US3351595A

US3351595A - Derivatives of 3, 4-dihydro-2h-1, 2, 4-benzothiadiazine-1, 1-dioxide

Info

Publication number: US3351595A
Application number: US242913A
Authority: US
Inventors: Stevens George De; Werner Lincoln Harvey
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1962-12-07
Filing date: 1962-12-07
Publication date: 1967-11-07
Anticipated expiration: 1984-11-07

Description

United States Patent 3,351,595 DERIVATIVES 0F 3,4-DIHYDRO-2H-1,2,4- BENZOTHIADIAZINE-1,1-DIOXIDE George de Stevens and Lincoln Harvey Werner, Summit, N.J., assignors to Ciha Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 7, 1962, Ser. No. 242,913 The portion of the term of the patent subsequent to Dec. 29, 1981, has been disclaimed 17 Claims. (Cl. 260243) This application is a continuation-in-part of our application Serial No. 12,679, filed March 4, 1960, now abandoned, which is in turn a continuation-in-part of our application Serial No. 855,275, filed November 25, 1959, now abandoned, which in turn is a continuation-in-part of our application Serial No. 791,044, filed February 4, 1959, now abandoned, which in turn is a continuationin-part of our application Serial No. 764,482, filed September 29, 1958, now abandoned, which in turn is a continuation-in-part of our application Serial No. 751,620, filed July 29, 1958, and now abandoned, which in turn is a continuation-in-part of our application Serial No. 740,- 582, filed June 9, 1958, and now abandoned, which in turn is a continuation-in-part of our application Serial No. 727,242, filed April 9, 1958, and now abandoned. This application is also a continuation-in-part of our application Serial No. 42,216, filed July 12, 1960, now abandoned.

The present invention concerns 3,4-dihydro-2H-l,2,4- benzothiadiazine-l,l-dioxide compounds. More particularly, it relates to the compounds of the formula in which R represents an aliphatic carbocyclic hydrocarbon or an aliphatic carbocyclic hydrocarbon-lower aliphatic hydrocarbon radical, each of the radicals R and R stands for hydrogen, aliphatic hydrocarbon, substituted aliphatic hydrocarbon or carbocyclic aryl-lower aliphatic hydrocarbon, R represents hydrogen or lower alkyl, and R represents lower alkyl, halogeno-lower alkyl or halogen, or alkali met-a1 salts thereof, as well as process for the preparation of such compounds.

Aliphatic carbocyclic hydrocarbon radicals R are radicals, in which the aliphatic carbocyclic (alicyclic) portion may be saturated or may contain one or more than one double bond depending on the number or ring carbon atoms. cycloalkyl may contain from three to eight, especially from five to six, and cycloalkenyl from four to eight, particularly from five to six, ring carbon atoms. Cycloalkyl may be represented by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, Whereas cycloalkenyl radicals may be, for example, 2- cyclo'butenyl, 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 3-cycloheptenyl, 2-cyclo-octenyl and the like.

Aliphatic carbocyclic hydrocarbon-lower aliphatic hydrocarbon radicals are primarily carbocyclic aliphatic hydrocarbon-lower alkyl radicals, in which the aliphatic carbocyclic (alicyclic) portion may be saturated or contain one or more than one double bond depending on the number of ring carbon atoms, which may 'be from three to eight, and in which lower alkyl is represented by a lower alkylene radical containing from one to seven, such as from one to four, especially from one to two, carbon atoms, e.g. methylene, l,1-ethylene, 1,2-ethylene, as well as l,l-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,4-butylene and the like.

3,351,595 Patented Nov. 7, 1967 Such radicals are particularly cycloalkyl-lower alkyl radicals, in which cycloalkyl contains from three to eight, especially from five to six, ring carbon atoms and lower alkyl contains from One to four carbon atoms, especially cycloalkylmethyl, in which cycloalkyl contains from three to eight, primarily from five to six, ring carbon atoms, e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclo-octylmethyl and the like, l-cycloalkylethyl, in which cycloalkyl contains from three to eight, particularly from five to six, ring carbon atoms, e.g. l-cyclopropylethyl, l-cyclobutylethyl, l-cyclopentylethyl, l-cyclohexylethyl, l-cycloheptylethyl and the like, or 2-cycloa1kyl-ethyl, in which cycloalkyl contains from three to eight, particularly from five to six, ring carbon atoms, e.g. 2-cyclopropylethyl, Z-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl and the like, as well as other cycloalkyl-lower alkyl radicals, in which cycloalkyl contains from three to eight, particularly from five to six, ring carbon atoms and lower alkyl contains from three to four carbon atoms, e.g. l cyclopentylpropyl, 2-cyclopentylpropyl, 3-cyclopentylpropyl, 4-cyclopentylbutyl, l-cyclohexylpropyl, 2- cyclohexylpropyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl and the like.

