IL32432A - P-aminoalkyl benzene sulphonyl urea derivatives and their preparation - Google Patents

Description

32432/3 p-Aminoalkyl benzene sulphonyl.urea derivatives and their preparation CIBA-GEIGY A.G.

C: 30643 . _ 32432/2 la - The present invention concerns a process for the production of new p-aminoalkyl benzene sulphonamide derivatives .

Compounds of the general formula I wherein m represents represents hydrogen or a methyl group , R2 represents a lower alkyl group or a phenyl group optionally mono- to di-substituted by halogen, lower alkyl or alkoxy groups, or a trifluotjomethylphenyl group, and their addition salts with inorganic or organic bases have not been known hitherto.

It has now been found that the new compounds possess interesting pharmacological properties' and a high therapeutic index. In the case of oral or parenteral administration, they exhibit hypoglycaemic action which characterises them as being suitable for the treatment of diabetes mellitus . The hypoglycaemic action was shown by standard tests on warm-blooded animals.

As demonstrated in Example 9 herein by comparative tests on rats and rabbits, N-[p-(2-(2-methoxy-5-chloro-benzamido)-ethyl)- phenyisulfonyll-N'-octahydro-l^^-methenopentalen-S-yl-ursa (as sodium salt) according to the present invention (Example 8, compound B in Example 9) has a stronger"blood sugar lowering effect and a faster onset of action than N-[p-(2-(2-methoxy-5-chloro-benzamido)-^.ethylJ-phenylsulfonylJ'-N'-.cyclohexyl-urea known from the Dutch Patent Application No. 6,610,580. The data given in French Patent specifica- - lb - tion No. 1,524:»754 (page 8) indicate that the compound Ν-[4-(β-( 2-methoxy-5-chlorobenzamido )-ethyl)-phenylsutfonyl]-N· - ( exo- ricyclo-[3.2.1.0 ]octane-3-anti)-urea described therein has at 10 mg/kg, a weaker blood sugar lowering effect than compound B of this invention (Example 8) at 0.3 mg/kg.

] As alkyl group can have, for example, the following meanings in the compounds of the general formula I: the methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl, iso-butyl, pentyl, isopentyl, 2 , 2-diinethylpropyl , 1-methylbutyl , 1-ethylpropyl , 1 , 2-dimethylpropyl or the hexyl groups.

The substituent or the substituents of , where contains a phenyl radical, can occupy the o- , m- or p-position. This substituent or these substituents can be for example the following groups: As halogen: chlorine, fluorine or bromine, as lower alkyl groups: the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl or the tert. butyl, group as as alkoxy group: the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec. butoxy or the tert. butoocy group.

Using the process according to the invention, compounds of the general formula I are produced by reacting a compound of the general formula II wherein m, R, and R have the meanings given under formula I, or an alkali metal derivative thereof , with octahydro-1 , 2 , -methenopentalae-5-isocyanate or with a reactive functional derivative of octahydro-1 , 2 , -metheno-pentalene-5-carbamic acid and, optionally, converting the reaction product with an inorganic or organic base into a salt.

Suitable reactive functional derivatives of octahydro-1 , 2 ,4-methenopentalene-carbamic acid are, e.g. the halideg, expecially the chloride, and the lower alkyl esters, especially the methyl or ethyl ester, also the phenyl ester. Also suitable are amides, the nitroamide, lower alkylamides, dialkylamides , diphenylamides , particularly the N-methylamide, the N,N-dimethylamide , also N-acylamides such as, e.g. the acetylamide and the benzoylamide .

The reaction is performed, for example, at room temperature or by heating in an inert organic solvent. Suitable inert organic solvents are, e.g. hydrocarbons such as benzene, toluene or xylene, ethereal liquids such as diethyl ether, dioxane or tetrahydrofuran , chlorinated hydrocarbons such as methylene chloride, and lower ketones such as acetone or methylethyl ketone.

