IL35225A - P-aminoalkyl-phenylsulphonyl-imidazolidine derivatives,their production and pharmaceutical compositions containing them - Google Patents

Description

35225/3 p«^inoalkyl<-phenylsulphonylliDidazolidine derivatives, their production and pharmacoutical compositions containing thorn CIBA-GEIOY A.O.

C. 33435 4-3154* PROCESS FOR THE PRODUCTION OF NEW p-AMI OALKYL BE ZE ESULPHO AMIDE DERIVATIVES The present invention relates to new derivatives of p-aininoalkyl benzenesulphonamide , to processes for their production, to medicaments containing the new compounds, and to the use thereof.

It has been found that p- substituted phenylsulphonyl-2-imino-imidazolidines of the general formula I: wherein R^ represents an optionally branched alkyl radical hav- : ing 1-6 carbon atoms, an allyl radical, a cycloalkyl radical or cycloalkenyl radical each having 5 to 8 car.b a oms , R2 represents hydrogen, an ethyl group or a methyl group, R^ represents an optionally branched' alkyl group having 1-6 carbon atoms, a cycloalkyl group having at most 8 carbon atoms, an alLyl group, a phenyl group or a phenylalkyl group having at most 9 carbon atoms, and m represents 2 or 3, as well as their addition salts with inorganic or orgariic acids, have a hypoglycaemic action in warm-blooded animals, which, coupled with a favourable therapeutic index, characterise these compounds as suitable for the treatment of diabetes mellitus mammals .

In the compounds of the general formula I, F rr.ay have, e.g. the following meanings: as the alkyl group, can denote the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, . ter -butyl , isobutyl, pentyl, isopentyl, 2 , 2- dimethylpropyl , 1-methylbutyl , l-ethylpropy or. he 1 , 2- dimethylpropyl group, or a straight chained or .branched hexyl radical, e.g. an n-hexyl, methylpentyl , dimethylbutyl , ethylbutyl grou ; as the alkenyl group; as the cycloalkyl group, R^ can denote the cyclopentyl group which can be optionally substituted by alkyl radicals having 1-3 carbon atoms, the cyclohexyl group which can be substituted by ethyl or methyl, and the cycloheptyl group optionally substituted by methyl, as well as the cyclooctyl group; as the cycloalkenyl group, ^ can denote the 2-cyclopenten-l-yl , the 2-cyclohexen-l-y , the 3-cycichexen-l-yl, the 2-methyl- 2-cyclchexen- I-yl , the 3-cyclohepten-l-yl group., or a cyclooc enyl group; The substituent comprises the same alkyl, cycloalkyl groups which were menti.oned for R. ; as the phenylalkyl group, can denote the benzyl group, the. phenylethyl group or . the a-methylphenylethyl group". \ .:■ .

Using the process according to the invention, compounds of 'the general formula I are produced by reactin a compound of the general formula II : NH wherein R^ , R and m have the meaning given under formula I, with a compound of the general formula III : 0 R3 - 0 - C - X wherein R^ has the meaning given under general formula I and X represents a halogen atom or an acyloxy group derived from a monoester of carbonic acid, and optionally converting the reaction products obtained into the salt of an inorganic or organic acid.

As compounds of the general formula III, chloro- and bromoformates are particula ly suitable in which has the meaning given under general formula I. Suitable acyloxy compounds of the general formula III are pyrocarbonic acid esters of the general formula Ilia: 0 - 0 R3 - 0 - C - 0 - C - 0R3 (Ilia) wherein has the meaning given under general formula I. These substances can, for example, be obtained by reacting chloroformates with alakli-metal salts of monoesters of carbonic acid. Mixed pyrocarbonic acid esters may, however, also be used. In this case one of the R^ radicals represents a methyl or an ethyl group. W. Thoma , H.Rinke tLiebigs Ann. Chem. 624, 30 (1959)].

The reaction is performed for example at temperatures between -20° and +20° C in an inert organic solvent.

Suitable examples are: hydrocarbons such as benzene, toluene or xylene, ethers such as diethy1ether , dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, and lower ketones such as acetone or methyl ethyl ketone.

