DE1229097B - Process for the preparation of 7-sulfamyl-3, 4-dihydro-1, 2, 4-benzothiadiazine-1, 1-dioxydes which are disubstituted in the 3-position - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

German class: 12 ρ -10/01

Number: 1229 097

File number: L 33937IV d / 12 ρ

Filing date: August 10, 1959

Opening day: November 24, 1966

It has been found that the previously unknown, 3-disubstituted 7-sulfamyl-3,4-dihydrol, 2,4-benzothiadiazine-1,1-dioxyde the general formula

H ₂ NO ₂ S

in which Ri is a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl. Methyl, methoxy, nitro or amino group, R ₂ a methyl group and R ₃ an acetyl group or a low molecular weight alkyl, haloalkyl, carbalkoxy or carbalkoxymethyl group or R ₂ and R3 together with the carbon atom to which they are attached, form a cycloaliphatic radical which can contain a double bond and / or be substituted by halogen atoms and / or low molecular weight alkyl or carbalkoxy radicals, in the case of oral or parenteral administration in the human body a much stronger saluretic effect than that in terms of the Na: K ratio known diuretic. 6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide and are therefore valuable drugs.

The invention relates to a process for the production of these new dioxides, which consists in that you have a 2,4-disulfamyl aniline compound ier general formula

NH ₂ SO ₂ NH ₂

in which Ri has the meaning given above, with a ketone of the general formula

R ₂ -CO-R ₃

in which R ₂ and R 3 have the meaning given above, or are reacted with a ketal, an enol ether, a hydrosulfite or a cyanohydrin of such a ketone and, if appropriate, subsequently reducing a nitro group present in the reaction product to an amino group in a manner known per se.

Process for the production of in 3-position &
disubstituted 7-sulf amyl-3,4-dihydrol, 2,4-benzothiadiazine-l, l-dioxydes

Applicant:

L0vens kemiske Fabrik ved A. Kongsted,

Ballerup (Denmark)

Representative:

Dr. Dr. J. Reitstötter, patent attorney,

Munich 15, Haydnstr. 5

Named as inventor:

Dipl.-Chem. Frantz Lund, Kongens Lyngby;
Dipl.-Chem. Wagn oils Godtfredsen,
Copenhagen-Br0nsh0j (Denmark)

Claimed priority:

Great Britain of 13 August 1958 (26 063),
of September 2, 1958 (28 199), of September 26, 1958 (30 798), of November 12, 1958 (36 437), of November 25, 1958 (37 997), of January 21, 1959 (2314),
dated June 18, 1959 (21 027) - -

example 1

A solution of 3.2 g of 5-trifluoromethyl-2,4-disulfamyl-aniline in 50 ml of acetone is refluxed for about hours after the addition of a catalytic amount of p-toluenesulfonic acid, whereupon most of the acetone still present is distilled off. Water is added to the distillation residue, and the crystals which separate out are recrystallized from ethanol-water. The thus obtained 3,3-dimethyl-6-trifiuormethyl-7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, l-di- oxide melts at 222.5 to 223.5 ⁰ C. Yield 57%. If the acetone used is replaced by a mixture of 10 ml of 2-methoxy-1-propylene and 20 ml of dioxane, the procedure gives the same compound.

Example 2

A solution of 3.0 g of 5-nitro-2,4-disulfamylai "■ 'iTi 50 ml of acetone is added after adding a catalyst

609 728,391

lytic amount of p-toluenesulfonic acid heated to boiling under reflux for about 15 hours. The crystals separated out by adding water to the cooled reaction mixture are filtered off and recrystallized from methanol-water. The thus obtained 3,3 - dimethyl - 6 - nitro - 7 - sulfamyl - 3,4-dihydro-l, 2,4-benzothiadiazine-l, 1-dioxide melting at 233 to 233.5% 50 ⁰ C. Yield.

Examples 3 to 7

. ίο

In the manner described in the preceding examples are substituted with others Anilines produced the following additional compounds.

3. When using 5-chloro-2,4-disulfamyl-

This becomes aniline after recrystallization from acetone

Water at 230-231 ⁰ C melting 3,3-dimethyl-6-chloro-7-sulfamyl-3,4-dihydro-l, 2,4-obtained benzothiadiazine 1,1-dioxide. Yield 80%.