The reaction of an isocyanate, carbamic acid ester or urea, can also be performed in the absence of solvents or diluents. Neither does it require in general a condensation agent. Optionally, however, it is possible to use as such, e.g. an alkali metal alcoholate. As further condensation agents in the case of the reaction of an isocyanate, tertiary organic bases may be used; isocyanates can, however, also be used in the form of an addition product, e.g. with a tertiary organic base.

A carbamic acid halide is reacted, according to the invention, with the compounds of formula II preferably in the presence of an acid-binding agent. Suitable as such are inorganic bases or salts such as, e.g. an alkali metal hydroxide, /acetate-, rogen carbonate, /carbonate and /phosphate such as sodium hydroxide, /acetate, /hydrogen carbonate, /carbonate and phosphate, or the corresponding potassium compounds. Further magnesium carbonate can also be used. Also suitable, instead of inorganic bases or salts, are organic bases such as, e.g. pyridine, trimethyl- or triethylamine , ,N-diisopropylamine , t_^ie^-ta»i»e- or collidine. Added in excess, these can also be used as solvents. For the reaction with a carbamic acid chloride, according to the invention, it . is possible to use, instead of sulphonamides of formula II an alkali metal derivative of these compounds such as, e.g. sodium, potassium or lithium derivatives.

Starting materials of the general formula II are described in the literature.

The isocyanic acid- (octahydro-1 , 2 , 4-methenopentalen-5-yl-ester) used as starting material, has not been known hitherto. It is obtained by decomposing a functional, reactive derivative of the octahydro-l^ ,4-methenopentalere-5 -carboxylic acid, according to Curtius or Hofmann. Suitable reactive functional derivatives are, e.g. the azide or the amide.

To produce the isocyanic acid ester, it is preferably to apply the decomposition of the azide according to Curtius. For this purpose, either the carboxylic acid is converted into the carboxylic acid chloride, which is then reacted with an alkali metal azide, e.g. with sodium azide, to obtain the desired carboxylic acid azide, or an ester, such as the methyl or ethyl ester, is transformed with hydrazine hydrate and nitrous acid by way of the hydrazide, in the presence of a' solvent or diluent, into the carboxylic acid azide. The conversion of the azide into the isocyanate is carried out by thermal decomposition in a solvent inert to the reactants such as, e.g. hydrocarbons such as benzene, toluene, xylenes, cyclohexane or higher-boiling ethers, such as dioxane. The decomposition temperature is -180°. Starting with this isocyanic acid ester, further starting materials of the process can be produced. The stated isocyanic acid ester yields, e.g. with a lower alkanol such as methanol, lower alkyl esters of the (octahydro-1 , 2 , 4-metheno-pentalen-5-yl) -carbamic acid; such as, e.g. the methyl ester and also, with ammonia in tetrahydrofuran , it yields the (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea . Further, urea derivatives of this type can be produced analogously by using, e.g. instead of ammonia, a lower alkylamine or dialkylamine , such as methylamine or dimethylamine .

Using a second process according to the invention, compoun of the general formula I are produced by reacting a reactive, functional derivative of a carbamic acid of the general formula III -2 (III) wherein m, and R2 have the meanings given under formula I with octahydro-1 , 2 ,4-methenopent alen— 5-amine and, optionally, converting the reaction product with an inorganic or organic base into a salt.

Suitable reactive functional derivatives of the carbamic acids of formula III are, e.g. the halides, especially the chlorides, and the lower alkyl esters, especially the methyl or ethyl esters, also the phenyl esters. Also suitable are amides, the nitroamides, lower alkyl amides, dialkylamides , diphenylamides , particularly N-methylamides , Ν,Ν-dimethylamides , also N-acylamides such as, e.g. the acetylamides and the benzoyl- amides and the corresponding sulphonyl isocyanate which is to be considered as the internal anhydride of the carbamic acid.

