DE1470019B - 7 sulfamyl 3,4 dihydro 1,2,4 benzo thiadiazine 1,1 dl oxide Compounds and process for their preparation - Google Patents

Description

The invention relates to 7-sulfamyl-3,4-di hydro-1, 2,4-benzothiadiazine-1,1-dioxide compounds of the general formula I

in which R ^{1 is} the methyl or ethyl group and R ^{2 is} a chlorine atom or the trifluoromethyl or nitro group or R ^{1 is} the sec-butyl group and R ^{2 is} a chlorine atom. These compounds are prepared by adding a compound of the general formula II in a manner known per se

in which R ^{2 has} the above meaning, with a sub-substituted cyclohexanone of the general formula III

R ¹

in which R ^{1 has} the above meaning .

The reaction is carried out with moderate heating. If feasible, excess ketone can be used because of its solvent properties, but other solvents can be used instead. Ak solvents are particularly suitable dimethylformamide, dioxane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether.

If it is desired to complete the reaction more quickly, it can be catalyzed with potassium fluoride in dimethylformamide or with an acid, for example sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or other aliphatic or aromatic sulfonic acids, in other media.

. In the preparation of the compounds according to the invention, the 4-substituted cyclohexanone of the general formula III can be replaced by a reactive functional derivative of this ketone, for example a ketal or an enol ether or a ketimine or a substance, which is subject to the reaction conditions in question is converted into the ketone, like the hydrosulfite or cyanohydrin of the ketone. The reaction can be carried out with or without added solvent and with or without a catalyst, but preferably with heating.

It is known that 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide compounds (Hydrochlorothiazide and related compounds) possess remarkable saluretic properties. The new compounds according to the invention are more effective saluretics than hydrochlorothiazide, such as results from the following comparative experiments: Rats with a weight of about 150 g will Maintained on a sodium- and potassium-free diet overnight. They are then given 5 ml of water

to drink. I ¹ I ₂ hours later, the test animals are injected intraperitoneally with the compound to be tested in the form of an aqueous suspension (5 ml). The total volume of urine excreted in the course of 5 hours and the total content of sodium, potassium and chloride in the urine are then measured.

16 rats each received 6-chloro-7-sulfamyl 2 H - 3,4 - dihydro -1,2,4 - benzothiadiazine -1,1-dioxide (Hydrochlorothiazide) in amounts of 0.16 and 0.64 mg / kg. In each case 8 rats received the Ver-II to be tested bindings in the quantities specified above.

The relative potencies compared to hydrochlorothiazide were based on the four measured values, namely the volume of excreted Urine and the measured values of sodium, potassium and chloride.

(When testing the compound of Examples 4 and 7, the amounts used were 0.01 and 0.04 mg / kg. When testing the compound of Example 8, the substances were given orally.)

The acute toxicities were determined as follows: White female Carworth CF ₁ mice weighing between 18 and 20 g were used in the toxicity determinations. The test substance is injected into the tail vein of the test animals at a rate of 0.05 ml / min. Immediately after the drug is administered, the mice are observed and any evidence of intoxication is noted. The occurrence of symptoms of poisoning and the time of death are determined for each mouse. The mice are observed for 7 days. At the end of this time, the number of mice killed in each individual group is determined, and the lethal dose (LD ₅₀ ) is determined according to the method as described in Biometrics, Vol. 8, No. 3, September 1952, p. 249 bis 252, is calculated.

The following table gives the relative potencies and acute toxicity data.

60

65

3 R ' R ² dose 4th N / A K Cl Vol. Relative
Really Acute mg / kg
intra- ml sameness toxicity
in mice Connection of example peritoneal Excretion in milliequivalents (N / A) LD ₅₀ 1.11 2.85 884 Hydrochlorothiazide methyl Cl 1.61 3.29 6th (HCTZ) / ' 0.16 0.57 1.45 548 1 to 3 0.64 0.97 2.68- 0.16 1.13 2.74 (HCTZ) methyl CF ₃ 0.64 1.71 3.80 6th 0.16 0.57 1.45 512 4th 0.64 0.97 2.68 0.16 0.04 0.28 0.36 (HCTZ) methyl NO ₂ 0.64 0.07 0.52 0.62 32 4th 0.01 1.17 1.27 3.02 42 > 400 5 ethyl Cl 0.04 1.42 1.45 3.45 47 3.6 (HCTZ) 0.16 0.46 0.78 1.42 49 > 400 6th 0.64 1.21 1.32 2.73 43 0.16 0.04 0.35 1.03 48 (HCTZ) ethyl CF ₃ 0.64 0.07 0.45 1.08 33 3 0.01 1.45 1.14 2.68 39 > 400 7th sec-butyl CI 0.04 0.78 0.85 1.77 76 2 (HCTZ) 0.1 *) 98 > 400 8th 0.1 (HCTZ)

*) per os.