Cycloalkenyl-l-ower alkyl radicals, in which cycloalkenyl contains from four to eight, especially from five to six, ring carbon atoms and lower alkyl contains from one to four carbon atoms, are primarily cycloalkenyl-methyl, in which cycloalkenyl contains from four to eight, particularly from five to six, ring carbon atoms, e.g. 2-cyclopentenylmethyl, 3cyclopentenylmethyl, 2-cyclohexenyl methyl, 3-cyclohexenylmethyl and the like, l-cycloalkenyl-ethyl, in which cycloalkenyl contains from four to eight, particularly from five to six, ring carbon atoms, e.g. l-(2-cyclopentenyl)-ethyl, l-(3-cyclopentenyl)-ethyl, 1-(2 cyclohexenyl)-ethyl, l-(3-cyclohexenyl)-ethyl and the like, or 2-cycloalkenyl-ethyl, in which cycloalkenyl contains from four to eight, particularly from five to six, carbon atoms, e.g. 2-(2-cyclopentenyl)-ethyl, 2-(3- -cyclopentenyl)-ethyl, 2 (2 cyclohexenyl)ethyl, 2-(3- cyclohexenyl)-ethyl and the like, as well as other cycloalkenyl-lower alkyl, in which cycloalkenyl contains from four to eight, especially from five to six, ring carbon atoms and lower alkyl contains from three to four carbon atoms, e.g. 1-(Z-cyclopentenyl)-propyl, l-(3-cyclopentenyl -propyl, 2- 2-cyclopentenyl) -propyl, 2- 3 -cyclopentenyl)-propyl, 3 (3 cyclopentenyl)-propyl, 4-(3-cyclopentenyD-butyl, 1-(2-cyclohexenyl)-propyl, 1-(3-cyclohexenyl)-pro-pyl, 2-(3-cyclohexenyl)-propyl, 3(3-cyclohexenyD-propyl, 4-(3-cyclohexenyl)-butyl and the like.

The above-mentioned carbocyclic alicyclic hydrocarbon radicals are preferably unsubstituted; substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, hydroxyl, etherified hydroxyl, such as lower alkoxy, e.g. methoxy, ethoxy and the like, esterified hydroxyl, such as lower alkoxycarbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, lower alkanoyloxy, e.g. acetoxy, propionoxy and the like, or halogeno, e.g. fiuoro, chloro, bromo and the like, etheri-fied mercapto, such as lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, or amino, such as unsubstituted amino, N-monosubstituted amino, for example, N-lower alkyl-amino, e.g. N-methyl-amino, N-ethyl-amino and the like, or N,N-disubstituted amino, for example, N,N- di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino, or N,N-lower alkylene-imino, e.g. l-pyrrolidino, 1-piperidino and the like.

The radicals R and R represent primarily hydrogen; they may also stand for lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl and the like, lower alkenyl, particularly allylic lower alkenyl containing from three to five carbon atoms e.g. Z-propenyl (allyl), 2-methyl-2-propenyl (Z-methylallyl), Z-butenyl (3-methyl-allyl) and the like, or monocyclic carbocyclic aryl-lower alkyl, particularly phenyllower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like. These groups may carry additional substituents, such as lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkyl-mercapto, e.g. methylmercapto, e-thylmercapto and the like, halogeno, e.g. fiuoro, chloro, bromo and the like.

The radical R represents primarily hydrogen; lower alkyl substituents may be, for example, methyl, ethyl and the like.

The substituent R in the 6-position of the 3,4-dihydro- 2H-1,2,4-benzothia-diazine-l,l-dioxides of this invention represents primarily halogeno, such as fiuoro, bromo or particularly chloro. Other substituents are, for example, lower alkyl, e.g. methyl, or, more advantageously, halogeno-lower alkyl, e.g. trifluo-romethyl and the like.

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

The 3,4 dihydro-ZH-l,2,4-benzothiadiazine-l,l-dioxide compounds of this invention have diuretic and natriuretic properties and can be used as diuretic and natriutetic agents with improved properties, such as, for example, a favorable sodium: potassium excretion ratio, to relieve states of excessive water and sodium retention, as for example, connected with heart troubles. In addition, these compounds have antihypertensive properties, which can be utilized in the treatment of hypertensive conditions, such as renal hypertension and the like.

Particularly useful as diuretic and natriuretic agents are the compounds of the formula in which R represents cycloalkyl containing from three to eight, particularly from five to six, ring carbon atoms, and R stands for halogeno or trifluoromethyl, or the alkali metal salts of such compounds. This group may be represented by the compounds of the formula (g2 rnNozs R3 (I3M (cycloalkyl) in which cycloalkyl contains from five to six ring carbon atoms and R stands for chloro or trifiuoromethyl.

