US3342815A - Alkylsubstituted-j,j-spiro-y-sulfamyl- tfflazide products - Google Patents

Alkylsubstituted-j,j-spiro-y-sulfamyl- tfflazide products Download PDF

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US3342815A
US3342815A US3342815DA US3342815A US 3342815 A US3342815 A US 3342815A US 3342815D A US3342815D A US 3342815DA US 3342815 A US3342815 A US 3342815A
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benzothiadiazine
sulfamylspiro
dioxide
cyclohexane
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems

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  • the 4-aliphatic substituent(s) advantageously is selected either from the straight or branched chain aliphatic radicals derived from a hydrocarbon such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, 1,1- dimethylpropyl, hexyl or any of the various branched chain, 6-carbon aliphatic radicals; or is selected from the alicyclic radicals preferably an aiicyclic radical derived from a hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, the alicyclic structures being either unsubstituted or alkyl substituted but preferably having no more than a total of 6 carbon atoms in the 4'- substituent grouping.
  • a hydrocarbon such as methyl, ethyl, propyl
  • novel compounds of this invention also contain a sulfamyl substituent attached to the benzenoid moiety of the benzothiadiazine structure and preferably at least one additional substituent selected from halogen or halogen-like radicals, such as chlorine, bromine, fluorine, iodine, trifluoromethyl, trichloromethyl, dichloromethyl and the like; lower alkyl such as methyl, ethyl, propyl and the like or similar alkyl groups having a substitutent, such as a halogen, attached to one or more of the carbons in the alkyl group; lower alkoxy such as methoxy, ethoxy, propoxy and the like; nitro or amino.
  • halogen or halogen-like radicals such as chlorine, bromine, fluorine, iodine, trifluoromethyl, trichloromethyl, dichloromethyl and the like
  • lower alkyl such as methyl, ethyl, propyl and the
  • the preferred compounds are those wherein the spiro structure is 4-mono-substituted, the sulfamyl substituent is attached to the 7-position of the benzothiadiazine structure and the other substituents are attached preferably to either or both of the 5- and/ or 6-positions of the benzothiadiazine nucleus.
  • novel compounds of this invention are substantially non-toxic, the therapeutic ratio is very great and the possibility of producing any undesirable side efiects is considerably less than with the use of other benzothi-adiazine type saluretic agents which also are known to be safe drugs for use in this type therapy.
  • novel compounds of this invenion can be prepared by several methods.
  • One method which has been found very useful in preparing the novel compounds involves reacting the appropriate aminobenzenedisulfonamide and 4-substitu ted cyclohex-anones with moderate heating.
  • excess ketone can be employed for its solvent properties, although other solvents can be used instead.
  • Some solvents which are found to be suitable include dimethylformamide, dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, and the like.
  • reaction can be catalyzed with potassium fluoride in dimethylformarnide or with an acid such as sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or other aliphatic or aromatic sulfonic acids in other media.
  • an acid such as sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or other aliphatic or aromatic sulfonic acids in other media.
  • the ketal can be cyclic in structure or acycylic or in the form of its enol ether which is readily generated from the ketal under acid conditions.
  • the reaction preferably is carried out with moderate heating in the presence of a solvent and a few drops of acid which catalyzes the reaction.
  • Butanol was found to be an entirely satisfactory solvent, though other alcohols as l-pentanol, propanol and the like or an alcohol admixed with other solvents as dioxane, diethylene glycol dimethyl'ether, ethylene glycol dimethyl ether and the like can be used.
  • novel compounds of this invention can be prepared by reacting the appropriate aminobenzenedisulfonamide with a 4-substituted-cyclohexanone and that said ketone can be replaced by a reactive, function-a1 derivative of the same, such as a ketal or an enol ether, or a ketimine or by a substancewhich under the reaction conditions in question is converted to the ketone, such as the hydrosulfite or cyanohydrin of the ketone, and that the reaction can be effected with or without an added solvent and with or without a catalyst, but preferably with heating.
  • a reactive, function-a1 derivative of the same such as a ketal or an enol ether, or a ketimine
  • a substancewhich under the reaction conditions in question is converted to the ketone, such as the hydrosulfite or cyanohydrin of the ketone
  • EXAMPLE 1 4' sec. butyl 6 trifluoromethyl 7 sulfamylspiro- [1,2,4 benzothiadiazine 3(4H),1 cyclohexane1- 1,1-dioxide 4 amino 6 trifluoromethyl 1,3 benzenedisulfonamide (6.4 g., 0.02 mole) and 4-sec.-butylcyclohexanone (6.1 g., 0.04 mole) aredissolved in dimethylformamide (25 ml.) and heated on a steam bath for 48 hours. The reaction mixture is cooled, treated with methanol (100 ml.) and then water (300 ml.) gradually is added with stirring.
  • the aqueous layer is decanted and the residual viscous oily product is triturated with petroleum ether (100 ml). The resulting solid is removed by filtration and dried. This material is dissolved in methanol (25 ml.) and treated with a few milliliters of water, and the small amount of oil that forms is removed by filtration. The filtrate is slowly treated with water (75 ml.) whereby a 71% yield of 4'-sec.-butyl-6-trifluoromethyl-7-sulfamylspiro [1,2,4 benzothiadiazine 3(4H), 1' cyclohexane]-1,1-dioxide is obtained as a pure crystalline product melting at 231.5232.5 C.
  • EXAMPLE 2 4' cyclohexyl 6 chloro 7 sulfamylspiro [1,2,4- benzothiadiazine-3 (4H ,1 '-cycl0hexane] -1,1 -dixide 4-amino-6-chloro-1,3-benzenedisulfonamide (17.1 g., 0.06 mole) and 4-cyclohexylcyclohexanone (14.42 g., 0.08 mole) are dissolved in dimethylformamide (90 ml.). Anhydrous potassium fluoride (7.0 g., 0.12 mole) is added and the mixture heated on the steam bath under anhydrous conditions for 20 hours. The solution is poured into 500 ml. of cold water.