The octahydro-1 , 2 , 4-methenopentalen-5 -amine , mentioned as starting material, which has not been known hitherto, can be produced by-- reacting the isocyanic acid ester either a) with glacial acetic acid and acetic acid anhydride, or b) with alkanol In the first case a), the acetamide is obtained as reaction product, which is converted by alkaline saponification into the free amine. In case b) , the carbamic acid esters corresponding to the applied alkanols are obtained, which can be converted both by acid and alkaline hydrolysis to the stated amine.

Suitable for the acid hydrolysis are, e.g. hydrohalic acids, glacial acetic acid, halogenated acetic acids or mixtures of suchlike acids with each other. In the case of the alkaline hydrolysis, alkali metal hydroxides, and alkaline-earth metal hydroxides are, for example, suitable. The hydrolysis can be performed either in water or in an alkanol, such as methanol or ethanol, or in diethylene glycol.

The above mentioned amine can also be obtained by means of the acid amide decomposition according to Hofmann. In this case, the acid amide is heated, e.g. in the presence of a bromine or chlorine-releasing agent, in the presence of an alkali metal hydroxide or alkaline-earth metal hydroxide, or of an acid.

Both water and a alkanol are suitable as a solvent whereby, in the cases where the decomposition is performed in an alkanol, e.g. methanol or ethanol, the corresponding alcoholates are used in place of the stated hydroxides.

The new active substances, or the pharmaceu ically acceptable salts thereof, are preferably administered orally. For salt formation, any of the methods known in the art may be employed and it is possible to use inorganic or organic bases such as, e.g. alkali or alkaline-earth hydroxides, carbonates or bicarbonates , triethanolamine , choline^ N^'-dimethyl or ^-(/3-phenylethyl) -biguanide . The daily dosages vary between 20 and 2000 mg for adult patients. Suitable dosage units, such as dragees or tablets, preferably contain 20-500 mg of an active substance according to the invention, i.e. 20 to 80% of a compound of the general formula I. They are produced by combining the active substance, e.g. with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria 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, to produce tablets or dragee cores. The latte: are coated, e.g. with concentrated sugar solutions, which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile, organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.

The following prescriptions further illustrate the production of tablets and dragees : phenylsulphonyl ] -3- (octahydro-1 ,2 , 4-methenopentalen-5-yl) -urea are mixed with 4¾6 g of lactose and 380 g of potato starch. The mixture is moistened with an aqueous solution of 4.0 g of gelatine and granulated through a sieve. After drying, 30.0 g of potato starch, 30.0 g of talcum, 10.0 g of magnesium stearate and 10.0 g of colloidal silicon dioxide are mixed in. The mixture is then pressed into 10,000 tablets each weighing 100 mg and each containing 10 mg of active substance. Optionally, the tablets can be provided with grooves for more accurate adjustment of the dosage amount. b) A granulate is produced from 100 g of 1- [p- [2- (2-methoxy- 5-chlorobenzamido) -ethyl ] -phenylsulphonyl ]-3- (octahydro-1 , 2 ,4- methenopentalen-5-yl) -urea , 200 g of lactose, 130 g of potato g of glycerol starchj/and the aqueous solution of 20.0 g of gelatine. After drying, the granulate is mixed with 35.0 g of talcum, 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 150 g of crystallised saccharose, 10.0 g of shellac, 7.0 g of gum arabic, 25 g of talcum, 5 g of colloidal silicon dioxide and 3.0 g of dyestuff, and dried. The obtained dragees each weigh 70 mg and each contain 10 mg of active substance.