The invention is illustrated by the following examples, in which the preparation of typical representatives of the compounds according to the invention is described. In these examples, all melting points given are decomposition points which, unless otherwise stated, are corrected; the petroleum ether used in the examples is Merck & Co., Inc.'s gasoline boiling range 30 to 6O ⁰ C. Some of the new compounds of the invention hydrolyze significantly in hot aqueous media. Since water is involved as a component in recrystallizations, the recrystallizations are then carried out at room temperature or below. These substances are usually dissolved in an organic solvent, cooled and stirred, and water is slowly added. Under these conditions the product often separates into crystalline forms. Form in high purity. If non-aqueous solvents are used, the recrystallizations are carried out in the customary manner, using hot solvents.

example 1

4'-methyl-6-chloro-7-sulfamyl-spiro-

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

_ 3,1'-cyclohexane] 1,1-dioxide

55

60

5.7 g (0.02 mol) of 4-amino-6-chloro-1,3-benzene disulfonamide, 60 ml of 4-methylcyclohexanone and 50 mg of p-toluenesulfonic acid are added under anhydrous conditions Heated under reflux for 15 minutes. After cooling, the reaction mixture is added to 450 ml Pour petroleum ether, the top layer is decanted, and the remaining oil is with rubbed in more petroleum ether. The solvent is decanted off and the residue with 100 ml treated with warm methanol. 2.9 g of a solid substance are formed which are filtered off and the filtrate is treated with cold water, forming another 4 g of product. The total yield 4'-methyl-6-chloro-7-sulfamyl-spiro [2H-3,4-dihydro-O ^ -benzothiadiazinO.r -cyclohexane-jljl-dioxide is 6.9 g (91%). This material is dissolved in 25 ml of warm 2-methoxyethanol, cooled and stirred and treated very slowly with 240 ml of cold water. 4'-Methylo-chloro ^ -sulfamyl-spiro ^ H ^ -dihydro-l ^ -benzothiadiazine-3, l'-cyclohexane] l-dioxide is obtained in 70% yield in the form of large white crystals from F. = 272 to 273 ° C.

Analysis: C ₁₃ H ₁₈ ClN ₃ O ₄ S ₂ .

Calculated ... C 41.10, H 4.78, N 11.06%;
Found ... C 40.99, H 4.93, N 10.96%.

. B is ρ ie 1 2
4'-methyl-6-chloro-7-sulfamylspiro [2H-3,4-dihydro-1,2,4-benzothiadiazine-
3, Γ-cyclohexane] 1,1-dioxide

0.02 mol of 4-amino-6-chloro-1,3-benzenedisulphonamide, 0.08 mol of 4-methylcyclohexanone and 100 mg of p-toluenesulphonic acid are suspended in 50 ml of p-dioxane. The mixture is refluxed for 30 hours and stirred mechanically, and the resulting solution is cooled and slowly treated with cold water, until the crystallization of the product has ended. The solid material is collected on a filter and dried. This gives 4'-methyl-6-chloro-7-sulfamyl-spiro [2 H-3,4-dihydro-1,2,4-benzothiadiazine-3,1 '-cyclohexane] 1,1 -dioxide.

Example 3

4'-methyl-6-chloro-7-sulfamyl-

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

3,1'-cyclohexane] 1,1 -dioxide

0.02 mol of 4-AmJnO-O-ChIor-1,3-benzenedisulfonamide and 0.04 mol of 4-methylcyclohexanone are dissolved in 25 ml of dimethylformamide and heated on a steam bath for 48 hours. The reaction mixture is cooled and treated with 100 ml of methanol: then 300 ml of water are gradually added with stirring. The aqueous layer is decanted off and the viscous oily product that remains is triturated with 100 ml of petroleum ether. The remaining solid substance is filtered off and dried. This material is dissolved in 25 ml of methanol and treated with a few milliliters of water. The small amount of oil that forms is removed by filtration. The filtrate is slowly treated with 75 ml of water, giving 4'-methyl-6-chloro-7-sulfamyl-spiro [2 H-3,4-dihydro-1,2,4-benzothiadiazine-3 , 1'-cyclohexane] 1,1-dioxide, which has a melting point of 272-273 ⁰ C after recrystallization from 2-methoxyethanol and water.

Analysis: C ₁₃ H ₁₈ ClN ₃ O ₄ S ₂ .

Calculated ... C 41.10, H 4.78, N 11.06%:
found ... C 40.77, H 4.92. N 11.24%.

Example 4

4'-methyl-6-trinuomethyl-7-sulfamyl-

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

3,1'-cyclohexane] 1,1 -dioxide

Analysis: C ₁₃ H ₁₈ N ₄ O ₆ S ₂ .

Calculated ... C 40.61, H 4.72, N 14.57%:
Found ... C 40.27, H 4.64, N 14.32%.

15th

20th

25th

30th

35

If you work practically in the same way as described in Example 3, it replaces that in the example 3 aminobenzene disulfonamide derivative used by an equimolar amount of 4-amino-6-trifluoromethyl-1,3-benzene disulfonainide, 4'-methyl-6-trifluoromethyl-7-sulfamyl-spiro [2H-3,4-dihydro-1,2,4-benzothiadiazine-3,1 is obtained in this way in a 61% yield '-cyclohexane] 1,1 -dioxide, which after recrystallization from methanol and water at 247 to 249 ° C melts.