  • the liquid is decanted and the residue is triturated in several portions of petroleum ether.
  • the solid that separates is removed by filtration, dried and recrystallized by dissolving in ethanol and slowly adding water giving a 24% yield of 4'-cyclohexyl- 6 chloro 7 sulfamylspiro[1,2,4 benzothiadiazine- 3(4H),1'-cyclohexane]-1,1-dioxide, melting point 252.5- 253.5 C.
  • Step B 4 amino 6 trifluoromethyl 1,3 benzenedisulfonamide (6.4 g., 0.02 mole) and 8-cyclohexyl- 1,4-dioxaspiro[4,5]decane (8.97 g., 0.04 mole) are placed in a 200 ml., 3-necked flask fitted with a thermometer, mechanical stirrer and reflux condenser capped with a drying tube. Dry n-butyl alcohol (70 ml.) and concentrated sulfuric acid (3 drops) are added and the stirrer started. The mixture is heated at 80 C. for 3 hours and then at reflux for 4 hours. The reaction mixture is concentrated at reduced pressure to a volume of 15-20 ml.
  • a final recrystallization is carried out by dissolving the compound in acetone (20 ml.) and adding a small volume of petroleum ether to precipitate a small amount of dark material which is removed by filtration. The filtrate is slowly treated with petroleum ether (220 ml. total) whereby the pure product separates as a white solid, M.P. 256-257 C. The yield of pure compound is 1.50 g. (16%).
  • EXAMPLE 5 4-methyl-6-chloro-7-sulfamylspir0- [1 ,2,4-benz0thiadiazine-3 (4H ,1 '-cycl0hexane] -1,1 -di0xide 4-amino-6-chloro 1,3 benzenedisulfonamide (0.02 mole), 4-methylcyclohexanone (0.08 mole) and p-toluenesulfonic acid (100 mg.) are suspended in p-dioxane (50 ml.). The mixture is refluxed and mechanically stirred for 30 hours and the solution that results is cooled and slowly treated with cold water until crystallization of the prodnot is complete.
  • EXAMPLE 6 By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-chloro-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Exam ple 1, there is obtained a 59% yield of 4'-methyl-6-chloro- 7-sulfamylspiro-[l,2,4 benzothiadiazine-3(4H),1-cyclohexane]-1,l-dioxide which, after recrystallization from 2- methoxyethanol and water, has a melting point of 272- 273 C.
  • EXAMPLE 7 4-methyl-6-triflu0r0methyl-7-sulfamylspir0- [1,2,4-benz0- thiadiazine-3 4H ,1 -cycl0hexane] -1,1-di0xide
  • ketone employed in Example 1 By replacing the ketone employed in Example 1 by an equimolecular quantity of 4-methylcyclohexanone and following substantially the same procedure described in Example 1 there is obtained a 61% yield of 4'-methyl-6- trifluoromethyl-7-sulfamylspiro [1,2,4-benzothiadiazine- 7 3(4H),1'-cyclohexane]-1,1-dioxide which, after recrystallization from methanol and water, melts at 247-249 C.
  • EXAMPLE 8 4 -methyl-5 ,6-dichl0r0-7-sul famylspiro- [1 ,2,.4-benz0thiaa' iazine-3 (4H) ,1 -cyclohexane] -1,1-di0xide
  • EXAMPLE 9 By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-nitro-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 1, there is obtained a 35% yield of 4'-methyl-6-nitro-7-sulfamylspi-ro-[1,2,4-benzothiadiazine 3(4H),l cyclohexane]-1,1-dioxide which, after recrystallization from acetone and water melts at 255-25 6 C.
  • the corresponding 6-amino compound can be prepared either by the process described in Example 9 using equimolecular quantities of 4,6-diamino-1,3-benzenedisulfonamide and the ketone reactants, or by reducing the 6-nitro compound obtained by the process of Example 9.
  • Reduction can be eifected by dissolving the 6-nitro compound in alcohol and shaking in an atmosphere of hydrogen in the presence of platinum until hydrogen absorption ceases.
  • the catalyst can be removed by filtration and the solvents removed by drying in vacuo to give 4-methyl-6-amino-7- sulfamylspiro-[1,2,4-benzothiadiazine-3 (4H) ,1'-cyclohexane]-1,1-dioxide.
  • EXAMPLE 12 4'-ethyl-6-trifluoromethyl-7-sulfamylspiro- [1,2,4-benz0- thiadiazine-3 4H) ,1 '-cycl0hexane] -1,1-di0xide
  • ketone employed in Example 1 By replacing the ketone employed in Example 1 by an equimolecular quantity of 4-ethylcyclohexanone, heating for 24 hours on a steam bath and following substantially the same procedure described in Example 1, there is obtained a 29% yield of 4-ethyl-6-trifluoromethyl-7-sulfamylspiro [1,2,4-benzothiadiazine-3(4H),1'-cyc1ohexane]-1,1-dioxide which, after several recrystallizations from methanol and Water, melts at 261262 C.
  • EXAMPLE 13 By replacing the aminobenzenedisulfonarnide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-chloro-1,3-benzenedisulfon amide and 4-propylcyclohexanone respectively, heating for 20 hours, and following substantially the same procedure described in Example 1, there is obtained a 36% yield of 4'-propyl-6-chloro-7-sulfamylspiro-[1,2,4-benzothiadiazine 3(4H),1'-cyclohexane]-1,1-dioxide which, after recrystallization from acetone and petroleum ether. melts at 245-246 C.
  • EXAMPLE 14 4'-pr0pyl 6 trifluoromethyl 7 sulfamylspiro [1,2,4- benz0thiadiazine-3 (4H),1-cyclohexane] -1,1-di0xide
  • ketone employed in Example 1 By replacing the ketone employed in Example 1 by an equimolecular quantity of 4-propylcyclolhexanone and following substantially the same procedure described in Example 1, there is obtained an 82% yield of 4'-propyl- 6-trifluoromethyl-7-sulfamylspiro-[ 1,2,4-benzothiadiazine- 3(4H),1'-cyclohexane]-1,1-dioxide which, after recrystallization from methanol and water, melts at 225227 C.
