dissolved in 30 ml. of diglyme'and 0.5 ml. of 3N hydrochloric acid in ethyl acetate and 2.04 g. of fl-ethoxy propionaldehyde are added. The reaction mixture is heated for 1 hour to 8090, then concentrated in vacuo. The residue is tr iturated with 30 ml. of water, followed by trituration with 30 ml. of hexane. The crude product is filtered off and dissolved in 2N sodium hydroxide and precipitated by acidifying with 2N hydrochloric acid. The product is then dissolved in ethyl acetate; on addition of hexane the pure 6-chloro-3-(2-ethoxyethyl)-3,4- dihydro-7-sulfamyl 1,2,4 benzothiadiazine-l,l-dioxide separates (melting point 224 C. with decomposition).

Example 6 By using 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamide and 2.5 g. of 2-al1yloxy proprionaldehyde and following the procedure of Example 5, 3 (2 allyloxyethyl)-6-chloro-3,4-dihydro-7-sulfamyl-1,2,4 benzothiadiazine-1,1-dioxide is obtained.

Example 7 A mixture of 114 g. of cyclohexanemethanol and 14 g. of acrolein containing 0.7 g. of catalyst (diethylamine and formic acid in a molar ratio of 1:1.75) is heated to 90100 for 14 hours, then fractionated by distillation to give 3-(cyclohexylmethoxy)-propionaldehyde.

5.9 g. of 4-amino-6-chloro-1,3-benezenedisulfonamide is dissolved in 30 ml. of diglyme and 3.5 g. of 3-(cyclohexylmethoxy)-propionaldehyde, and 0.5 ml. of approximately 3N hydrochloric acid in ethyl acetate is added. The reaction mixture is heated for 1 hour to 90, then concentrated in vacuo. The residue is first triturated with water, then with ether. On treatment with aqueous alcohol (1:1) the 6-chloro-3-(2-cyclohexyl methoxyethyl)-3,4 dihydro-7 sulfamyl 1,2,4-benzothiadiazine-1,1-dioxide crystallizes.

8 Example 8 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamide is dissolved in 30 ml. of diglyme and 3.6 g. of 3-benzoyloxypropionaldehyde and 0.5 ml. of approximately 3N hydrochloric acid in ethyl acetate is added. The reaction mixture is heated on a steam bath to 90 for 1 hour, then concentrated in vacuo. The residue is triturated with Water, then with hexane. On treatment with aqueous alcohol (1:1) the residue slowly crystallizes to give 3-(2-benzoyloxyethyl)-6-ohloro-3,4-dihydro-7 sulfamyl- 1,2,4-benzothiadiazine-1,1-dioxide.

Example 9 5.9 g. of 4-amino-6-chloro-1,3-benzenedisulfonamide is dissolved in 30 ml. of dimethyl formamide and 3.6 g. of 3-benzoyloxypropionaldehyde and 2.3 g. of anhydrous potassium fluoride is added. The reaction mixture is heated on a steam bath to 8090 for two hours, then the potassium fluoride is filtered off and the filtrate concentrated in vacuo. The residue is triturated with water, then with hexane. On treatment with aqueous alcohol (1:1) the residue slowly crystallizes to give 3-(2-benzoyloxyethyl)-6-chloro-3,4 dihydro 7 sulfamyl 1,2,4- benzothiadiazine-l,l-dioxide.

In resulting 3,4-dihydro-2-H-[1,2,4]-benzothiadiazine- 1,1-dioxides certain substituents may be converted to other sulbstituents; for example, the 3-acetoxymethyl-6- chloro-7-sulfamyl 3,4 dihydro-Z-H [1,2,4] benzothiadiazine-1,1-dioxide may be hydrolyzed to the 6- chloro-3-hydroxymethyl-7-sulfamyl 3,4 dihydro 2-H- [1,2,4]-benzothiadiazine-1,1-dioxide by treatment with an alkaline reagent, such as aqueous alkali metal hydroxide, e.g., sodium or potassium hydroxide.

The replacement in 3-acyloxy-lower alkyl-3,4-dihydro- 2-H-[1,2,4]-benzothiadiazine-1,l-dioxides with sulfamylnitrogen atoms containing hydrogens, of such hydrogens by lower alkyl, should be carried out in the absence of a hydrolyzing reagent unless a simultaneous hydrolysis of the acyloxy group is desired; the alkali metal salt is, therefore, formed under anhydrous conditions and a lower alkyl halide, e.g., methyl or ethyl chloride, bromide or iodide, may be used as an alkylating reagent, preferably in a sealed tube and at an elevated temperature.

What is claimed is:

1. A member of the group consisting of 3,4-dihydro-2- H-[1,2,4]-benzothiadiazine-1,l-dioxides of the formula:

in which R represents a member of the group consisting of hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-carbonyloxy-lower alkyl, benzyloxycarbonyloxy-lower alkyl, carboxy-lower alkanoyloxylower alkyl, monocyclic carbocyclic aryl-lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, lower alkenyloxy-lower alkyl, monocyclic carbocyclic aryloxy-lower alkyl and monocyclic carbocyclic aryl-lower alkoxylower alkyl, each of the radicals R R and R represents a member of the group consisting of hydrogen and lower alkyl, and R stands for a member of the group consisting of lower alkyl, halogeno-lower alkyl and halogen, and alkali metal salts thereof.

2. 3-Lower alkoxy-lower alkyl-6-halogeno-7-sulfamyl- 3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,l-dioxide.

3. 3-Methoxymethyl-6-chloro-7-sulfarnyl-3,4 dihydro- 2-H-[1,2,4]-benzothiadiazine-1,l-dioxide.

4. 6-Chloro-3-ethoxymethyl 7- sulfamyl-3,4-dihydro-2- H-[1,2,4]-benzothiadiazine-1,1-dioxide.

5. 6-Halogeno-3-monocyclic carbocyclic aryloxy-lower

Claims (1)

1. A MEMBER OF THE GROUP CONSISTING OF 3,4-DIHYDRO-2H-(1,2,4)-BENZOTHIADIAZINE-1,1-DIOXIDES OF THE FORMULA: