NO144278B - PROCEDURE AND APPARATUS FOR TESTING ROOM SHOES - Google Patents

Description

Process for the production of therapeutically effective 7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxides.

It is known that certain 3,3-spiro-substituted 7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides have diuretic properties of the same order of magnitude as the known diuretic agent hydrochlorothiazide. This applies, for example, to compounds such as 6-chloro-7-3ulfamyl-spiro-[1,2,4-benz othiadiazine-3 (4H)-C5^chlorohexane]-1, 1-

dioxyd, 6-trifluoromethyl-7-sulfamyl-spiro-1,2,4-benzothiadiazine-3(H)-cyclohexane]-1,1-dioxyd, 2'-methyl-6-trifluoromethyl-7-sulfamyl-spiro-[ 1, 2,4-benzothiadiazine-3 (4H), 1'-cyclohexane]-1,-1-dioxyd and 3'-methyl-6"-chloro-7-sulfamyl-spiro-[1,2,-4- benzothiadiazine-3(4H), 1*-cyclohexane]-1,1-dioxyd, which is known from British patent document No. 863,474-

It has now surprisingly been shown that certain closely related compounds, where the spiro substituent is eh 4<1->lower alkyl substituted cyclohexyl group, have significantly stronger diuretic action than the hydrochlorothiazide and the known .3,3-spiro substitutedp; benzo-thiadiazine compounds.

By means of the invention, a method is thus provided for the production of new, therapeutically effective 7-sulfamyl-spiro-[1,2,|4-benzothiadiaziri-3(4H),1'-cyclohexane]-1,1-dioxides of the general formula:

where ,R is chlorine or trifluoroethyl, and R-^ is lower alkyl, according to which a 4-araino-1,3-benzenedisulfonamide of the general formula: where R has the meaning given above, is reacted with a substituted cyclohexane of the general formula:

where R-j^ has the meaning indicated above, or a functional derivative thereof.

The table below shows a comparison between the diuretic action of two of the new compounds and the action of hydrochlorothiazide and the above-mentioned four compounds known from British Patent Document No. 863,474.

The data in the right-hand column of the table is taken from British patent document no. 863,474, while the data in the left-hand column has been obtained by for-sbk:utfort by the patent holder. Hydrochlorothiazide is given the reference value 1. The compound 3<1->methyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1- dioxyd, which has a somewhat stronger diuretic effect than hydrochlorothiazide and the other three known compounds listed in the table, no data are given in the British patent document. It can be seen from the table that the two new compounds have almost 6 times stronger action than hydrochlorothiazide and likewise far stronger action than the compounds known from the British patent document.

The new compounds have low toxicity and are therefore compatible with therapeutic use. Thus gives, e.g. 4'-methyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1*-cyclohexane]-1,1-dioxide by oral application to mice en ID^ Q of 2,750 mg per kg body weight and with intravenous use an LD^q of 548 mg per kg body weight. Furthermore, 4'-methyl-6-trifluoromethyl-7-sulfamyl-spiro-[<1>,2,4-benzpthiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide gives by intra-venbs application to mice an LD^q of 512 mg per kg body weight.

The new compounds are thus practically non-toxic, and can preferably be used in very large doses, and the possibility that these compounds will cause unwanted side effects is significantly less than when using other diuretics of benz<p>thia -the diazine type, which are also known as safe agents for this form of therapy.

The doses given by the new compounds vary within wide limits. Thus, tablets, pills, capsules, powders and the like can contain from 5 mg to 200 mg or more of the active compounds.

The new 7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]T1,1-dioxides are prepared as mentioned above by a suitably substituted 4-amino-1,3- benzenedisulfonamide is reacted with a suitable 4-substituted cyclohexanone or a functional derivative thereof. The reaction is carried out under moderate heating. When possible, an excess of the ketone can be used, due to its action as a solvent, however, other solvents can also be used. Among the solvents that were found to be suitable are dimethylformamide, dioxane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether.

When it is desired to accelerate the reaction, it can be catalyzed with potassium flupride in dimethylformamide 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.

As a functional derivative of the 4-substituted cyclohexanone, a ketal, an enol ether or a ketimine or a compound which, under the prevailing reaction conditions, is converted to such a ketone, such as e.g. the hydrosulphite or cyanohydrin of the ketone. The reaction is carried out with or without added solvent and with or without the use of a catalyst, but preferably under heating. If, for example, a ketal or an enol ether of such is used, the reaction is preferably carried out under moderate heating in the presence of a solvent and a few drops of an acid which catalyzes the reaction. Butanol is a fully satisfactory solvent, but other alcohols such as 1-pentanol, propanol or the like or an alcohol mixed with other solvents can also be used. such as dioxane, diethylene glycol diethyl ether, ethylene glycol dimethyl ether or the like.