  • EXAMPLE 15 4'-is0propyl-6-chloro-7-sz2lfamylspir0- [1,2,4-benz0thz'adiazine-S' (4H) ,1 '-cyclohexane] -1,1-dz'0xide
  • aminobenzenedisulfonamide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6 chloro-1,3-benzenedisulfonamide and 4-isopropylcyclohexanone respectively, heating for 72 hours on a steam bath and treating the solution with 70 ml.
  • EXAMPLE 16 4'-butyl-6-chl0ro-7-sulfamylspiro- [1,2,4-benz0thz'adiazine- 3 (4H ,1 '-cyclohexane] -1,l-di0xia'e
  • aminobenzenedisulfona'rnide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-chloro-l,3-benzenedisulfonamide and 4-butylcyclohexanone respectively, and following substantially the same procedure described in Example tract is washed with water, dried over sodium sulfate, concentrated to a volume of 100 ml. and added to liquid ammonia (250 ml.).
  • Step D Preparation of 4'-methyl-fi-pentafluoroethyl-7- sulfamylspiro [1 ,2,4 benzothiadiazine 3(4H),1-cycl0- hexane]-1,1-dioxide.By replacing the 4-amino-6-chloro- 1,3-benzenedisulfonamide employed in-Example 4 by an equimolecular quantity of 4-amino-6-pentafluoroethyl-l,3- benzenedisulfonamide, heating under reflux for 1% hours, and following substantially the same procedure described in Example 4, there is obtained a 56% yield of'4'-methyl- 6 pentafluoroethyl.
  • EXAMPLE 25 4-methyl-6-br0m0-7-sulfamylspir0- [1,2,4-bemothiadi zin'e-3 (4H) ,1 -cycl0hexane] -1,1-di0xide
  • 4-a.mino-6-bromo-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 2, there is obtained 4-methyl-6-bromo-7-sulfamylspiro-[1,2, 4-benzothiadiazine-3 (4H) ,1'-cyclohexane] -1,l-dioxide.
  • EXAMPLE 26 4 '-methyl-6-meth0xy-7 -sulfamylspir0- [1 ,2,4-benz0- thiadi zine-3 (4H) ,1 -cycl0hexane] -1,1-di0xiae
  • aminobenzenedisulfonamide and the ketone reactants employed in Example 2 by equimolecular quantities of 4-amino-6-methoxy-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 2, there is obtained 4'-methyl-6-methoxy-7-sulfamylspiro 1,2,4 benzothiadiazine 3(4H)-l'-cyclohexane]- 1,1-dioxide.
  • EXAMPLE 27 4 -methyl-6-fluar0-7-sulfamylspiro- [1 ,2,4-benz0- thiadi zine-3 (4H) ,1 -cycl0hexane] -1,1-dioxide
  • aminobenzenedisulfonamide and the ketone reactants employed in Example 2 by equimolecular quantities of 4-amino-6-fiuoro-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 2, there is obtained 4'-methyl-6-fiuoro-7-sulfamylspiro-[1,2, 4-benzothiadiazine-3 (4H 1'-cyc1oheXane] -1 ,l-dioxide.
  • EXAMPLE 28 4'-methyl-6-sulfamyl-7-chlorospiro- [1,2,4-bemothiadi zine-3 (4H) ,1 '-cycl0hexane] -1,1-di0xide
  • EXAMPLE 29 4 '-methyl-7-sul famylspiro- [1,2,4-benz0thiadidzine- 3 (4H) ,1 '-cyclohexane] -1,1-di0xide
  • the dosage of the novel compounds of this invention will vary over a wide range, and for this reason tablets, pills, capsules, powders and the like containing from about 5 mg. to about 200 mg. or more of active ingredient can be made available to the physician for the symptomatic adjustment of the dosage to the individual patient.
  • tablets, pills, capsules, powders and the like containing from about 5 mg. to about 200 mg. or more of active ingredient can be made available to the physician for the symptomatic adjustment of the dosage to the individual patient.
  • each of the compounds can be incorporated in a dosage form similar to those described in the following examples or in other dosage forms suitable for oral or parenteral administration which can be made by well known methods, only a few examples are included herein to illustrate the preparation of representative dosage forms.
  • EXAMPLE 30 Compressed tablet containing 4 mg. of active ingredient Per tablet,
  • the 4' methyl 6 chloro 7 sulfamylspiro [1,2,4- benzothiadiazine-3(4H), 1'-cyclohexane]-l,1-dioxide and the lactose are thoroughly mixed and then reduced to fine particle size.
  • the mixture then is granulated with the starch paste and passed through a No. 10 screen, dried overnight at C. and then dry-granulated through a No. 30 mesh.
  • the cornstarch and magnesium stearate then are added and thoroughly incorporated in the mixture and the tablets compressed on an inch fiat, bevelled scored punch.
  • the tablets produced have a thickness of 2.80 mm. and a hardness of 5% kg. when tested by the Monsanto gun.
  • EXAMPLE 31 Dry filled capsules containing 5 mg. of active ingredient Per capsule, mg. 4' methyl 6 trifluoromethyl 7 sulfamylspiro- [1,2,4 -benzothiadiazine-3(4H), 1'-cyclohexane]- 1,1-dioxide 1 Lactose
  • the 4'-methyl-6-trifiuoromethyl-7-sulfamylspir0-[1,2,4- benzothiadiazine-3 (4H), l'-cycl0hexane]-1,1-dioxide is reduced to a No. 60 powder. Lactose then is passed through a No. 60 bolting cloth onto the powder.
  • the combined in- 1 1 gredients are admixed for 10 minutes and then filled into No. 2 dry gelatin capsules.
  • each of the compounds of this invention can be incorporated in a dosage form similar to those described above or in other dosage forms suitable for oral or parenteral administration which can be prepared by well-known methods, no additional examples are included herein to illustrate the preparation of representative dosage forms.
  • NICHOLAS S. RIZZO Primary Examiner.

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  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
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Description

United States Patent No Drawing. Filed May 8, 1961, Ser. No. 108,298 2 Claims. (Cl. 260-243) This invention is concerned with novel 3,3-spiro-substituted 3,4 dihydro 1,2,4 benzothiadiazine 1,1 dioxides wherein the spiro substitutent is a 6-membered alicyclic ring having at least one aliphatic substituent attached to the 4'-carbon of the spiro structure. The aliphatic substituents(s) advantageously is lower aliphatic having a total of no more than 6 carbon atoms and is either straight chain, branched chain or alicyclic. The 4-aliphatic substituent(s) advantageously is selected either from the straight or branched chain aliphatic radicals derived from a hydrocarbon such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, 1,1- dimethylpropyl, hexyl or any of the various branched chain, 6-carbon aliphatic radicals; or is selected from the alicyclic radicals preferably an aiicyclic radical derived from a hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, the alicyclic structures being either unsubstituted or alkyl substituted but preferably having no more than a total of 6 carbon atoms in the 4'- substituent grouping.
The novel compounds of this invention also contain a sulfamyl substituent attached to the benzenoid moiety of the benzothiadiazine structure and preferably at least one additional substituent selected from halogen or halogen-like radicals, such as chlorine, bromine, fluorine, iodine, trifluoromethyl, trichloromethyl, dichloromethyl and the like; lower alkyl such as methyl, ethyl, propyl and the like or similar alkyl groups having a substitutent, such as a halogen, attached to one or more of the carbons in the alkyl group; lower alkoxy such as methoxy, ethoxy, propoxy and the like; nitro or amino.
The preferred compounds are those wherein the spiro structure is 4-mono-substituted, the sulfamyl substituent is attached to the 7-position of the benzothiadiazine structure and the other substituents are attached preferably to either or both of the 5- and/ or 6-positions of the benzothiadiazine nucleus.
While it is known that 7-sulfamyl-3,4-dihydro-1,2,4- benzothiadiazine-l,l-diox-ide compounds (hydrochlorothiazide and related compounds) possess marked saluretic properties, it was surprisingly discovered that many 4'-aliphatic-3,3-spiro substituted-3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide compounds are markedly more potent saluretic agents than hydrochlorothiazide and some of them possess from 5 to 10 times the potency of their nonspi-ro analogs. The novel compounds of this invention can be administered in dosage forms known to be suitable for the administration of the other benzothiadiazine saluretic agents either alone in the form of pills, capsules, tablets.
and the like or admixed with antihypertensive or other therapeutically effective compounds in a single .dosage form. However, while it is generally necessary to administer 50 mg. of hydrochlorothiazide to effect an enhanced excretion of sodium and chloride ions, a similar enhancement of the sodium and chloride ion excretion can be efiected by some of the novel compounds of this invention by oral administration of 5 or less milligrams of active ingredient. This dosage is far below the toxic dose as measured by acute toxicity studies in mice. For example 4'-methyl-6-chloro-7-sulfamylspiro-[1,2,4benzothiadiazine-3 (4H),l'-cyclohexane]-1,1-dioxide gives an oral ice LD in mice of 2,750 mg./kg., and an intravenous LD of 548 mg./kg., and the intravenous LD in mice of 4'- methyl 6 trifluoromethyl 7 sulfamylspiro [1,2,4- benzothiadiazine 3(4H),l cyclohexane] 1,1 dioxide is 512 mg./k-g. As the novel compounds of this invention are substantially non-toxic, the therapeutic ratio is very great and the possibility of producing any undesirable side efiects is considerably less than with the use of other benzothi-adiazine type saluretic agents which also are known to be safe drugs for use in this type therapy.
The novel compounds of this invenion can be prepared by several methods. One method which has been found very useful in preparing the novel compounds involves reacting the appropriate aminobenzenedisulfonamide and 4-substitu ted cyclohex-anones with moderate heating.
Where feasible, excess ketone can be employed for its solvent properties, although other solvents can be used instead. Some solvents which are found to be suitable include dimethylformamide, dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, and the like.
If it is desired to carry the reaction to completion more quickly, it can be catalyzed with potassium fluoride in dimethylformarnide or with an acid such as sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or other aliphatic or aromatic sulfonic acids in other media.
7 Another very satisfactory method involves reacting the appropriate aminobenzenedisulfonamide and ketal. The ketal can be cyclic in structure or acycylic or in the form of its enol ether which is readily generated from the ketal under acid conditions. The reaction preferably is carried out with moderate heating in the presence of a solvent and a few drops of acid which catalyzes the reaction. Butanol was found to be an entirely satisfactory solvent, though other alcohols as l-pentanol, propanol and the like or an alcohol admixed with other solvents as dioxane, diethylene glycol dimethyl'ether, ethylene glycol dimethyl ether and the like can be used. I
It will be apparent from the above discussion that the novel compounds of this invention can be prepared by reacting the appropriate aminobenzenedisulfonamide with a 4-substituted-cyclohexanone and that said ketone can be replaced by a reactive, function-a1 derivative of the same, such as a ketal or an enol ether, or a ketimine or by a substancewhich under the reaction conditions in question is converted to the ketone, such as the hydrosulfite or cyanohydrin of the ketone, and that the reaction can be effected with or without an added solvent and with or without a catalyst, but preferably with heating.
The preparation of representative compounds ofthis invention is described in more detail in the following examples wherein all melting points reported are decomposition points which are corrected except where otherwise stated and wherein the petroleum ether employed is Merck & Co. Inc.s Benzin, B.P. 30-60 C. Some of the novel compounds of this invention undergo appreciable hydrolysis in hot aqueous media. Recrystallizations involving a water component, therefore, were done at room temperature or below. These substances usually are dissolved in an organic solvent, cooled, stirred and water slowly added. Under these conditions the product often separates in crystalline form with high purity. When nonaqueous solvents are employed, recrystallizations are carried out in the conventional manner using hot solvents.