4. In the application of 5-bromo-2,4-disulfamylanilin is the melting after recrystallization from acetone-hexane at 228-229 ⁰ C 3,3-dimethyl-6-bromo-7-sulfamyl-3,4-dihydro-l , 2,4-benzothiadiazine-1,1-dioxide obtained. Yield 54%.

5. If application of 5-methoxy-2,4-disulfamylanilin is the melting after recrystallization from methanol at 240 to 240.5 ⁰ C 3,3-dimethyl-6-methoxy-7-sulfamyl-3,4-dihydro-l , 2,4-benzothiadiazine-l, l-dioxide obtained. Yield 75%.

6. When using 5-methyl-2,4-disulfamylaniline, this is after recrystallization from acetone- Ether, 3,3-dimethyl-6, melting at 243 to 244 ° C - methyl - 7 - sulfamyl - 3,4 - dihydro -1,2,4 - benzo thiadiazine-l, l-dioxide obtain. Yield 60%.

7. In the application of 2,4-Disulfamyl-aniline that is melting after recrystallization from methanol-water at 242 to 242.5 ⁰ C 3,3-dimethyl-7-sulfamyl-3,4-dihydro-1,2,4 -benzo thiadiazine-1,1-dioxide obtained. Yield 51%.

B e i s ρ i e 1 3

⁴ °

A solution of 2.9 g of 5-chloro-2,4-disulfamylaniline in 75 ml of methyl ethyl ketone is added after addition a catalytic amount of p-toluenesulfonic acid heated to boiling under reflux for about 15 hours. The reaction mixture is evaporated to dryness in vacuo and then recrystallized from methanol-water. The 3-methyl-3-ethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide melts at 231.5 to 233 ° C.

Example 9

In the manner indicated in Example 8, when using 5 - trifluoromethyl - 2,4 - disulfamylaniline instead of 5-chloro-2,4-disulfamyl-aniline, 3-methyl-3-ethyl-6-trifluoromethyl-7-sulfamyl-3,4-dihydro-1,2,4- benzo- thiadiazine-l, l-dioxide obtained.

B e i s ρ i e 1 10,

A solution of 3.2 g of 5-trifluoromethyl-2,4-disulfamyl-aniline in 25 ml of dioxane is treated with a catalytic amount of p-toluenesulfonic acid and with 5 ml of chloroacetone, whereupon the mixture is refluxed for about 15 hours . The cooled reaction mixture is mixed with methylene chloride and hexane, and the substance precipitated thereby is recrystallized twice from methanol-water. The thus obtained 3-methyl-3 - chloromethyl - 6 - trifluoromethyl - 7 - sulfamyl - 3,4 - dihydro-1,2,4-benzothiadiazine-l, 1-dioxide melts with decomposition at 227 to 227.5 ⁰ C.

Example 11

A solution of 3.0 g of 5-nitro-2,4-disulfamylaniline and 5 ml of chloroacetone in 35 ml of dioxane becomes after adding a catalytic amount of p-toluenesulfonic acid for about 15 hours at reflux to the Heated to boiling, and the resulting reaction mixture is evaporated to dryness in vacuo. Of the obtained dry residue is dissolved in ethyl acetate, and the solution is treated with a mixture of methylene chloride and hexane added. The precipitated substance is filtered off, and the filtrate is im Evaporated to dryness in vacuo and then dissolved in methanol and treated with water. That 3-methyl-3-chloromethyl-6-nitro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide which precipitates as a result melts at 238.5 to 239.5 ° C.

Example 12

A solution of 3.2 g of 5-trifluoromethyl-2,4-disulfamyl-aniline and 5 ml of ethyl pyruvate in 25 ml of dioxane is added after the addition of a catalytic Amount of p-toluenesulfonic acid heated to boiling under reflux for about 15 hours. That im received Dioxane present in the reaction mixture is distilled off in vacuo. The distillation residue is with Triturated chloroform and the resulting crystals are recrystallized from ethyl acetate-hexane. The -J-methyl-S-carbethoxy-o-trifluoromethyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide obtained in this way melts at 191 to 194 ° C.