A chloroformate of the general formula III is reacted according to the invention preferably in the presence of an acid-binding agent. For this purpose inorganic bases or salts such as, for example, an alkali hydroxide, acetate, hydrogen carbonate, carbonate or phosphate such as sodium hydroxide, acetate, hydrogen carbonate and phosphate, or the corresponding potassium compounds may be used. In addition, calcium oxide, carbonate and phosphate, and magnesium carbonate may also be used. Instead of inorganic bases or salts, organic bases such as, for example, pyridine, tri ethyl- or triethylamine , diisopropyla ine , or collidine are suitable. When these are used in excess they can also be used as solvent.

Instead of amines of the general formula II, in the reaction according to the inveiition with a chloroformate , N-alkali metal derivatives of these compounds , e.g. sodium, potassium or lithium derivatives may also be employed .· The starting materials of the general formula II are nev; compounds and can, e.g., be produced by reacting a reactive derivative of a sulphonic acid of the general formula IV: wherein R represents' a simple alkyl or aryl radical, for example a methyl or a phenyl group, and m has the meaning given in formula I, with 2-amino-2-'imidazoline derivatives of the general formula V: V7herein ^ and R2 have the meaning given under formula I, and then hydroly ically cleaving off the acyl protective grouping (R-CO-). The N-acyl compounds derived from those of formula II v;hich are obtained as intermediates have likewise previously no -been described in the literature.

• Suitable reactive derivatives of a sulphonic acid of the general formula V are halides, especially chlorides and anhydrides of the general formula IV : wherein m has the meaning given under formula I.

The anhydrides of the general formula IVa can be obtained in a simple manner by the reaction of corresponding substituted sulphonic acid halides with salts of correspondingly substituted sulphonic acids.

Using a further process, starting materials of the general formula II are obtained by reacting substituted p- (aminoalkyl) -benzenesulphonamides (produced analogously to the method of E. Miller, J.Amer.Chem.

Soc. 62, 2101 (1940)) of the general formula VI: wherein m has the meaning given under formula I, v:ith substituted K- (2-bromoalky1) -cyanoamides in an alkaline medium.

The starting materials of the general formula III are prepared by the commonly known methods for chloro- formates .

The nev; substances of general formula I , or the pharmaceuti cally acceptable salts thereof , can be administered orally or parenterall . For salt formation, it is possible to use physiologically harmless inorganic or organic acids such as , e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, lactic acid, succinic acid, tartaric acid and maleic acid, but also hypoglycaemic sulphonyl ureas such as, e.g. p- oluenesul honylb tyl urea, p- ch1o obenzenesulphony1-propyl urea and p- [ 2- (2~methoxy-5-chlorobenzamido) -ethyl ] -phenylsulphonyl- c.yclohexyl urea. The daily dosages are between -10 and 100 mg/kg for warm-blooded animals.

Suitable dosage units, such as dragees and tablets, contain preferably 10-200 mg of an active substance according to the invention, whereby the content of active substance is 20-80 per cent by weight. The tablets and dragees are produced by combining the active substance, e.g. with solid pulverulent carriers such as lactose, saccharose, sorbitol or mannitol; starches such as potato starch, maize ' starch .or amylopectin, also larninaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights. Tablets and dragee cores are coated, e.g, With concentrated sugar- solutions which may also contain, e.g. gum arable, talcum and/or titanium dioxide, or with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyes uffs can be added to these coatings, e.g. for identification of the various dosages of active substance.

Other suitable dosage units for oral administration are hard gelatine capsules, as well as soft closed capsules made from gelatine and a softener, such as glycerin.

The hard capsules contain the active substance prefereably as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and optionally stabilizers such as sodium metabisulphite oi: asco bic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby likewise stabilizers can be added.

The following prescriptions serve to further illustrate the production of tablets and dragees: a) Λη amount: of 1000 g of 1- [p- (2- butoxycarbonylamino- ethyl) -phenylsulphonyl ) -2-imino-3- etbyl-imidazolidine is mixed wi h 500 g of lactose and 270 g of potato starch; the mixture is then moistened with an aqueous solution of 8.0 g of gelatine, and granulated through a sieve.