Analysis: C ₁₄ H ₁₈ N ₃ O ₄ S ₂ .

Calculated ... C 40.67, H 4.39, N 10.16%:
Found ... C 40.78, H 4.49, N 10.09%.

Example 5

4'-methyl-6-nitro-7-sulfamyl-

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

3,1'-cyclohexane] 1,1-dioxide

If you work practically in the same way as described in Example 3, but replaces that in the example 3 aminobenzenesulfonamide reactant used by an equimolar amount 4-Amino-6-nitro-1,3-benzenedisulfonamide, 4'-methyl-6-nitro-7-sulfamyl is obtained in 35% yield - spiro [2 H - 3,4 - dihydro -1,2,4 - benzothiadiazine-3,1'-cyclohexane] 1,1-dioxide, which melts at 255 to 256 ° C after recrystallization from acetone and water.

Example 6

4'-ethyl-6-chloro-7-sulfamyl-

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

3,1'-cyclohexane] 1,1-dioxide

If the ketone used in Example 3 is replaced by an equimolar amount of 4-ethylcyclohexanone, heated on a steam bath for 20 hours and worked in practically the same manner as described in Example 3, 4'-ethyl is obtained in 56% yield - 6 - chloro - 7 - sulfamyl - spiro [2 H - 3,4-dihydro-1,2,4 - benzothiadiazine -3,1'-cyclohexanone] 1,1-dioxide, which after crystallization from acetone and petroleum ether at 248 melts up to 249 ° C.
Analysis: C ₁₄ H ₂₀ ClN ₃ O ₄ S ₂ .

Calculated ... C 42.68, H 5.12, N 10.67%:
Found ... C 43.16, H 5.20, N 10.58%.

Example 7

4'-ethyl-6-trifluorinethyl-7-sulfamyl-

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

3,1'-cyclohexane] 1,1 -dioxide

If one uses the aminobenzene disulfonamide and ketone reaction components used in Example 3 by equimolar amounts of 4-amino-6-trifluoromethyl-1,3-benzenedisulfonamide or 4-ethylcyclohexanone replaced, heated for 24 hours on a steam bath and practically following the same procedure as works in Example 3, 4 '- ethyl - 6 - trifluoromethyl 1 - 7 - sulfamyl - spiro- [2] is obtained in 29% yield H - 3,4 - dihydro -1,2,4 - benzothiadiazine - 3.1 '- cyclohexane] 1,1-dioxide, which after several recrystallizations from methanol and water at 261 to 262 ° C melts. .

Analysis: C ₁₅ H ₂₀ F ₃ N ₃ O ₄ S ₂ .

Calculated ... C 42.14, H 4.72, N 9.83%: found . .. C 42.45, H 4.89, N 9.76%. By S pi el 8

4'-sec-butyl-6-chloro-7-sulfamylspiro [2 H-S ^ -dihydro-l ^^ - benzothiadiazine-

3,1'-cyclohexane] 1,1 -dioxide

If the ketone used in Example 3 is replaced by an equimolar amount of 4-sec-butylcyclohexanone, heated for 21 hours and the solution treated with 100 ml of acetic acid and enough water to cause crystallization to begin, 25% are obtained Yield of 4'-sec-butyl-6-chloro-7-sulfamyl-spiro [2H-3,4-dihydro-1,2,4-benzothiadiazine-3,1'-cyclohexane] 1,1 -dioxide, the after recrystallization from acetone and petroleum ether at 248 to 249 ° C melts.
Analysis: C ₁₆ H ₂₄ ClN ₃ O ₄ S ₂ .

Calculated ... C 45.54, H 5.73, N 9.96%:
found ... C 45.83, H 5.73, N 9.89%.

Claims (6)

Patent claims: 1. 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadi Azine -1,1-dioxide compounds of the general formula I. 65 H ₂ NO ₂ S in which R 'denotes the methyl or ethyl group and R ² denotes a chlorine atom or the trifluoromethyl or nitro group or R ¹ denotes the sec-butyl group and R ² denotes a chlorine atom. 2. 4 '- methyl - 6 - chloro - 7 - sulfamyl - spiro- ^ dihdl y ^ J
hexane] l, l-dioxide. 3. 4 '- methyl - 6 - trifluoromethyl - 7 - sulfamylspiro [2H - 3,4 - dihydro - 1,2,4 - benzothiadiazine-3,1 '-cyclohexane] 1,1 -dioxide. 4. 4'-Ethyl-6-chloro-7-sulfamy] spiro [2 H-3,4-dihydro-1,2,4-benzothiadiazine -3, Γ -cyclohexane] -1,1-dioxide. 5.4'-methyl-6-nitro-7-sulfamy] spiro [2H-3,4-dihydro-1,2,4-benzothiadiazine-3,1 '-cyclohexanol dioxide. 6. Process for the preparation of the compounds according to Claims 1 to 5, characterized in that that in a known manner a compound of the general formula II in which R ^{2 has} the above meaning with a substituted cyclohexanone of the general formula III / ν o = \ y ~ R ¹ in in which R ^{1 has} the above meaning. 109524/370