An additional group of highly active compounds are those of the formula (52 HzNOzS- I (DH-R1 R in which R represents cycloalkenyl, containing from four to eight, particularly from five to six, ring carbon atoms, and R stands for halogeno or trifluoromethyl, or the alkali metal salts of such compounds. This group may be represented by the compounds of the formula in which cycloalkenyl contains from five to six ring carbon atoms and R represents chloro or trifluorornethyl.

Another group of compounds exerting particularly useful diuretic and antihypertensive effects, coupled with improved properties, are the compounds of the formula in which R stands for cycloalkyl-lower alkyl, in which cycloalkyl contains from three to eight, particularly from five to six, ring carbon atoms, and lower alkyl contains from one to four, particularly from one to two, carbon atoms and R represents halogeno or trifluoromethyl, or the alkali metal salts of such compounds. This group may be represented by the compounds of the formulae in which cycloalkyl contains from five to six ring carbon atoms and R stands for chloro or trifluoromethyl.

A further group of compounds showing useful diuretic and antihypertensive effects are the compounds of the formula 1 OH-CH- (cycloalkenyl) H CH HzNOgS CH-C HzGHr-(eycloalkenyl) in which cycloalkenyl contains from five to six ring carbon atoms and R stands for chloro 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-2H-1,2,4-benzothiadiazine-l,1-dioxides or the salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, e.g. 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, vegetable 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, sus: pensions 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 prepare-d by reacting an aniline compound of the formula Rz'-HNO2S SOzNI-I-Rz R3 NH 1&2]!

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 reactive derivative thereof, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a resulting free compound into a salt thereof.

The reaction may be performed in the absence of any condensing reagent, or in the pre:ence of a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, 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, e.g. hydrochloric, hydrobromic, sulfuric acid and the like, if desired, in anhydrous form. The presence of an acid may he advantageous, whenever the aldehyde is employed in the form of a reactive derivative thereof. For example, aldehydes may be given to the reaction medium in a form which yields the desired reactant in situ. Thus, an acetal of an aldehyde R -CHO with a lower alkanol, e.g. methanol, ethanol and the like, or an alkali metal, e.g. sodium or potassium, bisulfite addition compound is advantageously used in the presence of a mineral acid. Alkali metal bisulfite addition compounds are, for example, the sodium bisulfite addition compounds of cyclopentylacetaldehyde, 3-cyclopentyl-propionaldehyde and the like; reactive acetals are, for example, cyclopropane carbox-aldehyde diethyl acetal (cyclopropyl-diethoxy-methane), cyclobutane carboxaldehyde diethyl acetal (cyclobutyldiethoxy-methane), cyclopentane carboxyalehyde dimethyl acetal (cyclopentyl-dimethoxy-methane), cyclopentane carboxaldehyde diethyl acetal (cyclopentyl-diethoxymethane), cyclohexane carboxaldehyde diethyl acetal (cyclohexyl-diethoxy-methane), cycloheptane carboxaldehyde (cycloptyl-diethoxy-methane), cyclooctane carboxaldehyde diethyl acetal (cyclooctyl-diethoxy-methane), 3-cyclohexene carboxaldehyde diethyl acetal (Ii-cyclohexenyl-diethoxy-methane), cyclopentyl-acetaldehyde diethyl acetal (l-cyclopentyl-2,2-diethoxy-ethane), cyclohexylacetaldehyde diet-hylacetal (1 cyclohexyl 2,2-diethoxy-ethane), 2-(3-cyclohexenyl)-acetaldehyde diethyl acetal (l-[3-cyclohexenyl]-2,2-diethoxy-ethane) and the like.

The reaction may preferably be carried out in the presence of a solvent, for example, an .ether, e.g. tetrahydrofuran, p-dioxane, diethyleneglycol dimethylether and the like, a lower alkanol, e.g. methanol, ethanol and the like,

or a formamide, e.g. dimethylformamide and the like, a

lower alkanone, e.g. acetone and the like, a mixture of such solvents, an aqueous mixture of such solvents or water, or any other suitable diluent. If desired, it may be completed at an elevated temperature, for example, by heating on a steam bath or at the boiling temperature of the solvent. If necessary, the reaction may be per formed 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, of, 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 5-R -N-R "-aniline-2,4-disulfonyl chlorides. These are subsequently reacted with ammonia, e.g. liquid or gaseous ammonia, or with a solution of ammonia in water or in a lower alkanol, methanol or ethanol, or with an N-lower alkylamine, e.g. N-methylamine, N-ethylamine and the like, 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 an N-lower alkyl-amine 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. The acetals of the'aldehydes with lower alkanols, e.g. ethanol and the like, may be prepared, for example, by reacting a carbocyclic aliphatic hydrocarbon or a carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon halide, e.g. chloride, bromide, iodide, and the like, with magnesium, treating the resulting Grignard reagent with a lower alkyl ester of orthoformic acid, e.g. methyl orthoformate, or particularly ethyl orthoformate and the like, and isolating the desired carbocyclic aliphatic hydrocarbon carboxaldehyde lower alkyl acetal or the carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon carboxaldehyde lower alkyl acetal.