After drying of the granulate, 60.0 g of potato starch, 60.0 g of talcum, 10.0 g of magnesium stearate and .0 g of colloidal silicon dioxide are mixed in; the mixture is then pressed to form 10,000 tablets each weighing 200 mg and each containing 100 mg of active substance. Optionally, the tablets may be provided with grooves for a more precise adjustment of the dosage amount .. b) A granulate is produced from 1000 g of 1- [p- (2-butoxycarbonylamino- ethyl) -phenylsulphonyl ] -2- imino-3- cyclohexyl- irnida olidine , 345.0 g of lactose, and the aqueous solution of 6.0 g of gelatine; the granulate is then mixed, after being dried, with 10.0 g of colloidal silicon dioxide, 40.0 g of talcum, 40.0 g of potato starch and 5.0 g of magnesium stearate; and the mixture is pressed into 10,000 dragee cores. These are subsequently coated with a concentrated syrup made from 533.0 g of crystalline saccharose, 20.0 g of shellac, 75.0 g of gum airabic, 250 g of talcum, 20 g of colloidal silicon dioxide and 1.5 g of dyes tuff; and then dried. The obtained dragces each weigh 240 mg and each contain 100 mg of active substance.

The. following examples further illustrate the production of the new compounds of the general formula and of intermediate products not described hitherto; the examples in no way constitute, however, the only embodiments thereof. The temperatures are given in degrees Centigrade, Exam le. 1 From a solution of 37.0 g of 1- [p- (2-amino-ethyl)- phenyl- sulphon l ] - 2- i ino- 3- ethyl- imidazolidine dihydro- chloride, m.p. 242-244°, in 50 ml of water, the base, is set free by the addition of 120 ml of 2 N sodium hydroxide solution and extracted three times with 100 ml each of methylene chloride. The extract which has been dried v/ith sodium sulphate, is mixed with 11.0 g of triethylamine and transferred to a dropping funnel which is mounted on a reaction vessel which is fitted with a stirrer and a cooling arrangement. The reaction vessel has a second dropping funnel containing a solution of 13.7 g of butyl chlorofor ate in 100 ml of methylene chloride. The two solutions are then allowed to run. into the reactio . vessel in such a manner that, per time unit, about equimolar amounts of the rcactants flow into it while the temperature is constantly kept between 0 and +10°. After completion of the addition, the reaction solution is stirred for one hour at room temperature, washed with water, dried with sodium sulphate and the methylene chloride is removed by distillation. The residual, crude 1- [p- [ 2- (butoxyc.'irbonylamino) - ethyl ] -phenylsulphonyl ] -2-imino-3- ethyl- iinidazolidine , after recrys tallization from ethyl acetate, melts at 123-124°. · The dihydrochlorides of 1- [p- (2-amino-ethyl)-phenyl- · sulphonyl ]- 2- imino- imidazolidines of general formula II with various substituents in the 3-position which are used in this and the following examples as starting materials may, for. example, be obtained by reaction of the appropriately substituted 2-ainino-imidazolines with p- (2-acylamido-ethy1) -benzene- sulpho- chlorides and subsequent hydrolytic cleavage of the acyl radical with aqueous hydrochloric acid, as is described below for p- [2- (amino- ethyl) -phenylsulphony1 ] -2- imino- 3-butyl- imidazolidine dihydrochloride : a) 17.8 g of 1-buty1- 2- imino- imidazolidine hydrochloride are introduced into a solution of 8.5 g of sodium hydroxide in 85 ml of water. The clear splution obtained is then treated with a solution of 26.6 g of p- (2-acetamido - ethyl) -benzene- sulphochlo ide in. 100 ml of acetone, whereby heat is produced. The mixture is heated for. half an hour at 90° and then evaporated in vacuum to dryness. The residual, crude 1- [p- ( 2-acetamido-e hyl) -phenyIsulphony1 ] - 2- imino- 3-butyl- imidazolidine is recrys allized from ethyl acetate and then melts at 130-131°. p- (2-Acetamido-ethyl) -benzene- sulphochloride can be obtained as follows: 16.3 g of N-phenethyl-acetamide are introduced with stirring into 35.0 g of chlorosulphonic acid. The mixture obtained is stirred for 2 hours at 60° and then poured onto ice, whereby the crude p- ( 2-acetamido- ethyl) -benzene- . sulphochloride precipitates in crystalline form. It is removed by filtration, dried in vacuum and used directly as crude product. b) A solution of 36.7 g of 1- [p- (2-acetainido- ethyl) -phenylsulphonyl ] -2-imino-3-butyl-irnidazolidine in 370 ml of 2 N hydrochloric acid is refluxed for 6 hours and then evaporated in vacuum. The residual oil is taken up in warm ethanol. On cooling, the 1- [p- ( 2-amino- ethyl) -phenylsulphonyl ] -2-imino-3-butyl-irnidazolidine dihydrochloride, m.p. 231-233° , crystallizes .