Some of the compounds which are produced by the analogous method according to the invention are hydrolyzed to a remarkable extent in hot, aqueous media. Recrystallization ions in which water is present were therefore carried out at room temperature or lower temperatures. In general, the substances are dissolved in an organic solvent, after which the resulting solution is cooled, reformed and water is added slowly. Under such conditions, the product is excreted in many cases in crystalline form with high purity. When non-aqueous solvents are used, the recrystallization is carried out in a conventional manner using hot solvents.

The examples below illustrate the production of some of the new compounds. In the examples, all stated melting points are cleavage points which have been corrected when not otherwise stated. The petroleum ether used in the examples boils in the range 30-60°C.

Example 1

Preparation of 4'-sec.butyl-6-trifluoromethyl-7-sulfamyl-spiro-11,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd

6.4 g of 4-Amino-6-trifluoromethyl-1,3-benzenedisulfonamide

(0.02 mol) and 6.1 g of 4-sec.butylcyclohexanone (0.04 mol) are dissolved in 25 ml of dimethylformamide, and the solution is heated on a steam bath for 48 hours. It is then cooled, treated with 100 ml of ethanol and then gradually added with 300 ml of water while stirring. The aqueous layer is decanted off, and the remaining viscous, oily substance is triturated with 100 ml of petroleum ether. The solid substance thus obtained is separated by filtration and filtered. It is then dissolved in 25 ml of methanol, and the resulting solution is treated with a few ml of water, after which the small amount of oily substance that is formed is removed by filtration. The filtrate is slowly added to 75 ml of water, whereby 4'-sec.butyl-,6-trifluprmethyl-7-sulfamyl-spirb-[1,2*,4-benzithiadiazine-3(4H) is obtained with a 71% yield; 1'-cyclohexane]-1,1-dioxide as a pure crystalline product with a melting point of 231.5 - 232.5°C.

Analysis: calculated for C-^I^F^N^O^^: . Found: ....

Example 2

Preparation of 4*-methyl-6-chloro-7-sulfamyl-spiro-[1j2,-4tbenzothia--diaznr3(4H), 1'T-cyclohexane]-1,1-dioxyd

5.7 g of 4-Aniin6-6-chloro-1,3-benzenedisulfonamide (0.02 mol), 60 ra<l >4-methylcycl'ohéxanone and 50 mg of p-toluenesulfonic acid are heated under reflux under anhydrous conditions for 15 minutes. The reaction mixture is then cooled and poured into 450 ml of petroleum ether. The upper layer is decanted off, and the remaining oily substance is triturated with petroleum ether. The solvent is decanted off, and the residue is treated with 100 ml of hot methanol. Thereby, 2.9 g of a solid is formed, which is removed by filtration. The filtrate is treated with cold water, whereby a further 4 g of the product is obtained. The total yield of ■4'-methyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzo-thiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide is 6, 9 g, equivalent

91% of the theoretical. This compound is dissolved in 25 ml of hot 2-methoxyethanol, and the solution is cooled, stirred and cold water (240' ml) is added very slowly, whereby 4'-methyl-6-chloro-7-sulfamyl- spiro-[1,2,4-bezothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide in the form of large white crystals with a melting point of 272 - 273°C

Analysis: calculated for C^jH-^gClN-jO^^:

Example 3

Preparation of 4'-methyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzo-thiadiazine-3(4H),1'-cyclohexane]-j,1-dioxyd

0.02 mol of 4-amino-6-chloro-1,3-benzenedisulfonamide, 0.08 mol of 4-methylcyclohexanone and 100 mg of p-toluenesulfonic acid. 1.50 ml of p-dioxane are suspended. The mixture is heated under reflux and stirred with a mechanical stirrer for 30 hours, after which the resulting mixture is cooled and cold water is slowly added until the crystallization of the product is complete. The solid is collected on a filter and filtered, thereby obtaining 4 '-methyl-6-chloro-7-sulfamyl:-spiro.[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd.

Example 4

Preparation of 4,-methyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzo-thiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd

By using, instead of the aminobenzenedisulfonamide used in example 1, equimolecular amounts of 4-amino-6-chloro-1,3-benzenedisulfonamide, respectively 4-methylcyclohexanone-, and proceeding essentially as described in example 1, one with 59 yield.. 4'-methyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd. After recrystallization from 2-methoxyethanol and water, this compound has a melting point of 272 - 273°C.