EXAMPLE 1 4' sec. butyl 6 trifluoromethyl 7 sulfamylspiro- [1,2,4 benzothiadiazine 3(4H),1 cyclohexane1- 1,1-dioxide 4 amino 6 trifluoromethyl 1,3 benzenedisulfonamide (6.4 g., 0.02 mole) and 4-sec.-butylcyclohexanone (6.1 g., 0.04 mole) aredissolved in dimethylformamide (25 ml.) and heated on a steam bath for 48 hours. The reaction mixture is cooled, treated with methanol (100 ml.) and then water (300 ml.) gradually is added with stirring. The aqueous layer is decanted and the residual viscous oily product is triturated with petroleum ether (100 ml). The resulting solid is removed by filtration and dried. This material is dissolved in methanol (25 ml.) and treated with a few milliliters of water, and the small amount of oil that forms is removed by filtration. The filtrate is slowly treated with water (75 ml.) whereby a 71% yield of 4'-sec.-butyl-6-trifluoromethyl-7-sulfamylspiro [1,2,4 benzothiadiazine 3(4H), 1' cyclohexane]-1,1-dioxide is obtained as a pure crystalline product melting at 231.5232.5 C.
Analysis.-Calculated for C H- 'F N O 'S C, 44.82; H, 5.31; N, 9.23. Found: C, 45.04; H, 5.28; N, 9.16.
EXAMPLE 2 4' cyclohexyl 6 chloro 7 sulfamylspiro [1,2,4- benzothiadiazine-3 (4H ,1 '-cycl0hexane] -1,1 -dixide 4-amino-6-chloro-1,3-benzenedisulfonamide (17.1 g., 0.06 mole) and 4-cyclohexylcyclohexanone (14.42 g., 0.08 mole) are dissolved in dimethylformamide (90 ml.). Anhydrous potassium fluoride (7.0 g., 0.12 mole) is added and the mixture heated on the steam bath under anhydrous conditions for 20 hours. The solution is poured into 500 ml. of cold water. The liquid is decanted and the residue is triturated in several portions of petroleum ether. The solid that separates is removed by filtration, dried and recrystallized by dissolving in ethanol and slowly adding water giving a 24% yield of 4'-cyclohexyl- 6 chloro 7 sulfamylspiro[1,2,4 benzothiadiazine- 3(4H),1'-cyclohexane]-1,1-dioxide, melting point 252.5- 253.5 C.
Analysis.-Calculated for C H ClN O S C, 48.25; H, 5.85; N, 9.3-8. Found: C, 48.14; H, 5.64; N, 9.26.
EXAMPLE 3 4' cyclohexyl 6 trifluoromethyl 7 sulfamylspiro- [I,2,4 benzothiadiazine 3(4H),l' cyclohexane]- 1,1-dioxide Step A.-4-cyclohexylcyclohexanone (1 mole), ethylene glycol (1.05 mole), benzene (200 ml.) and p-toluenesulfonic acid (200 mg.) are placed in a flask fitted with a modified Dean-Stark constant water separator attached to a reflux condenser. The reaction mixture is vigorously refluxed until aqueous distillate no longer distilled and separated. The 8-cyclohexyl-1,4-dioxaspiro[4.5]decane, B.P. 117 C. at 0.4 mm. pressure, M.P. 42.5-43.5" C., is isolated by careful fractionation of the reaction mixture.
Analysis.Calculated for C H O C, 74.95; H, 10.75. Found: C, 75.16; H, 10.68.
Step B.4 amino 6 trifluoromethyl 1,3 benzenedisulfonamide (6.4 g., 0.02 mole) and 8-cyclohexyl- 1,4-dioxaspiro[4,5]decane (8.97 g., 0.04 mole) are placed in a 200 ml., 3-necked flask fitted with a thermometer, mechanical stirrer and reflux condenser capped with a drying tube. Dry n-butyl alcohol (70 ml.) and concentrated sulfuric acid (3 drops) are added and the stirrer started. The mixture is heated at 80 C. for 3 hours and then at reflux for 4 hours. The reaction mixture is concentrated at reduced pressure to a volume of 15-20 ml. The addition of petroleum ether gives a solid which is removed by filtration and dried. This crude product (10.1 g.) is dissolved in ethyl acetate (about 15 ml.) and slowly treated with petroleum ether. The crystalline solid that separates (6.5 g.) is dissolved in methanol (about 25 ml.), treated with decolorizing charcoal and filtered. The filtrate is stirred and slowly treated with water to incipient precipitation. Upon standing, 2 g. (21%) of nearly pure 4'- cyclohexyl 6 trifluoromethyl 7 sulfamylspiro[1,2,4- benzothiadiazine 3(4H),'1' cyclohexane] 1,1 dioxide separates, M.P. 245- 2465 C. A final recrystallization is carried out by dissolving the compound in acetone (20 ml.) and adding a small volume of petroleum ether to precipitate a small amount of dark material which is removed by filtration. The filtrate is slowly treated with petroleum ether (220 ml. total) whereby the pure product separates as a white solid, M.P. 256-257 C. The yield of pure compound is 1.50 g. (16%).
Analysis.Calculated for C H C1N O S C, 47.38; H, 5.44; N, 8.73. Found: C, 47.22; H, 5.67; N, 8.62.