Exam le 2 Analogously to Example 1 there are obtained: · · from in each case 39.8 g of 1- fp- ( 2-amino- ethyl) -phenyl-sulphonyl ) - 2- i ino- 3-but.yl- imidazolidine dihydrochloride , m.p. 231-233°, a) and 10.9 g of ethyl chloroformate , 1- [p- [ 2- (ethoxycarbonylarnino) - ethyl ] -phenylsulphonyl ] -2-i ino- 3-buty1- midazolidine , m.p. 112-113° (from ethyl aceta e) , b) and 12.1 g of allyl chloroformate , 1- [p- [ 2- (allyloxycarbonylamino) -ethyl ] -phenylsulphonyl ] - 2- irnino-3-butyl-imidazolidine , m.p. 108-109° (from ethyl acetate) , c) and 13.7 g of butyl chloro ormate , Hp- I 2- (bu oxycarbonylamino - ethyl ] -phenylsulphonyl ] - 2- - 1.3 - imino-3-butyl-imidazolidine, m. p. 114-115° (from ethyl acetate) , ' . d) and 13.7 g of isobutyl chloroformate, 1- fp- [2- (isobutoxycarbonylamino)--etbyl ] -phenylsulphony1 ] - 2- imino- 3-buty1- imidazolidine , m. p. 137-138° , e) and 12.3 g of isopropyl chloro ormate , 1- [p- [2- ( isopropoxycarbonylamino) -ethyl ] -pheny lsulphony13 2- imino- 3-buty1-imidazolidine, .p. 115-116°, f) and 15.7 g of phenyl chloroformate , 1- [p- [2- (phenoxycarbonylamino) -ethyl ] -phenylsulphonyl ] - 2- imino- 3-butyl- imidazolidine , m.p. 145-146°, g) and 17.1 g of benzyl chloroformate , 1- [p- [2-(benzylcarbonylamino) - ethy1 ] -pheny1sulphony1 ] - 2-imino- 3-butyl- imidazolidine , m.p. 106-108°.

Example 3 Analogously to Example 1 there are obtained: from in each case 41.0 g of 1- [p- (2-amino-ethyl) -phenyl-sulphonyl ] - 2- imino- 3- eyelopentyl- imidazolidine dihydro-chloride, m.p. 270° (decomposition), a) and 10.9 g of ethyl chloroformate , 1- fp- i 2- ( ethoxycarbonyla ino) - ethyl ] -phenylsulphonyl ]-2-imino-3-cyclopentyl- imidazolidine , m.p. 111-112°, b) and 12.3 g of isopropyl chloroformate , 1- [ρ·- [ 2- ( isopropoxycarbonylamino) -ethyl ] -phenylsulphonyl ] - 2- imino- 3-cyclopenty1- imidazolidine , m.p. 167-168° , c) and 13.7 g of butyl chloroformate , 1- [p- [ 2- (butoxycarbonylamino) -ethyl ] -phenyIsulphony1 ] - 2- i ino- 3- cyclopentyl- imidazolidine, m.p. 114-115° , d) and 13.7 g of isobutyl chloro ormate , 1- [p- [ 2- (isobutoxycarbonylamino) -ethyl ] -phenylsulphonyl. ] - 2- imino-3-cyclopentyl-- imidazolidine , in. p. 144-145° , e) and' 12.1 g of allyl chloroformate , 1- [p~ [2- (allyloxycarbonyla ino) -ethyl ] -phenylsulphonyl ] - 2- i ino- 3-cyclopenty1- imidazolidine , m.p. 113-115°..