Analysis: calculated for C1-jH1qC1NjO^S2:

Example 5

Preparation of 4'-methyl-6-trifluoromethyl-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd

If, instead of the ketone used in example 1, an equimolecular amount of 4-methylcyclohexanone is used and the procedure is essentially as described in example 1, 4<1->methyl-6-trifluoromethyl-7 is obtained with 61 <jt yield -sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd. After recrystallization from methanol and water, this compound melts at 247,249°C.

Analysis: calculated for ci4Hi8<F>3<N>3°4<S>2<:>

Example 6

Preparation of 4'-ethyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzo-thiadiazine-3(4H),1'-cyclohexane}-1,1-dioxyd

By using, instead of the aminobenzenedisulfonamide and ketone used in example 1, equimolecular amounts of 4-amino-6-chloro-1,3-benzenedisulfonamide, respectively 4-ethylcyclohexånone, heating for 20 hours in a steam bath and otherwise proceeding essentially as described in example 1, 4'-ethyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexanone]-1,1 is obtained in 56% yield -dioxyd which, after recrystallization from acetone and petroleum ether, melts at 248 - 249°C.

Analysis: calculated for C^E^qCIN-j-O^S,, :

Example 7

Preparation of 4N-ethyl-6-trifluoromethyl-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3-(4H),1'-cyclohexane]-1,1-dioxyd

By instead of the ketone used in example 1: using equimolecular amounts of 4-ethylcyclohexanone, heating for 24 hours in a steam bath and then proceeding essentially as described in example 1, one obtains 4 '-ethyl- 6-rtrifluoromethyl-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd, which after several recrystallizations from methanol and water melts at 261 - 262° C.

Analysis: calculated for C15^<2>0^3^4^2<:>

Example 8

Preparation of 4'-propyl-6-chloro-7-sulfaaryl-apiro-[1,2,4-benzo-thiadiazine-3(4H),1'-cyclohexane]-!,1-dioxyd

By instead of the aminoberizendi sulfonamide and ketone used in Example 1 using equimolecular amounts of 4-amino-6-chloro-1,3-benzenedisulfonamide, respectively. 4-propylcyclohexanone, heat for 20 hours and otherwise proceed as described in example 1, obtaining 4'-propyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzo-thiadiazine-3 (4H),1'-cyclohexane]-1,1-dioxide, which after oracrystallization from acetone and petroleum ether melts at 245 - 246°C.

Analysis: calculated for C^R^ClN^O^Sg:

Example 9

Preparation of 4'-propyl-6-trifluoromethyl-7-s.ulfamyl-sprio-[1,2,4-benzothiadiazine-3(4H),1,'-cyclohexane]-!,1-dioxyd

By using an equimolecular amount of 4-propyl-cyclohexanone instead of the ketone used in example 1 and proceeding in the same way as described in example 1, one obtains 4'-propyl-6- trifluoromethyl-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H), 1'-cyclohexane]-1,1-dioxyd, which after recrystallization from methanol and water melts at 225 - 227°C

Analysis: calculated for C-^I^FjNjO^Sg'

Example 10

Preparation of 4'-isopropyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzo-thiadiazine-3(4H),1'-cyclohexane]-1,1-dioxyd

By instead of the aminobenzenedisulfonamide and ketone used in example 1 using equimolecular amounts of 4-amino-6-chloro-1,3-benzenedisulfonamide, respectively 4-isopropyl-cyclohexanone, heating for 72 hours in a steam bath, treating the solution with 70 ml of acetic acid and a sufficient amount of water to produce incipient crystallization, 4'-isopropyl-6-chloro-7-sulfa-myl-sprio-[1,2,4-benzothiadiazine-3(4H) is obtained with a yield of 53%, 1'-cyclohexane]-1,1-dioxide, which after recrystallization from acetone and petroleum ether melts at 259 - 260°C.

Analysis: calculated for C-^H^ClNjO^Sg:

Example 11

Preparation of 4'-butyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothia-diazine-3(4H). 1 '- cyclohexane]-!^ 1- dloxyd

By instead of the aminobenzenedisulfonamide and ketone used in example 1, adding equimolecular amounts of 4-amino-6-chloro-1,3-benzenedisulfanamide, respectively 4-butylcyclohexanone and proceeding essentially as described in example 1 , one obtains with 40 # yield 4'-butyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide, which after recrystallization from acetone and petroleum ether melts at 216.5 217.5°C.