EXAMPLE 4 4-methyl-6-chl0r0-7-sulfamylspiro-[1,2,4-benzothiadiazz'ne-3 (4H) ,1 -cyclohexane]-1-dioxide 4-amino-6-chloro-1,3-benzenedisulfonamide (5.7 g., 0.02 mole), 4-methylcyclohexanone (60 ml.) and ptoluenesulfonic acid (50 mg.) are refluxed under anhydrous conditions for 15 minutes. After cooling, the reaction mixture is poured into petroleum ether (450 ml.), the upper layer is decanted and the residual oil triturated with more petroleum ether. The solvent is decanted and the residue treated with warm methanol ml.). A solid (2.9 g.) forms which is removed by filtration and the filtrate treated with cold water to give another 4 g. of product. The combined yield of 4'-methyl-6-chloro 7 sulfamylspiro [1,2,4 benzothiadiazine- 3(4H),1-cyclohexane]-1,1-dioxide is 6.9 g. (91%). This material is dissolved in warm 2-methoxyethanol (25 ml.), cooled, stirred and very slowly treated with cold water (240 ml.) to give a 70% yield of 4'-methyl-6-chloro-7- sulfamylspiro-[ 1,2,4-benzothiadiazine-3 4H 1'-cyclohexane]-1,1-dioxide in the form of large white crystals, M.P. 272-273 C.
Analysis.-Calculated for C H ClN O S C, 41.10; H, 4.78; N, 11.06. Found: C, 40.99; H, 4.93; N, 10.96.
EXAMPLE 5 4-methyl-6-chloro-7-sulfamylspir0- [1 ,2,4-benz0thiadiazine-3 (4H ,1 '-cycl0hexane] -1,1 -di0xide 4-amino-6-chloro 1,3 benzenedisulfonamide (0.02 mole), 4-methylcyclohexanone (0.08 mole) and p-toluenesulfonic acid (100 mg.) are suspended in p-dioxane (50 ml.). The mixture is refluxed and mechanically stirred for 30 hours and the solution that results is cooled and slowly treated with cold water until crystallization of the prodnot is complete. The solid material is collected on the filter and dried to give 4'-methyl-6-chloro-7-sulfamylspiro- [1,2,4-beuzothiadiazine-3 (4H),1- cyclohexane]-1,1- dioxide.
EXAMPLE 6 By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-chloro-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Exam ple 1, there is obtained a 59% yield of 4'-methyl-6-chloro- 7-sulfamylspiro-[l,2,4 benzothiadiazine-3(4H),1-cyclohexane]-1,l-dioxide which, after recrystallization from 2- methoxyethanol and water, has a melting point of 272- 273 C.
Analysis.-Calculated for C H ClN O S C, 41.10; H, 4.78; N, 11.06. Found: C, 40.77; H, 4.92; N, 11.24.
EXAMPLE 7 4-methyl-6-triflu0r0methyl-7-sulfamylspir0- [1,2,4-benz0- thiadiazine-3 4H ,1 -cycl0hexane] -1,1-di0xide By replacing the ketone employed in Example 1 by an equimolecular quantity of 4-methylcyclohexanone and following substantially the same procedure described in Example 1 there is obtained a 61% yield of 4'-methyl-6- trifluoromethyl-7-sulfamylspiro [1,2,4-benzothiadiazine- 7 3(4H),1'-cyclohexane]-1,1-dioxide which, after recrystallization from methanol and water, melts at 247-249 C.
Analysis.--Calculated for C H F N O S C, 40.67; H, 4.39; N, 10.16. Found: C, 40.78; H, 4.49; N,.10.09.
EXAMPLE 8 4 -methyl-5 ,6-dichl0r0-7-sul famylspiro- [1 ,2,.4-benz0thiaa' iazine-3 (4H) ,1 -cyclohexane] -1,1-di0xide EXAMPLE 9 By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-nitro-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 1, there is obtained a 35% yield of 4'-methyl-6-nitro-7-sulfamylspi-ro-[1,2,4-benzothiadiazine 3(4H),l cyclohexane]-1,1-dioxide which, after recrystallization from acetone and water melts at 255-25 6 C.
Analysis.--Calculated for C H N O S C, 40.61; H, 4.72; N, 14.57. Found: C, 40.27; H, 4.64; N, 14.32.
The corresponding 6-amino compound can be prepared either by the process described in Example 9 using equimolecular quantities of 4,6-diamino-1,3-benzenedisulfonamide and the ketone reactants, or by reducing the 6-nitro compound obtained by the process of Example 9. Reduction can be eifected by dissolving the 6-nitro compound in alcohol and shaking in an atmosphere of hydrogen in the presence of platinum until hydrogen absorption ceases. The catalyst can be removed by filtration and the solvents removed by drying in vacuo to give 4-methyl-6-amino-7- sulfamylspiro-[1,2,4-benzothiadiazine-3 (4H) ,1'-cyclohexane]-1,1-dioxide.
EXAMPLE 10 4,6-dimethyl-7-sulfamylspirw [1,2,4-benz0thiadiazine- 3(4H),1'-cyclohexane]-1,1-di0xide quantities of 4-amino-6-chloro-1,3 benzenedisulfonamide and 4-ethylcyclohexanone respectively, heating for 20 hours on a steam bath, and following substantially the,
same procedure described in Example 1, there is obtained a 56% yield of 4'-ethy1-6-chloro-7-sulfamylspiro-[1,2,4- benzothiadiazine 3(4H),1'-cyclohexanone]-1,1-di0xide,
6 a which, after crystallization from acetone and petroleum ether melts at 248249 C.
Analysis.-Calculated for C H ClN O S C, 42.68; H, 5.12; N, 10.67. Found: C, 43.16; H, 5.20; N, 10.58.
EXAMPLE 12 4'-ethyl-6-trifluoromethyl-7-sulfamylspiro- [1,2,4-benz0- thiadiazine-3 4H) ,1 '-cycl0hexane] -1,1-di0xide By replacing the ketone employed in Example 1 by an equimolecular quantity of 4-ethylcyclohexanone, heating for 24 hours on a steam bath and following substantially the same procedure described in Example 1, there is obtained a 29% yield of 4-ethyl-6-trifluoromethyl-7-sulfamylspiro [1,2,4-benzothiadiazine-3(4H),1'-cyc1ohexane]-1,1-dioxide which, after several recrystallizations from methanol and Water, melts at 261262 C.