A second procedure for the preparation of compounds of this invention comprises removing in compounds of the formulae in which R R R and R have the previously-given meaning, the C=N double bond of the l,*2,4-thiadiazinel,l-dioxide portion by reduction, and, if desired, carrying out the optional steps.

The removal of the O=N-- double bond may be achieved, for example, by treatment with a borohydride or an equivalent reducing agent capable of removing such double 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, and sodium dimethoxy borohydride is another possible reducing reagent. 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 solvents,

such as those mentioned hereinbelow; 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-dimethoxyethane, diethyleneglycol dimethylether and the like, lower alkanols, e.g. methanol, ethanol, propanol, isopropanol and the like, or liquid carboxylic acid amides, such as formamides, e.g. formamide, N,N-dimethylformamide and the like, 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.

Catalytic reduction under certain conditions may also be used for the removal of the O=N- double bond. For example, treatment of the starting material, particularly a solution thereof, with hydrogen in the presence of a catalyst containing a metal of the eighth group of the Periodic System, and of an organic base, may cause the removal of the double bond. Suitable solvents are, for example, lower alkanols, e.g. methanol, ethanol and the like, ethers, e.g. diethyleneglycol dimethylether and the like, or other equivalent solvents. Metals of the eighth group of the Periodic System, present in the catalysts, may be, for example, palladium, platinum and the like; these metals may be supported by adsorbents, such as charcoal, aluminum oxide, silicagel and the like. Palladium on charcoal, platinum oxide and the like may serve as catalysts. An organic base is particularly a heterocyclic basic compound, particularly an N,N-alkyleneimine, e.g. pyrrolidine, piperidine and the like, or an N,N-aza-alkyleneimine, e.g. piperazine and the like, or any other suitable base. The hydrogenation may be carried out under atmospheric or under increased pressure, if necessary, while heating.

The electrolytic reduction procedure provides for another possibility of removing the C=N double 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. amps./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 a platinum anode and a dilute sulfuric acid anolyte are preferred.

A current density greater than about 0.02 amps/cm. is sufficient to bring about the reduction of the C=N double bond; however, for practical reasons a current density higher than about 0.25 amps/cm. may diminish the efficiency 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 in additional solvent, such as, for example, a formamide, e.g. N,N-dimethyl-formamide and the like, may be added. Lower alkanols, e.g. methanol, ethanol and the like, may replace or may 'be added with a formamide to enhance the solubility of the starting material and the end product.

Diaphragms separating the anolyte and the catholyte are more especially ion exchange membranes, such as ion exchange resins (amberplex), alundum of parchment and the like.

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 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-

dioxides, containing sulfamyl-nitrogen atoms carrying hydrogen, such hydrogen may be replaced by aliphatic hydrocarbon radicals, such as lower alkyl, particularly lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl and the like, or lower alkenyl, particularly allylic lower alkenyl containing from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, but-Z-enyl and the like, or carbocyclic aryl-lower aliphatic hydrocarbon, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like. Generally, an alkali metal salt of the starting material is formed and such salt is then reacted with the reactive ester formed by an aliphatic hydrocarbon alcohol or a carbocyclic aryl-lower aliphatic hydrocarbon alcohol and strong mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like. For example, treatment of the starting material with a di-lower alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, in the presence of an alkaline reagent, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, represents a procedure for introducing lower alkyl radicals. As solvents, water or water miscible organic solvents, such as lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, ethers, e.g. diethyleneglycol di methylether and the like, or formamides, e.g. N,N-dimethyl-formamide and the like, may be used.

Or, an alkali metal, e.g. lithium, sodium or potassium, salt of the starting material, prepared by treating the latter with an alkali metal, e.g. lithium, sodium or potassium, hydride, amide or hydroxide may be reacted With a lower alkyl halide, e.g. methyl or ethyl chloride, bromide or iodide and the like, a lower alkenyl halide, e.g. allyl chloride, bromide or iodide and the like, or a phenyllower alkyl halide, e.g. benzyl or Z-phenylethyl chloride, bromide or iodide and the like. Diluents are primarily those previously mentioned and are chosen in accordance with their inertness towards the reactants and the solubility of the latter.

Generally, the above reaction is carried out under cooling, particularly if a di-lower alkyl sulfate is employed, at room temperature, or at an elevated temperature, and, if necessary, it is performed 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 attached to the 7- position of the molecule may react simultaneously with the reactive ester. 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, e.g. hydrochloric, sulfuric acid and the like. A free compound may be converted into an alkali metal salt, for example, by treatment with an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, 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 dimethyl-ether, solution, with an alkali metal hydride or amide, e.g. sodium or potassium hydride or amide, and removing the solvent. Monoor poly-salts may be obtained.