■Example 4 Analogously to Example 1 there are obtained: from in each case 42.4 g of 1- [p- ( 2-amino- ethyl) -phenyl-sulphonyl ] - 2- imino-3-cyclohexy1- imidazolidine dihydro-chloride, m.p. 247-250°, a) aiid 10.8 g of ethyl chloroformate , 1- [p- [2- (ethoxycarbonylamino) - ethyl ] -phenylsulphonyl ]- 2·· imino-3-cyclohexyl-imidazolidine , m.p. 116-117°, b) and 13.7 g of butyl chloroformate , ].- [p- [2- (ethoxycarbonylamino) - ethyl ] -phenyIsulphony1 ] - 2-imino- 3-cyclohexyl- imidazolidine , m.p. 123-124° , e) and 15.7 g of phenyl chloroformate ,. 1- [p- [ 2- (phenoxycarbonylarnino) -ethyl ] -phenylsulphony1 ] - 2- imino- 3-cyclohexyl-imidazolidine , m.p. 151-152°.

Example 5 Analogously to Example 1 there are obtained: from in each case 43.7 g of 1- ip- (2-amino~ethyl)-phenyl-sulphony1 ] - 2- imino- 3- ( -meth Icyc 1ohexy1 ) - imidazo1idine dihydrochloride , having a decomposition point of 260°, a) and 9.5 g of methyl chlorofor ate , 1- [p- [ 2- (methoxycarbonylamino) - ethyl ] -phenylsulphony1 ] - 2- imino- 3- (4-me hylcyclohexyl) ·- imida?:olidine , m. p . 118-120° b) and 10.9 g of ethyl chloroformate , 1- [p- [ 2- (ethoxycarbonylamino) - ethyl ] -phenylsulphony1 ] -2-imino- 3- (4-methylcyclohexyl) - imidazolidine , . p . 138- 140° .

Example 6 Analogously to Example 1 are obtained: a) from 42.5 g of 1- [p- (2-amino-ethyl) -phenylsulphony1 ] 2- imino-3- (1 , 2-'dimethyl-butyl) - imidazolidine-dihydrochlorid and 10.9 g of chloroforrnic acid-ethylester , l-[p-(2- (ethoxycarbony1amino) - ethy1) -pheny1sulphony1 ] - 2- imino-3- (1 , 2-dimethyl-butyl) -imidazolidine , m.p. 75 - 78°; b) from 38.1 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] 2-imino-3-all.ylimidazolidine-dihydrochloride and 10.9 g of chloroformic acid-ethylester, 1- [p- (2- (ethoxycarbonylamino) ethyl) -phenylsulphonyl ] -2-imino~3-allylimidazolidine , M.P. 123 - 125°; c) from 42.1 g of 1- fp- (2-amino-ethyl) -phenylsulphonyl ] imino-3- (3-cyclohexen- 1-yl) - imidazolidine-dihydrochloride and 16.3 g of chloroformic" acid-cyclohexylester , l-[p-(2-(cyclohexyloxycarbonylamino) -ethyl) -phenylsulphonyl ] -2-imino-3- (3-cyclohexen-l-yl) -imidazolidine , M.P. 146 - 148°; d) from 43.7 g of 1- [p- (2-amino-ethyl) -phenylsulphoiyl ] 2- imino- 3-cyclohexyl-4-methylimidazolidine-dihydrochloride and 10.9 g of chloroformic acid-ethylester, l-[p-(2-ethoxycarbonylamino) -ethyl) - phenylsulphonyl ] -2- imino- 3-cyclohexyl-4-methyl- imidazolidine , M.P. 136 - 138°; e) from 43.7 g of 1- fp- (2-amino-ethyl) -phenylsulphonyl ] -2-imino- 3- cyclopenty1-4-ethyl- imidazolidine-dihydrochloride and 10.9 g of chloroformic acid-ethylester , 1- [p- (2-ethoxy-carbonylamino) - ethyl) -phenylsulphonyl ] -2- imino-3-cyclopenty1-4-ethylimidazolidine , M.P. 75 - 77°; f) from 43.7 g of 1- [p- (2-amino-propyl-phenylsulphonyl ] -2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and .9 g of chloroformic acid-ethylester, 1- [p- (2- (ethoxy-carbonylamino) -propyl) -phenylsulphonyl ] -2- imino-3-cyclohexyl- imidazolidine , M.P. 100 - 103°; g) from 40.9 g of 1- [p- (2-amino-ethyl) -phenylsulphonyl ] -2-imino-3-cyclopentylimidazolidine-dihydrochloride and 13.7 g of chloroformic acid-isobutylester , 1- [p- (2- (isobutoxy-carbonylamino) -ethyl) -phenylsulphonyl ] -2-imino- 3-cyclopenty1-imidazolidine, M.P. 144 - 145°.