Analysis.Calculated for C H F N O S C, 42.14; H, 4.72; N, 9.83. Found: C, 42.45; H, 4.89; N, 9.76.
EXAMPLE 13 By replacing the aminobenzenedisulfonarnide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-chloro-1,3-benzenedisulfon amide and 4-propylcyclohexanone respectively, heating for 20 hours, and following substantially the same procedure described in Example 1, there is obtained a 36% yield of 4'-propyl-6-chloro-7-sulfamylspiro-[1,2,4-benzothiadiazine 3(4H),1'-cyclohexane]-1,1-dioxide which, after recrystallization from acetone and petroleum ether. melts at 245-246 C.
Analysis.Calculated for C H ClN O S C, 44,16'
H, 5.44; N, 10.30. Found: C, 44.08;H, 5.33; N, 10.21.
EXAMPLE 14 4'-pr0pyl 6 trifluoromethyl 7 sulfamylspiro [1,2,4- benz0thiadiazine-3 (4H),1-cyclohexane] -1,1-di0xide By replacing the ketone employed in Example 1 by an equimolecular quantity of 4-propylcyclolhexanone and following substantially the same procedure described in Example 1, there is obtained an 82% yield of 4'-propyl- 6-trifluoromethyl-7-sulfamylspiro-[ 1,2,4-benzothiadiazine- 3(4H),1'-cyclohexane]-1,1-dioxide which, after recrystallization from methanol and water, melts at 225227 C.
Analysis-Calculated for C H F N O S C, 43.52; H, 5.02; N, 9.52. Found: C, 43.93; H, 5.34; N, 9.39.
EXAMPLE 15 4'-is0propyl-6-chloro-7-sz2lfamylspir0- [1,2,4-benz0thz'adiazine-S' (4H) ,1 '-cyclohexane] -1,1-dz'0xide By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6 chloro-1,3-benzenedisulfonamide and 4-isopropylcyclohexanone respectively, heating for 72 hours on a steam bath and treating the solution with 70 ml. of acetic acid and sufiicient water to cause incipient crystallization there is obtained a 53% yield of 4'-isopropyl-6-chloro-7-sulfamylspiro-[1,2,4-benzothiadiazine-3(4H),1-cyclohexane]-1,1-dioxide which, after recrystallization from acetone and petroleum ether melts at 259-260 C.
Analysis.Calculated for C H ClN O S C, 44.16; H, 5.44; N, 10.30. Found: C, 44.56; H, 5.30; N, 10.19.
EXAMPLE 16 4'-butyl-6-chl0ro-7-sulfamylspiro- [1,2,4-benz0thz'adiazine- 3 (4H ,1 '-cyclohexane] -1,l-di0xia'e By replacing the aminobenzenedisulfona'rnide and the ketone reactants employed in Example 1 by equimolecular quantities of 4-amino-6-chloro-l,3-benzenedisulfonamide and 4-butylcyclohexanone respectively, and following substantially the same procedure described in Example tract is washed with water, dried over sodium sulfate, concentrated to a volume of 100 ml. and added to liquid ammonia (250 ml.). The solid that forms upon evaporation of the volatile material is triturated with hot benzene (two 100 ml. portions), dried and recrystallized twice from water to give 19.7 g. (56%) of 4-amino-6-pentafluoroethyl-l,3-benzenedisulfonamide, M.P. 242.5243 C.
Analysis.- Calculated for C H F N O S :v C, 26.02; H, 2.18; N, 11.38; S,. 17.91. Found: C, 26.59; H, 2.29; N, 11.26; S, 17.50.
(Step D) Preparation of 4'-methyl-fi-pentafluoroethyl-7- sulfamylspiro [1 ,2,4 benzothiadiazine 3(4H),1-cycl0- hexane]-1,1-dioxide.By replacing the 4-amino-6-chloro- 1,3-benzenedisulfonamide employed in-Example 4 by an equimolecular quantity of 4-amino-6-pentafluoroethyl-l,3- benzenedisulfonamide, heating under reflux for 1% hours, and following substantially the same procedure described in Example 4, there is obtained a 56% yield of'4'-methyl- 6 pentafluoroethyl. 7-sulfamylspiro-[1,2,4-benzothiadiazine-3 (4H),1'-c'yclohexane]-1,1-dioxide which, after recrystallization from acetic acid and water, melts at 222- 223.5 C.
Analysis.Calculated fOI' C15H18F5N3O4S2: C, 38.87; H, 3.91; N, 9.07. Found: C, 39.05; H, 4.18; N, 8.90.
EXAMPLE 24 4',4-dimethyl-6-chloro-7-sulfamylspiro- [1,2,4-benzethiadiwzine-l (4H) ,1 -cyclohexane] -1, I -dioxide By replacing the ketone employed in Example 2 by an equimolecular quantity of 4,4-dimethylcyclohexanone and following substantially the same procedure described in Example 2 there is obtained 4,4'-dimethyl-6-chloro-7- sulfamylspiro [1,2,4 benzothiadiazine-3 (4H),l-cyclohexane]-l,1-dioxide.
EXAMPLE 25 4-methyl-6-br0m0-7-sulfamylspir0- [1,2,4-bemothiadi zin'e-3 (4H) ,1 -cycl0hexane] -1,1-di0xide By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 2 by equimolecular quantities of 4-a.mino-6-bromo-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 2, there is obtained 4-methyl-6-bromo-7-sulfamylspiro-[1,2, 4-benzothiadiazine-3 (4H) ,1'-cyclohexane] -1,l-dioxide.
EXAMPLE 26 4 '-methyl-6-meth0xy-7 -sulfamylspir0- [1 ,2,4-benz0- thiadi zine-3 (4H) ,1 -cycl0hexane] -1,1-di0xiae By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 2 by equimolecular quantities of 4-amino-6-methoxy-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 2, there is obtained 4'-methyl-6-methoxy-7-sulfamylspiro 1,2,4 benzothiadiazine 3(4H)-l'-cyclohexane]- 1,1-dioxide.