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

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

Example 1 A mixture of 5.7 g. of -chloro-2,4-disulfarnyl-aniline, 2,2 g. of 3-cyclohexene carboxaldehyde and 1 ml. of ethyl acetate saturated With hydrogen chloride in 50 ml. of diethylene glycol dimethylether is heated on the steam bath for one hour. Two thirds of the solvent is stripped off under reduced pressure; the residue is added to water While stirring. The crystalline 6-chloro-3-(3-cyclohexenyl)-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1, l-dioxide is collected and recrystallized from methanol, M.P. 252-254".

In the above reaction, 5-chloro-2,4-disulfamyl-aniline may be replaced by 5-bromo-2,4'disulfamyl-aniline or 2, 4-disulfamyl-5-trifluoromethyl-aniline; when reacted with 3-cyclohexene carboxaldehyde as mentioned hereinabove, these aniline derivatives yield 6-bromo-3-(3-cyclohexenyl)-7-sulfamyl-3,4-dihydro-2H-1,2,4 benzothiadiazine- 1,1-dioxide or 3-(3-cyclohexenyl -7-sulfamyl-6-trifluoromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide.

Example 2 A mixture of 6.2 g. of cyclopentyl-diethoxy-methane (diethyl acetal of cyclopentane carboxaldehyde), 7.4 g. of 5-chloro'2,4-disulfamyl-aniline, S-ml. of diethyleneglycol dimethylether and 2 ml. of concentrated hydrochloric acid is heated on the steam bath for two hours. Upon cooling a crystalline precipitate is formed, which is collected and washed with ethanol. The 3-cyclopentyl- 6 chloro 7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-Ll-dioxide melts at 271272.

The 5-chloro-2,4-disfulfamyl-amine may be replaced by 2,4-disulfamyl-S-trifluoromethyl-aniline and reacted with the diethyl acetal of cyclopentane carboxaldehyde to yield the desired 3-cyclopentyl-7-sulfamyl-6-trifluorornethyl- 3,4-dihy'dro-2H-1,2,4-benZothiadiaZine-1 ,l-dioxide.

The cyclopentyl-diethoxy-methane (diethyl acetal of cyclopentane carboxaldehyde) used as the starting material may be prepared as follows: To a mixture of 20 g. of bromocyclopentane and 3.26 g. of magnesium turnings in ether is added one crystal of iodine; the mixture is refluxed until the magnesium has disappeared and is then cooled. 15.9 g. of ethyl orthoformate is given to the Grignard reagent, the reaction mixture is refluxed for sixteen hours and is then chilled. 79.5 g. of 6 percent aqueous hydrochloric acid is added dropwise while stirring and cooling. A yellow oil separates, which is dissolved in additional ether; the organic layer is separated, washed with water and dried over sodium sulfate. The solvent is evaporated and the crude cyclopentyl-diethoxy-methane (diethyl acetal of cyclopentane carboxaldehyde) is used without further purification,

' Example 3 A mixture of 5.0 g. of the cyclohexyl-diethoxy-methane (diethyl acetal of cyclohexane carboxaldehyde), 5.7 g. of 5-cl1loro-2,4-disulfamyl-aniline, 20 ml. of diethyleneglycol dimethylether and 2 ml. of concentrated hydrochloric acid is heated at 95 for three hours. The desired 6 chloro 3-cyclohexyl-7-sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine-l,l-dioxide precipitates and is collected; M.P. 278280.

An aqueous solution of the sodium salt of 6-chloro-3- cyclohexyl 7 sulfamyl 3,4 dihydro 2H 1,2,4- benzothiadiazine-1,1-dioxide may be obtained by dissolving 6-chloro-3-cyclohexyl-7-sulfamyl-3,4-dihydro-2H-1,2, 4-benzothiadiaZine-1,l-dioxide in an equivalent amount of 2N aqueous sodium hydroxide solution.

The starting material may be prepared as shown in Example 2, Le. the Grignard reagent formed from bromocyclohexane and magnesium is treated with ethyl orthoformate and the desired cyclohexyl-diethoxy-methane (diethyl acetal of cyclohexane carboxaldehyde) is used without further purification.

Other compounds prepared according to the above procedure by selecting the appropriate starting materials are, for example, 6 chloro 3-cyclopropyl-7-sulfamyl-3, 4 dihydro 2H 1,2,4-benzothiadiazine-1,l-dioxide, 6- chloro 3 cyclobutyl 7-sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1 dioxide, 6-chloro-3cycloheptyl- 7 sulfamyl 3,4 dihydro-2H-1,2,4-benzothiadiaZine-1, l-dioxide, 6 chloro 3 cyclooctyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide and the like.