The following examples further '.illustrate the production of the new compounds of the general formula I and of intermediate products not hitherto described, but the examples in no way constitute the only embodiment. The temperatures are given in Example 1 a) 36.8 g of p- [ 2- (2-methoxy-5-chlorobenzamido) - ethyl ] -benzene sulphonamide and 6 g of pulverised potassium hydroxide in 500 ml of dioxane are refluxed for 4 hours with 16.0 g of isocyanic acid- (octahydro-1 , 2 , 4-methenopentalen-5-yl-ester) . The reaction mixture is then concentrated by evaporation in vacuo, water is added and the mixture filtered off from insoluble matter, The filtrate is carefully acidified with 2N hydrochloric acid, whereupon the crude product crystallises out. The latter is filtered off, 2N ammonia solution is added, the small amount of insoluble matter removed by filtering and the filtrate is carefully acidified with 2N hydrochloric acid. The precipitated crystals are filtered off, thoroughly washed with water and subsequently dried in vacuo. The obtained 1- [ p- [ 2- (2-methoxy-5-chlorobenzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl)-urea decomposes at 158-168°.

The isocyanic acid- (octahydro- 1 , 2 , 4-rnethenopentalen- 5-yl-ester), used as starting material, is produced as follows: b) 3312 g of acrylic acid-/3-ethoxyethyl ester, stabilised with 0.2% of hydroquinone monomethyl ether, 1852 g of 2 , 5-no_rbornadiene and 148 g of nickel-tricarbonyl triphenylphosphine are mixed together. 500 ml of this mixture are heated to 170° in a flask provided with outlet tube, until the intensely exothermic reaction commences. Immediately after completion of the reaction (decreasing of the inside temperature from 180 to 170) , the ester-diene- catalyst mixture is added in such a manner that the inside temperature is 170 - 180°. At the same time, the reaction product, i.e. the octahydro- 1 , 2 , -metheno- pentalen-5-carboxylic acid-/3-ethoxyethyl ester, is drawn off through the outlet tube. Supply and discharge are so regulated that there are always 1500 ml of reaction mixture in the reaction vessel. The ■ reaction of the mixture has finished after 2.5 to 3 hours. For purifying, the ester is fractionated in vacuo; its boiling points are respectively 115° at 0.5 Torr (uncorr.) and 100° at 0.005 Torr . c) . 1000 g of hydrazine hydrate and 90 g of 2-ethoxyethanol are heated in a sulphonating flask to 115 and, while stirring vigorously, 2360 g of the octahydro- 1 , 2 , 4-methenopentalene-5-carboxylic acid-/3-ethoxyethyl ester are added dropwise within 5 hours. The reaction mixture is then refluxed, while stirring, for 10 hours. The major part of the unconverted hydrazine hydrate, water and solvent is then distilled off (normal pressure) and the residue added to ice-water (1:2). After stirring for two hours, the precipitate is filtered off, washed. with ice-water and dried for 24 hours in vacuo. The crude hydrazide has the melting point 74-96°. d) 178 g of the hydrazide, obtained according to c) , are dissolved in 1780 ml of boiling 1 , 2-dichloro- ethane. The solution is then cooled to 0° and kept for some minutes at this temperature. The obtained precipitate is separated. The thus obtained hydrazide is, according to NMR spectrum, pure octahydro- 1 , 2 , 4-rnethenopentalen-5-exo-carboxylic acid hydrazide, M.P. 126° e) A solution of the corresponding hydrazide-hydrochloride is obtained from 178 g of the octahydro-1, 2,4-methenopentalen-5-carboxylic acid hydrazide, 130 ml of water and 140 g of concentrated hydrochloric acid. The solution is added, simultaneously with a solution produced from 170 ml of water and 85 g of sodium nitrite, at 0 to 5° and while stirring vigorously to a mixture of 600 ml of water, 160 g of concentrated hydrochloric acid and 625 g of cyclohexane. The introduction of the two solutions is regulated so that 2 parts by volume of hydrazide-hydrochloride solution correspond to one part by volume of nitrite solution, with the temperature of the reaction mixture not exceeding 10°. After the addition is completed, the mixture is stirred for 30 minutes at 0° and then allowed to stand. Two layers form and of these the cyclohexane layer is separated and dried with sodium sulphate, whereby the aqueous layer is discarded. After filtering, the cyclohexane layer is heated, slowly and carefully within 2 hours, to 80°. The evolution of nitrogen commences at 30° and is completed at 70°. The cyclohexane is then distilled off and the residue fractionated. The octahydro-1 , 2 , A-methenopentalen-5-yl-exo-isocyanic acid ester has the boiling point: 45-50° under 0.3 Torr .