Example 13

A mixture of 3.2 g of 5-trifluoromethyl-2,4-disulfamyl-aniline, 50 ml of ethyl acetoacetate and a catalytic amount of p-toluenesulfonic acid is heated on the steam bath for about 15 hours, after which the unconsumed ethyl acetoacetate is removed from the reaction mass by vacuum distillation . The distillation residue is triturated with methylene chloride and the resulting crystals are recrystallized from dioxane-chloroform-hexane. The S-methyl-S-carbäthoxymethyl-o-trifluoromethyl-7-sulfamyl-3,4-dihydro-l thus obtained, 2,4-benzothiadiazine-1,1-dioxide melting at 150 to 152 ⁰ C.

Example 14

A solution of 5.9 g of 5-nitro-2,4-disulfamylaniline in 50 ml of ethyl acetoacetate is refluxed for about 15 hours after the addition of a catalytic amount of p-toluenesulfonic acid and then evaporated to dryness in vacuo. The dry residue is treated with methylene chloride and hexane and recrystallized first from ethanol (99%) and then from methanol-water. The S-methyl-S-carbäthoxymethyl-6-nitro-7-sulfamyl-3,4-dihydro-l thus obtained, 2,4-benzothiadiazine-1,1-dioxide melting at 218-219 ⁰ C.

Example 15

3.2 g of 5-trifluoromethyl-2,4-disulfamyl-aniline and a few crystals of p-toluenesulfonic acid are dissolved in 20 ml Cyclopentanone dissolved, and the solution is refluxed for 24 hours. The ab-

cooled reaction mixture is poured into 150 ml of petroleum ether (boiling range 105 to 120 ⁰ C), and the thus precipitated oily substance is brought by stirring for crystallization. The deposited crystals are washed with petroleum ether and, because of their dark color, further purified by suspension in ethanol, whereupon they are recrystallized from ethanol. The 6 - trifluoromethyl - 7 - sulfamyl - 3.4 - dihydrol ^^ - benzothiadiazine-ll-dioxide-S-spirocyclopentane melts at 232.5 to 234 ° C.

Example 16

A solution of 4 g of 5-chloro-2,4-disulfamyl-aniline in 35 ml of cyclopentanone is after the addition of a catalytic Amount of p-toluenesulfonic acid heated to boiling under reflux for 6 hours. The received A mixture of methylene chloride and hexane is added to the reaction mixture, and the precipitated thereby Product is made by dissolving in hot dioxane and adding a mixture of methylene chloride and hexane were reprecipitated to the cooled solution and then recrystallized from ethanol (99%). The 6-chloro-7-sulfamyl-3,4-dihydro-l ^^ - benzothiadiazine-l-l-dioxide-S-spirocyclopentane obtained in this way melts at 234 ° C. Yield 58%.

Example 17

A mixture of 5.0 g of 5-bromo-2,4-disulfamylaniline and 30 ml of cyclohexanone is refluxed for 24 hours and then cooled. The precipitated crystals are filtered off, washed with ether, dried and recrystallized from methanol. The thus obtained 6-bromo-7-sulfamyl-3,4-dihydro-1,2.4-benzothiadiazine-3-spirocyclohexane 1.1 -dioxyd melts at 281-283 ⁰ C. Yield 62%).

Examples 18-22

In the manner indicated in Example 17, using other 5-substituted 2,4-disulfamyl-anilines as 5-bromo-2,4-disulfamyl-aniline, the following additional compounds are prepared.

7 - - 18. In the application of 5-trifluoromethyl-2.4-disulfamyl-aniline the melting after recrystallization from ethanol at 261-262 ⁰ C is 6-trifluoromethyl sulfamyl - 3,4 - dihydro -1.2.4 - benzothiadiazine -1.1 - Dioxyd - 3 - spirocyclohexane obtained. Yield 81%).

19. When application of 5-chloro-2,4-disulfamylanilin the melting after recrystallization from ethanol at 283.5 to 285 ⁰ C 6-chloro-7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine is -l, l-dioxide-3-spirocyciohexane obtained. Yield 70%.

20. In application of 5-methyl-2,4-disulfamylanilin wi * J the melting after recrystallization from ethanol-hexane at 261.5 to 263 ⁰ C 6-methyl-7-sulfamyl-3,4-dihydro-1,2 , 4-benzothiadiazine-1,1-dioxide-3-spirocyclohexane. Yield 48%.