Example 4 A mixture of 1.0 g. of cyclopentyl-acetalclehyde, 2.6 g. of 5-chlor0-2,4-disulfamyl-aniline, 1 ml. of a concentrated solution of hydrogen chloride in ethyl acetate and 15 ml. of diethyleneglycol dimethylether is heated on the steam bath for 2 /2 to 3 hours and then allowed to stand overnight. The solution is concentrated to a small volume, the residue is poured into Water while stirring and the resulting precipitate is filtered off. The 6-cholo-3-cyclopentylmethyl 7 sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide is recrystallized from a mixture of ethanol and water, M.P. 230-231".

The aldehyde used as the starting material may be prepared, for example, by converting cyclopentyl-acetic acid into its chloride and treating the latter with hydrogen in the presence of palladium on barium sulfate as a catalyst according to the Rosenmund procedure.

Other 3,4 dihydro 2H 1,2,4-benzothiadiazine-1,1- dioxides, which may be manufactured according to the previously-given procedure by varying the starting materials, are 6-chloro 3 cyclopropylmethyl-7-sulfamyl-3, 4 dihydro 2H 1,2,4-benzothiadiazine-l,l-dioxide, 6- chloro 3 (3 cyclohexenylmethyl)-7-sulfamyl-3,4-dihydro 2H 1,2,4-benzothiadiazine-1,l-dioxide. 6-bromo- 3 cyclopentylmethyl 7 sulfamyl3,4-dihydro-2H-1,2, 4 benzothiadiazine 1,1-dioxide, 3-cyclopentylmethyl-7- sulfamyl 6 trifluoromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine'l,l-dioxide, 6-chloro-3 (2-cyclohexylethyl)- 7 sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide and the like.

Example 5 By treating a solution of 6-chlor0-3-(3-cyclohexenyl)- 7 sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide in aqueous sodium hydroxide with dimethyl sulfate at 10 and then at room temperature a mixture of the 6 chloro 3 (3-cyclohexenyl)-2-methyl-7-sulfamyl-3, 4 dihydro 2H-1,2,4-benzothiadiazine-1,l-dioxide and 6 chloro 3 (3-cyclohexenyl)-2-methyl-7-(N-methylsulfamyl) 3,4 dihydro-2H-1,2,4-benzothiadiaZine-1,ldioxide which can be separated into the two components by fractionated crystallization.

Example 6 By treating a solution of 6-chloro-3-(2-cyclopentylethyl) 7 sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in diethyleneglycol dimethylether with sodium borohydride at room temperature for tWo hours, concentrating the solution and adding water to the residue, the 6-chloro-3-(2- cyclopentylethyl) 7 sulfamyl 3,4-dlihydro-2H-1,2,4- benzothiadiazine-l,l-dioxide may be obtained.

The starting material used in the above reaction may be prepared by reacting 5-chloro-aniline-2,4-disulfonyl chloride with 3-cyclopentyl-propionyl chloride, treating the resulting 5 chloro N(3-cyclopentylpropionyl)-aniline- 2,4-disulfonyl chloride with ammonia and subsequently heating the resulting product to achieve ring closure to the desired 6 chloro 3 (2-cyclopentyl-ethyl)-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide.

The above described 6-chloro-3-(Z-cyclopentylethyl)-7- sulfamyl-3,4-dihydro-2H 1,2,4 benzothiadiazine-Ll-dioxide may also be prepared by treating 5-chloro-2,4-disulfamyl-aniline with 3-cyclopentyl-propionaldehyde or a reactive functional derivative thereof, such as an acetal or ing to the method described in Example 4.

Example 7 To a solution of 24.5 g. of the cyclopentylacetaldehyde sodium bisulfite addition compound in 17 ml. of water and 110 ml. of concentrated hydrochloric acid is added 31.2 g. of -chloro-2,4-disulfamyl-aniline and 250 ml. of ethanol; the mixture is refluxed for four hours on the steam bath and then filtered hot. Upon chilling, a crystalline precipitate is formed, which is filtered off and recrystallized from a mixture of ethanol and water to yield the pure 6chloro-3-cyclopentylmethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide, MP. 238- 240". The product is identical with the compound obtained according to the process of Example 4.

The above obtained 6-chloro-3-cyclopentylmethyl-7- sulfamyl-3,4-dihydro 2H-l,2,4 benzothiadiazine-1,1-dioxide may also be prepared, for example, by treating a solution of 6-chloro-3-cyclopentylmethyl-7-sulfamyl-1,2,4- benzothiadiazined,l-dioxide (prepared from S-chloroaniline-2,4-disulfonyl chloride, by reacting the latter with cyclopentyl-acetyl chloride and treating the resulting 5- chloro-N-cyclopentylacetyl-aniline-2,4-disulfonyl chloride with ammonia to form the sulfamyl derivative with simultaneous ring closure) in ethanol containing a small amount of aqueous sodium hydroxide with sodium borohydride.