Analysis: calculated for C-^H^ClNjO^^:

Example 12

Preparation of 4'-sec.butyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzo-thidiazine-3(4H),1'-cyclohexane]-!,1-dioxyd

By using, instead of the thyminobenzenedisulfonamide used in Example 1, an equimolecular amount of -4-Hmino-6-chloro-1,3-benzenedisulfonamide, heating for 21 hours, treating the solution with 100 ml of acetic acid and sufficient water to produce incipient crystallization, 4'-sec.butyl-6-chloro-7-sulfamyl-spiro-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1- dioxide, as after recrystallization from acetone and petroleum ether. melts at 248 - 249°C

Analysis: calculated for C-LgH2^ClN^0^S2:

Example 13

Preparation of 4'-tert.butyl-6-chloro-7-sulfamyl-apiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-!,1-dioxyd

By instead, for the aminobenzenedisulfonamide and ketone used in example 1, using an equimolecular amount of 4-amino-6-chloro-1,3-benzenedisulfonamide, respectively 4-tert.butylcyclohexanone, heating for 44 hours on a steam bath and treating the solution with 200 ml of acetic acid is obtained. with 30 1> yield 4'-tert.butyl^6-klbr-• 7-sulfamyl-apiro-[ 1,2,4-benzothiadiazine-3(4H) > 1'.-cyclohexaneJvL, 1-dioxyd which melts at 276 - 277°C.

Analysis: calculated for C^gR^ClNjO^^:

Example 14

Preparation of 4'-tert.butyl-6-trifluoromethyl-7-sulfamy-spi:eo-[1>2,4-benzothladiazine-3(4H),1'-cyclohexanyl-1.1-dloxyd';

6.4 g. 4-Amino-6-trifluoromethyl-1,3-benzenedisulfonamide ■

(0.02 mol) and. 9.3 g of 4-tert.butylcyclohexanone (0.06 mol) are dissolved

in 30 ml of dimethylformamide, and the resulting solution heated

in a steam bath for 45 hours. Its volume is then reduced to 15 ml and it is mixed with 100 ml of ether. The solution in ether is extracted with 50 ml of 10% aqueous sodium hydroxide solution. After neutralization

sation of the alkaline solution with 6N hydrochloric acid, mar;ri méd i;

69% yield 4'-tert.butyl-6-trifluoromethyl-7-sulfamyl-spiro-[1,2,4-benzo thiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide which, after recrystallization from acetone and petroleum ether f -'melts at 252.5-254°C

Analysis: calculated for C-^^^F^N-jO^^'

Example 15

Preparation of 4'-isopentyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H), 1'-ey. clohexan]- ltl- dioxide - ■-

By instead of the aminobenzenedisulfonamide and ketone used in example 1, using equimolecular amounts of 4-amino-6-chloro-1,3-benzenedisulfonamide, respectively 4-isopentylcyclohexanone, heating for 18 hours on a steam bath and treating the solution with 80 ml acetic acid and then with 375 ml of water, 4'-isopentyl-6-chloro-7-sulfamyl-spiro-[1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]- is obtained with 39 1° yield 1,1-dioxide, which after recrystallization from ethanol and water melts at 240 - 242°C.

Analysis: calculated for C-^H^ClN^O^Sj:

Bkseapel 16 \\ ;\ y-

Preparation of 4'-(1,1-dimethylpropyl-6-chloro-7-3ulfarayl-spiro-[1,2f 4-bangothiadlazln-3(4H).^-oyclohexane]-1,1-dioxyd

In addition, the aminobenzene disulfonamide and ketone used in example 1 were used in equimolecular amounts of 4-amino-6-chloro-1,3-banana-diulfonamide, respectively 4-(1,1-dimethylpropyl)-cyclohexanone, heating for 24 hours on a steam bath^ treating with 100 ml of acetic acid and then with water until crystallization begins, 4'-(1,1-dimethylpropyl)-6-chloro-7-sulfamyl-spiro-[ 1,2,4-benzbthiadiazin-3(4H),1'-cyclohexan]-1,1-dioxyd,- which after recrystallization from acetone and petroleum ether melts at 262-263°C

Analysis: calculated for ci7H26C1N3°4S2:

Claims (1)

Process for the production of therapeutically effective 7-sulfamyl-spiro-[],2,4-benzothiadiazine-3(4H),1'-cyclohexane]-1,1-dioxide of the general formula: where R is chlorine or trifluoromethyl, and R-^ is lower alkyl, characterized in that a 4-amino-1,3-benzenedisulfonamide of the general formula: where R has the meaning given above, is reacted with a substituted cyclohexanone of the general formula: where R-^ has the meaning indicated above, or a functional derivative thereof.