21. When using 5-methoxy-2,4-disulfamylaniline, this becomes water after recrystallization from dimethylformamide 6 - methoxy - 7 - sulfamyl - 3,4 - dihydro-1,2,4- melting at 268.5 to 269.5 ° C benzothiadiazine -1,1-dioxide - 3 - spirocyclohexane.

22. When application of 5-nitro-2,4-disulfamylanilin is the melting after recrystallization from formamide-water at ⁰ C 261.5 6-Nitro-7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine -l, l-dioxide-3-spirocyclohexane obtained.

Example 23

A solution of 4.0 g of 5-trifluoromethyl-2,4-disulfamyl-aniline in 20 ml of 2-methyl-cyclohexanone, after the addition of a catalytic amount, p-toluenesulfonic acid is added Heated to boiling under reflux for 24 hours. The cooled reaction mixture 200 ml of hexane are added and the product precipitated thereby is dissolved in 25 ml of propanol. When the solution is evaporated, unused starting material crystallizes first and then a product which is recrystallized from methanol. The 6-trifluoromethyl-7-sulfamyl-3,4-dihydro obtained in this way -1,2,4 - benzothiadiazine -1,1 - dioxide - 3 - spiror- (2'-methylcyclohexane) melts at 232 to 234 ° C.

Example 24

A solution of 4 g of 5-bromo-2,4-disulfamyl-aniline in 20 ml of 2-methyl-cyclohexanone is refluxed for about 15 hours after the addition of a catalytic amount of p-toluenesulfonic acid. The unconsumed 5-bromo-2,4-disulfamylaniline precipitated by cooling the reaction mixture is filtered off, and hexane is added to the filtrate until the reaction product has precipitated. The precipitated product is reprecipitated by dissolving in propanol and adding a mixture of methylene chloride and hexane and then recrystallized from methanol-water. The thus-obtained o-bromo ^ S ^ -dihydro--sulfamyl-l ^ -benzothiadiazin -1,1 - dioxide - 3 - spiro - Γ - {Τ - methylcyclohexane) melts at 231 to 233 ⁰ C.

Example 25

A solution of 6.4 g of 5-trifluoromethyl-2,4-disulfamyl-aniline and 4.6 g of l-diethoxy ^ -chloro-cyclohexane in 20 ml of dioxane is after addition of a catalytic amount of p-toluenesulfonic acid for 24 hours heated to boiling under reflux for a long time. The cooled reaction mixture is poured into 200 ml of hexane, and the product precipitated thereby is recrystallized twice from methanol-water. That so obtained o-trifluoromethyl ^ -sulfamyl ^^ - dihydro-1,2,4-benzothiadiazin-1, l-Dioxyd-3-spiro-1 '- (2'-chlorocyclohexane) melts with decomposition at 218 to 219 ° C.

Example 26

A solution of 5.8 g of 5-chloro-2,4-disulfamylaniline and 4.6 g of II-diethoxy-2-chlorocyclohexane in 50 ml of dioxane is refluxed for about 15 hours after addition of a catalytic amount of p-toluenesulfonic acid. The cooled reaction mixture is mixed with hexane, and the substance precipitated thereby is recrystallized after reprecipitation by dissolving in methanol and adding water to the solution from dimethylformamide-water. The 6-chloro-7-sulfamyl-3,4-dihydro -1,2,4-benzothiadia obtained in this way; in -1,1 - dioxide - 3 - spirol '- (2'-chlorocyclohexane) melts at 221 to 223 ⁰ C.

Example 27

A solution of 6.4 g of 5-trifluoromethyl-2,4-disulfamyl-aniline and 2.9 g of 4-chloro-cyclohexanone in 20 ml After adding a catalytic amount of p-toluenesulfonic acid, dioxane is refluxed for 20 hours

heated to boiling. The cooled reaction mixture is poured into 300 ml of hexane, and the substance precipitated thereby is recrystallized first from methanol-methylene chloride-hexane and then from methanol-water. The 6-trifluoromethyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-3-spiro-1 '- (4'-chlorocyclohexane) obtained in this way melts at 217 bis with decomposition 218 ⁰ C.