Claims (14)

4-3154* What we claim is :

1. p-Aminoalkyl benzenesulphonamide derivatives having the formula I NH wherein represents an optionally branched alkyl group having from 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group having from 5 to 8 carbon atoms, or an allyl group, R.2 represents a hydrogen atom or a methyl or ethyl group, represents an optionally branched alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having at most 8 carbon atoms, an allyl group, a phenyl group or a phenylalkyl group having at most 9 carbon atoms, and m represents the integer 2 or 3.

2. p-Aminoalkyl benzenesulphonamide derivatives as claimed in claim 1 wherein represents a hydrogen atom, represents an optionally branched alkyl group, ' and m represents the integer 2.

3. p-Aminoalkyl benzenesulphonamide derivatives as claimed in claim 2 wherein represents a cycloalkyl group

4. 1- [p- [2- (Ethoxycarbonylamino) -ethyl ] -phenylsulphonyl ] 2- imino~3-cyclohexyl~ imidazolidine .

5. 1- [p- [2- (Ethoxycarbonylamino) -ethyl ] -phenylsulphonyl ] .2- imino- 3-cyclopentyl-imidazolidine .

6. The pharmaceutically acceptable acid addition salts of a p-aminoalkyl benzenesulphonamide derivative as claimed in any one of claims 1 to 3.

7. The pharmaceutically acceptable acid addition salts of a p-aminoalkyl benzenesulphonamide derivative as claimed in either claim 4 or claim 5.

8. Process for the production of p-aminoalkyl benzenesulphonamide derivatives having the formula I as defined in claim 1 which comprises reacting the corresponding compound having the formula II - 20 - GB etc . with a' compound having the formula III. R3 - 0 - CO - X (III) wherein has the meaning given in claim.1 and X represents a halogen atom or an acyloxy group derived from a monoester of carbonic acid.

9. Process as defined in claim 8 wherein a p-aminoalkyl beiizenesulphonamide derivative thus obtained is converted into a pharmaceutically acceptable acid addition thereof .

10. Process as defined in claim 8 substantially as hereinbefore described with reference to any one of the Examples 1 to 5.

11. Process as defined in claim 8 substantially as hereinbefore described with reference to Example 6.

12. A p-aminoalkyl benzenesulphonaniide derivative as defined in claim 1 subs a tially, as hereinbefore described with reference to any one of Examples 1 to 5. - ·-

13. A p-aminoalkyl benzenesulphonamide derivative as defined in claim 1 substantially as hereinbefore described with reference to Example 6.

14. A p-aminoalkyl benzenesulphonamide derivative or pharmaceutically acceptable acid addition salt thereof whenever prepared by a process as claimed in claim 8 or 9 or by an obvious chemical equivalent thereof. 1-5. A pharmaceutical composition comprising a p-aminoalkyl benzenesulphonamide derivative as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier thereof. 9.8.1970/GSG/ h/ GB etc .