Generally, 6-chloro-3-cyclopentylmethyl 7 sulfamyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 dioxide or an alkali metal salt thereof may be prepared by reacting 5- chloro-2,4-disulfamyl-aniline with cyclopentylacetaldehyde or a reactive functional derivative thereof, such as an acetal thereof, e.g. dimethyl acetal, diethyl acetal and the like, or the sodium bisulfite addition compound thereof, or reducing in 6-chloro-3-cyclopentylmethyl-7-sulfamyl- 1,2,4-benzothiadiazine-1,1-dioxide the C=N double bond in the heterocyclic portion of the 1,2,4-benzothiadiazine-1,1-dioxide nucleus, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting the free compound into a salt thereof. These reactions are carried out according to the previously described procedures.

Example 8 A mixture of 2.5 g. of cyclohexyl-acetaldehyde, 5.8 g. of 5-chloro-2,4-disulfamyl-aniline, 50 ml. of diethyleneglycol dimethylether and 3 ml. of a saturated solution of hydrogen chloride in ethyl acetate is heated on the steam bath for three hours. The solution is evaporated to a small volume, the residue is poured into water, triturated and allowed to stand for several hours. The crystalline material is filtered olf and recrystallized from a 9: l-mixture of ethanol and water to yield the 6-chloro-3-cyclohexylmethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4 benzothiadiazine-1,1- dioxide, M.P. 224226; yield: 6.0 g.

The aldehyde used in the above preparation can be prepared according to the Rosenmund procedure as follows: A slow stream of hydrogen is passed through a mixture of 2.0 g. of palladium on barium sulfate (containing 5 percent palladium), 0.5 ml. of a solution of quinoline and sulfur in xylene (prepared by refluxing 8.5 g. of freshly distilled quinoline and 1.4 g. of sulfur for five hours, and diluting the mixture with xylene to a total volume of 99 ml.), and 125 ml. of xylene; about 10 ml. of the solvent is distilled off to remove any trace of water. 19.3 g. of cyclohexyl-acetic acid chloride is added; the reaction mixture is heated by keeping a bath temperature of 190-195 and a slow stream of hydrogen is passed through the mixture while stirring. The evolved hydrogen chloride is collected and titrated at intervals to determine the end point of the reduction. Treatment with hydrogen is terminated after 11 /2 hours (90 percent of the theoretical amount of hydrogen chloride has been generated), the reaction mixture is cooled, the catalyst is filtered off and the filtrate is diluted with 300 ml. of diethyl ether. The organic solution is diluted with 400 ml. of saturated aqueous sodium bisulfite and stirred for seventeen hours. The solid sodium bisulfite addition compound of the 12 cyclohexyl-acetaldehyde is filtered off and Washed with diethyl ether, yield: 28 g. The solid material is stirred with 30 ml. of a 20 percent aqueous solution of sodium carbonate until it dissolves. The organic material is extracted with diethyl ether, the organic layer is dried and evaporated to give 3.0 g. of crude cyclohexylacetaldehyde.

The following compounds may also be prepared according to the above methods by selecting the appropriate starting materials, whereby the aldehydes may be used as such or in the form of reactive derivatives, i.e., acetals, e.g. dimethyl acetal, diethyl acetal and the like, or sodium bisulfite addition compounds:

6-chloro-3-( l-cyclopentylethyl) -7-sulfamyl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-3-cyclobutylmethyl-7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3 l-cyclobutylethyl -7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-3 2-cyclopentenylmethyl -7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3 -[2(1-cyclopentenyl)-ethyl]-7-sulfamyl-3,4-

dihydro-ZH- 1 ,2,4-benzothiadiazine- 1 l-dioxide,

6-chloro-3-[1-(2-cyclopentenyl)-ethyl]-7-sulfamyl-3,4-

dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3-( l-cyclohexylethyl) -7-sulfamyl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1,l-dioxide,

6-chloro-3-( l-cyclohexylethyl -7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-3-[3-cyclohexenyl) -ethyl] -3,4-dihydro-2H-1,2,4-

benzothiadiazine- 1 1 -dioxide,

6-chloro-3-cycloheptylmethyl-7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benz0thiadiaZine-l, l-dioxide,

6-chloro-3 2-cycloheptenylmethyl -7-sulfamyl-3 ,4- dihydro-2H-1,2,4-benzothiadiazine-1, l-dioxide,

6-chlor0-3-cyclo-octylmethyl-7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1, l-dioxide, and the like.