Example 28

A solution of 5.8 g of 5-chloro-2,4-disulfamylaniline and 2.9 g of 4-chloro-cyclohexanone in 50 ml of diethylene glycol dimethyl ether is heated to 125 ° C. for about 15 hours after addition of a catalytic amount of p-toluenesulfonic acid. The cooled reaction mixture is mixed with hexane, and the substance precipitated thereby is reprecipitated by dissolving in methanol and adding a mixture of methylene chloride and hexane to the solution and then recrystallized from methanol-water. The 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-3-spiro-1 '- (4'-chlorocyclohexane) obtained in this way melts at 219.5 to 220.5 ⁰ C.

Example 29

A solution of 5.8 g of 5-chloro-2,4-disulfamylaniline and 15 ml of diacetyl in 50 ml of dioxane becomes after adding a catalytic amount of p-toluenesulfonic acid Heated to boiling for 5 hours under reflux and the reaction mixture is in vacuo evaporated to dryness. The dry residue is dissolved in ethyl acetate and added with hexane reprecipitated and then from methanol-water recrystallized. The 3-methyl-3-acetyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide obtained in this way melts with decomposition at 246 to 247 ° C. Yield 50%.

The saluretic effect of a number of compounds prepared according to the above examples was determined by animal experiments with rats. The experiments were carried out with groups of three animals each carried out with several groups for each test substance. Each test animal received a single one Dose of a solution of the substance to be tested administered orally. The urine separation in the first 6 hours after application of the substance was measured and the content of the urine of sodium, Potassium and chlorine ions determined. Average values for the excretion of sodium, potassium and chlorine ions in microequivalents in the 6 hours per Group of three animals calculated for each substance. The results obtained are in the following Table compiled.

dose number Calculated average Vlikroequivalents K ' Cl- substance mg / kg the animal values in for the elimination of 271 '85 (No. des p. O. groups 248 135 Example) to ever
three N / A· 229 76 Animals 120 268 236 control 165 control 100 control 12th 188 control 3

substance
(No. des
5 examples) dose
mg / kg
po 5.00 number
the animal
groups
to ever
three Calculated average
values in microequivalents
for the elimination of K ⁺ he 1.25 Animals Na ⁺ 248 149 (Average value) 5.00 151 438 1016 1 1.25
5.00 766 334 671 * 2 5.00 6th 469 432 690 3 0.625 615 278
384 322
537 4th 1.25
5.00 6th
6th 325
453 504 921 ¹⁵ 9 5.00 663 368 380 10 0.078 6th 445 313
463 432
921 13th 1.25 6th
6th 458
777 455 1043 ²⁰ 15 1.25 734 230 262 17th 1.25 3 313 535 1105 18th 1.25 6th 883 511 1358 19th 0.313
0.625 6th 1105 526 938 ²⁵ 20 0.625 3 688 485 873 22nd 0.156 6th 697 308
471 400
733 23 6th
6th 348
675 367 372 ³⁰ 25 6th 468 607 563 27 6th 511

* The average value was only calculated from experiments with three groups of three animals each.

The mean values determined in the same way for the excretion of sodium, potassium and chlorine ions in microequivalents by 5.00 mg / kg 6 - chlorine - 7 - sulfamyl -1,2,4 - benzothiadiazine-l, l-dioxide were Na ⁺ = 243, K ⁺ = 345 and Cl- = 414.

Claims (1)

Claim: Procedure for. Preparation of 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxydes which are disubstituted in the 3-position the general formula H2NO2S wherein Ri is a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, methyl, Methoxy, nitro or amino group, R2 a methyl group and R3 an acetyl group or denotes a low molecular weight alkyl, haloalkyl, carbalkoxy or carbalkoxymethyl group or R2 and R3 together with the carbon atom to which they are attached form one Form cycloaliphatic radical containing a double bond and / or by halogen atoms and or low molecular weight alkyl groups or carbalkoxy radicals can be substituted, characterized in that one 9 10 z, 4 "disulfaniyl-aniline compound of the general with a ketone of the general formula ^Formula R ₂ -CO-R ₃ in R2 and R3 the meaning given above "Have NH2 5, or with a ketal, an enol ether, a hydrosulfite or a cyanohydrin H2NO2S - ^ J> - SO2NH2 converts such ketone and optionally then reduces a nitro group present in the reaction product in a manner known per se to one in which Ri has the meaning given above, to amino group. When the application was announced, seven priority documents were displayed. 609 728/391 11.66 © Bundesdruckerei Berlin