Example 2 Starting with isocyanic acid- (octahydro-1 , 2 , 4-metheno-pentalen-5-yl ester), the following end products are obtained analogously to example 1: a) with 33.4 g of p- [2- (2-methoxybenzamido) -ethyl ] -benzene sulphonamide is obtained the 1- [p- (2- (2-methoxybenzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl)-urea, melting point 199-200°; b) with 33.8 g of p- [2- (2-chlorobenzamido) -ethyl ]-benzene sulphonamide is obtained the 1- [p- [2- (2-chlorobenzamido) -ethyl ]-phenylsulphonyl ]-3- (octahydro-1 ,2 , 4-methenopentalen-5-yl) -urea, melting point 187-189° ; c) with 33.8 g' of p- [1- (2-chlorobenzamido) -ethyl ]-benzene sulphonamide is obtained the 1- [p- [ 1- (2-chlorobenzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea , which melts at 201-204° ; d) with 40.1 g of p- [1- (3-trifluoromethyl-benzamido) -ethyl ]-benzene sulphonamide is obtained the 1- [p- [ 1- (3 -trifluoromethyl-benzamido) -ethyl ] -phenyl-sulphonyl ] -3- (octahydro-1 , 2 , 4-metheno-pentalen-5-yl) -urea , decomposition point 135-140°; e) with 24,2 g of p- (2-acetamido-ethyl) -benzene sulphonamide is obtained the 1- [p- (2-acetamido-ethyl) -phenylsulphonyl ] -3-(octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea hemihydrate , decomposition point 105-120°C; f) with 25.6 g of p- (2-pro pionamido-ethyl) -benzene sulphonamide is obtained the 1- [p- (2-propionamido-ethyl) -phenylsulphonyl ] -3-(octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea , melting point -1 ° g) with 27.0 g of p- (2-butyramido-ethyl) -benzene sulphonamide is obtained the 1~ [p- (2-butyramido-ethyl) -phenylsulphonyl ] -3- (octahydro-1 , 2 , -methenopentalen-5-yl) -urea hemihydrate , melting point 185-188° (from acetici acid ethyl ester) : h) with 27.0 g of p- [2- (N-methylacetamido) -propyl ] -benzene sulphonamide is obtained the 1- [p- [2- (N-methylacetamido) -propyl ] - phenylsulphonyl ] -3- (octahydro-1 , 2 , -methenopentalen-5~yl) -urea ■ hemihydrate, melting point 102-110°; i) with 28.4 g of p- (2-valeramido-ethyl) -benzene sulphonamide is obtained the 1- [p- (2-valeramido-ethyl) -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentale — 5-yl) -urea , melting point 199-200° (from acetone) ; k) with 31.8 g p- [2- (2-methylbenzamido) -ethyl ] -benzene sulphonamide is obtained the 1- [p- [2- (2-methylbenzamido) -ethyl ] - phenylsulphonyl ] -3- (octahydro-1 , 2 , -methenopentalen-5-yl) -urea , melting point 154-157° (from acetic acid ethyl ester); 1) with 33.4 g p- [2- (3-methoxybenzamido) -ethyl ] -benzene sulphonamide is obtained the 1- (p- [2- (3-methoxybenzamido) -ethyl ]- phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea , melting point 174-176° (from methanol/acetic acid ethyl ester); m) with 40.1 g p- [2- (3-trifluoromethylbenzamido) -ethyl ] - ene benz-eisulphonamide is obtained the 1- [p- [2- (3-trifluoromethylbenzamido) -ethyl ] -3- (octahydro-1,2 , 4-methenopentalen-5-yl) -urea , melting point 150-153° (from benzene) ; n) with 25.6 g p- (2-acetamido-propyl) -benzene sulphonamide is obtained the 1- [p- (2-acetamido-propyl) -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea-hemihydrate , melting point 110-117° .