EXAMPLE 27 4 -methyl-6-fluar0-7-sulfamylspiro- [1 ,2,4-benz0- thiadi zine-3 (4H) ,1 -cycl0hexane] -1,1-dioxide By replacing the aminobenzenedisulfonamide and the ketone reactants employed in Example 2 by equimolecular quantities of 4-amino-6-fiuoro-1,3-benzenedisulfonamide and 4-methylcyclohexanone respectively, and following substantially the same procedure described in Example 2, there is obtained 4'-methyl-6-fiuoro-7-sulfamylspiro-[1,2, 4-benzothiadiazine-3 (4H 1'-cyc1oheXane] -1 ,l-dioxide.
EXAMPLE 28 4'-methyl-6-sulfamyl-7-chlorospiro- [1,2,4-bemothiadi zine-3 (4H) ,1 '-cycl0hexane] -1,1-di0xide By replacing the aminobenzenedisulfon-amide and the ketone reactants employed in Example 2 by equimolecular EXAMPLE 29 4 '-methyl-7-sul famylspiro- [1,2,4-benz0thiadidzine- 3 (4H) ,1 '-cyclohexane] -1,1-di0xide By replacing the aminobenzenedisulfonamide employed in Example 1 by an equimolecular quantity of 4-amino- 1,3-benzenedisulfonamide and following substantially the same procedure described in Example 1 there is obtained 4' methyl 7 sulfamylspiro [1,2,4 benzothiadiazine- 3-(4H), l-cyclohexane]-l,l-dioxide, M.P. 24724'9 C.
Analysis.Caculated for C H N O S C, 45.20; H, 5.54; N, 12.16. Found: C, 45.20; H, 5.57; N, 12.09.
The dosage of the novel compounds of this invention will vary over a wide range, and for this reason tablets, pills, capsules, powders and the like containing from about 5 mg. to about 200 mg. or more of active ingredient can be made available to the physician for the symptomatic adjustment of the dosage to the individual patient. As each of the compounds can be incorporated in a dosage form similar to those described in the following examples or in other dosage forms suitable for oral or parenteral administration which can be made by well known methods, only a few examples are included herein to illustrate the preparation of representative dosage forms.
EXAMPLE 30 Compressed tablet containing 4 mg. of active ingredient Per tablet,
The 4' methyl 6 chloro 7 sulfamylspiro [1,2,4- benzothiadiazine-3(4H), 1'-cyclohexane]-l,1-dioxide and the lactose are thoroughly mixed and then reduced to fine particle size. The mixture then is granulated with the starch paste and passed through a No. 10 screen, dried overnight at C. and then dry-granulated through a No. 30 mesh. The cornstarch and magnesium stearate then are added and thoroughly incorporated in the mixture and the tablets compressed on an inch fiat, bevelled scored punch. The tablets produced have a thickness of 2.80 mm. and a hardness of 5% kg. when tested by the Monsanto gun.
EXAMPLE 31 Dry filled capsules containing 5 mg. of active ingredient Per capsule, mg. 4' methyl 6 trifluoromethyl 7 sulfamylspiro- [1,2,4 -benzothiadiazine-3(4H), 1'-cyclohexane]- 1,1-dioxide 1 Lactose The 4'-methyl-6-trifiuoromethyl-7-sulfamylspir0-[1,2,4- benzothiadiazine-3 (4H), l'-cycl0hexane]-1,1-dioxide is reduced to a No. 60 powder. Lactose then is passed through a No. 60 bolting cloth onto the powder. The combined in- 1 1 gredients are admixed for 10 minutes and then filled into No. 2 dry gelatin capsules.
As each of the compounds of this invention can be incorporated in a dosage form similar to those described above or in other dosage forms suitable for oral or parenteral administration which can be prepared by well-known methods, no additional examples are included herein to illustrate the preparation of representative dosage forms.
While the above examples describe the preparation of certain compounds which are illustrative of the novel compounds of this invention, and certain specific dosage forms suitable for administering the novel compounds and certain processes by which the novel compounds of this invention can be prepared, it is to be understood that the invention is not to be limited to the specific compounds described in the examples or by the specific reaction conditions described for the preparation of the compounds or by the specific ingredients included in the pharmaceutical preparations, but is to be understood to embrace variations and modifications thereof which fall within the scope of the appended claims.
What is claimed is:
1. 4' methyl 6 chloro 7 sulfamylspiro [1,2,4- benzothiadiazine-3 (4H) 1'-cyclohexane] -1,1-dioxide.
2. 4' methyl 6 trifiuoromethyl 7 sulfamylspiro- [1,2,4-benzothiadiazine-3 (4H), l-cyclohexane] -1,1-dioxide.
References Cited UNITED STATES PATENTS 5/1966 Lund et a1 260-243 OTHER REFERENCES .Derwent Belgian Patent Reports, vol. 58B, p. C12 (1959).
Derwent Commonwealth Patent Reports, vol. 186, GP3A, p. 4 (1960).
Holdrege et al.: Journal American Chemical Society, vol. 81, pp. 4807-10 (1959).
Wertheim: Textbook of Organic Chemistry, pp. 763- 764 (1945).
NICHOLAS S. RIZZO, Primary Examiner.

Claims (1)

1. 4'' - METHYL - 6 - CHLORO - 7 - SULFAMYLSPIRO-(1,2,4BENZOTHIADIAZINE-3 (4H), 1'' -CHYCLOHEXANE) -1,1-DIOXIDE. 2. 4'' - METHYL - 6 - TRIFLUOROMETHYL - 7 - SULFAMYLSPIRO(1,2,4-BENZOTHIADIAZINE-3(4H), 1'' -CYCLOHEXANE)-1,1-DIOXIDE.
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