In the above-described compounds with carbocyclic alicyclic hydrocarbon radicals containing double bonds in the 3-position, the latter may be converted into saturated carbocyclic alicyclic hydrocarbon radicals by reduction. The reduction may be achieved for example, by treatment of a liquid ammonia solution of the compound containing an unsaturated carbocyclic alicyclic hydrocarbon radical with an alkali metal, particularly lithium and the like. Catalytic reduction may also be used, but care has to be taken that the carbocyclic aryl portion of the benzothiadiazine ring system or any other groups, e.g. halogen and the like, are not affected; treatment with hydrogen in the presence of Raney nickel, using a lower alkanol, e.g. ethanol and the like, as a solvent, may be feasible.

What is claimed is:

1. A member of the group consisting of compounds of the formula in which R represents cycloalkyl having from three to eight ring carbon atoms and R stands for trifluoromethyl, and alkali metal salts thereof.

2. 6 trifluoromethyl 3 cyclopentyl-7-sulfamyl-3,4- dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide.

3. 6 trifluoromethyl 3 cyclohexyl-7-sulfamyl-3,4- dihydro-2H-1,2,4-benzothiadizine-1,l-dioxide.

4. A member of the group consisting of compounds of the formula in which R represents cycloalkenyl having from four to eight ring carbon atoms, and R stands for trifluoromethyl, and alkali metal salts thereof.

5. 6 trifluoromethyl 3 (2 cyclopentenyl)-7-sulfamyl 3,4 dihydro 2H-1,2,4'benzothiadiazine-1,1-dioxide.

6. 6 trifiuoromethyl 3 (3 cyc1ohexenyl)-7-sulfamyl 3,4 dihydro 2H-1,2,4-benzothiadiazine-1,1-dioxide.

7. A member of the group consisting of compounds of the formula in which R represents cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight ring carbon atoms and lower alkyl has from one to four carbon atoms, and R stands for trifluoromethyl, and alkali metal salts thereof.

8. 6 trifluoromethyl 3 cycloalkyl-lower alkyl-7- sulfamyl 3,4 dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide, in which cycloalkyl has from five to six ring carbon atoms and lower alkyl has from one to two carbon atoms.

9. 6 trifiuoromethyl 3 cyclopentylmethyl-7-sulfamyl 3,4 dihydro 2H-l,2,4-benzothiadiaZine-1,l-dioxide.

10. 6 trifiuoromethyl 3 (1-cyclopentylethyl)-7- sulfamyl 3,4 dihydro 2H-1,2,4-benzothiadiazine-1,1- dioxide.

11. 6 trifiuoromethyl 3 (2 cycIopentylethyl)-7- sulfamyl 3,4 dihydro ZH-l,2,4 benzothiadiazine-l,1- dioxide.

12. 6 trifluoromethyl 3 cyclohexylmethyl 7-sulfamyl 3,4 dihydro 2H 1,2,4-benzothiadiazine-1,1- dioxide.

13. A member of the group consisting of compounds of the formula in which R represents cycloalkenyl-lower alkyl, in which cycloalkenyl has from four to eight ring carbon atoms, and lower alkyl has from one to four carbon atoms, and R stands for trifiuo' romethyl and alkali metals salts thereof.

14. 6 trifluoromethyl 3 cycloalkenyl-lower alkyl- 7-sulfamyl-3,4-dihydro 2H 1,2,4 tbenzothiadiazine-Lldioxide, in which cycloalkenyl has from five to six carbon atoms, and lower alkyl has from one to two carbon atoms.

15. 6-trifluoromethy1 3 (2-cycl0pentenylmethyl)-7- sulfamyl 3,4 dihydro 2H-l,2,4-benzothiadiazine-1,1- dioxide.

16. 6-trifluoromethyl 3 [2-(1-cyclopentyl)-ethyl-7- sulfamyl 3,4 dihydro-ZH-l,2,4-benzothiadiazine-1,1-dioxide.

17. A compound of the formula and an alkali metal salt thereof, wherein n is selected from the group consisting of zero and one; and R is selected from the group consisting of cycloalkyl of four to seven carbon atoms, cyclopentenyl, cyclohexenyl and cycloheptenyl.

References Cited UNITED STATES PATENTS 3,163,644 12/1964 de Stevens et al. 260243 NICHOLAS S. RIZZO, Primary Examiner. IRVING MARCUS, Examiner,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,351,595 November 7, 1967 George de Stevens et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 49, "3(3-cyclo-" should read 3- (3- cyclo- Column 6 line 9 f" hould read or Column 9, line 2, "2,2" should read 2.2 line 31, "disfulfamyl-amine" should read disulfamyl-aniline Column 10, line 6, "6-ch1oro-3 cyclooctyl" should read 6-chloro-3-cyclooctyl Column 13, lines 15 to 20, the formula should appear as shown below:

2 H NO S NH RT- l Column 14, line 22, "ethyl" should read ethyl] Signed and sealed this 20th day of January 1970.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR

EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer

Claims

1. A MEMBER OF THE GROUP CONSISTING OF THE FORMULA