Example 3 A solution of 28.5 g 1- [p- (2-acetamido-ethyl) -phenylsulph-onyl]-urea and 13.5 g octahydro-l¾.2 , 4-methenopentalen-5-amine in 800 ml dry dioxane is refluxed under vigorous stirring until the evolution of ammonia ceases. Then the mixture is evaporated to dryness in vacuo and the residue is crystallised from acetic acid ethyl ester. The pure 1- [p- (2-acetamido-ethyl) -phenyl-sulphonyl ]-3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea hemi-hydrate thus obtained decomposes at 105-120° .

Example 4 Starting with 13.5 g of octahydro-1 , 2 , 4-methenopentalene-5-aminethe following end products are obtained analogously to example 3. a) with 37.6 g 1- [p- [2- (2-methoxybenzamido) -ethyl ] -benzene-sulphonyl ] -urea the 1- [p- [2- (2-methoxy-benzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea , melting point 199-200° (from acetone) b) with 36.0 g 1- [p- [2- (2-methylbenzamido) -ethyl ] -benzene-sulphonyl ] -urea the 1- [p- [2- (2-methyl-benzamido) -ethyl ] -phenyl-sulphonyl ]-3- (octahydro-1 ,2 ,4-methenopentalen-5-yl) -urea, melting point 154-157° ; c) with 29.9 g 1- [p- (2-propionamido-ethyl) -benzenesulphonyl ] -urea the 1- [p- (2-propionamido-ethyl) -phenylsulphonyl ] -3-octahydro-1 , 2 ,4-methenopentalen-5-yl) -urea , melting point •163-165% Example 5 A solution of 30.0 g N- [p- (2-acetamido-ethyl) -phenylsul-phonyl ] -methylurethane and 13.5 g octahydro-1 , 2 , 4-metheno-pentalen— 5-amine in 800 ml dioxane are refluxed under vigorous stirring, while the methanol formed during the reaction is distilled off. After 1 hour the dioxane is evaporated in vacuo and the residue is crystallised from acetic acid ethyl ester. The pure 1- [p- (2-acetamidoethy); -phenylsulphonyl ] -3- (octahydro-l,2,4-methenopentalen-5-yl)-urea-hemihydrate thus obtained melts at 105-120° .

Example 6 Starting with 13.5 g of octahydro-1 , 2 , -methenopentalene 5-amine the following end products are obtained analogously to Example 5. a) with 34.2 g N- [p- (2-valeramido-ethyl) -phenylsulphonyl ] -methylurethane the 1- [p- (2-valeramido-ethyl) -phenylsulphonyl ] 3- (octahydro-1 ,2 ,4-methenopentalen-5-yl) -urea, melting point 199-200° ; b) with 39.6 g N- [p- [2- (2-chlorobenzamido) -ethyl ] -phenylsul phonyl ] -methylurethane the 1- [p- [2- (2-chlorobenzamido) -ethyl ] phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea, melting point 187.189°.

Example 7 A mixture of 26.4 g p- (2-acetamido-ethyl) -benzenesul-phonamide-sodium, 20.0 g of potassium carbonate and 40.0 g (octahydro-1 , 2 , 4-methenopentalen-5-yl) -carbamic acid methyl ester is heated at 130-140° for 3 hours. After cooling to room temperature water is added to the reaction-mixture, and the excess of carbamic acid methyl ester is extracted with ether. The remaining aqueous solution is added to cold 2N hydrochloric acid, whereby the crude 1- [p- (2-acetamido-ethyl) -phenyl-sulphonyl ] -3- (octahydro-1 , 2 , -methenopentalen-5-yl) -urea precipitates. After recrystallisation from acetic acid ethyl ester it melts at 105-120°.

Example β Analogously to example 7 39*0 g p^[2-(2-methoxy-5~chloro»ben!san&do)-ethyl]÷b^ g potassium carbonate and 40 g (octahydro-1 , 2 , 4-metheno-pentalen-5*yl)"Tcarbamlc acid methyl ester are reacted as described in example 7 to obtain the l«[p~[2-(2-methoxy-5-chiorobenzamido)*ethyl J-phenylsulphonyl ]-3-(octahydro-1,2, -methenopentalen«5-yl)-urea, melting point 158-161°; (sodium salt m.p.248*255° EXAMPLE 9 \ Determination of hypoglycemic activity with rats and rabbits. as test animals 1 , Compounds tested A. N-[p-(2-(2-raethoxy-5-chloro-benzaraido)-ethyl)-phenyl- sulfonylj-N'-cyclohexyl-urea (Netherland Patent Application 6,610,580) B. N-[p-(2-(2-methoxy-5-chloro-benzamido)-ethyl)-phenyl- sulfonylJ- '-( octahydro-1.2. -methenopentalen-5-yl)- urea (as sodium sal ) . (Example 8 herein).

Test-Method . a) Rats The test substance was orally applied to rats which had recoived no food for 24 hours as a suspension in carboxymothylcclluloso by moans of a gnvagc. After a certain time the test animals were sacrificed and the blood sugar level was determined according to t.ho method of Hoffman , . J.Biol.Chem. 120 , 51 (1937 ) with the autoanalyzer. Five animals were usod for each determination. "_ b) Rabbits Each of the test compounds was applied orally as a suspension in 0.57o carboxymethylcolluloso to 8 normall fed rabbits having a body weigh of 2.5 to 3.5 kg by moans of a gavago. After certain times blood samples wore taken from the ear-vein and, after doprotoinating with 9 parts by volume of 37o trichloroace ic acid tho blood sugar was dotormincd according to the mothod o Hoffman,; J.Biol.Chem. 120 , 51 (1937) with the auto- onalyzor . - 20b - Discussion The test results in rats indicate that compound , B 'causes an essential effect on the blood sugar level of rats upon ! ■ j '■ administratio 'of- 1 mg/kg p.o., that compound. A is less effective even upon administration of 3 mg/kg p.o. and that it is ineffective upon administration of 1 mg/kg p.o.

A comparison in rabbits of the time of onset of the blood sugar lowering effects indicates that compound B has a faster onset than compound ;A upon administratioh via the i I same route and at the same dosage level.

Claims (28)

i What we claim is:

1. Process for the production of p-aminoalkyl benzene sulphonamide derivatives of the general formula I wherein m represents 2-3 R^ represents hydrogen or a methyl group, R2 represents lower alkyl group or a phenyl group optionally mono- to di-substituted by halogen, lower alkyl or alkoxy groups , or a trifluoromethylphenyl group and their addition salts with inorganic or organic bases, characterised by reacting a compound of the general formula II R - C - N - C H0 ~ Λ- S0oNH (II) 2 ^ 2 2 wherein m, R^ and R2 have the meanings given above with octa- hydro-1 , 2 ,4-methanopentalen-5~isocyanate or with a reactive functional derivative of octahydro-1 , 2 ,4-methanopentalene-5- carbamic acid and when required, converting a p-aminoalkyl • benzene sulphonamide derivative of the general formula I thus obtained into a pharmaceutically acceptable salt thereof with a base.

2. Modification of the process claimed in claim 1 wherein an alkali metal derivative of a compound of the general formula II is reacted with octahydro-1 ,2 ,4-methanopentalen-5-isocyanate or with a reactive functional derivative of octahydro-1 , 2 ,4- methanopentalen-5-carbamic acid.

3. Process for the production of p-aminoalkyl benzene sulph- onamide derivatives of the general formula I as defined in claim 1 which comprises reacting a reactive functional derivative of a carbamic acid of the general formula III R H (III. wherein m, R^ and R2 have the meanings given in claim 1 for formula I ith octahydro-1 , 2 , 4-methenopentalen-5-amine , And when required, converting a p-aminoalkyl benzene sulphona- mide derivative of the general formula I thus obtained into a pharmaceutically acceptable salt thereof with a base

4. A p-aminoalkyl benzene sulphonamide derivative of the general formula I as defined in claim 1.

5. 1- [p- [2- (2-methoxy-5-chlorobenzamido) -ethyl ] -phenylsul- phonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea .

6. 1- [p- [2- (2-methoxybenzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea .

7. 1- [p- [2- (2-chlorobenzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl ] -urea .

8. 1- [p- [ 1- (2-chlorobenzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea . - 22 - GB etc.

9. 1- [p- [1- (3-trifluoromethylbenzamido) -ethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-y.l) -urea .

10. 1- [ p- (2-acetamido-ethyl) -phenylsulphonyl ] -3- (octahydro-1,2, -methenopentalen-5-yl) -urea .

11. 1- [p- (2-propionamido-ethyl) -phenylsulphonyl ] -3- (octahydr 1,2, -methenopentalen-5-yl) -urea .

12. 1- [p- (2-butyramido-ethyl) -phenylsulphonyl ] -3- (octahydro-1,2, -methenopentalen-5-yl) -urea .

13. 1- [p- [2- (N-methylacetamido-propyl) -phenylsulphonyl ] -3-(octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea .

14. 1- [p- (2-valeramido-ethyl) -phenylsulphonyl ] -3- (octahydro-1 , 2 ,4-methenopen alen-5-yl) -urea .

15. 1- [p- [2- (2-methylbenzamido) -ethyl ] -phenylsulphonyl ] -3-(octahydro-1 , 2 ,4-methenopentalen-5-yl ] -urea .

16. 1- [p- [2- (3-methoxybenzamido) -ethyl ] -phenylsulphonyl ] -3-(octahydro-1 , 2 , 4-me henopentalen-5-yl) -urea .

17. 1- [p- [2- (3-trifluoromethylbenzamido) rethyl ] -phenylsulphonyl ] -3- (octahydro-1 , 2 , 4-methenopentalen-5-yl) -urea . - 23 - GB etc

18. 1- fp- (2-acetamidopropyl) -phenylsulphonyl ] -3- (octahydro-1,2, 4-methenopentalen-5-yl) -urea .

19. Process according to claim 1 and 2, substantially as herein described with reference to and as illustrated in any of the foregoing examples.

20. Pharmaceutical compositions containing as active ingredient at least one compound of formula I, defined in claim 1, together with at least one pharmaceutically acceptable carrier therefor.

21. A pharmaceutically acceptable salt of a p-aminoalkyl benzene sulphonamide derivative as claimed in any one of claims 5 to 13 with a base.

22. A pharmaceutically acceptable salt of a p-aminoalkyl benzene sulphonamide derivative as claimed in any one of claims 14 to 20 with a base.

23. Process for the production of p-aminoalkyl benzene sulphonamide derivatives of the general formula I as defined in claim 1 substantially as hereinbefore described with reference to any one of the examples 1 to 2h.

24. Process for the production of p-aminoalkyl benzene sulphonamide derivatives of the general formula I as defined in claim 1 substantially as hereinbefore described with reference

25. A p-aminoalkyl benzene sulphonamide derivative of the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof with a base, whenever prepared by a process as claimed in any one of claims 1, 3 or 23.

26. A p-aminoalkyl benzene sulphonamide derivative of the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof with a base, whenever prepared by a process as claimed in claim 2 or claim 24.

27. A pharmaceutical composition comprising a p-aminoalkyl benzene sulphonamide derivative of the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof with a base, together with a pharmaceutically acceptable diluent or carrier therefor.

28.5.69 GOT/GSG/ml - 25